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32 results on '"Center for Applied Medical Research [Plamplona] (CIMA)"'

1. A machine learning derived echocardiographic algorithm identifies people at risk of heart failure with distinct cardiac structure, function, and response to spironolactone: findings from the HOMAGE trial

Author

Kobayashi, Masatake, Huttin, Olivier, Ferreira, João Pedro, Duarte, Kevin, González, Arantxa, Heymans, Stephane, Verdonschot, Job A.J., Rocca, Hans‐peter Brunner‐la, Pellicori, Pierpaolo, Clark, Andrew, Petutschnigg, Johannes, Edelmann, Frank, Cleland, John, Rossignol, Patrick, Zannad, Faiez, Girerd, Nicolas, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Institute of Health Carlos III, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Glasgow, University of Hull [United Kingdom], Castle Hill Hospital, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), and European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013)

Subjects
collagen, spironolactone, [SDV]Life Sciences [q-bio], biomarkers, Heart failure, Heart failure echocardiogram collagen spironolactone biomarkers, echocardiogram
Abstract

International audience; Background: An echocardiographic algorithm derived by machine learning (e'VM) characterizes preclinical individuals with different cardiac structure and function, biomarkers, and long-term risk of heart failure (HF). Our aim was the external validation of the e'VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone.Methods: The HOMAGE (Heart OMics in Aging) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e'VM algorithm was applied to 416 participants (mean age 74±7years, 25% women) with available echocardiographic variables (i.e., e' mean, left ventricular [LV] end-diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e'VM phenotypes.Results: A majority (>80%) had either "diastolic changes (D)", or "diastolic changes with structural remodeling (D/S)" phenotype. D/S phenotype had the highest LVMi, left atrial volume, E/e', natriuretic peptide and troponin levels (all p0.10; Pinteraction

Published
2023

2. Effects of spironolactone on serum markers of fibrosis in people at high risk of developing heart failure

Author

Joseph J Cuthbert, Pierpaolo Pellicori, Johannes Petutschnigg, Franco Cosmi, Blerim Mujaj, João Pedro Ferreira, Fozia Z Ahmed, Nicolas Girerd, Faiez Zannad, Roberto Latini, Timothy Collier, Patrick Rossignol, Beatrice Mariottoni, Jan A. Staessen, John G.F. Cleland, Stephane Heymans, Andrew L. Clark, Job A J Verdonschot, Arantxa González, Hans-Peter Brunner-La Rocca, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Cortona Hospital, Department of Cardiology, Maastricht University Medical Center, Manchester Heart Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, London School of Hygiene and Tropical Medicine (LSHTM), Castle Hill Hospital, Hull York Medical School, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], DZHK (German Center of Cardiovascular Research), Partner Site Berlin, Research Unit Hypertension and Cardiovascular Epidemiology [Louvain, Belgique], Studies Coordinating Centre [Louvain, Belgique], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Queensland University of Technology [Brisbane] (QUT), Maastricht University [Maastricht], Cardiovascular Research Institute [Maastricht], Maastricht University Medical Centre - MUMC [Maastricht, The Netherlands], IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], Dutch Heart Foundation, CVON2016-Early HFPEF, 2015-10, CVON She-PREDICTS, grant 2017-21, Contrat de plan Etat-lorraine and FEDER lorraine, British Heart Foundation Centre of Research Excellence grant number RE/18/6/34217, ERA-Net-CVD project MacroERA, 01KL1706, IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), DE CARVALHO, Philippe, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, and Heart OMics in AGEing - HOMAGE - - EC:FP7:HEALTH2013-02-01 - 2019-01-31 - 305507 - VALID

Subjects
Male, Aging, [SDV]Life Sciences [q-bio], ALDOSTERONE ANTAGONISM, 030204 cardiovascular system & hematology, Spironolactone, Ventricular Function, Left, Coronary artery disease, chemistry.chemical_compound, DOUBLE-BLIND, 0302 clinical medicine, Interquartile range, Natriuretic Peptide, Brain, Clinical endpoint, Natriuretic peptide, Prospective Studies, COLLAGEN TURNOVER, Ejection fraction, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Atrial fibrillation, DIASTOLIC DYSFUNCTION, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], PRESERVED EJECTION FRACTION, BRAIN NATRIURETIC PEPTIDE, Cardiology, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, NT-PROBNP, EXTRACELLULAR-MATRIX TURNOVER, medicine.drug_class, BIOMARKERS, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, Aged, Heart Failure, business.industry, Stroke Volume, Study design, medicine.disease, Fibrosis, Peptide Fragments, Diabetes Mellitus, Type 2, chemistry, HOMAGE, MYOCARDIAL-INFARCTION, Heart failure, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; AIMS:Asymptomatic patients with coronary artery disease (CAD), hypertension and/or type 2 diabetes mellitus (T2DM) are at greater risk of developing heart failure (HF). Fibrosis, leading to myocardial and vascular dysfunction, might be an important pathway of progression. The Heart OMics in AGing (HOMAGE) trial aims to investigate the effects of spironolactone on serum markers of collagen metabolism and on cardiovascular structure and function in people at risk of developing HF and potential interactions with a marker of fibrogenic activity, galectin-3.METHODS AND RESULTS:The HOMAGE trial is a prospective, randomised, open-label, blinded endpoint (PROBE) study comparing spironolactone (up to 50 mg/day) and standard care over 9 months in people with clinical risk factors for developing HF, including hypertension, CAD and T2DM, and elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP, 125 to 1000 ng/L) or B-type natriuretic peptide (BNP, 35 to 280 ng/L). Exclusion criteria included left ventricular ejection fraction

Published
2020

3. Spatio-temporal soil drying in southeastern South America: the importance of effective sampling frequency and observational errors on drydown time scale estimates

Author

Haydee Karszenbaum, M. Salvia, Romina Ruscica, Anna Sörensson, Jan Polcher, Esteban G. Jobbágy, Maria Piles, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Instituto de Astronomía y Física del Espacio [Buenos Aires] (IAFE), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Universidad de Buenos Aires [Buenos Aires] (UBA), Image processing lab, Universitat Valencia, Valencia, Instituto de Matemática Aplicada San Luis (IMASL), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Facultad de Ciencias Físico Matemáticas y Naturales [San Luis], and Universidad Nacional de San Luis [San Luis] (UNSL)-Universidad Nacional de San Luis [San Luis] (UNSL)

Subjects
2. Zero hunger, 010504 meteorology & atmospheric sciences, [SDE.MCG]Environmental Sciences/Global Changes, 0211 other engineering and technologies, 02 engineering and technology, Land cover, 15. Life on land, 01 natural sciences, 13. Climate action, Climatology, General Earth and Planetary Sciences, Environmental science, Drainage, Scale (map), Water content, Soil drying, ComputingMilieux_MISCELLANEOUS, 021101 geological & geomatics engineering, 0105 earth and related environmental sciences
Abstract

The study of the spatio-temporal dynamics of surface soil moisture (SSM) drydowns integrates the soil response to climatic conditions, drainage and land cover and is key to advances in our knowledg...

Published
2020

4. Benefits of representing floodplains in a Land Surface Model: Pantanal simulated with ORCHIDEE CMIP6 version

Author

Jan Polcher, Anthony Schrapffer, Anna Sörensson, Lluis Fita, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Laboratoire de Météorologie Dynamique (UMR 8539) (LMD), Institut national des sciences de l'Univers (INSU - CNRS)-École polytechnique (X)-École des Ponts ParisTech (ENPC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Département des Géosciences - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)

Subjects
Atmospheric Science, geography, geography.geographical_feature_category, 010504 meteorology & atmospheric sciences, Floodplain, Discharge, [SDE.MCG]Environmental Sciences/Global Changes, Floodplains, Wetland, South America, 15. Life on land, 010502 geochemistry & geophysics, 01 natural sciences, Land-atmosphere interaction, Water balance, 13. Climate action, Climatology, Evapotranspiration, Land Surface Models, Environmental science, Common spatial pattern, Precipitation, Water cycle, 0105 earth and related environmental sciences
Abstract

International audience; Tropical floodplains have a significant impact on the regional water cycle and on land-atmosphere interaction but are not always considered in Land Surface Models (LSMs) or in Earth system models. This study evaluates the importance of representing tropical floodplains in an LSM to provide realistic river discharges, evapotranspiration fluxes and other variables crucial for land's interaction with the ocean and atmosphere. Off-line simulations of the world's largest tropical wetland, the Pantanal are conducted with ORCHIDEE, the LSM of IPSL's regional and global Earth system model. We analyse the period 1961-2000, which includes both dry and wet decades. Atmospheric uncertainty is considered through the utilization of three forcing data sets, each one in two versions: the original dataset and a regionally bias adjusted version. The activation of the floodplain module leads to a systematic improvement of intra-annual variability and extremes of river discharge. Temporal evolution and spatial distribution of flooded area are coherent with satellite estimations, although the model, due to the coarse resolution of the topography, underestimates the extent of the area. Considering floodplains in ORCHIDEE enhance the evapotranspiration since it permits the water from the upstream region to evaporate in the plains. This have strong consequences on the water balance and on the spatial pattern of surface fluxes. The simulations allow us to perform a model-guided residual estimation of evapotranspiration through a water balance obtaining an annual evapotranspiration over Pantanal of 1220 mm while precipitation is estimated to be 1250 mm with an uncertainty of 180 mm.

Published
2020

5. Cardiac remodelling - Part 1: From cells and tissues to circulating biomarkers. A review from the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology

Author

Arantxa González, A. Mark Richards, Rudolf A. de Boer, Thomas Thum, Henrike Arfsten, Martin Hülsmann, Inês Falcao‐Pires, Javier Díez, Roger S.Y. Foo, Mark Y. Chan, Alberto Aimo, Chukwuemeka G. Anene‐Nzelu, Magdy Abdelhamid, Stamatis Adamopoulos, Stefan D. Anker, Yuri Belenkov, Tuvia Ben Gal, Alain Cohen‐Solal, Michael Böhm, Ovidiu Chioncel, Victoria Delgado, Michele Emdin, Ewa A. Jankowska, Finn Gustafsson, Loreena Hill, Tiny Jaarsma, James L. Januzzi, Pardeep S. Jhund, Yuri Lopatin, Lars H. Lund, Marco Metra, Davor Milicic, Brenda Moura, Christian Mueller, Wilfried Mullens, Julio Núñez, Massimo F. Piepoli, Amina Rakisheva, Arsen D. Ristić, Patrick Rossignol, Gianluigi Savarese, Carlo G. Tocchetti, Sophie Van Linthout, Maurizio Volterrani, Petar Seferovic, Giuseppe Rosano, Andrew J.S. Coats, Antoni Bayés‐Genís, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Instituto de Salud Carlos III [Madrid] (ISC), Yong Loo Lin School of Medicine [Singapore], National University of Singapore (NUS), University of Otago [Dunedin, Nouvelle-Zélande], University Medical Center Groningen [Groningen] (UMCG), Hannover Medical School [Hannover] (MHH), Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), Medizinische Universität Wien = Medical University of Vienna, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Departments of Cardiology and Cardiac Surgery, and Nephrology, Clínica Universidad de Navarra, Clínica Universidad de Navarra [Pamplona], Scuola Universitaria Superiore Sant'Anna [Pisa] (SSSUP), Fondazione Toscana Gabriele Monasterio, Montreal Heart Institute - Institut de Cardiologie de Montréal, Cairo University - Faculty of Medicine, Onassis Cardiac Surgery Center [Athens] (OCSC), Charité Campus Virchow-Klinikum (CVK), Berlin-Brandenburg Center for Regenerative Medicine [Berlin, Germany] (BCRT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Université d'État Lomonossov de Moscou = Lomonosov Moscow State University (MSU), Cardiology Department, Rabin Medical Center, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Saarland University Hospital (UKS), Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C.C. Iliescu' [Bucharest, Romania], Leiden University Medical Center (LUMC), Wrocław Medical University, Hôpital national = Rigshospitalet [Copenhagen, Denmark] (HNC), Queen's University [Belfast] (QUB), Linköping University (LIU), Massachusetts General Hospital [Boston], Baim Institute for Clinical Research Boston MA, British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow-NHS Greater Glasgow and Clyde, Volgograd State Medical University [Russian Federation] (VSMU), Karolinska University Hospital [Stockholm], Karolinska Institutet [Stockholm], Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Brescia = University of Brescia (UniBs), University of Zagreb, Cardiology Department, Porto Armed Forces Hospital, University Hospital Basel [Basel], Ziekenhuis Oost-Limburg (ZOL), Universitat de València (UV), Hospital Clínico Universitario de Valencia, Cardiology Division, Castelsangiovanni Hospital, Scientific Research Institute of Cardiology and Internal Medicine [Almaty, Kazakhstan], University Clinical Centre of Serbia, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), University of Naples Federico II = Università degli studi di Napoli Federico II, IRCCS Ospedale San Raffaele [Milan, Italy], Serbian Academy of Sciences and Arts (SASA), University of Belgrade [Belgrade], St George’s University Hospitals, University of Warwick [Coventry], Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Universitat Autònoma de Barcelona (UAB), This work was supported by grants from the Spanish Ministry of Science, Innovation and Universities Institute of Health Carlos III (ISCIII) (PI18/01469 and PI21/00946 to A.G., CB16/11/00403 to A.B.-G and CB16/11/00483 to J.D. projects co-funded by the European Regional Development Funds), the European Commission (H2020 CRUCIAL project 2019–848109-2 to A.G.), the European Research Council (ERC CoG 818715 to R.A.d.B., ERC-PoC Megfib to T.T.), the National Medical Research Council of Singapore (NMRC, NMRC/STaR/0022/2014 to A.M.R. and MOH-000280 to M.Y.C.), the Health Research Council of New Zealand (02/152, 08/070, 11/1070), National Heart Foundation of New Zealand, New Zealand Lotteries Grant Board, Foundation for Research, Science and Technology and the Christchurch Heart Institute Trust to A.M.R., the Netherlands Heart Foundation (2017-21, 2017-11, 2018-30, 2020B005) to R.A.d.B., the leDucq Foundation (Cure-PLaN) to R.A.d.B., the Deutsche Forschungsgemeinschaft (KFO311 and TRR267 to T.T., TTR 219 to M.B., and TRR 1470 to S.V.L.), the Karolinska Institutet, the Swedish Research Council (523–2014-2336), the Swedish Heart Lung Foundation (20150557, 20190310), and the Stockholm County Council (20170112, 20190525) to L.H.L., European Project, BOZEC, Erwan, H2020 CRUCIAL project 2019–848109-2 - INCOMING, and Universiteit Leiden

Subjects
Heart Failure, Tissue, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Biomarkers, Cells, Remodeling, Endothelial Cells, Humans, Ventricular Remodeling, Cardiology, Cardiology and Cardiovascular Medicine, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Abstract

International audience; Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non-coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long-term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling.

Published
2022

6. Design and validation of a tunable inertial microfluidic system for the efficient enrichment of circulating tumor cells in blood

Author

Alejandro Rodríguez‐Pena, Estibaliz Armendariz, Alvaro Oyarbide, Xabier Morales, Sergio Ortiz‐Espinosa, Borja Ruiz‐Fernández de Córdoba, Denis Cochonneau, Iñaki Cornago, Dominique Heymann, Josepmaría Argemi, Delia D'Avola, Bruno Sangro, Fernando Lecanda, Ruben Pio, Iván Cortés‐Domínguez, Carlos Ortiz‐de‐Solórzano, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA), Automotive and Mechatronics R&D Foundation (Naitec) [Pamplona, Spain] (AMRDF), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Unité en Sciences Biologiques et Biotechnologies de Nantes - UMR CNRS 6286 (US2B), Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Clinica Universitaria de Navarra, Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), and Heymann, Dominique

Subjects
[SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Cell enrichment, Biomedical Engineering, Pharmaceutical Science, [SDV.CAN]Life Sciences [q-bio]/Cancer, circulating tumor cells, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], cell sorting, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Inertial forces, Liquid biopsy, liquid biopsy, Circulating tumor cells, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, CTC, inertial forces, Cell sorting, cell enrichment, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Biotechnology
Abstract

International audience; The analysis of circulating tumor cells (CTCs) in blood is a powerful noninvasive alternative to conventional tumor biopsy. Inertial-based separation is a promising highthroughput, marker-free sorting strategy for the enrichment and isolation of CTCs. Here, we present and validate a double spiral microfluidic device that efficiently isolates CTCs with a fine-tunable cutoff value of 9 μm and a separation range of 2 μm. We designed the device based on computer simulations that introduce a novel, customized inertial force term, and provide practical fabrication guidelines. We validated the device using calibration beads, which allowed us to refine the simulations and redesign the device. Then we validated the redesigned device using blood samples and a murine model of metastatic breast cancer. Finally, as a proof of principle, we tested the device using peripheral blood from a patient with hepatocellular carcinoma, isolating more than 17 CTCs/ml, with purity/removal values of 96.03% and 99.99% of white blood cell and red blood cells, respectively. These results confirmhighly efficient CTC isolation with a stringent cut-off value and better separationresults than the state of the art.

Published
2021

7. Prevalence and polymorphism of a mussel transmissible cancer in Europe

Author

Guillaume M. Charrière, Maryline Houssin, Maurine Hammel, John J. Welch, Christine Arbiol, Michael J. Metzger, Ismaël Bernard, Nicolas Bierne, Delphine Destoumieux-Garzón, E. A. V. Burioli, Antonio Villalba, Jean-Francois Pepin, Abdellah Benabdelmouna, Alexis Simon, Jean-Baptiste Lamy, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), Interactions Hôtes-Pathogènes-Environnements (IHPE), Université de Perpignan Via Domitia (UPVD)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Universidad de Alcala, Spain, University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), LABÉO, Pôle d’analyses et de recherche de Normandie (LABÉO), Laboratoire Environnement Ressources des Pertuis Charentais (LERPC), LITTORAL (LITTORAL), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Santé, Génétique et Microbiologie des Mollusques (SGMM), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), SAS Eurêka Mer, University of Cambridge [UK] (CAM), Pacific Northwest Research Institute (PNRI), ANR-18-CE35-0009,TRANSCAN,ECOLOGIE ET EVOLUTION DES CANCERS TRANSMISSIBLES(2018), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École pratique des hautes études (EPHE), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Perpignan Via Domitia (UPVD), CBET research group, Dept. of Zoology and Animal Cell Biology, Research Centre for Experimental Marine Biology and Biotechnology PiE and Science and Technology Faculty, University of the Basque Country (UPV/EHU), Sarriena z/g, E-48940 Leioa, Basque Country, Spain, Laboratoire Environnement Ressources des Pertuis Charentais (LER/PC), Santé, Génétique et Microbiologie des Mollusques (IFREMER SG2M), Institut Français de Recherche pour l'Exploitation de la Mer - Atlantique (IFREMER Atlantique), Hammel, Maurine [0000-0001-9937-5678], Simon, Alexis [0000-0002-6176-5045], Burioli, Erika AV [0000-0003-2666-9258], Pépin, Jean-François [0000-0001-8548-8938], Lamy, Jean-Baptiste [0000-0002-6078-0905], Bernard, Ismael [0000-0002-3666-7419], Charrière, Guillaume M [0000-0002-4796-1488], Destoumieux-Garzon, Delphine [0000-0002-8793-9138], Bierne, Nicolas [0000-0003-1856-3197], and Apollo - University of Cambridge Repository

Subjects
0106 biological sciences, Mytilus edulis, genetic chimerism, Single-nucleotide polymorphism, Biology, 010603 evolutionary biology, 01 natural sciences, Genetic analysis, Article, 03 medical and health sciences, Rare Diseases, Dogs, Polymorphism (computer science), Neoplasms, Genotype, disseminated neoplasia, Genetics, Prevalence, 2.1 Biological and endogenous factors, Animals, genetic polymorphism, Aetiology, Allele, Genotyping, Ecology, Evolution, Behavior and Systematics, Cancer, 030304 developmental biology, Mytilus, Evolutionary Biology, 0303 health sciences, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Biological Sciences, biology.organism_classification, Null allele, Mytilus sp, 3. Good health, Europe, mussels, Mytilus sp. mussels, transmissible cancer
Abstract

Transmissible cancers are parasitic malignant cell lineages that have acquired the ability to infect new hosts from the same species, or sometimes related species. First described in dogs and Tasmanian devils, transmissible cancers were later discovered in some marine bivalves affected by a leukaemia-like disease. In Mytilus mussels, two lineages of bivalve transmissible neoplasia (BTN) have been described to date (MtrBTN1 and MtrBTN2), both of which emerged in a Mytilus trossulus founder individual. Here, we performed extensive screening of genetic chimerism, a hallmark of transmissible cancer, by genotyping 106single nucleotide polymorphisms of 5,907 European Mytilus mussels. Genetic analysis allowed us to simultaneously obtain the genotype of hosts - Mytilus edulis, M.galloprovincialis or hybrids - and the genotype of tumours of heavily infected individuals. In addition, a subset of 222 individuals were systematically genotyped and analysed by histology to screen for possible nontransmissible cancers. We detected MtrBTN2 at low prevalence in M. edulis, and also in M.galloprovincialis and hybrids although at a much lower prevalence. No MtrBTN1 or new BTN were found, but eight individuals with nontransmissible neoplasia were observed at a single polluted site on the same sampling date. We observed a diversity of MtrBTN2genotypes that appeared more introgressed or more ancestral than MtrBTN1 and reference healthy M.trossulus individuals. The observed polymorphism is probably due to somatic null alleles caused by structural variations or point mutations in primer-binding sites leading to enhanced detection of the host alleles. Despite low prevalence, two sublineages divergent by 10% fixed somatic null alleles and one nonsynonymous mtCOI (mitochondrial cytochrome oxidase I) substitution are cospreading in the same geographical area, suggesting a complex diversification of MtrBTN2since its emergence and host species shift.

Published
2021

8. Bringing onco?innovation to Europe’s healthcare systems: The potential of biomarker testing, real world evidence, tumour agnostic therapies to empower personalised medicine

Author

Angelo Paradiso, Peter Riegman, Keith Kerr, Marina Chiara Garassino, Denis Horgan, Pierfranco Conte, Beata Jagielska, Frédérique Penault-Llorca, Michael J. Duffy, Elisabetta Munzone, Ettore Capoluongo, Jan P. van Meerbeeck, Vassiliki Fotaki, Denis Querleu, Núria Malats, Jasmina Koeva-Balabanova, Simonetta Buglioni, Giovanni Codacci-Pisanelli, Ivica Belina, Alastair Kent, Isabelle Ray-Coquard, Luis M. Montuenga, Anders Bjartell, Hein Van Poppel, Z. Maravic, Luis Seijo, Chiara Bernini, Fabrizia Galli, Giuseppe Curigliano, Gennaro Ciliberto, Pathology, UAM.Departamento de Química, Horgan, D., Ciliberto, G., Conte, P., Curigliano, G., Seijo, L., Montuenga, L. M., Garassino, M., Penault-llorca, F., Galli, F., Ray-coquard, I., Querleu, D., Riegman, P., Kerr, K., Van Poppel, H., Bjartell, A., Codacci-pisanelli, G., Koeva-balabanova, J., Paradiso, A., Maravic, Z., Fotaki, V., Malats, N., Bernini, C., Buglioni, S., Kent, A., Munzone, E., Belina, I., Van Meerbeeck, J., Duffy, M., Jagielska, B., Capoluongo, E., CIBER Enfermedades Respiratorias (CIBERES), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Léon Bérard [Lyon], Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Università degli studi di Napoli Federico II, and University of Naples Federico II = Università degli studi di Napoli Federico II

Subjects
0301 basic medicine, Cancer Research, Medicina, Universal design, [SDV.CAN]Life Sciences [q-bio]/Cancer, Guidelines, lcsh:RC254-282, biomarkers, cancers, Europe’s Healthcare Systems, HRD, oncogenomics, s Healthcare Systems, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Health care, medicine, Activity-based costing, Innovation, Reimbursement, Cancer, Genetic testing, Europe’s Healthcare System, Science & Technology, medicine.diagnostic_test, business.industry, Biomarker, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Biología y Biomedicina / Biología, 3. Good health, Oncogenomics, 030104 developmental biology, Oncology, Risk analysis (engineering), 030220 oncology & carcinogenesis, Preparedness, and Infrastructure, Biomarker (medicine), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Europe&#8217, Human medicine, Personalized medicine, SDG 9 - Industry, Innovation, and Infrastructure, business, Life Sciences & Biomedicine, SDG 9 - Industry, Biomarkers
Abstract

Simple Summary The increasing number of data supporting use of a personalized approach in cancer treatment, is changing the path of patient's management. In the same time, the availability of technologies should allow patients to receive the best test for the specific individual condition. This is theoretically true, when a specific test is designed for the specific disease condition, while it is difficult to implement in the setting of agnostic therapies. Financial sources availability related to the non homogeneous health systems working in the different countries do not allow for an immediate implementation of the technologies and test commercially available. Future perspectives for targeted oncology include tumor-agnostic drugs, which target a given mutation and could be used in treating cancers from multiple organ types. Therefore, the present paper is aimed to both underline a how much important is this new view and also to sensitize the international bodies that supervise health policies at the decision-making level, with the aim of harmonizing cancer treatment pathways in at least all European countries. Rapid and continuing advances in biomarker testing are not being matched by uptake in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. The potential that genomics has brought to biomarker testing in diagnosis, prediction and research is being realised, pre-eminently in many cancers, but also in an ever-wider range of conditions-notably BRCA1/2 testing in ovarian, breast, pancreatic and prostate cancers. Nevertheless, the implementation of genetic testing in clinical routine setting is still challenging. Development is impeded by country-related heterogeneity, data deficiencies, and lack of policy alignment on standards, approval-and the role of real-world evidence in the process-and reimbursement. The acute nature of the problem is compellingly illustrated by the particular challenges facing the development and use of tumour agnostic therapies, where the gaps in preparedness for taking advantage of this innovative approach to cancer therapy are sharply exposed. Europe should already have in place a guarantee of universal access to a minimum suite of biomarker tests and should be planning for an optimum testing scenario with a wider range of biomarker tests integrated into a more sophisticated health system articulated around personalised medicine. Improving healthcare and winning advantages for Europe's industrial competitiveness and innovation require an appropriate policy framework-starting with an update to outdated recommendations. We show herein the main issues and proposals that emerged during the previous advisory boards organised by the European Alliance for Personalized Medicine which mainly focus on possible scenarios of harmonisation of both oncogenetic testing and management of cancer patients.

Published
2021

9. Spironolactone effect on the blood pressure of patients at risk of developing heart failure: an analysis from the HOMAGE trial

Author

Lutgarde Thijs, Beatrice Mariottoni, Johannes Petutschnigg, Andrew L. Clark, Mamas A. Mamas, Patrick Rossignol, Frank Edelmann, Pierpaolo Pellicori, Timothy Collier, Franco Cosmi, Fozia Z Ahmed, Arantxa González, João Pedro Ferreira, Blerim Mujaj, Mark R. Hazebroek, Joe Cuthbert, Philippe Rouet, Stephane Heymans, Hans-Peter Brunner-La Rocca, Nicolas Girerd, Job A J Verdonschot, Jan A. Staessen, John G.F. Cleland, Faiez Zannad, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), London School of Hygiene and Tropical Medicine (LSHTM), University of Hull [United Kingdom], Castle Hill Hospital, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Keele University [Keele], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Clínica Universidad de Navarra [Pamplona], CIBERCV, Carlos III Institute of Health, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité Campus Virchow-Klinikum (CVK), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), University of Glasgow, Cortona Hospital, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), HOMAGE was funded by a grant from the European Union 7th Framework Programme for Research and Technological Development (HEALTH-F7-305507 HOMAGE (EU FP7 305507 http://www.homage-hf.eu). JPF, PR, NG, FZ are supported by the RHU Fight-HF, a public grant overseen by the French National Research Agency (ANR) as part of the second 'Investissements d’Avenir' program (reference: ANR-15-RHUS-0004), by the French PIA project 'Lorraine Université d’Excellence' (reference: ANR-15-IDEX-04-LUE), Contrat de Plan Etat Lorraine IT2MP and FEDER Lorraine., ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), ANR-15-IDEX-0004,LUE,Isite LUE(2015), European Project: 305507,EC:FP7:HEALTH,FP7-HEALTH-2012-INNOVATION-1,HOMAGE(2013), European Project, Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Freiburg University Medical Center, Hôpital de Rangueil, CHU Toulouse [Toulouse], Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H02 Cardiomyopathy, MUMC+: MA Med Staf Artsass Cardiologie (9), BOZEC, Erwan, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Heart OMics in AGEing - HOMAGE - - EC:FP7:HEALTH2013-02-01 - 2019-01-31 - 305507 - VALID, and Entreprises lorraines, parties prenantes et Développement Durable (FEDER) (Région Lorraine) - INCOMING

Subjects
cardiovascular risk, Male, medicine.medical_specialty, ALDOSTERONISM, hypertension, IMPACT, Developing heart, Blood Pressure, 030204 cardiovascular system & hematology, Spironolactone, Sitting, Coronary artery disease, RESISTANT HYPERTENSION, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Diabetes mellitus, Renin–angiotensin system, medicine, MANAGEMENT, FIBROSIS, Humans, Pharmacology (medical), 030212 general & internal medicine, Prospective Studies, Aged, Mineralocorticoid Receptor Antagonists, Heart Failure, business.industry, R735, medicine.disease, Omics, RC666, R1, PREVENTION, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Blood pressure, spironolactone, chemistry, renin, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, TASK-FORCE
Abstract

Aims Uncontrolled blood pressure (BP) increases the risk of developing heart failure (HF). The effect of spironolactone on BP of patients at risk of developing HF is yet to be determined. To evaluate the effect of spironolactone on the BP of patients at risk for HF and whether renin can predict spironolactone’s effect. Methods and results HOMAGE (Heart OMics in Aging) was a prospective multicentre randomized open-label blinded endpoint (PROBE) trial including 527 patients at risk for developing HF randomly assigned to either spironolactone (25–50 mg/day) or usual care alone for a maximum of 9 months. Sitting BP was assessed at baseline, Months 1 and 9 (or last visit). Analysis of covariance (ANCOVA), mixed effects models, and structural modelling equations was used. The median (percentile25–75) age was 73 (69–79) years, 26% were female, and >75% had history of hypertension. Overall, the baseline BP was 142/78 mmHg. Patients with higher BP were older, more likely to have diabetes and less likely to have coronary artery disease, had greater left ventricular mass (LVM), and left atrial volume (LAV). Compared with usual care, by last visit, spironolactone changed SBP by −10.3 (−13.0 to −7.5) mmHg and DBP by −3.2 (−4.8 to −1.7) mmHg (P Conclusion Spironolactone had a clinically important BP-lowering effect. Spironolactone should be considered for lowering blood pressure in patients who are at risk of developing HF.

Published
2021

10. The hCOMET project: International database comparison of results with the comet assay in human biomonitoring. Baseline frequency of DNA damage and effect of main confounders

Author

Pavel Rossner, Roger W. L. Godschalk, Lada Živković, Gunnar Brunborg, Mahara Valverde, Juliana da Silva, Emilio Rojas, E. S. Kuznetsova, Serena Galati, Palma Lamonaca, Mirta Milić, Ekaterina I. Surikova, Helga Stopper, Bozena Novotna, Ninoslav Djelic, Sabine A. S. Langie, Katarina Volkovova, Pierre Lebailly, Delia Cavallo, Karl-Heinz Wagner, Stefano Bonassi, Monica Neri, Malgorzata Dobrzyńska, Hervé Perdry, Carina Ladeira, Alena Kažimı́rová, Rudolf Stetina, Mojgan Najafzadeh, Diana Anderson, Amaya Azqueta, Semra Sardas, Zdenka Durackova, Paula Rohr, Cristiana Pereira, Bozena Smolkova, Annamaria Buschini, Andrew Collins, Dwi Ramadhani, Anna Safar, Goran Gajski, N. P. Sirota, Idoia Ibero-Baraibar, Avdulla J. Alija, Kirsten B. Holven, Ezgi Eyluel Bangkoglu, Marcello Ceppi, Cristian Del Boˊ, Francesca Marcon, Stine Marie Ulven, Elisa Boutet-Robinet, Inger Ottestad, Biljana Spremo-Potparević, Fisnik Asllani, Annemarie Grindel, Irina A. Goroshinskaya, Maria Dusinska, Zsuzsanna Nemeth, Ricard Marcos, Tania Mandina Cardoso, Lisa Giovannelli, Vanessa Moraes de Andrade, Cinzia Lucia Ursini, Maria João Silva, Massimo Moretti, Magdalena Barancokova, Nurşen Başaran, Monika Dvořáková, Solange Costa, Vesna Dimitrijević Srećković, Susana Pastor, Omar García Lima, Marta Staruchova, Vanessa Valdiglesias, Patrizia Riso, Carlos Hernández, Cristina Andreoli, Blanca Laffon, Alba Hernández, Kristine B. Gutzkow, Carla Costa, Marco Bruzzone, Zuzana Paduchova, Peter Møller, Ela Kadioglu, João Paulo Teixeira, Gudrun Koppen, Pavel Vodicka, Henriqueta Louro, Irene Orlow, Silvia Moretti, Institute for Medical Research and Occupational Health, Ospedale Policlinico San Martino [Genoa], Universidad de Navarra [Pamplona] (UNAV), Center for Applied Medical Research [Plamplona] (CIMA), Norwegian Institute of Public Health [Oslo] (NIPH), School of Nutrition and Translational Research in Metabolism [Maastricht] (NUTRIM), Maastricht University [Maastricht], Flemish Institute for Technological Research (VITO), University of Copenhagen = Københavns Universitet (KU), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), University of Prishtina, University of Bradford, University of Southern Santa Catarina [Florianopolis] (UNISUL), Istituto Superiore di Sanita [Rome], University of Würzburg, Slovak Medical University of Bratislava (SMU), Hacettepe University = Hacettepe Üniversitesi, Contaminants & Stress Cellulaire (ToxAlim-COMICS), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Chemistry, Life Sciences and Environmental Sustainability [Parma], University of Parma = Università degli studi di Parma [Parme, Italie], Istituto Nazionale per l’Assicurazione contro gli Infortuni sul Lavoro [Italian Workers Compensation Authority] (INAIL), Universidade Luterana do Brasil - ULBRA (BRAZIL), Universidade Luterana do Brasil (ULBRA), Department of Food Environmental and Nutritional Sciences, (DeFENS), University of Milan, School of Medecine [Belgrade], University of Belgrade [Belgrade], Faculty of Veterinary Medicine [Belgrade, Serbie], National Institute of Public Health - National Institute of Hygiene [Poland], Comenius University in Bratislava, Centro de Protección e Higiene de las Radiaciones [Cuba] (CPHR), NEUROFARBA Department [Firenze, Italy], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Petrov Research Insitut of Oncology, University of Vienna [Vienna], Universitat Autònoma de Barcelona (UAB), Institute of Health Carlos III, Instituto de Ciencias Básicas y Preclínicas Victoria de Girón, Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Gazi University, Institute Of Theoretical And Experimental Biophysics, Escola Superior de Tecnologia da Saude de Lisboa, Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), University of A Coruña (UDC), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Dept. of Pharmaceutical Sciences, University of Perugia, National center for public health [Hungary], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Czech Academy of Sciences [Prague] (CAS), Memorial Sloane Kettering Cancer Center [New York], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculty of Pharmacy, National Nuclear Energy Agency of Indonesia (BATAN), Instituto de Investigaciones Biomedicas, Universidad Nacional Autónoma de México (UNAM), Istinye University, the Russian Academy of Sciences [Moscow, Russia] (RAS), Slovak Academy of Science [Bratislava] (SAS), Faculty of Military Technology [Brno] (FMT / UoD), University of Defence in Brno (UoD), Centro de Investigacións Científicas Avanzadas (CICA), Institute of Clinical and Experimental Medicine, Norsk Institutt for Luftforskning (NILU), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, and Instituto de Saúde Pública da Universidade do Porto

Subjects
0301 basic medicine, DNA damage, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Environmental Genotoxicity, Population, Biomarkers, Comet assay, Human biomonitoring, Pooled analysis, HOST FACTORS, Computational biology, Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, HUMAN MICRONUCLEUS PROJECT, 0302 clinical medicine, Biomonitoring, Genetics, Humans, education, education.field_of_study, Confounding, Random effects model, 3. Good health, HUMAN-LYMPHOCYTES, Genómica Funcional e Estrutural, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, CELLS, Biomarker (medicine), Genotoxicidade Ambiental, SMOKING, DNA
Abstract

[Abstract] The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations. This article is based upon work from COST Action hCOMET CA15132, supported by COST (European Cooperation in Science and Technology www.cost.eu) - STSM fellowships for Mirta Milić (IMROH, EU 19); IMROH, Zagreb, Croatia, Institute for Medical Research and Occupational Health (IMROH), Zagreb, Croatia, and the Ministry of Science, Education and Sports of the Republic of Croatia (Grant No. 022-0222148-2125) (EU4); Cancer Plan for PestiBG; Grant number: no ENV201401(EU 8, EU9); Italian Ministry of Education, University and Research PRIN 2005, prot. 2005058197 and Cariplo Foundation (Milan, Italy), Rif. Pratica 2007-5810 and Rif. Pratica 2010.2303 (EU 18); Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 2015/17564). (EU19); European Union Integrated Projects New Generis, 6th Framework Programme, Priority 5: Food Quality and Safety; Newborns and Genotoxic Exposure Risks, FOOD-CT-2005-016320 (EU22); ACT project No. 036APy/09 and No. 005DBB/12 (EU 24); FCT-SFRH/BPD/96196/2013, SFRH/BPD/100948/2014, Portugal (EU 26); MZ 2012/8-UKBA-8; VEGA 1/0703/13, APVV 15-0063 (EU30); Xunta de Galicia (XUGA 10605B98; INCITE08PXIB106155PR; ED481B2016/190-0; Grants ED431B2019/02), Spain (EU 32); Grant 01 173034, Ministry of Education, Science and Technological Development of the Republic of Serbia (EU 42); The Centre for Industrial and Technological Development within National Strategic Consortia for Techical Research (Industrial Research diets and food with specific characteristics for elderly, SENIFOOD); University of Navarra LE/97; Physiopathology of Obesity and Nutrition (CIBER Obn); Carlos III Health Research Institute (CB12/03/30002); Ministerio de Economia y Compatitividad (‘Ramón y Cajal’ Programme, RYC-2013-14370) of the Spanish Government for personal support (EU 45); the Ministry of Education, Youth and Sports of the Czech Republic project Healthy Aging in Industrial Environment HAIE (CZ.02.1.01/0.0/0.0/16_019/0000798) which is co-financed by the European Union (European Structural and Investment funds; Operation Programme Research, Development and Education); MYES LO 1508 (EU 46); MICRODIAB Study; ClinicalTrials.org (#NCT02231736) (EU 52); The study was funded by the Italian Ministry for Education, University and Scientific Research (MIUR) - Research No. 2005-062547 (EU14, EU53); Projects financed from Serbian Ministry of Education, Science and Technological Development #11146002, #175035, #173034 (EU 54); Mehr foundation organisation, UK (EU 55); MCTI/CNPQ No. 01/2016-Universal; FAPESC No. 09/2015; MEC/MCTI/CAPES/CNPQ/FAPS/ No. 09/2014, Brazil (CSA 6); the National Nuclear Energy Agency of Indonesia (Badan Tenaga Nuklir Nasional) with contract number 080.01.06 3447.001 001.052.A (AS4); Slovak Grant Agency (APVT-21 013202, APVT-21- 017704); Ministry of Health, Slovak Republic (2005/43-SZU-21, 2006/07- SZU-02 MZ SR, 2005/42-SZU-20

Published
2021

11. COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology

Author

Wilfried Mullens, Dimitrios Farmakis, Tuvia Ben Gal, Gerasimos Filippatos, Tiny Jaarsma, Robin Ray, Ekaterini Lambrinou, Gianluigi Savarese, Carlo G. Tocchetti, Alain Cohen-Solal, Yuri N. Belenkov, Maurizio Volterrani, Stamatis Adamopoulos, Arsen D. Ristić, Brenda Moura, Amina Rakisheva, Arantxa González, Michele Senni, Finn Gustafsson, Antoni Bayes-Genis, Thomas Thum, Ovidiu Chioncel, Marco Metra, Magdy Abdelhamid, Fadi Jouhra, Y M Lopatin, Lars Lund, Giuseppe M.C. Rosano, Sophie Van Linthout, Davor Miličić, Petar M. Seferovic, Piotr Ponikowski, Andrew J.S. Coats, Mitja Lainscak, Massimo F Piepoli, Michael Böhm, Loreena Hill, Stefan D. Anker, Ewa A. Jankowska, Rosano, G, Jankowska, E, Ray, R, Metra, M, Abdelhamid, M, Adamopoulos, S, Anker, S, Bayes-Genis, A, Belenkov, Y, Gal, T, Böhm, M, Chioncel, O, Cohen-Solal, A, Farmakis, D, Filippatos, G, González, A, Gustafsson, F, Hill, L, Jaarsma, T, Jouhra, F, Lainscak, M, Lambrinou, E, Lopatin, Y, Lund, L, Milicic, D, Moura, B, Mullens, W, Piepoli, M, Ponikowski, P, Rakisheva, A, Ristic, A, Savarese, G, Seferovic, P, Senni, M, Thum, T, Tocchetti, C, Van Linthout, S, Volterrani, M, Coats, A, IRCCS San Raffaele [Rome, Italy], Wrocław Medical University, University of London [London], St George’s University Hospitals, Università degli Studi di Brescia = University of Brescia (UniBs), Civic Hospital of Brescia, Cairo University, Onassis Cardiac Surgery Center [Athens] (OCSC), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Berlin Institute of Health (BIH), Université de Barcelonne, Instituto de Salud Carlos III [Madrid] (ISC), Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Sechenov First Moscow State Medical University, Tel Aviv University (TAU), Universität des Saarlandes [Saarbrücken], University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Cyprus [Nicosia] (UCY), National and Kapodistrian University of Athens (NKUA), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), University of Copenhagen = Københavns Universitet (UCPH), Queen's University [Belfast] (QUB), Linköping University (LIU), University of Ljubljana, Cyprus University of Technology, Volgograd State Medical University [Russian Federation] (VSMU), Karolinska University Hospital [Stockholm], University of Zagreb, Universidade do Porto = University of Porto, Hasselt University (UHasselt), Ziekenhuis Oost-Limburg (ZOL), Università degli studi di Parma = University of Parma (UNIPR), Al-Farabi Kazakh National University [Almaty] (KazNU), University of Belgrade [Belgrade], Serbian Academy of Sciences and Arts (SASA), Azienda Ospedaliera Ospedale Papa Giovanni XXIII [Bergamo, Italy], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Fraunhofer Institute for Toxicology and Experimental Medicine (Fraunhofer ITEM), Fraunhofer (Fraunhofer-Gesellschaft), University of Naples Federico II = Università degli studi di Napoli Federico II, German Center for Cardiovascular Research (DZHK), University of Warwick [Coventry], leboeuf, Christophe, Publica, Rosano, G., Jankowska, E. A., Ray, R., Metra, M., Abdelhamid, M., Adamopoulos, S., Anker, S. D., Bayes-Genis, A., Belenkov, Y., Gal, T. B., Bohm, M., Chioncel, O., Cohen-Solal, A., Farmakis, D., Filippatos, G., Gonzalez, A., Gustafsson, F., Hill, L., Jaarsma, T., Jouhra, F., Lainscak, M., Lambrinou, E., Lopatin, Y., Lund, L. H., Milicic, D., Moura, B., Mullens, W., Piepoli, M. F., Ponikowski, P., Rakisheva, A., Ristic, A., Savarese, G., Seferovic, P., Senni, M., Thum, T., Tocchetti, C. G., Van Linthout, S., Volterrani, M., and Coats, A. J. S.

Subjects
medicine.medical_specialty, COVID-19 Vaccines, medicine.medical_treatment, media_common.quotation_subject, Frail Elderly, Frailty syndrome, Cardiology, Heart failure, Disease, Medical and Health Sciences, SARS‐CoV‐2, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, SDG 3 - Good Health and Well-being, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, COVID‐19, Hygiene, medicine, Humans, Intensive care medicine, media_common, Aged, Heart transplantation, HFA position paper, business.industry, SARS-CoV-2, Social distance, Vaccination, COVID-19, Iron Deficiencies, medicine.disease, failure, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Heart Failure, Position paper, Position Paper, Clinical Medicine, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Cardiology and Cardiovascular Medicine, business
Abstract

Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF. This article is protected by copyright. All rights reserved. [Abstract copyright: This article is protected by copyright. All rights reserved.]

Published
2021

12. Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma

Author

Carolina Zandueta, Patrick Couvreur, Fernando Lecanda, Carlos Rodríguez-Nogales, Didier Desmaële, Haritz Moreno, María J. Blanco-Prieto, Institut Galien Paris-Saclay (IGPS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), and Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA)

Subjects
0301 basic medicine, Cancer Research, Pediatric cancer, endocrine system diseases, medicine.medical_treatment, chemotherapy, Metastasis, squalenoyl-gemcitabine, chemistry.chemical_compound, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, Osteosarcoma, Squalenoyl–gemcitabine, [CHIM.ORGA]Chemical Sciences/Organic chemistry, gemcitabine, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Primary tumor, nanomedicine, edelfosine, 3. Good health, pediatric cancer, Nanomedicine, Oncology, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), Edelfosine, medicine.drug, squalenoyl–gemcitabine, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, Article, 03 medical and health sciences, In vivo, osteosarcoma, medicine, Chemotherapy, metastasis, business.industry, medicine.disease, Gemcitabine, 030104 developmental biology, chemistry, Cancer research, business
Abstract

Due to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl&ndash, gemcitabine (SQ&ndash, Gem) to form nanoassemblies (NAs) of 50 nm. SQ&ndash, Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ&ndash, Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ&ndash, Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy.

Published
2020

13. Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint

Author

Jörg Wischhusen, Ignacio Melero, Wolf Herman Fridman, University Hospital of Würzburg, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Clínica Universidad de Navarra [Pamplona], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Gestionnaire, Hal Sorbonne Université, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)

Subjects
0301 basic medicine, Placenta, Macrophage inhibitory cytokine-1 (MIC-1), Myocardial Infarction, Autoimmunity, Review, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mice, 0302 clinical medicine, Neurotrophic factors, Pregnancy, Neoplasms, Glial cell line-derived neurotrophic factor, Immunology and Allergy, Homeostasis, Immune Checkpoint Inhibitors, Tissue homeostasis, Cancer, biology, autoimmunity, Immune exclusion, 3. Good health, Anorexia, growth/differentiation factor-15 (GDF-15), [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, anorexia, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, embryonic structures, Biomarker (medicine), Female, Immunotherapy, immunotherapy, lcsh:Immunologic diseases. Allergy, Growth Differentiation Factor 15, Immunology, Autoimmune Diseases, Immunomodulation, 03 medical and health sciences, immune exclusion, medicine, cancer, Animals, Humans, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, Autoimmune disease, macrophage inhibitory cytokine-1 (MIC-1), Growth/differentiation factor-15 (GDF-15), medicine.disease, Immune checkpoint, 030104 developmental biology, Cancer research, biology.protein, GDF15, lcsh:RC581-607, Biomarkers, 030215 immunology, Transforming growth factor
Abstract

International audience; Growth/differentiation factor-15 (GDF-15), also named macrophage inhibitory cytokine-1, is a divergent member of the transforming growth factor β superfamily. While physiological expression is barely detectable in most somatic tissues in humans, GDF-15 is abundant in placenta. Elsewhere, GDF-15 is often induced under stress conditions, seemingly to maintain cell and tissue homeostasis; however, a moderate increase in GDF-15 blood levels is observed with age. Highly elevated GDF-15 levels are mostly linked to pathological conditions including inflammation, myocardial ischemia, and notably cancer. GDF-15 has thus been widely explored as a biomarker for disease prognosis. Mechanistically, induction of anorexia via the brainstem-restricted GDF-15 receptor GFRAL (glial cell-derived neurotrophic factor [GDNF] family receptor α-like) is well-documented. GDF-15 and GFRAL have thus become attractive targets for metabolic intervention. Still, several GDF-15 mediated effects (including its physiological role in pregnancy) are difficult to explain via the described pathway. Hence, there is a clear need to better understand non-metabolic effects of GDF-15. With particular emphasis on its immunomodulatory potential this review discusses the roles of GDF-15 in pregnancy and in pathological conditions including myocardial infarction, autoimmune disease, and specifically cancer. Importantly, the strong predictive value of GDF-15 as biomarker may plausibly be linked to its immune-regulatory function. The described associations and mechanistic data support the hypothesis that GDF-15 acts as immune checkpoint and is thus an emerging target for cancer immunotherapy.

Published
2020

14. A Role for MMP-10 (Matrix Metalloproteinase-10) in Calcific Aortic Valve Stenosis

Author

Josune Orbe, Jaime Ibarrola, Alicia Gainza, Virginia Alvarez, Victoria Cachofeiro, Carmen Roncal, Guillermo Zalba, Adela Navarro, Lara Matilla, Amaya Fernández-Celis, Jose A. Rodriguez, Rafael Sádaba, Vanessa Arrieta, Amaia Garcia-Peña, Natalia López-Andrés, Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Instituto de Salud Carlos III [Madrid] (ISC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), This work was supported by: Miguel Servet contract CP13/00221 from the 'Instituto de Salud Carlos III-FEDER', Fondo de Investigaciones Sanitarias [PI18/01875], Fondo de Investigaciones Sanitarias [PI18/01195], Departamento de Salud del Gobierno de Navarra (GºNa44/15), Sociedad Española de Cardiología, Sociedad Española de Arteriosclerosis, CIBERCV (CB16/11/00371), Ministerio de Educación y Ciencia (SAF2016-79151R)., European Project: PI18/01875, BOZEC, Erwan, and CP13/00221 - PI18/01875 - INCOMING

Subjects
0301 basic medicine, Aortic valve, Male, 030204 cardiovascular system & hematology, Matrix metalloproteinase, Matrix (biology), calcification, 0302 clinical medicine, Osteogenesis, Mechanisms, Medicine, Prospective Studies, Phosphorylation, Cells, Cultured, Inflammation aortic valve stenosis, Calcinosis, Middle Aged, Up-Regulation, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, Aortic valve stenosis, Aortic Valve, Cardiology, Female, medicine.symptom, Inflammation Mediators, MMP-10, Cardiology and Cardiovascular Medicine, valvular interstitial cells. Word count: 7196, Signal Transduction, Adult, medicine.medical_specialty, Inflammation, Gene Expression and Regulation, Pathophysiology, 03 medical and health sciences, Matrix Metalloproteinase 10, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Humans, Aged, business.industry, Calcific aortic valve stenosis, Aortic Valve Stenosis, medicine.disease, Fibrosis, Stenosis, 030104 developmental biology, inflammation, Case-Control Studies, Valvular Heart Disease, business, Proto-Oncogene Proteins c-akt, Calcification
Abstract

Objective: Aortic valve (AV) calcification plays an important role in the progression of aortic stenosis (AS). MMP-10 (matrix metalloproteinase-10 or stromelysin-2) is involved in vascular calcification in atherosclerosis. We hypothesize that MMP-10 may play a pathophysiological role in calcific AS. Approach and Results: Blood samples (n=112 AS and n=349 controls) and AVs (n=88) from patients undergoing valve replacement were analyzed. Circulating MMP-10 was higher in patients with AS compared with controls ( P S =0.451; P S =0.5045, P S =0.5003, P P Conclusions: MMP-10, which is overexpressed in aortic valve from patients with AS, seems to play a central role in calcification in AS through Akt phosphorylation. MMP-10 could be a new therapeutic target for delaying the progression of aortic valve calcification in AS.

Published
2020

15. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author

Ana Patiño-García, Thomas G. P. Grunewald, David G. Cox, Lindsay M. Morton, Michelle Manning, Sandrine Grossetête-Lalami, Gaëlle Pierron, Nadège Corradini, Stephen J. Chanock, Kathleen Wyatt, Udo Kontny, Gregory T. Armstrong, Jean Michon, Sakina Zaidi, Didier Surdez, Wolfgang Hartmann, Heinrich Kovar, Olivier Delattre, Jennifer Kriebel, Nathalie Gaspar, Perrine Marec Bérard, Valérie Laurence, Casey L. Dagnall, Thomas Kirchner, Stéphanie Reynaud, Uta Dirksen, Nathaniel Rothman, Konstantin Strauch, Margaret A. Tucker, Lisa Mirabello, Smita Bhatia, Markus Metzler, Laurie Burdett, Neal D. Freedman, Rebeca Alba Rubio, Franck Tirode, Andreas E. Kulozik, Meredith Yeager, Kristine Jones, Javier Alonso, Stelly Ballet, Olivier Mirabeau, Eve Lapouble, Robert N. Hoover, Weiyin Zhou, Wendy M. Leisenring, Leslie L. Robison, Piero Picci, Javed Khan, Thomas Meitinger, Anna González-Neira, Eric Karlins, Mitchell J. Machiela, Unión Europea, TIRODE, Franck, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unité de Génétique Somatique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research (FNLCR), Unité de Génétique Somatique [Institut Curie, Paris], Children’s Cancer Research Institute [Vienna, Austria], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany], Genotyping Unit (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Istituto Ortopedico Rizzoli [Bologna, Italy], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Epidemiology and Cancer Control [Memphis, TN, USA], Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA], Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA], University Children's Hospital of Heidelberg [Heidelberg, Germany], Research Unit of Molecular Biology [Neuherberg, Germany], Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Diseases [Neuherberg, Germany] (DZD), Institute of Human Genetics [Neuherberg] (IHG), Helmholtz Zentrum München = German Research Center for Environmental Health, Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen = Uniklinikum Erlangen, Gerhard-Domagk-Institute of Pathology, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Genetic Epidemiology [Neuherberg, Germany], Chair of Genetic Epidemiology [Munich, Germany] (IBE), Institute of Pathology [Munich, Germany], University Children's Hospital of Essen [Essen, Germany], This work was supported by the Intramural Research Program of the U.S. NationalCancer Institute and the Intramural Research Program of the American Cancer Society.This work was supported by grants from the Institut Curie, the Inserm, the LigueNationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs programand Recherche Epidémiologique 2009 program), the ANR-10-EQPX-03 from the AgenceNationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supportedby FP7 grant 'EURO EWING Consortium' No. 602856 and the following associations:Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M lavie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin andthe Société Française de lutte contre les Cancers et les leucémies de l’Enfant et del’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultätder LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellentwithin the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the WilhelmSander-Foundation (2016.167.1), and by the German Cancer Aid (DKH-111886 andDKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). Wethank the following clinicians for providing samples used in this study: C. Alenda, F.Almazán, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Beléndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D.Chauveaux, C. Calvo, A. Carboné, C. Clement, T. Contra, N. Corradini, A.S. Defachelles,V. Gandemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J.L.Fuster, P. García-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O.Lejars, R. López-Almaraz, B. López-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec Bérard,G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G.Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscardó, M. Munzer, B. Narciso, A.Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet,M.I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre,M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L.Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J.J. Uriz, J.P. Vannier, F. Watelle-Pichon. This work was supported by the Instituto de SaludCarlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa deAlex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y OncologíaPediátricas. The Childhood Cancer Survivor Study is supported by the NationalCancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with funding forgenotyping from the Intramural Research Program of the National Institutes ofHealth, National Cancer Institute. The KORA study was initiated and financed by theHelmholtz Zentrum München—German Research Center for Environmental Health,which is funded by the German Federal Ministry of Education and Research (BMBF) andby the State of Bavaria. Furthermore, KORA research was supported within the MunichCenter of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part ofLMUinnovativ, Helmholtz-Zentrum München (HZM), University Hospital Erlangen [Germany], Westfälische Wilhelms-Universität Münster (WWU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Candidate gene, Oncogene Proteins, Fusion, Medizin, General Physics and Astronomy, Genome-wide association study, Cell Cycle Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Science, Genetics, Multidisciplinary, Nuclear Proteins, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quality Control, Risk, Genotype, Science, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Genetic Predisposition to Disease, Allele, Alleles, Cell Proliferation, Homeodomain Proteins, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Zebrafish Proteins, Pediatric cancer, 030104 developmental biology, Expression quantitative trait loci, lcsh:Q, RNA-Binding Protein EWS, Transcription Factors, Genome-Wide Association Study
Abstract

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.

Published
2018

16. The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma: sVEGFR1, lung tumor progression and anti-angiogenics

Author

Jackeline Agorreta, Thibault Jacquet, Cherine Abou Faycal, Sylvie Gazzeri, Anouk Emadali, Anthony Lucas, Elisabeth Brambilla, Ruben Pio, Nicolas Lemaître, Pedro M Lacal, Nina Lepeltier, Beatrice Eymin, Luis M. Montuenga, Team 'RNA splicing, cell signaling and response to therapies' (U1209 Inserm - CNRS UMR5309 - UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Groupe de Recherche sur le Cancer du Poumon (EA2021), Institut Albert Bonniot, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Team 'Tumor Molecular Pathology and Biomarkers' (U1209 Inserm - CNRS UMR5309 - UGA), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Team 'RNA splicing, cell signaling and response to therapies', Team 'Tumor Molecular Pathology and Biomarkers', Department of Histology and Pathology, Team 'Genetics and Epigenetics of Lymphoid Cancers', University of Navarra, Department of Biochemistry and Genetics, Eymin, Beatrice, and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, RNA splicing, [SDV]Life Sciences [q-bio], Cell, Angiogenesis Inhibitors, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Proximity ligation assay, Article, Anti-angiogenic therapies, Mice, 03 medical and health sciences, β1 integrin, Carcinoma, Non-Small-Cell Lung, Tumor Cells, Cultured, medicine, Animals, Humans, Protein Isoforms, sVEGFR1, Autocrine signalling, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Vascular Endothelial Growth Factor Receptor-1, business.industry, Integrin beta1, Lung Cancer, Receptor Cross-Talk, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, [SDV] Life Sciences [q-bio], Blot, Autocrine Communication, 030104 developmental biology, medicine.anatomical_structure, Oncology, Cell culture, Carcinoma, Squamous Cell, Disease Progression, Cancer research, Immunohistochemistry, Adenocarcinoma, business, Tyrosine kinase
Abstract

International audience; BACKGROUND:While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known.METHODS:mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples.RESULTS:We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/β1 integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and β1 integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC.CONCLUSIONS:Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.

Published
2018

17. Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update

Author

Valerie Voon, Jose A. Obeso, Michael J. Frank, Pierre-Olivier Fernagut, Maria C. Rodriguez-Oroz, Anthony A. Grace, Véronique Sgambato-Faure, Erwan Bezard, T. Celeste Napier, Department of Psychiatry and Behavioural and Clinical Neurosciences Institute, University of Cambridge [UK] (CAM), Rush University Medical Center [Chicago], Department of Cognitive, Linguistic and Psychological Sciences and Department of Psychiatry and Human Behavior, Brown University, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Neurology Service, Clinica Universitaria de Navarra. CIBERNED., CIBER de Enfermedades Neurodegenerativas (CIBERNED), Division of Hepatology and Gene Therapy (CIMA), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV)-Universidad de Navarra [Pamplona] (UNAV), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France., Voon, Valerie [0000-0001-6790-1776], Apollo - University of Cambridge Repository, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), and Instituto de Salud Carlos III [Madrid] (ISC)-Instituto de Salud Carlos III [Madrid] (ISC)

Subjects
0301 basic medicine, Dyskinesia, Drug-Induced, medicine.medical_specialty, Levodopa, Parkinson's disease, Impulse control disorder, [SDV]Life Sciences [q-bio], Population, Disease, Impulsivity, Antiparkinson Agents, 03 medical and health sciences, 0302 clinical medicine, Binge-eating disorder, medicine, Humans, Psychiatry, education, education.field_of_study, Parkinson Disease, medicine.disease, nervous system diseases, 3. Good health, Disruptive, Impulse Control, and Conduct Disorders, 030104 developmental biology, Dyskinesia, Neurology (clinical), medicine.symptom, Psychology, Neuroscience, 030217 neurology & neurosurgery, medicine.drug
Abstract

International audience; Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.

Published
2017

18. Sparse force-bearing bridges between neighboring synaptic vesicles

Author

Léa Siksou, Sebastien Phan, Mark H. Ellisman, Serge Marty, John F. Wesseling, Eric A. Bushong, Isabel Pérez-Otaño, Universidad de Navarra, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), National Institutes of Health (US), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Universidad de Navarra [Pamplona] (UNAV), Center for Applied Medical Research [Plamplona] (CIMA), University of California [San Diego] (UC San Diego), University of California, Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Histology, RRP, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Models, Neurological, Presynaptic Terminals, Synaptic vesicle, Presynaptic, Exocytosis, 03 medical and health sciences, 0302 clinical medicine, Animals, Active zone, Reserve, Tomography, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Supply-rate depression, Chemistry, General Neuroscience, Vesicle, Synapsin, Synapsins, Electron tomography, Biophysics, Original Article, Synaptic Vesicles, Anatomy, 030217 neurology & neurosurgery
Abstract

Most vesicles in the interior of synaptic terminals are clustered in clouds close to active zone regions of the plasma membrane where exocytosis occurs. Electron-dense structures, termed bridges, have been reported between a small minority of pairs of neighboring vesicles within the clouds. Synapsin proteins have been implicated previously, but the existence of the bridges as stable structures in vivo has been questioned. Here we use electron tomography to show that the bridges are present but less frequent in synapsin knockouts compared to wildtype. An analysis of distances between neighbors in wildtype tomograms indicated that the bridges are strong enough to resist centrifugal forces likely induced by fixation with aldehydes. The results confirm that the bridges are stable structures and that synapsin proteins are involved in formation or stabilization., This work was funded by: the US National Institute of Health (NIHGM103412 to ME); the Unión Temporal de Empresas (UTE) project at the Centro de Investigación Médica Aplicada of the Universidad de Navarra; the Spanish Ministry of Science (BFU2009-12160, SAF2013-48983R, and BFU2016-80918R to JFW); a Salvador de Madariaga Visiting Scholarship award to JFW; and the Spanish Jerónimo de Ayanz program to IPO and JFW.

Published
2019

19. Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

Author

João Pedro, Ferreira, Job, Verdonschot, Timothy, Collier, Ping, Wang, Anne, Pizard, Christian, Bär, Jens, Björkman, Alessandro, Boccanelli, Javed, Butler, Andrew, Clark, John G, Cleland, Christian, Delles, Javier, Diez, Nicolas, Girerd, Arantxa, González, Mark, Hazebroek, Anne-Cécile, Huby, Wouter, Jukema, Roberto, Latini, Joost, Leenders, Daniel, Levy, Alexandre, Mebazaa, Harald, Mischak, Florence, Pinet, Patrick, Rossignol, Naveed, Sattar, Peter, Sever, Jan A, Staessen, Thomas, Thum, Nicolas, Vodovar, Zhen-Yu, Zhang, Stephane, Heymans, Faiez, Zannad, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Universidade do Porto, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], Maastricht University Medical Centre (MUMC), London School of Hygiene and Tropical Medicine (LSHTM), Institut de biologie de l'ENS Paris (IBENS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Molecular and Translational Therapeutic Strategies - IMTTS [Hannover, Germany], TATAA Biocenter AB, Casa di Cura Quisisana, University of Mississippi Medical Center (UMMC), Hannover Medical School [Hannover] (MHH), Hull York Medical School, Institute of Health and Wellbeing, University of Glasgow-Gartnavel General Hospital, Glasgow, University of Glasgow, Institute of Cardiovascular and Medical Sciences [Glasgow], Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institute of Health Carlos III, Instituto de Investigación Sanitaria de Navarra (IdiSNA), University Clinic of Navarra, Leiden University Medical Center (LUMC), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], ACS Biomarker, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), Université Paris Diderot - Paris 7 (UPD7), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mosaiques Diagnostics GmbH [Hannover, Germany], Mosaiques Diagnostics and Therapeutics AG [Hannover, Germany], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Imperial College London, Department of Cardiovascular Sciences [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IMPACT GEENAGE, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Universidade do Porto = University of Porto, Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS)

Subjects
Heart Failure, Male, Proteomics, Proteome, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Case-Control Studies, Disease Progression, Humans, Female, Biomarkers, Article, Aged
Abstract

International audience; Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.

Published
2019

20. CYR61 triggers osteosarcoma metastatic spreading via an IGF1Rβ-dependent EMT-like process

Author

Bojana Stefanovska, Dimitri Carène, Ana Patiño-García, Fernando Lecanda, Nadia Habel, Olivia Fromigué, Université Paris Diderot - Paris 7 (UPD7), Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), This work was supported in part by Inserm (France), Fondation de l’Avenir pour la Recherche Médicale Appliquée ET688 grant (France), AECC project (Spain), UTE project FIMA agreement (Spain), RTICCC C03/10, PI042284, and PI10/01580 grants (Spain). N. Habel was a recipient of a PhD award from the Ministère de la Recherche (Paris, France)., and Bodescot, Myriam

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, Cell Communication, Receptor, IGF Type 1, Metastasis, Mice, 0302 clinical medicine, Cell Movement, Medicine, Osteosarcoma, EMT, Cadherins, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, Primary tumor, Gene Expression Regulation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, CYR61, MET, Research Article, Ciencias de la Salud::Oncología [Materias Investigacion], Epithelial-Mesenchymal Transition, MAP Kinase Signaling System, Motility, Bone Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, Stroma, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Biomarkers, Tumor, Cell Adhesion, Genetics, Animals, Humans, IGF, Bone tumor, Insulin-like growth factor 1 receptor, business.industry, Receptors, Somatomedin, medicine.disease, 030104 developmental biology, Cancer research, business, CCN1, Cysteine-Rich Protein 61
Abstract

Background Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells. Methods Modified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC. Results CYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rβ levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rβ/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities. Conclusions Taken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway. Electronic supplementary material The online version of this article (10.1186/s12885-019-5282-4) contains supplementary material, which is available to authorized users.

Published
2019

21. Determinants of anti-fibrotic response to mineralocorticoid receptor antagonist therapy: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) and Early Eplerenone Treatment in Patients with Acute ST-elevation Myocardial Infarction without Heart Failure (REMINDER) trials

Author

Verdonschot, Job, Collier, Timothy, Wang, Ping, Pizard, Anne, Bär, Christian, Björkman, Jens, Boccanelli, Alessandro, Butler, Javed, Clark, Andrew, Cleland, John, Delles, Christian, Díez, Javier, González, Arantxa, Hazebroek, Mark, Huby, Anne-Cécile, Jukema, Wouter, Latini, Roberto, Leenders, Joost, Lévy, Daniel, Mebazaa, Alexandre, Mischak, Harald, Pinet, Florence, Sattar, Naveed, Sever, Peter, Staessen, Jan, Thum, Thomas, Vodovar, Nicolas, Zhang, Zhen-Yu, Heymans, Stephane, Stienen, Susan, Rossignol, Patrick, Barros, Antonio, Girerd, Nicolas, Pitt, Bertram, Zannad, Faiez, Ferreira, Joao Pedro, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Universidade do Porto, University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Contrat de plan Etat-lorraine and FEDER Lorraine, IMPACT GEENAGE, ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), DE CARVALHO, Philippe, ISITE - Isite LUE - - LUE2015 - ANR-15-IDEX-0004 - IDEX - VALID, Combattre l'insuffisance cardiaque - - FIGHT-HF2015 - ANR-15-RHUS-0004 - RHUS - VALID, Universidade do Porto = University of Porto, ANR-15-IDEX-0004,LUE,Isite LUE(2015), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University [Maastricht], London School of Hygiene and Tropical Medicine (LSHTM), Universität Potsdam, TATAA Biocenter AB, Queensland University of Technology [Brisbane] (QUT), Institute of Health and Wellbeing, University of Glasgow-Gartnavel General Hospital, Glasgow, BHF Glasgow Cardiovascular Research Centre (BHF GCRC), University of Glasgow, Universidad de Navarra [Pamplona] (UNAV), Center for Applied Medical Research [Plamplona] (CIMA), Remodelage et Reparation du Tissu Renal, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Leiden University Medical Center (LUMC), IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri' [Milan, Italy], Paris-Jourdan Sciences Economiques (PSE), École normale supérieure - Paris (ENS Paris)-Institut National de la Recherche Agronomique (INRA)-École des hautes études en sciences sociales (EHESS)-École des Ponts ParisTech (ENPC)-Centre National de la Recherche Scientifique (CNRS), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Cardiovascular and Medical Sciences [Glasgow], Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), Department of Pathological Biochemistry, Royal Infirmary, Imperial College London, Department of Epidemiology, Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School [Hannover] (MHH), Service de Biochimie et de Biologie Moléculaire [AP-HP Hôpital Lariboisière] (Inserm U942), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Cardiovascular Sciences [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of Porto, ANR-15-IDEX-04-LUE,LUE,Lorraine Université d'Excellence(2016), ANR: ANR-15-RHU-0004,Programme Investissement d'Avenir ANR-15-RHU-0004, CIC-Nancy, and Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Time Factors, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, 0302 clinical medicine, Mineralocorticoid receptor, Risk Factors, 030212 general & internal medicine, Myocardial infarction, Mineralocorticoid Receptor Antagonists, Randomized Controlled Trials as Topic, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Ventricular Remodeling, General Medicine, Middle Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Eplerenone, [SDV] Life Sciences [q-bio], Treatment Outcome, Cardiology, Female, Collagen, Cardiology and Cardiovascular Medicine, Procollagen, medicine.drug, medicine.medical_specialty, Randomization, Clinical Decision-Making, Placebo, 03 medical and health sciences, Reperfusion therapy, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Predictive Value of Tests, Internal medicine, Diabetes mellitus, medicine, Humans, Aged, Heart Failure, business.industry, Myocardium, Patient Selection, Reproducibility of Results, medicine.disease, Fibrosis, Peptide Fragments, Heart failure, ST Elevation Myocardial Infarction, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers
Abstract

International audience; INTRODUCTION:After myocardial infarction complicated by heart failure or diabetes, eplerenone (compared to placebo) significantly decreases amino-terminal propeptide of type III procollagen (PIIINP). Determining the subset of patients who are more prone to have a decrease in PIIINP and those who may respond better to the anti-fibrotic effects of mineralocorticoid receptor antagonists (MRA) therapy may be relevant for a personalized treatment approach. The aim of this study is to identify predictors of a PIIINP decrease and assess potential subgroups of "responders" to eplerenone.METHODS:Clinical factors and biomarkers were evaluated as predictors of a PIIINP decrease from randomization to month 9 in 323 patients from the biomarker substudy of Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Additionally, the association between PIIINP decrease and the composite of cardiovascular (CV) death or CV hospitalization were also explored. External validation was performed in the REMINDER trial.RESULTS:Female sex, eplerenone, reperfusion therapy, potassium

Published
2019

22. Preclinical Evaluation of a Cell-Based Gene Therapy Using the Sleeping Beauty Transposon System in Choroidal Neovascularization

Author

Patricia Fernandez-Robredo, Zsuzsanna Izsvák, Sergio Recalde, Jaione Bezunartea, Alfredo García-Layana, Severine Pouillot, Laura Garcia-Garcia, Sabine Diarra, Daniel Scherman, Maria Hernandez, Juan R. Rodriguez-Madoz, Sandra Johnen, Attila Sebe, Gabriele Thumann, Felipe Prosper, Zoltán Ivics, Corinne Marie, Martina Kropp, Csaba Miskey, Clínica Universidad de Navarra [Pamplona], Paul-Ehrlich-Institute - Federal Institute for Vaccines and Biomedicines (EPI), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), GENOSAFE, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Université de Genève = University of Geneva (UNIGE), ORANGE, Colette, RWTH Aachen University, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), and University of Geneva [Switzerland]

Subjects
0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Angiogenesis, Site selection, Genetic enhancement, Retroviral integration, Iris, vascular endothelial growth factor (VEGF), iris pigment epithelial cells (IPE), chemistry.chemical_compound, Retinal-pigment epithelium, angiogenesis, 0302 clinical medicine, Endothelial growth-factor, Medicine, retinal pigment epithelium (RPE), SB100X transposase, lcsh:Cytology, Transfection, RETINAL-PIGMENT EPITHELIUM, 3. Good health, Vascular endothelial growth factor, Choroidal neovascularization, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030220 oncology & carcinogenesis, Iris pigment epithelial cells (IPE), PEDF, Molecular Medicine, RCS rats, medicine.symptom, Epithelium-derived factor, Retinal pigment epithelium (RPE), lcsh:QH426-470, EPITHELIUM-DERIVED FACTOR, RCS RATS, Article, 03 medical and health sciences, TISSUE INHIBITOR, Genetics, pigment epithelium derived factor (PEDF), SITE SELECTION, ddc:610, lcsh:QH573-671, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Molecular Biology, Tissue inhibitor, business.industry, Macular degeneration, Vascular endothelial growth factor (VEGF), IRIS, Retinal, Sleeping Beauty transposon system, MACULAR DEGENERATION, eye diseases, ddc:616.8, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, lcsh:Genetics, 030104 developmental biology, chemistry, Cardiovascular and Metabolic Diseases, Pigment epithelium derived factor (PEDF), ENDOTHELIAL GROWTH-FACTOR, Cancer research, sense organs, RETROVIRAL INTEGRATION, business
Abstract

Age-related macular degeneration (AMD) is a progressive retinal disorder characterized by imbalanced pro- and antiangiogenic signals. The aim of this study was to evaluate the effect of ex vivo cell-based gene therapy with stable expression of human pigment epithelium-derived factor (PEDF) release using the non-viral Sleeping Beauty (SB100X) transposon system delivered by miniplasmids free of antibiotic resistance markers (pFAR4). Retinal pigment epithelial (RPE) cells and iris pigment epithelial (IPE) cells were co-transfected with pFAR4-inverted terminal repeats (ITRs) CMV-PEDF-BGH and pFAR4-CMV-SB100X-SV40 plasmids. Laser-induced choroidal neovascularization (CNV) was performed in rats, and transfected primary cells (transfected RPE [tRPE] and transfected IPE [tIPE] cells) were injected into the subretinal space. The leakage and CNV areas, vascular endothelial growth factor (VEGF), PEDF protein expression, metalloproteinases 2 and 9 (MMP-2/9), and microglial/macrophage markers were measured. Injection with tRPE/IPE cells significantly reduced the leakage area at 7 and 14 days and the CNV area at 7 days. There was a significant increase in PEDF and the PEDF/VEGF ratio with tRPE cells and a reduction in the MMP-2 activity. Our data demonstrated that ex vivo non-viral gene therapy reduces CNV and could be an effective and safe therapeutic option for angiogenic retinal diseases. Keywords: angiogenesis, iris pigment epithelial cells (IPE), retinal pigment epithelium (RPE), pigment epithelium derived factor (PEDF), vascular endothelial growth factor (VEGF), SB100X transposase

Published
2019

23. Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology

Author

Ida G. Lunde, Carsten Tschöpe, Johann Bauersachs, Faiez Zannad, Sanjay K Prasad, Gerasimos Filippatos, Xiao-Jun Du, Carlo G. Tocchetti, Piero Pollesello, Natalia López-Andrés, Wolfram-Hubertus Zimmermann, Theresa McDonagh, Manuel Mayr, Christoph Maack, Paul Ford, Stephane Heymans, Thomas Thum, Rudolf A. de Boer, Dirk L. Brutsaert, Alexander R. Lyon, John G.F. Cleland, Joost P.G. Sluijter, Frank R. Heinzel, Kenneth E. Lipson, Frank Ruschitzka, Gilles W. De Keulenaer, Merry L. Lindsey, Javier Díez, BOZEC, Erwan, HOMAGE (Heart Omics in Ageing consortium) - 305507 - INCOMING, Targeting cardiac fibrosis for heart failure treatment - FIBRO-TARGETS - - EC:FP7:HEALTH2013-09-01 - 2017-08-31 - 602904 - VALID, Hepatic and Cardiac Toxicity Systems modelling - HECATOS - - EC:FP7:HEALTH2013-10-01 - 2018-09-30 - 602156 - VALID, University Medical Center Groningen [Groningen] (UMCG), University of Antwerp (UA), Hannover Medical School [Hannover] (MHH), University of Glasgow, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Clínica Universidad de Navarra [Pamplona], Baker Heart and Diabetes Institute (AUSTRALIA), Galecto Biotech, Charité Campus Virchow-Klinikum (CVK), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], FibroGen Inc., King's College Hospital (KCH), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], University of Oslo (UiO), Oslo University Hospital [Oslo], Royal Brompton Hospital, Orion Pharma, University of Naples Federico II = Università degli studi di Napoli Federico II, King‘s College London, University Medical Center [Utrecht], Institute of Molecular and Translational Therapeutic Strategies (IMTTS), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), University Medical Center Göttingen (UMG), University hospital of Zurich [Zurich], University General Hospital ' Attikon ' [Athens, Greece], University of Mississippi Medical Center (UMMC), University of Würzburg = Universität Würzburg, University Hospital Wuerzburg / Universitäts­klinikum Würzburg, Maastricht University [Maastricht], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The Netherlands Heart Institute, R.A.d.B. is supported by the Netherlands Heart Foundation (CVON DOSIS, grant 2014-40, CVON SHE-PREDICTS-HF, grant 2017-21, and CVON RED-CVD, grant 2017-11), and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI, grant 917.13.350). J.B. is supported is supported by the Deutsche Forschungsgemeinschaft (DFG), Clinical Research Group 311 (KFO 311) ‘(Pre)terminal heart and lung failure: unloading and repair’ (DFG, TP1, BA 1742/9-1) and ‘MR-Focus’‘ (DFG BA 1742/8-1). J.S. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (consolidator grant Evicare #725229) and by the Netherlands Heart Foundation (CVON-HUSTCARE). M.M. is a BHF Chair Holder (CH/16/3/32406), with BHF program grant support (RG/16/14/32397), and was awarded a BHF Special Project grant to participate in the ERA-CVD Translational Grant MacroERA. M.M. and T.T. are members of a network funded by the Foundation Leducq. C.G.T. is supported by a Federico II University/Ricerca di Ateneo grant. S.H. has received funding from the European Union Commission's Seventh Framework programme under grant agreement n. 305507 (HOMAGE), n. 602904 (FIBROTARGETS) and FP7-Health-2013-Innovations-1 n. 602156 (HECATOS), CVON2016-Early HFPEF, 2015-10, and CVON SHE-PREDICTS-HF, grant 2017-21. C.M. is supported by the DFG (Ma 2528/7-1, SFB 894, TRR-219) and the Federal Ministry of Education and Science (BMBF, 01EO150, CF.3, RC2)., European Project: 305507, European Project: 602904,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,FIBRO-TARGETS(2013), European Project: 602156,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,HECATOS(2013), de Boer, Rudolf A, De Keulenaer, Gille, Bauersachs, Johann, Brutsaert, Dirk, Cleland, John G, Diez, Javier, Du, Xiao-Jun, Ford, Paul, Heinzel, Frank R, Lipson, Kenneth E, Mcdonagh, Theresa, Lopez-Andres, Natalia, Lunde, Ida G, Lyon, Alexander R, Pollesello, Piero, Prasad, Sanjay K, Tocchetti, Carlo G, Mayr, Manuel, Sluijter, Joost P G, Thum, Thoma, Tschöpe, Carsten, Zannad, Faiez, Zimmermann, Wolfram-Hubertu, Ruschitzka, Frank, Filippatos, Gerasimo, Lindsey, Merry L, Maack, Christoph, Heymans, Stephane, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: CARIM - R2.02 - Cardiomyopathy, RS: Carim - H02 Cardiomyopathy, University of Zurich, and Cardiovascular Centre (CVC)

Subjects
Cardiac & Cardiovascular Systems, Fibrosi, Myocardium/metabolism, Infarction, 030204 cardiovascular system & hematology, Heart Failure/diagnosis, Imaging, Translational Research, Biomedical, 0302 clinical medicine, Fibrosis, Fibrosis/classification, Myocardial infarction, Disease management (health), Non-U.S. Gov't, 1102 Cardiorespiratory Medicine and Haematology, Translational Medical Research, Societies, Medical, Extracellular Matrix Proteins, MOLECULAR-MECHANISMS, Research Support, Non-U.S. Gov't, Cardiac Imaging Techniques/methods, Disease Management, CARDIAC FIBROBLASTS, Prognosis, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Europe, HFA Position Statement, PRESERVED EJECTION FRACTION, Galectin-3, 10209 Clinic for Cardiology, Cardiology, Fibroblast, DIFFUSE MYOCARDIAL FIBROSIS, INFARCTION, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, INTERSTITIAL FIBROSIS, Extracellular Matrix Proteins/blood, medicine.medical_specialty, Myocarditis, INHIBITION, 610 Medicine & health, Translational research, Heart failure, Research Support, 2705 Cardiology and Cardiovascular Medicine, 03 medical and health sciences, LEFT-VENTRICULAR DYSFUNCTION, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Medical, medicine, EXTRACELLULAR-MATRIX, Journal Article, Humans, GALECTIN-3, Science & Technology, Matrix, business.industry, Myocardium, Research, Biomarker, medicine.disease, Cardiac Imaging Techniques, Cardiovascular System & Hematology, Cardiovascular System & Cardiology, Biomarkers, Human medicine, business, Societies, Biomarkers/blood
Abstract

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:21 issue:3 pages:272-285 ispartof: location:England status: published

Published
2019

24. Heart failure and diabetes

Author

Christoph, Maack1, Michael, Lehrke2, Johannes, Backs3, Heinzel4, Frank R., Jean-Sebastien, Hulot5, 6, Nikolaus, Marx2, Paulus7, Walter J., Patrick, Rossignol8, Heinrich, Taegtmeyer9, Johann, Bauersachs10, Antoni, Bayes-Genis11, Dirk, Brutsaert13, Heiko, Bugger14, Kieran, Clarke15, Francesco, Cosentino16, Gilles De Keulenaer17, Alessandra Dei Cas18, Arantxa, Gonza´lez20, Martin, Huelsmann21, Iaccarino, Guido, Ida Gjervold Lunde23, Lyon24, Alexander R., Piero, Pollesello25, Graham, Rena26, Riksen27, Niels P., Giuseppe, Rosano28, Bart, Staels30, 31, 32, van Laake34, Lindaw., Christophwanner35, Dimitrios, Farmakis36, Gerasimos, Filippatos36, Frank, Ruschitzka37, Petar, Seferovic38, de Boer39, Rudolf A., and Stephane Heymans, Clinicum, University of Helsinki, University Hospital Wuerzburg / Universitäts­klinikum Würzburg, Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Heidelberg University Hospital [Heidelberg], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], VU University Medical Center [Amsterdam], Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Hannover Medical School [Hannover] (MHH), Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Universitat Autònoma de Barcelona (UAB), University of Antwerp (UA), Department of Cardiology and Angiology I, University Heart Centre Freiburg - Bad Krozingen, University of Freiburg [Freiburg], University of Oxford, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], Università degli studi di Parma = University of Parma (UNIPR), Azienda Ospedaliero-Universitaria di Parma, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institute of Health Carlos III, Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Medizinische Universität Wien = Medical University of Vienna, Università degli Studi di Salerno = University of Salerno (UNISA), Oslo University Hospital [Oslo], University of Oslo (UiO), Royal Brompton Hospital, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Dundee, Ninewells Hospital and Medical School [Dundee], Radboud University Medical Center [Nijmegen], St George’s University Hospitals, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Utrecht University [Utrecht], National and Kapodistrian University of Athens (NKUA), 'Attikon' University Hospital, University hospital of Zurich [Zurich], University of Belgrade [Belgrade], University Medical Center Groningen [Groningen] (UMCG), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], The Netherlands Heart Institute, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Maack, C, Lehrke, M, Backs, J, Heinzel, Fr, Hulot, J, Marx, N, Paulus, Wj, Rossignol, P, Taegtmeyer, H, Bauersachs, J, Bayes-Genis, A, Brutsaert, D, Bugger, H, Clarke, K, Cosentino, F, De Keulenaer, G, Dei Cas, A, González, A, Huelsmann, M, Iaccarino, G, Lunde, Ig, Lyon, Ar, Pollesello, P, Rena, G, Riksen, Np, Rosano, G, Staels, B, van Laake, Lw, Wanner, C, Farmakis, D, Filippatos, G, Ruschitzka, F, Seferovic, P, de Boer, Ra, and Heymans, S.

Subjects
medicine.medical_specialty, Cardiac & Cardiovascular Systems, [SDV]Life Sciences [q-bio], education, VENTRICULAR DIASTOLIC FUNCTION, Context (language use), Translational research, 030204 cardiovascular system & hematology, 1102 Cardiovascular Medicine And Haematology, CARDIOVASCULAR OUTCOMES, 03 medical and health sciences, DOUBLE-BLIND, 0302 clinical medicine, Internal medicine, Residual morbidity, Journal Article, Medicine, THIAZOLIDINEDIONE THERAPY, 030212 general & internal medicine, Repurposing, Modern epidemic, IMPROVES CARDIAC-FUNCTION, Science & Technology, COTRANSPORTER 2 INHIBITION, GLUCAGON-LIKE PEPTIDE-1, business.industry, Type 2 Diabetes Mellitus, Heart Failure/Cardiomyopathy, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], medicine.disease, KETONE-BODIES, Comorbidity, 3. Good health, Review article, Heart failure (HF), Cardiovascular System & Hematology, PRESERVED EJECTION FRACTION, Current Opinion, Heart failure, 3121 General medicine, internal medicine and other clinical medicine, Cardiology, Cardiovascular System & Cardiology, Human medicine, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine, MYOCARDIAL TRIGLYCERIDE CONTENT, Kidney disease
Abstract

Altres ajuts: C.M. is supported by the Deutsche Forschungsgemeinschaft (DFG; SFB 894, TRR-219, and Ma 2528/7-1), the German Federal Ministry of Education and Science (BMBF; 01EO1504) and the Corona foundation. J.B. is supported by the DFG (SFB 1118) and the DZHK (German Centre for Cardiovascular Research) and by the BMBF. M.L. is supported by the DFG (SFB TRR 219M-03). R.B. is supported by the Netherlands Heart Foundation (CVON DOSIS 2014-40, CVON SHE-PREDICTS-HF 2017-21, and CVON RED-CVD 2017-11); and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VIDI, grant 917.13.350). N.M. is supported by the DFG (SFB TRR 219M-03, M-05). H.T. is supported by grants from the National Institutes of Health of the US Public Health Service (HL-RO1 061483 and HL-RO1 073162). A.B.G. was supported by grants from the Ministerio de Educación y Ciencia , Fundació La MARATÓ de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403), and AdvanceCat 2014-2020. H.B. is supported by the DFG (Bu2126/3-1). A.D.C. was supported by 'FIL' funds for research from University of Parma. A.G. was supported by grants from the European Union Commission's FP7 programme (HOMAGE and FIBROTARGETS) and ERA-CVD Joint Transnational Call 2016 LYMIT-DIS. G.R. acknowledges recent funding from The Cunningham Trust, MRC (MR/K012924/1) and the Diabetes UK RW and JM Collins studentship. S.H. received funding from the European Union Commission's Seventh Framework programme (2007-2013) under grant agreement N° 305507 (HOMAGE), N° 602904 (FIBROTARGETS) and N° 602156 (HECATOS). S.H. acknowledges the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation, CVON-ARENA-PRIME, CVON-EARLY HFPEF, and SHE-PREDICTS. This research is co-financed as a PPP-allowance Research and Innovation by the Ministry of Economic Affairs within Top Sector Life sciences & Health.

Published
2018

25. Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma

Author

Georges, S., Calleja, L. R., Jacques, C., Lavaud, M., Moukengue, B., Lecanda, F., Quillard, T., Gabriel, M. T., Cartron, P. -F, Baud Huin, M., Lamoureux, F., Dominique Heymann, Ory, B., Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Département de recherche en cancérologie, Université de Nantes (UN)-IFR26, Equipe LIGUE Nationale Contre le Cancer 2012, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Biologie des Cancers et de Théranostic [St Herblain, Nantes] (LabCT), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, maurice, sandrine, Adhesion and Metastasis Laboratory [Navarra, Spain] (Division of Oncology ), University Clinic of Navarra - CUN [Pamplona, Spain]-Center for Applied Medic al Research [Navarra, Spain], Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Réseau Epigénétique du Cancéropôle Grand-Ouest [Nantes] (REpiCGO), Cancéropôle Grand Ouest [Nantes]-Maison de la Recherche en Santé [Nantes], Thanks for the financial support of Région pays de la loire, Ligue contre le cancer, SFCE, Etoile de martin, Fondation ARC., Bernardo, Elizabeth, Center for Applied Medic al Research [Navarra, Spain]-University Clinic of Navarra - CUN [Pamplona, Spain], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)

Subjects
[SDV.CAN] Life Sciences [q-bio]/Cancer, osteosarcoma, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], metastasis, [SDV.CAN]Life Sciences [q-bio]/Cancer, C-Met, Research Paper, microRNAs
Abstract

International audience; The metastatic dissemination is a complex multistep process by which tumor cells from a primary site enter into the systemic circulation to finally spread at distant sites. Even if this mechanism is rare at the tumor level, it remains the major cause of Osteosarcoma-patients' relapse and mortality. MicroRNAs (miRNAs) have recently been described as novel epigenetics' genes' expression regulators actively implicated in cancer progression and dissemination. The understanding of their implication in the metastatic spreading could help clinicians to improve the outcome of osteosarcoma. We established the miRNA's expression-profile between primary bone-tumors (PTs), circulating tumor cells (CTCs) and lung metastatic (META) samples from in vivo mice xenograft models. Our results show that the expression level of the miR-198 and-206 was decreased in META samples, in which the expression of the metastasis-related receptor C-Met was up-regulated. Those expression variations were validated in osteosarcoma patient biopsies from matching primary tumors and lung metastasis. We validated in vitro the endogenous miRNAs inhibitory effects on both migration and invasion, as well as we confirmed by luciferase assays that the C-Met receptor is one of their bona-fide targets. The anti-metastatic effect of these miRNAs was also validated in vivo, as their direct injections into the tumors reduce the number of lung-metastases and prolongs the overall survival of the treated animals. All together, our results suggest the absence of the miR-198 and-206 as powerful predictive biomarkers of the tumor cell dissemination and the rationale of their potential therapeutic use in the treatment of Osteosarcoma.

Published
2018

26. The sVEGFR1-i13 splice variant regulates a β1 integrin/VEGFR autocrine loop involved in the progression and the response to anti-angiogenic therapies of squamous cell lung carcinoma

Author

Faycal, Cherine, Brambilla, Elisabeth, Agorreta, Jackeline, Lepeltier, Nina, Jacquet, Thibault, Lemaître, Nicolas, Emadali, Anouk, Lucas, Anthony, Lacal, Pedro, Montuenga, Luis, Pio, Ruben, Gazzeri, Sylvie, Eymin, Béatrice, Eymin, Beatrice, Team 'RNA splicing, cell signaling and response to therapies' (U1209 Inserm - CNRS UMR5309 - UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Groupe de Recherche sur le Cancer du Poumon (EA2021), Institut Albert Bonniot, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Team 'Tumor Molecular Pathology and Biomarkers' (U1209 Inserm - CNRS UMR5309 - UGA), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Anti-angiogenic therapies, [SDV] Life Sciences [q-bio], RNA splicing, β1 integrin, [SDV]Life Sciences [q-bio], Lung Cancer, sVEGFR1, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

International audience; BACKGROUND:While lung adenocarcinoma patients can somewhat benefit from anti-angiogenic therapies, patients with squamous cell lung carcinoma (SQLC) cannot. The reasons for this discrepancy remain largely unknown. Soluble VEGF receptor-1, namely sVEGFR1-i13, is a truncated splice variant of the cell membrane-spanning VEGFR1 that has no transmembrane or tyrosine kinase domain. sVEGFR1-i13 is mainly viewed as an anti-angiogenic factor which counteracts VEGF-A/VEGFR signalling in endothelial cells. However, its role in tumour cells is poorly known.METHODS:mRNA and protein status were analysed by Real-Time qPCR, western blotting, ELISA assay, proximity ligation assay or immunohistochemistry in human tumour cell lines, murine tumourgrafts and non small cell lung carcinoma patients samples.RESULTS:We show that anti-angiogenic therapies specifically increase the levels of sVEGFR1-i13 in SQLC cell lines and chemically induced SQLC murine tumourgrafts. At the molecular level, we characterise a sVEGFR1-i13/β1 integrin/VEGFR autocrine loop which determines whether SQLC cells proliferate or go into apoptosis, in response to anti-angiogenic therapies. Furthermore, we show that high levels of both sVEGFR1-i13 and β1 integrin mRNAs and proteins are associated with advanced stages in SQLC patients and with a poor clinical outcome in patients with early stage SQLC.CONCLUSIONS:Overall, these results reveal an unexpected pro-tumoural function of sVEGFR1-i13 in SQLC tumour cells, which contributes to their progression and escape from anti-angiogenic therapies. These data might help to understand why some SQLC patients do not respond to anti-angiogenic therapies.

Published
2018

27. Predictors of responses to immune checkpoint blockade in advanced melanoma

Author

Brigitte Dréno, Caroline Flament, Nicolas Jacquelot, B. Balme, Yaron Meirow, Mitchell P. Levesque, Jeffrey S. Weber, Christophe Borg, Lawrence Fong, Amir Khammari, Guido Kroemer, Sylvie Rusakiewicz, Morten Hartvig Hansen, Ignacio Melero, Gorana Tomasic, Henrik Schmidt, Meriem Messaoudene, Andrea Cavalcanti, Maria Paula Roberti, Sarah Jegou, Yoshinobu Koguchi, Stefan Michiels, Moshe Sade-Feldman, Michal Baniyash, Ana C. Anderson, Byoung S. Kwon, Lieping Chen, Aurélien Marabelle, David Enot, Arun Burra, Inge Marie Svane, Stéphane Dalle, A.M. Di Giacomo, Dirk Schadendorf, Nils Ternès, Laurence Zitvogel, Reinhard Dummer, Andressa L. Sodre, Serena S. Kwek, O Beatrix, Vijay K. Kuchroo, Alexander M.M. Eggermont, David M. Woods, Benjamin Weide, Mark J. Smyth, Michele Maio, Maha Ayyoub, François Aubin, Connie P.M. Duong, Michal Lotem, Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Université Paris-Saclay, Institut Gustave Roussy (IGR), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Microorganismes et physiopathologie intestinale (ERL INSERM U1157 - CNRS UMR 7203), Laboratoire des biomolécules (LBM UMR 7203), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laura & Isaac Perlmutter Cancer Center [New York, NY, USA], New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU)-NYU System (NYU), Department of Hematology and Oncology [Herlev, Denmark], Copenhagen University Hospital, The Lautenberg Center for General and Tumor Immunology [Jerusalem, Israel], The Hebrew University Hadassah Medical School -BioMedical Research institute Israel Canada of the Faculty of Medicine [Jerusalem, Israel], Division of Hematology-Oncology [San Francisco, CA, USA] (Department of Medicine), University of California [San Francisco] (UCSF), University of California-University of California, Department of Immunobiology [New Haven, CT, USA] (Yale School of Medicine), Yale University [New Haven], Eutilex Co., Ltd [Seoul, Korea], Section of Clinical Immunology, Allergy, and Rheumatology [New Orleans, LA, USA] (Department of Medicine), Tulane University Health Sciences Center [New Orleans, LA, USA], Evergrande Center for Immunologic Diseases [Boston, MA, USA] (Ann Romney Center for Neurologic Diseases), Brigham & Women's Hospital, Harvard Medical School, Department of Dermatology [Tubingen, Germany], University Medical Center [Tubingen, Germany], Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (EA 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Oncologie Médicale [CHRU Besançon], Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie [CHU Lyon-Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Département de biologie et pathologie médicales [Gustave Roussy], Division of Medical Oncology and Immunotherapy [Siena, Italy], University Hospital of Siena, Department of Dermatology [Heidelberg, Germany], University Duisburg-Essen [Germany]-University Hospital [Heidelberg, Germany]-Germany & German Cancer Consortium - DKTZ [Heidelberg, Germany], Division of Hepatology and Gene Therapy (CIMA), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV)-Universidad de Navarra [Pamplona] (UNAV), Oncology Department [Pamplona, Spain], University Clinic of Navarra - CUN [Pamplona, Spain], Centro de Investigación Biomedica en Red de Oncologia [Pamplona, Spain] (CIBERO), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Department of Dermatology [Zürich, Switzerland], Universität Zürich [Zürich] = University of Zurich (UZH)-University hospital of Zurich [Zurich], Earle A. Chiles Research Institute [Portland, OR, USA], Providence Portland Medical Center-Robert W. Franz Cancer Research Center, Sharett Institute of Oncology [Jerusalem, Israel], Hadassah Medical Organization [Jerusalem, Israel], Department of Oncology [Aarhus, Denmark], Aarhus University Hospital, Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Sorbonne Paris Cité (USPC), Pôle de biologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Département de chirurgie générale [Gustave Roussy], Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Immunology in Cancer and Infection Laboratory [Herston, QLD, Australia], QIMR Berghofer Medical Research Institute, School of Medicine [Herston, QLD, Australia], University of Southern Queensland (USQ), This work was supported by Institut National du Cancer INCa, ANR, Ligue contre le cancer (équipe labellisée de L.Z.) and Swiss Bridge Foundation, ISREC Foundation, LABEX OncoImmunology, la direction générale de l’offre de soins (DGOS), Université Paris-Sud, SIRIC SOCRATE (INCa/DGOS/INSERM 6043), PACRI network and PIA2 TORINO-LUMIERE. N.J. received a fellowship from Cancéropole Idf. M.J.S. was supported by a National Health and Medical Research Council of Australia Senior Principal Research Fellowship., Bernardo, Elizabeth, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Département de Chimie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Carcinogénèse épithéliale : facteurs prédictifs et pronostiques - UFC (UR 3181) (CEF2P / CARCINO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-University Hospital [Heidelberg, Germany]-Germany & German Cancer Consortium - DKTZ [Heidelberg, Germany], Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE)

Subjects
0301 basic medicine, Oncology, medicine.medical_treatment, Medizin, General Physics and Astronomy, 0302 clinical medicine, METASTATIC MELANOMA, TUMOR-INFILTRATING LYMPHOCYTES, lcsh:Science, Cancer, screening and diagnosis, Multidisciplinary, CD137, 3. Good health, Detection, 030220 oncology & carcinogenesis, Patient Safety, BREAST-CANCER PATIENTS, Nivolumab, Adjuvant, CIRCULATING SOLUBLE FAS, medicine.drug, medicine.medical_specialty, CELL LUNG-CANCER, Science, PROGNOSTIC IMPACT, Clinical Trials and Supportive Activities, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Clinical Research, Internal medicine, Journal Article, STAGE-III MELANOMA, medicine, CLINICAL-SIGNIFICANCE, business.industry, UNTREATED MELANOMA, General Chemistry, Immune checkpoint, Blockade, 4.1 Discovery and preclinical testing of markers and technologies, 030104 developmental biology, COMBINED NIVOLUMAB, Immunology, lcsh:Q, business, CD8
Abstract

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel., The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

Published
2017

28. Long-Term PEDF Release in Rat Iris and Retinal Epithelial Cells after Sleeping Beauty Transposon-Mediated Gene Delivery

Author

Daniel Scherman, Sergio Recalde, Zoltán Ivics, Sandra Johnen, Sabine Diarra, Gabriele Thumann, Zsuzsanna Izsvák, Maria Hernandez, Juan R. Rodriguez-Madoz, Felipe Prosper, Corinne Marie, Martina Kropp, Jaione Bezunartea, Patricia Fernandez-Robredo, Alfredo García-Layana, Laura Garcia-Garcia, IdiSNA, Navarra Institute for Health Research, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University, Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Paul-Ehrlich-Institute - Federal Institute for Vaccines and Biomedicines (EPI), University of Geneva [Switzerland], Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra (IdiSNA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA)-Universidad de Navarra [Pamplona] (UNAV)-Clínica Universidad de Navarra [Pamplona], Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Genève = University of Geneva (UNIGE), and ORANGE, Colette

Subjects
0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, THERAPY, chemistry.chemical_compound, 0302 clinical medicine, Drug Discovery, pFAR4 miniplasmids, Anatomy, INDUCED CHOROIDAL NEOVASCULARIZATION, 3. Good health, Cell biology, Vascular endothelial growth factor, medicine.anatomical_structure, Choroidal neovascularization, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, INTRAVITREAL BEVACIZUMAB, Molecular Medicine, Original Article, medicine.symptom, pigment epithelium-derived factor, primary pigment epithelial cells, VECTOR, Gene delivery, Biology, choroidal neovascularization, TRANSGENE EXPRESSION, 03 medical and health sciences, Sleeping Beauty transposon system, PEDF, medicine, Iris pigment epithelium, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Retina, lcsh:RM1-950, MACULAR DEGENERATION, RANIBIZUMAB, eye diseases, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, ddc:616.8, MODEL, Transplantation, lcsh:Therapeutics. Pharmacology, non-viral ex vivo gene therapy, 030104 developmental biology, chemistry, Cardiovascular and Metabolic Diseases, ENDOTHELIAL GROWTH-FACTOR, 030221 ophthalmology & optometry, sense organs, SYSTEM
Abstract

International audience; Pigment epithelium derived factor (PEDF) is a potent antiangiogenic, neurotrophic, and neuroprotective molecule that is the endogenous inhibitor of vascular endothelial growth factor (VEGF) in the retina. An ex vivo gene therapy approach based on transgenic overexpression of PEDF in the eye is assumed to rebalance the angiogenic-antiangiogenic milieu of the retina, resulting in growth regression of choroidal blood vessels, the hallmark of neovascular age-related macular degeneration. Here, we show that rat pigment epithelial cells can be efficiently transfected with the PEDF-expressing non-viral hyperactive Sleeping Beauty transposon system delivered in a form free of antibiotic resistance marker miniplasmids. The engineered retinal and iris pigment epithelium cells secrete high (141 +/- 13 and 222 +/- 14 ng) PEDF levels in 72 hr in vitro. In vivo studies showed cell survival and insert expression during at least 4 months. Transplantation of the engineered cells to the subretinal space of a rat model of choroidal neovascularization reduces almost 50% of the development of new vessels.

Published
2017

29. ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis

Author

Debashish Sahay, Leif W. Ellisen, Thibaut Quillard, Marc Baud'huin, Fernando Lecanda, Francois Lamoureux, Franck Verrecchia, Lidia Rodriguez Calleja, Dominique Heymann, Marta Tellez Gabriel, Céline Charrier, Régis Brion, Camille Jacques, Pierre Perrot, Jérôme Amiaud, Benjamin Ory, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Equipe Labellisée LIGUE 2012 [Nantes], Physiopathologie, diagnostic et traitements des maladies osseuses / Pathophysiology, Diagnosis & Treatments of Bone Diseases (LYOS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Massachusetts General Hospital Cancer Center [Boston, MA, USA], Harvard Medical School [Boston] (HMS), C. Jacques was funded by INSERM and Region Pays de la loire, Philippe Hulin, Nantes University, PICell for time-lapsemicroscopy., European Project: 264817,EC:FP7:PEOPLE,FP7-PEOPLE-2010-ITN,BONE-NET(2011), maurice, sandrine, European Training Network on Cancer-Induced Bone Diseases - BONE-NET - - EC:FP7:PEOPLE2011-02-01 - 2015-01-31 - 264817 - VALID, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Cancer Research, Lung Neoplasms, Apoptosis, Metastasis, Immunoenzyme Techniques, Transactivation, Mice, Cell Movement, Transforming Growth Factor beta, Tumor Cells, Cultured, Protein Isoforms, Regulation of gene expression, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Osteosarcoma, Reverse Transcriptase Polymerase Chain Reaction, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Transcriptional Activation, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Neoplasms, Biology, Real-Time Polymerase Chain Reaction, Article, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Downregulation and upregulation, [SDV.CAN] Life Sciences [q-bio]/Cancer, microRNA, medicine, Animals, Humans, RNA, Messenger, Psychological repression, Cell Proliferation, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Wound Healing, Tumor Suppressor Proteins, Transforming growth factor beta, medicine.disease, Xenograft Model Antitumor Assays, Transplantation, MicroRNAs, 030104 developmental biology, Immunology, Cancer research, biology.protein, Gene Deletion, Transcription Factors
Abstract

Primary cancer cell dissemination is a key event during the metastatic cascade, but context-specific determinants of this process remain largely undefined. Multiple reports have suggested that the p53 (TP53) family member p63 (TP63) plays an antimetastatic role through its minor epithelial isoform containing the N-terminal transactivation domain (TAp63). However, the role and contribution of the major p63 isoform lacking this domain, ΔNp63α, remain largely undefined. Here, we report a distinct and TAp63-independent mechanism by which ΔNp63α-expressing cells within a TGFβ-rich microenvironment become positively selected for metastatic dissemination. Orthotopic transplantation of ΔNp63α-expressing human osteosarcoma cells into athymic mice resulted in larger and more frequent lung metastases than transplantation of control cells. Mechanistic investigations revealed that ΔNp63α repressed miR-527 and miR-665, leading to the upregulation of two TGFβ effectors, SMAD4 and TβRII (TGFBR2). Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound-healing response. We show that ΔNp63α-mediated repression of miR-527/665 controls a TGFβ-dependent signaling node that switches off antimigratory miR-198 by suppressing the expression of the regulatory factor, KSRP (KHSRP). Collectively, these findings reveal that a novel miRNA network involved in the regulation of physiologic wound-healing responses is hijacked and suppressed by tumor cells to promote metastatic dissemination. Cancer Res; 76(11); 3236–51. ©2016 AACR.

Published
2015

30. Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential

Author

Heymans, Stephane, González, Arantxa, Pizard, Anne, Papageorgiou, Anna, López-Andrés, Natalia, Jaisser, Frederic, Thum, Thomas, Zannad, Faiez, Díez, Javier, Cardiovascular Research Institute [Maastricht], Maastricht University Medical Centre - MUMC [Maastricht, The Netherlands], Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Instituto de Investigación Sanitaria de Navarra (IdiSNA), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Fundación Miguel Servet, Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School [Hannover] (MHH), Clinica Universitaria, faculdad de medicina, universidad de Navarra (UNIVERSIDAD DE NAVARRA), Universidad de Navarra, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), MUMC+: MA Med Staf Spec Cardiologie (9), Cardiologie, RS: CARIM - R2 - Cardiac function and failure, Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique plurithématique Pierre Drouin (CIC-P), and Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Cytokines, MESH: Myocardium, MESH: Gene Expression, MESH: Humans, Interstitial fibrosis, Heart failure, MESH: NADPH Oxidases, MESH: Galectin 3, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Fibroblasts, MESH: Collagen, MESH: CCN Intercellular Signaling Proteins, MESH: Fibrosis, MESH: Heart Failure, Therapeutic targets, MESH: Animals, MESH: MicroRNAs, MESH: Protein-Lysine 6-Oxidase
Abstract

International audience; Myocardial fibrosis is the result of excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation. It causes cardiac dysfunction, arrhythmias, and ischaemia, and thereby determines the clinical course and outcome of cardiac patients even when adequately treated. Therefore, further research is needed to identify and better understand the factors that trigger and maintain the myocardial fibrotic response against different injuries in a variety of cardiac diseases. Here, we will focus on the following major areas of research: molecules that stimulate the differentiation of fibroblasts into myofibroblasts and subsequently alter collagen turnover (e.g. cardiotrophin-1, galectin-3, NADPH oxidases, and neutrophil gelatinase-associated lipocalin), microRNA-induced alterations of collagen gene expression, and matricellular protein- and lysyl oxidase-mediated alterations of collagen cross-linking and deposition.

Published
2015

31. NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients

Author

Manuela eMellone, Jennifer eStanic, Ledia F Hernandez, Elena eIglesias, Elisa eZianni, Annalisa eLonghi, Annick ePrigent, Barbara ePicconi, Paolo eCalabresi, Etienne C Hirsch, Jose A Obeso, Monica eDi Luca, Fabrizio eGardoni, HAL-UPMC, Gestionnaire, Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università degli Studi di Milano = University of Milan (UNIMI), Center for Applied Medical Research (CIMA), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione Santa Lucia [IRCCS], Clinical and Behavioral Neurology [IRCCS Santa Lucia], Clinica Neurologica, Università degli Studi di Perugia = University of Perugia (UNIPG), Division of Hepatology and Gene Therapy (CIMA), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV)-Universidad de Navarra [Pamplona] (UNAV), Università degli Studi di Milano [Milano] (UNIMI), and Università degli Studi di Perugia (UNIPG)

Subjects
Scaffold protein, Levodopa, Parkinson's disease, Protein subunit, striatum, Striatum, Pharmacology, patients, lcsh:RC321-571, cell-permeable peptides, Cellular and Molecular Neuroscience, Glutamatergic, levodopa-induced dyskinesias, Medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Original Research, business.industry, 6-OHDA rat model, MPTP monkey model, NMDA receptor, Parkinson’s disease, medicine.disease, 3. Good health, Settore MED/26 - NEUROLOGIA, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, Neuroscience, Glun2b subunit, medicine.drug
Abstract

International audience; Luca M and Gardoni F (2015) NMDA receptor GluN2A/GluN2B subunit ratio as synaptic trait of levodopa-induced dyskinesias: from experimental models to patients. Front. Cell. Neurosci. 9:245. Levodopa-induced dyskinesias (LIDs) are major complications in the pharmacological management of Parkinson's disease (PD). Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at: (i) characterizing N-methyl-D-aspartate (NMDA) receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs as well as in dyskinetic PD patients; and (ii) validating the potential therapeutic effect of a cell-permeable peptide (CPP) interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein postsynaptic density protein 95 (PSD-95) leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.

Published
2015

32. Whole-genome fingerprint of the DNA methylome during human B cell differentiation

Author

Simone Ecker, Reiner Siebert, Néria Verdaguer-Dot, Guillem Clot, Renée Beekman, Alfonso Valencia, Ralf Küppers, Julie Blanc, Seung-Tae Lee, Hendrik G. Stunnenberg, Marina E. Fomin, Marta Kulis, Daniel Rico, Bruno Paiva, Diego Alignani, Gersende Caron, Ivo Gut, Joseph L. Wiemels, Vera Pancaldi, Paul Flicek, Giancarlo Castellano, José I. Martín-Subero, Elias Campo, Lidia Agueda, Laura Clarke, Felipe Prosper, Marta Gut, Marcus O. Muench, Nuria Russiñol, Ronald P. Schuyler, Roser Vilarrasa-Blasi, Martí Duran-Ferrer, Thierry Fest, Simon Heath, Angelika Merkel, Avik Datta, Ana C. Queirós, Marien Pascual, Xabier Agirre, Emanuele Raineri, David S. Richardson, Anna Esteve, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centro Nacional de Análisi Genómico (CNAG), Centro Nacional de Análisis Genómico, Centre for Epidemiological Studies on HIV/AIDS and STI of Catalonia (CEEISCAT), Spanish National Cancer Research Center (CNIO), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Clinica Universitaria, faculdad de medicina, universidad de Navarra (UNIVERSIDAD DE NAVARRA), Universidad de Navarra, Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Laboratory Medicine [San Francisco], University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Blood Systems Research Institute, Yonsei University College of Medicine, Department of Epidemiology and Biostatistics, Department of Molecular Biology [Nijmegen], Radboud University Medical Center [Nijmegen], Institute of Human Genetics, Christian-Albrechts University and University Hospital Schleswig-Holstein, Campus Kiel, Institute of Cell Biology, IFZ, University Hospital Essen, This work was funded by the European Union's Seventh Framework Programme through the Blueprint Consortium (grant agreement 282510), the Spanish Ministry of Economy and Competitivity (MINECO) (project SAF2009-08663)., Jonchère, Laurent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University of California [San Francisco] (UCSF), and University of California-University of California

Subjects
Epigenomics, Cellular differentiation, [SDV]Life Sciences [q-bio], Bisulfite sequencing, Medizin, [SDV.GEN] Life Sciences [q-bio]/Genetics, Medical and Health Sciences, Epigenesis, Genetic, 0302 clinical medicine, Cells, Cultured, Leukemic, Regulation of gene expression, B-Lymphocytes, 0303 health sciences, Cultured, Leukemia, Genome, Gene Expression Regulation, Leukemic, Cell Differentiation, Methylation, Biological Sciences, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, CpG site, 030220 oncology & carcinogenesis, DNA methylation, Sequence Analysis, Human, Cells, Biology, Article, 03 medical and health sciences, Genetic, Leukemia, B-Cell, Genetics, medicine, Humans, Molecular Biology, B cell, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Genome, Human, Human Genome, B-Cell, Sequence Analysis, DNA, DNA, DNA Methylation, Molecular biology, Gene Expression Regulation, CpG Islands, Epigenesis, Developmental Biology
Abstract

International audience; We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.

Published
2015

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