CIBERehd Memoria 2011 by Ernest Figueras

2011 annual RePort

Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas

Instituto de Salud Carlos III

2011 annual RePort

Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas

Index

6 7 12

introduction

Dr. Jaume Bosch Genover CIBERehd in figures

15 ASSOCIATED CENTERS 18 TECHNOLOGICAL PLATFORMS AND COMMON INFRASTRUCTURES

20 E- CAHD: e-CATCH and e-Colon Risk Platform 22 Genome Platform 23 Proteomics Platform 24 Metabolomics Platform 25 Biobank 26 Bioinformatics Platform 28 Pyrosequencing Platform 29 CiberHEP 30 Rehevasc 32 Training Plan

34 scientific Activities of the programs

36 Program 1. Portal Hypertension and Mechanism of Cirrhosis Transition 37 Presentation: Dr. Agustín Albillos 46 Dr. Agustín Albillos Martínez 48 Dr. Vicente Arroyo Pérez 52 Dr. Rafael Bañares Cañizares 54 Dr. Jaume Bosch Genover 58 Dr. Juan Córdoba Cardona 60 Dr. Carlos Guarner Aguilar 62 Dr. Ramón Planas Vilà 64 Dr. José Such Ronda 66 Program 2. Viral Hepatitis 67 Presentation: Dr. J. I. Esteban Mur 70 Dr. Juan Ignacio Esteban Mur 72 Dr. Rafael Esteban Mur 74 Dr. Xavier Forns Bernhardt 76 Dr. Javier García-Samaniego Rey 78 Dr. Jordi Gómez Castilla 80 Dr. Ricardo Moreno Otero 82 Dr. Manuel Romero Gómez 84 Dr. Francisco Javier Salmerón Escobar 88 Program 3. Cholestasis, Metabolic Disorders and Hepatotoxicity 89 Presentation: Dr. Juan F. Medina 92 Dr. Raúl Andrade Bellido 94 Dr. José Vicente Castell Riopoll

96 Dr. José Fernández-Checa Torres 98 Dr. Javier González Gallego 100 Dr. José M. Mato de la Paz 104 Dr. Juan F. Medina Cabrera 106 Dr. Albert Parés Darnaculleta 108 Dr. Ignacio Vicente Sandoval 110 Dr. Paloma Martín Sanz 112 Dr. Carmelo García Monzón 114 Dr. Llorenç Caballeria 116 Program 4. Immunology and Liver Transplantation 117 Presentation: Dr. Antoni Rimola 122 Dr. Marina Berenguer Haym 124 Dr. Manuel de la Mata García 126 Dr. Pascual Parrilla Paricio 128 Dr. Antoni Rimola Castellá 130 Dr. Mª Rocío Álvarez López 132 Program 5. Hepatic and Gastrointestinal Oncology 133 Presentation: Dr. Jordi Bruix 142 Dr. Jordi Bruix Tudó 144 Dr. Luis Bujanda Fdez de Piérola 146 Dr. Antoni Castells Garangou 150 Dr. José Juan García Marín 152 Dr. Marçal Pastor-Anglada 154 Dr. Jesús Prieto Valtueña 158 Program 6. Gastrointestinal Inflammation or Motility 159 Presentation: Julián Panés Díaz 166 Dr. Fernando Azpiroz Vidaur 168 Dr. Eduard Cabré Gelada 170 Dr. Xavier Calvet Calvo 172 Dr. Pere Clavé Civit 174 Dr. Daniel Closa Autet 176 Dr. Javier Vicente Esplugues Moto 180 Dr. Francisco Guarner Aguilar 182 Dr. Ángel Lanas Arbeloa 184 Dr. Julián Panés Díaz 186 Dr. Javier Pérez Gisbert 190 Dr. Antonio Zarzuelo Zurita 192 Dr. María Esteve Comas 194 Dr. Belén Beltrán Niclós

196 PUBLICATIONS 230 HIGHLIGHTS

232 V CIBERehd’s Scientific Meeting 235 The 9 CIBER open social dialogue 237 Diffusion

238 FINANCIAL REPORT

Program guide

Program 1 Portal Hypertension and Mechanism of Cirrhosis Transition Program 2 Viral Hepatitis

Program 3 Cholestasis, Metabolic Disorders and Hepatotoxicity Program 4 Immunology and Liver Transplantation

Program 5 Hepatic and Gastrointestinal Oncology Program 6 Gastrointestinal Inflammation and Motility

Introduction

Introduction - 7

Introduction Dr. Jaume Bosch Genover. Scientific Director CIBERehd

hank you so much for following the scientific activity of the Biomedical Network Research Centre for Hepatic and Digestive Diseases (CIBERehd). We are deeply satisfied to present the 2011 annual report of scientific activities. It closes the first four-year action plan of CIBERehd that we have managed to carry out with success despite the economic difficulties of recent years.

biotechnological and pharmaceutical industry. d) Promoting the participation in activities of priority research in the national sphere and in the projects included in the European Framework Programs of R + D + I. e) Promoting the diffusion of its activities and the training of competitive researchers in the field of digestive and liver diseases.

CIBERehd is a public consortium the aim of which is to promote high level translational research through the interaction of the best Spanish groups. CIBERehd provides its member groups with economic support to finance research and support staff, collaborative projects, common technological platforms, scientific-technical infrastructure and the development of training activities. Established on November 29th, 2006, in 2011 it is made up by 51 groups (4 of them associate) from 30 centres distributed in 9 Autonomous Regions.

CIBERehd is directed by the Scientific Director, appointed by the ISCIII, who assumes the responsibility of all CIBERehd actions with the assistance of the Steering Committee (presided by the Scientific Director and comprising the Manager, the Training Coordinator and the Coordinators of Programs and Technological Platforms). He establishes the multiannual action plan and its budget. CIBERehd funding mostly comes (80%) from the ISCIII grants that are basically used to cover expenses of indefinite or temporary hiring of research and support staff, to buy scientific-technical infrastructure and, to a lesser extent, to train research staff and to cover management and current expenses. The consorted institutions contribute with their facilities, services, and part of their staff (their staff researchers adhered to CIBERehd). Likewise, CIBERehd self-finances more than 10% of its budget.

Our mission is: a) Execution of joint programmes of research, development and innovation in digestive and liver diseases promoting interaction and synergies among the best Spanish groups. b) Contributing to the resolution of health care problems related to the above mentioned areas. c) Promoting the transfer of results of the research processes toward clinical applications and to society, especially in the

The scientific policy of CIBERehd is supervised by the External Advisory Scientific Council, which also makes a yearly evaluation of its activity.

8 - CIBERehd - 2011 ANNUAL REPORT - INTRODUCTION

INTRODUCTION Board of Trustees Permanent Commission Scientific Council Steering Committee CIBERehd

Scientific Director Managing Director Program Coordinator

Steering Advisory Committee

Research Groups Investigators Multi-year plan based on objectives Continued follow-up and evaluation

The whole activity and its budget must be approved by the Governing Council, which is presided by the ISCIII Director and its members are all the consorted institutions. We also count on a Management Advisory Committee (advisor organ integrating outstanding personalities of Spanish hepatology and gastroenterology), Assistant Coordinators (who collaborate with programme coordinators in the development and coordination of the different research lines of each programme), and a Consultative Committee (to speed up communication and to collaborate in the elaboration of strategic plans). The internal structure of CIBERehd is summarized in Figure 1. This structure represented a great novelty in the Spanish scientific arena since it establishes that CIBER centres must be driven by their own researchers, who determine their needs, resources and the temporary execution plan. This implies elevated additional funding for the groups involved that have vocation of continuance throughout time. In this annual report we present the main data of our activity and the results obtained by CIBERehd during 2011. The scientific activity of CIBERehd is carried out chiefly through its research programmes and strategic actions. It is complemented with the training plan,

Figure 1.

the platforms and common resources, the agreements with consorted institutions for the creation of research laboratories and the provision of scientific and support infrastructure for certain research projects with external financing (Figure 2). In this report you will find CIBERehd’s global results, the main achievements of each of the 6 main research programmes, a more detailed description of the groups’ activity, together with a summary of data from previous years so as to have an overall view of CIBERehd’s scientific path since its establishment. In this year, I would like to highlight, first of all, the great effort done to keep the contracts of our staff (about 150 contracts) and, secondly, the results of the work done by the 51 research groups comprising CIBERehd. This year, 394 articles were published, 75% of them in journals within the first quartile, totalling 2,424.393 Impact Factor points, which means an average of 6.15 points per article. This clearly shows the quality of the research done, even more if we bear in mind that the ISCIII obliges to count also the publications in the second quartile. It is noteworthy that 160 articles appeared in journals ranking within the 10% best in the world (ISI first decile).

Introduction - 9

INTRODUCTION Hepatology Areas (Portal hypertension/ Hepatitis/ Cholestasis and metabolic disorders/ Immunology and liver transplantation/ Hepatic cancer) Gastroenterology (Hepatic and gastrointestinal oncology/ gastrointestinal inflammation and motility) Extramural program Technological Platforms (Biobank/ Genomic, Proteomic, Metabolonic and Gene Knockdown Platforms/ E-CAHD/Pyrosequencing Platform/ Bioinformatics Platform and ciberHEP platform) Strategic Actions

Training Plan

Strategic Actions Figure 2.

Steering Committee Scientific Director Managing Director Teaching Coordinator

Jaume Bosch Ernest Figueras Joan Caballería

PROGRAM

Coordinator

Deputy Coordinator

Program 1 Program 2 Program 3 Program 4 Program 5 Program 6

Agustín Albillos Juan I. Esteban Juan F. Medina Antoni Rimola Jordi Bruix Julián Panés

JC. García Pagán/P. Ginés/ J. Córdoba X. Forns/ M. Moreno JC. F-Checa/ A. Parés M. Berenguer/ A. Minguela A. Castells / JJ. García-Marín F. Azpiroz/ A. Lanas

10 - CIBERehd - 2011 ANNUAL REPORT - INTRODUCTION

INTRODUCTION Andalucía (6) • CSIC. Instituto de Parasitología y Biomedicina López Neyra (1) • Hospital Virgen de la Victoria (1) • Hospital Universitario de Valme (1) • Hospital Universitario Reina Sofía (1) • Hospital Universitario San Cecilio (1) • Universidad de Granada (1) Aragón (1) • Instituto Aragonés de Ciencias de la Salud (1) Cataluña (21) • Consejo Superior de Investigaciones Científicas (2) • Hospital Clínic de Barcelona (8) • Hospital de la Santa Creu i Sant Pau (1) • Corporació Sanitària Parc Taulí (1) • Hospital Germans Trias i Pujol (2) • Institut de Recerca de l’Hospital de la Vall d’Hebron (5) • Universidad de Barcelona (1) • Hospital de Mataró (1)

País Vasco Navarra

2 2

Cataluña

Castilla y León

Aragón

Madrid

5 Valencia Murcia

2 6

Andalucía

Castilla y León (2) • Universidad de León (1) • Universidad de Salamanca (1) Murcia (2) • Hospital Universitario Virgen de la Arrixaca (2) Valencia (5) • Hospital General Universitario de Alicante (1) • Hospital Universitario La Fe (3) • Universidad de Valencia (1)

Madrid (8) • Hospital Carlos III (1) • Hospital General Universitario Gregorio Marañón (1) • Hospital Universitario La Princesa (2) • Hospital Universitario Santa Cristina (1) • Universidad Alcalá de Henares (1) • CSIC (2)

CIBERehd funds 2009 2010 2011

REGISTERED GRANT (ISCIII) REGISTERED GRANT (ISCIII) REGISTERED GRANT (ISCIII)

5,607,710 4,533,360 4,272,510

Navarra (2) • Clínica Universitaria de Navarra (1) • Fundación para la Investigación Médica Aplicada (1) País Vasco (2) • CIC bioGUNE (1) • Hospital de Donostia (1)

Strategic actions ............................ 4% Platforms............................................ 4% Training ................................................ 1% Management & Cord. ................... 11% Staff .................................................... 55% Scientific equipment.................... 20% External collaborations �� 5%

Introduction - 11

INTRODUCTION These excellent publications stand for 40% of CIBERehd’s publications and their Impact Factor is 1,540.295. This represents an ongoing progress on the figures of previous years, in spite of the smaller subsidy received. In our opinion, this is a remarkably outstanding achievement considering the context in which it has been obtained. Likewise, cooperation within CIBERehd goes on rising through numerous collaborative studies that cover all programmes, without significant variations from one another. CIBERehd groups collaborated in 98 publications, which means a nearly 50% increase. In line with this, there has been a large number of international contributions, which represent the majority of the publications in the first quartile. This activity of excellence was developed at basic research level as well as in translational and clinical research. All research programmes of CIBERehd are involved in it. Among the results of our activity, we would like to emphasize new contributions to the treatment of: portal hypertension; the effect of anti-inflammatories in the gastric mucosa; setting up a catalogue of genes of the intestinal flora; characterization of signposting ways in liver and colorectal cancer; the study of genetic determinants that favour the occurrence of liver encephalopathy and inflammatory bowel disease; studies on mechanisms of liver fibrogenesis, hepatotoxicity by drugs, non-alcoholic liver steatosis, hepatitis B and C, cholestasis, bacterial translocation, circulatory dysfunction, liver vascular diseases, non-invasive evaluation, imaging tests and development of new biomarkers. It is also important to underline that CIBERehd has managed to keep a significant transferring activity, expressed in 150 clinical trials, 52 of them started in 2011, 12 patents, and the development of 25 clinical guides, both national and international. Outstanding members of CIBERehd take part in the Editorial Councils of the best journals in the sphere of hepatic and digestive diseases. I would also like to emphasize the positive comments on the part of the External Advisory Scientific Committee, which comprises Drs. G. Garcia-Tsao (University of Yale), Roger Butterworth (University of Montreal); Massimo Pinzani (University of Florence); Sophie Lotersztajn (University of Paris); Jean Pierre Vinel (University of Toulouse); Silvio Danese (University of Milan) and Evelien Dekker (University of Amsterdam). The report of this important advisory and supervisor organ qualifies the work of CIBERehd as Excellent in all his programmes, and it emphasizes the growing rhythm in publications of excellence, the increase of collaboration and of transferring and training activities. It acknowledges many

of CIBERehd’s researchers as international leaders in their respective fields of research. Given the difficult economic situation we are living and the important budgetary cuts it implies, there is no doubt that it is going to be hard, if not impossible, to keep with the extremely high level achieved in the first five years of existence. Nevertheless, in CIBERehd we are going to put all our efforts to get it. In this first five-year period, CIBERehd has been consolidated as the utmost excellence Spanish centre in this speciality and it is internationally outstanding. Among its researchers there are unquestioned opinion leaders such as Drs. Vicente Arroyo and Pere Ginés in ascites and renal function disorders in liver cirrhosis; Dr. Jaume Bosch in portal hypertension (Programme 1); Dr. Fernando Azpiroz in gastrointestinal motility (Programme 6); Dr. Jordi Bruix in hepatocell carcinoma; Dr Antoni Castells in digestive cancer, (Programme 5); Drs. Xavier Forns, María Buti and R and JI Esteban in Hepatitis B and C (Programme 2); Dr. Angel Wools in gastric toxicity by drugs; Dr. Julian Panés in inflammatory bowel disease (Programme 6); Dr. José Mª Mato in liver proteomics and metabolomics; Dr. Raúl Andrade in hepatotoxicity by drugs (Programme 4); and Dr. Jesus Prieto in gene therapy (Programme 5). Finally, it is worth reminding that digestive and liver diseases represent a particularly relevant area, so much in clinical practice as in research, since they are very common in Spain and they involve a high socio-economic cost. Thus, cirrhosis is the fifth cause of death in adults and digestive and liver cancers are the most frequent ones. More than 3% of the Spanish population is chronically infected by hepatitis C or B virus; 60% habitually consumes alcohol; and nonalcoholic steatohepatitis is on the rise, affecting more than 20% of the population, in a context in which 36% of people is overweight and 18% suffer from obesity. As usual, we would like to thank the authorities of the ISCIII, the members of the Governing Council and the Scientific Council and all the professionals that have made and still make it possible for CIBERehd to consolidate as a reference centre and to carry out its mission at the highest international level.

Dr. Jaume Bosch Scientific Director of CIBERehd

12 - CIBERehd - 2011 ANNUAL REPORT - INTRODUCTION

CIBERehd IN FIGURES HIRED PERSONNEL STAFF Percentage by Gender

Male Average Staff by Category

0% 8%

26%

49%

74%

43%

Doctor Licensed Diplomat Technician

Men Women

Female Average Staff by Category

Male Staff by Occupation

20%

30%

12% 38%

Doctor Licensed Diplomat Technician

83% Researcher Technician Administration

Introduction - 13

CIBERehd IN FIGURES

Female Staff by Occupation

Average Staff by Autonomous Community 4% 8% 3% 5% 6% 2%

9% 16%

Andalucía Aragón Cataluña Castilla y León Madrid Murcia Navarra Valencia País Vasco

12%

75%

58%

2% Researcher Technician Administration

Average Staff by Degree

OTHERS

VETERENINARY

LAB TECHNICIAN

CHEMISTRY

MEDICINE

PHARMACY

NURSERING

BIOTECNOLOGY

BIOCHEMISTRY

BIOLOGY

70 52 35 17

14 - CIBERehd - 2011 ANNUAL REPORT - INTRODUCTION

CIBERehd IN FIGURES ATTACHED STAFF First Quartile Publications by Program

Attached Staff

122

120 100 80

40%

60%

54 45

Men Women

FIRST QUARTILE PUBLICATIONS

FIRST DECILE PUBLICATIONS

First Decile Publications by Program 100

300 200

277 212

300

232

162

300 200 130

133

167

80 60

100

2008 2009 2010 2011

Associated centers - 15

Associated Centers

16 - CIBERehd - 2011 ANNUAL REPORT - ASSOCIATED CENTERS

ASSOCIATED CENTERS • Instituto de Salud Carlos III (ISCIII) • Consejo Superior de Investigaciones Científicas (CSIC) • Fundación para la Investigación Biomédica de Córdoba (FIBICO) • Fundación de Investigación Biosanitaria en Andalucía Oriental (FIBAO) • Fundación Pública Andaluza para la Investigación en Salud en Sevilla • Instituto Aragonés de Ciencias de la Salud • Universidad de León • Universidad de Salamanca • Corporació Sanitària Parc Taulí • Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol • Universitat de Barcelona • Fundación para la Investigación del Hospital General Universitario de Alicante • Fundación para la Investigación del Hospital La Fe • Universitat de València • Universidad de Alcalá de Henares • Fundación para la Formación e Investigación Sanitarias de la Región de Murcia • Hospital Clínic i Provincial de Barcelona • Institut d’Investigació de l’Hospital de la Santa Creu i Sant Pau • Clínica Universidad de Navarra • Fundación para la Investigación Médica Aplicada • Asociación Instituto Biodonostia • Fundación Privada Salud del Consorcio Sanitario del Maresme • Fundación Instituto Mediterráneo para el Avance de la Biotecnología Sanitaria (IMABIS) • Universidad de Granada • CIC bioGune • Institut de Recerca de l’Hospital Universitari Vall d’Hebron • Hospital Universitario de La Princesa • Fundación para la Investigación Biomédica del Hospital Carlos III • Fundación para la Investigación Biomédica del Hospital Gregorio Marañón

Associated centers - 17

FUNDA IA CI AR

DE INVE TO ST TU

LA FE - INST I ÓN

ÓN SAN ACI IT IG

18 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

Technological Platforms and Common Infrastructures

Technological Platforms and Common Infrastructures - 19

• • • • • • • • •

e-CAHD: e-CATCH and e-ColonRisk Platform Genome Analysis Platform Proteomics Platform Metabolomics Platform Biobank Platform Bioinformatics Platform Pyrosequencing Platform Clinical database of chronic hepatitis B patients (CIBERHEP) REHEVASC (Vascular Liver Disease Registry)

20 - CIBERehd - 2011 ANNUAL REPORT - e-CAHD

Technological Platforms AND COMMON INFRASTRUCTURES e-CATCH Platform

A technological platform to assist professionals and patients during the diagnosis and therapy of liver cancer, developed by the Hepatic Oncology Group of CIBERehd, led by Dr. Jordi Bruix.

This platform allows patients in any geographical area to benefit from clinical management based on expert knowledge derived from the most important clinical studies. Its use is open to every doctor, member of the National Health System, who can consult both specific cases and individual information. The information is provided by evidence-based medicine reports. It also helps to homogenize qualitatively the different preventive, diagnostic and therapeutic strategies as well as the new imaging techniques used in liverâ&#x20AC;&#x2122;s cancer. On the other hand, it will improve the understanding of the disease and its better management, while incorporating the latest information about ongoing clinical essays

Technological Platforms and Common Infrastructures - 21

Technological Platforms AND COMMON INFRASTRUCTURES e-Colon Risk

E-ColonRisk is the platform for risk assessment and prevention of colorectal cancer. Developed by the Pancreatic and Gastrointestinal Oncology CIBERehd group, led by Dr. Antoni Castells. The aim of this platform is to give the National Health Service a new way of preventing colorectal cancer based on a specific and specialized attention of patients with an increased risk of getting colorectal cancer, either because of personal or family factors. Through this initiative, the identification of individuals or patients with an increased risk of suffering from this cancer and the suggestion of appropriate measures to prevent its development, become possible. The globally pioneered initiative, aimsto assist centres where there is a lack of tools, primary care, or health workers in the prevention field, by making recommendations based on current and up-to-date scientific knowledge. The computer program brings together, for the first time in the world, the illustration of solutions and the analysis of clinical records and genetic studies (Progeny) with an intranet platform based on the CMS Plone/Zope, allowing unlimited number of users to access it through a simple web interface. The Platform, user-friendly, is accessible through its website www.colonrisk.org or at the CIBERehdâ&#x20AC;&#x2122;s website www.ciberehd.org. It is possible to exchange information between agents in a safe and confidential environment through its archive.

CIBERehd makes available to the National Health System its Risk Assessment and Prevention of Colorectal Cancer (e-ColonRisk) Platform, an innovative initiative for the prevention of cancer based on the specific care of people and patients with colorectal cancer risk.

22 - CIBERehd - 2011 ANNUAL REPORT - GENOME ANALISIS & PROTEOMICS PLATFORM

Technological Platforms AND COMMON INFRASTRUCTURES Genome Analysis Platform The word “biogune” means a site for biosciences, which is precisely what CIC bioGUNE is: a place that attracts talented researchers from all over the world. By setting up joint projects with other scientific institutions, it has become a center of excellence for biomedical research. With this vision, in 2007, CIC bioGUNE and CIBERehd signed a collaboration agreement that allows researchers, in this research network, access to technology platforms at CIC bioGUNE. The main goal of the Genome Analysis Platform is the optimisation of sample processing protocols for a set of sophisticated, state-of-the-art, highthroughput genome analysis technologies. The principal methodologies used deal with the characterisation of variants at gDNA sequence level (mainly Single Nucleotide Polymorphisms –SNPs and Copy Number Variations– CNVs), changes at mRNA or smallRNA expression level and epigenetic modifications. Recently, the group has also established appropriate workflow procedures for data analysis, and keeps on working to develop new bioinformatics tools. Services 1. High-throughput genotyping: standard panels from 10000 up to 4.5 million SNPs for different species and customised panels from 96 to 60000 SNPs. 2. High-throughput gene expression characterisation: whole genome transcripts analysis of human and mouse tissues using standard Illumina chips. 3. Characterisation of differential methylation as epigenetic modification: analysis of 450000 loci along the human genome. 4. Next-generation sequencing: - De novo sequencing and resequencing of genomic DNA:

• BAC (bacterial artificial chromosome) end sequencing • Genomic regions of interest • Complete genes • Complete chromosomes • Complete genomes - DNA methylation analysis at the complete genomelevel. - Expression analysis (complete transcriptome). - Identification and analysis of microRNA and smallRNA. - DNA-protein interactions (ChIP-Seq). 5. Assistance in designing customised SNP panels (for genotyping projects). 6. Results can be delivered as raw data or analysed after discussion with the responsible of the service. Equipment BeadStation 500 GT/GX (Illumina Inc.), Genome Analyzer II (Illumina Inc.). HiScaSQ (Illumina Inc.) In addition, we have all the equipment required to performvarious molecular biology experiments: Experion (BioRad) and Bioanalyzer (Agilent Technologies) systems, EpiMotion (Eppendorf) liquid handling workstation, centrifuges, electrophoresis apparatus, gel imaging systems, etc.

Technological Platforms and Common Infrastructures - 23

Technological Platforms AND COMMON INFRASTRUCTURES Proteomics Platform By analyzing the abundance of proteins under different physiological or experimental conditions it is possible to identify groups of proteins that are relevant for these specific conditions. Differential in-gel electrophoresis (DIGE) is nowadays the most powerful technique for gel-based differential proteomic analysis. During the last decade genomes from many organisms, including human, have been sequenced. The availability of genomic sequences has boosted the proteomic research as the data obtained by analyzing proteins and peptides by mass spectrometry can be directly linked to the genomic information, using bioinformatics methods. Continuous optimization of sample preparation while employing the latest generation of tandem mass spectrometers, with their constantly improving high mass accuracy, high resolution and sensitivity, makes the protein identification process increasingly fast and accurate. The Proteomics Platform provides services to in-house groups and external users and offers joining forces for collaborative research projects. Services 1. Molecular mass determination by MALDI TOF. Peptide and/or protein mass can be measured in a straight forward fashion by linear mode type of analysis. 2. Protein identification by MALDI TOF/TOF. The proteins previously purified or resolved on a gel can be identified by peptide mass fingerprinting (PMF). The process includes: protein digestion by trypsin, peptide extraction when required, sample preparation, analysis by MALDI TOF, data processing and database search by Mascot search engine. The sample, when possible, can also be analyzed by peptide fragment fingerprinting using MALDI TOF/TOF. 3. Protein identification by nano scale liquid chromatography coupled on-line to tandem mass spectrometry. Complex protein mixtures can be analysed and identified in such systems. 4. Differential in-gel-electrophoresis (DIGE). Due to the special nature of DIGE experiments, please contact the head of the unit. Useful information is shown in the web page like correct sample handling tips etc. On top of that we offer advice to choose the right sample preparation, handling procedures and analytical methodology of choice.

Equipment MALDI: 1. Autoflex III TOF/TOF (Bruker): this mass spectrometer allows performing different types of analysis: Intact peptide/protein molecular mass analysis can be performed. Protein identification by peptide mass fingerprinting (MALDI-TOF) and/or peptide fragment fingerprinting MALDI TOF/TOF). 2. Agilent 1200 nano scale chromatography system for offline MALDI TOF/TOF analysis. 3. Proteineer DP robotic station (Bruker) for automatic tryptic digestion of gel spots. Liquid chromatography coupled to tandem mass spectrometry systems: 4. Nano Acquity UPLC chromatography system coupled on-line to Synapt G2 (Waters). 5. Nano Acquity UPLC chromatography system coupled on-line to LTQ-Orbitrap XL (Thermo-Fisher). These two high sensitivity, mass accuracy and resolution systems have the latest technical features for optimal identification of proteins from complex mixtures. Differential in-gel electrophoresis (DIGE): 6. Typhoon TRIO, spot picker and DeCyder. DIGE is nowadays the most robust approach for gelbased differential proteomic analysis.

24 - CIBERehd - 2011 ANNUAL REPORT - METABOLOMICS & BIOBANK PLATFORM

Technological Platforms AND COMMON INFRASTRUCTURES Metabolomics Platform spectrometers coupled to ultra-performance liquid chromatography (UPLC).

Based on sophisticated mass spectrometric and statistical methods, the Metabolomics Platform offers a powerful approach in the search for biochemical pathways and biomarkers. By qualitative and quantitative analysis of small, endogenous molecules we are able to determine changes in physiological states pointing to disease, toxic events or pharmacological effects. In this “Global Systems Biology” era, metabolomics constitutes one of the most powerful technologies to understand how a living organism interacts with its environment. Metabolomics can be defined as the quantitative and qualitative analysis of all metabolites (small molecules with a molecular weight of less than 1,500 Da) in a given organism. This results in the construction of a metabolome or metabolic fingerprint, analogous to the genome or the proteome. Metabolomics has clear advantages in that metabolites are closely related to real biological end-points. Furthermore it takes into account the complete biological system, including e.g. interactions with other genomes like gut microflora. Because metabolomics makes use of biofluids (urine, serum, CSF) it is a minimal invasive technique. Metabolomics makes use of well established, robust analytical platforms, which results in very reproducible, fast and cost effective analysis. The metabolomics platform focuses primarily on changes in the metabolome since these can be indicative for alterations in the physiological state of the organism. Altered metabolic profiles can be caused disease or exposure to drugs and toxins. In order to detect relevant metabolites, the platform uses high-resolution mass

Services The aim of this platform is to provide support to research groups interested in including a full systems analysis in their current research line. The platform offers: • Assistance in the experimental design including attainable and appropriate statistical sampling and logistic aspects in order to achieve satisfactory data. • Untargeted metabolomics: analysis of metabolites in biofluids, cells and tissues with UPLC-MS/MS. Methionine cycle, retinol metabolism, polyamines, amino acids, and requested metabolites of particular interest for the research groups. • Hepatotoxicity: 1. Non-invasive detection and quantitation of liver toxicity based on targeted metabolic profiling of serum samples (LIVERTOX, in-vivo drug-toxicity analysis). 2. Analysis of reactive metabolites associated to hepatotoxicity using trapping agents (in-vitro drug-toxicity analysis). Equipment Waters LCT Premier XE coupled to acquity UPLC • High separation efficiency (UPLC) • High mass accuracy (ToF) • High full-scan sensitivity • High throughput Waters SYNAPT G2 HDMS coupled to acquity UPLC • High separation efficiency (UPLC) • High mass accuracy (ToF) • Tandem MS (up to MS3) • Ion mobility separation based on molecular shape of the analytes • High full-scan sensitivity

Contact: Juan M Falcón-Pérez (jfalcon@cicbiogune.es)

Technological Platforms and Common Infrastructures - 25

Technological Platforms AND COMMON INFRASTRUCTURES Biobank Platform Continuous improvement in the health of European citizens relies on the progression of our knowledge on cause of diseases and prediction of disease course and response to therapies to provide a personalized treatment tailored at patient’s needs and expectations. Research today needs new, bigger and better resources. BioBanking offers unique solutions to research, assessment and documentation of global diversity. CIBERehd created a BioBankplatform for the management of an ad-hoc facility that collects stores and distributes biological resources related to digestive diseases, and relies on the infrastructure of the IDIBAPS BioBank. This system incorporates an adaptive data model and developed processes for the management of intellectual property, policy issues, services and maintenance. The main objectives of the CIBERehd – IDIBAPS BioBank include: • Offer to the scientific community well standardized and characterized biologic samples of patients with digestive diseases, with high added value, to promote development of biomedical research according to current regulations. • To obtain large collections of samples of digestive diseases and/or phenotypes of high interest for research. • To distribute samples for the promotion and development of collaborative research projects among CIBERehd centers, and between these centers and other partners, according to current regulations. • To provide technical support to investigators interested in BioBanking, including standards for annotation, designation and procedures, tools to harmonize collections, informatics, support to track samples, associated data, and previously generated data, and current regulations. For fulfilling these objectives the CIBERehd – IDIBAPS BioBank is equipped with: • Freezers with security systems for -20ºC, -80ºC i -150ºC • Programmable freezer with controlled ramp freezing • Chemagic MSM1® robot for DNA extraction of large volume samples • Tecan EVO150® automated station to aliquot samples • CoulterZ1® cell and particle counter • Chambers for sterile cell isolation • Cell immortalization platform • Informatics for sample and data management

Outstanding achievements during 2010 relate to strategic and scientific areas. From a strategic perspective the Biobank includes now management of tissue samples, in addition to the fluid samples. From a scientific point of view, the samples and associated information of inflammatory bowel disease have provided a significant contribution to the international consortium for the study of IBD genetics resulting in the publication of meta-analyses and validation of candidate genes for ulcerative colitis and Crohn’s disease (Nat Genet. 2010 Dec;42(12):1118-25; Nat Genet. 2011 Mar;43(3):246-52, Nat Genet. 2011 Oct;43(11):1066-73). In addition, investigators of CIBERehd are coordinating the gastroenterology arm of a national project to discover common susceptibility genes and predictors of disease course in immune mediated inflammatory disorders including inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, psoriasis, and lupus. This project analyzes samples of 12000 patients and 3000 controls, and samples from CIBERehd are being used for the validation phase. Analysis of the data from this project was completed during 2011 and results are in the process of being disseminated.In the area of colorectal cancer a study has been completed and published on pharmacogenomics in colorectal cancer; a genome-wide association study has identified a set of markers to predict toxicity after 5-fluorouracil or FOLFOX administrationPharmacogenomics J. 2012 Feb 7. doi: 10.1038/tpj.2012.2). Also susceptibility genetic variants associated with early-onset colorectal cancer have been described (Carcinogenesis. 2012 Mar;33(3):613-9).In addition to investigator initiated studies, samples from Biobank have also been used for collaborations with pharmaceutical industry, in particular in two studies evaluating diagnostic tools for screening of colorectal cancer.

26 - CIBERehd - 2011 ANNUAL REPORT - BIOINFORMATICS PLATFORM

Technological Platforms AND COMMON INFRASTRUCTURES Bioinformatics Platform The main goal of Bioinformatics Platform is to give support to investigator staff in bioinformatics area. Platform works on the development and application of bioinformatic tools for data analysis from high-throughput experiments (basically microarrays) with the aim to help on medical diagnostic kits development.

(Dr. Sophie Brouard, joint collaboration with Dr. Alberto Sánchez-Fueyo) IDIBAPS Bioinformatic Unit (Dr. Susana G Kalko) Centre for Genomic Regulation Alternative Splicing (Dr. Juan Valcárcel)

Tools used are characterized for a suitable quality control and data process; this comes in an easy interpretation of results for clinic staff.

Publicactions Bohne F, Martínez-Llordella M, Lozano JJ, Miquel R, Benítez C, Londoño MC, Manzia TM, Angelico R, Swinkels DW, Tjalsma H, López M, Abraldes JG, Bonaccorsi-Riani E, Jaeckel E, Taubert R, Pirenne J, Rimola A, Tisone G, Sánchez-Fueyo A. “Intra-graft expression of genes involved in iron homeostasis predicts the development of operational tolerance in human liver transplantation”. J Clin Invest. 2012 Jan 3;122(1):368-82. doi: 10.1172/JCI59411. Epub 2011 Dec 12. PubMed PMID: 22156196; PubMed Central PMCID: PMC3248302.

Services – Bioinformatic tools development and application. – Webserver with different applications for microarray and Real-time RT-PCR data process. – File repository. – Bioinformatic collaborations, consultancy and advisory services for project planning. Collaborations Most relevant collaborations inside the CIBERehd are: Liver Transplant (Dr. Alberto Sánchez-Fueyo, Dr. Constantino Fondevila) Gastroenterology (Dr. Julià Panés and Dra. Azucena Salas) Colorectal and Pancreatic Cancer (Dr. Antoni Castells, Dr. Meritxell Gironella, Dr. Francesc Balaguer) Alcoholic Hepatitis (Dr. Ramon Bataller) Hepatic Cancer (Dr. Carolina Armengol) Helicobacter Pylori: Consorci Sanitari Parc Tauli (Dr. Xavier Calvet, Dr. Sergi Lario) Intestinal Inflammation: Hospital Germans Trias i Pujol (Dr. Elisabet Pedrosa) CiC Biogune (Dr. Mª Luz Martinez Chantar, Dr. José María Mato, Dr. Ana María Aransay) Cirrosis Hepatica (Dr. Joan Clarià, Esther Titos) Established collaborations outside the CIBERehd: Bladder Cancer: Urology service at Hospital Clinic: (Lourdes Mengual and Dr. Alcaraz) Prostate Cancer: Pathology group (Dr. Pedro L Fernandez, Dr. Timothy Thomson) Kidney Transplant: INSERM

Baños-González M, Cantú-Brito C, Chiquete E, Arauz A, Ruiz-Sandoval JL, Villarreal-Careaga J, Barinagarrementeria F, Lozano JJ. “Systolic blood pressure and functional outcome in patients with acute stroke: A Mexican registry of acute cerebrovascular disease (RENAMEVASC)”. Arch Cardiol Mex. 2011 Jul-Sep;81(3):169-75. Spanish. PubMed PMID: 21975228.

Principal Investigator: Juanjo Lozano Salvatella PhD

Technological Platforms and Common Infrastructures - 27

Technological Platforms AND COMMON INFRASTRUCTURES Bioinformatics Platform

Balaguer F, Moreira L, Lozano JJ, Link A, Ramirez G, Shen Y, Cuatrecasas M, Arnold M, Meltzer SJ, Syngal S, Stoffel E, Jover R, Llor X, Castells A, Boland CR, Gironella M, Goel A. “Colorectal cancers with microsatellite instability display unique miRNA profiles”. Clin Cancer Res. 2011 Oct 1;17(19):6239-49. Epub 2011 Aug 15. PubMed PMID: 21844009; PubMed Central PMCID: PMC3186834.

Title: “MicroRNAa as biomarkers for the identification of familial and non-familial colorectal cancer”. Inventors: Ajay Goel, C Robert Boland, Francesc Balaguer, Meritxell Gironella (CIBERehd), Antoni Castells, Leticia Moreira, Juan José Lozano (CIBERehd). BRI, CIBERehd, Hospital Clínic, Hospital Clínico y Provincial de Barcelona. 61/391,585. 08-oct-10. Int, US/PCT, Taiwan, Argentina.

Lozano JJ, Pallier A, Martinez-Llordella M, Danger R, López M, Giral M, Londoño MC, Rimola A, Soulillou JP, Brouard S, Sánchez-Fueyo A. “Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients”. Am J Transplant. 2011 Sep;11(9):191626. doi: 10.1111/j.1600-6143.2011.03638.x. Epub 2011 Aug 9. PubMed PMID: 21827613.

Title: “Method and kit for the diagnosis and prognosis of tolerance in liver transplantation employing liver tissue”. Inventors: Alberto Sánchez Fueyo, Félix Bohne, Marc MartínezLlordella, Antoni Rimola Castella, Juan José Lozano (CIBERehd). Hospital Clínic, Fundació per la Recerca Biomèdica y CIBERehd, Hospital Clínico y Provincial de Barcelona. EP10382224,3. 09ago-10. Int, EU/PCT.

Patents Title: “Plasma MicroRNAs for the Detection of Early Colorectal Cancer”. Inventors: Meritxell Gironella (CIBERehd), María Dolores Giráldez, Juan José Lozano (CIBERehd), Antoni Castells. Hospital Clínic, CIBERehd, Hospital Clínico y Provincial de Barcelona. 61/550,148. 21-oct-11. Int, US.

28 - CIBERehd - 2011 ANNUAL REPORT - Pyrosequencing & ciberHEP PLATFORM

Technological Platforms AND COMMON INFRASTRUCTURES Pyrosequencing Platform The recent availability of commercial platforms for massive parallel ultra-deep pyrosequencing (UDPS) offer the opportunity to characterize with unprecedented sensitivity the hepatitis C virus (HCV) quasiespecies, which infects 1-2.6 % of the general population in Spain. The UDPS will allow: (i) An accurate and quantitative characterization of the viral population in clinical samples. (ii) To design individualized treatment strategies according to the complexity of the infecting quasispecies and the presence/absence of Direct Antiviral Agents (DAAs) drug-resistant mutants both in treatment-naive and patients with relapse, slow or null-response to previous treatment with Peg-Interferon (those with a higher risk of selecting multi-drug resistant mutants). (iii) To identify novel viral or host-related factors influencing resistance to the new DAA drugs including minor viral variants present at frequencies as low as 0,5% within a complex viral population. Due to the great potential of this technology the Scientic Board of CIBERehd endorsed a strategic action to create a UDPS platform for all groups included in the viral hepatitis area 2, and granted €100.000 for its development.

The granting of over € 600.000 by the Fondo de Investigaciones Sanitarias for the acquisition of a 454-FLXRoche/Life Sciences equipment by the Vall d’Hebron Institut de Recerca Hospital Universitari Vall d’Hebron (VHIR-HUVH) finally located at the Unidad Científico Técnica de Soporte (UCTS) of the VHIR HUV H, further boosted the project and the establishment of an official collaboration agreement, between the CIBERehd and the VHIR-HUVH active throughout 2011, for the use of the UDPS service by all investigators belonging to the CIBERehd area 2. Roche, the VHIR-HUVH, ABL and the CIBERehd decided to create a consortium to explode the use of massive sequencing platforms to explore the full potential of the new technology in the field of viral hepatitis, specially for hepatitis B and C, and for Patient’s genomic polymorphisms. The consortium succeed in obtaining funding through the CDTI program (Centro para el Desarrollo Tecnológico Industrial) established by the actual Spanish Ministry of Economy and Competitiveness (MINECO) IDI-20110115.

GS-FLX Series Titanium tecchnology Bead Deposition

Technological Platforms and Common Infrastructures - 29

Technological Platforms AND COMMON INFRASTRUCTURES Clinical database of chronic hepatitis B patients (CiberHEP) CiberHEP is a registry on the clinical handling of chronic hepatitis B patients treated at the Spanish National Health System, mainly focused on the follow-up of patients treated with the current first-line antiviral treatment options. Participation in this registry is open for physicians integrated into the Spanish National Health System.

The aims of this registry are: â&#x20AC;˘ Provide data from a large number of patients from different centres of Spain to analyze the effectiveness of different antiviral treatments to optimize their use. â&#x20AC;˘ Make available to its users complete and easy access for monitoring patients their patients.

30 - CIBERehd - 2011 ANNUAL REPORT - REHEVASC

Technological Platforms AND COMMON INFRASTRUCTURES REHEVASC (Vascular Liver Disease Registry) Liver cirrhosis is the main cause of portal hypertension in the Western world. The large number of patients with this disease has allowed the realization of many studies, both unicenter and multicenter has allowed progress in understanding this disease. However, there are other liver diseases different than cirrhosis that can also lead to the development of portal hypertension. This group of diseases is included within the concept of non-cirrhotic portal hypertension (HTPNC). The diagnosis of patients with HTPNC is growing, probably favoured because nowadays we identify a number of patients who years ago were misdiagnosed as cryptogenic cirrhosis. HTPNC include several rare hepatic diseases (with prevalence less than 5/10.000 population): being the BuddChiari syndrome, non-cirrhotic portal vein thrombosis and idiopathic portal hypertension are main 3. Others diseases are much less prevalent as congenital hepatic fibrosis (CHF), schistosomiasis or hereditary hemorrhagic telangiectasia, among others. In recent years, several centers of our country have gained progressively experience in the diagnosis and treatment of patients with HTPNC. However, progress in understanding pathophysiology, natural history, and evaluation of new diagnostic alternatives and/or treatment of these diseases is hampered by the small number of patients who are diagnosed and visit these single centers. In addition, as a consequence, the diagnostic and therapeutic approach is quite heterogeneous, depending on the physician in charge of the patient. For all these reasons a â&#x20AC;&#x153;National Centers Cooperative Group for the Study of HTPNCâ&#x20AC;? has been set up. The main objectives are: 1. Dissemination of clinical protocols that define uniform criteria for diagnosis, treatment and monitoring of BuddChiari syndrome, non-cirrhotic portal vein thrombosis, idiopathic portal hypertension and congenital hepatic fibrosis in the participant centres. 2. Development of a centralized on-line registry using the website of the Biomedical Research Centre Network Liver and Digestive Diseases (CIBERehd) to record the patients with these rare vascular diseases.

The consolidation of this national cooperative group with interest in HTPNC will allow estimate the incidence of these diseases in Spain. Moreover, it will allow recognize a larger number of patients with these conditions have been diagnosed and treated homogenously. Altogether, this will increase the knowledge of these diseases, their natural history and we will have the ability to perform multicenter randomized trials or cohort studies.

Training Plan

Training Plan - 33

Training Plan Dr. Joan Caballería. Teaching Coordinator

IBER’s Hepatic and Digestive Disease Training Plan is based on “fellowship” stays in CIBERehd’s research groups for post-graduate researchers (postMIR; post-doctorate; and foreign), abroad with a variable timeframe (fundamentally for a short period for those with few financing options) and Intramural Visiting Professor Program that will last a semester/year, so that one senior researcher from each group will spend one week per year as a visiting professor in another institution subjected to the promotion of staff interaction and the collaboration of scientific researchers from different centers. Similarly, specific support will be provided for programs for invited professors and those who participate in courses and meetings. CIBERehd’s Extramural Program will assign groups with the Linked groups and those in the Outside Collaboration program. Linked Groups do not receive financing or resources from CIBER, but indirectly benefit from their association with it. This comes from its collaboration with their clinical/population studies, by receiving scientific advice or development, through participation in training activities and via educational programs. The Outside Collaboration Program is based on the concept

that it is not possible to understand CIBER’s Hepatic and Digestive Disease without locating it within a global context along with positive interaction. In 2011, 45 grants have been awarded to researchers for various activities under the program of the Training Plan. Despite the budget cuts we have been able to attend nearly all applications. The beneficiaries of the aid have been 13 investigators from CIBERehd institutions, 32 employees, of whom 9 were doctors, 16 licensed, 1 nurse graduate and 6 technicians. The activities funded were 2 stages of investigators in other centers CIBERehd, 1 short stay abroad (Germany), 1 short stay in Spain (Madrid), 2 phD, 1 Postgraduate Course, 32 training courses and activities nationwide, and 6 international ones. Among these activities we should like to highlight the stays in CIBERehd groups of EUGENIO ROSADO (Dr. BOSCH’s CIBERehd staff) who did a stay in the Liver Research Unit, Hospital Reina Sofía Córdoba, with Dr. De la Mata, and IRENE CRESPO (Dr. GONZALEZ-GALLEGO’s CIBERehd staff) who did a stay in Hospital CIMA, with Dr. PRIETO. In addition the inscriptions for PhD programs were funded to Drs. J PÉREZ-GISBERT (PhD in Medicine and Surgery), and R. Esteban (PhD in Biochemistry, Molecular Biology and Biomedicine), to two CIBERehd staff members.

34 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

Scientific Activities of the programs

• • • • • •

Portal Hypertension and Mechanism of Cirrhosis Transition Viral Hepatitis Cholestasis, Metabolic Disorders & Hepatotoxicity Immunology, and Liver Transplantation Hepatic and Gastrointestinal Oncology Gastrointestinal Inflamation and Motility

36 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

Program 1

Portal Hypertension and Mechanism of Cirrhosis Transition

P1 Scientific Activities of the Programs - 37

Portal Hypertension and Mechanism of Cirrhosis Transition Presentation: Dr. Agustín Albillos. Program Coordinator

IBERehd Program num. 1, named “Portal hypertension and mechanisms of transition to cirrhosis”, focuses on collaborative research on the pathogenesis, diagnosis and treatment of liver cirrhosis, portal hypertension and its complications. In particular, the cooperative translational research that holds the Program studies the pathogenic mechanisms of liver fibrogenesis and portal hypertension and seeks to develop drugs and therapeutic strategies to improve portal hypertension and its associated complications (bleeding gastroesophageal varices, ascites and renal failure, bacterial infection, hepatic encephalopathy). Research is systematized in the Program in five lines: 1) hepatic fibrogenesis, 2) portal hypertension, 3) ascites / renal function and liver insufficiency, 4) infection and bacterial translocation, and 5) hepatic encephalopathy.

The Program is formed by eight groups, five located in Barcelona and led by Drs. Arroyo (Hospital Clínic), Bosch (Hospital Clínic), Córdoba (Hospital Vall d’Hebron), Guarner (Hospital San Pablo) and Planas (Hospital Germán Trias Pujol), two in Madrid led by Drs. Albillos (Hospital Ramón y Cajal-University of Alcalá) and Bañares (Hospital Gregorio

Marañón), and one in Alicante led by Dr. Such (General Hospital). In spite of its clinical origin, all the groups included in the Program have incorporated experimental research. The latter fact enables the Program 1 to cover the whole spectrum of translational research in the field of its competence, including studies of cell and molecular biology, proof of concept in patients with cirrhosis and clinical trials to evaluate different drugs and treatment strategies. The strategic aim of CIBERehd is to promote clinical and experimental collaborative research. In this sense, the direction of CIBERehd has stimulated the development of collaborative projects among groups of Program 1, as well as with groups in other areas. The collaboration has included multicentered clinical trials, cooperation to evaluate prognostic markers and test and design strategies for diagnosis and treatment with a direct impact on clinical practice. One of the initial goals of CIBERehd was to extend this collaboration towards mechanistic basic research, using the advantages of cell and molecular biology. Cooperation in this sense has also been initiated among CIBERehd groups and is expected to continue rising in coming years.

38 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

PRESENTATION Portal Hypertension and Mechanism of Cirrhosis Transition

Research topics of the 8 groups in Program 1 Center

Principal investigator

Lines of research

Number of members

Universidad de Alcalá-Hospital Ramón y Cajal, Madrid

Agustín Albillos

Portal hypertension Infection/Translocation

Hospital Clínic Barcelona

Vicente Arroyo

Fibrogenesis Ascites/Renal function/ Liver failure Infection/Translocation Hepatic encephalopathy

Hospital Gregorio Marañón, Madrid

Rafael Bañares

Insufficiency

Hospital Clínic Barcelona

Jaime Bosch

Portal hypertension Infection/Translocation

Hospital Vall d’Hebron, Barcelona

Juan Córdoba

Ascites/Renal function /Liver failure Hepatic encephalopathy

Hospital San Pablo, Barcelona

Carlos Guarner

Portal hypertension Ascites/Renal function Infection/Translocation

Hospital Germans Trías i Pujol, Badalona

Ramón Planas

Portal hypertension Ascites/Renal function Infection/Translocation Hepatic encephalopathy

Hospital General Universitario, Alicante

José Such

Ascites/Renal function Infection/Translocation

Group

Scientific Activities of the Programs - 39

PRESENTATION Portal Hypertension and Mechanism of Cirrhosis Transition

Partnerships and collaborations amongst Program 1 groups FIBROGENESIS

PORTAL HYPERTENSION

ARROYO

BACTERIAL INFECTION/ TRANSLOCATION

ASCITES/RENAL FUNCTION/ LIVER INSUFFICIENCY

ENCEPHALOPATHY

ARROYO

BOSCH

ALBILLOS

ALBILLOS SUCH

SUCH

PLANAS

GUARNER

BAÑARES

BAÑARES CÓRDOBA

CÓRDOBA

ALBILLOS

CÓRDOBA SUCH

BAÑARES

GUARNER ARROYO PLANAS BOSCH

40 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

PROJECTS AND COLLABORATIONS Portal Hypertension and Mechanism of Cirrhosis Transition Collaborative clinical projects carried out by members of the program during 2011 “Multicenter, randomized, double-blind, placebocontrolled study on the efficacy of beta-blockers to prevent decompensation of cirrhosis with portal hypertension”. Clinical Research Project Institute of Health Carlos III EC08/00122. Code: PREDESCI. Year Started: 2008. Hospital/participating institutions: H. Santa Cruz and San Pablo, H. Clinic, H. Trias Pujol, H. Valle de Hebron, H. Ramon y Cajal-University of Alcalá, H. Gregorio Marañón, H. Puerta de Hierro Majadahonda, H. Arnau de Vilanova. Principal Investigator/Coordinator: Candido Villanueva, Hospital Santa Creu i Sant Pau, Barcelona. “Phase II study randomized, controlled, multicenter to evaluate the efficacy and safety of ribavirin monotherapy versus prolonged colchicine on the progression of chronic hepatitis C virus advanced fibrosis in patients not responding to conventional antiviral treatment”. Code: RIBA-CIR. Year Started: 2008. Hospital/participating institutions: H. Ramon y Cajal-University of Alcalá, H. Gregorio Marañón, H. Puerta de Hierro. Principal Investigator/Coordinator: Agustín Albillos, Ramon y Cajal Hospital, Madrid. “Efficacy and safety of self-expanding esophageal prosthesisballoon catheter versus Sengstaken as emergency hemostatic treatment in patients with acute bleeding from esophageal varices, and failure of medical and endoscopic treatment. Multicenter, prospective, randomized trial”. Health Research Project, Instituto de Salud Carlos III PI 080 504. Code: PE08001. Year Started: 2008. Hospital/participating institutions: H. Clinic, H. Santa Cruz and San Pablo, H. Valle de Hebron, H. Trias Pujol, H. Ramon y Cajal-University of Alcalá, H. Gregorio Marañón, H. Puerta de Hierro. Principal Investigator/ Coordinator: Angels Escorsell, Hospital Clínic, Barcelona. This project is a strategic action of Ciberehd. “Study to assess the efficacy of oral norfloxacin associated with intravenous cefotaxime compared with that demonstrated by intravenous cefotaxime (current standard treatment) in the treatment of spontaneous bacterial peritonitis (SBP) in cirrhotic patients with low and high risk of developing complications”. Code: 01.08 CIBERehd-Alicante. Year Started: 2009. Hospital/participating institutions: H. General de Alicante, H. Clinic, H. Santa Cruz and San Pablo, M del Mar, H. Trias Pujol, H. Bellvitge, H. John XXIII, Tarragona, H. Ramon y Cajal-University of Alcalá, H. Gregorio Marañón, H. Tajo, H. General de Elche. Principal Investigator/ Coordinator: José Such, General Hospital, Alicante.

“Effects of albumin infusion in the treatment of an episode of hepatic encephalopathy. Multicenter randomized study in patients with liver cirrhosis”. Alpha code. Year Started: 2009. Hospital/ participating institutions: H. H. Valle de Hebrón, H. Clinic, H. Santa Cruz and San Pablo, H. Parc Taulí. Principal Investigator/ Coordinator: Juan Cordoba, Hospital Vall d’Hebron, Barcelona. “Efficacy of albumin and midodrine in the prevention of the complications of cirrhosis in cirrhotic patients in the transplantation waiting list: a double-blind, randomized, controlled study”. Code: MACHT study. Year Started: 2009. Hospital / participating institutions: H. Clinic, H. Valle de Hebrón. Principal Investigator/ Coordinator: Pere Ginés, Hospital Clínic, Barcelona. “Efficacy of statins in combination with standard therapy in the prevention of variceal rebleeding in patients with cirrhosis: doubleblind, placebo-controlled study”. Health and Social Policy Ministery. Code: BLEPS study. Year Started: 2010. Hospital/participating institutions: H. Clinic, H. Santa Cruz and San Pablo, H. Valle de Hebron, H. Trias Pujol, H. Parc Taulí, H. General de Alicante, H. Ramon y Cajal-University of Alcalá, H. Gregorio Marañón, H. Puerta de Hierro. Principal Investigator/Coordinator: Angels Escorsell, Hospital Clínic, Barcelona. Principal Investigator/Coordinator: Jaime Bosch, Hospital Clínic, Barcelona. “Pilot randomized study to evaluate physical exercise in cirrhotic patients and branched aminoacid supplementation”. Mapfre Foundation. Year started: 2010. Hospital/participating institutions: H. Santa Cruz and San Pablo, H. Valle de Hebron. Principal Investigator/Coordinator: Germán Soriano, Santa Cruz and San Pablo, Barcelona. “Multicentered, randomized trial to evaluate the impact of weight loss on portal pressure in patients with cirrhosis and obesity/overweight”. Code: SPORTDIET study. Year Started: 2011. Hospital/participating institutions: H. Clinic, H. San Pablo, H. Valle de Hebron, H. Ramon y Cajal-University of Alcalá, H. Gregorio Marañón, H. Puerta de Hierro. This project is a strategic action of Ciberehd. Principal Investigator/ Coordinator: Jaime Bosch, Hospital Clínic, Barcelona. “Randomized double-blind controlled phase II trial on the effects induced by sapropterin in hepatic and systemic hemodynamics in patients with hepatic cirrhosis”. Code: TEHYLIC study. Year Started: 2011. Principal Investigator/ Coordinator: H. Clinic, H. Ramon y Cajal-University of Alcalá. Principal Investigator/Coordinator: Juan Carlos GarcíaPagán, Hospital Clínic, Barcelona.

Scientific Activities of the Programs - 41

PROJECTS AND COLLABORATIONS Portal Hypertension and Mechanism of Cirrhosis Transition 1. Diaz D, Chara L, Chevarria J, Ubeda M, Muñoz L, Barcenilla H, Sánchez MA, Moreno Z, Monserrat J, Albillos A, Prieto A, Alvarez-Mon M. “Loss of surface antigens is a conserved feature of apoptotic lymphocytes from several mammalian species”. Cell Immunol. 2011;271(1):163-72. 2. de Pablo R, Monserrat J, Reyes E, Diaz-Martin D, Rodríguez Zapata M, Carballo F, de la Hera A, Prieto A, Alvarez-Mon M. “Mortality in patients with septic shock correlates with antiinflammatory but not proinflammatory immunomodulatory molecules”. J Intensive Care Med. 2011 Mar-Apr;26(2):125-32. 3. Sturm N, Abalos P, Fernández A, Rodríguez G, Oviedo P, Arroyo V, Retamal P. “Salmonella enterica in pinnipeds, Chile”. Emerg Infect Dis. 2011 Dec;17(12):2377-8. 4. Titos E, Rius B, González-Périz A, López-Vicario C, MoránSalvador E, Martínez-Clemente M, Arroyo V, Claria J. “Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype”. J Immunol. 2011 Nov 15;187(10):5408-18. 5. Olson JC, Wendon JA, Kramer DJ, Arroyo V, Jalan R, GarciaTsao G, Kamath PS. “Intensive care of the patient with cirrhosis”. Hepatology. 2011 Nov;54(5):1864-72. 6. Arroyo V, Fernández J. “Management of hepatorenal syndrome in patients with cirrhosis”. Nat Rev Nephrol. 2011 Aug 9;7(9):517-26. 7: Arroyo V, Fernández J. “Pathophysiological basis of albumin use in cirrhosis”. Ann Hepatol. 2011 May;10 Suppl 1:S6-14. 8. Altamirano J, Higuera- de la Tijera F, Duarte-Rojo A, MartínezVázquez MA, Abraldes JG, Herrera-Jiménez LE, Michelena J, Zapata L, Perez-Hernández J, Torre A, Gonzáles-González JA, Cardenas A, Dominguez M, Arroyo V, Ginés P, Caballería J, Bataller R. “The amount of alcohol consumption negatively impacts short-term mortality in Mexican patients with alcoholic hepatitis”. Am J Gastroenterol. 2011 Aug;106(8):1472-80. 9. Morán-Salvador E, López-Parra M, GarcíaAlonso V, Titos E, Martínez-Clemente M, González-Périz A, López-Vicario C, Barak Y, Arroyo V, Claria J. “Role for PPAR in obesityinduced hepatic steatosis as determined by hepatocyte- and macrophagespecific conditional knockouts”. FASEB J.

2011 Aug;25(8):2538-50. 10. Guevara M, Arroyo V. “Hepatorenal syndrome”. Expert Opin Pharmacother. 2011 Jun;12(9):1405-17. 11. Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, Gerbes A, Angeli P, Moreau R, Davenport A, Jalan R, Ronco C, Genyk Y, Arroyo V. “Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis”. Gut. 2011 May;60(5):702-9. 12. Guevara M, Baccaro ME, Gómez-Ansón B, Frisoni G, Testa C, Torre A, Molinuevo JL, Rami L, Pereira G, Sotil EU, Córdoba J, Arroyo V, Ginés P. “Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy”. J Hepatol. 2011 Sep;55(3):564-73. 13. Martín-Llahí M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, Solá E, Pereira G, Marinelli M, Pavesi M, Fernández J, Rodés J, Arroyo V, Ginés P. “Prognostic importance of the cause of renal failure in patients with cirrhosis”. Gastroenterology. 2011 Feb;140(2):488-496.e4. 14. ReViS-TC Study Group. “Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation. 2011 Aug 15;92(3):334-40. Erratum in: Transplantation. 2012 Feb 15;93(3):e13.

42 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

PROJECTS AND COLLABORATIONS Portal Hypertension and Mechanism of Cirrhosis Transition Most important contributions published during 2010 by Program 1 researchers. 15. Sánchez-Conde M, Miralles P, Bellón JM, Rincón D, Ramírez M, Gutiérrez I, Ripoll C, López JC, Cosín J, Clemente G, Lo Iacono O, Bañares R, Berenguer J. “Use of transient elastography (FibroScan¬Æ) for the noninvasive assessment of portal hypertension in HIV/HCV-coinfected patients”. J Viral Hepat. 2011 Oct;18(10):685-91. 16. Bañares R, Catalina MV, Ripoll C, Rincón D. “Prognostic markers in patients who have recovered from an acute variceal bleeding: role of HVPG measurement”. Dis Markers. 2011;31(3):165-9. 17. Ripoll C, Yotti R, Bermejo J, Bañares R. “The heart in liver transplantation”. J Hepatol. 2011 Apr;54(4):810-22. Epub 2010 Nov 11. Review. 18. Escorsell A, Bosch J. “Self-expandable metal stents in the treatment of acute esophageal variceal bleeding”. Gastroenterol Res Pract. 2011;2011:910986. 19. Llop E, Berzigotti A, Reig M, Erice E, Reverter E, Seijo S, Abraldes JG, Bruix J, Bosch J, García-Pagan JC. “Assessment of portal hypertension by transient elastography in patients with compensated cirrhosis and potentially resectable liver tumors”. J Hepatol. 2012 Jan;56(1):103-8. 20. Castera L, Pinzani M, Bosch J. “Non invasive evaluation of portal hypertension using transient elastography”. J Hepatol. 2012 Mar;56(3):696-703. 21. La Mura V, Reverter JC, Flores-Arroyo A, Raffa S, Reverter E, Seijo S, Abraldes JG, Bosch J, García-Pagán JC. “Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension”. Gut. 2011 Aug;60(8):1133-8. 22. Luca A, Miraglia R, Caruso S, Milazzo M, Sapere C, Maruzzelli L, Vizzini G, Tuzzolino F, Gridelli B, Bosch J. “Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis”. Gut. 2011 Jun;60(6):846-52. 23. Pasarín M, Abraldes JG, Rodríguez-Vilarrupla A, La Mura V, García-Pagán JC, Bosch J. “Insulin resistance and liver microcirculation in a rat model of early NAFLD”. J Hepatol. 2011 Nov;55(5):1095-102. 24. Llop E, de Juan C, Seijo S, García-Criado A, Abraldes JG, Bosch J, García-Pagán JC. “Portal cholangiopathy: radiological classification and natural history”. Gut. 2011 Jun;60(6):853-60.

25. Berzigotti A, Nicolau C, Bellot P, Abraldes JG, Gilabert R, García-Pagan JC, Bosch J. “Evaluation of regional hepatic perfusion (RHP) by contrast-enhanced ultrasound in patients with cirrhosis”. J Hepatol. 2011 Aug;55(2):307-14. 26. García-Calderó H, Rodríguez-Vilarrupla A, Gracia-Sancho J, Diví M, Laviña B, Bosch J, García-Pagán JC. “Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats”. J Hepatol. 2011 Apr;54(4):660-5. 27. Bureau C, Métivier S, D’Amico M, Péron JM, Otal P, Pagan JC, Chabbert V, Chagneau-Derrode C, Procopet B, Rousseau H, Bosch J, Vinel JP. “Serum bilirubin and platelet count: a simple predictive model for survival in patients with refractory ascites treated by TIPS”. J Hepatol. 2011 May;54(5):901-7. 28. Soriano G, Román E, Córdoba J, Torrens M, Poca M, Torras X, Villanueva C, Gich IJ, Vargas V, Guarner C. “Cognitive dysfunction in cirrhosis is associated with falls: A prospective study”. Hepatology. 2011[Epub ahead of print]. 29. Garcia-Martinez R, Cordoba J. “Liver-induced inflammation hurts the brain”. J Hepatol. 2012 Mar;56(3):515-7. 30. García-Martínez R, Simón-Talero M, Córdoba J. “Prognostic assessment in patients with hepatic encephalopathy”. Dis Markers. 2011;31(3):171-9. Review. 31. Chavarria L, Alonso J, Rovira A, Córdoba J. “Neuroimaging in acute liver failure”. Neurochem Int. 2011 Dec;59(8):1175-80. 32. Oria M, Romero-Giménez J, Arranz JA, Riudor E, Raguer N, Córdoba J. “Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis”. J Hepatol. 2012 Jan;56(1):109-14. 33. Chavarria L, Alonso J, García-Martínez R, Aymerich FX, Huerga E, Jacas C, Vargas V, Cordoba J, Rovira A. “Biexponential analysis of diffusion-tensor imaging of the brain in patients with cirrhosis before and after liver transplantation”. AJNR Am J Neuroradiol. 2011 Sep;32(8):1510-7. 34. García-Martínez R, Córdoba J. “Acute-on-chronic liver failure: the brain”. Curr Opin Crit Care. 2011 Apr;17(2):177-83. 35. Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, Flavia M, Jacas C, Mínguez B, Vergara M, Soriano G, Vila C, Esteban R, Córdoba J. “Effects of branched-chain amino acids supplementation in patients with cirrhosis and a

Scientific Activities of the Programs - 43

PROJECTS AND COLLABORATIONS Portal Hypertension and Mechanism of Cirrhosis Transition previous episode of hepatic encephalopathy: a randomized study”. Am J Gastroenterol. 2011 Jun;106(6):1081-8. 36. Bajaj JS, Cordoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, Morgan MY; International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN). “Review article: the design of clinical trials in hepatic encephalopathy-an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement”. Aliment Pharmacol Ther. 2011 Apr;33(7):739-47. 37. Garcia-Martinez R, Rovira A, Alonso J, Jacas C, Simón-Talero M, Chavarria L, Vargas V, Córdoba J. “Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume”. Liver Transpl. 2011 Jan;17(1):38-46. 38. Córdoba J. “New assessment of hepatic encephalopathy”. J Hepatol. 2011 May;54(5):1030-40. 39. Román E, Córdoba J, Torrens M, Torras X, Villanueva C, Vargas V, Guarner C, Soriano G. “Minimal hepatic encephalopathy is associated with falls”. Am J Gastroenterol. 2011 Mar;106(3):476-82.

40. Poca M, Concepción M, Casas M, Alvarez-Urturi C, Gordillo J, Hernández-Gea V, Román E, Guarner-Argente C, Gich I, Soriano G, Guarner C. “Role of albumin treatment in patients with spontaneous bacterial peritonitis”. Clin Gastroenterol Hepatol. 2012 Mar;10(3):309-15. 41. Sabaté M, Ibáñez L, Pérez E, Vidal X, Buti M, Xiol X, Mas A, Guarner C, Forné M, Sola R, Castellote J, Rigau J, Laporte JR. “Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series”. BMC Gastroenterol. 2011 Jul 15;11:80. 42. Soriano G, Esparcia O, Montemayor M, Guarner-Argente C, Pericas R, Torras X, Calvo N, Román E, Navarro F, Guarner C, Coll P. “Bacterial DNA in the diagnosis of spontaneous bacterial peritonitis”. Aliment Pharmacol Ther. 2011 Jan;33(2):275-84. 43. Doménech E, Carrión S, Garcia-Planella E, Mañosa M, Gordillo J, Concepción M, Guarner C, Cabré E. “Smoking status and response to thiopurines in steroid-dependent inflammatory bowel disease”. Inflamm Bowel Dis. 2011 Apr;17(4):971-5.

44 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

PROJECTS AND COLLABORATIONS Portal Hypertension and Mechanism of Cirrhosis Transition 44. Poca M, Puente A, Graupera I, Villanueva C. “Prognostic markers in patients with cirrhosis and portal hypertension who have not bled”. Dis Markers. 2011;31(3):147-54.

with escitalopram of pegylated interferon alfa-2a-induced depression in hepatitis C: a 12-week, randomized, double-blind, placebo-controlled trial”. J Clin Psychiatry. 2011 Apr;72(4):522-8.

45. Gómez-Oliva C, Guarner-Argente C, Concepción M, Jiménez FJ, Rodríguez S, Gonzalez-Huix F, Mugica F, Cabriada JL, Rodríguez C, Aguilar CG; Collaborating Group of the COBIWA Register. “Partially covered self-expanding metal stent for unresectable malignant extrahepatic biliary obstruction: results of a large prospective series”. Surg Endosc. 2012 Jan;26(1):222-9.

53. Soldevila B, Alonso N, Martínez-Arconada MJ, Morillas RM, Planas R, Sanmartí AM, Martínez-Cáceres EM. “A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4(+) CD25(+) CD127(low/-) FoxP3(+) T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment”. J Viral Hepat. 2011 Jun;18(6):384-92.

46. Tural C, Sola R, Alvarez NP, Moltó J, Sánchez M, Zamora AM, Ornelas A, Laguno M, González J, von Wichmann M√Å, Téllez MJ, Paredes R, Clotet B; CORAL-2 study group. “Effect of an induction period of pegylated interferon-Œ±2a and ribavirin on early virological response in HIV-HCV-coinfected patients: results from the CORAL-2 study”. Antivir Ther. 2011;16(6):833-41. 47. Alvarez MA, Cirera I, Sola R, Bargalló A, Morillas RM, Planas R. “Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165 patients”. J Clin Gastroenterol. 2011 Nov-Dec;45(10):906-11. 48. Soldevila B, Alonso N, Martínez-Arconada MJ, Granada ML, Baía D, Vallejos V, Fraile M, Morillas RM, Planas R, Pujol-Borrell R, Martínez-Cáceres EM, Sanmartí AM. “A prospective study of lymphocyte subpopulations and regulatory T cells in patients with chronic hepatitis C virus infection developing interferoninduced thyroiditis”. Clin Endocrinol (Oxf). 2011 Oct;75(4):535-43. 49. Lorenzo-Zúñiga V, Moreno de Vega V, Doménech E, Mañosa M, Cabré E, Planas R, Boix J. “High-definition colonoscopy and risk factors for recurrence of advanced adenomas in patients with a personal history of polyps”. Eur J Gastroenterol Hepatol. 2011 May;23(5):425-30. 50: Martró E, Valero A, Jordana-Lluch E, Saludes V, Planas R, GonzálezCandelas F, Ausina V, Bracho MA. “Hepatitis C virus sequences from different patients confirm the existence and transmissibility of subtype 2q, a rare subtype circulating in the metropolitan area of Barcelona, Spain”. J Med Virol. 2011 May;83(5):820-6. 51. Lucena MI, Kaplowitz N, Hallal H, Castiella A, García-Bengoechea M, Otazua P, Berenguer M, Fernández MC, Planas R, Andrade RJ. “Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis”. J Hepatol. 2011 Oct;55(4):820-7. 52. Diez-Quevedo C, Masnou H, Planas R, Castellví P, Giménez D, Morillas RM, Martín-Santos R, Navinés R, Sola R, Giner P, Ardévol M, Costa J, Diago M, Pretel J. “Prophylactic treatment

54. Paredes B, Santana A, Arribas MI, Vicente-Salar N, de Aza PN, Roche E, Such J, Reig JA. “Phenotypic differences during the osteogenic differentiation of single cell-derived clones isolated from human lipoaspirates”. J Tissue Eng Regen Med. 2011 Aug;5(8):589-99. 55. Gutiérrez A, Holler E, Zapater P, Sempere L, Jover R, Pérez-Mateo M, Schoelmerich J, Such J, Wiest R, Francés R. “Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn’s disease is affected by NOD2/CARD15 genotype”. Inflamm Bowel Dis. 2011 Aug;17(8):1641-50. 56. Gómez-Hurtado I, Zapater P, Bellot P, Pascual S, Pérez-Mateo M, Such J, Francés R. “Interleukin-10-mediated heme oxygenase 1-induced underlying mechanism in inflammatory down-regulation by norfloxacin in cirrhosis”. Hepatology. 2011 Mar;53(3):935-44. 57. Tritto G, Bechlis Z, Stadlbauer V, Davies N, Francés R, Shah N, Mookerjee RP, Such J, Jalan R. “Evidence of neutrophil functional defect despite inflammation in stable cirrhosis”. J Hepatol. 2011 Sep;55(3):574-81. 58: Ruiz-Alcaraz AJ, Martínez-Esparza M, Caño R, HernándezCaselles T, Recarti C, Llanos L, Zapater P, Tapia-Abellán A, MartínOrozco E, Pérez-Mateo M, Such J, García-Peñarrubia P, Francés R. “Peritoneal macrophage priming in cirrhosis is related to ERK phosphorylation and IL-6 secretion”. Eur J Clin Invest. 2011 Jan;41(1):815. doi: 10.1111/j.1365-2362.2010.02368.x. Erratum in: Eur J Clin Invest. 2011 Apr;41(4):464. Tapia, Ana [corrected to Tapia-Abellán, Ana]. 59. Albilllos A, Garcia-Tsao G. “Classification of cirrhosis: the clinical use of HVPG measurements”. Dis Markers. 2011;31(3):121-8. Plessier A, Darwish-Murad S, Hernández-Guerra M, Consigny Y, Fabris F, Trebicka J, Heller J, Morard I, Lasser L, Langlet P, Denninger MH, Vidaud D, Condat B, Hadengue A, Primignani M, García-Pagán JC, Janssen HL, Valla D; European Network for Vascular Disorders of the Liver (EN-Vie). “Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow-up study”. Hepatology. 2010 Jan;51(1):210-8.

Scientific Activities of the Programs - 45

46 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. agustín albillos martínez Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid

Team leader Agustín Albillos Martínez

Team members Melchor Álvarez-Mon Soto Antonio De la Hera Martínez Jorge Monserrat Sanz Alberto Moreno Caparrós Eduardo Reyes Martín Alfredo Prieto Martín José Luis Calleja Panero Elba Llop Herrera

Staff Leticia Muñoz Zamarrón María Úbeda Cantero

Outputs CIBERehd

Nº of Publications 1st quartile: 2 Nº of Publications 2nd quartile: 2 IF total: 18.17 Nº of competitive projects: 11 Public funding: 1,059,528 Private funding: 1,540,487 Multicentric clinical trials: 21

FIRST QUARTILE PUBLICATIONS

10 22,357

33,834

Collaborations with other CIBERehd groups

100

Rafael Bañares

Hospital Gregorio Marañón, Madrid

Jaime Bosch

Hospital Clínic, Barcelona

Rafael Esteban

Hospital Vall d’Hebron-Institut de Recerca, Barcelona

Carlos Guarner

Hospital de la Santa Creu i Sant Pau, Barcelona

Ramón Planas

Hospital Germans Trias i Pujol, Barcelona

Manuel Romero

Hospital Universitario Nuestra Sra. De Valme, Sevilla

José Such

Fundación de la Comunidad Valenciana para la Investigación, Alicante

10 2

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• Portal hypertension: diagnostic and therapeutic optimization in portal hypertension and its complications, development of portal hypertension therapeutic options, and study of pathogenic mechanisms. • Immune system in cirrhosis: pathogenesis of the activation of immuneinflammatory system in cirrhosis and role in the progression of liver damage and the development of complications. • Complications of cirrhosis: significance of bacterial infection in the progression of chronic liver failure, and pathogenesis of bacterial infection in cirrhosis. • Immune mediated-mechanisms in chronic systemic diseases. • Viral hepatitis: new therapeutic agents.

300

16,450

Main Research Topics

Scientific Activities of the Programs - 47

1st decile publications Llop E, de Juan C, Seijo S, García-Criado A, Abraldes JG, Bosch J, García-Pagán JC. “Portal cholangiopathy: radiological classification and natural history”. Gut. 2011 Jun;60(6):853-60. IF 10.614 COLLABORATION Albillos/Bosch

Relevant projects 1. “Análisis de los mecanismos patogénicos de las alteraciones del sistema inmune/inflamatorio en la cirrosis: consecuencias fisiopatológicas en la traslocación bacteriana”. PS09/00485. ISCiii. PI: A. Albillos. Team Members: Leticia Muñoz, María José Borrero, Alberto Moreno, Eduardo Reyes, Ana Cano, Lourdes Lledó. 2010-2013. €94,531 2. “Estudio multicéntrico, aleatorizado, doble-ciego, controlado con placebo, sobre la eficacia del tratamiento con betabloqueantes para prevenir la descompensación de la cirrosis con hipertensión portal”. EC08/00122. ISCiii. PI: A. Albillos. Team Members: Cristina Martín, Beatriz Peñas, Enrique Vázquez, Juan Ángel González-Martín. 2009-2012. €44,366 3. “Eficacia y seguridad de la prótesis esofágica autoexpandible versus sonda-balón de Sengstaken como tratamiento hemostático de emergencia en pacientes con hemorragia aguda por varices esofágicas y fracaso del tratamiento farmacológico y endoscópico. Estudio multicéntrico, prospectivo y aleatorizado”. PE08001. ISCiii. PI: A. Escorsell. 2008-2011 4. “Estudio Traslacional de la distribución y estado funcional de los compartimentos linfocitario T, monocitario y de células dentríticas circulantes y del líquido sinovial en pacientes con artritis reumatoide”. PI-08-1890. ISCiii. PI: M. Álvarez-Mon. Team Members: Monserrat Sanz Jorge, Álvarez Mon Soto Melchor, Cuende Quintana Eduardo, Pérez Gómez Ana, Sanz Paz Ignacio, Mallo Palomares Ana Belén, Reyes Martín Eduardo, Díaz Martín David, Sánchez Atrio Ana. 2009-2011. €85,426 5. “Desarrollo y validación de un cuestionario de adherencia al tratamiento en pacientes con Infección por VHC”. ADHHEPC-2009-01. IMIM. PI: JL. Calleja. 2009-2011. 6. “Estudio traslacional del compartimento monocitario y linfocitario T CD4 de pacientes con artritis reumatoide caracterizados por su patrón de respuesta terapéutica”. PI-1102433. ISCIII. PI: M Álvarez-Mon. Team Members: Eduardo Cuende Quintana, Jorge Monserrat Sanz, David Díaz Martín, Ana

Isabel Sánchez Atrio, Miguel Ángel Sánchez Luengo, Eduardo Reyes Martín, Alfredo Prieto Martín, Ana Pérez Gómez, Ana Isabel Turrión Nieves, Ignacio Sanz Peres. 2012-2014. €134,541 7. “Medicina Individualizada Traslacional en Inflamación y Cáncer.” S2010/BMD-2502. CAM. PI: M Álvarez-Mon. Team Members: Ana Isabel Turrión Nieves, Agustín Albillos Martínez, Jorge Monserrat Sanz, David Díaz Martín, Alfredo Prieto Martín, Leticia Muñoz Zamarrón, Mª Pilar Ubeda Cantera, Mónica Arroyo Yustos, Ana Isabel Sánchez Atrio, José Barbarroja Escudero, Mercedes Rodríguez Rodríguez, Jose Luis López González, Eduardo Reyes Martín, Eduardo Cuende Quintana, Fernando Albarrán Hernández, Ana Pérez Gómez, Fátima Navarro Expósito. 2012-2015. €506,000 8. “Desarrollo y validación de un cuestionario de adherencia al tratamiento en pacientes con Infección por VHC ADHHEPC-2009-01”. IMIM. PI: JL Calleja. 2009-2011. 9. “Estudio aleatorizado, doble ciego, controlado con placebo, sobre los efectos de sapropterina en la hemodinámica hepática y sistémica en pacientes con cirrosis hepática e hipertensión portal”. EC-10-105. ISCiii. PI: A Albillos. Team Members: Juan Ángel González Martín, Enrique Vázquez Sequeiros, Beatriz Peñas García, Elena Garrido, Cristina Martín Martín. 2011-2012. €30,600 10. “Efectos de la disminución ponderal sobre la presión portal en pacientes con cirrosis hepática compensada y sobrepeso/ obesidad”. CIBERehd-ISCiii. PI: A Albillos. Team Members: Juan Ángel González Martín, Enrique Vázquez Sequeiros, Beatriz Peñas García, Elena Garrido, Cristina Martín Martín. 2011-2013. 11. “Ensayo clínico aleatorizado para evaluar si la administración oral de carvedilol es superior a la ligadura endoscópica con bandas en la prevención de la hemorragia por varices en pacientes con cirrosis y varices esofágicas medianas o grandes”. 1544-H-254. ISCiii. PI: A Albillos. Team Members: Juan Ángel González Martín, Enrique Vázquez Sequeiros, Beatriz Peñas García, Elena Garrido, Cristina Martín Martín. 2011-2014.

Thesis 1. Title: “Modelo predictivo in vitro de desensibilización rápida mastocito-IgE: aplicación clínica a quimioterápicos, anticuerpos monoclonales, antibióticos y alimentos en pacientes con anafilaxia”.

Doctorate Student: Tito Rodríguez Bouza. Directors: A. Albillos, M. Concepción Castells. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 12/07/2011.

48 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. vicente arroyo pérez Hospital Clínic, Barcelona

Team leader Vicente Arroyo Pérez

Team members Joan Clarià Wladimiro Jiménez Pere Ginès Gibert Manuel Morales Javier Fernández Gómez Mónica Guevara Montserrat Ramón Bataller Alberola Pau Sancho Bru

Staff Marco Pavesi Miriam Castro Villa Oriol Morales Ibañez Javier Michelena Escudero Jordi Ribera Sabate Guillermo Fernández Varo Esther Titos Rodríguez Montserrat Moreno Sánchez José Trinidad Altamirano Gómez Ana González Periz

Outputs CIBERehd

Nº of Publications 1st quartile: 16 Nº of Publications 2nd quartile: 2 IF total: 133.429 Nº of competitive projects: 12 Public funding: €787,964 Private funding: €14,000 Clinical guidelines: 1 Multicentric clinical trials: 7

FIRST QUARTILE PUBLICATIONS 128,475

126,876

100

5 0

10 13

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• Inflammation and fibrogenesis mechanisms that contribute to the development of liver cirrhosis and its progression. • Endothelial dysfunction, vasoactive agents, vascular morphogenesis and edema in liver cirrhosis. • Common complications of liver cirrhosis, pathogenesis and treatment (impaired renal function, infections and neuropsychiatric disorders). • Pathogenesis and treatment of acute dysfunction that occurs in patients with chronic liver disease (“acute-on-chronic”).

300

240,163

Main Research Topics

Collaborations with other CIBERehd groups Augustín Albillos

Universidad de Alcalá de Henares, Hospital Ramón y Cajal, Madrid

Juan Córdoba

Hospital Vall d’Hebron, Barcelona

Xavier Forns

Hospital Clínic, Barcelona

JC Fernández Checa

CSIC, Barcelona

Antoni Rimola

Hospital Clínic, Barcelona

Jaume Bosch

Hospital Clínic, Barcelona

Scientific Activities of the Programs - 49

1st decile publications Martín-Llahí M, Guevara M, Torre A, Fagundes C, Restuccia T, Gilabert R, Solá E, Pereira G, Marinelli M, Pavesi M, Fernández J, Rodés J, Arroyo V, Ginès P. “Prognostic importance of the cause of renal failure in patients with cirrhosis”. Gastroenterology. 2011 Feb;140(2):488-496.e4. IF: 12.032 COLLABORATION Bosch Gao B, Bataller R. “Alcoholic liver disease: pathogenesis and new therapeutic targets”. Gastroenterology. 2011 Nov;141(5):157285. IF: 12.032 Van Steenkiste C, Ribera J, Geerts A, Pauta M, Tugues S, Casteleyn C, Libbrecht L, Olievier K, Schroyen B, Reynaert H, van Grunsven LA, Blomme B, Coulon S, Heindryckx F, De Vos M, Stassen JM, Vinckier S, Altamirano J, Bataller R, Carmeliet P, Van Vlierberghe H, Colle I, Morales-Ruiz M. “Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice”. Hepatology. 2011 May;53(5):1629-40. IF: 10.885 Cárdenas A, Ginès P. “Management of patients with cirrhosis awaiting liver transplantation”. Gut. 2011 Mar;60(3):412-21. IF: 10.614 Melgar-Lesmes P, Pauta M, Reichenbach V, Casals G, Ros J, Bataller R, Morales-Ruiz M, Jiménez W. “Hypoxia and proinflammatory factors upregulate apelin receptor expression in human stellate cells and hepatocytes”. Gut. 2011 Oct;60(10):1404-11. IF: 10.614 Morales-Ibanez O, Bataller R. “Platelet-derived chemokines: new targets to treat liver fibrosis”. J Hepatol. 2011 Mar;54(3):5813. IF: 9.334

Ginès P.“Pharmacological management of hepatorenal syndrome: lessons from non-responder”. J Hepatol. 2011 Aug;55(2):268-9. IF: 9.334 Guevara M, Baccaro ME, Gómez-Ansón B, Frisoni G, Testa C, Torre A, Molinuevo JL, Rami L, Pereira G, Sotil EU, Córdoba J, Arroyo V, Ginès P. “Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy”. J Hepatol. 2011 Sep;55(3):564-73. IF: 9.334 COLLABORATION Córdoba Affò S, Bataller R. “RANTES antagonism: a promising approach to treat chronic liver diseases”. J Hepatol. 2011 Oct;55(4):936-8. IF: 9.334 Altamirano J, Higuera-de laTijera F, Duarte-Rojo A, MartínezVázquez MA, Abraldes JG, Herrera-Jiménez LE, Michelena J, Zapata L, Perez-Hernández J, Torre A, Gonzáles-González JA, Cardenas A, Dominguez M, Arroyo V, Ginès P, Caballería J, Bataller R. “The amount of alcohol consumption negatively impacts shortterm mortality in Mexican patients with alcoholic hepatitis”. Am J Gastroenterol. 2011 Aug;106(8):1472-80. doi: 10.1038/ajg.2011.141. IF: 6.882 COLLABORATION Bosch/Fernández-Checa Morán-Salvador E, López-Parra M, García-Alonso V, Titos E, Martínez-Clemente M, González-Périz A, López-Vicario C, Barak Y, Arroyo V, Clària J. “Role for PPARγ in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts”. FASEB J. 2011 Aug;25(8):2538-50. IF: 6.515 Martínez-Clemente M, Clària J, Titos E. “The 5-lipoxygenase/ leukotriene pathway in obesity, insulin resistance, and fatty liver disease”. Curr Opin Clin Nutr Metab Care. 2011 Jul;14(4):347-53. IF: 4.333

Relevant projects 1. “Disfunción renal en la cirrosis hepática. Investigación de nuevos métodos, diagnósticos y terapéuticos”. PI08/0126. Ministerio de Salud Instituto de Carlos III. PI: Dr. Pere Ginès. 2008-2012. €111,562 2. “Efectos de la infusión de albúmina en el episodio de encefalopatía hepática. Estudio aleatorizado y multicéntrico en pacientes con cirrosis hepática” . FIS07/0641. Ministerio de Salud Instituto de Carlos III. PI: Dr. Víctor Vargas. Team Members: Dr. Mónica Guevara. 2008-2011. €2,225

5. “Investigació Bàsica: recerca basica i experimental”. 2009_ SGR_1484. Generalitat de Catalunya. PI: Dr. Vicente Arroyo. Team Member: Dr. J Claria. 2009-2013. €8,736 5. “Polimorfisms genéticos del sistema iune innato (MBL/MASP2 y TLR2/4) y riesgo de infecciones bacterianas en la cirrosis avanzada”. FIS 10/01373. Ministerio de Salud Instituto de Carlos III. PI: Dr. Javier Fernández. Team Members: Dr. A Mas; Dr. J Acevedo. 2011-2013. €13,915

3. “Physiopathology of hepatic encephalopathy, clinical and experimental study”. FIS PI 080108. Ministerio de Salud Carlos III. PI: Dr. Mónica Guevara. 2008-2011. €12,826

6. “Investigación traslacional en pacientes con hepatopatías crónicas: Desarrollo de métodos pronósitcos e identificación de nuevas dianas terapéuticas”. FIS08/0237. Ministerio de Salud Instituto de Carlos III. PI: Dr Ramón Bataller. 2008-2011. €40,000

4. “Grup de Recerca en Hepatología Clínica”. 2009_SGR_1401. Generalitat de Catalunya. PI: Dr. Pere Ginès. Team Members: Dr. A Rimola, Dr. M Bruguera, Dr. J Caballeria, Dr. A Pares. 20092013. €9,152

7. “Desarrollo de un test genético para predecir la progresión de la fibrosis heapática en pacientes con hepatitis C Crónica”. PET2008_0304. Ministerio de Ciencia e Innovación. PI: Ramón Bataller. 2009-2011. €50,000

50 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 1

DR. vicente arroyo pérez Relevant projects 8. “Papel de los mediadores lipídicos en la inflamación del tejido adiposo y su influencia sobre la respuesta esteatogénica del hígado en la obesidad”. SAF 09/08767. Ministerio Ciencia e Innovación. PI: Dr. Joan Clària. 2009-2012. €80,913 “Remodelado tisular y disfunción circulatoria en modelos experimentales de enfermedad hepática. Identificación y caracterización de nuevas dianas terapéuticas”. SAF 200908839. Ministerio Ciencia e Innovación. PI: Dr. Wladimiro Jiménez. 2009-2012. €61,646

“Efecte d’un antagonista total de la vasopresina en l’hemodinàmica sistèmica, la pressió portal i la funció excretora renal en rates induïdes a cirrosi per mitjà de tetraclorur de carboni”. Ferring Research Institute Inc. PI: Dr. Wladimiro Jiménez. 2011-2012. €95,186 “Hepatic Microfluidic Bioreactor”. FP7-2010-TESTING. Katholike Universiteit Leuven. PI: Dr. Ramón Bataller. 2011-2015. €276,801

Thesis 1. Title: “Participación de la 5- y la 12/15-lipooxigenasa en el desarrollo y progresión de la inflamación y esteatosis hepática”. Doctorate student: Marcos Martínez Clemente. Director: Joan Clarià. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 06/05/2011.

2. Title: “Utilidad del MELD y el Sodio pretrasplante en el pronóstico del trasplante hepático a corto plazo”. Doctorate student: María Carlota Londoño Hurtado. Director: Pere Ginés. Qualification: Excelente “Cum Laude”. Date of lecture: 29/11/2011.

52 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. rafael bañares cañizares Hospital Gral. Universitario Gregorio Marañón, Madrid

Team leader Rafael Bañares Cañizares

Team members Gerardo Clemente Ricote Magdalena Salcedo Plaza Diego Rincón Rodríguez Ana Matilla Peña María Vega Catalina Rodríguez Cristina Ripoll Noiseux Luis Menchen Viso Javier Vaquero Martin Oreste Lo Iacono Oscar Núñez Martínez

Staff Marta Puerto Cantero Ismael Yepes Barreto Mª Teresa Chiva Robles Juan Antonio Rodríguez Feo

Outputs CIBERehd

Nº of Publications 1st quartile: 3 Nº of Publications 2nd quartile: 2 IF total: 30.21 Multicentric clinical trials: 8

Main Research Topics

50 10

FIRST QUARTILE PUBLICATIONS

300 100

53,417 23,900

5 0

6,012 7

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• • • •

Pathophysiology and treatment of complications of portal hypertension. Pathophysiology and treatment of exacerbated chronic liver failure. Pathophysiological and clinical implications of the intestinal barrier dysfunction. Immunological mechanisms in liver transplantation. Immunosuppression and graft dysfunction.

Collaborations with other CIBERehd groups Agustín Albillos

Hospital Ramón y Cajal, Madrid

Jaume Bosch

Hospital Clínic, Barcelona

Carlos Guarner

Hospital de Sant Pau, Barcelona

Ramón Planas

Hospital Germans Trias i Pujol, Badalona

Scientific Activities of the Programs - 53

1st decile publications Vaquero J, Campbell JS, Haque J, McMahan RS, Riehle KJ, Bauer RL, Fausto N. “Toll-like receptor 4 and myeloid differentiation factor 88 provide mechanistic insights into the cause and effects of interleukin-6 activation in mouse liver regeneration”. Hepatology. 2011 Aug;54(2):597-608. 24420. IF: 10,885

ReViS-TC Study Group. Castells LL, Campos I, Bilbao I, Navasa M, Carrion J, Forns X, Berenguer M, Aguilera V,

Prieto M, Fernández I, Meneu JC, Ulloa E, Fernández JR, Suárez MJ, Pascasio JM, Sousa JM, Casanovas T, Baliella C, Bárcena R, Rodríguez M, de la Mata M, Barrera P, Salcedo M, Bañares R, Otero A, Suárez F, Baños I, Tomé S, Herrero I, Guilera M.” Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation. 2011 Aug 15;92(3):334-40. IF: 3,676 COLLABORATION Dr. Bañares, Dr. Forns, Dra. Berenguer, Dr. de la Mata, Dr. Bañares, Dr. Prieto y Dr. JI Esteban

Relevant projects

Thesis

1. “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”. EC08/00292. ISCIII. PI: Rafael Bañares.

Title: “Valor pronóstico del gradiente de presión venosa hepática para la primera descompensación en pacientes con cirrosis secundaria al virus C de la hepatitis”. Doctorate student: Ismael Yepes Barreto. Director: Rafael Bañares/Diego Rincón. Qualification: “Cum Laude” por unanimidad. Date of lecture: 01/09/2011.

Ripoll C, Yotti R, Bermejo J, Bañares R. “The heart in liver transplantation”. J Hepatol. 2011 Apr;54(4):810-22. IF: 9,334

2. “Proyecto PETRA MICINN convocatoria INNCIDE 2011 (OTRI) PETRA-FIBHGM2011”. MICINN PI: Rafael Bañares. 2011-2013. €88,500 3. “Receptores nucleares de las células epiteliales intestinales como dianas terapéuticas en la enermedad de Crohn”. PI10/01912. ISCIII. PI: Luis Menchén. 2011-2013. €43,139

54 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. jaume bosch genover Hospital Clínic, Barcelona

Team leader

Jaume Bosch Genover

Team members Juan Carlos Garcia-Pagan Mercedes Fernández Lobato Juan Gonzalez-Abraldes Iglesias Annalisa Berzigotti Rosa Gilabert Sole Angels Escorsell Mañosa Ramon Deulofeu Piquet Jordi Gràcia Sancho

Staff Rosa Saez Carceller, Aina Rodríguez Vilarrupla Eva Erice Muñoz Eugenio Rosado Mateo Lucia Russo Héctor García Caldero Ester García Pras Neus Llarch Alfonso Giusi Marrone Eyal Ashkenazi Diana Hide Alferez Sergi Vila Munt Enric Reverter Segura

Main Research Topics

Outputs CIBERehd

Nº of Publications 1st quartile: 17 Nº of Publications 2nd quartile: 0 IF total: 157.52 Nº of competitive projects: 12 Public funding: €739,436,5 Private funding: €38,247,5 Multicentric clinical trials: 5

FIRST QUARTILE PUBLICATIONS 175,026

240,573

300 100

5 0

Collaborations with other CIBERehd groups

157,520

10 21

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• Factors regulating hepatic microcirculation in normal and in cirrhosis, studies of isolated liver perfusion and liver sinusoidal endothelial cells. • Post-transcriptional regulation of the activity of endothelial nitric oxide synthase (eNOS). Relevance in the treatment of portal hypertension. • Regulation of transcription of protective genes hepatic sinusoidal endothelium: relevance to the pathophysiology of portal hypertension in liver ex vivo preservation, and complications of cirrhosis. • Angiogenesis and portal hypertension: contribution to regulation of development of collateral circulation, hyperdynamic circulation and hepatic fibrogenesis. • New noninvasive evaluation of cirrhosis. • Randomized clinical trials of new treatments for portal hypertension. • Hepatic vascular disease. • Prevention of decompensated cirrhosis. • Diagnostic biomarker discovery and response to treatment. • Role of sinusoidal endothelium in ischemia-reperfusion injury liver.

Carlos Guarner

Hospital De Sant Pau, Barcelona

Agustín Albillos

Hospital Ramón y Cajal, Madrid

Rafael Bañares

Hospital Gregorio Marañón, Madrid

José Such

Hospital Universitario De Alicante

Juan Córdoba

Hospital Vall D’hebrón, Barcelona

Ramón Planas

Hospital Germans Trias I Pujol, Badalona

Xavier Calvet

Hospital Parc Tauli, Sabadell

Vicente Arroyo

Hospital Clínic De Barcelona

José M Mato

CIC BioGUNE, Vizcaya

Scientific Activities of the Programs - 55

Berzigotti A, Nicolau C, Bellot P, Abraldes JG, Gilabert R, García-Pagan JC, Bosch J. “Evaluation of regional hepatic perfusion (RHP) by contrast-enhanced ultrasound in patients with cirrosis”. J Hepatol. 2011 Aug; 55(2):307-14. IF: 9.334

Schouten JN, Garcia-Pagan JC, Valla DC, Janssen HL. “Idiopathic noncirrhotic portal hypertension”. Hepatology. 2011 Sep 2; 54(3):1071-81. doi: 10.1002/hep.24422. IF: 10,885

Pasarín M, Abraldes JG, Rodríguez-Vilarrupla A, La Mura V, García-Pagán JC, Bosch J. “Insulin resistance and liver microcirculation in a rat model of early NAFLD”. J Hepatol. 2011 Nov; 55(5):1095-102. IF: 9.334

Berzigotti A, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Morillas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Groszmann RJ; “Portal Hypertension Collaborative Group. Obesity is an independent risk factor for clinical decompensation in patients with cirrosis”. Hepatology. 2011 Aug; 54(2):555-61. IF: 10.885 COLLABORATION Planas Gracia-Sancho J, Russo L, García-Calderó H, García-Pagán JC, García-Cardeña G, Bosch J. “Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver”. Gut. 2011 Apr; 60(4):517-24. IF: 10,614 Llop E, de Juan C, Seijo S, García-Criado A, Abraldes JG, Bosch J, García-Pagán JC. “Portal cholangiopathy: radiological classification and natural history”. Gut. 2011 Jun; 60(6):853-60. IF: 10.614 COLLABORATION Albillos/Bosch Luca A, Miraglia R, Caruso S, Milazzo M, Sapere C, Maruzzelli L, Vizzini G, Tuzzolino F, Gridelli B, Bosch J. “Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrosis”. Gut. 2011 Jun; 60(6):846-52. IF: 10.614 La Mura V, Reverter JC, Flores-Arroyo A, Raffa S, Reverter E, Seijo S, Abraldes JG, Bosch J, García-Pagán JC. “Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension”. Gut. 2011 Aug; 60(8):1133-8. IF: 10.614 Smalberg JH, Koehler E, Darwish Murad S, Plessier A, Seijo S, Trebicka J, Primignani M, de Maat MP, Garcia-Pagan JC, Valla DC, Janssen HL, Leebeek FW; European Network for Vascular Disorders of the Liver (EN-Vie). “The JAK2 46/1 haplotype in BuddChiari syndrome and portal vein thrombosis”. Blood. 2011 Apr 14;117(15):3968-73. IF: 10.558

Talens S, Hoekstra J, Dirkx SP, Darwish Murad S, Trebicka J, Elias E, Primignani M, García-Pagán JC, Valla DC, Janssen HL, Leebeek FW, Rijken DC; EN-Vie Study Group. “Proteomic analysis reveals that apolipoprotein A1 levels are decreased in patients with Budd-Chiari síndrome”. J Hepatol. 2011 May; 54(5):908-14. IF: 9.334 Bureau C, Métivier S, D’Amico M, Péron JM, Otal P, Pagan JC, Chabbert V, Chagneau-Derrode C, Procopet B, Rousseau H, Bosch J, Vinel JP. “Serum bilirubin and platelet count: a simple predictive model for survival in patients with refractory ascites treated by TIPS”. J Hepatol. 2011 May; 54(5):901-7. IF: 9.334 Bosch J. “Soft technique, hard end-points”. J Hepatol. 2011 Nov; 55(5):955-6. IF: 9.334 García-Calderó H, Rodríguez-Vilarrupla A, Gracia-Sancho J, Diví M, Laviña B, Bosch J, García-Pagán JC. “Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats”. J Hepatol. 2011 Apr; 54(4):660-5. IF: 9.334 Altamirano J, Higuera-de laTijera F, Duarte-Rojo A, MartínezVázquez MA, Abraldes JG, Herrera-Jiménez LE, Michelena J, Zapata L, Perez-Hernández J, Torre A, Gonzáles-González JA, Cardenas A, Dominguez M, Arroyo V, Ginès P, Caballería J, Bataller R. “The amount of alcohol consumption negatively impacts short-term mortality in Mexican patients with alcoholic hepatitis”. Am J Gastroenterol. 2011 Aug;106(8):147280. doi: 10.1038/ajg. 2011.141. IF: 6.882 COLLABORATION Arroyo/Bosch/Fernández-Checa

Relevant projects 1. “Insulino resistencia y disfunción endotelial sinusoidal en las hepatopatías crónica. Mecanismos moleculares y significación clínica”. FIS, PI08/0193. ISCIII. PI: Abraldes JG. 2009-2011. €12,826

3. “Regulació de l’angiogenesi en la hipertensió portal. Avaluació de noves estratègies terapèutiques”. LA MARATO 2007. TV3. M. Fernández. PI: E. García-Pras. 2009-2011. €38,250

2. “Regulación de angiogenesis en hipertensión portal y cirrosis hepática. Evaluación de nuevos enfoques terapéuticos”. SAF200802461 Ministerio de Educacion y Ciencia. PI: M. Fernández. Team Member: E. García-Pras. 2009-2011. €36,520

4. “Hemorragia por varices esofágicas: optimización del tratamiento en situaciones complejas”. FIS PI 08/0504. ISCIII. PI: A. Escorsell. Team Members: R. Planas Y E. Llop. 20092011. €11,236

56 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 1

DR. jaume bosch genover Relevant projects 5.“Grup de Recerca Consolidat:“Hemodinàmica Hepàtica i Hipertensió Portal”. 2009SGR1108. AGAUR. PI: J. Bosch. Team Members: Juan Carlos García-Pagán, Juan González-Abraldes, Mercedes Fernández, Aina Rodríguez-Vilarrupla, Angels Escorsell, Rosa Gilabert, Annalisa Berzigotti, Ramón Deulofeu. 2009-2013. €9,568

con placebo, sobre la eficacia del tratamiento de betabloqueantes para prevenir la descompensación de la cirrosis con hipertensión portal”. EC 08/00091. ISCIII. PI: J. Bosch. Team Members: Juan Carlos García-Pagán, Rosa Saez y Juan González-Abraldes. 2009-2011. €31,157

6. “Mecanismos celulares y moleculares en la hipertensión portal no cirrótica”.ACI2009-0938. Subprograma FCCI 2009. PI: J. Bosch. Team Members: Juan Carlos García-Pagán. 2009-2012. €20,425

10. “Desarrollo de biomarcadores del grado de fibrosis hepática y del pronóstico de pacientes con enfermedades hepáticas avanzadas mediante el uso de herramientas metabolómicas”. IPT-010000-2010-013. LIVERBIOMARK. Ministerio de Ciencia e Innovación. PI: J. Bosch. Team Members: Joan Caballeria, Xavier Forns, Miquel Navasa y Jose Mª Mato. 2010-2012. €112,708

7. “Hepatic Hemodynamics and portal hypertension in cirrhosis. Advances in the pathophysiology, non-invasive evaluation and therapy” (Clinical & Experimental Studies)”. PS09/01261. ISCIII. PI: J. Bosch. Annalisa Berzigotti, Rosa Gilabert, Lucia Russo. 2010-2013. €84,095 8. “Asociación de estatinas al tratamiento estándar en la prevención de la recidiva hemorrágica en pacientes con cirrosis y hemorragia por varices”. TRA-074. Ministerio de Sanidad y Política Social. PI: J. Bosch. Team Members: Juan Carlos García-Pagán y Juan González-Abraldes. 2010 (extension 31.12.11). €204,000 9. “Estudio multicéntrico, aleatorizado, doble-ciego, controlado

Thesis Title: “Papel del factor de transcripción Kruppel-like factor 2 en la disfunción endotelial hepática asociada a la hipertensión portal y al daño por isquemia”. Doctorate Student: Lucia Russo. Director: Jaume Bosch y Jordi Gracia-Sancho. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 19/12/2011.

11.“Mecanismos moleculares de la disfunción endotelial intrahepática en la cirrosis. Nuevas dianas terapéuticas de la hipertensión portal”. SAF2007/61298. Ministerio de Educación y Ciencia. PI: JC. GarcíaPagan. A. Rodríguez-Vilarrupla. 2007-2010. €15,550 12. “ Estudio aleatorizado, doble ciego, controlado con placebo, sobre los efectos de la sapropterina en la hemodinámica hepática y sistémica en pacientes con cirrosis hepática e hipertensión portal”. EC10-069. Ministerio de Sanidad, Politica Social e Igualdad. PI: JC. García-Pagan. 2011. €108,000

58 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. JUAN CÓRDOBA CARDONA Institut de Recerca de l’Hospital de la Vall d’Hebron, Bcn

Team leader Juan Córdoba Cardona

Team members Juli Alonso Ferre Núria Raguer Sanz Carlos Jacas Escarcelle Beatriz Mínguez Rosique Víctor Vargas Blasco Joan Genescà Ferrer

Staff Laia Chavarria Vilarassau Lluís Palenzuela Díaz Marc Oria Alonso

Main Research Topics

Outputs CIBERehd

Nº of Publications 1st quartile: 11 Nº of Publications 2nd quartile: 1 IF total: 84.509 Nº of competitive projects: 8 Public funding: €328,114 Private funding: €50,000

FIRST QUARTILE PUBLICATIONS

71,901

10 5 0

86,188

10,933

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Collaborations with other CIBERehd groups Carlos Guarner

Hospital Sant Pau, Barcelona

Vicente Arroyo

Hospital Clínic, Barcelona

Ramon Planas

Hospital Germans Trias i Pujol, Badalona

Jaume Bosch

Hospital Clínic, Barcelona

Jordi Bruix

Hospital Clínic, Barcelona

Manuel Romero

Hospital Valme, Sevilla

1st decile publications 300 100 10

• Hepatic encephalopathy and portal hypertension: pathogenesis, diagnosis and treatment. • Experimental models of hepatic encephalopathy and portal hypertension. • Preclinical assessment of new therapies.

Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, Savic R, Ward SC, Thung S, Chiang DY, Alsinet C, Tovar V, Roayaie S, Schwartz M, Bruix J, Waxman S, Friedman SL, Golub T, Mazzaferro V, Llovet JM. “MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517ª”. Gastroenterology. 2011 May;140(5):1618-28.e16. IF: 12.032 COLLABORATION Bruix/Córdoba Soriano G, Román E, Córdoba J, Torrens M, Poca M, Torras X, Villanueva C, Gich IJ, Vargas

V, Guarner C. “Cognitive dysfunction in cirrhosis is associated with falls: a prospective study”. Hepatology. 2012 Jun;55(6):1922-30. IF: 10.885 COLLABORATION Córdoba/C Guarner Guevara M, Baccaro ME, Gómez-Ansón B, Frisoni G, Testa C, Torre A, Molinuevo JL, Rami L, Pereira G, Sotil EU, Córdoba J, Arroyo V, Ginès P. “Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with

Scientific Activities of the Programs - 59

cirrhosis without overt hepatic encephalopathy”. J Hepatol. 2011 Sep;55(3):564-73. IF: 9.334 COLLABORATION Arroyo/Córdoba Córdoba J. “New assessment of hepatic encephalopathy”. J Hepatol. 2011 May;54(5):1030-40. IF: 9.33 Mínguez B, Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S, Mandeli J, Sia D, April C, Fan JB, Lachenmayer A, Savic R, Roayaie S, Mazzaferro V, Bruix J, Schwartz M, Friedman SL, Llovet JM. “Gene-expression signature of vascular invasion in hepatocellular carcinoma”. J Hepatol. 2011 Dec;55(6):1325-31. IF: 9.334 COLLABORATION Bruix/Córdoba Augustin S, Altamirano J, González A, Dot J, Abu-Suboh M, Armengol JR, Azpiroz F, Esteban R, Guardia J, Genescà J. “Effectiveness of combined pharmacologic and ligation

therapy in high-risk patients with acute esophageal variceal bleeding”. Am J Gastroenterol. 2011 Oct;106(10):1787-95. IF: 6.882 COLLABORATION Azpiroz/Córdoba/Esteban R Román E, Córdoba J, Torrens M, Torras X, Villanueva C, Vargas V, Guarner C, Soriano G. “Minimal hepatic encephalopathy is associated with falls”. Am J Gastroenterol. 2011 Mar;106(3):47682. IF: 6.882 COLLABORATION Córdoba/C Guarner Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, Flavià M, Jacas C, Mínguez B, Vergara M, Soriano G, Vila C, Esteban R, Córdoba J. “Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study”. Am J Gastroenterol. 2011 Jun;106(6):1081-8. IF: 6.882 COLLABORATION Córdoba/C Guarner/Calvet/R Esteban

Relevant projects 1. “Papel del sistema nervioso simpático en la génesis y mantenimiento de las alteraciones hemodinámicas (vasodilatación mesentérica) de la hipertensión portal”. SAF200908354. MICINN. PI: Joan Genescà Ferrer. 2010-2012. €74,235 2. “Estudio multicéntrico, aleatorizado, doble-ciego, controlado con placebo, sobre la eficacia del tratamiento con betabloqueantes para pevenir la descompensación de la cirrosis con hipertensión portal”. EC08/00070. FIS. PI: Joan Genescà Ferrer. 2009-2011. €30,552 3. “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”. EC07/90744. FIS. PI: Victor Vargas. 2008-2011. €52,315 4. “Alteración de la barrera hemato-encefálica y edema cerebral en la insuficiencia hepática experimental”. PI080698. FIS. PI:

Juan Córdoba. 2008-2011. €62,315 5. “Efectos de la infusión de albúmina en el episodio de encefalopatía hepática. Estudio aleatorizado y multicéntrico en pacientes con cirrosis hepática”. PI07/0641. FIS. PI: Víctor Vargas. 2008-2011. €27,225 6. “Efectos de la administración de fenilacetato y ornitina en pacientes con cirrosis hepática que presentan una hemorragia digestiva”. TRA-190. MSPS. PI: Juan Córdoba. 2010. €43,962 7. “Identificación de biomarcadores en la encefalopatía hepática episódica: hacia la individualización del tratamiento en pacientes con cirrosis hepática”. PI10/01028 FIS. PI: Victor Vargas. 2011-13. €37,510 8. “Grup de recerca precompetitiu” . 2009. SGR.383. AGAUR. PI: Joan Genescà Ferrer. Grup de Malalties hepatobiliars. 2010 – 2013. €54,080

Thesis Title: “Relación entre encefalopatía hepática, calidad de vida y proteínas de la dieta en pacientes con cirrosis hepática”. Doctorate student: Iñigo Les. Director: Juan Córdoba. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 15/04/2011.

Title: “Alteracions funcionals de la via motora central en l’encefalopatia hepàtica experimental”. Doctorate student: Marc Oria. Director: Juan Córdoba. Qualification: Sobresaliente Cum Laude. Date of lecture: 25/03/2011.

Title: “Cognitive Function and Liver Implications of Hepatic Encephalopathy”. Doctorate student: Rita Garcia. Director: Juan Córdoba. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 18/04/2011.

Title: “Pronóstico de la hemorragia aguda por varices esofágicas en pacientes con cirrosis hepática”. Doctorate student: Salvador Agustín. Director: Joan Genescà. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 05/07/2011.

Transplantation:

60 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. CARLOS GUARNER AGUILAR Hospital de la Santa Creu i Sant Pau, Bcn

Team leader Carlos Guarner Aguilar

Team members Germán Soriano Pastor Cándido Villanueva Xavier Torras Colell Carlos Aracil Blanch

Staff Elisabet Sánchez Ardid Alan Colomo Eva M. Román Ana M. Boullosa Goberna

Outputs CIBERehd

Nº of Publications 1st quartile: 3 Nº of Publications 2nd quartile: 2 IF total: 24.664 Nº of competitive projects: 7 Public funding: €210,628,50 Private funding: €17,133,19 Multicentric clinical trials: 12

Main Research Topics • Gastrointestinal bleeding due to portal hypertension: prevention and treatment. • Bacterial infections in cirrhosis: diagnosis, prevention and treatment. • Hepatic encephalopathy: diagnosis and treatment. • Characterization of the experimental model of induced and spontaneous bacterial peritonitis.

FIRST QUARTILE PUBLICATIONS

300 100

37,422

51,498

22,238

5 0

Collaborations with other CIBERehd groups

10 4

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

José Such

Fundación de la Comunidad Valenciana para la Investigación, Alicante

Joan Córdoba

Hospital Vall d’Hebron, Barcelona

Vicente Arroyo

Hospital Clínic, Barcelona

Jaume Bosch

Hospital Clínic, Barcelona

Agustín Albillos

Hospital Ramón y Cajal, Madrid

Rafael Bañares

Hospital Gregorio Marañón, Madrid

Ramón Planas

Hospital Germans Trias i Pujol, Badalona

Manuel Romero

Hospital Universitario Nuestra Sra. de Valme, Sevilla

Raúl Andrade

Hospital Universitario Virgen de la Victoria, Málaga

Scientific Activities of the Programs - 61

1st decile publications Soriano G, Román E, Córdoba J, Torrens M, Poca M, Torras X, Villanueva C, Gich IJ, Vargas V, Guarner C. “Cognitive dysfunction in cirrhosis is associated with falls: a prospective study”. Hepatology. 2012 Jun;55(6):1922-30. IF: 10.885 COLLABORATION Córdoba/C Guarner Román E, Córdoba J, Torrens M, Torras X, Villanueva C, Vargas V, Guarner C, Soriano G. “Minimal hepatic encephalopathy is associated with falls”. Am J Gastroenterol. 2011 Mar;106(3):476-

82. IF: 6.882 COLLABORATION Córdoba/C Guarner Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, Flavià M, Jacas C, Mínguez B, Vergara M, Soriano G, Vila C, Esteban R, Córdoba J. “Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study”. Am J Gastroenterol. 2011 Jun;106(6):1081-8. IF: 6.882 COLLABORATION Córdoba/C Guarner/Calvet/R Esteban

Relevant projects 1. “Eficacia y seguridad de la prótesis esofágica autoexpandible versus sonda-balón de Sengstaken como tratamiento hemostático de emergencia en pacientes con hemorragia aguda por varices esofagicas y fracaso del tratamiento farmacológico y endoscópico. Estudio multicentrico, prospectivo y aleatorizado”. PI 08/0504. FIS. PI: Dr. C. Villanueva. Dr. A. Colomo. 2009-2011 2. “Modelo experimental de peritonitis bacteriana inducida o espontánea en ratas con cirrosis: caracterización humoral, hormonal y hemodinámica y evaluación de una nueva estrategia terapéutica”. PI080262. FIS. PI: Dr. C. Guarner. Team Member: Dr. E. Sánchez. 2009-2011. €12,826 3. “Estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo, sobre la eficacia del tratamiento con betabloqueantes para prevenir la descompensación de la cirrosis con hipertensión portal”. EC08/00087. FIS. PI: Dr. C. Villanueva. Team Member: Dr. A. Colomo. 2009-2011. €30,250 4. “Estudio aleatorizado y doble ciego sobre la eficacia de la administración de somatostatina en bolus seguido de una perfusión corta endovenosa como profilaxis de la pancreatitis aguda tras la realización de una colangiopancreatografía retrógrada endoscópica. EC08/00002. FIS. PI: Dra. C. Gómez. Team Members: Dr. C. Guarner, Dr. C. Villanueva. 2009-2011. €73,810

5. “Relación de Polimorfismos de Toll-like receptors (TLR) TLR2, TLR4, TLR9 con la incidencia de infecciones, evolución de la enfermedad y la respuesta inflamatoria en pacientes cirróticos”. PS09/00357. FIS. PI: Dr. G. Soriano. 2010-2012. €17,242 6. “Prevención del desarrollo de hypertensión portal clínicamente significactiva, en la cirrosis compensada mediante vasodilatación hepática selectiva. Estudio multicéntrico, doble ciego, aleatorizado. PI10/01552. FIS: PI: Dr. C. Villanueva. 20112013. €76,500 7. “Estudio aleatorizado y controlado comparando acenocumarol versus bemiparina en pacientes que necesitan reiniciar la anticoagulación tras un episodio de hemorragia digestiva grave”. EC10-135. PI: Dr. C. Villanueva. 2011

62 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. ramÓn planas vilà Hospital Germans Trias i Pujol, Badalona

Team leader Ramón Planas Vilà

Team members Rosa Morillas Cunill Margarita Sala Llinas Carolina Armengol Niell Mireia Miquel Planas

Staff Ramón Bartolí Solé Gemma Òdena García

Outputs CIBERehd

Nº of Publications 1st quartile: 3 IF total: 35.943 Nº of competitive projects: 7 Public funding: €213,014 Private funding: €145,200 Multicentric clinical trials: 13

Main Research Topics • Cirrhosis complications: Portal hipertension, ascites and hepatorenal syndrome, infections associated to cirrhosis. Physiopathology and therapeutic strategies. • Hepatitis C virus: Optimization of therapies and new strategies. • Hepatocelular cancer: Molecular mechanisms of cell proliferation and survival. • Hepatic fibrosis progression. Mechanisms. Role of endocannabinoid system.

Collaborations with other CIBERehd groups 50 10

FIRST QUARTILE PUBLICATIONS

51,668

100 39,397

23,471

5 0

300

10 6

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Vicente Arroyo

Hospital Clínic, Barcelona

Jaume Bosch

Hospital Clínic, Barcelona

José Such

Fundación de la Comunidad Valenciana para la Investigación, Alicante

Joan Cordoba

Hospital Vall d’Hebron, Barcelona

Carlos Guarner

Hospital de la Santa Creu i Sant Pau, Barcelona

Raúl Andrade

Hospital Universitario Virgen de la Victoria, Málaga

Manuel Romero

Hospital Universitario Nuestra Señora de Valme, Sevilla

Xavier Calvet

Corporació Sanitària Parc Taulí

Eduard Cabré

Hospital Germans Trias i Pujol, Badalona

Agustin Albillos

Hospital Ramón y Cajal, Universidad de Alcalá de Henares, Madrid

Rafael Bañares

Hospital Gral. Universitario Gregorio Marañón, Madrid

Scientific Activities of the Programs - 63

1st decile publications Berzigotti A, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Morillas R, Escorsell A, Garcia-Pagan JC, Patch D, Matloff DS, Groszmann RJ; Portal Hypertension Collaborative Group. “Obesity is an independent risk factor for clinical decompensation in patients with cirrosis”. Hepatology. 2011 Aug;54(2):555-61. IF: 10.885 COLLABORATION Bosch/ Planas

Lucena MI, Kaplowitz N, Hallal H, Castiella A, GarcíaBengoechea M, Otazua P, Berenguer M, Fernández MC, Planas R, Andrade RJ. “Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis”. J Hepatol. 2011 Oct;55(4):820-7. IF: 9.334 COLLABORATION Planas/Andrade/Berenguer

Relevant projects 1. “Bloqueo del receptor de endocanabinoides CB1 por SR141716A en ratas cirróticas con ascitis. Efecto sobre la progresión a cirrosis, la hipertensión portal, translocación bacteriana y encefalopatía”. PI80809. ISCIII. PI: Ramon Planas Vilà. Team Members: Ramon Bartolí, Gemma Òdena, Mireia Miquel. 2009-2011. €12,826 2. “Estudio multicéntrico aleatorizado doble ciego controlado con placebo sobre la eficacia del tratamiento con betabloqueantes para prevenir la descompensación de la cirrosis con hipertensión portal”. EC08/00259. ISCIII. PI: Rosa Morillas Cunill. 2009-2011. €30,673 3. “Prótesis esofágica autoexplandible frente a sondabalón de Sengstaken como tratamiento de emergencia en pacientes con hemorragia aguda por varices esofágicas y fracaso del tratamiento farmacológico y endoscópico”. PI080504. ISCIII. PI: Angels Escorsell. Team Members: Rosa Morillas. 2009-2011 4. “Identificación de marcadores diagnóstico y pronóstico en

Thesis Title: “Paper del receptor de cannabinoides 1 (cb1) a la cirrosi experimental. Efecte del bloqueig de cb1 sobre les complicacions de la cirrosi”. Doctorate student: Gemma Òdena Garcia. Director: Ramon Planas/Ramon Bartolí. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 10/11/2011.

plasma del cáncer hepático mediante análisis proteómico”. PS09/00751. ISCIII. PI: Margarita Salas Llinas. Team Members: Jose Angel Jiménez, Isabel Serra, Jorge Navines, Isabel Ojanguren. 2010-2012. €35,000 5. “Unitat de recerca en patologia digestiva. Grup consolidat”. 2009SGR00738. DURSI PI: Ramon Planas Vilà. Team Members: Rosa Morillas, Gemma Odena, Ramon Bartolí, Carolina Armengol. 2009-2012. €9,984 6. “Desarrollo de apósitos de colon para prevenir las complicaciones de las escaras tras terapéutica endoscópica”. PI10/00132. ISCIII. PI: Vicente Maria Lorenzo Zúñiga. Team members: Jaume Boix, Ramon Bartolí. 2011-2013. €110,715 7. “Estudio proteómico integral del cáncer de hígado infantil: identificación de factores diagnóstico y pronóstico, vías de señalización clave y nuevas dianas terapéuticas”. PI10/08082 ISCIII. PI: Carolina Armengol. Team members: Emilio Burgos, Eva Mª Rodríguez, Felix Elorza, Cristina Belendez, Elena Mateos. 2011-2013. €48,816

64 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 1

DR. josé such ronda Fundación de la Comunidad Valenciana para la Investigación, Alicante

Team leader José Such Ronda

Team members Rubén Francés Guarinos José Manuel Gónzalez Navajas Sonia Pascual José Mª Palazón Fernando Carnicer Pedro Zapater Pablo Bellot Garcia Carlos Muñoz Ruiz

Staff Irma García Martínez

Outputs CIBERehd

Nº of Publications 1st quartile: 7 IF total: 36,129 Nº of competitive projects: 6 Public funding: €250,198 Private funding: €80,000 Multicentric clinical trials: 3

Main Research Topics 50

FIRST QUARTILE PUBLICATIONS

10 17,566

51,558

47,014

5 0

300 100 10

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• Detection of bacterial translocation, inflammatory response and associated prognosis. • Treatment of spontaneous bacterial peritonitis. • Effect of norfloxacin on the immune response in the absence of antigen. • Identification of bacterial viability in patients with translocation by proteomic analysis.

Collaborations with other CIBERehd groups Carlos Guarner

Hospital de la Sta. Creu i St. Pau, Barcelona

Vicente Arroyo

Hospital Clínic i Provincial, Barcelona

Agustín Albillos

Hospital Ramón y Cajal. Madrid

Scientific Activities of the Programs - 65

1st decile publications Gómez-Hurtado I, Zapater P, Bellot P, Pascual S, PérezMateo M, Such J, Francés R. “Interleukin-10-mediated heme oxygenase 1-induced underlying mechanism in inflammatory down-regulation by norfloxacin in cirrhosis”. Hepatology. 2011 Mar;53(3):935-44. IF: 10.885

Tritto G, Bechlis Z, Stadlbauer V, Davies N, Francés R, Shah N, Mookerjee RP, Such J, Jalan R. “Evidence of neutrophil functional defect despite inflammation in stable cirrhosis”. J Hepatol. 2011 Sep;55(3):574-81. IF: 9.334

Relevant projects 1. “Efecto modulador de las concentraciones humorales e intracelulares de norfloxacino en la respuesta inflamatoria en sangre y líquido ascítico de pacientes con cirrosis. PI081075. Instituto de Salud Carlos III. PI: José Francisco Such Ronda. Team Memebers: Lucia Llanos Jimenez, Pedro Zapater Hernández, Sonia Pascual Bartolomé, Rubén Francés Guarinos, Pablo Bellot Garcia. 2008-2011. €9,348 2. “Desarrollo de un programa de trasplante hepático en el Hospital General Universitario de Alicante”. Diputación de Alicante. PI: José Such. 2009-2011. €35,000 3. “Ensayo clínico aleatorizado y controlado con paracetamol de la seguridad renal de metamizol en el tratamiento de pacientes cirróticos”. EC07/90557. Instituto de Salud Carlos III. PI: Pedro Zapater Hernández. Team members: José Mª Palazón Azorín, Jose Fco Horga, Ana Peiró, Fernando Carnicer, Jose Such, Miguel Pérez-Mateo, Ruben Frances, Sonia Pascual, Lucia Llanos, Angel Esteban. 2009-2011. €3,630 4. “Activación del inflamasoma en pacientes con cirrosis avanzada y ascitis estéril”. Instituto de Salud Carlos III. PI: Jose Manuel Gonzalez Navajas. Team members: Beatriz Lozano Ruiz. 2011-2014. €121,500 5. “Estudio de la activación del sistema nervioso simpático en respuesta a la presencia de fragmentos de adn bacteriano circulantes en sangre en pacientes cirróticos con ascitis no infectada”. PI11/00962. Instituto de Salud Carlos III. PI: Pedro Zapater Hernández. Team members: José Mª Palazón Azorín ,Sonia Pascual, Pablo Bellot, Montserrat Mauri, Fernando Carnicer, Cayetano Miralles. 2011-2014. €81,620 6. “Actividad simpática espláctica en el control de la traslocación bacteriana durante el desarrollo de cirrosis experimental inducida por la administración oral de tetracloruro de carbono en ratón”. AP-162/11. Conselleria de Sanidad. PI: Ruben Frances. Team members: Isabel Gomez, Jose Such, Pedro Zappater, Jose Manuel Gonzalez Navajas. 2011-2012. €9,500

7. “Detección y significado de la presencia de fragmentos de adn bacteriano circulantes en sangre en pacientes cirróticos portadores de un TIPS”. AP-164/11. Conselleria de Sanidad. PI: Pedro Zapater Hernández. Team members: Jose Maria Palazon, Ruben Frances, Francisco De España, Belen Martinez, Sonia Pascual, Pablo Bellot. 2011. €10,000 8. “Hemostasia y factores proinflamatorios en pacientes cirróticos con ascitis: relación con la traslocación bacteriana e impacto del norfloxacino”. C-05. Fundación HGUA. PI: Pedro Zapater Hernández. Team member: José Such. 2011. €8,589 9. “Efecto de la administración de bifidobacteria en el mecanismo de regulación de tarslocación bacteriana y respuesta inflamatoria en un modelo experimental de cirrosis inducida por tetracloruro de carbono”. C-06. Fundación HGUA. PI: Rubén Francés. Team members: José Such. 2011. €6,000

66 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

Program 2

Viral Hepatitis

P2 Scientific Activities of the Programs - 67

Viral Hepatitis

Presentation: Dr. Juan I. Esteban Mur. Program Coordinator Drs. Xavier Forns and Manuel Romero Gómez. Associate Coordinators

he Viral Hepatitis Program involves eight clinical and basic research groups led by Drs. Juan Ignacio Esteban (Hospital Universitari Vall d’Hebron. Barcelona), Rafael Esteban (Hospital Universitari Vall d’Hebron. Barcelona), Xavier Forns (Hospital Clínic de Barcelona), Javier García-Samaniego (Hospital Carlos III. Madrid), Jordi Gómez (CSIC Instituto Lopez Neyra. Granada), Manuel Romero (Hospital Universitario de Valme, Sevilla), Javier Salmeron (Hospital Universitario San Cecilio. Granada) and Ricardo Moreno (Hospital de la Princesa. Madrid). Research objectives common to all groups include diverse basic, clinical and therapeutic aspects of human viral hepatitis covering from epidemiological trends to personalized treatment strategies. During 2011 the Viral Hepatitis Program groups have consolidated their previously planned collaboration efforts. 1. A Public HBV database (CiberHEP), owned by CIBERehd, approved Sept 25th 2010 (BOE-B-2010-32871) and registered at the Spanish Data Protection Agency (AEPD Oct 22nd 2010). CiberHEP is coordinated by Drs. M. Buti and R. Esteban and

is open to all health professionals caring for hepatitis B virus infected patients. ciberHEP is fully operative and, to date, clinical and therapeutic data from more than 500 patients have been introduced.

2. Similarly, an HCV database named HepatiC originally developed as part of a collaborative CDTI research project between all groups in the CIBERehd viral hepatitis program, Roche Diagnostics and ABL (granted by the MINECO IDI-20110115) also owned by CIBERehd has received official approval (BOEB-2011-20823 June 20th 2011) and registered at the Spanish Data Protection Agency (AEPD Oct 22nd 2011). The HepatiC database, coordinated by Drs. J.I.Esteban and J.Quer, is intended to gather epidemiological, clinical and sequence data from HCV-infected patients in an open web-accessible platform. After some modifications the database was recently endorsed by the Spanish Association for the study of the Liver (AEEH). The CIBERehd, owner of the database is about to sign an agreement with the AEEH to open HepatiC to all national health professionals caring for hepatitis C virus infected patients willing to participate in the Project.

68 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

PROJECTS AND COLLABORATIONS Viral Hepatitis

3. The use of new technologies such as GWAS, Ultra-deep pyrosequencing (UDPS) using the 454/Roche platform and structural RNA biosensors using microarrays, have opened new research lines. In vitro HCV RNA transcripts have been generated as molecular controls to quantify minority mutants in HCV viral populations by UDPS and others. Such new technologies will allow the simultaneous study of HCV viral variability and DNA genomic polymorphisms (IL28B, HLA haplotypes, RBV transporters, etc.) from acute and chronically infected patients and offspring’s of carrier mothers for their potential correlation with spontaneous or treatment-associated outcome. Personalising therapy and defining the bases for new therapies are the main aims of these studies. 4. A CDTI (Centro para el Desarrollo Tecnológico Industrial) project in collaboration with Roche Diagnostics and ABL launched March 1st 2010 has been granted by the MINECO. IDI-20110115. This project entitled “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación” will continue until April 30th 2013. The Project involves the consortium of four Institutions: Roche Diagnostic Systems, ABL-Therapy Edge, CIBERehd, and VHIR-HUVH. 5. Another fully collaborative study, sponsored by a CIBERehd platform, still ongoing during 2011 and entitled “Se-

cuenciación a gran escala para el diagnóstico y planificación del tratamiento de hepatitis víricas” has focused on the analysis of the effect of Ribavirin on HCV “in vivo” and “in vitro”. UDPS sequencing data from control HCV subgenomic cell cultures are currently being concluded. Samples from patients treated with Ribavirin monotherapy have been obtained and the NS5A region will be amplified and subject to UDPS analysis. 6. We have also succeeded in using subgenomic and genomic HCV replicons to study HCV infection, replication, including the cloning of a fully replicating full-length HCV genome (Dr. X. Forns’ group), and investigation of the effect of anti-viral drugs on HCV quasispecies dynamics (Drs. J. Gomez and E. Domingo). 7. Epidemiological studies focused in HBV, HCV, HDV and recently in HEV infection has been reinforced including nosocomial HCV transmission studies thus supporting the National Health Spanish System. We are also studying the viral dynamics during antiviral therapy and during post-transplant recurrence and we are also involved in developing cooperative multicenter assays for antiviral treatments. In summary, the activity developed during 2011 by the groups included in the Viral Hepatitis Program of CIBERehd has increased the competitive research capability of the network.

70 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. juan ignacio esteban mur Institut de Recerca de l’Hospital Vall d’Hebron, Barcelona

Team leader Juan Ignacio Esteban Mur

Team members Jaume Guardia Massó Luís Castells Fusté Itxarone Bilbao Aguirre Sílvia Sauleda Oliveras Lluís Puig Rovira María Piron Piron Marta Bes Majó Mª Dolores Cubero León Isabel Campos Varela Josep Gregori Font Cristina Dopazo Taboada Marta Bes Majó

Staff

Main Research Topics

Josep Quer Sivila Damir García Cehic Ángeles Rico Blázquez

Outputs CIBERehd

Nº of Publications 1st quartile: 5 Nº of Publications 2nd quartile:1 IF total: 33.447 Public funding: €251,316 Private funding: €458,240 Nº of competitive projects: 8 Multicentric clinical trials: 22

FIRST QUARTILE PUBLICATIONS

10 19,159

300

29,945

5 0

Collaborations with other CIBERehd groups

100 31,508

10 58

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• Cloning and sequencing of different regions (NS3, NS5B) of hepatitis C virus (HCV) involved in resistance to antiviral inhibitors (proteasev and polymerase). • Assessment of the epidemiological changes and the morbidity and mortality associated with HCV infection in the European Union. • Studies of nosocomial infection of HCV. • Functional Restoration HCV-specific CD4 response in patients with chronic hepatitis C. • Functional Restoration HCV-specific CD8 response in patients with chronic hepatitis C. • Prospective determination of functional state of the adaptive immune response in HCV-specific liver transplant patients (pre and post-OLTx) and the kinetics of recurrent HCV infection in the graft. • Ultra-sequencing GS-FLX pyrosequencing platform (454/Roche) of HCV and HBV.

Esteban Domingo

Centro de Biología Molecular “Severo Ochoa”(CBMSO). Universidad Autónoma de Madrid

Rafael Esteban

Hospital Universitari Vall d´Hebron, Barcelona

Maria Buti

Hospital Universitari Vall d´Hebron, Barcelona

Xavier Forns

Hospital Clínic i Provincial, Barcelona

J.Garcia-Samaniego

Hospital Carlos III, Madrid

Jordi Gómez Castilla

Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada

Manuel Romero

Hospital Universitario de Valme, Sevilla

F. Javier Salmerón

Hospital Universitario San Cecilio, Granada

Ricardo Moreno

Hospital Universitario de La Princesa, Madrid

Scientific Activities of the Programs - 71

1st decile publications Echeverria I, Pereboev A, Silva L, Zabaleta A, Riezu-Boj JI, Bes M, Cubero M, Borras-Cuesta F, Lasarte JJ, Esteban JI, Prieto J, Sarobe P. “Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells”. Hepatology. 2011 Jul;54(1):28-37. IF: 10.885 COLLABORATION Esteban JI/Prieto

Relevant projects 1. “Estudio dinámico de quasispecies de vhc por pirosecuenciación en fase aguda y crónica durante tratamiento antiviral”. SAF2009-10403. MICINN. PI: Josep Quer Sivila. Team Members: J.Guardia, H.Allende, I. Bilbao, L.Castells, L.Viladomiu, M.Cubero, M.Schaper. 2010-2012. €8,165 2. “Expansión/restauración funcional de células CD4 NS3 específicas autólogas en la prevención de la recurrencia VHC post-trasplante hepático: Optimización del proceso para uso clínico”. PI10/01505. FIS. PI: Juan Ignacio Esteban Mur. Team Members: Marta Bes, Itxarone Bilbao, Isabel Campos, Lluís Castells, Madeleine Piron, Silvia Sauleda. 2010-2012. €54,450 3. “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”. EC07/90744. FIS. PI: Victor Vargas. Team members: Lluís Castells 2008-2011. €30,250 4. “Collection and storage of blood samples. BOTIA-6487. European Comission”. PI: Silvia Sauleda. €50,000 5. “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 (20092011)”. FIPSE/TOH/VIH. FIPSE. PI: Lluís Castells. 2006-012. €28,800 6. “Convenio de Colaboración en proyectos de Investigación entre la Fundació Institut de Recerca Hospital Universitari Vall

Thesis Title: “Tratamiento individualizado de la Hepatitis Crónica C en pacientes con infección por VIH”. Doctorate student: Eva Van den Eynde Otero. Director: Josep Quer Sivila. Manel Crespo Casal. Qualification: Apto “Cum Laude”. Date of lecture: 17/06/2011.

d’Hebron y la Sociedad Española del Transplante Hepático”. PR SETH CASTELLS. “Fundación Sociedad Española Transplante Hepático”. PI: Lluís Castells. 12/03/2010 . 7. “Estudio epidemiológico, observacional, prospectivo sobre el impacto de la replicación de citomegalovirus sobre la evolución de la recurrencia de la hepatitis C en pacientes receptores de trasplante hepático”. PR SETH CASTELLS. “Fundación Sociedad Española Transplante Hepático”. PI: Lluís Castells. €10,997 8. “Prevalencia del XMRV en pacientes con infección por VIH1”. FIPSE 241046/10 FIPSE. PI: Esteve Ribera. Team members: Maria Piron, Silvia Sauleda. 2011-2013. €14,574 9. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche, ABL, CIBERehd, VHIR-HUVH. PI: Juan I. Esteban. Team Members: Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic de Barcelona) Javier GarciaSamaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla (Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013.

72 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. RAFAEL esteban mur Institut de Recerca de l’Hospital Vall d’Hebron, Barcelona

Team leader Rafael Esteban Mur

Team members María Asunción Buti Ferret Francisco Rodríguez Frías Rosendo Jardí Margalef

Staff Melanie Schaper Maria Homs Riba David Tabernero Caellas

Outputs CIBERehd

Nº of Publications 1st quartile: 10 Nº of Publication 2nd quartile: 1 IF total: 117.733 Nº of competitive projects: 4 Public funding: € 452,686 Private funding: € 28,400 Multicentric clinical trials: 13

Main Research Topics • Phenotypic study of resistance to antiviral treatments. • Platform to collect clinical data from patients with chronic hepatitis B (CiberHEP). • Study of HBV quasispecies in different regions of its genome, using ultradeep pyrosequencing. • Hepatitis D Virus (HDV) infection. • Hepatitis E Virus (HEV) infection.

FIRST QUARTILE PUBLICATIONS

300

114,231

60,637

100

41,162

5 0

10 39

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Collaborations with other CIBERehd groups Esteban Domingo

Centro de Biología Molecular “Severo Ochoa”. Universidad Autónoma de Madrid, Madrid

J. Ignacio Esteban

Institut de Recerca de la Vall d’Hebron, Barcelona

Xavier Forns

Hospital Clínic, Barcelona

J. García - Samaniego Hospital Carlos III, Madrid Jordi Gómez

Instituto de Parasitología y Biomedicina “Lopez - Neyra”(CSIC), Granada

Manuel Romero

Hospital Universitario de Valme, Sevilla

Javier Salmerón

Hospital Universitario San Cecilio, Granada

Ricardo Moreno

Hospital Universitario de La Princesa, Madrid

Scientific Activities of the Programs - 73

1st decile publications Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, Poordad F, Goodman ZD, Sings HL, Boparai N, Burroughs M, Brass CA, Albrecht JK, Esteban R; HCV RESPOND-2 Investigators. “Boceprevir for previously treated chronic HCV genotype 1 infection”. N Engl J Med. 2011 Mar 31;364(13):1207-17. IF: 53,486 Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou E, Anderson J, Sorbel J, Rousseau F. “Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B”. Gastroenterology. 2011 Jan;140(1):132-43. IF: 12,032 Di Martino V, Richou C, Cervoni JP, Sanchez-Tapias JM, Jensen DM, Mangia A, Buti M, Sheppard F, Ferenci P, Thévenot T. “Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of randomized,

controlled trials and implications for the future”. Hepatology. 2011 Sep 2;54(3):789-800. IF: 10,885. COLLABORATION Forns/Esteban R Augustin S, Altamirano J, González A, Dot J, Abu-Suboh M, Armengol JR, Azpiroz F, Esteban R, Guardia J, Genescà J. “Effectiveness of combined pharmacologic and ligation therapy in high-risk patients with acute esophageal variceal bleeding”. Am J Gastroenterol. 2011 Oct;106(10):1787-95. IF: 6.882 COLLABORATION Azpiroz/Córdoba/Esteban R Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, Flavià M, Jacas C, Mínguez B, Vergara M, Soriano G, Vila C, Esteban R, Córdoba J. “Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study”. Am J Gastroenterol. 2011 Jun;106(6):1081-8. IF: 6,882 COLLABORATION Córdoba/C Guarner/Calvet/R Esteban

Relevant projects 1. “Análisis integrado del riesgo asociado al consumo de agua y alimentos contaminados con virus patógenos: estabilidad, desinfección y estudio de la trazabilidad del origen de la contaminación”. AGL: 2008-055275-C01. Ministerio de Educación y Ciencia. PI: Dra. Rosina Gironés. Team Members: Jesús Rodríguez-Manzano, Pilar Clemente-Casares, Anna Carratala, Maria Buti, Rosend Jardi. 2009-2011. €10,659 2. “Análisis de la quasiespecies viral en la infección por el virus de la hepatitis B: Evolución natural y asociada al tratamiento antiviral”. FIS: PS09/00899. Fondo de Investigaciones Sanitarias de la Seguridad Social. PI: Dr. Francísco Rodríguez-Frías. Team Members: Mª Asunción Buti Ferret, Maria Homs Riba, Rosendo Jardí Margalef, David Tabernero Caellas. 2009-2012. €22,687 3. “Estudio dinámico de quasispecies de vhc por pirosecuenciación en fase aguda y crónica durante tratamiento antiviral”. SAF2009-10403. MICINN. PI: Dr. Josep Quer. Team Members: Jaume Guardia, Helena Allende, Itxarone Bilbao, Lluis

Castells, Lluis Viladomiu, Maria Cubero, Melanie Schaper. 20102012. €106,090 4. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche, ABL, CIBERehd, VHIR-HUVH. PI: Juan I. Esteban. Team Members: Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic de Barcelona) Javier GarciaSamaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla (Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013.

74 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. xavier forns bernhardt Hospital Clínic, Barcelona

Team leader

Main Research Topics

Xavier Forns

Team members José María Sánchez Tapias Miguel Navasa Anadón Josep Costa Camps José María Barrera Sala Miguel Bruguera Cortada

Staff Sofía Pérez del Pulgar Gallart Patricia González Fdez de Córdoba Georgios Koutsoudakis Jakub Dragun

Outputs CIBERehd

Nº of Publications 1st quartile: 12 Nº of Publications 2nd quartile: 1 IF total: 84.919 Nº of competitive projects: 6 Public funding: €421,628,80 Multicentric clinical trials: 16

• Impact of antiviral treatment in patients with hepatitis C recurrence after liver transplantation and in the natural history of chronic hepatitis C. • Evaluation of new hepatitis C treatments. • Validation of non-invasive diagnostic methods of liver fibrosis in chronic hepatitis C and liver transplantation. • Identification of serum markers of liver fibrosis using metabolomic and proteomic tools. • Genetic evolution of hepatitis C virus in the liver transplantation setting using ultra-deep pyrosequencing. • Characterization of hepatitis C virus life cycle using in vitro cell culture models. • Cloning and characterization of in vitro replication of new hepatitis C virus isolates (genotypes 1b and 3). • Development reporter cell line models for the screening of serum derived from hepatitis C virus-infected patients. • Detection of hepatitis C antigens in liver tissue.

Collaborations with other CIBERehd groups Vicente Arroyo

Hospital Clínic, Barcelona

Antoni Rimola

Hospital Clínic, Barcelona

Rafael Esteban

Hospital Vall d’Hebron, Barcelona

Juan Ignacio Esteban Hospital Vall d’Hebron, Barcelona J. García-Samaniego Hospital Carlos III, Madrid

50 10

FIRST QUARTILE PUBLICATIONS

87,646

85,884

55,861

300 100

Manuel Romero

Hospital Universitario Nuestra Señora de Valme, Sevilla

Marina Berenguer

Hospital la Fe, Valencia

Manuel de la Mata

Hospital Reina Sofía, Córdoba

Rafael Bañares

Hospital General Gregorio Marañón

Jesús Prieto

Clínica Universitaria de Navarra

Jordi Bruix

Hospital Clínic, Barcelona

Jaume Bosch

Hospital Clínic, Barcelona

J. C. Fernández-Checa CSIC, Barcelona 5 0

10 8

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

José Mª Mato

CIC bio-GUNE

Javier Salmerón

Hospital Universitario San Cecilio, Granada

Jordi Gómez

CSIC, Granada

Ricardo Moreno

Hospital de la Princesa, Madrid

Scientific Activities of the Programs - 75

1st decile publications Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Serfaty L, De Backer K, Van Heeswijk R, Luo D, Picchio G, Beumont M. “Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C”. Gastroenterology. 2011 Feb;140(2):459-468. IF: 12.032 Martínez SM, Crespo G, Navasa M, Forns X. “Noninvasive assessment of liver fibrosis”. Hepatology. 2011 Jan;53(1):325-35. IF: 10,885 Mensa L, Crespo G, Gastinger MJ, Kabat J, Pérez del Pulgar S, Miquel R, Emerson SU, Purcell RH, Forns X. “Hepatitis C virus receptors claudin-1 and occludin after liver transplantation and influence on early viral kinetics”. Hepatology. 2011 May;53(5):1436-45. IF: 10.885 Di Martino V, Richou C, Cervoni JP, Sanchez-Tapias JM, Jensen DM, Mangia A, Buti M, Sheppard F, Ferenci P, Thévenot T. “Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of randomized, controlled trials and implications for the future”. Hepatology. 2011 Sep 2;54(3):789-800. IF: 10.885 COLLABORATION Forns/ Esteban R Dragun J, Pérez-Del-Pulgar S, Crespo G, Ramírez S, CotoLlerena M, Mensa L, García-Valdecasas JC, Navasa M, Forns X. “Characterization of the cross-neutralizing antibody response

against hepatitis C virus in the liver transplantation setting”. Am J Transplant. 2011 Apr;11(4):767-74. IF: 6.048 COLLABORATION Forns/Rimola Coto-Llerena M, Pérez-Del-Pulgar S, Crespo G, Carrión JA, Martínez SM, Sánchez-Tapias JM, Martorell J, Navasa M, Forns X. “Donor and recipient IL28B polymorphisms in HCV-infected patients undergoing antiviral therapy before and after liver transplantation”. Am J Transplant. 2011 May;11(5):1051-7. IF: 6.048 Forns X, Navasa M. “Cyclosporine A or tacrolimus for hepatitis C recurrence? An old debate”. Am J Transplant. 2011 Aug;11(8):1559-60. IF: 6.048 ReViS-TC Study Group. Castells LL, Campos I, Bilbao I, Navasa M, Carrion J, Forns X, Berenguer M, Aguilera V, Prieto M, Fernández I, Meneu JC, Ulloa E, Fernández JR, Suárez MJ, Pascasio JM, Sousa JM, Casanovas T, Baliella C, Bárcena R, Rodriguez M, de la Mata M, Barrera P, Salcedo M, Bañares R, Otero A, Suárez F, Baños I, Tomé S, Herrero I, Guilera M. “Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation. 2011 Aug 15;92(3):334-40. IF: 3.676 COLLABORATION Dr. Bañares, Dr. Forns, Dra. Berenguer, Dr. de la Mata, Dr. Bañares, Dr. Prieto y Dr. JI Esteban

Relevant projects 1. “Cultivo del virus de la hepatitis C (genotipos 1 y 3) a partir de suero de pacientes trasplantados hepáticos (TH). Estudio del efecto del TH en la cuasispecie viral mediante pirosecuenciación”. PI11/01907.ISCIII. PI: Xavier Forns. Team members: Georgios Koutsoudakis, Gonzalo Crespo, Patricia González, Sabela Lens. 2012-2015. €109,505 2. “Early identification of severe hepatitis C recurrence after liver transplantation”. CI 442035057. Roche Organ Transplantation Research Foundation (Switzerland). PI: Xavier Forns. Team members: Sofía Pérez del Pulgar, Georgios Koutsoudakis, Gonzalo Crespo, Mairene Coto. 2011-2013. €82,027 3. “Infección del injerto por el virus de la hepatitis C (VHC) en el trasplante hepático: cinética viral precoz, mecanismos de entrada e histopatología y diagnóstico no invasivo de la fibrosis”. PI10/01551. ISCIII. PI: Miquel Navasa. Team members: José María Sánchez Tapias, Rosa Miquel, Laura Mensa, Ignacio Barrau, Jakub Dragun. 2011-2013. €68,365 4. “Caracterización de la expresión hepática de los receptores de entrada del virus de la hepatitis C y su relación con la cinética de infección del injerto y la evolución clínica después del trasplante hepático”. PI080239. ISCIII. PI: Xavier Forns. Team Members: Sofía Pérez del Pulgar, Patricia González,

Santseharay Ramírez. 2009-2011. €25,410 5. “Desarrollo de biomarcadores del grado de fibrosis hepática y del pronóstico de pacientes con enfermedades hepáticas avanzadas mediante el uso de herramientas metabolómicas”. IPT-0100002010-013; LIVERBIOMARK MICINN-Convocatoria INNPACTO 2010. PI: Jaume Bosch. Team Members: Joan Caballeria, Xavier Forns, Miquel Navasa, José María Mato. 2010-2012. €112,708 6. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche, ABL, CIBERehd, VHIR-HUVH. PI: Juan I. Esteban. Team Members: Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic de Barcelona) Javier GarciaSamaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla (Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013. €105,640

76 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

Dr. Javier García-Samaniego Rey Hospital Carlos III, Madrid

Team leader Javier García-Samaniego

Team members Miriam Romero Portales Luz Martín Carbonero Julie Ann Sheldon Pablo Barreira Garcia Marina Nuñez Garcia Mª Belen Ramos Blazquez

Staff Antonio Madejón Seiz Marcelle Bottecchia Marta Sánchez Carrillo

Outputs CIBERehd

Nº of Publications 1st quartile: 4 Nº of Publications 2nd quartile: 2 IF total: 21.173 Nº of competitive projects: 1 Public funding: €22,000 Multicentric clinical trials: 10

FIRST QUARTILE PUBLICATIONS

73,179

300 100

39,772 9,798

5 0

10 4

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Main Research Topics • Study of hepatitis B, C and delta natural history and treatment in patients mono/ HIV co-infected. • Progression in patients coinfected with HIV. • Viral kinetics. • Response prognostic factors. • Interactions between hepatitis B virus and delta in different clinical situations. • Study of the immune response mediated by HCV-specific T cells. • Determination of genotypic and phenotypic resistance to HBV to nucleotics. • Development of noninvasive methods (Fibroscan) for the study of liver Fibrosis. • Study of epigenetic changes induced by HCV and HBV infection.

Collaborations with other CIBERehd groups Manuel Romero

Hospital Universitario Nuestra Sra. De Valme, Sevilla

Ricardo Moreno

Hospital Clínic, Barcelona

Jordi Gómez

CSIC, Granada

Xavier Forns

Hospital Clínic, Barcelona

J. Ignacio Esteban

Hospital Vall d’Hebron, Barcelona

Rafael Esteban

Hospital Vall d’Hebron, Barcelona

Fco Javier Salmerón

Hospital Universitario San Cecilio, Granada

I. Vicente Sandoval

CSIC, Madrid

Scientific Activities of the Programs - 77

Relevant projects 1. “Interacciones entre los virus B y delta de la hepatitis en diferentes situaciones clínicas. Efecto de la selección de mutaciones en el HBsAg tras la terapia con análogos de núcleos(t)ido sobre el fitness viral”. PI081486. FIS. PI: Javier GarcíaSamaniego. Team Members: Antonio Madejon Seiz, Marcelle Bottecchia. 2009-2011. €22,000 2. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche, ABL, CIBERehd, VHIR-HUVH. PI: Juan I. Esteban. Team Members:

Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic de Barcelona) Javier Garcia-Samaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla (Instituto de Parasitología y Biomedicina “Lopez-Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013.

78 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. Jordi Gómez Castilla CSIC. Instituto de Parasitología y Biomedicina López Neyra, Granada

Team leader Jordi Gómez

Team members Esteban Domingo Solans Carlos Briones Llorente Ana García Sacristán

Staff Celia Perales Viejo Rosa Díaz Toledano Isabel Gallego Jimenez

Outputs CIBERehd

Nº of Publications 1st quartile: 6 Nº of publications 2nd quartile: 4 IF total: 56.013 Nº of competitive projects: 8 Public funding: €186,817 Private funding: €43,811

Main Research Topics • • • •

FIRST QUARTILE PUBLICATIONS

10 37,470

53,478

100 41,356

5 0

300

10 5

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Hepatitis C virus replication in cell culture. Selection of drug-escape mutants. Antiviral protocols based on lethal mutagenesis. Ultra deep sequencing analysis of HCV populations in the process of selection of drug-escape mutants or in the process of loss of infectivity as a result of sequential or combination treatments. • Comparison of minority subpopulations with those of HCV of patients under treatment. • Fitness effects of escape mutations. • Characterization of interferon-resistant mutants.

Collaborations with other CIBERehd groups Manuel Romero

Hospital Universitario de Valme, Sevilla

J. Ignacio Esteban

Hospital Vall d’Hebron, Barcelona

Rafael Esteban

Hospital Vall d’Hebron, Barcelona

F. J. Salmerón

Hospital Universitario San Cecilio, Granada

Scientific Activities of the Programs - 79

1st decile publications Iranzo J, Perales C, Domingo E, Manrubia SC. “Tempo and mode of inhibitor-mutagen antiviral therapies: a multidisciplinary approach”. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):1600813. IF: 9.771

Ojosnegros S, García-Arriaza J, Escarmís C, Manrubia SC, Perales C, Arias A, Mateu MG, Domingo E. “Viral genome segmentation can result from a trade-off between genetic content and particle stability”. PLoS Genet. 2011 Mar;7(3):e1001344. IF: 9.543

Relevant projects 1. “Extinción de virus por mutagénesis incrementada. Bases moleculares de la defección letal”. BFU2008-02816. MICINN. PI: E. Domingo. 2009-2011. €38,629 2. “Eficiencia de la mutagénesis letal en infecciones agudas y persistentes del VIH-1. Nuevas perspectivas en terapia”. 360766/09. FIPSE. PI: E.Domingo. Team Members: C. LópezGalíndez, M.A. Martínez. 2010-2012. €43,811 3. “Desarrollo de biosensores basados en sondas de ácidos nucleicos para el genotipado de virus RNA y para la caracterización estructural de su RNA genómico”. BIO201020696. MICINN, Plan Nacional de I+D+i. PI: Carlos Briones. Team Members: Ana García Sacristán, Miguel Moreno Molina, Eva Lanagrán Valero. 2011-2013. €46,434 4. “Peptide nucleic acids as an emerging technology for the detection of H. pylori”. EUI2008-00158. MICINN, Prog. Nac. Internacionalización de la I+D. PI: Carlos Briones. Team Members: Eva Mateo-Martí, Celia Rogero Blanco, Ana García Sacristán. 2010-2011. €35,453 5. “Arquelogía del RNA. Sentido biológico y potencial terapéutico de una estructura tipo tRNA en las cuasiespecies del virus de la hepatitis C”. P07-CVI-3050. Junta de Andalucía Proyectos de Excelencia. PI: Jordi Gómez. Team Member: Rosa Díaz Toledano. 2008-2012. €133,000 6. “¿Existe un código de estructura en el RNA de las

Thesis 1. Title: “Identificación de motivos estructurales en la región 5’ del RNA genómico del West Nile Virus”. Doctorate student: Raquel Díaz Gonzalez. Director: Jordi Gómez Castilla y Alfredo Berzal Herranz. Qualification: Apto “Cum Laude”. Date of lecture: 19/10/2011.

cuasiespecies del virus de la hepatitis C? ¿Sería susceptible a las estrategias terapéuticas basadas en mutagénesis letal?”. BIO2010-15121. Plan Nacional I+D. Área de Biotecnología. PI: Jordi Gómez. Team Member: Rosa Díaz Toledano, Mª Ascensión Ariza Mateos, Samuel Prieto Vega. 2011. €36,300 7. “Rescate de ribozimas durmientes en los mRNAs celulares hepáticos”. BFU2010-11612-E. Ministerio de Ciencia e Innovación Subprograma. EXPLORA INGENIO-2010. PI: Jordi Gómez. Team Member: Rosa Díaz Toledano, Mª Ascensión Ariza Mateos, Samuel Prieto Vega. 2011. €30,000 8. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche, ABL, CIBERehd, VHIR-HUVH. PI: Juan I. Esteban. Team Members: Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic de Barcelona) Javier Garcia-Samaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla (Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013.

80 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. ricardo moreno otero Hospital Universitario de La Princesa, Madrid

Team leader Ricardo Moreno Otero

Team members Cecilia Muñoz Calleja Pedro Majano Rodríguez María Luisa García Buey Asunción García Sánchez Manuel López Cabrera María Trapero Marugán José Andrés Moreno Monteagudo

Staff Samuel Martín Vílchez Ignacio Benedicto Español Mª Jesús Alonso Martín Mª Paloma Sanz Cameno

Outputs CIBERehd

Nº of Publications 1st quartile: 6 Nº of Publications 2nd quartile: 6 IF total: 46.583 Nº of competitive projects: 10 Public funding: €281,146,25 Private funding: €33,034,88 Multicentric clinical trials: 11

Main Research Topics • • • • •

Angiogenesis in chronic liver disease. Hepatic fibrosis in chronic liver diseases. Viral and cellular determinants in early steps of the hepatic C virus infection. Hepatitis B virus X protein in hepatocellular carcinoma. Identification of genetic and serum prognostic markers of chronic liver diseases progression.

Collaborations with other CIBERehd groups Fsco Javier Salmerón Hospital Universitario San Cecilio, Granada 50 10

FIRST QUARTILE PUBLICATIONS

46,345

100 38,118

35,916

5 0

300

10 6

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Manuel Romero

Hospital Universitario de Valme, Sevilla

Jordi Bruix

Hospital Clínic, Barcelona

Xavier Forns

Hospital Clínic, Barcelona

J. García-Samaniego Hospital Carlos III, Madrid Ramón Planas

Hospital Germans Trias i Pujol, Badalona

Javier Pérez Gisbert

Hospital Universitario de La Princesa, Madrid

Rafael Esteban

Institut de Recerca de L’Hospital Vall D’hebron, Bcn

J. González Gallego

Universidad de León

José J. García Marin

Universidad de Salamanca

Jesús María Prieto

Clínica Universitaria De Navarra

Scientific Activities of the Programs - 81

1st decile publications McGarrity T, Heathcote EJ, Gonçales F, Diago M, Craxi A, Silva M, Boparai N, Griffel L, Burroughs M, Brass C, Albrecht J. “FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program”. J Hepatol. 2011 Feb;54(2):22735. IF: 9.334 COLLABORATION Bruix/Moreno de Rueda PM, López-Nevot MÁ, Sáenz-López P, Casado J, MartínCasares A, Palomares P, Quiles R, Gila A, Romero-Gómez M, Pavón EJ, Muñoz JA, Carazo A, Sanz-Cameno P, Moreno-Otero R, Diago M, León J, Ruiz-Extremera A, Salmerón J. “Importance of host genetic factors HLA and IL28B as predictors of response to pegylated interferon and ribavirin”. Am J Gastroenterol. 2011 Jul;106(7):1246-54. IF: 6.882 COLLABORATION Moreno/Romero/Salmerón

Lopez-Rodriguez R, Trapero-Marugan M, Borque MJ, Roman M, Hernández-Bartolome A, Rodriguez-Muñoz Y, Martin-Vilchez S, Abad-Santos F, Muñoz de Rueda P, Vidal-Castiñeira JR, Rodrigo L, Salmeron J, Moreno-Otero R, Sanz-Cameno P. “Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C”. Clin Pharmacol Ther. 2011 Nov;90(5):712-21. doi: 10.1038/ clpt.2011.189. IF: 6.378 COLLABORATION Moreno/ P Gisbert / Salmerón Martin-Vílchez S, Lara-Pezzi E, Trapero-Marugán M, MorenoOtero R, Sanz-Cameno P. “The molecular and pathophysiological implications of hepatitis B X antigen in chronic hepatitis B virus infection”. Rev Med Virol. 2011 Jul 14. IF: 5.600

Relevant projects 1. “Implicación del sistema angiopoyetinas/tie2 en los procesos angiogénicos y fibrogénicos asociados a la hepatitis crónica C”. SAF 2010/21805. Ministerio de Ciencia e Innovación. PI: Ricardo Moreno-Otero. 2010-2013. €66,550 2. “Implicación de polimorfismo genético de factores angiogénicos en la etiopatogenia de la hepatitis crónica C y su evolución a carcinoma hepatocelular”. AECC. PI: Paloma Sanz Cameno.2011-2013. €40,000 3. “Papel de la transición epitelio mesenquimal (TEM) de las células mesoteliales en fibrosis y metástasis peritoneal: TEM como marcador de enfermedad y como diana terapéutica”. SAF 2010-21249. Ministerio de Ciencia e Innovación. PI: Manuel Lopez Cabrera. 2011-2013. €73,666 4.“Estudio de la interrelación entre la polaridad celular y la infección por el virus de la hepatitis C: Posible implicación en el hepatocarcinoma”. FIS PI10/00101. ISCIII. PI: Pedro Lorenzo Majano. Team members: Ignacio Benedicto, Virginia Gondar. 2011-2013. €76,492 5. “Influencia de los virus de la hepatitis B (VHB) y C (VHC) en el desequilibrio estructural y funcional de la vasculatura intrahepática”. Mutua Madrileña. PI: Paloma Sanz Cameno. 2008-2011. €5,775 6. “Aplicación de la mediación de la elasticidad hepática (FibroScan®) como método de diagnóstico, estadiaje y control evolutivo en pacientes con enfermedades hepáticas crónicas”. Mutua Madrileña. PI: Ricardo Moreno-Otero, Jorge Mendoza Ridruejo. 2007-2011. 7. “Respuesta inmune celular, citocínica y apoptótica en paciente con hepatitis crónica C y transaminasas persistentemente

normales tratados con peg-interferon más ribavirina: correlación con la respuesta terapéutica”. Mutua Madrileña. PI: Ricardo Moreno-Otero. Team Members: María Trapero. 2007-2011. 8. “Implicación de polimorfismos genéticos de factores angiogénicos en la etiopatogenia de la hepatitis crónica C y su evolución a carcinoma hepatocelular”. Mutua Madrileña. PI: Ricardo Moreno-Otero. Team Members: Paloma Sanz, Rosario López, María Trapero. 2010-2013. €10,000 9. “Papel en el hepatocarcinoma de la alteración en las uniones intercelulares provocadas por la infección por el virus hepatitis C”. Mutua Madrileña. PI: Pedro Lorenzo Majano. Team members: Ignacio Benedicto, Virginia Gondar. 2011-2012. €8,662 10. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche, ABL, CIBERehd, VHIR-HUVH. PI: JI Esteban. Team Members: Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic, Barcelona) Javier GarciaSamaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla (Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013.

Thesis Title: “Interrelación entre intercelulares estrechas, polaridad de los hepatocitos y el virus de la hepatitis C”. Doctorate student: Ignacio Benedicto.

Director: Manuel López Cabrera, Pedro Lorenzo Majano. Qualification: Sobresaliente “Cum Laude” por unanimidad. Date of lecture: 17/06/2011.

82 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. Manuel Romero Gómez Hospital Universitario de Valme, Sevilla

Team leader Manuel Romero Gómez

Team members José Antonio Irles Rocamora Manuel Castro Fernández Juan Bautista Palomas Daniel Díaz Gómez Blanca Figueruela López Elena Hoyas Pablo Julio Vargas Romero Emilio Suárez García Inés Camacho Benítez Lourdes Grande Santamaria Antonio Robles Frias Emilio Suarez Garcia Isidora Ranchal Illescas

Staff Ángela Rojas Álvarez-Ossorio Raquel Millán Domínguez José Antonio Del Campo Castillo

Main Research Topics

Outputs CIBERehd

Nº of Publications 1st quartile: 5 Nº of Publications 2nd quartile: 5 IF total: 45.938 Nº of competitive projects: 7 Public funding: €185,279 Multicentric clinical trials: 23

• Hepatitis C and insulin resistance. • Complications of cirrhosis: hepatic encephalopathy. • Digestive cancer (Hpylori, colorrectal cancer, hepatocellular carcinoma). • Hepatotoxicity.

Collaborations with other CIBERehd groups 50

FIRST QUARTILE PUBLICATIONS

100 54,848

49,049

35,947

5 0

300

10 5

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Raúl Andrade

Hospital Universitario Virgen de la Victoria, Málaga

Javier Salmerón

Hospital Universitario San Cecilio, Granada

Manuel de la Mata

Hospital Universitario Reina Sofía, Córdoba.

José Mª Mato

CIC bioGUNE, Bilbao

Joan Córdoba

Hospital Vall d´Hebrón, Barcelona

J. Ignacio Esteban

Hospital Vall d´Hebrón, Barcelona

Xavier Forns

Hospital Clínic, Barcelona

Jordi Gómez

IPBLN, CSIC, Granada

Ricardo Moreno

Hospital de la Princesa, Madrid

J. García-Samaniego Hospital Carlos III, Madrid Jesús Prieto

CIMA Pamplona

Scientific Activities of the Programs - 83

1st decile publications Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, Day CP, Ruiz-Cabello F, Donaldson PT, Stephens C, Pirmohamed M, Romero-Gomez M, Navarro JM, Fontana RJ, Miller M, Groome M, Bondon-Guitton E, Conforti A, Stricker BH, Carvajal A, Ibanez L, Yue QY, Eichelbaum M, Floratos A, Pe’er I, Daly MJ, Goldstein DB, Dillon JF, Nelson MR, Watkins PB, Daly AK; Spanish DILI Registry; EUDRAGENE; DILIN; DILIGEN; International SAEC. “Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles”. Gastroenterology. 2011 Jul;141(1):338-47. IF: 12.032 COLLABORATION Romero/ Andrade

Romero-Gómez M. “APOC3 polymorphisms and non-alcoholic fatty liver disease: resolving some doubts and raising others”. J Hepatol. 2011 Dec;55(6):1184-6. IF: 9,334 de Rueda PM, López-Nevot MÁ, Sáenz-López P, Casado J, Martín-Casares A, Palomares P, Quiles R, Gila A, RomeroGómez M, Pavón EJ, Muñoz JA, Carazo A, Sanz-Cameno P, Moreno-Otero R, Diago M, León J, Ruiz-Extremera A, Salmerón J. “Importance of host genetic factors HLA and IL28B as predictors of response to pegylated interferon and ribavirin”. Am J Gastroenterol. 2011 Jul;106(7):1246-54. IF: 6.882 COLLABORATION Moreno/Romero/Salmerón

Relevant projects 1. “Farmacogenómica y Hepatitis C”. PI 448/2009. Consejería de Salud, Junta de Andalucía. PI: Manuel Romero Gómez. 20092011. €12,665 2. “Fatty Liver Inhibition Progression”. HEALTH-F2-2009-241762. 7th PM. PI: Vlad Ratziu. 2009-2011. €305,000 3. “Métodos de verificación del cumplimiento de la dieta en casos de intolerancias alimentarias mediante la detección de marcadores serológicos y/o de péptidos alimenticios”. DELIAC. IPT-2011-0952-900000. Ministerio de Ciencia e Innovacion. PI: Manuel Romero. 2011. €5,094 4. “Identificación de dianas terapéuticas para la hepatitis C: Implicación de los componentes de las vías de señalización de la insulina y señales extraídas de estudios de asociación de genoma completo (GWAS)”. PI10/0611. ISCIII. PI: Manuel Romero. Team members: Jose Antonio del Campo, Maria Cuaresma, Angela Rojas, Lourdes Grande, Maria Jover, Elena Hoyas, Benjmin Pardo. 2010-2013. €93,835 5. “Papel de la Resistencia a la Insulina promovidad por el estrés nitrosativo en el desarrollo de la disfunción endotelial y la progresión de la fibrosis en pacientes con enfermedad hepática por depósito de grasa”. cts-5368. Consejeria de Innovación y Ciencia. PI: Manuel Romero. 2009-2012. €86,250 6. “Utilidad del compuesto Thdp17 como Inhibidor Específico de la Actividad Glutaminasa en el Tratamiento de la Encefalopatía Hepática en ratas con derivación Porto-Cava”. cts7991. Consejería de Innovación y Ciencia. PI: Manuel Romero. Team members: Jose Antonio del Campo, Maria Cuaresma, Hoyas, Benjmin Pardo. 2011-2012. €100,485 7. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche, ABL, CIBERehd, VHIR-HUVH. PI: Juan I. Esteban. Team Members:

Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic de Barcelona) Javier GarciaSamaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla (Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013. €10,640

84 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. Francisco Javier Salmerón Escobar

Hospital Universitario San Cecilio, Granada

Team leader Francisco Javier Salmerón

Team members Ángela Ruiz Extremera, Paloma Muñoz de Rueda Josefa León López, Ángel Palacios Pérez Dolores Quintero Fuentes Esther Ocete Hita Trinidad Caballero Morales

Staff Rosa Quiles Pérez Ana Gila Medina

Outputs CIBERehd

Nº of Publications 1st quartile: 6 Nº of Publications 2nd quartile: 1 IF total: 37.338 Nº of competitive projects: 9 Public funding: €192,141 Private funding: €34,029 Multicentric clinical trials: 7

FIRST QUARTILE PUBLICATIONS

100 28,189

5 0

300

16,852

34,144

10 6

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Main Research Topics • • • •

Viral Hepatitis: HCV and HBV. Colorectal Cancer. Hepatocellular Carcinoma. Non alcoholic liver disease associated with obesity.

Collaborations with other CIBERehd groups Manuel de la Mata

Hospital Universitario Reina Sofía, Córdoba

Ricardo Moreno

Hospital de la Princesa, Madrid

Raúl J. Andrade

Hospital Universitario Virgen de la Victoria.

Manuel Romero

Hospital Universitario Nuestra Sra. De Valme, Sevilla

J. Ignacio Esteban

Hospital Universitario Vall d’Hebron

Jordi Gómez Castilla

IPBLN (CSIC)

Rafael Esteban

Hospital Universitario Vall d’Hebron

Scientific Activities of the Programs - 85

1st decile publications Ruiz-Extremera A, Muñoz-Gámez JA, Salmerón-Ruiz MA, de Rueda PM, Quiles-Pérez R, Gila-Medina A, Casado J, Belén Martín A, Sanjuan-Nuñez L, Carazo A, Pavón EJ, Ocete-Hita E, León J, Salmerón J. “Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCV-infected children”. Hepatology. 2011 Jun;53(6):1830-8. IF: 10.885 de Rueda PM, López-Nevot MÁ, Sáenz-López P, Casado J, Martín-Casares A, Palomares P, Quiles R, Gila A, RomeroGómez M, Pavón EJ, Muñoz JA, Carazo A, Sanz-Cameno P, Moreno-Otero R, Diago M, León J, Ruiz-Extremera A, Salmerón J. “Importance of host genetic factors HLA and

IL28B as predictors of response to pegylated interferon and ribavirin”. Am J Gastroenterol. 2011 Jul;106(7):1246-54. IF: 6.882 COLLABORATION Moreno/Romero/Salmerón Lopez-Rodriguez R, Trapero-Marugan M, Borque MJ, Roman M, Hernandez-Bartolome A, Rodriguez-Muñoz Y, MartinVilchez S, Abad-Santos F, Muñoz de Rueda P, Vidal-Castiñeira JR, Rodrigo L, Salmeron J, Moreno-Otero R, Sanz-Cameno P. “Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C”. Clin Pharmacol Ther. 2011 Nov;90(5):71221. doi: 10.1038/clpt.2011.189. IF: 6.378 COLLABORATION Moreno/ P Gisbert / Salmerón

Relevant projects 1. “Estudio de la variabilidad genética del VHC y la respuesta inmune del hospedador en los pacientes tratados con interferón pegilado y ribavirina. Bases racionales para la obtención de una vacuna terapéutica”. PI10/00717 . Proyecto Intrasalud financiado por el Fondo de Investigación Sanitaria. PI: Francisco Javier Salmerón Escobar. Team members: Ángel Palacios Pérez, Ana Gila Medina, Paloma Muñoz de Rueda, Rosa Quiles Pérez, José Antonio Muñoz Gámez, Ana Belén Martín, Esther José Pavón Castillero. 2011-2014. €54,550 2. “Estudio de los polimorfismos de la IL28B y HLA en la transmisión vertical del VHC” PI-SO-0771. Consejería de Salud de la Junta de Andalucía. PI: Ángeles Ruiz Extremera. Team members: Paloma Muñoz de Rueda, Rosa Quiles, Esther José Pavón Castillero, Esther Ocete Hita, Josefa León, Ana Belén Martín, Mª Angustias Salmerón Ruiz. 2011-2012. €19,585 3. “La sobre expresión de PARP-1 en el tejido hepático como factor de desarrollo de carcinoma hepatocelular”. PI-0783-2010. Consejería de Salud de la Junta de Andalucía. PI: Francisco Javier Salmerón Escobar. Team members: José Antonio Muñoz Gámez, Ángel Carazo Gallego, Esther Pavón Castillero, Jorge Casado, Ana Mª Gila Medina, María Pleguezuelo Navarro, Antonio Poyato González, Isidora Ranchall Illescas, Sandra González Rubio. 2011-2013. €8,829 4. “Virus de la hepatitis C: estudio de la variabilidad genética y la respuesta inmune del hospedador”. CTS-6194. Proyecto de Excelencia, Consejería de Salud de la Junta de Andalucía. PI: Francisco Javier Salmerón Escobar. Team members: José Antonio Campo Castillo, Ana Gila Medina, Miguel Ángel López Nevot, Paloma Muñoz de Rueda, José Antonio Muñoz Gámez, Esther José Pavón Castillero, Rosa Quilez Pérez, Dolores Quintero Fuentes, Manuel Romero Gómez. 2011-2014. €34,910 5. “Caracterización de la Hemo oxigenasa-1 en el cáncer de colon: antioxidantes naturales como tratamientos”. PI09/01684. Instituto de Salud Carlos III. FIS. PI: Josefa León López. Team

Members: Ángel Carazo Gallego, Huda Khaldy Bekaldy, José Luis Sánchez. 2010-2012. €12,705 6. “Estudio de las mutaciones del virus de la hepatitis C en pacientes con genotipo 1 tratados con ribavirina en monoterapia durante 4 semanas seguido del tratamiento combinado con interferón pegilado y ribavirina durante 48 semanas”. PI0415/08. Consejería de Salud de la Junta de Andalucía. PI: Javier Salmerón Escobar. Team Members: Paloma Muñoz de Rueda, Jorge Casado Ruiz, Dolores Quintero, Luis Rodríguez Ramos, Rosa Quiles, Ana Belén Martín, José Antonio Muñoz Gamez. 2009-2011. €13,760 7. “Influencia del tipo de grasa en el desarrollo de la enfermedad del hígado graso no alcohólica (EHGNA) en la obesidad mórbida. Estrés oxidativo y disfunción mitocondrial asociados a la secreción de citoquinas”. P08-CTS-4357. Proyecto de Excelencia de la Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía. PI: Javier Salmerón Escobar. Team Members: Manuel de la Mata, Antonio Zarzuelo, Josefa León López, Ángel Carazo Gallego, Rosa Quiles Pérez, Dolores Quintero, Ángel Palacios, Sergio Delgado, Jorge Casado, Enrique Fraga Rivas, Ana Gila Medina, Guadalupe Costal, Trinidad Caballero, Ángela Ruiz Extremera, Rocío López Posada, Olga Martinez. 2009-2011. €47,800 8 “Estudio de la dinámica de poblaciones del VHC en la gestación y en el puerperio: su importancia en la transmisión vertical y en el curso de la infección en las madres y en los recién nacidos”. PI08/0704. Fondo de Investigación Sanitaria (FIS). PI: Ángela Ruiz Extremera. Team Members: Ángel Carazo Gallego, Esther Ocete Hita, Dolores Quintero Fuentes, Mª Angustias Salmerón Ruiz, Rosa Quiles Pérez, Esther Pavón Castillero, Laura Sanjuán Núñez.2009-2011. €25,300 9. “Estudios de quasiespecies de los virus de la hepatitis B y C (VHB y VHC) y de polimorfismos genómicos asociados a la respuesta al tratamiento antiviral por pirosecuenciación”. Centro para el Desarrollo Tecnológico Industrial (CDTI). Roche,

86 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 2

DR. Francisco Javier Salmerón Escobar Relevant projects ABL, CIBERehd, VHIR-HUVH. PI: Juan I. Esteban. Team Members: Esteban Domingo (Centro de Biología Molecular “Severo Ochoa” (CBMSO), Universidad Autónoma de Madrid) Rafael Esteban y Maria Buti (Hospital Universitario Vall d´Hebron, Barcelona) Xavier Forns (Hospital Clínic de Barcelona) Javier GarciaSamaniego (Hospital Carlos III, Madrid) Jordi Gómez Castilla

(Instituto de Parasitología y Biomedicina “Lopez-.Neyra”, CSIC, Granada), Manuel Romero Gómez (Hospital Universitario de Valme, Sevilla), Francisco Javier Salmerón (Hospital Universitario San Cecilio de Granada), Ricardo Moreno (Hospital Universitario de La Princesa de Madrid), Juan Ignacio Esteban (Hospital Universitario Vall d’Hebron). 2010-2013

Thesis 1. Title: “Polimorfismos HLA como factor predictivo de respuesta virológica sostenida (RVS) en pacientes con hepatitis crónica C (HCC), genotipo 1, tratados con interferón pegilado y ribavirina (IFN-peg y RBV)”. Doctorate student: Pablo José Palomares Rivas. Director: Francisco Javier Salmerón Escobar, Ángeles Ruiz Extremera, Paloma Muñoz de Rueda. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 21/12/10.

2. Title: “Tasas plasmáticas de ribavirina (RBV) en pacientes con hepatitis C crónica (HCC) tratados con interferón pegilado (IFN-peg) más RBV: relación con la respuesta al tratamiento”. Doctorate student: José Miguel Candel Erenas. Director: Francisco Javier Salmerón Escobar, Ángeles Ruiz Extremera, Paloma Muñoz de Rueda. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 17/11/2011.

88 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

Program 3

Cholestasis, Metabolic Disorders and Hepatotoxicity

P3 Scientific Activities of the Programs - 89

Cholestasis, Metabolic Disorders and Hepatotoxicity Presentation: Dr. Juan F. Medina. Program Coordinator

he research activities carried out by the eleven groups included in Program 3 are mainly related to cholestasis, metabolic disorders and hepatotoxicity. A first branch in the Program is formed by three groups led by Dr. Albert Parés, Dr. Llorenç Caballería, and Dr. Juan F. Medina, and these groups focus on clinical, epidemiological, and basic studies of cholestasis. They are working towards the analysis of transport abnormalities of bile flow components and subsequent alterations in primary biliary cirrhosis and other chronic cholestatic diseases. The other remaining groups form a second branch in the program which researches metabolic disorders, and, more specifically, the study of steatohepatitis and liver

toxicity. Thus, these groups conduct studies related to the mechanisms of oxidative stress and apoptosis in hepatocytes and the role of cytokines and adipocytokines in metabolic, toxicological and infectious liver disorders. Highly relevant in this regard are the activities carried out by Dr. José M. Mato and Dr. José C. Fernández-Checa’s groups, which have been awarded a substantial number of projects and carry out multiple collaborations with other groups. Moreover, the groups led by Dr. Javier González Gallego, and Drs. Carmelo García Monzón and Paloma Martín Sanz maintain a close collaboration for the study of antioxidant therapies in models of hepatitis C. Finally, the groups led by Dr. Jose V. Castell, Dr. Ignacio V. Sandoval and Dr. Raúl Andrade are investigating different molecular mechanisms that cause hepatotoxicity.

90 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

PROJECTS AND COLLABORATIONS Cholestasis, Metabolic Disorders and Hepatotoxicity

The groups that form Program 3 have continued reinforcing collaborative networks among them (intra-Nodal collaborations) and among other external groups (inter- Nodal collaborations). The enthusiastic participation in the Strategic Action on Alcoholic and Non Alcoholic Steatohepatitis has continued since year 2009 until now. Dr. José M. Mato’s group, from CIC BioGUNE, has significantly potentiated these collaborations through their Genomics, Proteomics, Metabolomics and Gene Silencing Platforms, which are also available to all CIBERehd groups. Also, collaborations based on these platforms have consolidated through the organisation of formations activities such as training sessions.

Additionally, several high-impact publications further demonstrate the high quality of current collaborations, as indicated by the following few examples: 1. Miquilena-Colina ME, Lima-Cabello E, Sánchez-Campos S, García-Mediavilla MV, Fernández-Bermejo M, LozanoRodríguez T, Vargas-Castrillón J, Buqué X, Ochoa B,

Aspichueta P, González-Gallego J, García-Monzón C. “Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C”. Gut 2011,60:1394-402. 2. Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, Lucena MI, Castiella A, Lindor K, Björnsson E. “The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury”. Hepatology 2011,54:931-9. 3. Ruiz-Gaspà S, Martinez-Ferrer A, Guañabens N, Dubreuil M, Peris P, Enjuanes A, Martinez de Osaba MJ, Alvarez L, Monegal A, Combalia A, Parés A. “Effects of bilirubin and sera from jaundiced patients on osteoblasts: contribution to the development of osteoporosis in liver diseases”. Hepatology 2011,54:2104-13. 4. García-Monzón C, Lo Iacono O, Mayoral R, González-

Scientific Activities of the Programs - 91

PROJECTS AND COLLABORATIONS Cholestasis, Metabolic Disorders and Hepatotoxicity Rodríguez A, Miquilena-Colina ME, Lozano-Rodríguez T, García-Pozo L, Vargas-Castrillón J, Casado M, Boscá L, Valverde AM, Martín-Sanz P. “Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C”. J Hepatol 2011,54:142-52. 5. Tarrats N, Moles A, Morales A, García-Ruiz C, FernándezCheca JC, Marí M. “Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis”. Hepatology 2011,54:319-27. 6. Llacuna L, Fernández A, Montfort CV, Matías N, Martínez L, Caballero F, Rimola A, Elena M, Morales A, FernándezCheca JC, García-Ruiz C. “Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury”. J Hepatol 2011, 54:1002-10.

International networks are also important for Program 3. For instance: 1. Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, Day CP, Ruiz-Cabello F, Donaldson PT, Stephens C, Pirmohamed M, Romero-Gomez M, Navarro JM, Fontana RJ, Miller M, Groome M, Bondon-Guitton E, Conforti A, Stricker BH, Carvajal A, Ibanez L, Yue QY, Eichelbaum M, Floratos A, Pe’er I, Daly MJ, Goldstein DB, Dillon JF, Nelson MR, Watkins PB, Daly AK; Spanish DILI Registry; EUDRAGENE; DILIN; DILIGEN; International SAEC. “Susceptibility to amoxicillinclavulanate-induced liver injury is influenced by multiple HLA class I and II alleles”. Gastroenterology 2011,141:338-47. 2. Cano A, Buqué X, Martínez-Uña M, Aurrekoetxea I, Menor A, García-Rodríguez JL, Lu SC, Martínez-Chantar ML, Mato JM, Ochoa B, Aspichueta P. “Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice”. Hepatology 2011,54:1975-86.

92 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. Raúl Andrade Bellido Hospital Virgen de la Victoria, Málaga

Team leader Raúl Andrade Bellido

Team members María Isabel Lucena González María Del Rosario Cabello Poras Esperanza Crespo Gil Mercedes Robles Diaz Miren García Cortes Ramón Hidalgo Sánchez Eugenia Ulzurrun de Asanza y Vega

Staff Camilla Stephens Inmaculada Moreno Herrera Inmaculada Medina Cáliz

Outputs CIBERehd

Nº of Publications 1st quartile: 6 Nº of Publications 2nd quartile: 1 IF total: 55.996 Nº of competitive projects: 8 Public funding: €20,672 Private funding: €366,524 Multicentric clinical trials: 11

Main Research Topics • Epidemiologic research. • Causality assessment. • Identification of genetic factors and mechanisms of toxicicity.

Collaborations with other CIBERehd groups Manuel Romero-Gómez Hospital de Valme, Sevilla

FIRST QUARTILE PUBLICATIONS

55,996

300

10 3

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

CIC bioGUNE, Vizcaya

José Vicente Castell

Unidad de Hepatología Experimental. Hospital de La Fe, Valencia

Ricardo Moreno-Otero

Hospital de La Princesa, Madrid

Javier Salmerón

Hospital Universitario San Cecilio, Granada

Carlos Guarner

Hospital de la Santa Creu i Sant Pau, Barcelona

Ramon Planas

Hospital Germans Trias i Pujol, Badalona (Barcelona)

Marina Berenguer

Hospital Universitario La Fe, Valencia

100

25,202

José María Mato

1st decile publications Lucena MI, Kaplowitz N, Hallal H, Castiella A, García-Bengoechea M, Otazua P, Berenguer M, Fernández MC, Planas R, Andrade RJ. “Recurrent drug-induced liver injury (DILI) with different drugs

in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis”. J Hepatol. 2011 Oct;55(4):820-7. IF 9,334 COLLABORATION Berenguer / Planas

Scientific Activities of the Programs - 93 García-Cortés M, Stephens C, Lucena MI, Fernández-Castañer A, Andrade RJ; Spanish Group for the Study of Drug-Induced Liver Disease (Grupo de Estudio para las Hepatopatías Asociadas a Medicamentos GEHAM). “Causality assessment methods in drug induced liver injury: strengths and weaknesses”. J Hepatol. 2011 Sep;55(3):683-91. IF 9.334

Pe’er I, Daly MJ, Goldstein DB, Dillon JF, Nelson MR, Watkins PB, Daly AK; Spanish DILI Registry; EUDRAGENE; DILIN; DILIGEN; International SAEC. “Susceptibility to amoxicillin-clavulanateinduced liver injury is influenced by multiple HLA class I and II alleles”. Gastroenterology. 2011 Jul;141(1):338-47. IF 12.032 COLLABORATION Romero-Gomez

Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, Day CP, Ruiz-Cabello F, Donaldson PT, Stephens C, Pirmohamed M, Romero-Gomez M, Navarro JM, Fontana RJ, Miller M, Groome M, Bondon-Guitton E, Conforti A, Stricker BH, Carvajal A, Ibanez L, Yue QY, Eichelbaum M, Floratos A,

Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, Lucena MI, Castiella A, Lindor K, Björnsson E. “The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug-induced liver injury”. Hepatology. 2011 Sep 2;54(3):931-9. doi: 10.1002/hep.24481. IF 10.885

Relevant projects 1.“ProyectosdeInvestigaciónClínicanocomercialconmedicamentos de uso humano”. EC08/00116. Fondo de Investigaciones Sanitarias. PI: Dra. E. Ocete Hita (H. Clínico S Cecilio, Granada). Team Members: Drs Lucena, Andrade, Salmerón, Giménez (H.Torrecárdenas) , Flores (H. Puerta del Mar), Ibarra (H. Reina Sofía), Monteruel (H. De Cruces), Martinón (HCU de Santiago), Del Castillo (HGU Gregorio Marañón) y Romero (HUVN). 2009-2011. €10,486 2. “Estudio de la influencia de los polimorfismos funcionales de los genes de transportadores hepáticos de fármacos: ABCB4 (MDR3), ABCB11 (BSEP), ABCC2 (MPR2), ABCB1 (MDR1) Y DEL SLCO1B1 (OATP1B1) en el riesgo para desarrollar hepatotoxicidad idiosincrasica”. PS09/01384. Fondo de Investigaciones Sanitarias. PI: Raúl J Andrade. Team Members: María Cabello, Eugenia Ulzurrun, Mercedes Robles-Diaz, Esperanza Crespo, Miren Garcia-Cortes. 2010-2012. €20,672 3. “Estudio de la asociación de marcadores situados en la región hla con la susceptibilidad a desarrollar hepatotoxicidad”. Proyecto de Investigación de Excelencia. CTS-6470. Servicio Andaluz de Salud. PI: Mª Isabel Lucena. Team Members: Francisco Ruiz Cabello, Miguel Angel Lopez Nevot, Raúl J. Andrade, Camilla Stephens, Yolanda Borraz, Eugenia Ulzurrun. 2011-2014. 4. Grupo de Investigación: “Evaluación de eficacia, seguridad y economía de los medicamentos”. Código CTS 649. Consejería de Educación y Ciencia. PI: Mª Isabel Lucena. Team Members: Camilla Stephens, Yolanda Borraz, Miren García-Cortes, Mercedes RoblesDiaz, Eugenia Ulzurrun De Asanza Vega, Antonio J. Garcia Ruiz, Beatriz Garcia Muñoz, Francisca Leiva Fernández, Juan Daniel Prados Torres, María Rosario Cabello Porras, Nuria García-Agua Soler.

5. “Plataforma de ayuda a la decisión para la evaluación de medicamentos en entornos hospitalarios”. Proyecto de Investigación de Excelencia Andaluza P11-CTS-08150. Junta de Andalucía. PI: Jesus M Doña Fernandez. Team Members: Mª Isabel Lucena. Proyecto solicitado en 2011. 6. “Estudio de seguimiento a largo plazo tras daño hepatotóxico idiosincrásico por fármacos”. Ayudas de la Fundación Pública Andaluza Progreso y Salud para la financiación de la Investigación Biomédica y en Ciencias de la Salud en Andalucía. S0578. Fundación Pública Andaluza Progreso y Salud. PI: Beatriz Garcia Muñoz. Team Members: Maribel Lucena Gonzalez, Raul Andrade Bellido, Miren Garcia Cortes, Yolanda Borraz Pereira y Nuria Ortiz Lopez. Proyecto solicitado en 2011. 7. “European Union’s programme which supports the modernisation of higher education in the Partner Countries of Eastern Europe, Central Asia, the Western Balkans and the Mediterranean region, mainly through university cooperation projects”. Tempus grant. European Union’s programme. PI: Mª Isabel Lucena. Solicitado en 2011. 8. “Ayuda pci modalidad c. Red latinoamericana de hepatopatías asociadas a medicamentos”. AYUDA PCI MODALIDAD C de la AECID (Agencia Española de Cooperación Internacional para el Desarrollo). PI: Mª Isabel Lucena. Team Members: Raul Andrade Bellido, Miren Garcia Cortes, Eugenia Ulzurrun, Camilla Stephens, María R. Cabello, Mercedes Robles, Inmaculada Moreno, Inmaculada Medina Cáliz + los centros iberoamericanos participantes que son (Uruguay, México, Brasil, Argentina, Perú, Chile). Solicitado en 2011.

Thesis 1. Title: “Proteína C activada y polimorphismo genético en la sepsis grave”. Doctorate Student: Ángela García de la Torre. Director: María Victoria de la Torre Prados, Mª Isabel Lucena González. Qualification: Sobresaliente “Cum Laude” por unanimidad. Date of lecture: 14/10/2011.

2. Title: “Comportamiento del perfil hepático en pacientes que reciben tratamiento tuberculostático: análisis del riesgo y los factores asociados”. Doctorate Student: Eva Martinez Amate. Director: Mª Isabel Lucena González, Carmen Fernández y Marta Casado. Qualification: Sobresaliente “Cum Laude” por unanimidad. Date of lecture: 14/11/2011.

94 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. JOSÉ V. CASTELL RIPOLL Hospital Universitario La Fe, Valencia

Team leader José V. Castell Ripoll

Team members Mª José Gómez Lechón Ramiro Jover Atienza Mª Teresa Donato Martín Bernardo Roque Bort Martí

Staff Marta Benet Giménez

Outputs CIBERehd

Nº of Publications 1st quartile: 3 Nº of Publications 2nd quartile: 1 IF total: 15.522 Nº of competitive projects: 4 Public funding: €247,550 Private funding: €133,750 Multicentric clinical trials: 1

Main Research Topics • • • •

FIRST QUARTILE PUBLICATIONS

10 23,939

5 0

300 100

23,728

12,976

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Drug hepatotoxicity. Gene expression control and hepatic differentiation. Etiology of non-alcoholic fatty liver disease: transcriptional mechanisms involved. Cell Transplantation.

10 0

Collaborations with other CIBERehd groups Carmelo García Monzón

Hospital Universitario Santa Cristina, Madrid

Javier González Gallego

Instituto de Biomedicina Universidad de Leon, León

Raúl Andrade

Hospital Virgen de la Victoria, Málaga

Ignacio Vicente Sandoval

Centro de Biología Molecular Severo Ochoa, Madrid

Scientific Activities of the Programs - 95

1st decile publications Tolosa L, Bonora-Centelles A, Donato MT, Mirabet V, Pareja E, Negro A, López S, Castell JV, Gómez-Lechón MJ. “Influence of platelet lysate on the recovery and metabolic performance of cryopreserved human hepatocytes upon thawing”. Transplantation. 2011 Jun 27;91(12):1340-6. IF 3.676

Relevant projects 1. “Metabonómica y citómica como nuevos paradigmas y estrategias experimentales para el estudio de los mecanismos de hepatotoxicidad de fármacos, predicción de su potencial hepatotóxico y la transición de hepatitis iatrogénica a autoinmune”. PI-10/00923. Instituto de Salud Carlos III. PI: María Teresa Donato Team Members: Jose Vicente Castell, Mª José Gómez Lechón, Laia Tolosa. 2011-2013. €61,500

3. “Innovative strategies to generate human hepatocytes for treatment of metabolic Liver diseases: Tools for personalized cell therapy”. Research Project Ref FP7-278152; InnovaLiv. Unión Europea. PI: José V. Castell y María José GómezLechón. Team Members: José Vicente Castell, Mª José Gómez Lechón, María Teresa Donato,Eugenia Pareja, Laia Tolosa. 2011-2014. €120,000

2. “Mecanismos transcripcionales implicados en el hígado graso no alcohólico de origen metabólico e iatrogénico: influencia de la resistencia a insulina”. PI-10/0194. Instituto de Salud Carlos III. PI: Ramiro Jover. Team Members: Marta Benet, Marta Moya, Laia Tolosa. 2011-2013. €46,050

4. “Transdiferenciación de fibroblastos a hepatocitos mediante reprogramación cellular. SAF2010-15376. Ministerio de Ciencia e Innovación”. PI: Roque Bort. Team Members: Felipe Serrano. 2011-2011. €20,000

96 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. José Fernández-Checa Torres Consejo Superior de Investigaciones Científicas, Barcelona

Team leader José Fernández-Checa

Team members Juan Caballería Carmen García-Ruiz Albert Morales Muñoz Anna Colell Montserrat Marí Laura Conde de la Rosa Claudia Von Montfort Nuria Matías Nuria Tarrats Laura Martínez Milica Stefanovic Elisabet Barbero Anna Baulies Cristina Bárcena

Staff

Main Research Topics

Anna Fernández Fernández Raquel Fucho Susana Nuñez Pozuelo

Outputs CIBERehd

Nº of Publications 1st quartile: 5 IF total: 51.590 Nº of competitive projects: 10

50 10

FIRST QUARTILE PUBLICATIONS

62,442

300 100

76,392

• Role of cholesterol and sphingolipids in patients and experimental models of alcoholic and non-alcoholic steatohepatitis, and cancer. • Regulation of cell death by oxidative stress and characterization of its relevant intracellular mediators in different liver pathologies. • Role of Caveolin-1, STAR and PBR in mitochondrial cholesterol traffic and its contribution to the development of several pathologies. • Cathepsins and TNF in hepatic stellate cells activation and liver fibrosis. • Role of autophagy in Alzheimer’s disease. • Analyze protection mechanisms against liver damage caused by ischemiareperfusion injury.

Collaborations with other CIBERehd groups

36,286

5 0

10 8

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Vicente Arroyo

Hospital Clinic, Barcelona

Xavier Forns

Hospital Clinic, Barcelona

José M. Mato

CIC Biogune, Vizcaya

Jesus M. Prieto

Clínica Universitaria de Navarra, Pamplona

Jaume Bosch

Hospital Clinic, Barcelona

Scientific Activities of the Programs - 97

1st decile publications Altamirano J, Higuera-de laTijera F, Duarte-Rojo A, MartínezVázquez MA, Abraldes JG, Herrera-Jiménez LE, Michelena J, Zapata L, Perez-Hernández J, Torre A, Gonzáles-González JA, Cardenas A, Dominguez M, Arroyo V, Ginès P, Caballería J, Bataller R. “The amount of alcohol consumption negatively impacts short-term mortality in Mexican patients with alcoholic hepatitis”. Am J Gastroenterol. 2011 Aug;106(8):1472-80. IF 6.882 COLLABORATION Arroyo Tarrats N, Moles A, Morales A, García-Ruiz C, FernándezCheca JC, Marí M. “Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis”. Hepatology. 2011 Jul;54(1):319-27. IF 10.885

Bosch M, Marí M, Herms A, Fernández A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, González-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, García-Ruiz C, Pérez-Navarro E, Fernández-Checa JC, Pol A. “Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility”. Curr Biol. 2011 Apr 26;21(8):681-6. IF 10.026 Llacuna L, Fernández A, Montfort CV, Matías N, Martínez L, Caballero F, Rimola A, Elena M, Morales A, FernándezCheca JC, García-Ruiz C. “Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury”. J Hepatol. 2011 May;54(5):1002-10. IF 9.334 COLLABORATION Rimola

Relevant projects 1. “Catepsinas en la Fibrosis Hepática e Inflamación: Regulación por TNF”. PI10/02114. Ministerio Sanidad y Consumo. PI: M. Mari. 2011-2013. 2. “Papel de los esfingolípidos en la esteatohepatitis no alcohólica y resistencia a la insulina hepática”. SAF2008-02199. Ministerio Educación y Ciencia. PI: Carmen Garcia Ruiz. 2009-2011. 3. “Regulación mitocondrial de la citotoxicidad inducida por beta-amiloide”. SAF2010-15760. Ministerio Educación y Ciencia, PI: A Colell. 2011-2013. 4. “Papel de la ceramida y los esfingolípidos en la estetohepatitis”. MM08-CGR. Fundación Mutua Madrileña. PI: Carmen Garcia Ruiz. 2009-2011. 5. “Mitochondrial cholesterol and sphingolipids in ALD: trafficking and cross-talk with the ER”. P50-AA11999. National Institute of Alcohol Abuse and Alcoholism (NIAAA -NIH). PI: JC Fernández-Checa. 2009-2013. 6. “Desarrollo de métodos diagnósticos no invasivos para el diagnóstico y pronóstico de las enfermedades hepáticas inducidas”. PI09/1164. Ministerio Sanidad y Consumo. PI: J

Thesis 1. Title: “Hepatocyte growth factor and c-Met: Role of hypercholesterolemia and signal transduction”. Doctorate Student: Natalia Nuño Lambarri. Directors: Gómez L and Fernández-Checa JC. Qualification: Sobresaliente “Cum Laude” . Date of lecture: 20/09/2011.

Caballeria. 2010-2012. 7. “Mitocondria y cáncer: papel del colesterol, GSH y cardiolipina en la regulación de la permeabilización de la membrana mitocondrial y muerte celular”. SAF2009-11417. Ministerio Educación y Ciencia. PI: JC Fernández-Checa. 2010-2012. 8. “Interacción parénquima-estroma en patologías hepáticas asociadas al eje inflamación-cáncer e isquemia/reperfusión: implicaciones terapéuticas”. PI09/00056. Ministerio Sanidad y Consumo. PI: A Morales. 2010-2012. 9. “Desarrollo de biomarcadores del grado de fibrosis hepática y del pronóstico de pacientes con enfermedades hepáticas avanzadas mediante el uso de herramientas metabolómicas (proyecto LIVERBIOMARK)”. IPT-010000-2010013; LIVERBIOMARK. MICIN. PI: J Bosch. Team Members: J Caballeria, X Forns, M Navasa and JM Mato. 2010-2012. 10. “Colesterol y glicoesfingolípidos en la mitocondria hepática y del cerebro y la alteración del metabolismo contribuye a la patología de la enfermedad de Niemann Pick tipo C y caveolinopatías”. Fundació La Marató de TV3, 050506110015. PI: Fernández-Checa JC. 2011-2014.

98 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. Javier González Gallego Universidad de León

Team leader Javier González Gallego

Team members Mª Jesús Tuñon González Sonia Sánchez Campos José Luis Mauriz Gutiérrez Mª José Cuevas González José Luis Olcoz Goñi, Francisco Jorquera Plaza

Staff Irene Crespo Gómez Mª Victoria Garcia Mediavilla

Outputs CIBERehd

Nº of Publications 1st quartile: 8 Nº of Publications 2nd quartile: 1 IF total: 46.403 Nº of competitive projects: 9 Public funding: €125,000 Private funding: €65,439 Multicentric clinical trials: 5

FIRST QUARTILE PUBLICATIONS

• Development and validation of experimental models of liver and digestive disease. • Role of oxidative stress and inflammation in liver diseases. • Molecular mechanisms involved in development of steatosis in liver chronic diseases.

300 100

36,715

25,261

44,235

5 0

Main Research Topics

10 6

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Collaborations with other CIBERehd groups José V Castell Ripoll

Hospital Universitario La Fe, Valencia

Ricardo Moreno

Hospital de la Princesa, Madrid

Jesús Mª Prieto

Clínica Universitaria de Navarra

Scientific Activities of the Programs - 99

1st decile publications Tuñón MJ, San Miguel B, Crespo I, Jorquera F, Santamaría E, Alvarez M, Prieto J, González-Gallego J. “Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus”. J Pineal Res.2011 Jan;50(1):38-45. doi: 10.1111/j.1600-079X.2010.00807.x IF 5.855 COLLABORATION Prieto Miquilena-Colina ME, Lima-Cabello E, Sánchez-Campos S, García-Mediavilla MV, Fernández-Bermejo M, LozanoRodríguez T, Vargas-Castrillón J, Buqué X, Ochoa B, Aspichueta P, González-Gallego J, García-Monzón C. “Hepatic

fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C”. Gut. 2011 Oct;60(10):1394-402. IF 10.614 COLLABORATION García-Monzón Carbajo-Pescador S, García-Palomo A, Martín-Renedo J, Piva M, González-Gallego J, Mauriz JL. “Melatonin modulation of intracellular signaling pathways in hepatocarcinoma HepG2 cell line: role of the MT1 receptor”. J Pineal Res. 2011 Nov;51(4):46371. doi: 10.1111/j.1600-079X.2011.00910.x. IF 5.855

Relevant projects 1. “Estudio de los mecanismos patogénico involucrados en el desarrollo y evolución de esteatosis asociada a hepatitis C”. Papel del receptor LRXalfa. GRS482/A/10. Gerencia Regional de Salud, Junta de Castilla y León. PI: Francisco Jorquera. Team Members: Javier González Gallego; Sonia Sánchez Campos; Jesús Culebras; Mª Victoria García Mediavilla; Mª José Cuevas González. 2010-2012. €20,000 2. “Análisis in vitro de la contribución del receptor MT1 y de la vía MAPK al efecto antitumoral de la melatonina en el tratamiento del hepatocarcinoma”. LE117A11-2. Consejería de Educación, Junta de Castilla y León. PI: José Luis Mauriz Gutiérrez. Team Members: Mª Victoria García, Sara Carbajo, María José Cuevas, Javier Martín, Pilar Sánchez, Andrés García Palomo. 2010-2011. €15,000 3. “Eficacia de la glutamina en la prevención de enteritis rádica aguda y su efecto sobre el estrés oxidativo”. Gerencia Regional de Salud de Castilla y León. Junta de Castilla y León. PI: Jesús Manuel Culebras Fernández. Team Members: Irene Crespo, Jose Luis Mauriz, Juan Ortiz, Alfonso Vidal, María Jesús Tuñón, Beatriz San Miguel. 2011-2013. €30,000 4. “Papel del receptor nuclear LXRa y de los principales genes lipogénicos e inflamatorios en el desarrollo y evolución de esteatosis en modelos in vitro de hepatitis C”. Efecto de un tratamiento con quercetina. BFU2010-15784/BFI. Ministerio de Ciencia e Innovación. Plan Nacional de I+D+i. PI: Javier González Gallego. Team Members: Sonia Sánchez Campos, Mª Victoria García Mediavilla, María José Cuevas; José Luis Mauriz; José Luis Olcoz. 2010-2012. €30,000 5. Efecto de la cardiotrofina en un modelo animal de fallo

hepático fulminante de etiología vírica. 2008/00260/001. Digna Biotech. PI: Mª Jesús Tuñón. Team Members: Javier González Gallego; Irene Crespo; Beatriz San Miguel. 2008-2011. €35,000 6. “Efecto de la cardiotrofina-1 sobre los principales mecanismos moleculares y las vías de señalización involucradas en el fallo hepático fulminante: estudio en un modelo animal de hepatitis vírica”. BFU2011-30136. Plan Nacional de I+D+i. Subprograma de Proyectos de Investigación Fundamental. PI: Mª Jesús Tuñón. Team Members: Sonia Sánchez, José Luis Mauriz, Marcelino Álverez, Irene Crespo, Beatriz San Miguel, Francisco Jorquera. 2011-2012. €30,000 7. “Análisis de la contribución de las vías PI3K y MAPK a la progresión del hepatocarcinoma”. 2010/00141/001. Fundación de Investigación Sanitaria. PI: Javier González Gallego y José Luis Mauriz Gutiérrez. Team Members: María Jesús Tuñón, Sara Carbajo, María José Cuevas, Javier Martín, Andrés García Palomo. 2010-2011. €13,569 8. “Estudio de los efectos de la administración de glutamina en patología gastrointestinales.” Fundación de Investigación Sanitaria de León. PI: María Jesús Tuñón González y Javier González Gallego. Team Members: María José Cuevas, Beatriz San Miguel, Irene Crespo, Juan Ortiz. 2011-2012. €10,869 9. “Estudio de los mecanismos inmunes responsables de la resistencia a la insulina en pacientes con obesidad mórbida”. Posible papel de la infiltración de los linfocitos CD8+ y otras subpoblaciones linfocitarias en la grasa subcutánea y visceral. Fondo Caja Burgos de Apoyo a la Investigación Clínica. PI: José Luis Olcoz. Team Members: Sonia Sánchez Campos; Javier González Gallego; Francisco Jorquera. 2010-2011. €6,000

Thesis 1. Title: “Efecto de la administración de PPI-2458 sobre los procesos de proliferación celular y apoptosis en un modelo in vitro de hepatocarcinoma”. Doctorate Student: Javier Martín Renedo.

Directors: Javier González Gallego y Jose Luis Mauriz Gutiérrez. Qualifications: Sobresaliente “Cum Laude” con Mención Europea. Date of lecture: 20/10/2011.

100 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. JOSÉ M MATO DE LA PAZ CIC BioGUNE, Vizcaya

Team leader José M Mato De La Paz

Team members María Luz Martínez Chantar Manuel Rodríguez Medina Nicola G.A. Abrescia Naiara Beraza Aguilar Juan Manuel Falcón Pérez Félix Elortza Ana María Aransay

Staff Marta Varela Rey Félix Royo Aintzane González Lahera

Outputs CIBERehd

Nº of Publications 1st quartile: 10 Nº of Publications 2nd quartile: 4 IF total: 79.314 Nº of competitive projects: 17 Public funding: €857,906, Private funding: €50,600

Main Research Topics • • • •

50 10

FIRST QUARTILE PUBLICATIONS

98,504

119,227 65,436

5 0

300 100 10

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Metabolomics and Genomics approaches for NAFLD disease. SAMe metabolism and NAFLD disease Autophagy and NAFLD disease New Oncogenics drivers in HCC. Role of LKB1 and HuR in the absence of the tumor Suppresor GNMT. • Role of Neddylation in the development and progression of the HCC. New Therapeutical approaches. • Metaboloma associated to Neddylation in liver injury. • Implication of the innate immune system in the progression of NASH

Collaborations with other CIBERehd groups Jordi Bruix

Hospital Clínic, Barcelona

Juan Caballeria

Hospital Clinic. Barcelona

Carmelo García Monzón

Hospital Universitario Sta Cristina, Madrid

Jaume Bosch

Hospital Clínic, Barcelona

Manuel Romero

Hospital Universitario de Valme, Sevilla

Scientific Activities of the Programs - 101

1st decile publications Beraza N, Ofner-Ziegenfuss L, Ehedego H, Boekschoten M, Bischoff SC, Mueller M, Trauner M, Trautwein C. “Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis”. Gut. 2011 Mar;60(3):387-96. IF 10.614 Cano A, Buqué X, Martínez-Uña M, Aurrekoetxea I, Menor A, García-Rodríguez JL, Lu SC, Martínez-Chantar ML, Mato JM, Ochoa B, Aspichueta P. “Methionine adenosyltransferase 1A gene deletion disrupts hepatic very low-density lipoprotein assembly in mice”. Hepatology. 2011 Dec;54(6):1975-86. doi: 10.1002/hep.24607. IF 10.885 Abrescia NG, Grimes JM, Oksanen HM, Bamford JK, Bamford DH, Stuart DI. “The use of low-resolution phasing followed by phase extension from 7.6 to 2.5 Å resolution with noncrystallographic

symmetry to solve the structure of a bacteriophage capsid protein”. Acta Crystallogr D Biol Crystallogr. 2011 Mar;67(Pt 3):228-32. IF 6.326 Mato JM, Lu SC. “Where are we in the search for noninvasive nonalcoholic steatohepatitis biomarkers?” Hepatology. 2011 Oct;54(4):1115-7. doi: 10.1002/hep.24642. IF 10.885 Marcos-Villar L, Campagna M, Lopitz-Otsoa F, Gallego P, González-Santamaría J, González D, Rodriguez MS, Rivas C. “Covalent modification by SUMO is required for efficient disruption of PML oncogenic domains by Kaposi’s sarcomaassociated herpesvirus latent protein LANA2”. J Gen Virol. 2011 Jan;92(Pt 1):188-94. IF 3.568

Relevant projects 1. “Role of MAT and SAMe in Colon Cancer Pathogénesis and Treatment (Colon CA) - Role of SAMe in Liver Function and Injury (SAMe). NIH# R01AT004896-01 - NIH# R01AT001576-06 A1. Internacional”. PI: José María Mato de la Paz. Team Member: María Luz Martinez Chantar. 2008-2013. €104,117 2. “Regulation and functions of methione adenosyltransferase gener in liver.” NIH# R01DK051719-15. Internacional. PI: José María Mato de la Paz. Team Member: María Luz Martínez Chantar. 2011-2016. € 21,758 3. “Papel del same en la fisiología y patofisiología hepática” SAF2008-04800. Ministerio de Economía y Competitividad. PI: José María Mato de la Paz. Team Member: María Luz Martínez Chantar. 2009-2011. € 35,574 4. Proyecto Liverbiomark “Desarrollo de biomarcadores del grado de fibrosis hepática y del pronóstico de pacientes con enfermedades hepáticas avanzadas mediante el uso de herramientas metabolómicas”. IPT-010000-2010-13. Ministerio de Economía y Competitividad. PI: José María Mato de la Paz. Team Member: Juan Manuel Falcón. 2010-2013. € 109,305 5. “Desarrollo de un SW para predecir y cuantificar hepatotoxicidad basado en el análisis de perfiles metabólicos en suero – LIVERTOX”. 06/12/TK/2010/0004. Diputación Foral de Bizkaia. PI: José María Mato de la Paz. Team Member: Juan Manuel Falcón. 2010-2011. € 215,798 6. “Optimización de un biosensor electroquímico para la determinación de metionina y homocisteina en plasma METIOSENSOR”. 06/12/TK/2011/0008. Diputación Foral de Bizkaia. PI: José María Mato de la Paz. 2011-2012. €171,269 7. “Nanosight-modelo LM10-HSBF equipo para la determinación de la concentración y distribución de tamaño

de exosomas en suspensiones biológicas de interés en investigación biomédica”. EC 2011-4. Gobierno Vasco. PI: José María Mato de la Paz. 2011-2012. €21,000 8. “Valoración de marcadores pronósticos de respuesta al Sorefenib en pacientes con carcinoma hepatocelular avanzado y su utilidad para la individualización del tratamiento”. 2008111015. Departamento de Sanidad Gobierno Vasco. PI: María Luz Martínez Chantar. 2009-2011. €10,533 9. “Análisis de mecanismos moleculares implicados en el desarrollo del hepatócarcinoma y nuevas aproximaciones terapéuticas”. PI2011-29. Departamento de Educación Gobierno Vasco. PI: María Luz Martínez Chantar. 2011-2013. €14,360 10. “Mecanismos de especificidad que regulan la modificación de proteínas con ubicuitina y moléculas de tipo ubicuitina”. BFU200801108. MICINN. PI: Manuel Salvador Rodríguez. 2009-2011. €14,520 11. “Estudio de mecanismos de especificidad que regulan la modificación de proteínas con moléculas de la familia ubicuitina: Identificación de inhibidores alternativos del sistema ubicuitina-proteasoma y desarrollo de nuevos paradigmas experimentales”. PI2009-5. Departamento de Educación Gobierno Vvasco. PI: Manuel Salvador Rodríguez. 2009-2011. €7,500 12. “Estudios estructurales de la maquinaria de transcripción en archaea como sistema de modelo del proceso de pre-iniciación en la transcripción eucariota”. PI2010-20. Departamento de Educación Gobierno Vasco. PI: Nicola Abrescia. 2010-2012. €14,790 13. “Estudios estructurales de la partícula subviral de hepatitis C y sus complejos con el receptor humano CD81”. BFU200908123. MICINN. PI: Nicola Abrescia. 2010-2012. €25,773

102 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. JOSÉ M MATO DE LA PAZ Relevant projects 14. Implicación de las células NK/NKT en la progresión de NASH en la ausencia de GNMT. PI09/2010. Instituto de Salud Carlos III. PI: Naiara Beraza. 2010-2012. €55,660 15. Estudio bioquímico y funcional de los exosomas en condiciones normales y patológicas. PI09/0526. Instituto de Salud Carlos III. PI: Juan Manuel Falcón. 2010-2012. € 29,947

16. Adquisición de una cabina cerrada para trabajar en una atmósfera no oxidante (N2 liquido) con el objeto de obtener el mayor rendimiento en los estudios metabolómicos. AE20111-48. Departamento de Educación Gobierno Vasco. PI: Juan Manuel Falcón. 2011. €6,000 17. Ubiquitylation profile of PF and MTB infected cells. Tres cantos Open Lab Foundation. PI: Manuel Salvador Rodríguez. 2011-2012. €50,600

Thesis

Patents

1. Title: ”Molecular And Functional Study On Exosome-Like Vesicles As A New Source Of Non-Invasive Biomarkers For Liver Disease”. Doctorate Student: Javier Conde Vancells. Directors: Juan M Falcón. Qualifications: Sobresaliente “Cum Laude”. Date of lecture: 02/02/2011.

1. Title: ”Method for the diagnosis of liver injury based on a metabolomic profile”. Authors: Juan M. Falcón. European Patent Office. Number: P6435EP00. Date of lecture: 20/04/2011.

2. Title: ”The role of the serine/threonine kinase lkb1 in the proliferation of hepatocellular carcinomas derived from nonalcoholic steatohepatitis (nash)”. Doctorate Student: Nuria Martinez Lopez. Directors: M Luz Martínez- Chantar. Qualifications: Sobresaliente “Cum Laude”. Date of lecture: 22/03/2011. 3. Title: ”Feature selection methods for the generation of signatures to study the non alcoholic fatty liver disease”. Doctorate Student: Itziar Frades. Directors: M Luz Martínez- Chantar. Qualifications: Sobresaliente “Cum laude”. Date of lecture: 05/07/2011.

Scientific Activities of the Programs - 103

104 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. Juan Francisco Medina CIMA Universidad de Navarra, Pamplona

Team leader Juan Francisco Medina

Team members Carlos M Rodríguez-Ortigosa Nicolás García González Elena Sáez de Blas Sarai Sarvide Miriam Úriz Baráibar Alex Ferrer Galindo

Staff Ainhoa Portu García Sara Arcellus Echevárri

Outputs CIBERehd

Nº of Publications 1st quartile: 1 IF total: 4.411 Nº of competitive projects: 1 Public funding: €70,000

Main Research Topics • Molecular genetics of intrahepatic cholestasis; the role of the AE2 anion exchanger in the etiopathogenesis of primary biliary cirrhosis; ursodeoxycholic acid and AE2. • Analysis of the liver and immunologic phenotypes of the Ae2-deficient mice (in collaboration with Dr. Oude Elerink, AMC, Amsterdam). • Role of NO species for the choleretic effect of ursodeoxycholic acid. • Role of metalloproteases in polycystic liver diseases.

FIRST QUARTILE PUBLICATIONS

300

Collaborations with other CIBERehd groups

100

Albert Parés

Hospital Clínic, Barcelona

Jesús M. Prieto

University of Navarra Clinic, Pamplona

Juan J. G. Marín

University of Salamanca, Salamanca

Marçal Pastor-Anglada

University of Barcelona, Barcelona

Luis Bujanda

Hospital de Donostia, San Sebastián

Javier González Gallego

Universidad de León, León

José M. Mato

CIC bioGUNE, Vizaya

49,770 28,824

10 4,411

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Scientific Activities of the Programs - 105

Relevant projects

Thesis

1. “Ratones deficientes de AE2: Estudio de las alteraciones linfocitarias y biliares en este modelo animal de CBP”. SAF200911538. Ministerio de Ciencia e Innovación. PI: Juan F. Medina. Team Members: Jesús M. Bañales, January Salas, Alejandro Ferrer , Miriam Úriz , Fabián Arenas, Axel Concepción, Ronald P. J. Oude-Elferink, Martín E. Fernández-Zapico. 2010-2012. €70,000

Title: ”Deficiency of Ae2 in mice predisposes to liver injury associated with reduced glutathione, increased apoptosis and development of AMA”. Doctorate Student: Alejandro Ferrer Galindo. Directors: Dres. Juan F. Medina y Jesús M. Bañales. Qualification: Sobresaliente “Cum Laude” y Doctorado Europeo. Date of lecture: 17/12/2011.

106 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3

DR. Albert Parés Darnaculleta Hospital Clínic, Barcelona

Team leader Albert Parés Darnaculleta

Team members Nuria Guañabens Gay Antoni Mas Ordeig Pilar Peris Bernal Luisa Álvarez Domínguez Mª Jesús Martínez De Osaba Madariaga

Staff Silvia Ruiz-Gaspa Rosana Ahuir Rosello

Outputs CIBERehd

Nº of Publications 1st quartile: 3 IF total: 19.897 Nº of competitive projects: 4 Public funding: €127,754 Private funding: €26,365 Multicentric clinical trials: 3

Main Research Topics • Epidemiology, natural history and therapeutic response of chronic cholestatic diseases in adults, particularly primary biliary cirrhosis. • Pathogenic mechanisms of osteoporosis and development of fractures in primary biliary cirrhosis and in other chronic cholestatic diseases. • Pathogenesis of pruritus of chronic cholestasis and treatment response to albumin dialysis. • Efficacy and safety of the different procedures in a bioarticial liver.

Collaborations with other CIBERehd groups

FIRST QUARTILE PUBLICATIONS

100 28,543

38,626

15,486

5 0

300

10 4

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Juan F. Medina

CIMA Universidad de Navarra, Pamplona

JM Mato

CiC Biogune, Bilbao

Agustín Albillos

Hospital Ramón y Cajal, Madrid

Rafael Bañares

Hospital Gregorio Marañón, Madrid

Ricardo Moreno

Hospital de la Princesa, Madrid

Marina Berenguer

Hospital La Fe, Valencia

Rafael Esteban

Hospital Vall d’Hebron, Barcelona

Ramón Planas

Hospital Germans Trias i Pujol, Badalona

Carlos Guarner

Hospital de la Sta Creu i Sant Pau, Barcelona

José Fernández-Checa

Consejo Superior de Investigaciones Científicas, Barcelona

Raúl Andrade

Hospital Virgen de la Victoria, Málaga

Llorenç Caballeria

Instituto de Investigación en Atención Primaria Jordi Gol

Scientific Activities of the Programs - 107

1st decile publications Peris P, Torra M, Olivares V, Reyes R, Monegal A, MartínezFerrer A, Guañabens N. “Prolonged bisphosphonate release after treatment in women with osteoporosis. Relationship with bone turnover”. Bone. 2011 Oct;49(4):706-9. IF 4.601

Ruiz-Gaspà S, Martinez-Ferrer A, Guañabens N, Dubreuil M, Peris P, Enjuanes A, Martinez de Osaba MJ, Alvarez L, Monegal A, Combalia A, Parés A. “Effects of bilirubin and sera from jaundiced patients on osteoblasts: contribution to the development of osteoporosis in liver diseases”. Hepatology. 2011 Dec;54(6):2104-13. doi: 10.1002/hep.24605. IF 10.885

Relevant projects 1. “Prurito de la colestasis: fisiopatología y análisis proteómico”. SAF200804012. Ministerio de Educación. PI: Alberto Parés Darnaculleta. Team Member: Antonio Mas Ordeig. 20092011. €11,616

3. “Enfermedades hepáticas autoinmunes. Nuevos procedimientos diagnósticos mediante mapeo peptídico”. PI071318. ERARE-ISCIII. PI: Alberto Parés Darnaculleta. Team Member: Antonio Mas Ordeig. 2008-2011. €16,247

2. “Influencia de la bilirrubina y los ácidos biliares sobre la formación ósea”. Estudio ‘in vitro’ en osteoblastos humanos. PI080105. ISCIII. PI: Nuria Guañabens Gay. Team Members: Pilar Peris Bernal, Luisa Álvarez Domínguez, MJ Martínez de Osaba. Silvia Ruiz-Gaspà. 2009-2011. €31,200

4. “Prospective study of bone loss after spinal cord injury. Risk factors and role of osteocyte markers”. Fundació La Marató TV3. PI: Pilar Peris Bernal. Team Members: Nuria Guañabens Gay. 2011-2013. €68,691

Thesis 1. Title: “Prevalença i factors associats a la presència d’esteatosi hepàtica no alcohòlica en la població general”. Doctorate Student: Maria Antónia Auladell Llorens. Director: Albert Parés/ Llorenç Caballería. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 25/05/2011.

2. Title: ”Osteoporosis en la mujer posmenopáusica. Riesgo de Fractura en la enfermedad colestásica y prevalencia de otros procesos asociados”. Doctorate Student: Dacia Cerdà Gabaroi. Director: Núria Guañabens. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 13/10/2011.

108 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 3

DR. Ignacio Vicente Sandoval Consejo Superior de Investigación Científicas, Madrid

Team leader Ignacio Vicente Sandoval

Team members Juan José Berlanga Chiquero Diego Pulido Vega

Staff Vasiliki Lalioti Mariana Todorova

Outputs CIBERehd 2010

Nº of Publications 1st quartile: 1 IF total: 7.818 Nº of competitive projects: 2 Public funding: €442,000

Main Research Topics • Transport molecular mechanisms, activation of copper and glucose transporters. • TP7B and tight junctions.

Collaborations with other CIBERehd groups José M Mato

CIC BioGUNE, Vizcaya

1st decile publications 2010 Lalioti V, Sandoval I, Cassio D, Duclos-Vallée JC. “Molecular pathology of Wilson’s disease: a brief”. J Hepatol. 2010 Dec;53(6):11513. IF 7.818

Relevant projects 2010

FIRST QUARTILE PUBLICATIONS

10 5 0

300 100

12,457

13,693

7,818

2008 2009 2010 IF 1ST QUARTILE

PUBLICATIONS

10 0

1. “Mecanismos moleculares implicados en la regulación de la homeostasis de la glucosa y del cobre y su disfunción en la diabetes de tipo 2 y las toxicosis por cobre”. PI081242. FIS. PI: Ignacio V Sandoval. Team Members: Lalioti V, Pulido D, Todorova M. 2009-2011. €426,000

2. “Molecular mechanisms established between Sorcin I and Esyt I”. 2010IT0097. CSIS/CRI. PI: Ignacio V Sandoval and Gianni Colotti. 2010/2012. €16,000

Patents 1. Title: “Explotation by Santa Cruz Biotechnology of five mouse monoclonal antibodies raised to lysosomes and Golgi apparatus”. Application: The antibodies can be used as lysosomal and Golgi markers in immunofluorescence microscopy,

Western, ELISA and immunoprecipitation studies: They can be used by anatomopathologists as general biopsy markers as well as markers in lysosomal and secretory diseases. Author: Ignacio V. Sandoval. Since 2006.

110 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3 Linked group

DR. Paloma Martín Sanz Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid

Team leader Paloma Martín Sanz

Team members Marta Casado Pinna Lisardo Boscá Gomar Rafael Mayoral Moñibas

Outputs CIBERehd

Nº of Publications 1st quartile: 5 Nº of Publications 2nd quartile: 1 IF total: 33.622 Nº of competitive projects: 5 Public funding: €152,000

Main Research Topics • Dual role of COX-2 in liver physiopathology. • Contribution of caveolin-1 to the liver regeneration process. • Molecular mediators associated with non alcoholic fatty liver disease and chronic infection by the C virus. Role of autophagy and endoplasmic reticulum stress. • Thyroid hormones and liver regeneration

Collaborations with other CIBERehd groups Carmelo García Monzón Hospital Universitario Santa Cristina, Madrid Manuel de la Mata

Hospital Reina Sofía, Córdoba y Centro Andaluz de Biología Molecular y Medicina Regenerativa, CABIMER, Sevilla.

José M. Mato

CIC Biogune, Vizcaya

Scientific Activities of the Programs - 111

1st decile publications García-Monzón C, Lo Iacono O, Mayoral R, González-Rodríguez A, Miquilena-Colina ME, Lozano-Rodríguez T, García-Pozo L, Vargas-Castrillón J, Casado M, Boscá L, Valverde AM, MartínSanz P. “Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C”. J Hepatol. 2011 Jan;54(1):142-52. IF 9.334 COLLABORATION García-Monzón Llorente Izquierdo C, Mayoral R, Flores JM, García-Palencia P, Cucarella C, Boscá L, Casado M, Martín-Sanz P. “Transgenic

mice expressing cyclooxygenase-2 in hepatocytes reveal a minor contribution of this enzyme to Chemicals hepatocarcinogenesis”. Am J Pathol. 2011 Mar;178(3):1361-73. IF 5.224 Revuelta-Cervantes J, Mayoral R, Miranda S, GonzálezRodríguez A, Fernández M, Martín-Sanz P, Valverde AM. “Protein Tyrosine Phosphatase 1B (PTP1B) deficiency accelerates hepatic regeneration in mice”. Am J Pathol. 2011 Apr;178(4):1591-604. IF 5.224

Relevant projects 1. “Fisiopatología de la infiltración cardiaca. Papel de los macrófagos en la disfunción cardíaca”. BFU2008-02161. MICINN. PI: Lisardo Boscá Gomar. 2009-2011. € 60,000 2. “Papel de la ciclooxigenasa-2 en la fisiopatología cardíaca”. SAF2009-12602 MICINN. PI: Marta Casado Pinna. 2010-2012. €30,000 3. “Red Temática de Investigación Cooperativa de Enfermedades Cardiovasculares RECAVA”. RD06/0014/0006. PI: Lisardo Boscá Gomar. 2006-2011.

4. “Contribución de las prostaglandinas producidas por COX2 al desarrollo del carcinoma hepatocelular”. Regulación de la expresión de COX-2 en CHC. SA2010-16031. MICINN. PI: Paloma Martín Sanz. 2011-2013. €50,000 5. “Papel de la ciclooxigenasa-2 en la fisiopatología cardíaca”. ACOMP/2011/120. PI: Marta Casado Pinna. 2011. €12,000

112 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3 Linked group

Dr. Carmelo García Monzón Hospital Universitario Sta. Cristina, Madrid

Team leader Carmelo García Monzón

Team members Rodolfo Javier Vargas Castrillón Alicia Sáez Sáez Carlos Lozano Trotonda Luis Pita Fernandez

Outputs CIBERehd

Nº of competitive projects: 1 Public funding: €21,376

Main Research Topics • Impact of metabolic syndrome in the pathogenesis of non-alcoholic fatty liver disease. • Characterisation of alterations in the signalling pathway of insulin in the liver of patients with fatty liver disease and non-alcoholic chronic infection by hepatitis C. • Analysis of intrahepatic expression pattern of lipogenic genes and association with oxidative stress and hepatic injury in non-alcoholic fatty liver disease. • Role of endoglin, a co-receptor for TGF-B, in the process of transdiffe rentiation of hepatic stellate cells.

Relevant projects

FIRST QUARTILE PUBLICATIONS

100 14,653

5 0

300

8,899

xxxx

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

10 0

1. “Análisis comparativo de los mediadores moleculares relacionados con el síndrome metabólico en pacientes con enfermedad hepática grasa no alcohólica y en pacientes con hepatitis crónica C”. PI10/00067. Instituto

de Salud Carlos III. PI: Carmelo García Monzón. Team Members: Rodolfo Javier Vargas Castrillón, Alicia Sáez Sáez, María Eugenia Miquilena Colina, Tamara Lozano Rodríguez. 2011-2013. €21,376,66

Collaborations with other CIBERehd groups Javier G. Gallego

Universidad de León

JM Mato

Cicbiogune, Vizcaya

Paloma Martín Sanz

Csic-Universidad Autónoma de Madrid

Manuel Romero Gómez

Hospital Gregorio Marañón, Madrid

Javier García-Samaniego Rey

Hospital Carlos III, Madrid

José Vicente Castell

Hospital Universitario La Fe, Valencia

114 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 3 Linked group

DR. LlorenÇ caballería rovira Hospital Clínic, Barcelona

Team leader Llorenç Caballeria Rovira

Team members Mª Antonia Auladell LLorens Guillem Pera Blanco Lluis Rodríguez González José Darío Casas Curto Josep Auba Llambrich Alba Aluma Trullas Mª Dolores Miranda Badia Mª Carmen Sánchez García Jesús Bernad Suárez Santiago Canut Cavero Miren Maite Aizpurua Pérez Albert Tibau Catalán Laura Nieto Márquez Enriqueta Alcaraz Ferrer

Main Research Topics • Nonalcoholic fatty liver disease and steatohepatitis. • Noninvasive markers of liver fibrosis. • Alcoholic liver diseases.

Relevant projects 1. “Detección precoz de enfermedades crónicas del hígado en población adulta aparentemente sana”. PI11/02657. Fondo Investigación Sanitaria. PI: Lorenzo Caballería. Team Members: Pere Torán, Josep Mª Manresa, Núria Fabrellas, Lluís Rodriguez, José Dario Casas, Dolores Miranda, Miren Maite Aizpurua, Jesús Bernad, Santi Canut, Alba Alumà, Antonio Negrete.

Thesis 1. Title: “Prevalença i factors associats a la presència d’esteatosi hepàtica no alcohòlica en població general”. Docorate Student: Mª Antònia Auladell. Directors: Dr. Llorenç Caballeria/Albert Parés. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 25/011/2011.

2. “Efectividad de una intervención breve en mayores de 64 años con consumo de riesgo de alcohol en atención primaria. Ensayo clínico aleatorizado comunitario”. PI11/01569. Fondo Investigación Sanitaria. PI: Susana Montesinos. Team Members: Guillem Pera, Gregori Pizarro, Anna Altaba, Mª Dolores Reina, Sandra Santamaria, Margarita Roset.

Scientific Activities of the Programs - 115

116 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 4

Program 4

Immunology and Liver Transplantation

P4 Scientific Activities of the Programs - 117

Immunology and Liver Transplantation Presentation: Dr. Agustín Albillos. Program Coordinator

The most important problems in liver transplantation at present are the following: A. The marked imbalance between the high number of patients in need of this therapy and the scarce number of liver graft donors. B. The optimization of pharmacological immunosuppression with two objectives: a) to tailoring immunosuppressive regimes according to the characteristics of each particular liver transplant recipient, and b) to identify patients who are tolerant to their liver allografts. C. The post-transplant recurrence of the disease which indicated the liver transplantation, with especial emphasis in hepatitis C, which currently represents one of the ‘Achilles heels’ of liver transplantation.

Main lines of research of Program 4 Concordantly with the problems in liver transplantation described above, the research developed by the investigators of Program 4 is grouped into three main lines: 1. Liver graft viability, mainly associated with the ischemiareperfusion damage that necessarily occurs during liver transplantation, and which can be particularly deleterious when suboptimal grafts obtained from ‘extended criteria

donors (for example, steatotic livers, or livers from old donors) are used. Other circumstances, especially an insufficient or an excessive hepatic blood flow, can also impair the early postoperative graft function. The main objective of this line is to improve graft viability by different interventions leading to an improvement of either the ischemia-reperfusion injury or graft blood flow, which ultimately would expand the number of grafts for liver transplantation and increase their quality.

2. Immune response against the liver allograft. This line mainly involves several topics: the mechanisms of rejection and their modulation by immunosuppressive treatment, tolerance of liver grafts and biomarkers of these processes. The principal objectives of this line are to administer the most adequate immunosuppression in each particular liver transplant recipient according to his/her risk of rejection, adverse events and recurrence of the primary disease, and to identify patients who are tolerant with their grafts in order to withdraw all pharmacological immunosuppression.

3. Recurrence of hepatitis C after liver transplantation, one of the most characteristic and severe complications in liver transplant patients and responsible for most graft failures and post-transplant deaths. The aims of this line are to investigate the pathogenic mechanisms of post-transplant hepatitis C recurrence, to identify markers of its progression over time, and to address different aspects concerning antiviral treatment.

118 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 4

PROJECTS AND COLLABORATIONS Immunology and Liver Transplantation Groups of Program 4 Program 4 includes the following four groups:

LEADER

CENTER

Berenguer, Marina

Hospital Universitario La Fe, Valencia

De la Mata, Manel

Hospital Universitario Reina Sofía , Córdoba

Parrilla, Pascual

Hospital Virgen de la Arrixaca, Murcia

Rimola, Antonio

Hospital Clínico y Provincial, Barcelona

The research activity of these groups is predominantly clinical. Nevertheless, the groups of Dr. De la Mata and Dr. Rimola also perform basic research. The program also involves a linked group:

LEADER

CENTER

Alvarez, Rocío

Hospital Virgen de la Arrixaca, Murcia

The research activity of this group is essentially basic and deals with immunological aspects of transplantation.

Cooperative projects led by groups of Program 4: Impact of allelic incompatibility and functional HLA-C isomorfisms in the maintenance of tolerance in liver transplantation. Leading group: Alvarez (principal co-investigators: R. Alvarez and A. Minguela). Other participating groups from the CIBERehd: Parrilla. Influence of the interactions of KIR and LILRB1 receptors and their ligands on the short- and long-term outcome after liver transplantation. Leading group: Alvarez (principal investigator: M.R. Alvarez). Other participating CIBERehd groups: Berenguer, De La Mata, and Parrilla. Other international participating groups: J. LeMaoult (Paris). Re-treatment after virological relapse in post-transplant hepatitis C recurrence: efficacy, tolerance and viral kinetic response according to the type of maintenance immunosuppressive drugs. Leading group: Berenguer (principal investigator: M. Berenguer).

PROJECTS AND COOPERATIVE RESEARCH The four groups of Program 4 and the linked group participate in the different common lines of research of the Program, as depicted in the following table:

Lines of research

PARTICPATING GROUPS

Liver graft viability

De la Mata - Parrilla - Rimola

Immune response to allograft

Alvarez - Berenguer De la Mata - Parrilla - Rimola

Hepatitis C recurrence after liver transplantation

Berenguer - De la Mata Parrilla

During 2011, these groups collaborated in different projects. The most relevant of these projects and the most relevant publications by the groups of Program 4 in collaboration with other CIBERehd, national and/or international groups are the following:

Other participating CIBERehd groups:: Alvarez, De la Mata, and Parrilla. Other participating national and international groups: T. Serrano (Zaragoza), FJ. López-Labrador and JJ. Abellan (Valencia), and D. Samuel (Paris). Resistance to the new direct-acting antiviral agents and immunological escape mutants of hepatitis C virus. Leading group: Berenguer (principal investigator: M. Berenguer). In collaboration with the CIBER of Epidemiology and Public Health. Chronic renal failure in liver transplant patients: identification of risk factors and development of a time-dependent predictive model. Leading group: Berenguer (principal investigator: M. Berenguer). In collaboration with the Universita La Sapienza (Rome). Allocation of donors according to the characteristics of recipients in liver transplantation: development of an algorithm by using an artificial neural network (MADRE project).

Scientific Activities of the Programs - 119

PROJECTS AND COLLABORATIONS Immunology and Liver Transplantation

Leading group: De la Mata (principal investigator: M. De la Mata). Other participating CIBERehd groups: Berenguer and Forns. Efficacy of sorafenib in advanced hepatocellular carcinoma with radiologic progression: randomized clinical trial. Leading group: De la Mata (principal co-investigators: JL. Montero and M. De la Mata). In collaboration with other 14 liver transplant teams. Immunosuppression weaning in liver transplant patients with hepatitis C recurrence. Leading group: Rimola (principal investigator: Dr. A. S谩nchezFueyo). Other participating CIBERehd groups: M. Berenguer and X. Forns. Control of blood pressure in liver transplant patients. Leading group: Rimola (principal investigator: A. Rimola). Other participating CIBERehd groups: Berenguer, De la Mata and Parrilla. Other participating national group: T. Serrano (Zaragoza).

Search and validation of biomarkers capable of reflecting the individual response to immunosuppressive treatment. Leading group: Rimola (principal investigador: M. Brunet). Other participating CIBERehd groups: Parrilla. Other participating national groups: MJ. Castro (Madrid), M. L贸pez-Hoyos (Santander). Search for the immunological signature of tolerance in liver transplantation. Leading group: Rimola (principal investigator: A. S谩nchezFueyo). Other participating international groups: G. Tisone (Rome), J. Pirenne (Leuven), HD. Volk (Berlin), F. Class (Leyden). Liver transplantation in HIV-infected patients: a prospective Spanish multicenter study. Leading group: Rimola (principal co-investigator: A. Rimola, as Vice-Chair of the project; Chair: JM Mir贸, Barcelona). Other participating CIBERehd groups: Berenguer, De la Mata and Parrilla. Other participating national groups from Asturias, Barcelona,

120 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 4

PROJECTS AND COLLABORATIONS Immunology and Liver Transplantation Bilbao, Madrid, Malaga, Santiago de Compostela y Sevilla. In collaboration with the Organización Nacional de Trasplantes, the Sociedad de Trasplante Hepático and the Asociación Española para el Estudio del Hígado.

Relevant publications about cooperative studies: ReVIS-TC Study Group. “Cyclosporin A-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation 2011; 92: 334-40. The influence of the type of immunosuppressive drugs on the antiviral response in hepatitis C recurrence after liver transplantation is controversial. In this study, in which different groups from the CIBERehd have participated, including the Berenguer and De la Mata’s groups from Program 4, showed that patients receiving a cyclosporine-based regime had a higher sustained virological response to interferon plus ribavirin and a lower rate of relapse after a positive end-of-therapy response than patients receiving a tacrolimus-based regime (48% vs. 37% and 18% vs. 36%, respectively). These results suggest a beneficial effect of cyclosporine on the response to classical anti-HCV therapy after liver transplantation. Herencia C, Rodríguez-Ariza A, Canalejo A, Naranjo A, Briceño FJ, López-Cillero P, De la Mata M, Muñoz-Castañeda JR. “Differential bone marrow hematopoietic stem cells mobilization in hepatectomized patients”. J Gastrointest Surg 2011; 15: 1459-67. Regeneration is a very important process in early stages of liver transplantation and in living donor liver transplantation. The participation of bone marrow hematopoietic stem cells (BMHSC) in the multiple circumstances where liver regeneration occurs is not well characterized. In this clinical study, the De la Mata’s CIBERehd group from Cordoba together with other institutions showed that, after partial hepatectomy, there are two subsets of subjects depending on whether they increase circulating BMHSC after hepatectomy or not, so-called “mobilizers” and “non-mobilizers”, respectively. These two groups had a different cytokine and growth factor profile before and after the hepatectomy, thus suggesting that hepatectomy alone does not explain the BMHSC mobilization, a key step for further participation of these cells in hepatic regeneration, and that an adequate pro-regenerative environment is also necessary. González R, Cruz A, Ferrín G, López-Cillero P, Fernández-Rodríguez R, Briceño J, Gómez MA, Rufián S, Mata Mde L, Martínez-Ruiz A, Marin JJ, Muntané J. “Nitric oxide mimics transcriptional and post-translational regulation during α-tocopherol cytoprotection

against glycochenodeoxycholate-induced hepatocytes”. J Hepatol 2011; 55: 133-44.

cell

death

After liver transplantation, there are many situations that can cause cholestasis, in which some retained bile acids can be harmful for hepatocytes. This is particularly relevant in circumstances in which other potentially injurious factors also exist, such as hepatitis C recurrence. In fact, liver transplant patients with recurrent hepatitis C and cholestasis show a much more rapid liver impairment than that in patients with recurrent hepatitis C without cholestatic features. Therefore, the mechanisms of bile acid-induced hepatocyte damage and its prevention are of especial interest in liver transplantation. In this context, this investigation, led by the De la Mata’s group and participated by other national research teams, showed that NO and α-tocopherol are protective against glycochenodeoxycholate-induced hepatocyte death or against the hepatocyte damage caused by bile duct obstruction in rats through different transcriptional and post-translational mechanisms. Martínez-Alarcón L, Ríos A, Pons JA, González MJ, Ramis G, Ramírez P, Parrilla P. “Attitudinal study of organ xenotransplantation in patients on the kidney and liver transplant waiting list in a country with high rate of deceased donation”. Xenotransplantation 2011; 18: 168-75. In spite of the relatively high rate of deceased organ donation in Spain, the disproportion between the number of kidney and liver grafts and the number of patients needing kidney and liver transplantation is still important. Among the several lines of research addressing the different possibilities of increasing the number of grafts for transplantation, there is xenotransplantation. This cooperative study, involving the Parrilla’s group from CIBERehd and health authorities from Murcia, explored the attitude of patients in the waiting list for kidney or liver transplantation towards a potential xenotransplantation. Concerning liver transplantation, the most relevant result in this study was that approximately two thirds of patients waiting for liver transplantation would accept an animal organ if this transplant modality was as effective as human organ transplantation, thus suggesting a general positive position to xenotransplantation in these patients. Fondevila C, Hessheimer AJ, Maathuis MH, Muñoz J, Taura P, Calatayud D, Leuvenik H, Rimola A, Ploeg RJ, García-Valdecasas JC. “Superior preservation of DCD livers with continuous normothermic perfusion”. Ann Surg 2011; 254: 1000-7. Another possibility to increase the number of liver grafts available for transplantation is the use of liver from donation-after-

Scientific Activities of the Programs - 121

PROJECTS AND COLLABORATIONS Immunology and Liver Transplantation cardiac-death (DCD). One remarkable difficulty with this type of donation is the maintenance of the liver in good condition until it is transplanted. In this setting, this experimental, international, cooperative study in which the Rimola’s group from CIBERehd had the leadership, is of relevance because it demonstrated that the preservation of livers from DCD pig donors by the zuse of an ex vivo normothermic machine perfusion markedly improved the parameters assessing graft viability and, more importantly, allowed a survival rate of 100% of pig recipients. These results indicate that continuous normothermic perfusion of livers after DCD may be advantageous in the clinical setting. Lozano JJ, Pallier A, Martínez-Llordella M, Danger R, López M, Giral M, Londoño MC, Rimola A, Soulillou JP, Brouard S, Sánchez-Fueyo A. “Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients”. Am J Transplant 2011; 11: 1916-26. Operational tolerance, that is, long-term acceptance of organ allografts following discontinuation of all immunosuppression, spontaneously occurs in a little proportion of kidney transplant recipients but in a substantial proportion of liver transplant recipients. This international collaborative study, led by the Rimola’s CIBERehd group, showed that tolerant kidney and liver transplant recipients share some gene expression characteristics in their PBMCs, particularly involving NK cells. However, tolerant kidney transplant recipients also had an expansion of B cells, which exhibit specific transcriptional and immunophenotypic traits, not

shared by tolerant liver transplant recipients, thus suggesting that tolerance may be reached in a easier way in liver transplantation because the immunological requirements for this are fewer than for tolerance in kidney transplantation. Additionally, the study provided a series of potential biomarkers of tolerance which can be useful in future large-scale immunomonitoring trials. Blanco-García RM, López-Álvarez MR, Garrido IP, Salgado-Cecilia G, Campillo JA, Bolarín JM, Legaz I, Muro M, García-Alonso AM, Martínez-Sánchez MV, Moral JM, Pascual-Figal DA, Alvarez-López MR, Miras M, Minguela A. “CD28 and KIR2D receptors as sensors of the immune status in heart and liver transplantation”. Hum Immunol 2011; 72: 841-8. The investigation of biomarkers of rejection and other complications after organ transplantation has become one of the most prominent lines of research. In this setting, this study, led by the Alvarez CIBERehd group and in which the Parrilla’s group from the CIBERehd and other teams involved in heart transplantation and pathology also participated, suggests that the expression of CD28 and KIR2D on peripheral blood T lymphocytes could be helpful in the diagnosis of rejection (increased CD28 expression on CD4 cells), and as a predictive factor for favourable graft outcome (CD8+ CD28- KIR2D+) and cytomegalovirus infection development (abrogation of CD28 and KIR2D expression). Therefore, CD28 and KIR2D expression on peripheral T cells could be a sensor of the immune status in liver, as well as heart, transplantation.

122 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 4

DR. Marina Berenguer Haym Hospital Universitario La Fe, Valencia

Team leader Marina Berenguer Haym

Team members Martín Prieto Castillo Victoria Aguilera Sancho-Tello Ángel Rubín Suárez José Miguel Rayón Antonio Palau Canós Salvador Benlloch Pérez Cecilia Ortiz Cantó

Outputs CIBERehd

Nº of Publications 1st quartile: 7 Nº of Publications 2nd quartile: 0 IF total: 42.372 Nº of competitive projects: 4 Multicentric clinical trials: 8

Main Research Topics • • • • • •

FIRST QUARTILE PUBLICATIONS

42,372

33,797 7,222

5 0

2009 2010 2011 IF 1ST QUARTILE

300

Collaborations with other CIBERehd groups

100

Raúl Andrade

Hospital Virgen de la Victoria, Málaga

Manuel de la Mata

Hospital Universitario Reina Sofía, Córdoba

Pascual Parrilla

Hospital Virgen de la Arrixaca, Murcia

Antoni Rimola

Hospital Clínic, Barcelona

Manuel Romero

Hospital Universitario Nuestra Sra. De Valme, Sevilla

Jaume Bosch

Hospital Clínic, Barcelona

Albert Pares

Hospital Clínic, Barcelona

10 7

PUBLICATIONS

Immunological and virological markers of HCV recurrence after liver transplantation. Hepatitis C and liver transplantation (clinical, virological and immunological). Hepatitis B and liver transplantation (clinical and virological). Viral hepatitis in immunocompetent patient. Hepatocellular carcinoma and liver transplant. Study of Wilson Disease

Scientific Activities of the Programs - 123

1st decile publications ReViS-TC Study Group. !Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation. 2011 Aug 15;92(3):334-40. Erratum in: Transplantation. 2012 Feb 15;93(3):e13. IF 3.676 Lucena MI, Kaplowitz N, Hallal H, Castiella A, García-Bengoechea M, Otazua P, Berenguer M, Fernandez MC, Planas R, Andrade RJ. “Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to

autoimmune hepatitis”. J Hepatol. 2011 Oct;55(4):820-7. IF 9.334 COLLABORATION Planas/ Andrade López-Labrador FX, Berenguer M. “Genomic medicine reaches HCV-related liver transplantation: hopes and clinical and public health implications”. J Hepatol. 2011 Aug;55(2):270-2. IF 9.334 Selzner N, Guindi M, Renner EL, Berenguer M. “Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients”. J Hepatol. 2011 Jul;55(1):207-17. IF 9.334

Relevant projects 1. “Retratamiento tras recaída virológica en hepatitis c recurrente: eficacia, tolerancia y cinÉtica en función de la inmunosupresión de base”. PS09/01707. FIS, ISCIII. PI: Marina Berenguer Haym. Team Members: Martin Prieto Castilo, Victoria Aguilera Sancho-Tello, Angel Rubín Suarez. 2010-2013. €22,000

3. “Estudio multicéntrico español para investigar la utilidad del fibromax en la detección precoz y evaluación no invasiva de las enfermedades hepáticas prevalentes: enfermedad hepática por depósito de grasa y hepatitis C”. 2011/0425. PI: Marina Berenguer Haym. Team Members: Victoria Aguilera Sancho-Tello, Martín Prieto Castillo, Angela Zaragoza. 2011

2. “Creación de un grupo cooperativo nacional para el estudio de la hipertensión portal no cirrótica (htpnc)”. 2011/0421. Grupo Cooperativo Rehevasc. PI: Marina Berenguer Haym. Team Members: Victoria Aguilera Sancho-Tello, Martín Prieto Castillo. 2011

4. “Centro de Investigación Biomédica en Red (CIBER) en Enfermedades Hepáticas y Digestivas”. CB06/04/0065. ISCIII. PI: Marina Berenguer Haym. Team Members: Martín Prieto, Victoria Aguilera, Angel Rubín, Antonio Palau, Salvador Benlloch, José Miguel Rayón, Cecilia Ortiz, Martina Giménez. 2006-now.

124 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 4

Dr. Manuel De La Mata García Hospital Universitario Reina Sofía, Córdoba

Team leader Manuel De La Mata García

Team members José Luis Montero Álvarez Francisco Javier Briceño Delgado Guadalupe Costán Rodero Pedro López Cillero Enrique Fraga Rivas Pilar Barrera Baena Antonio Poyato González Raúl González Ojeda Ángel González Galilea Antonio José Hervás Molina Trinidad Marchal Molina Juan Carlos Pozo Laderas Antonio Naranjo Rodriguez Adolfo Cruz Muñoz

Staff Gustavo Ferrín Sánchez

Outputs CIBERehd

Nº of Publications 1st quartile: 2 Nº of Publications 2nd quartile: 7 IF total: 47.475 Nº of competitive projects: 8 Public funding: €128,004 Private funding: €26,228 Multicentric clinical trials: 10

Main Research Topics

50 10

FIRST QUARTILE PUBLICATIONS

50,074

40,878

300 100

19,408

5 0

10 5

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• Cytoprotection mechanisms and hepatocellular death. • Identification and characterization of biomarkers for detection of hepatocellular carcinoma by proteomic thecniques. • Treatment of advanced Hcc and immunossupression after liver transplant for Hcc. • Evaluation of liver graft dysfunction. • Management of the waiting list for liver transplantation.

Collaborations with other CIBERehd groups Francisco J. Salmerón Hospital Universitario San Cecilio, Granada Jesús Mª Prieto

Clínica Universitaria de Navarra, Pamplona

Antoni Rimola

Hospital Clínic, Barcelona

Marina Berenguer

Hospital Universitario La Fe, Valencia

Scientific Activities of the Programs - 125

1st decile publications González R, Cruz A, Ferrín G, López-Cillero P, FernándezRodríguez R, Briceño J, Gómez MA, Rufián S, Mata Mde L, Martínez-Ruiz A, Marin JJ, Muntané J. “Nitric oxide mimics transcriptional and post-translational regulation Turing α-tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes.” J Hepatol. 2011 Jul;55(1):133-44. IF 9.334 Ferrín G, Linares CI, Muntané J. “Mitochondrial drug targets in cell death and cancer”. Curr Pharm Des. 2011;17(20):200216. Review. IF 4.774 Muntané J. “Harnessing tumor necrosis factor receptors to enhance antitumor activities of drugs”. Chem Res Toxicol. 2011 Oct 17;24(10):1610-6. IF 4.148

Urtasun R, Latasa MU, Demartis MI, Balzani S, Goñi S, GarciaIrigoyen O, Elizalde M, Azcona M, Pascale RM, Feo F, BioulacSage P, Balabaud C, Muntané J, Prieto J, Berasain C, Avila MA. “Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation”. Hepatology. 2011 Dec;54(6):2149-58. doi: 10.1002/ hep.24587. IF 10.885 COLLABORATION Prieto ReViS-TC Study Group. “Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation. 2011 Aug 15;92(3):334-40. Erratum in: Transplantation. 2012 Feb 15;93(3):e13. IF 3.676 COLLABORATION Forns / Berenguer

Relevant projects 1. “Actividad antitumoral del óxido nítrico: Estudios in vitro e in vivo. 09/0185. Instituto de Salud Carlos III”. PI: Jordi Muntané Relat. Team Members: Enrique Fraga Rivas, Trinidad Marchal Molina, Rosario Inés Bello Gómez, Raúl González Ojeda, Clara Isabel Linares Luna, Ana Belén Hidalgo Mesones, Gustavo Ferrín Sánchez, Sandra González Rubio. 2010-2012. €23,500

Rivas, Pilar Barrera Baena, Antonio Poyato González, Raúl González Ojeda, Ángel González Galilea, Antonio José Hervás Molina, Trinidad Marchal Molina, Juan Carlos Pozo Laderas, Isidora Ranchal Illescas, Antonio Naranjo Rodriguez, Adolfo Cruz Muñoz, Francisco Javier Padillo Ruiz, Francisca Núñez García, Gustavo Ferrín Sánchez. 2011. €65,000

2. “Influencia del tipo de grasa en el desarrollo de la EHGNA en la obesidad mórbida. Estrés oxidativo y disfunción mitocondrial asociados a la secreción de citoquinas”. P08CTS-04357. Consejería de Innovación, Ciencia y Empresa. PI: Francisco J. Salmerón. Team Members: Jordi Muntané Relat, Ángela Ruiz Extremera, Ángel Palacios Pérez, Dolores Quintero Fuentes, Ana Gila Medina, Trinidad Caballero Morales, Josefa León López, Ángel Carazo Gallego, Jorge Casado Ruiz, Rosa Quiles Pérez, Fermín Sánchez de Medina, María Dolores Suárez Ortega, Olga Martínez Augustín, Raquel González Pérez, Rocío López Posadas, Pilar Requena Méndez, Manuel de la Mata García, Enrique Fraga Rivas, Gudalupe Costán Rodero, Gustavo Ferrín Sánchez, José Antonio del Campo Castillo, Sabah El Alaoui Bsim, Isidora Ranchal Illescas, Raúl González Ojeda, Ana Belén Hidalgo Mesones. 2009-2012. €10,000

4. “Estudio Afecciones Agudas de Aparato Digestivo”. CTS-273. Consejería de Innovación, Ciencia y Empresa. PI: Manuel de la Mata García. Team Members: J Muntané, E Fraga, G Costán, JL Montero, P Barrera, A Poyato, P López-Cillero, J Briceño, S Rufián. 2011. € 12,504

3. “CIBERehd”. CB06/04/0077. Instituto de Salud Carlos III. PI: Manuel de la Mata García. Team Members: Jordi Muntané Relat, José Luis Montero Álvarez, Francisco Javier Briceño Delgado, Guadalupe Costán Rodero, Pedro López Cillero, Enrique Fraga

5. “Disfunción mitocondrial en pacientes infectados por VHC/ VIH”. CS-08-0169. Consejería de Salud Junta de Andalucía. PI: Jordi Muntané Relat. Team Members: A. Rivero, G. Ferrín, P Barrera, J de la Torre. 2009-2011. €17,000,00 6. “Investigación Biomédica en Hepatitis Viral”. Roche Farma. PI: Manuel de la Mata García. 2011. €11,328 7. “Estudio Observacional de Adherencia y Efectos Adversos al Tratamiento con Sorafenib”. NEX-1. Bayer. PI: Manuel de la Mata García. 2011. €10,000 8. “Investigación Biomédica en Hepatitis Viral”. MSD. PI: Manuel de la Mata García. 2011. €4,900

Thesis 1. Title: “Intervenciones antioxidantes para el tratamiento del estrés oxidativo y muerte celular en hepatocitos primarios en cultivo”. Doctorate Student: Raúl González Ojeda.

Director: Jordi Muntané Relat. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 18/02/2011.

126 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 4

DR. Pascual Parrilla Paricio Hospital Virgen de la Arrixaca, Murcia

Team leader Pascual Parrilla Paricio

Team members Francisco Sánchez Bueno Pablo Ramírez Romero Ricardo Robles Campos Vicente Munitiz Ruíz Antonio Rios Zambudio Luisa Martínez de Haro Ángeles Ortíz Escandell Laura Martínez Alarcón Antonio Munoz Luna Juan Bermejo López Joaquín Molina Martínez José Antonio Pons Miñano María Juliana Majado Martínez Pedro Aparicio Alonso Pablo Pelegrin Vivancos José Yélamos López

Staff Beatriz Revilla Nuin Carlos Martínez Cáceres

Outputs CIBERehd

Nº of Publications 1st quartile: 4 Nº of Publications 2nd quartile: 2 IF total: 21.725 Nº of competitive projects: 9 Public funding: €294,247 Private funding: €10,000

FIRST QUARTILE PUBLICATIONS

100 11,212

5 0

300

• Barrett’s esophagus and esophageal motor disorders. • Reactions of poly-ADP-ribosylation and gastrointestinal disorders: acute pancreatitis; fulminant hepatic failure. • Liver: Laparoscopic liver surgery; clinical liver transplantation; operational tolerance; experimental liver. • Regeneración hepatica. • Carcinogenesis hepática.

18,325

10 4

2009 2010 2011 IF 1ST QUARTILE

Main Research Topics

PUBLICATIONS

Collaborations with other CIBERehd groups Marina Berenguer

Hospital La Fe, Valencia.

Antoni Rimola

Hospital Clínic, Barcelona

Scientific Activities of the Programs - 127

1st decile publications Gomez-Santos C, Hernandez-Morante JJ, Margareto J, Larrarte E, Formiguera X, Martínez CM, Garaulet M. “Profile of adipose tissue gene expression in premenopausal and postmenopausal women: site-specific differences”. Menopause. 2011 Jun;18(6):675-84. IF 3.318

Pelegrín P. “Many ways to dilate the P2X7 receptor pore”. Br J Pharmacol. 2011 Jul;163(5):908-11. doi: 10.1111/j.14765381.2011.01325.x. IF 4.925

Relevant projects 1. “Prevención de la progresión del esófago de Barrett a adenocarcinoma esofágico: Implicación del tratamiento (médico vs quirúrgico) e identificación de marcadores diagnósticos y pronósticos”. PI09/1808. FIS. PI: Pascual Parrilla Paricio Team Members: L.F. Martinez De Haro, A.Ortiz, V. Munitiz, B. Revilla-Nuin, C.M. Martínez, J. Molina, J. Bermejo, D.R. Angulo. €20,267 2. “Prevención de la progresión del esófago de Barrett a adenocarcinoma esofágico: Implicación del tratamiento (médico vs quirúrgico) e identificación de marcadores diagnósticos y pronósticos”. FMM. PI: L.F. Martinez De Haro. Team Members: P. Parrilla, A.Ortiz, V. Munitiz, B. Revilla-Nuin, C.M. Martínez, J. Molina, J. Bermejo, D.R. Angulo. €10,000 3. “Prevención de la progresión del esófago de Barrett a adenocarcinoma esofágico: Implicación del tratamiento (médico vs quirúrgico) e identificación de marcadores diagnósticos y pronósticos”. 08823/PI08. FUNDACIÓN SÉNECA. PI: Pascual Parrilla Paricio. Team Members: L.F. Martinez De Haro, A.Ortiz, V. Munitiz, B. Revilla-Nuin, J. Molina, J. Bermejo, J. Yélamos. €50,000 4. “Señalización purinérgica y función de los receptores P2X7 durante el rechazo al transplante de tejidos: nuevas estrategias y dianas terapéuticas”. PS09/00120. FIS. PI: Pablo Pelegrin. Team Members: A. Baroja, C.M. Martínez, M. Barberá, A. Gómez. €45,980

5. “Estudio de la función de los receptores P2X7 y panexina-1 en los síndromes periódicos asociados a criopirina”. 11922/ PI/09. FUNDACIÓN SÉNECA. PI: Pablo Pelegrin. Team Members: A. Baroja, C.M. Martínez, A. Gómez. €13,600 6. “Papel de Parp-1 y Parp-2 en el desarrollo del cáncer hepático”. FFIS/CM10/002. FUNDACIÓN CAJAMURCIA. PI: C.M. Martínez. Team Members: P.Parrilla, P. Ramírez, M.D. Lucas, M. Muñoz, J. Yélamos. €5,000 7. “Nuevas estrategias y dianas terapéuticas para tratar el rechazo al trasplante de órganos: papel de las principales citoquinas y función de los receptores purinérgicos P2X7”. EMER07/049. CONVENIO ISCIII CON LA CARM. PI: Pablo Pelegrin. Team Members: A. Baroja, M. Barberá, A. Gónez. €125,000 8. “Citorreducción y quimioterapia intraperitoneal hipertérmica intraoperatoria (hipec) versus citorreducción aislada en carcinomatosis peritoneal por carcinoma de ovario, trompa de Falopio o carcinoma”. EC10/020. Ministerio de Sanidad. PI: Pablo Ramírez. Team Members: P. Pelegrin, A. Baroja. €20,000 9. “Rutas de señalización dependientes de daño en el DNA mediadas por Poli-ADP-ribosa polimerasas durante la diferenciación de los linfocitos”. SAF2008-01572. Ministerio de Educación y Ciencia. PI: Jose Yelamos. Team Members: Aparicio, Magallón Tejada, Nicolás Gomariz, Llacuna Duran, Farrés Basiana. €14,400

128 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 4

DR. Antoni Rimola Castellá Hospital Clínic, Barcelona

Team leader Antoni Rimola Castellá

Team members Juan Carlos García-Valdecasas Salgado Constantino Fondevila Campo Alberto Sánchez Fueyo Mercedes Brunet Serra Carmen Peralta Uroz Joan Roselló Catafau

Staff Marta Massip Salcedo Olga Milán López Javier Muñoz Luque María Carlota Londoño Hurtado

Outputs CIBERehd

Nº of Publications 1st quartile: 12 Nº of Publications 2nd quartile: 2 IF total: 80.074 Nº of competitive projects: 7 Public funding: € 179,832 Private funding: € 8,500 Clinical guidelines: 1 Multicentric clinical trials: 2

Main Research Topics • Hepatic ischemia-reperfusion injury and liver graft viability: pathogenic mechanisms and protective strategies. • Tolerance to liver allograft. • Optimization of immunosuppression in liver transplantation.

Collaborations with other CIBERehd groups Jordi Bruix

Hospital Clínic, Barcelona

José Fernández-Checa Consejo Superior de Investigaciones Científicas

FIRST QUARTILE PUBLICATIONS

86,750

75,595

300 100

68,584

5 0

10 13

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Xavier Forns

Hospital Clínic, Barcelona

Marina Berenguer

Hospital La Fe, Valencia

Manuel de la Mata

Hospital Universitario Reina Sofía, Córdoba

Pascual Parrilla

Hospital Virgen de la Arrixaca, Murcia

1st decile publications Fondevila C, Hessheimer AJ, Maathuis MH, Muñoz J, Taurá P, Calatayud D, Leuvenink H, Rimola A, Ploeg RJ, García-Valdecasas JC. “Superior preservation of DCD livers with continuous normothermic perfusion”. Ann Surg. 2011 Dec;254(6):1000-7. IF 7,474

Lozano JJ, Pallier A, Martinez-Llordella M, Danger R, López M, Giral M, Londoño MC, Rimola A, Soulillou JP, Brouard S, SánchezFueyo A. “Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and

Scientific Activities of the Programs - 129

kidney recipients”. Am J Transplant. 2011 Sep;11(9):1916-26. doi: 10.1111/j.1600-6143.2011.03638.x. IF 6,048

reperfusion injury”. J Hepatol. 2011 May;54(5):1002-10. IF 9,334 COLLABORATION Fernández-Checa JC

Peralta C, Brenner C. “Endoplasmic reticulum stress inhibition enhances liver tolerance to ischemia/reperfusion”. Curr Med Chem. 2011;18(13):2016-24. Review. IF 4,63

Dragun J, Pérez-Del-Pulgar S, Crespo G, Ramírez S, CotoLlerena M, Mensa L, García-Valdecasas JC, Navasa M, Forns X. “Characterization of the cross-neutralizing antibody response against hepatitis C virus in the liver transplantation setting”. Am J Transplant. 2011 Apr;11(4):767-74. doi: 10.1111/j.16006143.2011.03440.x. IF 6,048 COLLABORATION Forns

Hessheimer AJ, Fondevila C, Taurá P, Muñoz J, Sánchez O, Fuster J, Rimola A, García-Valdecasas JC. “Decompression of the portal bed and twice-baseline portal inflow are necessary for the functional recovery of a “small-for-size” graft”. Ann Surg. 2011 Jun;253(6):1201-10. IF 7,474 Llacuna L, Fernández A, Montfort CV, Matías N, Martínez L, Caballero F, Rimola A, Elena M, Morales A, Fernández-Checa JC, García-Ruiz C. “Targeting colesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-

Sánchez-Fueyo A, “Strom TB. Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs”. Gastroenterology. 2011 Jan;140(1):51-64. IF 12,032 García-Valdecasas JC. “DCD donors: a unique source to significantly increase organ donation”. J Hepatol. 2011 Oct;55(4):745-6. IF 9,334

Relevant projects 1. “Estudio multicéntrico para la validación de los biomarcadores de elección que reflejan la respuesta individual de los pacientes trasplantados de órganos sólidos al tratamiento inmunosupresor”. PI080300. Instituto de Salud Carlos III. FIS. PI: Mercè Brunet. Team Members: A. Rimola, O. Millán, S. Sanchez, L. Guirado. 2008-2011. €11,200 2. “Estudio del efecto inmunomodulador de la Atorvastatina en trasplante renal: estudios in vitro e in vivo”. 08/247. Fundación de Investigación Médica Mutua Madrileña. Ministerio de Ciencia e Innovación. PI: Olga Millán. Team Members: M. Brunet, D. Guillen, F. Cofan, E. Ros, M. Cofan. 2008-2011. €8,500 3. “Regulación del RBP4 en trasplante de hígados esteatósicos”. BFU2009-07410. Ministerio de Ciencia e Innovación. PI: Carmen Peralta. Team Members: Marta Massip Salcedo, Arani Casillas Ramirez. 2009-2011. €67,064 4. “Una solución acuosa para la conservación de órganos”. VALTEC08-2-0033. ACCIÓ10, Generalitat de Catalunya. PI:

Carmen Peralta. Team Members: Mónica Jiménez Castro, Maria Elias Miro. 2010-2012. €29,400 5. “Valor predictivo de parámetros inmunológicos pre-trasplante de receptor y donante en el desarrollo de rechazo e infección en trasplante hepático”. PS09/00418. Ministerio de Ciencia e Innovación, isciii, FIS. PI: Antonio Rimola. Team Members: Jaime Martorell, Olga Millan, Lourdes Rafael, Angel Ruiz. 2010-2012. €23,292 6. “Evaluación de la modificación farmacológica del flujo portal para prevenir el síndrome de “small-for-size” en el trasplante hepático en cerdos”. PI08/0273. Ministerio de Ciencia e Innovación, isciii, FIS. PI: Constantio Fondevila. Team Members: David Calatayud, Angel Ruiz, Javier Muñoz, Pilar Taura, Amelia Hessheimer, Marina Vendrell. 2009-2011. €18,876 7. “Methods to induce and diagnose immunological tolerance in liver transplantation”. SAF2008-04092. Programa I+D Ministerio de Ciencia. PI: A.Sanchez-Fueyo. Team Members: Marc MartinezLlordella, Isabel Puig-Pey. 2008-2011. €30,000

Thesis 1. Title: ”Estudio del efecto inmunomodulador de las estatinas: estudios in vitro e in vivo”. Doctorate Student: David Guillen Tunica. Director: Mercè Brunet. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 21/12/2011. 2. Title: ”Papel diferencial de la Angiotensina II en resecciones hepáticas y trasplante de hígado”. Doctorate Student: Isabel Alfany Fernández.

Director: Carmen Peralta. Qualification: Excelente “Cum Laude” por unanimidad. Date of lecture: 01/02/2011. 3. Title: ”Estrategias para proteger el injerto esteatósico en el trasplante hepático”. Doctorate Student: Araní Casillas Ramirez. Director: Carmen Peralta. Qualification: Excelente “Cum Laude” por unanimidad. Date of lecture: 01/12/2011.

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Mª Rocío Álvarez López Hospital Universitario Virgen de La Arrixaca, Murcia

Team leader Mª Rocío Álvarez López

Team members Mª Rosa Moya Quiles Manuel Miras López José Antonio Campillo Marquina Ana María García Alonso Manuel Muro Amador Alfredo Minguela Puras

Staff Marta Massip Salcedo Olga Milán López Javier Muñoz Luque María Carlota Londoño Hurtado

Outputs CIBERehd

Nº of Publications 1st quartile: 1 Nº of Publications 2st quartile: 4 IF total: 15.69 Nº of competitive projects: 10 Public funding: €185,562

Main Research Topics • Transplant immunology and immunotolerance: New induction lines, maintaining and rupture of peripheral tolerance. (MR Álvarez López and A Minguela) • Cellular and molecular immunology: Transplant regulatory and suppressor cells, and response against vaccines. (A Minguela) • Receptor-ligand interactions in innate and specific immunity. Role in immunopathology, transplant and cancer. (MR Álvarez López) • Immunogenetics and immunitary response control in autoimmune and allergic diseases (M Muro) • Immunotolerance and immunoregulation in the response against solid tumours and the hepatopoietic system (JA Campillo and JA Martínez Escribano) • Primary and secondary immunodeficiencies. Immunogenetic and functional deficiencies. (AM García Alonso) • Inflammatory and neoplastic diseases in the digestive system. (M Miras)

Collaborations with other CIBERehd groups Antoni Rimola

Hospital Clínic, Barcelona

Marina Berenguer

Hospital Universitario La Fe de Valencia

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1st decile publications Bupesh M, Legaz I, Abellán A, Medina L. “Multiple telencephalic and extratelencephalic embryonic domains contribute neurons to the medial extended amygdala”. J Comp Neurol. 2011 Jun 1;519(8):1505-25. doi: 10.1002/cne. 22581. IF 3.774

Relevant projects 1. “Mecanismos de inducción y ruptura de tolerancia. Aplicación en inmunología de trasplantes y enfermedades con hipo o hiperreactividad inmunitaria”. 07745/GERM/07/PI523. Fundación Séneca. PI: M.R. Álvarez López. Team Members: AM García Alonso, A Minguela, M Muro, MR Moya, M Miras, JA Campillo. 2008-2012. €63,000 2. “Estudio multicéntrico para la validación de los biomarcadores de elección que reflejen la respuesta individual de los pacientes trasplantados de órganos sólidos al tratamiento inmunosupresor. FIS PI080446. Ministerio de Sanidad y Consumo, H 12 de Octubre, H Marqués de Valdecilla, H Virgen de la Arrixaca, Hospital Clinic. PI: MJ Castro, M López Hoyos, M Muro, M Brunet. Team Members: Ruth López Hernández, María del Rocío López Álvarez, Ana María García Alonso. 2009-2011. €1,876

isciii, FIS. PI: Mª Rocío Álvarez López. Team Members: M Miras, MR López, A Minguela. 2011-2013. €32,065 6. “Análisis molecular y funcional de linfocitos T CD8+ KIR2D+ generados tras estimulación alogénica: Aplicación al trasplante de órganos”. MM2011. Mutua Madrileña. PI: Alfredo Minguela Puras. Team Members: AM García Alonso, B Las Heras, S Soriano, JA Campillo, M Muro, M Miras, R López Álvarez, MR Álvarez López. 2010-2012. €12,500 7. “Caracterización molecular y funcional de células T CD8+ KIR2D+ generadas in vitro tras estimulación alogénica. FFIS/ CM10/007. Fundación CajaMurcia, FFIS. PI: L Gimeno. Team Members: S Soriano, MA Cánovas. 2011. €5,000

3. “Ensayos clínicos de terapia celular”. RedTERCEL. RD07/0010/2012. ISCIII. PI: J.M. Moraleda, Team Members: M.R. Álvarez, A. Minguela, M. Muro. 2009-2011. €34,716

8. “Mecanismos de inmunotolerancia en cáncer de piel tipo melanoma cutáneo”. PI11/02644. isciii, FIS. PI: José Antonio Campillo Marquina. Team Members: I Legaz Pérez, JA Martínez Escribano, B Las Heras Ferre. 2012-2014.

4. “Retratamiento tras recaída virológica en hepatitis C recurrenet: Eficacia, tolerancia y cinética de respuesta en función de la inmunosupresión de base”. PS 09/01707. ISCIII, FIS. PI: Marina Berenguer Haym. Team Members: N Montes Barqueros, A Minguela Puras. 2010-2012. €36,905

9. “Procesos biológicos implicados en el desarrollo del rechazo humoral o en fenómenos de acomodación en trasplante mediados por anticuerpos anti-antígeno leucocitario humano (HLA)“. PI11/02686. isciii, FIS. PI: Manuel Muro Amador. Team Members: MR Moya, Manuel Miras. 2012-2014

5. “Influencia de las interacciones de receptores KIR y LILRB1 y sus ligandos en el desenlace del trasplante hepático a corto y largo plazo. Papel de las patologías más representativas”. PI10/01964.

10. “Evaluación inmunológica en la fibromialgia”. PI11/01926. ISCIII, FIS. PI: Ana María García Alonso. Team Members: I Legaz, JM Bolarín, L Gimeno, MG Salgado, S Soriano. 2012-2014.

Thesis 1. Title: “HLA-C y células T CD8+ KIR2D+ en trasplante hepático”. Doctorate Student: María del Rocío López Álvarez. Directors: A Minguela, M Miras y MR Álvarez López. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 31/01/2010.

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Program 5

Hepatic and Gastrointestinal Oncology

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Hepatic and Gastrointestinal Oncology Presentation: Dr. Jordi Bruix. Program Coordinator

esearch in the hepatic and gastrointestinal area has focused on epidemiology, molecular mechanisms, diagnosis and treatment of digestive and liver cancer. Fieldwork has been carried out by six groups, all of which have studied different aspects of the hepatic and gastrointestinal area. These are:

“Molecular pharmacology and experimental therapeutics” (U.Barcelona) Principal Investigator. Dr. Marçal Pastor-Anglada This group has international recognition in the field of the molecular pharmacology of drug transporters, their pharmacogenetics, and the role these proteins play in chemoresistance. Transporters of interest are those implicated in the uptake of many drugs used in anticancer therapies as well as in the transport of most nucleoside-derived antiviral drugs. Additional interests of the group focus on the role some of these proteins play in tumor biology, a key issue in the understanding of mechanisms of cell neoplastic transformation. Transporter proteins might play novel roles in cell physiology, defining novel gene networks linked to pathways implicated

in cell transformation. Both in vitro and In vivo models of human cancer are available to fulfill these objectives. In this context a comprehensive in vivo platform suitable for drug screening in the treatment of pancreatic adenocarcinoma has recently been developed (see below). Collaborations within the program involve analysis of the biology of pancreatic and colon cancers (with the group of Dr. Castells) and the disturbances derived from the loss of expression of transporter proteins in hepatocarcinogenesis (with the group of Dr. Jordi Bruix). A comprehensive study of mechanisms of chemoresistance in gastrointestinal tumors is also being addressed in collaboration with the group of Dr. José J. García Marín. “Connexin-26 Is a Key Factor Mediating Gemcitabine Bystander Effect”. García-Rodríguez. L* Pérez-Torras S*, Carrió M., Cascante A., García-Ribas I., Mazo A.*, Fillat C.* *equally contributed. Mol.Cancer Ther, 10(3); 505–17 (2011). Phosphorylated nucleoside analogues have been shown to traffic through gap junctions. We investigated the participation of gap junctional intercellular communication (GJIC) as a possible mechanism spreading gemcitabine cytotoxicity in pancreatic tumors. Immunohistochemical analysis of pancreatic cancer biopsies revealed increased connexin 26 (Cx26) content but

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PROJECTS AND COLLABORATIONS Hepatic and Gastrointestinal Oncology loss of connexins 32 (Cx32) and 43 (Cx43) expression. Cx26 abundance in neoplastic areas was confirmed by Cx26 mRNA in situ hybridization. Heterogeneity on the expression levels and the localization of Cx26, Cx32, and Cx43 were identified in pancreatic cancer cells and found to be associated with the extent of GJIC, and correlated with the bystander cytotoxic effect of gemcitabine. The abundance of Cx26 at the contact points in tumor regions prompted us to study the involvement of Cx26 in the GJIC of gemcitabine toxic metabolites and their influence on the antitumor effects of gemcitabine. Knockdown of Cx26 led to decreased GJIC and reduced gemcitabine bystander killing whereas overexpression of Cx26 triggered increased GJIC and enhanced the gemcitabine cytotoxic bystander effect. Gemcitabine treatment of mice bearing tumors, with a high GJIC capacity, resulted in a significant delay in tumor progression. Interestingly, gemcitabine administration in mice bearing tumors that overexpress Cx26 triggered a dramatic tumor regression of 50% from the initial volume. This study shows for the first time that Cx26 participates in the gap junction–mediated bystander cytoxic effect of the nucleoside analog gemcitabine and provides evidence that up-regulation of Cx26 improves gemcitabine anticancer efficacy. “Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening” Pérez-Torras S., Vidal-Pla A., Miquel R., Almendro V., Fernández-Cruz L., Navarro S., Maurel J., Carbó N., Gascón P., Mazo A. Cell Oncol. 34(6):511-21. (2011). Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability. Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models.

This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses. “Expression and distribution of nucleoside transporter proteins in the human syncytiotrophoblast” ErrastiMurugarren E, Díaz P, Godoy V, Riquelme G, PastorAnglada M. Mol Pharmacol. 80(5):809-17 (2011). The distribution of drug transporters in epithelia might be variable depending upon the type of epithelial barrier under study. Moreover, in most cases, vectorial transport of drugs across these epithelial barriers might be major determinants of drug pharmacokinetics. Although this study is beyond the scope of the program, it is within the major framework of our group interests, focused on the analysis of nucleoside transporter (NT) expression in non-absorptive epithelia (i.e. hepatocytes, cholangiocytes, and here, syncitiotrophoblast). A variety of approaches were used for that purpose, including nucleoside uptake measurements into vesicles from selected plasma membrane domains, NT immunohistochemistry, and subcellular localization (basal, heavy, and light apical membranes as well as raft-enriched membranes from the apical domain). In contrast with other epithelia studied in our laboratory (i.e. hepatocytes, enterocytes, cholangiocytes), in this epithelium, we have identified the highaffinity pyrimidine-preferring human concentrative nucleoside transporter (hCNT) 1 as the only hCNT-type protein expressed at both the basal and apical membranes. hCNT1 localization in lipid rafts is also dependent on its subcellular localization in the apical plasma membrane, suggesting a complex cellular and regional expression. Different patterns of nucleoside transporter expression in epithelia might encompass variable biological functions beyond their mere role as drug transporters. “Experimental Hepatology and Drug Targeting” (U. Salamanca) Principal Investigator. Dr. José Juan García Marín The research group focuses on the following lines: • Role of membrane transporters of phase 0 (uptake) and phase III (export) in resistance to chemotherapy in liver and intestinal tumours. • The role of retrograde signalling from mitochondria to the nucleus, the nuclear receptor FXR and the response of liver cells to oxidative/chemical stress in the development of

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PROJECTS AND COLLABORATIONS Hepatic and Gastrointestinal Oncology resistance to chemotherapy. • Development of new methods of pharmacogenomic for predicting the lack of response to chemotherapy in liver and intestinal tumours. • Development of new strategies of drug targeting and cellular therapy for the treatment of liver and intestinal tumours. The interest of the research group focuses on the study of several aspects (molecular bases, prediction and strategies of overcoming) of the resistance to chemotherapy in liver and intestinal tumours. Part of these studies are carried out in close collaboration with Dr. Bujanda’s, Dr. Prieto’s and Dr. Pastor Anglada’s teams. The group is also involved in the development of novel methods of drug targeting to the liver. Metabolomic analyses based on GC-MS and LC-MS/MS to carry out studies on drug metabolism and disposition are available to and commonly used by other members of the CIBERehd. “A homozygous nonsense mutation (c.214C>A) in biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis”. Nytofte NS, Serrano MA, Monte MJ, Gonzalez-Sanchez E, Tumer Z, Ladefoged K, Briz O, Marin JJG. JOURNAL OF MEDICAL GENETICS (2011) 48(4):219-225.

in the liver uptake of many endogenous and xenobiotic compounds, such as bile acids and drugs, respectively. The later include many antitumor agents. Despite the interest in these transporters in physiology and pharmacology, important characteristics, such as their driving force and the transport mechanism, are not well known for most of them. This article describes the characterization regarding the dependence on plasma membrane potential and extracellular pH of the transport mechanism of two important OATP isoforms in human liver, OATP1B1 and OATP1B3. The results obtained in this study indicate that both are electrogenic transporters whose activity, and hence pharmacological role, may be strongly affected under circumstances of displacement of the local pH, which commonly occurs in tumor tissue.

Bilirubin has beneficial antioxidant properties, although they are limited to low concentrations of this potentially toxic pigment. An explanation for the antioxidant function of bilirubin is the redox cycle in which bilirubin is oxidised to biliverdin and then recycled back to bilirubin by the enzyme BVR (gene symbol BLVRA). Inactivation of this pathway results in the lack of ability to transform biliverdin into bilirubin. Whether this is accompanied by liver damage is not known, although green jaundice is a rare finding usually associated with end-stage liver disease. This article is the first report of a homozygous BLVRA inactivating mutation indicating that the complete absence “Gastrointestinal and Pancreatic Oncology” (IDIBAPS) of BVR activity is a non-lethal condition, the most evident Principal Investigator. phenotypic characteristic of which is the appearance of green Dr. Antoni Castells jaundice accompanying cholestasis episodes. This group has excellent projects in molecular epidemiology of “Further characterization of the electrogenicity and colorectal cancer and in the assessment of screening plans for this pH-sentitivity of human organic anion-transporting malignancy. The group’s research into new genetic abnormalities polypeptides OATP1B1 and OATP1B3”. Martinez-Becerra P, and their participation in international consortia has allowed them to Briz O, Romero MR, Macias RIR, Perez MJ, Sancho-Mateo C, update the risk criteria and policy conventions for effective prevention. Lostao MP, Fernandez-Abalos JM, Marin JJG. MOLECULAR In addition, they have investigated new techniques for endoscopic diagnosis of digestive cancer and evaluated the use of minimally PHARMACOLOGY (2011) 79(3):596-607. Organic anion-transporting polypeptides (OATPs) are involved invasive surgery as a means to treat digestive cancer. This group has

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PROJECTS AND COLLABORATIONS Hepatic and Gastrointestinal Oncology presided over the creation of EPICOLON, a project designed to study hereditary forms of colorectal cancer affecting Spanish families, in collaboration with Hospital del Mar in Barcelona, Alicante General Hospital, University of Illinois in Chicago, and the National Centre for Genotyping (CeGen) from Santiago de Compostela, and with the participation of more than 20 Spanish centres.

compared with normal colonic mucosa. The discovery of unique miRNA expression profiles that can successfully discriminate between Lynch syndrome, sporadic MSI, and sporadic MSS colorectal cancers provides novel insights into the role of miRNAs in colorectal carcinogenesis, which may contribute to the diagnosis, prognosis, and treatment of this disease.

Colorectal cancers with microsatellite instability display unique miRNA profiles. Balaguer F, Moreira L, Lozano JJ, Link A, Ramirez G, Shen Y, Cuatrecasas M, Arnold M, Meltzer SJ, Syngal S, Stoffel E, Jover R, Llor X, Castells A, Boland CR, Gironella M, Goel A. Clin Cancer Res 2011;17:6239-49.

Validation microsatellite path score in a population-based cohort of patients with colorectal cancer. Bessa X, Alenda C, Paya A, Álvarez C, Iglesias M, Seoane A, Dedeu JM, Abulí A, Ilzarbe L, Navarro G, Pellise M, Balaguer F, Castellvi-Bel S, Llor X, Castells A, Jover R, Andreu M. J Clin Oncol 2011; 29:3374-80.

MicroRNAs (miRNA) are small non-coding RNA molecules of approximately 18 to 22 nucleotides that negatively regulate gene expression by inhibiting translation or inducing mRNA degradation. Since their discovery, miRNAs have been implicated in various cellular processes, including apoptosis, differentiation, and cell proliferation, and play a key role in carcinogenesis. Altered miRNA expression has been reported in most tumors, and specific miRNAs dysregulated in certain types of cancers may act as biomarkers for diagnosis and outcome in that cancer type. In colorectal cancer (CRC), although the current evidence suggests that the miRNA profile can distinguish between microsatellite instability (MSI) and microsatellite stable (MSS) tumors, the miRNA signature in Lynch syndrome tumors remains unknown. The aim of this study was to analyze global miRNA signatures in various groups of CRC based on the presence of MSI. For this purpose, we analyzed genome-wide miRNA expression profiles in 54 CRC tissues (22 with Lynch syndrome, 13 with sporadic MSI due to MLH1 methylation, 19 MSS) and 20 normal colonic tissues by miRNA microarrays. Using an independent set of MSI-positive samples, we developed a miRNA-based predictor to differentiate both types of MSI by quantitative reverse transcriptase PCR. In this study, in collaboration with Baylor University Medical Center, we found that the expression of a subset of nine miRNAs significantly discriminated between tumor and normal colonic mucosa tissues. More importantly, Lynch syndrome tumors displayed a unique miRNA profile compared with sporadic MSI tumors; miR-622, miR-1238, and miR-192 were the most differentially expressed miRNAs between these two groups. We developed a miRNA-based predictor capable of differentiating between types of MSI in an independent sample set. In conclusion, CRC tissues show distinct miRNA expression profiles

Lynch syndrome is inherited in an autosomal-dominant pattern with variable penetrance. It occurs as a consequence of germline mutations in the mismatch repair (MMR) system, mainly in MLH1 and MSH2, but also in MSH6 and PMS2. DNA microsatellite instability (MSI) and loss of MMR protein expression are very sensitive markers for identifying tumors occurring in Lynch syndrome. From a clinical perspective, Bethesda guidelines are used to recognize patients with colorectal cancer (CRC) at risk for Lynch syndrome. However, obtaining personal and familial tumor data can sometimes be difficult. The Microsatellite Path Score (MsPath), a pathological score based on age, tumor location, and pathologic features, has been developed to effectively predict CRC with DNA MMR deficiencies. However, the MsPath model’s performance in unselected, population-based CRC patients is unknown. In this study, using data from the EPICOLON study, a prospective, multicenter, population-based cohort, we assessed the efficacy of the Ms-Path score in identifying patients with MMR deficiency (MSI-H or loss of MMR gene protein expression by immunohistochemistry), as well as germline MLH1/MSH2 mutations, among population-based, unselected patients with CRC. All patients underwent tumor MSI analysis and immunostaining for MLH1/MSH2, and those with MMR deficiency underwent tumor BRAF mutation analysis and MLH1/MSH2 germline testing. Results of this study demonstrated that MsPath score for prediction of having MSI high, with the recommended cutoff score >1.0, had a sensitivity, specificity, and positive predictive value (PPV) of 92.8%, 64.1% and 15.8%, respectively. MsPath score had a sensitivity, specificity, and PPV of 81.8%, 60.6% and 1.9%, respectively, for the identification of MLH1/MSH2 gene

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PROJECTS AND COLLABORATIONS Hepatic and Gastrointestinal Oncology carriers. Application of the MsPath score, resulted in two (18%) of 11 mutation carriers being missed, both of them with a pathogenic germline MSH2 mutation. In conclusion, in unselected, population-based CRC patients, the MsPath score accurately predicted the probability of bearing a MSI high tumor, but it was insufficiently accurate for the selection of individuals with Lynch syndrome. “Hepatic Oncology” (IDIBAPS) Principal Investigator. Dr. Jordi Bruix This group operates in two fields. It has received international recognition for their work in the diagnosis and treatment of liver cancer. Their contributions, based on scientific evidence, have laid the foundation for diagnostic and therapeutic recommendations that are part of clinical practice guidelines developed by national and international scientific associations and agencies. Indeed, members of the group have been the leaders for such relevant actions. The BCLC has shown the benefits of the drug sorafenib in treating advanced liver cancer and this has primed active research in molecular therapy aimed at establishing a basic molecular classification of liver cancer and elucidate the different signalling pathways involved in tumour progression. The group has led the creation of an international consortium for Genomic Research in collaboration with Mount Sinai Medical School in New York, Harvard University, Institute Nationale di Tumori di Milan and the IDIBAPS in Barcelona. Currently, the BCLC leads international research in phase 1, 2 and 3, evaluating various molecular therapies in first or second line and as adjuvant after surgical resection or chemoembolization. Combining Clinical, Pathology, and Gene Expression Data to Predict Recurrence of Hepatocellular Carcinoma. Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornella H, Liberzon A, Kobayashi M, Kumada H, Thung S, Bruix J, Newell P, Roayaie S, Mazzaferro V, Schwartz M, Golub T, Llovet JM. Gastroenterology 2011; 140:1501-1512. In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. In this study we developed a composite prognostic model for HCC recurrence, combining data from gene expression patterns in tumor and adjacent tissues and clinicopathological

parameters. We assessed the whole-genome expression profiles of 287 HCC patients with early tumoral stage (Barcelona-Clinic Liver Cancer 0/A) who underwent resection. Then, we tested the predictive ability of 22 previously reported gene signatures, associated with poor outcome, originated from tumor and non-tumor adjacent cirrhotic tissues. The analysis revealed that gene expression signatures that were associated with aggressive HCC were clustered, as well as those associated with tumors of progenitor cell origin and those from nontumor, adjacent, cirrhotic tissues. Cox modeling and random survival forests showed that the tumor-associated signature “G3-proliferation” and an “adjacent poor-survival” signature were independent predictors of HCC recurrence, along with satellites. The transcriptomic analysis in 15 additional tumors performed in two different regions, center and periphery of the tumor, showed that predictions at different sites in the same tumor were reproducible in 80% of the gene signatures used in the study. MicroRNA-Based Classification of Hepatocellular Carcinoma and Oncogenic Role of miR-517a. Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A., Cabellos L, Minguez B, Savic R, Ward S, Thung S, Chiang DY, Alsinet C, Tovar V, Roayaie S, April C, Fan JB, Schwartz M, Bruix J, Friedman SL, Golub T, Mazzaferro V, Llovet JM. Gastroenterology 2011; 140:1618-1628 During the last years it has been a challenge to identify molecular classes of Hepatocellular carcinoma (HCC), a highly heterogeneous tumor, and design novel treatment strategies for each specific subtype. MicroRNAs (miRNAs) are involved in HCC pathogenesis, and their expression profiles have been used to classify cancers. In this study the analysis of the miRNA expression profile of 89 HCC samples allowed the identification of 3 main subclasses, the wingless-type MMTV integration site, the interferon-related, and the proliferation subclass, along with the molecular features associated to each subclass, after integrating genomic data of copy number alterations, mutations and immunohistochemical analysis. A subset of tumors in the proliferation subclass overexpressed a family of poorly characterized miRNAs from chr19q13.42. The oncogenic role of ch19q13.42-selected miRNAs was further validated in cell lines and in an orthotopic model of HCC. Our results revealed that miR-517a and miR-520c increased proliferation, migration, and invasion of HCC cells in vitro. Futhermore, miR517a promoted tumorigenesis and metastatic dissemination in vivo, providing rationale for developing therapies that target miR-517a for patients with HCC.

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PROJECTS AND COLLABORATIONS Hepatic and Gastrointestinal Oncology “Experimental Hepatology and Gene Therapy” (CUN) Principal Investigator. Dr. Jesús Prieto CUN is a reference centre in Spain for liver disease and liver cancer in general. In addition to their general work in hepatology, the group has developed a pioneering gene therapy which has medium to long term objectives. Its dedication to innovative therapies make it a key centre for the development of successful clinical trials. Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells. Fernandez-Ruiz, V; Kawa, M; Berasain, C; Iniguez, M; Schmitz, V; MartinezAnso, E; Inarrairaegui, M; Herrero, I; Sangro, B; D’Avola, D; Quiroga, J; Qian, C; Prieto, J. Journal of Hepatology 2011;55:828-37.

Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C. Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, Berg T, Poo JL, Mello CB, Guenther R, Niederau C, Terg R, Bedossa P, Boparai N, Griffel LH, Burroughs M, Brass CA, Albrecht JK; EPIC3 Study Group.Gastroenterology. 2011 Jun;140(7):1990-9. Development of hepatocellular Carcinoma is the leading cause of death in patients with cirrhosis. Hence, effective intervention to prevent its occurrence is a major unmet need. For several years it has been suggested that long term Interferon administration could be beneficial in patients with cirrhosis due to chronic HCV infection. The study directed by J Bruix investigated this issue in a large placebo controlled trial that included patients from all over the world. Unfortunately, the impact of interferon administration was marginla with no significant and clinically meaningful reduction of cancer incidence and/or liver related mortality. There was a minor benefit in patients with potential portal hypertension as these patients presented less portal hypertensive complications. However, because of reduced sample size in this subgroup analysis, the administration of Interferon in conventional practice is not endorsed. While the results have been deceiving, the study has finished a long lasting controversy. It has also shown that prevention trials are feasible, and at the same time, has provided the assumptions for the investigation of any future intervention.

The use of cell and gene therapy to treat liver diseases has reached the frontier of clinical development. In this paper, we have evaluated whether genetic engineering of bone marrowderived mononuclear cells (MNC) or endothelial progenitor cells (EPC) may in fact enhance the hepatoprotective properties of these cells. In animal models of acute liver failure induced by concanavaline A or by the administration of an adenovirus encoding CD40L (AdCD40L), the effect of an intra-splenic injection of unmodified MNC or EPC or the same cells transduced ex vivo with an adenovirus expressing luciferase or encoding the hepatoprotective cytokine cardiotrophin-1 was tested by analyzing the extent of liver damage, the intensity of inflammatory reaction, and animal survival. After injection into the spleen, the engineered cells migrated efficiently to the damaged liver. In mice with ConA hepatitis, only EPC expressing cardiotrophin-1 significantly decreased serum transaminases and induced more intense histological improvement than other treatments. This better therapeutic effect was associated with upregulation of cytoprotective molecules including IGF-I and EGF, lower expression of proinflammatory cytokines, IL-1b and TNFa, and decreased granzyme B levels. In the AdCD40L-induced model, EPC expressing cardiotrophin-1 also exceeded other cell therapies in attenuating the expression of proinflammatory mediators and hepatic injury enabling 35.7% to survive (0% in control groups). In conclusion, genetic engineering of EPC to overexpress cardiotrophin-1 enhances the hepatoprotective properties of EPC and constitutes a therapy that deserves consideration for humans with acute liver failure.

Scientific Activities of the Programs - 139

PROJECTS AND COLLABORATIONS Hepatic and Gastrointestinal Oncology Survival AfterYttrium-90 Resin Microsphere Radioembolization of Hepatocellular Carcinoma Across Barcelona Clinic Liver Cancer Stages: A European Evaluation. Sangro, B; Carpanese, L; Cianni, R; Golfieri, R; Gasparini, D; Ezziddin, S; Paprottka, PM; Fiore, F; Van Buskirk, M; Bilbao, JI; Ettorre, GM; Salvatori, R; Giampalma, E; Geatti, O; Wilhelm, K; Hoffmann, RT; Izzo, F; Inarrairaegui, M; Maini, CL; Urigo, C; Cappelli, A; Vit, A; Ahmadzadehfar, H; Jakobs, TF; Lastoria, S. Hepatology 2011;54:868-878. Yttrium-90 radioembolization is a novel locorregional therapy for hepatic tumors, that has shown intense activity in terms of disease control and tumor response in the treatment of advanced hepatocellular carcinoma. In this paper, that is the largest cohort series published so far, we have lead the analysis of the main prognostic factors driving survival after radioembolization using yttrium-90–labeled resin microspheres in 325 hundred patients treated in 8 European institutions. Most patients were Child-Pugh class A, had underlying cirrhosis, and had good performance status, but many had multinodular disease invading both lobes and/or portal vein occlusion. Over half had advanced BCLC stage C. The median overall survival was 12.8 months which varied significantly by disease stage (BCLC A, 24.4 months; BCLC B, 16.9 months; BCLC C, 10.0 months). When considered within the framework of BCLC staging, variables reflecting tumor burden and liver function provided additional prognostic information. The most significant independent prognostic factors for survival upon multivariate analysis were ECOG status, tumor burden (nodules >5), international normalized ratio >1.2, and extrahepatic disease. Common adverse events were: fatigue, nausea/vomiting, and abdominal pain. Grade 3 or higher increases in bilirubin were reported in 5.8% of patients. All-cause mortality was 0.6% and 6.8% at 30 and 90 days, respectively. In conclusion, our work has provided robust evidence of the survival achieved with radioembolization that compares well to that obtained by TACE in the intermediate stage and sorafenib in the advanced stage. Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection. Riezu-Boj, JI; Larrea, E; Aldabe, R; Guembe, L; Casares, N; Galeano, E; Echeverria, I; Sarobe, P; Herrero, I; Sangro, B; Prieto, J; Lasarte, JJ. Journal of Hepatology 2011;54:422-31. HCV infection evolves frequently to chronicity due to a a remarkable ability of the virus to escape to the immune response. One of the mechanisms that may hamper the

development of effective anti-HCV T cell responses is the accumulation of Foxp3+ T regulatory cells (Treg) in HCV infected livers. However the cause for the abundance of Tregs in hepatic tissue of patients with chronic hepatitis C (CHC) remains elusive. In this work, we studied the role of chemokines CCL17 and CCL22 in this process. We found that Foxp3+ Treg were increased in CHC livers as compared to controls. Patients with CHC showed elevated intrahepatic levels of CCL17 mRNA compared to normal livers or livers from subjects with SVR or other forms of liver disease. Intrahepatic CCL22 expression was also higher in CHC than in healthy subjects or SVR patients but similar to that observed in other liver diseases. Dendritic cells producing CCL22 could be found inside the hepatic lobule in CHC patients. Contact between MDDC and HCV-JFH1-infected Huh7 cells induced the expression of CCL17 and CCL22 in a process partially dependent on ICAM-1. Transwell experiments showed that upregulation of these chemokines enhanced Treg migration. In summary we found that the contact of HCV-infected cells with dendritic cells induces the production of Treg-attracting chemokines, an effect which may favour liver accumulation of Treg in CHC. Our findings contribute to explain the mechanism by which HCV escapes the immune response and thus reveals novel targets for therapeutic intervention. “Colorectal Cancer” (San Sebastian) Principal Investigator. Dr. Luis Bujanda This group joined CIBERehd in 2008. The group had an established track record in the field of genetics of colorectal cancer and the evaluation of screening programs in the population. Along with the group led by Dr. Castells they are responsible for multiple programs that exist to strengthen state-level cancer screening and at the same time generate a criteria to achieve an optimal cost-effectiveness. A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22. Abulí A, Fernández-Rozadilla C, Giráldez MD, Muñoz J, Gonzalo V, Bessa X, Bujanda L, Reñé JM, Lanas A, García AM, Saló J, Argüello L, Vilella A, Carreño R, Jover R, Xicola RM, Llor X, Carvajal-Carmona L, Tomlinson IP, Kerr DJ, Houlston RS, Piqué JM, Carracedo A, Castells A, Andreu M, Ruiz-Ponte C, Castellví-Bel S; Gastrointestinal Oncology Group of the Spanish Gastroenterological Association.. Br J Cancer. 2011 Sep 6;105(6):870-5.

140 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

PROJECTS AND COLLABORATIONS Hepatic and Gastrointestinal Oncology 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Jover R, Nguyen TP, Pérez-Carbonell L, Zapater P, Payá A, Alenda C, Rojas E, Cubiella J, Balaguer F, Morillas JD, Clofent J, Bujanda L, Reñé JM, Bessa X, Xicola RM, Nicolás-Pérez D, Castells A, Andreu M, Llor X, Boland CR, Goel A. Gastroenterology 2011; 140:1174-81.

Colorectal cancer (CRC) is the second cause of cancerrelated death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q2231, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24. We studied 172 SNPs of 1416 CRC cases and 1524 controls Genotyping was performed for 172 singlenucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24. We observed as none of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 ( TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk.

Colorectal cancer (CRC) is a common disease that accounts for a large proportion of cancer cases in Western countries. In the last few years, there has been a growing recognition of the existence of a new pathway for CRC pathogenesis, which involves the transcriptional silencing of tumor suppressor genes by hypermethylation of CpG islands surrounding the promoter regions of various genes. Tumors with such features are classified as having the CpG island methylator phenotype (CIMP), and it is now believed that as many as one-third to one-half of all CRCs may evolve through this pathway. Our objective was determined the response of patients with colorectal tumors with CIMP to 5-FU-based therapy. We analyzed a population-based cohort of 302 patients with colorectal cancer (CRC) for a median follow-up time of 50.7 months. CIMP status was determined by analysis of the CACNAG1, SOCS1, RUNX3, NEUROG1, and MLH1 promoters; tumors were considered to be CIMP positive if at least 3 promoters were methylated. Tumors from 29.5% of patients (89/302) were CIMP positive; CIMP status did not influence disease-free survival (DFS; log-rank = 0.3). Of tumors of TNM stages II-III (n = 196), 32.7% were CIMP positive. Among patients with stages II-III CRC who did not receive adjuvant 5-FU chemotherapy, those with CIMP-positive tumors had longest times of DFS (log-rank = 0.04); In patients who received chemotherapy, those with CIMP-positive tumors had shorter times of DFS (log-rank = 0.02). In patients with CIMP-negative tumors, adjuvant 5-FU chemotherapy significantly increased time of DFS (log-rank = 0.00001). However, in patients with CIMP-positive tumors, adjuvant 5-FU chemotherapy did not affect time of DFS (log-rank = 0.7). Multivariate analysis showed a significant, independent interaction between 5-FU treatment and CIMP status (hazard ratio [HR], 0.6; 95% confidence interval [CI], 0.5-0.8). Among patients with CIMP-positive tumors, adjuvant chemotherapy was not an independent predictor of outcome (HR, 0.8; 95% CI, 0.3-2.0). In patients who did not receive adjuvant 5-FU chemotherapy, CIMP status was the only independent predictor of survival (HR, 2.0; 95% CI, 1.1-3.8). In conclusion, patients with CIMPpositive colorectal tumors do not benefit from 5-FU-based adjuvant chemotherapy.

142 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

Dr. Jordi Bruix Tudó Hospital Clínic, Barcelona

Team leader Jordi Bruix Tudó

Team members Ramon Vilana Puig Manel Sole Arques Josep Mª Llovet Bayer Concepció Bru Saumell Luis Bianchi Cardona Mª Isabel Real Martí Mª Carmen Ayuso Colella Josep Fuster

Staff Loreto Boix Ferrero Mª Elisa Reig Monzón Ingrid Rengel Gelada Augusto Villanueva Rodríguez Judit Peix Galofré Alejandro Forner González

Main Research Topics

Outputs CIBERehd

Nº of Publications 1st quartile: 15 Nº of Publicatios 2nd quartile: 1 IF total: 153.512 Nº of competitive projects: 4 Public funding: €348,846 Private funding: €520,678 Multicentric clinical trials: 11

FIRST QUARTILE PUBLICATIONS 275,714

124,950

300

140,524

100

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• This group operates in two fields. It has received international recognition for their work in the diagnosis and treatment of liver cancer. Their contributions, based on scientific evidence, have laid the foundation for diagnostic and therapeutic recommendations. • It has shown the benefits of the drug sorafenib in treating advanced liver cancer and this has primed active research in molecular 4 therapy. Moreover, in recent years the group has engaged in active translational research aimed at establishing a basic molecular classification of liver cancer and elucidate the different signalling pathways involved in tumour progression. • The group has led the creation of an international consortium for Genomic Re search in collaboration with Mount Sinai Medical School in New York, Harvard University, Institute Nationale di Tumori di Milan and the IDIBAPS in Barcelona. • Currently, the group leads international research in phase 1, 2 and 3, evaluating various molecular therapies in first or second line and as adjuvant after surgical resection or chemoembolization.

Collaborations with other CIBERehd groups Jaume Bosch

Hospital Clínic, Barcelona

Marçal Pastor Anglada

Universidad de Barcelona

José M Mato

CIC BioGUNE, Vizcaya

Xavier Forns

Hospital Clínic, Barcelona

Scientific Activities of the Programs - 143

1st decile publications Sherman M, Llovet JM. “Smoking, hepatitis B virus infection, and development of hepatocellular carcinoma”. J Natl Cancer Inst. 2011 Nov 16;103(22):1642-3. IF 14.697 Villanueva A, Hoshida Y, Llovet JM. “Hepatocellular carcinoma enters the sequencing era”. Gastroenterology. 2011 Nov;141(5):19435. IF 12.032 Bruix J, Reig M, Rimola J, Forner A, Burrel M, Vilana R, Ayuso C. “Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques”. Hepatology. 2011 Dec;54(6):2238-44. IF 10.885 Mínguez B, Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S, Mandeli J, Sia D, April C, Fan JB, Lachenmayer A, Savic R, Roayaie S, Mazzaferro V, Bruix J, Schwartz M, Friedman SL, Llovet JM. “Gene-expression signature of vascular invasion in hepatocellular carcinoma”. J Hepatol. 2011 Dec;55(6):1325-31. IF 9.334 Llovet JM, Paradis V, Kudo M, Zucman-Rossi J. “Tissue biomarkers as predictors of outcome and selection of transplant candidates with hepatocellular carcinoma”. Liver Transpl. 2011 Oct;17 Suppl 2:S67-71. IF 3.068 Reig M, Bruix J. “The search for an effective partner for sorafenib: the failure of doxorubicin”. Gastroenterology. 2011 May;140(5):1687-8. IF 12.032 Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, Berg T, Poo JL, Mello CB, Guenther R, Niederau C, Terg R, Bedossa P, Boparai N, Griffel LH, Burroughs M, Brass CA, Albrecht JK; EPIC3 Study Group. “Maintenance therapy with peginterferon alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C”. Gastroenterology. 2011 Jun;140(7):1990-9. IF 12.032

Villanueva A, Llovet JM. “Targeted therapies for hepatocellular carcinoma”. Gastroenterology. 2011 May;140(5):1410-26. IF 12.032 Bruix J, Sherman M; American Association for the Study of Liver Diseases. “Management of hepatocellular carcinoma: an update”. Hepatology. 2011 Mar;53(3):1020-2. doi: 10.1002/ hep.24199. IF 10.885 Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, Savic R, Ward SC, Thung S, Chiang DY, Alsinet C, Tovar V, Roayaie S, Schwartz M, Bruix J, Waxman S, Friedman SL, Golub T, Mazzaferro V, Llovet JM. “MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a”. Gastroenterology. 2011 May;140(5):1618-28.e16. IF 12.032 Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornella H, Liberzon A, Kobayashi M, Kumada H, Thung SN, Bruix J, Newell P, April C, Fan JB, Roayaie S, Mazzaferro V, Schwartz ME, Llovet JM. “Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma”. Gastroenterology. 2011 May;140(5):1501-12.e2. IF 12.032 Tremosini S, Bruix J. “Diagnosis of early hepatocellular carcinoma: ideal goal, but not yet there”. Gastroenterology. 2011 Jan;140(1):358-60. IF 12.032 Poynard T, Munteanu M, Colombo M, Bruix J, Schiff E, Terg R, Flamm S, Moreno-Otero R, Carrilho F, Schmidt W, Berg T, McGarrity T, Heathcote EJ, Gonçales F, Diago M, Craxi A, Silva M, Boparai N, Griffel L, Burroughs M, Brass C, Albrecht J. “FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program”. J Hepatol. 2011 Feb;54(2):227-35. IF 9.334

Relevant projects 1. “Identificación y caracterización de la población de células madre adultas tumorales en líneas celulares derivadas de carcinoma hepatocelular humano”. PI080146. Instituto de Salud Carlos III. PI: Jordi Bruix. Team Members: JM Lopez Oliva, ME Reig Monzón, A Forner González, L. Boix Ferrero. 2009-2011. €42,108

3. “Integrative genomic analysis of human intrahepatic cholangiocarcinoma”. PI041495. Fundación AECC Investigación Contra El Cáncer. PI: Josep M Llovet. Team Members: Jordi Bruix, Josep Fuster, Juan Carlos Garcia-Valdecasas, Manel Sole, Joana Ferrer, Augusto Villanueva, Victoria Tovar, Daniela Sia, Clara Alsinet, Helena Cornellà, Judit Peix. 2011-2016. €240,000

2. “Predictores genómicos pronósticos y nuevas dianas moleculares en el carcinoma hepatocelular”. PI040984. Ministerio de Ciencia e Innovación. PI: Josep M Llovet. Team Members: Victoria Tovar, Daniela Sia, Manel Solé, Josep Fuster, Clara Alsinet, Helena Cornellà. 2011-2013. €93,600

4. “Genomic Predictors and Oncogenic Drivers in HCC”. PI040929. EUROPEAN COMUNITY - FP7 - HEALTH- 2010 TWO STAGE. PI: Josep M Llovet. Team Members: Augusto Villanueva, Jordi Bruix, Josep Fuster, Manel Solé, Victoria Tovar, Daniela Sia, Clara Alsinet, Helena Cornellà, Judit Peix. 2010-2013

144 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

DR. Luis Bujanda Fdez. de Piérola Hospital de Donostia, Guipúzcoa

Team leader Luis Bujanda Fernández de Piérola

Team members Ángel Cosme Jiménez Juan Ignacio Arenas Mirave Juan Arenas Ruiz-Tapiador Elizabeth Hijona Muruamendiaraz Marta Herreros Villanueva Jesús María Bañales Asurmendi

Staff M. Asuncion Aranguren Redondo Ana Goitia Viaña

Outputs CIBERehd

Nº of Publications 1st quartile: 7 Nº of Publications 2nd quartile: 2 IF total: 47.319 Nº of competitive projects: 7 Public funding: €146,800 Multicentric clinical trials: 8

Main Research Topics

FIRST QUARTILE PUBLICATIONS

10 32,563

5 0

Collaborations with other CIBERehd groups

100

Antoni Castells

PUBLICATIONS

Hospital Clinic, Barcelona

José Juan García Marín Universidad de Salamanca, Salamanca 10

2009 2010 2011 IF 1ST QUARTILE

300

42,007

12,888

• Strategies for screening and molecular characterization of colon cancer and colon polyps. • Search for new therapeutic targets in pancreatic cancer, cholangiocarcinoma, hepa tocellular carcinoma and gastric cancer. • Study of environmental and genetic factors that act on etiology and prognosis of gastric cancer. • Treatment of Helicobacter pylori and its relationship with gastric lymphoma. • Gastrointestinal complications associated with NSAID consumption and genetic susceptibility.

Juan F. Medina

Clínica Universitaria de Navarra

Ángel Lanas

Hospial Clínico, Zaragoza

Javier Pérez-Gisbert

Hospital La Princesa, Madrid

Xavier Calvet

Hospital Parc Taulí, Sabadell

Julián Panés

Hospital Clinic, Barcelona

Scientific Activities of the Programs - 145

1st decile publications Jover R, Nguyen TP, Pérez-Carbonell L, Zapater P, Payá A, Alenda C, Rojas E, Cubiella J, Balaguer F, Morillas JD, Clofent J, Bujanda L, Reñé JM, Bessa X, Xicola RM, Nicolás-Pérez D, Castells A, Andreu M, Llor X, Boland CR, Goel A. “5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer”. Gastroenterology. 2011 Apr;140(4):1174-81. IF 12,032 COLLABORATION Castells

Relevant projects 1. “Efecto del resveratrol y la pravastatina en la prevención y tratamiento del hepatocarcinoma en un modelo murino.” GV 2009/11003. Gobierno Vasco. PI: Juan Arenas. 20092012. €15,000 2. “ Cribado del cáncer colorrectal en población de riesgo intermedio: estudio multicéntrico, aleatorizado y controlado en el que se compara la prueba de detección de sangre oculta en heces mediante método inmunológico y la colonoscopia.” PI08/90717. Ministerio Sanidad y Consumo. PI: Enrique Quintero. 2009-2011. €35,000 3. “Cribado del cáncer colorrectal en población de riesgo intermedio: estudio multicéntrico, aleatorizado y controlado en el que se compara la prueba de detección de sangre oculta en heces mediante método inmunológico y la colonoscopia”. BIO07/CA/019. Gobierno Vasco. PI: Luis Bujanda. 2009-2011. €12,000

4. “Estudio en fase III, multicéntrico, aleatorizado, doble ciego de grupos paralelos para comparar la eficacia y seguridad de sorafenib más pravastatina frente a sorafenib más placebo en pacientes con hepatocarcinoma avanzado”. MSAN 10/210. Ministerio de Sanidad. PI: Juan Arenas R. 2011-2012. €40,000 5. “Identificación de factores genéticos, ambientales y de expresión fenotípica asociados a la progresión de lesiones precursoras del cáncer gástrico. estudio coordinado español de seguimiento”. PI10/02328. Ministerio Sanidad-FIS. PI: Juan I. Arenas M. 2011-2013. €12,000 6. “Identificación de nuevas dianas terapéuticas en el cáncer de páncreas”. DGF/149/11. Diputación Guipúzcoa. PI: Marta Herreros. 2011-2011. €17,000 7.“Efecto de las estatinas en la grasa corporal y hepática”. DGF/11/001. Diputación Guipúzcoa. PI: Elizabeth Hijona. 2011-2012. €24,000

146 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

DR. Antoni Castells Garangou Hospital Clínic, Barcelona

Team leader Dr. Antoni Castells Garangou

Team members Francesc Balaguer Prunés Sergi Castellví Bel José Ignacio Elizalde Fez Laureano Fernández-Cruz Mª Gloria Fernández-Esparrach Mª Àngels Ginès Gibert Antoni Mª de Lacy Fortuny Joan Maurel Santasusana Cristina Nadal Sanmartí Salvador Navarro Colás Maria Pellisè Urquiza Eva Cristina Vaquero Raya

Staff Meritxell Gironella Cos Jenifer Múñoz Sancho Esther Samper Lirola Georgina Ramirez Ramal

Main Research Topics

Outputs CIBERehd

Nº of Publications 1st quartile: 19 Nº of Publications 2nd quartile: 7 IF total: 161.321 Nº of competitive projects: 15 Public funding: €324,508 Private funding: €129,200 Multicentric clinical trials: 10

• Hereditary and familial forms of colorectal cancer: strategies for its identification, screening and surveillance. • Study of molecular mechanisms involved in the development, progression and treatment-resistance of colorectal and pancreatic cancer. • Molecular epidemiology of colorectal cancer and assessment of screening strategies. • Diagnostic and therapeutic endoscopy and minimally invasive surgery in gastrointestinal and pancreatic oncology.

Collaborations with other CIBERehd groups 50

FIRST QUARTILE PUBLICATIONS 139,511

178,721

300

142,644

100

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Julià Panés

Hospital Clínic de Barcelona

Jordi Bruix

Hospital Clínic de Barcelona

Luis Bujanda

Hospital de Donostia, Vizcaya

Marçal Pastor

Universitat de Barcelona

Ángel Lanas

Hospital Clínico Lozano Blesa, Zaragoza

Francisco Guarner

Hospital Valle Hebron, Barcelona

Julio Ponce

Hospital la Fe, Valencia

Antonio Rimola

Hospital Clínic de Barcelona

Xavier Calvet

Hospital Parc Taulí, Sabadell

Javier Pérez-Gisbert

Hospital La Princesa, Madrid

Scientific Activities of the Programs - 147

1st decile publications Sánchez-Tilló E, de Barrios O, Siles L, Cuatrecasas M, Castells A, “Postigo A. β-catenin/TCF4 complex induces the epithelial-to mesenchymal transition(EMT)-activator ZEB1 to regulate tumor invasiveness”. Proc Natl Acad Sci USA. 2011 Nov 29;108(48):192049. IF 9,771 Balaguer F, Moreira L, Lozano JJ, Link A, Ramirez G, Shen Y, Cuatrecasas M, Arnold M, Meltzer SJ, Syngal S, Stoffel E, Jover R, Llor X, Castells A, Boland CR, Gironella M, Goel A. “Colorectal cancers with microsatellite instability display unique miRNA profiles”. Clin Cancer Res. 2011 Oct 1;17(19):6239-49. IF 7,338 COLLABORATION Lozano Dumonceau JM, Polkowski M, Larghi A, Vilmann P, Giovannini M, Frossard JL,Heresbach D, Pujol B, Fernández-Esparrach G, Vazquez-Sequeiros E, Ginès A; “European Society of Gastrointestinal Endoscopy. Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline”. Endoscopy. 2011 Oct;43(10):897-912. IF 6,096 Pellisé M, López-Cerón M, Rodríguez de Miguel C, Jimeno M, Zabalza M, Ricart E, Aceituno M, Fernández-Esparrach G, Ginès A, Sendino O, Cuatrecasas M, Llach J, Panés J. “Narrow-band imaging as an alternative to chromoendoscopy for the detection of dysplasia in long-standing inflammatory bowel disease: a prospective, randomized, crossover study”. Gastrointest Endosc. 2011 Oct;74(4):840-8. IF 5,647 COLLABORATION Panés Fernández-Esparrach G, Ayuso-Colella JR, Sendino O, Pagés M, Cuatrecasas M, Pellisé M, Maurel J, Ayuso-Colella C, González-Suárez B, Llach J, Castells A, Ginès A. “EUS and magnetic resonance imaging in the staging of rectal cancer: a prospective and comparative study”. Gastrointest Endosc. 2011 Aug;74(2):347-54. IF 5,647 Bessa X, Alenda C, Paya A, Álvarez C, Iglesias M, Seoane A, Dedeu JM, Abulí A, Ilzarbe L, Navarro G, Pellisé M, Balaguer F, Castellvi-Bel S, Llor X, Castells A, Jover R, Andreu M. “Validation microsatellite path score in a population-based cohort of patients with colorectal cancer”. J Clin Oncol. 2011 Sep 1;29(25):3374-80. IF 18,970

Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, Tenesa A, Jones AM, Howarth K, Palles C, Broderick P, Jaeger EE, Farrington S, Lewis A, Prendergast JG, Pittman AM, Theodoratou E, Olver B, Walker M, Penegar S, Barclay E, Whiffin N, Martin L, Ballereau S, Lloyd A, Gorman M, Lubbe S; COGENT Consortium; CORGI Collaborators; EPICOLON Consortium, Howie B, Marchini J, Ruiz-Ponte C, Fernandez-Rozadilla C, Castells A, Carracedo A, Castellvi-Bel S, Duggan D, Conti D, Cazier JB, Campbell H, Sieber O, Lipton L, Gibbs P, Martin NG, Montgomery GW, Young J, Baird PN, Gallinger S, Newcomb P, Hopper J, Jenkins MA, Aaltonen LA, Kerr DJ, Cheadle J, Pharoah P, Casey G, Houlston RS, Dunlop MG. “Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer”. PLoS Genet. 2011 Jun;7(6):e1002105. IF 9,543 Fernández-Esparrach G, Panés J. “Radiofrequency ablation for nondysplastic Barrett’s esophagus: to treat or not to treat?” Gastroenterology. 2011 Jun;140(7):2130-2. IF 12,032 COLLABORATION Panés King CE, Cuatrecasas M, Castells A, Sepulveda AR, Lee JS, Rustgi AK. “LIN28B promotes colon cancer progression and metastasis”. Cancer Res. 2011 Jun 15;71(12):4260-8. IF 8,234 Pellisé M, Panés J. “Confocal endomicroscopy in celiac disease”. Gastroenterology. 2011 Mar;140(3):1097-9. IF 12,032 COLLABORATION Panés Mongroo PS, Noubissi FK, Cuatrecasas M, Kalabis J, King CE, Johnstone CN, Bowser MJ, Castells A, Spiegelman VS, Rustgi AK. “IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2”. Cancer Res. 2011 Mar 15;71(6):2172-82. IF 8,234 Jover R, Nguyen TP, Pérez-Carbonell L, Zapater P, Payá A, Alenda C, Rojas E, Cubiella J, Balaguer F, Morillas JD, Clofent J, Bujanda L, Reñé JM, Bessa X, Xicola RM, Nicolás-Pérez D, Castells A, Andreu M, Llor X, Boland CR, Goel A. “5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer”. Gastroenterology. 2011 Apr;140(4):1174-81. IF 12,032 COLLABORATION Bujanda

148 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

DR. antoni castells garangou Relevant projects 1. “Genetic study of common hereditary bowel cancers in Hispania and the Americas (CHIBCHA). PI040378 European Commission, 7th Framework Programme”. PI: Sergi Castellví Bel. Team Members: Antoni Castells, Francesc Balaguer, Victoria Gonzalo. 2009-2012. € 21,320 2. “Implicación de los microRNAs en la fisiopatología y quimioresistencia del cáncer de páncreas”. FMM-MG2008-11 Fundación Investigación Médica Mutua Madrileña. PI: Meritxell Gironella. Team Members: Antoni Castells, Salvador Navarro, Rosa Miquel, MªÁngels Ginès, Virginia Alonso-Espinaco, Victoria Gonzalo, Georgina Ramírez. 2008-2011. €16,700 3. “Grup de Recerca en Oncologia Gastrointestinal i Pancreatica”. 2009-SGR-849. Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR). PI: Antoni Castells i Garangou. Team Members: Laureano Fernández-Cruz, Salvador Navarro, Antonio Mª de Lacy, Mª Àngels Ginès, José Ignació Elizalde, Mª Teresa Ocaña, Mª Pellisé, Sergi Castellví-Bel, Francesc Balaguer, Victoria Gonzalo, Oriol Sendino, Mº Glòria Fernández-Esparrach, Cristina Rodríguez, Eva Vaquero, Mariana Rickmann, Georgina Ramírez, Anna Serradesanferm, Mireya Jimeno, Mª Dolores Giráldez, María López-Cerón, Mertixell Gironella, Antonio Postigo, Virginia Alonso-Espinaco, Jenifer Muñoz. 2009-2014. €10,192

8. “Ayudas para contratos de formación en investigación para profesionales sanitarios que hayan acabado la FSE (Río Hortega) 2010”. CM10/00084. Instituto de Salud Carlos III. PI: Mª Dolores Giráldez. 2010-2013 9. “Estudi aleatoritzat prospectiu sobre els efectes del tractament mèdic intensiu amb o sense bypass gàstric en Y de Roux, sobre el gruix de la íntima mitja carotídea en malalts amb obesitat grau I”. 401/17/2008. Agència d’Avaluació de Tecnologia i Rercerca Mèdiques. PI: Josep Vidal. Team Members: Antonio Mª Lacy, Margarita Giménez, Enric Esmatjes, Salvadora Delgado, Ignacio Conget, Margarita Jansà, Violeta Moizè. 2009-2011. €35,270 10. “GLP-1 y resolución tras el bypass gástrico de la diabetes tipo 2 asociada a obesidad”. AP62572009. Fundación Investigación Médica Mutua Madrileña. PI: Josep Vidal. Team Members: Antonio Mª Lacy, Roser Casamitjana, Miguel A. Rubio, Antoni Torres. 2009-2011. €32,500 11. “Análisis de perfiles expresión de microRNAs en el diagnóstico no invasivo de las lesiones neoplásicas colónicas microRNA”. Fundació Olga Torres. PI: Meritxell Gironella. 20112012. €30,000

4. “Transición epitelio-mesénquima y reclutamiento de fibrocitos en el desarrollo y extensión del cáncer de páncreas”. PI080280. Instituto de Salud Carlos III. PI: Eva Vaquero. Team Members: Mariana Rickmann, Xavier Molero, Salvador Navarro, Rosa Miquel. 2009-2011. € 23,514

12. “MicroRNAs en el cáncer de páncreas: evaluación de su potencial diagnóstico y terapéutico”. PI10/02888. Instituto de Salud Carlos III. PI: Meritxell Gironella. Team Members: Juan José Lozano Salvatierra, Mª Ángeles Ginés, Mª Dolores Giraldez, Leticia Moreira. 2011-2013. €45,980

5. “Componentes genéticos comunes y de baja penetrancia imnplicados en cáncer colorrectal: correlación genotipofenotipo e identificación de variantes genómicas de riesgo”. FIS08/0024 (PI040074). Fondo de Investigación Sanitaria. PI: Sergi Castellví Bel. Team Members: Josep M. Piqué, Jenifer Muñoz, María Dolores Giráldez, Teresa Ocaña. 2009-2011. €31,823

13. “Implicación del metiloma en la patogénesis y diagnóstico del cáncer colorrectal”. PI10/00384. Instituto de Salud Carlos III. PI: Francesc Balaguer. Team Members: Faust Feu, Teresa Ocaña, Leticia Moreira. 2011-2013. €37,026

6. “Implicación de los focos de criptas aberrantes en la carcinogénesis colorrectal: estudio morfológico con técnicas de endoscopia avanzada y caracterización molecular”. PS09/00669. Instituto de Salud Carlos III. PI: María Pellisé. 2010-2012. €17,242 7. “Caracterización genómica del sindrome de Lynch mediante secuenciación de nueva secuenciación de nueva generación (NSG): correlación con perfil transcriptómico y epigenómico”. SAF-2010-19273. Ministerio de Ciencia e Innovación. PI: Antoni Castells i Garangou. Team Members: Antonio Mª Lacy Fortuny, Anna Serradesaferm Fabregas, Virginia Alonso Espiniaco, Juan José Lozano Salvatella, Niels de Wind, Juul Wijnen. 2010-2013. €52,428

14. “Mediastinoscopia transesofágica guiada por un sistema de registro de la imagen versus mediastinoscopia convencional”. Estudio comparativo en un modelo porcino. SAF-2010-15635. Ministerio de Ciencia e Innovación PI: Gloória FernándezEsparrach. Team Members: Henry Córdova, Graciela martínez Pallí, Josep Llach Vila, Josep M Gimferrer, Esther Cladellas, Pedro Arguis, Raul san José Estepar, Kirby Vosbourgh. 20112013. € 32,266 15. “Papel de las variaciones en el número de copias del genoma en el cáncer colorrectal”. AIOB110289CAMP. Asociación Española Contra el Cáncer. PI: Jordi Camps. Team Members: Antoni Castells. 2011-2015. € 50,000

Scientific Activities of the Programs - 149

Thesis 1. Title: “Efectos del Bypass en “Y de Roux” por laparoscopia como técnica de cirurgía bariátrica en el tratamiento del síndrome metabólico asociado a la obesidad mórbida”. Doctorate Student: Ricard Corcelles Codina. Director: Antonio Maria de Lacy. Quealification: Sobresaliente “Cum Laude” . Date of lecture: 04/05/2011.

2. Title: “Cambios fisiológicos e inmunológicos de la cirugía endoscópica transluminal a través de orificios naturales (NOTES) utilizando diferentes vías de acceso versus la laparoscopia: estudio comparativo en un modelo porcino”. Doctorate Student: Carlos Guarner Argente. Directors: Antonio Maria de Lacy y Glória Fernández-Esparrach. Qualification: Sobresaliente “Cum Laude” . Date of lecture: 19/12/2011.

Patents 1. Title: “MicroRNAs (miRNA) as biomarkers for the identification of familial and non-familial colorectal cancer”. Baylor Research Institute/Fundació Clínic/CIBERehd. Authors: Francesc Balaguer Prunés, Meritxell Gironella i Cos, Juan José Lozano, Leticia Moreira, Antoni Castells i Garangou, Ajay Goel, Richard C. Boland. (Pending). 2. Title: “LINE-1 hypomethylation as a biomarker for early-onset colorectal cancer”. Baylor Research Institute. Authors: Ajay Goel, Richard C. Boºland, Francesc Balaguer. US Application Serial Number: 13/419,744. (Pending).

3. Title: “Gene-expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5’fluoruracil-based adjuvant chemotherapy”. Hospital Clínic, Siemens Healthcare. Authors: Antoni Castells, Luis LaSalvia, Aurea Mira, Míriam Cuatrecasas, Christoph Petry. Number: US PTO 61/604,058.

150 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

DR. José Juan García Marín Universidad de Salamanca, Salamanca

Team leader José Juan García Marín

Team members María Ángeles Serrano García María Jesús Monte Río Rocío Isabel Rodríguez Macías Francisco González San Martín Felipe Jiménez Vicente María José Pérez García Oscar Briz Sánchez

Staff Marta Rodríguez Romero Alba María García Blazquez Laura Sánchez Vicente

Outputs CIBERehd

Nº of Publications 1st quartile: 6 Nº of Publications 2nd quartile: 1 IF total: 46.014 Nº of competitive projects: 7 Public funding: €118,043 Private funding: €4,500

FIRST QUARTILE PUBLICATIONS

300 100

42,942 17,843

25,972

5 0

10 45

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Main Research Topics • Role of membrane transporters of phase I and phase III in resistance to chemotherapy in liver and intestinal tumours. • The role of retrograde signalling from mitochondria to the nucleus and nuclear receptor FXR in the response of liver cells to chemical/oxidative stress and the development of resistance to chemotherapy. • Development of new methods of pharmacogenomic for predicting the lack of response to chemotherapy in liver and intestinal tumours. • Development of new strategies of drug targeting and cellular therapy for the treatment of liver and intestinal tumours. • Role of the nuclear receptor FXR in liver and intestinal carcinogenesis.

Collaborations with other CIBERehd groups Javier González Gallego

Universidad de León

Manuel de la Mata García

Hospital Universitario Reina Sofía, Córdoba

José M Mato

CIC bioGUNE

Juan F. Medina

Clínica Universitaria de Navarra

Jesús Prieto

Clínica Universitaria de Navarra

Marçal Pastor Anglada

Universidad de Barcelona

Antonio Zarzuelo

Universidad de Granada

Luis Bujanda

Fundación Vasca para la Innovación e Investigación Sanitarias

Scientific Activities of the Programs - 151

1st decile publications Groen A, Romero MR, Kunne C, Hoosdally SJ, Dixon PH, Wooding C, Williamson C, Seppen J, Van den Oever K, Mok KS, Paulusma CC, Linton KJ, Oude Elferink RP. “Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity”. Gastroenterology. 2011 Nov;141(5):1927-37.e1-4. IF 12.032 Pérez MJ, González-Sánchez E, González-Loyola A, GonzálezBuitrago JM, Marin JJ. “Mitochondrial genome depletion dysregulates bile acid- and paracetamol-induced expression of the transporters Mdr1, Mrp1 and Mrp4 in liver cells”. Br J Pharmacol. 2011 Apr;162(8):1686-99. IF 4.925 Martinez-Becerra P, Briz O, Romero MR, Macias RI, Pérez MJ, Sancho-Mateo C, Lostao MP, Fernandez-Abalos JM, Marin JJ. ”Further characterization of the electrogenicity and pH sensitivity of the human organic anion-transporting

polypeptides OATP1B1 and OATP1B3”. Mol Pharmacol. 2011 Mar;79(3):596-607. IF 4,725 COLLABORATION Romero González R, Cruz A, Ferrín G, López-Cillero P, FernándezRodríguez R, Briceño J, Gómez MA, Rufián S, Mata M de L, Martínez-Ruiz A, Marin JJ, Muntané J. “Nitric oxide mimics transcriptional and post-translational regulation Turing α-tocopherol cytoprotection against glycochenodeoxycholateinduced cell death in hepatocytes”. J Hepatol. 2011 Jul;55(1):13344. IF 9.334 COLLABORATION De la Mata Ghanem CI, Arias A, Novak A, Carpini GD, Villanueva S, Blázquez AG, Marin JJ, Mottino AD, Rubio MC. “Acetaminophen-induced stimulation of MDR1 expression and activity in rat intestine and in LS 174T human intestinal cell line”. Biochem Pharmacol. 2011 Jan 15;81(2):244-50. IF 4.889

Relevant projects 1. “Papel del genoma mitocondrial en el control de la señalización retrógrada de la expresión de proteínas de resistencia a la quimioterapia en células hepáticas”. PI080151. Instituto Salud Carlos III (FIS). PI: Pérez García, MJ. Team Members: P. Martínez Becerra, E. Keck. 2009-2011. €13,600 2. “Relación entre FXR y riesgo de carcinogénesis en tejidos del circuito enterohepático. Implicaciones terapéuticas”. SAF2010-15517. MICINN PI: García Marín, JJ. Team Members: M.A. Serrano García, M.J. Monte Río, F. González San Martín, M. Rodríguez Romero, E. Herraez, J. Vaquero Rodríguez. 20102013. Fecha de inicio 2011 3. “Vectorización de fármacos para el tratamiento del colangiocarcinoma Programa I3”. Univ. Salamanca. PI: Rodríguez Macias, RI. 2010-2011. €1,500 4. “Investigación de nuevas dianas moleculares para la detección y la quimioterapia del colangiocarcinoma” Conv.2009. Fundación Mutua Madrileña PI: Rodríguez Macias, RI. Team Members: F. Jiménez Vicente, F. González San Martín, B. Castaño Rodríguez, S. Jiménez Cabrera, O. Briz Sánchez. 2009-2011. €4,500

Thesis 1. Title: “Implicación de promotores y transportadores de aniones orgánicos de las familias OATP y ABC en patología, toxicología y terapia antitumoral”. Doctorate Student: Elisa Herraez Aguilar. Directors: García Marín JJ, Rodríguez Macias, Briz Sánchez O. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 18/06/2011.

5. “Evaluación de estrategias de supresión tumoral por inducción de diferenciación celular mediante la activación de la vía de señalización regida por el gen NR1H4”. SA023A11-2. Junta de Castilla y León. PI: Monte Río, MJ. Team Members: JJ García Marín, MA Serrano García, F González San Martín, M Rodríguez Romero, J Vaquero Rodríguez. 2011-2013. €14,196 6. “Valor diagnóstico e interés como diana farmacológica en tratamiento del colangiocarcinoma del gen SLC10A2”. SA070A11-2. Junta de Castilla y León. PI: Rodríguez Macias RI. Team Members: Jiménez Vicente F, Jiménez Cabrera A, García Blázquez R, Rosales Rodríguez E, Lozano Esteban. 2011-2012. €10,000 7. “Bases moleculares de la respuesta SOS mediada por el receptor nuclear FXR y su papel en la hepatocarcinógenesis SANIDAD2011/JDI6”. Junta de Castilla y León. PI: García Marín, JJ. Team Members: M.A. Serrano García, M.J. Monte Río, F. González San Martín, M.J. Perez Garcia, M. Rodriguez Romero, E. Herráez Aguilar, R. Rosales Rodríguez. 2011-2012. €18,000

152 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

DR. Marçal Pastor-Anglada Universidad de Barcelona

Team leader Marçal Pastor-Anglada

Team members Javier Casado Merediz F. Isabel Húber Ruano Itziar Pinilla Macua Miriam Molina Arcas Pedro Cano Soldado Sergi Purcet Gregori Ekaitz Errasti Murugarren

Staff Ekaitz Errasti Murugarren Ingrid Iglesias Garanto Sandra Pérez Torras

Outputs CIBERehd

Nº of Publications 1st quartile: 4 IF total: 21.819 Nº of competitive projects: 5

Main Research Topics • • • • • •

FIRST QUARTILE PUBLICATIONS

10 25,237

28,670

300

Collaborations with other CIBERehd groups

100

Jordi Bruix

Hospital Clínic, Barcelona

Antoni Castells

Hospital Clínic, Barcelona

José Juan García Marín

Universidad de Salamanca

Juan Ignacio Esteban

Hospital Vall d’Hebron, Barcelona

Juan Francisco Medina

Universidad de Navarra

Francisco Guarner

Hospital Vall d’Hebron, Barcelona

Antonio Zarzuelo

Universidad de Granada

21,819

10 5

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Pharmacogenetics and pharmacogenomics of anticancer drug transporters. Identification of new targets of anticancer drugs. Research on transport systems related to resistance to anticancer treatments. Role of plasma membrane transporters in tumor biology. Development of in vivo models of human cancer to assess drug efficacy. Role of CNT and ENT proteins in epithelial purinergic signalling.

Scientific Activities of the Programs - 153

1st decile publications Errasti-Murugarren E, Díaz P, Godoy V, Riquelme G, PastorAnglada M. “Expression and distribution of nucleoside transporter proteins in the human syncytiotrophoblast”. Mol Pharmacol. 2011 Nov;80(5):809-17. IF 4.725

Minuesa G, Huber-Ruano I, Pastor-Anglada M, Koepsell H, Clotet B, Martinez-Picado J. “Drug uptake transporters in antiretroviral therapy”. Pharmacol Ther. 2011 Dec;132(3):26879. IF 8.694

Relevant projects 1. “Regulación fisiológica y farmacológica de los transportadores CNT y ENT como herramientas de mejora en la respuesta terapéutica a fármacos derivados de nucleósidos”. SAF2008-00577. MCINN. PI: Marçal PastorAnglada. 2009-2011. €109,426 2. “Aumento de la potencia y selectividad de adenovirus oncolíticos portadores de genes supresores tumorales”. BIO2008-04692. MICINN. PI: Adela Mazo. Team Members: S. Pérez-Torras, A.Vidal Pla, N.Carbó Carbó, T. Sánchez Molero. 2009-2011. €56,074

Thesis 1. Title: “Regulación del tránsito a membrana de CNT2: determinantes estructurales y factores fisiológicos”. Doctorate Student: Itziar Pinilla Macua. Director: Marçal Pastor Anglada. Qualification: Apto “Cum Laude” Premio Extraordinario de Doctorado. Date of lecture: 31/01/2011.

3. “Generación de anticuerpos monoclonales contra hENT1 y hCNT1 como herramientas de diagnóstico”. FP2010-21. Programa IDEA – FBG. PI: Marçal PASTOR-ANGLADA. Team Members: S.Pérez-Torras. 2011. €9,500 4. “Grupo Consolidado de la Generalitat de Catalunya”. 2009SGR624. AGAUR. PI: Marçal Pastor-Anglada. Grupo MPET al completo. 2009-2013. €9,222 5. “Programa Intramural de Intensificación de la Actividad Investigadora”. UB. Marçal Pastor-Anglada. 2011. Dotación de una plaza de Profesor Asociado

154 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

DR. JesÚs Prieto Valtueña Clínica Universitaria de Navarra

Team leader Jesús Prieto Valtueña

Team members Jorge Quiroga Vila Bruno Sangro Gómez-Acebo Ignacio Herrero Santos Mercedes Iñarrairaegui Bastarrica Pilar Civeira Murillo

Staff Delia D’Avola Mercedes Reboredo Prol Eva Santa María Monasterio Roberto Barbero López Iker Uriarte Diaz-Varela

Outputs CIBERehd

Nº of Publications 1st quartile: 19 Nº of Publications 2nd quartile: 4 IF total: 146.183 Nº of competitive projects: 6 Public funding: €469,516 Multicentric clinical trials: 12

FIRST QUARTILE PUBLICATIONS

78,808

100

5 0

10 14

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• • • • •

Mechanisms of hepatocarcinogenesis and treatment of hepatocellular carcinoma. Application of gene and cell therapy to hepatocellular carcinoma. Hepatoprotection and stimulation of liver regeneration. Liver transplantation. Role of membrane transporters in hepatobiliary patology.

300

135,424 81,974

Main Research Topics

Collaborations with other CIBERehd groups Juan Francisco Medina

CIMA, Pamplona

José Juan García Marin

Universidad Salamanca

Javier González Gallego

Universidad de León

Manuel de la Mata

Hospital Reina Sofía

José María Mato

CIC bioGUNE

Juan Ignacio Esteban

Hospital Vall d’Hebron

Scientific Activities of the Programs - 155

1st decile publications Urtasun R, Latasa MU, Demartis MI, Balzani S, Goñi S, Garcia-Irigoyen O, Elizalde M, Azcona M, Pascale RM, Feo F, Bioulac-Sage P, Balabaud C, Muntané J, Prieto J, Berasain C, Avila MA. “Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yesassociated protein-mediated activation”. Hepatology. 2011 Dec;54(6):2149-58. IF 10.885 ReViS-TC Study Group.“Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation. 2011 Aug 15;92(3):334-40. Erratum in: Transplantation. 2012 Feb 15;93(3):e13. IF 3.676 Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, Paprottka PM, Fiore F, Van Buskirk M, Bilbao JI, Ettorre GM, Salvatori R, Giampalma E, Geatti O, Wilhelm K, Hoffmann RT, Izzo F, Iñarrairaegui M, Maini CL, Urigo C, Cappelli A, Vit A, Ahmadzadehfar H, Jakobs TF, Lastoria S; European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). “Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation”. Hepatology. 2011 Sep 2;54(3):868-78. IF 10.885 Echeverria I, Pereboev A, Silva L, Zabaleta A, Riezu-Boj JI, Bes M, Cubero M, Borras-Cuesta F, Lasarte JJ, Esteban JI, Prieto J, Sarobe P. “Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells”. Hepatology. 2011 Jul;54(1):28-37. IF 10,885 COLLABORATION Juan Ignacio Esteban Vanrell L, Di Scala M, Blanco L, Otano I, Gil-Farina I, Baldim V, Paneda A, Berraondo P, Beattie SG, Chtarto A, Tenenbaum L, Prieto J, Gonzalez-Aseguinolaza G. “Development of a liver-specific Tet-on inducible system for AAV vectors and its application in the treatment of liver cancer”. Mol Ther. 2011 Jul;19(7):1245-53. IF 7.149 Fernández-Ruiz V, Kawa M, Berasain C, Iñiguez M, Schmitz V, Martinez-Ansó E, Iñarrairaegui M, Herrero I, Sangro B, D’Avola D, Quiroga J, Qian C, Prieto J. “Treatment of murine

fulminant hepatitis with genetically engineered endothelial progenitor cells”. J Hepatol. 2011 Oct;55(4):828-37. IF 9.334 D’Avola D, Iñarrairaegui M, Pardo F, Rotellar F, Marti P, Bilbao JI, Martinez-Cuesta A, Benito A, Alegre F, Mauleón E, Herrero JI, Quiroga J, Prieto J, Sangro B. “Prognosis of hepatocellular carcinoma in relation to treatment across BCLC stages”. Ann Surg Oncol. 2011 Jul;18(7):1964-71. IF 4.182 Díaz-Valdés N, Manterola L, Belsúe V, Riezu-Boj JI, Larrea E, Echeverria I, Llópiz D, López-Sagaseta J, Lerat H, Pawlotsky JM, Prieto J, Lasarte JJ, Borrás-Cuesta F, Sarobe P. “Improved dendritic cell-based immunization against hepatitis C virus using peptide inhibitors of interleukin 10”. Hepatology. 2011 Jan;53(1):23-31. IF 10.885 Riezu-Boj JI, Larrea E, Aldabe R, Guembe L, Casares N, Galeano E, Echeverria I, Sarobe P, Herrero I, Sangro B, Prieto J, Lasarte JJ. “Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection”. J Hepatol. 2011 Mar;54(3):422-31. IF 9.334 Tuñón MJ, San Miguel B, Crespo I, Jorquera F, Santamaría E, Alvarez M, Prieto J, González-Gallego J. “Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus”. J Pineal Res. 2011 Jan;50(1):38-45. IF 5.855 COLLABORATION González Gallego Unzu C, Sampedro A, Mauleón I, Alegre M, Beattie SG, de Salamanca RE, Snapper J, Twisk J, Petry H, González-Aseguinolaza G, Artieda J, Rodríguez-Pena MS, Prieto J, Fontanellas A. “Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice”. Mol Ther. 2011 Feb;19(2):243-50. IF 7.149 Gonzalez-Aparicio M, Alzuguren P, Mauleon I, Medina-Echeverz J, Hervas-Stubbs S, Mancheno U, Berraondo P, Crettaz J, GonzalezAseguinolaza G, Prieto J, Hernandez-Alcoceba R. “Oxaliplatin in combination with liver-specific expresión of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice”. Gut. 2011 Mar;60(3):341-9. IF 10.614

156 - CIBERehd- 2011 ANNUAL REPORT - PROGRAM 5

DR. JesÚs Prieto Valtueña Relevant projects 1. “Interrelación funcional de cardiotrofina-1 e interleucina-6: hacia el diseño de nuevas moléculas quiméricas hepatoprotectoras”. SAF2008-02980. Proyectos de I+D del Ministerio de Ciencia e Innovación. PI: Jesús Prieto. Team Members: Ignacio Herrero, Fernando Pardo, Mercedes Iñarrairaegui, Mª Jose Domínguez, Nagore Martín. €33,333 2. “Ensayo clínico piloto (Fase I/II) para la valoración de la seguridad y efectos terapéuticos de la administración de células progenitoras endoteliales (EPC) autólogas obtenidas de médula ósea en pacientes con cirrosis hepática avanzada”. TRA-108. Investigación Clínica Independiente del FIS. PI: Jorge Quiroga. Team Members: Ignacio Bilbao, Veronica Fernández, Delia D’Avola, Ignacio Herrero, Jesús Prieto, Mercedes Iñarrairaegui, Javier Pérez Calvo. € 263,100 3. “Red de Inmunoterapia (INMUNONET)”. SOE1/P1/E014. Programa INTERREG. PI: José Luis Pérez Gracia. Team Members: Bruno Sangro, Álvaro González. €30,625 4. “Ensayo clínico en fase I-II de vacunación terapéutica de pacientes con hepatitis crónica C mediante la administración

de células dendríticas autólogas transducidas con un vector adenoviral que codifica la proteína NS3”. EC10-327. FIS Medicament. PI: Prieto Valtueña, Jesús. Team Members: Mercedes Iñarrairaegui Bastarrica, Jorge Quiroga Vila, Bruno Sangro Gómez-Acebo, Pilar Civeira Murillo, Javier Pérez Calvo, Pablo Sarobe Ugarriza, Delia D´Avola, José Ignacio Herrero Santos, José Ignacio Riezu Boj, Juan José Lasarte Sagastibelza. €125,000 5. “AIPgene - “Augmenting PBGD expression in the liver as a Novel Gene therapy for Acute Intermittent Porphyria”. 261506/ FP7 CP. PI: Prieto Valtueña, Jesús. Team Members: Fernández de Trocóniz, Iñaki. €169,600 6. “Valoración de la eficacia antitumoral y antiviral tras la expresión combinada de oncostatina M e interferón alfa: papel de la respuesta inmune”. PI10/00149 FIS I+D. PI: Larrea Leoz, Mª Esther. Team Members: Pilar Civeira Murillo, Edurne Elizalde Agurruza, José Ignacio Riezu Boj, Sandra Jusué Garces, Eva Galeano Galán. €31,258

Thesis 1. Title: “Cardiotrophin-1: evaluation of the possible therapeutic role in liver resection and transplantation”. Doctorate Student: Haisul Chang. Directors: Jesús Prieto, Ignacio Herrero. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 09/06/2011. 2. Title: “Estudio del daño hepático inducido por la radioembolización de tumores hepáticos”. Doctorate Student: Belén Gil Alzugaray.

Director: Bruno Sangro. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 14/06/2011. 3. Title: “Estudios sobre el papel de la radioembolización en el tratamiento del hepatocarcinoma”. Doctorate Student: Delia D’Avola. Director: Bruno Sangro. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 01/07/2011.

158 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

Program 6

Gastrointestinal Inflammation and Motility

P6 Scientific Activities of the Programs - 159

Gastrointestinal Inflammation and Motility Presentation: Dr. Julián Panés Díaz. Program Coordinator

he program on Gastrointestinal inflammation and motility, has continued building collaborations among the groups, resulting in achievement of significant milestones and deliverables during calendar year 2011.

The research for development of cell therapies for inflammatory bowel diseases has established the option of autologous hematopoietic stem cell transplantation as a clinically accepted alternative for treatment of refractory Crohn’s disease, which has been recognized in the recent guidelines of the European Bone Marrow Transplant group. Notably, the development process of another form of cell therapy, based on the administration of autologous conditioned tolerogenic dendritic cells, obtained from peripheral blood monocytes has been completed, and the production process has obtained a European patent, in which CIBERehd has a considerable participation. Furthermore, a phase I clinical trial is actively recruiting patients and will be completed in 2012. The majority of groups integrated in the program have provided a significant contribution in terms of samples and

associated high-quality clinical information for completion of a GWAS in inflammatory bowel diseases. So far, this project has led to the discovery of new susceptibility locus for Crohn’s disease. This will be continued by functional characterization of the genetic susceptibility variants. The project will also take advantage of the long prospective follow-up of patients, which makes this collection unique, to establish robust genotype-phenotype associations, overcoming the limitations of previous studies with limited clinical information associated to the samples. Collaborations between various groups have also resulted in relevant publications for development of new therapies for IBD, such as the elucidation of molecular mechanisms of resistance to corticosteroids, and optimization of current treatments such as thiopurines and anti-TNF antibodies, to get the maximum efficiency in the use of these drugs, that impose a significant cost to the public health system. In the subprogram of acid-related diseases, the groups have been actively working integrated in 2 main collaborative areas. One of them focused on the investigation of both

160 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

PROJECTS AND COLLABORATIONS Gastrointestinal Inflammation and Motility environmental and genetic factors linked to increased susceptibility to bleed in the GI tract in patients taking NSAIDS or antiplatelet agents. The other area deals with investigation in the treatment and management of H. pylori infection in humans, where substantial contributions has been made possible thanks to the extensive networks of hospitals leaded by investigators of this area of the CIBERehd. Both programs have provided a significant contribution in terms publications and of samples and associated high-quality clinical information for completion of ongoing genetic analysis in acid-related disease. The area of Neurogastroenterology and Motility has further developed collaborative studies between the different groups in CIBERehd and with other international teams. The flourishing areas include the electrophysiological and ultrastructural alterations in patients with gut dysfunctions+, and the relation of colonic flora with functional gastrointestinal symptoms. The former aspect may provide relevant results applicable to the diagnosis and subclassification of these

patients, that may facilitate their management. The crosstask between colonic flora and the host has originated a new concept in Neurogastroenterology: the microbiomegut-brain axis. This new insight has been presented in an international summit (Microbiota for Health) in France. This area of research has aroused tremendous interest and has promoted the incorporation of an international multidisciplinary section within the European Society of Neurogastroenterology and Motility, led by members of CIBERehd. Members of the program 6 have had a high participation and international visibility on the elaboration of practice guidelines and consensus documents, in various areas including Barrettâ&#x20AC;&#x2122;s esophagus, management of H. pylori infection, upper gastrointestinal bleeding,NSAID-related gastrointestinal complicationsinflammatory bowel disease and neurogastroenterology disorders. During 2011, some of the members of the group have had tenure of presidency of international medical societies or have served as associate editors of first decile journals.

Scientific Activities of the Programs - 161

162 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

PROJECTS AND COLLABORATIONS Gastrointestinal Inflammation and Motility

CENTER

STAFF

PI STAFF

Hospital Vall d’Hebrón, Barcelona

F. Azpiroz

Neurogastroenterology

Hospital Parc Tauli, Sabadell

X. Calvet

Inflammatory Bowel Disease/ Esophagus and Gastroduodenal Disorders

IIBB-CSIC, Barcelona

D. Closa

Inflammatory Bowel Disease/ Pancreatic Disoreders

Fac. Medicina. U. València, València

J.V. Esplugues

Esophagus and Gastroduodenal Disorders

H. Germans Trias i Pujol, Badalona

M.A. Gassull

Inflammatory Bowel Disease

Hospital Vall d’Hebrón, Barcelona

F. Guarner

Inflammatory Bowel Disease

Hospital Clínico, Zaragoza

A. Lanas

Esophagus and Gastroduodenal Disorders/ Colon Cancer

Hospital Clínic, Barcelona

J. Panés

Inflammatory Bowel Disease

D Farmacología. U. Granada

A. Zarzuelo

Inflammatory Bowel Disease/ Neurogastroenterology

Hospital La Princesa, Madrid

J. Pérez-Gisbert

Inflammatory Bowel Disease/ Esophagus and Gastroduodenal Disorders

Hospital Mataró, UAB

P. Clavé

Neurogastroenterología

Hospital La Fe, Valencia

B. Beltrán

Inflammatory Bowel Disease/ Neurogastroenterology

Hospital Mútua de Terrassa

M. Esteve

Inflammatory Bowel Disease/ Celiac

3 main research lines: • Esophagus and Gastroduodenal Disorders • Neurogastroenterology • Inflammatory Bowel Disease

Group Descriptors

Scientific Activities of the Programs - 163

PROJECTS AND COLLABORATIONS Gastrointestinal Inflammation and Motility Projects by Program 1. Esophagus and Gastroduodenal Disorders Project

CENTER

1.1

Identificacion de factores ambientales y genéticos de riesgo de lesiones y complicaciones de la mucosa gastro-intestinal orientadas al desarrollo de estrategias de prevención y tratamiento.

7, 2, 3, 4, 10, 12

1.2

Estudio de las alteraciones epigenéticas (hipermetilación de islas CpG e hipometilación global) en Esófago de Barrett orientado a su aplicación en la clínica como biomarcadores de progresión neoplásica.

7, 2, 8, 10, 12

1.3

Susceptibilidad genética e infección por Helicobacter pylori. Influencia en el desarrollo y pronóstico del cáncer gástrico.

7, 2, 10, 12

1.4

Fomento de la práctica clínica eficiente en pacientes con ERGE basada en la evidencia científica y el conocimiento de factores implicados en la gravedad de la enfermedad.

12, 2, 10

1.5

Analisis de marcadores de hipoxia y de funciónalismo mitocondrial en procesos gastrointestinales con componente inflamatorio.

4, 12, 2, 7, 10

1.6

Detección de H. pylori mediante RT-PCR e inmunohistoquímica en el paciente con linfoma MALT gástrico H. pylori negativo por métodos convencionales.

2, 10, 12, 7

1.7

Estudio de los factores determinantes de la aparición y evolución de las lesiones gastroduodenales.

10, 2, 12, 7, 5, 1

1.8

Evaluación de nuevos métodos diagnósticos de la infección por H. pylori y las lesiones gástricas asociadas.

10, 7, 2, 12

1.9

Evaluación de nuevas terapias para la erradicación de la infección por H. pylori.

10, 2, 12, 7

1.10

Evaluación de nuevos tratamientos de rescate en la erradicación de la infección por H. pylori.

10, 2, 12, 7

1.11

Elaboración y difusión del I Consenso Español sobre hemorragia digestiva por úlcera péptica.

2, 7, 10

1.12

Estudio del RNA no codificante (nc-RNA) en la infección por Helicobacter pylori.

2, 10

2. Neurogastroenterology Project

CENTER

2.1

Manejo de los pacientes con alteraciones funcionales digestivas

2.2

Estudio de la fisiopatología de los síntomas y complicaciones asociados a la disfagia orofaríngea y esofágica con aplicación específica a la validación de nuevos métodos diagnósticos, y estandarización de la práctica clínica.

5, 10, 11

2.3

Desarrollo de métodos de estudio in Vitro de las alteraciones de la motilidad gastrointestinal humana en segmentos orofaríngeos, esófago-gástricos, intestinales y colo-rectales humanos.

1, 11, 12

164 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

PROJECTS AND COLLABORATIONS Gastrointestinal Inflammation and Motility 3. Inflammatory Bowel Disease Project

CENTER

3.1

Caracterización de microbiota en la enfermedad inflamatoria intestinal.

2, 6, 12

3.2

Desarrollo de pancreatitis crónica y de cancer de pancreas. Exploración de opciones terapeúticas.

6, 8

3.3

Estudio de nuevas aproximaciones terapéuticas en la enfermedad inflamatoria intestinal mediante actuación sobre la microbiota intestinal: probioticos, prebioticos y antibióticos.

5, 6, 9

3.4

Estudios a nivel nacional sobre aspectos epidemiológicos de la enfermedad inflamatoria intestinal.

2, 5, 7, 10, 12, 13

3.5

Caracterización de las bases fisiopatológicas y clínicas de la enfermedad inflamatoria intestinal y de sus complicaciones.

2, 5, 7, 10, 12, 13

3.6

Infección en la enfermedad inflamatoria intestinal.

2, 5, 7, 8, 10, 12

3.7

Estudios genéticos en la enfermedad de Crohn relacionados con el estrés oxidativo. Aproximación para la búsqueda de nuevas dianas terapéuticas.

2, 5, 8, 10, 12

3.8

Estudio del papel de nuevos derivados lipídicos en la regulación de la respuesta inflamatoria en enfermedades gastrointestinales.

3, 8

3.9

Implicación de los factores angiogénicos y linfangiogénicos en la enfermedad inflamatoria intestinal.

2, 5, 10

3.10

Valor del test rápido de calprotectina fecal en la predicción de la recidiva de la enfermedad inflamatoria intestinal.

2, 5, 10

3.11

Desarrollo de un kit diagnóstico para las enfermedades inflamatorias mediadas por mecanismos inmunes (IMID-kit), con aplicación específica al diagnóstico y pronóstico de la enfermedad de Crohn.

2, 5, 7, 8, 10, 12, 13

3.12

Terapia celular en la enfermedad inflamatoria intestinal.

3.13

Eficacia y seguridad de los tratamientos biológicos en la enfermedad inflamatoria intestinal.

2, 5, 7, 8, 10, 12

3.14

Eficacia y seguridad de los tratamientos inmunomoduladores en la enfermedad inflamatoria intestinal.

2, 5, 7, 8, 10, 12, 13

3.15

Descubrimiento de genes de susceptibilidad para toxicidad asociada a la azatioprina basada en un estudio de asociación con barrido amplio del genoma (GWAS).

2, 5, 7, 8, 10, 12, 13

3.16

Cribado del cáncer colorrectal.

2, 5, 7, 8, 10, 12

3.17

Evaluación de implementación de guías clínicas y calidad asistencial en la Enfermedad Inflamatoria Intestinal.

10,7

3.18

Registro de colitis microscópica nacional (proyecto RECOMINA): estudio de factores ambientales de riesgo de colitis microscópica y creación de un banco de ADN.

13, 2, 5, 8, 10, 12

3.19

Elaboración y validación de un índice objetivo de discapacidad en la enfermedad de Crohn.

2, 5, 6

3.20

Reducción del cuestionario de percepción de discapacidad en la Enfermedad de Crohn (CPDC).

2, 5, 6

3.21

Mecanismos de inflamación intestinal y su modulación por péptidos y microrna.

3.22

Mecanismo de acción de los flavonoides como agentes antiinflamatorios intestinales.

3.23

Papel de los transportadores de nucleósidos en la respuesta de macrófagos a pancreatitis aguda.

Scientific Activities of the Programs - 165

166 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

Dr. Fernando Azpiroz Vidaur Hospital Vall d’Hebron, Barcelona

Team leader Fernando Azpiroz

Team members Anna Accarino Garaventa Carolina Malagelada Prats Juan-Ramón Malagelada Benaprès Javier Santos Vicente María Vicario Pérez Carmen Alonso Cotoner

Staff Gloria Santaliestra Vivaracho Sara Méndez Soriano Sandra Estrella Cano Elizabeth Barba Orozco

Outputs CIBERehd

Nº of Publications 1st quartile: 4 Nº of Publications 2nd quartile: 1 IF total: 39.134 Nº of competitive projects: 5 Public funding: €132,876 Private funding: €338,408

FIRST QUARTILE PUBLICATIONS

• • • • •

Inflammatory mediators in the irritable bowel syndrome. Ev aluation of intestinal motility by endoluminal image analysis. Abdominal distension: morfo-volumetric analysis. Abdominal accommodation: adaptation of abdominal muscle. activity to intraabdominal content. Digestive, cognitive and emotive effects of meals.

300 100

30,824

22,852

36,406

5 0

Main Research Topics

10 5

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Collaborations with other CIBERehd groups Francisco Guarner

Hospital Vall d’Hebron

Pere Clavé

Hospital de Mataró

Julio Ponce

Hospital La Fé, Valencia

Scientific Activities of the Programs - 167

Relevant projects 1. “Neurofisiología y neurofisiopatología digestiva”. SAF200907416. Ministerio de Ciencia e Innovación. PI: Fernando Azpiroz. Team Members: J.R. Malagelada, A.Accarino, M. Abu-Suboh, J.Dot, A.Benages, A.Garcia Puges, C.Castellarnau, C.Malagelada, E.Burri, S.Quiroga, E.Arcos, C.Hernández, A. Villoria, R.Boyé. 2010-2012. €12,035 2. “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”. FIS PI08/0940. Instituto de Salud Carlos III. PI: Javier Santos. Team Members: C Martínez, A Álvarez 2009-2011. €82,460 3. “Unitat de Recerca del Sistema Digestiu”. 2009SGR 219. AGAUR. PI: Fernando Azpiroz. Team Members: F.Guarner,

L.Guarner, C.Malagelada, A.Accarino, X.Molero, F.Casellas. 2010-2013. €10,400 4. “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)”. Centro para el Desarrollo Técnico Industria (CDT ), Ministerio de Economía y Competitividad. PI: Fernando Azpiroz. 20102013. €60,000 5. “Chronic idiopathic abdominal pain: pathophysiological mechanisms”. MARATV3_07210. Fundació La Marató de TV3. PI: Fernando Azpiroz. Team Members: A Accarino, J-R Malagelada, J Serra, A Villoria, C Malagelada, F Pérez. 20082011. €52,475

Thesis 1. Title: “Acomodación abdominal: fisiopatología de la distensión abdominal”. Doctorate Student: Albert Villoria Ferrer. Director: Fernando Azpiroz. Qualification: Sobresaliente “Cum Laude” . Date of lecture: 03/05/2011.

2. Title: “Mecanismos moleculares y papel del mastocito en la inflamación de la mucosa intestinal asociada al síndrome del intestino irritable”. Doctorate Student: Cristina Martínez. Director: Javier Santos y María Vicario. Qualification: Sobresaliente “Cum Laude” . Date of lecture: 26/07/2011.

Patents 1. Title: “Device, system and methods for measurement and analysis of contractile activity”. Inventors: Vilariño F, Spyridonos P, Radeva P, Vitriá J, Azpiroz F, Malagelada J-R. Number: PCT/IL07/00709. 2. Title: “Cascade analysis for intestinal contraction detection”. Inventors: Radeva P, Vitriá J, Vilariño F, Spyridonos P, Azpiroz F, Malagelada J-R, De Iorio F, Accarino A. Number: PCT/IL07/00323.

3. Title: “Method for automatic classification of in vivo images”. Inventors: Igual-Muñoz L, Vitriá J, Vilariño F, Segui-Mesquida S, Malagelada C, Azpiroz F, Radeva P. Number:12/543,977. 4. Title: “Device, system and method for automatic detection of contractile activity in an image frame”. Inventors: Spyridonos P, Vilariño F, Vitriá J, Radeva P, Azpiroz F, Malagelada J-R. Number: PCT/IL07/00322.

168 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Eduard Cabré Gelada Hospital Germans Trias i Pujol, Badalona

Team leader Eduard Cabré Gelada

Team members Eugeni Domènech Morral Jordi Serra Pueyo Vicente Lorenzo-Zúñiga García Ester Fernández Gimeno Elisabet Pedrosa tapias Yamile Zabana Abdo Joan Burgueño Banus Lourdes Fluvià Camps Miriam Mañosa Círia

Staff Josep Mañé Almero Violeta Lorén Moreno Aïda Raventós Massana

Outputs CIBERehd

Nº of Publications 1st quartile: 5 Nº of Publications 2nd quartile: 6 IF total: 35.526 Nº of competitive projects: 10 Public funding: €242,964 Private funding: €56,400 Multicentric clinical trials: 13

Main Research Topics • • •

Pathophysiological bases of inflammatory bowel disease, its complications and new treatment approaches. Functional genetics in inflammatory bowel disease. Biomarkers and predictive models of therapeutic response

Collaborations with other CIBERehd groups 50

FIRST QUARTILE PUBLICATIONS

10 5 0

300 100

13,172

31,942

19,478

10 6

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Ramón Planas

Instituto de Investigación Germans Trias i Pujol, Badalona

Antonio Zarzuelo

Universidad de Granada, Granada

Daniel Closa

Consejo Superior de Investigaciones Científicas (CSIC), Barcelona

Fernando Azpiroz

Institut de Recerca de l’Hospital Universitari Vall d’Hebron, Barcelona

Xavier Calvet

Corporación Sanitaria Parc Taulí, Sabadell

Julià Panés

Hospital Clínic i Provincial de Barcelona, Barcelona

Javier Pérez Gisbert

Hospital de la Princesa, Madrid

María Esteve

Hospital Universitari Mutua de Terrassa

Francisco Guarner

Hospital Universitari Vall d’Hebron

Carlos Guarner

Hospital Sant Pau

Pere Clavé i Civit

Consorci Sanitari de Mataró

Scientific Activities of the Programs - 169

Relevant projects 1. “Perfil genético funcional en la enfermedad de Crohn. Efecto sobre el desarrollo de recurrencia post-quirúrgica” . PS09/01294. FIS-Instituto de Salut Carlos III. PI: Dr. Eduard Cabré. Team Members: Yamile Zabana, Miriam Mañosa, Josep Mañé, Violeta Lorén. 2010-2012. €12,705 (2011) 2. “Perfil genètic funcional en la malaltia de crohn” Efecte sobre el desenvolupament de recurrència post-quirurgica”. TEM-2009-00046. Agència de Gestió d’Ajuts Universitaris i de la Recerca-Generalitat de Catalunya. PI: Dr. Josep Mañé. Team Member: Violeta Lorén. 2010-2012. €10,450 3. “Unitat de recerca en patologia degestiva”. 2009 SGR 738. Agència de Gestió d’Ajuts Universitaris i de la Recerca-Generalitat de Catalunya. PI: Dr. Ramón Planas. Team Members: Eduard Cabré; Eugeni Domènech, Miriam mañosa, Yamile Zabana, Violeta Lorén, Elisabet Pedrosa, Josep Mañé. 2009-2013. €4,500

Ulcerosa. PI: Miriam Mañosa. Team Member: Dr. Eugeni Domènech. 2009-2011. €3,000 6. “Estudio del impacto de la enfermedad inflamatoria intestinal sobre la vida sexual”. Beca Abbott:”A Obrador” 2008. Grupo Español de Trabajo sobre la Enfermedad de Crohn y la Colitis Ulcerosa. PI: Laura Martín. Team Member: Dr. Eugeni Domènech. 2009-2011. €3,000 7. “Desarrollo de apósitos de colon para prevenir las complicaciones de las escaras tras terapéutica endoscópica”. PI10/00132. FIS-Instituto de Salut Carlos III. PI: Vicente LorenzoZúñiga. Team Members: R. Bartolí, J. Boix . 2011-2013. € 110,715 8. “Efecto de los cambios físico/químicos en el contenido intestinal sobre la sensibilidad visceral y los síntomas abdominales en los trastornos funcionales digestivo”. PI10/02135. FIS-Instituto de Salut Carlos III. PI: Jordi Serra. 2011-2013. € 54,248

4. “Perfiles genéticos de miARN en plasma de pacientes con enfermedad inflamatoria intestinal”. Beca AEG-GETECCUABBOTT 2010. Asociación Española de Gastroenterología. PI: Dra Elisabet Pedrosa. Team Member: Dr. Eugeni Domènech. 2010-2011. €15,000

9. “Reparación epitelial a través de los ejes TLR2/NFkB e IL10/ STAT3 en la enfermedad inflamatoria intestinal”. Fundación AEG 2011. Asociación Española de Gastroenterología. PI: J. Mañé. Team Member: V. Lorén. 2011-2013. € 7,500

5. “Utilidad de la determinación de calprotectina fecal en la detección de recurrencia endoscópica postquirúrgica en la enfermedad de Crohn”. Beca Otsuka 2008. Grupo Español de Trabajo sobre la Enfermedad de Crohn y la Colitis

10. “Biobanco IMIDs diferencial permite identificar biomarcadores y nuevas terapias”. IPT-010000-2010-36. Ministerio de Ciencia e Innovacion (Subprograma INNPACTO). PI: Sara Marsal. Team Member: Eugeni Domènech. 2010-2013

Thesis 1. Title: “Ensayo clínico, aleatorizado, multicéntrico y controlado con placebo sobre la eficacia de asociar metronidazol a azatioprina en la prevención de la recurrencia postquirúrgica en la enfermedad de Crohn”. Doctorate Student: Miriam Mañosa . Directors: E. Cabrè, E. Domènech. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 15/07/2011.

170 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Xavier Calvet Calvo Corporació Sanitària Parc Taulí, Sabadell

Team leader Xavier Calvet Calvo

Team members Rafael Campo Fernández de los Ríos Félix Junquera Florez Emili Gené Tous Jordi Puig Domingo Mercè Vergara Gómez Jaume Almirall Daly Antonia Montserrat Torres Jordi Sánchez Delgado Joan Falcó Fages Nieves García Monforte Blai Dalmau Obrador Enric Brullet Benedi Thais López Alba Montserrat Gil Prades Albert Villoria Ferrer

Main Research Topics

Staff Sergio Lario García María José Ramírez Lázaro Ariadna Figuerola Ferrrer

• Helicobacter pylori and associated diseases. • Non-variceal upper gastrointestinal bleeding. • Social and laboral aspects of inflammatory bowel disease.

Outputs CIBERehd

Nº of Publications 1st quartile: 14 Nº of Publications 2nd quartile: 1 IF total: 94.735 Nº of competitive projects: 11 Public funding: €19,458 Private funding: €59,144 Multicentric clinical trials: 11

FIRST QUARTILE PUBLICATIONS

57,993 33,941

100 10

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Julià Panés

Hospital Clínic, Barcelona

Javier Pérez Gisbert

Hospital de la Princesa, Madrid

Luis Bujanda

Hospital de Donostia, Vizcaya

Ángel Lanas

Instituto Aragonés de Ciencias de la Salud, Zaragoza

Julio Ponce

Hospital La Fe, Valencia

Francisco Guarner

Hospital Vall d’Hebrón, Barcelona

300

37,345

Collaborations with other CIBERehd groups

1st decile publications Malfertheiner P, Bazzoli F, Delchier JC, Celiñski K, Giguère M, Rivière M, Mégraud F; Pylera Study Group. “Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based

triple therapy: a randomised, open-label, non-inferiority, phase 3 trial”. Lancet. 2011 Mar 12;377(9769):905-13. Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, Flavià M, Jacas C, Mínguez B, Vergara M, Soriano G, Vila

Scientific Activities of the Programs - 171

C, Esteban R, Córdoba J. “Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study”. Am J Gastroenterol. 2011 Jun;106(6):1081-8. Sánchez-Delgado J, Gené E, Suárez D, García-Iglesias P, Brullet E, Gallach M, Feu F, Gisbert JP, Calvet X. “Has H. pylori prevalence in bleeding peptic ulcer been underestimated? A

meta-regression”. Am J Gastroenterol. 2011 Mar;106(3):398-405. Wallon C, Persborn M, Jönsson M, Wang A, Phan V, Lampinen M, Vicario M, Santos J, Sherman PM, Carlson M, Ericson AC, McKay DM, Söderholm JD. “Eosinophils express muscarinic receptors and corticotropin-releasing factor to disrupt the mucosal barrier in ulcerative colitis”. Gastroenterology. 2011 May;140(5):1597-607.

Relevant projects 1. “Identificación de factores genéticos, ambientales y de expresión fenotípica asociados a la progresión de lesiones precursoras del cáncer gástrico: estudio coordinado español de seguimiento”. PI10/01203. Instituto salud Carlos III. Ministerio de Ciencia e Innovación. PI: Xavier Calvet. Team Members: María José Ramírez-Lázaro, Sergio Lario. 2010-2013 2. “Evaluación del riesgo de hemorragia digestiva alta y baja y de los factores de riesgo asociados al tratamiento con anti-inflamatorios no esteroideos o agentes antigregantes plaquetarios”. 2009/536. Instituto salud Carlos III. Ministerio de Ciencia e Innovación. PI: Ángel Lanas. Team Members: Xavier Calvet, Julio Ponce, Mª Angeles Perez Aisa,Teresa Martínez Gimenez Enrique Perez- Cuadrado, Luis Bujanda,Santiago García, Javier Perez Gisbert. 2009-2012 3. “Detección de H. pylori mediante RT-PCR e inmunohistoquímica en el paciente con linfoma MALT gástrico H. pylori negativo por métodos convencionales”. 2007/508. Beca Taulí de Recerca de la CSUPT. PI: Xavier Calvet. Team Members: Dr. Javier P Gisbert, Dr. Julio Ponce, Miguel Montoro, Manuel Rodríguez Téllez, Ángel Lanas, Pedro Alonso, Luis Rodrigo Sáez, Eduardo Bajador, Antonio Hervás, Francisco Polo, Enrique Quintero, Faust Feu, Luis Bujanda, Felipe Bory, Enrique Medina, Montse Forné, Ángeles Pérez Aisa, José Luis Márquez, Mercé Barenys. 2007-2012 4. “Desenvolupament i validació d’un score predictiu de recidiva després del tractament endoscòpic en l’hemorràgia digestiva alta secundària a úlcera péptica gastroduodenal”. Estudi Multicèntric. Societat Catalana de Digestologia. PI: Pilar García Iglesias. 2010-2013. €2,400 5. “Detection of Helicobacter pylori in stool specimens by ELISA and by PCR with simultaneous determination of clarithromycin resistance”. Bioanalytica AG, Luzern, Switzerland. PI: Martin Altwegg. Team Members: Konrad Egli Sergio Lario, Xavier Calvet. 2010-2011 6. “Evaluación de los RNA no codificantes circulantes como marcadores de infección por H.pylori”. 2010/057. Beca Taulí de Recerca de la CSUPT. PI: Xavier Calvet. Team Members: Sergio Lario, MªJosé Ramírez-Lázaro, Ignacio Puig Del Castillo, Pilar García Iglesias, Antònia Montserrat, Rafael Campo, Enric

Brullet, Félix Junquera, Alicia Sánchez-Rubio, Ruth Orellana, Alex Casalots, Ferrán Segura. 2010-2012 7. “Estudio de autoanticuerpos anti-células epiteliales basales en pacientes con hepatocarcinoma”. 2009/569. Beca Taulí de Recerca de la CSUPT. PI: Juan Francisco Delgado de la Poza. Team Members: M. José Amengual Guedan, Jordi Sánchez Delgado, Mercè Vergara Gómez, Blai Dalmau Obrador, Meritxell Casas Rodrigo, Mireia Miquel Planas, Montse Gil Prades. 20102012. €8,000 8. “Evaluación de la consulta de enfermería en el control de pacientes con enfermedad inflamatoria intestinal en tratamiento con inmunosupresores tiopurínicos”. PI10/02650. Instituto Salud Carlos III. Ministerio de Ciencia e Innovación. PI: Angelina Dosal. Team Members: María Jesús López Laura Moreno, Albert Villoria, Marta Pujol. 2010-2013. €4,719 9. “Caracterización de las células epiteliales en la progresión a cáncer gástrico, inducido por H. pylori, a través de un analizador celular a tiempo real”. CIR 2010058. Comitè Institucional de Recerca i Innovació. Hospital de Sabadell. PI: Ramírez Lázaro María José. Team Members: Xavier Calvet, Sergio Lario, Marta Gallach, Alicia Sánchez Rubio, Jordi Sánchez, Enric Brullet, Félix Junquera, Rafael Campo, Alex Casalots. 2011-2012. €2,000 10. “Estudio del papel de los factores angiogénicos en la aparición de gastripatía por hipertensión portal en pacientes cirróticos”. CIR2010018. Comitè Institucional de Recerca i Innovació. Hospital de Sabadell. PI: Casas Rodrigo Meritxell. Team Members: Xavier Calvet Calvo, Félix Junquera Flórez, Alicia Sánchez Rubio, Rafel Campo Fernández de los Ríos, Sergio Lario García, M. Rosa Bella Cueto i M. José Ramírez Lázaro. 20112012. €7,028 11. “Creación de una consulta específica de enfermería y elaboración de un protocolo para el control de la anemia ferropénica en las enfermedades digestivas”. CIR2010060. Comitè Institucional de Recerca i Innovació. Hospital de Sabadell. PI: Maria López Parra. Team Members: Albert Villoria Ferrer, Mireia Miquel Planas, Angelina Dosal Galguera, Xavier Calvet Calvo, Laura Moreno Salas i Núria Mañé Buixó. 20112012. €3,200

172 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Pere Clavé Civit Hospital de Mataró, Barcelona

Team leader Pere Clavé Civit

Team members Mateu Serra Prat Marcel Jiménez Farrerons Patrocinio Vergara Esteras Ricard Farré i Martí María Teresa Martín Ibañez Vicente Martínez Perea

Staff Diana Gallego Pérez Laia Rofes Salsench Claudia Arenas Bailon Irene López Costa

Outputs CIBERehd

Nº of Publications 1st quartile: 7 Nº of Publications 2nd quartile: 6 IF total: 55.871 Nº of competitive projects: 14 Public & private funding: €357,765 Multicentric clinical trials: 7

Main Research Topics

FIRST QUARTILE PUBLICATIONS

100 22,851

35,975

37,147

5 0

300

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

• • • • • • • • • •

Oropharyngeal and gastroesophageal motility. Oropharyngeal dysphagia and ageing. Neurogenic dysphagia. Gastrointestinal peptides, control of appetite and ageing. Myenteric mechanisms controlling oesophageal motility. Intestinal, colonic and anorectal motility. Neurotransmitters in the colon, small bowel and internal anal sphincter. Purines. Pacemaker function. Interstitial Cells of Cajal. NO. H2S. TRPV1. Mast cell differentiation and intestinal nerve function: Role of NGF and its implica tion in the Irritable Bowel Syndrome (IBS) and postoperative ileus. Pathophysiology of intestinal dismotility in IBS and IBD. Pathophysiology and treatment with new pharmacological strategies of dismotility in IBS, diverticular disease, anal fissure.

Collaborations with other CIBERehd groups

Fernando Azpiroz

Hospital Vall d’Hebron, Barcelona

Antonio Zarzuelo

Universidad de Granada

Eduard Cabré

Hospital Germans Trias i Pujol

Scientific Activities of the Programs - 173

1st decile publications Everaerts W, Gees M, Alpizar YA, Farre R, Leten C, Apetrei A, Dewachter I, van Leuven F, Vennekens R, De Ridder D, Nilius B, Voets T, Talavera K. “The capsaicin receptor TRPV1 is a crucial mediator of the noxious effects of mustard oil”. Curr Biol. 2011 Feb 22;21(4):316-21. IF 10.026

Farré R, Blondeau K, Clement D, Vicario M, Cardozo L, Vieth M, Mertens V, Pauwels A, Silny J, Jimenez M, Tack J, Sifrim D. “Evaluation of oesophageal mucosa integrity by the intraluminal impedance technique”. Gut. 2011 Jul;60(7):885-92. IF 10.614 COLLABORATION Azpiroz

Relevant projects 1. “Papel del sulfhídrico (H2S) como neuromodulador de la motilidad intestinal. Interacciones con la vía nitrérgica y purinérgica”. BFU2009-11118 (subprograma BFI). Dirección General de Investigación. PI: M Jiménez (UAB). Team Members: D. Gallego (CIBERehd). 2010-2012. €25,000 2. “Evaluación de los agonistas naturales del receptor TRPV1 en el tratamiento de la disfagia orofaríngea asociada a enfermedades neurológicas y al envejecimiento”. (IS Carlos III). FIS PS09/01012. PI: P. Clavé (CSdM). Team Members: L. Rofes (CIBERehd). 2010-2012. €18,452 3. “Estudio de la fisiopatología de la anorexia del anciano: relación entre anorexia, vaciamiento gástrico y vesicular y señales neuroendocrinas periféricas”. PI080478. IS Carlos III. PI: M. SerraPrat (CSdM). Team Members: P. Clavé (CSdM). 2009-2011. €6,776 4. “Diferenciación mastocitaria y regulación nerviosa intestinal: Función del NGF e implicaciones en el síndrome del intestino irritable y el ileo postoperatorio”. BFU2010-15401. Dirección General de Investigación. PI: P. Vergara (UAB). Team Members: E. Bombuy (CSdM). 2010-2013. €33,333 5. “Estudi de la Fsiopatologia del Ili postoperatori”. Acadèmia de Ciencies Mediques i de la Salut de Catalunya i Balears. PI: P. Clavé (CSdM). Team Members: E. Bombuy (CSdM). 2010-2011. €6,000 6. “Grup de Recerca per a l’estudi de la motilitat digestiva i la seva alteració en les malalties cròniques”. 2009SGR 708. Generalitat de Catalunya. Direcció General de Recerca. PI: Vergara P (UAB). Team Members: Clavé P, Jiménez M, Martín M, Martíne V, Rofes L, Gallego D, Farré R, et al. 2009-2013. €11,700

8. “Influencia de la microbiota intestinal en los mecanismos nociceptivos viscerales y la función barrera intestinal”. BFU200908229. Ministerio de Ciencia e Innovación. Secretaria de Estado de Investigación. PI: Martínez V (UAB). 2009-2011. €31,460 9. “I3SNS Intensificación Actividad Investigadora”. INT10/228. IS Carlos III. PI: P. Clavé (CSdM). 2011. €30,000 10. “Evaluación del impacto clínico y económico de una intervención orientada a disminuir la medicación potencialmente inapropiada en sujetos mayores de 70 años polimedicados”. EC11-313. Ministerio de Sanidad, Servicios Sociales e Igualdad . PI: Mateu Serra-Prat. 2011. €77,112 11. “Support for incorporating RD Teams in international cooperation in the area of image and audio signal (Signal Prcessing Laboratory)”. CZ 1.07/2.3.00/20.0094. European Union and Czech Ministry of Education, Youth and Sport. Jan Karasek. Department of Telecomunications, Brno. PI: Clavé P. 2011-2014. €22,000 12. “Evaluación de la seguridad y eficacia de la electroestimulación transcutánea en la respuesta motora orofaríngea de los pacientes con disfagia orofarígena secundaria a ictus”. ACMCB2011. ACMCB. PI: Clavé P. Team Members: Rofes L. 2011-2012. €6,000 13. “Efecte de l’estimulació sensorial aferent de la orofaringe en la resposta a la deglució i en l’activació cortical en pacients amb ictus i disfàgia orofaríngia”. LaMarató-11. Fundació La Marató TV3. PI: Clavé P. Team Members: Rofes L. 2011-14. €66,182

7. “Programa de autoevaluación para laboratorios de diagnóstico sanitario en animales de experimentación”. ACI2008-0829. Ministerio de Ciencia e Innovación. Secretaria de Estado de Investigación. PI: Vergara P (UAB). 2010-2013. €16,250

14. “Estudio clínico randomizado controlado para evaluar la eficacia del aumento de estímulo sensorial oral como estrategia terapeútica para el tratamiento de pacientes ancianos con disfagia”. FAGMUTUA-12. Fundació Agrupació Mutua. PI: Clavé P. Team Members: Rofes L. 2011-12. €7,500

Thesis

Patents

1. Title: “Estudio de la fisiología del esfínter anal interno porcino y de la rata, y de la fisiopatología de las alteraciones de la motilitdad en pacientes con fisura anal”. Doctorate Student: Álvaro Opazo Valdés. Director: Pere Clavé. Qualification: Sobresaliente “Cum Laude”. Date of lecture: July 2011.

1. Title: “System and procedure for the analysis of the swallowing process in humans.” PCT/EP2005/04252 (Europe)/ PCT/EP2005/04252 (USA). Authors: Blanco A, Clavé P. Image Physiology, SL. Operation: S. 2. Title: “Sistema y procedimiento para el análisis del proceso de deglución en humanos”. (Spain). Number: 200401179. Authors: Blanco A, Clavé P. Image - Physiology, SL. Operation: S.

174 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. daniel closa autet Consejo Superior de Investigaciones Científicas, Barcelona

Team leader Daniel Closa Autet

Team members Emma Folch Puy Oriol Bulbena Moreu Emilio Gelpí Monteys Sabrina Gea Sorlí

Staff Neus Franco Pons

Outputs CIBERehd

Nº of Publications 1st quartile: 1 IF total: 7.274 Nº of competitive projects: 2 Public funding: €26,700 Private funding: €9,000

1st decile publications

Relevant projects

Gea-Sorlí S, Guillamat R, Serrano-Mollar A, Closa D. “Activation of lung macrophage subpopulations in experimental acute pancreatitis”. J Pathol. 2011 Feb;223(3):41724. IF 7.274

1. “Trasplante de macrófagos reprogramados ex vivo como terapia para la pancreatitis aguda experimental. SAF2006-08449. Ministerio Educacion y Ciencia”. PI: Daniel Closa. Team Members: Neus Franco Pons, Sabrina Gea Sorlí. 2010-2012. €26,667 2. “Derivados lipídicos como agentes moduladores de la respuesta hiperinflamatoria sistémica”. 201022002. Fundación Mutua Madrileña. PI: Daniel Closa. Team Members: Neus Franco Pons; Sabrina Gea Sorlí. 2010. €18,900

Main Research Topics 50

FIRST QUARTILE PUBLICATIONS

10 5 0

5,511

6,466

7,274

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

300

• • • •

Acute pancreatitis and the role of macrophages in systemic affection. Role of peripancreatic adipose tissue in the progression of pancreatitis. Involvement of halogenated fatty acids in the pathogenesis of inflammatory diseases. Pancreatic cancer: role of Pancreatitis associated protein.

100

Collaborations with other CIBERehd groups

Antonio Zarzuelo

Universidad Granada

Xavier Calvet

Corporació Sanitaria parc Taulí

Eduard Cabré

Hospital Germans Trias i Pujol

Francisco Guarner

Hospital Vall d’Hebron

Julià Panés

Hospital Clínic Barcelona

176 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Juan Vicente Esplugues Mota Universidad de Valencia

Team leader Juan Vicente Esplugues Mota

Team members Mª Dolores Barrachina Sancho Sara Calatayud Romero Ángeles Álvarez Ribelles Mª Ángeles Martínez Cuesta Miguel Martí Cabrera Víctor Manuel Víctor González Milagros Rocha Barajas Nadezda Apostolova Atanasovska

Staff Mª Dolores Ortiz Masià Brian Normanly

Main Research Topics

Outputs CIBERehd

Nº of Publications 1st quartile: 20 Nº of Publications 2nd quartile: 2 IF total: 117,993 Nº of competitive projects: 9 Public funding: €282,386 Private funding: €60,000

FIRST QUARTILE PUBLICATIONS

• • • •

Inflammation: Role of hypoxia and HIF-1 in the inflammation produced by non-steroid anti-inflam matory drugs (NSAID) and in inflammatory bowel disease. Regulation of the inflammatory process by gastrointestinal hormones. Mechanisms of toxicity and inflammation produced by ARVs.

• Nitric Oxide: • NO and oxygen consumption: physiological and pathophysiological implications.

300

112,694

100

52,619 28,343

5 0

10 5

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Collaborations with other CIBERehd groups Ángel Lanas

Instituto Aragonés de Ciencias de la Salud, Zaragoza

Julio Ponce

Hospital La Fe, Valencia

Xavier Calvet

Corporació Sanitària Parc Taulí, Sabadell

Manuel de la Mata

Hospital Universitario Reina Sofía, Córdoba

Scientific Activities of the Programs - 177

1st decile publications Blas-Garcia A, Apostolova N, Esplugues JV. “Oxidative stress and mitochondrial impairment after treatment with anti-HIV drugs: clinical implications”. Curr Pharm Des. 2011 Dec 1;17(36):4076-86. IF 4.774 Rocha M, Banuls C, Bellod L, Jover A, Victor VM, Hernandez-Mijares A. “A review on the role of phytosterols: new insights into cardiovascular risk”. Curr Pharm Des. 2011 Dec 1;17(36):406175. IF 4.774 Apostolova N, Blas-Garcia A, Esplugues JV. Mitochondria sentencing about cellular life and death: a matter of oxidative stress. Curr Pharm Des. 2011 Dec 1;17(36):404760. IF 4.774 Victor VM, Rocha M, Herance R, Hernandez-Mijares A. “Oxidative stress and mitochondrial dysfunction in type 2 diabetes”. Curr Pharm Des. 2011 Dec 1;17(36):3947-58. IF 4.774 Victor VM. “Editorial: new developments in therapy for oxidative stress-related diseases: pathophysiological and clinical consequences”. Curr Pharm Des. 2011 Dec 1;17(36):3945-6. IF 4.774 Apostolova N, Blas-García A, Esplugues JV. “Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition”. Trends Pharmacol Sci. 2011 Dec;32(12):71525. IF 11.050

Apostolova N, Blas-García A, Esplugues JV. “Mitochondrial toxicity in HAART: an overview of in vitro evidence.” Curr Pharm Des. 2011;17(20):2130-44. IF 4,774 Victor VM, Rocha M, Bañuls C, Bellod L, Hernandez-Mijares A. “Mitochondrial dysfunction and targeted drugs: a focus on diabetes”. Curr Pharm Des. 2011;17(20):19862001. IF 4.774 Apostolova N. “Mitochondria as a pharmacological target: a clue for efficacy and a reason for toxicity” Curr Pharm Des. 2011;17(20):1984-5. PubMed PMID: 21718243. IF 4.774 Rojas S, Gispert JD, Martín R, Abad S, Menchón C, Pareto D, Víctor VM, Alvaro M, García H, Herance JR. “Biodistribution of amino-functionalized diamond nanoparticles. In vivo studies based on 18F radionuclide emission”. ACS Nano. 2011 Jul 26;5(7):5552-9. IF 9.855 Apostolova N, Gomez-Sucerquia LJ, Gortat A, Blas-Garcia A, Esplugues JV. “Compromising mitochondrial function with the antiretroviral drug efavirenz induces cell survival-promoting autophagy”. Hepatology. 2011 Sep 2;54(3):1009-19. IF 10.885 Blas-Garcia A, Esplugues JV, Apostolova N.” Twenty years of HIV-1 non-nucleoside reverse transcriptase inhibitors: time to reevaluate their toxicity”. Curr Med Chem. 2011;18(14):2186-95. IF 4.630

Relevant projects 1. “Farmacología experimental del tracto digestivo”. PROMETEO/2010/060. Conselleria d'Educació, Generalitat Valenciana. PI: Juan V. Esplugues Mota. Team Members: Mª Dolores Barrachina, Sara Calatayud, Ángeles Álvarez, Víctor Manuel Víctor, Nadezda Apostolova, Jose Mª Vila, Martín Aldasoro. €51,800

4. “Estudio de los mecanismos celulares y vasculares que median la toxicidad vascular inducida por la terapia antirretroviral”. SAF2010-16030. Ministerio de Ciencia e Innovación. PI: Ángeles Álvarez Ribelles. Team Members: Carmen de Pablo, Samuel Orden, Mª Ángeles Martínez-Cuesta, José Esteban Peris, Amando Blanquer, Jorge Carmena. €36,300

2. “Toxicidad mitocondrial por fármacos antirretrovirales: caracterizacióndeunnuevomecanismoagudodeacción”.PI081325. FIS, Instituto de Salud Carlos III. PI: Juan V. Esplugues Mota. Team Members: Daniel Ballesteros, Ana Blas, Sara Calatayud, Nadezda Apostolova, Miriam Valezquez, Miguel Marti, Brian Normanly, Mª Dolores Ortiz. €50,215

5. “Factores de riesgo cardiovascular en pacientes con diabetes mellitas tipo 2 y relación con la disfunción eréctil”. AP192/11. Conselleria de Sanitat, Generalitat Valenciana. PI: Víctor M Víctor González. Team Members: Antonio Hernandez-Mijares, Milagros Rocha, Eva Sola, Juan Vicente Esplugues, Celia Bañuls, Lorena Bellod, Nadezda Apostolova, Carlos Morillas, Ana Jover, Ana Blas. €6,000

3. “Relevancia fisiopatalógica de la expresión génica inducida por HIFen la enfermedad inflamatoria intestinal”. SAF201020231. Ministerio de Ciencia e Innovación. PI: Mª Dolores Barrachina Sancho. Team Members: Joaquín Hinojosa, Carlos Hernández, Leysa Jackeline Gómez, Elsa Quintana, Irene Díez, Annia Riaño, Mª Angeles Martínez-Cuesta. €44,366

6. “Disfunción mitocondrial y diabetes tipo 2: Implicaciones patofisiológicas y clínicas”. PI10/01195. Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad. PI: Víctor M Víctor González. Team Members: Milagros Rocha, Carlos Morillas, Ana Jover, Lorena Bellod, Susana Rovira. €24,805

178 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Juan Vicente Esplugues Mota Relevant projects 7. “Contratos de investigadores en el SNS Miguel Servet: Papel de la disfunción mitocondrial en las complicaciones macrovasculares de los diabéticos tipo 2: Efecto de la mitoquinona, un antioxidante mitocondrial”. CP10/00360. Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Economia y Competitividad. PI: Milagros Rocha Barajas. €40,000

8. “Contrato Vali +d”. APOSTD/2011/049. Conselleria d'Educació, Generalitat Valenciana. PI: Nadezda Apostolova Atanasovska. €26.970 (6 meses: 01/06 - 31/12/2011) 9. “Contrato Sara Borrell”. CD11/00192. Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Ministerio de Economíua y Competitividad. PI: Nadezda Apostolova Atanasovska. €25,200

Thesis 1. Title: “Influencia de la gastrina sobre la respuesta inflamatoria e inmune”. Doctorate Student: Wilfredo Romero Alvarado. Director : Juan V. Esplugues, Sara Calatayud. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 13/05/2011. 2. Title: “Relevancia fisiopatológica de HIF-1 en la inflamación gastrointestinal inducida por AINE”. Doctorate Student: Irene Díez Sancho. Directors: Mª Dolores Barrachina, Sara Calatayud.

Qualification: Sobresaliente "”Cum Laude”" Date of lecture: 13/07/2011. 3. Title: “Papel del óxido nítrico sobre la respiración mitocondrial y respuesta de los vasos a hipoxia. Acción vascular de la nitroglicerina”. Doctorate Student: Cristina Nuñez Reyes. Directors: Juan V. Esplugues, Pilar D'Ocon, Victor M. Victor. Qualification: Sobresaliente ”Cum Laude”. Date of lecture: 07/10/2011.

180 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Francisco Guarner AGuilar Hospital Vall d’Hebron, Barcelona

Team leader Francisco Guarner Aguilar

Team members María C. Antolín Maté Jaume Vilaseca Momplet Natalia Borruel Sainz Francesc Casellas Jordá Luisa Guarner Aguilar Chaysavanh Manichanh Xavier Molero Richard

Staff Alicia Murcia Muños Antonio Torrejón Herrera Encarnación Varela Castro

Outputs CIBERehd

Nº of Publications 1st quartile: 6 Nº of Publications 2nd quartile: 2 IF total: 63.416 Nº of competitive projects: 6

Main Research Topics

FIRST QUARTILE PUBLICATIONS

10 5 0

59,553

57,716

8,685

PUBLICATIONS

Inflammatory mechanisms of the intestinal mucosa Intestinal mucosal barrier Microbiota and the mucosal immune system Inflammatory bowel disease and quality of life Chronic Pancreatitis and Pancreatic Cancer

300

Collaborations with other CIBERehd groups

100

Xavier Calvet

Hospital Parc Tauli, Sabadell

Eduard Cabré

H. Germans Trias i Pujol Badalona

Julian Panés

Hospital Clinic, Barcelona

Maria Esteve

Hospital Mutua, Terrasa

Javier Pérez Gisbert

Hospital Princesa, Madrid

Carlos Guarner

Hospital Sant Pau, Barcelona

Fernando Azpiroz

Hospital Vall d’Hebron, Barcelona

2009 2010 2011 IF 1ST QUARTILE

• • • • •

Scientific Activities of the Programs - 181

1st decile publications Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernandez L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J; MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A,

Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van HylckamaVlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M’rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sanchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P. “Enterotypes of the human gut microbiome”. Nature. 2011 May 12;473(7346):174-80. IF 36,101

Relevant projects 1.“La Célula Dendrítica como eje central de respuestas a bacterias”. PS09/00471. FIS. PI: Maria Antolin Mate Team Members: Natalia Borruel, Francesc Casellas, Alicia Murcia. €12,100 2. “Análisis de la microbiota asociada al sindrome del intestino irritable”. PI10/00902. FIS. PI: Chaysavanh Manichanh. Team Members: Francisco Guarner, Encarna Varela, Antonio Torrejón. €122,815 3. “Metagenomics of the Human Intestinal Tract”. HEALTH-F4-2007-201052. Comisión Europea. PI: Francisco Guarner. Team Members: Chaysavan Manichanh, Maria Antolin, Antonio Torrejon, Francesc Casellas, Natalia Borruel. € 44,211

4. “Inflammatory Bowel Disease: an integrated approach for characterizing its molecular multifactorial mechanisms”. PIRSESGA-2010-26932. Comisión Europea. PI: Francisco Guarner. Team Members: Chaysavan Manichanh, Maria Antolin, Antonio Torrejon, Francesc Casellas, Natalia Borruel. €38,115 5. “Desarrollo de un nuevo simbiótico”. CENIT-2010-04. Ministerio Industria (CDTI). PI: Francisco Guarner. Team Members: Chaysavan Manichanh, Maria Antolin, Antonio Torrejon, Francesc Casellas, Natalia Borruel. €71,500

182 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Ángel Lanas Arbeloa Instituto Aragonés de Ciencias de la Salud

Team leader Ángel Lanas Arbeloa

Team members Mark Strunk Groot, Francisco Esteva Díaz Ángel Ferrández Arenas Asunción García González Lidia Gutiérrez González Fco Javier Ortego Fernández De Retana Eduardo Bajador Andreu Ricardo Sainz Samitier Rafael Benito Ruesca María Teresa Arroyo Villarino Federico Sopeña Biarge Fernando Gomollón García Elena Piazuelo Ortega

Staff Pilar Jiménez Molinos Eduardo Chueca Puente Samantha P Arechabaleta Tabuenca Patricia Carrera Lasfuentes

Outputs CIBERehd

Nº of Publications 1st quartile: 11 Nº of Publications 2nd quartile: 4 IF total: 64.023 Nº of competitive projects: 5 Public funding: €140,651 Private funding: €31,109 Multicentric clinical trials: 1

FIRST QUARTILE PUBLICATIONS

300

155,875

54,588

54,973

5 0

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Main Research Topics • • •

Gastrointestinal diseases related to inhibition of acid, cyclooxygenase activity, and infection by H. Pylori. Immunogenetic factors in inflammatory or neoplastic diseases of the gastrointestinal tract. Genetic and environmental factors in populations with different risk of colon cancer.

100

Collaborations with other CIBERehd groups

Xavier Calvet

Corporació Sanitària Parc Taulí, Sabadell

Luis Bujanda

Hospital de Donostia, Vizcaya

Javier Pérez-Gisbert

Hospital de la Princesa, Madrid

Julián Panés

Hospital Clínic, Barcelona

Antoni Castells

Hospital Clínic, Barcelona

Scientific Activities of the Programs - 183

1st decile publications Appelman HD, Umar A, Orlando RC, Sontag SJ, Nandurkar S, El-Zimaity H, Lanas A, Parise P, Lambert R, Shields HM. “Barrett’s esophagus: natural history”. Ann N Y Acad Sci. 2011 Sep;1232:292-308. IF 2.847 Lanas A, Garcia-Tell G, Armada B, Oteo-Alvaro A. “Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis”. BMC Med. 2011 Apr 14; 9:38. IF 5.750

Gutierrez-Gonzalez L, Graham TA, Rodriguez-Justo M, Leedham SJ, Novelli MR, Gay LJ, Ventayol-Garcia T, Green A, Mitchell I, Stoker DL, Preston SL, Bamba S, Yamada E, Kishi Y, Harrison R, Jankowski JA, Wright NA, McDonald SA. “The clonal origins of dysplasia from intestinal metaplasia in the human stomach”. Gastroenterology. 2011 Apr;140(4):1251-1260.e1-6. IF 12.032

Relevant projects 1. “Evaluación del riesgo de hemorragia digestiva alta y baja y de los factores de riesgo asociados al tratamiento con anti-inflamatorios no esteroideos o agentes antigregantes plaquetarios”. PI081301. ISCIII. PI: Ángel Lanas Arbeloa. 2009-2011. €56,870 2. “Valoración de polimorfismos en genes reparadores de ADN como marcadores de susceptibilidad y/o pronóstico del adenocarcinoma gástrico. Interacción con factores ambientales e infección por H. pylori”. PI0900213. ISCIII. PI: Asunción García González. 2010-2012. €62,315 3. “Aspirina a dosis baja asociada a inhibición ácida como estrategia de quimioprevención en esófago de Barrett: estudio

de los mecanismos implicados y marcadores de respuesta”. PI081047. ISCIII. PI: Elena Piazuelo Ortega. 2009-2011. €18,876 4. “Grupo de Excelencia DGA 2010: B-01”. Diputación General de Aragón. Departamento de Ciencia, Tecnología y Universidad. PI: Ángel Lanas Arbeloa. 2011. €24,491 5. “Identificación de factores genéticos, ambientales y de expresión fenotípica asociados a la progresión de lesiones precursoras del cáncer gástrico: estudio coordinado español de seguimiento”. PI10/02934. ISCIII. PI: Ángel Ferrandez Arenas. 2011-2013. €8,954

184 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Julián Panés Díaz Hospital Clínic, Barcelona

Team leader Julián Panés Díaz

Team members Josep M Bordas Faust Feu Josep Llach Josep M Pique Azucena Salas Elena Ricart Miquel Sans Ingrid Ordás Arantza Jáuregui

Staff Daniel Benítez Núria Planell Miriam Esteller Carolina España Anna Ramírez

Outputs CIBERehd

Nº of Publications 1st quartile: 16 Nº of Publications 2nd quartile: 4 IF total: 149.108 Nº of competitive projects: 5 Public funding: €400,269 Private funding: €191,333 Multicentric clinical trials: 11

FIRST QUARTILE PUBLICATIONS

118,289

300 100 10

2009 2010 2011 IF 1ST QUARTILE

Collaborations with other CIBERehd groups Javier Pérez- Gisbert Hospital de la Princesa, Madrid

5 0

• The research pln of the group is oriented to the generation of knowledge that provides a benefit to patients in a foresseable future. • The plan has three estrategic objectives: - Develop new therapies for Crohn’s disease with special interest in stem cell therapies, and tolerogenic dendritic cell therapies. - Gain insights in to the genetic and environmental factors involved in disease initiation and progression to provide a personalized care. - Optimize radiologic and biochemical diagnostic exams to tailor therapies to patient needs.

138,586

67,173

Main Research Topics

PUBLICATIONS

Xavier Calvet

Hospital Parc Taulí Sabadell

María Esteve

Hospital Mútua de Terrassa

Eduard Cabré

Hospital Germans Trias i Pujol, Badalona

Ángel Lanas

Instituto Aragonés de Ciencias de la Salud, Zaragoza

Scientific Activities of the Programs - 185

1st decile publications Ordás I, Feagan BG, Sandborn WJ.“Early use of immunosuppressives or TNF antagonists for the treatment of Crohn’s disease: time for a change”. Gut. 2011 Dec; 60(12):1754-63. IF 10,614 Pellisé M, López-Cerón M, Rodríguez de Miguel C, Jimeno M, Zabalza M, Ricart E, Aceituno M, Fernández-Esparrach G, Ginès A, Sendino O, Cuatrecasas M, Llach J, Panés J. “Narrow-band imaging as an alternative to chromoendoscopy for the detection of dysplasia in long-standing inflammatory bowel disease: a prospective, randomized, crossover study”. Gastrointest Endosc. 2011 Oct; 74(4):840-8. IF 5,647 COLLABORATION Castells Fernández-Esparrach G, Panés J. “Radiofrequency ablation for nondysplastic Barrett’s esophagus: to treat or not to treat?” Gastroenterology. 2011 Jun;140(7):2130-2; discussion 2132. IF 12,032 COLLABORATION Castells Panés J, Benitez-Ribas D, Salas A. “Mesenchymal stem cell therapy of Crohn’s disease: are the far-away hills getting closer?” Gut. 2011 Jun;60(6):742-4. IF 10,614 Vermeire S, Ghosh S, Panes J, Dahlerup JF, Luegering A, Sirotiakova J, Strauch U, Burgess G, Spanton J, Martin SW, Niezychowski W. “The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study.” Gut. 2011 Aug;60(8):1068-75. IF 10,614 Sánchez-Delgado J, Gené E, Suárez D, García-Iglesias P, Brullet E, Gallach M, Feu F, Gisbert JP, Calvet X. “Has H. pylori prevalence in bleeding peptic ulcer been underestimated? A meta-regression”. Am J Gastroenterol. 2011Mar;106(3):398-405. IF 6,882 COLLABORATION Gisbert/ Calvet

Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A, Lagacé C, Scott R, Amininejad L, Bumpstead S, Baidoo L, Baldassano RN, Barclay M, Bayless TM, Brand S, Büning C, Colombel JF, Denson LA, De Vos M, Dubinsky M, Edwards C, Ellinghaus D, Fehrmann RS, Floyd JA, Florin T, Franchimont D, Franke L, Georges M, Glas J, Glazer NL, Guthery SL, Haritunians T, Hayward NK, Hugot JP, Jobin G, Laukens D, Lawrance I, Lémann M, Levine A, Libioulle C, Louis E, McGovern DP, Milla M, Montgomery GW, Morley KI, Mowat C, Ng A, Newman W, Ophoff RA, Papi L, Palmieri O, Peyrin-Biroulet L, Panés J, Phillips A, Prescott NJ, Proctor DD, Roberts R, Russell R, Rutgeerts P, Sanderson J, Sans M, Schumm P, Seibold F, Sharma Y, Simms LA, Seielstad M, Steinhart AH, Targan SR, van den Berg LH, Vatn M, Verspaget H, Walters T, Wijmenga C, Wilson DC, Westra HJ, Xavier RJ, Zhao ZZ, Ponsioen CY, Andersen V, Torkvist L, Gazouli M, Anagnou NP, Karlsen TH, Kupcinskas L, Sventoraityte J, Mansfield JC, Kugathasan S, Silverberg MS, Halfvarson J, Rotter JI, Mathew CG, Griffiths AM, Gearry R, Ahmad T, Brant SR, Chamaillard M, Satsangi J, Cho JH, Schreiber S, Daly MJ, Barrett JC, Parkes M, Annese V, Hakonarson H, Radford-Smith G, Duerr RH, Vermeire S, Weersma RK, Rioux JD. “Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47”. Nat Genet. 2011 Mar;43(3):24652. IF 36,377 Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y; International Inflammatory Bowel Disease Genetics Constortium, Cotsapas C, Daly MJ. “Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology”. PLoS Genet. 2011 Jan 13;7(1):e1001273. IF 9,543

Relevant projects 1. “New mediators of T effector responses and therapeutic potential of administration of tolerogenic dendritic cells in inflammatory bowel disease”. BFU2008-02683/BFI. Ministerio de Innovación y Ciencia. PI: Azucena Salas. Team Members: Elena Ricart, Josep Maria Piqué. 2008-2011. €33,333 2. “Delivering nanopharmaceuticals through BIological Barriers”. PI10/02998. ERANET, Euro Nano Med. PI: Azucena Salas. Team Members: Patrick Boisseau, Patrice Marché, Claus-Michael Lehr, Pascal Van de Veire, Caroline Maake, Damián García-Olmo. 2011-2014. €94,380 3. “Terapia con células dendríticas tolerogénicas en la enfermedad de Crohn refractaria”. SAF2009_07272. Ministerio de Innovación y Ciencia. PI: Julián Panés. Team Members: Elena Ricart, Daniel Benítez, Faust Feu, Josep Llach. 2010-2012. €92,500 4. “Tratamiento de la enfermedad de Crohn refractaria con células dendríticas reguladoras: estudio piloto”. TRA-097.

Ministerio de Sanidad, Política Social e Igualdad. PI: Julián Panés. Team Members: Daniel Benítez, Elena Ricard, Ingrid Ordás. 2010-2011. €155,856 5. “Estudio de los principales determinantes moleculares implicados en la fibrosis intestinal en la enfermedad de Crohn. Evaluación de estrategias de tratamiento anti-fibrogénico”. SAF2010-18434. Ministerio de Ciencia y Tecnología . PI: Miquel Sans. Team Members: Salvadora Delgado, Maica Masamunt. 2011-2012. €24,200

Patents Title: “Production of tolerogenic dendritic cells for treatment of immune mediated inflammatory disorders”. CIBERehd, Hospital Clínic de Barcelona. Inventors: Julián Panés, Elena Ricart, Daniel Benítez. C-26.05.11. 11382174.8 2011-2012.

186 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Javier Pérez Gisbert Hospital Universitario de La Princesa, Madrid

Team leader Javier Pérez Gisbert

Team members Cecilio Santander Francisco Abad Carlos Gamallo José Maté Trinidad Parra Santiago Torrado Luis G. Guijarro María Chaparro Encarna Fernández Amelia Rodríguez Alicia Marín

Main Research Topics • Gastric H. pylori induced proliferation/apoptosis: - Effect of infection status, bacterial strain, patients’ genotype and H. pylori eradication. - Genetic and epidemiological factors in the progression of pre-cancerous lesions.

Staff Pablo Muñoz Linares Adrian McNicholl Almudena Durán

• Angiogenesis and lymphangiogenesis in IBD: - Correlation with the pathological behaviour of the disease. - Effect of the therapy .

Outputs CIBERehd

Nº of Publications 1st quartile: 20 Nº of Publications 2nd quartile: 11 IF total: 124.999 Nº of competitive projects: 12 Public funding: €227,911 Private funding: €92,106 Multicentric clinical trials: 11

50 10

FIRST QUARTILE PUBLICATIONS

96,651 63,408

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Strategies for optimization of anti-TNF treatment in IBD patients: - Candidate genes for the prediction of response. - Correlation between serologic TNFα levels and response. - Mechanism of production of antibodies against anti-TNF drugs. - Serum levels of anti-TNF drugs, and of antibodies against them, and response of anti-TNF therapy. • New therapies: - New antibiotic combinations and formulations (hydrogels) for H. pylori treatment. - Photodynamic therapy for H. pylori. - New therapeutic targets in IBD. - Vaccination in IBD patients.

Collaborations with other CIBERehd groups

100

Xavier Calvet

Corporació Sanitària Parc Taulí, Sabadell

Julio Ponce

Hospital La Fe, Valencia

Luis Bujanda

Hospital de Donostia, Vizcaya

Ángel Lanas

Instituto Aragonés de Ciencias de la Salud, Zaragoza

Ricardo Moreno

Hospital de la Princesa, Madrid

Julián Panés

Hospital Clínic, Barcelona

Eduard Cabré

Hospital Germans Trias i Pujol, Badalona

10 14 15

•

300

44,637

• New diagnostic methods: - Serological, histological, fecal, and genetic studies.

Scientific Activities of the Programs - 187

1st decile publications Nuñez-Andrade N, Lamana A, Sancho D, Gisbert JP, GonzalezAmaro R, Sánchez-Madrid F, Urzainqui A. “P-selectin glycoprotein ligand-1 modulates immune inflammatory responses in the enteric lamina propria”. J Pathol. 2011. Jun;224(2):212-21. IF 7.274 Sánchez-Delgado J, Gené E, Suárez D, García-Iglesias P, Brullet E, Gallach M, Feu F, Gisbert JP, Calvet X. “Has H. pylori prevalence in bleeding peptic ulcer been underestimated? A meta-regression”. Am J Gastroenterol. 2011 Mar;106(3):398-405. IF 6.882 COLLABORATION Panés/ Calvet

Rahier JF, Papay P, Salleron J, Sebastian S, Marzo M, PeyrinBiroulet L, Garcia-Sanchez V, Fries W, van Asseldonk DP, Farkas K, de Boer NK, Sipponen T, Ellul P, Louis E, Peake ST, Kopylov U, Maul J, Makhoul B, Fiorino G, Yazdanpanah Y, Chaparro M; European Crohn’s and Colitis Organisation (ECCO). “H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy”. Gut. 2011 Apr;60(4):456-62. IF 10.614

Relevant projects 1. “Implicación de los factores angiogénicos y linfangiogénicos en la enfermedad inflamatoria intestinal”. PS09/02369. FIS. PI: J P. Gisbert. Team Members: P. Muñoz, A. G. McNicholl, E. Fernández, M. Chaparro. 2010-2012. €27,527

y de los factores de riesgo asociados al tratamiento con antiinflamatorios no esteroideos”. P108/1301. Instituto de Salud Carlos III. PI: A. Lanas. Team Members: C. Santander. 20092011. €51,566

2. “Estudio Fase IV, prospectivo, aleatorizado y comparativo entre la terapia secuencial y concomitante para la erradicación de Helicobacter pylori en la práctica clínica habitual”. TRA-047. Ministerio de Sanidad y Política Social. PI: J P. Gisbert. Team Members: A. Marín, A. G. McNicholl, B. Ruberte, A. Figuerola, P. Gª Iglesias, X. Bessa, C. Álvarez, E. Sainz, B. Belloc, P. Aranguren, R. Milán, E. Lamas. 2010-11. €61,348

8. “Búsqueda de marcadores genéticos predictores de respuesta a fármacos biológicos en el tratamiento de la psoriasis.” PI10/01740. Acción Estratégica en Salud del Subprograma de Proyectos de Investigación en Salud del Instituto de Salud Carlos III. PI: F. Abad Santos. Team Members: T. Cabaleiro Ocampo, M. Román Martínez, D. Ochoa Mazarro, E. Dauden Tello, E. Gallo Gutiérrez, F. Tudelilla Fernández. 2011-2013. €29,403

3. “Errores en el manejo ambulatorio de los pacientes con enfermedad inflamatoria intestinal: estudio ERRATA”. Beca GETECCU-ABBOTT de la. Teoría a la Práctica. PI: J.P. Gisbert. Team Members: M.Chaparro. 2010-2011. €10,000

9. “Metilfenidato de liberación inmediata en la mejoría sintomática de la manía aguda”. EC10-110. Ministerio de Sanidad - ayudas para el fomento de la investigación clínica independiente. PI: J. L. Ayuso Mateos. Team Members: P. López, J. Valle Fernández, F. Abad Santos, D. Ochoa Mazarro. 2011. €26,000

4. “PROYECTO IMID-Inc, Biobanco IMIDs diferencial permite identificar Biomarcadores y nuevas terapias (INNPACTO)”. IPT010000-2010-036. Ministerio de Educación y Ciencia (Proyectos Científico-Tecnológicos Singulares y de Carácter Estratégico). PI: S. Marsal. Team Members: J.P. Gisbert. M. Chaparro, A. Rodríguez. 2010-2013. €818,098 5. “Identificación de factores genéticos, ambientales y de expresión fenotípica asociados a la progresión de lesiones precursoras del cáncer gástrico: estudio coordinado español de seguimiento”. PI10/02654. FIS. PI: C. López Elzaurdia. Team Members: J.P. Gisbert, A Marín, F. Casals, J. Mendoza, M. Adrados 2011-2013. €8,954 6. “Cribado del cáncer colorrectal en población de riesgo intermedio: estudio multicéntrico, en el que se compara la prueba de detección de sangre oculta en heces con método inmunológico y la colonoscopía”. FIS (P108/90717). Instituto de Salud Carlos III. (Evaluación de Tecnologías Sanitarias). PI: E. Quintero. Team Members: C. Santander, M. Chaparro, A. Rodríguez, A. Marín, R. Moreno. 2009-2018. €419,870 7. “Evaluación del riesgo de hemorragia digestiva alta y baja

10. “Papel del EGF en la regeneración de la mucosa del colon durante la colitis ulcerosa. Implicación del IRS-4”. SAF. 200805355. Ministerio de Educación y Ciencia. Plan Nacional de I+D+I . PI: L. González Guijarro. Team Members: J P. Gisbert. 2008-2011. €15,000 11. “Respuesta T reguladora (CD4+CD25+FOXP3) y patogenia de la infección por H. pylori: relación con el estatus oxidativo de la mucosa gástrica”. PI-2008/34. Fundación para la Investigación Sanitaria de Castilla La Mancha (FISCAM) . PI: T. Parra Cid. Team Memebers: S. Benito Martínez, J. R. Larrubia Marfil, M. Maiques Camarero, M.Calvino Fernández, J.P. Gisbert, A. G. McNicholl, F. González Mateos, M. Dolores Sánchez-Tembleque Zaraonda 2009-11. €17,136 12. “Estudio de la cascada de señalización del igf-1 en el colon de ratas que presentan enfermedad inflamatoria intestinal”. CCG10-UAH/BlO-5971. Universidad de Alcalá/ Comunidad de Madrid. PI: I.D. Román Curto. Team Members: D. Fernández Moreno, I. García del Rosal, L.González Guijarro, B. Hernández Breijo, I. Moreno Villena. 2011. €15,000

188 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Javier Pérez Gisbert Thesis

Patents

1. Title: “Hemocromatosis en la provincia de Guadalajara: prevalencia, frecuencia de mutaciones (C282Y, H63D y S65C) del gen HFE, penetrancia, expresión fenotípica, factores moduladores y patologías asociadas”. Doctorate Student: María Maiques Camarero. Director: Trinidad Parra Cid. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 2011.

1. Title: “Uso de una combinación de Azatioprina y L-Butionina[S,R]-Sulfoximina en la preparación de un medicamento útil para el tratamiento de un tumor refractario”. Universidad de Alcalá (95%), Universidad Autónoma de Madrid (5%). Inventors: Luis González Guijarro, Borja Hernández-Breijo, Irene de los Dolores Román Curto, María de los Dolores Fernández Moreno, Javier Pérez Gisbert. S-29/7/11. P201131315.

Scientific Activities of the Programs - 189

190 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6

DR. Antonio Zarzuelo Zurita Universidad de Granada

Team leader Antonio Zarzuelo

Team members Mónica Comalada Vila Jordi Xaus Pei Pilar Utrilla Navarro Mónica Olivares Ángel Concha López Olga Martínez Augustín Fermín Sánchez de Medina López-Huertas Mª Dolores Suárez Ortega

Staff M. Elena Rodríguez Cabezas Raquel González Pérez

Outputs CIBERehd

Nº of Publications 1st quartile: 5 Nº of Publications 2nd quartile: 2 IF total: 29.342 Nº of competitive projects: 8 Public funding: 100,575€ Private funding: 38,877€

Main Research Topics • • •

Novel therapeutic approaches to inflammatory bowel disease, specially via the use of natural products. Pathophysiological alterations in inflammatory bowel disease. - Alkaline phosphatase. - Ionic transport - Barrier function Targeting obesity and metabolic syndrome via nutritional products.

Collaborations with other CIBERehd groups 50

FIRST QUARTILE PUBLICATIONS

100 29,001

38,789

22,237

5 0

300

10 6

2009 2010 2011 IF 1ST QUARTILE

PUBLICATIONS

Javier Salmerón

Hospital Universitario San Cecilio

JJ García Marín

Universidad de Salamanca

M. Pastor Anglada

Universidad de Barcelona

Eduard Cabré

Hospital Germans Trias i Pujol, Badalona

Fernando Azpiroz

Hospital Vall d’Hebron, Barcelona

Daniel Closa

IIBB-CSIC, Barcelona

Xavier Calvet

Corporació Sanitària Parc Taulí, Sabadell

Pere Clavé

Hospital de Mataró, Mataró

Pascual Parrilla

Hospital Virgen de la Arrixaca, Murcia

Scientific Activities of the Programs - 191

1st decile publications Garrido-Mesa N, Utrilla P, Comalada M, Zorrilla P, GarridoMesa J, Zarzuelo A, Rodríguez-Cabezas ME, Gálvez J. “The association of minocycline and the probiotic Escherichia coli Nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice”. Biochem Pharmacol. 2011 Dec 15;82(12):1891-900. IF 4.889

González R, Ballester I, López-Posadas R, Suárez MD, Zarzuelo A, Martínez-Augustin O, Sánchez de Medina F. “Effects of flavonoids and other polyphenols on inflammation”. Crit Rev Food Sci Nutr. 2011 Apr;51(4):331-62. IF 4.510

Relevant projects 1. “Determinación de las acciones directas de los oligosacáridos sobre la mucosa intestinal. Estudio del papel inmunomodulador de nuevos prebióticos en la inflamación intestinal y en la enterocolitis necrotizante”. AGL2008-4332/ALI . MICINN. PI: Olga Martínez Augustin. Team Members: María Dolores Suárez, Patricia Martínez-Moya, Mercedes Ortega, Enrique Martínez, Pilar Requena, Abdelali Daddaoua. 2009-2011. €5,227 2. “Evaluación de las propiedades inmunomoduladoras de antibióticos en el tratamiento de la enfermedad inflamatoria intestinal. Potencial efecto sinérgico con probióticos”. SAF200802616. Ministerio de Educación y Ciencia. PI: Julio Galvez. Team Members: Maria Elena Rodríguez Cabezas, Pilar Utrilla Navarro. 2009-2011. €36,666 3. “Influencia del tipo de grasa en el desarrollo de la enfermedad del hígado graso no alcohólica (EHGNA) en la obesidad mórbida. Estrés oxidativo y disfunción mitocondrial asociados a la secreción de citoquinas”. P08-CTS-4357. Junta de Andalucía. PI: Javier Salmerón. Team Members: Fermín Sánchez de Medina López-Huertas, Olga Martínez Augustin. 2009-2012. €30,000 4. “Caracterización de las alteraciones en el transporte epitelial intestinal en la enfermedad inflamatoria intestinal y modulación por agentes antiinflamatorios experimentales”. SAF2008-01432. MICINN. PI: Fermín Sánchez de Medina López-Huertas. Team Members: Cristina Mascaraque, Rocío López Posadas, Raquel

Thesis 1. Title: “Minocycline in inflammatory bowel disease: far beyond an antibiotic”. Doctorate Student: Natividad Garrido Mesa. Directors: Antonio Zarzuelo Zurita, Julio Juan Gálvez Peralta, Maria Elena Rodríguez Cabezas. Qualification: Sobresaliente “Cum Laude”. Date of lecture: 20/12/2011.

González Pérez, Antonio Zarzuelo. 2009-2011. €4,356 5. “Bases biotecnológicas para el desarrollo de alimentos funcionales en el campo de la maduración intestinal, la enfermedad inflamatoria intestinal y el síndrome de intestino irritable”. Fundación Ramón Areces. PI: Fermín Sánchez de Medina López-Huertas. Team Members: Rocío López Posadas, Raquel González, Mercedes González, Isabel Romero Calvo, María Dolores Suárez, Fermín Sánchez de Medina Contreras. 2010-2012. €38,877 6. “Investigaciones dirigidas a la validación etnofarmacológica de plantas medicinales de la comunidad autónoma andaluza con actividad antiinflamatoria y antitumoral”. AGR-6826. Junta de Andalucía. PI: Julio Juan Gálvez Peralta. Team Members: María Elena Rodríguez Cabezas, Pilar Utrilla Navarro, Antonio Zarzuelo Zurita. 2010-2014. €24,103 7. “Función de la Inmunidad innata en la tolerancia intestinal: Papel de los TLRs y la microbiota”. SAF2012-16755. MICINN. PI: Mònica Comalada Vila. 2011-2013. €35,937 8. “Estudio de la función de los miRNA en la diferenciación del epitelio intestinal in vivo e in vitro. Efectos de los agentes moduladores”. P10.CTS.6736. Junta de Andalucía. PI: Antonio Zarzuelo Zurita. Team Members: Fermín Sánchez de Medina López-Huertas, Olga Martínez Augustin, María Dolores Suárez Ortega, Raquel González Pérez. 2010-2014. €35,039

192 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6 Linked group

DR. María Esteve Comas Hospital Universitari Mútua de Terrassa

Team leader María Esteve Comas

Team members Fernando Fernandez Bañares Montserrat Forne Bardera Josep Mª Viver Pi-Sunyer Antonio Salas Caudevilla Rebeca Santaolalla Sala Meritxell Marine Guillem Carme Loras Alastruey Merce Rosinach Ribera Anna Carrasco Garcia

Outputs CIBERehd

Nº of Publications 1st quartile: 8 Nº of Publications 2nd quartile: 6 IF total: 50.127 Nº of competitive projects: 8 Public funding: €117,036 Private funding: €18,750

Main Research Topics • Inflammatory Bowel Disease • Microscopic Colitis • Celiac Disease

Collaborations with other CIBERehd groups Javier Pérez Gisbert

Hospital de la Princesa

Julián Panés

Hospital Clínic

Eduard Cabré

Hospital Universitari Germans Trias i Pujol

Luis Bujanda

Hospital de Donostia

Belén Bertrán

Hospital La Fe, Valencia

Scientific Activities of the Programs - 193

Relevant projects 1. “Estudio multicéntrico, doble ciego, controlado con placebo para valorar la eficacia de la colestiramina en el tratamiento de la diarrea crónica acuosa atribuida a malabsorción de ácidos biliares”. EC08/00085. Fondo de Investigación Sanitaria. PI: Fernando Fernández Bañares. Team Members: Maria Esteve; Mercè Rosinach. 2010-2012.

Rosinach; Victoria Gonzalo; Antonio Salas. 2011-2013

2. “Papel de la interleucina 10 en la fisiopatología de la refractariedad a fármacos en la enfermedad de Crohn. Relación con la apoptosis de linfocitos T y B y la capacidad de respuesta a esteroides”. BFU 2010-19888. Ministerio de Ciencia e Innovación -Subprograma BFI. PI: Maria Esteve. Team Members: Anna Carrasco Garcia; Jorge Espinós; Antonio Salas Caudevila; Carme Loras Alaustrey; Judith Vidal; Josefina Mallolas. 2011-2013. € 48,000

6. “Análisis “OMICO” integrado en la enteritis linfocítica secundaria a enteropatía sensible al gluten. Búsqueda de biomarcadores, su interés fisiopatológico y diagnóstico”. Sociedad de Celíacos de Madrid. PI: Fernando Fernández-Bañares. Team Members: Maria Esteve; Anna Carrasco; Mercè Rosinach; Lourdes Fluvià; Jose Maria Hernandez. €9,000

5. “Análisis Fenotípico y apoptosis de células implicadas en la respuesta inmune de la EII”. Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU). PI: Maria Esteve. Team Members: Anna Carrasco. 2010-2011. €6,000

3. “Inmunopatogénesis de la enteritis linfocitica secundaria a enteropatia sensible al gluten: interés fisiopatológico y diagnóstico”. FIS PI10/00892. Fondo de Investigación Sanitaria (Instituto de Salud Carlos III). PI: Fernando Fernández-Bañares. Team Members: Mercè Rosinach; Anna Carrasco; Clarisa González. 2011-2013. €60,300

7. “Estudio multicéntrico, doble ciego, controlado con placebo para valorar la eficacia de la dieta sin gluten en el tratamiento de la diarrea crónca acuosa atribuida a enteropatía sensible al gluten en forma de enteritis linfocítica (lesión tipo Marsh I)”. Ayuda a la Investigación Médica de la Fundación Mutua Madrileña. PI: Fernando Fernández-Bañares. Team Members: Maria Esteve. 2011- 2012. € 3,750

4. “Caracterización de les poblaciones linfocitarias de la mucosa colónica en pacientes con colitis colágena i colitis linfocítica. Valoración de la presencia de células T reguladores FOXP3+ y de linfocitos T productores de citocinas”. Acadèmia de Ciències Mèdiques i de la Salut de Catalunya. PI: Fernando FernándezBañares. Team Members: Maria Esteve; Anna Carrasco; Mercè

8. “Reconocimiento como grupo consolidado del AGAUR”. 2009 SGR1316. AGAUR. PI: Maria Esteve. Team Members: Fernando Fernandez-Bañares, Montserrat Forné, Josep Mª Viver, Jorge C Espinós, Mercè Rosinach, Carme Loras, Jaume Casalots, Clara Isabel González, Antonio Salas, Montserrat Alsina, Meritxell Mariné, Helena Monzón, Anna Carrasco. 2009- 2013. €8,736

Thesis 1. Title: “Prevalença global de Malaltia celíaca a Catalunya. Impacte del cribratge poblacional en població en edat laboral”. Doctorate Student: Meritxell Mariné Guillem. Director: Maria Esteve. Qualification: Sobresaliente “Cum Laude” por unanimidad. Date of lecture: 04/10/2011.

194 - CIBERehd - 2011 ANNUAL REPORT - PROGRAM 6 Linked group

DR. Belén Beltrán Niclós Hospital Universitario La Fe, Valencia

Team leader Belén Beltrán Niclós

Team members Belén Beltrán Niclós Pilar Nos Mateu Guillermo Bastida Paz Mariam Aguas Peris Marisa Iborra Colomino Inés Moret Tatay Luis Tortosa Seguí Francisco Rausell Palamós

Outputs CIBERehd

Nº of Publications 1st quartile: 2 Nº of Publications 2nd quartile: 7 IF total: 27.579 Nº of competitive projects: 5 Public funding: €79,000 Private funding: €52,520

Main Research Topics • Gastrointestinal motility and acid-related diseases. • Basic and clinical research in inflammatory bowel disease. • Technology assessment, diagnostic, therapeutic and health outcomes.

Relevant projects 1. “Análisis proteico, genético farmacológico de la Catalasa y otros enzimas antioxidantes en la Enfermedad de Crohn: Impacto terapéutico”. PS09/01827. ISCIII. PI: Dra. Belén Beltrán. Team Members: G. Bastida, M. Iborra, I. Moret, E. Buso. 2010-2012. €38,000 2. “Patrones de expresión de microRNAs en la enfermedad inflamatoria intestinal: utilidad en el diagnóstico, pronóstico y respuesta al tratamiento”. 2010_0468_GETECCU_IBORRA. VII Beca Geteccu/Otsuka. PI: Dra. Marisa Iborra. 2011-2012. €6,000 3. “Ayudas para contratos de apoyo a la investigación”. CA10/01027. ISCIII. PI: Dra. Pilar Nos. Team Member: I. Moret. 20112012. €33,000.

4. “Caracterización de la variabilidad de la microbiótica humana. Correlaciones entre la microbiótica intestinal y la Enfermedad de Crohn. Metahit I”. 2009/0167. 7º Programa Marco Europeo. PI: Dra. Pilar Nos. Team Members: G. Bastida, F. Guarner, M. Iborra. 2009-2011. €4,000 5. “Estudio prospectivo en pacientes con Enfermedad de Crohn para investigar la microbiótica intestinal mediante nuevas técnicas moleculares y evaluar su utilidad para predecir respuesta inicial al tratamiento con anticuerpos antitnf. Metahit II”. 2009/0169. 7º Programa Marco Europeo. PI: Dra. Pilar Nos. Team Members: M. Aguas, G. Bastida. 20112012. €4,000

Collaborations with other CIBERehd groups Eugeni Domenech

Hospital Universitari Germans Trias i Pujol, Barcelona

María Esteve

Hospital Mutua Terrassa, Barcelona

Javier Pérez Gisbert

Hospital Universitario La Princesa, Madrid

Francisco Guarner

Hospital Universitari Vall d’Hebron, Barcelona

Julián Panés

Hospital Clínic, Barcelona

Publications

198 - CIBERehd - 2011 ANNUAL REPORT - PUBLICATIONS

Publications 1st and 2nd Quartile CIBERehd Publications 1. “Pneumatic dilation versus laparoscopic Heller’s myotomy for idiopathic achalasia”. N Engl J Med Authors: Boeckxstaens GE, Annese V, des Varannes SB, Chaussade S, Costantini M, Cuttitta A, Elizalde JI, Fumagalli U, Gaudric M, Rohof WO, Smout AJ, Tack J, Zwinderman AH, Zaninotto G, Busch OR, European Achalasia Trial Investigators. Authors CIBERehd: Elizalde JI. 2. “Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease”. Nat Genet Authors: Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, Boucher G, Ripke S, Ellinghaus D, Burtt N, Fennell T, Kirby A, Latiano A, Goyette P, Green T, Halfvarson J, Haritunians T, Korn JM, Kuruvilla F, Lagacé C, Neale B, Lo KS, Schumm P, Törkvist L, National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC), United Kingdom Inflammatory Bowel Disease Genetics Consortium, International Inflammatory Bowel Disease Genetics Consortium, Dubinsky MC, Brant SR, Silverberg MS, Duerr RH, Altshuler D, Gabriel S, Lettre G, Franke A, D’Amato M, McGovern DP, Cho JH, Rioux JD, Xavier RJ, Daly MJ. Authors CIBERehd: Panés J. 3. “Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47”. Nature Genetics Authors: Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, Lee JC, Goyette P, Imielinski M, Latiano A, Lagacé C, Scott R, Amininejad L, Bumpstead S, Baidoo L, Baldassano RN, Barclay M, Bayless TM, Brand S, Büning C, Colombel JF, Denson LA, De Vos M, Dubinsky M, Edwards C, Ellinghaus D, Fehrmann RS, Floyd JA, Florin T, Franchimont D, Franke L, Georges M, Glas J, Glazer NL, Guthery SL, Haritunians A, Hayward NK, Hugot JP, Jobin G, Laukens D, Lawrance I, Lémann M, Levine A, Libioulle C, Louis E, McGovern DP, Milla M, Montgomery GW, Morley KI, Mowat C, Ng, W Newman A, Ophoff RA, Papi L, Palmieri O, PeyrinBiroulet L, Panés J, Phillips A, Prescott NJ, Proctor DD, Roberts R, Russell R, Rutgeerts P, Sanderson J, Sans M, Schumm P, Seibold F, Sharma Y, Simms LA, Seielstad M, Steinhart AH, Targan SR, van den Berg, M Vatn, H Verspaget, T Walters, C Wijmenga, DC Wilson LH, Westra HJ, Xavier RJ, Zhao ZZ, Ponsioen CY, Andersen V, Torkvist L, Gazouli M, Anagnou NP, Karlsen TH, Kupcinskas L, Sventoraityte, JC Mansfield, S Kugathasan, MS Silverberg, J Halfvarson J, Rotter JI, Mathew CG, Griffiths AM, Gearry R, Ahmad T, Brant SR, Chamaillard M, Satsangi J, Cho JH, Schreiber S, Daly MJ, Barrett JC, Parkes M, Annese V, Hakonarson H, Radford-Smith

G, Duerr RH, Vermeire S, Weersma RK, Rioux JD. Authors CIBERehd: Panés J, Sans M. 4. “Enterotypes of the human gut microbiome”. Nature Authors: Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, Fernandes GR, Tap J, Bruls T, Batto JM, Bertalan M, Borruel N, Casellas F, Fernández L, Gautier L, Hansen T, Hattori M, Hayashi T, Kleerebezem M, Kurokawa K, Leclerc M, Levenez F, Manichanh C, Nielsen HB, Nielsen T, Pons N, Poulain J, Qin J, Sicheritz-Ponten T, Tims S, Torrents D, Ugarte E, Zoetendal EG, Wang J, Guarner F, Pedersen O, de Vos WM, Brunak S, Doré J, MetaHIT Consortium, Antolín M, Artiguenave F, Blottiere HM, Almeida M, Brechot C, Cara C, Chervaux C, Cultrone A, Delorme C, Denariaz G, Dervyn R, Foerstner KU, Friss C, van de Guchte M, Guedon E, Haimet F, Huber W, van Hylckama-Vlieg J, Jamet A, Juste C, Kaci G, Knol J, Lakhdari O, Layec S, Le Roux K, Maguin E, Mérieux A, Melo Minardi R, M’rini C, Muller J, Oozeer R, Parkhill J, Renault P, Rescigno M, Sánchez N, Sunagawa S, Torrejon A, Turner K, Vandemeulebrouck G, Varela E, Winogradsky Y, Zeller G, Weissenbach J, Ehrlich SD, Bork P. Authors CIBERehd: Borruel N, Casellas F, Manichanh C, Guarner F, Antolín M, Torrejón A, Varela E. 5. “Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, openlabel, non-inferiority, phase 3 trial”. Lancet Authors: Malfertheiner P, Bazzoli F, Delchier JC, Celiñski K, Giguère M, Rivière M, Mégraud F, Pylera Study Group. Authors CIBERehd: Gisbert JP, Calvet X (dentro del Pylera Study Group). 6. “Validation microsatellite path score in a populationbased cohort of patients with colorectal cancer”. J Clin Oncol Authors: Bessa X, Alenda C, Paya A, Álvarez C, Iglesias M, Seoane A, Dedeu JM, Abulí A, Ilzarbe L, Navarro G, Pellise M, Balaguer F, Castellví-Bel S, Llor X, Castells A, Jover R, Andreu M. Authors CIBERehd: Pellisé M, Balaguer F, Castellví-Bel S, Llor X, Castells A, Jover R. 7. “Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study.” J Clin Oncol Authors: García-Del-Muro X, López-Pousa A, Maurel J, Martín J, Martínez-Trufero J, Casado A, Gómez-España A, Fra J, Cruz J, Poveda A, Meana A, Pericay C, Cubedo R, Rubió J, De Juan A,

Publications - 199

Publications 1st and 2nd Quartile CIBERehd Publications Laínez N, Carrasco JA, de Andrés R, Buesa JM, Spanish Group for Research on Sarcomas. Authors CIBERehd: Maurel J.

failure of Doxorubicin”.¡ Gastroenterology Authors: Reig M, Bruix J. Authors CIBERehd: Reig M, Bruix J.

8. “Smoking, hepatitis B virus infection, and development of hepatocellular carcinoma”. Journal of the National Cancer Institute Authors: Sherman M, Llovet JM. Authors CIBERehd: Llovet JM.

15. “Maintenance therapy with Peginterferon Alfa-2b does not prevent hepatocellular carcinoma in cirrhotic patients with chronic hepatitis C”. Gastroenterology Authors: Bruix J, Poynard T, Colombo M, Schiff E, Burak K, Heathcote EJ, Berg T, Poo JL, Mello CB, Guenther R, Niederau C, Terg R, Bedossa P, Boparai N, Griffel LH, Burroughs M, Brass CA, Albrecht JK, EPIC3 Study Group. Authors CIBERehd: Bruix J.

9. “Hepatocellular carcinoma enters the sequencing era”. Gastroenterology Authors: Villanueva A, Hoshida J, Llovet JM. Authors CIBERehd: Villanueva A, Llovet JM. 10. “Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets”. Gastroenterology Authors: Gao B (1), Bataller (2). Authors CIBERehd: Bataller R. 11. “Complementary function of the flippase ATP8B1 and the floppase ABCB4 in maintenance of canalicular membrane integrity”. Gastroenterology Authors: Groen AK, Romero MR, Kunne C, Hoosdally SJ, Dixon PH, Wooding C, Williamson C, Seppen J, van den Oever K, Mok KS, Paulusma CC, Linton KJ, Oude Elferink RP. Authors CIBERehd: Romero MR. 12. “Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles”. Gastroenterology Authors: Lucena MI, Molokhia M, Shen Y, Urban TJ, Aithal GP, Andrade RJ, Day CP, Ruiz-Cabello F, Donaldson PT, Stephens C, Pirmohamed M, Romero-Gómez M, Navarro JM, Fontana RJ, Miller M, Groome M, Bondon-Guitton E, Conforti A, Stricker BH, Carvajal A, Ibánez L, Yue QY, Eichelbaum M, Floratos A, Pe’er I, Daly MJ, Goldstein DB, Dillon JF, Nelson MR, Watkins PB, Daly AK, Spanish DILI Registry, EUDRAGENE, DILIN, DILIGEN, International SAEC. Authors CIBERehd: Lucena MI, Andrade RJ, Stephens C, Romero-Gómez M. 13. “Radiofrequency ablation for nondysplastic Barrett’s esophagus: to treat or not to treat?”. Gastroenterology Authors: Fernández-Esparrach G, Panés J. Authors CIBERehd: Fernández- Esparrach G. 14. “The search for an effective partner for sorafenib: the

16. “Targeted therapies for hepatocellular carcinoma”. Gastroenterology Authors: Villanueva A, Llovet JM. Authors CIBERehd: Villanueva A, Llovet JM. 17. “MicroRNA-Based Classification of Hepatocellular Carcinoma and Oncogenic Role of miR-517a”. Gastroenterology Authors: Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, Savic R, Ward SC, Thung S, Chiang DY, Alsinet C, Tovar V, Roayaie S, Schwartz M, Bruix J, Waxman S, Friedman SL, Golub T, Mazzaferro V, Llovet JM. Authors CIBERehd: Villanueva A, , Minguez B, Tovar V, Bruix J, Llovet JM. 18. “Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma”. Gastroenterology Authors: Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornellà H, Liberzon A, Kobayashi M, Kumada H, Thung SN, Bruix J, Newell P, April C, Fan JB, Roayaie S, Mazzaferro V, Schwartz ME, Llovet JM. Authors CIBERehd: Villanueva A, Bruix J, Llovet JM. 19. “Eosinophils express muscarinic receptors and corticotropin-releasing factor to disrupt the mucosal barrier in ulcerative colitis”. Gastroenterology Authors: Wallon C, Persborn M, Jonsson M, Wang A, Phan V, Lampinen M, Vicario M, Santos J, Sherman PM, Carlson M, Ericson AC, McKay DM, Soderholm JD. Authors CIBERehd: Vicario M, Santos J. 20. “Confocal endomicroscopy in celiac disease”. Gastroenterology Authors: Pellisé M, Panés J.

200 - CIBERehd - 2011 ANNUAL REPORT - PUBLICATIONS

Publications 1st and 2nd Quartile CIBERehd Publications Authors CIBERehd: Pellisé M, Panés J. 21. “The clonal origins of dysplasia from intestinal metaplasia in the human stomach”. Gastroenterology Authors: Gutierrez-González L, Graham TA, Rodríguez-Justo M, Leedham SJ, Novelli MR, Gay LJ, Ventayol-García T, Green A, Mitchell I, Stoker DL, Preston SL, Bamba S, Yamada E, Kishi Y, Harrison R, Jankowski JA, Wright NA, McDonald SA. Authors CIBERehd: Gutierrez-González L. 22. “5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer”. Gastroenterology Authors: Jover R, Nguyen TP, Pérez-Carbonell L, Zapater P, Payá A, Alenda C, Rojas E, Cubiella J, Balaguer F, Morillas JD, Clofent J, Bujanda L, Reñé JM, Bessa X, Xicola RM, Nicolás-Pérez D, Castells A, Andreu M, Llor X, Boland CR, Goel A. Authors CIBERehd: Castells A. 23. “Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs”. Gastroenterology Authors: Sánchez-Fueyo A, Strom TB. Authors CIBERehd: Sánchez-Fueyo A. 24. “Telaprevir is effective given every 8 or 12 hours with ribavirin and peginterferon alfa-2a or -2b to patients with chronic hepatitis C”. Gastroenterology Authors: Marcellin P, Forns X, Goeser T, Ferenci P, Nevens F, Carosi G, Drenth JP, Serfaty L, De Backer K, Van Heeswijk R, Luo D, Picchio G, Beumont M. Authors CIBERehd: Forns X. 25. “Three-Year Efficacy and Safety of Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B”. Gastroenterology Authors: Heathcote EJ, Marcellin P, Buti M, Gane E, De Man RA, Krastev Z, Germanidis G, Lee SS, Flisiak R, Kaita K, Manns M, Kotzev I, Tchernev K, Buggisch P, Weilert F, Kurdas OO, Shiffman ML, Trinh H, Gurel S, Snow-Lampart A, Borroto-Esoda K, Mondou, E, Anderson J, Sorbel J, Rousseau F. Authors CIBERehd: Buti M. 26. “Prognostic Importance of the Cause of Renal Failure in Patients With Cirrhosis”. Gastroenterology Authors: Martín-Llahi M (1,2,3), Guevara M (1,2,3), Torre A (1,2,3), Fagundes C (1,2,3), Restuccia T (1,2,3), Gilabert R (1,2,3), Sola E (1,2,3), Pereira G (1,2,3), Marinelli M (1,2,3), Pavesi M (1,2,3), Fernández J (1,2,3), Rodes J (1,2,3), Arroyo V (1,2,3), Gines P (1,2,3).

Authors CIBERehd: Guevara M, Gilabert R, Pavesi M , Fernández J , Arroyo V , Gines P. 27. “Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition”. Trends Pharmacol Sci. Authors: Apostolova N, Blas-García A, Esplugues JV. Authors CIBERehd: Apostolova N, Blas-García A, Esplugues JV. 28. “Cognitive dysfunction in cirrhosis is associated with falls. A prospective study”. Hepatology Authors: Soriano G, Román E, Córdoba J, Torrens M, Poca M, Torras X, Villanueva C, Gich IJ, Vargas V, Guarner C. Authors CIBERehd: Soriano G, Córdoba J, Vargas V, Guarner C. 29. “Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques”. Hepatology Authors: Bruix J, Reig M, Rimola J, Forner A, Burrel M, Vilana R, Ayuso C. Authors CIBERehd: Bruix J, Reig M, Forner A. 30. “Where are we in the search of noninvasive NASH biomarkers?”. Hepatology Authors: Mato JM, Lu SC. Authors CIBERehd: Mato JM. 31. “Methionine adenosyltransferase 1A gene deletion disrupts hepatic VLDL assembly in mice” Hepatology Authors: Cano A, Buqué X, Martínez-Uña M, Aurrekoetxea I, Menor A, García-Rodríguez JL, Lu SC, Martínez-Chantar ML, Mato JM, Ochoa B, Aspichueta P. Authors CIBERehd: Martínez-Chantar ML, Mato JM. 32. “Effects of bilirubin and sera from jaundiced patients on osteoblasts: contribution to the development of osteoporosis in liver diseases”. Hepatology Authors: Ruiz-Gaspà S, Martínez-Ferrer A, Guañabens N, Dubreuil M, Peris P, Enjuanes A, Martínez de Osaba MJ, Álvarez L, Monegal A, Combalia A, Parés A. Authors CIBERehd: Ruiz-Gaspà S, Guañabens N, Dubreuil M, Peris P, Martínez de Osaba MJ, Álvarez L, Parés A. 33. “Connective Tissue Growth Factor Autocriny in Human Hepatocellular Carcinoma: Oncogenic Role and Regulation by Epidermal Growth Factor Receptor/Yes-Associated Protein-Mediated Activation”. Hepatology

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Publications 1st and 2nd Quartile CIBERehd Publications Authors: Urtasun R, Latasa MU, Demartis MI, Balzani S, Goni S, García-Irigoyen O, Elizalde M, Azcona M, Pascale RM, Feo F, BioulacSage P, Balabaud C, Muntane J, Prieto J, Berasain C, Avila MA. Authors CIBERehd: Muntane J, Prieto J.

Hepatology Authors: Vaquero J, Campbell JS, Haque J, McMahan RS, Riehle KJ, Bauer RL, Fausto N. Authors CIBERehd: Vaquero J.

34. “The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis vs. Drug-Induced Liver Injury”. Hepatology 2011 Authors: Suzuki A, Brunt EM, Kleiner DE, Miquel R, Smyrk TC, Andrade RJ, Lucena MI, Castiella A, Lindor K, Björnsson E. Authors CIBERehd: Andrade RJ, Lucena MI.

40. “Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis”. Hepatology Authors: Berzigotti A, García-Tsao G, Bosch J, Grace N, Burroughs A, Morillas R, Escorsell A, García-Pagan JC, Patch D, Matloff DS, Groszmann RJ, the Portal Hypertension Collaborative Group. Authors CIBERehd: Berzigotti A, Bosch J, Morillas R, Escorsell A, García-Pagan JC.

35. “Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: meta-analyses of randomized, controlled trials and implications for the future”. Hepatology Authors: Di Martíno V, Richou C, Cervoni JP, Sánchez-Tapias JM, Jensen DM, Mangia A, Buti M, Sheppard F, Ferenci P, Thévenot T. Authors CIBERehd: Di Martíno V, Richou C, Cervoni JP, SánchezTapias JM, Jensen DM, Mangia A, Buti M, Sheppard F, Ferenci P, Thévenot T. 36. “Compromising mitochondrial function with the antiretroviral drug efavirenz induces cell survival-promoting autophagy”. Hepatology Authors: Apostolova N, Gómez-Sucerquia LJ, Gortat A, BlasGarcía A, Esplugues JV. Authors CIBERehd: Apostolova N, Blas-García A, Esplugues JV. 37. “Survival After Yttrium-90 Resin Microsphere Radioembolization of Hepatocellular Carcinoma Across Barcelona Clinic Liver Cancer Stages: A European Evaluation”. Hepatology Authors: Sangro B, Carpanese L, Cianni R, Golfieri R, Gasparini D, Ezziddin S, Paprottka PM, Fiore F, Van Buskirk M, Bilbao JI, Ettorre GM, Salvatori R, Giampalma E, Geatti O, Wilhelm K, Hoffmann RT, Izzo F, Inarrairaegui M, Maini CL, Urigo C, Cappelli A, Vit A, Ahmadzadehfar H, Jakobs TF, Lastoria S. Authors CIBERehd: Sangro B. 38. “Idiopathic noncirrhotic portal hypertension”. Hepatology Authors: Schouten JN, García-Pagan JC, Valla DC, Janssen HL. Authors CIBERehd: García-Pagan JC. 39. “Toll-Like Receptor 4 and Myeloid Differentiation Factor 88 Provide Mechanistic Insights Into the Cause and Effects of Interleukin-6 Activation in Mouse Liver Regeneration”.

41. “Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis”. Hepatology Authors: Tarrats N, Moles A, Morales A, García-Ruiz C, Fernández-Checa JC, Marí M. Authors CIBERehd: Morales A, García-Ruiz C, Fernández-Checa JC, Marí M. 42. “Inhibition of Placental Growth Factor Activity Reduces the Severity of Fibrosis, Inflammation, and Portal Hypertension in Cirrhotic Mice”. Hepatology Authors: Van Steenkiste C (1), R()ibera J (3), Geerts A (1), Pauta M (3), Tugues S (3,5), Casteleyn C (6), Libbrecht L (2), Olievier K (1), Schroyen B (7), Reynaert H (7), van Grunsven LA (7), Blomme EB (1), Coulon S (1), Heindryckx F (1), De Vos m (1), Stassen JM (8), Vinckier S (9), Altamirano J (4), Bataller R (4), Carmeliet P (10,9), Van Vlierberghe H (1), Colle I (1), Morales-Ruiz M (3). Authors CIBERehd: Altamirano J, Bataller R, Morales-Ruiz M. 43. “Enhanced T cell responses against hepatitis C virus by ex vivo targeting of adenoviral particles to dendritic cells”. Hepatology Authors: Echeverria I, Pereboev A, Silva L, Zabaleta A, Riezu-Boj JI, Bes M, Cubero M, Borras-Cuesta F, Lasarte JJ, Esteban JI, Prieto J, Sarobe P. Authors CIBERehd: Cubero M, Esteban JI, Prieto J. 44. “Genetic Variation in IL28B with respect to Vertical Transmission of Hepatitis C Virus and Spontaneous Clearance in HCV Infected Children”. Hepatology Authors: Ruiz-Extremera, Angela, Muñoz-Gámez, Jose Antonio, Salmeron-Ruiz, Maria Angustias Muñoz de Rueda, Paloma, Quiles-Pérez, Rosa, Gila-Medina, Ana, Casado, Jorge, Martín, Ana, Sanjuan-Nuñez, Laura, Carazo, Angel, Pavon, Esther Jose, Ocete-Hita E, León J, Salmeron Javier.

202 - CIBERehd - 2011 ANNUAL REPORT - PUBLICATIONS

Publications 1st and 2nd Quartile CIBERehd Publications Authors CIBERehd: Ruiz-Extremera A, Muñoz de Rueda P, Quiles-Pérez R, Gila-Medina A, León J, Salmeron J. 45. “Management of hepatocellular carcinoma: an update”. Hepatology Authors: Bruix J, Sherman M. Authors CIBERehd: Bruix J.

receptor expression in human stellate cells and hepatocytes”. Gut Authors: Melgar-Lesmes P, Pauta M, Reichenbach V, Casals G, Ros J, Bataller R, Morales-Ruiz M, Jiménez W. Authors CIBERehd: Bataller R, Morales-Ruiz M , Jiménez W. 53. “Mesenchymal stem cell therapy of Crohn’s disease: are the far-away hills getting closer?”. Gut Authors: Panés J, Benitez-Ribas D, Salas A. Authors CIBERehd: Panés J.

46. “Interleukin 10-mediated Heme Oxygenase 1-induced underlying mechanism in inflammatory downregulation by norfloxacin in cirrhosis”. Hepatology Authors: Gómez-Hurtado I, Zapater P, Bellot P, Pascual S, PérezMateo M, Such J, Francés R. Authors CIBERehd: Pedro Zapater, Pablo Bellot, Pascual S, Such J, Francés R.

54. “Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension”. Gut Authors: La Mura V, Reverter JC, Flores-Arroyo A, Raffa S, Reverter E, Seijo S, Abraldes JG, Bosch J, García-Pagán JC. Authors CIBERehd: Abraldes JG, Bosch J, García-Pagán JC.

47. “Hepatitis C virus receptors claudin-1 and occludin after liver transplantation and influence on early viral kinetics”. Hepatology Authors: Mensa L, Crespo G, Gastinger MJ, Kabat J, Pérez-delPulgar S, Miquel R, Emerson SU, Purcell RH, Forns X. Authors CIBERehd: Pérez-del-Pulgar S, Forns X.

55. “Short- and long-term effects of the transjugular intrahepatic portosystemic shunt on portal vein thrombosis in patients with cirrhosis”. Gut Authors: Luca A, Miraglia R, Caruso S, Milazzo M, Sapere C, Maruzzelli L, Vizzini G, Tuzzolino F, Gridelli B, Bosch J. Authors CIBERehd: Bosch J.

48. “Noninvasive assessment of liver fibrosis”. Hepatology Authors: Martínez SM, Crespo G, Navasa M, Forns X. Authors CIBERehd: Navasa M, Forns X.

56. “The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study”. Gut Authors: Vermeire S, Ghosh S, Panés J, Dahlerup JF, Luegering A, Sirotiakova J, Strauch U, Burgess G, Spanton J, Martín SW, Niezychowski W. Authors CIBERehd: Panés J.

49. “Improved Dendritic Cell-Based Immunization Against Hepatitis C Virus Using Peptide Inhibitors of Interleukin 10”. Hepatology Authors: Díaz-Valdes, N, Manterolal, L, Belsue, V, Riezu-Boj, JI, Larrea, E, Echeverria, I, Llopiz, D, López-Sagaseta, J, Lerat, H, Pawlotsky, JM, Prieto, J, Lasarte, JJ, Borras-Cuesta, F, Sarobe, P. Authors CIBERehd: Prieto J. 50. “Critical role of the liver in the induction of systemic inflammation in rats with preascitic cirrhosis”. Hepatology Authors: Úbeda M, Muñoz M, Borrero MJ, Díaz D, Francés R, Montserrat J, Lario M, Lledó L, Such J, Álvarez-Mon M, Albillos A. Authors CIBERehd: Francés R, Such J, Álvarez-Mon M, Albillos A. 51. “Early use of immunosuppressives or TNF antagonists for the treatment of Crohn’s disease: time for a change”. Gut Authors: Ordás I, Feagan BG, Sandborn WJ. Authors CIBERehd: Ordás I. 52. “Hypoxia and proinflammatory factors upregulate apelin

57. “Evaluation of esophageal mucosa integrity by intraluminal impedance technique”. Gut Authors: Farré R, Blondeau K, Clement D, Vicario M, Cardozo L, Vieth M, Mertens V, Pauwels A, Jiménez M, Tack J, Sifrim D. Authors CIBERehd: Farré R, Jiménez M, Viacario M. 58. “H1N1 vaccines in a large observational cohort of patients with inflammatory bowel disease treated with immunomodulators and biological therapy”. Gut Authors: Rahier JF, Papay P, Salleron J, Sebastian S, Marzo M, Peyrin-Biroulet L, García-Sánchez V, Fries W, Van Asseldonk DP, Farkas K, de Boer NK, Sipponen T, Ellul P, Louis E, Peake STC, Kopylov U, J Maul, Makhoul B, Fiorino G, Yazdanpanah Y, Chaparro M, for the European Crohn’s and Colitis Organisation (ECCO). Authors CIBERehd: M Chaparro. 59. “Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and

Publications - 203

Publications 1st and 2nd Quartile CIBERehd Publications increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C”. Gut Authors: Miquilena-Colina ME, Lima-Cabello E, SánchezCampos S, García-Mediavilla MV, Fernández-Bermejo M, Lozano-Rodríguez T, Vargas-Castrillón J, Buqué X, Ochoa B, Aspichueta P, González-Gallego J, García-Monzón C. Authors CIBERehd: Sánchez-Campos S, García-Mediavilla MV, Vargas-Castrillón J, González-Gallego J, García-Monzón C. 60. “Management of patients with cirrhosis awaiting liver transplantation”. Gut Authors: Cardenas A (1,2), Gines P (2,3). Authors CIBERehd: Gines P. 61. “Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis”. Gut Authors: Beraza N, Ofner-Ziegenfuss L, Ehedego H, Boekschoten M, Bischoff SC, Muelle M, Trauner M, Trautwein CH. Authors CIBERehd: Beraza N. 62. “Endothelial expression of transcription factor Kruppellike factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver”. Gut Authors: Gracia-Sancho J, Russo L, García-Calderó H, GarcíaPagán JC, García-Cardeña G, Bosch J. Authors CIBERehd: Gracia-Sancho J, Russo L, García-Calderó H, García-Pagán JC, Bosch J. 63. “Diagnosis of early hepatocellular carcinoma: ideal goal, but not yet there”. Gut Authors: Bruix J, Tremosini S. Authors CIBERehd: Bruix J. 64. “Oxaliplatin in combination with liverspecific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice”. Gut Authors: González-Aparicio, M, Alzuguren, P, Mauleon, I, MedinaEcheverz, J, Hervas-Stubbs, S, Mancheno, U, Berraondo, P, Crettaz, J, González-Aseguinolaza, G, Prieto, J, Hernández-Alcoceba, R. Authors CIBERehd: Prieto J. 65. “Portal cholangiopathy: radiological classification and natural history”. Gut Authors: Llop E, de Juan C, Seijo S, García-Criado A, Abraldes JG, Bosch J, García-Pagán JC. Authors CIBERehd: Llop E, de Juan C, Seijo S, García-Criado A, Abraldes JG, Bosch J, García-Pagán JC.

66. “The JAK2 46/1 haplotype in Budd-Chiari syndrome and portal vein thrombosis”. Blood Authors: Smalberg JH, Koehler E, Darwish Murad S, Plessier A, Seijo S, Trebicka J, Primignani M, de Maat MP, García-Pagan JC, Valla DC, Janssen HL, Leebeek FW. European Network for Vascular Disorders of the Liver (EN-Vie). Authors CIBERehd: García-Pagan JC. 67. “Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility”. Current Biology Authors: Bosch M, Marí M, Herms A, Fernández A, Fajardo A, Kassan A, Giralt A, Colell, A, Balgoma D, Barbero E, GonzálezMoreno E, Matias N, Tebar F, Balsinde J, Camps, M, Enrich C, Gross SP, García-Ruiz C, Pérez-Navarro E, Fernández-Checa JC, Pol A. Authors CIBERehd: Marí M, Fernández A, Colell A, García-Ruiz C, Fernández-Checa JC. 68. “The Capsaicin Receptor TRPV1 Is a Crucial Mediator of the Noxious Effects of Mustard Oil”. Current Biology Authors: Everaerts W, Gees M, Alpizar YA, Farré R, Leten C, Apetrei A, Dewachter I, Van Leuven F, Vennekens R, De Ridder D, Nilius B, Voets T, Talavera K. Authors CIBERehd: Farré R. 69. “Biodistribution of amino-functionalized diamond nanoparticles. In vivo studies based on 18F radionuclide emission”. ACS Nano Authors: Rojas S, Gispert JD, Martín R, Abad S, Menchón C, Pareto D, Víctor VM, Alvaro M, García H, Herance JR. Authors CIBERehd: Victor VM. 70. “β-catenin/TCF4 complex induces the epithelial-tomesenchymal transition (EMT)-activator ZEB1 to regulate tumor invasiveness”. Proc Natl Acad Sci U S A Authors: Sánchez-Tilló E, de Barrios O, Siles L, Cuatrecasas M, Castells A, Postigo A. Authors CIBERehd: Cuatrecasas M, Castells A. 71. “Tempo and mode of inhibitor-mutagen antiviral therapies: A multidisciplinary approach”. P Natl Acad Sci USA Authors: Iranzo J, Perales C, Domingo E, Manrubia SC. Authors CIBERehd: Perales C, Domingo E 72. “Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer”. PLoS Genet Authors: Tomlinson IP, Carvajal-Carmona LG, Dobbins SE,

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Publications 1st and 2nd Quartile CIBERehd Publications Tenesa A, Jones AM, Howarth K, Palles C, Broderick P, Jaeger EE, Farrington S, Lewis A, Prendergast JG, Pittman AM, Theodoratou E, Olver B, Walker M, Penegar S, Barclay E, Whiffin N, Martín L, Ballereau S, Lloyd A, Gorman M, Lubbe S, COGENT Consortium, CORGI Collaborators, EPICOLON Consortium, Howie B, Marchini J, Ruiz-Ponte C, Fernández-Rozadilla C, Castells A, Carracedo A, Castellví-Bel S, Duggan D, Conti D, Cazier JB, Campbell H, Sieber O, Lipton L, Gibbs P, Martín NG, Montgomery GW, Young J, Baird PN, Gallinger S, Newcomb P, Hopper J, Jenkins MA, Aaltonen LA, Kerr DJ, Cheadle J, Pharoah P, Casey G, Houlston RS, Dunlop MG. Authors CIBERehd: Castells A, Castellví-Bel S. 73. “Viral genome segmentation can result from a tradeoff between genetic content and particle stability”. PLoS Genetics Authors: Ojosnegros S, García-Arriaza J, Escarmí C, Manrubia SC, Perales C, Arias A, García-Mateu M and Domingo E. Authors CIBERehd: Perales C, Domingo E. 74. “Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology”. Plos Genetics Authors: Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y, International Inflammatory Bowel Disease Genetics Constortium, Cotsapas C, Daly MJ. M Sans es parte del consorcio. Authors CIBERehd: Sans M, Panés J. 75. “Soft technique, hard end-points”. J Hepatol Authors: Bosch J. Authors CIBERehd: Bosch J. 76. “RANTES antagonism: A promising approach to treat chronic liver diseases”. J Hepatol Authors: Affo S, Bataller R. Authors CIBERehd: Bataller R. 77. “DCD donors: a unique source to significantly increase organ donation”.J Hepatol Authors: García-Valdecasas JC. Authors CIBERehd: García-Valdecasas JC. 78. “APOC3 polymorphisms and non-alcoholic fatty liver disease: resolving some doubts and raising others”. J Hepatol Authors: Romero-Gómez M. Authors CIBERehd: Romero-Gómez M. 79. Gene-expression signature of vascular invasion in

hepatocellular carcinoma. J Hepatol Authors: Mínguez B, Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S, Mandeli J, Sia D, April C, Fan JB, Lachenmayer A, Savic R, Roayaie S, Mazzaferro V, Bruix J, Schwartz M, Friedman SL, Llovet JM. Authors CIBERehd: Mínguez B, Villanueva A, Bruix J, Llovet JM. 80. “Insulin resistance and liver microcirculation in a rat model of early NAFLD”. J Hepatol Authors: Pasarín M, Abraldes JG, Rodríguez-Vilarrupla A, Mura VL, García-Pagán JC, Bosch J. Authors CIBERehd: Abraldes JG, Rodríguez-Vilarrupla A, García-Pagán JC, Bosch J. 81. “Causality assessment methods in Drug Induced Liver Injury”. J Hepatol Authors: García-Cortés M, Stephens C, Lucena MI, FernándezCastañer A, Andrade RJ Authors CIBERehd: García-Cortés M, Stephens C, Lucena MI, Andrade RJ. 82. “Phamacological Management of hepatorenal syndrome: lessons from non-responders”. J Hepatol Authors: Ginès P. Authors CIBERehd: Ginès P. 83. “Recurrent drug-induced liver injury (DILI) with different drugs in the Spanish Registry: the dilemma of the relationship to autoimmune hepatitis”. J Hepatol Authors: Lucena MI, Kaplowitz N, Hallal H, Castiella A, GarcíaBengoechea M, Otazua P, Berenguer M, Fernández MC, Planas R, Andrade RJ. Authors CIBERehd: Lucena MI, Berenguer M, Planas R, Andrade RJ. 84. “Treatment of murine fulminant hepatitis with genetically engineered endothelial progenitor cells”. J Hepatol Authors: Fernández-Ruiz, V, Kawa, M, Berasain, C, Iniguez, M, Schmitz, V, Martínez-Anso, E, Inarrairaegui, M, Herrero, I, Sangro, B, DAvola, D, Quiroga, J, Qian, C, Prieto, J. Authors CIBERehd: Inarrairaegui M, Herrero I, Sangro B, DAvola D, Quiroga J, Prieto J. 85. “Genomic medicine reaches HCV-related liver transplantation: hopes and clinical and public health implications”. Journal of Hepatology Authors: López-Labrador FX, Berenguer M. Authors CIBERehd: Berenguer M.

Publications - 205

Publications 1st and 2nd Quartile CIBERehd Publications 86. “Evidence of neutrophil functional defect despite inflammation in stable cirrhosis”. J Hepatol Authors: Tritto G, Bechlis Z, Stadlbauer V, Davies N, Francés R, Shah N, Mookerjee RP, Such J, Jalan R. Authors CIBERehd: Francés R. 87. “Evaluation of Regional Hepatic Perfusion (RHP) by Contrast-ENHANCED Ultrasound in Patients with Cirrhosis”. J Hepatol Authors: Berzigotti A, Nicolau C, Bellot P, Abraldes JG, Gilabert R, García-Pagan JC, Bosch J. Authors CIBERehd: Berzigotti A, Nicolau C, Bellot P, Abraldes JG, Gilabert R, García-Pagan JC, Bosch J. 88. “Cerebral magnetic resonance imaging reveals marked abnormalities of brain tissue density in patients with cirrhosis without overt hepatic encephalopathy”. J Hepatol Authors: Guevara M, Baccaro ME, Gómez-Anson B, Frisoni G, Testa C, Torre A, Luis Molinuevo J, Rami L, Pereira G, Urtasun Sotil E, Córdoba J, Arroyo V, Gines P. Authors CIBERehd: Guevara M, Fri, Córdoba J , Arroyo V , Gines P. 89. “Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats”. J Hepatol Authors: García-Calderó H, Rodríguez-Vilarrupla A, GraciaSancho J, Diví M, Laviña B, Bosch J, García-Pagán JC. Authors CIBERehd: García-Calderó H, Rodríguez-Vilarrupla A, Gracia-Sancho J, Bosch J, García-Pagán JC. 90. “New assessment of hepatic encephalopathy”. J Hepatol Authors: Córdoba J. Authors CIBERehd: Córdoba J. 91. “Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients”. J Hepatol Authors: Selzner N, Guindi M, Renner EL, Berenguer M. Authors CIBERehd: Berenguer M. 92. “Nitric oxide mimics transcriptional and posttranslational regulation during α-Tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes”. J Hepatol Authors: González R, Cruz A, Ferrín G, López-Cillero P, Fernández-Rodríguez R, Briceño J, Gómez MA, Rufián S, Mata M de L, Martínez-Ruiz A, Marin JJ, Muntané J. Authors CIBERehd: Marin JJ, Muntané J.

93. “The heart in liver transplantation”. J Hepatol Authors: Ripoll C, Yotti R, Bermejo J, Bañares R. Authors CIBERehd: Ripoll C, Bañares R. 94. “Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver gainst ischemiareperfusion injury”. J Hepatol Authors: Llacuna L, Fernández A, Montfort CV, Matías N, Martínez L, Caballero F, Rimola A, Elena M, Morales A, FernándezCheca JC, García-Ruiz C. Authors CIBERehd: Fernández A, Rimola A, Morales A, Fernández-Checa JC, García-Ruiz C. 95. “Proteomic analysis reveals that apolipoprotein a1 levels are decreased in patients with budd-chiari syndrome”. J Hepatol Authors: Talens S, Hoekstra J, Dirkx SP, Murad SD, Trebicka J, Elias E, Primignani M, García-Pagán JC, Valla DC, Janssen HL, Leebeek FW, Rijken DC, for the EN-Vie Study Group. Authors CIBERehd: García-Pagan JC. 96. “Serum bilirubin and platelet count: a simple predictive model for survival in patients with refractory ascites treated by TIPS”. J Hepatol Authors: Bureau C, Métivier S, D’Amico M, Péron JM, Otal P, Pagan JC, Chabbert V, Chagneau-Derrode C, Procopet B, Rousseau H, Bosch J, Vinel JP. Authors CIBERehd: Pagan JC, Bosch J. 97. “Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection”. J Hepatol Authors: Riezu-Boj JI, Larrea E, Aldabe R, Guembe L, Casares N, Galeano E, Echeverria I, Sarobe P, Herrero I, Sangro B, Prieto J, Lasarte JJ. Authors CIBERehd: Larrea E, Herrero I, Sangro B, Prieto J. 98. “Platelet-derived chemokines: New targets to treat liver fibrosis”. J Hepatol Authors: Morales-Ibánez O (1), Bataller R (1). Authors CIBERehd: Morales O, Bataller R. 99. “FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program”. J Hepatol Authors: Poynard T, Munteanu M, Colombo M, Bruix J, Schiff E, Terg R, Flamm S, Moreno-Otero R, Carrilho F, Schmidt W, Berg T, McGarrity T, Heathcote EJ, Gonçales F, Diago M, Craxi A, Silva M,

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Publications 1st and 2nd Quartile CIBERehd Publications Boparai N, Griffel L, Burroughs M, Brass C, Albrecht J. Authors CIBERehd: Bruix J, Moreno-Otero R. 100. “Hepatic insulin resistance contributes to increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C”. J Hepatol Authors: García-Monzón C, Lo lacono O, Mayoral R, GonzálezRodríguez A, Miquilena-Colina ME, Lozano-Rodríguez T, GarcíaPozo L, Vargas-Castrillón J, Casado M, Boscá L, Valverde AM & martín-Sanz P. Authors CIBERehd: García-Monzón C, Mayoral R, García-Pozo L, Casado M, Boscá L, martín-Sanz P. 101. “Drug uptake transporters in antiretroviral therapy”. Pharmacol Ther Authors: Minuesa G, Huber-Ruano I, Pastor-Anglada M, KoepsellH, Clotet B, Martínez-Picado J. Authors CIBERehd: Huber-Ruano I, Pastor-Anglada M. 102. “LIN28B promotes colon cancer progression and metastasis”. Cancer Res Authors: King CE, Cuatrecasas M, Castells A, Sepulveda AR, Lee JS, Rustgi AK. Authors CIBERehd: Castells A. 103. “IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2”. Cancer Res Authors: Mongroo PS, Noubissi FK, Cuatrecasas M, Kalabis J, King CE, Johnstone CN, Bowser MJ, Castells A, Spiegelman VS, Rustgi AK. Authors CIBERehd: Cuatrecasas M, Castells A. 104. “RNA Self-cleavage Activated by Ultraviolet LightInduced Oxidation”. Nucleic Acids Res Authors: Ariza-Mateos M, Prieto Vega S, Díaz-Toledano R, Birk A, Szeto H, Mena I, Berzal-Herranz A, Gómez J. Authors CIBERehd: Díaz-Toledano R, Gómez J. 105. “Structural basis for the biological relevance of the invariant apical stem in IRES-mediated translation. Nucleic Acids Res Authors: Fernández N, Fernández-Miragall O, Ramajo J, GarcíaSacristán A, Bellora N, Eyras E, Briones C, Martínez-Salas E. Authors CIBERehd: García-Sacristán A, Briones C. 106. “Ultra-deep pyrosequencing analysis of the hepatitis B virus preCore region and main catalytic motif of the viral

polymerase in the same viral genome”. Nucleic Acids Res Authors: Homs M, Buti M, Quer J, Jardí R, Schaper M, Tabernero D, Ortega I, Sánchez A, Esteban R, Rodríguez-Frias F. Authors CIBERehd: Homs M, Buti M, Quer J, Jardí R, Schaper M, Tabernero D, Ortega I, Sánchez A, Esteban R, Rodríguez-Frias F. 107. “Superior preservation of DCD livers with continuous normothermic perfusion”. Ann Surg Authors: Fondevila C, Hessheimer AJ, Maathuis MH, Muñoz J, Taurá P, Calatayud D. Authors CIBERehd: Fondevila C, Muñoz J. 108. “Decompression of the portal bed and twice-baseline portal inflow are necessary for the functional recovery of a “small-for-size” graft”. Ann Surg Authors: Hessheimer AJ, Fondevila C, Taurá P, Muñoz J, Sánchez O, Fuster J, Rimola A, García-Valdecasas JC. Authors CIBERehd: Fondevila C, Muñoz J, Rimola A, GarcíaValdecasas JC. 109. “Colorectal cancers with microsatellite instability display unique miRNA profiles”. Clinc Cancer Res. Authors: Balaguer F, Moreira L, Lozano JJ, Link A, Ramírez G, Shen Y, Cuatrecasas M, Arnold M, Meltzer SJ, Syngal S, Stoffel E, Jover R, Llor X, Castells A, Boland CR, Gironella M, Goel A. Authors CIBERehd: Castells A, Gironella M 110. “Transforming growth factor-beta type 1 receptor (ALK5) and Smad proteins mediate TIMP-1 and collagen synthesis in experimental intestinal fibrosis”. J Pathol Authors: Medina C, Santos-Martínez MJ, Santana A, PazCabrera MC, Johnston MJ, Mourelle M, Salas A, Guarner F. Authors CIBERehd: Guarner F. 111. “P-Selectin Glycoprotein Ligand-1 modulates immune inflammatory responses in the enteric lamina propria”. J Pathol Authors: N Nuñez, A Lamana, D Sancho, P Martín, JP Gisbert, F Sánchez-Madrid, A Urzainqui. Authors CIBERehd: JP Gisbert. 112. “Activation of lung macrophage subpopulations in experimental acute pancreatitis”. J Pathol Authors: S. Gea-Sorlí, R. Guillamat, A. Serrano-Mollar, D. Closa. Authors CIBERehd: Gea-Sorlí S, Closa D. 113. “Development of a Liver-specific Tet-On Inducible System for AAV Vectors and Its Application in the Treatment

Publications - 207

Publications 1st and 2nd Quartile CIBERehd Publications of Liver Cancer”. Mol Ther Authors: Vanrell L, Di Scala M, Blanco L, Otano I, Gil-Farina I, Baldim V, Paneda, A, Berraondo P, Beattie SG, Chtarto A, Tenenbaum L, Prieto, J, González-Aseguinolaza G. Authors CIBERehd: Prieto J. 114. “Sustained Enzymatic Correction by rAAV-Mediated Liver Gene Therapy Protects Against Induced Motor Neuropathy in Acute Porphyria Mice”. Mol Ther Authors: Unzu C, Sampedro A, Mauleon I, Alegre M, Beattie SG, de Salamanca RE, Snapper J, Twisk J, Petry H, González-Aseguinolaza G, Artieda J, Rodríguez-Pena MS, Prieto J, Fontanellas A. Authors CIBERehd: Prieto J. 115. “A homozygous nonsense mutation (c.214C->A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis”. J Med Genetics Authors: Nytofte NS, Serrano MA, Monte MJ, González-Sánchez E, Tumer Z, Ladefoged K, Briz O, Marin JJ. Authors CIBERehd: Serrano MA, Monte MJ, Briz O, Marin JJ. 116.”The London position statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn’s and Colitis Organisation: safety”. Am J Gastroenterol Authors: Van Assche G, Lewis JD, Lichtenstein GR, Loftus EV, Ouyang Q, Panes J, Siegel CA, Sandborn WJ, Travis SP, Colombel JF. Authors CIBERehd: Panés J. 117. “Importance of host genetic factors HLA and IL28B as predictors of response to pegylated interferon and ribavirin”. Am J Gastroenterol Authors: de Rueda PM, López-Nevot MÁ, Sáenz-López P, Casado J, Martín-Casares A, Palomares P, Quiles R, Gila A, RomeroGómez M, Pavón EJ, Muñoz JA, Carazo A, Sanz-Cameno P, Moreno-Otero R, Diago M, León J, Ruiz-Extremera A, Salmerón J. Authors CIBERehd: de Rueda PM, Quiles R, Gila A, RomeroGómez M, Sanz-Cameno P, Moreno-Otero R, León J, RuizExtremera A, Salmerón J. 118. “Effectiveness of combined pharmacologic and ligation therapy in high-risk patients with acute esophageal variceal bleeding”. Am J Gastroenterol Authors: Augustin S, Altamirano J, González A, Dot J, Abu-Suboh M, Armengol JR, Azpiroz F, Esteban R, Guardia J, Genescà J. Authors CIBERehd: Altamirano J, Azpiroz F, Esteban R, Guardia J, Genescà J.

119. “The Amount of Alcohol Consumption Negatively Impacts Short-Term Mortality in Mexican Patients With Alcoholic Hepatitis”. Am J Gastroenterol Authors: Altamirano J, Higuera-de Latijera F, Duarte-Rojo A, Martínez-Vázquez MA, Abraldes JG, Herrera-Jiménez LE, Michelena J, Zapata L, Pérez-Hernández J, Torre A, Gonzáles-González JA, Cardenas A, Dominguez M, Arroyo V, Ginès P, Caballería J, Bataller R. Authors CIBERehd: Altamirano J , Abraldes JG , Michelena J , Arroyo V , Gines P, Caballeria J, Bataller R. 120. “Abdomino-phrenic dyssynergia in patients with abdominal bloating and distension”. Am J Gastroenterol Authors: Villoria A, Azpiroz F, Burri E, Cisternas D, Soldevilla A, Malagelada J-R. Authors CIBERehd: Azpiroz F, Malagelada JR. 121. “Effects of branched-chain amino acids supplementation in patients with cirrhosis and a previous episode of hepatic encephalopathy: a randomized study”. Am J Gastroenterol Authors: Les I, Doval E, García-Martínez R, Planas M, Cárdenas G, Gómez P, Flavià M, Jacas C, Mínguez B, Vergara M, Soriano G, Vila C, Esteban R, Córdoba J. Authors CIBERehd: Jacas C, Mínguez B, Soriano G, Esteban R, Córdoba J. 122. “Has H. pylori prevalence in bleeding peptic ulcer been underestimated? A meta-regression”. Am J Gastroenterol Authors: J Sánchez-Delgado, E Gené, D Suárez, P GarcíaIglesias, E Brullet, M Gallach, F Feu, JP Gisbert, X Calvet. Authors CIBERehd: J Sánchez-Delgado, E Gené, E Brullet, F Feu, JP Gisbert, X Calvet. 123. “Minimal hepatic encephalopathy is associated with falls”. Am J Gastroenterol Authors: Román E, Córdoba J, Torrens M, Torras X, Villanueva C, Vargas V, Guarner C, Soriano G. Authors CIBERehd: Román E, Córdoba J, Vargas V, Guarner C, Soriano G. 124. “Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: Available evidence and expert opinion on the use of transarterial chemoembolization”. Cancer Treat Rev Authors: Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L, Lencioni R Authors CIBERehd: Forner A.

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Publications 1st and 2nd Quartile CIBERehd Publications 125. “Autophagy as a rescue mechanism in efavirenzinduced mitochondrial dysfunction: a lesson from hepatic cells”. Autophagy Authors: Apostolova N, Gómez-Sucerquia LJ, Gortat A, BlasGarcía A, Esplugues JV. Authors CIBERehd: Apostolova N, Blas-García A, Esplugues JV. 126. “Role for PPAR gamma in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophagespecific conditional knockouts”. FASEB J Authors: Moran-Salvador E, López-Parra M, García-Alonso V, Titos E, Martínez-Clemente M, González-Periz A, López-Vicario C, Barak Y, Arroyo V, Claria J. Authors CIBERehd: Titos E , Arroyo V, Claria J. 127. “Induction of oxidative stress and human leukocyte/ endothelial cell interactions in polycystic ovary syndrome patients with insulin resistance”. J Clin Endocrinol Metab Authors: Victor VM, Rocha M, Bañuls C, Álvarez A, de Pablo C, Sánchez-Serrano M, Gómez M, Hernández-Mijares A. Authors CIBERehd: Victor VM, Rocha M, Álvarez A. 128. “Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C”. Clin Pharmacol Ther Authors: López-Rodríguez R, Trapero-Marugan M, Borque MJ, Roman M, Hernández-Bartolome A, Rodríguez-Muñoz Y, MartínVílchez S, Abad-Santos F, Muñoz de Rueda P, Vidal-Castiñeira JR, Rodrigo L, Salmeron J, Moreno-Otero R, Sanz-Cameno P. Authors CIBERehd: Trapero-Marugan M, Muñoz de Rueda P,Martín-Vílchez S, Abad-Santos F, Salmeron J, Moreno-Otero R, Sanz-Cameno P.

Authors CIBERehd: Abrescia NGA. 131. “Indications, results, and clinical impact of endoscopic ultrasound (EUS)-guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline”. Endoscopy Authors: Dumonceau JM, Polkowski M, Larghi A, Vilmann P, Giovannini M, Frossard JL, Heresbach D, Pujol B, FernándezEsparrach G, Vazquez-Sequeiros E, Ginès A, European Society of Gastrointestinal Endoscopy. Authors CIBERehd: Fernández-Esparrach G, Ginés A. 132. “Cyclosporine A or tacrolimus for hepatitis C recurrence? An old debat”. Am J Transplant Authors: Forns X, Navasa M. Authors CIBERehd: Forns X, Navasa M. 133. “Donor and recipient IL28B polymorphisms in HCVinfected patients undergoing antiviral therapy before and after liver transplantation”. Am J Transplant Authors: Coto-Llerena M, Pérez-Del-Pulgar S, Crespo G, Carrión JA, Martínez SM, Sánchez-Tapias JM, Martorell J, Navasa M, Forns X. Authors CIBERehd: Pérez-del-Pulgar S, Sánchez-Tapias JM, Navasa M, Forns X. 134. “Characterization of the cross-neutralizing antibody response against hepatitis C virus in the liver transplantation setting”. Am J Transplant Authors: Dragun J, Pérez-Del-Pulgar S, Crespo G, Ramírez S, Coto-Llerena M, Mensa L, García-Valdecasas JC, Navasa M, Forns X. Authors CIBERehd: Pérez-del-Pulgar S, García-Valdecasas JC, Navasa M, Forns X.

129. “Case Definition and Phenotype Standardisation in Drug-Induced Liver Injury (DILI)”. Clinical Pharmacology & Therapeutics 2011 Authors: Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, Hunt CM, Wilke RA, Avigan M, Kaplowitz N, Bjornsson E, Daly AK. Authors CIBERehd: Andrade RJ.

135. “Comparison of transcriptional and blood cellphenotypic markers between operationally tolerant liver and kidney recipients”. Am J Transplant Authors: Lozano JJ, Pallier A, Martínez-Llordella M, Danger R, López M, Giral M, Londoño MC, Rimola A, Soulillou JP, Brouard S, Sánchez-Fueyo A. Authors CIBERehd: Lozano JJ, Rimola A, Sánchez-Fueyo A.

130. “The use of low resolution phasing followed by phase extension from 7.6Å to 2.5Å resolution with noncrystallographic symmetry to solve the structure of a bacteriophage capsid protein”. Acta Cryst Authors: Abrescia N.G.A, Grimes JM, Oksanen HM, Bamford JKH, Bamford DH and Stuart DI.

136. “Melatonin modulation of intracellular signaling pathways in hepatocarcinoma HepG2 cell line: role of the MT1 receptor”. J Pineal Res Authors: Carbajo-Pescador S, García-Palomo A, Martín-Renedo J, Piva M, González-Gallego J, Mauriz JL. Authors CIBERehd: González-Gallego J, Mauriz JL.

Publications - 209

Publications 1st and 2nd Quartile CIBERehd Publications 137. “Melatonin attenuates apoptotic liver damage in fulminant hepatic failure induced by the rabbit hemorrhagic disease virus”. Journal of Pineal Research Authors: Tuñón MJ, San Miguel B, Crespo I, Jorquera F, Santamaría E, Álvarez M, Prieto J, González-Gallego J. Authors CIBERehd: Tuñón MJ, Crespo I, Jorquera F, Santamaría E, Prieto J, González-Gallego J. 138. “Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis”. BMC Med Authors: Lanas A, García-Tell G, Armada B, Oteo-Alvaro A. Authors CIBERehd: Lanas A. 139. “Resolvin D1 and Its Precursor Docosahexaenoic Acid Promote Resolution of Adipose Tissue Inflammation by Eliciting Macrophage Polarization toward an M2-Like Phenotype”. J Immunol Authors: Titos E, Rius B, González-Periz A, López-Vicario C, Moran-Salvador E, Martínez-Clemente M, Arroyo V, Claria J. Authors CIBERehd: Titos E , Arroyo V, Claria J. 140. “P2X7 receptor-dependent intestinal afferent hypersensitivity in a mouse model of post-infectious irritable bowel syndrome”. J Immunol Authors: Keating C, Pelegrin P, Martínez CM, Surprenant A, Grundy D. Authors CIBERehd: Pelegrin P, Martínez CM. 141. “Successful Colon Cancer Eradication after Chemoimmunotherapy Is Associated with Profound Phenotypic Change of Intratumoral Myeloid Cells” J Immunol Authors: Medina-Echeverz J, Fioravanti J, Zabala M, Ardaiz N, Prieto J, Berraondo P. Authors CIBERehd: Prieto J. 142. “Reciprocal regulation of NADPH oxidases and the cyclooxygenase-2 pathway”. Free Radic Biol Med Authors: Sancho P, Martín-Sanz P & Fabregat I. Authors CIBERehd: Martín-Sanz P. 143. “Mitochondrial complex I impairment in leukocytes from type 2 diabetic patients”. Free Radic Biol Med Authors: Hernández-Mijares A, Rocha M, Apostolova N, Borras C, Jover A, Bañuls C, SolaE, Victor VM. Authors CIBERehd: Rocha M, Apostolova N, Victor VM. 144.“Narrow-bandimagingasanalternativetochromoendoscopy

for the detection of dysplasia in long-standing inflammatory bowel disease: a prospective, randomized, crossover study”. Gastrointest Endosc Authors: Pellisé M, López-Cerón M, Rodríguez de Miguel C, Jimeno M, Zabalza M, Ricart E, Aceituno M, Fernández-Esparrach G, Ginès A, Sendino O, Cuatrecasas M, Llach J, Panés J. Authors CIBERehd: Pellisé M, López-Cerón M, FernándezEsparrach G, Ginès A, Cuatrecasas M, Panés J. 145. “EUS and magnetic resonance imaging in the staging of rectal cancer: a prospective and comparative study”. Gastrointest Endosc Authors: Fernández-Esparrach G, Ayuso-Colella JR, Sendino O, Pagés M, Cuatrecasas M, Pellisé M, Maurel J, Ayuso-Colella C, González-Suárez B, Llach J, Castells A, Ginès A. Authors CIBERehd: Fernández-Esparrach G, Pellisé M, Maurel J, Castells A, Ginés A. 146. “The molecular and pathophysiological implications of hepatitis B X antigen in chronic hepatitis B virus infection”. Rev Med Virol Authors: Martín-Vílchez S, Lara-Pezzi E, Trapero-Marugán M, Moreno-Otero R, Sanz-Cameno P. Authors CIBERehd: Trapero-Marugán M, Moreno-Otero R, Sanz-Cameno P. 147. “A comprehensive untargeted metabonomic analysis of human steatotic liver tissue by RP and HILIC chromatography coupled to mass spectrometry reveals important metabolic alterations”. J Proteome Res Authors: García-Cañaveras JC, Donato MT, Castell JV, Lahoz A. Authors CIBERehd: Donato MT, Castell JV. 148. “Human SREBP1c expression in liver is directly regulated by peroxisome proliferator-activated receptor alpha (PPARalpha)”. Journal of Biological Chemistry Authors: Fernández-Álvarez A, Álvarez MS, González R, Cucarella C, Muntane J, Casado M. Authors CIBERehd: González R, Muntane J, Casado M. 149. “Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding”. Clin Gastroenterol Hepatol Authors: Greenspoon J, Barkun A, Bardou M, Chiba N, Leontiadis GI, Marshall JK, Metz DC, Romagnuolo J, Sung J, International Consensus Upper Gastrointestinal Bleeding Conference Group. Authors CIBERehd: Lanas A, Calvet X (dentro del International Consensus Upper Gastrointestinal Bleeding Conference Group).

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Publications 1st and 2nd Quartile CIBERehd Publications 150. “Low doses of acetylsalicylic acid increase risk of gastrointestinal bleeding in a meta-analysis”. Clin Gastroenterol Hepatol Authors: Lanas A, Wu P, Medin J, Mills EJ. Authors CIBERehd: Lanas A. 151. “Mitochondrial cholesterol: a connection between caveolin, metabolism, and disease”. Traffic Authors: Bosch M, Marí M, Gross SP, Fernández-Checa JC, Pol A. Authors CIBERehd: Marí M, Fernández-Checa JC 152. “Connexin-26 is a key factor mediating gemcitabine bystander effect”. Molecular Cancer Therapeutics Authors: García-Rodríguez L, Pérez-Torras S, Carrió M, Cascante A, García-Ribas I, Mazo A, Fillat C. Authors CIBERehd: Pérez-Torras S, Mazo A. 153. “PTP1B deficiency accelerates hepatic regeneration in mice”. Am J Pathol Authors: Revuelta-Cervantes J, Mayoral R, Miranda S, GonzálezRodríguez A, Fernández M, Martín-Sanz P & valverde AM. Authors CIBERehd: Mayoral R, Martín-Sanz P. 154. “Transgenic mice expressing cyclooxygenase-2 in hepatocytes reveal a minor contribution of this enzyme to chemical hepatocarcinogenesis”. Am J Pathol Authors: Llorente-Izquierdo C, Mayoral R, Flores JM, GarcíaPalencia P, Boscá L, Cucarella C, Casado M & Martín-Sanz P. Authors CIBERehd: Mayoral R, Boscá L, Casado M & Martín-Sanz P. 155. “Hepatitis C Virus, Oxidative Stress and Steatosis: Current Status and Perspectives”. Curr Mol Med Authors: González-Gallego J, García-Mediavilla MV, SánchezCampos S. Authors CIBERehd: González-Gallego J, García-Mediavilla MV, Sánchez-Campos S.

Marcos-Villar L, González D, Gallego P, Lopitz-Otsoa F, Guerra S, Rodríguez MS, Esteban M, Rivas C. Authors CIBERehd: Rodríguez MS. 158. “Lethal mutagenesis of foot-and-mouth disease virus involves shifts in sequence space”. J Virol Authors: Perales C, Henry M, Domingo E, Wain-Hobson S, Vartanian JP. Authors CIBERehd: Perales C, Domingo E. 159. “Ribavirin can be mutagenic for arenaviruses”. J Virol Authors: Moreno H, Gallego I, Sevilla N, de la Torre JC, Domingo E and Martín V. Authors CIBERehd: Gallego I, Domingo E. 160. “Integrative analysis of the ubiquitin proteome isolated using Tandem Ubiquitin Binding Entities (TUBEs)”. J Proteomics Authors: Lopitz-Otsoa F, Rodríguez-Suárez E, Aillet F, CasadoVela J, Lang V, Matthiesen R, Elortza F, Rodríguez MS. Authors CIBERehd: Aillet F, Lang V, Elortza F, Rodríguez MS. 161. “Prophylactic Treatment With Escitalopram of Pegylated Interferon Alfa-2a-Induced Depression in Hepatitis C: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial”. J Clin Psyc Authors: Diez-Quevedo C, Masnou H, Planas R, Castellví P, Giménez D, Morillas RM, Martín-Santos R, Navinés R, Solà R, Giner P, Ardèvol M, Costa J, Diago M, Pretel J. Authors CIBERehd: Planas R, Morillas R. 162. “Insulin-like growth factor 1 activates methionine adenosyltransferase 2A transcription by multiple pathways in human colon cancer cells”. Biochem J Authors: Yang H, Li TW, Peng J, Mato JM, Lu SC. Authors CIBERehd: Mato JM

156. “Cardiotrophin-1 Promotes a High Survival Rate in Rabbits with Lethal Fulminant Hepatitis of Viral Origin”. J Virol Authors: Tunon MJ, San Miguel B, Crespo I, Riezu-Boj JI, Larrea E, Álvarez M, González I, Bustos M, González-Gallego J, Prieto J. Authors CIBERehd: González-Gallego J, Prieto J, Crespo I, Larrea E.

163. “Mortality in patients with septic shock correlates with anti-inflammatory but not proinflammatory immunomodulatory molecules”. Intensive Care Med Authors: de Pablo R, Monserrat J, Reyes E, Díaz-Martín D, Rodríguez Zapata M, Carballo F, de la Hera A, Prieto A, Álvarez-Mon M. Authors CIBERehd: Monserrat J, Reyes E, de la Hera A, Prieto A, Álvarez-Mon M.

157. “Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins “. J Virol Authors: González-Santamaría J, Campagna M, García MA,

164. “Effects of inhibitors of hydrogen sulphide synthesis on rat colonic motility”. Br J Pharmacol Authors: Gil V, Gallego D, & Jiménez M.

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Publications 1st and 2nd Quartile CIBERehd Publications Authors CIBERehd: Gallego D, & Jiménez M. 165. “Many ways to dilate the P2X7 receptor pore”. Br J Pharmacol Authors: Pelegrin P. Authors CIBERehd: Pelegrin P. 166. “Mitochondrial genome depletion dysregulates bile acid- and paracetamol-induced expression of the transporters Mdr1, Mrp1 and Mrp4 in liver cells”. Br J Pharmacol Authors: Pérez MJ, González-Sánchez E, González-Loyola A, González-Buitrago JM, Marin JJ. Authors CIBERehd: Pérez MJ, Marín JJ. 167. “The association of minocycline and the probiotic Escherichia coli Nissle 1917 results in an additive beneficial effect in a DSS model of reactivated colitis in mice”. Biochem Pharmacol Authors: Garrido-Mesa N, Utrilla P, Comalada M, Zorrilla P, Garrido-Mesa J, Zarzuelo A, Rodríguez-Cabezas ME, Gálvez J. Authors CIBERehd: Garrido-Mesa N, Utrilla P, Comalada M, Zorrilla P, Garrido-Mesa J, Zarzuelo A, Rodríguez-Cabezas ME, Gálvez J. 168. “Acetaminophen-induced stimulation of MDR1 expression and activity in rat intestine and in LS 174T human intestinal cell line”. Biochem Pharmacol Authors: Ghanem CI, Arias A, Novak A, Carpini GD, Villanueva S, Blazquez AG, Marin JJ, Mottino AD, Rubio MC. Authors CIBERehd: Blazquez AG, Marin JJ 169. “Inhibition of poly (ADP-ribose) polymerase-1 enhances doxorubicin activity against liver cancer cells”. Cancer Letter Authors: Muñoz-Gámez JA, Quiles-Pérez R, Ruiz-Extremera A, Martín-Álvarez AB, Sanjuan-Nuñez L, Carazo A, León J, Oliver FJ, Salmerón J. Authors CIBERehd: Quiles-Pérez R, Ruiz-Extremera A, León J, Salmerón J. 170. “DRD2 Taq1A polymorphism modulates prolactin secretion induced by atypical antipsychotics in healthy volunteers”. J Clin Psychopharmacol Authors: López-Rodríguez R, Román M, Novalbos J, Pelegrina ML, Ochoa D, Abad-Santos F Authors CIBERehd: Abad-Santos F

171. “A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22”. Br J Cancer Authors: Abulí A, Fernández-Rozadilla C, Giráldez MD, Muñoz J, Gonzalo V, Bessa X, Bujanda L, Reñé JM, Lanas A, García AM, Saló J, Argüello L, Vilella A, Carreño R, Jover R, Xicola RM, Llor X, Carvajal-Carmona L, Tomlinson IP, Kerr DJ, Houlston RS, Piqué JM, Carracedo A, Castells A, Andreu M, Ruiz-Ponte C, Castellví-Bel S, Gastrointestinal Oncology Group of the Spanish Gastroenterological Association. Authors CIBERehd: Giráldez MD, Muñoz J, Castells A, Castellví-Bel S. 172. “Adeno-Associated Virus Liver Transduction Efficiency Measured by in Vivo [(18)F]FHBG Positron Emission Tomography Imaging in Rodents and Nonhuman Primates”. Human Gene Therapy Authors: Paneda, A, Collantes, M, Beattie, SG, Otano, I, Snapper, J, Timmermans, E, Guembe, L, Petry, H, Lanciego, JL, Benito, A, Prieto, J, Rodríguez-Pena, MS, Penuelas, I, González-Aseguinolaza, G. Authors CIBERehd: Prieto J. 173. Oxidative stress and mitochondrial impairment after treatment with anti-HIV drugs, clinical implications. Curr Pharm Des Authors: Blas-García A, Apostolova N, Esplugues JV Authors CIBERehd: Blas-García A, Apostolova N, Esplugues JV 174. “A review on the role of phytosterols: new insights into cardiovascular risk”. Curr Pharm Des Authors: Rocha M, Banuls C, Bellod L, Jover A, Victor VM, Hernández-Mijares A. Authors CIBERehd: Rocha M, Victor VM 175. “Mitochondria sentencing about cellular life and death: a matter of oxidative stress”. Curr Pharm Des Authors: Apostolova N, Blas-García A, Esplugues JV. Authors CIBERehd: Apostolova N, Blas-García A, Esplugues JV. 176. “Oxidative stress and mitochondrial dysfunction in type 2 diabetes”. Curr Pharm Des Authors: Victor VM, Rocha M, Herance R, Hernández-Mijares A. Authors CIBERehd: Victor VM, Rocha M. 177. “New developments in therapy for oxidative stress-related diseases: pathophysiological and clinical

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Publications 1st and 2nd Quartile CIBERehd Publications consequences”. Curr Pharm Des Authors: Victor VM. Authors CIBERehd: Victor VM. 178. “Metabolic therapy: lessons from liver diseases”. Curr Pharm Des Authors: García-Ruiz C, Mari M, Colell A, Morales A, FernándezCheca JC. Authors CIBERehd: García-Ruiz C, Mari M, Colell A, Morales A, Fernández-Checa JC. 179. “Mitochondrial drug targets in cell death and cancer”. Curr Pharm Des Authors: Ferrín G, Linares CI, Muntané J. Authors CIBERehd: Ferrín G, Muntané J. 180. “Mitochondrial toxicity in HAART: an overview of in vitro evidence”. Curr Pharm Des Authors: Apostolova N, Blas-García A, Esplugues JV. Authors CIBERehd: Apostolova N, Blas-García A, Esplugues JV. 181. “Mitochondrial dysfunction and targeted drugs: a focus on diabetes”. Curr Pharm Des Authors: Victor VM, Rocha M, Bañuls C, Bellod L, HernándezMijares A. Authors CIBERehd: Victor VM, Rocha M. 182. “Mitochondria as a pharmacological target: a clue for efficacy and a reason for toxicity”. Curr Pharm Des Authors: Apostolova N. Authors CIBERehd: Apostolova N. 183. “Expression and distribution of nucleoside transporter proteins in the human syncytiotrophoblast”. Mol Pharmacol Authors: Errasti-Murugarren E, Díaz P, Godoy V, Riquelme G, Pastor-Anglada M. Authors CIBERehd: Errasti-Murugarren E, Godoy V, PastorAnglada M. 184. “Further characterization of the electrogenicity and pH sensitivity of the human organic anion-transporting polypeptides OATP1B1 and OATP1B3”. Mol Pharmacol Authors: Martínez-Becerra P, Briz O, Romero MR, Macias RI, Pérez MJ, Sancho-Mateo C, Lostao MP, Fernández-Abalos JM, Marin JJ. Authors CIBERehd: Briz O, Romero MR, Macias RI, Pérez MJ, Marín JJ. 185. “Prevention of peptic ulcers with esomeprazole in patients

at risk of ulcer development treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON)”. Heart Authors: Scheiman JM, Devereaux PJ, Herlitz J, Katelaris PH, Lanas A, Veldhuyzen van Zanten S, Nauclér E, Svedberg LE. Authors CIBERehd: Lanas A. 186. “Antimicrobial peptide response to blood translocation of bacterial DNA in Crohn’s disease is affected by NOD2/CAED15 genotype”. Inflam Bowel Dis Authors: Gutierrez A, Holler E, Zapater P, Sempere L, Jover R, Pérez-Mateo M, Schoelmerich J, Such J, Wiest R, Francés R. Authors CIBERehd: Zapater P, Such J, Francés R. 187. “Antimicrobial Peptide Response to Blood Translocation of Bacterial DNA in Chrohn’s Disease is Affected by NOD2/CARD15 Genotype”. Inflam Bowel Dis Authors: Gutiérrez A, Holler E, Zapater P, Sempere L, Jover R, Pérez-Mateo M, Schoelmerich J, Such J, Wiest R, Francés R. Authors CIBERehd: Such J, Frances R. 188. “Hepatic safety of antibiotics used in primary care”. J Antimicrob Chemother Authors: AndradeE RJ, Tulkens PM. Authors CIBERehd: AndradeE RJ. 189. “Detection of hepatitis B virus genotype A3 and primary drug resistance mutations in African immigrants with chronic hepatitis B in Spain”. J Antimicrob Chemother Authors: Bottecchia M, Madejón A, Puente S, García-Samaniego J, Rivas P, Herrero D, Soriano V. Authors CIBERehd: Bottechia M, Madejón A, García-Samaniego J. 190. “Novel MLH1 duplication identified in Colombian families with Lynch syndrome”. Genet Med Authors: Alonso-Espinaco V, Giráldez MD, Trujillo C, van der Klift H, Muñoz J, Balaguer F, Ocaña T, Madrigal I, Jones AM, Echeverry MM, Velez A, Tomlinson I, Milà M, Wijnen J, Carvajal-Carmona L, Castells A, Castellví-Bel S. Authors CIBERehd: Alonso- Espinaco V, Giráldez MD, Muñoz J, Balaguer F, Ocaña T, Castells A, Castellví-Bel S. 191. “Twenty years of HIV-1 non-nucleoside reverse transcriptase inhibitors: time to reevaluate their toxicity”. Curr Med Chem Authors: Blas-García A, Esplugues JV, Apostolova N. Authors CIBERehd: Blas-García A, Esplugues JV, Apostolova N. 192. “Endoplasmic reticulum stress inhibition enhances

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Publications 1st and 2nd Quartile CIBERehd Publications liver tolerance to ischemia/reperfusion”. Curr Med Chem Authors: Peralta C, Brenner C. Authors CIBERehd: Peralta C. 193. “DNFB-DNS hapten-induced colitis in mice should not be considered a model of inflammatory bowel disease”. Inflamm Bowel Dis Authors: Bailón E, Cueto-Sola M, Utrilla P, Nieto A, Garrido-Mesa N, Celada A, Zarzuelo A, Xaus J, Gálvez J, Comalada M. Authors CIBERehd: Utrilla P, Zarzuelo A, Xaus J, Gálvez J, Comalada M. 194. “Role of growth factors in the development of lymphangiogenesis driven by inflammatory bowel disease: a review”. Inflamm Bowel Dis Authors: P M Linares, JP Gisbert. Authors CIBERehd: P M Linares, JP Gisbert. 195. “Magnetic resonance imaging for evaluation of Crohn’s disease: Validation of parameters of severity and quantitative index of activity”. Inflamm Bowel Dis Authors: J Rimola, I Ordás, S Rodríguez, O García-Bosch, M Aceituno, J Llach, C Ayuso, E Ricart, J Panés. Authors CIBERehd: J Llach, J Panés. 196. “Apoptosis resistance of mucosal lymphocyes and IL-10 deficency in patients with steroid refractory Crohn’s Disease”. Inflamm Bowel Dis Authors: Santaolalla R, Mañé J, Pedrosa E, Lorén V, FernándezBañares F, Mallolas J, Carrasco A, Salas A, Rosinach M, Forné M, Espinós JC, Loras C, Donovan M, Puig P, Mañosa M, Gasull MA, Viver JM, Esteve M. Authors CIBERehd: Santaolalla R, Mañé J, Pedrosa E, Lorén V, Fernández-Bañares F, Carrasco A, Salas A, Rosinach M, Forné M, Loras C, Mañosa M, Gasull MA, Viver JM, Esteve M. 197. “Long-term durability of response to adalimumab in Crohn’s disease”. Inflamm Bowel Dis Authors: Chaparro M, Panés J, García V, Merino O, Nos P, Domènech E, Peñalva M, García-Planella E, Esteve M, Hinojosa J, Andreu M, Muñoz F, Gutiérrez A, Mendoza, JL, Barrio J, Barreirode M, Vera I, Vilar P, Cabriada JL, Montoro MA, Aldeguer, X, Saro C, Gisbert JP. Authors CIBERehd: Chaparro M, Panés J, Nos P, Domènech E, Esteve M, Gisbert JP. 198. “Decision tree for early introduction of rescue therapy in active ulcerative colitis”. Inflamm Bowel Dis

Authors: Mañosa M, Cabré E, García-Planella E, Bernal I, Gordillo J, Esteve M, Zabana Y, Gassull MA, Domenech E. Authors CIBERehd: Mañosa M, Cabré E, Esteve M, Zabana Y, Gassull MA, Domenech E. 199. “Predictors of fibrostenotic Crohn’s disease”. Inflamm Bowel Dis Authors: Rieder F, Lawrance IC, Leite A, Sans M. Authors CIBERehd: Sans M. 200. “Development and validation of the Crohn’s disease perceived work disability questionnaire”. Inflamm Bowel Dis Authors: Vergara M, Montserrat A, Casellas F, Gallardo O, Suárez D, Motos J, Villoria A, Miquel M, Martínez-Bauer E, Calvet X. Authors CIBERehd: Vergara M, Montserrat A, Casellas F, Gallardo O, Suárez D, Motos J, Villoria A, Miquel M, Martínez-Bauer E, Calvet X. 201. “Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in nonalcoholic fatty liver disease and hepatitis C.” Clin Sci (Lond) Authors: Lima-Cabello E, García-Mediavilla MV, MiquilenaColina ME, Vargas-Castrillón J, Lozano-Rodríguez T, FernándezBermejo M, Olcoz JL, González-Gallego J, García-Monzón C, Sánchez-Campos S. Authors CIBERehd: García-Mediavilla MV, Vargas-Castrillón J, Olcoz JL, González-Gallego J, García-Monzón C, Sánchez-Campos S. 202. “Smoking status and response to thiopurines in steroid-dependent inflammatory bowel disease”. Inflamm Bowel Dis Authors: Domènech E, Carrión S, García-Planella E, Mañosa M, Concepción M, Guarner C, Cabré E. Authors CIBERehd: Domènech E, García-Planella E, Mañosa M, Guarner C, Cabré E. 203. “Tocotrienols have potent antifibrogenic effects in human intestinal fibroblasts”. Inflamm Bowel Dis Authors: Luna J, Masamunt MC, Rickmann M, Mora R, España C, Delgado S, Llach J, Vaquero EC, Sans M. Authors CIBERehd: Vaquero EC 204. “Tissue-nonspecific alkaline phosphatase is activated in enterocytes by oxidative stress via changes in glycosylation”. Inflamm Bowel Dis Authors: López-Posadas R, González R, Ballester I, MartínezMoya P, Romero-Calvo I, Suárez MD, Zarzuelo A, MartínezAugustin O, Sánchez de Medina F.

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Publications 1st and 2nd Quartile CIBERehd Publications Authors CIBERehd: López-Posadas R, González R, Ballester I, Martínez-Moya P, Romero-Calvo I, Suárez MD, Zarzuelo A, Martínez-Augustin O, Sánchez de Medina F. 205. “Prolonged bisphosphonate release after treatment in women with osteoporosis”. Bone Authors: Peris P, Torra M, Olivares V, Reyes R, Monegal A, Martínez-Ferrer A, Guañabens N. Authors CIBERehd: Peris P, Guañabens N. 206. “Alcoholic liver disease: pathogenesis and new targets for therapy”. Nat Rev Gastroenterol Hepatol Authors: Altamirano J, Bataller R. Authors CIBERehd: Altamirano J, Bataller R. 207. Intravenous iron in IBD—what’s the best preparation? Nat Rev Gastroenterol Hepatol Authors: F Gomollon, JP Gisbert Authors CIBERehd: F Gomollon, JP Gisbert 208. “Viral hepatitis: Ciclosporin versus tacrolimus for HCV transplant recipients”. Nat Rev Gastroenterol Hepatol Authors: Berenguer M. Authors CIBERehd: Berenguer M. 209. “Gastrointestinal effects of aspirin”. Nat Rev Gastroenterol Hepatol Authors: Sostres C, Lanas A. Authors CIBERehd: Lanas A. 210. “Helicobacter pylori eradication: A new, singlecapsule bismuth-containing quadruple therapy”. Nat Rev Gastroenterol Hepatol Authors: JP Gisbert. Authors CIBERehd: JP Gisbert. 211. “Portal hypertension: Nonselective β-blockers in patients with refractory ascites”. Nat Rev Gastroenterol Hepatol Authors: García-Pagán JC. Authors CIBERehd: García-Pagan JC. 212. “Self-inactivating helper virus for the production of high-capacity adenoviral vectors”. Gene Ther Authors: González-Aparicio M, Mauleon I, Alzuguren P, Bunuales M, González-Aseguinolaza G, San Martín C, Prieto, J, Hernández-Alcoceba R. Authors CIBERehd: Prieto J.

213. “Effects of flavonoids and other polyphenols on inflammation”. Crit Rev Food Sci Nutr Authors: González R, Ballester I, López-Posadas R, Suárez MD, Zarzuelo A, Martínez-Augustin O, Sánchez de Medina F. Authors CIBERehd: González R, Ballester I, López-Posadas R, Suárez MD, Zarzuelo A, Martínez-Augustin O, Sánchez de Medina F. 214. “Mitochondrial antioxidants alleviate oxidative and nitrosative stress in a cellular model of sepsis”. Pharm Res Authors: Apostolova N, García-Bou R, Hernández-Mijares A, Herance R, Rocha M, Victor VM. Authors CIBERehd: Apostolova N, Rocha M, Victor VM. 215. “An engineered inhibitor RNA that efficiently interferes with hepatitis C virus translation and replication. Antivir Res Authors: Romero-López, C., Berzal-Herranz, B., Gómez, J. and Berzal-Herranz, A. Authors CIBERehd: Gómez J. 216. “Efficacy and tolerance of a combination of tenofovir disoproxil fumarate plus emtricitabine in patients with chronic hepatitis B: a European multicenter study”. Antivir Res Authors: Si-Ahmed SN, Pradat P, Zoutendijk R, Buti M, Mallet V, Cruiziat C, Deterding K, Dumortier J, Bailly F, Esteban R, Wedemeyer H, Janssen HL, Zoulim F. Authors CIBERehd: Buti M, Esteban R. 217. “Ursodeoxycholic Acid Is Conjugated with Taurine to Promote Secretin-Stimulated Biliary Hydrocholeresis in the Normal Rat”. PLoS One Authors: Uriz M, Saez E, Prieto J, Medina JF, Banales JM. Authors CIBERehd: Prieto J, Medina JF, Banales JM. 218. “Genetic associations in the vitamin D receptor and colorectal cancer in African Americans and Caucasians”. PLoS One Authors: Kupfer SS, Anderson JR, Ludvik AE, Hooker S, Skol A, Kittles RA, Keku TO, Sandler RS, Ruiz-Ponte C, Castellví-Bel S, Castells A, Carracedo A, Ellis NA. Authors CIBERehd: Castellví-Bel S, Castells A. 219. “Role of monoubiquitylation on the control of IκBα degradation and NF-κB activity”. PLoS One Authors: Da Silva-Ferrada E, Torres-Ramos M, Aillet F, Campagna M, Matute C, Rivas C, Rodríguez MS, Lang V. Authors CIBERehd: Aillet F, Rodríguez MS, Lang V.

Publications - 215

Publications 1st and 2nd Quartile CIBERehd Publications 220. “Esophagitis in a high H. pylori prevalence area: severe disease is rare but concomitant peptic ulcer is frequent”. PLoS One Authors: J Ponce, X Calvet, M Gallach, M Ponce. Authors CIBERehd: J Ponce, X Calvet, M Gallach, M Ponce.

227. “The 5-lipoxygenase/leukotriene pathway in obesity, insulin resistance, and fatty liver disease”. Curr Opin Clin Nutr Metab Care Authors: Martínez-Clemente, Marcos, Claria, Joan, Titos, Esther Authors CIBERehd: Claria J, Titos E

221. “Transketolase-like 1 expression is modulated during colorectal cancer progression and metastasis formation”. PLoS One Authors: Díaz-Moralli S, Tarrado-Castellarnau M, Alenda C, Castells A, Cascante M. Authors CIBERehd: Castells A

228. “Suppression of Amphiregulin/Epidermal Growth Factor Receptor Signals Contributes to the Protective Effects of Quercetin in Cirrhotic Rats”. J Nutr Authors: Cuevas MJ, Tieppo J, Marroni NP, Tuñón MJ, González-Gallego J. Authors CIBERehd: Cuevas MJ, Tuñón MJ, González-Gallego J.

222. “Cell culture replication of a genotype 1b hepatitis C virus isolate cloned from a patient who underwent liver transplantation”. PLoS One Authors: Koutsoudakis G, Pérez-del-Pulgar S, Coto-Llerena M, González P, Dragun J, Mensa L, Crespo G, Navasa M, Forns X. Authors CIBERehd: Pérez-del-Pulgar S, Navasa M, Forns X.

229. “HCV-Specific T cell Responses in HIV/HCV coinfected patients on HAART are comparable to those observed in HCV-monoinfected individuals”. Journal of Acquired Immune Deficiency Syndromes Authors: Rallón NI, Soriano V, Restrepo C, García-Samaniego J, Labarga P, López M, Peris A, González-Lahoz J, Benito J. Authors CIBERehd: García-Samaniego J.

223. “Proteomic analysis of polypeptides captured from blood during extracorporeal albumin dialysis in patients with cholestasis and resistant pruritus”. PLoS One Authors: Gay M, Pares A, Carrascal M, Bosch-i-Crespo P, Gorga M, Mas A, Abian J. Authors CIBERehd: Pares A, Mas A. 224. “Real-Time PCR Improves Helicobacter pylori Detection in Patients with Peptic Ulcer Bleeding”. PLoS One Authors: Ramírez-Lázaro MJ, Lario S, Casalots A, Sanfeliu E, Boix L, García-Iglesias P, Sánchez-Delgado J, Montserrat A, BellaCueto MR, Gallach M, Sanfeliu I, Segura F, Calvet X. Authors CIBERehd: Ramírez-Lázaro MJ, Lario S, Boix L, GarcíaIglesias P, Sánchez-Delgado J, Montserrat A, Calvet X. 225. “Probiotic sonicates selectively induce mucosal immune cells apoptosis through ceramide generation via neutral sphingomyelinase”. PLoS One Authors: Angulo S, Morales A, Danese S, Llacuna L, Masamunt MC, Pultz N, Cifone MG, De Simone C, Delgado S, Vila J, Panés J, Donskey C, Fernández-Checa JC, Fiocchi C, Sans M. Authors CIBERehd: Morales A, Panés J, Fernández-Checa JC, Sans M. 226. “P2X7 receptor antagonism in the treatment of cancers”. Expert Opinion on Investigational Drugs Authors: Roger S, Pelegrin P. Authors CIBERehd: Pelegrin P.

230. “Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases”. Medicine (Baltimore) Authors: Pérez-Álvarez R, Díaz-Lagares C, García-Hernández F, López-Roses L, Brito-Zerón P, Pérez-de-Lis M, Retamozo S, Bové A, Bosch X, Sánchez-Tapias JM, Forns X, Ramos-Casals M, BIOGEAS Study Group. Authors CIBERehd: Sánchez-Tapias JM, Forns X. 231. “Prognosis of Hepatocellular Carcinoma in Relation to Treatment Across BCLC Stages”. Ann Surg Oncol Authors: D’Avola D, Inarrairaegui M, Pardo F, Rotellar F, Marti P, Bilbao JI, Martínez-Cuesta A, Benito A, Alegre F, Mauleon E, Herrero JI, Quiroga J, Prieto J, Sangro B. Authors CIBERehd: D’Avola D, Herrero JI, Quiroga J, Prieto J, Sangro B. 232. “1990-2010: two decades of interferon-based therapy”. Clin Liver Dis Authors: Buti M, Esteban R. Authors CIBERehd: Buti M, Esteban R. 233. “Harnessing tumor necrosis factor receptors to enhance antitumor activities of drugs”. Chemical Research in Toxicology Authors: Muntané J. Authors CIBERehd: Muntané J.

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Publications 1st and 2nd Quartile CIBERehd Publications 234. “Retinol-binding protein 4 and peroxisome proliferator-activated receptor-γ in steatotic liver transplantation”. J Pharmacol Exp Ther Authors: Casillas-Ramírez A, Alfany-Fernández I, MassipSalcedo M, Juan ME, Planas JM, Serafín A, Pallàs M, Rimola A, Rodés J, Peralta C. Authors CIBERehd: Massip-Salcedo M, Rimola A, Peralta C. 235. “Influence of mutagenesis and viral load on the sustained, low-level replication of an RNA virus”. J Mol Biol Authors: Perales C, Agudo R, Manrubia SC, and Domingo E. Authors CIBERehd: Perales C, Domingo E. 236. “Archaeal RNA polymerase: the influence of the protruding stalk in crystal packing and preliminary biophysical analysis of the Rpo13 subunit”. Biochem Soc Trans Authors: Wojtas M, Peralta B, Ondiviela M, Mogni M, Bell SD and Abrescia NGA. Authors CIBERehd: Abrescia NGA. 237. “Relationship between erectile dysfunction and silent myocardial ischemia in type 2 diabetic patients with no known macrovascular complications”. J Sex Med Authors: García-Malpartida K, Mármol R, Jover A, GómezMartínez MJ, Solá-Izquierdo E, Victor VM, Rocha M, Sanmiguel D, Hernández-Mijares A. Authors CIBERehd: Victor VM, Rocha M. 238. “Utility of Measuring anti-TNF agents and anti-drug antibodies serum concentrations in inflammatory bowel disease”. Current Drug Metabolism Authors: I Guerra, M Chaparro, F Bermejo, JP Gisbert. Authors CIBERehd: M Chaparro, JP Gisbert. 239. “Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study”. Aliment Pharmacol Ther Authors: Chaparro M, Burgueño P, Iglesias E, Panés J, Muñoz F, Bastida G, Castro L, Jiménez C, Mendoza JL, Barreiro-de Acosta M, Senent SG, Gomollón F, Calvet X, García-Planella E, Gómez M, Hernández V, Hinojosa J, Mañosa M, Nyssen OP, Gisbert JP. Authors CIBERehd: Chaparro M, Iglesias E, Panés J, Bastida G, Barreiro-de Acosta M, Senent SG, Gomollón F, Calvet X, GarcíaPlanella E, Hernández V, Mañosa M, Gisbert JP. 240. “Review article: The effectiveness of standard tripletherapy for Helicobacter pylori has not changed over the last

decade, but it is not good enough”. Aliment Pharmacol Ther Authors: Gisbert JP, Calvet X. Authors CIBERehd: Gisbert JP, Calvet X. 241. “Review article: Common misconceptions in the management of H. pylori-associated gastric MALTlymphoma”. Aliment Pharmacol Ther Authors: Gisbert JP, Calvet X. Authors CIBERehd: Gisbert JP, Calvet X. 242.“Meta-analysis: Predictors of rebleeding after endoscopic treatment for bleeding peptic ulcer”. Aliment Pharmacol Ther Authors: García-Iglesias P, Villoria A, Suárez D, Brullet E, Gallach M, Feu F, Gisbert JP, Barkun A, Calvet X. Authors CIBERehd: Brullet E, Feu F, Gisbert JP, Calvet X. 243. “Peripheral blood monocyte subsets predict antiviral response in chronic hepatitis C”. Aliment Pharmacol Ther Authors: Rodríguez-Muñoz Y, Martín-Vílchez S, López-Rodríguez R, Hernández-Bartolomé A, Trapero-Marugán M, Borque MJ, Moreno-Otero R, Sanz-Cameno P. Authors CIBERehd: Trapero-Marugán M, Moreno-Otero R, SanzCameno P. 244. “Pregnancy Outcome in Inflammatory Bowel Disease: Prospective European Case-control ECCO-EpiCom Study, 2003-2006”. Aliment Pharmacol Ther Authors: Bortoli A, Pedersen N, Duricova D, D´Inca R, Gionchetti P, Panelli MR, Ardizzone S, López Sanroman A, Gisbert JP, Arena I, Riegler G, Kohn A, Valpiani D, Corbellini A, Segato S, Castiglione F, Munkholm P, on behalf of the European Crohn-Colitis Organisation study group. Authors CIBERehd: Gisbert JP. 245. “Haemoglobin decreases in NSAID users over time: an analysis of two large outcome trials”. Aliment Pharmacol Ther Authors: Goldstein JL, Chan FK, Lanas A, Wilcox CM, Peura D, Sands GH, Berger MF, Nguyen H, Scheiman JM. Authors CIBERehd: Lanas A. 246. “Review article: Non-bismuth quadruple (concomitant) therapy for Helicobater pylori eradication”. Aliment Pharmacol Ther Authors: JP Gisbert, X Calvet. Authors CIBERehd: JP Gisbert, X Calvet.

Publications - 217

Publications 1st and 2nd Quartile CIBERehd Publications 247. “Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients”. Aliment Pharmacol Ther Authors: González-Lama Y, Bermejo F, López-Sanromán A, García-Sánchez V, Esteve M,Cabriada JL, McNicholl AG, Pajares R, Casellas F, Merino O, Carpio D, Vera MI,Muñoz C, Calvo M, Benito LM, Bujanda L, García-Fernández FJ, Ricart E, Ginard D, Velasco M, Carneros JA, Manceñido N, Calvo M, Algaba A, Froilan C, Cara C, Maté J, Abreu L, Gisbert JP. Authors CIBERehd: González-Lama Y, Esteve M,Cabriada JL, McNicholl AG, Muñoz C, Bujanda L, Ricart E, Maté J, Gisbert JP. 248. “Randomised clinical trial: otilonium bromide improves frequency of abdominal pain, severity of distention and time to relapse in patients with irritable bowel syndrome”. Aliment Pharmacol Ther Authors: Clavé P, Acalovschi M, Triantafillidis JK, Uspensky YP, Kalayci C, Shee V, Tack J, OBIS Study Investigators. Authors CIBERehd: Clavé P. 249. “Meta-analysis: insulin resistance and sustained virological response in hepatitis C”. Aliment Pharmacol Ther Authors: Eslam M, Aparcero R, Kawaguchi T, Del Campo JA, Sata M, Khattab MA, Romero-Gómez M. Authors CIBERehd: del Campo A, Romero-Gómez M. 250. “Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn’s disease”. Aliment Pharmacol Ther Authors: Panés J, Bouzas R, Chaparro M, García-Sánchez V, Gisbert JP, Martínez de Guereñu B, Mendoza JL, Paredes JM, Quiroga S, Ripollés T, Rimola J. Authors CIBERehd: Panés J, Chaparro M, Gisbert JP. 251. “Clinical predictors of poor outcomes among patients with nonvariceal upper gastrointestinal bleeding in Europe”. Aliment Pharmacol Ther Authors: Lanas A, Aabakken L, Fonseca J, Mungan ZA, Papatheodoridis GV, Piessevaux H, Cipolletta L, Nuevo J, Tafalla M. Authors CIBERehd: Lanas A. 252. “Prevention and management of hepatitis B and C infection in Inflammatory Bowel Disease”. Aliment Pharmacol Ther Authors: Gisbert JP, Chaparro M, Esteve M. Authors CIBERehd: Gisbert JP, Chaparro M, Esteve M.

253. “Review article: the design of clinical trials in hepatic encephalopathy--an International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) consensus statement”. Aliment Pharmacol Ther Authors: Bajaj JS, Córdoba J, Mullen KD, Amodio P, Shawcross DL, Butterworth RF, Morgan MY. Authors CIBERehd: Córdoba J. 254. “The changing face of hospitalization due to gastrointestinal bleeding and perforation”. Aliment Pharmacol Ther Authors: Lanas A, García Rodríguez LA, Polo-Tomas M, Ponce M, Quintero E, Pérez-Aisa, JP Gisbert A, Bujanda L, Castro M, M Muñoz, Del-Pino D, García S, Calvet X. Authors CIBERehd: Lanas A, Polo-Tomas M, Ponce M, Gisbert JP, Bujanda L, Castro M, Calvet X. 255. “Adalimumab induction and maintenance therapy for ulcerative colitis patients previously treated with Infliximab”. Aliment Pharmacol Ther Authors: Taxonera C, Estellés J, Fernández-Blanco I, Merino O, Marín-Jiménez I, Barreiro M, Saro C, García V, García-Morán S, Bastida G, Gisbert JP, Vera I, Martínez MP, García Morán S, Chaparro M, Mendoza JL. Authors CIBERehd: Gisbert JP, Chaparro M. 256. “Bacterial DNA in the diagnosis of spontaneous bacterial peritonitis”. Aliment Pharmacol Ther Authors: Soriano G, Esparcia O, Montemayor M, GuarnerArgente C, Pericas R, Torras X, Calvo N, Román E, Navarro F, Guarner C, Coll P. Authors CIBERehd: Soriano G, Guarner C, Roman E. 257. “Assessment of liver fibrosis before and after antiviral therapy by different serum marker panels in patients with chronic hepatitis C”. Aliment Pharmacol Ther Authors: Martínez SM, Fernández-Varo G, González P, Sampson E, Bruguera M, Navasa M, Jiménez W, Sánchez-Tapias JM, Forns X. Authors CIBERehd: Fernández-Varo G, Bruguera M, Navasa M, Jiménez W, Sánchez-Tapias JM, Forns X. 258. “Review article: Defining remission in ulcerative colitis”. Aliment Pharmacol Ther Authors: Travis SP, Higgins PD, Orchard T, Van Der Woude CJ, Panaccione R, Bitton A, O’Morain C, Panés J, Sturm A, Reinisch W, Kamm MA, D’Haens G. Authors CIBERehd: Panés J.

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Publications 1st and 2nd Quartile CIBERehd Publications 259. “Phenotypic differences during the osteogenic differentiation of single-cell derived clones isolated from human lipoaspirates”. Journal of Tissue Engineering and Regenerative Medicine Authors: Paredes B, Santana A, Arribas MI, Vicente-Salar N, de Aza PN, Roche E, Such J, Reig JA. Authors CIBERehd: Such J.

266. “Abacavir coadministration does not interfere with the suppressive activity of ribavirin in an HCV replicon system”. Antivir Ther Authors: Van den Eynde E, Quer J, Cubero M, Curran A, Homs M, García-Cehic D, Falco V, Ribera E, Esteban JI, Pahissa A, Crespo M. Authors CIBERehd: Quer J, Cubero M, Homs M, García-Cehic D, Esteban JI, Crespo M.

260. “Steatotic liver: a suitable source for the isolation of hepatic progenitor cells”. Liver Int Authors: Tolosa L, Bonora-Centelles A, Teresa Donato M, Pareja E, Negro A, López S, Castell JV, José Gómez-Lechón M. Authors CIBERehd: Teresa Donato M, Castell JV, José GómezLechón M.

267. “Natural polymorphisms associated with resistance to new antivirals against HCV in newly diagnosed HIV-HCVcoinfected patient”. Antivir Ther Authors: Treviño A, de Mendoza C, Parra P, Rodríguez C, Madejón A, Plaza Z, del Romero J, Poveda E, Soriano V. Authors CIBERehd: Madejón A.

261. “Brain biomolecules oxidation in portacaval-shunted rats”. Liver Int Authors: Carbonero-Aguilar P, Díaz-Herrero Mdel M, Cremades O, Romero-Gómez M, Bautista J. Authors CIBERehd: Romero-Gómez M, Bautista J.

268. “Multiple telencephalic and extratelencephalic embryonic domains contribute neurons to the medial extended amygdala”. Journal of Comparative Neurology Authors: Bupesh M, Legaz I, Abellán A, Medina L. Authors CIBERehd: Legaz I.

262. “A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel”. Liver Int Authors: Cornberg M, Razavi HA, Alberti A, Bernasconi E, Buti M, Cooper C, Dalgard O, Dillion JF, Flisiak R, Forns X, Frankova S, Goldis A, Goulis I, Halota W, Hunyady B, Lagging M, Largen A, Makara M, Manolakopoulos S, Marcellin P, Marinho RT, Pol S, Poynard T, Puoti M, Sagalova O, Sibbel S, Simon K, Wallace C, Young K, Yurdaydin C, Zuckerman E, Negro F, Zeuzem S. Authors CIBERehd: Buti M, Forns X.

269. “HBV core region variability: effect of antiviral treatments on main epitopic regions”. Antivir Ther Authors: Homs M, Jardi R, Buti M, Schaper M, Tabernero D, Fernandez-Fernández P, Quer J, Esteban R, Rodríguez-Frias F. Authors CIBERehd: Homs M, Jardi R, Buti M, Schaper M, Tabernero D, Quer J, Esteban R, Rodríguez-Frias F

263. “Genes and hepatitis C: susceptibility, fibrosis progression and response to treatment”. Liver Int Authors: Romero-Gómez M, Eslam M, Ruiz A, Maraver M. Authors CIBERehd: Romero-Gómez M. 264. “Insulin resistance and sustained virological response in hepatitis C: from bench to bedside”. Liver Int Authors: Romero-Gómez M. Authors CIBERehd: Romero-Gómez M. 265. “[(11)C]-DASB microPET imaging in the aged rat: frontal and meso-thalamic increases in serotonin transporter binding”. Exp Gerontol Authors: Hoekzema E, Rojas S, Herance R, Pareto D, Abad S, Jiménez X, Figueiras FP, Popota F, Ruiz A, Flotats N, Fernández FJ, Rocha M, Rovira M, Víctor VM, Gispert JD. Authors CIBERehd: Rocha M, Victor VM.

270. “Intestinal inflammation and the enterocyte transportome”. Biochem Soc Trans Authors: Romero-Calvo I, Mascaraque C, Zarzuelo A, Suárez MD, Martínez-Augustin O, Sánchez de Medina F. Authors CIBERehd: Zarzuelo A, Suárez MD, Martínez-Augustin O, Sánchez de Medina F. 271. “Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study”. Transplantation Authors: Castells LL, Campos I, Bilbao I, Navasa M, Carrion J, Forns X, Berenguer M, Aguilera V, Prieto M, Fernández I, Meneu JC, Ulloa E, Fernández JR, Suárez MJ, Pascasio JM, Sousa JM, Casanovas T, Baliella C, Bárcena R, Rodríguez M, de la Mata M, Barrera P, Salcedo M, Bañares R, Otero A, Suárez F, Baños I, Tomé S, Herrero I, Guilera M. Authors CIBERehd: Castells Ll, Campos I, Bilbao I, Navasa M, Forns X, Berenguer M, Aguilera V, Prieto M, de la Mata M, Barrera P, Salcedo M, Bañares R, Herrero I.

Publications - 219

Publications 1st and 2nd Quartile CIBERehd Publications 272. “Influence of platelet lysate on the recovery and metabolic performance of cryopreserved human hepatocytes upon thawing”. Transplantation Authors: Tolosa L, Bonora-Centelles A, Donato MT, Mirabet V, Pareja E, Negro A, López S, Castell JV, Gómez-Lechón MJ. Authors CIBERehd: Donato MT,Castell JV, Gómez-Lechón MJ. 273. “S-Adenosylmethionine regulates connexins subtypes expressed by hepatocytes” European Journal of Cell Biology Authors: Yamaji S, Droggiti A, Lu SC, Martínez-Chantar ML, Warner A, Varela-Rey M. Authors CIBERehd: Martínez-Chantar ML, Varela-Rey M. 274. “The intestinal anti-inflammatory effect of minocycline in experimental colitis involves both its immunomodulatory and antimicrobial properties”. Pharmacol Res Authors: Garrido-Mesa N, Camuesco D, Arribas B, Comalada M, Bailón E, Cueto-Sola M, Utrilla P, Nieto A, Zarzuelo A, RodríguezCabezas ME, Gálvez J. Authors CIBERehd: Camuesco D, Arribas B, Comalada M, Bailón E, Cueto-Sola M, Utrilla P, Nieto A, Zarzuelo A, RodríguezCabezas ME, Gálvez J. 275. “Nitric oxide induces HIF-1α stabilization and expression of intestinal trefoil factor in the damaged rat jejunum and modulates ulcer healing”. J Gastroenterol Authors: Riaño A, Ortiz-Masià D, Velázquez M, Calatayud S, Esplugues JV, Barrachina MD. Authors CIBERehd: Ortiz-Masià D, Calatayud S, Esplugues JV, Barrachina MD. 276. “Covalent modification by SUMO is required for Kaposi’s sarcoma-associated herpesvirus latent protein LANA2 to efficiently disrupt PML Oncogenic Domains”. J Gen Virol Authors: Marcos-Villar L, Campagna M, Lopitz-Otsoa F, Gallego P, González-Santamaria J, González D, Rodríguez MS, Rivas C. Authors CIBERehd: Rodríguez MS.

human esophagus”. Am J Physiol Authors: Lecea B, Gallego D, Farre R, Opazo A, Auli M, Jiménez M, Clavé P. Authors CIBERehd: Lecea B, Gallego D, Farre R, Jiménez M, Clavé P. 279. “Use of transient elastography (FibroScan (R)) for the noninvasive assessment of portal hypertension in HIV/ HCV-coinfected patients”. J Viral Hep Authors: Sánchez-Conde M, Miralles P, Bellon JM, Rincon D, Ramírez M, Gutierrez I, Ripoll C, López JC, Cosin J, Clemente G, Lo Iacono O, Bañares R, Berenguer J. Authors CIBERehd: Rincon D, Ripoll C, Clemente G, Lo Iacono O, Bañares R. 280. “Use of HOMA-IR in hepatitis C”. J Viral Hep Authors: Eslam M, Kawaguchi T, Del Campo JA, Sata M, Khattab MA, Romero-Gómez M. Authors CIBERehd: del Campo A, Romero-Gómez M. 281. “The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference”. J Viral Hep Authors: Hatzakis A, Wait S, Bruix J, Buti M, Carballo M, Cavaleri M, Colombo M, Delarocque-Astagneau E, Dusheiko G, Esmat G, Esteban R, Goldberg D, Gore C, Lok AS, Manns M, Marcellin P, Papatheodoridis G, Peterle A, Prati D, Piorkowsky N, Rizzetto M, Roudot-Thoraval F, Soriano V, Thomas HC, Thursz M, Valla D, van Damme P, Veldhuijzen IK, Wedemeyer H, Wiessing L, Zanetti AR, Janssen HL. Authors CIBERehd: Bruix J 282. “Clinical outcome of acute and chronic hepatitis delta over time: a long-term follow-up study”. J Viral Hep Authors: Buti M, Homs M, Rodríguez-Frias F, Funalleras G, Jardí R, Sauleda S, Tabernero D, Schaper M, Esteban R. Authors CIBERehd: Buti M, Homs M, Rodríguez-Frias F, Jardí R, Sauleda S, Tabernero D, Schaper M, Esteban R.

277. “Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis”. Am J Physiol Authors: González AM, García T, Samper E, Rickmann M, Vaquero EC, Molero X. Authors CIBERehd: Vaquero EC, Molero X.

283. “A prospective study of T- and B-lymphocyte subpopulations, CD81 expression levels on B cells and regulatory CD4+CD25+CD127low/-FoxP3+T cells in patients with chronic HCV infection during pegylated interferon-alpha2a plus ribavirin treatment” J Viral Hep Authors: Soldevila B, Alonso N, Martínez-Arconada MJ, Morillas RM, Planas R, Sanmartí AM, Martínez-Cáceres EM. Authors CIBERehd: Morillas RM, Planas R.

278. “Regional functional specialization and inhibitory nitrergic and nonnitrergic coneurotransmission in the

284. “Hepatitis C virus (HCV) treatment uptake and changes in the prevalence of HCV genotypes in HIV/HCV-

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Publications 1st and 2nd Quartile CIBERehd Publications coinfected patients”. J Viral Hep Authors: J Medrano, S Resino, E Vispo, A Madejón, P Labarga, P Tuma, L Martín-Carbonero, P Barreiro, S Rodríguez-Novoa, I Jiménez-Nacher, V Soriano. Authors CIBERehd: Madejón A. 285. “Molecuar pathogenesis of hepatocellular carcinoma”. Alcohol Clin Exp Res Authors: Cornellà H, Alsinet C, Villanueva A. Authors CIBERehd: Villanueva A. 286. “The Hepatocarcinogenic Effect of Methionine and Choline Deficient Diets: An Adaptation to the Warburg Effect?”. Alcohol Clin Exp Res Authors: Mato JM, Lu SC. Authors CIBERehd: Mato JM. 287. “Biexponential analysis of diffusion-tensor imaging of the brain in cirrhosis patients before and after liver transplantation”. AJNR Am J Neuroradiol Authors: Chavarria L, Alonso J, García-Martínez R, Aymerich X, Huerga E, Jacas C, Vargas V, Córdoba J, Rovira A. Authors CIBERehd: Chavarria L, Alonso J, García-Martínez R, Aymerich X, Huerga E, Jacas C, Vargas V, Córdoba J, Rovira A. 288. “Transplacental transfer of immunosuppresants and biologics used for the treatment of inflammatory bowel disease”. Current Pharmaceutical Biotechnology Authors: Chaparro M, Gisbert JP. Authors CIBERehd: Chaparro M, Gisbert JP. 289. “Palm oil tocotrienol rich fraction reduces extracellular matrix production by inhibiting transforming growth factor-beta 1 in human intestinal fibroblasts in human intestinal fibroblasts”. Clin Nutr Authors: Luna J, Masamunt MC, Llach J, Delgado S, Sans M. Authors CIBERehd: Luna J, Masamunt MC, Llach J, Delgado S, Sans M. 290. “Low intestinal cholesterol absorption is associated with a reduced efficacy of phytosterol esters as hypolipemic agents in patients with metabolic syndrome”. Clin Nutr Authors: Hernández-Mijares A, Bañuls C, Jover A, Solá E, Bellod L, Martínez-Triguero ML, Lagarda MJ, Víctor VM, Rocha M. Authors CIBERehd: Víctor VM, Rocha M. 291. “A signature of six genes highlights defects on cell growth and specific metabolic pathways in murine and human

hepatocellular carcinoma”. Functional & Integrative Genomics Authors: Schroder PC, Segura V, Riezu JI, Sangro B, Mato JM, Prieto J, Santamaria E, Corrales FJ. Authors CIBERehd: Sangro B, Mato JM, Prieto J. 292. “Should prophylactic low-dose aspirin therapy be continued in peptic ulcer bleeding?”. Drugs Authors: Sostres C, Lanas A. Authors CIBERehd: Lanas A. 293. “Assessment of nonsteroidal anti-inflammatory druginduced hepatotoxicity”. Expert Opinion on Drug Metabolism & Toxicology 2011 Authors: Agúndez JA, Lucena MI, Martínez C, Andrade RJ, Blanca M, Ayuso P, García-Martín E. Authors CIBERehd: Lucena MI, Andrade RJ. 294. “Treatment of IBS-D with 5-HT3 receptor antagonists vs spasmolytic agents: similar therapeutical effects from heterogeneous pharmacological targets” Neurogastroenterology and Motility Authors: Clavé P. Authors CIBERehd: Clavé P. 295. “Persistent epithelial barrier alterations in a rat model of postinfectious gut dysfunction”. Neurogastroenterology and Motility Authors: Fernández-Blanco JA, Barbosa S, de Medina FS, Martínez V, Vergara P. Authors CIBERehd: Vergara P. 296.“Characterization of purinergic inhibitory neuromuscular transmission in the human colon”. Neurogastroenterology and Motility Authors: Gallego D, Gil V, Aleu J, Martínez-Cutillas M, Clavé P and Jiménez M. Authors CIBERehd: Gallego D, Gil V, Clavé P and Jiménez M. 297. “Specific and complementary roles for nitric oxide and ATP in the inhibitory motor pathways to rat internal anal sphincter”. Neurogastroenterology and Motility Authors: Opazo A, Lecea B, Gil V, Jiménez M, Clavé P, Gallego D. Authors CIBERehd: Opazo A, Lecea B, Gil V, Jiménez M, Clavé P, Gallego D. 298. “A prospective study of lymphocyte subpopulations and regulatory T cells in patients with chronic hepatitis C virus infection developing interferon-induced thyroiditis”.

Publications - 221

Publications 1st and 2nd Quartile CIBERehd Publications Clin Endocrinol Authors: Soldevila B, Alonso N, Martínez-Arconada MJ, Granada ML, Baía D, Vallejos V, Fraile M, Morillas RM, Planas R, Pujol-Borrell R, Martínez-Cáceres EM, Sanmartí AM. Authors CIBERehd: Morillas RM, Planas R.

in colorectal cancer”. Molecular Carcinogenesis Authors: León J, Casado J, Carazo A, Sanjuán L, de la Cueva P, Muñoz P, Quiles R, Ruíz-Extremera Á, Salmerón J. Authors CIBERehd: León J, Muñoz P, Quiles R, Ruíz-Extremera Á, Salmerón J.

299. “Profile of adipose tissue gene expression in Pre- and postmenopausal women. Site-specific differences”. Menopause Authors: Gómez-Santos, C., J.J. Hernández-Morante, J. Margareto, E. Larrarte, X. Formiguera, C.M. Martínez, M. Garaulet. Authors CIBERehd: C.M. Martínez.

306. “Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening”. Cellular Oncology Authors: Pérez-Torras S, Vidal-Pla A, Miquel R, Almendro V, Fernández-Cruz L, Navarro S, Maurel J, Carbó N, Gascón P, Mazo A. Authors CIBERehd: Pérez-Torras S, Mazo A.

300. “Structural analysis provides insights into the modular organization of picornavirus IRES”. Virology Authors: Noemí Fernández, Ana García-Sacristán, Jorge Ramajo, Carlos Briones, Encarna Martínez-Salas. Authors CIBERehd: García-Sacristán A, Briones C. 301. “Capsid protein identification and analysis of mature Triatoma virus (TrV) virions and naturally occurring empty particles”. Virology Authors: Agirre J, Aloria K, Arizmendi JM, Iloro I, Elortza F, Sánchez-Eugenia R, Marti GA, Neumann E, Rey FA, Guérin DM (plataforma proteomica CIC bioGUNE). Authors CIBERehd: Elortza F. 302. “Cryopreservation impact on blood progenitor cells: influence of diagnoses, mobilization treatments, and cell concentration”. Transfusion Authors: Majado MJ, Salgado-Cecilia G, Blanquer M, Funes C, González-García C, Insausti CL, Parrado A, Morales A, Minguela A,Moraleda JM. Authors CIBERehd: Minguela A. 303. “Ultrasound in portal hypertension - part 1”. Ultraschall Med Authors: Berzigotti A, Piscaglia F. Authors CIBERehd: Berzigotti A. 304. “Ileal inducible nitric oxide synthase mRNA expression in response to stress is modified in Sprague-Dawley rats exposed to a previous intestinal inflammation”. Stress Authors: Jorge E, Vergara P, Martín MT. Authors CIBERehd: Jorge E, Vergara P, Martín MT. 305. “Gender-related invasion differences associated with mRNA expression levels of melatonin membrane receptors

307. “Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins”. BMC Cancer Authors: Abulí A, Fernández-Rozadilla C, Alonso-Espinaco V, Muñoz J, Gonzalo V, Bessa X, González D, Clofent J, Cubiella J, Morillas JD, Rigau J, Latorre M, Fernández-Bañares F, Peña E, Riestra S, Payá A, Jover R, Xicola RM, Llor X, Carvajal-Carmona L, Villanueva CM, Moreno V, Piqué JM, Carracedo A, Castells A, Andreu M, Ruiz-Ponte C, Castellví-Bel S. Authors CIBERehd: Alonso-Espinaco V, Muñoz J, Jover R, Castells A, Castellví-Bel S. 308. “Key points for designing and reporting Helicobacter pylori therapeutic trials: A personal view”. Helicobacter Authors: Calvet X, Gisbert JP, Suárez D. Authors CIBERehd: Calvet X, Gisbert J 309. “Treatment of Helicobacter pylori infection 2011”. Helicobacter Authors: O’Connor A, Gisbert JP, McNamara D, O’Morain CA. Authors CIBERehd: Gisbert JP. 310. “Hepatic expression of adiponectin receptors increases with non alcoholic fatty liver disease progression in morbid obesity in correlation with GPx1”. Obesity Surgery Authors: Carazo A, León J, Casado J, Gila A, Delgado S, Martín A, Sanjuan L, Caballero T, Muñoz J, Quiles R, Ruiz-Extremera A, Salmerón J. Authors CIBERehd: León J, Gila A, Quiles R, Ruiz-Extremera A, Salmerón J. 311. “Guidelines for the design, conduct and reporting of human intervention studies to evaluate the health benefits of foods”. Br J Nutr Authors: Welch RW, Antoine JM, Berta JL, Bub A, de Vries J, Guarner F, Hasselwander O, Hendriks H, Jäkel M, Koletzko BV, Patterson CC, Richelle M, Skarp M, Theis S, Vidry S, Woodside JV Authors CIBERehd: Guarner F.

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Publications 1st and 2nd Quartile CIBERehd Publications 312. “Hepatic expression of sodium-dependent vitamin C transporters: ontogeny, subtissular distribution and effect of chronic liver diseases”. Br J Nutr Authors: Macias RI, Hierro C, Cuesta de Juan S, Jiménez F, González-San Martín F, Marin JJ. Authors CIBERehd: Macias RI, Jiménez F, González-San Martín F, Marin JJ. 313. “Therapeutic effect of antisecretory factor-rich egg yolk on the late phases of 2,4,6-trinitrobenzenesulphonic acid colitis in mice”. Br J Nutr Authors: Mañé J, Lorén V, Pedrosa E, Ojanguren I, Domènech E, Gassull MA, Cabré E. Authors CIBERehd: Mañé J, Lóren V, Pedrosa E, Domènech E, Cabré E. 314. “Hepatorenal Syndrome, Pharmacological Therapy, and Liver Transplantation”. Liver Transpl Authors: Gines P. Authors CIBERehd: Gines P. 315. “Hot-topic debate on tolerance: Immunosuppression withdrawa”. Liver Transpl Authors: Sánchez-Fueyo A. Authors CIBERehd: Sánchez-Fueyo A. 316. “Anemia is not predictive of sustained virological response in liver transplant recipients with hepatitis C virus who are treated with pegylated interferon and ribavirin”. Liver Transpl Authors: Giusto M, Rodríguez M, Navarro L, Rubin A, Aguilera V, San-Juan F, Ortiz C, López-Andujar R, Prieto M, Berenguer M Authors CIBERehd: Rubin A, Aguilera V, Ortiz C, Prieto M, Berenguer M. 317. “Cyclic adenosine 3’,5’-monophosphate in rat steatotic liver transplantation”. Liver Transpl Authors: Jiménez-Castro MB, Casillas-Ramírez A, MassipSalcedo M, Elias-Miro M, Serafin A, Rimola A, Rodes J, Peralta C. Authors CIBERehd: Massip-Salcedo M, Rimola A, Peralta C. 318. “Does adiponectin benefit steatotic liver transplantation?”. Liver Transpl Authors: Elias-Miro M, Massip-Salcedo M, Jiménez-Castro M, Peralta C. Authors CIBERehd: Massip-Salcedo M, Peralta C. 319. “Hot topic in hepatitis C virus research: the type of

immunosuppression does not matter”. Liver Transpl Authors: Berenguer M. Authors CIBERehd: Berenguer M. 320. “Tissue Biomarkers as Predictors of Outcome and Selection of Transplant Candidates With Hepatocellular Carcinoma”. Liver Transpl Authors: Llovet JM, Paradis V, Kudo M, Zucman-Rossi J. Authors CIBERehd: Llovet JM. 321. “Risk Factors of Lung, Head and Neck, Esophageal, and Kidney and Urinary Tract Carcinomas After Liver Transplantation: The Effect of Smoking Withdrawal”. Liver Transpl Authors: Herrero JI, Pardo F, D’Avola D, Alegre F, Rotellar F, Inarrairaegui M, Marti P, Sangro B, Quiroga J. Authors CIBERehd: D’Avola D, Inarrairaegui M, Sangro B, Quiroga J. 322.“Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume”. Liver Transpl Authors: García-Martínez R, Rovira A, Alonso J, Jacas C, SimónTalero M, Chavarria L, Vargas V, Córdoba J. Authors CIBERehd: Chavarria L, Vargas V, Córdoba J. 323. “Lessons to Learn from Crohn’s Disease Clinical Trials: Implications for Ulcerative Colitis”. Curr Drug Targets Authors: Jáuregui-Amézaga A, Ricart E, Panés J. Authors CIBERehd: Ricart E, Panés J. 324. “Cyclooxygenase as a target for colorectal cancer chemoprevention”. Curr Drug Targets Authors: Moreira L, Castells A. Authors CIBERehd: Moreira L, Castells A. 325. “Role of AMP-activated protein kinase in the control of hepatocyte priming and proliferation during liver regeneration”. Exp Biol Med (Maywood) Authors: Varela-Rey M, Beraza N, Lu SC, Mato JM, MartínezChantar ML. Authors CIBERehd: Varela-Rey M, Mato JM, Martínez-Chantar ML. 326. “Co-expression of matrix metalloproteinase-7 (MMP7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: a GEMCAD study”. Cancer Biol Ther Authors: Hörndler C, Gallego R, García-Albéniz X, AlonsoEspinaco V, Alonso V, Escudero P, Jimeno M, Ortego J, Codony-

Publications - 223

Publications 1st and 2nd Quartile CIBERehd Publications Servat J, Fernández-Martos C, Calatrava A, Marín-Aguilera M, Muñoz J, Castellví-Bel S, Castells A, Rubini M, Gascón P, Maurel J. Authors CIBERehd: Alonso-Espinaco V, Muñoz J, Castellví-Bel S, Castells A, Maurel J. 327. “Quasispecies as a matter of fact: viruses beyond”. Virus Res Authors: Ojosnegros S, Perales C, Mas A and Domingo E. Authors CIBERehd: Perales C, Domingo E. 328. “Regenerating gene Iα is a biomarker for diagnosis and monitoring of celiac disease: a preliminary study”. Transl Res Authors: Planas R, Pujol-Autonell I, Ruiz E, Montraveta M, Cabre E, Lucas-Martín A, Pujol-Borrell R, Martínez-Caceres E, Vives-Pi M. Authors CIBERehd: Cabré E. 329. “Characterization of Woodchuck Apolipoprotein A-I: A New Tool for Drug Delivery and Identification of Altered Isoforms in the Woodchuck Chronic Hepatitis Model” J Med Virol Authors: Fioravanti J, Gomar C, Medina-Echeverz J, Otano I, Benito A, Prieto J, González-Aseguinolaza G, Berraondo P. Authors CIBERehd: Prieto J. 330. “Hepatitis C Virus Sequences From Different Patients Confirm the Existence and Transmissibility of Subtype 2q, a Rare Subtype Circulating in the Metropolitan Area of Barcelona, Spain”. J Med Virol Authors: Martró E, Valero A, Jordana-Lluch E, Saludes V, Planas R, González-Candelas F, Ausina V, Bracho MA. Authors CIBERehd: Planas R. 331. “CD28 and KIR2D receptors as sensors of the immune status in heart and liver transplantation”. Human Immunology Authors: Blanco-García RM, López-Álvarez MR, Garrido IP, Salgado-Cecilia G, Campillo JA, Bolarín JM, Legaz I, Muro M, García-Alonso AM, Martínez-Sánchez MV, de la Peña Moral JM, Pascual-Figal DA, Álvarez-López MR, Miras M, Minguela A. Authors CIBERehd: López-Álvarez MR, Campillo JA, Legaz I, Muro M, García-Alonso AM, Álvarez-López MR, Miras M, Minguela A. 332. “Human and mouse DOCK10 splicing isoforms with alternative first coding exon usage are differentially expressed in T and B lymphocytes”. Human Immunology Authors: Alcaraz García MJ, Ruiz Lafuente N, Sebastián Ruiz S, Majado MJ, González García C, Bernardo MV, Álvarez-López MR, Parrado A.

Authors CIBERehd: Álvarez-López MR. 333. “Divergences in the KIR2D+ NK and KIR2D+ CD8+ T cells reconstitution following liver transplantation”. Human Immunology Authors: López-Álvarez MR, Campillo JA, Legaz I, Blanco-García RM, Salgado-Cecilia G, Bolarín JM, Gimeno L, Gil J, García-Alonso AM, Muro M, Álvarez-López MR, Miras M, Minguela A. Authors CIBERehd: López-Álvarez MR, Campillo JA, Legaz I, García-Alonso AM, Muro M, Álvarez-López MR, Miras M, Minguela A. 334. “Barrett’s esophagus: natural history”. Ann N Y Acad Sci Authors: Appelman HD, Umar A, Orlando RC, Sontag SJ, Nandurkar S, El-Zimaity H, Lanas A, Parise P, Lambert R, Shields HM. Authors CIBERehd: Lanas A. 335. “Prevalence and Pathophysiology of Functional Constipation among Women in Catalonia, Spain”. Diseases of the Colon Rectum Authors: Ribas Y, Saldaña E, Martí-Ragué J, Clavé P. Authors CIBERehd: Clavé P. 336. “The management of portal hypertensive gastropathy and gastric antral vascular ectasia”. Dig Liver Dis Authors: Ripoll C, García-Tsao G. Authors CIBERehd: Ripoll C. 337. “Role of reactive oxygen species in the early stages of liver regeneration in streptozotocin-induced diabetic rats”. Free Rad Res Authors: Francés D, Ronco M, Monti J, Ingaramo P, Pisani G, Parody J, Pellegrino J, Carrillo M, Martín-Sanz P and Carnovale C. Authors CIBERehd: Martín-Sanz P. 338. “Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165 patients” J Clin Gastroenterol Authors: Álvarez MA, Cirera I, Solà R, Bargalló A, Morillas RM, Planas R. Authors CIBERehd: Morillas RM, Planas R. 339. “Soluble angiogenic factors in patients with acute pancreatitis”. J Clin Gastroenterol Authors: Espinosa L, Linares PM, Bejerano A, López C, Sánchez A, Moreno-Otero R, Gisbert JP. Authors CIBERehd: Moreno-Otero R, Gisbert JP.

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Publications 1st and 2nd Quartile CIBERehd Publications 340. “Long-term durability of infliximab treatment in Crohn’s disease and efficacy of dose “escalation” in patients loosing response”. J Clin Gastroenterol Authors: Chaparro M, Panés J, García V, Mañosa M, Esteve M, Merino O, Cabriada JL, Montoro MA, Mendoza JL, Nos P, Gutierrez A, Gomollón F, Gisbert JP. Authors CIBERehd: Chaparro M, Panés J, García V, Mañosa M, Esteve M, Merino O, Cabriada JL, Montoro MA, Mendoza JL, Nos P, Gutierrez A, Gomollón F, Gisbert JP.

of functional outlet obstruction”. Colorectal Dis Authors: Puigdollers A, Cisternas D, Azpiroz F. Authors CIBERehd: Puigdollers A, Azpiroz F.

341. “Effect of weight loss on C3 and C4 components of complement in obese patients”. Eur J Clin Invest Authors: Hernández-Mijares A, Bañuls C, Bellod L, Jover A, Solá E, Morillas C, Víctor VM, Rocha M. Authors CIBERehd: Víctor VM, Rocha M.

349. “Peritoneal macrophage priming in cirrhosis is related to ERK phosphorylation and IL-6 secretion”. Eur J Clin Invest Authors: Ruiz-Alcaraz AJ, Martínez-Esparza M, Caño R, Hernández-Caselles T, Recarti C, Zapater P, Martín-Orozco E, Pérez-Mateo M, Such J, García-Penarrubia P, Francés R. Authors CIBERehd: Zapater P, Such J, Francés R.

342. “Bacteria and spontaneous experimental colitis: immunological changes”. Eur J Clin Invest Authors: Pedrosa E, Lorén V, Cabré E, Doménech E, Ojanguren I, Gassull MA, Mañé J. Authors CIBERehd: Pedrosa E, Lorén V, Cabré E, Doménech E, Gassull MA, Mañé J. 343. “Elevated TGF-b1 levelsmight protect HCV⁄ HIVcoinfected patients from liver fibrosis”. Eur J Clin Invest Authors: Rallon NI, Barreiro P, Soriano V, García-Samaniego J, López M, Benito JM. Authors CIBERehd: García-Samaniego J. 344. “Differential bone marrow hematopoietic stem cells mobilization in hepatectomized patients”. Journal of Gastrointestinal Surgery Authors: Herencia C, Rodríguez-Ariza A, Canalejo A, Naranjo A, Briceno FJ, López-Cillero P, De la Mata M, Muñoz-Castañeda JR Authors CIBERehd: Rodríguez-Ariza A, Naranjo A, Briceno FJ, López-Cillero P, De la Mata M, Muñoz-Castañeda JR. 345. “Totally transrectal endoscopic total mesorectal excision (TME)”. Colorectal Dis Authors: Lacy AM, Adelsdorfer C. Authors CIBERehd: Lacy AM. 346. “Changing trends in polypoid colorectal cancer diagnosed by colonoscopy”. Colorectal Dis Authors: Lorenzo-Zúñiga V, Moreno de Vega V, Boix J. Authors CIBERehd: Lorenzo-Zúñiga V. 347. “Postopertaive pain after haemorrhoidectomy: role

348. “Gastrointestinal bleeding associated with lowdose aspirin use: relevance and management in clinical practice”. Expert Opin Drug Saf Authors: Lanas A. Authors CIBERehd: Lanas A.

350. “Cutaneous lymphoma in a patient with ulcerative colitis after immunosuppressive therapy”. J Crohns Colitis Authors: Rojas-Feria M, Eslam M, Castro-Fernández M, Guerrero P, Larraona-Moreno JL, Romero-Gómez M. Authors CIBERehd: Romero-Gómez M. 351. “Results of the 2nd part Scientific Workshop of the ECCO. II: Measures and markers of prediction to achieve, detect, and monitor intestinal healing in inflammatory bowel disease”. J Crohns Colitis Authors: Daperno M, Castiglione F, de Ridder L, Dotan I, Färkkilä M, Florholmen J, Fraser G, Fries W, Hebuterne X, Lakatos PL, Panés J, Rimola J, Louis E. Authors CIBERehd: Panés J. 352. “Methotrexate in ulcerative colitis: a Spanish multicentric study on clinical use and efficacy”. J Crohns Colitis Authors: Mañosa M, García V, Castro L, García-Bosch O, Chaparro M, Barreiro-de Acosta M, Carpio D, Aguas M Authors CIBERehd: Mañosa M, García-Bosch O, Chaparro M, Aguas M 353. “Perianal disease in patients with ulcerative colitis: A case-control study”. J Crohns Colitis Authors: Zabana Y, Van Domselaar M, García-Planella E, Mañosa M, López San Román A, Gordillo J, Cabré E, Domènech E. Authors CIBERehd: Zabana Y, Mañosa M, Cabré E, Domènech E. 354. “Nursing resources and responsibilities according to hospital organizational model for management of

Publications - 225

Publications 1st and 2nd Quartile CIBERehd Publications inflammatory bowel disease in Spain”. J Crohns Colitis Authors: Marín L, Torrejón A, Oltra L, Seoane M, HernándezSampelayo P, Vera MI, Casellas F, Alfaro N, Lázaro P, GarcíaSánchez V. Authors CIBERehd: Torrejón A, Casellas F. 355. “Improvement of capecitabine antitumoral activity by melatonin in pancreatic cancer”. Pancreas Authors: Ruiz-Rabelo J, Vazquez R, Arjona A, Perea D, Montilla P, Tunez I, Muntane J, Padillo J. Authors CIBERehd: Muntane J, Padillo J. 356. “Evaluation of the potential protective effects of ad libitum black grape juice against liver oxidative damage in whole-body acute X-irradiated rats”. Food Chem Toxicol Authors: Andrade ER, Cruz IB, Andrade VV, Piccoli JC, GonzálezGallego J, Barrio JP, González P. Authors CIBERehd: González-Gallego J. 357. “Loss of surface antigens is a conserved feature of apoptotic lymphocytes from several mammalian species”. Cell Immunol Authors: Díaz D, Chara L, Chevarria J, Ubeda M, Muñoz L, Barcenilla H, Sánchez MA, Moreno Z, Monserrat J, Albillos A, Prieto A, Álvarez-Mon M. Authors CIBERehd: Ubeda M, Muñoz L, Monserrat J, Albillos A, Prieto A, Álvarez-Mon M. 358. “Serum lipid responses to phytosterol-enriched milk in a moderate hypercholesterolemic population is not affected by apolipoprotein E polymorphism or diameter of low-density lipoprotein particles”. Eur J Clin Nutr. Authors: Bañuls C, Martínez-Triguero ML, López-Ruiz A, Morillas C, Jarabo MM, Bellod L, Víctor VM, Rocha M, Hernández-Mijares A. Authors CIBERehd: Víctor VM, Rocha M.

hepatotoxicity assessment”. Toxicol In Vitro Authors: Tolosa L, Donato MT, Pérez-Cataldo G, Castell JV, Gómez-Lechón MJ. Authors CIBERehd: Donato MT, Castell JV, Gómez-Lechón MJ. 362. “Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome”. BMC Med Genet Authors: Castillejo A, Guarinos C, Martínez-Canto A, Barbera VM, Egoavil C, Castillejo MI, Pérez-Carbonell L, Sánchez-Heras AB, Segura A, Ochoa E, Lazaro R, Ruiz-Ponte C, Bujanda L, Andreu M, Castells A, Carracedo A, Llor X, Clofent J, Alenda C, Paya A, Jover R, Soto JL. Authors CIBERehd: Castells A. 363. “Diagnostic accuracy of a 16S ribosomal DNA genebased molecular technique (RT-PCR, microarray, and sequencing) for bacterial meningitis, early-onset neonatal sepsis, and spontaneous bacterial peritonitis”. Diagn Microbiol Infect Dis Authors: Esparcia O, Montemayor M, Ginovart G, Pomar V, Soriano G, Pericas R, Gurgui M, Sulleiro E, Prats G, Navarro F, Coll P. Authors CIBERehd: Soriano G. 364. “Esophageal motor abnormalities in eosinophilic esophagitis identified by high-resolution manometry”. J Gastroenterol Hepatol Authors: Martín Martín L, Santander C, López Martín MC, EspinozaRíos J, Chavarría-Herbozo C, Gisbert JP, Moreno-Otero R. Authors CIBERehd: Santander C, Moreno-Otero R, Gisbert JP. 365. “Hepatorenal syndrome”. Expert Opin Pharmacother Authors: Guevara M, Arroyo V. Authors CIBERehd: Guevara M, Arroyo V.

359. “Acute-on-chronic liver failure: the brain”. Curr Opin Crit Care Authors: Martínez-García R, Córdoba J. Authors CIBERehd: García-Martínez R, Córdoba J.

366. “Transarterial therapies for hepatocellular carcinoma”. Expert Opin Pharmacother Authors: Sangro, B, D’Avola, D, Inarrairaegui, M, Prieto, J Authors CIBERehd: Sangro B, D’Avola D, Inarrairaegui M, Prieto J.

360. “Acute-on-chronic liver failure: the kidneys” Curr Opin Crit Care Authors: Cardenas A (2), Gines P (1,3). Authors CIBERehd: Gines P.

367. “A new validation of the Spanish Work Productivity and Activity Impairment Questionnaire-Crohn’s disease version”. Value Health Authors: Vergara M, Montserrat A, Casellas F, Villoria A, Suárez D, Maudsley M, Gallardo O, Ricart E, Calvet X. Authors CIBERehd: Casellas F, Villoria A, Suárez D, Ricart E, Calvet X.

361. “Upgrading cytochrome P450 activity in HepG2 cells co-transfected with adenoviral vectors for drug

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Publications 1st and 2nd Quartile CIBERehd Publications 368. “Preclinical evaluation of azathioprine plus buthionine sulfoximine in the treatment of human hepatocarcinoma and colon carcinoma”. World J Gastroenterol Authors: Hernández-Breijo B, Monserrat J, Rubio SR, Cuevas EP, Vara D, Díaz-Laviada I, Fernández-Moreno MD, Román ID, Gisbert JP, Guijarro LG. Authors CIBERehd: Gisbert JP, Guijarro LG. 369. “Management of Crohn’s disease in smokers: is an alternative approach necessary?”. World J Gastroenterol Authors: Nos P, Domènech E. Authors CIBERehd: Nos P, Domènech E. 370. “Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease”. World J Gastroenterol Authors: Gisbert JP, Chaparro M, Gomollón F. Authors CIBERehd: Gisbert JP, Chaparro M, Gomollón F. 371. “How to protect liver graft with nitric oxide”. World J Gastroenterol Authors: Ben Abdennebi H, Zaoualí MA, Alfany-Fernandez I, Tabka D, Roselló-Catafau J. Authors CIBERehd: Roselló-Catafau J. 372. “Interplay among cellular polarization, lipoprotein metabolism and hepatitis C virus entry”. World J Gastroenterol Authors: Benedicto I, Molina-Jiménez F, Moreno-Otero R, López-Cabrera M, Majano PL. Authors CIBERehd: Benedicto I, Moreno-Otero R, LópezCabrera M, Majano PL. 373. “Gastrotomy closure with a new tissue anchoring device: a porcine survival study”. World J Gastroenterol Authors: Guarner-Argente C, Córdova H, Martínez-Pallí G, Navarro-Ripoll R, Rodríguez-d’Jesús A, de Miguel CR, Beltrán M, Fernández-Esparrach G. Authors CIBERehd: Fernández- Esparrach G. 374. “Clinical significance of occult hepatitis B virus infection”. World J Gastroenterol Authors: Romero M, Madejón A, Fernández-Rodríguez C, García-Samaniego J. Authors CIBERehd: Romero M, Madejón A, García-Samaniego J 375. “Long-term outcome of chronic hepatitis C patients with sustained virological response to peginterferon plus ribavirin”. World J Gastroenterol

Authors: Trapero-Marugán M, Mendoza J, Chaparro M, González-Moreno L, Moreno-Monteagudo JA, Borque MJ, Moreno-Otero R. Authors CIBERehd: Trapero-Marugán M, Moreno-Monteagudo JA, Moreno-Otero R. 376. “Impact of Age on Liver Regeneration Response to Injury After Partial Hepatectomy in a Rat Model”. J Surg Res Authors: Sánchez-Hidalgo JM, Naranjo A, Ciria R, Ranchal I, Aguilar-Melero P, Ferrín G, Valverde A, Rufián S, López-Cillero P, Muntané J, Briceño J. Authors CIBERehd: Naranjo A, Ranchal I, Ferrín G, López-Cillero P, Muntané J, Briceño J. 377. “Step-by-step guide for a simplified model of porcine orthotopic liver transplant”. J Surg Res Authors: Fondevila C, Hessheimer AJ, Flores E, Vendrell M, Muñoz J, Escobar B. Authors CIBERehd: Fondevila C, Muñoz J. 378. “Role of quercetin in preventing thioacetamideinduced liver injury in rats”. Toxicol Pathol Authors: de David C, Rodrigues G, Bona S, Meurer L, GonzálezGallego J, Tuñón MJ, Marroni NP. Authors CIBERehd: González-Gallego J, Tuñón MJ. 379. “Morphofunctional changes underlying intestinal dysmotility in diabetic RIP-I⁄hIFNb transgenic mice International Journal of Experimental Pathology”. Authors: Domenech A, Pasquinelli G, De Giorgio R, Gori A, Bosch F, Pumarola M, Jiménez M. Authors CIBERehd: Jiménez M. 380. “Factors associated with hepatic steatosis in obese children and adolescents”. Journal of Pediatric Gastroenterology & Nutrition Authors: Ruiz-Extremera Á, Carazo Á, Salmerón Á, León J, Casado J, Goicoechea A, Fernandez JM, Garofano M, Ocete E, Martín AB, Pavón E, Salmerón J. Authors CIBERehd: Ruiz-Extremera Á, León J, Salmerón J. 381. “Familial Aggregation in IBD – Is It Genes or Environment?”. World J Gastroenterol Authors: Nunes T, Fiorino G, Danese S, Sans M. Authors CIBERehd: Sans M. 382. “Attitudinal study of organ xenotransplantation in patients on the kidney and liver transplant waiting list in a

Publications - 227

Publications 1st and 2nd Quartile CIBERehd Publications country with a high rate of deceased donation”. Xenotransplantation Authors: Martínez-Alarcón L, Ríos A, Pons JA, González MJ, Ramis G, Ramírez P, Parrilla P. Authors CIBERehd: Martínez-Alarcón L, Ríos A, Pons JA, Ramírez P, Parrilla P. 383. “Research Reporting Standards for Radioembolization of Hepatic Malignancies”. J Vasc Interv Radiol Authors: Salem R, Lewandowski RJ, Gates VL, Nutting CW, Murthy R, Rose SC, Soulen MC, Geschwind JFH, Kulik L, Kim YH, Spreafico C, Maccauro M, Bester L, Brown DB, Ryu RKW, Sze DY, Rilling WS, Sato KT, Sangro B, Bilbao JI, Jakobs TF, Ezziddin S, Kulkarni S, Kulkarni A, Liu DM, Valenti D, Hilgard P, Antoch G, Muller SP, Alsuhaibani H, Mulcahy MF, Burrel M, Real MI, Spies S, Esmail AA, Raoul JL, Garin E, Johnson MS, Benson A, Sharma RA, Wasan H, Lambert B, Memon K, Kennedy AS, Riaz A. Authors CIBERehd: Sangro B. 384. “Corticosteroids modulate angiogenic soluble factors in ulcerative colitis patients”. Dig Dis Sci Authors: Pousa ID, Algaba A, Linares PM, Sanz-Cameno P, Maté J, Moreno-Otero R, Bermejo F, Gisbert JP. Authors CIBERehd: Sanz-Cameno P, Moreno-Otero R, Gisbert JP. 385. “Epidemiology and risk factors for late infection in solid organ transplant recipients”. Transpl Infect Dis Authors: Cervera C, Fernández-Ruiz M, Valledor A, Linares L, Antón A, Angeles Marcos M, Sanclemente G, Hoyo I, Cofán F, Ricart MJ, Pérez-Villa F, Navasa M, Pumarola T, Moreno A. Authors CIBERehd: Navasa M. 386.“Extended criteria donors in liver transplant candidates with hepatorenal syndrome”. Clinical Transplantation Authors: Briceno J, Ciria R, de la Mata M, Montero JL, Rufian S, López-Cillero P. Authors CIBERehd: Briceno J, de la Mata M, Montero JL, LópezCillero P. 387. “Classification of cirrhosis: the clinical use of HVPG measurements”. Disease Markers Authors: Albilllos A, García-Tsao G. Authors CIBERehd: Albillos A. 388. “Infection during natural orifice transluminal endoscopic surgery peritoneoscopy: a randomized comparative study in a survival porcine model”. J Minim Invasive G

Authors: Guarner-Argente C, Beltrán M, Martínez-Pallí G, Navarro-Ripoll R, Martínez-Zamora MÀ, Córdova H, Comas J, de Miguel CR, Rodríguez-D’Jesús A, Almela M, Hernández-Cera C, Lacy AM, Fernández-Esparrach G. Authors CIBERehd: Lacy AM, Fernández-Esparrach G. 389. “Evaluation of liver fibrosis by transient elastography in methotrexate treated patients”. Med Clin (Barc) Authors: Barbero-Villares A, Mendoza J, Trapero-Marugan M, González-Alvaro I, Daudén E, Gisbert JP, Moreno-Otero R Authors CIBERehd: Trapero-Marugan M, Gisbert JP, MorenoOtero R. 390. “Malignancy predictive factors in pancreatic intraductal papillary mucinous neoplasm”. Med Clin (Barc) Authors: Adet Caldelari AC, Miquel R, Bombi JA, Ginés A, Fernández-Esparrach G, Ayuso JR, Maurel J, Feu F, Castells A, Fernández-Cruz L, Navarro S. Authors CIBERehd: Ginés A, Fernández-Esparrach G, Ayudo JR, Maurel J, Castells A, Fernández- Cruz L, Navarro S. 391. “[Low penetrance gene polymorphisms involved in Helicobacter pylori-immune response. Relevance on gastric cancer risk]”. Med Clin (Barc) Authors: Badía Martínez M, García-González MA. Authors CIBERehd: García-González MA. 392. “[Chronic C hepatitis genotype 4]”. Med Clin (Barc) Authors: González-Casas R, Trapero-Marugán M, Moreno-Otero R Authors CIBERehd: Trapero-Marugán M, Moreno-Otero R. 393. “Multiple cutaneous mast cell tumors in a pig Journal of Veterinary Diagnostic Investigation”. Authors: Martínez J, Martínez V, Grau-Roma L, López J, Segalés J. Authors CIBERehd: Martínez V. 394. “Cyclooxygenase-2 expression is related with localization, proliferation, and overall survival in canine melanocytic neoplasms”. Veterinary pathology Authors: Martínez CM, Peñafiel-Verdú C, Vilafranca M, Ramírez G, Méndez-Gallego M, Buendía AJ, Sánchez J. Authors CIBERehd: Martínez CM.

228 - CIBERehd - 2011 ANNUAL REPORT - PUBLICATIONS

Publications CIBERehd Publications on the first decile of the ISI-JCR during 2011 CIBERehd publications in the ISI-JCR first decile during 2011

Impact Factor

NUMBER

Colaboration between CIBERehd groups

ACS Nano

9,865

Chemistry, Multidisciplinary Sciences

Acta Cryst

6,326

Biomedical Research Methods

Am J Pathol

5,224

Pathology

Am J Gastroenterol

6,882

Gastroenterology and Hepatology

Am J Transplant

6,051

Transplantation & Surgery

Ann N Y Acad Sci

2,847

Multidisciplinary Sciences

Ann Surg

7,474

Surgery

Ann Surg Oncol

4,182

Surgery

Biochem Pharmacol

4,889

Pharmacology & Pharmacy

Blood

10,558

Hematology

BMC Med

5,75

Medicine, General and Internal

Bone

4,601

Endocrinology & Metabolism

Br J Pharmacol

4,925

Pharmacology & Pharmacy

Cancer Res

8,234

Oncology

Chemical Research in Toxicology

4,148

Chemistry, Medicinal

Clin Gastroenterol Hepatol

5,286

Gastroenterology & Hepatology

Clinc Cancer Res.

7,274

Oncology

Crit Rev Food Sci Nutr

4,51

Food Science & Technology

Curr Med Chem

4,63

Chemistry, Medicinal

Curr Opin Clin Nutr Metab Care

4,333

Nutrition & Dietetics

Curr Pharm Des.

4,774

Pharmacology & Pharmacy

Current Biology

10,026

Biochemistry & Molecular Biology

Endoscopy

6,096

Gastroenterology & Hepatology

FASEB J

6,515

Biology

Gastroenterology

12,032

Gastroenterology and Hepatology

Gastrointest Endosc

5,647

Gastroenterology & Hepatology

Gut

10,614

Gastroenterology

Hepatology

10,885

Gastroenterology & Hepatology

Journal