AREA 1 - IIS LA PRINCESA
Transcripción
AREA 1 - IIS LA PRINCESA
2012 ANNUAL REPORT OF SCIENTIFIC ACTIVITY Line 1.1 Line 1.4 Line 1.5 Line 1.6 Line 1.7 Line 1.8 Line 1.9 Line 1.10 Line 1.11 Line 2.5 Line 2.6 Line 3.1 Line 3.2 Line 3.3 Line 3.4 Line 3.5 Line 3.6 Line 3.7 Line 3.8 2012 Neuropharmacology and neuroprotection. Neurotransmission in the hippocampus. Clinical pharmacology and pharmacogenetics. Diagnostic and therapeutic advances in affective disorders. Neurosurgery of epilepsy. Cerebrovascular diseases. Prognostic and predictor markers in autoimmune diseases. Esophagogastrointestinal inflammatory diseases. Progenitors and cell therapy. Advanced therapies in oncohematology. Biological, cellular and molecular monitoring in oncohematology. New diagnostic and therapeutic advances in cardiovascular diseases. New therapies in infectious pathologies. Individualized medicine in solid tumors. ANNUAL REPORT OF SCIENTIFIC ACTIVITY AREA 2 AREA 3 Line 2.1 Line 2.2 Line 2.3 Line 2.4 AREA 1 Line 1.2 Line 1.3 Intercellular communication in the inflammatory response. Cellular and molecular responses to Hypoxia. Animal models of inflammatory diseases and intercellular signalling. Etiopathogenic and immunological mechanisms of dermatological diseases. Cellular mechanisms and molecular determinants of allergy-based diseases. Inflammatory processes in nephrological diseases. Inflammatory mechanisms in pulmonary diseases. Inflammatory response in hepatic diseases. Mechanisms and mediators of endocrine diseases. Children´s development (obesity and growth). Metabolic syndrome and vascular risk. INDEX FOREWORD IP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Letter from the Scientific Director . . . . . . . . . . . . . . . . . . . . . . . . . 6 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 AREA 1 · Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases . . . . . . . . . . . . . . . . . . . . . .27 2012 ANNUAL REPORT OF SCIENTIFIC ACTIVITY Line 1.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .29 © INSTITUTO DE INVESTIGACIÓN SANITARIA Hospital Universitario de La Princesa Line 1.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45 Line 1.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .52 Line 1.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54 Line 1.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57 Line 1.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .60 Line 1.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64 AREA 1 Line 1.9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .69 Line 1.10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72 Line 1.11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .76 AREA 2 · Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases . . . . . . . . . . . . .81 Line 2.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .83 Line 2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87 Line 2.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88 Line 2.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92 AREA 2 Editing: Ibáñez&Plaza Asociados S.L. Line 1.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .37 Line 2.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .96 Line 2.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .99 AREA 3 · Advanced therapies and individualized medicine . . . . . . . . . . . . . .107 Line 3.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109 Line 3.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .117 Line 3.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 Line 3.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131 Line 3.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .138 Line 3.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .141 Line 3.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147 Line 3.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .155 AREA 3 Diego de León, 62 28006 Madrid Phone 91 520 25 08 e-mail: [email protected] Web: www.iis-princesa.org –3– PRÓLOGO FOREWORD Prólogo IP Foreword IP IIS-Princesa 2012 –5– Carta del director científico Letter from the Scientific Director Francisco Sánchez Madrid Director Científico / Scientific Director La producción científica del IP durante el año 2012 muestra una consolidación de su tendencia creciente durante los últimos años, con 340 publicaciones que suponen un factor de impacto de 1672.99 –6– E s una enorme satisfacción poder presentar un año más la memoria científica del Instituto de Investigación Sanitaria del Hospital Universitario de la Princesa (IP). La difusión de la actividad de investigación que se lleva a cabo en el IP es un elemento de gran importancia. En primer lugar resulta esencial para dar a conocer la actividad investigadora que se desarrolla dentro del propio IP, como reconocimiento expreso del esfuerzo llevado a cabo por todos y cada uno de los investigadores que trabajamos en él, dentro de un año particularmente complicado, como fuera de él poniendo de manifiesto ante otras instituciones la gran capacidad de investigación del IP. Para ello intentaremos en esta memoria recoger la actividad científica del IP durante el pasado 2012. La producción científica del IP durante el año 2012 muestra una consolidación de su tendencia creciente durante los últimos años, con 340 publicaciones que suponen un factor de impacto de 1672.99. Estos datos evidencian la tendencia creciente del IP no sólo en número de publicaciones, sino en la calidad de los mismos. Durante el último año el número de publicaciones en revistas en primer quartil se ha incrementado en más de un 45% respecto al año 2011. Desde el punto de vista económico y a pesar de las dificultades del momento actual, la capacidad de captación de fondos para la investigación a diferentes niveles, ha seguido su tendencia ascendente. En este nce again, it is a great pleasure to present the Annual Scientific Report of the Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (La Princesa Hospital Institute for Health Research, IP). The research activity of our Institute is the result of the combined effort of our professionals who have worked with strong commitment and great dedication during 2012. To acknowledge the effort of our researches, after a year specially difficult for our institution, and to show to the Public the outstanding research capacity of the IP it is particularly important to communicate the results of our research. In the present report we will gather and present the research activity of IP during 2012. The scientific output during 2012, with 340 publications and a total impact factor of 1672.99, confirms the steady tendency to increase in recent years. Our scientific output has improved both in the number of publications and their quality. During the last year the number of publications in fist quartile journal was augmented 45% compared to 2011. Despite the great difficulties faced in the current economic environment, the capacity of IP to attract research funds has maintained an increasing trend. In this scenario, it is important to emphasize the crucial role of the Biomedical Research Foundation (FIB) and its great effort dedicated to O punto, es importante resaltar el importante papel de la Fundación para la Investigación Biomédica y el gran esfuerzo de gestión que realiza para intentar mantener las complicadas condiciones económicas actuales, y así mantener los compromisos adquiridos y las prestaciones ofrecidas a los investigadores del IP. Sin duda, es esencial realizar un gran esfuerzo para mantener la capacidad investigadora del IP al menos en los mismos parámetros en años previos, por lo que el trabajo en equipo resulta un pilar fundamental para ello. Como prueba de ello, resaltar que el pasado año 2012 se puso en marcha la Unidad de Terapias Biológicas que tiene como participantes a investigadores del IP de los servicios de Reumatología, Digestivo, Neurología, Dermatología y Farmacia. Esta Unidad (la primera de la comunidad de Madrid) tiene como objetivo la aplicación de una terapia individualizada para los pacientes con enfermedades crónicas de base inmunológica, mejorando así las enfermedades asociadas; favoreciendo con ello la optimización de los recursos hospitalarios, Desde aquí quiero agradecer a los todos los jefes de áreas, jefes de líneas y grupos de investigación, a todos los investigadores así como a las plataformas de apoyo, su comprometida participación que desde hace años vienen realizando y no siempre bajo unas condiciones fáciles. Es por ello que los resultando obtenidos durante el año 2012 resultan aún más gratificantes. the management of resources to keep up with the services provided to all the IP researches. Our institution has pioneered in 2012 the formation of the multidisciplinary Biological Therapies Unit. In this new unit (the first of this nature in Madrid) participate IP researchers from the Rheumatology, Neurology, Gastroenterology, Dermatology and Pharmacy services of la Princesa Hospital in a project aimed to integrate and optimize the use of Biological Therapies in immune mediated inflammatory disorders. The main goal of this Unit is the integration of the use of these treatments from the perspective of increasing efficiency, safety, and cost effectiveness. The new Unit is an excellent example of joint collaborative effort that will foster further research projects. Finally, I would like to express here my gratitude to all personnel for their great effort and committed dedication working for IP during the last few years. It makes it more gratifying to present the results of our activity during 2012. The scientific output during 2012, with 340 publications and a total impact factor of 1672.99, confirms the steady tendency to increase in recent years –7– PRÓLOGO IP / FOREWORD IP ESTRUCTURA ORGANIZATIVA ORGANISATIONAL CHART CONSEJO RECTOR GOVERNING COUNCIL PRESIDENTE / CHAIRMAN Patricia Flores Cerdán Viceconsejera de Asistencia Sanitaria de la Comunidad de Madrid Deputy Minister of Health Care, Comunidad de Madrid VICEPRESIDENTE / VICE-CHAIRMAN José Mª Sanz Martínez Vicerector de la UAM Vice-chancelor of UAM MIEMBROS / MEMBERS Miguel Ángel Andrés Molinero Director Gerente, Hospital U. La Princesa General Manager, Hospital U. La Princesa Margarita González Grande Director Gerente, Hospital U. Niño Jesús Managing Director Hospital U. Niño Jesús Ana Miquel Gómez Gerente adjunto de Planificación y Calidad de Atención Primaria de la Consejería de Sanidad de la Comunidad de Madrid Deputy Manager of Planning and Care Quality, Atención Primaria, Consejería de Sanidad de la Comunidad de Madrid Rosar Mª Ramos Pérez Director Gerente, Hospital U. Santa Cristina Managing Director Hospital U. Santa Cristina Alfonso Garrigós Garnica Dirección de Gestión, Hospital U. La Princesa José Antonio Gutierrez Fuentes Director de la Fundación Lilly Director of Lilly Foundation Miguel López-Bravo Bascán Director General de Planificación, Infraestructuras y Equipamientos Sanitarios de la Comunidad de Madrid Federico Mayor Menéndez Centro Biología Molecular Severo Ochoa, Madrid Severo Ochoa Molecular Biology Centre, Madrid Julio Ancochea Bermúdez Servicio de Neumología, Hospital U. La Princesa Respiratory Department, Hospital U. La Princesa Francisco Sánchez Madrid Director Científico, Instituto Investigación Sanitaria IP Scientific Director of IP SECRETARIA / SECRETARY Rosario Ortiz de Urbina Barba, Directora de la Fundación de Investigación Biomédica (FIB), Hospital U. de La Princesa Director of FIB, Hospital U. La Princesa. COMISIÓN DELEGADA EXECUTIVE COMITEE PRESIDENTE / CHAIRMAN Miguel Ángel Andrés Molinero Director Gerente, Hospital U. La Princesa General Manager, Hospital U. La Princesa VICEPRESIDENTE / VICE-CHAIRMAN Antonio García García Director del Instituto Teófilo Hernando, UAM Servicio de Frmacología Clínica, Hospital U. La Princesa. Director of Instituto Teófilo Hernando, UAM Clinical Farmacology Department, Hospital U. La Princesa MIEMBROS / MEMBERS Francisco Sánchez Madrid Director Científico, Instituto Investigación Sanitaria IP Scientific Director of IP Alfonso Garrigós Garnica Director de Gestión Y SS.GG, Hospital U. La Princesa Gustavo Casero Balboa Subdirector de Gestión/RR.HH, Hospital U. La Princesa –9– ESTRUCTURA ORGANIZATIVA ORGANISATIONAL CHART Manuel Fresno Escudero Centro Biología Molecular Severo Ochoa, Madrid Severo Ochoa Molecular Biology Centre, Madrid Emilio Úcar Corral Subdirector Médico, Hospital U. Santa Cristina Medical Sub-director, Hospital U. Santa Cristina Luis Madero López Servicio de Hematología, Hospital U. Niño Jesús Hematology Department, Hospital. U. Niño Jesús Ana Miquel Gómez Gerente adjunto de Planificación y Calidad de Atención Primaria de la Consejería de Sanidad de la Comunidad de Madrid Deputy Manager of Planning and Care Quality, Atención Primaria, Consejería de Sanidad de la Comunidad de Madrid. Javier Aspa Marco Director Médico, Hospital U. La Princesa Medical Director, Hospital U. La Princesa SECRETRIA / SECRETARY Rosario Ortiz de Urbina Barba Directora de la Fundación de Investigación Biomédica, Hospital U. de La Princesa Director of FIB, Hospital U. La Princesa. DIRECTOR CIENTÍFICO / SCIENTIFIC DIRECTOR Francisco Sánchez Madrid Director Científico, Instituto Investigación Sanitaria IP Scientific Director of IP COMITÉ CIENTÍFICO EXTERNO / EXTERNAL SCIENTIFIC COMMITTEE Carlos López Otín Departamento de Bioquímica y Biología Molecular, Universidad de Oviedo. Department of Biochemistry and Molecular Biology, University of Oviedo Miguel López-Botet Arbona Director Científico del IMIN, Barcelona Scientific Director of IMIN, Barcelona Jaime Bosch Genover Director Científico del CIBERHED Scientific Director of CIBEREHD Xosé R. Bustelo Centro de Investigación del Cáncer, Salamanca Cancer Research Center, Salamanca – 10 – Felipe Rodriguez de Castro, Decano de la Facultad de Medicina, Universidad de Las Palmas de Gran Canaria. Dean of Medical School, University of Las Palmas de Gran Canaria José López Barneo Director del Instituto de Investigación Biomédica, Sevilla Director of Biomedical Research Institute, Sevilla COMISIÓN DE INVESTIGACIÓN RESEARCH COMMITTEE PRESIDENTE / CHAIRMAN Francisco Sánchez Madrid Director Científico, Instituto Investigación Sanitaria IP Scientific Director of IP Manuel Ortiz de Landázuri Servicio de Inmunología, Hospital U. La Princesa Immunology Department, Hospital U. La Princesa Julio Ancochea Bermúdez Servicio de Neumología, Hospital U. La Princesa Respiratory Department, Hospital U. La Princesa Ricardo Moreno Otero Servicio de Digestivo, Hospital U. La Princesa Gastroenterology Department, Hospital U. La Princesa Amaro García Díez Servicio de Dermatología, Hospital U. La Princesa Dermatology Department, Hospital U. La Princesa Antonio García García Servicio de Farmacología Clínica, Hospital U. La Princesa Clinical Farmacology Department, Hospital U. La Princesa Isidoro González Álvaro Servicio de Reumatología, Hospital U. La Princesa Rheumatology Department, Hospital U. La Princesa Mónica Marazuela Azpiroz Servicio de Endocrinología, Hospital U. La Princesa Endocrinology Department, Hospital U. La Princesa Adrián Alegre Amor Servicio de Hematología, Hospital U. La Princesa Hematology Department, Hospital U. La Princesa Federico Mayor Menéndez Centro Biología Molecular Severo Ochoa, Madrid Severo Ochoa Molecular Biology Centre, Madrid Francisco Abad Santos PRÓLOGO IP / FOREWORD IP Servicio de Farmacología Clínica, Hospital U. La Princesa Clinical Farmacology Department, Hospital U. La Princesa Carmelo García Monzón Servicio de Medicina Interna, Hospital U. Santa Cristina Internal Medicine Department, Hospital U. Santa Cristina Jesús Argente Oliver Servicio de Endocrinología, Hospital U. Niño Jesús Endocrinology Department, Hospital U. Niño Jesús Luis García Olmos Coordinador de Docencia e Investigación, Atención Primaria, Madrid Teaching and Research Coordinator, Atención Primaria, Madrid Ramón Colomer Bosch Servicio de Oncología Médica, Hospital U. La Princesa Medical Oncolgy Department, Hospital U. La Princesa Carmen Súarez Fernández Servicio de Medicina Interna, Hospital U. La Princesa Internal Medicine Department, Hospital U. La Princesa Dolores Ochoa Mazarro Igor Pinedo García Carolina Pozuelo González Eduardo Sánchez Sánchez Alberto Sebastián Palomino Alba Serrano Ruiz Tania Tineo Drove SECRETARIA / SECRETARY Mara Ortega Gómez FUNDACIÓN INVESTIGACIÓN BIOMÉDICA (FIB) FOUNDATION FOR BIOMEDICAL RESEARCH (FBR) DIRECTOR / DIRECTOR Rosario Ortiz de Urbina Barba SECRETARIA / SECRETARY Mª Ángeles Vallejo COMITÉ ÉTICO DE INVESTIGACIÓN CLÍNICA CLINICAL RESEARCH ETHICS COMMITTEE PRESIDENTE / CHAIRMAN Francisco Abad Santos VICEPRESIDENTE/ DEPUTY CHAIRMAN Rosario Ortiz de Urbina Barba MIEMBROS / MEMBERS Enrique Alday Muñoz Ramón Colomer Bosch Carmen del Arco Galán Mª José Galán Sánchez Heredero D. Carmelo García-Monzón Jesús González Cajal Andrés López Romero Elena Martín Pérez Concepción Martínez Nieto Licinio Medina Moreno – 11 – PRODUCCIÓN CIENTÍFICA SCIENTIFIC OUTPUT PRODUCCIÓN CIENTÍFICA SCIENTIFIC OUTPUT El análisis de la producción científica del IP medido por el factor de impacto (IF) de las revistas académicas, es uno de los indicadores bibliométricos más utilizados que muestran la calidad de los trabajos publicados. Este índice, es una medida que se calcula anualmente y refleja el número de veces que los artículos son citados, referidos al total de las publicaciones “citables” de una revista concreta. Consideraremos como Factor de Impacto (FI) de las revistas el indicado en el Journal Citation Report (JCR) 2011. Cada publicación será computada una sola vez cuando sean referidos al total de las publicaciones y del factor de impacto acumulado del IP. Sin embargo aquellas que involucren a diferentes grupos de investigación se computan individualmente a cada uno de ellos y así se muestra con detalle en la actividad científica de cada grupo. Sólo se mostrarán las publicaciones publicadas en revistas con factor de impacto superior a 0,9. Impact factor (IF) of the academic journals in which articles are published is one of the indicators used most frequently to show the quality of published articles. This index is calculated yearly and reflects for each journal the number of times that its articles are cited, referred to the total number of cited articles in a particular field. In this report we have used for our analysis the IF indicated in Journal Citation Report (JCR) 2011. Each article is counted only once when referred to the total number of publications and the accumulated impact factor of the IP. However, those involving different research groups are ascribed to each of the groups and are shown in detail in the scientific output of the groups. Only the publications in journals with IF higher than 0.9 are shown En 2012 un total de 340 artículos fueron publicados en revistas indexadas con FI superior a 0,9; este dato supone un incremento del 15% respecto al año 2011. El factor de impacto acumulado fue de 1672.99. Esto significa que el factor de impacto medio por artículo fue de 4.92, implicando un aumento significativo respecto al 4.7 del año 2011. In 2012, a total of 340 articles were published in indexed journals with IF higher than 0,9, representing a 15% increased from 2011. The accumulated IF was 1672.99. These data resulted in a mean IF per article of 4.92 which represented a significant increase from the 4.7 of 2011. – 12 – En el siguiente gráfico se muestran los artículos del IP distribuidos por quartiles. Durante el año 2012 se ha producido un incremento en los artículos publicados en revistas de quartil 1, lo que supone un 57% de todas de las publicaciones. The following graphic shows distribution of IP articles in different quartiles. In 2012 the number of articles published in quartile 1 journal has increased. Articles in quartile 1 represent 55% of total. PRÓLOGO IP / FOREWORD IP LISTADO REVISTAS JOURNAL INDEX JOURNAL Articles 6,8 1 CEREB CORTEX 6,544 1 ANN ONCOL 6,425 1 HAEMATOL-HEMATOL J 6,424 3 J INFECT DIS 6,41 1 JACC-CARDIOVASC INTE The tables listed below shows the fifty high impact factor journal in which IP researchers published articles during 2012. The tables listed below show the fifty high impact factor journals in which IP researchers published articles during 2012. JOURNAL IF IF Articles NEW ENGL J MED 53,298 3 ONCOGENE 6,373 1 NAT REV MOL CELL BIO 39,123 1 J PATHOL 6,318 1 LANCET 38,278 3 AIDS 6,245 4 ANN INTERN MED 16,733 1 MOL CELL 14,178 1 WORLD PSYCHIATRY 6,233 2 CELL METAB 13,668 1 J CELL SCI 6,111 1 J CLIN INVEST 13,069 1 CARDIOVASC RES 6,064 1 GASTROENTEROLOGY 11,675 1 CANCER TREAT REV 6,054 1 HEPATOLOGY 11,665 1 PLOS BIOL 11,452 1 J CLIN ENDOCR METAB 5,967 2 GUT 10,111 1 EUR RESPIR J 5,895 1 BLOOD 9,898 4 J IMMUNOL 5,788 3 J AM SOC NEPHROL 9,663 1 J THROMB HAEMOST 5,731 2 J HEPATOL 9,264 1 EMBO J 9,205 1 STROKE 5,729 2 CLIN INFECT DIS 9,154 3 FASEB J 5,712 1 PLOS PATHOG 9,127 1 BBA-MOL CELL RES 5,538 1 8,8 1 J INTERN MED 5,483 1 ANN RHEUM DIS 8,727 4 CLIN CHEM 7,905 1 INTENS CARE MED 5,399 1 CLIN CANCER RES 7,742 1 CHEST 5,25 1 HUM MOL GENET 7,636 2 ENDOSCOPY 5,21 1 SCI SIGNAL 7,499 2 MOL CELL PROTEOMICS 7,398 1 TRENDS PARASITOL 5,144 1 AM J GASTROENTEROL 7,282 3 CURR DRUG METAB 5,113 4 SCHIZOPHRENIA BULL – 13 – ESTRUCTURA ORGANIZATIVA ORGANISATIONAL CHART GUÍAS CLÍNICAS CLINICAL GUIDELINES Uno de los retos de nuestra investigación, es poder trasladar los avances desarrollados en nuestro al IP al beneficio de los pacientes. Este hecho se materializa en la creación de guías de Práctica Clínica. A continuación, se listan las guías publicadas durante el año 2012. TITLE One of our biggest challenges is to translate our research to the benefit of patients. Our researchers contribute to this effort participating actively in the elaboration of clinical guidelines. The guidelines published during 2012 are listed below. AUTHORS JOURNAL AREA GROUP Latex allergy: Position Paper Cabañes N, Igea JM, de la Hoz B, Agustín P, Blanco C, Domínguez J, Lázaro M, Lleonart R, Méndez J, Nieto A, Rodríguez A, Rubia N, Tabar A, Beitia JM, Dieguez MC, Martínez-Cócera C, Quirce S. J Investig Allergol Clin Immunol 22(5):313-30. 2012. PMID: 23101306. 1 20 Guía de Práctica Clínica para el Tratamiento de Pacientes con Enfermedad Pulmonar Obstructiva Crónica (EPOC) Julio Ancochea Bermúdez. MSC 2012 1 22 COPD Guidelines (GesEPOC): pharmacological treatment of stable COPD Miravitlles M, Soler-Cataluña JJ, Calle M, Molina J, Almagro P, Quintano JA, Riesco JA, Trigueros JA, Piñera P, Simón A, López-Campos JL, Soriano JB, Ancochea J. Arch Bronconeumol. 48(7):247257. 2012. PMID: 22561012. 1 22 Recommendations for the prevention and management of suicidal behavior. Guía clínica para el manejo de la conducta suicida derivada de un proyecto Subvencionado por la Comunidad de Madrid. Ayuso-Mateos JL, Baca-García E, Bobes J, Giner J, Giner L, Pérez V, Sáiz PA, Saiz Ruiz J; Grupo RECOMS Rev Psiquiatr Salud Ment 5(1):823. 2012. PMID: 22854500. 2 33 Guidelines for the preventive treatment of ischaemic stroke and TIA (I). update of risk factors and life style Fuentes B, Gállego J, Gil-Nuñez A, Morales A, Purroy F, Roquer J, Segura T, Tejada J, Lago A, Díez-Tejedor E; por el Comitéad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la SEN:, Alonso de Leciñana M, Alvarez-Sabin J, Arenillas J, Calleja S, Casado I, Castellanos M, Castillo J, Dávalos A, Díaz-Otero F, Egido JA, López-Fernández JC, Freijo M, García Pastor A, Gilo F, Irimia P, Maestre J, Masjuan J, MartíFábregas J, Martínez-Sánchez P, Martínez-Vila E, Molina C, Nombela F, Ribó M, Rodríguez-Yañez M, Rubio F, Serena J, Simal P, Vivancos J. Neurologia 27(9):560-574. 2012. PMID: 21890241. 2 35 Ultrasound measurement of carotid stenosis: recommendations from the Spanish Society of Neurosonology. Serena J, Irimia P, Calleja S, Blanco M, Vivancos J, Ayo-Martín O Neurologia. 2012 Oct 4. pii: S0213-4853(12)00251-4. 2012. PMID: 23040716. doi: 10.1016/j.nrl.2012.07.011 2 35 – 14 – PRÓLOGO IP / FOREWORD IP TITLE AUTHORS JOURNAL AREA GROUP Clinical management guidelines for subarachnoid haemorrhage. Diagnosis and treatment. Vivancos J, Gilo F, Frutos R, Maestre J, García-Pastor A, Quintana F, Roda JM, Ximénez-Carrillo A, Díez Tejedor E, Fuentes B, Alonso de Leciñana M, AlvarezSabin J, Arenillas J, Calleja S, Casado I, Castellanos M, Castillo J, Dávalos A, Díaz-Otero F, Egido JA, Fernández JC, Freijo M, Gállego J, Gil-Núñez A, Irimia P, Lago A, Masjuan J, Martí-Fábregas J, MartínezSánchez P, Martínez-Vila E, Molina C, Morales A, Nombela F, Purroy F, Ribó M, Rodríguez-Yañez M, Roquer J, Rubio F, Segura T, Serena J, Simal P, Tejada J; por el Comitéad hoc del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología (SEN). Neurologia. 2012 Oct 6. pii: S0213-4853(12)00249-6. 2012. PMID: 23044408. doi: 10.1016/j.nrl.2012.07.009. 2 35 Validation of a new tool to assess healthrelated quality of life in psoriasis: the PSOLIFE questionnaire Dauden E, Herrera E, Puig L, Sánchez-Carazo JL, Toribio J, Caloto MT, Nocea G, Roset M, Lara N. Health Qual Life Outcomes. 10:56. 2012. PMID: 22624984. doi: 10.1186/1477-7525-10-56. 3 37 Clinical practice guideline for an integrated approach to comorbidity in patients with psoriasis. Daudén E, Castañeda S, Suárez C, GarcíaCampayo J, Blasco AJ, Aguilar MD, Ferrándiz C, Puig L, Sánchez-Carazo JL; on behalf of the Working Group on Comorbidity in Psoriasis. J Eur Acad Dermatol Venereol. [Epub ahead of print]. 2012. PMID: 23134338. doi: 10.1111/ jdv.12024 3 37 Clinical practice guideline on the management of patients with dyspepsia. Gisbert JP, Calvet X, Ferrándiz J, Mascort J, AlonsoCoello P, Marzo M. Aten Primaria. 44(12):727.e1727.e38. 2012. PMID: 23036729. 3 38 Managing of the patient with dyspepsia. Gisbert JP, Calvet Calvo X, Ferrándiz Santos J, Mascort Roca JJ, Alonso-Coello P, Marzo Castillejo M. Aten Primaria. 44(12):728-33. 2012. PMID:23089244. doi: 10.1016/j.aprim.2012.07.008 3 38 Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. P. Malfertheiner, F. Megraud, C. A. O'Morain, J. Atherton, A. T. Axon, F. Bazzoli, G. F. Gensini, J. P. Gisbert, D. Y. Graham, T. Rokkas, E. M. El-Omar y E. J. Kuipers & the European Helicobacter Study Group (EHPSG). Gut 61(5):646-664. 2012. PMID:22491499. DOI: 10.1136/ gutjnl-2012-302084. 3 38 Guías españolas de diagnóstico y tratamiento de los síndromes mielodisplásicos y la leucemia mielomonocítica crónica. Grupo Español de Síndromes Mielodisplásicos (GESMD) Valle Gómez García de Soria (colaboradora). Haematologica 97(supl 5). 2012. ISSN 1138-0381. 3 44 Comparative study of talc poudrage versus pleural abrasion for the treatment of primary spontaneous pneumothorax Moreno-Merino S, Congregado M, Gallardo G, Jimenez-Merchan R, Trivino A, Cozar F, LopezPorras M, Loscertales J. Interact Cardiovasc Thorac Surg. 15(1):81-5. 2012. Entidad: Sponsor: European Soc Thorac Surg (ESTS). PMID: 22514256. DOI: 10.1093/icvts/ivs027 3 44 – 15 – PRODUCCIÓN CIENTÍFICA SCIENTIFIC OUTPUT INNOVACIÓN Y TRANSFERENCIA DE RESULTADOS INNOVATION AND TRANSFERENCE Es esencial para el IP potenciar todos los trabajos llevados a cabo en materia de innovación. Como prueba de ellos es la Unidad de terapias Biológicas de nuestro centro, siendo la primera de la Comunidad de Madrid. La creación de esta unidad es un reto para la aplicación de los avances en áreas de Neurología, Reumatología, Dermatología, Digestivo y Farmacia, que favorece no sólo la posibilidad de instaurar terapias personalizadas para los pacientes, sino también para optimizar los recursos existentes. Por otro lado los trabajos de innovación de los investigadores del IP han dado lugar a la solicitud de 5 nuevas patentes y a la concesión durante el pasado año 2012 de otras 7. A continuación se muestras los detalles de cada grupo. TITLE REF. NUMBER One of the great achievements of our Institute in the area of innovation in health care has been the multidisciplinary Biological Therapies Unit. This new unit (the first of this nature in Madrid) was established in 2012 by the collaborative effort of researchers from the Rheumatology, Neurology, Gastroenterology, Dermatology and Pharmacy services of la Princesa Hospital within IP. It aims to integrate the use of Biological Therapies in immune mediated inflammatory disorders, trying to optimize the use of these treatments from the perspective of increasing efficiency, safety, and cost effectiveness. During 2012 seven new patent applications have been filed by researchers of IP and seven applications were granted. Details for each group are listed below. AUTHORS COUNTRY ENTIDAD GROUP Secuencias nucleotídicas motivo que dirigen la localización de los ácidos nucleicos P201231503 Villarroya-Beltri, C., Mittelbrunn, M., Gutierrez-Vazquez, C., Sanchez-Cabo, F. and Sanchez-Madrid, F España CNIC / UAM 1 Uso de al menos una molécula de ADN para preparar un medicamento destinado al tratamiento del cáncer P201231393 Julián Aragones, Ainara Elorza, Manuel O. Landazuri España UAM 9, 6 Método in vitro de pronóstico de fibrosis hepática grave P201230368 Ricardo Moreno Otero, Rosario López Rodríguez, Paloma Sanz Cameno España UAM / CIBERehd 23 Método in vitro de pronóstico de cirrosis hepática P201230365 Ricardo Moreno Otero, Rosario López Rodríguez, Paloma Sanz Cameno España UAM / CIBERehd 23 P201230827 Rosa Perez Gomariz, Mª Carmen Martínez Mora, Yasmina Juarranz, Javier Leceta, Isidoro González Álvaro y Ana Mª Ortiz España FIB del HUP/ Universidad Complutense de Madrid 36 Uso de VIP como marcador pronóstico de enfermedades autoinmunes – 16 – PRÓLOGO IP / FOREWORD IP ENTIDAD ENTIDAD EXPLOTADORA GROUP España Instituto Biomar, S.L Instituto Biomar, S.L 12, 39 María Yañez Mo, Francisco SánchezMadrid, Francisco Domínguez Hernández, Carlos Simón Vallés España CNIC/UAM/ IVI 3,1 P200900085 Piqueras, J.F., Hernández, S., Villa-Morales, M, González-Sanchez, Laura, Fresno, M. & Fernández-Navarro España UAM 12 P200930936 Rodríguez Franco, Mª Isabel, Conde Ruzafa, Santiago, López Iglesias, Beatriz, Pérez Martín, Concepción, Villarroya Sánchez, Mercedes, García López, Manuela, García García, Antonio España UAM / CSIC 28 P200930931 Rodríguez Franco, Mª Isabel, Conde Ruzafa, Santiago, López Iglesias, Beatriz, Pérez Martín, Concepción, Villarroya Sánchez, Mercedes, García López, Manuela, García García, Antonio España UAM / CSIC 28 Compuestos derivados de 1,8-naftiridinas y su uso en el tratamiento de enfermedades neurodegenerativas P200930903 PCT/ES2010/ 070687 Cristóbal de los Ríos Salgado, Alejandro Romero Martínez, Javier Egea Máiquez, Rafael León Martínez, Mercedes Villarroya Sánchez, Manuela García López, Antonio García García, José Luis Marco Contelles, Elena Soriano Santamaría, Abdelouahid Samadi, Chioua Mourad España UAM / CSIC 28 Utilização de cromonas, seus derivados, seus sais farmaceuticamente aceitáveis e seus pró-fármacos com actividade inibidora da monoamina oxidase e aplicações terapêuticas relacionadas PT104487 Borges, M.F.M., Gaspar, A.M.N., Garrido, J.M.P.J., Milhazes, N.J.S.P., Uriarte, E., Yáñez, M., Orallo, F España UAM 28 P201030762 Manuel López-Brea Calvo, Teresa Alarcón Cavero, Sandra Rodrigo Gil, Alfonso-Vicente Carrascosa Santiago, Adolfo José Martínez Rodríguez España CSIC / UAM 52 TITLE REF. NUMBER AUTHORS Hexacyclic polyketides as kinase inhibitors PCT/EP2011/ 062379 Sánchez López, José Mª, Martínez Insua, Marta, Romero Millán, Francisco, Fernández-Medarde, Antonio, Fernández Chimeno, Rosa Isabel, Fresno Escudero, Manuel, Sánchez Valdepeñas, María del Carmen, Ramírez Orellana, Manuel Uso de CD98 como marcador de receptividad endometrial P200902193 Prostaglandina E2 para la prevención o el tratamiento de linfomas linfoblásticos Derivados de bis(aralquil amino y sistemas [6+5]heteroaromáticos y su uso en el tratamiento de patologías neurodegenerativas, incluida la enfermedad de Alzheimer Derivados de bis(aralquil) amino y sistemas (hetero) aromáticos de seis miembros y su uso en el tratamiento de patologías neurodegenerativas, incluida la enfermedad de Alzheimer Uso de compuestos fenólicos para el tratamiento de patologías causadas por Helicobacter pylori COUNTRY – 17 – PRODUCCIÓN CIENTÍFICA SCIENTIFIC OUTPUT TESIS DOCTORALES DOCTORAL THESES Para potenciar la calidad de los trabajos de investigación es fundamental tener personal bien formado, por lo que este aspecto es fundamental dentro del IP. Como prueba de ellos durante el pasado año se ha dado lectura a 14 tesis doctorales que se detallan a continuación. DOCTORATE THESIS READER Training of PhD students is fundamental for IP. As a result of this effort, during 2012 seven theses have been defended by members of IP. Details are listed below: TITLE DIRECTOR/S AREA GROUP Itziar Leal Leturia Espectroscopia por resonancia magnética de protón del cíngulo anterior en pacientes diagnosticados de esquizofrenia y trastorno bipolar José Luis Ayuso Mateos, Roberto Nuevo Benítez 2 33 María Cabello Salmerón Discapacidad laboral y depresión: prevalencia, evolución y factores relacionados desde una aproximación multiple José Luis Ayuso Mateos, Marta Miret García, Roberto Nuevo Benítez 2 33 Yolanda Rodríguez Muñoz Caracterización de subpoblaciones monocíticas en sangre periférica de pacientes con hepatitis crónica C: implicación de monocitos proangiogénicos Tie-2 en el establecimiento y progreso de la enfermedad Ricardo Moreno Otero 1 23 Ángela Somodevilla Solís Factores de virulencia, aspectos inmunológicos y patrones de sensibilidad en aislamientos clínicos de Helicobacter pylori Manuel López-Brea Calvo, Teresa Alarcón Cavero 3 52 Iván Ballesteros Martín Acciones antiinflamatorias del receptor nuclear PPARgamma en isquemia cerebral: Papel de la 5-lipoxigenasa en la neuroprotección por rosiglitazona María Ángeles Moro Sánchez, Ignacio Lizasoain Hernández, Olivia Hurtado Moreno 3 Assoc. 3 Ana María Gómez García Estudio de quemoquinas en la Leucemia Linfoblástica Aguda infantil. Papel del eje CXCR3/CXCL10 en la recaída del Sistema Nervioso Central Manuel Ramírez Orellana 3 39 Ana I. Sánchez Moya Infección y enfermedad tuberculosa en el paciente con psoriasis en tratamiento biológico Esteban Daudén Tello 3 37 Paloma Guillem Llobat Efectos de los ligandos de receptores LXR sobre la activación de macrófagos y el desarrollo de aneurismas aórticos abdominales Miguel Ángel Íñiguez Peña 1 18 Inés Claire Osma García Prostaglandinas dependientes de ciclooxigenasa-2: Moléculas clave en el conrol funcional de los macrófagos Manuel Fresno Escudero 1 12 Elba Alonso Álvarez Las concentraciones nanomolares de ouabaína activan la vía intrínseca de la apoptosis en las células HeLa Antonio García García, María Francisca Cano Abad 2 28 – 18 – PRÓLOGO IP / FOREWORD IP DOCTORATE THESIS READER TITLE DIRECTOR/S AREA GROUP Eva María Pérez Sacristán La Escuela de Farmacología de Madrid: de Teófilo Hernando al Instituto de I+D del Medicamento en la UAM Antonio García García 2 28 Liliana González Espinosa Bases clínicas y moleculares para el uso de la Pentoxifilina como tratamiento del estado microinflmatorio y de la disfunción endotelial de pacientes en diálisis Abelardo Isaac Aguilera Peralta, José Antonio Sánchez Tomero 1 21 Felipe de La Morena Utilidad de la aplicación de lidocaína como anestesia tópica faríngea en las esofagogastroduodenoscopias realizadas bajo sedación con propofol Cecilio Santander Vaquero 3 55 Eduardo Balsa Martínez Regulación de la cadena de transporte de electrones bajo condiciones de hipoxia Manuel Ortiz de Landázuri Busca 1 6 COMUNICACIÓN Y DIFUSIÓN COMMUNICATION AND DIFUSSION En el momento actual es de vital importancia contar con las nuevas herramientas para divulgar cualquier actividad la actividad científica. Desde la página Web de nuestro IP (www.iis-princesa.org), no sólo se hace difusión de los avances y novedades en el ámbito científico, sino también convocatorias, ofertas de empleo, cursos, congresos y noticias de relevancia para el IP. En la siguiente gráfica se muestran los datos del año 2012 y su comparativa con el año 2011. Como se observa el número de visitas tuvo un incremento del 26,6% respecto al año 2011 y los nuevos usuarios que consultaban la Web se incrementaron en un 21,6%. La difusión de las actividades del IP no sólo tiene alcance en nuestro país, a continuación se muestra la distribución de las visitas a la Web por países y una tabla con los que más nos visitan. It is currently of vital importance to use the new information tools to widely communicate the scientific activity. From the IP website (www.iis-princesa.org), we communicate not only the new scientific discoveries, but also research calls, courses, scientific congresses and news relevant to IP. The following graphic shows data from 2012 and their comparison to 2011. As depicted, the number of visits to the website increased 26.6% compared to 2011 with a 21.6% raise in the number of new users. The diffusion of our activities goes beyond our country. A distribution of the number of visits to the Web by countries is shown together with a table listing the nationalities most frequently consulting the Web. – 19 – PRODUCCIÓN CIENTÍFICA SCIENTIFIC OUTPUT COUNTRY ESPAÑA 2012 2011 IMPROVEMENT 24295 19008 +26.67% COLOMBIA 390 281 +38.79% REINO UNIDO 321 196 +68.78% NO DETERMINADO 300 87 +244.83% ALEMANIA 207 86 +140.70% En el siguiente gráfico, se muestra la distribución del número de visitas de las noticias por trimestres. The following graphic shows a quarterly distribution of the number of visits. PLATAFORMAS CIENTÍFICAS SCIENTIFIC PLATFORMS BIOBANCO BIOBANK Responsable Científica Scientifc Coordinator Dra. Mara Ortega Gómez El Biobanco Hospital Universitario de La Princesa (acreditado por la Comunidad de Madrid) se organiza como una Plataforma de apoyo – 20 – a la investigación dentro del Instituto de Investigación Sanitaria Hospital de La Princesa (IIS-IP). Constituye un banco de muestras biológicas de interés científico, procesadas para su explotación, cuyos principales objetivos son 1). Coordinar la recopilación, el procesamiento, el almacenamiento y la transferencia de muestras biológicas humanas para promover la investigación biomédica de más alto nivel. 2). Estandarizar las colecciones de muestras de investigación del Instituto (de conformidad con el artículo 67 de la LIB 14/2007 y RD 1716/2011 relacionados con la Investigación Biomédica con muestras humanas).3). Optimizar los recursos humanos y materiales, ofreciendo una gama de servicios para el procesamiento y análisis de las muestras recogidas por los grupos de investigación. Con el objetivo de optimizar los recursos humanos y materiales el Biobanco ofrece una amplia gama de servicios para el procesamiento y análisis de las muestras recogidas por los grupos de investigación. El Biobanco dispone de muestras de ADN, PBMCs, suero, plasma, sangre, orina y tejidos procedentes de las siguientes colecciones: • Patología Oncológica Genitourinaria. • Carcinoma tiroideo primario. • Hiperparatiroidismo Primario. • Controles sanos. Biobank Hospital Universitario de La Princesa (accredited by the Comunidad de Madrid) is organized as a platform to support research within the Instituto de Investigación IP. It is a biological sample bank with great scientific interest, processed for their use, whose main objectives are 1). Coordinate the collection: processing, storage and transfer of human biological samples to promote high-level research. 2). Standardize sample collections of the Institute (in accordance with article 67 of LIB 14/2007 and RD 1716/2011, about research with human samples). 3). Optimize human and material resources, offering a range of services for the processing and analysis of samples collected by the research groups. With the aim of optimizing the human and material resources, Biobank offers a wide range of services for the processing and analysis of samples collected by the research groups. Biobank has samples of DNA, PBMCs, serum, plasma, blood, urine and tissues from the following collections: • Oncology Genitourinary Pathology. • Primary thyroid carcinoma. • Primary Hyperparathyroidism. • Healthy controls . PRÓLOGO IP / FOREWORD IP UNIDAD ENSAYOS CLÍNICOS CLINICAL RESEARCH AND CLINICAL TRIALS UNIT Coordinador Coordinator Dr. Francisco Abad Santos Es un servicio de apoyo a la investigación acreditado por la Comunidad de Madrid, dirigido a todos los investigadores que requieran apoyo para la realización de investigación clínica. Sus principales funciones son: • Proporcionar asistencia los investigadores tanto en recursos humanos y materiales como en procedimientos operativos y funcionales. • Dar soporte en la gestión de la documentación para evaluación de CEIC y autoridades competentes. • Asesorar y apoyar en la elaboración de la documentación vinculada a la investigación clínica. • Coordinar, asesorar la puesta en marcha de los ensayos clínicos y mantener el seguimiento de los mismos . Clinical Trials Unit (accredited by the Comunidad de Madrid) is a service aimed at all researchers who need support for conducting clinical trials. The main functions are: • Provide assistance to researchers, both in human and material resources and operating and functional procedures • Provide management support of documentation by the Clinical Research Ethics Committee and competent authorities. • Advising and support in the preparation of documentation related to clinical research. • Coordinate the start-up and follow up clinical trials. UNIDAD METODOLOGÍA METHODOLOGICAL UNIT Coordinador Coordinator Dr. Francisco Rodríguez Salvanés En coherencia con los objetivos generales del IP, la Unidad de Apoyo Metodológico (UM) tiene como fin proporcionar a los equi- pos de investigación del IP el apoyo preciso para la elaboración y ejecución de los proyectos de investigación, con el fin de incrementar la excelencia de la actividad científica del IIS. Las prioridades de la UM son: • Asesorar en el diseño de protocolos de investigación de calidad que puedan resultar competitivos en las distintas convocatorias. • Asesoramiento para la preparación de comunicaciones y publicación de artículos originales en revistas científicas de amplia difusión. • Análisis de resultados de investigación que puedan trasladarse a la práctica clínica. According with main objectives of IP, Methodological Support Unit (UM) is designed to provide support to the researchers of IP so the making and implementation of scientific projects, in order to increase the excellence of the scientific activity of the IP. UM's priorities are: • Advising of quality protocols designs in order to be competitive in all different calls. • Advising and development of communications and original articles in order to publish them in scientific journals of large diffusion. • Research results analysis to be translated into clinical practice. PLATAFORMAS TÉCNICAS DE APOYO SCIENTIFIC PLATFORMS Coordinadora Coordinator Dra. María Yañez Mó El principal objetivo de esta Unidad es la coordinación de todos servicios científico-técnicos del Instituto de Investigación Sanitaria Hospital Universitario de La Princesa. Las principales funciones son: • Proporcionar soporte tecnológico a todos los grupos de investigación y planificar la cartera de servicios de las plataformas. • Desarrollar y mejorar las instalaciones en cuanto a infraestructuras científicas, asegurando la adecuada renovación y actualización del equipo científico-tecnológico disponible. – 21 – PRODUCCIÓN CIENTÍFICA SCIENTIFIC OUTPUT • Mejorar los servicios prestados optimizando el uso de instalaciones científicas y tecnológicas. • Gestionar el mantenimiento de las infraestructuras científicas y la relación con las plataformas tecnológicas de ámbito autonómico y estatal. Las plataformas gestionadas desde esta unidad son las siguientes: The main objective of this Unit is coordinating all scientific and technical services of IP. The main functions are: • Provide technical support to all research groups and plan platforms activity. • Develop and improve scientific infrastructure facilities, ensuring appropriate renewal and updating of scientific and technological equipment available. • Optimizing use of scientific and technological facilities. • Manage the maintenance of scientific infrastructure and related technology platforms regional and state level. Platforms managed from this unit are: Sala Blanca IP (Hospital U. Niño Jesús) Clean Room IP (Hospital U. Niño Jesús) Director Técnico Technical Director Dra. Maria Antonia Varela-Portas San Juan Servicio de Citometría Cytometry Service Coordinadora Coordinator Dra. Cecilia Muñoz Calleja Servicio de Genómica CBMSO IP Genomic Unit CBMSO IP Director Técnico Technical Director Dr. Fernando Carrasco Ramiro Servicio Microscopía Electrónica CBMSO IP Electronic Microscope Service CBMSO IP Director Técnico Technical Director Dra María Teresa Rejas Marco Servicio de Proteómica CBMSO IP Proteomic Unit CBMSO IP – 22 – Coordinador Coordinator Ana Isabel Marina Ramirez Servicio de Videomicroscopía Confocal Confocal Microscopy Service Coordinador Coordinator Dra. María Yáñez Mó Gabinete Veterinario UAM Animal Facility UAM Directora Director Carmen Fernández Criado ÁREAS DE INVESTIGACIÓN RESEARCH AREAS EL IP se estructura en tres áreas prioritarias que poyan la actividad investigadora del personal del Instituto. A continuación se desglosa la actividad de cada una de ellas mostrando el número de publicaciones con su factor de impacto acumulado y medio, así como su evolución en los 3 últimos años. The research groups are organized in three main areas that cover all the research activity of IP. The scientific output of these areas is presented bellow, showing the number of articles, mean and accumulated impact factor and their evolution in the last three years. PRÓLOGO IP / FOREWORD IP AREA 1: Cellular and Molecular Etiopathogenic Mechanisms in Inflammatory and Autoimmune Diseases Coordinator: Francisco Sánchez Madrid LINE NAME DIRECTOR 1.1 Intercellular communication In the inflammatory response Francisco Sánchez Madrid 1.2 Cellular and molecular responses to hypoxia Manuel Ortiz De Landázuri Busca 1.3 Animal models of inflammatory diseases and intercellular signalling Federico Mayor Menéndez 1.4 Etiopathogenic and immunological mechanisms of dermatological diseases Amaro García Diez 1.5 Cellular mechanisms and molecular determinants of allergy-based diseases Carlos Blanco Guerra 1.6 Inflammatory processes in nephrological diseases José Antonio Sánchez Tomero 1.7 Inflammatory mechanisms in pulmonary diseases Julio Ancochea Bermúdez 1.8 Inflammatory response in hepatic diseases Ricardo Moreno Otero 1.9 Mechanisms and mediators of endocrine diseases Mónica Marzuela Azpiroz 1.10 Children´s development (obesity and growth) Jesús Argente Oliver 1.11 Metabolic syndrome and vascular risk Carmelo García Monzón – 23 – PRODUCCIÓN CIENTÍFICA SCIENTIFIC OUTPUT AREA 2: Neurotransmission, Pharmacological Neuroprotection and Neurodegenerative and Neuropsychiatric Diseases Coordinator: Antonio García García LINE NAME DIRECTOR 2.1 Neuropharmacology and neuroprotection Antonio García García 2.2 Neurotransmission in the hippocampus Luis Gandía Juan 2.3 Clinical pharmacology and pharmacogenetics Francisco Abad Santos 2.4 Diagnostic and therapeutic advances in affective disorders José Luis Ayuso Mateos 2.5 Neurosurgery of epilepsy Rafael García de Sola 2.6 Cerebrovascular diseases José Aurelio Vivancos Mora – 24 – PRÓLOGO IP / FOREWORD IP AREA 3: Advanced Therapies and Individualized Medicine Coordinator: Isidoro González Álvarez LINE NAME DIRECTOR 3.1 Prognostic and predictor markers in autoimmune diseases Isidoro González Álvaro 3.2 Esophagogastrointestinal inflammatory diseases Javier Pérez Gisbert 3.3 Progenitors and cell therapy Luis Madero López 3.4 Advanced therapies in oncohematology Juan Luis Steegmann Olmedillas 3.5 Biological, cellular and molecular monitoring in oncohematology Elena Fernández Ruiz 3.6 New diagnostic and therapeutic advances in cardiovascular diseases Luis Jesús Jiménez Borreguero 3.7 New therapies in infectious pathologies Ignacio de los Santos Gil 3.8 Individualized medicine in solid tumors Almudena Zapatero Laborda – 25 – AREA 1 CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES Line 1.1 Intercellular Communication in the Inflammatory Response. Line 1.2 Cellular and molecular responses to Hypoxia. Line 1.3 Animal models of inflammatory diseases and intercellular signalling. Line 1.4 Etiopathogenic and immunological mechanisms of dermatological diseases. Line 1.5 Cellular mechanisms and molecular determinants of allergy-based diseases. Line 1.6 Inflammatory processes in nephrological diseases. Line 1.7 Inflammatory mechanisms in pulmonary diseases. Line 1.8 Inflammatory response in hepatic diseases. Line 1.9 Mechanisms and mediators of endocrine diseases. Line 1.10 Children´s development (obesity and growth). Line 1.11 Metabolic syndrome and vascular risk. – 27 – AREA 1 CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES – 28 – AREA 1 CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES Line 1.1 Intercellular Communication in the Inflammatory Response HEAD OF LABORATORY Francisco Sánchez-Madrid. Scientific Director, Inmmunology. GROUP MEMBERS • Olga Barreiro del Río • Noa Beatriz Martín Cófreces • Gloria Martínez del Hoyo Cañizares • María Mittelbrunn Herrero • Vera Rocha Perugini • Hortensia de la Fuente Flores • Adela Matesanz Marín • Emilio Tejera Puente • Francesc Baixauli Celda • Cristina Gutiérrez Vázquez • Noelia Blas Rus • Carolina Villarroya Beltri • Olga Moreno Gonzalo • Mª Ángeles Ursa Pecharromán • María José López Campos • Marta Esther Ramírez Huesca The immune synapse acts as a platform facilitating the passage of genetic material between cells. During immune synapse, the molecules involved in antigen recognition (such as T cell receptor (TCR) and peptide-loaded major histocompatibility complex (pMHC) molecules) move to a central cluster surrounded by a peripheral ring enriched in adhesion molecules (such as the integrin leukocyte function-associated antigen 1 (LFA-!) and intercellular cell adhesion molecules (ICAMs) and the actin cytoskeleton. The T lymphocyte orients its microtubuleorganizing center (MTOC) and secretory compartments (such as the Golgi apparatus and multivesicular bodies (MVBs), towards the antigen presenting cell (APC). izing complex (MTOC), by controlling cytoskeletal rearrangements at the immune synapse (IS), provides a mechanism for macromolecular transport and the concentration of signaling molecules during synaptic contact. This research program has the potential to reveal how transfer of miRNA between the T cell and the cognate antigen presenting cell (APC) regulates the early initiation of immunity. We are also developing methodologies for the in vivo imaging of immune cell infiltration, the inflammatory response and the role of immunoregulatory molecules (galectins and tetraspanins) in animal models of inflammation and human diseases. RESEARCH INTEREST The group’s present work focuses on key cell-to-cell communication events during cognate immune interactions. A key goal is to define how the microtubule organ- Our current specific objectives are the following: 1. To assess the role of MTOC polarization as a signaling and structural platform for the control of secretion during IS formation. – 29 – AREA 3 AREA 2 AREA 1 GROUP 1 Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases 2. To investigate the mechanisms and functional consequences of intercellular transfer of miRNA via the IS. 3. To image immune-inflammatory responses in vivo in order to define the role of immunoregulatory molecules in autoimmune inflammatory diseases. Martín-Cófreces NB, Baixauli F, López MJ, Gil D, Monjas A, Alarcón B, Sanchez-Madrid F. End-binding protein 1 controls signal propagation from the T cell receptor. EMBO J. 31(21):4140-52. 2012. PMID: 22922463. IF: 9,205. DOI: 10.1038/emboj.2012.242 MAJOR GRANTS de la Fuente H, Cibrián D, Sanchez-Madrid F. Immunoregulatory molecules are master regulators of inflammation during the immune response. FEBS Lett. 586(18):2897-2905. 2012. PMID: 22819828. IF: 3,538. DOI: 10.1016/j.febslet.2012.07.032 • Francisco Sánchez Madrid. Plataforma de análisis genético y proteínas. ISCIII. PI10/03659. Duration: 2011 - 2012. • Francisco Sánchez Madrid. Red temática de enfermedades cardiovasculares (RECAVA). ISCIII. RD060014-0030. Duration: 2011 - 2012. • Francisco Sánchez Madrid. Nuevos mecanismos de inmunomodulación: moléculas reguladoras, polaridad celular y transferencia de información genética en la comunicación intercelular. MICINN. SAF-2011-25834. Duration: 2012 - 2014. • Proyecto Coordinado. Redes moleculares y celulares en enfermedades inflamatorias. Programa Biomedicina. CAM. INDISNET S2011/BMD-2332. Duration: 2012 2015. • Francisco Sánchez Madrid. Mechanisms of MTOC guidance and Genetic Transfer at the Immune Synapse: novel modes of Immuno-modulation. European Research Council. ERCEA-AdG-2011-294340_GENTRIS. Duration: 2012 - 2017. PUBLICATIONS (13) [IF: 121,394] YEAR Total IF Publication No. Q1 2010 77,391 11 11 2011 74,667 12 11 1 2012 121,394 13 10 3 Fernández-Pisonero I, Dueñas AI, Barreiro O, Montero O, Sanchez-Madrid F, García-Rodríguez C. Lipopolysaccharide and sphingosine-1-phosphate cooperate to induce inflammatory molecules and leukocyte adhesion in endothelial cells. J Immunol. 188(11):54025410. 2012. PMID: 23089395. IF: 5,788. DOI: 10.4049/jimmunol.1201309 Gordón-Alonso M, Sala-Valdés M, Rocha-Perugini V, Pérez-Hernández D, López-Martín S, Ursa A, Alvarez S, Kolesnikova TV, Vázquez J, Sanchez-Madrid F, YáñezMó M. EWI-2 association with -actinin regulates T cell immune synapses and HIV viral infection. J Immunol. 189(2):689-700. 2012. PMID: 22689882. IF: 5,788. DOI: 10.4049/jimmunol.1103708 Q2 Sanchez-Cuellar S, de la Fuente H, Cruz-Adalia A, Lamana A, Cibrian D, Giron RM, Vara A, Sanchez-Madrid F, Ancochea J. Reduced expression of galectin-1 and galectin-9 by leucocytes in asthma patients. Clin Exp Immunol. 170(3):365-374. 2012. PMID: 23121677. IF: 3,36. DOI: 10.1111/j.1365-2249.2012.04665.x – 30 – Sala-Valdés M, Gordón-Alonso M, Tejera E, Ibáñez A, Cabrero JR, Ursa A, Mittelbrunn M, Lozano F, SanchezMadrid F, Yáñez-Mó M. Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions. J Cell Sci. 125(Pt 5):1235-46. Epub 2012 Feb 20. 2012. PMID: 22349701. IF: 6,111. DOI: 10.1242/jcs.094912 Fuente HD, Perez-Gala S, Bonay P, Cruz-Adalia A, Cibrian D, Sanchez-Cuellar S, Dauden E, Fresno M, García-Diez A, Sanchez-Madrid F. Psoriasis in humans is associated with downregulation of galectins in dendritic cells. J Pathol. 228: 193-203. 2012. PMID: 22271227. IF: 6,318. DOI: 10.1002/path.3996 Gordón-Alonso M, Rocha-Perugini V, Álvarez S, MorenoGonzalo O, Ursa A, López-Martín S, Izquierdo-Useros N, Martínez-Picado J, Muñoz-Fernández MÁ, Yáñez-Mó M, AREA 1 Elorza A, Soro-Arnáiz I, Meléndez-Rodríguez F, Rodríguez-Vaello V, Marsboom G, de Cárcer G, AcostaIborra B, Albacete-Albacete L, Ordóñez A, SerranoOviedo L, Giménez-Bachs JM, Vara-Vega A, Salinas A, Sánchez-Prieto R, Martín Del Río R, Sanchez-Madrid F, Malumbres M, Landázuri MO, Aragonés J. HIF2 Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5. Molecular Cell. 48(5):681-91. 2012. PMID: 23103253. IF: 14,178. DOI: 10.1016/j.molcel.2012.09.017 Mittelbrunn M, Sanchez-Madrid F. Intercellular communication: diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol. 13(5):328-335. 2012. PMID: 22510790. IF: 39,123 Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, Bond VC, Borràs FE, Breakefield X, Budnik V, Buzas E, Camussi G, Clayton A, Cocucci E, FalconPerez JM, Gabrielsson S, Gho YS, Gupta D, Harsha HC, Hendrix A, Hill AF, Inal JM, Jenster G, Krämer-Albers EM, Lim SK, Llorente A, Lötvall J, Marcilla A, MinchevaNilsson L, Nazarenko I, Nieuwland R, Nolte-'t Hoen EN, Pandey A, Patel T, Piper MG, Pluchino S, Prasad TS, Rajendran L, Raposo G, Record M, Reid GE, SanchezMadrid F, Schiffelers RM, Siljander P, Stensballe A, Stoorvogel W, Taylor D, Thery C, Valadi H, van Balkom BW, Vázquez J, Vidal M, Wauben MH, Yáñez-Mó M, Zoeller M, Mathivanan S. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 10(12):e1001450. 2012. PMID: 23271954. IF: 11,452. DOI: 10.1371/ journal.pbio.1001450 de Andrés C, Teijeiro R, Alonso B, Sanchez-Madrid F, Martínez ML, Guzmán de Villoria J, Fernández-Cruz E, Sánchez-Ramón S. Long-term decrease in VLA-4 expression and functional impairment of dendritic cells during natalizumab therapy in patients with multiple sclerosis. PLoS One. 7(4):e34103. 2012. PMID: 22496780. IF: 4,092. DOI: 10.1371/journal. pone.0034103 Citterio C, Menacho-Márquez M, García-Escudero R, Larive RM, Barreiro O, Sanchez-Madrid F, Paramio JM, Bustelo XR. The rho exchange factors vav2 and vav3 control a lung metastasis-specific transcriptional program in breast cancer cells. Sci Signal 5(244):ra71. 2012. PMID: 23033540. IF: 7,499. DOI: 10.1126/scisignal.2002962 GROUP 2 HEAD OF LABORATORY Esteban Veiga Chacón GROUP MEMBERS • Carmen Calabia Linares • Aranzazu Cruz Adalia • Guillermo Ramírez Santiago • Mónica Torres Torresano MAJOR GRANTS Esteban Veiga Chacón. Sinapsis inmunológica y control bacteriano del sistema inmune. MICINN. BFU201129450. Duration: 2012 - 2014. PUBLICATIONS (2) [IF: 9,678] YEAR Total IF Publication No. Q1 Q2 2010 13,114 3 2 1 2011 20,235 3 2 1 2012 9,678 2 1 1 Sanchez-Cuellar S, de la Fuente H, Cruz-Adalia A, Lamana A, Cibrian D, Giron RM, Vara A, SanchezMadrid F, Ancochea J. Reduced expression of galectin-1 and galectin-9 by leucocytes in asthma patients. Clin Exp Immunol. 170(3):365-374. 2012. – 31 – AREA 3 AREA 2 AREA 1 Sanchez-Madrid F. The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry. Mol Biol Cell 23(12):2253-2263. 2012. PMID: 22535526. IF: 4,942. DOI: 10.1091/mbc.E11-12-1003 Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases PMID: 23121677. IF: 3,36. DOI: 10.1111/j.13652249.2012.04665.x Fuente HD, Perez-Gala S, Bonay P, Cruz-Adalia A, Cibrian D, Sanchez-Cuellar S, Dauden E, Fresno M, García-Diez A, Sanchez-Madrid F. Psoriasis in humans is associated with downregulation of galectins in dendritic cells. J Pathol. 228: 193-203. 2012. PMID: 22271227. IF: 6,318. DOI: 10.1002/path.3996 GROUP 3 Syntenin-1 is polarized in migrating lymphocytes. T lymphoblastic HSB2 cells were transfected with GFP–syntenin-1 and monitored at 30 second intervals after stimulation with 100 ng/ml SDF-1a. Representative pseudocolored maximal projections are shown. Scale bar: 5 mm. Arrows indicate the uropod (U) and leading edge (LE). HEAD OF LABORATORY María Yáñez Mó GROUP MEMBERS • Soraya López Martín RESEARCH INTEREST Tetraspanin-enriched microdomains (TEM) are ubiquitous specialized membrane platforms formed by the engagement of tetraspanins in molecular associations with lipids and selected transmembrane proteins, mostly integrins, immunoglobulin-superfamily receptors and metalloproteinases. Most studies on tetraspanins have emphasized their role as scaffolds of membrane microdomains, however, emerging evidence suggests that tetraspanins might also connect receptors to signalling cascades and the cytoskeleton. We analyzed the connection of TEM with the actin cystoskeleton via actinin and syntenin-1. We demonstrated that actinin regulates the immune synapse formation and is required for efficient T cell activation. We extended these observations to virological synapses induced by HIV and so that our data suggest that the TEM-actinin complex is involved in the regulation of the actin cytoskeleton at T cell – 32 – Syntenin-1–M-RIP regulates F-actin polymerization at the immune synapse. (A) Relocalization of endogenous syntenin-1 and M-RIP in antigen-induced conjugates. Maximal projections of the confocal image stacks are shown, together with the corresponding DIC images. Scale bars: 5 mm. immune and virological synapses, providing a link between membrane microdomains and the formation of polarized membrane structures involved in T cell recognition. On the other hand, syntenin-1 controls cell asymmetry. We found that syntenin-1 controls actin polymerization through a specific association with the myosin phosphatase Rho interacting protein (M-RIP), which occurs in response to phosphorylation of syntenin-1 by Src. Our data provide a novel mechanistic link between receptor activation and actin polymerization and accumulation in response to extracellular stimulation. AREA 1 María Yañez Mó. Papel de las tetraspaninas en la regulación de proteasas de membrana y GTPasas de bajo peso molecular durante la extravasación leucocitaria y en la biogénesis de exosomas. ISCIII. PI11/01645. Duration: 2012 - 2015. PUBLICATIONS (4) [IF: 28,293] YEAR Total IF Publication No. Q1 Q2 2010 16,562 3 3 2011 19,372 4 2 1 2012 28,293 4 3 1 Sala-Valdés M, Gordón-Alonso M, Tejera E, Ibáñez A, Cabrero JR, Ursa A, Mittelbrunn M, Lozano F, Sánchez-Madrid F, Yáñez-Mó M. Association of syntenin-1 with M-RIP polarizes Rac-1 activation during chemotaxis and immune interactions. J Cell Sci. 125(Pt 5):1235-46. Epub 2012 Feb 20. 2012. PMID: 22349701. IF: 6,111. DOI: 10.1242/jcs.094912 Gordón-Alonso M, Sala-Valdés M, Rocha-Perugini V, Pérez-Hernández D, López-Martín S, Ursa A, Alvarez S, Kolesnikova TV, Vázquez J, SánchezMadrid F, Yáñez-Mó M. EWI-2 association with actinin regulates T cell immune synapses and HIV viral infection. J Immunol. 189(2):689-700. 2012. PMID: 22689882. IF: 5,788. DOI: 10.4049/jimmunol.1103708 Gordón-Alonso M, Rocha-Perugini V, Álvarez S, Moreno-Gonzalo O, Ursa A, López-Martín S, Izquierdo-Useros N, Martínez-Picado J, MuñozFernández MÁ, Yáñez-Mó M, Sánchez-Madrid F. The PDZ-adaptor protein syntenin-1 regulates HIV-1 entry. Mol Biol Cell 23(12):2253-2263. 2012. PMID: 22535526. IF: 4,942. DOI: 10.1091/mbc.E11-121003 Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, Bond VC, Borràs FE, Breakefield X, Budnik V, Buzas E, Camussi G, Clayton A, Cocucci E, Falcon-Perez JM, Gabrielsson S, Gho YS, Gupta D, Harsha HC, Hendrix A, Hill AF, Inal JM, Jenster G, Krämer-Albers EM, Lim SK, Llorente A, Lötvall J, Marcilla A, Mincheva-Nilsson L, Nazarenko I, Nieuwland R, Nolte-'t Hoen EN, Pandey A, Patel T, Piper MG, Pluchino S, Prasad TS, Rajendran L, Raposo G, Record M, Reid GE, Sánchez-Madrid F, Schiffelers RM, Siljander P, Stensballe A, Stoorvogel W, Taylor D, Thery C, Valadi H, van Balkom BW, Vázquez J, Vidal M, Wauben MH, Yáñez-Mó M, Zoeller M, Mathivanan S. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 10(12):e1001450. 2012. PMID: 23271954. IF: 11,452. DOI: 10.1371/journal.pbio.1001450 GROUP 4 HEAD OF LABORATORY Miguel Vicente Manzanares GROUP MEMBERS • Álvaro Ortega Carrión • Cristina Delgado Arévalo • Lidia Feo Lucas • Rocío Aguilar Cuenca • Irene Ríos Guillén • Alba Juanes García RESEARCH INTEREST During 2012, the Mechanotransduction group at the IIS-IP has incorporated one PhD student and two Masters students as well as one Research Specialist. The group has obtained new funding from the Ramón Areces Foundation and from Wimasis S.L. through the Invest in Spain Program. Scientifically, the Mechanotransduction group has continued evaluating the role of phosphorylation of the force-generating mol- – 33 – AREA 3 AREA 2 AREA 1 MAJOR GRANTS Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Under the auspices of the Ramón Areces funding, the group has begun investigating the role of myosin II in stem cell differentiation. Preliminary data suggest that differential targeting of the signaling cascades that end in myosin II may skew hMSC differentiation in response to extracellular mechanical cues, which will have repercussion in the regenerative schemes aimed at novel organ generation based in these cells. Scheme for preparation of traction force microscopy substrates. Images are obtained using the confocal microscope Leica SP5 that belongs to the IIS-IP. A detailed protocol can be found in the lab webpage (http://web.uam.es/personal_pdi/medicina/mvicente/default.html) Finally, the group has developed a novel approach in the Institute aimed to quantify forces in migrating cells. This technique, traction force microscopy, is being used to evaluate the effect of myosin II mutations that cause monogenic disease (May-Hegglin syndrome) in wound healing and adhesion. This is a novel and powerful technique that will help set the group at the forefront of Mechanotransduction field. The group has set in the Institute and has been heavily involved in the research to acquire a new, state-of-theart TIRF microscope that will widen the capabilities of the microscopy unit. We have also established collaborations with other groups in and out of the IIS-IP, including that of Prof. Sanchez-Madrid (IP), Dr. YáñezMó (IP), Prof. Juan Manuel García Aznar (out of IP, U. Zaragoza), Prof. Carlos Ortiz de Solorzano (out of IP, U. Navarra) and Dr. Brenton Hoffman (U. Duke, USA). MAJOR GRANTS Super-quantitative maps of force exerted by tumor cells. Force is quantified by displacement of fluorescent beads lying on the substrate. ecule non-muscle myosin II in cell adhesion and migration. Novel sites have been unveiled and their role in cell mechanics assessed using high-end microscopy and other quantitative techniques. Our data has revealed the existence of an alternative switch in myosin II that controls the activation of the molecule and its role in dynamic actin assembly, thus constituting a novel “druggable” site with potential therapeutic application in metastasis. – 34 – • Miguel Vicente Manzanares. La miosina no muscular de clase II coordina la señalización adhesiva y de citocinas con la respuesta celular a las propiedades mecánicas del microentorno inflamatorio. MICINN. SAF2011-24953. Duration: 2012 - 2014. • Miguel Vicente Manzanares. Estudio de la función de la miosina no muscular de clase II en inflamación. Marie Curie Career Reintegration Grant (CIG). Duration: 2011 - 2014. • Miguel Vicente Manzanares. La miosina II integra las señales mecánicas del microentorno celular y controla la migración y diferenciación de las células madre. Fundación Ramon Areces CIVP16A1831. Duration: 2012 – 2015. AREA 1 PUBLICATIONS 2) [IF: 7,745] YEAR Total IF Publication No. Q1 Q2 2012 7,745 2 1 1 Toplak T, Pandzic E, Chen L, Vicente-Manzanares M, Horwitz AR, Wiseman PW. STICCS reveals matrix-dependent adhesion slipping and gripping in migrating cells. Biophys J. 103(8):1672-82. 2012. PMID: 23083710. IF: 3,653. DOI: 10.1016/j.bpj.2012.08.060 1-/- mice have reduced thymic CD4+ Treg population and more immunogenic DCs. Recently, we reported that PSGL-1 interacts with the metalloproteinase ADAM8, whose activation cuts PSGL-1 regulating its membrane expression. In a mouse model of experimental ulcerative colitis, we found that PSGL-1 is implicated in maintaining the mice colonic lamina propria tolerance, indicating that homeostatic PSGL-1/PSelectin interactions during leukocyte recirculation are important for maintaining the peripheral tolerance. Chen L, Vicente-Manzanares M, Potvin-Trottier L, Wiseman PW, Horwitz AR. The integrin-ligand interaction regulates adhesion and migration through a molecular clutch. PLoS One. 7(7):e40202. 2012. PMID: 22792239. IF: 4,092. DOI: 10.1371/journal.pone.0040202 HEAD OF LABORATORY Ana Carmen Urzainqui Mayayo GROUP MEMBERS • Alicia Pérez Frías • Rafael González Tajuelo RESEARCH INTEREST PSGL-1 leukocyte adhesion receptor is responsible for the initial interactions of leukocytes with the activated endothelium and their recruitment to sites of inflammation. PSGL-1 is also important for the homeostatic homing and entry of leukocytes into different tissues and organs such as skin, thymus or lymph nodes. We described that PSGL-1 signaling makes human monocyte-derived DC become tolerogenic and drive the differentiation of naïve T cells to Treg. Accordingly, PSGL- Figure 1. PSGL-1 KO mice develop skin fibrosis and spontaneously generate autoantibodies related with connective tissue autoimmune diseases. A) Photographs of a 4 month-old and an aged female PSGL-1 deficient mice showing skin lesions. B) Hematoxilin/Eosin (H/E) and Masson´s trichrome staining 5x microphotographs showing representative skin samples of young and aged WT and PSGL-1 deficient mice. C) Percentage of PSGL-1 deficient mice with fibrotic skin from 1.5 to 24 months after birth. D) and E) Hypodermis width (D) and Dermis width (E) of WT and PSGL-1 deficient mice. F) Dermis/hypodermis ratios in WT and PSGL-1 deficient mice from 1.5 to 24 months after birth. C to F:At least 10 mice per group of age were analyzed. Bars represent the mean plus SD.Statistical significance was determined by Mann-Whitney U test.G) Immunofluorescence microphotographs of Hep-2 cells incubated with blood serum of either WT or PSGL-1 KO mice. H) Percentage of mice positive for Scl-70, U3-RNP, Sm, Jo-1 and SSA-Ro autoantibodies. G and H: 25 mice per group of age were analyzed. – 35 – AREA 3 AREA 2 AREA 1 GROUP 56 Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases activation with production of auto-antibodies, widespread fibrosis in the skin and internal organs –including kidneys and lungs-and vascular damage. Regarding the vascular damage, we have found that the small arterioles have the light of vessel reduced and the media wall layer increased, suggesting that they could develop pulmonary arterial hypertension. Our findings indicate that this could be an accurate mouse model for human scleroderma. MAJOR GRANTS Figure 2.A) 5x representative microphotographs of H/E stained kidney sections of WT and PSGL-1 KO mice.B) and C): 20x and 40x representative microphotographs of H/E (B) and Masson´s trichrome stained (C) kidney samples of WT and PSGL-1 KO mice.D and E): 10x, 20x, 40x microphotrographsof H/E (D) and Masson’s trichromic (E) stained representative sections of lung parenchimal areas from WT and PSGL-1-/- mice.F)anti-αSMA staining of lung sections. 40x immunohistochemistry microphotographs of alveolar parenchyma showing 10-30 μm-diameter arterioles in lungs of WT and PSGL-1-/- mice. Our present work focuses on a recent observation of our laboratory that adult PSGL-1 deficient mice present lesions in their back skin. We have found thatPSGL-1 deficiency develops an autoimmune disease that recapitulates the main hallmarks of the human diffuse systemic sclerosis: immune system – 36 – • Ana Carmen Urzainqui Mayayo. Caracterización de una enfermedad espontánea autoinmune desarrollada en ratones deficientes en PSGL-1. Contribución de PSGL-1 al desarrollo de enfermedades autoinmunes en humanos. ISCIII. PI11/01418. Duration: 2012 - 2014. • Ana Carmen Urzainqui Mayayo. Estudio del papel de PSGL-1 en el control del desarrollo de enfermedades autoinmunes. Fundación Ramón Areces. Duration: 2012 - 2015. PUBLICATIONS (0) [IF: 0] YEAR Total IF Publication No. Q1 2010 9,273 1 1 2011 17,735 3 3 Q2 AREA 1 Line 1.2 Cellular and molecular responses to Hypoxia GROUP 6 HEAD OF LABORATORY Manuel Ortiz de Landázuri Busca Model showing the involvement of NDUFA4L2 induction by HIF-1a in hypoxic adaptation. HIF-1α stabilization by hypoxia upregulates NDUFA4L2, which inhibits ETC Complex I activity. As a result, oxygen consumption decreases and ROS production is abrogated, thereby allowing cells to adapt to the hypoxic conditions. In addition, hypoxia decreases Complex IV levels, which represents a further regulatory point in hypoxic adaptation. RESEARCH INTEREST 1) Electron transport chain adaptations to low oxygen tensions Fine regulation of the mitochondrial electron transport chain (ETC) has proven to be an essential regulatory point under hypoxia. Over the last years our work have been focused on how the different complexes within the ETC are modulated by low oxygen availability. Specifically, we have found that hypoxic stabilization of HIF-1 controls Complex I inhibition and reactive oxygen species (ROS) abrogation. This is mediated by the induction of the new HIF-1 target gene: NDUFA4L2. Our later results showed how reduction in oxygen availability is sensed by the mitochondria and rapidly trigger a degradation response over Complex IV subunits. The final outcome is that Complex IV is reduced while its subunit composition is gradually altered, adjusting the ETC to better fit to low oxygen tensions. 2) Role of the ubiquitin ligate SART-1 in the progression of renal cell carcinomas SART-1 is a novel E3 ubiquitin ligase able to degrade HIF-1 but not HIF-2 . We are exploring the role of this ubiquitin ligase in the regulation of HIF transcription factors in renal cell carcinoma. HIF-1 is considered to have tumor suppressor activities whereas HIF-2 is a promoter of tumor progression. Therefore it is important to study new players that may regulate the expression of the HIF transcription factors. Preliminary data of our lab indicate that depending of the mutation of VHL protein, the ubiquitin ligase SART-1 may play an important role in the degradation of HIF-1 in these tumors. Progression of renal cell carcinoma tumors has been shown to be dependent on the loss of HIF-1 and the maintenance of HIF-2 , and studies indicate that SART-1 may negatively regulate the levels of HIF-1 . Therefore, the ubiquitin ligase SART-1 might play and important role in the malignancy of renal cell carcinomas, eliminating HIF-1 and preserving HIF2 . – 37 – AREA 3 AREA 2 AREA 1 GROUP MEMBERS • Ángel Ordóñez Navadijo • Bárbara Acosta Iborra • Eduardo Balsa Martínez • Esther Fuertes Yebra • Alicia Vara Vega Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases MAJOR GRANTS • Manuel Ortiz de Landázuri Busca. Sensores de oxigeno: reprogramación metabólica y supervivencia celular. MICINN. SAF2010-14851. Duration: 2010 - 2012. • Manuel Ortiz de Landázuri Busca. Red temática de enfermedades cardiovasculares (RECAVA). ISCIII. RD06-0014-0031. Duration: 2011 - 2012. • Manuel Ortiz de Landázuri Busca. Inflamación e hipoxia: Mecanismos de desarrollo y progresión en EPOC y SAHS. Programa Biomedicina. CAM. S2011/BMD-2542. Duration: 2012 - 2015. PUBLICATIONS (5) [IF: 43,040] YEAR Total IF Publication No. Q1 2010 10.462 2 2 Q2 2011 21,077 3 2 1 2012 43,04 5 4 1 Balsa E, Marco R, Perales-Clemente E, Szklarczyk R, Calvo E, Landázuri MO, Enríquez JA. NDUFA4 is a subunit of complex IV of the mammalian electron transport chain. Cell Metab. 16(3):378-86. Epub 2012 Aug 16. 2012. PMID: 22902835. IF: 13,668. DOI: Palazon A, Aragones Lopez J, Morales-Kastresana A, Ortiz De Landázuri M, Melero IJ. Molecular Pathways: Hypoxia response in immune cells fighting or promoting cancer. Clin Cancer Res 18(5):1207-13. Epub 2011 Dec 28. 2012. PMID: 22205687. IF: 7,742. DOI: 10.1158/1078-0432.CCR-11-1591 Sanchez-Cuellar S, de la Fuente H, Cruz-Adalia A, Lamana A, Cibrian D, Giron RM, Vara A, SanchezMadrid F, Ancochea J. Reduced expression of galectin1 and galectin-9 by leucocytes in asthma patients. Clin Exp Immunol. 170(3):365-374. 2012. PMID: 23121677. IF: 3,36. DOI: 10.1111/j.13652249.2012.04665.x Elorza A, Soro-Arnáiz I, Meléndez-Rodríguez F, Rodríguez-Vaello V, Marsboom G, de Cárcer G, – 38 – Acosta-Iborra B, Albacete-Albacete L, Ordóñez A, Serrano-Oviedo L, Giménez-Bachs JM, Vara-Vega A, Salinas A, Sánchez-Prieto R, Martín Del Río R, Sánchez-Madrid F, Malumbres M, Landázuri MO, Aragonés J. HIF2 Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5. Molecular Cell. 48(5):681-91. 2012. PMID: 23103253. IF: 14,178. DOI: 10.1016/j.molcel.2012.09.017 Conde E, Alegre L, Blanco-Sánchez I, Sáenz-Morales D, Aguado-Fraile E, Ponte B, Ramos E, Sáiz A, Jiménez C, Ordoñez A, López-Cabrera M, del Peso L, de Landázuri MO, Liaño F, Selgas R, Sanchez-Tomero JA, García-Bermejo ML. Hypoxia inducible factor 1alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. PLoS One 7(3):e33258. 2012. PMID: 22432008. IF: 4,092. DOI: 10.1371/ournal .pone.0033258 GROUP 7 HEAD OF LABORATORY Antonio Martínez Ruiz GROUP MEMBERS • Alicia Izquierdo Álvarez • Pablo Hernansanz Agustín • Elena Ramos Serrano RESEARCH INTEREST Non-enzymatic post-translational modifications in vascular pathophysiology The research of the group is centred on the study of non-enzymatic post-translational modifications induced by reactive oxygen and nitrogen species, especially cysteine reversible oxidative modifications. We also study their relevance in cell function and AREA 1 pathophysiology, mainly in the molecular and cellular responses to hypoxia. We have developed new proteomic methodologies for analyzing these modifications (simultaneously with protein abundance changes), both with two-dimensional electrophoresis (“redox fluorescence switch”, RFS), and second-generation proteomic techniques (“GELSILOX” method, in collaboration with Dr. Jesús Vázquez, from the CBMSO and CNIC). We have reviewed the role of S-nitrosylation in the immune system, including the mechanistic and therapeutic approaches of nitrosothiols in autoimmune diseases. We have also reviewed the particularities of S-nitrosylation as a short-distance nonclassical NO signalling mechanism. MAJOR GRANTS Short-range and long-range NO signaling. Classical NO signaling, such as sGC activation, can be exerted at a relatively long distance from NO sources (NOS enzymes), even if NO concentration diminishes while targets are farther from the NOS. We postulate that S-nitrosylation of target proteins (TP) or interacting proteins (IP) is essentially a short-range mechanism, limited to a tiny sphere around NOS. Among other factors, RNS formation requires higher NO concentrations, which are easier to achieve in the NOS surroundings, and denitrosylases such as Trx or GSNOR with GSH can narrow the range of action by reducing target protein S-nitrosylation. • Antonio Martínez Ruiz. Papel funcional del estrés oxidativo y nitrosativo en grandes sistemas biológicos (consorcio ROSAS - “Reactive Oxygen Species And Systems”). MEC. Consolider-Ingenio 2010. CSD200700020. Duration: 2007 - 2012. • Antonio Martínez Ruiz. Papel de las especies reactivas de oxígeno y nitrógeno y de las modificaciones oxidativas de proteínas en la respuesta a hipoxia en fisiopatología cardiovascular. ISCIII. PS09/00101. Duration: 2010 - 2012. • Antonio Martínez Ruiz. Identificación proteómica de proteínas vegetales S-nitrosiladas en la respuesta a – 39 – AREA 3 AREA 2 AREA 1 2DE gels of endothelial cells extracts subjected to the Redox Fluorescence Switch (RFS). The green fluorescent signal corresponds to reversibly oxidised proteins; the red signal corresponds to total protein staining in the same gel. Differential green spots are the proteins reversibly oxidised in hypoxia (2 h, 1% O2). Nine more differential spots can be found; the solution is in Izquierdo-Álvarez et al., 2012. We have applied both techniques to analyze differential reversible cysteine oxidations in the acute response of endothelial cells subjected to hypoxia. We have observed a number of proteins that are oxidized after 2 hours in hypoxia, which is reverted by a 30-minutes reoxygenation. We have identified some of these proteins, among which we have found several proteins that take part in different protein signalling pathways, as well as metabolic enzymes that could have their function altered. The latter could be part of the acute responses to hypoxia before the transcriptional response by the canonical HIF pathway is initiated. Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases auxina. MICINN. PRI-AIBAR-2011-0782. Duration: 2011 - 2013. • Antonio Martínez Ruiz. Identificación de dianas de Snitrosilación en la estimulación de la neurogénesis endógena. MICINN. PRI-AIBPT-2011-1015. Duration: 2011 - 2013. PUBLICATIONS (2) [IF: 12,276] I YEAR Total IF Publication No. Q1 2010 6,051 1 1 2011 44,908 5 5 2012 12,276 2 2 Q2 RESEARCH INTEREST Our research interests have centered on the mechanisms that regulate TSP-1 and its counter receptor CD47, in particular the role of hypoxia and how this regulation is important in different pathophysiological aspects. In renal carcinomas, hypoxic conditions enhance the expression of angiogenic factors that help adapt tumour cells to their hostile environment. Conversely, we proved that hypoxia stimulates multiple signals that independently contribute to diminish thrombospondin-1 in ccRCC and proved to be important for ccRCC cell migration and invasion (Bienes R. et al. Nature Scintific Reports 2012). Another pathophysi- Izquierdo-Álvarez A, Ramos E, Villanueva J, HernansanzAgustín P, Fernández-Rodríguez R, Tello D, Carrascal M, Martínez-Ruiz A. Differential redox proteomics allows identification of proteins reversibly oxidized in cysteines in endothelial cells during acute response to hypoxia. J Proteomics 75(17):5449-5462. 2012. PMID: 22800641. IF: 4,878. DOI: 10.1016/j.jprot.2012.06.035 Martínez-Acedo P, Núñez E, Sánchez-Gómez FJ, Moreno M, Ramos E, Izquierdo-Álvarez A, MiróCasas E, Mesa R, Rodriguez P, Martínez-Ruiz A, Garcia-Dorado D, Lamas S, Vázquez J. A novel strategy for the global analysis of the dynamic thiol redox proteome. Mol Cell Proteomics 11(9):800813. 2012. PMID: 22647871. IF: 7,398. DOI: 10.1074/mcp.M111.016469 TSP1 regulation by hypoxia in ccRCC cell lines. Hypoxia stimulates multiple signals that contribute to the decrease in TSP-1 in ccRCC. TSP1 suppression by hypoxia elicits an autocrine stimulation of ccRCC migration. GROUP 8 HEAD OF LABORATORY María Josefa Calzada García GROUP MEMBERS • Raquel Bienes Martínez • Cristina Sánchez Corzo – 40 – CD47 activation promotes PAH through suppressing constituative Caveolin-1 inhibtion of eNOS. Under hypoxia, the CD47 ligand TSP1 is upregualted. On binding with TSP1 the cell receptor CD47 is activated leading to disrruption of the constitutive interaction between CD47 and membrane caveolin-1 (Cav-1). This in turn leads to decreased Cav-1 and increased eNOS activity. Monomeric hyperactive eNOS then produces superoxide rather than NO resulting in tissue oxidation and nitration. AREA 1 ological aspect we were interested in was the role of TSP-1/CD47 in promoting pulmonary aortic hypertension (PAH) since TSP1 and CD47 null mice are protected in a classic murine hypoxia model of PAH. It has been previously shown that activation of CD47 by TSP1 inhibits eNOS. In this respect, our studies in animals and hypoxic cell cultures demonstrated that activation of CD47 by TSP1, inhibits caveolin-1 (Cav-1), promoting eNOS-dependent superoxide production, oxidative stress and PAH (Bauer PM et al. Cardiovascular Res. 2012). However it is not completely clear whether this is a unique mechanism or there are other pathways regulated by the TSP-1/CD47 nexus involved in the onset and maturation of PAH and whether hypoxia could be a condition of these phenomena trigger. Ongoing areas of interest also include the implications of this new paradigm in relation to cardiac function and inflammatory diseases. 2012. PMID: 22215724. 10.1093/cvr/cvr356 MAJOR GRANTS GROUP 9 6,064. DOI: Fernández-Sánchez R, Berzal S, Sánchez-Niño MD, Neria F, Gonçalves S, Calabia O, Tejedor A, Calzada MJ, Caramelo C, Deudero JJ, Ortiz A. AG490 promotes HIF-1 accumulation by inhibiting its hydroxylation. Curr Med Chem 19(23):4014-4023. 2012. PMID: 22709000. IF: 4,859 Fernández-Barral A, Orgaz JL, Gomez V, del Peso L, Calzada MJ, Jiménez B. Hypoxia negatively regulates antimetastatic PEDF in melanoma cells by a hypoxia inducible factor-independent, autophagy dependent mechanism. PloS One 7(3):e32989. 2012. PMID: 22457728. IF: 4,092. DOI: 10.1371/journal.pone.0032989 HEAD OF LABORATORY Julián Aragonés López GROUP MEMBERS • Ainara Elorza Peregrina • Inés Soro Arnaíz • Florinda Meléndez Rodríguez PUBLICATIONS (3) [IF: 15,015] RESEARCH INTEREST YEAR Total IF Publication No. Q1 Q2 2010 1,254 1 2011 16,603 2 1 1 2012 15,015 3 3 Philip M. Bauer, Eileen M. Bauer, Mingyi Yoa, Xiaojun Huang, Monica Feijoo-Cuaresma, Joesph M. Pilewski, Hunter C. Champion, Brian S. Zuckerbraun, Maria J. Calzada, Jeff S. Isenberg. Activated CD47 Promotes Pulmonary Arterial Hypertension Through Suppression of Caveolin-1. Cardiovascular Research 93(4):682-93. The HIF oxygen-sensing pathway in tumor biology Local O2 supply to cells or tissues becomes limited during the development of numerous pathological scenarios such cardiac ischemia, inflammation, solid tumor formation (malignant cells localized in the inner core of the tumour). Cell respond to these O2 fluctuations by activating the hypoxia-inducible factors HIF-1 and HIF-2 . We have implemented loss or gain of function animal models to assess the role of these two oxygen-sensing pathways in vivo. – 41 – AREA 3 AREA 2 AREA 1 • María Josefa Calzada García. TSP1 in Pathophysiology: Role in Renal Cancer and Ischemic Tissue Damage and Regeneration. MICINN. SAF2009-11113. • María Josefa Calzada García. TSP1-CD47 in Promotion of PAH-Associated Vasoconstriction and Vascular Overgrowth. NIH. FOA: PA10-067, period 2011-2015 IF: Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases MAJOR GRANTS mTORC1 activation by the HIF2α-SLC7A5 pathway. The HIF2α oxygen pathway upon Vhl gene inactivation or hypoxia in vivo induces the expression of the amino acid carrier SLC7A5, which facilitates the amino acid-dependent mTORC1 activity. This HIF2α-SLC7A5mTORC1 axis mediates tumor progression of Vhl deficient tumors and provide molecular basis of proliferative responses in non-tumoral scenarios as hypoxic lung. In particular, our research has been focused on the role of the HIF-dependent rewiring of cell metabolism and autonomous tumour cell proliferation. We recently found that the pro-proliferative activity of HIF2 can be explained by its effects on amino acid metabolism. Indeed, we found that HIF2 induces the expression of the amino acid carrier SLC7A5 (Solute carrier family 7A5), a protein that mediates the uptake of extracellular amino acids, and it also activates mTORC1, a central element in the growth and proliferation of cells driven by amino acid availability and the energy status of the cell (Figure 1) (Elorza et al. Molecular Cell 2012). Therefore these studies are aimed to unravel the molecular mechanisms by which HIFs factors contribute to tumour development and open new opportunities for therapeutic intervention. Overall our aim is to understand the molecular pathways executed by the HIF oxygen sensing pathways, which are critical (i) to understand the molecular bases of numerous pathologies and (ii) to design novel therapeutical and efficient interventions. – 42 – • Julián Aragonés López. Gaining sage on the Epoetins' saga: assessing long term risks and advancing towards better Epoetin driven treatment modalities. European Comission. 282551. Duration: 2011 - 2014. • Julián Aragonés López. Rutas de señalización del oxÍgeno mediadas por los factores de respuesta a hipoxia, HIF1 and HIF2, en obesidad y enfermedad cardiaca isquémica. MICINN. SAF2011-29716. Duration: 2012 - 2013. • Julián Aragonés López. Inflamación e hipoxia: mecanismos en desarrollo y progresión en EPOC y SAHS. CAM. P2010 / BMD-2542. Duration: 2012 2015. PUBLICATIONS (2) [IF: 21,920] YEAR Total IF Publication No. Q1 2010 35,531 5 5 2011 21,077 3 2 2012 21,92 2 2 Q2 1 Palazon A, Aragones Lopez J, Morales-Kastresana A, Ortiz Del Landazuri M, Melero IJ. Molecular Pathways: Hypoxia response in immune cells fighting or promoting cancer. Clin Cancer Res 18(5):1207-13. Epub 2011 Dec 28. 2012. PMID: 22205687. IF: 7,742. DOI: 10.1158/10780432.CCR-11-1591 Elorza A, Soro-Arnáiz I, Meléndez-Rodríguez F, Rodríguez-Vaello V, Marsboom G, de Cárcer G, Acosta-Iborra B, Albacete-Albacete L, Ordóñez A, Serrano-Oviedo L, Giménez-Bachs JM, Vara-Vega A, Salinas A, Sánchez-Prieto R, Martín Del Río R, Sánchez-Madrid F, Malumbres M, Landázuri MO, Aragonés J. HIF2 Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5. Molecular Cell. 48(5):681-91. 2012. PMID: 23103253. IF: 14,178. DOI: 10.1016/j.molcel.2012.09.017 AREA 1 GROUP 10 HEAD OF LABORATORY Susana Cadenas Álvarez GROUP MEMBERS • Andrea Anedda • Elia López Bernardo Research in our group is focused on the function of mitochondria within cells and their implication in the development of pathological conditions. We have followed several lines of research as described below. 1) We studied the ability of intact mitochondria to generate nitric oxide (NO) and the effect of mitochondrial NO on respiration in skeletal muscle mitochondria from control mice and mice injected with E. coli lipopolysaccharide (LPS). Mitochondria from LPStreated mice had lower respiration rates and higher P50 values than control mitochondria, suggesting that mitochondrially derived NO is generated by an LPSinducible NO synthase protein that modulates oxygen consumption. Aguirre et al. (2012) Mitochondrion, 12:126-131. 2) In collaboration with Dr. F. Díaz-González (Hospital Universitario de Canarias, La Laguna) and Dr. F. Sánchez-Madrid (Hospital Universitario de La Princesa, Madrid), we analyzed the involvement of reactive oxygen species in the down-regulation of Lselectin induced by non-steroidal anti-inflammatory drugs in human neutrophils. We reported the implication of superoxide anion generated by plasma membrane NADPH-oxidase in this effect. Dominguez-Luis et al. (2013) Biochem. Pharmacol., 85:245-256. 3) We have also studied the regulation of mitochondrial uncoupling protein 3 (UCP3) expression and function under oxidative stress. We found that hydrogen H2O2 increases UCP3 expression via Nrf2 promoting cell survival under conditions of oxidative stress. Model showing the activation and nuclear translocation of Nrf2 induced by H2O2-generated oxidative stress. The binding of Nrf2 to an ARE within the UCP3 promoter increases UCP3 expression, while superoxide and 4-HNE increase UCP3 activity. Increased UCP3 expression together with protein activation induces a slight decrease in the membrane potential (mild uncoupling), and an ensuing decrease in superoxide production. This mechanism promotes cell survival under conditions of oxidative stress. Anedda et al. (2013) Free Radic. Biol. Med., 61:395-407. peroxide (H2O2) treatment increases both UCP3 mRNA and protein in C2C12 and HL-1 cells, and that this effect is mediated by the transcription factor Nrf2, an essential regulator of the cellular redox homeostasis. UCP3 up-regulation increases proton leak and promotes survival, suggesting a role for this protein in attenuating ROS-induced damage. Anedda et al. (2013) Free Radic. Biol. Med., 61:395-407. MAJOR GRANTS • Susana Cadenas Álvarez. Desacoplamiento mitocondrial en isquemia experimental y clínica. ISCIII. PS09/00116. Duration: 2009 - 2012. • Susana Cadenas Álvarez. La mitocondria y su implicación en patología humana. Programas de actividades de I+D entre grupos de investigación de la Comunidad de Madrid en Biomedicina. S2010/BMD-2402. Duration: 2012 - 2015. – 43 – AREA 3 AREA 2 AREA 1 RESEARCH INTEREST Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases PUBLICATIONS (1) [IF: 3,615] – 44 – YEAR Total IF Publication No. Q1 2010 16,315 3 3 2011 19,091 2 2 2012 3,615 1 Q2 1 Aguirre E, López-Bernardo E, Cadenas S. Functional evidence for nitric oxide production by skeletal-muscle mitochondria from lipopolysaccharide-treated mice. Mitochondrion 12(1):126-31. Epub 2011 Jun 12. 2012. PMID: 21664300. IF: 3,615. DOI: 10.1016/j.mito.2011.05.010. AREA 1 Line 1.3 Animal models of inflammatory diseases and intercellular signalling GROUP 11 HEAD OF LABORATORY Federico Mayor Menéndez GROUP MEMBERS • Catalina Ribas Núñez • Petronila Penela Márquez • Guzmán Sánchez Fernández • Laura Nogués Vera • Susana Rojo Berciano • Verónica Rivas Guerrero • Julia Palacios García • Almudena Inés Santos Bajo • Adolfo Molejón García • Paula Ramos Barbeito • Clara Reglero Gómez • Sofía Cabezudo Violero Pathophysiological implications of the GRK2 interactome. RESEARCH INTEREST G protein-coupled-receptor kinase 2 (GRK2) is emerging as a key integrative node in many signaling networks. GRK2 displays a complex network of functional interactions (“interactome”) that underlies a variety of novel physiological roles. Changes in GRK2 expression occur in several relevant inflammatory, metabolic, cardiovascular or cancer diseases, suggesting that those alterations may contribute to the development of these pathologies. In order to assess the feasibility of GRK2 as a useful biomarker and/or therapeutic target, our main objectives are the identification of the relevant GRK2 interactome in specific physiopathological contexts and the evaluation of the functional impact of alterations in GRK2 levels using cellular and animal models. During 2011, we have: a) Revealed the existence of multiple scaffolding functions in the degradation of GRK2 by the proteasome pathway, and identified a direct interaction between GRK2 and the Mdm2 E3-ubiquitin ligase (Nogués L et al., J. Biol. Chem. 2011) b) Identified a novel Galpha-q/ PKCzeta/ ERK5 pathway that has an important role in angiotensin-mediated heart hypertrophy in vivo (Garcia-Hoz C , SanchezFernández G et al. , J. Biol. Chem. 2012) c) In collaboration with Dr. J. De Celis (CBM Madrid), revealed the participation of Drosophila GRKs and – 45 – AREA 3 AREA 2 AREA 1 The complex GRK2 interactome (adapted from Penela et al., Brit J. Pharmacol. 2010). Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases arrestin homologs in the control of the Smoothened signaling pathway (Molnar C et al., Plos Genetics 2011) d) In collaboration with the group of Dr. Cristina Murga (UAM-IISLP), further developed a new type of p38 MAPK inhibitors based on the mechanism of regulation of p38MAPK by GRK2 (two patents filed) e) Also in collaboration with the group of Dr. Cristina Murga (UAM-IISLP), continued investigating the role of GRK2 in obesity and insulin resistance as well as in cardioprotection. f) Discovered that GRK2 modulates tubulin acetylation in a HDAC6-dependent manner in order to regulate key cellular processes relying on cytoskeletal rearrangements such as migration, polarity and cell spreading (Lafarga V et al., EMBO Journal, 2011) MAJOR GRANTS • Catalina Ribas Núñez. Señalización a través de receptores acoplados a Proteínas G. Interacciones funcionales entre las vías Mapk, G Q Y GRKS y su relación con enfermedades cardiovasculares. ISCIII. PI080461. Duration: 2009 - 2012. • Federico Mayor Menéndez. GRK2(G protein-coupled receptor kinase 2) as a key node in signal transduction networks. Role in physiopathology. MICINN. SAF201123800. Duration: 2012 - 2014. • Federico Mayor Menéndez. La quinasa GRK2(G proteincoupled receptor kinase 2) como un nodo central en las redes de señalización celular. Papel en fisiopatología. MICINN. SAF2011-23800. Duration: 2012 - 2014. • Federico Mayor Menéndez. Redes Moleculares y Celulares en Enfermedades Inflamatorias. CAM. S2010/BMD-2332 - Programa de Actividades I+D en BIOMEDICINA. Duration: 2012 - 2015. • Catalina Ribas Núñez. Nuevas vías de señalización iniciadas por interacción entre proteínas GALFAQ y PKCZ tras activación por GPCRS: su regulación e implicación en enfermedades cardiovasculares. ISCIII. PI11/00126. Duration: 2012 - 2014. • Petronila Penela Márquez. Repercusiones de la regu- – 46 – lación de Mdm2 y p53 por la quinasa GRK2 en cáncer de mama: estabilidad genómica y quimioresistencia. ISCIII. PI11/ 00859. Duration: 2012 - 2014. PUBLICATIONS (6) [IF: 39,542] YEAR Total IF Publication No. Q1 2010 23,585 3 3 2011 36.765 5 5 2012 27,961 6 5 Q2 Lafarga V, Mayor F Jr, Penela P. The interplay between G protein-coupled receptor kinase 2 (GRK2) and histone deacetylase 6 (HDAC6) at the crossroads of epithelial cell motility. Cell Adh Migr. 6(6):495-501. 2012. PMID: 23076141. IF: 1,816. DOI: 10.4161/cam.21585 García-Zaragoza E, Pérez-Tavarez R, Ballester A, Lafarga V, Jiménez-Reinoso A, Ramírez A, Murillas R, Gallego MI. Intraepithelial paracrine Hedgehog signaling induces the expansion of ciliated cells that express diverse progenitor cell markers in the basal epithelium of the mouse mammary gland. Dev. Biol. 372(1):28-44. 2012. PMID: 23000969. IF: 4,069. DOI: 10.1016/j.ydbio.2012.09.005 Vila-Bedmar R, Garcia-Guerra L, Nieto-Vazquez I, Mayor F Jr,, Lorenzo M, Murga C, Fernández-Veledo S. GRK2 contribution to the regulation of energy expenditure and brown fat function. FASEB J 26(8):3503-3514. 2012. PMID: 22516294. IF: 5,712. DOI: 10.1096/fj.11-202267 García-Hoz C, Sánchez-Fernández G, García-Escudero R, Fernández-Velasco M, Palacios-García J, Ruiz-Meana M, Díaz-Meco MT, Leitges M, Moscat J, García-Dorado D, Boscá L, Mayor F Jr, Ribas C. Protein kinase C (PKC) mediated G q stimulation of ERK5 protein pathway in cardiomyocytes and cardiac fibroblasts. J Biol Chem. 287(10):7792-7802. 2012. PMID: 22232556. IF: 4,773. DOI: 10.1074/jbc.M111.282210 Buitrago-Pérez Á, Hachimi M, Dueñas M, Lloveras B, Santos A, Holguín A, Duarte B, Santiago JL, Akgül B, Rodríguez-Peralto JL, Storey A, Ribas C, Larcher F, del Rio M, Paramio JM, García-Escudero R. A humanized mouse AREA 1 model of HPV-associated pathology driven by E7 expression. PLoS One 7(7):e41743. 2012. PMID: 22911850. IF: 4,092. DOI: 10.1371/journal.pone.0041743 Penela P, Lafarga V, Tapia O, Rivas V, Nogués L, Lucas E, Vila-Bedmar R, Murga C, Mayor F Jr,. Roles of GRK2 in cell signaling beyond GPCR desensitization: GRK2-HDAC6 interaction modulates cell spreading and motility. Sci Signal 5(224):pt3. 2012. PMID: 22589388. IF: 7,499. DOI: 10.1126/scisignal.2003098 PMEPA1, a downstream target of Cox-2 may control epithelial mesechymal transition of ovarian carcinoma cells Skov3. Cells stained with phalloidin to visualize actin filaments. GROUP 12 GROUP MEMBERS • Nuria Gironés Pujol • Ruth Álvarez Díaz • Isabel M. Chico-Calero • Natalia Cuesta Rubio • Carmen Mª Sánchez-Valdepeñas • María Gema Marín Alberca • Inés Claire Osma García • Carmen Punzón Gálvez • Beatriz Barrocal López • Carlos Chillón Marinas • Mª de los Ángeles de Chorro y de Villa• Konstantinos Stamatakis Andriani • Alberto Jiménez Buiza • Marta Jiménez Martínez • Alba Jiménez Segovia RESEARCH INTEREST There are similarities between recognition of pathogens by Toll-like receptors (TLR), the immune response to infection and chronic inflammation. We are analysing the involvement of TLR/NFAT/Cox-2/prostaglandins (PGs) in novel functions of the immune system and in inflammato- Different types of myocarditis induced by three different T. cruzi strains. ry pathologies as Atherosclerosis, Obesity and Cancer. We have unravelled a link between TLRs and NFAT activation that regulates Cox-2, increasing inflammatory responses. Besides, PGs trigger migration activation of macrophages and T lymphocytes, including the duration of antigen presenting cell interaction with T lymphocytes. TLR2-TLR4/NFATc4 induces expression of some adipogenic and repressed the antiadipogenic genes in adipocytes, promoting or preventing Obesity. Finally, we have identified PMEPA1 and DUSP10 as Cox-2 induced molecules that control differentiation and stress response, respectively, key in promoting tumorogenicity on colon or ovarian carcinoma. Different genetic lineages have been defined in Trypanosoma cruzi, the causative agent of Chagas’ dis- – 47 – AREA 3 AREA 2 AREA 1 HEAD OF LABORATORY Manuel Fresno Escudero Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases ease. However, understanding of their comparative biology and pathogenesis is fragmentary. We have defined the protective immune mechanism and the double-edge role of NO. Th1/Th17/Treg/MDSC (myeloid derived suppressor cells) balance determines resistance/susceptibility in murine Chagas’s disease, depending on both host genetics and parasite strain. In general, Th1 are protective but need to be counterbalanced by Tregs to avoid excessive inflammatory damage. Th17 effect depends on host genetic and parasite background. Arginase I+ MDSC play a detrimental role. Besides, we are studying how the parasite enters, infects and escapes destruction by myeloid cells, defining Slamf1 as a new T. cruzi receptor. All intended for improved understanding and prevention of Chagas’ disease. MAJOR GRANTS • Manuel Fresno Escudero. Estudios para el tratamiento sintomático de la inflamación y el dolor. Neogenius Pharma AIE (Lab Almirall). CENIT-E 2009. Duration: 2010 - 2012. • Manuel Fresno Escudero. Receptores toll-like, prostanoides y redes de señalización en enfermedades inflamatorias. MICINN. SAF2010-18733. Duration: 2011 - 2013. • Manuel Fresno Escudero. Redes Moleculares y Celulares en Enfermedades Inflamatorias. CAM. S-2010/BMD2332 - Programa de Actividades I+D en BIOMEDICINA. Duration: 2012 - 2015. PUBLICATIONS (8) [IF: 44,972] YEAR Total IF Publication No. Q1 Q2 2010 47,566 8 5 2 2011 23,852 5 4 1 2012 44,972 8 7 1 Díaz-Muñoz MD, Osma-García IC, Fresno M, Iñiguez MA. Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem. J 443(2):451-461. – 48 – 2012. PMID: 22268508. 10.1042/BJ20111052 IF: 4,897. DOI: Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E2 and T cells: friends or foes?. Immunol Cell Biol 90(6):579586. 2012. PMID: 21946663. IF: 3,661. DOI: 10.1038/icb.2011.75 Wang G, Abadía-Molina AC, Berger SB, Romero X, O'Keeffe MS, Rojas-Barros DI, Aleman M, Liao G, Maganto-García E, Fresno M, Wang N, Detre C, Terhorst C. Cutting edge: Slamf8 is a negative regulator of Nox2 activity in macrophages. J Immunol. 188(12):5829-5832. 2012. PMID: 22593622. IF: 5,788. DOI: 10.4049/jimmunol.1102620 Fuente HD, Perez-Gala S, Bonay P, Cruz-Adalia A, Cibrian D, Sanchez-Cuellar S, Dauden E, Fresno M, García-Diez A, Sanchez-Madrid F. Psoriasis in humans is associated with downregulation of galectins in dendritic cells. J Pathol. 228: 193-203. 2012. PMID: 22271227. IF: 6,318. DOI: 10.1002/path.3996 Donnini S, Finetti F, Terzuoli E, Giachetti A, Iñiguez MA, Hanaka H, Fresno M, Rådmark O, Ziche M. EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity. Oncogene 31(29):3457-3466. 2012. PMID: 22081067. IF: 6,373. DOI: 10.1038/onc.2011.503 Calvo-Álvarez E, Guerrero NA, Alvarez-Velilla R, Prada CF, Requena JM, Punzón C, Llamas MÁ, Arévalo FJ, Rivas L, Fresno M, Pérez-Pertejo Y, Balaña-Fouce R, Reguera RM. Appraisal of a Leishmania major strain stably expressing mCherry fluorescent protein for both in vitro and in vivo studies of potential drugs and vaccine against cutaneous leishmaniasis. PLoS Negl Trop Dis. 6(11):e1927. 2012. PMID: 23209866. IF: 4,716. DOI: 10.1371/journal.pntd.0001927 Aquilino C, Gonzalez Rubio ML, Seco EM, Escudero L, Corvo L, Soto M, Fresno M, Malpartida F, Bonay P. Differential trypanocidal activity of novel macrolide antibiotics; correlation to genetic lineage. PLoS One 7(7):e40901. 2012. PMID: 22859958. IF: 4,092. DOI: 10.1371/journal.pone.0040901 AREA 1 Calderón J, Maganto-Garcia E, Punzón C, Carrión J, Terhorst C, Fresno M. The receptor Slamf1 on the surface of myeloid lineage cells controls susceptibility to infection by Trypanosoma cruzi. PLoS Pathog 8(7):e10027. 2012. PMID: 22807679. IF: 9,127. DOI: 10.1371/journal.ppat.1002799 GROUP 17 HEAD OF LABORATORY Cristina Murga Montesinos The effects of GRK2 levels on insulin signalling and adiposity add up to the previously described regulation of G protein-coupled effects and other intracellular pathways by this kinase. GROUP MEMBERS • Rocío Vila Bedmar • Elisa Lucas Fernández During the past year 2012, the group has developed the following lines of research: 1.- Establishment of a proof of concept that a deletion of GRK2 could hamper the development of obesity and/or insulin resistance when deleted during an established condition of weight gain or insulin resistance (in collaboration with the groups of Dr. Federico Mayor and Dr. Annemieke Kavelaars and Dr. Cobi Heijnen in MD Anderson Cancer Center, University of Texas at Houston). 2.- Analysis of the cellular, molecular and systemic mechanisms by which lower levels of GRK2 protect from the development obesity and/or insulin resistance (following previous publications of our group). 2.- Studies on the gene expression analysis and transcriptional profile of the cardiac tissue of adult (9 months-old) mice hemizygous for GRK2 as well as the status of key cardioprotective signaling routes with age in this mice model.(Lucas E et al, manuscript submitted Decreased lipid accumulation and increased core temperature in hemizygous GRK2 mice.(A) Representative microscopy images of paraffinembedded sections of BAT stained with hematoxylin and eosin from WT and GRK2+/- 9-month-old mice (magnification 10x). Individual adipocyte areas were determined using image analysis software (ImageJ).(B)BAT from3 and9 month-oldWT and GRK2+/- mice was isolated and the expression of GRK2 as well as GAPDH was examined by Western blot. (C) Core temperature (expressed as ºC) was measured in WT and GRK2+/- 9-month-old mice maintained at room temperature (24±2°C). (D) BAT of 9 month oldWT and GRK2+/- mice was weighted after sacrifice and results expressed as BAT weight (g)/mouse weight (g). in collaboration with the groups of Dr. W.J.KochTemple University-and Dr. Javier Díez-CIMA-). 3.- Analysis of the vascular response to vasodilatatory and vasoconstrictory neurohumoral stimuli, structure and biomechanics of the vasculature and the development of hypertension by chronic infusion of angiotensin II in mice hemizygous for the GRK2 protein (Lucas E et al, manuscript submitted in collaboration with the group of Dr. Mercedes Salaíces/Dr. Ana Briones). – 49 – AREA 3 AREA 2 AREA 1 RESEARCH INTEREST Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases 4.- In silico identification of candidate small molecule compounds for p38MAPK based on virtual screening of molecules and peptidomimetic approaches, followed by in vitro validation, and further characterization in cells and in animal models of autoimmune diseases and hyperalgesia.(Willhemen et al, manuscript submitted in collaboration with the group of of Dr. Annemieke Kavelaars and Dr. Cobi Heijnen and Dr. Federico Mayor). Also, derived from this line of research are the following registered patents: • ES P201031673 (2010) & PCT /ES2011/070774 (2011): "Péptido inhibidor de p38 y sus aplicaciones" • ES 201131754 (2011) & PCT/ES2012/070762 (2012). "Fármacos inhibidores de p38 y sus apicaciones" MAJOR GRANTS • Cristina Murga Montesinos. Evaluación de compuestos neuroprotectores. Neuron BIOPHARMA, S.L. 409. Duration: 2010 - 2012. • Cristina Murga Montesinos. Caracterización de las rutas de señalización de GRK2 y MAPK en hipertrofia y disfunción cardiaca: desarrollo de inhibidores farmacológicos y validación de biomarcadores diagnósticos. ISCIII - MSC. Proyectos de Cooperación Interuniversitaria UAM Banco Santander con Estados Unidos. PS09/01208. Duration: 2010 - 2012. PUBLICATIONS (2) [IF: 13,211] YEAR Total IF Publication No. Q1 2010 13,814 2 2 2011 12,714 2 2 2012 13,211 2 2 Q2 Vila-Bedmar R, Garcia-Guerra L, Nieto-Vazquez I, Mayor F Jr, Lorenzo M, Murga C, Fernández-Veledo S. GRK2 contribution to the regulation of energy expenditure and brown fat function. FASEB J 26(8):3503-3514. 2012. PMID: 22516294. IF: 5,712. DOI: 10.1096/fj.11-202267 – 50 – Penela P, Lafarga V, Tapia O, Rivas V, Nogués L, Lucas E, Vila-Bedmar R, Murga C, Mayor F Jr. Roles of GRK2 in cell signaling beyond GPCR desensitization: GRK2-HDAC6 interaction modulates cell spreading and motility. Sci Signal 5(224):pt3. 2012. PMID: 22589388. IF: 7,499. DOI: 10.1126/scisignal.2003098 GROUP 18 HEAD OF LABORATORY Miguel Ángel Iñiguez Peña GROUP MEMBERS • Elena Hernández Subirá • Paloma Guillem Llobat • Raquel Nieto Pintado • Ana Renshaw Calderón RESEARCH INTEREST Lipid mediators as prostanoids and cholesterol derivatives play an essential role in inflammatory processes associated to the onset and development of a number of pathologies as cardiovascular diseases. Prostanoids participate in the inflammatory response and exert important actions in the cardiovascular system, modulating vascular homeostasis and participating in the pathogenesis of vascular diseases. Their importance in inflammation and in maintaining cardiovascular homeostasis is highlighted by clinical experience with drugs inhibiting their production as NSAIDs. In spite of their well-known properties as anti-inflammatory drugs, recent studies have shown that cyclooxygenase -2 selective NSAIDs inhibitors increase the risk of adverse cardiovascular side effects. On the other hand, oxysterols and drugs acting as LXR ligands play a central regulatory role in lipid uptake, metabolism and efflux through their properties as transcriptional regulators of gene AREA 1 and investigation of the contribution of prostanoid –mediated events and LXR ligands to the progression of abdominal aortic aneurysm, by the use of cellular models and an experimental model of this disease in Apo-E null mice and Cox-2 null mice. Research on the molecular and cellular basis of the actions of prostanoids and LXRs in the cardiovascular pathophysiology is required to clearly understand the benefits and risks of pharmaceutical intervention with COX inhibitors as NSAIDs or synthetic LXR ligands on cardiovascular diseases. MAJOR GRANTS Miguel Ángel Íñiguez Peña. Acciones de prostanoides y ligandos del receptor LXR en procesos inflamatorios y sus implicaciones en la fisiopatología cardiovascular. MICINN. SAF2011-23971. Duration: 2012 - 2014. PUBLICATIONS (2) [IF: 11,231] YEAR Total IF Publication No. Q1 Q2 2010 13,906 3 1 1 2011 3,536 1 1 2012 11,27 2 2 expression. In addition to their function in lipid metabolism, LXRs have also been found to modulate the immune response and inflammation. These properties have made them particularly attractive targets for intervention in human cardiovascular diseases. Díaz-Muñoz MD, Osma-García IC, Fresno M, Iñiguez MA. Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem. J 443(2):451-461. 2012. PMID: 22268508. IF: 4,897. DOI: 10.1042/BJ20111052 Based on these observations and our previous studies, the main objectives of our line of research include:analysis of the effects of prostanoids and LXR ligands in different cell types as leukocytes and cardiomyocytes, among others; study of the signal transduction pathways mediating hypertrophic effects of prostanoids on cardiomyocytes; Donnini S, Finetti F, Terzuoli E, Giachetti A, Iñiguez MA, Hanaka H, Fresno M, Rådmark O, Ziche M. EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity. Oncogene 31(29):3457-3466. 2012. PMID: 22081067. IF: 6,373. DOI: 10.1038/onc.2011.503 – 51 – AREA 3 AREA 2 AREA 1 Coordinated regulation of the expression of COX-2 and mPGES1 in macrophages. Our group have presented evidences indicating that COX-2 and mPGES-1 share common signaling pathways and transcription factors (NF-κB, Egr-1 and CREBP) that drive a coordinated expression of both genes in LPS-activated macrophages. The figure shows a model integrating these signaling pathways for the coordinated expression of COX-2 and mPGES-1 in macrophages. LPS treatment triggers NF-κB activation and Egr-1 expression. These transcription factors are involved in the early induction of COX-2 and mPGES-1. PGE2 produced at this stage promotes an autocrine positive feedback resulting in increased COX-2 and mPGES-1 expression through a signaling pathway involving an EP2-dependent increase of intracellular cAMP. This second messenger leads to the sequential activation of PKA and CREB that, in turns, promote an induction in the synthesis of COX-2 and mPGES-1, and hence in PGE2 production. Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Line 1.4 Etiopathogenic and immunological mechanisms of dermatological diseases Dermatol. 148(6):755-60. 2012. PMID: 22710460. IF: 3,888. DOI: 10.1001/archderm.148.6.755-b Fernandez-Peñas P, Jones-Caballero M, Espallardo O, García-Díez A. Comparison of Skindex-29, Dermatology Life Quality Index, Psoriasis Disability Index and Medical Outcome Study Short Form 36 in patients with mild to severe psoriasis. Br J Dermatol. 166(4):884-7. 2012. PMID: 22229951. IF: 3,666. DOI: 10.1111/j.13652133.2012.10806.x GROUP 19 HEAD OF LABORATORY Amaro García Díez Gallo E, Llamas-Velasco M, Navarro R, Fraga J, GarcíaDíez A. Eccrine squamous syringometaplasia secondary to cutaneous extravasation of docetaxel: report of three cases. J Cutan Pathol. 2012 Nov 21. [Epub ahead of print]. 2012. PMID: 23170995. IF: 1,561. DOI: 10.1111/cup.12041 GROUP MEMBERS • Maximiliano Aragüés Montañés • Silvia Pérez Gala • Javier Fraga Fernández Fuente HD, Perez-Gala S, Bonay P, Cruz-Adalia A, Cibrian D, Sanchez-Cuellar S, Dauden E, Fresno M, García-Díez A, Sanchez-Madrid F. Psoriasis in humans is associated with downregulation of galectins in dendritic cells. J Pathol. 228: 193-203. 2012. PMID: 22271227. IF: 6,318. DOI: 10.1002/path.3996 MAJOR GRANTS Amaro García Díez. Estudio Epidemiológico Psoriasis. Schering Plough. Duration: 2008 - 2012. PUBLICATIONS (7) [IF: 23,542] YEAR Total IF Publication No. Q1 Q2 2010 32,326 11 4 7 2011 5,846 3 1 1 2012 23,542 7 5 1 Llamas-Velasco M, Sánchez-Pérez J, Gallo E, Fraga J. Hyperpigmented asymptomatic macule in a fingertip with suspicious dermoscopic pattern--quiz case. Arch Dermatol. 148(2):247-252. 2012. PMID: 22351829. IF: 3,888. DOI: 10.1001/archdermatol.2011.1073a Pedraz J, Onate MJ, García-García C, Fraga J, Daudén E. Long-term nasal plaque with nasal obstruction. Arch – 52 – García-Martín P, De Argila D, To-Figueras J, LlamasVelasco M, Fraga J, García-Díez A. Phototolerance induced by narrow-band UVB phototherapy in severe erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. 28(5):261-3. 2012. PMID: 22971192. IF: 1,305. DOI: 10.1111/j.16000781.2012.00677.x Navarro R, Daudén E, Gallo E, Santiago Sánchez-Mateos D, García-Díez A. Alopecia areata during treatment of psoriasis with adalimumab and leflunomide: a case and review of the literature. Skin Pharmacol Physiol. 25(2):107-10. 2012. PMID: 22301842. IF: 2,916. DOI: 10.1159/000335264 CLINICAL TRIALS PRINCIPAL INVESTIGATOR: ARAGUES MONTAÑES, MAXIMILIANO AREA 1 con psoriasis en placas de moderada a grave: AMAGINE2; (versión 20-02-12). AMGEN INC. 20120103. EudraCT: 2012-000656-34 AREA 3 AREA 2 AREA 1 Estudio de fase 3 para evaluar la eficacia y la seguridad de las pautas de inducción y mantenimiento de brodalumab en comparación con placebo y ustekinumab en sujetos – 53 – Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Line 1.5 Cellular mechanisms and molecular determinants of allergy-based diseases GROUP 20 HEAD OF LABORATORY Carlos Blanco Guerra GROUP MEMBERS • Álvaro Daschner • Francisco Félix Vega de la Osada • Consolación de Frutos Moreno • Ana Valls Sánchez • M. Paloma Las Heras Almazán • Tania María Ramos García This figure shows the proposed immunologic mechanisms leading to different clinical outcome after an acute parasitism by Anisakis simplex. GA: gastric Anisakiasis. GAA: Gastro-allergic Anisakiasis. CU+: A. simplex sensitization associated chronic urticaria. (Trends in Parasitology 2012) RESEARCH INTEREST Our group has focused on three different research areas throughout 2012: - Anisakis simplex allergy: Within the project on characterizing Anisakis simplex sensitization associated chronic urticaria as a differential phenotype, leaded be Dr. A. Daschner, we published the results on the use of recombinant allergens for the differentiation of clinical entities associated with Anisakis simplex sensitization Whereas anti- Ani s 7 IgE is able to confirm a previous parasitic episode by this nematode in patients with urticaria, in chronic urticaria anti- Ani s 1 IgE is detected in less than 50% of patients and is thus not a major allergen. Our pluri-disciplinary teaching and research activities in Evolutionary medicine have further contributed to a high impact publication in the field of Parasitology, in which a model has been proposed explaining necessary immunologic features leading – 54 – Co-sensitization graph of lipid transfer protein (LTP) allergens. Each node represents one allergen (LTP, white ovals; non-LTP allergens, blue squares) and the links represent co-sensitization of one or more sera for the linked allergens. The weight of each link, between 0 and 1, measures the degree of co-sensitization. (PLoS One. 2012). AREA 1 Clin Immunol 22(5):313-30. 23101306. IF: 2,269 - Food allergy: we have collaborated with Centro de Biotecnología y Genómica de Plantas (UPMINIA), to deepen sensitization mechanisms to lipid transfer proteins (LTP). Sensitization profiles have been checked by protein microarrays and co-sensitization graph approach, demonstrating that LTP are relevant allergens (Fig. 2). Now we are focusing on kiwi and plane tree allergy. Palacín A, Gómez-Casado C, Rivas LA, Aguirre J, Tordesillas L, Bartra J, Blanco C, Carrillo T, CuestaHerranz J, de Frutos C, Alvarez-Eire GG, Fernández FJ, Gamboa P, Muñoz R, SánchezMonge R, Sirvent S, Torres MJ, Varela-Losada S, Rodríguez R, Parro V, Blanca M, Salcedo G, DíazPerales A. Graph based study of allergen crossreactivity of plant lipid transfer proteins (LTPs) using microarray in a multicenter study. Plos One 7(12):e50799. 2012. PMID: 23272072. IF: 4,092. DOI: 10.1371/journal.pone.0050799 - Respiratory allergy: in the context of the MEICA research project formerly funded by Fundación Genoma España, a phase IV clinical trial has been finished, and a 2 yr study prolongation has been approved, to check immunological changes induced by grass-pollen immunotherapy. A new placebo controlled clinical trial has been also designed, in collaboration with ALK laboratory and the CNB (Biotechnological National Centre). PUBLICATIONS (5) [IF: 17,876] YEAR Total IF Publication No. Q1 Q2 2010 18,62 6 2 2 2011 4,87 2 2012 17,876 5 3 1 Cuéllar C, Daschner A, Valls A, De Frutos C, Fernández-Fígares V, Anadón AM, Rodríguez E, Gárate T, Rodero M, Ubeira FM. Ani s 1 and Ani s 7 recombinant allergens are able to differentiate distinct Anisakis simplex-associated allergic clinical disorders. Arch Dermatol Res 304(4):283-288. 2012. PMID: 22249742. IF: 2,279. DOI: 10.1007/s00403-012-1206-8 Cabañes N, Igea JM, de la Hoz B, Agustín P, Blanco C, Domínguez J, Lázaro M, Lleonart R, Méndez J, Nieto A, Rodríguez A, Rubia N, Tabar A, Beitia JM, Dieguez MC, Martínez-Cócera C, Quirce S. Latex allergy: Position Paper. J Investig Allergol 2012. PMID: Palacín A, Rivas LA, Gómez-Casado C, Aguirre J, Tordesillas L, Bartra J, Blanco C, Carrillo T, Cuesta-Herranz J, Bonny JA, Flores E, GarcíaAlvarez-Eire MG, García-Nuñez I, Fernández FJ, Gamboa P, Muñoz R, Sánchez-Monge R, Torres M, Losada SV, Villalba M, Vega F, Parro V, Blanca M, Salcedo G, Díaz-Perales A. The involvement of thaumatin-like proteins in plant food cross-reactivity: a multicen ter study using a specific protein microarray. PLOS One 7(9):e44088. 2012. PMID: 22970164. IF: 4,092. DOI: 10.1371/journal. pone.0044088 Daschner A, Cuéllar C, Rodero M. The Anisakis allergy debate: dose an evolutionary approach help?. Trends in Parasitology 28(1):9-15. 2012. PMID: 22079162. IF: 5,144. DOI: 10.1016/j.pt.2011.10.001 BOOKS Carlos Blanco Guerra. Alergia al látex. Libro de las enfermedades alérgicas de la Fundación BBVA. 2012. Nerea S.A. ISBN: 978-84-92937-15-8. Alvaro Daschner. Una visión evolucionista de la hipótesis de la higiene en alergia y las enfermedades inflamatorias crónicas. Medicina – 55 – AREA 3 AREA 2 AREA 1 to a different outcome after parasitism by A. simplex (Fig.1). Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Evolucionista: Aportaciones pluridisciplinares. 2012. MedEvo. ISBN: 978-84-695-3141-9. Alvaro Daschner. Consideraciones evolucionistas en las enfermedades alérgicas. Medicina Evolucionista: Aportaciones pluridisciplinares. 2012. MedEvo. ISBN: 978-84-695-3141-9. Alvaro Daschner, José Luis Gómez Pérez, Editores. Medicina Evolucionista: Aportaciones pluridisciplinares. 2012. MedEvo. ISBN: 978-84695-3141-9. – 56 – CLINICAL TRIALS PRINCIPAL INVESTIGATOR: BLANCO GUERRA, CARLOS Estudio multicéntrico, aleatorizado, doble ciego, de grupos paralelos, para evaluar la eficacia y la seguridad de cuatro concentraciones de Depigoid« Phleum en pacientes con Rinitis Alérgica y/o Rinoconjuntivitiscon o sin Asma Intermitente; (Versión 2.0: 15-03-12). LETI PHARMA GMBH. 6043-PG-PSC-192. EudraCT: 2012-000416-28 AREA 1 Line 1.6 Inflammatory processes in nephrological diseases GROUP 21 • • • • • • • • • • GROUP MEMBERS Carmen Bernis Carro Vicente Álvarez Chiva Guillermina Barril Cuadrado Carmen Sánchez González Abelardo Isaac Aguilera Peralta Antonio Carlos Fernández Perpén Isabel Herráez Jiménez Martín Giorgi González Pablo Ruano Suárez Laura Salanova Villanueva RESEARCH INTEREST These are the most relevant areas of interest during 2012. 1. Renal Nutrition: Multidisciplinary consensus on the approach to hospital malnutrition in Spain. Influence of endogenous testosterone, muscle strength and fat-free mass in men with chronic kidney disease (CKD). Organization of the Annual National Meeting on Nutrition in CKD. 2. Virology and CKD: Hepatitis C haemodialysis, epidemiology and prevention of virus transmission. Long-term virological follow up of patients with occult hepatitis C virus infection. 3. Peritoneal Dialysis: Studies about more biocompatible fluids and evaluation of peritoneal membrane response: Influence of bicarbonate/low-GDP peritoneal dialysis fluid on in vitro and ex vivo epithelial-to-mesenchymal transition of mesothelial cells. 4. Mechanisms associated with Acute Renal Failure: Hypoxia inducible factor 1alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. 5. Haemodialysis procedures and complications manage- Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. HIF-1a is expressed exclusively in non-damaged proximal tubules of human post-transplant renal biopsies. (a) PAS staining for renal structure and immunohistochemistry for HIF-1a in paraffin-embedded human renal biopsies. HIF-1 a is expressed in non-damaged proximal tubules (biopsy nu4). Images of representative biopsies are presented: severe ATN (biopsies nu6 and nu14) and ATN regeneration (biopsy nu4). Magnification:6400. (b) Spearman Rho-Correlation coefficient between ATN grade and HIF-1a expression in all biopsies, with statistical significance p#0.01.doi:10.1371/journal.pone.0033258.g009 ment: Spanish study of anticoagulation in haemodialysis. Successful treatment with sodium thiosulfate for calcific uraemic arteriolopathy. Inflammation and resistance to erythropoietin in patients with tuberous sclerosis on haemodialysis. 6. Mechanisms and treatment of glomerular diseases: – 57 – AREA 3 AREA 2 AREA 1 HEAD OF LABORATORY José Antonio Sánchez Tomero Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases MAJOR GRANTS Influence of bicarbonate/low-gdp peritoneal dialysis fluid (bicavera) on in vitro and ex vivo epithelial-to-mesenchymal transition of mesothelial cells. Effects of peritoneal dialysis (PD) fluids on mesothelial cells (MCs) in vitro. (A) Effects on MC morphology at 48 and 72 hours. Images are representative of 5 independent experiments. (B) Western blot results show expression of E-cadherin in exposed MCs. Tubulin was used as a loading control. Images are representative of 5 independent experiments. (C) Levels of E-cadherin messenger RNA (mRNA) analyzed by quantitative reverse transcription polymerase chain reaction [for MCs treated with PD fluids or with transforming growth factor β1 (TGF-β1) relative to untreated cells]. Results are mean ± standard error of 5 experiments. (D) Production of vascular endothelial growth factor (VEGF) in supernatant (picograms per milligram of cell pro¬tein) by omentum-derived MCs treated with PD fluids or with TGF-β1. The box plots show 75th percentile, 25th percentile, median, maximum, and minimum values from 5 experiments. BicaVera: solution from Fresenius Medical Care, Bad Homburg, Germany. R.U. = relative units. Long-Term Outcomes of IA Nephropathy presenting with minimal or no-proteinuria. A Randomized Trial to study the effect of dual blockade of the Renin-Angiotensin System on the progression of type 2 diabetic nephropathy. 7. Ethical aspects and Nephrology: Exploring the opinion of CKD patients on dialysis regarding end-of-life and advance care planning¸ Unplanned start of dialysis and instruction protocols. 8. Economical Studies: Advantages of the peritoneal dialysis procedure for the public health system sustainability; Cost comparison between haemodialysis and peritoneal dialysis outsourcing agreements. – 58 – • José Antonio Sánchez Tomero. Mecanismos moleculares que regulan el daño renal provocado por isquemia-reperfusión. Amgen SA. IRSIN 2322006. Duration: 2010 - 2012. • Guillermina Barril Cuadrado. Infección silente por virus C de la hepatitis en unidades de diálisis: análisis de la respuesta inmunoserológica y repercusiones diagnósticas. Fundacion Mutua Madrileña. Duration: 2010 - 2012. • Abelardo Isaac Aguilera Peralta. Looking for a new, more biocompatible peritoneal dialysis solution based in glicosides as osmotic agent. Fresenius Medical Care. Duration: 2010 - 2012. • Abelardo Isaac Aguilera Peralta. Validación de la Transición Epitelio Mesenquimal de Células Mesoteliales como Herramienta para el Diagnóstico y Pronóstico del Fracaso de la Membrana Peritoneal en Pacientes en Diálisis Peritoneal. Sociedad Española de Nefrología. Duration: 2010 - 2012. • Abelardo Isaac Aguilera Peralta. Modulación de la transición epitelio mesenquimal (EMT) de las células mesoteliales (CM) como aproximación para mejorar la función peritoneal de pacientes en diálisis peritoneal. ISCIII. FIS: 009/00774. Duration: 2010-2012 PUBLICATIONS (11) [IF: 27,840] YEAR Total IF Publication No. Q1 Q2 2010 32,685 11 4 3 2011 33,655 12 5 2012 27,84 11 3 1 Sánchez-Fructuoso AI, Ruiz JC, Torregrosa JV, González E, Gómez E, Gallego RJ, Troya MI, Jimenez C, Llamas F, Romero R, Bernis C, Crespo JF, Guirado L; AnemiaTrans Study Group. Anemia control in renal transplant recipients receiving continuous erythropoietin receptor activator (C.E.R.A.) treatment: the AnemiaTrans Study. Adv Ther 29(11):979-991. 2012. PMID: 23160946. IF: 2,105. DOI: 10.1007/s12325-012-0063-3 Jadoul M, Barril G. Hepatitis C in hemodialysis: epidemiology and prevention of hepatitis C virus transmission. Contrib Nephrol. 176:35-41. Epub 2012 Jan 30. 2012. PMID: 22310779. IF: 1,487. DOI: 10.1159/000333761 AREA 1 Herrero-Calvo JA, González-Parra E, Pérez-García R, Tornero-Molina F; Grupo de Estudio Español Sobre Anticoagulación en Hemodiálisis (..,Barril G, ..). Spanish study of anticoagulation in haemodialysis. Nefrologia 32(2):143-152. 2012. PMID: 22425796. IF: 1. DOI: 10.3265/Nefrologia.pre2011.Nov.11106 Arrieta J, Rodríguez-Carmona A, Remón C, Pérez-Fontán M, Ortega F, Sánchez-Tomero JA, Selgas R. Cost comparison between haemodialysis and peritoneal dialysis outsourcing agreements. Nefrologia 32(2):247-248. 2012. PMID: 22466267. IF: 1. DOI: 10.3265/Nefrologia.pre2011 .Dec.11311 Bernis-Carro C. What happens to the specialty of nephrology?. Nefrología 32(4):535-6. 2012. PMID: 22806289. IF: 1. DOI: 10.3265/Nefrologia.pre2012.Apr.11467 Selgas R, López-Cabrera M, Sánchez-Tomero JA. Influence of bicarbonate/low-GDP peritoneal dialysis fluid (BicaVera) on in vitro and ex vivo epithelial-to-mesenchymal transition of mesothelial cells. Perit Dial Int 32(3):292-304. 2012. PMID: 22215656. IF: 2,097. DOI: 10.3747/pdi.2010.00315 Conde E, Alegre L, Blanco-Sánchez I, Sáenz-Morales D, Aguado-Fraile E, Ponte B, Ramos E, Sáiz A, Jiménez C, Ordoñez A, López-Cabrera M, del Peso L, de Landázuri MO, Liaño F, Selgas R, Sánchez-Tomero JA, GarcíaBermejo ML. Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. PLoS One 7(3):e33258. 2012. PMID: 22432008. IF: 4,092. DOI: 10.1371/journal.pone.0033258 BOOKS Aguilera A, Loureiro J, Gónzalez-Mateo G, Selgas R, López-Cabrera M. The mesothelial to mesenchymal transition a pathogenic and therapeutic key for peritoneal membrane failure. Text book of Peritoneal Dialysis. 2012. Boston, USA. Fernández-Perpén A, Sánchez-Tomero JA. Unplanned start of dialysis and instruction protocols. Nefrologia Suppl Ext 3(3):8-11. 2012. IF: 1. DOI: 10.3265/Nefrologia SuplementoExtraordinario.pre2012.Feb.11406 Barril Caudrado G. Infecciones víricas en pacientes en Hemodiálisis. Manual de Nefrología al día. 2012. Plus Medical, Badalona. ISBN: 978-84-96727-97-7. Giorgi M, Jerico S. Paciente con esclerosis tuberosa en Hemodiálisis. Inflamación y resistencia a la eritropoyetina. Nefrología. Suppl Extra 3(5):63-66. 2012. IF: 1 CLINICAL TRIALS Del Peso G, Bajo MA, Perez Fontán M, Martínez J, Marrón B, Selgas R, Group of Study on ‘Bemidextrin’. Fernandez Perpen A. Effect of self-administered intraperitoneal bemiparin on peritoneal transport and ultrafiltration capacity in peritoneal dialysis patients with membrane dysfunction. A randomized, multi-centre open clinical trial. Nephrol Dial Transplant. 27(5):2051-2058. Epub 2011 Oct 12. 2012. PMID: 21993377. IF: 3,396. DOI: 10.1093/ndt/gfr546 Fernández-Perpén A, Pérez-Lozano ML, Bajo MA, AlbarVizcaino P, Correa PS, del Peso G, Castro MJ, Aguilera A, Ossorio M, Peter ME, Passlick-Deetjen J, Aroeira LS, PRINCIPAL INVESTIGATOR: BARRIL CUADRADO, GUILLERMINA Estudio de la mejora de la tolerancia intrahemodialisis asociada al control de la volemia. "EMTIACO"; (versión 26-0612). EMTIACO PRINCIPAL INVESTIGATOR: SANCHEZ TOMERO, JOSE A. Biodisponibilidad de tres formulaciones de hierro tras su administración oral a pacientes en hemodiálisis en ayunas; (versión 1: 13-07-12). LABORATORIOS ZAMBON S.A.U. FIFERJ01. EudraCT: 2012-003419-71 – 59 – AREA 3 AREA 2 AREA 1 Gutiérrez E, Zamora I, Ballarín JA, Arce Y, Jiménez S, Quereda C, Olea T, Martínez-Ara J, Segarra A, Bernis C, García A, Goicoechea M, García de Vinuesa S, RojasRivera J, Praga M. Long-Term Outcomes of IA Nephropathy Presenting with Minimal or No Proteinuria. J Am Soc Nephrol 23(10):1753-1760. 2012. PMID: 22956820. IF: 9,663. DOI: 10.1681/ASN.2012010063 Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Line 1.7 Inflammatory mechanisms in pulmonary diseases GROUP 22 HEAD OF LABORATORY Julio Ancochea Bermúdez GROUP MEMBERS • Rosa María Girón Moreno • Carolina Cisneros Serrano • Enrique Domingo Zamora García • Silvia Sánchez Cuéllar • Ana Martínez Meca RESEARCH INTEREST COPD (chronic obstructive pulmonary disease) is a major problem worldwide. In 2012, the GesEPOC (Spanish Guide of COPD) was developed as an initiative of SEPAR (Spanish Society of Respiratory Disease), in which many scientific societies, and various services, including the Pneumology Department of Hospital de La Princesa have participated. This guide describes the classification of the severity and pharmacotherapy of stable COPD. GesEPOC is a new approach to more individualized treatment of COPD according to the clinical characteristics of patients. Our group also participated in a national study where the objective was to determine the frequency, severity, geographical variability and determinants of individual consequences of a restrictive ventilatory defect measured by spirometry in the Spanish population. We have worked with the Immunology Department of the Hospital to study the role that galectins as – 60 – Surface expression of galectin (gal)-1 and gal-9 is reduced in leucocytes from induced sputum of asthma patients. (a) cells from sputum samples were stained as in Fig.2 and galectin expression was analysed on macrophages (CD16* HLA-DR*). Representative histograms from a healthy donor and an asthma patient are shown. Isotype control (dotted line), gal expression (solid line). (b) Gal-1, gal-3 and gal-9 expression on leucocytes grom asthma (n=15) and healthy donors (n=10). Bars represent mean +- standard error of the mean of mean fluorescence intestity (MFI) of galectins expression. Differences were tested by Mann-Whitney U-test. (c) gal expression according to allergic state. Differences between atopy and non-atopy against healthy donors were tested by Mann-Whitney U-test. immunoregulatory molecules in controlled stable asthma. In addition, our group is involved with the ConsEPOC consortium of the Community of Madrid to identify genetic variations that alter HIF-mediated response in patients with COPD/ Sleep Apnea Hypopnea Syndrome (SAHS) and analyze their correlation with disease progression. AREA 1 • Rosa María Girón Moreno. Estudio multicéntrico de la estructura poblacional de P. aeruginosa en primocolonización y cololonización patogénica crónica broncopulmonar y la dinámica del microbioma en fibrosis quística. PI12/00734. Duration: 2012 2015. PUBLICATIONS (4) [IF: 16,936] MAJOR GRANTS • Julio Ancochea Bermúdez. Desarrollo de nuevas estrategias terapéuticas en la LAM: estudio sobre su origen celular y diseminación. SEPAR. Duration: 2011 - 2013. • Julio Ancochea Bermúdez. Programa de I+D Biomedicina. CONSEPOC-CM. Inflamación e hipoxia: mecanismos de desarrollo y progresión en EPOC y SAHS. Consejería de Educación - CAM. Duration: 2011 - 2014. • Rosa María Girón Moreno. Prevalencia de la Miocardiopatía Dilatada en pacientes con Fibrosis Quística y estudio de posibles factores etiológicos. Beca Pablo Motos. Duration: 2011 - 2013. • Silvia Sánchez Cuéllar. El papel de las Galectinas como molécula de inmunoregulación en el asma. Neumomadrid. Duration: 2011 - 2013. • Julio Ancochea Bermúdez. Inflamación e hipoxia: mecanismos en desarrollo y progresión en EPOC y SAHS. CAM. P2010 / BMD-2542. Duration: 2012 2015. • Rosa María Girón Moreno. Estudio Dayca. SEPAR. Duration: 2012 - 2014. YEAR Total IF Publication No. Q1 Q2 2010 26,616 7 3 1 2011 54,608 3 3 2012 16,936 4 2 2 Yañez AM, Guerrero D, Pérez de Alejo R, GarciaRio F, Alvarez-Sala JL, Calle-Rubio M, Malo de Molina R, Valle Falcones M, Ussetti P, Sauleda J, Zamora García E, Rodríguez-González-Moro JM, Franco Gay M, Torrent M, Agustí A. Monitoring breathing rate at home allows early identification of COPD exacerbations. Chest 142(6):1524-9. 2012. PMID: 22797131. IF: 5,25. DOI: 10.1378/chest.112728 Sanchez-Cuellar S, de la Fuente H, Cruz-Adalia A, Lamana A, Cibrian D, Giron RM, Vara A, SanchezMadrid F, Ancochea J. Reduced expression of galectin-1 and galectin-9 by leucocytes in asthma patients. Clin Exp Immunol. 170(3):365-374. 2012. PMID: 23121677. IF: 3,36. DOI: 10.1111/j.13652249.2012.04665.x Fuente HD, Perez-Gala S, Bonay P, Cruz-Adalia A, Cibrian D, Sanchez-Cuellar S, Dauden E, Fresno M, García-Diez A, Sanchez-Madrid F. Psoriasis in humans is associated with downregulation of galectins in dendritic cells. J Pathol. 228: 193-203. 2012. PMID: 22271227. IF: 6,318. DOI: 10.1002/path.3996 Cisneros C. A female patient with asthma in the emergency room. Rev Clín Esp. 212(11):540-544. 2012. PMID: 23092746. IF: 2,008. DOI: 10.1016/j.rce.2012.08.001 – 61 – AREA 3 AREA 2 AREA 1 Induced sputum cells of asthma patients show altered mRNA expression of galectins (gal) and Th2 cytokines. Total RNA was isolated from induced sputum of asthma patients (n=16) and healthy donors (n=11), and real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed. (a) Gal-1, gal-3 and gal-9 mRNA expression. (b) Interlukin (IL)-5 and IL-13 mRNA expression. mRNA levels are expressed as arbitrary units respect to B-actin expression. Differences between groups were tested by Mann-Whitney Utest. Bars correspond to mean +- standard error of the mean. Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases BOOKS Carolina Cisneros Serrano. Módulo: Asma. Proyecto SEPAR: Pulmón Virtual. 2012. WEB Online SEPAR. Carolina Cisneros Serrano. Pruebas de provocación bronquial. Programa AGER: Módulo de pruebas funcionales. 2012. WEB Online SEPAR. A. Xaubet Mir, F. Morell Brotad, J. Ancochea Bermúdez. Enfermedades Difusas del Pulmón. Medicina InternaFarreras/Rozman. 2012. Elsevier España. ISBN: 978-848086-896-9. Carolina Cisneros Serrano, Gonzalo Segrelles Calvo, Ana Martínez Meca. Provocación bronquial inespecífica. Monografía de Neumomadrid: “Exploración funcional respiratoria". 2012. Ergon. ISBN: 978-84-8473-983-8. Madruga D, Girón R. Alteración de la densidad Mineral ósea. Tratado de Fibrosis Quística. 2012. Editorial Justim. ISBN: 978-84-695-0562-5. Girón R, Antelo C. Terapia inhalada. Tratado de Fibrosis Quística. 2012. Editorial Justim. ISBN: 978-84-695-0562-5. Carolina Cisneros Serrano. De la sospecha al diagnóstico de Asma. Curso de formación continuada de Neumomadrid sobre Asma. 2012. Acceso WEB Neumomadrid. Salcedo A, Gartner S, Girón R, García-Novo D. Tratado de Fibrosis Quística. 2012. Editorial Justim. ISBN: 978-84695-0562-5. CLINICAL TRIALS PRINCIPAL INVESTIGATOR: ANCOCHEA BERMUDEZ, JULIO Estudio clínico aleatorizado, doble ciego, controlado con placebo para evaluar el efecto sobre la función endotelial de roflumilast en pacientes con enfermedad pulmonar obstructiva crónica; (versión 1.0:28-9-11). CIBERES. CIBROF-2011-01. EudraCT: 2011-005047-27 – 62 – PRINCIPAL INVESTIGATOR: ANCOCHEA BERMUDEZ, JULIO Ensayo clínico de extensión, abierto, para evaluar la seguridad a largo plazo de BIBF 1120 administrado por vía oral en pacientes con Fibrosis Pulmonar Idiopática; (versión 1.0:27-1-12). BOEHRINGER INGELHEIM ESPAÑA, S.A. 1199.33. EudraCT: 2011-002766-21 PRINCIPAL INVESTIGATOR: CISNEROS SERRANO, CAROLINA Estudio multicéntrico aleatorizado, doble ciego, de doble enmascaramiento, grupos paralelos, controlado con placebo, sobre la eficacia y la seguridad del tratamiento complementario con mepolizumab, en sujetos con asma grave no controlada, refractaria al tratamiento; (versión 00: 18-0512). GLAXOSMITHKLINE ESPAÑA, S.A. MEA115588. EudraCT: 2012-001251-40 PRINCIPAL INVESTIGATOR: ANCOCHEA BERMUDEZ, JULIO Estudio aleatorizado multicéntrico de 52 semanas de duración para evaluar la monitorización remota de pacientes utilizando el cuestionario EXACT de resultados notificados por el paciente en la reducción de hospitalizaciones por exacerbaciones en pacientes con Enfermedad Pulomonar Obstructiva Crónica en comparación con pacientes controlados según práctica clínica habitual; (versión V00:20-01-12). NOVARTIS FARMACEUTICA, S.A. CIDD001D2401 PRINCIPAL INVESTIGATOR: ANCOCHEA BERMUDEZ, JULIO Estudio aleatorizado, doble ciego y de grupos paralelos de 12 semanas de tratamiento para evaluar la eficacia y la seguridad de QMF149 (150micro gramos/160 microgramos 1 vez al día) en comparación con xinafoato de salmeterol/propionato de fluticasona (50 microgramos/500 microgramos 2 veces al día) en pacientes con enfermedad pulmonar obstructiva crónica; (versión 00: 04-04-12). NOVARTIS PHARMA SERVICES AG. CQMF149F2202. EudraCT: 2012-001172-12 PRINCIPAL INVESTIGATOR: GIRON MORENO, ROSAMARIA Estudio de la eficacia del tratamiento a largo plazo con ácido docosahexanóico sobre la inflamación pulmonar, AREA 1 PRINCIPAL INVESTIGATOR: GIRON MORENO, ROSAMARIA Estudio observacional de calidad de vida relacionada con la salud y cumplimiento terapéutico en pacientes con fibrosis quística e infección pulmonar crónica por Pseudomonas aeruginosa que reciben tratamiento anti-biótico crónico nebulizado (estudio CAPA-FQ); (versión 1:29-02-12). AMPARO SOLER JOVER (H.U. LA FE DE VALENCIA). AMP-AZT-2012-01 AREA 3 AREA 2 AREA 1 sistémica e intestinal en pacientes con fibrosis quística; (versión 6:29-06-12). FUNDACION INVESTIGACION BIOMEDICA H. RYC. DHA-FQ-1 PRINCIPAL INVESTIGATOR: CISNEROS SERRANO, CAROLINA Evaluación transversal y longitudinal internacional sobre el control del asma (LIAISON); (Versión 1.0:0603-12). CHIESI FARMACEUTICI, S.P.A. DFIDM1101/CHI-ANT-2012-01 – 63 – Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Line 1.8 Inflammatory response in hepatic diseases GROUP 23 HEAD OF LABORATORY Ricardo Moreno Otero GROUP MEMBERS • Luisa Consuelo García Buey • María Trapero Marugán • Jorge Mendoza Jiménez-Ridruejo • Leticia González Moreno • Asunción García Sánchez • Ángel Hernández Bartolomé • María Jesús Borque Iñurrita • María Jesús Alonso Martín • María Paloma Sanz Cameno • Samuel Martín Vílchez • Yolanda Rodríguez Muñoz • Rosario López Rodríguez • Yolanda Real Martínez Our previous results showed the significant involvement of the Angiopoietin/Tie-2 axis on CHC progression and therapy response, finding a notable unbalance of peripheral blood expression of Angiopoietin 1 and 2 (Ang1 and Ang2). Interestingly, we could observe the relative increase of TEMs in the blood of CHC patients, monocytes that express the tyrosine kinase receptor of angiopoietins, Tie-2. This subtype of circulating myeloid cells, with marked proangiogenic properties but notable immunosuppressive nature, was also found at CHC inflamed portal tracts (Figure 1) and has recently been proposed as a diagnostic biomarker for HCC by other authors. Monocytes are essential precursors of antigen-presenting cells, such as macrophages and dendritic cells, and notably contribute to the pathogenesis of chronic inflammatory diseases and cancer; thus, we aimed to analyze the expression of Tie2 and Angs throughout monocyte differentiation and maturation. Such approach pointed out to the sustained expression of Ang2 by macrophages and dendritic cells derived from CHC monocytes, which additionally resulted poorly dif- RESEARCH INTEREST During last years our research group has been particularly focused on identifying useful non invasive prognostic biomarkers of chronic hepatitis C (CHC) progression to cirrhosis and hepatocellular carcinoma (HCC). The infection by hepatitis C virus often becomes chronic due to the inefficacy of immune system to eradicate the virus; consequently, the inflammatory response is continuously stimulated, altering the self-limiting nature of tissue repairing mechanisms. Therefore, the expression of multiple angiogenic and fibrogenic-related factors is deeply modified, behaving as useful markers of disease evolution. – 64 – Intrahepatic identification of TEMs in livers from CHC patients. Immunofluorescence experiments were performed on cryostat sections from CHC liver biopsies. Image acquisition of single fluorescence identified in the same section CD14, CD31 and Tie-2 (AC and E-G, respectively) of different representative CHC patients. Their combined immunofluorescences are also shown (D & H). Tie-2 expression was observed surrounding the hepatic infiltrates, in which TEMs could be distinguished (A-D, arrows). Intrahepatic Tie-2 expressing cells were frequently associated with endothelial CD31 positive cells (E-H). Original magnifications: x400. Left bottom squares denote amplified sections. AREA 1 ferentiated, in contrast to healthy subjects (Figure 2). These findings might highlight the relevant role of the Angiopoietin/Tie-2 system on the regulation of inflammatory response during the progression of chronic diseases throughout its influence on functionality of antigen presenting cells. • Proyecto Coordinado. Estimulación pan-poblacional de la respuesta de los linfocitos T frente a epítopos CD8 conservados del virus de la hepatitis C. MICINN. SAF 2009/08103. Duration: 2009 - 2012. • Ricardo Moreno Otero. Implicación de polimorfismos genéticos de factores angiogénicos en la etiopatogenia de la hepatitis crónica C y su evolución a carcinoma hepatocelular. Fundación Mutua Madrileña. Duration: 2010 - 2013. • Ricardo Moreno Otero. Implicación del Sistema Angiopoyetinas/Tie2 en los procesos angiogénicos y fibrogénicos asociados a la hepatitis crónica C. MEC. SAF2010-21805. Duration: 2010 - 2013. Tie2 and angiopoietins 1 and 2 expression in peripheral blood monocytes and Mo-DCs from healthy volunteers and CHC patients. Points represent the median fold-induction of Tie2-expressing cells (A and B) and the median concentrations of Ang1, Ang2 and Ang2/Ang1 ratio (C-H) in the supernatants of peripheral blood monocytes, MDDCs (A, C, E, & G) and MDMs (B, D, F and H) from CHC patients (black line) and controls (grey line). The concentration of Ang1 was lower in monocytes and mature MDDDs supernatants from CHC patients (C, p<0.001 and D, p<0.05). Ang2 levels notably fell after differentiation of control monocytes to MDDC and MDM (p<0.001, both) but persisted during the differentiation of CHC cells (E & F). Thus, Ang2 release was significantly higher in the supernatants from immature MDDCs, mature MDDCs (p <0.05 and p <0.01, respectively, E), and MDMs (p <0.05, F) of CHC patients compared with controls. Ang2/Ang1 values in supernatants of CHC mature MDDCs and MDMs were quite similar to those of CHC monocytes (G & H). Statistical significance was calculated by Mann-Whitney test, represented as # p< 0.05 or ## p< 0.01 and *p< 0.05 or ***p< 0.001, where # represents CHC versus controls and * shows statistical significance during differentiation/maturation. PUBLICATIONS (9) [IF: 23,378] YEAR Total IF Publication No. Q1 Q2 2010 82,467 16 10 4 2011 66,493 18 8 6 2012 23,378 9 2 2 Santander C, Moreno-Otero R. Commentary: ursodeoxycholic acid as chemoprevention in inflammatory bowel disease and primary sclerosing cholangitis. Aliment Pharmacol Ther 35(7):846-846. 2012. PMID: 22404405. IF: 3,769. DOI: 10.1111/j.13652036.2012.05019.x Casals-Seoane F, Arberas-Diez B, Moreno-Otero R. Letter: acute hepatitis B - to treat or not to treat?. Aliment Pharmacol Ther 36(1):76-77. 2012. PMID: 22650494. IF: 3,769. DOI: 10.1111/j.13652036.2012.05123.x – 65 – AREA 3 AREA 2 AREA 1 MAJOR GRANTS Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Moreno-Otero R, García-Buey L, Trapero-Marugán M. Safety of methotrexate for inflammatory bowel disease. Dig Liver Dis 44(8):706-707. 2012. PMID: 22538205. IF: 3,054. DOI: 10.1016/j.dld.2012.03.012 Moreno-Otero R, Trapero-Marugan M. Antioxidant agents in the prevention of hepatocellular carcinoma. Eur J Cancer Prev 21(4):323-5. 2012. PMID: 22044850. IF: 2,13. DOI: 10.1097/CEJ.0b013e32834 dbc6d Rodziewicz M, Moreno-Otero R. Role of percutaneous liver biopsy. Hepat Mon 12(4):294-295. 2012. PMID: 22690239. IF: 2,19. DOI: 10.5812/hepatmon.854 Miranda-García P, López-Martín MC, Alvarez-Malé T, Casanova-González MJ, Santander C, Bañares R, Moreno-Otero R, Trapero-Marugán M. Idiopathic portal hypertension complicated by ischemic hepatitis: the diagnostic importance of hemodynamics and liver biopsy. Rev Esp Enferm Dig 104(1):45-47. 2012. PMID: 22300122. IF: 1,548 Benedicto I, Molina-Jiménez F, García-Buey L, Gondar V, López-Cabrera M, Moreno-Otero R, Majano PL. Role of tight junctions in hepatitis C virus infection. Rev Esp Enferm Dig 104(5):255-263. 2012. PMID: 22662778. IF: 1,548 Barbero-Villares A, Mendoza J, Taxonera C, LópezSanromán A, Pajares R, Bermejo F, Pérez-Calle J, Mendoza J, Algaba A, Moreno-Otero R, Maté J, Gisbert J. Evaluation of liver fibrosis by transient elastography (Fibroscan®) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial. Scand J Gastroenterol 47(5):575-579. 2012. PMID: 22229701. IF: 2,019. DOI: 10.3109/00365521. 2011.647412 Molina-Jimenez F, Benedicto I, Dao Thi VL, Gondar V, Lavillette D, Marin JJ, Briz O, Moreno-Otero R, Aldabe R, Baumert TF, Cosset FL, Lopez-Cabrera M, Majano PL. Matrigel-embedded 3D culture of Huh-7 cells as a hepatocyte-like polarized system to study hepatitis C virus cycle. Virology 425(1):31-39. 2012. PMID: 22280897. IF: 3,351. DOI: 10.1016/j.virol.2011.12.021 – 66 – BOOKS Moreno-Otero R. Patogénesis de las hepatitis crónicas víricas. Hepatitis Víricas. 2012. Juan GonzálezLahoz y Vicente Soriano. CLINICAL TRIALS PRINCIPAL INVESTIGATOR: GARCIA BUEY, LUISACONSUELO Estudio observacional retrospectivo para evaluar la eficacia y la seguridad a largo plazo de la monoterapia con entecavir en la práctica clínica habitual en pacientes con Hepatitis B Crónica naive al tratamiento con análogos de núcleos(T)Idos. Estudio Oriente 2; (versión 1:08-03-12). FUNDACIO DE LLUITA CONTRA LA SIDA-UNIDAD VIH. FLS-ENT-2012-01 GROUP 24 HEAD OF LABORATORY Pedro Lorenzo Majano Rodríguez GROUP MEMBERS • Ignacio Benedicto Español • Francisca Molina Jiménez • Virgínia Manuela Gondar de Sousa e Silva RESEARCH INTEREST Hepatotropic viruses, including Hepatitis C virus (HCV), chronically infect millions of people worldwide. Infection can lead to fibrosis, cirrhosis and hepatocellular carcinoma, and is the major reason for liver transplantation. Current standard-of-care therapy against chronic hepatitis C, pegylated IFN-alpha in combination with ribavirina, is frequently not effective depending on both viral and host factors. AREA 1 These three dimensional cultures supported the entire HCV infection cycle and produced infective viral particles. In overall, these studies may provide new insights for our understanding of virus-host interactions and the molecular mechanisms underlying hepatotropic viruses-related pathogenesis of progressive liver disease. MAJOR GRANTS PUBLICATIONS (5) [IF: 16,724] Human hepatocyte-derived cells (Huh7) stably transfected with MAV-GFP protein. Cells were infected with HCVcc. MAV-GFP protein (green): nuclei stained with DAPI (blue). Nuvlear translocation of protein indicates viral infection. We are interested in understanding how HCV interacts with target cells, with particular emphasis on the role of the cellular factors implicated in different steps of the viral life cycle including entry, replication, morphogenesis and egress. Our studies have demonstrated that HCV promotes structural and functional alterations of intercellular junctions and that occludin, a tigh junction associated protein, plays an essential role in HCV infection. We have also described a novel use of Matrigel-embedded hepatocytes cultures to study the HCV infection in a more polaryzed context. YEAR Total IF Publication No. Q1 2010 23,67 3 3 Q2 2011 12,134 2 1 1 2012 16,724 5 3 1 García-Mediavilla MV, Pisonero-Vaquero S, LimaCabello E, Benedicto I, Majano PL, Jorquera F, González-Gallego J, Sánchez-Campos S. Liver X receptor -mediated regulation of lipogenesis by core and NS5A proteins contributes to HCV-induced liver steatosis and HCV replication. Laboratory Investigation 92(8):1191-1202. 2012. PMID: 22641099. IF: 3,641. DOI: 10.1038/labinvest.2012.88 Martin Caballero J, Garzón A, González-Cintado L, Kowalczyk W, Jimenez Torres I, Calderita G, Rodriguez M, Gondar V, Bernal JJ, Ardavín C, Andreu D, Zürcher – 67 – AREA 3 AREA 2 AREA 1 Immunohistochemical detection of MRP2 in liver sections. An intense immunoreactivity to MRP2 (brown) was observed within the canalicular membrane of the hepatocytes. • Pedro Lorenzo Majano Rodríguez. Estudio de la interrelación entre la polaridad celular y la infección por el virus de la hepatitis C: Posible implicación en el hepatocarcinoma. ISCIII. PI10/00101. Duration: 2011 - 2013. • Pedro Lorenzo Majano Rodríguez. Papel en el hepatocarcinoma de la alteración en las uniones intercelulares provocadas por la infección por el virus hepatitis c. Fundación Mutua Madrileña. VIII Convocatoria de Becas y Ayudas a la Investigación Médica de la Fundación Mutua Madrileña. Duration: 2011 - 2013. Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases T, von Kobbe C. Chimeric infectious bursal disease virus-like particles as potent vaccines for eradication of established HPV-16 E7-dependent tumors. PLoS One 7(12):e52976. 2012. PMID: 23300838. IF: 4,092. DOI: 10.1371/journal.pone.0052976 Benedicto I, Molina-Jiménez F, García-Buey L, Gondar V, López-Cabrera M, Moreno-Otero R, Majano PL. Role of tight junctions in hepatitis C virus infection. Rev Esp Enferm Dig 104(5):255-263. 2012. PMID: 22662778. IF: 1,548 Strippoli R, Benedicto I, Perez Lozano ML, Pellinen T, Sandoval P, Lopez-Cabrera M, del Pozo MA. Inhibition of transforming growth factor-activated kinase 1 (TAK1) blocks and reverses epithelial to mesenchymal transition of mesothelial cells. PLoS One 7(2):e31492. 2012. PMID: 22384029. IF: 4,092. DOI: 10.1371/journal.pone.0031492 Molina-Jimenez F, Benedicto I, Dao Thi VL, Gondar V, Lavillette D, Marin JJ, Briz O, Moreno-Otero R, Aldabe R, Baumert TF, Cosset FL, Lopez-Cabrera M, Majano PL. Matrigel-embedded 3D culture of Huh-7 cells as a hepatocyte-like polarized system to study hepatitis C virus cycle. Virology 425(1):31-39. 2012. PMID: 22280897. IF: 3,351. DOI: 10.1016/j.virol.2011.12.021 – 68 – AREA 1 Line 1.9 Mechanisms and mediators of endocrine diseases GROUP 25 GROUP MEMBERS • Manuel Luque Ramírez • Susanna Leskelä • Ana Rodríguez Muñoz • Javier Riveiro Villanueva • Ana Serrano Somavilla RESEARCH INTEREST Our current and future work involves different research fields in endocrine diseases. First, we are studying the role of (tolerogenic) dendritic cells (DCs) in patients with autoimmune thyroid diseases (AITD) including primarily Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). During last year, we have discovered that patients with AITD have diminished levels of plasmacytoid DCs in their peripheral blood and these cells show both an enhanced production of IFNand defective expression of different immunoregulatory receptors. This abnormal proportion and phenotype of pDCs may contribute to the pathogenesis of AITD. In the course of 2012, we have initiated new projects in this field, One aiming to characterize the regulatory T cells and the other the role of galectins, both in AITD and healthy controls. Quantitative and phenotypic analysis of pDCs in thyroid tissue from patients with AITD. A-E) Hematopoeitic mononuclear cells were isolated from thyroid tissue (TMC) and blood samples (PBMC) of five patients with HT (black) and five with GD (red, dashed line). The percent of pDCs (A) or the MFI values of the expression of the indicated immunoregulatory receptors (B-E) was determined by multiparametric flow cytometry analysis. Results from Paired t-tests, *p<0.05. F) Immunofluorescence analysis of CD123+ (pDCs, red fluorescence) cells expressing ILT2 (F) or PSGL-1 (G) (green fluorescence) in thyroid tissue sections from a representative patient with HT. Cell nuclei were stained with the Hoechst 33342 dye (blue fluorescence). Original magnification x400. Another area of investigation is the process of angiogenesis in neuroendocrine gastroentero-pancreatic tumors (TNE-GP) and their relation to the somatostatin receptors. We are studying the role of angiopoietins-1 and -2 and their receptor Tie-2 in the tumoral cells, as well as their association with somatostatin receptors and also clinical and pathological factors. Furthermore, we are studying the role of key molecules in GH secreting tumors, especially those related to treatment response with the GH antagonist pegvisomant. These studies will include techniques of molecular biology, including their characterization through qRT-PCR, genotyping and sequencing with association studies with the clinical data available. – 69 – AREA 3 AREA 2 AREA 1 HEAD OF LABORATORY Mónica Marazuela Azpíroz Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases ción con células T reguladoras y linfocitos Th17 en pacientes con enfermedad tiroidea autoinmune. ISCIII. PI 10-2521. Duration: 2011 - 2013. PUBLICATIONS (3) [IF: 13,15] YEAR Total IF Publication No. Q1 Q2 2010 33,692 6 5 1 2011 14,934 4 1 2 2012 13,15 3 1 1 Escobar-Morreale HF, Samino S, Insenser M, Vinaixa M, Luque-Ramírez M, Lasunción MA, Correig X. Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS. Clin Chem. 58(6):999-1009. 2012. PMID: 22427353. IF: 7,905. DOI: 10.1373/clinchem.2011.176396 % IGF-I evolution (a) and percentage of change of IGF-I level (b) during combination therapy with pegvisomant and cabergoline for each individual patient (Female: blue dot lines and blue bars; Male: brown lines and bars). Dr. M. Luque-Ramirez has been studying the role of different inflammatory markers in hyperandrogenic disorders in women, in particular in polycystic ovary syndrome. MAJOR GRANTS • Mónica Marazuela Azpíroz. Pilot study of the influence of truncated GH receptor isoforms, related to polymorphisms in exon 9 on GHR, on clinical expressivity and on response to pegvisomant treatment in acromegaly. Laboratorios Pfizer S.L.U. Duration: 2010 - 2012. • Mónica Marazuela Azpíroz. Estudio del potencial tolerogénico de células dendríticas y su interac- – 70 – Roset M, Merino-Montero S, Luque-Ramírez M, Webb SM, López-Mondéjar P, Salinas I, Soto A, Bernal C, Villabona C, De Luis D, Donnay S, Pascual H, Pérez-Luis J; Spanish group of the OASIS study. Cost of clinical management of acromegaly in Spain. Clin Drug Investig. 32(4):23545. 2012. PMID: 22397307. IF: 1,822. DOI: 10.2165/11599680-000000000-00000 Oriola J, Lucas T, Halperin I, Mora M, Perales MJ, Alvarez-Escolá C, Paz de MN, Díaz Soto G, Salinas I, Julián MT, Olaizola I, Bernabeu I, Marazuela M, Puig-Domingo M. Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. Eur J Endocrinol. 168(1):9-13. 2012. PMID: 23038625. IF: 3,423. DOI: 10.1530/EJE-120457 CLINICAL TRIALS PRINCIPAL INVESTIGATOR: MARAZUELA AZPIROZ, MONICA Caracterización de la expresión génica en tumores AREA 1 ESPAÑOL DE TUMORES NEUROENDOCRINOS (GETNE). GETNE1105_GENEX AREA 3 AREA 2 AREA 1 neuroendocrinos gastro-enteropancreáticos y su correlación con aspectos clínicos y de comportamiento del tumor; (versión 2: 7-06-12). GRUPO – 71 – Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Line 1.10 Children´s development (obesity and growth) GROUP 26 HEAD OF LABORATORY Jesús Argente Oliver GROUP MEMBERS • Julie Ann Chowen King • Vicente Barrios Sabador • Laura María Frago Fernández • Gabriel Ángel Martos Moreno • Oscar Rubio Cabezas • Jesús Pozo Román • María Teresa Muñoz Calvo • Emma Burgos Ramos • Silvia Tapia González • Eva Baquedano Caballero • Esther de la Fuente Martín • Cristina García Cáceres • Pilar Argente Arizón • David Castro González • Sandra Canelles Ortiz • Francisca Díaz González RESEARCH INTEREST How the genetic make-up of an individual interacts with the early maternal/neonatal and postnatal environments to culminate in obesity and its secondary complications, is being studied with both clinical and basic approaches. Genetic studies are performed to identify new mutations in genes involved in monogenic obesity, to identify new candidate genes and to analyze polygenic and epigenetic causes of obesity. Diverse new candidate genes have been identified and are being further investigated, as well as the interaction geno- – 72 – Effects of maternal diet on glial coverage and glucose sensitivity of proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus. Electron micrographs showing astroglial coverage (in green) of POMC neurons from male mice born to mothers on A)a control diet or B)high fat diet (HFD). Offspring of HFD mothers have a higher percentage of somal membrane ensheathed by astrocytes (C). The frequency of resting mIPSCs was significantly decreased with no change in mEPSC frequency in HFD offspring. D) The response to changes in glucose concentration was also modified in HFD offspring, with a reduction in the concentration of glucose decreasing action potential frequency in POMC neurons. *p<0.05, **p<0.001, *** p<0.0001. (Fuente-Martín et al., JCI, 2012). type/phenotype and ethnic influences. Metabolomic studies are underway to better understand the processes involved in the development of insulin resistance and type 2 diabetes. Animal models are employed to analyze how poor maternal and/or neonatal nutrition, stress or changes in specific hormones during neonatal life affect adult metabolism, with special attention focused on the differential responses of males and females. Studies analyzing the effect of increased central leptin levels on insulin signaling in the CNS and adipose tissue demonstrate a relationship between insulin resistance, inflammation and energy homeostasis. Hypothalamic glial cells are a main focus of investigation for their important AREA 1 • Jesús Argente Oliver. Fisiopatología de la Obesidad. ISCIII. CIBER: CB06/03/0022. Duration: 2006 indefinido. • Jesús Argente Oliver. Obesidad infantil grave de comienzo precoz: fundamentos metabólicos, genéticos y proteomicos. ISCIII. PI10/00747. Duration: 2011 - 2013. • Julie Ann Chowen King. Regulación de los astrocitos hipotalámicos por la leptina: implicaciones en el control metabólico sistémico. MICINN. BFU2011-27492. Duration: 2012 - 2014. The metabolic hormone leptin directly modifies glutamate and glucose uptake in hypothalamic astrocytes. A) Levels of the glutamate trasporter GLAST in primary hypothalamic astrocyte cultures treated with saline (control) or leptin (Lep, 100 ng/ml) for 1 or 24 hours. B) Glutamate uptake in response to leptin at 30 min and 24 hours. C) Leptin modifies the levels of glucose transporter (GLUT)-2 in hypothalamic astrocytes and D) glucose up-take. (Fuente-Martín et al., JCI, 2012). # p<0.0005. role in metabolic control. We have recently shown them to respond to dietary changes and metabolic hormones, both pre and postnatally, and that astrocytes are most likely involved in controlling metabolic neuronal function (Fig. 1 & 2). MAJOR GRANTS • Vicente Barrios Sabador. Red de centros de Genética clínica y molecular. Integración de la investigación clínica, molecular y epidemiológica en Genética humana. ISCIII. C03/07. Duration: 2002 - Actualidad. YEAR Total IF Publication No. Q1 Q2 2010 83,646 21 10 9 2011 57,965 16 7 4 2012 90,732 22 12 9 Fuente-Martín E, García-Cáceres C, Granado M, Sánchez-Garrido MA, Tena-Sempere M, Frago LM, Argente J, Chowen JA. Early postnatal overnutrition increases adipose tissue accrual in response to a sucrose-enriched diet. Am J Physiol Endocrinol Metab. 302(12):E1586-E1598. 2012. PMID: 22510708. IF: 4,746. DOI: 10.1152/ajpendo.00618.2011 Bang P, Ahmed SF, Argente J, Backeljauw P, Bettendorf M, Bona G, Coutant R, Rosenfeld RG, Walenkamp MJ, Savage MO. Identification and management of poor response to growth-promoting therapy in children with short stature. Clin Endocrinol (Oxf). 77(2):169-181. 2012. PMID: 22540980. IF: 3,168. DOI: 10.1111/j.1365-2265.2012.04420.x Stucchi P, Gil-Ortega M, Merino B, Guzmán-Ruiz R, Cano V, Valladolid-Acebes I, Somoza B, Le Gonidec S, Argente J, Valet P, Chowen JA, Fernández-Alfonso M, Ruiz-Gayo M. Circadian Feeding Drive of Metabolic Activity in Adipose Tissue and not Hyperphagia Triggers Overweight in Mice: Is There a Role of the Pentose-Phosphate Pathway?. Endocrinology 153(2):690-9. Epub 2011 Dec 6. 2012. – 73 – AREA 3 AREA 2 AREA 1 PUBLICATIONS (22) [IF: 90,732] Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases PMID: 22147018. IF: 4,459. DOI: 10.1210/en.20111023 Burgos-Ramos E, González-Rodríguez A, Canelles S, Baquedano E, Frago LM, Revuelta-Cervantes J, Gómez-Ambrosi J, Frühbeck G, Chowen JA, Argente J, Valverde AM, Barrios V. Differential Insulin Receptor Substrate-1 (IRS1)-Related Modulation of Neuropeptide Y and Proopiomelanocortin Expression in Nondiabetic and Diabetic IRS2-/- Mice. Endocrinology 153(3):112940. Epub 2011 Dec 30. 2012. PMID: 22210743. IF: 4,459. DOI: 10.1210/en.2011-1278 Fraser CS, Rubio-Cabezas O, Littlechild JA, Ellard S, Hattersley AT, Flanagan SE. Amino acid properties may be useful in predicting clinical outcome in patients with Kir6.2 neonatal diabetes. Eur J Endocrinol 167(3):417-421. 2012. PMID: 22648966. IF: 3,423. DOI: 10.1530/EJE-12-0227 Coutant R, Dörr HG, Gleeson H, Argente J. Limitations of the IGF-I generation test in children with short stature. Eur J Endocrinol. 166(3):351-7. Epub 2011 Nov 2. 2012. PMID: 22048966. IF: 3,423. DOI: 10.1530/EJE-11-0618 Linglart A, Fryssira H, Hiort O, Holterhus PM, Perez de Nanclares G, Argente J, Heinrichs C, Kuechler A, Mantovani G, Leheup B, Wicart P, Chassot V, Schmidt D, Rubio-Cabezas Ó, Richter-Unruh A, Berrade S, Pereda A, Boros E, Muñoz-Calvo MT, Castori M, Gunes Y, Bertrand G, Bougnères P, Clauser E, Silve C. PRKAR1A and PDE4D mutations cause acrodysostosis but two distinct syndromes with or witho ut GPCR-signaling hormone resistance. J Clin Endocrinol Metab 97(12):2328-2338. 2012. PMID: 23043190. IF: 5,967. DOI: 10.1210/jc.20122326 Perez-Nanclares G, Romanelli V, Mayo S, Garin I, Zazo C, Fernandez-Rebollo E, Martínez F, Lapunzina P, de Nanclares GP; Spanish PHP Group. Detection of hypomethylation syndrome among patients with epigenetic alterations at the GNAS locus. J Clin Endocrinol Metab. 97(6):E1060-1067. 2012. PMID: 22492776. IF: 5,967. DOI: 10.1210/jc.2012-1081 – 74 – Mela V, Díaz F, Gertler A, Solomon G, Argente J, Viveros MP, Chowen JA. Neonatal treatment with a pegylated leptin antagonist has a sexually dimorphic effect on hypothalamic trophic factors and neuropeptide levels. J Neuroendocrinol 24(5):756-765. 2012. PMID: 22236109. IF: 3,138. DOI: 10.1111/j.13652826.2012.02279.x Fuente-Martín E, García-Cáceres C, Granado M, de Ceballos ML, Sánchez-Garrido MA, Sarman B, Liu ZW, Dietrich MO, Tena-Sempere M, Argente-Arizón P, Diaz F, Argente J, Horvath TL, Chowen JA. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes. J. Clin. Invest. 122(11):3900-13. 2012. PMID: 23064363. IF: 13,069. DOI: 10.1172/JCI64102 Burgos-Ramos E, Sackmann-Sala L, Baquedano E, Cruz-Topete D, Barrios V, Argente J, Kopchick JJ. Central leptin and insulin administration modulates serum cytokine- and lipoprotein-related markers. Metabolism 61(11):1646-57. 2012. PMID: 22658937. IF: 2,664. DOI: 10.1016/j.metabol.2012.05.001 Fuente-Martín E, Granado M, García-Cáceres C, Sanchez-Garrido MA, Frago LM, Tena-Sempere M, Argente J, Chowen JA. Early nutritional changes induce sexually dimorphic long-term effects on body weight gain and the response to sucrose intake in adult rats. Metabolism 61(6):812-822. 2012. PMID: 22209665. IF: 2,664. DOI: 10.1016/j.metabol.2011.11.003 Perianes-Cachero A, Burgos-Ramos E, PueblaJiménez L, Canelles S, Viveros MP, Mela V, Chowen JA, Argente J, Arilla-Ferreiro E, Barrios V. Leptininduced downregulation of the rat hippocampal somatostatinergic system may potentiate its anorexigenic effects. Neurochem Int. 61(8):1385-96. 2012. PMID: 23073237. IF: 2,857. DOI: 10.1016/j.neuint.2012.09.019 Granado M, Fuente-Martín E, García-Cáceres C, Argente J, Chowen JA. Leptin in early life: a key factor for the development of the adult metabolic profile. Obes Facts 5(1):138-150. 2012. PMID: 22433625. IF: 1,856. DOI: 10.1159/000336967 AREA 1 Rachmiel M, Rubio-Cabezas O, Ellard S, Hattersley AT, Perlman K. Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INS gene. Pediatr Diabetes 13(6):26-29. 2012. PMID: 21910811. IF: 2,16. DOI: 10.1111/j.13995448.2011.00809.x García-Herrero CM, Rubio-Cabezas O, Azriel S, Gutierrez-Nogués A, Aragonés A, Vincent O, Campos-Barros A, Argente J, Navas MA. Functional characterization of MODY2 mutations highlights the importance of the fine-tuning of glucokinase and its role in glucose sensing. PLoS One 7(1):e30518. 2012. PMID: 22291974. IF: 4,092. DOI: 10.1371/journal.pone.0030518 Burgos-Ramos E, Canelles S, Perianes-Cachero A, Arilla E, Argente J, Barrios V. Adipose tissue promotes a serum cytokine profile related to lower insulin sensitivity after chronic central infusion. Plos One 7(10):e46893. 2012. PMID: 23056516. IF: 4,092. DOI: 10.1371/journal.pone.0046893 23251400. IF: 4,092. DOI: 10.1371/journal.pone. 0050894 Fernández O, Agüera E, Izquierdo G, Millán-Pascual J, Ramió I Torrentà L, Oliva P, Argente J, Berdei Y, Soler JM, Carmona O, Errea JM, Farrés J; Group on Adherence to IFNb-1b in Spain. Adherence to interferon -1b treatment in patients with multiple sclerosis in Spain. PLoS One 7(5):e35600. 2012. PMID: 22615737. IF: 4,092. DOI: 10.1371/journal.pone. 0035600 Sáinz N, Rodríguez A, Catalán V, Becerril S, Ramírez B, Lancha A, Burgos-Ramos E, Gómez-Ambrosi J, Frühbeck G. Leptin reduces the expression and increases the phosphorylation of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4 in muscle of ob/ob mice. PLoS One. 7(1):e29389. 2012. PMID: 22253718. IF: 4,092. DOI: 10.1371/journal. pone.0029389 Mela V, Llorente-Berzal A, Díaz F, Argente J, Viveros MP, Chowen JA. Maternal deprivation exacerbates the response to a high fat diet in a sexually dimorphic manner. PLOS One. 7(11):e48915. 2012. PMID: 23145019. IF: 4,092. DOI: 10.1371/journal. pone.0048915 BOOKS Granell S, Serra-Juhé C, Martos-Moreno GÁ, Díaz F, Pérez-Jurado LA, Baldini G, Argente J. A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct folding. PLoS One 7(12):e50894. 2012. PMID: Burgos-Ramos E, Martos-Moreno GA, Argente J, Barrios V. Multiplexed bead immunoassays: advantages and limitations in Pediatrics. Advances in Immunoassay Technology. 2012. ISBN: 978-95351-0440-7. – 75 – AREA 3 AREA 2 AREA 1 Rubio-Cabezas O, Flanagan SE, Damhuis A, Hattersley AT, Ellard S. KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Pediatr Diabetes 13(4):315-18. 2012. PMID: 21981029. IF: 2,16. DOI: 10.1111/j.13995448.2011.00824.x Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases Line 1.11 Metabolic syndrome and vascular risk receptor subtype agonists on endothelial vasodilation in human microvessels. Exp Gerontol. 47(9):734-40. 2012. PMID: 22776133. IF: 3,741. DOI: 10.1016/j.exger.2012 06.014 Kozakova M, Palombo C, Eng MP, Dekker J, Flyvbjerg A, Mitrakou A, Gastaldelli A, Ferrannini E; RISC Investigators (.., Carraro R, Friera A, Novella B, ..). Fatty liver index, gammaglutamyltransferase, and early carotid plaques. Hepatology. 55(5):1406-15. 2012. PMID: 22334565. IF: 11,665. DOI: 10.1002/hep.25555 GROUP 27 HEAD OF LABORATORY Raffaele Carraro Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean ME, Niskanen L, Rasmussen MF, Rissanen A, Rössner S, Savolainen MJ, Van Gaal L. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J Obes (Lond). 36(6):890. 2012. PMID: 21844879. IF: 4,691. DOI: 10.1038/ijo.2011.158 GROUP MEMBERS • María Concepción Peiró Vallejo • Carlos Félix Sánchez Ferrer • Isabelle Sharmiashvili • Andrea Azcárate Villalón • Iñigo Tejado Elviro • Tania del Mar Romacho Romero • Marta Vázquez Bella • Laura Alicia Villalobos Rodríguez • Erika Palacios Rosas • Elena Cercas Alonso • Lourdes Martínez-Piñeiro Muñoz Handberg A, Højlund K, Gastaldelli A, Flyvbjerg A, Dekker JM, Petrie J, Piatti P, Beck-Nielsen H; RISC Investigators (.., Carraro R, Friera A, Novella B, ..). Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. J Intern Med. 271(3):294-304. 2012. PMID: 21883535. IF: 5,483. DOI: 10.1111/j.1365-2796.2011.02442.x MAJOR GRANTS Carmelo García Monzón. 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. ISCIII. PI10/00067 Bobbioni-Harsch E, Pataky Z, Makoundou V, Laville M, Disse E, Anderwald C, Konrad T, Golay A; RISC Investigators(.., Carraro R, Friera A, Novella B,..). From metabolic normality to cardiometabolic risk factors in subjects with obesity. Obesity (Silver Spring). 20(10):2063-9. 2012. PMID: 22421925. IF: 4,284. DOI: 10.1038/oby.2012.692011. PMID: 20888662. IF: 9,334 PUBLICATIONS (5) [IF: 29,864] YEAR Total IF Publication No. Q1 2010 36,377 6 6 2011 39,347 7 5 2012 29,864 5 5 Q2 2 Angulo J, Vallejo S, El Assar M, García-Septiem J, SánchezFerrer CF, Rodríguez-Mañas L. Age-related differences in the effects of and peroxisome proliferator-activated – 76 – GROUP 5 HEAD OF LABORATORY Carmelo García Monzón AREA 1 GROUP MEMBERS • Rodolfo Javier Vargas Castrillón • Alicia Sáez Sáez • María Eugenia Miquilena Colina • Faustino Manuel La Banda Brusi • Enrique Chávez Jiménez • Javier Rodríguez de Cía RESEARCH INTEREST Triglyceride accumulation in nonalcoholic fatty liver (NAFL) results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors, such as the Foxa subfamily. In the mouse liver, unlike Foxa2, the role of Foxa1 has not yet been investigated in detail. Therefore, we wanted to evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Our findings demonstrated that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways. Moreover, Foxa1 repressed the fatty acid transporter protein FATP2 and lowered fatty acid uptake. We also found that human and rat NAFL have a reduced Foxa1 expression, possibly through a Analysis of autophagy levels in liver biopsies of HCV patients. (A) Immunoblotting analysis of total protein extracts from liver biopsies of HCV patients using an anti-LC3 antibody. (B) Signal intensities of LC3-I and -II bands have been measured and used for the correlation analysis with microvesicular steatosis and other clinical parameters (see table 1). Glyceraldehyde-3phosphate dehydrogenase (GAPDH) was analyzed as a protein loading control. protein kinase C-dependent pathway. The results of our work (2) demonstrate that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. Evidence links increased hepatic fatty acid translocase (FAT)/CD36 protein amount and gene expression with hyperinsulinemia in animal models and patients with fatty liver, but whether insulin regulates FAT/CD36 expression, amount, distribution, and function in hepatocytes is currently unknown. To investigate this, FAT/CD36 protein content and FA uptake was analyzed in isolated hepatocytes from obese and lean Zucker rats. We found that FAT/CD36 protein amount at the plasma membrane (PM) was higher in hepatocytes from obese rats than from lean controls. Interestingly, increased amount of FAT/CD36 protein at the PM and enhanced FA uptake of obese Zucker rat hepatocytes were maintained only when exposed to hyperinsulinemic conditions. Thus, we showed in this work (3) that high insulin levels are required for FAT/CD36 translocation – 77 – AREA 3 AREA 2 AREA 1 Despite the growing number of studies linking nonalcoholic fatty liver disease (NAFLD) with altered serum metabolite levels, an obstacle to the development of metabolome-based NAFLD predictors has been the lack of large cohort data from biopsy-proven patients matched for key metabolic features such as obesity. In order to shed light on this matter, we studied 467 biopsied individuals with normal liver histology or diagnosed with NAFLD. We showed in this study (1) that body mass index-dependent serum metabolic profile may be able to reliably distinguish nonalcoholic steatohepatitis (NASH) from simple steatosis patients, and could have significant implications for the development of NASH biomarkers and potential novel targets for therapeutic intervention. Cellular and molecular etiopathogenic mechanisms in inflammatory and autoimmune diseases otic cells, occur during infection of cells with hepatitis C virus (HCV), but the clinical relevance of this process is not clear. In order to gain insight on this issue, levels of autophagy were analyzed in liver biopsy samples from patients with HCV infection. We found that there was an inverse correlation between microvesicular steatosis and level of autophagy. In addition, we observed that HCV selectively induced autophagy of lipids in virusinfected and replicon cells as well as autophagosomes frequently colocalized with lipid deposits, mainly formed by unesterified cholesterol. Interestingly, inhibition of the autophagic process in these cells significantly increased the induction of cholesterol accumulation by HCV. The findings of our work (4) indicate that autophagy counteracts the alterations in lipid metabolism induced by HCV, suggesting that disruption of the autophagic process might contribute to development of steatosis in patients with HCV. MAJOR GRANTS Cholesterol synthesis is required for autophagy induction in hCV replicon cells. (A) Reduced LC3 cleavage in mevastatintreated HCV replicon cells. Protein extracts were prepared from HuH7 and Rep Blast cells treated with mevastatin for 36 h and subjected to immunoblotting to determine LC3 and nonstructural protein 5A (NS5A) protein levels. Tubulin was used as a protein loading control. (B) Reduced number of autophagosomes in mevastatin-treated cells. GFP-LC3-expressing Rep Blast cells were treated with mevastatin for 36 h, fixed, and stained with Filipin (blue signal). Scale bar=10 um. to the PM in obese rat hepatocytes to enhance FA uptake and triglyceride synthesis. • Carmelo García Monzón. 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. ISCIII. PI10/00067. Duration: 2011 - 2013. • Carmelo García Monzón. Valor de la determinación sérica de la fracción soluble de la ácido graso translocasa CD36 (FAT/CD36) para el diagnóstico no invasivo de la enfermedad hepática grasa no alcohólica: Papel de la insulina en la regulación de la expresión y función de FAT/CD36 en el hepatocito humano. Fundación Mutua Madrileña. Duration: 2012 - 2013. PUBLICATIONS (4) [IF: 25,626] YEAR On the other hand, high levels of autophagy, a lysosome-mediated catabolic process that mediates degradation and recycling of all major components of eukary- – 78 – Total IF Publication No. Q1 2010 6,115 1 1 2011 23,692 3 3 2012 25,626 4 4 Q2 AREA 1 Buqué X, Cano A, Miquilena-Colina ME, GarcíaMonzón C, Ochoa B, Aspichueta P. High insulin levels are required for FAT/CD36 plasma membrane translocation and enhanced fatty acid uptake in obese Zucker rat hepatocytes. Am J Physiol Endocrinol Metab 303(9):E504-E514. 2012. PMID: 22693206. IF: 4,746. DOI: 10.1152/ajpendo.00653.2011 Reduces Lipid Accumulation in Human Hepatocytes and Is Down-Regulated in Nonalcoholic Fatty Liver. PLoS ONE 7(1):e30014. 2012. PMID: 22238690. IF: 4,092. DOI: 10.1371/ journal.pone.0030014 BOOKS Vescovo T, Romagnoli A, Perdomo AB, Corazzari M, Ciccosanti F, Alonzi T, Nardacci R, Ippolito G, Tripodi M, García-Monzón C, Lo Iacono O, Piacentini M, Fimia GM. Autophagy Protects Cells From HCVInduced Defects in Lipid Metabolism. Gastroenterology 142(3):644-653.e3. 2012. PMID: 22155365. IF: 11,675. DOI: 10.1053/j.gastro.2011.11.033 Carmelo García Monzón. Enfermedad hepática grasa no alcohólica. Gastroenterología y Hepatología. Problemas comunes en la práctica clínica. 2012. Jarpyo Editores S.A. ISBN: 978-84-92982-31-8. Moya M, Benet M, Guzmán C, Tolosa L, GarcíaMonzón C, Pareja E, Castell JV, Jover R. Foxa1 PRINCIPAL INVESTIGATOR: GARCIA MONZON, CARMELO Estudio para evaluar la eficacia y la seguridad de GFT505 una vez al día para esteatohepatitis en pacientes con esteatohepatitis no alcohólica (EHNA). Estudio multicéntrico, aleatorizado, doble ciego y controlado con placebo, con un diseño adaptativo para permitir la administración inicial de GFT505 80 mg frente a placebo, seguido de una segunda fase en la que se incluirá una dosis de GFT505 de 120 mg, tras la revisión del análisis de la seguridad a los seis meses, de los datos de 80 mg en al menos el 50% de los pacientes; (Versión 3.0: 01-08-12). GENFIT. GFT505212-7. EudraCT: 2012-000295-42 – 79 – AREA 3 AREA 2 AREA 1 CLINICAL TRIALS Barr J, Caballería J, Martínez-Arranz I, DomínguezDíez A, Alonso C, Muntané J, Pérez-Cormenzana M, García-Monzón C, Mayo R, Martín-Duce A, RomeroGómez M, Lo Iacono O, Tordjman J, Andrade RJ, Pérez-Carreras M, Le Marchand-Brustel Y, Tran A, Fernández-Escalante C, Arévalo E, García-Unzueta M, Clement K, Crespo J, Gual P, Gómez-Fleitas M, Martínez-Chantar ML, Castro A, Lu SC, VázquezChantada M, Mato JM. Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression. Journal of Proteome Research 11(4):2521-2532. 2012. PMID: 22364559. IF: 5,113. DOI: 10.1021/pr201223p AREA 2 NEUROTRANSMISSION, PHARMACOLOGICAL NEUROPROTECTION AND NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISEASES Line 2.1 Neuropharmacology and neuroprotection. Line 2.2 Neurotransmission in the hippocampus. Line 2.3 Clinical pharmacology and pharmacogenetics. Line 2.4 Diagnostic and therapeutic advances in affective disorders. Line 2.5 Neurosurgery of epilepsy. Line 2.6 Cerebrovascular diseases. – 81 – AREA 2 NEUROTRANSMISSION, PHARMACOLOGICAL NEUROPROTECTION AND NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISEASES – 82 – AREA 2 NEUROTRANSMISSION, PHARMACOLOGICAL NEUROPROTECTION AND NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISEASES Line 2.1 Neuropharmacology and neuroprotection GROUP 28 GROUP MEMBERS • Manuela García López • Mercedes Villarroya Sánchez • Cristóbal de los Ríos Salgado • Manuel Alejandro Romero Martínez • Matilde Yáñez Jato • Elba Alonso Álvarez • Laura del Barrio Díaz • José Carlos Fernández Morales • Antonio Miguel García de Diego • María Dolores Martín de Saavedra • Lorena Cortés Gil • Francisco Javier Egea Máiquez • Santos Morais Nicolau • Patricia Velasco Jurado • Marcos Maroto Pérez • Esther Parada Pérez RESEARCH INTEREST For the last two decades, most efforts on new drug development to treat neurodegenerative diseases have been done. However, all these compounds have so far failed in clinical trials or have not contributed to ameliorate the disease advance. It seems therefore desirable to explore new concepts Fig. 1. Multitarget compounds acting on VDCCs of soma of vulnerable neurons (A; a DHP-like moiety to mitigate excess Ca2+ entry) and on the MNCX (B; benzothiazepine moiety to abort the futile MCC) as well as on oxidative stress linked to distorted Ca2+ homeostasis (C; a polyphenol-like moiety to sequester excess free radicals) could be a more efficacious strategy to rescue neurons from death in neurodegenerative diseases. In this scheme, we propose that a trifunctional compound (i.e., a hybrid molecule with dihydropyridine benzothiazepine, and polyphenol moieties) could effectively mitigate the augmented neuronal (NCC) and mitochondrial Ca2+ cycling (MCC), thereby exerting a protective survival effects on vulnerable neurons in neurodegenerative diseases. and strategies in the field of drug development for neurodegenerative diseases. We analyze in our project the hypothesis that a trifunctional chemical entity acting on the L subtype of voltage-dependent Ca2+ channels (VDCCs) and on the mitochondrial Na+/Ca2+ exchanger (MNCX), and having additional antioxidant properties, may efficiently delay or stop the death of vulnerable neurons in the brain of patients with neurodegenerative diseases (see figure 1). In the last year, we have published – 83 – AREA 3AREA 2 AREA 1 HEAD OF LABORATORY Antonio García García Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Fig. 2. Exocytotic response to high K+ depolarization measured with amperometry. Graph depicted the average of control and APP/PS1 spikes. four review articles focused on the functional triad hypothesis, the mitochondrial importance on the regulation of cytosolic Ca2+, and new strategies for drug development [1-4]. In this context of drug design and development, we have published two original articles; one of them is about the mechanism of action of the neuroprotective and natural drug resveratrol. Here, we have proposed that resveratrol is able to mitigate the catecholamine surge occurring during stress, through its ability to elicit mild local [Ca2+]c transients and enhanced NO production, that blocks the last steps of exocytosis [5]. The other article is about a new class of neuroprotective agents based on 4,6diaryl-1,4-dihydropyridines chemical structure. These compounds lack the structural features needed for vascular activity, were found to prevent calcium overload and behave as neuroprotective agents. One of the compounds, bearing a 2-thienyl substituent at C-4, showed the highest neuroprotective activity and was also a moderate antioxidant, being a good compound for further studies in this area [6]. In addition to new drug development, we have tested our hypothesis of the homeostatic control of cytosolic Ca2+ by the functional triad in transgenic – 84 – mice models of Alzheimer disease (AD). We have assessed how homeostatic Ca2+ imbalance affect to exocytosis machinery in chromaffin cells as periphery neuronal model in this transgenic mouse. Obviously, the search for synaptic dysfunctions in AD has been focused on the brain. However, the analysis of the last steps of exocytosis in the millisecond-time range has been best studied in peripheral chromaffin cells, using amperometry. This technique provides information on subtle differences in fast exocytotic mechanisms, which have not been possible to study in CNS. In this study, we have compared the kinetic parameters of singlevesicle amperometric events in chromaffin cells from control C57 mice and the APP/PS1 transgenic mouse model of AD. Given that cholinergic neuron loss is prominent in AD brains, we used the AChE activity technique to assess alterations in both, the cholinergic innervations and the activity of the enzyme itself which is substantially depleted in the brains of patients with AD. Finally we assayed the presence of amyloid plaque deposition in the adrenal medullae and brain of these mice. In this study, we have described alterations in the last steps of regulated exocytosis in a peripheral neuroendocrine cell of a mouse model of AD. Due to accessibility and available methodological approaches to study minute changes of the kinetics of the last steps of exocytosis, chromaffin cells may become invaluable models to study the potential changes of exocytotic machine in the various mouse models of AD available (see figure 2). These studies would aid to shed light on other central pathophysiological alterations produced by the disease [7]. Finally, we aimed to investigate the effects of chondroitin sulphate (CS) on voltage- and currentclamped rat embryo hippocampal neurons in primary cultures. We found that CS elicited a wholecell Na+-dependent inward current (ICS) that produced drastic cell depolarization, and a cytosolic calcium transient ([Ca2+]c). Those effects were mediated throughout -amino-3-hydroxy-5methylisoxazole-4-propionate (AMPA) and kainite receptors. Because CS proteoglicanes have been attributed Ca2+-dependent roles, such as neural AREA 2 MAJOR GRANTS • Antonio García García. Modulación farmacológica del intercambiador sodio-calcio mitocondrial: una nueva estrategia para tratar la enfermedad de Alzheimer. Proyecto Fundación CIEN Instituto de Salud Carlos III. PI 016/09. Duration: 2009 2012. • Antonio García García. Neurotoxicidad del líquido cefalorraquídeo de pacientes con esclerosis lateral amiotrófica (ELA): una nueva estrategia para la búsqueda de fármacos neuroprotectores. Agencia Laín Entralgo-Consejería de Sanidad. NDG09/8. Duration: 2010 - 2012. • Antonio García García. Perturbación de la liberación cuantal de adrenalina en la hipertensión arterial. Cooperación Interunivesitaria UAMBanco de Santander. Duration: 2011 - 2012. • Antonio García García. Tríada funcional y especialización de los subtipos de canales de calcio para controlar la exocitosis en la célula cromafín. MICINN. SAF2010-21795. Duration: 2011 2013. • Cristóbal de los Ríos Salgado. The CALHM1 channel and its Alzheimer's disease-linked mutated form P86L-CALHM1. A new biological target for the finding of neuroprotective drugs. MICINN. CP10/00531. Duration: 2011 - 2013. • Antonio García García. Esclerosis lateral amiotrófica: neuroprotección basada en la regulación farmacológica de la circulación neuronal del calcio. Fundación Eugenio Rodríguez Pascual. Duration: 2012 - 2013. PUBLICATIONS (8) YEAR Total IF 2010 2011 2012 [IF: 30,209] Publication No. Q1 Q2 45,614 12 6 4 45,763 14 5 7 30,209 8 3 4 Fernández-Morales, J.C. Arranz-Tagarro, J.A. Calvo-Gallardo, E. Maroto, M. Padin, J.F. García, A.G. Stabilisers of neuronal and mitochondrial calcium cycling as a strategy for developing a medicine for Alzheimer´s disease. ACS Chemical Neuroscience. 2012. IF: 3,676 González-Lafuente, L. Egea, J. León, R. MartínezSanz, F.J. Monjas, L. Perez, C. Merino, C. GarcíaDe-Diego, A.M. Rodríguez-Franco, M.I. García, A.G. Villarroya, M. López, M.G. De Los Ríos, C. Benzothiazepine CGP37157 and its isosteric 2’methyl analogue provide neuroprotection and block cell calcium entry. ACS Chemical Neuroscience 3(7):519-529. 2012. PMID: 22860221. IF: 3,676. DOI: 10.1021/cn300009e de Diego AM, Lorrio S, Calvo-Gallardo E, García, A.G. Smaller quantal size and faster kinetics of single exocytotic events in chromaffin cells from the APP/PS1 mouse model of Alzheimer's disease. Biochem Biophys Res Commun. 428(4):482-6. 2012. PMID: 23123627. IF: 2,484. DOI: 10.1016/j.bbrc.2012.10.082 García, A.G. Padin, J.F. Fernández-Morales, J.C. Maroto, M. García-Sancho, J. Cytosolic organelles shape calcium signals and exo-endocytotic responses of chromaffin cells. Cell Calcium 51(34):309-320. 2012. PMID: 22209033. IF: 3,766. DOI: 10.1016/j.ceca.2011.12.004 – 85 – AREA 3AREA 2 AREA 1 network development, axon pathfinding, plasticity and regeneration after central nervous system injury, CS action after extracellular matrix degradation could be contributing to the mediation of these effects through its interaction with AMPA and kainate receptors [8]. We have also presented the development, characterization and functional validation of a new polymeric support able to induce neuronal differentiation in both PC12 cell line and adult primary skin-derived precursor cells (SKPs) in vitro. This support is based in the combination of a photolithographic technique with use of neural extracellular matrix as a substrate, and a biocompatible and efficient microenvironment for neuronal differentiation [9] Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Padín J.F. De Diego, A.M.G. Fernández-Morales, J.C. Merino, C. Maroto, M. Calvo-Gallardo, E. Arranz, J.A. Yáñez, M. García, A.G. Resveratrol augments nitric oxide generation and causes store calcium reléase in chromaffin cells. European Journal of Pharmacology 685(1-3):99-107. 2012. PMID: 22498000. IF: 2,516. DOI: 10.1016/j.ejphar.2012.03.040 Egea, F.J. Martín de Saavedra, M.D. Parada, E. Romero, A. Del Barrio,L. Rosa, A.O. García, A.G. López, M.G. Galantamine elicits neuroprotection by inhibiting iNOS, NADPH oxidase and ROS in hippocampal slices stressed with anoxia/reoxygenation. Neuropharmacology 62(2):10821090. 2012. PMID: 22085833. IF: 4,814. DOI: 10.1016/j.neuropharm.2011.10.022 Lorrio, S. Gómez-Rangel, V. Negredo, P. Egea, J. León, R. Romero, A. Dal-Cim, T. Villarroya, M. Rodríguez-Franco, M.I. Conde, S. Arce, M. Roda, J.M. García, A.G. López, M.G. Novel multitarget ligand ITH33/IQM9.21 provides neuroprotection in in vitro and in vivo models related to brain ischemia. Neuropharmacology 67:403-411. 2012. PMID: 23228428. IF: 4,814. DOI: 10.1016/j.neuropharm.2012.12.001 García-Sancho, J. García, A.G. De Diego, A.M.G. Mitochondria and chromaffin cell function. Pflügers Archiv European Journal of Physiology 464(1):33-41. 2012. PMID: 22278417. IF: 4,463. DOI: 10.1007/s00424-012-1074-2 GROUP 29 HEAD OF LABORATORY María Francisca Cano Abad GROUP MEMBERS • Ana Ruiz Nuño • Ana José Moreno Ortega MAJOR GRANTS Ana Ruiz Nuño. Estudio del potencial efecto neuroprotector del nuevo compuesto ITH12233 en modelos TDP-43 in vitro e in vivo de esclerosis lateral amiotrófica. ISCIII. FIS.10/01426. Duration: 2011 - 2013. PUBLICATIONS (2) [IF: 8,610] YEAR Total IF Publication No. Q1 2010 2,595 1 6 2011 10,593 3 1 2012 8,61 2 2 Q2 1 Hernández-Vivanco A, Pérez-Alvarez A, Caba-González JC, Alonso MT, Moreno-Ortega AJ, Cano-Abad M, Ruiz-Nuño A, Carmona-Hidalgo B, Albillos A. Selectivity of action of pregabalin on Ca(2+) channels but not on fusion pore, exocytotic machinery, or mitochondria in chromaffin cells of the adrenal gland. J Pharmacol Exp Ther. 342(2):263-72. 2012. PMID: 22537772. IF: 3,828. DOI: 10.1124/jpet.111.190652 BOOKS De Diego, A.M.G. Lorrio, S. Hernández-Guijo, J.M. Gandia, L. García, A.G. Multitarget drugs for Stabilization of Calcium Cycling and Neuroprotection in Neurodegenerative Diseases and Stroke. Therapeutic Targets: Modulation, Inhibition and Activation. 2012. Wiley & Sons, Inc. ISBN: 978-0470-58719-5. – 86 – Paredes-Gamero EJ, Casaes-Rodrigues RL, Moura GE, Domingues TM, Buri MV, Ferreira VH, Trindade ES, Moreno-Ortega AJ, Cano-Abad MF, Nader HB, Ferreira AT, Miranda A, Justo GZ, Tersariol IL. Cell-permeable gomesin peptide promotes cell death by intracellular Ca(2+) overload. Mol Pharm. 9(9):2686-97. 2012. PMID: 22873645. IF: 4,782. DOI: 10.1021/mp300251j AREA 2 GROUP 31 Line 2.2 Neurotransmission in the hippocampus HEAD OF LABORATORY Jesús Miguel Hernández Guijo GROUP 30 GROUP MEMBERS • José Carlos González San Frutos • Elisa Albiñana Durá HEAD OF LABORATORY Luis Gandía Juan PUBLICATIONS (2) [IF: 7,582] MAJOR GRANTS • Luis Gandía Juan. Receptores nicotínicos alfa7 e inflamación en un modelo animal de distrofia muscular. CEAL-SANTANDER. Duration: 2011 2012. • Luis Gandía Juan. Receptores nicotínicos y liberación de neurotransmisores. MICINN. SAF2010-18837. Duration: 2011 - 2013. • Luis Gandía Juan. Receptores nicotínicos alfa7 e inflamación en un modelo animal de distrofia muscular. MECD. PHB2011-0031-PC. Duration: 2012 2013. YEAR Total IF Publication No. Q1 Q2 2010 11,994 4 1 2011 10,933 3 1 2 2012 7,582 2 1 1 MSegura-Chama P, Rivera-Cerecedo CV, GonzálezRamírez R, Felix R, Hernández-Guijo JM, HernándezCruz A. Atypical Ca2+ currents in chromaffin cells from SHR and WKY rat strains result from the deficient expression of a splice variant of the 1D Ca2+ channel. Am. J. Physiol. Heart and Circulatory Physiology 302(2):467-478. 2012. PMID: 22081701. IF: 3,708. DOI: 10.1152/ajpheart.00849.2011 Lopez-Jimenez ME, González JC, Lizasoain I, Sánchez-Prieto J, Hernández-Guijo JM, Torres M. Functional cGMP-gated channels in cerebellar granule cells. J Cell Physiol. 227(5):2252-63. 2012. PMID: 21809342. IF: 3,874. DOI: 10.1002/jcp.22964 PUBLICATIONS (0) [IF: 0] YEAR Total IF Publication No. Q1 Q2 2010 16,783 5 2 3 2011 12,287 4 2 1 2012 – 87 – AREA 3AREA 2 AREA 1 GROUP MEMBERS • Ángela Orozco Alarcón • Carmen Pérez de Nanclares Fernández • Ricardo de Pascual y del Castillo • Inés Colmena Crespo Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Line 2.3 Clinical pharmacology and pharmacogenetics GROUP 32 HEAD OF LABORATORY Francisco Abad Santos GROUP MEMBERS • Dolores Ochoa Mazarro • María Isabel Moreno Arza • Manuel Román Martínez • Sergio Daniel Sánchez Rojas • María Fagoaga Torija • María Talegón García • María Teresa Cabaleiro Ocampo • Ana María Tello Miller • Igone Marrodán Remírez • Javier Soriano Ventura • Rocío María Prieto Pérez • Angela Rivas Acosta • Carmen Verge González Comparison of TPMT genotype frequencies obtained by LightSNiP and sequencing methods, and differences by gender. Reference: Román M, Cabaleiro T, Ochoa D, Novalbos J, Chaparro M, Gisbert JP, Abad-Santos F. Validation of a genotyping method for analysis of TPMT polymorphisms. Clin Ther. 2012; 34(4): 878-84. the efficacy of new drugs in collaboration with several specialists in the hospital and primary care. During 2012, 15 clinical trials (phase I to IV) were performed. Pharmacogenetic research is related with various clinical diseases, trying to look for new pharmacogenetic markers to predict drug response, both therapeutic and toxic, that could help physicians to decide the best treatment for every patient. In 2012, 524 patients benefited from pharmacogenetic testing. During 2012, our group published 6 articles related to pharmacogenetics and clinical trials (Agúndez et al., 2012; Cabaleiro et al., 2012; Carcas et al., 2012; Gallo et al., 2012; González-Vacarezza et al., 2012; Román et al., 2012). RESEARCH INTEREST The aim of the investigation performed in this group is to evaluate the pharmacokinetics, pharmacodynamics and pharmacogenetics of drugs in order to predict the response of patients to drugs, in terms of both efficacy and safety. Our group has wide experience in the performance of numerous phase I, II and III clinical trials, with Dr. AbadSantos and Dolores Ochoa as principal investigators. We have available a Clinical Trials Unit, with capacity for 14 patients (7th floor, Hospital Universitario de la Princesa). Clinical trials performed include safety, pharmacokinetics, pharmacodynamics, interaction and bioequivalence studies in healthy volunteers, and studies in patients to probe – 88 – In addition, we are participating in 2 projects: Búsqueda de marcadores genéticos predictores de respuesta a fármacos biológicos en el tratamiento de la psoriasis, supported by the Instituto de Salud Carlos III (Ref. PI10/01740); Nuevos medicamentos genéricos para el tratamiento de patologías de alto impacto socioeconómico supported by the Ministerio de Ciencia e Innovación (Ref. IPT-2011-1663-900000). MAJOR GRANTS • Francisco Abad Santos. Búsqueda de marcadores genéticos predictores de respuesta a fármacos AREA 2 PUBLICATIONS (3) [IF: 9,930] YEAR Total IF Publication No. Q1 Q2 2010 14,591 5 2 3 2011 13,854 4 2 1 2012 9,93 3 1 2 M Román, T Cabaleiro, J Novalbos, M Chaparro, JP Gisbert, F Abad-Santos. Validation of a genotyping method for analysis of TPMT polymorphisms. Clin Ther 34(4):878-884. 2012. PMID: 22421577. IF: 2,321. DOI: 10.1016/j.clinthera.2012.02.017 Cabaleiro T, Roman M, Gisbert JP, Abad-Santos F. Utility of assesing thiopurine S-methyltransferase polymorphism before azathioprine therapy. Current Drug Metabol. 13(9):1277-93. 2012. PMID: 22493988. IF: 5,113 Carcas AJ, Borobia AM, Velasco M, Abad-Santos F, Díaz MQ, Fernández-Capitán C, Ruiz-Giménez N, Madridano O, Sillero PL; PGX-ACE Spanish Investigators Group (..., Ochoa D, Marrodan I, Moreno I, Román M, Verge C,...). Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial. Trials 13:239. 2012. PMID: 23237631. IF: 2,496. DOI: 10.1186/1745-6215-13-239 CLINICAL TRIALS PRINCIPAL INVESTIGATOR: ABAD SANTOS, FRANCISCO Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de comprimidos de aripiprazol 10 mg, tras su administración oral en dosis única a voluntarios sanos; (versión 1: 02-10-12). LABORATORIOS ALTER, S.A. ITHUEC-ARI/12-4. EudraCT: 2012-004241-32 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado aleatorizado de bioequivalencia de dos formulaciones de clopidogrel comprimidos de 75mg, tras su administración en dosis única a voluntarios sanos en ayunas; (Versión 1:16-04-12). LABORATORIOS ALTER, S.A. ITHUEC-CLO/12-1. EudraCT: 2012-000702-30 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico aleatorizado, abierto y cruzado de tres vías de bioequivalencia de tres formulaciones de ibuprofeno 400mg (ibuprofene en suspensión 100mg/5ml e ibuprofeno suspensión 200mg/5ml) frente a junifen suspensión 100mg/5ml) tras su administración oral en dosis única a voluntarios sanos; (versión 1.0:16-05-12). LABORATORIOS FARMALIDER, S.A. FMLD-CALISTO 2%4%-15. EudraCT: 2012-002310-40 PRINCIPAL INVESTIGATOR: ABAD SANTOS, FRANCISCO Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de diclofenaco de 50mg comprimidos gastrorresistentes, tras su administración oral en dosis única con comida a voluntarios sanos; (Versión 1:17-04-12). LABORATORIOS NORMON, S.A. N-DIC-11-176. EudraCT: 2012-000176-41 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de amlodipino/atorvastatina 10mg/10mg comprimidos recubiertos, tras su administración oral en dosis única a voluntarios sanos en ayunas con diseño cruzado replicado; (Versión 1:1605-12). LABORATORIOS NORMON, S.A. N-AMLATO- – 89 – AREA 3AREA 2 AREA 1 biológicos en el tratamiento de la psoriasis. ISCIII. PI10/01740. Duration: 2010 - 2013. • Francisco Abad Santos. Nuevos medicamentos genéricos para el tratamiento de patologías de alto impacto socioeconómico. MEC. IPT-2011-1663900000. Duration: 2011 - 2014. Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases 12-178. EudraCT: 2012-001846-16 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado y aleatorizado de bioequivalencia de tres formulaciones de efavirenz comprimidos recubiertos de 600mg, tras su administración oral en dosis única a voluntarios sanos; (Versión 1: 03-10-12). LABORATORIOS KERN PHARMA S.L. KP-EFA-53. EudraCT: 2012-004402-96 PRINCIPAL INVESTIGATOR: ABAD SANTOS, FRANCISCO Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de comprimidos bucodispersables de aripiprazol 10mg, tras su administración oral en dosis única a voluntarios sanos en ayunas; (versión 1:16-07-12). LABORATORIOS KERN PHARMA S.L. KP-ARI-51. EudraCT: 2012-003196-19 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones en comprimidos de aripiprazol 10mg, tras su administración oral en dosis única a voluntarios sanos en ayunas; (Versión 1:16-05-12). LABORATORIOS KERN PHARMA S.L. KP-ARI-46. EudraCT: 2012-002016-97 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de diclofenaco 50mg comprimidos gastrorresistentes, tras su administración oral en dosis única a voluntarios sanos en ayunas; (Versión 1: 29-02-12). LABORATORIOS NORMON, S.A. N-DIC11-175. EudraCT: 2012-000189-40 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado y aleatorizado para evaluar la biodisponibilidad y tolerabilidad de una nueva formulación de ibuprofeno arginato comparada con la formu- – 90 – lación estándar oral de ibuprofeno arginina administrada en dosis única a voluntarios sanos en ayunas; (versión 1.0: 16-07-12). LABORATORIOS FARMALIDER, S.A. FMLD-FEBE-17. EudraCT: 2012-003264-53 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado aleatorizado de bioequivalencia de dos formulaciones de quetiapina comprimidos de liberación prolongada de 50mg, tras su administración oral en dosis única con comida a voluntarios sanos seguido de dosis múltiple; (versión 1: 20-09-12). LABORATORIOS ALTER, S.A. ITHUEC-QUE50/12-5. EudraCT: 2012-004287-22 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Estudio piloto cruzado, aleatorizado para evaluar la farmacocinética tras la administración de dosis única de progesterona (tres formulaciones de EF800 y Utrogestan« 200mg) por vía oral en mujeres postmenopáusicas o mujeres con ovarectomía bilateral; (versión 1: 31-10-12). EFFIK GROUP. 2013001_ORAL. EudraCT: 2012-005011-10 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de metformina comprimidos recubiertos de 850mg, tras su administración en dosis única con comida a voluntarios sanos;(Versión1:8-5-12). LABORATORIOS KERN PHARMA S.L. KP-MET-47. EudraCT: 2012-002006-48 PRINCIPAL INVESTIGATOR: ABAD SANTOS, FRANCISCO Ensayo clínico aleatorizado, abierto y cruzado de bioequivalencia de dos formulaciones de ibuprofeno 400mg (ibuprofeno 400mg polvo oral frente a dalsy 400 mg comprimidos recubiertos con película) tras su administración oral en dosis única a voluntarios sanos; (versión 1.0: 12-07-12). LABORATORIOS FARMALIDER, S.A. FMLD-SINOPE-16. EudraCT: 2012-003263-21 AREA 2 PRINCIPAL INVESTIGATOR: ABAD SANTOS, FRANCISCO Ensayo clínico pivotal, aleatorizado, cruzado y replicado de bioequivalencia de dos formulaciones de barnidipino 20mg capsulas de liberación modificada tras su administración oral en dosis única a voluntarios sanos en ayunas; (versión 1: 17-10-12). LABORATORIOS LICONSA S.A., SPAIN. LIE1-CH-BARN-0159-CT-B02-12. EudraCT: 2012-004843-59 QUE50/12-2. EudraCT: 2012-002986-36 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado, replicado y aleatorizado de biodisponibilidad comparada de dos formulaciones de albendazol comprimidos de 400mg, tras su administración en única dosis a voluntarios sanos, junto con un desayuno estándar y un desayuno rico en grasas; (versión 2:11-01-12). FUNDACION TEOFILO HERNANDO. ITHUEC-ALB/10-6. EudraCT: 2010-021006-38 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de rasagilina comprimidos de 1mg, tras su administración oral en dosis única a voluntarios sanos en ayunas; (versión 1: 15-10-12). LABORATORIOS NORMON, S.A. N-RAS-12-184. EudraCT: 2012-004433-17 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico aleatorizado de bioequivalencia de dos formulaciones de Telmisartán/hidroclorotiazida comprimidos de 80/25 mg, tras su administración en dosis única a voluntarios sanos en ayunas con diseño cruzado replicado; (Versión 1: 20-09-12). LABORATORIOS ALTER, S.A. ITHUEC-TEL-HTZ/12-3. EudraCT: 2012-004242-14 – 91 – AREA 3AREA 2 AREA 1 PRINCIPAL INVESTIGATOR: OCHOA MAZARRO, DOLORES Ensayo clínico cruzado aleatorizado de bioequivalencia de dos formulaciones de quetiapina comprimidos de liberación prolongada de 50mg, tras su administración en dosis única a voluntarios sanos en ayunas; (versión 1:21-06-12). LABORATORIOS ALTER, S.A. ITHUEC- PRINCIPAL INVESTIGATOR: ABAD SANTOS, FRANCISCO Ensayo clínico cruzado y aleatorizado de bioequivalencia de dos formulaciones de comprimidos bucodispersables de aripiprazol 10mg, tras su administración oral en dosis única a voluntarios sanos en ayunas; (versión 1: 03-1212). LABORATORIOS ALTER, S.A. ITHUEC-ARI/12-6. EudraCT: 2012-005274-60 Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Line 2.4 Diagnostic and therapeutic advances in affective disorders GROUP 33 HEAD OF LABORATORY José Luis Ayuso Mateos GROUP MEMBERS • Marta Miret García • Matilde Hernández Álvarez • Celia Anaya Suárez • María del Mar Rivas Rodríguez • María Cabello Salmerón • Eduardo García-Camba de la Muela • Jesús Valle Fernández • Elena Ezquiaga Terrazas • Miguel Ángel Gorriti Irigai • Itziar Leal Leturia • Luis Miguel García Olmos • Herminio Martínez Cano • Pilar López García • Blanca Mellor Marsá • Francisco Félix Caballero Díaz • José David Albillo Labarra Clinicians ’ organization of mental disorders by 2 dimensions: internalizing/externalizing disorders and Functional/Organic disorders. Figure taken from: Roberts MC, Reed GM, Medina-Mora ME, Keeley JW, Sharan P, Johnson DK, Mari Jde J, Ayuso-Mateos JL, Gureje O, Xiao Z, Maruta T, Khoury B, Robles R, Saxena S. A global clinicians' map of mental disorders to improve ICD-11: analysing meta-structure to enhance clinical utility.Int Rev Psychiatry. 2012 Dec;24(6):578-90. • • RESEARCH INTEREST In 2012 our group conducted research in the following key areas: • 1. Study of the risk factors for psychotic disorders: Our team started working in a multi-center study to clarify the role of genes, social environment, and other clinical variables in the onset of psychotic episodes. • 2. Application and assessment of interventions in affective disorders: Clinical researchers of our team were involved in testing the effectiveness of new ther- – 92 – • • apeutic agents in bipolar disorders and treatment resistant depression. 3. Nosology of mental disorders. Members of our team have participated in the working groups for the revision of ICD-10th chapter for mental and behavioral disorders. Currently, our team also leads the implementation of the field studies in Spanish speaking countries. 4. Analysis and prevention of suicidal behaviour, mental disorders and promotion of mental health: Our group leads studies in the analysis of suicidal behaviour in different settings and organizes training workshops addressed to mental health professionals and other non-specialized mental health professionals to prevent suicidal behavior in Madrid. 5. Improvement of mental health services performance in LAMICs countries. Clinicians and researchers are working to identify key health system barriers to, and solutions for, the scaled-up delivery of mental health services in low- and middle-income countries (LAMICs). 6. Analysis of health status and well-being: Our group published in 2012 the validation of a short version of an instrument for measuring subjective well-being in large population samples. In addition; researchers worked in the elaboration a roadmap for mental health and well-being research in Europe. • 7. Evaluation of common psychosocial problems in mental disorders: Our team collected a sample of 80 depressive patients from primary care centers to validate a new generic tool for gathering psychosocial difficulties in day-to-day clinical practice. MAJOR GRANTS • José Luis Ayuso Mateos. Centros de investigación biomédica en Red CIBER de Salud Mental. FIS. Acciones CIBER. CB07TEMP/003. Duration: 2008 2012. • José Luis Ayuso Mateos. Collaborative Research on AGEing in Europe. COURAGE. CE. VII Programa Marco Union Europea. Convocatoria FP7 HEALTH2007- 3.2-6: Health outcome measures and population ageing. FP7 HEALTH-2007-3.2-6. Duration: 2008 - 2012. • José Luis Ayuso Mateos. Centro de Investigación Biomédica en Red de Salud Mental: CIBER-SAM. ISCIII. CIBER CB07/09/0013. Duration: 2008 - 2012. • José Luis Ayuso Mateos. Capacidad de reserva cognitiva en el trastorno bipolar eutímico: impacto en el funcionamiento y en el rendimiento cognitivo. Ministerio de Educación y cultura. concesión de una beca FPU para la realización del proyecto de tesis de Celia Anaya dirigida por Jose Luis Ayuso Mateos. AP2008-00915. Duration: 2009 - 2012. • José Luis Ayuso Mateos. Estudio Colaborativo del Envejecimiento en Europa (COURAGE in Europe). MCINN. Programa de Internacionalización de la I+D. Fomento de la Cooperación Científica Internacional. Modalidad ACI-Promociona. ACI2009-2010. Duration: 2010 - 2012. • José Luis Ayuso Mateos. Psycho-social Aspects Relevant to Brain Disorders in Europe. PARADISE. VII Programa Marco de la Unión Europea. Convocatoria: FP7-HEALTH-2009-single-stage. FP7-HEALTH2009-241572. Duration: 2010 - 2012. • José Luis Ayuso Mateos. Scaling up services for mental, neurological and substance use (MNS) disorders within WHO mental health Gap Action Programme (mhGAP). Unión Europea. Convocatoria: EuropeAid/129197/C/ACT/Multi. 129197/C/ACT/ Multi. Duration: 2010 - 2012. • José Luis Ayuso Mateos. Estado de Salud, Calidad de Vida y Bienestar de la Población Española de Edad Avanzada: un Estudio Epidemiológico. ISCIII. PS09/00295. Duration: 2010 - 2012. • José Luis Ayuso Mateos. Metilfenidato de liberación inmediata en la mejoría sintomática de la Manía aguda: un estudio frente a placebo. Ministerio de Sanidad y Política Social. EC10-110. Duration: 2011 - 2012. • José Luis Ayuso Mateos. Psycho-social Aspects Relevant to Brain Disorders in Europe. PARADISE. Comisión Europea. VII Programa Marco. FP7/20072013-241572. Duration: 2011 - 2012. • José Luis Ayuso Mateos. Use of antidepressants in the last decade and its relation to mortality and suicide-related events, with special focus on children and adolescents. CIBERSAM. Convocatoria Intramural. 11INT1. Duration: 2011 - 2013. • José Luis Ayuso Mateos. Long-term Safety and Tolerability of BMS-820836 in the Treatment of Patients With Treatment Resistant Major Depression. Bristol-Myers Squibb. CN162-010. Duration: 2011 2013. • José Luis Ayuso Mateos. Efficacy and Safety of Fixed Doses of BMS 820836 in the Treatment of Patients With Treatment Resistant Major Depression. BMS. C162-007. Duration: 2011 - 2013. • José Luis Ayuso Mateos. Una hoja de ruta para la investigación en salud mental y bienestar en Europa: ROAMER. MICINN. ACI Promociona. ACI-PRO2011-1080. Duration: 2011 - 2013. • Proyecto Coordinado. Metilfenidato de liberación inmediata en la mejoría sintomática de la Manía aguda: un estudio frente a placebo. CAIBER. 1392-D-079EudraCT 2010-023992-24. Duration: 2011 - 2013. • Proyecto Coordinado. An age-friendly city for successful ageing. Caixa Reserca. Duration: 2011 2013. • José Luis Ayuso Mateos. Metilfenidato de liberación inmediata en la mejoría sintomática de la Manía – 93 – AREA 3AREA 2 AREA 1 AREA 2 Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases aguda: un estudio frente a placebo. CIBERSAM. Convocatoria Intramural. 11INT2. Duration: 2011 2013. • Proyecto Coordinado. A Roadmap for Mental Health Research in Europe (ROAMER). Comisión Europea. VII Programa Marco. Health - F3 - 2011 - 282586. Duration: 2011 - 2014. • José Luis Ayuso Mateos. Ambiente y genes en esquizofrenia-grupos de investigacion de la comunidad de Madrid. CAM. S2010/BMD-2422. Duration: 2011 - 2015. • José Luis Ayuso Mateos. Emerging mental health systems in low- and middle-income countries. EMERALD. VI Programa marco de la UE. FP7305968. Duration: 2012 - 2017. PUBLICATIONS (16) [IF: 56,606] YEAR Total IF Publication No. Q1 Q2 2010 2011 91,793 14 6 7 60,29 12 8 2012 3 56,606 16 9 7 Avila CC, Cieza A, Anaya C, Ayuso-Mateos JL. The patients' perspective on relevant areas and problems in the bipolar spectrum disorder: individual interviews using the international classification of functioning, disability and health as a reference tool. Am J Phys Med Rehabil 91(13):S181-S188. 2012. PMID: 22193328. IF: 1,581. DOI: 10.1097/PHM.0b013e318 23d54db Leonardi M, Ayuso-Mateos JL, Hollenweger J, Pessina A, Bickenbach JE. Multidisciplinary research and training network on health and disability in Europe: the MURINET project. Am J Phys Med Rehabil 91(13):S1S4. 2012. PMID: 22193330. IF: 1,581. DOI: 10.1097/PHM.0b013e31823d699e Veronese A, Ayuso-Mateos JL, Cabello M, Chatterji S, Nuevo R. Work disability and depressive disorders: impact on the European population. Am J Phys Med Rehabil 91(13):S62-S68. 2012. PMID: 22193312. IF: 1,581. DOI: 10.1097/PHM.0b013e31823d4f02 – 94 – Rodríguez MR, Nuevo R, Chatterji S, Ayuso-Mateos JL. Definitions and factors associated with subthreshold depressive conditions: a systematic review. BMC Psychiatry 12:181. 2012. PMID: 23110575. IF: 2,552. DOI: 10.1186/1471-244X-12-181 Almaraz MC, González-Romero S, Bravo M, Caballero FF, Palomo MJ, Vallejo R, Esteva I, Calleja F, Soriguer F. Incidence of lower limb amputations in individuals with and without diabetes mellitus in Andalusia (Spain) from 1998 to 2006. Diabetes Res Clin Pract 95(3):399-405. 2012. PMID: 22133651. IF: 2,754. DOI: 10.1016/j.diabres.2011.10.035 Roberts MC, Reed GM, Medina-Mora ME, Keeley JW, Sharan P, Johnson DK, Mari Jde J, Ayuso-Mateos JL, Gureje O, Xiao Z, Maruta T, Khoury B, Robles R, Saxena S. A global clinicians' map of mental disorders to improve ICD11: analysing meta-structure to enhance clinical utility. Int Rev Psychiatry 24(6):578-590. 2012. PMID: 23244613. IF: 1,798. DOI: 10.3109/09540261.2012.736368 Bonnín CM, Sánchez-Moreno J, Martínez-Arán A, Solé B, Reinares M, Rosa AR, Goikolea JM, Benabarre A, Ayuso-Mateos JL, Ferrer M, Vieta E, Torrent C. Subthreshold symptoms in bipolar disorder: Impact on neurocognition, quality of life and disability. J Affect Disord 136(3):650-9. Epub 2011 Nov 3. 2012. PMID: 22051075. IF: 3,517. DOI: 10.1016/j.jad.2011.10.012 Anaya C, Martinez Aran A, Ayuso-Mateos JL, Wykes T, Vieta E, Scott J. A systematic review of cognitive remediation for schizo-affective and affective disorders. J Affect Disord 142(1-3):13-21. 2012. PMID: 22840620. IF: 3,517. DOI: 10.1016/j.jad.2012.04. 020 Reinares M, Papachristou E, Harvey P, Mar Bonnín C, Sánchez-Moreno J, Torrent C, Ayuso-Mateos JL, Ploubidis GB, Vieta E, Frangou S. Towards a clinical staging for bipolar disorder: Defining patient subtypes based on functional outcome. J Affect Disord 144(12):65-71. 2012. PMID: 22862890. IF: 3,517. DOI: 10.1016/j.jad.2012.06.005 Cabello M, Mellor-Marsá B, Sabariego C, Cieza A, Bickenbach J, Ayuso-Mateos JL. Psychosocial features AREA 2 of depression: A systematic literature review. J Affect Disord. 141(1):22-33. 2012. PMID: 22209189. IF: 3,517. DOI: 10.1016/j.jad.2011.12.009 De Dios C, Ezquiaga E, Agud JL, Vieta E, Soler B, GarcíaLópez A. Subthreshold symptoms and time to relapse/recurrence in a community cohort of bipolar disorder outpatients. J Affect Disord. 143(1-3):160-5. 2012. PMID: 22925351. IF: 3,517. DOI: 10.1016/j.jad.2012. 05.047 Nuevo R, Chatterji S, Verdes E, Naidoo N, Arango C, Ayuso-Mateos JL. The Continuum of Psychotic Symptoms in the General Population: A Crossnational Study. Schizophr Bull. 38(3):475-85. Epub 2010 Sep 13. 2012. PMID: 20841326. IF: 8,8. DOI: 10.1093/schbul/sbq099 AAyuso-Mateos JL. Prototype diagnosis of psychiatric syndromes and the ICD-11. World Psychiatry 11(1):3031. 2012. PMID: 22295005. IF: 6,233 Miret M, Caballero FF, Mathur A, Naidoo N, Kowal P, AyusoMateos JL, Chatterji S. Validation of a measure of subjective well-being: an abbreviated version of the day reconstruction method. PLoS One 7(8):e43887. 2012. PMID: 22952801. IF: 4,092. DOI: 10.1371/journal.pone. 0043887 Ayuso-Mateos JL, Lopez-Garcia P. Severity of depressive disorders: considerations for ICD-11. World Psychiatry 11(Suppl. 1):48-52. 2012. IF: 6,233 De Dios C, Agud JL, Ezquiaga E, García-López A, Soler B, Vieta E. Syndromal and subsyndromal illness status and five-year morbidity using criteria of the International Society for Bipolar Disorders compared to alternative criteria. Psychopathology. 45(2):102-8. 2012. PMID: 22269982. IF: 1,816. DOI: 10.1159/000329740 BOOKS AREA 3AREA 2 AREA 1 Ayuso-Mateos JL, Saiz-Ruiz J, Morant C, Baca-García E, Miret M, Nuevo R. Estudio de la Conducta Suicida en la Comunidad de Madrid. 2012. Comunidad de Madrid. Libro online en http://www.madrid.org. – 95 – Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Line 2.5 Neurosurgery of epilepsy GROUP 34 HEAD OF LABORATORY Rafael García de Sola GROUP MEMBERS • Jesús Pastor Gómez • Guillermo Ortega Rabbione • Luís Domínguez Gadea • Desislava Panova Tzonova • Rybel Wix Ramos • María Luisa Meilán Paz • José Luís Martínez-Chacón Crespo • Eva de Dios Tomás • Eduardo García Navarrete • Paloma Pulido Rivas Localization of coefficient of variation for electrodes 1 [CV(1)] to 5 [CV(5)] and resected tissue in each patient (Pearson correlation coefficient). (A) Cortical grid electrodes: Gray areas represent the approximate lateral cortical tissue resected during surgery. Superimposed, CV minima are displayed according to the key bar (right): CV(1) = 1st, CV(2) = 2nd, CV(3) = 3rd, CV(4) = 4th, and CV(5) = 5th. Patients with postoperative seizures are highlighted in blue. G1 is always at the bottom left and G20 at the top right position. (B) Mesial strip electrodes: Same schematic diagram as in panel (A). RESEARCH INTEREST The groups included in this line are focused on epilepsy, one of the most prevalent and sometimes devastating neurologic diseases in humans. We address the problem from different aspects, ranging from basic mechanisms of epileptogenesis, to new analytical and pharmacological diagnostic tools. There are three different Programs in the group: Temporal lobe epilepsy is commonly associated with synchronous, hyper-synchronous and des-synchronous activity. However, in patients suffering from temporal lobe epilepsy there exist a clear tendency in the mesial area of the epileptic side to be organized as isolated clusters of electrical activity as compared with the contra-lateral side, which is organized in the form of large clusters of synchronous activity. We addressed the synchronization and the stability of highly synchronized areas in a group of patients. Our results show the – 96 – Ca2+ signal in human astrocytes in situ. (A) Pseudocolor images of fluo-4-filled hippocampal and cortical slices, and representative Ca2+ levels showing spontaneous Ca2+ elevations from hippocampal and cortical astrocytes. Scale bar: 60 µm (left), 40 µm (right). (B) Relative number of active astrocytes and oscillation frequency in control and TTX (n=46 and 39 astrocytes for the hippocampus and the cortex, respectively; n ≥ 6 slices for each bar). (C) Fluorescence images of a fluo4-loaded hippocampal slice depicting the experimental arrangement (left), and Ca2+ levels 10 s before and after ATP application. Scale bar 60 µm. (D) Astrocyte Ca2+ responses (at the regions shown in C) to 2 s application of WIN (300 µM), glutamate (0.8 mM), or ATP (20 mM). (E) Astrocyte Ca2+ wave extension and speed in control and TTX (n ≥ 4 slices for each bar). Error bars indicate SEM. *P<0.05. AREA 2 MAJOR GRANTS • Guillermo Ortega Rabbione. Identificación, caracterización y papel de los clusters de sincronización sobre la actividad epileptogénica en pacientes con epilepsia del lóbulo temporal. Fundación Mutua Madrileña. Duration: 2008 - 2012. • Jesús Pastor Gómez. Papel de la albúmina y de la permeabilidad de la barrera hematoencefálica, en la activación de los astrocitos en la epilepsia focal humana. ISCIII. PS09/02116. Duration: 2010 - 2012. • Guillermo Ortega Rabbione. Análisis de registros de EEG-EFO por medio de redes complejas en pacientes con epilepsia del lóbulo temporal y sus aplicaciones clínicas. MICINN. SAF2009-09406. Duration: 2010 - 2013. • Guillermo Ortega Rabbione. Análisis de los registros EEG-EFO por medio de redes complejas en pacientes con epilepsia del lóbulo temporal y sus aplicaciones clínicas. ISCIII. PI10/00160. Duration: 2010 - 2013. PUBLICATIONS (2) [IF: 5,890] YEAR Total IF Publication No. Q1 Q2 2010 13,676 8 1 2 2011 5,824 2 2012 5,89 2 1 1 Palmigiano A, Pastor J, Sola RG, Ortega GJ. Stability of synchronization clusters and seizurability in temporal lobe epilepsy. PLoS One. 7(7):e41799. 2012. PMID: 22844524. IF: 4,092. DOI: 10.1371/journal.pone. 0041799 Navarrete EG, Torres C, Gallego I, Navas M, Pastor J, Sola RG. Long-term results of vagal nerve stimulation for adults with medication-resistant epilepsy, who have been on unchanged antiepileptic medication. Seizure 22(1):9-13. 2012. PMID: 23041031. IF: 1,798. DOI: 10.1016/j.seizure.2012.09.008 BOOKS Pastor J, Sola RG, Ortega GJ. Hyper-synchronization, de-synchronization, synchronization and seizures. Epileptic seizures. 2012. InTech. ISBN: 978-953-307737-6. Pastor J. Estudios neurofisiológicos durante el postoperatorio inmediato. Manual de cuidados postoperatorios de pacientes neuroquirúrgicos. 2012. Ergon SA. ISBN: 97884-1551-40-5. Pascual JM, Carrasco R, Navas M, Pastor J. Cirugía de la fosa posterior: técnica quirúrgica, complicaciones y cuidados perioperatorios. Manual de cuidados postoperatorios de pacientes neuroquirúrgicos. 2012. Ergon SA. ISBN: 978-84-1551-40-5. Págs.: 527-582. de Dios Tomás E, Meilán ML, Hernando Requejo V. Utilidad de la monitorización con BIS en el paciente neurológico/neuroquirúrgico. Manual de cuidados postoperatorios de pacientes neuroquirúrgicos. 2012. Ergon SA. ISBN: 978-84-1551-40-5. – 97 – AREA 3AREA 2 AREA 1 existence of highly localized and stable synchronization areas in both the lateral and the mesial areas of the temporal lobe ipsilateral to the clinical seizures. Synchronization areas seem to play a central role in the capacity of the epileptic network to generate clinical seizures. Resection of stable synchronization areas is associated with elimination of seizures; nonresection of synchronization clusters is associated with the persistence of seizures after surgery (Figure 1). We suggest that synchronization clusters and their stability play a central role in the epileptic network, favoring seizure onset and propagation. We further speculate that the stability distribution of these synchronization areas would differentiate normal from pathologic cases. On the other hand, continuing with the previous work, we have shown that human astrocytes are able to release the gliotransmitter glutamate, which affects neuronal excitability through activation of NMDA receptors in neurons. These results reveal the existence of reciprocal signaling between neurons and astrocytes in human brain tissue, indicating that astrocytes are relevant in human neurophysiology and are involved in human brain function (Figure 2). Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Pulido P. Monitorización de la PIC. Técnicas, dispositivos, indicaciones. Manual de cuidados postoperatorios de pacientes neuroquirúrgicos. 2012. Ergon SA. ISBN: 97884-1551-40-5. – 98 – Torres CV, García de Sola R. Consideraciones quirúrgicas en el postoperatorio en la cirugía estereotáxica y de estimulación profunda. Manual de cuidados postoperatorios de pacientes neuroquirúrgicos. 2012. Ergon SA. ISBN: 978-84-1551-40-5. AREA 2 GROUP 35 HEAD OF LABORATORY José Aurelio Vivancos Mora GROUP MEMBERS • Florentino Nombela Merchán • Mónica Sobrado Sanz • Gemma Reig Roselló • Lydia López Manzanares • Virginia Meca Lallana • Teresa Carreras Rodríguez • Álvaro Ximenez-Carrillo Rico • Noemí Mora Pérez GROUP ASSOCIATED 1 HEAD OF LABORATORY Ignacio Lizasoain Hernández GROUP MEMBERS • María Ángeles Moro Sánchez • Olivia Hurtado Moreno • Macarena Hernández Jiménez • Ana Moraga Yébenes • ván Ballesteros Martín • Isaac García de Yébenes y Castro • María Isabel Cuartero Desviat • Víctor Manuel González Romera • Tamara Atanes Pérez • Roberto Cañadas Martín RESEARCH INTEREST (G.35 & G.ASSOC 1) The Neurological Service And Stroke Unit Of Hospital Universitario De La Princesa is a medical service of the Spanish public health system specialized in neurological diseases. It is public provider of neurological medical care for the entire health district #2 (metropolitan population of Madrid, 320.744 people). For the rest of the population of health district #2: Hospital de Henares (164.810 people) and throughout health district #3 (Hospital Universitario Principe de Asturias 380.757 people), we are the reference Center for specific processes and special procedures such as stroke center and stroke unit, Madrid region stroke code system, thrombolysis and emerging therapies and interventional neuroradiology unit. We are doing 17.000 outpatient visits and more than 700 admissions per year. The Neurology Service of Hospital Universitario de la Princesa has a neurology teaching program certified for pre and post-degree, assigned to Universidad Autonoma de Madrid and an accredited clinical research tradition for nearly 50 years. The main research lines of The Neurology Service of Hospital Universitario de la Princesa are: • Stroke and Cerebrovascular Diseases, - Biomolecular markers of ischemia and new therapeutic targets - Interventional neuroradiology and emerging therapies - Population-based health services delivery / stroke code system - Telemedicine • Epilepsy - Drug-refractory Epilepsy • Movement Disorders - Parkinson disease in young patients - Parkinson disease. Follow up and control helped by new technologies • Cognitive impairment and dementia - Mild Cognitive impairment and dementia in very old patients - Cognitive impairment and dementia in Down syndrome • Multiple Sclerosis. - Outcome markers and new therapies – 99 – AREA 3AREA 2 AREA 1 Line 2.6 Cerebrovascular diseases Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Neuronal excitotoxicity after carotid angioplasty and stent placement procedures. Graph shows glutamate plasma levels in patients subjected to Carotid Angioplasty and Stenting (CAS) and control groups (cerebral angiography without carotid stenosis and coronary angioplasty stenting). Increased Glu levels in plasma decreased into the baseline range at 24 hours, unrelated to stroke, and remained stable up to 72 hours after CAS. Glutamate concentrations remained unchanged over time in both control groups. Nombela et al., Radiology, 2013. The results obtained by our group during 2012 include: 6 papers published in international journals belonging to the Neurosciences field and directly related to stroke (J. Vasc. Int. Rad., Stroke Res. Treat., Radiology, Cerebrovasc. Dis., Eur. J. Neurol.); 1 guideline in Stroke; 2 book chapters (Neurology; Cerebrovascular diseases); 3 epidemiological studies in stroke. Extension of a competitive project (clinical trial and translational study in Stroke) and about 10 ongoing clinical trials (in Stroke, Multiple Sclerosis and Alzheimer´s and Parkinson´s disease -private companies). The Neurovascular Research Unit (UIN), located at the Department of Pharmacology of the School of Medicine at the Universidad Complutense is an associated group of the “Instituto de Investigacion Sanitaria La Princesa (IIS IP)”. It was formed in 1996 and since then our team has been studying the pathophysiology and pharmacology of stroke. Our unit is devoted to the study of the cerebrovascular disease (stroke) from a basic point of view but also with a strong translational projection, a vocation due to our location in a School of – 100 – Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Effects of JWH-133 on microglial activation after pMCAO. A, Representative images of Iba1+ cells in the contralateral healthy and the ipsilateral peri-infarct hemispheres I untreated or JWH-133-treated animals. B, Densitometry of peri-infarct microglia in pMCAO mice treated either with vehicle or JWH-133. Sq dashed lines show the ROIs (Regions of interest) where the images were taken. N=4 in each group. Data were expressed as mean±SD, *P<0.05 vs MCAO contralesional+vehicle, #P<0.05 vs MCAO+vehicle. ANOVA and Bonferroni post hoc test. Zarruk et al., Stroke 2012. Medicine and developed through a tight partnership with IIS IP. The results obtained by our group during 2012, include more than 10 papers published in international journals belonging to the Neurosciences field and directly related to cerebral ischemia (Stroke, J Neuroinflammation, Biochim Biophys Acta, etc…) and 1 PhD Thesis. AREA 2 • José Aurelio Vivancos Mora. Estudio doble ciego aleatorizado, controlado con placebo de dosis escaladas de deferoxamina intravenosa en pacientes con ictus isquémico agudo tratados con activador tisular de plasminógeno. MEC. ISCIII. FIS. EC 07/90793. Duration: 2008 - 2012. • José Aurelio Vivancos Mora. Open, randomized and controlled study of safety and viability, to evaluate the neuroprotective effect of plasma glutamate dialysis in acute ischemic stroke. MSPSI. EC11-109 (SAS/2885/2011). Duration: 2012 - 2013. • José Aurelio Vivancos Mora. Imagen molecular multimodal de la inflamación. S2010/BMD-23494. Duration: 2012 - 2015. MAJOR GRANTS GR.AS.1 • María Ángeles Moro Sánchez. Papel de los Receptores Nucleares PPARgamma y LXR en la isquemia cerebral: De la inflamación a la neurorreparación. MICINN. SAF2009-08145 (Subprograma NEF). Duration: 2010 - 2012. • María Ángeles Moro Sánchez. Estudio del efecto neuroprotector de compuestos de origen marino en los daños causados por la isquemia cerebral. MICINN. Consorcio DENDRIA. Subproyecto 10/DEN005. Duration: 2010 - 2013. • Ignacio Lizasoain Hernández. Doble función de los receptores "Toll-like" en el ictus: reguladores de daño y reparación. MICINN. SAF2011-23354. Duration: 2011 - 2014. • María Ángeles Moro Sánchez. Brain dysfunction during aging: relevance for Alzheimer’s disease. MICINN. CSD2010-00045. Duration: 2011 - 2015. • María Ángeles Moro Sánchez. Grupo de Investigación 962088. Unidad de Investigación Neurovascular (UIN). Santander-Universidad Complutense. Convocatoria GR42/10. Duration: 2012 - 2012. • María Ángeles Moro Sánchez. Estudio de la biología de células madre neurales para su empleo en terapia celular en enfermedades neurodegenerativas (NEUROSTEM-CM). Comunidad de Madrid. S2010/BMD-2336, Programas de Actividades de I+D entre Grupos de Investigación en Biomedicina de la Comunidad de Madrid. Duration: 2012 2015. • Olivia Hurtado Moreno. Estudio de la sirtuina1 como diana terapéutica en la neuroprotección y en la neurorreparación tras isquemia cerebral. MEC. SAF201237008. Duration: 2012 - 2013. PUBLICATIONS GR.35 (8) [IF GR35: 5,890] YEAR Total IF Publication No. Q1 Q2 2010 6,974 2 1 2011 23,427 5 4 1 2012 26,977 8 3 4 Matute MC, Masjuan J, Egido JA, Fuentes B, Simal P, Díaz-Otero F, Reig G, Díez-Tejedor E, Gil-Nuñez A, Vivancos J, Alonso de Leciñana M. Safety and outcomes following thrombolytic treatment in stroke patients who had received prior treatment with anticoagulants. Cerebrovasc Dis. 33(3):231-239. 2012. PMID: 22261670. IF: 2,723. DOI: 10.1159/000334662 Fuentes B, Martínez-Sánchez P, Alonso de Leciñana M, Simal P, Reig G, Díaz-Otero F, Masjuán J, Egido J, Vivancos J, Gil-Nuñez A, Díez-Tejedor E, Madrid Stroke Network. Diabetes and previous stroke: hazards for intravenous thrombolysis?. Eur J Neurol 19(4):587593. 2012. PMID: 22050315. IF: 3,692. DOI: 10.1111/j.1468-1331.2011.03576.x Fuentes B, Martínez-Sánchez P, de Leciñana MA, Egido J, Reig-Roselló G, Díaz-Otero F, Sánchez V, Simal P, Ximenez-Carrillo A, García-Pastor A, Ruiz-Ares G, García-García A, Masjuan J, Vivancos-Mora J, GilNuñez A, Díez-Tejedor E. Efficacy of intravenous thrombolysis according to stroke subtypes: the Madrid Stroke Network Data. Eur J Neurol. 19(12):1568-1574. 2012. PMID: 22742869. IF: 3,692. DOI: 10.1111/j.1468-1331.2012.03790.x de Leciñana MA, Fuentes B, Masjuan J, Simal P, DíazOtero F, Reig G, Díez-Tejedor E, Gil-Nuñez A, Vivancos J, Egido JA. Thrombolytic therapy for acute ischemic stroke after recent transient ischemic attack. Int J – 101 – AREA 3AREA 2 AREA 1 MAJOR GRANTS GR.35 Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases Stroke. 7(3):213-8. Epub 2011 Nov 9. 2012. PMID: 22098785. IF: 2,382. DOI: 10.1111/j.17474949.2011.00690.x Sobrado M, Ramirez BG, Neria F, Lizasoain I, Arbonés ML, Minami T, Redondo JM, Moro MA, Cano E. Regulator of Calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury. J Neuroinflammation 9:48. 2012. PMID: 22397398. IF: 3,827. DOI: 10.1186/1742-2094-9-48 Cristobo I, Brea D, Blanco M, Vázquez F, RodríguezYáñez M, Vivancos J, Silva Y, de la Ossa NP, Pumar JM, Forteza J, Castillo J. Usefulness of material recovered from distal embolic protection devices after carotid angioplasty for proteomic studies. J Vasc Interv Radiol. 23(6):818-824. 2012. PMID: 22626270. IF: 2,075. DOI: 10.1016/j.jvir.2012.02.004 García-Yébenes I, Sobrado M, Moraga A, Zarruk JG, Romera VG, Pradillo JM, Perez de la Ossa N, Moro MA, Dávalos A, Lizasoain I. Iron overload, measured as serum ferritin, increases brain damage induced by focal ischemia and early reperfusion. Neurochem Int 61(8):1364-9. 2012. PMID: 23036361. IF: 2,857. DOI: 10.1016/j.neuint.2012.09.014 Zarruk JG, Fernández-López D, García-Yébenes I, García-Gutiérrez MS, Vivancos J, Nombela F, Torres M, Burguete MC, Manzanares J, Lizasoain I, Moro MA. Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 43(1):211-219. 2012. PMID: 22020035. IF: 5,729. DOI: 10.1161/STROKEAHA.111.631044 PUBLICATIONS GR.AS.1 (9) [IF GRAS1: 37,137] YEAR Total IF Publication No. Q1 Q2 2010 17,911 4 3 1 2011 33,486 5 5 2012 37,137 9 4 4 Hernández-Jiménez M, Ayuso MI, Pérez-Morgado MI, García-Recio EM, Alcázar A, Martín ME, González VM. – 102 – eIF4F complex disruption causes protein synthesis inhibition during hypoxia in nerve growth factor (NGF)-differentiated PC12 cells. Biochim Biophys Acta 1823(2):4308. 2012. PMID: 22178387. IF: 5,538. DOI: 10.1016/j.bbamcr.2011.11.008 Redondo M, Zarruk JG, Ceballos P, Pérez DI, Pérez C, Perez-Castillo A, Moro MA, Brea J, Val C, Cadavid MI, Loza MI, Campillo NE, Martínez A, Gil C. Neuroprotective efficacy of quinazoline type phosphodiesterase 7 inhibitors in cellular cultures and experimental stroke model. Eur J Med Chem 47(1): 175-185. 2012. PMID: 22100138. IF: 3,346. DOI: 10.1016/j.ejmech.2011.10.040 Lopez-Jimenez ME, González JC, Lizasoain I, SánchezPrieto J, Hernández-Guijo JM, Torres M. Functional cGMP-gated channels in cerebellar granule cells. J Cell Physiol. 227(5):2252-63. 2012. PMID: 21809342. IF: 3,874. DOI: 10.1002/jcp.22964 Sobrado M, Ramirez BG, Neria F, Lizasoain I, Arbonés ML, Minami T, Redondo JM, Moro MA, Cano E. Regulator of Calcineurin 1 (Rcan1) has a protective role in brain ischemia/reperfusion injury. J Neuroinflammation 9:48. 2012. PMID: 22397398. IF: 3,827. DOI: 10.1186/1742-2094-9-48 Hurtado O, Ballesteros I, Cuartero MI, Moraga A, Pradillo JM, Ramírez-Franco J, Bartolomé-Martín D, Pascual D, Torres M, Sánchez-Prieto J, Salom JB, Lizasoain I, Moro MA. Daidzein has neuroprotective effects through ligand-binding-independent PPAR activation. Neurochem Int 61(1):119-127. 2012. PMID: 22521773. IF: 2,857. DOI: 10.1016/j.neuint.2012. 04.007 García-Yébenes I, Sobrado M, Moraga A, Zarruk JG, Romera VG, Pradillo JM, Perez de la Ossa N, Moro MA, Dávalos A, Lizasoain I. Iron overload, measured as serum ferritin, increases brain damage induced by focal ischemia and early reperfusion. Neurochem Int 61(8):1364-9. 2012. PMID: 23036361. IF: 2,857. DOI: 10.1016/j.neuint.2012.09.014 Fernández-López D, Faustino J, Derugin N, Wendland M, Lizasoain I, Moro MA Vexler ZS. Reduced infarct size AREA 2 Zarruk JG, Fernández-López D, García-Yébenes I, García-Gutiérrez MS, Vivancos J, Nombela F, Torres M, Burguete MC, Manzanares J, Lizasoain I, Moro MA. Cannabinoid type 2 receptor activation downregulates stroke-induced classic and alternative brain macrophage/microglial activation concomitant to neuroprotection. Stroke 43(1):211-219. 2012. PMID: 22020035. IF: 5,729. DOI: 10.1161/STROKEAHA.111.631044 ElAli A, Urrutia A, Rubio-Araiz A, HernandezJimenez M, Colado MI, Doeppner TR, Hermann DM. Apolipoprotein-E Controls Adenosine Triphosphate-Binding Cassette Transporters ABCB1 and ABCC1 on Cerebral Microvessels After Methamphetamine Intoxication. Stroke 43(6):16471653. 2012. PMID: 22426312. IF: 5,729. DOI: 10.1161/STROKEAHA.111.648923 BOOKS GR.35 G. Reig Roselló, L. López Manzanares, F. Nombela Merchán y J. Vivancos Mora. Enfermedades venosas. Tratado de Neurología. 2012. Luzan 5 SA. ISBN: 978-84-7989-698-0. F. Nombela Merchán, J. Vivancos Mora. Mecanismos de producción. Factores de riesgo. Etiologías. Fisiopatología. Enfermedades vasculares cerebrales. 2012. Mayo. ISBN: 978-84-9905156-7. BOOKS GR.AS.1 Lorenzo P, Moreno A, Leza JC, Lizasoain I, Moro MA, Portolés A. (Eds.). Velázquez. Manual de Farmacología Básica y Clínica. 2012. Panamericana. ISBN: 978-849835-437-9. CLINICAL TRIALS GR.35 PRINCIPAL INVESTIGATOR: MECA LALLANA, VIRGINIA Registro REDEM: Registro de pacientes con esclerosis múltiple (EM) tratados con natalizumab en España; (Versión 1:28-10-11). ACADEM. ACA-NAT-2011-02 PRINCIPAL INVESTIGATOR: MECA LALLANA, VIRGINIA Registro español de pacientes tratados con Gilenya (Fingolimod); (Versión enmienda 1: 20-02-12). ACADEM. ACA-FIN-2011-01 PRINCIPAL INVESTIGATOR: VIVANCOS MORA, AURELIO Efecto del tratamiento con F2695 (75mg una vez al día) durante 3 meses en la mejoría de la recuperación funcional de pacientes con accidente cerebrovascular isquémico. Estudio multicéntrico, aleatorizado, doble ciego, en grupos paralelos y controlado con placebo. Estudio LIFE; (Versión 2: 16-05-12). PIERRE FABRE MEDICAMENT. F02695 LP 2 05. EudraCT: 2012-001592-37 PRINCIPAL INVESTIGATOR: CARRERAS RODRIGUEZ, MARIA-TERESA Eficacia y seguridad de 3 dosis de S38093 (2,5y 20 mg/día) frente a placebo asociado a donepezilo (10mg/día) en pacientes con Enfermedad de Alzheimer moderada. Estudio de fase IIb, internacional, multicéntrico, aleatorizado, doble ciego, controlado frente a placebo, de 24 semanas de duración (Versión final:27-03-12). LABORATORIOS SERVIER, S.L. CL2-38093-012. EudraCT: 2011-005862-40 PRINCIPAL INVESTIGATOR: CARRERAS RODRIGUEZ, MARIA-TERESA Estudio multicéntrico, aleatorizado y controlado para evaluar la eficacia y seguridad de intercambio de plasmático a corto plazo seguido de plasmaféresis con infusión de albúmina humana combinada con inmunoglobulina intravenosa en pacientes con Enfermedad de Alzheimer de leve-moderada; (Versión 1.6: 01-04-12). INSTITUTO GRIFOLS S.A. IG1002. EudraCT: 2011-001598-25 PRINCIPAL INVESTIGATOR: MECA LALLANA, VIRGINIA Efectividad a largo plazo de Copaxone« en la práctica clíni- – 103 – AREA 3AREA 2 AREA 1 and accumulation of microglia/macrophages in rats treated with WIN55,212-2 after neonatal stroke. Neuroscience 207:307-315. 2012. PMID: 22285309. IF: 3,38. DOI: 10.1016/j.neuroscience.2012.01.008 Neurotransmission, pharmacological neuroprotection and neurodegenerative and neuropsychiatric diseases ca habitual. Estudio observacional (Xperiencia-5); (Versión final:21-03-12). TEVA PHARMA S.L.U. TEV_ACE_2012_01 PRINCIPAL INVESTIGATOR: MECA LALLANA, VIRGINIA MITRA: Estudio observacional retrospectivo y transversal de adherencia al tratamiento con interferón beta 1a subcutáneo en pacientes con esclerosis múltiple en brotes mediante el dispositivo electrónico RebiSmart« y el software MITRA; (versión 1.0: 06-07-12). MERCK S.L. MER-INT2012-01 PRINCIPAL INVESTIGATOR: CARRERAS RODRIGUEZ, MARIA-TERESA Estudio de los biomarcadores en LCR para el diagnóstico de EA prodrómica en pacientes con deterioro cognitivo ligero. Estudio PREDEM; (versión final: 21-12-11). NOVARTIS FARMACEUTICA, S.A. NOV-SNC-2011-01 PRINCIPAL INVESTIGATOR: CARRERAS RODRIGUEZ, MARIA-TERESA Estudio de fase IIa para evaluar el efecto del rilapladib (SB 659032) sobre los biomarcadores relacionados con la patogenia y progresión de la Enfermedad de Alzheimer; (Versión 00:11-03-11). GLAXOSMITHKLINE, S.A. LPZ114458. EudraCT: 2010-020993-41 – 104 – PRINCIPAL INVESTIGATOR: VIVANCOS MORA, AURELIO Estudio de viabilidad y seguridad, abierto, aleatorizado y controlado, para evaluar el efecto neuroprotector de la diálisis de glutamato plasmático en la fase aguda del infarto cerebral; (versión 1: 14-02-12). FUNDACION INVESTIGACION BIOMEDICA H. LA PRINCESA. JVM-GLU-12. EudraCT: 2012-000791-42 PRINCIPAL INVESTIGATOR: MECA LALLANA, VIRGINIA Estudio observacional, transversal, multicéntrico, nacional para evaluar el cumplimiento terapéutico y la satisfacción de los pacientes con esclerosis múltiple remitente-recurrente en tratamiento con fingolimod. Estudio Compliance in MS II;(versión final: 08-06-12, enmienda 1:02-08-12). NOVARTIS FARMACEUTICA, S.A. NOV-FIN-2012-002 PRINCIPAL INVESTIGATOR: MECA LALLANA, VIRGINIA Estudio observacional prospectivo para evaluar la influencia del resultado del test de anticuerpos antivirus JC sobre la percepción del riesgo en el tratamiento con natalizumab (Tysabri«) en pacientes con esclerosis múltiple y sus neurólogos; (versión final: 27-04-12). BIOGEN IDEC IBERIA. BIO-NAT2012-01/PERCEPT AREA 3 ADVANCED THERAPIES AND INDIVIDUALIZED MEDICINE Line 3.1 Prognostic and predictor markers in autoimmune diseases. Line 3.2 Esophagogastrointestinal inflammatory diseases. Line 3.3 Progenitors and cell therapy. Line 3.4 Advanced therapies in oncohematology. Line 3.5 Biological, cellular and molecular monitoring in oncohematology. Line 3.6 New diagnostic and therapeutic advances in cardiovascular diseases. Line 3.7 New therapies in infectious pathologies. Line 3.8 Individualized medicine in solid tumors. – 105 – AREA 3 ADVANCED THERAPIES AND INDIVIDUALIZED MEDICINE – 106 – AREA 3 ADVANCED THERAPIES AND INDIVIDUALIZED MEDICINE Line 3.1 Prognostic and predictor markers in autoimmune diseases GROUP 36 been granted by ISCIII for the next four years. Our research is mainly focused on the detection of prognostic and cardiovascular risk factor in rheumatoid arthritis, as well as the study of security aspects in biological therapies. However, many other rheumatologic diseases such as scleroderma, systemic lupus erythematosus, systemic vasculitis, osteoporosis, osteoarthritis, etc. are objectives of the research work conducted by our HEAD OF LABORATORY Isidoro González Álvaro AREA 3AREA 2 AREA 1 GROUP MEMBERS • Rosario García de Vicuña Pinedo • Ana María Ortiz García • Jesús Alberto García Vadillo • Santos Castañeda Sanz • José María Álvaro-Gracia Álvaro • Carlos Gamallo Amat • Eva Gloria Tomero Muriel • Esther Patiño Ruiz • Amalia Lamana Domínguez • Esther Francisca Vicente Rabaneda • Isabel Castrejón Fernández • Teresa Velasco Ripoll • María de las Nieves Gómez León • Belén Díaz Sánchez RESEARCH INTEREST During year 2012, once more our main source of publications comes from the intense collaborative effort with groups of the Network of Inflammation and Rheumatic Diseases (RIER) that belongs to the RETICS program from the Instituto de Salud Carlos III (ISCIII). Interestingly, this year RIER has Lamana A, Balsa A, Rueda B, Ortiz AM, Nuno L, Miranda-Carus ME, Gonzalez-Escribano MF, Lopez-Nevot MA, Pascual-Salcedo D, Martin J et al: The TT Genotype of the STAT4 rs7574865 Polymorphism Is Associated with High Disease Activity and Disability in Patients with Early Arthritis. PLoS One 2012, 7(8):e43661. – 107 – Advanced therapies and individualized medicine Luis Fernandez Sueiro who died suddenly in November 2012 during the ACR Meeting. MAJOR GRANTS Lamana A, Balsa A, Rueda B, Ortiz AM, Nuno L, Miranda-Carus ME, Gonzalez-Escribano MF, Lopez-Nevot MA, Pascual-Salcedo D, Martin J et al: The TT Genotype of the STAT4 rs7574865 Polymorphism Is Associated with High Disease Activity and Disability in Patients with Early Arthritis. PLoS One 2012, 7(8):e43661. researchers. Once again, as a result of this intense activity of the group, some of its members have been requested to participate in the drafting of several documents to establish consensus guidelines for the rational use of biological therapies or imaging techniques in which the establishment of proper cost / benefit ratio is of great importance in the current economic situation. For second consecutive year, a research project of one of our investigators (Dr Santos Castañeda Sanz) has been granted in the last call for Health Research Grants from the ISCIII three projects. This means that currently our group has four active research proyect in the FIS program of ISCIII. We would like to acknowledge the generous collaboration of our patients in our research projects. Their willingness to participate in our studies support the notion that they support our efforts to discover new biomarkers allowing us to treat them more efficiently. The figures accompanying this summary represent two good examples of this kind of research. The figure related to biomarkers in psoriasis is in memoriam of our collegue from A Coruña Dr Jose – 108 – • Isidoro González Álvaro. Red de Investigación en Inflamación y Enfermedades Reumáticas. ISCIII. RD08/0075/0004. Duration: 2009 - 2012. • Santos Castañeda Sanz. Valor predictivo de la pérdida mineral ósea cortical determinada mediante radiogrametría como marcador pronóstico en pacientes con artritis de inicio. PFIZER España. Duration: 2011 - 2012. • Santos Castañeda Sanz. Valor predictivo de la radiogrametría de manos como factor pronóstico en una cohorte de artritis de inicio. Financiado por Pfizer a través de la FIB del HUP. Duration: 2011 2012. • Isabel Castrejón Fernández. Relative efficiencies of 7 RA core data set measures and 3 indices to distinguish between tight control in the GUEPARD cohort (DAS28-ESR-driven therapy with anti-TNF agents) versus routine care in the ESPOIR cohort. NYUHospital for Joint Diseases and Hospital Cochin, Paris. Duration: 2011 - 2012. • Isabel Castrejón Fernández. Evaluation of the proposed ACR/EULAR criteria and traditional DAS28, CDAI and RAPID3 definitions of remission in Rheumatoid Arthritis in routine clinical care. Internal support (NYU-Hospital for Joint Dise ases). Duration: 2011 - 2012. • Isabel Castrejón Fernández. Development of an online “toolbox” including indices and measures in rheumatology with special emphasis on Patient Reported Outcomes (PRO). EULAR. Duration: 2011 - 2013. • Isidoro González Álvaro. Factores genéticos asociados a niveles elevados de interleuquina 15 en sangre de pacientes con artritis reumatoide. Papel modulador de CD69 en la gravedad de esta enfermedad. PI11/00551. Duration: 2012 - 2014. • Rosario García de Vicuña Pinedo. Proyecto VALORA: “Estudio de la Variablidad en el Hospital de Día en Reumatología”. Sociedad Española Reumatología - Roche. Duration: 2012 - 2013. AREA 3 • Ana María Ortiz García. Factores genéticos asociados a niveles elevados de IL15 en sangre de pacientes con artritis reumatoide. Estudio preliminar para el desarrollo de un kit marcador de mal pronóstico. Financiado por UCB a través de la FIB del HUP. Duration: 2012 - 2014. • Ana María Ortiz García. Estudio de los niveles de VIP y sus receptores en pacientes con artritis de reciente comienzo. Determinación de su potencial como biomarcador pronóstico. ISCIII. PI11/00505. Duration: 2012 - 2014. PUBLICATIONS (31) [IF: 138,584] Total IF Publication No. Q1 2010 2011 116,956 29 14 8 151,416 36 15 14 2012 138,584 31 15 8 Bykerk VP, Ostör AJ, Alvaro-Gracia J, Pavelka K, Ivorra JA, Graninger W, Bensen W, Nurmohamed MT, Krause A, Bernasconi C, Stancati A, Sibilia J. Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice. Ann Rheum Dis. 71(12):1950-4. 2012. PMID: 22615456. IF: 8,727. DOI: 10.1136/annrheumdis-2011-201087 Q2 Ruiz-Tovar J, Gamallo C. Duodenitis associated with non-steroidal anti-inflammatory drug use causing mesenteric panniculitis. Am Surg. 78(3):E137-8. 2012. PMID: 22524738. IF: 1,285 Pincus T, Castrejon I, Yazici Y. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis. Ann Intern Med. 157(4):299. 2012. PMID: 22910946. IF: 16,733. DOI: 10.7326/0003-4819-157-4-201208210-00018 Gómez-Reino JJ, Rodríguez-Lozano C, CamposFernández C, Montoro M, Descalzo MÁ, Carmona L; BIOBADASER 2.0 Study Group (..,Tomero E, Ortiz AM,..). Change in the discontinuation pattern of tumor necrosis factor antagonist in rheumatoide arthritis over 10 years: data from the Spanish registry BIOBADASER 2.0. Ann Rheum Dis 71(3):382-5. Epub 2011 Oct 13. 2012. PMID: 21998116. IF: 8,727. DOI: 10.1136/annrheumdis-2011-200302 Carmona FD, Gutala R, Simeón CP, Carreira P, OrtegoCenteno N, Vicente-Rabaneda E, García-Hernández FJ, García de la Peña P, Fernández-Castro M, Díaz-Gallo LM, Garcia S, Ortego-Centeno N, JiménezAlonso J, Sánchez-Román J, de Ramón E, GonzálezEscribano MF, Balsa A, Fernández-Gutierrez B, González-Alvaro I, González-Gay MA, Martin J. Association study of BAK1 gene polymorphisms in Spanish rheumatoid arthritis and systemic lupus erythematosus cohorts. Ann Rheum Dis. 71(2):314-6. Epub 2011 Aug 17. 2012. PMID: 21852253. IF: 8,727. DOI: 10.1136/annrheumdis-2011-200062 Descalzo MÁ, Carbonell J, González-Alvaro I Sanmartí R, Balsa A, Hernandez-Barrera V, Román-Ivorra JA, IvorraCortés J, Lisbona P, Alperi M, Jiménez-Garcia R, Carmona L; SERAP (.., Ortiz AM, Garcia-Vicuña R,..) and PROAR Study Groups (.., Garcia-Vicuña R,..). Effectiveness of a clinical practice intervention in early rheumatoid arthritis. Arthritis Care Res (Hoboken). 64(3):321-30. 2012. PMID: 22052599. IF: 4,851. DOI: 10.1002/acr.20682 Castrejon I, McCollum L, Tanriover MD, Pincus T. Importance of patient history and physical examination in rheumatoid arthritis compared to other chronic diseases: Results of a physician survey. Arthritis Care Res (Hoboken). 64(8):1250-1255. 2012. PMID: 22371298. IF: 4,851. DOI: 10.1002/acr.21650 Celis R, Planell N, Fernández-Sueiro JL, Sanmartí R, Ramírez J, González-Alvaro I, Pablos JL, Cañete JD. – 109 – AREA 3AREA 2 AREA 1 YEAR Martínez-Estupiñán L, Egurbide MV, Tsao BP, Gourh P, Agarwal SK, Assassi S, Mayes MD, Arnett FC, Tan FK, Martín J; Spanish Scleroderma Group. Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemi c sclerosis. Ann Rheum Dis. 71(1):114-9. 2012. PMID: 21926187. IF: 8,727. DOI: 10.1136/annrheumdis-2011-200275 Advanced therapies and individualized medicine Synovial cytokine expression in psoriatic arthritis and associations with lymphoid neogenesis and clinical features. Arthritis Res Ther. 14(2):R93. 2012. PMID: 22541888. IF: 4,445. DOI: 10.1186/ar3817 López-Mejías R, García-Bermúdez M, GonzálezJuanatey C, Castañeda S, Miranda-Filloy JA, GómezVaquero C, Fernández-Gutiérrez B, Balsa A, PascualSalcedo D, Blanco R, González-Álvaro I, Llorca J, Martín J, González-Gay MA. NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis. 224(2):426-9. 2012. PMID: 22742859. IF: 3,794. DOI: 10.1016/j.atherosclerosis.2012.06.008 Castañeda S, Roman-Blas JA, Largo R, HerreroBeaumont G. Subchondral bone as a key target for osteoarthritis treatment. Biochem Pharmacol. 83(3):315-23. Epub 2011 Sep 22. 2012. PMID: 21964345. IF: 4,705. DOI: 10.1016/j.bcp.2011.09.018 Sanchez-Cuellar S, de la Fuente H, Cruz-Adalia A, Lamana A, Cibrian D, Giron RM, Vara A, SanchezMadrid F, Ancochea J. Reduced expression of galectin1 and galectin-9 by leucocytes in asthma patients. Clin Exp Immunol. 170(3):365-374. 2012. PMID: 23121677. IF: 3,36. DOI: 10.1111/j.13652249.2012.04665.x Garcia-Bermudez M, González-Juanatey C, LopezMejias R, Rodriguez-Rodriguez L, Pérez-Esteban S, Castañeda S, Urcelay E, Miranda-Filloy JA, GómezVaquero C, Fernández-Gutierrez B, Balsa A, GonzálezAlvaro I, Blanco R, Llorca J, Martín J, Gonzalez-Gay MA. Influence of MHCIITA rs3087456 and rs4774 polymorphisms in the susceptibility to cardiovascular disease of patients with rheumatoid arthritis. Clin Exp Rheumatol. 30(1):51-7. 2012. PMID: 22272574. IF: 2,148 Pincus T, Castrejón I, Bergman MJ, Yazici Y. Treat-totarget: not as simple as it appears. Clin Exp Rheumatol. 30(4 Suppl 73):S10-20. 2012. PMID: 23072741. IF: 2,148 Castrejón I, Pincus T. Patient self-report outcomes to guide a treat-to-target strategy in clinical trials and – 110 – usual clinical care of rheumatoid arthritis. Clin Exp Rheumatol. 30(4 Suppl 73):S50-55. 2012. PMID: 23079199. IF: 2,148 García-Bermúdez M, López-Mejías R, GonzálezJuanatey C, Castañeda S, Miranda-Filloy JA, Blanco R, Fernández-Gutiérrez B, Balsa A, González-Alvaro I, Gómez-Vaquero C, Llorca J, Martín J, González-Gay MA. Lack of association between TLR4 rs4986790 polymorphism and risk of cardiovascular disease in patients with rheumatoid arthritis. DNA Cell Biol. 31(7):1214-20. 2012. PMID: 22360682. IF: 2,072. DOI: 10.1089/dna.2011.1582 García-Bermúdez M, López-Mejías R, GonzálezJuanatey C, Corrales A, Castañeda S, Miranda-Filloy JA, Gómez-Vaquero C, Fernández-Gutiérrez B, Balsa A, Pascual-Salcedo D, Blanco R, González-Álvaro I, Llorca J, Martín J, González-Gay MA. Association Study of MIA3 rs17465637 Polymorphism with Cardiovascular Disease in Rheumatoid Arthritis Patients. DNA Cell Biol. 31(8):1412-7. 2012. PMID: 22577832. IF: 2,072. DOI: 10.1089/dna.2012.1672 Martin JE, Carmona FD, Broen JC, Simeón CP, Vonk MC, Carreira P, Ríos-Fernández R, Espinosa G, Vicente-Rabaneda E, Tolosa C, García-Hernández FJ, Castellví I, Fonollosa V, González-Gay MA, SáezComet L, Portales RG, de la Peña PG, FernándezCastro M, Díaz B, Martínez-Estupiñán L, Coenen M, Voskuyl AE, Schuerwegh AJ, Vanthuyne M, Houssiau F, Smith V, de Keyser F, De Langhe E, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Palm Ø, Chee MM, van Laar JM, Denton C, Herrick A, Worthington J, Koeleman BP, Radstake TR, Fonseca C, Martín J; Spanish Scleroderma Group. The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis. Genes Immun. 13(2):191-6. 2012. PMID: 22012429. IF: 3,872. DOI: 10.1038/gene.2011.72 López-Mejías R, García-Bermúdez M, GonzálezJuanatey C, Castañeda S, Miranda-Filloy JA, GómezVaquero C, Fernández-Gutiérrez B, Balsa A, PascualSalcedo D, Blanco R, González-Álvaro I, Llorca J, Martín J, González-Gay MA. Lack of association AREA 3 Martin JE, Broen JC, Carmona FD, Teruel M, Simeon CP, Vonk MC, van 't Slot R, RodriguezRodriguez L, Vicente E, Fonollosa V, OrtegoCenteno N, González-Gay MA, García-Hernández FJ, de la Peña PG, Carreira P; Spanish Scleroderma Group, Voskuyl AE, Schuerwegh AJ, van Riel PL, Kreuter A, Witte T, Riemekasten G, Airo P, Scorza R, Lunardi C, Hunzelmann N, Distler JH, Beretta L, van Laar J, Chee MM, Worthington J, Herrick A, Denton C, Tan FK, Arnett FC, Assass i S, Fonseca C, Mayes MD, Radstake TR, Koeleman BP, Martin J. Identification of CSK as a systemic sclerosis genetic risk factor through Genome Wide Association Study follow-up. Hum Mol Genet. 21(12):2825-35. 2012. PMID: 22407130. IF: 7,636. DOI: 10.1093/hmg/dds099 Castelblanco E, Gallel P, Ros S, Gatius S, Valls J, DeCubas AA, Maliszewska A, Yebra-Pimentel MT, Menarguez J, Gamallo C, Opocher G, Robledo M, Matias-Guiu X. Thyroid paraganglioma. Report of 3 cases and description of an immunohistochemical profile useful in the differential diagnosis with medullary thyroid carcinoma, based on complementary DNA array results. Hum Pathol. 43(7):1103-12. 2012. PMID: 22209341. IF: 2,876. DOI: 10.1016/j.humpath.2011. 08.022 Augustin M, Alvaro-Gracia JM, Bagot M, Hillmann O, van de Kerkhof PC, Kobelt G, Maccarone M, Naldi L, Schellekens H. A framework for improving the quality of care for people with psoriasis. J Eur Acad Dermatol Venereol. 26(Supl 4):1-16. 2012. PMID: 22725729. IF: 2,98. DOI: 10.1111/j.1468-3083.2012.04576.x Robledo G, González-Gay MA, Fernández-Gutiérrez B, Lamas JR, Balsa A, Pascual-Salcedo D, Castañeda S, Blanco R, González-Alvaro I, García A, Raya E, Gómez-Vaquero C, Delgado M, Martín J. NPSR1 gene is associated with reduced risk of rheumatoid arthritis. J Rheumatol. 39(6):1166-70. 2012. PMID: 22548958. IF: 3,695. DOI: 10.3899/jrheum.111205 Carmona FD, Serrano A, Rodríguez-Rodríguez L, Callejas JL, Simeón CP, Carreira P, Castañeda S, Solans R, Blanco R; The Spanish Scleroderma Group; The Spanish Giant Cell Arteritis Group, González-Gay MA, Martín J. Evaluation of a Shared Autoimmune Disease-associated Polymorphism of TRAF6 in Systemic Sclerosis and Giant Cell Arteritis. J Rheumatol. 39(6):1275-1279. 2012. PMID: 22589256. IF: 3,695. DOI: 10.3899/jrheum.120038 Fernández-Nebro A, de la Fuente JM, Carreño L, Izquierdo MG, Tomero E, Rúa-Figueroa I, HernándezCruz B, Narváez J, Ucar E, Olivé A, Zea A, FernándezCastro M, Raya-Álvarez E, Pego-Reigosa J, Freire M, Martínez-Taboada V, Pérez-Venegas J, Sánchez-Atrio A, Villa-Blanco I, Manrique-Arija S, López-Longo F, Carreira P, Martínez-Pérez R, García-Vicuña R. Multicenter longitudinal study of B-lymphocyte depletion in refractory systemic lupus erythematosus: the LESIMAB study. Lupus. 21(10):1063-76. 2012. PMID: 22786985. IF: 2,337. DOI: 10.1177/0961203312446627 García-Bermúdez M, López-Mejías R, GonzálezJuanatey C, Corrales A, Robledo G, Castañeda S, Miranda-Filloy JA, Blanco R, Fernández-Gutiérrez B, Balsa A, González-Alvaro I, Gómez-Vaquero C, Llorca J, Martín J, González-Gay MA. Analysis of the interferon gamma (rs2430561, +874T/A) functional gene variant in relation to the presence of cardiovascular events in rheumatoid arthritis. PLoS One. 7(10):e47166. 2012. PMID: 23077565. IF: 4,092. DOI: 10.1371/journal. pone.0047166 García-Bermúdez M, González-Juanatey C, LópezMejías R, Teruel M, Corrales A, Miranda-Filloy JA, Castañeda S, Balsa A, Fernández-Gutierrez B, González-Álvaro I, Gómez-Vaquero C, Blanco R, Llorca J, Martín J, González-Gay MA. Study of association of CD40-CD154 gene polymorphisms with disease susceptibility and cardiovascular risk in Spanish rheumatoid arthritis patients. PLoS One. 7(11):e49214. 2012. PMID: 23166616. IF: 4,092. DOI: 10.1371/journal. pone.0049214 – 111 – AREA 3AREA 2 AREA 1 between the CXCL12 rs501120 polymorphism and cardiovascular disease in Spanish patients with rheumatoid arthritis. Hum Immunol. 73(5):543-6. 2012. PMID: 22386691. IF: 2,837. DOI: 10.1016/j.humimm. 2012.02.012 Advanced therapies and individualized medicine Lamana A, Balsa A, Rueda B, Ortiz AM, Nuño L, Miranda-Carus ME, Gonzalez-Escribano MF, LopezNevot MA, Pascual-Salcedo D, Martin J, GonzálezÁlvaro I. The TT Genotype of the STAT4 rs7574865 Polymorphism Is Associated with High Disease Activity and Disability in Patients with Early Arthritis. PLoS One. 7(8):e43661. 2012. PMID: 22937072. IF: 4,092. DOI: 10.1371/journal.pone.0043661 K Shum, I Castrejón, C-E Tseng, A Askanase. Authors' reply. Scand J Rheumatol. 41(5):409-410. 2012. IF: 2,472. DOI: 10.3109/03009742.2012.676808 Ruiz-Tovar J, Gamallo C. Streptococcus salivarius causing multiple liver abscesses in a patient with situs inversus. Surg Infect (Larchmt). 13(2):130-1. 2012. PMID: 22439778. IF: 1,8. DOI: 10.1089/sur.2011.082 Cénit MC, Simeón CP, Fonollosa V, Espinosa G, Beltrán E, Sáez-Comet L, Vicente-Rabaneda E, García-Hernández FJ, Martínez-Estupiñán L, Rodríguez-Carballeira M, Hernández V, de la Peña PG, Fernández-Castro M, Narváez FJ, Pros A, Gallego M, Ríos-Fernández R, Camps MT, Fernández-Nebro A, Egurbide MV, Carreira P, González-Gay MA, Martín J; Spanish Scleroderma Group. No evidence of association between functional polymorphisms located within IL6R and IL6ST genes and systemic sclerosis. Tissue Antigens. 80(3):254-8. 2012. PMID: 22742541. IF: 2,588. DOI: 10.1111/j.1399-0039.2012.01915.x BOOKS Esther F. Vicente Rabaneda, Santos Castañeda Sanz. Diagnóstico diferencial de la artrosis tipo II de la mujer menopáusica. Módulo 2. Curso virtual para ginecólogos y generalistas 2012-13. 2012. Santos Castañeda, Gabriel Herrero-Beaumont. Futuro en la atención y abordaje de la artrosis. Módulo 4. Curso virtual para ginecólogos y generalistas 2012-13. 2012. – 112 – CLINICAL TRIALS PRINCIPAL INVESTIGATOR: GARCIA DE VICUÑA PINEDO, ROSARIO Estudio sobre el perfil y el manejo clínico de los pacientes con artritis reumatoide tratados con terapias biológicas en monoterapia. "EstudioBIO MONO; (versión 9.00:22-12-11). ROCHE FARMA, S.A. ROC-BIO2011-01 PRINCIPAL INVESTIGATOR: GARCIA DE VICUÑA PINEDO, ROSARIO Inmunogenicidad de las terapias Anti-TNF en los pacientes con enfermedades reumáticas. Estudio REASON; (versión 4: 21-02-12). LABORATORIOS PFIZER ESPAÑA, S.A. PFI-ANT-2012-01 PRINCIPAL INVESTIGATOR: ALVARO-GRACIA ALVARO, JOSE M. Estudio multicéntrico, aleatorizado, en doble ciego y controlado con placebo, para evaluar la eficacia y la seguridad de certolizumab pegol en combinación con metotrexato en la inducción y el mantenimiento de la respuesta clínica en adultos con artritis reumatoide activa en fase inicial no tratados previamente con Farme; (versión enmienda: 25-10-11). UCB PHARMA, S. A. RA0055. EudraCT: 2011-001729-25 PRINCIPAL INVESTIGATOR: GARCIA DE VICUÑA PINEDO, ROSARIO Estudio observacional, comparativo, global, en pacientes con artritis reumatoide (AR) tratados con un inhibidor de TNF o tocilizumab como primera terapia biológica; (Versión 3.0:25-11-11). F. HOFFMANN-LA ROCHE LTD. MA27950/FHO-TOC-2011-01 PRINCIPAL INVESTIGATOR: GARCIA VADILLO, JESUS Proyecto Sjögren-SER: Creación de un registro de pacientes con Síndrome de Sjögren primario; (versión marzo 2012). SOCIEDAD ESPAÑOLA DE REUMATOLOGIA. SER-TRA-2012-01 PRINCIPAL INVESTIGATOR: GARCIA DE VICUÑA PINEDO, ROSARIO Estudio multicéntrico, internacional, aleatorizado, doble AREA 3 PRINCIPAL INVESTIGATOR: GARCIA VADILLO, JESUS Estudio aleatorizado, doble ciego y con control activo para evaluar la eficacia y seguridad de denosumab comparado con risedronato en pacientes tratados con glucocorticoides; (Versión 06-12-11). AMGEN INC. 20101217. EudraCT: 2010-024393-19 PRINCIPAL INVESTIGATOR: ORTIZ GARCIA, ANAMARIA Estudio de extensión de cuatro años de seguimiento para evaluar la eficacia, seguridad y tolerabilidad a largo plazo de secukinumab en pacientes con artritis reumatoide activa; (versión V00:29-06-12). NOVARTIS FARMACEUTICA, S.A. CAIN457F2309E1. EudraCT: 2012-002760-27 GRUPO 37 HEAD OF LABORATORY Esteban Daudén Tello GROUP MEMBERS • María Carmen García García • Diego de Argila Fernández-Durán • Javier Sánchez Pérez • Fátima Tudelilla Fernández • María Jesús Gómez Gago MAJOR GRANTS Esteban Daudén Tello. Estudio sobre comorbilidad en Psoriasis. Laboratorio PFIZER y Cátedra de Psoriasis de la UAM. Duration: 2010 - 2012. PUBLICATIONS (10) [IF: 39,348] YEAR Total IF Publication No. Q1 Q2 2010 28,877 10 5 4 2011 31,284 12 6 4 2012 39,348 10 8 1 Sánchez-Moya AI, Daudén E. Peripheral lymph node recurrence of tuberculosis after ustekinumab treatment. Arch Dermatol. 148(11):1332-3. 2012. PMID: 23165852. IF: 3,888. DOI: 10.1001/archdermatol.2012.2958 Llamas-Velasco M, Sánchez-Pérez J, Gallo E, Fraga J. Hyperpigmented asymptomatic macule in a fingertip with suspicious dermoscopic pattern--quiz case. Arch Dermatol. 148(2):247-252. 2012. PMID: 22351829. IF: 3,888. DOI: 10.1001/archdermatol.2011.1073a Garcia-Doval I, Carretero G, Vanaclocha F, Ferrandiz C, Daudén E, Sánchez-Carazo JL, Alsina M, HerreraCeballos E, Gómez-García FJ, Ferrán M, LópezEstebaranz JL, Hernanz JM, Belinchón-Romero I, Vilar-Alejo J, Rivera R, Carrascosa JM, Carazo C. Risk of serious adverse events associated with biologic and nonbiologic psoriasis systemic therapy: patients ineligible vs eligible for randomized controlled trials. Arch Dermatol. 148(4):463-470. 2012. PMID: 22508869. IF: 3,888. DOI: 10.1001/archdermatol.2011.2768 Pedraz J, Onate MJ, García-García C, Fraga J, Daudén E. Long-term nasal plaque with nasal obstruction. Arch Dermatol. 148(6):755-60. 2012. PMID: 22710460. IF: 3,888. DOI: 10.1001/archderm.148.6.755-b Uter W, Aberer W, Armario-Hita JC, FernandezVozmediano JM, Ayala F, Balato A, Bauer A, BallmerWeber B, Beliauskiene A, Fortina AB, Bircher A, Brasch J, Chowdhury MM, Coenraads PJ, Schuttelaar ML, Cooper S, Czarnecka-Operacz M, Zmudzinska M, Elsner P, English JS, Frosch PJ, Fuchs T, García-Gavín J, Fernández-Redondo V, Gawkrodger DJ, Giménez-Arnau A, Green CM, Horne – 113 – AREA 3AREA 2 AREA 1 ciego, controlado con alendronato para determinar la eficacia y seguridad de AMG 785en el tratamiento de mujeres con osteoporosis postmenopáusica; (versión 22-12-11). AMGEN INC. 20110142. EudraCT: 2011-003142-41 Advanced therapies and individualized medicine HL, Johansen JD, Jolanki R, Pesonen M, King CM, Krêcisz B, Chomiczewska D, Kiec-Swiercz ynska M, Larese F, Mahler V, Ormerod AD, Peserico A, Rantanen T, Rustemeyer T, Sánchez-Pérez J, Sansom JE, Silvestre JF, Simon D, Spiewak R, Statham BN, Stone N, Wilkinson M, Schnuch A. Current patch test results with the European baseline series and extensions to it from the 'European Surveillance System on Contact Allergy' network, 2007-2008. Contact Dermatitis. 67(1):9-19. 2012. PMID: 22500724. IF: 3,509. DOI: 10.1111/j.1600-0536.2012.02070.x Daudén E, Herrera E, Puig L, Sánchez-Carazo JL, Toribio J, Caloto MT, Nocea G, Roset M, Lara N. Validation of a new tool to assess health-related quality of life in psoriasis: the PSO-LIFE questionnaire. Health Qual Life Outcomes. 10:56. 2012. PMID: 22624984. IF: 2,112. DOI: 10.1186/1477-7525-10-56 Julià A, Tortosa R, Hernanz JM, Cañete JD, Fonseca E, Ferrándiz C, Unamuno P, Puig L, Fernández-Sueiro JL, Sanmartí R, Rodríguez J, Gratacós J, Daudén E, Sánchez-Carazo JL, López-Estebaranz JL, MorenoRamírez D, Queiró R, Montilla C, Torre-Alonso JC, Pérez-Venegas JJ, Vanaclocha F, Herrera E, MuñozFernández S, González C, Roig D, Erra A, Acosta I, Fernández-Nebro A, Zarco P, Alonso A, LópezLasanta M, García-Montero A, Gelpí JL, Absher D, Marsal S. Risk variants for psoriasis vulgaris in a large case-control collection and association with clinical subphenotypes. Hum Mol Genet. 21(20):4549-57. 2012. PMID: 22814393. IF: 7,636. DOI: 10.1093/hmg/dds295 Fuente HD, Perez-Gala S, Bonay P, Cruz-Adalia A, Cibrian D, Sanchez-Cuellar S, Daudén E, Fresno M, García-Diez A, Sanchez-Madrid F. Psoriasis in humans is associated with downregulation of galectins in dendritic cells. J Pathol. 228: 193-203. 2012. PMID: 22271227. IF: 6,318. DOI: 10.1002/path.3996 García-Martín P, De Argila D, To-Figueras J, LlamasVelasco M, Fraga J, García-Diez A. Phototolerance – 114 – induced by narrow-band UVB phototherapy in severe erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. 28(5):261-3. 2012. PMID: 22971192. IF: 1,305. DOI: 10.1111/j.16000781.2012.00677.x Navarro R, Daudén E, Gallo E, Santiago SánchezMateos D, García-Diez A. Alopecia areata during treatment of psoriasis with adalimumab and leflunomide: a case and review of the literature. Skin Pharmacol Physiol. 25(2):107-10. 2012. PMID: 22301842. IF: 2,916. DOI: 10.1159/000335264 CLINICAL TRIALS PRINCIPAL INVESTIGATOR: DAUDEN TELLO, ESTEBAN Efecto de la inmunogenicidad de las terapias anti-TNF sobre la respuesta terapéutica obtenida en los pacientes con psoriasis en placas moderada agrave. Estudio PREDIR, (Versión final:20-02-12). LABORATORIOS PFIZER S.L.U. PFI-ETA-2012-01 PRINCIPAL INVESTIGATOR: DAUDEN TELLO, ESTEBAN Estudio observacional de los efectos hepáticos del ustekinumab; versión septiembre-octubre 2012. AAHUP PRINCIPAL INVESTIGATOR: DAUDEN TELLO, ESTEBAN Estudio epidemiológico observacional para evaluar la retención en el tratamiento de los pacientes con psoriasis de moderada a grave en la práctica clínica; (versión ESP/CGL/CNTO1275PSO4024/Protocolo/v1.0:29-1111). Estudio SAHARA. JANSSEN-CILAG, S.A. JANPSO-2011-01 PRINCIPAL INVESTIGATOR: SANCHEZ PEREZ, ABILIO JAVIER El uso de alitretinoina oral en el tratamiento del eczema crónico de manos en el ámbito sanitario público español: descripción y análisis de la práctica clínica actual; (Versión 04: enero 2012). ALMIRALL S.A. 11-ALL-04-RETRO AREA 3 Line 3.2 Esophagogastrointestinal inflammatory diseases GRUPO 38 GROUP MEMBERS • José Maté Jiménez • María Encarnación Fernández Contreras • María Chaparro Sánchez • Adrián Gerald Mcnicholl • Pablo Muñoz Linares • Carlos Castaño Milla • Alicia Marín Gómez • María José Beceiro Pedreño • Almudena Durán Vegue • Mercedes Ramas López RESEARCH INTEREST Our Group leads a CIBERehd (Networked Biomedical Research Centre on Hepatic and Digestive Diseases) research team focused on the understanding and management of Helicobacter pylori infection and Inflammatory Bowel Disease (IBD). Clinical and epidemiological projects are performed coordinating networks of gastroenterologists from hospitals all over Spain. Different projects have been developed in collaboration with the Pathology service, the Immunology service and the Clinical Pharmacology service of La Princesa Hospital, the Research Unit of Guadalajara’s Hospital, the Pharmaceutical Technology Department and the Organic Chemistry department of the Complutense University of Madrid, the Biochemistry and Molecular Biology Department of Alcalá de Henares University, the Oncology Institute of Catalunya, the Galician Genomics Foundation, and numerous Digestive Services throughout Spain. In 2012 the group has focused on increasing its activity in European and international contexts: • Dr. Gisbert (Group Leader) has been elected President of the European Helicobacter Study Group. • Our team leads the organization of the International Workshop on Helicobacter to be hold in Madrid, September 2013. • Coordinates the ‘Pan-European Registry on Helicobacter pylori infection management’ in which 300 gastroenterologists from 30 European countries participate, making it the largest study on an infectious agent. • The United European Gastroenterology has granted this team a long-term educational and research – 115 – AREA 3AREA 2 AREA 1 HEAD OF LABORATORY Javier Pérez Gisbert Advanced therapies and individualized medicine project entitled ‘Optimal H. pylori management in Primary Care’ aiming to improve the knowledge and implementation of the ‘Maastricht IV European Consensus on Helicobacter pylori infection’ in 8 European countries. Main research Topics • Gastric H. pylori induced proliferation/apoptosis - Effect of infection status, bacterial strain, patients’ genotype and the type and severity of gastric lesions - Comparison pre and post H. pylori eradication - Genetic and epidemiological factors in the progression of pre-cancerous lesions • Angiogenesis and lymphangiogenesis in IBD - Ulcerative colitis vs. Crohn’s disease - Pathological behavior of the disease - Effect of the therapy • Immunity in IBD - Vaccination optimization in IBD patients - Immunological alterations after Hepatitis B virus (HBV) vaccination - Predictive variables to HBV vaccination response - Mechanisms of production of antibodies against anti-TNF treatments • New diagnostic methods - Serologic diagnosis of Duodenal Ulcer - Diagnosis of H. pylori infection with novel monoclonal fecal kits - Clinical utility of biological markers like fecal calprotectin as well as azathioprine metabolites - Theragnosis (Genetic/Pharmacogenetic) and individualized medicine in IBD - Improved diagnosis of concomitant diseases in IBD • New therapies - Routine-data-based studies on the efficacy and safety of novel and traditional treatments on H. pylori eradication - New antibiotic combinations and formulations (hydrogels) for H. pylori treatment - Photodynamic therapy applied to the inactivation of H. pylori - Identification of new therapeutic targets in IBD (PSGL-1, MT1-MMP, IFG-1, ER , CB1 and CB2) – 116 – MAJOR GRANTS • Javier Pérez Gisbert. Registro de colitis microscópica nacional (proyecto RECOMINA): estudio de factores ambientales de riesgo de colitis microscópica y creación de un banco de ADN. ISCIII. PI061577. Duration: 2009 - 2012. • Javier Pérez Gisbert. Implicación de los factores angiogénicos y linfangiogénicos en la enfermedad inflamatoria intestinal. ISCIII. PS09/02369. Duration: 2010 - 2012. • Javier Pérez Gisbert. Biobanco IMIDs diferencial permite identificar biomarcadores y nuevas terapias. Subprograma INNPACTO MICINN. IPT010000-2010-036. Duration: 2010 - 2013. • Javier Pérez Gisbert. Estudio genético en pacientes con Enfermedad Inflamatoria Intestinal con mielotoxicidad por tiopurinas con actividad de la TPMT normal. Asociación Castellana de Aparato Digestivo. Duration: 2011 - 2012. • Javier Pérez Gisbert. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD). Ministerio de Sanidad y Consumo (ISCIII). ISCIII. Duration: 2012 - . • Javier Pérez Gisbert. Desarrollo de un método basado en ELISA par la medición de los niveles séricos de anti-TNF y anticuerpos contra el fármaco. PRE-PREDICROHN. MSD. Duration: 2012 - . • María Encarnación Fernández Contreras. Involvement of estrogen receptor beta (ER ) and thymidylate syntase polymorphisms in inflammatory bowel disease. Duration: 2012 - . • María Chaparro Sánchez. Impacto de la vacuna frente al virus de la hepatitis B en el sistema inmune. GETTECCU-Otsuka. Duration: 2012 2013. PUBLICATIONS (47) [IF: 313,775 YEAR Total IF Publication No. Q1 Q2 2010 76,409 21 8 10 2011 172,025 34 22 9 2012 313,775 47 32 11 AREA 3 M Barreiro-de Acosta, JP Gisbert. Letter: surgery for ulcerative colitis mostly follows anti-TNF drugs - a new 'therapeutic package'?. Aliment Pharmacol Ther 2012 36(3):297-298. 2012. PMID: 22747458. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05158.x JP Gisbert, L Menchén, V García-Sánchez, I Marín, JR Villagrasa, M Chaparro. Comparison of the effectiveness of two protocols for vaccination (standard and double dosage) against hepatitis B virus in patients with inflammatory bowel disease. Aliment Pharmacol Ther 35(12):1379-1385. 2012. PMID: 22530631. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05110.x JP Gisbert on behalf of the H. pylori Study Group of the Spanish Gastroenterology Association. Letter: third-line rescue therapy with levofloxacin after failure of two treatments to eradicate Helicobacter pylori infection. Aliment Pharmacol Ther 35(12):1484-1485. 2012. PMID: 22582841. IF: 3,769. DOI: 10.1111/j.13652036.2012.05117.x JP Gisbert, X Calvet. Review article: Rifabutin in the treatment of refractory Helicobacter pylori infection. Aliment Pharmacol Ther 35(2):209-221. 2012. PMID: 22129228. IF: 3,769. DOI: 10.1111/j.13652036.2011.04937.x M Chaparro, P Burgueño, E Iglesias, J Panés, F Muñoz, P Nos, L Castro, C Jiménez, JL Mendoza, M Barreiro, S Gómez Senent, F Gomollón, X Calvet, E García-Planella, M Gómez, V Hernández, J Hinojosa, M Mañosa, O Pérez Nyssen, JP Gisbert. Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study. Aliment Pharmacol Ther 35(2):275-283. 2012. PMID: 22142227. IF: 3,769. DOI: 10.1111/j.1365-2036.2011.04934.x Y González-Lama, JP Gisbert. Why Thiopurine metabolites are relevant: authors’ reply. Aliment Pharmacol Ther 35(3):401-402. 2012. IF: 3,769. DOI: 10.1111/j.13652036.2011.04957.x JP Gisbert. The ethics of using inferior regimens in H. pylori randomised trials - invited comment. Aliment Pharmacol Ther 35(7):856-857. 2012. PMID: 22404413. IF: 3,769. DOI: 10.1111/j.1365-2036.2011.04985.x JP Gisbert, M Castro-Fernandez, A Perez Aisa, A Cosme, J Molina-Infante, L Rodrigo, I Modolell, JL Cabriada, JL Gisbert, E Lamas, E Marcos, X Calvet. Fourth-line rescue therapy with rifabutin in patients with three H. pylori eradication failures. Aliment Pharmacol Ther 35(8):941-947. 2012. PMID: 22372560. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05053.x M Chaparro, I Guerra, PM Linares, JP Gisbert. Systematic review: Antibodies and anti-TNF-a levels in inflammatory bowel disease. Aliment Pharmacol Ther 35(9):971-986. 2012. PMID: 22443153. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05057.x J Sánchez-Delgado, P García-Iglesias, M CastroFernández, F Bory, M Barenys, L Bujanda, J Lisozain, MM Calvo, S Torra, JP Gisbert, X Calvet. High-dose, tenday esomeprazole, amoxicillin and metronidazole triple therapy achieves high H. pylori eradication rates. Aliment Pharmacol Ther 36(2):190-196. 2012. PMID: 22591220. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05137.x Y Gonzalez-Lama, JP Gisbert. Letter: TPMT - not all that glitters is gold. Aliment Pharmacol Ther 36(2):208-209. 2012. PMID: 22703467. IF: 3,769. DOI: 10.1111/j.13652036.2012.05148.x A McNicholl, PM Linares, OP Nyssen, X Calvet, JP Gisbert. Meta-analysis: esomeprazole or rabeprazole vs. first generation pump inhibitors in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 36(5):414-425. 2012. PMID: 22803691. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05211.x I Guerra, JP Gisbert. Anti-TNFs and psoriasis: friends or foes?. Aliment Pharmacol Ther 36(5):497. 2012. PMID: 22860613. IF: 3,769. DOI: 10.1111/j.13652036.2012.05136.x – 117 – AREA 3AREA 2 AREA 1 AG McNicholl, JP Gisbert. Commentary: comparators in H. pylori eradication - stating the ethics of statins. Aliment Pharmacol 36(4):400-401. 2012. PMID: 22803647. IF: 3,769. DOI: 10.1111/j.13652036.2012.05191.x Advanced therapies and individualized medicine A Lopez-Sanroman, JP Gisbert. Infliximab and adalimumab in the management of Crohn’s disease: are they really comparable?. Aliment Pharmacol Ther 36(5):498499. 2012. PMID: 22860615. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05185.x X Calvet, JP Gisbert. Letter: are idiopathic (non-NSAID, non-Helicobacter pylori) ulcers really increasing?. Aliment Pharmacol Ther 36(6):600-601. 2012. PMID: 22913848. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05218.x F Fernández-Bañares, JP Gisbert. Are lymphocytic colitis and collagenous colitis really the same disease?. Aliment Pharmacol Ther 36(6):606. 2012. PMID: 22913854. IF: 3,769. DOI: 10.1111/j.13652036.2012.05230.x E Domenech, JP Gisbert. Letter: real-life management of new onset ulcerative colitis and proctitis. Aliment Pharmacol Ther 36(7):685-686. 2012. PMID: 22966799. IF: 3,769. DOI: 10.1111/apt.12003 JP Gisbert, X Calvet, A Cosme, P Almela, F Feu, F Bory, S Santolaria, R Aznárez, M Castro, N Fernández, R García-Grávalos, A Benages, N Cañete, M Montoro, F Borda, A Pérez-Aisa, JM Piqué. Long-Term Follow-Up of 1,000 Patients Cured of Helicobacter pylori Infection Following an Episode of Peptic Ulcer Bleeding. Am J Gastroenterol 107(8):1197-1204. 2012. PMID: 22613904. IF: 7,282. DOI: 10.1038/ajg.2012.132 Gisbert JP, Villagrasa JR, Rodríguez-Nogueiras A, Chaparro M. Efficacy of hepatitis B vaccination and revaccination and factors impacting on response in patients with inflammatory bowel disease. Am J Gastroenterol. 107(10):1460-6. 2012. PMID: 23034605. IF: 7,282. DOI: 10.1038/ajg.2012.79 Curr Drug Metab. 13(9):1266. 2012. PMID: 22998087. IF: 5,113 Guijarro LG, Román ID, Fernández-Moreno MD, Gisbert JP, Hernández-Breijo B. Is the autophagy induced by thiopurines beneficial or deleterious?. Current Drug Metabol. 13(9):1267-76. 2012. PMID: 22493985. IF: 5,113 Cabaleiro T, Roman M, Gisbert JP, Abad-Santos F. Utility of assesing thiopurine S-methyltransferase polymorphism before azathioprine therapy. Current Drug Metabol. 13(9):1277-93. 2012. PMID: 22493988. IF: 5,113 DR Serrano, S Torrado, S Torrado-Santiago, JP Gisbert. The influence of CYP2C19 genetic polymorphism on the pharmacokinetics/pharmacodynamics of proton pump inhibitor-containing Helicobacter pylori treatments. Current Drug Metabol. 13(9):1303-12. 2012. PMID: 22493986. IF: 5,113 B Velayos, L Fernández-Salazar, F Pons-Renedo, MF Muñoz, A Almaraz, R Aller, L Ruíz, L Del Olmo, JP Gisbert, JM González-Hernández. Accuracy of urea breath test performed immediately after emergency endoscopy in peptic ulcer bleeding. Dig Dis Sci 57(7):1880-1886. 2012. PMID: 22453995. IF: 2,117. DOI: 10.1007/s10620-012-2096-5 Y González-Lama, C Taxonera, A López-Sanromán, JL Pérez-Calle, F Bermejo, R Pajares, AG McNicholl, V Opio, JL Mendoza, P López, A Algaba, J Estelles, A Barbero, JL Mendoza, J Maté, JP Gisbert. Methotrexate in inflammatory bowel disease: A multicenter retrospective study focused on long-term efficacy and safety. The Madrid experience. Eur J Gastroenterol Hepatol 24(9):1086-1091. 2012. PMID: 22713509. IF: 1,757. DOI: 10.1097/MEG.0b013e3283556db5 M Román, T Cabaleiro, J Novalbos, M Chaparro, JP Gisbert, F Abad-Santos. Validation of a genotyping method for analysis of TPMT polymorphisms. Clin Ther 34(4):878-884. 2012. PMID: 22421577. IF: 2,321. DOI: 10.1016/j.clinthera.2012.02.017 JP Gisbert. Rescue therapy for Helicobacter pylori infection 2012. Gastroenterol Res Pract. 2012:974594. 2012. PMID: 22536225. IF: 0,978. DOI: 10.1155/2012/974594 JP Gisbert. Drugs and the Upper and Lower Gastrointestinal Tract: From Inflammation to Malignancy. P. Malfertheiner, F. Megraud, C. O'morain, J. Atherton, A. Axon, F. Bazzoli, E. El-omar, G. Gensini, JP Gisbert, D. – 118 – AREA 3 JP Gisbert, AG McNicholl. Maintenance of Helicobacter pylori eradication rates with triple therapy over 12 years in a Spanish hospital. Helicobacter 17(2):160-161. 2012. PMID: 22404448. IF: 3,151. DOI: 10.1111/j.15235378.2011.00922.x J Molina-Infante, C Pazos-Pacheco, G VinagreRodriguez, B Perez-Gallardo, C Dueñas-Sadornil, M Hernandez-Alonso, G Gonzalez-Garcia, JM MateosRodriguez, M Fernandez-Bermejo, JP Gisbert. Non-bismuth quadruple (concomitant) therapy: empirical and tailored efficacy versus standard triple therapy for clarithromycin-susceptible Helicobacter pylori and vs. sequential therapy for clarithromycin-resistant strains. Helicobacter 17(4):269-276. 2012. PMID: 22759326. IF: 3,151. DOI: 10.1111/j.1523-5378.2012.00947.x B Tepes, A O'Connor, JP Gisbert, CA O'Morain. Treatment of Helicobacter pylori infection 2012. Helicobacter. 17 Suppl 1:36-42. 2012. PMID: 22958154. IF: 3,151. DOI: 10.1111/j.15235378.2012.00981.x M Chaparro, J Panés, V García, O Merino, P Nos, E Domènech, M Peñalva, E García-Planella, M Esteve, J Hinojosa, M Andreu, F Muñoz, A Gutiérrez, JL Mendoza, J Barrio, M Barreiro, I Vera, P Vilar, JL Cabriada, MA Montoro, X Aldeguer, C Saro, JP Gisbert. Long-term durability of response to adalimumab in Crohn’s disease. Inflamm Bowel Dis 18(4):685-690. 2012. PMID: 21618353. IF: 4,855. DOI: 10.1002/ibd.21758 F Bermejo, E Garrido, M Chaparro, J Gordillo, M Mañosa, A Algaba, A López-Sanromán, JP Gisbert, E. García-Planella, E Doménech, I Guerra. Efficacy of different therapeutic options for spontaneous abdominal abscesses in Crohn’s disease: are antibiotics enough?. Inflamm Bowel Dis 18(8):1509-1514. 2012. PMID: 22674826. IF: 4,855. DOI: 10.1002/ibd.21865 L Katz, JP Gisbert, B Manoogian, L Kirk, C Steenholdt, GJ Mantzaris, A Atreja, Y Ron, A Swaminath, S Shah, A Harts, PL Lakatos, P Ellul, E Israeli, MN Svendsen, J van der Woude, KH Katsanos, L Yun, EV Tsianos, T Nathan, M Abreu, I Dotan, B Lashner, J Brynskov, JP Terdiman, P Higgins, M Chaparro, S Ben-Horin. Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response. Inflamm Bowel Dis. 18(11):2026-33. 2012. PMID: 22294554. IF: 4,855. DOI: 10.1002/ibd.22902 Gisbert JP, Villagrasa JR, Rodríguez-Nogueiras A, Chaparro M. Kinetics of anti-hepatitis B surface antigen titers after hepatitis B vaccination in patients with inflammatory bowel disease. Inflamm Bowel Dis. 19(3):554-8. 2012. PMID: 23380936. IF: 4,855. DOI: 10.1097/MIB.0b013e31827febe9 G de la Poza, A Lopez-Sanroman, C Taxonera, I Marín, JP Gisbert, F Bermejo, V Opio, A Muriel. Genital fistulas in female Crohn’s disease patients. Clinical characteristics and response to therapy. J Crohn Colitis 6(3):276280. 2012. PMID: 22405162. IF: 2,566. DOI: 10.1016/j.crohns.2011.08.015 I. Guerra, A. Algaba, J. Pérez-Calle, M. Chaparro, I. Marín-Jiménez, A. López-Sanromán, R. GarcíaCastellanos, Y. González-Lama, N. Manceñido, P. Martínez, E. Quintanilla, C. Taxonera, M. Villafruela, A. Romero, P. López-Serrano, JP Gisbert, F. Bermejo. Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: a report of 21 cases. J Crohn Colitis 6(5):518-523. 2012. PMID: 22398059. IF: 2,566. DOI: 10.1016/j.crohns. 2011.10.007 J Hinojosa, JP Gisbert, F Gomollon, AL San Roman. Adherence of gastroenterologists to European Crohn’s and Colitis Organisation consensus on Crohn’s disease: A real-life survey in Spain. J Crohn Colitis 6(7):763-770. 2012. PMID: 22398092. IF: 2,566. DOI: 10.1016/j.crohns.2011.12.013 P Marticorena-Álvarez, M Chaparro, A Pérez-Casas, MA Muriel-Herrero, JP Gisbert. Probable diffuse retinopathy caused by adalimumab in a patient with Crohn’s dis- – 119 – AREA 3AREA 2 AREA 1 Graham, T. Rokkas, E. Kuipers & the European Helicobacter Study Group (EHPSG). Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. Gut 61(5):646-664. 2012. PMID: 22491499. IF: 10,111. DOI: 10.1136/gutjnl-2012302084 Advanced therapies and individualized medicine ease. J Crohn Colitis 6(9):950-953. 2012. PMID: 22537636. IF: 2,566 M Chaparro, P Martínez-Montiel, M Van-Domselaar, F Bermejo, JL Pérez-Calle, B Casis, A López-SanRomán, A Algaba, J Maté, JP Gisbert. Intensification of infliximab therapy in Crohn’s disease: efficacy and safety. J Crohn’s Colitis 6(1):62-67. 2012. PMID: 22261529. IF: 2,566. DOI: 10.1016/j.crohns.2011.07.005 Casanova MJ, Chaparro M, Martínez S, Vicuña I, Gisbert JP. Severe adalimumab-induced thrombocytopenia in a patient with Crohn’s disease. J Crohn's Colitis. 6(10):10347. 2012. PMID: 22534313. IF: 2,566. DOI: 10.1016/j.crohns.2012.04.001 D Laharie, A Bourreille, J Branche, M Allez, Y Bouhnik, J Filippi, F Zerbib, M Nachury, G Savoye, J Moreau, JC Delchier, E Ricart, J Cosnes, A López-Sanroman, O Dewit, JL Dupas, F Carbonnel, G Bommelaer, B Coffin, X Roblin, G Van Assche, M Esteve, M Färkkilä, JP Gisbert, P Marteau, S Nahon, M de Vos, D Franchimont, JY Mary, JF Colombel, M Lémann. Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial. Lancet. 380(9857):1909-15. 2012. PMID: 23063316. IF: 38,278. DOI: 10.1016/S01406736(12)61084-8 Rutgeerts, S Ghosh, WJS de Villiers,R Panaccione, G Greenberg, S Schreiber, S Lichtiger, BG Feagan, for the CERTIFI Study Group (..., Pérez Gisbert, J, ...). Ustekinumab Induction and Maintenance Therapy in Refractory Crohn's Disease. N Engl J Med. 367(16):1519-1528. 2012. PMID: 23075178. IF: 53,298. DOI: 10.1056/NEJMoa1203572 Barbero-Villares A, Mendoza J, Taxonera C, LópezSanromán A, Pajares R, Bermejo F, Pérez-Calle J, Mendoza J, Algaba A, Moreno-Otero R, Maté J, Gisbert J. Evaluation of liver fibrosis by transient elastography (Fibroscan®) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial. Scand J Gastroenterol 47(5):575-579. 2012. PMID: 22229701. IF: 2,019. DOI: 10.3109/00365521.2011. 647412 Chaparro M, Andreu M, Barreiro-de Acosta M, García-Planella E, Ricart E, Domènech E, Esteve M, Merino O, Nos P, Peñalva M, JP Gisbert. Effectiveness of infliximab after adalimumab failure in Crohn's disease. World J Gastroenterol. 18(37):521924. 2012. PMID: 23066316. IF: 2,471. DOI: 10.3748/wjg.v18.i37.5219 BOOKS Quintero E, Castells A, Bujanda L, Cubiella J, Salas D, Lanas Á, Andreu M, Carballo F, Morillas JD, Hernández C, Jover R, Montalvo I, Arenas J, Laredo E, Hernández V, Iglesias F, Cid E, Zubizarreta R, Sala T, Ponce M, Andrés M, Teruel G, Peris A, Roncales MP, Polo-Tomás M, Bessa X, Ferrer-Armengou O, Grau J, Serradesanferm A, Ono A, Cruzado J, Pérez-Riquelme F, Alonso-Abreu I, de la VegaPrieto M, Reyes-Melian JM, Cacho G, Díaz-Tasende J, Herreros-de-Tejada A, Poves C, Santander C, GonzálezNavarro A; COLONPREV Study Investigators (...,Mª Chaparro, Gisbert JP,...). Colonoscopy versus Fecal Immunochemical Testing in Colorectal-Cancer Screening. N Engl J Med 366(8):697-706. 2012. PMID: 22356323. IF: 53,298. DOI: 10.1056/NEJMoa1108895 WJ Sandborn, C Gasink, LL Gao, MA Blank, J Johanns, C Guzzo, BE Sands, SB Hanauer, St Targan, P – 120 – M Chaparro, JP Gisbert. Antimetabolite therapy in ulcerative colitis: Azathioprine, mercaptopurine and methotrexate. 2012. Editores: Lichtestein G. M Chaparro, JP Gisbert, I Marín, L Menchén, F Gomollón. Diagnóstico diferencial de las estenosis intestinales y su manejo en los pacientes con enfermedad de Crohn. Diagnóstico diferencial de la enfermedad inflamatoria intestinal. 2012. Eds. Elsevier Doyma. ISBN: 978-84-75927-466. M Chaparro, JP Gisbert. Desintensificación de la dosis de adalimumab en pacientes con enfermedad de Crohn. Casos clínicos en Enfermedad de Crohn. 2012. Publicaciones Permanyer 2012. ISBN: 978-84-9926326-7. AREA 3 M Chaparro, JP Gisbert. Dudas frecuentes sobre el embarazo y la lactancia en pacientes con enfermedad de Crohn. 2012. M Chaparro, JP Gisbert. Eficacia del adalimumab en el mantenimiento de la remisión a largo plazo en pacientes con enfermedad de Crohn con intolerancia a las tiopurinas. 2012. JP Gisbert. Estómago: Helicobacter pylori. Curso sobre trastornos digestivos. 2012. Gastroenterol Hepatol; Eds: V Arrolyo, JP Piq. Págs.: 23-33. JP Gisbert, X Calvet, A Lanas, JI Elizalde, L Bujanda. Enfermedades del estómago y del duodeno (capítulo 15). Farreras-Rozman, Medicina Interna Decimoséptima Edición. 2012. Págs.: 92123. M Chaparro, JP Gisbert. Eficacia de adalimumab en el mantenimiento de la remisión a largo plazo en pacientes con enfermedad de Crohn con intolerancia a las tiopurinas.Eds: M Chaparro, E Torrella. Evidencia vs experiencia. Paciente en tratamiento continuado durante 2 años con adalimumab. 2012. Publicaciones Permanyer. Págs.: 15-20. M Chaparro, JP Gisbert. Desintensificación de la dosis de adalimumab en pacientes con enfermedad de Crohn. Casos clínicos en Enfermedad de Crohn. 2012. Publicaciones Permanyer. Pags.: 35-41. B Hernández-Breijo, J Monserrat, D FernándezMoreno, ID Román, JP Gisbert, LG Guijarro. La azatioprina produce autofagia en células HepG2. 2012. M Chaparro, A Rodríguez-Nogueiras, JP Gisbert. Nutrición y tabaco en pacientes con enfermedad inflamatoria intestinal (Módulo Enfermería). 2012. CLINICAL TRIALS PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio aleatorizado, doble ciego, controlado con placebo, con grupos paralelos, multicéntrico para investigar la seguridad y la eficacia de -CP-690,550 como tratamiento de mantenimiento en sujetos con Enfermedad de Crohn de moderada a grave; (Versión enmienda 2: 14-09-11). PFIZER INC. A3921084. EudraCT: 2011-001754-28 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio abierto multicéntrico para evaluar el impacto de adalimumab en la calidad de vida, la utilización de la asistencia sanitaria y coste delos pacientes con Colitis Ulcerosa en la práctica clínica habitual; (versión amendment: 19-09-11). ABBOTT GMBH & CO. KG. M13-045. EudraCT: 2011-002411-29 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio de tratamiento aleatorizado, doble ciego, activo para inducir respuesta clínica y/o remisión con GSK1605786A en pacientes con Enfermedad de Crohn activa moderada o grave; (versión original: 2807-11). GLAXOSMITHKLINE RESEARCH & DEVELOPMENT LIMITED. CCX114643. EudraCT: 2011-002817-12 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio aleatorizado, doble ciego, controlado con placebo y de 52 semanas de duración para evaluar la eficacia y seguridad de GSK1605786A en el mantenimiento de la remisión en pacientes con Enfermedad de Crohn; (versión 1: 03-08-11). GLAXOSMITHKLINE RESEARCH & DEVELOPMENT LIMITED. CCX114157. EudraCT: 2010-022383-12 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio abierto de extensión para evaluar la seguridad de GSK1605786A en pacientes con Enfermedad de – 121 – AREA 3AREA 2 AREA 1 JP Gisbert, M Chaparro. Errores más frecuentes en el manejo de pacientes con colitis ulcerosa y enfermedad de Crohn. Conductas de actuación en la Enfermedad Inflamatoria Intestinal. Manual práctico, 5ª edición. 2012. Editores: J Hinojosa, P Nos. Advanced therapies and individualized medicine Crohn; (versión 02:02-08-11). GLAXOSMITHKLINE RESEARCH & DEVELOPMENT LIMITED. CCX114644. EudraCT: 2010-022384-35 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Ensayo clínico en fase II, aleatorizado y controlado con placebo para estudiar la seguridad e inmunogenicidad de V212 en pacientes adultos con enfermedades autoinmunitarias; (Versión 00:11-11-11). MERCK SHARP & DOHME CORP. V212-009. EudraCT: 2011-002313-11 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio de fase III, de grupos paralelos, controlado con placebo, doble ciego, aleatorizado, multicéntrico, internacional, para investigar la seguridad y eficacia de los comprimidos de liberación modificada de propionil-Lcarnitina clorhidrato(ST 261) en pacientes afectados por colitis ulcerosa leve bajo tratamiento oral estable; (versión final:1.0:30-09-11). SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A. ST261 DM 11 006. EudraCT: 2011-004770-28 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio fase III, multicéntrico, aleatorizado, doble ciego, de grupos paralelos y controlado con placebo para evaluar la eficacia y la seguridad de células madre alogénicas expandidas derivadas del tejido adiposo (eASC) para el tratamiento de la Enfermedad de Crohn fistulizante perianal tras un periodo de 24 semanas. Estudio ADMIRE-CD; (Versión 1.0: 13-12-11). CELLERIX S.A. CX601-0302. EudraCT: 2011-006064-43 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Evaluación de la respuesta a la vacunación de la Hepatitis B en los pacientes con Enfermedad Inflamatoria Intestinal;(version1:30-04-12). PRECOMVI-B PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER – 122 – Efectividad del tratamiento Anti TNF-alfa en pacientes con Enfermedad de Crohn que no han respondido a un Anti TNF-alfa previo. JAVIER P. GISBERT. GIS-201202-NORES PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio para conocer la eficacia de dos pautas de la vacuna frente al virus de la Hepatitis B en pacientes con enfermedad inflamatoria; (versión 1: 30-04-12). GIS-2012-VHB PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio aleatorizado, doble ciego, controlado con placebo para investigar la eficacia y la seguridad de GSK1605786A en el tratamiento de pacientes con Enfermedad de Crohn activa de moderada a grave; (versión 01:27-07-11). GLAXOSMITHKLINE RESEARCH & DEVELOPMENT LIMITED. CCX114151. EudraCT: 2010-022382-10 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo y de grupos paralelos de CP690,550 por vía oral como tratamiento de mantenimiento en pacientes con colitis ulcerosa; (Versión final:30-09-11). PFIZER INC. A3921096. EudraCT: 2011-004580-79 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio para evaluar las preferencias declaradas por los pacientes respecto al tratamiento de la Enfermedad de Crohn. -Estudio Implica-; (Versión: cambio administrativo nº1:09-02-12). ABBOTT LABORATORIES, S.A. ABB-BIO-2011-01 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio multicéntrico abierto de CP-690,550 en pacientes con colitis ulcerosa entre moderada e intensiva; (versión final: 30-09-11). PFIZER INC. A3921139. EudraCT: 2011-004581-14 AREA 3 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio de extensión abierto de CP-690,550 como tratamiento de mantenimiento en pacientes con Enfermedad de Crohn; (versión final: 23-09-11). PFIZER INC. A3921086. EudraCT: 2011-003622-27 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER UC-CARES- Colitis ulcerosa: Condición, actitud y recursos; Estudio Educativo; (versión 3.00 final: 22-1211). MERCK&CO, INC. MER-TCU-2012-01 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Tratamiento erradicado de H. pylori de rescate de 3Línea con una terapia cuádruple con bismuto. GIS2012-CUADRUPLE PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo y de grupos paralelos de CP690,550 por vía oral como tratamiento de inducción en pacientes con colitis ulcerosa entre moderada e intensa; (Versión final: 30-09-11). PFIZER INC. A3921094. EudraCT: 2011-004578-27 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Tratamiento triple con levofloxacino tras el fracaso de las terapias cuádruples "secuencial" o "concomitante" en la erradicación de Helicobacter Pylori; (versión 1:108-12). GIS-2012-LEVO-SECCON PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Estudio clínico para evaluar el efecto de un complemento alimenticio en el alivio de síntomas de antibioterapia en pacientes tratados para la infección por Helicobacter pylori; (versión 2: 25-06-12). LABORATORIOS CASEN FLEET, S.L.U. QTM/ABB009 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Prevalencia, perfil clínico y manejo terapéutico del paciente con Colitis Ulcerosa (CU) en servicios hospitalarios de gastroenterología de España. Estudio EPICURE; (versión2.0:10-05-12). ABBOTT LABORATORIES, S.A. ABB-TCU-2012-01 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Registro europeo de manejo de la infección por Helicobacter Pylori; (versión 1: 04-12-12). EUROPEAN HELICOBACTER STUDY GROUP. HP-EUREG PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Proteómica de la úlcera duodenal e infección por Helicobacter Pylori; (versión 1: 12-09-12). NRGH-12231V1 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Mejora de la seguridad en pacientes con Enfermedad Inflamatoria Intestinal en tratamiento con biológicos mediante el perfeccionamiento en la detección de tuberculosis latente; (versión 2:28-10-11). GETECCU. SEGURTB/GET-BIO-2011-01 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Correlación entre los marcadores biológicos y la actividad clínica en pacientes con enfermedad inflamatoria intestinal; (versión 1:15-06-12). GIS-MARCA-2012 – 123 – AREA 3AREA 2 AREA 1 PRINCIPAL INVESTIGATOR: PEREZ GISBERT, FRANCISCO JAVIER Fístulas enterourinarias en la Enfermedad de Crohn prevalencia y características clínicas; (Versión 2). HOSPITAL CLINICO SAN CARLOS. CTS-FIS-2012-01 Advanced therapies and individualized medicine Line 3.3 Progenitors and cell therapy GRUPO 39 HEAD OF LABORATORY Luis Madero López GROUP MEMBERS • Julián Sevilla Navarro • Álvaro Lassaletta Atienza • África González Murillo • Evangelina Muñoz Mayoral • Manuel Ramírez Orellana • Isabel Colmenero Blanco • Lucía Chamorro Casanova • Ana María Gómez García • Carolina Martínez Laperche • Antonio Pérez Martínez • Miguel Ángel Díaz Pérez • Marta González Vicent • Jaime Valentín Quiroga RESEARCH INTEREST The main results from the activity of the group led by Dr. Luís Madero during 2012 were as follows: • The Group published a total of 17 articles in scientific journals, either as its own work or as collaborations with other groups. • The predoctoral candidate Ana María Gómez, supervised by Dr. Manuel Ramírez, obtained their doctoral degree at School of Medicine, Universidad Autónoma de Madrid, with the maximum grade. • Dr. Manuel Ramírez and his group participate in the consortium “Una nueva generación de medicamentos celulares más eficaces y seguros. CellCAM (S2010/BMD-2420)” funded by Comunidad de Madrid. – 124 – (a) Reconstitution of T cells, (b) CD4+ cells, (c) CD8+ cells, (e) NK bright CD56+ CD16- cells, (f) NK dim CD56+ CD16+, (g)DCs, (h) myeloid DCs, (i) lymphoid DCs DC2+ and (j) lymphoid DC2 cells in MUD and HP CD3/CD19-depleted grafts. Data are expressed as means +- s.e.m. *is used to highlight statiscally significant differences. The following work by several members of the group was published in the journal Bone Marrow Transplantation in November 2012 (Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia. PérezMartínez A, González-Vicent M, Valentín J, Aleo E, Lassaletta A, Sevilla J, Vicario JL, Ramírez M, Díaz MA. Bone Marrow Transplant. 2012 Nov;47(11):1419-27. doi: 10.1038/bmt.2012.43. Epub 2012 Mar 12.). This work describes the kinetics of immune reconstitution in the first 3 months after transplanting a hematopoietic graft from either an unrelated donor or a haploidentical donor, in children with high-risk leukemias. MAJOR GRANTS • Luis Madero López. Generación y diferenciación de células madre pluripotentes inducidas (iPS) de pacientes con enfermedades genéticas del sistema inmuno-hematopoyético. MICINN. PLE2009-0100. Duration: 2009 - 2012. • Manuel Ramírez Orellana. Utilización de células madre adultas como agentes terapéuticos antitumorales. MICINN. PLE2009-0115. Duration: 2009 - 2012. • Luis Madero López. Detección de infiltración leptomeníngea en niños con tumores del sistema nervioso AREA 3 • • • • • • • PUBLICATIONS (16) [IF: 38,060] YEAR Total IF Publication No. Q1 Q2 2010 30,791 10 3 5 2011 52,329 14 6 2 2012 38,06 16 2 4 Carrillo J, Martínez P, Solera J, Moratilla C, González A, Manguán-García C, Aymerich M, Canal L, Del Campo M, Dapena JL, Escoda L, García-Sagredo JM, Martín-Sala S, Rives S, Sevilla J, Sastre L, Perona R. High resolution melting analysis for the identification of novel mutations in DKC1 and TERT genes in patients with dyskeratosis congenita. Blood Cells Mol Dis 49(3-4):140-146. 2012. PMID: 22664374. IF: 2,351. DOI: 10.1016/j.bcmd. 2012.05.008 Pérez-Martínez A, González-Vicent M, Valentín J, Aleo E, Lassaletta A, Sevilla J, Vicario JL, Ramírez M, Díaz MA. Early evaluation of immune reconstitution following allogeneic CD3/CD19-depleted grafts from alternative donors in childhood acute leukemia. Bone Marrow Transplant. 47(11):1419-27. 2012. PMID: 22410752. IF: 3,746. DOI: 10.1038/bmt.2012.43 Navajas A, Lassaletta A, Morales A, López-Ibor B, Sábado C, Moscardó C, Mateos E, Molina J, Sagaseta M, Sastre A. Efficacy and safety of liposomal cytarabine in children with primary CNS tumours with leptomeningeal involvement. Clin Transl Oncol. 14(4):280-6. 2012. PMID: 22484635. IF: 1,327. DOI: 10.1007/s12094-012-0796-0 Pérez-Martínez A, de Prada Vicente I, Fernández L, González-Vicent M, Valentín J, Martín R, Maxwell H, Sevilla J, Vicario JL, Angel Díaz M. Natural killer cells can exert a graft-vs-tumor effect in haploidentical stem cell transplantation for pediatric solid tumors. Exp Hematol 40(11):882-891.e1. 2012. PMID: 22771496. IF: 2,905. DOI: 10.1016/j.exphem.2012.07.004 Lehrnbecher T, Aplenc R, Rivas Pereira F, Lassaletta A, Caselli D, Kowalczyk J, Chisholm J, Sung L; SIOP Supportive Care Working. Variations in non-pharmacological anti-infective measures in childhood leukemia-results of an international survey. Haematologica. 97(10):1548-52. 2012. PMID: 22419572. IF: 6,424. DOI: 10.3324/haematol.2012.062885 Tolar J, Becker PS, Clapp DW, Hanenberg H, de Heredia CD, Kiem HP, Navarro S, Qasba P, Rio P, Schmidt M, Sevilla J, Verhoeyen E, Thrasher AJ, Bueren J. Gene therapy for fanconi anemia: one step closer to the clinic. Hum – 125 – AREA 3AREA 2 AREA 1 • central. ISCIII. PI10/02811. Duration: 2011 - 2013. Manuel Ramírez Orellana. Estudio de la regulación de la vía de FAS por NIK en trasplante alogénico. ISCIII. PI10/02802. Duration: 2011 - 2013. Proyecto Coordinado. Ensayo clínico Fase I/II para evaluar la seguridad y eficacia de la movilización y colecta de células CD34+ tras tratamiento con plerixafor y filgrastim en pacientes con anemia de Fanconi. MSPSI. EC11-559. Duration: 2012 - 2013. Proyecto Coordinado. Células Natural Killer autólogas activadas y expandidas para el tratamiento del Mieloma Múltiple. ISCIII. EC11/036. Duration: 2012 - 2013. Proyecto Coordinado. Una nueva generación de medicamentos celulares más eficaces y seguros. CellCAM. CAM. S2010/BMD-2420. Duration: 2012 2015. Julián Sevilla Navarro. Ensayo clínico Fase I/II para evaluar la seguridad y eficacia de la infusión de células CD34+ autólogas transducidas con un vector lentiviral portador del gen FANCA (medicamento huérfano) para pacientes con Anemia de Fanconi del Subtipo A. MSPSI. EC11-060. Duration: 2012 - 2013. Manuel Ramírez Orellana. Ensayo clínico de seguridad y eficacia de infusiones de infusiones repetidas de Celyvir en niños y adultos con tumores sólidos metastásicos y refractarios. MSPSI. EC11-061. Duration: 2012 - 2013. Antonio Pérez Martínez. Infusión de células natural killer activadas y expandidas en combinación con quimioterapia en pacientes pediátricos con leucemia/linfoma T refractaria. ISCIII. EC11/057. Duration: 2012 - 2013. Miguel Ángel Díaz Pérez. Trasplante de progenitores hematopoyéticos de donante familiar haploidentico con infusion de linfocitos del donante tras alo-depleCción selectiva “in vitro”, en pacientes pediatricos con hemopatías malignas de alto riesgo. ISCIII. EC11/024. Duration: 2012 - 2013. Advanced therapies and individualized medicine Gene Ther 23(2):141-144. 2012. PMID: 22248350. IF: 4,218. DOI: 10.1089/hum.2011.237 Rodriguez-Milla MA, Mirones I, Mariñas-Pardo L, Melen GJ, Cubillo I, Ramírez M, García-Castro J. Enrichment of neural-related genes in human mesenchymal stem cells from neuroblastoma patients. Int J Mol Med. 30(2):365373. 2012. PMID: 22641458. IF: 1,573. DOI: 10.3892/ijmm.2012.1008 Sevilla J, Schiavello E, Madero L, Pardeo M, Guggiari E, Baragaño M, Luksch R, Massimino M. Priming of Hematopoietic Progenitor Cells by Plerixafor and Filgrastim in Children With Previous Failure of Mobilization With Chemotherapy and/or Cytokine Treatment. J Pediatr Hematol Oncol 34(2):146-50. 2012. PMID: 22009006. IF: 1,159. DOI: 10.1097/MPH.0b013e3182 1c2cb8 González-Vicent M, Molina B, Pérez A, Díaz MA. Oncedaily intravenous busulfan for 47 pediatric patients undergoing autologous hematopoietic stem cell transplantation: a single center study. J Pediatr Hematol Oncol 34(3):180-183. 2012. PMID: 22430583. IF: 1,159. DOI: 10.1097/MPH.0b013e3182431e1b Herrero B, Ruiz de la Fuente J, Aleo E, Carceller F, Lassaletta A, Orellana MR, Pérez-Martínez A. Spontaneous Resolution of Hypereosinophilic Syndrome in an Infant Without Treatment. J Pediatr Hematol Oncol 34(6):450-2. 2012. PMID: 22510769. IF: 1,159. DOI: 10.1097/MPH.0b013e318249579b Cabeza B, Oñoro G, Salido AG, Lassaletta A, de Prada I, Albi G, de Mingo L, Serrano A. Pleuropulmonary blastoma as characteristic cause of pneumothorax. J Pediatr Hematol Oncol. 34(1):e42-4. 2012. PMID: 22134609. IF: 1,159. DOI: 10.1097/MPH.0b013e3182287d88 González-Vicent M, Díaz MA. Unrelated cord blood transplantation in adolescent and young adults with hematologic malignancies. Leuk Res 36(2):123-4. 2012. PMID: 22071140. IF: 2,923. DOI: 10.1016/j.leukres.2011.10.021 Cantarín-Extremera V, González-Gutiérrez-Solana L, Ramírez-Orellana M, López-Marín L, Duat-Rodríguez A, – 126 – Ruíz-Falcó-Rojas ML. Immune-Mediated Mechanisms in the Pathogenesis of Hopkins Syndrome. Pediatr Neurol. 47(5):373-4. 2012. PMID: 23044022. IF: 1,522. DOI: 10.1016/j.pediatrneurol.2012.08.006 Lassaletta A, Portugal R, Arce B, Gonzalez-Vicent M, Andion M, Cormenzana M, Madero L. Intrathecal steroids reduce the severity and frequency of adverse events associated with intrathecal liposomal cytarabine administration in children with cancer. Pediatric Blood & Cancer. 59(6):1092-1092. 2012. IF: 1,891 López E, Madero L, López-Pascual J, Latterich M. Clinical proteomics and OMICS clues useful in translational medicine research. Proteome Sci. 10(1):35. 2012. PMID: 22642823. IF: 2,328. DOI: 10.1186/1477-595610-35 Molina B, Gonzalez-Vicent M, Albi G, Andión M, Herrero B, Sevilla J, Díaz MA. Varicella zoster central nervous system vasculitis after allogeneic hematopoietic stem cell transplant successfully treated with cyclophosphamide. Transpl Infect Dis 14(5):107-110. 2012. PMID: 22967359. IF: 2,216. DOI: 10.1111/j.13993062.2012.00783.x CLINICAL TRIALS PRINCIPAL INVESTIGATOR: SEVILLA NAVARRO, JULIÁN Ensayo clínico fase I/II para evaluar la seguridad y eficacia de la infusión de células CD34+autólogas transducidas con un vector lentiviral portador del gen FANCA (medicamento huérfano) para pacientes con anemia de Fanconi del subtipo A. FANCOLEN-1. EudraCT: 2011-006100-12 PRINCIPAL INVESTIGATOR: SEVILLA NAVARRO, JULIÁN Ensayo clínico fase I/II para evaluar la seguridad y eficacia de la movilización y colecta de células CD34+ tras tratamiento con plerixafor y filgrastim en pacientes con anemia de Fanconi para su posterior transducción con un vector lentiviral portador del gen FANCA y rein- AREA 3 PRINCIPAL INVESTIGATOR: SEVILLA NAVARRO, JULIÁN Estudio abierto, de farmacocinética y farmacodinámica, y tolerabilidad de AVE5026 administrado en dosis ajustadas al peso a pacientes menores de 18 años con una vía venosa central (vvc). PKM11204. EudraCT: 2011-005155-14 PRINCIPAL INVESTIGATOR: SEVILLA NAVARRO, JULIÁN Estudio de dos partes, doble ciego, aleatorizado, controlado con placebo y abierto para investigar la eficacia, seguridad y tolerabilidad de eltrombopag, un agonista del receptor de la trombopoyetina, en sujetos pediátricos con púrpura trobocitopénica inmune (idiopática) (PTI) crónica previamente tratados. TRA115450. EudraCT: 2011-002184-17 PRINCIPAL INVESTIGATOR: PÉREZ MARTÍNEZ, ANTONIO Infusión de células Natural Killer en combinación con quimioterapia en pacientes pediátricos con leucemia/linfoma Trefractaria. HNJ-NKAES-2012 EudraCT: 2012-000054-63 PRINCIPAL INVESTIGATOR: DÍAZ, PÉREZ, MIGUEL ÁNGEL Trasplante de progenitores hematopoyéticos de donante familiar haploidéntico con infusión de linfocitos del donante tras alo-deplección selectiva “in vitro” en pacientes pediátricos con hemopatías malignas de alto riesgo. HNJ-LINF-2012 EudraCT: 2012-000029-34 PRINCIPAL INVESTIGATOR: LASSALETTA ATIENZA, ÁLVARO Estudio en fase I/II de sunitinib en pacientes jóvenes con tumor avanzado del estroma gastrointestinal. A6181196 EudraCT: 2011-002008-33 PRINCIPAL INVESTIGATOR: LASSALETTA ATIENZA, ÁLVARO Estudio de fase Ib de farmacocinética y farmacodinamia, abierto, aleatorizado, adaptativo y multicéntrico de oseltamivir (Tamiflu®) en el tratamiento de la gripe en menores inmunocomprometidos, entre 0 a 18 años, con infección de gripe confirmada. NV25719 EudraCT: 2012-002633-11 PRINCIPAL INVESTIGATOR: LASSALETTA ATIENZA, ÁLVARO Ensayo fase II multicéntrico y prospectivo con gemcitabina y rapamicina en segunda línea de osteosarcoma metastásico. EC11-4444 OSTEOSARC EudraCT: 2012-001106-26 PRINCIPAL INVESTIGATOR: LASSALETTA ATIENZA, ÁLVARO Estudio piloto multicéntrico, de brazo único, abierta para explorar la seguridad, tolerabilidad, la farmacocinética y la eficacia de administraciones múltiples intravenosas de NI-0501, un anticuerpo monoclonal anti-interferón gamma (anti-ifny), en paciente pediátricos con linfohistiocitosis hemofagocítica primaria que se ha reactivado. NI-0501-04 EudraCT: 2012-003632-23 PRINCIPAL INVESTIGATOR: MADERO LÓPEZ, LUIS Estudio fase III, multicéntrico, abierto, aleatorizado, controlado, que evalúa la seguridad y eficacia de LDE225 oral frente a temozolomida en pacientes con meduloblastoma en recidiva que tengan activación de la vía Hh. CLDE225C2301 EudraCT: 2012-003066-40 GRUPO 43 HEAD OF LABORATORY Guillermo Reyes Copa GROUP MEMBERS • Beatriz Aguado Bueno – 127 – AREA 3AREA 2 AREA 1 fusión en el paciente. FANCOSTEM-1. EudraCT: 2011-006197-88 Advanced therapies and individualized medicine RESEARCH INTEREST Our scientific investigation has been focused mainly in two aspects: The clinical performance of aortic valve prosthesis and the outcomes of a new treatment for multiple myeloma. Regarding the multiple myeloma we reported the efficacy, safety and health-related quality-of-life (HRQoL) associated with long-term lenalidomide and dexamethasone (Len + Dex) treatment in patients with relapsed or refractory multiple myeloma (RRMM) enrolled in the Spanish cohort of the MM-018 study. In this open-label, multicenter, single-arm expanded access study, 63 patients received Len + Dex until disease progression. The overall response rate was 78%, with 21% of the patients achieving a complete response. The quality of response improved with continuous treatment. Median time-to-progression and progression-free survival was 13.3 months for both; median overall survival was not reached. Len + Dex had a manageable safety profile consistent with previously reported phase III studies. Considering heart diseases, we described a total of 168 patients (104 males, 64 females; mean age 62 ± 9.9 years) that underwent aortic valve replacement with the Bicarbon Overline valve between September 2004 and June 2010. All patients were monitored by means of clinical examination and serial echocardiography. At the 12-month follow up, peak and mean transprosthetic gradients were 23.6 ± 8.1 mmHg and 12.9 ± 4.9 mmHg, respectively. Preoperatively, the average effective orifice area (EOA) was 0.80 ± 0.41 cm2, while the postoperative average EOA was 2.01 – 128 – Overall cumulative survival for up to four years after surgery. ± 0.26 cm2. No prosthesis-patient mismatch (PPM) was observed. Freedom from any valve-related event at three, 12 and 24 months was 98.6%, 97.8% and 93.3%, respectively. PUBLICATIONS (0) [IF: 0] YEAR Total IF Publication No. Q1 Q2 2010 6,74 3 1 1 2011 3,373 2 2012 AREA 3 Line 3.4 Advanced therapies in oncohematology GRUPO 44 HEAD OF LABORATORY Juan Luis Steegmann Olmedillas In vitro dendrogram depicting the kinase targets of imatinib, nilotinib and dasatinib. Illustration. Reproduced courtesy of Cell Signaling Technology, Inc. (http://www.cellsignal.com). Steegmann, J.L., et al., LeukLymphoma, 2012. 53(12): p. 2351-61. RESEARCH INTEREST Our Group has produced, in the year 2012, twenty-four papers, with an accumulated impact factor of 172. The spectrum covers all hematologic neoplasms. The group continues very active in its presence in Spanish and International collaborative groups, and most of our production comes from this source, although this year has shown more presence of our “home-made” production. In this summary, we comment only the findings coming from papers. Here follows a selection. In Chronic Myeloid Leukemia (CML), Dr. Steegmann has been the first author of a review of adverse events (Fig 1) and coauthor of two papers on international guidelines for management of CML, and on research methodology and definitions (Fig 2). In Multiple myeloma (MM), Dr Alegre was the first author of a paper which summarized the Spanish experience with lenalidomide plus dexamethasone in relapsed MM, and coauthor of an important paper on Outcomes and events in CML. Outcomes and events that may potentially occur during the course of CML disease are presented from diagnosis to death. Intercurrent events (IC) pertain to adverse events (ie, toxicities resulting from treatment) or events unrelated with the disease or its treatment.Guilhot J, …, Steegmann JL, Zaritskey A, Hehlmann R: Blood 2012, 119:5963-5971 induction therapy of this disease. In Lymphoma, Dr. Arranz has been coauthor in an study focused in prognosis of advanced Hodgkin`s Lymphoma, a field in which she continues a long-term work. Dr. Loscertales has been coauthor of a study which shows the efficacy of Bendamustine in CLL. Dr. GarciaNoblejas continued to publish in CMV infections after BMT, with a nice study of the kinetics of NK cells. Finally, Dr. Figuera and Dr. Steegmann have been coauthors in a PLoS paper mastered by Dr. CuestaDominguez and Fernández Ruiz, describing the tumorigenic activity of a novel BCR-JAK2 kinase – 129 – AREA 3AREA 2 AREA 1 GROUP MEMBERS • Adrián Alegre Amor • Ángela Figuera Álvarez • María Reyes Arranz Sáez • Javier Loscertales Pueyo • Valle Gómez García de Soria • María Jimena Cannata Ortiz • Ana María García-Noblejas Moya • Jimena Jiménez Braña Advanced therapies and individualized medicine MAJOR GRANTS • Juan Luis Steegmann Olmedillas. European treatment and outcome study on CML, EUTOS. European Leukemia Net. Proyecto EUTOS de la European LeukemiaNet. Duration: 2009 - 2013. • Juan Luis Steegmann Olmedillas. Aspectos de toxicidad, farmacocinética y farmacogenética que determinan la respuesta al tratamiento con inhibidores de tirosina cinasa, en pacientes con leucemia mieloide crónica. ISCIII. Red Europea de Leucemia. PI07/91015 y Proyecto EUTOS de la European LeukemiaNet. Duration: 2012 - 2014. PUBLICATIONS (22) [IF: 164,100] YEAR Total IF Publication No. Q1 Q2 2010 99,48 15 8 7 2011 85,353 16 9 3 2012 164,1 22 15 4 Baccarani M, Pileri S, Steegmann JL, Muller M, Soverini S, Dreyling M, Grp, ESMO Guidelines Working. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 23(Suppl 7):vii72-77. 2012. PMID: 22997458. IF: 6,425. DOI: 10.1093/annonc/mds228 Robak T, Windyga J, Trelinski J, von Depka Prondzinski M, Giagounidis A, Doyen C, Janssens A, AlvarezRomán MT, Jarque I, Loscertales J, Rus GP, Hellmann A, Jedrzejczak WW, Kuliczkowski K, Golubovic LM, Celeketic D, Cucuianu A, Gheorghita E, Lazaroiu M, Shpilberg O, Attias D, Karyagina E, Svetlana K, Vilchevska K, Cooper N, Talks K, Prabhu M, Sripada P, Bharadwaj TP, Næsted H, Skartved NJ, Frandsen TP, Flensburg MF, Andersen PS, Petersen J. Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia. Blood 120(18):3670-6. 2012. PMID: 22915649. IF: 9,898. DOI: 10.1182/blood-2012-06-438804 Paiva B, Vídriales MB, Montalbán MA, Pérez JJ, Gutiérrez NC, Rosiñol L, Martínez-López J, Mateos MV, Cordón L, Oriol A, Terol MJ, Echeveste MA, De Paz R, De Arriba F, Palomera L, la Rubia JD, DíazMediavilla J, Sureda A, Gorosquieta A, Alegre A, Martin A, Lahuerta JJ, Bladé J, Orfao A, San Miguel JF. Multiparameter Flow Cytometry Evaluation of Plasma Cell DNA Content and Proliferation in 595 Transplant-Eligible Patients with Myeloma Included in the Spanish GEM2000 and GEM2005. American Journal Pathology 181(5):1870-8. 2012. PMID: 22974582. IF: 4,89. DOI: 10.1016/j.ajpath.2012. 07.020 Rosiñol L, Oriol A, Teruel AI, Hernández D, LópezJiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, MartínRamos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; on behalf of the Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pre- transplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 120(8):1589-1596. 2012. PMID: 22791289. IF: 9,898. DOI: 10.1182/blood-2012-02-408922 Font P, Loscertales J, Benavente C, Bermejo A, Callejas M, Garcia-Alonso L, Garcia-Marcilla A, Gil S, Lopez-Rubio M, Martin E, Muñoz C, Ricard P, Soto C, Balsalobre P, Villegas A. Inter-observer variance with the diagnosis of myelodysplastic syndromes (MDS) following the 2008 WHO classification. Ann Hematol. 92(1):19-24. 2012. PMID: 22948274. IF: 2,615. DOI: 10.1007/s00277-0121565-4 Paiva B, Gutiérrez NC, Rosiñol L, Vídriales MB, Montalbán MÁ, Martínez-López J, Mateos MV, Cibeira MT, Cordón L, Oriol A, Terol MJ, Echeveste MA, de Paz R, de Arriba F, Palomera L, de la Rubia J, DíazMediavilla J, Sureda A, Gorosquieta A, Alegre A, Martin A, Hernández MT, Lahuerta JJ, Bladé J, San Miguel JF; PETHEMA/GEM (Programa para el Estudio de la Terapéutica en Hemopatías Malignas/Grupo Español de Mieloma) Cooperative Study Groups. – 130 – AREA 3 Guilhot J, Baccarani M, Clark RE, Cervantes F, Guilhot F, Hochhaus A, Kulikov S, Mayer J, Petzer AL, Rosti G, Rousselot P, Saglio G, Saussele S, Simonsson B, Steegmann JL, Zaritskey A, Hehlmann R. Definitions, methodological and statistical issues for phase 3 clinical trials in chronic myeloid leukemia: a proposal by the European LeukemiaNet. Blood. Epub 2012 Apr 16 119(25):5963-5971. 2012. PMID: 22508936. IF: 9,898. DOI: 10.1182/blood-2011-10383711 Ljungman P, Locasciulli A, de Soria VG, Békássy AN, Brinch L, Espigado I, Ferrant A, Franklin IM, O'Riordan J, Rovira M, Shaw P, Einsele H. Long-term follow-up of HCV-infected hematopoietic SCT patients and effects of antiviral therapy. Bone Marrow Transplant. 47(9):1217-1221. Epub 2011 Dec 12. 2012. PMID: 22158388. IF: 3,746. DOI: 10.1038/bmt.2011.238 Delgado J, Espinet B, Oliveira AC, Abrisqueta P, de la Serna J, Collado R,Loscertales J, Lopez M, Hernandez-Rivas JA, Ferra C, Ramirez A, Roncero JM, Lopez C, Aventin A, Puiggros A, Abella E, Carbonell F, Costa D, Carrio A, Gonzalez M; on behalf of the Grupo Español de Leucemia Linfatica Cronica (GELLC) y Grupo Español de Citogenetica Hematologica (GECGH). Chronic lymphocytic leukaemia with 17p deletion: a retrospective analysis of prognostic factors and therapy results. Br J Haematol 157(1):67-74. 2012. PMID: 22224845. IF: 4,941. DOI: 10.1111/j.1365-2141.2011.09000.x Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol 159(1):67-77. 2012. PMID: 22861163. IF: 4,941. DOI: 10.1111/bjh.12000 Dimopoulos MA, Terpos E, Goldschmidt H, Alegre A, Mark T, Niesvizky R. Treatment with lenalidomide and dexamethasone in patients with multiple myeloma and renal impairment. Cancer Treatment Reviews. 38(8):1012-9. 2012. PMID: 22609463. IF: 6,054. DOI: 10.1016/j.ctrv.2012.02.009 Bustos A, Álvarez R, Aramburo PM, Carabantes F, Díaz N, Florián J, Lázaro M, de Segovia JM, Gasquet JA, Alegre A; RADAR Study Group. Evaluation of clinical use and effectiveness of darbepoetin alfa in cancer patients with chemotherapy-induced anemia. Curr Med Res Opin. 28(1):57-67. Epub 2011 Nov 23. 2012. PMID: 22070513. IF: 2,38. DOI: 10.1185/03007995. 2011.639352 Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M, Passweg J, Martino R, Valcarcel D, Besalduch J, Duarte R, Leon A, Pascual MJ, GarciaNoblejas A, Lopez Corral L, Xicoy B, Sierra J, Schmitz N. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin'slymphoma. Results of the HDRALLO study - a prospectiveclinical tr ial by the Grupo Espanol de Linfomas/ Trasplante deMedula Osea (GEL/TAMO) and the Lymphoma Working Party ofthe European Group for Blood and Marrow Transplantation. Haematologica 97(2):310-317. Epub 2011 Oct 11. 2012. PMID: 21993674. IF: 6,424. DOI: 10.3324/haematol.2011.045757 Rosiñol L, García-Sanz R, Lahuerta JJ, HernándezGarcía M, Granell M, de la Rubia J, Oriol A, HernándezRuiz B, Rayón C, Navarro I, García-Ruiz JC, Besalduch J, Gardella S, Jiménez JL, Díaz-Mediavilla J, Alegre A, Miguel JS, Bladé J; on behalf of the PETHEMA/Spanish Myeloma Group. Benefit from autologous stem cell transplantation in primary refractory myeloma? Different outcomes in progressive versus stable disease. Haematologica. 97(4):616-621. Epub 2011 Nov 4. 2012. PMID: 22058223. IF: 6,424. DOI: 10.3324/haematol.2011.051441 – 131 – AREA 3AREA 2 AREA 1 High-risk cytogenetics and persistent minimal residual disease by multiparameter flow cytometry predict unsustained complete response after autologous stem cell transplantation in multiple myeloma. Blood. 119(3):687-91. Epub 2011 Nov 29. 2012. PMID: 22128143. IF: 9,898. DOI: 10.1182/blood-2011-07370460 Advanced therapies and individualized medicine Llamas-Velasco M, Cannata J, Dominguez I, GarcíaNoblejas A, Maximiliano Aragües, Fraga J, Arranz R. Coexistence of Langerhans cell histiocytosis, RosaiDorfman disease and splenic lymphoma with fatal outcome after rapid development of histiocytic sarcoma of the liver. J Cutan Pathol. 39(12):1125-30. 2012. PMID: 23043641. IF: 1,561. DOI: 10.1111/cup.12013 Steegmann JL, Cervantes F, Le Coutre P, Porkka K, Saglio G. Off-target effects of BCR-ABL1 inhibitors and their potential long-term implications in patients with chronic myeloid leukemia. Leuk Lymphoma 53(12):2351-61. 2012. PMID: 22616642. IF: 2,58. DOI: 10.3109/10428194.2012.695779 Guisado-Vasco P, Arranz-Saez R, Canales M, Cánovas A, Garcia-Laraña J, García-Sanz R, Lopez A, López JL, Llanos M, Moraleda JM, Rodriguez J, Rayón C, Sabin P, Salar A, Marín-Niebla A, Morente M, Sánchez-Godoy P, Tomás JF, Muriel A, Abraira V, Piris MA, Garcia JF, Montalban C. Stage IV and age over 45 years are the only prognostic factors of the International Prognostic Score for the outcome of advanced Hodgkin lymphoma in the Spanish Hodgkin Lymphoma Study Group series. Leuk Lymphoma. 53(5):812-9. 2012. PMID: 22185637. IF: 2,58. DOI: 10.3109/10428194. 2011.635861 Leukemia & Lymphoma. 53(9):1714-1721. 2012. PMID: 22292853. IF: 2,58. DOI: 10.3109/10428194. 2012.662643 Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators (.., Alegre A, ..). Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 366(19):1759-69. 2012. PMID: 22571200. IF: 53,298. DOI: 10.1056/NEJMoa1112704 Cuesta-Domínguez Á, Ortega M, Ormazábal C, Santos-Roncero M, Galán-Díez M, Steegmann JL, Figuera Á, Arranz E, Vizmanos JL, Bueren JA, Río P, Fernández-Ruiz E. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCR-JAK2 tyrosine-kinase. PLoS One. Epub 2012 Feb 27. 7(2):e32451. 2012. PMID: 22384256. IF: 4,092. DOI: 10.1371/journal. pone.0032451 BOOKS Sanchez-Gonzalez B, Peñalver FJ, Medina A, Guillén H, Calleja M, Gironella M, Arranz R, Sebastian E, de Oña R, Cánovas A, de la Fuente I, Grande C, Sancho JM, Perez R, Domingo E, Lopez-Lorenzo JL, Prieto E, Panizo C, Gorosquieta A, Perez I, Cervera JM, Marin M, Mencha C, Ramila E, Salar A. Clinical experience of bendamustine treatment for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Spain. Leuk Res. Epub 2011 Dec 7. 36(6):709-14. 2012. PMID: 22154023. IF: 2,923. DOI: 10.1016/j.leukres. 2011.10.024 Alegre A, Oriol-Rocafiguera A, Garcia-Larana J, Mateos MV, Sureda A, Martinez-Chamorro C, Cibeira MT, Aguado B, Knight R, Rosettani B. Efficacy, safety and quality-of-life associated with lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma: the Spanish experience. – 132 – A Alegre, A Villegas. La formación de especialistas de Hematología y Hemoterapia. Libro Blanco de Hematología en España. Ed. SEEH. 2012. EDIMSA Madrid. María Reyes Arranz Sáez. Actualización del tratamiento del LDCGB. Cuadernos de Hematología. Fundación Leucemia y Linfoma Año 2012. 2012. You and Us. Reyes Arranz, Coordinadora de la monografía: Actualización del tratamiento en Linfomas. Online web F.L.L. María Reyes Arranz Sáez. Actualización del Tratamiento del Linfoma Folicular. Cuadernos de Hematología. Fundación Leucemia y Linfoma. 2012. You and Us. Reyes Arranz, Coordinadora de la monografía: Actualización del tratamiento en Linfomas. Online web. AREA 3 Gómez García de Soria, Valle. Guía Madrileña de Síndromes Mielodisplásicos. 2012. Asociación Madrileña de Hematología y Hemoterapia. ISBN: 97884-15351-41-2. A Alegre, JM Fernández Rañada, N Cuenca y Pilar Calvo-Sotelo. Las Fundaciones y Asociaciones de Pacientes de Hematología. Libro Blanco de Heamtología en España. Ed. SEEH. 2012. EDIMSA Madrid. Editor asociado Adrián Alegre. Monografía Bendamustina en Síndromes Linfoproliferativos Crónicos. Casos Clínicos. 2012. You and Us. Adrián Alegre. Actualización en el Tratamiento de los Síndromes Linfoproliferativos. Módulo 2.- Cuadernos de Hematología 2012. 2012. Editorial You and Us. Editor asociado. Adrián Alegre. Actualización en el Tratamiento de Gammapatías Monoclonales Atípicas. Módulo 1.Cuadernos de Hematología 2012. 2012. Editorial You and Us. Editor asociado. Javier Loscertales. Bendamustina en monoterapia tras FCR. Archivos Clínicos de Sindromes Linfoproliferativos Crónicos. 2012. Ana García Noblejas. Linfoma de células del manto. Linfomas B y T: Biología, clínica y tratamiento. 2012. ISBN: 978-84-7885-541-4. Ana García Noblejas. Actualización del tratamiento del linfoma folicular. Módulo 1.- Cuadernos de Hematología 2012. 2012. Ana García Noblejas. Actualización del tratamiento del linfoma de células del manto. Módulo 1.- Cuadernos de Hematología 2012. 2012. A Alegre, EM Ocio. ¿Cuál es el futuro de los Nuevos Agentes en el Mieloma Múltiple?. 100 Preguntas sobre el Mieloma Múltiple. 2012. You and Us. JJ Lahuerta Ed. María Reyes Arranz Sáez. Linfoma de células del manto. 2012. Ediciones Aula Médica. ISBN: 978-847885-541. CLINICAL TRIALS PRINCIPAL INVESTIGATOR: ALEGRE AMOR, ADRIAN Estudio multicéntrico, aleatorizado y doble ciego de denosumab en comparación con ácido zoledrónico (Zometa«) para el tratamiento de enfermedad ósea en sujetos con mieloma múltiple de nuevo diagnóstico; (versión amend1: 18-08-11). AMGEN INC. 20090482. EudraCT: 2010-020454-34 PRINCIPAL INVESTIGATOR: ALEGRE AMOR, ADRIAN Estudio de fase 2/3, multicéntrico, aleatorizado, doble ciego, controlado con placebo, en el que se evalúa la administración de tabalumab en combinación con bortezomib y dexametasona en pacientes con mieloma múltiple previamente tratados; (versión a: 28-0212). LILLY, S.A. H9S-MC-JDCG. EudraCT: 2011-005103-32 PRINCIPAL INVESTIGATOR: GOMEZ GARCIA-SORIA, VALLE Estudio fase Ib/IIb, abierto, multicéntrico, de panobinostat (LBH589) oral administrado con 5-azacitidina (vidaza), en pacientes adultos con síndromes mielodisplásicos (SMD), leucemia mielomonocítica crónica (LMMC) o leucemia mieloide aguda (LMA); (versión 02: 24-10-12). NOVARTIS FARMACEUTICA, S.A. CLBH589H2101. EudraCT: 2009-010548-32 PRINCIPAL INVESTIGATOR: LOSCERTALES PUEYO, JAVIER Estudio fase II, multicéntrico para investigar la seguridad y eficacia de la combinación de ofatumumab y bendamustina en pacientes con leucemialinfocítica crónica (LLC) no tratada o en recaída; (versión 2011N125324/00(España):17-11-11). – 133 – AREA 3AREA 2 AREA 1 María Reyes Arranz Sáez. Actualización del Tratamiento de Linfoma de células del manto. Cuadernos de Hematología. Fundación Leucemia y Linfoma. 2012. You and Us. Reyes Arranz, Coordinadora de la monografía: Actualización del tratamiento en Linfomas. Online web F.L.L. Advanced therapies and individualized medicine GLAXOSMITHKLINE, S.A. OMB115991. EudraCT: 2011-005178-43 PRINCIPAL INVESTIGATOR: ALEGRE AMOR, ADRIAN Estudio multicéntrico, abierto y de un solo brazo con pomalidomida en combinación con dexametasona a dosis bajas en sujetos con mieloma múltiple refractario o mieloma múltiple en recaída y refractario; (versión final: 23-05-12). CELGENE CORPORATION. CC4047-MM-010. EudraCT: 2012-001888-78 PRINCIPAL INVESTIGATOR: ARRANZ SAEZ, MARIAREYES Ensayo multicéntrico, internacional, de fase 3, de dos grupos, aleatorizado y abierto de alisertib (MLN8237) o la elección del investigador (agente único seleccionado) en pacientes con linfoma de células T periféricas recidivante o resistentes al tratamiento; (Versión enmienda 105-01-12). MILLENNIUM PHARMACEUTICALS, INC. C14012. EudraCT: 2011-003545-18 PRINCIPAL INVESTIGATOR: ARRANZ SAEZ, MARIAREYES Estudio fase 3, aleatorizado, controlado, abierto y multicéntrico del inhibidor de la Tirosina Quinasa de Bruton (BTK), ibrutinib, frente a temsirolimus en sujetos con linfoma de células del manto en recaída o refractario que han recibido al menos un tratamiento previo;(Versión final: 26-06-12). JANSSEN-CILAG INTERNATIONAL NV. PCI-32765MCL3001. EudraCT: 2012-000601-74 PRINCIPAL INVESTIGATOR: ALEGRE AMOR, ADRIAN Estudio de fase 3, aleatorizado, controlado, abierto, multicéntrico para evaluar la seguridad y la eficacia de dexametasona mas MLN9708 en comparación con el tratamiento elegido por el médico administrado a pacientes amiloidosis sistémica de cadenas ligeras recidivante o refractaria;(versión Amend.1: 01-06-12). MILLENNIUM PHARMACEUTICALS, INC. C16011. EudraCT: 2011-005468-10 PRINCIPAL INVESTIGATOR: ALEGRE AMOR, ADRIAN Registro observacional post autorización para evaluar – 134 – el impacto clínico del inicio de la terapia antitumoral de rescate en pacientes con mieloma múltiple (MM) en recaída biológica asintomática frente al inicio del tratamiento en el momento de la recaída sintomática; (Versión final: 17-09-12). (Estudio EPA-MMBR). CELGENE, S.L. CEL-MIE-2012-02 PRINCIPAL INVESTIGATOR: STEEGMANN OLMEDILLAS, JUAN-LUIS Ensayo clínico fase II multicéntrico, abierto, no aleatorizado de dasatinib en pacientes con leucemia mieloide crónica en fase crónica (LMC- -FC) con criterios de respuesta subóptima tardía tras tratamiento con imatinib; (versión 2: 10-9-12). FUNDACION PETHEMA. DASAPOST. EudraCT: 2012-004259-36 PRINCIPAL INVESTIGATOR: ARRANZ SAEZ, MARIAREYES Estudio retrospectivo del tratamiento con el esquema R-COMP de pacientes mayores de 70 años con linfoma no Hodgkin B de alto grado;(versión draftv03: diciembre 2011). MD ANDERSON IE. MDA-LNH-2011-01 PRINCIPAL INVESTIGATOR: FIGUERA ALVAREZ, ANGELA Estudio de fase III, aleatorizado y doble ciego de Febuxostat para la prevención del síndrome de lisis tumoral en las neoplasias malignas hematológicas en comparación con alopurinol; (versión 1.1:2-04-12). MENARINI RICERCHE S.P.A. FLO-01. EudraCT: 2012-000776-42 PRINCIPAL INVESTIGATOR: ALEGRE AMOR, ADRIAN Estudio de fase 2, aleatorizado, de bortezomib/dexametasona, con o sin elotuzumab, en sujetos con mieloma múltiple en recidiva o resistente al tratamiento; (versión orig+amd1: 20-07-11). BRISTOL MYERS SQUIBB INTERNATIONAL CORPORATION. CA204009. EudraCT: 2011-002695-16 PRINCIPAL INVESTIGATOR: GOMEZ GARCIA-SORIA, VALLE Estudio de fase III, multicéntrico, aleatorizado y controlado para evaluar la eficacia y la seguridad de ON AREA 3 PRINCIPAL INVESTIGATOR: ARRANZ SAEZ, MARIAREYES Estudio fase 2, multicéntrico, de un solo brazo de tratamiento para evaluar la eficacia y seguridad del inhibidor de la Tirosina Quinasa de Bruton (Btk), ibrutinib, en monoterapia, en sujetos con Linfoma de Células del Manto que progresan después de la terapia con bortezomib; (versión final: 06-04-12). JANSSEN-CILAG INTERNATIONAL NV. PCI-32765 MCL2001. EudraCT: 2012-000711-88 PRINCIPAL INVESTIGATOR: ALEGRE AMOR, ADRIAN Estudio de fase 3 aleatorizado y abierto de carfilzomib y dexametasona en comparación con bortezomib y dexametasona en pacientes con mieloma múltiple en recidiva; (Versión 13-03-12). ONYX THERAPEUTICS, INC. 2011-003. EudraCT: 2012-000128-16 PRINCIPAL INVESTIGATOR: LOSCERTALES PUEYO, JAVIER Estudio fase 3, aleatorizado, doble ciego, controlado con placebo, de ibrutinib, un inhibidor de la Tirosina Quinasa de Bruton (Btk), en combinación con bendamustina y rituximab (BR) en sujetos con Leucemia Linfocítica Crónica/Linfoma Linfocítico de Células Pequeñas en recaída o refractario;(Versión final:09-0512). JANSSEN-CILAG INTERNATIONAL NV. PCI32765CLL3001. EudraCT: 2012-000600-15 PRINCIPAL INVESTIGATOR: LOSCERTALES PUEYO, JAVIER Estudio de fase 3, aleatorizado, doble ciego, controlado con placebo para evaluar la eficacia y seguridad de GS-1101 (CAL-101) en combinación con bendamustina y rituximab para la leucemia linfocítica crónica tratada previamente; (Versión 1:16-03-12). GILEAD SCIENCES, INC. GS-US-312-0115. EudraCT: 2011-006292-20 – 135 – AREA 3AREA 2 AREA 1 01910.Na al administrarse mediante infusión intravenosa continua de 72 horas en semanas alternas a pacientes con síndrome mielodisplásico con exceso de blastocitos que presentan recurrencia tras el tratamiento con azacitidina o decitabina, o resistencia o intolerancia a dichos fármacos, (versión 11-08-11). ONCONOVA THERAPEUTICS INC. abr-21. EudraCT: 2010-019755-21 Advanced therapies and individualized medicine Line 3.5 Biological, cellular and molecular monitoring in oncohematology GRUPO 45 HEAD OF LABORATORY Elena Fernández Ruiz GROUP MEMBERS • Álvaro Cuesta Domínguez • Matilde Santos Roncero • Irene Bodega Mayor • Mónica Sala Valdés RESEARCH INTEREST JAK2 is a non-receptor tyrosine kinase, essential for signaling through a variety of cytokine receptors and required for normal hematopoiesis. Activation of the JAK2-cytokine receptor complex leads to STAT5 phosphorylation and nuclear translocation triggering survival gene transcription. We have described the transforming and tumorigenic activity of a new chimeric protein, BCR-JAK2, obtained from a patient with acute lymphocytic leukemia (ALL) and nonfavorable cytogenetics. Patients with BCR-ABL negative leukemia with JAK2 rearrangements are not responders to small tyrosine-kinase inhibitors targeting ABL as Imatinib. The finding that JAK2 inhibitors down regulate BCR-JAK2 in vitro indicates that patients with leukemia and JAK2 rearrangements may benefit from targeted therapies. That could be extended to pediatric B-progenitor ALL with JAK2 mutations. To prove that BCR-JAK2 could be a driving force in leukemia, we have studied the functional behavior of this tyrosine kinase in a mouse model of bone marrow transplantation. Lin- progenitors have been transduced with retroviral vectors bearing BCR-JAK2 and transplanted into – 136 – TG101209, a JAK2 inhibitor, down-regulates JAK2, BCR-JAK2, and STAT5 tyrosine-phosphorylation, as well as target gene expression of Ba/F3BCR-JAK2 transduced cells. (A) Sigmoidal dose-response curve showing viability of Ba/F3-mock growing with IL-3 (IC50= 3180 nM) and Ba/F3BCR-JAK2 and Ba/F3-TEL-JAK2 growing in absence of IL-3 (IC50= 246 and 369 nM, respectively). The percentage of growth, relative to that of cells in the absence of drug, is plotted for increasing concentrations of TG101209 (where X axis is the logarithm of concentration). (B) Western blot analysis of transduced Ba/F3 cells treated for 12 h with 1 μM TG101209 (TG) or the vehicle (DMSO). Cellular lysates were immunoprecipitated with anti-pTyr Ab and immunoblotted with anti-JAK2 (upper panel). Whole cell lysates were probed with anti-pSTAT5, anti-STAT5 and anti-Bcl-xL Ab’s (bottom). The expression levels of tubulin were used as a loading control. STAT5 levels were used as a loading control for pSTAT5. (C) qPCR for Bcl-xL, Osm and Cis expression on Ba/F3-mock, Ba/F3-BCRJAK2 and Ba/F3-TEL-JAK2 cells treated for 12 h with 1 μM TG. For comparative purposes, mRNA levels in untreated cells were normalized to 1. Bars represent fold changes of each gene after normalization with GADPH levels. Samples from three independent experiments were measured. Results are given as mean ± SEM (n=3). previously irradiated syngenic mice to assess its ability to give rise to leukemia. These mice developed a myeloproliferative neoplasm. Therefore, BCR-JAK2 is a chimeric protein with oncogenic potential. We will use this model to develop a preclinical study of the efficacy of new JAK2 inhibitors in disease reversion. MAJOR GRANTS Elena Fernández Ruiz. Implicación de JAK2 en el reconocimiento de patógenos y en la respuesta inmune innata. ISCIII. PI11/00128. Duration: 2012 - 2014. AREA 3 RESEARCH INTEREST PUBLICATIONS (1) [IF: 4,092] YEAR Total IF Publication No. Q1 Q2 2010 7,013 2 1 1 4,092 1 1 2011 2012 Cuesta-Domínguez Á, Ortega M, Ormazábal C, SantosRoncero M, Galán-Díez M, Steegmann JL, Figuera Á, Arranz E, Vizmanos JL, Bueren JA, Río P, Fernández-Ruiz E. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCRJAK2 tyrosine-kinase. PLoS One. Epub 2012 Feb 27. 7(2):e32451. 2012. PMID: 22384256. IF: 4,092. DOI: 10.1371/journal.pone.0032451 GRUPO 46 HEAD OF LABORATORY Cecilia Muñoz Calleja GROUP MEMBERS • Amada Elia Beltrán Núñez • Carlos Cuesta Mateos • Fernando Gómez-Reino Carnota • Beatriz Somovilla Crespo CCR7 mediates the pathogenesis of graft-versus-host disease (GVHD) GVHD represents one of the major complications associated with allogeneic stem cell transplantation. Our results imply that receiving a high number of CCR7+ T-cells, able to migrate to the recipient´s secondary lymphoid organs, increases the incidence of GVHD. Therefore, the absolute numbers of CCR7+ T-cells in the allograft might provide a predictive indicator of GVHD. In addition, our study indicates that alloreactive cells predominate within the CCR7+CD62L+ subsets and supports the approaches of selective T-cell depletion aiming to prevent GVHD. The tyrosine kinase inhibitor dasatinib modifies NK cell phenotype It has been suggested that NK cells improve therapy responses in dasatinib-treated chronic myeloid leukemia (CML) patients, but the mechanism is unclear. We show that the NK cells in dasatinib-treated patients have similar phenotype to chronically activated NK cells, which might be a sign of an anti-CML immune response, suggesting a role of NK cells in the enhanced therapy response. Predictive markers in rituximab treated rheumatoid arthritis patients Rheumatoid arthritis (RA) is a chronic inflammatory disease, which has been successfully treated with Rituximab (Rtx). We show that no B cell subset predict an early relapse in RA patients treated with Rtx. Conversely, the increase of effector-memory T cells and CXCR5+ T cells, which are supposed to support antibody secretion, predicts an early relapse. Therefore, we propose that these subsets may be used as biomarkers to predict poor response to Rtx treatment. – 137 – AREA 3AREA 2 AREA 1 Lin- primary progenitor cells expressing BCR-JAK2 show increased survival compared to wild-type (wt) and mock progenitor cells. Linprogenitor cells obtained from male Balb/c mice were transduced with pLZR (mock cells) or pLZR-BCR-JAK2 retroviral particles and seeded for proliferation assay during 30 days. Cortactin controls CCR7-dependent motility and invasion of breast cancer cells This work uncovered important aspects of cortactin regulation induced by CCL19/CCL21 engagement of CCR7. Our findings reveal that CCR7 and cortactin may contribute to breast cancer progression by promoting cellular structures and processes like lamellipodia and invadopodia, which are essential for metastasis. These results bring us closer to understanding the link between CCR7 and the pathogenesis of breast cancer. Advanced therapies and individualized medicine PUBLICATIONS (0) [IF: 0] YEAR Total IF Publication No. Q1 Q2 2010 12,114 3 1 2 2011 2012 GRUPO 47 HEAD OF LABORATORY Eva Arranz Muñoz Serine phosphorylation of cortactin is required for CCR7-mediated migration and invasion of MCF-7 breast cancer cells. A) Schematic cartoon of the cortactin protein constructs used in this study. We show the relevant sites of serine (S) and tyrosine (Y) phosphorylation as well as the mutants used in this study (D, aspartic; A, alanine). B) Assessment of MCF-7 cell invasion in transiently transfected cells with an empty GFP-fusion vector (GFP), or the 2A or SD GFP-cortactin mutants. Transfectants were first seeded on top of gelatin-coated inserts in transwell chambers. Then, cells were allowed to invade towards incomplete medium (white columns) or incomplete medium supplemented with 1 µg/mL CCL19 (grey columns) or CCL21 (black columns) that were added to the bottom wells. Cells were allowed to invade for 48 h, and they were deattached of the bottom side of the insert and were counted. Columns represent the average of four separate experiments, each with duplicate determinations; bars, SE. **, P < 0.01. C) MCF-7 cells transiently transfected with an empty GFP-fusion vector (GFP), or the 2A or SD GFP-cortactin mutants were seeded on p60 plates and allowed to achieve 100% confluence. Then the monolayer of MCF-7 cells was scratched with a pipette tip and cells were incubated in serumfree media with CCL19, CCL21 or without chemokines. The gaps were measured after 48 h. Migration of MCF-7 cells in a representative wound-healing experiment from three is shown. Pictures shown were taken at 0 and 48 hours. D) Percentage of open area relative to time 0. Quantification of wound closure data at 48h and 72h. Change in wound area was calculated as described in Materials and Methods. Results represent the average of three experiments at each time point. Columns represent the mean of experiments. Error bars indicate SEM. *, P < 0.05; **, P<0.01; ***, P < 0.001; ns, not significant. – 138 – GROUP MEMBERS • María Ángeles Sanz de Benito • Francisco Sanz Garrido PUBLICATIONS (1) [IF: 4,092] YEAR Total IF Publication No. Q1 Q2 2010 5,272 2 1 1 4,092 1 1 2011 2012 Cuesta-Domínguez Á, Ortega M, Ormazábal C, SantosRoncero M, Galán-Díez M, Steegmann JL, Figuera Á, Arranz E, Vizmanos JL, Bueren JA, Río P, FernándezRuiz E. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCR-JAK2 tyrosine-kinase. PLoS One. Epub 2012 Feb 27. 7(2):e32451. 2012. PMID: 22384256. IF: 4,092. DOI: 10.1371/journal.pone.0032451 BOOKS Eva Arranz, Angeles Sanz. Citogenética de los síndromes mielodisplásicos. Guía Madrileña de Síndromes Mielodisplásicos. Documentos de consenso en SMD. Asociación Madrileña de Hematología y Hemoterapia. 2012. Ergon. AREA 3 Line 3.6 New diagnostic and therapeutic advances in cardiovascular diseases GRUPO 48 arterial en pacientes mayores de 65 años con hipertensión sistólica aislada refractaria. MSPSI. EC11-111(SPI/2885/ 2011). Duration: 2012 2013. • Iluminada García Polo. Efecto de los nitratos orales sobre la presión de pulso y la elasticidad arterial en pacientes mayores de 65 años con hipertensión sistólica aislada refractaria. MCyT a través de la convocatoria de Ensayos no comerciales. EC11-111. Duration: 2012 - 2014. HEAD OF LABORATORY Luis Jesús Jiménez Borreguero PUBLICATIONS (20) [IF: 149,991] MAJOR GRANTS • Carmen del Arco Galán. Impacto de la implantación de un registro electrónico compartido en la eliminación de los errores de transcripción de la prescripción. MSPSI. EC11-107(SPI/2885/2011). Duration: 2012 - 2013. • Iluminada García Polo. Efectos de los nitratos orales sobre la presión de pulso y la elasticidad YEAR Total IF Publication No. Q1 2010 43,518 8 3 Q2 4 2011 181,383 27 17 10 2012 149,991 20 12 6 Ibanez B, Fuster V, Macaya C, Sánchez-Brunete V, Pizarro G, López-Romero P, Mateos A, JiménezBorreguero J, Fernández-Ortiz A, Sanz G, FernándezFriera L, Corral E, Barreiro MV, Ruiz-Mateos B, Goicolea J, Hernández-Antolín R, Acebal C, GarcíaRubira JC, Albarrán A, Zamorano JL, Casado I, Valenciano J, Fernández-Vázquez F, de la Torre JM, Pérez de Prado A, Iglesias-Vázquez JA, MartínezTenorio P, Iñiguez A. Study design for the "effect of METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion" (METOCARD-CNIC): a randomized, controlled parallel-group, observer-blinded clinical trial of early pre-reperfusion metoprolol administration in ST-segment elevation myocardial infarction. Am Heart J. 164(4):473-480.e5. 2012. PMID: 23067904. IF: 4,651. DOI: 10.1016/j.ahj.2012.07.020 Sarraj A, Zarra KV, Jiménez-Borreguero LJ, Caballero P, Nuche JM. Isolated cardiac involvement of RosaiDorfman disease. Ann Thorac Surg. 94(6):2118-20. 2012. PMID: 23176929. IF: 3,741. DOI: 10.1016/j.athoracsur.2012.04.134 Caballero P, Alonso R, Rosado P, Mata N, FernándezFriera L, Jiménez-Borreguero LJ, Badimon L, Mata P. Detection of subclinical atherosclerosis in familial – 139 – AREA 3AREA 2 AREA 1 GROUP MEMBERS • Luis Martínez Elbal • Carmen Suárez Fernández • Nuria Ruiz-Giménez Arrieta • Ramón Puchades Rincón de Arellano • Carmen del Arco Galán • Iluminada García Polo • Paloma Gil Martínez • Fernando Moldenhauer Díaz • Javier Roldan Núñez • Patricia Ibáñez Sanz • Natividad Gómez Gómez • Rosa María Moreno Carriles • Antonio Reyes García • Alfonsa Friera Reyes • María José Olivera Serrano • Amparo Benedicto Buendía • Bernhard Seidelberger • Fernando Rivero Crespo • Paloma Caballero Sánchez-Robles Advanced therapies and individualized medicine hypercholesterolemia using non-invasive imaging modalities. Atherosclerosis. 222(2):468-72. 2012. PMID: 22460051. IF: 3,794. DOI: 10.1016/j.atherosclerosis.2012.02.043 Real de Asúa D, Puchades R, García-Polo I, Suárez C. Influence of multiple blood pressure measurements on the estimation of the ankle-brachial index and the consequent diagnosis of peripheral artery disease. Blood Press Monit. 17(2):73-5. 2012. PMID: 22343750. IF: 1,52. DOI: 10.1097/MBP.0b013e328351de79 Sánchez-Gómez LM, Fernández-Luque MJ, Ruiz-Díaz L, Sánchez-Alcalde R, Sierra-García B, MayayoVicente S, Ruiz-López M, Loeches-Belinchón P, López-Gónzález J, González-Gamarra A, GallegoArenas A, Cubillo-Serna A, Gil-Juberias G, PérezCayuela P, Cañedo-Arguelles CA, García-Pascual JN, Ruiz-Chércoles E, Suarez-Fernández C, Garcia-Polo I, Abad-Perez D, Ballesteros-Arribas JM, IzquierdoMartínez M, Salvador-Alcaide E, Arribas-Vela AB, Alonso-Pérez JM, Veja-Piris L, Rodríguez-Salvanés F, Novella-Arribas B. A cluster-randomised clinical trial comparing two cardiovascular health education strategies in a child population: the Savinghearts project. BMC Public Health. 12:1024. 2012. PMID: 23176593. IF: 1,997. DOI: 10.1186/1471-2458-12-1024 Kozakova M, Palombo C, Eng MP, Dekker J, Flyvbjerg A, Mitrakou A, Gastaldelli A, Ferrannini E; RISC Investigators (.., Carraro R, Friera A, Novella B, ..). Fatty liver index, gamma-glutamyltransferase, and early carotid plaques. Hepatology. 55(5):1406-15. 2012. PMID: 22334565. IF: 11,665. DOI: 10.1002/hep.25555 Di Micco P, Fontanella A, Falvo N, Bonithon-Kopp C, Decousus H, Riera-Mestre A, Monreal M; RIETE Investigators (.., Ruiz-Giménez N, ..). Natural history of patients developing thrombocytopenia while receiving anticoagulant therapy for venous thromboembolism. Int Angiol. 31(1):92-5. 2012. PMID: 22330631. IF: 1,652 Merino P, Álvarez J, Cruz Martín M, Alonso Á, Gutiérrez I; SYREC Study Investigators (Reyes García A). Adverse events in Spanish intensive care units: the – 140 – SYREC study. Int J Qual Health Care. 24(2):105-13. 2012. PMID: 22190588. IF: 1,958. DOI: 10.1093/intqhc/mzr083 Handberg A, Højlund K, Gastaldelli A, Flyvbjerg A, Dekker JM, Petrie J, Piatti P, Beck-Nielsen H; RISC Investigators (.., Carraro R, Friera A, Novella B, ..). Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. J Intern Med. 271(3):294-304. 2012. PMID: 21883535. IF: 5,483. DOI: 10.1111/j.1365-2796.2011.02442.x Tzoran I, Saharov G, Brenner B, Delsart D, Román P, Visoná A, Jiménez D, Monreal M; RIETE Investigators (.., Ruiz-Giménez N, ..). Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs. J Thromb Haemost. 10(4):564-71. 2012. PMID: 22288520. IF: 5,731. DOI: 10.1111/j.15387836.2012.04648.x Nauffal D, Ballester M, Reyes RL, Jiménez D, Otero R, Quintavalla R, Monreal M; RIETE Investigators (.., RuizGiménez N, ..). Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism. J Thromb Haemost. 10(9):1752-60. 2012. PMID: 22726525. IF: 5,731. DOI: 10.1111/j.15387836.2012.04829.x Alfonso F, Pérez-Vizcayno MJ, Dutary J, Zueco J, Cequier A, García-Touchard A, Martí V, Lozano I, Angel J, Hernández JM, López-Mínguez JR, Melgares R, Moreno R, Seidelberger B, Fernández C, Hernandez R; RIBS-III Study Investigators (under the auspices of the Working Group on Interventional Cardiology of the Spanish Society of Cardiology)(.., Martinez Elbal L,..). Implantation of a drug-eluting stent with a different drug (switch strategy) in patients with drug-eluting stent restenosis. Results from a prospective multicenter study (RIBS III [Restenosis Intra-Stent: Balloon Angioplasty Versus Drug-Eluting Stent]). JACC Cardiovasc Interv. 5(7):728-37. 2012. PMID: 22814777. IF: 6,8. DOI: 10.1016/j.jcin.2012.03.017 Camenzind E, Wijns W, Mauri L, Kurowski V, Parikh K, Gao R, Bode C, Greenwood JP, Boersma E, Vranckx P, AREA 3 Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Erokhin VV, Ershova J, Gler MT, Kazennyy BY, Kim HJ, Kliiman K, Kurbatova E, Kvasnovsky C, Leimane V, van der Walt M, Via LE, Volchenkov GV, Yagui MA, Kang H; Global PETTS Investigators, Akksilp R, Sitti W, Wattanaamornkiet W, Andreevskaya SN, Chernousova LN, Demikhova OV, Larionova EE, Smirnova TG, Vasilieva IA, Vorobyeva AV, Barry CE 3rd, Cai Y, Shamputa IC, Bayona J, Contreras C, Bonilla C, Jave O, Brand J, Lancaster J, Odendaal R, Chen MP, Diem L, Metchock B, Tan K, Taylor A, Wolfgang M, Cho E, Eum SY, Kwak HK, Lee J, Lee J, Min S, Degtyareva I, Nemtsova ES, Khorosheva T, Kyryanova EV, Egos G, Perez MT, Tupasi T, Hwang SH, Kim CK, Kim SY, Lee HJ, Kuksa L, Norvaisha I, Skenders G, Sture I, Kummik T, Kuznetsova T, Somova T, Levina K, Pariona G, Yale G, Suarez C, Valencia E, Viiklepp P. Prevalence of and risk factors for resistance to second-line drugs in people with multidrug-resistant tuberculosis in eight countries: a prospective cohort study. Lancet. 380(9851):1406-17. 2012. PMID: 22938757. IF: 38,278. DOI: 10.1016/S01406736(12)60734-X Bobbioni-Harsch E, Pataky Z, Makoundou V, Laville M, Disse E, Anderwald C, Konrad T, Golay A; RISC Investigators(.., Carraro R, Friera A, Novella B,..). From metabolic normality to cardiometabolic risk factors in subjects with obesity. Obesity (Silver Spring). 20(10):2063-9. 2012. PMID: 22421925. IF: 4,284. DOI: 10.1038/oby.2012.69 Ruiz-Giménez Arrieta N. Scope of the latest RE-LY substudies: clinical implications. Rev Clin Esp. 212(Supl 2):4-14. 2012. PMID: 23117716. IF: 2,008. DOI: 10.1016/S0014-2565(12)70013-9 Marchena PJ, Nieto JA, Guil M, García-Bragado F, Rabuñal R, Boccalon H, Trujillo-Santos J, Monreal M; RIETE Investigators (.., Ruíz-Giménez N, ..). Long-term therapy with low-molecular-weight heparin in cancer patients with venous thromboembolism. Thromb Haemost. 107(1):37-43. 2012. PMID: 22116496. IF: 5,044. DOI: 10.1160/TH11-06-0423 Soler S, Delgado C, Ballaz A, Cisneros E, Malý R, Babalis D, Monréal M; RIETE Investigators (.., RuizGiménez N, ..). Unsuspected pulmonary embolism in patients with cancer. Thromb Res. 129(Suppl 1):S1619. 2012. PMID: 22682127. IF: 2,44. DOI: 10.1016/S0049-3848(12)70010-5 Nuñez MJ, Villalba JC, Cebrián E, Visoná A, Lopez-Jimenez L, Núñez M, Szwebel TA, Luque JM, Jaras MJ, Monreal M; RIETE Investigators (.., Ruíz-Giménez N, ..). Venous thromboembolism in immobilized patients with dementia. Findings from the RIETE registry. Thromb Res. 130(2):1737. 2012. PMID: 22374336. IF: 2,44. DOI: 10.1016/j.thromres.2012.02.006 Carcas AJ, Borobia AM, Velasco M, Abad-Santos F, Díaz MQ, Fernández-Capitán C, Ruiz-Giménez N, Madridano O, Sillero PL; PGX-ACE Spanish Investigators Group (..., Ochoa D, Marrodan I, Moreno I, Román M, Verge C,...). Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial. Trials 13:239. 2012. PMID: 23237631. IF: 2,496. DOI: 10.1186/1745-6215-13-239 CLINICAL TRIALS PRINCIPAL INVESTIGATOR: ARCO GALAN, CARMEN Estudio de registro prospectivo y observacional para caracterizar las condiciones normales de uso, la dosis y la seguridad tras la administración del concentrado estéril de vernakalant i.v.;(Versión 5-05-11). MERCK SHARP & DOHME CORP. MSD-VER-2011-01/6621049-00 – 141 – AREA 3AREA 2 AREA 1 McFadden E, Serruys PW, O'Neil WW, Jorissen B, Van Leeuwen F, Steg PG; PROTECT Steering Committee and Investigators (.., Martinez Elbal L,..). Stent thrombosis and major clinical events at 3 years after zotarolimus-eluting or sirolimus-eluting coronary stent implantation: a randomised, multice ntre, open-label, controlled trial. Lancet. 380(9851):1396-405. 2012. PMID: 22951082. IF: 38,278. DOI: 10.1016/S01406736(12)61336-1 Advanced therapies and individualized medicine PRINCIPAL INVESTIGATOR: RIVERO CRESPO, FERNANDO Ensayo internacional en fase IV de 30 días de duración, aleatorizado, de grupos paralelos, doble ciego, controlado con placebo, para evaluar eficacia y seguridad del inicio del tratamiento con ticagrelor prehospitalización vs hospitalización, en pacientes con síndrome coronario agudo con elevación del segmento ST, a los que se les realizará una ICP;(versión 1.0: 15-02-11). ASTRA ZENECA. D5130L00006. EudraCT: 2011-000214-19 PRINCIPAL INVESTIGATOR: GARCIA POLO, ILUMINADA Ensayo clínico aleatorizado, doble ciego controlado con placebo, para comparar el efecto, a tres meses de seguimiento, sobre la presión de pulso y la función vascular de mononitrato de isosorbide de acción prolongada, asociado al tratamiento antihipertensivo en pacientes mayores de 65 años con hipertensión sistólica aislada refractaria; (versión 1: 11-07-12). FUNDACION DE INVESTIGACION BIOMEDICA HUP. 1392-GJK-303. EudraCT: 2012-002988-10 PRINCIPAL INVESTIGATOR: BENEDICTO BUENDIA, AMPARO Pronóstico a largo plazo de los pacientes diabéticos y pre-diabéticos tratados con stent coronario liberador de everolimus; (versión 3.0:15-02-12). FUNDACION DE INVESTIGACION SANITARIA DE LEON. DISCO 8 PRINCIPAL INVESTIGATOR: SUAREZ FERNANDEZ, CARMEN XALIA - Xarelto« para la anticoagulación a largo plazo e inicial en el Tromboembolismo Venoso (TEV); (Versión 1.2: 09-02-12). BAYER HISPANIA S.L. BAYRIV-2012-01 PRINCIPAL INVESTIGATOR: JIMENEZ BORREGUERO, LUIS-JESUS Fluctuaciones circadianas del tamaño del infarto en el IAMCEST y el efecto del beta-bloqueo en éstas;(versión 1.0: 27-11-11). CNIC (CENTRO NACIONAL DE INVEST. CARDIOLOGICAS). ESTUDIO METOCARD-CLOCK – 142 – PRINCIPAL INVESTIGATOR: ARCO GALAN, CARMEN Estudio EMERG-AF (EMergency dEpartment stRoke prophylaxis and Guidelinesimplementation in Atrial Fibrilation): Implementación de las Guías de Fibrilación Auricular y profilaxis de ictus de los Servicios de Urgencias; (versión final: 20-07-12). BAYER HISPANIA S.L. BAY-FIB-2012-01 PRINCIPAL INVESTIGATOR: SUAREZ FERNANDEZ, CARMEN GLORIA-AF: Registro global del tratamiento antitrombótico oral a largo plazo en pacientes con fibrilación auricular; (versión 3.0: 23-03-12). BOEHRINGER INGELHEIM ESPAÑA, S.A. 1160.136/BOE-DAB2012-01 GRUPO 49 HEAD OF LABORATORY Blanca Novella Arribas GROUP MEMBERS • Amelia González Gamarra • Ana Cubillo Serna • Ángela Gallego Arenas • Belén Sierra García • Francisco José Rodríguez Salvanés • María Lourdes Ruiz Díaz • Luis María Sánchez Gómez • María Jesús Fernández Luque • María del Pilar Loeches Belinchón • M. Soledad Mayayo Vicente • Javier López González • Rosa María Sánchez Alcalde RESEARCH INTEREST Research is essential to respond to specific questions to help us manage uncertainty and help us in making AREA 3 bide mononitrate prolonged action on pulse pressure and vascular function associated with antihypertensive treatment in elderly patients 65 with isolated refractory systolic hypertension, a three-month follow-up., In this project the group is part of a research collaboration seeking an alternative to refractory hypertension in the elderly, and is currently recruiting patients. • María del Pilar Loeches Belinchón. Control de la presión arterial (PA) en pacientes diabéticos: estudio comparativo entre el tratamiento basado en la PA medida en la consulta médica y el basado en la automedición de la PA en el domicilio del paciente (AMPA en DM2). ISCIII. 10/01927. Duration: 2011 2013. • Blanca Novella Arribas. A Clinical Trial Of Two Educational Strategies In Cardiovascular Health In Child Population (SAVINHEARTS). ISCIII. CAIBER: expediente Nº 1668-BK-148. FIS: PI11/00798. Duration: 2012 - 2014. Study desing and participant plow through the trial. The Savinghearts project. BMC Public Health 2012, 12:1024 PUBLICATIONS (5) [IF: 25,426] decisions. Our commitment to study cardiovascular risk has led us this year to participate in two projects. The first one, the hearts saving project, is a cluster-randomized clinical trial of cardiovascular health education comparing two strategies in a child population., The group members are IP and ICs. At this point we have completed the field work. The assay combines education in prevention and promotion of healthy knowledge in cardiovascular risk based on the WHO NAOS strategy to prevent childhood obesity and health education. The study compares 2 strategies for changes: one measure but not fully utilized, the healthy breakfasts and another beginning to take hold in other fields of education, but not in terms of health: healthy concerts. Table 1 describes the study design. The second project is a randomized, double-blind, placebo-controlled trial to compare the effect of isosor- YEAR Total IF Publication No. Q1 Q2 2010 40,111 6 5 1 2011 37,684 8 4 3 2012 25,426 5 3 2 Sánchez-Gómez LM, Fernández-Luque MJ, Ruiz-Díaz L, Sánchez-Alcalde R, Sierra-García B, MayayoVicente S, Ruiz-López M, Loeches-Belinchón P, López-Gónzález J, González-Gamarra A, GallegoArenas A, Cubillo-Serna A, Gil-Juberias G, PérezCayuela P, Cañedo-Arguelles CA, García-Pascual JN, Ruiz-Chércoles E, Suarez-Fernández C, Garcia-Polo I, Abad-Perez D, Ballesteros-Arribas JM, IzquierdoMartínez M, Salvador-Alcaide E, Arribas-Vela AB, Alonso-Pérez JM, Veja-Piris L, Rodríguez-Salvanés F, Novella-Arribas B. A cluster-randomised clinical trial comparing two cardiovascular health education strate- – 143 – AREA 3AREA 2 AREA 1 MAJOR GRANTS Advanced therapies and individualized medicine gies in a child population: the Savinghearts project. BMC Public Health. 12:1024. 2012. PMID: 23176593. IF: 1,997. DOI: 10.1186/1471-2458-12-1024 Sanz-Cuesta T, González-Escobar P, Riesgo-Fuertes R, Garrido-Elustondo S, del Cura-González I, MartínFernández J, Escortell-Mayor E, Rodríguez-Salvanés F, García-Solano M, González-González R, Martín-de la Sierra-San Agustín MÁ, Olmedo-Lucerón C, Sevillano Palmero ML, Mateo-Ruiz C, Medina-Bustillo B, Valdivia-Pérez A, García-de Blas-González F, MariñoSuárez JE, Rodríguez-Barrientos R, Ariza-Cardiel G, Cabello-Ballesteros LM, Polenti nos-Castro E, RicoBlázquez M, Rodríguez-Monje MT, Soto-Díaz S, Martín-Iglesias S, Rodríguez-González R, BretónLesmes I, Vicente-Herrero M, Sánchez-Díaz J, GómezGascón T, Drake-Canela M, Asúnsolo-del Barco Á; OB12 Group. Oral versus intramuscular administration of vitamin B12 for the treatment of patients with vitamin B12 deficiency: a pragmatic, randomised, multicentre, non-inferiority clinical trial undertaken in the primary healthcare setting (Project OB12). BMC Public Health. 12:394. 2012. PMID: 22650964. IF: 1,997. DOI: 10.1186/1471-2458-12-394 – 144 – Kozakova M, Palombo C, Eng MP, Dekker J, Flyvbjerg A, Mitrakou A, Gastaldelli A, Ferrannini E; RISC Investigators (.., Carraro R, Friera A, Novella B, ..). Fatty liver index, gamma-glutamyltransferase, and early carotid plaques. Hepatology. 55(5):1406-15. 2012. PMID: 22334565. IF: 11,665. DOI: 10.1002/hep.25555 Handberg A, Højlund K, Gastaldelli A, Flyvbjerg A, Dekker JM, Petrie J, Piatti P, Beck-Nielsen H; RISC Investigators (.., Carraro R, Friera A, Novella B, ..). Plasma sCD36 is associated with markers of atherosclerosis, insulin resistance and fatty liver in a nondiabetic healthy population. J Intern Med. 271(3):294-304. 2012. PMID: 21883535. IF: 5,483. DOI: 10.1111/j.1365-2796.2011.02442.x Bobbioni-Harsch E, Pataky Z, Makoundou V, Laville M, Disse E, Anderwald C, Konrad T, Golay A; RISC Investigators(.., Carraro R, Friera A, Novella B,..). From metabolic normality to cardiometabolic risk factors in subjects with obesity. Obesity (Silver Spring). 20(10):2063-9. 2012. PMID: 22421925. IF: 4,284. DOI: 10.1038/oby.2012.69 AREA 3 Line 3.7 New therapies in infectious pathologies GRUPO 50 HEAD OF LABORATORY Ignacio de los Santos Gil RESEARCH INTEREST Activity in Hematology The use of prophylactic posaconazol in a population at high risk of invasive fungal infection (IFI) (LAM patients treated with intensive chemotherapy) is associated with a saving of 1800 euros per patient compared with fluconazole or itraconazole prophylaxis. This economic benefit is in addition to the clinical benefits: lower incidence of IFI and longer survival in those who received posaconazole. These facts have made posaconazole prophylaxis in these patients the first choice in the most prestigious international guidelines. Causes of death in the Spanish HIV Cohort (CoRIS) between 2004 and 2008 Activity in Infectious Diseases We are involved in the study of treatment, epidemiology, evolution and mortality in HIV-infection. All of this work is in the context of the CoRIS, the Spanish HIVcohort. Also, we are involved in the treatment of HIVHCV coinfected patients with the new protease inhibitors of HCV. One of our publications refers to the differences in the causes of death of HIV-positive patients in a cohort study by data sources and coding algorithms. In this study we concluded that there is substantial variation in CoDs in HIV-infected persons according to sources and algorithms. ICD-10 in patients known to be HIV-positive overestimates HIV/AIDS-related deaths at the expense of underestimating liver-related diseases, infections and ill defined causes. CoDe seems to be the best option for cohort studies. MAJOR GRANTS Results of the base case of posaconazole versus SAT in the prevention of IFI among high-risk neutropenic patients Ignacio de los Santos Gil. Prevalencia de infección por VIH no diagnosticada en pacientes que acuden al Servicio de Urgencias, cuyo objetivo principal es estimar la prevalencia de infección por VIH no diagnosticada en personas mayores de 15 años que acuden al Servicio de Urgencias. GILEAD SCIENCIES, S.L. Duration: 2011 - 2012. – 145 – AREA 3AREA 2 AREA 1 GROUP MEMBERS • Jesús Sanz Sanz • Cristina Sarriá Cepeda • José Rafael De la Cámara de Llanza • Ana Salas Aparicio • María Teresa Sánchez Casasola Advanced therapies and individualized medicine PUBLICATIONS (22) [IF: 104,505] YEAR Total IF Publication No. Q1 Q2 2010 121,683 26 9 11 2011 117,881 28 13 8 2012 104,505 22 12 4 Mira JA, Rivero A, de Los Santos-Gil I, López-Cortés LF, Girón-González JA, Márquez M, Merino D, del Mar Viloria M, Téllez F, Ríos-Villegas MJ, Omar M, RiveroJuárez A, Macías J, Pineda JA; Grupo HEPAVIR de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI). Hepatitis C virus genotype 4 responds better to pegylated interferon with ribavirin tan genotype 1 in HIV-infected patients. AIDS 26(13):1721-1724. 2012. PMID: 22695304. IF: 6,245. DOI: 10.1097/QAD.0b013e3283568884 Berenguer J, Alejos B, Hernando V, Viciana P, Salavert M, Santos I, Gómez-Sirvent JL, Vidal F, Portilla J, Del Amo J; CoRIS (AIDS Research Network Cohort) (colaboradores J Sanz, A Salas, C Sarriá). Trends in mortality according to hepatitis C virus serostatus in the era of combination antiretroviral therapy. AIDS 26(17):22412246. 2012. PMID: 22781223. IF: 6,245. DOI: 10.1097/QAD.0b013e3283574e94 Blanco JR, Jarrín I, Vallejo M, Berenguer J, Solera C, Rubio R, Pulido F, Asensi V, del Amo J, Moreno S; CoRIS (.., de los Santos I, Sanz Sanz J, Salas Aparicio A, Sarriá Cepeda C, ..). Definition of advanced age in HIV infection: looking for an age cut-off. AIDS Res Hum Retroviruses. 28(9):1000-6. 2012. PMID: 22607516. IF: 2,246. DOI: 10.1089/AID.2011.0377 the causes of death of HIV-positive patients in a cohort study by data sources and coding algorithms. AIDS. 26(14):1829-34. 2012. PMID: 22410685. IF: 6,245. DOI: 10.1097/QAD.0b013e328352ada4 de la Cámara R, Jarque I, Grau S, Carreras E. Inadequate references in recent article. Am J Health Syst Pharm 69(11):917-922. 2012. PMID: 22610019. IF: 1,962. DOI: 10.2146/ajhp120091 Sobrino-Vegas P, Rodríguez-Urrego J, Berenguer J, Caro-Murillo AM, Blanco JR, Viciana P, Moreno S, Bernardino I, del Amo J; CoRIS. Colaboradores: I. de los Santos, J. Sanz. Educational gradient in HIV diagnosis delay, mortality, antiretroviral treatment initiation and response in a country with universal health care. Antiviral Therapy 17(1):1-8. 2012. PMID: 22267463. IF: 3,161. DOI: 10.3851/IMP1939 Grau S, de la Cámara R, Sabater FJ, Jarque I, Carreras E, Casado MA, Sanz MA. Cost-effectiveness of posaconazole versus fluconazole or itraconazole in the prevention of invasive fungal infections among high-risk neutropenic patients in Spain. BMC Infect Dis 12:83. 2012. PMID: 22471553. IF: 3,118. DOI: 10.1186/1471-2334-12-83 HIV-CAUSAL Collaboration (.., de los Santos I, Sanz Sanz J, ..). Impact of antiretroviral therapy on tuberculosis incidence among HIV-positive patients in highincome countries. Clin Infect Dis. 54(9):1364-72. 2012. PMID: 22460971. IF: 9,154. DOI: 10.1093/cid/cis203 HIV-CAUSAL Collaboration (.., de los Santos I, Sanz Sanz J, ..). The effect of efavirenz versus nevirapinecontaining regimens on immunologic, virologic and clinical outcomes in a prospective observational study. AIDS. 26(13):1691-705. 2012. PMID: 22546987. IF: 6,245. DOI: 10.1097/QAD.0b013e328354f497 Mira JA, García-Rey S, Rivero A, de Los Santos-Gil I, López-Cortés LF, Girón-González JA, Téllez F, Márquez M, Merino D, Ríos-Villegas MJ, Macías J, Rivero-Juárez A, Pineda JA. Response to pegylated interferon plus ribavirin among HIV/Hepatitis C virus-coinfected patients with compensated liver cirrhosis. Clin Infect Dis. 55(12):1719-1726. 2012. PMID: 22955435. IF: 9,154. DOI: 10.1093/cid/cis779 Hernando V, Sobrino-Vegas P, Burriel MC, Berenguer J, Navarro G, Santos I, Reparaz J, Martínez MA, Antela A, Gutiérrez F, del Amo J; CoRIS cohort (.., Sanz Sanz J, Salas Aparicio A, Sarriá Cepeda C, ..). Differences in Berenguer J, Rodríguez E, Miralles P, Von Wichmann MA, López-Aldeguer J, Mallolas J, Galindo MJ, Van Den Eynde E, Téllez MJ, Quereda C, Jou A, Sanz J, Barros C, Santos I, Pulido F, Guardiola JM, Ortega E, – 146 – AREA 3 Monge S, Guillot V, Alvarez M, Peña A, Viciana P, García-Bujalance S, Pérez Elias MJ, Iribarren JA, Gutiérrez F, Itziar Casado M, Garcia F; CoRIS (.., de los Santos I, Sanz Sanz J, Salas Aparicio A, Sarriá Cepeda C, ..). Analysis of transmitted drug resistance in Spain in the years 2007-2010 documents a decline in mutations to the non-nucleoside drug class. Clin Microbiol Infect. 18(11):E485-90. 2012. PMID: 23016666. IF: 4,54. DOI: 10.1111/1469-0691.12011 Podzamczer D, Tiraboschi JM, Mallolas J, Curto J, Cárdenes MA, Casas E, Castro A, Echevarría S, Leal M, Lopez Bernaldo de Quirós JC, Moreno S, Puig T, Ribera E, Villalonga C, Gómez-Sirvent JL, GarcíaHenarejos JA, Lopez-Aldeguer J, Barrufet P, Force L, Santos I, Sanz J. Long-term benefits of nevirapine-containing regimens: multicenter study with 506 patients, followed-up a median of 9 years. Curr HIV Res. 10(6):513-520. 2012. PMID: 22716109. IF: 1,745. DOI: 10.2174/157016212802429820 Monge S, Del Romero J, Rodríguez C, de Mendoza C, de Górgolas M, Cosín J, Dronda F, Pérez-Cecilia E, Peña JM, Santos I, Rubio R, Del Amo J; Grupo de Seroconvertores de la Comunidad de Madrid. Sociodemographic factors associated with the progression of HIV infection and the impact of HAART in a seroconverter cohort in Madrid (1986-2009). Enferm Infecc Microbiol Clin 30(3):117-123. 2012. PMID: 22014512. IF: 1,491. DOI: 10.1016/j.eimc.2011.07.016 Macías J, Viloria MM, Rivero A, de los Santos I, Márquez M, Portilla J, Di Lello F, Camacho A, SanzSanz J, Ojeda G, Mata R, Gómez-Mateos J, Pineda JA; FIBROCEL study group. Lack of short-term increase in serum mediators of fibrogenesis and in non-invasive markers of liver fibrosis in HIV/hepatitis C virus-coinfected patients starting maraviroc-based antiretroviral therapy. Eur J Clin Microbiol Infec Dis 31(8):2083-2088. 2012. PMID: 22258426. IF: 2,859. DOI: 10.1007/s10096-012-1546-5 Macías J, Neukam K, Mallolas J, López-Cortés LF, Cartón JA, Domingo P, Moreno S, Iribarren JA, Clotet B, Crespo M, de los Santos I, Ortega E, Knobel H, Jiménez-Expósito MJ, Pineda JA; COINS Study Team. Liver toxicity of initial antiretroviral drug regimen including two nucleoside analogs plus one non-nucleoside analog or one ritonavir-boosted protease inhibitor in HIV/HCV coinfected patients. HIV Clin Trials 13(2):6169. 2012. PMID: 22510353. IF: 1,638. DOI: 10.1310/hct1302-61 Labarga P, Barreiro P, da Silva A, Guardiola JM, Rubio R, Aguirrebengoa K, Miralles P, Portu J, Téllez MJ, Morano L, Castro A, Pineda JA, Terrón A, HernándezQuero J, Mariño A, Ríos MJ, Echeverría S, Asensi V, Vispo E, Soriano V; PERICO Study Group (colaboradores de los Santos I). Comparison of high ribavirin induction versus standard ribavirin dosing, plus peginterferon-alfa for the treatment of chronic hepatitis C in HIV-infected patients: the PERICO trial. J Infect Dis. 206(6):961-968. 2012. PMID: 22807523. IF: 6,41. DOI: 10.1093/infdis/jis449 Muñoz-Cobo B, Solano C, Benet I, Costa E, Remigia MJ, de la Cámara R, Nieto J, López J, Amat P, GarciaNoblejas A, Bravo D, Clari MÁ, Navarro D. Functional profile of cytomegalovirus (CMV)-specific CD8+ T cells and kinetics of NKG2C+ NK cells associated with the resolution of CMV DNAemia in allogeneic stem cell transplant recipients. J Med Virol 84(2):259-267. 2012. PMID: 22170546. IF: 2,82. DOI: 10.1002/jmv.22254 Yebra G, de Mulder M, Martín L, Rodríguez C, Labarga P, Viciana I, Berenguer J, Alemán MR, Pineda JA, García F, Holguín A; Cohort of the Spanish AIDS Research Network (CoRIS) (colaboradores I. de los Santos, J. Sanz). Most HIV type 1 non-B infections in the Spanish cohort of antiretroviral treatment-naïve HIV-infected patients (CoRIS) are due to recombinant viruses. Journal of Clinical Microbiology 50(2):407-413. 2012. PMID: 22162552. IF: 4,153. DOI: 10.1128/JCM.05798-11 – 147 – AREA 3AREA 2 AREA 1 Rubio R, Jusdado JJ, Montes ML, Gaspar G, Esteban H, Bellón JM, González-García J; GESIDA HIV/HCV Cohort Study Group. Sustained virological response to interferon plus ribavirin reduces non-liver-related mortality in patients coinfected with HIV and Hepatitis C virus. Clin Infect Dis. 55(5):728-36. 2012. PMID: 22610932. IF: 9,154. DOI: 10.1093/cid/cis500 Advanced therapies and individualized medicine Hernando V, Perez-Cachafeiro S, Lewden C, Gonzalez J, Segura F, Oteo JA, Rubio R, Dalmau D, Moreno S, Amo JD (colsboradores I. de los Santos, J Sanz, C Sarria, A Salas). All-cause and liver-related mortality in HIV positive subjects compared to the general population: differences by HCV co-infection. Journal of Hepatology 57(4):743-751. 2012. PMID: 22709620. IF: 9,264. DOI: 10.1016/j.jhep.2012.06.010 Pineda JA, Neukam K, Mallolas J, López-Cortés LF, Cartón JA, Domingo P, Moreno S, Iribarren JA, Clotet B, Crespo M, de Los Santos I, Ortega E, Knobel H, Jiménez-Expósito MJ, Macías J. Hepatic safety of efavirenz in HIV/hepatitis C virus-coinfected patients with advanced liver fibrosis. Journal of Infection 64(2):204-211. 2012. PMID: 22138553. IF: 4,126. DOI: 10.1016/j.jinf.2011.10.016 Ferrera C, Vilacosta I, Fernández C, López J, Olmos C, Sarriá C, Revilla A, Vivas D, Sáez C, Rodríguez E, San Román JA. Reassessment of Blood Culture-Negative Endocarditis: Its Profile Is Similar to That of Blood Culture-Positive Endocarditis. Rev Esp Cardiol. 65(10):891-900. 2012. PMID: 22771081. IF: 2,53. DOI: 10.1016/j.recesp.2012.04.004 CLINICAL TRIALS PRINCIPAL INVESTIGATOR: SANZ SANZ, JESUS Estudio multicéntrico observacional retrospectivo de la eficacia y tolerabilidad de tratamientos antiretrovirales que contienen maraviroc (MVC) en la práctica clínica. Estudio MVCohort; (versión 1:23-1-12). JOSEP M. LLIBRE, SANTIAGO MORENO Y ANTONIO RIVERO. LMR-MAR-2012-01 PRINCIPAL INVESTIGATOR: SANTOS GIL, IGNACIO DE LOS Medidas de salud autopercibidas por los pacientes infectados por VIH que cambian su targa previo a un régimen de un comprimido una vez al día por intolerancia en la práctica clínica habitual (Estudio PRO-STR) (Versión 2:10-11-11). DANIEL PODZAMCZER ENFERMEDAD.INFECC. H.U.BELLVITGE. POD-TAR-2011-01 – 148 – PRINCIPAL INVESTIGATOR: SANTOS GIL, IGNACIO DE LOS Estudio en fase 3b abierto para determinar la eficacia y la seguridad de telaprevir, interferon-alfa2a pegilado y ribavirina en sujetos con coinfección por el virus de la Hepatitis C Crónica de genotipo 1 y el virus de la inmunodeficiencia humana de tipo 1 (VHC-1/VIH-1), con y sin tratamiento previo para el virus de la Hepatitis C; (Versión final:26-07-12). JANSSEN-CILAG INTERNATIONAL NV. VX-950HPC3008. EudraCT: 2011-004928-35 PRINCIPAL INVESTIGATOR: CAMARA LLANZA, JOSE-RAFAEL Estudio observacional para determinar la tasa de incidencia de enfermedad invasiva por hongos filamentosos y los resultados de los tratamientos en pacientes de riesgo: una auditoría prospectiva europea (PIMDA); (Versión: 1.0: 22-07-11). EUROPEAN CONFEDERATION OF MEDICAL MYCOLOGY (ECMM). PIMDA/ECM-ANT-2012-01 GRUPO 51 HEAD OF LABORATORY Javier Aspa Marco GROUP MEMBERS • Olga Rajas Naranjo • María del Mar Ortega Gómez • Jose Andrés García Romero de Tejada • Rosa Mar Gómez Punter • Emma Vázquez Espinosa RESEARCH INTEREST During 2012, the group 51, has continued to work on various aspects of genetic factors regulating response to pulmonary infections, working with dif- AREA 3 MAJOR GRANTS Proyecto Coordinado. Variabilidad genética en la señalización mediada por los TLRs/IL-1R en enfermedades respiratorias: neumonía comunitaria y alergia respiratoria. ISCIII. FIS PI10/01718. Duration: 2011 - 2013. Martín-Loeches I, Solé-Violán J, Rodríguez de Castro F, García-Laorden MI, Borderías L, Blanquer J, Rajas O, Briones ML, Aspa J, Herrera-Ramos E, Marcos-Ramos JA, Sologuren I, González-Quevedo N, Ferrer-Agüero JM, Noda J, Rodríguez-Gallego C. Variants at the promoter of the interleukin-6 gene are associated with severity and outcome of pneumococcal communityacquired pneumonia. Intensive Care Med 38(2):25662. 2012. PMID: 22113815. IF: 5,399. DOI: 10.1007/s00134-011-2406-y Menéndez R, Torres A, Reyes S, Zalacain R, Capelastegui A, Rajas O, Borderías L, MartínVillasclaras JJ, Bello S, Alfageme I, de Castro FR, Rello J, Molinos L, Ruiz-Manzano J. Compliance with guidelines-recommended processes in pneumonia: impact of health status and initial signs. PLoS One 7(5):e37570. 2012. PMID: 22629420. IF: 4,092. DOI: 10.1371/journal.pone.0037570 Cuesta-Domínguez Á, Ortega M, Ormazábal C, Santos-Roncero M, Galán-Díez M, Steegmann JL, Figuera Á, Arranz E, Vizmanos JL, Bueren JA, Río P, Fernández-Ruiz E. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCR-JAK2 tyrosine-kinase. PLoS One. Epub 2012 Feb 27. 7(2):e32451. 2012. PMID: 22384256. IF: 4,092. DOI: 10.1371/journal. pone.0032451 PUBLICATIONS (4) [IF: 19,478] CLINICAL TRIALS YEAR Total IF Publication No. 2010 4,691 2 Q1 2011 10,937 2 2 2012 19,478 4 4 Q2 1 Menéndez R, Torres A, Reyes S, Zalacain R, Capelastegui A, Aspa J, Borderías L, MartínVillasclaras JJ, Bello S, Alfageme I, de Castro FR, Rello J, Molinos L, Ruiz-Manzano J. Initial management of pneumonia and sepsis: factors associated with improved outcome. Eur Respir J 39(1):156-62. 2012. PMID: 21828033. IF: 5,895. DOI: 10.1183/09031936. 00188710 PRINCIPAL INVESTIGATOR: GOMEZ PUNTER, ROSA MAR Estimación de utilidades en pacientes con enfermedad pulmonar obstructiva crónica en España; (versión 1.0:28-06-12). GLAXOSMITHKLINE, S.A. HZC116842 PRINCIPAL INVESTIGATOR: GOMEZ PUNTER, ROSA MAR Caracterización fenotípica de la población EPOC en España: Clasificación de fenotipos clínicos de la EPOC y evaluación del diagnóstico y el tratamiento en práctica clínica habitual; Estudio FENEPOC;(versión – 149 – AREA 3AREA 2 AREA 1 ferent groups in Spain: Hospital Dr. Negrin, Las Palmas de Gran Canaria; Corporació Sanitaria Parc Tauli Sabadell; Hospital San Jorge, Huesca; Hospital Clinic and University, Valencia; Hospital Jose Molina Orosa, Lanzarote. The group has been involved in a prospective epidemiological study of hospital-based surveillance of invasive pneumococcal disease in adults over 18 years of age in Spain. The project has been active for two years and will continue enrolling patients in the next year. Dra. Olga Rajas also participated in two research project studying different relevant aspects related to the management of community-acquired pneumonia in Spain. Furthermore, at the end of this year, our group has obtained a grant from FIS (Instituto de Salud Carlos III) for the next 3 years, to start a new line: Incidence of cardiovascular events after hospitalization for community-acquired pneumonia in adults and its association with different inflammation markers. Advanced therapies and individualized medicine final:enmienda1,5-10-12). NOVARTIS FARMACEUTICA, S.A. NOV-EPO-2012-01 PRINCIPAL INVESTIGATOR: RAJAS NARANJO, OLGA Estudio observacional, de no intervención, de la viabilidad de la recogida prospectiva de datos demográficos y clínicos en los pacientes con Cáncer de Pulmón en un entorno Pan-Europeo; (versión 1.0:17-02-12). EUROPEAN RESPIRATORY SOCIETY. EULUCA PRINCIPAL INVESTIGATOR: RAJAS NARANJO, OLGA Estudio NEUMO-NAC. Influencia de la vacunación antineumocócica en la epidemiología, serotipo y complicaciones de la NAC; (Versión. NEUMONAC GRUPO 52 HEAD OF LABORATORY Manuel López-Brea Calvo GROUP MEMBERS • Teresa Alarcón Cavero • María Josefa Martínez Gómez • Diego Domingo García • Laura María Cardeñoso Domingo • Buenaventura Buendía Moreno • Justo Martiáñez Rodríguez • Sandra Rodrigo Gil • Elisea Lomas Lomas • Carmen María Serrano Morago • Ángela Somodevilla Solís • María del Carmen Martínez Jiménez • Marina Espínola Docio • Ana Correa Ruiz • Alba Guiu Martínez RESEARCH INTEREST 1.- Helicobacter pylori infection One H. pylori strain was completely sequenced and – 150 – IL-12 levels detected with different Helicobacter pylori clinical isolates after coculture of strains with peripheral blood mononuclear cells. it is 1,6 Mb. Prophage Finder was used to detect 4 possible prophage in its genome. CRISPRs and CRISPRs associated proteins was found by using CRISPR Finder: 2 confirmed and one possible. IL12 production was quantified in coculture of H. pylori isolates and peripheral blood mononuclear cells in order to detect association with its virulence factors. High levels of IL-12 production was detected (5.860-27.486pg/ml) indicating an important role of H. pylori as cytokine inductor. IL-12 level was not associated with presence of dupA gene or other virulence factors. 2.- Resistance to antibiotic in several bacteria. Distribution of Streptococcus pneumoniae serotypes, its antimicrobial susceptibility profiles and relationship with vaccines in pneumococcal strains isolated from blood cultures of adult patients were studied. A clinical case of an abdominal abscess due to NDM-1-producing Klebsiella pneumoniae in a 35-year-old Spanish patient after hospitalization in India due to perforated appendicitis and peritonitis was detected in our Department. 3.- in vitro activity of antifungal agents. The epidemiology of fungaemia episodes in Spain were studied in a multicentre study. Epidemiological cutoff values were proposed and would be useful for monitoring the emergence of isolates with reduced susceptibility by use of the Sensititre YeastOne method. AREA 3 4.- CMV infection The COBAS AmpliPrep/COBAS TaqMan CMV Test (CAP/CTM CMV test) was compared to local assays used by 5 laboratories at transplant centers in the United States and Europe and a high interlaboratory agreement and precision of the test was found. 22563775. IF: 4,54. DOI: 10.1111/j.1469-0691. 2012.03883.x Gavín P, Iglesias MJ, Jiménez MS, Rodríguez-Valín E, Ibarz D, Lezcano MA, Revillo MJ, Martín C, Samper S; Spanish Working Group on MDR-TB (.., Cardeñoso L, ..). Long-term molecular surveillance of multidrug-resistant tuberculosis in Spain. Infect Genet Evol. 12(4):701-10. 2012. PMID: 21669301. IF: 3,128. DOI: 10.1016/j.meegid.2011.05.016 MAJOR GRANTS PUBLICATIONS (6) [IF: 23,741] YEAR Total IF Publication No. Q1 Q2 2010 14,705 4 2 1 2011 10,243 2 2 2012 23,741 6 4 2 Alcalá L, Martín A, Marín M, Sánchez-Somolinos M, Catalán P, Peláez T, Bouza E; Spanish Clostridium difficile Study Group (M. Lopez-Brea). The undiagnosed cases of Clostridium difficile infection in a whole nation: where is the problem?. Clin Microbiol Infect. 18(7):204-213. 2012. PMID: Pemán J, Cantón E, Quindós G, Eraso E, Alcoba J, Guinea J, Merino P, Ruiz-Pérez-de-Pipaon MT, Pérez-del-Molino L, Linares-Sicilia MJ, Marco F, García J, Roselló EM, Gómez-G-de-la-Pedrosa E, Borrell N, Porras A, Yagüe G; FUNGEMYCA Study Group (B. Buendia). Epidemiology, species distribution and in vitro antifungal susceptibility of fungaemia in a Spanish multicentre prospective survey. J Antimicrob Chemother. 67(5):1181-1187. 2012. PMID: 22351683. IF: 5,068. DOI: 10.1093/jac/dks019 Cantón E, Pemán J, Hervás D, Iñiguez C, Navarro D, Echeverría J, Martínez-Alarcón J, Fontanals D, Gomila B, Buendía B, Torroba L, Ayats J, Bratos A, Sánchez-Reus F, Fernández-Natal I; the FUNGEMYCA Study Group. Comparison of three statistical methods to establish the tentative wild-type population and epidemiological cutoff values for echinocandins, amphotericin B and flucytosine and six Candida species determined bycolorimetric Sensititre YeastOne(R). J Clin Microbiol. 50(12):3921-3926. 2012. PMID: 23015676. IF: 4,153. DOI: 10.1128/JCM.01730-12 Oteo J, Domingo-García D, Fernández-Romero S, Saez D, Guiu A, Cuevas O, Lopez-Brea M, Campos J. Abdominal abscess due to NDM-1-producing Klebsiella pneumoniae in Spain. J Med Microbiol. 61(6):864-867. 2012. PMID: 22383442. IF: 2,502. DOI: 10.1099/jmm.0.043190-0 Pintado V, Pazos R, Jiménez-Mejías ME, Rodríguez-Guardado A, Gil A, García-Lechuz JM, Cabellos C, Chaves F, Domingo P, Ramos A, Pérez- – 151 – AREA 3AREA 2 AREA 1 • Teresa Alarcón Cavero. Helicobacter pylori: aislamiento y estudio de fagovirus como mecanismo de transferencia de resistencia a antimicrobianos y fuente de nuevas estrategias terapéuticas. ISCIII. PI08/1775 . Duration: 2009 - 2012. • Teresa Alarcón Cavero. Estudio de aspectos moleculares e inmunológicos de la infección por helicobacter pylori en pacientes pediátricos y adultos. Impacto en salud pública. Argentina. PROIPRO 0310. Duration: 2010 - 2012. • Teresa Alarcón Cavero. Validación de la pirosecuenciación como técnica de genotipado exacto en cuadros de ACV y otras patologías de base infectocontagiosa. BlackBio. Duration: 2011 2012. • Teresa Alarcón Cavero. Tigecycline European Surveillance Trial (TEST). Pfizer. EPI 252. Duration: 2012 - 2013. Advanced therapies and individualized medicine Cecilia E, Domingo D. Methicillin-resistant Staphylococcus aureus meningitis in adults: a multicenter study of 86 cases. Medicine (Baltimore). 91(1):10-7. 2012. PMID: 22198499. IF: 4,35. DOI: 10.1097/MD.0b013e 318243442b – 152 – BOOKS A. Somodevilla, M. Espínola, T. Alarcón. Microbiología aplicada a la clínica. Manual de Infecciones Perioperatorias "Casos Clínicos". 2012. Ergón. ISBN: 978-84-8473-991-3. AREA 3 Line 3.8 Individualized medicine in solid tumors GRUPO 53 HEAD OF LABORATORY Almudena Zapatero Laborda RESEARCH INTEREST During the last two years several projects in prostate cancer have focused our current research work. The main one is a multi-institutional, “Spanish Phase III Trial comparing Long-Term Versus Short-Term Androgen Deprivation Combined With High-Dose Radiotherapy For Localized Prostate Cancer: GICOR Protocol DART01/05. EudraCT 2005-000417-36”. The encouraging preliminary results have been presented in national and international meetings along 2011and 2012. Our most immediate major project related to DART01/05 trial is the participation in the “INTERMEDIATE CLINICAL ENDPOINTS IN CANCER OF THE PROSTATE (ICECaP) INITIATIVE”, a meta-analysis that will be carried out by the ICECaP Working Group, a multidisciplinary team of academic cancer researchers from the Dana-Farber Cancer Institute -Harvard Medical School-. This meta-analysis will use individual patient data of all prostate cancer adjuvant clinical trials with the goal of identifying a validated intermediate clin- (a) 3D reconstruction of the rectum and its internal filings, showing the centerline of the rectum: (b) 3D reconstruction of the straightened rectum and its internal filings, showing the straightened centerline; (c) Representation of the surface of the rectum wall using cylindrical coordinates theta in the X-axis, Z in the y-axis, and radius in the Z-axis. Rodríguez-Vila, García-Vicente, and Gómez: Metodology for registration distended rectums pelvic CT Medical Physics, Vol. 39, No 10, October 2012 ical endpoint that will serve as an acceptable surrogate endpoint for overall survival. We have also finished the cooperative study with the CNIO titled “Comparison Of Biological-Molecular Markers Predictive Of Radiation Response In Localized Prostate Cancer Ref.: CaPr-HLP-RT-01/ PI 197”. The results are the subject of two presentations and will be published in due course in specialized journals. Our ongoing projects include the participation in a cooperative project of organ deformation and adaptive radiotherapy in collaboration with the Bio-Ingeniería y – 153 – AREA 3AREA 2 AREA 1 GROUP MEMBERS • María del Carmen Martín de Vidales • José Alfonso Cruz Conde • Inmaculada Fernández González • Mariano Rabadán Ruiz • Ramón Cristóbal Arellano Gañán • Feliciano García Vicente • María Magdalena Adrados de Llano • Leopoldo Pérez González Advanced therapies and individualized medicine Telemedicina group from Universidad Politécnica de Madrid that have led to a Doctoral Thesis and a paper published in 2012 American Association of Physicists in Medicine (Med. Phys), but also two studies in translational research: 1) A cooperative study, protocol-RTCTC-01/PI 197, entitled: Prognostic value of tumor cell levels circulating (CTCS) in peripheral blood in patients with prostate cancer high risk (stage IIB-III) undergoing radical treatment with radiotherapy and hormone to study the predictive value of CTCs (circulating tumoral cells) in high-risk localized prostate cancer. 2) The participation in an EUROPEAN PROTOCOL FOR ASSESSING MULTICENTER Heterogeneity GENES BY TUMOR CELL CYCLE PROGRESSION IN PROSTATE CANCER PATIENTS WITH STAGE T1-3, N0-X, M0-X ACRONYM: EMPATHY-P Zapatero A, Martin De Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology 80(5):1056-1062. 2012. PMID: 22999456. IF: 2,428. DOI: 10.1016/j.urology.2012.07.045 BOOKS Almudena Zapatero, Guillermo Andrés, Javier Angulo, Ignacio Durán, Helena Gimbernat, Fernando Lista, José Ignacio López, Erika Mateo. Cáncer de próstata. Guías Prácticas en Urología. 2012. Elsevier España, S.L. ISBN: 978-84-7592-757-2. Editor: Javier Angulo. PUBLICATIONS (4) [IF: 10,295] CLINICAL TRIALS YEAR Total IF Publication No. Q1 2010 21,259 7 5 2011 11,174 3 3 2012 10,295 4 1 Q2 2 García-Vicente F, Fernández V, Bermúdez R, Gómez A, Pérez L, Zapatero A, Torres JJ. Sensitivity of a helical diode array device to delivery errors in IMRT treatment and establishment of tolerance level for pretreatment QA. J Appl Clin Med Phys. 13(1):111123. 2012. PMID: 22231218. IF: 1,291 Rodriguez-Vila B, Garcia-Vicente F, Gomez EJ. Methodology for registration of distended rectums in pelvic CT studies. Med Phys. 39(10):6351-9. 2012. PMID: 23039671. IF: 2,83. DOI: 10.1118/1.4754798 Fernandez, I, Celada, G, Brime, R, Diego, V, Bocardo, G, Romero, E, Olivier, C. Opportunity of ureteroscopy in the management of complex lithiasis in a center without extracorporeal lithotripsy. The Journal of Urology 187(4S):E693-E694. 2012. IF: 3,746. DOI: 10.1016/j.juro.2012.02.1680 – 154 – PRINCIPAL INVESTIGATOR: ZAPATERO LABORDA, MARIA-ALMUDENA Deprivación androgénica y radioterapia a altas dosis con o sin radioterapia pélvica completa en cáncer de próstata de riesgo intermedio desfavorable o de alto riesgo favorable: Ensayo aleatorizado fase III; (versión vo: 16-0611). GICOR. RTOG0924 PRINCIPAL INVESTIGATOR: ZAPATERO LABORDA, MARIA-ALMUDENA Estudio observacional sobre la prevalencia de síndrome metabólico y osteoporosis en el cáncer de próstata tratado con deprivación androgénica y su repercusión en la calidad de vida: SIMBOSPROST;(versión 16-8-11). GICOR. SIMBOSPROST PRINCIPAL INVESTIGATOR: ZAPATERO LABORDA, MARIA-ALMUDENA Valor pronóstico de los niveles de células tumorales circulantes (CTCs) en sangre periférica en pacientes con Cáncer de Próstata de alto riesgo (estadios IIb-III) sometidos a tratamiento radical con radioterapia y hormonoterapia; (versión 1: 23-07-12). CAPR-RTCTC-01/PI 197 AREA 3 GRUPO 54 HEAD OF LABORATORY Laura Cerezo Padellano GROUP MEMBERS • Mario López Rodríguez • Margarita Martín Martín • Eduardo Raboso García-Baquero • Luis Naval Gías • Consuelo López Elzaurdia • Alicia Marín Palomo • Adolfo Hinojar Gutiérrez • Mario Fernando Muñoz Guerra Hematoxylin and eosin. prominent basaloid morphology, lobular growth, infiltrating lymphocytes. During the year 2012, the group has advanced in its research lines on head and neck cancer. The multicentric study on the Incidence of Human Papillomavirus related oropharyngeal cancers, sponsored by Fundación Mutua Madrileña, has been accepted for publication in Head&Neck journal and in Clinical & Translational Oncology, both included in Medline. This work has also been commented on general media this year, including El Mundo, El País and ABC. Another important line of investigation has been the analysis of Polymorphisms in HIF-1alpha in carcinomas of the larynx, that has been carried out in the Otorhinolaryngology Department and the Pathology Department and has been published in Clinical & Translational Oncology. We continue to participate in clinical trials on the prevention and treatment of mucositis in head and neck patients receiving radiotherapy or chemoradiotherapy. One of these multicentric trials is testing the value of Clonidine Lauriad, and is still recruiting patients. The other observational study analyze the efficacy of intranasal Fentanyl for the treatment of pain associat- P16 immunostaining. p16 + staining: strong and diffuse nuclear and cytoplasmatic staining ed with oral mucositis. The results of these trials will help to improve the quality of life of head and neck cancer patients. MAJOR GRANTS • Consuelo López Elzaurdia. Identificación de factores genéticos, ambientales y de expresión fenotípica – 155 – AREA 3AREA 2 AREA 1 RESEARCH INTEREST Advanced therapies and individualized medicine asociados a la progresión de lesiones precursoras del cáncer gástrico: estudio coordinado español de seguimiento. ISCIII. PI10/02654. Duration: 2011 - 2013. • Consuelo López Elzaurdia. Identificación de factores genéticos, ambientales y de expresión fenotípica asociados a la progresión de lesiones precursoras del cáncer gástrico: estudio coordinado español de seguimiento. Carlos A. González Svatetz. PI-436. Duration: 2011 2014. • Adolfo Hinojar Gutiérrez. Papel de las células madre tumorales en la evolución clínica del carcinoma escamoso de laringe. Estudio de la expresión de Podoplanina, CD44 y ALDH-1. Fundación Mutua Madrileña. Duration: 2011 2013.. PUBLICATIONS YEAR (3) [IF: 4,607] Total IF Publication No. Q1 Q2 2010 9,046 6 1 4 2011 25,234 5 2 2012 4,607 3 2 Mañas A, Cerezo L, de la Torre A, García M, Alburquerque H, Ludeña B, Ruiz A, Pérez A, Escribano A, Manso A, Glaria LA; Grupo de Investigación Clínica en Oncología Radioterápica (GICOR). Epidemiology and prevalence of oropharyngeal candidiasis in Spanish patients with head and neck tumors undergoing radiotherapy treatment alone or in combination with chemotherapy. Clin Transl Oncol. 14(10):740-746. Epub 2012 Sep 8. 2012. PMID: 22960994. IF: 1,327. DOI: 10.1007/s12094-012-0861-8 Muñoz-Guerra M, Rodríguez-Campo F, RosónGómez S, Naval-Gías L. A New Method to Improve Defects of the Mandibular Angle Using an Asymmetrical Bone Distraction Technique. J Oral Maxillofac Surg. 70(4):925-30. Epub 2011 Jul 18. 2012. PMID: 21764495. IF: 1,64. DOI: 10.1016/j.joms.2011.02.080 – 156 – Mancha de la Plata M, Gías LN, Díez PM, MuñozGuerra M, González-García R, Lee GY, CastrejónCastrejón S, Rodríguez-Campo FJ. Osseointegrated Implant Rehabilitation of Irradiated Oral Cancer Patients. J Oral Maxillofac Surg. 70(5):1052-63. Epub 2011 Jul 22. 2012. PMID: 21778009. IF: 1,64. DOI: 10.1016/j.joms.2011.03.032 BOOKS Luis Naval Gías, Raúl González-García. Reconstrucción Maxilomandibular Compleja. 2012. Panamericana. ISBN: 978-84-9835-607-6. Cerezo L, Martín M, López M. Radioterapia sobre el hueso maxilomandibular reconstruido mediante microcirugía o distracción ósea. Reconstrucción Maxilomandibular Compleja. 2012. Panamericana. ISBN: 978-84-9835-607-6. Naval Gías L. Rehabilitación implantológica sobre colgajo libre microvascularizado de peroné. Reconstrucción Maxilomandibular Compleja. 2012. Panamericana. ISBN: 978-84-9835-607-6. Naval Gías L. Distracción osteogénica en la reconstrucción de defectos complejos del tercio medio facial y la calota craneal. Reconstrucción Maxilomandibular Compleja. 2012. Panamericana. ISBN: 978-84-9835-607-6. Muñoz Guerra M. Distracción osteogénica en colgajos óseos microvascularizados. Reconstrucción Maxilomandibular Compleja. 2012. Panamericana. ISBN: 978-84-9835-607-6. Naval Gías L, Rosón Gómez S. Rehabilitación implantológica sobre hueso distraído en defectos maxilomandibulares complejos. Reconstrucción Maxilomandibular Compleja. 2012. Panamericana. ISBN: 978-84-9835-607-6. Martín M, Carrasco M. Radioterapia paliativa. Enfermería en Cuidados Paliativos y al Final de la Vida. 2012. Elsevier. ISBN: 978-84-8086-754-2. AREA 3 PRINCIPAL INVESTIGATOR: CEREZO PADELLANO, LAURA Calidad de vida en dolor irruptivo (COP-Qol). Comparación de su percepción por pacientes y médicos;(Versión final: 23-12-11). TEVA PHARMA S.L.U. DIOQOL PRINCIPAL INVESTIGATOR: CEREZO PADELLANO, LAURA Valoración de la capacidad del fentanilo intranasal en pectina en la prevención de los episodios de dolor irruptivo en pacientes con mucositis actínica orofaringea; (versión 1.0:6-06-12). GICOR. GIC-FEN2012-01 GRUPO 55 HEAD OF LABORATORY Cecilio Santander Vaquero GROUP MEMBERS • Ana Isabel Ballesteros García • José Cantero Perona • José Andrés Moreno Monteagudo • Jesús González Cajal • María del Mar Pérez Pérez • Olga Donnay Candil • Elena Martín Pérez • Francisco E. Viamontes Ugalde • María Mercedes Guijarro Rojas • Montserrat Alcañiz Rodríguez • María José Galán Sánchez-Heredero • Concepción Alonso Cerezo • Yat Wah Pun Tam • Ramón Moreno Balsalobre • José Luis García Fernández • Erich Alberto Vargas Díez • Yolanda Delgado Jiménez • Lourdes del Campo del Val • Ramón Colomer Bosch RESEARCH INTEREST Our Group leads a team focused on the diagnosis and management of cancer. Main research Topics: Diagnosis • Colonoscopy versus Fecal Immunochemical Testing in Colorectal- Cancer Screening • Anaemia in patients with non-myeloid cancer • The diagnostic importance of hemodynamics and liver biopsy • Abdominal Complications Following Hematopoietic Stem Cell Transplantation Therapies • Extended-spectrum beta-lactamase producing bacteria • Clinical experience with ertapenem in the treatment of infections of the biliary tract • Bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radiochemotherapy Pancreas diseases • Bronchial-pancreatic fistula • Colloid carcinoma of the pancreas • Association of thymidylate synthase and hypoxia inducible factor-1alpha DNA polymorphisms with pancreatic cancer Genetics • Appropriate use of the Unit Family Cancer Genetic Counseling from primary Care • Sexual development disorder in a patient 45,X/46,X,DIC(Y) Training • Study on the activity of general and digestive surgery residents based on the use of the computerised logbook – 157 – AREA 3AREA 2 AREA 1 CLINICAL TRIALS Advanced therapies and individualized medicine PUBLICATIONS (7) [IF: 69,717] YEAR Total IF Publication No. Q1 Q2 2010 90,213 13 5 4 2011 70,961 21 10 9 2012 69,717 7 4 1 Santander C, Moreno-Otero R. Commentary: ursodeoxycholic acid as chemoprevention in inflammatory bowel disease and primary sclerosing cholangitis. Aliment Pharmacol Ther 35(7):846-846. 2012. PMID: 22404405. IF: 3,769. DOI: 10.1111/j.1365-2036.2012.05019.x Pergolizzi J, Ahlbeck K, Aldington D, Alon E, Collett B, Coluzzi F, Huygen F, Jaksch W, Kocot-Kepska M, Mangas AC, Margarit C, Mavrocordatos P, Morlion B, Müller-Schwefe G, Nicolaou A, Pérez Hernández C, Sichere P, Varrassi G. The chronic pain conundrum: should we CHANGE from relying on past history to assessing prognostic factors?. Curr Med Res Opin. 28(2):249-56. 2012. PMID: 22181344. IF: 2,38. DOI: 10.1185/03007995.2011.651525 A. Herreros de Tejada, J. L. Calleja, M. Jiménez, V. Rojo, C. Santander, J. C. Rial, R. García, J. Chennat, A. L. Picardo, L. Abreu. Gastric band cutter to remove a migrated gastric band. Endoscopy 44(Suppl 2 UCTN):E40-E41. 2012. PMID: 22396269. IF: 5,21. DOI: 10.1055/s-00311291520 Torres A, Llinares P, Turegano F, Martin-Perez E, Lobo E, Martin-Antona E, Granizo JJ, Aguilar L; Study Group. Clinical experience with ertapenem in the treatment of infections of the biliary tract in daily practice in five Spanish hospitals. J Chemother. 24(6):338-43. 2012. PMID: 23174098. IF: 1,084. DOI: 10.1179/1973947812Y.0000000041 Quintero E, Castells A, Bujanda L, Cubiella J, Salas D, Lanas Á, Andreu M, Carballo F, Morillas JD, Hernández C, Jover R, Montalvo I, Arenas J, Laredo E, Hernández V, Iglesias F, Cid E, Zubizarreta R, Sala T, Ponce M, Andrés M, Teruel G, Peris A, Roncales MP, Polo-Tomás M, Bessa X, – 158 – Ferrer-Armengou O, Grau J, Serradesanferm A, Ono A, Cruzado J, Pérez-Riquelme F, AlonsoAbreu I, de la Vega-Prieto M, Reyes-Melian JM, Cacho G, Díaz-Tasende J, Herreros-de-Tejada A, Poves C, Santander C, González-Navarro A; COLONPREV Study Investigators (...,Mª Chaparro, Gisbert JP,...). Colonoscopy versus Fecal Immunochemical Testing in Colorectal-Cancer Screening. N Engl J Med 366(8):697-706. 2012. PMID: 22356323. IF: 53,298. DOI: 10.1056/NEJMoa1108895 Miranda-García P, López-Martín MC, Alvarez-Malé T, Casanova-González MJ, Santander C, Bañares R, Moreno-Otero R, Trapero-Marugán M. Idiopathic portal hypertension complicated by ischemic hepatitis: the diagnostic importance of hemodynamics and liver biopsy. Rev Esp Enferm Dig 104(1):45-47. 2012. PMID: 22300122. IF: 1,548 Zapatero A, Martin De Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radiochemotherapy. Urology 80(5):1056-1062. 2012. PMID: 22999456. IF: 2,428. DOI: 10.1016/j.urology.2012.07.045 GROUP ASSOCIATED 2 HEAD OF LABORATORY Carlos Manuel Olivier Gómez GROUP MEMBERS • Gloria Bocardo Fajardo • Estefanía Romero Selas • Ricardo Brime Menéndez • Victoria Diego García • Guillermo Celada Luis AREA 3 PUBLICATIONS (4) [IF: 10,429] Our group focused on three different research areas. Prostate cancer(PC): We analyzed the relationship between circulating tumor cells (CTC) levels and different parameters (PSA levels, Gleason score and TNM staging) in patients with metastatic hormonesensitive PC and established the prognostic value in the overall and progression-free survival. The risk of mortality and progression with ≥ 4 CTC were 4.1 (IC 95 %: 1.1-14.6; P = 0.029) and 8.5 (IC 95 %: 2.626.9; P < 0.001) times higher. The immunomagnetic test allows us to quantify the CTC in peripheral blood and could provide a possibility for correctly staging and estimate the prognostic value of the metastatic hormone-sensitive PC. Bladder cancer (BC): We establish a protein expression pattern of high risk progression superficial BC. It may be an instrument to discern the appropriate candidates for more aggressive treatments. By using a 2DElectrophoresis, Mass Spectrometry and silver staining for protein visualization we analyzed cytoskeleton, apoptosis and cellular metabolism related proteins. Cytoskeleton related proteins show differences between invasive BC (IBC) and non invasive BC (NIBC) versus the control. Proteins related with apoptosis are significantly increased in NIBC vs IBC group. Erectile Dysfunction (ED): We determined changes in the plasma proteome of proteins associated with inflammation and atherogenesis in diabetic patients with ED after vardenafil administration. The treatment significantly reduced circulating plasma levels of different biomarkers mainly associated with inflammation and atherogenesis. These results may suggest that vardenafil plays an antiinflammatory and protective effect on atherogenesis in diabetic patients with ED. Resel Folkersma L, San José Manso L, Galante Romo I, Moreno Sierra J, and Olivier Gómez C. Prognostic significance of circulating tumor cell count in patients with metastatic hormone-sensitive prostate cancer. Urology 80(6):1328-1332. 2012. PMID: 23063057. IF: 2,428. DOI: 10.1016/j.urology.2012.09.001 MAJOR GRANTS CLINICAL TRIALS Carlos Manuel Olivier Gómez. Exosomas como marcadores de la progresión tumoral del carcinoma de células transicionales (CCT) vesical. FIB-HUP. Proyecto Intramural. Duration: 2012 - 2012. PRINCIPAL INVESTIGATOR: OLIVIER GOMEZ, CARLOS Estudio exploratorio de la actividad del extracto lípido esterólico de Serenoa repens (Permixon« 160mg cápsulas duras) frente a tamsulosina LP sobre biomar- YEAR Total IF Publication No. Q1 Q2 2011 4,105 21 10 9 2012 10,429 7 4 1 2010 Galante Romo, I., San José Manso, L.A., Casado Varela, J., López Farré, A., Blázquez Izquierdo, J., Hernando Arteche, A., Sanz Ortega, J., Carballido Rodríguez, J., Olivier Gómez, C.M. Transitional cell bladder cancer proteomic mapping and risk of progression. European Urology Suppl 11(1):E897-U887. 2012. IF: 1,827 Fernandez, I, Celada, G, Brime, R, Diego, V, Bocardo, G, Romero, E, Olivier, C. Opportunity of ureteroscopy in the management of complex lithiasis in a center without extracorporeal lithotripsy. The Journal of Urology 187(4S):E693-E694. 2012. IF: 3,746. DOI: 10.1016/j.juro.2012.02.1680 Zapatero A, Martin De Vidales C, Arellano R, Ibañez Y, Bocardo G, Perez M, Rabadan M, García Vicente F, Cruz Conde JA, Olivier C. Long-term results of two prospective bladder-sparing trimodality approaches for invasive bladder cancer: neoadjuvant chemotherapy and concurrent radio-chemotherapy. Urology 80(5):1056-1062. 2012. PMID: 22999456. IF: 2,428. DOI: 10.1016/j.urology.2012.07.045 – 159 – AREA 3AREA 2 AREA 1 RESEARCH INTEREST Advanced therapies and individualized medicine cadores inflamatorios en el tratamiento de los síntomas urinarios relacionados con la HPB. Estudio prospectivo multinacional, multicéntrico, aleatorizado, doble ciego y de grupos paralelos;(Versión 0106-02-12). PIERRE FABRE MEDICAMENT. P00048GP403. EudraCT: 2011-005307-33 GROUP ASSOCIATED 3 HEAD OF LABORATORY Concepción Pérez Hernández Saldaña MT, Pérez C, Navarro A, Masramón X, Rejas J. Pain alleviation and patient-reported health outcomes following switching to pregabalin in individuals with gabapentin-refractory neuropathic pain in routine medical practice. Clin Drug Investig. 32(6):401-12. 2012. PMID: 22480279. IF: 1,822. DOI: 10.2165/11599400-000000000-00000 Molina-Manso D, Del Prado G, Ortiz-Pérez A, Manrubia-Cobo M, Gómez-Barrena E, CorderoAmpuero J, Esteban J. In vitro susceptibility of Staphylococcus aureus and Staphylococcus epidermidis isolated from prosthetic joint infections. J Antibiot (Tokyo). 65(10):505-8. 2012. PMID: 22854340. IF: 1,651. DOI: 10.1038/ja.2012.62 GROUP MEMBERS • José Cordero Ampuero • Emilio Marín Aráez • Vicente Casa de Pantoja • Antonio Gómez Pan • Francisco Clement Fernández • Enrique Alday Muñoz • Fernando Teba del Pino • Javier Izaguirre Anduaga Gómez-Barrena E, Esteban J, Medel F, Molina-Manso D, Ortiz-Pérez A, Cordero-Ampuero J, Puértolas JA. Bacterial adherence to separated modular components in joint prosthesis: A clinical study. J Orthop Res. 30(10):1634-1639. 2012. PMID: 22467526. IF: 2,811. DOI: 10.1002/jor.22114 PUBLICATIONS (8) [IF: 17,281] YEAR Total IF Publication No. Q1 Q2 2010 67,605 6 2 4 2011 3,205 1 2012 17,281 8 1 4 de Salas-Cansado M, Pérez C, Saldaña MT, Navarro A, Rejas J. A cost-effectiveness analysis of the effect of pregabalin versus usual care in the treatment of refractory neuropathic pain in routine medical practice in Spain. Pain Med. 13(5):699-710. 2012. PMID: 22594706. IF: 2,346. DOI: 10.1111/j.15264637.2012.01375.x 2 Esteban J, Alonso-Rodriguez N, del-Prado G, OrtizPérez A, Molina-Manso D, Cordero-Ampuero J, Sandoval E, Fernández-Roblas R, Gómez-Barrena E. PCR-hybridization after sonication improves diagnosis of implant-related infection. Acta Orthop. 83(3):299304. 2012. PMID: 22616742. IF: 2,168. DOI: 10.3109/17453674.2012.693019 Muñoz-Mahamud E, Pons M, Matamala A, Tibau R, Puig L, Cordero-Ampuero J, García S. Hematogenous – 160 – septic arthritis of the hip in adult patients. Am J Emerg Med. 30(4):630-1. 2012. PMID: 22306386. IF: 1,976. DOI: 10.1016/j.ajem.2011.12.042 Navarro A, Saldaña MT, Pérez C, Masramón X, Rejas J. Costs and health resources utilization following switching to pregabalin in individuals with gabapentinrefractory neuropathic pain: a post hoc analysis. Pain Pract. 12(5):382-93. 2012. PMID: 22004531. IF: 2,207. DOI: 10.1111/j.1533-2500.2011.00515.x Cordero-Ampuero J, Darder A, Santillana J, Caloto MT, Nocea G. Evaluation of patients' and physicians' expectations and attributes of osteoarthritis treatment using Kano methodology. Qual Life Res. 21(8):1391- 404. Epub 2011 Dec 2. 2012. PMID: 22134806. IF: 2,3. DOI: 10.1007/s11136-011-0058-6 CLINICAL TRIALS inmediato de los pacientes sometidos a cirugía de resección pulmonar como profilaxis de las complicaciones respiratorias postoperatorias;(versión 2.0: 30-12-11). FUNDACION GREGORIO MARAÑON. FIBHGM-ECNC010-2010. EudraCT: 2010-022863-36 PRINCIPAL INVESTIGATOR: PEREZ HERNANDEZ, CONCEPCION Eficacia y seguridad del apósito adhesivo medicamentoso de lidocaína al 5% en el dolor neuropático posoperatorio localizado crónico; (Versión 2.0:26-04-12). GRUNENTHAL GMBH. KF10004/10. EudraCT: 2012-000347-28 PRINCIPAL INVESTIGATOR: PEREZ HERNANDEZ, CONCEPCION Estudio epidemiológico para determinar las diferencias en el impacto sobre la calidad de vida en pacientes con dolor crónico de moderado a intenso de tipo nociceptivo, neuropático y mixto; (versión final v7: 12-04-12). GRUNENTHAL PHARMA S.A. GRU-DOL-2012-01 PRINCIPAL INVESTIGATOR: PEREZ HERNANDEZ, CONCEPCION Estudio prospectivo observacional, para valorar la eficacia de la capsaicina al 8% en los distintos signos y síntomas positivos en el dolor neuropático periférico localizado; Título corto: ECASIDONEP; (versión 1.00:23-07-12). PER-CAP-2012 PRINCIPAL INVESTIGATOR: CORDERO AMPUERO, JOSE Estudio prospectivo, internacional, doble ciego, controlado para evaluar los efectos de ranelato de estroncio frente a placebo en la reducción de pérdida ósea periprotésica en pacientes con artroplastia total de cadera. Estudio de "pérdida ósea periprotésica"; (versión final: 5-1-11, enmienda 1:28-1011). LABORATORIOS SERVIER, S.L. CL3-12911037. EudraCT: 2010-020215-36 PRINCIPAL INVESTIGATOR: PEREZ HERNANDEZ, CONCEPCION Ensayo clínico exploratorio en fase II, aleatorizado, doble ciego, controlado con placebo y con grupos paralelos para evaluar la eficacia y seguridad de E52862 (400 mg) por vía oral en pacientes con neuralgia postherpética (NPH); (versión 1.0:13-04-12). LABORATORIOS ESTEVE, S.A. ESTEVE-SIGM203. EudraCT: 2012-000399-41 PRINCIPAL INVESTIGATOR: ALDAY MUÑOZ, ENRIQUE Estudio en fase 4, aleatorizado, controlado de eficacia y seguridad del uso de la presión continua de la vía aérea CPAP en el periodo postoperatorio PRINCIPAL INVESTIGATOR: PEREZ HERNANDEZ, CONCEPCION Ensayo clínico en fase III, multicéntrico, aleatorizado, doble ciego, controlado con placebo, con diseño de grupos paralelos, de aumento de dosis escalonada para investigar la eficacia, seguridad y tolerabilidad de naloxona HCI LP en comprimidos administrada en un intervalo de dosis de 3 mg a 24 mg dos veces al día en pacientes con estreñimiento inducido por opioides; (versión final 2.0: 30-0812). DEVELCO PHARMA SCHWEIZ AG. 0176/DEV. EudraCT: 2012-003218-14 – 161 – AREA 3AREA 2 AREA 1 AREA 3 Advanced therapies and individualized medicine ENSAYOS HUP PRINCIPAL INVESTIGATOR: GONZALEZ GUIJARRO, JUAN-JACOBO Estudio aleatorizado, frente a placebo, doble enmascarado de eficacia y seguridad de gevokizumab en el tratamiento de pacientes con uveítis no infecciosa intermedia, posterior o panuveítis, actualmente controlada con tratamiento sistémico. Estudio EYEGUARD-C; (versión final: 31-08-12). XOMA (US) LLC. X052131/CL3-78989-006. EudraCT: 2012-001609-25 PRINCIPAL INVESTIGATOR: PLANAS ROCA, ANTONIO Estudio multicéntrico, aleatorizado, doble ciego, de grupos paralelos, controlado con placebo, para evaluar la eficacia y seguridad de una nueva formulación IV de ibuprofeno 800mg cada 6 horas para el manejo del dolor postoperatorio; (versión 1: 14-12-11). LABORATORIOS BIOMENDI S.A.U. BIBEC02. EudraCT: 2011-005007-33 PRINCIPAL INVESTIGATOR: MARTINEZ NIETO, MARIA-CONCEPCION Estudio de persistencia en pacientes con psoriasis que inicien tratamiento con fármacos biológicos, en la práctica clínica habitual;(versión 1:09-10-12). CONCEPCION MARTINEZ NIETO. MAR-UST-2012-01 PRINCIPAL INVESTIGATOR: GONZALEZ DEL PINO VILLANUEVA, JUAN Condrosarcoma de la mano; Versión 1: 18-10-12. JGP-1-2012 PRINCIPAL INVESTIGATOR: SPOTTORNO RUBIO, MARIA-PIA Estudio epidemiológico, observacional, prospectivo, para evaluar la prevalencia de las distintas etiologías de la artrosis en el ámbito sanitario español;(Versión Final 27 de julio de 2012, Enmienda no relevante 1.0 de 02 de octubre de 2012). MUNDIPHARMA PHARMACEUTICALS, S. L. ESTUDIO STAR PRINCIPAL INVESTIGATOR: GONZALEZ GUIJARRO, JUAN-JACOBO – 162 – Estudio aleatorizado, frente a placebo, doble enmascarado de eficacia y seguridad de gevokizumab en el tratamiento de la uveítis no infecciosa activa intermedia, posterior o panuveítis; (versión final: 05-09-12). XOMA (US) LLC. X052130/CL3-78989-005. EudraCT: 2012-001610-42 PRINCIPAL INVESTIGATOR: MONTES LOPEZ, CARMEN Estudio clínico multicéntrico, aleatorizado, controlado con placebo y de simple ciego para evaluar la eficacia y la tolerabilidad de la asociación de crema de ubidecarenona, dexpantenol y clorhexidina y una pasta de clorhidrato de diltiazem al 2% en el tratamiento de la fisura anal crónica; (versión 7: 24-01-12). TECNIMEDE SOCIEDADE TECNICO-MEDICINAL, S.A. DIL-UBIDEX-CLO II/2003/003/PT. EudraCT: 2005-005675-15 PRINCIPAL INVESTIGATOR: RAMASCO RUEDA, FERNANDO Estudio para determinar si la utilización de la concentración sérica de procalcitonina puede condicionar una menor duración del tratamiento antibiótico en la infección intrabdominal complicada. Estudio multicéntrico, aleatorizado. Subtitulo PROCIA. EMILIO MASEDA GARRIDO (H.U. LA PAZ). PROCIA PRINCIPAL INVESTIGATOR: RAMASCO RUEDA, FERNANDO Estudio descriptivo SATURSEPSIS: Saturación cerebral como predictor de saturación venosa central de oxígeno y de resultados clínicos en pacientes con sepsis de origen abdominal; (Versión 1: 14-05-12). STSEO 1 PRINCIPAL INVESTIGATOR: MUÑOZ DE NOVA, JOSE LUIS Influencia de las variantes anatómicas del tronco celíaco en las cirugías hepática y pancreática; (versión 1). VATC PRINCIPAL INVESTIGATOR: DUDLEY PORRAS, FRANCISCO J. Utilización de recursos sanitarios y costes asociados al tratamiento de Dupuytren en España; (Versión 4:24- AREA 3 PRINCIPAL INVESTIGATOR: GIL-DIEZ USANDIZAGA, JOSE-LUIS Ensayo clínico de fase II aleatorizado, doble ciego, controlado con tratamiento activo (tramadol 100mg) y placebo, de grupos paralelos, para establecer la dosis eficaz de entre 4 concentraciones de E-58425 para dolor dental de moderado a intenso; (versión 1.5:1811-11). LABORATORIOS ESTEVE, S.A. ESTEVESACO4-201. EudraCT: 2011-002778-21 PRINCIPAL INVESTIGATOR: PEREZ FERNANDEZ, MARIA CARMEN Estudio para evaluar el efecto del tratamiento mediante hemoperfusión en sepsis grave y shock séptico secundarios a peritonitis postquirúrgica; (versión 1: 19-6-12). CLS-EO1 PRINCIPAL INVESTIGATOR: CASADO ESCRIBANO, PEDRO PABLO Ensayo clínico aleatorizado para evaluar la efectividad de un programa de intervención multimodal en pacientes diabéticos tipo 2 prefrágiles y frágiles sobre la fragilidad y la calidad de vida: Estudio MIDFrail; (versión 2:21-06-12). FUNDACION INVESTIGACION BIOMEDICA HOSPITAL GETAFE. MIDFRAIL PRINCIPAL INVESTIGATOR: PATIÑO RODRIGUEZ, EVA Estudio epidemiológico, observacional, prospectivo, para evaluar la prevalencia de las distintas etiologías del dolor lumbar en el ámbito sanitario español;(versión final: 28-10-11). MUNDIPHARMA PHARMACEUTICALS, S. L. SMILE PRINCIPAL INVESTIGATOR: ROMAN GUERRERO, JESUS-CARLOS Estudio observacional retrospectivo y no intervencionista para registrar el uso, seguridad y eficacia de anidulafungina en el paciente crítico; (versión 1.0: 2409-11). EMILIO MASEDA GARRIDO (H.U. LA PAZ). GTI-ANI-2011-01 PRINCIPAL INVESTIGATOR: AGUILAR MULET, JUANMARIANO Ensayo clínico en fase IV randomizado doble ciego y multicéntrico para la evaluación del uso de una mezcla de oxígeno y óxido nitroso 50/50 en el tratamiento del cólico renal en el servicio de urgencias; (Versión 1: 13-01-12). FUNDACION INVESTIGACION BIOMEDICA H. LA PRINCESA. PG-ON-09. EudraCT: HUP PRINCIPAL INVESTIGATOR: VEGA GONZALEZ, GEMA Ensayo clínico en fase IV aleatorizado, no ciego, controlado para comparar la oxigenoterapia de alto flujo (grupo de intervención) frente a la oxigenoterapia convencional (grupo control) en pacientes con insuficiencia Respiratoria Aguda (IRA) severa;(versión 1: 04-0412). FUNDACION INVESTIGACION BIOMEDICA H. LA PRINCESA. EC11-103. EudraCT: HUP PRINCIPAL INVESTIGATOR: RUBIO PEREZ, INES Infección por microorganismos gram negativos multiresistentes en pacientes de cirugía general: epidemiología, factores de riesgo y perfil microbiológico; (versión 1: 17-07-12).Titulo abreviado: Infección multiresistente cirugía. IMRC PRINCIPAL INVESTIGATOR: ORTS RODRIGUEZ, MARIA DEL MAR Ensayo clínico aleatorizado y doble ciego, controlado con placebo, de esteroides perioperatorios en pacientes adultos de alto riesgo sometidos a cirugía cardiaca con circulación extracorpórea;(Versión 1: 2206-11). INSTITUT DE RECERCA H.SANTA CREU I SANT PAU. IIBSP-EST-2011-35. EudraCT: 2010-023093-39 PRINCIPAL INVESTIGATOR: RAMASCO RUEDA, FERNANDO Relación entre las saturaciones cerebral y venosa central de oxígeno con las complicaciones perioperatorias en cirugía torácica;(Versión 3). SATOR-DOS PRINCIPAL INVESTIGATOR: CORTAZAR SAEZ, MILAGROS TERESA – 163 – AREA 3AREA 2 AREA 1 5-12). LABORATORIOS PFIZER ESPAÑA. PFI-COL2012-01 Advanced therapies and individualized medicine Estudio coste-efectividad de la atención especializada en ostomia, (Versión 2:15-03-12.). HOLLISTER IBERICA S.A. HOL-OST-2012-01 PRINCIPAL INVESTIGATOR: MARTINEZ NIETO, MARIA-CONCEPCION Estudio de la influencia de las variaciones de dosis de tratamiento con inhibidores de la proteasa en la eficacia y coste de pacientes en tratamiento de Hepatitis C Crónica en la práctica clínica habitual;(versión 1:2-0712). ALBERTO MORELL (SERVICIO DE FARMACIA HUP). MOR-TEL-2012-01 PRINCIPAL INVESTIGATOR: BUSTAMANTE MUNGUIRA, JUAN Registro europeo de reparación de la válvula mitral; – 164 – (versión rev 4: octubre 2011).Estudio MiCardia. TP 10046 PRINCIPAL INVESTIGATOR: TIENO DROVE, TANIA Estudio multicéntrico de validez y fiabilidad de la Escala de Conductas indicadoras de dolor ESCID para medir el dolor en pacientes críticos, no comunicativos y sometidos a ventilación mecánica. FISESCID PRINCIPAL INVESTIGATOR: CHOCANO HIGUERAS, ALBERTO Registro europeo multinacional sobre la prevención de episodios tromboembólicos en fibrilación auricular; (versión 1.0: 29-08-11). DAIICHI SANKYO EUROPE GMBH. DSE-EAF-01-11 www.iis-princesa.org