annual report 2010 - VHIR

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VHIR is accredited as a Health Care Research Institute by the Carlos III Health Institute

© Fundació Institut de Recerca Hospital Universitari Vall d’Hebron (VHIR), 2011 Edifici Mediterrània, 2nd floor Passeig Vall d’Hebron, 119-129 08035 Barcelona www.vhir.org Published by: Rubes Editorial Legal Deposit No: SE-9003-2011 Printed in Spain Printed in Publidisa This book is printed on totally chlorine-free paper.

Contents Presentation

8 9 10 11 12

Presentation, Carles Constante Presentation, Antoni Castellà Presentation, Ana Ripoll Presentation, José Luis de Sancho Introduction, Joan X. Comella

VHIR

14 14 14 14 15 16 17 18 19

Mission Vision Governing bodies Trustees Governing board / Executive Committee Management From Internal Scientific Committee to Internal Scientific Council From External Scientific Committee to External Scientific Council Where we are

Research Support Units

20 20 21 21 22 22 23 24 24 24 25 25 26 29 29 30 31 32 33 33 33

Innovations Innovation model Administrative structure CEIC Support Unit Communication Management Unit Computer Management Unit Financial Management Unit Development Unit Human Resources Unit Occupational Risk Prevention Unit Project Management Unit Services UCTS UEB VHUHBB Animal facility UCICAC Laboratory Coordination Service Ethics Committees CEEA CREC

Summary of Research Activity

34 36 37 52 53

Researchers and Technicians VHIR’s economic summary Presence in publications in national and international JCR Research projects Clinical trials

VHIR INFORMATION

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Scientific Report

56 57 58 60

New contracts awarded to researchers and technicians funded by different organizations and programs Online Biomedical Research Center (CIBER) Collaborative research thematic networks at the ISCIII Research groups recognized by the Generalitat de Catalunya Thesis

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Scientific Activities

VHIR RESEARCH ACTIVITY Area 1. Oncology and Genetics

70 71 73 74 75 78 80 82 83 84 85 88 89 91 92 102 105 120 123 131

Vall d’Hebron Institute of Oncology (VHIO) 1.1 VHIO-Experimental Therapeutics 1.2 VHIO-Breast Cancer 1.3 VHIO-Gastrointestinal Tumors 1.4 VHIO-Gene Expression and Cancer 1.5 VHIO-Genitourinary, CNS, Sarcoma and Cancer of Unknown Primary Site 1.6 VHIO-Growth Factors 1.7 VHIO-Head, Neck and Gynecological Tumors 1.8 VHIO-High Risk and Cancer Prevention 1.9 VHIO-Oncogenetics 1.10 VHIO-Proteomics 1.11 VHIO-Radiation Oncology 1.12 VHIO-Stem Cells and Cancer 1.13 VHIO-Thoracic Tumors 1.14 VHIO-Tumors Biomarkers 1.15 Animal Models 1.16 Unit in Biomedicine and Translational and Pediatrics Oncology 1.17 Experimental Hematology 1.18 Molecular Pathology 1.19 Oncology and Molecular Pathology

Area 2. Endocrinology, Growth, Metabolism and Diabetes

134 137 140

2.1 Diabetes and Metabolism 2.2 Nephrology 2.3 Paediatric Endocrinology

Area 3. Cardiovascular Diseases, Hemostasis and Hypertension

144 154

3.1 Cardiovascular Diseases, Hemostasis and Hypertension 3.2 Reparative and Therapy of the Heart

Area 4. Neurosciences

156 158 160 168 170 174 177 180 184 195

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10

Alzheimer Cell Signaling and Apoptosis Clinical Neuroimmunology Headache and Neurological Pain Magnetic Resonance and Neuroradiology Neurodegenerative Diseases Neuromuscular and Mitochondrial Pathology Neurotraumatology and Neurosurgery (UNINN) Neurovascular Diseases Pediatric Neurology

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198 200

4.11 Peripheral Nervous System 4.12 Psychiatry and Mental Health

Area 5. Digestive Physiopathology and Hepatology

204 206 210

5.1 Digestive Transplants 5.2 Liver Diseases 5.3 Physiology and Pathophysiology of the Digestive Tract

Area 6. Infectious Diseases

216 220 226 230

6.1 Clinical Research and Innovation in Pneumonia & Sepsis 6.2 Infectious Diseases Department 6.3 Microbiology 6.4 Shock, Organ Dysfunction and Resuscitation (SODIR)

Area 7. Respiratory and Systemics Diseases

232 234 236 238 243

7.1 Chronic Fatigue 7.2 Ear, Nose and Throat Disorders 7.3 Immunology 7.4 Pneumology 7.5 Systemic Diseases

Area 8. Pathology, Cellular and Gene Therapy

252 254 256 259 261 266

8.1 8.2 8.3 8.4 8.5 8.6

Area T1. Epidemiology, Pharmacology, New Therapies, Clinical Research

268 270 273 276

T1.1 Cell and Gene Therapy T1.2 Clinical Pharmacology T1.3 Epidemiology and Public Health (EPIDEM) T1.4 Molecular Diagnosis and Therapy

Area T2. Nanomedicine

278 280 285 290 293 295 300

Molecular Biology and Biochemistry Research Center for Nanomedicine (CIBBIM-Nanomedicine) T2.1 CIBBIM-Nanomedicine. Drug Delivery and Targeting T2.2 CIBBIM-Nanomedicine. Molecular Oncology T2.3 CIBBIM-Nanomedicine. Immunobiology T2.4 CIBBIM-Nanomedicine. Lysosomal Storage Disease and Cell Pathophysiology T2.5 CIBBIM-Nanomedicine. Renal Pathophysiology T2.6 CIBBIM-Nanomedicine. Basic Research in Aging

Other Research Units

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Other Research Units

ANNUAL REPORT 2010

306 312

Memòria Anual 2010 Memoria Anual 2010

INDEX

321 329

Index of Authors Index of Journals

Bioengineering, Orthopedics and Surgery in Pediatrics Genetics Maternal Fetal Medicine Neuro-spinal Pathology Study Ophthalmology Robotic and Craniofacial Surgery

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VHIR Research Activity

VHIR Information

Presentation This scientific report, the first in which I have the honour to make the presentation as General Director for Regulation, Health Planning and Resources at the Health Department of the Catalonian Government explains the increase in the quantity and quality of scientific output of Vall d’Hebron Research Institute (VHIR), the center that coordinates all the research at the Vall d’Hebron University Hospital, one of the leaders of the Catalan Institute of Health (ICS). A center that has experienced the second year of the new direction that has seen coming true expansion of its facilities with the new Building Collserola and that, with the collaboration of the Govern-

ment of Catalonia, has faced a major investment in operation and equipment to accomplish its objectives. VHIR has been recognized by its efforts and leadership in translational research with the setting up of EATRIS, a European infrastructure for translational research in which acts as the scientific coordinator of the Spanish health sciences centers that belong to it. The interrelationship between research done in laboratories and patient diaries problems, translational research and clinical research, is one of the objectives of this and other Catalan centers, leading this task in Spain and

fighting for a place among the international reference centres. From this Department we congratulate VHR for the quality of its research, with increases in its impact factor, publications, clinical trials and projects despite the complications of the economic situation. We also celebrate the achievements in innovation, a very successful movement and very necessary in these difficult times. Vall d’Hebron, one of the hospitals that had to apply the economic adjustments that we had to implement to improve the viability of the Catalan health system, has therefore with VHIR a reason to feel proud and a success flag to add to the work and effort of all the professionals.

Dr. Carles Constante i Beitia General Director for Regulation, Health Planning and Resources at the Health Department of the Catalonian Government

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Presentation It’s been a year of progress in the struggle against serious diseases such as diabetes, Alzheimer, cancer or multiple sclerosis. A year of awards for researchers, research units and programs, as well as an intensive period of knowledge transfer, value and pursuit of opportunities in the market.

Antoni Castellà i Clapé Research and University Secretary Economy and Knowledge Department Catalonian Government

2010 has been a relevant year to Vall d’Hebron Research Institute (VHIR), a leading center of scientific and health care excellence. It has been significant in many ways: in basic research and a growing number of publications and scientific impact index. In recognition and prestige with the awards received throughout the year, and funding for new research lines.

VHIR is a good example of the successful policies developed in recent years. It stands out as an example of biomedical research in Catalonia. We excel in biomedicine and biotechnology, for which we are recognized as the knowledge reference regional cluster. VHIR is a leading center for biomedical research because of its privileged relationship with Vall d’Hebron University Hospital, the first hospital complex in Catalonia, and its relationship with the Universitat Autònoma de Barcelona (UAB). This model of university hospital, in which teaching, research and patient care services are connected, contributes to making of VHIR one of the main reference of our excellence. The fact that VHIR was chosen in 2010 as coordinator of a great European project is a prime example, amongst others, of the success of a research institute that fosters, moreover, that all members participate in the biomedical

and clinical research in an integrated manner. VHIR’s demonstrated willingness to network collaboration, internationalization and bringing innovation to the market is fully aligned with the values of CERCA, the research consortium of the Government of Catalonia. CERCA has opted to include the research institutes linked to the referral hospitals. VHIR is also a good example of the governance model and operation of CERCA centers, which promotes flexibility, efficiency in management and strategic planning. The will showed by VHIR to network collaboration, internationalization and bring innovation to the market, it fits perfectly within the values of institution CERCA of the Government of Catalonia, which has opted to include in the center system the research institutes of referral hospitals. VHIR is also a good example of the model of governance and operation of CERCA centers, which promotes flexibility, efficiency in management and strategic planning. For all the above, I am honoured to invite you to discover in the next pages the activities that, during the year 2010, have helped to bring this center to a position of leadership in biomedical research.

Antoni Castellà i Clapé Research and University Secretary Economy and Knowledge Department Catalonian Government

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VHIR Information

Presentation The Vall d’Hebron Research Institute (VHIR) annual report once again reveals the excellent research being carried out by the research groups created to date in different scientific areas. VHIR has a clear vocation to serve the general public, and understands that its research is aimed at transferring knowledge to society. In other words, the research institute knows that its mission is to improve the health of the citizens, not only of this country, to whom it dedicates great effort, but of the world as a whole, given that its increasing internationalisation aims to share the results of research with as many people as possible. Ana Ripoll Aracil Second Vice President of the VHIR Board of Trustees Rector of Universitat Autònoma de Barcelona

The activities carried out by the institute demonstrate that VHIR is succeeding in what was one of its founding principles: to become one of Europe’s leading centres in biomedical research. To my understanding, this is possible because VHIR is strongly committed to

quality results based on combining the efforts of scientists from multiple disciplines. This means that groups are formed by researchers with diverse scientific profiles, as well as by clinical experts and academics working at the prestigious first-rate university hospital Vall d’Hebron, and teaching or carrying out research at the Universitat Autònoma de Barcelona. For this reason I wish to congratulate all the people at VHIR for the magnificent work being done, for its scientific rigour and commitment to society. I hope this ability to innovate and transfer will not be lost, not only for the benefit of the research institute itself and a better future for society, but also for the benefit of this country, which is in need of reorienting its productive model towards the industry of knowledge. And the Vall d’Hebron Research Institute is a clear example of successfully achieving this goal.

Ana Ripoll Aracil Second Vice President of the VHIR Board of Trustees Rector of Universitat Autònoma de Barcelona

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Presentation The continued growth of Vall d’Hebron Research Institute (VHIR) is reflected in the data that we present in this scientific report. As manager of Vall d’Hebron University Hospital (HUVH), and because of its significance to the hospital, I am proud of the steady increase in VHIR’s activity and quality, bearing in mind that its purpose is simply to improve the care of patients treated in this hospital and the care of society in general.

José Luis de Sancho Former General Manager of Vall d’Hebron University Hospital

The excellent scientific results of VHIR compete with top Catalan and Spanish centers. All the researchers and their teams work with unceasing energy to make important breakthroughs towards its internationalization. Despite the complexities and trends of this year, 2010, I specially value and appreciate the efforts of all professionals involved, those who are devoted exclusively to research and those who combine it with clinical patient care. They are all are the architects of this determined evolution of HUVH and VHIR.

This year’s difficulties have meant that VHIR received 6% less funding as compared to 2009. Nonetheless it should be emphasized that good management of these resources has allowed it to go ahead with major projects with a smaller budget, to which the hospital has contributed 3.8 million Euros. With regard to funding, in 2010 VHIR obtained 36.3 million Euros, primarily from the private sector, and particularly from agreements with industry, clinical trials and donations. The data illustrate economic effort, but it is talent, dedication and ability to overcome obstacles displayed by our researchers and staff that make our Hospital and the Research Institute a clear example and an inspiration for the future. This document reflects the work of all those who have given and give much of their time to research. They have my trust and full support for what this collective effort brings to society. To all, I offer my deepest appreciation.

José Luis de Sancho Former General Manager of Vall d’Hebron University Hospital

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Introduction and 27.2% in the first decile. With a slight increase in human capital in the management structure and around 1,200 people dedicated to research we have also managed to increase the number of active clinical trials (428, an increase of 3.6%), as well as the number of research projects (242, an increase of 5.2% since 2009). In 2010, 16 of our 17 research team groups were part of the Thematic Network of Health Centers (RETICS) of the Instituto de Salud Carlos III (ISCIII). We have received external funding for 242 projects and 28 of our groups have been granted recognition from the Generalitat de Catalunya. Joan X. Comella VHIR’s Director

2010 has been a fruitful year for Vall d’Hebron Research Institute (VHIR). The general economic situation has not been an impediment to achieving new milestones. As a research center we have achieved our goals through the efforts of our researchers and the support staff of all the different units. We have improved on most of the challenges that we set every day, we have achieved many advances in research and have made strategic decisions that strengthen us as an institution. In 2010 we have increased more than 27% the impact factor of our scientific production over the previous year. We’ve gone from 540 to 595 publications and from a total impact factor of 2,474.71 to one of 3,149.5. With respect to the average impact factor per paper, we have grown from 4.58 to 5.29. 55% of our publications are in the first quartile

But beyond the positive scientific production data, 2010 was the year of the inauguration of a new space, the Collserola Building, for which we were granted a FEDER fund of 2 million Euros. Following an agreement, the Department of Health of the Generalitat de Catalunya provided us with a grant of 1.5 million Euros for operating expenses, plus 500,000 Euros for equipment. The Collserola Building is a step forward but not the end of the journey, since our potential drives us to seek new horizons and more space to continue growing, despite the economic context. 2010 has also been the year of our commitment to innovation. Including the creation of a new unit dedicated to looking for opportunities to exploit the results of our research and transfer our knowledge, creating partnerships with companies from different sectors in order to become a benchmark. VHIR, a brand established in the biomedical world, has opened up to other productive sectors of Catalonia, the rest of Spain and beyond our borders, be-

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cause if our researchers come from anywhere in the world our strategic movements must also be worldwide. Along with innovation, we strongly believe in communication, because we are in the era of communication and nothing one does is fully recognized if it is not known about. We have explained in an increasingly thorough manner what we do, internally and externally, and reached more audiences, beyond the boundaries of biomedicine and the healthcare environment. But it is only a beginning, because there is still a long way to go. Always serving society, we strive to explain to our stakeholders what we do, to ask for their support, to this end we have also created a development unit, which has recently started operating and must also represent a step forward in our goals. The quality of our research and the dedication of the support units have been recognized by the Spanish and the European scientific community. And so we have been chosen as Spain’s scientific coordinators, along with the institutional coordination of ISCIII, and the European translational research project EATRIS, of which we will be proud to be part once it has been launched. During 2010, the second year under this direction, many of the challenges outlined in 2009 have come to pass, others have evolved and a few new ones have emerged and will become reality in the near future, as part of the strategic plan 2011-2015 currently being developed. Nothing will stop us, not even the economic difficulties.

Joan X. Comella VHIR’s Director

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VHIR Information Vall d’Hebron Institut de Recerca (VHIR)

Vall d’Hebron Institut de Recerca (VHIR) MISSION

TRUSTEES

The Vall d’Hebron Research Institute - VHIR - is a public sector institution that promotes and develops innovative biomedical research at the University Hospital Vall d’Hebron. VHIR is oriented towards finding solutions to the health problems of citizens and aims to contribute to scientific, educational, social and economic development within its area of competence.

The Board is the Foundation’s governing body, it represents, manages, and assumes all powers and functions necessary to achieve the aims of VHIR.

VISION We want our research and innovation, carried out by the people who make up the institution, to expand the frontiers of knowledge and become an active and important reference for our society, our health system and our citizens, attracting talent and ensuring that our activities correspond in terms of excellence, quality and translation, with the leading position that the Hospital Vall d’Hebron deserves.

GOVERNING BODIES The Management and decision making infrastructure of VHIR is located in the Foundation University Hospital Vall d’Hebron Research Institute, where the governing bodies include:

Trustees to 16th December 2010 President Marina Geli Fàbrega Catalonian Regional Minister of Health

Joan Berenguer i Maimó Chief Executive Officer Imaging Diagnostic Institute (IDI) Antoni Esteve Cruella President Blood and Tissue Bank (HUVH) Pedro Fontana i García President Advisory Council Banco Bilbao Vizcaya Argentaria (BBVA) David García-Dorado Coordinator Research Group in Cardiocirculatory Pathology (VHIR)

1st Vice President Enric Argelagués Vidal Director Catalonian Institute of Health (ICS)

Francesc Gòdia i Casablancas Appointee by the Rector for Biotechnology and Biomedicine. Universitat Autònoma de Barcelona (UAB)

2nd Vice President Ana Ripoll Aracil Rector Universitat Autònoma de Barcelona (UAB)

Joan-Ramon Laporte Roselló General Director Catalonian Institute of Pharmacology Foundation (ICF)

3rd Vice President José Luis de Sancho Martín General Manager Vall d’Hebron University Hospital (HUVH)

Carles Miquel i Colell Coordinator of Health-care Research and Innovation Programme Department of Health

Treasurer Eduard Jaurrieta i Mas Deputy Director Professional Development Catalonian Institute of Health (ICS) Members Jesús Acebillo Marín President Health, Innovation & Society Foundation (Novartis) José Baselga Torres Chief of Service Medical Oncology (HUVH)

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Ramon Pau Pla Illa Managing Director Blood and Tissue Bank (HUVH) José Sánchez de Toledo Codina Chief of Service Pediatrics Oncology (HUVH) Oriol de Solà-Morales Serra Director Agència d’Avaluació de Tecnologia i Recerca Mèdiques Joaquim Tosas i Mir President CIMA Clinic

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Miquel Vilardell i Tarrés Chief of Service Internal Medicine (HUVH) Concepció Violán Fors Manager Research Institute Jordi Gol Attendee Joan X. Comella Carnicé Director Vall d’Hebron Research Institute (VHIR) Secretary Lluís Massó i Guitart Manager Vall d’Hebron Research Institute (VHIR)

Current Trustees from December 16th President Boi Ruiz i Garcia Catalonian Regional Minister of Health 1st Vice President Andreu Mas-Colell Catalonian Regional Minister of Economy and Knowledge 2nd Vice President Ana Ripoll Aracil Rector of Universitat Autònoma de Barcelona Members José Luis de Sancho Martín General Manager Vall d’Hebron University Hospital (HUVH) (until July 2011) Jaume Raventós i Monjo General Manager Vall d’Hebron University Hospital (HUVH) (from July 2011) Enric Argelagués Vidal Managing Director Catalonian Health Institute (ICS) (until July 2011) Joaquim Casanovas Managing Director Catalonian Health Institute (ICS) (from July 2011)

Manuel Armengol Carrasco Coordinator of the Educational Unit (HUVH) Joaquim Esperalba Iglesias General Director of Regulation, Planning and Health Resources at the Catalonian Regional Minister of Health Manel López Béjar Vice Chancellor for Research. Universitat Autònoma de Barcelona (UAB) Josep Maria Martorell i Rodón General Director of Research. Catalonian Government. Ramon Pau Pla Illa Manager Blood and Tissue Bank (BST) Lluís Rovira Pato Director Research Centers of Catalonia (ICERCA) Josep Tabernero Caturla Clinical Research Director. Vall d’Hebron Institute of Oncology (VHIO) Attendee Joan X. Comella Carnicé Director Vall d’Hebron Research Institute (VHIR) Secretary Lluís Massó i Guitart Manager Vall d’Hebron Research Institute (VHIR)

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GOVERNING BOARD / EXECUTIVE COMMITTEE On December 16th, 2010 the Governing Board became the Executive Committee, with the following functions: a) To carry out the resolutions adopted by the Board that this body may require. b) To periodically monitor the tasks of leadership and school management. c) To develop the proposed agenda for meetings of the Board and review the documentation to be submitted, if applicable. d) To propose to the Board the adoption of agreements that apply to this body. e) To monitor the covenants and agreements subscribed by the Foundation. f) To report on the borrowing requirements of the Foundation. g) To carry out the leadership and management tasks of the Foundation, especially with regard to its relationships with the founding institutions.

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VHIR Information Vall d’Hebron Institut de Recerca (VHIR)

Governing Board (until December 2010) President José Luis de Sancho Martín General Manager, Vall d’Hebron University Hospital Vice President Joan X. Comella Carnicé Director, VHIR Members Manuel Armengol Carrasco Coordinator of the Educational Unit, HUVH Joan Fernández Náger Director of Medical Processes, HUVH David García-Dorado García President, Internal Scientific Committee VHIR

Members Lluís Rovira Pato Director Research Centers of Catalonia (ICERCA) Josep Maria Martorell i Rodón General Director of Research. Catalonian Government. Manel López Béjar Vice chancellor for research. Universitat Autònoma de Barcelona (UAB) Secretary José Luis de Sancho Martín General Manager Vall d’Hebron University Hospital (HUVH) (until July 2011) Jaume Raventós i Monjo General Manager Vall d’Hebron University Hospital (HUVH) (from July 2011)

Vicenç Martínez Ibáñez Director of Surgical Processes, HUVH Joan Montaner Villalonga Vicepresident, Internal Scientific Committee VHIR

MANAGEMENT Director

Ana Ochoa de Echaguen Aguilar Director of Mother&Child Processes

and, if necessary: e) To coordinate obtaining the necessary resources to be able to carry out the Foundation’s objectives. f) Reporting the development of the Foundation’s research activities and programs to the Board. g) To manage the selection process of researchers and research support staff.

j) To formalize collaboration agreements with public or private institutions, below the maximum amount expressly authorized by the Board.

Miquel Vilardell i Tarrés Chief of Service Internal Medicine, HUVH

President Joaquim Esperalba Iglesias General Director of Regulation, Planning and Health Resources at the Catalonian Regional Minister of Health (until July 2011)

d) To propose the appointment of individuals to fill management and consulting posts to the Board

i) To propose rules of procedure to the Board.

Pilans Solans Julián Director of Health Care, HUVH

Executive Committee (from December 2010)

c) To present the Foundation’s proposed annual budget to the Board.

h) To propose services that may be required for the Foundation to develop assigned activities and functions.

Rafael Simó Canonge Clinical Trials Unit (UCICAC) Scientific Responsible, HUVH

Secretary Lluís Massó i Guitart VHIR Manager

Board, specifying the research, cost and anticipated funding sources.

Joan X. Comella [email protected]

The Director is responsible for developing the executive management of the Foundation. He has the following functions: a) To direct, organize and manage the research activities of the Foundation. b) To propose the Foundation’s schedule of activities to the

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k) Other duties as may be expressly assigned or delegated by the Board, under the terms provided in the Bylaws. Assistant Director in Clinical Research Joan Genescà [email protected] Direction Secretariat Irene Sendiu Gubianes Tel. 93 489 38 63 [email protected]

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Manager

man resources, staffing, incidents, separation and termination of labour and services contracts, as well as the management of grants.

Lluís Massó Guitar [email protected]

The duties of the Management: a) To direct financial and accounting management, the management of funds from other institutions or agencies, the preparation of annual accounts and to ensure the Foundation’s administrative tasks are carried out properly, the processing of documents and preparation of the management report. b) To run works, services and supply contracts on behalf of the Foundation, as delegated by the Board. c) To manage, in accordance with the guidelines set by the Board, the Foundation’s hu-

d) To provide the necessary administrative support for meetings of the Board and other bodies of the Foundation. e) To ensure the proper condition and operation of the Foundation’s assets and tracking the goods inventory. To run treasury borrowing operations. To conduct all required legal matters and management transactions for all property and securities, in accordance with guidelines approved by the Board. f) Anything that may be assigned or delegated by the bodies of the Foundation.

Secretary Trinidad Gutiérrez Morente Tel. 93 489 41 01 [email protected]

FROM INTERNAL SCIENTIFIC COMMITTEE TO INTERNAL SCIENTIFIC COUNCIL On December 16th, 2010, the Internal Scientific Committee became the Internal Scientific Council. The Board names, proposed by the Director, an Internal Scientific Council with a minimum of three and a maximum of twenty researchers from Research Groups of the Foundation, which aims to advise the direction in the performance of its functions. This body does not represent the Foundation nor hold management functions of any kind.

Internal Scientific Committee (until December 2010) President David García-Dorado Coordinator Research Group in Cardiocirculatory Pathology Vice President Joan Montaner Villalonga Research Group in Neurovascular Diseases Members Antònia Andreu Domingo Research Group in Microbiology Antoni Andreu Périz Research Group in Neuromuscular and Mitochondrial Pathology Joaquín Arribas López Research Group in Growth Factors and Cancer Laura Audí Parera Research Group in Pediatric Endocrinology

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VHIR Information Vall d’Hebron Institut de Recerca (VHIR)

Joan X. Comella Carnicé General Director, FIR-HUVH (From September 2009)

Miquel Casas Brugué Chief of Psychiatry Service and Chief of Research Group in Psychiatry and Mental Health

María Jesús Cruz Carmona Research Group in Pneumology

María Jesús Cruz Carmona Research Group in Pneumology

Joan Genescà Ferrer Research Group in Hepatic Diseases

Carmen Fuentelsaz Gallego Chief of Research Group in Health Care Research

Francisco Guarner Aguilar Research Group in Physiology and Digestive Physiopathology

David García-Dorado García Clinical Director of Heart Cardiology Area and Chief of Research Group in Cardiocirculatory Pathology

Monserrat Martínez Muñoz Deputy Director Nursing, Continuing Education, HUVH Francina Munell Casadesús Research Unit in Biomedicine and Translational and Pediatric Oncology Rosanna Paciucci Research Unit in Biomedicine and Translational and Pediatric Oncology Simó Schwartz Navarro Research Group in Nanomedicine

Internal Scientific Council (from December 2010)

Joan Gavaldà Santapau Research Group in Infectious Diseases Joan Genescà Ferrer Deputy Director of Research and Research Group in Liver Diseases Francisco Guarner Aguilar Research Group in Physiology and Digestive Physiopathology Xavier Montalban Gairín Clinical Director of Neuroscience Area and Chief of Research Group in Clinical Neuroimmunology Joan Montaner Villalonga Chief of Research Group in Neurovascular Diseases

President Joan X. Comella Carnicé Director, VHIR

Josep Ordi Ros Research Group in Systemics Diseases

Members Antoni Andreu Périz Director of Program in Molecular Medicine

Ricard Pujol Borrell Chief of Immunology Service and Chief of Research Group in Immunology

Joaquín Arribas López Chief of Research Group in Growth Factors and Cancer

Santiago Ramón y Cajal Agüeras Chief of Pathology Service and Chief of Research Group in Molecular Pathology

José Antonio Barrabés Riu Research Group in Cardiovascular Diseases Enric Cáceres Palou Chief of Service Department of Orthopedics and Rehabilitation, HUVH

Jaume Reventós Puigjaner Chief of Research Unit in Biomedicine and Translational and Pediatrics Oncology Simó Schwartz Navarro Coordinator of CIBBIM

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Joan Seoane Suárez Chief of Research Group in Gene Expression and Cancer Rafael Simó Calonge Chief of Research Group in Diabetes and Metabolism

FROM EXTERNAL SCIENTIFIC COMMITTEE TO EXTERNAL SCIENTIFIC COUNCIL On December 16th, 2010 External Scientific Committee became the External Scientific Council. The External Scientific Council is the body responsible for advising on the scientific activities of the Foundation and for ensuring its scientific quality. This body does not represent the Foundation nor hold management functions of any kind. The External Scientific Council is comprised of a minimum of three and a maximum of twenty internationally renowned scientists who are widely recognized in the Foundation’s fields of research. In no case can any member of the External Scientific Council engage in research linked to, or collaborate regularly with, the Foundation.

External Scientific Committee (until December 2010) Jesús Ávila de Grado Director, Severo Ochoa Molecular Biology Center, Universidad Autónoma de Madrid María Blasco Marhuenda Director Molecular Oncology Program, National Oncology Research Center (CNIO) Carlos Diéguez González Professor Physiology, Medical School University of Santiago de Compostela Francisco Fernández Avilés Director Institute of Heart Sciences (IDICOR), Valladolid

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José López Barneo Professor Physiology, University of Sevilla Carlos López Otín Professor Biochemistry and Molecular Biology, University of Oviedo

Dra. Barbara Casadei Professor in Cardiovascular Medicine Department of John Radcliffe Hospital, Oxford

Dra. Nancy Hynes Senior Group Leader of Friedrich Miescher Institute for Biomedical Research, Basel

Dr. Carlos Diéguez González Chairperson in Physiology of Faculty of Medicine, Santiago de Compostela University

Dr. José López Barneo Chairperson in Physiology, University of Seville

José María Martín Moreno Professor Public Health, University of Valencia

Dra. Ruth Duncan Emeritus Chairperson, Cardiff

José María Mato de la Paz Director Bioscience Operational Research Center (CIC Biogune) Vizcaya Technological Park

Dr. Stanislav D. Ehrlich Macrobiotics Genetics Unit Director, National Institute for Regional Research, Paris

External Scientific Council (from December 2010) Dr. Ernest Arenas Chief of Department of Medical Biochemistry and Biophysics. Chief of Molecular Neurobiology Research in Karolinska Institute in Stockholm

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Dr. Francisco Fernández Avilés Director of Institute of Heart Sciencies (ICICOR), Hospital Clínico Universitario de Valladolid, and Head of Cardiology, Hospital Universitario Gregorio Marañón, Madrid

Dr. Jesús Ávila de Grado Research Professor in CBM (CSIC-UAM)

Dr. Jay A. Fishman Director of Transplant, Infectious Diseases and Program in immunologically compromised patients, Massachusetts General Hospital, Boston

Dra. María Blasco Marhuenda Director of Molecular Oncology Programme of the National Center for Cancer Research

Dr. Seija Grénman President of Obstetrics and Gynecology Department, Turku University Hospital, Turku

Dra. Catherine Lubetzki Chairperson and Neurology, Hôpital Pitié-Salpêtrière, Paris Dr. Michael Manns President of Gastroenterology, Hepatology and Endocrinology Department in Medical School of Hannover Dr. José María Mato de la Paz Director of Center for Cooperative Research in Biosciences (CIC Biogune). Technology Park of Bizkaia Dr. Benoit Nemery Chairperson, Occupational Medicine and Toxicologists. President of Public Health Department, Leuven Dra. Marina Pollán President of Cancer Epidemiology Unit, National Center of Epidemiology, Madrid Dra. Sylvie Robine President of Morphogenesis and Cell Signaling Unit, Institute Curie, Paris Dr. Martin Wehling Director of Institute of Experimental and Clinical Pharmacological and Toxicology, Mannheim

WHERE WE ARE Vall d’Hebron Research Institute Passeig Vall d’Hebron, 119-129 08035 Barcelona www.vhir.org twitter.com/@VHIR_ facebook.com/VHIR.org

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VHIR Information Research Support Units

Research Support Units

Everyone at VHIR works together to support our research effort. Innovative new technologies, services and administrative staff are always available to support and advance the work of our researchers.

INNOVATIONS Head of Unit Francesc Iglesias García Tel. 93 489 4523 [email protected] Innovations Secretary Ana Lucía Román Mora Tel. 93 489 4187 [email protected] Advice Coordinator Raquel Egea Martínez Tel. 93 274 61 00 (ext. 6426) [email protected] Legal Advisor Lourdes Salomón Sancho Tel. 93 489 30 00 (ext. 4945) [email protected] Business Development & Marketing Cecília López García Tel. 93 489 30 00 (ext. 4947) [email protected] Financial Advisor Frederic Horta Sellarès Tel. 93 489 30 00 (ext. 4882) [email protected]

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Innovation Model The Vall d’Hebron University Hospital has created its own model of innovation in the Vall d’Hebron Institut de Recerca (Research Institute), with the joint goals of promoting innovation in order to create a more competitive hospital which operates both as an economic development agency and generates research findings that are beneficial to society. The Innovations team is made up of highly qualified senior personnel with extensive experience in marketing the institute’s innovative work results to both the public and private sectors. Work carried out by this unit includes; advising on strategies to protect intellectual property rights, technological brokering, patent licensing negotiations, assistance in creating spin offs, providing coaching for collaborative projects and “Innovation Initiatives”, etc.

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ADMINISTRATIVE STRUCTURE CEIC Support Unit Head of Unit Mireia Navarro Sebastián Tel. 93 489 46 51 [email protected] Research Project Staff Vanessa Rojas Sotomayor Tel. 93 489 38 91 [email protected] Administrative Support Staff Immaculada Pérez Gladiador Tel. 93 489 46 51 [email protected] Montserrat Fernández Recio Tel. 93 489 40 10 [email protected]

This unit provides support for clinical trials and post authorization studies involving medicines, medical devices and therapeutic interventions. The unit supports both projects launched by in-house researchers as well as those originating in other public agencies. It focuses on the ethical, methodological and logistical aspects of research. Portfolio of Services.

Management – Project development, management and protocol design.

– Management of agreements and contracts between centers.

– Informed consent forms for subjects taking part in medical research.

– Monitoring.

– Center for Review and Dissemination CRD (presented on digital or paper formats) design, development and data management (presented as digital CRD or Databases).

– Archive management (Master file).

– Processing trial results at the CEIC and other public agencies.

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– Adverse event management.

– Compilation of periodical and final reports.

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Communication Management Unit Head of Unit Fran García Morales Tel. 93 489 30 00 (ext. 4835) [email protected] Web and Corporate Image Elena Casaldàliga Albisu Tel. 93 489 30 00 (ext. 4668) [email protected] Multimedia and Corporate Image Roland Peralta Díez Tel. 93 489 40 59 [email protected] Communication Montserrat Ferrando Pastor Tel. 93 274 67 28 [email protected] Seminars Marçal Farrés Juste [email protected] Documentation Laura Llopart Estrems [email protected]

The communication unit is responsible for the following functions: – Using the broadcast and social media to inform the public about the VHIR’s scientific research and related activities.

– Publishing the majority of information in English due to the global nature of scientific research.

Computer Management Unit Project Manager Domènec Far Macia Tel. 93 489 45 64 [email protected] Systems Manager Jesús María Vicente Pérez Tel. 93 489 41 27 [email protected]

– Producing communication campaigns to report VHIR research activities at press conferences, in interviews and to the broadcast media. – Developing and maintaining the institutional website as an essential tool for internal and external communication. – Internal communication of publications and activities carried out by our researchers. Internal communication, intranet, web 2.0. – The writing of an annual analytic report of the scientific output of the VHIR.

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Programming Technician Xavier López Soriano Tel. 93 489 48 07 [email protected] Computer Assistance Joan Aymà Comas Tel. 93 274 20 02 [email protected] Toni Vega Gala Tel. 93 274 20 02 [email protected]

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VHIR Computer Services support our researchers by managing and coordinating all computer related issues. The unit created a comprehensive centralized database designed to manage the institution’s research findings, which covers both internal research processes as well as external agents’ research processes. Many useful research tools have been developed from this database: The GIR platform (www.vhir.org/gir) is a dynamic, interactive and participative tool that incorporates online services and allows researchers access to interactive data in real time, wherever they are.

Financial Management Unit Head of Unit Montserrat Giménez Prous Tel. 93 489 41 28 [email protected] Bids and Contracts Ingrid Feliubadaló Díaz Tel. 93 489 30 00 [email protected]

Economic Reports Anna Corominas Ruiz Tel. 93 489 45 91 [email protected]

Purchasers Imma Jiménez Ariza Tel. 93 489 40 27 [email protected]

Joaquim Cahors Gómez Tel. 93 489 30 00 [email protected]

Mercè Garcia Vidal Tel. 93 489 30 00 [email protected]

Marta Esteve Costal Tel. 93 489 41 48 [email protected]

Secretary Trinidad Gutiérrez Morente Tel. 93 489 41 01 [email protected]

Invoices/Income Meri Montero Cueto Tel. 93 274 60 34 [email protected]

Index

Treasurer Montse Abad de la Vega Tel. 93 489 44 59 [email protected]

Laia Batet Candela Tel. 93 489 40 18 [email protected] Technical Manager Xavier Bros Marín Tel. 93 489 45 91 [email protected] Legal Advisors Marta Pina Martí Tel. 93 489 30 00 [email protected] Marta González Barcelò Tel. 93 489 69 52 [email protected]

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The Financial Management Unit aims to optimize the VHIR’s economic resources to improve the efficiency and effectiveness of research management. The Financial Management Unit supports the economic management of the various research projects and clinical trials developed at the HUVH and at the VHIR, both through financial tracking and the writing of financial reports.

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Human Resources Unit Head of Unit Roger Verdejo Torras Tel. 93 489 43 39 [email protected] Human Resources Personnel Laia Pérez Lasarte Tel. 93 489 40 08 [email protected]

Development Unit Head of Unit Carmen Netzel Riera Tel. 93 489 30 00 (ext. 4931) [email protected]

The Development Unit is responsible for generating philanthropic support for biomedical research, coordinating external relations and alliances with international groups. We pay special attention to:

Miriam Izquierdo Sans Tel. 93 489 40 26 [email protected] Natàlia Tibau Llarden Tel. 93 489 43 37 [email protected]

The Human Resources Unit promotes and facilitates working relationships within the VHIR. It provides workforce suited to VHIR requirements and guidelines, respecting existing ethic and legal frameworks.

– Raising awareness about the importance of research in the curing of diseases. – Fostering and nurturing partnerships with corporate contributors, donors and friends of the VHIR. – Providing support for researchers and clinicians in their relationships with donors and philanthropic partners.

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Occupational Risk Prevention Unit Safety at Work Team Ana Elena Ruiz Querol Tel. 93 489 43 31 [email protected] Mª Teresa de la Campa Alonso Tel. 93 489 43 31 [email protected]

The Occupational Risk Prevention Unit advises on and works to promote health and safety at work, according to the regulations laid out in Law 31/95 of Occupational Risk Prevention. It assesses and controls risk, producing safety instructions, analyzing work accidents, training and informing employees, promoting healthy work habits and preventing the contraction of occupational diseases.

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Project Management Unit Head of Unit Laura Casado Castells Tel. 93 489 40 11 [email protected] International Projects Anaïs Le Corvec Tel. 93 489 40 13 [email protected] Manuel Morillas Díaz Tel. 93 489 40 13 [email protected] Project Monitoring Raquel Fornells Fiestas Tel. 93 489 30 00 [email protected] Research Grants and Fellowships Maribel Corral Zabala Tel. 93 489 40 12 [email protected]

SERVICES Advancing Health Research The Project Management Unit provides support to VHIR and HUVH researchers in preparing, presenting, and monitoring research projects, funded by regional, national and international private and public agencies. Its main functions are: – The selection and dissemination of information on available resources and financial support.

The Vall d’Hebron Research Institute has a number of important services whose role is to support research and to provide the complex environments currently required in biomedicine research. These include the scientific and technical Support Unit (UCTS), the Statistics and Bioinformatics Unit (UEB), the Support Unit for Biomedical Research Methodology (USMIB), the Clinical Research Eth-

– The monitoring of resources and funded projects. – Working towards a more effective use of resources in research project development at VHIR. – The dissemination and organization of training on resources available for the development of research projects.

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ics Committee (CEIC), the Animal Facility and Laboratory Coordination Unit. The two most recently created services are the biobank and the Central Unit of Clinical Research and Clinical Trials (UCICAC). Which in addition to providing researchers with up-to-date services and technology works towards increasing profitability and improving selfsufficiency.

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Scientific and Technical Support Unit (UCTS) The Scientific and Technical Support Unit (UCTS) offers a range of high-tech services to support teaching and research activities in the field of biomedics. The centralized nature of STSU permits it to offer researchers the most advanced tools available in genomics, bioinformatics, proteomics, cytomics and microscopy at a reduced cost, with frequent updates and specialized advice. Head of Unit Fátima Núñez Mangado Tel. 93 489 41 89 [email protected]

Researchers Francisca Gallego Valadés Tel. 93 489 41 79 [email protected] Marta Valeri Sala Tel. 93 489 41 79 [email protected] Mª Ángeles Artaza Marino Tel. 93 489 41 79 [email protected] vhir.org Ricardo Gonzalo Sanz Tel. 93 489 41 79 [email protected] vhir.org Àlex Bote Tronchoni Tel. 93 489 41 79 [email protected] vhir.org Rosa Mª Prieto Sánchez Tel. 93 489 41 79 [email protected] vhir.org Rosa Arjona Martos Tel. 93 489 41 79 [email protected] vhir.org

1. GENOMICS UNIT Real-Time Quantitative PCR System Head of Unit Francisca Gallego Valadés Tel. 93 489 41 78 [email protected] Scientific Advisor Joan Seoane Suárez Tel. 93 274 60 26 [email protected]

Equipment • 1 Real-Time PCR system PCR ABI PRISM 7000-SDS. • 1 Real-Time PCR system PCR ABI PRISM 7900-SDS. • 2 single cell PCR system.

DNA Sequencing Service Irene Sales Pardo Tel. 93 489 41 79 [email protected] vhir.org Àlex Sànchez Pla Tel. 93 489 40 07 [email protected] vhir.org Israel Ortega Serrano Tel. 93 489 40 07 [email protected] vhir.org Josep Lluís Mosquera Mayo Tel. 93 489 40 07 [email protected] vhir.org

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Head of Service Rosa Arjona Martos Tel. 93 489 41 81 [email protected] vhir.org Scientific Advisor Antoni Lluís Andreu Périz Tel. 93 489 40 57 [email protected]

Equipment • 1 Applied Biosystems ABI PRISM 3100 Automatic sequencer.

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Bioanalysis Service Heads of Service Ricardo Gonzalo Sanz Tel. 93 489 41 78 [email protected] vhir.org Rosa Arjona Martos Tel. 93 489 41 78 [email protected] vhir.org

Equipment • 1 Agilent Bioanalyzer 2100.

2. MOLECULAR DIAGNOSTIC PLATFORM Ultrasequencing Service Head of Service Rosa Mª Prieto Sánchez Tel. 93 489 41 79 [email protected] vhir.org Operator Francisca Gallego Valadés Tel. 93 489 41 79 [email protected]

Equipment • 1 Roche/454GS-FLX system. • 1NimbleGen Microarray Scanner MS 200. • 1 sequence enrichment system on a solid bracket. • 1 sequence enrichment system in solution.

Genetic Expression Analysis Service Head of Service Ricardo Gonzalo Sanz Tel. 93 489 41 78 [email protected] vhir.org Operator Francisca Gallego Valadés Tel. 93 489 41 79 [email protected] Scientific Advisor Joan Seoane Suárez Tel. 93 274 60 26 [email protected]

Equipment • 1 Affymetrix GeneChip Microarray systems with two fluid stations and an automatic array charger. • 1 Affymetrix GeneTitan system to process arrays automatically.

Protein Microarray Service Head of Service Francisca Gallego Valadés Tel. 93 489 41 79 [email protected] Staff Team Marta Valeri Sala Tel. 93 489 41 79 [email protected] Àlex Bote Tronchoni Tel. 93 489 41 79 [email protected] vhir.org

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Index

Equipment • 1 system for high-density microarrays - Zeptosens Reverse Array System (including Zepto Reader Scanner and NanoPlotter).

3. PROTEOMICS PLATFORM Proteomics Service Head of Service Francesc Canals Tel. 93 489 41 75 [email protected] Researchers Núria Colomé Calls Tel. 93 489 4174 [email protected] Joan Josep Bech Serra Tel. 93 489 41 74 [email protected] Marta Monge Azemar Tel. 93 489 41 74 [email protected]

Equipment • 1 Amersham Bio -Sciences system for two-dimensional electrophoresis of proteins, composed of: – 2 units a pH-gradient strip for isoelectric focusing IPGPHOR. – 2 electrophoresis units DALT VI for gels of 26 x 20 cm. • 1 Amersham BioSciences scanner and imaging analysis Image Master Platinum software. • 1 GE Healthcare DIGE System (Differential Gel Electrophoresis, Amersham), composed of: – 1 Typhoon 9400 scanner to obtain fluorescence images of 2D electrophoresis gels. – 1 GE Healthcare DeCyder for quantitative analysis of differences. – 1 Nonlinear Dynamics SameSpots software for quantitative analysis of images. • 1 GE Healthcare Spot Picker robot. • 1 Bruker Proteineer DP robot.

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• 1 Bruker mass spectrometry MALDITOF/ TOF Autoflex Speed. • 1 Ettan LC system by Amersham of liquid chromatography from micro- to analytical scale. • 1 LC-Packings nano-HPLC system. • 1 nano-HPLC Proxeon system. • 1 Bruker Ionic trap-electrospray mass spectrometry Esquire Ultra-ETD. • 1 Bruker mass spectrometry Ultra High Resolution Q-TOF Maxis.

4. METABOLOMICS SCIENCE PLATFORM Metabolomics Service (Cardiocirculatory Pathology) Head of Service Ignasi Barba Vert Tel. 93 489 41 86 [email protected] Group Leader David García-Dorado Tel. 93 489 40 38 [email protected]

Equipment • 1 RMN Bruker Avance 400 WB spectrometer, with z-axis gradient with the following probes: – 1 5 mm 1H-BB inverse probe. – 1 20 mm 1H-BB probe. – 1 HR-MAS 1H-31P-13C probe. • 1 BCUC05 unit to regulate temperature. • 1 Equipment Bruker Mini-imaging 0.5 to obtain images. • 1 Animal monitoring equipment.

Metabolomics Service (STSU) Head of Service Mª Ángeles Artaza Marino Tel. 93 489 41 79 [email protected] Operator Ricardo Gonzalo Sanz Tel. 93 489 41 79 [email protected]

6. MICROSCOPY PLATFORM Equipment • 1 Waters ACQUITY UPLC system. • 1 Waters mass spectometer MS/MS X¬evo TQ. • 1 nano-HPLC Tempo system. • 1 Applied Biosystems hybrid mass spectometer triple quadrupole with ionic trap 4000 Q TRAP LC/MS/MS.

5. CITOMICS PLATFORM Cytometry Analysis and Cell Sorting Service Head of Service Irene Sales Pardo Tel. 93 489 41 82 [email protected] vhir.org Operator Àlex Bote Tronchoni Tel. 93 489 41 77 [email protected] vhir.org Scientific Advisors Jordi Barquinero Máñez Tel. 93 489 67 26 [email protected] Jordi Pétriz González Tel. 93 489 31 23 [email protected]

Equipment • 3 flow cytometers: – 2 Becton & Dickinson FACScalibur flow cytometer analyzers. – 1 Becton & Dickinson LSR Fortessa. • 2 high-speed cell sorters: – Becton & Dickinson FacsAria. – Beckman Coulter MOFLO.

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Confocal Microscopy Service Head of Service Marta Valeri Sala Tel. 93 489 41 83 [email protected] Operator Rosa Mª Prieto Sánchez Tel. 93 489 41 79 [email protected] vhir.org Scientific Advisor Rosanna Paciucci Tel. 93 489 40 63 [email protected]

Equipment • 1 Olympus spectral confocal microscopy FV1000. • 1 Olympus multidimensional microscopy TIRFM high-speed CellR. • 1 Olympus conventional fluorescence microscopy BX61.

Microdissection Service Head of Service Mª Ángeles Artaza Marino Tel. 93 489 41 80 [email protected] vhir.org Scientific Advisor Santiago Ramón y Cajal Tel. 93 274 68 09 [email protected]

Equipment • 1 microdissection microscopy: Leica LMD 6000 with optical tweezers and adapted to microdissect living cells. • 1 cryostat Leica CM3050 S.

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Vall d’Hebron University Hospital Biobank (VHUHBB)

Bioinformatics and Statistics Platform (UEB) The Bioinformatics and Statistics Platform is part of the Scientific and Technical Support Unit whose main objectives are: – To provide statistical and bioinformatics support to analyze high performance data (high throughput) generated during the biomedical research carried out at VHIR. – To develop our own research lines in statistics and bioinformatics; with special emphasis on fields that may enhance the array of services provided by this unit. – To establish a training program in statistics and bioinformatics for biomedical research.

Services offered – High-performance data analysis. – Advice when applying for project funding or compiling research protocols. – To develop and maintain bioinformatics applications. – To carry out general or specific training activities. Equipment • 3 HP workstations with 2 processors and 8/16 Gb RAM. • 1 server spreadsheet with 4 processors and 16 Gb RAM. • Free software (R, PHP or mySQL). • Propietary software (i.e. Partek Genomics Suite or Ingenuity System).

Head of Service Àlex Sánchez Pla Tel. 93 489 40 07 [email protected] Staff Team Israel Ortega Serrano Tel. 93 489 40 07 [email protected] Josep Lluís Mosquera Mayo Tel. 93 489 40 07 [email protected]

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The Vall d’Hebron University Hospital Biobank (VHUHBB) is a research support unit which collects biological samples of human origin for biomedical research projects in compliance with current legislation. Its main objective is to provide the scientific community with the high quality biological material required for research to ensure competitiveness and research excellence.

Scientific Director Santiago Ramón y Cajal Tel. 93 274 68 09 [email protected] Technical Director Fátima Núñez Mangado Tel. 93 489 41 89 [email protected] Coordinator Isabel Novoa García Tel. 93 274 60 00 (ext. 4842) [email protected] Operator Maribel Velasco García Tel. 93 274 60 00 (ext. 4842) [email protected]

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Services – Advice for the proper collection, processing, storage and use of human biological samples for biomedical research. – Registration, processing and storage of the human biological samples in the biobank collections.

Animal Facility The animal facility of the Vall d’Hebron Research Institute focuses on teaching related to the use of laboratory animals. Located in the Mediterrània Building, it occupies a single floor of 745 m2. The animal facility operates within current legislation. It is registered at the “Departament de Medi Ambient i Habitatge” with number B9900062. The facility is divided into two areas: The Rodent Area with a standard clean area, a passive quarantine, a barrier area to accommodate immunodeficient mice, six manipulation rooms and the Molecular Imaging Platform; as well as the Big Animals Area with space enough to accommodate rabbits, pigs and sheep with fully equipped experimental operating rooms to carry out teaching and experimental surgical procedures. The animal facility has an advisory committee composed of Institute research staff, whose role is to create, improve and modify animal testing procedures.

Head of Facility Marta Rosal Fontana Tel. 93 489 40 09 [email protected] Veterinarians Marielle Esteves Tel. 93 489 43 11 [email protected] Àlex Rojo Amigo Tel. 93 489 38 97 [email protected] Animal Laboratory Technicians (Felasa B) Raquel García Ontivero Tel. 93 489 43 10 [email protected] Cristina León Català Tel. 93 489 43 10 [email protected] Animal Caretakers (Felasa A) Martha Irene Giraldo Sánchez Tel. 93 489 43 10 [email protected] Sílvia Gil López Tel. 93 489 43 10 [email protected] Daniel Martínez Falconero Tel. 93 489 43 10 [email protected] Secretary Montserrat Molano i Flores Tel. 93 489 38 97 [email protected]

Equipment • Automatic control system and environmental parameters regulation: ventilation and pressure, temperature, relative humidity and lighting. • Support structures, cages and accessories for animal maintenance. • Ventilated racks with positive pressure. • Biological safety cabinets. • Bottle and rack cleaners to automatically clean and disinfect shelves, cages and other accessories. • Autoclave. • Micronebulizer to disinfect/sterilize all rooms. • Water treatment: filtration apparatus and ultraviolet radiation. • Experimental operating rooms: – E2 for pigs and sheep. – 1 for rabbits. – 7 manipulation rooms for rodents: 6 strictly conventional rooms and 1 SPF room. • Experimental operating rooms equipment: – Inhalatory anesthesia equipment. – Mono or bipolar Electronic scalpel. – Laparoscopy and endoscopy towers. – Scopy arch. – 4 surgical microscopes. Animal House Species Mouse, rat, rabbit, pig, sheep.

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Molecular Imaging Platform The Molecular Imaging Platform (PIM) is an optical imaging system using bioluminescence and fluorescence and was established through the combined efforts of CIBER-BBN, CIBBIM-Nanomedicine and the VHIR as a service provided for research groups and pharmaceutical companies. Its mission consists of providing the capacity to develop non-invasive optical images in vivo at cellular, molecular and functional level, including fluorescence and bioluminescence. The main equipment consists of: – Xenogen IVIS® Spectrum. – Leica Macro Fluo: precision macroscope for fluorescence. – Hammamatsu ORCA-2BT-512.

Head of Service Yolanda Fernández Amurgo Tel. 93 489 30 00 (ext. 3375) [email protected] Technician Anna Pujol Esclusa Tel. 93 489 30 00 (ext. 4661) [email protected] Location Mediterrània Building Ground floor, Vall d’Hebron Research Institute. Vall d’Hebron University Hospital

UCICAC The Central Unit of Clinical Research and Clinical Trials (UCICAC) was established by a professional multidisciplinary team and offers researchers a comprehensive program of services (start-to-finish) to assist them to develop clinical research projects and clinical trials. It guarantees that HUVH biomedical research remains a competi-

1. URAC tive and appealing proposition. The UCICAC generates and promotes both projects and instruments to facilitate clinical research. Additionally, the UCICAC promotes training activities in clinical research and clinical trials. In the future, its functions will be offered from a single central location on the 13th floor of the Maternity Hospital, where the following units will be located: – Research and Clinical Trial Unit (URAC) (link below). – Methodological Support for the Biomedical Research Unit (USMIB) (link, USMIB new web site or information repetition below).

Head of Unit Antonio Salgado Remigio [email protected] Scientific Director CAIBER Rafael Simó Canonge [email protected] Coordinator Claudia Cases [email protected] Project Manager Mònica Anglada Bàguena [email protected] Secretary Ester Carceller Delgado [email protected]

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Coordinator Immaculada Fuentes Camps [email protected] Nursing Patricia Fernández Vandellòs [email protected] Instructor Silvia Garcia Matas [email protected]

The Research and Clinical Trial Unit (URAC) supports clinical trials and post-authorization studies involving medicines, medical devices and therapeutic interventions. It supports both projects launched by in-house researchers as well as those originating in other public agencies. It focuses on the ethical, methodological and logistical aspects of research. Additionally, the Research and Clinical Trials Unit aims to promote continuing training in clinical research and clinical trials.

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2. USMIB Coordinators Antonio Salgado Remigio [email protected] Claudia Cases [email protected] Methodologists Xavier Vidal Guitart [email protected] Santiago Pérez Hoyos [email protected] Lluis Armadans Gil [email protected] Eva López Guerrero [email protected]

The Biomedical Research Methodological Support Unit (USMIB) was developed by the Vall d’Hebron Research Institute (VHIR) with the institutional support of the Vall d’Hebron University Hospital (HUVH) management and the collaboration of the “Servei de Farmacologia Clínica” - Clinical Pharmacology Service and the “Servei de Medicina Preventiva i Epidemiologia” - Preventive Medicine Service. The USMIB offers scientific methodology services to promote and facilitate biomedical research at the Vall d’Hebron University Hospital, to both primary healthcare providers and independent health service operators requiring advanced research services. One of its tasks is to establish a training program in methodology for biomedical research.

Laboratory Coordination Service Head of Service Núria Prim Vilaró Tel. 93 489 43 23 [email protected] Laboratory Technicians Fátima Jiménez Mamolar Tel. 93 274 67 99 [email protected] Eulàlia Joseph Munné Tel. 93 489 30 00 (ext. 4904) [email protected] Secretaries Anna Pedrol Clará Tel. 93 274 67 99 [email protected] Rosa Guillén Vidal Tel. 93 489 49 05 [email protected]

Maintenance Staff María Pilar Alonso Alonso Tel. 93 489 30 00 (ext. 4902) Flora Díaz Ramos Tel. 93 489 40 39 Tao González Zaragoza Tel. 93 489 30 00 (ext. 4902) Esther Mateos Mullor Tel. 93 489 30 00 (ext. 4970) Raimundo Molina Martínez Tel. 93 489 30 00 (ext. 4902) Xavier Pardos Benito Tel. 93 489 40 39 Joaquim Solà Santesmases Tel. 93 489 40 39 Pablo Vilalta Gras Tel. 93 489 40 39 Margarita Ruiz Olivart Tel. 93 489 40 39 Laboratory Cleaners Flor Menéndez Parraga Tel. 93 489 30 00 (ext. 4672) Patricia Hinojosa Casanova Tel. 93 489 30 00 (ext. 4669) Rosario Molano Flores Tel. 93 489 30 00 (ext. 4948)

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The main objectives of the Laboratory Coordination Service are: – To coordinate the operational aspects of all laboratories at the “Institut de Recerca” – To manage resources such as nursing personnel, nursing technicians and auxiliary staff supporting biomedical investigation services. These objectives are achieved by acting as a link between the various laboratories and General Management whilst providing know-how, managing vacancies and facilitating the implementation and monitoring of regulations concerning both hospital and Research Institute areas.

Members María Antolín Mate Pharmacist Researcher at “Unitat de Fisiologia i Fisiopatologia Digestiva” María Teresa Martín Gómez Microbiologist doctor Researcher at the “Malalties Infeccioses” group José Luis Peiró Ibáñez Doctor Pediatric surgery expert Diego Arango del Corro Biologist Researcher at the CIBBIM group Ramón Gimeno Martínez Doctor Researcher at the “Teràpia Cel·lular i Gènica” group

Index

Members Lluís Armadans Gil Doctor Fernando Azpiroz Vidaur Doctor Arantxa Catalán Ramos Primary health care pharmacist Esther Cucurull Folgera Pharmacologist-doctor Inés M. de Torres Ramírez Doctor Ignacio Ferreira González Doctor Carmen Fuentelsaz Gallego Qualified nurse Inmaculada Fuentes Camps Qualified nurse Jaume Guardia Massó Doctor

ETHICS COMMITTEES

ANIMAL EXPERIMENTATION ETHICS COMMITTEE (CEEA) The Animal Experimentation Ethics Committee (CEEA) was created on the 8th January 1998 to ensure the care and welfare of animals used in experimentation. Its functions include the following: producing reports on experimental procedures, eliminating unnecessary pain and providing humanitarian euthanasia, assessing the professional profiles of personnel involved in procedures, and assessing the suitability of the procedures used.

President Carmen Espejo Ruiz Biologist “Neuroimmunologia Clínica” group researcher Secretary Marta Rosal Fontana Veterinarian Animal facility manager. Animal welfare adviser

CLINICAL RESEARCH ETHICS COMMITTEE (CREC) The CREC collaborates with and provides support to the VHIR. The CREC is an independent body comprising health and non health professionals. It is responsible for ensuring that the rights, safety and welfare of subjects taking part in clinical trials are protected. It guarantees adequate trial protocols, researcher suitability, the suitability of facilities, as well as ensuring that adequate procedure and documentation is in place to obtain informed consent.

President Soledad Gallego Melcón Doctor Vice President Joan Bagó Granell Doctor Secretary Mireia Navarro Sebastián Chemist

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Juan Carlos Hortal Ibarra University law professor Francisco de la Torre Arteche Doctor Joan-Ramon Laporte Roselló Pharmacologist-doctor Isabel Miró Muixi Doctor J. Bruno Montoro Ronsano Hospital pharmacist Alexis Rodríguez Gallego Pharmacologist-doctor Joan Segarra Sarries Lawyer Marta Solé Orsola Qualified nurse Pilar Suñé Martín Hospital pharmacist

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VHIR Research Activity

VHIR Information Summary of Research Activity

Summary of Research Activity

The VHIR’s research activities, outlined in this 2010 Annual Report can be summarized as follows.

RESEARCHERS AND TECHNICIANS Table 1 VHIR researchers and technicians

57 Research Groups Research staff (65%) Researchers Doctors Biologists Biochemists Pharmacists Psychologists Chemists Veterinarians Others

489 393 27 15 5 13 4 3 29

Postdocs Predocs

Researchers (41%)

Supporting research staff (35%)

77 213

Supporting research staff (35%) Supporting research staff Graduates Nurses. ATS. DUI Laboratory technicians Administrative staff Others

417 143 34 89 79 72

Postdocs (6%)

Predocs (18%)

Figure 1 VHIR researchers and technicians

Total

1,196

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677  36.2%

497 454

448

VHIR’s ascribed staff VHIR’s funded staff Structure staff Total

457

 8.8%

411

378

452

477

51

59

63

70

826

865

909

974

2006

2007

2008

2009

519

 11.4%

 22.8%

78 1,196

Figure 2 Evolution of the staff over the last 5 years

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Other

17

Catalonian Institute of Pharmacology (ICF)

9

Institut de Diagnòstic per la Imatge (IDI)

9

Banc de Sang i Teixits (BST)

49

Vall d’Hebron Institute of Oncology (VHIO)

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Centro de Investigación Biomédica en Red (CIBER)

524

Vall d’Hebron University Hospital (HUVH)

519

Vall d’Hebron Institut de Recerca (VHIR)

2010

43.4% Figure 3 Contracting entities. Staff funded by the VHIR: 519 (43.4%)

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VHIR Research Activity

VHIR Information Summary of Research Activity

VHIR’S ECONOMIC SUMMARY

1.5

2

4

4.1

3.2

– 5.3%

1.5 3.8

– 6.4%

3.7

23.4

24.9

36.5

38.5

36.2

26.6

28.6

42.6

44

41.5

2006

2007

2008

2009

2010

CIBER HUVH VHIR Total

Figure 4 VHIR financing during the period 2006 to 2010 in millions of Euros

Table 2 2010 VHIR’s income breakdown

2010 Income Breakdown

Million of Euros

Projects funded by agencies Agreements with industry Donations Clinical Trials Teaching Other

13.4 6.6 3.9 6.7 1.6 4

Total

36.2

HUVH contributions (Staff, Goods and Direct Services and other €)

36

3.8

305

319

Index

Annual Report 2010

PRESENCE IN PUBLICATIONS IN NATIONAL AND INTERNATIONAL JOURNAL CITATION REPORTS (JCR) In 2010, 595 papers by VHIR’s researchers were published in scientific journals, achieving a combined impact factor of 3,149.576, with an average impact factor per review of 5.293. 2010 Journal Citation Reports (JCR) was used to calculate the impact factor for 2010. Original papers, reviews and editorials were included, while conference correspondence was excluded.

Table 3 VHIR’s 2010 international and national publications

Number

Impact Factor

Papers in international journals Papers in national journals Reviews in international journals Reviews in national journals Editorials in international journals Editorials in national journals

440 69 41 8 29 8

2,583.252 98.314 201.615 9.205 245.902 11.288

Total

595

3,149.576

 27.27%

Total Impact Factor Number of publications Average Impact Factor per publication

Figure 5 VHIR scientific production in the last five years

1,565.598

1,909.890

2,321.300

2,474.709

3,149.576

401

415

515

540

595

3.90

4.60

4.51

4.58

5.293

2006

2007

2008

2009

2010

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VHIR Information Summary of Research Activity

It is also significant that 54.789% of publications in scientific journals by VHIR’s researchers appear in the first quartile of publication data sets. If we consider the category and impact factor they belong to, 27.226% of these publications belong in the first decile of these data sets.

Figure 7 Distribution of publications per quartiles and first deciles according to category and Impact Factor

54.789%

Table 4

(326)

Publications per quartiles

Quartile Q1

Number 326

First decile D1

% 54.789%

162

27.226%

D1 27.226%

19.663%

25.546%

Q2 > Q2

117 152

19.663% 25.546%

(162)

(117)

(152)

Total

595

100.00%

Q1

Q2

> Q2

208

Area 1. Oncology and Genetics

1,453.258 27 116.848

Area 2. Endocrinology, Growth, Metabolism and Diabetes

373.593

Area 3. Cardiovascular Diseases, Hemostasis and Hypertension

161

Area 4. Neurosciences

62

812.659 51 Number of publications Total 740

281.302

Area 5. Digestive Physiopathology and Hepatology

70

Area 6. Infectious Diseases

268.263 Impact Factor Total 3,912.728

86

Area 7. Respiratory and Systemic Diseases

310.808 26

Area 8. Pathology, Cellular and Gene Therapy

99.591 Figure 6 2010 Impact Factor per research area Publications shared by two or more research areas are analyzed independently, counting the publication and its impact factor in each of the research areas

19 67.594

Area T1. Epidemiology, Pharmacology, new Therapies, Clinical Research

25

Area T2. Nanomedicine

113.587

38

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319

Index

Annual Report 2010

Table 5 2010 Impact Factor per research area/group

Total Impact Factor

Total Publications

Average Impact Factor

1,453.258

208

6.987

121.380 216.587 43.500 19.941 48.851 11.809 554.055 7.135 228.090 70.214 3.570 109.306 18.820

28 41 7 4 2 3 68 1 28 13 1 10 2

4.335 5.283 6.214 4.985 24.426 3.936 8.148 7.135 8.146 5.401 3.570 10.931 9.410

Area 2. Endocrinology, Growth, Metabolism and Diabetes Diabetes and Metabolism Paediatric Endocrinology Nephrology

116.848 63.491 14.354 39.003

27 16 4 7

4.328 3.968 3.589 5.572

Area 3. Cardiovascular Diseases, Hemostasis and Hypertension Cardiovascular Diseases Reparative and Therapy of the Heart

373.593 364.079 9.514

62 59 3

6.026 6.171 3.171

Area 4. Neurosciences Clinical Neuroimmunology Pediatric Neurology Psychiatry and Mental Health Neurovascular Diseases Neurotraumatology and Neurosurgery (UNINN) Magnetic Resonance and Neuroradiology Alzheimer Neurodegenerative Diseases Neuromuscular and Mitochondrial Pathology Cell Signaling and Apoptosis Headache and Neurological Pain Peripheral Nervous System

812.659 194.695 24.345 106.222 192.676 34.519 82.348 51.246 78.772 23.480 7.178 3.702 13.476

161 40 7 25 34 9 15 9 7 6 1 3 5

5.057 4.867 3.478 4.249 5.667 3,835 5.490 5.694 11.253 3.913 7.178 1.234 2.695

Research Groups Area 1. Oncology and Genetics Unit in Biomedicine and Translational and Pediatric Oncology Molecular Pathology VHIO-Growth Factors VHIO-Proteomics VHIO-Gene Expression and Cancer Animal Models VHIO-Experimental Therapeutics VHIO-Stem Cells and Cancer VHIO-Gastrointestinal Tumors VHIO-Radiation Oncology VHIO-Tumors Biomarkers Experimental Hematology Oncology and Molecular Pathology

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VHIR Information Summary of Research Activity

Table 5 2010 Impact Factor per research area/group (Cont.)

Research Groups

Total Impact Factor

Area 5. Digestive Physiopathology and Hepatology Digestive Transplants Liver Diseases Physiology and Pathophysiology of the Digestive Tract

Total Publications

Average Impact Factor

281.302 18.298 155.762

51 4 26

5.516 4.575 5.991

107.242

21

5.107

Area 6. Infectious Diseases Infectious Diseases Microbiology Clinical Research and Innovation in Pneumonia & Sepsis

268.263 93.304 57.332

70 26 17

3.832 3.589 3.372

117.627

27

4.357

Area 7. Respiratory and Systemic Diseases Systemic Diseases Pneumology Immunology Chronic Fatigue

310.808 158.067 122.241 28.146 2.354

86 39 40 5 2

3.614 4.053 3.056 5.629 1.177

99.591 7.483 24.126 22.134 45.848

26 2 6 9 9

3.830 3.742 4.021 2.459 5.094

10.275

4

2.569

67.594 42.287 20.562 4.745

19 10 8 1

3.558 4.229 2.570 4.745

113.587

25

4.543

49.014 18.452 5.328

8 3 1

6.127 6.151 5.328

19.774 4.351 16.668

5 1 7

3.955 4.351 2.381

53.946

18

2.997

Area 8. Pathology, Cellular and Gene Therapy Neuro-spinal Pathology Study Ophthalmology Maternal Fetal Medicine Genetics Bioengineering, Orthopedics and Surgery in Pediatrics Area T1. Epidemiology, Pharmacology, New Therapies, Clinical Research Epidemiology and Public Health (EPIDEM) Clinical Pharmacology Cell and Gene Therapy Area T2. Nanomedicine CIBBIM-Nanomedicine. Drug Delivery and Targeting CIBBIM-Nanomedicine. Molecular Oncology CIBBIM-Nanomedicine. Immunobiology CIBBIM-Nanomedicine. Lysosomal Storage Diseases and Cell Pathophysiology. CIBBIM-Nanomedicine. Renal Pathophysiology CIBBIM-Nanomedicine. Basic Research in Aging Other Research Units

40

305

319

Index

Annual Report 2010

Table 6 Number of papers published in relevant scientific journals during 2010

Journal Nejm - New England Journal of Medicine Nature Cell Lancet JAMA - Journal of the American Medical Cancer Cell Cell Stem Cell Lancet Neurology Journal of Clinical Oncology Annals of Internal Medicine Journal of Clinical Investigation Molecular Psychiatry Circulation Lancet Oncology Nature Neuroscience British Medical Journal Plos Medicine Gastroenterology Journal of the American College of Cardiology Biochimica et Biophysica Acta-Reviews on Cancer Genome Research Hepatology American Journal of Respiratory and Critical Care Medicine Blood

41

Published papers

IF

2 2 1 5 2 3 1 1 17 1 1 2 7 2 1 1 1 2 1 1 1 2 2 2

47.050 34.480 31.152 30.758 28.899 25.288 23.563 18.126 17.793 16.225 15.387 15.049 14.816 14.470 14.345 13.660 13.050 12.899 12.535 11.685 11.342 10.840 10.689 10.555

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Table 7 Publications in international journals

Publication

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

1.472 1.768 3.406 4.909 2.683 2.178 4.357 4.357 3.575 6.012 1.721 2.404 3.481 4.466 3.296 5.673 4.013

1.472 1.768 3.406 19.636 2.683 2.178 4.357 8.714 3.575 6.012 1.721 4.808 10.443 4.466 3.296 11.346 4.013

1 1 1 4 1 1 1 2 1 1 1 2 3 1 1 2 1

1.472 1.768 3.406 4.909 2.683 2.178 4.357 4.357 3.575 6.012 1.721 2.404 3.481 4.466 3.296 5.673 4.013

10.689 4.062 6.433 5.354 1.097 2.457 16.225 9.317 5.647 4.130

21.378 4.062 19.299 5.354 1.097 2.457 16.225 27.951 135.528 4.130

2 1 3 1 1 1 1 3 24 1

10.689 4.062 6.433 5.354 1.097 2.457 16.225 9.317 5.647 4.130

2.670 8.111 9.940 4.802 3.686 0.912 9.813

2.670 16.222 9.940 4.802 7.372 0.912 9.813

1 2 1 1 2 1 1

2.670 8.111 9.940 4.802 3.686 0.912 9.813

7.235 7.332

7.235 7.332

1 1

7.235 7.332

Decile Quartile (D) (Q)

International journals (n = 290)

Acta Neurochirurgica Acta Paediatrica Advances in Clinical Chemistry AIDS AIDS Patient Care and STDs AIDS Research and Human Retroviruses Alimentary Pharmacology & Therapeutics American Heart Journal American Journal of Cardiology American Journal of Gastroenterology American Journal of Industrial Medicine American Journal of Medical Genetics Part A American Journal of Medical Genetics Part B American Journal of Medicine American Journal of Neuroradiology American Journal of Pathology American Journal of Physiology-Cell American Journal of Respiratory and Critical Care Medicine American Journal of Surgical Pathology American Journal of Transplantation Anesthesiology Angiology Annals of Allergy Asthma & Immunology Annals of Internal Medicine Annals of Neurology Annals of Oncology Annals of Surgical Oncology Annals of the New York Academy of Sciences Annals of the Rheumatic Diseases Annual Review of Medicine Antimicrobial Agents and Chemotherapy Applied and Environmental Microbiology Archives of Gynecology and Obstetrics Archives of Internal Medicine Arteriosclerosis, Thrombosis and Vascular Biology Arthritis and Rheumatism

42

1

1

1 1 1 1

1 1 1

1

1 1

Q3 Q2 Q1 Q1 Q2 Q3 Q1 Q1 Q1 Q1 Q2 Q3 Q2 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q4 Q2 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q4 Q1 Q1 Q1

305

319

Index

Annual Report 2010

Publication Asian Pacific Journal of Allergy and Immunology Atherosclerosis Autoimmunity Reviews Autophagy Biochimica et Biophysica Acta-Reviews on Cancer Biology of Blood and Marrow Transplantation Bioorganic & Medicinal Chemistry BJU International Blood BMC Bioinformatics BMC Cancer BMC Infectious Diseases BMC Neurology BMC Psychiatry BMC Public Health Bone Marrow Transplantation Brain Brain, Behavior and Immunity Breast Cancer Research and Treatment British Journal of Clinical Pharmacology British Journal of Haematology British Journal of Nutrition British Journal of Ophthalmology British Medical Journal Burns Canadian Medical Association Journal Cancer Cell Cancer Journal Cancer Research Cancer Treatment Reviews Cardiology in the Young Cardiovascular and Interventional Radiology Cardiovascular Research Cell Cell Stem Cell Cellular Physiology and Biochemistry Cerebrovascular Diseases Circulation

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

0.562 4.522 6.368 6.829

0.562 18.088 12.736 6.829

1 4 2 1

0.562 4.522 6.368 6.829

11.685

11.685

1

11.685

3.149 2.822 2.865 10.555 3.428 2.736 2.550 2.109 1.832 2.223 2.998 9.490 5.061 4.696 3.246 4.597 3.446 2.917 13.660 1.950 7.271 25.288 3.471 7.543 5.295 1.183 1.949 5.801 31.152 23.563 3.563 3.535 14.816

3.149 2.822 5.730 21.110 3.428 5.472 2.550 6.327 1.832 2.223 2.998 9.490 5.061 23.480 3.246 4.597 3.446 2.917 13.660 1.950 7.271 75.864 3.471 37.715 5.295 1.183 1.949 23.204 31.152 23.563 3.563 3.535 103.712

1 1 2 2 1 2 1 3 1 1 1 1 1 5 1 1 1 1 1 1 1 3 1 5 1 1 1 4 1 1 1 1 7

3.149 2.822 2.865 10.555 3.428 2.736 2.550 2.109 1.832 2.223 2.998 9.490 5.061 4.696 3.246 4.597 3.446 2.917 13.660 1.950 7.271 25.288 3.471 7.543 5.295 1.183 1.949 5.801 31.152 23.563 3.563 3.535 14.816

43

Decile Quartile (D) (Q)

Q4 Q1 Q1 Q1 1

1

1

1 1 1 1

1 1 1

1

Q1 Q2 Q2 Q2 Q1 Q1 Q2 Q2 Q3 Q3 Q2 Q2 Q1 Q1 Q1 Q2 Q1 Q1 Q1 Q1 Q2 Q1 Q1 Q2 Q1 Q1 Q3 Q2 Q1 Q1 Q1 Q2 Q1 Q1

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VHIR Information Summary of Research Activity

Table 7 Publications in international journals (Cont.)

Publication Circulation-Heart Failure Clinica Chimica Acta Clinical & Translational Oncology Clinical and Experimental Immunology Clinical and Experimental Rheumatology Clinical Breast Cancer Clinical Cancer Research Clinical Cardiology Clinical Infectious Diseases Clinical Microbiology and Infection Clinical Neurology and Neurosurgery Clinical Nuclear Medicine Cochrane Database of Systematic Reviews Comprehensive Psychiatry Contemporary Clinical Trials Critical Care Critical Care Medicine Current Hypertension Reports Current Opinion in Investigational Drugs Current Opinion in Rheumatology Current Pharmaceutical Design Cytotherapy Chest Chirurg Dermatology Diabetes-Metabolism Research and Reviews Diabetologia Diagnostic Microbiology and Infectious Disease Digestive Surgery Drug and Alcohol Dependence Drugs & Aging EJSO Europace European Heart Journal European Journal of Applied Physiology European Journal of Clinical Pharmacology European Journal of Echocardiography European Journal of Gastroenterology & Hepatology European Journal of Gynaecological Oncology

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

3.433 2.535 1.146 3.009 2.396 2.065 6.747 1.602 8.195 4.014 1.303 3.915 5.653 2.082 1.506 4.931 6.373 2.377 3.549 4.600 4.414 2.204 6.360 0.601 2.741 2.762 6.551

3.433 2.535 3.438 3.009 4.792 4.130 26.988 1.602 8.195 24.084 1.303 3.915 5.653 2.082 1.506 4.931 19.119 2.377 3.549 4.600 4.414 2.204 19.080 0.601 2.741 5.524 6.551

1 1 3 1 2 2 4 1 1 6 1 1 1 1 1 1 3 1 1 1 1 1 3 1 1 2 1

3.433 2.535 1.146 3.009 2.396 2.065 6.747 1.602 8.195 4.014 1.303 3.915 5.653 2.082 1.506 4.931 6.373 2.377 3.549 4.600 4.414 2.204 6.360 0.601 2.741 2.762 6.551

2.451 1.372 3.599 2.209 2.564 1.871 9.800 2.047 2.743 1.476

2.451 1.372 3.599 2.209 2.564 1.871 19.600 2.047 5.486 2.952

1 1 1 1 1 1 2 1 2 2

2.451 1.372 3.599 2.209 2.564 1.871 9.800 2.047 2.743 1.476

1.662 0.614

1.662 0.614

1 1

1.662 0.614

44

Decile Quartile (D) (Q)

1

1

1

1

1

1

Q2 Q1 Q4 Q2 Q3 Q3 Q1 Q3 Q1 Q1 Q3 Q1 Q1 Q3 Q3 Q1 Q1 Q2 Q1 Q2 Q1 Q2 Q1 Q4 Q2 Q2 Q1 Q3 Q2 Q2 Q2 Q1 Q3 Q1 Q1 Q2 Q3 Q3 Q4

305

319

Index

Annual Report 2010

Publication European Journal of Human Genetics European Journal of Neurology European Journal of Nuclear Medicine and Molecular Imaging European Journal of Obstetrics Gynecology and Reproductive Biology European Journal of Radiology European Respiratory Journal European Spine Journal European Urology Experimental Diabetes Research Expert Opinion on Pharmacotherapy Expert Review of Anticancer Therapy Expert Review of Proteomics Eye Familial Cancer Fertility and Sterility Free Radical Biology and Medicine Future Microbiology Gastroenterology Gene Therapy Genes and Immunity Genes Brain and Behavior Genome Research Gerontology Gut Haematologica-the Hematology Journal Health and Quality of Life Outcomes Heart Hepatology Histopathology HIV Medicine Human Brain Mapping Human Genetics Human Molecular Genetics Human Reproduction IEEE Transactions on Medical Imaging Infection Inflammatory Bowel Diseases Intensive Care Medicine International Journal of Antimicrobial Agents

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

3.564 2.510

3.564 5.020

1 2

3.564 2.510

4.531

4.531

1

4.531

1.582 2.645 5.527 1.956 7.667 2.574 2.018 2.493 3.570 1.974 2.189 3.970 6.081 2.875 12.899 4.745 4.222 3.795 11.342 1.661 9.357 6.416 2.456 5.385 10.840 3.855 2.878 6.256 4.523 7.386 3.859 3.540 2.051 4.643 5.168 3.032

3.164 2.645 22.108 1.956 7.667 2.574 2.018 4.986 3.570 1.974 4.378 7.940 6.081 2.875 25.798 4.745 8.444 3.795 11.342 1.661 18.714 25.664 4.912 10.770 21.680 3.855 2.878 6.256 9.046 7.386 15.436 3.540 2.051 4.643 10.336 6.064

2 1 4 1 1 1 1 2 1 1 2 2 1 1 2 1 2 1 1 1 2 4 2 2 2 1 1 1 2 1 4 1 1 1 2 2

1.582 2.645 5.527 1.956 7.667 2.574 2.018 2.493 3.570 1.974 2.189 3.970 6.081 2.875 12.899 4.745 4.222 3.795 11.342 1.661 9.357 6.416 2.456 5.385 10.840 3.855 2.878 6.256 4.523 7.386 3.859 3.540 2.051 4.643 5.168 3.032

45

Decile Quartile (D) (Q) Q2 Q2 1

1 1

1

1

1 1

1

1

1

Q1 Q3 Q2 Q1 Q2 Q1 Q2 Q3 Q3 Q1 Q2 Q3 Q1 Q1 Q2 Q1 Q1 Q1 Q1 Q1 Q3 Q1 Q1 Q1 Q1 Q1 Q1 Q2 Q1 Q1 Q1 Q1 Q1 Q3 Q1 Q1 Q2

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VHIR Information Summary of Research Activity

Table 7 Publications in international journals (Cont.)

Publication International Journal of Cancer International Journal of Colorectal Disease International Journal of Geriatric Psychiatry International Journal of Gynecological Pathology International Journal of Neuroscience International Journal of Radiation Oncology International Reviews of Immunology Investigative Ophthalmology & Visual Science JAMA-Journal of the American Medical Journal of Affective Disorders Journal of Alzheimer’s Disease Journal of Allergy and Clinical Immunology Journal of Antimicrobial Chemotherapy Journal of Biological Chemistry Journal of Biomedical Materials Research Part A Journal of Biomedicine and Biotechnology Journal of Cardiothoracic Surgery Journal of Cellular Biochemistry Journal of Clinical Endocrinology & Metabolism Journal of Clinical Investigation Journal of Clinical Microbiology Journal of Clinical Oncology Journal of Crohns & Colitis Journal of Heart and Lung Transplantation Journal of Hepatology Journal of Hypertension Journal of Immunological Methods Journal of Immunology Journal of Infectious Diseases Journal of Interferon and Cytokine Research Journal of Lipid Research Journal of Medical Genetics Journal of Minimally Invasive Gynecology Journal of Molecular and Cellular Cardiology Journal of Molecular Diagnostics Journal of Neural Transmission Journal of Neurochemistry

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

4.722 2.102 1.981

4.722 2.102 1.981

1 1 1

4.722 2.102 1.981

Q1 Q2 Q2

2.179 0.855 4.592 2.641

4.358 0.855 4.592 2.641

2 1 1 1

2.179 0.855 4.592 2.641

Q2 Q4 Q1 Q3

3.431 28.899 3.763 3.832 9.165 4.352 5.328

3.431 57.798 3.763 15.328 18.330 21.760 21.312

1 2 1 4 2 5 4

3.431 28.899 3.763 3.832 9.165 4.352 5.328

2.816 1.750 0.737 2.935

2.816 1.750 0.737 2.935

1 1 1 1

2.816 1.750 0.737 2.935

Q1 Q3 Q4 Q2

6.202 15.387 4.162 17.793 1.729 3.541 7.818 4.988 2.347 5.646 5.865 1.627 4.917 5.751 1.920 4.965 3.413 2.259 3.999

12.404 15.387 8.324 302.481 3.458 3.541 23.454 4.988 2.347 5.646 5.865 1.627 4.917 11.502 1.920 4.965 3.413 2.259 3.999

2 1 2 17 2 1 3 1 1 1 1 1 1 2 1 1 1 1 1

6.202 15.387 4.162 17.793 1.729 3.541 7.818 4.988 2.347 5.646 5.865 1.627 4.917 5.751 1.920 4.965 3.413 2.259 3.999

Q1 Q1 Q1 Q1 Q3 Q1 Q1 Q1 Q3 Q1 Q1 Q3 Q1 Q1 Q2 Q1 Q1 Q2 Q2

46

Decile Quartile (D) (Q)

1

1

1

1 1

1

1

Q1 Q1 Q1 Q2 Q1 Q1 Q1

305

319

Index

Annual Report 2010

Publication Journal of Neuroimmunology Journal of Neurology Journal of Neuropathology and Experimental Neurology Journal of Neuroscience Journal of Neurosurgery Journal of Nuclear Cardiology Journal of Nutrition Health & Aging Journal of Pediatric Endocrinology & Metabolism Journal of Pediatric Orthopaedics Journal of Pediatric Surgery Journal of Physiology-London Journal of Proteome Research Journal of Psychiatric Research Journal of Rheumatology Journal of Sleep Research Journal of the American College of Cardiology Journal of the Neurological Sciences Journal of Thoracic and Cardiovascular Surgery Journal of Translational Medicine Journal of Trauma-Injury Infection and Critical Care Journal of Urology Journal of Viral Hepatitis Journal of Water and Health Journal of Womens Health Lancet Lancet Neurology Lancet Oncology Leukemia & Lymphoma Life Sciences Liver International Lung Cancer Lupus Medicine Metabolic Brain Disease Microvascular Research Mitochondrion

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

2.841 2.903

8.523 8.709

3 3

2.841 2.903

4.564 7.178 2.594 2.777 1.712

4.564 14.356 5.188 2.777 1.712

1 2 2 1 1

4.564 7.178 2.594 2.777 1.712

0.738 1.226 1.430 4.764 5.132 3.723 3.854 3.500

0.738 1.226 1.430 9.528 5.132 3.723 3.854 3.500

1 1 1 2 1 1 1 1

0.738 1.226 1.430 4.764 5.132 3.723 3.854 3.500

12.535 2.324

12.535 11.620

1 5

12.535 2.324

3.063 3.407

3.063 3.407

1 1

3.063 3.407

Q1 Q2

2.626 4.016 3.348 1.469 1.770 30.758 18.126 14.470 2.397 2.560 2.987 3.140 2.586 5.054 1.959 3.075 4.145

2.626 4.016 3.348 1.469 1.770 153.790 18.126 28.940 4.794 2.560 8.961 3.140 5.172 10.108 1.959 3.075 4.145

1 1 1 1 1 5 1 2 2 1 3 1 2 2 1 1 1

2.626 4.016 3.348 1.469 1.770 30.758 18.126 14.470 2.397 2.560 2.987 3.140 2.586 5.054 1.959 3.075 4.145

Q2 Q1 Q1 Q3 Q2 Q1 Q1 Q1 Q3 Q2 Q2 Q1 Q3 Q1 Q3 Q2 Q1

47

Decile Quartile (D) (Q) Q2 Q2

1

1

1

1 1 1

1

Q1 Q1 Q2 Q2 Q3 Q4 Q3 Q2 Q1 Q1 Q1 Q2 Q1 Q1 Q2

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VHIR Information Summary of Research Activity

Table 7 Publications in international journals (Cont.)

Publication Molecular Biology of the Cell Molecular Cancer Research Molecular Cancer Therapeutics Molecular Genetics and Metabolism Molecular Psychiatry Movement Disorders Multiple Sclerosis Nature Nature Neuroscience Nature Reviews Neurology Nephrology Dialysis Transplantation Neurobiology of Aging Neurobiology of Disease Neurogastroenterology and Motility Neurology Neuropsychopharmacology Neuroradiology Neuroscience Letters New England Journal of Medicine Obesity Reviews Obesity Surgery Obstetrical & Gynecological Survey Oncogene Oncologist Ophthalmology Pediatric Infectious Disease Journal Pediatric Neurology Pediatric Radiology Pediatric Research Pediatric Transplantation Pharmacogenomics PLoS Genetics PLoS Medicine PLoS One Proceedings of the National Academy of Sciences Prostate Psychiatric Genetics Psychiatry Research-Neuroimaging Respiratory Care Respiratory Medicine

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

5.979 4.162 4.953 2.897 15.049 4.014 3.279 34.480 14.345 0.000 3.306 5.937 4.518 3.568 8.172 6.993 2.616 1.925 47.050 5.086 2.934 3.097 7.135 6.701 5.491 2.854 1.497 1.186 2.607 1.573 3.893 9.532 13.050 4.351

5.979 4.162 4.953 2.897 30.098 8.028 22.953 68.960 14.345 0.000 6.612 5.937 4.518 7.136 40.860 6.993 2.616 1.925 94.100 5.086 5.868 3.097 21.405 6.701 16.473 11.416 1.497 1.186 2.607 1.573 11.679 9.532 13.050 21.755

1 1 1 1 2 2 7 2 1 2 2 1 1 2 5 1 1 1 2 1 2 1 3 1 3 4 1 1 1 1 3 1 1 5

5.979 4.162 4.953 2.897 15.049 4.014 3.279 34.480 14.345 0.000 3.306 5.937 4.518 3.568 8.172 6.993 2.616 1.925 47.050 5.086 2.934 3.097 7.135 6.701 5.491 2.854 1.497 1.186 2.607 1.573 3.893 9.532 13.050 4.351

9.432 3.081 2.327 3.435 1.524 2.331

9.432 12.324 2.327 3.435 1.524 9.324

1 4 1 1 1 4

9.432 3.081 2.327 3.435 1.524 2.331

48

Decile Quartile (D) (Q)

1

1 1 1

1 1

1

1 1 1

1 1

1

Q1 Q2 Q1 Q2 Q1 Q1 Q2 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q2 Q3 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q1 Q2 Q3 Q1 Q2 Q1 Q1 Q1 Q1 Q1 Q2 Q3 Q1 Q3 Q2

305

319

Index

Annual Report 2010

Publication Respirology Retina-the Journal of Retinal and Vitreous Rheumatology Sarcoidosis Vasculitis and Diffuse Lung Diseases Scandinavian Journal of Rheumatology Seminars in Arthritis and Rheumatism Seminars in Liver Disease Stem Cells Stroke Thorax Thrombosis and Haemostasis Thyroid Transfusion and Apheresis Science Transplant Infectious Disease Transplant International Transplantation Tumori Urologia Internationalis Urology Vox Sanguinis World Journal of Biological Psychiatry World Journal of Surgery World Journal of Urology Worldviews on Evidence-Based Nursing

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

1.853 2.932 4.236

1.853 2.932 4.236

1 1 1

1.853 2.932 4.236

Q3 Q1 Q2

1.056 2.507 4.724 5.171 7.747 7.041 7.041 4.451 2.602 0.938 2.063 3.254 3.498 0.863 0.902 2.365 2.585 5.564 2.696 2.629 1.944

1.056 2.507 4.724 5.171 7.747 77.451 7.041 4.451 2.602 0.938 2.063 3.254 3.498 0.863 0.902 2.365 5.170 5.564 2.696 2.629 1.944

1 1 1 1 1 11 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1

1.056 2.507 4.724 5.171 7.747 7.041 7.041 4.451 2.602 0.938 2.063 3.254 3.498 0.863 0.902 2.365 2.585 5.564 2.696 2.629 1.944

Q4 Q3 Q1 Q1 Q1 Q1 Q1 Q1 Q3 Q4 Q3 Q1 Q1 Q4 Q4 Q2 Q2 Q1 Q1 Q2 Q1

3,028.152

503

6.020

Total International Journals

49

Decile Quartile (D) (Q)

1 1 1

1

1

1

8

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VHIR Information Summary of Research Activity

Table 8 Publications in national journals

Publication

Impact Factor

Total Imp. Fac.

Published Papers

Average Imp. Fac.

0.515 0.630 0.363 2.166 1.146 1.393 1.172 1.231 0.533 0.247 0.596 1.065 0.584 1.234 2.746 0.994 0.765

0.515 0.630 1.815 23.826 9.168 12.537 3.516 23.389 0.533 0.741 2.980 2.130 0.584 13.574 21.968 1.988 1.530

1 1 5 11 8 9 3 19 1 3 5 2 1 11 8 2 2

0.515 0.630 0.363 2.166 1.146 1.393 1.172 1.231 0.533 0.247 0.596 1.065 0.584 1.234 2.746 0.994 0.765

121.424

92

1.320

Decile Quartile (D) (Q)

Spanish journals (n = 17)

Actas Españolas de Psiquiatría Allergologia et immunopathologia Anales de Pediatría Archivos de Bronconeumología Clinical & Translational Oncology Enfermedades Infecciosas y Microbiología Gaceta Sanitaria Medicina Clínica Nefrología Neurocirugía Neurología Nutrición Hospitalaria Revista Clínica Española Revista de Neurología Revista Española de Cardiología Revista Española de Enfermedades Digestivas Revista Española de Medicina Nuclear Total Spanish Journals

Q4 Q4 Q4 Q3 Q4 Q4 Q3 Q3 Q4 Q4 Q4 Q4 Q3 Q3 Q2 Q4 Q4

Table 9 Total national and international journals

Publication

Total Impact Factor

Published Papers

Average Impact Factor

International Journals Spanish Journals

3,028.152 121.424

503 92

6.020 1.320

Total National and International Journals

3,149.576

595

5.293

50

305

Annual Report 2010

Figure 8 Co-authors international publications

51

319

Index

8

69

13

Presentation

VHIR Research Activity

VHIR Information Summary of Research Activity

RESEARCH PROJECTS Active research projects funded by public and private institutions are listed below.

During 2010, 84 projects were awarded funding. On December 31st 2010 there were 242 active research projects and these are listed below.

Table 10 List of active research projects in 2010

Number of active sponsored projects

Sponsors Fondo de Investigación Sanitaria (FIS) Instituto de Salud Carlos III European Commission Ministerio de Ciencia e Innovación Fundació La Marató de TV3 Fundación de la Investigación Médica – Mutua Madrileña Automovilista Agència d’Avaluació de Tecnologia i Recerca Mèdiques (AATRM) Fundación para la Investigación y la Prevención del Sida en España (FIPSE) Fundación Ramón Areces Centro para el Desarrollo Tecnológico Industrial (CDTI) Centro Nacional de Investigaciones Cardiovasculares (CNIC) Asociación Española contra el Cáncer Genoma España Fundación Alicia Koplowitz Fundació Santiago Dexeus Font CIDEM – ACC1Ó Other

121 13 22 13 13 3 2 1 4 2 4 2 2 3 1 36

Total

242

Number of projects Total 242

40

Area 1. Oncology and genetics

12

Area 2. Endocrinology, growth, metabolism and diabetes

25

Area 3. Cardiovascular diseases, hemostasis and hypertension

56

Area 4. Neurosciences

25

Area 5. Digestive physiopathology and hepatology

14

Area 6. Infectious diseases

15

Area 7. Respiratory and systemic diseases

18

Area 8. Pathology, cellular and gene therapy

7

Area T1. Epidemiology, pharmacology, new therapies, clinical research

17

Area T2. Nanomedicine

13

Other researchers Figure 9 List of active research projects according to research area

52

305

319

Index

Annual Report 2010

CLINICAL TRIALS In 2010, 238 clinical trials were submitted to the HUVH Clinical Research Ethical Committee (CREC) for approval. 205 (86%) of them were multicenter trials and 33 (14%) unicenter trials. Of these

Cancelled 6 Denied 8

205 multicenter trials, 85 centers acted as reference groups CREC (41%) and the remaining 120 centers acted as involved CREC (59%). Of these 238 submitted trials, 199 (84%) were sponsored by the

pharmaceutical Industry, 8 (3%) were sponsored by VHIR researchers and 31 (13%) were sponsored by other hospitals. On 31st December 2010, there were 428 active clinical trials.

Phase IV 17 - 8%

Postponed 1

Phase I 36 - 16%

Phase II 103 - 46%

Total 238

Total 223 - 100%

Approved 223

Figure 12 Clinical trials approved by CREC in 2010 classified according to trial phase

Figure 10 Clinical trials submitted to CREC in 2010

Maternity 25 Traumatology 4

Phase II 67 - 30%

Central Services 9

Cancelled 2

Postponed 1

Not Approved 3

Total 428

Total 57

General 390

Approved 51

Figure 13 Post-authorization studies submitted to CREC in 2010

Figure 11 List of active clinical trials on 31st December 2010, classified according to service

53

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VHIR Information Summary of Research Activity

Table 11 List of active clinical trials on 31st December 2010, classified according to service

Hospital Services General Area Oncology Internal Medicine - Hepatology Neurotraumatology Internal Medicine - Infectious Diseases Cardiology Pneumology Internal Medicine Nephrology Hematology General Surgery Endocrinology Digestive Apparatus Urology ICU Haemophilia Neuroimmunology Allergies Internal Medicine - Rheumatology Ophthalmology Neurophysiology. Neurology and Neurosurgery Dermatology

Number

Hospital Services

390

Radiotherapy Hemodynamics Resuscitation systemic Diseases “Institut de Diagnòstic per la Imatge”

186 20 4 8 16 19 5 7 23 3 14 5 5 2 6 25 2 6 7

Maternity and Children’s Area Pediatric Cardiology Pediatric Oncohematology Pediatric Endocrinology Neonatology Pediatric Pneumologya Pediatric Genetics Pediatric Neurology Obstetrics and Gynecology

15 1

4 4 1 1 1 25 1 9 1 1 2 1 1 9

Traumatology Area Rehabilitation Anesthesiology Burn Unit

1 2 1

Central services Psychiatry

9

Total

54

Number

4

9

428

305

319

Index

Annual Report 2010

NEW CONTRACTS AWARDED TO RESEARCHERS AND TECHNICIANS FUNDED BY DIFFERENT ORGANIZATIONS AND PROGRAMS

Table 12 New VHIR contracts for researchers

New contracts for researchers

Number

Senior Researchers Miguel Servet Programme Intensification Programme contracts – Instituto de Salud Carlos III Research Retainment Programme – Instituto de Salud Carlos III Postdoc Researchers Rio Hortega Programme Juan de la Cierva Programme Beatriu de Pinós - Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) Contracts stemming from Research Projects Predoc Researchers Instituto de Salud Carlos III Fundació VHIR Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) Contracts stemming from Research Projects Support Staff Instituto de Salud Carlos III Contracts stemming from Research Projects

10 3 6 1 11 5 1 3 2 16 4 2 1 9 8 3 5

Total

45

55

8

69

13

Presentation

VHIR Research Activity

VHIR Information Summary of Research Activity

ONLINE BIOMEDICAL RESEARCH CENTER (CIBER) The Online Biomedical Research Center (CIBER) is a research organization with its own legal entity. Its main objective is conducting highly specific research into pathologies or concrete health disorders. CIBER is an amalgam of various independent research groups operating in the public and private sector with their own research lines and objectives. CIBER aims to generate larger translational research centers of a multidisciplinary and multiinstitutional character to carry out basic clinical and population research. CIBER aims to develop a single common research program, focusing on pathologies which are considered strategic or relevant to the National Health System due to their prevalence or social impact.

The VHIR is involved in the following CIBER projects: CIBER: Bioenginyeria. biomaterials i nanomedicina CIBER: Malalties respiratòries CIBER: Malalties hepàtiques i digestives CIBER: Malalties neurodegeneratives CIBER: Malalties rares CIBER: Epidemiologia i salut pública CIBER: Diabetis i malalties metabòliques

Table 13 List of CIBER projects with VHIR involvement

CIBER File

Title

Project Manager

CB06/01/0012 CB06/06/0030 CB06/04/0021 CB06/04/0025 CB06/04/0028 CB06/04/0062 CB06/04/0007 CB06/05/0017 CB06/07/0015 CB06/07/0063 CB06/02/0009 CB06/07/0027 CB07/08/0024

CIBER: Bioenginyeria, biomaterials i nanomedicina CIBER: Malalties respiratòries CIBER: Malalties hepàtiques i digestives CIBER: Malalties hepàtiques i digestives CIBER: Malalties hepàtiques i digestives CIBER: Malalties hepàtiques i digestives CIBER: Malalties hepàtiques i digestives CIBER: Malalties neurodegeneratives CIBER: Malalties rares CIBER: Malalties rares CIBER: Epidemiologia i salut pública CIBER: Malalties rares CIBER: Diabetis i malalties metabòliques

Simó Schwartz Navarro Ferran Morell Brotad Fernando Azpiroz Vidaur Rafael Esteban Mur Juan Ignacio Esteban Mur Francisco Guarner Aguilar Juan Córdoba Cardona Miquel Vila Bover Antonio Luis Andreu Périz Antonio Carrascosa Lezcano Gaietà Permanyer Miralda Mari Carmen Domínguez Luengo Rafael Simó Canonge

56

305

Annual Report 2010

319

Index

COLLABORATIVE RESEARCH THEMATIC NETWORKS AT THE INSTITUTO DE SALUD CARLOS III Thematic Networks are organizational structures sponsored by the Instituto de Salud Carlos III (ISCIII) composed of different biomedical centers and multidisciplinary research groups, whose aim is to conduct collaborative research projects of general interest. The networks were set up in response to the priorities of the Plan Nacional (20002003) in the field of healthcare and are composed of different research projects as a strategy to reduce the distance that currently exists be-

tween new knowledge generated and its transfer and application to medical practice. The VHIR takes part in the following Thematic Network Centers: – Red Temática de Investigación Cooperativa de Centros de Cáncer. – Factores de Riesgo. Evolución y Tratamiento de las Enfermedades Cardiovasculares (RECAVA). – Red Española de Investigación en Patología Infecciosa (REIPI).

– Red Neurovascular (RENEVAS). – Red de Investigación en Sida (RIS). – Patología ocular del envejecimiento. calidad visual y calidad de vida. – Red Española de Esclerosis Múltiple (REEM). – Red de Salud Materno-Infantil y del Desarrollo. – Red de Innovación en Tecnologías Médicas y Sanitarias. – Red Temàtica de Investigación Cooperativa de Biobancos.

Table 14 List of ISCIII Thematic Network Centers that the VHIR is involved in

Nets of Centers File RD06/0020/0022 RD06/0020/0075 RD06/0014/0025 RD06/0008/0030 RD06/0026/0010 RD06/0008/0026 RD06/0020/0104 RD06/0020/0058 RD06/0006/0039 RD06/0020/1021 RD06/0014/1014 RD07/0062/0010 RD07/0060/0020 RD08/0072/0034 RD09/0077/00090 RD09/0076/00066

Title

Project Manager

Red Temática de Investigación Cooperativa de Centros de Cáncer Red Temática de Investigación Cooperativa de Centros de Cáncer Factores de Riesgo. Evolución y Tratamiento de las Enfermedades Cardiovasculares (RECAVA) Red Española de Investigación en Patología Infecciosa (REIPI) Red Neurovascular (RENEVAS) Red Española de Investigación en Patología Infecciosa (REIPI) Red Temática de Investigación Cooperativa de Centros de Cáncer Red Temática de Investigación Cooperativa de Centros de Cáncer Red de Investigación en Sida (RIS) Red Temática de Investigación Cooperativa de Centros de Cáncer Factores de Riesgo. Evolución y Tratamiento de las enfermedades cardiovasculares (RECAVA) Patología ocular del envejecimiento. calidad visual y calidad de vida Red Española de Esclerosis Múltiple (REEM) Red de Salud Materno-Infantil y del Desarrollo Red de Innovación en Tecnologías Médicas y Sanitarias Red Temàtica de Investigación Cooperativa de Biobancos

Joaquin Arribas López José Baselga Torres David García-Dorado

57

Antoni Julià Font Joan Montaner Villalonga Albert Pahissa Berga Santiago Ramón y Cajal Agüeras Jaume Reventós Puigjaner Esteban Ribera Pascuet Josep Sánchez de Toledo Codina Rafael Simó Canonge José García Arumí Xavier Montalban Gairín Lluís Cabero Roura Francesc Iglesias García Santiago Ramón y Cajal Agüeras

8

69

13

Presentation

VHIR Research Activity

VHIR Information Summary of Research Activity

RESEARCH GROUPS RECOGNIZED BY THE GENERALITAT DE CATALUNYA One of the objectives of the research program of the “Generalitat de Catalunya” is to provide support to research groups based in Catalan universities and research centers which are articulated around a stable group of researchers with convergent

paths. This support is provided by taking part in collaborative research projects publications and common activities promoting training for junior researchers. The VHIR has 28 groups recognized by the “Generalitat de Catalunya”.

Table 15 List of VHIR research groups recognized by the “Generalitat de Catalunya”

Area

File

Title

Project Manager

Oncology and genetics

2009 SGR 604 2009 SGR 756 2009 SGR 487

Oncologia i patologia molecular Patologia molecular Oncologia traslacional

Matilde Lleonart Pajarín Santiago Ramón y Cajal Agüeras Jaume Reventós Puigjaner

Endocrinology, growth, metabolism and diabetes

2009 SGR 31 2009 SGR 739

Fisiopatologia del creixement Grup de recerca en Diabetis i Metabolisme

Antonio Carrascosa Lezcano Rafael Simó Canonge

Cardiovascular diseases, hemostasis and hypertension

2009 SGR 802

Patologia cardiocirculatòria

David García-Dorado

Neurosciences, mental health and senescence

2009 SGR 1520 2009 SGR 346 2009 SGR 78

Patologia neuromuscular i mitocondrial Senyalització cel·lular i apoptosi Grup de recerca en neurologia infantil de l’HUVH Unitat de Neuroimmunologia Clínica (UNic) Grup de recerca en malalties neurovasculars Unitat d’Investigació de Neurotraumatologia i Neurocirurgia (UNINN) Grup de recerca en malalties neurodegeneratives

Antonio Luis Andreu Périz Joan Xavier Comella Carnicé Alfons Macaya Ruíz

2009 SGR 793 2009 SGR 432 2009 SGR 495 2009 SGR 664

58

Xavier Montalban Gairín Joan Montaner Villalonga Joan Sahuquillo Barris Miquel Vila Bover

305

Annual Report 2010

Table 15 List of VHIR research groups recognized by the “Generalitat de Catalunya” (Cont.)

Area

File

Title

Project Manager

Digestive physiopathology and hepatology

2009 SGR 219 2009 SGR 383 2009 SGR 256

Unitat de recerca del sistema digestiu Unitat de recerca en malalties hepatobiliars Grup de recerca en patologia pancreàtica exocrina

Fernando Azpiroz Vidaur Joan Genescà Ferrer Francesc Xavier Molero Richard

Infectious diseases and AIDS

2009 SGR 86

Malalties infeccioses

Albert Pahissa Berga

Immunology: respiratory, systemic and genetic disorders

2009 SGR 257 2009 SGR 296

Unitat de recerca en pneumologia Grup d’investigació en Microbiologia de l’Hospital Vall d’Hebron Autoimmunitat i malaltia trombòtica

Ferran Morell Brotad Guillem Prats Pastor

Pathology, cellular and gene 2009 SGR 157 therapy 2009 SGR 75 2009 SGR 758 2009 SGR 493

Grup d’oncologia molecular Patologia cel·lular Direccionament i alliberament farmacològic Immunobiologia

Diego Arango Corro Anna Meseguer Navarro Simó Schwartz Navarro Joan Sayós Ortega

R+D, new technologies and experimental surgery

José García Arumí

2009 SGR 130

Grup de recerca en oftalmologia Vall d’Hebron Ortopèdia pediàtrica

César Galo García Fontecha

2009 SGR 537 2009 SGR 412

Grup de recerca en medicina materna i fetal Fundació Institut Català de Farmacologia

Lluís Cabero Roura Joan-Ramon Laporte Roselló

2009 SGR 661

Other

2009 SGR 384

59

Miquel Vilardell Tarrés

319

Index

8

69

13

Presentation

VHIR Research Activity

VHIR Information Summary of Research Activity

THESIS The doctoral thesis read in 2010 by VHIR’s researchers was 62: of which, 55 were read in several departments of the Autonomous

University of Barcelona (UAB), 6 at the University of Barcelona (UB), and 1 at the University of Navarra.

Table 16 Doctoral thesis read in 2010 or supervised by VHIR’s staff

Phd

Title

Directors

Department

Albert Brotons, Dimpna Calila

Ecocardiografía Doppler y Doppler tisular en recién nacido pretérmino: influencia del ductus arterioso y foramen oval en el llenado ventricular izquierdo y su correlación con la evolución clínica

Salvador Salcedo Abizanda

Pediatria, UAB d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent CumLaude

Juan Lorente Guerrero, Enrique Perelló Scherdel

Cirurgia

UAB

Excellent CumLaude

El cáncer de laringe en mujeres en Almeida Prado Nino, Joel Eduardo Cataluña

University Qualification

Alonso Cotoner, Carmen

Disfunción e inflamación de la mucosa intestinal inducida por el estrés psicosocial crónico y su relevancia translacional para el síndrome del intestino irritable

Juan Ramon Malagelada Benaprés, Javier Santos Vicente

Medicina

UAB

Excellent CumLaude

Álvarez Bulnes, Olga

Descripción y análisis del grosor de la capa de fibras nerviosas retinianas obtenidas mediante tomografía de coherencia óptica en pacientes sometidos a cirugía combinada de glaucoma

José García Arumí

Cirurgia

UAB

Excellent

Álvarez-Uria Miyares, Gerardo

Factores asociados al éxito del tratamiento del virus de la hepatitis B y C

Manel Crespo Casal, Vicente Falcó Ferrer

Medicina

UAB

Excellent CumLaude

Balbuena Delgado, Jana

Implicación de células madre tumorales de la Side Population e hipoxia en la resistencia a fármacos en líneas celulares de astrocitomas

Jordi Pétriz

Unidad de Biología de Tumores Cerebrales

Universidad Navarra

Excellent CumLaude

60

305

319

Index

Annual Report 2010

Table 16 Doctoral thesis read in 2010 or supervised by VHIR’s staff (Cont.)

Phd

Title

Bielsa Carrafa, Ana Estudio neurofisiológico por neuroimagen del trastorno por déficit de atención e hiperactividad (TDAH). Comparación pre y postratamiento con metilfenidato

Directors

Department

University Qualification

Isabel Roca Bielsa, Óscar Vilarroya Oliver

Psiquiatría i de Medicina Legal

UAB

Excellent CumLaude

Boerno, Rafael Luis

Relación entre el haplogrupo del DNA mitocondrial y el grado de pérdida auditiva en la presbiacusia

Ana María García Arumí, Enrique Perelló Scherdel

Cirurgia

UAB

Excellent CumLaude

Calbo Sebastián, Esther

Resposta inflamatòria en la pneumònia neumocòcica greu

Vicenç Falcó Ferrer, Xavier Garau Alemany

Medicina

UAB

Excellent CumLaude

Camilotti Gasperin, Alexandre

El triángulo luminoso de la laringe. Los Juan Lorente pliegues vocales no son blancos, se ven Guerrero, Enrique Perelló Scherdel blancos

Cirurgia

UAB

Excellent CumLaude

Coll Loperena, Maria del Mar

Inhibició i atròfia simpàtica: nou mecanisme implicat en la vasodilatació esplàncnica associada a la hipertensió portal

Juan Genescà Ferrer, Maria Martell PérezAlcalde, Joaquín Ariño Carmona

Bioquímica i de Biologia Molecular

UAB

Excellent CumLaude

Corominas Casti, Roser

Avaluació de gens de susceptibilitat a formes comunes de migranya

Alfons Macaya Ruíz

Genètica

UB

Apte CumLaude

Corona Gutiérrez, América Aime

Índice de masa corporal previo al embarazo y resultados perinatales

Lluís Cabero Roura

Pediatria, UAB d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent

Corripio Collado, Raquel

Niños obesos prepuberales: efecto de una intervención dietética y en el estilo de vida sobre las lipocalinas y el brain-derived neurotrophic factor. Estudio longitudinal de dos años de duración

Diego Yeste Fernández

UAB Pediatria, d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent CumLaude

Domingo Sábat, Montserrat

Genética de la butirilcolinesterasa en les sinucleïnopaties: establiment d’una eina per all diagnòstic diferencial de la demència amb cossos de Lewy

Katrin Beyer, Catalina Casas Louzao

Biologia Cel·lular, de Fisiologia i d’Immunologia

UAB

Excellent CumLaude

61

8

69

13

Presentation

VHIR Research Activity

VHIR Information Summary of Research Activity

Table 16 Doctoral thesis read in 2010 or supervised by VHIR’s staff (Cont.)

Phd

Title

Directors

Department

University Qualification

Domingues, Sophie

Identification of genetic risk factors for ischemic stroke

José Álvarez Sabín, Israel Fernández Cadenas, Joan Montaner Villalonga

Medicina

UAB

Excellent CumLaude

Dopeso González, José Higinio

Papel funcional de los receptores EPH en el cáncer colorrectal

Diego Arango del Corro

Genètica

UB

Excellent CumLaude

Estrada Cuxart, Josep Oriol

Anàlisi dels indicadors de seguretat i Vicente Fonollosa Pla, Medicina eficàcia per a l’avaluació del programa Alfons Cuxart Melich de tractament antibiòtic endovenós d’una unitat d’hospitalització a domicili

UAB

Excellent CumLaude

Ferrer Menduiña, Maria Queralt

Función cardíaca fetal en casos afectos de restricción de crecimiento intrauterino y/o preclampsia y evolución postnatal: Fetal Programming

Jaume Casaldàliga

ACOR-Cardiologia pediàtrica

UAB

Excellent CumLaude

Ferrer Oliveras, Raquel

Prevalencia y valor clínico de los anticuerpos antifosfolípido y antifactor en la preeclampsia

Jaime Alijotas Reig, Elisa Llurba Olivé

Pediatria, UAB d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent CumLaude

Gallofré López, Miquel

Els audits com a mètode d’avaluació de l’atenció hospitalària a una malaltia prevalent a Catalunya: la malaltia vascular cerebral

Gabriel Sampol Rubio

Medicina

UAB

Excellent CumLaude

Giné Soca, Eva

Estudi del fenomen de la tranformació histològica en síndromes limfoproliferatius indolents

Francesc Bosch

Medicina

UB

Excellent CumLaude

Gómez Lanza, Esther

Análisis de la concentración sérica de vitamina D como factor de riesgo de cáncer de próstata y agresividad tumoral

Juan Morote Robles

Cirurgia

UAB

Excellent CumLaude

Hernando Martínez, Víctor

Activación de calpaínas durante la reperfusión miocárdica. Importancia como sistema efector de muerte celular y como diana terapéutica

David García-Dorado, Javier Inserte Igual

Departament de Bioquímica i de Biologia Molecular

UAB

Excellent CumLaude

62

305

319

Index

Annual Report 2010

Phd

Title

Hernecki, Jaroslaw Programa de cribaje de la retinopatía Jerzy diabética en el Vallès Oriental mediante cámara no midriática. Estudio de 5228 pacientes diabéticos tipo 2

Directors

Department

University Qualification

José García Arumí

Cirurgia

UAB

Excellent CumLaude

Julia Cano, Antonio

Genomic approaches for the indentification of risk loci for Rheumatoid Arthritis

Sara Marsal, Joaquín Ariño Carmona

Bioquímica i Biologia Molecular

UAB

Excellent CumLaude

Leal Blanquet, Juan

Influència del suport audiovisual sobre les expectatives preoperatòries del malalt candidat a una artroplàstia total de genoll

Enric Cáceres Palou

Cirurgia

UAB

Excellent CumLaude

López Fauqued, Marta

Estudio preclínico de inhibidores de PI3K y BRAF en melanoma maligno

Juan A. Recio Conde

Bioquímica i Biologia Molecular

UB

Excellent CumLaude

López Peig, Cristina

Análisis de un programa de deshabituación de benzodiazepinas destinado a ser aplicado por enfermería en las consultas de atención primaria

Eduard Diogene Fadini

Medicina

UAB

Excellent CumLaude

López Vicente, Laura

Estudi de l’expressió d’RSK4 en tumors humans i la seva implicació amb senescència

Santiago Ramón y Cajal Agüeras, Gemma Armengol Rosell, Anna Meseguer Navarro

Bioquímica i de Biologia Molecular

UAB

Excellent CumLaude

Malagelada Prats, Carolina

Evaluación de la motilidad intestinal mediante análisis de imágenes endoluminales

Fernando Azpiroz Vidaur

Medicina

UAB

Excellent CumLaude

Manso García, Begoña

Evaluación de función coronaria mediante resonancia magnética de perfusión miocárdica en pacientes con transposición de grandes arterias (TGA) intervenidos con cirugía tipo Switch arterial

Jaume Casaldàliga

ACOR-Cardiologia pediàtrica

UAB

Excellent CumLaude

63

8

69

13

Presentation

VHIR Research Activity

VHIR Information Summary of Research Activity

Table 16 Doctoral thesis read in 2010 or supervised by VHIR’s staff (Cont.)

Phd

Title

Directors

Department

University Qualification

Martín Begué, Nieves

Tratamiento de la retinopatía del prematuro con láser de diodo: correlación de la retinopatía grave y la presencia de enfermedad plus con factores clínicos de riesgo predictivo

José García Arumí

Cirurgia

UAB

Excellent CumLaude

Martínez Alonso, Mónica

Engineering and Production of Quality Viral Proteins in Prokaryotic and Eukaryotic Systems

Neus Ferrer Miralles, Antonio Pedro Villaverde Corrales, Rob Noad

Genètica i de Microbiologia

UAB

Excellent CumLaude

Mendioroz Iriarte, María Tere

Utilidad de los biomarcadores plasmáticos en el diagnóstico, tratamiento y pronóstico de la enfermedad cerebrovascular aguda

Joan Montaner, Israel Fernández Cadenas, José Álvarez Sabín

Cirurgia

UAB

Excellent CumLaude

Monteagudo Jiménez, Manuel

Las plaquetas reticuladas medidas por citometría de flujo: un marcador indirecto de la actividad trombocitopoyética

Vicente Fonollosa Pla

Medicina

UAB

Excellent CumLaude

Antonio San José Laporte, Carlos Brotons Cuixart

Medicina

UAB

Excellent CumLaude

Monteserín Nadal, Ensayo clínico aleatorizado sobre la María Rosa eficacia de una intervención tras una valoración geriátrica integral en el ámbito de la atención primaria Navarro Sobrino, Miriam

Influència de les cèl·lules endotelials progenitores sobre la modulació espaial i temporal de l’angiogènesi i la vasculogènesi després de l’ictus isquèmic humà

Joan Montaner, Anna Rosell, José Álvarez Sabín

Medicina

UAB

Excellent CumLaude

Olloquequi González, Jordi

Cèl·lules inflamatòries en la malaltia pulmonar obstructiva crònica

Jaume Ferrer Sancho, José García Valero, Juan Francisco Montes Castillo

Biologia cel·lular

UB

Excellent CumLaude

Pagola Pérez Blanca, Jorge

Trombosis de la arteria basilar. Tolerancia isquémica, respuesta a la sonotronolisis potenciada y transformación hemorrágica postratamiento

José Álvarez Sabín, Marc Ribó Jacobi, Carlos Molina Cateriano

Medicina

UAB

Excellent CumLaude

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Phd

Title

Directors

Department

University Qualification

Pascual Angulo, Gloria

Generación de modelos transgénicos para el estudio fisiopatológico de la proteína KAP en el riñón murino

Anna Meseguer Navarro

Departament de Genètica

UB

Excellent CumLaude

Pidemunt Molí, Gemma

Factores determinantes en el deterioro de la función y la calidad de vida del anciano afecto de fractura de cadera

Enric Cáceres Palou

Cirurgia

UAB

Excellent CumLaude

Pons López, Berta

Estudi de 4E-BP1 i la seva regulació en càncer de mama

Santiago Ramón y Cajal, Gemma Armengol

Bioquímica i de Biologia Molecular

UAB

Excellent CumLaude

Porta Balanyà, Rut

La vía del receptor EP4 de la prostaglandina E2 y de la 15-hidroxiprostaglandina deshidrogenasa en el cáncer de pulmón de célula no pequeña: relevancia clinicopatológica

Antonio González Fernández, Joan Brunet i Vidal

Medicina

UAB

Excellent CumLaude

Puig Verdie, Lluís

Estudi comparatiu entre el cultiu de la sonicació de l’implant i el teixit del voltant en el diagnòstic d’infecció postquirúrgica en cirurgia ortopèdica

Enric Cáceres Palou

Cirurgia

UAB

Excellent CumLaude

Ramos Terrades, Natalia

Marcadores bioquímicos de lesión endotelial, sistema fibrinolítico y microalbuminuria en HTA esencial

Alfons Segarra Medrano, Vicente Fonollosa Pla

Medicina

UAB

Excellent CumLaude

Roca Gas, Oriol

Qualitat de vida i alteracions morfofuncionals en supervivents a una síndrome del destret respiratori agut

Joan Ramon Masclans Medicina Enviz, Xavier Muñoz Gall

UAB

Excellent CumLaude

Roca Tey, Ramón

Diagnòstic precoç de l’estenosi de l’accés vascular per hemodiàlisi mitjançant la determinació no invasiva del flux sanguini

Vicente Fonollosa Pla

Medicina

UAB

Excellent CumLaude

Rodríguez Diez, Basilio

Artritis idiopática juvenil: estudio de la incidencia y prevalencia en Catalunya

Consuelo Modesto Caballero, A. Selva O’ Callaghan

Medicina

UAB

Excellent CumLaude

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VHIR Information Summary of Research Activity

Table 16 Doctoral thesis read in 2010 or supervised by VHIR’s staff (Cont.)

Phd

Title

Directors

Department

University Qualification

Romero Cullerés, Georgia

Aplicació de toxina botulinítica tipus A via transperineal en la hipertonia esfínter uretral extern en la retenció urinària crònica secundaria a una lesió medul·lar

Joan Nardi Vilardaga, Joan Conejero Sugrañes, Miguel Ángel González Viejo

Cirurgia

UAB

Excellent CumLaude

Ruiz Riol, Marta

Análisis de los mecanismos de tolerancia central y periférica implicados en la patogénesis de las enfermedad de Graves-Basedow

Ricardo Pujol Borrell

Biologia Cel·lular, de Fisiologia i d’Immunologia

UAB

Excellent CumLaude

Ruiz Romance, María del Mar

Valor clínico de las micropartículas circulantes en las pérdidas gestacionales, en la preeclampsia y en el retraso de crecimiento intrauterino

Jaume Alijotas Reig

Medicina

UAB

Excellent

Saltor Pons, Manuel

Estudio de la torsión femoral en la vida prenatal. Evolución de las rotaciones de la cadera entre los 7 y 14 años

Joan Nardi Vilardaga

Cirurgia

UAB

Excellent CumLaude

Sánchez, Antonio

Correlación clínico-ecocardiográfico, hemodinámica del derrame pericárdico

Jaume Sagristá

ACOR-Cardiologia pediàtrica

UAB

Excellent CumLaude

Soler Palacín, Pere

Hiperlactacidèmia en fills de mare VIH Concepció Figueras i exposats a antiretrovirals (2004-2007). Nadal Estudi de cohorts, obert i prospectiu

Pediatria, UAB d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent CumLaude

Sordia Hernández, Luis Humberto

Menopausia: La severidad de su sintomatología y depresión

Lluís Cabero Roura

Pediatria, UAB d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent

Trasovares Navarrete, María Victoria

Condicionament clàssic aversiu i al context: el paper de la conciència de contingència i l’ansietat tret

Miguel Casas Brugué

Departament de Psiquiatria i de Medicina Legal

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UAB

Excellent CumLaude

305

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Phd

Title

Directors

Department

Treviño Salinas, Emilio Modesto

Valor de la estereotaxia en el diagnóstico de neoplasia en las lesiones no palpables de mama, de acuerdo a las diferentes imágenes mamográficas

Jordi Xercavins Montosa

Pediatria, UAB d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent

Vázquez Suárez, Ana

Equilibrio entre las citoquinas pro y antiinflamatorias en los derrames pleurales infecciosos

José Alegre Martín

Medicina

UAB

Excellent CumLaude

Vélez Villa, Roberto

Estimulación de la regeneración ósea mediante células madre en un modelo preclínico de osteonecrosis de la cabeza femoral

Marius Aguirre, Vicenç Martínez Ibáñez, Joan Nardi

Departament de Cirurgia

UAB

Excellent CumLaude

Vidaur Tello, Loreto

Patrones de resolucion clínica de neumonía asociada a ventilación mecánica

Jordi Rello Condomines

Medicina

UAB

Excellent CumLaude

Vizmanos Lamotte, Gerardo

Antonio Moreno Tipificación del fenotipo inflamatorio Galdo, Antonio en el asma bronquial en niños de 7 a Carrascosa Lezcano 14 años, mediante recuento celular y determinación de citoquinas en esputo inducido

UAB Pediatria, d’Obstetrícia i Ginecologia i de Medicina Preventiva

Excellent CumLaude

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University Qualification

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VHIR Information Scientific Report

Scientific Report

The scientific activities organized during 2010 by VHIR were 148, stressing the great importance of teaching in our institute.

Table 17 VHIR’s activities

Activities Extraordinary Conferences XIV Conferència Anual HUVH 4th Scientific Meeting VHIR Jornada “Papel de los virus y la respuesta” Seminars VHIR Oncology Cardiology Gastroenterology Neuroscience Neurosurgery Nano Seminars CIBBIM-Nanomedicina VHIR briefing (3) Courses USMIB UEB UCTS Other courses

One thing that stands out in comparison with 2009 is the increase in the number of VHIR Seminars held (75%), and a further increase in the number of courses offered (140%). The VHIR website is available in www.vhir.org to consult the list of scientific activities by a search by date and type of activity. In

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3 1 1 1 109 28 4 26 21 6 19 2

36 7 6 9 14

2010, VHIR opened a YouTube Channel where further scientific activities can be viewed on video. Visit us at: www.youtube.com/user/VHIRtv For further information consult the online version of the scientific report.

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VHIR Research Activity

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Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

VHIO: ADVANCING PERSONALIZED AND TARGETED THERAPIES AGAINST CANCER With the explosion of novel genomic and pathway data and the stunning advancement in new diagnostic and therapeutic options, there has never been a more exciting time in oncology. But research progress can only be translated into genuine benefit for cancer patients within an environment that provides the appropriate infrastructure, expertise, and essential interconnectivity between all oncology specialists en force. Since it was established in 2006, the Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, has been organized and structured to do just that. By adopting a purely translational research model, VHIO is proof of the benchbedside-bench principle – a term

describing the process by which research from the laboratory is directly applied to patients and from the clinical side, patient samples are analyzed in the laboratory. The translational approach is nothing new and clearly facilitates the detailed and direct study of each patient and each tumor. The strength of the VHIO is that it can ‘translate’ more swiftly and dynamically. With direct access to our patients at the Vall d’Hebron University Hospital, one of the largest hospitals within Spain, our multidisciplinary teams strive to improve survival and quality of life for all our patients today, and in so doing turn research into more effective, personalized treatments and better practice for the future.

22010 Impact Factor:

778.818

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Vall d’Hebron Institute of Oncology (VHIO)

1.1 VHIO-Experimental Therapeutics Group Leader José Manuel Baselga Torres Tel. 93 274 60 85 [email protected] Researchers Maurizio Scaltriti, PhD Violeta Serra, PhD Pieter Eichhorn, PhD Yasir Ibrahim, PhD Celina García-García, PhD Research Associates Marta Guzmán Olga Rodríguez Pilar Antón Administrative Staff Susana Muñiz

OBJECTIVES The Experimental Therapies Program aims to develop novel breast cancer targeted therapies along with phase I clinical trials at VHIO. Our program works in close collaboration with the Growth Factors Group as well as the Molecular Pathology Group.

RESEARCH LINES Truncated p95HER2 receptor and novel anti-HER2 therapies We previously showed that the expression of truncated forms of the HER2 receptor, p95HER2, correlate with a lack of response to the anti-HER2 antibody trastuzumab. Lapatinib, a HER2 tyrosine kinase

inhibitor, has proven to be efficacious in p95HER2-expressing cells in our preclinical models. We have now interrogated clinical samples from patients treated with lapatinib and found that patients with p95HER2-overexpressing tumors were as sensitive to this agent as p95HER2 negative tumors. This finding represents an additional step towards a rational subclassification of HER2-positive disease and a better selection of therapy for these patients. We have also explored new combinations of anti-HER2 therapies. Indeed, the combination of trastuzumab and lapatinib has already shown enhanced efficacy in the neoadjuvant setting for patients with

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metastatic breast cancer. We had previously identified the potential mechanism for the enhanced clinical activity of this combination, namely an enhanced immunemediated trastuzumab dependent cytotoxicity as a result of the lapatinib induced HER2 accumulation at the plasma membrane.

Additional mechanisms of resistance to targeted therapy against the HER2/PI3K pathway As with the majority of anticancer agents, acquired resistance to anti-HER2 agents becomes an unavoidable phenomenon. Therefore, identifying potential “escape” mechanisms could lead to im-

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Area 1. Oncology and Genetics

proved therapeutic strategies. In the light of these considerations, and in order to identify resistance mechanisms, we used a molecular barcode-screen approach to identify mediators of lapatinib resistance. We showed that deregulation of the PI3K pathway, either through PTEN down-modulation, or through overexpression of the two most frequent breast cancer mutations in PI3KCA (E545K and H1047R), confers resistance to trastuzumab and lapatinib. We then confirmed these observations by showing that PI3K-mediated trastuzumab and lapatinib resistance can be abrogated with the PI3K/mTOR inhibitor NVPBEZ235. We understood that the enhanced efficacy of combining anti-HER2 compounds with PI3K/ mTOR inhibitors is due to prevention of compensatory pathway activation. Such combinations are presently under investigation in phase Ib clinical trials. Using a different approach, we also generated cells with acquired resistance to either trastuzumab

or lapatinib. These cells represent a powerful tool in gaining a better understanding of the molecular mechanisms responsible for the resistant phenotype and, hence, the testing of new compounds that may overcome it. We explored the genetic aberrations in trastuzumab-resistant cell lines, by both microarray (Luminex) and genome-wide single nucleotide polymorphism (SNPs) analysis (Affymetrix 500K SNP array). These analyses have shown that cyclin E gene is amplified and its protein product upregulated in our resistant cell lines. We then confirmed these findings by FISH and IHC in a cohort of 50 HER2 positive patients where cyclin E amplification/overexpression was found in approximately 30% of the cases. We reasoned that deregulation of cyclin E expression may play a causative role in the acquisition of trastuzumab resistance, and we have tested this hypothesis both preclinically and in trastuzumab treated breast cancer patients. In cell lines

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with cyclin E overexpression we found that CDK2 inhibitors were very effective in inducing cell death and slowing down tumor growth. In the clinical setting we confirmed that presence of cyclin E amplification/overexpression negatively correlates with clinical benefit rate and progression-free survival of patients treated with trastuzumab-based therapy. We plan to confirm these results in a larger cohort of patients and, if these data are in line with the previous findings, design ad hoc clinical trial with CDK inhibitors together with anti-HER2 agents. Finally, with the help of a cDNA library we have identified novel kinases that mediate resistance to PI3K inhibition. We are further elucidating the precise mechanism by which these kinases confer resistance to PI3K-targeted therapy, with the aim of improving the clinical efficacy of these agents upon overexpression of the given kinases.

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AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.2 VHIO-Breast Cancer Group Leader Javier Cortés Tel. 93 274 60 85 [email protected] Attending Physicians Meritxell Bellet Serena di Cosimo Patricia Gómez José Pérez Cristina Saura Fellows Eva Muñoz María Vidal Vanesa Ortega Leticia de Mattos Clinical Trials Coordinators Susana Muñoz Raquel Espallargas Violeta Esteban Beatriz García Olga Vidal

RESEARCH LINES Optimization of the treatment of breast cancer with the incorporation of new drugs aimed at biological targets

OBJECTIVES • Implement sequencing of tumors in patients with breast cancer.

• Implement therapeutic strategies and clinical trials differentiated by tumor subtype.

• Study the efficacy of inhibitors of the PI3K/mTOR pathway and their relationship with the mutational state.

• Study new chemotherapeutic agents in metastatic breast cancer.

• Continue investigating the factors involved in resistance to anti-HER2 treatments and strategies aimed at reversing them.

• Study new therapeutic approaches to patients with luminal b and triple negative metastatic breast cancer.

Optimization of multidisciplinary treatment in patients with stage I-III breast cancer, incorporating studies with translational objectives

Participation in the development of new chemotherapy drugs

Incorporation of proteomic and genomic platforms as well as platforms of circulating tumor cells in breast cancer studies

• Study the efficacy of PARP inhibitors in breast cancer.

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Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.3 VHIO-Gastrointestinal Tumors Group Leader Josep Tabernero Caturla Tel. 93 489 43 01 [email protected] Researchers Jaume Capdevila Castillón María Elena Elez Fernández Teresa Macarulla Mercadé Maria Alsina Maqueda Researchers in Training Irene Braña García Guillem Argilés Martínez

OBJECTIVES The Medical Oncology Department’s Gastrointestinal Tumors Program is an integral component of the multidisciplinary team of the Vall d’Hebron Gastrointestinal Tumors Project which consists of gastrointestinal surgeons, medical oncologists, radiation oncologists, pathologists, molecular biologists, radiologists, palliative care and clinical trials specialists. The program is dedicated to patient care, research, training and education in gastrointestinal tumors. As a clinical academic unit, it is committed to clinical excellence, clinical and translational research, and a broad range of teaching (to undergraduates, medical trainees and fellows, nurses, clinical researchers, and others).The Gastrointestinal Tumors Program’s approach is based on the principle that clini-

cians provide the best quality cancer care when they are members of a multidisciplinary cancer institute, meeting regularly to discuss the most appropriate management of each individual patient.

RESEARCH LINES Clinical Research The clinical trials conducted by this group can be classified in three different major areas: • Phase II and III clinical trials aimed to demonstrate clinical benefit with new chemotherapy schedules and targeted agents in gastrointestinal malignancies. • Phase I pharmacokinetic and pharmacodynamic studies with targeted agents directed to different critical signal transduction pathways.

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• Phase I pharmacokinetic and pharmacodynamic studies with cytotoxic agents.

Translational Research Translational research devoted to improving knowledge of prognostic and predictive biomarkers in the different gastrointestinal malignancies.

Basic Research Basic research in collaboration with the VHIO Stem Cells, Gene Expression, Tumor Biomarkers, Experimental Therapeutics and Growth Factors Groups as well as other international research groups (University of Michigan, Vanderbilt University, Harvard University, Broad Institute-MIT, Weizmann Institute, and Leuven University).

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Vall d’Hebron Institute of Oncology (VHIO)

1.4 VHIO-Gene Expression and Cancer Group Leader Joan Seoane Suárez Tel. 93 489 41 67 [email protected] Researchers M. Àngels Carmona Heredia Anna Cascante Cirera Andrea Sáez Borderías Joan Seoane Suarez Researchers in Training Gerard Folch Codera Alba González Junca Laura Rodón Ahnert Nursing, Technical and Administrative Staff Alexandra Arias Piñeiro Mª Isabel Cuartas Maza Rosa Gil Villaverde Eva Paradell Salinas Carolina Raventós Bernal

OBJECTIVES Our group’s research focuses on the study of glioma, the most common and aggressive brain tumor, and works with cell cultures and with mouse models of glioma. Gliomas are the most common primary tumors of the brain and the most malignant form of glioma (glioblastoma multiforme) is one of the most aggressive human cancers. Treatment for these malignancies remains elusive and progress in this area of research is still needed. Gliomas have morphologic and gene-expression characteristics similar to glia, the support cells of the

brain. Gliomas can be divided into four clinical grades on the basis of their histology and prognosis. Grade IV gliomas (glioblastoma multiforme, GBM) are highly malignant, usually recalcitrant to radio- and chemotherapy and have a median survival of 1-2 years. Until recently, radiation has been the main standard-of-care treatment with a minimal role for systemic chemotherapy. However in a recent study, concurrent treatment with temozolomide with radiation improved median survival by 2.5 months compared with radiation therapy alone. Thus, temozolomide has become a standard

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adjuvant therapy for gliomas although providing modest clinical benefits. Novel molecularly-targeted therapies against these devastating tumors are required. Our studies are mostly based on the study of cells obtained from patient-derived tumors. We obtain tumor samples 30 minutes after surgery and we set up primary cultures and isolate cell populations from the tumor such as the cancer stemcell-like pool. The study of the cells gives us more reliable information about the original tumor than the study of established cell

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Area 1. Oncology and Genetics

Figure 14 Patient-derived mouse model of glioma

RESEARCH LINES lines. Moreover, we inoculate the patient-derived glioma stem cells into the brain of immunocompromised mice and we are able to generate tumors with the same characteristics as the original human tumor which we can monitor by MRI. This mouse model for human glioma is of great interest in studying the molecular mechanisms involved in cancer as well as evaluating the efficiency of pharmacological compounds.

Patient-derived glioma stem cells Recently, a subpopulation of tumor cells with stem-cell-like properties was identified in gliomas. This pool of cells, known as glioma stem cells, is considered to be responsible for the initiation, propagation and recurrence of tumors indicating that more effective therapies will result from approaches aimed at targeting the stem-cell-like component of gliomas. Glioma stem cells are characterized by their self-renewing capacity, their multilineage differentiation properties, their

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high oncogenic potential, and their ability to generate detached spherical cellular structures (neurospheres) when cultured in a serum-free medium. Several markers, most of them previously described for neuroprogenitor cells, have been reported to identify glioma stem cells. Specifically, it has been shown that a glioma subpopulation of cells expressing the cell surface protein, CD133, is enriched for cancer stem cells. Little is known however regarding the molecular characteristics, and

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regulatory mechanisms that control glioma stem cell biology. We have studied glioma stem cells derived from patients, comparing their molecular characteristics with the rest of the tumor cells in order to obtain biomarkers of glioma stem cells and elucidate the oncogenic aberrations present in this type of cells.

The TGF-beta signal transduction pathway in glioma The best-characterized pathways involved in glioma are the tyrosine kinase receptor pathways (EGFR, PDGFR) and many reports have shown that these pathways tend to be hyperactive and promote glioma genesis. However, other pathways such as the TGFbeta pathway have recently been shown to play a relevant role in glioma progression. Little is known about the mechanisms of signal transduction of the TGFbeta pathway and its role in on-

cogenesis. We are characterizing the activity and function of the TGF-beta pathway in human glioma and how it is interconnected with other pathways. We are studying how this pathway regulates glioma cell proliferation, invasion, motility, angiogenesis and differentiation. We aim to understand why and how the TGF-beta pathway is aberrantly regulated in cancer and we expect our results to contribute to the knowledge of the signal transduction mechanisms of TGF-beta in the context of cancer and normal development. Our work is based on the study of patient-derived tumor cells and biopsies.

Role of the forkhead transcription factor FoxG1 in glioma We are studying a transcriptional factor that may have a crucial role in the genesis of glioma. FoxG1 (previously known as BF1) is a transcription factor of the fork-

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Index

head family and is the cellular homolog of Qin, the oncogene of the avian sarcoma virus 31. Importantly, FoxG1 is expressed in the neuroprogenitors of the telencephalon but not in differentiated cells and is essential for forebrain formation. Its ablation causes premature differentiation and cell cycle arrest of neuroprogenitors, impairing the development of the telencephalon. Interestingly, data from our laboratory have shown that FoxG1 is expressed in human high grade gliomas as well as in glioma cell lines and we have some indications that FoxG1 might be relevant in glioma genesis and progression as a putative new oncogene. We are studying FoxG1 transcriptional regulation and determining why FoxG1 is aberrantly expressed in gliomas. We are studying the regulation of its activity identifying FoxG1 posttranscriptional modifications. In addition, we are identifying the set of genes regulated by FoxG1.

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VHIR Information

Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.5 VHIO-Genitourinary, Central Nervous System (CNS), Sarcoma and Cancer of Unknown Primary Site

Group Leader Joan Carles Galcerán Tel. 93 274 62 73 [email protected] Medical Oncologists Jordi Rodón Cristina Suárez Claudia Valverde Clinical Fellows Rafael Morales César Serrano

OBJECTIVES • Design and development of clinical trials for genitourinary malignancies with the active participation of investigators from the Urology, Radiation Therapy and Medical Oncology Departments. • Creation of a translational research platform for Urologic Cancer. • Collaboration of physicians from the different disciplines involved in the Urologic cancer Board

for the carrying out of doctoral theses of fellows belonging to each department. • Collaboration with the Spanish Oncology Genitourinary Group (SOGUG) in order to conduct clinical trials at different stages of the disease with emphasis on a histologic-tailored design. • Consolidation of the CNS Committee with the development of several multidisciplinary clinical trials.

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• Consolidation of a translational research platform for Glioblastoma, in collaboration with the lab of Joan Seoane. • Collaboration with the Spanish Sarcoma Group (GEIS) in order to conduct clinical trials at different stages of the disease with emphasis on a histologictailored design. • Creation of a translational platform for Sarcomas and Basic Research in close collaboration

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with the Biomedical Research Institute of Bellvitge (IDIBELL) and the Cancer Research Center of Salamanca (CIC). • The option for every member of the group to spend a minimum of 3 months in centers of acknowledged prestige in a specific area. In the following years, the program will promote shorter stays for the development of joint projects.

RESEARCH LINES Implementation of a Urologic Oncology Functional Unit (Vall d’Hebron Urologic Tumors Center)

Development of a translational platform in prostate cancer in parallel with the development of innovative clinical trials, with special focus on the androgen receptor

Consolidation of the Committee on Nervous System Tumors, with the development of several multidisciplinary clinical trials, with special focus on drugs in early development (phase I and early phase II) with TGF inhibitors and PI3K inhibitors Our main focus surrounds innovative trial designs in first line in combination with radiation therapy and in second/third line of treatment.

Consolidation of the Bone and Soft Tissue Sarcoma Committee

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Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.6 VHIO-Growth Factors Group Leader Joaquín Arribas López Tel. 93 274 68 60 [email protected] Researchers Joaquín Arribas López Kim Pedersen Josep Lluís Parra Palau Mariano Zacarias Fluck Beatriz Morancho Armisen Aniello Cerrato Researchers in Training Pier David Angelini Cristina Bernadó Morales Nursing, Technical and Administrative Staff Marta Escohiruela Baez Maria Cristina Ferrer Ramon Antonio Luque García Elena Guzmán Guerrero

OBJECTIVES The Growth Factors Laboratory explores the role of certain signal transduction pathways in the progression of breast cancer. Breast cancer is the most common cancer among women; according to the World Health Organization, more than 1.2 million women will be diagnosed with breast cancer each year worldwide and over 500,000 will die from the disease. Approximately 30% of patients with breast cancer express excessive levels of the tyrosine kinase receptor HER2. The prognosis of these patients is clearly worse than that of patients with normal levels of the receptor. HER2 (ErbB2) be-

longs to the family of the epidermal growth factor receptor (EGFR), which also includes HER3 (ErbB3) and HER4 (ErbB4). We are currently investigating the relevance of novel isoforms of HER2 in tumor progression and treatment.

RESEARCH LINES The HER signaling pathway Dimerization of the extracellular domains leads to interaction between the intracellular kinases of the HER receptors and subsequent transphosphorylation of certain tyrosine residues in the C-terminal tail. These phosphotyrosines act as docking sites for a group of intracellular phosphotyrosine-

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binding proteins that transduce signals from the plasma membrane to the nucleus via different signalling pathways, including the mitogen activated protein kinases (MAPKs), PI(3)K-activated Akt, Src and phospholipase C gamma (PLCgamma) pathways. These signalling circuits control the expression of target genes that act in coordination to modify key aspects of cellular biology, including proliferation, migration, survival and differentiation.

Novel signaling abilities of HER receptors and their fragments In addition to the canonical mode, HER receptors, or fragments of them, seem to be endowed with

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direct signalling abilities. HER2 is a substrate of metalloproteases collectively known as alpha-secretases, which release the extracellular domain, leaving behind the transmembrane-cytoplasmic fragment, known as P95. By analogy with other transmembrane proteins also cleaved by alpha-secretases, it has been suggested that the cleavage of P95 can also be achieved by gamma-secretases, which release the intracellular domain in a process known as RIP (regulated intramembrane proteolysis). Although P95 has been poorly characterized, partly because it is produced at very low levels in cultured cell lines, it has been suggested that it is active. However, since P95 lacks the extracellular domain, it is not predicted to form hetero- or homodimers. Thus, the mechanism of activation of P95 remains unexplained. We have recently identified alternative initiation of translation as an additional mechanism that generates CTFs of HER2 similar, but not identical, to P95. Initiation of translation from methionine codons, located upstream or downstream of the trans-

membrane domain, leads to the generation of two different CTFs. Although preliminary evidence suggests that CTFs generated by translation are active, as in the case of P95, the mechanism of activation is unknown. In summary, at least four different HER2 CTFs are generated by two independent mechanisms: proteolytic processing and alternative initiation of translation. Two HER2 CTFs contain the transmembrane and cytoplasmic domains while two are predicted to be soluble intracellular proteins encompassing most of the cytoplasmic domain.

HER2 fragments and breast cancer progression and treatment Breast cancer patients expressing CTFs of HER2 are more likely to develop nodal metastasis and have a worse prognosis than those expressing predominantly the fulllength receptor. Furthermore, the presence of CTFs seems to be relevant for tumor treatment. Currently, two types of drugs targeting HER2 are used in clinical practice: monoclonal antibodies against the

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extracellular domain and smallmolecule inhibitors that block the kinase activity of the receptor. We have recently shown that approximately 90% of breast cancer patients expressing CTFs are resistant to treatment with the anti-HER2 antibody Herceptin (trastuzumab). However, the CTFs expressed in tumors have not been characterized in detail and it is not known if these fragments arise in tumors by proteolysis and/or alternative initiation of translation. Furthermore, since the activity of the different CTFs has not been analyzed individually, their relative contribution to the malignant phenotype has not been determined.

Development of specific antibodies against HER2 CTFs In 2010 we finished a comprehensive analysis of the different CTFs of HER2 expressed in breast cancers. In addition we were able to generate and characterize monoclonal antibodies that recognize epitopes exposed in the fragments but masked in full-length HER2. These antibodies constitute a useful tool to identify p95HER2-positive tumors and to find a better treatment for this subtype of patients.

Figure 15 Full-length HER2 (middle, blue), the 100- to 115-kDa p95HER2 fragment generated by alternative initiation of translation from the AUG codon in position 611 (left) and the 95- to 100-kDa p95HER2 generated by proteolytic cleavage of full-length HER2 (right). Note that the names of different domains are marked in the soluble extracellular domain of HER2 (HER2 ECD). Top, the antip95HER2 antibodies recognize epitopes in 100- to 115-kDa p95HER2 that are masked in fulllength HER2 and absent in 95- to 100-kDa p95HER2. Within the cytoplasm, the red globes represent selected components of signaling pathway activated by HER2 and p95HER2. Bottom, gene expression is regulated by the different HER2 forms. Note that a group of genes specifically regulated by 100- to 115-kDa p95HER2, such as MMP1, ANGPTL4, MET, and IL-11, have been causally involved in the metastatic progression

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.7 VHIO-Head, Neck and Gynecological Tumors Group Leader Josep Maria del Campo Tel. 93 489 48 25 [email protected] Attending Physicians Isabela Díaz de Corcuera Ana Oaknin Victor G.Freixinos Clinical Trials Coordinators Cristina González Mireia Sanchis Olga Padros

OBJECTIVES Our team aims to consolidate itself as a reference center by creating high-level multidisciplinary teams. To this end, we encourage training of specialists involved in gynecological and head and neck tumors through a Fellowship in hospitals of international reference. • Create a regional network of hospitals to facilitate patient access to novel treatment in clinical trials that are currently limited to centers of reference. • Form part of the Management structures of the cooperative groups of the utmost International relevance (ENGOT, GCIG)

and strengthen relations with highly specialized centers in our areas of interest (NCIC, Peter McCallum CC, Irvine MC, HSK Wiesbaden). • Develop our own database for each disease to facilitate exhaustive reviews of practical interest and publishing potential.

Highly specialized in treatment

Training in Gynecological Oncology

Fellowships

International projection • Increase dissemination via international forums and impact factor publications.

Potentiate scientific activity

Publications in high impact factor journals

RESEARCH LINES Reference Center in Patient Care and Clinical Research

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Presenting at International conferences

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Vall d’Hebron Institute of Oncology (VHIO)

1.8 VHIO-High Risk and Cancer Prevention Group Leader Judith Balmaña Tel. 93 274 60 00 (ext. 4713) [email protected] Staff Scientist Nina Bosch Clinical Nurse Specialist Neus Gadea Research Fellow Begoña Graña Graduate Student Maria Coma

OBJECTIVES We are continuing to develop specific new therapies for patients with hereditary cancer and patients with sporadic cancer who share molecular abnormalities similar to those of hereditary cancer. We are also participating in several clinical trials with these new compounds, from phase I to II, in patients with early and advanced cancer. We are performing in-depth analysis into the long-term psychosocial impact of genetic studies in hereditary syndromes, specifically after BRCA disclosure and in the male population. We are also analyzing the intake of prophylactic surgeries among BRCA mutation carriers.

BRCA2 gene, and we are also taking part in a national study to determine the role of breast density as a risk factor for breast cancer in women with mutations in the BRCA1/2 genes. We have started to run next generation studies to search for mutations in new genes conferring predisposition to hereditary breast cancer. We are participating in an international collaboration to validate and compare the PREMM1,2,6 predictive model for identification of Lynch syndrome patients with a mutation.

RESEARCH LINES At international level, we are participating in a study aimed at analyzing the efficacy of early detection of prostate cancer in patients with a mutation in the BRCA1 or a

Development of clinical and molecular tools to identify people with Lynch syndrome or hereditary breast and ovarian cancer

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syndrome associated with BRCA1 or BRCA2, or P53 mutations

Analysis of the medical and psychosocial impact of genetic studies in hereditary cancer syndromes (BRCA and Lynch syndrome)

Development of specific therapeutic strategies for tumors associated with hereditary genetic alterations

Identification of new genes causing predisposition to hereditary breast cancer

Evaluation of the risk of cancer and follow up strategies for adult patients with Fanconi anemia and survivors of other childhood hereditary cancer syndromes with genetic predisposition to late-onset cancer

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.9 VHIO-Oncogenetics Group Leader Orland Díez Tel. 93 489 48 26 [email protected] Staff Scientists Sara Gutiérrez Enríquez

Post-Doctoral Fellow Sandra Bonache Real Graduate Student Gemma Montalbán Canudas Technicians Miriam Masas Castro Anna Tenés Felipe

RESEARCH LINES Identification and characterization of new germ line sequence variants in BRCA1, BRCA2, and TP53 in cancer families

Development of probability models for predicting BRCA1 and BRCA2 mutations in 3.500 Spanish families with breast/ovarian cancer

Analysis of genetic modifiers of risk in BRCA1/BRCA2 breast/ovarian cancer families. Collaboration in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)

Identification of new genes of predisposition to familiar breast/ovarian cancer by targeted capture and massively parallel sequencing

OBJECTIVES • Molecular analysis of the genetic predisposition to hereditary cancer (breast/ovarian cancer syndrome, Li-Fraumeni syndrome). • Application of massively parallel sequencing for the study of cancer predisposition genes. • Molecular analysis of the genetic predisposition to side effects of radiotherapy.

Collaboration in the Evidencebased Network for the Interpretation of Germline Mutant Alleles (ENIGMA) International Consortium for the analysis of variants with potential splicing effects, unknown biological significance, and transcriptional isoforms in BRCA1 and BRCA2

Molecular analysis of other DNA repair genes related to breast/ ovarian cancer predisposition (CHEK2, RAD51C, RAD51D, PALB2, ATM, etc.)

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Characterization of transcriptional profiles induced by ionising radiation in cells with mutations in BRCA1 or BRCA2 genes

Identification of genes for susceptibility to radiotherapy side-effects by genetic association studies. Collaboration with the International Radiogenomics Consortium

Transcriptional profiles and apoptosis analysis as biomarkers for radiotherapy toxicity in breast cancer patients

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Vall d’Hebron Institute of Oncology (VHIO)

1.10 VHIO-Proteomics Group Leader Francesc Canals Suris Tel. 93 489 41 75 [email protected] Researchers Joan Josep Bech Serra Francesc Canals Suris Marta Monge Azemar Nursing, technical and administrative staff Adelina Acosta Martín Núria Colomé Calls

OBJECTIVES The Proteomics Laboratory provides services to research groups on latest-generation proteomics methodologies. The importance of the interaction between tumor cells and their microenvironment in malignant progression has been recently highlighted. Different metalloproteases play a crucial role in the regulation of the tumor microenvironment by mediating the remodeling of the extracellular matrix and the processing of extracellular and membrane proteins. Knowledge of the substrate repertoire (degradome) of these proteases is needed to elucidate their role in tumor growth and metastasis, in order to evaluate their potential use as therapeutic targets. We have demonstrated

the utility of proteomic techniques to explore these degradomes. The present focus of our research is to extend these studies, incorporating new proteomic analysis techniques, to study metalloproteases known to play key roles in tumor progression. Metalloproteases of the ADAM family (ADAM10, ADAM17/TACE), and of the ADAMTS family (ADAMTS1) will be the object of study. TACE and ADAM10 are involved in the proteolytic cleavage of the transmembrane forms of EGFR ligands (shedding), required for the activation of the receptor, and are also involved in regulation of cell migration and adhesion. Several metalloproteases of this family are overexpressed in different types

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of tumors. The thrombospondindomain containing protease ADAMTS1 has been recently found to be highly overexpressed in highly invasive mammary tumor cells, suggesting a major role for this protease in metastatic processes. The proposed proteomic studies aim for the identification and characterization of new substrates of these proteases in the context of cancer cells. The putative substrates identified will then be validated through characterization in vitro. The importance of the newly identified substrates in tumor development will be analyzed in preclinical models and their expression and shedding will be determined in mammary tumor samples.

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

RESEARCH LINES Identification of substrates of ADAM10 and ADAM17 proteases using SILAC analysis In order to search for substrates of the ADAM10 and ADAM17 metalloproteases, we have used model breast cancer cells in which conditional expression has been introduced, using the tet-off system, of either the protease or siRNA to knock down specifically the protease of interest. The comparison between conditions where the protease is either inactive or active can be then carried out in the same cell clone. Differential proteomic analysis of the conditioned culture media of these cells has been performed using a SILAC (stable isotope labeling through aminoacids in culture) approach, and an analytical workflow comprising 1D-SDS-PAGE fractionation followed by liquid-chromatography coupled to electrospray mass spectrometry (LC-MS). Labeling is accomplished supplying specific labeled amino acids in the cell culture medium, thus allowing the labeling of all the proteins in the cell through its own metabolic processes. In this way, quantitative information can be obtained for all the proteins detected in the analysis. A number of known substrates of both proteases were identified as such in the analysis, showing the expected decrease of the shed extracellular domain abundance in the medium upon knock down of the protease. In addition, several new candidate substrates of both proteases were identified. Among them, the GPIanchored protein C4.4A, was identified and further validated as substrate of both ADAM10 and ADAM17 proteases. According to the identified peptides, both proteases cleave this protein close to the juxtamembrane region, releasing a soluble form devoid of the GPI-anchor. C4.4A protein, homologous to the urokinase-type plasminogen activator receptor,

Other collaborative projects with VHIO groups has been related to tumor invasion and metastasis. Cleavage of this protein by ADAMs constitutes a previously unknown level of regulation of its function. Work is in progress to validate and further characterize other proteins identified as potential substrates of these proteases.

Identification of ADAMTS1 substrates using DIGE and SILAC proteomic analysis We have applied two complementary proteomic approaches, 2D electrophoresis DIGE and SILAC LC-MS analysis, to the search for substrates of the metalloprotease ADAMTS1, in a model breast cancer cell line where conditional overexpression of the protease was introduced. Glycoproteins of the conditioned media from parental and ADAMTS1 overexpressing cells were purified and analyzed using a 2D-DIGE electrophoresis approach (Figure 2) and a SILAC methodology similar to the one described above for the ADAM10 and ADAM17 experiments. Both approaches led to the identification of trombospondin-1 as a substrate of ADAMTS1, which has been reported recently by others, and shown to play a role in modulating angiogenesis. Semaphorin 3C was also identified by both methodologies, and further validated as a substrate of both ADAMTS1 and ADAM17. This family of extracellular matrix proteins plays different roles in cell axon guidance in the nervous system, as well as in angiogenesis and tumor progression. The role of Semaphorin 3C in cancer cell migration is currently being investigated.

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• Signaling through C-terminal fragments of HER-2 in breast cancer (with J. Arribas Lab.): SILAC proteomic analysis was used to analyze protein-protein interaction partners of HER-2. Several potential mediators of HER-2 signalling, as well as previously unreported phosphorylation sites have been identified. • Screening for surface marker proteins of glioma-initiating stem-cells (with J. Seoane Lab.): Several candidate proteins have been identified as putative surface markers of glioma neurosphere forming cells through cell-surface proteome analysis. • Biomarkers to monitor response to Hsp-90 inhibitor IPI-504 treatment (with M. Scaltriti- J.Baselga Lab.): Several candidate biomarkers of IPI-504 action have been identified by SILAC proteomic analysis of model cells.

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Facility and Collaborative Work The Proteomics Laboratory has continued providing services as a member of the “Instituto de Salud Carlos III” Cancer Research Network, and of the “Instituto Nacional de Proteómica ProteoRed”, funded by “Fundación Genoma España”. This year, the laboratory has provided services to more than 30 research groups, not only from the Vall Hebron Hospital, but also to the main hospitals, research centers and universities in the area. In summary, the analyses performed include 40 2D-DIGE gels, 20 quantitative ICPL or SILAC experiments, representing a total of more than 450 LC-MS runs, and around 500 protein identifications by peptide

mass fingerprint. In conjunction with the services provided, the laboratory has actively participated in several projects involving proteomic analysis. In collaboration with Dr. R. Simó, of the Endocrinology Unit at the VHIR we have continued to apply DIGE technology to study alterations in the protein content of vitreous fluid of proliferative diabetic retinopathy patients subjected to vitrectomy. Together with the Department of Immunology at the Universitat Autònoma, Barcelona, led by Dr. Dolores Jaraquemada, we have been working on the analysis of repertoires of HLA associated peptides of cell lines related to autoimmune

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diseases or cancer. In the framework of the ProteoRed network, the laboratory has coordinated a multicentric study to evaluate reproducibility of a 2D-DIGE differential proteomic experiment. The results of the study show the robustness of the methodology used, and demonstrate the feasibility of across-lab validation schemes, pointing towards development of inter-lab QC strategies for proteomics research. The results were presented at the ABRF’09 Meeting, the 3rd SEPROT-LAHUPO Congress, and at the HUPO special meeting on reproducibility studies as preliminary requirements to launch the HUPO Human Proteome Project.

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.11 VHIO-Radiation Oncology Group Leader Jordi Giralt Tel. 93 274 60 86 [email protected] Radiation Oncologists Manel Altabas Sergi Benavente Xavier Maldonado Meritxell Molla Begoña Navalpotro Mónica Ramos Victoria Reyes Ramona Vergés

RESEARCH LINES OBJECTIVES

Technology developments: Highly conformal Radiotherapy

• Continuation of the IMRT program in pediatric, gynecological and gastrointestinal tumors.

Translational research: EGFR inhibitors plus Radiotherapy

• Development of the extracranial stereotactic radiotherapy program in lung cancer and liver metastases. • To improve quality control programs and develop new techniques. • Study new therapeutic combinations with radiotherapy and EGFR inhibitors in head and neck cancer and gastrointestinal tumors.

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AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.12 VHIO-Stem Cells and Cancer Group Leader Héctor García Palmer Tel. 93 274 49 25 [email protected] Researchers Héctor García Palmer Isabel Puig Borreil Stephan Tenbaum Nursing, Technical and Administrative Staff Irene Chicote Ramos

OBJECTIVES The main interest of our laboratory is to understand the molecular mechanisms that control the initiation and progression of epithelial tumors. In particular, we are focused on the study of the intra-tumoral cell heterogeneity inherent to colon cancer and its consequences for the progression of the disease. Among the different cell populations present in colon carcinomas we are currently identifying those responsible for drug-resistance and relapse as well as those with enhanced metastatic capacity. Relapse and metastasis frequently occur and patients at these advanced stages present short life expectancy. Some cells among drug-resistant and metastatic populations retain properties similar to stem cells and have been termed “cancer

stem cells”. In colon cancer, they represent rare populations with long-term self-renewing capacity that perpetuate tumors and give rise to all types of malignant cells present in the cancerous tissue. At the molecular level, we are analyzing the relevance of Wnt/catenin and PI3K/AKT pathways controlling the fate of colon cancer stem cells. We have recently discovered that these oncogenic pathways play a central role promoting metastasis and resistance to a new generation of drugs directed to inhibit PI3K or AKT signalling. Our results could impact directly on treatment with these target-directed drugs which are currently being tested in numerous clinical trials worldwide.

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We are specifically interested in novel mechanisms of gene transcription-dependent on these pathways and their relevance in driving stem cell decisions: selfrenewal vs. differentiation, apoptosis vs. survival, proliferation vs. quiescence. Our technical approaches include cellular and molecular biology, mouse models of cancer and, most importantly, the analysis of cells directly derived from patients with colon carcinomas directly upon surgery. This line of work is extremely exciting since it allows us to work with human cancer stem cells - a privileged opportunity in the field of cancer research.

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

RESEARCH LINES To study the role of cancer stem cells in the initiation, progression and self-renewal of epithelial tumors

To investigate the enhanced capacity of colon cancer stem cells to resist target-directed drugs and their contribution to patient relapse and metastasis

Characterization of new molecular features of Wnt/beta-catenin and PI3K/AKT signalling pathways and their relevance in normal and cancer stem cells physiology Figure 16 Working circuit to study colon cancer patient-derived cells. Cells are derived from patients immediately after surgery. Cell suspension is obtained and different analyses in vivo and in vitro are performed. Particular target-directed drugs are tested in the laboratory and the results are translated to oncologists to design safer and more personalized clinical trials for colon cancer patients

Figure 17 Normal and Cancer Stem Cells are the source of cell heterogeneity in human colon epithelium and carcinomas. (a) Programmed mechanisms that drive lineage selection in normal colon crypts are retained in carcinomas. (b) Normal colon crypt with stem cells at the bottom (red), proliferative cells in the middle (white) and differentiated cells in the upper part (green, yellow and blue). (c) Immunofluorescence and confocal microscopy showing differentiated cells positive for Cytokertatin 20 (CK20) in green and the expression of beta-catenin in red. (d) Immunofluorescence and confocal microscopy showing differentiated cells positive for Villin1 (VIL1) in red and heterogeneous expression of beta-catenin in green. (c,d) Nuclei were stained with Hoechst 33342. Scale bar, 100 m

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AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.13 VHIO-Thoracic Tumors Group Leader Enriqueta Felip Tel. 93 274 60 98 [email protected] Attending Physicians Susana Cedrés Pablo Martínez Alex Martínez Victor Freixinós Head of Study Coordinator Irene Marimón Clinical Trials Coordinators Oriol Nualart Meritxell Soler Marta Beltrán

OBJECTIVES

RESEARCH LINES

• Implement the determination ALK translocation.

Optimization of multidisciplinary treatment in patients with stage IIII Cancer

• Study the efficacy of PI3K/mTOR inhibitors in patients with lung cancer resistant to EGFRTKIs. • Research the efficacy of PARP inhibitors in lung cancer.

Early integration of genetic determinations to personalize treatments

• Analyze the epidemiologic/clinical characteristics of women diagnosed with lung cancer.

Participation in the development of new drugs

• Play an active role in organizing a European consensus meeting on lung cancer.

Active intervention in the fight against smoking

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

Vall d’Hebron Institute of Oncology (VHIO)

1.14 VHIO-Tumors Biomarkers Group Leader Josep Villanueva Cardús Tel. 93 489 41 75 [email protected] Researchers Olga Méndez Fernández Josep Villanueva Cardús Laura Villarreal Tolchinsky Researchers in Training Cándida Salvans Gorjon Sílvia Torrents Zapata Nursing, Technical and Administrative Staff Laura Córcoles Pujadas

OBJECTIVES The aim of this group is to discover new tumor-specific biomarkers and therapeutic targets using proteomic methodologies to improve cancer diagnostics and therapeutic treatment. Our specific goals are: • The characterization of the mechanisms used by tumor cells to communicate with their microenvironment during tumorigenesis, and its exploitation for biomarker discovery.

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• The discovery of secreted signaling pathway-based tumor biomarkers and therapeutic targets using quantitative proteomics. • The discovery of secreted response/resistance biomarkers to targeted drug therapy measurable through non-invasive methods.

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Figure 18 Scientific strategy of the Tumor Biomarkers Laboratory

RESEARCH LINES Tumor cell communication with its microenvironment plays a key role in tumor initiation and progression Tumor cells hijack the tumor microenvironment ecosystem via paracrine signaling to promote a pro-oncogenic microenvironment that is critical for the establishment of primary and metastatic tumors. The working hypothesis of the laboratory is that cellular signaling pathways are altered during the tumorigenesis process, and that these alterations are translated into differential protein secretion, which potentially can be exploited to discover secreted markers. Furthermore, some of the differentially regulated proteins could be direct extracellular messengers of intracellular signaling pathways contributing to key steps in cancer initiation and progression, therefore becoming potential therapeutic targets.

The aim of the laboratory therefore is to discover secreted tumorspecific biomarkers and therapeutic targets to improve cancer diagnostics and therapeutic treatment Proteomic technologies offer the advantage of a genome-scale search for tumor-specific biomarkers and drug targets and could revolutionize early detection and molecular characterization of cancer through non-invasive methods. However, the field of cancer proteomics has encountered problems with reproducibility and limitations related to the massive complexity of biological samples.

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The laboratory will consequently focus on the discovery of biomarkers and drug targets using the proteomic profiling of subproteomes, rather than whole tissues or plasma/serum By using a new proteomics approach capable of the quantitative profiling of the secreted subproteome (“secretome”) of cells, we will generate secretome signatures in different cancer model systems, as well as from clinical samples. We are confident that the discovery of secreted tumorspecific biomarkers will play a key role in cancer therapeutics and diagnostics.

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

CURRENT RESEARCH PROJECTS INSTITUT DE RECERCA – VHIO PI: José Manuel Baselga Torres Targeting PI3K in Women’s Cancer Funding Agency: AACR- American Association for Cancer Research Reference: SU2C-AACR-DT0209 Funding: 954,250 $ Duration: 2009 to 2012

PI: José Manuel Baselga Torres Overcoming resistance to antiHER2 therapy with PI3K inhibitors. Anticipating emerging resistance to PI3K pathway inhibition Funding Agency: Novartis Reference: Novartis-CIBOT2009 Funding: 699,000 € Duration: 2009 to 2012

PI: José Manuel Baselga Torres Novel Cancer Therapies to overcome resistance to anti-HER2 and PI3k inhibitors in breast cancer Funding Agency: BCRF-Breast Cancer Research Foundation Reference: BCRF2009 Funding: 200,000 $ Duration: 2009 to 2010

PI: José Manuel Baselga Torres Inhibiting the PI3K pathway as a therapeutic strategy in breast cancer Funding Agency: BCRF-Breast Cancer Research Foundation Reference: BCRF2010 Funding: 223,000 $ Duration: 2010 to 2011

PI: José Manuel Baselga Torres Estrategias de Reversión de la Resistencia Funding Agency: ISCIII-Instituto de Salud Carlos III Reference: PS09/00623 Funding: 714,505 € Duration: 2010 to 2014

PI: José Manuel Baselga Torres RTICC - Red Temática de Investigación cooperativa de cáncer Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0020/0075 Funding: 324,898.82 € Duration: 2007 to 2012

PI: José Manuel Baselga Torres Ajuts de Suport a la Recerca. Grup de Recerca Consolidat Funding Agency: AGAUR- Agència de Gestió d’Ajuts Universitaris i de Recerca Reference: 2009SGR342 Funding: 42,640 € Duration: 2010 to 2014

PI: Josep Tabernero RD06/0020/0075. ISCIII. Red Temática de Investigación Cooperativa en Cáncer (RTICC) del Instituto de Salud Carlos III, MSC. Co-Principal Investigator. 2006-2010, renewed 2011.

PI: Josep Tabernero Genentech 09/001. “In vitro and in vivo activity of the AKT inhibitor GDC-0068 in breast and colon cancer cells”. Co-Principal Investigator. 2009-2010.

PI: Josep Tabernero Fidelity UK Foundation. “Towards Personalized Medicine in Cancer: Acquisition of a Sequenom MassARRAY Platform to match the right patient with the right anticancer therapy“. Co-Investigator. 2009-2010.

PI: Josep Tabernero Rafael del Pino Foundation “Circulating Tumor Cells”. Co-Principal Investigator. 2009-2010, renewed 2011.

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PI: Josep Tabernero FP7-HEALTH-2010 (COLTHERES). “Modelling and predicting sensitivity to targeted therapies in colorectal cancers”. Co-Principal Investigator 2010-2013.

PI: Joaquín V. Arribas Functional characterization of novel factors mediating the oncogenic activity of HER2. Role in the progression of breast cancer Funding Agency: Breast Cancer Research Foundation Funding: 230,000 $ Duration: 2010 to 2011

PI: Joaquín V. Arribas Red Temática de Investigación Cooperativa del Cáncer Funding Agency: Instituto de Salud Carlos III Reference: RD06/0020/0022 Funding: 272,000 € Duration: 2011

PI: Joaquín V. Arribas Fragmentos C-terminales (CTFs) de HER2 en la progresión y el tratamiento de tumores de mama Funding Agency: Instituto de Salud Carlos III (Proyecto Intrasalud) Funding: 794,970 € Duration: 2008 to 2011

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PI: Joaquín V. Arribas SGR Suport a Grups d’Investigació de Qualitat Funding Agency: AGAUR Generalitat de Catalunya Funding: 44,720 € Duration: 2009 to 2014

PI: Joan Seoane Suárez Mecanismos moleculares implicados en la génesis del glioma y estudio de las células madre tumorales. Identificación de nuevas dianas terapéuticas y marcadores para la estratificación de pacientes y respuesta a fármacos Funding Agency: Asociación Española contra el Cáncer – AECC Duration: 2010

PI: Joan Seoane Suárez EMBO YIP (European Molecular Biology Organization Young Investigator Programme) Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2008-04778-E Duration: 2009 to 2013

PI: Joan Seoane Suárez An Integrated approach to posttranscriptional regulation of gene expression and its role in human disease Funding Agency: Ministerio de Ciencia e Innovación Reference: Consolider RNAREG Duration: 2009 to 2012

PI: Joan Seoane Suárez SGR Suport a Grups de Recerca de Qualitat Funding Agency: Agencia de Gestió d’Ajuts Universitaris i de Recerca Reference: 2009SGR504 Duration: 2009 to 2014

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PI: Joan Seoane Suárez Molecular mechanisms of glioma genesis and progression (Glioma) Grant No 205819ERC Starting Grant Funding Agency: European Commission Reference: GLIOMA-205819 Duration: 2008 to 2013

PI: Josep Villanueva Proteómica cuantitativa de perfiles de secretomas para el descubrimiento de biomarcadores Funding Agency: ISCIII (Miguel Servet) Duration: 2009 to 2011

PI: Josep Villanueva Secretomas de cáncer de mama basados en vías de señalización para el descubrimiento de biomarcadores Funding Agency: ISCIII (FIS) Duration: 2010 to 2012

PI: Joan Seoane Suárez Pathway based secretomes in breast cancer biomarker discovery Funding Agency: European Union IRG Marie Curie Duration: 2010 to 2012

PI: Joan Seoane Suárez Modelling and predicting resistance to molecular therapies in colorectal cancer Funding Agency: European Union FP7 Duration: 2011 to 2014

PI: Héctor G. Palmer Human Colon Cancer Stem Cells and Wnt pathway Funding Agency: Fundació Vall d´Hebron Institut d´Oncología (VHIO) Duration: 2008 to 2011

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PI: Héctor G. Palmer Human Colon Cancer Stem Cells and Wnt/-catenin pathway Funding Agency: Instituto de Salud Carlos III Reference: FIS - PI081356 Duration: 2009 to 2012

PI: Héctor G. Palmer Human Colon Cancer Stem Cells Funding Agency: Olga Torres Foundation Duration: 2009 to 2011

PI: Héctor G. Palmer Colon Cancer Stem Cells and Wnt/ -catenin pathway Funding Agency: Fundación de la Asociación Española Contra el Cáncer (AECC) Duration: 2010 to 2013

PI: Francesc Canals Suris Identificación mediante análisis proteómico de nuevos sustratos de metaloproteasas implicadas en cáncer y caracterización de su papel funcional Funding Agency: Fondo de Investigación Sanitaria Reference: PI07/1058 Funding: 286,770 € Duration: 2008 to 2010

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

PUBLICATIONS INSTITUT DE RECERCA – VHIO (Impact Factor: 778.818) Adam R, Haller DG, Poston G, Raoul JL, Spano JP, Tabernero J, Cutsem E van. Toward optimized front-line therapeutic strategies in patients with metastatic colorectal cancer – an expert review from the International Congress on Anti-Cancer Treatment (ICACT) 2009. Ann Oncol 2010 Aug; 21 (8): 1579-84.  IF: 5.647. Altorki N, Lane ME, Bauer T, Lee PC, Guarino MJ, Pass H, Felip E, Peylan-Ramu N, Gurpide A, Grannis FW, Mitchell JD, Tachdjian S, Swann RS, Huff A, Roychowdhury DF, Reeves A, Ottesen LH, Yankelevitz DF. Phase II Proof-of-Concept Study of Pazopanib Monotherapy in Treatment-Naive Patients With Stage I/II Resectable Non-SmallCell Lung Cancer. J Clin Oncol 2010 Jul 1; 28 (19): 3131-7.  IF: 17.793. Andreu-Pérez P, Hernández-Losa J, Moliné T, Gil R, Grueso J, Pujol A, Cortés J, Ávila MA, Recio JA. Methylthioadenosine (MTA) inhibits melanoma cell proliferation and in vivo tumor growth. BMC Cancer 2010 Jun 8; 10 (1): 265.  IF: 2.736. Anido J, Sáez-Borderías A, González-Junca A, Rodón L, Folch G, Carmona MA, PrietoSánchez RM, Barba I, Martínez-Saez E, Prudkin L, Cuartas I, Raventós C, MartínezRicarte F, Poca MA, García-Dorado D, Lahn MM, Yingling JM, Rodón J, Sahuquillo J, Baselga J, Seoane J. TGF-beta Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell 2010 Dec 14; 18 (6): 655-68.  IF: 25.288.

Arribas J, Parra-Palau JL, Pedersen K. HER2 fragmentation and breast cancer stratification. Clin Cancer Res 2010 Aug 15; 16 (16): 4071-3.  IF: 6.747. Balmaña J, Castells A, Cervantes A. Familial colorectal cancer risk: ESMO Clinical Practice Guidelines. Ann Oncol 2010 May; 21 Suppl 5: v78-81.  IF: 5.647. Balmaña J, Diez O, Rubio I, Castiglione M. BRCA in breast cancer: ESMO Clinical Practice Guidelines. Ann Oncol 2010 May; 21 Suppl 5: v20-2.  IF: 5.647. Bancells C, Canals F, Benítez S, Colomé N, Julve J, Ordoñez-Llanos J, Sánchez-Quesada JL. Proteomic analysis of electronegative low-density lipoprotein. J Lipid Res 2010 Dec; 51 (12): 3508-15.  IF: 4.917. Barbachano A, Ordoñez-Morán P, García JM, Sánchez A, Pereira F, Larriba MJ, Martínez N, Hernández J, Landolfi S, Bonilla F, Palmer HG, Rojas JM, Muñoz A. SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity. Oncogene 2010 Aug 26; 29 (34): 4800-13.  IF: 7.135. Baselga J. Treatment of HER2-overexpressing breast cancer. Ann Oncol 2010 Oct; 21 Suppl 7: vii36-40.  IF: 5.647. Baselga J, Cervantes A, Martinelli E, Chirivella I, Hoekman K, Hurwitz HI, Jodrell DI, Hamberg P, Casado E, Elvin P, Swaisland A, Iacona R, Tabernero J. Phase I safety, pharmacokinetics, and inhibition of SRC activity study of saracatinib in patients with solid tumors. Clin Cancer Res 2010 Oct 1; 16 (19): 4876-83.  IF: 6.747.

Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortés J, McNally VA, Ross GA, Fumoleau P, Gianni L. Phase II Trial of Pertuzumab and Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer That Progressed During Prior Trastuzumab Therapy. J Clin Oncol 2010 Mar 1; 28 (7): 1138-44.  IF: 17.793. Baselga J, Swain SM. CLEOPATRA: A Phase III Evaluation of Pertuzumab and Trastuzumab for HER2-Positive Metastatic Breast Cancer. Clin Breast Cancer 2010 Dec 1; 10 (6): 489-91.  IF: 2.065. Bellmunt J, Maroto-Rey P, Trigo JM, Carles J, Guillém V, López-Martín JA, Antón-Torres A, Urruticoechea L. A phase II trial of firstline sorafenib in patients with metastatic renal cell carcinoma unwilling to receive or with early intolerance to immunotherapy: SOGUG Study 06-01. Clin Transl Oncol 2010 Jul; 12 (7): 503-8.  IF: 1.146. Bellmunt J, Orsola A, Maldonado X, Kataja V. Bladder cancer: ESMO Practice Guidelines for diagnosis, treatment and followup. Ann Oncol 2010 May; 21 Suppl 5:v1346.  IF: 5.647. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, et al. The landscape of somatic copy-number alteration across human cancers. Nature 2010 Feb 18; 463 (7283): 899-905.  IF: 34.480. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O’Shaughnessy J. Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast Cancer. J Clin Oncol 2010 Mar 1; 28 (7): 1124-30.  IF: 17.793. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010 Jan; 11 (1): 21-8.  IF: 14.470.

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Borras E, Pineda M, Blanco I, Jewett EM, Wang F, Teule A, Caldes T, Urioste M, Martínez-Bouzas C, Brunet J, Balmaña J, Torres A, Ramón y Cajal T, Sanz J, Pérez-Cabornero L, Castellví-Bel S, Alonso A, Lanas A, González S, Moreno V, Gruber SB, Rosenberg NA, Mukherjee B, Lázaro C, Capella G. MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families. Cancer Res 2010 Oct 1; 70 (19): 7379-91.  IF: 7.543. Borras JM, Baselga J. The impact of cancer in Spain: consequences for cancer prevention and care. Ann Oncol 2010 May; 21 Suppl 3:iii1-2.  IF: 5.647. Brana I, Tabernero J. Cardiotoxicity. Ann Oncol 2010 Oct; 21 Suppl 7:vii173-vii179.  IF: 5.647. Cabrera S, Franco-Camps S, García A, Vergés R, Díaz-Feijoo B, Pérez-Benavente MA, Poza JL, Bradbury M, Xercavins J, Gil-Moreno A. Total laparoscopic radical hysterectomy for cervical cancer in prolapsed uterus. Arch Gynecol Obstet 2010 Jul; 282 (1): 63-7.  IF: 0.912. Campo JM del, Muñoz-Couselo E, Díaz de Corcuera I, Oaknin A. Trabectedin combined with liposomal doxorubicin in women with relapsed ovarian cancer. Expert Rev Anticancer Ther 2010 Jun; 10 (6): 795-805.  IF: 2.493. Cebrecos I, Córdoba O, Deu J, Xercavins J, Rubio IT. Can we predict local recurrence in breast conserving surgery after neoadjuvant chemotherapy? Eur J Surg Oncol 2010 Jun; 36 (6): 528-34.  IF: 2.564. Cedres S, Quispe I, Martínez P, Longo M, Rodríguez E, Serrano C, Muñoz E, Pallisa E, Felip E. Computed tomography (CT) predicts accurately the pathologic tumour size in stage I non-small-cell lung cancer (NSCLC). Clin Transl Oncol 2010 Dec; 12 (12): 829-35.  IF: 1.146. Chan AT, Gregoire V, Lefebvre JL, Licitra L, Felip E. Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May; 21 Suppl 5: v187-9.  IF: 5.647. Chandarlapaty S, Scaltriti M, Angelini P, Ye Q, Guzmán M, Hudis CA, Norton L, Solit DB, Arribas J, Baselga J, Rosen N. Inhibitors of HSP90 block p95-HER2 signaling in Trastuzumab-resistant tumors and suppress their growth. Oncogene 2010 Jan 21; 29 (3):32534.  IF: 7.135.

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Cherny NI, Baselga J, Conno F de, Radbruch L. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid Policy Initiative. Ann Oncol 2010 Mar; 21 (3): 615-26.  IF: 5.647. Ciruelos EM, Cortés J, Cortés-Funes H, Mayordomo JI, Bermejo B, Ojeda B, García E, Rodríguez CA, Muñoz M, Gómez P, Manso L, Andres R, Lluch A, Saura C, Mendiola C, Baselga J. Gemcitabine and capecitabine in previously anthracycline-treated metastatic breast cancer: a multicenter phase II study (SOLTI 0301 trial). Ann Oncol 2010 Jul; 21 (7): 1442-7.  IF: 5.647. Colomé N, Collado J, Bech-Serra JJ, Liiv I, Antón LC, Peterson P, Canals F, Jaraquemada D, Álvarez I. Increased apoptosis after autoimmune regulator expression in epithelial cells revealed by a combined quantitative proteomics approach. J Proteome Res 2010 May 7; 9 (5): 2600-9.  IF: 5.132. Colomer R, Alba E, González-Martín A, PazAres L, Martín M, Llombart A, Rodríguez Lescure A, Salvador J, Albanell J, Isla D, Lomas M, Rodríguez CA, Trigo JM, Germa JR, Bellmunt J, Tabernero J, Rosell R, Aranda E, Cubedo R, Baselga J. Treatment of cancer with oral drugs: a position statement by the Spanish Society of Medical Oncology (SEOM). Ann Oncol 2010 Feb; 21 (2): 195198.  IF: 5.647. Córdoba O, Llurba E, Cortés J, Sabadell MD, Lirola JL, Ferrer Q, Xercavins J. Complete pathological remission in a patient with hormone-receptor positive and c-erbB-2 expression-negative breast cancer treated with FAC chemotherapy during pregnancy. Tumori 2010 Jul-Aug; 96 (4): 629-32.  IF: 0.863. Cortés J, Vahdat L, Blum JL, Twelves C, Campone M, Roche H, Bachelot T, Awada A, Paridaens R, Goncalves A, Shuster DE, Wanders J, Fang F, Gurnani R, Richmond E, Cole PE, Ashworth S, Allison MA. Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol 2010 Sep 1; 28 (25): 3922-8.  IF: 17.793. Crino L, Weder W, Meerbeeck J van, Felip E. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May; 21 Suppl 5: v103-15.  IF: 5.647.

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Cuadrado E, Rosell A, Colomé N, Hernández-Guillamón M, García-Berrocoso T, Ribó M, Alcázar A, Ortega-Aznar A, Salinas M, Canals F, Montaner J. The Proteome of Human Brain After Ischemic Stroke. J Neuropathol Exp Neurol 2010 Nov; 69 (11): 110515.  IF: 4.564. Cutsem E van, Dicato M, Arber N, Berlín J, Cervantes A, Ciardiello F, Gramont A de, Díaz-Rubio E, Ducreux M, Geva R, Glimelius B, Jones RG, Grothey A, Gruenberger T, Haller D, Haustermans K, Labianca R, Lenz HJ, Minsky B, Nordlinger B, Ohtsu A, Pavlidis N, Rougier P, Schmiegel W, Velde C van de, Schmoll HJ, Sobrero A, Tabernero J. Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009. Ann Oncol 2010 Jun; 21 Suppl 6:vi110.  IF: 5.647. D’Addario G, Fruh M, Reck M, Baumann P, Klepetko W, Felip E. Metastatic non-smallcell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May; 21 Suppl 5: v116-9.  IF: 5.647. Dienstmann R, Tabernero J. Necitumumab, a fully human IgG1 mAb directed against the EGFR for the potential treatment of cancer. Curr Opin Investig Drugs 2010 Dec; 11 (12):1434-41.  IF: 3.549.

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Díez O, Gutiérrez-Enríquez S, Balmaña J. Heterogeneous prevalence of recurrent BRCA1 and BRCA2 mutations in Spain according to the geographical area: implications for genetic testing. Fam Cancer 2010 Jun; 9 (2): 187-91.  IF: 2.189. Díez O, Gutiérrez-Enriquez S, Masas M, Tenes A, Yague C, Arcusa A, Llort G. Identification of a new complex deleterious mutation in exon 18 of the BRCA2 gene in a hereditary male/female breast cancer family. Breast Cancer Res Treat 2010 Sep; 123 (2): 587-90.  IF: 4.696. Díez O, Gutiérrez-Enríquez S, Mediano C, Masas M, Saura C, Gadea N, Balmaña J. A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer. Breast Cancer Res Treat 2010 May; 121 (1): 221-5.  IF: 4.696. Dopeso H, Mateo-Lozano S, Elez E, Landolfi S, Ramos Pascual FJ, Hernández-Losa J, Mazzolini R, Rodrigues P, Bazzocco S, Carreras MJ, Espín E, Armengol M, Wilson AJ, Mariadason JM, Ramon y Cajal S, Tabernero J, Schwartz S Jr, Arango D. Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. Clin Cancer Res 2010 Apr 15; 16 (8): 237582.  IF: 6.747. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Wolf M, Gansert J. Randomized, Phase III Trial of Panitumumab With Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) Versus FOLFOX4 Alone As First-Line Treatment in Patients With Previously Untreated Metastatic Colorectal Cancer: The PRIME Study. J Clin Oncol 2010 Nov 1; 28 (31): 4697-705.  IF: 17.793.

Eichhorn PJ, Baselga J. HER2 Signatures in Breast Cancer: Ready to Go to Print? J Clin Oncol 2010 Apr 10; 28 (11): 1809-10.  IF: 17.793. Elez E, Alsina M, Tabernero J. Panitumumab - an effective long-term treatment for patients with metastatic colorectal cancer and wild-type KRAS status. Cancer Treat Rev 2010 Feb; 36 Suppl 1: S15-6.  IF: 5.295. Ellis MJ, Lin L, Crowder R, Tao Y, Hoog J, Snider J, Davies S, DeSchryver K, Evans DB, Steinseifer J, Bandaru R, Liu W, Gardner H, Semiglazov V, Watson M, Hunt K, Olson J, Baselga J. Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res Treat 2010 Jan; 119 (2): 379-90.  IF: 4.696. Esselens C, Malapeira J, Colomé N, Casal C, Canals F, Arribas J. The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration. J Biol Chem 2010 Jan 22; 285 (4): 2463-73.  IF: 5.328. Felip E, Cedres S, Checa E, Martínez P. How to integrate current knowledge in selecting patients for first line in NSCLC? Ann Oncol 2010 Oct; 21 Suppl 7: vii230-vii233.  IF: 5.647. Felip E, Rosell R, Maestre JA, RodríguezPaniagua J, Morán T, Astudillo J, Alonso G, Borro JM, González-Larriba JL, Torres A, Camps C, Guijarro R, Isla D, Aguiló R, Alberola V, Padilla J, Sánchez-Palencia A, Sánchez JJ, Hermosilla E, Massuti B. Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non-SmallCell Lung Cancer. J Clin Oncol 2010 Jul 1; 28 (19): 3138-45.  IF: 17.793.

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Frias C, Cortés J, Segui MA, Oyaguez I, Casado MA. Cost-effectiveness analyses of docetaxel versus paclitaxel once weekly in patients with metastatic breast cancer in progression following anthracycline chemotherapy, in Spain. Clin Transl Oncol 2010 Oct; 12 (10): 692-700.  IF: 1.146. García-Carbonero R, Capdevila J, CrespoHerrero G, Díaz-Pérez JA, Martínez Del Prado M, Alonso Orduna V, Sevilla-García I, Villabona-Artero C, Beguiristain-Gómez A, LlanosMuñoz M, Marazuela M, Álvarez-Escola C, Castellano D, Vilar E, Jiménez-Fonseca P, Teule A, Sastre-Valera J, Benavent-Vinuelas M, Monleón A, Salazar R. Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Ann Oncol 2010 Sep; 21 (9): 1794-803.  IF: 5.647. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vázquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2negative cohort. Lancet 2010 Jan 30; 375 (9712): 377-384.  IF: 30.758. Gianni L, Lladó A, Bianchi G, Cortés J, Kellokumpu-Lehtinen , Cameron DA, Miles D, Salvagni S, Wardley A, Goeminne JC, Hersberger V, Baselga J. Open-Label, Phase II, Multicenter, Randomized Study of the Efficacy and Safety of Two Dose Levels of Pertuzumab, a Human Epidermal Growth Factor Receptor 2 Dimerization Inhibitor, in Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol 2010 Mar 1; 28 (7):1131-7.  IF: 17.793.

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Markman B, Atzori F, Pérez-García J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol 2010 Apr; 21 (4): 683-91.  IF: 5.647. Markman B, Ramos FJ, Capdevila J, Tabernero J. EGFR and KRAS in colorectal cancer. Adv Clin Chem 2010;51:71-119.  IF: 3.406. Markman B, Rodríguez-Freixinos, Tabernero J. Biomarkers in colorectal cancer. Clin Transl Oncol 2010 Apr; 12 (4): 261-70.  IF: 1.146.

Gramont A de, Haller DG, Sargent DJ, Tabernero J, Matheson A, Schilsky RL. Toward Efficient Trials in Colorectal Cancer: The ARCAD Clinical Trials Program. J Clin Oncol 2010 Feb 1; 28 (4): 527-30.  IF: 17.793. Gregoire V, Lefebvre JL, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May; 21 Suppl 5: v184-6.  IF: 5.647. Guedea F, Ramos A, Herruzo I, Sánchez Calzado JA, Contreras J, Romero J, CravenBartle J, Willisch P, López Torrecilla JL, Maldonado X, Sancho G, Zapatero A, Ferrer M, Pardo Y, Fernández P, Marino A, Hervas A, Macis V, Boladeras A, Ferrer F, Davis BJ. Treatment of localised prostate cancer with radiation therapy: evidence versus opinion. Clin Transl Oncol 2010 May;12 (5): 315-7.  IF: 1.146. Hernández C, García-Ramírez M, Colomé N, Villarroel M, Corraliza L, García-Pacual L, Casado J, Canals F, Simó R. New pathogenic candidates for diabetic macular edema detected by proteomic analysis. Diabetes Care 2010 Jul; 33 (7): e92.  IF: 6.718. Leyland-Jones B, Colomer R, Trudeau ME, Wardley A, Latreille J, Cameron D, Cubedo R, Al-Sakaff N, Feyereislova A, Catalani O, Fukushima Y, Brewster M, Cortés J. Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated. J Clin Oncol 2010 Feb 20; 28 (6): 960-6.  IF: 17.793.

Macarulla T, Cervantes A, Elez E, RodríguezBraun E, Baselga J, Roselló S, Sala G, Blasco I, Danaee H, Lee Y, Ecsedy J, Shinde V, Chakravarty A, Bowman D, Liu H, Eton O, Fingert H, Tabernero J. Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics. Mol Cancer Ther 2010 Oct; 9 (10): 2844-52.  IF: 4.953. Mancebo G, Gil-Moreno A, Vergés R, Martínez-Palones JM, Checa MA, Carreras JM, Giralt J, Xercavins J. Out-of-protocol concurrent use of cisplatin and radiation therapy in locally advanced cervical cancer: feasibility and survival. Eur J Gynaecol Oncol 2010; 31 (1): 18-22.  IF: 0.614. Manchon Walsh P, Borras JM, Ferro T, Espinàs JA, Alfaro J, Arnau JM, Artigas V, Aunon MC, Barrios P, Bellmunt J, Biondo S, Bolibar I, Cambray M, Canals E, Caro M, Casado E, Castells A, Companys A, Darnell A, Torres IM de, Espín E, Estévez M, Figueras J, Gallen M, González D, Lema L, Losa F, Lloreta J, Macias V, Marcuello E, Manzano JL, Martin-Richard M, Maurel J, Membrive I, Mira M, Moreno de Vega V, Murio JE, Panadés A, Pericay C, Pujol J, Queralt B, Ramos E, Reig A, Roca JM, Rodríguez F, Saigi E, Salas A, Salazar R, Sanjuan X, Serra X, Solé JM, Tabernero J, Targarona EM, Torras J. Colorectal Cancer OncoGuia. Clin Transl Oncol 2010 Mar; 12 (3): 188-211.  IF: 1.146.

Martín-Broto J, Gutiérrez A, García-delMuro X, López-Guerrero JA, MartínezTrufero J, Sande LM de, Lainez N, Maurel J, Juan A de, Losa F, Andres R, Casado A, Tejido PG, Blanco R, Carles J, Bellmunt J, Gómez-España A, Ramos R, Martínez-Serra J, Llombart-Bosch A, Poveda A. Prognostic time dependence of deletions affecting codons 557 and/or 558 of KIT gene for relapse-free survival (RFS) in localized GIST: a Spanish Group for Sarcoma Research (GEIS) Study. Ann Oncol 2010 Jul; 21 (7): 1552-7.  IF: 5.647. Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III Study of Bevacizumab Plus Docetaxel Compared With Placebo Plus Docetaxel for the First-Line Treatment of Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol 2010 Jul 10; 28 (20): 3239-47.  IF: 17.793. Milne RL, Osorio A, Ramón y Cajal T, Baiget M, Lasa A, Díaz-Rubio E, Hoya M de la, Caldes T, Teule A, Lázaro C, Blanco I, Balmaña J, Sánchez-Ollé G, Vega A, Blanco A, Chirivella I, Esteban Cardenosa E, Durán M, Velasco E, Martínez de Dueñas E, Tejada MI, Miramar MD, Calvo MT, Guillén-Ponce C, Salazar R, San Roman C, Urioste M, Benítez J. Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2010 Jan; 119 (1): 221-32.  IF: 4.696. Morales-Barrera R, Valverde C, Rodón J, Pérez J, Maldonado X, Suárez C, Trilla E, Carles J. Bilateral testicular germ cell tumours: a single hospital experience. Clin Transl Oncol 2010 Apr; 12 (4): 299-302.  IF: 1.146. Navajas A, Giralt J. Evidence in medulloblastomas. Clin Transl Oncol 2010 Apr; 12 (4): 271-7.  IF: 1.146.

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Area 1. Oncology and Genetics

Peters LJ, O’Sullivan B, Giralt J, Fitzgerald TJ, Trotti A, Bernier J, Bourhis J, Yuen K, Fisher R, Rischin D. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck cancer: results from TROG 02.02. J Clin Oncol 2010 Jun 20; 28 (18): 2996-3001.  IF: 17.793. Pierce LJ, Phillips KA, Griffith KA, Buys S, Gaffney DK, Moran MS, Haffty BG, BenDavid M, Kaufman B, Garber JE, Merajver SD, Balmaña J, Meirovitz A, Domchek SM. Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. Breast Cancer Res Treat 2010 Jun; 121 (2): 389-98.  IF: 4.696. Pomerantz MM, Shrestha Y, Flavin RJ, Regan MM, Penney KL, Mucci LA, Stampfer MJ, Hunter DJ, Chanock SJ, Schafer EJ, Chan JA, Tabernero J, Baselga J, Richardson AL, Loda M, Oh WK, Kantoff PW, Hahn WC, Freedman ML. Analysis of the 10q11 Cancer Risk Locus Implicates MSMB and NCOA4 in Human Prostate Tumorigenesis. PLoS Genet 2010 Nov 11; 6 (11): e1001204.  IF: 9.532. Navarro S, Vaquero E, Maurel J, Bombi JA, Juan C de, Feliu J, Fernández Cruz L, Ginés A, Girela E, Rodríguez R, Sabater L, Álvarez E, Maranon G, Arguello L, Barranco L, Cárdenas A, Conill C, Cuatrecasas M, Madaria E de, Delgado F, Díaz R, Domínguez E, Fabregat J, Farré A, Fernández Esparrach, Ferrandez A, del Pino Florez M, IglesiasGarcía J, Lluis F, López Serrano A, Macarulla T, Martin Richard M, Mendez R, Molero X, Navalpotro B, Pérez Mateo M, Salas A, Santoyo J, Solé M, Sendino O, Vázquez E, Zarco A. [Recommendations for diagnosis, staging and treatment of pancreatic cancer (Part I). Grupo Espanol de Consenso en Cancer de Pancreas]Med Clin (Barc) 2010 May 15; 134 (14): 643-55.  IF: 1.231.

Navarro S, Vaquero E, Maurel J, Bombi JA, Juan C de, Feliu J, Fernández Cruz L, Ginés A, Girela E, Rodríguez R, Sabater L, Álvarez E, Arguello L, Barranco L, Cárdenas A, Conill C, Cuatrecasas M, Madaria E de, Delgado F, Díaz R, Domínguez E, Fabregat J, Farré A, Fernández Esparrach, Ferrandez A, Florez M del P, Iglesias-García J, Lluis F, López Serrano A, Macarulla T, Martin Richard M, Méndez R, Molero X, Navalpotro B, Pérez Mateo M, Salas A, Santoyo J, Solé M, Sendino O, Vázquez E, Zarco A. [Recommendations for diagnosis, staging and treatment of pancreatic cancer (Part II).] Med Clin (Barc) 2010 May 22; 134 (15): 692702.  IF: 1.231.

Nicolantonio F di, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, Geuna M, Frattini M, Baselga J, Gallicchio M, Biffo S, Bardelli A. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 2010 Aug 2; 120 (8): 2858-66. doi: 10.1172/JCI37539.  IF: 15.387. Oaknin A, Barretina P, Pérez X, Jiménez L, Velasco M, Alsina M, Brunet J, Germa JR, Beltrán M. CA-125 Response Patterns in Patients With Recurrent Ovarian Cancer Treated With Pegylated Liposomal Doxorubicin (PLD). Int J Gynecol Cancer 2010 Jan; 20 (1): 87-91.  IF: 2.179. Orsola A, Cecchini L, Raventós CX, Trilla E, Planas J, Landolfi S, Torres I de, Morote J. Risk factors for positive findings in patients with high-grade T1 bladder cancer treated with transurethral resection of bladder tumour (TUR) and bacille Calmette-Guerin therapy and the decision for a repeat TUR. BJU Int 2010 Jan; 105 (2): 202-7.  IF: 2.865. Parra-Palau JL, Pedersen K, Peg V, Scaltriti M, Angelini PD, Escorihuela M, Mancilla S, Sánchez Pla A, Ramón y Cajal S, Baselga J, Arribas J. A Major Role of p95/611-CTF, a Carboxy-Terminal Fragment of HER2, in the Down-modulation of the Estrogen Receptor in HER2-Positive Breast Cancers. Cancer Res 2010 Nov 1; 70 (21): 8537-46.  IF: 7.543.

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Quispe I, Balmaña J. [Predictive models for identification of germline mutation carriers in Lynch syndrome.] Med Clin (Barc) 2010 Apr 3;134 (9): 412-7.  IF: 1.231. Ramos M, Benavente S, Giralt J. Management of squamous cell carcinoma of the head and neck: updated European treatment recommendations. Expert Rev Anticancer Ther 2010 Mar; 10 (3): 339-44.  IF: 2.493. Reck M, Frickhofen N, Cedres S, Gatzemeier U, Heigener D, Fuhr HG, Thall A, Lanzalone S, Stephenson P, Ruiz-García A, Chao R, Felip E. Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study. Lung Cancer 2010 Nov; 70 (2): 180-7.  IF: 3.140. Rischin D, Peters LJ, O’Sullivan B, Giralt J, Fisher R, Yuen K, Trotti A, Bernier J, Bourhis J, Ringash J, Henke M, Kenny L. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol 2010 Jun 20; 28 (18): 2989-95.  IF: 17.793. Rodón J, Pérez J, Kurzrock R. Combining targeted therapies: practical issues to consider at the bench and bedside. Oncologist 2010; 15 (1): 37-50.  IF: 6.701.

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Roock W de, Claes B, Bernasconi D, Schutter J de, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, Penault-Llorca F, Rougier P, Vincenzi B, Santini D, Tonini G, Cappuzzo F, Frattini M, Molinari F, Saletti P, Dosso S de, Martini M, Bardelli A, Siena S, Sartore-Bianchi A, Tabernero J, Macarulla T, Fiore F di, Gangloff AO, Ciardiello F, Pfeiffer P, Qvortrup C, Hansen TP, Cutsem E van, Piessevaux H, Lambrechts D, Delorenzi M, Tejpar S. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapyrefractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol 2010 Aug; 11 (8): 753-62.  IF: 14.470. Rubio IT, Aznar F, Lirola J, Peg V, Xercavins J. Intraoperative assessment of sentinel lymph nodes after neoadjuvant chemotherapy in patients with breast cancer. Ann Surg Oncol 2010 Jan; 17 (1): 235-9.  IF: 4.130. Sánchez A, Villanueva J. PI3K-based molecular signatures link high PI3K pathway activity with low ER levels in ER(+) breast cancer. Expert Rev Proteomics 2010 Dec; 7 (6): 819-21.  IF: 3.570. Sanjuán X, Salas A, Lloreta J, Manchon Walsh P, Alfaro J, Arnau JM, Artigas V, Auñon MC, Barrios P, Bellmunt J, Biondo S, Bolibar I, Cambray M, Canals E, Caro M, Casado E, Castells A, Companys A, Darnell A, Torres IM de, Espín E, Estévez M, Figueras J, Gallen M, González D, Lema L, Losa F, Lloreta J, Macias V, Marcuello E, Manzano JL, Martin-Richard M, Maurel J, Membrive I, Mira M, Moreno de Vega V, Murio JE, Panadés A, Pericay C, Pujol J, Queralt B, Ramos E, Reig A, Roca JM, Rodríguez F, Saigi E, Salas A, Salazar R, Sanjuan X, Serra X, Solé JM, Tabernero J, Targarona EM, Torras J. Colorectal Cancer OncoGuia: surgical pathology report guidelines. Clin Transl Oncol 2010 Mar; 12 (3): 211-214.  IF: 1.146. Sanz J, Ramón y Cajal T, Torres A, Darder E, Gadea N, Velasco A, Fortuny D, López C, Fisas D, Brunet J, Alonso MC, Balmaña J. Uptake of predictive testing among relatives of BRCA1 and BRCA2 families: a multicenter study in northeastern Spain. Fam Cancer 2010 Sep; 9 (3): 297-304.  IF: 2.189. Scaltriti M, Chandarlapaty S, Prudkin L, Aura C, Jiménez J, Angelini PD, Sánchez G, Guzmán M, Parra JL, Ellis C, Gagnon R, Koehler M, Gómez H, Geyer C, Cameron D, Arribas J, Rosen N, Baselga J. Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res 2010 May 1; 16 (9): 2688-95.  IF: 6.747.

Seoane J. NO Signals from the Cancer Stem Cell Niche. Cell Stem Cell 2010 Feb 5; 6 (2): 97-98.  IF: 23.563. Serrano C, García A, Brana I, Pérez-Benavente A, Oaknin A. Angiosarcoma of the Ovary: Is It Always a Lethal Disease? J Clin Oncol 2010 Nov 20; 28 (33): e675-7.  IF: 17.793. Serrano C, Markman B, Tabernero J. Integration of anti-epidermal growth factor receptor therapies with cytotoxic chemotherapy. Cancer J 2010 May-Jun; 16 (3): 22634.  IF: 3.471. Sorensen M, Pijls-Johannesma M, Felip E. Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May; 21 Suppl 5: v120-5.  IF: 5.647. Stahel RA, Weder W, Lievens Y, Felip E. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010 May; 21 Suppl 5: v126-8.  IF: 5.647. Suárez C, Morales R, Muñoz E, Rodón J, Valverde CM, Carles J. Molecular basis for the treatment of renal cell carcinoma. Clin Transl Oncol 2010 Jan; 12 (1): 15-21.  IF: 1,146. Tabernero J, Baselga J. Multigene assays to improve assessment of recurrence risk and benefit from chemotherapy in early-stage colon cancer: has the time finally arrived, or are we still stage locked? J Clin Oncol 2010 Sep 1; 28 (25): 3904-7.  IF: 17.793. Tabernero J, Cervantes A, Rivera F, Martinelli E, Rojo F, Heydebreck A von, Macarulla T, Rodríguez-Braun E, Vega-Villegas ME, Senger S, Ramos FJ, Roselló S, Celik I, Stroh C, Baselga J, Ciardiello F. Pharmacogenomic and Pharmacoproteomic Studies of Cetuximab in Metastatic Colorectal Cancer: Biomarker Analysis of a Phase I Dose-Escalation Study. J Clin Oncol 2010 Mar 1; 28 (7):1181-9.  IF: 17.793. Tabernero J, Ciardiello F, Rivera F, Rodríguez-Braun E, Ramos FJ, Martinelli E, Vega-Villegas ME, Roselló S, Liebscher S, Kisker O, Macarulla T, Baselga J, Cervantes A. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/ pharmacodynamic phase I dose-escalation study. Ann Oncol 2010 Jul; 21 (7): 1537-45.  IF: 5.647.

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Tan EH, Ramlau R, Pluzanska A, Kuo HP, Reck M, Milanowski J, Au JS, Felip E, Yang PC, Damyanov D, Orlov S, Akimov M, Delmar P, Essioux L, Hillenbach C, Klughammer B, McLoughlin P, Baselga J. A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer. Ann Oncol 2010 Feb; 21 (2): 217-22.  IF: 5.647. Twelves C, Cortés J, Vahdat LT, Wanders J, Akerele C, Kaufman PA. Phase III Trials of Eribulin Mesylate (E7389) in Extensively Pretreated Patients With Locally Recurrent or Metastatic Breast Cancer. Clin Breast Cancer 2010 Apr; 10 (2): 160-3.  IF: 2.065. Vergote I, Pujade-Lauraine E, Pignata S, Kristensen GB, Ledermann J, Casado A, Sehouli J, Mirza M, Fossati R, Marth C, Creutzberg C, Campo J del, Siddiqui N, Calvert P, Bamias A, Tulunay G, Zee AG van der, Bois A du. European Network of Gynaecological Oncological Trial Groups’ requirements for trials between academic groups and pharmaceutical companies. Int J Gynecol Cancer 2010 Apr; 20 (3): 476-8.  IF: 2.179. Zilli T, Jorcano S, Rouzaud M, Dipasquale G, Nouet P, Toscas JI, Casanova N, Wang H, Escude L, Molla M, Linero D, Weber DC, Miralbell R. Twice-Weekly Hypofractionated Intensity-Modulated Radiotherapy for Localized Prostate Cancer with Low-Risk Nodal Involvement: Toxicity and Outcome from a Dose Escalation Pilot Study. Int J Radiat Oncol Biol Phys 2010 Sep 29.  IF: 4.592. Zwierzina H, Bardelli A, Ciardiello F, Gariboldi M, Hakansson L, Lambrechts D, Lind GE, Loeffler-Ragg J, Schmoll H, Siena S, Tabernero J, Cutsem E van. Molecularly targeted therapies for colorectal cancer: Strategies for implementing translational research in clinical trials. Curr Opin Mol Ther 2010 Dec; 12 (6):703-11.  IF: 3.452.

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VHIR Information

Area 1. Oncology and Genetics

AREA 1 ONCOLOGY AND GENETICS

1.15 Animal Models

Group Leader Juan Ángel Recio Conde Tel. 93 489 40 75 [email protected] Researchers in Training Pedro A. Andreu Pérez Rosaura Esteve Puig Ana Carolina Rhodes Cabrerizo Animal Work Technician Rosa Gil Villaverde Lab technician Judit Grueso

OBJECTIVES

RESEARCH LINES

Our main interest is to investigate the genetic and molecular mechanisms underlying tumor development and progression. More precisely, our research is directed to understand melanoma. Melanoma represents the most deadly form of skin cancer. If it is not recognized and treated early, the cancer can advance and spread to other parts of the body, where it becomes hard to treat and can be fatal.

Discovery of novel molecules involved in melanoma Using proteomic screenings (DIGE, SILAC) applied to tumor cell lines obtained from primary tumors raised on relevant animal models that recapitulate the human disease (such as: HGF mouse melanoma model), we isolated and identified 56 novel phospho-proteins in response to growth factors that participate in the tumor behavior

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and maintenance. Among the molecules identified was the LKB1 energy sensor kinase. This molecule is deleted or mutated in different type of tumors (lung, colon, melanoma…). Our results indicated an important link between RAS pathway activation and the LKB1 kinase that belongs to the energy sensor pathway. Importantly, BRAF is mutated in 70% of melanomas. BRAF mutant melanoma cell lines showed constitutive levels of LKB1 phosphorylated, indicating the crosstalk between RAS and LKB1 pathways, and an unusual resistance to energy stress conditions. Further investigations lead us to discover that BRAF signaling was mediating the uncoupling of LKB1

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Figure 19 Crossing strategy to generate the HGF Tg/+;LKB1+/- mice to investigate tumor development in response to UVB. Representative images of UVB induced skin hyperplasia, expression of LKB1 in normal skin and nuclear localization of LKB1 in melanocytes within the hair follicle

and its downstream target AMPK disconnecting the energy sensor pathway, making these mutant cells resistant to low energy conditions. Importantly, the inhibition of BRAF signaling in combination with metabolic stress or activators of AMPK, lead the cells to apoptosis (Esteve-Puig et al. PLoS ONE (2009) 4 [3]: e4771).

Role of LKB1 in tumor biology. LKB1 role in UVB-induced DNA damage response Our own results and the previous literature revealed the role of LKB1 as a tumor suppressor involved in cell cycle control, and transcription regulation. In view of this, we wanted to investigate the possible interaction of LKB1 with proteins

Figure 20 A model of the metabolic stress response regulation by oncogenic BRAF in melanoma cells. Resistance to stress conditions is essential for melanoma cell survival. We propose that oncogenic BRAFV600E signaling (left panel) protects from apoptosis by regulating BH3-family members and confers resistance to low energy conditions promoting the uncoupling of LKB1 and AMPK through Erk1/2 and p90Rsk. Under this condition BRAF mutant cells have a limited response to low energy conditions. On the right panel the inhibition of BRAF signaling allows the formation of the LKB1-AMPK complexes restoring the energy stress pathway and promoting the downregulation of anti-apoptotic proteins such as Mcl1. The activation of AMPK by metabolic stress conditions and the inhibition of BRAF signaling would have synergistic effects promoting apoptosis

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involved in the cell cycle and in the response to DNA damage. We have discovered a novel LKB1 binding protein involved in the cell cycle and DNA damage responses. The aim is to elucidate the role of LKB1 in DNA damage responses in skin cancer and it mutational status in human tumors as a predictor of risk factor.

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Area 1. Oncology and Genetics

Novel therapeutic strategies for melanoma treatment Preclinical study using PI3K/mTOR dual inhibitors and sorafenib in melanoma treatment. We have also assessed the in vitro and in vivo inhibition potential of the dual PI3K/mTOR inhibitor, PI-103 and sorafenib, as single agents and in combination in primary melanoma cell lines. Although PI-103 and sorafenib inhibited melanoma in vitro cell proliferation and viability, the inhibition of RAS pathway appeared to be more effective. The combination of the two agents in vitro showed a synergistic effect inhibiting RAS and PI3K pathways in a cell line dependent manner. However, no cooperative effect was observed in blocking in vivo tumor growth in immunocompetent mice. Contrary to what was expected, the data indicate that PI-103 induced immunosuppression by inducing thymus atrophy and the upregulation of IL6, IL10 and VEGF, promoting in vivo tumor growth and inhibiting apoptosis. Furthermore, in vitro studies examining the effects of the PI3K/mTOR inhibitor in tumor derived cell lines indicated that PI-103 induced the activation of STAT3 and the upregulation of the anti-apoptotic BH3 family proteins Mcl1, Bcl2 and BclxL favoring, the in vitro survival of sorafenib treated melanoma cells. These data certainly make an argument for investigating unexpected effects of rational drug combinations on immunocompetent animal models prior to conducting clinical studies (LópezFauqued et al. Int J Cancer 2009; 126 [7]: 1549-1561).

CURRENT RESEARCH PROJECTS

PUBLICATIONS (Impact Factor: 11.809)

PI: Juan Ángel Recio Conde Papel de LKB1 en melanoma maligno Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMMA/12/2006 Funding: 61,000 € Duration: 2007 to 2010

PI: Juan Ángel Recio Conde Papel de LKB1 en respuesta a factores de crecimiento y en el desarrollo y progresión del melanoma Funding Agency: Fondo de Investigación Sanitaria Reference: PI080653 Funding: 225,907 € Duration: 2009 to 2011

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Andreu-Pérez P, Hernández-Losa J, Moliné T, Gil R, Grueso J, Pujol A, Cortés J, Avila MA, Recio JA. Methylthioadenosine (MTA) inhibits melanoma cell proliferation and in vivo tumor growth. BMC Cancer 2010 Jun 8; 10 (1): 265.  IF: 2.736. Latasa MU, Gil-Puig C, Fernández-Barrena MG, Rodríguez-Ortigosa C, Banales JM, Urtasun R, Goni S, Méndez M, Arcelus S, Juanarena N, Recio JA, Lotersztajn S, Prieto J, Berasain C, Corrales FJ, Lecanda J, Ávila MA. Oral methylthioadenosine administration attenuates fibrosis and chronic liver disease progression in Mdr2-/- mice. PLoS One 2010 Dec 29; 5(12): e15690.  IF: 4.351. López-Fauqued M, Gil R, Grueso J, Hernández J, Pujol A, Moliné T, Recio JA. The dual PI3K/mTOR inhibitor (PI-103) promotes immunosupression, in vivo tumor growth and increases survival of sorafenib treated melanoma cells. Int J Cancer 2010 Apr 1; 126 (7): 1549-61.  IF: 4.722.

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AREA 1 ONCOLOGY AND GENETICS

1.16 Unit in Biomedicine and Translational and Pediatrics Oncology Group Leader Jaume Reventós Puigjaner Tel. 93 489 40 52 [email protected] Researchers Maria Antònia Arbós Via Pilar Bastida Vila Silvia Cabrera Díaz Lluís Cecchini Rosell Jose Luis Dapena Díaz Maria Cristina Díaz de Heredia Rubio Andreas He Doll Izaskun Elorza Álvarez Soledad Gallego Melcón Antonio Gil Moreno Luis Gros Subias Anna Llort Sales Joan Morote Robles Ma Teresa Olivé Oliveras Rosanna Paciucci Barzanti Jordi Petriz González Ma Teresa Quiles Pérez Jaume Reventós Puigjaner Ma Victoria Ribera Canudas Josep Roma Castanyer Ana Ruiz Nel·lo Constantino Sábado Álvarez Josep Sánchez de Toledo Codín Marta Sesé Faustino Enric Trilla Herrera Jorge Xercavins Montosa Researchers in Training Ana Almazan Moga Angélica Betancourt Suárez Eva Colas Ortega Tugce Sevgi Ertekin Marta García López Marta Llauradó Fernández Guillermo López Torrents Blanca Majem Cavaller Lorena Marín Buera Neus Marques Bescos Anna Masià Fontana Melania Montes Pérez

Jesús Planagumà Valls Verónica Pons Escoll Noelia Purroy Zuriguel Pablo Velasco Puyó María del Mar Zardoya Ávila Nursing, Technical and Administrative Staff Oriol Abelló Ramia Meritxell Cucurell Bigas Luna Martín Castel Raúl Morales Alarcón Nuria Pedrola Montero Marta Rebull Santamaria

OBJECTIVES Our group is focused on the molecular and translational research of several cancers including those of the prostate, the endometrium, the ovary, the pancreas as well as the pediatric neuroblastoma and rhabdomyosarcoma. We aim to identify and characterize new molecules which might play relevant roles in the neoplastic cell transformation, and/or growth, progression or dissemination of those tu-

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Area 1. Oncology and Genetics

cal samples. The final goal of this research is the establishment of a reliable diagnostic test, which can be used in hospitals and outpatient routines.

mors. All of our projects are based on unresolved clinical needs. Using experimental models, we develop new research strategies that could lead to preclinical validation. We are also studying several molecules of extracellular matrix and their roles in tissue injury and reparation as well as their interactions with biomaterials. Our final aim is to identify new and valuable molecules and biomarkers to improve diagnosis, prognosis and therapy.

Research Focus Our overall goal focuses several aspects of translational urology mainly based on the knowledge of the molecular bases of prostate cancer, in particular, but also on the role of inflammatory mechanisms as critical regulators of tumor progression. Our central hypothesis is that a deeper understanding of these pathways will advance the development of preventive treatment strategies.

RESEARCH LABORATORIES A) Laboratory of Translational Urological Research Group Leaders Jaume Reventós Joan Morote Andreas Doll Principal Investigators Jaume Reventós (MD, PhD) Joan Morote (MD, PhD) Andreas Doll (PhD) Maite Quiles (PhD) Maria Antònia Arbós (MD, PhD) Research Team Marta García (Graduate Student) Marina Rigau (Graduate Student) Jacques Planas (Clinical Associated Investigator) Enrique Trilla (Clinical Associated Investigator) Carlos Raventós (Clinical Associated Investigator) José Placer (Clinical Associated Investigator) Carlos Salvador (Resident) Jordi Ropero (Resident) Marta Alué (Resident) María Carmen Mir (Resident) Luis Castro (Resident) Geisy Delgado (Resident) Juan M. Bastarós (Resident)

Research Lines in Prostate Cancer (PC)

Development of non-invasive methods for the early detection of PC in biological fluids We have determined the specific, differential proteomic profiles to be found in the urine of patients with PC, as compared to age matched controls, with the ultimate goal of settling on a non-invasive diagnostic tool using urine that could help to circumvent the low specificity of the currentlyused PSA serum measurements. We use liquid chromatography, mass spectrometry and triple quadrupole mass spectrometry (LC/MSMS SRM). The Selected Reaction Monitoring technique (SRM) is an emerging technology that ideally complements the discovery capabilities of shotgun strategies through its unique potential for the reliable quantification of low abundance analytes in complex mixtures, such as urine samples. Using this technique we quantify and detect different selected proteins with high sensitivity and a good chromatographic separation within the complex biologi-

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Identification of the molecular markers of bone metastases in prostate cancer We have developed humanized animal models for metastatic prostate cancer able to mimic the human dissemination of PC cells to bones. We use immunocompromised mice transplanted with human bone. Human prostate cancer cells, which over-express luciferase, are injected, allowing metastasis detection and the continued monitoring of the living animals. This permits the identification of bone metastasis markers, patients with a high risk of recurrence and could define new therapeutic targets that will act to block bone lesions through conventional therapies

Development of improved bone metastasis animal models, very close to the clinics, in order to monitor the process of in vivo metastasis We use an animal model of immunocompromised mice with a transplantation of human bone fragments. Subsequently, human PCa cell lines, over-expressing luciferase, are injected. This allows the detection and monitoring of metastasis in the living animal, since the implanted bone fragments maintain their human microenvironment.

Identification of the molecules responsible for the formation of human bone metastasis By analyzing the changes in protein expression levels by proteomics in the metastases obtained from this animal model, we examine whether the reinjection of bone metastasis cells affects the specificity or phenotype, due to reprogram-

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ming. We attempt to identify the factors that attract human prostate cancer cells to human bone and the mechanisms that are involved in the process of metastasis. This is accomplished by proteomics, using a fluorescence-based differential gel electrophoresis (DIGE) with mass spectrometry (MALDI / TOF), as well as isotope-based techniques (iTRAC etc.) and LC-MS/ MS with SRM.

display significant phenotypic and transcriptional differences from their normal associated fibroblast (NAF) counterparts:

Efficacy of new adjuvant therapies for PC bone metastasis We use intra-tibial injection of prostate cancer cells overexpressing luciferase in immunocompromised balb/c nude mice, a straightforward method to induce local growth in bone marrow. This Bioluminescent Imaging (BLI)based metastasis model allows us a regular monitoring of the development and progression of experimental bone metastases in living animals with high sensitivity. Fewer laboratory animals are needed as due to the noninvasive nature of the methods repetitive measurements can be taken from the same animal, which also increases the reliability of observed effects. This approach will enable us to include the micro-environmental growth support system of the bone for the treatment of metastatic disease.

Currently we are studying the differential response of the monocytic cell line THP1 in front of CAFs/ NAFs (cell-cell adhesion, chemotaxis, gene and protein expression, matrix metalloproteinase activation).

i)

an invasive and migratory phenotype,

ii) expression of epithelial-mesenchymal transition genes and

Molecular analysis of “proliferative inflammatory atrophy” (PIA) as a premalignant condition in prostate cancer development We also focus our research on the potential importance of chronic inflammatory microenvironments as premalignant condition in prostate cancer development. Currently we are studying a common lesion, often associated with inflammation, termed “proliferative inflammatory atrophy” (PIA), which has been postulated to represent an intermediate step between normal tissue and cancer. It may, therefore, serve as a risk factor lesion

Extracellular matrix and inflammatory mechanisms regulated by prostate cancer-associated fibroblasts We are interested in understanding extracellular matrix and inflammatory mechanisms regulated by cancer-associated fibroblasts (CAFs) as promoting forces for prostate cancer progression. Cancer-associated fibroblasts support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, invasion and tumor-enhancing inflammation. Using primary cell cultures, we have learned that prostate CAFs

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for prostate cancer. Using microdissection and microarray technology we have performed paired comparative analysis of gene expression in the following prostatic tissues: benign, PIA, high grade prostatic intraepithelial neoplasia (HGPIN) and cancer lesions. Our objective is to test whether:

i) iii) enhanced expression of inflammatory molecules.

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our data support the notion that PIA may be considered a premalignant lesion, and

ii) we can detect and characterize common transcriptionally altered pathways among these pathologies. These studies have implications for prevention and chemoprevention of prostate cancer.

Decrease of bone mass during androgen deprivation in prostate cancer Decrease of plasmatic levels of testosterone produced by androgen deprivation indirectly alters the mineral bone metabolism and produces loss of bone mass and there is increased the risk of fractures and mortality. This research line contains studies of prevalence of osteoporosis and osteopenia, prediction of the pace of bone mass loss, study of the molecular mediators, specifics diagnosis methods and prevention.

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VHIR Research Activity

VHIR Information

Area 1. Oncology and Genetics

Dyslipemia and metabolic syndrome during androgen deprivation in prostate cancer Cardiovascular mortality is the leading cause of death in patients with prostate cancer and it is believed that androgen deprivation is the intermediate reason. This research line includes studies of metabolic syndrome prevalence and dyslipemia as the most frequent cause of cardiovascular mortality, molecular mediators analysis, early diagnosis methods of cardiovascular risk and prevention.

Cognitive alterations during androgen deprivation in prostate cancer Androgen suppression in prostate cancer patients produces cognitive alterations that are not well studied despite being very important for quality of life. The purpose of this research line is to study the cognitive alteration profile that produces androgen deprivation, the mediators who generate these alterations at central level, early diagnosis and possible forms of prevention.

High grade intraepithelial neoplasia and prostate cancer High grade intraepithelial neoplasia is preneoplasics prostate cancer damage. Nevertheless, it is unknown the molecular mechanisms who define his neoplasic transformation or his persistence as high grade intraepithelial neoplasia isolated. High grade intraepithelial neoplasia detection in a prostatic biopsy entails a repeat biopsy strategy that has not yet been clearly established. This research line integrates the analysis of molecular predictors of neoplasic transformation (genomics and proteomics), the analysis of metabolic image (RNM and spectroscopy) and possible prevention mechanisms of prostate cancer chemoprofilaxis.

B) Laboratory of Gynecological Oncology

Research Lines in Kidney Diseases

Research Focus

Pneumoperitoneum impact of laparoscopic surgery on renal function

We are focused on the understanding of the molecular bases of endometrial and ovarian cancers. In particular, in new molecules involved in progression and dissemination. Our search also includes new molecular biomarkers of precocious diagnosis as well as molecular therapeutic targets.

Analysis of molecular mechanisms of renal oncogeny

Group Leaders Jaume Reventós Anna Ruiz, Antonio Gil Principal Investigators Jaume Reventós (MD, PhD) Anna Ruiz (PhD) Antonio Gil (MD) Jordi Xercavins (MD, PhD) Research Team Marta Llauradó (Graduate Student) Eva Colás (Graduate Student) Núria Pedrola (Graduate Student) Sílvia Cabrera (Clinical Associated Investigator) Assumpció Pérez (Clinical Associated Investigator).

Research Lines in Endometrial Cancer (EC)

Differential gene expression in endometrial cancer: analysis of the roles of transcription factors Runx1 and ETV5 in the progression and dissemination of tumors Previous research in our lab has identified ETV5 and RUNX1 proteins as key determinants of myometrial invasion and dissemination. The main objective of the project is the investigation of the molecular mechanisms regulated by the ETV5 and RUNX1 transcription factors that are responsible for endometrial cancer cell invasion and dissemination. To achieve these objectives we have already developed some

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tools such as endometrial cancer cell lines with ETV5 overexpression or downregulation. The identification of proteins involved in the invasion and dissemination processes will lead to the design of new experimental therapies that will be evaluated (tumor growth, metastasis) in the orthotopic animal models that we have developed for endometrial cancer.

Development of highly-sensitive and highly-efficient molecular tools for the diagnosis of endometrial cancer in uterine aspirates Through a proteomic approach, our lab has identified and validated new robust biomarkers for endometrial carcinoma using human samples obtained from uterine aspirates. Our objective is to develop a reliable tool for screening EC risk using endometrial biopsies, which will enhance sensitivity and specificity, as well as preclude unnecessary hysteroscopy.

Development of endometrial orthotopic murine models to test new therapies We have developed two different orthotopic endometrial cancer murine models that might be useful tools in endometrial cancer preclinical studies. The generation of these murine models for endometrial cancer has been achieved by inoculation of either a tumor cell line or human tumor tissue intra-uterus. The Hec-1A endometrial cancer cell line derived model represents advanced disease and can be used to test the efficacy of antimetastastic drugs. In this model, the follow-up of disease progression is performed using bioluminescence in vivo and correlating bioluminescence ex vivo with metastasis generation. The human tissue derived model maintains the histological pattern and represents local and locally-advanced disease, and can be used to test drugs against specific targets of endometrial cancer.

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Characterization by proteomics and genomics of markers expressed differentially at the EC invasion front and in metastasis Using an orthotopic mouse model we have shown the involvement of RUNX1 in distant metastasis in endometrial cancer. Using proteomics, we have also shown a series of promising proteins involved in myometrial invasion that are differently expressed between cancer and age-matched uterine tissue. Our goal is to identify the gene clusters involved in invasion and metastasis and to study their therapeutic potential using preclinical mouse models.

Research Lines in Ovarian Cancer (OC)

New biomarker identification for ovarian cancer diagnosis, prognosis and drug treatment This project proposes the identification of new molecular biomarkers for the diagnosis and prognosis of ovarian cancer. Microarray technology has been used to identify molecules differentially expressed between tumoral tissue and control samples. The final goal is to identify a panel of biomarkers that can distinguish the presence or absence of ovarian cancer.

Mechanisms of cancer cell dissemination regulated by ETV5 in ovarian cancer Previous research in our lab has identified ETV5 as a protein overexpressed in ovarian cancer. We have characterized its role in ovarian tumour progression. Currently, we are characterizing ETV5 target genes involved in ovarian cancer dissemination through the peritoneal cavity. The final goal is to design new therapies to stop ovarian cancer cell dissemination.

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Molecular pathways involved in ovarian cancer cell dissemination Ovarian cancer disseminates to secondary sites through the peritoneal cavity. Ovarian cancer cells are shed from the ovarian primary tumor, aggregate as spheroids within the abdominal cavity and subsequently attach to the peritoneal wall. We are interested in the identification of those molecular pathways involved in ovarian cell dissemination through the peritoneal cavity in order to design new therapies that target ovarian cancer dissemination and therefore ovarian cancer spread to secondary sites.

Cohort study comparing surgical vs laparoscopic staging and treatment in primary endometrial cancer (clinical stage I)

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C) Laboratory of Cell Signalling and Cancer Progression Group Leader Rosanna Paciucci Principal Investigators Rosanna Paciucci (PhD) Marta Sesé (postdoct, PhD) Neus Marqués (PhD student) Lide Alaña (PhD student) Raul Morales (Technician)

Research Interests Other Clinical Research Projects • Prospective study of validation of sentinel lymph node detection technique in cervical cancer in initial stages. • Prospective study of validation of sentinel lymph node detection technique in vulvar cancer in initial stages. • Prospective comparative study of laparoscopic versus laparotomic radical hysterectomy approach in initial cervical cancer treatment. • Prospective study of validation of extra-peritoneal aortic laparoscopic or robotic assisted lymphadenectomy in locally advanced or bulky cervical cancer. • Prospective comparative study of robotic assisted versus laparoscopic versus laparotomic approaches in endometrial cancer (supported by AATRM, Technology and Medical Research Evaluation Agency).

• Follow-up in women with HPV 16 infection. • CIN and pregnancy. • Follow-up of women treated for H-SIL cervical cancer lesions. • Endocervical sample as a marker of relapse in cervical intraepithelial neoplasia. • Results of neo-adjuvant concomitant chemo-radiotherapy in the treatment of locally advanced cervical cancer.

The primary interests of the group are the identification of new and selective targets for anti-cancer therapy and markers potentially useful to identify aggressive tumors from non-aggressive. Our studies aim to broaden our knowledge on the biology of aggressive cancer cells and shed light on the molecular circuits that are established in aggressive tumors. We have been approaching our aims studying carcinomas of the exocrine pancreas and, more recently, prostate cancer by:

i) • Validation of robotic assisted and laparoscopic aortic extraperitoneal lymphadenectomy in recurrences of gynaecologic malignancies. • Evaluation of robotic surgery in the treatment of gynaecologic malignancies. • Borderline ovarian tumours. • Endoscopic treatment of ovarian cancer in initial stages.

• Pre-neoplasic vaginal and vulvar pathology: VIN and VAIN.

• Ressecability predictive value of laparoscopic approach in advanced ovarian cancer.

• Study of p-16 as a progression marker in cervical pre-invasive lesions.

• Results of neo-adjuvant chemotherapy in the treatment of advanced ovarian cancer.

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the identification of mis-expressed genes in tumors versus normal tissues using different methodologies to analyze gene expression;

ii) the selected genes are being studied for their contribution to tumor aggressiveness through the analysis of phenotypes obtained with the gain-of-function/knockdown in vitro and in vivo; iii) the relevant targets are further studied to understand their function and mechanisms of action on major cellular signaling pathways implicated in cancer progression.

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Figure 21 HeLa cells depleted of Flotillin-1 by specific siRNA were stained for tubulin (green), kinetochores (red) and DNA (blue) and the images captured by confocal microscopy

Specific Lines of Research

In pancreas cancer, we are studying tissue plasminogen activator (tPA) specifically overexpressed in cancer cells (Paciucci et al., 1998). Our findings indicate that tPA activates cell proliferation in vitro and in vivo, in immuno-deficient mice, and contributes to pancreas cancer growth and progression (Díaz et al., 2002). tPA is a serine protease that specifically activates plasminogen to plasmin. In pancreas cancer cells we identified specific binding sites for tPA on the membrane of tumor cells (Díaz et al., 2004.). tPA bound to these receptors induces a proteolytic cascade with the consecutive activation of plasmin and the pro-MMP9. The latter allows heparin-bound EGF to engage the epidermal growth factor receptor (EGFR) producing its activation (Hurtado et al., 2007). This activation event is required for the mitogenic action of tPA on pancreas cancer cells. Using specific substrates to detect the activity of tPA in cancer cells, we are screening for specific inhibitors.

In prostate cancer, we are studying the newly identified protein Prostate Tumor OVerxpressed-1 (PTOV1), a protein well conserved in mammals, flies and simpler eukaryotes, the protein defines a

new family of proteins containing a structurally unknown new domain (PTOV), also encountered in other mammalian proteins (i.e. PTOV2/MED25) (Benedit et al., 2001). PTOV1 is overexpressed in

Figure 22 The image shows the expression of the protein PTOV1 in a prostate carcinoma

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D) Laboratory of Translational Research in Paediatric Cancer pre-malignant lesions of HGPIN and in prostate cancer, where it promotes cell proliferation and invasion (Santamaría et al., 2003). Its detection in prostate biopsy is useful to predict the presence of cancer (Morote et al., 2008). PTOV1 interacts with Flotillin-1 and both proteins are required for cell proliferation (Santamaría et al., 2005). Our results show that Flotillin-1, a major component of lipid-rafts compartments of cellular membranes, is required for Aurora kinase B function in mitosis (Gómez et al., 2010). PTOV1 protein is overexpressed in numerous other human cancers, including bladder and renal cell carcinoma, colon carcinoma, endometrial and ovary carcinomas. We are studying the mechanisms implicated in the PTOV1-promoted cell proliferation and invasion. With this aim in mind, are following three major strategies: • We are studying the interactions of PTOV1 with known cellular proteins implicated in tumor progression obtained by yeast-two-hybrid assays. One such interaction, the PTOV1-

RACK1, stimulates the specific translation of several proteins required for the PTOV1-mediated cell invasion effect. We are now defining the mechanisms implicated in this action. • In the second approach, we are analyzing the functional interaction of PTOV1 with major cellular pathways implicated in cancer progression. We are presently studying the interference of PTOV1 with the signaling of Notch and its importance in prostate cancer establishment and progression. • Finally, we are using the D. melanogaster model to study and confirm the function of the protein PTOV1 in the signaling circuits identified in cancer cells that might be active during development.

In colon cancer, we are studying the contribution of the alteration of protein translation in the expression of genes associated with oncogenesis and progression of carcinomas.

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Group Leaders Josep Roma Josep Sánchez de Toledo Soledad Gallego Principal Investigator Josep Roma (PhD) Research Team Anna Almazán (Researcher in training) Anna Masià (Graduate Student) Pablo Velasco (Graduate Student) Marta Rebull (Technician) Josep Sánchez de Toledo (Clinical Associated Investigator) Soledad Gallego (Clinical Associated Investigator)

Research Focus Malignant neoplasms in children and adolescents are rare diseases with different prognoses and biologic behaviour. The prognosis of childhood cancer has improved considerably in recent decades and survival is approximately 70% in western countries. However, even with the current multimodal therapies, a considerable number of these patients still relapse and eventually die due to progressive or refractory ne-

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oplasms. Consequently, paediatric oncologists need new approaches to improve the efficacy of anticancer therapies. Molecular diagnosis, detection of microdisseminated disease and the search for new therapeutic strategies would help to improve the results of the current treatments of paediatric cancer. Our research group is focused on:

developed the European consensus protocol for the study of MRD in RMS. In neuroblastoma, MDD study is performed by analysing tyrosine hydroxylase gene expression in peripheral blood, and bone marrow using real-time RT-PCR.

• Molecular diagnosis of malignant tumors in children: neuroblastoma, Ewing’s sarcoma, soft tissue sarcomas, nephroblastoma, brain tumors.

• NOTCH pathway and rhabdomyosarcoma: The main objective of this line is to ascertain the effects of NOTCH pathway inhibition using in vitro models as well as a murine xenograft model of RMS in an attempt to establish new molecular targets for treating patients with RMS. Our studies in vitro suggest that inhibition of the NOTCH pathway by gamma-secretase inhibitors produces a significant decrease in the invasiveness of rhabdomyosarcoma cells. Moreover, NOTCH pathway activation seems to play a crucial role in sustaining the rare population of tumorinitiating cells in some neoplasms and it has recently been reported that RMS cells positive for the fibroblastic growth factor receptor 3 (FGFR3) are able to generate tumors from a single cell. The main objective of this line is to identify and separate tumor-initiating cells in rhabdomyosarcoma tumors and characterise the NOTCH pathway in this subpopulation as a possible candidate for the development of targeted therapies.

• Analysis of the prognostic impact of minimal disseminated disease (MDD). • Search for new molecular therapeutic targets in children with cancer.

Research Lines

Molecular diagnosis We systematically perform molecular characterisation using PCR of the most common types of cancer in children i.e. neuroblastoma, soft tissue sarcomas, bone sarcomas, non-Hodgkin lymphomas, nephroblastoma and brain tumors. Our laboratory is the National Reference Centre for Biological Studies in soft tissue sarcomas, receiving tumor material from most of the cases included in the current therapeutic protocols in Spain.

Minimal disseminated disease (MDD) The presence of occult rhabdomyosarcoma cells in peripheral blood and bone marrow is systematically analysed by testing the expression of multiple genes using real-time RT-PCR. In collaboration with Dr. A Rosolen (University of Padua) and Dr. J Stutterheim (AMC, Amsterdam) and under the auspices of the EpSSG (European Pediatric Soft Tissue Sarcoma Group) we have

Therapeutic targets

• Cancer stem cells in paediatric cancers: We attempt to isolate progenitor cancer cells (stem cells) in soft tissue sarcomas, bone sarcomas, neuroblastoma, high-grade non-Hodgkin lymphomas and brain tumors. The analysis of the expression profiles of this putative stem cell population could permit us to identify new therapeutic targets that will overcome resistance to chemotherapy.

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E) Laboratory of Bioengineering and Cellular Interactions Group Leaders Maria Antònia Arbós María Teresa Quiles Manel Armengol Research Team Maria Antònia Arbós (MD, PhD, Researcher) María Teresa Quiles (PhD, Researcher) Manuel Armengol (MD, PhD, Clinical Associated Investigator) Manuel López-Cano (MD, PhD, Clinical Associated Investigator) Marta Rebull (Technician)

Research Focus Our laboratory is interested in the role of cell-extracellular matrix (ECM) interactions in the fields of tissue repair and inflammation, with a special focus on abdominal wall defects. Our studies are mostly based on patient-derived tissue samples and primary cells, as well as on surgically-induced

Figure 23 Ultrastructural appearance of a primary fibroblast derived from the fascia of an incisional hernia patient, displaying autophagic vacuoles, autophagolysomelike structures, multilayered lamellar and fingerprint profiles and mitochondrial swelling

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models. Moreover, soft-tissue repair devices are being investigated by means of “in vitro” and “in vivo” experimental models.

Research Lines

Extracellular matrix, inflammation and abdominal wall The reconstruction of abdominal wall defects is the problem with which surgeons are confronted most often. These defects may have an acute (trauma, cancer, infections) or chronic (hernia pathology) origin. Despite technical advances, both physiopathology and treatment of the disease remains controversial, and further knowledge is needed.

Basic Research We are trying to unravel the cellular and molecular mechanisms triggering incisional hernia (IH) formation. IH often occurs following laparotomy and can be a source of serious problems. There is evidence that a biological cause may underlie its development, but the mechanistic link between the local tissue microenvironment and tissue rupture is lacking. We have found de-regulated proteolytic and molecular inflammatory signaling in the abdominal wall tissues (fascia

and skeletal muscle) of IH patients. Also, we have identified an ongoing complex interplay of cell death induction, aberrant fibroblast function and tissue loss in IH tissues, which eventually may give rise to tissue rupture in vivo. Currently, we are investigating changes in subsets of genes from IH-derived primary fibroblasts. Overall, these studies may provide a molecular mechanistic framework for better understanding IH formation, and reveal new molecular biomarkers and potential therapeutic targets. Current surgical practice supports the use of permanent prosthetic meshes as the best method for hernia repair. Still, no material has gained a preference for universal use and numerous complications are still reported. The understanding of cell-substrate interactions is fundamental for the improvement of tissue repair and regenerative medicine. We analyze different soft-tissue repair devices. Our approach includes surface and biomechanical characterization, as well as the analyses of host-implant interactions, using both “in-vitro” (primary fibroblasts derived from control and IH patients) and “in-vivo” (rats) experimental models. Our ultimate goal is to impact on the development of new tailored implants based on fibroblasts and biomimetic materials, which are clinically useful to repair damaged organs.

Clinical Research

Simulation and virtual reality In collaboration with Politechnic University of Catalonia and Rovira-Virgili University: • Virtual reality model of inguinal hernia: Educational purposes: simulator of inguinal area; Clinical Research purposes: protective mechanisms against inguinal hernia formation. • Virtual reality model of the whole abdominal wall: Educational purposes: simulator of abdominal wall; Clinical Research purposes: abdominal wall mechanical behavior. • Virtual reality model of synthetic mesh contraction: Clinical/Translational research of physical contraction of synthetic mesh and its influence on hernia recurrence.

Hernia occurrence prevention • Parastomal hernia prevention with synthetic mesh by laparoscopic approach: clinical study. • Incisional hernia prevention with synthetic mesh: experimental study.

Surgical devices applied in abdominal wall surgery In collaboration with Politechnic University of Catalonia and RoviraVirgili University: • 3D surgical vision. • Surgical sutures – European Project.

Figure 24 Representative vimentin-stained primary fibroblasts derived from the fascia of incisional hernia patients, grown on polypropylene meshes

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F) Laboratory of Stem Cells and Cancer Group Leader Jordi Pétriz Principal Investigator Jordi Pétriz (PhD) Research Team Noelia Purroy (MD) Verónica Pons (MD) Jana Balbuena (Graduate Student) Gisela Pachón (PhD) Anna Esquerra (Technician)

Research Focus The focus of the laboratory are the basic mechanisms that regulate Side Population stem cells. Stem cells reside in most tissues in a quiescent state, but rapidly become activated to both repair and regenerate the adjacent tissues. We are studying several genes involved in different aspects of stem cell activation, including some that encode for ABC transporters, and others that regulate self-renewal and differentiation. We are also interested in multidrug resistance and we use functional flow cytometry to examine the changes that occur in the accumulation of drugs into the cells over time.

Research Lines

Murine xenograft models for human ovary, testis, prostate, pancreas and colon cancers: Detection of bone marrow infiltration by Side Population cells We are using xenograft models to examine the genes that regulate bone marrow infiltration in cancer. We isolate Side Population (SP) stem cells from normal tissue and from tumor cells, mainly for cell culture experiments as well as for transplantation in murine xenograft models and for the independent analysis and compari-

son of gene expression. We also develop non immortalized and non transformed cell models from stem cells with SP phenotype. We study the gene expression profiles to test the hypothesis that the expression of certain genes are associated with an immature cell phenotype as well as with a phenotype of tumor stem cell. We map the signaling pathways, self-renewal, and differentiation of cell SP, as well as stem cell miRNAs and ABC transporters and the mechanisms by which gene expression and resistance to chemotherapy are regulated. We study the presence of SP cells in human solid tumors, orthotopically implanted in athymic mice as well as their dissemination and infiltration in different tissues (i.e. bone marrow), with and without the expression of the green fluorescent protein as a marker gene.

Development of a new Cytomics Platform for the study of stem cell systems Cancer is increasingly being viewed as a stem cell disease, both in its propagation by a minority of cells with stem cell-like properties and in its possible derivation from normal tissue stem cells. Recent findings suggest that stem cell biology may be more complex than originally anticipated and a subset of stem cells may alter their function in a manner that is more plastic and dynamic than previously thought. Considerable progress has been made by studying stem cell function based on the high efflux of fluorescent dyes. ABCG2, a half-transporter that belongs to the ATP binding cassette superfamily, is expressed in primitive stem cells, and is responsible for the formation of a Side Population (SP) with a Hoechst 33342 (Ho324) fluorescent profile blocked in the presence of multidrug reversal agents. SP cells are present in a wide variety of tissues and ABCG2 expression is believed

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to represent a common molecular mechanism for stem cells possessing multi-organ plasticity. The majority of SC enrichment protocols rely on fluorescence activated cell sorting (FACS), which allows cells to be selected based on the expression of a set of cell surface proteins. ABCG2 gene is an important determinant of the SP, and it might serve as a marker for stem cells from various sources. Cell sorting for the expression of ABC transporters provides a new strategy for stem-cell purification that could be used for cells from different organ sources. We also study single-cell gene expression profiling to relate the expression of specific genes to a particular cellular phenotype. FACS-based isolation of SP cells, in association with the mRNA expression analysis of gene expression in highly purified preparations of SC subsets on the basis of ABCG2 expression, provides important insights in stem cell biology. We apply the Cytomics Platform for the detection and isolation of SP cells from: • Adipose tissue (in collaboration with Dr. Simó, MD, PhD, FIR-HUVH). • Brain tumors (in collaboration with Dr. Sáez Castresana, MD, PhD, CIFA, University of Navarra). • Xenograft models (in collaboration with Dr. Capellà, MD, PhD, IDIBELL). • Peripheral blood and bone marrow from leukemic patients (in collaboration with Dr. Prósper, MD, PhD, CIMA and with Dr. Bosch, MD, PhD, HUVH).

Flow cytometry counting of CD34+ cells Blood formation is sustained by a population of undifferentiated and metabolically quiescent hematopoietic stem cells (HSC) mainly found in the bone marrow. HSC

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remain in the G0 compartment of the cell cycle, are able to self-renew, and differentiate into progenitors of all hematopoietic lineages. Their self-renewal and differentiation are regulated by a number of cytokines. A subset of hematopoietic cells presumably containing HSC express the cell surface antigen CD34; CD34+ purified fractions are enriched in colony-forming units and long-term culture initiating cells, whereas CD34- fractions are depleted. CD34+ cells obtained from either bone marrow or peripheral blood are commonly used in hemopoietic stem cell transplantation. They can be mobilized from bone marrow into peripheral blood by means of chemotherapy and/or cytokine stimulatory treatments, then collected for use in malignant disease therapy, HSC expansion studies, and gene therapy. The accurate enumeration of CD34+ cells has been shown to be important for predicting the success of engraftment after transplantation, as it can assure the presence of sufficient numbers of progenitor cells remaining in the graft. We have developed a new flow cytometry protocol for CD34+ progenitor counting in collaboration with the Quality Assessment of Haematopoietic Stem Cell Grafts Committee from The European Group for Blood and Marrow Transplantation (EBMT).

CURRENT RESEARCH PROJECTS PI: Joan Morote Robles Análisis del perfil transcripcional genómico en la Atrofia Proliferativa Inflamatoria (PIA) como lesión precursora del cáncer de próstata humano Funding Agency: Fondo de Investigación Sanitaria Reference: PI070536 Funding: 124,630 € Duration: 2008 to 2010

PI: Soledad Gallego Melcón Identificación de nuevas dianas terapéuticas en el rabdomiosarcoma: efectos de la silenciación de las vías de señalización celular de NOTCH, Hedgehog y RAS en esta neoplasia Funding Agency: Asociación Española Contra el Cáncer Reference: AECC_CAT_01_2007 Funding: 18,000 € Duration: 2008 to 2010

PI: Joan Morote Robles Identificación de marcadores proteómicos en orina para la detección precoz del cáncer de próstata: Convocatoria “Pedro Cifuentes Díaz” 2007 Funding Agency: Fundación Investigación Urologia Reference: FIU_01_2007 Funding: 36,300 € Duration: 2008 to 2010

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PI: Jordi Petriz González Desarrollo de una Plataforma de Citómica para el estudio funcional de células madre Funding Agency: Fondo de Investigación Sanitaria Reference: CP07/00098 Funding: 42,000 € Duration: 2008 to 2010

PI: Rosanna Paciucci Barzanti Estudio de la modulación de la proliferación y progresión tumoral medida por PTOV1; interacción con las rutas de IGF-1, Notch y Wnt y expresión en tissue-arrays de tumores Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2008-03936 Funding: 181,500 € Duration: 2009 to 2011

PI: Jaume Reventós Puigjaner Caracterización molecular de los procesos de infiltración y diseminación tumorales y desarrollo de metástasis en cáncer de endometrio. Papel del RUNX1 en la promoción de las metástasis Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2008-03996 Funding: 96,800 € Duration: 2009 to 2011

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PI: Jordi Petriz González Estudio de la contribución de las células de la Side Population en la infiltración de la médula ósea en modelos de xenotrasplante murino de tumores humanos de ovario, testículo, próstata, páncreas y colon Funding Agency: Fondo de Investigación Sanitaria Reference: PI081132 Funding: 153,791 € Duration: 2009 to 2011

PI: Rosanna Paciucci Barzanti Estudio de la modulación de la proliferación y progresión tumoral medida por PTOV1; interacción con las vías de transducción de señal mediadas por IGF-1, Notch y Wnt y expresión en tissue arrays de tumores Funding Agency: Fondo de Investigación Sanitaria Reference: PI080547 Funding: 171,941 € Duration: 2009 to 2011

PI: Andreas He Doll Identificación de moléculas responsables de metástasis óseas en un modelo de ratones SCID humanizados Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00496 Funding: 96,800 € Duration: 2010 to 2012

PI: Jaume Reventós Puigjaner Identificación de marcadores proteómicos en orina para la detección precoz del cáncer de próstata Funding Agency: Ministerio de Ciencia e Innovación Reference: CIT-300000-2009-002 Funding: 386,420 € Duration: 2010 to 2010

PI: Josep Roma Castanyer Efectos de la silenciación de la vía de celular de Notch en el rabdomiosarcoma in vivo Funding Agency: Asociación Española Contra el Cáncer Reference: AECC-JB2009/02 Funding: 18,000€ Duration: 2010 to 2012

PI: Rosanna Paciucci Barzanti Oncogénesis mediada por reprogramación traduccional en cáncer Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMM-2010-07 Funding: 24,000 € Duration: 2010 to 2013

PI: Soledad Gallego Melcón Name Notch patway inhibition as therapeutic target in rhabdomyosarcoma Funding Agency: Fundació La Marató de TV3 Reference: MARATV3/2010/101310 Funding: 179,720 € Duration: 2010 to 2013

PI: Jaume Reventós Puigjaner RTICC - Red Temática de Investigación Cooperativa de Cáncer Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0020/0058 Funding: 293,652.32 € Duration: 2007 to 2011

PI: Jaume Reventós Puigjaner Oncología Translacional Funding Agency: AGAUR Reference: 2009 SGR 487 Funding: 57,200 € Duration: 2010 to 2013

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PUBLICATIONS (Impact Factor: 121.380) Andriole GL, Bostwick DG, Brawley OW, Gomella LG, Marberger M, Montorsi F, Pettaway CA, Tammela TL, Teloken C, Tindall DJ, Somerville MC, Wilson TH, Fowler IL, Rittmaster RS, Chechile Toniolo G, Morote J, et al. «Effect of dutasteride on the risk of prostate cancer». N Engl J Med 2010 Apr 1; 362 (13): 1192-202.  IF: 47.050. Armengol G, Canellas A, Álvarez Y, Bastida P, Toledo JS, Pérez-Iribarne M del M., Camos M, Tuset E, Estella J, Coll MD, Caballín MR, Knuutila S. Genetic changes including gene copy number alterations and their relation to prognosis in childhood acute myeloid leukemia. Leuk Lymphoma 2010 Jan; 51 (1): 114-24.  IF: 2.397. Cabrera S, Gil-Moreno A. «Micrometastases in para-aortic lymph nodes in advanced cervical cancer patients - Are a true predictor of recurrence at this level?». Gynecol Oncol 2010 Dec 27.  IF: 3.733.

of benign prostate hyperplasia in a canine model». Prostate 2010 Sep 15; 70 (13): 1402-12.  IF: 3.081. Gallego S, Llort A, Gros L, Bueno J, Moreno A, Nieto J, Sánchez de Toledo J. «Post-transplant lymphoproliferative disorders in children: the role of chemotherapy in the era of rituximab». Pediatr Transplant 2010 Feb; 14 (1): 61-6.  IF: 1.573. Gómez V, Sesé M, Santamaría A, Martínez JD, Castellanos E, Soler M, Thomson TM, Paciucci R. «Regulation of Aurora B kinase by the lipid raft protein Flotillin-1». J Biol Chem 2010 Jul 2; 285 (27): 20683-90.  IF: 5.328. Lavaggi ML, Cabrera M, Aravena M de L, Olea-Azar C, López de Cerain A, Monge A, Pachón G, Cascante M, Bruno AM, Pietrasanta LI, González M, Cerecetto H. «Study of benzo[a]phenazine 7,12-dioxide as selective hypoxic cytotoxin-scaffold. Identification of aerobic-antitumoral activity through DNA fragmentation». Bioorg Med Chem 2010 Jun 15; 18 (12): 4433-40.  IF: 2.822.

Casas F, Borras JM, Ferrer F, Guanyabens N, Gutiérrez del Pozo R, León C, López Torrecilla J, Mellado B, Morote J, Puig M, Ribal MJ, Ruscalleda C, Serra A, Valls V, Zapatero A. «Evidence-based consensus recommendations to improve the quality of life in prostate cancer treatment». Clin Transl Oncol 2010 May; 12 (5): 346-55.  IF: 1.146. Cebrecos I, Córdoba O, Deu J, Xercavins J, Rubio IT. «Can we predict local recurrence in breast conserving surgery after neoadjuvant chemotherapy?». Eur J Surg Oncol 2010 Jun; 36 (6): 528-34.  IF: 2.564. Córdoba O, Llurba E, Cortés J, Sabadell MD, Lirola JL, Ferrer Q, Xercavins J. «Complete pathological remission in a patient with hormone-receptor positive and c-erbB-2 expression-negative breast cancer treated with FAC chemotherapy during pregnancy». Tumori 2010 Jul-Aug; 96 (4): 629-32.  IF: 0.863.

Franco-Camps S, Cabrera S, Pérez-Benavente A, Diaz-Feijoo B, Bradbury M, Xercavins J, GilMoreno A. «Extraperitoneal laparoscopic approach for diagnosis and treatment of aortic lymph node recurrence in gynecologic malignancy». J Minim Invasive Gynecol 2010 Sep-Oct; 17 (5): 570-5.  IF: 1.920. Gallardo-Arrieta F, Doll A, Rigau M, Mogas T, Juanpere N, García F, Morote J, Nuñez F, Abal M, Lloreta J, Reventós J. «A transcriptional signature associated with the onset

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Mancebo G, Gil-Moreno A, Vergés R, Martínez-Palones JM, Checa MA, Carreras JM, Giralt J, Xercavins J. «Out-of-protocol concurrent use of cisplatin and radiation therapy in locally advanced cervical cancer: feasibility and survival». Eur J Gynaecol Oncol 2010; 31 (1): 18-22.  IF: 0.614. Martín A, Soler-Palacín P, Español T, Dapena JL, Urrutia E, Navarro M, Álvez F, Figueras C. [Spanish paediatric infectious diseases society consensus document on the treatment of fungal infections based on the immune response.] An Pediatr (Barc) 2010 Dec; 73 (6): 362.e1-8.  IF: 0.363. Morales-Barrera R, Valverde C, Rodón J, Pérez J, Maldonado X, Suárez C, Trilla E, Carles J. «Bilateral testicular germ cell tumours: a single hospital experience». Clin Transl Oncol 2010 Apr; 12 (4): 299-302.  IF: 1.146.

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Morote J, Amo J del, Borque A, Ars E, Hernández C, Herranz F, Arruza A, Llarena R, Planas J, Viso MJ, Palou J, Raventós CX, Tejedor D, Artieda M, Simón L, Martínez A, Rioja LA. «Improved prediction of biochemical recurrence after radical prostatectomy by genetic polymorphisms». J Urol 2010 Aug; 184 (2): 506-11.  IF: 4.016. Morote J, Planas J, Ramírez C, Gómez E, Raventós CX, Placer J, Catalán R, Torres IM de. «Evaluation of the serum testosterone to prostate-specific antigen ratio as a predictor of prostate cancer risk». BJU Int 2010 Feb; 105 (4): 481-4.  IF: 2.865. Morote J, Rigau M, García M, Mir C, Ballesteros C, Planas J, Raventós CX, Placer J, de Torres IM, Reventós J, Doll A. «Behavior of the PCA3 gene in the urine of men with high grade prostatic intraepithelial neoplasia».World J Urol 2010 Dec; 28 (6): 677-80.  IF: 2.629. Oriol A, Vives S, Hernández-Rivas JM, Tormo M, Heras I, Rivas C, Bethencourt C, Moscardo F, Bueno J, Grande C, Potro E del, Guardia R, Brunet S, Bergua J, Bernal T, Moreno MJ, Calvo C, Bastida P, Feliu E, Ribera JM. «Outcome after relapse of acute lymphoblastic leukemia (ALL) in adult patients included in four consecutive riskadapted trials from the PETHEMA Study Group». Haematologica 2010 Apr; 95 (4): 589-96.  IF: 6.416.

Orsola A, Cecchini L, Raventós CX, Trilla E, Planas J, Landolfi S, Torres I de, Morote J. «Risk factors for positive findings in patients with high-grade T1 bladder cancer treated with transurethral resection of bladder tumour (TUR) and bacille Calmette-Guerin therapy and the decision for a repeat TUR». BJU Int 2010 Jan; 105 (2): 202-7.  IF: 2.865. Pinos T, Barbosa-Desongles A, Hurtado A, Santamaría-Martínez A, Torres I de, Reventós J, Munell F. «Human SHBG mRNA Translation Is Modulated by Alternative 5’-Non-Coding Exons 1A and 1B». PLoS One 2010 Nov 4; 5 (11): e13844.  IF: 4.351. Quiles MT, Arbós MA, Fraga A, Torres IM de, Reventós J, Morote J. «Antiproliferative and apoptotic effects of the herbal agent Pygeum africanum on cultured prostate stromal cells from patients with benign prostatic hyperplasia (BPH)». Prostate 2010 Jul 1; 70 (10): 1044-53.  IF: 3.081. Quintar AA, Doll A, Leimgruber C, Palmeri CM, Roth FD, Maccioni M, Maldonado CA. «Acute inflammation promotes early cellular stimulation of the epithelial and stromal compartments of the rat prostate». Prostate 2010 Aug; 70 (11): 1153-65.  IF: 3.081. Raventós CX, Orsola A, Torres I de, Cecchini L, Trilla E, Planas J, Morote J. «Preoperative Prediction of Pathologically Insignificant Prostate Cancer in Radical Prostatectomy Specimens: The Role of Prostate Volume and the Number of Positive Cores». Urol Int 2010; 84 (2): 153-158.  IF: 0.902.

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Rigau M, Morote J, Mir MC, Ballesteros C, Ortega I, Sánchez A, Colas E, García M, Ruiz A, Abal M, Planas J, Reventós J, Doll A. «PSGR and PCA3 as biomarkers for the detection of prostate cancer in urine». Prostate 2010 Dec 1; 70 (16): 1760-7.  IF: 3.081. Rubio IT, Aznar F, Lirola J, Peg V, Xercavins J. «Intraoperative assessment of sentinel lymph nodes after neoadjuvant chemotherapy in patients with breast cancer». Ann Surg Oncol 2010 Jan; 17 (1): 235-9.  IF: 4.130. Schulman CC, Irani J, Morote J, Schalken JA, Montorsi F, Chlosta PL, Heidenreich A. Testosterone Measurement in Patients with Prostate Cancer». Eur Urol 2010 Jul; 58 (1): 65-74.  IF: 7.667. Torre J de la, Sabadell MD, Rojo F, Lirola JL, Salicru S, Reventós J, Ramon y Cajal S, Xercavins J. «Cyclo-oxygenase type 2 is dysregulated in breast ductal carcinoma in situ and correlates with poor outcome». Eur J Obstet Gynecol Reprod Biol 2010 Jul; 151 (1): 72-6.  IF: 1.582. Wartenberg M, Richter M, Datchev A, Gunther S, Milosevic N, Bekhite MM, Figulla HR, Arán JM, Petriz J, Sauer H. «Glycolytic pyruvate regulates P-Glycoprotein expression in multicellular tumor spheroids via modulation of the intracellular redox state». J Cell Biochem 2010 Feb 1; 109 (2): 434-46.  IF: 2.935.

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AREA 1 ONCOLOGY AND GENETICS

1.17 Experimental Hematology

Group Leader Francesc Bosch Albareda Tel. 93 27 46 00 (ext. 4946) [email protected] Researchers Pablo Abrisqueta Costa Pere Barba Suñol David Beneitez Pastor Javier Bueno Aribayos Marta Crespo Maull Mercedes Gironella Mesa Andrés López Hernández Isabel Massagué Ferrer Margarita Ortega Blanco Carlos Palacio García Verónica Pons Escoll David Valcárcel Ferreiras Maria Teresa Vallespí Solé Researchers in Training Eva Calpe Berdiel Anny Coro Jaramillo Rodríguez Laura López Andreoni Oriol Olivé Noguer Noelia Purroy Zuriguel Esther Sancho Ponce Nursing, Technical and Administrative Staff Elisenda Alonso Arias

OBJECTIVES The main objectives of the Experimental Hematology group are the study of pathogenesis mechanisms and the progression of lymphoid neoplasies, as well as studying ex-vivo effects and ways of action of new experimental therapeutic regimens.

RESEARCH LINES Pathogenesis mechanisms of Chronic Lymphocytic Leukemia (CLL) Exploration of pathogenesis mechanisms in CLL with two objectives: identifying the cell of origin of the disease and the genetic or epigenetic mechanisms which cause the lack of growth regulation and cellullar proliferation.

progression factors and mechanisms in Chronic Lymphocytic Leukemia Studying molecular and microenvironmental mechanisms related to clinical and biological progression of the disease.

22010 Impact Factor:

109.306

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Figure 25 BCR signaling in B cells with ectopic ZAP-70 expression. After IgM stimulation ZAP-70 translocates from the cytoplasm to the membrane, whereas IgD stimulation does not affect ZAP-70 localization

PUBLICATIONS (Impact Factor: 109.306)

CURRENT RESEARCH PROJECTS Ex-vivo assessment of new therapeutic proposals in lymphoproliferative syndromes Ex-vivo assessment of the response to new treatments taking into account the icroenvironmental protection that neoplastic cells find at lymphoidtissues. Investigation of action mechanism and affected signaling pathways.

Immunologic modulation and response to new treatments in myelodysplastic syndromes Studying the 5q- syndrome and its response to treatment with immunomodulatory agents. Studying the effect in different lymphoid populations.

PI: Andrés López Hernández Estudio fase II prospectivo, abierto, multicéntrico de Gemcitabina y Oxaliplatino + Rituximab en pacientes con linfomas agresivos (difuso de células grandes B y del manto) en recaída o resistencia no subsidiarios de ser sometidos a quimioterapia intensa Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00140 Funding: 751,410 € Duration 2009 to 2011

PI: Francesc Bosch Albareda Biología y valor prónostico del comportamiento celular proliferante en la leucemia linfática crónica Funding Agency: Fondo de Investigación Sanitaria Reference: PI08/0211 Funding: 116,638.88 € Duration: 2009 to 2011

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Antón A, López-Iglesias AA, Tórtola T, RuizCamps I, Abrisqueta P, Llopart L, Marcos MA, Martínez MJ, Tudó G, Bosch F, Pahissa A, Anta MT de, Pumarola T. Selection and viral load kinetics of an oseltamivir-resistant pandemic influenza A (H1N1) virus in an immunocompromised patient during treatment with neuraminidase inhibitors. Diagn Microbiol Infect Dis 2010 Nov; 68 (3): 214-9.  IF: 2.451.

Figure 26 Signaling through the B Cell Receptor (BCR) in Chronic Lymphocytic Leukemia (CLL) cells with positive ZAP-70 expression

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Area 1. Oncology and Genetics

Gutiérrez-García G, Colomo L, Villamor N, Arenillas L, Martínez A, Cardesa T, GarcíaHerrera A, Setoain X, Rodríguez S, Ghita G, Abrisqueta P, Gine E, Bosch F, Campo E, Montserrat E, López-Guillermo A. Clinicobiological characterization and outcome of primary nodal and extranodal diffuse large B-cell lymphoma in the rituximab era. Leuk Lymphoma 2010 Jul; 51 (7): 1225-32.  IF: 2.397. Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, Grunhagen U von, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jager U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Buhler A, Winkler D, Zenz T, Bottcher S, Ritgen M, Mendila M, Kneba M, Dohner H, Stilgenbauer S, Hillmen P, Dighiero G, Bosch F, Brugiatelli M, Pigeot I. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010 Oct 2; 376 (9747): 116474.  IF: 30.758.

Figure 27 Lack of ZAP-70 expression in normal B lymphocytes (lymph node and peripheral blood)

Elorza I, Palacio C, Dapena JL, Gallur L, Toledo JS de, Díaz de Heredia C. Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia. Haematologica 2010 Jun; 95 (6): 936-41.  IF: 6.416. Fernández de Larrea , Martínez C, Gaya A, López-Guillermo A, Rovira M, FernándezAvilés F, Lozano M, Bosch F, Esteve J, Nomdedeu B, Montserrat E, Carreras E. Salvage chemotherapy with alternating MINE-ESHAP regimen in relapsed or refractory Hodgkin’s lymphoma followed by autologous stemcell transplantation. Ann Oncol 2010 Jun; 21 (6): 1211-6.  IF: 5.647.

Fernández V, Salamero O, Espinet B, Solé F, Royo C, Navarro A, Camacho F, Bea S, Hartmann E, Amador V, Hernández L, Agostinelli C, Sargent RL, Rozman M, Aymerich M, Colomer D, Villamor N, Swerdlow SH, Pileri SA, Bosch F, Piris MA, Montserrat E, Ott G, Rosenwald A, López-Guillermo A, Jares P, Serrano S, Campo E. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 2010 Feb 15; 70 (4): 1408-18.  IF: 7.543. Giné E, Martínez A, Villamor N, López-Guillermo A, Camos M, Martínez D, Esteve J, Calvo X, Muntañola A, Abrisqueta P, Rozman M, Rozman C, Bosch F, Campo E, Montserrat E. Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia (“accelerated” chronic lymphocytic leukemia) with aggressive clinical behavior. Haematologica 2010 Sep; 95 (9): 1526-33.  IF: 6.416.

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Klein U, Lia M, Crespo M, Siegel R, Shen Q, Mo T, Ambesi-Impiombato A, Califano A, Migliazza A, Bhagat G, Dalla-Favera R. The DLEU2/miR-15a/16-1 cluster controls B cell proliferation and its deletion leads to chronic lymphocytic leukemia. Cancer Cell 2010 Jan 19; 17(1): 28-40.  IF: 25.288. Montesinos P, González JD, González J, Rayon C, Lisa E de, Amigo ML, Ossenkoppele GJ, Penarrubia MJ, Pérez Encinas M, Bergua J, Deben G, Sayas MJ, Serna J de la, Ribera JM, Bueno J, Milone G, Rivas C, Brunet S, Lowenberg B, Sanz M. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with alltrans-retinoic Acid and anthracycline-based chemotherapy. J Clin Oncol 2010 Aug 20; 28 (24): 3872-9.  IF: 17.793. Zini G, Bain B, Bettelheim P, Cortez J, Onofrio G d’, Faber E, Haferlach T, Kacirkova P, Lewandowski K, Matutes E, Maynadie M, Meletis J, Petersen BL, Porwit A, Terpos E, Tichelli A, Vallespí T, Woessner S, Bennett J, Bene MC. A European consensus report on blood cell identification: terminology utilized and morphological diagnosis concordance among 28 experts from 17 countries within the European LeukemiaNet network WP10, on behalf of the ELN Morphology Faculty. Br J Haematol 2010 Nov; 151 (4): 359-64.  IF: 4.597.

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AREA 1 ONCOLOGY AND GENETICS

1.18 Molecular Pathology

Group Leader Santiago Ramón y Cajal Agüeras Tel. 93 274 68 09 [email protected] Researchers Elena Allende Monclús Josep Castellví Vives Mª Carme Dinares Fernández Ángel García Jiménez Javier Hernández Losa Carmela Iglesias i Felip Stefania Landolfi Elena Antima Martínez Saez María Ángeles Montero Fernández Arantxa Ortega Aznar Carlos Parada Cobo Santiago Ramón y Cajal Agüeras Carmen Ruiz Marcellán Natalia Tallada Serra Inés de Torres Ramírez Researchers in Training Trond Aasen Alba Martínez Díaz Berta Pons López Cristina Teixido Febrero María A Vázquez Sánchez Nursing, Technical and Administrative Staff Berta Domínguez Pascuet Isabel Espinosa Sanahuja Laura Fernández Cabré Roso Marès Pagès Teresa Moliné Marimón César Javier Sevillano Aguilera María Rosa Somoza López de Haro

OBJECTIVES Clinical Research

Basic research

• Characterize potential tumor markers that have a role as prognostic factors in cancer.

• Study of the factors which control cap dependent and independent translation in tumors.

• Study the cell signaling pathway and the role of the 4E-BP1 and eIFs factors in cancer.

• Studying the mechanisms controlling senescence at the cellular level.

• Study of senescence genes and their biochemical pathways in human tumors.

• Study the role of gap junctions in tumour biology and malignant progression.

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Figure 28 Overexpression of RSK4 induces mechanisms of cellular senescence including X-gal staining

RESEARCH LINES Study of Cell Signalling pathway in human tumors. Identification of funnel factors Santiago Ramón y Cajal Agüeras We have characterized the levels of activation in Cell Signalling in a spectrum of solid tumors and correlated the levels of various factors, including mTOR and downstream proteins (p70S6K, S6, 4EBP1, eIF4E) with prognosis and grade of malignancy. Also, the factors involved in controlling the translation cap dependent and independent in malignant tumors are being characterized at the molecular level.

Study of gene expression of senescence in human tumors Santiago Ramón y Cajal Agüeras The expression of mARN genes identified by Dr.R. Bernards has been studied in normal and tumor tissue of cancer patients. This study identifies for the first time, RSK4 and KIAA0828 genes as genes whose role may be relevant in cancer. The expression of these genes is being studied in protein by Western blot and

immunohistochemistry. We are also characterizing the biochemical pathways where these genes may be involved.

Identification of molecular targets associated with tumor progression and therapy resistance in colorectal carcinoma Santiago Ramón y Cajal Agüeras Studying colorectal cancer mechanisms of action of the central signal transduction pathways, identify potential molecular alterations that can be used as therapeutic targets and characterize the degree of genetic instability.

Study of new genes involved in proliferation Matilde Lleonart Pajarín Searching for new proliferative genes/tumor suppressor genes is being performed at our laboratory by carring out genetic screens. By the use of retroviral vectors as carriers of cDNA libraries (formed by mRNA from murine embryonic stem cells), primary cells are infected and screening for those clones able to bypass senescence are selected for further characteri-

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zation. The marked morphological heterogeneity observed in several tumorigenic processes, support the hypothesis that several cancers have their origin in a stem cell. It is believed that genes expressed by embryonic stem cells, may play an important role in the tumorigenic mechanism. This project unravels the effect of immortal genes existing in embryonic stem cells, when they are forced to be expressed in primary and thereby mortal cells. These immortal genes are future candidate markers in tumors with potential prognosis value. The novel genes discovered are being analyzed in biopsies from patients with different kinds of tumors collected at the Pathology Department of the Vall d´Hebron Hospital.

Genomic transcriptional profile analysis in proliferative inflammatory atrophy (PIA) as a possible precursor of human prostate cancer Inés de Torres Ramírez To analyse transcriptional profiles of normal, PIA (proliferative inflammatory atrophy), PIN (prostatic intraepithelial neoplasia) and tu-

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moral prostate using microarrays of selected tumoral tissue of prostatectomy specimens, in order to characterize gene expression modifications in prostate cancer versus PIN and PIA. To analyse the biological response in tumoral / non-tumoral and coculture them with monocytes in order to study transcriptional profile changes. From all the data obtained, overexpressed / underexpressed genes are being identified and validated. Stromal and inflammatory genes will also be explored for their potential use as early markers for prostatic cancer and their ability to identify PIA as a precursor lesion. (Prostate Research Traslational Unit.)

Long-term mast cell stabilization downregulates mucosal microinflammation in the jejunum of diarrhea-prone irritable bowel syndrome (IBS) Inés de Torres Ramírez Study of the effect of mast-cell stabilization on mucosal inflammation and clinical response. Immunohistochemistry analysis of microinflammation (mast cells, intraepithelial lymphocytes and eosinophils) in Irritable Bowel Syndrome (IBS). Biological inflammation was evaluated in pooled biopsies by quantitative real time PCR to analyze the expression of preselected genes implicated in innate immunity [Toll-like receptors (TLR) and defensins (DEF)], mast cell activation and growth and neuronal regulation. Mucosal eosinophils show restrained activation in the jejunum of diarrhea –prone irritable bowel syndrome patients. Pharmacological stabili-

zation of mucosal mast cells effectively reduces pro-inflammatory gene expression profiles in the jejunal mucosa of D-IBS patients and concomitantly improves clinical manifestations. (Digestive Disease Research Unit.)

Study of PTOV1 modulation in tumor proliferation and progression: Interaction with IGF1 pathways. Notch and Wnt expression in TMAs of tumors Inés de Torres Ramírez To evaluate the expression (nuclear and cytoplasmatic) of PTOV1, Notch and Wnt on TMAs in c different histological types of carcinomas with low and high grades of malignancy. To correlate the immunoexpression with classical parameters of tumor behaviour: tumoral size, grade of malignancy, vascular permeation, lymph node metastasis in each histological subtype and demonstrated the role of PTOV1 as predictive molecular marker in carcinomas. (Research Biomedical Unit.)

Involvement of the human Hepatitis A Viral Receptor (hHAVcr-1) in renal cancer development and progression. Value as a diagnostic and prognostic biomarker in renal carcinomas Inés de Torres Ramírez We have postulated that hHAVcr-1 might constitute an important biomarker for early detection of ccRCC and could also be used as a target for therapy of kidney carcinomas, since immunotoxins directed against the monkey homologue of hHAVcr-1 could kill kidney cells.

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Specific aims are focused to: i) determine the diagnostic and prognostic potential of hHAVcr-1 expression in renal cell carcinomas, by correlating hHAVcr-1 levels in archive, fresh surgical and TMA tissues with tumor anatomo-pathological characteristics and patient outcome and, ii) determine the function of hHAVcr-1, which remains elusive, in the development and progression of kidney carcinomas, using ccRCC derived cell lines with silenced or overexpressed hHAVcr-1. Tumors overexpressing or defective in hHAVcr-1 will be compared with controls, in relation to their behavior and anatomo-pathological characteristics. Differences are being correlated with proteomic and gene expression profiles obtained in each case. Differential expression pathways and target molecules correlating with absence/presence of hHAVcr-1 shall be identified. New strategies for diagnosis, prognosis and treatment of ccRCC must be further developed. (Programa de Recerca en Càncer Renal CIBBIM-IRHUVH.)

Study of genes involved in genotoxic response in carcinomas Carlos Parada Cobo The modulation of the response in chemotherapy agents that generate DNA alterations in human tumors allows surviving classic anticancer therapies. Knowledge of the key proteins that define this resistance can incorporate new prognostic markers in solid tumors. The characterisation of better diagnostic and prognostic markers is paramount to improve early diagnosis and treatment of

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cancer. In that respect, we are studying two main protein networks in human carcinomas and their involvement in oncogenesis and sensitivity to chemotherapeutical agents. The first one involves the network that regulates glycogen synthesis and depolymerisation, and thus, the regulatory elements in glucose storage. We have found some of these proteins to be good markers in early (low grade) tumors. The second one studies the implications of ND10 associated proteins in response to classic anticancer treatments. ND10 is a nuclear multiprotein complex associated with functions such as DNA damage response, gene expression regulation and apoptosis. We have found that at least three of the ND10 proteins are putative new prognostic markers in some types of human carcinoma.

Role of HER3 expression in carcinogenesis of endometrial and breast tumors. Search for new predictive markers to anti-HER treatments Javier Hernández Losa The cell signalling pathways downstream of epidermal growth

factor receptor family members is tightly regulated in normal epithelial cells, and its alteration induce different cell processes (cell proliferation, cell growth, etc...) which trigger cellular transformation. Within this family of receptors, HER1/EGFR and HER2/neu are the best known, with other family members such as HER3 being subject to interest. The aim of the study is establish the role of HER3 protein expression by immunohistochemistry in endometrial and breast tumors, and establish any association with clinic-pathological parameters. Furthermore, we would like to know how HER3 is implicated in resistance mechanisms to antiHER treatment agents.

Exercise capacity, peripheral muscle dysfunction and genotype in adults with cystic fibrosis Arantxa Ortega Aznar To study the degree and type of skeletal muscle involvement in CF patients who present exercise intolerance and their relationship with the genotype. To determine the relationship between the type and/or degree of skeletal muscle involvement by histologic and

Figure 29 High p-4EBP1 expression correlate with tumoral grade. Immunohistochemistry in breast carcinomas

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mitochondrial respiratory chain function study, and the CF genotype. Correlation study between exercise capacity, pulmonary function and genotype.

Mechanisms of cerebral aging: role of GSK3ß/cdk5 and sirtuins Arantxa Ortega Aznar Aging may be considered as an accumulation of changes in cells and tissues that increases the risk of disease and death. The senescence-accelerated prone mice SAMP8 is an aging model with brain histopathological signs and other aging-related disorders, such as ß-amyloid and tau protein aggregates and increased oxidative stress. If hyperphosphorylated, tau protein contributes to the development of a tauopathy, process linked to neurodegenerative diseases of the aging brain such as Alzheimer disease. Several kinases (PKC, ERK, CDK5 or GSK3ß) perform this tau protein posttranscriptional modification. We plan to determine the effect that inhibitors of these kinases such as lithium, in vivo and in vitro, could have in slowing down the brain neurodegenerative processes. Additionally, we will study the role of a newly described protein family, sirtuins. Sirtuins are ontogenically preserved proteins related to longevity. We will evaluate the gene and protein expression of Sirt 1, 2 and 3 in cultured neurons and in the brain of this mouse strain. We seek to elucidate the participation of sirtuins in cerebral ageing, using as a tools resveratrol, a flavonoid described as activator of these proteins, and caloric restriction, two paradigms that lead to an elongation of lifespan and neuroprotection in several animal models. In the in vitro studies, the role of GDNF in maintaining neuronal functionality and its correlation with sirtuins will be investigated because this trophic factor decreases with aging and shows a lesser expression in SAMP8 mice.

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These studies will contribute to the development of new therapeutic strategies to prevent agerelated neurodegenerative diseases.

Study of CAP-dependent and CAPindependent signalling pathways in breast carcinomas Josep Castellví Vives In previous work we studied several factors involved in cell signalling pathways that control cell growth. We found that the phosphorylated form of 4E-BP1 was the only factor that correlated with prognosis, and histologic aggressive features in several types of cancers. 4E-BP1 is a key regulator of CAP-dependent traslation and its main function is the inactivation of eIF4E. However, not all aggressive tumors show activation of this factor. On the other hand, it has been shown that under hypoxia conditions in cells the translation of some key factors can be regulated by CAP-independent pathways, mediated by factors known as ITAFs. The aim of our study is to find the CAP-dependent/CAP-independent balance in tumors in relation to hypoxia, and evaluate its impact on prognosis. Expression analysis and functional elucidation of connexins and pannexins in relation to human cancer progression and malignancy Trond Aasen Connexins and pannexins are structural units of gap junctions permitting direct intercellular communication. Deregulation of gap junctions is a frequent feature of carcinogenesis. We are characterizing the expression level of a variety of connexins and pannexins in primary and metastatic human tumors. In vitro we are studying how these proteins affect features related to the degree of malignancy such as migration, invasion and resistance to hypoxia. In connexin-deficient cell lines we are over-expressing specific wild-type

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CURRENT RESEARCH PROJECTS PI: Arantxa Ortega Aznar Morfologia i genètica de la malaltia d’Alzheimer Funding Agency: Fundació La Marató de TV3 Reference: MARATV3/97/3115 Funding: 36,060.72 € Duration: 1997 to 2010

PI: Santiago Ramón y Cajal Agüeras Correlación de la expresión de factores embudo 4EBP1, con la expresión de diferentes receptores epidérmicos: papel de HER3, HER2 y sus formas truncadas en diferentes tipos de tumor Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMMA/13/2008 Funding: 75,000 € Duration: 2008 to 2011

or truncated forms of connexins and pannexins using recently generated retroviral constructs. In cell lines expressing high levels of specific connexins, we knockdown the expression levels using established lentiviral shRNA strategies. We aim to correlate connexin expression and cell communication with malignancy using a variety of well characterized assays with particular focus on colony formation, migration, invasion, epithelial-to-mesenchymal transition, changes in tumor stem cell populations, and hypoxia and drug resistance. The aim of the study is to: 1) Identify any significant correlation between the expression of various gap junction proteins and malignancy, prognosis, chemo-resistance and overall survival in a variety of cancers 2) Gain mechanistic insight and identify direct functional roles of connexins and pannexins during tumor progression.

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PI: Santiago Ramón y Cajal Agüeras Factores centrales o embudos en vías de señalización y senescencia: estudio molecular de las vías de activación e inhibición de receptores epidérmicos y de 4EBP1 y el F4E, así como de RSK4 en senescencia Funding Agency: Fondo de Investigación Sanitaria Reference: PI080143 Funding: 147,862 € Duration: 2009 to 2011

PI: Cleofé Romagosa PérezPortabell Papel de algunas moléculas clave de señalización celular y reparación del ADN en el pronóstico y patogénesis de los Sarcomas de Partes Blandas en Adultos Funding Agency: Grupo Español Investigación Sarcomas (GEIS) Reference: GEIS/2008 Funding: 18,000 € Duration: 2008 to 2011

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PUBLICATIONS (Impact Factor: 216.587)

PI: Javier Hernández Losa Papel de HER3 en la carcinogénesis de tumores de mama y endometrio. Búsqueda de nuevos factores predictivos de respuesta a tratamientos anti-HER Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMM2009/02 Funding: 49,200 € Duration: 2009 to 2011

PI: Santiago Ramón y Cajal Agüeras Estudio de factores moleculares y vías de señalización asociados a resistencia/sensibilidad al tratamiento con Irvalec Funding Agency: Centro para el Desarrollo Técnico Industrial (CDTI) Reference: CENIT2009/01 Funding: 356,298.75 € Duration: 2009 to 2012

PI: Javier Hernández Losa Papel de receptores epidermoides en cáncer. Papel de HER3 en tumores de mama y endometrio Funding Agency: Fundación Caja Navarra Reference: CAN2009-16662 Funding: 6,713.87 € Duration: 2010 to 2010

PI: Santiago Ramón y Cajal Agüeras RTICC - Red Temática de Investigación cooperativa de cáncer Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0020/0104 Funding: 566,495.18 € Duration: 2007 to 2011

PI: Carlos Parada Cobo Mejoras diagnósticas y pronósticas del melanoma uveal (cáncer intraocular) Funding Agency: Fundación Caja Navarra Reference: CAN2009-16641 Funding: 1,116.75 € Duration: 2010 to 2010

PI: Matilde Lleonart Pajarín Oncología y patología molecular Funding Agency: AGAUR Reference: 2009 SGR 604 Funding: 39,520 € Duration: 2010 to 2013

PI: Josep Castellví Vives Implicación de la traducción capindependiente, como vía alternativa a la cap-dependiente en condiciones de hipoxia en carcinomas de mama Funding Agency: Fundació Santiago Dexeus Font Reference: FSDF2009/03 Funding: 6,000 € Duration: 2009 to 2011

PI: Santiago Ramón y Cajal Agüeras Patologia molecular Funding Agency: AGAUR Reference: 2009 SGR 756 Funding: 41,600 € Duration: 2010 to 2013

PI: Santiago Ramón y Cajal Agüeras RETICS de Biobancos Funding Agency: Fondo de Investigación Sanitaria Reference: RD09/0076/00066 Funding: 299,000 € Duration: 2010 to 2013

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Andreu-Pérez P, Hernández-Losa J, Moliné T, Gil R, Grueso J, Pujol A, Cortés J, Ávila MA, Recio JA. Methylthioadenosine (MTA) inhibits melanoma cell proliferation and in vivo tumor growth. BMC Cancer 2010 Jun 8; 10 (1): 265.  IF: 2.736. Anido J, Sáez-Borderias A, González-Juncà A, Rodón L, Folch G, Carmona MA, PrietoSánchez RM, Barba I, Martínez-Saez E, Prudkin L, Cuartas I, Raventós C, MartínezRicarte F, Poca MA, García-Dorado D, Lahn MM, Yingling JM, Rodón J, Sahuquillo J, Baselga J, Seoane J. TGF-beta Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell 2010 Dec 14; 18 (6): 655-68.  IF: 25.288. Audi L, Fernández-Cancio M, Carrascosa A, Andaluz P, Torán N, Piro C, Vilarò E, Vicens-Calvet E, Gussinyé M, Albisu MA, Yeste D, Clemente M, Hernández de la Call, Campo M del, Vendrell T, Blanco A, Martínez-Mora J, Granada ML, Salinas I, Forn J, Calaf J, Angerri O, MartínezSopena MJ, Valle J del, García E, GraciaBouthelier R, Lapunzina P, Mayayo E, Labarta JI, Lledó G, Sánchez del Pozo J, Arroyo J, Pérez-Aytes A, Beneyto M, Segura A, Borras V, Gabau E, Caimari M, Rodríguez A, Martínez-Aedo MJ, Carrera M, Castaño L, Andrade M, Bermudez de la Vega . Novel (60%) and Recurrent (40%) Androgen Receptor Gene Mutations in a Series of 59 Patients with a 46,XY Disorder of Sex Development. J Clin Endocrinol Metab 2010 Apr; 95 (4): 1876-88.  IF: 6.202. Barbachano A, Ordóñez-Morán P, García JM, Sánchez A, Pereira F, Larriba MJ, Martínez N, Hernández J, Landolfi S, Bonilla F, García Palmer H, Rojas JM, Muñoz A. SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity. Oncogene 2010 Aug 26; 29 (34): 4800-13.  IF: 7.135. Bielanska J, Hernández-Losa J, Moliné T, Somoza R, Ramón y Cajal S, Condom E, Ferreres JC, Felipe A. Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human fetus. Cell Physiol Biochem 2010; 26 (2): 219-26.  IF: 3.563. Boix H, Ortega-Aznar A, Vázquez E, Salcedo S, Roig-Quilis M. Brainstem dysgenesis in an infant prenatally exposed to cocaine. Pediatr Neurol 2010 Apr; 42 (4): 295-7.  IF: 1.497.

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Cabrera S, Franco-Camps S, García A, Vergés R, Díaz-Feijoo B, Pérez-Benavente MA, Poza JL, Bradbury M, Xercavins J, Gil-Moreno A. Total laparoscopic radical hysterectomy for cervical cancer in prolapsed uterus. Arch Gynecol Obstet 2010 Jul; 282 (1): 63-7.  IF: 0.912. Casal C, Torres-Collado AX, Plaza-Calonge MD, Martino-Echarri E, Ramón y Cajal S, Rojo F, Griffioen AW, Rodríguez-Manzaneque. ADAMTS1 Contributes to the Acquisition of an Endothelial-like Phenotype in Plastic Tumor Cells. Cancer Res 2010 Jun 1; 70 (11): 4676-86.  IF: 7.543. Coll M, Martell M, Raurell I, Ezkurdia N, Cuenca S, Hernández-Losa J, Esteban R, Guardia J, Bosch J, Genescà J. Atrophy of mesenteric sympathetic innervation may contribute to splanchnic vasodilatation in rat portal hypertension. Liver Int 2010 Apr; 30 (4): 593-602.  IF: 2.987. Cruz-Sánchez FF, Gironés X, Ortega A, Alameda F, Lafuente JV. Oxidative stress in Alzheimer’s disease hippocampus: A topographical study. J Neurol Sci 2010 Dec 15; 299 (1-2): 163-7.  IF: 2.324. Cuadrado E, Rosell A, Colomé N, Hernández-Guillamón M, García-Berrocoso T, Ribó M, Alcázar A, Ortega-Aznar A, Salinas M, Canals F, Montaner J. The Proteome of Human Brain after Ischemic Stroke. J Neuropathol Exp Neurol 2010 Nov; 69 (11): 110515.  IF: 4.564. Dopeso H, Mateo-Lozano S, Elez E, Landolfi S, Ramos Pascual FJ, Hernández-Losa J, Mazzolini R, Rodrigues P, Bazzocco S, Carreras MJ, Espín E, Armengol M, Wilson AJ, Mariadason JM, Ramón y Cajal S, Tabernero J, Schwartz S Jr, Arango D. Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. Clin Cancer Res 2010 Apr 15; 16 (8): 237582.  IF: 6.747. Fontecha CG, Aguire M, Soldado F, Peiró JL, Torán N, Vidal N, Martínez V. Effects of birth advancement in Chiari malformation in a surgical myelomeningocele model in rabbits. J Pediatr Surg 2010 Mar; 45 (3): 594-599.  IF: 1.430. Fusté V, Pino M del, Pérez A, García A, Torné A, Pahisa J, Ordi J. Primary squamous cell carcinoma of the vagina: human papillomavirus detection, p16(INK4A) overexpression and clinicopathological correlations. Histopathology 2010 Dec; 57 (6): 907-16. doi: 10.1111/j.1365-2559.2010.03727.x.  IF: 3.855.

García-Matas S, Vera N de, Aznar AO, Marimón JM, Adell A, Planas AM, Cristofol R, Sanfeliu C. In vitro and in vivo activation of astrocytes by amyloid-beta is potentiated by pro-oxidant agents. J Alzheimers Dis 2010; 20 (1): 229-45.  IF: 3.832. Hernández-Guillamón, García-Bonilla L, Solé M, Sosti V, Parés M, Campos M, Ortega-Aznar A, Domínguez C, Rubiera M, Ribó M, Quintana M, Molina CA, Álvarez-Sabín J, Rosell A, Unzeta M, Montaner J. Plasma VAP-1/SSAO Activity Predicts Intracranial Hemorrhages and Adverse Neurological Outcome After Tissue Plasminogen Activator Treatment in Stroke. Stroke 2010 Jul; 41 (7): 1528-35.  IF: 7.041. Hiatt MJ, Ivanova L, Torán N, Tarantal AF, Matsell DG. Remodeling of the fetal collecting duct epithelium. Am J Pathol 2010 Feb; 176 (2): 630-7.  IF: 5.673. Jubany L, Selva-O’Callaghan A, PérezVega C, Grau-Junyent J, Hernández-Losa J, Vilardell-Tarrés M. The patient has the diagnosis. Lancet 2010 Oct 23; 376 (9750): 1436.  IF: 30.758. López-Beltrán A, Amin MB, Oliveira PS, Montironi R, Algaba F, McKenney JK, Torres I de, Mazerolles C, Wang M, Cheng L. Urothelial Carcinoma of the Bladder, Lipid Cell Variant: Clinicopathologic Findings and LOH Analysis. Am J Surg Pathol 2010 Mar; 34 (3): 371-6.  IF: 4.062. López-Fauqued M, Gil R, Grueso J, Hernández J, Pujol A, Moliné T, Recio JA. The dual PI3K/mTOR inhibitor (PI-103) promotes immunosupression, in vivo tumor growth and increases survival of sorafenib treated melanoma cells. Int J Cancer 2010 Apr 1; 126 (7): 1549-61.  IF: 4.722. Manchón Walsh P, Borras JM, Ferro T, Espinas JA, Alfaro J, Arnau JM, Artigas V, Aunón MC, Barrios P, Bellmunt J, Biondo S, Bolibar I, Cambray M, Canals E, Caro M, Casado E, Castells A, Companys A, Darnell A, Torres IM de, Espín E, Estévez M, Figueras J, Gallen M, González D, Lema L, Losa F, Lloreta J, Macías V, Marcuello E, Manzano JL, MartinRichard M, Maurel J, Membrive I, Mira M, Moreno de Vega V, Murio JE, Panadès A, Pericay C, Pujol J, Queralt B, Ramos E, Reig A, Roca JM, Rodríguez F, Saigi E, Salas A, Salazar R, Sanjuan X, Serra X, Solé JM, Tabernero J, Targarona EM, Torras J. Colorectal Cancer OncoGuia. Clin Transl Oncol 2010 Mar; 12 (3): 188-211.  IF: 1.146.

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Montero MA, Gracia J de, Morell F. [Hard metal interstitial lung disease.] Arch Bronconeumol 2010 Sep; 46 (9): 489-91.  IF: 2.166. Montes-Moreno S, González-Medina AR, Rodríguez Pinilla SM, Maestre L, SánchezVerde L, Roncador G, Mollejo M, García JF, Menarguez J, Montalbán C, Ruiz-Marcellán C, Conde E, Piris M. Aggressive large B cell lymphoma with plasma cell differentiation: immunohistochemical characterization of plasmablastic lymphoma and diffuse large B cell lymphoma with partial plasmablastic phenotype. Haematologica 2010 Aug; 95 (8): 1342-9.  IF: 6.416. Morote J, Planas J, Ramírez C, Gómez E, Raventós CX, Placer J, Cataln R, Torres IM de. Evaluation of the serum testosterone to prostate-specific antigen ratio as a predictor of prostate cancer risk. BJU Int 2010 Feb; 105 (4): 481-4.  IF: 2.865. Morote J, Rigau M, García M, Mir C, Ballesteros C, Planas J, Raventós CX, Placer J, Torres IM de, Reventós J, Doll A. Behaviour of the PCA3 gene in the urine of men with high grade prostatic intraepithelial neoplasia. World J Urol 2010 Dec; 28 (6): 677-80.  IF: 2.629.

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Area 1. Oncology and Genetics

Navarro S, Vaquero E, Maurel J, Bombi JA, Juan C de, Feliu J, Fernández Cruz L, Ginés A, Girela E, Rodríguez R, Sabater L, Álvarez E, Marañón G, Arguello L, Barranco L, Cárdenas A, Conill C, Cuatrecasas M, Madaria E de, Delgado F, Díaz R, Domínguez E, Fabregat J, Farré A, Fernández Esparrach, Ferrández A, Pino Florez M del, IglesiasGarcía J, Lluis F, López Serrano A, Macarulla T, Martin Richard M, Méndez R, Molero X, Navalpotro B, Pérez Mateo M, Salas A, Santoyo J, Solé M, Sendino O, Vázquez E, Zarco A. [Recommendations for diagnosis, staging and treatment of pancreatic cancer (Part I). Grupo Español de Consenso en Cáncer de Páncreas.] Med Clin (Barc) 2010 May 15; 134 (14): 643-55.  IF: 1.231. Olloquequi J, Ferrer J, Montes JF, Rodríguez E, Montero MA, García-Valero J. Differential lymphocyte infiltration in small airways and lung parenchyma in COPD patients. Respir Med 2010 Sep; 104 (9): 1310-8.  IF: 2.331. Orsola A, Cecchini L, Raventós CX, Trilla E, Planas J, Landolfi S, Torres I de, Morote J. Risk factors for positive findings in patients with high-grade T1 bladder cancer treated with transurethral resection of bladder tumour (TUR) and bacille Calmette-Guerin therapy and the decision for a repeat TUR. BJU Int 2010 Jan; 105 (2): 202-7.  IF: 2.865. Parra-Palau JL, Pedersen K, Peg V, Scaltriti M, Angelini PD, Escorihuela M, Mancilla S, Sánchez Pla A, Ramón y Cajal S, Baselga J, Arribas J. A Major Role of p95/611-CTF, a Carboxy-Terminal Fragment of HER2, in the Down-modulation of the Estrogen Receptor in HER2-Positive Breast Cancers. Cancer Res 2010 Nov 1; 70 (21): 8537-46.  IF: 7,543. Pinos T, Barbosa-Desongles A, Hurtado A, Santamaría-Martínez , Torres I de, Reventós J, Munell F. Human SHBG mRNA Translation Is Modulated by Alternative 5’-Non-Coding Exons 1A and 1B. PLoS One 2010 Nov 4; 5 (11): e13844.  IF: 4.351. Quiles MT, Arbós MA, Fraga A, Torres IM de, Reventós J, Morote J. Antiproliferative and apoptotic effects of the herbal agent Pygeum africanum on cultured prostate stromal cells from patients with benign prostatic hyperplasia (BPH). Prostate 2010 Jul 1; 70 (10): 1044-53.  IF: 3.081. Raventós CX, Orsola A, Torres I de, Cecchini L, Trilla E, Planas J, Morote J. Preoperative Prediction of Pathologically Insignificant Prostate Cancer in Radical Prostatectomy Specimens: The Role of Prostate Volume and the Number of Positive Cores.Urol Int 2010; 84 (2): 153-158.  IF: 0.902.

Rubio IT, Aznar F, Lirola J, Peg V, Xercavins J. Intraoperative assessment of sentinel lymph nodes after neoadjuvant chemotherapy in patients with breast cancer. Ann Surg Oncol 2010 Jan; 17 (1): 235-9.  IF: 4.130. Sánchez-Espiridión B, Montalbán C, López A, Menarguez J, Sabín P, Ruiz-Marcellán C, López A, Ramos R, Rodríguez J, Cánovas A, Camarero C, Canales M, Álves J, Arranz R, Acevedo A, Salar A, Serrano S, Bas A, Moraleda JM, Sánchez-Godoy P, Burgos F, Rayón C, Fresno MF, García Larana J, GarcíaCosio M, Santonja C, López JL, Llanos M, Mollejo M, González-Carrero J, Marín A, Forteza J, García-Sanz R, Tomas JF, Morente MM, Piris MA, García JF. A molecular risk score based on four functional pathways for advanced classical Hodgkin lymphoma. Blood 2010 Aug 26; 116 (8): e12-7.  IF: 10.555. Sanjuan X, Salas A, Lloreta J, Manchón Walsh P, Alfaro J, Arnau JM, Artigas V, Aunón MC, Barrios P, Bellmunt J, Biondo S, Bolibar I, Cambray M, Canals E, Caro M, Casado E, Castells A, Companys A, Darnell A, Torres IM de, Espín E, Estévez M, Figueras J, Gallén M, González D, Lema L, Losa F, Lloreta J, Macías V, Marcuello E, Manzano JL, MartinRichard M, Maurel J, Membrive I, Mira M, Moreno de Vega V, Murio JE, Panadès A, Pericay C, Pujol J, Queralt B, Ramos E, Reig A, Roca JM, Rodríguez F, Saigi E, Salazar R, Serra X, Solé JM, Tabernero J, Targarona EM, Torras J. Colorectal Cancer OncoGuia: surgical pathology report guidelines. Clin Transl Oncol 2010 Mar; 12 (3): 211-214.  IF: 1.146. Sapisochin G, Bilbao I, Balsells J, Dopazo C, Caralt M, Lázaro JL, Castells L, Allende H, Charco R. Optimization of Liver Transplantation as a Treatment of Intrahepatic Hepatocellular Carcinoma Recurrence After Partial Liver Resection: Experience of a Single European Series. World J Surg 2010 Sep; 34 (9): 2146-54.  IF: 2.696. Sardón O, Marhuenda C, Santiago M, Torán N, Korta J, Corcuera P, Barceló C, Pérez-Yarza EG. [Endobronchial chondromesenchymal hamartoma.] An Pediatr (Barc) 2010 Apr; 72 (4): 263-6.  IF: 0.363. Serrano C, García A, Brana I, Pérez-Benavente A, Oaknin A. Angiosarcoma of the Ovary: Is It Always a Lethal Disease? J Clin Oncol 2010 Nov 20; 28 (33): e675-7.  IF: 17.793.

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Simonetti S, Molina MA, Queralt C, Aguirre I de, Mayo C, Bertrán-Alamillo J, Sánchez JJ, González-Larriba JL, Jiménez U, Isla D, Morán T, Viteri S, Camps C, García-Campelo R, Massuti B, Benlloch S, Ramon y Cajal S, Taron M, Rosell R. Detection of EGFR mutations with mutation-specific antibodies in stage IV non-small-cell lung cancer. J Transl Med 2010 Dec 18; 8 (1):135.  IF: 3.407. Toiber D, Azkona G, Ben-Ari S, Toran N, Soreq H, Dierssen M. Engineering DYRK1A overdosage yields Down syndrome-characteristic cortical splicing aberrations. Neurobiol Dis 2010 Oct; 40 (1): 348-59.  IF: 4.518. Torre J de la, Sabadell MD, Rojo F, Lirola JL, Salicru S, Reventós J, Ramon y Cajal S, Xercavins J. Cyclo-oxygenase type 2 is dysregulated in breast ductal carcinoma in situ and correlates with poor outcome. Eur J Obstet Gynecol Reprod Biol 2010 Jul; 151 (1): 72-6.  IF: 1.582.

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AREA 1 ONCOLOGY AND GENETICS

1.19 Oncology and Molecular Pathology

Group Leader Matilde Lleonart Pajarín Tel. 93 489 41 69 [email protected] Researchers Matilde Lleonart Pajarín Researchers in Training Ana Artero Castro Mónica Bouzo Lorenzo Andrea Francheska Feliciano Aguirre Beatriz Sánchez Sendra

OBJECTIVES The main objective of our group is the identification of novel prognosis and diagnosis factors which unveil novel strategies to design anti-cancer therapies. For such purposes, we have carried out massive genetic screens by using cDNA (sense and antisense) libraries

to infect primary cells and target those cellular clones which have adquired immortalized properties. The complete characterization is carried out in vitro and in vivo. In vitro, it is performed at mRNA and protein level in infected cells with the putative oncogene or tumor suppressor gene versus the control cells. Proteins partners are

identified and extensively characterized. Our final aim is to search for the importance of the identified genes in human tumors. We are therefore looking for identified genes/tumor suppressors in a broad range of human samples. We expect to find new strategies to target novel therapeutical pathways important in tumorigenesis.

22010 Impact Factor:

18.820

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Area 1. Oncology and Genetics

Figure 30 Overexpression of RSK4 induces mechanisms of cellular senescence including ?-gal staining

Figure 31 Immunohistochemistry in breast carcinomas. High p-4EBP1 expression correlates with tumoral grade

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RESEARCH LINES Detection of novel genes and tumor suppressor genes involved in senescence which have an important role in human tumors Novel genes such as CIRP and RPLP1 have been discovered as well as tumor suppressor genes (SAHH). The proliferative genes have been found to be overexpressed in breast, colon and prostate tumors and the anti-proliferative genes have been found downregulated in nearly all main tumor types.

Detection of microRNAs as a novel tool for cancer therapy We have performed a microRNA screen in primary cells to detect the microRNAs responsible for bypassing Ras-induced senescence. More than 30 different hits have been discovered that are being characterized in our laboratory.

Characterization of ribosomal proteins: Importance and function in tumorigenesis We are studying the effect of a subgroup of ribosomal proteins in their role as proliferative genes in primary and cancer cell lines. The fact that ribosomal proteins are not only responsible for stabilizing the ribosome structure but they might have independent functions, place these proteins in an important scenario in tumorigenesis.

Figure 32 Proposed model for the dual role of CIRP in its contribution to bypassing senescence and providing immortalization in murine primary cells. To bypass senescence, CIRP might influence proliferation through two pathways: a) CIRP directly or indirectly induces mRNA/s and proteins involved in the initiation of translation to promote proliferation; b) CIRP binds and stabilizes specific mRNAs by direct interaction to provoke their activation. Certain mRNAs might be antioxidant mRNAs (e.g., TRX) that counteract the effects of ROS. High ROS accumulation provokes a stress response which forces wild-type cells to enter senescence. A considerable number of oncogenic proteins owe their proliferative potential to their ability to counteract the accumulation of ROS. Evidence that this might be the case for CIRP is discussed in the text. Note the presence of -galactosidase positive cells (blue) in senescent cells

CURRENT RESEARCH PROJECTS

PUBLICATIONS

PI: Matilde Lleonart Pajarín Identificación de nuevas dianas terapéuticas basadas en micro-RNA sobreexpresados en cáncer Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/02193 Funding: 147,015 € Duration: 2010 to 2012

Lleonart ME. A new generation of proto-oncogenes: Cold-inducible RNA binding proteins. Biochim Biophys Acta 2010 Jan;1805(1):43-52.  IF: 11.685.

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(Impact Factor: 18.820)

Lleonart ME, Borgdorff V, Bishop CL, Fessart D, Bergin AH, Overhoff MG, Beach DH. Multiple microRNAs rescue from Ras-induced senescence by inhibiting p21(Waf1/Cip1). Oncogene 2010 Apr 15; 29 (15): 2262-71.  IF: 7.135.

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VHIR Information

Area 2. Endocrinology, Growth, Metabolism and Diabetes

AREA 2 ENDOCRINOLOGY, GROWTH, METABOLISM AND DIABETES

2.1 Diabetes and Metabolism

Group Leader Rafael Simó Canonge Tel. 93 489 41 72 / 73 [email protected] Researchers Marta García Ramírez Cristina Hernández Pascual Albert Lecubé Torelló David Martínez Selva Jorge Mesa Manteca Rafael Simó Canonge Josep A. Villena Delgado Researchers in Training Anna Barbosa Desongles Lidia Corraliza Márquez Natàlia Enguix Elena Jaime Lasheras Márquez Marta Villarroel Fandos Nursing, Technical and Administrative Staff Olga Mestres Soler Rosario Pardo Díaz Lorena Ramos Pérez

STATE OF THE ART

OBJECTIVES

The Diabetes and Metabolism Research Group has been recognized as a consolidated group by the Generalitat de Catalunya, as well as a group of excellence by the ANEP. Apart from belonging to CIBERDEM, our group is associated with the cardiovascular diseases network (RECAVA). Our research is mainly addressed to the pathophysiology of diabetic retinopathy and obesity with the final goal of discovering new therapeutic targets. Our combination of basic and clinical research is important not only in obtaining relevant results, but also in facilitating the rapid transference of these results to clinical practice.

Our general aim in the field of diabetic retinopathy is to discover new therapeutic targets. In the next two years the main objectives will be: • To identify the mechanisms that trigger neurodegeneration and its consequences in the early stages of diabetic retinopathy through the use of integrated systems biology. • To determine the molecular mechanisms involved in bloodretinal barrier disruption and to evaluate potential new drugs for the treatment of diabetic macular edema.

22010 Impact Factor:

63.491

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• To explore the proteomic and metabonomic profile of the vitreous fluid of diabetic patients vs. non diabetic patients. In the field of obesity research we are investigating new candidates involved in its pathogenesis. The main objectives during the next years will be: • To identify by proteomic analysis of cerebrospinal fluid new regulators of food intake. • To determine the influence of SHBG/sex-steroids on fat properties and distribution and the incidence of diabetes. • To investigate the role of the mitochondria in obesity, insulin resistance and type 2 diabetes. Regarding endothelial dysfunction and cardiovascular disease in type 2 diabetic patients, we are testing new methods of evaluating endothelial damage and the prevalence of and the main factors accounting for true silent ischemia.

RESEARCH LINES Physiopathology of diabetic retinopathy. A new approach using integrated biological systems. This is the main area of our research

Insulin resistance and obesity: new pathogenic candidates and the study of co-morbidities

Endothelial dysfunction, dyslipideamia and cardiovascular disease in type 2 diabetes

CURRENT RESEARCH PROJECTS PI: Josep A. Villena Delgado Papel del coactivador PGC-1 beta en tejido adiposo blanco y su contribución al desarrollo de la obesidad y la diabetes de tipo 2 Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2008-03644 Funding: 168,190 € Duration: 2009 to 2011

PI: Josep A. Villena Delgado Implication of Estrogen-Related Receptors in the etiology of diabetic cardiomyopathy: identification of ERRs as potential pharmacological targets for treatment of diabetic cardiomyopathy Funding Agency: Fundació La Marató de TV3 Reference: MARATV3/2008/082610 Funding: 199,138 € Duration: 2009 to 2012

PI: Josep A. Villena Delgado Función del coactivador transcripcional PGC-1 en tejido adiposo: contribución al desarrollo de la obesidad y diabetes del tipo 2 Funding Agency: Fondo de Investigación Sanitaria Reference: PI080681 Funding: 148,830 € Duration: 2009 to 2011

PI: David Martínez Selva Sex hormone-binding globulin (SHBG): Identification of the molecular mechanisms that regulate its expression and role in body fat distribution and in the development of type 2 diabetes Funding Agency: Fondo de Investigación Sanitaria Reference: CP08/00058 Funding: 42,000 € Duration: 2009 to 2011

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PI: Rafael Simó Canonge Neurodegeneración en la patogénesis de la retinopatía diabética incipiente. Estudio de los mecanismos implicados a través de un abordaje integrado de biología de sistemas Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2009-07408 Funding: 181,500 € Duration: 2010 to 2012

PI: David Martínez Selva Papel de la Sex Hormone-Binding Globulin (SHBG) y de los esteroides sexuales en la distribución de la grasa corporal en la aparición de la diabetes mellitus tipo 2 Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00144 Funding: 81,070 € Duration: 2010 to 2012

PI: Rafael Simó Canonge Neurodegeneration as an early event in the pathogenesis of diabetic retinopathy. Study of involved mechanisms and new therapeutic strategies Funding Agency: European Foundation for the Study of Diabetes Reference: EFSD-2010-02 Funding: 100,000 € Duration: 2010 to 2012

PI: Rafael Simó Canonge RECAVA - Red Temática de Investigación en Enfermedades Cardiovasculares Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0014/1014 Funding: 27,840 € Duration: 2008 to 2011

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VHIR Information

Area 2. Endocrinology, Growth, Metabolism and Diabetes

PUBLICATIONS (Impact Factor: 63.491) PI: Rafael Simó Canonge Grup de Recerca en Diabetis i Metabolisme Funding Agency: AGAUR Reference: 2009 SGR 739 Funding: 43,680 € Duration: 2010 to 2013

PI: Rafael Simó Canonge Identification of neurodegenerative mechanisms that promote development of diabetic retinopathy: the role of insulin signalling and apoptosis Funding Agency: CIBERDEM Reference: NEURORET-DIAB Funding: 32,000 € Duration: 2009 to 2010

PI: Rafael Simó Canonge Glycogen-Induced Dysfunctions in Pancreas and Retina and their involvement in the Ethiogenesis of Diabetes mellitus Funding Agency: CIBERDEM Reference: GIDIPRED Funding: 30,000 € Duration: 2009 to 2010

PI: Rafael Simó Canonge Determinants of insulin resistance and of disorders of glucose tolerance, including diabetes, in severe obesity, and their changes after bariatric surgery-induced weight loss Funding Agency: CIBERDEM Reference: DIASOBS Funding: 25,000 € Duration: 2009 to 2010

PI: Rafael Simó Canonge Adult Adipose Tissue-Derived Progenitor Cells: Influence of the clinical phenotype and adipose depot origen in their biological properties Funding Agency: CIBERDEM Reference: StemOb Funding: 30,000 € Duration: 2009 to 2010

Barba I, García-Ramírez M, Hernández C, Alonso MA, Masmiquel L, García-Dorado D, Simó R. Metabolic fingerprints of proliferative diabetic retinopathy. An 1H NMR-based metabonomic approach using vitreous humor. Invest Ophthalmol Vis Sci 2010 Sep; 51 (9): 4416-21.  IF: 3.431. Castro A, Lázaro I, Selva DM, Céspedes E, Girona J, Plana N, Guardiola M, Cabré A, Simó R, Masana L. APOH is increased in the plasma and liver of type 2 diabetic patients with metabolic syndrome. Atherosclerosis 2010 Mar; 209 (1):201-5.  IF: 4.522. Ciudin A, Hernández C, Simó R. Iron overload in diabetic retinopathy: a cause or a consequence of impaired mechanisms? Exp Diabetes Res 2010; 2010. pii: 714108.  IF: 2.574.

Lecubé A, Sampol G, Muñoz X, Hernández C, Mesa J, Simó R. Type 2 diabetes impairs pulmonary function in morbidly obese women: a case-control study. Diabetologia 2010 Jun; 53 (6): 1210-6.  IF: 6.551. Lecubé A, Sampol G, Muñoz X, Lloberes P, Hernández C, Simó R. Insulin resistance is related to impaired lung function in morbidly obese women: a case-control study. Diabetes Metab Res Rev 2010 Nov; 26 (8): 639-45. doi: 10.1002/dmrr.1131.  IF: 2.762. Núñez-Cortés JM, Pedro-Botet Montoya J, Pintó Sala X, Montoya JP, Simó Canonge R, Santos PG, Soldevilla JG, Mijares AH, Sánchez LF. Residual vascular risk: recommendations of the Spanish Initiative for the Reduction of Residual Risk. Med Clin (Barc) 2010 Jul 3; 135 (4): 165-71.  IF: 1,231.

Gerstein HC, Ratner RE, Cannon CP, Serruys PW, García-García HM, Es GA van, Kolatkar NS, Kravitz BG, Miller DM, Huang C, Fitzgerald PJ, Nesto RW, Ratner R, Domingo E, Mesa J, Anivarro I, Kaplinsky E, Otaegui I, García del Blanco B, Batalla N, et al. Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial. Circulation 2010 Mar 16; 121 (10): 1176-87.  IF: 14.816.

Pardina E, Ferrer R, Baena-Fustegueras JA, Lecubé A, Fort JM, Vargas V, Catalán R, Peinado-Onsurbe J. The Relationships Between IGF-1 and CRP, NO, Leptin, and Adiponectin During Weight Loss in the Morbidly Obese. Obes Surg 2010 May; 20 (5): 623-32.  IF: 2.934.

Hernández C, Ortega F, García-Ramírez M, Villarroel M, Casado J, García-Pascual L, Fernández-Real JM, Simó R. Lipopolysaccharide-binding protein and soluble CD14 in the vitreous fluid of patients with proliferative diabetic retinopathy. Retina 2010 Feb; 30 (2): 345-52.  IF: 2.932.

Simó R, Villarroel M, Corraliza L, Hernández C, García-Ramírez M. The retinal pigment epithelium: something more than a constituent of the blood-retinal barrier-implications for the pathogenesis of diabetic retinopathy. J Biomed Biotechnol 2010; 2010: 190724.  IF: 1.750.

Hernández C, Zapata MA, Losada E, Villarroel M, García-Ramírez M, García-Arumí J, Simó R. Effect of intensive insulin therapy on macular biometrics, plasma VEGF and its soluble receptor in newly diagnosed diabetic patients. Diabetes Metab Res Rev 2010 Jul; 26 (5): 386-92.  IF: 2.762.

Tamagno G, Celik Y, Simó R, Dihne M, Kimura K, Gelosa G, Lee BI, Hommet C, Murialdo G. Encephalopathy associated with autoimmune thyroid disease in patients with Graves’ disease: clinical manifestations, follow-up, and outcomes. BMC Neurol 2010 Apr 28; 10 (1): 27.  IF: 2.109.

Lecubé A, Sampol G, Lloberes P, Romero O, Mesa J, Morell F, Simó R. Asymptomatic sleep-disordered breathing in premenopausal women awaiting bariatric surgery. Obes Surg 2010 Apr; 20 (4): 454-61.  IF: 2.934.

Zafón C, Lecubé A, Simó R. Iron in obesity. An ancient micronutrient for a modern disease. Obes Rev 2010 Apr; 11 (4): 322-8.  IF: 5.086.

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Pinos T, Barbosa-Desongles A, Hurtado A, Santamaría-Martínez , Torres I de, Reventós J, Munell F. Human SHBG mRNA Translation Is Modulated by Alternative 5’-Non-Coding Exons 1A and 1B. PLoS One 2010 Nov 4; 5 (11): e13844.  IF: 4.351.

Zamora E, Simó R, Lupon J, Galán A, Urrutia A, González B, Mas D, Valle V. Serum myostatin levels in chronic heart failure. Rev Esp Cardiol 2010 Aug; 63 (8): 992-6.  IF: 2.746.

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AREA 2 ENDOCRINOLOGY, GROWTH, METABOLISM AND DIABETES

2.2 Nephrology

Group Leader Daniel Serón Micas Tel. 93 274 62 19 [email protected] Researchers Irene Agraz Pamplona Jorge-Juan Bartolomé Espinosa M. Carme Cantarell Aixendri María Eugenia Espinel Garuz Joan Fort Ros María Asunción Galicia Basart Francesc Moreso Mateos Mario Morlans Molina Manel Perelló Carrascosa Daniel Serón Micas José Luis Tovar Méndez Josepa Vila Presas Nursing, Technical and Administrative Staff Iván Gil Carballeira

OBJECTIVES The Renal Unit is divided into three areas: clinical nephrology, dialysis and transplantation. There is a head of department, 15 staff nephrologists, 4 part time nephrologists and 8 training nephrologists. The hospitalization area has 26 beds, and its own peritoneal and haemodialysis units. In 2009 there were 1270 inpatients, 9000 outpatient visits and 75 renal transplants were performed. Three staff mem-

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ber are professors at the Autonomous University of Barcelona. The Renal Unit has undertaken a deep transformation in order to reinforce clinical and basic research that focuses on two main topics: progression of renal insufficiency and atheromatosis in chronic kidney disease. A clinical research facility to monitor observational studies and clinical trials has been built.

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Area 2. Endocrinology, Growth, Metabolism and Diabetes

RESEARCH LINES Progression of renal insufficiency This area is focused on native kidney diseases and renal transplantation. Multicentre clinical trials evaluating treatment of different glomerular diseases constitute the main area of interest in the study of glomerular disease as well as risk factors and mediators of renal damage in the progression of IgA nephropathy. In renal transplantation, main areas of interest are treatment of chronic humoral rejection, proteomic studies of cultured renal tubular cells to evaluate markers of injury and specific markers for nephrotoxicity due to immunosuppressive agents such as mTOR inhibitors and anticalcineurinic drugs and its possible clinical application. Recurrence of renal disease after transplantation, especially focal segmental glomerulosclerosis is another ongoing study.

Atheromatosis in chronic kidney disease Influence of innate immunity alterations in the progression of subclinical atheromatosis in patients with renal insufficiency of the native kidney and recipients of a kidney transplant. In this study classical and new risk factors such as low grade inflammation, oxidative stress, endothelial damage and regeneration are considered.

CURRENT RESEARCH PROJECTS PI: M. Carme Cantarell Aixendri Estudio piloto de selección del régimen inmunodepresor basado en anti-calcineurínico o libre de anti-calcineurínico dependiendo de la aloreactividad celular donante-específica mediante técnica de elipost en receptores de un injerto renal D Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90455 Funding: 6,897 € Duration: 2007 to 2011

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PI: María Eugenia Espinel Garuz Efecto del ARA-II Olmesartan en el metabolismo del potasio en pacientes con insuficiencia renal crónica Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-197 Funding: 43,482.09 € Duration: 2010 to 2011

PI: Francesc Moreso Mateos Inmunosupresión óptima en pacientes con alto riesgo de diabetes de novo tras el trasplante renal: un estudio prospectivo, multicéntrico, controlado y randomizado Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00158 Funding: 54,907.50 € Duration: 2009 to 2011

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PUBLICATIONS (Impact Factor: 39.003) Fort J, Cuevas X, García F, Pérez-García R, Llados F, Lozano J, Martín-Malo A, et al. Mortality in incident haemodialysis patients: time-dependent haemoglobin levels and erythropoiesis-stimulating agent dose are independent predictive factors in the ANSWER study. Nephrol Dial Transplant 2010 Aug; 25 (8): 2702-10.  IF: 3.306. Hueso M, Navarro E, Moreso F, O’Valle F, Pérez-Riba M, Moral RG del, Grinyo JM, Serón D. Intragraft expression of the IL-10 gene is up-regulated in renal protocol biopsies with early interstitial fibrosis, tubular atrophy, and subclinical rejection. Am J Pathol 2010 Apr; 176 (4): 1696-704.  IF: 5.673. Lozano L, Tovar JL, Sampol G, Romero O, Jurado MJ, Segarra A, Espinel E, Ríos J, Untoria MD, Lloberes P. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens 2010 Oct; 28 (10): 2161-8.  IF: 4.988. Moreso F, Alonso A, Gentil MA, GonzálezMolina M, Capdevila L, Marcen R, Pascual J, Serón D, et al. Improvement in late renal allograft survival between 1990 and 2002 in Spain: results from a multicentre casecontrol study. Transpl Int 2010 Sep; 23 (9): 907-13.  IF: 3.254.

Otero A, Francisco A de, Gayoso P, Garcia F, Valveny N, Calbet D, Lara MA de, Vega F, Laviades C, Vives PJ, Pena Porta JM, Marco J, Solis A, González AL, Fresnedo GF, Navarro JF, Joga JA, Fort J, Castelao AM, Fonseré N, Tornero F, Quintana M, Villoria López K, Rubio E, Bernis C, Gironés M, Asin JL, Jaras JH, Rius A, Rico MG. Prevalence of chronic renal disease in Spain: results of the EPIRCE study. Nefrologia. 2010; 30 (1): 78-86. doi: 10.3265/Nefrologia.pre2009. Dic.5732.  IF: 0.533. Pladevall M, Brotons C, Gabriel R, Arnau A, Suárez C, Figuera M de la, Márquez E, Coca A, Sobrino J, Divine G, Heisler M, Williams LK, Tovar JL, et al. Multicenter cluster-randomized trial of a multifactorial intervention to improve antihypertensive medication adherence and blood pressure control among patients at high cardiovascular risk (the COM99 study). Circulation 2010 Sep 21; 122 (12):1183-91.  IF: 14.816. Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, Solez K, Baldwin WM 3rd, Bracamonte ER, Broecker V, Cosio F, Demetris AJ, Drachenberg C, Serón D, et al. Banff ‘09 Meeting Report: Antibody Mediated Graft Deterioration and Implementation of Banff Working Groups. Am J Trans-

plant 2010 Mar; 10 (3): 464-71.  IF: 6.433.

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Area 2. Endocrinology, Growth, Metabolism and Diabetes

AREA 2 ENDOCRINOLOGY, GROWTH, METABOLISM AND DIABETES

2.3 Paediatric Endocrinology

Group Leader Antonio Carrascosa Lezcano Tel. 93 489 30 63 [email protected] Researchers Marian Albisu Aparicio Laura Audí Parera Núria Camats Tarruella María Clemente León Mónica Fernández Cancio Norma I García Reyna Sandra Gussinyé Canabal Miguel Gussinyé Cañadel Diego Yeste Fernández Researchers in Training Agnès Moretones Barnès Nursing, Technical and Administrative Staff Ana Agudo Canales Pilar Andaluz López

RESEARCH LINES

OBJECTIVES Translational (clinical, biochemical and molecular) research into paediatric endocrine diseases.

Normal growth and development patterns in children Our group contributed to the establishment of normal charts for both sexes for height, weight and BMI from birth to adult height in Spain (Spanish Growth Studies 2008 and 2010: cross-sectional and longitudinal studies). The charts are for autochthonous and immigrant populations. The cross-sec-

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tional autochthonous charts comprise those for: newborns from 26 to 42 weeks GA and normal children from birth to 22 years. The longitudinal autochthonous study comprises charts according to age at onset of the pubertal growth spurt (very early, early, intermediate, late and very late). The charts for the immigrant population now available comprise those at birth for children of parents from the Magreb, SubSaharan Africa and Central and South America and those to adult height for children from the Magreb and SubSaharan Africa. These charts are necessary for the correct evaluation of children with skeletal growth and nutrition disorders.

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Growth delay in children: phenotype-genotype (GH1, GHRHR, GHR genes) associations Children with growth retardation are being molecularly analysed (GH1 and GHRHR depending on the clinical and biochemical phenotypes) and differences between gene sequences in the normal population and patients are being progressively described. Potentially pathogenic mutations detected are being functionally analysed in children with growth retardation (idiopathic growth retardation and SGA) and treated with GH. The association between growth responses at different periods up to the end of growth and the genotypes for the GHR gene exon 3 deletion have been analysed and are continuously monitored up to final height.

Genetic contribution to adult height (GH1 and GHRHR genes) Our Group established the complete map of SNPs in GH1 (proximal promotor and complete coding and non-coding introns) and GHRHR (promoter and exons) genes and the frequency of the GHR gene exon 3-deletion polymorphism in our normal adult height control population of both sexes with height between -2 and +2 SDS. A significant association between several of the detected SNPs and height-SDS has been demonstrated.

Human epiphyseal growth cartilage chondrocyte proliferation and gene expression regulation Postnatal regulation of skeletal growth by growth hormone (GH), insulin-like growth factor I (IGFI), thyroid hormone, androgens and oestrogen, and the need for their adequate circulating concentrations which vary depending on developmental stages, is well known; however, the physiological role of glucocorticoid (GC) on skeletal growth is poorly understood, except for the deleterious effects of its excess. Vitamin D (VitD) has been well described as a calcium homeostasis regulator as has its deficiency as a deleterious effect; however, possible direct effects of VitD on growth plate biology have scarcely been studied. To analyze the mechanisms involved in androgen, thyroid hormone, oestrogen, glucocorticoid (GC), vitamin D (VitD), growth hormone (GH) and insulin-like growth factor I (IGF-I) regulation of epiphyseal growth cartilage biology during human foetal life, we used chondrocytes obtained in primary and first passage cultures as a cellular model.

Figure 33 The main genes involved in 46,XY male sex development during foetal life with chromosomal location and cloning year

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Bone mass in children Our Group established the charts for bone mineral density (BMD) in normal children from birth to adulthood. These charts are necessary for the correct evaluation of skeletal bone mass in children at risk of developing diminished mineral density before the maximum BMD peak is attained, which predisposes to osteopenia and osteoporosis in adulthood.

Predisposing environmental and genetic factors of rickets Our Group contributed to an initial epidemiological study on the prevalence of rickets in Primary Care Areas of Catalonia involving autochthonous and immigrant infants. We further contributed to an international study conducted within the European Society for Paediatric Endocrinology (ESPE) on epidemiological and genetic factors in rickets in Middle Eastern countries. We are now contributing to further studies on the biochemical and genetic characteristics of autochthonous and immigrant children, in relation to vitamin D and calcium metabolism.

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Area 2. Endocrinology, Growth, Metabolism and Diabetes

Familial isolated glucocorticoid deficiency (FGD) (MC2R, MRAP, StAR genes) Novel mutations in MC2R and StAR genes are now being described in patients with FGD. Functional analysis of novel mutations will be established in collaboration with the Paediatric Endocrinology and Diabetology Unit of the Berne University Hospital for Children.

Figure 34 Analysis of postnatal skeletal growth regulating genes

Congenital hypothyroidism: Catalan referral center for diagnosis and therapy. Identification of mutations in thyroid hormone synthesis genes Our Group forms a reference centre for the diagnosis and treatment of congenital hypothyroidism. The approach is multidisciplinary with the collaboration of paediatric endocrinologists, psychologists and the research laboratory. The latter, located in Hospital La Paz (Madrid) contributes to the molecular diagnosis of thyroid hormone synthesis genes.

Hypothyroxynaemia in extreme preterm infants Our Group established the values of thyroid hormones (T4, T3, freeT4, free-T3 and TSH) from birth to 1 year of age in preterm infants 27-37 weeks of gestational age and contributes to the evaluation of hypothyroxinemia of preterm infants.

Disorders of sex development (DSD): clinical and molecular diagnosis (AR, SRD5A2, HSD17B3, CYP17A1, NR5A1, MAMLD1) Our Group forms a reference centre for the diagnosis and treatment of DSD. The approach is multidisciplinary with the collaboration of paediatric endocrinologists, geneticists, pathologists, paediatric surgeons, psychologists and the research laboratory. The latter contributes to the molecular diagnosis of 46,XY DSD patients, with diagnoses being offered to all other hospital centres in Spain. Functional analysis of novel mutations in NR5A1 gene are being performed in collaboration with the Paediatric Endocrinology and Diabetology Unit of the Berne University Hospital for Children.

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Hyperinsulinism and hypoglycaemia Our Group forms a reference centre for the diagnosis and treatment of infants and children with hyperinsulinaemia and hypoglycaemia syndrome. The approach is multidisciplinary with the collaboration of paediatric endocrinologists, paediatric surgeons and the research laboratory. The latter contributes to the molecular diagnosis of genes involved in this syndrome.

Type 1 diabetes: new therapeutic immunomodulators (international clinical trial) D/P3/07/4 “A phase III 3 arm randomized, double-blind, placebocontrolled multicentre study to investigate the impact of Diamyd on the progression of diabetes in patients newly diagnosed with type 1 Diabetes Mellitus”. Promoted by Dyamid Therapeutics.

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Childhood obesity: metabolic complications and therapeutic approaches Our Group forms a reference centre for the diagnosis and treatment of infants and children with obesity. The approach is multidisciplinary with the collaboration of paediatric endocrinologists, nutritionists and psychologists. We have developed a new therapeutic program “niñ@s en movimiento” and have begun training medical professionals as educators in childhood obesity. More than 250 medical professionals have been trained and our program is applied now in 32 health centres in Spain and one in Mexico. The metabolic complications of childhood obesity are also evaluated.

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CURRENT RESEARCH PROJECTS

PUBLICATIONS

PI: Laura Audí Parera Marcadores moleculares de la acción de los andrógenos: aplicaciones básicas al conocimiento de la regulación de la diferenciación sexual y diagnósticas en el pseudohermafroditismo masculino Funding Agency: Fondo de Investigación Sanitaria Reference: PI060903 Funding: 125,840 € Duration: 2007 to 2010

Audí L, Fernández-Cancio M, Carrascosa A, Andaluz P, Torán N, Piro C, Vilaró E, VicensCalvet E, Gussinyé M, Albisu MA, Yeste D, Clemente M, Hernández de la Calle I, Campo M del, et al. Novel (60%) and Recurrent (40%) Androgen Receptor Gene Mutations in a Series of 59 Patients with a 46,XY Disorder of Sex Development. J Clin Endocrinol Metab 2010 Apr; 95 (4): 187688.  IF: 6.202.

PI: Antonio Carrascosa Lezcano Estudio funcional de nuevas mutaciones en el gen GH1 en una población de 728 pacientes con retraso crónico de crecimiento secundario a deficiencia de GH o a GH con actividad biológica disminuida y buena respuesta clínica al tratamiento con GH Funding Agency: Fondo de Investigación Sanitaria Reference: PI070145 Funding: 148,830 € Duration: 2008 to 2011

PI: Antonio Carrascosa Lezcano Fisiopatologia del creixement Funding Agency: AGAUR Reference: 2009 SGR 31 Funding: 47,840 € Duration: 2010 to 2013

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(Impact Factor: 14.354)

Camina-Tato M, Morcillo-Suárez C, Bustamante MF, Ortega I, Navarro A, Muntasell A, López-Botet M, Sánchez A, Carmona P, Julia E, Tórtola MT, Audí L, Oksenberg JR, Martín R, Montalban X, Comabella M. Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis. J Immunol 2010 Nov 1; 185 (9): 5392-404.  IF: 5.646. Clemente M, Gussinyeé M, Arranz JA, Riudor E, Yeste D, Albisu M, Carrascosa A. Glycogen storage disease type III with hypoketosis. J Pediatr Endocrinol Metab 2010 Aug; 23 (8): 833-6.  IF: 0.738. Padilla N, Perapoch J, Carrascosa A, AcostaRojas R, Botet F, Gratacós E. Twelve-month neurodevelopmental outcome in preterm infants with and without intrauterine growth restriction. Acta Paediatr 2010 Oct; 99 (10): 1498-503. doi: 10.1111/j.16512227.2010.01848.x.  IF: 1.768.

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AREA 3 CARDIOVASCULAR DISEASES, HEMOSTASIS AND HYPERTENSION

3.1 Cardiovascular Diseases, Hemostasis and Hypertension Group Leader David García-Dorado García Tel. 93 489 40 38 [email protected] Researchers Elena Abad Adán Santiago Aguadé Bruix Francesc Xavier Armengol Castells Ignasi Barba Vert José Antonio Barrabés Riu Neus Bellera Gotarda Pedro Betrián Blasco Bart Bijnens Albert Brotons Dimpna Calila Jaume Candell Riera Jaume Casaldàliga Ferrer Joan Castell Conesa Josefa Cortadellas Àngel Enric Domingo Ribas Laura Dos Subirà Arturo Evangelista Masip Ignacio Ferreira González Joan Àngel Ferrer Queralt Ferrer Menduina Jaume Figueras Bellot Enrique Galve Basilio Bruno García del Blanco David García-Dorado García Gemma Giralt García Josep Girona Comas Teresa González Alujas Ferran Gran Ipiña Laura Gutiérrez García-Moreno Javier Inserte Igual Rosa María Lidón Corbi Begoña Manso García Eli Miró Casas Àngel Moya Mitjans Imanol Otaegui Irurueta Gaietà Permanyer Miralda Núria Rivas Gándara Ivo Roca Luque Jordi Pérez Rodón Antonia Pijuan Domènech Josep Pinar Sopena José Rodríguez Palomares Antonio Rodríguez Sinovas

Principal investigators of research lines Marisol Ruiz Meana Jaume Sagristà Sauleda Armando Salas Lobato Antonia Sambola Ayala Joan Sánchez de Toledo Sancho Vicenç Serra García Teresa Subirana Pilar Tomos Mas Asunción Torrents Fernández Clinical Research Mª Ángeles Carmona Ramírez Úrsula Gimeno Mañas Nadia Llavero Muñoz Post MIR Omar Abdul-Jawad Altisent Gerard Martí Aguasca Mireia Andrés Villarreal Jordi Bañeras Rius Eduard Bosch Peligero Sergio Moral Torres Gisela Teixidó Tura Eduardo Villacorta Argüelles Predoc Verónica Aliaga Amelia Carro Hevia Gemma Cuberas Borros Celia Fernández Sanz Giuliana Garibaldi Josep Ramón Marsal Mora

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Axel Mercè Sarrias Marcos Poncelas Nozal María Nazarena Pizzi Roger Quispe Marca Laura Romero Grillo Paula Andrea Rudenick José A. Sánchez García Nuria Norma Tejerina Postdoc Elena Abad Adán Amanda Denuc Isern Ana María Díaz Calvo Víctor Hernando Martínez Nursing, Technical and Administrative Staff Rodrigo Berguenda Pinto Maria Dolors Bofill Rovira Anna Casanovas Hernández Purificación Cascant Castelló Mª Teresa Fernández Taranilla Maria Angels Garcia Sánchez Daniel Gómez García Manuel Valero Gómez Guillén Lourdes Muelas Godoy Elsa Nieto Santa Mª Teresa Pastor Amorós Dorita Quiroga Brañas Aida Ribera Solé Giuliana Ríos Quiñones Ángeles Rojas López

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Area 3. Cardiovascular Diseases, Hemostasis and Hypertension

OBJECTIVES

RESEARCH LINES

The Mission of the Research Group on Cardiovascular Diseases (Consolidated Research Group of the Generalitat de Catalunya, DURSI 2009SGR0802) is to reduce the social and sanitary impact of cardiovascular diseases by improving their prevention, diagnosis and treatment. This mission is achieved through a highly multidisciplinary, translational research program including molecular and cellular investigation, clinical studies, and epidemiological and outcome research studies. The group is a member of the Spanish Network for Research of Cardiovascular Diseases and of the Center for Epidemiology and Public Health of the Instituto de Salud Carlos III (Ministry of Science).

Myocardial protection during ischemia and reperfusion David García-Dorado García This line investigates the molecular mechanisms of cell injury, in particular cell death, secondary to myocardial ischemia-reperfusion syndrome. The final aim is the development of new therapeutic strategies to limit infarct size in patients with acute coronary or other conditions causing myocardial ischemia. Sub-lines: 1.1. Mitochondrial changes and mitochondria-sarcoplasmic reticulum interaction during myocardial ischemia-reperfusion. 1.2. Role of Connein43, in particular in its mitochondrial localization in cell death and cardioprotection signalling during ischemia-reperfusion. 1.3. Cytoskeletal fragility and calpain activation as a mechanism of reperfusion injury. 1.4. Microvascular injury in reperfused myocardium.

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1.5. Prevention of LV remodelling by siRNA inhibition in reperfused myocardium. 1.6. Effect of ageing on myocardial tolerance to ischemia. 1.7. Coadjuvant cardioprotection in patients with STEMI undergoing primary percutaneous coronary intervention. 1.8. NMR-based metabolomics in ischemia-reperfusion. 1.9. Systems biology approaches to myocardial diseases.

Pathophysiology of acute coronary syndrome Jaume Figueras Bellot The aim of this line is to provide the basis for the pathophysiological stratification of patients with acute coronary syndrome that will allow optimization of evaluation and treatment. Sub-lines: 2.1. Platelet functions in acute coronary syndromes. 2.2. Determinants of LV remodelling. 2.3. Tissue factor as a predictor of final infarct size in patients with STEMI receiving primary PCI. 2.4. Antithrombotic treatment in patients with high thromboembolic risk receiving coronary stents.

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Figure 35 Molecular models: Confocal image showing (in red) expression of Cx43 in a cardiac slice obtained from an ischemic (30 min) heart from a wild-type mice. Intercalated disks were identified by staining with antibody raised against pan-Cadherin (Cad.) (green). Nuclei were marked with Hoeschst 33342 (blue)

Prognostic stratification of patients with ischemic heart disease by nuclear cardiology Jaume Candell Riera This line aims to develop new methodologies for the evaluation of the functional significance of coronary disease. Sub-lines: 3.1. Evaluation of non-significant coronary stenos. 3.2. Assessment of myocardial viability. 3.3. Prognostic significance of silent ischemia. 3.4. Multimodal imaging and 3D image fusion.

Myocardial diseases and heart failure Enrique Galve Basilio Molecular mechanisms of cardiomyopathies and determinants of heart failure. Sub-lines: 4.1. Genotype/phenotype relation in hyperthrophyc cardiomyopathy.

4.2. Analysis of myocardial fibrosis by NMR and new biomakers. 4.3. Mitochondrial function in heart failure.

Valvular heart disease Pilar Tornos Mas The aim of this line is the improvement in survival and quality of life of patients with heart valve disease through improving pathophysiologic understanding, diagnostic characterization and treatment. Sub-lines: 5.1. Epidemiology, pathophysiology and treatment of aortic stenosis, with emphasis on trans-catheter aortic valve implantation. 5.2. Determinants of the results of surgical treatment of cardiac valve diseases. 5.3. Endocarditis: natural history and results of early surgical treatment.

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Arrhythmias and syncope Àngel Moya Mitjans Diagnosis and treatment of syncope, arrhythmias and heart failure. Sub-lines: 6.1. Diagnostic work-up in syncope. 6.2. Pharmacological treatment of syncope. 6.3. Predictors of adequate ICD discharge. 6.4. Early resynchronization therapy after AMI. 6.5. Application of robotics to ablation procedures in patients with atrial fibrillation.

Pericardial diseases Jaume Sagristà Sauleda Studies on the pathophysiology, natural history, prognostic stratification and treatment of patients with pericardial and diseases. Sub-lines: 7.1. Pathophysiology of pericardial syndromes. 7.2. Prevention of recidives in patients with pericarditis. 7.3. Pericarditis in patients with cancer.

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Area 3. Cardiovascular Diseases, Hemostasis and Hypertension

Diseases of the aorta Arturo Evangelista Masip The general purpose of this line is to improve our understanding of the pathophysiology and natural history of the differnt forms of acute and chronic diseases of the aorta, including aneurism, ulcer, intramural hematoma and dissection, with particular attention paid to genetic alterations of the connective tissue, with the final aim of improving their diagnosis and treatment. Sub-lines: 8.1. Diagnostic evaluation of aortic dissection. 8.2. Prognostic determinants in aortic dissection. 8.3. Intramural hematoma as a new form of aortic disease. 8.4. Molecular pathophysiology, prognostic evaluation and treatment of Marphan syndrome. 8.5. Models of aortic diseases in silico, physical, biological.

Congenital heart disease Jaume Casaldàliga Ferrer Studies on the pathophysiology and clinical management of congenital heart diseases from intrautero life to adulthood.

Sub-lines:

Sub-lines:

9.1. Pathophysiology and evolution of systemic right ventricle. 9.2. Pharmacological treatment in patients with systemic right ventricle. 9.2. Chronic volume overload of the right ventricle. 9.3. Predictors of arrhythmic events after surgical treatment of TOF. 9.4. Remodelling of the right ventricle after surgery. 9.5. Consequences of LV outflow obstruction in TGV treated with atrial switch. 9.6. Percutanous transcatheter pulmonary valve implantation.

10.1. Variability in clinical practice and long term results of drug eluting stent implantation in Spain. 10.2. Evaluation of resources and strategies for myocardial reperfusion in patients with acute myocardial infarction in Spain. 10.3. Evaluation of risk stratification algorithms and results in cardiac surgerycoronary artery stenting with drug eluting stents. 10.4. Quality of life in very old patients with aortic valve stenosis receiving aortic valve prostheses. 10.5. Evaluation of Health-care delivery in relation to cerebrovascular disease in Catalonian hospitals. 10.6. Evaluation of the social impact of biomedical research in Catalonia.

Outcome research and evaluation of health technologies Ignacio Ferreira González This line aims to generate knowledge on the impact patient care methodologies and biomedical research programs, including analysis of effectivity of therapeutic strategies in acute coronary syndromes and cardiovascular procedures, quality of life studies, theoretical studies on methodological aspects of clinical trials and registries, and methods to evaluate the social impact of biomedical research.

Figure 36 Human samples: Analysis of intracoronary thrombi obtained from patiens with acute myocardial infarction submitted to primary percutaneous coronary intervention

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CURRENT RESEARCH PROJECTS PI: Gaietà Permanyer Miralda Assessment of stroke care in Catalonia after the implementation of an organised and integrated acute stroke care plan Funding Agency: Fundació La Marató de TV3 Reference: TV3/062810 Funding: 191,813 € Duration: 2007 to 2010

PI: Àngel Moya Mitjans Safety, feasibility and efficacy of bone marrow mononuclear stem cells intracoronary transplantation and of cardiac resynchronization therapy in patients with acute myocardial infarction Funding Agency: Fondo de Investigación Sanitaria Reference: PI070932 Funding: 163,350 € Duration: 2008 to 2011

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PI: Arturo Evangelista Masip Eficacia y seguridad de losartan vs atenolol en la prevención de la dilatación progresiva de la aorta en la población de pacientes con síndrome de Marfan Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90396 Funding: 249,865 € Duration: 2007 to 2011

PI: David García-Dorado García Protección miocárdica durante la reperfusión pacientes síndrome coronario agudo con elevación del segmento ST sometidos a angioplastia primaria: efecto de la adenosina intracoronaria sobre el tamaño del infarto y remodelado ventricular Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90511 Funding: 461,010 € Duration: 2007 to 2012

PI: Jaume Figueras Bellot Nitratos nocturnos en la prevención del edema agudo de pulmón Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90720 Funding: 52,030 € Duration: 2007 to 2010

PI: Pilar Tornos Mas Degenerative-calcific aortic valve disease: from pathogenical to epidemiological characterization Funding Agency: CNIC Reference: CNIC-09 Funding: 415,955 € Duration: 2008 to 2012

PI: Joan Castell Conesa Neuroimatge amb SPECT en cefalea per abús de medicaments Funding Agency: Fundació La Marató de TV3 Reference: MARATV3_072210 Funding: 199,800 € Duration: 2008 to 2011

PI: Josep Pinar Sopena Prevalence of degenerative aortic stenosis and aortic sclerosis in the Spanish population Funding Agency: CNIC Reference: CNIC_2_2007 Funding: 301,530 € Duration: 2008 to 2010

PI: Ignacio Ferreira González Interrupción de la doble antiagregación durante el primer año tras la implantación de stent liberador fármacos: factores determinantes e impacto sanitario Funding Agency: Fondo de Investigación Sanitaria Reference: PI07/90031 Funding: 71,995 € Duration: 2008 to 2010

PI: Santiago Aguadé Bruix Evaluation of Integrated Cardiac Imaging for the Detection and Characterization of Ischemic Heart Disease. EVINCY-StudyGrant No 222915 Funding Agency: European Commission Reference: EVINCY-222915 Funding: 56,266 € Duration: 2009 to 2011

PI: Laura Dos Subirá Antagonistas aldosterónicos en el tratamiento de pacientes con ventrículo derecho sistémico: ensayo clínico aleatorizado Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90112 Funding: 195,204.86 € Duration: 2007 to 2011

Figure 37 Bioinformatics and computer simulation: Maps of pressure, shear stress and velocity in an in silico model of aortic dissection

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PI: David García-Dorado García Modulación de la función mitocondrial y señalización de la cardiopatía endógena por canales mitocondriales de Conexina 43 Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2008-03067 Funding: 665,500 € Duration: 2009 to 2013

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Area 3. Cardiovascular Diseases, Hemostasis and Hypertension

Figure 38 High throughput methods and systems biology: NMR proton based two-dimensional spectra obtained in the NMR spectroscopy and metabolomics platform

PI: Jaume Casaldàliga Ferrer Predictors of right ventricular positive remodelling after pulmonary valve replacement in adult patients with repaired tetralogy of fallot and long stading pulmonary regurgitation Funding Agency: Fundació La Marató de TV3 Reference: MARATV3/2008/082510 Funding: 80,750 € Duration: 2009 to 2011

PI: Arturo Evangelista Masip Análisis de la biomecánica de la disección de aorta descendente. Base experimental y estudio mediante técnicas de imagen de los predictores de dilatación severa. Implicaciones terapéuticas Funding Agency: Fondo de Investigación Sanitaria Reference: PI080608 Funding: 50.578,00 € Duration: 2009 to 2011

PI: Javier Inserte Igual Caracterización de los mecanismos de regulación de la proteasa calpaína durante la isquemia/ reperfusión miocárdica y su contribución a la muerte celular Funding Agency: Fondo de Investigación Sanitaria Reference: PI080238 Funding: 43,802 € Duration: 2009 to 2011

PI: Jaume Sagristà Sauleda Eficacia de la colchicina administrada en el primer brote de pericarditis para evitar la aparición de recidivas Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00290 Funding: 26,015€ Duration: 2009 to 2011

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PI: Antonia Sambola Ayala Características inmunohistoquímicas y moleculares del trombo resistente a la fibrinólisis Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01014 Funding: 57,475 € Duration: 2010 to 2012

PI: Marisol Ruiz Meana Efecto de la edad sobre la función mitocondrial y el tipo de muerte celular durante la isquemia-reperfusión miocárdica Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/02034 Funding: 50,215 € Duration: 2010 to 2012

PI: Antonio Rodríguez Sinovas Papel de la conexina 43 en el daño miocárdico por isquemiareperfusión en las arritmias de la isquemia y en la cardioprotección por precondicionamiento Funding Agency: Sociedad Española de Cardiologia Reference: SEC2009/01 Funding: 12,000 € Duration: 2010 to 2010

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Figure 39 Cardiologists at the bench: A Resident in cardiology during her stay in the lab as part of her training, a young cardiologist in his post-MIR research training, and a biochemist, funded by RECAVA RETICS, analyze mitochondrial respiration and genetics in a human myocardial sample

PI: Ignacio Ferreira González Estudio ACDC (Adherencia al Tratamiento en Pacientes Coronarios después de un cateterismo con colocación de un stent liberador de fármacos). Seguimiento de dos años Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/90598 Funding: 31,884 € Duration: 2010 to 2011

PI: Antonia Sambola Ayala Eficacia y seguridad de la doble antiagregación comparada con anticoagulación oral+doble antiagregación en pacientes con fibrilación auricular de bajo-moderado riesgo sometidos a la implantación de un stent coronario Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-200 Funding: 408,000 € Duration: 2010 to 2011

PI: Ignacio Ferreira González Implantación de prótesis aórtica transcatéter respecto a la cirugía convencional en pacientes con estenosis aórtica severa: daño neurológico y su repercusión funcional Funding Agency: Sociedad Española de Cardiología Reference: SEC-2010-01 Funding: 18,000 € Duration: 2010 to 2012

PI: Arturo Evangelista Masip Valoración del remodelado ventricular y de la reserva contráctil en el síndrome de Marfan Funding Agency: Sociedad Española de Cardiología Reference: SEC2009/02 Funding: 16,000 € Duration: 2010 to 2011

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PI: David García-Dorado García RECAVA - Red Temática de Investigación en Enfermedades Cardiovasculares Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0014/0025 Funding: 1,297,449.59 € Duration: 2007 to 2011

PI: David García-Dorado García Patologia cardiocirculatòria Funding Agency: AGAUR Reference: 2009 SGR 802 Funding: 56,160 € Duration: 2010 to 2013

PI: David García-Dorado García Cardio Repair European Multidisciplinary Initiative (CARE-MI) Funding Agency: European Comission Funding: 557,746 € Duration: 2010 to 2015

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PUBLICATIONS (Impact Factor: 364.079) Abu-Assi E, Ferreira-González I, Ribera A, Marsal JR, Cascant P, Heras M, Bueno H, Sánchez PL, Aros F, Marrugat J, García-Dorado D, Pena-Gil C, González-Juanatey JR, Permanyer-Miralda G. “Do GRACE (Global Registry of Acute Coronary events) risk scores still maintain their performance for predicting mortality in the era of contemporary management of acute coronary syndromes?”. Am Heart J 2010 Nov; 160 (5): 826-834.e3.  IF: 4.357. Abu-Assi E, Gracia-Acuna JM, FerreiraGonzález I, Pena-Gil C, Gayoso-Diz P, González-Juanatey JR. Evaluating the Performance of the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) bleeding score in a contemporary Spanish cohort of patients with non-ST-segment elevation acute myocardial infarction. Circulation 2010 Jun 8; 121 (22): 2419-26.  IF: 14.816. Adam P, Permanyer-Miralda G, Sola-Morales O, Canela-Soler J. [Information, knowledge and healthcare practice: professionals participation as the key element of the gear.] Med Clin (Barc) 2010 Feb; 134 Suppl 1: 105.  IF: 1.231. Aguadé-Bruix S, Romero-Farina G, CuberasBorros G, Mila-López M, Pubul-Nuñez V, Siurana-Escuer R, García-Dorado D, CandellRiera J. Interassay reproducibility of myocardial perfusion gated SPECT in patients with atrial fibrillation. J Nucl Cardiol 2010 Jun; 17 (3): 450-8.  IF: 2.777. Akdi A, Giménez EM, García-Quispes W, Pastor S, Castell J, Biarnes J, Marcos R, Velázquez A. WDR3 gene haplotype is associated with thyroid cancer risk in a Spanish population. Thyroid 2010 Jul; 20 (7): 803-9.  IF: 2.602.

Alcalde O, Domingo E, Figueras J. Recurrent severe acute pulmonary edema caused by transient left ventricular insufficiency with mitral regurgitation related to severe coronary artery spasm. Circ Heart Fail 2010 Mar 1; 3 (2): 332-5.  IF: 3.433. Anido J, Saez-Borderias A, González-Junca A, Rodón L, Folch G, Carmona MA, PrietoSánchez RM, Barba I, Martínez-Saez E, Prudkin L, Cuartas I, Raventós C, MartínezRicarte F, Poca MA, García-Dorado D, Lahn MM, Yingling JM, Rodón J, Sahuquillo J, Baselga J, Seoane J. TGF-beta Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell 2010 Dec 14; 18 (6): 655-68.  IF: 25.288. Barba I, García-Ramírez M, Hernández C, Alonso MA, Masmiquel L, García-Dorado D, Simó R. Metabolic fingerprints of proliferative diabetic retinopathy. An 1H NMR-based metabonomic approach using vitreous humor. Invest Ophthalmol Vis Sci 2010 Sep; 51 (9): 4416-21.  IF: 3.431. Bardají A, Barrabés JA, Sanchis J, Sánchez PL. [Ischemic heart disease: 2009 update.] Rev Esp Cardiol 2010 Jan; 63 Suppl 1: 49-60.  IF: 2.746. Baron-Esquivias G, Martínez-Alday J, Martín A, Moya A, García-Civera R, Paz LópezChicharro M, Martín-Méndez M, Arco C del, Laguna P. Epidemiological characteristics and diagnostic approach in patients admitted to the emergency room for transient loss of consciousness: Group for Syncope Study in the Emergency Room (GESINUR) study. Europace 2010 Jun; 12 (6): 869-76.  IF: 1.871. Barrabés JA, Galian L. Endogenous thrombolysis: a hidden player in acute coronary syndromes? J Am Coll Cardiol 2010 May 11; 55 (19): 2116-7.  IF: 12.535.

Barrabés JA, Inserte J, Mirabet M, Quiroga A, Hernando V, Figueras J, García-Dorado D. Antagonism of P2Y12 or GPIIb/IIIa receptors reduces platelet-mediated myocardial injury after ischaemia and reperfusion in isolated rat hearts. Thromb Haemost 2010 Jul 5; 104 (1): 128-35.  IF: 4.451. Bassler D, Briel M, Montori VM, Lane M, Glasziou P, Zhou Q, Heels-Ansdell D, Walter SD, Guyatt GH, Flynn DN, Elamin MB, Murad MH, Abu Elnour NO, Ferreira-González I, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 2010 Mar 24; 303 (12): 1180-7.  IF: 28.899. Baumgartner H, Bonhoeffer P, Groot NM de, Haan F de, Deanfield JE, Galie N, Gatzoulis MA, Gohlke-Baerwolf C, Kaemmerer H, Kilner P, Meijboom F, Mulder BJ, Tornos P, et al. ESC Guidelines for the management of grownup congenital heart disease (new version 2010): The Task Force on the Management of Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC). Eur Heart J 2010 Dec; 31 (23): 915-57.  IF: 9.800. Bertrand OF, Poirier P, Rodes-Cabau J, Rinfret S, Title LM, Dzavik V, Natarajan M, Angel J, Batalla N, Almeras N, Costerousse O, Larochelliere R de, Roy L, Despres JP. Cardiometabolic effects of rosiglitazone in patients with type 2 diabetes and coronary artery bypass grafts: A randomized placebo-controlled clinical trial. Atherosclerosis 2010 Aug; 211 (2): 565-73.  IF: 4.522. Candell-Riera J, Romero-Farina G, AguadéBruix S, Castell-Conesa J, Aliaga V, CuberasBorros G, García-Dorado D. [Short exerciserest versus long myocardial perfusion gated SPECT protocols in patients with ischemic cardiomyopathy.] Rev Esp Med Nucl 2010 Jul-Aug; 29 (4):151-6.  IF: 0.765. Candell-Riera J, Romero-Farina G, Mila M, Aguadé-Bruix S, Cuberas G, García-Dorado D. Negative Contractile Reserve With LowDose Dobutamine in Patients With Ischemic Cardiomyopathy Investigated by Gated Myocardial Perfusion SPECT. Rev Esp Cardiol 2010 Feb; 63 (2): 181-189.  IF: 2.746. Capdevila Bert R, Marsal Mora JR, Pujol Salud J, Anguera Farran R. [Prevalence study of iodine deficiency in a 6-year-old school population.] An Pediatr (Barc) 2010 May; 72 (5): 331-8.  IF: 0.363. Cordero A, Facila L, Galve E, Mazón P. [Progress in hypertension and diabetes mellitus.] Rev Esp Cardiol 2010 Jan; 63 Suppl 1: 101-15.  IF: 2.746.

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Cuberas-Borros G, Aguadé-Bruix S, Boronatde Ferrater , Muxi-Pradas MA, Romero-Farina G, Castell-Conesa J, Aliaga V, García-Dorado D, Candell-Riera J. Normal myocardial perfusion SPECT database for the Spanish population. Rev Esp Cardiol 2010 Aug; 63 (8): 934-42.  IF: 2.746.

Gámez J, Lorenzo-Bosquet C, CuberasBorros G, Carmona F, Hernández-Vara J, Castillo J, Castell-Conesa J. Does reduced [(123)I]-FP-CIT binding in Huntington’s disease suggest pre-synaptic dopaminergic involvement? Clin Neurol Neurosurg 2010 Dec; 112 (10): 870-5.  IF: 1.303.

Evangelista A, Avegliano G, Aguilar R, Cuellar H, Igual A, González-Alujas T, RodríguezPalomares JF, Mahia P, García-Dorado D. Impact of contrast-enhanced echocardiography on the diagnostic algorithm of acute aortic dissection. Eur Heart J 2010 Feb; 31 (4): 472-9.  IF: 9.800.

Gerstein HC, Ratner RE, Cannon CP, Serruys PW, García-García HM, Es GA van, Kolatkar NS, Kravitz BG, Miller DM, Huang C, Fitzgerald PJ, Nesto RW, Ratner R, Domingo E, Mesa J, Anivarro I, Kaplinsky E, Otaegui I, García del Blanco B, Batalla N, et al. Effect of rosiglitazone on progression of coronary atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial. Circulation 2010 Mar 16; 121 (10): 1176-87.  IF: 14.816.

Evangelista A, Flachskampf FA, Erbel R, Antonini-Canterin F, Vlachopoulos C, Rocchi G, Sicari R, Nihoyannopoulos P, Zamorano J, Pepi M, Breithardt OA, Plonska-Gosciniak E. Echocardiography in aortic diseases: EAE recommendations for clinical practice. Eur J Echocardiogr 2010 Sep; 11 (8): 645-58.  IF: 1.476. Evangelista A. Aneurysm of the ascending aorta. Heart 2010 Jun; 96 (12): 979-85.  IF: 5.385.

Goldenberg I, Subirana I, Boyko V, Vila J, Elosua R, Permanyer-Miralda G, FerreiraGonzález I, Benderly M, Guetta V, Behar S, Marrugat J. Relation between renal function and outcomes in patients with nonST-segment elevation acute coronary syndrome: real-world data from the European Public Health Outcome Research and Indicators Collection Project. Arch Intern Med 2010 May 24; 170 (10): 888-95.  IF: 9.813.

Ferreira González I, Marsal JR, Ribera A, Permanyer-Miralda G, García del Blanco B, Martí G, Cascant P, Martín Yuste V, Sánchez Gila J, García Dorado D, et al. Background, incidence, and predictors of antiplatelet therapy discontinuation during the first year after drug-eluting stent implantation. Circulation 2010 Sep 7; 122 (10): 1017-25.  IF: 14.816.

González-Loyola A, Barba I. Mitochondrial metabolism revisited: a route to cardioprotection. Cardiovasc Res 2010 Nov 1; 88 (2): 209-10.  IF: 5.801.

Figueras J, Barrabés JA, Serra V, Cortadellas J, Lidon RM, Carrizo A, García-Dorado D. Hospital Outcome of Moderate to Severe Pericardial Effusion Complicating ST-Elevation Acute Myocardial Infarction. Circulation 2010 Nov 9; 122 (19): 1902-9.  IF: 14.816.

Gunduz D, Thom J, Hussain I, López D, Hartel FV, Erdogan A, Grebe M, Sedding D, Piper HM, Tillmanns H, Noll T, Aslam M. Insulin Stabilizes Microvascular Endothelial Barrier Function via Phosphatidylinositol 3-Kinase/Akt-Mediated Rac1 Activation. Arterioscler Thromb Vasc Biol 2010 Jun; 30 (6): 1237-45.  IF: 7.235.

Flores-Flores A, Sueiras-Gil M, Toledo M, García B, Lorenzo-Bosquet C, Rovira A, Cuberas-Borros G, Auger-Acosta C, SalasPuig J. [Non-convulsive status epilepticus secondary to subarachnoid haemorrhage as the presenting symptom of a cerebral amyloid angiopathy.] Rev Neurol 2010 Mar 1; 50 (5): 279-82.  IF: 1.234.

Hausenloy DJ, Ruiz-Meana M. Not just the powerhouse of the cell: emerging roles for mitochondria in the heart. Cardiovasc Res 2010 Oct 1; 88 (1): 5-6.  IF: 5.801.

Galve E, Sambola A, Saldana G, Quispe I, Nieto E, Díaz A, Evangelista A, Candell-Riera J. Late benefits of dual-chamber pacing in obstructive hypertrophic cardiomyopathy: a 10-year follow-up study. Heart 2010 Mar; 96 (5): 352-6.  IF: 5.385.

Hernando V, Inserte J, Sartorio CL, Parra VM, Poncelas-Nozal M, García-Dorado D. Calpain translocation and activation as pharmacological targets during myocardial ischemia/reperfusion. J Mol Cell Cardiol 2010 Aug; 49 (2): 271-9.  IF: 4.965. Hernando-Harder AC, Serra J, Azpiroz F, Mila M, Aguadé S, Malagelada C, Tremolaterra F, Villoria A, Malagelada JR. Colonic Responses to Gas Loads in Subgroups of Patients with Abdominal Bloating. Am J Gastroenterol 2010 Apr; 105 (4): 876-82.  IF: 6.012.

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Jiménez-Navarro MF, Ramírez-Marrero MA, Anguita-Sánchez M, Castillo JC, Domínguez Barrio P, España Barrio E, Batlle López E, Sogorb Garri F, Climent Paya V, Méndez S, Galve E, et al. Influence of gender on longterm prognosis of patients with chronic heart failure seen in heart failure clinics. Clin Cardiol 2010 Mar; 33 (3): E13-8.  IF: 1.602. León G de, Aguadé Bruix S, Aliaga V, Cuberas Borros G, Romero Farina G, Castell Conesa J, García-Dorado D, Candell Riera J. Submaximal Exercise Testing Plus Atropine in Myocardial Perfusion SPECT. Rev Esp Cardiol 2010 Oct; 63 (10): 1155-1161.  IF: 2.746. Manso B, Castellote A, Dos L, Casaldàliga J. Myocardial perfusion magnetic resonance imaging for detecting coronary function anomalies in asymptomatic paediatric patients with a previous arterial switch operation for the transposition of great arteries. Cardiol Young 2010 Aug; 20 (4): 410-7.  IF: 1.183. Medrano López C, García-Guereta L, Medrano López C, Ballesteros F, Casaldàliga J, Cuenca V, Escudero F, García de la Calzada, Grueso J, Insa B, et al. Community-acquired respiratory infections in young children with congenital heart diseases in the palivizumab era: the Spanish 4-season civic epidemiologic study. Pediatr Infect Dis J 2010 Dec; 29 (12): 1077-82.  IF: 2.854. Miquel M, Bartoli R, Ódena G, Serafin A, Cabré E, Galán A, Barba I, Córdoba J, Planas R. Rat CCl(4)-induced cirrhosis plus total portal vein ligation: a new model for the study of hyperammonaemia and brain oedema. Liver Int 2010 Aug; 30 (7): 979-87.  IF: 2.987. Narvaez-Reinaldo JJ, Barba I, González-López J, Tunnacliffe A, Manzanera M. Rapid method for isolation of desiccation-tolerant strains and xeroprotectants. Appl Environ Microbiol 2010 Aug; 76 (15): 5254-62.  IF: 3.686. Nazarena Pizzi M, Aguadé Bruix S, Cuellar Calabria H, Aliaga V, Candell Riera J. [Image fusion of gated-SPECT and CT angiography in coronary artery disease. Importance of anatomic-functional correlation.] Rev Esp Med Nucl 2010 Nov - Dec; 29 (6): 299-303.  IF: 0.765. Ovize M, Baxter GF, Lisa F di, Ferdinandy P, García-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R. Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 2010 Aug 1; 87 (3): 406-23.  IF: 5.801.

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Pardos-Gea J, Ordi-Ros J, Avegliano G, Cortés-Hernández J, Balada E, Evangelista A, Vilardell M. Echocardiography at diagnosis of antiphospholipid syndrome provides prognostic information on valvular disease evolution and identifies two subtypes of patients. Lupus 2010; 19 (5): 575-82.  IF: 2.586.

Pujadas S, Vidal-Pérez R, Hidalgo A, Leta R, Carreras F, Barros A, Bayes-Genis A, Subirana MT, Pons-Lladó G. Correlation between myocardial fibrosis and the occurrence of atrial fibrillation in hypertrophic cardiomyopathy: a cardiac magnetic resonance imaging study. Eur J Radiol 2010 Aug; 75 (2):e88-91.  IF: 2.645.

Pepi M, Evangelista A, Nihoyannopoulos P, Flachskampf FA, Athanassopoulos G, Colonna P, Habib G, Ringelstein EB, Sicari R, Zamorano JL, Sitges M, Caso P, European Association. Recommendations for echocardiography use in the diagnosis and management of cardiac sources of embolism: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr 2010 Jul; 11 (6): 461-76.  IF: 1.476.

Rodríguez-Sinovas A, Sánchez JA, GonzálezLoyola A, Barba I, Morente M, Aguilar R, Agulló E, Miró-Casas E, Esquerda N, RuizMeana M, García-Dorado D. Effects of substitution of Cx43 by Cx32 on myocardial energy metabolism, tolerance to ischemia and preconditioning protection. J Physiol 2010 Apr 1; 588 (Pt 7): 1139-51.  IF: 4.764.

Permanyer Miralda G. [Are prevention and compassion antagonic values?] Med Clin (Barc) 2010 Nov 13; 135 (14): 650-2.  IF: 1.231. Pifarre P, Cuberas G, Hernández J, Lorenzo C, Miquel F, Castell-Conesa J. Cortical and Subcortical Patterns of I-123 Iodobenzamide SPECT in Striatal D2 Receptor Parkinsonisms. Clin Nucl Med 2010 Apr; 35 (4): 228-33.  IF: 3.915. Pinedo M, Villacorta E, Tapia C, Arnold R, López J, Revilla A, Gómez I, Fulquet E, San Román JA. Inter- and intra-observer variability in the echocardiographic evaluation of right ventricular function. Rev Esp Cardiol 2010 Jul; 63 (7): 802-9.  IF: 2.746. Prendergast BD, Tornos P. Surgery for infective endocarditis: who and when? Circulation 2010 Mar 9; 121 (9): 1141-52.  IF: 14.816.

Ruiz-Meana M, Fernández Sanz C, GarcíaDorado D. The SR-mitochondria interaction: a new player in cardiac pathophysiology. Cardiovasc Res 2010 Oct 1; 88 (1): 30-9.  IF: 5.801. Sambola A, Fernández-Hidalgo N, Almirante B, Roca I, González-Alujas T, Serra B, Pahissa A, García-Dorado D, Tornos P. Sex differences in native-valve infective endocarditis in a single tertiary-care hospital. Am J Cardiol 2010 Jul 1; 106 (1): 92-8.  IF: 3.575. Shamshad F, Kenchaiah S, Finn PV, SolerSoler J, McMurray JJ, Velázquez EJ, Maggioni AP, Califf RM, Swedberg K, Kober L, Belenkov Y, Varshavsky S, Pfeffer MA, Solomon SD. Fatal myocardial rupture after acute myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALsartan In Acute myocardial iNfarcTion Trial (VALIANT). Am Heart J 2010 Jul; 160 (1): 145-51.  IF: 4.357.

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Soriano N, Ribera A, Marsal JR, Brotons C, Cascant P, Permanyer-Miralda G. Improvements in Health-Related Quality of Life of Patients Admitted for Heart Failure. The HFQoL Study. Rev Esp Cardiol 2010 Jun; 63 (6): 668-676.  IF: 2.746. Sutton R, Brignole M, Benditt D, Moya A. The Diagnosis and Management of Syncope. Curr Hypertens Rep 2010 Oct; 12 (5): 316-22.  IF: 2.377. Swedberg K, Komajda M, Bohm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L, Galve E, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010 Sep 11; 376 (9744): 875-85.  IF: 30.758. Trimarchi S, Eagle KA, Nienaber CA, Pyeritz RE, Jonker FH, Suzuki T, O’Gara PT, Hutchinson SJ, Rampoldi V, Grassi V, Bossone E, Muhs BE, Evangelista A, Tsai TT, Froehlich JB, Cooper JV, Montgomery D, Meinhardt G, Myrmel T, Upchurch GR, Sundt TM, Isselbacher EM. Importance of refractory pain and hypertension in acute type B aortic dissection: insights from the international registry of acute aortic dissection (IRAD). Circulation 2010 Sep 28; 122 (13): 1283-9.  IF: 14.816. Trimarchi S, Eagle KA, Nienaber CA, Rampoldi V, H W Jonker F, De Vincentiis C, Frigiola A, Menicanti L, Tsai T, Froehlich J, Evangelista A, Montgomery D, Bossone E, Cooper JV, Li J, G Deeb M, Meinhardt G, Sundt TM, Isselbacher EM. Role of age in acute type A aortic dissection outcome: Report from the International Registry of Acute Aortic Dissection (IRAD). J Thorac Cardiovasc Surg 2010 Oct; 140 (4): 784-9.  IF: 3.063.

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AREA 3 CARDIOVASCULAR DISEASES, HEMOSTASIS AND HYPERTENSION

3.2 Reparative and Therapy of the Heart

Group Leader Manuel Galiñanes Hernández Tel. 93 489 40 38 [email protected] Researchers Kelly Casós Vásquez Miguel Ángel Castro Alba Juan Manuel Gracia Baena María López Cavanillas

OBJECTIVES The two main objectives of the group are: • To reduce myocardial injury induced by ischemia and reperfusion through a better understanding of the underlining mechanisms and the design of new therapeutic approaches.

• To repair the damaged myocardium by elucidating the mechanisms of stem cell homing, proliferation and differentiation and exploitation of their therapeutic potential.

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RESEARCH LINES Characterization of the susceptibility of the human myocardium to ischaemic/reperfusion-induced injury and its response to protective interventions as compared to other mammalian hearts. This project will also determine the role of protein kinases in the induction of injury or protection in various animal species, including human beings.

Elucidation of the differential timecourse responses of the various myocardial cell components to ischaemic/reperfusion-induced injury and their own recovery/repair following reperfusion and the administration of growth factors and stem cells

CURRENT RESEARCH PROJECTS

PUBLICATIONS (Impact factor: 9.514)

PI: Manuel Galiñanes Hernández Cardio Repair European Multidisciplinary Initiative (CARE-MI)Project number: 242038 Funding Agency: European Commission Reference: CARE-MI-242038 Funding: 557,746 € Duration: 2010 to 2015

Ang KL, Raheel F, Bajaj A, Sosnowski A, Galiñanes M. Early impact of aortic wrapping on patients undergoing aortic valve replacement with mild to moderate ascending aorta dilatation. J Cardiothorac Surg 2010 Aug 6; 5:58.  IF: 0.737. Ang KL, Shenje LT, Reuter S, Soonpaa MH, Rubart M, Field LJ, Galiñanes M. Limitations of conventional approaches to identify myocyte nuclei in histologic sections of the heart. Am J Physiol Cell Physiol 2010 Jun; 298 (6): C1603-9.  IF: 4.013. Linares-Palomino J, Husainy MA, Lai VK, Dickenson JM, Galiñanes M. Selective blockade of protein kinase B protects the rat and human myocardium against ischaemic injury. J Physiol 2010 Jun 15; 588 (Pt 12): 2173-91.  IF: 4.764.

Utility of stem cell therapy and growth factors to repair the damaged heart

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AREA 4 NEUROSCIENCES

4.1 Alzheimer

Group Leader Mercè Boada Rovira Tel. 93 274 61 41 [email protected] Researchers Mercè Boada Rovira Francesc Pujadas Navinés Neurologists Mikel Olabarrieta Paul Antoni Palasí Franco Neuropsychologist Belén Gutiérrez

• To investigate the preventive value of nutritional factors related with oxidative stress, antinflammatory and neurovascular risk.

Psychologist Diana Liébana Gutiérrez

• Design and experimental development of new pharmacologic treatments in Alzheimer’s disease.

OBJECTIVES • To correlate the specific biomarkers in CSF (beta-amyloid 42 protein, total and phosphorilated Tau) in the extracerebral compartment (plasma). • Determine, at a molecular level, a risk profile associated with other biomarkers to complete the basic range that gathers different Alzheimer’s clinical phenotypes and therapeutic strategies on specific targets.

• Research in genetics to identify new genes associated with Alzheimer’s disease.

RESEARCH LINES Signaling proteins Mercè Boada Rovira To determine which proteins, related to neurodegenerative diseases and congophilic angiopathy, can, en bloc, be a marker for disease prediction or evolution.

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51.246

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Research in genetics Mercè Boada Rovira GWAS Project (Study with CHARGE, GERAD1 and EASI1 groups). Identification of genetic factors linked to the risk of developing late onset Alzheimer’s disease (LOAD). We use Candidate Gene Approach Strategies or Genome Wide Association Studies (GWAS) to select genetic markers that are assessed in a wide series of cases and controls. (Sudha Seshadri, Annette L. Fitzpatrick, M. Arfan Ikram, Anita L. DeStefano, Vilmundur Gudnason, Mercè Boada et al. Genome-wide Association Studies of Alzheimer’s Disease. JAMA 2010 May 12; 303 [18]: 1832-40.) The design of this research process includes well defined validation strategies and a final metaanalysis from the obtained results. The identification of new genes for LOAD means a big step in the ethiopathogenic knowledge of the disease and will allow the development of new preventive and therapeutic medium term strategies. In this line, the project will be extended in order to obtain the identifi-

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Figure 40 Location on chromosome 2 of a new gene for Alzheimer’s disease

cation of genetic factors linked to tau positive and granulin positive mutations in fronto-temporal lobar degenerations, understood as an orphan treatment disease.

CURRENT RESEARCH PROJECTS PI: Mercè Boada Roviraa,b Collaborators: J. Montanerc, F. Pujadasa, L. Tárragab, O. Lópezd, J. T. Beckerd, S. Valeroe, J. Castellsf, G. Cuberasf, A. Espinosab, G. Vinyesb, M. Rosende-Rocab, M. Ibarriab, C. Lorenzof

Study of prodromal Alzheimer’s disease and memory complaints in biomarkers and neuroimaging, as well as in transversal study of the amnesic disorder as a key symptom of conversion to AD. Funding Agency: Fondo de Investigación Sanitaria Reference: PI10/00945 Funding: 135,520 € Duration: 2008 to 2013 a

Neurology Department. Hospital Universitari Vall d’Hebron – VHIR-UAB. Barcelona. Spain. Fundació ACE. Institut Català de Neurociències Aplicades. Barcelona. Spain. c Neurovascular Research Laboratory and Neurovascular Unit. Neurology and Medicine Departments-Hospital Universitari Vall d’Hebron – VHIR-UAB. Barcelona. Spain. d Departments of Neurology, Psychiatry, and Psychology, University of Pittsburgh School of Medicine. Pittsburgh, Pennsylvania. e Psychiatry Department. Hospital Universitari Vall d’Hebron. UAB. Barcelona. Spain. f Nuclear Medicine Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain. g Neurology Department, Clínica Universidad de Navarra, Pamplona, Navarra. Spain. h Nuclear Medicine Service, CRC- Hospital Quiron. Department of Medicine, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. b

PI: Mercé Boada Roviraa,b and Joan Montaner Villalongac Participación de sistemas proteolíticos en la progresión de la angiopatía amiloide cerebral Funding Agency: Fondo de Investigación Sanitaria Reference: PI070737 Funding: 161,535 € Duration: 2008 to 2011

PI: Mercè Boada Roviraa,b Collaborators: L. Tárragab, I. Hernándezb, M. Rosende-Rocab, A. Lafuenteb, M. Alegretb, A. Espinosab, G. Vinyesb, J. Arbizug, M. Simóh, J. Castellf, I. Rocad, C. Lorenzof, G. Cuberasf, O. Lópezd

Identification of prodromal Alzheimer’s disease by amyloid and neuronal damage imaging markers in PIB-PET, FDG-PET and MR spectroscopy and diffusion-tensor imaging in subjects with probable amnnestic MCI. Funding Agency: Agència d’Avaluació de Tecnologia i Recerca Mèdiques. Departament de Salut de la Generalitat de Catalunya. Reference: 390 Funding: 108,812.70 € Duration: 2009 to 2012

PUBLICATIONS (Impact Factor: 51.246) Aguera-Ortiz LF, Sánchez Ortiz C, Durán Alonso JC, García López MT, Garzón Maldonado F, Gómez Camello A, Boada M, et al. [Memantine in the pharmacologic treatment of moderately severe to severe Alzheimer’s disease in Spain (MEMORY study)]. Rev Neurol 2010 Nov 1; 51 (9): 52534.  IF: 1.234.

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Alegret M, Vinyes-Junque G, Boada M, Martínez-Lage P, Cuberas G, Espinosa A, Roca I, Hernández I, Valero S, Rosende-Roca M, Mauleon A, Becker And JT, Tárraga L. Brain Perfusion Correlates of Visuoperceptual Deficits in Mild Cognitive Impairment and Mild Alzheimer’s Disease. J Alzheimers Dis 2010; 21 (2): 557-67.  IF: 3.832. Boada M, Antunez C, López-Arrieta J, Galán JJ, Morón FJ, Hernández I, Marín J, Martínez-Lage P, Alegret M, Carrasco JM, Moreno C, Real LM, González-Pérez A, Tarraga L, Ruiz A. CALHM1 P86L Polymorphism is Associated with Late-Onset Alzheimer’s Disease in a Recessive Model. J Alzheimers Dis 2010; 20 (1): 247-51.  IF: 3.832. Francisco J de, Pujadas F, Toledo M, Santamarina E, Quintana M, Edo MC, Centeno M, Álvarez Sabín J. A study of right-left shunt in transient global amnesia. Neurologia 2010 Mar; 25 (2): 83-89.  IF: 0.596. Gustavsson A, Jonsson L, McShane R, Boada M, Wimo A, Zbrozek AS. Willingness-topay for reductions in care need: estimating the value of informal care in Alzheimer’s disease. Int J Geriatr Psychiatry 2010 Jun; 25 (6): 622-32.  IF: 1.981. Gustavsson A, Jonsson L, Rapp T, Reynish E, Ousset PJ, Andrieu S, Cantet C, Winblad B, Vellas B, Wimo A, Boada M, et al. Differences in resource use and costs of dementia care between European countries: baseline data from the ICTUS study. J Nutr Health Aging 2010 Aug; 14 (8): 648-54.  IF: 1.712. Hernández-Guillamón , Mawhirt S, Fossati S, Blais S, Parés M, Peñalba A, Boada M, Couraud PO, Neubert TA, Montaner J, Ghiso J, Rostagno A. Matrix metalloproteinase 2 (MMP-2) degrades soluble vasculotropic amyloid-beta E22Q and L34V mutants delaying their toxicity for human brain microvascular endothelial cells. J Biol Chem 2010 Aug 27; 285 (35): 27144-58.  IF: 5.328. Lambert JC, Sleegers K, González-Pérez A, Ingelsson M, Beecham GW, Hiltunen M, Combarros O, Bullido MJ, Brouwers N, Bettens K, Berr C, Pasquier F, Richard F, Boada M, et al. The CALHM1 P86L Polymorphism is a Genetic Modifier of Age at Onset in Alzheimer’s Disease: a Meta-Analysis Study. J Alzheimers Dis 2010; 22 (1): 247-55.  IF: 3.832. Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EM, Ramírez-Lorca R, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 2010 May 12; 303 (18): 1832-40.  IF: 28.899.

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4.2 Cell Signaling and Apoptosis

Group Leader Joan Xavier Comella Carnicé Tel. 93 489 42 75 [email protected] Researchers Paulina Carriba Domínguez Joan Xavier Comella Carnicé Joaquín López Soriano Rana Moubarak Stéphanie Reix Researchers in Training Koen Galenkamp Fernando Marqués Fernández Laura Planells Ferrer Jorge Urresti Ibáñez

OBJECTIVES The main goal of the group is the study of programmed death cell events in the vertebrate nervous system. We are mainly interested in the characterization of proteins with capability for antagonizing death receptor-mediated cell death, mainly that promoted by TNFRs and Fas, and its relation with survival and signaling pathways. This approach may

contribute to a better understanding of the physiopathology of neurodegenerative illnesses (such as Alzheimer or Parkinson), characterized by an excess of cell death, or neurooncologic processes (such as neuroblastoma or glioblastoma), which present a lack of cell death. In addition, our studies may improve our knowledge in a way that will open new therapeutic targets for these illnesses.

RESEARCH LINES Characterization of the role of LFG (lifeguard) as an antiapoptotic protein, antagonist of Fas receptors and highly expressed in the nervous system. We want to know its antiapoptotic mechanism of action, and to characterize the proteins functionally interacting with it, in particular SoxN.

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Investigate the relevance and function of the two isoforms of FAIM, the short form (S) and the long form (L), in the nervous system. Faim-S promotes neural differentiation, while Faim-L is an antagonist of different death receptors. We want to know why there is a dual function, through identification and characterization of proteins selectively associated with each isoform.

PI: Joan X. Comella Caracterización del proceso de muerte neuronal inducido por el factor de necrosis tumoral Funding Agency: Dirección General de Investigación – Ministerio de Educación y Ciencia Reference: SAF2007_60287 Funding: 143,000 € Duration: 2007 to 2010

TNF is classically considered as a promoter of cell death through its specific receptor. However, in certain circumstances TNF promotes cell survival and differentiation. We want to study the antiapoptotic mechanisms of TNF, and to analyze its potential neuroprotector role in brain damage.

PUBLICATIONS (Impact Factor: 7.178) Moubarak RS, Solé C, Pascual M, Gutiérrez H, Llovera M, Pérez-García MJ, Gozzelino R, Segura MF, Iglesias-Guimarais V, Reix S, Soler RM, Davies AM, Soriano E, Yuste VJ, Comella JX. The death receptor antagonist FLIP-L interacts with Trk and is necessary for neurite outgrowth induced by neurotrophins. J Neurosci 2010 Apr 28; 30 (17): 6094-105.  IF: 7.178.

Figure 41 HeLa transfected with GFP-Lifeguard-FLAG

We aim to characterize death receptor antagonist function in the development of neuroblastoma. We will generate in vivo and in vitro models that will allow us to study the apoptotic/antiapoptotic machinery expression status, and the role of certain death receptor antagonists in the resistance to apoptosis in these tumors. We are also interested in demonstrating the existence of cancer stem cells in this kind of tumor.

CURRENT RESEARCH PROJECTS PI: Francisco Javier Vitorica Fernández (University of Seville) Activación glial en el proceso neuroinflamatorio: una potencial diana terapéutica para la enfermedad de Alzheimer Funding Agency: CIBERNED (Proyectos Cooperativos) Reference: 2010/08 Funding: 250,000 € (40,000 € Joan Comella’s subproject) Duration: 2010 to 2012

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4.3 Clinical Neuroimmunology

Group Leader Xavier Montalban Gairín Tel. 93 274 62 02 [email protected] Researchers Luis Agulló Rueda Manuel Comabella López Carme Costa Riu Herena Eixarch Ahufinger Carmen Espejo Ruiz Nicolás Fissolo Ingrid Galán Cartañá Carlos Nos Llopis Ramil Nurtdinov Jordi Río Izquierdo Jaume Sastre Garriga Mar Tintoré Subirana Researchers in Training Mª Jesús Arévalo Navines Georgina Arrambide García Ana Belén Caminero Rodríguez Ester Cantó Puig Joaquín Castillo Justribó Mª del Carmen Edo Cobos Marta Fernández Bustamante Ana Gutiérrez Franco Alejandro Horga Hernández Sunny Malhotra Mª José Mansilla López Susana Otero Romero Francisco Pérez Miralles Carmen Tur Gómez

OBJECTIVES Nursing, Technical and Administrative Staff Mireia Castillo Juárez Zoraida Castro Ruiz Joana Fitó Guillamón Milagros Fraga Pereira Carmen González Triguero Josep Graells Salvador Rosalía Horno Ocaña Ilaria Laganà Olga Montón Belenguer Elisabeth Morilla Castillo Dúnia Muñoz Valdivieso Gemma Rodríguez Martín Marta Sallent Borsot Eva Simón Marcó Silvia Soler García Sergio Vergara Ruiz Mª José Vicente Pecino Núria Vilarrasa Díaz

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The main objectives of the Clinical Neuroimmunology group through research are to improve the quality of life of persons living with multiple sclerosis (MS) and attain a greater understanding of the pathogenic mechanisms, aiming to develop new and more effective therapeutic means. Other interests in research are: therapeutic tools in MS; disease susceptibility, diagnostic and prognostic markers in MS; study of the response to interferon-beta treatment in MS patients; clinical and radiological study of primary-progressive MS; research for therapeutic targets and/or therapeutic approaches; epidemiology of MS.

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Figure 42 Possible mechanisms of immune tolerance induction by DNA vaccines. Vaccines that aim to induce immune tolerance in MS consist of bacterial plasmids into which gene sequences encoding for myelin antigens are incorporated. Plasmids are then delivered into cells either by intramuscular needle immunization (syringe) or by intradermal injection into the skin via gene gun. Afterwards, plasmids are taken up by different cell types, antigens processed and presented to the immune cells such that a specific immune response is generated or altered

RESEARCH LINES Therapeutic Research in multiple sclerosis Carlos Nos Llopis During 2010, the Clinical Neuroimmunology Research Group participated in 21 international clinical trials, namely, 10 phase II, 10 phase III, and 1 phase IV trials as well as 11 extension studies of previous trials, i.e. 6 phase II and 5 phase III trials. Xavier Montalban is involved, as a member of the Steering Committee, in the conduct of seven of these trials and is the principal investigator of 3 international phase III clinical trials.

Susceptibility, diagnostic and prognostic markers in multiple sclerosis Search for candidate genes in susceptibility regions for multiple sclerosis Manuel Comabella This line of research seeks to characterize the genetic component of multiple sclerosis by genotyping candidate genes involved in disease etiopathogenesis.

Search for clinical, radiological and biological prognostic markers in patients presenting with a clinically isolated syndrome (CIS) suggestive of MS Mar Tintoré Since 1995, patients presenting with a CIS or first attack suggestive of MS are included in a prospective cohort study. Clinical variables (age, gender topography of the syndrome), radiological variables (number of lesions, number

22010 Impact Factor:

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Figure 43 This algorithm only applies to patients with typical CIS, aged 14 to 50 years and after having performed a complete diagnostic workup. Gd gadolinium-enhancing lesion; PV periventricular; JC juxtacortical; PF posterior fossa; BS brainstem; SC spinal cord; DIS dissemination in space; DIT dissemination in time

Study of the response to interferon-beta treatment in multiple sclerosis patients of Barkhof criteria, topography of the lesions, atrophy measures), neurophysiological variables (visual, brainstem and somestesic evoked potentials) as well as biological markers (IgG and IgM oligoclonal bands, neurofilaments light and heavy chains, fetuin A, GFAP, anti-neurofascin antibodies, anti-glycan panel) are studied as predictors of conversion to MS and as predictors of disability progression. Mathematical models with different combinations of the variables listed above are investigated.

Search for biomarkers associated with conversion to multiple sclerosis in patients with clinically isolated syndromes Manuel Comabella The main objective of this line of research is to validate diagnostic and prognostic biomarkers that may be playing given roles in the conversion to multiple sclerosis in patients with a first neurological event suggestive of demyelinating disease.

Value of NMO-IgG determination in patients with clinically isolated syndromes who develop a relapsing optic neuritis or myelitis phenotype Carme Costa The objective is to study the value of NMO-IgG determination in a cohort of clinically isolated syndrome (CIS) patients who develop an NMO phenotype consisting of sequential or relapsing optic neuritis and myelitis.

Study of the cognitive deficit in patients with clinically isolated syndromes suggestive of multiple sclerosis Mª Jesús Arévalo Since 2002, patients presenting with a CIS or first attack suggestive of MS are included in a prospective cohort study of cognition. Clinical, radiological (conventional and non-conventional MRI techniques) and neuropsychological variables are studied.

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Clinical and radiological prognostic factors of response to treatment with interferon-beta Jordi Río Cohort study to establish outcome measures for clinical trials with clinical validity and clinical and radiological indicators associated with poor response to treatment.

Search for biomarkers involved in the response to interferon-beta in patients with multiple sclerosis Manuel Comabella Study to identify gene signatures that may predict the good or bad response to interferon-beta in patients with multiple sclerosis before initiating treatment or in the first months of treatment.

Prediction studies of development of neutralizing antibodies in patients with multiple sclerosis treated with interferon-beta Manuel Comabella This project aims to identify gene expression signatures that may help to predict patients who will develop neutralizing antibodies against interferon-beta.

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Clinico-radiological investigation of PPMS (Primary Progressive Multiple Sclerosis) Jaume Sastre and Carmen Tur Primary Progressive Multiple Sclerosis (PPMS) lacks effective treatment at the present time to slow disability progression. This is, at least, partly due to the scarcity of scientifically sound outcome measures, that are able to readily detect changes induced by experimental therapies. It is, therefore, fundamental to incorporate newly developed outcome measures, with higher sensitivity to change providing better correlations with clinical parameters. A prospective study is now in place to investigate such issues. Other projects related to this line of investigation in patients with PPMS are: clinical and radiological correlations, prognostic markers and diagnostic criteria.

Investigation of brain activation underpinnings of cognitive function using fMRI Jaume Sastre and Mª Jesús Arévalo Cognitive impairment is frequent in MS patients and has a major impact on activities and participation of people with MS. Cognitive performance is only partially related to MRI visible brain damage as the brain neuroplastic potential may compensate for loss of neurons and axons through use of alternative pathways. fMRI is potentially useful tool to monitor the affected brain neuroplastic potential as it enables us to visualize brain activation in such alternative pathways. Its use as a surrogate marker in clinical trials aiming at cognitive restoration also warrants further investigation. In our unit we are involved in several studies aiming at a further delineation of such potential.

Research for therapeutic targets and/or therapeutic approaches Genomic signature-based small molecule screening of neural stem cells to identify novel compounds to enhance oligodendrogenesis Carme Costa Genomic signatures will be defined in the different stages of differentiation from neural stem cells to mature oligodendrocyte. The signatures will be used to identify new drugs that could induce oligodendrogenesis. In vitro validation will be performed to confirm that the addition of these compounds to cells under different stages of lineage commitment produces the desired gene expression signature. The selected compounds will be finally tested in vivo, in an experimental autoimmune encephalomyelitis mouse model.

DNA vaccination as a therapy of multiple sclerosis Nicolás Fissolo To evaluate the potential of DNA vaccines as a possible treatment of MS, plasmid vectors expressing auto-antigens involved in the disease will be created and tested in experimental autoimmune encephalomyelitis, the animal model of MS.

Tolerance induction in experimental autoimmune encephalomyelitis using gene therapy Jordi Barquinero and Carmen Espejo Previous collaborative works with the group of Gene and Cell Therapy of our institution resulted in the development of a therapeutic strategy in which bone marrow cells were genetically modified to express a self-antigen with the aim of inducing antigen-specific tolerance. We could see a therapeutic effect even in the absence of myeloablation, thus suggesting that a concrete population of cells generated in the cell culture, but not cells with a repopulating capacity, were responsible for the therapeutic effect seen in these mice. We have identified a candidate population, called myeloid derived suppressor cells that might be mediating the antigen-specific effect.

Role of the heat shock protein (HSP)-70 in the pathogenesis of multiple sclerosis Carmen Espejo By means of interfering RNA, we are studying whether silencing HSP-70 expression changes the level of protection of the cells from the central nervous system in front of stimulus like the inflammation typical of MS.

Role of semaphorins 3A and 7A in neuroregeneration and immune regulation in EAE model Carmen Espejo This project aims to study the role of semaphorin 3A (sema3A) and sema7A, two axonal guidance molecules also involved in the regulation of immune responses, in experimental autoimmune encephalomyelitis (EAE) pathogenesis as well as their therapeutic implications.

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Inhibition of Delta-like ligand-4 as a therapy in a murine model of multiple sclerosis Herena Eixarch Delta-like ligand-4 (Dll4) is one of the ligands for Notch, which has been specifically implicated in the differentiation of Th1 T-cells and may have a role in the development of Th17 immune responses. Taking into account that Th17 responses are directly involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), our hypothesis is that the inhibition of Dll4 could have a beneficial effect on a MOG-induced EAE model.

TNF signaling pathway in multiple sclerosis Luís Agulló This project has 3 main objectives: first, to find changes in the immune response resulting from TNFRSF1A polymorphisms, that could allow the development of specific treat-

ments for these patients in the future, second, to evaluate in animal models the selective blockade of type 1 and 2 receptors of TNF by siRNA as a potential therapy in EM, and, finally, to propose pharmacophores that interact selectively with TNF receptors 1 or 2 and that could be the structural base for the development of new drugs.

Intrathecal IgM and IgG synthesis in experimental autoimmune encephalomyelitis Carmen Espejo Experimental autoimmune encephalomyelitis (EAE) is an inducible demyelinating disease serving as animal model for multiple sclerosis (MS). Both Cerebrospinal fluid (CSF)-restricted oligoclonal IgG and IgM bands are detectable in MS patients. In addition, IgG oligoclonal bands are used as a paraclinical tool to help in MS diagnosis. We aim to study intrathecal IgG and IgM synthesis over time in EAE model.

EpidEMcat Susana Otero The CEM-Cat and its Medical Advisory Committee (established in 2008 and composed of lead neurologists specialized in the management and research of MS in Catalonia) coordinates a project that aims to characterize the epidemiology of MS in Catalonia. A prevalence study in the Osona region has been finalized and sent for publication. At the present time the ongoing research line is an incidence study in Catalonia using an official MS Registry of new cases, with a wide representation of hospitals throughout Catalonia. The Registry as well as the results from previous studies will lead to collaborative studies on possible risk factors associated with the disease.

Clinical practice guidelines on multiple sclerosis Susana Otero A collaborative project to develop clinical practice guidelines on Multiple Sclerosis undertaken by the Catalan Agency for Health Information, Assessment and Quality (AIAQS) and the Multiple Sclerosis Center of Catalonia (CEM-Cat) was launched in 2010. The guideline is based on the methodology set by the National Guidelines Program of the Spanish National Health Service. This process seeks the participation of all opinion leading healthcare professionals involved in the management of MS with the aim to provide a useful tool for integrated care. As a distinct feature, the guideline will incorporate the subjective perceptions and preferences of people living with MS, their families and caregivers.

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CURRENT RESEARCH PROJECTS PI: Manuel Comabella López Estudio de genes candidatos en regiones de susceptibilidad para la esclerosis múltiple Funding Agency: Fondo de Investigación Sanitaria Reference: PI061906 Funding: 131,890 € Duration: 2007 to 2010

PI: Xavier Montalban Gairín Estudio de la heterogeneidad de la esclerosis múltiple remitenterecurrente mediante resonancia magnética y perfiles de expresión génica Funding Agency: Fondo de Investigación Sanitaria Reference: PI061334 Funding: 150,040 € Duration: 2007 to 2010

PI: Manuel Comabella López Búsqueda de nuevos tratamientos para la esclerosis múltiple mediante screening masivo de librerías de fármacos basado en perfiles de expresión génica usando mapas de conectividad Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMMA/04/2008 Funding: 73,250 € Duration: 2008 to 2011

PI: Carmen Espejo Ruiz Función de las proteínas de choque técnico (HSP, heat shock protein)-70 en la patogenia de la esclerosis múltiple Funding Agency: Fondo de Investigación Sanitaria Reference: CP07/00146 Funding: 42,000 € Duration: 2008 to 2010

PI: Mar Tintoré Subirana Estudio de marcadores biológicos pronóstico en pacientes con síndromes clínicos aislados sugestivos de esclerosis múltiple Funding Agency: Fondo de Investigación Sanitaria Reference: PI080788 Funding: 59,229.50 € Duration: 2009 to 2011

PI: Manuel Comabella López United Europeans for the development of Pharmacogenomics in Multiple Sclerosis (UEPHA-MS) Grant Agreement No 212877 Funding Agency: European Commission Reference: UEPHA-MS-212877 Funding: 186,640.70 € Duration: 2008 to 2012

PI: Manuel Comabella López Estudio con células madre para encontrar nuevos tratamientos en la esclerosis múltiple Funding Agency: Fundación Caja Navarra Reference: CAN-15271 Funding: 42,843.62 € Duration: 2009 to 2010

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PI: Carmen Espejo Ruiz ¿Podemos retrasar o evitar la neurodegeneración en la esclerosis múltiple? Funding Agency: Fundación Caja Navarra Reference: CAN2009-16365 Funding: 15,753.98 € Duration: 2010 to 2010

PI: Manuel Comabella López Validación de marcadores biológicos asociados con la conversión a esclerosis múltiple en pacientes que presentan síndromes clínicos aislados Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00788 Funding: 134,915 € Duration: 2010 to 2012

PI: Carmen Espejo Ruiz Función de las semaforinas 3A y 7A, moléculas de guía axonal, en la neurorregeneración y la regulación de la respuesta inmunitaria en la encefalomielitis autoinmune experimental Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01180 Funding: 173,030 € Duration: 2010 to 2012

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PI: Manuel Comabella López Búsqueda de marcadores de bioactividad del interferón-beta alternativos a la proteína MXA Funding Agency: Fundación Salud 2000 Reference: MERCK-2009-05 Funding: 20,000 € Duration: 2010 to 2011

PI: Manuel Comabella López Estudio de la heterogeneidad en la susceptibilidad a la muerte celular por apoptosis en pacientes con esclerosis múltiple: búsqueda de dianas terapéuticas Funding Agency: Fundación Alicia Koplowitz Reference: FAK-2010-03 Funding: 75,000 € Duration: 2010 to 2012

PI: Xavier Montalban Gairín REEM - Red Española de Esclerosis Múltiple Funding Agency: Fondo de Investigación Sanitaria Reference: RD07/0060/0020 Funding: 277,004.53 € Duration: 2008 to 2011

PI: Xavier Montalban Gairín Unitat de Neuroimmunologia Clínica (UNiC) Funding Agency: AGAUR Reference: 2009 SGR 793 Funding: 43,680 € Duration: 2010 to 2013

PI: Susana Otero Romero EpidEMcat Funding Agency: Departament de Salut, Generalitat de Catalunya Funding: 200,000 € Duration: 2008 to 2011

PUBLICATIONS (Impact Factor: 194.695) Alcina A, Vandenbroeck K, Otaegui D, Saiz A, González JR, Fernández O, Cavanillas ML, Cenit MC, Arroyo R, Alloza I, García-Barcina M, Antigüedad A, Leyva L, Comabella M, Montalban X, et al. The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis. Genes Immun 2010 Jul; 11 (5): 439-45.  IF: 4.222. Blanco Y, Hankiewicz K, Llufriu S, Sabater L, Graus F, Saiz A, Quilez A, Guerrero AL, Horga A, Montalban X, Munoz D, et al. Clinical spectrum associated with aquaporin-4 antibodies (NMO-IgG). Neurologia 2010 JanFeb; 25 (1): 5-12.  IF: 0.596. Bosma L, Kragt J, Brieva L, Khaleeli Z, Montalban X, Polman C, Thompson A, Tintoré M, Uitdehaag B. Progression on the Multiple Sclerosis Functional Composite in MS: what is the optimal cut-off for the three components? Mult Scler 2010 Jul; 16 (7): 862-7.  IF: 3.279. Camina-Tato M, Fernández M, MorcilloSuárez C, Navarro A, Julia E, Edo MC, Montalban X, Comabella M. Genetic association of CASP8 polymorphisms with primary progressive multiple sclerosis. J Neuroimmunol 2010 May; 222 (1-2): 70-5.  IF: 2.841. Camina-Tato M, Morcillo-Suárez C, Bustamante MF, Ortega I, Navarro A, Muntasell A, López-Botet M, Sánchez A, Carmona P, Julia E, Tórtola MT, Audi L, Oksenberg JR, Martín R, Montalban X, Comabella M. Gender-Associated Differences of Perforin Polymorphisms in the Susceptibility to Multiple Sclerosis. J Immunol 2010 Nov 1; 185 (9): 5392-404.  IF: 5.646. Cohen JA, Barkhof F, Comi G, Hartung HP, Khatri BO, Montalban X, Pelletier J, Capra R, Gallo P, Izquierdo G, Tiel-Wilck K, Vera A de, Jin J, Stites T, Wu S, Aradhye S, Kappos L. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. N Engl J Med 2010 Feb 4; 362 (5): 402-15.  IF: 47.050. Comabella M, Fernández M, Martín R, Rivera-Vallvé S, Borras E, Chiva C, Julia E, Rovira A, Canto E, Álvarez-Cermeno JC, Villar LM, Tintoré M, Montalban X. Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis. Brain 2010 Apr; 133 (Pt 4): 1082-93.  IF: 9.490.

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Comabella M, Montalban X, Horga A, Messmer B, Kakalacheva K, Strowig T, Caballero E, Munz C, Lunemann J. Antiviral immune response in patients with multiple sclerosis and healthy siblings. Mult Scler 2010 Mar; 16 (3): 355-8.  IF: 3.279. Comabella M, Montalban X, Kakalacheva K, Osman D, Nimmerjahn F, Tintoré M, Lunemann JD. B cell expression of the inhibitory Fc gamma receptor is unchanged in early MS. J Neuroimmunol 2010 Jun; 223 (1-2): 135-7.  IF: 2.841. Comi G, Abramsky O, Arbizu T, Boyko A, Gold R, Havrdova E, Komoly S, Selmaj K, Sharrack B, Filippi M, Montalban X, et al. Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multicentre, randomized, double-blind, parallelgroup placebo-controlled study. Mult Scler 2010 Nov; 16 (11): 1360-6.  IF: 3.279. Comi G, O’Connor P, Montalban X, Antel J, Radue EW, Karlsson G, Pohlmann H, Aradhye S, Kappos L, Tintoré M, et al. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results. Mult Scler 2010 Feb; 16 (2): 197-207.  IF: 3.279. Espósito F, Patsopoulos NA, Cepok S, Kockum I, Leppa V, Booth DR, Heard RN, Stewart GJ, Cox M, Scott RJ, Lechner-Scott J, Goris A, Dobosi R, Dubois B, Rioux JD, Comabella M, et al. IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci. Genes Immun 2010 Jul; 11 (5): 397-405.  IF: 4.222. Fernández M, Montalban X, Comabella M. Orchestrating innate immune responses in multiple sclerosis: Molecular players. J Neuroimmunol 2010 Aug 25; 225 (1-2): 5-12.  IF: 2.841. Fernández O, Fernández V, Arbizu T, Izquierdo G, Bosca I, Arroyo R, García Merino JA, Ramon E de, Montalban X, Perkal HD, et al. Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (The Novo Study). J Neurol 2010 Sep; 257 (9): 1500-7.  IF: 2.903. Flachenecker P, Khil L, Bergmann S, Kowalewski M, Pascu I, Pérez-Miralles F, SastreGarriga J, Zwingers T. Development and pilot phase of a European MS register. J Neurol 2010 Oct; 257 (10): 1620-7.  IF: 2.903. Francisco J de, Pujadas F, Toledo M, Santamarina E, Quintana M, Edo MC, Centeno M, Álvarez-Sabín J. A study of right-left shunt in transient global amnesia. Neurologia 2010 Mar; 25 (2): 83-89.  IF: 0.596.

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Gámez J, Lorenzo-Bosquet C, CuberasBorros G, Carmona F, Hernández-Vara J, Castillo J, Castell-Conesa J. Does reduced [(123)I]-FP-CIT binding in Huntington’s disease suggest pre-synaptic dopaminergic involvement? Clin Neurol Neurosurg 2010 Dec; 112 (10): 870-5.  IF: 1.303. García Merino A, Fernández O, Montalban X, Andres C de, Arbizu T. Spanish Neurology Society consensus document on the use of drugs in multiple sclerosis: escalating therapy. Neurologia 2010 Jul; 25 (6): 378-390.  IF: 0.596. Horga A, Castillo J, Montalban X. Fingolimod for relapsing multiple sclerosis: an update. Expert Opin Pharmacother 2010 May; 11 (7): 1183-96.  IF: 2.018. Kakalacheva K, Comabella M. Epstein-Barr virus and multiple sclerosis: causation or association? Future Microbiol 2010 Nov; 5: 1617-9.  IF: 2.875. Lunemann JD, Tintoré M, Messmer B, Strowig T, Rovira A, Perkal H, Caballero E, Munz C, Montalban X, Comabella M. Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol 2010 Feb; 67 (2): 159-69.  IF: 9.317. Mendioroz M, Fernández Cadenas I, Río Espinola A del, Rovira A, Solé E, Fernández Figueras M, García Patos V, Sastre Garriga J, Domíngues Montanari, Álvarez-Sabín J, Montaner J. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population. Neurology 2010 Nov 30; 75 (22): 2033-5.  IF: 8.172. Mesaros S, Rocca M, Sormani M, Valsasina P, Markowitz C, Stefano N de, Montalban X, Barkhof F, Ranjeva J, Sailer M, Kappos L, Comi G, Filippi M. Bimonthly assessment of magnetization transfer magnetic resonance imaging parameters in multiple sclerosis: a 14-month, multicentre, follow-up study. Mult Scler 2010 Mar; 16 (3): 325-31.  IF: 3.279. Montalban X, Tintoré M, Swanton J, Barkhof F, Fazekas F, Filippi M, Frederiksen J, Kappos L, Palace J, Polman C, Rovaris M, Stefano N de, Thompson A, Yousry T, Rovira A, Miller DH. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 2010 Feb 2; 74 (5): 427-34.  IF: 8.172.

Otero S, Batlle J, Bonaventura I, Brieva L, Bufill E, Cano A, Carmona O, Escartín A, Marco M, Moral E, Munteis E, Nos C, Pericot I, Perkal H, Ramio-Torrenta L, RamoTello C, Saiz A, Sastre-Garriga J, Tintoré M, Vaqué J, Montalban X, Pérez-Miralles F, et al. Multiple sclerosis epidemiological situation update: pertinence and set-up of a population based registry of new cases in Catalonia. Rev Neurol 2010 May 16; 50 (10): 623-33.  IF: 1.234. Pelayo R, Montalban X, Minoves T, Moncho D, Río J, Nos C, Tur C, Castillo J, Horga A, Comabella M, Perkal H, Rovira A, Tintoré M. Do multimodal evoked potentials add information to MRI in clinically isolated syndromes? Mult Scler 2010 Jan; 16 (1): 5561.  IF: 3.279. Petzold A, Altintas A, Andreoni L, Bartos A, Berthele A, Blankenstein MA, Buee L, Castellazzi M, Cepok S, Comabella M, Constantinescu CS, Deisenhammer F, Deniz G, et al. Neurofilament ELISA validation. J Immunol Methods 2010 Jan 31; 352 (1-2): 23-31.  IF: 2.347. Radue EW, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Rudick RA, Lublin FD, Weinstock-Guttman B, Wynn DR, Fisher E, Papadopoulou A, Lynn F, Panzara MA, Sandrock AW, Montalban X, Nos C, Pelayo R, Tellez N, Río J, Tintoré M, et al. Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis. J Neurol Sci 2010 May 15; 292 (1-2): 28-35.  IF: 2.324. Rovira A, Tintoré M, Álvarez-Cermeno JC, Izquierdo G, Prieto JM. Recommendations for using and interpreting magnetic resonance imaging in multiple sclerosis. Neurologia 2010 May; 25 (4): 248-65.  IF: 0,596. Sastre-Garriga J, Tintoré M, Nos C, Tur C, Río J, Téllez N, Castillo J, Horga A, Perkal H, Comabella M, Rovira A, Montalban X. Clinical features of CIS of the brainstem/cerebellum of the kind seen in MS. J Neurol 2010 May; 257 (5): 742-6.  IF: 2.903. Sellner J, Boggild M, Clanet M, Hintzen RQ, Illes Z, Montalban X, Pasquier RA du, Polman CH, Sorensen PS, Hemmer B. EFNS guidelines on diagnosis and management of neuromyelitis optica. Eur J Neurol 2010 Aug; 17 (8): 1019-32.  IF: 2.510.

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Sierra-Marcos A, Mitjana R, Castillo J, Edo MC, Horga-Hernández A, Tintoré M, RioIzquierdo J, Auger-Acosta C, Rovira A, Montalban X. Demyelinating lesions as incidental findings in magnetic resonance imaging: a study of 11 cases with clinicoradiological follow-up and a review of the literature. Rev Neurol 2010 Aug; 51 (3): 129-34.  IF: 1.234. Stefano N de, Giorgio A, Battaglini M, Rovaris M, Sormani MP, Barkhof F, Korteweg T, Enzinger C, Fazekas F, Calabrese M, Dinacci D, Tedeschi G, Gass A, Montalban X, Rovira A, Thompson A, Comi G, Miller DH, Filippi M. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology 2010 Jun 8; 74 (23): 1868-1876.  IF: 8.172. Teunissen CE, Tumani HT, Bennett JL, Berven FS, Brundin L, Comabella M, Franciotta D, Federiksen JL, Fleming JO, Furlan R, Hintzen RQ, Hughes SG, et al. Short commentary on ‘a consensus protocol for the standardization of cerebrospinal fluid collection and biobanking’. Mult Scler 2010 Feb; 16 (2): 129-32.  IF: 3.279. Tintoré M, Rovira A, Arrambide G, Mitjana R, Río J, Auger C, Nos C, Edo MC, Castillo J, Horga A, Pérez Miralles F, Huerga E, Comabella M, Sastre Garriga J, Montalban X. Brainstem lesions in clinically isolated syndromes. Neurology 2010 Nov 23; 75 (21): 1933-8.  IF: 8.172. Vandenbroeck K, Comabella M. Singlenucleotide polymorphisms in response to interferon-Beta therapy in multiple sclerosis. J Interferon Cytokine Res 2010 Oct; 30 (10): 727-32.  IF: 1.627. Vandenbroeck K, Urcelay E, Comabella M. IFN- pharmacogenomics in multiple sclerosis. Pharmacogenomics 2010 Aug; 11 (8): 1137-48.  IF: 3.893. Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J, O’Neill G, Neyer L, Sheridan J, Wang C, Fong A, Rose JW. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet Neurol 2010 Apr; 9 (4): 381-90.  IF: 18.126.

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4.4 Headache and Neurological Pain

Group Leader Patricia Pozo Rosich Tel. 93 274 66 06 [email protected] Researchers in Training Joan Durà Miralles Jessica Fernández Morales Nursing, Technical and Administrative Staff Susana Gómez Baeza

OBJECTIVES

RESEARCH LINES

Translational studies

Primary headaches (migraine, cluster headache) are very prevalent and extremely disabling. The mission of the Headache & Pain Group is to study the pathophysiology of primary headaches (migraine and trigemino-autonomic cephalalgias) and other neurological pain disorders using preclinical, translational and clinical research. This is the first laboratory in Catalonia and Spain solely dedicated to the study of headache as a brain disorder.

Genetics

• Neuroimaging using SPECT in medication overuse headache and migraine patients

• CHROMIG project: genotyping migraine (chronic & episodic) • Pharmacogenomics

• Serum biomarkers in migraine (metaloproteases) • Neurophysiology evaluation in migraine, ERPs (event related potentials - cortical mapping), study of the emotional and neurophysiological response towards an affective multimodal dictionary. • Headache & Intracraneal Idiopathic Hypertension. • Neuropsychological evaluation of migraine and medicationoveruse headache patients.

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PUBLICATIONS (Impact Factor: 3.702) Pascual J, Sanchez del Río M, Jiménez MD, Lainez-Andres JM, Mateos V, Leira R, Pozo Rosich P, Guzman-Quilo C. [Approach of neurologists in Spain to migraine: results of the CIEN-mig project (I).] Rev Neurol 2010 May 16; 50 (10): 577-83.  IF: 1.234. Pascual J, Sánchez del Río M, Jiménez MD, Lainez-Andres JM, Mateos V, Leira R, PozoRosich P, Guzman-Quilo C. [Satisfaction of the migraine patient attending neurology clinics: results of CIEN-mig project (II).] Rev Neurol 2010 Jun 1; 50 (11): 641-5.  IF: 1.234. Pascual J, Sánchez del Río M, Jiménez MD, Lainez-Andres JM, Mateos V, Leira R, Pozo-Rosich P, Guzmán-Quilo C. [Chronic migraine as seen by neurologists and patients: results of the CIEN-mig project (III).] Rev Neurol 2010 Jun 16; 50 (12): 705-710.  IF: 1.234.

Figure 44 Synapsis which enables a nerve impulse

Preclinical studies Neurophysiological studies of the trigeminovascular and the thalamocortical systems

Clinical trials During the last few years we have conducted 6 clinical trials in phase II for the treatment of acute migraine and 2 clinical trials for the prevention of migraine.

Figure 45 Brain circuitry

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4.5 Magnetic Resonance and Neuroradiology Group Leader Àlex Rovira Cañellas Tel. 93 274 67 32 [email protected] Researchers Juli Alonso Farré Cristina Auger Acosta Francisco Javier Aymerich Martínez Laura Frascheri Verzelli José Luis Munuera del Cerro Deborah Pareto Onghena Àlex Rovira Cañellas Researchers in Training Raquel Mitjana Penella Silvana Isabel Sarria Estrada Sahyly Siurana Montilva Nursing, Technical and Administrative Staff Juan Francisco Corral Gámez Silvia Gelabert Udina Elena Huerga Núñez Ana Maria Nieto Montoya

Welcome to the Neuro Magnetic Resonance research group. We invite you to have a look at a viable and efficient way to use MR technology to carry out research projects. In the pages that ensue, you will find a broad description of who we are and how we work. The unit is directed by Dr. Àlex Rovira (neuroradiologist). Overall MR research coordination is under Dr. Juli Alonso (biochemist), while clinical coordination is under Dr. Cristina Auger (neuroradiologist).

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OBJECTIVES The multidisciplinary character of our group (neuroradiologists, physicists, biochemists, engineers, and MR technologists) allows us to divide objectives into two aspects. The first focuses on the pathophysiologic mechanisms implicated in pathologies such as multiple sclerosis (MS), hepatic encephalopathy, and stroke through the application of MR techniques, carrying out qualitative and quantitative analyses. Second, with the experience acquired along the years in performing MR studies, we can act as a platform for designing projects, processing images, and quantitative analysis of MR data. As a major imaging resource for the Hospital, the unit strives for excellence in its dual mission of research and service.

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RESEARCH LINES Application of MR imaging and spectroscopy techniques to the study of multiple sclerosis Àlex Rovira Cañellas This research line is focussed on studying the predictive value of magnetic resonance imaging variables in MS and investigation in brain plasticity. Other current interests include obtaining information about pathophysiologic processes (neural damage and demyelination) and incorporating pattern recognition techniques into analysis of magnetic resonance spectra for differentiating between demyelinating lesions and glial tumors, or between clinical forms of multiple sclerosis.

Functional MR imaging Deborah Pareto Onghena In this line we work on the implementation of protocols for investigating motor, visual, and cognitive tasks as well as to the analysis of functional MR imaging (fMRI). We believe that the capability of fMRI to detect cortical areas that activate when a specific task is being performed may be of great importance as a monitoring tool to determine the effect of disease and assess the efficacy of therapies.

Development of software for image analysis Francisco Javier Aymerich Martínez The application of computer vision techniques, image processing, pattern recognition and diffuse logic to the analysis of magnetic resonance images allows the development of software focused specifically on this type of images.

Application of MR imaging and spectroscopy techniques to the study of hepatic encephalopathy Juli Alonso Farré The objective of this line is to obtain information about the pathophysiologic mechanisms involved in the development of hepatic encephalopathy. It is mainly focussed on cerebral edema: its characteristics, evolution, and relationship with clinical variables.

Figure 46 Lesion probability maps of clinically isolated syndrome patients whose first attack was optic neuritis, myelitis or brainstem syndrome and the conversion to multiple sclerosis

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Figure 47 Brain fast fluid attenuated inversion recovery (top) and T1-weighted (bottom) axial images of a cirrhotic patient before liver transplantation (left), at short term (center), and at long term (right) after transplantation. Top images show a decrease in lesion volume in the short term followed by an increase in the long term after liver transplantation. Bottom images show an enlargement of ventricles in the consecutives assessments

PUBLICATIONS (Impact Factor: 82.348)

Design of MR protocols and quantitative analysis of the images Àlex Rovira Cañellas With the development of research projects centred on the lines described above we have acquired an important experience that allows us to offer services involving protocol design and quantitative image analysis with existing or inhouse-developed computer tools for projects carried out in other public or private institutions.

Chavarria L, Oria M, Romero-Giménez J, Alonso J, Lope-Piedrafita S, Córdoba J. Diffusion tensor imaging supports the cytotoxic origin of brain edema in a rat model of acute liver failure. Gastroenterology 2010 Apr; 138 (4): 1566-73.  IF: 12.899.

Gutiérrez LG, Rovira A, Portela LA, Leite Cda C, Lucato LT. CT and MR in non-neonatal hypoxic-ischemic encephalopathy: radiological findings with pathophysiological correlations. Neuroradiology 2010 Nov; 52 (11): 949-76.  IF: 2.616.

Comabella M, Fernández M, Martín R, Rivera-Vallvé S, Borras E, Chiva C, Julia E, Rovira A, Canto E, Álvarez-Cermeno JC, Villar LM, Tintoré M, Montalban X. Cerebrospinal fluid chitinase 3-like 1 levels are associated with conversion to multiple sclerosis. Brain 2010 Apr; 133 (Pt 4): 108293.  IF: 9.490.

Lunemann JD, Tintoré M, Messmer B, Strowig T, Rovira A, Perkal H, Caballero E, Munz C, Montalban X, Comabella M. Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol 2010 Feb; 67 (2): 159-69.  IF: 9.317.

Flores-Flores A, Sueiras-Gil M, Toledo M, García B, Lorenzo-Bosquet C, Rovira A, Cuberas-Borros G, Auger-Acosta C, SalasPuig J. [Non-convulsive status epilepticus secondary to subarachnoid haemorrhage as the presenting symptom of a cerebral amyloid angiopathy] Rev Neurol 2010 Mar 1; 50 (5): 279-82.  IF: 1.234. García-Martínez R, Rovira A, Alonso J, Aymerich FX, Huerga E, Jacas C, Simón-Talero M, Vargas V, Córdoba J. A Long-Term Study of Changes in the Volume of Brain Ventricles and White Matter Lesions After Successful Liver Transplantation. Transplantation 2010 Mar 15; 89 (5): 589-94.  IF: 3.498.

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Mendioroz M, Fernández Cadenas I, Río Espinola A del, Rovira A, Solé E, Fernández Figueras M, García Patos V, Sastre Garriga J, Domingues Montanari, Álvarez Sabín J, Montaner J. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population. Neurology 2010 Nov 30; 75 (22): 2033-5.  IF: 8.172. Montalban X, Tintoré M, Swanton J, Barkhof F, Fazekas F, Filippi M, Frederiksen J, Kappos L, Palace J, Polman C, Rovaris M, Stefano N de, Thompson A, Yousry T, Rovira A, Miller DH. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 2010 Feb 2; 74 (5): 427-34.  IF: 8.172.

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Pelayo R, Montalban X, Minoves T, Moncho D, Río J, Nos C, Tur C, Castillo J, Horga A, Comabella M, Perkal H, Rovira A, Tintoré M. Do multimodal evoked potentials add information to MRI in clinically isolated syndromes? Mult Scler 2010 Jan; 16 (1): 55-61.  IF: 3.279. Poca MA, Benejam B, Sahuquillo J, Riveiro M, Frascheri L, Merino MA, Delgado P, Álvarez-Sabín J. Monitoring intracranial pressure in patients with malignant middle cerebral artery infarction: is it useful? J Neurosurg 2010 Mar;112(3):648-57.  IF: 2.594. Rovira A, Tintoré M, Álvarez-Cermeno JC, Izquierdo G, Prieto JM. [Recommendations for using and interpreting magnetic resonance imaging in multiple sclerosis] Neurologia 2010 May; 25 (4): 248-65.  IF: 0.596. Sastre-Garriga J, Tintoré M, Nos C, Tur C, Río J, Tellez N, Castillo J, Horga A, Perkal H, Comabella M, Rovira A, Montalban X. Clinical features of CIS of the brainstem/cerebellum of the kind seen in MS. J Neurol 2010 May; 257 (5): 742-6.  IF: 2.903.

Sierra-Marcos A, Mitjana R, Castillo J, Edo MC, Horga-Hernández A, Tintoré M, RíoIzquierdo J, Auger-Acosta C, Rovira A, Montalban X. [Demyelinating lesions as incidental findings in magnetic resonance imaging: a study of 11 cases with clinico-radiological follow-up and a review of the literature] Rev Neurol 2010 Aug; 51 (3): 129-34.  IF: 1.234. Stefano N de, Giorgio A, Battaglini M, Rovaris M, Sormani MP, Barkhof F, Korteweg T, Enzinger C, Fazekas F, Calabrese M, Dinacci D, Tedeschi G, Gass A, Montalban X, Rovira A, Thompson A, Comi G, Miller DH, Filippi M. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology 2010 Jun 8; 74 (23): 1868-1876.  IF: 8.172. Tintoré M, Rovira A, Arrambide G, Mitjana R, Río J, Auger C, Nos C, Edo MC, Castillo J, Horga A, Pérez Miralles F, Huerga E, Comabella M, Sastre Garriga J, Montalban X. Brainstem lesions in clinically isolated syndromes. Neurology 2010 Nov 23; 75 (21): 1933-8.  IF: 8.172.

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4.6 Neurodegenerative Diseases

Group Leader Miquel Vila Bover Tel. 93 489 45 43 [email protected] Researchers Jordi Bové Badell Iria Carballo Carbajal Marta Martínez Vicente Celine F Perier Miquel Vila Bover Researchers in Training Ariadna Recasens Ibabe Nursing, Technical and Administrative Staff Mireia Humà Pérez Annabelle Parent Esther Pérez Gracia

OBJECTIVES The research conducted in our group is geared toward elucidating the molecular mechanisms of neuron cell death occurring in neurodegenerative disorders, with the aim of finding a cure for this group of disabling, currently incurable, neurological diseases. To this end, our work has mostly focused so far on Parkinson’s

disease (PD), a particular neurodegenerative disorder mainly characterized by the degeneration of a specific set of neurons that are anatomically confined to a small region of the brain called substantia nigra pars compacta (SNpc) and that produce the neurotransmitter dopamine. Elucidating the molecular mech-

anisms underlying neurodegeneration in Parkinson’s disease should allow the development of new therapeutic strategies aimed at blocking neuronal death in this disorder, as well as elicit important clues to identifying molecular pathways that might be common to other neurodegenerative conditions.

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Figure 48 Post-mortem brain sample from a PD patient showing a Lewy body in a pigmented dopaminergic nigral, which classically appear with hematoxylin/eosin staining as one or more eosinophilic spherical body (pink colour) with a dense core surrounded by a halo

RESEARCH LINES Mitochondrial dysfunction and Parkinson’s disease Miquel Vila Bover Mitochondrial dysfunction, in particular at the level of complex I of the mitochondria respiratory chain, has long been implicated in the pathogenesis of PD. However, a primary direct pathogenic role of complex I deficiency in PD-related neurodegeneration remains to be elucidated. Some of our current research projects are aimed at determining the cause and role of mitochondrial alterations in PD.

Targeting programmed cell death in Parkinson’s disease Miquel Vila Bover Programmed cell death (PCD), a physiological process that occurs naturally during development in which molecular programs intrinsic to the cell are activated to cause its own destruction, is inappropriately re-activated in PD, causing SNpc dopaminergic neurodegeneration. We are currently exploring the mechanisms that activate and regulate PCD pathways in PD in order to identify new molecular targets of potential therapeutic significance to attenuate or prevent dopaminergic neurodegeneration.

Role of intracytoplasmic neuronal inclusions in Parkinson’s disease Miquel Vila Bover From a neuropathological point of view, PD is characterized not only by the loss of nigrostriatal dopaminergic neurons but also by the presence in affected brain regions of intraneuronal proteinacious cytoplasmic inclusions, called Lewy bodies (LB). However, the mechanisms of formation and significance of LB to the disease process remains to be elucidated. Our group is currently studying the potential involvement of lysosomal- and proteasomal-mediated cellular degradation pathways on the formation of LB, as well as the mechanisms of spread of LB pathology.

Role of mutated proteins associated to familial forms of Parkinson’s disease Miquel Vila Bover In the past few years, mutations that cause familial forms of PD have been identified in several genes, including alpha-synuclein, parkin, DJ-1, PINK-1 and Dardarin/ LRRK2. Exploring how these muta-

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tions lead to familial forms of PD should provide important clues to understanding the pathogenesis of the sporadic forms of the disease and allow the development of new genetic models of PD.

Autophagy alterations in Huntington’s disease Marta Martinez Vicente and Miquel Vila Bover Autophagy is the degradation of intracellular components inside lysosomes, it is a highly conserved mechanism of quality control in the cells and is essential for the maintenance of cellular homeostasis and the control of an efficient cellular response to stress. Intracellular accumulation of altered and misfolded proteins is the basis of most neurodegenerative disorders; recent studies have shown that a primary failure in autophagy could be responsible for the accumulation of these altered proteins inside the affected neurons. Alterations in autophagy have been associated with Huntington’s disease. Preliminary results show a failure in macroautophagy, the main lysosomal

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pathway responsible for the degradation of cytosolic proteins and organelles. This failure can be compensated for by the activation of other alternative proteolytic pathways that can degrade cytosolic soluble proteins; however the insoluble aggregates (one of the main hallmarks of this disease) and organelles remain inside the cell. The long term accumulation of undigested organelles, especially mitochondria, can be a new source of intracellular oxidative stress. Indeed, dysfunctional mitochondria and oxidative stress have already been described as major contributors to neuronal loss in Huntington’s disease and the deficient degradation of dysfunctional mitochondria by autophagy becomes an aggravating factor in the pathophysiology of this disease. The overall goal of the project is to study the failure of mitochondria turnover by autophagy (mitophagy) in Huntington’s disease. Identifying the role of huntington protein in autophagy and the molecular mechanism of its failure in Huntington’s disease would be essential for future efforts to restore proper autophagic activity and make sure that dysfunctional organelles will be properly eliminated.

CURRENT RESEARCH PROJECTS PI: Miquel Vila Bover Mecanismos y relevancia de la formación de cuerpos de Lewy en la enfermedad de Parkinson Funding Agency: Fondo de Investigación Sanitaria Reference: PI071019 Funding: 217,679 € Duration: 2008 to 2011

PUBLICATIONS (Impact Factor: 78.772) PI: Celine F Perier Control de calidad de las mitocondrias: implicación en la enfermedad de Parkinson Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00255 Funding: 160,325 € Duration: 2010 to 2012

PI: Miquel Vila Bover Mecanismos de propagación y progresión de la enfermedad de Parkinson: rol de los cuerpos de Lewy Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2009-06575-E Funding: 35,000 € Duration: 2010 to 2011

PI: Marta Martínez Vicente Altered autophagy in Huntington’s disease Funding Agency: Fondo de Investigación Sanitaria Reference: CP09/00184 Funding: 34,836.65 € Duration: 2010 to 2012

Figure 49 Dopaminergic neuron in the substantia nigra of a mouse ventral midbrain revealed by immunohistochemistry against tyrosinehydroxilase (TH, brown colour), the ratelimiting enzyme of dopamine synthesis

PI: Miquel Vila Bover Grup de Recerca en Malalties Neurodegeneratives Funding Agency: AGAUR Reference: 2009 SGR 664 Funding: 41,600 € Duration: 2010 to 2013

PI: Marta Martínez Vicente Alteración de la autofagia en la enfermedad de Huntington Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2009-08374 Funding: 110,395.65 € Duration: 2010 to 2012

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Cuervo AM, Wong ES, Martínez-Vicente M. Protein degradation, aggregation, and misfolding. Mov Disord 2010; 25 Suppl 1: S49-54.  IF: 4.014. Dehay B, Bové J, Rodríguez-Muela N, Perier C, Recasens A, Boya P, Vila M. Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 2010 Sep 15; 30 (37): 12535-44.  IF: 7.178. Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM, Wolfe DM, Martínez-Vicente M, Massey AC, Sovak G, Uchiyama Y, Westaway D, Cuervo AM, Nixon RA. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010 Jun 25; 141 (7): 1146-58.  IF: 31.152. Martínez Vicente M, Talloczy Z, Wong E, Tang G, Koga H, Kaushik S, Vries R de, Arias E, Harris S, Sulzer D, Cuervo AM. Cargo recognition failure is responsible for inefficient autophagy in Huntington’s disease. Nat Neurosci 2010 May; 13 (5): 567-76.  IF: 14.345. Perier C, Bové J, Dehay B, Jackson-Lewis V, Rabinovitch PS, Przedborski S, Vila M. Apoptosis-inducing factor deficiency sensitizes dopaminergic neurons to parkinsonian neurotoxins. Ann Neurol 2010 Aug; 68 (2): 184-92.  IF: 9.317. Sotiriou E, Vassilatis DK, Vila M, Stefanis L. Selective noradrenergic vulnerability in alpha-synuclein transgenic mice. Neurobiol Aging 2010 Dec; 31 (12): 2103-14.  IF: 5.937. Wang Y, Martínez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E. Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy 2010 Jan; 6 (1): 182-3.  IF: 6.829.

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AREA 4 NEUROSCIENCES

4.7 Neuromuscular and Mitochondrial Pathology Group Leader Antonio Luis Andreu Périz Tel. 93 489 49 80 [email protected] Researchers Yolanda Cámara Navarro Elena García Arumí Emiliano González Vioque Ramón Martí Seves Gisela Nogales Gadea Tomas Pinós Figueras Researchers in Training Marc Cuadros Arasa Javier Torres Torronteras Nursing, Technical and Administrative Staff Ramiro Martínez Estéfano Mª Jesús Melia Grimal

RESEARCH LINES

OBJECTIVES The group focuses on the study of pathogenic mechanisms of mitochondrial DNA mutations (mtDNA) associated with diverse neuromuscular syndromes. It is especially interested in understanding the pathogenic mechanisms involved in mutations of structural genes of mtDNA, as well as the adaptative mechanisms of the cell in mtDNA depletion syndrome. In addition, it performs the genetic and molecular study of diverse neurological syndromes and glycogenosis type III and V.

Study of pathogenic mechanisms of mutations in mitochondrial DNA (mtDNA) structural genes Antonio Luis Andreu Périz and Elena García Arumí Characterization of phenotypic effects of mitochondrial DNA mutations using a model of transmitocondrial hybrids. We are currently working with mutations in; ribosomal RNA (12S rRNA), in tRNA (tRNA lys, tRNA Leu (UUR)), and subunits; complex I (ND6), complex IV (COI) and complex V (ATP6).

Characterization of genotype-phenotype association in McArdle’s disease Antonio Luis Andreu Périz We are characterizing the elements that define genotype-phenotype association in McArdle’s disease, produced by mutations in the gene of the muscular isoform of glycogen phosphorylase. In addition, we are generating the knock-in mouse for the common mutation in Caucasian population (R50X) studying its phenotypic effects.

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Figure 50 Southern blot analysis of mitochondiral DNA (mtDNA) from several muscle samples. DNA isolated from muscle biopsies was digested with the restriction enzyme PvuII (which cuts the circular human mtDNA in a single target), resolved in an agarose gel, transferred to a nylon membrane and hybridized with a radioactive probe, specific for mtDNA. Lane 1: patient with a mtDNA single deletion; lanes 2 and 5: patients with mtDNA multiple deletions; lanes 3 and 4: patients with no mtDNA deletions; lane 6: uncut DNA

CURRENT RESEARCH PROJECTS PI: Antonio Luis Andreu Périz Acción coordinada para el estudio de los mecanismos determinantes de la expresión fenotípica de las mutaciones en genes reguladores del sistema de fosforilación oxidativa (parte 1: Aproximación en modelos celulares) Funding Agency: Fondo de Investigación Sanitaria Reference: PI070347 Funding: 233,409 € Duration: 2008 to 2010

Genetic and biochemical study of mitochondrial DNA depletion syndromes: MNGIE, depletion due to deficiency of TK2 and dGK. Implications on the control of nucleotide pool Ramón Martí Seves Experimental studies to determine the influence of imbalances in concentrations of nucleotides on the maintenance of mtDNA.

Study of possible therapeutic approaches for the Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) disease Ramón Martí Seves Study the effects of restoring tymidine phosphorylase activity on the biochemical phenotype and mitochondrial function in MNGIE, as a preliminary approach for a possible treatment by gene therapy.

PI: Antonio Luis Andreu Périz Automatización de métodos de diagnóstico molecular de enfermedades mitocondriales. (Parte 2, Hospital Vall d’Hebron: Validación del Mitochip (V2.0) de Affymetrix para el Screening de mutaciones en el DNA mitocondrial) Funding Agency: Fondo de Investigación Sanitaria Reference: PI08/90355 Funding: 82,885 € Duration: 2009 to 2010 PI: Ramón Martí Seves Estudio preclínico del tratamiento del MNGIE mediante terapia génica, usando un vector lentivírico en un modelo murino. Seguimiento a largo plazo y bajo sobrecarga de timidina Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01591 Funding: 126,445 € Duration: 2010 to 2012

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PI: Elena García Arumí Caracterización del transcriptoma de las enfermedades producidas por mutaciones del DNA mitocondrial: aproximación en modelos celulares Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01602 Funding: 97,405 € Duration: 2010 to 2012

PI: Antonio Luis Andreu Périz Patologia Neuromuscular i Mitocondrial Funding Agency: AGAUR Reference: 2009 SGR 1520 Funding: 0,00 € Duration: 2010 to 2013

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PUBLICATIONS (Impact Factor: 23.480) Domingo P, Torres Torronteras J, Pomar V, Giralt M, Domingo JC, Gutiérrez MD, Gallego-Escuredo JM, Mateo MG, Cano-Soldado P, Fernández I, Pastor-Anglada M, Vidal F, Villarroya F, Andreu A, Martí R. Uridine Metabolism in HIV-1-Infected Patients: Effect of Infection, of Antiretroviral Therapy and of HIV-1/ART-Associated Lipodystrophy Syndrome. PLoS One 2010 Nov 15; 5 (11): e13896.  IF: 4.351. Martí R, Nascimento A, Colomer J, Lara MC, López-Gallardo E, Ruiz-Pesini E, Montoya J, Andreu AL, Briones P, Pineda M. Hearing loss in a patient with the myopathic form of mitochondrial DNA depletion syndrome and a novel mutation in the TK2 gene. Pediatr Res 2010 Aug; 68 (2): 151-4.  IF: 2.607. Nogales-Gadea G, Mormeneo E, GarcíaConsuegra I, Rubio JC, Orozco A, Arenas J, Martín MA, Lucia A, Gómez-Foix AM, Martí R, Andreu AL. Expression of Glycogen Phosphorylase Isoforms in Cultured Muscle from Patients with McArdle’s Disease Carrying the p.R771PfsX33 PYGM Mutation. PLoS One 2010 Oct 5; 5 (10). pii: e13164.  IF: 4.351. Rae DE, Noakes TD, San Juan AF, Pérez M, Nogales-Gadea G, Ruiz JR, Morán M, Martín MA, Andreu AL, Arenas J, Lucia A. Excessive skeletal muscle recruitment during strenuous exercise in McArdle patients. Eur J Appl Physiol 2010 Nov; 110(5): 1047-55.  IF: 2.047. Rivera H, Merinero B, Martínez-Pardo M, Arroyo I, Ruiz-Sala P, Bornstein B, Serra-Suhe C, Gallardo E, Martí R, Morán MJ, Ugalde C, Pérez-Jurado LA, Andreu AL, Garesse R, Ugarte M, Arenas J, Martín MA. Marked mitochondrial DNA depletion associated with a novel SUCLG1 gene mutation resulting in lethal neonatal acidosis, multi-organ failure, and interrupted aortic arch. Mitochondrion 2010 Jun; 10 (4): 362-8.  IF: 4.145. Vives-Bauza C, Magrané J, Andreu AL, Manfredi G. Novel role of ATPase subunit C targeting peptides beyond mitochondrial protein import. Mol Biol Cell 2010 Jan; 21 (1): 131-9.  IF: 5.979.

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AREA 4 NEUROSCIENCES

4.8 Neurotraumatology and Neurosurgery (UNINN) Group Leader Joan Sahuquillo Barris Tel. 93 274 62 13 / 93 489 41 88 [email protected] Researchers Fuat Arikan Abelló Marcelino Bàguena Martínez María Dolores de la Calzada Álvarez Jannet Paola Cano Granda Alejandro Farré Mas Ángel Garnacho Vega Francisco Ramón Martínez Ricarte Miriam de Nadal Clanchet Ma. Antonia Poca Pastor Marylín Riveiro Vilaboa Ángel Robles González Joan Sahuquillo Barris María Sueiras Gil Ramón Torné Torné Jordi Vilalta Castan Researchers in Training Carmen Airado Cerrato Beatriz García López Tamara Martínez Valverde M. Ángeles Merino Ojer Alba Peña Paris Irina Andreea Radoi Ángela Sánchez Guerrero Elisabeth Solana Díaz Mª Ángeles Vidal Jorge Nursing, Technical and Administrative Staff Mercedes Arribas Serrano Lourdes Expósito Mozas Joana Segura Segura Mónica Tarradas Ustrell

The Neurotraumatology and Neurosurgery Research Unit (UNINN) was established in late 1990 and since 2007 it has been part of the Universitat Autònoma de Barcelona (Spain) research groups. The UNINN has been audited and given the accreditation of “Consolidated Research Group” by the Catalan autonomous government (2005 SGR 0411, recently re-accreditated in 2009: SGR2009-00495). Our research projects, traditionally clinically oriented, have incorporated basic research without losing a patient-centered orientation,

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and aim at increasing the amount of translational research that may improve prognosis and quality of life. The UNINN is fully integrated into the European research community, acting as the coordinator of multicenter and international studies and routinely collaborating in the drafting of clinical practice guidelines. Our most recent contribution in this area is a Cochrane review on the indications and benefits of decompressive craniectomies in head-injured patients and refractory intracranial hypertension.

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OBJECTIVES

RESEARCH LINES

The main aim of the UNINN is to increase understanding of the neurobiological, physiopathological and functional mechanisms taking place in patients with different neurological disorders (neurotraumatic injuries, CSF dynamics abnormalities, craniocervical malformations, malignant middle cerebral artery infarction, and neuro-oncology), in order to acquire new knowledge that when transferred to the clinical setting, might improve functional outcome in these patients. To achieve our mission, our research unit will create more partnerships with multidisciplinary research groups at different national and international centers, conducting translational research in the above mentioned disorders.

Consolidated Lines

Figure 51 Human brain tissue slices cultured in vitro for five days, stained with immunofluorescence against the glial marker GFAP (glial fibrillary acidic protein) [green] and counterstained with DAPI (4’,6-diamidino-2-phenylindole) [blue]

Neurotraumatology Joan Sahuquillo Barris and Ángel Garnacho Vega GENERAL AIMS: To study alterations in brain metabolism, neurochemical alterations, pathophysiology, and new monitoring techniques and treatments in traumatic brain injury (TBI) and in neurocritical patients. SPECIFIC AIMS: 1) To increase knowledge of tissular metabolic and O2 transport alterations in acute brain lesions. 2) To study cerebral and systemic neuro-inflammatory response through high resolution microdialysis techniques. 3) To analyze peri-infarct depolarization phenomena in patients with acute brain injury (COSBID European study). 4) To apply high-resolution microdialysis to define the molecular profile of post-traumatic brain edema and the contribution of non-selective cationic channels to its formation; and 5) To study mitochondrial dysfunction after traumatic brain injury (TBI) in patients and in histotoxic hypoxia can be modelled and reproduced in adult human brain slices obtained from surgically extracted specimens.

Hydrocephalus and alterations in the dynamics of cerebrospinal fluid (CSF) Ma. Antonia Poca Pastor and Joan Sahuquillo Barris GENERAL AIM: To study the pathophysiology of intracranial pressure (ICP) and alterations in CSF dynamics in patients with hydrocephalus and other intracranial pathologies. SPECIFIC AIMS: 1) To gain greater insight into the physiopathology of normal pressure hydrocephalus and idiopathic intracranial hypertension (pseudotumor cerebri) and to study new diagnostic and therapeutic strategies. 2) To determine the biochemical alterations (neurotransmitters and neuropeptides) in these patients, as well as their role in cognitive function and sleep disturbances; and 3) To correlate cognitive deficit with morphological and functional alterations in different cerebral structures, such as the corpus callosum and subcortical white matter.

Malignant Middle Cerebral Artery Infarction (MMCAI) Joan Sahuquillo Barris GENERAL AIM: To expand on the physiopathology, metabolic alterations, and monitoring of patients with malignant MCA infarction. SPECIFIC AIMS: 1) To gain greater insight into the physiopathology, metabolic alterations, and monitoring of patients with malignant middle cerebral artery infarction. 2) To optimize treatment through the use of novel techniques, such as moderate hypothermia and decompressive craniectomy. 3) To characterize the inflammatory response profile (cerebral and systemic) triggered by massive ischemic stroke. 4) To optimize the treatment of severe head injury and MMCAI using new therapeutic techniques such as the combination of moderate hypothermia and decompressive craniotomy;

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CURRENT RESEARCH PROJECTS PI: Ma. Antonia Poca Pastor Implicación de los neuropéptidos hipocretina-1, melatonina y cortistatina en las alteraciones de los ciclos sueño-vigilia de los pacientes con hidrocefalia normotensiva Funding Agency: Fondo de Investigación Sanitaria Reference: PI070681 Funding: 59,176.26 € Duration: 2008 to 2011

Figure 52 Cognitive assessment of a patient undergoing intracranial pressure monitoring

and 5) To study and evaluate the quality of life of patients who survive a malignant middle cerebral artery infarction (MMCAI).

Emerging lines Congenital malformations of the cranio-vertebral junction Ma. Antonia Poca Pastor and Joan Sahuquillo Barris AIMS: 1) To improve knowledge of the physiopathology of craniocervical malformations, particularly Chiari Type I (MC-I), and quantify the clinical, social and occupational repercussions of this malformation. 2) To study the genetic bases of this malformation and its penetrance in family members. 3) To study sleep disturbances (particularly type and frequency of sleep apneas) associated with Chiari Type I malformations; and 4) To study the quality of life of patients with a craniocervical malformation without surgical treatment, as well as those with surgical treatment before and after surgery.

Neuro-oncology Joan Sahuquillo Barris and Francisco Ramón Martínez Ricarte In this new line of translational research, we collaborate actively with the Vall d’Hebron Institute of Oncology (VHIO) lead by Dr. J. Baselga and especially with the “Gene Expression and Cancer” laboratory led by Dr. J. Seoane. AIMS: 1) To develop a patient registry, centralized in external servers, to study the epidemiology, diagnosis and treatment results of primary and secondary brain tumors (Gliomas and metastases). 2) To develop a methodology for studying quality of life and costeffectiveness of surgery and certain treatments in patients with malignant CNS tumors. 3) To study the cost-effectiveness of cortical mapping in low-grade tumors removed by awake craniotomy. 4) To develop cell lines of glioma primary cultures and glioma stem cells for improving knowledge of route regulation at all levels, especially pre- and-post-transcriptional; and 5) To study potential therapeutic targets derived from knowledge of the factors involved in the regulation of neuro-oncogenesis in glial cell tumors.

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PI: Joan Sahuquillo Barris Advanced Arterial Hypotension Adverse Event Prediction Through a Novel Bayesian Neural Network (AVERT-IT ) Grant No 217049 Funding Agency: European Commission Reference: AVERT-IT-217049 Funding: 129,304 € Duration: 2008 to 2011

PI: Joan Sahuquillo Barris Respuesta metabólica e inflamatoria de los fenómenos de despolarización propagada (spreading depresión y SD -like) en pacientes con lesiones cerebrales traumáticas e isquémicas. Aproximación a una potencial nueva diana terapéutica Funding Agency: Fondo de Investigación Sanitaria Reference: PI080480 Funding: 85,789 € Duration: 2009 to 2011

PI: Joan Sahuquillo Barris Análisis del perfil temporal de los mediadores de respuesta neuroinflamatoria en el espacio extracelular cerebral mediante microdiálisis cerebral de alta resolución en pacientes con un traumatismo craneoencefálico grave Funding Agency: Fundación Mapfre Medicina Reference: MAPFRE/2009/01 Funding: 14,629 € Duration: 2010 to 2011

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PUBLICATIONS (Impact Factor: 34.519) PI: Joan Sahuquillo Barris Análisis del perfil temporal de los mediadores de respuesta neuroinflamatoria en el espacio extracelular cerebral mediante microdiálisis cerebral de alta resolución en pacientes con un traumatismo craneoencefálico grave Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMM-2010-10 Funding: 44,736 € Duration: 2010 to 2013

PI: Joan Sahuquillo Barris Mecanismos moleculares implicados en la génesis del glioma y estudio de las células madre tumorales. Identificación de nuevas dianas terapéuticas y marcadores para la estratificación en pacientes y respuesta a fármacos Funding Agency: Asociación Española Contra el Cáncer Reference: AECC-GE2010-07 Funding: 175,000 € Duration: 2010 to 2015

Anido J, Saez-Borderias A, González-Junca A, Rodón L, Folch G, Carmona MA, PrietoSánchez RM, Barba I, Martínez-Saez E, Prudkin L, Cuartas I, Raventós C, MartínezRicarte F, Poca MA, García-Dorado D, Lahn MM, Yingling JM, Rodón J, Sahuquillo J, Baselga J, Seoane J. TGF-beta Receptor Inhibitors Target the CD44(high)/Id1(high) Glioma-Initiating Cell Population in Human Glioblastoma. Cancer Cell 2010 Dec 14; 18 (6): 655-68.  IF: 25.288. Arikan F, Vilalta J, Romero FJ, Porta I, Martínez-Ricarte FR, Sahuquillo J. Primary decompressive craniectomy in patients with aneurysmatic subarachnoid hemorrhage. Results of a pilot study in 11 cases. Neurocirugia (Astur) 2010 Dec; 21 (6): 452-460.  IF: 0.247. Calzada MD de la, Poca MA, Sahuquillo J, Matarín M, Mataró M, Solana E. Cognitive event-related brain potentials (P300) in patients with normal pressure hydrocephalus. Results of a prospective study. Neurologia 2010 Jan-Feb; 25 (1): 32-9.  IF: 0.596. Merino MA, Sahuquillo J, Borrull A, Poca MA, Riveiro M, Expósito L. Is lactate a good indicator of brain tissue hypoxia in the acute phase of traumatic brain injury? Results of a pilot study in 21 patients. Neurocirugia (Astur) 2010 Aug; 21 (4): 289-301.  IF: 0.247.

PI: Joan Sahuquillo Barris Unitat d’Investigació de Neurotraumatologia i Neurocirurgia (UNINN) Funding Agency: AGAUR Reference: 2009 SGR 495 Funding: 0,00 € Duration: 2010 to 2013

Piper I, Chambers I, Citerio G, Enblad P, Gregson B, Howells T, Kiening K, Mattern J, Nilsson P, Ragauskas A, Sahuquillo J, Donald R, Sinnott R, Stell A, Sahuquillo J, Pickard JD, Mins R, Whittle I, Dunn L, Rydenhag B, Kiening K, Iencean S, Pavalkis D, Meixensberger J, Goffin J, Vajkoczy P, Stocchetti N, Citerio G, Chambers IR, Corte F della, Hell J, Enblad P, Mascia L, Jarzemaskas E, Stocker R. The brain monitoring with Information Technology (BrainIT) collaborative network: EC feasibility study results and future direction. Acta Neurochir (Wien) 2010 Nov; 152 (11): 1859-71.  IF: 1.472. Poca MA, Benejam B, Sahuquillo J, Riveiro M, Frascheri L, Merino MA, Delgado P, Álvarez-Sabín J. Monitoring intracranial pressure in patients with malignant middle cerebral artery infarction: is it useful? J Neurosurg 2010 Mar; 112 (3): 648-57.  IF: 2.594. Sarabia R, Lagares A, Fernández-Alen JA, Arikan F, Vilalta J, Ibañez J, Maillo A, Gabarros A, Domínguez J, Horcajadas A, Ballenilla F, Rodríguez-Boto G, Llacer JL, Arrese I, Lama A de la, Santamarta D, Delgado P, Muñoz MF. Idiopathic subarachnoid hemorrhage: a multicentre series of 220 patients. Neurocirugia (Astur) 2010 Dec; 21 (6): 441-51.  IF: 0.247. Solana E, Poca MA, Sahuquillo J, Benejam B, Junque C, Dronavalli M. Cognitive and motor improvement after retesting in normal-pressure hydrocephalus: a real change or merely a learning effect? J Neurosurg 2010 Feb; 112 (2): 399-409.  IF: 2.594. Vilalta A, Sahuquillo Barris J, Poca MA. Matrix metaloproteinases in neurological brain lesions: a new therapeutic target? Rev Neurol 2010 Jul 16; 51 (2): 95-107.  IF: 1.234.

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4.9 Neurovascular Diseases

Group Leader Joan Montaner Villalonga Tel. 93 489 40 29 / 93 489 40 73 [email protected] Researchers José Álvarez Sabín Mª Pilar Delgado Martínez Israel Fernández Cadenas Lidia García Bonilla Maria del Mar Hernández Guillamón Carlos Molina Cateriano Joan Montaner Villalonga Marc Ribó Jacobi Anna Rosell Novel Marta Rubiera Esteban Santamarina Researchers in Training Mireia Campos Martorell Sophie Domingues Teresa García Berrocoso Andreu Massot Maite Mendioroz Anna Morancho Retana Cristina Nafría Pérez Miriam Navarro Jorge Pagola Pérez Blanca Mireia Parés Oliva Yolanda Riba Llena Alberto del Río Espinola David Rodríguez Luna Nursing, Technical and Administrative Staff Veronica Barceló Romero Cristina Boada Llamas Natalia Corbeto López Laura Deu Lozano Borja Felix Rojas Sandra García Menéndez Dolors Giralt Casellas Gonzalo Pablo Mazuela Águila Mª Pilar Meler Amella Gema Mª Ortega Linares Laura Ortega Torres Anna Penalba Manuel Quintana Luque

OBJECTIVES One in six persons in the world will suffer a stroke during their lifetime; in fact neurovascular disease is the number one killer among Spanish women. To change these dramatic figures, the Neurovascular research group is focused on the discovery of new diagnostic and therapeutic targets to improve the prevention, diagnosis and treatment of neurovascular diseases. For that purpose six consolidated lines of research work in concert to try to achieve these goals, looking for stroke biomarkers that would be useful as diagnostic and prognostic tools; the genetic risk factors that allow us to identify people at

risk of suffering a stroke or new prevention strategies, especially in cases of silent neurovascular disease. Moreover, our studies and characterization of some molecular processes following cerebral ischemia, might improve stroke treatment, especially those pharmacological therapies to improve the thrombolytic approaches in the acute phase and cell therapy strategies used to trigger neurorepair after the ischemic insult. We are also experts in the research of some specific stroke subtypes such as Cerebral Amyloid Angiopathy in the border of neurovascular and Alzheimer disease.

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RESEARCH LINES Biomarkers Joan Montaner Villalonga, Teresa García Berrocoso, Anna Penalba Morenilla and Cristina Boada Llamas The use of plasma biomarkers is becoming increasingly popular in several fields of medicine. In fact, decision-making processes using biomarkers are widely accepted in medical situations such as initiating lipid lowering therapies (LDL), diagnosing acute myocardial infarction (troponins), and ruling out pulmonary embolism suspicions (D-dimer), among others. Therefore we believe that biochemical markers of strokes, will really open “a window to the brain…”. In fact, in this research line we aim to answer relevant clinical questions through the use of biomarkers. Our main objectives using mainly plasma proteins are: • To predict stroke risk. • To make stroke diagnoses. • To differentiate stroke subtypes. • To establish evolution and prognosis. • To use Biomarkers as treatment end-points. Some of our findings might have therapeutic implications since biological markers described by the group such as MMP-9 are well associated with Blood Brain Barrier disruption. In this direction, we have described MMP-9 predicting haemorrhagic complications among stroke patients receiving thrombolytic treatment. These approaches might contribute to increase safety of reperfusion treatments. The impact of this research line is clear, since this article (Circulation 2003) has been cited more than 180 times since

Figure 53 We are using a combination of discovery techniques and biological human and animal samples to identify new stroke-related biomarkers

its publication. The study of these molecules will also have diagnostic implications because we have proposed the biochemical diagnosis of strokes by means of the identification of a biomarkers panel that distinguishes between a stroke and other stroke-mimicking conditions. This might contribute to ensurin that only genuine stroke patients are referred to stroke centers, saving the system huge resources. These two examples, identification of biomarkers to predict tPA related bleedings and a diagnostic stroke test are examples of translational research in which the Neurovascular Research Lab is filing patents to be licensed to Biotech companies able to develop diagnostic kits in which our biomarkers might be placed and used in clinical practice. This might close the circle of applied research. Reviews of our group in which you may find detailed info about these biomarkers: • Foerch C, Montaner J, Furie KL, Ning MM, Lo EH. Searching for

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oracles? Blood biomarkers in acute stroke. Neurology 2009; 73 (5): 393-9. • Montaner J. Blood biomarkers to guide stroke thrombolysis. Front Biosci (Elite Ed). 2009 Jun 1; 1: 200-208. • García-Berrocoso T, FernándezCadenas I, Delgado P, Rosell A, Montaner J. Blood Biomarkers to Identify Stroke Etiologies. Therapy 2010 (in press). PROJECTS: We are involved in several projects with public or private funding supporting our research on stroke biomarkers. One such exciting project is FIS PI 08/361 “Identificación y uso de biomarcadores pronósticos en el ictus isquémico”, aiming to identify biomarkers that predict the main causes of stroke worsening (Infarct growth, cardiac complications, hemorrhagic transformation, infections, recurrence or new vascular events) to guide Stroke Unit allocation and in-patient stays for our patients.

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Figure 54 Example of the WMH volume calculation using currently available MRI imaging software

INTERNATIONAL COLLABORATIONS: The discovery and validation of good candidate biomarkers requires multidisciplinary approaches and replication in well designed multicentric and international studies. For that purpose we are actively collaborating with well known leading stroke research groups: • Eng Lo, Xiaoing Wang, Ming Ming Ning (Boston, USA). • Jean Charles Sanchez, Natacha Turck (Geneva, Switzerland). • Denis Vivien, Carine Ali, Eduardo Anglés-Cano (Caen, France). RESEARCH TOOLS AND TECHNIQUES: We are using a combination of discovery techniques and biological human and animal samples to identify new stroke-related biomarkers: One example is “protein arrays”. In our laboratory, we have been using these new technologies and we currently use the SearchLight Assays (Aushon Biosystems) which allows us to study more than 170 human proteins and also many candidates from different animal species. We offer access to

our technology to other groups. For more information, please refer to http://www.lin-bcn.com/ Also these biomarkers may be specifically tested not only as circulating markers in plasma or serum but in the components of interest of the Neurovascular Unit, that we dissect by using the LCM Leica LMD6000 microscope, for Laser Capture microdissection. An example which combines both techniques may be found at: Cuadrado E, Rosell A, Penalba A, Slevin M, Álvarez-Sabín J, Ortega-Aznar A, Montaner J. Vascular MMP-9/TIMP-2 and neuronal MMP-10 up-regulation in the human brain after stroke: a combined Laser Microdissection and Protein Array Study. Journal of Proteome Research 2009; 8 (6): 3191-7. BIOBANKS: All these results have been made possible due to the development of a “blood library” including more than 2000 stroke samples and a “brain library” that allowed us to describe for the first time the “human stroke proteome” with the outstanding collaboration of so many patients, relatives and clinicians of the Stroke Unit.

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Stroke prevention Mª Pilar Delgado Martínez and Iolanda Riba Llena Since cerebrovascular diseases and dementia are responsible for a huge economic burden, the early detection of patients at high risk of them, and the implementation of preventive measures as soon as possible, is of great interest and may result in health care savings. The purposes of our research are: • To promote awareness and knowledge of strokes in the general population and enhance collaboration between primary care services and hospital departments. • To accurately predict those patients at high-risk of first stroke by the determination of novel risk factors or markers (neuroimaging or biological markers), and therefore to improve stroke risk stratification. • To incorporate a standardized assessment of cognition in stroke research. • To determine why interventions may be widely applied or not by means of cost-efficiency studies. • To study quantitative predictors of preventive treatment compliance.

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FUTURE PROJECT: “Silent cerebral infarction detection and biomarkers associated with the risk of stroke in the hypertensive Spanish population”. Silent cerebral infarctions (SCI) detected with neuroimaging techniques, particularly with brain MRI, are common in the healthy aged population and even more frequent in selected patients at risk, such as hypertensive patients. SCI constitute a preclinical stage of cerebrovascular disease and might precede both stroke and cognitive decline; therefore we think that their identification in hypertensive patients would be an appropriate and cost-efficient tool, to prevent further strokes and dementia. Our current project will include a estimated sample size of 1000 hypertensive patients, with no known history of cerebrovascular disease or dementia. Silent Cerebral Infarctions (SCI) will be detected by MRI and the determination of several clinical and biological factors (plasma and genetic biomarkers) will be performed on baseline. The patients will be followed-up for at least 3 years, to assess the presence of incident strokes and/or cognitive impairment. This study will allow

brain vessels. It is the second leading cause of cerebral hemorrhages. However, nowadays, factors related to brain bleedings following amyloid deposition are largely unknown. The understanding of the molecular mechanisms that lead to cerebral hemorrhage may be the basis for future treatments. Previous evidences of our group have shown that Matrix Metalloproteinases (MMPs) are related to brain bleeding. Now, we aim to investigate the relationship between these proteolytic systems and the appearance of intracraneal hemorrages in CAA. Our study includes:

us to determine the largely unknown prevalence of silent cerebral infarctions in our setting. Also, the identification of SCI will help us to better define the risk stratification in hypertensive patients. Patients at higher risk will be our target population for the development of new preventive strategies based on the results of randomized clinical trials. Finally, this project will be carried out thanks to the collaboration between Neurovascular Research Laboratory, Primary Care Physicians Services and Nephrology Department of Vall d’Hebron, among others, and will result in the improvement of the link between Primary Care Systems and the remaining hospitalary services, will favor the future of the preventive treatment and care of patients.

• The identification of both tissue and plasma biomarkers for the diagnosis and prognosis of CAA-related hemorrhages.

Cerebral Amyloid Angiopathy Maria del Mar Hernández Guillamón, Mª Pilar Delgado Martínez and Mireia Parés Oliva CURRENT PROJECT: Involment of proteolytic systems in the progression of Cerebral amyloid angiopathy (CAA) is produced by the accumulation of -amyloid protein within the meningeal and

• The search for the genetic markers related to proteolytic systems that could determine the risk of suffering a recurrence in CAA. We are studying a cohort of probable CAA patients that have been recruited in Hospital Vall d’Hebron in collaboration with the Stroke Project of the Cerebrovascular Diseases Study Group (Spanish Society of Neurology).

Figure 55 Thioflavin-S staining of fibillar -amyloid within brain vessels of CAA patient’s sections

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Figure 56 Global changes in brain gene expression (microarrays) after human intracerebral haemorrhage (ICH)

• The study of the role of MMPs in -amyloid stimulated vascular cells in vitro. Cultured cells of the neurovascular unit are challenged with different amyloid peptides and the implication of MMPs in -amyloid cleavage and cell toxicity are studied using cellular and molecular biology methodology. For this purpose, we use the human cerebral endothelial cell line hCMEC/D3, primary cultures of human leptomeningeal smooth muscle cells and rat/ mouse glial and neuronal cultures. Thioflavin-S staining of fibillar -amyloid within brain vessels of CAA patient’s sections.

RELATED BIBLIOGRAPHY: • Álvarez-Sabín J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribó M, Santamarina E, Quintana M, Monasterio J, Montaner J. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke 2004 Jun; 35 (6): 1316-22.4. • Hernández-Guillamón M, Delgado P, Ortega L, Parés M, Rosell A, García-Bonilla L, Fernández-Cadenas I, Borrell-Pagès M, Boada M, Montaner J. Neuronal TIMP-1 release accompanies astrocytic MMP-9 secretion and

enhances astrocyte proliferation induced by beta-amyloid 25-35 fragment. J Neurosci Res 2009 Jul; 87 (9): 2115-25. • Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribó M, Quintana M, ÁlvarezSabín J. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 2003 Feb 4; 107 (4): 598-603. • Rosell A, Ortega-Aznar A, Álvarez-Sabín J, Fernández-Cadenas I, Ribó M, Molina CA, Lo EH, Montaner J. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke 2006 Jun; 37 (6): 1399-406.3.

Figure 57 Left: In vitro angiogenesis of human EPCs (red) and mature endothelial cells (hCMEC/D3). Right: In vitro cell adhesion of human EPCs (red) on a mature endothelial cell layer

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COLLABORATIONS: • Mercè Boada, Fundació ACE, Barcelona, Spain (www.fundacioace.com). • Jorge Ghiso and Agueda Rostagno, Pathology Dept. Langone Medical Center. New York University, New York, USA. • Ignacio Romero, Life Science Dept. Open University. Milton Keynes, UK.

Neurorepair Anna Rosell Novel, Miriam Navarro Sobrino, Anna Morancho Retana and Verònica Barceló Romero New therapies beyond the hyperacute phase of stroke are needed to be able to treat many more patients in delayed phases of this devastating disease. The idea that neurovascular plasticity contributes to stroke recovery is a powerful concept for stroke therapy. Obviously, the therapeutic time window for interventions based on promoting recovery would be much larger than those for targeting acute stroke. In this context, long-term neuroreparative therapies will have to target two essential phenomena to achieve brain neurorecovery after stroke: to restore the cerebral blood flow and to promote neuroregeneration. To achieve these major goals, both angiogenesis and neurogenesis need to be enhanced in the ischemic brain. Classically, the formation of new blood vessels was thought to be mediated exclusively by embryogenic vasculogenesis followed by the sprouting of endothelial cells from preexisting vessels during angiogenesis. In the last decade, this standard dogma was overturned with the identification of the existence of circulating bone marrow-derived endothelial progenitor cells (EPCs). These cells are capable of differentiating, ex vivo, into endothelial-phenotyped cells,

and now comprise a new model for endothelial generation and vessel repair (Asahara et al., 1997). These cells comprise a potential cellbased and growth-factor source of an alternate approach to enhance angio-neurogenic responses. In fact, newborn neurons (neurogenesis) and new vascular components (angiogenesis) form a microenvironment that has been termed the neurovascular niche [Ohab et al., 2006] were angiogenesis and neurogenesis are linked thorough specific growth factors. Angiogenesis and neurogenesis occur endogenously after stroke. Our goal is to study these two complex phenomena both in experimental and human studies to finally potentiate them correctly to improve brain function and neurorecovery after stroke. EXPERIMENTAL MODELS AND TECHNIQUES In vivo stroke models: Cerebral ischemia affecting the cortical territory of the Middle Cerebral Artery (MCA) is occluded at the level of the M1 portion (distal occlusion). This model has been chosen because it presents very low mortality rates allowing long-term studies. Besides, the infarct is restricted to the cortex with clear boundary areas with normal cerebral blood flow and never affects neuroblast-rich areas such as the subventricular zone (then, both angiogenesis and neurogenesis can occur). Functional outcome is assessed by the cylinder and corner tests which have been reported to be appropriate tests for this type of cortical infarct. Additionally, histology and immunohistochemistry studies are conducted to evaluate brain repair and angioneurogenic processes. Endothelial Progenitor Cell Cultures: EPCs are obtained from the Mononuclear cell fraction of human blood and from mouse

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spleen. MNCs are cultured in fibronectin-coated plates with complete cell culture medium EGM2MV. Both human and murine cell cultures yield an early EPC population (also called Circulating Angiogenic Cells) obtained at day 4-7 after plating and late outgrowth. EPC colonies (also called Endothelial Colony Forming Cells) appear from day 10 as colonies with high proliferation capacity and tubulogenic capacity. In vitro Oxygen-Glucose Deprivation: Endothelial cells and endothelial progenitor cells are challenged to a transitory oxygen and glucose deprivation to study their angio-vasculogenic responses to ischemia and to test how potential treatments that could modify these responses. Angiogenesis-related techniques: Angio-vasculogenic mechanisms are studied in a variety of in vitro assays including Matrigel® tubulogenesis, cell migration using trans-well assays or cell adhesion to a mature monolayer of endothelial cells. Our studies focus on the angio-vasculogenic responses of both endothelial progenitor cells and mature endothelial cells such as the human cell line of microvascular endothelial cells (hCMEC/D3).

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NMR Imaging: Bruker-BIOSPEC 70/30 USR, 7 T Preclinical MRI System is used for the neuroimaging studies. Neuroimaging studies are conducted in vivo to follow-up the ischemic lesion. Specific sequences are performed to assess axonal degeneration/regeneration and changes in cerebral blood flow and angiogenesis.

Neuroprotection Lidia García Bonilla and Mireia Campos Martorell BACKGROUND: The only approved stroke treatment so far is acute thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) when administered within 3-4.5 hours after onset of symptoms. However, a limited number of patients (5-8%) profit from this treatment, primarily because of the narrow therapeutic time-window and the risk of brain bleedings beyond thrombolytic therapy to achieve the recanalization of the occluded artery. Moreover, the inflammatory response that accompanies necrotic brain injury contributes to acutely aggravate the progression of ischemic pathology. Inflammatory and brain damaged cells release a variety of cytotoxic agents including cytokines, MMPs and ROS which induce more cell damage as well as dis-

ruption of BBB and brain edema. Therefore, it would be desirable to improve the efficacy and safety of thrombolytic therapy for stroke using combined anti-inflammatory strategies that may ameliorate the ischemic injury and means the best therapy translated at the clinical level. Our research, conducted on experimental models of cerebral ischemia, is focused on the development of neuroprotective strategies aimed to salvage ischemic brain tissue by means complementary to reperfusion. Our goal is to find a multimodal treatment that combines the administration of tPA together with other co-agents (as simvastatin and/or anti-aggregants with anti-inflammatory and neuro-protective properties) in an attempt to obtain the most therapeutic benefit in the acute phase of ischemic stroke. EXPERIMENTAL MODELS AND TECHNIQUES: Ischemic stroke has a complex pathophysiology involving the interplay of many different cells and tissues. Animal models of ischemic stroke are procedures inducing cerebral ischemia, which satisfactorily mimic this cerebrovascular disease. Therefore, stroke research conducted on animal models has been shown to be essential for the treatment approach of ischemic stroke.

Figure 58 Image of TTC staining on rat brain slices that show infarction in MCA-supplied lateral cortex and striatum territories after induction of focal cerebral ischemia

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Intra-arterial Suture Occlusion Model of Focal Cerebral Ischemia. Infarction in the territory of the middle cerebral artery (MCA) is induced by extracranial vascular occlusion in rats. A heat-blunted 4/0 nylon-monofilament is used to block the origin of MCA during 90 or 120 min and then, the monofilament is removed and reperfusion is allowed during the followed 24, 48 or 72 h. This model mimics a clinical situation where recanalization of the occluded artery takes place, allowing test neuroprotectants that could potentially be co-administered with reperfusion agents like tPA. Embolic Model of Focal Cerebral Ischemia. There is great clinical scientific interest in the animal stroke model by clot embolism due to the high incidence of human thrombotic stroke and the use of reperfusion therapy with tPA, which can be assayed on this model. Thromboembolic occlusion at the proximal level of MCA is achieved by injection of a rich fibrin clot through the internal carotid artery in the rat. Clots were previously performed using arterial blood from a donor rat. Thrombolytic therapy with tPA (9 mg/kg) is administered by tail vein infusion (2 mg/mL; 75 ?L/ min) at different times points (2, 3, 4 hours) after occlusion. Relative Cerebral Blood Flow (rCBF) is measured in the cortex supplied by the MCA by continuous Laser Doppler flowmetry (LDF) to ensure the success of the artery occlusion or reperfusion in these models. To examine the grade of infarction on rats, analysis of the infarct volume is evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining and the neurological score is assayed with a 9-point neurological at baseline (1-2 h) and each 24 h after occlusion. NMR ImagingBruker-BIOSPEC 70/30 USR, 7 T Preclinical MRI System is used for neuroimaging studies. Neuroimaging studies are conducted in vivo to evaluate the

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cytotoxic edema and ischemic lesion (DWI, ADC map and T2WI) in the acute phase. Specific sequences are performed to assess BrainBlood Barrier disruption (DCE) and occurrences of intracranial hemorrhages (T2*WI). Angiography is performed to document MCA occlusion or recanalization.

Genetics Israel Fernández Cadenas, Maite Mendioroz Iriarte, Sophie Domingues and Alberto del Río Espinola Neurovascular Genetics is an important part of the research of our Laboratory. FIRSTLY, we are participating in the first pharmacogenomic study in patients treated with tPA, the Geno-tPA project. In this project, we work on polymorphisms in genes related to biological processes such as inflammation, proteolysis and hemostasis, which are capable of modifying the response to thrombolysis treatment. The goal is to analyze about 200 polymorphisms in 540 patients. More than 13 mutations have already been studied and more than 6 articles have been published in international journals, showing, for example, for the first time the risk of suffering hemorrhagic complications. Recanalization rates after treatment are determined genetically through genes such as the factor XIII (PMID: 16857944), the Angiotensin Converting Enzyme (PMID: 16442232) and the Thrombin-activatable fibrinolysis inhibitor (PMID: 17723126). SECONDLY, the GRECOS project (Genotyping RECurrence Of Stroke) is a genetic ongoing multi-center prospective longitudinal cohort study whose primary objective is to identify the genetic markers that determine the risk of suffering a stroke recurrence. The recruiting process started in February 2007, and the final cohort is composed of about 1800

Figure 59 Experimental model of distal Middle Cerebral Artery occlusion in mice showing histological (TTC) and neuroimaging (MRI) correspondence of the obtained cortical brain infarction

patients who suffered a first episode of ischemic or hemorrhagic stroke, with a follow up of three years. In this group of patients, we have analyzed about 200 polymorphisms in candidate genes related to inflammation, hemostasis, apoptosis, angiogenesis, proteolisis, and other processes. The genotyping was performed through the SNPlex platform of the National Centre of Genotyping (http://www.cegen.org) and at present we are replicating the results in a new cohort. THIRDLY, the CONIC project is a case-control study which attempts to determine the genetic risk factors associated with stroke. Two different groups of persons will be recruited and various biological samples will be extracted, such as DNA, RNA, plasma and serum, as well as routine information. The first group, the “cases” will be composed of patients from the Geno-tPA study

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and have suffered an ischemic stroke. The second group, the “controls” will be formed by 540 healthy persons free of vascular disease. 200 polymorphisms have been analyzed and differences between the case and control groups have been studied. This will lead to the identification of genes and genetic variants (polymorphisms but also haplotypes or copy number variants) implicated in stroke disease. Moreover, functional studies will be performed to determine the exact contribution of each variant described at the biological level. FOURTHLY, we are performing the first Genome Wide Analysis in Spanish stroke samples, identifying up to 1 million SNPs in 240 patients. The project, called project GRECAS, is in the genotyping process and we will have the results next year. In addition a new GWAs has been funded by the Spanish government called GWAs Geno

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tPA. Apart from these studies, our group offers a service of Neurovacular Genetic Consultation by a neurologist. This consultation aims to specifically diagnose patients (and their families) with cerebrovascular diseases of genetic origin. Special attention will be dedicated to diseases such as Fabry’s disease, CADASIL, CARASIL, Rendu-Osler, but we also regularly attend patients with any suspicion of genetic and hereditary cerebrovascular disease. From this consultation, we recently published the first case of CARASIL syndrome in a Caucasian population demonstrating that this disease is common and not restricted to the Asian population. SERVICES OFFERED BY OUR GENETIC DEPARTMENT. We offer consultation by a specialized neurologist and genetic diagnosis of CADASIL: Exons 3 y 4: 365 Euros - Time necessary: about 3 weeks. Complete gene: 1,177 Euros Time necessary: about 2 months (Prices obtained from the Diario Oficial de Galícia Nº141 21 julio 2006, Anexo V). The Neurovascular Research Laboratory actively collaborates with two consortia: The IGSC (International Genetic Stroke Consortium), a consortium that joins the most remarkable international groups working in the genetic component of stroke. The other one is the GeneStroke consortium (www. genestroke.com), a national consortium in which we are the coordinators. The aim of this consortium is collaboration among different centers, and to perform genome-Wide Analysis in the Spanish population.

CURRENT RESEARCH PROJECTS PI: Joan Montaner Villalonga GRECOS Project: Genotyping Recurrence risk of Stroke Funding Agency: Fundació La Marató de TV3 Reference: TV3/062610 Funding: 198,662 € Duration: 2007 to 2010

PI: José Álvarez Sabín Influencia de las células endoteliales progenitoras sobre la modulación espacio-temporal de la angiogénesis y la vasculogénesis tras el ictus isquémico humano Funding Agency: Fondo de Investigación Sanitaria Reference: PI060471 Funding: 240,185 € Duration: 2007 to 2010

PI: Marc Ribó Jacobi Búsqueda de patrones genéticos predictivos de la evolución del paciente con ictus isquémico después del tratamiento con tPA Funding Agency: Fondo de Investigación Sanitaria Reference: PI060586 Funding: 211,145 € Duration: 2007 to 2010

PI: Joan Montaner Villalonga Geno-tPA: búsqueda de patrones genéticos predictivos de la evolución del paciente con ictus isquémico después del tratamiento con tPA Funding Agency: Fundación Ramón Areces Reference: ARECES/1/2006 Funding: 110,000 € Duration: 2007 to 2010

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PI: Joan Montaner Villalonga Estrategias para mejorar la eficacia y seguridad del tratamiento con simvastatina en la fase aguda del ictus isquémico: STARS trial Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90195 Funding: 175,450 € Duration: 2007 to 2011

PI: Joan Montaner Villalonga European Stroke Research Network (EUSTROKE) Grant Agreement No 202213Health-F2-2008-202213 Funding Agency: European Commission Reference: EUSTROKE-202213 Funding: 463,200 € Duration: 2008 to 2013

PI: Joan Montaner Villalonga Identificación y uso de biomarcadores pronósticos en el ictus isquémico Funding Agency: Fondo de Investigación Sanitaria Reference: PI080361 Funding: 228,690 € Duration: 2009 to 2011

PI: Maria Mar Hernández Guillamón Beneficio de la simvastatina en el tratamiento trombólico combinado del ictus en modelos de isquemia cerebral en rata Funding Agency: Fondo de Investigación Sanitaria Reference: PI080481 Funding: 126,687 € Duration: 2009 to 2011

PI: Joan Montaner Villalonga GRECAS: genotipando el riesgo y eficacia de clopidogrel o aspirina tras el ictus; hacia una prevención secundaria personalizada Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00137 Funding: 289,190 € Duration: 2009 to 2011

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PI: Joan Montaner Villalonga European Stroke Research Network Funding Agency: Ministerio de Ciencia e Innovación Reference: EUS2008-03610 Funding: 97,000 € Duration:2009 to 2013

PI: Marc Ribó Jacobi Neuroprotección mediante sistema de “perfusión artificial” de la penumbra isquémica con sangre arterial oxigenada Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01660 Funding: 77,440 € Duration: 2010 to 2012

PI: Joan Montaner Villalonga RENEVAS - Red de Investigación Cooperativa Neurovascular Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0026/0010 Funding: 719,909.78 € Duration: 2007 to 2011

PI: Joan Montaner Villalonga Grup de Recerca en Malalties Neurovasculars Funding Agency: AGAUR Reference: 2009 SGR 432 Funding: 46,800 € Duration: 2010 to 2013

PUBLICATIONS (Impact Factor: 192.676) PI: Joan Montaner Villalonga Fomento de la equidad de género en la atención al ictus Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/90401 Funding: 24,200 € Duration: 2010 to 2011

PI: María Pilar Delgado Martínez Silent clinical infarction detection and biomarkers associated with the risk of stroke in the hypertensive Spanish population Funding Agency: Fondo de Investigación Sanitaria Reference: CP09/00136 Funding: 44,400 € Duration: 2010 to 2012

PI: Anna Rosell Novel Neurorepair Treatments for Cerebral Ischemia using Endothelial Progenitor Cells (EPCs) Funding Agency: Fondo de Investigación Sanitaria Reference: CP09/00265 Funding: 45,000 € Duration: 2010 to 2012

Alexandrov AV, Tsivgoulis G, Rubiera M, Vadikolias K, Stamboulis E, Molina CA, Alexandrov AW. End-Diastolic Velocity Increase Predicts Recanalization and Neurological Improvement in Patients With Ischemic Stroke With Proximal Arterial Occlusions Receiving Reperfusion Therapies. Stroke 2010 May; 41 (5): 948-52.  IF: 7.041. Arsava EM, Ballabio E, Benner T, Cole JW, Delgado-Martínez MP, Dichgans M, Fazekas F, Furie KL, Illoh K, Jood K, Kittner S, Lindgren AG, Majersik JJ, Montaner J, et al. The Causative Classification of Stroke system: An international reliability and optimization study. Neurology 2010 Oct 5; 75 (14): 1277-1284.  IF: 8.172. Biffi A, Sonni A, Anderson CD, Kissela B, Jagiella JM, Schmidt H, Jiménez-Conde J, Hansen BM, Fernández-Cadenas I, Cortellini L, Ayres A, Schwab K, Juchniewicz K, Montaner J, et al. Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann Neurol 2010 Dec; 68 (6): 934-43.  IF: 9.317. Blanco M, Sobrino T, Montaner J, Medrano V, Jiménez C, Masjuan J, Gómez-Escalonilla C, Luis P de, Arboix A, Castillo J, Blanco M, Castillo J, Álvarez-Sabín J, et al. Stroke with polyvascular atherothrombotic disease. Atherosclerosis 2010 Feb; 208 (2): 587-92.  IF: 4.522. Cuadrado E, Rosell A, Colomé N, HernándezGuillamón M , García-Berrocoso T, Ribó M, Alcázar A, Ortega-Aznar A, Salinas M, Canals F, Montaner J. The Proteome of Human Brain After Ischemic Stroke. J Neuropathol Exp Neurol 2010 Nov; 69 (11): 1105-15.  IF: 4.564.

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Domingues-Montanari, Fernández-Cadenas I, Río-Espinola A del, Corbeto N, Krug T, Manso H, Gouveia L, Sobral J, Mendioroz M, Fernández-Morales J, Álvarez-Sabín J, Ribó M, Rubiera M, Obach V, Martí-Fábregas J, Freijo M, Serena J, Ferro JM, Vicente AM, Oliveira SA, Montaner J. Association of a Genetic Variant in the ALOX5AP with Higher Risk of Ischemic Stroke: A Case-Control, Meta-Analysis and Functional Study. Cerebrovasc Dis 2010 Mar 30; 29 (6): 528537.  IF: 3.535. Domingues-Montanari, Fernández-Cadenas I, Río-Espinola A del, Mendioroz M, Fernández-Morales J, Corbeto N, Delgado P, Ribó M, Rubiera M, Obach V, Martí-Fábregas J, Freijo M, Serena J, Montaner J. KCNK17 genetic variants in ischemic stroke. Atherosclerosis 2010 Jan; 208 (1): 203-9.  IF: 4.522. Domingues-Montanari, Fernández-Cadenas I, Río-Espinola A del, Mendioroz M, Ribó M, Obach V, Martí-Fábregas J, Freijo M, Serena J, Corbeto N, Chacón P, ÁlvarezSabín J, Montaner J. The I/D polymorphism of the ACE1 gene is not associated with ischaemic stroke in Spanish individuals. Eur J Neurol 2010 Nov; 17 (11): 1390-2.  IF: 2.510. Domínguez C, Delgado P, Vilches A, Martín-Gallán P, Ribó M, Santamarina E, Molina C, Corbeto N, Rodríguez-Sureda V, Rosell A, Álvarez-Sabín J, Montaner J. Oxidative Stress After Thrombolysis-Induced Reperfusion in Human Stroke. Stroke 2010 Apr; 41 (4): 653-60.  IF: 7.041. Fernández-Cadenas I, Río-Espinola A del, Rubiera M, Mendioroz M, Domingues-Montanari, Cuadrado E, Hernández-Guillamón M, Rosell A, Ribó M, Álvarez-Sabín J, Molina CA, Montaner J. PAI-1 4G/5G polymorphism is associated with brain vessel reocclusion after successful fibrinolytic therapy in ischemic stroke patients. Int J Neurosci 2010 Apr; 120 (4): 245-51.  IF: 0.855. Francisco J de, Pujadas F, Toledo M, Santamarina E, Quintana M, Edo MC, Centeno M, Álvarez Sabín J. A study of right-left shunt in transient global amnesia. Neurologia 2010 Mar; 25 (2): 83-89.  IF: 0.596. Haley EC Jr, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, Fanale C, Libman R, Kwiatkowski TG, Llinas RH, Levine SR, Johnston KC, Buchsbaum R, Levy G, Levin B, Ribó M, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke 2010 Apr; 41 (4): 707-11.  IF: 7.041.

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Hernández-Guillamón M, García-Bonilla L, Solé M, Sosti V, Parés M, Campos M, Ortega-Aznar A, Domínguez C, Rubiera M, Ribó M, Quintana M, Molina CA, Álvarez-Sabín J, Rosell A, Unzeta M, Montaner J. Plasma VAP-1/SSAO Activity Predicts Intracranial Hemorrhages and Adverse Neurological Outcome After Tissue Plasminogen Activator Treatment in Stroke. Stroke 2010 Jul; 41 (7): 1528-35.  IF: 7.041. Hernández-Guillamón M, Mawhirt S, Fossati S, Blais S, Parés M, Penalba A, Boada M, Couraud PO, Neubert TA, Montaner J, Ghiso J, Rostagno A. Matrix metalloproteinase 2 (MMP-2) degrades soluble vasculotropic amyloid-beta E22Q and L34V mutants delaying their toxicity for human brain microvascular endothelial cells. J Biol Chem 2010 Aug 27; 285 (35): 27144-58.  IF: 5.328. Ibrahim MM, Sebastian J, Hussain M, AlHussain F, Uchino K, Molina C, Khan K, Demchuk AM, Alexandrov AV, Saqqur M; CLOTBUST Investigators. Does current oral antiplatelet agent or subtherapeutic anticoagulation use have an effect on tissueplasminogen-activator-mediated recanalization rate in patients with acute ischemic stroke? Cerebrovasc Dis. 2010; 30 (5): 50813.  IF: 3.535 Lees KR, Bluhmki E, Kummer R von, Brott TG, Toni D, Grotta JC, Albers GW, Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W, Allen K, ÁlvarezSabín J, Molina C, et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010 May 15; 375 (9727): 1695703.  IF: 30.758. Lemmens R, Buysschaert I, Geelen V, Fernández-Cadenas I, Montaner J, Schmidt H, Schmidt R, Attia J, Maguire J, Levi C, Jood K, Blomstrand C, Jern C, Wnuk M, Slowik A, Lambrechts D, Thijs V. The association of the 4q25 susceptibility variant for atrial fibrillation with stroke is limited to stroke of cardioembolic etiology. Stroke 2010 Sep; 41 (9): 1850-7.  IF: 7.041. Mendioroz M, Fernández Cadenas I, Río Espinola A del, Rovira A, Solé E, Fernández Figueras M, García Patos V, Sastre Garriga J, Domingues Montanari , Álvarez Sabín J, Montaner J. A missense HTRA1 mutation expands CARASIL syndrome to the Caucasian population. Neurology 2010 Nov 30; 75 (22): 2033-5.  IF: 8.172.

Mikulik R, Dusek L, Hill MD, Fulep E, Grotta JC, Ribó M, Molina C, Alexandrov AV. Pattern of Response of National Institutes of Health Stroke Scale Components to Early Recanalization in the CLOTBUST Trial. Stroke 2010 Mar; 41 (3): 466-70.  IF: 7.041. Molina CA. Futile Recanalization in Mechanical Embolectomy Trials. A Call to Improve Selection of Patients for Revascularization. Stroke 2010 May; 41 (5): 842-3.  IF: 7.041. Molina CA, Selim MH. General or Local Anesthesia During Endovascular Procedures. Sailing Quiet in the Darkness or Fast Under a Daylight Storm. Stroke 2010 Nov; 41 (11): 2720-1.  IF: 7.041. Morancho A, Rosell A, García-Bonilla L, Montaner J. Metalloproteinase and stroke infarct size: role for anti-inflammatory treatment? Ann N Y Acad Sci 2010 Oct; 1207: 12333. doi: 10.1111/j.1749-6632.2010.05734.x.  IF: 2.670. Navarro-Sobrino M, Rosell A, HernándezGuillamón M, Penalba A, Ribó M, ÁlvarezSabín J, Montaner J. Mobilization, endothelial differentiation and functional capacity of endothelial progenitor cells after ischemic stroke. Microvasc Res 2010 Dec; 80 (3): 317-23.  IF: 3.075. Parees I, Hernández-Vara J, Álvarez-Sabín J. Post-stroke hemichorea: observation-based study of 15 cases. Rev Neurol 2010 Oct 16; 51 (8): 460-4.  IF: 1.234. Parees I, Horga A, Santamarina E, Mendioroz M, Fernández-Cadenas I, Río-Espinola A del, Álvarez-Sabín J. Stroke after prolonged air travel associated with a pulmonary arteriovenous malformation. J Neurol Sci 2010 May 15; 292 (1-2): 99-100.  IF: 2.324. Poca MA, Benejam B, Sahuquillo J, Riveiro M, Frascheri L, Merino MA, Delgado P, Álvarez-Sabín J. Monitoring intracranial pressure in patients with malignant middle cerebral artery infarction: is it useful? J Neurosurg 2010 Mar;112 (3):648-57.  IF: 2.594. Ribó M, Rubiera M, Pagola J, Rodríguez Luna D, Meler P, Flores A, Álvarez Sabín J, Molina CA. Bringing Forward Reperfusion with Oxygenated Blood Perfusion beyond Arterial Occlusion during Endovascular Procedures in Patients with Acute Ischemic Stroke. AJNR Am J Neuroradiol 2010 Nov; 31 (10): 1899-902.  IF: 3.296.

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Río Espinola A del, Fernández Cadenas I, Mendioroz M, Gutiérrez Agullo M, Fernández MT, Fernández Morales J, Maisterra O, Domingues Montanari S, García Patos V, Solé E, Montaner J. Novel human pathological mutations. Gene symbol: NOTCH3. Disease: CADASIL. Hum Genet 2010 Apr; 127 (4): 474.  IF: 4.523.

Río Espinola A del, Solé E, Montaner J. Pathophysiology of CADASIL disease. Med Clin (Barc) 2010 Jul 10; 135 (5): 222-30.  IF: 1.231. Rio-Espinola A del, Fernández-Cadenas I, Rubiera M, Quintana M, DominguesMontanari, Mendioroz M, Fernández-Morales J, Giralt D, Molina CA, Álvarez-Sabín J, Montaner J. CD40-1C>T polymorphism (rs1883832) is associated with brain vessel reocclusion after fibrinolysis in ischemic stroke. Pharmacogenomics 2010 Jun; 11 (6): 763-72.  IF: 3.893. Selim MH, Molina CA. Platelet function assays in stroke management: more study is needed. Stroke 2010 Oct; 41 (10): 2396-7.  IF: 7.041. Selim MH, Molina CA. Management of Acute Stroke Patients With Rapidly Resolving Deficits and Persistent Vascular Occlusion. A Real Clinical Equipoise. Stroke 2010 Dec; 41 (12): 3007-8.  IF: 7.041. Tsivgoulis G, Eggers J, Ribó M, Perren F, Saqqur M, Rubiera M, Sergentanis TN, Vadikolias K, Larrue V, Molina CA, Alexandrov AV. Safety and efficacy of ultrasoundenhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke 2010 Feb; 41 (2): 280-7.  IF: 7.041. Yang Y, Candelario-Jalil E, Thompson JF, Cuadrado E, Estrada EY, Rosell A, Montaner J, Rosenberg GA. Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia. J Neurochem 2010 Jan 1; 112 (1): 134-49.  IF: 3.999.

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AREA 4 NEUROSCIENCES

4.10 Pediatric Neurology

Group Leader Alfons Macaya Ruiz Tel. 93 489 43 34 [email protected] Researchers Susana Boronat Guerrero Daniel Carranza Rojo Alfons Macaya Ruiz Solange Miguel Queralt Francina Munell Casadesús Miquel Raspall Chaure Manuel Roig Quilis Mireia del Toro Riera Researchers in Training Alba Berlanga Bustos Ingrid Figueras León Marina Flotats Bastardas Iris García Martínez Laura Monlleó Neila Aintzane Urbizu Serrano Maria Àngels Vidal Jorge Marta Vila Pueyo

RESEARCH LINES

Technician Marta Rebull Santamaria

OBJECTIVES The Pediatric Neurology Research group is mainly involved in the study of genetic diseases of the developing nervous system. The main emphasis is on paroxysmal neurological disorders and neuromuscular disorders. A common theme across the different pro-

jects, besides the identification of the molecular basis of several of these rare disorders, is the investigation of molecules involved in their pathophysiological mechanisms and the effective translation of these findings into the fields of molecular diagnosis, genetic counselling and newly developed gene or drug therapies.

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Pediatric neurogenetics Alfons Macaya Ruiz Neurogenetics of paroxysmal neurological disorders (neuronal channelopathies). Genetic and epigenetic basis of neural tube defects and Chiari type I malformation. Clinical researchers have collected samples from more than 2000 patients with paroxysmal neurological disorders (migraine, epilepsy, paroxysmal movement disorders and episodic ataxias) and over 300 patients with Chiari I malformation. Current strategies include wholegenome linkage analysis, exome sequencing, customized array resequencing, SNP-based genetic association studies and expression analysis in fetal tissues. The goals in this area are:

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• To identify novel genetic variants responsible for these diseases. • To establish a correlation between the genetic variants and the clinical forms of the disease. • To perform functional studies of the mutant proteins. • To design an animal model of cortical spreading depression, with emphasis on epigenetic modification of susceptibility genes.

Figure 60 Top: identified mutations in the CACNA1A gene, encoding the alpha subunit of the CaV2.1 neuronal channel, associated with various pediatric paroxysmal neurological phenotypes. Bottom, left: MRI scan of a patient with Chiari I malformation. Bottom, right: a pedigree segregating the CACNA1A p.Arg583Gln mutation with variable clinical expressivity: EA2= Episodic ataxia type 2; CA= cerebellar atrophy, MA= migraine with aura; HM= hemiplegic migraine. Solid symbols denote D19S1150 allele co-seggregating with the disease phenotypes

Neuromuscular disorders Francina Munell Casadesús The main goal is the development of novel approaches and models for the study of genetic neuromuscular disorders. Our main objectives are: • To identify the molecular pathways involved in skeletal muscle regeneration. • To identify potential therapeutic targets to improve skeletal muscle regeneration in muscular dystrophies. • To study the role of steroid hormones and their receptors in myogenesis. • To identify the molecular pathways involved in the pathogenesis of spinal muscular atrophy (in spinal cord and skeletal muscle). • To design an exon-array to identify mutations in patients with neuromuscular disorders of unknown etiology by massive sequencing.

CURRENT RESEARCH PROJECTS PI: Alfons Macaya Ruiz Genetic basis of Chiari type I malformation Funding Agency: Fundació La Marató de TV3 Reference: MARATV3_062710 Funding: 194,125 € Duration: 2007 to 2011

PI: Manuel Roig Quilis Papel del TGF en la progresión de la distrofia muscular de Duchenne Funding Agency: Fondo de Investigación Sanitaria Reference: PI061164 Funding: 98,010 € Duration: 2007 to 2010

PI: Alfons Macaya Ruiz Bases genéticas de la malformación de Chiari tipo I Funding Agency: Fondo de Investigación Sanitaria Reference: PI061606 Funding: 84,216 € Duration: 2007 to 2010

PI: Manuel Roig Quilis Defining targets for therapeutics in Spinal Muscular Atrophy. GENAME Project Funding Agency: Fundación Genoma España Reference: GENAME Funding: 168,800 € Duration: 2007 to 2010

PI: Mireia del Toro Riera Estudio del metabolismo de la glucosa y el glucógeno en células musculares en cultivo y fibroblastos de paciente afecto de la forma infantil de la enfermedad de Pome y controles sanos Funding Agency: Fundación Genzyme Reference: FEEL2008/01 Funding: 10,000 € Duration: 2009 to 2011

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Figure 61 • Anticlockwise: The mdx mouse, a commonly used model for the study of dystrophin deficiency. • H&E staining depicting muscle necrosisregeneration. • Immunohistochemical analysis of extracellular proteins in human myoblasts from a DMD patient. • Functional interaction of genes differentially expressed in dystrophic muscle along the disease course

PUBLICATIONS (Impact Factor: 24.345) PI: Alfons Macaya Ruiz Genes y migraña: clonaje posicional en migraña familiar y expresión en la depresión cortical propagada experimental Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2009-13182-C03-03 Funding: 90,750.02 € Duration: 2010 to 2012

PI: Francina Munell Casadesús Acciones de los receptores de andrógenos y estrógenos en la diferenciación miogénica y su modulación como estrategia terapéutica para revertir la diferenciación anómala del músculo deficiente en distrofia Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00097 Funding: 154,275 € Duration: 2010 to 2012

PI: Alfons Macaya Ruiz Grup de Recerca en Neurologia Infantil HUVH Funding Agency: AGAUR Reference: 2009 SGR 78 Funding: 41,600 € Duration: 2010 to 2013

Boix H, Ortega-Aznar A, Vázquez E, Salcedo S, Roig-Quilis M. Brainstem dysgenesis in an infant prenatally exposed to cocaine. Pediatr Neurol 2010 Apr; 42 (4): 295-7.  IF: 1.497. Burton BK, Guffon N, Roberts J, Ploeg AT van der, Jones SA, Toro M del, et al. Home treatment with intravenous enzyme replacement therapy with idursulfase for mucopolysaccharidosis type II - data from the Hunter Outcome Survey. Mol Genet Metab 2010 Oct-Nov; 101 (2-3): 123-9.  IF: 2.897. Corominas R, Sobrido MJ, Ribases M, Cuenca-León E, Blanco-Arias P, Narberhaus B, Roig M, Leira R, López-González J, Macaya A, Cormand B. Association study of the serotoninergic system in migraine in the Spanish population. Am J Med Genet B Neuropsychiatr Genet 2010 Jan 5; 153B (1): 177-84.  IF: 3.481. Couce ML, Aldamiz-Echevarría L, Baldellou A, Blasco J, Bueno MA, Dalmau J, Vega A de la, Toro M del, Díaz C, Lama R, Leao E, Marrero M, Navas VM, Pintos G. Recommendations and management of Type I hereditary or hepatorenal Tyrosinemia. An Pediatr (Barc) 2010 Nov; 73 (5): 279.e1-4.  IF: 0.363.

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Pinos T, Barbosa-Desongles A, Hurtado A, Santamaría-Martínez, Torres I de, Reventós J, Munell F. Human SHBG mRNA Translation Is Modulated by Alternative 5’-Non-Coding Exons 1A and 1B. PLoS One 2010 Nov 4; 5(11): e13844.  IF: 4.351. Serra SA, Cuenca-León E, Llobet A, RubioMoscardo F, Plata C, Carreno O, Fernández-Castillo N, Corominas R, Valverde MA, Macaya A, Cormand B, Fernández-Fernández. A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis. Proc Natl Acad Sci U S A 2010 Jan 26; 107 (4): 1672-7.  IF: 9.432. Urbizu A, Cuenca-León E, Raspall-Chaure M, Gratacòs M, Conill J, Redecillas S, RoigQuilis M, Macaya A. Paroxysmal exercise-induced dyskinesia, writer’s cramp, migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense mutation. J Neurol Sci 2010 Aug 15; 295 (1-2): 110-3.  IF: 2.324.

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AREA 4 NEUROSCIENCES

4.11 Peripheral Nervous System

Group Leader José Gámez Carbonell Tel. 93 274 65 96 [email protected] Researcher José Gámez Carbonell Nursing, Technical and Administrative Staff Ma. Mercè Badía Canto

OBJECTIVES Our laboratory, in the Neuromuscular Disorders Unit of the Neurology Department, has a twentyyear history of providing clinical care and research in amyotrophic lateral sclerosis (ALS) and other motor neuron diseases (hereditary spastic paraplegias, postpolio syndrome, Hirayama’s disease, spinal muscular atrophies), myasthenia gravis, genetically determined myopathies, and peripheral neuropathies. We believe that some ALS cases may be due to missing or surplus genetic information in the chro-

mosomes, which are the structures in each cell that package an individual’s genetic information. Our research aims to ascertain the specific genes involved in ALS, and the contribution of DNA rearrangements in causing the disease. As a result, our main research lines are Molecular Mechanisms of ALS, and Genetic Mutations in Familial ALS, including predisposing or modifying gene factors. Despite the fact that several major genes are known to cause ALS, the precise connection between mutant proteins

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and their pathological pathways is uncertain. We are currently investigating the role of signalling genes in the pathogenesis of familial and sporadic forms of ALS. Our work also involves searching for effective biomarkers in blood and CSF which enable assessment of new candidate drugs for treatment of this devastating disease. The success of translational medicine depends on the results in animal models, and biomarkers of the disease’s progression are therefore important tools for new therapies in humans. Our research is also currently focused on myasthenia gravis, myopathies and peripheral neuropathies in order to achieve a better understanding of the clinical, genetic and pathological correlations of these diseases.

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RESEARCH LINES Molecular Mechanisms of ALS

Genetic Mutations in Familial ALS

PUBLICATIONS (Impact Factor: 13.476) Álvarez V, Sánchez-Ferrero E, Beetz C, Díaz M, Alonso B, Corao AI, Gámez J, Esteban J, Gonzalo JF, Pascual-Pascual SI, López de Munain A, Moris G, Ribacoba R, Marquez C, Rosell J, García-Barcina MJ, Marín R, Castillo E del, Benito C, Coto E, The Genetics Of Spas. Mutational spectrum of the SPG4 (SPAST) and SPG3A (ATL1) genes in Spanish patients with hereditary spastic paraplegia. BMC Neurol 2010 Oct 8; 10 (1): 89.  IF: 2.109. Bernal S, Alias L, Barceló MJ, Also-Rallo E, Martínez-Hernández R, Gámez J, GuillénNavarro E, Rosell J, Hernando I, RodríguezÁlvarez FJ, Borrego S, Millán JM, Hernández-Chico C, Baiget M, Fuentes-Prior P, Tizzano EF. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J Med Genet 2010 Sep; 47 (9): 640-2.  IF: 5.751.

Fernández M, Gobartt AL, Balaña M, Abellán J, Abellán T, Aguado ML, Alastuey C, Alayón A, Alfonso S, Almajano J, Álvarez J, Andrés M, Andrés RM, Aranceta S, Asencio JJ, Blanco M, Bergareche A, Burriel A, Cabello LM, Calatayud T, Campayo A, Campos DM, Carballo M, Cardozo A, Carnero C, Cerda J, Delgado G, Dobato JL, Domíguez JA, Dueñas DR, Escudero J, Fernández D, Ferreres C, Franquet E, Frutos MT, Gahete C, Galiano ML, Gámez J, et al. Behavioural symptoms in patients with Alzheimer’s disease and their association with cognitive impairment. BMC Neurol 2010 Sep 28; 10: 87.  IF: 2.109.

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Gámez J, Carmona F, Raguer N, Ferrer-Sancho J, Martín-Henao GA, Martí-Beltrán S, Badía M, Gratacós M, Rodríguez-González E, Seoane JL, Pallero-Castillo M, Burgos R, Puiggros C, Pasarín A, Bori-Fortuny I. Cellular transplants in amyotrophic lateral sclerosis patients: an observational study. Cytotherapy 2010 Sep; 12 (5): 669-77.  IF: 2.204. Gámez J, Lorenzo-Bosquet C, CuberasBorros G, Carmona F, Hernández-Vara J, Castillo J, Castell-Conesa J. Does reduced [(123)I]-FP-CIT binding in Huntington’s disease suggest pre-synaptic dopaminergic involvement? Clin Neurol Neurosurg 2010 Dec; 112 (10): 870-5.  IF: 1.303.

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AREA 4 NEUROSCIENCES

4.12 Psychiatry and Mental Health

Group Leader Miquel Casas Brugué Tel. 93 489 42 94 [email protected] Researchers Marisol Ampudia Rodríguez Óscar Andión Pérez José María Argüello Alonso M Carmen Barral Picado Nuria Bassas Bolivar Miquel Jordi Bel Aguado Ana Bielsa Carrafa Rosa Maria Bosch Munsó Mª Dolores Braquehais Conesa Eugeni Bruguera Cortada Natalia Calvo Piñero Miquel Casas Brugué Francisco Collazos Sánchez Marina Comín Zafón Margarita Corominas Roso Montserrat Corrales de la Cruz Joan Creixell Sureda Constanza Daigre Blanco

Francisco Javier Eiroa Orosa Sara Guila Fidel Kinori Gideoni Fusté Coetzee Beatriz Gancedo Villegas Javier Agustín Gastaminza Pérez Andrea di Genova Begoña P Gonzalvo Cirac Lara Grau López Carlos Jacas Escarcellé Pilar Lusilla Palacios Nieves Gu Martinez Luna Laia Miquel de Montagut José Eduardo Montejo Celis Mariana I Morais Nogueira José Antonio Navarro Sanchís Gemma Nieva Rifa Gemma Parramón Puig Marta Quesada Franco Adil Qureshi José Antonio Ramos Quiroga Marta Ribases Haro Vanesa Richarte Fernández Amanda Rodríguez Urrutia Carlos Roncero Alonso

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Xavier Salas Puig Sergi Valero Ventura Researchers in Training Xavier Castells Cervelló Albert de Bonis Freixes Hilda Wara Revollo Escudero María Victoria Trasovares Navarrete Nursing, Technical and Administrative Staff Olga Corcoles Verdejo Maria Emilia Dip Pérez Gemma Escuder Romeva Esther García Giménez Anna Giannoni Pastor Victoria López Craver María Cecilia Navarro Marfisis María Begoña Olivares Mariscal Cristina P Sánchez Mora Yolanda Santaella Andres Ruth Tasqué Cebrián Yemima Villegas Urbina

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OBJECTIVES Consolidating Clinical Research Programs already started, emphasizing the interaction of various diseases and research of genetic-based common etiopathogenic mechanisms.

RESEARCH LINES

CURRENT RESEARCH PROJECTS

Trimorbility: TDAH, TLP and Addictions Miquel Casas Brugué

Obsessive - compulsive disorders Miquel Casas Brugué Disorder and Attention Deficit Hyperactivity Disorder in adults (ADHD) José Antonio Ramos Quiroga

Borderline Personality Disorders (BPD) Marc Ferrer Vinardel

Interconsultation Psychiatry in children’s Hospitals and Liaison Psychiatry Javier Agustín Gastaminza Pérez

Sexual Dysfunctions José Antonio Navarro Sanchís

Chronic Fatigue Naia Saez Francàs

Suicide Marta Quesada Franco

Post-Traumatic Stress Disorder José María Argüello Alonso

Tabagism Eugeni Bruguera Cortada

PI: Miquel Casas Brugué Estudio de la eficacia de la cafeína en el tratamiento de mantenimiento de pacientes con dependencia de cocaína Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90713 Funding: 119,548 € Duration: 2007 to 2012

PI: Marta Ribases Haro Genetic susceptibility factors in attention- deficit/hyperactivity disorder (ADHD): a two stage genome-wide association study Funding Agency: Fundació La Marató de TV3 Reference: MARATV3/2009/01 Funding: 149,712.50 € Duration: 2010 to 2012

Gender Abuse Joan Creixell Sureda

Dual Pathology Carlos Roncero Alonso

Psychiatric Genetics Marta Ribases Haro

Transcultural Psychiatry Francisco Collazos Sánchez

Interconsultation Psychiatry in general Hospitals and Liaison Psychiatry Gemma Parramón Puig

Developmental Disorders Ana Bielsa Carrafa

Obsessive - compulsive disorder in Children and Young People Nuria Bassas Bolivar

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PI: Marta Ribases Haro Genetic susceptibility factors in Attention-Deficit/Hiperactivity Disorder (ADHD) Funding Agency: Fondo de Investigación Sanitaria Reference: CP09/00119 Funding: 44,700 € Duration: 2010 to 2012

PI: José Antonio Ramos Quiroga Estudio farmacogenético con metilfenidato en niños con trastorno por déficit de atención con hiperactividad Funding Agency: Fundación Alicia Koplowitz Reference: FAK-2010-04 Funding: 75,000 € Duration: 2010 to 2012

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PI: Sara Guila Fidel Kinori Protección de la confidencialidad en las historias clínicas informatizadas: los pacientes en la consulta de Salud Mental hospitalaria Funding Agency: Fundació Víctor Grífols i Lucas Reference: VGL-2010-01 Funding: 5,000 € Duration: 2010 to 2011

PUBLICATIONS (Impact Factor: 106.222) Alegret M, Vinyes-Junque G, Boada M, Martínez-Lage P, Cuberas G, Espinosa A, Roca I, Hernández I, Valero S, Rosende-Roca M, Mauleon A, Becker And JT, Tarraga L. Brain Perfusion Correlates of Visuoperceptual Deficits in Mild Cognitive Impairment and Mild Alzheimer’s Disease. J Alzheimers Dis 2010; 21 (2): 557-67.  IF: 3.832. Arcos-Burgos M, Jain M, Acosta MT, Shively S, Stanescu H, Wallis D, Domene S, Vélez JI, Karkera JD, Balog J, Berg K, Kleta R, Gahl WA, Roessler E, Long R, Lie J, Pineda D, Londono AC, Palacio JD, Arbelaez A, Lopera F, Elia J, Hakonarson H, Johansson S, Knappskog PM, Haavik J, Ribases M, Cormand B, Bayes M, Casas M, Ramos-Quiroga JA, Hervas A, Maher BS, Faraone SV, Seitz C, Freitag CM, Palmason H, Meyer J, Romanos M, Walitza S, Hemminger U, Warnke A, Romanos J, Renner T, Jacob C, Lesch KP, Swanson J, Vortmeyer A, Bailey-Wilson JE, Castellanos FX, Muenke M. A common variant of the latrophilin 3 gene, LPHN3, confers susceptibility to ADHD and predicts effectiveness of stimulant medication. Mol Psychiatry 2010 Nov; 15 (11): 1053-66.  IF: 15.049. Braquehais MD, Oquendo MA, Baca-García E, Sher L. Is impulsivity a link between childhood abuse and suicide? Compr Psychiatry 2010 Mar-Apr; 51 (2): 121-9.  IF: 2.082. Braquehais MD, Sher L. Posttraumatic stress disorder in war veterans: a discussion of the Neuroevolutionary Time-depth Principle. J Affect Disord 2010 Sep; 125 (1-3): 1-9.  IF: 3.763. Castells X, Casas M, Pérez-Mana C, Roncero C, Vidal X, Capella D. Efficacy of psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev 2010 Feb 17; 2: CD007380.  IF: 5.653. Corominas M, Roncero C, Casas M. Corticotropin releasing factor and neuroplasticity in cocaine addiction. Life Sci 2010 Jan 2; 86 (1-2):1-9.  IF: 2.560. Corominas R, Sobrido MJ, Ribases M, Cuenca-León E, Blanco-Arias P, Narberhaus B, Roig M, Leira R, López-González J, Macaya A, Cormand B. Association study of the serotoninergic system in migraine in the Spanish population. Am J Med Genet B Neuropsychiatr Genet 2010 Jan 5; 153B (1): 177-84.  IF: 3.481.

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Daigre C, Comín M, Rodríguez Cintas L, Voltes N, Álvarez A, Roncero C, Gonzalvo B, Casas M. Users’ perception of a harm reduction program in an outpatient drug dependency treatment center. Gac Sanit 2010 Nov-Dec; 24 (6): 446-52.  IF: 1.172. Eiroa-Orosa FJ, Haasen C, Verthein U, Dilg C, Schafer I, Reimer J. Benzodiazepine use among patients in heroin-assisted vs. methadone maintenance treatment: findings of the German randomized controlled trial. Drug Alcohol Depend 2010 Dec 1; 112 (3): 226-33.  IF: 3.599. Fernández-Castillo N, Ribases M, Roncero C, Casas M, Gonzalvo B, Cormand B. Association study between the DAT1, DBH and DRD2 genes and cocaine dependence in a Spanish sample. Psychiatr Genet 2010 Dec; 20 (6): 317-20.  IF: 2.327. Franke B, Vasquez AA, Johansson S, Hoogman M, Romanos J, Boreatti-Hummer A, Heine M, Jacob CP, Lesch KP, Casas M, Ribases M, Bosch R, Sánchez-Mora C, GómezBarros N, Fernández-Castillo N, Bayes M, Halmoy A, Halleland H, Landaas ET, Fasmer OB, Knappskog PM, Heister AJ, Kiemeney LA, Kooij JJ, Boonstra AM, Kan CC, Asherson P, Faraone SV, Buitelaar JK, Haavik J, Cormand B, Ramos-Quiroga JA, Reif A. Multicenter analysis of the SLC6A3/DAT1 VNTR haplotype in persistent ADHD suggests differential involvement of the gene in childhood and persistent ADHD. Neuropsychopharmacology 2010 Feb; 35 (3): 656-64.  IF: 6.993. Ganz D, Braquehais MD, Sher L. Secondary prevention of suicide. PLoS Med 2010 Jun 1; 7 (6): e1000271.  IF: 13.050. Gratacós M, Escaramis G, Bustamante M, Saus E, Aguera Z, Bayes M, Cellini E, Cid R de, Fernández-Aranda F, Forcano L, González JR, Gorwood P, Hebebrand J, Hinney A, Mercader JM, Nacmias B, Ramoz N, Ribases M, Ricca V, Romo L, Sorbi S, Versini A, Estivill X. Role of the neurotrophin network in eating disorders’ subphenotypes: body mass index and age at onset of the disease. J Psychiatr Res 2010 Oct; 44 (13): 834-40.  IF: 3.723. Hoekzema E, Carmona S, Tremols V, Gispert JD, Guitart M, Fauquet J, Rovira M, Bielsa A, Soliva JC, Tomas X, Bulbena A, Ramos A, Casas M, Tobeña A, Vilarroya O. Enhanced neural activity in frontal and cerebellar circuits after cognitive training in children with attention-deficit/hyperactivity disorder. Hum Brain Mapp 2010 Dec; 31 (12): 1942-50. doi: 10.1002/hbm.20988.  IF: 6.256.

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Area 4. Neurosciences

Johansson S, Halmoy A, Mavroconstanti T, Jacobsen KK, Landaas ET, Reif A, Jacob C, Boreatti-Hummer A, Kreiker S, Lesch KP, Kan CC, Kooij JJ, Kiemeney LA, Buitelaar JK, Franke B, Ribases M, Bosch R, Bayes M, Casas M, Ramos-Quiroga JA, Cormand B, Knappskog P, Haavik J. Common variants in the TPH1 and TPH2 regions are not associated with persistent ADHD in a combined sample of 1,636 adult cases and 1,923 controls from four European populations. Am J Med Genet B Neuropsychiatr Genet 2010 Jul; 153B (5): 1008-15.  IF: 3.481. Kooij SJ, Bejerot S, Blackwell A, Caci H, Casas-Brugué M, Carpentier PJ, Edvinsson D, Fayyad J, Foeken K, Fitzgerald M, Gaillac V, Ginsberg Y, Henry C, Krause J, Lensing M, Manor I, Niederhofer H, Nunes-Filipe C, Ohlmeier MD, Oswald P, Pallanti S, Pehlivanidis A, Ramos-Quiroga JA, Rastam M, Ryffel-Rawak D, Stes S, Asherson P. European consensus statement on diagnosis and treatment of adult ADHD: the European Network adult ADHD. BMC Psychiatry 2010 Sep 3; 10 (1): 67.  IF: 1.832. Landaas ET, Johansson S, Jacobsen KK, Ribases M, Bosch R, Sánchez-Mora C, Jacob CP, Boreatti-Hummer A, Kreiker S, Lesch KP, Kiemeney LA, Kooij JJ, Kan C, Buitelaar JK, Faraone SV, Halmoy A, Ramos-Quiroga JA, Cormand B, Reif A, Franke B, Mick E, Knappskog PM, Haavik J. An international multicenter association study of the serotonin transporter gene in persistent ADHD. Genes Brain Behav 2010 Jul; 9 (5): 449-58.  IF: 3.795.

Les I, Doval E, Flavia M, Jacas C, Cárdenas G, Esteban R, Guardia J, Córdoba J, Jacas C. Quality of life in cirrhosis is related to potentially treatable factors. Eur J Gastroenterol Hepatol 2010 Feb; 22 (2): 221-7.  IF: 1.662. Mercader JM, Fernández-Aranda F, Gratacós M, Aguera Z, Forcano L, Ribases M, Villarejo C, Estivill X. Correlation of BDNF blood levels with interoceptive awareness and maturity fears in anorexia and bulimia nervosa patients. J Neural Transm 2010 Apr; 117 (4): 505-12.  IF: 2.259. Montanes-Rada F, Gastaminza-Pérez X, Català MA, Ruiz-Sanz F, Ruiz-Lázaro PM, Herreros-Rodríguez O, Garcia-Giral M, OrtizGuerra J, Alda-Diez JA, Mojarro-Praxedes D, Canto-Diez T, Mardomingo-Sanz MJ, Sasot-Llevadot J, Pamias M, Rey-Sánchez F. GEITDAH consensus on attention deficit hyperactivity disorder. Rev Neurol 2010 Nov 16; 51 (10): 633-7.  IF: 1.234. Pons R, Serrano M, Ormazabal A, Toma C, García-Cazorla A, Area E, Ribases M, Kanavakis E, Drakaki K, Giannakopoulos A, Orfanou I, Youroukos S, Cormand B, Artuch R. Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation. Mov Disord 2010 Jun 15; 25 (8): 1086-90.  IF: 4.014.

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Rosler M, Casas M, Konofal E, Buitelaar J. Attention deficit hyperactivity disorder in adults. World J Biol Psychiatry 2010 Aug; 11(5): 684-98.  IF: 5.564. Sánchez-Mora C, Ribases M, Ramos-Quiroga JA, Casas M, Bosch R, Boreatti-Hummer A, Heine M, Jacob CP, Lesch KP, Fasmer OB, Knappskog PM, Kooij JJ, Kan C, Buitelaar JK, Mick E, Asherson P, Faraone SV, Franke B, Johansson S, Haavik J, Reif A, Bayes M, Cormand B. Meta-analysis of brain-derived neurotrophic factor p.Val66Met in adult ADHD in four European populations. Am J Med Genet B Neuropsychiatr Genet 2010 Mar 5; 153B (2): 512-23.  IF: 3.481. Soliva JC, Fauquet J, Bielsa A, Rovira M, Carmona S, Ramos-Quiroga JA, Hilferty J, Bulbena A, Casas M, Vilarroya O. Quantitative MR analysis of caudate abnormalities in pediatric ADHD: Proposal for a diagnostic test. Psychiatry Res 2010 May 18.  IF: 3.435. Soliva JC, Moreno A, Fauquet J, Bielsa A, Carmona S, Gispert JD, Rovira M, Bulbena A, Vilarroya O. Cerebellar neurometabolite abnormalities in pediatric attention/deficit hyperactivity disorder: a proton MR spectroscopic study. Neurosci Lett 2010 Feb 5; 470 (1): 60-4.  IF: 1.925.

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VHIR Information

AREA 5 DIGESTIVE PHYSIOPATHOLOGY AND HEPATOLOGY

5.1 Digestive Transplants

Group Leader Ramon Charco Torra Tel. 93 274 61 13 [email protected] Researchers Joaquín Balsells Valls Itxarone Izaskun Bilbao Aguirre Laia Blanco Cuso Francisco Javier Bueno Recio Mieria Caralt Barba Ramon Charco Torra Cristina Dopazo Taboada Francisco José Espín Álvarez José Luis Lázaro Fernández Javier Naval Álvaro Roberto Rodríguez Revuelto Gonzalo Sapisochin Cantis

OBJECTIVES • Clinical studies on immunosuppression in human liver transplantation. • Experimental research in minimally invasive surgery through naturals orifices or NOTES together with Dr. J.R. Armengol Miró from Endoscopy Service.

RESEARCH LINES Morbidity and quality of life after liver transplantation Itxarone Izaskun Bilbao Aguirre, Javier Bueno Recio and Cristina Dopazo Taboada Risk factors of early and late morbimortality after liver transplantation in adults and children.

• Experimental research in hepatic surgery.

Treatment of hepatocellular carcinoma Ramon Charco Torra, Gonzalo Sapisochin Cantis, Joaquin Balsells Valls and Lluís Castells Fusté Management of different treatments for hepatocarcinoma using resection, transplantation, percutaneous methods, chemoembolization and chemotherapy.

• Clinical research in hepatic and bile-pancreatic surgery. • Clinical research in intestinal transplantation.

22010 Impact Factor: • Clinical research in partial hepatic transplantation (Vivo donations and/or split).

18.298

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Treatment of liver metastases of colorectal cancer Ramon Charco Torra, José Luis Lázaro Fernández, Cristina Dopazo Taboada, Gonzalo Sapisochin Cantis and Josep Tabernero Caturla New surgical techniques and chemotherapy treatments.

Technical advances in hepatobiliopancreatic surgery and transplantation Joaquín Balsells Valls, José Luis Lázaro Fernández and Ramon Charco Torra Evaluating new technologies: laparoscopy, robotics and image processing.

Pancreatic function after pancreatectomy Joaquin Balsells Valls and Javier Naval Álvaro Evaluating antibiotic elimination by pancreatic liquid.

Figure 62 Liver transplantation. Biliary anastomosis

PUBLICATIONS (Impact Factor: 18.298)

Advances in staging of pancreatic cancer Joaquin Balsells Valls and Javier Naval Álvaro Studying sentinel ganglion.

Bueno J, Pérez-Lafuente M, Venturi C, Segarra A, Barber I, Molino JA, Romero A, Ortega J, Bilbao I, Martínez-Ibáñez V, Charco R. No-touch hepatic hilum technique to treat early portal vein thrombosis after pediatric liver transplantation. Am J Transplant 2010 Sep; 10 (9): 2148-53.  IF: 6.433.

Treatment of plaquetopenia after liver transplantation Gonzalo Sapisochin Cantis, Itxarone Izaskun Bilbao Aguirre, José Luis Lázaro Fernández, Lluís Castells Fusté and Ramon Charco Torra Evaluating splenic flow occlusion.

Sapisochin G, Bilbao I, Balsells J, Dopazo C, Caralt M, Lázaro JL, Castells L, Allende H, Charco R. Optimization of Liver Transplantation as a Treatment of Intrahepatic Hepatocellular Carcinoma Recurrence After Partial Liver Resection: Experience of a Single European Series. World J Surg 2010 Sep; 34 (9): 2146-54.  IF: 2.696.

Post-transplant monitoring in paediatric liver transplantation Javier Bueno Recio and Ramon Charco Torra Advances in vascular thrombosis prevention.

Schnitzbauer AA, Zuelke C, Graeb C, Rochon J, Bilbao I, et al. A prospective randomised, open-labelled, trial comparing sirolimuscontaining versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 2010 May 11; 10(1): 190.  IF: 2.736.

Figure 63 Intestinal graft

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Trunecka P, Boillot O, Seehofer D, Pinna AD, Fischer L, Ericzon BG, Troisi RI, Baccarani U, Ortiz de Urbina J, Wall W, McCaughan G, Jones R, Troisi RI, Roover A de, Mies S, Moreira L, Lima A, Cantisani G, Wall W, Kneteman N, Grant D, Roy A, Scudamore C, Tchervenkov J, Trunecka P, Clavien P, Candinas D, Seehofer D, Fischer L, Schmidt J, Schlitt J, Ortiz de Urbina J, Bilbao I, Charco R, et al. Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant 2010 Oct; 10 (10): 2313-23. doi: 10.1111/j.1600-6143.2010.03255.x.  IF: 6.433.

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VHIR Information

AREA 5 DIGESTIVE PHYSIOPATHOLOGY AND HEPATOLOGY

5.2 Liver Diseases

Group Leader Jaume Guardia Massó Tel. 93 274 61 10 [email protected] Researchers Maria Buti Ferret Lluis Castells Fusté Rafael Esteban Mur Juan Ignacio Esteban Mur Joan Genescà Ferrer Antonio González Fernández Jaume Guardia Massó Rosendo Jardí Margalef Maria Martell Pérez-Alcalde Beatriz Mínguez Rosique Lluís Palenzuela Díaz Josep Quer Sivila Francisco Rodríguez Frias Silvia Sauleda Oliveras Victor Manuel Vargas Blasco Lluís Viladomíu Catà Researchers in Training José Trinidad Altamirano Gómez Salvador Augustin Recio Nerea Beguiristain Celayeta Laia Chavarria Vilarasau Maria del Mar Coll Loperena María Dolores Cubero León Nahia Ezcurdia Garmendia Rita García Martínez Maria Homs Riba Marc Oria Alonso David Tabernero Caellas Nursing, Technical and Administrative Staff Judit Carbonell Segura Silvia Maritza Cuenca Barrero Damir García Cehic Mª del Tránsito González García Laura Millán Segovia Immaculada Raurell Saborit Jordi Romero Giménez Maria Margarita Torrens Buscató

OBJECTIVES Our group is interested in the clinical and basic aspects of liver diseases. We have two main research areas: viral hepatitis (etiology, virology, epidemiology, pathogene-

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sis and therapy) and liver cirrhosis and its complications (portal hypertension, encephalopathy, hepatocellular carcinoma, liver failure), including liver transplantation.

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RESEARCH LINES Hepatitis B, Molecular biology and therapy Maria Buti Ferret and Rosendo Jardí Margalef Genomic variability of hepatitis B virus, epidemiology. Mutations related to antiviral resistance. New therapies. Natural history.

Hepatitis C, molecular biology, immune response and therapy Rafael Esteban Mur, Juan Ignacio Esteban Mur and Josep Quer Sivila Genomic variability of hepatitis C virus, quaiespecies. Immune response in chronic disease. Natural history. New therapies. Molecular markers of antiviral response.

Portal hypertension Joan Genescà Ferrer and Maria Martell Pérez-Alcalde Physiopatholy of splanhnic arterial vasodilation. Treatment of variceal bleeding.

Liver failure and metabolic encephalopaties Juan Córdoba Cardona Physiopathology and treatment of cerebral edema and liver failure. Mechanisms implicated in metabolic encephalopaties.

Liver transplantation and hepatocarcinoma Víctor Manuel Vargas Blasco, Lluis Castells Fusté and Beatriz Mínguez Rosique Hepatitis C postransplantation. New inmmunosuppressors. Prognostic factors and new therapies for hepatocarcinoma.

Figure 64 Hepatitis C virus (HCV) pyrosequencing results. Raw data from a Genome Sequencer FLX Titanium picotiter plate using the Ultra-deep Pyrosequencing 454/Roche platform. Left image shows one of the two lanes in which the picotiter plate was divided. Upper right image is a magnification of a small region (yellow circle) and the Flowgram obtained from one of the 3.2million wells that compose the plate. From each flowgram, GS-FLX software generates a text file with the sequence for a total of around 1 million correct reads (one read = one sequence). Bottom-left graphic indicates the number of wells that have passed the internal 454 filter. Bottom-right image shows the length of the sequences obtained and the number of reads per length

CURRENT RESEARCH PROJECTS PI: Lluís Castells Fusté TOH/VIH-05: Trasplante hepático en pacientes infectados por el VIH en España (2005-2007)TOH/ VIH-09: Trasplante hepático en pacientes infectados por el VIH en España (2009-2011) Funding Agency: Fundación invest. y prevención SIDA - FIPSE Reference: FIPSE/TOH/VIH Funding: 28,800 € Duration: 2006 to 2012

22010 Impact Factor:

155.762

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PI: Víctor Manuel Vargas Blasco Efectos de la infusión de albúmina en el episodio de encefalopatía hepática. Estudio aleatorizado y multicéntrico en pacientes con cirrosis hepática Funding Agency: Fondo de Investigación Sanitaria Reference: PI070641 Funding: 71,390 € Duration: 2008 to 2011

PI: Silvia Sauleda Oliveras Caracterización serológica, inmunológica y molecular de donantes de sangre con infección oculta por virus de la hepatitis B Funding Agency: Fondo de Investigación Sanitaria Reference: PI070754 Funding: 45,980 € Duration: 2008 to 2010

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VHIR Information

PI: Víctor Manuel Vargas Blasco Estudio doble ciego, aleatorizado y controlado sobre la eficacia de la administración combinada de albúmina y midodrina en la prevención de las complicaciones de pacientes con cirrosis en lista de espera de trasplante hepático Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90744 Funding: 30,250 € Duration: 2007 to 2011

PI: Juan Córdoba Cardona Alteración de la barrera hematoencefálica y edema cerebral en la insuficiencia hepática experimental Funding Agency: Fondo de Investigación Sanitaria Reference: PI080698 Funding: 258,335 € Duration: 2009 to 2011

PI: Joan Genescà Ferrer Estudio multicéntrico, aleatorizado, doble-ciego, controlado con placebo, sobre la eficacia del tratamiento con beta-bloqueantes para prevenir la descompensación de la cirrosis con hipertensión portal Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00070 Funding: 122,815 € Duration: 2009 to 2011

PI: Joan Genescà Ferrer Papel del sistema nervioso simpático en la génesis y mantenimiento de las alteraciones hemodinámicas (vasodilatación mesentérica) de la hipertensión portal (SIMPATHAL) Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2009-08354 Funding: 84,700 € Duration: 2010 to 2012

PI: Josep Quer Sivila Estudio dinámico de quasiespecies de VHC por pirosecuenciación en fase aguda y crónica durante tratamiento antiviral (PIROVIRUSC) Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2009-10403 Funding: 121,000 € Duration: 2010 to 2012

PI: Francisco Rodríguez Frías Análisis de la cuasiespecie viral en la infección por virus de la hepatitis B: evolución natural y asociada al tratamiento antiviral Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00899 Funding: 90,750 € Duration: 2010 to 2012

PI: Juan Córdoba Cardona Efectos de la administración de fenilacetato y ornitina en pacientes con cirrosis hepática que presentan una hemorragia digestiva Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-190 Funding: 43,962 € Duration: 2010 to 2011

PI: Juan Ignacio Esteban Mur Estudio de quasiespecies de los virus de la hepatits B y C (VHB y VHC) y de polimorfismos genómicos asociados a respuesta al tratamiento antiviral por pirosecuenciación Funding Agency: Centro para el Desarrollo Técnico Industrial (CDTI) Reference: CDTI-2010-01 Funding: 875,000 € Duration: 2010 to 2013

PI: Joan Genescà Ferrer Unitat de Recerca en Malalties Hepatobiliars Funding Agency: AGAUR Reference: 2009 SGR 383 Funding: 54,080 € Duration: 2010 to 2013

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Figure 65 Immunofluorescence of superior mesenteric ganglion of a rat: adrenergic neuronal bodies stained with tyrosine hydroxilase (in green) surrounded by nitrergic axons stained by neuronal nitric oxide synthase (in red)

PUBLICATIONS (Impact Factor: 155.762) Boixadera H, Tomasello A, Quiroga S, Córdoba J, Pérez M, Segarra A. Successful Embolization of a Spontaneous Mesocaval Shunt Using the Amplatzer Vascular Plug II. Cardiovasc Intervent Radiol 2010 Oct; 33 (5): 1044-8.  IF: 1.949. Buti M, Homs M, Rodríguez-Frias F, Funalleras G, Jardí R, Sauleda S, Tabernero D, Schaper M, Esteban R. Clinical outcome of acute and chronic hepatitis delta over time: a long-term follow-up study. J Viral Hepat 2010 Jun 8. doi: 10.1111/j.13652893.2010.01324.x.  IF: 3.348. Buti M, Lurie Y, Zakharova NG, Blokhina NP, Horban A, Teuber G, Sarrazin C, Balciuniene L, Feinman SV, Faruqi R, Pedicone LD, Esteban R, Berr F, et al. Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks in patients with hepatitis C virus genotype 1 and slow virologic response. Hepatology 2010 Oct; 52 (4): 12017.  IF: 10.840. Chavarria L, Oria M, Romero-Giménez J, Alonso J, Lope-Piedrafita S, Córdoba J. Diffusion tensor imaging supports the cytotoxic origin of brain edema in a rat model of acute liver failure. Gastroenterology 2010 Apr; 138 (4): 1566-73.  IF: 12.899. Coll M, Martell M, Raurell I, Ezkurdia N, Cuenca S, Hernández-Losa J, Esteban R, Guardia J, Bosch J, Genescà J. Atrophy of mesenteric sympathetic innervation may contribute to splanchnic vasodilatation in rat portal hypertension. Liver Int 2010 Apr; 30 (4): 593-602.  IF: 2.987.

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Córdoba J, García-Martínez R, Simón-Talero M. Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence. Metab Brain Dis 2010 Mar; 25 (1): 73-80.  IF: 1.959. Erceg S, Ronaghi M, Oria M, Roselló MG, Aragó MA, López MG, Radojevic I, MorenoManzano V, Rodríguez-Jiménez FJ, Bhattacharya SS, Córdoba J, Stojkovic M. Transplanted oligodendrocytes and motoneuron progenitors generated from human embryonic stem cells promote locomotor recovery after spinal cord transection. Stem Cells 2010 Sep; 28 (9): 1541-9.  IF: 7.747. García-Martínez R, Rovira A, Alonso J, Aymerich FX, Huerga E, Jacas C, Simón-Talero M, Vargas V, Córdoba J. A Long-Term Study of Changes in the Volume of Brain Ventricles and White Matter Lesions After Successful Liver Transplantation. Transplantation 2010 Mar 15; 89 (5): 589-94.  IF: 3.498. Hoshida Y, Toffanin S, Lachenmayer A, Villanueva A, Mínguez B, Llovet JM. Molecular classification and novel targets in hepatocellular carcinoma: recent advancements. Semin Liver Dis 2010 Feb; 30 (1): 35-51.  IF: 5.171. Les I, Doval E, Flavia M, Jacas C, Cárdenas G, Esteban R, Guardia J, Córdoba J, Jacas C. Quality of life in cirrhosis is related to potentially treatable factors. Eur J Gastroenterol Hepatol 2010 Feb; 22 (2): 221-7.  IF: 1.662. Miquel M, Bartoli R, Odena G, Serafin A, Cabré E, Galán A, Barba I, Córdoba J, Planas R. Rat CCl(4)-induced cirrhosis plus total portal vein ligation: a new model for the study of hyperammonaemia and brain oedema. Liver Int 2010 Aug; 30 (7): 979-87.  IF: 2.987. Miravitlles M, Herr C, Ferrarotti I, Jardí R, Rodríguez-Frias F, Luisetti M, Bals R. Laboratory testing of individuals with severe alpha1-antitrypsin deficiency in three European centres. Eur Respir J 2010 May; 35 (5): 960-8.  IF: 5.527. Muntaner L, Altamirano JT, Augustin S, González A, Esteban R, Guardia J, Genescà J. High doses of beta-blockers and alcohol abstinence improve long-term rebleeding and mortality in cirrhotic patients after an acute variceal bleeding. Liver Int 2010 Sep; 30 (8): 1123-30.  IF: 2.987.

Niesters HG, Zoulim F, Pichoud C, Buti M, Shapiro F, Heuvaert N D’, Celis L, Doutreloigne J, Sablón E. Validation of the INNOLiPA HBV DR v2 assay in HBV-infected patients under nucleoside analog treatment. Antimicrob Agents Chemother 2010 Mar; 54 (3): 1283-9.  IF: 4.802. Oria M, Chatauret N, Chavarria L, RomeroGiménez J, Palenzuela L, Pardo-Yules B, Arranz JA, Bodega G, Raguer N, Córdoba J. Motor-evoked potentials in awake rats are a valid method of assessing hepatic encephalopathy and of studying its pathogenesis. Hepatology 2010 Dec; 52 (6): 2077-85. doi: 10.1002/hep.23938.  IF: 10.840. Pardina E, Ferrer R, Baena-Fustegueras JA, Lecube A, Fort JM, Vargas V, Catalán R, Peinado-Onsurbe J. The Relationships Between IGF-1 and CRP, NO, Leptin, and Adiponectin During Weight Loss in the Morbidly Obese. Obes Surg 2010 May; 20 (5): 623-32.  IF: 2.934. Reesink HW, Panzer S, Wendel S, Levi JE, Ullum H, Ekblom-Kullberg S, Seifried E, Schmidt M, Shinar E, Prati D, Berzuini A, Ghosh S, Flesland O, Jeansson S, Zhiburt E, Pirón M, Sauleda S, Ekermo B, Eglin R, Kitchen A, Dodd RY, Leiby DA, Katz LM, Kleinman S. The use of malaria antibody tests in the prevention of transfusion-transmitted malaria. Vox Sang 2010 Apr; 98 (3 Pt 2): 468-78.  IF: 2.585. Reijnders JG, Deterding K, Petersen J, Zoulim F, Santantonio T, Buti M, Bommel F van, Hansen BE, Wedemeyer H, Janssen HL. Antiviral effect of entecavir in chronic hepatitis B: Influence of prior exposure to nucleos(t)ide analogues. J Hepatol 2010 Apr; 52 (4): 493-500.  IF: 7.818. Rodríguez-Manzano J, Miagostovich M, Hundesa A, Clemente-Casares P, Carratala A, Buti M, Jardí R, Gironés R, Hundesa A, Clemente-Casares P. Analysis of the evolution in the circulation of HAV and HEV in Eastern Spain by testing urban sewage samples. J Water Health 2010 Jun; 8 (2): 346-54.  IF: 1.469. Romero-Gómez M, Jover M, Campo JA del, Royo JL, Hoyas E, Galán JJ, Montoliu C, Baccaro E, Guevara M, Córdoba J, Soriano G, Navarro JM, Martínez-Sierra C, Grande L, Galindo A, Mira E, Mañes S, Ruiz A. Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. Ann Intern Med 2010 Sep 7; 153 (5): 281-8.  IF: 16.225.

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Sapisochin G, Bilbao I, Balsells J, Dopazo C, Caralt M, Lázaro JL, Castells L, Allende H, Charco R. Optimization of Liver Transplantation as a Treatment of Intrahepatic Hepatocellular Carcinoma Recurrence After Partial Liver Resection: Experience of a Single European Series. World J Surg 2010 Sep; 34 (9): 2146-54.  IF: 2.696. Schaper M, Rodríguez-Frias F, Jardí R, Tabernero D, Homs M, Ruiz G, Quer J, Esteban R, Buti M. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol 2010 May; 52 (5): 658-64.  IF: 7.818. Tabernero D, Sánchez MJ, Homs M, Rodríguez-Frias F, Jardí R, Schaper M, Esteban R, Buti M. Main mutations in the hepatitis B virus basic core promoter (A1762T/G1764A) before HBeAg loss are markers that identify patients who will require long-term treatment. Aliment Pharmacol Ther 2010 Jul; 32 (1): 97-104.  IF: 4.357. Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, Shianna KV, Urban T, Afdhal NH, Jacobson IM, Esteban R, Poordad F, Lawitz EJ, McCone J, Shiffman ML, et al. IL28B Polymorphism Improves Viral Kinetics and Is the Strongest Pre-treatment Predictor of SVR in HCV-1 Patients. Gastroenterology 2010 Jul; 139 (1): 120-9.e18.  IF: 12.899. Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Solé M, Thung S, Moyano S, Toffanin S, Mínguez B, Cabellos L, Peix J, Schwartz M, Mazzaferro V, Bruix J, Llovet JM. IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage. J Hepatol 2010 Apr; 52 (4): 550-9.  IF: 7.818. Villanueva A, Mínguez B, Forner A, Reig M, Llovet JM. Hepatocellular carcinoma: novel molecular approaches for diagnosis, prognosis, and therapy. Annu Rev Med 2010; 61: 317-28.  IF: 9.940.

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AREA 5 DIGESTIVE PHYSIOPATHOLOGY AND HEPATOLOGY

5.3 Physiology and Pathophysiology of the Digestive Tract Group Leader Fernando Azpiroz Vidaur Tel. 93 274 62 59 [email protected] Researchers Ana María Accarino Garaventa Carmen Alonso Cotoner María Antolín Mate Fernando Azpiroz Vidaur Natalia Borruel Sainz Francesc Casellas Jordà Francisco Guarner Aguilar Luisa Guarner Aguilar Mar Guilarte Clavero Carlos Hernández Ballesteros Joan Ramon Malagelada Benaprés Carolina Malagelada Prats Chaysavanh Manichanh Francesc Xavier Molero Richard Francisco Javier Santos Vicente María Vicario Pérez Jaume Vilaseca Momplet Researchers in Training Monder Abu-Suboh Abadia Sílvia Cardona Morito Ana María González Castro Meritxell Guila Matarín Carlos Hernández Ballesteros Beatriz Lobo Álvarez Cristina Martínez Martínez Virginia Robles Alonso Antonio Torrejón Herrera Encarna Varela Castro Marc Pigrau Pastor Nursing, Technical and Administrative Staff Raimunda Carmen Alastrue Borbón Montserrat Casellas Bartomeus Milagros Gallart Mora Sandra Estrella Cano Josefa Mª Heredia Montiel Sara Mendez Soriano Gloria Santaliestra Vivaracho

OBJECTIVES To investigate the integrated function of the intestinal tract including secretion, motility and absorption in health and disease, prioritising the transmission of knowledge to clinical practice. The research on digestive motility interacts with the disorders of visceral sensitivity, brain-gut axis and intestinal allergy. The research line on intestinal inflammation also interaction with some aspects of enteric flora in inflammatory bowel disease.

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RESEARCH LINES Hypersensitivity and dysmotility of the gastrointestinal tract Fernando Azpiroz Vidaur Research has been focused on the origin and mechanisms of the disorders of digestive function. Major advancements have been achieved in relation to the diagnostic methods to detect neuromyopathic disorders of the digestive tract. Noninvasive evaluation of intestinal motility has been approached using an original program of endoluminal image analysis applying computer learning techniques and automatic learning methods to videos obtained by means of capsule endoscopy. Furthermore, the possible mechanisms involved in

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symptoms without apparent cause have been investigated; specifically, the mechanism of abdominal distension has been identified by means of morpho-volumetric analysis of the abdominal cavity and electromyography of the abdominal walls.

Inflammatory pathways in the gut and therapeutic targets Francisco Guarner Aguilar This research programme includes five projects (supported by Spanish and European public research agencies) aimed at the investigation of the cross-talk and effects of live bacteria of the gut microbiota on the intestinal mucosa. In addition, the program includes four clinical/physiological studies that address the potential application of new knowledge gained in basic research on inflammatory bowel diseases.

Pathophysiology and treatment of pancreatic disorders Francesc Xavier Molero Richard The focus of our research is to study the series of pathophysiologic events leading to acute and chronic pancreatitis and, eventually, pancreatic cancer. We aim to take advantage of knowledge gained at our basic research program to design therapeutic strategies intended to prevent or ameliorate human pancreatic disorders. In rodent models of acute and chronic pancreatitis we examine pancreatic regeneration, fibrogenesis, acino-ductal trandifferentiation, stellate cell activation, epithelial-to-mesenchymal transition and cancer development. In human pancreatitis we investi-

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Figure 66 Esophageal high resolution manometry. A) Normal manometry: note the synchronous relaxation of the upper oesophageal sphincter (UOS) and lower oesophageal sphincter (LOS) and the increasing pressure and duration of the peristaltic wave. B) Type III or Vigorous Achalasia: note the characteristic impaired deglutive lower oesophageal sphincter relaxation and spastic contraction of the oesophageal body

gate environmental and genetic determinants (with special focus on CFTR dysfunction) and new treatment modalities for acute and chronic pancreatitis.

Neuro-Immuno-Gastroenterology Francisco Javier Santos Vicente Irritable bowel syndrome (IBS), the group of microscopical enteritides, food allergy, gastrointestinal eosinophilopaties, and other functional disorders of the gastrointestinal tract represent more than 50% of digestive consultations. Their clinical course is chronic and recurrent. However, sensitive and specific diagnostic biological markers are lacking and clinical management is sub-

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optimal. Interestingly, a common finding in the intestine of these patients is the presence of barrier dysfunction, mucosal inflammation and immune activation. Moreover, this finding may be related to the onset and severity of some major clinical symptoms, particularly in IBS. Therefore, our group pursues the detailed comprehension (genetic/gender, immunological, metabolic, cellular and molecular basis) of the mechanisms connecting environmental determinants (stress and infections) to the development of intestinal mucosal microscopical inflammation, with special focus in IBS. Our approach includes experimental studies in animal models and humans as well, yet remains inherently translational in the search for better targets helpful in the diagnosis, prevention and treatment of IBS and related disorders. In addition, preclinical and clinical assays are also being carried out.

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Figure 67 The intestinal microvilli from the enterocytes are microscopic cellular membrane protrusions that increase the area of nutrient absorption in the gastrointestinal tract, and are involved in biological functions such as secretion, cellular adhesion, mechanotransduction and defense against nocive substances present in the intestinal lumen (Bar=0.2μm)

PI: Francisco Guarner Aguilar Metagenomics of the Human Intestinal Tract (MetaHIT). Grant Agreement No 201052 Funding Agency: European Commission Reference: METAHIT-201052 Funding: 652,590 € Duration: 2008 to 2011

CURRENT RESEARCH PROJECTS PI: Francisco Guarner Aguilar Señales antiinflamatorias del ecosistema microbiano intestinal Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2007-64411 Funding: 169,400 € Duration: 2007 to 2010

PI: Fernando Azpiroz Vidaur Dolor abdominal idiopàtic crònic: mecanismes fisiopatològics Funding Agency: Fundació La Marató de TV3 Reference: MARATV3_072010 Funding: 177,425 € Duration: 2008 to 2011

PI: Francisco Javier Santos Vicente Efecto de la estabilización prolongada del mastocito intestinal con cromoglicato disódico en la evolución clínica y la microinflamación de la mucosa intestinal en los pacientes con síndrome de intestino irritable tipo diarrea Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90148 Funding: 168,190 € Duration: 2007 to 2011

PI: Francesc Xavier Molero Richard Evaluation of the antifibrogenicanti-inflammatory properties of the cox-2 inhibitor celecoxib in chronic pancreatitis Funding Agency: Fundación Pfizer Reference: PFIZER_01_2007 Funding: 63,952 € Duration: 2007 to 2010

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PI: Francesc Xavier Molero Richard Transición epitelio-mesénquima y reclutamiento de fibrocitos en la reparación pancreática y en el desarrollo de pancreatitis crónica Funding Agency: Fondo de Investigación Sanitaria Reference: PI080342 Funding: 105,149 € Duration: 2009 to 2011

PI: Francisco Javier Santos Vicente Mecanismos moleculares subyacentes a la respuesta diferencial (género dependiente) de la barrera epitelial al estrés en el yeyuno humano. Papel del mastocito e implicaciones en el intestino irritable Funding Agency: Fondo de Investigación Sanitaria Reference: PI080940 Funding: 246,840 € Duration: 2009 to 2011

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PI: Fernando Azpiroz Vidaur Neurofisiología y neuropatología digestiva Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2009-07416 Funding: 217,800 € Duration: 2010 to 2012

PI: María Antolín Mate La célula dendrítica como eje central en la respuesta a bacterias en la mucosa de pacientes con enfermedad inflamatoria intestinal Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00471 Funding: 85,910 € Duration: 2010 to 2012

PI: Francisco Javier Santos Vicente Role of mucosal eosinophols in the physiopathology of irritable bowel syndrome Funding Agency: Rome Foundation Reference: ROMEF-2010 Funding: 38,959.02 € Duration: 2010 to 2011

PI: Fernando Azpiroz Vidaur Desarrollo de nuevas metodologías y tecnologías emergentes de evidenciación de la eficacia de alimentos con propiedades de salud, para la reducción de riesgos de patologías crónicas en la edad media de vida (HENUFOOD) Funding Agency: Centro para el Desarrollo Técnico Industrial (CDTI) Reference: CENIT-2010-03 Funding: 450,000 € Duration: 2010 to 2013

PI: Francisco Guarner Aguilar Desarrollo de nuevas metodologías y tecnologías emergentes de evidenciación de la eficacia de alimentos con propiedades de salud, para la reducción de riesgos de patologías crónicas en la edad media de vida (HENUFOOD) Funding Agency: Centro para el Desarrollo Técnico Industrial (CDTI) Reference: CENIT-2010-04 Funding: 163,000 € Duration: 2010 to 2013

PI: Francisco Javier Santos Vicente Sistema de comunicació, col·laboració i compartició del coneixement a l’àmbit de la salut (Co4Salut) Funding Agency: Generalitat de Catalunya - CIDEM Reference: RD10-1-0041 Funding: 64,643.14 € Duration: 2010 to 2012

Figure 68 Network plots of shared microbial diversity. The relationships between phylotypes and samples are represented as a bipartite graph in which nodes are either phylotypes (small) or samples (large), and connecting lines between small and large nodes mean that the phylotype was found in the given sample. The gut microbiome includes more than one thousand different bacterial species, and only a subpopulation of them is found to be shared between individuals, as illustrated by the network plot created using Cytoscape (http://www.cytoscape.org/). Alteration of the gut microbiome has been associated with several intestinal disorders. As a potencial therapy, transplantation of the gut microbiome is revealed as a promising alternative to the use of prebiotics, probiotics, or antibiotics for reshaping this microbial ecosystem. [For details, see Manichanh et al., 2011. PMID:20736229, Genome Research.])

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Figure 69 Representative microscopy images of two Dendritic Cells in the Lamina Propria co-expressing DC-SIGN and CX3CR1 from a Chron’s Disease patient. “Dapi”: cell nuclei staining (in blue ); “DC-SIGN”: DC-SIGN+DCs (in red) and “CX3CR1”: CX3CR1+DCs (in green). Magnification x400

PI: Francesc Xavier Molero Richard Grup de Recerca en Patologia Pancreàtica Exocrina Funding Agency: AGAUR Reference: 2009 SGR 256 Funding: 0.00 € Duration: 2010 to 2013

PI: Fernando Azpiroz Vidaur Unitat de Recerca del Sistema Digestiu Funding Agency: AGAUR Reference: 2009 SGR 219 Funding: 50,960 € Duration: 2010 to 2013

PUBLICATIONS (Impact Factor: 107.242) Amselem C, Puigdollers A, Azpiroz F, Sala C, Videla S, Fernández-Fraga X, Whorwell P, Malagelada JR. Constipation: a potential cause of pelvic floor damage? Neurogastroenterol Motil 2010 Feb; 22 (2): 150-3, e48.  IF: 3.568. Azpiroz F, Baudet JS, Benages A, Canga F, Carrasco J, Ciriza C, Cucala M, Domínguez E, Faro V, Garrigues V, Giganto F, Herrerias JM, Iglesias J, Lacima G, López P, Serra J, et al. Normal values in ambulatory oesophageal pH monitoring at two levels in Spain. Rev Esp Enferm Dig 2010 Jul; 102 (7): 40612.  IF: 0.994. Casellas F. Crohn’s disease, feeling well or healthy? Rev Esp Enferm Dig 2010 Nov; 102 (11): 621-623.  IF: 0.994.

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Casellas F, Torrejón A, Vilaseca J, Aparici A, Casaus M, Rodríguez P, Guarner F. Influence of colectomy on hydrogen excretion in breath. Int J Colorectal Dis 2010 Apr; 25 (4): 485-9.  IF: 2.102. Garrido A, Iborra MI, Saperas E, de Sousa M, et al. [Prevalence of rebleeding from peptic ulcer in patients treated with proton pump inhibitors]. Med Clin (Barc) 2010 May 8; 134 (13): 577-82.  IF: 1.231. Garriga T, Guilarte M, Luengo O, Guillén M, Labrador-Horrillo M, Fadeeva T, Sala A, Cardona V. Frozen fruit skin prick test for the diagnosis of fruit allergy. Asian Pac J Allergy Immunol 2010 Dec; 28 (4): 275-8.  IF: 0.562. Guarner F, Requena Rolania T, Marcos Sánchez A. Consensus statements from the Workshop “Probiotics and Health: Scientific Evidence”. Nutr Hosp 2010 Oct; 25 (5): 700-704.  IF: 1.065.

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Hernández-Sampelayo , Seoane M, Oltra L, Marín L, Torrejón A, Vera MI, García V, Lázaro P, Parody E, Blasco AJ, Casellas F. Contribution of nurses to the quality of care in management of inflammatory bowel disease: A synthesis of the evidence. J Crohns Colitis 2010 Dec; 4 (6): 611-22.  IF: 1.729. Hernando-Harder AC, Serra J, Azpiroz F, Milà M, Aguadé S, Malagelada C, Tremolaterra F, Villoria A, Malagelada JR. Colonic Responses to Gas Loads in Subgroups of Patients With Abdominal Bloating. Am J Gastroenterol 2010 Apr; 105 (4): 876-82.  IF: 6.012. Huaman J, Casellas F, Borruel N, Pelaez A, Torrejón A, Castells I, Masachs M, Varela E, Guarner F. Cutoff values of the Inflammatory Bowel Disease Questionnaire to predict a normal health related quality of life. J Crohns Colitis 2010 Dec; 4 (6): 637-41.  IF: 1.729. Manichanh C, Reeder J, Gibert P, Varela E, Llopis M, Antolín M, Guigó R, Knight R, Guarner F. Reshaping the gut microbiome with bacterial transplantation and antibiotic intake. Genome Res 2010 Oct; 20 (10): 1411-9.  IF: 11.342. Masachs M, Casellas F, Borruel N, Torrejón A, Castells I, Malagelada JR. Validation of the Spanish version of a questionnaire to measure quality of care through the eyes of patients with inflammatory bowel disease (QUOTE-IBD). Inflamm Bowel Dis 2010 Jun; 16 (6): 982-92.  IF: 4.643. Navarro S, Vaquero E, Maurel J, Bombi JA, Juan C de, Feliu J, Fernández Cruz L, Ginés A, Girela E, Rodríguez R, Sabater L, Álvarez E, Marañon G, Arguello L, Barranco L, Cárdenas A, Conill C, Cuatrecasas M, Macarulla T, Martin Richard M, Méndez R, Molero X, et al. [Recommendations for diagnosis, staging and treatment of pancreatic cancer (Part I). Grupo Español de Consenso en Cancer de Pancreas] Med Clin (Barc) 2010 May 15; 134 (14): 643-55.  IF: 1.231. Navarro S, Vaquero E, Maurel J, Bombí JA, Juan C de, Feliu J, Fernández Cruz L, Ginés A, Girela E, Rodríguez R, Sabater L, Macarulla T, et al. [Recommendations for diagnosis, staging and treatment of pancreatic cancer (Part II)]. Med Clin (Barc) 2010 May 22; 134 (15): 692-702.  IF: 1.231.

Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T, Mende DR, Li J, Xu J, Li S, Li D, Cao J, Wang B, Liang H, Guarner F, Antolín M, Borruel N, Casellas F, Torrejón, Varela E, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 2010 Mar 4; 464 (7285): 59-65.  IF: 34.480. Roberfroid M, Gibson GR, Hoyles L, McCartney AL, Rastall R, Rowland I, Wolvers D, Watzl B, Szajewska H, Stahl B, Guarner F, Respondek F, Whelan K, Coxam V, Davicco MJ, Leotoing L, Wittrant Y, Delzenne NM, Cani PD, Neyrinck AM, Meheust A. Prebiotic effects: metabolic and health benefits. Br J Nutr 2010 Aug; 104 Suppl 2: S1-63.  IF: 3.446. Serra J, Villoria A, Azpiroz F, Lobo B, Santos J, Accarino A, Malagelada JR. Impaired intestinal gas propulsion in manometrically proven dysmotility and in irritable bowel syndrome. Neurogastroenterol Motil 2010 Apr; 22 (4): 401-6, e91-2.  IF: 3.568.

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Vicario M, Blanchard C, Stringer KF, Collins MH, Mingler MK, Ahrens A, Putnam PE, Abonia JP, Santos J, Rothenberg ME. Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis. Gut 2010 Jan; 59 (1): 12-20.  IF: 9.357. Vicario M, Guilarte M, Alonso C, Yang P, Martínez C, Ramos L, Lobo B, González A, Guila M, Pigrau M, Saperas E, Azpiroz F, Santos J. Chronological assessment of mast cell-mediated gut dysfunction and mucosal inflammation in a rat model of chronic psychosocial stress. Brain Behav Immun 2010 Oct; 24 (7): 1166-75.  IF: 5.061. Vicario M, Martínez C, Santos J. Role of microRNA in IBS with increased gut permeability. Gut 2010 Jun; 59 (6): 710-2.  IF: 9.357. Vilarino F, Spyridonos P, Deiorio F, Vitria J, Azpiroz F, Radeva P. Intestinal motility assessment with video capsule endoscopy: automatic annotation of phasic intestinal contractions. IEEE Trans Med Imaging 2010 Feb; 29 (2): 246-59.  IF: 3.540.

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AREA 6 INFECTIOUS DISEASES

6.1 Clinical Research and Innovation in Pneumonia & Sepsis Group Leader Jordi Rello Condomines Tel. 93 274 62 09 [email protected] Researchers Rosa Alcaraz Peñarrocha Roser Anglès Coll Elena Arnau Faidella Laura Campos García Mercè Farré Viladrich Elisabet Gallart Vive Rosa Maria Gracia Gozalo César Laborda Soriano Lluís Llopart Corsà Sandra Marquina Escoz Joan Ramon Masclans Enviz Núria Masnou Burralló Mercedes Palomar Martínez Marcos Pérez Carrasco Águeda Pérez García Isabel Porta Pampalona Jordi Rello Condomines Maria Alba Riera Badia Judith Sacanell Lacasa Lluís Tenorio López Researchers in Training Bárbara Borgatta Berta Caralt Ramisa Nuria Duran Mateo Marina García García de Acilu Alejandra García Roche Sandra Leal Murillo Carlos Andres López Rojas Karla Malpica Basurto Ana Parra Castillo Purificación Pérez Terán Jordi Riera del Brío Marta Ulldemolins Gómez Nursing, Technical and Administrative Staff Paquita Cornet Ciurana Rosa María Luque de la Roza

OBJECTIVES The aim of this group is to develop translational and clinical research in critical care. This group focuses on the most prevalent aspects of infections in the ICU (Ventilator-associated pneumonia, Severe Community-acquired pneumonia -and HCAP-, and opportunistic respiratory infections in severe immunocompromised patients), which represent the Research Lines of CIBERES, where Jordi Rello is head of cooperative research on Hospital-acquired pneumonia. These activities focus on severe bacterial, fungal and viral (including influenza) infections. Diagnostic, Preventive and Management Issues are strategic. Infection control and surveillance in ICU are the main safety concerns in support of a WHO project on safety endorsed by the Spanish Ministry of Health. Several projects involving development, implementation and assessment of European care packages are ongoing. Team work is essen-

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tial and we have the tranversal support of nursing staff and allied professional in multiple lines of research, as well as in specific lines of critical care nursing research. Relevant operational objectives involve pk-pd modeling to achieve optimal dosage of chemotherapy agents to improve antibiotic policy reducing the emergence of resistance and optimizing outcomes. These objectives are achieved by the multidisciplinary team, including different medical specialities, Nurses, Engineers, Biotechnologists Pharmacists and other Health Care Workers. Special objectives in Innovation areas in collaboration with pharmaceutical companies (therapies and vaccinations), other biotechnology companies (diagnosis, prevention and management), participating in technology transference projects with other research groups from CIBERES, and involvement in projects and networks endorsed by European Scientific Societies.

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Figure 70 Computed tomography scan of the lung in a patient with Influenza A (H1N1)

RESEARCH LINES Ventilator-associated pneumonia (VAP) Jordi Rello Condomines Translational research on respiratory infections in intubated patients. Prevention, Risk Factors, Management including dose optimization are priorities. Development and visualization of the VH-ICU paradigm, as a tool for management.

Severe Community-acquired Pneumonia (sCAP) & HCAP Jordi Rello Condomines Severe CAP is considered a Systemic Disease. Analysis of outcomes based on the contribution of genetic bacterial load, immunologic response and defenses. Research issues concern severe pneumococcal pneumonia, influenza viral pneumonia and other pathogens. Also the implementation of research projects on health-care associated pneumonia.

Respiratory Infections in Immunocompromised ICU patients Jordi Rello Condomines Research priorities include viral respiratory infections, yeasts and invasive fungal infections in immunocompromised ICU patients. Leading an international project on invasive pulmonary aspergillosis and a large multicentre study on infections in neutropenic patients.

Epidemiology and Infection Control in ICU Safety Mercedes Palomar Martínez Infection control and surveillance, as part of Safety projects in the ICU. In collaboration with ECDC and WHO endorsed projects. Includes collaboration with the metanalysis unit of the ESICM.

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Clinical Research in Critical Care Nursing Maria Alba Riera Badia and Elisabet Gallart Vive Multidisciplinary research projects, where nurse participation is crucial. Focusing on prevention of infections in patients with invasive devices, implementation of care packages, safety issues and outcome research.

Sepsis and Biomarkers (Emergent line) Jordi Rello Condomines

Lung Transplant in ICU Judith Sacanell Lacasa Research in one of the core clinical Hospital projects, studying epidemiological variables as well as early morbidity and mortality of lung transplant patients and developing pharmacokinetic studies of immunosuppressive medications.

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PUBLICATIONS (Impact Factor: 117.627)

Acute Respiratory Failure and Mechanical Ventilation Joan Ramon Masclans Enviz Translational research on ALI/ARDS patients in the ICU (pathophysiology and treatment) and the long term alterations observed in survivors. The group also includes an Experimental Research Line, focused on the effects of pharmacological treatments or treatment with modified mesenchymal stem cells in LPS-induced lung injury in mice.

Antón A, López-Iglesias AA, Tórtola T, RuizCamps I, Abrisqueta P, Llopart L, Marcos MA, Martínez MJ, Tudó G, Bosch F, Pahissa A, Anta MT de, Pumarola T. Selection and viral load kinetics of an oseltamivir-resistant pandemic influenza A (H1N1) virus in an immunocompromised patient during treatment with neuraminidase inhibitors. Diagn Microbiol Infect Dis 2010 Nov; 68 (3): 214-9.  IF: 2.451.

CURRENT RESEARCH PROJECTS

Arikan F, Vilalta J, Romero FJ, Porta I, Martínez-Ricarte FR, Sahuquillo J. Primary decompressive craniectomy in patients with aneurysmatic subarachnoid hemorrhage. Results of a pilot study in 11 cases. Neurocirugia (Astur) 2010 Dec; 21 (6): 452-460.  IF: 0.247.

PI: Jordi Rello Condomines Grup de recerca en sèpsia i infecció respiratòria greu Funding Agency: AGAUR Reference: 2009 SGR 1226 Funding: 0,01 € Duration: 2010 to 2013

Ariano RE, Sitar DS, Zelenitsky SA, Zarychanski R, Pisipati A, Ahern S, Kanji S, Rello J, Kumar A. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ 2010 Mar 9; 182 (4): 357-63.  IF: 7.271.

Arnold FW, Brock GN, Peyrani P, Rodríguez EL, Díaz AA, Rossi P, Ramírez JA, Allen M, Nakamatsu R, Bordon J, File T Jr, Gross P, Marrie T, Weiss K, Blasi F, Cosentini R, Legnani D, Torres A, Bodi M, Porras J, Rello J, Menéndez R, Lode H, Roig J, Benchetrit G, Corral J, González J, Vedia L de, Lopardo G, Luna C, Martínez J, Marzoratti L, Rodríguez M, Videla A, Arteta F, Levy G, Fernández P, Parada M, Luna JM, Mateo M, Mendoza M, Feldman C. Predictive accuracy of the pneumonia severity index vs CRB-65 for time to clinical stability: results from the Community-Acquired Pneumonia Organization (CAPO) International Cohort Study. Respir Med 2010 Nov; 104 (11): 1736-43.  IF: 2.331.

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Bermejo-Martín JF, Martín-Loeches I, Rello J, Anton A, Almansa R, Xu L, López-Campos G, Pumarola T, Ran L, Ramírez P, Banner D, Cheuk Ng D, Socias L, Loza A, Andaluz D, Maravi E, Gómez-Sánchez MJ, Gordon M, Gallegos MC, Fernández V, Aldunate S, León C, Merino P, Blanco J, Martín-Sánchez F, Rico L, Varillas D, Iglesias V, Marcos MA, Gandía F, Bobillo F, Nogueira B, Rojo S, Resino S, Castro C, Ortiz de Lejarazu R, Kelvin D. Host adaptive immunity deficiency in severe pandemic influenza. Crit Care 2010 Sep 14; 14 (5): R167.  IF: 4.931. Carvajal C, Pobo A, Díaz E, Lisboa T, Llauradó M, Rello J. Oral hygiene with chlorhexidine on the prevention of ventilator-associated pneumonia in intubated patients: A systematic review of randomized clinical trials. Med Clin (Barc) 2010 Oct 9; 135 (11): 491-7.  IF: 1.231. Díaz LA, Llauradó M, Rello J, Restrepo MI. Non-pharmacological prevention of ventilator-associated pneumonia. Arch Bronconeumol 2010 Apr; 46 (4):188-95.  IF: 2.166. Falagas ME, Koletsi PK, Vouloumanou EK, Rafailidis PI, Kapaskelis AM, Rello J. Effectiveness and safety of neuraminidase inhibitors in reducing influenza complications: a meta-analysis of randomized controlled trials. J Antimicrob Chemother 2010 Jul; 65 (7): 1330-46.  IF: 4.352. Falagas ME, Vouloumanou EK, Baskouta E, Rafailidis PI, Polyzos K, Rello J. Treatment options for 2009 H1N1 influenza: evaluation of the published evidence. Int J Antimicrob Agents 2010 May; 35 (5): 421-30.  IF: 3.032.

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Hansen S, Schwab F, Asensio A, Carsauw H, Heczko P, Klavs I, Lyytikainen O, Palomar M, Riesenfeld-Orn I, Savey A, Szilagyi E, Valinteliene R, Fabry J, Gastmeier P. Methicillinresistant Staphylococcus aureus (MRSA) in Europe: which infection control measures are taken? Infection 2010 Jun; 38 (3): 15964.  IF: 2.051. Labeau SO, Witdouck SS, Vandijck DM, Claes B, Rello J, Vandewoude KH, Lizy CM, Vogelaers DP, Blot SI. Nurses’ knowledge of evidence-based guidelines for the prevention of surgical site infection. Worldviews Evid Based Nurs 2010 Mar; 7 (1): 16-24.  IF: 1.944. Lisboa T, Waterer G, Rello J. We should be measuring genomic bacterial load and virulence factors. Crit Care Med 2010 Oct; 38 (10 Suppl): S656-62.  IF: 6.373. Lorente L, Blot S, Rello J. New issues and controversies in the prevention of ventilator-associated pneumonia. Am J Respir Crit Care Med 2010 Oct 1; 182 (7): 870-6.  IF: 10.689. Lujan M, Gallego M, Belmonte Y, Fontanals D, Vallés J, Lisboa T, Rello J. Influence of pneumococcal serotype group on outcome in adults with bacteraemic pneumonia. Eur Respir J 2010 Nov; 36 (5): 1073-9.  IF: 5.527. Magret M, Amaya-Villar R, Garnacho J, Lisboa T, Díaz E, Dewaele J, Deja M, Manno E, Rello J. Ventilator-Associated Pneumonia in Trauma Patients Is Associated With Lower Mortality: Results From EU-VAP Study. J Trauma 2010 Oct; 69 (4): 849-854.  IF: 2.626. Martín-Loeches I, Lisboa T, Rodríguez A, Putensen C, Annane D, Garnacho-Montero J, Restrepo MI, Rello J. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive Care Med 2010 Apr; 36 (4): 612-20.  IF: 5.168. Monforte V, Ussetti P, Gavaldà J, Bravo C, Laporta R, Len O, García-Gallo CL, Tenorio L, Soler J, Román A. Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation. J Heart Lung Transplant 2010 May; 29 (5): 523-30.  IF: 3.541. Pérez M, Sánchez A, Rello J. Broadening horizons: research priorities in pneumonia. Crit Care Med 2010 Jul; 38 (7): 1602-3.  IF: 6.373.

Rello J, Afessa B, Anzueto A, Arroliga AC, Olson ME, Restrepo MI, Talsma SS, Bracken RL, Kollef MH. Activity of a silver-coated endotracheal tube in preclinical models of ventilator-associated pneumonia and a study after extubation. Crit Care Med 2010 Apr; 38 (4): 1135-40.  IF: 6.373. Rello J, Lode H, Cornaglia G, Masterton R, Masterton R, Rello J, Struelens M, Chastre J, Ortqvist A, Lode H, Giamarellou H, Eraksoy H, Davey P, Dickson K, Campbell D. A European care bundle for prevention of ventilator-associated pneumonia. Intensive Care Med 2010 May; 36 (5): 773-80.  IF: 5.168. Rello J, Lujan M, Gallego M, Vallés J, Belmonte Y, Fontanals D, Díaz E, Lisboa T. Why mortality is increased in health-care-associated pneumonia: lessons from pneumococcal bacteremic pneumonia. Chest 2010 May; 137 (5): 1138-44.  IF: 6.360. Restrepo MI, Mortensen EM, Rello J, Brody J, Anzueto A. Late admission to the ICU in patients with community-acquired pneumonia is associated with higher mortality. Chest 2010 Mar; 137 (3): 552-7.  IF: 6.360. Roca O, Gómez-Ollés S, Cruz MJ, Muñoz X, Griffiths MJ, Masclans JR. Mechanical ventilation induces changes in exhaled breath condensate of patients without lung injury. Respir Med 2010 Jun; 104 (6): 822-8.  IF: 2.331. Roca O, Riera J, Torres F, Masclans JR. Highflow oxygen therapy in acute respiratory failure. Respir Care 2010 Apr; 55 (4): 40813.  IF: 1.524. Rodríguez A, Lisboa T, Rello J. Pandemic influenza A (H1N1)v in the intensive care unit: what have we learned? Arch Bronconeumol 2010; 46S2: 24-31.  IF: 2.166. Torres A, Rello J. Update in community-acquired and nosocomial pneumonia 2009. Am J Respir Crit Care Med 2010 Apr 15; 181 (8): 782-7.  IF: 10.689. Ulldemolins M, Roberts JA, Wallis SC, Rello J, Lipman J. Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics. J Antimicrob Chemother 2010 Aug; 65 (8): 1771-8.  IF: 4.352.

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AREA 6 INFECTIOUS DISEASES

6.2 Infectious Diseases Department

Group Leader Albert Pahissa Berga Tel. 93 274 60 57 / 90 [email protected] Researchers Benito Almirante Gragera Manuel Crespo Casal Adrian Curran Fábregas Vicente Falcó Ferrer Nuria Fernández Hidalgo Joan Gavaldà Santapau Óscar Len Abad Israel Molina Romero Inmaculada Ocaña Rivera Albert Pahissa Berga Carles Pigrau Serrallach Esteve Ribera Pascuet Mª Dolores Rodríguez Pardo Isabel Ruíz Camps Sara Villar del Saz Cano Researchers in Training Joaquín Burgos Cibrian Evelyn Lorena Cabral Galeano Mireia Puig Asensio Fernando Salvador Vélez Roger Sordé Masip Eva van de Eynde Otero Nursing, Technical and Administrative Staff Carmen Ferrer Barberà Javier Gomis Rodríguez Claudia Orbegozo Rubio Mercè Pérez Bernal Inmaculada Verdeguer Almaraz

OBJECTIVES Since its origin the Infectious Diseases Service, founded in 1996, has had a vocation for teaching and research related to the health care field. The majority of the research developed by the service is clinical, carried out with the intention of deepening our knowledge of and attempting to provide answers to the problems that we see every day as doctors working in the complex environment of a hospital for patients with infectious diseases. Each line of research has a lead physician who is a permanent member of the service staff and works directly on individual problems.

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The service develops most of its research in the setting of two research networks; “Instituto de Salud Carlos III”, REIPI (Spanish Network for Research in Infectious Pathology) and RIS (Spanish Network for Research on AIDS). Since 1999 our group has been considered to be a Consolidated Research Group in Catalonia.

RESEARCH LINES Coinfection HIV / HCV Manuel Crespo Casal Use of the dynamics of viral response as a tool to individually tailor the duration of HCV treatment in HIV-coinfected patients. Study of the interaction between ribavirin and nucleoside-analogues inhibitors of HIV reverse transcriptase in a subgenomic HCV replicon.

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Opportunistic infections in HIV+ patients Esteve Ribera Pascuet and Vicente Falcó Ferrer The aim of this research is to analyze the incidence and the changes in clinical presentation of opportunistic infections in the era of highly active antiretroviral therapy. The improvements in the immunological status of HIV infected patients have led to new clinical problems, such as immune reconstitution inflammatory syndrome, that justify this clinical research.

Pharmacokinetics and toxicity of antiretroviral medication Esteve Ribera Pascuet Patients with HIV infection are treated with different drugs, including antiretrovirals and drugs for other purposes, which can have pharmacokinetic interactions with clinical significance or resulting in increased toxicity. This research is divided into pharmacokinetics and toxicity lines. The main objective of the pharmacokinetic research line is studying drug plasma levels of those drugs susceptible to presenting interactions, knowing whether drug levels are within the therapeutic range, evaluating potential interactions and evaluating the impact of some co-infections in plasma concentrations (chronic HCV infection, tuberculosis,…) and whether it is necessary to modify doses in these cases. The main objective of the toxicity line of research is to evaluate the side effects that can occur with antiretroviral therapy, especially mitochondrial toxicity, lypodistrophy and metabolic complications, looking for factors that contribute to their appearance and looking for potential solutions.

Orthopaedic bone and joint infection Carles Pigrau Serrallach and Mª Dolores Rodríguez Pardo The aim of the research is to evaluate epidemiological, etiological, diagnostic or therapeutical aspects of osteoarticular infections associated or not with the presence of metallic implants (prosthesis).

Community-acquired pneumonia. Streptococcus pneumoniae infections Vicente Falcó Ferrer In 2000 a 7 valent conjugate pneumococcal vaccine was approved for children. The implementation of this vaccine has led to clinical changes in the incidence and clinical presentation of pneumococcal invasive disease not only in children but also in adults. We are studying changes in incidence, clinical presentation of pneumococcal infection in adults, serotype distribution and antimicrobial resistance of Streptococcus pneumoniae. In the near future novel antipneumococcal vaccines will be implemented and a continuous monitoring of these infections is needed.

Figure 71 Tuberculoses disseminated with ganglionic affectation

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Infection in oncohematologic patients Isabel Ruiz Camps To establish the risk and type of infection in different populations receiving chemotherapy according to induced immunitary alteration. Prevention measures of infection, before and after chemotherapy. To create new protocols of diagnosis and prevention of infections with the use of new biological therapies in different oncological settings. To study the incidence, prevention and characteristics of the infections presented by the immigrant population undergoing chemotherapy.

Invasive fungal infections (IFI) Joan Gavaldà Santapau and Isabel Ruiz Camps Surveillance studies of invasive candidiasis in Spain. PK/PD antifungal studies in animal model. To study voriconazole and posaconazole plasma levels and their applications in the clinical management of IFI. To establish the risks, incidence, types and natural history of IFI in different settings to apply more rational and successful preventative strategies.

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Figure 72 These kinds of infections are studied in this group

Central catheter infection Benito Almirante Gragera and Nuria Fernández Hidalgo An in vivo experimental model of Staphylococci and Candida centralvenous catheter-related infections has been developed. We are evaluating several courses of antimicrobials alone or in combination with anticoagulants.

Infections in solid organ transplant Joan Gavaldà Santapau and Oscar Len Abad The research into infection in solid organ transplantation is based on knowledge of the epidemiology and risk factors for acquiring infections resulting from surgery, donation and immunosuppression as well as the development of intervention studies to prevent and treat these diseases.

Clostridium difficile infection Dolores Rodríguez Cumplido and Benito Almirante Gragera Due to the increasing number of cases of Clostidium difficile associated diarrhoea (CDAD) reported worldwide, our research line attempts to investigate the epidemiology of CDAD in the Barcelona area. Our aims are to determine the average annual incidence and the pooled-mean rate of CDAD for hospitalized patients, to describe the clinical characteristics and to obtain an overview of the antimicrobial susceptibility pattern, toxigenicity and genotypic features of CD isolates.

Imported infection Benito Almirante Gragera and Israel Molina Romero The main lines of research are focused on those cosmopolitan and tropical diseases often associated with poverty (Chagas disease, tuberculosis, leishmaniasis, malaria). We are developing new techniques for diagnosing and monitoring patients and new therapeutic schemes that offer a better option to those affected by these diseases. We are also devoting efforts to strengthen health systems in developing countries by supporting vertical programs, promoting research at local level, and creating new tools for non-attendance training of local health staff.

Infection caused by multiresistant microorganisms Benito Almirante Gragera We are studying the most relevant epidemiological, clinical, and therapeutic features of infections caused by multidrug-resistant pathogens, specially methicillin-resistant S. aureus and multidrug-resistant gramnegative bacilli.

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Infective endocarditis Benito Almirante Gragera and Nuria Fernández Hidalgo We are studying the likely epidemiological changes to infective endocarditis at the beginning of the XXI century, focusing on their consequences for clinical outcome. Research is focused on modifiable risk factors for mortality.

Infections secondary to cytomegalovirus and Epstein Barr virus Joan Gavaldà Santapau Infections by virus of the family Herpesviridae and specifically cytomegalovirus (CMV) and Eppstein Barr virus (EBV) are common in recipients of solid allografts. Besides the direct effects related to disease caused by the infection itself, indirect effects caused by its appearance are significant. CMV induces both immunosuppression of the host by producing superinfection due to opportunistic fungi and immunomodulation which can induce acute or chronic rejection of the graft. EBV is an oncogen virus which is related to Posttrasplant Lymphoproliferative Disease. In this research line includes several projects that are trying to find answers to the questions previously asked.

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Animal models of infection Joan Gavaldà Santapau The aim of the Research Line using Animal Models of Infection carried out in the Research Lab on Infectious Diseases is to try to find answers to questions asked in the Clinical trial which cannot be answered by various methodological problems, and that once answered in the animal model allows us to consider different controlled clinical studies. Then, we have worked with the endocarditis models due to viridans streptococci, S. aureus, E. faecalis, pneumonia due to S. pneumoniae, peritonitis, invasive aspergilosis and catheter-related septicemia due to Candida spp. and Staphylococcus spp. trying to solve some problems we found in the clinics.

CURRENT RESEARCH PROJECTS

PI: Manuel Crespo Casal Estudio de la efectividad a largo plazo del tratamiento de la hepatitis crónica C en pacientes coinfectados por VIH y VHC Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90735 Funding: 13,310 € Duration: 2007 to 2011

PI: Manuel Crespo Casal Cohorte de GESIDA de pacientes coinfectados por VIH y virus de hepatitis C que reciben tratamiento para la hepatitis C (2008-2010) Funding Agency: Fundación invest. y prevención SIDA - FIPSE Reference: FIPSE_36702_07 Funding: 3,300 € Duration: 2008 to 2011

PI: Esteve Ribera Pascuet Tratamiento antirretroviral una vez al día en pacientes con infección por el VIH-1 no tratados previamente y con cifras de linfocitos CD4+ inferiores a 100 cels/mm3. Estudio prospectivo aleatorizado, multicéntrico y abierto. Estudio ADVANZ-3 Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90942 Funding: 7,865 € Duration: 2007 to 2011

PI: Carles Pigrau Serrallach Estudio comparativo de la eficacia de pautas «cortas» y «largas» de la combinación RifampicinaLevofloxacino en la infección estafilocócica posquirúrgica precoz y hematógena de prótesis articular Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00223 Funding: 9,680 € Duration: 2009 to 2011

PI: Joan Gavaldà Santapau Estudio in vitro e in vivo de la eficacia de antimicrobianos para la erradicación de biopelículas de S. aureus (SA) y Candida spp. (CAN) formadas sobre materiales sintéticos, particularmente catéteres venosos centrales Funding Agency: Fondo de Investigación Sanitaria Reference: PI070394 Funding: 100,717.98 € Duration: 2008 to 2010

Figure 73 Pneumonia infection

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PI: Albert Pahissa Berga Incidencia de la infección por virus respiratorios en el trasplante de pulmón. Repercusión de la infección por virus respiratorios en la historia natural del rechazo crónico Funding Agency: Fondo de Investigación Sanitaria Reference: PI080554 Funding: 200,860 € Duration: 2009 to 2011

PI: Albert Pahissa Berga Protocolo de ensayo clínico de fase II, aleatorizado y abierto para el tratamiento etiológico de la enfermedad de chagas crónica con posaconazol y benznidazol Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-201 Funding: 360,687.30 € Duration: 2010 to 2011

PI: Israel Molina Romero iNTER Support Action (International Network of Teleconsultation Excellence & Referral)Acronym: iSAGrant number: 223610 Funding Agency: European Commission Reference: ISA-223610 Funding: 33,590 € Duration: 2009 to 2012

PI: Albert Pahissa Berga Malalties infeccioses Funding Agency: AGAUR Reference: 2005SGR 01039 Funding: 50,600 € Duration: 2006 to 2010

PI: Esteve Ribera Pascuet Concentraciones plasmáticas de fármacos antirretrovirales en pacientes con infección por VIH y VHC y cirrosis hepática Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/02123 Funding: 82,280 € Duration: 2010 to 2012

PI: Isabel Ruiz Camps Estudio de la relevancia clínica de la resistencia a zoles en un modelo animal de aspergilosis invasora: caracterización de parámetros PD/PK Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00433 Funding: 62,920 € Duration: 2010 to 2012

PI: Albert Pahissa Berga REIPI - Red Española de Investigación en Patología Infecciosa Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0008/0026 Funding: 717,528.16 € Duration: 2007 to 2011

PI: Esteve Ribera Pascuet RIS - Red de Investigación en Sida Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0006/0039 Funding: 259,958.31 € Duration: 2007 to 2011

PI: Albert Pahissa Berga Malalties infeccioses Funding Agency: AGAUR Reference: 2009 SGR 86 Funding: 0,00 € Duration: 2010 to 2013

PUBLICATIONS (Impact Factor: 93.304) Almirante B, Campos J, Canton R, Gudiol F, Pachon J, Pascual A, Rodríguez-Bano J, Segura F. Prudent use of antimicrobials: Have we done the best we can? The SEIMC and REIPI statement. Enferm Infecc Microbiol Clin 2010 Oct; 28 (8): 485-6.  IF: 1.393. Almirante B, Pigrau C. Acute cholangitis. Enferm Infecc Microbiol Clin 2010 Sep; 28S2: 18-24.  IF: 1.393. Almirante B, Pigrau C. [Acute cholangitis.] Enferm Infecc Microbiol Clin 2010 Sep; 28S2: 18-24.  IF: 1.393. Antón A, López-Iglesias AA, Tórtola T, RuizCamps I, Abrisqueta P, Llopart L, Marcos MA, Martínez MJ, Tudó G, Bosch F, Pahissa A, Anta MT de, Pumarola T. Selection and viral load kinetics of an oseltamivir-resistant pandemic influenza A (H1N1) virus in an immunocompromised patient during treatment with neuraminidase inhibitors. Diagn Microbiol Infect Dis 2010 Nov; 68 (3): 214-9.  IF: 2.451. Cabrero E, Griffa L, Burgos A, Merino D, Sánchez V, Muñoz Medina L, Hidalgo C, Curra A, Falcó V, et al. Prevalence and impact of body physical changes in HIV patients treated with highly active antiretroviral therapy: results from a study on patient and physician perceptions. AIDS Patient Care STDS 2010 Jan; 24 (1): 5-13.  IF: 2.683. Curran A, Gutiérrez M, Deig E, Mateo G, López RM, Imaz A, Crespo M, Ocaña I, Domingo P, Ribera E. Efficacy, safety and pharmacokinetics of 900/100 mg of darunavir/ritonavir once daily in treatment-experienced patients. J Antimicrob Chemother 2010 Oct; 65 (10): 2195-203.  IF: 4.352. Eynde E van den, Tiraboschi JM, Tural C, Sola R, Mira JA, Podzamczer D, Jou A, Canete N, Pineda JA, Pahissa A, Crespo M. Ability of treatment week 12 viral response to predict long-term outcome in genotype 1 hepatitis C virus/HIV coinfected patients. AIDS 2010 Apr 24; 24 (7): 975-82.  IF: 4.909. Fernández-Hidalgo N, Gavaldá J, Almirante B, Martín MT, López Onrubia P, Gomis X, Pahissa A. Evaluation of linezolid, vancomycin, gentamicin and ciprofloxacin in a rabbit model of antibiotic-lock technique for Staphylococcus aureus catheter-related infection. J Antimicrob Chemother 2010 Mar; 65 (3): 525-30.  IF: 4.352.

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Fortun J, Martín-Dávila P, Pascual J, Cervera C, Moreno A, Gavaldà J, Aguado JM, Pereira P, Gurgui M, Carratala J, Fogueda M, Montejo M, Blasco F, Bou G, Torre-Cisneros J. Immunosuppressive therapy and infection after kidney transplantation. Transpl Infect Dis 2010 Oct; 12 (5): 397-405. doi: 10.1111/j.13993062.2010.00526.x.  IF: 2.063.

Poveda E, Anta L, Blanco JL, Pérez-Elias MJ, García F, Leal M, Ribera E, Gutiérrez F, Soriano V, Mendoza C de. Etravirine resistance associated mutations in HIV-infected patients failing efavirenz or nevirapine in the Spanish antiretroviral resistance database. AIDS 2010 Jan 28; 24 (3): 469-71.  IF: 4.909.

Marshall V, Martro E, Labo N, Ray A, Wang D, Mbisa G, Bagni RK, Volfovsky N, Casabona J, Whitby D, Ocaña I, et al. Kaposi sarcoma (KS)-associated herpesvirus microRNA sequence analysis and KS risk in a European AIDS-KS case control study. J Infect Dis 2010 Oct 1; 202 (7): 1126-35.  IF: 5.865.

Rodríguez D, Almirante B, Cuenca-Estrella M, Rodríguez-Tudela JL, Mensa J, Ayats J, Sánchez F, Pahissa A. Predictors of Nonalbicans Candida Species Candidemia: Results of a Population-Based Surveillance in Barcelona, Spain. Clin Microbiol Infect 2010 Nov; 16 (11): 1676-82. doi: 10.1111/j.14690691.2010.03208.x.  IF: 4.014.

Martínez E, Larrousse M, Llibre JM, Gutiérrez F, Saumoy M, Antela A, Knobel H, Murillas J, Berenguer J, Pich J, Pérez I, Gatell JM, Curran A, Ribera E, et al. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS 2010 Jul 17; 24 (11): 1697-707.  IF: 4.909. Martínez E, Larrousse M, Podzamczer D, Pérez I, Gutiérrez F, Lonca M, Barragán P, Deulofeu R, Casamitjana R, Mallolas J, Pich J, Gatell JM, Ribera E, Curran A, et al. Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction. AIDS 2010 Jan 28; 24 (3): F1-9.  IF: 4.909. Miró JM, Manzardo C, Pich J, Domingo P, Ferrer E, Arribas JR, Ribera E, Arrizabalaga J, Lonca M, Cruceta A, Lazzari E de, Fuster M, Podzamczer D, Plana M, Gatell JM, Azuaje C, Villar S, et al. Immune reconstitution in severely immunosuppressed antiretroviralnaive HIV type 1-infected patients using a nonnucleoside reverse transcriptase inhibitor-based or a boosted protease inhibitorbased antiretroviral regimen: three-year results (The Advanz Trial): a randomized, controlled trial. AIDS Res Hum Retroviruses 2010 Jul; 26 (7): 747-57.  IF: 2.178. Monforte V, Ussetti P, Gavaldá J, Bravo C, Laporta R, Len O, García-Gallo CL, Tenorio L, Soler J, Roman A. Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation. J Heart Lung Transplant 2010 May; 29 (5): 523-30.  IF: 3.541. Moreno S, López Aldeguer J, Arribas JR, Domingo P, Iribarren JA, Ribera E, Rivero A, Pulido F. The future of antiretroviral therapy: challenges and needs. J Antimicrob Chemother 2010 May; 65 (5): 827-35.  IF: 4.352.

Rodríguez D, Pigrau C, Euba G, Cobo J, García-Lechuz J, Palomino J, Riera M, Toro MD del, Granados A, Ariza X. Acute haematogenous prosthetic joint infection: prospective evaluation of medical and surgical management. Clin Microbiol Infect 2010 Dec; 16 (12): 1789-1795. doi: 10.1111/j.1469-0691.2010.03157.x.  IF: 4.014. Rodríguez-Bano J, Picón E, Gijón P, Hernández JR, Cisneros JM, Pena C, Almela M, Almirante B, Grill F, Colomina J, Molinos S, Oliver A, Fernández-Mazarrasa C, Navarro G, Coloma A, López-Cerero L, Pascual A. Risk Factors and Prognosis of Nosocomial Bloodstream Infections Caused by Extended-Spectrum beta-Lactamase-Producing Escherichia coli. J Clin Microbiol 2010 May; 48 (5): 1726-31.  IF: 4.162. Rodríguez-Bano J, Picón E, Gijón P, Hernández JR, Ruiz M, Pena C, Almela M, Almirante B, Grill F, Colomina J, Giménez M, Oliver A, Horcajada JP, Navarro G, Coloma A, Pascual A. Community-onset bacteremia due to extended-spectrum beta-lactamaseproducing Escherichia coli: risk factors and prognosis. Clin Infect Dis 2010 Jan 1; 50 (1): 40-8.  IF: 8.195. Rubio R, Serrano O, Carmena J, Asensi V, Echevarria S, Flores J, Ribera E, Zárraga M, Ocampo A, Fuente B de la, Sepúlveda MA, Marino AI, Mínguez C, Vicent R, Carton JA, Moyano B, Esteban H, Mahillo B, Serrano L, González-García J. Effect of simplification from protease inhibitors to boosted atazanavir-based regimens in real-life conditions. HIV Med 2010 Oct 1; 11 (9): 545-53.  IF: 2.878.

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Rubio-Terres C, Garau J, Grau S, MartínezMartínez L, Pascual A, Rodríguez-Bano J, Prats G, Bartolomé R, Pahisa A, Almirante B, Campany D, et al. Cost of bacteraemia caused by methicillin-resistant vs. methicillin-susceptible Staphylococcus aureus in Spain: a retrospective cohort study. Clin Microbiol Infect 2010 Jun; 16 (6): 722-8.  IF: 4.014. Ruiz-Camps I, Aguado JM, Almirante B, Bouza E, Ferrer Barbera C, Len O, LópezCerero L, Rodríguez-Tudela JL, Ruiz M, Solé A, Vallejo C, Vázquez L, Zaragoza R, Cuenca-Estrella M. [Recommendations of the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC) on the prevention of invasive fungal infection due to filamentous fungi.] Enferm Infecc Microbiol Clin 2010 Mar; 28 (3): 172.e1-172.e21.  IF: 1.393. Sambola A, Fernández-Hidalgo N, Almirante B, Roca I, González-Alujas T, Serra B, Pahissa A, García-Dorado D, Tornos P. Sex differences in native-valve infective endocarditis in a single tertiary-care hospital. Am J Cardiol 2010 Jul 1; 106 (1):92-8.  IF: 3.575. Sopena B, Crespo M, Beiras X, García del Campo E, Rivera A, Gimena B, Maure B, Martínez-Vázquez C. Individualized management of bacteraemia in patients with a permanent endocardial pacemaker. Clin Microbiol Infect 2010 Mar; 16 (3): 274-80.  IF: 4.014. Teira R, Suaárez-Lozano I, Lozano F, Viciana P, Domingo P, Galindo P, Geijo P, Terrón A, González J, Cosin J, Ribera E, Roca B, GarcíaAlcalde ML, Sánchez T, Muñoz-Sánchez A, Vergara A, López-Aldeguer J, Pedrol E, Vidal F, Garrido M, Santamaría JM. Characteristics and outcome of HIV infection in gypsies in the Spanish VACH Cohort. Enferm Infecc Microbiol Clin 2010 May; 28 (5): 26672.  IF: 1.393. Treviño A, Soriano V, Rodríguez C, Romero J del, Tuset C, Marcaida G, Tuset T, Caballero E, Molina I, et al. [Current situation of human immunodeficiency virus type 2 and Human T lymphotropic virus in Spain.] Enferm Infecc Microbiol Clin 2010 Aug-Sep; 28 (7): 442-5.  IF: 1.393.

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AREA 6 INFECTIOUS DISEASES

6.3 Microbiology

Group Leader Guillem Prats Pastor Tel. 93 274 68 67 [email protected] Researchers Antònia Andreu Domingo Rosa María Bartolomé Comas Estrella Caballero Requero Gema Codina Grau Alicia Coelho Juan José González López Núria Martín Casabona Anna Maria Planes Reig Guillem Prats Pastor Teresa Tórtola Fernández Researchers in Training María Nieves Larrosa Escartín Nuria Piedra Carrasco Julieth Natalia Quintero Zárate Eva Maria Roselló Mayans Elena Sulleiro Igual Nursing, Technical and Administrative Staff Eva Borras López Thais Cornejo Sánchez

OBJECTIVES Microbiology group objectives are: • Working on its main basic lines of activity: mechanisms of resistance to antimicrobials, pathogenicity, taxonomy and epidemiology, and infectious disease diagnostics. • Promoting clinical research resulting from welfare work.

• Actively taking part in the RETIC network of the “Instituto de Salud Carlos III: Red Española de Investigación en Patologia Infecciosa (REIPI)”. • Continuing working in the “Laboratori de Suport a la Direcció General de Salut Pública de la Generalitat de Catalunya”.

22010 Impact Factor:

57.332

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RESEARCH LINES

Pathogenicity

Mechanism of antimicrobial resistance

Escherichia coli: Extraintestinal infection, population drifts and virulence factors Antònia Andreu Study of virulence factors, philogenic groups and pathogenicity islands of E.coli which cause extraintestinal infections through molecular techniques. Evaluating the pathogenic capacity of strains of various philogenic groups with a variable number of virulence factors through and animal-experimentation model. Evaluating the resistance to phagocytosis by polynuclears and macrophages and the induction capacity of interleukines production.

Klebsiella pneumoniae and Escherichia coli which carry -lactamases blaCTX-M-15 Alicia Coelho Epidemiological and molecular study of K. pneumoniae clones and multiresistant E. coli which produce this enzyme. Our main goal is to define the epidemic expansion of these strains and to compare the vectors that carry these genes.

Plasmid mediated blaoxy Juan José González López Description of the first plasmid carrying blaoxy beta-lactamase; and study of its diffusion capacity.

Study of antimicrobial activity of new antimicrobials Rosa M. Bartolomé The progressive increase of resistance has promoted new research in new antimicrobials. This work evaluates the activity of new molecules on multiresistant bacterium with different mechanisms of molecular resistance.

Clostridium difficile phatogenicity Rosa M. Bartolomé Multicentric study, where different hospitals in the Barcelona metropolitan area take part, that studies the epidemiology of infections caused by C. difficile, the susceptibility to antimicrobials and the virulence molecular factors (toxins and genetic regulation) of the isolated strains.

Mycobacterium resistance to tuberculostatics Núria Martín Casabona Standardization techniques to study the sensitivity of M. tuberculosis and M. avium. Participating in the international WHO and IUATLD networks. Acting as Supranational Reference Laboratory for WHO in the control of the quality of the susceptibility tests of M. tuberculosis. Standardization susceptibility tests of M. tuberculosis to secondline drugs.

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Epidemiology and pathogenicity of Meticillin-resistant Staphylococcus aureus (MRSA) in the outpatient environment Nieves Larrosa Escartín Multicentric work between our group and other state centers that study the relationship between epidemiology of colonization and the pathological processes that cause MRSA and their relationship with strains of virulence factors.

Figure 74 A. Selecting the microorganisms to be studied B. Establishing the phylogenic group C. Clonality relationship between related microorganisms D. Studying the correlation, in animal testing, between the potential pathogen of the microorganism and its phylogenic drift

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Figure 75 -lactamase characterization A. Bacterial isolation B. Got’s test C. Cloning D. Sequencing E. Antibiogram

CURRENT RESEARCH PROJECTS Taxonomy Comparing the capacity of phenotypic and genotypic methods to classify enterobacteria Juan José González López Evaluating and studying new molecular targets to be used for the identification of bacteria when identifying bacterial species of clinical interest that are difficult to identify by means of traditional methods through sequencing and mass spectrometry.

Epidemiology and infectious disease diagnostic Evaluating the effectiveness of the antipneumococcal vaccine conjugated 7-valente in the prevention of invasive pneumococcal disease in children under 5 years Anna M. Planes Reig Multicentric work that studies the effectiveness of the antipneumococcal vaccine conjugated 7-valent against the invasive disease caused by vaccine serotypes and also by those that have cross-reactivity, in children under 5 years; and the serotypes, clones and

resistance profile distribution of Streptococcus pneumoniae in different clinical shapes of the invasive disease in children under 5 years, and also in carriers in order to evaluate the consequent drift after vaccination.

PI: Antònia Andreu Domingo Patogenicidad de E. coli uropatógeno y comensal en un modelo de infección urinaria ascendente en ratón Funding Agency: Fondo de Investigación Sanitaria Reference: PI070971 Funding: 78,650 € Duration: 2008 to 2011

Incidence of infection by respiratory viruses in lung transplantation. Impact of infection by respiratory viruses in the natural history of chronic rejection Gema Codina Grau Diagnosis and dynamic tracking of the infection by respiratory viruses to investigate their incidence in lung transplantation in our country and evaluate the role played by respiratory viruses in the evolution of chronic rejection in patients subject to lung transplantation.

PI: Guillem Prats Pastor Utilización de la secuencia del gen de la beta-lactamasa cromosómica y de la espectrometría de masas MALDI-TOF para la identificación de las especies del género Enterobacter y géneros relacionados Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01702 Funding: 44,165 € Duration: 2010 to 2012

Quick identification of infections by Candida yeasts Eva Roselló Mayans Evaluation of the fungemia detection by PCR in hemoculture and in direct blood samples with Candida yeasts.

PI: Guillem Prats Pastor Grup d’Investigació en Microbiologia de l’Hospital Vall d’Hebron Funding Agency: AGAUR Reference: 2009 SGR 296 Funding: 42,640 € Duration: 2010 to 2013

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PUBLICATIONS (Impact factor: 57.332) Alijotas-Reig J, Miró-Mur F, Planells-Romeu I, García-Aranda N, García-Giménez V, Vilardell-Tarrés M. Are Bacterial Growth and/or Chemotaxis Increased by Filler Injections? Implications for the Pathogenesis and Treatment of Filler-Related Granulomas. Dermatology 2010; 221 (4): 356-64.  IF: 2.741. Andreu A, Matas L. [Laboratory unification: advantages and disadvantages for clinical microbiology.] Enferm Infecc Microbiol Clin 2010 Oct; 28S3: 63-68.  IF: 1.393. Antón A, López-Iglesias AA, Tórtola T, RuizCamps I, Abrisqueta P, Llopart L, Marcos MA, Martínez MJ, Tudó G, Bosch F, Pahissa A, Anta MT de, Pumarola T. Selection and viral load kinetics of an oseltamivir-resistant pandemic influenza A (H1N1) virus in an immunocompromised patient during treatment with neuraminidase inhibitors. Diagn Microbiol Infect Dis 2010 Nov; 68 (3): 214-9.  IF: 2.451. Arias C, Sala MR, Domínguez A, Torner N, Ruiz L, Martínez A, Bartolomé RM, Simón M de, Buesa J. Epidemiological and clinical features of norovirus gastroenteritis in outbreaks: a population-based study. Clin Microbiol Infect 2010 Jan; 16 (1): 39-44.  IF: 4.014. Barrabeig I, Rovira A, Buesa J, Bartolomé RM, Pinto R, Prellezo H, Domínguez A. Foodborne norovirus outbreak: the role of an asymptomatic food handler. BMC Infect Dis 2010 Sep 15; 10 (1): 269.  IF: 2.550.

Borrell S, Español M, Orcau A, Tudó G, March F, Cayla JA, Jansa JM, Alcaide F, Martín-Casabona N, Salvadó M, Martínez JA, Vidal R, Sánchez F, Altet N, Rey E, Coll P, González-Martín J. Tuberculosis transmission patterns among Spanish-born and foreign-born populations in the city of Barcelona. Clin Microbiol Infect 2010 Jun; 16 (6): 568-74.  IF: 4.014. Brotons M, Campins M, Méndez L, Juste C, Rodrigo JA, Martínez X, Hermosilla E, Pinos L, Vaqué J. Effectiveness of varicella vaccines as postexposure prophylaxis. Pediatr Infect Dis J 2010 Jan; 29 (1): 10-3.  IF: 2.854. Camiña-Tato M, Morcillo-Suárez C, Bustamante MF, Ortega I, Navarro A, Muntasell A, López-Botet M, Sánchez A, Carmona P, Julià E, Tórtola MT, Audí L, Oksenberg JR, Martín R, Montalban X, Comabella M. Gender-associated differences of perforin polymorphisms in the susceptibility to multiple sclerosis. J Immunol 2010 Nov 1; 185 (9): 5392-404.  IF: 5.646. Coelho A, González-López JJ, Miró E, Alonso-Tarrés C, Mirelis B, Larrosa MN, Bartolomé RM, Andreu A, Navarro F, Johnson JR, Prats G. Characterisation of the CTX-M15-encoding gene in Klebsiella pneumoniae strains from the Barcelona metropolitan area: plasmid diversity and chromosomal integration. Int J Antimicrob Agents 2010 Jul; 36 (1): 73-8.  IF: 3.032. Comabella M, Montalban X, Horga A, Messmer B, Kakalacheva K, Strowig T, Caballero E, Munz C, Lunemann J. Antiviral immune response in patients with multiple sclerosis and healthy siblings. Mult Scler 2010 Mar; 16 (3): 355-8.  IF: 3.279.

Cortés P, Blanc V, Mora A, Dahbi G, Blanco JE, Blanco M, López C, Andreu A, Navarro F, Alonso MP, Bou G, Blanco J, Llagostera M. Isolation and characterization of potentially pathogenic antimicrobial-resistant Escherichia coli strains from chicken and pig farms in Spain. Appl Environ Microbiol 2010 May; 76 (9): 2799-805.  IF: 3.686. Díaz MA, Hernández-Bello JR, RodríguezBano J, Martínez-Martínez L, Calvo J, Blanco J, Pascual A, Peinado CM, Ordas JF, Garduno E, Domínguez MA, Navarro F, Prats G, et al. Diversity of Escherichia coli strains producing extended-spectrum beta-lactamases in Spain: second nationwide study. J Clin Microbiol 2010 Aug; 48 (8): 2840-5.  IF: 4.162. Frick MA, Moraga-Llop FA, Bartolomé RM, Larrosa N, Campins M, Román Y, Vindel A, Figueras C. Community-acquired methicillin-resistant Staphylococcus aureus infections in children. Enferm Infecc Microbiol Clin 2010 Jul 31.  IF: 1.393. Lunemann JD, Tintoré M, Messmer B, Strowig T, Rovira A, Perkal H, Caballero E, Munz C, Montalban X, Comabella M. Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses predict conversion to multiple sclerosis. Ann Neurol 2010 Feb; 67 (2): 159-69.  IF: 9.317. Rubio-Terres C, Garau J, Grau S, MartínezMartínez L, Pascual A, Rodríguez-Bano J, Pena A, Toledano G, Coll P, Gurgui M, Farré R, Ausina V, Mateo L, Lite J, Pla R, Prats G, Bartolomé RM, Pahisa A, Almirante B, Campany D, et al. Cost of bacteraemia caused by methicillin-resistant vs. methicillin-susceptible Staphylococcus aureus in Spain: a retrospective cohort study. Clin Microbiol Infect 2010 Jun; 16 (6): 722-8.  IF: 4.014. Simón MD, Sabaté S, Cristina Osanz A, Bartolomé RM, Dolores Ferrer M. Investigation of a neonatal case of Enterobacter sakazakii infection associated with the use of powdered infant formula. Enferm Infecc Microbiol Clin 2010 Dec; 28 (10): 713-5.  IF: 1.393. Treviño A, Soriano V, Rodríguez C, Romero J del, Tuset C, Marcaida G, Tuset T, Caballero E, Molina I, Aguilera A, Rodríguez-Calvino JJ, Cortizo S, Regueiro B, et al. Current situation of human immunodeficiency virus type 2 and Human T lymphotropic virus in Spain. Enferm Infecc Microbiol Clin 2010 Aug-Sep; 28 (7): 442-5.  IF: 1.393.

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AREA 6 INFECTIOUS DISEASES

6.4 Shock, Organ Dysfunction and Resuscitation (SODIR) Group Leader Joaquín Serra Vich Tel. 93 274 60 73 [email protected] Researchers José Luis Bóveda Treviño Jesús Caballero López Xavier Nuvials Casals María Lourdes Pérez Rodríguez Juan Carlos Ruiz Rodríguez Researchers in Training Alejandra García Roche Simone Gattarello Helena Puigderrajols Vehils Jordi Riera del Brío Adolf Ruiz Sanmartín Nursing, Technical and Administrative Staff Tatiana Acero Bailén José Carlos Martín Santos

RESEARCH LINES

OBJECTIVES The aim of the SODIR research group is integrated research on shock, sepsis and cardiopulmonary resuscitation (CPR). We have special interest in severe sepsis pathophysiology and its relationship with clinical outcome, analysis of prognostic factors, development of prognostic scores and analysis of biomarkers in severe sepsis. The group is also developing echocardiography studies to identify haemodynamic alterations in critically ill patients and searching for precipitant factors of in-hospital cardiac arrest. Another

areas of interest to our group is the study of therapeutic hypothermia as a neuroprotection after cardiopulmonary arrest. The study of haemostasis in critically ill patients is another target. In the area of technology transfer our group is developing, in collaboration with the biomedical technology industry, a platform for data integration of critically ill patients with severe sepsis (SepsisNet Project) and a new system for continuous and non-invasive haemodynamic and respiratory monitoring.

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Sepsis, severe sepsis and septic shock Joaquín Serra Vich The objectives of this research are investigation into the pathophysiology of systemic inflammatory response induced by infection and the study of biomarkers, analysis of factors related to the development of multiple organ dysfunction and outcome of severe sepsis and the development of early mortality prediction scales in severe sepsis. The group works in collaboration with the “Universitat Politècnica de Catalunya” in the application of artificial intelligence in the management of severe sepsis and is involved in a research consortium that is developing a project funded by the “Subprograma Avanza R + D + I” (Ministerio de

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Industria, Turismo y Comercio. FEDER) which aims to generate intelligent alarms in critically ill patients, especially in severe sepsis, septic shock and multiple organ dysfunction. With the applied medical technology and applied research of PCB (Sabirmedical), the group is developing a system of intelligent data management of patients with severe sepsis [sub-project funded by the “Subprograma Avanza R + D + I” (Ministerio de Industria, Turismo y Comercio. FEDER)]. Currently, the group is participating in a decisive way in a new phase of the Surviving Sepsis Campaign and in several trials in septic shock and distributive shock.

Cardiopulmonary resuscitation Joaquín Serra Vich Evaluation of the implementation of a new methodology that enables audio improving data collection in medical care to inpatients experiencing cardiac arrest. Identification of precipitating factors of in-hospital cardiac arrest and peri-cardiac arrest situations.

Therapeutic hypothermia Joaquín Serra Vich Study of factors influencing the response to therapeutic hypothermia as neuroprotection in comatose survivors after in or out-ofhospital cardiac arrest and study of biomarkers of acute neurological injury in this patients.

Figure 76 Toxic monocytes and neutrophils in severe sepsis

Monitoring the critically ill Joaquín Serra Vich Application of echocardiography and other non-invasive monitoring or minimally invasive systems in the study of pathophysiologic mechanisms of cardiac and hemodynamic dysfunction of critically ill patients. Collaboration in the development of a continuous and noninvasive new monitoring system of the hemodynamic and respiratory function. This project works in collaboration with the applied medical technological research of the “Parc Científic of Barcelona”. Another objective is to deep in the knowledge of perfusion and tissue oxygenation through the study of the microcirculation and its involvement in the pathophysiology of severe sepsis with multiorgan dysfunction.

Acute kidney injury Joaquín Serra Vich Identification of biomarkers and mechanisms of inflammation. Dialysis registration techniques. Study of coagulation, inflammation and endothelial injury in acute renal failure. Study of nephrotoxicity, alteration of renal tubule and pathophysiology of acute kidney injury. Drug dosage in renal dysfunction.

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CURRENT RESEARCH PROJECTS PI: Juan Carlos Ruiz Rodríguez Sistema para la gestión de los datos clínicos de pacientes con Sepsis (SEPSISNET) Funding Agency: Ministerio de Industria, Turismo y Comercio Reference: TSI-020100-2009-204 Funding: 146,817 € Duration: 2010 to 2011

PI: Juan Carlos Ruiz Rodríguez Plataforma de Investigación para pacientes críticos (INTEGRA-UCI) Funding Agency: Ministerio de Industria, Turismo y Comercio Reference: TSI-020100-2010-625 Funding: 109,362.24 € Duration: 2010 to 2011

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AREA 7 RESPIRATORY AND SYSTEMICS DISEASES

7.1 Chronic Fatigue

Group Leader José Alegre Martín Tel. 93 489 47 02 [email protected]

• Cognitive impairment in chronic fatigue syndrome.

Researcher José Alegre Martín

• Nitric oxide metabolite production during exercise in chronic fatigue syndrome.

• Sexual dysfunction in CFS. • XRMV retrovirus infection and differential cellular response in patients with chronic fatigue syndrome (CFS) and healthy blood donors.

OBJECTIVES • Creation of a DNA bank for research in fibromialgia and chronic fatigue syndrome. • Genetic susceptibility factors in chronic fatigue syndrome. • Psychopathology of chronic fatigue syndrome.

• Establishment of a population database for patients diagnosed with CFS. • Development of protocols to evaluate the functional reserve and capacity for physiological adaptation of patients with CFS.

• Functional repercussions of neurovegetative alterations in patients with chronic fatigue syndrome.

RESEARCH LINES Population-based registry of chronic fatigue syndrome patient diagnoses in Spain

Genetic susceptibility factors in chronic fatigue syndrome

22010 Impact Factor: DNA bank for the study of patient diagnosed with fibromialgia and chronic fatigue syndrome

2.354

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Prevalence of XRMV retrovirus infection in patients with chronic fatigue syndrome (CFS) and healthy blood donors, in Catalonia, Spain

XRMV retrovirus infection and differential cellular response in patients with chronic fatigue syndrome (CFS) and healthy blood donors

Neurovegetative dysfunction in patients with chronic fatigue syndrome

Randomized clinical trial of the effectiveness of nurse intervention in patients with chronic fatigue syndrome

Randomized clinical trial of the effectiveness of nurse intervention in patients with chronic fatigue after cancer treatment

Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome

Alpha-1-antitrypsin in patients with chronic fatigue syndrome Physiological responses to leg exercise in patients with chronic fatigue syndrome

Nitric oxide metabolite production during exercise in chronic fatigue syndrome: A case-control study

Brain SPET quantification in chronic fatigue syndrome

Emergent pattern of cognitive alteration in chronic fatigue syndrome

Psychopathology of chronic fatigue syndrome

Study of ergometer parameters, cognitive function and biological markers in patients with chronic fatigue syndrome

Chronic fatigue syndrome and female sexual functioning

Partner relationship influence on the functional capacity in women with chronic fatigue syndrome

Physical exercise programme in the treatment of chronic fatigue syndrome

Group Cognitive Therapy in the treatment of chronic fatigue syndrome

Proinflammatory and antiinflammatory cytokines in pleural effusion

Study of tuberculous pleural effusions

Randomized clinical trial of the effectiveness of alteplase in patients with paraneumonic pleural effusions

CURRENT RESEARCH PROJECTS PI: José Alegre Martin Registro de base poblacional de los pacientes afectos del síndrome de fatiga crónica Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMMA/14/2006 Funding: 38,000 € Duration: 2007 to 2010

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PI: José Alegre Martín Ensayo clínico para evaluar la eficacia de la intervención de enfermería en la mejora del impacto y la calidad de vida en el paciente diagnosticado del síndrome de fatiga crónica Funding Agency: Becas de Investigación Colegio de Enfermeria de Barcelona Duration: 2008 to 2010

IP: José Alegre Martín Estudio del retrovirus XMRV en los pacientes diagnosticados del síndrome de fatiga crónica y un grupo de donantes aparentemente sanos en Cataluña Funding Agency: Banco de Sangre y Tejidos de Cataluña Duration: 2010

PI: José Alegre Martín Estudio del retrovirus XMRV en los pacientes infectados por el VIH Funding Agency: FIPSE Duration: 2010

PUBLICATIONS (Impact Factor: 2.354) Alegre J, Roses JM, Javierre C, Ruíz-Baques A, Segundo MJ, Sevilla TF de. [Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome.] Rev Clin Esp 2010 Jun; 210 (6): 284-8.  IF: 0.584. Suárez A, Guillamo E, Roig T, Blazquez A, Alegre J, Bermudez J, Ventura JL, GarcíaQuintana AM, Comella A, Segura R, Javierre C. Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study. J Womens Health (Larchmt) 2010 Jun; 19 (6): 1073-7.  IF: 1.770.

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7.2 Ear, Nose and Throat Disorders

Group Leader Juan Lorente Guerrero Tel. 93 274 64 15/63 80 [email protected] Researchers Ana María García Arumí Juan Lorente Guerrero Enrique Perelló Scherdel Joan Piñas Massó Juan Luis Quesada Martínez Pedro Quesada Marín Researcher in Training Jennifer Knäpper Martín

OBJECTIVES • Defining similarities and differences between human patients and animals regarding this disease in order to use, if suitable, brachiocephalic dogs as an animal model in treatment options for human disease.

• Validating diagnostic accuracy of sentinel ganglion in pharyngeallaryngeal carcinoma T1-2 N0 as stadiage tool, through a lympho-gammagraphy with SPECTTC the day before the operation and the surgical localization of sentinel ganglion through a probe during the surgery.

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• Determining the prevalence of gastroesophageal reflux in patients diagnosed with conventional sleep obstructive apnea syndrome, and evaluating the effectiveness of symptom quest in gastroesophageal reflux diagnosis in these patients.

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RESEARCH LINES Research group in obstructive sleep apnea syndrome (OSAS) Juan Lorente Guerrero The research group in obstructive sleep apnea syndrome (OSAS), using the brachiocephalic breed, Boxer (English and French) as animal model constitutes Drs. Juan Lorente Guerrero (UAB Lecturer, “Hospital de la Vall d’Hebron”), Santiago Lavin González (Professor), Rafaela Cuenca Valera (Lecturer), Josep Pastor Milán (Lecturer), Roser Velarde Nieto (Specialized Technician in Research Support) and Marta Planellas Bachs (Associate Professor at the “Hospital Clínico Veterinario de la UAB”). The main objective of this investigation is to define similarities and differences between human patients and animals regarding this particular disease in order to, if suitable, use brachiocephalic breed as animal models in treatment options for the human disease. OBJECTIVES: The specific objectives of this research line are the following: 1. Defining the histopathological and immunohistochemical changes with regard to myosin fiber distribution of type I and II, that produce soft palate in brachiocephalic dogs affected by upper airway obstruction syndrome, in dogs without this pathology which have been euthanized for different reasons.

2. Establishing existing similarities and differences between soft palates in brachiocephalic dogs affected by upper airway obstruction syndrome and the uvula of human patients with OSAS. 3. Determining the correlation between degree of injuries observed at histopathological and immunohistochemical level and the clinical presentation of each patient, firstly for the individual species and then a comparison between species. 4. Determining levels of canine acute-phase proteins (C-reactive protein, haptoglobin), as inflation indicators, and levels of cardiac troponin I, as myocardial damage indicator, in animals affected by upper airway obstruction syndrome to compare them afterwards with those that present in dogs that are not affected by this pathology. 5. Evaluating surgical treatment efficacy as a therapeutic alternative, in dogs affected by upper airway obstruction syndromes, through clinical monitoring, supported by complementary diagnostic tests.

Sentinel ganglion in pharynx and larynx carcinoma In this project, we are working on the patient collection phase. Currently we have 5 patients. OBJECTIVES: 1. Validating sentinel ganglion diagnostic accuracy in carcinoma pharyngolaryngeal T1-2 N0 as staging tool, through a SPECTCT lymphoscintigraphy the day before surgery and surgical location of sentinel ganglion using a probe during surgery. 2. Studying and identifying lymphatic drainage of these tumors. 3. Comparing its usefulness versus conventional staging in clinics and CT.

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4. Avoiding overtreatment of patients, eliminating VCG in N0 when Sentinel Ganglion is negative (once this technique is validated).

Gastroesophageal reflux prevalence in patients with obstructive sleep apnea syndrome Juan Lorente Guerrero, Juan Luis Quesada Martínez, Mª José Jurado Luque, Ana María Accarino Garaventa and Enrique Perelló Scherdel Different studies suggest the association between gastroesophageal reflux disease (GERD) and OSAS, but GERD prevalence in OSAS and the severity of the influence of OSAS upon GERD is not yet known. OBJECTIVE: The main objective of this study is to determine the prevalence of GERD in patients with obstructive sleep apnea syndrome using conventional polygraphic sleep. With this study we also want to assess the efficacy of a symptom questionnaire in the diagnosis of gastroesophageal reflux in these patients. PURPOSE: Identifying patients with gastroesophageal reflux among patients affected by obstructive sleep apnea, in order to establish therapeutic measures to prevent GERD complications.

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7.3 Immunology

Group Leader Ricardo Pujol Borrell Tel. 93 274 60 00 (ext. 6968) [email protected] Researchers Isabel Caragol Urgelles Roger Colobran Teresa Español Borén Manuel Hernández González Mónica Martínez Gallo

Figure 77 Lung cyst in a patient with Hyper IgE syndrome and a mutation in STAT3

OBJECTIVES

RESEARCH LINES

• We are interested in the physiopathogenic mechanisms (immunologic factors, infections, etc.) involved in the evolution and prognosis of patients with Primary Immunodeficiencies (PID).

Studies on the physiopathogenic mechanisms (immunologic factors such as regulatory cells, memory B-cells, role of different infections, etc) involved in the evolution and prognosis of patients with Primary Immunodeficiencies (PID) Teresa Español Borén and Drahomira Detkova Jancigova

• Also in the familial incidence of PID, mainly in Antibody production defects (Common variable and IgA deficiency) with the immunological studies and molecular defects already described.

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28.146

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Immunological studies of relatives of patients with Common variable immunodeficiency and IgA deficiency to discover the real incidence of these defects in family clusters, in order to will facilitate further genetic studies Teresa Español Borén, Isabel Caragol Urgelles and Drahomira Detkova Jancigova

At the end of 2010, one new research line has been added. It deals with autoimmunity and tolerance and is based on previous experience of the group plus the newly incorporated Dr Pujol and the known association between immunodeficiency and autoimmunity.

PUBLICATIONS (Impact Factor: 28.146) Albert MH, Bittner TC, Nonoyama S, Notarangelo LD, Burns S, Imai K, Español T, Fasth A, Pellier I, Strauss G, Morio T, Gathmann B, Noordzij JG, Fillat C, Hoenig M, Nathrath M, Meindl A, Pagel P, Wintergerst U, Fischer A, Thrasher AJ, Belohradsky BH, Ochs HD. X-linked thrombocytopenia (XLT) due to WAS mutations: Clinical characteristics, long-term outcome, and treatment options. Blood 2010 Apr 22; 115 (16): 3231-8.  IF: 10.555. Beaucoudrey L de, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S, Feinberg J, AlMuhsen S, Janniere L, Rose Y, Suremain M de, Kong XF, Filipe-Santos O, Caragol I, et al. Revisiting Human IL-12Rbeta1 Deficiency: A Survey of 141 Patients From 30 Countries. Medicine (Baltimore) 2010 Nov; 89 (6): 381402.  IF: 5.054. Kreuz W, Erdos M, Rossi P, Bernatowska E, Español T, Marodi L. A multi-centre study of efficacy and safety of Intratect((R)), a novel intravenous immunoglobulin preparation. Clin Exp Immunol 2010 Sep; 161 (3):512-7. doi: 10.1111/j.1365-2249.2010.04187.x.  IF: 3.009. Martín A, Soler-Palacín P, Español T, Dapena JL, Urrutia E, Navarro M, Alvez F, Figueras C. [Spanish paediatric infectious diseases society consensus document on the treatment of fungal infections based on the immune response]. An Pediatr (Barc) 2010 Dec; 73 (6): 362.e1-8.  IF: 0.363. Woellner C, Gertz EM, Schaffer AA, Lagos M, Perro M, Glocker EO, Pietrogrande MC, Cossu F, Franco JL, Matamoros N, Pietrucha B, Heropolitanska-Plisz, Yeganeh M, Español T, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol 2010 Feb; 125 (2): 424-432.e8.  IF: 9.165.

Figure 78 Visceral leishmaniasis in a patient with XL-CGD who developed a macrophage activation syndrome

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7.4 Pneumology

Group Leader Ferran Morell Brotad Tel. 93 274 61 57 [email protected] Researchers Carles Bravo Masgoret María Jesús Cruz Carmona Jaume Ferrer Sancho Susana Gómez Ollés Javier de Gracia Roldán Mª José Jurado Luque Patricia Lloberes Canadell Sergi Martí Beltrán Víctor Monforte Torres Ferran Morell Brotad Antonio Moreno Galdó Francisco Javier Muñoz Gall Ramón Orriols Martínez Oriol Roca Gas Antonio Román Broto Odile Romero Santo-Tomás Gabriel Sampol Rubio Rafael Vidal Pla Researchers in Training Antonio Álvarez Fernández Daniel Álvarez Simón Cristina Berastegui García Mario Culebras Amigo Marta Ollé Monge Mercedes Pallero Castillo Esther Rodríguez González Laura Ruano Burgos Mónica Sánchez Ortiz Sara Sánchez Vidaurre Ramón Antonio Toribio Abreu Maria Isabel Velasco García Ana Villar Gómez

Nursing, Technical and Administrative Staff Edelia Catalán Hernández Tatiana Lasheras Muñoz Rosa Lloria Vergés

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Sonia López Rodríguez Montserrat Murillo Andres Nuria Pelaz García de Ríos Mª Antonia Ramón Belmonte Mª Dolores Untoria Corral

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OBJECTIVES The Grupo de Investigación en Neumología del Hospital Vall d’Hebron (Pulmonology Research Group of Hospital Vall d’Hebron) is comprised of investigators with accredited experience in several areas, including clinical research, respiratory pathophysiology and basic/applied research. The Group encompasses professionals from various specialities (e.g., pulmonologists, biologists, anatomical pathologists, nursing staff, laboratory technicians, and physiotherapists) and has an organised structure of personnel dedicated to research, including pre-doctorate and post-doctorate interns, laboratory technicians, nurses, etc. This multidisciplinary team brings added value to the Group and guarantees the critical mass required to develop scientific projects. Moreover, the Group is integrated in Ciber de Enfermedades Respiratorias (CibeRes), a network established by the Instituto Carlos III, and is considered a Grup Consolidat (Consolidated Group) by the Departament d’Universitats, Recerca i Societat de la Informació (Department of Universities, Research and the Information Society) of the Generalitat de Catalunya (Autonomous Government of Catalonia). With respect to teaching activity, the Pulmonology Service is accredited to train three medical residents per year, with one titled professor and four associates. In addition, the Service carries out educational activity in the field of pulmonology in the Teaching Unit of the UAB (Autonomous University of Barcelona), and organises two doctorate courses per year in the setting of continuing education.

Figure 79 Whole body plethysmograph to measure the ventilatory function in mice

RESEARCH LINES The clinical and basic research activity of the Pulmonary Research Group is mainly centred on inflammation and repair, respiratory failure, and tissue hypoxia. Moreover, there is an interrelationship between these efforts and the study of pathologies such as asthma, chronic obstructive pulmonary disease (COPD), lung fibrosis, infections, lung transplantation, pulmonary hypertension, and respiratory sleep disorders.

22010 Impact Factor:

122.241

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Work-related diseases, asthma and fibrosis Ferran Morell Brotad The Group is considered a referral team for the diagnosis and treatment of work-related lung diseases in Catalonia, focusing mainly on occupational asthma, hypersensitivity pneumonitis, and occupational disease caused by asbestos exposure. It is responsible for the creation and monitoring of the Spanish Registry of Occupational Diseases (EROL), an important task that had not been covered previously. The Group forms a part of the Grup Col.laboratiu per la Investigació de l’Asma per Soja a Barcelona (Collaborative Research Group for Soy Asthma in Barcelona). Moreover, it is an officially accredited center to carry out daily determinations of environmental levels of soy aeroallergens in Barcelona. For this purpose, the Group has an agreement with the Servicio de Medio Ambiente del Puerto de Barcelona (Environmental Service of the Port of Barcelona), which uses the re-

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Lung transplantation and pulmonary hypertension Antonio Román Broto The Group performed the first successful lung transplantation in Spain. Currently, it is one of the hospitals where the largest number of lung transplants are carried out annually, which places it among the leading centers in Europe and the world for this activity.

Figure 80 Asbestos bodies in lung

sults of these analyses to monitor the unloading of soy products in the city’s port. This daily monitoring of soy aeroallergen in the city has helped the authorities begin to eliminate further asthma epidemics The Group has been given several awards for its work in the area of soy asthma, such as the Fundació Cor Vilacasas award (1993), the Science Award of the City of Barcelona (1995), and the Josep Trueta Award from the “Acadèmia de Ciències Mèdiques” (1995). The team also has broad experience in the study of hypersensitivity pneumonitis, with a series of 150 patients that is one of the largest in the country, given the low prevalence of this condition. In addition, our center is considered a national referral hospital for the diagnosis and treatment of this pathology. Within the research into occupational disease due to asbestos exposure, our research laboratory is the only one in Spain that carries out determinations of asbestos bodies in the lung.

Cystic fibrosis and primary immunodeficiencies Javier de Gracia Roldán The Group has a dedicated outpatient care center for primary immunodeficiency and is the referral center for this disease. There is also a Catalonian Referral Unit for Cystic Fibrosis, which maintains the Spanish registry of bronchiectasis and patients with alpha1antitrypsin deficit. Moreover, the team is considered to be expert in the control of tuberculous disease.

COPD and pleural diseases Jaume Ferrer Sancho In the field of COPD, the main research lines have centred on genetic aspects of the disease, with special emphasis on patents with emphysema due to alpha-1 antitrypsin deficit and exacerbation of COPD. Moreover, a research line has been initiated based on the study of inflammation in lung tissue by molecular biology techniques.

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Sleep disorders Gabriel Sampol Rubio The research effort also focuses on the various diagnostic and therapeutic options for respiratory sleep disorders, and, recently, on the vascular repercussions of these disorders. Currently the Group is participating in several multicenter endeavours in non-invasive mechanical ventilation and in a project financed by the FIS to assess the efficacy of treatment with continuous positive air pressure (CPAP) through a nasal route to reduce arterial pressure values in patients with sleep apnoea and arterial hypertension.

Paediatric respiratory diseases Antonio Moreno Galdó The Paediatric Pulmonology and Cystic Fibrosis Unit is a Spanish referral center for paediatric lung transplantation and pulmonary hypertension and a Catalonia referral center for children with cystic fibrosis, including the neonatal screening program. The main lines of research include the study of inflammation and bronchial hyperresponsiveness in asthma in infants and older children, the determination of reference values for spirometry in children and the study of lung function in children with sequelae of neonatal respiratory disease (bronchopulmonary dysplasia). The Unit has established a new line of study of ciliary motility and ultrastructure in primary ciliary dyskinesia to allow further study of this rare disease.

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CURRENT RESEARCH PROJECTS PI: María Jesús Cruz Carmona Asociación de los alelos HLA clase II y riesgo de susceptibilidad en el asma ocupacional inducida por sustancias de bajo peso molecular en una población española: Implicaciones diagnósticas y terapéuticas Funding Agency: Fondo de Investigación Sanitaria Reference: PI06/0256 Funding: 26,837.80 € Duration: 2007 to 2010

PI: Javier de Gracia Roldán Capacidad de esfuerzo, disfunción muscular periférica y genotipo en adultos con fibrosis quística Funding Agency: Fondo de Investigación Sanitaria Reference: PI061298 Funding: 72,600 € Duration: 2007 to 2010

PI: Francisco Javier Muñoz Gall Desarrollo de un modelo animal para el estudio del asma ocupacional ocasionada por la exposición a sales de persulfato Funding Agency: Societat Catalana de Pneumologia Reference: SOCAP/01/2007 Funding: 18,000 € Duration: 2007 to 2010

PI: Francisco Javier Muñoz Gall Desarrollo de un modelo animal para el estudio del asma ocupacional ocasionada por la exposición a sales de persulfato Funding Agency: Fondo de Investigación Sanitaria Reference: PI080204 Funding: 34,848 € Duration: 2009 to 2011

PI: Patricia Lloberes Canadell Efecto del tratamiento con presión continua positiva en la vía aérea (CPAP) sobre las cifras tensionales en pacientes con hipertensión arterial resistente. Estudio multicéntrico y aleatorizado. Estudio HIPARCO Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01574 Funding: 7,865 € Duration: 2010 to 2012

PI: Ferran Morell Brotad Unitat de Recerca de Pneumologia Funding Agency: AGAUR Reference: 2009 SGR 257 Funding: 54,080 € Duration: 2010 to 2013

PUBLICATIONS (Impact Factor: 122.241) Alberti C, Orriols R, Manzanera R, Jardi J. [Flu and other acute respiratory infections in the working population. the impact of influenza A (H1N1) epidemic]. Arch Bronconeumol 2010 Dec; 46 (12): 634-9.  IF: 2.166. Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farran-Codina I, Llurba-Olivé E, Vilardell-Tarrés M, Casellas-Caro M, Alijotas-Reig, J. Anti-annexin A5 antibodies in women with spontaneous pregnancy loss. Med Clin (Barc) 2010 Apr 10; 134 (10): 433438.  IF: 1.231. Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farran-Codina I, Cabero-Roura L, Vilardell-Tarrés M, Alijotas-Reig, J. Antibeta(2)-glycoprotein-I and anti-phosphatidylserine antibodies in women with spontaneous pregnancy loss. Fertil Steril 2010 May 1; 93 (7): 2330-6.  IF: 3.970. Balcells E, Gea J, Ferrer J, Serra I, OrozcoLevi M, Batlle JD, Rodríguez E, Benet M, Donaire-González D, Anto JM, Garcia-Aymerich J, Study Group PC. Factors affecting the relationship between psychological status and quality of life in COPD patients. Health Qual Life Outcomes 2010 Sep 27; 8 (1): 108.  IF: 2.456. Barcala JG, Portal JA, Carmona MJ, González CM. [Exposure to Environmental Contaminants and Respiratory Disease. Spotlight on the Year 2009.] Arch Bronconeumol 2010; 46S1: 17-20.  IF: 2.166.

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Batlle J de, Barreiro E, Romieu I, Méndez M, Gómez FP, Balcells E, Ferrer J, OrozcoLevi M, Gea J, Anto JM, Garcia-Aymerich J. Dietary modulation of oxidative stress in chronic obstructive pulmonary disease patients. Free Radic Res 2010 Nov; 44 (11): 1296-303.  IF: 6.081. Borderias L, Morell F, Vera J, Briz H, Muñoz X, Cruz MJ. [Starling-induced hypersensitivity pneumonitis: minimal but persistent antigen exposure]. Arch Bronconeumol 2010 Nov; 46 (11): 607-9.  IF: 2.166. Borrell S, Español M, Orcau A, Tudó G, March F, Cayla JA, Jansa JM, Alcaide F, Martín-Casabona N, Salvadó M, Martínez JA, Vidal R, Sánchez F, Altet N, Rey E, Coll P, González-Martín J. Tuberculosis transmission patterns among Spanish-born and foreign-born populations in the city of Barcelona. Clin Microbiol Infect 2010 Jun; 16 (6): 568-74.  IF: 4.014. Crespo A, Muñoz X, Torres F, Martí S, Ferrer J, Morell F. Noninvasive home mechanical ventilation in elderly patients. Gerontology 2010; 56 (2): 150-6.  IF: 1.661. Durán-Cantolla J, Aizpuru F, Montserrat JM, Ballester E, Teran-Santos J, Aguirregomoscorta JI, González M, Lloberes P, Masa JF, Peña M de la, Carrizo S, Mayos M, Barbe F, Sanpol G, et al. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ 2010 Nov 24; 341: c5991. doi: 10.1136/bmj. c5991.  IF: 13.660. Gallego S, Llort A, Gros L, Bueno J, Moreno A, Nieto J, Sánchez de Toledo J. Post-transplant lymphoproliferative disorders in children: the role of chemotherapy in the era of rituximab. Pediatr Transplant 2010 Feb; 14 (1): 61-6.  IF: 1.573. Gámez J, Carmona F, Raguer N, Ferrer-Sancho J, Martín-Henao GA, Martí-Beltrán S, Badia M, Gratacòs M, Rodríguez-González E, Seoane JL, Pallero-Castillo M, Burgos R, Puiggros C, Pasarín A, Bori-Fortuny I. Cellular transplants in amyotrophic lateral sclerosis patients: an observational study. Cytotherapy 2010 Sep; 12 (5):669-77.  IF: 2.204. Gómez-Ollés S, Madrid-San Martín F, Cruz MJ, Muñoz X. Occupational asthma due to colistin in a pharmaceutical worker. Chest 2010 May; 137 (5):1 200-2.  IF: 6.360.

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González-Martín J, García-García JM, Anibarro L, Vidal R, Esteban J, Blanquer R, Moreno S, Ruiz-Manzano J. [Consensus document on the diagnosis, treatment and prevention of tuberculosis.] Enferm Infecc Microbiol Clin 2010 May; 28 (5): 297.e1297.e20.  IF: 1.393. González-Martín J, García-García JM, Anibarro L, Vidal R, Esteban J, Blanquer R, Moreno S, Ruiz-Manzano J. [Consensus document on the diagnosis, treatment and prevention of tuberculosis.] Arch Bronconeumol 2010 May; 46 (5): 255-74.  IF: 2.166. Lecube A, Sampol G, Lloberes P, Romero O, Mesa J, Morell F, Simó R. Asymptomatic sleep-disordered breathing in premenopausal women awaiting bariatric surgery. Obes Surg 2010 Apr; 20 (4): 454-61.  IF: 2.934. Lecube A, Sampol G, Muñoz X, Hernández C, Mesa J, Simó R. Type 2 diabetes impairs pulmonary function in morbidly obese women: a case-control study. Diabetologia 2010 Jun; 53 (6): 1210-6.  IF: 6.551. Lecube A, Sampol G, Muñoz X, Lloberes P, Hernández C, Simó R. Insulin resistance is related to impaired lung function in morbidly obese women: a case-control study. Diabetes Metab Res Rev 2010 Nov; 26 (8): 639-45. doi: 10.1002/dmrr.1131.  IF: 2.762. Lloberes P, Lozano L, Sampol G, Romero O, Jurado MJ, Ríos J, Untoria MD, Tovar JL. Obstructive sleep apnoea and 24-h blood pressure in patients with resistant hypertension. J Sleep Res 2010 Dec; 19 (4): 597-602. doi: 10.1111/j.1365-2869.2010.00839.x.  IF: 3.500. Lozano L, Tovar JL, Sampol G, Romero O, Jurado MJ, Segarra A, Espinel E, Ríos J, Untoria MD, Lloberes P. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens 2010 Oct; 28 (10): 2161-8.  IF: 4.988. Martí S, Pallero M, Ferrer J, Ríos J, Rodríguez E, Morell F, Muñoz X. Predictors of mortality in chest wall disease treated with noninvasive home mechanical ventilation. Respir Med 2010 Dec; 104 (12): 1843-9.  IF: 2.331. Monforte V, Ussetti P, Gavaldà J, Bravo C, Laporta R, Len O, García-Gallo CL, Tenorio L, Soler J, Román A. Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation. J Heart Lung Transplant 2010 May; 29 (5): 523-30.  IF: 3.541.

Montero MA, Gracia J de, Morell F. [Hard metal interstitial lung disease]. Arch Bronconeumol 2010 Sep; 46 (9): 489-91.  IF: 2.166. Moreno A, Sánchez F, Nelson J, Miró JM, Cayla JA, Alcaide Fernández de, Altet N, Cantos A, Cayla JA, Vidal R , et al. [On the way to shortening tuberculosis treatments: clinical trials of the Unitat d’ Investigacio en Tuberculosi de Barcelona supported by the Centers for Disease Control and Prevention] Gac Sanit 2010 Mar-Apr; 24 (2): 171. e1-6.  IF: 1.172. Nelson JL, Moreno A, Orcau A, Altet N, Martínez-Roig A, Cayla JA, Casals M, Millet JP, Moraga-Llop F, Ballabriga J, Bertrán J, Boronat M, Vidal R, Cobos N, et al. Transmission Of childhood tuberculosis risk factors associated with an unidentified index case and outbreak evolution in Barcelona (19872007). Pediatr Infect Dis J 2010 Sep; 29 (9): 876-9.  IF: 2.854. Olloquequi J, Ferrer J, Montes JF, Rodríguez E, Montero MA, García-Valero J. Differential lymphocyte infiltration in small airways and lung parenchyma in COPD patients. Respir Med 2010 Sep; 104 (9): 1310-8.  IF: 2.331. Orriols R, Isidro I, Abu-Shams K, Costa R, Boldu J, Rego G, Zock JP, Muñoz X, et al. Reported occupational respiratory diseases in three Spanish regions. Am J Ind Med 2010 Sep; 53 (9): 922-30.  IF: 1.721. Pozo-Rodríguez F, Álvarez CJ, Castro-Acosta A, Melero Moreno C, Capelastegui A, Esteban C, Hernández Carcereny , López-Campos JL, Izquierdo Alonso JL, López Quilez A, Agustí A, Rodríguez E. [Clinical audit of patients admitted to hospital in Spain due to exacerbation of COPD (AUDIPOC study): method and organisation]. Arch Bronconeumol 2010 Jul; 46 (7): 349-57.  IF: 2.166. Roca O, Gómez-Ollés S, Cruz MJ, Muñoz X, Griffiths MJ, Masclans JR. Mechanical ventilation induces changes in exhaled breath condensate of patients without lung injury. Respir Med 2010 Jun; 104 (6): 822-8.  IF: 2.331. Roca O, Riera J, Torres F, Masclans JR. Highflow oxygen therapy in acute respiratory failure. Respir Care 2010 Apr; 55 (4): 40813.  IF: 1.524. Rodrigo MJ, Postigo I, Wangensteen O, Guisantes JA, Martínez J. A new application of Streptavidin ImmunoCAP for measuring IgG antibodies against non-available commercial antigens. Clin Chim Acta 2010 Nov 11; 411 (21-22): 1675-8.  IF: 2.535.

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Rosell-Murphy M, Abos-Herrandiz R, Tarrés J, Martínez-Artés X, García-Allas I, Krier I, Cantarell G, Gallego M, Orriols R, Alberti C. Prospective study of asbestos-related diseases incidence cases in primary health care in an area of Barcelona province. BMC Public Health 2010 Apr 22; 10:203.  IF: 2.223. Rovira E, Cuadras A, Gaig P, Gazquez V, Dalmau G, Gómez Ollés S, Cruz MJ. [Soybean hull unloading in Tarragona (Spain) and asthma outbreak risk] Gac Sanit 2010 MarApr; 24 (2): 109-14.  IF: 1.172. Samolski D, Tárrega J, Antón A, Mayos M, Martí S, Farrero E, Guell R. Sleep hypoventilation due to increased nocturnal oxygen flow in hypercapnic COPD patients. Respirology 2010 Feb; 15 (2): 283-8.  IF: 1.853. Sampol G, Rodés G, Ríos J, Romero O, Lloberes P, Morell F. [Acute hypercapnic respiratory failure in patients with sleep apneas] Arch Bronconeumol 2010 Sep; 46 (9): 466-72.  IF: 2.166. Troosters T, Celli B, Lystig T, Kesten S, Mehra S, Tashkin DP, Decramer M, Ferrer J, et al. Tiotropium as a first maintenance drug in COPD: secondary analysis of the UPLIFT trial. Eur Respir J 2010 Jul; 36 (1): 65-73.  IF: 5.527. Velasco-García MI, Recuero R, Cruz MJ, Panadès R, Martí G, Ferrer J. [Prevalence and Distribution of Asbestos Lung Residue in a Spanish Urban Population.] Arch Bronconeumol 2010 Apr; 46 (4): 176-81.  IF: 2.166. Vizmanos Lamotte G, Moreno Galdo A, Cruz Carmona MJ, Muñoz Gall X, Gómez Ollés S, Mir Messa I de, Gartner S, Martín de Vicente C. [Sputum induction in children: Technical development]. An Pediatr (Barc) 2010 Mar; 72 (3): 199-204.  IF: 0.363. Vooght V de, Cruz MJ, Haenen S, Wijnhoven K, Muñoz X, Hoet PH, Morell F, Nemery B, Vanoirbeek JA. Ammonium persulfate can initiate an asthmatic response in mice. Thorax 2010 Mar; 65 (3): 252-7.  IF: 7.041. Xaubet A, Fu WJ, Li M, Serrano-Mollar A, Ancochea J, Molina-Molina M, RodríguezBecerra E, Morell F, Rodríguez-Arias JM, Pereda J, Casanova A, Molins L, Picado C. A haplotype of cyclooxygenase-2 gene is associated with idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 2010 Jul; 27 (2): 121-30.  IF: 1.056.

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AREA 7 RESPIRATORY AND SYSTEMICS DISEASES

7.5 Systemic Diseases

Group Leader Miguel Vilardell Tarrés Tel. 93 274 63 30 [email protected] Researchers Juan José de Agustín de Oro Cayetano Alegre de Miguel Cristina Arnal Guimerà Eva Balada Prades Pere Barceló Garcia José Àngel Bosch Gil Victòria Cardona Dahl Jesús Castro Marrero Josefina Cortés Hernández Vicenç Fonollosa Pla Antonio Julià Cano Moisés Labrador Horrillo Joan Lima Ruiz Olga Luengo Sánchez Sara Marsal Barril Fernando Martínez Valle Consuelo Modesto Caballero José Ordi Ros Mari Carmen Pérez Bocanegra Antonio San José Laporte Agustí Sellas Fernández Albert Selva O’Callaghan Carmen Pilar Simeón i Aznar Roser Solans Laque Raül Tortosa Méndez Miguel Vilardell Tarrés Mª del Mar Villar Casares Researchers in Training Arnald Alonso Pastor Anna Sala Cunill Mª Teresa Torres Salido Nursing, Technical and Administrative Staff Cristina Canaleta Mireia Castilla Rodríguez Elena Granell Pallarés Maria Lidon Felip Pascual David Muro Fernández Silvia Serrano Acedo

22010 Impact Factor:

158.067

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Figure 81 The Rheumatology Research Group works on the development of personalized medicine in chronic inflammatory arthritis using genomic approaches, and is specialized in biobanking and the development of new bioinformatic tools

OBJECTIVES

RESEARCH LINES

Systemic autoimmune diseases are illnesses of unknown aetiology which present an autoantibody-mediated pathogenicity with heterogeneous clinical behaviour characterized by different clinical manifestations. Our research is aimed at studying: i) their aetiology (both at the genetic and immunologic regulation levels); ii) their biological and clinical expression (detection of new markers that can help us to characterize each systemic autoimmune disease); iii) their morbimortality (by performing epidemiologic studies), iv) their response to the drugs given to the patients. With these objectives in mind, we seek to improve the diagnosis, clinical follow-up and prognosis of our patients.

Study of IFN-gamma/STAT and TGFbeta/SMAD pathways in lupus patients with skin involvement. Role in the evolution to fibrosis José Ordi Ros With this project we aim to study the status of the IFN-gamma/ STAT and the TGF-beta/SMAD intracellular signal pathways in cutaneous biopsies of patients with lupus. We are now analyzing the expression of several molecules involved in these pathways to be able both to discern the main differences among the different types of cutaneous lupus and to interpret the residual fibrotic lesions observed in discoid lupus.

Lupus and apoptosis: Mechanisms of action of thalidomide and its analogues in refractory cutaneous lupus. Clinical and therapeutic implications Jesús Castro Marrero The main goal of this research line consists of studying the effect that thalidomide may have on skin viability and cellular proliferation processes. These mechanisms contribute to wound reepithelization

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in patients with cutaneous lupus. We are currently analyzing the expression level of several molecules involved in the apoptotic phenomena (Fas/FasL, Bcl-2, Bax, …) and cell matrix regeneration in keratinocyte and fibroblast primary cell cultures treated with different doses of thalidomide.

DNA methylation study in Systemic Lupus Erythematosus (SLE) patients Eva Balada Prades DNA is hypomethylated in T cells from SLE patients. This may lead to an increase in the expression of some genes that are usually silenced and, consequently, autoimmune phenomena may develop. On the other hand, this “unprotected” DNA could be responsible for triggering anti-DNA antibodies. To find out why this DNA hypomethylation is taking place, we have evaluated the expression levels of different DNA methylases and demethylases. We have observed that two demethylases (MBD2 and MBD4) are overexpressed in T CD4+ lymphocytes of patients with SLE. We are now studying the effect the overex-

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pression of these proteins may have in the expression regulation of different molecules involved in the immunologic response.

Infection and Autoimmunity: relevance of Human Endogenous Retrovirus (HERV) in Systemic Lupus Erythematosus (SLE) Eva Balada Prades Antibodies against HERVs have been detected in patients suffering from some autoimmune diseases such as SLE, rheumatoid arthritis, Sjögren’s syndrome, and multiple sclerosis. We mainly focus our research on trying to detect these antibodies in our patients affected with SLE. We have recently cloned some recombinant proteins specific to HERVs. We are simultaneously evaluating the transcription levels of several HERV proteins in T CD4+ lymphocytes from SLE patients.

Detection of retrovirus XMRV in peripheral blood mononuclear cells of patients with Systemic Lupus Erythematosus Eva Balada Prades The presence of the recently discovered retrovirus XMRV (“xenotropic murine leukaemia virusrelated virus”) is currently being studied in our lab in patients with

SLE. This virus has been detected in the blood samples of patients suffering from chronic fatigue syndrome (CFS). Interestingly, many patients with lupus also suffer from CFS. Based on these facts, in this project we establish as a hypothesis the possibility of finding XMRV DNA and RNA sequences in peripheral blood mononuclear cells from SLE patients, especially in those with CFS. We are currently setting up the previously described XMRV-specific PCR and RT-PCR assays. We will also study the immunologic response of these patients to particular XMRV proteins.

Immunologic lesional mechanisms in late adverse reactions to bioimplants Jaume Alijotas Reig The late clinical manifestations that arise when bioimplants are applied seem to have an immunologic basis. We are studying both the histological characteristics and the lesional mechanisms of the most frequently used implants. We try to analyze the role that bacteria may have in the induction and/or maintenance of these reactions and the possible correlation between particular HLA haplotypes and adverse effects.

Urinary biomarker detection in lupus nephritis José Ordi Ros Our main goal in this project is to try to avoid the repeated renal biopsies needed for establishing both the diagnosis and the following up of patients who suffer with lupus nephritis. By using just urine from the patients, we want to find out whether there is one/several biomarker/s (MCP-1, TWEAK, NGAL, APRIL, RANTES, ...) that would allow us to establish particular diagnosis and prognostic criteria that are equally effective or even more accurate than those obtained with renal biopsy.

Predictive kit to detect the possible establishment of late adverse effects related to bioimplants used in clinical practice Jaume Alijotas Reig There seems to be a high variability in the prevalence of adverse effects with an immunologic basis in relation to any implant used in clinical practice. We have managed to find a particular association of HLA haplotypes that increase the risk of developing these effects up to 600 times. We are currently working on setting up a safe and reliable biochip or kit which predicts this risk easily in a routine test.

Figure 82 Pharmacologic mechanisms in cutaneous lupus. Induction of metalloproteinases (MMP2 i MMP9) in human skin fibroblasts after being treated with thalidomide

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Figure 83 Dendritic cell infiltration (CD123+) in the skin of a patient with discoid lupus

Characterization of mastocyte mediators released at intestinal level in patients with food allergy and irritable bowel syndrome. Relationship with stress and intestinal permeability Francisco Javier Santos Vicente and Mar Guilarte Clavero This study establishes the importance of intestinal mastocytes in the regulation of intestinal permeability in two inflammatory diseases such as food allergy and irritable bowel syndrome. It includes both experimental animal models and human studies.

Serological marker study in anaphylaxis Moisés Labrador Horrillo We are performing a follow up study of different serological markers in patients who have suffered some anaphylactic episodes. The main goal consists of detecting anaphylaxis patients in the intensive care unit and to determine different serological and plasma markers, mainly tryptase and carboxypeptidase levels by means of a sandwich ELISA.

RECORD study (RECOmbinant allergens in diagnosis resolution) Victòria Cardona Dahl This study aims to detect the prevalence of specific IgE in patients polisensitized to pollen in Barcelona by means of the “component resolved diagnosis” technique from ISAC® (IgE specific microarray).

Cancer and myositis. Relevance of anti-p155 antibodies and importance of screening for cancer by Positron Emission Tomography and Computed Tomography (PET/CT) Albert Selva O’Callaghan Anti-p155 antibodies seem to be useful for the diagnosis of paraneoplastic myopathies. We have studied their prevalence and their diagnostic value in a cohort of 137 patients with inflammatory myopathies and we have observed that they have a high negative predictive value. On the other hand, screening by PET/TC does not contribute much to the conventional screening of cancer in these patients.

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MYOGEN study. Genome Wide Association study in myositis Albert Selva O’Callaghan We are currently enrolled in this worldwide study to detect global genetic alterations in patients with myositis. Twenty centres in Europe and the United States are participating in this study. We are contributing by adding the genetic information of the patients from our population. Professor Frederick W. Miller (Bethesda, USA) and Dr. Ingrid Lundberg (Stockholm, Sweden) lead the project.

International Classification Criteria Project Albert Selva O’Callaghan This is a multicentric study aimed at defining new diagnostic criteria for muscular inflammatory diseases. Although criteria established by Bohan and Peter are still used in clinical practice, some inflammatory diseases such as inclusion body myositis are not included. The hytopathological classification compiled by Dalakas includes the latter entity but it does not take into account either paraneoplastic myositis nor those associated with systemic diseases.

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Lung involvement in inflammatory myopathies Albert Selva O’Callaghan In this study we are investigating the natural history of this syndrome as mediated by anti-synthetase antibodies and the characterization of new antibodies that may be used as markers of lung involvement. It is also our aim to better understand the etiopathogenicity and the treatment of this organic illness in patients with myositis.

Canine-myositis study Albert Selva O’Callaghan We are collaborating with the Veterinary Faculty of the Barcelona Autonomous University (Dr. Santiago Lavin) along with the Department of Pathology of the University of California (Prof G. Diane Shelton). The only spontaneous animal myositis model is found in dogs, especially Collies, and when accompanied by cancer, in Boxers. Several antibodies have been described in dogs but it is not known if they are also found in humans. In dogs, myositis specific antibodies may be positive or negative. If human beings and dogs share a common autoimmune response, a new door might be opened to deepen our understanding of the etiopathogenia and the speciesspecificity of these illnesses.

Immunobiology and immunopathology of recurrent pregnancy loss and spontaneous loss Jaume Alijotas Reig Around 2-3% of reproductive-age couples suffer recurrent pregnancy losses. Almost 18% of couples that wish to have children suffer infertility problems. Simultaneously, 2-3% of all pregnant women are diagnosed with spontaneous loses. The expression of HLA molecules, specially type G, the degree of trophoblastic apoptosis, the outsourcing of new neoantigens such as phospholipids, the balance between

Th1/Th2/Th3 cytokines, the type and quantity of CD4+CD25+Foxp3+ lymphocytes, the kind and the activity of uterine NK cells (uNK) cells, the presence or absence of blocking antibodies, and other mechanisms play different roles in the achievement of the so-called “tolerant microenvironment” needed to develop a normal pregnancy. Therefore, both autoimmune and alloimmune mechanisms are important. We aim to study which isolated, and specifically associated, anomalies can be identified as risk markers to be able to evaluate possible treatments.

Cellular microparticle study in women with and without antiphospholipid antibodies with recurrent pregnancy losses and preeclampsia Jaume Alijotas Reig Cellular microparticles (CMP) are released depending on the activation and/or the presence of cell apoptosis. They are capable of activating both inflammatory and coagulation pathways. It seems that levels of CMP are higher in healthy pregnant women. A working hypothesis establishes that an increase of CMP levels may be found in recurrent pregnancy losses and preeclampsia. It is thought that their thrombophilic capacity may be higher in those patients with anti-phospholipid antibodies, especially among those with lupus anticoagulant. We want to determine MPC levels in non-pregnant healthy women, pregnant women without previous abnormal obstetric events, women with recurrent pregnancy losses, and women with severe preeclampsia. We are also evaluating whether there are differences related to the presence or absence of antiphospholipid antibodies. Finally, we will also characterize the exact type of CMP (endothelial, platelet-like, leuco-monocyte, and throphoblastic).

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Pathogenic role of cellular microparticles and anti-phospholipid/ anti-cofactor antibodies in recurrent implantation failures related to In Vitro Fertilization (IVF) Jaume Alijotas Reig The prevalence of failed IVF is high or very high. Besides problems intrinsic to the technique, we know almost nothing about the possible underlying causes. Anti-phospholipid/anti-cofactor (aPL/aCF) antibodies have been associated with several obstetric complications. Nevertheless, the role that these aPL/aCF antibodies may have in failed IVF is not well defined. With this randomized study we want to understand better the use that these antibodies may have on a clinical daily basis. Along with microparticle analysis, we could find several elements that might act as risk markers, which in turn might even help us to fine-tune currently used therapeutic approaches.

Development of the European Registry on Obstetric Antiphospholipid Syndrome (EUROAPS/EUROMAP) Jaume Alijotas Reig and Inmaculada Farrán Codina So-called obstetric antiphospholipid syndrome seems to have pathogenic, biological, therapeutic, and evolution features somehow different from those observed in patients who suffer from “classic” antiphospholipid syndrome. Although experience and scientific evidence seem to support this idea, there is a lack of information that would permit us to suggest changes in the classification and/or therapeutic criteria. The European Forum on Antiphospholipid Antibody Syndrome has decided to continue this project and it has chosen the Vall d’Hebron Hospital as the European Coordinating Centre. Many leading Spanish and European hospitals will participate in this multicentric study.

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Proinflammatory cytokines TNF and IL-6 in cellular senescence. A HUVEC aging model Jaume Alijotas Reig Cells that are chronically exposed to inflammatory signals are more prone to aging than those which are not exposed to such signals. Human vascular endothelial cell (HUVEC) primary cultures activated with TNF-alpha probably increase the expression of ICAM and VCAM, synthesize ROS, and express senescence markers. It is not known what the principal intracellular pathway is (although it is thought that STAT may play a role) and it is unknown if one or more proinflammatory cytokines are needed to activate NF-KB. We are trying to find out the role that IFN-alpha and/or IL-6 and IL-1B may have on the aging inflammatory phenomena and we aim to detect the intracellular signal pathways (STAT). We are also working on the characterization of the genes involved in these abnormal biological responses.

Specific Antinuclear antibodies of scleroderma as markers for different clinical patterns Carmen Pilar Simeón i Aznar and Vicenç Fonollosa Pla We want to establish the relationship between the presence of specific autoantibodies for scleroderma (anti-centromere, antitopoisomerase 1, anti-polymerase III, anti-U3 RNP, Anti-Th/To, AntiPm/Scl, anti-Ku) and the different demographic and clinical features as well as with the disease prognosis.

Genetic basis of scleroderma Carmen Pilar Simeón i Aznar and Vicenç Fonollosa Pla With this study we aim to study the genetic background of the disease to deepen knowledge of its pathogenesis, to be able to establish links between genetic variations and different clinicalbiological patterns. This research is based on a multicentric study and it is led by Prof. Javier Martín of the “Instituto López-Neyra” of Parasitology, CSIC (Granada). We contribute to it by sending samples from our cohort of patients along with the clinical data.

Spanish Registry of Scleroderma patients (Systemic Autoimmune Diseases Group, Spanish Internal Medicine Association) Carmen Pilar Simeón i Aznar and Vicenç Fonollosa Pla This multicentric study includes 14 hospitals with a cohort of 916 scleroderma patients. Its main goal consists of determining both the prognostic factors and the survival of these patients.

Significance of Capillaroscopy in Raynaud’s phenomenon and scleroderma Carmen Pilar Simeón i Aznar and Vicenç Fonollosa Pla We want to describe the capillaroscopy alterations observed in patients with Raynaud’s phenomenon and scleroderma. Our main objective is to establish the different patterns that may be related to visceral involvement and to the prognosis in the early stages of the disease.

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Protein expression of small collagenase 3 and leucine-rich proteoglycans in cutaneous tissue of patients with diffuse scleroderma Carmen Pilar Simeón i Aznar and Vicenç Fonollosa Pla This study, carried out along with researchers from the “Hospital del Mar” and from the “Institut Municipal d’Investigació Mèdica”, aims to correlat the expression of SLRPs and MMP-13 with the severity of cutaneous involvement, hand dysfunctional capacity, capillaroscopy patterns, and cutaneous ultrasonography of patients affected with diffuse scleroderma in different evolutive stages of the disease.

Molecular basis of Rheumatoid Arthritis Sara Marsal Barril Genomewide Association Studies (GWAS) and whole genome gene expression analyses are being carried out to study the genetic basis of RA as well as to identify new biological markers of the response to biological therapies in this disease. The systematic analysis of RA and other directly related Immunomediated Inflammatory Diseases (i.e. IMIDs), will allow us to identify disease-specific molecular mechanisms but also more general processes associated to autoimmunity. One important objective is the identification of biomarkers that are specific for disease subtypes that are more relevant clinically. In parallel to this research, one of our main goals it the development of bioinformatic tools that allow us to improve the analysis of different types of genomic data.

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Fybromialgia. Clinical and epidemiological aspects Cayetano Alegre de Miguel A systematic revision of the efficacy and security of pharmacological interventions in fybromialgia has been performed. A research line for the identification of biological markers for this disease has been recently initiated.

Juvenile Idiopathic Arthritis. Epidemiological, genetic and clinical aspects Consuelo Modesto Caballero An epidemiological study characterizing for the first time the incidence and prevalence of JIA in Catalonia has been coordinated. In this study, pediatric doctors from multiple primary health care centres have been collaborating. In low prevalence cases, genes recently characterized for the susceptibility to other inflammatory entitites like RA are being analyzed to identify potential causal mutations. The inclusion of Doppler Ecography technique in the systematic analysis of the musculoskeletical system of JIA will enable the identification of those cases having minimal residual forms of the disease.

CURRENT RESEARCH PROJECTS PI: Sara Marsal Barril Efectivitat, seguretat i adecuació dels medicaments biotecnològics en el tractament dels pacients amb artritis reumatoide Funding Agency: Agència d’Informació Avaluació i Qualitat en Salut Reference: AATRM053/02/2006 Funding: 46,560 € Duration: 2007 to 2010

PI: Albert Selva O’Callaghan Aticuerpos antitransglutaminasa en biopsias musculares de pacientes con miopía inflamatoria Funding Agency: Fondo de Investigación Sanitaria Reference: PI080450 Funding: 33,880 € Duration: 2009 to 2011

PI: Miguel Vilardell Tarrés Lupus y apoptosis: Mecanismo de acción de la talidomida y sus análogos en el lupus cutáneo refractario. Implicaciones clínicas y terapéuticas Funding Agency: Fondo de Investigación Sanitaria Reference: PI080112 Funding: 13,189 € Duration: 2009 to 2011

PI: Sara Marsal Barril Diagnóstico precoz de artritis reumatoide, psoriasis y enfermedad inflamatoria intestinal Funding Agency: Fundación Caja Navarra Reference: CAN-15450 Funding: 6,002.41 € Duration: 2009 to 2010

PI: Victòria Cardona Dahl Estudi RECORD (al·lergen RECOmbinants en Resolució Diagnòstica) Funding Agency: Stat. Catalana d’Allèrgia i Immunologia Clínica Reference: SCAIC2009/01 Funding: 9,000 € Duration: 2009 to 2011

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PI: Josefina Cortés Hernández Ensayo clínico aleatorizado y controlado para evaluar la eficacia de la azatioprina vs. micofenolato sódico para el tratamiento de la fase de inducción y mantenimiento de la remisión de los brotes extra renales del lupus eritematoso sistémico (EUDRA 2008-008934-35) Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-188 Funding: 213,508.13 € Duration: 2010 to 2011

PI: José Ordi Ros Estudio para evaluar la eficacia y seguridad de la lenalidomida en el tratamiento del lupus eritematoso cutáneo Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-194 Funding: 204,000 € Duration: 2010 to 2010

PI: Sara Marsal Barril Proyecto IMID-Inc, “Biobanco IMIDs permite identificar biomarcadores y nuevas terapias”. FEDER Funding Agency: Ministerio de Ciencia e Innovación Reference: IPT-010000-2010-36 Funding: 2,058,748.99 € Duration: 2010 to 2013

PI: Miguel Vilardell Tarrés Autoimmunitat i malaltia trombòtica Funding Agency: AGAUR Reference: 2009 SGR 661 Funding: 49,920 € Duration: 2010 to 2013

PI: Consuelo Modesto Caballero Artritis inflamatòries de la infància: estudi prospectiu de la seva incidència i prevalència a Catalunya Funding Agency: Fundació La Marató de TV3 Reference: TV3/032010 Funding: 111,384 € Duration: from 2004 to 2011

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PI: Sara Marsal Barril Estudio de asociación de genoma completo en las enfermedades inflamatorias mediadas por mecanismos inmunes “WGAS-IMID” Funding Agency: Ministerio de Ciencia e Innovación Reference: PSS-010000-2008-36 Funding: 3,269,849 € Duration: from 2008 to 2010

PI: Sara Marsal Barril Estudio de asociación de genoma completo en nuevas enfermedades inflamatorias mediadas por mecanismos inmunes “WGAS-newIMID” Funding Agency: Ministerio de Ciencia e Innovación Reference: PSS-010000-2008-39 Funding: 732,973 € Duration: from 2008 to 2010

PI: Sara Marsal Barril Construcción de un predictor diagnóstico para las enfermedades inflamatorias mediadas por mecanismos inmunes “Predictor-IMID” Funding Agency: Ministerio de Ciencia e Innovación Reference: PSS-010000-2009-1 Funding: 1,448,244 € Duration: from 2009 to 2010

PUBLICATIONS (Impact Factor: 158.067) Águila-Maturana AM, Alegre de Miquel C. [Treatment on fatigue of patients with postpolio syndrome. A systematic review]. Rev Neurol. 2010 May 16; 50 (10): 595-602.  IF: 1.234. Alijotas-Reig, J. [The complement system as a main actor in the pathogenesis of obstetric antiphospholipid syndrome]. Med Clin (Barc) 2010 Jan 23; 134 (1): 30-4.  IF: 1.231. Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farrán-Codina I, Llurba-Olivé E, Vilardell-Tarrés M, Casellas-Caro M. Anti-annexin A5 antibodies in women with spontaneous pregnancy loss. Med Clin (Barc) 2010 Apr 10; 134 (10): 433-438.  IF: 1.231. Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farrán-Codina I, Cabero-Roura L, Vilardell-Tarrés M. Anti-beta(2)-glycoprotein-I and anti-phosphatidylserine antibodies in women with spontaneous pregnancy loss. Fertil Steril 2010 May 1; 93 (7): 2330-6.  IF: 3.970. Alijotas-Reig J, Hindie M, Kandhaya-Pillai R, Miró-Mur F. Bioengineered hyaluronic acid elicited a nonantigenic T cell activation: Implications from cosmetic medicine and surgery to nanomedicine. J Biomed Mater Res A 2010 Oct; 95 (1): 180-90.  IF: 2.816. Alijotas-Reig J, Miró-Mur F, Planells-Romeu I, García-Aranda N, García-Giménez V, Vilardell-Tarrés M. Are Bacterial Growth and/ or Chemotaxis Increased by Filler Injections? Implications for the Pathogenesis and Treatment of Filler-Related Granulomas. Dermatology 2010; 221 (4):356-64.  IF: 2.741.

Branco JC, Zachrisson O, Perrot S, Mainguy Y, Alegre C, et al. European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia. J Rheumatol 2010 Apr; 37 (4):851-9.  IF: 3.854. Cortés-Hernández J, Torres-Salido MT, Medrano AS, Vilardell-Tarrés M, Ordi-Ros J. Long-term outcomes--mycophenolate mofetil treatment for lupus nephritis with addition of tacrolimus for resistant cases. Nephrol Dial Transplant 2010 Dec; 25 (12): 3939-48.  IF: 3.306. Cuatrecasas G, González MJ, Alegre C, Sesmilo G, Fernández-Solà J, Casanueva FF, García-Fructuoso F, Poca-Dias V, Izquierdo JP, Puig-Domingo M. High prevalence of growth hormone deficiency in severe fibromyalgia syndromes. J Clin Endocrinol Metab 2010 Sep; 95 (9):4331-7.  IF: 6.202. Docampo E, Rabionet R, Riveira E, Escaramis G, Julia A, Marsal S, Martín JE, GonzálezGay MA, Balsa A, Raya E, Martín J, Estivill X. Deletion of the late cornified envelope genes, LCE3C and LCE3B, is associated with rheumatoid arthritis. Arthritis Rheum 2010 May; 62 (5): 1246-51.  IF: 7.332. Fadeeva T, Asín JL, Horrillo ML, Baraut TG, Vela RF, Conde SL, Hontoria OE, Valero CB, Molina AM. Results of the oral eggchallenge test performed on two different groups of children. One group with a history, suggestive of allergic reaction with egg intake and the other group sensitised to hen’s egg without previous egg intake. Allergol Immunopathol (Madr) 2010 SepOct; 38 (5): 233-40.  IF: 0.630.

Alijotas-Reig J, Vilardell-Tarrés M. Is obstetric antiphospholipid syndrome a primary nonthrombotic, proinflammatory, complement-mediated disorder related to antiphospholipid antibodies? Obstet Gynecol Surv 2010 Jan; 65 (1): 39-45.  IF: 3.097.

García-Doval I, Pérez-Zafrilla B, Descalzo MA, Roselló R, Hernández MV, GómezReino JJ, Carmona L, Sellas A, Rodríguez B, Barceló M, et al. Incidence and risk of hospitalisation due to shingles and chickenpox in patients with rheumatic diseases treated with TNF antagonists. Ann Rheum Dis 2010 Oct; 69 (10): 1751-5.  IF: 8.111.

Alonso A, Julia A, Tortosa R, Canaleta C, Canete JD, Ballina J, Balsa A, Tornero J, Marsal S. CNstream: a method for the identification and genotyping of copy number polymorphisms using Illumina microarrays. BMC Bioinformatics 2010 May 19; 11: 264.  IF: 3.428.

García-Martínez R, Rovira A, Alonso J, Aymerich FX, Huerga E, Jacas C, Simón-Talero M, Vargas V, Córdoba J. A Long-Term Study of Changes in the Volume of Brain Ventricles and White Matter Lesions After Successful Liver Transplantation. Transplantation 2010 Mar 15; 89 (5): 589-94.  IF: 3.498.

Balada E, Vilardell-Tarrés M, Ordi-Ros J. Implication of human endogenous retroviruses in the development of autoimmune diseases. Int Rev Immunol 2010 Aug; 29 (4): 351-70.  IF: 2.641.

Garriga T, Guilarte M, Luengo O, Guillén M, Labrador-Horrillo M, Fadeeva T, Sala A, Cardona V. Frozen fruit skin prick test for the diagnosis of fruit allergy. Asian Pac J Allergy Immunol 2010 Dec; 28 (4): 275-8.  IF: 0.562.

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Area 7. Respiratory and Systemics Diseases

Jubany L, Selva-O’Callaghan A, PérezVega C, Grau-Junyent J, Hernández-Losa J, Vilardell-Tarrés M. The patient has the diagnosis. Lancet 2010 Oct 23; 376 (9750): 1436.  IF: 30.758. Les I, Doval E, Flavia M, Cárdenas G, Esteban R, Guardia J, Córdoba J, Jacas C. Quality of life in cirrhosis is related to potentially treatable factors. Eur J Gastroenterol Hepatol 2010 Feb; 22 (2):221-7.  IF: 1.662. Marsal S, Julia A. Rheumatoid arthritis pharmacogenomics. Pharmacogenomics 2010 May; 11 (5): 617-9.  IF: 3.893. Martín-Trujillo A, Rietschoten JG van, Timmer TC, Rodríguez FM, Huizinga TW, Tak PP, Marsal S, Ibrahim SM, Dijkmans BA, Pouw Kraan T van der, Verweij CL. Loss of imprinting of IGF2 characterises high IGF2 mRNA-expressing type of fibroblast-like synoviocytes in rheumatoid arthritis. Ann Rheum Dis 2010 Jun; 69 (6): 1239-42.  IF: 8.111. Martínez-Valle F, Solans-Laque R, Bosch-Gil J, Vilardell-Tarrés M. Aortic involvement in giant cell arteritis. Autoimmun Rev 2010 May; 9 (7): 521-4.  IF: 6.368. Miquel CA de, Campayo JG, Flórez MT, Arguelles JM, Tarrio EB, Montoya MG, Martín AP, Salio AM, Fuentes JV, Alberch EA, Camara AG de la. Interdisciplinary consensus document for the treatment of fibromyalgia. Actas Esp Psiquiatr 2010 Mar; 38 (2): 108-20.  IF: 0.515. Modesto C, Antón J, Rodríguez B, Bou R, Arnal C, Ros J, Tena X, Rodrigo C, Rotes I, Hermosilla E, Barceló P. Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain). Scand J Rheumatol 2010 Nov; 39 (6): 472-9.  IF: 2.507. Moorthy LN, Peterson MG, Baratelli MJ, Hassett AL, Lehman TJ, Modesto C, et al. Preliminary cross-cultural adaptation of a new pediatric health-related quality of life scale in children with systemic lupus erythematosus: an international effort. Lupus 2010 Jan; 19 (1): 83-8.  IF: 2.586. Naredo E, Moller I, Acebes C, Batlle-Gualda E, Brito E, Agustín JJ de, Miguel E de, Martínez A, Mayordomo L, Moragues C, Rejón E, Rodríguez A, Usón J, Garrido J. Threedimensional volumetric ultrasonography. Does it improve reliability of musculoskeletal ultrasound? Clin Exp Rheumatol 2010 Jan-Feb; 28 (1): 79-82.  IF: 2.396.

Pardos-Gea J, Ordi-Ros J, Avegliano G, Cortés-Hernández J, Balada E, Evangelista A, Vilardell M. Echocardiography at diagnosis of antiphospholipid syndrome provides prognostic information on valvular disease evolution and identifies two subtypes of patients. Lupus 2010; 19 (5): 575-82.  IF: 2.586. Pardos-Gea J, Pérez-López J, San José Laporte A, Vilardell Tarrés M. [Home intravenous antibiotic therapy of hepatic abscess: Safety, efficacy and predictive factor of hospital readmission.] Med Clin (Barc) 2010 Apr 17; 134 (11): 473-6.  IF: 1.231. Pérez-Bocanegra C, Solans-Laque R, Simeón-Aznar CP, Campillo M, FonollosaPla V, Vilardell-Tarrés M. Age-related survival and clinical features in systemic sclerosis patients older or younger than 65 at diagnosis. Rheumatology (Oxford) 2010 Jun; 49 (6): 1112-7.  IF: 4.236. Ramos-Casals M, García-Hernández FJ, Ramón E de, Callejas JL, Martínez-Berriotxoa, Pallarés L, Caminal-Montero L, SelvaO’Callaghan A, Oristrell J, Hidalgo C, PérezÁlvarez R, Mico ML, Medrano F, Gómez de la Torre R, Díaz-Lagares C, Camps MT, Ortego N, Sánchez-Román J. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin Exp Rheumatol 2010 Jul-Aug; 28 (4): 468-76.  IF: 2.396. Ramos-Casals M, Pérez-Álvarez R, DíazLagares C, Cuadrado MJ, Khamashta MA, Selva-O’Callaghan A, et al. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev 2010 Jan; 9 (3): 188-93.  IF: 6.368. Sabadell J, Casellas M, Alijotas-Reig J, Arellano-Rodrigo E, Cabero L. Inherited antithrombin deficiency and pregnancy: Maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol 2010 Mar; 149 (1): 4751.  IF: 1.582. Sala Cunill A, Soler-Palacín P, Martín de Vicente C, Labrador Horrillo M, Luengo Sánchez O, Figueras Nadal C. [Common variable immunodeficiency. Prognostic factors for lung damage.] Med Clin (Barc) 2010 Jan 30; 134 (2): 64-7.  IF: 1.231. Selva-O’Callaghan A, Fonollosa-Pla V, Trallero-Araguas E, Martínez-Gómez X, SimeónAznar CP, Labrador-Horrillo M, VilardellTarrés M. Nailfold capillary microscopy in adults with inflammatory myopathy. Semin Arthritis Rheum 2010 Apr; 39 (5): 398-404.  IF: 4.724.

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Selva-O’Callaghan A, Grau JM, Gámez-Cenzano C, Vidaller-Palacín A, Martínez-Gómez X, Trallero-Araguas E, Andia-Navarro E, Vilardell-Tarrés M. Conventional cancer screening versus PET/CT in dermatomyositis/polymyositis. Am J Med 2010 Jun; 123 (6): 558-62.  IF: 4.466. Selva-O’Callaghan A, Trallero-Araguas E, Grau-Junyent JM, Labrador-Horrillo M. Malignancy and myositis: novel autoantibodies and new insights. Curr Opin Rheumatol 2010 Nov; 22 (6): 627-32.  IF: 4.600. Simons FE, Betschel S, Bilo B, Bisyuk Y, Cardona V, et al. World Allergy Organization survey on global availability of essentials for the assessment and management of anaphylaxis by allergy-immunology specialists in health care settings. Ann Allergy Asthma Immunol 2010 May; 104 (5): 40512.  IF: 2.457. Trallero-Araguas E, Labrador-Horrillo M, Selva-O’Callaghan A, Martínez MA, Martínez-Gómez X, Palou E, Rodríguez-Sánchez JL, Vilardell-Tarrés M. Cancer-associated myositis and anti-p155 autoantibody in a series of 85 patients with idiopathic inflammatory myopathy. Medicine (Baltimore) 2010 Jan; 89 (1): 47-52.  IF: 5.054. Vallejo MA, Rivera J, Esteve-Vives J, Alegre C, Alperi M, Ballina FJ, Belenguer R, Belmonte M, Beltran J, Blanch J, Collado A, Fernández-Dapica P, Hernández FM, García-Monforte A, González-Hernández T, González-Polo J, Hidalgo C, Mundo J, Muñoz-Carreno P, Queiro R, Riestra N, Salido M, Vallejo I, Vidal J. Development of a selfreporting tool to obtain a combined index of severity of fibromyalgia (ICAF). Health Qual Life Outcomes 2010 Jan 7; 8 (1):2.  IF: 2.456.

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AREA 8 PATHOLOGY, CELLULAR AND GENE THERAPY

8.1 Bioengineering, Orthopedics and Surgery in Pediatrics Group Leader César Galo García Fontecha Tel. 93 489 43 55/31 54/30 75 [email protected] AREA PAEDIATRIC ORTHOPAEDICS Coordinators César Galo García Fontecha Mario Aguirre Canyadell Francisco Soldado Carrera Roberto Vélez Villa AREA PAEDIATRIC SURGERY Coordinators José Luis Peiró Ibáñez Carlos Giné Prades Gabriela Guillén Burrieza Vicenç Martínez Ibáñez José Fernando Vuletín Solís AREA BIOENGINEERING Margarita Codinach Creus Mario Marotta Baleriola Luciano Rodríguez Gómez

CURRENT RESEARCH PROJECTS PI: Francisco Soldado Carrera Determinación de marcadores de riesgo ecográficos de amputación en bridas amnióticas de extremidades en el feto ovino Funding Agency: Fondo de Investigación Sanitaria Reference: PI07/0503 Funding: 41,745 € Duration: 2008 to 2011

22010 Impact Factor:

10.275

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PI: Mario Aguirre Canyadell Efectos del plasma rico en factores de crecimiento en la consolidación del callo óseo de elongación Funding Agency: Fondo de Investigación Sanitaria Reference: PI070874 Funding: 28,314 € Duration: 2008 to 2010

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Figure 84 Femoral head necrosis

Figure 85 Induction of cleft in fetal sheep

PUBLICATIONS (Impact Factor: 10.275) Bueno J, Pérez-Lafuente M, Venturi C, Segarra A, Barber I, Molino JA, Romero A, Ortega J, Bilbao I, Martínez-Ibáñez V, Charco R. No-touch hepatic hilum technique to treat early portal vein thrombosis after pediatric liver transplantation. Am J Transplant 2010 Sep; 10 (9): 2148-53.  IF: 6.433.

PI: César Galo García Fontecha Aplicación de células madre obtenidas de líquido amniótico para la regeneración neural y ósea en la reparación fetal del MMC en feto ovino Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMMA/15/2008 Funding: 35,000 € Duration: 2008 to 2011

Fontecha CG, Aguire M, Soldado F, Peiró JL, Torán N, Vidal N, Martínez V. Effects of birth advancement in Chiari malformation in a surgical myelomeningocele model in rabbits. J Pediatr Surg 2010 Mar; 45 (3): 594-599.  IF: 1.430.

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Kozin SH, Chafetz RS, Shaffer A, Soldado F, Filipone L. Magnetic Resonance Imaging and Clinical Findings Before and After Tendon Transfers About the Shoulder in Children With Residual Brachial Plexus Birth Palsy: A 3-year Follow-up Study. J Pediatr Orthop 2010 Mar; 30 (2): 154-60.  IF: 1.226. Valdivielso-Ortiz A, Barber I, Soldado F, Aguirre Canyadell M, Enriquez G. Solitary osteochondroma: spontaneous regression. Pediatr Radiol 2010 Oct; 40 (10): 1699-701. IF: 1.186.

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AREA 8 PATHOLOGY, CELLULAR AND GENE THERAPY

8.2 Genetics

Group Leader Alberto Plaja Rustein Tel. 93 489 30 00 [email protected] Researchers Miguel del Campo Casanelles Anna María Cueto González Carmen Mediano Vizuete Alberto Plaja Rustein Teresa Vendrell Bayona Nursing, Technical and Administrative Staff Asunción Fernández Rodríguez

OBJECTIVES

RESEARCH LINES

The study of the genetic basis of human diseases, with special emphasis on those of chromosomal and genomic origin.

Study of complex and cryptic chromosomal reorganization and its phenotypic consequences

Study of the genetic basis of autism spectrum disorders (ASD)

Study of fetal alcohol syndrome Study of aneuploidy and chromosomal instability Clinical and molecular studies of Williams syndrome Study of segmental duplications, genomic reorganization and phenotypic consequences

Elaboration of computer tools for welfare development of clinical genetics and attention to rare diseases

22010 Impact Factor: Genetics of cardiopathies

45. 848

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PUBLICATIONS (Impact Factor: 45.848) Antonell A, Campo M del, Magano LF, Kaufmann L, Iglesia JM de la, Gallastegui F, Flores R, Schweigmann U, Fauth C, Kotzot D, PérezJurado LA. Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile. J Med Genet 2010 May; 47 (5): 312-20.  IF: 5.751.

CURRENT RESEARCH PROJECTS PI: Miguel del Campo Casanelles Rare Disease Portal RD-PORTALGrant No 2006119Funding agency: Public Health Executive Agency (PHEA) Funding Agency: European Commission Reference: ORPHANET-2006119 Funding: 72,072 € Duration: 2007 to 2010

PI: Miguel del Campo Casanelles Evaluación de la eficacia y seguridad de Losartán en la reducción del estrés oxidativo y la disminución de la Tensión Arterial (TA) en pacientes con síndrome de Williams (SW) y dos o más copias del gen NCF1 Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90123 Funding: 161,305.10 € Duration: 2007 to 2010

Audí L, Fernández-Cancio M, Carrascosa A, Andaluz P, Torán N, Piro C, Vilaró E, Vicens Calvet E, Gussinyé M, Albisu MA, Yeste D, Clemente M, Hernández de la Calle I, Campo M del, et al. Novel (60%) and Recurrent (40%) Androgen Receptor Gene Mutations in a Series of 59 Patients with a 46,XY Disorder of Sex Development. J Clin Endocrinol Metab 2010 Apr; 95 (4): 1876-88.  IF: 6.202. Badenas C, Rodríguez-Revenga L, Morales C, Mediano C, Plaja A, Pérez-Iribarne MM, Soler A, Clusellas N, Borrell A, Sánchez MA, Miró E, Sánchez A, Milà M, Jiménez W. Assessment of QF-PCR as the first approach in prenatal diagnosis. J Mol Diagn 2010 Nov; 12 (6): 828-34.  IF: 3.413. Díez O, Gutiérrez Enríquez S, Mediano C, Masas M, Saura C, Gadea N, Balmaña J. A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer. Breast Cancer Res Treat 2010 May; 121 (1): 221-5.  IF: 4.696. Jones KL, Hoyme HE, Robinson LK, Campo M del, Manning MA, Prewitt LM, Chambers CD. Fetal alcohol spectrum disorders: Extending the range of structural defects. Am J Med Genet A 2010 Nov; 152A (11): 2731-5.  IF: 2.404.

PI: Alberto Plaja Rustein Investigación del papel de las reorganizaciones genómicas en los defectos congénitos del corazón (DGC) y desarrollo de nuevas herramientas de diagnóstico genético prenatal y postnatal Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00632 Funding: 109.505,00 € From: 2010 to 2012

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Micale L, Turturo MG, Fusco C, Augello B, Jurado LA, Izzi C, Digilio MC, Milani D, Lapi E, Zelante L, Merla G. Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis. Eur J Hum Genet 2010 Mar; 18 (3): 317-23.  IF: 3.564. Prat E, Rey JD, Ponsa I, Nadal M, Camps J, Plaja A, Campillo M, Algaba F, Gelabert A, Miró R. Comparative Genomic Hybridization Analysis Reveals New Different Subgroups in Early-Stage Bladder Tumors. Urology 2010 Feb; 75 (2): 347-55.  IF: 2.365. Rodríguez-Santiago B, Brunet A, Sobrino B, Serra-Juhe C, Flores R, Armengol L, Vilella E, Gabau E, Guitart M, Guillamat R, Martorell L, Valero J, Gutiérrez-Zotes A, Labad A, Carracedo A, Estivill X, Pérez-Jurado LA. Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia. Mol Psychiatry 2010 Oct; 15 (10): 1023-33.  IF: 15.049. Romanelli V, Belinchon A, Benito-Sanz S, Martínez-Glez V, Gracia-Bouthelier R, Heath KE, Campos-Barros A, García-Minaur S, Fernández L, Meneses H, López-Siguero JP, Guillén-Navarro E, Gómez-Puertas P, Wesselink JJ, Mercado G, Esteban-Marfil V, Palomo R, Mena R, Sánchez A, Campo M del, Lapunzina P. CDKN1C (p57(Kip2)) analysis in Beckwith-Wiedemann syndrome (BWS) patients: Genotype-phenotype correlations, novel mutations, and polymorphisms. Am J Med Genet A 2010 Jun; 152ª (6): 1390-7.  IF: 2.404.

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AREA 8 PATHOLOGY, CELLULAR AND GENE THERAPY

8.3 Maternal Fetal Medicine

OBJECTIVES

Group Leader Lluís Cabero Roura Tel. 93 489 30 85 [email protected] Researchers Lluís Cabero Roura Elena Carreras Moratonas María del Mar Goya Canino Teresa Higueras Elisa Llurba Anna Suy Researcher in Training María Carme Merced Vázquez

The Maternal Fetal Medicine Research Group within the Department of Obstetrics of Vall d`Hebron University Hospital is one of the largest maternity units in Spain with more than 5,000 deliveries per year it constitutes a tertiary reference centre, fully accredited as a training centre, with 28 residents by the European Board and College of Obstetrics and Gynaecology (EBCOG) and the European Association of Perinatal Medicine (EAPM). The Maternal Fetal Medicine Research group work together with the Research Institute Vall d’Hebron (VHIR) wich promotes basic and applied research and hosts the laboratories of HUVH. The Maternal Fetal Medicine Research Group is formed by a network of interdisciplinary researches from clinical and basic science with the same focus of interest: • Maternal and fetal specialist. • Fetal and pediatric cardiologists specialist. • Neonatal pediatrics specialist. • Pediatric surgeons. • The Investigation Center of Biochemistry and Molecular Biology (CIBBIM) group.

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• The Immunology and Ageing Research group. • Geneticians. • Fetal and pediatric Radiologist. • Anesthesiologist. • Anatomopathologist specialized in congenital diseases. There is a powerful and established synergy within the Maternal and Fetal Health Research Centre (www. medfetal.org) and the Research Institute of Vall d’Hebron Hospital (www.vhir.org), that provides the resources to develop eight different lines of research: 1) Lipid metabolism and oxidative stress in PE; 2) Angiogenic factors and uterine artery Doppler in the prediction of PE and IUGR; 3) Maternal and fetal cardiac function in PE and IUGR: cardiovascular risk; 4) Preterm birth: prediction and prevention; 5) Obesity in pregnancy; 6) Use of 3D-4D in fetal abnormalities; 7) Twin-to-twin transfusion syndrome, and 8) Experimental and clinical fetal therapy.

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In the last 6 years this group has obtained 10 national grants and is currently coordinating two clinical trials on preterm birth (PECEP) and screening of PE and IUGR (UTOPIA) (clinicaltrials.gov). It is also involved in 3 other international clinical trials. This group has generated more than 72 original papers published in high impact factor international medical journals.

RESEARCH LINES Prevention of preterm birth María del Mar Goya Canino, Laia Pratcorona Alicart and María Carme Merced Vázquez • Efficacy of the combined use of ultrasonographic cervical length and cervical fibronectin in the optimization of the clinical management of premature labour and labour induction. • Prevention of preterm birth using cervical pessary in preg-

nant women with short cervix” (PECEP trial): randomized control trial to demonstrate the efficacy of pessary in the prevention of preterm birth. • Cervical Occlusion Trial in women with cervical incompetence (European Multicentric Study).

Fetal Medicine Elena Carreras Moratonas, José Luis Peiró Ibáñez, Silvia Arévalo Martínez, María Ángeles Sánchez Durán and Mª Teresa Higueras Sanz This group has considerable experience in fetal surgery, being considered one of the pioneers in the field in Spain and Europe. Our present focuses of investigation are: • Laser therapy for monochorionic pregnancy complications: twinto-twin transfusion syndrome and selective intrauterine growth restriction (IUGR).

• Fetal surgery: in utero treatment for congenital diaphragmatic hernia intrauterine blood transfusion, Thoracic Shunting, amniotic band release, percutaneous dilatation of aortic valve estenosis.

Metabolic diseases: diabetes and obesity María del Mar Goya Canino, Mari Carmen Domínguez Luengo, Juan Carlos Bello Muñoz and María Carme Merced Vázquez • Fetal programming: evaluation in fetal life of the patological mechanisms that lead to cardiovascular risk factors later in life. • Oxidative stress and lipid metabolism in women with Diabetes. • Perinatal Outcomes in Twins with Pregestational Diabetes (National Multicenter study). • Effect of TRA techniques on perinatal outcomes of twins with pregestational and gestational diabetes- GLOBE Study: Effect of racial differences on Obesity during pregnancy (International Study).

22010 Impact Factor:

22.134

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Preeclampsia and intrauterine growth restriction Elisa Llurba Olivé, Mari Carmen Domínguez Luengo, Maria Queralt Ferrer Menduiña, Olga Sánchez García and Maria Gemma Soro González • UTOPIA study: randomized multi-centre trial to evaluate if uterine artery Doppler screening in mid-pregnancy is able to identify women at risk for PE and/ or IUGR in whom an exhaustive control of pregnancy might decrease maternal and fetal complications. • Pregnancy as a stress test for cardiovascular disease: evaluation of cardiac and biochemical markers of atherosclerosis in mothers and children with preeclampsia (PE) and/or intrauterine growth restriction (IUGR). • Fetal programming: evaluation in the fetal life of the pathological mechanisms that lead to cardiovascular risk factors later in life. • Role of angiogenic and anti-angiogenic factors in preeclampsia and intrauterine growth restriction. • Prediction of PE and IUGR by uterine artery Doppler and biochemical markers of placental underperfusion in the first trimester of pregnancy. • Oxidative stress and lipid metabolism in women with PE.

CURRENT RESEARCH PROJECTS PI: Lluís Cabero Roura Eficacia de la medición Doppler del flujo de las arterias uterinas a las 11-14 semanas para la predicción de preeclampsia/RCIU y la prevención de complicaciones maternofetales en la población española Funding Agency: Fondo de Investigación Sanitaria

Reference: PI061312 Funding: 137,335 € Duration: 2007 to 2010

PI: Elena Carreras Moratonas Prevención del parto pretérmino mediante pesario cervical en gestantes con longitud cervical disminuida Funding Agency: Fondo de Investigación Sanitaria Reference: PI071086 Funding: 132,011 € Duration: 2008 to 2011

PI: Mª Teresa Higueras Sanz Sistema Nervioso Central Fetal: desarrollo de un programa interactivo de segmentación asistida de imágenes ecográficas Funding Agency: Fondo de Investigación Sanitaria Reference: PI08/90912 Funding: 18,150 € Duration: 2009 to 2010

PI: Elena Carreras Moratonas Neurografía fetal: sustituye a la resonancia magnética? Funding Agency: Fundació Santiago Dexeus Font Reference: FSDF2009/05 Funding: 6,000 € Duration: 2009 to 2011

PUBLICATIONS (Impact Factor: 22.134) Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farrán-Codina I, Cabero-Roura L, Vilardell-Tarrés M. Anti-beta(2)-glycoprotein-I and anti-phosphatidylserine antibodies in women with spontaneous pregnancy loss. Fertil Steril 2010 May 1; 93 (7): 2330-6.  IF: 3.970. Brieno-Enriquez MA, Robles P, García-Cruz R, Roig I, Cabero L, Martínez F, Garciía Caldes M. A new culture technique that allows in vitro meiotic prophase development of fetal human oocytes. Hum Reprod 2010 Jan; 25 (1): 74-84.  IF: 3.859.

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Campoy C, Cabero L, Sanjurjo P, Serra-Majem L, Anadon A, Morán J, Fraga JM. [Update of knowledge, recommendations and full consensus about the role of long chain polyunsaturated fatty acids in pregnancy, lactating period and first year of life.] Med Clin (Barc) 2010 Jun 12; 135 (2): 75-82.  IF: 1.231. García-Cruz R, Brieno MA, Roig I, Grossmann M, Velilla E, Pujol A, Cabero L, Pessarrodona A, Barbero JL, Caldes MG. Dynamics of cohesin proteins REC8, STAG3, SMC1 beta and SMC3 are consistent with a role in sister chromatid cohesion during meiosis in human oocytes. Hum Reprod 2010 Sep; 25 (9): 2316-27.  IF: 3.859. García-Cruz R, Casanovas A, Brieno-Enríquez M, Robles P, Roig I, Pujol A, Cabero L, Durban M, García Caldes M. Cytogenetic analyses of human oocytes provide new data on non-disjunction mechanisms and the origin of trisomy 16. Hum Reprod 2010 Jan; 25 (1): 179-91.  IF: 3.859. Khan K, Zamora J, Lamont RF, Geijn Hp H van, Svare J, Santos-Jorge C, Jacquemyn Y, Husslein P, Helmer HH, Dudenhausen J, Renzo GC Di, Cabero Roura L, Beattie B. Safety concerns for the use of calcium channel blockers in pregnancy for the treatment of spontaneous preterm labour and hypertension: a systematic review and meta-regression analysis. J Matern Fetal Neonatal Med 2010 Sep; 23 (9): 1030-8.  IF: 1.362. Marín RC, Bello-Muñoz JC, Martínez GV, Martínez SA, Moratonas EC, Cabero Roura L. Use of 3-dimensional sonography for prenatal evaluation and follow-up of fetal goitrous hypothyroidism. J Ultrasound Med 2010 Sep; 29 (9): 1339-43.  IF: 1.181. Sabadell J, Casellas M, Alijotas-Reig J, ArellanoRodrigo E, Cabero L. Inherited antithrombin deficiency and pregnancy: Maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol 2010; 149 (1): 47-51.  IF: 1.582. Vilca Yengle LM, Campins Martí M, Cabero Roura L, Rodrigo Pendás JA, Martínez Gómez X, Hermosilla Pérez E , Vaqué Rafart J. Influenza vaccination in pregnant women. Coverage, practices and knowledge among obstetricians. Med Clin (Barc). 2010 Feb 13; 134 (4): 146-151.  IF: 1.231.

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AREA 8 PATHOLOGY, CELLULAR AND GENE THERAPY

8.4 Neuro-spinal Pathology Study

Group Leader Carlos Villanueva Leal Tel. 93 489 34 81 / 34 79 [email protected] Researchers Juan Bagó Granell José Manuel Casamitjana Ferrandiz M. José Clara Colomina Soler Montserrat Domingo Sábat Ferran Pellisé Urquiza Carlos Villanueva Leal Researcher in Training Alba Vila Casademunt

OBJECTIVES

RESEARCH LINES

• International multicentric data base of adult scoliosis.

Perioperative anaesthesia management M. José Clara Colomina Soler

• Identification of peri-operative factors related to postoperative infection in spinal surgery. • Data base of metastatic tumors of the spine. Scoliosis outcome after surgical deformity correction.

Degenerative lumbar spine problems Ferran Pellisé Urquiza

Scoliosis and other spinal deformities Juan Bagó Granell

Thoracolumbar Fractures Carlos Villanueva Leal

Cervical spine José Manuel Casamitjana Ferrandiz

Spinal tumors Ferran Pellisé Urquiza and Ainhoa Arias Baile

Postoperative Infections in Spinal Surgery Ferran Pellisé Urquiza and Susana Núñez Pereira

22010 Impact Factor:

7.483

Adult scoliosis Ferran Pellisé Urquiza

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CURRENT RESEARCH PROJECTS PI: M. José Clara Colomina Soler Ensayo clínico, multicéntrico, aleatorizado y controlado con placebo para evaluar la eficacia de la utilización perioperatoria de ácido tranexámico sobre los requerimientos transfusionales y la hemorragia quirúrgica en la cirugía compleja de columna Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-189 Funding: 78,611.40 € Duration: 2010 to 2011

PUBLICATIONS (Impact Factor: 7.483) Martínez-Llorens J, Ramírez M, Colomina MJ, Bagó J, Molina A, Cáceres E, Gea J. Muscle dysfunction and exercise limitation in adolescent idiopathic scoliosis. Eur Respir J 2010 Aug; 36 (2): 393-400.  IF: 5.527. Nuñez S, Bagó J, Pellisé F. Posterior spinal instrumented fusion and decompression. Eur Spine J 2010 Mar; 19 (3): 513-4.  IF: 1.956.

Figure 86 Surgical treatment of thoracolumbar kyphosis in Hurler’s syndrome

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AREA 8 PATHOLOGY, CELLULAR AND GENE THERAPY

8.5 Ophthalmology

Group Leader José García Arumí Tel. 93 274 60 08 [email protected] Researchers Laia Bisbe López Ana Boixadera Espax Carme Macià Badia Sara Martín Nalda Vicente Martínez Castillo Researchers in Training Álvaro Barraza Meneses Laura Distefano Diana Paola Mora Ramírez Andrea Reg Rodrigues Carvalho Pau Tarrús Bozal Nursing, Technical and Administrative Staff Anna Salas Torras

OBJECTIVES Our main areas of research include retinal vascular disease, inside which we are focused on the physiopathology of diabetic macular edema; physiopathology and treatment of retinal vein occlusions and new treatments for retinal artery occlusions through

experimental models; retinal detachment, for which we are interested in the development of a new surgical technique for its treatment. The physiopathology of vitreoretinal proliferation; age-related macular degeneration (ADM), for which we are studying genetic

risk factors and the role played by inflammation in the pathogeny of uveitis, concretely the pathogeny of uveitic macular edema and the role played by antiangiogenic drugs in the treatment of this disorder.

22010 Impact Factor:

24.126

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Figure 87 Rat model in the study of diabetic retinopathy. Ocular specimen stained by hematoxilin-eosin technique

RESEARCH LINES Diabetic retinopathy research group José García Arumí, Miguel Ángel Zapata Victori, Andrea Reg Rodrigues Carvalho and Anna Salas Torras Our research group investigates new therapeutic approaches for diabetic retinopathy (DR). DR is one of the most prevalent and invalidated diseases present in the active age population. Our research focus on clinic and basic science: • Collaboration in multicentre clinical trials for new DR therapies. • Research of angiogenic and anti-angiogenic factors in animal model of DR. • “In vitro” and “in vivo” research of anti-angiogenic factors. • Development of an anti-angiogenic gene therapy using nonviral vectors in an attempt to improve DR treatment and patient quality of life.

Retinal artery occlusion research group José García Arumí, Miguel Ángel Zapata Victori, Andrea Reg Rodrigues Carvalho and Anna Salas Torras Our research group investigates physiopathology as well as novel surgical approaches to retinal artery occlusion. Our research focuses on clinic/ surgery and basic science: • Development and improvement of surgical treatment. • Development of an animal model of branch retinal artery occlusion (BRAO). • Research focusing on retinal neuronal death, structural changes and electrophysiology regarding time points of BRAO. Research on erythropoietin (EPO) and EPOr, VEGF and PEDF in ischemic retina.

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Retinal vascular diseases José García Arumí, Miguel Ángel Zapata Victori, Anna Boixadera and Carme Macià Badia In diabetic retinopathy we are evaluating the efficacy of the new treatments that are used in this disease (anti-VEGF [vascular endothelial growth factor] agents) and designing new therapeutic approaches. In vascular retinal vein occlusions were are studying the vitreous factors that are related to the pathogenesis of macular edema. In retinal arterial occlusions we are evaluating foveal photoreceptor survival time after a branch retinal artery occlusion. For this purpose we are using an animal model (pig).

Age related macular degeneration Miguel Ángel Zapata Victori Our research group investigates one of the most prevalent and invalidated diseases present in the population over 50 years old. Our research focuses on clinical and basic science:

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• Collaboration in multicentre clinical trials for new exudative age related macular degeneration therapies, with both industry and public funds. • Collaboration in multicentre studies of the macular degeneration genotype. • Collaboration in multicentre studies in the progression of atrophic macular degeneration.

CURRENT RESEARCH PROJECTS PI: José García Arumí Expresión diferencial de citocinas y metaloproteinasas en el edema macular secundario a trastornos oclusivos venosos retinianos y el edema macular uveítico: análisis comparativo en humor vítreo Funding Agency: Fondo de Investigación Sanitaria Reference: PI06/0803 Funding: 58,080 € Duration: 2007 to 2011

• Independent clinical trial research with new medications to treat exudative macular degeneration. • Research of biomarkers and risk factors in intermediary macular degeneration. • In vitro research into antiangiogenic and neuroprotective factors using primary and cell line retinal pigmentary epithelium cultures.

Uveitis Carme Macià Badia We are mainly investigating macular edema, which is a major important cause of vision loss in uveitis. We have not a completely effective treatment nowadays for this entity. A better understanding of the pathophysiology would allow a more successful therapeutical management. We are determinating intravitreal concentration of some interleukines and metalloproteinases in patients with macular edema secondary to these disease. We are evaluating the role of bevacizumab injections for the treatment of uveitic macular edema.

Figure 88 Immunofluorescence of transfected retina with non-viral vector

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PI: José García Arumí Papel de la somatostatina-28 en la fisiopatología del edema macular secundario a uveítis Funding Agency: Fondo de Investigación Sanitaria Reference: PI070414 Funding: 94,985 € Duration: 2008 to 2011

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Figure 89 Immunofluorescence of retinal pigment epithelium cell line

PI: José García Arumí Evaluación de la eficacia y seguridad de la inyección intravítrea de bevacizumab en el tratamiento de la neovascularización coroidea asociado a miopía magna Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90808 Funding: 39,204 € Duration: 2007 to 2010

PI: José García Arumí Estudio de la eficacia y seguridad de inyecciones intravítreas de bevacizumab en el edema macular secundario a obstrucciones venosas retinianas (EBOVER) Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00171 Funding: 42,737.20 € Duration: 2009 to 2012

PI: Álex Fonollosa Calduch Estudio aleatorizado y abierto de la eficacia, seguridad y tolerabilidad de dosis repetidas de bevacizumab intravítreo en pacientes con edema macular uveítico refractario Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00117 Funding: 3,025 € Duration: 2009 to 2011

PI: Vicente Martínez Castillo Roturas retinianas en las esclerotomías en el tratamiento del desprendimiento de retina rhegmatógeno primario mediante vitrectomía vía pars plana sin indentación escleral Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/01444 Funding: 19.965,00 € Duration: 2010 to: 2012

PI: Miguel Ángel Zapata Victori Ensayo clínico, abierto, de seguridad y eficacia de adalimumab intravítreo en pacientes con neovascularización coroidea secundaria a degeneración macular asociada a la edad no respondedores al tratamiento convencional con ranibizumab Funding Agency: Ministerio de Sanidad y Política Social Reference: TRA-196 Funding: 20,400 € Duration: 2010 to 2011

PI: José García Arumí OFTARED - Red de Patología Ocular del Envejecimiento, Calidad Visual y Calidad de Vida Funding Agency: Fondo de Investigación Sanitaria Reference: RD07/0062/0010 Funding: 99,310.45 € Duration: 2008 to 2011

PI: José García Arumí Grup de Recerca en Oftalmologia Vall d’Hebron Funding Agency: AGAUR Reference: 2009 SGR 384 Funding: 0,00 € Duration: 2010 to 2013

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Figure 90 Fluorescein angiography of a patient with macular edema secondary to paunveítis

PUBLICATIONS (Impact Factor: 24.126) Fonollosa A, García-Arumi J, Santos E, Macià C, Fernández P, Segura RM, Zapata MA, Rodríguez-Infante R, Boixadera A, Martínez-Castillo V. Vitreous levels of interleukine-8 and monocyte chemoattractant protein-1 in macular oedema with branch retinal vein occlusion. Eye (Lond) 2010 Jul; 24 (7): 1284-90.  IF: 1.974.

Rojas J, Fernández I, Pastor JC, GarcíaGutiérrez MT, Sanabria MR, Brión M, Coco RM, Ruiz-Moreno JM, García-Arumí J, Elizalde J, Ruiz-Miguel M, Gallardo JM, Corrales RM, Carracedo A. A Strong Genetic Association between the Tumor Necrosis Factor Locus and Proliferative Vitreoretinopathy: The Retina 4 Project. Ophthalmology 2010 Dec; 117 (12): 2417-2423.e1-2.  IF: 5.491.

Zapata MA, Badal J, Fonollosa A, Boixadera A, García-Arumí J. Insulin resistance and diabetic macular oedema in type 2 diabetes mellitus. Br J Ophthalmol 2010 Sep; 94 (9): 1230-2.  IF: 2.917.

Haller JA, Bandelló F, Belfort R Jr, Blumenkranz MS, Gillies M, Heier J, Loewenstein A, Yoon YH, Jacques ML, Jiao J, Li XY, Whitcup SM, García Arumí J, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010 Jun; 117 (6): 1134-1146.e3.  IF: 5.491. Hernández C, Zapata MA, Losada E, Villarroel M, García-Ramírez M, García-Arumí J, Simó R. Effect of intensive insulin therapy on macular biometrics, plasma VEGF and its soluble receptor in newly diagnosed diabetic patients. Diabetes Metab Res Rev 2010 Jul; 26 (5): 386-92.  IF: 2.762. Pavesio C, Zierhut M, Bairi K, Comstock TL, Usner DW, Abboud E, Amoaku W, Becker M, Brancato R, Benítez del Castillo JM, Calonge M, Carmona M, Marano RC, Caspers-Velu L, Díaz Llopis M, Smet M de, Dick A, Eldem B, Figueroa M, Forrester J, Frau E, García-Arumí J, et al. Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology 2010 Mar; 117 (3): 567-75, 575.e1.  IF: 5.491.

Figure 91 Retinography of a pig model in the study of branch retinal artery obstruction

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AREA 8 PATHOLOGY, CELLULAR AND GENE THERAPY

8.6 Robotic and Craniofacial Surgery

Group Leaders Guillermo Raspall Martín Tel. 93 274 61 79 [email protected] Juan Antonio Hueto Tel. 93 274 60 85 [email protected] Researchers Coro Bescós Atin Javier Gutiérrez Santamaría Juan Antonio Hueto Madrid Jorge Pamias Romero Guillermo Raspall Martín Manuel Sáez Barba

OBJECTIVES

RESEARCH LINES

Research and development into the applications of robotics and information and image technologies in craniofacial surgery.

Robotics Dr. Juan Antonio Hueto MD1, Prof. Alícia Casals PhD2, Prof. Josep Amat PhD2, Dr. Javier Gutiérrez MD1 1 2

Hospital General Universitario Vall d’Hebron. Departament d’Enginyeria de Sistemes, Automàtica i Informàtica Industrial (ESAII), Universitat Politècnica de Catalunya (UPC)

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Imaging technologies and virtual reality Dr. Juan Antonio Hueto MD1, Prof. Isabel Navazo PhD2, Prof. Pere Brunet PhD2, Dr. Josep Rubio MD DDS1 1 2

Hospital General Universitario Vall d’Hebron. Departament de Llenguatges i Sistemes Informatics (LSI), Universitat Politècnica de Catalunya (UPC)

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Microsurgery Dra. Coro Bescós MD PhD1, Dr. Jordi Pamias MD1, Dr. Manel Sáez MD PhD1 1

Hospital General Universitario Vall d’Hebron

Figure 92 Example of craniofacial surgery

Figure 93 Imaging technology and virtual reality

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AREA T1 EPIDEMIOLOGY, PHARMACOLOGY, NEW THERAPIES, CLINICAL RESEARCH

T1.1 Cell and Gene Therapy

Group Leader Jordi Barquinero Mañez Tel. 93 274 67 26 [email protected] Researchers Jordi Barquinero Mañez Ramón Gimeno Martínez Researchers in Training Silvia Casacuberta Serra Rebeca Sánchez Domínguez Nursing, Technical and Administrative Staff Sergio López Estévez

OBJECTIVES • To investigate the mechanisms by which transplantation of hematopoietic cells expressing autoantigens induce tolerance in experimental autoimmune encephalomyelitis(EAE), a murine model of multiple sclerosis.

• To develop novel gene therapy strategies for MNGIE. • To optimize hematopoietic differentiation from human induced pluripotent stem cells (iPSC).

22010 Impact Factor:

4.745

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RESEARCH LINES Immune tolerance induction through enforced expression of autoantigens in hematopoietic cells using gene therapy and non myeloablative strategies (in collaboration with Drs. C. Espejo, H. Eixarch and X. Montalban, Clinical Neuroimmunology Unit / CEM-Cat) Jordi Barquinero

PI: Jordi Barquinero Mañez Generación y diferenciación de células madre pluripotentes inducidas (IPS) de pacientes con enfermedades genéticas del sistema inmuno-hematopoyético Funding Agency: Ministerio de Ciencia e Innovación Reference: PLE2009-0100 Funding: 302,540 € Duration: 2009 to 2012

PUBLICATIONS (Impact Factor: 4.745) Álvarez E, Moga E, Barquinero J, Sierra J, Briones J. Dendritic and tumor cell fusions transduced with adenovirus encoding CD40L eradicate B-cell lymphoma and induce a Th17-type response. Gene Ther 2010 Apr; 17 (4): 469-77.  IF: 4.745.

Applications of induced pluripotent stem cells (iPSC) on the diagnosis and therapy of diseases of the hematopoietic system (in collaboration with research groups at CIEMAT, CMRB and Hospital Niño Jesús) Juan Bueren (CIEMAT, Madrid)

Preclinical development of a gene therapy strategy in hematopoietic cells for mitochondrial neurogastrointestinal encephalopathy (MNGIE) (in collaboration with Drs. R. Martí, J. Torres and A. Andreu, mitochondrial and neuromuscular pathology group) Ramon Martí Seves

CURRENT RESEARCH PROJECTS PI: Jordi Barquinero Mañez Nuevas estrategias basadas en las células mieloides supresoras expresando autoantígenos para inducir tolerancia. Aplicación en un modelo experimental de esclerosis múltiple Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/00237 Funding: 134,915 € Duration: 2010 to 2012 Figure 94 Human iPSC colony and the same colony after alkaline phosphatase staining

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AREA T1 EPIDEMIOLOGY, PHARMACOLOGY, NEW THERAPIES, CLINICAL RESEARCH

T1.2 Clinical Pharmacology

Group Leader Joan-Ramon Laporte Roselló Tel. 93 489 41 05 [email protected] Researchers Cristina Aguilera Maria Antònia Agustí Escasany Josep Castel Llobet Gloria Cereza García Immaculada Danés Carreras Eduard Diogène Fadini Pili Ferrer Argelés Albert Jesús Figueras Suñé Immaculada Fuentes Camps Núria García Dolade Luisa Ibáñez Mora Dolores Rodríguez Cumplido Mònica Sabaté Gallego Xavier Vidal Guitart Nursing, Technical and Administrative Staff Elena Ballarín Alins José J Barroso García Eulàlia Pérez Esquirol Montserrat Pérez González Ramón Puig Tressera Lourdes Vendrell Bosch

OBJECTIVES

RESEARCH LINES

The main research field of the Foundation Catalan Institute of Pharmacology is pharmacoepidemiology, with a focus on research on effectiveness of medicine utilization and adverse effects of medicines in clinical practice. FICF is part of the ENCePP (European Network of Centres for Pharmacoepidemiology and Pharmacovigilance) research network, which is coordinated by the European Medicines Agency and of the PROTECT Group, a public-private consortium funded by the European Commission’s IMI Initiative. It is also part of the Autonomous University of Barcelona Research Park.

Risk of agranulocytosis associated with use of medicines Joan-Ramon Laporte Roselló In collaboration with all the Haematology services of the Metropolitan Area of Barcelona, and with support from the Spanish Agency on Medicines and Health Products and Sanofi-Aventis. This is a scheme for the case-control surveillance of agranulocytosis and aplastic anaemia.

22010 Impact Factor:

20.562

270

Study on drug-induced liver disease Luisa Ibáñez Mora and Mònica Sabaté Gallego In collaboration with 12 Hepatology Units in the Metropolitan Area of Barcelona, the group performed a case-population study with the aim of estimating the risk of acute hepatitis associated with the use of medicines. A study of a cohort of patients who initiate treatment or prophylaxis with antituberculous drugs, and with the

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aim of identifying those presenting a high risk of developing hepatotoxicity is being developed. The serum proteomic profiles of these patients will be analyzed.

Acute renal failure Maria Antònia Agustí Escasany In collaboration with three hospitals of the Metropolitan Area of Barcelona the group performs two studies to identify hospital admissions due to acute renal failure and hospital-acquired acute renal failure related to rennin-angiotensin-aldosterone system and other drugs with in-hospital use. The aim is to estimate the incidence rate and severity, describe the clinic characteristics and clinical course, the drugs involved, other associated risk factors, the length of the hospital stay, and the economical impact of acute renal failure.

PROTECT (Pharmacoepidemiological Research on Outcome of Therapeutics by a European ConsorTium Joan-Ramon Laporte Roselló and Luisa Ibáñez Mora The goal of this project is to strengthen the benefit-risk monitoring of medicines in Europe by developing innovative methods that will enhance the early detection and assessment of adverse drug reaction from different data sources (clinical trials, spontaneous reporting and observational studies). Our group is responsible for working on the use of national drug utilisation data. The specific tasks are to build and update an inventory of data sources on the consumption of the medicines of interest, to evaluate and disseminate methodologies for drug utilisation studies in order to estimate the potential public health impact of adverse drug reactions.

CURRENT RESEARCH PROJECTS PI: Maria Antònia Agustí Escasany Estudio prospectivo multicéntrico de la incidencia, relevancia clínica, factores de riesgo y preventibilidad del ingreso hospitalario por fracaso renal agudo asociado al uso de fármacos Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00244 Funding: 43,318 € Duration: 2009 to 2011

PI: Luisa Ibáñez Mora Caracterización de perfiles proteómicos predictivos de hepatotoxicidad asociada a medicamentos antituberculosos: un estudio exploratorio Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00250 Funding: 150,645 € Duration: 2009 to 2011

Figure 96 We use standard and up to date web technologies and tools to build and run our products

PI: Joan-Ramon Laporte Roselló Fundació Institut Català de Farmacologia Funding Agency: AGAUR Reference: 2009 SGR 412 Funding: 42,640 € Duration: 2010 to 2013

Figure 95 On the FICF website informative materials, databases and publications are freely accessible

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Figure 97 We design databases and develop electronic forms that can be accessed via the Internet

PUBLICATIONS (Impact Factor: 20.562) Bosch Ferrer M, Lalueza Broto P. New oral anticoagulants for the prevention of venous thromboembolism. Med Clin (Barc) 2010 Mar 6; 134 (6): 279-81.  IF: 1.231. Cartoafa M, Agustí MA. Beta-blocking agents in the perioperative period of the non-cardiac surgery. Med Clin (Barc) 2010 Apr 24; 134 (12): 544-6.  IF: 1.231. Castells X, Casas M, Pérez-Mana C, Roncero C, Vidal X, Capella D. Efficacy of psychostimulant drugs for cocaine dependence. Cochrane Database Syst Rev 2010 Feb 17; 2 : CD007380.  IF: 5.653.

Cereza G, Agustí A, Pedros C, Vallano A, Aguilera C, Danés I, Vidal X, Arnau JM. Effect of an intervention on the features of adverse drug reactions spontaneously reported in a hospital. Eur J Clin Pharmacol 2010 Sep; 66 (9): 937-45.  IF: 2.743. Duran M, Pérez E, Abanades S, Vidal X, Saura C, Majem M, Arriola E, Rabanal M, Pastor A, Farré M, Rams N, Laporte JR, Capella D. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol 2010 Nov; 70 (5): 656-63. doi: 10.1111/j.13652125.2010.03743.x.  IF: 3.246. Hereu P, Pérez E, Fuentes I, Vidal X, Suñé P, Arnau JM. Consent in clinical trials: What do patients know? Contemp Clin Trials 2010 Sep; 31 (5): 443-6.  IF: 1.506.

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Ruiz-Antorán B, Agustí Escasany A, Vallano Ferraz A, Danés Carreras I, Riba N, Mateu Escudero S, Costa J, Sánchez Santiago MB, Laredo L, Duran Quintana JA, Castillo JR, Abad-Santos F, Payares Herrera C, Sadaba Díaz de Rada , Gómez Ontanón E. Use of non-specific intravenous human immunoglobulins in Spanish hospitals; need for a hospital protocol. Eur J Clin Pharmacol 2010 Jun; 66 (6): 633-41.  IF: 2.743. Secoli SR, Figueras A, Lebrao ML, Lima FD de, Santos JL. Risk of potential drug-drug interactions among Brazilian elderly: a population-based, cross-sectional study. Drugs Aging 2010 Sep 1; 27 (9): 759-70. doi: 10.2165/11538460-000000000-00000.  IF: 2.209.

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AREA T1 EPIDEMIOLOGY, PHARMACOLOGY, NEW THERAPIES, CLINICAL RESEARCH

T1.3 Epidemiology and Public Health (EPIDEM) Group Leader Josep Vaqué Rafart Tel. 93 489 42 10 [email protected] Researchers Lluis Armadans Gil Magda Campins Martí José Rosselló Urgell Josep Vaqué Rafart Researcher in Training Susana Otero Romero Nursing, Technical and Administrative Staff Maria Elena Ballarín Alins Eduard Hermosilla Pérez Eva María López Guerrero Santiago Pérez Hoyos

OBJECTIVES

RESEARCH LINES

Expand research on hospital epidemiology, preventive vaccines, health services and public health.

Nosocomial infections epidemiology Josep Vaqué Rafart Studying the evolution, features, host and healthcare-associated factors and impact of these infections.

Preventive vaccines Magda Campins Martí Developing studies on the effectiveness and characteristics of use of preventive vaccines in hospital and community contexts.

22010 Impact Factor:

42.287

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Figure 98 Distribution of confirmed cases of influenzavirus A (H1N1) which were seen at Hospital Universitari Vall d’Hebron, from 2nd July, 2009 until 22nd January, 2010

CURRENT RESEARCH PROJECTS PREVALENCIA DE PACIENTES CON INFECCIÓ INFECCIÓN NOSOCOMIAL ESPAÑ ESPAÑA. Estudio EPINE 19901990-2010 2010: 287 hospitales participantes Prevalencia % 10 8,5 7,8 8

7,3

7,1 7,2

6,9

7,2

6,9

6,7

6,9 6,9

6,7 6,7

6,5 6,5

6,9 6,8

7

7

6,8 6,7

PI: Josep Vaqué Rafart Estudio de la efectividad de la vacunación antigripal en la reducción del riesgo de muerte y hospitalizaciones en los ancianos Funding Agency: Fondo de Investigación Sanitaria Reference: PI070560 Funding: 63,525 € Duration: 2008 to 2010

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Figure 99 Evolution of prevalence of patients with nosocomial infection in Spain, EPINE Study 1990-2010

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PUBLICATIONS (Impact Factor: 42.287) Brotons M, Campins M, Méndez L, Juste C, Rodrigo JA, Martínez X, Hermosilla E, Pinos L, Vaqué J. Effectiveness of varicella vaccines as postexposure prophylaxis. Pediatr Infect Dis J 2010 Jan; 29 (1): 10-3.  IF: 2.854. Felip E, Rosell R, Maestre JA, RodríguezPaniagua J, Morán T, Astudillo J, Alonso G, Borro JM, González-Larriba JL, Torres A, Camps C, Guijarro R, Isla D, Aguiló R, Alberola V, Padilla J, Sánchez-Palencia A, Sánchez JJ, Hermosilla E, Massuti B. Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non-SmallCell Lung Cancer. J Clin Oncol 2010 Jul 1; 28 (19): 3138-45.  IF: 17.793. Frick MA, Moraga-Llop FA, Bartolomé RM, Larrosa N, Campins M, Román Y, Vindel A, Figueras C. Community-acquired methicillin-resistant Staphylococcus aureus infections in children. Enferm Infecc Microbiol Clin 2010 Jul 31.  IF: 1.393.

López-Cano M, Manas MJ, Hermosilla E, Espín E. Multivisceral Resection for Colon Cancer: Analysis of Prognostic Factors. Dig Surg 2010 Aug; 27 (3): 238-45.  IF: 1.372. Otero S, Batlle J, Bonaventura I, Brieva L, Bufill E, Cano A, Carmona O, Escartín A, Marco M, Moral E, Munteis E, Nos C, Pericot I, Perkal H, Ramio-Torrenta L, SastreGarriga J, Tintoré M, Vaqué J, Montalban X, Pérez-Miralles F, et al. Multiple sclerosis epidemiological situation update: pertinence and set-up of a population based registry of new cases in Catalonia. Rev Neurol 2010 May 16; 50 (10): 623-33.  IF: 1.234. Selva-O’Callaghan A, Fonollosa-Pla V, Trallero-Araguas E, Martínez-Gómez X, SimeónAznar CP, Labrador-Horrillo M, VilardellTarrés M. Nailfold capillary microscopy in adults with inflammatory myopathy. Semin Arthritis Rheum 2010 Apr; 39 (5): 398-404.  IF: 4.724.

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Selva-O’Callaghan A, Grau JM, Gámez-Cenzano C, Vidaller-Palacín A, Martínez-Gómez X, Trallero-Araguas E, Andia-Navarro E, Vilardell-Tarrés M. Conventional cancer screening versus PET/CT in dermatomyositis/polymyositis. Am J Med 2010 Jun; 123 (6): 558-62.  IF: 4.466. Trallero-Araguas E, Labrador-Horrillo M, Selva-O’Callaghan A, Martínez MA, Martínez-Gómez X, Palou E, Rodríguez-Sánchez JL, Vilardell-Tarrés M. Cancer-associated myositis and anti-p155 autoantibody in a series of 85 patients with idiopathic inflammatory myopathy. Medicine (Baltimore) 2010 Jan; 89 (1): 7-52.  IF: 5.054. Vaqué J. Epidemiology of influenza A (H1N1) worldwide and in Spain. Arch Bronconeumol 2010; 46S2: 3-12.  IF: 2.166. Vilca Yengle LM, Campins Martí M, Cabero Roura L, Rodrigo Pendas JA, Martínez Gómez X, Hermosilla Pérez E, Vaqué Rafart J. Influenza vaccination in pregnant women. Coverage, practices and knowledge among obstetricians. Med Clin (Barc) 2010 Feb 13; 134 (4): 146-151.  IF: 1.231.

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AREA T1 EPIDEMIOLOGY, PHARMACOLOGY, NEW THERAPIES, CLINICAL RESEARCH

T1.4 Molecular Diagnosis and Therapy

Group Leader Francisco Vidal Pérez Tel. 93 274 67 26 [email protected] Researchers Lluis Martorell Cedres Francisco Vidal Pérez Researcher in Training Irene Corrales Insa Nursing, Technical and Administrative Staff Lorena Ramírez Orihuela

OBJECTIVES Since its foundation in 1998 the Molecular Diagnosis and Therapy Unit (UDTM) of the Blood and Tissue Bank, has had a dual character providing-diagnostic support in congenital coagulation disorders as well as other hereditary diseases and research and development into new approaches in the field of medical diagnostics and therapeutics. In addition an important part of the current objectives are innovation in technological tools and their transfer to the laborato-

RESEARCH LINES ry routine. The research activity of the UDTM is linked to its commitment to the Hemophilia Unit of Vall d’Hebron Hospital (reference centre for congenital coagulopathies in Catalonia) in the development of molecular protocols applicable to genetic counselling, prenatal and preimplantation diagnosis. In- depth studies of the molecular events discovered in some affected individuals and the genotype-phenotype relationship constitute the most basic area of the team’s goals.

Identification of the mutations responsible for hemophilia A and B in the Spanish population. Applications to therapeutic orientation, genetic counseling, prenatal and preimplantation diagnosis Francisco Vidal Pérez

Molecular diagnosis of von Willebrand disease: study of genotypephenotype relationship and application to clinical diagnosis Francisco Vidal Pérez

Establishment of protocols and genetic study of the rare monogenic bleeding disorders: FXI deficiency, FXIII deficiency, combined deficit of FV and FVIII, FVII deficiency, the genetic platelet disorder Glanzmann’s thrombasthenia, etc. Francisco Vidal Pérez

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Figure 100 Home page of the website Hemobase (http://www.hemobase.com). Devoted to Hemophila and von Willebrand disease (VWD), it includes the first registry of mutations characterized from patients in the Spanish population. It is a dynamic registry with constant updates. General facts on coagulopathies, the classification, clinical features and diagnostic difficulties as well as biochemical and molecular characteristics of genes are also included. Design, development and maintenance of the website is carried out directly by the research team. The Hemobase website is recognized and linked, among others, by the NCBI and the Orphaned registries as locus specific mutation databases for the F8, F9 and VWF genes

Exploring alternatives for the recombinant human factor VIII production by means of novel yeast expression systems Francisco Vidal Pérez

CURRENT RESEARCH PROJECTS

PUBLICATIONS

PI: Francisco Vidal Pérez Aplicación de tecnologías optimizadas al diagnóstico molecular de la enfermedad de Von Willebrand: Análisis de la heterogeneidad genética Funding Agency: Fondo de Investigación Sanitaria Reference: PI080385 Funding: 91,113 € Duration: 2009 to 2011

Corrales I, Ramírez L, Ayats J, Altisent C, Parra R, Vidal F. Integration of molecular and clinical data of 40 unrelated von Willebrand Disease families in a Spanish locusspecific mutation database: first release including 58 mutations. Haematologica 2010 Nov; 95 (11): 1982-4.

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Ramírez L, Altisent C, Parra R, Vidal F. The ‘royal disease’ mutation in a Spanish patient. J Thromb Haemost 2010 Oct; 8 (10): 2316-7.

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AREA T2 NANOMEDICINE

Molecular Biology and Biochemistry Research Center for Nanomedicine (CIBBIM-Nanomedicine)

Director Simón Schwartz Riera Tel. 93 489 40 60 [email protected] Coordinator Simó Schwartz Jr. Secretary Direction Montserrat Capella Tomás Silvia Vellosillo Almajano Laboratory Monitoring Isabel Mougan Albela

The CIBBIM was created in 1995 as the result of a joint effort by several scientists from different fields of research, surgeons and clinicians, in which the complementation of their respective expertises ensure the achievement of higher goals and top quality standards. In 2007 the CIBBIM opened a new and very successful Nanomedicine Research Program which allowed the center to get involved in several national and International nanomedicine research networks and industrial partnerships. As a consequence, the CIBBIM re-oriented its main research purpose and goals towards the fast-emerging field of nanomedicine and nanotechnology in biomedicine and became the new CIBBIM-Nanomedicine.

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The research effort of CIBBIMNanomedicine has been focused on two main fields, nanodiagnosis and nanotherapy. The final mission of the CIBBIM-Nanomedicine is to foster basic research on biomarker discovery and new therapeutic agents, as well as to provide the industry and other research groups with the optimal technology for preclinical validation of new nanomedicines. The center is now organized in three interconnected experimental areas covering different aspects of nanomedicine research and biomedical applications: i) Biomarkers and Therapeutics Targets, ii) Experimental Chemistry and Applied Nanotechnology and iii) Functional Validation and Preclinical Studies

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AREA 1

AREA 2

AREA 3

Biomarkers and Therapeutic Targets

Experimental Chemistry and Applied Nanotechnology

Functional Validation and Preclinical Research

Obtention of new disease specific biomarkers is a must to achieve success in “nanodiagnostics”, as well as in “targeted delivery”. There is an increasingly growing need for them to confront several diseases and clinical conditions (i.e. markers for treatment response, immune system activation or disease stratification). These biomarkers are also essential for developing targeting strategies needed to biofunctionalyze nanoparticles against them to deliver traceable particles (imaging) and therapeutic drugs (drug delivery). Research Groups:

This is a new area, which currently focuses on the development of its own biodegradable polymers (based on polyglutamic acid) for drug delivery. The study of nanomedicines of polymeric nature is more easily affordable from the view of chemical synthesis and has a promising potential, not just for the delivery of conventional drugs, but also for genomic therapies (iRNA). It is also worth mentioning that these polymers are completely biodegradable and have been proved to be non-toxic in in vivo approaches. We also collaborate with external groups on the design and validation of nanoparticles of alternative natures, such as dendrimers, liposomes, silica nanoparticles, carbon nanotubes or magnetic nanoparticles.

Besides providing the field with top scientific research on biomarker discovery and new therapeutic targets, one additional aim of CIBBIM Nanomedicine is to provide the Industry and other research groups with an optimal in vitro and in vivo validation platforms for “proof of concept” demonstrations and initial preclinical studies of new nanotechnological based approaches. To this end this area is formed by two technological platforms, one for in vitro analyses (In vitro Experimental Platform), and another for those studies requiring animal experimentation (In vivo Experimental Platform).

• Drug Delivery and Targeting • Molecular Oncology • Immunobiology • Cellular Physiopathology and Lisosomal Diseases • Renal Physiopathology • Neuromuscular and Mitochondrial Diseases

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• Basic Aging Research

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AREA T2 NANOMEDICINE

CIBBIM-Nanomedicine

T2.1 Drug Delivery and Targeting Group Leader Simó Schwartz Navarro Tel. 93 489 40 60 [email protected] Researchers Ibane Abasolo Olaortua Manuel Armengol Carrasco Eloy Espín Basany Yolanda Fernández Amurgo Manuel López Cano Simó Schwartz Navarro Simó Schwartz Riera Researchers in Training José Higinio Dopeso González Lucía Lima Correia Helena Plà Solans Yuko Saruta Nursing, Technical and Administrative Staff Josefa Argadoña Escribano Montse Capella Tomás Laura García Latorre Natalia García Aranda Mª Eugenia López Sánchez Sonia Miranda Blázquez Isabel Mougan Albela Anna Pujol Esclusa Ramon Roca Puig

OBJECTIVES

RESEARCH LINES

The Drug Delivery and Targeting group has two main goals; first, the identification of new disease biomarkers and therapeutic targets, with special focus on cancer molecular pathways; second, the development of new delivery strategies in applied nanomedicine, with a particular interest in new delivery and targeting approaches for clinical applications.

Identification of new disease biomarkers and therapeutic targets There are several research lines dedicated to the study of oncogenic molecular pathways related with: i)

Genomic and microsatellite instability in gastrointestinal tumors;

ii) Condensin complexes in colorectal tumorigenesis, iii) Molecular alterations caused by defects in the DNA repair system (basically, mismatch repair –MMR- pathway and repair of double strand breaks –DSB-)

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and their relationship with tumor resistance to chemotherapy, and iv) Identification and validation of new biomarkers and therapeutic targets by means of highthroughput screening (HTS).

Genomic and microsatellite instability in gastrointestinal tumors Simó Schwartz Navarro This project aims to explain the striking contrast in survival and metastatic capacity between chromosomal instable (CIN, 85% incidence), and microsatellite instable (MSI, 15% incidence) colorectal carcinomas, of the different aggressiveness among tumors bearing diverse K-ras point mutants, and of the distinct mutational selectivity of the K-ras and B-raf oncogenes. To that purpose, whole-body optical imaging will be used to perform a longitudinal analysis of metastatic dissemination, as well as an evaluation of the requirement for K-ras and/or B-raf oncogene expression in maintaining metastatic foci growth. This model will allow the dissection of the molecular path-

ways activated by B-raf and K-ras mutants, as well as the transition from dormant micrometastases to expansive metastases at the different target sites.

Condensin complexes in colorectal tumorigenesis Simó Schwartz Navarro We focus on the involvement of chromatin remodelling and chromosomal condensation complexes and protein partners in the development of colorectal tumors and cancer progression. We also address functional studies related to the involvement of these complexes in gene transcriptional regulation and their interactions with DNA repair complexes and the histone code.

DNA repair system and tumor resistance to chemotherapy Simó Schwartz Navarro This research line focuses on the identification of new signal transducers involved in DNA damage control pathways which are the main responsible of controlling cell death and repair mechanisms. We are also studying their altera-

tions and biological involvement in tumor cell development and metastasis spread, together with the consequences excerted at the level of tumor treatment response to classical and non-classical chemotherapy. Validation of new checkpoint targets are also done in C. elegans models by using hydroxylurea treatments and specific transgenic mutants and siRNA of target genes.

Applied Nanomedicine: new drug delivery and targeting strategies for biomedical applications We focus on new targeting strategies to ensure a specific delivery of therapeutic compounds into the most appropriate target cell to improve treatment response and achieve lower toxicity and higher therapeutic activities in several human diseases, with particular interest in delivery of chemotherapeutic drugs to cancer cells and enzyme replacement therapies for rare diseases. In addition, alternative targeting strategies are being designed to improve imaging-based diagnostics by using

Figure 101 Par-5 inactivation disrupts HU-induced cell cycle arrest. Staged Wild Type (N2) or par -5 mutant (it55) young adults were treated with Hydroxyurea (HU) (replication inhibitor during 24 h at 20ºC. After the treatment the gonads were dissected and DAPI stained to conunt the cell number in the mitotic region of the germline. The images on the left show representative mitotic regions used for the counting. in WT worms HU induces a cell cycle arrest that can be observed as a decrease in the number of germ cells comparing with the untreated (–HU). Par-5 mutation significantly compromise this checkpoint-induced arrest, suggesting a role of these gene in the DNA damage response pathway

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new cell-targeted nanoconjugates. Some of the projects explained bellow are developed in collaboration with other groups at CIBERBBN (Centro de Investigaciones en Red en Biomateriales, Bioingenería y Nanomedicina, Instituto de Salud Carlos III) or within specific European consortiums.

Enzyme replacement therapy for storage diseases: new therapeutic strategies Simó Schwartz Navarro Fabry disease is an X-linked recessive disorder caused by a deficiency of lysosomal hydrolase -galactosidase A (GLA). This enzymatic defect causes the progressive cellular accumulation of neutral glycosphingolipids, giving rise to a multisystemic clinical symptomatology. Current enzyme replacement therapy (ERT) has a limited treatment efficacy in patients with advanced stages of the disease. The objective of this research line is to improve the ERT by using new therapeutic compounds (nanoparticles or specifically designed

proteins) of GLA targeted to the endothelial cells, one of the main cell type affected by GLA substrate accumulation. In addition, we also collaborate in a project focused on the validation of new integrated, multi-host approaches for the improved microbial production of high quality GLA enzymes for industrial purposes (IMAPPROT).

NANOSTEM: Targeting Combined Therapy to Cancer Stem Cells Simó Schwartz Navarro In many solid tumors, resistance to therapy and metastatic disease seem to be sustained by the presence within the tumors of cancer stem cells (CSC) capable of regenerating a tumor after chemotherapy and/or radiation treatment. In breast cancer, these cells correspond to a small fraction of cells within the tumor that express stem cell markers (CD44+/ CD24-/low/lin-) which provides a useful target to the delivery of therapeutic agents to CSC. In this network project some of the partners will focus on the design of

specific vehicles for the simultaneous delivery of chemotherapeutic drugs and/or shRNAs with known antitumor activity on breast CSC. To this end, different types of nanoparticles will be directed at the CSC compartment by using the CD44 receptor as a target. Such systems will allow specific CSCtargeting, and together with enhanced retention, a permeability effect (EPR) will improve accumulation of drugs in the tumor area and should yield a better therapeutic response. At CIBBIM-Nanomedicine, therapeutic activity, nanoparticle internalization and toxicology of these nanoparticulated systems will be addressed by using adequate in vitro and in vivo CSC models.

ONCONANOTARGET: Advancing the field of drug delivery - combined targeted treatments against human breast cancer and human leukemia Simó Schwartz Navarro The idea of the ONCONANOTARGET Network is to selectively abrogate tumour-protective functions aiming at either improving sensitivity of tumor cells to chemotherapy or finding synergistic combinations that may improve the clinical outcome for the treatment of breast cancer or leukaemia patients. Therefore, the main objectives of this project are: • To design and characterise ligand-targeted nanosystems for nucleic acid (siRNA) and drug delivery.

Figure 102 Condensin interactors. Expression and its sensitivity to camptothecin. A. Condensin-interactor was found to be overexpressed in 24 out of 48 colorectal cancer (CRC) samples analyzed by expression microarrays. B. protein expression was further confirmed by Western Blot analysis in a panel of CRC cell lines. C. Furthermore, camptothecin (CPT), a drug commonly used in the treatment of CRC, increased the expression of the protein in HeLa cells, suggesting that this interactor could be used as a response prediction factor for CPT treatments

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• To compare, in vitro, the genesilencing efficiency of the developed targeted lipid-based or polymeric-based nanosized systems containing nucleic acids against Bcl-2 oncogene in breast cancer leukaemia and cells. • To evaluate the cytotoxic activity of individual treatments with ei-

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ther gene silencing with targeted system previously selected or targeted polymer-anticancer drug conjugate as compared to combined treatments (targeted gene silencing combined with targeted polymer-anticancer drug conjugates) against leukaemia and breast tumour cells, and

CURRENT RESEARCH PROJECTS • Therapeutic evaluation of the treatment modality previously selected in an animal model of human breast cancer. In this project, in vivo proof of concept will be limited to breast cancer.

Treatment of advanced colorectal cancer by novel drug delivery systems, sensitive to metalloproteinases Simó Schwartz Navarro Current chemotherapeutic treatment for colorectal cancer implies the use of high doses of cytotoxic medications, specifically adjuvant combinations of 5-fluorouracil and Irinotecan, which cause the affected patient many adverse effects. This project proposes a program centred on the development of new nanomedicines, based on polymers of multifunctional character that bring together different chemotherapeutic agents, allowing a combined double or triple therapy using much lower systemic doses and significantly reducing undesirable side-effects. In this case, we will focus on increasing these advantages with the utilization of synthetic peptides sensitive to degradation by matrix metalloproteases (MMP), which will bind the polymeric nanocarrier to the chemotherapeutic drug. The activity of MMPs favours the liberation of the drug and its activity in MMP rich environments, such as primary tumors and metastatic sites. The project includes the processes of synthesis, chemical characterization and optimization of nanomedicines, as well as their in vitro and in vivo validation.

IP: Manuel Armengol Carrasco Cambios en las características del tejido conectivo abdominal de pacientes con hernia incisional. Activación de fibroblastos. Integración a biomateriales blandos. Funding Agency: Fondo de Investigación Sanitaria Reference: PI070507 Funding: 73,205 € Duration: 2008 to 2010

PI: Julian Cerón Madrigal Modelling cancer in Caenorhabditis elegans. GRANT number 206584MIRG-CT-2007-206584 Funding Agency: European Commission Reference: CANCEROMICS-206584 Funding: 100,000 € Duration: 2007 to 2011

PI: Simó Schwartz Navarro Activación de vías dependientes del oncogén BRAF en la tumorogénesis y metástasis del cáncer colorectal en modelos in vivo Funding Agency: Fondo de Investigación Sanitaria Reference: PI080771 Funding: 219,252 € Duration: 2009 to 2011

PI: Simó Schwartz Navarro Integrated approach for the improved microbial production of high quality therapeutic enzymes (IMAPPROT) Funding Agency: Ministerio de Ciencia e Innovación Reference: EUI2008-03741 Funding: 164,000 € Duration: 2009 to 2012

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PI: Simó Schwartz Navarro Advancing on drug delivery-combined targeted treatments against human breast cancer and Leukemia (Oncotarget/Nano) Funding Agency: Ministerio de Ciencia e Innovación Reference: EUI2008-0170 Funding: 28,300 € Duration: 2009 to 2011

PI: Ibane Abasolo Olaortua POLYSFERA: Nanocápsulas poliméricas para liberación controlada y dirigida de fármacos antitumorales Funding Agency: Ministerio de Ciencia e Innovación Reference: IPT-090000-2010-0001 Funding: 505,955 € Duration: 2010 to 2013

PI: Manuel López Cano Development of a robotic manipulator of human tubular tissues for suture and support in anastomosis surgery interventions Funding Agency: European Commission Reference: ECHORD-231143 Funding: 52,181.74 € Duration: 2010 to 2014

PI: Simó Schwartz Navarro Direccionament i alliberament farmacològic Funding Agency: AGAUR Reference: 2009 SGR 758 Funding: 43,680 € Duration: 2010 to 2013

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PUBLICATIONS (Impact Factor: 49.014) PI: Simó Schwartz Navarro Nanostem (targeting combined therapy to cancer stem cells) Funding Agency: Euronanomed Funding: 1.8 M € for the partners: 3 academic and 1 SME Duration: 2009 to 2011

PI: Simó Schwartz Navarro Funding for Research Groups of Excellence (2009SGR 758) Funding Agency: AGAUR. Dept of science and universities. Catalonia Funding: 44.720 € Duration: 2010 to 2013

CIBER-BBN Projects Targeting combined therapy to cancer stem cells (NANOTEMNESS)

Development of a nanoparticles as vehicles for the treatment of metastatic colorectal cancer (NANOCOMETS)

Bacterially produced nanopills, dor a novel, protein-based cancer therapy (NANOPILLS)

Dopeso H, Mateo-Lozano S, Elez E, Landolfi S, Ramos Pascual FJ, Hernández-Losa J, Mazzolini R, Rodrigues P, Bazzocco S, Carreras MJ, Espín E, Armengol M, Wilson AJ, Mariadason JM, Ramon y Cajal S, Tabernero J, Schwartz S Jr, Arango D. Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. Clin Cancer Res 2010 Apr 15; 16 (8): 237582.  IF: 6.747. López-Cano M, Manas MJ, Hermosilla E, Espín E. Multivisceral Resection for Colon Cancer: Analysis of Prognostic Factors. Dig Surg 2010 Aug; 27 (3): 238-45.  IF: 1.372. Manchon Walsh P, Borrás JM, Ferro T, Espinás JA, Alfaro J, Arnau JM, Artigas V, Aunon MC, Barrios P, Bellmunt J, Biondo S, Bolibar I, Cambray M, Canals E, Caro M, Casado E, Castells A, Companys A, Darnell A, Torres IM de, Espín E, Estévez M, Figueras J, Gallén M, González D, Lema L, Losa F, Lloreta J, Macías V, Marcuello E, Manzano JL, Martin-Richard M, Maurel J, Membrive I, Mira M, Moreno de Vega V, Murio JE, Panadés A, Pericay C, Pujol J, Queralt B, Ramos E, Reig A, Roca JM, Rodríguez F, Saigi E, Salas A, Salazar R, Sanjuan X, Serra X, Solé JM, Tabernero J, Targarona EM, Torras J. Colorectal Cancer OncoGuia. Clin Transl Oncol 2010 Mar; 12 (3): 188-211.  IF: 1.146. Martínez-Barriocanal, Comas-Casellas E, Schwartz S, Martín M, Sayos J. CD300 heterocomplexes, a new and family-restricted mechanism for myeloid cell signaling regulation. J Biol Chem 2010 Dec 31; 285 (53): 41781-94.  IF: 5.328.

Improving diagnosis, prognosis and therapy response in human glioma. Preclinical and translational studies (PROGLIO)

New orthotopic/ectopic nude mice model of human thyroid undifferentiated/analplastic carcinoma: useful tool for new cell-therapies, drug testing and validation in humans (CELL-NANO_THYROID)

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Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, Fernández AF, Dávalos V, Villanueva A, Montoya G, Yamamoto H, Schwartz S Jr, Esteller M. A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. Cancer Cell 2010 Oct 19; 18 (4): 303-15.  IF: 25.288. Sanjuan X, Salas A, Lloreta J, Manchon Walsh P, Alfaro J, Arnau JM, Artigas V, Aunon MC, Barrios P, Bellmunt J, Biondo S, Bolibar I, Cambray M, Canals E, Caro M, Casado E, Castells A, Companys A, Darnell A, Torres IM de, Espín E, Estévez M, Figueras J, Gallen M, Gonzalez D, Lema L, Losa F, Lloreta J, Macias V, Marcuello E, Manzano JL, Martin-Richard M, Maurel J, Membrive I, Mira M, Moreno de Vega V, Murio JE, Panadés A, Pericay C, Pujol J, Queralt B, Ramos E, Reig A, Roca JM, Rodríguez F, Saigi E, Salas A, Salazar R, Sanjuan X, Serra X, Solé JM, Tabernero J, Targarona EM, Torras J. Colorectal Cancer OncoGuia: surgical pathology report guidelines. Clin Transl Oncol 2010 Mar; 12 (3): 211-214.  IF: 1.146. Velho S, Oliveira C, Paredes J, Sousa S, Leite M, Matos P, Milanezi F, Ribeiro AS, Mendes N, Licastro D, Karhu A, Oliveira MJ, Ligtenberg M, Hamelin R, Carneiro F, Lindblom A, Peltomaki P, Castedo S, Schwartz S Jr, Jordan P, Aaltonen LA, Hofstra RM, Suriano G, Stupka E, Fialho AM, Seruca R. Mixed lineage kinase 3 gene mutations in mismatch repair deficient gastrointestinal tumours. Hum Mol Genet 2010 Feb 15; 19 (4): 697-706.  IF: 7.386. Vilallonga R, Stoica RA, Cotirlet A, Armengol M, Iordache N. Single incision laparoscopic surgery (SILS) cholecystectomy. A novel technique. Chirurgia (Bucur) 2010 Mar-Apr; 105 (2): 239-41.  IF: 0.601.

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AREA T2 NANOMEDICINE

CIBBIM-Nanomedicine

T2.2 Molecular Oncology Group Leader Diego Arango Corro Tel. 93 274 67 39 [email protected] Researchers Hafid Alazzouzi Silvia Mateo Lozano Researchers in Training Sarah Bazzocco Paulo André Gonçalves Rodrigues Rocco Mazzolini Erica Serrano Barbero

OBJECTIVES

RESEARCH LINES

The main interest of our Laboratory is the study of molecular events underlying the oncogenic process, especially in colorectal cancer. Colorectal cancer is the second leading cause of cancer related deaths in the western world. In 2004 colorectal cancer accounted for approximately 13% of all cancer cases and cancer-related deaths in the European Union, with over 375,000 new cases and

more than 200,000 deaths due to this disease. Understanding of the molecular mechanisms underlying the tumorigenic process is a key step that will allow the identification of new prognostic markers, response to therapy and therapeutic targets. These in turn will lead to an improvement of the survival and quality of life of a large number of patients with colorectal cancer.

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Identification of new prognostic markers and response to treatment for colorectal cancer patients Diego Arango Corro Colorectal cancer is the second leading cause of cancer related deaths in the western world and represents a serious health concern. To put the magnitude of the problem posed by colorectal cancer in perspective it is important to highlight that approximately one in 17 EU citizens will develop malignant tumors in their colon or rectum in the course of their lifetime. Patients diagnosed with early stage (I and II) tumors have a good prognosis (more than 80% have a survival rate of 5 years). However, the majority of patients

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Figure 103 Aprataxin tumor levels and survival of patients with advanced colorectal cancer receiving irinotecan-based treatment. Immunohistochemical staining of colorectal tumors demonstrates a gradient of expression, with some tumors having no detectable Aprataxin (A), high levels (D) or intermediate levels of expression (B-C). Progression-free (E) and overall survival (F) protein levels according to Aprataxin are shown (Kaplan-Meier plots). Log-rank p-values are shown

have advanced disease (stage III or IV) at the moment of their initial diagnosis and the 5-year survival rates for these patients’ ranges from 40% to less than 5%. There is, therefore, great need to improve the treatment of these patients. We use high throughput techniques to find new markers that when used alone or in combination with other markers, can be used to discriminate between patients that have high and low probability of recurrence after treatment. We then follow up these experiments using in vitro and in vivo experiments to investigate the functional relevance of these new markers for colorectal cancer initiation and progression.

Role of EPH signaling in cancer Diego Arango Corro EPH receptors are the largest family of tyrosine kinases receptor (RTKs) proteins, which play a crucial role in many biological processes such as embryonic development, cell proliferation and differentiation. The first member of the EPH family was identified and cloned in 1987 by Hirai et al. from an Erytropoietin Producing Hepatocellular carcinoma cell line (EPH). To date, 16 receptors (14 found in mammals) and 9 ligands (8 in mammals) have been described. EPH receptors and ephrins (ligands) are implicated in a great variety of processes such as regulation of cell proliferation, migration, cell attachment and shape, axon guidance and synaptic plasticity.

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EPH receptors play important roles in tumorigenesis and metastasis and high levels of EPH have been related to angiogenesis in many tumor types including breast and lung. Although overexpression of EPHB2 is observed in some tumor types, in gastrointestinal cancers, low levels of EPHB2 expression have been reported and found to be significantly associated with advance disease stage and poor survival (Lugli et al., 2005). In colorectal carcinoma (CRC), a progressive reduction in EPHB2 levels has been reported in the progression from normal epithelial cells to benign adenomas and to low and high stage tumors as well as lymph node and liver metastases, demonstrating a clear tendency to decreasing EPHB2

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levels as CRC progresses towards a more aggressive and metastatic phenotype. The loss of EPHB2 expression is also significantly associated with poor tumor differentiation and shorter patient survival. We have made some contributions towards increasing our understanding of the mechanisms responsible for this EPHB2 downregulation in CRC (Alazzouzi et al. 2005 Cancer Res 65:10170; Dávalos et al. 2007 Oncogene 26:308). Similarly, EPHB4 expression in cancer is up- or down-regulated depending on the tumor type. A drastic increase of EPHB4 protein has been observed in endometrial hyperplasias and carcinomas, sug-

gesting EPHB4 as an early indicator of malignant development. Moreover, EPHB4 overexpression has been associated with high histological grade and certain clinical stages in endometrial cancer. An increase in breast carcinoma has been also reported and high levels of EPHB4 correlated with histological grade and stage. In addition, strategies to block EPHB4 expression, both using siRNA and antisense led to dose-dependent reduction in cell survival and increased apoptosis in breast. In the normal colonic mucosa, we revealed a gradient of EPHB4 expression from the lower crypt to the colonic flat mucosa, and a

substantial variability of EPHB4 expression in colorectal tumors from complete lack of immunoreactivity to very high levels of expression (Dávalos et al. 2006 Cancer Res 66:8943). Furthermore, our group has shown that low EPHB4 tumor levels identify a subset of colorectal cancer patients with poor prognosis and high risk of recurrence, and demonstrated that promoter hypermethylation was a common mechanism associated with the loss of EPHB4 expression. Moreover, reintroduction of EPHB4 into EPHB4-deficient tumor cells significantly reduced their long-term clonogenic potential, which taken together have contributed to es-

Figure 104 MYO1A A8->A7 mutations affect the localization of the protein and the polarization of colon cancer cells. A-C) Co-transfection of wild type EGFP-MYO1Awt and mutant ERFP-MYO1AA7MUT demonstrated that the mutant protein mislocalized to the cytoplasm of undifferentiated Caco2 cells. Panels D-I show an orthogonal view of differentiated Caco2BBe cells. Alexa 568 labeled Phalloidin was used to visualize F-actin. Wild type MYO1A EGFP-tailwt showed membrane localization (D-F) compared to the cytoplasmic localization of mutant MYO1A EGFP-tailA7MUT (G-I). F-actin was reduced in the apical membrane of MYO1A EGFP-tailA7MUT-expressing cells (G; white arrow head). ZO-1 immunostaining demonstrated that MYO1A EGFP-tailA7MUT-expressing Caco2BBe cells exhibit loss of tight junctional integrity (Z-axis stack; J-K). The inset shows higher magnification of the indicated areas demonstrating loss of ZO-1 membrane staining in EGFP-TailA7MUT transfected cells. Induction of LKB1/STK11 expression resulted in the polarization of most LS174T-W4 cells characterized by the apical accumulation of actin within 24h (white arrowheads in L and M). The number of polarized cells 24h after LKB1/STK11 activation was significantly reduced following transfection of either mutant EGFP-MYO1AA7MUT (L; mean ± SE; Student’s t-test, p=0.03) or co-transfection of EGFP and shMYO1A (M; mean ± SE; Student’s t-test, p=0.01), compared to the corresponding pEGFP-C3 empty vector, EGFPMYO1AWT and non-target shRNA (shNT) controls. Rhodamine-Phalloidin was used to visualize F-actin (red). White arrows show un-polarized transfected cells. The average (±SE) of 3 independent experiments is shown

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tablish EPHB4 as a new putative tumor suppressor gene, and a useful prognostic marker in colorectal cancer (Dávalos et al. 2006 Cancer Res 66:8943).

Identification of new genetic and epigenetic causes predisposing to colorectal cancer Diego Arango Corro A significant proportion of colorectal cancers are hereditary. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) and Familial Adenomatous Polyposis (FAP) are the two most common forms of

hereditary predisposition to colorectal cancer. FAP is characterized by the presence of hundreds to thousands of adenomatous polyps in the colon and rectum of affected individuals and would lead to colorectal cancer in virtually all the patients if left untreated. An attenuated form of FAP (AFAP) is characterized by a reduced number of polyps compared to classical FAP and a later age of onset. Together, FAP and AFAP affect up to 1 in 5,000 individuals. Inherited mutation or deletion of one allele of the adenomatous polyposis coli (APC)

gene is responsible for 80% of FAP or AFAP cases. A small proportion of FAP/AFAP individuals that do not have germline mutations in APC carry homozygous mutations in the gene MutY homolog (MUTYH). However, the underlying genetic cause of FAP/AFAP is not known for approximately 20% of affected families. Precise identification of the genetic cause of this condition has a profound impact on the management of FAP/AFAP family members, and there is therefore an acute need to identify new genetic abnormalities that could be responsible for a significant number of these adenomatous polyposis syndromes in APC/MUTYH mutation negative families. We are actively investigating new genetic and epigenetic causes of colorectal cancer predisposition, both to FAP and HNPCC.

Role of small GTPAses in colorectal cancer Diego Arango Corro RhoA is a member of the small GTPase family that regulates cytoskeletal remodeling, protein and lipid trafficking, transcriptional activation and cell growth. We have recently demonstrated that patients whose tumors have low levels of RhoA have a significantly worse prognosis than patients with high RhoA tumor levels (Arango et al., 2005). The membrane-bound small GTPase RAS was one of the first oncogenes to be identified (Sukumar et al., 1983). Activating mutations in KRAS have been found in more than one third of the human tumors of the colon and rectum (Oliveira et al., 2004), highlighting the importance of this protein in promoting tumor initiation and progression. The role of RhoA and other members of the small GTPase super-family on colorectal carcinogenesis have not been as extensively studied. In contrast to the high frequency of KRAS mutations in colorectal

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tumors, no mutations have been identified in RHOA in this tumor type (Arango et al., 2005; Rihet et al., 2001). However, RhoA signaling regulates an important signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. This signaling cascade can regulate cell morphology, attachment to the substrate and motility, and this regulation is cell type dependent (Van Aelst & D’Souza-Schorey, 1997). In addition, RhoA signaling has been shown to regulate the expression and activity of multiple key members of the cell cycle machinery. Thus, inhibition of RhoA activity can lead to either cell cycle arrest or increased growth, depending on the cellular contest (Bellovin et al., 2005; Bellovin et al., 2006; Pille et al., 2005). We are studying the molecular mechanism underlying our previous observation showing that low RhoA levels are associated with poor prognosis of colorectal cancer patients. For this purpose, we are using in vitro isogenic systems as well as animal studies and analysis of materials obtained from human tumor samples.

CURRENT RESEARCH PROJECTS PI: Diego Arango Corro Los receptores EPH y el cáncer colorrectal Funding Agency: Ministerio de Ciencia e Innovación Reference: SAF2008-00789 Funding: 169,400 € Duration: 2009 to 2011

PI: Diego Arango Corro La GTPasa RhoA en cáncer colorrectal Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMMA/12/2008 Funding: 50,000 € Duration: 2008 to 2011

PI: Diego Arango Corro Marcadores de respuesta a Irinotecan en pacientes con cáncer colorrectal Funding Agency: Ministerio de Ciencia e Innovación Reference: TRA2009-0093 Funding: 230,478.80 € Duration: 2010 to 2012

PI: Diego Arango Corro Grup d’Oncologia Molecular Funding Agency: AGAUR Reference: 2009 SGR 157 Funding: 40,560 € Duration: 2010 to 2013

PUBLICATIONS (Impact Factor: 18.452) Alhopuro P, Bjorklund M, Sammalkorpi H, Turunen M, Tuupanen S, Bistrom M, Niittymaki I, Lehtonen HJ, Kivioja T, Launonen V, Saharinen J, Nousiainen K, Hautaniemi S, Nuorva K, Mecklin JP, Jarvinen H, Orntoft T, Arango D, Lehtonen R, Karhu A, Taipale J, Aaltonen LA. Mutations in the Circadian Gene CLOCK in Colorectal Cancer. Mol Cancer Res 2010 Jul; 8 (7): 952-60.  IF: 4.162. Dopeso H, Mateo-Lozano S, Elez E, Landolfi S, Ramos Pascual FJ, Hernández-Losa J, Mazzolini R, Rodrigues P, Bazzocco S, Carreras MJ, Espín E, Armengol M, Wilson AJ, Mariadason JM, Ramon y Cajal S, Tabernero J, Schwartz S Jr, Arango D. Aprataxin tumor levels predict response of colorectal cancer patients to irinotecan-based treatment. Clin Cancer Res 2010 Apr 15; 16 (8): 237582.  IF: 6.747. Wilson AJ, Chueh AC, Togel L, Corner GA, Ahmed N, Goel S, Byun DS, Nasser S, Houston MA, Jhawer M, Smartt HJ, Murray LB, Nicholas C, Heerdt BG, Arango D, Augenlicht LH, Mariadason JM. Apoptotic sensitivity of colon cancer cells to histone deacetylase inhibitors is mediated by a Sp1/Sp3-activated transcriptional program involving immediate-early gene induction. Cancer Res 2010 Jan 15; 70 (2): 609-20.  IF: 7.543.

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T2.3 Immunobiology Group Leader Juan Sayós Ortega Tel. 93 489 37 53 [email protected] Researchers Aroa Ejarque Ortiz Águeda Martínez Barriocanal Researcher in Training Emma Comas Casellas

OBJECTIVES The CD300 family of immunoreceptors is composed of six members, CD300a/IRP60, CD300b/ IREM3, CD300c/CMRF35, CD300d, CD300e/IREM2 and CD300f/IREM1. All of them share an extracellular region comprising a single Ig-like domain and, with the exception of CD300a, a myeloid linage restricted pattern of expression. In addition to the expression on myeloid cells, CD300a is found in some subsets of T, B and NK cells. The Immunobiology group is focused on the study of the structure and function of the CD300 family of immune receptors, as well as in their involvement in different human pathologies.

RESEARCH LINES Molecular and functional characterization of the family of immunoreceptors CD300 In the last few years the existence of a number of multigenic families of activating and inhibitory immune receptors belonging to the immunoglobulin superfamily has been shown. The physiologic ligand of some of these receptors has been identified, though the ligand of most of them remains unknown. The importance of these receptors for immune system reg-

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ulation was revealed by showing that dysfunction in some of them increases their susceptibility to autoimmune disorders in experimental models. Our main goal will be the molecular and functional characterization of a new family of activating/inhibitory immune receptors called CD300. This novel immunoglobulin superfamily gene cluster maps to a region of human chromosome 17q25 that has been linked to psoriasis susceptibility. The analysis of the structure, distribution and function of the members of this family of immune receptors may provide clues to understanding the mechanisms involved in the development of autoimmune disorders.

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Figure 105 Schematic representation of the CD300 family of Immunoreceptors

The role of the CD300 family of inmunoreceptors in the function of microglial cells In the last few years we have been working on the identification and functional characterization of the CD300 family of immunoreceptors. We have described these molecules as being expressed by cells of myeloid lineage and with some of them activating receptors while others act as negative regulators. We want to analyze the expression and possible role of CD300 molecules in the function of microglial cells in the central nervous system (CNS). We expect that the data generated by this project could help to understand how CD300 receptors modulate microglia function and how to use these molecules as a therapeutic target in processes of acute brain damage.

The involment of CD300 immunoreceptors in the pathogenesis of demyelinating processes Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (SNS) that affects more than 2.5 million individuals worldwide. The first symptoms appear between 20 and 30 years and it is the main neurological disease in young adults, with higher incidence in women. Although the mechanisms underlying MS pathogenesis are still un-

clear, it is well known that patients’ blood-brain barrier allows the passage of macrophages and lymphocytes to the NHS, thereby initiating an inflammatory process. This inflammatory response includes

activation of microglial cells and autoimmune attack against white matter oligodendrocytes. We propose, based on previous experimental data, the study of the role of the CD300f in the patho-

Figure 106 CD300c and CD300b interact through their Ig-like domains. COS-7 cells were transiently transfected with HA-tagged CD300c in combination with FLAG-tagged CD300b. Wild type forms were tested against transmembrane substitution mutants (A), intracellular deletion mutants (B), extracellular deletion mutants (C), cysteine substitution mutants (D) or point mutants affecting the protruding body in the Ig fold (E) in order to map the interaction between both molecules

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Figure 107 Increased staining for the ligand of CD300f in lesioned rat brain. Normal brain (A-B) showed a dotted staining with hCD300f-IgG2a fusion protein mainly in white matter areas like corpus callosum, external capsule (B: arrow) or the anterior commisure (B: arrowhead). Brains subjected to intra-striatal injection of NMDA showed an increased hCD300f-IgG2a staining in the lesion core (C, D) in comparison to the non-injured brain (A, B)

CURRENT RESEARCH PROJECTS PI: Juan Sayós Ortega Papel de la familia de inmunorreceptores CD300 en la función de las células microgliales Funding Agency: Fondo de Investigación Sanitaria Reference: PI080366 Funding: 220,825 € Duration: 2009 to 2011

PI: Juan Sayós Ortega Immunobiologia Funding Agency: AGAUR Reference: 2009 SGR 493 Funding: 42,620 € Duration: 2010 to 2013 physiology of this disease. First, we are working in the identification of the physiological ligand for this receptor that we know is expressed by certain cells in the SNS. Secondly, the analysis of the role of soluble forms of CD300f in the development of the disease by studying their expression in fluid samples of multiple sclerosis patients. Since activation of microglia

and macrophages is critical in the development and expansion of MS lesions, the study of the mechanisms that regulate the activation of these cells may be of vital importance in the development of new therapeutic agents for the treatment of this disease.

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PUBLICATIONS (Impact Factor: 5.328) Martínez-Barriocanal, Comas-Casellas E, Schwartz S, Martín M, Sayós J. CD300 heterocomplexes, a new and family-restricted mechanism for myeloid cell signaling regulation. J Biol Chem 2010 Dec 31; 285 (53): 41781-94.  IF: 5.328.

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AREA T2 NANOMEDICINE

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T2.4 Lysosomal Storage Disease and Cell Pathophysiology Group Leader Mª Carmen Domínguez Luengo Tel. 93 489 40 66 [email protected] Researchers Mª Carmen Domínguez Luengo Elisa Llurba Olivé Víctor Manuel Rodríguez Sureda Olga Sánchez García Researcher in Training Ángel Vilches García

OBJECTIVES • Diagnosis and study of critical cellular mechanisms in the pathogenesis of lysosomal storage diseases. • Involvement of oxidative stress in the pathophysiology and evolution of type 1 diabetes mellitus, gestational diabetes and metabolic syndrome in children. Molecular mechanisms of cellular toxicity of oxidative hyperglycaemia and toxic dyslipidaemia.

RESEARCH LINES • Study of pathogenic mechanisms and cellular stress response in preeclampsia, congenital heart defects and intrauterine growth restriction. Identification of maternal risk factors for these diseases. • In vitro study of pathogenic mechanisms of endothelial and neuronal damage in cerebral ischaemia: relationship with in vivo oxidative processes in acute stroke patients.

Role of angiogenic factors in fetal heart development: congenital heart disease and fetal programming. Study of early markers of endothelial damage, cardiac dysfunction and angiogenesis regulation in pregnancy Mª Carmen Domínguez Luengo, Elisa Llurba Olivé, Olga Sánchez García and María del Mar Goya Canino

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PUBLICATIONS (Impact Factor: 19.774 ) Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farran-Codina I, Llurba-Olivé E, Vilardell-Tarrés M, Casellas-Caro M. Anti-annexin A5 antibodies in women with spontaneous pregnancy loss. Med Clin (Barc) 2010 Apr 10; 134 (10): 433-438.  IF: 1.231. Córdoba O, Llurba E, Cortés J, Sabadell MD, Lirola JL, Ferrer Q, Xercavins J. Complete pathological remission in a patient with hormone-receptor positive and c-erbB-2 expression-negative breast cancer treated with FAC chemotherapy during pregnancy. Tumori 2010 Jul-Aug; 96 (4): 629-32.  IF: 0.863.

CURRENT RESEARCH PROJECTS Figure 108 Free radical generation in dermal fibroblasts with and without pro-oxidant treatment

Diagnostic and disease progression biomarkers in lysosomal storage diseases, ischaemic stroke and multiple sclerosis Mª Carmen Domínguez Luengo, Víctor Manuel Rodríguez Sureda and Ángel Vilches García

PI: Elisa Llurba Olivé La gestación como situación de estrés para el desarrollo de enfermedad cardiovascular: Evaluación de marcadores de riesgo hemodinámicos y bioquímicos para la enfermedad arterioesclerótica en madres y fetos con preeclampsia y/o retraso de crecimiento Funding Agency: Fondo de Investigación Sanitaria Reference: PI07/1095 Funding: 61,226 € Duration: 2008 to 2011

Study of new therapeutic options in some lysosomal storage diseases: substrate reduction therapy, enzyme replacement therapy and chaperone enzyme activation Mª Carmen Domínguez Luengo, Víctor Manuel Rodríguez Sureda, Olga Sánchez García and María Pilar Martín Gallán

Figure 109 Dermal fibroblasts of control and patient with a lysosomal disorder. Mitochondria staining (green, Mitotracker) and lysosomes (orange, Lysotracker)

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Domínguez C, Delgado P, Vilches A, Martín-Gallán P, Ribó M, Santamarina E, Molina C, Corbeto N, Rodríguez-Sureda V, Rosell A, Álvarez-Sabín J, Montaner J. Oxidative Stress After Thrombolysis-Induced Reperfusion in Human Stroke. Stroke 2010 Apr; 41 (4): 653-60.  IF: 7.041. Hernández-Guillamón M, García-Bonilla L, Solé M, Sosti V, Parés M, Campos M, OrtegaAznar A, Domínguez C, Rubiera M, Ribó M, Quintana M, Molina CA, Álvarez-Sabín J, Rosell A, Unzeta M, Montaner J. Plasma VAP-1/SSAO Activity Predicts Intracranial Hemorrhages and Adverse Neurological Outcome After Tissue Plasminogen Activator Treatment in Stroke. Stroke 2010 Jul; 41 (7): 1528-35.  IF: 7.041. San Millan B, Teijeira S, Domínguez C, Vieitez I, Navarro C. Chorionic villi ultrastructure in the prenatal diagnosis of glycogenosis type II. J Inherit Metab Dis 2010 Feb 16.  IF: 3.598.

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T2.5 Renal Pathophysiology Group Leader Anna Meseguer Navarro Tel. 93 489 40 61 [email protected] Researchers Joan López Hellín Anna Meseguer Navarro Eduard Sarró Tauler Researchers in Training Beatriz Bardají de Quixano Andrea Caballero Garralda Antoni Cuevas Alcalà Conxita Jacobs Cachà Haizea Lekuona Gómez Nursing, Technical and Administrative Staff María Fernández Escobar

OBJECTIVES A major foucs of our laboratory has been to investigate the role of androgens in kidney pathophysiology, by identifying androgenregulated genes whose expression is restricted to the proximal tubule cells of the kidney. The molecular mechanisms that control specific expression of those genes in tubular epithelia have been studied in different mouse

models and in androgen-responsive proximal tubule derived cell lines. Some of these novel identified genes have also been investigated at the functional level. The interaction found between the kidney androgen-regulated (KAP) gene and Cyclophilin B (CypB), one of the receptors of the potent immunossupressant Cyclosporine A (CsA), prompted us to investi-

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gate the molecular and cellular mechanisms underlying kidney tubular injury induced by renal nephrotoxicants and isquemiareperfusion processes. The role of KAP, CypB and other members of the immunophylin family in processes related with kidney injury and regeneration are currently being investigated by using genomic approaches in proximal tubule derived cell lines and in Tg and KO mice. Recent data from our laboratory has shown that Tg mice overexpressing the KAP protein in proximal tubule cells develop hypertension mediated by oxidative stress and focal segmental glomeruloesclerosis. We are currently working with this Tg model

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Figure 110 (A) Two-dimensional gels of pooled plasma from patients with focal segmental glomerulosclerosis in the genetic group (G), in the group without podocyte protein mutations (idiopathic group [I]), and in healthy control individuals (HC). The vertical scale shows the molecular weight (kDa) and the horizontal scale shows the isoelectric point. (B) Magnification of the boxed regions indicated in (A). Results are shown for 7 replicate gels of the genetic group pooled sample, 5 replicates of the idiopathic group pooled sample, and 2 replicates of the healthy control sample. In the first genetic group gel, the differential spots are labeled with their corresponding spot numbers

and producing KAP KO mice to further investigate the role of KAP in renal pathophysiology. Another gene of interest is the one coding for the hepatitis A viral receptor (hHAVR), first identified in our laboratory by its overexpression in clear cell renal cell carcinomas (ccRCC), the most malignant and frequent form of renal cancer that arises in proximal tubule cells and is more prevalent in men than women. We are currently investigating the role of hHAVR in the development and progression of human ccRCC. An important part of the group’s efforts is focused on the identification of early, specific and sensitive biomarkers of renal dysfunction by means of high-throughput proteomic analyses in urine and blood samples of

transplanted patients under different immunosuppressant regimes. These techniques are also used for the identification of putative plasma permeabilizating factors in patients suffering idiopathic nonfamilial focal segmental glomeruloesclerosis and in ccRCC patients. Our close relationship with nephrologists, urologists and pathologists from our Institution promotes collaborations aiming towards the identification of potential biomarkers and therapeutical targets that might be useful for future clinical interventions. Finally, the possibility of using nanoconjugates for drug delivery opens new perspectives for targeted therapy.

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RESEARCH LINES Role of Hepatitis A viral receptor (HAVR) / kidney injury molecule-1 (KIM-1) in the development and progression of clear-cell renal carcinoma (ccRCC), as well as, in the renal tubule injury/regeneration processes Overexpression of this protein in 60% of the ccRCCs has already been described. HAVR/KIM-1 overexpression in human ccRCC cell lines blocks cell differentiation and promotes cell scattering. We aim to determine the role of HAVR/ KIM-1 in the development and progression of ccRCC, and its possible value as a diagnostic and prognostic biomarker. We also focus on KIM-1’s role in ischemia/reperfusion- or ne-

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phrotoxic-induced renal tubular injury. Overexpression of this protein in kidney injury has been described. However, whether its involvement is associated with processes enabling tubular epithelium to recover, or potentially increasing damage is not known to this date. With the assistance of cultured renal tubular cell models, we are now investigating whether KIM-1 expression shifts are correlated with renal proximal tubule regeneration ability and, as a consequence, investigating its potential therapeutic application.

Androgen activity in renal pathophysiology. Identification of androgen-regulated kidney-specific genes and their role in the pathogenesis of renal, cardiovascular disease and metabolic disorders Among the genes identified in our laboratory that are kidneyspecific and regulated by androgens at the transcriptional level we are particularly focused on the one that codes for the kidney androgen-regulated protein (KAP). Besides characterization of the functional promoter elements that enable KAP expression in proximal tubule epithelial

cells, we have generated a transgenic (Tg) mouse model that overexpresses KAP in proximal tubule cells under the presence of androgens, in order to mimick the endogenous KAP expression pattern. KAP Tg mice show altered lipid metabolism, glycosuria, proteinuria and hypertension, as well as focal segmental glomerulosclerosis mediated by increased oxidative stress. We are currently working in this Tg model and also preparing conditional knock-out mice to further characterize the role of KAP in renal pathophysiology.

Figure 111 Effects of CsA on Na/K-ATPase in HK-2 cells A–B: Dose-and time-response effects of CsA on Na/K-ATPase activity. CsA inhibited Na/K-ATPase activity at concentrations of 10 mM (A). Time course inhibition of Na/K-ATPase activity after 2 h, 4 h, 10 h and 24 h, at 10 mM CsA (B). C: Na/Kb1 stady-state levels after CsA treatment. Effects of different doses of CsA on Na/K-b1 protein expression levels. b-actin was used as a loading control. D–E: Effects of CsA on Na/K-b1 and CypB localization. Immunocitochemistry assays using anti-CypB and anti-Na/K-b1 rabbit polyclonal antibodies were performed on untreated (upper panel) and 10 mM CsA treated (lower panel) HK-2 cells. F–G: Effects of CsA on CypB expression. Intracellular (F) and secreted (G) CypB levels in HK-2 cells treated with different doses of CsA. Ratios between CypB and actin signals in cell lysates have been represented upon quantification. Figures are representative of at least three independent experiments. doi:10.1371/journal.pone.0013930.g003

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CURRENT RESEARCH PROJECTS Pathological mechanisms leading to chronic allograft disease and its potential mediators. Detection of early markers of the chronic kidney disease of the graft Chronic allograft nephropathy (CAN) is one of the major causes of graft loss in kidney-transplanted patients. The pathogenetic mechanisms of CAN are probably multifactorial, including early noxious agents as a consequence of ischemia / reperfusion of the graft or high loading doses of anticalcineurinics (aCN), and also chronic damage following aCN therapy, rejection or for other reasons. We want to determine the proteomic and genomic changes occurring in tubular cells after different noxious agents are applied (cyclosporine, tacrolimus, other renal toxicants, hypoxia), and also the effects caused by immunophilin silencing (anticalcineurin receptors) in the renal proximal tubule cells. Our objective is to identify specific markers of kidney injury that would be useful to anticipate toxicity or injury in early stages. These putative markers will be clinically validated in collaboration with the Nephrology and the Pathology services of Vall d’Hebron Hospital.

Focal segmental glomerulosclerosis Idiopathic nonfamilial focal segmental glomerulosclerosis (FSG) is a disease with no treatment, whose usual outcome is endstage renal disease frequently recidivating after transplantation. In close cooperation with the Nephrology and Paediatric Nephrology services of Vall d’Hebron hospital together with hospitals throughout the country providing a significant number of patients, we intend to identify the hypothetical blood factor that causes the proteinuria observed in this disease. Identification of such a plasma factor, by means of differential proteomic analysis, would allow the definition of therapeutic targets for the disease, which currently lacks an effective treatment. Our second objective is to find biomarkers that enable us to foresee a potential recidivation and the consequent loss of the graft following renal transplantation to FSG patients.

PI: Anna Meseguer Navarro Implicacions del receptor del virus de l’hepatitis A humà (hHAVcr-1) en el desenvolupament i la progressió del carcinoma renal. Valor com a marcador diagnòstic i pronòstic en els carcinomes de bufeta i renals Funding Agency: Fundació La Marató de TV3 Reference: TV3/052410 Funding: 204,625 € Duration: 2006 to 2010

PI: Anna Meseguer Navarro Acción androgénica y función renal: Implicación de la Kidney androgen-regulated protein (KAP) Funding Agency: Fondo de Investigación Sanitaria Reference: PI081351 Funding: 441,045 € Duration: 2009 to 2011

PI: Anna Meseguer Navarro Acción androgénica y función renal: Implicación de la Kidney androgen-regulated protein (KAP) Funding Agency: Sociedad Española de Nefrología (S.E.N.) Reference: SENEFRO/01/08 Funding: 18,000 € Duration: 2009 to 2011

Figure 112 Changes in arterial pressure in response to intracerebroventricular injections of tempol  WT mice (n=5)  KAP Tg mice (n=6) SAP, Systolic arterial pressure

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Figure 113 KAP levels in KAP Tg and control littermates after CsA treatment. (A) KAP expression levels were assessed by immunohistochemical staining in kidney sections of KAP Tg and control littermates using specific anti-KAP antibodies. Polyclonal antibodies against KAP were raised by rabbit immunization with the NH2-CPKIPLAGNPVSPTS-CONH2 KAP peptide. Mice were treated with CsA (50 mg/kg/day) for 28 days with standard diet or 21 days with a low-salt diet, as indicated in Fig 1. Vehicletreated mice are marked as VH. Data shown are representative of six animals per group. Magnification: 40x. (B) Quantification of KAP levels in Tg and littermates, under control conditions and following different injuries, using the Image J software (Image J 1.44p, National Institutes of Health, Bethesda, Maryland, USA). Data represent means ± SD of six animals per group. There are statistically significant differences for both standard (p<0.0001) and low salt (p<0.0001) diets, being littermateCsA KAP levels (*) lower than the others groups, and KAP Tg-VH KAP levels (**) higher than the other groups (ANOVA, with Turkey post-hoc test)

PI: Anna Meseguer Navarro Role of the kidney androgen-regulated protein (KAP) as a mediator of cardiometabolic syndrome Funding Agency: Fundación Renal íñigo Álvarez de Toledo Reference: FRIAT-2009-01 Funding: 9,000 € Duration: 2010 to 2010

PUBLICATIONS (Impact Factor: 4.351) Suñé G, Sarró E, Puigmule M, López-Hellín J, Zufferey M, Pertel T, Luban J, Meseguer A. Cyclophilin B Interacts with Sodium-Potassium ATPase and Is Required for Pump Activity in Proximal Tubule Cells of the Kidney. PLoS One 2010 Nov 10; 5 (11): e13930.  IF: 4.351.

PI: Anna Meseguer Navarro Patologia cel·lular Funding Agency: AGAUR Reference: 2009 SGR 75 Duration: 2010 to 2013

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T2.6 Basic Research in Aging Group Leader Jaune Alijotas Reig Tel. 93 489 31 85 [email protected] Researcher Jaume Alijotas Reig Researcher in Training Renuka Kandhaya Pillai Nursing, Technical and Administrative Staff Natalia García

OBJECTIVES

RESEARCH LINES

Our goal is the study of the molecular and immunological alterations associated with the aging process. In particular, the association and correlation of cellular aging and endothelial cell senescence with epigenetic and telomeric alterations, taking the immunological alterations as the basis of cellular immunosenescence. Identification of such alterations might provide us with new candidates for therapeutic intervention.

Immunological alterations as the basis of immunosenescence in pathological aging Jaume Alijotas Reig This research line is centred on the study of the role of cross-reactivity among oxidized lipoproteins (oxLDL), antiB2-GP1 and membrane phospholipids, as well as between these complex and heat shock proteins. We also focus on the role of proinflammatory (IL2 / IL6 / TNF) and anti-inflammatory (IL4 / IL-10) cytokines, as well as on the different activation profiles

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of TCR and/or CD14 (TLR4) and the role of hormones such as melatonin and growth hormone.

Endothelial senescence and its pleiotropic effects on inflammatory processes, immunological response and angiogenesis Jaume Alijotas Reig Identification at the molecular level of pathways and proteins associated with the senescence of endothelial cells linked to aging and inflammatory responses. New candidate targets for therapeutic intervention at the clinical level and as new molecular moieties for nanomedicine approaches to improve aging related pathologies caused by endothelial inflammatory based senescence.

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Figure 114 Characterization of monocytic and lymphocytic populations in healthy and pathological donors

CURRENT RESEARCH PROJECTS

PUBLICATIONS (Impact Factor: 16.668)

PI: Francesc Miró Mur Envejecimiento endotelial y sus efectos pleiotrópicos sobre procesos inflamatorios, de la respuesta inmune y angiogénesis Funding Agency: Fundación Invest. Médica Mutua Madrileña Reference: FMMA/05/2008 Funding: 36,000 € Duration: 2008 to 2011

PI: Jaume Alijotas-Reig Estudio de las reacciones inflamatorias inmuno-mediadas relacionadas con los materiales de relleno de uso médico. Funding Agency: SEMCC

Alijotas-Reig J. [The complement system as a main actor in the pathogenesis of obstetric antiphospholipid syndrome.] Med Clin (Barc) 2010 Jan 23; 134 (1): 30-4.  IF: 1.231. Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farrán-Codina I, Llurba-Olivé E, Vilardell-Tarrés M, Casellas-Caro M. Anti-annexin A5 antibodies in women with spontaneous pregnancy loss. Med Clin (Barc) 2010 Apr 10; 134 (10): 433-438.  IF: 1.231. Alijotas-Reig J, Ferrer-Oliveras R, RodrigoAnoro MJ, Farrán-Codina I, Cabero-Roura L, Vilardell-Tarrés M. Anti-beta(2)-glycoprotein-I and anti-phosphatidylserine antibodies in women with spontaneous pregnancy loss. Fertil Steril 2010 May 1; 93 (7): 2330-6.  IF: 3.970.

Alijotas-Reig J, Hindie M, Kandhaya-Pillai R, Miró-Mur F. Bioengineered hyaluronic acid elicited a nonantigenic T cell activation: Implications from cosmetic medicine and surgery to nanomedicine. J Biomed Mater Res A 2010 Oct; 95 (1): 180-90.  IF: 2.816. Alijotas-Reig J, Miró-Mur F, Planells-Romeu I, García-Aranda N, García-Giménez V, Vilardell-Tarrés M. Are Bacterial Growth and/or Chemotaxis Increased by Filler Injections? Implications for the Pathogenesis and Treatment of Filler-Related Granulomas. Dermatology 2010; 221 (4): 356-64.  IF: 2.741. Alijotas-Reig J, Vilardell-Tarrés M. Is obstetric antiphospholipid syndrome a primary nonthrombotic, proinflammatory, complement-mediated disorder related to antiphospholipid antibodies? Obstet Gynecol Surv 2010 Jan; 65 (1): 39-45.  IF: 3.097. Sabadell J, Casellas M, Alijotas-Reig J, Arellano-Rodrigo E, Cabero L. Inherited antithrombin deficiency and pregnancy: Maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol 2010 Mar; 149 (1): 4751.  IF: 1.582.

Figure 115 Accumulation of p21 and p53 within senescent endothelial cell nucleis

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OTHER RESEARCH UNITS

CURRENT RESEARCH PROJECTS PI: María Inmaculada Bori de Fortuny L’ictus a Catalunya: anàlisi de la situació funcional al 4rt dia i als 6 mesos. Necessitats de rehabilitació i recursos disponibles Funding Agency: Agència d’Informació Avaluació i Qualitat en Salut Reference: AATRM047/04/2006 Funding: 61,200 € Duration: 2007 to 2010

PI: Claudia Marhuenda Irastorza Estudio exploratorio multicéntrico para comparar la eficacia de la uroquinasa con la videotoracoscopia en el tratamiento del empiema paraneumónico complicado en la infancia Funding Agency: Fondo de Investigación Sanitaria Reference: EC07/90385 Funding: 50,215 € Duration: 2007 to 2011

PI: Daniel Pacha Vicente Estudio in vivo de la resistencia a la tensión de una sutura estriada para tendones flexores comparada con el punto de Kessler con hilo convencional Funding Agency: Fondo de Investigación Sanitaria Reference: PI070093 Funding: 20,110.20 € Duration: 2008 to 2010

PI: Jordi Teixidor Serra Valoración coste-efectividad del tratamiento quirúrgico con enclavado endomedular o clavo-placa dinámico en las fracturas pertrocantéricas estables de fémur en el anciano Funding Agency: Fondo de Investigación Sanitaria Reference: PI081212 Funding: 10,406 € Duration: 2009 to 2011

PI: Eduardo Muñiz Díaz Implementación y desarrollo de una nueva estrategia para la prevención de la trombocitopenia fetal/neonatal aloinmune incluyendo un protocolo de diagnóstico preimplantacional Funding Agency: Fondo de Investigación Sanitaria Reference: PI070758 Funding: 34,668.92 € Duration: 2008 to 2010

PI: Daniel Pacha Vicente Estudio clínico prospectivo y randomizado comparando la inyección subacromial de plasma rico en plaquetas, o de betametasona y bupivacaina en la tendinosis del manguito rotador del hombro Funding Agency: Fondo de Investigación Sanitaria Reference: EC08/00284 Funding: 36,905 € Duration: 2009 to 2011

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PI: Concepción Figueras Nadal VOR-IIG-49: Invasive fungal infection in children: clinical presentation, management with Voriconazole and therapeutic drug monitoring Funding Agency: Pfizer SA Reference: PFIZER_01-2008 Funding: 42,000 € Duration: 2008 to 2010

PI: María Amparo Cuxart Fina Rehabilitation Garning System Funding Agency: Fondo de Investigación Sanitaria Reference: PI08/90941 Funding: 196,625 € Duration: 2009 to 2011

PI: Óscar González López Evaluación y validación clínica de la biopsia selectiva del ganglio centinela en el diagnóstico de extensión ganglionar del cáncer papilar de tiroides Funding Agency: Fondo de Investigación Sanitaria Reference: PI09/90440 Funding: 41,436 € Duration: 2010 to 2011

PI: Antoni Julià Font REIPI - Red Española de Investigación en Patología Infecciosa Funding Agency: Fondo de Investigación Sanitaria Reference: RD06/0008/0030 Funding: 20,940 € Duration: 2007 to 2010

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Other Research Units

PUBLICATIONS (Impact Factor: 53.946) Canet J, Gallart L, Gomar C, Paluzie G, Vallés J, Castillo J, Sabaté S, Mazo V, Briones Z, Sanchís J, Roige J, Sala R, Bascunana P, Rodríguez A, Serrano E, Ribas M, Cortiella P, Medel J, Márquez E, Salgado I, Lozano C, Serrat A, Morros C, Pérez D, Serra JM, Lorenzo JP, et al. Prediction of postoperative pulmonary complications in a populationbased surgical cohort. Anesthesiology 2010 Dec; 113 (6): 1338-50.  IF: 5.354. Carnero A. The PKB/AKT Pathway in Cancer. Curr Pharm Des 2010; 16 (1): 34-44.  IF: 4.414. Esteban C, Pérez P, Fernández-Llamazares J, Surinach JM, Camafort M, Martorell A, Monreal M. Clinical outcome in patients with peripheral artery disease and renal artery stenosis. Angiology 2010 Feb-Mar; 61 (1): 58-65.  IF: 1.097. Ferran C, Sanz J, Delacamara R, Sanz G, Bermudez A, Valcárcel D, Rovira M, Serrano D, Caballero D, Espigado L, Morgades M, Heras I, Solano C, Duarte R, Barrenetxea C, García-Noblejas A, Diez-Martín JL, Iriondo A, Carreras E, Sierra J, Sanz MA, Ribera JM. Unrelated Transplants For Poor Prognosis Adult Acute Lymphoblastic Leukemia: Long-Term Outcome Analysis And Study Of The Impact Hematopoietic Graft Source. Biol Blood Marrow Transplant 2010 Jul; 16 (7): 957-66.  IF: 3.149.

Maertens JA, Madero L, Reilly AF, Lehrnbecher T, Groll AH, Jafri HS, Green M, Nania JJ, Bourque MR, Wise BA, Strohmaier KM, Taylor AF, Kartsonis NA, Chow JW, Arndt CA, DePauw BE, Walsh TJ, Maertens J, Berthold F, Groll A, Lehrnbecher T, Simón A, Castel Sánchez P, García Miguel P, Madero-López L, Sánchez de Toledo J, et al. A randomized, double-blind, multicenter study of caspofungin versus liposomal amphotericin B for empiric antifungal therapy in pediatric patients with persistent fever and neutropenia. Pediatr Infect Dis J 2010 May; 29 (5): 415-20.  IF: 2.854. Martínez C, Virgili N, Cuerda C, Chicharro L, Gómez P, Moreno JM, Álvarez J, Martí E, Matia P, Penacho MA, Garde C, Luis D de, Gonzalo M, Lobo G, Chicharro L, et al. Transversal study on the prevalence of Metabolic Bone Disease (MBD) and Home Parenteral Nutrition (HPN) in Spain: data from NADYA group. Nutr Hosp 2010 Dec; 25 (6): 920-924.  IF: 1.065. Obradors A, Rius M, Cuzzi J, Daina G, Gutiérrez-Mateo C, Pujol A, Marina F, Márquez C, Benet J, Navarro J. Errors at mitotic segregation early in oogenesis and at first meiotic division in oocytes from donor females: Comparative genomic hybridization analyses in metaphase II oocytes and their first polar body. Fertil Steril 2010 Feb; 93 (2): 675-9.  IF: 3.970.

García J. Allogeneic unrelated cord blood banking worldwide: An update. Transfus Apher Sci 2010 Jun; 42 (3): 257-63.  IF: 0.938.

Palao R, Monge I, Ruiz M, Barret JP. Chemical burns: pathophysiology and treatment. Burns 2010 May; 36 (3): 295-304.  IF: 1.950.

Luceno F, Castilla JA, Gómez-Palomares JL, Cabello Y, Hernández J, Marqueta J, Herrero J, Vidal E, Fernández-Shaw S, Coroleu B. Comparison of IVF cycles reported in a voluntary ART registry with a mandatory registry in Spain. Hum Reprod 2010 Dec; 25 (12): 3066-71.  IF: 3.859.

Querol S, Gómez SG, Pagliuca A, Torrabadella M, Madrigal JA. Quality rather than quantity: the cord blood bank dilemma. Bone Marrow Transplant 2010 Jun; 45 (6): 970-8.  IF: 2.998. Recio-Iglesias J, Grau-Amorós J, Formiga F, Camafort-Babkowski M, Trullas-Vila JC, Rodriguez A. Chronic obstructive pulmonary disease on inpatients with heart failure. GESAIC study results. Med Clin (Barc) 2010 Apr 10; 134 (10): 427-32.  IF: 1.231.

22010 Impact Factor:

53.946

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Reesink HW, Panzer S, González CA, Lena N, Muntaabski P, Gimbatti S, Wood E, Lambermont M, Deneys V, Sondag D, Alport T, Towns D, Devine D, Turek P, Auvinen MK, Koski T, Lin CK, Lee CK, Tsoi WC, Lawlor E, Grazzini G, Piccinini V, Catalano L, Pupella S, Kato H, Takamoto S, Okazaki H, Hamaguchi I, Wiersum-Osselton JC, Tilborgh AJ van, Zijlker-Jansen PY, Mangundap KM, Schipperus MR, Dinesh D, Flanagan P, Flesland O, Steinsvag CT, Espinosa A, Letowska M, Rosiek A, Antoniewicz-Papis J, Lachert E, Koh MB, Alcántara R, Corral Alonso M, Muñiz-Diaz E. Haemovigilance for the optimal use of blood products in the hospital. Vox Sang 2010 Oct; 99 (3): 278-93.  IF: 2.585. Roca I. Highlights of the EANM Congress Barcelona 2009: increasing our impact in diagnostic imaging. Eur J Nucl Med Mol Imaging 2010 Apr; 37 (4): 799-820.  IF: 4.531. Romero-Pinel L, Pujal JM, Martínez-Yelamos S, Gubieras L, Matas E, Bau L, Torrabadella M, Azqueta C, Arbizu T. Epistasis between HLA-DRB1 parental alleles in a Spanish cohort with multiple sclerosis. J Neurol Sci 2010 Nov 15; 298 (1-2): 96-100.  IF: 2.324. Santos C, Arnal C. Stop in bone remodeling in imperfect osteogenesis. Med Clin (Barc) 2010 Apr 10; 134 (10): 472.  IF: 1.231. Simoes EA, Carbonell-Estrany X, Rieger CH, Mitchell I, Fredrick L, Groothuis JR, Stephan V, Munch G, Berner R, Carbonell-Estrany X, Figueras J, Pedraz C, Remesal Escalero A, Fraga J, Martínez Soto MI, Pérez Frías J, Blasco Alonso J, Narbona E, Maldonado Lozano J, Roques V, Salas Hernández S, Tabeada Perianes M, Fernández Trisac JL, Echaniz I, Aguirre Conde A, Salcedo Abizanda S, Vinzo Gil, JM et al. The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children. J Allergy Clin Immunol 2010 Aug; 126 (2): 256-62.  IF: 9.165. Yebra-Yebra M, Recio J, Arévalo-Lorido JC, Cornide-Santos L, Cerqueiro-González J, Manzano L, Amorós Martínez F, Cámara T, Carretero Gómez J, Cepeda JM, Chivite Guillén D, Duran M, Ferreira E, Grau Amorós J, Mena E, Moreno Palomares JJ, Nieto J, Recio J, Román Sánchez P, Serrado Iglesias A. Safety and tolerance of beta-blocker treatment in elderly patients with heart failure. BETANIC study. Med Clin (Barc) 2010 Feb 13; 134 (4): 141-5.  IF: 1.231.

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ÒRGANS DE DIRECCIÓ La infraestructura de direcció i presa de decisió del VHIR pertany a la Fundació Institut de Recerca Hospital Universitari Vall d’Hebron i inclou, des del patronat del 16 de desembre 2010, els òrgans de direcció següents: el Patronat, la Comissió delegada, la Direcció, i els Consells Científics Interns i Externs.

Direcció OBJECTIUS Vall d’Hebron Institut de Recerca (VHIR) es una institució del sector públic que promou i desenvolupa la investigació i la innovació biosanitària de l’Hospital Universitari Vall d’Hebron, estant orientada a trobar solucions als problemes de salut de la ciutadania i amb la voluntat de contribuir al desenvolupament científic, docent, social i econòmic del seu àmbit de competència. Volem que la nostra recerca i innovació, realitzada per les persones que conformen la institució, ampliï la frontera del coneixement i es consolidi com un actiu rellevant i referent per a la nostra societat, el nostre sistema de salut i la seva ciutadania, sent un pol d’atracció de talent i aconseguint que la nostra activitat, en termes d’excel·lència, qualitat i translació, respongui a la posició de lideratge que ha de tenir l’Hospital Universitari Vall d’Hebron.

El director s’encarrega de desenvolupar la direcció executiva de la Fundació. Té les següents funcions:

a) Dirigir, organitzar i gestionar les activitats de recerca de la Fundació. b) Proposar al Patronat la programació d’activitats que ha de concretar les línies de recerca, el seu cost i les fonts de finançament previstes. c) Proposar al Patronat el pressupost anual de la Fundació. d) Proposar al Patronat el nomenament de persones que assumeixin la gerència, i subdireccions i assessories, si s’escau. e) Coordinar les actuacions encaminades a l’obtenció dels recursos necessaris perquè es puguin dur a terme els objectius de la Fundació. f) Informar i retre comptes al Patronat del desenvolupament de les activitats i programes de recerca de la Fundació.

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g) Dirigir el procés selectiu del personal investigador i de suport a la recerca, o per a l’acceptació de l’adscripció del personal investigador i científic i tècnic d’altres institucions a la Fundació. h) Proposar els serveis que calguin perquè la Fundació desenvolupi les activitats i funcions que li corresponen. i) Proposar al Patronat les normes de funcionament intern. j) Formalitzar els convenis de col·laboració amb institucions públiques o privades d’import inferior al màxim que expressament li hagi autoritzat el Patronat. k) Qualsevol altres funcions que li siguin expressament encomanades o delegades pel Patronat, en els termes previstos en aquests Estatuts.

Patronat El Patronat és l’òrgan de govern i d’administració de la Fundació, la representa i gestiona, i assumeix totes les facultats i funcions necessàries per a la consecució dels fins fundacionals.

De Junta de Govern a Comissió delegada Des del 16 de desembre de 2010 la Junta de Govern es converteix en Comissió delegada i té les següents funcions:

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a) Dur a terme els acords adoptats pel Patronat que aquest òrgan l’encomani. b) Fer el seguiment periòdic de les tasques de direcció i de gestió del centre. c) Elaborar la proposta d’ordre del dia de les sessions del Patronat i revisar la documentació a presentar, si escau. d) Proposar al Patronat l’adopció dels acords que corresponguin a aquest òrgan. e) Realitzar el seguiment dels convenis i acords subscrits per la Fundació. f) Informar de les necessitats d’endeutament de la Fundació. g) Facilitar les tasques de direcció i gestió de la Fundació, especialment en allò relatiu a les seves relacions amb les entitats fundadores.

De Comitè Científic Intern a Consell Científic Intern Des del 16 de desembre de 2010 el Comitè Científic Intern es converteix en Consell Científic Intern. El Patronat nomena, a proposta de la Direcció, un Consell Científic Intern format per un mínim de tres i un màxim de vint Investigadors dels Grups de Recerca de la Fundació, que té per objecte assessorar la Direcció en el desenvolupament de les seves funcions. Aquest òrgan no ostenta, en cap cas, funcions de gestió o de representació de la Fundació.

De Comitè Científic Extern a Consell Científic Extern Des del 16 de desembre de 2010 el Comitè Científic Extern es converteix en Consell Científic Extern. El Consell Científic Extern és l’òrgan encarregat d’assessorar sobre les activitats científiques de la Fundació i de vetllar per la seva qualitat científica. Aquest òrgan

no ostenta, en cap cas, funcions de gestió o de representació de la Fundació. El Consell Científic Extern està format per un mínim de tres i un màxim de vint persones científiques de prestigi internacional i competència reconeguda en els àmbits de recerca de la Fundació. En cap cas, els membres del Consell Científic Extern poden ser persones investigadores vinculades a la Fundació o que hi col·laborin habitualment.

AGÈNCIA D’ASSAIGS CLÍNICS Organisme independent que vetlla per la protecció de drets, la seguretat i el benestar dels subjectes que participen en un assaig i projectes d’investigació en humans o en aquells que utilitzen mostres humanes. Ofereix garantia pública al respecte mitjançant un dictamen sobre el protocol de l’assaig, la idoneïtat dels investigadors i l’adequació de les instal·lacions, així com els mètodes i els documents que s’utilitzin per informar als subjectes de l’assaig per a obtenir el seu consentiment informat.

UNITATS DE SUPORT A LA RECERCA L’activitat de la Fundació s’articula a través de múltiples Unitats de Suport a la Recerca, coordinades des de la Direcció dividida en tres blocs principals: Innovació, Estructura administrativa i Serveis.

1. Innovació L’Hospital Universitari Vall d’Hebron, mitjançant l’Institut de Recerca, vol impulsar un pla d’innovació que permeti estructurar i ordenar les accions pròpies d’aquest àmbit, concretades amb les següents línies d’actuació: detecció d’iniciatives d’innovació, el seu registre i la cerca de sinergies entre elles, recolzament als professionals de l’organització en la identificació d’oportunitats i en la seva concreció, anàlisi de la innovació tecnològica susceptible de ser transferida i avaluació i priorització de les innovacions transferides. 312

2. Estructura administrativa L’estructura administrativa de suport a la recerca del VHIR, amb capacitat per a gestionar, generar recursos i contractar personal tècnic, s’articula en diferents unitats:

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UNITAT BÀSICA DE PREVENCIÓ DE RISCOS LABORALS La Unitat Bàsica de Prevenció de Riscos Laborals assessora i vetlla per la seguretat i salut dels llocs de treball, d’acord amb els preceptes de la Llei 31/95 de Prevenció de Riscos Laborals, avaluant i controlant els riscos, elaborant instruccions de seguretat, analitzant els accidents, informant i formant als treballadors, vigilant i promocionant la salut i prevenint les malalties laborals dels professionals.

UNITAT DE COMUNICACIÓ I IMATGE Vincula la recerca científica i la resta d’activitats de l’Institut i la societat a través dels mitjans de comunicació. Dóna a conèixer les activitats de l’Institut i els seus investigadors mitjançant notes i rodes de premsa, entrevistes, vídeos divulgatius i campanyes de comunicació concretes, desenvolupa i fa servir la web institucional com a eina fonamental per comunicar-se de manera interna i externa.

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UNITAT DE FUNDRAISING

UNITAT DE GESTIÓ ECONÒMICA

Impulsa i promou un model de mecenatge per tal de cercar la participació i la generositat de persones, empreses, fundacions, obres socials i entitats públiques i privades que desitgin recolzar econòmicament i invertir en recerca biomèdica. Identifica l’univers de donants i possibles finançadors i defineix una estratègia de captació de fons per a la Fundació VHIR. Dóna suport als investigadors en les seves relacions amb els donants i entitats col·laboradores.

La Unitat de Gestió Econòmica rep els ingressos i donacions, realitza els pagaments de factures ordenades pels investigadors, realitza els procediments de contractació pública per a les grans compres, subministra informació econòmica, des de dades agregades per serveis o grups de recerca fins a la confecció de memòries econòmiques per projectes, i assessora jurídicament quant a contractes, convenis, etc.

UNITAT DE RECURSOS HUMANS UNITAT DE GESTIÓ DE PROJECTES La Unitat de Gestió de Projectes gestiona la sol·licitud i el seguiment dels projectes de recerca que es duen a terme a l’HUVH i al VHIR, finançats per agències públiques i privades, autonòmiques, nacionals i internacionals. Selecciona i difon la informació sobre recursos i ajuts econòmics, canalitza el seguiment dels recursos i ajuts finançats, optimitza i promou la gestió dels recursos de personal, instal·lacions i serveis implicats en el desenvolupament dels projectes de recerca que es duen a terme al VHIR, i promou activitats formatives sobre recursos i ajuts.

UNITAT DE GESTIÓ INFORMÀTICA Els Serveis Informàtics del VHIR coordinen tots els aspectes informàtics relacionats amb l’Institut i donen suport als investigadors. Un dels objectius principals ha estat la creació d’una base de dades centralitzada per a la gestió del coneixement integral de la institució que cobreix tant l’àmbit dels processos interns com el de relació amb els agents externs d’interès.

La Unitat de Gestió de Recursos Humans promou i facilita les relacions laborals del VHIR. Adequa els recursos laborals a les directrius i necessitats de l’Institut tot respectant els marcs jurídics, legals i ètics.

3. Serveis Amb la finalitat de proporcionar els complexos mitjans que requereix la biomedicina actual, el Vall d’Hebron Institut de Recerca disposa d’un seguit de serveis importants per donar suport a la Recerca. Són la Unitat Científico-Tècnica de Suport (UCTS), la Unitat d’Estadística i Bioinformàtica (UEB), la Unitat de Suport en Metodologia per a la Investigació Biomèdica (USMIB), l’Estabulari i la Coordinació de Laboratoris de Recerca. Els dos últims serveis incorporats són el Biobanc i la Unitat Central d’Investigació Clínica i Assaigs Clínics (UCICAC). D’aquesta forma, a més de facilitar als investigadors la tecnologia i els serveis més actuals, s’augmenta la rendibilitat i es millora l’autosuficiència.

UNITAT CIENTÍFICO-TÈCNICA DE SUPORT La Unitat Científico-Tècnica de Suport (UCTS) és un conjunt de serveis de tecnologia puntera que donen suport a les activitats docents i de recerca de l’àmbit biomèdic. El caràcter centralitzat de la UCTS permet posar a l’abast de qualsevol investigador les eines més avançades en les àrees de genòmica, bioinformàtica, proteòmica, citòmica i microscòpia a un cost reduït, amb una actualització constant i amb l’assessorament de personal especialitzat. La UCTS ofereix les següents plataformes: Citòmica, Diagnòstic Molecular, Genòmica, Microscòpia, Proteòmica, Metabolòmica, i d’Estadística i Bioinformàtica (UEB).

UEB La Unitat d’Estadística i Bioinformàtica (UEB) es crea dins de l’Institut de Recerca de l’Hospital Universitari Vall d’Hebron amb l’objectiu de potenciar l’ús i el desenvolupament dels moderns recursos estadístics i bioinformàtics en la recerca efectuada en el seu entorn. Així doncs, els objectius principals de la UEB, són: – Proporcionar suport estadístic i bioinformàtic especialment per al tractament de dades d’alt rendiment (high troughput) generades en la investigació en el nostre centre i l’àmbit biomèdic. – Desenvolupar línies pròpies de recerca en el camp de l’estadística i la bioinformàtica i particularment en aquells camps que puguin revertir en una millora dels serveis proporcionats per la Unitat. – Establir un programa de formació en estadística i bioinformàtica per a la recerca biomèdica.

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BIOBANC El Biobanc de l’Hospital Universitari Vall d’Hebron (BBHUVH) és una unitat de suport a la recerca que acull mostres biològiques d’origen humà amb finalitats d’investigació biomèdica en compliment amb la legislació vigent, i l’objectiu del qual és posar a disposició de la comunitat científica el material biològic necessari per a la recerca en unes òptimes condicions que assegurin la competitivitat i excel·lència de la investigació.

ESTABULARI La recerca i la docència vinculades a l’ús d’animals de laboratori es centralitzen a l’Estabulari de l’Institut de Recerca de l’Hospital Universitari Vall d’Hebron. Ubicat a l’edifici Mediterrània, ocupa una superfície construïda de 745 m2 i una superfície útil de 683 m2 en una sola planta. L’Estabulari compleix amb la legislació vigent i està registrat en el Departament de Medi Ambient i Habitatge amb el número de registre B9900062. La instal·lació està dividida en dues àrees: l’Àrea de Rosegadors amb una zona convencional neta, una quarantena passiva, una zona de barrera per allotjar ratolins immunodeficients, sis sales de manipulació i la Plataforma d’Imatge Molecular; i l’Àrea de Grans Animals amb espaï per allotjar conills, porcs i ovelles amb quiròfans experimentals complets per realitzar projectes de cirurgia experimental i docència. L’Estabulari disposa d’una Comissió que es compon per investigadors de l’Institut que assessoren en temes científics relacionats amb l’Estabulari. La Plataforma d’Imatge Molecular (PIM) està situada dins de l’Estabulari del VHIR, i està equipada amb un sistema Xenogen IVIS® Spectrum d’imatge òptica no invasiva i un macroscopi Leica MacroFluo, manipulats per personal especialitzat.

UNITAT CENTRAL D’INVESTIGACIÓ CLÍNICA I ASSAIGS CLÍNICS La UCICAC, constituïda per un equip de professionals multidisciplinars, ofereix un programa de serveis integrals (start-to-end) als investigadors per al desenvolupament de projectes d’investigació clínica així com assaigs clínics, garantint l’atracció i la competitivitat de la investigació biomèdica de l’HUVH. La UCICAC genera i promou tant projectes com instruments per facilitar la recerca clínica. Addicionalment, la UCICAC promou activitats formatives en recerca clínica i assaigs clínics. En un futur oferirà la centralització de les seves funcions en un espai únic a la planta 13a. de l’Hospital Materno-Infantil i en la que s’hi ubicaran les unitats: – Unitat de Recerca i Assaigs Clínics (URAC). – Unitat de Suport Metodològic per a la Investigació Biomèdica (USMIB).

USMIB La Unitat de Suport en Metodologia per a la Investigació Biomèdica (USMIB) està promoguda per la Fundació Institut de Recerca de l’Hospital Universitari Vall d’Hebron (VHIR) amb el suport institucional de la Gerència de l’Hospital Universitari Vall d’Hebron (HUVH) i la col·laboració del Servei de Farmacologia Clínica i del Servei de Medicina Preventiva i Epidemiologia. La Unitat de Suport en Metodologia per a la Investigació Biomèdica (USMIB) proporciona serveis en metodologia científica per facilitar, promoure i potenciar la investigació biomèdica en l’Hospital Universitari Vall d’Hebron, l’àrea d’atenció primària corresponent i usuaris externs que demanin els seus serveis. Així mateix, dins les

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seves tasques hi ha l’establiment d’un programa de formació en metodologia per a la investigació biomèdica.

URAC La Unitat de Recerca i Assaigs Clínics (URAC) dóna recolzament a la realització d’assaigs clínics i estudis postautorització amb medicaments, productes sanitaris i altres teràpies promoguts per investigadors de la institució o de promoció pública, en aspectes ètics, metodològics, regulatoris i logístics. Addicionalment, la Unitat de Recerca i Assaigs Clínics té l’objectiu de promoure la formació continuada en recerca clínica i assaigs clínics.

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COORDINACIÓ DE LABORATORIS La coordinació de laboratoris té com a finalitat gestionar els recursos i vetllar pel funcionament dels laboratoris que formen l’Institut de Recerca, així com la gestió del personal d’infermeria, tècnics i auxiliars d’infermeria que donen suport a la investigació biomèdica. Les activitats que depenen d’aquesta coordinació són: exercir com a nexe d’unió entre els laboratoris i la Direcció, facilitar el coneixement, la implantació i seguiment de les normatives tant pel que fa a l’àmbit hospitalari com a l’Institut de Recerca, així com centralitzar la borsa de treball en els àmbits anteriorment mencionats.

COMITÈS ÈTICS Comitè Ètic d’Investigació Clínica (CEIC) Dependent de l’HUVH, el CEIC collabora i proporciona el seu suport a l’Institut de Recerca. El CEIC és un organisme independent, constituït per professionals sanitaris i membres no sanitaris, encarregat de vetllar per la protecció dels drets, la seguretat i el benestar dels subjectes que participen en un assaig i d’oferir garantia pública al respecte mitjançant un dictamen sobre el protocol de l’assaig, la idoneïtat dels investigadors i l’adequació de les instal·lacions, així com els mètodes i els documents que s’utilitzin per informar als subjectes de l’assaig amb la finalitat d’obtenir el seu consentiment informat.

funcions es troben: informar sobre la realització dels procediments d’experimentació, eliminar el patiment innecessari i proporcionar eutanàsia humanitària, contrastar la competència del personal que hi participa, així com l’adequació dels procediments emprats.

RESUM DE L’ACTIVITAT INVESTIGADORA Les activitats de recerca del VHIR que es presenten en aquesta Memòria de l’any 2010 queden reflectides de forma resumida en els següents apartats:

PERSONAL INVESTIGADOR I TÈCNIC El 2010 el VHIR tenia un total de 57 grups de recerca amb 489 investigadors (metges, biòlegs, psicòlegs, bioquímics, farmacèutics, químics, veterinaris, i altres) amb 77 investigadors postdoctorals, 213 investigadors en formació i 417 personal de suport a la recerca (infermers, tècnics de laboratori, administratius i altres).

DADES FINANCERES El finançament total de recerca ha estat de 36,2 milions d’euros format per organitzacions oficials, donacions, assaigs clínics, convenis amb la indústria, ingressos d’infraestructura i altres contribucions.

Comitè Ètic d’Experimentació Animal (CEEA) Creat el 8 de gener de 1998, el Comitè Ètic d’Experimentació Animal (CEEA) va ser format per vetllar per la cura i el benestar dels animals d’experimentació. Entre les seves

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PUBLICACIONS INTERNACIONALS I NACIONALS Un total de 595 publicacions han estat realitzades per investigadors del VHIR, i s’han publicat en revistes científiques el 2010, amb un factor d’impacte total de 3149,576. El factor d’impacte mig per publicació ha estat de 5,293. La distribució d’aquestes publicacions queda de la manera següent: 440 articles, 41 revisions, 29 editorials en revistes internacionals, i 69 articles, 8 revisions, 8 editorials en revistes nacionals. El factor d’impacte del 2010 es calcula utilitzant el Journal Citation Reports (JCR) del 2010, amb el càlcul basat en articles originals, revisions i editorials. Les cartes i abstracts s’exclouen del càlcul.

PROJECTES DE RECERCA El 2010, hi havia 242 projectes de recerca en curs, completament finançats per agències oficials i institucions privades.

ESTUDIS CLÍNICS Un total de 238 assaigs clínics se sotmetien al Comitè Ètic d’Investigació Clínica per a la seva aprovació, dels quals 205 (un 86 %) eren estudis multicentre i el resta 33 (14 %) eren estudis unicentre. Dels 238 assaigs presentats, 199 (84 %) eren patrocinats per la indústria farmacèutica, 8 (3 %) per investigadors del VHIR, i la resta, 31 (13 %), eren patrocinats per uns altres hospitals.

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NOUS CONTRACTES A INVESTIGADORS I TÈCNICS FINANÇATS PER DIFERENTS ORGANISMES I PROGRAMES

XARXES TEMÀTIQUES DE RECERCA COOPERATIVA DE L’INSTITUTO DE SALUD CARLOS III

Al 2010, se signaven 10 contractes d’investigadors sèniors, 11 contractes d’investigadors postdoctorals, 16 contractes d’investigadors predoctorals i 8 contractes de tècnics de suport, fi nançats per diverses institucions públiques i privades.

Les Xarxes Temàtiques són estructures organitzatives, afavorides per l’Instituto de Salud Carlos III (ISCIII), d’un conjunt variable de centres i grups de recerca en biomedicina, de caràcter multidisciplinari, l’objectiu dels quals és la realització de projectes de recerca cooperativa d’interès general. Respon a les prioritats del Pla Nacional (2000-2003) en l’àmbit sanitari i l’integren els diferents tipus de recerca com a estratègia per retallar la distància entre la producció d’un nou coneixement i la seva transferència i aplicabilitat a la pràctica mèdica. El VHIR participa en deu Xarxes Temàtiques de Centres i setze de projectes.

CENTRE DE RECERCA BIOMÈDICA EN XARXA (CIBER) El Centre de Recerca Biomèdica en Xarxa (CIBER) és un organisme de recerca, dotat de personalitat jurídica pròpia, i que té com a missió la recerca monogràfica sobre una patologia o un problema de salut concret. Els CIBER pretenen generar grans Centres de Recerca traslacional, de caràcter multidisciplinari i multiinstitucional on s’integri la recerca bàsica, clínica i poblacional a fi de desenvolupar un únic programa comú de recerca, focalitzat en certes patologies que són rellevants per al Sistema Nacional de Salut per la seva prevalença o que degut a la seva repercussió social, són considerades estratègiques per al mateix. Tretze projectes del VHIR participen en set CIBER.

GRUPS DE RECERCA RECONEGUTS PER LA GENERALITAT DE CATALUNYA Un dels objectius de la Generalitat de Catalunya, dins dels seus plans de recerca, ha estat el de proporcionar suport a aquells grups de recerca d’universitats i de centres de recerca de Catalunya que s’articulen al voltant d’una dimensió mínima estable d’investigadors, amb una trajectòria convergent,

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mitjançant la participació en projectes de recerca conjunts, la realització de publicacions o d’activitats comunes que impulsin la formació de joves investigadors. El VHIR compta amb el reconeixement de 28 d’aquests grups en les àrees d’Oncologia i genètica; Endocrinologia, creixement, metabolisme i diabetis; Fisiopatologia digestiva i hepatologia; Malalties cardiovasculars, hemostàsia i hipertensió; Neurociències, salut mental i envelliment; Malalties infeccioses i SIDA; Immunologia: malalties respiratòries, genètiques i sistèmiques; i Patologia i teràpia cel·lular i gènica, R+D, noves tecnologies i cirurgia experimental.

TESIS DOCTORALS Un total de 62 tesis doctorals supervisades i dirigides per personal del VHIR es llegeixen al 2010. D’aquestes, 55 pertanyen a la Universitat Autònoma de Barcelona (UAB), 6 a la Universitat de Barcelona (UB), i 1 a la Universitat de Navarra.

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OBJETIVOS

Dirección

Vall d’Hebron Institut de Recerca (VHIR) es una institución del sector público que promueve y desarrolla la investigación y la innovación biosanitaria del Hospital Universitari Vall d’Hebron, orientada a hallar soluciones a los problemas de salud de la ciudadanía y con la voluntad de contribuir al desarrollo científico, docente, social y económico de su ámbito de competencia.

El director se encarga de desarrollar la dirección ejecutiva de la Fundación. Tiene las siguientes funciones:

Queremos que nuestra investigación e innovación, realizada por las personas que conforman la institución, amplíe la frontera del conocimiento y se consolide como un activo relevante y referente para nuestra sociedad, nuestro sistema de salud y su ciudadanía, siendo un polo de atracción de talento y consiguiendo que nuestra activitad, en términos de excelencia, calidad y translación, responda a la posición de liderazgo que debe tener el Hospital Universitari Vall d’Hebron.

ÓRGANOS DE DIRECCIÓN La infraestructura de dirección y toma de decisión del VHIR pertenece a la Fundació Institut de Recerca Hospital Universitari Vall d’Hebron, e incluye, desde el 16 de diciembre de 2010, los siguientes órganos de dirección: el Patronato, la Comisión delegada, la Dirección, y los Consejos Científicos Internos y Externos.

a) Dirigir, organizar y gestionar las actividades de investigación de la Fundación. b) Proponer al Patronato la programación de actividades que debe concretar las líneas de investigación, su coste y las fuentes de financiación previstas. c) Proponer al Patronato el presupuesto anual de la Fundación. d) Proponer al Patronato el nombramiento de personas que asuman la gerencia, y subdirecciones y asesorías, si fuera necesario. e) Coordinar las actuaciones encaminadas a la obtención de los recursos necesarios para que se puedan llevar a cabo los objetivos de la Fundación. f) Informar y dar cuentas al Patronato del desarrollo de las actividades y programas de investigación de la Fundación. g) Dirigir el proceso selectivo del personal investigador y de apoyo a la investigación, o para la aceptación de la adscripción del personal investigador y científico y técnico de otras instituciones a la Fundación. h) Proponer los servicios que hagan falta para que la Fundación desarrolle las actividades y funciones que le correspondan. i) Proponer al Patronato las normas de funcionamiento interno.

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j) Formalizar los convenios de colaboración con instituciones públicas o privadas de importe inferior al máximo que expresamente le haya autorizado el Patronato. k) Otras funciones que le sean expresamente encomendadas o delegadas por el Patronato, en los términos previstos en estos Estatutos.

Patronato El Patronato es el órgano de gobierno y de administración de la Fundación, la representa y gestiona, y asume todas las facultades y funciones necesarias para la consecución de los fines fundacionales.

De Junta de Gobierno a Comisión delegada Desde el 16 de diciembre de 2010, la Junta de Gobierno se convierte en Comisión delegada y tiene las siguientes funciones:

a) Llevar a cabo los acuerdos adoptados por el Patronato que este órgano le encomiende. b) Hacer el seguimiento periódico de las tareas de dirección y de gestión del centro. c) Elaborar la propuesta de orden del día de las sesiones del Patronato y revisar la documentación a presentar, si procede. d) Proponer al Patronato la adopción de los acuerdos que correspondan a este órgano.

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e) Realizar el seguimiento de los convenios y acuerdos suscritos por la Fundación. f) Informar de las necesidades de endeudamiento de la Fundación. g) Facilitar las tareas de dirección y gestión de la Fundación, especialmente en aquello relativo a sus relaciones con las entidades fundadoras.

De Comité Científico Interno a Consejo Científico Interno Desde diciembre de 2010 el Comité Científico Interno se convierte en Consejo Científico Interno. El Patronato nombra, a propuesta de la Dirección, un Consejo Científico Interno formado por un mínimo de tres y un máximo de veinte investigadores de los Grupos de Investigación de la Fundación, que tiene por objeto asesorar a la Dirección en el desarrollo de sus funciones. Este órgano no ostenta, en caso alguno, funciones de gestión o de representación de la Fundación.

De Comité Científico Externo a Consejo Científico Externo Desde diciembre de 2010 el Comité Científico Externo se convierte en Consejo Científico Externo. El Consejo Científico Externo es el órgano encargado de asesorar sobre las actividades científicas de la Fundación y de velar por su calidad científica. Este órgano no ostenta, en caso alguno, funciones de gestión o de representación de la Fundación.

tigadoras vinculadas a la Fundación o que colaboren habitualmente.

UNIDADES DE APOYO A LA INVESTIGACIÓN La actividad de la Fundación se articula a través de múltiples Unidades de Apoyo a la Investigación, coordinadas desde la Dirección y divididas en tres bloques principales: Innovación, Estructura administrativa y Servicios.

1. Innovación El Hospital Universitari Vall d’Hebron, mediante el lnstitut de Recerca, quiere impulsar un plan de innovación que permita estructurar y ordenar las acciones propias de este ámbito, concretadas con las siguientes líneas de actuación: Detección de iniciativas de innovación, su registro y búsqueda de sinergias entre ellas, apoyo a los profesionales de la organización en la identificación de oportunidades y en su concreción, análisis de la innovación tecnológica susceptible de ser transferida, y evaluación y priorización de las innovaciones transferidas.

2. Estructura administrativa La estructura administrativa de apoyo a la investigación del VHIR, con capacidad para gestionar, generar recursos y contratar personal técnico, se articula en diferentes unidades:

AGENCIA DE ENSAYOS CLÍNICOS El Consejo Científico Externo está formado por un mínimo de tres y un máximo de veinte personas científicas de prestigio internacional y competencia reconocida en los ámbitos de investigación de la Fundación. En ningún caso los miembros del Consejo Científico Externo pueden ser personas inves-

Organismo independiente que vela por la protección de derechos, la seguridad y el bienestar de los sujetos que participan en un ensayo y proyectos de investigación en humanos o en aquellos que utilizan muestras humanas. Ofrece garantía pública al respec-

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to mediante un dictamen sobre el protocolo del ensayo, la idoneidad de los investigadores y la adecuación de las instalaciones, así como los métodos y los documentos que se utilicen para informar a los sujetos del ensayo para obtener su consentimiento informado.

UNIDAD BÁSICA DE PREVENCIÓN DE RIESGOS LABORALES La Unidad Básica de Prevención de Riesgos Laborales asesora y vela por la seguridad y salud de los puestos de trabajo, de acuerdo con los preceptos de la Ley 31/95 de Prevención de Riesgos Laborales, evaluando y controlando los riesgos, elaborando instrucciones de seguridad, analizando los accidentes, informando y formando a los trabajadores, vigilando y promocionando la salud y previniendo las enfermedades laborales de los profesionales.

UNIDAD DE COMUNICACIÓN E IMAGEN Vincula la investigación científica y el resto de actividades del Instituto y la sociedad a través de los medios de comunicación. Da a conocer las actividades del Instituto y sus investigadores mediante notas y ruedas de prensa, entrevistas, vídeos divulgativos y campañas de comunicación concretas, desarrolla y utiliza la página web institucional como herramienta fundamental para comunicarse tanto interna como externamente.

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UNIDAD DE FUNDRAISING Impulsa y promueve un modelo de mecenazgo con el fin de buscar la participación y la generosidad de personas, empresas, fundaciones, obras sociales y entidades públicas y privadas que deseen apoyar económicamente e invertir en investigación biomédica. Identifica el universo de donantes y posibles financiadores y define una estrategia de captación de fondos para la Fundación VHIR. Da soporte a los investigadores en sus relaciones con los donantes y entidades colaboradoras.

UNIDAD DE GESTIÓN INFORMÁTICA Los Servicios Informáticos del VHIR coordinan todos los aspectos informáticos relacionados con el Instituto y ofrecen apoyo a los investigadores. Uno de los objetivos principales ha sido la creación de una base de datos centralizada para la gestión del conocimiento integral de la institución que cubre tanto el ámbito de los procesos internos como el de relación con los agentes externos de interés.

UNIDAD DE GESTIÓN ECONÓMICA UNIDAD DE GESTIÓN DE PROYECTOS La Unidad de Gestión de Proyectos gestiona la solicitud y el seguimiento de los proyectos de investigación que se llevan a cabo en el HUVH y en el VHIR, financiados por agencias públicas y privadas, autonómicas, nacionales e internacionales. Selecciona y difunde la información sobre recursos y ayudas económicas, canaliza el seguimiento de los recursos y ayudas financiadas, optimiza y promueve la gestión de los recursos de personal, instalaciones y servicios implicados en el desarrollo de los proyectos de investigación que se llevan a cabo en el VHIR, y promueve actividades formativas sobre recursos y ayudas.

La Unidad de Gestión Económica recepciona los ingresos y donaciones, realiza los pagos de facturas ordenadas por los investigadores, realiza los procedimientos de contratación pública para las grandes compras, suministra información económica, desde datos agregados por servicios o grupos de investigación hasta la confección de memorias económicas para proyectos, y asesora jurídicamente en cuanto a contratos, convenios, etc.

UNIDAD DE RECURSOS HUMANOS La Unidad de Gestión de Recursos Humanos promueve y facilita las relaciones laborales del VHIR. Adecua los recursos laborales a las directrices y necesidades del Instituto respetando los marcos jurídicos, legales y éticos.

3. Servicios Con la finalidad de proporcionar los complejos medios que requiere la biomedicina actual, el Vall d’Hebron Institut de Recerca dispone de una serie de importantes servicios para prestar apoyo a la Investigación. Son la Unidad Cien-

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tífico-Técnica de Soporte (UCTS), la Unidad de Estadística y Bioinformática (UEB), la Unidad de Soporte en Metodología para la Investigación Biomédica (USMIB), el Estabulario y la Coordinación de Laboratorios de Investigación. Los últimos servicios incorporados son: el Biobanco y la Unidad Central de Investigación Clínica y Ensayos Clínicos (UCICAC). De esta forma, además, de facilitar a los investigadores la tecnología y los servicios más actuales, se aumenta la rentabilidad y se mejora la autosuficiencia.

UNIDAD CIENTÍFICO-TÉCNICA DE SOPORTE La Unidad Científico-Técnica de Soporte (UCTS) es un conjunto de servicios de tecnología puntera que dan soporte a las actividades docentes y de investigación del ámbito biomédico. El carácter centralizado de la UCTS permite poner al alcance de cualquier investigador las herramientas más avanzadas en las áreas de genómica, bioinformática, proteómica, citómica y microscopia a un coste reducido, con una actualización constante y con el asesoramiento de personal especializado. La UCTS ofrece las siguientes plataformas: Citómica, Diagnóstico Molecular, Genómica, Microscopia, Proteómica, Metabolómica, y de Estadística y Bioinformática (UEB).

UEB La Unidad de Estadística y Bioinformática (UEB) se crea dentro del Institut de Recerca del Hospital Universitari Vall d’Hebron con el objetivo de potenciar el uso y el desarrollo de los modernos recursos estadísticos y bioinformáticos en la investigación efectuada en su entorno. Así pues, los objetivos principales de la UEB, son:

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– Proporcionar soporte estadístico y bioinformático especialmente para el tratamiento de datos de alto rendimiento (high troughput) generados en la investigación en nuestro centro y el ámbito biomédico. – Desarrollar líneas propias de investigación en el campo de la estadística y la bioinformática y particularmente en aquellos campos que puedan revertir en una mejora de los servicios proporcionados por la Unidad. – Establecer un programa de formación en estadística y bioinformática para la investigación biomédica.

BIOBANCO El Biobanco del Hospital Universitari Vall d’Hebron (BBHUVH) es una unidad de soporte a la investigación que acoge muestras biológicas de origen humano con fines de investigación biomédica en cumplimiento con la legislación vigente, y cuyo objetivo es poner a disposición de la comunidad científica el material biológico necesario para la investigación en unas óptimas condiciones que aseguren la competitividad y excelencia de la investigación.

ESTABULARIO La investigación y la docencia vinculadas al uso de animales de laboratorio se centralizan en el Estabulario del Institut de Recerca del Hospital Universitari Vall d’Hebron. Ubicado en el edificio Mediterrània, ocupa una superficie construida de 745 m2 y una superficie útil de 683 m2 en una sola planta. El Estabulario cumple con la legislación vigente y está registrado en el Departamento de Medio Ambiente y Vivienda con el número de registro B9900062. La instalación está dividida en dos áreas: el Área de

Roedores con una zona convencional limpia, una cuarentena pasiva, una zona de barrera para alojar ratones inmunodeficientes, seis salas de manipulación y la Plataforma de Imagen Molecular; y el Área de Grandes Animales, con espacio para alojar conejos, cerdos y ovejas con quirófanos experimentales completos para realizar proyectos de cirugía experimental y docencia. El Estabulario dispone de una Comisión compuesta por investigadores del Instituto que asesoran en temas científicos relacionados con el mismo. La Plataforma de Imagen Molecular (PIM), situada dentro del Estabulario del VHIR, está equipada con un sistema Xenogen IVIS® Spectrum de imagen óptica no invasiva y un macroscopio Leica MacroFluo, manipulados por personal especializado.

UNIDAD CENTRAL DE INVESTIGACIÓN CLÍNICA Y ENSAYOS CLÍNICOS (UCICAC) La UCICAC, constituida por un equipo de profesionales multidisciplinares, ofrece un programa de servicios integrales (start-toend) a los investigadores para el desarrollo de proyectos de investigación clínica así como ensayos clínicos, garantizando la atracción y la competitividad de la investigación biomédica del HUVH. La UCICAC genera y promueve tanto proyectos como instrumentos para facilitar la investigación clínica. Adicionalmente, la UCICAC promueve actividades formativas en investigación clínica y ensayos clínicos. En un futuro ofrecerá la centralización de sus funciones en un espacio único en la planta 13ª del Hospital Materno-Infantil y en la que se ubicarán las unidades: – Unidad de Investigación y Ensayos Clínicos (URAC). – Unidad de Soporte Metodológico para la Investigación Biomédica (USMIB).

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USMIB La Unidad de Soporte en Metodología para la Investigación Biomédica (USMIB) está promovida por la Fundació Institut de Recerca Hospital Universitari Vall d’Hebron (VHIR) con el soporte institucional de la Gerencia del Hospital Universitari Vall d’Hebron (HUVH) y la colaboración del Servicio de Farmacología Clínica y del Servicio de Medicina Preventiva y Epidemiología. La Unidad de Soporte en Metodología para la Investigación Biomédica (USMIB) proporciona servicios en metodología científica para facilitar, promover y potenciar la investigación biomédica en el Hospital Universitari Vall d’Hebron, el área de atención primaria correspondiente y usuarios externos que pidan sus servicios. Asimismo, dentro de sus tareas está el establecimiento de un programa de formación en metodología para la investigación biomédica.

URAC La Unidad de Investigación y Ensayos Clínicos da apoyo a la realización de ensayos clínicos y estudios postautorización con medicamentos, productos sanitarios y otras terapias promovidos por investigadores de la institución o de promoción pública, en aspectos éticos, metodológicos, regulatorios y logísticos. Adicionalmente, la URAC tiene el objetivo de promover la formación continuada en investigación clínica y ensayos clínicos.

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COORDINACIÓN DE LABORATORIOS La Coordinación de Laboratorios tiene como finalidad gestionar los recursos y velar por el funcionamiento de los laboratorios que forman el Instituto de Investigación, así como la gestión del personal de enfermería, técnicos y auxiliares de enfermería que dan soporte a la investigación biomédica. Las actividades que dependen de esta coordinación son: ejercer como nexo de unión entre los laboratorios y la Dirección, facilitar el conocimiento, la implantación y seguimiento de las normativas tanto con respecto al ámbito hospitalario como al Institut de Recerca, así como centralizar la bolsa de trabajo en los ámbitos anteriormente mencionados.

COMITÉS ÉTICOS Comité Ético de Investigación Clínica (CEIC) Dependiente del HUVH, el CEIC colabora y proporciona apoyo al Institut de Recerca. Se trata de un organismo independiente, constituido por profesionales sanitarios y miembros no sanitarios, que se encarga de velar por la protección de los derechos, la seguridad y el bienestar de los sujetos que participan en un ensayo y de ofrecer garantía pública al respecto mediante un dictamen sobre el protocolo del ensayo, la idoneidad de los investigadores y la adecuación de las instalaciones, así como los métodos y los documentos que se utilicen para informar a los sujetos del ensayo con la finalidad de obtener su consentimiento informado.

cuidado y el bienestar de los animales de experimentación. Entre sus funciones se encuentran: informar sobre la realización de los procedimientos de experimentación, eliminar el padecimiento innecesario y proporcionar eutanasia humanitaria, contrastar la competencia del personal que participa, así como la adecuación de los procedimientos utilizados.

DATOS FINANCIEROS La financiación total de investigación ha sido de 36,2 millones de euros, formada por organizaciones oficiales, donaciones, ensayos clínicos, convenios con la industria, ingresos de infraestructura y otras contribuciones.

PUBLICACIONES INTERNACIONALES Y NACIONALES

RESUMEN DE LA ACTIVIDAD INVESTIGADORA Las actividades de investigación del VHIR que se presentan en esta Memoria del 2010 quedan reflejadas de forma resumida en los siguientes apartados:

PERSONAL INVESTIGADOR Y TÉCNICO En 2010, el VHIR tenía un total de 57 grupos de investigación con 489 investigadores (médicos, biólogos, psicólogos, bioquímicos, farmacéuticos, químicos, veterinarios, y otros) con 77 investigadores postdoctorales, 213 investigadores en formación y 417 personal de apoyo a la investigación (enfermeros, técnicos de laboratorio, administrativos y otros).

Comité Ético de Experimentación Animal (CEEA) Creado el 8 de enero de 1998, el Comité Ético de Experimentación Animal se formó para velar por el

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Un total de 595 publicaciones han sido realizadas por investigadores del VHIR, y se han publicado en revistas científicas en el 2010, con un factor de impacto total de 3149,576. El factor de impacto medio por publicación ha sido de 5,293. La distribución de estas publicaciones es la siguiente: 440 artículos, 41 revisiones, 29 editoriales en revistas internacionales, y 69 artículos, 8 revisiones, 8 editoriales en revistas nacionales, El factor de impacto del 2010 se calcula utilizando el Journal Citation Reports (JCR) del 2010, con el cálculo basado en artículos originales, revisiones y editoriales. Las cartas y abstracts se excluyen del cálculo.

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PROYECTOS DE INVESTIGACIÓN En el 2010, hubo 242 proyectos de investigación en curso, completamente financiados por agencias oficiales e instituciones privadas.

ESTUDIOS CLÍNICOS Un total de 238 ensayos clínicos se sometieron al Comité Ético de Investigación Clínica para su aprobación, de los cuales 205 (un 85 %) eran estudios multicéntricos y el resto 33 (14 %) eran estudios unicéntricos. De los 238 ensayos presentados, 199 (84 %) fueron patrocinados por la industria farmacéutica, 8 (3 %) por investigadores del VHIR, y el resto, 31 (13 %), fueron patrocinados por otros hospitales.

NUEVOS CONTRATOS A INVESTIGADORES Y TÉCNICOS FINANCIADOS POR DIFERENTES ORGANISMOS Y PROGRAMAS En el 2010, se firmaron 10 contratos de investigadores seniors, 11 contratos de investigadores postdoctorales, 16 de investigadores predoctorales y 8 de técnicos de soporte, financiados por diversas instituciones públicas y privadas.

CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED (CIBER) El Centro de Investigación Biomédica en Red (CIBER) es un organismo de investigación, dotado de personalidad jurídica propia,

y que tiene como misión la investigación monográfica sobre una patología o un problema de salud concreto. Los CIBER pretenden generar grandes Centros de Investigación traslacional, de carácter multidisciplinar y multiinstitucional donde se integre la investigación básica, clínica y poblacional con el fin de desarrollar un único programa común de investigación, focalizado en ciertas patologías que son relevantes para el Sistema Nacional de Salud por su prevalencia o que debido a su repercusión social, son consideradas estratégicas para lo mismo. Trece proyectos del VHIR participan en siete CIBER.

REDES TEMÁTICAS DE INVESTIGACIÓN COOPERATIVA DEL INSTITUTO DE SALUD CARLOS III Las Redes Temáticas son estructuras organizativas, auspiciadas por el Instituto de Salud Carlos III (ISCIII), de un conjunto variable de centros y grupos de investigación en biomedicina, de carácter multidisciplinar, el objetivo de los cuales es la realización de proyectos de investigación cooperativa de interés general. Responde a las prioridades del Plan Nacional (2000-2003) en el ámbito sanitario y lo integran los diferentes tipos de investigación como estrategia para recortar la distancia entre la producción de un nuevo conocimiento y su transferencia y aplicabilidad a la práctica médica. El VHIR participa en diez Redes Temáticas de Centros y dieciséis de proyectos.

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GRUPOS DE INVESTIGACIÓN RECONOCIDOS POR LA GENERALITAT DE CATALUNYA Uno de los objetivos de la Generalitat de Catalunya, dentro de sus planes de investigación, ha sido el de proporcionar soporte a aquellos grupos de investigación de universidades y de centros de investigación de Cataluña que se articulan en torno a una dimensión mínima estable de investigadores, con una trayectoria convergente, mediante la participación en proyectos de investigación conjuntos, la realización de publicaciones o de actividades comunes que impulsen la formación de jóvenes investigadores. El VHIR cuenta con el reconocimiento de 28 de estos grupos en las áreas de Oncología y genética; Endocrinología, crecimiento, metabolismo y diabetes; Fisiopatología digestiva y hepatología; Enfermedades cardiovasculares, hemostasia e hipertensión; Neurociencias, salud mental y envejecimiento; Enfermedades infecciosas y SIDA; Inmunología: enfermedades respiratorias, genéticas y sistémicas; y Patología y terapia celular y génica, I+D, nuevas tecnologías y cirugía experimental.

TESIS DOCTORALES Un total de 62 tesis doctorales supervisadas y dirigidas por personal del VHIR se leen en 2010. De estas, 55 pertenecen a la Universidad Autónoma de Barcelona (UAB), 6 a la Universidad de Barcelona (UB), y 1 a la Universidad de Navarra (UN).

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Index of Authors

Abal Posada, Miguel, 118, 119 Abrisqueta Costa, Pablo, 121, 122, 218, 224, 229 Accarino Garaventa, Ana María, 215 Acosta Rojas, Emilia Rut, 143 Aguadé Bruix, Santiago, 151, 152, 215 Aguilar Torres, Jorge Río, 152, 153 Aguilera, Cristina, 272 Aguirre Canyadell, Mario, 253 Agulló Pascual, Esperanza, 153 Agustí Escasany, Maria Antònia, 272 Albisu Aparicio, Marian, 143, 255 Alegre Martín, José, 232, 233 Alegre de Miguel, Cayetano, 250, 251 Alegret Llorens, Montserrat, 157, 202 Aliaga, Verónica, 151, 152 Alijotas Reig, Jaume, 229, 241, 250, 251, 258, 294, 300, 301 Allende Monclús, Elena, 130, 205, 209 Almirante Gragera, Benito, 153, 224, 225, 229 Alonso Cotoner, Carmen, 101, 136, 151, 215 Alonso Farré, Juli, 172, 208, 209, 250 Alonso Pastor, Arnald, 97, 139, 250 Altamirano Gómez, José Trinidad, 209 Álvarez Sabín, José, 129, 166, 167, 172, 173, 183, 193, 194, 199, 294, 303 Andaluz López, Pilar, 128, 143, 255 Andreu Domingo, Antònia, 179, 229 Andreu Pérez, Pedro A., 96, 104, 128 Andreu Périz, Antonio Luis, 177, 179

Ángel Ferrer, Joan, 151 Angelini, Pier David, 97, 100, 101, 130 Anido Folgueira, Judith, 96, 128, 151, 183 Anivarro Blanco, Inocencio, 136, 152 Antolín Mate, María, 215 Arango Corro, Diego, 98, 129, 284, 285, 289 Arbós Via, María Antonia, 119, 130 Arellano Rodrigo, Eduardo, 251, 258, 301 Arikan Abello, Fuat, 183, 218 Armengol Carrasco, Manuel, 98, 129, 284, 289 Arnal Guimerà, Cristina, 251, 303 Arrambide García, Georgina, 167, 173 Arranz Amo, José Antonio, 143, 209 Arribas López, Joaquín Vicente, 80, 96, 97, 98, 100, 101, 130 Atzori, Francesco, 99 Audí Parera, Laura, 128, 143, 166, 229, 255 Auger Acosta, Cristina, 152, 167, 172, 173 Aura, Claudia M., 101 Avegliano, Gustavo, 152, 153, 251 Aymerich Martínez, Fco. Javier, 172, 209, 250 Aznar Mañas, Fernando M., 101, 119, 130 Azpiroz Vidaur, Fernando, 210, 152, 214, 215 Azuaje Tovar, Carlos, 225

Badal Lafulla, Josep, 265 Badia Canto, Ma. Mercè, 199, 241 Baena Fustegueras, Juan Antonio, 136, 209 Bagó Granell, Juan, 260

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Balada Prades, Eva, 153, 250, 251 Ballabriga Vidaller, Javier, 242 Balmaña Gelpi, Judith, 83, 96, 97, 98, 99, 100, 101, 255 Balsells Valls, Joaquin, 130, 205, 209 Barba Vert, Ignasi, 96, 128, 136, 151, 152, 153, 183, 209 Barbosa Desongles, Anna, 119, 130, 136, 197 Barceló Bru, Mireia, 250 Barquinero Mañez, Jordi, 268, 269 Barrabés Riu, José Antonio, 151, 152 Barrenetxea Lecue, María Cristina, 303 Barret Nerín, Juan Pedro, 303 Bartolomé Comas, Rosa María, 225, 229, 275 Bascuñana Fornells, Patricia, 303 Baselga Torres, José, 71, 96, 97, 98, 99, 100, 101, 128, 130, 151, 183 Bastida Vila, Pilar, 118, 119 Batalla Sahun, Núria, 136, 151, 152 Bayés Colomer, Mònica, 202, 203 Bazzocco, Sarah, 98, 129, 284, 289 Bech Serra, Joan Josep, 97 Benavente Norza, Sergio, 100 Benejam Paul, Bessy, 173, 183, 194 Bertrán Sanges, José M.ª, 242 Bielsa Carrafa, Ana, 202, 203 Bilbao Aguirre, Itxarone Izaskun, 130, 205, 209, 253 Boada Rovira, Mercè, 156, 157, 194, 202 Boix Alonso, Héctor, 128, 197 Boixadera Espax, Ana, 265 Bori de Fortuny, María Inmaculada, 199, 241 Boronat Rom, Mercè, 242 Borruel Sainz, Natalia, 215 Borrull Mendez, Aida, 183

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Bosch Albareda, Francesc, 120, 122, 218, 224, 229 Bosch Gil, José Ángel, 251 Bosch Munsó, Rosa Maria, 202, 203 Bové Badell, Jordi, 176 Braquehais Conesa, M.ª Dolores, 202 Bravo Masgoret, Carles, 219, 225, 242 Brieva Ruiz, Lluís, 166, 167, 275 Brotons Cuixart, Carlos, 138, 153 Bueno Aribayos, J, 118, 119, 122, 241 Bueno Recio, Francisco Javier, 205, 241, 253 Burgos Peláez, Rosa, 199, 241 Buti Ferret, Maria, 208, 209

Caballero Requero, Estrella, 166, 167, 172, 225, 229 Cabero Roura, Lluís, 241, 250, 251, 256, 258, 275, 301 Cabrera Díaz, Silvia, 97, 118, 129 Calzada Álvarez, María Dolores de la, 183 Camina Tato, Montserrat, 143, 166, 229 Campany Herrero, David, 225, 229 Campins Martí, Magda, 229, 258, 275 Campo Casanelles, Miguel del, 128, 143, 255 Campo Fornís, Josep Maria del, 82, 97, 101 Campos Martorell, Mireia, 129, 194, 294 Canaleta Safont, Cristina, 250 Canals Surís, Francesc, 85, 96, 97, 98, 99, 129, 193 Candell Riera, Jaume, 151, 152 Cantó Puig, Ester, 166, 172 Capdevila Castillón, Jaume, 98, 99 Capdevila Plaza, Lluís, 139 Capellà Hereu, Dolors, 202, 272 Caragol Urgellés, Isabel, 237 Caralt Barba, Mireia, 130, 205, 209 Cárdenas Lagranja, Guillermo, 203, 209, 251 Cardona Dahl, Victòria, 214, 250, 251 Carles Galcerán, Joan, 78, 96, 99, 101, 118 Carmona Heredia, M. Àngels, 96, 128, 151, 183, Carrascosa Lezcano, Antonio, 128, 140, 143, 255

Carreras Soler, Maria Josep, 98, 129, 284, 289 Carrizo, Álvaro, 152 Casado González, Esther, 96, 99, 101, 129, 130, 284 Casaldàliga Ferrer, Jaume, 152 Casas Brugué, Miquel, 200, 202, 203, 272 Cascant Castelló, Purificación, 151, 152, 153 Casellas Caro, Manuel, 241, 250, 251, 258, 294, 301 Casellas Jordá, Francesc, 214, 215 Castell Conesa, Joan, 151, 152, 153, 167, 199 Castellote Alonso, Amparo, 152 Castells Cervelló, Xavier, 202, 272 Castells Fusté, Lluís, 130, 205, 209 Castillo Justribo, Joaquín, 152, 167, 173, 193, 199, 303 Catalán Gili, Roberto, 119, 136, 209 Cebrecos Lerena, Isaac, 97, 118 Cecchini Rosell, Lluís, 100, 119, 130 Cedres Pérez, Susana, 97, 98, 100 Cereza García, María Gloria, 272 Chacón Castro, Pilar, 193 Charco Torra, Ramon, 130, 204, 205, 209, 253 Chatauret, Nicolas, 209 Chavarria Vilarasau, Laia, 172, 208, 209 Chechile Toniolo, Gilberto, 118 Chicharro Serrano, M Luisa, 151, 303 Ciudin, Andreea, 136 Clemente León, María, 128, 143, 255 Cobos Barroso, Nicolás, 242 Coelho, Alicia, 229 Colas Ortega, Eva, 119 Coll Loperena, Maria del Mar, 118, 129, 208 Colomé Calls, Núria, 96, 97, 98, 99, 129, 193 Colomina Soler, M. José Clara, 260 Comabella López, Manuel, 143, 166, 167, 172, 173, 229 Comas Casellas, Emma, 284, 292 Comella Carnicé, Joan Xavier, 158, 159 Comín Zafón, Marina, 202 Corbeto López, Natalia, 193, 294 Córdoba Cardona, Juan, 152, 172, 203, 208, 209, 250, 251

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Córdoba Cardona, Octavi, 97, 118, 294 Cormand Rifà, Bru, 202, 203 Corominas Casti, Roser, 197, 202 Corominas Roso, Margarita, 202 Corraliza Márquez, Lidia, 99, 136 Cortadellas Ángel, Josefa, 152 Cortés Castán, Javier, 73, 96-99, 101, 104, 118, 128, 294 Cortés Hernández, Josefina, 250, 251 Crespo Casal, Manuel, 224, 225 Crespo Lessmann, Astrid, 241 Crespo Maull, Marta, 122 Cruz Carmona, María Jesús, 219, 241, 242 Cuadrado Godia, Eloy, 97, 129, 193, 194 Cuartas Maza, M.ª Isabel, 96, 128, 151, 183 Cuatrecasas Freixas, Miriam, 100, 130, 215 Cuberas Borros, Gemma, 151, 152, 157, 167, 172, 199, 202 Cuéllar Calabria, Hugo, 152 Cuenca Barrero, Silvia Maritza, 129, 208 Cuenca León, Ester, 197, 202 Curran Fábregas, Adrián, 224, 225

Daigre Blanco, Constanza, 202 Danes Carreras, Immaculada, 272 Dapena Díaz, José Luis, 118, 122, 237 Dehay Michel, Benjamín, 176 Delgado Martínez, María Pilar, 173, 183, 185, 188, 193, 194, 294 Díaz de Corcué Frutos, Isabel, 97 Díaz de Heredia Rubio, María Cristina, 122, 197, 229 Díaz Feijoo, Berta, 97, 118, 129 Díez Gibert, Orland, 84, 96, 98, 255 Doll, Andreas, 118, 119, 129 Domingo Ribas, Enric, 136, 151, 152 Domingues Montanari, Sophie, 167, 172, 193, 194 Domínguez García, Ángela, 229 Domínguez Luengo, M.ª Carmen, 129, 193, 194, 293, 294 Dopazo Taboada, Cristina, 130, 205, 209 Dopeso González, José Higinio, 98, 129, 284, 289

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Dos Subirá, Laura, 152 Duran Delmas, Marta, 99, 272, 303

Edo Cobos, María del Carmen, 157, 166, 167, 173, 193 Eichhorn, Pieter, 98 Eiroa Orosa, Francisco Javier, 202 Elez Fernández, M. Elena, 98, 99, 129, 284, 289 Elorza Álvarez, Izaskun, 122 Español Boren, Teresa, 118, 237 Espín Basany, Eloy, 98, 99, 101, 129, 130, 275, 284, 289 Espinel Garuz, María Eugenia, 139, 242 Esquerda Gras, Neus, 153 Esselens, Cary Wally, 98 Esteban Mur, Rafael, 129, 203, 208, 209, 251 Esteso Hontoria, Olga, 250 Evangelista Masip, Arturo, 152, 153, 251

Falcó Ferrer, Vicente, 224 Farrán Codina, Inmaculada, 241, 250, 258, 294, 301 Felip Font, Enriqueta, 91, 96, 97, 98, 99, 100, 101, 275 Fernández Bustamante, Marta, 143, 166, 229 Fernández Cadenas, Israel, 167, 172, 179, 193, 194, 265 Fernández Cancio, Mónica, 143 Fernández Hidalgo, Nuria, 153, 224, 225 Fernández Morales, Jessica, 193, 194 Fernández Sanz, Celia, 153 Fernández de Sevilla Ribó, Tomás, 233 Ferreira González, Ignacio, 151, 152 Ferrer Costa, Roser, 136, 209 Ferrer Menduiña, Maria Queralt, 97, 99, 118, 294 Ferrer Sancho, Jaume, 130, 199, 241, 242 Ferreres Piñas, Joan Carles, 128 Figueras Bellot, Jaume, 99, 101, 129, 130, 151, 152, 275, 284, 303 Figueras Nadal, Concepción, 118, 229, 237, 251 Figueras Suñé, Albert, 272 Flavià Olivella, Montserrat, 203, 209, 251

Flores Flores, Alan Alberto, 152, 172, 194 Folch Codera, Gerard, 96, 128, 151, 183 Fonollosa Calduch, Àlex, 265 Fonollosa Pla, Vicenç, 251, 275 Fort López-Barajas, José Manuel, 136, 209 Fort Ros, Joan, 139 Fortuny Gimeno, Daniel, 101 Fraga Salord, Antonia, 119, 130 Frascheri Verzelli, Laura, 173, 183, 194 Frick, Antoinette, 229, 275 Fuentes Camps, Immaculada, 272

Gadea Font, Neus, 98, 101, 255 Galiñanes Hernández, Manuel, 154, 155 Gallego Melcón, Soledad, 118, 241 Gallur Cuenca, Laura, 122 Galve Basilio, Enrique, 151, 152, 153 Gámez Carbonell, José, 152, 167, 198, 199, 241 García Aranda, Natalia, 250, 301 García Arumí, José, 261, 265 García del Blanco, Bruno, 136, 152 García Bonilla, Lidia, 129, 194, 294 García Fontecha, César Galo, 252, 253 García Jiménez, Ángel, 129, 130 García Martínez, Rita, 209 García Palmer, Héctor, 89, 96, 128 García Ramírez, Marta, 99, 136, 151, 265 García-Dorado García, David, 96, 128, 144, 151-153, 183, 225 García-Patos Briones, Vicente, 167, 172, 194 Garriga Baraut, Maria Teresa, 214, 250 Gartner Tizzano, Silvia, 242 Gastaminza Pérez, Javier Agustín, 203 Gavaldà Santapau, Joan, 219, 224, 225, 242 Genescà Ferrer, Joan, 129, 208, 209 Gibert, Prudence, 215 Gil Moreno, Antonio, 97, 99, 118, 129 Gil Villaverde, Rosa, 96, 104, 128, 129 Giralt Casellas, Dolors, 194 Giralt, Jordi, 88, 96, 99, 100, 118

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Girones Llop, Rosina, 209 Gómez Barros, Núria, 202 Gómez Martínez, Valentí, 118 Gómez Olles, Susana, 219, 241, 242 Gomis Rodríguez, Javier, 224 Gonçalves Rodrigues, Paulo André, 97 González Alujas, Teresa, 152, 153, 225 González Junca, Alba, 96, 128, 151, 183 González López, Juan José, 152, 229 González Loyola, Alejandra, 152, 153 Gonzalvo Cirac, Begoña P, 202 Gracia Roldán, Javier de, 129, 242 Gratacós Solsona, Eduard, 143 Gratacós Viñola, Margarita, 197, 199, 202, 203, 241 Gros Subias, Luis, 118, 241 Grueso Gragera, Judit, 96, 104, 128, 129, 152 Guardia Massó, Jaume, 129, 203, 206, 208, 209, 251 Guarner Aguilar, Francisco, 214, 215 Guerrero Zotano, Ángel Luis, 166 Guila Matarin, Meritxell, 215 Guilarte Clavero, Mar, 214, 215, 250 Gussinyé Cañadel, Miguel, 128, 143, 255 Gutiérrez Agulló, María, 194, 224 Gutiérrez Enríquez, Sara I., 98, 255 Guzmán Torres, Marta, 97, 101

Hereu Boher, Maria Pilar, 272 Hermosilla Pérez, Eduard, 98, 229, 251, 258, 275, 284 Hernández de la Calle, I., 143, 255 Hernández Guillamón, Maria Mar, 97, 129, 188, 193, 194, 294 Hernández Losa, Javier, 96, 98, 104, 128, 208, 251, 284, 289 Hernández Pascual, Cristina, 99, 119, 136, 151, 242, Hernández Vara, Jorge, 152, 167, 194, 199 Hernando Martínez, Víctor, 151, 152 Herrero García, Julio, 303 Hindié, Mathilde, 250, 301 Homs Riba, Maria, 208, 209 Horga Hernández, Alejandro, 166, 167, 173, 194, 229 Huerga Núñez, Elena, 167, 172, 173, 209, 250

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Hurtado Rodríguez, Antoni, 119, 130, 136, 197

Igual Barceló, Albert, 152 Imaz Vacas, Arkaitz, 224 Inserte Igual, Javier, 151, 152

Jacas Escarcellé, Carlos, 172, 203, 209, 250, 251 Jardí Margalef, Rosendo, 208, 209 Jiménez Flores, José Antonio, 101 Jubany Marí, Lluís, 129, 251 Julia Arteaga, Eva, 166, 172, 229 Julià Cano, Antonio, 250, 251 Jurado Luque, M.ª José, 139, 242 Juste Sánchez, Concepción, 229, 275

Kandhaya Pillai, Renuka, 250, 301 Kaplinsky, Edgardo J, 136, 152

Labrador Horrillo, Moisés, 214, 250, 251, 275 Lalueza Broto, Pilar, 272 Landolfi, Stefania, 96, 98, 100, 119, 128-130, 284, 289 Laporte Roselló, Joan-Ramon, 270, 272 Lara Castillo, Maria del Carmen, 179 Larrosa Escartín, María Nieves, 229, 275 Lázaro Fernández, José Luis, 130, 205, 209 Lecube Torelló, Albert, 136, 209, 242 Len Abad, Óscar, 219, 225, 242 León Pereyra, Gustavo Avelino de, 152 Les Bujanda, Iñigo, 203, 209, 251 Lidón Corbi, Rosa María, 152 Llauradó Serra, Mireia, 218 Lleonart Pajarín, Matilde, 131, 133 Lloberes Canadell, Patricia, 136, 139, 241, 242 Llopart Corsà, Lluís, 212, 218, 224, 229 Llopis Pagès, Marta, 215, 265 Llort Sales, Anna, 118, 241 Llurba Olivé, Elisa, 97, 118, 241, 250, 294, 301 Lobo Álvarez, Beatriz, 215 López Cano, Manuel, 275, 284

López Fauqued, Marta, 104, 129 López Galera, Rosa M., 224 López Hellín, Joan, 153, 299 López Hernández, Andrés, 130 López Martínez, Diego, 152 López Onrubia, Pedro M., 214, 224 Lorente Guerrero, Juan, 234 Lorenzo Bosquet, Carles, 152, 153, 167, 172, 199 Luengo Sánchez, Olga, 214, 250, 251

Macarulla Mercadé, Teresa, 99, 100, 101, 130, 215 Macaya Ruiz, Alfons, 195, 197, 202 Macià Badia, Carme, 265 Maestre Alcacer, José Antonio, 98, 275 Magrané Fonts, Jordi, 179 Mahia Casado, Patricia, 152 Maisterra Santos, Olga, 194 Malagelada Benaprés, Joan Ramon, 152, 214, 215 Malagelada Prats, Carolina, 152, 215 Malapeira Argilaga, Jordi, 98 Maldonado Pijoan, Xavier, 96, 99, 118 Mancilla Zamora, Sandra, 100, 130 Manichanh, Chaysavanh, 215 Marhuenda Irastorza, Claudia, 130 Marin Molina, Anna Maria, 130 Markman, Benjamin, 99, 101 Márquez Guevara, Carmen, 199, 303 Márquez Martínez, Esther, 139, 303 Marsal Barril, Sara, 250, 251 Marsal Mora, Josep Ramon, 151153 Martell Pérez-Alcalde, Maria, 129, 208 Martí Aguasca, Gerard, 152, 242 Martí Beltrán, Sergi, 199, 241, 242 Martí Seves, Ramon, 179 Martín Andorrà, Margarita, 97, 284, 292 Martín Casabona, Nuria, 229, 241 Martín Gallán, Maria Pilar, 193, 294 Martín Gómez, M. Teresa, 224 Martín Trujillo, Alejandro, 118, 151, 237, 251 Martín de Vicente, Carlos Luis, 242, 251 Martín Yuste, Victoria, 152

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Martínez Barriocanal, Águeda, 119, 122, 229, 251, 284, 292 Martínez Castillo, Vicente, 129, 253, 265 Martínez Gómez, Xavier, 229, 251, 253, 258, 275 Martínez Ibáñez, Vicenç, 202, 253 Martínez Martínez, Cristina, 122, 215, 303 Martínez Palones, Jose M.ª, 99, 118, 218 Martínez Ricarte, Francisco Ramón, 96, 128, 151, 183, 218 Martínez Rodríguez, Pablo, 97, 98 Martínez Sáez, Elena Antima, 96, 123, 128, 151, 183, 225 Martínez Selva, David, 122, 134, 135 Martínez Valle, Fernando, 251, 258 Martínez Vicente, Marta, 176 Masachs Peracaula, Miquel, 215 Masas Castro, Miriam, 98, 255 Masclans Enviz, Joan Ramon, 219, 242 Mataró Serrat, Maria, 183 Mateo Lozano, Silvia, 98, 129, 284, 289 Mazzolini, Rocco, 98, 129, 284, 289 Medel Rebollo, Francisco Javier, 303 Mediano Vizuete, Carmen, 98, 255 Meler Amella, Maria Pilar, 194 Mendioroz Iriarte, Maite, 167, 172, 193, 194 Merino Ojer, M. Ángeles, 173, 183, 194 Mesa Manteca, Jorge, 136, 152, 242 Meseguer Navarro, Anna, 295, 299 Mínguez Rosique, Beatriz, 209 Miquel Rodríguez, Francesc, 153 Mirabet Pérez, María Isabel, 151 Miró Casas, Elisabet, 153, 229, 255 Miró Mur, Francesc, 229, 250, 301 Mitjana Penella, Raquel, 167, 173 Modesto Caballero, Consuelo, 251 Molero Richard, Francesc Xavier, 100, 130, 215 Molina Cateriano, Carlos, 129, 193, 194, 294 Molina Romero, Israel, 225, 229 Moliné Marimón, Teresa, 96, 104, 128, 129 Monforte Torres, Víctor, 219, 225, 242 Monge Castresana, Iván, 303 Montalban Gairín, Xavier, 143, 160, 166, 167, 172, 173, 229, 275 Montaner Villalonga, Joan, 97, 129, 157, 167, 172, 184, 193, 194, 294

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Montero Fernández, María Ángeles, 129, 130, 242 Montes Castillo, Juan Francisco, 130, 242 Moraga Llop, Fernando, 229, 242, 275 Morales Barrera, Rafael, 99, 101 Morancho Retana, Anna, 194 Morell Brotad, Ferran, 129, 136, 238, 241, 242 Moreno Galdó, Antonio, 118, 203, 225, 241, 242 Morente Llenes, Miriam, 130, 153 Moreso Mateos, Francesc, 139 Morote Robles, Joan, 100, 118, 119, 129, 130 Moubarak, Rana, 159 Moya Mitjans, Ángel, 151, 153 Munell Casadesus, Francina, 119, 130, 136, 197 Muñiz Díaz, Eduardo, 303 Muñoz Couselo, Eva, 97, 101 Muñoz Gall, Fco. Javier, 136, 219, 241, 242 Muñoz Valdivielso, Dunia, 166 Muntaner Muñoz, Laura, 209 Murio Pujol, Josep Enric, 99, 101, 129, 130, 284

Navalpotro Yagüe, Begoña, 100, 130 Navarro Sobrino, Miriam, 118, 194, 237 Nieto Rey, José Luciano, 118, 241, 303 Nieto Santa, Elsa, 152 Nogales Gadea, Gisela, 179 Nos Llopis, Carlos, 167, 173, 275 Núñez Mangado, Fátima, 118 Núñez Pereira, Susana, 260

Oaknin Benzaquen, Ana Mazaltob, 97, 100, 101, 130 Ocaña Rivera, Inmaculada, 224, 225 Olloquequi González, Jordi, 130, 242 Ordi Ros, José, 129, 153, 250, 251 Oria Alonso, Marc, 172, 208, 209 Orriols Martínez, Ramón, 241, 242 Orsola de los Santos, Anna, 96, 100, 119, 130 Ortega Aznar, Arantxa, 97, 128, 129, 193, , 194, 197 Ortega Serrano, Israel, 119, 143, 166, 229 Otero Romero, Susana, 167, 275

Pachón Peña, Gisela, 118, 224 Paciucci Barzanti, Rosanna, 118 Padilla Gómez, Nelly Fabi, 143 Pagola Pérez Blanca, Jorge, 194 Pahissa Berga, Albert, 121, 153, 218, 220, 224, 225, 229 Palacio García, Carlos, 122 Palao Domènech, Ricard, 303 Palenzuela Díaz, Lluís, 209 Pallero Castillo, Mercedes, 199, 241, 242 Palomar Martínez, Mercedes, 219 Palou Rivera, Eduard, 251, 275 Pardo Yules, Benjamín, 99, 209 Parés Oliva, Mireia, 129, 157, 194, 294 Parra Palau, Josep Lluis, 96, 100, 101, 130 Peg Cámara, Vicente, 100, 101, 119, 130 Peinado Onsurbe, Julia, 136, 209 Peiró Ibáñez, José Luis, 129, 253 Peláez Gutiérrez, Andrés, 215 Pelayo Vergara, Raúl, 167, 173 Pellisé Urquiza, Ferran, 260 Penalba Morenilla, Anna, 157, 194 Perapoch López, Josep, 143 Pérez Benavente, María Asunción, 97, 101, 118, 129, 130 Pérez Bocanegra, Mari Carmen, 251 Pérez Carrasco, Marcos, 179, 219 Pérez Esquirol, Eulàlia, 272 Pérez García, José, 99, 118, 139, 159 Pérez Jurado, Luís Alberto, 179, 255 Pérez Lafuente, Mercedes, 205, 208, 219, 253 Pérez López, Jorge, 99, 118, 251 Pérez Miralles, Francisco, 166, 167, 173, 275 Pericot Nierga, Imma, 167, 275 Perier, Celine F., 176 Perkal, Héctor Daniel, 166, 167, 172, 173, 229, 275 Permanyer Miralda, Gaietà, 151-153 Pétriz González, Jordi, 119 Pigrau Pastor, Marc, 215 Pigrau Serrallach, Carles, 224, 225 Pinos Tella, Laia, 229, 275 Placer Santos, José, 119, 129 Plaja Rustein, Alberto, 254, 255 Planas Morin, Jacques, 100, 119, 129, 130 Planells Romeu, Irene, 229, 250, 301

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319

Index

Poca Pastor, Ma. Antònia, 96, 128, 151, 173, 183, 194 Poncelas Nozal, Marcos, 152 Porta Pampalona, Isabel, 183, 218 Pozo Rosich, Patricia, 168, 169 Prats Pastor, Guillem, 225, 226, 229 Prieto Sánchez, Rosario M, 96, 128, 151, 183 Puiggròs Llop, Carolina, 199, 241 Puigmule Raurich, Marta, 299 Pujadas Navinés, Francesc, 157. 166, 193 Pujol Borrell, Ricardo, 236 Pujol Esclusa, Anna, 96, 104, 128, 129, 258, 303

Quer Sivila, Josep, 209 Querol Giner, Sergi, 303 Quiles Pérez, M.ª Teresa, 119, 130 Quilez Martínez, Alejandro, 166 Quintana Luque, Manuel, 129, 139, 157, 166, 193, 194, 294 Quiroga Gómez, Sergi, 208 Quiroga Valera, Anna, 151

Raguer Sanz, Nuria, 199, 209, 241 Ramón y Cajal Agüeras, Santiago, 98, 100, 119, 123, 128-130, 284, 289 Ramos Albiac, Mónica, 100 Ramos López, Laura, 215 Ramos Pascual, Fco. Javier, 98, 99, 101, 129, 284, 289 Ramos Quiroga, José Antonio, 202, 203 Raspall Martín, Guillermo, 266 Raurell Saborit, Immaculada, 129, 208 Raventós Bernal, Carolina, 96, 128 Raventós Busquets, Carles, 100, 119, 129, 130, 151, 183 Recasens Ibabe, Ariadna, 176 Recio Conde, Juan Ángel, 96, 102, 104, 128, 129 Recio Iglesias, Jesús Pedro, 303 Recuero González, Raquel, 242 Redecillas Ferreiro, Susana, 197 Reix, Stéphanie, 159 Rello Condomines, Jordi, 216, 218, 219 Reventós Puigjaner, Jaume, 106, 118, 119, 129, 130, 136, 197 Ribases Haro, Marta, 197, 202, 203 Ribera Pascuet, Esteve, 224, 225

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Ribera Solé, Aida, 151-153 Ribó Jacobi, Marc, 97, 129, 93, 194, 294 Riera del Brío, Jordi, 151, 219, 242 Rigau Resina, Marina, 118, 119, 129 Río Espinola, Alberto del, 167, 172, 193, 194 Río Izquierdo, Jordi, 167, 173 Riveiro Vilaboa, Marylin, 173, 183, 194 Roca Bielsa, Isabel, 202, 225, 303 Roca Gas, Oriol, 219, 242 Roca Luque, Ivo, 153, 157, 202, 225, 303 Rodón Ahnert, Jordi, 96, 99-101, 118, 151, 183 Rodón Ahnert, Laura, 96, 128, 151, 183 Rodrigo Anoro, M. José, 241, 242, 250, 258, 294, 301 Rodrigo Pendás, José Ángel, 229, 258, 275, Rodríguez Cintas, Laia, 202 Rodríguez Frías, Francisco, 208, 209, 303 Rodríguez González, Esther, 199, 241 Rodríguez Infante, Rafael, 265 Rodríguez Luna, David, 194 Rodríguez Palomares, José Fernando, 152 Rodríguez Sinovas, Antonio, 153 Rodríguez Sureda, Víctor Manuel, 193, 294 Roig Quilis, Manuel, 128, 197, 202 Roigé i Solé, Jaume, 303 Rojo Todo, Federico Gustavo, 101, 119, 129, 130 Romero Giménez, Jordi, 99, 172, 208, 209 Romero Santo-Tomás, Odile, 136, 139, 242 Romero Vidal, Francisco Javier, 183, 218, Roncero Alonso, Carlos, 202, 272 Rosell Novel, Anna, 97, 129, 185, 186, 188, 193, 194, 294 Rovira Cañellas, Alex, 166, 167, 170, 172, 173, 194, 209, 229, 250 Rubiera del Fueyo, Marta A, 129, 193, 194, 294 Rubio Rodríguez, Isabel Teresa, 97, 101, 118, 119, 130, Ruiz Camps, Isabel, 121, 218, 224, 225, 229 Ruiz Marcellán, Carmen, 129, 130

Ruiz Meana, Marisol, 152, 153, 225, 303 Ruiz Nel lo, Ana, 119

Sabadell García, Jordi, 251, 258, 301 Sabadell Mercadal, Maria Dolors, 97, 118, 119, 130, 294 Sáez Borderias, Andrea, 128, 151, 183 Sahuquillo Barris, Joan, 96, 128, 151, 173, 180, 183, 194, 218 Sala Cunill, Anna, 214, 250, 251 Sala de Vedruna, Gemma, 99 Salazar Soler, Ramón, 98, 99, 101, 129, 130, 284 Salcedo Abizanda, Salvador, 128, 197, 303 Saldana Ríos, Germán, 152 Sambola Ayala, Antonia, 152, 153, 225 Sampol Rubio, Gabriel, 136, 139, 242 San José Laporte, Antonio, 251 Sánchez Durán, María Ángeles, 255 Sánchez García, José A, 153 Sánchez Mora, Cristina P., 202, 203 Sánchez Ollé, Gessamí, 99, 101 Sánchez Pla, Àlex, 100, 101, 130 Sánchez de Toledo Codín, Josep, 118, 241, 303 Santamaría Margalef, Anna, 118 Santamaría Martínez, Albert, 119, 130, 136, 197 Santamarina Pérez, Esteban, 157, 166, 188, 193, 194, 294 Santos Blanco, Maria Esther, 265 Santos Ramírez, Carlos, 303 Santos Vicente, Francisco Javier, 215 Saperas Franch, Esteban, 214, 215 Sapisochin Cantis, Gonzalo, 130, 205, 209 Sarró Tauler, Eduard, 299 Sartorio, Carmen L., 152 Sastre Garriga, Jaume, 166, 167, 172, 173, 194, 275 Sauleda Oliveras, Silvia, 208, 209 Saura Manich, Cristina, 97, 98, 255, 272 Sayós Ortega, Juan, 284, 290, 292 Scaltriti, Maurizio, 97, 100, 101, 130 Schaper, Melanie, 208, 209 Schwartz Navarro, Simó, 98, 129, 280, 284, 289

326

Schwartz Riera, Simón, 278, 284, 292, Segarra Medrano, Alfons, 139, 208, 242 Segarra Medrano, Antoni, 205, 253 Segura Cardona, Rosa Maria, 265 Sellas Fernández, Agustí, 250 Selva O’Callaghan, Albert, 129, 251, 275 Seoane Reboredo, José Luis, 199, 241 Seoane Suárez, Joan, 75, 96, 101, 128, 151, 182, 183 Serón Micas, Daniel, 137, 139 Serra, Vicenç, 152 Serra Pueyo, Jordi, 152, 214, 215 Serra Vich, Joaquín, 230 Serrano García, César, 97, 101, 130, Sesé Faustino, Marta, 118 Sierra Marcos, Alba, 167, 173, Simeón i Aznar, Carmen Pilar, 251, 275 Simó Canonge, Rafael, 99, 134, 136, 151, 242, 265 Simón-Talero Horga, Macarena, 209, 250 Solana Díaz, Elisabeth, 183 Solans Laque, Roser, 251 Soldado Carrera, Francisco, 129, 253 Solé Llop, Maria Esther, 167, 172, 194 Soler Palacín, Pere, 118, 237 Soler Soler, Jordi, 153, 219, 225, 242 Somoza López de Haro, María Rosa, 128 Soriano Palacios, Nuria, 153 Sosti Sosa, M. Victoria, 129, 194, 294 Suárez Rodríguez, Cristina, 99, 101, 118, 139, 143, 166 Subirana, Maria Teresa, 153 Sueiras Gil, María, 152, 172 Suñé Martín, Pilar, 272 Suñé Rodríguez, Guillermo, 299 Surinach Caralt, José María, 303

Tabernero Caellas, David, 208, 209 Tabernero Caturla, Josep, 74, 94, 96-101, 129, 130, 284, 289 Téllez Lara, M. Nieves, 167, 173 Tenés Felipe, Anna, 98

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Annual Report 2010

Tenorio López, Lluís, 219, 225, 242 Tintoré Subirana, Mar, 166, 167, 172, 173, 229, 275 Toledo Argany, Manuel, 152, 157, 166, 172, 193 Torán Fuentes, Núria, 128-130, 143, 253, 255 Tornos Mas, Pilar, 151, 153, 225 Toro Riera, Mireia del, 197, 225 Torrabadella de Reynoso, Marta, 303 Torrejón Herrera, Antonio, 214, 215 Torres Ramírez, Inés de, 129, 130, 136, 284 Torres Salido, M. Teresa, 250 Torres Torronteras, Javier, 179, Tórtola Fernández, Teresa, 121, 143, 166, 218, 224, 229, Tortosa Méndez, Raül, 250 Tovar Méndez, José Luis, 139, 242 Trallero Araguas, Ernesto, 251, 275 Trilla Herrera, Enric, 99, 100, 118, 119, 130 Tur Gómez, Carmen, 167, 173

Ulldemolins Gómez, Marta, 219 Untoria Corral, María Dolores, 139, 242

Unzeta López, Mercè, 129, 194, 294 Urbizu Serrano, Aintzane, 197

Valero Ventura, Sergi, 157, 202 Vallano Ferraz, Antoni, 272 Vallespí Solé, Maria Teresa, 122 Valverde Morales, Claudia María, 99, 101, 118 Vaqué Rafart, Josep, 167, 229, 273, 275 Vaquero Raya, Eva, 100, 130, 215 Varela Castro, Encarna, 215 Vargas Blasco, Víctor Manuel, 136, 172, 209, 250 Vázquez Méndez, Josefa Élida, 100, 128, 130, 197 Velasco García, María Isabel, 242 Vergés Capdevila, Ramona, 97, 99, 118, 129 Vicario Pérez, María, 215 Vidal Guitart, Xavier, 202, 272 Vidal Pérez, Francisco, 276 Vidal Pla, Rafael, 229, 241, 242 Videla Ces, Sebastián, 214 Vila Bover, Miquel, 174, 176 Vilallonga Puy, Ramon, 284 Vilalta Castan, Jordi, 183, 218 Vilalta Saura, Anna, 183

327

319

Index

Vilardell Tarrés, Miquel, 129, 153, 229, 241, 243, 250, 251, 258, 275, 294, 301 Vilaró Gordillo, Ester, 128, 143, 255 Vilaseca Momplet, Jaume, 214 Vilches García, Ángel, 193, 294 Villacorta Argüelles, Eduardo, 153 Villanueva Cardús, Josep, 92, 101, 209 Villanueva Leal, Carlos, 259 Villar del Saz Cano, Sara, 225 Villarroel Fandos, Marta, 99, 136, 265 Villoria Ferrer, Alberto, 152, 215 Vinzo Gil, Juan M., 303 Vives Bauzà, Cristòfol, 179 Voltés Manils, Núria, 202

Xercavins Montosa, Jorge, 97, 99, 101, 118, 119, 129, 130, 294

Yeste Fernández, Diego, 128, 143, 255

Zafón Llopis, Carles, 136 Zamora Serrallonga, Elisabet, 136 Zapata Victori, Miguel Ángel, 136, 265

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Annual Report 2010

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Index

Index of Journals

Acta Neurochirurgica, 42, 183 Acta Paediatrica, 42, 143 Actas Españolas de Psiquiatría, 50, 251 Advances in Clinical Chemistry, 42, 99 AIDS, 42, 224, 225 AIDS Patient Care and STDs, 42, 224 AIDS Research and Human Retroviruses, 42, 225 Alimentary Pharmacology & Therapeutics, 42, 209 Allergologia et Immunopathologia, 50, 250 American Heart Journal, 42, 151, 153 American Journal of Cardiology, 42, 153, 225 American Journal of Gastroenterology, 42, 152, 215 American Journal of Industrial Medicine, 42, 242 American Journal of Medical Genetics Part A, 42, 255 American Journal of Medical Genetics Part B, 42, 197, 202, 203 American Journal of Medicine, 42, 251, 275 American Journal of Neuroradiology, 42, 194 American Journal of Pathology, 42, 129, 139 American Journal of PhysiologyCell , 42, 155 American Journal of Respiratory and Critical Care Medicine , 41, 42, 219 American Journal of Surgical Pathology, 42, 129 American Journal of Transplantation, 42, 139, 205, 253 Anesthesiology, 42, 54, 303 Angiology, 42, 303

Anales de Pediatría, 50, 118, 130, 151, 197, 237, 242 Annals of Allergy Asthma & Immunology, 42, 251 Annals of Internal Medicine, 41, 42, 209 Annals of Neurology, 42, 167, 172, 176, 193, 229 Annals of Oncology, 42, 96-99, 101, 122 Annals of Surgical Oncology, 42, 101, 119, 130 Annals of the New York Academy of Sciences, 42, 194 Annals of the Rheumatic Diseases, 42, 250, 251 Annual Review of Medicine, 42, 209 Antimicrobial Agents and Chemotherapy, 42, 209 Applied and Environmental Microbiology, 42, 152, 229 Archives of Gynecology and Obstetrics, 42, 97, 129 Archives of Internal Medicine, 42, 152, 209 Archivos de Bronconeumología, 50, 129, 218, 219, 241, 241, 275 Arteriosclerosis, Thrombosis and Vascular Biology, 42, 152, Arthritis and Rheumatism, 42, 49, 250, 251, 275 Asian Pacific Journal of Allergy and Immunology, 43, 214, 250 Atherosclerosis, 43, 136, 151, 193 Autoimmunity Reviews, 43, 251 Autophagy, 43, 176

Biochimica et Biophysica ActaReviews on Cancer, 41, 43, 133 Biology of Blood and Marrow Transplantation, 43, 303

329

Bioorganic & Medicinal Chemistry, 43, 118 BJU International, 43, 100, 119, 129, 130 Blood, 41, 43, 130, 237 BMC Bioinformatics, 43, 250 BMC Cancer, 43, 96, 104, 128 BMC Infectious Diseases, 43, 229 BMC Neurology, 43, 136, 199 BMC Psychiatry, 43, 203 BMC Public Health, 43, 242 Bone Marrow Transplantation, 43, 303 Brain, 43, 166, 172, Brain, Behavior and Immunity, 43, 203 Breast Cancer Research and Treatment, 43, 98-100, 255 British Journal of Clinical Pharmacology, 43, 272 British Journal of Haematology, 43, 122 British Journal of Nutrition, 43, 215 British Journal of Ophthalmology, 43, 265 British Medical Journal, 41, 43, 241 Burns, 43, 303

Canadian Medical Association Journal, 43, 218 Cancer Cell, 41, 43, 96, 122, 128, 151, 183, 284 Cancer Journal, 43, 101 Cancer Research, 43, 97, 100, 12, 129, 287-289 Cancer Treatment Reviews, 43, 98 Cardiology in the Young, 43, 152 Cardiovascular and Interventional Radiology, 43, Cardiovascular Research, 43, 152, 153

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Cell, 41, 43, 176 Cell Stem Cell, 41, 43, 101 Cellular Physiology and Biochemistry, 43, 128 Cerebrovascular Diseases, 43, 193, 194 Circulation, 41, 43, 136, 139, 151154, 185, 188 Circulation-Heart Failure, 44, 151 Clinica Chimica Acta, 44, 242 Clinical & Translational Oncology, 44, 50, 96-99, 101, 118, 129, 284 Clinical and Experimental Immunology, 44, Clinical and Experimental Rheumatology, 44, 237, 251 Clinical Breast Cancer, 44, 96, 101 Clinical Cancer Research, 44, 96, 98, 101, 129, 284, 289 Clinical Cardiology, 44, 152 Clinical Infectious Diseases, 44, 255 Clinical Microbiology and Infection, 44, 225, 229, 241 Clinical Neurology and Neurosurgery, 44, 152, 167, 199 Clinical Nuclear Medicine, 44, 153 Cochrane Database of Systematic Reviews, 44, 202, 272 Comprehensive Psychiatry, 44, 202 Contemporary Clinical Trials, 44, 272 Critical Care, 44, 218 Critical Care Medicine, 44, 219 Current Hypertension Reports, 44, 153 Current Opinion in Investigational Drugs, 44, 97 Current Opinion in Rheumatology, 44, 251 Current Pharmaceutical Design, 44, 303 Cytotherapy, 44, 199, 241 Chest, 44, 219, 241 Chirurg, 44, 284

Dermatology, 44, 219, 250, 301 Diabetes-Metabolism Research and Reviews, 44, 136, 242 Diabetologia, 44, 136, 242 Diagnostic Microbiology and Infectious Disease, 44, 121, 218, 224, 229

Digestive Surgery, 44, 275, 284 Drug and Alcohol Dependence, 44, 202 Drugs & Aging, 44, 272

EJSO, 44, 97, 118 Enfermedades Infecciosas y Microbiología, 50, 97-99, 101, 118, 129, 130, 284 Europace, 44, 151 European Heart Journal, 44, 151, 152 European Journal of Applied Physiology, 44, 179 European Journal of Clinical Pharmacology, 44, 272 European Journal of Echocardiography, 44, 152, 153 European Journal of Gastroenterology & Hepatology, 44, 203, 209, 251 European Journal of Gynaecological Oncology, 44, 99, 118 European Journal of Human Genetics, 45, 255 European Journal of Neurology, 45, 167, 193 European Journal of Nuclear Medicine and Molecular Imaging, 45, 303 European Journal of Obstetrics Gynecology and Reproductive Biology, 45, 119, 130, 251, 258, 301 European Journal of Radiology, 45, 153 European Respiratory Journal, 45, 209, 219, 242, 260 European Spine Journal, 45, 260 European Urology, 45, 119 Experimental Diabetes Research, 45, 136 Expert Opinion on Pharmacotherapy, 45, 167 Expert Review of Anticancer Therapy, 45, 97 Expert Review of Proteomics, 45, 101 Eye, 45, 265

Familial Cancer, 45, 98, 101 Fertility and Sterility, 45 Free Radical Biology and Medicine, 45, 241 Future Microbiology, 45, 167

330

Gaceta Sanitaria, 50, 202, 242 Gastroenterology, 41, 45, 172, 208, 209, 211 Gene Therapy, 45, 269 Genes and Immunity, 45, 166 Genes Brain and Behavior, 45, 203 Genome Research, 41, 45, 215 Gerontology, 45, 241 Gut, 45, 215

Haematologica-the Hematology Journal, 45, 119, 122, 129, 277 Health and Quality of Life Outcomes, 45, 241, 251 Heart, 45, 151, 152 Hepatology, 41, 45, 208, 209 Histopathology, 45, 129 HIV Medicine, 45, 225 Human Brain Mapping, 45, 202 Human Genetics, 45, 194 Human Molecular Genetics, 45, 284 Human Reproduction, 45, 258, 303

IEEE Transactions on Medical Imaging, 45, 215 Infection, 45, 219 Inflammatory Bowel Diseases, 45, 215 Intensive Care Medicine, 45, 219 International Journal of Antimicrobial Agents, 45, 218, 229 International Journal of Cancer, 46, 104, 129 International Journal of Colorectal Disease, 46, 214 International Journal of Geriatric Psychiatry, 46, 157 International Journal of Gynecological Pathology, 46, 100, 101 International Journal of Neuroscience, 46, 193 International Journal of Radiation Oncology , 46, 101 International Reviews of Immunology, 46, 250 Investigative Ophthalmology & Visual Science, 46, 136, 151

JAMA-Journal of the American Medical, 41, 46, 151, 156, 157 Journal of Affective Disorders, 46, 202

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Annual Report 2010

Journal of Alzheimer’s Disease, 46, 129, 156, 157, 202 Journal of Allergy and Clinical Immunology, 46, 214, 237, 250, 303 Journal of Antimicrobial Chemotherapy, 46, 218, 219, 224, 225 Journal of Biological Chemistry, 46, 98, 118, 157, 194, 284, 292 Journal of Biomedical Materials Research Part A, 46, 250, 301 Journal of Biomedicine and Biotechnology, 46, 136 Journal of Cardiothoracic Surgery, 46, 155 Journal of Cellular Biochemistry, 46, 119 Journal of Clinical Endocrinology & Metabolism, 46, 128, 143, 250, 255 Journal of Clinical Investigation, 41, 46, 100 Journal of Clinical Microbiology, 46, 225, 229 Journal of Clinical Oncology, 41, 46, 96-101, 122, 130, 275 Journal of Crohns & Colitis, 46, 215 Journal of Heart and Lung Transplantation, 46, 219, 225, 242 Journal of Hepatology, 46, 209 Journal of Hypertension, 46, 139, 242 Journal of Immunological Methods, 46, Journal of Immunology, 46, 167 Journal of Infectious Diseases, 46, 143, 166, 229 Journal of Interferon and Cytokine Research, 46, 167 Journal of Lipid Research, 46, 96 Journal of Medical Genetics, 46, 199, 255 Journal of Minimally Invasive Gynecology, 46, 118 Journal of Molecular and Cellular Cardiology, 46, 152 Journal of Molecular Diagnostics, 46, 255 Journal of Neural Transmission, 46, 203 Journal of Neurochemistry, 46, 194 Journal of Neuroimmunology, 47, 166 Journal of Neurology, 47, 166, 167, 173, 193

319

Index

Journal of Neuropathology and Experimental Neurology, 47, 97, 129, 193 Journal of Neuroscience, 47, 159, 176, 188, 194 Journal of Neurosurgery, 47, 173, 183, 194 Journal of Nuclear Cardiology, 47, 151 Journal of Nutrition Health & Aging, 47, 157, 215 Journal of Pediatric Endocrinology & Metabolism, 47, 143 Journal of Pediatric Orthopaedics, 47, 253 Journal of Pediatric Surgery, 47, 129, 253 Journal of Physiology-London, 47, 153, 155 Journal of Proteome Research, 47, 97 Journal of Psychiatric Research, 47, 202 Journal of Rheumatology, 47, 250, 251 Journal of Sleep Research, 47, 242 Journal of the American College of Cardiology, 47, 151 Journal of the Neurological Sciences, 47, 159, 176, 188, 194, 197, 303 Journal of Thoracic and Cardiovascular Surgery, 47, 153 Journal of Translational Medicine, 47, 130 Journal of Trauma-Injury Infection and Critical Care, 47, 219 Journal of Urology, 47, 119, 129 Journal of Viral Hepatitis, 47, 208 Journal of Water and Health, 47, 209 Journal of Womens Health, 47, 233

Medicina Clínica, 50, 100, 130, 136, 151, 153, 194, 214, 215, 218, 241, 250, 251, 258, 272, 275, 294, 301 Medicine, 47, 237, 251, 275 Metabolic Brain Disease, 47, 209 Microvascular Research, 47, 194 Mitochondrion, 47, 179 Molecular Biology of the Cell, 41, 48, 179 Molecular Cancer Research, 48, 289 Molecular Cancer Therapeutics, 48, 99 Molecular Genetics and Metabolism, 48, 197 Molecular Psychiatry, 48, 202, 255 Movement Disorders, 48, 176, 203 Multiple Sclerosis, 48, 166, 167, 173, 229

Lancet, 41, 47, 98, 101, 122, 129, 153, 192, 251 Lancet Neurology, 41, 47, 167 Lancet Oncology, 41, 47, 96, 101 Leukemia & Lymphoma, 47, 118, 122 Life Sciences, 47, 202 Liver International, 47, 129, 152, 208, 209 Lung Cancer, 47, 100 Lupus, 47, 153, 251

Obesity Reviews, 48, 136 Obesity Surgery, 48, 136, 209, 242 Obstetrical & Gynecological Survey, 48, 250, 301 Oncogene, 48, 96, 97, 128, 133 Oncologist, 48, 100 Ophthalmology, 48, 265

331

Nature, 41, 48, 96, 215 Nature Neuroscience, 41, 48, 176 Nature Reviews Neurology, 48 Nefrología, 50, 139 Nephrology Dialysis Transplantation, 48, 139, 250 Neurobiology of Aging, 48, 176 Neurobiology of Disease, 48, 130 Neurocirugía, 50, 183, 218 Neurogastroenterology and Motility, 48, 214, 215 Neurología, 50, 157, 166, 167, 173, 183, 193 Neurology, 48, 167, 172, 173 185, 193, 194 Neuropsychopharmacology, 48, 202 Neuroradiology, 48, 172 Neuroscience Letters, 48, 203 New England Journal of Medicine, 41, 48, 118, 166 Nutrición Hospitalaria, 50, 214, 303

Pediatric Infectious Disease Journal, 48, 152, 229, 242, 275, 303

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Pediatric Neurology, 48, 128, 197 Pediatric Radiology, 48, 253 Pediatric Research, 48, 179 Pediatric Transplantation, 48, 118, 241 Pharmacogenomics, 48, 167, 194, 251 PLoS Genetics, 48, 100 PLoS Medicine, 48, 202 PLoS One, 48, 104, 119, 130, 136, 179, 197, 299 Proceedings of the National Academy of Sciences, 48, 197 Prostate, 48, 118, 119, 130 Psychiatric Genetics, 48, 202 Psychiatry Research-Neuroimaging, 48, 203

Respiratory Care, 48, 219, 242 Respiratory Medicine, 48, 130, 218, 219, 242 Respirology, 49, 242 Retina-the Journal of Retinal and Vitreous, 49, 136 Revista Clínica Española, 50, 233

Revista Española de Cardiología, 50, 136, 151-153 Revista Española de Enfermedades Digestivas, 50, 214 Revista Española de Medicina Nuclear, 50, 151, 152 Revista de Neurología, 50, 152, 157, 167, 169, 172, 173, 183, 194, 203, 250, 275 Rheumatology, 49, 251

Sarcoidosis Vasculitis and Diffuse Lung Diseases, 49, 242 Scandinavian Journal of Rheumatology, 49, 251 Seminars in Arthritis and Rheumatism, 49, 251, 275 Seminars in Liver Disease, 49, 209 Stem Cells, 41, 49, 209 Stroke, 49, 188, 193, 194, 294

Thorax, 49, 242 Thrombosis and Haemostasis, 49, 151, 277

332

Thyroid, 49, 151 Transfusion and Apheresis Science, 49, 303 Transplant Infectious Disease, 49, 225 Transplant International, 49, 139 Transplantation, 49, 172, 209, 250 Tumori, 49, 97, 118, 294

Urologia Internationalis, 49, 119, 130 Urology, 49, 255

Vox Sanguinis, 49, 209, 303

World Journal of Biological Psychiatry, 49, 203 World Journal of Surgery, 49, 130, 205, 209 World Journal of Urology, 49, 119, 129 Worldviews on Evidence-Based Nursing, 49, 219

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