ANNUAL REPORT OF SCIENTIFIC ACTIVITY - IIS LA PRINCESA · Zarruk Serrano, Juan Guillermo Papel Del...

2011ANNUAL REPORT OFSCIENTIFIC ACTIVITY

AREA 1Line 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. AREA 2

AREA 3

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.

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 oncohema-

tology.Line 3.6 New diagnostic and therapeutic advances in cardiovascu-

lar diseases.Line 3.7 New therapies in infectious pathologies.Line 3.8 Individualized medicine in solid tumors.

2011 ANNUAL REPORT OFSCIENTIFIC ACTIVITY

It is a great pleasure to present the 2011Annual Scientific Report of the Institutode Investigación Sanitaria Hospital Uni-

versitario de La Princesa (La PrincesaHospital Institute for health Research. IIS-IP). Our Institute groups 449 researchersthat conform 51 research teams distrib-uted among the different centres thatmake up the IIS-IP (Hospital Universitariode La Princesa, Hospital Niño Jesús,Hospital Santa Cristina, Atención Primariaand Universidad Autónoma de Madrid).All our professionals work with strongdedication and commitment to improvethe quality of our research aimed at theimprovement of Public Health. This effortis reflected in the quality of our publica-tions during 2011. In this year, IIS-IP re-searchers have published 249 articles injournals of first or second quartile withmean impact factor per article of 5.4. Ofthe total number of articles 51% werepublished in fist quartile journals and23.7% in fist decile journals.

In 2011, despite the difficult eco-nomic environment, IIS-IP has main-tained its commitment to consolidateresearch space and infrastructures andto support new emerging researchgroups. We have allocated resources tofully equip 650 m2 of space for researchin Santa Cristina Hospital creating a new

Research Unit. The new Unit has startedthis year with four brand new laborato-ries that host four emerging researchgroups. IIS-IP also obtained funding thisyear from Instituto de Salud Carlos III totackle the refurbishment of the CentralResearch Unit in La Princesa Hospital.We make a constant effort to improveresearch infrastructures and facilities toease the work of our professionals.

The research activity of IIS-IP is organ-ized in three main areas: 1. Cellular andmolecular ethiopathogenic mechanismsin inflammatory and autoimmune dis-eases; 2. Neurotransmission pharmaco-logical neuroprotection and neurodegen-erative and neuropsychiatric diseases;and 3. Advanced therapies and individu-alized medicine. These research areas areintegrated by 25 research lines that coverdifferent aspects of basic, clinical andtranslational research. The scientific re-port presented here summarizes the con-figuration, research interests and activityduring 2011 of all the different groups. Weexpect that it will show to the readers aclear perspective of our research and en-courage everybody to keep working hardto improve in the future.

Francisco Sánchez MadridScientific Director

Letter from the Scientific Director

In 2011, despitethe difficult economic environ-ment, IIS-IP hasmaintained itscommitment toconsolidate research spaceand infrastructuresand to supportnew emerging research groups

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Letter from the Scientific Director . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

AREA 1 · CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES . . . . . . . . . . . . . . . . .17

LINE 1.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

LINE 1.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27

LINE 1.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35

LINE 1.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42

LINE 1.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44

LINE 1.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46

LINE 1.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50

LINE 1.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54

LINE 1.9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61

LINE 1.10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .64

LINE 1.11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .68

AREA 2 · NEUROTRANSMISSION, PHARMACOLOGICAL NEUROPROTECTION ANDNEURODEGENERATIVE AND NEUROPSYCHIATRIC DISEASES . . . . . . .75

LINE 2.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .77

LINE 2.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .83

LINE 2.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .88

LINE 2.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92

LINE 2.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .97

LINE 2.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .100

AREA 3 · ADVANCED THERAPIES AND INDIVIDUALIZED MEDICINE . . . . . . . . .107

LINE 3.1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109

LINE 3.2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .119

LINE 3.3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .128

LINE 3.4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .133

LINE 3.5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .146

LINE 3.6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .150

LINE 3.7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .158

LINE 3.8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .171

Diego de León, 6228006 MadridPhone 91 520 24 76 Fax 91 520 25 60e-mail: [email protected]

2011 ANNUAL REPORT OF SCIENTIFIC ACTIVITY

© INSTITUTO DE INVESTIGACIÓN SANITARIAHospital Universitario de La Princesa

Editing: Ibáñez&Plaza Asociados S.L.

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Summary ReportScientific ActivityIIS-Princesa 2011

7

SUMMARYSCIENTIFIC PRODUCTION

The number of publications and their impact factorrepresents one of the best indicators of the quality ofour research. In the last year 338 articles had beenpublished in scientific journals included in the“Journal Citation Report (JCR)”.

The following graphic represents all these publica-tions (distributed by areas) and their global impact

factor. Each publication is ascribed to one group,although most of them are the result of the collabo-ration between different teams. The impact factoraccumulated has reached 1483.775 with an averageimpact factor per article of 4.4.

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8

Summary

CLINICAL TRIALS

Clinical research is a fundamental pillar of develop-ment for our Institute. Coupled with the results ofbasic research, it seeks to improve the diagnosis andtreatment of diseases, ultimately benefiting thepatient.

During 2011 a total of 436 clinical trials were carriedout in our Institute. Their distribution by areas isshown below.

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Summary

9

DOCTORAL THESES

As a result of the effort dedicated to training by ourInstitute fourteen PhD theses have been defended by

members of IIS-IP in 2011. Information about thee the-ses is summarized below.

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DOCTORATE THESIS READER TITLE DIRECTOR GROUP

Benedicto Español, IgnacioInterrelación entre proteínas asociadas a uniones intercelulares estre-chas, polaridad de los hepatocitos y el virus de la hepatitis C.

Pedro Lorenzo Maja-no Rodríguez

24

Blanco Sánchez, IgnacioEstudio del efecto de darbepoetina α en isquemia7reperfusión renal. Suuso como agente protector y reparador del daño renal isquémico.

José Antonio Sán-chez Tomero

21

Calderón Deago, JosselaImplicación del receptor SLAM (CD150) en la infección por Trypanosomacruzi

Manuel Fresno Escu-dero

12

Cardeñoso Domingo, LauraMaría

Aportación de las técnicas moleculares al diagnóstico de "citomegalovi-rus" en el receptor de trasplante alogénico de progenitores

Manuel López-BreaCalvo

12

Casanova Fernández, Lucía Papel de la Quinasa Inductora de NF-kB en el trasplante hematopoyético.Manuel Ramírez Ore-llana

52

Cruz Adalia, ArantxaLa molécula de activación leucocitaria CD69 como regulador de los pro-cesos inflamatorios

Francisco SánchezMadrid

1

De la Fuente Martín, Esther

Implicación de los astrocitos hipotalámicos en las alteraciones metabóli-cas y en los cambios de composición corporal inducidos por malnutri-ción en los periodos neonatal y adulto: nuevas acciones de la leptina y laghrelina

Jesús Argente Oliver,Julie Ann ChowenKing

26

García Cáceres, CristinaCambios morfológicos y funcionales de los astrocitos hipotalámicos enlas alteraciones metabólicas centrales y periféricas inducidas por unadieta rica en grasa durante la etapa prenatal y postnatal.

Jesús Argente Oliver,Julie Ann Chowen King 26

Martínez Laperche, CarolinaEstudio de la infiltración del sistema nervioso central en niños con leuce-mia linfoblástica aguda y el papel de BMP4

Manuel Ramírez Ore-llana

39

Martorell, AlmudenaLa salud mental en la discapacidad intelectual: un recorrido de interrela-ciones

José Luis Ayuso Ma-teos

33

Pérez de José, Ana Fallo renal agudo en la cirugía cardiaca. Carmen Bernis Carro 21

Sreeramkumar, Vinatha Role of Prostaglandin E2 in T cell activation and migration

Manuel Fresno Escu-dero, Natalia CuestaRubio, Federico Ma-yor Menéndez

12,11

Trullats Vila, Joan CarlesEnfermedad Renal Crónica y terapia renal sustitutiva en pacientes con in-fección por el virus de la inmunodeficiencia humana. Prevalencia y super-vivencia

Guillermina BarrilCuadrado

21

Zarruk Serrano, Juan GuillermoPapel Del Receptor Cannabinoide Tipo 2 En Procesos De Neuroprotec-ción y Neurorreparación Tras La Isquemia Cerebral Experimental

María Ángeles MoroSánchez, Ignacio Li-zasoain Hernández,María EncarnaciónFernández

Associated 1,38

10

Summary

GUIDELINES

Area 1: Cellular and molecular etiopathogenic mecha-nisms in inflammatory and autoimmune diseases

Line 7: Inflammatory mechanisms in pulmonary diseasesGroup 22Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J,Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA,Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J,Bouros D, Carvalho C, Costabel U, Ebina M, HansellDM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J,Müller NL, Nicholson AG, Richeldi L, Selman M, DuddenRF, Griss BS, Protzko SL, Schünemann HJ. An officialATS/ERS/JRS/ALAT statement: idiopathic pulmonaryfibrosis: evidence-based guidelines for diagnosis andmanagement. Am J Respir Crit Care Med. 183(6): 788-824. 2011. PMID: 21471066.

Area 2: Neurotransmission, Pharmacological Neuropro-tection and Neurodegenerative and Neuropsychiatricdiseases

Line 4: Diagnostic and therapeutic advances in affectivedisordersGroup 33International Experts: Clive Adams, Reino Unido;Robert Ali, Australia; Alan Apter, Israel; Yael Apter,Israel; José Ayuso-Mateos *, España; Corrado Barbui*, Italia; Erin Barriball, Australia; Ettore Beghi, Italia; GailBell, Reino Unido; Gretchen Birbeck *, Estados Unidos;Jonathan Bisson, Reino Unido; Philip Boyce, Australia;Vladimir Carli, Suecia; Erico Castro- Costa, Brasil;Andrew Mohanraj Chandrasekaran §, Indonesia; SoniaChehil, Canadá; Colin Coxhead, Suiza; Jair de JesusMari, Brasil; Carlos de Mendonça Lima, Portugal;Diego DeLeo, Australia; Christopher Dowrick, ReinoUnido; Colin Drummond, Reino Unido; Julian Eaton §,Nigeria; Eric Emerson, Reino Unido; Cleusa P Ferri,Reino Unido; Alan Flisher †*, África del Sur; EricFombonne, Canadá; Maria Lucia Formigoni §, Brasil;Melvyn Freeman *, África del Sur; Linda Gask, ReinoUnido; Panteleimon Giannakopoulos *, Suiza; Richard

P Hastings, Reino Unido; Allan Horwitz, EstadosUnidos; Takashi Izutsu, Fondo de Población de lasNaciones Unidas; Lynne M Jones §, Reino Unido;Mario F Juruena, Brasil; Budi Anna Keliat §; Indonesia;Kairi Kolves, Australia; Shaji S Kunnukattil §, India; StanKutcher, Canadá; Tuuli Lahti, Finlandia; Noeline Latt,Australia; Itzhak Levav *, Israel; Nicholas Lintzeris,Australia; Jouko Lonnqvist, Finlandia; Lars Mehlum,Noruega; Nalaka Mendis, Sri Lanka; Ana-Claire Meyer,Estados Unidos; Valerio Daisy Miguelina Acosta,República Dominicana; Li Li Min, Brazil; CharlesNewton §, Kenia; Isidore Obot *, Nigeria; LubomirOkruhlica§, Eslovaquia; Olayinka Omigbodun *§,Nigeria; Timo Partonen, Finlandia; Vikram Patel *, Indiay Reino Unido; Michael Phillips *§, China; Pierre-MariePreux, Francia; Martin Prince *§, Reino Unido; AtifRahman *§, Pakistán y Reino Unido; Afarin Rahimi-Movaghar *, Irán; Janet Robertson, Reino Unido;Josemir W Sander *, Reino Unido; Sardarpour GudarziShahrokh, Irán; John Saunders *, Australia; ChiaraServili §, Italia; Pratap Sharan §, I ndia; LorenzoTarsitani, Italia; Rangaswamy Thara *§, India; Graham Thornicroft *§,Reino Unido; Jürgen Ünutzer *, Estados Unidos; MarkVakkur, Suiza; Peter Ventevogel *§, Holanda; LakshmiVijayakumar *§, India; Eugenio Vitelli, Italia; Wen-zhiWang §, China. MhGAP Intervention Guide for mental,neurological and substance use disorders in non-specia-lized health settings. World Health Organization Press.2011. Entidad: Organización Mundial de la Salud. ISBN:978-92-4-354806-7.

Javier Jiménez Pietropaolo, Silvia Martín Ulloa,TeresaPacheco Tabuenca, José Luís Pérez-Iñigo Gancedo,José Ignacio Robles Sánchez, Paloma Santiago García,Andrés Torras García, José Luís Ayuso Mateos,Francisco Rodríguez Pulido, Guillermo PetersenGuitarte. Guía para familiares. Detección y prevención dela conducta suicida. Comunidad de Madrid. DirecciónGeneral de Hospitales. 2011. Entidad: Comunidad deMadrid. Disponible online. http://www.madrid.org/cs/Satellite?c=CM_Publicaciones_FA&cid=1142662965405&idConsejeria=1109266187266&idListConsj=1109265444710&idOrganismo=1142439319720&language=es&pagename=ComunidadMadrid%2FEstructura&sm=1109266101003.

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11

Dua T, Barbui C, Clark N, Fleischmann A, Poznyak V, vanOmmeren M, Yasamy MT, Ayuso-Mateos JL, BirbeckGL, Drummond C, Freeman M, Giannakopoulos P,Levav I, Obot IS, Omigbodun O, Patel V, Phillips M,Prince M, Rahimi-Movaghar A, Rahman A, Sander JW,Saunders JB, Servili C, Rangaswamy T, Unützer J,Ventevogel P, Vijayakumar L, Thornicroft G, Saxena S.Evidence-Based Guidelines for Mental, Neurological,and Substance Use Disorders in Low- and Middle-Income Countries: Summary of WHORecommendations. PLoS Med 8(11):e10011. 2011.PMID: 22110406.

Area 3: Advanced therapies and individualized medicine.

Line 1: Prognostic and predictor markers in autoimmunediseasesGroup 36Pérez Edo L, Alonso Ruiz A, Roig Vilaseca D, GarcíaVadillo A, Guañabens Gay N, Peris P, Torrijos Eslava A,Beltrán Audera C, Fiter Aresté J, Arboleya Rodríguez L,Graña Gil J, Carbonell Abelló J, Nolla JM, Holgado PérezS, Salas Heredia E, Zubieta Tabernero J, Del PinoMontes J, Blanch i Rubió J, Caamaño Freire M,Rodríguez Pérez M, Castañeda S, Cerdá D, GómezVaquero C, Calvo Catalá J, Ciria M, Loza E. 2011 Up-date of the consensus statement of the Spanish Societyof Rheumatology on osteoporosis. Reumatol Clin.7(6):357-79. Epub 2011 Sep 15. 2011. PMID:22078694.

Gómez Reino J, Loza E, Andreu JL, Balsa A, Batlle E,Cañete JD, Collantes Estévez E, Fernández CarballidoC, Fernández Sueiro JL, García de Vicuña R, González-Álvaro I, González Fernández C, Juanola X, Linares LF,Marenco JL, Martín Mola E, Moreno Ramos M, MuleroMendoza J, Muñoz Fernández S, Queiro R, Richi AlbertiP, Sanz J, Tornero Molina J, Zarco Montejo P, CarmonaL. Consensus statement of the Spanish Society ofRheumatology on risk management of biologic therapyin rheumatic patients. Reumatol Clin. 7(5):284-98. Epub2011 Aug 4. 2011. PMID: 21925444.

Juanola Roura X, Zarco Montejo P, Sanz Sanz J, MuñozFernández S, Mulero Mendoza J, Linares Ferrando LF,

Gratacós Masmitja J, García de Vicuña R, FernandezCarballido C, Collantes Estevez E, Batlle Gualda E, ArizaAriza R, Loza Santamaría E. Consensus Statement ofthe Spanish Society of Rheumatology on the manage-ment of biologic therapies in spondyloarthritis except forpsoriatic arthritis. Reumatol Clin. 7(2):113-123. Epub2011 Feb 22. 2011. PMID: 21794794. doi:10.1016/j.reuma.2010.12.002.

C Jose Luis Fernández Sueiro, Xavier Juanola Roura,Juan de Dios Cañete Crespillo, Juan Carlos Torre Alonso,Rosario García de Vicuña, Rubén Queiro Silva, RafaelAriza Ariza, Enrique Batlle Gualda, Estíbaliz LozaSantamaría. Consensus statement of the SpanishSociety of Rheumatology on the management of biologictherapies in psoriatic arthritis. Reumatol Clin. 7(3):179-88.Epub 2011 Mar 21. 2011. PMID: 21794810.

Panelistas: José Luis Andréu Sánchez, Alejandro BalsaCriado, Enrique Batlle Gualda, Federico Díaz González,Ángel Elena Ibáñez, Mariano Tomás Flórez García,Fernando García Pérez, Nuria Guañabens Gay, CésarHernández García, Mª Victoria Irigoyen Oyarzabal, JoséLuis Marenco de la Fuente, Víctor Manuel MartínezTaboada, José María Salazar Vallinas, Alejandro TejedorVarillas, Juana de la Torre Aboki. Coordinadores: PabloLázaro de Mercado, Mª Dolores Aguilar Conesa, LoretoCarmona, Revisores: Ana Ortiz García, AntonioFernández Nebro, Blanca Hernández Cruz, CayetanoAlegre de Miquel, Claudia Alejandra Pereda Testa,Eugenio Chamizo Carmona, Jesús Maese, José de laMata Llord, Ramón Esteban Mazzucchelli, LydiaAbásolo Alcázar, Mª Betina Nishishinya, Mª RosaGonzález Crespo, Miguel Ángel Abad Hernández,Santiago Muñoz. Guía de práctica clínica para el mane-jo de la Artritis Reumatoide. GUIPCAR. 2011. Entidad:Sociedad Española de Reumatología.http://www.ser.es/ArchivosDESCARGABLES/Proyectos/GUIPCAR_2007/GUIPCAR2007-Completa.pdf Últimaactualización 2011 en: http://www.ser.es/practicaClinica/GUIPCAR_2007/Metodologia/Menu1_Metodologia_Actualizacion_I5.php.

Group 37Carrascosa JM, López-Estebaranz JL, Carretero G,Daudén E, Ferrándiz C, Vidal D, Belinchón I, Sánchez-

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Summary

12

Summary

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Regaña M, Puig L; Group Español de Psoriasis de laAcademia Española de Dermatología y Venereología.Narrowband UV-B, monochromatic excimer laser, andphotodynamic therapy in psoriasis: a consensus state-ment of the Spanish Psoriasis Group. ActasDermosifiliogr. 102(3):175-86. 2011. PMID: 21310368.Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, NastA, Franke J, Antoniou C, Arenberger P, Balieva F, Bylaite M,Correia O, Daudén E, Gisondi P, Iversen L, Kemény L, LahfaM, Nijsten T, Rantanen T, Reich A, Rosenbach T, Segaert S,Smith C, Talme T, Volc-Platzer B, Yawalkar N. Definition oftreatment goals for moderate to severe psoriasis: aEuropean consensus. Arch Dermatol Res. 303(1):1-10.Epub 2010 Sep 21. 2011. PMID: 20857129.

Line 2: Esophagogastrointestinal inflammatory diseasesGroup 38J.P. Gisbert. Guía de Práctica Clínica sobre Dispepsia.2011. Desarrollado conjuntamente por la AsociaciónEspañola de Gastroenterología (AEG), la SociedadEspañola de Medicina de Familia y Comunitaria(semFYC) y la Colaboración Centro CochraneIberoamericano. J. P Gisbert: Revisor y coordinador deAparato Digestivo.

JP Gisbert. Revisor y coordinador. Current concepts inthe management of Helicobacter pylori infection: theMaastricht IV Consensus Report. 2011. Entidad:European Helicobacter Study Group. 2010-2011.Group Español de Trabajo en Enfermedad de Crohn yColitis Ulcerosa (GETECCU) y desarrollado junto con laColaboración Cochrane. JP Gisbert Coordinador (2007-2011). Guías de Práctica Clínica en EnfermedadInflamatoria Intestinal (incuyendo la Guía de colitis ulcerosa,de enfermedad de Crohn y de enfermedad perianal). 2011.

J.P. Gisbert Revisor y Coordinador (2010-2011).Proyecto AHEAD2010 (Optimización del uso de inmuno-supresores y esteroides en la enfermedad de Crohn).2011. Entidad: GETECCU. Avalado por GETECCU.J.P. Gisbert. Algoritmos de tratamiento de la anemiaferropénica en enfermedades digestivas con hierro intra-venoso. 2011. J.P. Gisbert: Revisor general yCoordinador del tema “Papel del hierro intravenoso en lahemorragia digestiva aguda”.

Line 3: Progenitors and cell therapyGroup 39Aguado JM, Ruiz-Camps I, Muñoz P, Mensa J, AlmiranteB, Vázquez L, Rovira M, Martín-Dávila P, Moreno A,Alvarez-Lerma F, León C, Madero L, Ruiz-Contreras J,Fortún J, Cuenca-Estrella M; Group de Estudio deMicología Médica de la SEIMC (GEMICOMED).Guidelines for the treatment of Invasive Candidiasis andother yeasts. Spanish Society of Infectious Diseases andClinical Microbiology (SEIMC). 2010 Update. EnfermInfecc Microbiol Clin 29(5): 345-361. 2011. PMIP:21459489.

Line 7: New therapies in infectious pathologiesGroup 50Fortun J, Carratala J, Gavalda J, Lizasoain M, SalavertM, de la Camara R, Borges M, Cervera C, Garnacho J,Lassaleta A, Lumbreras C, Sanz MA, Ramos JT, Torre-Cisneros J, Aguado JM, Cuenca-Estrella M. Guidelinesfor the Treatment of Invasive Fungal Disease byAspergillus spp. and Other Fungi Issued by the SpanishSociety of Infectious Diseases and Clinical Microbiology(SEIMC). 2011 Update. Enfermedades infecciosas ymicrobiologia clinica. 29(6):435-54. 2011. PMID:21474210.Jesús Sanz Sanz, entre otros miembros del panel deexpertos. Documento de consenso de Gesida/PlanNacional sobre el Sida sobre el tratamiento antirretroviraldel adulto. www.gesidaseimc.org. 2011. Entidad:Gesida / PNS.

Group 51Blanquer J, Aspa J, Anzueto A, Ferrer M, Gallego M,Rajas O, Rello J, Rodríguez de Castro F, Torres A.SEPAR Guidelines for Nosocomial Pneumonia. ArchBronconeumol. 47(10):510-520. Epub 2011 Sep 9.2011. PMID: 21908091. doi:10.1016/j.arbres.2011.05.013.

Line 8: Individualized medicine in solid tumoursGroup 54Cerezo L, Martin M. Guía Clínica del Cáncer de CanalAnal. Guías clínicas en Oncología Radioterápica sobreTumores Digestivos: 171-190. 2011. Entidad: Sociedad

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Española de Oncología Radioterápica. ISBN: 978-84-92977-09-3.

Group 55Freixinet Gilart J, Hernández Rodríguez H, MartínezVallina P, Moreno Balsalobre R, Rodríguez Suárez P;SEPAR. Guidelines for the diagnosis and treatment ofthoracic traumatism. Arch Bronconeumol. 47(1):41-9.Epub 2010 Dec 28. 2011. PMID: 21190767.

Moreno Balsalobre R, Moreno Mata N, RamosIzquierdo R, Aragón Valverde FJ, Molins López-RodoL, Rivas de Andrés JJ, García Fernández JL,Cañizares Carretero MÁ, Congregado Loscertales M,Carbajo Carbajo M; SEPAR. Guidelines on surgery ofthe thoracic sympathetic nervous system. ArchBronconeumol. 47(2):94-102. Epub 2011 Feb 20.2011. PMID: 21342743.

Summary

14

Summary

PATENTS

During 2011 three new patent applications have beenfiled by researchers from our Institute and four new

patents have been granted. Information about thesepatents is summarized below.

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TITTLE AUTHORAPPLICATION

NUMBERGROUP

Composición farmacéuticapara el tratamiento de las enfer-medades cerebrovasculares

Lizasoain I, Moro MA, Hurtado O, Pradillo J 201101263 Associated 1

Uso de una composición en laelaboración de una soluciónde diálisis para el tratamientode las enfermedades cerebro-vasculares mediante diálisisperitoneal

Moro MA, Lizasoain I, Sánchez-Prieto J, Torres M, Godino MC, SobradoM, González VM, Vivancos J

201100829Associated 1

35

Péptido inhibidor de p38 y apli-caciones

F. Mayor, Jr., C. Murga, P. Campos, J. Heijnen, A. Kavelaars, A. Morreale 201131754 11

TITTLE AUTHORAPPLICATION

NUMBERGROUP

Uso de cepas de LeishmaniaDHSP70-II como vacuna

Carrión, J., Folgueira, C., Fresno, M. & Requena, J.M 200900387 12

Método de obtención de datosútiles para el diagnóstico de ne-oplasias de células T

Piqueras, J.F., Hernández, S., Villa-Morales, M, González-Sanchez, Laura,Fresno, M. & Fernández-Navarro

200900084 12

Uso de derivados de 3-fenilcu-marinas 6-sustituídas y prepara-ción de nuevos derivados

Santana L, Orallo F, Viña D, Correia MJ, Quezada E, Yáñez M, Vilar S,Uriarte E

200900224 3

Lipopolysaccharide of ochro-bactrum intermedium and theiruse as immunostimulant ofmamalians

Ovejero Guisasola, Juan Ignacio y Fresno Escudero, Manuel 200930265 12

Patents applied for

Patents granted

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AREA

1

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.

CELLULAR AND MOLECULAR ETIOPATHOGENICMECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES

AREA 1CELLULAR AND MOLECULAR

ETIOPATHOGENIC MECHANISMS ININFLAMMATORY AND

AUTOIMMUNE DISEASES

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Line 1.1Intercellular Communication in theInflammatory Response

GROUP 1

HEAD OF LABORATORYFrancisco Sánchez-Madrid. Scientific Director, Inmmunology.

GROUP MEMBERS• Francesc Baixauli Celda• Olga Barreiro del Río• Marta Barrero Villar• José Román Cabrero García• Hortensia de la Fuente Flores• Manuel Gómez Gutiérrez• Cristina Gutiérrez Vázquez• María José López Campos• Noa Beatriz Martín Cófreces• Gloria Martínez del Hoyo Cañizares• Adela Matesanz Marín• María Mittelbrunn Herrero

• Isabel María Olazábal Olarreaga• Manuel Pérez Martínez• Marta Esther Ramírez Huesca• Javier Robles Valero• Vera Rocha Perugini• Mónica Sala Valdés• Emilio Tejera Puente• Mª Ángeles Ursa Pecharromán

RESEARCH INTEREST

The group’s present work focuses on key cell-to-cellcommunication events during cognate immune inter-actions. The study of immune cell activation and differ-entiation during different physiological and pathologi-cal situations has been performed ex vivo in samplesfrom patients and healthy donors, as well as in vitro incellular samples of antigen- and superantigen-specificimmune synapses and in vivo in animal models.

A key goal is to define how the microtubule-organiz-ing complex (MTOC), by controlling cytoskeletalrearrangements at the immune synapse (IS), providesa mechanism for macromolecular transport and theconcentration of signaling molecules during synapticcontact. In this regard, the role of Mitochondria inorganizing the IS has been analyzed. This researchprogram has the potential to reveal how transfer ofmicroRNA between the T cell and the cognate anti-gen-presenting cell (APC) regulates the early initiationof immunity. The specific transfer of microRNA to theAPC through exosomes produced by the T cell dur-ing the formation of the IS has been identified. We arealso developing methodologies for the in vivo imag-ing of immune cell infiltration, the inflammatoryresponse and the role of immunoregulatory mole-cules (CD69, galectins and tetraspanins) in animalmodels of inflammation and human diseases. Thus,CD69 has been identified as a modulator of sphingo-

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CELLULAR AND MOLECULAR ETIOPATHOGENIC MECHANISMS IN INFLAMMATORY AND AUTOIMMUNE DISEASES

AREA 1

AREA

1

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sine-1-phosphate-induced migration of skin dendriticcells.

Our current specific objectives are the following:1. To assess the role of MTOC polarization as a signal-

ing and structural platform for the control of secre-tion during IS formation.

2. To investigate the mechanisms and functional con-sequences of intercellular transfer of microRNA viathe IS.

3. To image immune-inflammatory responses in vivo inorder to define the role of immunoregulatory mole-cules in autoimmune inflammatory diseases.

MAJOR GRANTS

• Francisco Sánchez Madrid. Regulation of immuneinflammatory responses: Adhesive platforms and regu-latory molecules in leukocyte-endothelial and T lympho-cyte-dendritic cell interactions, and the mechanism ofMTOC translocation during T cell activation. Ministeriode Educación y Ciencia (SAF). SAF 2008-02635.

• Francisco Sánchez Madrid. Un abordaje multidisci-plinario para el estudio de las células dendríticasderivadas de la médula ósea: Aspectos básicos yclínicos (FONCICYT, Proyecto EU-México). ProyectoEU-México FONCICYT. FONCICYT-C002-2008-1ALA/127249

• Francisco Sánchez Madrid. Molecular and Cellularmechanisms in Chronic Inflammatory and Autoimmunediseases (MEICA). Genoma España. MEICA.

• Francisco Sánchez Madrid. Red temática de enfer-medades cardiovasculares (RECAVA). ISCIII. RD06-0014-0030.

• Francisco Sánchez Madrid. Plataforma de análisisgenético y proteínas. ISCIII. PI2010/03659.

PUBLICATIONS (12) [IF: 74,629]

Lamana A, Martin P, de la Fuente H, Martinez-Muñoz L,Cruz-Adalia A, Ramirez-Huesca M, Escribano C,Gollmer K, Mellado M, Stein JV, Rodriguez-FernandezJL, Sanchez-Madrid F, Del Hoyo GM. CD69 ModulatesSphingosine-1-Phosphate-Induced Migration of SkinDendritic Cells. J Invest Dermatol. 131(7): 1503-12.2011. PMID: 21412255. IF: 6,27

Martín P, Sánchez-Madrid F. CD69: An UnexpectedRegulator of TH17 Cell-Driven InflammatoryResponses. Sci Signaling 4 (165): pe14. 2011. PMID:21427408. IF: 6,354

➢ Delgado-Pinar E, Albelda MT, Frías JC, Barreiro O,Tejera E, Kubícek V, Jiménez-Borreguero LJ, Sánchez-Madrid F, Tóth E, Alarcón J, García-España E.Lanthanide complexes as imaging agents anchored onnano-sized particles of boehmite. Dalton Trans. 40(24):6451-7. 2011. PMID: 21584297. IF: 3,647

Cellular and molecular etiopathogenic mechanismsin inflammatory and autoimmune diseases

T cells transfer microRNA-loaded exosomes to antigen presentingcells. The image shows confocal microscopy detection of the exoso-mal marker CD63-GFP (green) on the surface of recipient APCs (Raji)after incubation with J77-CD63-GFP exosomes. CD45 is stained redand nuclei are blue.

Distribution of dendritic cells in peripheral lymph nodes. Dendriticcells from wild-type (red) and CD69-/- (blue)mice were transferredinto C57BL6 recipient mice together with a marker of high endothelialvenules (green). Two-photon analysis of draining lymph nodes showedthat DCs were mostly located near high endothelial venules and theouter T cell zone inside the lymph node.

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Baixauli F, Martín-Cófreces NB, Morlino G, CarrascoYR, Calabia-Linares C, Veiga E, Serrador JM, Sánchez-Madrid F. The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling atthe immune synapse. EMBO J 30(7): 1238-50. 2011.PMID: 21326213. IF: 10,124

Jean-Mairet RM, López-Menéndez C, Sánchez-Ruiloba L, Sacristán S, Rodríguez-Martínez M, Riol-Blanco L, Sánchez-Mateos P, Sánchez-Madrid F,Rodríguez-Fernández JL, Campanero MR, Iglesias T.The neuronal protein Kidins220/ARMS associates withICAM-3 and other uropod components and regulatesT-cell motility. Eur J Immunol 41 (4): 1035-1046. 2011.PMID: 21381019. IF: 4,942

Carmen Calabia-Linares, Manuel Perez-Martinez, NoaMartín-Cofreces, Manuel Alfonso-Pérez, Cristina Gutierrez-Vázquez, María Mittelbrunn, Sales Ibiza, Francisco R.Urbano-Olmos, Covadonga Aguado-Ballano, CarlosOscar Sánchez-Sorzano, Francisco Sanchez-Madrid andEsteban Veiga. Endosomal clathrin drives actin accumula-tion at the immunological synapse. J Cell Sci 124 (Pt 5):820-830. 2011. PMID: 21321329. IF: 6,29

Yáñez-Mó M, Sánchez-Madrid F, Cabañas C.Membrane proteases and tetraspanins. Biochem SocTrans. 39 (2): 541-546. 2011. PMID: 21428936. IF:3,989

Cuesta N, Martín-Cófreces NB, Murga C, van SantenHM. Receptors, signaling networks, and disease. SciSignal. 4(161): mr3. 2011. PMID: 21343616. IF: 6,354

Gutiérrez-López MD, Gilsanz A, Yáñez-Mó M, Ovalle S,Lafuente EM, Domínguez C, Monk PN, González-Alvaro I, Sánchez-Madrid F, Cabañas C. The sheddaseactivity of ADAM17/TACE is regulated by thetetraspanin CD9. Cell Mol Life Sci 68(19): 3275-92.2011. PMID: 21365281. IF: 7,047

Domínguez-Luis M, Lamana A, Vazquez J, García-Navas R, Mollinedo F, Sánchez-Madrid F, Díaz-González F, Urzainqui A. The metalloprotease ADAM8is associated with and regulates the function of theadhesion receptor PSGL-1 through ERM proteins. Eur

J Immunol. 41(12): 3436-3442. 2011. PMID:22229154. IF: 4,942

Nuñez-Andrade N, Lamana A, Sancho D, Gisbert JP,Gonzalez-Amaro R, Sanchez-Madrid F, Urzainqui A. P-selectin glycoprotein ligand-1 modulates immune inflam-matory responses in the enteric lamina propria. J Pathol224(2): 212-21. 2011. PMID: 21432853. IF: 7,274

María Mittelbrunn, Cristina Gutiérrez-Vázquez, CarolinaVillarroya-Beltri, Susana González,Fátima Sánchez-Cabo, Manuel Ángel González, Antonio Bernad andFrancisco Sánchez-Madrid. Unidirectional transfer ofmicroRNA-loaded exosomes from T cells to antigen-presenting cells. Nature Communications 2:282. 2011.PMID: 21505438. IF: 7,396

GROUP 2

HEAD OF LABORATORYEsteban Veiga Chacón

GROUP MEMBERS• Carmen Calabia Linares• Cruz Adalia, Arantxa• Feo Lucas, Lidia• Ramírez Santiago, Guillermo• Torres Torresano, Mónica

AREA 1

AREA

1

RESEARCH INTEREST

Our group is interested in the molecular and cellularmechanisms allowing the formation of the immunologicalsynapses.

To become activated, T-cells must establish cell–cell con-tact with antigen-presenting cells (APCs). This contact,known as the immune synapse (IS), drives major mor-phological and functional changes in T-cells, includingmassive actin rearrangements necessary for productiveIS formation. IS serves as a platform for large-scalemolecular exchange between the IS forming cells.Multiple cytokines and vesicles, which drive intercellularcommunication, are released to the synaptic cleft.We showed for the first time that clathrin, present at theMultivesicular Bodies (MVB) membranes is essential for themassive actin polymerization observed at the IS. This find-ing, observed in cell lines and primary cells, underscore therole of clathrin as a molecular platform for the recruitmentof proteins that promote actin polymerization at the inter-face of T cells and APCs, and is of outstanding relevancenot only to Immunologist but also to Cellular Biologists, andscientists in the field of Cellular Microbiology.

Currently, we are also carrying on studies on the molecu-lar mechanisms driving pathogen infections and extend-ing these studies to the intimate relation between bacte-rial and fungal pathogens with the cells of the immunesystem. We are also exploring the possible therapeuticuse of bacterial products able to modify the immunologi-cal system.


Carmen Calabia-Linares, Manuel Perez-Martinez, NoaMartín-Cofreces, Manuel Alfonso-Pérez, CristinaGutierrez-Vázquez, María Mittelbrunn, Sales Ibiza,Francisco R. Urbano-Olmos, Covadonga Aguado-Ballano, Carlos Oscar Sánchez-Sorzano, FranciscoSanchez-Madrid and Esteban Veiga. Endosomalclathrin drives actin accumulation at the immunologicalsynapse. J Cell Sci 124 (Pt 5): 820-830. 2011. PMID:21321329. IF: 6,29

Visvikis O, Boyer L, Torrino S, Doye A, Lemonnier M,Lorès P, Rolando M, Flatau G, Mettouchi A, Bouvard D,

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Combination fluorescence and phase- contrast image showing anAPC-conjugated T cell expressing td- Tomato-tagged clathrin lightchain. td-Tomato–LCa (clathrin) is shown in red, endogenous CD3 ingreen, and the antigen-primed APC in blue; the T cell is not stained.

Electron micrograph of the contact of a T cell (left) with an antigen pre-senting cell (APC; right). Arrows indicate multivesicular bodies close tothe cell–cell contact.


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AREA 1Veiga E, Gacon G, Cossart P, Lemichez E. Escherichiacoli producing CNF1 toxin hijacks Tollip to triggerRac1-dependent cell invasion. Traffic 12(5): 579-590.2011. PMID: 21291504. IF: 5,278

Baixauli F, Martín-Cófreces NB, Morlino G, CarrascoYR, Calabia-Linares C, Veiga E, Serrador JM, Sánchez-Madrid F. The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling atthe immune synapse. EMBO J 30(7): 1238-50. 2011.PMID: 21326213. IF: 10,124

GROUP 3

HEAD OF LABORATORYMaría Yáñez Mó

GROUP MEMBERS• Mónica Gordón Alonso• Soraya López Martín

RESEARCH INTEREST

During the last year our group has focused its atten-tion on the role of tetraspanin-enriched microdomains(TEM) in the regulation of membrane proteases.Different membrane-bound proteases such as MT1-MMP (Yáñez-Mó et al., 2008) or TACE/ADAM-17

Functional regulation of sheddase ADAM17 by tetraspanins. The shed-dase activity of dispersed ADAM17 is stimulated by phorbol esters re-sulting in the release of the ectodomains of its substrates TNFα andICAM-1. Recruitment of ADAM17 into CD9-centered TEMs is inducedby overexpression or antibody engagement of this tetraspanin, whichexerts negative regulation on the ADAM17 sheddase activity, resultingin reduced ectodomain release of TNFα and ICAM-1.

Functional regulation of MT1-MMP by tetraspanins. Tetraspanins di-rectly associate with the membrane-anchored metalloproteinaseMT1-MMP/ MMP14 in different cell types. Association with tetraspa-nins regulates the rate of MT1-MMP degradation at lysosomes. At theplasma membrane tetraspanins may function as a molecular link withother transmembrane proteins. Thus, in endothelial cells, CD151 spa-tiotemporally coordinates MT1-MMP with integrins for extracellularmatrix degradation. MT1-MMP subcellular localization is also depen-dant on its association with CD44, which is in turn shed by the protea-se, and is also a component of TEMs.

AREA

1

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(Gutierrez-López et al., 2011) are included into thespecialized platforms that constitute TEM. Insertioninto these microdomains directly modulates theirenzymatic activity, so that overexpression of the asso-ciated tetraspanin results in an inhibition of shedding,while silencing of the expression of the tetraspaninincreases proteolysis. Pericellular matrix proteolysis isa central process in cell invasion and migration.Proteolytic shedding of membrane receptors is alsoone of the fastest ways for changing a cell phenotype;it can switch pericellular signals into systemic orsequester soluble mediators by shedding of theirreceptors. Thus, shedding inhibitors are currentlyused as anti-inflammatory drugs, and shedding phe-nomena are in the etiopathology of diseases such asAlzheimer, cardiac hypertrophy, inflammation, tumorinvasion, etc.

MAJOR GRANTS

María Yáñez Mó. Plataformas adherentes basadas enmicrodominios ricos en tetraspaninas y su conexióncon el citoesqueleto y vías de señalización intracelu-lares. Papel en la extravasación leucocitaria y en la pre-sentación de antígeno. ISCIII. PI08/0794


Yáñez-Mó M, Gutiérrez-López MD, Cabañas C.Functional interplay between tetraspanins and proteas-es. Cell Mol Life Sci. 68(20): 3323-3335. 2011. PMID:21687991. IF: 7,047

Yáñez-Mó M, Sánchez-Madrid F, Cabañas C.Membrane proteases and tetraspanins. Biochem SocTrans. 39 (2): 541-546. 2011. PMID: 21428936. IF:3,989

Gutiérrez-López MD, Gilsanz A, Yáñez-Mó M, Ovalle S,Lafuente EM, Domínguez C, Monk PN, González-Alvaro I, Sánchez-Madrid F, Cabañas C. The sheddaseactivity of ADAM17/TACE is regulated by the

tetraspanin CD9. Cell Mol Life Sci 68(19): 3275-92.2011. PMID: 21365281. IF: 7,047

Ramírez MÁ, Pericuesta E, Yáñez-Mó M, Palasz A,Gutiérrez-Adán A. Effect of long-term culture of mouseembryonic stem cells under low oxygen concentrationas well as on glycosaminoglycan hyaluronan on cellproliferation and differentiation. Cell Prolif. 44(1): 75-85.2011. PMID: 21199012. IF: 2,742

GROUP 56

HEAD OF LABORATORYAna Carmen Urzainqui Mayayo

GROUP MEMBERS• Rafael González Tajuelo• Alicia Pérez Frías

RESEARCH INTEREST

The adhesion receptor PSGL-1, ligand of P-, E- and L-Selectins, is responsible of the initial contacts of leuko-cytes with the activated endothelium and the rolling onthe endothelial cells previous to their extravasation tothe surrounding tissues at infection or inflammatoryfoci. In addition to this important function as an adhe-sion receptor, we have described a new functional role


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of PSGL-1 in dendritic cells as tolerogenic receptorimplicated in the generation of regulatory T cells.Moreover, we have demonstrated in a mice model ofulcerative colitis, that PSGL-1 is implicated in the main-tenance of the intestinal tolerance/immunity balance bymodulating the immune inflammatory responses in theenteric lamina propria.

Our current research is focused in the characterizationof autoimmune problems that we have observed inboth, PSGL-1 Knock-out and P-Selectin Knock-outmice (KO mice). We are analyzing the autoantibodies

present in serum, evaluating the histological problemsin internal organs and studying different clinical param-eters in both KO mice. We are also studying theinvolvement of PSGL-1 and P-Selectin in the develop-ment of different autoimmune diseases in humans, byanalyzing the expression of these molecules inpatients with different autoimmune diseases.Remarkably, we have recently published the interac-tion of human PSGL-1 with the metalloproteaseADAM8 and the regulation of PSGL-1 cellular expres-sion and function by the activation of this metallopro-tease that has been implicated in the development ofsome inflammatory diseases such as asthma. We arealso studying the possible implications of ADAM8 inthe onset and evolution of different human autoim-mune diseases.

MAJOR GRANTS

Ana Carmen Urzainqui Mayayo. Contribución de PSGL-1 y sus ligandos (selectinas) en la distribución tisular delas poblaciones de linfocitos y dcs. Estudio del papel dePSGL-1 en tolerancia periférica y en la regulación derespuestas inflamatorias. ISCIII. PI08/0894.

AREA 1

PSGL-1 plays two important functions during the tethering and rollingof leukocytes: 1) As adhesion receptor, activating the integrins andpromoting the firm adhesion and extravasation of leukocytes and 2) Ashomeostatic receptor, controlling the cytokine production of the leu-kocytes and, consequently, modulating the immune response.

A) Role of PSGL-1 in dendritic cells interacting with Selectins P and Ein the generation of Treg and peripheral tolerance. B) The homeostaticexpression of PSGL-1 is controlled by ADAM8. The expression level andmodification of PSGL-1 will determine the PSGL-1/Selectin contactsand the immune system activation.

AREA

1


Nuñez-Andrade N, Lamana A, Sancho D, Gisbert JP,Gonzalez-Amaro R, Sanchez-Madrid F, Urzainqui A. P-selectin glycoprotein ligand-1 modulates immuneinflammatory responses in the enteric lamina propria. JPathol 224(2): 212-21. 2011. PMID: 21432853. IF:7,274

Domínguez-Luis M, Lamana A, Vazquez J, García-Navas R, Mollinedo F, Sánchez-Madrid F, Díaz-González F, Urzainqui A. The metalloprotease ADAM8

is associated with and regulates the function of theadhesion receptor PSGL-1 through ERM proteins. EurJ Immunol. 41(12): 3436-3442. 2011. PMID:22229154. IF: 4,942


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AREA 1Line 1.2Cellular and molecular responses to Hypoxia

GROUP 6

HEAD OF LABORATORYManuel Ortiz de Landázuri Busca

GROUP MEMBERS• Bárbara Acosta Iborra• Eduardo Balsa Martínez• Esther Fuertes Yebra• Gemma Muruáis Martínez• Ángel Ordóñez Navadijo• Alicia Vara Vega• Silvia Noemí Vázquez Cuesta

RESEARCH INTEREST

1) Postnatal inactivation of genes implicated in thehypoxia pathway. Inactivation of HIF-1α y HIF2α andVHLA results in embryonic lethality,that we have cir-cumvented by their inactivation in adult mice usingfloxed alleles in combination with an ubiquitous tamox-

ifen inducible recombinase Cre-er. The functional con-sequences of their inactivation in adults have been ana-lyzed.Vhl gene inactivation rapidly resulted in a markedsplenomegaly and skin erythema, accompanied byrenal and hepatic induction of the erythropoietin (Epo)gene, indicative of the in vivo activation of the oxygensensing HIF pathway. We showed that acute Vhl geneinactivation also induced Epo gene expression in theheart, revealing cardiac tissue to be an extra-renalsource of EPO. Indeed, primary cardiomyocytes andHL-1 cardiac cells both induce Epo gene expressionwhen exposed to low O(2) tension in a HIF-dependentmanner. Thus, as well as demonstrating the potential ofdietary tamoxifen administration for gene inactivationstudies in UBC-Cre-ER(T2) mouse lines, this data pro-vides evidence of a cardiac oxygen-sensingVHL/HIF/EPO pathway in adult mice.

2) Regulation of Mitochondrial function by hypoxia. Thefine regulation of mitochondrial function has proved tobe an essential metabolic adaptation to fluctuations inoxygen availability. During hypoxia, cells activate ananaerobic switch that favors glycolysis and attenuatesthe mitochondrial activity. This switch involves the

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Model showing the involvement of NDUFA4L2 induction by HIF-1alphain hypoxic adaptation. HIF-1α stabilization by hypoxia up-regulatesNDUFA4L2, which inhibits ETC Complex I activity. As a result, oxygenconsumption decreases and ROS production is abrogated, therebyallowing cells to adapt to the hypoxic conditions. In contrast, hypoxiadecreases NDUFA4 protein levels.

AREA

1

hypoxia-inducible transcription factor-1 (HIF-1). Wehave identified a HIF-1 target gene, the mitochondrialNDUFA4L2 (NADH dehydrogenase [ubiquinone] 1alpha subcomplex, 4-like 2). Our results, obtainedemploying NDUFA4L2-silenced cells and NDUFA4L2knockout murine embryonic fibroblasts, indicate thathypoxia-induced NDUFA4L2 attenuates mitochondrialoxygen consumption involving inhibition of Complex Iactivity, which limits the intracellular ROS productionunder low-oxygen conditions. Thus, reducing mito-chondrial Complex I activity via NDUFA4L2 appears tobe an essential element in the mitochondrial repro-gramming induced by HIF-1.

MAJOR GRANTS

• Manuel Ortiz de Landázuri Busca. Red temática deenfermedades cardiovasculares (RECAVA). ISCIII.RD06/0014/0031.

• Manuel Ortiz de Landázuri Busca. Sensores deoxigeno: reprogramación metabólica y supervivenciacelular. MICINN. SAF2010-14851.


Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E,Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A,Enríquez JA, Aragonés J, Cadenas S, Landázuri MO.Induction of the mitochondrial NDUFA4L2 protein byHIF-1a decreases oxygen consumption by inhibitingcomplex I activity. Cell Metab 14(6): 768-779. 2011.PMID: 22100406. IF: 18,207

Aragonés J, Elorza A, Acosta-Iborra B, LandázuriMO. Myeloid hypoxia-inducible factors in inflammato-ry diseases. Crit Rev Immunol 31(1): 1-13. 2011.PMID: 21395507. IF: 3,857

Miró-Murillo M, Elorza A, Soro-Arnáiz I, Albacete-AlbaceteL, Ordoñez A, Balsa E, Vara-Vega A, Vázquez S, Fuertes

E, Fernández-Criado C, Landázuri MO, Aragonés J. AcuteVhl gene inactivation induces cardiac HIF-dependent ery-thropoietin gene expression. PLoS ONE 6(7): e22589.2011. PMID: 21811636. IF: 4,411

GROUP 7

HEAD OF LABORATORYAntonio Martínez Ruiz

GROUP MEMBERS• Pablo Hernansanz Agustín• Alicia Izquierdo Álvarez• Elena Ramos Serrano

RESEARCH INTEREST

The research of the group is centred on the study of non-enzymatic post-translational modifications induced byreactive oxygen and nitrogen species, especially cysteinereversible oxidative modifications. We also study their rel-evance in cell function and pathophysiology, mainly in themolecular and cellular responses to hypoxia.

Part of our work is the innovation in proteomic methodolo-gies for analyzing these modifications. In collaboration withDr. Jesús Vázquez (CBMSO), we have developed a speci-

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AREA 1

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fic approach for labelling, detecting and quantifying thesemodifications, simultaneously with protein abundancechanges, by employing second-generation proteomic tech-niques (“shotgun proteomics”, based on LC-MS/MS).

We also use the fluorescent derivatization, detection andquantitation in two-dimensional electrophoresis. We havepreviously described a methodology, called “fluorescenceswitch”, for detecting S-nitrosylated proteins by this kind ofderivatization. We have now used a related method todetect reversibly oxidized cysteines, and we called it “redoxfluorescence switch” (RFS).

We have applied the RFS to analyze differential reversiblecysteine oxidations in the acute response of endothelialcells subjected to hypoxia. We have observed a number ofproteins that are oxidized after 2 hours in hypoxia, which isreverted by a 30-minutes re-oxygenation. We have identi-fied some of these proteins, among which we have foundseveral proteins that take part in different protein signallingpathways, as well as metabolic enzymes that could havetheir function altered. The latter could be part of the acuteresponses to hypoxia before the transcriptional responseby the canonical HIF pathway is initiated.

MAJOR GRANTS

• Antonio Martínez Ruiz. Papel de las modificacionespostraduccionales inducidas por especies reactivas de

nitrógeno y oxígeno en la señalización por hipoxia encontextos de fisiopatología cardiovascular. ISCIII.CP07/00143.

• Antonio Martínez Ruiz. Papel funcional del estrésoxidativo y nitrosativo en grandes sistemas biológicos(consorcio ROSAS – “Reactive Oxygen Species AndSystems”). MEC. Consolider-Ingenio 2010. CSD2007-00020.

• Antonio Martínez Ruiz. Papel de las especies reactivasde oxígeno y nitrógeno y de las modificaciones oxida-tivas de proteínas en la respuesta a hipoxia en fisiopa-tología cardiovascular. ISCIII. PS09/00101.

• Antonio Martínez Ruiz. Identificación de dianas de S-nitrosilación en la estimulación de la neurogénesisendógena. MICINN. PRI-AIBPT-2011-1015.

• Antonio Martínez Ruiz. Identificación proteómica deproteínas vegetales S-nitrosiladas en la respuesta aauxina. MICINN. PRI-AIBAR-2011-0782.


González R, Cruz A, Ferrín G, López-Cillero P,Fernández-Rodríguez R, Briceño J, Gómez MA, RufiánS, Mata MD, Martínez-Ruiz A, Marin JJ, Muntané J. Nitricoxide mimics transcriptional and post-translational regu-lation during a-Tocopherol cytoprotection against gly-cochenodeoxycholate-induced cell death in hepatocytes.J Hepatol 55(1): 133-44. 2011. PMID: 21145864. IF:9,334

Overview of classical, less classical and non-classical signaling me-chanisms induced by nitric oxide. Non classical pathways (dashedorange lines) include production of NO from nitrite and formation ofpost-translational modifications, whose main mechanisms and reac-tions are depicted.

Schematic of the “redox fluorescent switch” (RFS) technique used tolabel reversibly oxidized protein cysteines, and example of a two-di-mensional electrophoresis showing the oxidized RFS signal (green),total protein staining (red), and merge of both.

AREA

1

Martínez-Ruiz A, Cadenas S, Lamas S. Nitric oxidesignaling: classical, less classical and nonclassicalmechanisms. Free Radic Biol Med 51(1): 17-29.2011. PMID: 21549190. IF: 5,707

Leon L, Subramaniam S, Cauvard O, Plenchette-Colas S, Paul C, Godard C, Martinez-Ruiz A,Legembre P, Jeannin JF, Bettaieb A. S-Nitrosylationof the Death Receptor Fas Promotes Fas Ligand-Mediated Apoptosis in Cancer Cells.Gastroenterology 140(7): 2009-18, 2018.e1-4.2011. PMID: 21354149. IF: 12,032

Izquierdo-Álvarez A, Martínez-Ruiz A. Thiol redoxproteomics seen with fluorescent eyes: the detec-tion of cysteine oxidative modifications by fluores-cence derivatization and 2-DE. J Proteomics 75(2):329-338. 2011. PMID: 21983555. IF: 5,074

Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E,Elorza A, Ordóñez A, Corral-Escariz M, Soro I,López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S,Landázuri MO. Induction of the mitochondrialNDUFA4L2 protein by HIF-1a decreases oxygenconsumption by inhibiting complex I activity. CellMetab 14(6): 768-779. 2011. PMID: 22100406. IF:18,207

GROUP 8

HEAD OF LABORATORYMaría Josefa Calzada García

GROUP MEMBERS• Raquel Bienes Martínez• María Corral Escariz• Gloria Mateo Jiménez

RESEARCH INTEREST

Activated CD47 Promotes Pulmonary ArterialHypertension Through Suppression of Caveolin-1Pulmonary arterial hypertension (PAH) is a progressivelung disease characterized by pulmonary vasoconstric-tion and vascular remodeling leading to increased pul-monary vascular resistance and right heart failure. Lossof nitric oxide (NO) signaling and endothelial nitric oxidesynthase (eNOS)-derived oxidative stress are keyevents in the pathogenesis of PAH yet the mechanismsinvolved remain incompletely known. Previously it hasbeen shown that activation of the cell receptor CD47by its ligand thrombospondin-1 (TSP1) inhibits eNOS.We have investigated the role activated CD47 plays inpromoting PAH. Our results proved that TSP1-mediat-ed activation of CD47 is increased in experimental andhuman PAH, and promotes disease by limiting Cav-1inhibition of dysregulated eNOS.

Hypoxia Negatively Regulates Anti-angiogenic andAnti-metastatic PEDF in Melanoma Cells by a HIF-Independent, Autophagy Dependent Mechanism Pigment epithelium-derived factor (PEDF), a member ofthe serine protease inhibitor (SERPIN) superfamily, dis-plays a potent anti-angiogenic and anti-metastaticactivity in a broad range of tumor types. Melanocytesand low aggressive melanoma cells secrete high levelsof PEDF, while its expression is lost in highly aggressivemelanomas. In this study, we identify hypoxia as a rel-evant negative regulator of PEDF in melanocytes andlow aggressive melanoma cells. Hypoxia decreasedPEDF expression by a posttranslational mechanisminvolving degradation by autophagy and could there-fore contribute to the acquisition of highly metastaticpotential characteristic of aggressive melanoma cells.

Hypoxia down-regulates the expression of the anti-angiogenic protein thrombospondin-1 in a hypoxia

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AREA 1

inducible factor-independent and prolyl hydroxylases-dependent manner in clear cell renal carcinoma celllinesThrombospondin-1 (TSP-1) is a multifunctional matrixprotein with potent antitumor activities due in part to itsability to inhibit angiogenesis. Its expression levels deter-mine the fate of many different tumors and more recent-ly it has been shown that TSP-1 loss contributes to theangiogenic phenotype of renal carcinomas (RCC), how-ever the factors involved in its regulation remain unclear.The results of our investigation indicate that the loss ofthe von Hippel-Lindau tumor suppressor gene (VHL) andhypoxic conditions contribute to TSP-1 levels in thesetumors. Furthermore, this autocrine TSP1 regulationproved to be important in ccRCC cell motility. These datasubstantiate a regulation pattern for TSP1 in the VHL-hypoxia axis that demonstrates to be important forccRCC cell behaviour.

Renal carcinoma cells regulate VCAM-1 expression toovercome the immune responseVCAM-1 is an adhesion molecule that belongs to theimmunoglobulin’s family and its expression has beenmostly assigned to the activated endothelium mediat-ing immune cells adhesion and extravasation.

However, it is also expressed in healthy renal epitheliumand renal carcinomas, and most importantly its expres-sion in these renal carcinomas inversely correlates withtumor malignancy, and therefore more advancedtumors have decreased VCAM-1 levels. Our studies onVCAM-1 regulation in renal cell carcinomas demon-strate that VCAM-1 is significantly down-regulatedunder hypoxic conditions and also in ccRCC lines lack-ing VHL. This regulation might be relevant to tumor cellimmune evasion in that this molecule elicits immunecell binding and interaction specifically mediated byVCAM-1 expressed in the tumor cells with VLA4 recep-tor expressed in the immune cells. We are working onthe hypothesis that the decrease on VCAM-1 levelsmay be an adaptive response of tumor cells to escapefrom the immune system

MAJOR GRANTS

• María Josefa Calzada García. TSP1 inPathophysiology: Role in Renal Cancer and IschemicTissue Damage and Regeneration. MICINN.SAF2009-11113.

• María Josefa Calzada García. TSP1-CD47 inPromotion of PAH-Associated Vasoconstriction andVascular Overgrowth. NIH. FOA: PA10-067, period2011-2015


Martin-Manso G, Calzada MJ, Chuman Y, Sipes JM,Xavier CP, Wolf V, Kuznetsova SA, Rubin JS, RobertsDD. sFRP-1 binds via its netrin-related motif to the N-module of thrombospondin-1 and blocks throm-bospondin-1 stimulation of MDA-MB-231 breast carci-noma cell adhesion and migration. Arch BiochemBiophys. 509(2): 147-56. Epub 2011 Mar 21. 2011.PMID: 21402050. IF: 3,022

Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E,Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A,

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CD47 activation promotes PAH through suppressing constitutiveCaveolin-1 inhibition of eNOS. Under hypoxia, the CD47 ligand TSP1is upregualted. On binding with TSP1 the cell receptor CD47 is acti-vated leading to disruption of the constitutive interaction betweenCD47 and membrane caveolin-1 (Cav-1). This in turn leads to decre-ased Cav-1 and increased eNOS activity. Monomeric hyperactiveeNOS then produces superoxide rather than NO resulting in tissueoxidation and nitration.

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1

Enríquez JA, Aragonés J, Cadenas S, Landázuri MO.Induction of the mitochondrial NDUFA4L2 protein byHIF-1a decreases oxygen consumption by inhibitingcomplex I activity. Cell Metab 14(6): 768-779. 2011.PMID: 22100406. IF: 18,207

GROUP 9

HEAD OF LABORATORYJulián Aragonés López

GROUP MEMBERS• Ainara Elorza Peregrina• Glenn Marsboom• Florinda Meléndez Rodríguez• Noelia Sánchez Bolívar• Inés Soro Arnaíz

RESEARCH INTEREST

The VHL/HIF oxygen sensing pathway in pathologyO2 supply to cells or tissues becomes limited during thedevelopment of numerous pathological scenarios such car-diac ischemia, inflammation or expansion of white adiposetissue. Cells respond to these O2 fluctuations by activatingthe hypoxia-inducible factors HIF-1α and HIF-2α. In ourresearch group we aim to study the in vivo contribution of

these factors in pathology. We have developed the neces-sary technology to inactivate in adult mice HIF-1α or HIF-2α(loss of function models) as well as their main repressor VHLleading to a constituive activation of both HIFs (gain of func-tion model). VHL-deficient animals have allowed to inducethe HIF system in vivo on adulthood which results in aremarkable erythema possibly associated to peripheralvasodilatation, and importantly to identify the cardiac tissueas a source of extrarenal erythropoietin (EPO) (Miro-Murilloet al. PlosOne 2011) (Figure 1A). The previously recognizedcardioprotective ability of EPO indicates that this cardiomy-ocyte autonomous response is part of the tolerance pro-gram against cardiac ischemic episodes. On the other hand(i) animals deficient in HIF-1α have allowed us to determinethat HIF1α is essential for development of obesity in murinemodels associated to a white adipose tissue metabolicreprogramming (Figure 1B) and (ii) animals deficient in HIF-2α have allowed to unravel its role in tumor progression andcell autonomous proliferation (manuscript under review inMolecular Cell). Therefore these studies are aimed to unrav-el the molecular mechanisms by which HIF factors con-tribute to pathological stage and open new opportunities fortherapeutic intervention.

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(A) Gross appearance of mice upon VHl gene inactivation. Representa-tive images of the erhythema in snouts and paws of Vhlfloxed-UBC-Cre-ERT2 mice when compared with control Vhlfloxed mice areshown. (B) Body weight under high fat diet conditions upon globalHif1α gene inactivation. Images of a Hif1αfloxed-UBC-Cre-ERT2 andcontrol mice showing reduced adiposity upon Hif1αgene inactivation.gWAT (gonadal WAT) is inidicated with an arrow (upper panel). Increa-se in body weight of Hif1αfloxed-UBC-Cre-ERT2 and control mice afterthey were switched to a high fat diet (HFD) (lower panel).


AREA 1MAJOR GRANTS

• Julián Aragonés López. Estudio del papel biológicode los sensores de oxígeno prolina hidroxilasa.MEC. BFU2008-03407/BMC

• Julián Aragonés López. Gaining sage on theEpoetins' saga: assessing long term risks andadvancing towards better Epoetin driven treatmentmodalities. European Comission. 282551


Miró-Murillo M, Elorza A, Soro-Arnáiz I, Albacete-Albacete L, Ordoñez A, Balsa E, Vara-Vega A,Vázquez S, Fuertes E, Fernández-Criado C,Landázuri MO, Aragonés J. Acute Vhl gene inactiva-tion induces cardiac HIF-dependent erythropoietingene expression. PLoS ONE 6(7): e22589. 2011.PMID: 21811636. IF: 4,411

Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E,Elorza A, Ordóñez A, Corral-Escariz M, Soro I,López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A, Enríquez JA, Aragonés J, Cadenas S,Landázuri MO. Induction of the mitochondrialNDUFA4L2 protein by HIF-1a decreases oxygenconsumption by inhibiting complex I activity. CellMetab 14(6): 768-779. 2011. PMID: 22100406. IF:18,207

Aragonés J, Elorza A, Acosta-Iborra B, LandázuriMO. Myeloid hypoxia-inducible factors in inflammato-ry di-seases. Crit Rev Immunol 31(1): 1-13. 2011.PMID: 21395507. IF: 3,857

GROUP 10

HEAD OF LABORATORYSusana Cadenas Álvarez

GROUP MEMBERS• Andrea Anedda• Elia López Bernardo• Cristina Vaca Sanz

RESEARCH INTEREST

Metabolic reprogramming induced by HIFDecreased oxygen concentration has significanteffects on gene transcription through activation ofhypoxia-inducible factor (HIF), an oxygen dependenttranscription factor. HIF activates a number of genesinvolved in the adaptation of tissues to hypoxia.Hypoxia also modulates the balance between aerobicand anaerobic (glycolytic) energy production onnumerous tissues. This metabolic reprogramminginduced by HIF includes the diversion of pyruvateaway from the mitochondria, increased glucose trans-port into the cell and increased glycolysis. Anotheradaptation to reduced oxygen levels is a subunitswitch that occurs in Complex IV, whereby the COX4-1 regulatory subunit is replaced by the COX4-2 iso-form. These metabolic responses to hypoxia haveadaptive significance in the context of protectionagainst excessive reactive oxygen species production(Figure 1). In collaboration with Dr. M.O. Landázuri, wehave studied the effects of hypoxia-inducedNDUFA4L2 on oxygen consumption (Figure 2). Ourresults indicate that hypoxia-induced NDUFA4L2attenuates mitochondrial oxygen consumptionthrough the inhibition of Complex I activity. This effectprevents excessive intracellular ROS productionunder low-oxygen conditions.

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UCPs in ischaemia toleranceThe uncoupling proteins (UCPs) are mitochondrial innermembrane proteins that belong to the superfamily ofmitochondrial anion carriers. Unlike UCP1, which isexpressed in brown adipose tissue and that mediatesadaptive thermogenesis, the physiological functions ofUCP2 and UCP3, two UCP1 homologues present inthe heart, remain unclear. We are currently studying therole of these proteins in ischaemia tolerance and thesignalling pathways involved.

MAJOR GRANTS

Susana Cadenas Álvarez. Desacoplamiento mitocon-drial en isquemia experimental y clínica. ISCIII.PS09/00116


Martínez-Ruiz A, Cadenas S, Lamas S. Nitric oxide sig-naling: classical, less classical and nonclassical mech-anisms. Free Radic Biol Med 51(1): 17-29. 2011. PMID:21549190. IF: 5,707

Tello D, Balsa E, Acosta-Iborra B, Fuertes-Yebra E,Elorza A, Ordóñez A, Corral-Escariz M, Soro I, López-Bernardo E, Perales-Clemente E, Martínez-Ruiz A,Enríquez JA, Aragonés J, Cadenas S, Landázuri MO.Induction of the mitochondrial NDUFA4L2 protein byHIF-1a decreases oxygen consumption by inhibitingcomplex I activity. Cell Metab 14(6): 768-779. 2011.PMID: 22100406. IF: 18,20

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Regulation of metabolism by HIF. In response to cellular hypoxia, incre-ased HIF-1 activity leads to the following: increased glucose transportinto the cell; increased glycolysis and conversion of pyruvate into lacta-te; decreased conversion of pyruvate into acetyl-CoA (AcCoA); and al-tered cytochrome c oxidase (COX) subunit composition that maintainsefficient electron transport and minimizes superoxide production.

NDUFA4L2 decreases oxygen consumption in hypoxia. Oxygen con-sumption rates were measured by high-resolution respirometry inHeLa cells transfected with a scramble control or NDUFA4L2 siRNA (B),or the empty vector (EV) or pCMV-NDUFA4L2 (D), and exposed to hypo-xic (1% O2) conditions for 24 h. Data represent mean ± SEM of four in-dependent experiments; *P < 0.05; **P < 0.01

AREA 1Line 1.3Animal models of inflammatory diseases and intercellular signalling

GROUP 11

HEAD OF LABORATORYFederico Mayor Menéndez

GROUP MEMBERS• Raúl Alvarado Arroyo• Vanesa Lafarga Berciano• Adolfo Molejón García• Laura Nogués Vera• Julia Palacios García• Petronila Penela Márquez• Paula Ramos Barbeito• Catalina Ribas Núñez• Verónica Rivas Guerrero• Susana Rojo Berciano• Guzmán Sánchez Fernández• Almudena Inés Santos Bajo

RESEARCH INTEREST

G protein-coupled-receptor kinase 2 (GRK2) is emerging asa key integrative node in many signaling networks. GRK2

displays a complex network of functional interactions (“inter-actome”) that underlies a variety of novel physiological roles.Changes in GRK2 expression occur in several relevantinflammatory, metabolic, cardiovascular or cancer diseases,suggesting that those alterations may contribute to thedevelopment of these pathologies. In order to assess thefeasibility of GRK2 as a useful biomarker and/or therapeutictarget, our main objectives are the identification of the rele-vant GRK2 interactome in specific physiopathological con-texts and the evaluation of the functional impact of alter-ations in GRK2 levels using cellular and animal models.During 2011, we have:

a) Revealed the existence of multiple scaffolding functions inthe degradation of GRK2 by the proteasome pathway, andidentified a direct interaction between GRK2 and the Mdm2E3-ubiquitin ligase (Nogués L et al., J. Biol. Chem. 2011)b) Identified a novel Galpha-q/ PKCzeta/ ERK5 pathwaythat has an important role in angiotensin-mediated heart

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GRK2 and HDAC6-mediated tubulin deacetylation in epithelial cell migra-tion. In the lamellipodium, GRK2 would be recruited in a Gβγ-dependentmanner to sites of the plasma membrane wherein chemotactic activationis taking place. At such specific locations, chemokine receptor stimulationwould promote the phosphorylation of GRK2 at S670 by MAPK, what wouldin turn switch on the ability of GRK2 to phosphorylate co-localized HDAC6.Phosphorylated HDAC6 would display a higher de-acetylase activity to-ward tubulin at such location, contributing to keep down MT acetylationspecifically at the lamellipodium. The presence of highly dynamic, hipo-acetylated MTs would stimulate cortical F-actin polymerization and enhan-ce cell migration (adapted from Lafarga V et al., EMBO Journal, 2011)

AREA

1

hypertrophy in vivo (Garcia-Hoz C , Sanchez-Fernández Get al. , J. Biol. Chem. 2012)

c) In collaboration with Dr. J. De Celis (CBM Madrid),revealed the participation of Drosophila GRKs and arrestinhomologs in the control of the Smoothened signaling path-way (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 MAPKinhibitors based on the mechanism of regulation ofp38MAPK by GRK2 (two patents filed)

e) Also in collaboration with the group of Dr. Cristina Murga(UAM-IISLP), continued investigating the role of GRK2 inobesity and insulin resistance as well as in cardioprotection.

f) Discovered that GRK2 modulates tubulin acetylation in aHDAC6-dependent manner in order to regulate key cellularprocesses relying on cytoskeletal rearrangements such asmigration, polarity and cell spreading (Lafarga V et al.,EMBO Journal, 2011)

MAJOR GRANTS

• Catalina Ribas Núñez. Señalización a través de recep-tores acoplados a Proteínas G. Interacciones uncionalesentre las vías Mapk, G?Q Y GRKS y su relación conenfermedades cardiovasculares. ISCIII. PI080461

• Federico Mayor Menéndez. Quinasas de receptoresacoplados a proteínas G: interactoma e implicacionesfisiopatológicas. Ministerio de Ciencia e Innovación.SAF2008-00552


V. Lafarga, I. Aymerich, O. Tapia, F. Mayor, jr., and P. Penela.A novel GRK3/HDAC6 interaction modulates cell spreadingand motility. EMBO J 31(4): 856-69. 2011. PMID:22193721. IF: 10,124

Casafont I, Palanca A, Lafarga V, Berciano MT, Lafarga M.

Effect of ionizing radiation in sensory ganglion neurons:organization and dynamics of nuclear compartments ofDNA damage/repair and their relationship with transcriptionand cell cycle. Acta Neuropathol. 122(4): 481-493. 2011.PMID: 21915754. IF: 7,695

Nogués L, Salcedo A, Mayor F Jr, Penela P. Multiple scaf-folding functions of {beta}-arrestins in the degradation of Gprotein-coupled receptor kinase 2. J Biol Chem. 286(2):1165-1173. 2011. PMID: 21081496. IF: 5,328

Baltanás, F.C., Casfont, I., Lafarga, V., Weruaga, E., Alonso,J.R., Berciano, M.T., and Lafarga, M. Purkinje cell degener-ation in pcd mice reveals large scle chromatin reorganiza-tion and gene silencing linked to defective DNA repair. J BiolChem. 286(32): 28287-28302. 2011. PMID: 21700704. IF:5,328

Aymerich MS, López-Azcárate J, Bonaventura J, NavarroG, Fernández-Suárez D, Casadó V, Mayor F, Lluís C,Valencia M, Artieda J, Franco R. Real-time g-protein-cou-pled receptor imaging to understand and quantify receptordynamics. ScientificWorldJournal. 11: 1995-2010. 2011.PMID: 22125451. IF: 1,524

Molnar C, Ruiz-Gómez A, Martín M, Rojo-Berciano S,Mayor F, de Celis JF. Role of the Drosophila non-visual ß-arrestin kurtz in hedgehog signalling. PLoS Genet 7(3):e1001335. Epub 2011 Mar 17. 2011. PMID: 21437272. IF:9,543

GROUP 12

HEAD OF LABORATORYManuel Fresno Escudero

GROUP MEMBERS• Ruth Álvarez Díaz• Beatriz Barrocal López• Isabel M. Chico-Calero• Carlos Chillón Marinas• Natalia Cuesta Rubio

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• Mª de los Ángeles de Chorro y de Villa-Ceballos• Nuria Gironés Pujol• Néstor Adrián Guerrero Gutiérrez• Alberto Jiménez Buiza• María Gema Marín Alberca• Cristóbal Moreno Delgado• Inés Claire Osma García• Carmen Punzón Gálvez• Carmen Mª Sánchez-Valdepeñas Villegas• Julien Santi-Rocca• Konstantinos Stamatakis Andriani

RESEARCH INTEREST

Inflammation lies behind many of the most prevalentdiseases of the developed countries. We studied themolecular and cellular mechanisms regulatingprostanoid synthesis and the function of pathogen-recognition-receptors as Toll-like (TLRs) in inflammationand leukocyte migration and their involvement in ColonCancer, Obesity, Atherosclerosis, and graft vs. HostDisease (GVHD). We analyzed the expression and reg-ulation of Cyclooxygenases (Cox) and prostaglandinsynthases (PGS) in T lymphocytes and macrophages.T cells produce PGF2alfa and PGE2, which viaEP2/EP4 receptor control their migration to lymphnodes and the duration of dendritic cell-CD4 T lympho-cytes in lymph nodes. Cox-2-deficient monocytes havean impaired ability to adhere to endothelium and tomigrate in vitro and in vivo. Nonetheless, in vivo cox-2selective deficiency in monocytes increases plateletaggregation and atheroma formation.

Cox-2/mPGES1 coordinated transcriptional regulationrequires NF-kappaB/Egr1 I macrophages and PGE2 act inautocrine fashion to upregulate its own synthesis. Moreoverin cancer cells, mPGES1 is induced by EGF also involvingEgr-1 and leading to enhanced tumorigenicity. Also Cox-2is overexpressed in Colon Carcinoma and is induced byCalcineurin/NFAT. Genetic manipulation of this pathwayalters growth and metastasis of tumors. NFAT is expressed

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Figure Blocking of T cell EP receptors reduced the duration of T cell-DCinteractions but did not alter the egress phenotype of Th cells from drai-ning LNs during inflammation. (A) Representative graph from a homingassay indicating the ratio of antagonizing PGE2 receptors (EPA)-treatedand DMSO-treated CD4+ T cells in draining LNs of mice, 5 hours afterimmunization. (B) Representative image stack from 30 minute-videorecorded during the late phase of T cell activation using an intravitaltwo-photon microscope. Green cells: CFSE-labelled DMSO-treated con-trol CD4+ T cells, blue cells: Cell tracker blue-EPA-treated CD4+ T cells,red cells: Cell tracker orange-stained DCs, pale brown: PNAd labelledHEV. White arrow in the top right panel shows a DMSO treated controlCD4+ T cell interacting with a DC. White arrow in the 2nd row, left panelindicates a blue EPA-treated CD4+ T cell in interaction with a DC. (C)Quantitative analysis of T cell-DC interactions in the early and late pha-ses of T cell activation. (D) Histograms showing S1P1 (left panel) andS1P3 (right panel) expression in mouse CD4+ T cells activated in vitrofor 72 hours. (E) Percentages of recovered EPA and DMSO-treated cellsfrom draining LNs in the egress assays.

AREA 1

AREA

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in macrophages and dendritic cells and is activated by TLRsthrough Cot/NIK/PKCzeta pathway-induced phosphoryla-tion. Adipocytes express NFATc1-4 and NFATc4 regulatestheir differentiation.

Trypanosoma cruzi, the agent of Chagas’ disease, has dif-ferent genetic lineages. We have analyzed theimmunopathogenesis, and pathological differencesbetween genetic lineages of T. cruzi. We are analyzing themechanism of cardiac infiltration by Arginase I-myeloid sup-pressor cells, Th1, Th2, Th17 and Tregs and its role in car-diac pathology associated to infection and in the modula-tion of the immune response. We have also investigated themolecular mechanism by which T. cruzi infects myeloidcells. We have defined SLAMF1 as a new receptor for T.cruzi entry and its blockade prevent T. cruzi infection.Slamf1 deficiency or blockade of this receptor completelyprotects from T. cruzi infection.

MAJOR GRANTS

• Manuel Fresno Escudero. Comparative epidemiology ofgenetic lineages of trypanosoma cruzi-chagasepinet.Project ChagasEpiNet. Unión Europea. HEALTH-FE-2008-223034. Seventh Framework Programme

• Manuel Fresno Escudero. Inmunopatogenia de la enfer-medad de Chagas: nuevas aproximaciones biotecnológ-icas. Instituto de Cooperación Iberoamericana.A/031735/10

• Manuel Fresno Escudero. Receptores toll-like,prostanoides y redes de señalización en enfermedadesinflamatorias. MICINN. SAF2010-18733

• Manuel Fresno Escudero. Estudios para el tratamientosintomático de la inflamación y el dolor. NeogeniusPharma AIE (Lab Almirall). CENIT-E 2009


Carrión J, Folgueira C, Soto M, Fresno M, Requena JM.Leishmania infantum HSP70-II null mutant as candidatevaccine against leishmaniasis: a preliminary evaluation.Parasit Vectors 4: 150. 2011. PMID: 21794145. IF: 2,13

Cuervo H, Guerrero NA, Carbajosa S, Beschin A, DeBaetselier P, Gironès N, Fresno M. Myeloid-derived sup-pressor cells infiltrate the heart in acute Trypanosoma cruziinfection. J Immunol. 187(5): 2656-2665. 2011. PMID:21804013. IF: 5,745

Sreeramkumar V, Fresno M, Cuesta N. Prostaglandin E(2)and T cells: friends or foes?. Immunol Cell Biol. [Epub aheadof print]. 2011. PMID: 21946663. IF: 3,741

Cuesta N, Martín-Cófreces NB, Murga C, van Santen HM.Receptors, signaling networks, and disease. Sci Signal.4(161): mr3. 2011. PMID: 21343616. IF: 6,354

Alvarez S, Blanco A, Fresno M, Muñoz-Fernández MÁ.TNF-a contributes to caspase-3 independent apoptosis inneuroblastoma cells: role of NFAT. PLoS One. 6 (1):e16100. 2011. PMID: 21298033. IF: 4,411

Alique M, Calleros L, Luengo A, Griera M, Iñiguez MA,Punzón C, Fresno M, Rodríguez-Puyol M, Rodríguez-PuyolD. Changes in extracellular matrix composition regulatecyclooxygenase- 2 (COX-2) expression in human mesangialcells. Am J Physiol Cell Physiol. 300(4): C907-18. 2011.PMID: 21209362. IF: 3,817

Donnini S, Finetti F, Terzuoli E, Giachetti A, Iñiguez MA,Hanaka H, Fresno M, Rådmark O, Ziche M. EGFR signal-ing upregulates expression of microsomal prostaglandin Esynthase-1 in cancer cells leading to enhanced tumori-genicity. Oncogene. 2011 Nov 14. [Epub ahead of print].2011. PMID: 22081067. IF: 7,414

GROUP 17

HEAD OF LABORATORYCristina Murga Montesinos

GROUP MEMBERS• Elisa Lucas Fernández• Rocío Vila Bedmar

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RESEARCH INTEREST

During the past year 2011, the group has developedthe following lines of research:

1) Analysis of the cellular, molecular and systemicmechanisms by which lower levels of GRK2 protectfrom the development obesity and/or insulin resistance(Vila-Bedmar et al, manuscript under review in TheFASEB Journal). Also, we have begun to study theeffects that a deletion of GRK2 could have in the pro-gression towards obesity and/or insulin resistancewhen performed exclusively in determined cell types, oralong the development of the pathological condition (Incollaboration with the groups of Dr. Federico Mayorand Dr. Cobi Heijnen).

2) Studies on the gene expression analysis and tran-scriptional profile of the cardiac tissue of adult (9months-old) mice hemizygous for GRK2 as well as thestatus of key cardioprotective signaling routes with agein this mice model. (Lucas E et al, manuscript in prepa-ration in collaboration with the groups of Dr. W.J. Kochand Dr. Javier Díez)

3) Analysis of the vascular response to vasodilatatory andvasoconstrictory neurohumoral stimuli, structure and bio-mechanics of the vasculature and the development ofhypertension by chronic infusion of angiotensin II in micehemizygous for the GRK2 protein (Lucas E et al, manu-script under preparation in collaboration with the group ofDr. Mercedes Salaíces).

4) In silico identification of candidate small moleculecompounds for p38MAPK based on virtual screeningof molecules and peptidomimetic approaches, fol-lowed by in vitro validation, and further characteriza-tion in cells and in animal models of autoimmune dis-eases and hyperalgesia. In collaboration with thegroup of Dr. Federico Mayor.

MAJOR GRANTS

• Cristina Murga Montesinos. Evaluación de compuestosneuroprotectores. Neuron BIOPHARMA, S.L. 409

• Cristina Murga Montesinos. Caracterización de las rutasde señalización de GRK2 y MAPK en hipertrofia y disfun-ción cardiaca: desarrollo de inhibidores farmacológicos yvalidación de biomarcadores diagnósticos. UAM.PS09/01208


Sorribes A, Armendariz BG, Lopez-Pigozzi D, Murga C,de Polavieja GG. The origin of behavioral bursts in deci-

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AREA 1

Signaling by Insulin is regulated by GRK2. Recent findings by our groupand others have uncovered a negative role for GRK2 protein in the regula-tion of insulin sensitivity, insulin-dependent metabolic actions, as well asin the control of obesity and adiposity. These effecs of altered GRK2 levelsmay also affect cardiac cell metabolism in response to insulin.

AREA

1

sion-making circuitry. PLoS Comput Biol. 7(6): e10020.Epub 2011 Jun 23. 2011. PMID: 21731478. IF: 5,515

Cuesta N, Martín-Cófreces NB, Murga C, van Santen HM.Receptors, signaling networks, and disease. Sci Signal.4(161): mr3. 2011. PMID: 21343616. IF: 6,354

GROUP 18

HEAD OF LABORATORYMiguel Ángel Iñiguez Peña

GROUP MEMBERS• Cristina Cacheiro Llaguno• Paloma Guillem Llobat• Elena Hernández Subirá• Raquel Nieto Pintado• Ana Renshaw Calderón

RESEARCH INTEREST

Several studies have shown that bioactive lipids,including prostanoids and oxysterols, are involved in

a variety of pathophysiological processes, includingvascular homeostasis, inflammation and cardiovas-cular pathology. Prostanoids family includeprostaglandins (PGs) and thromboxanes (TXs),potent lipid mediators derived from arachidonic acidby the action of Cyclooxygenases (COX-1 and COX-2) and different PG and TX synthases. These agentsare important signalling molecules in an array ofphysiological processes, besides playing a centralrole in the progress of the inflammatory reactionassociated to a variety of severe diseases. On theother hand, LXRs (Liver X Receptors) and their lig-ands, including cholesterol derivatives as oxysterols,have been shown to play a key role in the regulationof cholesterol transport and lipid metabolism, beingable to act as anti-inflammatory agents through theregulation of gene expression. Our investigations areaimed to the study of the molecular mechanismsinvolved in the effects of these bioactive lipids,focusing on their influence in cardiovascular patho-physiology. To this end, we analyze the effect ofprostanoids, and LXR ligands –mediated signaling,in cell types that play a key role in cardiovascularpathophysiology and the associated inflammatoryprocess as leukocytes, vascular cells, and cardiomy-ocytes, through the examination of their influence ontranscriptional activation and gene expression. In

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Hypertrophic actions mediated by prostaglandin (PG) F2α in car-diomyocytes involve signalling through its G protein coupled recep-tor FP and activation of the Ca++/calcineurin/NFAT pathway thatpromotes transcriptional activation of target genes.

addition to cellular models, we are interested in howthe effects of these compounds are translated intothe context of the cardiovascular pathology by theuse of mice models of disease including cardiac

hypertrophy, atherosclerosis and abdominal aorticaneurysm.

MAJOR GRANTS

Miguel Ángel Íñiguez Peña. Mediadores inflamatorioslipídicos en la fisiopatología cardiovascular. MICINN.BFU2010-21055


Alique M, Calleros L, Luengo A, Griera M, IñiguezMA, Punzón C, Fresno M, Rodríguez-Puyol M,Rodríguez-Puyol D. Changes in extracellular matrixcomposition regulate cyclooxygenase- 2 (COX-2)expression in human mesangial cells. Am J PhysiolCell Physiol. 300(4): C907-18. 2011. PMID:21209362. IF: 3,817

Donnini S, Finetti F, Terzuoli E, Giachetti A, IñiguezMA, Hanaka H, Fresno M, Rådmark O, Ziche M.EGFR signaling upregulates expression of microso-mal prostaglandin E synthase-1 in cancer cellsleading to enhanced tumorigenicity. Oncogene.2011 Nov 14. [Epub ahead of print]. 2011. PMID:22081067. IF: 7,414

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AREA 1

Abdominal aortic aneurysm (AAA) formation in apoE-/- mice infu-sed with Angiotensin II (AngII) or saline as a control. Left; repre-sentative photographs showing aortic dilatation of suprarenalaorta in AAAs of apoE-/- mice infused with AngII. Right; Masson´strichrome staining of cross sections taken from the suprarenalregion of the aorta showing thickening of the abdominal aorticwall, disruption of the media (med) and adventitia (adv) layers,destruction of the elastic lamina, cellular infiltration, extracellu-lar matrix deposition and thrombus formation in mice treatedwith AngII.

AREA

1

Line 1.4Etiopathogenic and immunological mechanisms of dermatological diseases

GROUP 19

HEAD OF LABORATORYAmaro García Díez

GROUP MEMBERS• Maximiliano Aragüés Montañés• Javier Fraga Fernández• Silvia Pérez Gala

RESEARCH INTEREST

The activity of the Group is focused in the creation ofdermatology basic and applied research projects thatcould answer questions of clinical interest. We are work-ing in several multidisciplinary groups with the collabora-tion of pathologists, haematologist and immunologist tobring basic research to applied research.

MAJOR GRANTS

• Amaro García Díez. Psoriasis y moléculas inmunor-reguladoras (GADD-45, ICOSL, trombospondina-1,y galectinas). Sus implicaciones terapéuticas. ISCIII.PI08/0946

• Amaro García Díez. Mecanismos moleculares y celu-lares en enfermedades inflamatorias crónicas yautoinmunes. Proyecto MEICA. Proyectos deI+D+Ide Cooperación público-privada de GenómicaAplicada y Biotecnología de Genoma España.Genoma España

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Lesional and non-lesional skin from psoriasis patients expresses lowlevels of gal-1 and IL-10. RT–PCR analysis of the indicatedlectin (A) and cytokine (B) genes in non-lesional and lesional skin frompsoriasis patients and healthy subjects; expression levels werenormalized to GAPDH. Bars represent mean ± SEM from 24 lesional(black), 24 non-lesional (grey) and 10 healthy samples (empty);differences between groups were analysed by the Kruskall–Wallis andBonferroni tests (∗p < 0.05 compared with healthy). (C) Correlationanalysis of gal-1, IL-17 and IL-10 mRNA levels from lesional and non-lesional skin of psoriasis patients; the correlation was tested usingthe Spearman test.


• Amaro García Díez. Estudio EpidemiológicoPsoriasis. Schering Plough.


Navarro R, Llamas M, Gallo E, Sánchez-Pérez J, Fraga J,García-Diez A. Follicular mucinosis in a mycosis fun-goides-like hypersensitivity syndrome induced by oxcar-bamazepine. J Cutan Pathol. 38(12): 1009-11. Epub2011 Sep 7. 2011. PMID: 21899590. IF: 1,744

Santiago-et-Sánchez-Mateos D, Juárez Martín A,González De Arriba A, Delgado Jiménez Y, Fraga J,Hashimoto T, García-Diez A. IgG/IgA pemphiguswith IgA and IgG antidesmoglein 1 antibodiesdetected by enzyme-linked immunosorbent assay:presentation of two cases. J Eur Acad DermatolVenereol 25 (2): 110-112. 2011. PMID: 20477924.IF: 3,309

Llamas-Velasco M, Argila DD, Eguren C, García-MartinP, Ibañes S, García-Diez A. Solar urticaria unresponsiveto intravenous immunoglobulins. PhotodermatolPhotoimmunol Photomed 27 (1): 53-54. 2011. PMID:21198885. IF: 1,424

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: AMARO GARCIA DIEZAsociación de amorolfina al 5% en forma de lca unguealcon itraconazol por vía oral en el tratamiento de lasmicosis con afectación de la matriz. M04033794EudraCT: 333

PRINCIPAL INVESTIGATOR: MAXIMILIANO ARAGUESMONTAÑESEstudio fase II de LBH589 oral, en pacientes adultos conlinfoma cutáneode células T refractario; (versión final: 21-06-06). CLBH589B2201EudraCT: 2006-000880-27

PRINCIPAL INVESTIGATOR: AMARO GARCIA DIEZElaboración y validación de un cuestionario específicode calidad de vida relacionada con la salud (CVRS) enpacientes con urticaria crónica; (versión: 05-07-07).ESTUDIO URQOL

PRINCIPAL INVESTIGATOR: AMARO GARCIA DIEZEstudio post-comercialización observacional, de 10años de registro de datos de HUMIRA®(Adalimumab) en pacientes adultos con psoriasiscrónicaen placas (PS); (versión: 12-03-08). ABB-ADA-2008-01

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Gal-1, gal-3 and gal-9 are expressed in Langerhans cells in nor-mal skin. (A) Double immunofluorescence analysis of skin from ahealthy subject for the expression of gal-1, -3, -7 or -9 (green) andMHC-II (red); nuclei were counterstained with Hoechst (blue);arrowheads mark galectin expression on LCs. (B) Three-colourflow cytometry analysis of galectin expression in DCs isolated exvivo from the epidermal sheet of normal skin. Cells were gated forHLA-DR expression and galectin expression was then determinedon CD1a+ cells.

AREA 1

AREA

1

Line 1.5Cellular mechanisms and molecular determinants of allergy-based diseases

GROUP 20

HEAD OF LABORATORYCarlos Blanco Guerra

GROUP MEMBERS• Álvaro Daschner• Consolación de Frutos Moreno• M. Paloma Las Heras Almazán• Tania María Ramos García• Ana Valls Sánchez• Francisco Félix Vega de la Osada

RESEARCH INTEREST

Our group has focused on three different research areasthroughout 2011:

1) Anisakis simplex allergy: Dr. A. Daschner is leading theproject on characterizing Anisakis simplex sensitization

associated chronic urticaria as a differential phenotype.This project is on its final steps and several contributionsare dealing with data on the relationship between fisheating habits, severity of symptoms and search for asso-ciation with pro- and anti-inflammatory cytokines (Fig 1).Our data are demonstrating that fish intake is not onlyassociated with A. simplex sensitization risk, but alsowith modulating factors induced by fish-intake per se.Our pluri-disciplinary teaching and research activities inEvolutionary medicine have further contributed to sever-al published papers dealing with new concepts andinterpretation of IgE-mediated immune responses asso-ciated with parasite-induced allergic phenomena.

2) Food allergy: a new research project, in collabora-tion with Centro de Biotecnología y Genómica dePlantas (UPM-INIA), is intended to deepen sensitiza-tion mechanisms (pre-phase IgE response) to certainplant proteins and the role of different external factorsin this process. As a model, we have selected someof the most relevant allergens in food allergy in Spain,such as Pru p 3, a lipid transfer protein from peach.

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Serum levels of significant cytokines. Due to distribution pat-terns, IL-10, IFN-γ and IL-17 are shown as boxplots and TGF-β asmean bars +/- SD. GAA: Gastro-allergic Anisakiasis (acute urtica-ria), CU+: Anisakis simplex (A. simplex) sensitization associatedchronic urticaria, CU-: chronic urticaria without sensitizationagainst A. simplex.(Daschner A. et al., Parasite Immunology 2011).

AREA 1The study aims to be addressed at different levels ofcomplexity: epidemiological, molecular and cellularlevels.

3) Respiratory allergy: Finally, in the context of theMEICA research project funded by FundaciónGenoma España, a phase IV clinical trial is currentlybeing performed, focused on the immunologicalresponse to grass pollen specific immunotherapy, incollaboration with ALK and the CNB (BiotechnologicalNational Centre).

MAJOR GRANTS

Carlos Blanco Guerra. Mecanismos moleculares ycelulares en enfermedades inflamatorias crónicas yautoinmunes. Proyecto MEICA. Proyectos de I+D+I deCooperación público-privada de Genómica Aplicada yBiotecnología de Genoma España. Genoma España.Proyecto MEICA


Daschner A, Rodero M, De Frutos C, Valls A, Vega F,Blanco C, Cuéllar C. Different serum cytokine levels inchronic vs. acute Anisakis simplex sensitization-asso-ciated urticaria. Parasite Immunology 33(6): 357-362.2011. PMID: 21554330. IF: 2,357

Daschner A, Rodero M, Cuéllar C. Low immunoglob-ulin E response in gastroallergic anisakiasis could beassociated with impaired expulsion of parasite. JInvestig Allergol Clin Immunol 21(4): 330-331. 2011.PMID: 21728268. IF: 1,489

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRAMecanismos moleculares y celulares de rinitis alérgica enpacientes tratados con GRAZAX; (versión final: 30-04-09). GT-20EudraCT: 2009-011453-41

PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRAEstudio de evaluación de las preferencias y expectativasdel paciente en el tratamiento de la alergia coninmunoterapia específica subcutánea; (versión 1:Octubre 2009). ESTUDIO ARIES

PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRAEstudio abierto para valorar la tolerabilidad de lainmunoterapia con AVANZ Phleum pratense; (versiónfinal: 13-01-11). AV-G-01EudraCT: 2011-000057-23

PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRADosis de mantenimiento de AVANZ Phleum pratense;(versión final:29-3-11). AV-G-02EudraCT: 2011-000120-15

PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRAEstandarización biológica del extracto alergénico deDactylis glomerata para determinar la actividad biológicaen unidades equivalentes de Histamina (HEP); (versión1.0:25-03-11). 6038-PR-PRI-181EudraCT: 2010-023948-33

PRINCIPAL INVESTIGATOR: CARLOS BLANCO GUERRAEstudio Smile: Satisfacción con el tratamiento y calidadde vida de los pacientes en inmunoterapia sublingual.Creencias y actitudes de los especialistas en sutratamiento; (versión 4.00: 4-7-11). STA-SMI-2011-03SMI-2011-03

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AREA

1

Line 1.6Inflammatory processes innephrological diseases

GROUP 21HEAD OF LABORATORYJosé Antonio Sánchez Tomero

GROUP MEMBERS• Abelardo Isaac Aguilera Peralta• Vicente Álvarez Chiva• Guillermina Barril Cuadrado• Carmen Bernis Carro• Antonio Carlos Fernández Perpén• Martín Giorgi González• Isabel Herráez Jiménez• Pablo Ruano Suárez• Laura Salanova Villanueva• Carmen Sánchez González

RESEARCH INTEREST

During 2011 we have continued working in the areas ofresearch previously described.

1) Peritoneal dialysis: we have published two studiesanalyzing the influence of the new more biocompatible

dialysis fluids on the conservation of the peritoneal mem-brane including ex vivo cell cultures and functional stud-ies. Moreover, we have shown that blocking TGF-β1with specific peptides protects the peritoneal membranefrom dialysate-induced damage.

2) We have published a collaborative study analyzing theoutcome and prognostic factors in HIV-1 infectedpatients on dialysis in the cART era.

3) In the field of glomerular diseases we have beeninvolved in a collaborative study to evaluate the clinicalvalue of NPHS-2 analysis in early- and adult-onset

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Outcome and Prognostic Factors in HIV-1–Infected Patients on Dialy-sis in the cART Era: a GESIDA/SEN Cohort Study Joan-Carles Trullas,Federico Cofan, Guillermina Barril, Alberto Martínez-Castelao, RosaJofre, Maite Rivera, Jorge Martínez-Ara, Silvia Ros, Iñaki Perez, Asun-ción Moreno, and Jose M. Miro, the Spanish HIV Infection in DialysisStudy Group. J Acquir Immune Defic Syndr 2011;57:276–283)


AREA 1steroid-resistant nephrotic syndrome and published areview of membranous nephropathy in collaboration withDr Bomback from Columbia University Medical Centerto be published shortly by Saunders – Elservier.

4) We participated in a collaborative study on anemiamanagement in kidney transplant patients treated withMethoxy polyethylene glycol-epoetin beta (Mircera). 5. Inthe field of management in nephrology we have pub-lished two papers. A paper that analyzes the number ofnephrology residents needed in the near future andanother work about the sustainability of treatment renalfunction replacement in Spain.

5) Finally, we have published a collaborative study, coor-dinated by the service, which analyzes the opinion ofpatients on dialysis with respect to end of life andadvance care planning.

MAJOR GRANTS

• Abelardo Isaac Aguilera Peralta. Development of a newand more biocompatible peritoneal dialysis solutionbased in stevioside as osmotic agent. Fresenius MedicalCare Deutschland GMBH y Fresenius Medical CareEspaña. IRSIN 1110017

• Abelardo Isaac Aguilera Peralta. Study of the effects ofParicalcitol on the epithelial-to-mesenchymal transitionprocess of mesothelial cells. Abbot.

• Abelardo Isaac Aguilera Peralta. Modulación de la transi-ción epitelio mesenquimal (EMT) de las célulasmesoteliales (CM) como aproximación para mejorar lafunción peritoneal de pacientes en diálisis peritoneal.ISCIII. FIS: 009/00774

• Abelardo Isaac Aguilera Peralta. Looking for a new, morebiocompatible peritoneal dialysis solution based in glico-sides as osmotic agent. Fresenius Medical Care.

• Abelardo Isaac Aguilera Peralta. Validación de laTransición Epitelio Mesenquimal de Células Mesotelialescomo Herramienta para el Diagnóstico y Pronóstico delFracaso de la Membrana Peritoneal en Pacientes enDiálisis Peritoneal. Sociedad Española de Nefrología.

• José Antonio Sánchez Tomero. Mecanismos molecu-lares que regulan el daño renal provocado por isquemia-reperfusión. Amgen SA. IRSIN 2322006

• Proyecto Coordinado. Repercusiones sistémicas,metabólicas y arterioscleróticas, de los efectos intraperi-toneales inducidos por la diálisis peritoneal. Un modelohumano para estudiar la génesis abdominal de la arte-riosclerosis. ISCIII. PS-09/00641

• Guillermina Barril Cuadrado. Infección silente por virus Cde la hepatitis en unidades de diálisis: análisis de larespuesta inmunoserológica y repercusiones diagnósti-cas. Fundacion Mutua Madrileña.

• Guillermina Barril Cuadrado. Detección del genoma delvirus C de la hepatitis en suero de pacientes en diálisiscon infección silente por virus C mediante ultracentrifu-gación y PCR. Fundación Mutua Madrileña. 2551/08

• Guillermina Barril Cuadrado. Supervivencia de lospacientes con infección por el VIH en terapia renal susti-tutiva o trasplante renal en España. FIPSE. 24-0858-09

• José Antonio Sánchez Tomero. Estudio de los mar-cadores de riesgo cardiovascular en la enfermedad renaly proyección pronóstica. Baxter, Palex Nipro.


Loureiro J, Aguilera A, Selgas R, Sandoval P, Albar-VizcaínoP, Pérez-Lozano ML, Ruiz-Carpio V, Majano PL, Lamas S,Rodríguez-Pascual F, Borras-Cuesta F, Dotor J, López-Cabrera M. Blocking TGF-B1 protects the peritoneal mem-brane from dialysate-induced damage. J Am Soc Nephrol22(9): 1682-1695. 2011. PMID: 21742730. IF: 8,288

Santín S, Tazón-Vega B, Silva I, Cobo MÁ, Giménez I, RuízP, García-Maset R, Ballarín J, Torra R, Ars E; FSGS SpanishStudy Group (Bernis C). Clinical value of NPHS2 analysis inearly- and adult-onset steroid-resistant nephrotic syn-drome. Clin J Am Soc Nephrol 6(2): 344-354. 2011. PMID:20947785. IF: 4,763

Castillo I, Bartolomé J, Quiroga JA, Barril G, Carreño V.Long-term virological follow up of patients with occult hep-atitis C virus infection. Liver Int 31(10): 1519-1524. 2011.PMID: 22093326. IF: 3,84

Bajo MA, Pérez-Lozano ML, Albar-Vizcaino P, del Peso G,Castro MJ, Gonzalez-Mateo G, Fernández-Perpén A,Aguilera A, Sánchez-Villanueva R, Sánchez-Tomero JA,López-Cabrera M, Peter ME, Passlick-Deetjen J, Selgas R.

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AREA

1

Low-GDP peritoneal dialysis fluid ('balance') has less impactin vitro and ex vivo on epithelial-to-mesenchymal transition(EMT) of mesothelial cells than a standard fluid. Nephrol DialTransplant 26(1): 282-291. 2011. PMID: 20571097. IF:3,564

Trullàs JC, Cofan F, Barril G, Martínez-Castelao A, Jofre R,Rivera M, Martínez-Ara J, Ros S, Perez I, Moreno A, MiróJM; Spanish HIV Infection in Dialysis Study Group.Outcome and prognostic factors in HIV-1-infected patientson dialysis in the cART era: a GESIDA/SEN cohort study. JAcquir Immune Defic Syndr 57(4): 276-283. 2011. PMID:21623213. IF: 4,262

S. Cigarrán Guldrís, G. Barril Cuadrado. Balance de agua ysodio en diálisis. ¿Qué nos aporta la bioimpedancia?.Nefrologia 2(5 Sup2): 20-24. 2011. PMID: . IF: 0,738

Bernis C, Comisión Nacional de la Especialidad deNefrología en España. Trends in resident positions offeredin nephrology (1985-2008). Nefrología 31(2): 155-161.2011. PMID: 21461008. IF: 0,738

Salanova Villanueva L, Sánchez González MC, SánchezTomero JA, Sanz P. Successful treatment with sodium thio-sulfate for calcific uraemic arteriolopathy. Nefrologia 31(3):366-368. 2011. PMID: 21629345. IF: 0,738

J. Portolés, F. Moreno, P. López-Sánchez, J. Mancha, M.Gómez, E. Corchete, G. del Peso, M.A. Bajo, R. Llópez-Carratalá, A. Fernández-Perpén, GROUP Centro de DiálisisPeritoneal (GCDP)*. Peritoneal dialysis and kidney trans-plant. A two-way ticket in an integrated renal replacementtherapy model. Nefrologia 31(4): 441-448. 2011. PMID:21738247. IF: 0,738

Sánchez-Tomero JA, Rodríguez-Jornet A. Balda S,Cigarrán S, Herrero JC, Maduell F, Martín J, Palomar R.Exploring the opinion of CKD patients on dialysis regardingend-of-life and Advance Care Planning. Nefrología 31(4):449-56. 2011. PMID: 21738248. IF: 0,738

Arrieta J, Rodríguez-Carmona A, Remón C, Pérez-FontánM, Ortega F, Sánchez Tomero JA, Selgas R. GROUPde Apoyo al Desarrollo de la Diálisis Peritoneal enEspaña. Peritoneal dialysis is the best cost-effective

alternative for maintaining dialysis treatment.Nefrologia 31(5): 505-513. 2011. PMID: 21959716.IF: 0,738

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: GUILLERMINA BARRILCUADRADOEfecto de la permeabilidad de la membrana sobre la evolu-ción de los pacientes con IRC (revisión 3.5). MPO STUDYEudraCT: NA

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEstudio multicéntrico prospectivo, doble ciego, controla-do con placebo, aleatorizado, de tres grupos paralelospara evaluar la eficacia y seguridad del tratamiento coneritropoyetina recombinante humana en la prevenciónde la nefrotoxicidad asociada a la utilización de con-trastes yodados en pacientes con alto riesgo de disfun-ción renal. EPOCONT-FRACAM-01EudraCT: 2007-000994-40

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEstudio observacional retrospectivo para evaluar la vari-abilidad de los niveles de hemoglobina en pacientesreceptores de un trasplante renal con anemia renalcrónica; (versión final: 27-09-11). SET-ANE-2011-01

PRINCIPAL INVESTIGATOR: GUILLERMINA BARRILCUADRADOEstudio sobre las alteraciones del metabolismo oseo ymineral (AMOM) en la Enfermedad Renal Crónica (ERC)en España, (versión final: Noviembre 2008). OSERCE II

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEstudio observacional retrospectivo para conocer elcontrol de la anemia con metoxi-polietilenglicol epoetinabeta en pacientes trasplantados renales; (versión final:17-08-09). ANEMIA TRANS

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEfecto del ácido acetilsalicílico en la prevención primariadel riesgo cardiovascular en paciente con enfermedadrenal crónica (Estudio AASER); (versión: 02-11-09).

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AREA 1MG001EudraCT: 2009-01347-21

PRINCIPAL INVESTIGATOR: JOSE A. SANCHEZTOMEROEstudio observacional, prospectivo y multicéntrico paraestablecer un modelo de valoración de la enfermedadaterosclerótica y su valor predictivo de eventos cardio-vasculares en pacientes con enfermedad renal crónicaen España; (Versión: 1-09-2009). PROYECTONEFRONA

PRINCIPAL INVESTIGATOR: GUILLERMINA BARRILCUADRADOEstudio, abierto multicéntrico, aleatorizado y de 3 gru-pos paralelos para comparar la eficacia y la seguridad dela carboximaltosa férrica por vía intravenosa (regímenesen dosis bajas y altas de Ferinject®) con las del hierropor vía oral en el tratamiento de la anemia ferropénica enpacientes con nefropatía crónica sin diálisis; (Versión:112/08/2009). FER-CKD-01EudraCT: 2009-015579-28

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEstudio fase III, multicéntrico, aleatorizado, abierto degrupos paralelos para comparar la eficacia y seguridadde la pauta Prednisona-Ac Micofenólico-Ciclosporina aPrednisona-Ac Micofenólico en el tratamiento de lasnefropatias lúpicas tipo III-IV-V; (Versión:1). CSA-LESEudraCT: 2009-017273-38

PRINCIPAL INVESTIGATOR: ANTONIO FERNANDEZPERPENIniciativa para la Evolución Clínica de los Pacientes enDiálisis-DP (Estudio IPOD-PD); (versión final 1.0: 21-05-10).BCM-PD-02-INT

PRINCIPAL INVESTIGATOR: GUILLERMINA BARRILCUADRADOEstudio de observación poscomercialización de Renvela®para vigilar el uso clínico en pacientes adultos hiperfos-fatémicos con insuficiencia renal crónica no sometidos adiálisis y con concentraciones séricas de fósforo

mayor/igual 1,78 mmol/l; (versión final 1: 28-1-11).SVCARB06009

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEstudio epidemiológico del fracaso renal agudo en laComunidad de Madrid GEFRAM 2011; (Versión: 30-03-11). GEFRAM 2011

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEstudio ACERCA: Estudio transversal no intervencionistapara evaluar el manejo de la anemia en la enfermedad renalcrónica en pacientes no en diálisis, en la práctica clínicadiaria, tras las recomendaciones del grupo de trabajo enAnemia-ERBP; (versión final: 04-03-11). SEN-AEE-2011-01

PRINCIPAL INVESTIGATOR: JOSE A. SANCHEZTOMEROEstudio multicéntrico, prospectivo, observacional, para elanálisis de factores de progresión de la enfermedad renalcrónica en pacientes diabéticos vs no diabéticos. PRO-GRESER

PRINCIPAL INVESTIGATOR: VICENTE ALVAREZ CHIVASEfecto de paricalcitol sobre la albuminuria, la inflamación yla fibrosis en pacientes con enfermedad renal proteinúricacrónica (Estudio PALIFE): ensayo controlado randomizado,(versión 1.0: 15-06-11). PALIFE-2011-01EudraCT: 2011-002877-46

PRINCIPAL INVESTIGATOR: JOSE A. SANCHEZTOMEROEstudio clínico multicéntrico, prospectivo, aleatorizado,abierto y controlado, para la prevención de la infeccióndel orificio externo (IOE) del catéter peritoneal con unapasta antibiótica tópica; (Versión:1 fecha 19/11/2009).PREVIOE-DPEudraCT: 2009-016835-36

PRINCIPAL INVESTIGATOR: CARMEN BERNIS CARROEstudio piloto: valor pronóstico de la determinación deNGAL en orina al ingreso en la unidad de cuidados inten-sivos (UCI). NGAL

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Line 1.7Inflammatory mechanisms in pulmonary diseases

GROUP 22HEAD OF LABORATORYJulio Ancochea Bermúdez

GROUP MEMBERS• Carolina Cisneros Serrano• Rosa María Girón Moreno• Ana Martínez Meca• Silvia Sánchez Cuéllar• Enrique Domingo Zamora García

RESEARCH INTEREST

Respiratory diseases represent a social and health prob-lem of first order, given its high prevalence and high mor-bidity and mortality. This group has worked throughout2011 mainly in Chronic Obstructive Pulmonary Disease(COPD) and Asthma, two highly prevalent respiratorydiseases.

Asthma is a serious global health chronic problem. Wehave collaborated with the Immunology Department of the

Hospital in order to investigate the precise role of theGalectins in patients with asthma, as well as their possibleimplication in the immunopathogenesis of this disease.

The department of Pneumology of La Princesa Hospitalparticipated in 2009 in the project AudiEPOC Spain,where we assessed the quality of care of patients hospi-talized for an exacerbation of COPD. In 2011, in order toperform an auditory in Europe about COPD, theEuropean Respiratory Society has created a project thatinvolves 13 countries, including Spain and La PrincesaHospital.

In addition to the previous study with COPD patients, thedepartment of Pneumology together with general practi-tioners has created a project to evaluate two alternativesin the care of patients with COPD: “HealthcareTelemonitoring versus Conventional”. The PROMETEstudy: “Telemedicine in patients with advanced COPD”aims to evaluate the effectiveness of telemonitoring sys-tem, measured by number of exacerbations, hospitaladmissions and death during the study period in patientswith COPD. This project will allow evaluating the qualityof life related to the health of these patients comparingtwo methods.

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Composition of study groups. LLN = lower limit of normal. Sub-jects were classified according to the presence of airflow obs-truction, which was defined by a postbronchodilator FEV1/FVCratio of < 0.70 or < LLN obtained from Spanish prediction equa-tions. [23] Subjects were included in the ratio-only group if theirFEV1/FVC was < 0.70 but > LLN. Subjects with an FEV1/FVC < LLNwere included in the COPD group and stratified into mild or mode-rate to severe categories according to their predicted FEV1. [6]The remaining subjects were assigned to the non-COPD group.

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Finally, the department of Pneumology of La PrincesaHospital is the only Spanish center that has participatedin the new official guidelines for diagnosis and manage-ment of Idiophatic Pulmonary Fibrosis elaborated byInternacional Respiratory Societies [(AmericanRespiratory Society (ATS), European Respiratory Society(ERS), Japan Respiratory Society (JRS) and LatinAmerican Thoracic Association (ALAT)].

MAJOR GRANTS

• Silvia Sánchez Cuéllar. La implicación del CD69 enla modulación inmune de pacientes asmáticosmediante el análisis de la capacidad de diferen-ciación de los distintos tipos de células T helper;Th1, Th2 y Th17. ISCIII. SEPAR.

• Silvia Sánchez Cuéllar. El papel de las Galectinas comomolécula de inmunoregulación en el asma.Neumomadrid.

• Julio Ancochea Bermúdez. Desarrollo de nuevas estrate-gias terapéuticas en la LAM: estudio sobre su origencelular y diseminación. SEPAR.

• Julio Ancochea Bermúdez. Programa de I+DBiomedicina. CONSEPOC-CM. Inflamación e hipoxia:mecanismos de desarrollo y progresión en EPOC ySAHS. Consejería de Educación - CAM.


Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J,Brown KK, Colby TV, Cordier JF, Flaherty KR, LaskyJA, Lynch DA, Ryu JH, Swigris JJ, Wells AU,Ancochea J, Bouros D, Carvalho C, Costabel U,Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr,Kondoh Y, Myers J, Müller NL, Nicholson AG, RicheldiL, Selman M, Dudden RF, Griss BS, Protzko SL,Schünemann HJ. An official ATS/ERS/JRS/ALATstatement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. AmJ Respir Crit Care Med. 183(6): 788-824. 2011.PMID: 21471066. IF: 10,191

García-Rio F, Soriano JB, Miravitlles M, Muñoz L,Duran-Tauleria E, Sánchez G, Sobradillo V, AncocheaJ. Overdiagnosing subjects with COPD using the 0.7fixed ratio: correlation with a poor health-related qual-ity of life. Chest. 139(5): 1072-80. Epub 2010 Dec 23.2011. PMID: 21183609. IF: 6,519

Noble PW, Albera C, Bradford WZ, Costabel U,Glassberg MK, Kardatzke D, King TE Jr, Lancaster L,Sahn SA, Szwarcberg J, Valeyre D, du Bois RM;Colaborators: Agostini C, Allen J, Andrews C, Antin-Ozerkis D, Baughman R, Burge S, Chan A,Confalonieri M, Cordier J, Cordova F, Cuomo A,Delaval P, Dhar A, Duarte A, Dushay K, Flaherty K,Frost A, Ginns L, Girod C, Glaspole I, Golden J,Gottfried M, Haller H Jr, Harari S, Helmersen D,Hodder R, Hollingsworth H, Homik L, Khalil N, Kus J,Leonard C, Malouf M, Mette S, Meyer K, Meziane H,Nathan S, Padilla M, Panos R, Pantano J, Patel N,Poletti V, Ramesh W, Richeldi L, Rolf J, Rottoli P,Russell T, Saltini C, Selman M, Shigemitsu H,Sinkowitz D, Stollery D, Strek M, Tino G, Wallaert B,Wells A, Whelan T, Wilcox P, Zibrak J, Ziora D,Zisman D, Acosta O, Ancochea J, Bonnet R, Brantly

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Distribution of overdiagnosed and severity levels of COPD accor-ding to sex and age group. The sex and age distribution of the pre-valence of overdiagnosed COPD using the fixed ratio and of mildand moderate to severe COPD. The relationship of COPD overdiag-nosis with increasing age and male sex can be observed. In addi-tion, the prevalence of overdiagnosed COPD doubles that of mildCOPD and becomes even greater in the > 60 age strata.

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M, Chapman J, Davis G, de Andrade J, Doherty D,Egan J, Ettinger N, Fairman P, Geiser T, Gibson K,Habib M, Horiuchi T, Ingrassia T, Kallay M, Landis J,Lasky J, Lorch D, Magnussen H, Morrell F, MorrisonL, Musk M, Pfeifer M, Roman J, Rosen G, Sakkhija H,Schaumberg T, Scholand M, Serfilippi G, SlabbynckH, Sussman R, Swigris J, Thomeer M, Thompson A,Verghese G, Wencel M, Wirtz J, Wesselius L, WorthH, Xaubet A, Yagan M, Yung G. Pirfenidone inpatients with idiopathic pulmonary fibrosis (CAPACI-TY): two randomised trials. Lancet 377(9779): 1760-1769. 2011. PMID: 21571362. IF: 33,633

Casanova A, Ancochea J. Lymphangioleiomyomato-sis:new therapeutic approaches. Arch Bronconeu-mol.47(12): 579-580. 2011. PMID: 21924539. IF: 2,166

Miravitlles M, Calle M, Soler-Cataluña JJ, SorianoJB, Ancochea J, Escarrabill J, Almagro P, López D,Marco E, Antonio Riesco J, Antonio Quintano J,Antonio Trigueros J, Molina J, Marzo M, Piñera P,Simón A, Cachinero A, Dolors Navarro M, LlamasM. Moving towards a new focus on COPD. TheSpanish COPD Guidelines (GESEPOC). ArchBronconeumol. 47(8): 379-381. 2011. PMID:21757283. IF: 2,166

Casanova A, María Girón R, Acosta O, Barrón M,Valenzuela C, Ancochea J. Lymphangioleiomyomato-sis treatment with sirolimus. Arch Bronconeumol.47(9): 470-472. 2011. PMID: 21440356. IF: 2,166

Girón Moreno RM, Salcedo Posadas A, Mar Gómez-Punter R. Inhaled antibiotic therapy in cystic fibrosis.Arch Bronconeumol. 47(Suppl): 14-18. 2011. PMID:21703474. IF: 2,166

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: JULIO ANCOCHEABERMUDEZEstudio epidemiológico, prospectivo y multicéntrico de val-idación de la versión en español del cuestionario CAT(COPD Assesment Test) para EPOC; (versión final: 20-10-09). ESTUDIO CAT

PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRONMORENOEstudio de la eficacia del tratamiento a largo plazo consuero salino hipertónico sobre las exacerbaciones pul-monares en pacientes con fibrosis quística; (versión 1: 08-04-08). SSH-FQ1EudraCT: 2008-001284-11

PRINCIPAL INVESTIGATOR: ENRIQUE ZAMORA GARCIAAUDIPOC: Auditoría clínica Nacional sobre exacerbacionesde la EPOC en España. PI-07/90516

PRINCIPAL INVESTIGATOR: JULIO ANCOCHEABERMUDEZEstudio de extensión de etiqueta abierta de la seguri-dad a largo plazo de pirfenidona en pacientes confibrosis pulmonar idiopática (FPI) que completan losestudios CAPACITY; (versión final: 13-12-07). PIPF-012EudraCT: 2007-007800-13

PRINCIPAL INVESTIGATOR: ENRIQUE ZAMORA GARCIAAUDIPOC Europa. COPD ERS

PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRONMORENOPrevalencia e impacto de la depresión y la ansiedad enpacientes con fibrosis quística y sus cuidadores. TIDES

PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRONMORENORegistro europeo y madrileño de pacientes con FibrosisQuística. ECFR

PRINCIPAL INVESTIGATOR: CAROLINA CISNEROSSERRANOMejora el tratamiento con CPAP la evolución del asma enpacientes con Síndrome de Apneas-Hipopneas delSueño?. ESTUDIO CPASMA

PRINCIPAL INVESTIGATOR: CAROLINA CISNEROS SER-RANOEnsayo clínico fase IIb, aleatorizado, doble ciego para eval-uar la eficacia de tralokinumab en pacientes adultos conasma grave no controlada (Versión final:21-06-11). CD-RI-CAT-354-1049EudraCT: 2011-001360-21

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AREA 1PRINCIPAL INVESTIGATOR: JULIO ANCOCHEABERMUDEZEnsayo clínico aleatorizado, doble ciego, controlado conplacebo, de 52 semanas de duración, para evaluar el efec-to de 150mg de BIBF 1120 oral, dos veces al día, en lacaída anual de la Capacidad Vital Forzada en pacientes conFibrosis Pulmonar Idiopática; (versión 1 final:06-01-11).1199.34EudraCT: 2010-024252-29

PRINCIPAL INVESTIGATOR: CAROLINA CISNEROS SER-RANOEstudio de la correlación entre los niveles séricos de lgEtotal y la gravedad del asma en pacientes asmáticos alérgi-cos en España. Estudio SIGE; (versión final: 17-09-10).NOV-ASM-2010-01

PRINCIPAL INVESTIGATOR: CAROLINA CISNEROS SER-RANOValoración del flujo inspiratorio en el asma bronquial medi-ante un medidor portátil. Estudio INSPIRA; (versión 2: 26-04-10). B-12391005

PRINCIPAL INVESTIGATOR: ROSA-MARIA GIRONMORENOCalidad de vida y trastornos psicológicos en pacientes conbronquiectasias no relacionadas con fibrosis quística; (ver-sión 1.0: 23-09-10). CVPSBQ-10

PRINCIPAL INVESTIGATOR: ENRIQUE ZAMORA GARCIAFrecuencia respiratoria y agudización en la EPOC. FRAE-POC

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Line 1.8Inflammatory response in hepatic diseases

GROUP 23HEAD OF LABORATORYRicardo Moreno Otero

GROUP MEMBERS• María Jesús Alonso Martín• María Jesús Borque Iñurrita• Luisa Consuelo García Buey• Asunción García Sánchez• Leticia González Moreno• Ángel Hernández Bartolomé• Rosario López Rodríguez• Samuel Martín Vílchez• Jorge Mendoza Jiménez-Ridruejo• Yolanda Real Martínez• Yolanda Rodríguez Muñoz• María Paloma Sanz Cameno• María Trapero Marugán

RESEARCH INTEREST

During last year, our group has been mainly focused oncharacterizing serum and genetic biomarkers ofChronic hepatitis C (CHC) progression or response toantiviral treatment based on peg-Interferon plusRibavirin. The inability of the immune system to eradi-cate the hepatitis C virus (HCV) infection triggers thepersistent stimulation of repairing mechanisms, includ-ing inflammation, angiogenesis and fibrosis. Therefore,we hypothesised that molecules involved in theseprocesses, such as Angiopoietins/Tie2, might reflectthe progression of CHC or the response to treatment.Firstly, the study of angiopoietins serum levels in CHCpatients allowed us to formulate an accurate non-inva-

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CD16 and Tie-2 expression by peripheral blood monocytes fromhealthy volunteers and CHC patients. Peripheral blood propor-tions CD16high and CD16low (A), and Tie-2high and Tie-2low (C)monocytes from control subjects and CHC patients. Relative pro-portions of CD16high and Tie-2high expressing cells were signifi-cantly raised in peripheral blood of CHC patients compared tocontrols (**p<0.01 and *** p<0.001 by Mann Whitney U test, res-pectively). Box plots show the median percentages +/-95 CI andoutlier values of CD16h (B), and Tie-2h (D) monocytes with regardto the response to treatment. C: Controls; R: Responders; NR: Non-responders; N: Naïves.

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sive predictive model of liver fibrosis (manuscript inpreparation). Additionally, we described the relation ofperipheral Tie2 expressing monocytes (TEMs) propor-tions to the failure of response of CHC patients toantiviral treatment (Rodriguez-Muñoz et al., 2011).Furthermore, we denoted the up-regulation of Tie2

receptor during the activation of hepatic stellate cells,crucial event in liver fibrogenesis, which was enhancedby HCV-expressing replicons (manuscript in prepara-tion). Finally, we also studied the implication of geneticpolymorphisms in interferon stimulated genes (ISGs) inCHC response to antiviral treatment, finding two SNPs,located in OASL and IFIT1 genes, independently asso-ciated with the achievement of response (López-Rodríguez et al., 2011).

MAJOR GRANTS

• María Paloma Sanz Cameno. Influencia de los virusde la hepatitis B (VHB) y C (VHC) en el desequilibrioestructural y funcional de la vasculatura intrahepáti-ca. Implicación del sistema Angiopoyetinas/Tie-2 enla progresión de la hepatitis y respuesta al tratamien-to antiviral. Fundación Mutua Madrileña. MutuaMadrileña

• Ricardo Moreno Otero. Influencia de los virus de lahepatitis B (VHB) y C (VHC) en el desequilibrioestructural y funcional de la vascularización intrahep-ática. Implicación del sistema angiopoyetinas/Tie-2en: 1) La progresión de la hepatitis y respuesta altratamiento antiviral; y, 2) rechazo y reactivación víri-ca post-trasplante de hígado. Fundación MutuaMadrileña. Mutua Madrileña

• Ricardo Moreno Otero. Implicación de polimorfismosgenéticos de factores angiogénicos en la etiopatoge-nia de la hepatitis crónica C y su evolución a carcino-ma hepatocelular. Fundación Mutua Madrileña.

• Proyecto Coordinado. Estimulación pan-poblacionalde la respuesta de los linfocitos T frente a epítoposCD8 conservados del virus de la hepatitis C.MICINN. SAF 2009/08103

• Ricardo Moreno Otero. Implicación del SistemaAngiopoyetinas/Tie2 en los procesos angiogénicos yfibrogénicos asociados a la hepatitis crónica c. MEC.SAF2010-21805

• Ricardo Moreno Otero. Continuación del VX-950-c16 en pacientes que recibieron placebo en lugar detelaprevir. Tibotec BVBA. VX950-TIDP24-C219

• María Paloma Sanz Cameno. Influencia de las his-tonas desacetilasas en la progresión de la hepatitis

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Additive effects of interferon-stimulated genes and IL-28B poly-morphisms on the outcome of the combination antiviral therapy.a) The OASL A allele (rs12819210) predisposed to a better SVRrate within both IL-28B genotypes. Among patients carrying theIL-28B C/C genotype and the OASL A allele, a higher percentagewere responders than among those with the IL-28B G/G genoty-pes (OR=1.48, 95% CI=0.44-4.98, NS). Patients with IL-28BT andOASL A alleles also displayed higher SVR rates (OR=1.81, 95%CI=0.93-3.53, NS). b) Among the group of patients carrying theIFIT A/A genotype (rs304478), the percentages of those attainingSVR were higher for both IL-28BT allele also had better responserates if they also carried the IFIT A/A genotype, although thesedifferences were not significant. c) Schedule showing the in-fluence of IFIT-1, IL-28B, and OASL on the treatment outcome. Piecharts indicate the rate (%) of response (black and nonresponse(gray) for each group of patients after splitting for each single-nucleotide polymorphism. Below each chart are the number ofpatients who attained SVR, the total number of patients carryingthose genotypes, and the percentage that they represent in theoverall population.

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crónica C a carcinoma hepatocelular: polimorfimosgenéticos, niveles de expresión y funcionalidad.Mutua Madrileña.


Moreno-Otero R, Trapero-Marugan M. Antioxidantagents in the prevention of hepatocellular carcinoma.Eur J Cancer Prev [Epub ahead of print]. 2011. PMID:22044850. IF: 2,536

González-Casas R, Trapero-Marugán M, Moreno-Otero R. Chronic C hepatitis genotype 4. Med Clin(Barc) 137(1): 31-5. 2011. PMID: 20466389. IF: 1,413

Martín Martín L, Santander C, Lopez Martín MC,Espinoza-Ríos J, Chavarría-Herbozo C, Gisbert JP,Moreno-Otero R. Esophageal motor abnormalities ineosinophilic esophagitis identified by high-resolutionmanometry. J Gastroenterol Hepatol 26(9): 1447-1450.2011. PMID: 21575059. IF: 2,41

Barbero-Villares A, Mendoza J, Trapero-Marugan M,Gonzalez-Alvaro I, Daudén E, Gisbert JP, Moreno-Otero R. Evaluation of liver fibrosis by transient elastog-raphy in methotrexate treated patients. Med Clin (Barc)137(14): 637-639. 2011. PMID: 21719043. IF: 1,413

Poynard T, Munteanu M, Colombo M, Bruix J, Schiff E,Terg R, Flamm S, Moreno-Otero R, Carrilho F, SchmidtW, Berg T, McGarrity T, Heathcote EJ, Gonçales F,Diago M, Craxi A, Silva M, Boparai N, Griffel L,Burroughs M, Brass C, Albrecht J. FibroTest is an inde-pendent predictor of virologic response in chronic hep-atitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC³ program. J Hepatol 54 (2):227-235. 2011. PMID: 21056496. IF: 9,334

Lopez-Rodriguez R, Trapero-Marugan M, Borque MJ,Roman M, Hernandez-Bartolome A, Rodriguez-MuñozY, Martin-Vilchez S, Abad-Santos F, Muñoz de RuedaP, Vidal-Castiñeira JR, Rodrigo L, Salmeron J, Moreno-Otero R, Sanz-Cameno P. Genetic variants of interfer-on-stimulated genes and IL-28B as host prognostic

factors of response to combination treatment forchronic hepatitis C. Clin Pharmacol Ther 90(5): 712-721. 2011. PMID: 21993426. IF: 6,378

de Rueda PM, López-Nevot MÁ, Sáenz-López P, CasadoJ, Martín-Casares A, Palomares P, Quiles R, Gila A,Romero-Gómez M, Pavón EJ, Muñoz JA, Carazo A, Sanz-Cameno P, Moreno-Otero R, Diago M, León J, Ruiz-Extremera A, Salmerón J. Importance of host genetic fac-tors HLA and IL28B as predictors of response to pegylatedinterferon and ribavirin. Am J Gastroenterol 106(7): 1246-1254. 2011. PMID: 21670772. IF: 6,882

Trapero-Marugan M, Mendoza J, Chaparro M,Gonzalez Moreno L, Moreno-Monteagudo JA, BorqueMJ, Moreno-Otero R. Long-Term outcome of chronichepatitis C patients with sustained virological responseto peginterferon plus ribavirin. World J Gastroenterol17(4): 493-498. 2011. PMID: 21274379. IF: 2,24

García-Buey L, Moreno-Otero R. Mycophenolatemofetil for patients with autoimmune hepatitis andoverlap syndromes. Aliment Pharmacol Ther 34(6):682-684. 2011. PMID: 21851370. IF: 3,861

Rodríguez-Muñoz Y, Martín-Vílchez S, López-Rodríguez R, Hernández-Bartolomé A, Trapero-Marugán M, Borque MJ, Moreno-Otero R, Sanz-Cameno P. Peripheral blood monocyte subsets predictantiviral response in chronic hepatitis C. AlimentPharmacol Ther 34(8): 960-971. 2011. PMID:21848603. IF: 3,861

Martin-Vilchez S, Lara-Pezzi E, Trapero-Marugán M,Moreno-Otero R, Sanz-Cameno P. The molecular andpathophysiological implications of hepatitis B X antigenin chronic hepatitis B virus infection. Rev Med Virol.21(5): 315-329. Epub 2011 Jul 14. 2011. PMID:21755567. IF: 5,6

Trapero-Marugán M, Mendoza J, Moreno MonteagudoJA, Chaparro M, García-Buey L, González-Moreno L,Borque MJ, Moreno-Otero R. Current antiviral combina-tion therapy for chronic hepatitis C patients who failed tointerferon alfa-based treatment. J Clin Pharm Ther. 36(6):695-703. 2011. PMID: 21175705. IF: 1,649

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AREA 1Hinojar-Gutierrez A, Nieto-LLanos S, Mera-MenendezF, Fernandez-Contreras ME, Mendoza J, Moreno R.Laryngeal metastasis as first presentation of hepatocel-lular carcinoma. Rev Esp Enferm Dig 103(4): 222-224.2011. PMID: 21526881. IF: 1,13

Almoguera B, Riveiro-Alvarez R, Lopez-Castroman J,Dorado P, Lopez-Rodriguez R, Fernandez-Navarro P,Baca-García E, Fernandez-Piqueras J, Dal-Ré J, Abad-Santos F, LLerena A, Ayuso C. ATA homozigosity in theIL-10 gene promoter is a risk factor for schizophrenia inSpanish females: a case control study. BMC MedicalGenetics 12(81): 1-6. 2011. PMID: 21658228. IF: 2,439

Benedicto I, Molina-Jiménez F, Moreno-Otero R, López-Cabrera M, Majano PL. Interplay among cellular polariza-tion, lipoprotein metabolism and hepatitis C virus entry.World J Gastroenterol 17(22): 2683-2690. 2011. PMID:21734774. IF: 2,24

Ayuso C, Abad-Santos F, Dal-Ré R, Gracia D. Ethics ongenetic research (1). Pharmacogenetic studies. Med Clin(Barc). 136(15): 678-682. 2011. PMID: 20044101. IF: 1,413

Pousa ID, Algaba A, Linares PM, Sanz-Cameno P, Maté J,Moreno-Otero R, Bermejo F, Gisbert JP. Corticosteroidsmodulate angiogenic soluble factors in ulcerative colitispatients. Dig Dis Sci 56 (3): 871-879. 2011. PMID:20632101. IF: 2,06

Espinosa L, Linares PM, Bejerano A, Lopez C, Sanchez A,Moreno-Otero R, Gisbert JP. Soluble angiogenic factors inpatients with acute pancreatitis. J Clin Gastroenterol. 45(7):630-637. 2011. PMID: 21750433. IF: 2,752

Trapero-Marugán M, Moreno-Borque R, Arberas B,Santander-Vaquero C. Colonic mast cells: a new target inchronic constipation?. Aliment Pharmacol Ther. 34(5):585-6. 2011. PMID: 21806646. IF: 3,861

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: RICARDO MORENOOTERO

Estudio de fase 2, aleatorizado, doble ciego y contro-lado con placebo para evaluar la seguridad y la efica-cia de filibuvir más interferón alfa-2A pegilado y ribavi-rina en el tratamiento de pacientes infectados por elVHC de genotipo 1 y no tratados previamente; (ver-sión Enmienda 1: 02-04-09). A8121014EudraCT: 2009-009214-40

PRINCIPAL INVESTIGATOR: RICARDO MORENOOTEROEstudio observacional, aleatorizado de Entecavir paraevaluar los resultados a largo plazo asociados a lamonoterapia con nucleósido/nucleótido en pacientescon infección crónica por el VHB: el estudio REALM;(versión 2.0: 19-09-06); (Hoja de Información alPaciente y Consentimiento Informado, (versiónespañola 1.0: 28-11-06). AI463-080EudraCT: 2005-003284-22

PRINCIPAL INVESTIGATOR: LUISA-CONSUELOGARCIA BUEYEnsayo clínico de tenofovir en profilaxis de pacienteshematológicos Anti-HBc positivo y AgHBs negativoen tratamiento con rituximab (EstudioPREBLIN); (ver-sión 1: 1-03-11). REM-TEN-2011-01EudraCT: 2011-000905-30

PRINCIPAL INVESTIGATOR: RICARDO MORENOOTEROEstudio fase 3 de seguridad y eficacia de bocepreviren pacientes con Hepatitis C Crónica genotipo 1 querecayeron tras el tratamiento previo con peginterfer-ón/ribavirina; (versión final: 22-05-08). PO5101

PRINCIPAL INVESTIGATOR: RICARDO MORENOOTEROEfecto del tratamiento con dosis altas de Ribavirinafrente a dosis estándar en pacientes infectados con elvirus de la Hepatitis C Crónica genotipo 3 y carga viralalta sin respuesta en semana 4; (versión: 27-11-07).DARGEN-3EudraCT: 2008-000328-16

PRINCIPAL INVESTIGATOR: RICARDO MORENOOTERO

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Estudio multicéntrico aleatorizado, controlado conplacebo, para evaluar la eficacia y la seguridad deeltrombopag en sujetos trombocitopénicos infecta-dos por el virus de la hepatitis C (VHC) que, por lodemás, resulten elegibles para iniciar tratamientoantiviral (peginterferón alfa-2bmás ribavirina); (versión1: 04-05-07). TPL108390EudraCT: 2007-000292-42

PRINCIPAL INVESTIGATOR: MARIA TRAPEROMARUGANEnsayo de continuación abierto, de un solo grupo detelaprevir en combinación con interferón pegiladoalfa-2a (pegasys) y ribavirina (copegus) realizado consujetos procedentes del grupo del control del ensayoVX-950-TIDP24-C216 con fracaso virológico deltratamiento; (Versión final: 30-11-09). VX-950-TIDP24-C219EudraCT: 2009-012613-21

PRINCIPAL INVESTIGATOR: LUISA-CONSUELOGARCIA BUEYEnsayo clínico fase I/II, multicéntrico, aleatorizado,abierto y controlado sin placebo para evaluar la farma-cocinética, farmacodinámica, seguridad y toleranciadel Interferón Alfa 5, administrado 3 veces por semana,durante 29 días, para pacientes con tratamiento previopara Hepatitis C Crónica Genotipo-1; (versión 1.0: 22-05-09). NAHE001-CHC-01EudraCT: 2009-012924-10

PRINCIPAL INVESTIGATOR: RICARDO MORENOOTEROEstudio multicéntrico aleatorizado, controlado conplacebo, para evaluar la eficacia y la seguridad deeltrombopag en sujetos trombocitopénicos infecta-dos por el virus de la hepatitis C (VHC) que, por lodemás, resulten elegibles para iniciar tratamientoantiviral (peginterferon alfa-2amás ribavirina); (versión00: 11-04-07). TPL103922EudraCT: 2006-004946-17

PRINCIPAL INVESTIGATOR: MARIA TRAPEROMARUGANEstudio de fase II, aleatorizado, multicéntrico y abier-to de TG4040 (MVA-VCH) en combinación con inter-

ferón alfa-2A pegilado y ribavirina frente a interferónalfa-2A pegilado y ribavirina en pacientes conHepatitis C Crónica de genotipo 1 no tratada previa-mente; (Versión final: 25-11-2009). TG4040.02EudraCT: 2009-011121-13

PRINCIPAL INVESTIGATOR: MARIA TRAPEROMARUGANEstudio aleatorizado, abierto, fase 3 de telapreviradministrado dos veces al día o cada 8 horas encombinación con interferon pegilado alfa-2a y ribavi-rina en sujetos con infección crónica por el virus dela hepatitis C, genotipo 1, no tratados previamente;(versión final:13-9-10). VX-950-C211EudraCT: 2010-021628-84

PRINCIPAL INVESTIGATOR: LETICIA GONZALEZMORENOEstudio en fase II, multicéntrico, aleatorizado, dobleciego, de grupos paralelos para comparar la eficaciay seguridad de sorafenib más pravastatina frente asorafenib más placebo en pacientes con hepatocar-cinoma avanzado; (versión nº 2: 09-03-11). ESTA-HEP-2010EudraCT: 2010-024421-21

PRINCIPAL INVESTIGATOR: LUISA-CONSUELOGARCIA BUEYEstudio de fase II, doble ciego, aleatorizado y contro-lado con placebo para determinar el efecto antiviral,la seguridad y la farmacocinética de la administracióndurante 24 semanas de BI 201335 NA junto con laadministración de interferon pegilado alfa 2a y ribavi-rina, en pacientes con hepatitis c de genotipo 1 notratados previamente y en pacientes con experienciade tratamiento. 1220.5EudraCT: 2008-003538-11

PRINCIPAL INVESTIGATOR: LUISA-CONSUELOGARCIA BUEYPrograma de acceso temprano, multicéntrico yabierto, de telaprevir en combinación con interferonpegilado alfa y ribavirina, para el tratamiento de lainfección crónica por el genotipo 1 del virus de laHepatitis C en pacientes con fibrosis avanzada o cir-rosis compensada; (versión final: 11-1-11). VX-

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AREA 1950HEP3002EudraCT: 2010-023669-23

PRINCIPAL INVESTIGATOR: MARIA TRAPEROMARUGANEstudio de superioridad de fase 4, aleatorizado,abierto, con control activo, para evaluar la eficacia yla seguridad de fumarato de disoproxilo de tenofoviren combinación con interferón pegilado alfa-2a(Pegasys®) frente al tratamiento estándar confumarato de disoproxilo detenofovir en monoterapiao interferon pegilado alfa-2a en monoterapiadurante 48 semanas en pacientes no cirróticos conHepatitis B Crónica (HBc) HBeAg-positivo oHBeAg-negativo; (versión 01:12-1-11). GS-US-174-0149EudraCT: 2010-024586-45

PRINCIPAL INVESTIGATOR: MARIA TRAPEROMARUGANEnsayo clínico de simplificación con tenofovir enpacientes con Hepatitis Crónica B resisitentes alamivudina y carga viral indetectables en tratamientocon lamivudina mas adefovir dipivoxil (EstudioTenosimp-B); (versión 1: 1-03-11). MRG-TEN-2011-01EudraCT: 2011-000629-55

PRINCIPAL INVESTIGATOR: LUISA-CONSUELOGARCIA BUEYEstudio observacional, postautorización, prospectivopara desarrollar y validar una herramienta pronósticaque permita optimizar las terapias enpacientes conhepatitis crónica C genotipo 1y 4; (version 1: 06-09-10). Estudio OPTIM. FPS-PEG-2010-01

PRINCIPAL INVESTIGATOR: MARIA TRAPEROMARUGANValidación de un cuestionario de adherencia altratamiento en pacientes en infección por virus de laHepatitis B; (Version 9: 14/03/2010). IMI-VHB-2010-01 (HABIT-01)

PRINCIPAL INVESTIGATOR: LUISA-CONSUELOGARCIA BUEYEstudio observacional no intervencionista paraanalizar el perfil clínico de los pacientes con Hepatitis

C Crónica, su manejo y seguimiento en los hospitalesde España. ESTUDIO DISHCOVERY (versión 1.0:30-05-11). JAN-HEP-2011-01

GROUP 24

HEAD OF LABORATORYPedro Lorenzo Majano Rodríguez

GROUP MEMBERS• Ignacio Benedicto Español• Virgínia Manuela Gondar de Sousa e Silva• Francisca Molina Jiménez

RESEARCH INTEREST

Hepatotropic viruses, including the Hepatitis C virus (HCV),chronically infect millions of people worldwide. HCV infec-tion can lead to fibrosis, cirrhosis and hepatocellular carci-noma, and is the major reason for liver transplantation.HCV infects mainly hepatocytes, which are highly polarizedcells. Hepatocytes present basolateral and apical poles,separated by tight junctions, in contact with blood and bilerespectively. Cell polarity features play a crucial role in hepa-tocyte metabolism to perform many diverse functions,such as canalicular and sinusoidal secretion. We are inter-ested in understanding how HCV interacts with polarized

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target cells, with particular emphasis on the role of the cel-lular factors implicated in different steps of the viral cycleincluding entry, replication, morphogenesis and egress.

In plasma, HCV particles appear to be associated withlipoproteins. Interestingly, several evidences supportthat a relationship among hepatocyte polarization,lipoprotein metabolism and HCV infection exists. Veryrecently, we have developed a novel use for Matrigel-

embedded cell culture method in which hepatocyte-likepolarity is observed and it also allows the study of theentire HCV cycle. Overall, these studies may providenew insights for our understanding of virus-host interac-tions and the molecular mechanisms underlying hepa-totropic viruses-related pathogenesis of progressiveliver disease.

MAJOR GRANTS

• Pedro Lorenzo Majano Rodríguez. Estudio de lainterrelación entre la polaridad celular y la infecciónpor el virus de la hepatitis C: Posible implicación enel hepatocarcinoma. ISCIII. PI10/00101

• Pedro Lorenzo Majano Rodríguez. Papel en el hepa-tocarcinoma de la alteración en las uniones intercelu-lares provocadas por la infección por el virus hepati-tis c. Fundación Mutua Madrileña. VIII Convocatoriade Becas y Ayudas a la Investigación Médica de laFundación Mutua Madrileña


Benedicto I, Molina-Jiménez F, Moreno-Otero R,López-Cabrera M, Majano PL. Interplay among cellularpolarization, lipoprotein metabolism and hepatitis Cvirus entry. World J Gastroenterol 17(22): 2683-2690.2011. PMID: 21734774. IF: 2,24

Loureiro J, Aguilera A, Selgas R, Sandoval P, Albar-Vizcaíno P, Pérez-Lozano ML, Ruiz-Carpio V, MajanoPL, Lamas S, Rodríguez-Pascual F, Borras-Cuesta F,Dotor J, López-Cabrera M. Blocking TGF-B1 protectsthe peritoneal membrane from dialysate-induced dam-age. J Am Soc Nephrol 22(9): 1682-1695. 2011. PMID:21742730. IF: 8,288

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Human hepatocyte-derived cells (Huh7 cells) infected with theHCV. Huh7 cells were infected with the HCV (JFH1 isolate) andprocessed for double-label immunofluorescence. HCVcore pro-tein (green); Tubulin (red); nuclei were stained with DAPI (blue).

Human hepatocyte-derived cells (Huh7 cells) infected with theHCV. Huh7 cells were infected with the HCV (JFH1 isolate) andprocessed for double-label immunofluorescence. HCVcore pro-tein (green); Tubulin (red); nuclei were stained with DAPI (blue).

AREA 1Line 1.9Mechanisms and mediators of endocrine diseases

GROUP 25

HEAD OF LABORATORYMónica Marazuela Azpiroz

GROUP MEMBERS• Susanna Leskelä• Manuel Luque Ramírez• Ana Rodríguez Muñoz

RESEARCH INTEREST

Our current and future work involves different researchfields in endocrine diseases. First, we are studying therole of (tolerogenic) dendritic cells (DCs) in patients withautoimmune thyroid diseases (AITD) including primarilyHashimoto’s thyroiditis (HT) and Graves’ disease (GD).Our purpose is to assess the possible mechanismsrelated to the tolerogenic role of DCs including theexpression and function of the inhibitory and action ofthe main cytokines involved, and to test their tolero-genic potential and effect on Treg and Th17 function

Another area of investigation is the process of angio-genesis in neuroendocrine gastroentero-pancreatictumors (TNE-GP) and their relation to the somatostatinreceptors. We are studying the role of angiopoietins-1and -2 and their receptor Tie-2 in the tumor cells, aswell as the expression of somatostatin receptors. Inaddition, we are currently studying their relation withclinical and pathological factors.

Furthermore, we are studying the role of key moleculesin GH secreting tumors, especially those related to theresponse to treatment with the GH antagonist pegviso-mant. We are aiming to characterize thoroughly mole-cules related to better clinical response as well as thoseassociated with disease progress. These studies willinclude techniques of molecular biology, including theircharacterization through qRT-PCR, genotyping andsequencing with association studies with the clinicaldata available.

Dr. M. Luque-Ramirez has been studying the role ofdifferent inflammatory markers in hyperandrogenicdisorders in women, in particular in polycystic ovarysyndrome.

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Right panel. Serial coronal images from MRI scans with gadoli-nium contrast from one patient with tumor growth after pegvi-somant therapy. The images show the greatest tumor sizes andare arranged chronologically before and 6 months after the-rapy. Left panel. In this patient the somatotroph adenoma (leftpanel) showed a characteristic solid pattern of growth (hema-toxylin-eosin, original magnification X400). Somatotroph cellhyperplasia (right panel) with expansion of acini but an intact re-ticulin pattern and strong positivity for GH was also found in theadjacent tissue (immunostain for GH, original magnificationX400).

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MAJOR GRANTS

• Manuel Luque Ramírez. CIBER de diabetes y enfer-medades metabólicas asociadas (CIBERdem). ISCI-II. CB07/0008/0005

• Manuel Luque Ramírez. Influencia de los andrógenosen el desarrollo de la adiposidad abdominal y de ladisfunción metabólica del tejido adiposo visceral enhumanos, como factores etiopatogénicos de laresistencia insulínica y la diabetes. ISCIII. PI080944

• Mónica Marazuela Azpíroz. Estudio del potencialtolerogénico de células dendríticas y su interacción concélulas T reguladoras y linfocitos Th17 en pacientes conenfermedad tiroidea autoinmune. ISCIII. PI 10-2521


Doníz-Padilla L, Paniagua AE, Sandoval-Correa P,Monsiváis-Urenda A, Leskela S, Marazuela M, González-Amaro R. Analysis of expression and function of theinhibitory receptor ILT2 in lymphocytes from patients withautoimmune thyroid disease. Eur J Endocrinol 165(1):129-136. 2011. PMID: 21551166. IF: 3,482

Paniagua AE, Bernabeu I, Leskela S, Marazuela M.Lanreotide Autogel-induced tumour shrinkage in thy-rotrophin-secreting pituitary macroadenomas. ClinEndocrinol 74 (3): 406-408. 2011. PMID: 21091752.IF: 3,323Fernandez-Rodriguez E, Quinteiro C, Barreiro J,Marazuela M, Pereiro I, Peinó R, Cabezas-Agrícola JM,Dominguez F, Casanueva FF, Bernabeu I. Pituitary stalkdysgenesis-induced hypopituitarism in adult patients:prevalence, evolution of hormone dysfunction andgenetic analysis. Neuroendocrinology 93(3): 181-188.2011. PMID: 21304225. IF: 3,272

Marazuela M, Paniagua AE, Gahete MD, Lucas T,Alvarez-Escolá C, Manzanares R, Cameselle-Teijeiro J,Luque-Ramirez M, Luque RM, Fernandez-Rodriguez E,Castaño JP, Bernabeu I. Somatotroph tumor progres-sion during pegvisomant therapy: a clinical and molec-ular study. J Clin Endocrinol Metab 96 (2): 251-259.2011. PMID: 21068147. IF: 6,495

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: MONICA MARAZUELAAZPIROZEstudio fase III, multicéntrico, aleatorizado, de gruposparalelos para evaluar la eficacia y la seguridad depasireotida LAR 40 mg y de pasireo-tida LAR 60 mgdoble ciego frente a octreotida LAR o lanreotida ATGabierto, en pacientes con acromegalia insifuciente-mente controlada; (Version: 04/03/2010).CSOM230C2402EudraCT: 2009-016722-13

PRINCIPAL INVESTIGATOR: MONICA MARAZUELAAZPIROZEstudio mundial sobre el control y las complicacionesdel hipopituitarismo (HypoCCS) (versión 3-6-03, hojade información 4-7-03). B9R-MC-GDGGA

PRINCIPAL INVESTIGATOR: MONICA MARAZUELAAZPIROZAcrostudy: Estudio multicéntrico de vigilancia post-comercilaización del tratamiento con somavert® enpacientes con acromegalia en los EEUU y Europa; (ver-sión: 18-04-05). A6291010

PRINCIPAL INVESTIGATOR: MONICA MARAZUELAAZPIROZEstudio multicéntrico y retrospectivo sobre el uso com-binado de lanreótida con agonistas dopaminérgicosy/o antagonistas del receptor de la GH en el tratamien-to de la acromegalia en la práctica clínica; (versión5:30-09-11). ACROCOMB

PRINCIPAL INVESTIGATOR: MANUEL LUQUERAMIREZEvaluación del riesgo cardiovascular según la tablaUKPDS en pacientes diabéticos fumadores compara-dos con ex fumadores; (versión 7-09-11).NRA3050026

PRINCIPAL INVESTIGATOR: MANUEL LUQUERAMIREZProyecto de investigación sobre la restricción óptimade yodo en la preparación previa a la administración dedosis ablativa deI 131 tras estimulacion con tirotropina

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AREA 1humana recombinante alfa, (TSHrh) frente ahipotiroidismo tras suspensión del tratamiento con lev-otiroxina en pacientes con cáncer diferenciado detiroides. ENDYODO12EudraCT: NA

PRINCIPAL INVESTIGATOR: MONICA MARAZUELAAZPIROZValidación de un cuestionario de calidad de vida rela-cionado con la salud en pacientes con hiperparatiroidis-mo primario (PHPQoL); (versión 4.2:22-09-11). PHPQOL

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Line 1.10Children´s development (obesity and growth)

GROUP 26HEAD OF LABORATORYJesús Argente Oliver

GROUP MEMBERS• Pilar Argente Arizón• Eva Baquedano Caballero• Vicente Barrios Sabador• Emma Burgos Ramos• Sandra Canelles Ortiz• David Castro González• Julie Ann Chowen King• Esther de la Fuente Martín• Francisca Díaz González• Laura María Frago Fernández• Cristina García Cáceres• Miriam Granado García• Gabriel Ángel Martos Moreno• María Teresa Muñoz Calvo• Jesús Pozo Román• Oscar Rubio Cabezas• Silvia Tapia González

RESEARCH INTEREST

How being obese during childhood affects growth andpubertal development and its long-term effects arebeing studied with both clinical and basic approaches.Genetic studies are performed to identify new muta-tions in genes known to be involved in monogenic obe-

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Effect of chronic central leptin exposure on glial proteins andactivation in the hypothalamus. Relative levels of GFAP (A), vi-mentin (B), and actin (C) in the hypothalamus of adult maleWistar rats treated icv for 14 d with either leptin (Lep; 15 µg/d)or vehicle (Ct; n = 6/group). Representative Western blots areshown for each protein. #, P <0.05; *, P< 0.01. Results are re-presented as mean± SEM. Immunohistochemistry for vimentinin the arcuate nucleus of control (D and F) and leptin-treatedrats (E and G) are shown. Quantitative analysis demonstrated asignificant increase (***, P <0.0001) in the number of vimentinfibers, most likely tanycytes, in the arcuate nucleus of leptin-treated rats (H). Vimentin-labeled astrocytes are clearly visiblein leptin-treated rats (arrows). Scale bar, 40 µm (D and E); 20µm (F and G). García-Cáceres et al. Endocrinology 2011.

sity, to identify possible new candidate genes and toanalyze polygenic and epigenetic causes of obesity. Todate we have identified at least 10 possible new candi-date genes that are being further investigated, as wellas the interaction genotype/phenotype and ethnic influ-ences.

Animal models are employed to analyze how poormaternal and/or neonatal nutrition, maternal stress orchanges in specific hormones during neonatal life affectadult metabolism. We have recently reported thatmaternal stress reduces cell turnover in the adult brainand this is associated with modifications in metabolism,as well as other functions and early hormon-al/nutritional changes affect hypothalamic architecture. Obesity is associated with insulin and leptin resistanceand studies analyzing the effect of chronic increasedcentral leptin levels on insulin signaling in the CNS andadipose tissue have established a relationship betweeninsulin signaling, inflammation and changes in energyhomeostasis. Moreover, hypothalamic glial cells arecurrently underinvestigation for their important role inobesity as they control neuronal function, synaptictransmission and reorganization and inflammatoryprocesses. We have recently reported that metabolichormones such as leptin have direct effects onmicroglia, as well as astrocytes and tanycytes (Fig. 1),indicating that these cells most likely participate in themetabolic response to this hormone.

MAJOR GRANTS

• Jesús Argente Oliver. Efectos de la malnutrición pre-natal y perinatal sobre la respuesta central y periféri-ca a la leptina e insulina en la etapa adulta.Fundación Mutua Madrileña. AP2561/2008

• Jesús Argente Oliver. Fisiopatología de la Obesidad.ISCIII. CIBER: CB06/03/0022

• Laura María Frago Fernández. Alteraciones cau-sadas por el estrés prenatal: papel de la ghrelina y laleptina. Ministerio de Ciencia e Innovación.BFU2008-02950-C03-03

• Vicente Barrios Sabador. Red de centros deGenética clínica y molecular. Integración de la inves-

tigación clínica, molecular y epidemiológica enGenética humana. ISCIII. C03/07

• Jesús Argente Oliver. Obesidad infantil grave decomienzo precoz: fundamentos metabólicos, genéti-cos y proteomicos. ISCIII. PI10/00747


Yi CX, Habegger KM, Chowen JA, Stern J, Tschöp MH.A role for astrocytes in the central control of metabo-lism. Neuroendocrinology. 93(3): 143-149. 2011.PMID: 21372559. IF: 3,272

Tapia-González S, García-Segura LM, Tena-SempereM, Frago LM, Castellano JM, Fuente-Martín E, García-Cáceres C, Argente J, Chowen JA. Activation ofmicroglia in specific hypothalamic nuclei and the cere-bellum of adult rats exposed to neonatal overnutrition.J Neuroendocrinol. 23(4): 365-370. 2011. PMID:21314736. IF: 4,65

Menoyo D, Serrano MP, Barrios V, Valencia DG, LázaroR, Argente J, Mateos GG. Cereal type and heat pro-cessing of the cereal affect nutrient digestibility anddynamics of serum insulin and ghrelin in weanling pigs.J Anim Sci. 89(9): 2793-2800. 2011. PMID: 21478449.IF: 2,58

Burgos-Ramos E, Chowen JA, Arilla-Ferreiro E,Canelles S, Argente J, Barrios V. Chronic central leptininfusion modifies the response to acute central insulininjection by reducing the interaction of the insulinreceptor with IRS2 and increasing its association withSOCS3. J Neurochem 117 (1): 175-185. 2011. PMID:21255014. IF: 4,337

Benito-Sanz S, Barroso E, Heine-Suñer D, Hisado-Oliva A, Romanelli V, Rosell J, Aragones A, Caimari M,Argente J, Ross JL, Zinn AR, Gracia R, Lapunzina P,Campos-Barros A, Heath KE. Clinical and molecularevaluation of SHOX/PAR1 duplications in Leri-Weilldyschondrosteosis (LWD) and idiopathic short stature(ISS). J Clin Endocrinol Metab 96 (2): E404-E412.2011. PMID: 21147883. IF: 6,495

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García-Cáceres C, Fuente-Martín E, Burgos-RamosE, Granado M, Frago LM, Barrios V, Horvath T,Argente J, Chowen JA. Differential acute and chroniceffects of leptin on hypothalamic astrocyte morpholo-gy and synaptic protein levels. Endocrinology 152(5):1809-1818. 2011. PMID: 21343257. IF: 4,993

Barca-Tierno V, Aza-Carmona M, Barroso E, Heine-Suner D, Azmanov D, Rosell J, Ezquieta B, Montané LS,Vendrell T, Cruz J, Santos F, Rodríguez JI, Pozo J,Argente J, Kalaydjieva L, Gracía R, Campos-Barros A,Benito-Sanz S, Heath KE. Identification of a GypsySHOX mutation (p.A170P) in Léri-Weill dyschondrosteo-sis and Langer mesomelic dysplasia. Eur J Hum Genet.19(12): 1218-1225. 2011. PMID: 21712857. IF: 4,38

Granado M, García-Cáceres C, Tuda M, Frago LM,Chowen JA, Argente J. Insulin and growth hormone-releasing peptide-6 (GHRP-6) have differential benefi-cial effects on cell turnover in the pituitary, hypothala-mus and cerebellum of streptozotocin (STZ)-induceddiabetic rats. Mol Cell Endocrinol. 337(1-2): 101-113.2011. PMID: 21352888. IF: 4,119

Baquedano E, García-Cáceres C, Diz-Chaves Y,Lagunas N, Calmarza-Font I, Azcoitia I, Garcia-Segura LM, Argente J, Chowen JA, Frago LM.Prenatal stress induces long-term effects in cellturnover in the hippocampus-hypothalamus-pituitaryaxis in adult male rats. PLoS One 6(11): e27549.2011. PMID: 22096592. IF: 4,411

Aguado-Llera D, Puebla-Jiménez L, Barrios V,Hernández-Pinto A, Arilla-Ferreiro E. Role ofethanolamine phosphate in the hippocampus of ratswith acute experimental autoimmune encephalomye-litis. Neurochem Int. 58(1): 22-34. 2011. PMID:20974204. IF: 3,601

Martos-Moreno GA, Kratzsch J, Körner A, Barrios V,Hawkins F, Kiess W, Argente J. Serum visfatin andvaspin levels in prepubertal children: effect of obesityand weight loss after behavior modifications on theirsecretion and relationship with glucose metabolism.Int J Obes (Lond) 35(10): 1355-62. 2011. PMID:21266955. IF: 5,125

Aza-Carmona M, Shears DJ, Yuste-Checa P, Barca-Tierno V, Hisado-Oliva A, Belinchón A, Benito-Sanz S,Rodríguez JI, Argente J, Campos-Barros A, ScamblerPJ, Heath KE. SHOX interacts with the chondrogenictranscription factors SOX5 and SOX6 to activate theaggrecan enhancer. Hum Mol Genet 20 (8): 1547-1559. 2011. PMID: 21262861. IF: 8,058

Fuente-Martín E, Granado M, García-Cáceres C,Sanchez-Garrido MA, Frago LM, Tena-Sempere M,Argente J, Chowen JA. Early nutritional changesinduce sexually dimorphic long-term effects on bodyweight gain and the response to sucrose intake inadult rats. Metabolism 2011 Dec 28 [Epub ahead ofprint]. 2011. PMID: 22209665. IF: 2,538

Pita J, Rado-Peralta S, Gavela-Pérez T, Aragón I,Barrios V, Rovira A, Argente J, Soriano-Guillén L.Plasma kisspeptin levels are elevated in cord bloodand present sexual dimorphism in the adult popula-tion: Relation with leptin, gonadotropins and anthro-pometrical data. Peptides 32(5): 983-8. 2011. PMID:21295095. IF: 2,654

Pita J, Barrios V, Gavela-Pérez T, Martos-Moreno GÁ,Muñoz-Calvo MT, Pozo J, Rovira A, Argente J,Soriano-Guillén L. Circulating kisspeptin levels exhibitsexual dimorphism in adults, are increased in obeseprepubertal girls and do not suffer modifications ingirls with idiopathic central precocious puberty.Peptides 32(9): 1781-1786. 2011. PMID: 21827808.IF: 2,654

Martos-Moreno GA, Barrios V, Martínez G, Hawkins F,Argente J. Acylated ghrelin levels in prepubertalobese children at diagnosis and after weight reduc-tion; effect of oral glucose ingestion. J EndocrinolInvest 34(2): 117-23. 2011. PMID: 20585204. IF:1,476

López-Siguero JP, López-Canti LF, Espino R, Caro E,Fernández-García JM, Gutiérrez-Macías A, Rial JM,Lechuga JL, Macías F, Martínez-Aedo MJ, Rico S,Rodríguez I, Guillén J, Arroyo FJ, Bernal S, EspigaresR, Núñez M, Escribano A, Barrionuevo JL, Gentil J,Barrios V, Fernández-Nistal A, Martos-Moreno GA,

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Martínez V, Argente J. Effect of recombinant growthhormone on leptin, adiponectin, resistin, IL-6, TNF-alpha and ghrelin levels in growth hormone deficientchildren. J Endocrinol Invest 34(4): 300-6. 2011.PMID: 20634639. IF: 1,476

Argente J, Sotos JF. Overgrowth with and withoutobesity: clinical and molecular principles. An Pediatr(Barc). [Epub ahead of print]. 2011. PMID: 22098786.IF: 0,57

Martos-Moreno GA, Burgos-Ramos E, Canelles S,Argente J, Barrios V. Analysis of insulin and cytokinesduring development using a multiplexed immunoas-say: implications in pediatrics. An Pediatr (Barc).

74(6): 356-362. 2011. PMID: 21349782. IF: 0,57Argente J. Obesity in childhood and adolescence: aheterogeneous disease with new pathophysiologicalbases. An Pediatr (Barc). 75(1): 1-5. 2011. PMID:21693365. IF: 0,57

Martos-Moreno GA, Argente J. Paediatric obesities:from childhood to adolescence. An Pediatr (Barc).75(1): 63.e1-63.e23. 2011. PMID: 21602112. IF: 0,57

Caballero Mora FJ, Muñoz Calvo MT, LópezRobledillo JC, Argente J. Severe polyarthritis as a rareadverse effect associated with methimazole therapyin a patient with Graves' disease. An Pediatr (Barc).75(1): 74-75. 2011. PMID: 21441081. IF: 0,57

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Line 1.11Metabolic syndrome and vascular risk

GROUP 5HEAD OF LABORATORYCarmelo García Monzón

GROUP MEMBERS• Enrique Chávez Jiménez• Faustino Manuel La Banda Brusi• María Eugenia Miquilena Colina• Javier Rodríguez de Cía• Alicia Sáez Sáez• Rodolfo Javier Vargas Castrillón

RESEARCH INTEREST

While there is growing clinical evidence that insulinresistance may contribute to disease progression innon-alcoholic fatty liver disease (NAFLD) and chronichepatitis C (HCV) infection, the extent of impairment ofhepatic insulin signaling, the pathways involved andtheir impact on liver injury and fibrosis in both conditionsremain to be defined. Therefore, we aimed to determinethe extent of impairment of hepatic insulin signaling and

the pathways involved as well as to assess its relation-ship with liver damage parameters such as apoptosisand fibrosis in NAFLD and HCV patients. We have alsoevaluated the effects of lipid accumulation and the HCVper se on insulin signaling in cultured human hepato-cytes. The findings of our work indicate that hepaticinsulin signaling is impaired in non-alcoholic steatohep-atitis (NASH) and HCV patients, and down-regulation ofinsulin-sensitive targets is associated with increasedapoptosis and fibrogenesis in both conditions. In addi-tion, we found evidence, in HCV-transfected humanhepatocytes, that JNK might be a target for HCV-induced insulin resistance (1).

With the current epidemics of metabolic syndrome inWestern countries, there is an urgent need to improveour knowledge on the molecular basis underlying thedevelopment of fatty liver. In that regard, we are cur-rently investigating the hepatic expression profile oflipogenic genes, such as liver X receptor (LXR) α, in dif-ferent patient cohorts. We observed that LXRα and its

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An excess of FAT/CD36 protein is found in the liver of patientswith NAFLD and HCV G1. Upper panels: representative westernblotting showing the specific band of FAT/CD36 in each patientgroup. Lower panels: immunoblots were quantified by densito-metry and normalised against B-actin as a control for proteinloading. Thick horizontal bars crossing vertical ones show themedian fold increase in the amount of hepatic protein in liverbiopsies from distinct patient groups with respect to NL (nor-malised value, 1.0). Vertical bars represent the range of values.^p=0.001 vs NL; *p<0.001 vs NL; #p=0.002 vs HCV G1.FAT/CD36, fatty acid translocase CD36; HCV G1, hepatitis C vi-rus genotype 1; HCV G1 + NAS, hepatitis C virus genotype 1 withnon-alcoholic steatosis; NAS, non-alcoholic steatosis; NASH,non-alcoholic steatohepatitis; NL, normal liver.

related lipogenic and inflammatory genes are over-expressed within the liver of NAFLD patients and inHCV patients with steatosis, suggesting a central roleof LXRα in the pathogenesis of hepatic steatosis andinflammation in these chronic liver diseases (2).

On the other hand, it is well known that free fatty acidsare taken up into cells by passive diffusion and by pro-tein-mediated mechanisms involving a number of fattyacid-transporters, being the fatty acid translocase CD36(FAT/CD36) the best characterised. There is increasingexperimental evidence that FAT/CD36 plays a key role inthe steatosis setup in rodents, but little is known about

the significance of this fatty acid transporter in humanliver diseases. In order to shed light on this issue, wecarried out a study aimed to quantify the expression ofFAT/CD36 as well as to determine its cellular and sub-cellular distribution in the liver of NAFLD and HCVpatients, searching for potential correlations between thehepatic expression level of FAT/CD36 and metabolic andhistologic features of these liver diseases. The results ofour work demonstrate that FAT/CD36 is abnormallyover-expressed within the liver of NAFLD and HCVpatients with steatosis, being its expression predomi-nantly located at the plasma membrane of hepatocytes.Interestingly, we found that hepatic FAT/CD36 expres-sion level is significantly associated with insulin resist-ance, hyperinsulinemia and increased steatosis in NASHand HCV patients with fatty liver, suggesting that translo-cation of this fatty acid transporter to the plasma mem-brane of hepatocytes may contribute to liver fat accumu-lation in NAFLD and HCV patients (3).

MAJOR GRANTS

Carmelo García Monzón. Análisis comparativo de losmediadores moleculares relacionados con el síndromemetabólico en pacientes con enfermedad hepáticagrasa no alcohólica y en pacientes con hepatitis cróni-ca C. ISCIII. PI10/00067


Lima-Cabello E, García-Mediavilla MV, Miquilena-ColinaME, Vargas-Castrillón J, Lozano-Rodríguez T,Fernández-Bermejo M, Olcoz JL, González-Gallego J,García-Monzón C, Sánchez-Campos S. Enhancedexpression of liver X receptor and its lipogenic andinflammatory target genes in nonalcoholic fatty liver dis-ease and chronic hepatitis C. Clinical Science (Lond)120 (6): 239-250. 2011. PMID: 20929443. IF: 4,613

María Eugenia Miquilena-Colina, Elena Lima-Cabello,Sonia Sánchez-Campos, María Victoria García-Mediavilla, Miguel Fernández-Bermejo, Tamara

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AREA 1

Altered subcellular distribution of FAT/CD36 in hepatocytes ofpatients with NAFLD and HCV G1. (A) In NL, FAT/CD36 is weaklyexpressed in the cytoplasm of some hepatocytes (red arrows).In contrast, FAT/CD36 staining is predominantly detected at theplasma membrane of numerous hepatocytes (red arrowheads)in (B) patients with NAS an (C) patients with NASH. In (D) pa-tients with HCV G1 without steatosis, FAT/CD36 expression wasmainly observed in the cytoplasm of hepatocytes (red arrows)whereas FAT/CD36 staining was largely detected at the plasmamembrane of hepatocytes (red arrowheads) in (E) patients withHCV G1 with steatosis. Noteworthy, FAT/CD36 expression wassimilarly observed on the plasma membrane of both steatoticand non-steatotic hepatocytes. (F) Negative controls showedthat immunostaining was minimal or absent when liver biopsysections were incubated with rabbit immunoglobulins. This pa-nel shows an example of NC in a liver biopsy with NAS. Originalmagnification for all microphotographs 400x. HCV G1, hepatitis C virus genotype 1; HCV G1 + NAS, hepatitis Cvirus genotype 1 with non-alcoholic steatosis; NAS, non-alco-holic steatosis; NAS, non-alcoholic steatohepatitis; NC, negati-ve control; NL, normal liver.

AREA

1

Lozano-Rodríguez, Javier Vargas-Castrillón, XabierBuqué, Begoña Ochoa, Patricia Aspichueta, JavierGonzález-Gallego, and Carmelo García-Monzón.Hepatic fatty acid translocase CD36 upregulation isassociated with insulin resistance, hyperinsulinemiaand increased steatosis in nonalcoholic steatohepatitisand chronic hepatitis C. Gut 60(10): 1394-1402. 2011.PMID: 21270117. IF: 10,614

García-Monzón C, Lo Iacono O, Mayoral R, González-Rodríguez A, Miquilena-Colina ME, Lozano-RodríguezT, García-Pozo L, Vargas-Castrillón J, Casado M,Boscá L, Valverde AM, Martín-Sanz P. Hepatic insulinresistance is associated with increased apoptosis andfibrogenesis in nonalcoholic steatohepatitis and chron-ic hepatitis C. Journal of Hepatology 1 (54): 142-152.2011. PMID: 20888662. IF: 9,334

GROUP 27

HEAD OF LABORATORYRaffaele Carraro

GROUP MEMBERS• Andrea Azcárate Villalón• Elena Cercas Alonso• Lourdes Martínez-Piñeiro Muñoz• Erika Palacios Rosas• María Concepción Peiró Vallejo• Tania del Mar Romacho Romero• Carlos Félix Sánchez Ferrer• Isabelle Sharmiashvili• Iñigo Tejado Elviro• Marta Vázquez Bella• Laura Alicia Villalobos Rodríguez

RESEARCH INTEREST

In 2011 valuable results have been gathered in themain lines of investigation of our group. In the basic

area, new data on the molecular mechanismsthrough which the adipokine visfatin directly affectsvascular tone have been collected, since the obser-vation that in type 2 diabetes mellitus and chronickidney disease, a positive correlation between plas-ma visfatin levels and those of several markers ofendothelial injury and systemic inflammation wasfound.

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Visfatin impairs the vasodilation induced by ACh in rat mesen-teric microvessels. (A) After pre-incubation with visfatin (10 to 100 ng/mL), the mi-crovessels were contracted with 1 mmol/L NA and then expo-sed to cumulative concentrations of the endothelium-depen-dent vasodilator ACh (100 pmol/L to 3 mmol/L). Results are ex-pressed as mean 6 SEM of 35 segments obtained from 5 ani-mals. *P,0.05 vs control curve. (B) Correlation between the con-centrations of visfatin used for pre-incubation and the pD2 va-lues for ACh. (C) The microvessels were pre-incubated with vis-fatin (100 ng/mL), the endothelial oxide synthase inhibitor L-NAME (100 mmol/L), the cyclooxygenase inhibitor indometha-cin (Indo; 10 mmol/L) or different combinations of these com-pounds, and then contracted with 1 mmol/L NA and exposed tocumulative concentrations of Ach (100 pmol/L to 3 mmol/L).Results are expressed as mean 6 SEM of 56 segments obtainedfrom 12 animals. *P,0.05 vs control curve. (D) After preincuba-tion or not with visfatin (50 ng/mL) and contraction with 1mmol/L NA, the microvessels were exposed to the endothe-lium-independent vasorelaxant sodium nitroprusside (SNP; 1nmol/L to 3 mmol/L). Results are expressed as mean 6 SEM of19 segments obtained from 4 animals. doi: 10.1371/jour-nal.pone.0027299.g002

To this aim, we explored the influence of visfatin onboth contractile and vasorelaxant microvascularresponses in mesenteric arteries from both rat andhuman origin, with special attention to the role playedby two enzymes, namely nicotinamide adenine dinu-cleotide phosphate (NADPH) oxidase, closely associ-ated to endothelial dysfunction, and Nampt. Theresults of our experiments (1), indicated that Visfatin(10 to 100 ng/mL) concentration-dependentlyimpaired the relaxation to acetylcholine (ACh; 100pmol/L to 3 mmol/L, Fig. 1), without interfering withthe endothelium-independent relaxation to sodiumnitroprusside, suggesting that visfatin affectsendothelium-dependent relaxation through a mecha-nism involving NADPH oxidase stimulation and relyingon Nampt enzymatic activity, and arising as a poten-tial new player in the development of endothelial dys-function.

In the clinical ground, we have described an earlyweight-independent reduction of hyperleptinemia inmorbidly obese patients with or without type 2 dia-betes mellitus after bariatric surgery, that can play arole in the early metabolic improvement associated tothis surgery (2).

Moreover, as a part of an international clinical trial onsafety and efficacy of liraglutide in the treatment ofobesity, very promising 2-year results have been pub-lished (3).

1) Vallejo S, Romacho T, Angulo J, Villalobos LA, Cercas E, et al.

(2011) Visfatin Impairs Endothelium-Dependent Relaxation in Rat

and Human Mesenteric Microvessels through Nicotinamide

Phosphoribosyltransferase Activity. PLoS ONE 6(11): e27299.

doi:10.1371/journal.pone.0027299

2) Tejado Elviro I, Bermejo E, Romacho T, Cercas E, Vallejo S, Peiró

C, Sanchez Ferrer C, Gomez-Pan A, Carraro R. “Regulación aguda

de la leptinemia tras cirugía bariátrica”. 53 Congreso Nacional

SEEN. Santiago de Compostela 18-20 Mayo 2011

3) Astrup A, Carraro R, Finer N, Harper A, Kunesova M, Lean MEJ,

Niskanen L, Rasmussen MF, Rissanen A, Rössner S, Savolainen MJ,

Van Gaal L on behalf of the NN8022-1807 Investigators. Safety,

Tolerability and Sustained Weight Loss over 2 Years with the Once-daily

Human GLP-1 Analogue, Liraglutide Int. J Obes Relat Dis 2011 online

pub, 16 August 2011; doi:10.1038/ijo.2011.158. PMID: 21844879

MAJOR GRANTS

• Carlos Félix Sánchez Ferrer. Mecanismos de dañovascular en la Diabetes Mellitus. Interacción entreinflamación e hiperglucemia. Plan Nacional deI+D+I. SAF2008-00942

• Carlos Félix Sánchez Ferrer. The role of Nrf2 in dia-betic vasculopathy, oxidative stress and inflamma-tion. Marie Curie International ReintegrationGrants. European Commission 7th FrameworkProgramme.

• María Concepción Peiró Vallejo. Adipoquinas:¿Nexo común entre obesidad, resistencia a insuli-na e inflamación vascular? Papel de visfatina,resistina y apelina. Ministerio de Ciencia eInnovación - Plan Nacional de I+D+I. SAF2008-01291

• María Concepción Peiró Vallejo. Disfunciónendotelial inducida por la inhibición genética o far-macológica del receptor Mas. MICINN - Plan I+D -Acción integrada hispano-alemana (HD2008-0056). HD2008-0056


Vangipurapu J, Stancáková A, Kuulasmaa T,Paananen J, Kuusisto J; EGIR-RISC Study Group(..., Carraro R, Friera A, Novella B, ...), Ferrannini E,Laakso M. A novel surrogate index for hepatic insulinresistance. Diabetologia 54 (3): 540-543. 2011.PMID: 21107521. IF: 6,973

Rebelos E, Muscelli E, Natali A, Balkau B, MingroneG, Piatti P, Konrad T, Mari A, Ferrannini E; RISCStudy Investigators. R. Carraro, A. Friera, B. Novellapor el GROUP RISC study. Body weight, not insulinsensitivity or secretion, may predict spontaneousweight changes in nondiabetic and prediabetic sub-jects: the RISC study. Diabetes 60(7): 1938-1945.2011. PMID: 21617179. IF: 8,889

Angulo J, Peiró C, Romacho T, Fernández A, CuevasB, González-Corrochano R, Giménez-Gallego G, deTejada IS, Sánchez-Ferrer CF, Cuevas P. Inhibition of

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AREA 1

AREA

1

vascular endothelial growth factor (VEGF)-inducedendothelial proliferation, arterial relaxation, vascularpermeability and angiogenesis by dobesilate. Eur JPharmacol 667(1-3): 153-9. 2011. PMID: 21703259.IF: 2,737

Bonnet F, Ducluzeau PH, Gastaldelli A, Laville M,Anderwald CH, Konrad T, Mari A, Balkau B. R.Carraro, A. Friera, B. Novella por el GROUP RISCstudy. Liver enzymes are associated with hepaticinsulin resistance, insulin secretion, and glucagonconcentration in healthy men and women. Diabetes60(6): 1660-1667. 2011. PMID: 21521874. IF: 8,889

Ferrannini E, Natali A, Muscelli E, Nilsson PM, GolayA, Laakso M, Beck-Nielsen H, Mari A; RISCInvestigators. R. Carraro, A. Friera, B. Novella por elGROUP RISC study. Natural history and physiologi-cal determinants of changes in glucose tolerance ina non-diabetic population: the RISC Study.Diabetologia 54(6): 1507-1516. 2011. PMID:21424899. IF: 6,973

Sánchez-Rodríguez C, Peiró C, Vallejo S, MatesanzN, El-Assar M, Azcutia V, Romacho T, Sánchez-Ferrer CF, Rodríguez-Mañas L, Nevado J. Pathwaysresponsible for apoptosis resulting from amadori-induced oxidative and nitrosative stress in humanmesothelial cells. Am J Nephrol. 34(2): 104-14.2011. PMID: 21701161. IF: 2,658

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, toler-ability and sustained weight loss over 2 years withthe once-daily human GLP-1 analog, liraglutide. Int JObes (Lond). [Epub ahead of print]. 2011. PMID:21844879. IF: 5,125

Vallejo S, Romacho T, Angulo J, Villalobos LA,Cercas E, Leivas A, Bermejo E, Carraro R, Sánchez-Ferrer CF, Peiró C. Visfatin impairs endothelium-dependent relaxation in rat and human mesentericmicrovessels through nicotinamide phosphoribosyl-transferase activity. PLoS One 6(11): e27299. 2011.PMID: 22073309. IF: 4,411

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: RAFFAELE CARRARO Ensayo clínico de eficacia y no inferioridad, cruzado,aleatorizado y multicéntrico entre dos formulacionestópicas de capsaicina para el alivio del dolor moderadoa severo en la neuropatía diabética dolorosa; (Versiónfinal 1.1: 14-07-10). ITHUEC-CAP/10-5EudraCT: 2010-021977-35

PRINCIPAL INVESTIGATOR: RAFFAELE CARRARO Estudio fase III, de 24 semanas de duración y 28 sem-anas de seguimiento, multicéntrico, aleatorizado, dobleciego, controlado con placebo, para evaluar la seguri-dad y la eficacia de dapagliflozina de 10mg una vez aldía en pacientes con diabetes tipo 2 con un controlglucémico inadeacuado sobre un tratamiento de basecombinado de metformina y sulfonilurea; (versión 1ES:5-7-11). D1693C00005EudraCT: 2011-002231-26

PRINCIPAL INVESTIGATOR: RAFFAELE CARRARO Efecto de liraglutida sobre el peso corporal en sujetosobesos sin diabetes. Ensayo de 20 semanas deduración, aleatorizado, doble ciego, controlado conplacebo, en seis grupos paralelos, multicéntrico, multi-nacional con una rama abierta de comparación conorlistat; (versión 2: 10-08-06). NN8022-1807EudraCT: 2006-004481-13

PRINCIPAL INVESTIGATOR: RAFFAELE CARRARO Efecto de liraglutida en el peso corporal en sujetos nodiabéticos obesos o con sobrepeso y comorbilidad.Ensayo clínico aleatorizado, doble-ciego, controladocon placebo, grupos paralelos, multicéntrico, multina-cional, con estratificación de sujetos a 56 ó 160 sem-anas de tratamiento basada en el estatus pre-diabéti-co en la aleatorización. NN8022-1839EudraCT: 2008-001049-24

PRINCIPAL INVESTIGATOR: ISABELLE SHARMI-ASHVILI Estudio observacional retrospectivo en pacientessometidas a linfadenectomía axilar en las que se utilizaTachosil para mejorar la hemostasia y el sellado de losvasos linfáticos

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AREA

2

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.

NEUROTRANSMISSION, PHARMACOLOGICALNEUROPROTECTION AND NEURODEGENERATIVEAND NEUROPSYCHIATRIC DISEASES

AREA 2

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NEUROTRANSMISSION, PHARMACOLOGICAL NEUROPROTECTION

AND NEURODEGENERATIVE AND NEUROPSYCHIATRIC DISEASES

Line 2.1Neuropharmacology and neuroprotection

GROUP 28

HEAD OF LABORATORYAntonio García García

GROUP MEMBERS• Elba Alonso Álvarez• Lorena Cortés Gil• Cristóbal de los Ríos Salgado• Laura del Barrio Díaz• Francisco Javier Egea Máiquez• José Carlos Fernández Morales• Antonio Miguel García de Diego• Marcos Maroto Pérez• María Dolores Martín de Saavedra Álvarez-Uribarri• Santos Morais Nicolau• Esther Parada Pérez• Manuel Alejandro Romero Martínez• Patricia Velasco Jurado

• Mercedes Villarroya Sánchez• Matilde Yáñez Jato

RESEARCH INTEREST

During 2011 we were working on basic ionic andreceptor mechanisms involved in the regulation of exo-cytotic neurotransmitter release. We were particularlyinterested in developing the hypothesis that the func-tional triad formed by voltage-dependent calcium

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NEUROTRANSMISSION, PHARMACOLOGICALNEUROPROTECTION AND NEURODEGENERATIVEAND NEUROPSYCHIATRIC DISEASES

AREA 2

Inhibition by ITH/IQM of the quantal catecholamine release ampero-metrically measured with a carbon fibre microelectrode. A, originaltraces obtained from an example cell challenged with three sequential10-s pulses (P1, P2, P3) given with a Krebs-Hepes solution containing75 mM K+ (isoosmotic reduction of Na+) and 2 mM Ca2+. ITH/IQM (10μM) was present since 5 min before and during P2 (bottom short hori-zontal bar). B, pooled results of 11 cells subjected to the protocolshown in A. Cumulative secretion was calculated in each cell by inte-grating the areas of all spikes obtained in each K+ pulse (Qamp , leftordinate). Number of spikes per each K+ pulse are expressed in theright ordinate. Data are means ± S.E. of 11 cells from 2 different cultu-res. *P<0.05 with respect to P1; ### P<0.001 with respect to P1.

AREA

2

channels, the endoplasmic reticulum, and mitochon-dria shape the cytosolic calcium signals required toregulate pre-exocytotic and exocytotic steps.

We were also working on design, synthesis and phar-macology of neuroprotective compounds with potentialtherapeutic application in neurodegenerative diseasesand stroke. We work on neurotoxicity mechanismslooking for targets to develop new chemical entitieswith potential neuroprotective actions and therapeuticapplications to Alzheimer’s disease and to cerebrovas-cular diseases.

MAJOR GRANTS

• Antonio García García. Modulación farmacológicadel intercambiador sodio-calcio mitocondrial: unanueva estrategia para tratar la enfermedad deAlzheimer. Proyecto Fundación CIEN Instituto deSalud Carlos III. PI 016/09

• Antonio García García. Señales de calcio y exocitosisde neurotransmisores. Ministerio de Educación yCiencia. SAF2006-03589

• Antonio García García. Neurotoxicidad del líquidocefalorraquídeo de pacientes con esclerosis lateralamiotrófica (ELA): una nueva estrategia para labúsqueda de fármacos neuroprotectores. AgenciaLaín Entralgo-Consejería de Sanidad. NDG09/8

• Cristóbal de los Ríos Salgado. The CALHM1 channeland its Alzheimer's disease-linked mutated formP86L-CALHM1. A new biological target for the find-ing of neuroprotective drugs. MICINN. CP10/00531

• Antonio García García. Tríada funcional y especial-ización de los subtipos de canales de calcio paracontrolar la exocitosis en la célula cromafín. MICINN.SAF2010-21795


del Barrio L, Egea J, León R, Romero A, Ruiz A,Montero M, Alvarez J, López MG. Calcium signallingmediated through a7 and non-a7 nAChR stimulation is

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Neurotransmission, pharmacological neuroprotection andneurodegenerative and neuropsychiatric diseases

Protection by CGP37157 (CGP) against the cytotoxic effects of veratri-dine (Ver). A, cells were incubated for 24 h with increasing concentra-tions of CGP. Basal, no drug added. B, cells were incubated first withCGP for 30 min followed by an incubation of 23.5 h with combined CGP(at the concentrations shown in the abscissa) and Ver (at 30 M in allcases). C, cells were incubated first for 30 min (at the concentrationsshown in the abscissa) followed by an incubation of 23.5 h with com-bined CGP and Ver. In A and B, cell death was monitored by measuringin each individual plaque, the LDH present in the medium and in thecells at the end of the 24-h incubation period; these two parameterswere added and named 100%, or total LDH. The released LDH (ordina-tes) elicited by each treatment was expressed as percentage of totalLDH. In C, cell viability was measured with use of the mitochondrialprobe MTT Data are means ± S.E. of the number of triplicate experi-ments shown in parentheses; each experiment was made in a diffe-rent cell culture. ***, p<0.001, with respect to basal (A); ###, p<0.001,with respect to basal (B and C); **, p<0.01, ***, p< 0.001, with respectto Ver alone (B and C).

AREA 2differentially regulated in bovine chromaffin cells toinduce catecholamine release. Br J Pharmacol. 162(1):94-110. 2011. PMID: 20840468. IF: 4,925

Samadi, A., Valderas, C., De Los Ríos, C., Bastida, A.,Chioua, M., González-Lafuente, L., Colmena. I.,Gandía, L., Romero, A., Del Barrio, L., Martín-De-Saavedra. M.D., López, M.G., Villarroya, M. AndMarco-Contelles, J.L. Cholinergic and NeuroprotectiveDrugs for the Treatment of Alzheimer and NeuronalVascular Diseases. II. Synthesis, BiologicalAssessment, and Molecular Modelling of New TacrineAnalogues from Highly Substituted 2-Aminopyridine-3-carbonitriles. Bioorg. Med. Chem. 19 (1): 122-133.2011. PMID: 21163662. IF: 2,978

Martín-de-Saavedra MD, del Barrio L, Cañas N, EgeaJ, Lorrio S, Montell E, Vergés J, García AG, López MG.Chondroitin sulfate reduces cell death of rat hippocam-pal slices subjected to oxygen and glucose deprivationby inhibiting p38, NF kappa B and iNOS. NeurochemInt. 58(6): 676-683. 2011. PMID: 21335047. IF: 3,601

Pereira JD, Caricati-Neto A, Miranda-Ferreira R, SmailiSS, Godinho RO, de los Rios C, Léon R, Villaroya M,Samadi A, Marco-Contelles J, Jurkiewicz NH, GarciaAG, Jurkiewicz A. Effects of novel tacripyrinesITH12117 and ITH12118 on rat vas deferens contrac-tions, calcium transients and cholinesterase activity.Eur J Pharmacol. 660(2-3): 411-419. 2011. PMID:21497158. IF: 2,737

Hernández A, Segura-Chama P, Jiménez N, GarcíaAG, Hernández-Guijo JM, Hernández-Cruz A.Modulation by endogenously released ATP and opioidsof chromaffin cell calcium channels in mouse adrenalslices. Am J Physiol Cell Physiol. 300(3): 610-623.2011. PMID: 21160033. IF: 3,817

Maroto M, de Diego AMG, Albiñana E, Fernandez-Morales JC, Caricati-Neto A, Jurkiewicz A, Yáñez M,Rodriguez-Franco MI, Conde S, Arce MP, Hernández-Guijo JM, García AG. Multi-target novel neuroprotec-tive compound ITH33/IQM9.21 inhibits calcium entry,calcium signals and exocytosis. Cell Calcium 50(4):356-369. 2011. PMID: 21839513. IF: 3,553

González-Muñoz GC, Arce MP, López B, Pérez C,Romero A, del Barrio L, Martín-de-Saavedra MD, EgeaJ, León R, Villarroya M, López MG, García AG, CondeS, Rodríguez-Franco MI. N-acylaminophenothiazines:neuroprotective agents displaying multifunctional activ-ities for a potential treatment of Alzheimer's disease.Eur J Med Chem. 46(6): 2224-2235. 2011. PMID:21420206. IF: 3,193

León R, Garcia AG, Marco-Contelles J. Recent advancesin the multitarget-directed ligands approach for the treat-ment of Alzheimer's disease. Med Res Rev. [Epub aheadof print]. 2011. PMID: 21793014. IF: 10,228

Tomassoli, I., Ismaili, L., Pudlo, M., De Los Ríos, C.,Soriano, E., Colmena, I., Gandía, L., Rivas, L., Samadi,A., Marco-Contelles, J. And Refouvelet, B. Synthesis,biological assessment and molecular modeling of newdihydroquinoline-3-carboxamides and dihydroquino-line-3-carbohydrazide derivatives as cholinesteraseinhibitors, and Ca channel antagonists. Eur. J. Med.Chem. 46 (1): 1-10. 2011. PMID: 21111515. IF: 3,193

Samadi A, Soriano E, Revuelta J, Valderas C, ChiouaM, Garrido I, Bartolomé B, Tomassolli I, Ismaili L,González-Lafuente L, Villarroya M, García AG, Oset-Gasque MJ, Marco-Contelles J. Synthesis, structure,theoretical and experimental in vitro antioxi-dant/pharmacological properties of a-aryl, N-alkylnitrones, as potential agents for the treatment of cere-bral ischemia. Bioorg Med Chem. 19(2): 951-960.2011. PMID: 21190861. IF: 2,978

Yáñez M, Galán L, Matías-Guiu J, Vela A, Guerrero A,García AG. CSF from amyotrophic lateral sclerosispatients produces glutamate independent death of ratmotor brain cortical neurons: protection by resveratrolbut not riluzole. Brain Res 1423: 77-86. 2011. PMID:21983205. IF: 2,623

Milla J, Montesinos MS, Machado JD, Borges R,Alonso E, Moreno-Ortega AJ, Cano-Abad MF, GarcíaAG, Ruiz-Nuño A. Ouabain enhances exocytosisthrough the regulation of calcium handling by the endo-plasmic reticulum of chromaffin cells. Cell Calcium50(4): 332-42. 2011. PMID: 21741086. IF: 3,553

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2

Rosa, J.M., Torregrosa-Hetland, C.J., Colmena, I.,Gutierrez, L.M., Garcia, A.G. And Gandia, L. Calciumentry through slow-inactivating L-type calcium chan-nels preferentially triggers endocytosis rather than exo-cytosis, in bovine chromaffin cells. Am J Physiol CellPhysiol 301(1): C86-98. Epub 2011 Mar 30. 2011.PMID: 21451100. IF: 3,817

Rosa JM, Conde M, Nanclares C, Orozco A, ColmenaI, de Pascual R, García AG, Gandía L. Paradoxical facil-itation of exocytosis by inhibition of L-type calciumchannels of bovine chromaffin cells. Biochem BiophysRes Commun. Epub 2011 May 31 410(2): 307-11.2011. PMID: 21663733. IF: 2,595

González JC, Albiñana E, Baldelli P, García AG,Hernández-Guijo JM. Presynaptic muscarinicreceptor subtypes involved in the enhancement ofspontaneous GABAergic postsynaptic currents inhippocampal neurons. Eur J Neurosci. 33(1): 69-81.Epub 2010 Nov 23. 2011. PMID: 21091801. IF:3,658

GROUP 29

HEAD OF LABORATORYMaría Francisca Cano Abad

GROUP MEMBERS• Ana José Moreno Ortega• Ana Ruiz Nuño

RESEARCH INTEREST

One of our main projects is about a new calcium chan-nel, CALHM1, Calcium Homeostasis Modulator 1, in itsmutated form, P86L-CALHM1 as a prognostic factor ofAlzheimer disease (AD). P86L-CALHM1 could triggerAD's homozygous individuals with a probability of 20%.We have found that the expression of P86-CALHM1: (i)alters the kinetics of entry of calcium cation (Ca2+) inthe cytosol and the nucleus, (ii) modulates Ca2+dependent genes as CREB and phospho-CREB, (iii)affects the viability of cells that contain it. On the otherhand, we found that the compound, CGP-37157, (ablocker of the mitochondrial Na+/Ca2+ exchanger)blocks the mutated form of the channel. It is the first

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Changes of [Ca2+]c elicited by K+ in fura-2 loaded human hippocam-pal neurons. (a) Sequential images showing the [Ca2+]c elevation indifferent regions of interest (ROI) elicited by a 10-s pulse of high K+(75mM) depolarization, using a pseudocolor scale. Cells were culturedin neurobasal medium containing, plasma and B27. Initially the[Ca2+]c increased at dendrites and then it extended to the soma. (b)Original recordings of [Ca2+]c variations after a K+ pulse of 30 s.

AREA 2

time that a selective blocker of the channel is described.In conclusion, we propose that CGP-37157 and deriva-tives may be candidates for the treatment of AD, in thosepersons suffering the mutation of the channel.

Another project of our laboratory is related to the proteinTDP-43 (TARD DNA-binding protein 43) that is linked toamyotrophic lateral sclerosis (ALS), a motoneuron dis-ease leading to progressive paralysis. ALS has no effec-tive treatment; only riluzol delays disease progression anddeath a few months. In this research project we studiedthe cytotoxicity and vulnerability of NSC-34 cells againstvarious oxidative stress stimuli such as PAO,

oligomycin/rotenone and H2O2. The ITH33 showed neu-roprotection against PAO at a concentration of 3 µM andagainst oligomycin/ rotenone at 0.3, 1 and 3 µM. We alsotested other compounds that have shown neuroprotec-tion in our laboratory such as resveratrol and chondroitinsulfate. The first one showed protection againstoligomycin/ rotenone to 1 µM and the second oneagainst PAO at 3 and 10 µM. These experiments will pro-vide us a better understanding of this model of motoneu-ron to study new drugs in the treatment of ALS.

Figures of the most relevant publications in 2011. Reference:

• Cano-Abad M.F., Herrera-Peco I., G de Sola R., Pastor J., Navarrete

E., Carrasco Moro R., Pizzo P. and Ruiz-Nuño A. Morphological and

functional characterization of human cells from tissue coming from

epileptic patients under surgery. Int J Dev Neurosci. 2011; 29:121-9.

• Milla J, Montesinos MS, Machado JD, Borges R, Alonso E, Moreno-

Ortega AJ, Cano-Abad MF, García AG, Ruiz-Nuño A. Ouabain

enhances exocytosis through the regulation of calcium handling by

the endoplasmic reticulum of chromaffin cells. Cell Calcium. 2011;

50:332-42.

MAJOR GRANTS

• María Francisca Cano Abad. ¿El calcio a través de lamutación P86L-CALHM1, para el Alzheimer, activarutas apoptóticas? Posibles fármacos neuroprotec-tores. CAM-UAM. UAM-CAM Consoli-dación deGroups. UAM/SAL5053. Referencia: 1004040047

• Ana Ruiz Nuño. Estudio del potencial efecto neuropro-tector del nuevo compuesto ITH12233 en modelosTDP-43 in vitro e in vivo de esclerosis lateral amiotrófi-ca. ISCIII. FIS.10/01426


Milla J, Montesinos MS, Machado JD, Borges R, AlonsoE, Moreno-Ortega AJ, Cano-Abad MF, García AG, Ruiz-Nuño A. Ouabain enhances exocytosis through the reg-ulation of calcium handling by the endoplasmic reticulumof chromaffin cells. Cell Calcium 50(4): 332-42. 2011.PMID: 21741086. IF: 3,553

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Ouabain induces the release of Ca2+ from the ER. Cells were transfec-ted with the Ca2+ probe cameleon-D1 targeted to the ER. Three or fourdays after transfection, the changes of [Ca2+]ER were estimated asnormalised ratio of fluorescence 512/480 (F/Fo). Cells were conti-nuously perifused with a Krebs-HEPES solution containing 2 mMCa2+. The different compounds were applied for the times indicatedwith at least 10 min washout from any preceding application. (A) Ori-ginal example traces showing the effect of 5-min perifusion with oua-bain (OUB 10 and 100 µM) and 1 min perifusion with histamine (His100 µM) on [Ca2+]ER (thick black line) on three different bovine chro-maffin cells. The effect of a second challenge with the compounds onthe same cells, but after 10 min perifusion with 2-APB (10 µM) isshown as a thin grey line. (B) Pooled data shown in black bars aremean + s.e. of the decreases in [Ca2+]ER originated by perifusion of 10and 100 µM ouabain and 100 µM histamine expressed as F/F0. The re-sults were obtained by the application of histamine and one of the oua-bain concentrations to 71 cells from 6 different cultures. The number ofresponsive cells to each stimulus is shown in parentheses. The effectof a second stimulus applied to the same cell, but after 10-min perifu-sion with 10 µM 2-APB is shown in the grey bars (4 experiments foreach group). Statistical significance was assessed by ANOVA withBonferroni post-hoc test (* p<0.05 with respect to control).

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2

Cano-Abad MF, Herrera-Peco I, Sola RG, Pastor J,García-Navarrete E, Moro RC, Pizzo P, Ruiz-Nuño A.New insights on culture and calcium signaling in neuronsand astrocytes from epileptic patients. Int. J. DevNeurosci 29(2): 121-129. 2011. PMID: 21238565. IF:1,938

del Barrio L, Egea J, León R, Romero A, Ruiz A, MonteroM, Alvarez J, López MG. Calcium signalling mediatedthrough a7 and non-a7 nAChR stimulation is differential-ly regulated in bovine chromaffin cells to induce cate-cholamine release. Br J Pharmacol. 162(1): 94-110.2011. PMID: 208404-68. IF: 4,925

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AREA 2Line 2.2Neurotransmission in the hippocampus

GROUP 30HEAD OF LABORATORYLuis Gandía Juan

GROUP MEMBERS• Inés Colmena Crespo• Ricardo de Pascual y del Castillo• Ángela Orozco Alarcón• Carmen Pérez de Nanclares Fernández

RESEARCH INTEREST

VDCCs and endocytosis in bovine chromaffin cellsAlthough calcium has been suggested to regulate endocy-tosis and vesicle recycling in synapses and neuroendocrinecells, a controversy still looms over the precise role of Ca2+in membrane retrieval during endocytosis. In an attempt toestablish the precise relationship between Ca2+ entry, exo-cytosis and endocytosis in bovine chromaffin cells, werecently found that the variations in Ca2+ entry induced bythe application of depolarizing pulses (DPs) of increasinglength (50-2000 ms) produced different patterns of exo-endocytosis, as measured by changes in membranecapacitance (ΔCm). In this study, ΔCm changes weremeasured during the 8 s period that followed the DP. A lin-ear relationship between exocytotic responses and DPduration was found; however, endocytotic responses wereabsent with short DPs (50-200 ms) and were presentand/or were more pronounced with longer DPs (500-2000ms). These data raise a question: what is the relationshipbetween Ca2+ entry, exocytosis and endocytosis, i.e., isthe Ca2+ entry that triggers exocytosis also responsible toinitiate endocytosis?

As far as specific contributions of different VDCCs incontrolling endocytosis are concerned, we have recent-

ly provided evidence that L-channels are much moredominant than N- or PQ-channels in controlling endocy-tosis. This was examined in voltage-clamped bovineadrenal chromaffin cells by applying single DPs of longduration. In this work, specific blockers of the differentsubtypes VDCCs were used and the Ca2+ current andexo-endocytosis induced by a 500 mg DP were studied.We found that, despite the small contribution of L-typeVDCCs to the total global Ca2+ current, their inhibitionby the DHP nifedipine (L-channel blocker) almost com-pletely abolished the endocytotic response without sig-nificantly affecting exocytosis. ω-Conotoxin GVIA (N-channel blocker) affected little the exo-endocytoticresponses while ω-agatoxin IVA (P/Q-channel blocker)markedly blocked those responses in a parallel manner.These data support the following hypotheses that L-typeCa2+ channels might have a selective action for the con-trol of endocytosis in bovine chromaffin cells, a functionthat seems to depend on Ca2+ entry through N- or P/Q-types of VDCCs to a much lesser extent. Similar resultswere obtained in a related study by using FM-dyemethodology, in which we found that endocytosis wasinhibited by about 50% after long stimulation with highK+ of bovine chromaffin cells when the L-channel block-er nifedipine was present.

This functional coupling between L-type channels andendocytosis observed in bovine chromaffin cells couldbe related to: 1) the existence of a close co-localizationbetween endocytosis proteins and L-type channels; 2)the total amount of Ca2+ entering the chromaffin cellthrough a given VDCC; and/or 3) the mode of Ca2+entry, i.e. a slow and prolonged Ca2+ entry through theless inactivating L-type channels.

Related to the possible co-localisation between L-typechannels and endocytosis proteins we sought to iden-tify the possible co-localization of the different VDCCsubtypes with other endocytosis-related proteins suchas dynamin and/or clathrin. Immunofluorescenceexperiments on bovine chromaffin cells showed thatthe co-localization of clathrin was practically negligiblewith the three VDCC subtypes (CaV1.3, CaV2.1 andCaV2.2) studied. Also, only a mild co-localization rate(about 20-30%) was observed between VDCCs anddynamin. Taken together, these experiments do notsupport the existence of a close co-localization of

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VDCC subtypes with the endocytotic proteins clathrinand dynamin in bovine chromaffin cells.

To characterize the influence of the total amount ofCa2+ (QCa) on the endocytotic process, we comparedthe endocytic behavior of cells treated with nifedipinewith others treated with a low concentration of ω-aga-toxin IVA (to block P/Q-channels). The low ω-agatoxinIVA concentration decreased the calcium current about20%,that represents an extent similar to that producedby nifedipine on L-channels. We found that in the pres-ence of 10 mM extracellular Ca2+, 200 nm ω-agatox-in IVA caused a 59% reduction of total Ca2+ enteringthe bovine chromaffin cell during a 500 ms DP, a valuecomparable with those obtained in the presence ofnifedipine (50% blockade of QCa). Despite this effecton QCa, 200 nM ω-agatoxin IVA reduced endocytosisonly by 37%, whereas nifedipine caused 93% inhibi-tion. Thus, it seems that more relevant than the totalCa2+ entry into the cell during the 500-ms depolarizingpulse is the manner used by Ca2+ to trigger endocyto-sis, i.e. the slow-inactivating L-type of VDCCs.

If reduction of Ca2+ entry through L-type channelsdecreases endocytosis, one could test if increasingCa2+ entry through this pathway enhances thisresponse. To test this assumption, bovine chromaffincells were treated with the L-type VDCC activatorFPL64176 (FPL). In the presence of FPL, L-channels

inactivated more slowly and deactivated also at a slow-er rate. Related to its effects on the exo-endocytosisprocesses, we found that FPL caused only around a18% increase in total Ca2+ entry, but this augmenta-tion of Ca2+ entry gave rise to an almost 3-foldincrease in the endo/exocytosis ratio. Additional exper-iments were performed with isolation of L from N/PQ-channels by blocking the non-L-channels with ω-conotoxin MVIIC (MVIIC). It was found that, in cellstreated with MVIIC, FPL increased Ca2+ entry anddoubled the endo/exocytosis ratio, indicating a selec-tive augmentation of endocytosis related to this Ca2+entry through L-type channels.

Similar results were obtained when exo/endocytosisresponses were monitored with immunofluorescencetechniques using FM1.43 dye. When the effect ofVDCC blockers on the FM1-43 exo-endocytoticresponses was characterized, we found that theendo/exocytosis relationship was not affected by GVIA.However, MVIIC reduced by 40% the endo/exocytosisratio and a 53% reduction of endo/exocytosis ratio wasobserved in the presence of nifedipine. In cells treatedwith MVIIC to abolish non-L-type channels, FPLincreased the endo/exocytosis ratio. Although lessclearly than the data derived from patch-clamp experi-ments, the FM1-43 data also support the view thatCa2+ entering through L-type VDCCs is preferentiallycoupled to endocytosis.

Related to the influence of the mode of Ca2+ entry onthe control of the endocytosis, we had found that aslow-inactivating Ca2+ channel such as the L-type,that contributes only by about 30% to the initial peakICa, carried more than half of the total Ca2+ entry alongthe 500-ms depolarizing pulse. Conversely, the fast-inactivating N-type channel that also contributes byabout 30% to the initial ICa peak, only contributed byabout 24% to the total QCa. These data suggestedthat a low-rate, non-inactivating Ca2+ entry might bemore critical to trigger compensatory as well as excessendocytosis.

We therefore explored the possibility that a more sus-tained Ca2+ entry through non-L (N/PQ) VDCCs couldalso activate endocytosis. For this, we used the cyclin-

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Original Cm traces elicited by 200-ms depolarizing pulses from -80 to0 mV in bovine chromaffin cells under different experimental condi-tions. In control cells (left panel), DP caused a Cm jump of about 150 fFfollowed by an endocytosis that reached a value of 200 fF. In contrast,the Cm trace morphology in cells perfused with nifedipine (3 μM; rightpanel) did not show any significant endocytotic (endocytosis was de-creased to only 30 fF in the presence of the L-channel blocker).


AREA 2dependent kinase inhibitor roscovitine. Roscovitine isknown to delay N/PQ channel deactivation, therebyprolonging channel opening time and thus producing aslower Ca2+ entry. This mimics the slow mode of Ca2+entry through L-channels to activate endocytosis. Wefound that when roscovitine was given in the presenceof nifedipine, endocytosis could be recovered to nearcontrol levels (Rosa et al., 2011)(unpublished data). It isconceivable that a sustained Ca2+ entry through N/PQchannels would also be able to maintain an endocytot-ic response even though the Ca2+ entry through L-channels, that is the responsible to initiate the mem-brane retrieval, is inhibited.

MAJOR GRANTS

• Luis Gandía Juan. Receptores nicotínicos alfa7 einflamación en un modelo animal de distrofia muscu-lar. CEAL-SANTANDER.

• Luis Gandía Juan. Receptores nicotínicos y lib-eración de neurotransmisores. MICINN. SAF2010-18837


Rosa, J.M., Torregrosa-Hetland, C.J., Colmena, I.,Gutierrez, L.M., Garcia, A.G. And Gandia, L. Calciumentry through slow-inactivating L-type calcium chan-nels preferentially triggers endocytosis rather than exo-cytosis, in bovine chromaffin cells. Am J Physiol CellPhysiol 301(1): C86-98. Epub 2011 Mar 30. 2011.PMID: 21451100. IF: 3,817

Rosa JM, Conde M, Nanclares C, Orozco A, ColmenaI, de Pascual R, García AG, Gandía L. Paradoxical facil-itation of exocytosis by inhibition of L-type calciumchannels of bovine chromaffin cells. Biochem BiophysRes Commun. Epub 2011 May 31 410(2): 307-11.2011. PMID: 21663733. IF: 2,595

Samadi, A., Valderas, C., De Los Ríos, C., Bastida, A.,Chioua, M., González-Lafuente, L., Colmena. I.,

Gandía, L., Romero, A., Del Barrio, L., Martín-De-Saavedra. M.D., López, M.G., Villarroya, M. AndMarco-Contelles, J.L. Cholinergic and NeuroprotectiveDrugs for the Treatment of Alzheimer and NeuronalVascular Diseases. II. Synthesis, BiologicalAssessment, and Molecular Modelling of New TacrineAnalogues from Highly Substituted 2-Aminopyridine-3-carbonitriles. Bioorg. Med. Chem. 19 (1): 122-133.2011. PMID: 21163662. IF: 2,978

Tomassoli, I., Ismaili, L., Pudlo, M., De Los Ríos, C.,Soriano, E., Colmena, I., Gandía, L., Rivas, L., Samadi,A., Marco-Contelles, J. And Refouvelet, B. Synthesis,biological assessment and molecular modeling of newdihydroquinoline-3-carboxamides and dihydroquino-line-3-carbohydrazide derivatives as cholinesteraseinhibitors, and Ca channel antagonists. Eur. J. Med.Chem. 46 (1): 1-10. 2011. PMID: 21111515. IF: 3,193

GROUP 31

HEAD OF LABORATORYJesús Miguel Hernández Guijo

GROUP MEMBERS• Elisa Albiñana Durá• José Carlos González San Frutos

RESEARCH INTEREST

The main objective performed in 2011 has been toexamine the effects of nicotinic and muscarinic recep-tor activation on neurotransmission in the hippocam-pus and provide data that support the nomination ofnew targets and strategies for treating diseases asso-ciated with alterations of the cholinergic system.

We conducted studies of synaptic transmission in cul-tured neurons and slices of rat hippocampus:

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AREA

2

• We have shown that muscarinic receptor subtypesm2, m3, m4 and m5 exert a potentiation ofGABAergic synaptic transmission, through a mecha-nism involving their presynaptic colocalization withthe exocytotic machinery and mobilization of calciumfrom intracellular stores.

• We have characterized the cellular mechanismsunderlying the muscarinic modulation of synaptictransmission. The muscarinic receptor activationenhances GABAergic transmission by an increment inboth the vesicular recycling and the neurotransmitterrelease. In addition, there is an attenuation of thedepression induced by tetanic stimulation. These datagive a strong resistance of inhibitory transmissionunder periods of intense maintained synaptic activity.

• We demonstrated that selective agonists of alpha7nicotinic receptor exert a selective modulation ofGABAergic activity. But unlike the results obtainedon isolated neuron in culture, in hippocampal slices,

the nicotinic receptors are those primarily involved inthis modulation because this effect was not reversedby the application of selective antagonists. Thecholine uptaker was not involved in this effect. Theseresults force us to think of other alternative mecha-nisms responsible for this modulatory effect mediat-ed by nicotinic agonists. The search for this amazingalternative mechanism is what is currently focusingour attention.

MAJOR GRANTS

• Jesús Miguel Hernández Guijo. El receptor nicotíniconeuronal como diana terapéutica en enfermedadesneurodegenerativas. ISCIII. PI080227

• Proyecto Coordinado. Estudio de las alteracionesfuncionales que se producen en las células cro-

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Effect of mAChRs activation on the paired pulse depression. A Repre-sentative eIPSCs recorded in response to paired stimuli separated by50 ms and repeated every 10 s in control (a), during application of me-thacholine (b) and after its wash-out (c). B Time course of PPR (I2/I1)over consecutive responses as indicated in A. Note that methacholineapplied as indicated by the top horizontal bar, enhanced the PPR, thatrecovered to control values after methacholine wash-out. C eIPSCs re-corded in control (left) and during methacholine perfusion (right) inresponse to paired stimuli separated by the indicated interpulse inter-vals (Δt). D The mean PPD were plotted as a function of the interpulseinterval and fitted by a double exponential function (control, squaresymbols; methacholine, circle symbols). Inset represents an enhance-ment of the figure to ease the observation at the low inter-event times.Data are mean ± S.E.M. of 15-16 neuron evaluated.

mAChRs activation enhanced the Pves but did not affect the RRP size.A Representative recordings during a train of 40 stimuli at 40 Hz in sin-gle control and methacholine treated neurons. B Cumulative eIPSCamplitude profile. To estimate the cumulative eIPSC amplitude beforesteady-state depression (RRP) data points in the range of 0.4–1 s werefitted by linear regression and back-extrapolated to time 0 (control,square symbols; methacholine, circle symbols). C, The size of RRP(left), the calculated Pves (middle) and the number of SVs (Nsyn) for-ming the RRP (right) are shown as means ± S.E.M. (control, white bars;methacholine treated, black bars) (n=11). **p<0.01 vs control, Studen-t’s t test.

AREA 2mafines de la médula suprarrenal en un modelo dehipertensión arterial esencial en rata. CONACYT(México). 79763


González JC, Albiñana E, Baldelli P, García AG,Hernández-Guijo JM. Presynaptic muscarinic receptorsubtypes involved in the enhancement of spontaneousGABAergic postsynaptic currents in hippocampal neu-rons. Eur J Neurosci. 33(1): 69-81. Epub 2010 Nov 23.2011. PMID: 21091801. IF: 3,658

Hernández A, Segura-Chama P, Jiménez N, GarcíaAG, Hernández-Guijo JM, Hernández-Cruz A.Modulation by endogenously released ATP and opioidsof chromaffin cell calcium channels in mouse adrenalslices. Am J Physiol Cell Physiol. 300(3): 610-623.2011. PMID: 21160033. IF: 3,817

Maroto M, de Diego AMG, Albiñana E, Fernandez-Morales JC, Caricati-Neto A, Jurkiewicz A, Yáñez M,Rodriguez-Franco MI, Conde S, Arce MP, Hernández-Guijo JM, García AG. Multi-target novel neuroprotec-tive compound ITH33/IQM9.21 inhibits calcium entry,calcium signals and exocytosis. Cell Calcium 50(4):356-369. 2011. PMID: 21839513. IF: 3,553

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Line 2.3Clinical pharmacology and pharmacogenetics

GROUP 32HEAD OF LABORATORYFrancisco Abad Santos

GROUP MEMBERS• María Teresa Cabaleiro Ocampo• María Fagoaga Torija• Igone Marrodán Remírez• María Isabel Moreno Arza• Dolores Ochoa Mazarro• Rocío María Prieto Pérez• Manuel Román Martínez• Sergio Daniel Sánchez Rojas• Javier Soriano Ventura• María Talegón García• Ana María Tello Miller

RESEARCH INTEREST

The aim of the investigation performed in this group isto evaluate the pharmacokinetics, pharmacodynamics

and pharmacogenetics of drugs in order to predict theresponse of the patients to drugs, both in terms of effi-cacy and safety.

Our group has wide experience in the performance ofnumerous phase I, II and III clinical trials, with Dr. Abad-Santos and Dolores Ochoa as principal investigators.We have available a Clinical Trials Unit, with capacity for14 patients (7th floor, Hospital Universitario de laPrincesa). Clinical trials performed include safety, phar-macokinetics, pharmacodynamics, interaction andbioequivalence studies in healthy volunteers, and stud-ies in patients to probe the efficacy of new drugs in col-laboration with several specialists in the hospital andprimary care. During 2011 21 clinical trials (phase I toIV) were performed.

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Prolactin concentration versus time curve according to sex (M=men,W=women) and DRD2 Taq1A polymorphism after receiving a singledose of 5 mg olanzapine (Fig. 2ª) or 1 mg risperidone (Fig. 2B). Valuesare mean +- SEM.

AREA 2Pharmacogenetic research is related with various clini-cal diseases, trying to look for new pharmacogeneticmarkers to predict drug response, both therapeuticand toxic, that could help physician to decide the besttreatment for every patient. In 2011, more than 450patients benefited from pharmacogenetic testing.

During 2011, our group had published 4 articles relat-ed to pharmacogenetics (Ayuso et al., 2011;Almoguera et al., 2011; López-Rodríguez et al.,2011a,b), and 2 book chapters about ethics in clinicaltrials (Abad-Santos et al., 2011). In addition, we areparticipating in the project International randomizeddouble-blind placebo-controlled study on the initialtreatment of acute mania with methylphenilate(MEMAP), supported by the Convocatoria para la con-cesión de ayudas para el fomento de la investigaciónclínica independiente (Ref. EC10-110).

Figures of publication in 2011. Reference:

• López-Rodriguez R, Roman M, Novalbos J, Pelegrina ML, Ochoa

D, Abad-Santos F. DRD2 Taq1A Polymorphism Modulates

Prolactin Secretion Induced by Atypical Antipsychotics in Healthy

Volunteers. J Clin Psychopharmacol 2011; 31: 555-562.

MAJOR GRANTS

• Francisco Abad Santos. Búsqueda de marcadoresgenéticos predictores de respuesta a fármacosbiológicos en el tratamiento de la psoriasis. ISCIII.PI10/01740

• Francisco Abad Santos. Nuevos medicamentosgenéricos para el tratamiento de patologías de altoimpacto socioeconómico. MEC. IPT-2011-1663-900000


Lopez-Rodriguez R, Roman M, Novalbos J, PelegrinaML, Ochoa D, Abad-Santos F. DRD2 Taq1APolymorphism Modulates Prolactin Secretion Inducedby Atypical Antipsychotics in Healthy Volunteers. J Clin

Psychopharmacol 31(5): 555-562. 2011. PMID:21869700. IF: 4,857

Ayuso C, Abad-Santos F, Dal-Ré R, Gracia D. Ethicson genetic research (1). Pharmacogenetic studies. MedClin (Barc). 136(15): 678-682. 2011. PMID: 20044101.IF: 1,413

Almoguera B, Riveiro-Alvarez R, Lopez-Castroman J,Dorado P, Lopez-Rodriguez R, Fernandez-Navarro P,Baca-García E, Fernandez-Piqueras J, Dal-Ré J, Abad-Santos F, LLerena A, Ayuso C. ATA homozigosity in theIL-10 gene promoter is a risk factor for schizophrenia inSpanish females: a case control study. BMC MedicalGenetics 12(81): 1-6. 2011. PMID: 21658228. IF:2,439

Lopez-Rodriguez R, Trapero-Marugan M, Borque MJ,Roman M, Hernandez-Bartolome A, Rodriguez-MuñozY, Martin-Vilchez S, Abad-Santos F, Muñoz de RuedaP, Vidal-Castiñeira JR, Rodrigo L, Salmeron J, Moreno-Otero R, Sanz-Cameno P. Genetic variants of interfer-on-stimulated genes and IL-28B as host prognosticfactors of response to combination treatment forchronic hepatitis C. Clin Pharmacol Ther 90(5): 712-721. 2011. PMID: 21993426. IF: 6,378

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: DOLORES OCHOAMAZARROEnsayo clínico cruzado y aleatorizado de bioequivalen-cia de dos formulaciones de cilostazol comprimidos de100 mg, tras su administración oral en dósis única avoluntarios sanos; (versión 1: 24-03-11). N-CIL-11-167EudraCT: 2011-001239-22

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SAN-TOSEnsayo clínico aleatorizado de bioequivalencia de dosformulaciones de omeprazol cápsulas de 40mg, trassu administración en dósis única a voluntarios sanos,en ayunas con diseño cruzado y con comida con dis-eño cruzado replicado; (versión 1: 18-11-10). ITHUEC-

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2

OME/10-8EudraCT: 2010-024029-19

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEnsayo clínico cruzado y aleatorizado de bioequiva-lencia de tres formulaciones de diacereína cápsulasde 50mg, tras su administración en dosis única a vol-untarios sanos; (versión: 28 de junio de 2010).ITHUEC-DIA/09-4EudraCT: 2009-016630-27

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEnsayo clínico cruzado y aleatoriado de bioequivalen-cia de dos formulaciones de pentoxifilina comprimidosde liberación prolongada de 600 mg, tras su adminis-tración en dosis única a voluntarios sanos; (versión: 05-12-08). ITHUEC-PEN/08-8EudraCT: 2008-008325-30

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEstudio abierto, aleatorizado, estratificado por sexos ycontrolado para evaluar el efecto del aumento de laingestión de agua en 2 litros al día sobre el índice deriesgo de cristalización de los sujetos sanos; (versión1.2: 30-10-07). NU250

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEnsayo cruzado y aleatorizado entre dos formulacionesde desloratadina comprimidos de 5mg y entre dos for-mulaciones de desloratadina comprimidos bucodis-persables de 5mg, tras su administración en dósisúnica a voluntarios sanos; (versión 1:3-12-10).ITHUEC-DES/10-7EudraCT: 2010-023995-23

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSBúsqueda de marcadores genéticos predictores derespuesta a fármacos biológicos en el tratamiento de lapsoriasis; (versión 1: 17-11-10). FAS-PSO-2010-01

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEnsayo clínico cruzado y aleatorizado de bioequivalenciade dos formulaciones de dexketoprofeno comprimidos de25mg, tras su administración oralen dosis única a voluntar-ios sanos; (versión 1: 15-9-11). FMLD-DESPINA-14EudraCT: 2011-003800-19

PRINCIPAL INVESTIGATOR: FRANCISCO ABAD SANTOSEnsayo clínico cruzado y aleatorizado de bioequivalenciade dos formulaciones de ibuprofeno comprimidos de600mg, tras su administración en dosis única a voluntar-ios sanos; (versión 1: 12-07-06). ITHUEC-IBU/06-8EudraCT: 2006-003930-13

PRINCIPAL INVESTIGATOR: DOLORES OCHOAMAZARROEnsayo clínico aleatorizado de bioequivalencia de dos for-mulaciones de valsartán/hidroclorotiazida comprimidosde 320/25 mg, tras su administración en dosis única avoluntarios sanos, en ayunas con diseño cruzado replica-do; (versión 1:05-05-11). ITHUEC-VAL-HTZ/11-1EudraCT: 2011-002183-24

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEnsayo clínico cruzado y aleatorizado de bioequivalenciade dos formulaciones de trazodona 100mg comprimidos,tras su administración oral en dosis única a voluntariossanos en ayunas; (versión: 29-07-11). N-TRA-11-172EudraCT: 2011-003160-72

PRINCIPAL INVESTIGATOR: DOLORES OCHOAMAZARROEnsayo clínico cruzado y aleatorizado de bioequivalen-cia de dos formulaciones de dexketoprofeno comprim-idos de 25mg, tras su administración oral en dosisúnica a voluntarios sanos; (versión 1:07-07-11). N-DEX-11-171EudraCT: 2011-002725-22

PRINCIPAL INVESTIGATOR: DOLORES OCHOAMAZARROEnsayo clínico cruzado y aleatorizado de bioequivalen-cia de dos formulaciones de dexketoprofeno comprim-idos de 25mg, tras su administración oral en dosisúnica a voluntarios sanos; (versión 1:13-06-11). N-DEX-11-170EudraCT: 2011-002728-42

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEnsayo clínico cruzado y aleatorizado para evaluar latolerabilidad y biodisponibilidad de una nueva formu-lación de ibuprofeno comparada con ibuprofenoestandar administrado en dosis única a voluntarios

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AREA 2sanos en ayunas; (versión 1: 18-05-11). BIBEC01EudraCT: 2011-002148-29

PRINCIPAL INVESTIGATOR: DOLORES OCHOAMAZARROEnsayo clínico cruzado aleatorizado de bioequivalenciade dos formulaciones de candesartan-hidroclorotiazidacomprimidos de 32/25mg, tras suadministración endósis única a voluntarios sanos; (versión 1: 5-12-11).ITHUEC-CAN-HTZ/11-3EudraCT: 2011-005546-35

PRINCIPAL INVESTIGATOR: FRANCISO ABAD SANTOSEnsayo clínico cruzado y aleatorizado de bioequiva-

lencia de dos formulaciones de almotriptan com-primidos de 12.5mg, tras su administración oral endósis única a voluntarios sanos; (versión 1: 13-01-11). N-ALM-10-165EudraCT: 2010-024560-18

PRINCIPAL INVESTIGATOR: DOLORES OCHOAMAZARROEnsayo clínico aleatorizado de bioequivalencia de dosformulaciones de celecobix cápsulas de 200 mg, trassu administración en dosis única a voluntarios sanosen ayunas con diseño cruzado replicado; (versión 1:12-09-11). ITHUEC-CEL/11-2EudraCT: 2011-003781-33

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Line 2.4Diagnostic and therapeutic advances in affective disorders

GROUP 33

HEAD OF LABORATORYJosé Luis Ayuso Mateos

GROUP MEMBERS• José David Albillo Labarra• Celia Anaya Suárez• Francisco Félix Caballero Díaz• María Cabello Salmerón• Elena Ezquiaga Terrazas• Luis Miguel García Olmos• Eduardo García-Camba de la Muela• Miguel Ángel Gorriti Irigai• Matilde Hernández Álvarez• Itziar Leal Leturia• Pilar López García• Herminio Martínez Cano• Blanca Mellor Marsá• Marta Miret García• Roberto Nuevo Benítez• María del Mar Rivas Rodríguez• Jesús Valle Fernández

RESEARCH INTEREST

The Multidisciplinary Group for Research in AffectiveDisorders, headed by Dr. José Luis Ayuso Mateos, islocated in the Psychiatry Department at the AutónomaUniversity of Madrid and in La Princesa TeachingHospital. The research team is part of CIBERSAM fromits start, and it is comprised of professionals from dif-ferent backgrounds: psychiatrists, statistics, primarycare doctors and psychologists.

On 2011, the Multidisciplinary Group for Research inAffective Disorders has focused on five key areas:

1) Application and assessment of interventions for themanagement of affective disorders: Our team carriedout three different randomized clinical trials, (two of

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Effect of psychotic symptoms on diabetes mediated by Body Mass in-dex and alcohol consumption.

Global capacity and performance scores in 10 chronic health condi-tions* divided into three groups of severity.* Chronic widespread pain, low back pain, traumatic brain injury, de-pression, migraine, bipolar disorder, Parkinson’s, Stroke, Multiplesclerosis and osteoarthritis

AREA 2them are non-sponsored by industry). Recruitment ofsamples, organization of workshop trainings and man-agement of approvals, were the main developed tasks.

2) Nosology of mental disorders. Members of the teamparticipated in working groups for the revision of men-tal disorders in the ICD-10th. In addition, our team pro-vided logistic support for the coordination of theseworking groups.

3) Prevention and promotion of mental health: Dr JoseLuis Ayuso, participated in the development of a newclinical guideline to prevent suicide behavior and mem-bers of his team are collaborating in the implementationof a World Health Organization’s clinical guideline forthe management of mental disorders in non-special-ized settings in Ethiopia.

4) Analysis of health status and well-being in Europe:Results of a large European survey on health statusand wellbeing in Europe were analyzed by the team on2011. In addition, the team is currently working on thestate of the art focused on research on well-being inEurope to define future research priorities in this area.

5) Development of new strategies to evaluate the psy-chosocial burden of depressive disorders: Our teamworked on the development of a new protocol for thecollection of psychosocial difficulties experienced bypatients with mental disorders.

MAJOR GRANTS

• Jesús Valle Fernández. Eficacia Comparativa de dosEstrategias de Intervención Psicosocial(Neurocognitiva versus Psicoeducativa) comoTratamiento Coadyuvante al Farmacológico versusTratamiento Habitual en el Trastorno Bipolar. ISCIII.FIS. PI08/90327

• José Luis Ayuso Mateos. Detección y Prevención delRiesgo de Conductas Suicidas en Personas en EdadGeriátrica. MSPS. Ministerio de Sanidad y politicassociales. Convocatoria Estrategia en SaludMental.2009

• José Luis Ayuso Mateos. Psycho-social AspectsRelevant to Brain Disorders in Europe. PARADISE. VIIPrograma Marco de la Unión Europea. Convocatoria:FP7-HEALTH-2009-single-stage. FP7-HEALTH-2009-241572

• José Luis Ayuso Mateos. Capacidad de reserva cog-nitiva en el trastorno bipolar eutímico: impacto en elfuncionamiento y en el rendimiento cognitivo.Ministerio de Educación y cultura. concesión de unabeca FPU para la realización del proyecto de tesis deCelia Anaya dirigida por Jose Luis Ayuso Mateos.AP2008-00915

• José Luis Ayuso Mateos. Collaborative Research onAGEing in Europe. COURAGE. CE. Convocatoria FP7HEALTH-2007- 3.2-6: Health outcome measures andpopulation ageing. FP7 HEALTH-2007-3.

• José Luis Ayuso Mateos. Estrategias terapéuticas enel trastorno depresivo mayor resistente al tratamien-to de Inhibidores selectivos de la recaptación deSerotonina. Ensayo Clínico Pragmático paralelo,aleatorizado con evaluación enmascarada. DEPRES.ISCIII. EC07/90394.

• José Luis Ayuso Mateos. Multidisciplinary trainningnetwork on health and disability in Europe. MURINET.Unión Europea VI programa Marco. Marie Curie train-ning networks (Call FP&2005 Mobidity 1 UE Proposalnumber: MRTN-CT-2006-035794. MRTN-CT-2006-035794.

• José Luis Ayuso Mateos. Centros de investigaciónbiomédica en Red CIBER de Salud Mental. FIS.Acciones CIBER. CB07TEMP/003. CIBER

• José Luis Ayuso Mateos. Centro de InvestigaciónBiomédica en Red de Salud Mental: CIBER-SAM.ISCIII. CIBER CB07/09/0013. CIBER

• Luis Miguel García Olmos. Nuevos servicios asis-tenciales basados en telemedicina orientados apacientes crónicos y personas mayores dependi-entes. AmiVital y Ud. Investigación enTelemedicina y e-salud del Instituto de SaludCarlos III. CENIT (MICINN - CDTI). Entorno per-sonal digital para la salud y el bienestar - AmiVital(2007 - 2011).

• José Luis Ayuso Mateos. Estado de Salud, Calidadde Vida y Bienestar de la Población Española deEdad Avanzada: un Estudio Epidemiológico. ISCIII.PS09/00295.

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• José Luis Ayuso Mateos. Estudio Colaborativo delEnvejecimiento en Europa (COURAGE in Europe).MICINN. ACI2009/1010.

• Marta Miret García. Evaluación de servicios paratrastornos mentales, neurológicos y de abuso desustancias en Etiopía. Agencia Española deCooperación Internacional para el Desarrollo.Ministerio de Asuntos Exteriores y Cooperación.C/032127/10.

• Roberto Nuevo Benítez. Consumo de alcohol en per-sonas mayores en diferentes países europeos: determi-nantes y efectos en la salud, el funcionamiento y la dis-capacidad. Instituto de Mayores y Servicios Sociales(IMSERSO). Ministerio de Sanidad y Política Social.Convocatoria 2009 de Proyectos de InvestigaciónCientífica, Desarrollo e Innovación Tecnológica. 35/10.

• José Luis Ayuso Mateos. Scaling up services formental, neurological and substance use (MNS) disor-ders within WHO mental health Gap ActionProgramme (mhGAP). Unión Europea. Convocatoria:E u r o p e A i d / 1 2 9 1 9 7 / C / A C T / M u l t i .129197/C/ACT/Multi.

• José Luis Ayuso Mateos. Use of antidepressants inthe last decade and its relation to mortality and sui-cide-related events, with special focus on childrenand adolescents. CIBERSAM. ConvocatoriaIntramural. 11INT1.

• José Luis Ayuso Mateos. Metilfenidato de liberacióninmediata en la mejoría sintomática de la Maníaaguda: un estudio frente a placebo. CIBERSAM.Convocatoria Intramural. 11INT2.

• José Luis Ayuso Mateos. Metilfenidato de liberacióninmediata en la mejoría sintomática de la Maníaaguda: un estudio frente a placebo. Ministerio deSanidad y Política Social. EC10-110.

• José Luis Ayuso Mateos. Long-term Safety andTolerability of BMS-820836 in the Treatment ofPatients With Treatment Resistant Major Depression.Bristol-Myers Squibb. CN162-010.

• José Luis Ayuso Mateos. Efficacy and Safety of FixedDoses of BMS 820836 in the Treatment of Patients WithTreatment Resistant Major Depression. BMS. C162-007

• José Luis Ayuso Mateos. Una hoja de ruta para lainvestigación en salud mental y bienestar en Europa:ROAMER. MICINN. ACI Promociona. ACI-PRO-2011-1080

• José Luis Ayuso Mateos. Psycho-social AspectsRelevant to Brain Disorders in Europe. PARADISE.Comisión Europea. VII Programa Marco. FP7/2007-2013-241572

• Proyecto Coordinado. A Roadmap for Mental HealthResearch in Europe (ROAMER). Comisión Europea.VII Programa Marco. Health - F3 - 2011 - 282586

• Roberto Nuevo Benítez. Bienestar y salud mental yfísica en población general: un análisis longitudinal.ISCIII. PI11/02915

• Proyecto Coordinado. Metilfenidato de liberacióninmediata en la mejoría sintomática de la Maníaaguda: un estudio frente a placebo. CAIBER. 1392-D-079-EudraCT 2010-023992-24

• José Luis Ayuso Mateos. Ambiente y genes enesquizofrenia-Grupos de investigación de la comu-nidad de Madrid. CAM. S2010/BMD-2422


International Advisory Group for the Revision of ICD-10Mental and Behavioural Disorders (J.L. Ayuso-Mateos).A conceptual framework for the revision of the ICD-10classification of mental and behavioural disorders.World Psychiatry 10(2): 86-92. 2011. PMID: 21633677.IF: 5,562

Anarte Ortiz MT, Caballero FF, Ruiz de Adana MS,Rondán RM, Carreira M, Domínguez-López M,Machado A, Gonzalo-Marín M, Tapia MJ, Valdés S,González-Romero S, Soriguer FC. Development of anew fear of hypoglycemia scale: FH-15. PsycholAssess 23(2): 398-405. 2011. PMID: 21381839. IF:2,589

Barbui C, Cipriani A, Patel V, Ayuso-Mateos JL, vanOmmeren M. Efficacy of antidepressants and benzodi-azepines in minor depression: systematic review andmeta-analysis. Br J Psychiatry 198(1): 11-16. 2011.PMID: 21200071. IF: 5,947

Dua T, Barbui C, Clark N, Fleischmann A, Poznyak V,van Ommeren M, Yasamy MT, Ayuso-Mateos JL,Birbeck GL, Drummond C, Freeman M,

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Giannakopoulos P, Levav I, Obot IS, Omigbodun O,Patel V, Phillips M, Prince M, Rahimi-Movaghar A,Rahman A, Sander JW, Saunders JB, Servili C,Rangaswamy T, Unützer J, Ventevogel P,Vijayakumar L, Thornicroft G, Saxena S. Evidence-Based Guidelines for Mental, Neurological, andSubstance Use Disorders in Low- and Middle-Income Countries: Summary of WHORecommendations. PLoS Med 8(11): e10011. 2011.PMID: 22110406. IF: 15,617

Ortuño F, Guillén-Grima F, López-García P, Gómez J,Pla J. Functional neural networks of time perception:challenge and opportunity for schizophrenia research.Schizophr Res 2-3 (125): 129-135. 2011. PMID:21041067. IF: 4,374

Carmona M, García-Olmos LM, Alberquilla A, Muñoz A,García-Sagredo P, Somolinos R, Pascual-Carrasco M,Salvador CH, Monteagudo JL. Heart failure in the fam-ily practice: a study of the prevalence and co-morbidi-ty. Family Practice 28(2): 128-133. 2011. PMID:20978242. IF: 1,709

Nuevo R, Chatterji S, Fraguas D, Verdes E, Naidoo N,Arango C, Ayuso-Mateos JL. Increased risk of diabetesmellitus among persons with psychotic symptoms:results from the WHO World Health Survey. J ClinPsychiatry 72(12): 1592-1599. 2011. PMID:22244021. IF: 5,023

Ferrando L, Galea S, Sainz Cortón E, Mingote C,García Camba E, Fernandez Líria A, Gabriel R. Long-term psychopathology changes among the injured andmembers of the community after a massive terroristattack. Eur Psychiatry. 26(8): 513-7. 2011. PMID:20943349. IF: 3,365

Ezquiaga Terrazas E, García López A, Huerta Ramírez R,Pico Rada A. Prevalence of depression in primary careaccording to the methodology of the studies. Med Clin(Barc).137(13): 612-5. 2011. PMID: 20934195. IF: 1,413

Cabello M, Mellor-Marsá B, Sabariego C, Cieza A,Bickenbach J, Ayuso-Mateos JL. Psychosocial fea-tures of depression: A systematic literature review. J

Affect Disord. [Epub ahead of print]. 2011. PMID:22209189. IF: 3,74

Almansa J, Ayuso-Mateos JL, Garin O, Chatterji S,Kostanjsek N, Alonso J, Valderas JM, Cieza A, RaggiA, Svestkova O, Burger H, Racca V, Vieta E, LeonardiM, Ferrer M; MHADIE Consortium. The InternationalClassification of Functioning, Disability and Health:development of capacity and performance scales. JClin Epidemiol. 64(12): 1400-1411. 2011. PMID:21669511. IF: 3,753

Ayuso-Mateos JL, Wykes T, Arango C. The MadridDeclaration: why we need a coordinated Europe-wide effort in mental health research. Br JPsychiatry 198(8): 253-255. 2011. PMID:21972274. IF: 5,947

Almaraz MC, González-Romero S, Bravo M,Caballero FF, Palomo MJ, Vallejo R, Esteva I, CallejaF, Soriguer F. Incidence of lower limb amputations inindividuals with and without diabetes mellitus inAndalusia (Spain) from 1998 to 2006. Diabetes ResClin Pract [Epub ahead of print]. 2011. PMID:22133651. IF: 2,134

Ezquiaga E, Manzano-Luque M, Garcia-Polo I, vonWermitz A. Lethal catatonia as a manifestation ofmalignant bipolar disease. Rev Neurol 53(10): 638-639.2011. PMID: 22052179. IF: 1,218

Miret M, Nuevo R, Morant C, Sainz-Cortón E, Jiménez-Arriero MÁ, López-Ibor JJ, Reneses B, Saiz-Ruiz J,Baca-García E, Ayuso-Mateos JL. The role of suiciderisk in the decision for psychiatric hospitalization after asuicide attempt. Crisis 32(2): 65-73. 2011. PMID:21616755. IF: 1,383

Rivas Rodríguez M, Reed GM, First MB, Ayuso-MateosJL. Contributions from two Latin American psychiatricclassifications to the development of ICD-11. RevPanam Salud Publica 29(2): 130-137. 2011. PMID:21437371. IF: 0,762

Gallego I, Ezquiaga E, Betancor D, Sola RG, Pastor J.Psychogenic non-epileptic seizures in an epilepsy sur-

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gery unit. Rev Neurol. 52(8): 449-456. 2011. PMID:21425097. IF: 1,218

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: JOSE-LUIS AYUSOMATEOSEnsayo internacional: Metifenidato de liberacióninmediata en el tratamiento sintomático de la maníaaguda; (versión 1: 16-11-10). MEMAP1EudraCT: 2010-023992-24

PRINCIPAL INVESTIGATOR: JOSE-LUIS AYUSOMATEOSAplicación coordinada de un protocolo común para la doc-umentación de dificultades psicosociales. PARADISE

PRINCIPAL INVESTIGATOR: JOSE-LUIS AYUSOMATEOSEstudio de extensión, multicéntrico, doble ciego, de 58semanas de duración, para evaluar la seguridad y tol-erabilidad de BMS-820836 en pacientes con trastorno

depresivo mayor resistentes al tratamiento; (versión1.0.21-04-11). CN162-010EudraCT: 2010-024371-12

PRINCIPAL INVESTIGATOR: JOSE-LUIS AYUSOMATEOSEstudio multicéntrico, aleatorizado, doble ciego, con-trolado, comparativo con dosis fijas y de respuesta a ladosis, para evaluar la eficacia y seguridad de BMS-820836 en pacientes con trastorno depresivo mayorresistentes al tratamiento; (versión 1.0:25-04-11).Enmienda 1 de muestras de sangre para farmaco-genética v.3 de 25-04-11. CN162-007EudraCT: 2011-000778-71

PRINCIPAL INVESTIGATOR: JESUS VALLE FERNANDEZEstudio doble ciego, controlado frente a placebo,de grupos paralelos, a dosis fija, para evaluar la efi-cacia y la seguridad del tratamiento con armodafini-lo (150 y 200 mg/día) como terapia adjunta en adul-tos con Depresión Mayor asociada a TrastornoBipolar tipo I; (versión enmienda 3: 15-10-10).C10953/3071EudraCT: 2009-016667-11

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Line 2.5Neurosurgery of epilepsy

GROUP 34

HEAD OF LABORATORYRafael García de Sola

GROUP MEMBERS• Eva de Dios Tomás• Luís Domínguez Gadea• Eduardo García Navarrete• José Luís Martínez-Chacón Crespo• María Luisa Meilán Paz• Guillermo Ortega Rabbione• Desislava Panova Tzonova• Jesús Pastor Gómez• Paloma Pulido Rivas• Rybel Wix Ramos

RESEARCH INTEREST

The groups included in this line are focused in epilepsy,one of the most prevalent and sometimes devastatingneurologic diseases in humans. We address the prob-lem from different aspects, ranging from basic mecha-nisms of epileptogenesis, to new analytical and phar-

macological diagnostic tools. There are three differentPrograms inside the group:• Non-linear analysis of bioelectrical activity in patients

with epilepsy- Program Director: Guillermo J. Ortega.

Neurosurgery.• Activation of the epileptogenic area by etomidate in

patients with focal epilepsy- Program Director: Jesús Pastor. Clinical

Neurophysiology.• Role of astrocytes in epileptogenesis in human tem-

poral lobe epilepsy- Program Director: Jesús Pastor. Clinical

Neurophysiology.José Luis Martínez-Chacón. Anaesthesiology

Temporal lobe epilepsy is commonly associated withsynchronous, hyper-synchronous and des-synchro-nous activity. However, in patients suffering from tem-poral lobe epilepsy there exists a clear tendency in themesial area of the epileptic side to be organized as iso-lated clusters of electrical activity as compared with thecontra-lateral side, which is organized in the form oflarge clusters of synchronous activity. The number ofdesynchronized areas is larger in the epileptic side thanin the contra-lateral side in most of the patients.Therefore, the mesial area responsible for seizures isless synchronous than the contra-lateral one; the differ-ent kind of synchronous organization accounts for alower synchronization activity at the epileptic side, sug-gesting that this lack of synchronous cluster organiza-tion would favour the appearance of seizures. Ourresults shed new light regarding synchronization issuesin temporal lobe epilepsy and also it would help inreducing drastically the time of study. These results canhelp during the pre-surgical evaluation and also inimproving the understanding we have today of thispathophysiology.

On the other hand, we have revisited diverse aspectsrelated to epilepsy and astrocytes. Presently, one cannotbe certain which of these changes are causal or conse-quential to the epileptic process. However, there cannotbe doubt with regard to the participation of thesechanges in the disease. Properly understanding theprocess of epileptogenesis might lead to the develop-

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ment of new approaches directed at preventing theappearance of epilepsy. Diagnosis can be improved bymeasuring the levels of molecules in the brain by PET orSPECT scanning. A large body of data has been gleanedfrom animal models. However, animal models and thehuman pathology are not exactly equivalent; therefore,

most of these hypothesis must be tested in humans,where the actual illness occurs. To summarize, we canaffirm that astrocytes are undoubtedly very importantplayers in the process of epileptogenesis, although theirtrue role still needs to be completely uncovered.

MAJOR GRANTS

• Guillermo Ortega Rabbione. Identificación, caracteri-zación y papel de los clusters de sincronizaciónsobre la actividad epileptogénica en pacientes conepilepsia del lóbulo temporal. Fundación MutuaMadrileña.

• Jesús Pastor Gómez. Proyecto de la UniversidadSan Pablo-CEU para Grupos pre-competitivos.Universidad San Pablo-CEU para Grupos pre-com-petitivos. USPPPC08/09

• Jesús Pastor Gómez. Papel de la albúmina y de lapermeabilidad de la barrera hematoencefálica, en laactivación de los astrocitos en la epilepsia focalhumana. ISCIII. PS09/02116

• Jesús Pastor Gómez. Papel de la albúmina y de lapermeabilidad de la barrera hematoencefálica, en laactivación de los astrocitos en la epilepsia focalhumana. Universidad CEU-San Pablo. USP-PPC9/09

• Guillermo Ortega Rabbione. Análisis de registros deEEG-EFO por medio de redes complejas enpacientes con epilepsia del lóbulo temporal y susaplicaciones clínicas. MICINN. SAF2009-09406

• Guillermo Ortega Rabbione. Análisis de los registrosEEG-EFO por medio de redes complejas enpacientes con epilepsia del lóbulo temporal y susaplicaciones clínicas. ISCIII. PI10/00160


Herrera-Peco I, Pastor J, Alonso-Cerezo C, Sola RG,Ortega GJ. Significance of complex analysis of electri-cal activity in temporal lobe epilepsy: foramen ovaleelectrodes records. Rev Neurol. 52(1): 3-12. 2011.PMID: 21246488. IF: 1,218

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Cover of the journal. Lateral view of the fluoroscopy performed in theoperating room showing the final placement of the electrodes. Mesialaspect of the right temporal lobe and the right cerebellar hemispherein a model of brain and skull. Representative segments of FOE time se-ries. B) Up. Distance matrix for a particular temporal window. Rf1–Rf6stands for right FOE’s#1 to #6. Rf1 is the most rostral electrode. Lf1–Lf6stands for left FOE’s#1 to #6. Lf1 is the most rostral electrode. The otherlabels are according with the standard 10–20 nomenclature. Down.Dendogram extracted by using the agglomerative single-linkage pro-cedure from the distance matrix.(Ortega et al, Clin. Neurophysiol. 2011)C) Mechanisms of action of albumin in astrocytes. Depicted is the IP3-cytosolic calcium pathway with its proposed effect on gene transcrip-tion, indicated by the asterisk. TGF-βR signaling pathway is alsoshown. Both of these pathways are present in cultured human as-trocytes. * Hypothesized action (Pastor, Sola Underlying Mechanismsof Epilepsy, 2011).

Gallego I, Ezquiaga E, Betancor D, Sola RG, Pastor J.Psychogenic non-epileptic seizures in an epilepsy sur-gery unit. Rev Neurol. 52(8): 449-456. 2011. PMID:21425097. IF: 1,218

Alonso-Cerezo MC, Herrera-Peco I, Fernández-Millares V, Pastor J, Palacios-Espichan J,Hernando-Requejo V, Ortega GJ, Sola RG. Familyhistory of epilepsy resistant to treatment. RevNeurol. 52(9): 522-526. 2011. PMID: 21484723. IF:1,218

Torres C, Pastor J, Navarrete EG, Sola RG. Thalamicdeep brain stimulation for refractory epilepsy. RevNeurol. 53(2): 99-106. 2011. PMID: 21720980. IF:1,218

Torres C, Pastor J, Navarrete EG, Sola RG. Deep brainstimulation for refractory epilepsy: extrathalamic tar-gets. Rev Neurol. 53(3): 153-164. 2011. PMID:21748713. IF: 1,218

Ortega GJ, Peco IH, Sola RG, Pastor J. Impairedmesial synchronization in temporal lobe epilepsy. ClinNeurophysiol. 122(6): 1106-16. Epub 2010 Dec 24.2011. PMID: 21185775. IF: 2,786

Cano-Abad MF, Herrera-Peco I, Sola RG, Pastor J,García-Navarrete E, Moro RC, Pizzo P, Ruiz-Nuño A.New insights on culture and calcium signaling in neu-rons and astrocytes from epileptic patients. Int. J. DevNeurosci 29(2): 121-129. 2011. PMID: 21238565. IF:1,938

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Line 2.6Cerebrovascular diseases

GROUP 35HEAD OF LABORATORYJosé Aurelio Vivancos Mora

GROUP MEMBERS• Teresa Carreras Rodríguez• Lydia López Manzanares• Virginia Meca Lallana• Noemí Mora Pérez• Florentino Nombela Merchán• Gemma Reig Roselló• Mónica Sobrado Sanz

GROUP ASSOCIATED 1

HEAD OF LABORATORYIgnacio Lizasoain Hernández

GROUP MEMBERS• Tamara Atanes Pérez• Iván Ballesteros Martín• Roberto Cañadas Martín• María Isabel Cuartero Desviat• Isaac García de Yébenes y Castro• Víctor Manuel González Romera• Macarena Hernández Jiménez• Olivia Hurtado Moreno• Ana Moraga Yébenes• María Ángeles Moro Sánchez

RESEARCH INTEREST (G.35 & G.ASSOC 1)

The Neurological Service and Stroke Unit of HospitalUniversitario de la Princesa is a medical service of theSpanish public health system specialized in neurologicaldiseases. It is public provider of neurological medical carefor the entire health district #2 (metropolitan population ofMadrid, 320.744 people), the rest of the population ofhealth district #2: Hospital de Henares (164.810 people)and throughout health district #3 (Hospital UniversitarioPríncipe de Asturias 380.757 people). We are the refer-ence Center for specific processes and special proce-dures such as stroke center and stroke unit, Madridregion stroke code system, thrombolysis and emergingtherapies and interventional neuroradiology unit.

We are doing 17.000 outpatient visits and more than700 admissions per year.

The Neurology Service of Hospital Universitario de laPrincesa has a neurology teaching program certified for


pre and post-degree, assigned to UniversidadAutónoma de Madrid and an accredited clinicalresearch tradition for nearly 50 years.

The main research lines of The Neurology Service ofHospital Universitario de la Princesa are:• Stroke and Cerebrovascular Diseases,

- Biomolecular markers of ischemia and new thera-peutic targets

- Interventional neuroradiology and emerging thera-pies

- Population-based health services delivery / strokecode 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 oldpatients

- Cognitive impairment and dementia in Down syn-drome

• Multiple Sclerosis.- Outcome markers and new therapies

The results obtained by our group during 2011 include:4 guidelines and 7 papers published in internationaljournals belonging to the Neurosciences field anddirectly related to stroke (Eur J Med, Stroke,Neuroimage, etc…), 1 major grant (in Stroke; publicagency), about 10 clinical trials (in Stroke, MultipleSclerosis and Alzheimer´s and Parkinson´s disease; pri-vate companies) and 1 patent application.

The Neurovascular Research Unit (UIN), located at theDepartment of Pharmacology of the School ofMedicine at the Universidad Complutense is an associ-ated group of the “Instituto de Investigación SanitariaLa Princesa”. It was formed in 1996 and since then ourteam has been studying the pathophysiology and phar-macology of stroke. Our unit is devoted to the study ofthe cerebrovascular disease (stroke) from a basic pointof view but also with a strong translational projection, avocation due to our location in a School of Medicineand developed through a tight partnership with Institutode Investigación Sanitaria La Princesa.

The results obtained by our group during 2011, includemore than 10 papers published in international journalsbelonging to the Neurosciences field and directly relat-ed to cerebral ischemia (Ann Neurol, Stroke,Neuroimage, etc…), 1 PhD Thesis and 2 patents.

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Study of recruited and recoverable tissue by using 18F-FDG uptake,ADC and CBF values in a transient focal ischemia model. (Sobrado etal., Neuroimage, 2011)

Effect of early or late administration of tPA on macroscopic hemorrha-ges. Hemorrhages were classified by type and extension in 4 groups:(1) no-hemorrhage; (2) HI-1; (3) HI-2; and (4) PH-1. (García-Yébenes etal., Stroke, 2011).

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MAJOR GRANTS

• Ignacio Lizasoain Hernández. Diseño de modelos para eldesarrollo de terapias neuroreparadoras en ictus.CIDEM-Ferrer Internacional SA.

• María Ángeles Moro Sánchez. Estudio del efecto neuro-protector de compuestos de origen marino en los dañoscausados por la isquemia cerebral. MICINN. ConsorcioDENDRIA. Subproyecto 10/DEN005

• Ignacio Lizasoain Hernández. Doble función de losreceptores "Toll-like" en el ictus: reguladores de daño yreparación. MICINN. SAF2011-23354

• Ignacio Lizasoain Hernández. Implicacion de los recep-tores "Toll-like" en el ictus. MICINN. SAF2008-03122

• María Ángeles Moro Sánchez. Brain dysfunction duringaging: relevance for Alzheimer’s disease. MICINN.CSD2010-00045

• María Ángeles Moro Sánchez. Papel de los ReceptoresNucleares PPARgamma y LXR en la isquemia cerebral:De la inflamación a la neurorreparación. MICINN.SAF2009-08145 (Subprograma NEF)

PUBLICATIONS (12) [IF G35: 27,913] [IF GA1: 34,114]

Rodríguez-Yáñez M, Sobrino T, Arias S, Vázquez-Herrero F, Brea D, Blanco M, Leira R, Castellanos M,Serena J, Vivancos J, Dávalos A, Castillo J. Early bio-markers of clinical-diffusion mismatch in acute ischemicstroke. Stroke 42(10): 2813-2818. 2011. PMID:21836082. IF: 5,756

Martínez-Sánchez P, Fuentes B, de Leciñana MA, MasjuanJ, Simal P, Egido J, Díaz-Otero F, García-Pastor A, Gil-Nuñez A, Reig G, Vivancos J, Díez-Tejedor E. Female gen-der is a factor of worse outcome in acute stroke even afterthrombolytic treatment. Madrid Stroke Network. Int JStroke. 6(4): 371-372. 2011. PMID: 21745351. IF: 3,125

Vera R, Lago A, Fuentes B, Gállego J, Tejada J, Casado I,Purroy F, Delgado P, Simal P, Martí-Fábregas J, Vivancos J,Díaz-Otero F, Freijo M, Masjuan J; Stroke Project of theSpanish Cerebrovascular Diseases Study Group. In-hospi-tal stroke: a multi-centre prospective registry. Eur J Neurol18 (1): 170-176. 2011. PMID: 20550562. IF: 3,765

Fuentes B, Gállego J, Gil-Nuñez A, Morales A, Purroy F,Roquer J, Segura T, Tejada J, Lago A, Díez-Tejedor E; porel Comitéad hoc del GROUP de Estudio de EnfermedadesCerebrovasculares de la SEN: , Alonso de Leciñana M,Alvarez-Sabin J, Arenillas J, Calleja S, Casado I, CastellanosM, 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, Martí-Fábregas J, Martínez-SánchezP, Martínez-Vila E, Molina C, Nombela F, Ribó M,Rodríguez-Yañez M, Rubio F, Serena J, Simal P, Vivancos J.Guidelines for the preventive treatment of ischaemic strokeand TIA (I). Update of risk factors and life style. Neurologia[Epub ahead of print]. 2011. PMID: 21890241. IF: 0,589

Rodríguez-Yáñez M, Castellanos M, Freijo MM, LópezFernández JC, Martí-Fàbregas J, Nombela F, Simal P,Castillo J; por el Comitéad hoc del GROUP de Estudio deEnfermedades Cerebrovasculares de la SEN: , Díez-TejedorE, Fuentes B, Alonso de Leciñana M, Alvarez-Sabin J,Arenillas J, Calleja S, Casado I, Dávalos A, Díaz-Otero F,Egido JA, Gállego J, García Pastor A, Gil-Núñez A, Gilo F,Irimia P, Lago A, Maestre J, Masjuan J, Martínez-SánchezP, Martínez-Vila E, Molina C, Morales A, Purroy F, Ribó M,Roquer J, Rubio F, Segura T, Serena J, Tejada J, VivancosJ. Clinical practice guidelines in intracerebral haemorrhage.Neurologia [Epub ahead of print]. 2011. PMID: 21570742.IF: 0,589

Fuentes B, Martínez-Sánchez P, Alonso de Leciñana M,Simal P, Reig G, Díaz-Otero F, Masjuán J, Egido J, VivancosJ, Gil-Nuñez A, Díez-Tejedor E. Guidelines for the preventivetreatment of ischaemic stroke and TIA (II).Recommendations according to aetiological sub-type.Neurologia [Epub ahead of print]. 2011. PMID: 21937151.IF: 0,589

Alonso de Leciñana M, Egido JA, Casado I, Ribó M,Dávalos A, Masjuan J, Caniego JL, Martínez Vila E,Díez Tejedor E; por el Comitéad hoc del GROUP deEstudio de Enfermedades Cerebrovasculares de laSEN: , Fuentes Secretaría B, Alvarez-Sabin J, ArenillasJ, Calleja S, Castellanos M, Castillo J, Díaz-Otero F,López-Fernández JC, Freijo M, Gállego J, García-Pastor A, Gil-Núñez A, Gilo F, Irimia P, Lago A, MaestreJ, Martí-Fábregas J, Martínez-Sánchez P, Molina C,Morales A, Nombela F, Purroy F, Rodríguez-Yañez M,


Roquer J, Rubio F, Segura T, Serena J, Simal P, TejadaJ, Vivancos J. Guidelines for the treatment of acuteischaemic stroke. Neurologia [Epub ahead of print].2011. PMID: 22152803. IF: 0,589

García-Yébenes I, Sobrado M, Zarruk JG, Castellanos M,Pérez de la Ossa N, Dávalos A, Serena J, Lizasoain I, MoroMA. A mouse model of hemorrhagic transformation bydelayed tissue plasminogen activator administration after insitu thromboembolic stroke. Stroke 42(1): 196-203. 2011.PMID: 21106952. IF: 5,756

Sobrado M, Delgado M, Fernández-Valle E, García-GarcíaL, Torres M, Sánchez-Prieto J, Vivancos J, Manzanares R,Moro MA, Pozo MA, Lizasoain I. Longitudinal studies ofischemic penumbra by using 18F-FDG PET and MRI tech-niques in permanent and transient focal cerebral ischemia inrats. Neuroimage 57(1): 45-54. 2011. PMID: 21549205. IF:5,937

Zarruk JG, Garcia-Yebenes I, Romera VG, Ballesteros I,Moraga A, Cuartero MI, Hurtado O, Sobrado M, PradilloJM, Fernandez-Lopez D, Serena J, Castillo-Melendez M,Moro MA, Lizasoain I. Neurological tests for functional out-come assessment in rodent models of ischaemic stroke.Rev Neurol. 53(10): 607-618. 2011. PMID: 22052176. IF:1,218

Bustamante MF, Fissolo N, Río J, Espejo C, Costa C,Mansilla MJ, Lizasoain I, Moro MA, Carmen Edo M,Montalban X, Comabella M. Implication of the Toll-likereceptor 4 pathway in the response to interferon-ß in multi-ple sclerosis. Ann Neurol 70(4): 634-645. 2011. PMID:22028223. IF: 10,746

Hurtado O, Lizasoain I, Moro MÁ. Neuroprotection andrecovery: recent data at the bench on citicoline. Stroke42(S1): S33-S35. 2011. PMID: 21164125. IF: 5,756

Rodríguez-González R, Millán M, Sobrino T, Miranda E,Brea D, de la Ossa NP, Blanco M, Perez J, Dorado L,Castellanos M, Lomas DA, Moro MA, Dávalos A,Castillo J. The natural tissue plasminogen activatorinhibitor neuroserpin and acute ischaemic stroke out-come. Thromb Haemost 105(3): 421-429. 2011. PMID:21174006. IF: 4,701

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: LYDIA LOPEZ MAN-ZANARESEstudio Epidemiológico prospectivo sobre la evolución de laEnfermedad de Parkinson idiopática en pacientes en esta-dios iniciales (Estudio EPI-PARK); (versión 2.0: 27-03-09).H.LU: 12945A

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORACiticolina en el tratamiento del ictus isquémico agudo.Estudio internacional, multicéntrico, aleatorizado y controla-do con placebo; (versión final: 28-10-05). GF-ICTUS-04EudraCT: 2005-004825-25

PRINCIPAL INVESTIGATOR: CAMINO SEVILLA GOMEZEstudio observacional de satisfacción con fármacos para eltratamiento de la Enfermedad de Alzheimer. A2501058

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEnsayo de fase III, multicéntrico, aleatorizado, en dobleciego, controlado con placebo y de grupos paralelos, sobrela eficacia y la seguridad del bapineuzumab (AAB-001,ELN115727) en pacientes con enfermedad de Alzheimerde grado leve a moderado que son portadores de laapolipoproteína E (ApoE)e4; (versión original: 26-11-07).3133K1-3001-WWEudraCT: 2007-005995-14

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEnsayo de fase III, multicéntrico, aleatorizado, en dobleciego, controlado con placebo y de grupos paralelos, sobrela eficacia y la seguridad del bapineuzumab (AAB-001,ELN115727) en pacientes con enfermedad de Alzheimerde grado leve a moderado que no son portadores de laapoli-poproteína E(ApoE)e4; (versión original: 26-11-07).3133K1-3000-WWEudraCT: 2007-005994-79

PRINCIPAL INVESTIGATOR: GEMMA REIG ROSELLOENOS. Eficacia del Óxido Nítrico en el Ictus; (versión 1.3:16-08-01). RA2363EudraCT: 2004-003870-27

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEnsayo de extensión de fase 3, multicéntrico, en doble

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ciego y de gruposparalelos, sobre la seguridad y la tolera-bilidad a largo plazo del bapineuzumab (AAB-001,ELN115727) en sujetos con enfermedad de Alzheimer queno son portadores de la apolipoproteína E E4 y han partic-ipado en elestudio 3133K1-3000-WW; (versión: 01-10-09).3133K1-3002-WWEudraCT: 2009-015079-29

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEnsayo de extensión de fase 3, multicéntrico, sobre laseguridad y la tolerabilidad a largo plazo del bapineuzumab(AAB-001, ELN115727) en sujetos con enfermedad deAlzheimer que son portadores de la apolipoproteína E E4 yhan participado en el estudio 3133K1-3001-WW; (vesión:01-10-09). 3133K1-3003-WWEudraCT: 2009-015080-13

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEstudio fundamental aleatorizado, con doble ciego, con-trolado con placebo, con grupos paralelos, multicéntri-co, en fase III, para evaluar la seguridad y la eficacia de1 mg/kg/día de DP-b99 administrado por vía intra-venosa durante 4 días consecutivos frente a placebo,cuando se inicia en el plazo de nueve horas desde el ini-cio del Ictus isquémico; (Versión: 30-08-09). 01373EudraCT: 2009-012025-11

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAEstudio multicéntrico, doble ciego, controlado con placebo,de grupos paralelos para evaluar la eficacia y seguridad deteriflunomida en pacientes con esclerosis múltiple recur-rente que están en tratamiento con interferón-beta; (versión2: 04-10-10). Estudio TERACLES. EFC6058EudraCT: 2010-023172-12

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORARegistro internacional, prospectivo, basado en una clínicade AIT, en linea y con seguimiento a largo plazo;(Versión:30-10-2008). TIAREGISTRY

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEstudio fase III, controlado con warfarina, aleatorizado,doble ciego y de brazos paralelos, para evaluar la seguridady la eficacia de Apixabanen la prevención de accidentecerebrovascular y embolismo sistémico en pacientes confibrilación auricular no valvular; (versión española 1.0: 04-

11-06). CV185-030EudraCT: 2006-002147-91

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAAX200 para el tratamiento del accidente cerebral isquémi-co. Un estudio de fase II multinacional, multicéntrico,aleatorizado, doble ciego, controlado con placebo; (versiónfinal 1.1: 12-01-09). AX200-101

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAEstudio de fase III, multicéntrico, aleatorizado, de gruposparalelos, doble ciego,controlado con placebo para evaluarla eficacia y la seguridad de ocrelizumab en adultos conesclerosis múltiple progresiva primaria; (versión A: 23-06-10). WA25046EudraCT: 2010-020338-25

PRINCIPAL INVESTIGATOR: FLORENTINO NOMBELAMERCHANEstudio de calidad de vida en pacientes con espasticidaddebida a esclerosis múltiple. Estudio CANDLE; (versión 3.1:27-8-10). DMM02SAT10

PRINCIPAL INVESTIGATOR: GEMMA REIG ROSELLOHiperglucemia en el infarto cerebral agudo. Oportunidad dela reducción de la glucemia capilar >155mg/dl y su impactoen la evolución. GLIAS2

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAEstudio observacional para evaluar el cumplimiento ter-apéutico de los pacientes con esclerosis múltiple entratamiento con terapias modificadoras de la enfermedadde primera línea. Estudio COMPLIANCE in MS; (versionfinal: 06-10-10). NOV-TME-2010-01

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAEnsayo clínico fase IIa, multicéntrico, doble ciego para eval-uar la eficacia y seguridad de dosis bajas de diazoxida oralen el tratamiento dela Esclerosis Múltiple; (versión 1.0: 22-11-10). NT-KO-003-2010-01

PRINCIPAL INVESTIGATOR: MARIA-TERESA CARRERASRODRIGUEZEstudio multicéntrico, aleatorizado, doble-ciego, controladocon placebo de 4 grupos paralelos y 26 semanas deduración para evaluar la eficacia, seguridad y tolerabilidad


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de dos dosis orales y dos regimenes de tideglusib versusplacebo en pacientes con Enfermedad de Alzheimer leve omoderada (ESTUDIO ARGO); (versión 1:24-12-10).NP031112-10B04EudraCT: 2010-023322-21

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAEnsayo clínico, abierto, no aleatorizado, de grupos parale-los, multicéntrico para evaluar la eficacia de fingolimodcomo terapia en pacientes de novo vs. fingolimod comoterapia en pacientes previamente tratados con interferoneso acetato de glatirámero, en base a la presencia de brotes,en pacientes con esclerosis múltiple remitente-recurrente.Estudio EARLIMS; (versión final: 10-03-11).CFTY720DES03

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAEnsayo clínico multicéntrico en Fase IIIb, de un solo brazo,para investigar el valor predictivo del estatus cognitivo basalen la conversión a esclerosis múltiple de pacientes CIS entratamiento con Rebif44 mcg una vez por semana; (versión1:8-07-11). MER-INT-2011-02EudraCT: 2011-003481-32

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANACambios de tratamiento con fármacos modificadores de laenfermedad en esclerosis múltiple remitente recurrente:causas y consecuencias; Estudio CAFeem: (Versión 3: 3-03-11). DIREG_L_05751

PRINCIPAL INVESTIGATOR: MARIA-TERESA CARRERASRODRIGUEZEstudio ROSA: Validación de la versión española de laescala Relevant Outcome Scale for Alzheimer's disease(ROSA); (Versión 1.0: 07-09-11). GRU-ALZ-2011-01

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAEstudio observacional retrospectivo sobre la conductamédica ante un paciente con un primer episodio de enfer-medad inflamatoria desmielinizante; (Versión 2 trasEnmienda, 30-03-10). COMETA DIREG_L_04819

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEstudio multicéntrico, doble ciego, aleatorizado, controladocon placebo de dosis escaladas de deferoxamina intra-venosa en pacientes con ictusisqémico agudo tratado conactivador tisular de plasminógeno. versión1: 30-11-07.TANDEM-1EudraCT: 2007-006731-31

PRINCIPAL INVESTIGATOR: VIRGINIA MECA LALLANAAdaptación cultural y validación al español del MSTreatment Concerns Questionnaire-MSTCQ". Estudio SAT-ISFACTION; (Versión 2.0: 21-2-11). NOV-INT-2011-01

PRINCIPAL INVESTIGATOR: AURELIO VIVANCOS MORAEstudio de costes en pacientes con infarto cerebral car-dioembólico en la Comunidad de Madrid. Estudio CODICE;(versión 2:10-10-11). PFI-ICT-2011-01

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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.

ADVANCED THERAPIES AND INDIVIDUALIZED MEDICINE

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ADVANCED THERAPIES AND INDIVIDUALIZED MEDICINE

Line 3.1Prognostic and predictor markers in autoimmune diseases

GROUP 36

HEAD OF LABORATORYIsidoro González Álvaro

GROUP MEMBERS• José María Álvaro-Gracia Álvaro• Santos Castañeda Sanz• Isabel Castrejón Fernández• Belén Díaz Sánchez• Carlos Gamallo Amat• Jesús Alberto García Vadillo• Rosario García de Vicuña Pinedo• María de las Nieves Gómez León• Amalia Lamana Domínguez• Ana María Ortiz García• Esther Patiño Ruiz• Eva Gloria Tomero Muriel• Teresa Velasco Ripoll• Esther Francisca Vicente Rabaneda

RESEARCH INTEREST

Our group had an exceptional scientific productionduring the year 2011. Most of our publications werethe result of an intense collaborative effort eitherwith other groups that belong to the IIS La Princesaor with groups of the Network of Inflammation andRheumatic Diseases (RIER) that belongs to theRETICS program from the Instituto de Salud CarlosIII (ISCIII). Our research is mainly focused on thedetection of cardiovascular risk factors and prog-nostic factors in rheumatoid arthritis, as well as thestudy of security aspects in biological therapies.However, many other rheumatologic diseases suchas systemic lupus erythematosus, systemic vasculi-tis, osteoporosis, osteoarthritis, etc. are objectives

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Intensity of treatment in a population of early arthritis patients. A) Cumulative DMARD treatment during the follow-up period, estima-ted through the IDT variable (a variable designed to assess the inten-sity of treatment with DMARD irrespective of which one was use), inthe different subpopulations clustered by the elevated IL-15 serum le-vels (IL-15 h), the presence of rheumatoid factor (RF+) and/or anti-ci-trullinated peptides antibodies (ACPA+). B) Distribution of the cumulative glucocorticoid dose adjusted to thenumber of days of follow-up in the different subpopulations clusteredby the elevated sIL-15, RF and/or ACPA. Grey boxes represent thosepatients with high IL-15 alone or in combination with other biomar-kers. In all panels the data are presented as the interquartile range (p75 up-per edge of the box, p25 lower edge, p50 midline in the box), as well asthe p95 (upper line from the box) and p5. Dots represent the outliers.Statistical significance was established through Kruskal-Wallis test.

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of the research work conducted by our researchers.Thus, as a result of this intense activity of the group,some of its members have been requested to partic-ipate in the drafting of several documents to estab-lish consensus guidelines for the rational use of bio-logical therapies or imaging techniques in which theestablishment of proper cost / benefit ratio is ofgreat importance in the current economic situation.It is also a privilege and a pleasure that in the last callfor Health Research Grants from the ISCIII threeprojects, whose principal investigators are membersof our group (Dr. Nieves Gómez León, Dr. Ana MOrtiz and Dr Isidoro Gonzalez-Alvaro), have beengranted. We would like to emphasize that the resultsof this year are the consequence of long years ofeffort. The figure accompanying this summary is agood example, since the work for this paper pub-lished in late 2011 in PLoS One began in September2001.

Finally, we thank our patients for their generous collab-oration in our research projects. Most likely their willing-ness to participate in our studies is that it is clear tothem our intention to discover biomarkers that allow usto treat them more efficiently.

MAJOR GRANTS

• Isidoro González Álvaro. Estudio del efecto de lospolimorfismos de CD69, HLA-DRB1, PTPN22 ySTAT-4 en el curso clínico de pacientes con artritis dereciente comienzo. ISCIII. FIS PI080754

• Isidoro González Álvaro. Mecanismos moleculares ycelulares en enfermedades inflamatorias crónicas yautoinmunes. Proyecto MEICA. Proyectos de I+D+ide Cooperación público-privada de GenómicaAplicada y Biotecnología de Genoma España.Genoma España

• Isidoro González Álvaro. Red de Investigación enInflamación y Enfermedades Reumáticas. ISCIII.RD08/0075/0004

• Santos Castañeda Sanz. Predictive value of corticalbone mineral density variation determined by radi-ogrammetry at metacarpal bones as a prognosticmarker in early arthritis. Pfizer.

• Isabel Castrejón Fernández. Development of anonline “toolbox” including indices and measures inrheumatology with special emphasis on PatientReported Outcomes (PRO). EULAR.

• Jesús Alberto García Vadillo. Estudio de prevalenciade fracturas en mujeres con Artritis Reumatoide oLupus Eritematoso Sistémico en tratamiento crónicocon glucocorticoides. Eli Lilly and Company. ProtocolB3D-XM-GHDP

• María de las Nieves Gómez León. Evaluación de latécnica TC multidetector 64 frente a la PET/CT en elEstudio clínico de pacientes con Linfoma y su estu-dio de Coste efectividad: Estudio Multicéntrico. ISCI-II. PI11/01800

• Isabel Castrejón Fernández. Relative efficiencies of 7RA core data set measures and 3 indices to distin-guish between tight control in the GUEPARD cohort(DAS28-ESR-driven therapy with anti-TNF agents)versus routine care in the ESPOIR cohort. NYU-Hospital for Joint Diseases and Hospital Cochin,Paris.

• Proyecto Coordinado. RELESSER. Registro españolde pacientes con lupus eritematoso sistémico. SER.

• Santos Castañeda Sanz. Valor predictivo de la pérdi-da mineral ósea cortical determinada mediante radi-ogrametría como marcador pronóstico en pacientescon artritis de inicio. PFIZER España.


Carmona FD, Serrano A, Rodríguez-Rodríguez L,Castañeda S, Miranda-Filloy JA, Morado IC, Narváez J,Solans R, Sopeña B, Marí-Alfonso B, Unzurrunzaga A,Ortego-Centeno N, Blanco R, de Miguel E, Hidalgo-Conde A, Martín J, González-Gay MA. A nonsynony-mous functional variant of the ITGAM gene is notinvolved in biopsy-proven giant cell arteritis. JRheumatol. 38(12): 2598-601. Epub 2011 Oct 1. 2011.PMID: 21965647. IF: 3,551

Busquets N, Tomero E, Descalzo MÁ, Ponce A, Ortiz-Santamaría V, Surís X, Carmona L, Gómez-Reino JJ;BIOBADASER 2.0 Study Group. Age at treatment pre-dicts reason for discontinuation of TNF antagonists:data from the BIOBADASER 2.0 registry.

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Advanced therapies and individualized medicine

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AREA 3Rheumatology (Oxford) 50(11): 1999-2004. 2011.PMID: 21856725. IF: 4,171

Teruel M, Martin JE, González-Juanatey C, López-Mejias R, Miranda-Filloy JA, Blanco R, Balsa A,Pascual-Salcedo D, Rodriguez-Rodriguez L,Fernández-Gutierrez B, Ortiz AM, González-AlvaroI, Gómez-Vaquero C, Bottini N, Llorca J, González-Gay MA, Martin J. Association of acid phosphataselocus 1*C allele with the risk of cardiovascularevents in rheumatoid arthritis patients. Arthritis ResTher. 13(4): R116. 2011. PMID: 21767392. IF:4,357

Herrero-Beaumont G, Roman-Blas JA, Largo R,Berenbaum F, Castañeda S. Bone mineral density andjoint cartilage: four clinical settings of a complex rela-tionship in osteoarthritis. Ann Rheum Dis. 70(9): 1523-5. Epub 2011 Jul 7. 2011. PMID: 21742638. IF: 9,082

Carmona L, Abasolo L, Descalzo MA, Pérez-Zafrilla B,Sellas A, de Abajo F, Gomez-Reino JJ; BIOBADASERStudy Group (Ortiz AM, Tomero E); EMECAR StudyGroup (González-Alvaro I). Cancer in patients withrheumatic diseases exposed to TNF antagonists.Semin Arthritis Rheum 41(1): 71-80. 2011. PMID:21093020. IF: 4,744

Castrejón I, Silva-Fernández L, Bombardier C,Carmona L. Clinical composite measures of diseaseactivity for diagnosis and followup of undifferentiatedperipheral inflammatory arthritis: a systematic review. JRheumatol Suppl (87): 48-53. 2011. PMID: 21364057.IF: 3,551

Cruz Fernández-Espartero M, Pérez-Zafrilla B, NaranjoA, Esteban C, Ortiz AM, Gómez-Reino JJ, Carmona L;BIOBADASER Study Group (Tomero E). Demyelinatingdisease in patients treated with TNF antagonists inrheumatology: data from BIOBADASER, a pharma-covigilance database, and a systematic review. SeminArthritis Rheum 41(3): 524-33. 2011. PMID: 22152489.IF: 4,744

Silva-Fernández L, Castrejón I, Bombardier C,Carmona L. Diagnostic and prognostic value of genet-ics in undifferentiated peripheral inflammatory arthritis:

a systematic review. J Rheumatol Suppl (87): 38-44.2011. PMID: 21364055. IF: 3,551

Pinilla I, Gómez-León N, Del Campo-Del Val L,Hernandez-Maraver D, Rodríguez-Vigil B, Jover-DíazR, J Coya J. Diagnostic value of CT, PET and com-bined PET/CT performed with low-dose unenhancedCT and full-dose enhanced CT in the initial staging oflymphoma. Q J Nucl Med Mol Imaging. 55(5): 567-75.Epub 2010 Dec 9. 2011. PMID: 21150860. IF: 2,537

Bellido M, Lugo L, Roman-Blas JA, Castañeda S, CalvoE, Largo R, Herrero-Beaumont G. Improving subchondralbone integrity reduces progression of cartilage damage inexperimental osteoarthritis preceded by osteoporosis.Osteoarthritis Cartilage. 19(10): 1228-36. Epub 2011 Jul23. 2011. PMID: 21820069. IF: 3,953

Pérez-Sola MJ, Torre-Cisneros J, Pérez-Zafrilla B,Carmona L, Descalzo MA,Gómez-Reino JJ;BIOBADASER Study Group (Tomero E). Infections inpatients treated with tumor necrosis factor antagonists:incidence, etiology and mortality in the BIOBADASERregistry. Med Clin (Barc). 137(12): 533-40. 2011. PMID:21514606. IF: 1,413

Tak PP, Rigby WF, Rubbert-Roth A, Peterfy CG, vanVollenhoven RF, Stohl W, Hessey E, Chen A, Tyrrell H,Shaw TM; IMAGE Investigators (Alvaro-Gracia JM).Inhibition of joint damage and improved clinical out-comes with rituximab plus methotrexate in early activerheumatoid arthritis: the IMAGE trial. Ann Rheum Dis 1(70): 39-46. 2011. PMID: 20937671. IF: 9,082

González-Álvaro I, Ortiz AM, Alvaro-Gracia JM,Castañeda S, Díaz-Sánchez B, Carvajal I, García-Vadillo JA, Humbría A, López-Bote JP, Patiño E,Tomero EG, Vicente EF, Sabando P, García-Vicuña R.Interleukin 15 levels in serum may predict a severe dis-ease course in patients with early arthritis. PLoS One.6(12): e29492. 2011. PMID: 22242124. IF: 4,411

López-Mejías R, García-Bermúdez M, González-Juanatey C, Castañeda S, Pérez-Esteban 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. Lack of

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AREA

3

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association between IL6 single nucleotide polymor-phisms and cardiovascular disease in Spanishpatients with rheumatoid arthritis. Atherosclerosis.219(2): 655-8. Epub 2011 Aug 5. 2011. PMID:21889771. IF: 4,086

López-Mejías R, García-Bermúdez M, González-Juanatey C, 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. Lack of association ofIL6R rs2228145 and IL6ST/gp130 rs2228044 genepolymorphisms with cardiovascular disease in patientswith rheumatoid arthritis. Tissue Antigens. 78(6): 438-41. Epub 2011 Oct 10. 2011. PMID: 21981268. IF:3,024

Machado P, Castrejon I, Katchamart W, Koevoets R,Kuriya B, Schoels M, Silva-Fernández L, Thevissen K,Vercoutere W, Villeneuve E, Aletaha D, Carmona L,Landewé R, van der Heijde D, Bijlsma JW, Bykerk V,Canhão H, Catrina AI, Durez P, Edwards CJ,Mjaavatten MD, Leeb BF, Losada B, Martín-Mola EM,Martinez-Osuna P, Montecucco C, Müller-Ladner U,Østergaard M, Sheane B, Xavier RM, Zochling J,Bombardier C. Multinational evidence-based recom-mendations on how to investigate and follow-up undif-ferentiated peripheral inflammatory arthritis: integratingsystematic literature research and expert opinion of abroad international panel of rheumatologists in the 3EInitiative. Ann Rheum Dis 1 (70): 15-24. 2011. PMID:20724311. IF: 9,082

Rodríguez-Vigil Junco B, Gómez León N, PinillaFernández I, del Campo L, Hernández Maraver D,Coya J. Non-Hodgkin's lymphoma staging: a prospec-tive study of the value of positron emission tomogra-phy/computed tomography (PET/CT) versus PET andCT. Med Clin (Barc). 137(9): 383-9. Epub 2011 Jun 23.2011. PMID: 21703647. IF: 1,413

Askanase AD, Castrejon I, Pincus T. Quantitative datafor care of patients with systemic lupus erythematosusin usual clinical settings: a patient MultidimensionalHealth Assessment Questionnaire and physician esti-mate of noninflammatory symptoms. J Rheumatol 38:

1309-16. Epub 2011 Mar 21. 2011. PMID: 21459938.IF: 3,551

Rodríguez-Rodríguez L, Carmona FD, Castañeda S,Miranda-Filloy JA, Morado IC, Narváez J, Marí-Alfonso B, Gómez-Vaquero C, Amigo-Díaz E, Ríos-Fernández R, Blanco R, Llorca J, Fernández-Gutiérrez B, Martín J, González-Gay MA. Role ofrs1343151 IL23R and rs3790567 IL12RB2 polymor-phisms in biopsy-proven giant cell arteritis. JRheumatol. 38(5): 889-92. Epub 2011 Feb 1. 2011.PMID: 21285166. IF: 3,551

Carmona L, Descalzo MA, Ruiz-Montesinos D,Manero-Ruiz FJ, Perez-Pampin E, Gomez-Reino JJ;BIOBADASER 2.0 Study Group (..., Ortiz AM, ...).Safety and retention rate of off-label uses of TNFantagonists in rheumatic conditions: data from theSpanish registry BIOBADASER 2.0. Rheumatology(Oxford). 50(1): 85-92. Epub 2010 Jul 3. 2011. PMID:20601654. IF: 4,171

Pato E, Muñoz-Fernández S, Francisco F, Abad MA,Maese J, Ortiz A, Carmona L; Uveitis Working Groupfrom Spanish Society of Rheumatology. Systematicreview on the effectiveness of immunosuppressantsand biological therapies in the treatment of autoim-mune posterior uveitis. Semin Arthritis Rheum 40(4):314-323. 2011. PMID: 20656330. IF: 4,744

Rodríguez-Rodríguez L, Taib WR, Topless R, Steer S,González-Escribano MF, Balsa A, Pascual-SalcedoD, González-Gay MA, Raya E, Fernandez-GutierrezB, González-Álvaro I, Bottini N, Witte T, Viken MK,Coenen MJ, van Riel PL, Franke B, den Heijer M,Radstake TR, Wordsworth P, Lie BA, Merriman TR,Martín J. The PTPN22 R263Q polymorphism is a riskfactor for rheumatoid arthritis in Caucasian case-control samples. Arthritis Rheum 63(2): 365-372.2011. PMID: 21279993. IF: 8,435

López-Santalla M, Salvador-Bernáldez M, González-Alvaro I, Castañeda S, Ortiz AM, García-García MI,Kremer L, Roncal F, Mulero J, Martínez-A C, SalvadorJM. Tyr³²³-dependent p38 activation is associatedwith rheumatoid arthritis and correlates with disease

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AREA 3activity. Arthritis Rheum. 63(7): 1833-42. 2011.PMID: 21452291. IF: 8,435

Ruiz-Tovar J, Martín-Pérez E, Fernández-ContrerasME, Reguero-Callejas ME, Gamallo-Amat C.Identification of prognostic factors in pancreatic can-cer. Cir Cir 79(4): 313-22. 2011. PMID: 21951885.IF: 0,133

Carmona FD, Rodríguez-Rodríguez L, Castañeda S,Miranda-Filloy JA, Morado IC, Narváez J, Marí-Alfonso B, Unzurrunzaga A, Ríos-Fernández R,Blanco R, de Miguel E, Martín J, González-Gay MA.Role of the CCR5/?32CCR5 polymorphism in biop-sy-proven giant cell arteritis. Hum Immunol. 72(5):458-61. Epub 2011 Feb 25. 2011. PMID: 21354457.IF: 2,872

García-Bermúdez M, López-Mejias R, Rodriguez-Rodriguez L, Fernández-Gutierrez B, García A, RayaE, Ortiz AM, Coenen MJ, van Riel PL, Radstake TR,González-Gay MA, Martín J. No evidence of associa-tion of the KLF12 gene with rheumatoid arthritis inSpanish and Dutch cohorts and a meta-analysis ofpublished data. Hum Immunol. 72(9): 779-82. Epub2011 May 24. 2011. PMID: 21658422. IF: 2,872

Castrejon I, Shum K, Tseng CE, Askanase A.Association between myasthaenia gravis and systemiclupus erythematosus: three case reports and review ofthe literature. Scand J Rheumatol 40(6): 486-90. 2011.PMID: 21722072. IF: 2,594

Pincus T, Castrejon I, Sokka T. Long-term prednisonein doses of less than 5 mg/day for treatment ofrheumatoid arthritis: personal experience over 25years. Clin Exp Rheumatol 29(5 Suppl 68): S130-8.Epub 2011 Oct 22. 2011. PMID: 22018199. IF:2,358

Rodríguez-Rodríguez L, Castañeda S, Vázquez-Rodríguez TR, Morado IC, Gómez-Vaquero C, Marí-Alfonso B, Miranda-Filloy JA, Narvaez J, Ortego-Centeno N, Vicente EF, Blanco R, Amigo-Diaz E,Fernández-Gutiérrez B, Martin J, González-Gay MA.Role of the rs6822844 gene polymorphism at the IL2-

IL21 region in biopsy-proven giant cell arteritis. Clin ExpRheumatol. 29(1 suppl 64): S12-6. Epub 2011 May 11.2011. PMID: 21269573. IF: 2,358

García-Bermúdez M, González-Juanatey C,Rodríguez-Rodríguez L, Miranda-Filloy JA, Perez-Esteban S, Vazquez-Rodriguez TR, Castañeda S,Balsa A, Fernández-Gutierrez B, Llorca J, González-Alvaro I, Martín J, González-Gay MA. Lack of associ-ation of NAMPT rs9770242 and rs59744560 poly-morphisms with disease susceptibility and cardiovas-cular risk in patients with rheumatoid arthritis. ClinExp Rheumatol. 29(4): 681-8. Epub 2011 Aug 31.2011. PMID: 21906432. IF: 2,358


Gutiérrez-López MD, Gilsanz A, Yáñez-Mó M, Ovalle S,Lafuente EM, Domínguez C, Monk PN, González-Alvaro I, Sánchez-Madrid F, Cabañas C. The sheddaseactivity of ADAM17/TACE is regulated by thetetraspanin CD9. Cell Mol Life Sci 68(19): 3275-92.2011. PMID: 21365281. IF: 7,047

Barbero-Villares A, Mendoza J, Trapero-Marugan M,Gonzalez-Alvaro I, Daudén E, Gisbert JP, Moreno-Otero R. Evaluation of liver fibrosis by transient elas-tography in methotrexate treated patients. Med Clin(Barc) 137(14): 637-639. 2011. PMID: 21719043. IF:1,413

Musculoskeletal disorders in HIV-infected patients.National AIDS Plan (PNS) and the AIDS Study Group(GESIDA). GROUP de Expertos del Plan Nacionalsobre el Sida y GROUP de Estudio de Sida: Polo R,Negredo E, Javier Pascua F, Vicente Estrada R,Flores J, José Galindo M, García Vadillo JA, GutiérrezF, Locutura J, Longueira Suárez R, Mariño A,Ocampo A, Polo R, Rojo P, Laura Capa R, GarcíaVadillo JA, Gisbert I, Knobel H, José Mellado M,

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3

Negredo E, Javier Pascua F, Sanz J. Musculoskeletaldisorders in HIV-infected patients. Enferm InfeccMicrobiol Clin 29(7): 515-523. 2011. PMID:21474209. IF: 1,656


Domínguez-Luis M, Lamana A, Vazquez J, García-Navas R, Mollinedo F, Sánchez-Madrid F, Díaz-González F, Urzainqui A. The metalloproteaseADAM8 is associated with and regulates the functionof the adhesion receptor PSGL-1 through ERM pro-teins. Eur J Immunol. 41(12): 3436-3442. 2011.PMID: 22229154. IF: 4,942

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: JOSE M. ALVARO-GRA-CIA ALVAROEstudio de extensión abierto y de un solo brazo paraevaluar la seguridad a largo plazo y la eficacia continu-ada de Denosumab (AMG 162) en el tratamiento de laosteoporosis posmenopáusica; (versión: 29-05-07).20060289EudraCT: 2007-001041-17

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOEstudio observacional, multicéntrico, para la descripciónde patrones de uso y dosificación de Ro-Actemra®(tocilizumab) en el tratamiento de pacientes conartritis reumatoide en la práctica clínica habitual. EstudioACT-LIFE; (Versión A: 08-02-10). ROC-TOC-2010-01

PRINCIPAL INVESTIGATOR: JOSE M. ALVARO-GRA-CIA ALVAROEstudio internacional, randomizado, doble ciego, paraevaluar la eficacia y seguridad de diversos regímenesde retratamiento con rituximab en combinación conmetotrexato, en pacientes con AR que manifiestan una

respuesta inadecuada a metotrexato; (versión A: 27-09-05). WA17044EudraCT: 2005-002396-33

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOCoste y calidad de vida de enfermos con artritispsoriásica en España y coste-efectividad de infliximaben pacientes con artritis psoriásica; (versión. 20-07-06). SCH-INF-2006-01

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOEvaluación de las comorbilidades en la artritis reuma-toide; (versión 25-8-11). ESTUDIO COMORA

PRINCIPAL INVESTIGATOR: JOSE M. ALVARO-GRA-CIA ALVAROEstudio abierto de la eficacia y seguridad de losretratamientos con rituximab (MabThera® / Rituxan ®)en pacientes con artritis reumatoide activa (versión: 21-08-03). WA16855/U2653GEudraCT: NA

PRINCIPAL INVESTIGATOR: SANTOS CASTAÑEDASANZFactores predictivos de la respuesta terapéutica enpacientes con espondilitis anquilosante activa: éxito yfracaso de la terapia biológica, (versión final: 02-01-08).WYE-ETA-2008-01 (ANTES 0881A3-4452)

PRINCIPAL INVESTIGATOR: JOSE M. ALVARO-GRA-CIA ALVAROEstudio internacional randomizado, doble ciego, congrupos de tratamiento paralelos para evaluar la seguri-dad y eficacia de ocrelizumab administrado en un rég-imen de una o dos infusiones, comparado con place-bo, en pacientes con artritis reumatoide activa quemanifiestan una respuesta inadecuada a tratamientocon metotrexato; (versión A: 11-12-07). WA20496EudraCT: 2007-005759-41

PRINCIPAL INVESTIGATOR: ESTHER VICENTERABANEDAEstudio abierto y multicéntrico de evaluación de larespuesta temprana a abatacept con metotrexato de

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fondo mediante ecografía Power-Doppler enpacientescon artritis reumatoide activa y respuesta insuficiente ametotrexato; (versión 01: 17-07-08). IM101179EudraCT: 2008-001523-57

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOEstudio de comorbilidad y de expresión clínica de lasenfermedades inflamatorias mediadas inmunológica-mente (psoriasis, espondiloartropatías y enfermedadinflamatoria intestinal). Estudio Aquiles; (versión 5:02-02-07). VAN-EIMI-2007-01

PRINCIPAL INVESTIGATOR: JESUS GARCIA VADILLOEstudio en fase IIa aleatorizado, doble ciego, controla-do con placebo para evaluar los efectos de odanacat-ib (MK-0822) sobre la densidad mineral ósea (DMO) yla seguridad general en el tratamiento de la osteoporo-sis en mujeres posmenopáusicas previamente tratadascon alendronato; (versión: 09-12-08). 0822-042EudraCT: 2008-008257-30

PRINCIPAL INVESTIGATOR: JOSE M. ALVARO-GRA-CIA ALVAROEstudio fase IIIb, multicéntrico, con un periododoble ciego controlado con placebo y aleatorizadode 12 semanas, seguido de una fase de extensiónabierta para evaluar la seguridad y la eficacia decertolizumabpegol administrado a pacientes conartritis reumatoide activa; (versión final: 30-10-08).C87094EudraCT: 2008-005427-28

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOEnsayo clínico fase Ib/IIa, escala de dosis, simpleciego, para evaluar la seguridad de la administraciónintravenosa de células madre mesenquimales alogéni-cas expandidas derivadas de tejido adiposo (eASCs) apacientes con artritis reumatoide (AR) refractaria; (ver-sión 1.0:1-10-10). CX611-0101EudraCT: 2010-021602-37

PRINCIPAL INVESTIGATOR: SANTOS CASTAÑEDA SANZEstudio observacional, retrospectivo y multicéntricopara analizar el impacto de la autoinflamación en

pacientes con gota. Estudio IL-luminate (versión final:02-11-10). NOV-BON-2010-01

PRINCIPAL INVESTIGATOR: JOSE M. ALVARO-GRA-CIA ALVAROEstudio multicéntrico, randomizado, ciego, con gruposde tratamiento paralelos, para evaluar la reducción delos signos y síntomas en pacientes con artritis reuma-toide durante el tratamiento en monoterapia con 8 mg/kg de tocilizumab por vía intravenosa, comparado con40 mg de adalimumab por vía subcutánea; (Versión A:27-01-2010). WA19924EudraCT: 2009-015845-21

PRINCIPAL INVESTIGATOR: SANTOS CASTAÑEDA SANZArtritis de cadera asociada a la EA. Eficacia y seguridaddel tratamiento precoz con infliximab (REMICADE®);(Versión 1.0: 30-11-2009). P06451EudraCT: 2009-016587-36

PRINCIPAL INVESTIGATOR: JOSE M. ALVARO-GRA-CIA ALVAROEstudio multicéntrico, doble ciego, randomizado, congrupos de tratamiento paralelos, para evaluar la seguri-dad, la remisión de la enfermedad yla prevención deldaño estructural articular durante el tratamiento contocilizumab (TCZ) en monoterapia y en combinacióncon metotrexato (MTX), frente a metrotexato enmonoterapia, en pacientes con artritis reumatoide pre-coz, moderada a severa; (versión A: 17-07-09). WA19926EudraCT: 2009-012759-12

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOEvaluación de la respuesta a etoricoxib en pacientescon Espondilitis Anquilosante (EA) e inadeacuadarespuesta a mayor o igual a 2 AINES; (versión 2.0:27-8-11). GRE-2009-01EudraCT: 2009-017309-12

PRINCIPAL INVESTIGATOR: SANTOS CASTAÑEDA SANZUtilidad de la herramienta FRAX para predecir el riesgode fractura en pacientes atendidos en consultas dereumatología en España; Estudio FRATER; (versión4.3: 02-02-10). SAL-OSTEOP-2010-01

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AREA 3

AREA

3

PRINCIPAL INVESTIGATOR: SANTOS CASTAÑEDA SANZExperiencia a largo plazo con abatacept en la prácticaclíncia habitual; (versión 4: 09-07-10). BMS-ABA-2010-01

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOSCORE: Seguimiento y control en reumatología-enfer-mería; (versión 1: 22-11-10). SCORE-2010-01

PRINCIPAL INVESTIGATOR: ROSARIO GARCIA DEVICUÑA PINEDOEstudio de fase Ib aleatorizado, doble ciego, controladocon placebo y de aumento escalonado de la dosis queinvestiga la seguridad, tolerabilidad, farmacocinética, far-macodinámica y eficacia de inyecciones subcutáneasrepetidas de MT203 en pacientes con artritis reumatoideleve o moderada que reciben tratamiento con metotrex-ato; (versión 2.0:16-2-11). M1-1188-002-EMEudraCT: 2010-018502-36

PRINCIPAL INVESTIGATOR: ANA-MARIA ORTIZ GARCIAEstudio aleatorizado, doble ciego, controlado conplacebo y con control activo de secukinumab parademostrar la eficacia en 24 semanas y evaluarla seguri-dad, tolerabilidad y eficacia a largo plazo durante 1 añoen pacientes con artritis reumatoide activa que tienenuna respuesta inadecuada a anti-TNFalfa; (versión 00:29-04-11). CAIN457F2309EudraCT: 2011-000102-21

PRINCIPAL INVESTIGATOR: JESUS GARCIA VADILLOPrevalencia de fracturas en mujeres con artritis reuma-toide o lupus eri-tematoso sistémico en tratamientocrónico de glucocorticoides; (Versión:26-11-2009).B3D-XM-GHDP

PRINCIPAL INVESTIGATOR: ANA-MARIA ORTIZ GARCIAEstudio prospectivo, Fase IIb/III, multicéntrico, random-izado, doble ciego, controlado, de 3 grupos paralelos y24 semanas de duración con posible extensión, paracomparar la eficacia y seguridad de masitinib, a ladosis de 3 y 6 mg/kg/día, con metotrexato, con ran-domización 1:1:1, para el tratamiento de pacientescon artritis reumatoide activa y con artritis reumatoideactiva y con una respuesta inadecuada a 1. metotrex-

ato, a 2. cualquier FAME incluido al menos un fármacobiológico si previamente resultó ineficaz en pacientestratados con metotrexato o a 3.metotrexato en combi-nación con cualquier FAME incluidos fármacos.AB06012EudraCT: 2010-020992-21

PRINCIPAL INVESTIGATOR: EVA TOMERO MURIELRegistro nacional de Lupus de la SER; (Versión 1.4: 23-11-10). RELES-SER-2009-01

GRUPO 37

HEAD OF LABORATORYEsteban Daudén Tello

GROUP MEMBERS• Diego de Argila Fernández-Durán• María Carmen García García• María Jesús Gómez Gago• Javier Sánchez Pérez• Fátima Tudelilla Fernández

RESEARCH INTEREST

The activity of the Group is focused in cutaneousinflammatory diseases, particularly psoriasis, otherdesquamative dermatoses, eczema and photobiology.

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The principal lines of our investigation have led to thedevelopment of four doctoral thesis at the present.• Gene Expression Profile as a marker of response in

patients with psoriasis treated with biologic therapy(Elena Gallo). Director: Esteban Daudén

• Tuberculosis and Biologic therapy (Ana I. Sánchez-Moya). Director: Esteban Daudén

• Psoriasiform reactions in patients treated with biolog-ics (Raquel Navarro). Director: Esteban Daudén

• Study of galectins in dendritic cells in psoriasis (SilviaPérez Gala). Director: Esteban Daudén

MAJOR GRANTS

• Esteban Daudén Tello. Anti-interleukina 12-23(P40) vs MTX, en Ps moderada severa. Abbott.MO6-855

• Esteban Daudén Tello. Desarrollo y validación de unÍndice Combinado de las Uñas para evaluar elimpacto de la afectación ungueal en la calidad devida de los pacientes con psoriasis vulgar


Navarro R, Ibañes S, Llamas M, Sotomayor E, García-Martín P, Daudén E. Awareness about possible reacti-vation of HBsAg-negative patients when prescribingbiological therapy. J Eur Acad Dermatol Venereol.

25(10): 1232-3. Epub 2010 Aug 18. 2011. PMID:20726937. IF: 3,309

Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE,Nast A, Franke J, Antoniou C, Arenberger P, Balieva F,Bylaite M, Correia O, Daudén E, Gisondi P, Iversen L,Kemény L, Lahfa M, Nijsten T, Rantanen T, Reich A,Rosenbach T, Segaert S, Smith C, Talme T, Volc-Platzer B, Yawalkar N. Definition of treatment goals formoderate to severe psoriasis: a European consensus.Arch Dermatol Res. 303(1): 1-10. Epub 2010 Sep 21.2011. PMID: 20857129. IF: 2,011

Sánchez-Moya AI, Daudén E. Diagnosing latent tuber-culosis infection in patients with psoriasis under antitu-mour necrosis factor-a treatment: every new solutionbreeds new doubts. Br J Dermatol. 164(1): 208-9.Epub 2010 Nov 4. 2011. PMID: 21054332. IF: 4,353

Daudén E; BASALE Study Group. Effectiveness andsatisfaction with imiquimod for the treatment ofsuperficial basal cell carcinoma in daily dermatologicalpractice. J Eur Acad Dermatol Venereol. 25(11):1304-10. Epub 2011 Feb 23. 2011. PMID:21348896. IF: 3,309

Naredo E, Möller I, de Miguel E, Batlle-Gualda E,Acebes C, Brito E, Mayordomo L, Moragues C, UsonJ, de Agustín JJ, Martínez A, Rejón E, Rodriguez A,Daudén E; Ultrasound School of the Spanish Society ofRheumatology and Spanish ECO-APs Group. Highprevalence of ultrasonographic synovitis and enthe-sopathy in patients with psoriasis without psoriaticarthritis: a prospective case-control study.Rheumatology (Oxford). 50(10): 1838-48. Epub 2011Jun 23. 2011. PMID: 21700682. IF: 4,171

Sánchez-Moya AI, Dauden E. Incidence of tuberculosisinfection in psoriatic patients on anti-TNF therapy:report of a case series with 144 patients. J Eur AcadDermatol Venereol. 25(6): 730-3. Epub 2010 Sep 14.2011. PMID: 21564322. IF: 3,309

García-Gavín J, Armario-Hita JC, Fernández-RedondoV, Fernández-Vozmediano JM, Sánchez-Pérez J,Silvestre JF, Uter W, Giménez-Arnau AM. Nickel allergy

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Definition of successful and non-successful therapy after induction andduring maintenance treatment of moderate to severe plaque psoriasis. Inthe eventuality that a treatment regimen should be modified, the followingmeasures should be employed; dose adjustment, addition of another the-rapy (combination treatment) or transition to another drug or modality

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in Spain needs active intervention. Contact Dermatitis.64(5): 289-91. 2011. PMID: 21480915. IF: 3,672

Latorre N, Borrego L, Fernández-Redondo V, García-Bravo B, Giménez-Arnau AM, Sánchez J, Silvestre JF.Patch testing with formaldehyde and formaldehyde-releasers: multicentre study in Spain (2005-2009).Contact Dermatitis. 65(5): 286-92. Epub 2011 Jul 18.2011. PMID: 21767276. IF: 3,672

Alvarez AC, Rodríguez-Nevado I, De Argila D, Rubio FP,Rovira I, Torrelo A, Zambrano A. Recalcitrant pustularpsoriasis successfully treated with adalimumab. PediatrDermatol. 28(2): 195-7. Epub 2011 Mar 15. 2011.PMID: 21504452. IF: 1,117

Navarro R, Llamas M, Gallo E, Sánchez-Pérez J,Fraga J, García-Diez A. Follicular mucinosis in amycosis fungoides-like hypersensitivity syndromeinduced by oxcarbamazepine. J Cutan Pathol.38(12): 1009-11. Epub 2011 Sep 7. 2011. PMID:21899590. IF: 1,744

Llamas-Velasco M, Argila DD, Eguren C, García-Martin P, Ibañes S, García-Diez A. Solar urticariaunresponsive to intravenous immunoglobulins.Photodermatol Photoimmunol Photomed 27 (1): 53-54. 2011. PMID: 21198885. IF: 1,424

Barbero-Villares A, Mendoza J, Trapero-Marugan M,Gonzalez-Alvaro I, Daudén E, Gisbert JP, Moreno-OteroR. Evaluation of liver fibrosis by transient elastography inmethotrexate treated patients. Med Clin (Barc) 137(14):637-639. 2011. PMID: 21719043. IF: 1,413

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: ESTEBAN DAUDEN TELLOPsoriasis, fármacos biológicos y prueba tuberculínica

PRINCIPAL INVESTIGATOR: ABILIO JAVIERSANCHEZ PEREZEstudio en fase 3, multicéntrico, aleatorizado, dobleciego, controlado con placebo y con grupos paralelos

para evaluar la eficacia y la seguridad de 2 dosis oralesde CP 690,550 y 1 dosis subcutánea de etanercept ensujetos con psoriasis en placas crónica moderada ograve; (Versión final: 21-06-10). A3921080EudraCT: 2010-020004-30

PRINCIPAL INVESTIGATOR: DIEGO DE ARGILA FER-NANDEZ-DURANEstudio fase III, multicéntrico, randomizado, dobleciego, controlado con placebo, de eficacia y seguridadde Apremilast (CC-10004) en pacientes con psoriasiscon placas moderada o severa; (versión final:26-8-10).CC-10004-PSOR-009EudraCT: 2010-019992-30

PRINCIPAL INVESTIGATOR: ESTEBAN DAUDENTELLOEstudio en fase 3, multicéntrico y abierto de la seguridad yla tolerabilidad a largo plazo de 2 dosis orales de CP-690,550 en sujetos con psoriasis en placas crónica demoderada a grave; (version final: 09-06-10). A3921061EudraCT: 2010-020002-15

PRINCIPAL INVESTIGATOR: ESTEBAN DAUDENTELLORegistro epidemiológico observacional para evaluar el perfilclínico de los pacientes con psoriasis de moderada a graveen España; (Versión 1.0: 16-04-10). JAN-PSO-2010-01

PRINCIPAL INVESTIGATOR: ESTEBAN DAUDENTELLOEstudio de fase 3, multicéntrico, abierto, para la contin-uación del tratamiento de sujetos con psoriasis en pla-cas crónica de moderada a graveque completaron unestudio anterior en psoriasis con ABT-874; (versiónEnmienda 2: 13-10-08). M10-016EudraCT: 2007-005955-40

PRINCIPAL INVESTIGATOR: ESTEBAN DAUDENTELLOEstudio de fase III multicéntrico, aleatorizado y condoble enmascaramiento para comparar la seguridad yla eficacia de ABT-874 con la de metotrexato en suje-tos con psoriasis en placas crónica de moderada agrave (enmienda 1: 11-02-08). M10-255EudraCT: 2007-004687-47

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Line 3.2Esophagogastrointestinalinflammatory diseases

GRUPO 38HEAD OF LABORATORYJavier Pérez Gisbert

GROUP MEMBERS• Carlos Castaño Milla• Almudena Durán Vegue• María Encarnación Fernández Contreras• Adrián Gerald Mcnicholl• Alicia Marín Gómez• José Maté Jiménez• Pablo Muñoz Linares• Amelia Rodríguez Nogueiras

RESEARCH INTEREST

Our Group leads a CIBERehd research team focusedon the understanding and management of

Helicobacter pylori infection and Inflammatory BowelDisease (IBD). Clinical and epidemiological projectsare performed coordinating networks of gastroen-terologists from hospitals all over Spain. Differentprojects have been developed in collaboration withthe Pathology service and the Clinical Pharmacologyservice of La Princesa Hospital, the Research Unit ofGuadalajara’s Hospital, the PharmaceuticalTechnology Department and the Organic Chemistrydepartment of the Complutense University of Madrid,the Biochemistry and Molecular Biology Departmentof Alcalá de Henares University, the OncologyInstitute of Catalunya and the Galician GenomicsFundation.Main research Topics• Gastric H. pylori induced proliferation/apoptosis

- Effect of infection status, bacterial strain,patients’ genotype and the type and severity ofgastric lesions

- Comparison of pre and post eradication- Genetic and epidemiological factors in the pro-

gression of pre-cancerous lesions• Angiogenesis and lymphangiogenesis in IBD

- Ulcerative colitis vs. Crohn’s disease- Pathological behaviour of the disease- Effect of the therapy

• New diagnostic methods - Serologic diagnosis of atrophic gastritis- Diagnosis of H. pylori infection with the "Ultra-

rapid" urease test- Clinical utility of biological markers like faecal

calprotectin and lactoferrin as well as azathioprine metabolites

- IBD Genetic/Pharmacogenetic studies- Recent findings indicating differences in the risk

of IBD associated carcinogenesis have lead usto study the involvement of female hormones inthis clinical entity. UC and CD will be studiedunder an innovative perspective.

• New therapies- 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- Vaccination optimization in IBD patients

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MAJOR GRANTS

• Javier Pérez Gisbert. Centros de InvestigaciónBiomédica en Red (CIBER) de EnfermedadesHepáticas (CIBEREHD). Instituto de Salud Carlos III.ISCIII. Centros de Investigación Biomédica en Red(CIBER) de Enfermedades Hepáticas y Digestivas(CIBEREHD). Instituto de Salud Carlos III

• Javier Pérez Gisbert. Implicación de los factoresangiogénicos y linfangiogénicos en la enfermedadinflamatoria intestinal. ISCIII. PS09/02369

• Javier Pérez Gisbert. Respuesta T reguladora(CD4+CD25+FOXP3) y patogenia de la infección porH. pylori: relación con el estatus oxidativo de lamucosa gástrica. FISCAM. FISCAM Ref. PI-2008/34

• Proyecto Coordinado. Desarrollo de un kit diagnósti-co para las enfermedades inflamatorias mediadaspor mecanismos inmunes (“IMID-Kit”). MEC(Proyectos Científico-Tecnológicos Singulares y deCarácter Estratégico). PSE-010000-2006-6

• Javier Pérez Gisbert. Helicobacter pylori y apoptosisgástrica: influencia de la infección y efecto de laerradicación. Fundación de Investigación MédicaMutua Madrileña.

• Javier Pérez Gisbert. Registro de colitis microscópi-ca nacional (proyecto RECOMINA): estudio de fac-tores ambientales de riesgo de colitis microscópica ycreación de un banco de ADN. ISCIII. PI061577

• Javier Pérez Gisbert. Pruebas diagnósticas de infec-ción tuberculosa en pacientes con enfermedadInflamatoria intestinal bajo tratamiento con fármacosbiológicos frente al factor de necrosis tumoral alfa


C. Taxonera, J. Estellés, I. Fernandez-Blanco, O. Merino,I. Marín-Jimenez, M. Barreiro, C. Saro, V. García, S.García-Morán, G. Bastida, JP. Gisbert, I. Vera, M. P.Martinez, Sara Garcia Morán, MD, María Chaparro, MD,J. L. Mendoza. Adalimumab induction and maintenancetherapy for ulcerative colitis patients previously treatedwith Infliximab. Aliment Pharmacol Ther 33 (3): 340-348.2011. PMID: 21133961. IF: 3,861

Gisbert JP, Chaparro M, Gomollón F. Common mis-conceptions about 5-aminosalicylates and thiopurinesin inflammatory bowel disease. World J Gastroenterol17(30): 3467-3478. 2011. PMID: 21941413. IF: 2,24

Ponce J, Calvet X, Gallach M, Ponce M; EsophagitisStudy Group of the Asociación Española deGastroenterología (AEG). Morillas JD, Bixquert M,Gonzalvo JM, Rodrigo L, Domínguez E, Sobrino M,Simón MA, Díaz Roca AB, Orive V, Salvador P,Ojembarrena E, Bermejo F, Carnero JA, Pérez-Gisbert J, de la Morena F, Chaparro M, Borda F,Brullet E, Casellas JA, Alonso P, Blanca M, BajadorE, Martín-Herrera L, Martín de Argila C, Gómez-Camacho F, Castillo L, Almansa C, Ramírez-Armengol JA, Bujanda L, Muñoz C, Montoro M,Alcedo J, Dolz C, Escudero M, Monés J, Ginard D,Parra A, Pons V, Castro M, Pleguezuelo J, Pellicer F,Morales ML. Esophagitis in a high H. pylori preva-lence area: severe disease is rare but concomitantpeptic ulcer is frequent. PLoS One. 6(10): e25051.2011. PMID: 22022373. IF: 4,411

J Sánchez-Delgado, E Gené, D Suarez, P García-Iglesias, E Brullet, M Gallach, F Feu, JP Gisbert, XCalvet. Has H. pylori prevalence in bleeding pepticulcer been underestimated? A meta-regression. Am JGastroenterol 106(3): 398-405. 2011. PMID:21304499. IF: 6,882

Malfertheiner P, Bazzoli F, Delchier JC, Celiñski K,Giguère M, Rivière M, Mégraud F; Pylera StudyGroup. Collaborators: Aisene A, Bougnol M,Cassigneul J, Coulom P, Houcke P, Lamarque D,Lamouliatte D, Roques JF, Thevenin A, Delchier JC,Ecuer S, Bagnouls G, Helbert T, Andree H, Bouzo H,Brandt W, Cordes HJ, Dettmer A, Juergens H,Malfertheiner P, Rehmann I, Ryschka A, Schaefer T,O'Morain C, Bazzoli F, Gasbarrini G, Cipolletta L,Stanghellini V, Kuipers E, A de Boer W, Celiñski K,Gachowski W, Huk J, Jamrozik-Kruk Z, Karnafel W,Kleczkowski D, Kujawski K, Linke K, Petryka R,Serwin D, Wozniak B, Wysokinski A, Castro M, CallejaJL, Calvet X, Gisbert J, Muñoz ED, Bundy C, Orpen I,Mohr DS, Parker I, Cahill T. Helicobacter pylori eradi-cation with a capsule containing bismuth subcitrate


potassium, metronidazole, and tetracycline given withomeprazole versus clarithromycin-based triple thera-py: a randomised, open-label, non-inferiority, phase 3trial. Lancet 377(9769): 905-913. 2011. PMID:21345487. IF: 33,633

Gisbert JP. Helicobacter pylori eradication: A new, sin-gle-capsule bismuth-containing quadruple therapy. NatRev Gastroenterol Hepatol 8(6): 307-309. 2011. PMID:21643037. IF: 4,558

Gomollón F, Gisbert JP. IBD: Intravenous iron in IBD--what's the best preparation?. Nat Rev GastroenterolHepatol. 8(9): 477-478. 2011. PMID: 21788975. IF:4,558

Calvet X, Gisbert JP, Suarez D. Key points for design-ing and reporting Helicobacter pylori therapeutic trials:A personal view. Helicobacter 16(5): 346-355. 2011.PMID: 21923680. IF: 3,109Molina-Infante J, Gisbert JP. Levofloxacin in first-lineeradication regimens for Helicobacter pylori: better testantibiotic susceptibility before treating. Gut 60(11):1605-6. 2011. PMID: 21193443. IF: 10,614

M Chaparro, J Panes, V García, M Mañosa, M Esteve,O Merino, JL Cabriada, MA Montoro, JL Mendoza, PNos, A Gutierrez, F Gomollón, JP Gisbert. Long-termdurability of infliximab treatment in crohn’s disease andefficacy of dose “escalation” in patients loosingresponse. J Clin Gastroenterol 45 (2): 113-118. 2011.PMID: 21242747. IF: 2,752

García-Iglesias P, Villoria A, Suarez D, Brullet E, GallachM, Feu F, Gisbert JP, Barkun A, Calvet X. Meta-analy-sis: predictors of rebleeding after endoscopic treat-ment for bleeding peptic ulcer. Aliment Pharmacol Ther34(8): 888-900. 2011. PMID: 21899582. IF: 3,861

Hernández-Breijo B, Monserrat J, Ramírez-Rubio S,Cuevas EP, Vara D, Díaz-Laviada I, Fernández-MorenoMD, Román ID, Gisbert JP, Guijarro LG. Preclinicalevaluation of azathioprine plus buthionine sulfoximine inthe treatment of human hepatocarcinoma and coloncarcinoma. World J Gastroenterol. 17(34): 3899-3911.2011. PMID: 22025878. IF: 2,24

Bortoli A, Pedersen N, Duricova D, D'Inca R, Gionchetti P,Panelli MR, Ardizzone S, Sanroman AL, Gisbert JP, ArenaI, Riegler G, Marrollo M, Valpiani D, Corbellini A, Segato S,Castiglione F, Munkholm P; European Crohn-ColitisOrganisation (ECCO) Study Group of EpidemiologicCommittee (EpiCom). Pregnancy outcome in inflammato-ry bowel disease: prospective European case-controlECCO-EpiCom study, 2003-2006. Aliment PharmacolTher 34(7): 724-734. 2011. PMID: 21815900. IF: 3,861

Gisbert JP, Calvet X. Review article: common miscon-ceptions in the management of Helicobacter pylori-associated gastric MALT-lymphoma. AlimentPharmacol Ther 34(9): 1047-1062. 2011. PMID:21919927. IF: 3,861

Gisbert JP, Calvet X. Review article: non-bismuthquadruple (concomitant) therapy for eradication ofHelicobater pylori. Aliment Pharmacol Ther 34(6): 604-617. 2011. PMID: 21745241. IF: 3,861

JP Gisbert, M Chaparro, M Esteve. Review article:Prevention and management of hepatitis B and Cinfection in patients with inflammatory bowel disease.Aliment Pharmacol Ther 33(6): 619-633. 2011. PMID:21416659. IF: 3,861

Gisbert JP, Calvet X. Review article: the effectivenessof standard triple therapy for Helicobacter pylori hasnot changed over the last decade, but it is not goodenough. Aliment Pharmacol Ther 34(11-12): 1255-1268. 2011. PMID: 22017749. IF: 3,861

Linares PM, Gisbert JP. Role of growth factors in thedevelopment of lymphangiogenesis driven by inflam-matory bowel disease: a review. Inflamm Bowel Dis.17(8): 1814-1821. 2011. PMID: 21744436. IF: 4,613

Espinosa L, Linares PM, Bejerano A, Lopez C,Sanchez A, Moreno-Otero R, Gisbert JP. Solubleangiogenic factors in patients with acute pancreatitis. JClin Gastroenterol. 45(7): 630-637. 2011. PMID:21750433. IF: 2,752

M Chaparro, JP Gisbert. Successful use of infliximabfor perianal Crohn’s disease in pregnancy. Inflamm

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Bowel Dis 17(3): 868-869. 2011. PMID: 20564533.IF: 4,613

A Lanas, LA Garcia Rodriguez, M Polo-Tomas, MPonce, E. Quintero, A Pérez-Aisa, JP Gisbert, LBujanda, M Castro, M Muñoz, D Del-Pino, S García, XCalvet. The changing face of hospitalization due to gas-trointestinal bleeding and perforation. AlimentPharmacol Ther 33 (5): 585-591. 2011. PMID:21205256. IF: 3,861

Y González-Lama, JP Gisbert. Thiopurine metabolitemeasurement -not for everyone. Aliment PharmacolTher 34(9): 1039-1040. 2011. PMID: . IF: 3,861

Y González-Lama, JP Gisbert. Thiopurine metabolitesand TPMT activity measurement in inflammatory boweldisease: authors’ reply. Aliment Pharmacol Ther 34(9):1139-1140. 2011. PMID: . IF: 3,861González-Lama Y, Bermejo F, López-Sanromán A,García-Sánchez V, Esteve M, Cabriada JL, McNichollAG, Pajares R, Casellas F, Merino O, Carpio D, Vera MI,Muñoz C, Calvo M, Benito LM, Bujanda L, García-Fernández FJ, Ricart E, Ginard D, Velasco M, CarnerosJA, Manceñido N, Calvo M, Algaba A, Froilan C, CaraC, Maté J, Abreu L, Gisbert JP; "GROUP Español deTrabajo en Enfermedad de Crohn y Colitis Ulcerosa(GETECCU)". Thiopurine methyl-transferase activityand azathioprine metabolite concentrations do not pre-dict clinical outcome in thiopurine-treated inflammatorybowel disease patients. Aliment Pharmacol Ther 34(5):544-554. 2011. PMID: 21722149. IF: 3,861

Chaparro M, Gisbert JP. Transplacental transfer ofimmunosuppressants and biologics used for the treatmentof inflammatory bowel disease. Curr Pharm Biotechnol12(5): 765-773. 2011. PMID: 21342120. IF: 3,455

O'Connor A, Gisbert JP, McNamara D, O'Morain C.Treatment of Helicobacter pylori infection 2011.Helicobacter 16(1): 53-58. 2011. PMID: 21896086. IF:3,109

Guerra I, Chaparro M, Bermejo F, Gisbert JP. Utility ofmeasuring serum concentrations of anti-TNF agentsand anti-drug antibodies in inflammatory bowel dis-

ease. Curr Drug Metab 12(6): 594-598. 2011. PMID:21495977. IF: 3,896

MA Montoro, S Santolaria, B Sánchez Puértolas, J Vera,L Bujanda, A Cosme, JL Cabriada, M. Durán, L Mata, ASantamaría, G Ceña, JM Blas, J Ponce, M Ponce, LRodrigo, J. Fernandez Sordo, C Muñoz, G. Arozena, DGinard, A López-Serrano, M Castro, M Sans, R. Campo,A. Casalots, V Orive, A. Loizate, L Titó, E Portabella, POtazua, M. Calvo, MT Botella, C Thomson, JL Mundi, EQuintero, D Nicolás, F Borda, B Martinez, JP Gisbert, MChaparro, A Jimenez Bernadó, F Gómez-Camacho, ACerezo, E. Casal Nuñez, Workgroup for the Study ofIschaemic Colitis of the Spanish GastroenterologicalAssociation (GTECIE-AEG). Clinical patterns and out-comes of ischemic colitis: Results of the Working Groupfor the Study of Ischemic Colitis in Spain (CIE study).Scand J Gastroenterol 46 (2): 236-246. 2011. PMID:20961178. IF: 1,966

Pousa ID, Algaba A, Linares PM, Sanz-Cameno P,Maté J, Moreno-Otero R, Bermejo F, Gisbert JP.Corticosteroids modulate angiogenic soluble factors inulcerative colitis patients. Dig Dis Sci 56 (3): 871-879.2011. PMID: 20632101. IF: 2,06

Gisbert JP. Is culture necessary before first-line treat-ment for Helicobacter pylori infection?. Intern Med.50(21): 271. 2011. PMID: 22041399. IF: 1,037

Panés J, Bouzas R, Chaparro M, García-Sánchez V,Gisbert JP, Martínez de Guereñu B, Mendoza JL,Paredes JM, Quiroga S, Ripollés T, Rimola J.Systematic review: the use of ultrasonography, com-puted tomography and magnetic resonance imagingfor the diagnosis, assessment of activity and abdomi-nal complications of Crohn's disease. AlimentPharmacol Ther 34(2): 125-145. 2011. PMID:21615440. IF: 3,861

Martín Martín L, Santander C, Lopez Martín MC, Espinoza-Ríos J, Chavarría-Herbozo C, Gisbert JP, Moreno-Otero R.Esophageal motor abnormalities in eosinophilic esophagitisidentified by high-resolution manometry. J GastroenterolHepatol 26(9): 1447-1450. 2011. PMID: 21575059. IF: 2,41Ruiz-Tovar J, Martín-Pérez E, Fernández-Contreras ME,

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Reguero-Callejas ME, Gamallo-Amat C. Identification ofprognostic factors in pancreatic cancer. Cir Cir 79(4):313-22. 2011. PMID: 21951885. IF: 0,133


Barbero-Villares A, Mendoza J, Trapero-Marugan M,Gonzalez-Alvaro I, Daudén E, Gisbert JP, Moreno-Otero R. Evaluation of liver fibrosis by transient elastog-raphy in methotrexate treated patients. Med Clin (Barc)137(14): 637-639. 2011. PMID: 21719043. IF: 1,413

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio piloto para comprobar la eficacia del tratamien-to con antibióticos (amoxicilina-clavulánico y roxitro-micina) en formas de liberación sostenida junto con uninhibidor de la bomba de protones para la erradicaciónde Helicobacter pylori; (versión: 1, 05-05-06). H06EudraCT: 2006-003367-32

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio multicéntrico, ciego, controlado con placebo,aleatorizado, de fase 3, sobre la inducción y el manten-imiento de la respuesta clínica y la remisión convedolizumab (MLN0002) en pacientes con enfermedadde Crohn moderada o grave. C13007EudraCT: 2008-002783-33

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio de fase IIB, multicéntrico, aleatorizado, dobleciego, controlado con placebo y de grupos paralelospara evaluar la eficacia y seguridad del tratamiento conustekinumab en pacientes con enfermedad de Crohnactiva de moderada a grave tratados previamente conantagonistas del factor de necrosis tumoral; (versión:

12-08-08). C0743T26EudraCT: 2008-000649-77

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio multicéntrico, ciego, controlado con placebo,aleatorizado, de fase 3, sobre la inducción y el manten-imiento de la respuesta clínica y la remisión convedolizumab (MLN0002) en pacientes con colitisulcerosa moderada o grave. C13006EudraCT: 2008-002782-32

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio de 5 años, no intervencionista, de registro dedatos de HUMIRA® (Adalimumab) en pacientes conEnfermedad de Crohn (EC) activa moderada agrave;(versión: 27-12-07). ABB-ADA-2007-01

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio randomizado, multicéntrico, abierto que com-para ciclosporina coninfliximab en brotes graves decolitis ulcerosa resistente a esteróides (Estudio CYSIF);(versión: 11-01-07). CYSIFEudraCT: 2006-005299-42

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio abierto, randomizado, multicéntrico para com-parar la eficacia y la seguridad de la prednisona y gran-ulocitoféresis con Adacolumn® versusla prednisonasola en el tratamiento de pacientes con colitis ulcerosaactiva corticodependiente leve a moderada; (versión1.1: 29-06-07). ADA-UC-07-102EudraCT: 2007-003815-30

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio clínico multicéntrico, aleatorizado, a dobleciego y con doble simulación de fase III sobre la efica-cia y l tolerabilidad de las capsulas de budesonidafrente a los gránulos de mesalazina frente a un place-bo en los pacientes con colitis colágena; (versión 2.0:26-02-07, incluye enmienda 01). BUC-60/COCEudraCT: 2006-004159-39

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PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio genético en pacientes con enfermedad inflam-atoria intestinal con mielotoxicidad por tiopurinas conactividad de la TPMT normal; (Versión 4). GIS-2010-05- MIELOTOXICIDAD

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTDesintensificación del tratamiento con fármacos Anti-TNF-alpha en pacientes con enfermedad de Crohn;(versión 1: 09-06-10). GIS-2010-03 DESINTENSIFICA-CION

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTSeguridad del tratamiento con fármacos inmunodepre-sores y biológicos durante el embarazo en pacientescon enfermedad inflamatoria intestinal. (versión 1: 14-06-10). GIS-2010-04 EMBARAZO

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTRegistro europeo de colitis ulcerosa. Programa de vig-ilancia de la seguridad post-comercialización, prospec-tivo, observacional, no intervencionista; (versión final:04-10-06), (Enmienda 1: 15-01-07). PO4808 (SCH-INF-2007-01)

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTCoste, efectividad, utilidad y eficiencia del adalimumaben el manejo de la enfermedad de Crohn (proyecto EFI-CADEC); (versión: 02-06-08). GET-ADA-2008-01

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio abierto, de fase 3 para determinar la eficacia yla seguridad a largo plazo de vedolizumab (MLN0002)en los pacientes concolitis ulcerosa (CU) y enfermedadde Crohn (EC). C13008EudraCT: 2008-002784-14

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEfecto del tratamiento con condroitín sulfato en

pacientes con enfermedad inflamatoria intestinal; (ver-sión 1.0: 30-07-09). GIS-CON-2009-01

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTSeguridad de la vacuna del virus de la gripe H1N1 enpacientes con enfermedad inflamatoria intestinal entratamiento con inmunosupresores; (versión 1.0: 02-12-09). INFLUENZA_A

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio en fase 3b/4, abierto, multicéntrico y prospec-tivo para evaluar el efecto del estado de la remisiónsobre la capacidad para mantener o alcanzar laremisión clínica y endoscópica durante una fase demantenimiento a largo plazo de 12 meses con 2,4g/día de MMX mesalamina/mesalazina una vez al díaen pacientes adultos con colitis ulcerosa; (Versión 2.0:16-02-10). SPD476-409EudraCT: 2009-017044-13

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTBases Etiopatogénicas de la subfertilidad asociada aenfermedad inflamatoria intestinal. FERTIL 1

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio fase IV, prospectivo, aleatorizado y comparativoentre la terapia "secuencial" y "concomitante" para laerradicación de Helicobacter Pylori en la práctica clínicahabitual. (Version1: 01/12/2009). SEQVSCONCEudraCT: 2009-016517-14

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEnsayo en fase III, abierto, aleatorizado, con control acti-vo que compara el ferumoxitol con la sacarosa férricapara el tratamiento de la anemia por deficiencia de hier-ro; (versión original: 16-03-10). AMAG-FER-IDA-302EudraCT: 2010-018961-50

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTRegistro europeo de enfermedad de Crohn. Registro

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prospectivo y observacional de farmacovigilancia enpacientes tratados con Remicade o con tratamientoestándar; (versión final: 28-02-03). Modificación S1para España del 18 de septiembre de 2003. SCH-INF-2003-20 (P03164)

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio abierto, aleatorizado, de grupos paralelos y unaño de seguimiento para evaluar la eficacia y tolerabil-idad de rifaximina en la prevención de recaídas dediverticulitis y en la mejoría de los síntomas enpacientes con enfermedad diverticular del colón; (ver-sión 4.0:31-10-06+ enmienda general nº 1: 18-01-07).DAR-01EudraCT: 2006-006157-27

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio epidemiológico sobre la prevalencia de anemiay ferropenia en los pacientes hospitalizados con enfer-medades gastrointestinales en España (EstudioREGIS); (Versión 1:06-09-10). URI-EPI-2009-03

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEfectividad de adalimumab en el tratamiento de las fís-tulas perianales en pacientes con enfermedad deCrohn Naïve al tratamineto con ANTI-TNF; (Versión 1,fecha 24/05/2010). GIS-2010-01

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTPruebas diagnósticas de infección tuberculosa enpacientes con enfermedad inflamatoria intestinal bajotratamiento con fármacos biológicos frente al factor denecrosis tumoral alfa; (versión 29-11-10). GIS-2011-01-MANTOUX

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio doble ciego, aleatorizado, controlado conplacebo, de búsqueda de dosis para evaluar la eficaciay la seguridad de PF-00547659 en sujetos conEnfermedad de Crohn que no responden adecuada-mente al tratamiento anti-TNF (OPERA); (versión

enmienda 1:07-02-11). A7281006EudraCT: 2010-023437-30

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEfecto de adalimumab sobre la expresión de factoresangiogénicos y linfangiogénicos en la enfermedadinflamatoria intestinal; (versión 1: 13-07-10). GIS-ADA-2010-01

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio ADACAL: calprotectina y proteina C reacti-va de alta sensibilidad como marcadores de unanueva estrategia diagnóstica-terapeútica queevalúa la actividad mucosa para personalizar eltratamiento y mejorar el pronóstico de lospacientes con Enfermedad de Cronh tratados coninmunosupresores; (versión final 1.0: 25-07-11).A12-771EudraCT: 2011-003966-34

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio aleatorizado, a doble ciego, controlado conplacebo para evaluar la seguridad, tolerabilidad y efica-cia de AMG827 en sujetos con Enfermedad de Crohnde moderada a severa; (versión enmienda 1: 22-06-10). 20090072EudraCT: 2010-019544-39

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTMedida de la respuesta terapeútica con resonanciamagnética en la enfermedad de Crohn. GIS-2010-08-RM

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTErrores en la atención ambulatoria de los pacientes conenfermedad inflamatoria intestinal: Estudio"Errata";(versión 1.0:01-12-10). GIS-2010-07-ERRATA

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTUna evaluación a largo plazo de la seguridad y la efica-

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cia del tratamiento con AMG 827 en sujetos con enfer-medad de Crohn; (versión original: 21-06-10).20100008EudraCT: 2010-020881-53

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio aleatorizado, doble ciego, controlado conplacebo, con grupos paralelos, multicéntrico parainvestigar la seguridad y la eficacia de CP-690,550como tratamiento de inducción en sujetos conEnfermedad de Crohn de moderada a grave; (versiónfinal 07-09-11). A3921083EudraCT: 2011-001733-16

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEnsayo clínico multicéntrico, prospectivo, aleatorizadoy comparativo para evaluar la eficacia de dos vacunasfrente al virus de la hepatitis B (VHB) en pacientes conenfermedad inflamatoria intestinal; (version 1:11-10-10). COMVI-BEudraCT: 2010-023947-14

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio de fase IIa, multicéntrico, randomizado, dobleciego, controlado con placebo, de cohortes secuen-ciales, de búsqueda de rango de dosis para evaluar laseguridad, tolerabilidad, y el efecto clínico de escaladade dosis de laquinimod en la Enfermedad de Crohnactiva de moderada a grave (versión final: 01-07-08).CD-LAQ-201EudraCT: 2008-004272-49

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTUtilidad de la calprotectina fecal semicuantitativa en lapredicción de recidiva en la colitis ulcerosa; (versiónjunio 2011). PRECUCAL

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio de extensión abierto y multicéntrico de PF-00547659 (OPERA II). A7281007EudraCT: 2010-024638-48

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio en fase 2A, aleatorizado, doble ciego, sinenmascaramiento para el promotor, controlado conplacebo, de dosis múltiples para evaluar la farmacod-inámica, la farmacocinética y la seguridad de anruk-inzumab en pacientes con colitis ulcerosa activa; (ver-sión enmienda1:6-1-11). B2421003EudraCT: 2010-023762-49

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio de fase 3, aleatorizado, en doble ciego, contro-lado con placebo, de grupos paralelos y multicéntrico,para evaluar la seguridad y la eficacia del tratamientode mantenimiento con ustekinumab en sujetos conEnfermedad de Crohn de actividad moderada a sev-era; (versión 31-03-11). CNTO1275CRD3003EudraCT: 2010-022760-12

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio de fase 3, aleatorizado, en doble ciego, contro-lado con placebo, de grupos paralelos y multicéntrico,para evaluar la seguridad y la eficacia del tratamientode inducción con ustekinumab en sujetos conEnfermedad de Crohn de actividad moderada a severaque han fracasado o que presentan intolerancia altratamiento con un antagonista del TNF (UNITI-1); (ver-sión A0:24-03-11). CNTO1275CRD3001

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio de fase 3, aleatorizado, en doble ciego, contro-lado con placebo, de grupos paralelos y multicéntrico,para evaluar la seguridad y la eficacia del tratamientode inducción con ustekinumab en sujetos conEnfermedad de Crohn de actividad moderada a severa(UNITI-2); (versión A0:24-3-11). CNTO1275CRD3002EudraCT: 2010-022759-42

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEnsayo clínico multicéntrico, aleatorizado, con simpleciego y de grupos paralelos para comparar la eficaciade adalimumab con la de azatioprina en la prevención

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de la recurrencia postquirúrgica en la Enfermedad deCrohn después de 52 semanas de tratamiento; (ver-sión 0.11: 30-05-11). APPRECIAEudraCT: 2011-000885-36

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio multicéntrico, aleatorizado, con doble enmas-caramiento en grupos paralelos, sobre la dexameta-sona intraeritrocitaria comparada con placebo enpacientes con Enfermedad de Cronh dependiente deesteroides; (versión 4.0: 22-06-11). CRODEX01EudraCT: 2008-007329-38

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEstudio abierto, multicéntrico, que evalúa la eficacia yseguridad de 2 algortimos de tratamiento en pacientescon enfermedad de Crohn de moderada a grave;

(Versión: 08-06-10). M11-271EudraCT: 2010-020137-10

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTPredicción de respuesta a corto y largo plazo altratamiento con fármacos Anti-TNF en pacientes conEnfermedad de Crohn. Estudio PREDICROHN; (ver-sión:agosto de 2010). PREDICROHN

PRINCIPAL INVESTIGATOR: FRANCISCO JAVIERPEREZ GISBERTEficacia y seguridad de PYLERA (subcitrato potásicode bismuto, metronidazol y clorhidrato de tetraciclina)con omeprazol, administrados 10 días en sujetos confracaso del tratamiento de erradicación deHelicobacter Pylori; (versión amend2: 15-3-11). MA-PY-HP09-01EudraCT: 2010-019064-36

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Line 3.3Progenitors and cell therapy

GRUPO 39HEAD OF LABORATORYLuis Madero López

GROUP MEMBERS• Lucía Chamorro Casanova• Isabel Colmenero Blanco• Miguel Ángel Díaz Pérez• Ana María Gómez García• África González Murillo• Marta González Vicent• Álvaro Lassaletta Atienza• Carolina Martínez Laperche• Evangelina Muñoz Mayoral• Antonio Pérez Martínez• Manuel Ramírez Orellana• Julián Sevilla Navarro• Jaime Valentín Quiroga

RESEARCH INTEREST

The main results from the activity of the group led by Dr.Luis Madero during 2011 were as follows:• The Group published a total of 21 articles in scientific

journals, either as its own work or as collaborationswith other groups.

• Results of a research project from Dr. Manuel Ramírezsupported a patent application at PCT offices.

• Two predoctoral candidates, Lucía Fernández andCarolina Martínez, supervised by Dr. Manuel Ramírez,obtained their doctoral degree at School of Medicine,Universidad Autónoma de Madrid, with the maximumgrade.

• Four independent proposals dealing with AdvancedTherapies in children were funded by Ministerio de

Sanidad. Dr. Antonio Pérez (use of activated NaturalKiller cells for relapsed childhood leukemias), Dr. MiguelÁngel Díaz (pharmacological allodepletion for hap-loidentical transplantation), Dr. Julián Sevilla (gene ther-apy for children with Fanconi Anemia) and Dr. ManuelRamírez (oncolytic and cellular therapy for children withrefractory tumors) are principal investigators in these 4projects.

The following work by Dr. Antonio Pérez was published inthe journal Biology of Blood and Marrow Transplantationin May 2011 (Blood dendritic cells suppress NK cell func-tion and increase the risk of leukemia relapse afterhematopoietic cell transplantation. Perez-Martinez A, etal. Biol Blood Marrow Transplant. 2011 May;17(5):598-607. Epub 2010 Oct 25). The final figure of the paperdepicts a two-signal model in hematopoietic transplantfor leukemia (see Figure attached). In the presence ofleukemia cells and TLR ligands (first signal), various

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AREA 3immune cells may provide NK cells a different second sig-nal (A) toward ‘‘effector’’ and ‘‘helper’’ phenotype, or (B)toward ‘‘indolent’’ and ‘‘tolerant’’ phenotype. The NK celleffects on leukemia may be direct (solid arrows), especial-ly in T cell–depleted HCT setting as described herein, ormediated through T cell priming (dotted arrows).

MAJOR GRANTS

• Antonio Pérez Martínez. Trasplante de progenitoreshematopoyéticos de donante haploidéntico en niñoscon cáncer refractario. ISCIII. EC08/00291

• Luis Madero López. Generación y diferenciación decélulas madre pluripotentes inducidas (iPS) depacientes con enfermedades genéticas del sistemainmuno-hematopoyético. MICINN. PLE2009-0100

• Luis Madero López. Tratamiento de tumores infantilesdel sistema nervioso central refractarios o recurrentescon ICOVIR-5. ISCIII. EC08/00094

• Manuel Ramírez Orellana. Utilización de células madreadultas como agentes terapéuticos antitumorales.MICINN. PLE2009-0115

• Luis Madero López. Detección de infiltración lep-tomeníngea en niños con tumores del sistema nerviosocentral. ISCIII. PI10/02811

• Manuel Ramírez Orellana. Estudio de la regulación dela vía de FAS por NIK en trasplante alogénico. ISCIII.PI10/02802


González-Vicent M, Molina B, Andión M, Sevilla J,Ramirez M, Pérez A, Díaz MA. Allogeneic hematopoietictransplantation using haploidentical donor vs. unrelatedcord blood donor in pediatric patients: a single-center ret-rospective study. Eur J Haematol 87(1): 46-53. 2011.PMID: 21692851. IF: 2,785

Perez-Martinez A, Iyengar R, Gan K, Chotsampan-charoen T, Rooney B, Holladay M, Ramírez M, Leung W.Blood dendritic cells suppress NK cell function andincrease the risk of leukemia relapse after hematopoietic

cell transplantation. Biol Blood Marrow Transplant 17(5):598-607. 2011. PMID: 20977942. IF: 3,275

Castella M, Pujol R, Callén E, Ramírez MJ, Casado JA,Talavera M, Ferro T, Muñoz A, Sevilla J, Madero L, CelaE, Beléndez C, de Heredia CD, Olivé T, de Toledo JS,Badell I, Estella J, Dasí Á, Rodríguez-Villa A, Gómez P,Tapia M, Molinés A, Figuera Á, Bueren JA, Surrallés J.Chromosome fragility in patients with Fanconi anaemia:diagnostic implications and clinical impact. J MedGenet 48(4): 242-250. 2011. PMID: 21217111. IF:7,037

Caronia D, Patiño-Garcia A, Peréz-Martínez A, Pita G,Moreno LT, Zalacain-Díez M, Molina B, Colmenero I,Sierrasesúmaga L, Benítez J, Gonzalez-Neira A. Effect ofABCB1 and ABCC3 polymorphisms on osteosarcomasurvival after chemotherapy: a pharmacogenetic study.PLoS One 6(10): e26091. 2011. PMID: 22016816. IF:4,411

Gómez AM, Martínez C, Fiuza-Luces C, Herrero F, PérezM, Madero L, Ruiz JR, Lucia A, Ramírez M. Exercisetraining and cytokines in breast cancer survivors. Int JSports Med 32(6): 461-467. 2011. PMID: 21380980. IF:2,381

Thiel U, Wawer A, Wolf P, Badoglio M, Santucci A,Klingebiel T, Basu O, Borkhardt A, Laws HJ, Kodera Y,Yoshimi A, Peters C, Ladenstein R, Pession A, Prete A,Urban EC, Schwinger W, Bordigoni P, Salmon A, DiazMA, Afanasyev B, Lisukov I, Morozova E, Toren A,Bielorai B, Korsakas J, Fagioli F, Caselli D, Ehninger G,Gruhn B, Dirksen U, Abdel-Rahman F, Aglietta M,Mastrodicasa E, Torrent M, Corradini P, Demeocq F, DiniG, Dreger P, Eyrich M, Gozdzik J, Guilhot F, Holler E,Koscielniak E, Messina C, Nachbaur D, Sabbatini R,Oldani E, Ottinger H, Ozsahin H, Schots R, Siena S, SteinJ, Sufliarska S, Unal A, Ussowicz M, Schneider P,Woessmann W, Jürgens H, Bregni M, Burdach S; SolidTumor Working Party (STWP) and the PediatricDiseaseWorking Party (PDWP) of the European Group forBlood and Marrow Transplantation (EBMT); Asia PacificBlood and Marrow Transplantation (APBMT); PediatricRegistry for Stem Cell Transplantations (PRST);MetaEICESS Study Group. No improvement of survival

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with reduced- versus high-intensity conditioning for allo-geneic stem cell transplants in Ewing tumor patients. AnnOncol 22(7): 1614-1621. 2011. PMID: 21245159. IF:6,452

Verdeguer A, de Heredia CD, González M, Martínez AM,Fernández-Navarro JM, Pérez-Hurtado JM, Badell I,Gómez P, González ME, Muñoz A, Díaz MA; GETMON:Spanish Working Party for Blood and MarrowTransplantation in Children. Observational prospectivestudy of viral infections in children undergoing allogeneichematopoietic cell transplantation: a 3-year GETMONexperience. Bone Marrow Transplant 46(1): 119-124.2011. PMID: 20228849. IF: 3,66

Castella M, Pujol R, Callén E, Trujillo JP, Casado JA, GilleH, Lach FP, Auerbach AD, Schindler D, Benítez J, PortoB, Ferro T, Muñoz A, Sevilla J, Madero L, Cela E,Beléndez C, de Heredia CD, Olivé T, de Toledo JS, BadellI, Torrent M, Estella J, Dasí A, Rodríguez-Villa A, GómezP, Barbot J, Tapia M, Molinés A, Figuera A, Bueren JA,Surrallés J. Origin, functional role, and clinical impact ofFanconi anemia FANCA mutations. Blood 117(14): 3759-69. 2011. PMID: 21273304. IF: 10,558

Navas-Garcia M, Goig-Revert F, Villarejo-Ortega FJ,Robla J, de Prada I, Madero L, Perez-Diaz C, Rivero-Martin MB, Pascual Martin-Gamero A, Budke M,Cordobes-Tapia F. Tumours in the pineal region in thepaediatric age. Reports of 23 cases and a review of theliterature. Rev Neurol 52(11): 641-652. 2011. PMID:21563115. IF: 1,218

Aguado JM, Ruiz-Camps I, Muñoz P, Mensa J, AlmiranteB, Vázquez L, Rovira M, Martín-Dávila P, Moreno A,Alvarez-Lerma F, León C, Madero L, Ruiz-Contreras J,Fortún J, Cuenca-Estrella M; GROUP de Estudio deMicología Médica de la SEIMC (GEMICOMED).Guidelines for the treatment of Invasive Candidiasis andother yeasts. Spanish Society of Infectious Diseases andClinical Microbiology (SEIMC). 2010 Update. EnfermInfecc Microbiol Clin 29(5): 345-361. 2011. PMID:21459489. IF: 1,656

Fortún J, Sanz MÁ, Madero L, López J, de la Torre J,Jarque I, Vallejo C. Update on bacteraemia in oncology

and hematology. Enferm Infecc Microbiol Clin 29(Suppl):48-53. 2011. PMID: 21458720. IF: 1,656

Molina B, Alonso L, Gonzalez-Vicent M, Andion M,Hernandez C, Lassaletta A, Cormenzana M, Lopez-IborB, Villa M, Molina J, Diaz MA. High-dose busulfan andmelphalan as conditioning regimen for autologousperipheral blood progenitor cell transplantation in high-risk neuroblastoma patients. Pediatr Hematol Oncol28(2): 115-123. 2011. PMID: 21299340. IF: 0,81

Oñoro G, Hernández C, Sirvent S, Aleo E, Molina B,Atienza AL, Pérez-Martínez A. Unusual sites of extrapul-monary metastases of osteosarcoma after several lines oftreatment. Pediatr Hematol Oncol 28(7): 604-608. 2011.PMID: 21875323. IF: 0,81

Gonzalez-Vicent M, Diaz MA. Higher doses of CD34+PBPC are associated with a rapid acquisition of full donorchimerism and lower risk of relapse after allogeneic trans-plantation in pediatric patients with hematological malig-nancies. J Pediatr Hematol Oncol 33(3): 185-189. 2011.PMID: 21325973. IF: 0,998

Andion M, Molina B, Gonzalez-Vicent M, Alonso L,Hernandez C, Lassaletta A, Lopez-Ibor B, Villa M, DiazMA. High-dose busulfan and cyclophosphamide as aconditioning regimen for autologous peripheral bloodstem cell transplantation in childhood non-Hodgkin lym-phoma patients: a long-term follow-up study. J PediatrHematol Oncol 33(3): e89-e91. 2011. PMID: 21358341.IF: 0,998

Alonso L, Sevilla J, Gonzalez-Vicent M, Abad L,Gonzalez-Mediero I, Diaz MA. Pulmonary glial heterotopiain a child diagnosed with fanconi anemia and epilepsy. JPediatr Hematol Oncol 33(6): 462-464. 2011. PMID:21792042. IF: 0,998

Calleja Gero ML, Sevilla J, Madero L. What is the progno-sis of chronic immune thrombocytopenia?. An Pediatr74(5): 317-23. 2011. PMID: 21334273. IF: 0,57

Hernández Marqués C, Lassaletta-Atienza A, González-Vicent M, Sevilla J, Molina B, Andión M, Cormenzana M,Pérez Martínez A, Díaz MA, Madero L. Hepatosplenic

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AREA 3candidiasis in paediatric haematology-oncology patients.An Pediatr 75(1): 26-32. 2011. PMID: 21419736. IF: 0,57

Calleja ML, Lassaletta A, Albi G, Ruano D, Andión M,Madero L. Lower extremity paralysis as a sign of theonset of neuroblastoma. An Pediatr 75(2): 154-156.2011. PMID: 21565567. IF: 0,57

Ljungman P, de la Camara R, Perez-Bercoff L, AbecasisM, Nieto Campuzano JB, Cannata-Ortiz J, Cordonnier C,Einsele H, Gonzalez-Vincent M, Espigado I, Halter J,Martino R, Mohty B, Sucak G, Ullmann AJ, Vasques L,Ward KN, Engelhard D Infectious Diseases WorkingParty, European Group for Blood and MarrowTransplantation; Infectious Complications Subcommittee,Spanish Group of Haematopoietic Stem-cellTransplantation (García Noblejas A, de las Heras N, ...,Lassaletta Á). Outcome of pandemic H1N1 infections inhematopoietic stem cell transplant recipients.Haematologica 96(8): 1231-1235. 2011. PMID:21546495. IF: 6,532

GRUPO 43

HEAD OF LABORATORYGuillermo Reyes Copa

GROUP MEMBERS• Beatriz Aguado Bueno

RESEARCH INTEREST

Our group has been developing from the scientific pointof view different aspects regarding cardiac surgery andhematology. Our group has published the need oftransfusions of blood products in patients undergoingcardiac surgery. This is a randomized trial in low riskpatients in order to analyze the impact of a cell saverdevice in these patients. We could demonstrate thatthe general use of transfusion in patients undergoingcardiac surgery is very common and that the use of acell saver device does not reduce the need of transfu-sions of blood products (Figure 1). Our group has alsoparticipated in the publishing of one book regardingventricle assist devices, and we have also editedanother book considering the same aspect of medi-cine.

We have published the positive effect of lenalidomide incombination with dexamethasone as an effective agentfor treating plasmacytoma. The additional benefit oflenalidomide has been analyzed in refractory orrelapsed multiple myeloma. This study analyzes theSpanish Compassionate use registry in advancedpatients with multiple myeloma, comparing the results

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Blood packages transfusions in different times after the procedure.CS: Cell saver

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of 13 participating hospitals. Figure 2 shows theKaplan-Meier curve for survival time since multiplemyeloma diagnosis. The study of lenalidomide hasbeen completed with a publication regarding the safe-ty and efficacy of this drug. All these publications haveunveiled to the international scientific community therole that lenalidomide may have in patients with multi-ple myeloma.


Aguado B, Iñigo B, Sastre JL, Oriol A. ExtramedullaryPlasmacytomas in the Context of Multiple Myeloma.Adv Ther 28(7): 7-13. 2011. PMID: 22105528. IF:1,668

Alegre A, Aguado B, Giraldo P, Ríos E, Cánovas A,Ibáñez A, Castillo I, Hernández MT, Oriol A, Palomera

L, Rodríguez JN, García FL, Calvo JM, Martínez-Chamorro C, de la Serna J, Lahuerta JJ. Lenalidomideis effective as salvage therapy in refractory or relapsedmultiple myeloma: analysis of the SpanishCompassionate Use Registry in advanced patients. IntJ Hematol. 93(3): 351-60. 2011. PMID: 21360065. IF:1,324

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: GUILLERMO REYESCOPAEstudio aleatorizado, multicéntrico doble ciego, desecuencias de grupos para evaluar la eficacia, lainmunogenia y la seguridad de una dosis única de lavacuna de Merck contra staphylococcus aureus 0657nI (V710) en pacientes adultos citados para una inter-vención de cirugía cardiotorácica; (versión: 09-07-07).V710-003EudraCT: 2007-004018-15

PRINCIPAL INVESTIGATOR: BEATRIZ AGUADOBUENOEstudio de seguridad post-comercialización, observa-cional y no-intervencionista, de sujetos tratados conlenalidomida; (versión: 29-11-07). CC-5013-PASS-001

PRINCIPAL INVESTIGATOR: GUILLERMO REYESCOPAEnsayo clínico prospectivo, controlado y aleatorizadode regeneración celular cardíaca con láser y célulasmadre autólogas de médula ósea, en pacientes conenfermedad coronaria y angina refractaria; (Versión 1:17-11-2009). TMR-SC-02EudraCT: 2009-017966-21

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Kaplan-Meier curve for survival time since multiple myeloma diag-nosis.

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AREA 3Line 3.4Advanced therapies in oncohematology

GRUPO 44HEAD OF LABORATORYJuan Luis Steegmann Olmedillas

GROUP MEMBERS• Adrián Alegre Amor• María Reyes Arranz Sáez• María Jimena Cannata Ortiz• Ángela Figuera Álvarez• Ana María García-Noblejas Moya• Valle Gómez García de Soria• Jimena Jiménez Braña• Javier Loscertales Pueyo

RESEARCH INTEREST

Our Group has produced, in the year 2011, nineteenpapers and has presented thirty-four communicationsto meetings, mostly international. The spectrum coversall hematologic neoplasms, but in 2011 most publica-tions of the group center in multiple myeloma, lym-phoma, infectious complications, bone marrow trans-

plantation (BMT), myelodysplasia( MDS), and cellularbiology. The group is very active in its presence inSpanish and international collaborative groups, andmost of our production comes form this source.

Besides, the group has thirty-seven active clinical trials.In this summary, we shall comment only the findingscoming from papers.

In Multiple myeloma ( MM), some findings merit to bestressed, such as the description of the patterns ofextramedullary relapse. To confront this problem, the roleof lenalidomide is of interest. Nailing the importance ofobtaining a complete response after autologous BMT forMM, both with standard techniques or by cytometry, andthe predictive value of baseline FISH, have been majorfindings of the Spanish Group, in which Dr. Alegre is amain contributor. In Lymphoma, Dr. Arranz has beenauthor in two papers focused in prognosis, a field inwhich she and Dr. Cannata have been quite active.Infections are one of the major obstacles for the successof oncohematologic therapies. CMV, Pneumocystiscarinii, and HCV have been targets of research for Dr.Garcia-Noblejas, Cannata, and Gómez-García de Soria.This author has contributed to establish the prognosticvalue of cytogenetics and thrombocytopenia in MDS.

Dr. Figuera’s participation in the Fanconi network has givena nice information about chromosomes fragility. Analyzing

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Long-term prognostic significance of response in multiple myelomaafter stem cell transplantation. Martinez-Lopez J, Blade J, Mateos MV,Grande C, Alegre A, García-Laraña J, Sureda A, de la Rubia J, Conde E,Martinez R, de Arriba F, Viguria MC, Besalduch J, Cabrera R, Gonzalez-San Miguel JD, Guzman-Zamudio JL, Gomez del Castillo MC, MoraledaJM, García-Ruiz JC, San Miguel J, Lahuerta JJ; Grupo Español de MM;Programa para el Estudio de la Terapéutica en Hemopatía Maligna.Blood. 2011 Jul 21, 118(3):529-34.

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the role of imaging techniques in the response evaluationhas been the purpose of a study in which Dr.Loscertalesparticipated. Finally, Dr. Steegmann, in a review paper, hasaddressed a somewhat new field in cancer biology, such isthe role of iron in tumor proliferation.

MAJOR GRANTS

• Juan Luis Steegmann Olmedillas. European treat-ment and outcome study on CML, EUTOS.European Leukemia Net. Proyecto EUTOS de laEuropean LeukemiaNet

• María Reyes Arranz Sáez. Asociación de Rituximabal esquema CVP+INTERFERÓN en el tratamiento deprimera Line del linfoma folicular. FundaciónLeucemia Linfoma. LNH-Pro-05

• Juan Luis Steegmann Olmedillas. Estudio deFármaco-Vigilancia de los Fármacos Inhibidoresde las Tirosin Kinasa empleados en el tratamientode la Leucemia Mieloide Crónica (LMC). MEC.AEMPS


Such E, Cervera J, Costa D, Solé F, Vallespí T, Luño E,Collado R, Calasanz MJ, Hernández-Rivas JM,Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F,Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, del Cañizo C, Gómez V, Marco V, Xicoy B,Bonanad S, Pedro C, Bernal T, Sanz GF. Cytogeneticrisk stratification in chronic myelomonocytic leukemia.Haematologica 96 (3): 375-383. 2011. PMID:21109693. IF: 6,532

Camacho FI, Bellas C, Corbacho C, Caleo A, Arranz-Sáez R, Cannata J, Menárguez J, Sánchez-Verde L,González-Camacho L, Pérez-Martín ME, Martínez-González MA, Alvaro T, Mollejo M, Ruíz-Marcellán C,Montalbán C, Piris MA. Improved demonstration ofimmunohistochemical prognostic markers for survivalin follicular lymphoma cells. Mod Pathol 24(5): 698-707. 2011. PMID: 21240256. IF: 4,176

Calvo-Villas JM, Alegre A, Calle C, Hernández MT,García-Sánchez R, Ramírez G; GEM-PETHE-MA/Spanish Myeloma Group, Spain. Lenalidomide iseffective for extramedullary disease in relapsed orrefractory multiple myeloma. Eur J Haematol. 87(3):281-4. 2011. PMID: 21557775. IF: 2,785

Eichhorst BF, Fischer K, Fink AM, Elter T, Wendtner CM,Goede V, Bergmann M, Stilgenbauer S, Hopfinger G,Ritgen M, Bahlo J, Busch R, Hallek M; German CLL StudyGroup (GCLLSG. Collab.: Loscertales J). Limited clinicalrelevance of imaging techniques in the follow-up ofpatients with advanced chronic lymphocytic leukemia:results of a meta-analysis. Blood. Epub 117(6): 1817-21.2010 Dec 7. 2011. PMID: 21139079. IF: 10,558

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 ofHCV-infected hematopoietic SCT patients and effects ofantiviral therapy. Bone Marrow Transplant. 2011 Dec 12.[Epub ahead of print]. 2011. PMID: 22158388. IF: 3,66

Martinez-Lopez J, Blade J, Mateos MV, Grande C,Alegre A, García-Laraña J, Sureda A, de la Rubia J,Conde E, Martinez R, de Arriba F, Viguria MC,Besalduch J, Cabrera R, Gonzalez-San Miguel JD,Guzman-Zamudio JL, Gomez del Castillo MC,Moraleda JM, García-Ruiz JC, San Miguel J, LahuertaJJ; GROUP Español de MM; Programa para el Estudiode la Terapéutica en Hemopatía Maligna. Long-termprognostic significance of response in multiple myelo-ma after stem cell transplantation. Blood 118(3): 529-34. 2011. PMID: 21482708. IF: 10,558

Gonzalez-Porras JR, Cordoba I, Such E, Nomdedeu B,Vallespi T, Carbonell F, Luño E, Ardanaz M, Ramos F,Pedro C, Gomez V, de Paz R, Sanchez-Barba M, SanzGF, Del Cañizo AC; Spanish Myelodysplastic SyndromeRegistry. Prognostic impact of severe thrombocytope-nia in low-risk myelodysplastic syndrome. Cancer.117(24): 5529-37. 2011. PMID: 21638279. IF: 5,131

Sanchez-Gonzalez B, Peñalver FJ, Medina A, GuillénH, Calleja M, Gironella M, Arranz R, Sebastian E, deOña R, Cánovas A, de la Fuente I, Grande C, Sancho

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AREA 3JM, Perez R, Domingo E, Lopez-Lorenzo JL, Prieto E,Panizo C, Gorosquieta A, Perez I, Cervera JM, MarinM, Mencha C, Ramila E, Salar A. Clinical experience ofbendamustine treatment for non-Hodgkin lymphomaand chronic lymphocytic leukemia in Spain. Leuk Res.2011 Dec 7 [Epub ahead of print]. 2011. PMID:22154023. IF: 2,555

García-Noblejas A, Velasco A, García-León N,Cananta-Ortiz J, Steegmann JL. Pneumocystis jiroveciipneumonia as first manifestation of late relapseangioimmunoblastic T-cell lymphoma. Leuk Res. Epub2011 May 13. 35(9): e143-4. 2011. PMID: 21570116.IF: 2,555

Novo, A; Llorente, A; Cladera, A; Rubio, D; Valcarcel, D;Amutio, E; Conde, E; Martin, E; Diaz-Mediavilla, J; Rifon,JJ; Diez, JL; Cabrera, JR; Serrano, J; Besalduch, J;Ruiz, JCG; Zueco, JCG; Vallejo, JC; Vazquez, L; Cuesta,MA; Diaz, ML; Batlle, M; Rovira, M; Abellan, PF; Rojas,R; Tabares, S; Olave, T; Gomez, V. This document hasbeen written by Gilead Medical Department (GileadSciences). Invasive fungal infections in onco-haematol-ogy: a Spanish perspective. Rev Esp Quimioter 24(3):168-72. 2011. PMID: 21947102. IF: 0,667

Alegre A, Aguado B, Giraldo P, Ríos E, Cánovas A,Ibáñez A, Castillo I, Hernández MT, Oriol A, PalomeraL, Rodríguez JN, García FL, Calvo JM, Martínez-Chamorro C, de la Serna J, Lahuerta JJ. Lenalidomideis effective as salvage therapy in refractory or relapsedmultiple myeloma: analysis of the SpanishCompassionate Use Registry in advanced patients. IntJ Hematol. 93(3): 351-60. 2011. PMID: 21360065. IF:1,324

Steegmann-Olmedillas, J.L. The role of iron in tumourcell proliferation. Clin Transl Oncol 13 (2): 71-76. 2011.PMID: 21324793. IF: 1,254

Castella M, Pujol R, Callén E, Ramírez MJ, Casado JA,Talavera M, Ferro T, Muñoz A, Sevilla J, Madero L, CelaE, Beléndez C, de Heredia CD, Olivé T, de Toledo JS,Badell I, Estella J, Dasí Á, Rodríguez-Villa A, Gómez P,Tapia M, Molinés A, Figuera Á, Bueren JA, Surrallés J.Chromosome fragility in patients with Fanconi anaemia:

diagnostic implications and clinical impact. J Med Genet48(4): 242-250. 2011. PMID: 21217111. IF: 7,037

Castella M, Pujol R, Callén E, Trujillo JP, Casado JA, GilleH, Lach FP, Auerbach AD, Schindler D, Benítez J, PortoB, Ferro T, Muñoz A, Sevilla J, Madero L, Cela E,Beléndez C, de Heredia CD, Olivé T, de Toledo JS,Badell I, Torrent M, Estella J, Dasí A, Rodríguez-Villa A,Gómez P, Barbot J, Tapia M, Molinés A, Figuera A,Bueren JA, Surrallés J. Origin, functional role, and clini-cal impact of Fanconi anemia FANCA mutations. Blood117(14): 3759-69. 2011. PMID: 21273304. IF: 10,558

Aguado B, Iñigo B, Sastre JL, Oriol A. ExtramedullaryPlasmacytomas in the Context of Multiple Myeloma.Adv Ther 28(7): 7-13. 2011. PMID: 22105528. IF:1,668

Solano C, Tormo N, de la Cámara R, Bartolo Nieto J,López J, Benet I, Muñoz-Cobo B, Costa E, RemigiaMJ, Garcia-Noblejas A, Bravo D, Navarro D. Effect ofcytomegalovirus (CMV) serostatus on the incidenceand virological features of active CMV infection in allo-geneic stem cell transplant recipients. Clin Infect Dis.53(3): 313-5; author reply 315-6. 2011. PMID:21765090. IF: 8,186

Ljungman P, de la Camara R, Perez-Bercoff L,Abecasis M, Nieto Campuzano JB, Cannata-Ortiz J,Cordonnier C, Einsele H, Gonzalez-Vincent M,Espigado I, Halter J, Martino R, Mohty B, Sucak G,Ullmann AJ, Vasques L, Ward KN, Engelhard DInfectious Diseases Working Party, European Group forBlood and Marrow Transplantation; InfectiousComplications Subcommittee, Spanish Group ofHaematopoietic Stem-cell Transplantation (GarcíaNoblejas A, de las Heras N, ..., Lassaletta Á). Outcomeof pandemic H1N1 infections in hematopoietic stemcell transplant recipients. Haematologica 96(8): 1231-1235. 2011. PMID: 21546495. IF: 6,532

Tormo N, Solano S, Nieto J, Benet I, Nieto J, de la CámaraR, Lopez J, Garcia-Noblejas A, Muñoz-Cobo B, Costa E,Clari MA, Hernández-Boluda JC, Remigia MJ andNavarro D. Reconstitution of CMV pp65 and IE-1-specificIFN-? CD8(+) and CD4(+) T-cell responses affording pro-

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tection from CMV DNAemia following allogeneichematopoietic SCT. Bone Marrow Transplant 46(11):1437-1443. 2011. PMID: 21243030. IF: 3,66

Muñoz-Cobo B, Solano S, Nieto J, de la Cámara R,Remigia MJ, Garcia-Noblejas A, López J, Benet I,Hernández-Boluda JC, Costa E, Bravo D, and NavarroD. Surveillance for adenovirus DNAemia early aftertransplantation in adult recipients of unrelated-donorallogeneic stem cell transplants in the absence of clini-cally suspected infection. Bone Marrow Transplant46(11): 1484-1486. 2011. PMID: 21217790. IF: 3,66

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio fase III nacional, abierto, multicéntrico, ran-domizado, comparativo de VBMCP-VBAD/velcadeversus talidomida/dexametasona versus vel-cade/talidomida/dexametasona como terapia deinducción seguido de altas dosis de quimioterapia contrasplante autólogo hematopoyético y posteriortratamiento de mantenimiento con interferón alfa-2bversus talidomida versus talidomida/velcade enpacientes con mieloma múltiple sintomático de nuevodiagnóstico de edad menor o igual a 65 años; (Versiónfinal: 26-01-05). GEM05MENOS65EudraCT: 2005-001110-41

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEstudio en fase III de STI571 versus interferón alfa (IFN-alfa), combinado con citarabina (Ara-C), en pacientescon leucemia mieloide crónica con cromosomaFiladelfia positivo, en fase crónica, recién diagnostica-da y no tratada previamente. (Versión 14-4-00).CSTI571 0106

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio de fase III, abierto, multicéntrico, randomizado,comparativo, para evaluar la eficacia y seguridad de rit-uximab en combinación con fludarabina y ciclofosfami-da (FCR) frente a fludarabina y ciclofosfamida (FC) en

pacientes con leucemia linfática crónica (LLC) de célu-las B CD20-positivo tratados previamente. BO17072

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio aleatorizado con grupo control de doxil/caelyx(doxorrubicina HCL en liposoma inyectable) y velcade(bortezomib) o velcade en monoterapia para eltratamiento de mieloma múltiple en recaída, (versión 2:27-07-04). DOXIL-MMY-3001EudraCT: 2004-001842-34

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio aleatorizado, abierto de VELCADE TM /melfalán / prednisona vs melfalán / prednisona en suje-tos con mieloma múltiple sin tratamiento previo;(Versión final: 11-10-04, fecha de emisión: 14-10-04).26866138-MMY-3002

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio fase III nacional, abierto, multicéntrico, ran-domizado, comparativo de tratamiento de induccióncon melfalán/prednisona/velcade versus talidomi-da/prednisona/velcade seguido de tratamiento demantenimiento con talidomida/velcade versus pred-nisona/velcade en pacientes con mieloma múltiple sin-tomático de nuevo diagnóstico mayores de 65 años;(Versión final: 26-01-05). GEM05MAS65EudraCT: 2005-001111-21

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZTratamiento con R-Mega CHOP y rescate precoz con R-IFE y trasplante autólogo de progenitores hematopoyéti-cos (TAPH) según respuesta medida por tomografía poremisión de positrones (PET) en pacientes con linfomadifuso de célula grande B (LDCGB) de mal pronóstico;(versión 1:19-07-06). GEL/TAMO-2006EudraCT: 2006-005254-68

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZPRELUDE: Ensayo clínico en fase 3 para estudiar laprevención de la recaída en pacientes con línfomamediante el tratamiento diario con enzastaurina; (ver-sión (a): 17-01-06). H6Q-MC-JCBJEudraCT: 2005-004630-41

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AREA 3PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEstudio fase III aleatorizado 2x2, abierto, multicéntricode BMS-354825 administrado por vía oral a dosis de50 mg ó 70 mg dos veces al día o de 100 mg o 140mg una vez al día en sujetos con leucemia mieloidecrónica en fase crónica, con cromosoma Philadelphiao BCR-ABL positivo, resistentes o intolerantes a ima-tinib mesilato (Glivec®) CA180-034EudraCT: 2005-001294-99

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio de seguridad, post-autorización, observa-cional, no intervencionista, para el seguimiento contin-uo de los resultados de seguridad y gestación, en unacohorte de sujetos con trombocitemia esencial (TE) dealto riesgo en tratamiento con Xagrid® comparado conotros tratamientos citoreductores convencionales (ver-sión española 2.0: 1-04-05; hoja de información yconsentimiento informado versión española 1.0:28/04/05). SPD422-401

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZAsociación de rituximab al esquema CVP + interferonen el tratamiento de primera línea del linfoma folicular;(versión 1.0: 14-10-05). LNH-PRO-05EudraCT: 2005-004761-42

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio fase II nacional, abierto, multicéntrico, no con-trolado de pacientes con mieloma múltiple tratadoscon bortezomib (velcade) pre y post trasplante alogéni-co de progenitores hematopoyéticos con acondi-cionamiento no mieloablativo; (versión: 10-10-05).MINIALOVELCADE 2005/26866138MMY2021EudraCT: 2005-004858-27

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEnsayo clínico de fase III de inmunoquimioterapia com-binada con fludarabina, ciclofosfamida y rituximab(FCR) frente a quimioterapia con fludarabina y ciclofos-famida (FC) sola, en pacientes con leucemia linfocíticacrónica no tratados previamente. (Versión: Enmienda

1: 27-07-04; Hoja de información al paciente yConsentimiento Informado,versión inglesa Enmiendanº2 y versión española Enmienda nº2: 12-09-04). CLL-8/ML17102EudraCT: 2004-002787-15

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio abierto, multicéntrico, randomizado, de fase IIIpara investigar la eficacia y seguridad de bendamusti-na en comparación con bendamustina + RO5072759(GA101) en pacientes con linfoma no Hodgkin indo-lente, refractario a rituximab; (versión A2: 28-07-10).GAO4753GEudraCT: 2009-015504-25

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEstudio de fase 1/2 de SKI-606 en leucemias con cro-mosoma filadelfia positivo; (versión incial: 28-09-05).3160A4-200-WWEudraCT: 2005-004230-40

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio internacional, multicéntrico, aleatorizado, dobleciego de vorinostat (MK-0683) o placebo en combi-nación con bortezomib en pacientes con mielomamúltiple; (versión: 02-07-08). MK-0683-088EudraCT: 2008-003752-30

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMORRegistro de datos de pacientes tratados con ben-damustina por uso compasivo en MM refrectario o enrecidiva avanzados; (versión final: 02-11). BENDA-MMRR-11

PRINCIPAL INVESTIGATOR: ANGELA FIGUERAALVAREZEstudio de fase 2, abierto, de la eficacia de la monoter-apia con AC220 en pacientes con leucemia mieloideaguda (LMA) con mutaciones activadoras de FLT3-ITD;(versión 3: 16-11-09). AC220-002EudraCT: 2009-013093-41

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio nacional, multicéntrico, aleatorizado, abierto,

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fase III de Revlimid (Lenalidomida) más dexametasona(Redex) versus observación en pacientes con mielomamúltiple (MM) quiescente (MM smoldering) con altoriesgo de progresión a MM sintomático; (versiónprimera: 01-02-07). QUIREDEXEudraCT: 2007-000649-36

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZTrasplante autólogo de progenitores hemopoyéticos conacondicionamiento que incluye Zevalin + BEAM enpacientes con linfoma difuso de célula grande B refractario;(versión final: 11-06-07). GELTAMO-Z-BEAM LDCGBEudraCT: 2007-003198-22

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZTrasplante alogénico de progenitores hematopoyéticostras acondicionamiento no mieloablativo con melfalan,fludarabina y zevalin en pacientes con linfoma NoHodgkin B agresivo; (versión final: 18-06-07). GELTA-MO-Z-RIC-ALLOEudraCT: 2007-003302-10

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEnsayo fase III, abierto, aleatorizado, multicéntrico:dasatinib (SPRYCEL) frente a la dosis estándar de ima-tinib (400 mg) en el tratamiento de pacientes conleucemia mieloide crónica con cromosomaPhiladelphia positivo en fase crónica de reciente diag-nóstico; (versión v02:03-04-07). CA180-056EudraCT: 2006-005712-27

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEstudio fase III, multicéntrico, abierto, aleatorizado de ima-tinib frente a nilotinib, en pacientes adultos con leucemiamieloide crónica cromosoma Filadelfia positivo (Ph+) enfase crónica (LMC-FC) de nuevo diagnóstico; (versiónfinal: 05-02-07, incluida Modificación internacional nº2 alprotocolo versión: 19-06-07). CAMN107A2303EudraCT: 2007-000208-34

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase II, multicéntrico, aleatorizado, abierto y

de grupos paralelos, para evaluar la seguridad y la efi-cacia de VELCADE® en combinación con dexameta-sona o VELCADE® en combinación con dexameta-sona y ciclofosfamida o VELCADE® en combinacióncon dexametasona y lenalidomida en pacientes conmieloma múltiple que son refractarios al tratamientoprimario o que han recaído o progresado tras eltratamiento primario y que han alcanzado una enfer-medad estable tras 4 ciclos de tratamiento con VEL-CADE® y dexametasona; (versión final: 30-08-07).26866138-MMY-2045EudraCT: 2007-001462-33

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio de fase 1, multicéntrico, abierto y de búsque-da de dosis de forodesina en pacientes con leucemialinfocítica crónica de células B recidivante; (versión 3.0:07-09-07). BCX1777-110EudraCT: 2007-000256-14

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio fase III, abierto, multicéntrico, aleatorizado, detres brazos para comparar la eficacia y la seguridad deRO5072759 + clorambucilo (GCIb), rituximab + clo-rambucilo (RCIb) o clorambucilo (CIb) en monoterapiaen pacientes con comorbilidades y LLC no tratadospreviamente; (versión B: 24-08-09). BO21004EudraCT: 2009-012476-28

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio aleatorizado, abierto, multicéntrico y en fase 3de la combinación de rituximab, ciclofosfamida, dox-orubicina, velcade y prednisona (VCR-CAP) o ritux-imab, ciclofosfamida, doxorubicina, vincristina y pred-nisona (R-CHOP) en pacientes con linfoma de célulasdel manto de nuevo diagnóstico que no son can-didatos a trasplante de médula ósea; (versión 3.0: 13-12-07). 26866138-LYM-3002EudraCT: 2007-005669-37

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio de fase 3, abierto y aleatorizado, de inotuzumab


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AREA 3ozogamicina (CMC-544) administrado en combinacióncon rituximab, comparado con un tratamiento definido aelección del investigador, a sujetos con linfoma noHodgkin de células B folicular, CD22 positivo, en recidivao refracta-rio; (versión: 14-11-07). 3129K4-3301-WWEudraCT: 2007-000219-27

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEGMANNOLMEDILLASEstudio de fase 3, abierto y aleatorizado, de bosutinib com-parado con imatinib en sujetos con leucemia mieloide cróni-ca cromosoma filadelfia positiva en fase crónica, de diag-nóstico reciente; (versión: 06-11-07). 3160A4-3000-WWEudraCT: 2007-003780-50

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase I-Ib/II, abierto, multicéntrico de AUY922administrado como agente único así como en combi-nación con bortezomib, con o sin dexa-metasona, apacientes adultos con mieloma múltiple en recidiva orefractario; (versión: 25-03-08). CAUY922A2103EudraCT: 2007-006279-35

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio fase II de panobinostat oral, en pacientes adul-tos con linfoma de Hodgkin clásico refractario/en recaí-da, después de fallo a dosis altas de quimioterapia contransfusión autóloga de células madre y un régimen quecontiene gemcitabina o vinorelbina o vinblastina; (ver-sión: 02-05-08). CLBH589E2214EudraCT: 2008-003016-35

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio del perfil de expresión génica, como un biomar-cador innovador en el cáncer, de ayuda en el pronósticoy en la selección del tratamiento de la LeucemiaLinfocítica Crónica (LLC); HEMATOCHIP-Pronóstico yRespuesta al tratamiento; (versión final: 15-02-08, adap-tado a la Enmiendanº 1 de fecha 12-08-08). HMC06

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase III, multicéntrico, aleatorizado, dobleciego, controlado con placebo, de tres grupos parale-los para determinar la eficacia y seguridad de lenalido-

mida (Revlimid®) en combinación con melfalán y pred-nisona frente a placebo más melfalán y prednisona enpacientes con mieloma múltiple recién diagnosticadode 65 años de edad o mayores; (versión final: 12-09-06). CC-5013-MM-015EudraCT: 2006-001865-41

PRINCIPAL INVESTIGATOR: VALLE GOMEZ GARCIA-SORIAEstudio aleatorizado, doble-ciego, controlado conplacebo para evaluar la eficacia y seguridad deRomiplostim en el tratamiento de la trombocitopenia enpacientes con síndrome mielodisplásico (SMD) de ries-go bajo o intermedio-1; (versión: 01-02-08). 20060198EudraCT: 2007-007258-75

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio observacional transversal multicéntrico depacientes con leucemia de células plasmáticas trata-dos con esquemas que contengan bortezomib; (ver-sión final: 21-10-08). GEM/LCP/2008/01

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMORTratamiento de mantenimiento del mieloma múltiple(MM) postrasplante autólogo de sangre periférica(TASPE) mediante Interferon alfa-2b conjugado conpolietilenglicol (PegIntron) (versión: mayo-2002). PI-MM-01

PRINCIPAL INVESTIGATOR: ANGELA FIGUERAALVAREZEstudio aleatorizado fase III de Elacitarabina compara-da con la elección del investigador en pacientes conLeucemia Mieloide Aguda en estadio avanzado;(Versión 2: 25-03-2010). Estudio Clavela. CP4055-306EudraCT: 2009-014445-80

PRINCIPAL INVESTIGATOR: VALLE GOMEZ GARCIA-SORIAEstudio de perfil de citocinas solubles en pacientesdiagnosticados de un síndrome melodisplásico; (ver-sión 1: 22-04-08). 4383/001

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio fase III, abierto, aleatorizado de ofatumumab

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añadido a fludarabina-ciclofosfamida frente a la combi-nación fludarabina-ciclofosfamida en sujetos conleucemia linfocitica crónica a recaída; (versión: 22-08-08). OMB110913EudraCT: 2008-005811-16

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio fase 3, multicéntrico, aleatorizado, dobleciego, controlado conplacebo, de grupos paralelospara valorar la eficacia y la seguridad deLenalidomida (REVLIMID®) como terapia de manten-imiento en pacientes con leucemia linfocítica crónicade células B tras tratamiento de segunda línea. (ElEnsayo CONTINUUM); (versión Enmienda 3: 17-10-08). CC-5013-CLL-002EudraCT: 2007-001626-27

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio observacional, transversal, multicéntrico, depacientes tratados con Lenalidomida en mielomamúltiple refractario o en recidiva, de forma compasiva;(versión final: 17-09-08). GEM/LEN/2008/01

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio multicéntrico fase II, no aleatorizado, deRituximab en combinación con Bendamustina comoprimer tratamiento sistémico en linfoma de células B dela zona marginal extraganglionar del tejido linfoide aso-ciado a mucosas (MALT); (versión final: 28-10-2008).MALT2008-01EudraCT: 2008-007725-39

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEnsayo intergrupos (GELTAMO/GETH) fase II, abierto,multicéntrico, de uso de alemtuzumab(MabCampath®) en trasplante alogénico de donanteno emparentado con acondicionamiento de intensidadreducida en pacientes con neoplasias hematológicas;(versión 1.0 final: 03-12-07). ALOTIRNE-EC06007EudraCT: 2007-006440-22

PRINCIPAL INVESTIGATOR: VALLE GOMEZ GARCIA-SORIA

Estudio retrospectivo de la evolución de la sobrecargaférrica de los pacientes con Síndrome Mielodisplásico(SMD) de bajo riesgo en España; (versión final: 20-05-09). Estudio IRON2. NOV-000-2009-01

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio aleatorizado, doble-ciego, controlado conplacebo, multicéntrico de fase III, para evaluar la ter-apia adyuvante con RAD001 frente a placebo, enpacientes con linfoma difuso de células grandes B(LDCGB) de elevado riesgo que hayan alcanzado unarespuesta completa tras una primera línea dequimioterapia con rituximab; (versión 00: 11-02-09).CRAD001N2301EudraCT: 2008-000498-40

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio fase II aleatorizado y abierto de CNTO328(anticuerpo monoclonalanti-IL-6) y VELCADE-Melfalán-Prednisona comparado con Velcade-Melfalán-Prednisona para el tratamiento de MielomaMúltiple no tratado previamente; (versión A0: 22-01-2009). CNTO328MMY2001EudraCT: 2008-007157-12

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio en fase 2, multicéntrico, aleatorizado y abier-to para determinar la eficacia de Lenalidomida(Revlimid®) frente al tratamiento de elección delinvestigador en pacientes que han recidivado o queson resistentes al linfoma de células del manto; (ver-sión 2: 21-10-2008). CC-5013-MCL-002EudraCT: 2008-003389-25

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio fase 3, multicéntrico, aleatorizado, abierto yde grupos paralelos para valorar la eficacia y seguri-dad de lenalidomida (Revlimid®) frente a clorambuci-lo como terapia de primera línea en pacientesancianos con leucemia linfocítica crónica de células Bno tratados previamente (Ensayo Origin); (versiónfinal, PA1: 24-03-09). CC-5013-CLL-008EudraCT: 2008-003079-32

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AREA 3PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio abierto internacional multicéntrico de vorinos-tat (MK-0683) en combinación con bortezomib enpacientes con mieloma múltiple recidivante y resistenteal tratamiento; (versión: 02-07-08). MK-0683-095EudraCT: 2008-003753-33

PRINCIPAL INVESTIGATOR: ANGELA FIGUERAALVAREZEnsayo aleatorizado, abierto, multicéntrico, en 2 fases,con grupos paralelos, para evaluar la eficacia, seguri-dad y tolerabilidad de AZD1152 sólo y en combinacióncon dosis bajas de arabinósido de citosina (DBAraC)comparado con DBAraC sólo, en pacientes de edadmayor o igual a 60 años con leucemia mieloide aguda(LMA) de nuevo diagnóstico, que se han consideradono candidatos a quimioterapia intensiva de inducción;(versión 110-03-09). D1531C00009EudraCT: 2009-010114-30

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio de fase II, abierto, multicéntrico única dosisintravenosa, de búsqueda de dosis para determinar laseguridad y eficacia de Sym001 en el tratamiento de lapúrpura trombocitopénica inmune (PTI) en pacientesadultos no esplenectomizados y RhD positivos; (ver-sión 1.00: 30-01-08). SYM001-03EudraCT: 2007-006081-15

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZQuimioinmunoterapia de rescate con ofatumumabfrente a quimioinmunoterapia de rescate con rituximabseguido de trasplante autólogo de células madre en ellinfoma difuso de células grandes B (LDCGB) en recaí-da o refractario; (versión 00: 02-06-09). OMB110928EudraCT: 2009-009256-20

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio en fase II, multicéntrico y abierto de YM155más rituximab en pacientes con Linfoma No Hodgkinde células B CD20 positivas, previamente tratados,que hayan sido sometidos a autotrasplante de célulasmadre(ATCM) o que no sean elegibles para ATCM;

(versión Enmienda 1: 05-06-09). 155-CL-031EudraCT: 2009-010777-20

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio fase III, multicéntrico, abierto, aleatorizado deofatumumab añadido a clorambucilo frente a monoter-apia con clorambucilo en sujetos con leucemia linfocíti-ca crónica no tratados previamente; (versiónYM2007/00115/01 -España-: 11-08-08). OMB110911EudraCT: 2008-004932-19

PRINCIPAL INVESTIGATOR: VALLE GOMEZ GARCIA-SORIAEstudio de extensión abierto para evaluar la seguridadde la administración a largo plazo de romiplostim ensujetos trombocitopénicos con síndromes mielodis-plásicos (SMD); (versión Amd 3 Sup: 25-09-09).20060197EudraCT: 2007-001516-24

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio en Fase 3, abierto, aleatroizado de ozogam-icina de inotuzumab administrado en combinacióncon rituximab comparado con un tratamientodefinido elegido por el investigador en pacientes conlinfoma no hodgkiniano agresivo, positivo al CD-22,recidivante o refractario no candidatos a quimioter-apia intensiva a altas dosis; (vesrión final: 22-09-10).B1931008EudraCT: 2010-020147-12

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio de fase Ib adaptativo, comparativo, aleatoriza-do, de grupos paralelos, multicéntrico, de rituximabpor vía subcutánea (s.c.) frente a rituximab por víaintravenosa (i.v.), ambos en combinación conquimioterapia (fludarabina y ciclofosfamida), enpacientes con LLC previamente no tratada; (Versión A:19-07-10). BO25341EudraCT: 2010-021380-32

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYO

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AREA

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Carga de enfermedad de los pacientes con leucemialinfocítica crónica en cinco países europeos; (Versión2.3: 23-11-09). M2-8403

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEstudio fase IIIb, multicéntrico, abierto, de nilotinib, enpacientes adultos con LMC Ph positivo de nuevo diag-nóstico en fase crónica y/o BCR-ABL positivo;(Versión: 17-01-10). CAMN107EIC01EudraCT: 2009-017775-19

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio fase IIb nacional, abierto, multicéntrico, ran-domizado, comparativo de tratamiento con un esque-ma secuencial melfalán/prednisona/borte-zomib(Velcade®) (MPV) seguido de lenalidomida(Revlimid®/dexametasona) a bajas dosis (Rd) versusun esquema alternante de melfalán/prednisona/Velcade® (MPV) con lenalidomida/dexametasona abajas dosis (Rd) en pacientes con Mieloma Múltiple(MM) sintomático de nuevo diagnóstico mayores de 65años; (Versión 1: 1-02-2010). GEM2010MAS65EudraCT: 2010-018379-70

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio abierto para determinar la dosis máxima toler-ada y evaluar la eficacia y seguridad de CEP-18770 enpacientes con Mieloma Múltiple recidivante y resistenteal tratamiento más reciente; (Versión enmienda 1:9-09-2009). C18770/2043EudraCT: 2009-0133778-41

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio retrospectivo a nivel nacional para evaluar eluso de darbepoetin alfa administrado en pauta prefer-encial cada tres semanas en la práctica clínica entumores no mieloides; (Versión 1: 26-03-2010). ALE-DAR-2010-01

PRINCIPAL INVESTIGATOR: VALLE GOMEZ GARCIA-SORIARegistro nacional de pacientes diagnosticados deLeucemia Mielodide Aguda según los criterios de laOMS y sometidos a tratamiento con azacitidina; (ver-sión final: 3-01-11). FCL-AZA-2011-01

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio abierto de fase Ib/II para evaluar la seguridad yeficacia de TRU 016 en combinación con bendamusti-na frente a bendamustina en monoterapia en pacientescon leucemia linfocítica crónica recidivante; (Versiónfinal: 26-05-10). 16201EudraCT: 2010-019554-41

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASPredicción de la respuesta hematológica, citogenéticay molecular a la terapia con inhibidores de laTirosincinasa de segunda línea en la Leucemia MieloideCrónica Ph positivo. Estudio PREST; (Versión 08: 9-12-2009). EPI-NOV-003-009

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio de fase III en dos etapas, abierto, internacional,multicéntrico, aleatorizado y controlado para investigarla farmacocinética, la eficacia y la seguridad de ritux-imab s.c. conjuntamente con CHOP o CVP en com-paración a rituximab i.v. conjuntamente con CHOP oCVP en pacientes con linfoma folicular sin tratar previ-amente, seguido por un tratamiento de mantenimientobien con rituximab s.c. o bien con rituximab i.v.;(Versión A: 16-07-10). BO22334EudraCT: 2010-021377-36

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio randomizado en fase IIIb de MabThera® (ritux-imab) agregado a quimioterapia, bendamustina o clo-rambucilo en pacientes con leucemia linfática crónica;(versión 1: 23-07-10). MO22468EudraCT: 2009-012072-28

PRINCIPAL INVESTIGATOR: ANGELA FIGUERAALVAREZEnsayo clínico en fase III, multicéntrico, aleatorizado, dobleciego y controlado con placebo para evaluar la seguridad,la tolerabilidad, la eficacia y la inmunogenicidad de V212 enreceptores de autotrasplantes de células hematopoyéticas(auto-TCH);(versión 01: 20-05-10). V212-001EudraCT: 2010-020150-34

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AREA 3PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZBendamustina, citabirina, etopósido y melfalán como régi-men de acondicionamiento para el transplante atuólogo deprogenitores hematopoyéticos en pacientes con linfomaagresivo; (versión final 1.0: 30-09-10). BENDA-EAM2010-01EudraCT: 2010-020926-17

PRINCIPAL INVESTIGATOR: VALLE GOMEZ GARCIA-SORIAEstudio de fase 3, doble ciego, multicentrico, aleatorizado,controlado con placebo, para evaluar la eficacia, seguridady tolerabilidad del tratamiento profiláctico con anfotericina Bliposomal (AmBisome®) para la prevención de infeccionesfúngicas invasivas (IFI) en sujetos que reciben quimioterapiade inducción a la remisión para la leucemia linfoblásticaaguda (LLA); (versión 2: 13-10-10). GS-EU-131-0247EudraCT: 2010-019562-91

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREnsayo de fase 3, aleatorizado y abierto, de lenalidomi-da/dexametasona, con o sin elotuzumab, en sujetos conmieloma múltiple no tratados previamente; (versiónorig+amed01: 11-04-11). CA204006EudraCT: 2010-022445-20

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEGMANNOLMEDILLASEstudio abierto, aleatorizado de nilotinib vs. imatinib están-dar (400/600 mg QD) comparando la cinética de larespuesta molecular completa en pacientes con LMC-FCcon evidencia de leucemia persistente por RQ-RCP; (ver-sión 02: 26-06-09). CAMN107A2405EudraCT: 2009-012616-40

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase II abierto, nacional, multicéntrico de ben-damustina, bortezomib (Velcade®) y prednisona (BVP) enpacientes con mieloma múltiple de nuevo diagnóstico; (ver-sión final 1.0: 03-01-11). GEM11-BENVELPRESEudraCT: 2011-000293-62

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio clínico en fase 2, doble ciego, controlado conplacebo y aleatorizado de BHQ880, anticuerpo mono-

clonal (AcM) anti-Dickkopf1 (DKK1), en pacientes conmieloma múltiple no tratado e insuficiencia renal; (ver-sión 00 final:18-03-11). CBHQ880A2203EudraCT: 2009-010875-26

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio abierto, multicéntrico, de grupo único, paraestudiar la seguridad y eficacia de pomalidomida(CC 4047) en monoterapia en pacientes con mielo-ma múltiple refractario o recidivante y refractarioestudio complementario del ensayo clínico CC4047 MM; (versión final: 20-10-10). CC-4047-MM-003/CEudraCT: 2010-023343-16

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZRegistro de linfomas del manto tratados con ben-damustina; (versión final: marzo de 2011). RLMBPRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREnsayo de fase 3, aleatorizado y abierto, de lenalidomi-da/dexametasona, con o sin elotuzumab, en elMieloma Múltiple en recidiva o resistente al tratamien-to. CA204004EudraCT: 2010-020347-12

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEstudio multicéntrico de fase Ib de búsqueda de dosisde un único brazo del antagonista oral de SmoothenedLDE225 en combinación con nilotinib en pacientes conleucemia mieloide crónica en fase crónica que han fal-lado a la terapia previa con otros inhibidores de la tirosi-na-quinasa BCR-ABL; (versión 00: 17-03-11).CAMN107Y2101EudraCT: 2011-000282-12

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio de fase III, multicéntrico, aleatorizado, dobleciego y controlado con placebo de panobinostat para elmantenimiento de la respuesta en pacientes con linfomade Hodgkin con riesgo de recidiva después de recibirquimioterapia en dosis altas y autotrasplante de célulasmadre; (Versión 1.0:09-12-09). CLBH589E23 01EudraCT: 2009-014846-26

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PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase 3, prospectivo, multicéntrico, aleator-izado, doble ciego controlado con placebo, de 2 gru-pos paralelos, para comparar la eficacia y la seguri-dad de masitinib 6 mg/kg/día en combinación conbortezomib y dexametasona, con placebo en combi-nación con bortezomib y dexametasona en eltratamiento de pacientes con mieoloma múltiplerecidivante que han recibido una terapia previa; (ver-sión 7.0 ROW: 23-03-11). AB06002EudraCT: 2009-017930-35

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio de fase 3, aleatorizado, de decitabina frente ala elección por parte del paciente, bajo consejo médi-co de cuidados de soporte o citarabina a dosis bajas,para el tratamiento de pacientes ancianos conleucemia mieloide aguda de nuevo diagnóstico; (ver-sión: 18-07-05, incluye enmienda nº 1: 30-11-05).DACO-016EudraCT: 2005-004503-11

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase 1/2, de aumento de dosis, abierto, dela formulación oralde MLN9708, un inhibidor del pro-teasoma de nueva generación, administrado en com-binación con un régimen habitual de melfalán y pred-nisona en pacientes con mieloma múltiple de nuevodiagnóstico que precisan tratamiento sistémico; (ver-sión: 22-12-10). C16006EudraCT: 2010-023772-71

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase III, multicéntrico, aleatorizado, abier-to, para comparar la eficacia y la seguridad de lapomalidomida en combinación con dosis bajas dedexametasona frente a dosis altas de dexametasonaen pacientes con mieloma múltiple refractario o recidi-vante y refractario; (versión 15-10-10). CC-4047-MM-003EudraCT: 2010-019820-30

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOOfatumumab como parte del régimen de acondi-

cionamiento de intensidad reducida para pacientescon leucemia linfática crónica de alto riesgo quereciben un trasplante alogénico de progenitoreshematopoyéticos: un estudio piloto conjunto delgrupo español de trasplante hematopoyéticos y ter-apia celular (GETH) y del grupo español de leucemialinfática crónica(GELLC); (versión final 5.0: 17-05-11).GETH-CLL4EudraCT: 2010-024467-40

PRINCIPAL INVESTIGATOR: JAVIER LOSCERTALESPUEYOEstudio de distintas subpoblaciones de linfocitos Bclonales y normales en individuos con leucemia linfáti-ca crónica; (versión final:01-06-11). ORF-ANT-2011-01

PRINCIPAL INVESTIGATOR: MARIA-REYES ARRANZSAEZEstudio epidemiológico para evaluar las percepcionesde astenia y la calidad de vida de pacientes con ane-mia, diagnosticados de linfoma o mieloma múltiple enEspaña; (versión 5.0: noviembre 2010). PERFORM V

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio fase 2, aleatorizado, doble ciego controladocon placebo para comparar la combinación de CNTO328 (Anticuerpo monoclonal Anti-IL-6) y Velcade®versus Velcade sólo en sujetos con mieloma múltipleen recaída o refractario; (versión A0: 31-05-06).CO328T06EudraCT: 2006-001904-36

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio fase II, multicéntrico, abierto, no aleatorizadode TKI258 en pacientes con mieloma múltiple refrac-tario o en recidiva con o sin traslocación t(4;14); (ver-sión 02: 2-12-10). CTKI258A2204EudraCT: 2009-012417-22

PRINCIPAL INVESTIGATOR: ADRIAN ALEGRE AMOREstudio de fase III, aleatorizado, para evaluar la eficaciay la seguridad de la perifosina añadida a la combinaciónde bortezomib y dexametasona en pacientes con mielo-ma múltiple tratados previamente con bortezomib; (ver-sión 6.2: 24-2-11). PERIFOSINE339EudraCT: 2010-018893-19

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AREA 3PRINCIPAL INVESTIGATOR: VALLE GOMEZ GAR-CIA-SORIAEstudio observacional de vigilancia en pacientes conhemosiderosis transfusional tratados con Exjade® enla práctica clínica habitual; (versión 00:22-09-10).CICL670A2301

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEnsayo clínico abierto, multicéntrico, de accesoexpandido de INC424 en pacientes con mielofibrosisprimaria (PMF) o mielofibrosis secundaria apolicitemia (PPV MF) o mielofibrosis secundaria a

trombocitemia esencial(PET-MF); (versión 00:25-1-11). CINC424A2401EudraCT: 2010-024473-39

PRINCIPAL INVESTIGATOR: JUAN-LUIS STEEG-MANN OLMEDILLASEstudio fase 2, abierto, randomizado, multicéntircocon dasatinib (Sprycel®) vs dasatinib más antago-nista de Smoothened (BMS-833923) en el tratamien-to de pacientes con LMC cromosoma Philadelphiapositivo en fase crónica de diagnóstico reciente; (ver-sión 1.0:30-3-11). CA180-363EudraCT: 2011-000083-10

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Line 3.5Biological, cellular and molecular monitoring in oncohematology

GRUPO 45

HEAD OF LABORATORYElena Fernández Ruiz

GROUP MEMBERS• Álvaro Cuesta Domínguez• Alba García Rodríguez• Matilde Santos Roncero

RESEARCH INTEREST

Chromosomal translocations in tumors frequently pro-duce fusion genes coding for chimeric proteins with akey role in oncogenesis. JAK2 is a non-receptor tyro-sine kinase (TK) that is essential for signaling through avariety of cytokine receptors and is required for normalhematopoiesis. Activation of the JAK2-cytokine recep-tor complex leads to the recruitment and JAK2-medi-ated phosphorylation of STAT5 proteins whose nucleartranslocation induces target gene transcription. Several

fusion proteins involving the catalytic active JH1domain of JAK2 have been reported to be associatedwith leukemia. Moreover, gain-of-function JAK2 muta-tions are common in myeloproliferative neoplasms andin up to 15% of adult and high-risk pediatric B-acutelymphoblastic leukemia (ALL) lacking BCR-ABLrearrangements. These observations have supportedthe search for selective inhibitors of JAK2 and severalcompounds are currently undergoing clinical trials formyelofibrosis. Our group has described a BCR-JAK2fusion gene from a patient with ALL and the functionalbehavior of this chimeric protein has been character-ized. The results demonstrate that BCR-JAK2 is ahyperactive TK with transforming and tumorigenicproperties based on sustained STAT5 activation andantiapoptotic gene induction leading to increased sur-vival. Thus, we hypothesize that BCR-JAK2 could playa central role in the induction of lymphoproliferative dis-ease in this patient. JAK2 inhibitors abrogate BCR-JAK2 function by blocking the JAK2/STAT5 activationpathway, which in turn leads to cell death by apoptosis.We believe that abnormal fusion transcripts involvingJAK2 and gain-of-function JAK2 mutations should beinvestigated in patients with atypical CML and acutetypes of leukemia. JAK2 inhibitors warrant furtherinvestigation for use alone or in combination with stan-dard chemotherapy in treating human cancers withJAK2 overexpression.

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BCR-JAK2 is located in the cytoplasm. Immunofluorescence analysisof HEK293T cells transiently transfected with pLZR carrying BCR-JAK2(HEK293T-BJ) or control vector (HEK293T-mock) analyzed by confocalmicroscopy. Transfected cells were detected by EGFP expression.JAK2 expression was shown in red only in the cytoplasm of HEK293T-BJ cells. The merged image showed nuclei stained with DAPI (blue),EGFP (green), and anti-JAK2 antibody (red) on HEK293T-BJ transfec-ted cells. Scale bar = 5 µm.


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AREA 3

MAJOR GRANTS

• Elena Fernández Ruiz. Caracterización de larespuesta de macrófagos y células dendríticas amutantes de las rutas de las map quinasas de can-dida albicans: búsqueda de nuevas dianas terapéu-ticas. ISCIII. PI08/1772

• Elena Fernández Ruiz. Redes Temáticas deInvestigación Cooperativa en Salud (RETICS) - RedEspañola de Investigación en Patología Infecciosa(REIPI). ISCIII. RED07/0008/06

GRUPO 46

HEAD OF LABORATORYCecilia Muñoz Calleja

GROUP MEMBERS• Amada Elia Beltrán Núñez• Carlos Cuesta Mateos• Fernando Gómez-Reino Carnota• Beatriz Somovilla Crespo

RESEARCH INTEREST

We have identified the chemokine receptor CCR7 asa potential therapeutic target for different lymphoidtumors. The therapeutic efficacy of an anti-CCR7 anti-body was evaluated in a murine model of early-stagedisease of mantle cell lymphoma (MCL). In a subcuta-neous model of MCL, the anti-CCR7 therapy signifi-cantly reduced the tumor volume and the infiltratingcells in lymphoid organs. In the intravenous model,anti-CCR7 antibody completely prevented the devel-opment of lymphoma with no clinical signs during 120days of observation which is considered a bona fidefree-disease period (Figure 1).

Recent publications suggest that CCR7 triggers thedevelopment of breast cancer metastasis. We have

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Nude mice injected with Ba/F3 cells transduced with BCR-JAK2 (Ba/F3-BCR-JAK2) develop tumors. (A) Mice were subcutaneously injected with107 Ba/F3-mock cells (left flank) and Ba/F3-BCR-JAK2 cells (right flank).(B) Left panel: white light photograph showing mice bearing a tumor onlyon the right side, where Ba/F3-BCR-JAK2 cells were injected. Right panel:EGFP+ tumor captured on a digital photostation showing the reflectedimage of the mice (right side). No EGFP expression was detected whenBa/F3-mock cells were injected (left side).

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identified the actin regulatory protein cortactin as anew link between the activation of CCR7 and chemo-taxis and formation of rich-actin cortical structures ina breast cancer cell line. CCR7 activation inducestransitory translocation of cortactin from internal cyto-plasm compartments to the cell cortex where it accu-mulates in lamellipodia and invadopodia (Figure 2).CCR7 stimulation increased phosphorylation of cor-tactin in an ERK-dependent manner which is crucialfor the CCR7-mediated migration of carcinoma cells.

We also wondered whether chemokines involved intumor growth like CXCL12 are able to signalthrough Cyclooxygenase-2 (Cox-2). CXCL12induced Cox-2 in MCL lines. Culture supernatantsfrom CXCL12-treated cells in the presence ofAMD3100, a pharmacological CXCR4 or Rosicoxib,an inhibitor of Cox-2, abolished the migrationinduced by CXCL12, suggesting that migration ofMCL cells to CXCL12 is mediated, at least in part,by the induction of Cox-2.

In conclusion, the control of these axes may representan important pharmacological tool to regulate tumormigration and metastasis.

MAJOR GRANTS

• Cecilia Muñoz Calleja. Red de Inmunoterapia“INMUNONET”. Programa de Cooperación TerritorialSudoeste Europeo. INMUNONET-SOE1/P1/E014

• Cecilia Muñoz Calleja. Red de Investigación enInflamación y Enfermedades Reumáticas “RIER”. ISCIII. RD08/0075/0001

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Anti-CCR7 monoclonal antibodies significantly increase the survi-val of xenografted mice with mantle cell lymphoma.Kaplan-Meier estimates of overall survival of mice treated with theanti-CCR7 mAb. NOD/SCID mice were xenografted by intravenousinoculation with Granta 519 cells (0.5x106 per mouse). Diamond:mice were treated intraperitoneally with anti-CCR7 mAb at 200 mi-crograms/mouse, days 2, 6, and 10. Black square: mice were treatedwith PBS intraperitoneally, days 2, 6, and 10.

CCR7 ligands induce formation of cortical structures involved in mi-gration of MCF-7 breast cancer cells. A) Percentage of cells with cortactin localized in lamellipodia.By fluorescence microscopy we determined that activation ofCCR7 in MCF-7 cells results in transitory translocation of cor-tactin from cytoplasmic compartments to the cell peripherywhere is accumulated in lamellipodia. This effect is maximumafter 3 minutes of stimulation and is neutralized with anti-CCR7 blocking antibody. *(p-value<0.05); **(p-value<0.01); ***(p-value<0.001).B) Percentage of cells with invadopodia. Activation of CCR7 increa-ses the number of invadopodia at early stages (identified by co-lo-cation of actin and cortactin) per cell. This effect is inhibited when aCCR7 blocking antibody is used. *(p-value<0.05); **(p-value<0.01);*** (p-value<0.001).

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AREA 3CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: FERNANDO GOMEZ-REINO CARNOTA

Registro español de acontecimientos adversos deterapias biológicas en enfermedades reumáticas (faseII); (versión 2.1: 27-10-06). BIOBADASER

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Line 3.6New diagnostic and therapeutic advances in cardiovascular diseases

GRUPO 48

HEAD OF LABORATORYLuis Jesús Jiménez Borreguero

GROUP MEMBERS• Amparo Benedicto Buendía• Paloma Caballero Sánchez-Robles• Carmen del Arco Galán• Alfonsa Friera Reyes• Iluminada García Polo• Paloma Gil Martínez• Natividad Gómez Gómez• Patricia Ibáñez Sanz• Luis Martínez Elbal• Fernando Moldenhauer Díaz• Rosa María Moreno Carriles• María José Olivera Serrano• Ramón Puchades Rincón de Arellano• Antonio Reyes García• Fernando Rivero Crespo• Javier Roldan Núñez• Nuria Ruiz-Giménez Arrieta

• Bernhard Seidelberger• Carmen Suárez Fernández

RESEARCH INTEREST

Cardiology departmentCardiology department research focus is dedicated toapplying clinical enrichment to the basic cardiovascu-lar research through the collaboration with consolidat-ed basic research groups at the Hospital de la Princesaand the National Center for Cardiovascular Research(CNIC). This collaboration is focused on the study ofthe role of heart inflammation and Trends in the controlof cardiomyopathy in human myocarditis, Tako-Tsubolike cardiomyopathy and in the progression of heart fail-ure (collaboration with Dr P Martín and Dr F SánchezMadrid).

Other research in the translational area:• Participation in preclinical model of heart failure, led

by Dr. JM Redondo (CNIC).• Participation in preclinical model of non-compacted

cardiomyopathy, led by Dr. JL de la Pompa (CNIC).• Participation in preclinical model of cardiovascular

and the influence of progeria, led by Dr V Andrés(CNIC).

The cardiology department is also focused on usingimaging techniques for clinical research on atherosclero-sis. The work with the department of radiology in clinicalroutine and in imaging research has led to the originalresults in a project on Familiar Hypercholesterolemia(Figure) (P Caballero et al. Atherosclerosis. Publishedahead of print. 2012). (Described below)

Other research in cardiology in the clinical area:• Clinical study with imaging of acute myocardial injury

with normal coronary arteries. (Collaboration withDepartment of Radiology)

• Cardio-protection with metoprolol in acute myocar-dial infarction (METOCARD trial). Clinical and preclin-ical multicentre collaboration with CNIC.

• CLOCK study. It is a multicentre clinical study ofcircadian effect on the extension of necrosis in

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acute myocardial infarction, in collaboration withCNIC.

• Early detection of subclinical atherosclerosis in pop-ulation PESA study. In collaboration with CNIC.

• Early detection of subclinical atherosclerosis in pop-ulation AWHS study. In collaboration with CNIC.

• Study of subclinical atherosclerosis in individuals withHIV infection. In collaboration with Internal Medicinedepartment and CNIC.

• Clinical trials of new devices intracoronary stent.

Internal Medicine DepartmentCardiovascular research in internal medicine hasfocused on the study of hypertension in the elderly.

Main cardiovascular lines of clinical research are:• Vitamin D and parameters of vascular function.• Vascular involvement in adult subjects with Down

Syndrome• Subclinical disease in HIV-infected patients.• Arterial stiffness• Isolated systolic Hypertension• Prevention of venous thromboembolic disease.

Radiology Department• As results of the collaboration between our depart-

ments of Radiology and Cardiology and the Fundación

Jiménez Díaz for the study of patients with familiarhypercholesterolemia (FH), we have obtained originaldata. Assessment of atherosclerosis by MRI hasdetected lipid-rich plaques in FH subjects that wereassociated with family history of premature coronaryartery disease (Figure) (P Caballero et al.Atherosclerosis. Published ahead of print. 2012).

Intensive Care Department• Participation in the research group in the areas of

vascular stroke and aortic dissection.• Postoperative follow up of patients undergoing car-

diac surgery with cardiopulmonary bypass withoutthe use of blood or blood products.

• Ultrasound assessment of right ventricular functionafter cardiac surgery with cardiopulmonary bypass.

• Multicenter project for management of patients withright ventricular failure after bypass surgery.

In 2011, work has been extensive in both, new diag-nostic advances in cardiovascular disease and newtherapeutic advances in cardiovascular disease.Collaborations between different groups of clinicalinvestigators and researchers on preclinical investiga-tions have been efficient.

MAJOR GRANTS

Luis Jesús Jiménez Borreguero. Cooperative projectHYPERImage: Preclinical validation for cardiovascularapplications of a Hybrid PET/MRI prototype. EuropeanFrame Program 8. FP7-Health-2007-201651


Bertoletti L, Righini M, Bounameaux H, López-JiménezL, Tiraferri E, Visonà A, Monreal M; RIETE Investigators( ..., Ruíz-Giménez N, ...). Acute venous thromboem-bolism after non-major orthopaedic surgery or post-traumatic limb immobilisation. Findings from the RIETEregistry. Thromb Haemost 105(4): 739-41. 2011.PMID: 21225101. IF: 4,701

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Magnetic resonance imaging (MRI) of atherosclerotic plaques the des-cending thoracic aorta in a patient with Familiar Hypercholesterolemia(FH) without (A) and with (B) tracing of the inner and outer boundariesof the aorta vessel wall. Mean aortic wall volume in aorta was signifi-cantly higher in FH cases (P < 0.001). Lipid-rich plaques assessed byMRI were observed only in FH cases (33%) and were associated withfamily history of premature coronary artery disease (P < 0.05). (P Ca-ballero et al. Atherosclerosis. Published ahead of print. 2012).

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3

Goldhaber SZ, Leizorovicz A, Kakkar AK, Haas SK,Merli G, Knabb RM, Weitz JI; ADOPT Trial Investigators( ..., Suarez C, ...). Apixaban versus enoxaparin forthromboprophylaxis in medically ill patients. N Engl JMed 365(23): 2167-77. 2011. PMID: 22077144. IF:53,486

Soto MJ, Grau E, Gadelha T, Palareti G, BounameauxH, Villalta J, Monreal M; RIETE Investigators ( ..., Ruíz-Giménez N, ...). Clinical significance of a negative D-dimer level in patients with confirmed venous throm-boembolism. Thromb Haemost 9(2): 407-410. 2011.PMID: 21083645. IF: 4,701

Muñoz-Torrero JF, Escudero D, Suárez C, SanclementeC, Pascual MT, Zamorano J, Trujillo-Santos J, MonrealM; Factores de Riesgo y ENfermedad Arterial (FRENA)Investigators. Concomitant use of proton pumpinhibitors and clopidogrel in patients with coronary,cerebrovascular, or peripheral artery disease in the fac-tores de Riesgo y ENfermedad Arterial (FRENA) reg-istry. J Cardiovasc Pharmacol 57(1): 13-9. 2011. PMID:21164357. IF: 2,406

Mostaza JM, Manzano L, Suarez C, Fernandez C,García de Enterría MM, Tirado R, Nicolás F, Sanchez-Zamorano MA. Different prognostic value of silentperipheral artery disease in type 2 diabetic and non-diabetic subjects with stable cardiovascular disease.Atherosclerosis 214(1): 191-5. 2011. PMID: 21075374.IF: 4,086

Parra Caballero P, Curbelo García JJ, Gullón Ojesto A,Ruiz-Giménez Arrieta N, Suárez Fernández C, Del ArcoGalán C. Early mortality in a tertiary care hospital:analysis of quality of care. Emergencias 23: 430-436.2011. PMID: IF: 3,085

Cacoub PP, Zeymer U, Limbourg T, Baumgartner I,Poldermans D, Röther J, Bhatt DL, Steg PG; REACHRegistry Investigators (& , Suarez C, & ). Effects ofadherence to guidelines for the control of major cardio-vascular risk factors on outcomes in the REduction ofAtherothrombosis for Continued Health (REACH)Registry Europe. Heart 97(8): 660-7. 2011. PMID:21357372. IF: 4,708

Muñoz-Torrero JF, Bounameaux H, Pedrajas JM,Lorenzo A, Rubio S, Kearon C, Hernández L, MonrealM; Registro Informatizado de la EnfermedadTromboEmbólica (RIETE) Investigators ( ..., Ruíz-Giménez N, ...). Effects of age on the risk of dying frompulmonary embolism or bleeding during treatment ofdeep vein thrombosis. J Vasc Surg 54(6 Supp): 26S-32S. 2011. PMID: 21908150. IF: 3,853

Moreno-Palanco MA, Ibáñez-Sanz P, Pablo CC,Pizarro-Portillo A, Rodríguez-Salvanés F, Suárez-Fernández C. Impact of Comprehensive and IntensiveTreatment of Risk Factors Concerning CardiovascularMortality in Secondary Prevention: MIRVAS Study. RevEsp Cardiol 64 (3): 179-185. 2011. PMID: 21330034.IF: 2,157

Ibanez B, Fuster V, Jiménez-Borreguero J, BadimonJJ. Lethal myocardial reperfusion injury: A necessaryevil?. Int J Cardiol. 151(1): 3-11. 2011. PMID:21093938. IF: 6,802

Ibáñez B, Fuster V, Macaya C, Jiménez-Borreguero J,Iñiguez A, Fernández-Ortiz A, Sanz G, Sánchez-Brunete V. Modulation of the beta-adrenergic systemduring acute myocardial infarction: rationale for a newclinical trial. Rev Esp Cardiol. 64(Supp 2): 28-33. 2011.PMID: 21807284. IF: 2,157

Leiter LA, Lundman P, da Silva PM, Drexel H, JüngerC, Gitt AK; DYSIS investigators ( ..., Suarez C, ...).Persistent lipid abnormalities in statin-treatedpatients with diabetes mellitus in Europe andCanada: results of the Dyslipidaemia InternationalStudy. Diabet Med. 28(11): 1343-51. 2011. PMID:21679231. IF: 3,036

Armario P, Oliveras A, Hernández Del Rey R, RuilopeLM, De La Sierra A; GROUP de Investigadores delRegistro de Hipertensión refractaria de la SociedadEspañola de Hipertensión/Liga Española para la Luchacontra la Hipertensión Arterial (SEH-LELHA) ( ...,Suarez C, ...). Prevalence of target organ damage andmetabolic abnormalities in resistant hypertension. MedClin (Barc) 137(10): 435-9. 2011. PMID: 21719041. IF:1,413

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de la Torre Hernandez JM, Hernández Hernandez F,Alfonso F, Rumoroso JR, Lopez-Palop R, Sadaba M,Carrillo P, Rondan J, Lozano I, Ruiz Nodar JM, Baz JA,Fernandez Nofrerias E, Pajin F, Garcia Camarero T,Gutierrez H; LITRO Study Group (Spanish Working Groupon Interventional Cardiology. Other participating and corre-sponding investigators: Rivero F, et al). Prospective appli-cation of pre-defined intravascular ultrasound criteria forassessment of intermediate left main coronary arterylesions results from the multicenter LITRO study. J Am CollCardiol. 58(4): 351-8. 2011. PMID: 21757111. IF: 14,293

Esteban V, Méndez-Barbero N, Jiménez-BorregueroLJ, Roqué M, Novensá L, García-Redondo AB,Salaices M, Vila L, Arbonés ML, Campanero MR,Redondo JM. Regulator of calcineurin 1 mediatespathological vascular wall remodeling. J Exp Med.208(10): 2125-39. 2011. PMID: 21930771. IF: 14,776

Suárez C. Single-pill telmisartan and amlodipine: a ration-al combination for the treatment of hypertension. Drugs.71(17): 2295-305. 2011. PMID: 22085386. IF: 3,738

Oliveras A, Armario P, Martell-Clarós N, Ruilope LM, de laSierra A; Spanish Society of Hypertension-ResistantHypertension Registry ( ..., Suarez C, ...). Urinary albuminexcretion is associated with nocturnal systolic bloodpressure in resistant hypertensives. Hypertension 57(3):556-60. 2011. PMID: 21220713. IF: 6,908

Ahmed WH, Mendiz OA, Thomas MR; TAXUSOLYMPIA Participating Physicians (Martínez Elbal L, etal). Usage patterns and 1-year outcomes with theTAXUS Liberté stent: results of the TAXUS OLYMPIAregistry. Catheter Cardiovasc Interv. 77(7): 979-92.Epub 2010 Dec 3. 2011. PMID: 20853350. IF: 2,398

Lobo JL, Nieto JA, Zorrilla V, Garrido N, Madridano O,Ruiz J, Farge-Bancel D, Tiberio G, Uresandi F, MonrealM; RIETE Investigators ( ..., Ruíz-Giménez N, ...).Venous thromboembolism in patients with intracranialhaemorrhage. Thromb Haemost 106(4): 750-2. 2011.PMID: 21901229. IF: 4,701

Puchades R, Rodríguez F, Gabriel R, Suárez C.Prevalence of kidney disease in an elderly community

cohort. Rev Clin Esp. 211(4): 221-2. Epub 2011 Mar21. 2011. PMID: 21420667. IF: 0,762

Alvarez-Sala Walther LA, Suárez Fernández C,Camafort Babkowski M; GROUP de Trabajo de RiesgoVascular de la SEMI. 2010. What novelties are there invascular risk?. Rev Clin Esp. 211(8): 410-22 Epub2011 Aug 4. 2011. PMID: 21816397. IF: 0,762

Delgado-Pinar E, Albelda MT, Frías JC, Barreiro O,Tejera E, Kubícek V, Jiménez-Borreguero LJ, Sánchez-Madrid F, Tóth E, Alarcón J, García-España E.Lanthanide complexes as imaging agents anchored onnano-sized particles of boehmite. Dalton Trans.40(24):6451-7. 2011. PMID: 21584297. IF: 3,647

Vangipurapu J, Stancáková A, Kuulasmaa T, Paananen J,Kuusisto J; EGIR-RISC Study Group (..., Carraro R, FrieraA, Novella B, ...), Ferrannini E, Laakso M. A novel surro-gate index for hepatic insulin resistance. Diabetologia 54(3): 540-543. 2011. PMID: 21107521. IF: 6,973

Rebelos E, Muscelli E, Natali A, Balkau B, Mingrone G,Piatti P, Konrad T, Mari A, Ferrannini E; RISC StudyInvestigators. R. Carraro, A. Friera, B. Novella por elGROUP RISC study. Body weight, not insulin sensitivi-ty or secretion, may predict spontaneous weightchanges in nondiabetic and prediabetic subjects: theRISC study. Diabetes 60(7): 1938-1945. 2011. PMID:21617179. IF: 8,889

Bonnet F, Ducluzeau PH, Gastaldelli A, Laville M,Anderwald CH, Konrad T, Mari A, Balkau B. R. Carraro,A. Friera, B. Novella por el GROUP RISC study. Liverenzymes are associated with hepatic insulin resistance,insulin secretion, and glucagon concentration inhealthy men and women. Diabetes 60(6): 1660-1667.2011. PMID: 21521874. IF: 8,889

Ferrannini E, Natali A, Muscelli E, Nilsson PM, Golay A,Laakso M, Beck-Nielsen H, Mari A; RISC Investigators.R. Carraro, A. Friera, B. Novella por el GROUP RISCstudy. Natural history and physiological determinants ofchanges in glucose tolerance in a non-diabetic popula-tion: the RISC Study. Diabetologia 54(6): 1507-1516.2011. PMID: 21424899. IF: 6,973

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Francisco Rodríguez-Salvanés, Blanca NovellaArribas, María Jesús Fernández Luque, Luis MaríaSánchez-Gómez, Lourdes Ruiz Díaz, Rosa SánchezAlcalde, Belén Sierra García Soledad Mayayo Vicente,Marta Ruiz López, Pilar Loeches Belinchón, JavierLópez Gónzález and Amelia González Gamarra onbehalf of the SIRVA2 group (..., C Suárez, ...). Efficacyof a strategy for implementing a guideline for the con-trol of cardiovascular risk in a primary healthcare set-ting: the SIRVA2 study a controlled, blinded communi-ty intervention trial randomised by clusters. BMCFamily Practice 12: 21. 2011. PMID: 21504570. IF:1,467

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: ILUMINADA GARCIAPOLOEstudio internacional predictivo de la adiposidadintraabdominal y su relación con el riesgo car-diometabólico/adiposidad intraabdominal; (versiónfinal con enmienda 1: 31-03-06; hoja de información alpaciente versión final con enmienda 1: 31-03-06).C_00046

PRINCIPAL INVESTIGATOR: LUIS MARTINEZ ELBALEstudio prospectivo multicéntrico y aleatorizado (balónde paclitaxel vs stent farmacoactivo) del tratamiento per-cutáneo de los pacientes con reestenosis de un stentmetálico convencional; (Versión A03: 15-01-10). RIBS VEudraCT: 2010-018231-18

PRINCIPAL INVESTIGATOR: LUIS MARTINEZ ELBALEstudio prospectivo multicentrico y aleatorizado (balónde paclitaxel vsstent farmacoactivo) del tratamientopercutáneo de los pacientes con re-estenosis de unstent farmacoactivo; (versión A03:17-12-09). RIBS-IVEudraCT: 2009-017637-21

PRINCIPAL INVESTIGATOR: LUIS MARTINEZ ELBALEstudio en fase III, doble ciego, aleatorizado y contro-lado con placebo, para evaluar los efectos deRO4607381 sobre el riesgo cardiovascular(cv)enpacientes con enfermedad coronaria cardiaca estable

que tengan documentado un síndrome coronarioagudo (SCA) reciente; (versión B: 28-01-08).NC20971EudraCT: 2007-005103-18

PRINCIPAL INVESTIGATOR: LUIS MARTINEZ ELBALComparación de un Stent Bio-Activo con el Stenteurolimus-eluting en el síndrome coronario Agudo.BASE-ACS

PRINCIPAL INVESTIGATOR: AMPARO BENEDICTOBUENDIAApixaban para la prevención de AcontecimientosIsquémicos Agudos-2. Estudio en fase 3, aleatorizadoy doble ciego para evaluar la seguridad y eficacia deApixaban en pacientes con síndrome coronario agudoreciente; (versión 1.0: 17-12-08 + Enmienda nº1específica para todos los centros para la obtención deuna muestra hematológica para estudios farmaco-genéticos (versión 1.0: 17-12-08). CV185068EudraCT: 2008-008298-77

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEficiencia de Sevikar® comparado con la combi-nación de perindoprilo/amlo-dipino sobre la PresiónArterial Central en pacientes con hipertensión moder-ada a severa - SEVITENSION; (versión 1.0: 25-06-09).DSE-SEV-02-09EudraCT: 2009-012966-30

PRINCIPAL INVESTIGATOR: AMPARO BENEDICTOBUENDIAEstudio de resultados clínicos de darapladib en com-paración con placebo en pacientes con síndromecoronario agudo, para comparar la incidencia deacontecimientos cardiovasculares adversos impor-tantes (ACAI). (versión 1: 08-10-09). SB-480848/033EudraCT: 2009-012581-32

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEnsayo clínico randomizado para evaluar la eficienciay efectividad de la dosificación individualizada deacenocumarol mediante un algoritmo farmacogenéti-co vesus ajuste estánder en pacientes que indican

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anticoagulación oral; (versión 1: 06-10-09).FC/HULP_002EudraCT: 2009-016643-18

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEstudio de los efectos de Aliskiren o Losartán sobrelos bioMARKadores del remodelado miocárdico.Estudio ALLMARK; (versión final: 23-11-09).CSPP100AES02EudraCT: 2009-016735-36

PRINCIPAL INVESTIGATOR: LUIS MARTINEZ ELBALEstudio de resultados en pacientes tras laimplantación de stents Endeavor frente a Cypher.Estudio prospectivo, multicéntrico, aleatorizado, de 2brazos y abierto; (versión final castellana 1.1: 27-06-07), (versión final inglesa 1.0: 12-04-07). PROTECT

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEstudio COMBICONTROL: control de la presión arte-rial en pacientes en tratamiento con terapia combina-da antihipertensiva; (versión 5-07-11). MEN-HTA-2011-01

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEstudio de la prevalencia de tromboembolismovenoso(TEV) y Riesgo de TEV y Riesgo de TEV enpacientes médicos hospitalizados; (versión 17-3-11).BAY-TEV-2011-01

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEstudio de fase III, multicéntrico, internacional, aleator-izado, de grupos paralelos, doble ciego, de seguridadcardiovascular de BI 10773 (10 mg y 25 mg admin-istrados por vía oral una vez al día) comparado con eltratamiento habitual en pacientes con diabetes melli-tus de tipo 2 con un riesgo cardiovascular aumentado;(versión 001: 10-05-10). 1245.25EudraCT: 2009-016178-33

PRINCIPAL INVESTIGATOR: LUIS MARTINEZ ELBALEnsayo prospectivo, multicéntrico y aleatorizado para

evaluar el sistema de endoprótesis coronaria liber-adora de everolimus (PROMUS Element) para larevascularización coronaria en una población norestringida de pacientes; (Versión 1.3: 03-06-10).PLATINUM PLUS

PRINCIPAL INVESTIGATOR: LUIS-JESUS JIMENEZBORREGUERODaño por isquemia-reperfusión: nuevos datos en elconocimiento en los mecanismos de acción repsons-ables de la cardioprotección conferida por el B-blo-queo en el infarto agudo de miocardio. Traslación deresultados pre-clínicos al cuidado humano; (versión2.0: 30-05-10). METOCARDEudraCT: 2010-019939-35

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEvaluación del déficit de vitamina D y su influencia en elperfil de riesgo cardiovascular; (versión 1: 17-11-10).D3RIESGO

PRINCIPAL INVESTIGATOR: CARMEN ARCO GALANEstudio HERMES (hospital emergency departmentmanagment strategies of atrial fibrillation): Decisionesde manejo de la fibrilación auricular en los servicios deurgencias en España; (versión final: 23-03-10). SAN-FIB-2010-01

PRINCIPAL INVESTIGATOR: LUIS MARTINEZ ELBALAngioplastia coronaria con el stent Titan2 en el InfartoAgudo de Miocardio; (versión 1: 23-11-10). TITAN-AMI

PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEstudio de la prevalencia de tromboembolismovenoso(TEV) y riesgo de TEVen pacientes médicoshospitalizados; (Versión 14-03-11). ESTUDIO MED-ITROM

PRINCIPAL INVESTIGATOR: CARMEN DEL ARCOGALANManejo de la Fibrilación Auricular en fase aguda en losservicios de urgencias hospitalarios en España; estudioRHYTHM-AF-España; (Versión 2.0:07-04-10). MSD-FA-2010-01

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PRINCIPAL INVESTIGATOR: CARMEN SUAREZ FER-NANDEZEstudio multicéntrico, fase III, aleatorizado, dobleciego, de brazos paralelos para evaluar la eficacia yseguridad de apixaban para la profilaxis de tromboem-bolismo venoso en pacientes médicos con enfer-medad aguda durante y después de la hospitalización;(versión 2: 27-02-07); Enmienda nº1 para estudiofamacogenético versión 2: 27-02-07). CV185-036EudraCT: 2006-003674-96

GRUPO 49

HEAD OF LABORATORYBlanca Novella Arribas

GROUP MEMBERS• Ana Cubillo Serna• María Jesús Fernández Luque• Ángela Gallego Arenas• Amelia González Gamarra• María del Pilar Loeches Belinchón• Javier López González• M. Soledad Mayayo Vicente• Francisco José Rodríguez Salvanés• María Lourdes Ruiz Díaz• Rosa María Sánchez Alcalde• Luis María Sánchez Gómez• Belén Sierra García

RESEARCH INTEREST

Research in primary care (PC) is essential to manageuncertainty in decision making, reduce the gapbetween efficacy and effectiveness and ultimatelyimprove clinical practice and serve our users, seekingexcellence in the organization.We believe that research is essential to enable the transferof research results from the hospital to the population.Our experience reinforces the commitment of the PC

researcher, developing epidemiological studies andclinical trials in the community framework.

Our main area of concern is the cardiovascular risk inboth primary and secondary prevention. From the epi-demiological point of view we are interested in theknowledge of cardiovascular risk in the elderly, factorsinvolved in insulin resistance and type 2 diabetes melli-tus and circadian rhythm of blood pressure in hyperten-sive patients.

We consider very important the implementation ofresearch projects in the effectiveness of communityintervention on compliance nonpharmacological andpharmacological strategies, as well as the training ofhealth professionals in intervention in our patients.

Finally, we consider essential the participation of pri-mary care patients in studies of drug efficacy and effec-tiveness.

MAJOR GRANTS

• Blanca Novella Arribas. Evaluación en Términos deMorbimortalidad y control de los FRCV de la imple-mentación de una adaptación de una GPC en RCV.ISCIII. 09/90146

• María del Pilar Loeches Belinchón. Control de la pre-sión arterial (PA) en pacientes diabéticos: estudiocomparativo entre el tratamiento basado en la PAmedida en la consulta médica y el basado en laautomedición de la PA en el domicilio del paciente(AMPA en DM2). ISCIII. 10/01927


Francisco Rodríguez-Salvanés, Blanca Novella Arribas,María Jesús Fernández Luque, Luis María Sánchez-Gómez, Lourdes Ruiz Díaz, Rosa Sánchez Alcalde,Belén Sierra García Soledad Mayayo Vicente, MartaRuiz López, Pilar Loeches Belinchón, Javier LópezGónzález and Amelia González Gamarra on behalf of

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the SIRVA2 group (..., C Suárez, ...). Efficacy of a strat-egy for implementing a guideline for the control of car-diovascular risk in a primary healthcare setting: theSIRVA2 study a controlled, blinded community inter-vention trial randomised by clusters. BMC FamilyPractice 12: 21. 2011. PMID: 21504570. IF: 1,467

Ortiz-Lobo A, García-Moratalla B, Lozano-Serrano C,de la Mata-Ruiz I, Rodríguez-Salvanés F. Conditionsthat do not reach the threshold for mental disorder inSpanish psychiatric outpatients: prevalence, treatmentand management. Int J Soc Psychiatry 57(5): 471-9.2011. PMID: 20430820. IF: 1,106

Vangipurapu J, Stancáková A, Kuulasmaa T, Paananen J,Kuusisto J; EGIR-RISC Study Group (..., Carraro R, FrieraA, Novella B, ...), Ferrannini E, Laakso M. A novel surro-gate index for hepatic insulin resistance. Diabetologia 54(3): 540-543. 2011. PMID: 21107521. IF: 6,973

Rebelos E, Muscelli E, Natali A, Balkau B, Mingrone G, PiattiP, Konrad T, Mari A, Ferrannini E; RISC Study Investigators.R. Carraro, A. Friera, B. Novella por el GROUP RISC study.Body weight, not insulin sensitivity or secretion, may predictspontaneous weight changes in nondiabetic and prediabet-ic subjects: the RISC study. Diabetes 60(7): 1938-1945.2011. PMID: 21617179. IF: 8,889Bonnet F, Ducluzeau PH, Gastaldelli A, Laville M,

Anderwald CH, Konrad T, Mari A, Balkau B. R. Carraro,A. Friera, B. Novella por el GROUP RISC study. Liverenzymes are associated with hepatic insulin resistance,insulin secretion, and glucagon concentration inhealthy men and women. Diabetes 60(6): 1660-1667.2011. PMID: 21521874. IF: 8,889

Ferrannini E, Natali A, Muscelli E, Nilsson PM, Golay A,Laakso M, Beck-Nielsen H, Mari A; RISC Investigators.R. Carraro, A. Friera, B. Novella por el GROUP RISCstudy. Natural history and physiological determinants ofchanges in glucose tolerance in a non-diabetic popula-tion: the RISC Study. Diabetologia 54(6): 1507-1516.2011. PMID: 21424899. IF: 6,973

Moreno-Palanco MA, Ibáñez-Sanz P, Pablo CC,Pizarro-Portillo A, Rodríguez-Salvanés F, Suárez-Fernández C. Impact of Comprehensive and IntensiveTreatment of Risk Factors Concerning CardiovascularMortality in Secondary Prevention: MIRVAS Study.Rev Esp Cardiol 64 (3): 179-185. 2011. PMID:21330034. IF: 2,157

Puchades R, Rodríguez F, Gabriel R, Suárez C.Prevalence of kidney disease in an elderly communitycohort. Rev Clin Esp. 211(4): 221-2. Epub 2011 Mar21. 2011. PMID: 21420667. IF: 0,762

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Line 3.7New therapies in infectious pathologies

GRUPO 50HEAD OF LABORATORYIgnacio de los Santos Gil

GROUP MEMBERS• José Rafael De la Cámara de Llanza • Ana Salas Aparicio• María Teresa Sánchez Casasola• Jesús Sanz Sanz• Cristina Sarriá Cepeda

RESEARCH INTEREST

Dr. de la Cámara has published an original article aboutthe “Outcome of pandemic H1N1 infections inhematopoietic stem cell transplant Recipients”(Haematologica 2011; 96: 1231-1235). During 2009, a new strain of A/H1N1 influenza appearedand became pandemic. A prospective study was per-formed to collect data regarding risk factors and outcomeof A/H1N1 in hematopoietic stem cell transplant recipi-ents. 286 patients were reported, 222 allogeneic and 64

autologous recipients. The median age was 38.3 yearsand the median time from transplant was 19.4 months.Ninety-three patients (32.5%) developed lower respirato-ry tract disease. In multivariate analysis, risk factors wereage and lymphopenia. Thirty-three patients (11.5%)required mechanical ventilation. Eighteen patients (6.3%)died from A/H1N1 infection or its complications. The2009 A/H1N1 influenza pandemic caused severe compli-cations in stem cell transplant recipients.

And the participants of the group belonging to theDepartment of Infectious Diseases have collaborated withthe CoRIS and have published, with the rest of the net-work “The Cohort of the Spanish HIV Research Network(CoRIS) and its associated biobank; organizationalissues, main findings and losses to follow-up” (EnfermInfecc Microbiol Clin. 2011 Nov;29: 645-53). This articledescribes the development of the Cohort of the SpanishResearch Network (CoRIS), its methodological and orga-nizational aspects, the demographic and clinical charac-teristics of the subjects enrolled and quantifies the lossesto follow-up and associated factors. Multicentre cohort ofHIV-positive naïve subjects recruited in 28 sites of Spainfrom 2004-onwards. As of October 2009, 5,514 subjectshad been recruited, representing 11,708 person-yearswith a median follow-up time of 1.81 years. Most are men(78.8%), infected by sexual transmission (46.1% menwho have sex with men and 35.2% heterosexual per-sons) and Spanish (69.7%). During follow-up 64.5% havestarted Antiretroviral Therapy (ART) and 201 deaths haveoccurred. New HIV diagnoses accounted for 80.7% of

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Distribution of the frequency of lower respiratory tract disease by pa-tient age group.

the sample. Some 52% of subjects had at least onebaseline sample in the BioBank while naïve to ART. Theimplementation of CoRIS has been successful; thecohort has wide representation at national level, is active-ly recruiting new members and blood samples, and hasexcellent data quality.

MAJOR GRANTS

• José Rafael De la Cámara de Llanza. Implicación delos antígenos menores de histocompatibilidad en eléxito del trasplante alogénico de progenitoreshematopoyéticos. Fundación Mutua Madrileña.

• José Rafael De la Cámara de Llanza.Polimorfismos genéticos implicados en la enfer-medad del injerto contra el huésped y en la super-vivencia tras trasplante alogénico de progenitoreshematopoyéticos. Banco Nacional de ADN. ISCIII.PI080413

• José Rafael De la Cámara de Llanza. Marcadoresinmunológicos y genotípicos de protección frente alcitomegalovirus en el trasplante alogénico de precur-sores hematopoyéticos. Aplicabilidad en el manejoterapéutico de la infección activa virémica. ISCIII.PS09/01117

• Ignacio de los Santos Gil. Prevalencia de infecciónpor VIH no diagnosticada en pacientes que acudenal Servicio de Urgencias, cuyo objetivo principal esestimar la prevalencia de infección por VIH no diag-nosticada en personas mayores de 15 años que

acuden al Servicio de Urgencias. GILEAD SCIEN-CIES, S.L.


Pérez-Cachafeiro S, Caro-Murillo AM, Berenguer J, etal. Colaboradores: de los Santos Gil I, Sanz Sanz J,Sarriá Cepeda C, Salas Aparicio A. Association ofpatient’s geographic origins with viral hepatitis coinfec-tion patterns, Spain. Emerg Infect Dis 17(6): 1116-1119. 2011. PMID: 21749785. IF: 6,859

Berenguer J, von Wichmann MA, Quereda C, MirallesP, Mallolas J, López-Aldeguer J, Alvarez-Pellicer J, DeMiguel J, Crespo M, Guardiola JM, Tellez MJ, GalindoMJ, Arponen S, Barquilla E, Bellón JM, González-García J; GESIDA 36/03 and 50/06 Study Groups.Colaborador: de los Santos Gil, Ignacio. Effect ofaccompanying antiretroviral drugs on virologicalresponse to pegylated interferon and ribavirin inpatients co-infected with HIV and hepatitis C virus. JAntimicrob Chemother 66(12): 2843-2849. 2011.PMID: 21965432. IF: 4,659

Solano C, Tormo N, de la Cámara R, Bartolo Nieto J,López J, Benet I, Muñoz-Cobo B, Costa E, Remigia MJ,Garcia-Noblejas A, Bravo D, Navarro D. Effect ofcytomegalovirus (CMV) serostatus on the incidence andvirological features of active CMV infection in allogeneicstem cell transplant recipients. Clin Infect Dis. 53(3): 313-5; author reply 315-6. 2011. PMID: 21765090. IF: 8,186

Manzano C, Vilacosta I, Fernández C, San Román JA,Sarriá C, Pozo E, López J, Silva J. Evolution of vegeta-tion size in left-sided endocarditis. Is it a prognostic fac-tor during hospitalization?. Rev Esp Cardiol 64(8): 714-717. 2011. PMID: 21420223. IF: 2,157

Tuma P, Pineda JA, Labarga P, et al. Colaboradores: delos Santos Gil I, Sanz Sanz J, Sarriá Cepeda C, SalasAparicio A. HBV primary drug resistance in newly diag-nosed HIV-HBV-coinfected individuals in Spain.Antiviral Therapy 16(4): 585-589. 2011. PMID:21685546. IF: 3,774

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Subjects recruited in CoRIS from January 2004 to October 2009.

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Carlos Solano, Isabel Benet, María José Remigia,Rafael de la Cámara, BeatrizMuñoz-Cobo, Elisa Costa,María Ángeles Clari, Dayana Bravo, Paula Amat, DavidNavarro. Immunological Monitoring for Guidance ofPreemptive Antiviral Therapy of Active CytomegalovirusInfection in Allogeneic-Stem Cell Transplant Recipients:A Pilot Experience. Transplantation 92(4): 17-20. 2011.PMID: 21814124. IF: 3,676

López-Wolf D, Vilacosta I, San Román JA, FernándezC, Sarriá C, López J, Revilla A, Manchado R.Infective endocarditis in octogenarian patients. RevEsp Cardiol 64(4): 329-333. 2011. PMID: 21411214.IF: 2,157

López J, Fernández-Hidalgo N, Revilla A, Vilacosta I,Tornos P, Almirante B, Sevilla T, Gómez I, Pozo E,Sarriá C, San Román JA. Internal and external valida-tion of a model to predict adverse outcomes in patientswith left-sided infective endocarditis. Heart 97(14):1138-1142. 2011. PMID: 21357640. IF: 4,708Macías J, Neukam K, Portilla J, Iribarren JA, de LosSantos I, Rivero A, Márquez M, Delgado M, Téllez F,Merino D, Giner L, von Wichmann MA, Pineda JA;HEPRAL study team. Liver tolerance of raltegravir-con-taining antiretroviral therapy in HIV-infected patientswith chronic hepatitis C. J Antimicrob Chemother 66(6):1346-1350. 2011. PMID: 21398295. IF: 4,659

Neukam K, Mira JA, Ruiz-Morales J, Rivero A, ColladoA, Torres-Cornejo A, Merino D, de Los Santos-Gil I,Macías J, González-Serrano M, Camacho A, Parra-García G, Pineda JA; SEGURIDAD HEPÁTICA StudyTeam of the GROUP HEPAVIR de la SociedadAndaluza de Enfermedades Infecciosas (SAEI). Livertoxicity associated with antiretroviral therapy includingefavirenz or ritonavir-boosted protease inhibitors in acohort of HIV/hepatitis C virus co-infected patients. JAntimicrob Chemother 66(11): 2605-2614. 2011.PMID: 21903660. IF: 4,659

López J, Revilla A, Vilacosta I, Sevilla T, García H, GómezI, Pozo E, Sarriá C, San Román JA. Multiple-valve infec-tive endocarditis: clinical, microbiologic, echocardio-graphic, and prognostic profile. Medicine (Baltimore)90(5): 231-236. 2011. PMID: 21694644. IF: 4,256

Ljungman P, de la Camara R, Perez-Bercoff L,Abecasis M, Nieto Campuzano JB, Cannata-Ortiz J,Cordonnier C, Einsele H, Gonzalez-Vincent M,Espigado I, Halter J, Martino R, Mohty B, Sucak G,Ullmann AJ, Vasques L, Ward KN, Engelhard DInfectious Diseases Working Party, European Groupfor Blood and Marrow Transplantation; InfectiousComplications Subcommittee, Spanish Group ofHaematopoietic Stem-cell Transplantation (GarcíaNoblejas A, de las Heras N, ..., Lassaletta Á).Outcome of pandemic H1N1 infections inhematopoietic stem cell transplant recipients.Haematologica 96(8): 1231-1235. 2011. PMID:21546495. IF: 6,532

Pett SL, Carey C, Lin E, Wentworth D, Lazovski J, MiróJM, Gordin F, Angus B, Rodriguez-Barradas M, RubioR, Tambussi G, Cooper DA, Emery S; INSIGHT-ESPRITStudy Group. (Collaborators: Sanz J et al). Predictorsof bacterial pneumonia in Evaluation of SubcutaneousInterleukin-2 in a Randomized International Trial(ESPRIT). HIV Med 12(4): 219-227. 2011. PMID:20812949. IF: 3,575

Tormo N, Solano S, Nieto J, Benet I, Nieto J, de la CámaraR, Lopez J, Garcia-Noblejas A, Muñoz-Cobo B, Costa E,Clari MA, Hernández-Boluda JC, Remigia MJ and NavarroD. Reconstitution of CMV pp65 and IE-1-specific IFN-?CD8(+) and CD4(+) T-cell responses affording protectionfrom CMV DNAemia following allogeneic hematopoieticSCT. Bone Marrow Transplant 46(11): 1437-1443. 2011.PMID: 21243030. IF: 3,66

Yebra G, de Mulder M, Martín L, Pérez-Cachafeiro S,Rodríguez C, Labarga P, García F, Tural C, Jaén A,Navarro G, Holguín A; Cohort of Spanish AIDSResearch Network (CoRIS) Collaborators: Sanz J, delos Santos I, Salas A, Sarriá C. Sensitivity of seven HIVsubtyping tools differs among subtypes/recombinantsin the Spanish cohort of naïve HIV-infected patients(CoRIS). Antiviral Res 89(1): 19-25. 2011. PMID:21070813. IF: 4,439

Muñoz-Cobo B, Solano S, Nieto J, de la Cámara R,Remigia MJ, Garcia-Noblejas A, López J, Benet I,Hernández-Boluda JC, Costa E, Bravo D, and

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Navarro D. Surveillance for adenovirus DNAemia earlyafter transplantation in adult recipients of unrelated-donor allogeneic stem cell transplants in the absenceof clinically suspected infection. Bone MarrowTransplant 46(11): 1484-1486. 2011. PMID:21217790. IF: 3,66

Dwyer DE; INSIGHT Influenza Study Group (…, SanzSanz J,...). Surveillance of illness associated with pan-demic (H1N1) 2009 virus infection among adults usinga global clinical site network approach: the INSIGHTFLU 002 and FLU 003 studies. Vaccine 29(Suppl2):B56-B62. 2011. PMID: 21757105. IF: 3,572

Yuan J, Guo S, Hall D et al. Colaboradores: De LosSantos I, Sanz J. Toxicogenomics of nevirapine-associat-ed cutaneous and hepatic adverse events among popu-lations of African, Asian, and European descent. AIDS25(10): 1271-1280. 2011. PMID: 21505298. IF: 6,348Maertens J, Groll AH, Cordonnier C, de la Camara R,Roilides E, Marchetti O. Treatment and timing in inva-sive mould disease. Journal of AntimicrobialChemotherapy 66(Sup 1): 37-43. 2011. PMID:21177402. IF: 4,659

Ruiz-Camps I, Len O, de la Camara R, Gurgui M,Martino R, Jarque I, Barrenetxea C, Diaz de Heredia C,Batlle M, Rovira M, de la Torre J, Torres A, Aguilar M,Espigado I, Martin-Davila P, Bou G, Borrell N, AguadoJM, Pahissa A. Valganciclovir as preemptive therapy forcytomegalovirus infection in allogeneic hematopoieticstem cell transplant recipients. Antiviral Ther 16(7):951-957. 2011. PMID: 22024510. IF: 3,774

The HIV-CAUSAL Collaboration. Colaboradores: de losSantos Gil I, Sanz Sanz J, Sarriá Cepeda C, SalasAparicio A. When to initiate combined antiretroviraltherapy to reduce mortality and AIDS-defining illness inHIV-infected persons in developed countries: an obser-vational study. Ann Intern Med 154(8): 509-515. 2011.PMID: 21502648. IF: 16,729

Panel de expertos de GESIDA y Plan Nacional sobre elSida: Lozano F, Pedrol PD, Polo R, Aguirrebengoa K,Berenguer J, Pedrol PD, Galindo MJ, Knobel H, MartínezE, Miralles C, Podzamczer D, Rivero A, Santos J, Sanz J,

Tuset M, Arribas JR, Arrizabalaga J, Boix V, Clotet B,Estrada V, García F, Gatell JM, Gutiérrez F, Llibre JM, MiróJM, Moreno S, Pulido F, Soriano V, Aldeguer JL. Nationalconsensus document by GESIDA/National Aids Plan onantiretroviral treatment in adults infected by the humanimmunodeficiency virus (January 2011 update). EnfermInfecc Microbiol Clin 29(3): 209.e1-103. 2011. PMID:21388714. IF: 1,656

Musculoskeletal disorders in HIV-infected patients.National AIDS Plan (PNS) and the AIDS Study Group(GESIDA). GROUP de Expertos del Plan Nacionalsobre el Sida y GROUP de Estudio de Sida: Polo R,Negredo E, Javier Pascua F, Vicente Estrada R, FloresJ, José Galindo M, García Vadillo JA, Gutiérrez F,Locutura J, Longueira Suárez R, Mariño A, Ocampo A,Polo R, Rojo P, Laura Capa R, García Vadillo JA,Gisbert I, Knobel H, José Mellado M, Negredo E, JavierPascua F, Sanz J. Musculoskeletal disorders in HIV-infected patients. Enferm Infecc Microbiol Clin 29(7):515-523. 2011. PMID: 21474209. IF: 1,656

Sobrino-Vegas P, Gutiérrez F, Berenguer J et al.Colaboradores: de los Santos I, Sanz Sanz J, SalasAparicio A, Sarriá Cepeda C. The cohort of the spanishhiv research network (coris) and its associatedbiobank; organizational issues, main findings and loss-es to follow-up. Enferm Infecc Microbiol Clin 29(9):645-653. 2011. PMID: 21820763. IF: 1,656

Carreras E, Vazquez L, Rodriguez Tudela JL, Pahisa A,Azanza JR, Rovira M, de la Camara R. Update onfungemia in oncology and hematology. Enfermedadesinfecciosas y microbiologia clinica 29 (SUPL4): 42-47.2011. PMID: 21458719. IF: 1,656

Fortun J, Carratala J, Gavalda J, Lizasoain M, SalavertM, de la Camara R, Borges M, Cervera C, Garnacho J,Lassaleta A, Lumbreras C, Sanz MA, Ramos JT, Torre-Cisneros J, Aguado JM, Cuenca-Estrella M. Guidelinesfor the Treatment of Invasive Fungal Disease byAspergillus spp. and Other Fungi Issued by the SpanishSociety of Infectious Diseases and Clinical Microbiology(SEIMC). 2011 Update. Enfermedades infecciosas ymicrobiologia clinica. 29(6): 435-54. 2011. PMID:21474210. IF: 1,656

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Dronda F, Sobrino P, Hernández-Novoa B, Caro-MurilloAM, Montero M, Iribarren JA, Sanz J, Del Mar Alonso M,Labarga P, Bernal E, Moreno S; CoRIS. Colaboradores:de los Santos Gil I, Sarriá Cepeda C, Salas Aparicio A.Response to HAART in treatment-naive HIV-infectedpatients with a prior diagnosis of tuberculosis or otheropportunistic infections. Current HIV Research 9(4):229-236. 2011. PMID: 21631429. IF: 1,923

Vallejo C, Rios E, de la Serna J, Jarque I, Ferra C,Sanchez-Godoy P, Solano C, de la Camara R, RosellAI, Varela R, Garcia MD, Gonzalez-Barca E, Lopez J,Perez E, Ferrer S, Casado LF, Vazquez L, Villalon L,Garcia-Marco JA. Incidence of cytomegalovirusinfection and disease in patients with lymphoprolifer-ative disorders treated with alemtuzumab. ExpertRev Hematol 4(1): 9-16. 2011. PMID: 21322774. IF:0,459

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEnsayo clínico aleatorizado, doble ciego, doble enmas-carado, de grupos paralelos con control activo para eval-uar la eficacia antiviral de 400mgQD de Nevirapina lib-eración prolongada (ne Virapine Extended Release) encomparación con 200mg BID de nevirapina liberacióninmediata (ne Virapine E immediate release) en combi-nación con Truvada® en pacientes infectados por VIH-1que no hayan recibido tratamiento antiretroviral previo(naïve). (VERXVE); (versión final: 10-08-07). 1100.1486EudraCT: 2007-003654-29

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio aleatorizado y abierto de 400/100mg deLopinavir/ritonavir en comprimidos dos veces al día +coformulación de emtricitabina/tenofovir disoproxilfumarato, 200/300mg una vez al día, frente a400/100mg una vez de lopinavir/ritanavir en comprim-idos dos veces al día + raltegravir 400mg dos veces aldía, en sujetos infectados por el VIH-1 sin tratamientoantirretroviral previo; (versión Enmienda 1: 23-04-08).M10-336EudraCT: 2008-000881-22

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEnsayo en fase III, aleatorizado, doble ciego, TMC27825 mg una vez al día comparado con efavirenz 600 mguna vez al día, en combinación con una terapia defondo fija, consistente en tenofovir disoproxil fumaratoy emtricitabina, en pacientes infectados por el VIH-1,sin tratamiento antirretroviral previo; (versión: 31-08-07). TMC278-TIDP6-C209EudraCT: 2007-002646-38

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEstudio piloto, multicéntrico, aleatorizado y abiertopara evaluar el tratamiento concomitante de la co-infección por el VHC/VIH con peg-interferón + ribaviri-na y lopinavir como único agente retroviral; (versión:29-06-07). ACA-SPAI-05-06EudraCT: 2007-003544-30

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEstudio abierto, multicéntrico de fase IV para evaluar laeficacia y seguridad de interferón pegilado alfa-2a (40KD) asociado a ribavirina para hepatitis crónica C conALT persistentemente normales, en pacientes coinfec-tados por el virus de la inmunodeficiencia humana;(versión: 28-10-05). CONTRAEudraCT: 2006-001243-55

PRINCIPAL INVESTIGATOR: CRISTINA SARRIACEPEDAEnsayo multicéntrico, aleatorizado, doble ciego, controla-do con placebo con un nuevo antagonista CCR5, UK-427, 857 en combinación con la terapia de base óptimafrente a únicamente la terapia de base óptima para eltratamiento de sujetos infectados con VIH-1 tratados conantirretrovirales; (versión 1: 24-08-04). A4001028

PRINCIPAL INVESTIGATOR: CRISTINA SARRIACEPEDAUn estudio internacional, multicéntrico, observacional,prospectivo, sobre la seguridad de maraviroc utilizadojunto con la terapia de base optimizada en pacientesinfectados por el VIH-1 que han recibido tratamiento;(versión 1: 16-01-08). A4001067

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PRINCIPAL INVESTIGATOR: JOSE-RAFAEL CAMARALLANZAEstudio multicéntrico con asignación aleatoria que com-para valganciclovir oral con ganciclovir intravenoso enpacientes que han recibido un transplante alogénico decélulas madre; (Versión 2.0: 05-01-10). ML22371EudraCT: 2009-015965-29

PRINCIPAL INVESTIGATOR: JOSE-RAFAEL CAMARALLANZAEnsayo abierto de fase 3 para evaluar la seguridad,tolerabilidad e inmunogenia de la vacuna antineu-mocócica conjugada tridecavalente seguida de lavacuna antineumocócica polisacárida de 23 seroti-pos en receptores de trasplante alogénico de célu-las germinales hematopoyéticas de 2 o más años deedad; (versión original: 27-08-09). 6115A1-3003-WWEudraCT: 2009-012087-13

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio doble ciego, doble enmascarado, multicéntrico,aleatorizado en fase 3 de la seguridad y la eficacia deelvitegravir reforzado con ritonavir (EVG/r) en comparacióncon raltegravir (RAL) cada uno administrado con 1 régimende fondo en sujetos adultos infectados por VIH-1 que hanrecibido tratamiento antirretroviral; (versión 1.1: 24-10-08,Enmienda al protocolo). GS-US-183-0145EudraCT: 2007-004225-26

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio internacional observacional para la caracteri-zación de adultos hospitalizados por complicacionesde la Gripe A pandémica H1N1 (H1N1v). Estudio dehospitalizados de INSGHT H1N1 (FLU003); (versión1.0: 18-08-09; Enmienda 1: 15-09-09). INSGHT 003:FLU 003

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEstudio abierto, randomizado para evaluar un cambio derégimen terapéutico de dos inhibidores nucleósidos dela transcriptasa inversa y tercer agente a un régimen deatazanavir/ritonavir una vez al día y raltegravir dos vecesal día o a un régimen de atazanavir/ritonavir una vezal díay tenofovir/emitricitabina una vez al día en pacientes

infectadospor el VIH-1 con supresión virológica que pre-sentan problemas de seguridad y/o tolerabilidad en surégimen de tratamiento actual; (Estudio HARNESS);(versión 2.0: 15-02-11). AI424-402EudraCT: 2009-017032-41

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZMomento estratégico para el inicio de la terapia antir-retroviral (START) (versión 1.0: 09-12-08).INSIGHT001:START-DAIDSID:10619EudraCT: 2008-006439-12

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILSeguridad a largo plazo de pautas que incluyen nevi-rapina; (versión: 0210-08). POD-NEV-2008-01

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILUtilidad de Raltegravir para mejorar la tolerancia o lacomodidad del TAR en pacientes virologicamente suprim-idos (TORAL); (versión: 16-11-09). POD-RAL-2009-01

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEstudio de la eficacia, seguridad y calidad de vida (cdv)de AERIUS comprimidos (en dosis de 5, 10 ó 20 mguna vez al día) en pacientes con urticaria crónicaidiopática; (versión: Enmienda 2 (09-10-06). PERICOEudraCT: 2006-05940-99

PRINCIPAL INVESTIGATOR: JOSE-RAFAEL CAMARALLANZAEstudio piloto fase II multicéntrico, no aleatorizado paraevaluar la eficacia y seguridad de dasatinib tras trasplantealogénico de progenitores hemopoyéticos en pacientescon leucemia aguda linfoblástica filadelfia positiva (BCR-ABL +) de novo; (versión 1.0: 22-04-09). DASA-TRASEudraCT: 2009-015118-23

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio internacional observacional para la caracteri-zación de adultos con gripe A pandémica H1N1(H1N1v). Estudio de pacientes ambulatoriosdeINSIGHT H1N1v (FLU 002);(versión 1.0: 18-08-09;Enmienda 1: 15-09-09). INSIGHT 002: FLU 002

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PRINCIPAL INVESTIGATOR: JOSE-RAFAEL CAMARALLANZAEstudio prospectivo y aleatorizado para comparar la efi-cacia de la combinación de anidulafungina y voriconazolcon la del voriconazol solo cuando se usan para eltratamiento primario de la aspergilosis invasiva demostra-da o probable; (versión final: 07-08-07). A8851009EudraCT: 2007-002445-20

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEnsayo clínico abierto, aleatorizado, para comparar lacalidad de vida de los pacientes VIH+ que inicianmonoterapia con comprimidos de LPV/r vs triple ter-apia que contengan un IP potenciado; (versión 1: 24-07-09). SAI-CDV-2009-01EudraCT: 2009-014430-25

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEnsayo abierto con TMC278 25mg al día en combi-nación con una pauta de base con dos inhibidores dela transcriptasa inversa nucleosídicos/nucleotídicos enpacientes infectados por el VIH-1 que participaron enestudios clínicos con TMC278; (versión final: 30-07-10). TMC278-TIDP6-C222EudraCT: 2010-021209-18

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILInfluencia de nevirapina en los niveles de carga viralplasmática del virus de la Hepatitis C en pacientescoinfectados por VIH/VHC (ESTUDIO HELICON);(versión final: septiembre de 2010). JAP-NEV-2010-01

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEstudio observacional no comparativo para describir laduración y los resultados del tratamiento de pacientesinfectados por el VIH sin experiencia previa detratamiento que han iniciado regímenes targa basadosen ATV/RTV; (versión 17-06-10). AI424-401

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZCalidad de vida, función neurocognitiva y característi-

cas clínicas de las mujeres madruas VIH+ en España.Comparción con controles sin infección por el VIH.Etapas EVhA. Parte 3. Estudio EVhA-3; (versión 1.1:09-09-10). ABB-TAR-2010-03

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio fase III, aleatorizado, doble ciego, para eval-uar la eficacia y la seguridad de GSK1349572 masabacavir/lamivudina en combinación a dosis fijas,administrado una vez al día frente a Atripla® duranteun periodo de 96 semanas en pacientes adultosinfectados por el VIH-1 que no han recibidotratamiento antirretroviral previo; (versión 00: 09-09-10). ING114467EudraCT: 2010-020983-39

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio fase III, aleatorizado, doble ciego, para eval-uar la eficacia y la seguridad de 50 mg deGSK1349572 una vez al día, frente a 400mg de ral-tegravir dos veces al día, ambos adminsitrados conuna combinación doble, a dosis fija, de inhibidoresde la transcriptasa inversa análogos de los nucleósi-dos durante un periodo de 96 semanas, enpacientes adultos infectados por el VIH-1 que no hanrecibido tratamiento antirretroviral previo; (ver-sión:02-08-10). ING113086EudraCT: 2009-017950-11

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio epidemiológico no intervencionista para cono-cer la prevalencia relativa de Diarrea Crónica entre lospacientes con VIH en seguimiento en las consultasespañolas: corte de prevalencia en las consultas deVIH (Versión ESP/FLP/TMC114IFD4007/Protocolo/V1.0.:02NOV2011). JAN-VIH-2011-01

PRINCIPAL INVESTIGATOR: IGNACIO DE LOS SAN-TOS GILEstudio sobre los efectos metabólicos deatazanavir/ritonavir versus darunavir/ritonavir en com-binación con tenofovir/emtricitabina en pacientes infec-tados por el VIH-1 sin tratamiento previo: ensayo clíni-co controlado, abierto con asignación aleatoria; (ver-sión 1.0: 25-05-10). ATADAREudraCT: 2010-021002-38

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PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEficacia y tolerabilidad de una pauta de tratamientoantirretroviral que incluye ABC/3TC/NVP. EstudioKIVI; (versión 1.2:25-07-11). DPP-VIH-2011-01

PRINCIPAL INVESTIGATOR: CRISTINA SARRIACEPEDAInfluencia de la cirugía cardiaca precoz en el pronos-tico a corto y largo plazo de la endocarditis infec-ciosa; (versión final: 29-11-06), (Enmienda 1: 03-08-07). END-VAL-01

PRINCIPAL INVESTIGATOR: JESUS SANZ SANZEstudio para evaluar la actividad y la tolerabilidad dela biterapia conlopinavir/ritonavir y 3TC en sustitu-ción de una triple terapia que incluyalopinavir/ritonavir y 3TC o FTC en pacientes coninfección por VIH y supresión virológica: ensayoclínico controlado, abierto con asignación aleatoria,de 48 semanas de duración; (versión 1.0: 24-1-11).OLEEudraCT: 2010-024652-28

PRINCIPAL INVESTIGATOR: CRISTINA SARRIACEPEDAPrevalencia y manejo clínico de pacientes hospital-izados infectados por grampositivos con insuficien-cia renal en España Estudio DAPTOKIDNEY: FasesPrevenir y Evaluar; (versión final: 03-03-11). NOV-ANT-2011-01

PRINCIPAL INVESTIGATOR: IGNACIO DE LOSSANTOS GILEstudio observacional retrospectivo para evaluar elcambio de análogo de Timidina a Raltegravir enpacientes VIH-Positivo multirresistentes con toxici-dad relacionada con el análogo de nucleósido;(Versión: 2-03-10). ESTUDIO SWIMIVIR

PRINCIPAL INVESTIGATOR: JOSE-RAFAEL CAMA-RA LLANZAEstudio en fase II, multicéntrico, prospectivo, abier-to, de tratamiento anticipado de la infección por cit-omegalovirus (CMV) guiado por la monitorizaciónvirológica y la cuantificación de linfocitos T

CD8pp65/IE-1-IFNgamma+ en el transplantealogénico de progenitores hematopoyéticos; (ver-sión 1.0.04-04-11). CMV-INMUNOGUIAEudraCT: 2011-001449-34

PRINCIPAL INVESTIGATOR: IGNACIO DE LOSSANTOS GILAnálisis epidemiológico transversal para describir lasrazones del cambio de la terapia antirretroviral en elpaciente VIH postivio (SWITCH AUDIT); (versiónfinal: 27-04-10). GIL-VIH-2010-02

PRINCIPAL INVESTIGATOR: IGNACIO DE LOSSANTOS GILEstudio abierto de fase III para evaluar la seguridad,la tolerabilidad y la eficacia de TMC435 en triple ter-apia con peginterferón-2a (Pegasys)® y ribavirina(Copegus)® en pacientes con infección crónica porel genotipo 1 del virus de la Hepatitis C (VHC) coin-fectados con el virus de la inmunodeficienciahumana tipo 1 (VIH-1); (versión 08-07-11). TMC435-TIDP16-C212EudraCT: 2010-021337-31

PRINCIPAL INVESTIGATOR: IGNACIO DE LOSSANTOS GILAcortando distancias entre las directrices deltratamiento antirretroviral y la práctica clínica habitu-al: estudio de las barreras para el comienzo del TARen aquellos pacientes con indicación; (versión final:26-07-11). IRH-VIH-2011-01

PRINCIPAL INVESTIGATOR: IGNACIO DE LOSSANTOS GILEstudio de fase III aleatorizado, doble ciego, paraevaluar la seguridad y eficacia de 50 mg una vez aldia de GSK1349572 frente a 400 mg dos veces aldia de raltegravir, ambos administrados en combi-nación con una terapia de base seleccionada por elinvestigador durante 48 semanas en sujetos adultosinfectados por el VIH-1, que han recibido tratamien-to antirretroviral previo con la execpción de uninhibidor de la integrasa; (versión:02-08-10).ING111762EudraCT: 2009-018001-51

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GRUPO 51

HEAD OF LABORATORYJavier Aspa Marco

GROUP MEMBERS• Jose Andrés García Romero de Tejada• Rosa Mar Gómez Punter• Mara Ortega Gómez• Olga Rajas Naranjo• Emma Vázquez Espinosa

RESEARCH INTEREST

The interest of our research is related to differentaspects of the community-acquired pneumonia (CAP).CAP severity varies widely, from almost asymptomatic

to septic shock, multiple organ dysfunctions syndromeand eventually death, and despite effective antimicro-bial agents, the mortality rate in hospitalized patientsrange from 2% to 30%. Several factors have beeninvolved in the severity of pneumonia, some related tothe patients genetic variability, others with the type ofinflammatory response, the quality of care provided, orthe aggressiveness of the involved microorganisms,mainly pneumococcus. It is also important to analyzeaspects of prevention such as vaccination.

Genetic variability of the pulmonary surfactant proteinsA and D affects clearance of microorganisms and theextent of the inflammatory response. The genes ofthese collectins (SFTPA1, SFTPA2 and SFTPD) arelocated in a cluster at 10q21-24. The study publishedthis year by members of our group (Garía-Laorden et al.Critical Care 2011) indicates that missense singlenucleotide polymorphisms and haplotypes of SFTPA1,SFTPA2 and SFTPD are associated with susceptibilityto CAP, and that several haplotypes also influenceseverity and outcome of CAP.

Genetic variability may also affect the host response.Leukocyte receptors for the Fc portion of immunoglobu-lin g (IgG) (FcγR) confer effector functions to the IgG. Theaim of the study published this year by members of ourgroup (Solé-Violan et al. Critical Care Med 2011) was toassess the potential association of the functional poly-morphism rs1801274 in the gene for receptor IIa for theFc portion of IgG (FcγRIIa) (FCGR2A-H131R) with thesusceptibility to and the severity of CAP. Our results donot support a role of FCGR2A-H131R polymorphism in

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Influence of genetic variability at the surfactant proteins A ad D in community-acquired pneumonia: a prospective, observational, genetic study.Crit Care 2011, 15: R57Kaplan-meier stimation of survival at 28 and 90 days in the 682 CAP patients. CAP, community-acquired pneumonia. Solid curves, represent the ha-lotypes under study, being dotted curves the rest of halotypes. The vertical dotted line is depicted at 28 days.

susceptibility to CAP or pneumococcal CAP. However,we provide the insight that homozygosity for FCGR2A-H131R predisposes to bacteremic CAP, which wasassociated with higher severity in our study.

It is known since 1993 that patients diagnosed with CAPhave a greater long-term mortality than patients of thesame age and degree of co-morbidity, estimated at anaverage 10% higher than the expected. Also, there isenough information showing that patients with anepisode of CAP have a higher proportion of cardiovascu-lar events, both at short and long term. These eventsreferred the occurrence of atrial fibrillation and other car-diac arrhythmias, myocardial infarction, congestive heartfailure, pulmonary oedema and unstable angina and theoccurrence of a stroke, or pulmonary thromboembolism.While the association between the two statements is notyet fully established, a relationship between cardiovascu-lar events and increased mortality rates of patients withCAP who require admission could be suspected. Theexplanation for this association rests on the hypothesisthat an imbalanced inflammatory response is cause ofpoor prognosis or death. In this sense, persistent inflam-mation at the time of discharge of patients with CAP,defined by high circulating levels of IL-6 and IL-10 isassociated with increased mortality after episode, and

certain inflammatory mechanisms are suggested to be atthe origin of the occurrence of cardiovascular events.Other components of the immune response such as Tlymphocyte effector (Th1, Th17) and regulatory ( Treg.)subsets, anti-inflammatory cytokines or solubleendothelial adhesion molecules have not been ade-quately explored. Our group has applied for various grants aimed to con-duct research that can meet the following objectives: 1.- To quantify the incidence of cardiovascular disease inadult patients, within a year after admission for anepisode of CAP and establish the possible relationship tomortality. 2. - To describe the distribution of differentinflammatory biomarkers at admission and discharge ofpatients with an episode of CAP and determine its pos-sible relationship with the incidence of cardiovasculardisease.

We participate in the ODIN project, that is a prospectiveepidemiological study focused in the invasive pneumoccaldisease occurred in hospitalized adult patients in eightSpanish general hospitals. We analyzed some clinical andmicrobiological variables, and the implication of differentpneumococcal serotypes in the outcome of the CAP.

MAJOR GRANTS

• Javier Aspa Marco (Coordinador del centro).Proyecto Coordinado. Variabilidad genética en laseñalización mediada por los TLRs/IL-1R en enfer-medades respiratorias: neumonía comunitaria y aler-gia respiratoria. ISCIII. FIS PI10/01718


García-Laorden MI, Rodríguez de Castro F, Solé-ViolánJ, Rajas O, Blanquer J, Borderías L, Aspa J, BrionesML, Saavedra P, Marcos-Ramos JA, González-Quevedo N, Sologuren I, Herrera-Ramos E, Ferrer JM,Rello J, Rodríguez-Gallego C. Influence of genetic vari-ability at the surfactant proteins A and D in community-acquired pneumonia: a prospective, observational,

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SP-D serum levels (ng/ml) regarding to SFTPD genotypes in healthycontrols. The comparision of the three groups showed a significant dif-ference (ANOVA P=0.017). Horizontal lines denote mean value for eachgenotype.

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genetic study. Crit Care 15(1): R57. 2011. PMID:21310059. IF: 4,595

Solé-Violán J, García-Laorden MI, Marcos-Ramos JA,de Castro FR, Rajas O, Borderías L, Briones ML,Herrera-Ramos E, Blanquer J, Aspa J, Florido Y,García-Bello MA, Ferrer-Agüero JM, Sologuren I,Rodriguez-Gallego C. The Fc? receptor IIA-H/H131genotype is associated with bacteremia in pneumo-coccal community-acquired pneumonia. Crit Care Med39(6): 1388-9. 2011. PMID: 21317643. IF: 6,254

Blanquer J, Aspa J, Anzueto A, Ferrer M, Gallego M,Rajas O, Rello J, Rodríguez de Castro F, Torres A.SEPAR Guidelines for Nosocomial Pneumonia. ArchBronconeumol. 47(10): 510-520. Epub 2011 Sep 9.2011. PMID: 21908091. IF: 2,166

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: F. JAVIER ASPA MARCOEstudio epidemiológico prospectivo de vigilancia hos-pitalaria de la enfermedad neumocócica invasora enadultos mayores de 18 años en España; Estudio ODIN;(versión 1: 29-04-10). PFI-PRE-2010-01

GRUPO 52

HEAD OF LABORATORYManuel López-Brea Calvo

GROUP MEMBERS• Teresa Alarcón Cavero• Buenaventura Buendía Moreno• Laura María Cardeñoso Domingo• Ana Correa Ruiz• Diego Domingo García• Marina Espínola Docio• Alba Guiu Martínez• Elisea Lomas Lomas

• Justo Martiáñez Rodríguez• María Josefa Martínez Gómez• María del Carmen Martínez Jiménez• Sandra Rodrigo Gil• Carmen María Serrano Morago• Ángela Somodevilla Solís

RESEARCH INTEREST

Phages in Helicobacter pyloriPhages are bacteria-infecting viruses. Being the mostabundant organisms on the planet (about 1031), theylive in ocean waters, lakes and stream, soils and sedi-ments, and inside other organisms. Prophages are theintegration of the temperate phage genome in one ofthe host's replicons and they can be passed to daugh-ter cells silently. The Induction of lytic cycle could beobtained by chemical (as Mitomycin C), physical (as UVlight) and presumably environmental factors.Prophages affect bacterial fitness in many differentways and contribute to genetic diversity.

The presence of intracellular bacteriophage-like parti-cles in H. pylori in biopsy specimens was reported inthe first studies describing H. pylori by Marshall et al.and Goodwin et al, although no further characterizationof them has been described.

During the 2011 year, the growth of H. pylori in anautomatized system for blood culture was achievedincluding foetal calf serum and antibiotics within thecommercially available bottles (Bactec Ped Plus).Phages were induced with mitomycin C and phageDNA of 20kb was obtained after purification. DNAsedegradation showed that it was a bicatenary DNA andelectronic microscope showed the presence of aphage-like structure.

Detection of antimicrobial resistance and virulence fac-tors in Helicobacter pyloriClarithromycin susceptibility is an important factor topredict Helicobacter pylori eradication failure. In addi-tion, the resistance to this antibiotic is high in Spain.


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Therefore, early detection of resistance is important intreatment of H. pylori infection. Several molecularmethods have been used for detection of H. pyloristrains that are clarithromycin and/or fluoroquinoloneresistant and compare it with conventional protocols.According to data obtained by our group 47.1% of thestrains were clarithromycin susceptible and 52.9% clar-ithromycin resistant: 89% showed A2143G, 6.2%showed A2142G mutation and 4.7% double mutationsA21423C-A2143G. Seventeen of them showed het-eroresistance (wild type and mutation simultaneously).

H. pylori are involved in different digestive or non diges-tive diseases and a continuous effort is being done toclassify the strains according to the virulence factors.The factors more widely studied are cagA gene andvacA alleles (s1 and s2). The more virulent strains arethose with vacA s1 allele and cagA positive althoughthere are more factors still unknown. dupA gen (duode-nal ulcer promoting gene) has been studied in ourSpanish population with a 35% positivity. Among pedi-atric patients results showed a 25.58% of positivity fordupA, while the prevalence for adult patients was45.95%.

Infection by citomegalovirus The main research interest in this subject is to evaluatenew molecular methods for Citomegalovirus (CMV)monitoring in allo-Stem Cell Transplanted (SCT)patients. During 2011, the department of Microbiologywas selected by Roche Diagnostics for a multi centric

study with other 5 centers in the world (Mount SinaiMedical Center, New York; Johns Hopkins MedicalInstitutions, Baltimore; University of Basel, Switzerland;Stanford Clinical Virology Laboratory, Palo Alto; andHelsinki University Hospital, Finland, to evaluate a newReal Time PCR for CMV detection. The new Real TimePCR was developed to optimize the diagnosis andtreatment of patients with this infection.

HIV infectionThe molecular epidemiology of HIV-1 is constantlychanging, mainly as a result of human migratory flowsand the high adaptive ability of the virus. In recentyears, Spain has become one of Europe’s main desti-nations for immigrants and one of the westernEuropean countries with the highest rates of HIV-positive patients.

Using a phylogeographic approach, the relation-ship between HIV-1 variants detected in immigrantand native populations of the urban area of Madridwas analyzed. A large data set (n 2,792) from 11Madrid hospitals of viral pol sequences was includedand the impact of immigration in the epidemiologicaltrends of HIV-1 variants circulating in the largestSpanish city was studied. The prevalence of infec-tions by non-B HIV-1 variants in the studied cohortwas 9%, rising to 25% among native Spanishpatients. Multiple transmission events involving differ-ent lineages and subsubtypes were observed in allthe subtypes and recombinant forms studied. Ourresults also revealed strong social clustering amongthe most recent immigrant groups, such as Russiansand Romanians, but not in those groups who havelived in Madrid for many years. Additionally, we doc-

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Phage-like structures observed after mitomycin C induction in brothBactec Ped Plus.

Distribution of HIV-1subtypes and recombinants in Madrid obtained ina multicentre study.

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ument for the first time the presence of CRF47_BFand CRF38_BF in Europe, and a new BG recombi-nant form found in Spaniards and Africans is tenta-tively proposed. These results suggest that the HIV-1epidemic will evolve toward a more complex epi-demiological landscape.

MAJOR GRANTS

• Teresa Alarcón Cavero. Helicobacter pylori: ais-lamiento y estudio de fagovirus como mecanismo detransferencia de resistencia a antimicrobianos yfuente de nuevas estrategias terapéuticas. ISCIII.PI08/1775

• Teresa Alarcón Cavero. Estudio de aspectos molec-ulares e inmunológicos de la infección por helicobac-ter pylori en pacientes pediátricos y adultos. Impactoen salud pública.. Argentina. PROIPRO 0310

• Teresa Alarcón Cavero. Validación de la pirosecuen-ciación como técnica de genotipado exacto encuadros de ACV y otras patologías de base infecto-contagiosa. BlackBio.

• Laura María Cardeñoso Domingo. InternationalInvestigator CMV Evaluation (IntICE). RocheMolecular Systems.


González-Alba JM, Holguín A, Garcia R, García-Bujalance S, Alonso R, Suárez A, Delgado R,Cardeñoso L, González R, García-Bermejo I, Portero F,de Mendoza C, González-Candelas F, Galán JC.Molecular surveillance of HIV-1 in Madrid, Spain: a phy-logeographic analysis. J Virol. 85(20): 10755-63. Epub2011 Jul 27. 2011. PMID: 21795343. IF: 5,189

Cantón E, Pemán J, Quindós G, Eraso E, Miranda-Zapico I, Álvarez M, Merino P, Campos-Herrero I,Marco F, de la Pedrosa EG, Yagüe G, Guna R, RubioC, Miranda C, Pazos C, Velasco D; FUNGEMYCAStudy Group (..,Buendía B,..). Prospective multicenterstudy of the epidemiology, molecular identification, andantifungal susceptibility of Candida parapsilosis,Candida orthopsilosis, and Candida metapsilosis iso-lated from patients with candidemia. Antimicrob AgentsChemother. 55(12): 5590-6. Epub 2011 Sep 19. 2011.PMID: 21930869. IF: 4,672

Agudo S, Pérez-Pérez G, Alarcón T, López-Brea M. Rapiddetection of clarithromycin resistant Helicobacter pyloristrains in Spanish patients by polymerase chain reaction-restriction fragment length polymorphism. Rev EspQuimioter 24(1): 32-36. 2011. PMID: 21412667. IF: 0,667


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Line 3.8Individualized medicine in solid tumors

GRUPO 53HEAD OF LABORATORYAlmudena Zapatero Laborda

GROUP MEMBERS• María Magdalena Adrados de Llano• Ramón Cristóbal Arellano Gañán• José Alfonso Cruz Conde• Inmaculada Fernández González• Feliciano García Vicente• María del Carmen Martín de Vidales Cervantes• Leopoldo Pérez González• Mariano Rabadán Ruiz

RESEARCH INTEREST

Prostate cancerDuring the last two years several projects in prostatecancer have focused our current research work. Thefirst one is a multi-institutional, “Spanish Phase IIITrial comparing Long-Term Versus Short-TermAndrogen Deprivation Combined With High-DoseRadiotherapy For Localized Prostate Cancer: GICORProtocol DART01/05. EudraCT 2005-000417-36”.The encouraging preliminary results suggesting thatlong-term androgen deprivation could be superior toshort-term hormones in patients with high-riskprostate cancer treated with high dose radiotherapyhave been presented in national and internationalmeetings: SEOR 2011 (oral presentation), ASCO2011 (poster), ASTRO 2011(oral communication)and EMUC 2011 (oral communication). These datahave been also published in the prestigious pro-ceedings corresponding journals (CTO, JCO,IJROP).

Along this last year we have also completed the proce-dures to participate, as IP from Spain on behalf ofGICOR group, in one of the most important internation-al phase III trials on Prostate cancer: RTOG 0924 titled:“Androgen Deprivation Therapy And High DoseRadiotherapy With Or Without Whole-PelvicRadiotherapy In Unfavorable Intermediate Or FavorableHigh Risk Prostate Cancer: A Phase III Randomized Trial”

Our ongoing projects include not only the participation ina cooperative project of organ deformation and adaptiveradiotherapy in collaboration with the “Bio-Ingeniería yTelemedicina” group from Universidad Politécnica deMadrid, but also two studies in translational research: 1) A cooperative study with the CNIO to study the profileand differences in existing patterns in biological molecu-lar markers measured in diagnostic prostate biopsiesand after treatment in patients treated with high-doseradiation therapy (with or without concomitant androgensuppression. This study titled “Comparison OfBiological-Molecular Markers Predictive Of RadiationResponse In Localized Prostate Cancer Ref.: CaPr-HLP-RT-01/ PI 197” is sponsored by a grant from ABBOT andwill be completed by June 2012.

2) A cooperative study with the Santiago University tostudy the predictive value of CTCs (circulating tumoralcells) in high-risk localized prostate cancer.

Bladder cancerOver the past years we have investigated 2 prospectiveapproaches in the conservative treatment of invasivebladder cancer. The updated results that were present-

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Biomarker Reference Type Clon

p21-PAK6GeneTexGTX78127

Rabbit policlonal

Policlonal

HIF1alfaAbcam ab51608

Rabbit monoclonal

EP1215Y

PSMB4AbnovaH5692-M01

Monoclonal 6G7-E8

P53 Dako Monoclonal DO7AR

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ed in the International ASTRO meeting as oral commu-nication (proceedings IJROBP) confirm that trimodalitytherapy with bladder preservation represents a real alter-native to radical cystectomy in selected patients.

MAJOR GRANTS

Almudena Zapatero Laborda. Análisis comparativode marcadores biológicos moleculares predictivos

de respuesta a radiación en cáncer de próstatalocalizado. Grant Abbott. CaPr-HLP-RT-01/PI 197


Zapatero, A. Guerrero, X. Maldonado, A. Alvarez,A. Cabeza, C. Gonzalez San Segundo, V. Macias,F. Casas, A. Pedro-Olive, A. Boladeras. Long-termvs. Short-term Androgen Deprivation Combinedwith High-dose Radiotherapy for Intermediate andHigh-risk Prostate Cancer: Preliminary Results of aGICOR Phase III Randomized Trial. Int J RadiatOncol Biol Phys 81(2-Supp): S40-S40. 2011.PMID: . IF: 4,503

García-Martín ML, Adrados M, Ortega MP,Fernández González I, López-Larrubia P, Viaño J,Garcia-Segura JM. Quantitative (1) H MR spectro-scopic imaging of the prostate gland usingLCModel and a dedicated basis-set: correlationwith histologic findings. Magnetic Resonance inMedicine 65 (2): 329-339. 2011. PMID: 20939087.IF: 3,268

A. Zapatero, C. Martin Vidales, R. Arellano, Y. Ibañez,O. Liñan, G. Bocardo, M. Rabadan, M. Perez, F.Garcia-Vicente, C. Olivier. Long-term Results of TwoSequential Bladder-sparing Trimodality Approachesfor Invasive Bladder Cancer: NeoadjuvantChemotherapy or Concomitant Radio-chemotherapy.Int J Radiat Oncol Biol Phys 81(2-Supp): S71-S72.2011. PMID: . IF: 4,503

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: MARIA-ALMUDENA ZAPA-TERO LABORDAEstudio de Evaluación de la calidad de vida relaciona-da con la salud y cormobilidades en pacientes concáncer de próstata localizado con tratamiento pri-mario con Radioterapia; (versión 2.0: 31-03-09).ONC-RT 01-09


HIF 1 alfa. Próstata 20x.

PSMB4.Próstata 100x

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PRINCIPAL INVESTIGATOR: MARIA-ALMUDENAZAPATERO LABORDAEstudio descriptivo del perfil del paciente con cáncer depróstata en consulta de oncología radioterápica; (estu-dio CAPORT); (VERSIÓN 2: 11-5-10). ONC-RT01-10

PRINCIPAL INVESTIGATOR: MARIA-ALMUDENAZAPATERO LABORDAEstudio postautorización observacional prospectivopara evaluar la prevalencia de alteraciones cognitivasen pacientes con cáncer de próstata antes y despuésde seis meses de tratamiento con análogos de laLHRH (Estudio ANAMEM); (versión final: 24-03-10).IPS-TRI-2010-02

PRINCIPAL INVESTIGATOR: MARIA-ALMUDENAZAPATERO LABORDAAnálisis de la práctica clínica en los servicios deoncología radioterápica españoles en pacientes concáncer de próstata; (versión final 1.00: 28-1-11).RECAP-2011-01

PRINCIPAL INVESTIGATOR: MARIA-ALMUDENAZAPATERO LABORDAEstudio sobre el manejo del paciente con cáncer depróstata tras cirugía radical en los servicios deoncología radioterápica; (versión 15.0013-07-11).ONC-RT-01-11

PRINCIPAL INVESTIGATOR: MARIA-ALMUDENAZAPATERO LABORDAEnsayo fase III aleatorizado y multicéntrico de depri-vación androgénica adyuvante en combinación conradioterapia conformacional tridimensional altas dosisen cáncer de próstata localizado riesgo intermedio-alto; (Versión final: 07-02-2005). DART01/05EudraCT: 2005-000417-36

PRINCIPAL INVESTIGATOR: MARIA-ALMUDENAZAPATERO LABORDAEstudio post-autorización observacional prospectivopara evaluar la prevalencia de síndrome metabólicoen pacientes con cáncer de próstata antes y despuésde doce meses de tratamiento con formulacionestrimestrales de análogos de la LHRH (EstudioANAMET), (versión: 09-07-08). IPS-TRI-2008-01

GRUPO 54

HEAD OF LABORATORYLaura Cerezo Padellano

GROUP MEMBERS• Adolfo Hinojar Gutiérrez• Consuelo López Elzaurdia• Mario López Rodríguez• Alicia Marín Palomo• Margarita Martín Martín• Mario Fernando Muñoz Guerra• Luis Naval Gías• Eduardo Raboso García-Baquero

RESEARCH INTEREST

During the year 2011, the group has advanced in hisresearch lines on head and neck cancer. The multi-centric study on the incidence of HumanPapillomavirus related oropharyngeal cancers, spon-sored by Fundación Mutua Madrileña, has been fin-ished on December 2011 and several abstracts havebeen submitted to Head and Neck international meet-ings. This work has also been presented by Dr. Liñánas her predoctoral investigational sufficiency at theRey Juan Carlos University. The significant data is thatthe incidence of HPV-related oropharyngeal carcino-mas in our media is 26%, similar to the incidence

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found in other European countries, and apparentlylower than in USA. HPV-positive carcinomas presentbetter response to chemoradiation and higher rates ofoverall survival.

Another important line of investigation has been theImplant rehabilitation of irradiated oral cancer patients,which has been carried out in the Department of Oraland Maxillofacial Surgery and has produced two origi-nal articles in indexed maxillofacial journals.

About quality of life research, the Palifermin phase 3 study,in which the Radiation Oncology Department participatedtwo years ago, was published in a high impact oncologyjournal. The conclusion of this study was that palifermin

prevents grade 3 mucositis in advanced head and neckcancer treated with postoperative chemoradiation.

Finally, a special issue for the Reports of PracticalOncology and Radiotherapy journal has been edited byL. Cerezo and M. López, on Acute Radiation Syndromewhich was timely published with the Fukusima nuclearaccident occurring in March 2011. The various contri-butions to the issue will help to better manage peopleinvolved in these accidents.

MAJOR GRANTS

• Laura Cerezo Padellano. Detección del virus delpapiloma humano en el cáncer de orofaringe:Prevalencia de la infección y valor pronóstico.Fundación Mutua Madrileña.

• Consuelo López Elzaurdia. Identificación de factoresgenéticos, ambientales y de expresión fenotípicaasociados a la progresión de lesiones precursorasdel cáncer gástrico: estudio coordinado español deseguimiento. Carlos A. González Svatetz.

• Consuelo López Elzaurdia. Identificación de factoresgenéticos, ambientales y de expresión fenotípicaasociados a la progresión de lesiones del cáncergástrico: estudio coordinado español de seguimien-to. ISCIII. PI10/2654

• Adolfo Hinojar Gutiérrez. Papel de las células madretumorales en la evolución clínica del carcinomaescamoso de laringe. Estudio de la expresión dePodoplanina, CD44 y ALDH-1. Fundación MutuaMadrileña.


Cerezo L. Is loss of cadherin expression predictive ofhigh aggressiveness in oropharyngeal squamous cellcarcinoma?. Oral Oncol 47(8): 685. 2011. PMID:21414836. IF: 2,871

Henke M, Alfonsi M, Foa P, Giralt J, Bardet E, CerezoL, Salzwimmer M, Lizambri R, Emmerson L, Chen MG,Berger D. Palifermin decreases severe oral mucositis of


Implants placed in a patient with fasciocutaneous radial forearm flapreconstruction. Mancha de la Plata et al. Implant Rehabilitation AfterIrradiation. J Oral Maxillofac Surg 2011

Overall survival of patients with oropharyngeal cancer, Human Papillo-ma Virus positive or negative (n = 102 patients, p = 0.09)

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patients undergoing postoperative radiochemotherapyfor head and neck cancer: a randomized, placebo-con-trolled trial. J Clin Oncol 29(20): 2815-2820. 2011.PMID: 21670447. IF: 18,97

L. Cerezo, E. Raboso, MI Ballesteros. Unknown pri-mary cancer of the head and neck: a multidisciplinaryapproach. Clin Transl Oncol 13 (2): 88-97. 2011. PMID:21324796. IF: 1,254

Hinojar-Gutierrez A, Nieto-LLanos S, Mera-MenendezF, Fernandez-Contreras ME, Mendoza J, Moreno R.Laryngeal metastasis as first presentation of hepatocel-lular carcinoma. Rev Esp Enferm Dig 103(4): 222-224.2011. PMID: 21526881. IF: 1,13

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: CONSUELO LOPEZELZAURDIAEstudio epidemiológico sobre HER2 en el cáncergástrico inicial/avanzado: evaluación del estado deHER2 en muestras de tejido tumoral de cáncer gástri-co y de la unión gastroesofágica (GE); (versión 17-08-10). MO23009

PRINCIPAL INVESTIGATOR: LAURA CEREZO PADEL-LANOEstudio de fase II para evaluar la eficacia y la seguridadde la quimiorradioterapia con 5-fluorouracilo, mitomici-na C y panitumumab como tratamiento del carcinomaanal de células escamosas; (versión 1.0: 30-05-09).GEMCAD-09-02EudraCT: 2010-018430-48

PRINCIPAL INVESTIGATOR: LAURA CEREZO PADEL-LANOEstudio de fase II multicéntrico, aleatorizado, doble ciegoy controlado con placebo para comparar la eficacia yseguridad de Clonidine Lauriad® 50 Ág y 100 Ág com-primido bucal mucoadhesivo (CBM) administrado una vezal día frente a placebo en la prevención y el tratamiento dela mucositis oral inducida por radioquimioterapia enpacientes con cáncer de cabeza y cuello; (versión amend-

ment 3: 14-06-10). BA2009-28-01EudraCT: 2009-014870-16

PRINCIPAL INVESTIGATOR: LAURA CEREZO PADEL-LANOEnsayo aleatorizado en fase II de panitumumab yradioterapia (PRT) comparado con quimioradioterapia(QRT) en pacientes con carcinoma no resecado decélulas escamosas de cabeza y cuello localmenteavanzado; (versión: 13-04-07). 20062079EudraCT: 2007-001438-15

PRINCIPAL INVESTIGATOR: MARIO-ANIBAL LOPEZRODRIGUEZEstudio fase IV observacional y multicéntrico con radioter-apia hipofraccionada acelerada en carcinoma infiltrante demama; (versión 1.0: 29-09-10). GICOR-2010-01

GRUPO 55

HEAD OF LABORATORYCecilio Santander Vaquero

GROUP MEMBERS• Montserrat Alcañiz Rodríguez• Concepción Alonso Cerezo• Ana Isabel Ballesteros García• José Cantero Perona

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• María Chaparro Sánchez• Lourdes del Campo del Val• Yolanda Delgado Jiménez• Olga Donnay Candil• María José Galán Sánchez-Heredero• José Luis García Fernández• Jesús González Cajal• María Mercedes Guijarro Rojas• Elena Martín Pérez• Ramón Moreno Balsalobre• José Andrés Moreno Monteagudo• María del Mar Pérez Pérez• Yat Wah Pun Tam• Erich Alberto Vargas Díez• Francisco E. Viamontes Ugalde

MAJOR GRANTS

Cecilio Santander Vaquerizo (Coordinador del Centro).Proyecto Coordinado. Evaluación del riesgo de hemor-ragia digestiva alta y baja y de los factores de riesgoasociados al tratamiento con anti-inflamatorios noesteroideos o agentes antigregantes plaquetarios. ISCI-II. PI08/1301.


Trapero-Marugán M, Moreno-Borque R, Arberas B,Santander-Vaquero C. Colonic mast cells: a new targetin chronic constipation?. Aliment Pharmacol Ther.34(5): 585-6. 2011. PMID: 21806646. IF: 3,861

JF Rahier, P Papay, J Salleron, S Sebastian, M Marzo,L Peyrin-Biroulet, V Garcia-Sanchez, W Fries, DP vanAsseldonk, K Farkas, NK de Boer, T Sipponen, P Ellul,E Louis, STC Peake, U Kopylov, J Maul, B Makhoul, GFiorino, Y Yazdanpanah, M Chaparro, for the EuropeanCrohn’s and Colitis Organisation (ECCO). H1N1 vac-cines in a large observational cohort of patients withinflammatory bowel disease treated with immunomod-ulators and biological therapy. Gut 60(4): 456-462.2011. PMID: 21270121. IF: 10,614

Rahier JF, Papay P, Salleron J, Sebastian S, Ellul P,Teich N, Fiorino G, Blaha B, Garcia-Sanchez V, Haas T,Van Gossum A, Abitbol V, Yazdanpanah Y, ChaparroMC. Influenza A (H1N1)v infection in patients withinflammatory bowel disease: a case series. AlimentPharmacol Ther. 33(4): 499-500. 2011. PMID:21235603. IF: 3,861

Alonso-Cerezo MC, Pérez-Pérez P. Li-Fraumeni syn-drome. Med Clin (Barc). 137(9): 425-6. Epub 2011 Feb22. 2011. PMID: 21345471. IF: 1,413Mañosa M, García V, Castro L, García-Bosch O,Chaparro M, Barreiro-de Acosta M, Carpio D, AguasM. Methotrexate in ulcerative colitis: a Spanish multi-centric study on clinical use and efficacy. J CrohnsColitis. Epub 2011 Apr 22 5(5): 397-401. 2011. PMID:21939912. IF: 2,628

Panés J, Bouzas R, Chaparro M, García-Sánchez V,Gisbert JP, Martínez de Guereñu B, Mendoza JL,Paredes JM, Quiroga S, Ripollés T, Rimola J.Systematic review: the use of ultrasonography, com-puted tomography and magnetic resonance imagingfor the diagnosis, assessment of activity and abdomi-nal complications of Crohn's disease. AlimentPharmacol Ther 34(2): 125-145. 2011. PMID:21615440. IF: 3,861

Freixinet Gilart J, Hernández Rodríguez H, MartínezVallina P, Moreno Balsalobre R, Rodríguez Suárez P;SEPAR. Guidelines for the diagnosis and treatment ofthoracic traumatism. Arch Bronconeumol. 47(1): 41-9.Epub 2010 Dec 28. 2011. PMID: 21190767. IF: 2,166

Moreno Balsalobre R, Moreno Mata N, RamosIzquierdo R, Aragón Valverde FJ, Molins López-RodoL, Rivas de Andrés JJ, García Fernández JL, CañizaresCarretero MÁ, Congregado Loscertales M, CarbajoCarbajo M; SEPAR. Guidelines on surgery of the tho-racic sympathetic nervous system. ArchBronconeumol. 47(2): 94-102. Epub 2011 Feb 20.2011. PMID: 21342743. IF: 2,166

Santiago-et-Sánchez-Mateos D, Juárez Martín A,González De Arriba A, Delgado Jiménez Y, Fraga J,Hashimoto T, García-Diez A. IgG/IgA pemphigus with


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IgA and IgG antidesmoglein 1 antibodies detected byenzyme-linked immunosorbent assay: presentation oftwo cases. J Eur Acad Dermatol Venereol 25 (2): 110-112. 2011. PMID: 20477924. IF: 3,309

Trapero-Marugán M, Mendoza J, Moreno MonteagudoJA, Chaparro M, García-Buey L, González-Moreno L,Borque MJ, Moreno-Otero R. Current antiviral combina-tion therapy for chronic hepatitis C patients who failed tointerferon alfa-based treatment. J Clin Pharm Ther. 36(6):695-703. 2011. PMID: 21175705. IF: 1,649

Martín Martín L, Santander C, Lopez Martín MC,Espinoza-Ríos J, Chavarría-Herbozo C, Gisbert JP,Moreno-Otero R. Esophageal motor abnormalities ineosinophilic esophagitis identified by high-resolutionmanometry. J Gastroenterol Hepatol 26(9): 1447-1450.2011. PMID: 21575059. IF: 2,41

Trapero-Marugan M, Mendoza J, Chaparro M,Gonzalez Moreno L, Moreno-Monteagudo JA,Borque MJ, Moreno-Otero R. Long-Term outcome ofchronic hepatitis C patients with sustained virologicalresponse to peginterferon plus ribavirin. World JGastroenterol 17(4): 493-498. 2011. PMID:21274379. IF: 2,24

Alonso-Cerezo MC, Herrera-Peco I, Fernández-Millares V, Pastor J, Palacios-Espichan J, Hernando-Requejo V, Ortega GJ, Sola RG. Family history ofepilepsy resistant to treatment. Rev Neurol. 52(9):522-526. 2011. PMID: 21484723. IF: 1,218

Herrera-Peco I, Pastor J, Alonso-Cerezo C, Sola RG,Ortega GJ. Significance of complex analysis of electri-cal activity in temporal lobe epilepsy: foramen ovaleelectrodes records. Rev Neurol. 52(1): 3-12. 2011.PMID: 21246488. IF: 1,218

Pinilla I, Gómez-León N, Del Campo-Del Val L,Hernandez-Maraver D, Rodríguez-Vigil B, Jover-DíazR, J Coya J. Diagnostic value of CT, PET and com-bined PET/CT performed with low-dose unenhancedCT and full-dose enhanced CT in the initial staging oflymphoma. Q J Nucl Med Mol Imaging. 55(5): 567-75. Epub 2010 Dec 9. 2011. PMID: 21150860. IF:

2,537Ruiz-Tovar J, Martín-Pérez E, Fernández-Contreras ME,Reguero-Callejas ME, Gamallo-Amat C. Identification ofprognostic factors in pancreatic cancer. Cir Cir 79(4):313-22. 2011. PMID: 21951885. IF: 0,133

Rodríguez-Vigil Junco B, Gómez León N, PinillaFernández I, del Campo L, Hernández Maraver D,Coya J. Non-Hodgkin's lymphoma staging: a prospec-tive study of the value of positron emission tomogra-phy/computed tomography (PET/CT) versus PET andCT. Med Clin (Barc). 137(9): 383-9. Epub 2011 Jun 23.2011. PMID: 21703647. IF: 1,413

C. Taxonera, J. Estellés, I. Fernandez-Blanco, O.Merino, I. Marín-Jimenez, M. Barreiro, C. Saro, V.García, S. García-Morán, G. Bastida, JP. Gisbert, I.Vera, M. P. Martinez, Sara Garcia Morán, MD, MaríaChaparro, MD, J. L. Mendoza. Adalimumab inductionand maintenance therapy for ulcerative colitis patientspreviously treated with Infliximab. Aliment PharmacolTher 33 (3): 340-348. 2011. PMID: 21133961. IF:3,861

Gisbert JP, Chaparro M, Gomollón F. Common mis-conceptions about 5-aminosalicylates and thiop-urines in inflammatory bowel disease. World JGastroenterol 17(30): 3467-3478. 2011. PMID:21941413. IF: 2,24

MA Montoro, S Santolaria, B Sánchez Puértolas, J Vera,L Bujanda, A Cosme, JL Cabriada, M. Durán, L Mata, ASantamaría, G Ceña, JM Blas, J Ponce, M Ponce, LRodrigo, J. Fernandez Sordo, C Muñoz, G. Arozena, DGinard, A López-Serrano, M Castro, M Sans, R. Campo,A. Casalots, V Orive, A. Loizate, L Titó, E Portabella, POtazua, M. Calvo, MT Botella, C Thomson, JL Mundi, EQuintero, D Nicolás, F Borda, B Martinez, JP Gisbert, MChaparro, A Jimenez Bernadó, F Gómez-Camacho, ACerezo, E. Casal Nuñez, Workgroup for the Study ofIschaemic Colitis of the Spanish GastroenterologicalAssociation (GTECIE-AEG). Clinical patterns, and out-comes of ischemic colitis: Results of the Working Groupfor the Study of Ischemic Colitis in Spain (CIE study).Scand J Gastroenterol 46 (2): 236-246. 2011. PMID:20961178. IF: 1,966

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M Chaparro, J Panes, V García, M Mañosa, M Esteve,O Merino, JL Cabriada, MA Montoro, JL Mendoza, PNos, A Gutierrez, F Gomollón, JP Gisbert. Long-termdurability of infliximab treatment in crohn’s disease andefficacy of dose “escalation” in patients loosingresponse. J Clin Gastroenterol 45 (2): 113-118. 2011.PMID: 21242747. IF: 2,752

JP Gisbert, M Chaparro, M Esteve. Review article:Prevention and management of hepatitis B and Cinfection in patients with inflammatory bowel disease.Aliment Pharmacol Ther 33(6): 619-633. 2011. PMID:21416659. IF: 3,861

M Chaparro, JP Gisbert. Successful use of infliximabfor perianal Crohn’s disease in pregnancy. InflammBowel Dis 17(3): 868-869. 2011. PMID: 20564533. IF:4,613

Chaparro M, Gisbert JP. Transplacental transfer ofimmunosuppressants and biologics used for the treat-ment of inflammatory bowel disease. Curr PharmBiotechnol 12(5): 765-773. 2011. PMID: 21342120. IF:3,455

Guerra I, Chaparro M, Bermejo F, Gisbert JP. Utility ofmeasuring serum concentrations of anti-TNF agentsand anti-drug antibodies in inflammatory bowel dis-ease. Curr Drug Metab 12(6): 594-598. 2011. PMID:21495977. IF: 3,896

A. Zapatero, C. Martin Vidales, R. Arellano, Y. Ibañez,O. Liñan, G. Bocardo, M. Rabadan, M. Perez, F.Garcia-Vicente, C. Olivier. Long-term Results of TwoSequential Bladder-sparing Trimodality Approaches forInvasive Bladder Cancer: Neoadjuvant Chemotherapyor Concomitant Radio-chemotherapy. Int J RadiatOncol Biol Phys 81(2-Supp): S71-S72. 2011. PMID: .IF: 4,503

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCO

Estudio multicéntrico fase II de distribución aleatoria,para evaluar la eficacia de tratamiento neoadyuvanteselectivo según subtipo imnunohisto-químico encáncer de mama HER2 negativo; (versión 1: 08-08-06). GEICAM/2006-03EudraCT: 2006-004510-41

PRINCIPAL INVESTIGATOR: ULPIANO JIMENEZBERLANAEstudio de fase III, multicéntrico, randomizado, doble-ciego, para investigar la eficacia y seguridad de laadministración oral de BIBF 1120 junto con docetaxelcomo terapia estándar comparado con placebo juntocon docetaxel como terapia estándar en pacientes concáncer de pulmón nomicrocítico en estadio IIIB/IV orecurrente después del fracaso de la quimioterapia deprimera línea; (versión: 01-07-08). 1199.13EudraCT: 2007-004803-36

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOHERA: Estudio multicéntrico randomizado, de tres bra-zos, comparando la administración de Herceptindurante uno y durante dos años versus la no adminis-tración de Herceptin en mujeres con cáncer de mamaprimario HER2-positivo que han completado laquimioterapia adyuvante. (Versión en castellano 17-7-01). BO16348/BIGO101EudraCT: 2005-002385-11

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEnsayo clínico fase IV.III randomizado en el que seevalúa la fiabilidad predictiva de un test basado en laexpresión de un determinado pérfil genético (chipgenético), para seleccionar la quimioterapia neoadyu-vantebasada en taxanos y/o antraciclinas en pacientescon cáncer de mama en estadios I-III; (versión final enespañol: 17-01-05). GEICAM/2004-04EudraCT: 2005-000403-33

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio de fase III abierto, randomizado de tratamientointermitente con capecitabina oral en combinación conoxaliplatino intravenoso frente a fluorouracilo/leucovorina


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como tratamiento adyuvante para pacientes tratados concirugía para carcinoma de colon en estadio III AJCC/UICC(Estadio C de Dukes). NO16968

PRINCIPAL INVESTIGATOR: OLGA DONNAY CANDILEnsayo clínico fase III randomizado para evaluar el valorpronóstico del estado mutacional del gen K-RAS enpacientes con cáncer colorrectal metastásico estadioIV no previamente tratados; (versión A: 15-12-10).ML25686EudraCT: 2010-024569-34

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEnsayo clínico multicéntrico fase III randomizado com-parando 6 ciclos de regimen FAC (flurouracilo, doxoru-bicina, ciclofosfamida) con 4 ciclos de régimen FACseguido de 8 administraciones de Taxol semanal enrégimen secuencial, como tratamiento coadyuvante enpacientes con cáncer de mama operado y sinafectación axilar (versión 23-6-03, hoja de informaciónversión 1, 21-7-03). GEICAM 2003-02EudraCT: 2005-003109-10PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEnsayo clínico de fase II de cisplatino y trastuzumab(herceptin®) en el tratamiento de primera línea delcáncer gástrico avanzado con sobreexpresión de c-erbB-2; (versión: 26-05-03). GASTROHER2EudraCT: NA

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEnsayo clínico multicéntrico fase III, randomizado para lacomparación de la combinación de epirubicina y ciclofos-famida (EC) seguido de docetaxel (T) con epirubicina ydocetaxel (ET) seguido de capecitabina (X) en el tratamien-to adyuvante de pacientes con cáncer de mama operabley ganglios linfáticos axilares positivos (versión 1-10-03,hoja de información 12-1-04). GEICAM/2003-10EudraCT: NA

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio fase II abierto no aleatorizado de eficacia yseguridad de tarceva (Erlotinib) en monoterapia para

pacientes con carcinoma no microcítico de pulmón(CNMP) avanzado; (versión: 04-12-03; hoja de infor-mación al paciente: 20-11-03, adaptada al CEIC-R:10-05-04). ML17915

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEnsayo fase II, de la administración secuencial de lascombinaciones gemcitabina-cisplatino y carboplatino-paclitaxel en el tratamiento de pacientes con carcino-ma de ovario con citorreducción subóptima; (versión:13-02-04). B9E-XM-0421EudraCT: 2004-002473-23

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio aleatorizado, multicéntrico, fase III, para estu-diar la eficacia y seguridad de bevacizumab solo o encombinación con capecitabina y oxa-liplatino, comoterapia de mantenimiento, tras tratamiento inicial dequimioterapia con capecitabina, oxaliplatino y beva-cizumab en pacientes con adenocarcinoma colorrectalmetastásico; (versión final: 15-07-05). TTD-05-02EudraCT: 2005-003325-67

PRINCIPAL INVESTIGATOR: ULPIANO JIMENEZBERLANAEstudio aleatorizado de quimioterapia adyuvante indi-vidualizada según los niveles de ARNm de BRCA1 enpacientes con cáncer de pulmón no microcítico (esta-dios II-IIIA); (versión final: 12-01-07). GECP-SCATEudraCT: 2007-000067-15

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio fase IV.III multicéntrico, abierto, de asignaciónaleatoria de tratamiento, para evaluar la eficacia de ter-apia de mantenimiento con capecitabina (X) trasquimioterapia adyuvante estándar en pacientes concáncer de mama operable, receptores hormonales yHER2neu Negativos; (versión final 3: 10-06-05). CIBO-MA/2004-01EudraCT: 2005-002838-36


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Estudio fase III aleatorizado, multicéntrico, abierto deLapatinib, tras-tuzumab, la administración secuencial deambos y la administración combinada de ambos comotratamiento adyuvante en pacientes con cáncer de mamaHER2/ErbB2 positivo; (versión 01: 05-02-07). EGF106708EudraCT: 2006-000562-36

PRINCIPAL INVESTIGATOR: ULPIANO JIMENEZBERLANAEstudio fase III, multicéntrico, abierto, randomizado detratamiento conerlotinib (Tarceva®) versus quimioter-apia en pacientes con carcinoma no microcítico de pul-món avanzado que presentan mutaciones en eldominio tirosina quinasa (TK) del receptor del factor decrecimiento epidérmico (EGFR); (versión B: 22-12-06);(Modificación 4: 01-06-07). GECP06/01EudraCT: 2006-003568-73

PRINCIPAL INVESTIGATOR: ULPIANO JIMENEZBERLANAEstudio fase III, internacional, doble ciego, randomiza-do, de grupos paralelos y multicéntrico para evaluar laeficacia de ZD6474(ZACTIMA TM) más los cuidadosde soporte óptimos versus placebo más los cuidadosde soporte óptimos en pacientes con cáncer nomicrocítico de pulmón (CPNM) localmente avanzado ometastásico (Estadio IIIB-IV) después de la terapia conel inhibidor de la tirosin quinasa del receptor del factorde crecimiento epidérmico (EGFR TKI); (versión 1: 10-05-07), (Modificación nº2: Incorporación de 4 nuevoscentros). D4200C00044EudraCT: 2006-002384-12

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio multicéntrico fase II de distribución aleatoria,para comparar el tratamiento de epirubicina y ciclofos-famida seguido de docetaxel y trastuzumab versusepirubicina y ciclofosfamida seguido de docetaxel ylapatinib en mujeres con cáncer de mama primarioresecable o localmente avanzado HER 2 positivo; (ver-sión 1: 08-05-08). GEICAM/2006-14EudraCT: 2007-007031-13

PRINCIPAL INVESTIGATOR: OLGA DONNAY CANDILEstudio de fase III randomizado, abierto del Intergroup:

Efecto de la adición de bevacizumab a quimioterapia(QT) basada en fluoropirimidinas como tratamiento ensegunda línea de pacientes con cáncer colorrectalmetastático que han manifestado progresión de laenfermedad durante un tratamiento de combinacióncon QT estándar/bevacizumab en primera línea; (ver-sión A: 11-06-08). ML18147EudraCT: 2006-004634-32

PRINCIPAL INVESTIGATOR: MARIA DEL MAR PEREZPEREZEstudio multicéntrico, observacional retrospectivo paraevaluar la efectividad y seguridad del tratamiento deprimera línea con Avastin® mantenido hasta la progre-sión de la enfermedad, en pacientes con cáncer col-orectal metastásico. Estudio AVAMAX; (versión final:21-10-08). AVAMAX

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOTratamiento adyuvante con FOLFOX-4 versus FOL-FOX-4 + cetuximab para el cáncer de colón en estadioIII extirpado completamente; (versión 8.022: 16-11-05).PETACC8EudraCT: 2005-003463-23

PRINCIPAL INVESTIGATOR: OLGA DONNAY CANDILRed temática de investigación cooperativa en cáncer(RTICC): Programa de investigación translacional.Plataforma de Servicio de determinación de célulastumorales circulantes en cáncer colorrectal estadio III;(versión1.0: 26-12-08). RTICC-CTC-08

PRINCIPAL INVESTIGATOR: MARIA DEL MAR PEREZPEREZEnsayo fase 3, aleatorizado, doble ciego, multicén-trico para comparar Orteronel (TAK-700) másprednisona frente a placebo más prednisona enpacientes con cáncer de próstata metastásicoresistente a la castración no tratados previamentecon quimioterapia; (versión original: 21-07-10).C21004EudraCT: 2010-018661-35



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Estudio observacional, transversal, multicéntricodescriptivo del perfil clínico de pacientes que debutancon carcinoma de mama mestastásico HER2+ o biendesarrollan una metástasis después o durante eltratamiento adyuvante (PrimHER); (versión final: 14-03-11). ACI-CMM-2010-01

PRINCIPAL INVESTIGATOR: OLGA DONNAY CANDILEnsayo fase IIb randomizado para evaluar la eficacia deGemcitabina-Erlotinib vs Gemcitabina-Erlotinib-Capecitabina en pacientes con cáncer de páncreasmetastásico. Título abreviado GECA; (versión final:02-09-10). TTD-10-01EudraCT: 2010-022599-30

PRINCIPAL INVESTIGATOR: OLGA DONNAY CANDILTratamiento selectivo en cáncer colorrectal: selección decapecitabina o5-fluorouracilo para ser combinados conoxaliplatino o irinotecan como quimioterapia en combi-nación con bevacizumab en primera línea en cáncer col-orectal avanzado; (versión 1.0: 18-05-09). TTD-09-01EudraCT: 2009-012562-31

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio de fase 3, aleatorizado y doble ciego deIMC-1121B y el mejor tratamiento complemen-tario (MTC) en comparación con placebo y MTC enel tratamiento del adenocarcinoma metastásicogástrico o de la unión gastro-esofágica después dela progresión de la enfermedad con terapia combi-nada en primera línea que contenga platino o fluo-ropirimidina; (versión 4:01-07-09). IMCL_CP12-0715EudraCT: 2008-005964-15

PRINCIPAL INVESTIGATOR: YOLANDA DELGADOJIMENEZEstudio de validación de un cuestionario para valorar elgrado de estigmatización del paciente con psoriasis enpoblación española; (Versión 2: 23-3-11). SCI-SPAI-2011-02

PRINCIPAL INVESTIGATOR: CECILIO SANTANDERImpedanciometría intraluminal multicanal esofágicaestacionaria; (versión 3: 17-12-09). IIME

PRINCIPAL INVESTIGATOR: ULPIANO JIMENEZBERLANAEstudio aleatorizado fase III multicéntrico para evalu-ar el tratamiento individualizado valorando BRCA1 enpacientes con cáncer de pulmón no microcíticoavanzado. BREC study (BRCA1 expresión cus-tomization); (versión 1: 30-07-07). GECP-BRECEudraCT: 2007-004278-20

PRINCIPAL INVESTIGATOR: ULPIANO JIMENEZBERLANAEstudio REASON: estudio epidemiológico para laevaluación del estado mutacional en pacientes concáncer de pulmón no células pequeñas avanzado ometastásico (estadio IIIB o IV) recién diagnosticado;(Versión 2:19-01-10). NIS-OES-DUM-2009/1

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio traslacional prospectivo de determinación defactores predictivos de eficacia y toxicidad enpacientes con cáncer; (versión 1.3: septiembre2010). SEOM-1001

PRINCIPAL INVESTIGATOR: ANA-ISABEL BALLES-TEROS GARCIAEstudio europeo sobre el dolor neuropático oncológi-co (EUROPECAN); (versión modificado: 20-05-10).A0081248

PRINCIPAL INVESTIGATOR: MARIA DEL MARPEREZ PEREZEnsayo fase 3, aleatorizado, doble ciego, multicéntri-co para comparar orteronel (TAK-700) más pred-nisona frente a placebo más prednisona enpacientes con cáncer de próstata metastásicoresistente a la castración que ha progresado duranteo después de un tratamiento basado en docetaxel;(versión original: 21-07-10). C21005EudraCT: 2010-018662-23

PRINCIPAL INVESTIGATOR: ULPIANO JIMENEZBERLANAEstudio farmacogenómico para explorar la relaciónentre marcadores angiogénicos y la respuesta altratamiento con carboplatino, paclitaxel y bevacizumab

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en primera línea de cáncer de pulmón no microcíticoavanzado con histología no escamosa (Angiomet);(versión 1: 30-03-10). GEC-BEV-2010-01

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOVariabilidad de la práctica clínica en el manejo delpaciente con carcinoma colorrectal metastático(CCRm) KRAS nativo en tratamiento de primera líneacon cetuximab en España; Estudio Epitex; (versiónfinal: 16-06-10). MER-CET-2010-01

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio postautorización de tipo observacional trans-versal para evaluar la influencia de determinados fac-tores pronósticos en la elección del tratamientoquimioterápico asociado a bevacizumab en eltratamiento de primera línea del cáncer de mamametastásico en la práctica clínica habitual; (versiónfinal: 10-05-10). ONC-BEV-2010-01

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio en fase II de everolimus, un inhibidor mTOR(de formulación oral) junto con octeotride LAR® enpacientes adultos con tumores neuroendocrinosgastrointestinales avanzados, no funcionales y biendiferenciados (TNE GI); (versión 1.0: 11-10-10).ESTUDIO EVERLAR. GETNE1003EudraCT: 2010-023422-20

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio global para evaluar la adición de bevacizumaba carboplatino y paclitaxel como tratamiento enprimera línea del cáncer epitelial de ovario, carcinomade trompas de Falopio o carcinoma peritoneal primario(versión 1.0: 27-07-10). Estudio ROSIA. MO22923EudraCT: 2010-019525-34

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio multicéntrico, observacional posautorizacióntransversal, para conocer los esquemas detratamiento de pacientes con carcinoma de mama

de tamaño tumoral igual o menor de 1,5 cm quereciben un tratamiento anti-Her2 en adyuvancia contrastuzumab; (versión 1: 11-11-10). CHU-TRA-2010-01-SMALLHER

PRINCIPAL INVESTIGATOR: ANA-ISABEL BALLES-TEROS GARCIAEstudio multicéntrico, randomizado, cruzado, paraevaluar la preferencia de las pacientes y la satisfac-ción de los profesionales sanitarios (PS) con laadministración subcutánea (SC) de trastuzumab encáncer de mama precoz (CMP) HER2-positivo; (ver-sión 1.0:30-05-11). MO22982EudraCT: 2010-024099-25

PRINCIPAL INVESTIGATOR: AMALIA VELASCO-ORTIZ DE TARANCOEstudio en fase 2 aleatorizado y doble ciego deAxitinib (AG-013736) con o sin ajuste de la dosis enpacientes con carcinoma de células renalesmetastásico; (versión final: 03-11-08). A4061046EudraCT: 2008-007786-23

PRINCIPAL INVESTIGATOR: CECILIO SANTANDERSintomas de enfermedad por reflujo gastroesofágico(ERGE): clasificación de sujetos adultos que padecensíntomas típicos de ERGE y descripción de los per-files de síntomas más frecuentes y sus característi-cas-estudio observacional europeo; (Versión final:28-01-2010). JAN-ERG-2010-01

GROUP ASSOCIATED 2

HEAD OF LABORATORYCarlos Manuel Olivier Gómez

GROUP MEMBERS• Gloria Bocardo Fajardo• Ricardo Brime Menéndez• Guillermo Celada Luis• Victoria Diego García• Estefanía Romero Selas


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RESEARCH INTEREST

Our group focused on three different researchareas. Prostate cancer(PC): We analyzed the rela-tionship between circulating tumor cells (CTC) levelsand different parameters (PSA levels, Gleason scoreand TNM staging) in patients with metastatic hor-mone-sensitive PC and established the prognosticvalue in the overall and progression-free survival.The risk of mortality and progression with ≥ 4 CTCwere 4.1 (IC 95 %: 1.1-14.6; P = 0.029) and 8.5 (IC95 %: 2.6-26.9; P < 0.001) times higher. Theimmunomagnetic test allows us to quantify the CTCin peripheral blood and could provide a possibilityfor correctly staging and estimate the prognosticvalue of the metastatic hormone-sensitive PC.Bladder cancer (BC): We establish a proteinexpression pattern of high risk progression superfi-cial BC. It may be an instrument to discern theappropriate candidates for more aggressive treat-ments. By using a 2DElectrophoresis, MassSpectrometry and silver staining for protein visuali-zation we analyzed cytoskeleton, apoptosis andcellular metabolism related proteins. Cytoskeletonrelated proteins show differences between invasiveBC (IBC) and non invasive BC (NIBC) versus thecontrol. Proteins related with apoptosis are signifi-cantly increased in NIBC vs IBC group. ErectileDysfunction (ED): We determined changes in theplasma proteome of proteins associated withinflammation and atherogenesis in diabetic patientswith ED after vardenafil administration. The treat-ment significantly reduced circulating plasma levelsof different biomarkers mainly associated withinflammation and atherogenesis. These results maysuggest that vardenafil plays an anti-inflammatoryand protective effect on atherogenesis in diabeticpatients with ED.


A. Zapatero, C. Martin Vidales, R. Arellano, Y. Ibañez,O. Liñan, G. Bocardo, M. Rabadan, M. Perez, F.Garcia-Vicente, C. Olivier. Long-term Results of Two

Sequential Bladder-sparing Trimodality Approaches forInvasive Bladder Cancer: Neoadjuvant Chemotherapyor Concomitant Radio-chemotherapy. Int J RadiatOncol Biol Phys 81(2-Supp): S71-S72. 2011. PMID: .IF: 4,503

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: CARLOS OLIVIERGOMEZEstudio observacional para determinar la presencia eincidencia de células tumorales circulantes (CTCs) yexplorar su valor predictor en una cohorte de pacientesrecién diagnosticados de cáncer de próstata hormono-sensible o renal con metástasis óseas; (Versión 1.0:14-10-2009). CZOL446EES21/ESTUDIO ZIRTUS

PRINCIPAL INVESTIGATOR: CARLOS OLIVIERGOMEZEnsayo clínico, fase IIIb, multicéntrico, doble ciego, paraevaluar la eficacia de vardenafilo bucodispersable vsplacebo, en pacientes con disfunción eréctil mas comor-bilidad y el impacto en la calidad de vida sexual de supareja; (versión 2.0: 03-02-10). URO-VAR-2010-01EudraCT: 2009-017686-34

PRINCIPAL INVESTIGATOR: RICARDO BRIMEMENENDEZEstudio para valorar el impacto del tratamiento de blo-queo androgénico en la incidencia de alteracionesmetabólicas en pacientes con cáncer de próstata; (ver-sión 1: 22-09-10). NIS-OES-DUM-2010/1

GROUP ASSOCIATED 3

GROUP MEMBERS• Enrique Alday Muñoz• Vicente Casa de Pantoja• Francisco Clement Fernández• José Cordero Ampuero• Antonio Gómez Pan

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• Javier Izaguirre Anduaga• Emilio Marín Aráez• Concepción Pérez Hernández• Fernando Teba del Pino

CLINICAL TRIALS

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio multicéntrico de un brazo, abierto, de laadministración repetida de QUTENZA® para eltratamiento del dolor neuropático periférico; (ver-sión final 1.1: 10-05-10). E05-CL-3001EudraCT: 2009-016457-18

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio epidemiológico, observacional, prospecti-vo, para evaluar la relación entre los recursos uti-lizados en el cuidado de los pacientes atendidos enlas unidades de dolor, y su grado de satisfacción(versión final-E1: 29-06-11). SATEN

PRINCIPAL INVESTIGATOR: EMILIO MARIN ARAEZEmpleo de la telemedicina para una correcta apli-cación de las guías de práctica clínica en eltratamiento betabloqueante de la insuficiencia car-diaca crónica. Ensayo controlado. FIS06-90166

PRINCIPAL INVESTIGATOR: VICENTE J. CASA DEPANTOJAEstudio en fase 2 aleatorizado, controlado, abierto(ciego para la dosis), multicéntrico, de búsqueda dedosis de seguridad y eficacia de I-0401 en eltratamiento de pacientes con fractura de mesetatibial que requieran injerto; (versión final: 15-11-06).CS I-040101/02EudraCT: 2006-003688-30

PRINCIPAL INVESTIGATOR: ANTONIO GOMEZ-PANEvaluación de los factores predictivos de controlhormonal bajo tratamiento con análogos de lasomatostatina en pacientes acromegálicos con per-

sistencia de enfermedad tras cirugía; (versión 3: 29-01-07)

PRINCIPAL INVESTIGATOR: FRANCISCOCLEMENT FERNANDEZEnsayo clínico, aleatorizado, controlado dobleciego, multicéntrico para evaluar la eficacia yseguridad del bevacizumab (Avastin,Genentech,Inc) versus ranibizumab (lucentis,Genentech, Inc) intravítreos en la degeneraciónmacular asociada a la edad; (versión final 1.0: 30-10-07). FIG-DMAEEudraCT: 2007-006093-28

PRINCIPAL INVESTIGATOR: EMILIO MARIN ARAEZEstudio multicéntrico, aleatorizado, doble ciego ycontrolado con placebo, para evaluar la seguridad yeficacia de SCH 530348 añadido al tratamientoestándar, en sujetos con antecedentes de enfer-medad aterosclerótica: Antagonista del receptor detrombina en prevención secundaria de episodiosisquémicos aterotrombóticos (TRA 2§P-TIMI-50);(versión final: 31-05-07). P04737EudraCT: 2006-002942-12

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio europeo, multicéntrico, abierto, del doloroncológico irruptivo: Evaluación del ajuste de ladosis y del tratamiento con comprimidos bucalesde fentanilo en pacientes que están recibiendo opi-oides; (versión: 23-04-08). C25608/4027/BP/EUEudraCT: 2008-001841-24

PRINCIPAL INVESTIGATOR: FRANCISCOCLEMENT FERNANDEZEnsayo clínico de fase II, controlado, abierto aleatoriza-do y multicéntrico, para comparar la eficacia y laseguridad de ranibizumab (inyección intravítrea) frentea fotocoagulación láser en pacientes con alteraciónvisual secundaria a edema macular diabético; (versión2.0: 20-02-2009). CRFB002DES01EudraCT: 2009-010825-37

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZ


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Estudio multicéntrico, aleatorizado, doble ciego,controlado con placebo para evaluar la eficacia,seguridad y tolerabilidad de JNJ-42160443 enpacientes con neuralgia postherpética y neuralgiapostraumática, seguido de un período de extensióndoble ciego de seguridad y una extensión abiertade seguridad; (versión final INT3: 29-05-09).42160443-NPP-2001EudraCT: 2008-007478-39

PRINCIPAL INVESTIGATOR: JAVIER IZAGUIRREANDUAGASeguridad y eficacia de exenatida semanal frente aliraglutida, en pacientes con diabetes tipo 2 y con-trol glucémico inadecuado, tratados con modifica-ciones del estilo de vida y antidiabéticos orales;(versión:02-09-09). H8O-MC-GWDEEudraCT: 2009-012011-17

PRINCIPAL INVESTIGATOR: EMILIO MARIN ARAEZEstudio multicéntrico, doble ciego y aleatorizadopara establecer la seguridad y los efectos clínicosbeneficiosos de vytorin (comprimido de ezetimi-ba/simvastatina) frente a simvastatina en monoter-apia en sujetos que presentan un síndrome coro-nario agudo de alto riesgo (Improved Reduction ofOutcomes: Vytorin Efficacy International Trial-Improve IT, Reducción mejorada de los resultados:ensayo internacional sobre la eficacia de vytorin-IMPROVE IT); (versión final: 06-05-05). P04103EudraCT: 2005-001059-39

PRINCIPAL INVESTIGATOR: VICENTE J. CASA DEPANTOJAEstudio XAMOS: "Rivaroxaban para la prevencióndel tromboembolismo venoso posquirúrgicodespués de una cirugía mayor programada decadera o de rodilla"; (versión 1: 14-04-09). BAY-RIV-2009-01

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio epidemiológico, observacional, prospecti-vo, para evaluar la prevalencia de dolor neuropáticoy el valor diagnóstico de las diferentes escalas dedolor neuropático en pacientes oncológicos con

quimioterapia activa; (Versión final: 29-03-10).ONPST

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio para determinar la prevalencia de DolorNeuropático en Unidades de Dolor de España; (ver-sión final, 30-09-10). SP-GRT-EPI-1002

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEvaluación de la efectividad, seguridad y tolerabili-dad de tapentadol de liberación prolongada frente auna combinación de tapentadol de liberación pro-longada y pregabalina en pacientes con lumbalgiacrónica severa con un componente de dolor neu-ropático; (version 3.0: 20-10-10). KF5503/58EudraCT: 2010-019998-14

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio abierto, observacional, prospectivo, paraevaluar los costes y la eficacia del tratamiento deldolor secundario al Síndrome de espalda fallida enpacientes tratados en una Unidad del Dolor; (ver-sión 01-02-11). SEFUDOCE

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio de desarrollo y validación de dos testsadaptativos informatizados para la evaluación deldolor. Estudio QCATS; (versión final: 14-02-11). AS-QCATS-2011-01

PRINCIPAL INVESTIGATOR: FERNANDO TEBA DELPINOEstudio de evaluación de la Vejiga Hiperactiva y laHiperactividad del detrusor en varones conSíntomas del Tracto Urinario Inferior (STUI) de llena-do que acuden a unidades de urología funcional yurodinámica; (versión final: 04-03-11). VH02-11

PRINCIPAL INVESTIGATOR: ENRIQUE ALDAYMUÑOZEstudio exploratorio para comparar la eficacia yseguridad de micafungina como tratamiento

AREA 3

AREA

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anticipado de la candidiasis invasiva frente aplacebo en pacientes de alto riesgo quirúrgico -Estudio doble ciego, multicéntrico aleatorizado defase II INTENSE; (Versión 1.0: 03-11-09). 9463-EC-0002EudraCT: 2008-006409-18

PRINCIPAL INVESTIGATOR: CONCEPCION PEREZHERNANDEZEstudio transversal para evaluar la frecuencia, lascaracterísticas y el impacto del dolor irruptivo en elpaciente onocológico; (versión 2: 24-11-09). EPI-DOL-09


Cordero-Ampuero J, Darder A, Santillana J, CalotoMT, Nocea G. Evaluation of patients' and physicians'expectations and attributes of osteoarthritis treatmentusing Kano methodology. Qual Life Res. 2011 Dec 2.[Epub ahead of print]. 2011. PMID: 22134806. IF:1,958

Esteban J, Cordero-Ampuero J. Treatment of pros-thetic osteoarticular infections. Expert OpinPharmacother. 12(6): 899-912. 2011. PMID:21405943. IF: 2,403


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