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151. Cardiovascular Events, Sleep Apnoea, and Pulmonary Hypertension in Primary Sjögren’s Syndrome: Data from the French Health Insurance Database

Author: Erik Arnaud, Nicolas Malafaye, Lucie Barateau, Jacques Morel, Pierre Fesler, Philippe Guilpain, David Montani, Thibault Mura, Camille Roubille, Radjiv Goulabchand, Arnaud Bourdin, Benoit Lattuca, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Initial MAnagement and prevention of acute orGan failures IN critically ill patiEnts (IMAGINE), Retiveau, Nolwenn, and Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM)
Subjects: medicine.medical_specialty, Population, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, pulmonary hypertension, Medicine, education, Prospective cohort study, Stroke, 030203 arthritis & rheumatology, education.field_of_study, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, ischemic heart diseases, business.industry, Incidence (epidemiology), sleep apnoea syndrome, Hazard ratio, venous thromboembolic events, Retrospective cohort study, General Medicine, medicine.disease, Pulmonary hypertension, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, cardiovascular diseases, stomatognathic diseases, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Heart failure, Sjögren’s syndrome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Primary Sjögren’s syndrome (pSS) is an autoimmune disease, associated with a high risk of lymphoma. Mounting evidence suggests that cardiovascular morbidity and mortality are higher in patients with pSS, although data are heterogeneous. The aim of this study was to assess whether pSS patients are at higher risk of hospitalisation for cardiovascular events (CVEs), venous thromboembolic events (VTEs), pulmonary hypertension (PH), and sleep apnoea syndrome (SAS). Through a nationwide population-based retrospective study using the French health insurance database, we selected new-onset pSS in-patients hospitalised between 2011 and 2018. We compared the incidence of CVEs (ischemic heart diseases (IHDs), strokes, and heart failure), SAS, VTEs, and PH with an age- and sex-matched (1:10) hospitalised control group. The calculations of adjusted hazard ratios (aHR) included available confounding factors. We studied 25,661 patients hospitalised for pSS compared with 252,543 matched patients. The incidence of hospitalisation for IHD, SAS, and PH was significantly higher in pSS patients (aHR: 1.20 (1.06–1.34), p = 0.003, aHR: 1.97 (1.70–2.28), p &lt, 0.001, and aHR: 3.32 (2.10–5.25), 0.001, respectively), whereas the incidence of stroke, heart failure, and VTE was the same between groups. Further prospective studies are needed to confirm these results and to explore the pathophysiological mechanisms involved.
Published: 2021

152. Compliance with Prescription Guidelines for Glucose-Lowering Therapies According to Renal Function: Real-Life Study in Inpatients of Internal Medicine, Endocrinology and Cardiology Units

Author: Laura Lohan, Florence Galtier, Thibault Manson, Thibault Mura, Audrey Castet-Nicolas, Delinger Faure, Nicolas Chapet, Florence Leclercq, Jean Luc Pasquié, François Roubille, Camille Roubille, Hubert Blain, Philippe Guilpain, Maxime Villiet, Antoine Avignon, Ariane Sultan, Cyril Breuker, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biocommunication en Cardio-Métabolique (BC2M), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), EuroMov - Digital Health in Motion (Euromov DHM), IMT - MINES ALES (IMT - MINES ALES), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Retiveau, Nolwenn
Subjects: Medicine (General), Cardiology, Inappropriate Prescribing, 030204 cardiovascular system & hematology, Kidney, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Article, 03 medical and health sciences, Endocrinology, R5-920, 0302 clinical medicine, Internal Medicine, Humans, Hypoglycemic Agents, Prospective Studies, 030212 general & internal medicine, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Inpatients, glucose-lowering drugs, prescription guidelines, renal function, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, Glucose, diabetes mellitus, cardiovascular medicine, Diabetes Mellitus, Type 2, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Guideline Adherence
Abstract: Background and objectives: Renal failure is a contraindication for some glucose-lowering drugs and requires dosage adjustment for others, particularly biguanides, sulfonylureas, and inhibitors of dipeptidyl peptidase 4. In this study, we assessed adherence to prescription recommendations for glucose-lowering drugs according to renal function in hospitalized diabetic subjects. Materials and Methods: This prospective cohort study was carried out over a 2-year period in a university hospital. Glomerular filtration rate (GFR) was determined by averaging all measurements performed during hospitalization. Glucose-lowering drug dosages were analyzed according to the recommendations of the relevant medical societies. Results: In total, 2071 diabetic patients (53% hospitalized in cardiology units) were examined. GFR was 2 in 13.4% of these patients, 30–44 in 15.1%, 45–60 in 18.3%, and >60 in 53.3%. Inappropriate oral glucose-lowering treatments were administered to 273 (13.2%) patients, including 53 (2.6%) with a contraindication. In cardiology units, 53.1% and 14.3% of patients had GFRs of 2, respectively, and 179 (15.4%) patients had a contraindication or were prescribed an excessive dose of glucose-lowering drugs. Conclusions: We showed that the burden of inappropriate prescriptions is high in diabetic patients. Given the high number of patients receiving these medications, particularly in cardiology units, a search for potential adverse effects related to these drugs should be performed.
Published: 2021

153. Roles of Mesenchymal Cells in the Lung: From Lung Development to Chronic Obstructive Pulmonary Disease

Author: Amel Nasri, Florent Foisset, Engi Ahmed, Zakaria Lahmar, Isabelle Vachier, Christian Jorgensen, Said Assou, Arnaud Bourdin, John De Vos, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), MORNET, Dominique, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Epithelial-Mesenchymal Transition, QH301-705.5, Organogenesis, mesenchyme, Respiratory Mucosa, Review, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Epithelium, lung, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, COPD, Biology (General), development, 030304 developmental biology, 0303 health sciences, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Cell Differentiation, Mesenchymal Stem Cells, General Medicine, respiratory system, respiratory tract diseases, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, 030228 respiratory system, Airway Remodeling, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Abstract: International audience; Mesenchymal cells are an essential cell type because of their role in tissue support, their multilineage differentiation capacities and their potential clinical applications. They play a crucial role during lung development by interacting with airway epithelium, and also during lung regeneration and remodeling after injury. However, much less is known about their function in lung disease. In this review, we discuss the origins of mesenchymal cells during lung development, their crosstalk with the epithelium, and their role in lung diseases, particularly in chronic obstructive pulmonary disease.
Published: 2021

154. Moderate deformation of cartilage micropellets in a fluidic custom-made device enhances the expression of chondrocyte markers

Author: PETITJEAN, Noémie, Maumus, Marie, Dusfour, Gilles, Cañadas, Patrick, Jorgensen, Christian, Royer, Pascale, Lefloch, S., Noël, Danièle, Gibier, François, Biomécanique des Interactions et de l'Organisation des Tissus et des Cellules (BIOTIC), Laboratoire de Mécanique et Génie Civil (LMGC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: [SPI.MECA.BIOM] Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

155. COMBINATION OF AMOXICILLIN/CLAVULANATE AND PREDNISOLONE IN SEVERE ALCOHOLIC HEPATITIS: RESULTS OF THE ANTIBIOCOR RANDOMIZED CONTROLLED TRIAL

Author: Louvet, Alexandre, Labreuche, Julien, Dao, Thong, Thevenot, Thierry, Oberti, Frederic, Bureau, Christophe, Paupard, Thierry, Nguyen-Khac, Eric, Franza, Anne Minello, Chabert, Brigitte Bernard, Anty, Rodolphe, Wartel, Faustine, Carbonell, Nicolas, Pageaux, Georges-Philippe, Leroy, Vincent, Legros, Ludivine, Nahon, Pierre, Potey, Camille, Duhamel, Alain, Mathurin, Philippe, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], 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), Service d'Hépatologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Toulouse [Toulouse], Centre Hospitalier de Dunkerque, Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre d'Endoscopie Digestive [CHU Saint-Antoine], CHU Saint-Antoine [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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pontchaillou [Rennes], Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de PharmacoVigilance Nord-Pas-de-Calais [CHU Lille] (CRPV), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille, Physiopathologie des Maladies Inflammatoires de l'Intestin, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

156. International study on the outcome of locoregional therapy for liver transplant in hepatocellular carcinoma beyond Milan criteria

Author: Helena Degroote, Federico Piñero, Charlotte Costentin, Andrea Notarpaolo, Ilka F. Boin, Karim Boudjema, Cinzia Baccaro, Aline Lopes Chagas, Philippe Bachellier, Giuseppe Maria Ettorre, Jaime Poniachik, Fabrice Muscari, Fabrio Di Benedetto, Sergio Hoyos Duque, Ephrem Salame, Umberto Cillo, Adrián Gadano, Claire Vanlemmens, Stefano Fagiuoli, Fernando Rubinstein, Patrizia Burra, Daniel Cherqui, Marcelo Silva, Hans Van Vlierberghe, Christophe Duvoux, Filomena Conti, Olivier Scatton, Pierre Henri Bernard, Claire Francoz, Francois Durand, Sébastien Dharancy, Marie-lorraine Woehl, Alexis Laurent, Sylvie Radenne, Jérôme Dumortier, Armand Abergel, Louise Barbier, Pauline Houssel-Debry, Georges Philippe Pageaux, Laurence Chiche, Victor Deledinghen, Jean Hardwigsen, J. Gugenheim, M. Altieri, Marie Noelle Hilleret, Thomas Decaens, Aline Chagas, Paulo Costa, Elaine Cristina de Ataide, Emilio Quiñones, Sebastián Marciano, Margarita Anders, Adriana Varón, Alina Zerega, Alejandro Soza, Martín Padilla Machaca, Diego Arufe, Josemaría Menéndez, Rodrigo Zapata, Mario Vilatoba, Linda Muñoz, Ricardo Chong Menéndez, Martín Maraschio, Luis G. Podestá, M. Fauda, A. Gonzalez Campaña, Lucas McCormack, Juan Mattera, Adrian Gadano, Ilka S.F. Fatima Boin, Jose Huygens Parente García, Flair Carrilho, Giulia Magini, Lucia Miglioresi, Martina Gambato, Fabrizio Di Benedetto, Cecilia D’Ambrosio, Alessandro Vitale, Michele Colledan, Domenico Pinelli, Paolo Magistri, Giovanni Vennarecci, Marco Colasanti, Valerio Giannelli, Adriano Pellicelli, Cizia Baccaro, Callebout Eduard, Iesari Samuele, Dekervel Jeroen, Schreiber Jonas, Pirenne Jacques, Verslype Chris, Ysebaert Dirk, Michielsen Peter, Lucidi Valerio, Moreno Christophe, Detry Olivier, Delwaide Jean, Troisi Roberto, Lerut Jan Paul, Ghent University Hospital, 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 (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Arcispedale S Maria Nuova, University of Campinas [Campinas] (UNICAMP), CHU Pontchaillou [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), CHU Strasbourg, Hôpital de Rangueil, CHU Toulouse [Toulouse], Universidad de Antioquia = University of Antioquia [Medellín, Colombia], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Degroote, H, Piñero, F, Costentin, C, Notarpaolo, A, Boin, I, Boudjema, K, Baccaro, C, Chagas, A, Bachellier, P, Ettorre, G, Poniachik, J, Muscari, F, Di Benedetto, F, Duque, S, Salame, E, Cillo, U, Gadano, A, Vanlemmens, C, Fagiuoli, S, Rubinstein, F, Burra, P, Cherqui, D, Silva, M, Van Vlierberghe, H, Duvoux, C, Universidade Estadual de Campinas = University of Campinas (UNICAMP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Rennes (UR), and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: RFA, LRT, Hepatocellular carcinoma, ITT, University of California San Francisco downstaging, medicine.medical_treatment, RC799-869, Liver transplantation, Gastroenterology, United Network for Organ Sharing, SHR, hazard ratio, 0302 clinical medicine, HR, UCSF-DS, HCC, 10. No inequality, All-comer, Milan criteria, AC, all-comers, Hazard ratio, intention to treat, Diseases of the digestive system. Gastroenterology, 3. Good health, MVI, MVI, microvascular invasion, 030220 oncology & carcinogenesis, liver resection, 030211 gastroenterology & hepatology, radiofrequency ablation, Cohort study, UNOS, medicine.medical_specialty, education, AFP, LT, liver transplantation, 03 medical and health sciences, alpha-foetoprotein, Downstaging, UNOS, United Network for Organ Sharing, TACE, medicine.disease, HR, hazard ratio, UCSF downstaging protocol, AC, ITT, intention to treat, PEI, Clinical trial, DS, downstaging, SHR, subdistribution hazard ratio, locoregional therapies, percutaneous ethanol ablation, AFP, alpha-foetoprotein, EASL, European Association for the Study of the Liver, [SDV]Life Sciences [q-bio], microvascular invasion, LR, LT, Medicine and Health Sciences, UCSF-DS, University of California San Francisco downstaging, Immunology and Allergy, MC, DS, PEI, percutaneous ethanol ablation, all-comers, liver transplantation, waiting list, COMPETING RISKS, CANCER, Research Article, European Association for the Study of the Liver, ALPHA-FETOPROTEIN, MC, Milan criteria, WL, waiting list, EASL, VALIDATION, Internal medicine, Internal Medicine, medicine, subdistribution hazard ratio, WL, LRT, locoregional therapies, RFA, radiofrequency ablation, transarterial chemoembolisation, Intention-to-treat analysis, Hepatology, business.industry, TACE, transarterial chemoembolisation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, All-comers, Alpha-foetoprotein, HCC, hepatocellular carcinoma, LR, liver resection, MODEL, Transplantation, business
Abstract: Background & Aims Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and ‘all-comers’. Methods This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000–2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. Results From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8–55.8) and 38.2% (CI 25.4–52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p, Graphical abstract, Highlights • Successful downstaging from UCSF criteria resulted in a similar outcome compared with the group initially within Milan criteria. • Patients within UCSF-DS criteria and with AFP values below or equal to 20 ng/ml at listing have excellent survival and recurrence rates. • All-comers have a higher recurrence after downstaging to Milan criteria, with frequent microvascular invasion in the explant.
Published: 2021

157. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

Author: Sylvain Vergnet, Jean Phillipe Azulay, Isabelle Meunier, Audrey Riquet, Olivier Patat, Anna Castrioto, Laurent Pasquier, Cyril Charlin, Lena Damaj, Cécile Acquaviva, Nicolas Lebouc, Bérénice Doray, Cecilia Marelli, Morgane Pointaux, Pierre Meyer, Perrine Charles, Danielle Cuntz-Shadfar, Caroline Tillikete, Frederic Villega, Cathy Lieutard-Haag, Michel Koenig, François Rivier, Idriss Bousquet, Ganaëlle Remerand, Ulrike Walther-Louvier, Clarisse Carra-Dalliere, Victoria Gonzales, Alexandre Eusebio, Brigitte Chabrol, Emilie Carme, Pierre Labauge, Adrian Degardin, Elise Brischoux-Boucher, Brice Laurens, Laurent Kremer, Giovanni Castelnovo, Mélanie Fradin, Mehdi Benkirane, Karine Nguyen, Jean-Marie Ravel, Vincent Laugel, Emilien Bernard, Claire Guissart, Cyril Goizet, Samira Sissaoui, Agathe Roubertie, Christine Francannet, Sylvie Odent, Yosra Halleb, Xavier Ayrignac, Shahram Attarian, Fabienne Ory Magne, David Geneviève, Joel Victor Fluss, Alain Verloes, Anne Rolland, Martial Mallaret, Lydia Abou Haidar, Nadia Bahi-Buisson, David Baux, Catherine Sarret, Nicolas Carrière, Christine Coubes, Mathilde Renaud, Claire Ewenczyk, Patrick Calvas, Solène Frismand, Leila Lazaro, Bertrand Isidor, Annabelle Chaussenot, Sophie Julia, Valerie Fraix, Elsa Kaphan, Tatiana Witjas, Frédérique Fluchère, Mathieu Anheim, Christine Tranchant, William Camu, Eric Thouvenot, Lise Larrieu, Eric Bieth, Ariane Choumert, Raoul Morales, Marinha Costa Moreira, Elizabeth Ollagnon, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), 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)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Bordeaux [Bordeaux], Institut NeuroMyoGène (INMG), 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), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Strasbourg, CHU Pontchaillou [Rennes], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospitals and Geneva University, Hôpital Robert Debré, and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: medicine.medical_specialty, Ataxia, Cerebellar Ataxia, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Genomics, Biology, PEX10, Cohort Studies, Peroxins, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, Translation reinitiation, 0303 health sciences, Molecular pathology, 030305 genetics & heredity, Phenotype, Human genetics, United States, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, medicine.symptom, 030217 neurology & neurosurgery
Abstract: International audience; Purpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
Published: 2021

158. Effet thérapeutique des vésicules extracellulaires isolées à partir de cellules stromales mésenchymateuses dans la sclérodermie systémique

Author: Rozier, Pauline, STAR, ABES, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Montpellier, Philippe Guilpain, and Danièle Noel
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Cellules stromales mésenchymateuses, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, integumentary system, Vésicules extracellulaires, TGFβ1, Mesenchymal stromal cells, Systemic sclerosis, Fibrose, Extracellular vesicles, Fibrosis, Sclérodermie systémique, MiR-29a-3p
Abstract: Systemic sclerosis (SSc) is a rare and severe disease characterized by generalized fibrosis, vasculopathy and deregulation of immune cells. No curative treatment is validated to date. Mesenchymal stromal cells (MSCs) are being evaluated in clinical trials as they are effective in several preclinical models of SSc. They exert their anti-fibrotic, pro-angiogenic and immunomodulatory properties through the secretion of mediators contained in extracellular vesicles (EVs). We investigate here the role of EVs released by MSCs in their systemic effect during SSc.In a murine model of hypochlorous acid-induced SSc, we demonstrate that EVs can stop the disease course and improve histological and molecular parameters in skin and lung samples. We identify miR-29a-3p expression in both MSCs and their EVs and prove that miR-29a-3p is responsible for a large part of their therapeutic effect, targeting Dnmt3a and Pdgfr-bb, two novel targets identified in SSc.We improve the therapeutic efficacy of EVs on lung abnormalities in SSc mice by stimulating MSCs with IFNγ before EVs production whereas increasing the amount of injected EVs did not have any benefit. IFNγ modulates the expression of known immunosuppressive factors in both MSCs and EVs, potentiating their therapeutic properties.While the role of MSCs from SSc patients (SSc MSCs) in the development of the disease is debated, we show that SSc MSCs inhibit in vitro T lymphocyte proliferation and improve the myofibroblastic phenotype obtained after fibroblast stimulation using TGFβ1 which display a similar profile as fibroblasts from SSc patients in the in vitro model used here.Overall, MSC-EVs are as effective as MSCs to stop the progression of murine SSc and EVs from IFNγ-preconditioned MSCs improve their beneficial effect in the lungs. SSc MSCs maintain their anti-fibrotic and immunosuppressive properties in vitro and one of our perspectives is to evaluate their therapeutic efficacy in vivo., La sclérodermie systémique (ScS) est une maladie rare et sévère, caractérisée par une dérégulation des cellules immunitaires, une fibrose et une vasculopathie généralisées. Aucun traitement curatif n’est validé à ce jour. Les cellules stromales mésenchymateuses (CSMs), dont l’efficacité a été démontrée dans plusieurs modèles précliniques de ScS, sont actuellement évaluées dans des essais cliniques. Elles exercent leurs propriétés régénératrices au travers de la sécrétion de médiateurs libérés dans le milieu extracellulaire ou contenus dans des vésicules extracellulaires (EVs). Nous nous intéressons ici au rôle des EVs libérées par les CSMs dans leur effet systémique au cours de la ScS.Dans un modèle murin de ScS induit par des injections d’acide hypochloreux, nous démontrons que les EVs stoppent l’évolution de la maladie au niveau cutané et pulmonaire sur le plan clinique, histologique et moléculaire. Nous identifions miR-29a-3p au sein des CSMs et de leurs EVs et prouvons qu’il est garant de leur effet thérapeutique, en ciblant Dnmt3a et Pdgfr-bb, deux nouvelles cibles identifiées dans la ScS.Nous améliorons l’efficacité thérapeutique des EVs sur les anomalies pulmonaires en pré-activant les CSMs à l’aide d’IFNγ alors que l’augmentation de la quantité d’EVs injectées n’a aucun effet. L’IFNγ module l’expression de molécules immunosuppressives dans les CSMs et leurs EVs, potentialisant ainsi leurs propriétés thérapeutiques.Alors que le rôle des CSMs de patients (CSMs-ScS) dans le développement de la maladie est sujet à débat, nous montrons que les CSMs-ScS inhibent in vitro la prolifération des lymphocytes T de manière similaire à des CSMs saines. En outre, elles sont capables d’améliorer le phénotype myofibroblastique de fibroblastes stimulés par du TGFβ1 qui présentent un comportement similaire à celui de fibroblastes de patients dans le modèle in vitro mis en place.En conclusion, les EVs sont aussi efficaces que les CSMs pour traiter la ScS murine et le pré-conditionnement des CSMs par l’IFNγ améliore leur effet au niveau pulmonaire. Les CSMs de patients conservent leurs fonctions anti-fibrotique et immunosuppressive in vitro et une de nos perspectives est d’évaluer leur efficacité thérapeutique in vivo.
Published: 2021

159. Customized frozen embryo transfer after identification of the receptivity window with a transcriptomic approach improves the implantation and live birth rates in patients with repeated implantation failure

Author: Haouzi, Delphine, Entezami, Frida, Torre, Antoine, Innocenti, Charlène, Antoine, Yannick, Mauries, Charlotte, Vincens, Claire, Bringer-Deutsch, Sophie, Gala, Anna, Ferrieres-HOA, Alice, Ohl, Jeanine, Gonzalez Marti, Beatriz, Brouillet, Sophie, Hamamah, Samir, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Développement Embryonnaire, Fertilité et Environnement (DEFE), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Américain de Paris, Clinique de la Muette, University of Nottingham, UK (UON), Centre Médico-chirurgical Obstétrique (CMCO ), CHU Strasbourg, Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), This work was partially supported by a grant from the Gedeon Richter Pharmaceutical Company (N° FORWARD2018_4), Salvy-Córdoba, Nathalie, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Time Factors, Pregnancy Rate, MESH: Treatment Failure, Fertilization in Vitro, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Win-Test, MESH: Gene Expression Profiling, MESH: Embryo Implantation, MESH: Pregnancy, Pregnancy, Receptivity window, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Cryopreservation, Humans, Embryo Implantation, Prospective Studies, Treatment Failure, MESH: Infertility, Cryopreservation, MESH: Pregnancy Rate, MESH: Humans, Gene Expression Profiling, MESH: Transcriptome, MESH: Time Factors, MESH: Adult, MESH: Embryo Transfer, Embryo Transfer, MESH: Prospective Studies, MESH: Fertilization in Vitro, MESH: France, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Implantation window, Infertility, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], MESH: Live Birth, Original Article, Female, France, Transcriptome, Live Birth, MESH: Female
Abstract: The aim of this prospective study was to evaluate outcome benefits expected in repeated implantation failure (RIF) patients (n = 217) after customized embryo transfer based upon identification of the receptivity window by transcriptomic approach using the Win-Test. In this test, the expression of 11 endometrial genes known to be predictive of endometrial receptivity is assessed by RT-PCR in biopsies collected during the implantation window (6–9 days after the spontaneous luteinizing hormone surge during natural cycles, 5–9 days after progesterone administration during hormone replacement therapy cycles). Then, patients underwent either customized embryo transfer (cET, n = 157 patients) according to the Win-Test results or embryo transfer according to the classical procedure (control group, n = 60). Pregnancy and live birth rates were compared in the two groups. The Win-Test showed that in 78.5% of women, the receptivity window lasted less than 48 h, although it could be shorter ( 48 h, 12%). This highlighted that only in 20% of patients with RIF the endometrium would have been receptive if the classical embryo transfer protocol was followed. In the other 80% of patients, the receptivity window was delayed by 1–3 days relative to the classical timing. This suggests that implantation failure could be linked to inadequate timing of embryo transfer. In agreement, both implantation (22.7% vs. 7.2%) and live birth rates per patient (31.8% vs. 8.3%) were significantly higher in the cET group than in the control group. cET on the basis of the Win-Test results could be proposed to improve pregnancy and live birth rates. ClinicalTrials.gov ID: NCT04192396; December 5, 2019, retrospectively registered. Electronic supplementary material The online version of this article (10.1007/s43032-020-00252-0) contains supplementary material, which is available to authorized users.
Published: 2021

160. Musculoskeletal Progenitor/Stromal Cell-Derived Mitochondria Modulate Cell Differentiation and Therapeutical Function

Author: Christian Jorgensen, Maroun Khoury, Retiveau, Nolwenn, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universidad de los Andes [Santiago] (UANDES), and Universidad de los Andes [Bogota] (UNIANDES)
Subjects: 0301 basic medicine, MESH: Oxidation-Reduction, MESH: Signal Transduction, Cellular differentiation, Cell Culture Techniques, Cell- and Tissue-Based Therapy, Review, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Mitochondrion, 0302 clinical medicine, Immunology and Allergy, MESH: Animals, MESH: Cell- and Tissue-Based Therapy, MESH: Myoblasts, Skeletal, Stem cell, Chemistry, MESH: Energy Metabolism, MESH: Reactive Oxygen Species, Cell Differentiation, Cellular Reprogramming, Cell biology, Mitochondria, 030220 oncology & carcinogenesis, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Oxidation-Reduction, Signal Transduction, lcsh:Immunologic diseases. Allergy, MESH: Cell Differentiation, Stromal cell, MESH: Mitochondria, Myoblasts, Skeletal, Immunology, MESH: Immunomodulation, Oxidative phosphorylation, Mesenchymal Stem Cell Transplantation, Musculoskeletal progenitor/stromal cells, MESH: Cellular Reprogramming, Immunomodulation, 03 medical and health sciences, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, MESH: Mesenchymal Stem Cell Transplantation, Protein kinase B, PI3K/AKT/mTOR pathway, MESH: Cell Culture Techniques, Immunometabolism, MESH: Humans, Mesenchymal stem cell, Mesenchymal Stem Cells, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, 030104 developmental biology, MESH: Mesenchymal Stem Cells, Anaerobic glycolysis, MESH: Biomarkers, lcsh:RC581-607, Energy Metabolism, Reactive Oxygen Species, Biomarkers, Immunosuppression
Abstract: Musculoskeletal stromal cells’ (MSCs’) metabolism impacts cell differentiation as well as immune function. During osteogenic and adipogenic differentiation, BM-MSCs show a preference for glycolysis during proliferation but shift to an oxidative phosphorylation (OxPhos)-dependent metabolism. The MSC immunoregulatory fate is achieved with cell polarization, and the result is sustained production of immunoregulatory molecules (including PGE2, HGF, IL1RA, IL6, IL8, IDO activity) in response to inflammatory stimuli. MSCs adapt their energetic metabolism when acquiring immunomodulatory property and shift to aerobic glycolysis. This can be achieved via hypoxia, pretreatment with small molecule-metabolic mediators such as oligomycin, or AKT/mTOR pathway modulation. The immunoregulatory effect of MSC on macrophages polarization and Th17 switch is related to the glycolytic status of the MSC. Indeed, MSCs pretreated with oligomycin decreased the M1/M2 ratio, inhibited T-CD4 proliferation, and prevented Th17 switch. Mitochondrial activity also impacts MSC metabolism. In the bone marrow, MSCs are present in a quiescent, low proliferation, but they keep their multi-progenitor function. In this stage, they appear to be glycolytic with active mitochondria (MT) status. During MSC expansion, we observed a metabolic shift toward OXPhos, coupled with an increased MT activity. An increased production of ROS and dysfunctional mitochondria is associated with the metabolic shift to glycolysis. In contrast, when MSC underwent chondro or osteoblast differentiation, they showed a decreased glycolysis and inhibition of the pentose phosphate pathway (PPP). In parallel the mitochondrial enzymatic activities increased associated with oxidative phosphorylation enhancement. MSCs respond to damaged or inflamed tissue through the transfer of MT to injured and immune cells, conveying a type of signaling that contributes to the restoration of cell homeostasis and immune function. The delivery of MT into injured cells increased ATP levels which in turn maintained cellular bioenergetics and recovered cell functions. MSC-derived MT may be transferred via tunneling nanotubes to undifferentiated cardiomyocytes and leading to their maturation. In this review, we will decipher the pathways and the mechanisms responsible for mitochondria transfer and activity. The eventual reversal of the metabolic and pro-inflammatory profile induced by the MT transfer will open new avenues for the control of inflammatory diseases.
Published: 2021

161. Using deep-neural-network-driven facial recognition to identify distinct Kabuki syndrome 1 and 2 gestalt

Author: Didier Lacombe, Claire Duflos, David Geneviève, Jeanne Amiel, Elodie Sanchez, Yline Capri, Damien Sanlaville, Marlène Rio, Alexandra Afenjar, Fabienne Giuliano, Elise Brischoux-Boucher, Mathilde Nizon, Stanislas Lyonnet, Sébastien Moutton, Vincent Gatinois, Stéphanie Arpin, Annick Toutain, Mouna Barat-Houari, Guilaine Boursier, Flavien Rouxel, Sophie Julia, Klaus Dieterich, Aurélia Jacquette, Boris Keren, Kevin Yauy, Patricia Blanchet, Marie-Line Jacquemont, Damien Haye, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Lausanne (UNIL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), CHU Grenoble, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), GRC ConCer-LD, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maison de Santé Protestante Bagatelle, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), and Hospices Civils de Lyon (HCL)
Subjects: Image Series, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Biology, [INFO.INFO-NE]Computer Science [cs]/Neural and Evolutionary Computing [cs.NE], Facial recognition system, Article, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Artificial neural network, Receiver operating characteristic, business.industry, Significant difference, Genetic disorder, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, medicine.disease, Hematologic Diseases, Vestibular Diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, Gestalt psychology, Artificial intelligence, business, Kabuki syndrome, Facial Recognition
Abstract: International audience; Kabuki syndrome (KS) is a rare genetic disorder caused by mutations in two major genes, KMT2D and KDM6A, that are responsible for Kabuki syndrome 1 (KS1, OMIM147920) and Kabuki syndrome 2 (KS2, OMIM300867), respectively. We lack a description of clinical signs to distinguish KS1 and KS2. We used facial morphology analysis to detect any facial morphological differences between the two KS types. We used a facial-recognition algorithm to explore any facial morphologic differences between the two types of KS. We compared several image series of KS1 and KS2 individuals, then compared images of those of Caucasian origin only (12 individuals for each gene) because this was the main ethnicity in this series. We also collected 32 images from the literature to amass a large series. We externally validated results obtained by the algorithm with evaluations by trained clinical geneticists using the same set of pictures. Use of the algorithm revealed a statistically significant difference between each group for our series of images, demonstrating a different facial morphotype between KS1 and KS2 individuals (mean area under the receiver operating characteristic curve = 0.85 [p = 0.027] between KS1 and KS2). The algorithm was better at discriminating between the two types of KS with images from our series than those from the literature (p = 0.0007). Clinical geneticists trained to distinguished KS1 and KS2 significantly recognised a unique facial morphotype, which validated algorithm findings (p = 1.6e-11). Our deep-neural-network-driven facial-recognition algorithm can reveal specific composite gestalt images for KS1 and KS2 individuals.
Published: 2021

162. Deportalization, Venous Congestion, Venous Deprivation: Serial Measurements of Volumes and Functions on Morphofunctional 99mTc-Mebrofenin SPECT-CT

Author: François Quenet, Margaux Hermida, Eric Assenat, Georges-Philippe Pageaux, Nicolas Molinari, Emmanuel Deshayes, Christophe Cassinotto, Boris Guiu, Carole Allimant, Fabrizio Panaro, Lauranne Piron, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Montpelliérain Alexander Grothendieck (IMAG), Herrada, Anthony, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: medicine.medical_treatment, Clinical Biochemistry, Scintigraphy, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, hepatectomy, Venous congestion, interventional radiology, medicine, hepatic veins, Embolization, radionuclide imaging, liver regeneration, lcsh:R5-920, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, 99mTc mebrofenin, business.industry, Interventional radiology, Liver regeneration, 030220 oncology & carcinogenesis, Hepatectomy, lcsh:Medicine (General), Nuclear medicine, business, Emission computed tomography, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The objective was to assess the changes in regional volumes and functions under venous-impaired vascular conditions following liver preparation. Twelve patients underwent right portal vein embolization (PVE) (n = 5) or extended liver venous deprivation (eLVD, i.e., portal and right and middle hepatic veins embolization) (n = 7). Volume and function measurements of deportalized liver, venous-deprived liver and congestive liver were performed before and after PVE/eLVD at days 7, 14 and 21 using 99mTc-mebrofenin hepatobiliary scintigraphy with single-photon emission computed tomography and computed tomography (99mTc-mebrofenin SPECT-CT). Volume and function progressed independently in the deportalized liver (p = 0.47) with an early decrease in function (median −18.2% (IQR, −19.4–−14.5) at day 7) followed by a decrease in volume (−19.3% (−22.6–−14.4) at day 21). Volume and function progressed independently in the venous deprived liver (p = 0.80) with a marked and early decrease in function (−41.1% (−52.0–−12.9) at day 7) but minimal changes in volume (−4.7% (−10.4–+3.9) at day 21). Volume and function progressed independently in the congestive liver (p = 0.21) with a gradual increase in volume (+43.2% (+38.3–+51.2) at day 21) that preceded a late and moderate increase in function at day 21 (+34.8% (−8.3–+46.6)), concomitantly to the disappearance of hypoattenuated congestive areas in segment IV (S4) on CT, initially observed in 6/7 patients after eLVD and represented 35.3% (22.2–46.4) of whole S4 volume. Liver volume and function progress independently whatever the vascular condition. Hepatic congestion from outflow obstruction drives volume increase but results in early impaired function.
Published: 2021

163. Atteintes myocardiques au cours de la maladie à coronavirus 19 (Covid-19) : principaux mécanismes physiopathologiques et utilité clinique des biomarqueurs cardiaques

Author: Kamel, Saïd, Raynor, Alexandre, Zozor, Samuel, Lacape, Geneviève, Brunel, Valéry, Nivet-Antoine, Valérie, Collin-Chavagnac, Delphine, Peoc’h, Katell, Cohen, Ariel, Lassoued, Amin Ben, Chévrier, Marc, Alemann, Mathieu, Lessinger, Jean-Marc, Bérard, Annie, Sapin, Vincent, Beauvieux, Marie-Christine, Levy, Pacifique, Lehmann, Sylvain, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Bordeaux [Bordeaux], Université de Bordeaux (UB), Laboratoire de biochimie générale [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Saint-Antoine [AP-HP], Thrombose, atherothrombose et pharmacologie appliquée, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Hôpital de la Timone [CHU - APHM] (TIMONE), Hospices Civils de Lyon (HCL), Nouvel Hôpital Civil de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA), Centre de résonance magnétique des systèmes biologiques (CRMSB), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Pour le Groupe de Travail de la SFBC « Marqueurs Biochimiques de la pathologie Covid-19 »: Isabelle Aimone-Gastin, Stéphanie Alcaraz, Stéphane Allouche, Malika Balduyck, Françoise Barbé, Yann Barguil, Jean-Philippe Bastard, Jean-Louis Beaudeux, Marie-Christine Beauvieux, Amin Ben Lassoued, Isabelle Benz de Bretagne, Annie Bérard, Laurent Bermont, Edith Bigot-Corbel, Muriel Bost, Valery Bourbonneux, Valery Brunel, Jean-Luc Carré, Camille Chenevier-Gobeaux, Marc Chevrier, Giulia Chinetti, Delphine Collin-Chavagnac, Hervé Delacour, Delphine Delevallée, François Desroys du Roure, Patrice Faure, Jean-Philippe Galhaud, Anne Galinier, Thierry Hauet, Carine Helj, Emilie Jolly, Said Kamel, Sylvain Lehmann, Aline Leroy, Jean-Marc Lessenger, Pacifique Levy, Anne-Marie Lorec-Penet, Samir Mesli, Dagui Monnet, Caroline Moreau, Laurence Mouly, Valérie Nivet-Antoine, Nathalie Oueidat, Mathieu Pecquet, Katell Peoc’h, Laurence Piéroni, Carole Poupon, Martine Roubille, Benoit Rucheton, Medhi Sakka, Vincent Sapin, Vincent Saunier, Florian Scherrer, François Schmitt, Sabine Zaepfel, Samuel Zozor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), VIAUD, Karine, Normandie Université (NU)-Centre hospitalier universitaire de Rouen, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)
Subjects: Adult, Male, medicine.medical_specialty, Myocarditis, [SDV]Life Sciences [q-bio], Myocardial Infarction, troponine, Disease, Systemic inflammation, Predictive Value of Tests, Internal medicine, myocarde, Coagulopathy, medicine, myocardium, Humans, Hospital Mortality, Myocardial infarction, Pandemics, Aged, Aged, 80 and over, Endocarditis, biology, business.industry, SARS-CoV-2, troponin, Heart, General Medicine, Middle Aged, Prognosis, medicine.disease, Troponin, Pathophysiology, 3. Good health, myocardite, [SDV] Life Sciences [q-bio], peptides natriurétiques, biology.protein, Cardiology, Female, France, Myocardial infarction diagnosis, medicine.symptom, myocarditis, business, Covid-19, natriuretic peptides, Biomarkers
Abstract: International audience; Covid-19 is responsible for myocardial injury in many infected patients, which is associated with severe disease and critical illness. The mechanisms by which SARS-CoV-2 may cause myocardial damage involve direct effect of the virus in cardiac cells and indirect effect due to the clinical consequences of Covid-19. Cardiomyocytes are well known to express Angiotensin-Converting Enzyme-2 receptors (ACE-2) to facilitate the virus cell entry, which could explain the occurrence of myocarditis, functional alterations in the myocardium, and more rarely, myocardial infarction. Myocardial injury may also be secondary to systemic inflammation or coagulopathy due to complicated Covid-19. The existence of a cardio-intestinal axis with alteration of tryptophan metabolism in the small bowel leading first to colitis and then to systemic inflammation has also been evoked to explain the myocardial injury. Morphological and metabolic disturbances of the heart during the Covid-19 are associated with elevated concentrations of cardiac blood biomarkers, mainly troponins and natriuretic peptides. The determination of these biomarkers has proven to be very useful for diagnosis, prognosis, and risk stratification. Indeed, recent data demonstrated that about 20% of infected patients admitted to the hospital have elevated troponin or BNP levels, and Covid-19 patients with elevated troponin concentrations beyond the diagnostic threshold (99th percentile) were associated with a higher risk of in-hospital mortality. In conclusion, after more than a year of a unique global pandemic, it is now clearly established that myocardial injury during Covid-19 is frequent and strongly contributes to the severity of the disease. Cardiac alterations secondary to direct infection of cardiac cells by SARS-CoV-2 or to the clinical consequences of Covid-19 are associated with elevated levels of cardiac biomarkers in blood, whose measurement is crucial in clinical decision making.
Published: 2021

164. Targeted therapy in eosinophilic chronic obstructive pulmonary disease

Author: Aurélie Fort, Engi Ahmed, Arnaud Bourdin, Said Assou, Amel Nasri, Isabelle Vachier, John De Vos, Mathieu Fieldes, Chloé Bourguignon, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), MORNET, Dominique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Desbrest de santé publique (IDESP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_treatment, Review, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Eosinophilic, medicine, Eosinophilia, 030212 general & internal medicine, Asthma, COPD, Lung, business.industry, Incidence (epidemiology), [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, respiratory system, medicine.disease, Pathophysiology, 3. Good health, respiratory tract diseases, medicine.anatomical_structure, 030228 respiratory system, Immunology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Medicine, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.symptom, business
Abstract: Chronic obstructive pulmonary disease (COPD) is a common and preventable airway disease causing significant worldwide mortality and morbidity. Lifetime exposure to tobacco smoking and environmental particles are the two major risk factors. Over recent decades, COPD has become a growing public health problem with an increase in incidence. COPD is defined by airflow limitation due to airway inflammation and small airway remodelling coupled to parenchymal lung destruction. Most patients exhibit neutrophil-predominant airway inflammation combined with an increase in macrophages and CD8+ T-cells. Asthma is a heterogeneous chronic inflammatory airway disease. The most studied subtype is type 2 (T2) high eosinophilic asthma, for which there are an increasing number of biologic agents developed. However, both asthma and COPD are complex and share common pathophysiological mechanisms. They are known as overlapping syndromes as approximately 40% of patients with COPD present an eosinophilic airway inflammation. Several studies suggest a putative role of eosinophilia in lung function decline and COPD exacerbation. Recently, pharmacological agents targeting eosinophilic traits in uncontrolled eosinophilic asthma, especially monoclonal antibodies directed against interleukins (IL-5, IL-4, IL-13) or their receptors, have shown promising results. This review examines data on the rationale for such biological agents and assesses efficacy in T2-endotype COPD patients., Patients with severe COPD and eosinophilic inflammation experience uncontrolled symptoms despite optimal pharmaceutical treatment. The development of new biomarkers is needed for better phenotyping of patients to propose innovative targeted therapy. https://bit.ly/2KzWuNO
Published: 2021

165. Dynamic prediction of renal survival among deeply phenotyped kidney transplant recipients using artificial intelligence: an observational, international, multicohort study

Author: Raynaud, Marc, Aubert, Olivier, Divard, Gillian, Reese, Peter P, Kamar, Nassim, Yoo, Daniel, Chin, Chen-Shan, Bailly, Élodie, Buchler, Matthias, Ladrière, Marc, Le Quintrec, Moglie, Delahousse, Michel, Jurić, Ivana, Bašić-Jukić, Nikolina, Crespo, Marta, Silva, Helio Tedesco, Linhares, Kamilla, Ribeiro de Castro, Maria Cristina, Soler Pujol, Gervasio, Empana, Jean-Philippe, Ulloa, Camilo, Akalin, Enver, Böhmig, Georg, Huang, Edmund, Stegall, Mark D, Bentall, Andrew J, Montgomery, Robert A, Jordan, Stanley C, Oberbauer, Rainer, Segev, Dorry L, Friedewald, John J, Jouven, Xavier, Legendre, Christophe, Lefaucheur, Carmen, Loupy, Alexandre, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Pennsylvania, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Néphrologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Lorraine (UL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Foch [Suresnes], University of Zagreb, University Hospital Centre Zagreb, Partenaires INRAE, IMIM-Hospital del Mar, Generalitat de Catalunya, Universidade Federal de São Paulo, Universidade de São Paulo = University of São Paulo (USP), Albert Einstein College of Medicine [New York], Cedars-Sinai Medical Center, Mayo Clinic [Rochester], New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Medizinische Universität Wien = Medical University of Vienna, Johns Hopkins University School of Medicine [Baltimore], Northwestern University Feinberg School of Medicine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hopital Saint-Louis [AP-HP] (AP-HP), and Herrada, Anthony
Subjects: Male, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, MESH: Allografts, Kidney, MESH: Risk Assessment, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Kidney Transplantation, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Postoperative Complications, MESH: Postoperative Complications, MESH: Renal Insufficiency, artificial intelligence, kidney transplant, Renal Insufficiency, MESH: Middle Aged, Middle Aged, Allografts, Prognosis, MESH: Reproducibility of Results, Proteinuria, Area Under Curve, Female, Glomerular Filtration Rate, Adult, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], MESH: Transplant Recipients, MESH: Bayes Theorem, Computer applications to medicine. Medical informatics, R858-859.7, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Models, Biological, Risk Assessment, MESH: Prognosis, Artificial Intelligence, MESH: Proteinuria, Humans, MESH: Artificial Intelligence, MESH: Humans, MESH: Models, Biological, Reproducibility of Results, Bayes Theorem, MESH: Adult, MESH: Kidney, Kidney Transplantation, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Transplant Recipients, MESH: Male, MESH: Glomerular Filtration Rate, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Area Under Curve, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female
Abstract: Summary: Background: Kidney allograft failure is a common cause of end-stage renal disease. We aimed to develop a dynamic artificial intelligence approach to enhance risk stratification for kidney transplant recipients by generating continuously refined predictions of survival using updates of clinical data. Methods: In this observational study, we used data from adult recipients of kidney transplants from 18 academic transplant centres in Europe, the USA, and South America, and a cohort of patients from six randomised controlled trials. The development cohort comprised patients from four centres in France, with all other patients included in external validation cohorts. To build deeply phenotyped cohorts of transplant recipients, the following data were collected in the development cohort: clinical, histological, immunological variables, and repeated measurements of estimated glomerular filtration rate (eGFR) and proteinuria (measured using the proteinuria to creatininuria ratio). To develop a dynamic prediction system based on these clinical assessments and repeated measurements, we used a Bayesian joint models—an artificial intelligence approach. The prediction performances of the model were assessed via discrimination, through calculation of the area under the receiver operator curve (AUC), and calibration. This study is registered with ClinicalTrials.gov, NCT04258891. Findings: 13 608 patients were included (3774 in the development cohort and 9834 in the external validation cohorts) and contributed 89 328 patient-years of data, and 416 510 eGFR and proteinuria measurements. Bayesian joint models showed that recipient immunological profile, allograft interstitial fibrosis and tubular atrophy, allograft inflammation, and repeated measurements of eGFR and proteinuria were independent risk factors for allograft survival. The final model showed accurate calibration and very high discrimination in the development cohort (overall dynamic AUC 0·857 [95% CI 0·847–0·866]) with a persistent improvement in AUCs for each new repeated measurement (from 0·780 [0·768–0·794] to 0·926 [0·917–0·932]; p
Published: 2021

166. From diagnosis to prognosis:Revisiting the meaning of muscle ISG15 overexpression in juvenile inflammatory myopathies

Author: Rodero, Mathieu P, Hou, Cyrielle, Durrleman, Chloé, Periou, Baptiste, Barnerias, Christine, Bodemer, Christine, Desguerre, Isabelle, Quartier, Pierre, Melki, Isabelle, Rice, Gillian, Rodero, Mathieu, Charuel, Jean‐Luc, Relaix, Fréderic, Bader‐Meunier, Brigitte, Authier, FrançoisJérôme, Gitiaux, Cyril, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Filière Neuromusculaire (FILNEMUS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Manchester [Manchester], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)
Subjects: 030203 arthritis & rheumatology, Muscle biopsy, medicine.diagnostic_test, business.industry, Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], Immunology, Autoantibody, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Real-time polymerase chain reaction, Rheumatology, Immunology and Allergy, Medicine, Biomarker (medicine), Juvenile, business, 030217 neurology & neurosurgery, Juvenile dermatomyositis, Myositis, ComputingMilieux_MISCELLANEOUS
Abstract: OBJECTIVE Juvenile idiopathic inflammatory/immune myopathies (IIMs) constitute a highly heterogeneous group of disorders with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) have been recognized as reliable tools for patient substratification. Considering the key role of type I interferon (IFN) up-regulation in juvenile IIM, we undertook the present study to investigate whether IFN-induced 15-kd protein (ISG-15) could be a reliable biomarker for stratification and diagnosis and to better elucidate its role in juvenile IIM pathophysiology. METHODS The study included 56 patients: 24 with juvenile dermatomyositis (DM), 12 with juvenile overlap myositis (OM), 10 with Duchenne muscular dystrophy, and 10 with congenital myopathies. Muscle biopsy samples were assessed by immunohistochemistry, immunoblotting, and real-time quantitative polymerase chain reaction. Negative regulators of type I IFN (ISG15 and USP18) and positive regulators of type I IFN (DDX58 and IFIH1) were analyzed. RESULTS ISG15 expression discriminated patients with juvenile IIM from those with nonimmune myopathies and, among patients with juvenile IIM, discriminated those with DM from those with OM. Among patients with juvenile DM, up-regulation of the type I IFN positive regulators DDX58 and IFIH1 was similar regardless of MSA status. In contrast, the highest levels of the type I IFN negative regulator ISG15 were observed in patients who were positive for melanoma differentiation-associated gene 5 (MDA-5). Finally, ISG15 levels were inversely correlated with the severity of muscle histologic abnormalities and positively correlated with motor performance as evaluated by the Childhood Myositis Assessment Scale and by manual muscle strength testing. CONCLUSION Muscle ISG15 expression is strongly associated with juvenile DM, with patients exhibiting a different ISG-15 muscle signature according to their MSA class. Patients with juvenile DM who are positive for MDA-5 have higher expression of ISG15 in both gene form and protein form compared to the other subgroups. Moreover, our data show that negative regulation of type I IFN correlates with milder muscle involvement.
Published: 2021

167. Long term results of liver transplantation for alpha-1 antitrypsin deficiency

Author: Alain Lachaux, Eduardo Couchonnal, Christophe Duvoux, Jean Gugenheim, Dominique Debray, Sylvie Radenne, Marie-Noëlle Hilleret, Emmanuel Jacquemin, Filomena Conti, Audrey Coilly, Claire Vanlemmens, Olivier Guillaud, Florence Lacaille, Yasmina Chouik, Valérie A. McLin, Didier Samuel, Nassim Kamar, Georges-Philippe Pageaux, Emmanuel Gonzales, Oanez Ackermann, Jean-Charles Duclos-Vallée, Claire Francoz, Jérôme Dumortier, Mathias Ruiz, Pauline Houssel-Debry, Martine Neau-Cransac, Herrada, Anthony, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Clinique de la Sauvegarde [Lyon], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d’Hépatologie [Hôpital Beaujon], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], 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), Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Grenoble, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Pontchaillou [Rennes], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Nice (CHU Nice), Université de Lyon, Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpitaux Universitaires de Genève (HUG), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, CHU Toulouse [Toulouse], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de Rangueil, and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Survival, medicine.medical_treatment, Kaplan-Meier Estimate, Liver transplantation, Gastroenterology, Disease-Free Survival, 03 medical and health sciences, Liver disease, 0302 clinical medicine, alpha 1-Antitrypsin Deficiency, Internal medicine, Genotype, medicine, Humans, Child, Alpha1 antitrypsin, Outcome, Alpha 1-antitrypsin deficiency, ddc:618, Hepatology, business.industry, Medical record, Graft Survival, Retrospective cohort study, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Population study, Female, 030211 gastroenterology & hepatology, business, Follow-Up Studies
Abstract: International audience; Introduction: Liver transplantation (LT) is the therapeutic option for end-stage liver disease associated with alpha1 antitrypsin (A1AT) deficiency. The aim of the present retrospective study was to report on long-term outcomes following LT for A1AT deficiency.Methods: The medical records of 90 pediatric and adult patients transplanted between 1982 and 2017 in France and Geneva (Switzerland) were reviewed.Results: The study population consisted of 32 adults and 58 children; median age at transplant was 13.0 years (range: 0.2-65.1), and 65 were male (72.2%). Eighty-two patients (94.8% of children and 84.4% of adults) had the PI*ZZ genotype/phenotype and eight patients (8.9%) had the Pi*SZ genotype/phenotype. Eighty-four patients (93.3%) were transplanted for end-stage liver disease and six (all Pi*ZZ adults) for HCC. Median follow-up after LT was 13.6 years (0.1-31.7). The overall cumulative patient survival rates post-transplant were 97.8% at 1 year, and 95.5%, 95.5%, 92.0%, 89.1% at 5, 10, 15, 20 years respectively. The overall cumulative graft survival rates were 92.2% at 1 year, and 89.9%, 89.9%, 84.4%, 81.5% at 5, 10, 15 and 20 years, respectively.Conclusions: In a representative cohort of patients having presented with end-stage-liver disease or HCC secondary to A1AT, liver transplantation offered very good patient and graft survival rates.
Published: 2021

168. PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury

Author: Nitirut Nernpermpisooth, Charlotte Sarre, Christian Barrere, Rafaël Contreras, Patricia Luz-Crawford, Gautier Tejedor, Anne Vincent, Christophe Piot, Sarawut Kumphune, Joel Nargeot, Christian Jorgensen, Stéphanie Barrère-Lemaire, Farida Djouad, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Naresuan University, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universidad de los Andes [Santiago] (UANDES), Clinique du Millénaire - Oc Santé [Montpellier], Oc Santé [Montpellier], Chiang Mai University (CMU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Salvy-Córdoba, Nathalie
Subjects: medicine.medical_treatment, Ischemia, Cardioprotection, Cardiovascular Medicine, Pharmacology, PPAR, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fibrosis, Diseases of the circulatory (Cardiovascular) system, Medicine, Original Research, Inflammation, business.industry, Mesenchymal stem cell, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, CXCL1, Reperfusion injury, Myocardial infarction, Cytokine, RC666-701, Mesenchymal stem cells, Cardiology and Cardiovascular Medicine, business, Ex vivo
Abstract: Myocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARβ/δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARβ/δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.105, 6.105, and 24.105 cells/heart) and the dose of 6.105 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARβ/δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARβ/δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARβ/δ-dependent but not related to their anti-inflammatory effects.
Published: 2021

169. Effet thérapeutique des vésicules extracellulaires isolées à partir de cellules stromales mésenchymateuses dans la sclérodermie systémique

Author: Rozier, Pauline, STAR, ABES, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier, Philippe Guilpain, and Danièle Noël
Subjects: Cellules stromales mésenchymateuses, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, integumentary system, Vésicules extracellulaires, TGFβ1, Mesenchymal stromal cells, Systemic sclerosis, Fibrose, Extracellular vesicles, Fibrosis, Sclérodermie systémique, MiR-29a-3p
Abstract: Systemic sclerosis (SSc) is a rare and severe disease characterized by generalized fibrosis, vasculopathy and deregulation of immune cells. No curative treatment is validated to date. Mesenchymal stromal cells (MSCs) are being evaluated in clinical trials as they are effective in several preclinical models of SSc. They exert their anti-fibrotic, pro-angiogenic and immunomodulatory properties through the secretion of mediators contained in extracellular vesicles (EVs). We investigate here the role of EVs released by MSCs in their systemic effect during SSc.In a murine model of hypochlorous acid-induced SSc, we demonstrate that EVs can stop the disease course and improve histological and molecular parameters in skin and lung samples. We identify miR-29a-3p expression in both MSCs and their EVs and prove that miR-29a-3p is responsible for a large part of their therapeutic effect, targeting Dnmt3a and Pdgfr-bb, two novel targets identified in SSc.We improve the therapeutic efficacy of EVs on lung abnormalities in SSc mice by stimulating MSCs with IFNγ before EVs production whereas increasing the amount of injected EVs did not have any benefit. IFNγ modulates the expression of known immunosuppressive factors in both MSCs and EVs, potentiating their therapeutic properties.While the role of MSCs from SSc patients (SSc MSCs) in the development of the disease is debated, we show that SSc MSCs inhibit in vitro T lymphocyte proliferation and improve the myofibroblastic phenotype obtained after fibroblast stimulation using TGFβ1 which display a similar profile as fibroblasts from SSc patients in the in vitro model used here.Overall, MSC-EVs are as effective as MSCs to stop the progression of murine SSc and EVs from IFNγ-preconditioned MSCs improve their beneficial effect in the lungs. SSc MSCs maintain their anti-fibrotic and immunosuppressive properties in vitro and one of our perspectives is to evaluate their therapeutic efficacy in vivo., La sclérodermie systémique (ScS) est une maladie rare et sévère, caractérisée par une dérégulation des cellules immunitaires, une fibrose et une vasculopathie généralisées. Aucun traitement curatif n’est validé à ce jour. Les cellules stromales mésenchymateuses (CSMs), dont l’efficacité a été démontrée dans plusieurs modèles précliniques de ScS, sont actuellement évaluées dans des essais cliniques. Elles exercent leurs propriétés régénératrices au travers de la sécrétion de médiateurs libérés dans le milieu extracellulaire ou contenus dans des vésicules extracellulaires (EVs). Nous nous intéressons ici au rôle des EVs libérées par les CSMs dans leur effet systémique au cours de la ScS.Dans un modèle murin de ScS induit par des injections d’acide hypochloreux, nous démontrons que les EVs stoppent l’évolution de la maladie au niveau cutané et pulmonaire sur le plan clinique, histologique et moléculaire. Nous identifions miR-29a-3p au sein des CSMs et de leurs EVs et prouvons qu’il est garant de leur effet thérapeutique, en ciblant Dnmt3a et Pdgfr-bb, deux nouvelles cibles identifiées dans la ScS.Nous améliorons l’efficacité thérapeutique des EVs sur les anomalies pulmonaires en pré-activant les CSMs à l’aide d’IFNγ alors que l’augmentation de la quantité d’EVs injectées n’a aucun effet. L’IFNγ module l’expression de molécules immunosuppressives dans les CSMs et leurs EVs, potentialisant ainsi leurs propriétés thérapeutiques.Alors que le rôle des CSMs de patients (CSMs-ScS) dans le développement de la maladie est sujet à débat, nous montrons que les CSMs-ScS inhibent in vitro la prolifération des lymphocytes T de manière similaire à des CSMs saines. En outre, elles sont capables d’améliorer le phénotype myofibroblastique de fibroblastes stimulés par du TGFβ1 qui présentent un comportement similaire à celui de fibroblastes de patients dans le modèle in vitro mis en place.En conclusion, les EVs sont aussi efficaces que les CSMs pour traiter la ScS murine et le pré-conditionnement des CSMs par l’IFNγ améliore leur effet au niveau pulmonaire. Les CSMs de patients conservent leurs fonctions anti-fibrotique et immunosuppressive in vitro et une de nos perspectives est d’évaluer leur efficacité thérapeutique in vivo.
Published: 2021

170. Correction to: Assessment of anti-infective medication adherence in pediatric outpatients

Author: Alexia Janes, Marion Warembourg, M Knight, Géraldine Leguelinel-Blache, Nelly Lonca, Anne Filleron, Ian Soulairol, Tu Anh Tran, LEGUELINEL-BLACHE, Géraldine, Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), and Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Subjects: [SDV.EE]Life Sciences [q-bio]/Ecology, environment, medicine.medical_specialty, business.industry, Medication adherence, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.EE] Life Sciences [q-bio]/Ecology, environment, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, Anti infectives, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; No abstract available
Published: 2021

171. Expanded NK cells from umbilical cord blood and adult peripheral blood combined with daratumumab are effective against tumor cells from multiple myeloma patients

Author: Javier Hernandez, Isabel Marzo, Isabel Izquierdo, Luis Palomera, Javier Naval, Rosana Díez, Martin Villalba, Michael Constantinides, Jessy Présumey, Alberto Anel, Gemma Azaceta, Guillaume Cartron, Chantal Reina-Ortiz, Alexis Fayd-Herbe-de-Maudave, David Giraldos, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Aragón Health Research Institute [Zaragoza, Spain], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Hospital Universitario Miguel Servet, Hospital Clínico Universitario 'Lozano Blesa' [Zaragoza, Spain], ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), Herrada, Anthony, Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Adult, endocrine system, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, NK cells, CD16, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, PD-1, medicine, Immunology and Allergy, Cytotoxic T cell, Humans, cell Therapy and Immunotherapy, education, RC254-282, Original Research, Antibody-dependent cell-mediated cytotoxicity, education.field_of_study, business.industry, Daratumumab, Antibodies, Monoclonal, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC581-607, medicine.disease, Fetal Blood, daratumumab, 3. Good health, Killer Cells, Natural, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, cytotoxicity, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, Immunologic diseases. Allergy, business, Multiple Myeloma, Monoclonal gammopathy of undetermined significance, Ex vivo, Research Article
Abstract: International audience; In this study we evaluated the potential of expanded NK cells (eNKs) from two sources combined with the mAbs daratumumab and pembrolizumab to target primary multiple myeloma (MM) cells ex vivo. In order to ascertain the best source of NK cells, we expanded and activated NK cells from peripheral blood (PB) of healthy adult donors and from umbilical cord blood (UCB). The resulting expanded NK (eNK) cells express CD16, necessary for carrying out antibody-dependent cellular cytotoxicity (ADCC). Cytotoxicity assays were performed on bone marrow aspirates of 18 MM patients and 4 patients with monoclonal gammopathy of undetermined significance (MGUS). Expression levels of PD-1 on eNKs and PD-L1 on MM and MGUS cells were also quantified. Results indicate that most eNKs obtained using our expansion protocol express a low percentage of PD-1+ cells. UCB eNKs were highly cytotoxic against MM cells and addition of daratumumab or pembrolizumab did not further increase their cytotoxicity. PB eNKs, while effective against MM cells, were significantly more cytotoxic when combined with daratumumab. In a minority of cases, eNK cells showed a detectable population of PD1+ cells. This correlated with low cytotoxic activity, particularly in UCB eNKs. Addition of pembrolizumab did not restore their activity. Results indicate that UCB eNKs are to be preferentially used against MM in the absence of daratumumab while PB eNKs have significant cytotoxic advantage when combined with this mAb.
Published: 2021

172. Combination of amoxicillin/clavulanate and prednisolone in severe alcoholic hepatitis: results of the randomized controlled trial Antibiocor

Author: Louvet, Alexandre, Labreuche, Julien, Dao, Thong, Thevenot, Thierry, Oberti, Frederic, Bureau, Christophe, Paupard, Thierry, Nguyen-Khac, Eric, Franza, Anne Minello, Chabert, Brigitte Bernard, Anty, Rodolphe, Wartel, Faustine, Carbonell, Nicolas, Pageaux, Georges-Philippe, Leroy, Vincent, Legros, Ludivine, Nahon, Pierre, Potey, Camille, Duhamel, Alain, Mathurin, Philippe, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], 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), Service d'Hépatologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier de Dunkerque, Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pontchaillou [Rennes], Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Régional de PharmacoVigilance Nord-Pas-de-Calais [CHU Lille] (CRPV), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Faculté de Médecine Henri Warembourg - Université de Lille, Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, and DESSAIVRE, Louise
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

173. The Role of Macrophages During Mammalian Tissue Remodeling and Regeneration Under Infectious and Non-Infectious Conditions

Author: Candice Bohaud, Matt D. Johansen, Christian Jorgensen, Laurent Kremer, Natacha Ipseiz, Farida Djouad, Kremer, Laurent, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), University of Technology Sydney (UTS), Hôpital Lapeyronie [Montpellier] (CHU), Cardiff University, and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: 0301 basic medicine, Programmed cell death, Tuberculosis, Immunology, Review, Infections, 03 medical and health sciences, 0302 clinical medicine, Immune system, Macrophages, Alveolar, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, 1107 Immunology, 1108 Medical Microbiology, Immunology and Allergy, Macrophage, Animals, Humans, Regeneration, Process (anatomy), [SDV.BDD]Life Sciences [q-bio]/Development Biology, Mammals, Wound Healing, Lung, business.industry, SARS-CoV-2, Regeneration (biology), Macrophages, COVID-19, RC581-607, medicine.disease, Infectious conditions, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Airway Remodeling, Non-infectious conditions, Immunologic diseases. Allergy, Wound healing, business, Repair
Abstract: Several infectious pathologies in humans, such as tuberculosis or SARS-CoV-2, are responsible for tissue or lung damage, requiring regeneration. The regenerative capacity of adult mammals is limited to few organs. Critical injuries of non-regenerative organs trigger a repair process that leads to a definitive architectural and functional disruption, while superficial wounds result in scar formation. Tissue lesions in mammals, commonly studied under non-infectious conditions, trigger cell death at the site of the injury, as well as the production of danger signals favouring the massive recruitment of immune cells, particularly macrophages. Macrophages are also of paramount importance in infected injuries, characterized by the presence of pathogenic microorganisms, where they must respond to both infection and tissue damage. In this review, we compare the processes implicated in the tissue repair of non-infected versus infected injuries of two organs, the skeletal muscles and the lungs, focusing on the primary role of macrophages. We discuss also the negative impact of infection on the macrophage responses and the possible routes of investigation for new regenerative therapies to improve the recovery state as seen with COVID-19 patients.
Published: 2021

174. TNFR1-d2 carrying the p.(Thr79Met) pathogenic variant is a potential novel actor of TNFα/TNFR1 signalling regulation in the pathophysiology of TRAPS

Author: Cécile Rittore, Déborah Méchin, Elodie Sanchez, Léa Marinèche, Vuthy Ea, Stephan Soler, Marion Vereec, Aude Mallavialle, Eric Richard, Isabelle Duroux-Richard, Florence APPARAILLY, Isabelle Touitou, Sylvie Grandemange, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), APPARAILLY, Florence, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Tumor Necrosis Factor-alpha, Science, Hereditary Autoinflammatory Diseases, NF-kappa B, Functional genomics, Exons, respiratory system, Article, Cell Line, HEK293 Cells, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Receptors, Tumor Necrosis Factor, Type I, Cell Line, Tumor, Mutation, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Medicine, NF-kappaB, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, HeLa Cells, Signal Transduction
Abstract: International audience; Binding of tumour necrosis factor α (TNFα) to its receptor (TNFR1) is critical for both survival and death cellular pathways. TNFα/TNFR1 signalling is complex and tightly regulated at different levels to control cell fate decisions. Previously, we identified TNFR1-d2, an exon 2-spliced transcript of TNFRSF1A gene encoding TNFR1, whose splicing may be modulated by polymorphisms associated with inflammatory disorders. Here, we investigated the impact of TNFRSF1A variants involved in TNFR-associated periodic syndrome (TRAPS) on TNFR1-d2 protein expression and activity. We found that TNFR1-d2 could be translated by using an internal translation initiation codon and a de novo internal ribosome entry site (IRES), which resulted in a putative TNFR1 isoform lacking its N-terminal region. The kinetic of assembly of TNFR1-d2 clusters at the cell surface was reduced as compared with full-length TNFR1. Although co-localized with the full-length TNFR1, TNFR1-d2 neither activated nuclear factor (NF)-κB signalling, nor interfered with TNFR1-induced NF-κB activation. Translation of TNFR1-d2 carrying the severe p.(Thr79Met) pathogenic variant (also known as T50M) was initiated at the mutated codon, resulting in an elongated extracellular domain, increased speed to form preassembled clusters in absence of TNFα, and constitutive NF-κB activation. Overall, TNFR1-d2 might reflect the complexity of the TNFR1 signalling pathways and could be involved in TRAPS pathophysiology of patients carrying the p.(Thr79Met) disease-causing variant.
Published: 2021

175. French recommendations for the management of systemic necrotizing vasculitides (polyarteritis nodosa and ANCA-associated vasculitides)

Author: Terrier, Benjamin, Darbon, Raphaël, Durel, Cécile-Audrey, Hachulla, Eric, Karras, Alexandre, Maillard, Hélène, Papo, Thomas, Puechal, Xavier, Pugnet, Grégory, Quemeneur, Thomas, Samson, Maxime, Taille, Camille, Guillevin, Loïc, Audard, Vincent, Aumaître, Olivier, Briot, Karine, Cacoub, Patrice, Cathebras, Pascal, Chauveau, Dominique, Chosidow, Olivier, Chouchana, Laurent, Cottin, Vincent, Cornec, Divi, Daugas, Eric, Diot, Elisabeth, Dupin, Nicolas, El Karoui, Khalil, Fain, Olivier, Gobert, Pierre, Guilpain, Philippe, Hamidou, Mohamed, Hummel, Aurelie, Jachiet, Marie, Jouneau, Stephane, Jourde-Chiche, Noémie, Landron, Cédric, Le Jeunne, Claire, Lega, Jean-Christophe, Mariette, Xavier, Morel, Nathalie, Pagnoux, Christian, Remy, Philippe, Vandergheynst, Frederic, Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Association France Vascularites [Paris], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Néphrologie et Hémodialyse [CHU HEGP], 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), AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Toulouse [Toulouse], Centre hospitalier [Valenciennes, Nord], Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Pediatrics, medicine.medical_specialty, lcsh:Medicine, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Disease, Churg-Strauss Syndrome, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Eosinophilic, Necrotizing Vasculitis, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Position Statement, Genetics (clinical), 030203 arthritis & rheumatology, Polyarteritis nodosa, business.industry, lcsh:R, Granulomatosis with Polyangiitis, General Medicine, medicine.disease, 3. Good health, Polyarteritis Nodosa, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Quality of Life, Granulomatosis with polyangiitis, business, Microscopic polyangiitis, Vasculitis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Systemic necrotizing vasculitis comprises a group of diseases resembling polyarteritis nodosa and anti-neutrophil cytoplasmic antibody-associated vasculitis (ANCA): granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis. The definitive diagnosis is made in cooperation with a reference center for autoimmune diseases and rare systemic diseases or a competency center. The management goals are: to obtain remission and, in the long term, healing; to reduce the risk of relapses; to limit and reduce the sequelae linked to the disease; to limit the side effects and the sequelae linked to the treatments; to improve or at least maintain the best possible quality of life; and to maintain socio-professional integration and/or allow a rapid return to school and/or professional activity. Information and therapeutic education of the patients and those around them are an integral part of the care. All health professionals and patients should be informed of the existence of patient associations. The treatment of vasculitis is based on variable combinations of glucocorticoids and immunosuppressants, chosen and adapted according to the disease concerned, the severity and/or extent of the disease, and the underlying factors (age, kidney function, etc.). Follow-up clinical and paraclinical examinations must be carried out regularly to clarify the progression of the disease, detect and manage treatment failures and possible relapses early on, and limit sequelae and complications (early then late) related to the disease or treatment. A distinction is made between the induction therapy, lasting approximately 3–6 months and aimed at putting the disease into remission, and the maintenance treatment, lasting 12–48 months, or even longer. The role of the increase or testing positive again for ANCA as a predictor of a relapse, which has long been controversial, now seems to have greater consensus: Anti-myeloperoxidase ANCAs are less often associated with a relapse of vasculitis than anti-PR3 ANCA.
Published: 2020

176. Cellules souches dentaires : mythe ou espoir en médecine neurorégénératrice ?

Author: Aroa Relaño-Ginés, Syrine Dimassi, Dominique Deville de Périère, Sylvain Lehmann, Christophe Hirtz, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: cellules souches mésenchymateuses, MESH: Neural Stem Cells, MESH: Nerve Regeneration, 030213 general clinical medicine, Degeneration (medical), Disease, Regenerative Medicine, MESH: Neurodegenerative Diseases, Cell therapy, Tissue Culture Techniques, 0302 clinical medicine, Neural Stem Cells, Medicine, MESH: Animals, MESH: Tissue Banks, education.field_of_study, MESH: Tooth, Stem Cells, maladies neurodégénératives, thérapie cellulaire, Cell Differentiation, Neurodegenerative Diseases, cellular therapy, General Medicine, 3. Good health, MESH: Stem Cell Transplantation, MESH: Cell Differentiation, medicine.medical_specialty, Neurogenesis, Population, MESH: Stem Cells, Tissue Banks, 03 medical and health sciences, Animals, Humans, dental stem cells, MESH: Tissue Culture Techniques, education, Intensive care medicine, mesenchymal stem cells, MESH: Humans, business.industry, Public health, Mesenchymal stem cell, cellules souches dentaires, Embryonic stem cell, MESH: Neurogenesis, Nerve Regeneration, Clinical trial, MESH: Regenerative Medicine, business, Tooth, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Stem Cell Transplantation
Abstract: International audience; The use of dental stem cells has raised many hopes in the development of new treatments for neurodegenerative diseases. According to current statistics, about 1 in 6 people in the world would be affected by a neurological disease. This number continues to increase as the world's population ages, making neurodegenerative diseases probably the one of the major challenges of public health in the 21st century. Neurodegenerative diseases are characterized mainly by a progressive loss of cognitive abilities and patient autonomy related to loss and degeneration of neurons in brain structures. Unfortunately, today, the only treatments available for this type of disease do only relieve the symptoms, they do not treat them, and few clinical trials have been truly convincing to date. Hence, hope lies for these diseases in the development of other therapeutic approaches. As such, dental stem cells could be a promising area of research because of their rapid growth, their great capacity for differentiation into different types of cells (among neuronal ones for some of them) and how easy they can be obtained, without raising ethical issues as for example for embryonic stem cells.; L’utilisation des cellules souches dentaires a fait naître de nombreux espoirs dans le développement de nouveaux traitements destinés aux maladies neurodégénératives. Si l’on se réfère aux statistiques actuelles, environ 1 personne sur 6 dans le monde serait atteinte par une maladie neurologique. Ce nombre ne cesse d’augmenter au fur et à mesure que la population mondiale vieillit, faisant des maladies neurodégénératives probablement l’un des principaux défis de la santé publique du XXIe siècle. Les maladies neurodégénératives se caractérisent principalement par une perte progressive des facultés cognitives et de l’autonomie des patients liée à une perte et une dégénérescence des neurones des structures cérébrales. Malheureusement, force est de constater que les seuls traitements disponibles actuellement pour ce type de pathologies ne font que soulager les symptômes et non les traiter et que peu d’essais cliniques à ce jour ont été véritablement probants. L’espoir réside donc pour ces maladies neurodégénératives dans le développement de nouvelles approches thérapeutiques. Les cellules souches dentaires pourraient constituer une nouvelle voie de recherche en thérapie cellulaire, de par leur croissance rapide, leur grande capacité de différenciation en différents types cellulaires (y compris en cellules neuronales pour certaines) et la facilité avec laquelle elles peuvent être obtenues sans soulever de problèmes d’éthique comme par exemple pour les cellules souches embryonnaires.
Published: 2020

177. A rare case of small-vessel necrotizing vasculitis of the bone marrow revealing granulomatosis with polyangiitis

Author: Jonathan Broner, Agathe Artiaga, Myriam Fantone, Samia Gonzalez, Sirivanh Bisiou, Radjiv Goulabchand, Erik Arnaud, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Male, Pathology, medicine.medical_specialty, Myeloblastin, Mastoiditis, Angiodysplasia, Antibodies, Antineutrophil Cytoplasmic, 03 medical and health sciences, Necrosis, 0302 clinical medicine, Necrotizing vasculitis, Rheumatology, Bone Marrow, Biopsy, Necrotizing Vasculitis, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Pharmacology (medical), 030212 general & internal medicine, Fibrinoid necrosis, 030203 arthritis & rheumatology, medicine.diagnostic_test, business.industry, Wegener granulomatosis, Hemostasis, Endoscopic, Granulomatosis with Polyangiitis, Anemia, Middle Aged, medicine.disease, Thrombocytopenia, 3. Good health, medicine.anatomical_structure, Epistaxis, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Bone marrow, Varices, Vasculitis, Granulomatosis with polyangiitis, business, Gastrointestinal Hemorrhage, Small blood vessel
Abstract: International audience; A 62-year-old man, who was a heavy drinker, presented with deep asthenia, isolated fever, inflammatory syndrome (CRP 120 mg/l) and cytopenias (Hb 6.5 g/dl, platelet count 100 G/l). A whole-body CT scan found dysmorphic hepatomegaly and splenomegaly. Endoscopy revealed bleeding gastrointestinal angiodysplasia and non-bleeding oesophageal varices. After coagulation for angiodysplasia and blood transfusions, the Hb level remained around 8.5 g/dl. To investigate blood malignancy, a bone marrow biopsy revealed small-vessel vasculitis (Fig. 1A, 2), fibrinoid necrosis affecting the small vessel walls (Fig. 1A, 3), multinucleated giant cells (Fig. 1A, 1) constituting microgranulomas (Fig. 1A, 4) and...
Published: 2020

178. Nouveau dispositif fluidique pour la stimulation et la caractérisation biomécanique de microsphères : preuve de concept et application aux micropellets de cartilage

Author: Noémie Petitjean, Biomécanique des Interactions et de l'Organisation des Tissus et des Cellules (BIOTIC), Laboratoire de Mécanique et Génie Civil (LMGC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier, Danièle Noël, and Pascale Royer
Subjects: Caractérisation, Characterization, Biomécanique, Stimulation, Ingénierie tissulaire, Mesenchymal stem cells, [SPI.MECA.BIOM]Engineering Sciences [physics]/Mechanics [physics.med-ph]/Biomechanics [physics.med-ph], Tissue engineering, Biomechanics, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cellules souches mésenchymateuses, Cartilage articulaire, Articular cartilage
Abstract: Articular cartilage (AC) pathologies have emerged as a public health problem. Tissue engineering, whose objective is to create new tissues with cells, is a promising therapeutic solution for the repair of AC lesions but still requires research to improve the mechanical properties of the new tissues. The objective of this PhD thesis work was to analyze the impact of mechanical stimuli in the development and maintenance of AC, based on the model of cartilage micropellet, derived from the aggregation of mesenchymal stem cells. For this purpose, a fluidic device able to mechanically stimulate and characterize small and irregularly shaped cartilage micropellets was developed. Six cartilage micropellets in six conical wells can be simultaneously stimulated by compression and characterized through different pressure signals. Associated to a numerical model, the fluidic device has been shown to allow the characterization of the mechanical properties of various microspheres made of alginate, collagen or cross-linked collagen as compared to a conventional characterization method by compression between two planar surfaces. The reliability of the device for the application of mechanical stimuli have been confirmed by analyzing the pressure signals generated. Stimulation of 21-day cartilage micropellets with a square-wave signal with various amplitudes, frequencies and durations have shown that chondrocyte gene expression could be modulated by mechanical stimuli. Moderate levels of deformation of the micropellets were observed without any obvious damage. The mechanical characterization of 21-day micropellets have shown results consistent with the literature. This proof of concept shows the interest of the fluidic device allowing the stimulation and characterization of cartilage micropellets and highlighted possibilities to improve the system and associated numerical analysis methods as well as directions to improve our understanding of cartilage micropellet development under mechanical stimulations.; Les pathologies du cartilage articulaire (CA) constituent aujourd’hui un problème de santé publique. L’ingénierie tissulaire, dont l’objectif est la création de nouveaux tissus contenant des cellules, est une solution thérapeutique prometteuse pour la réparation de lésions du CA mais nécessite encore des recherches pour améliorer les propriétés mécaniques des néo-tissus. Ce travail de thèse avait pour objectif l’analyse de l’impact de stimulations mécaniques sur le développement et le maintien du CA. Le micropellet de cartilage, conçu à partir de l’agrégation de cellules souches mésenchymateuses, a été choisi comme modèle biologique d’étude. Pour ce faire, un dispositif fluidique capable de stimuler et caractériser mécaniquement les micropellets de cartilage de petite taille et de forme irrégulière a été développé. Il permet de stimuler et caractériser simultanément 6 micropellets de cartilage par leur compression dans 6 puits coniques, grâce à différents signaux de pression. L’association du dispositif fluidique à un modèle numérique a rendu possible la caractérisation mécanique de diverses microsphères à base d’alginate, de collagène ou de collagène réticulé par comparaison à une méthode de caractérisation conventionnelle par compression entre deux surfaces planes. L’analyse des signaux de pression générés a permis de vérifier la fiabilité du dispositif pour l’application de stimuli mécaniques. La stimulation de micropellets de cartilage de 21 jours par un signal carré avec diverses amplitudes, fréquences et durées a montré que l’expression des gènes chondrocytaires pouvait être modulée par les stimulations mécaniques. Des déformations importantes des micropellets ont été observées sans toutefois les altérer structurellement. La caractérisation mécanique de micropellets de 21 jours a montré des résultats cohérents avec la bibliographie. Cette preuve de concept a montré l’intérêt du dispositif fluidique permettant la stimulation et la caractérisation de micropellets de cartilage, et a mis en évidence des pistes d’amélioration du système et des méthodes d’analyses numériques associées ainsi que des pistes de travail pour améliorer notre compréhension du développement du micropellet de cartilage lors de stimulations mécaniques.
Published: 2020

179. Improvement of cellular and tissue regeneration during aging

Author: Alle, Quentin, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Montpellier, Ollivier Milhavet, Jean-Marc Lemaitre, and STAR, ABES
Subjects: Aging, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cellules souches, Regeneration, Régénération, Reprogramming, Stem cells, Sénescence, Senescence, Vieillissement, Reprogrammation, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Aging is a complex process modulated by genetic and epigenetic factors and marked by progressive appearance of age-related pathologies and decrease of cell and tissue regenerative capacity. Our objective is to delay these effects by inducing global rejuvenation or increasing the organismal regenerative capacity.In 2007, Dr. Yamanaka showed that human fibroblasts can be converted into pluripotent stem cells by inducing the expression of four transcription factors. Ourselves, we showed in 2011 that senescent cells which are accumulating in aging organisms can be reprogrammed and regained a rejuvenated physiology and metabolism.Our hypothesis is that in vivo induction of a transient reprogramming process could erase the marks of cellular aging and improve tissue regeneration to restore altered cell physiology and delay tissue aging and deleterious consequences.For this, we used a transgenic mouse model to control the induction of the expression of the reprogramming factors in order to reprogram the cells of the whole organism. These mice also recapitulate the human phenotype of Hutchinson-Gilford progeria syndrome, mimicking accelerated physiological aging.Our results showed a significant increase in life expectancy and improvement in tissue integrity related to activation of tissue regeneration. The impact of controlled transient reprogramming on age-related pathologies has also been monitored and a protective role in osteoarthritis and osteoporosis has been observed in these animals at eight months of age. Also, a two-week low-dose treatment, at two months of age, allows for increased life expectancy in later ages while decreasing phenotypic markers associated with aging suggesting a memory effect of transient reprogramming maintained along the entire life.This work demonstrates how transient cellular reprogramming reduces the negative impacts of aging at the organismal level., Le vieillissement est un processus complexe modulé par des facteurs génétiques et épigénétiques. Il est caractérisé par une apparition progressive de pathologies associées à l’âge associées à un déclin progressif des capacités régénératrices cellulaires et tissulaires. Notre objectif est de retarder ces effets en induisant un rajeunissement global ou en améliorant les capacités régénératrices de l’organisme. En 2007, le Dr. Yamanaka a montré que des fibroblastes humains pouvaient être convertis en cellules pluripotentes en induisant l’expression de 4 facteurs de transcription. Notre équipe a montré en 2011 que les cellules sénescentes, qui s’accumulent au cours du vieillissement, pouvaient également être reprogrammées et retrouver une physiologie et un métabolisme rajeuni. Notre hypothèse est qu’une reprogrammation transitoire in vivo pourrait effacer les marques du vieillissement cellulaire et améliorer la régénération tissulaire afin de restaurer la physiologie cellulaire, retarder le vieillissement tissulaire et leurs conséquences délétères. Pour ce faire, nous avons utilisé un modèle murin transgénique pour contrôler l’induction de l’expression des facteurs de reprogrammation. Ces animaux récapitulent également le phénotype humain du syndrome d’Hutchinson-Gilford aussi appelé Progéria, mimant un vieillissement physiologique accéléré. Nos résultats montrent une augmentation significative de l’espérance de vie et une amélioration de l’intégrité tissulaire liée à une activation de la régénération tissulaire. L’impact d’une reprogrammation transitoire contrôlée sur les pathologies liées à l’âge a aussi été étudié et un rôle protecteur dans l’ostéoarthrite et l’ostéoporose est observé chez des animaux âgés de 8 mois. De plus, une induction à faible dose pendant 2 semaines à un âge précoce, permet un allongement de l’espérance de vie sur les âges tardifs associé à une diminution des marqueurs phénotypiques associés à l’âge. Ceci suggère un effet mémoire de la reprogrammation transitoire tout au long de la vie. Ce travail démontre comment la reprogrammation cellulaire transitoire réduit l’impact négatif du vieillissement au niveau de l’organisme.
Published: 2020

180. Correspondance on ‘Clinical characteristics and genetic analyses of 187 patients with undefined autoinflammatory diseases’

Author: Patrice Cacoub, Guillaume Sarrabay, Gonçalo Boleto, Véronique Hentgen, L. Biard, Guilaine Boursier, Isabelle Touitou, Isabelle Koné-Paut, David Saadoun, Carolla El Chamieh, Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], 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), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [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)-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), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CH Versailles] (CeRéMAIA - Hôpital André Mignot), Centre Hospitalier de Versailles André Mignot (CHV), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (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)-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)-Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Herrada, Anthony
Subjects: 0301 basic medicine, medicine.medical_specialty, cryopyrin-associated periodic syndromes, Immunology, Familial Mediterranean fever, Disease, Recurrent aphthous stomatitis, General Biochemistry, Genetics and Molecular Biology, Malaise, polymorphism, 03 medical and health sciences, Pericarditis, 0302 clinical medicine, Rheumatology, familial Mediterranean fever, Internal medicine, medicine, Immunology and Allergy, Stomatitis, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, business.industry, Cryopyrin-associated periodic syndrome, medicine.disease, Pharyngitis, 3. Good health, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, inflammation, medicine.symptom, genetic, business
Abstract: We read with great interest the article by Ter Haar et al 1 who describe the clinical characteristics, treatment response and genetic findings in a cohort of patients (n=187) with undefined systemic autoinflammatory diseases (sAIDs). The authors observed that patients with pericarditis were older at disease onset and had milder disease whereas patients with intellectual impairment were younger at disease onset and often had affected relatives. Of note, among patients with recurrent disease course, 30% (n=53/180) had aphthous stomatitis. Moreover, after complete gene screening, screening of most relevant exons or screening of most relevant point mutations, 9.4% (n=15/159) of patients carried likely pathogenic variants or variants of uncertain significance. Our recent French multicentre study on targeted next-generation sequencing (NGS) gives further insight into the clinical characteristics and genetic findings in patients with sAIDs associated with recurrent aphthous stomatitis (RAS). RAS (ie, adult onset, association with other features such as fever and malaise) can represent a diagnostic challenge. RAS especially when associated with fever, pharyngitis and lymphadenopathy may be the first presentation of sAIDs.2 sAIDs arise from impaired inflammatory responses due to variants in gene coding proteins …
Published: 2020

181. Spectrum of Kidney Involvement in Patients with Myelodysplastic Syndromes

Author: Nora Schwotzer, Noémie Jourde-Chiche, Fadi Fakhouri, Simon Ville, Jean-François Augusto, Awena Le Fur, Hélène Perrochia, Laurent Daniel, Jean-Michel Goujon, Stanislas Bataille, Viviane Gnemmi, Sébastien Kissling, François Provôt, Samuel Rotman, Moglie Le Quintrec, Anne Moreau, Alexandre Karras, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), 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), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Prémilleux, Annick, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, CHU Montpellier, and Hôpital Lapeyronie [Montpellier] (CHU)
Subjects: Nephrology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, 030204 cardiovascular system & hematology, Myelodysplastic syndromes, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Gastroenterology, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Membranous nephropathy, Clinical Research, Internal medicine, medicine, Minimal change disease, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, acute tubulointerstitial nephritis, autoimmunity, myelodysplastic syndromes, business.industry, Acute kidney injury, Glomerulonephritis, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, [SDV] Life Sciences [q-bio], IgA vasculitis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Kidney disease
Abstract: Introduction Myelodysplastic syndromes (MDS) are characterized by a high prevalence of associated autoimmune manifestations. Kidney involvement has been rarely reported in MDS patients. We report on the spectrum of kidney pathological findings in MDS patients. Methods We retrospectively identified MDS patients who had undergone a kidney biopsy between 2001 and 2019 in nine Swiss and French nephrology centres. Results Nineteen patients (median age 74 years [63-83]) were included. At the time of kidney biopsy, eleven (58%) patients had extra-renal auto-immune manifestations and sixteen (84%) presented with acute kidney injury. Median serum creatinine at diagnosis was 2.8 mg/dL [0.6-8.3] and median urinary protein to creatinine ratio was 1.2 g/g [0.2-11]. Acute tubulo-interstitial nephritis (TIN) was present in seven (37%) patients. Immunofluorescence study in one patient with acute TIN disclosed intense IgG deposits along the tubular basement membrane and Bowman’s capsule. Other kidney pathological features included ANCA-negative pauci-immune necrotizing and crescentic glomerulonephritis (n = 3), membranous nephropathy (n = 2), IgA nephropathy (n = 1), IgA vasculitis (n = 1), immunoglobulin-associated membrano-proliferative glomerulonephritis type I (n=1), crescentic C3 glomerulopathy (n = 1), fibrillary glomerulonephritis (n = 1) and minimal change disease (n = 1). Eleven (58%) patients received immunosuppressive treatments, among whom one developed a severe infectious complication. After a median follow-up of 7 month [1-96], nine (47%) patients had chronic kidney disease stage 3 (n = 6) or 4 (n = 3) and five (26%) progressed to end-stage kidney disease. Three patients died. Conclusions MDS are associated to several autoimmune kidney manifestations, predominantly acute TIN. MDS are to be listed among the potential causes of autoimmune TIN., Graphical abstract
Published: 2020

182. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author: Anne Miret, Lola Lemasson, Benjamin Cogné, Laurence Perrin, Frédéric Tran Mau-Them, Rémi Mathevet, Marion Boucon, Elise Schaefer, Christel Thauvin-Robinet, Christine Juif, Juliette Piard, Solène Bourgouin, Jenny Cornaton, Bertrand Isidor, Catherine Sarret, Fabienne Prieur, Coralie Gonin-Olympiade, Alexandra Afenjar, Christine Coubes, Boris Keren, Bénédicte Gérard, Catherine Vincent-Delorme, Kim Giraudat, Laurence Faivre, Amélie Piton, Antonio Vitobello, Thomas Smol, Annick Toutain, Arthur Sorlin, Sylvie Odent, Yann Trousselet, Fanny Tessier, Martin Chevarin, David Geneviève, Sébastien Moutton, Anne-Claire Gelineau, Ange-Line Bruel, Claire Nicolas, Aurore Garde, Philippe Khau-Van-Kien, Christophe Philippe, Solveig Heide, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], 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 Saint-Etienne, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, [SDV]Life Sciences [q-bio], Neurocognitive Disorders, Transposases, Neuropsychological Tests, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, [SCCO]Cognitive science, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Global developmental delay, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Dysexecutive syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Neuropsychology, Genetic Variation, medicine.disease, 3. Good health, Developmental disorder, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Mutation, Autism, Female, France, business, Neurocognitive
Abstract: White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.
Published: 2020

183. Generation of a human induced pluripotent stem cell line (iPSC) from peripheral blood mononuclear cells of a patient with a myasthenic syndrome due to mutation in COLQ

Author: Cécile Martinat, Romain Desprat, Claire Legay, Bruno Eymard, Susie Barbeau, Jean-Marc Lemaitre, Saints-Pères Paris Institute for Neurosciences (SPPIN - UMR 8003), Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Gestionnaire, Hal Sorbonne Université
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Muscle Proteins, Biology, Peripheral blood mononuclear cell, Neuromuscular junction, Cell Line, 03 medical and health sciences, chemistry.chemical_compound, Kruppel-Like Factor 4, 0302 clinical medicine, SOX2, COLQ, medicine, Humans, Induced pluripotent stem cell, lcsh:QH301-705.5, health care economics and organizations, Myasthenic Syndromes, Congenital, Cell Biology, General Medicine, Acetylcholinesterase, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), chemistry, KLF4, Mutation, Cancer research, Leukocytes, Mononuclear, Collagen, Reprogramming, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Congenital myasthenic syndromes (CMS) are a class of inherited disorders affecting the neuromuscular junction, a synapse whose activity is essential for movement. CMS with acetylcholinesterase (AChE) deficiency are caused by mutations in COLQ, a collagen that anchors AChE in the synapse. To study the pathophysiological mechanisms of the disease in human cells, we have generated iPSC from a patient's Peripheral Blood Mononuclear cells (PBMC) by reprogramming these cells using a non-integrative method using Sendai viruses bearing the four Yamanaka factors Oct3/4, Sox2, Klf4, and L-Myc.
Published: 2020

184. DISSEQ: Double-blind Next-Generation-Sequencing technologies (exome and gene panel) in the diagnosis of a cohort of 330 patients with an intellectual disability: concordance, discrepancies, and efficiencies

Author: Bruel, A., Gerard, B., Piton, A., Mau-Them, F. Tran, Sorlin, A., Sorly, A., Lacombe, D., Manouvrier, S., Edery, P., Philip, N., Genevieve, D., Verloes, A., Odent, S., Thevenon, J., Toutain, A., Bonneau, D., El Chehadeh, S., Doco-Fenzy, M., Isidor, B., Goldenberg, A., Vincent-Delorme, C., Boute-Benejean, O., Lambert, L., Asensio, M., Callier, P., Duffourd, Y., Lejeune, C., Christine Binquet, Philippe, C., Faivre, L., Thauvin-Robinet, C., Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Lille Nord de France (COMUE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire [Grenoble] (CHU), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Centre hospitalier universitaire de Nantes (CHU Nantes), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CRHU Nancy, Chard-Hutchinson, Xavier, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-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)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

185. Dissecting the NK cell population in hematological cancers confirms the presence of tumor cells and their impact on NK population function

Author: Martin Villalba, Catherine Alexia, Dang-Nghiem Vo, Michael Constantinides, Nerea Allende-Vega, Guillaume Cartron, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, KARLI, Mélanie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Trogocytosis, medicine.drug_class, Lymphocyte, Population, Cell, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, NK cells, Biology, Stem cell marker, Monoclonal antibody, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, AML, medicine, trogocytosis, education, Antibody-dependent cell-mediated cytotoxicity, education.field_of_study, Innate immune system, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, allergology, lcsh:R, UMAP, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, 3. Good health, medicine.anatomical_structure, Cancer research, Hodgkin lymphoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The lymphocyte lineage natural killer (NK) cell is part of the innate immune system and protects against pathogens and tumor cells. NK cells are the main cell effectors of the monoclonal antibodies (mAbs) that mediates antibody-dependent cell cytotoxicity (ADCC). Hence, it is relevant to understand NK physiology and status to investigate the biological effect of mAbs in the clinic. NK cells are heterogeneous with multiple subsets that may have specific activity against different attacks. The presence of viral-sculpted NK cell populations has already been described, but the presence of cancer-sculpted NK cells remains unknown. Cancer induces a broad NK cell dysfunction, which has not been linked to a specific population. Here, we investigated the NK cell population by Uniform Manifold Approximation and Projection (UMAP) embed maps in Hodgkin lymphoma (HL) and acute myeloid leukemia (AML) patients at diagnosis and at least 30 days after treatment, which correlates with tumor cell clearance. We found that the NK lineage largely responded to the tumor by generating antitumor NK cells and renewing the population with a subset of immature NK cells. However, we failed to identify a specific &ldquo, memory-like&rdquo, subset with the NK cell markers used. Moreover, in patients in relapse, we found essentially the same NK populations as those found at diagnosis, suggesting that NK cells equally respond to the first or second tumor rise. Finally, we observed that previous cytomegalovirus (CMV) infection largely affects the tumor-associated changes in NK population, but the CMV-associated CD57+NKG2C+ NK cell population does not appear to play any role in tumor immunity.
Published: 2020

186. Artificial intelligence solution to classify pulmonary nodules on CT

Author: Nathalie Lassau, N. Abassebay, I. Hammouamri, A. Loubet, M. Deloche, J.-A. Broyelle, D. Blanc, J. Brehant, M. Fiammante, Mathieu Lederlin, Guillaume Chassagnon, Gilbert Ferretti, Mickaël Ohana, V. Racine, Yann Diascorn, François Laurent, Hugo Veyssière, Pierre-Yves Brillet, Xavier Durando, J. Behr, Antoine Khalil, E. Verdier, Imad Bousaid, Caroline Caramella, E. Sinitambirivoutin, T. Besson, P. Cuingnet, Alexandre Sadate, Lucie Cassagnes, Angeline Ginzac, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IBM France (IBM), IBM, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), CHU Pontchaillou [Rennes], CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Hôpital Cochin [AP-HP], CHU Grenoble, Hôpital Pasteur [Nice] (CHU), Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, Hôpital Avicenne [AP-HP], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Gustave Roussy (IGR), Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier [Douai, Nord], Nouvel Hôpital Civil de Strasbourg, Hôpital JeanMinjoz, 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), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and CCSD, Accord Elsevier
Subjects: Lung Neoplasms, Support vector machine, [SDV]Life Sciences [q-bio], education, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pulmonary nodule, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Lung segmentation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Artificial Intelligence, Medicine, Humans, Radiology, Nuclear Medicine and imaging, Machine learning, Radiological and Ultrasound Technology, Receiver operating characteristic, business.industry, Deep learning, Pattern recognition, General Medicine, Confidence interval, 3. Good health, [SDV] Life Sciences [q-bio], Patient diagnosis, ComputingMethodologies_PATTERNRECOGNITION, 030220 oncology & carcinogenesis, Multiple Pulmonary Nodules, Artificial intelligence, Lung cancer, business, Tomography, X-Ray Computed, Classifier (UML)
Abstract: International audience; Purpose: The purpose of this study was to create an algorithm to detect and classify pulmonary nodules in two categories based on their volume greater than 100 mm3 or not, using machine learning and deep learning techniques.Materials and method: The dataset used to train the model was provided by the organization team of the SFR (French Radiological Society) Data Challenge 2019. An asynchronous and parallel 3-stages pipeline was developed to process all the data (a data "pre-processing" stage; a "nodule detection" stage; a "classifier" stage). Lung segmentation was achieved using 3D U-NET algorithm; nodule detection was done using 3D Retina-UNET and classifier stage with a support vector machine algorithm on selected features. Performances were assessed using area under receiver operating characteristics curve (AUROC).Results: The pipeline showed good performance for pathological nodule detection and patient diagnosis. With the preparation dataset, an AUROC of 0.9058 (95% confidence interval [CI]: 0.8746-0.9362) was obtained, 87% yielding accuracy (95% CI: 84.83%-91.03%) for the "nodule detection" stage, corresponding to 86% specificity (95% CI: 82%-92%) and 89% sensitivity (95% CI: 84.83%-91.03%).Conclusion: A fully functional pipeline using 3D U-NET, 3D Retina-UNET and classifier stage with a support vector machine algorithm was developed, resulting in high capabilities for pulmonary nodule classification.
Published: 2020

187. IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT)

Author: Olivier Thaunat, Camille Legeai, Dany Anglicheau, Lionel Couzi, Gilles Blancho, Marc Hazzan, Myriam Pastural, Emilie Savoye, Florian Bayer, Emmanuel Morelon, Yann Le Meur, Olivier Bastien, Sophie Caillard, Charlene Levi, Fanny Buron, Alice Koenig, Thomas Barba, Bruno Moulin, Samira Fafi-Kremer, Anglicheau Dany, Alexandre Hertig, Jérôme Tourret, Benoit Barrou, Pierre Merville, Anna Kaminski, Valérie Moal, Tristan Legris, Pierre-François Westeel, Maïté Jaureguy, Luc Frimat, Didier Ducloux, Jamal Bamoulid, Dominique Bertrand, Michel Tsimaratos, Florentine Garaix-Gilardo, Jérôme Dumortier, Sacha Mussot, Antoine Roux, Laurent Sebbag, Yannick Le Meur, Christophe Masset, Nassim Kamar, Hélène Francois, Eric Rondeau, Nicolas Bouvier, Christiane Mousson, Matthias Buchler, Philippe Gatault, Jean-François Augusto, Agnès Duveau, Cécile Vigneau, Marie-Christine Morin, Jonathan Chemouny, Leonard Golbin, Philippe Grimbert, Marie Matignon, Antoine Durrbach, Clarisse Greze, Renaud Snanoudj, Charlotte Colosio, Betoul Schvartz, Paolo Malvezzi, Christophe Mariat, Antoine Thierry, Moglie Le Quintrec, Antoine Sicard, Jean Philippe Rerolle, Anne-Élisabeth Heng, Cyril Garrouste, Henri Vacher Coponat, Éric Epailly, Olivier Brugiere, Sébastien Dharancy, Éphrem Salame, Faouzi Saliba, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Cellules B normales et pathogéniques - Normal and pathogenic B cell responses (NOPAB), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Agence de la biomédecine [Saint-Denis la Plaine], Service Néphrologie et transplantation rénale Adultes [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), 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), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHRU Brest - Service de Nephrologie (CHU - BREST - Nephrologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, French nationwide Registry of Solid Organ Transplant Recipients with COVID-19: Olivier Thaunat, Emmanuel Morelon, Charlene Levi, Fanny Buron, Alice Koenig, Thomas Barba, Sophie Caillard, Bruno Moulin, Samira Fafi-Kremer, Marc Hazzan, Anglicheau Dany, Alexandre Hertig, Jérôme Tourret, Benoit Barrou, Lionel Couzi, Pierre Merville, Anna Kaminski, Valérie Moal, Tristan Legris, Pierre-François Westeel, Maïté Jaureguy, Luc Frimat, Didier Ducloux, Jamal Bamoulid, Dominique Bertrand, Michel Tsimaratos, Florentine Garaix-Gilardo, Jérôme Dumortier, Sacha Mussot, Antoine Roux, Laurent Sebbag, Yannick Le Meur, Gilles Blancho, Christophe Masset, Nassim Kamar, Hélène Francois, Eric Rondeau, Nicolas Bouvier, Christiane Mousson, Matthias Buchler, Philippe Gatault, Jean-François Augusto, Agnès Duveau, Cécile Vigneau, Marie-Christine Morin, Jonathan Chemouny, Leonard Golbin, Philippe Grimbert, Marie Matignon, Antoine Durrbach, Clarisse Greze, Renaud Snanoudj, Charlotte Colosio, Betoul Schvartz, Paolo Malvezzi, Christophe Mariat, Antoine Thierry, Moglie Le Quintrec, Antoine Sicard, Jean Philippe Rerolle, Anne-Élisabeth Heng, Cyril Garrouste, Henri Vacher Coponat, Éric Epailly, Olivier Brugiere, Sébastien Dharancy, Éphrem Salame, Faouzi Saliba, CCSD, Accord Elsevier, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Pediatrics, MESH: Registries, Registry study, 030232 urology & nephrology, Kidney transplant, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Kidney Transplantation, Postoperative Complications, 0302 clinical medicine, MESH: Aged, 80 and over, MESH: Postoperative Complications, Pandemic, MESH: COVID-19, Registries, Wasting, Kidney transplantation, Aged, 80 and over, MESH: Aged, MESH: Middle Aged, Middle Aged, renal transplantation, 3. Good health, MESH: Waiting Lists, Nephrology, Female, France, medicine.symptom, Adult, medicine.medical_specialty, Waiting Lists, Coronavirus disease 2019 (COVID-19), 03 medical and health sciences, Intensive care, medicine, Humans, ESRD, Epidemics, MESH: Epidemics, Aged, Retrospective Studies, MESH: Humans, business.industry, SARS-CoV-2, COVID-19, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, medicine.disease, Kidney Transplantation, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, mortality, MESH: Male, MESH: France, 030104 developmental biology, business, MESH: Female
Abstract: International audience; End stage kidney disease increase the risk of COVID-19 related death but how the kidney replacement strategy should be adapted during the pandemic is unknown. Chronic hemodialysis makes social distancing difficult to achieve. Alternatively, kidney transplantation could increase the severity of COVID-19 due to therapeutic immunosuppression and contribute to saturation of intensive care units. For these reasons, kidney transplantation was suspended in France during the first epidemic wave. Here, we retrospectively evaluated this strategy by comparing the overall and COVID-19 related mortality in kidney transplant recipients and candidates over the last three years. Cross-interrogation of two national registries for the period 1 March and 1 June 2020, identified 275 deaths among the 42812 kidney transplant recipients and 144 deaths among the 16210 candidates. This represents an excess of deaths for both populations, as compared with the same period the two previous years (mean of two previous years: 253 in recipients and 112 in candidates). This difference was integrally explained by COVID-19, which accounted for 44% (122) and 42% (60) of the deaths in recipients and candidates, respectively. Taking into account the size of the two populations and the geographical heterogeneity of virus circulation, we found that the excess of risk of death due to COVID-19 was similar for recipients and candidates in high viral risk area but four-fold higher for candidates in the low viral risk area. Thus, in case of a second epidemic wave, kidney transplantation should be suspended in high viral risk areas but maintained outside those areas, both to reduce the excess of deaths of candidates and avoid wasting precious resources.
Published: 2020

188. How did the private labs fit onto COVID-19 crisis?

Author: Galhaud, Jean-Philippe, Scherrer, Florian, Kemeny, Stephan, Beauvieux, Marie-Christine, Delevallee, Céline, Aimone-Gastin, Isabelle, Alcaraz, Stéphanie, Allouche, Stephane, Balduyck, Malika, Barbe, Françoise, Barguil, Yann, Bastard, Jean Philippe, Beaudeux, Jean-Louis, Ben Lassoued, Amin, Benz-de Bretagne, Isabelle, Bérard, Annie, Bermont, Laurent, Bigot-Corbel, Edith, Bost, Muriel, Bourbonneux, Valery, Brunel, Valéry, Carré, Jean-Luc, Chenevier-Gobeaux, Camille, Chevrier, Marc, Chinetti, Giulia, Collin-Chavagnac, Delphine, Delacour, Hervé, Delevallée, Delphine, Desroys du Roure, François, Faure, Patrice, Galinier, Anne, Hauet, Thierry, Helj, Carine, Jolly, Emilie, Kamel, Saïd, Lehmann, Sylvain, Leroy, Aline, Lessenger, Jean-Marc, Levy, Pacifique, Lorec-Penet, Anne-Marie, Mesli, Samir, Monnet, Dagui, Moreau, Caroline, Mouly-Badina, Laurence, Nivet-Antoine, Valerie, Oueidat, Nathalie, Pecquet, Mathieu, Peoc'h, Katell, Pieroni, Laurence, Poupon, Carole, Roubille, Martine, Rucheton, Benoit, Sakka, Medhi, Sapin, Vincent, Saunier, Vincent, Schmitt, François, Zaepfel, Sabine, Zozor, Samuel, Groupe Labexa, Synlab Vallée du Rhône, Gen-Bio, CHU Bordeaux [Bordeaux], Centre de résonance magnétique des systèmes biologiques (CRMSB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: 030213 general clinical medicine, Medical laboratory, Pre-Analytical Phase, MESH: Medical Staff, 0302 clinical medicine, Medical Staff, MESH: COVID-19, Intersectoral Collaboration, MESH: Intersectoral Collaboration, Cross Infection, Equipment Safety, MESH: Clinical Laboratory Services, General Medicine, Clinical Laboratory Services, MESH: Pre-Analytical Phase, 3. Good health, MESH: Patient Safety, Private Sector, Medical emergency, France, Patient Safety, MESH: Private Sector, MESH: Hospital Units, Hospital Units, health crisis, 2019-20 coronavirus outbreak, MESH: Pandemics, private medical laboratories, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS CoV-2, Specimen Handling, 03 medical and health sciences, medicine, Humans, MESH: SARS-CoV-2, MESH: Specimen Handling, Pandemics, MESH: Clinical Laboratory Techniques, MESH: Humans, Health professionals, business.industry, Clinical Laboratory Techniques, SARS-CoV-2, pandemia, Cornerstone, COVID-19, MESH: Cross Infection, Front line, medicine.disease, MESH: Equipment Safety, MESH: France, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Confronted with the COVID-19 crisis, healthcare professionals have had to tackle an epidemic crisis of a huge magnitude for which they were not prepared. Medical laboratories have been on the front line, from collecting samples to performing the analysis required to diagnose this new pathology. Responding to the needs and to the urgency of the situation, the authorities relied on the network of private laboratories. In France, private laboratory medicine represents 70% of overall activity, and with a network of more than 4,000 local laboratories, private laboratory medicine has been the cornerstone of the « screen-trace-isolate » strategy. This article gives feedback from private laboratory medicine professionals, directly involved in the reorganization carried out at the pre-analytical, analytical and post-analytical stages, during the crisis from March to October 2020.
Published: 2020

189. Generation of three Duchenne Muscular Dystrophy patient-specific induced pluripotent 4 stem cell lines DMD_YoTaz_PhyMedEXp, DMD_RaPer_PhyMedEXp, 5 DMD_OuMen_PhyMedEXp (INSRMi008-A, INSRMi009-A and INSRMi010-A)

Author: Souidi, Monia, Amedro, Pascal, Meyer, Pierre, Desprat, Romain, Lemaitre, Jean-Marc, Rivier, Francois, Lacampagne, Alain, Meli, Albano C, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and MORNET, Dominique
Subjects: [SDV] Life Sciences [q-bio], musculoskeletal diseases, [SDV]Life Sciences [q-bio]
Abstract: International audience; Abstract: Duchenne Muscular Dystrophy (DMD) is a X-linked degenerative pathology with a prevalence of 1/3600-6000 boys due to the absence of functional dystrophin in muscles. This muscular disease leads to skeletal muscle damages, respiratory failure and in the later stages dilated cardiomyopathy (DCM) leading to heart failure. We generated iPSC lines from three different DMD patients carrying respectively deletions of exons 1, 52 and 55 in the dystrophin gene. The reprogrammed iPSC lines showed expression of pluripotent markers, capacity to differentiate in trilineage embryonic layers and a normal karyotype.
Published: 2020

190. Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

Author: Chantal Reina-Ortiz, Diego Sánchez-Martínez, Carlos Vilches, Daniel Woods, Isabel Marzo, Tania Calvo, Gemma Azaceta, Joaquín Marco-Brualla, Luis Palomera, María Gascón, Martin Villalba, Isabel Izquierdo, Alberto Anel, David Giraldos, Javier Naval, Judit Asenjo, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Hospital Universitario Puerta de Hierro-Majadahonda [Madrid, Spain], Hospital Clínico Universitario 'Lozano Blesa' [Zaragoza, Spain], Hospital Universitario Miguel Servet, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), This work was supported by grant SAF2016-76338-R from Ministerio de Economía y Competitividad (MINECO) to AA, the PRT-K program 2018-021 to MV, the Grant GCB15152947MELE from Asociación Española contra el Cáncer (AECC) to CV, and by Gobierno de Aragón (Group B31_17R) cofinanced by Feder 2014-2020 'Building Europe from Aragon'. TC was supported by an FPI fellowship from MINECO., Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and roussel, pascale
Subjects: 0301 basic medicine, Cytotoxicity, Immunologic, Adoptive cell transfer, Cell biology, endocrine system, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, lcsh:Medicine, Antineoplastic Agents, CD16, Immunotherapy, Adoptive, B7-H1 Antigen, Article, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Cytotoxic T cell, Humans, Cytotoxicity, lcsh:Science, Cells, Cultured, Cancer, Multidisciplinary, Effector, Chemistry, lcsh:R, Immunotherapy, Flow Cytometry, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Killer Cells, Natural, [SDV] Life Sciences [q-bio], 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Cancer research, lcsh:Q, Idelalisib
Abstract: Adoptive transfer of allogeneic natural killer (NK) cells is becoming a credible immunotherapy for hematological malignancies. In the present work, using an optimized expansion/activation protocol of human NK cells, we generate expanded NK cells (eNK) with increased expression of CD56 and NKp44, while maintaining that of CD16. These eNK cells exerted significant cytotoxicity against cells from 34 B-CLL patients, with only 1 sample exhibiting resistance. This sporadic resistance did not correlate with match between KIR ligands expressed by the eNK cells and the leukemic cells, while cells with match resulted sensitive to eNK cells. This suggests that KIR mismatch is not relevant when expanded NK cells are used as effectors. In addition, we found two examples of de novo resistance to eNK cell cytotoxicity during the clinical course of the disease. Resistance correlated with KIR-ligand match in one of the patients, but not in the other, and was associated with a significant increase in PD-L1 expression in the cells from both patients. Treatment of one of these patients with idelalisib correlated with the loss of PD-L1 expression and with re-sensitization to eNK cytotoxicity. We confirmed the idelalisib-induced decrease in PD-L1 expression in the B-CLL cell line Mec1 and in cultured cells from B-CLL patients. As a main conclusion, our results reinforce the feasibility of using expanded and activated allogeneic NK cells in the treatment of B-CLL.
Published: 2020

191. An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants

Author: Sophie Caillard, Dany Anglicheau, Marie Matignon, Antoine Durrbach, Clarisse Greze, Luc Frimat, Olivier Thaunat, Tristan Legris, Valerie Moal, Pierre Francois Westeel, Nassim Kamar, Philippe Gatault, Renaud Snanoudj, Antoine Sicard, Dominique Bertrand, Charlotte Colosio, Lionel Couzi, Jonathan M. Chemouny, Christophe Masset, Gilles Blancho, Jamal Bamoulid, Agnes Duveau, Nicolas Bouvier, Nathalie Chavarot, Philippe Grimbert, Bruno Moulin, Yannick Le Meur, Marc Hazzan, Samira Fafi-Kremer, Alexandre Hertig, Jérôme Tourret, Benoit Barrou, Emmanuel Morelon, Pierre Merville, Valérie Moal, Pierre-François Westeel, Maïté Jaureguy, Didier Ducloux, Michel Tsimaratos, Florentine Garaix-Gilardo, Jérôme Dumortier, Sacha Mussot, Antoine Roux, Laurent Sebbag, Hélène Francois, Eric Rondeau, Christiane Mousson, Matthias Buchler, Jean-François Augusto, Agnès Duveau, Cécile Vigneau, Marie-Christine Morin, Jonathan Chemouny, Leonard Golbin, Betoul Schvartz, Paolo Malvezzi, Christophe Mariat, Antoine Thierry, Moglie Le Quintrec, Jean Philippe Rerolle, Anne-Élisabeth Heng, Cyril Garrouste, Henri Vacher Coponat, Éric Epailly, Olivier Brugiere, Sébastien Dharancy, Éphrem Salame, Faouzi Saliba, CHU Amiens-Picardie, Nouvel Hôpital Civil de Strasbourg, Service Néphrologie et transplantation rénale Adultes [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Assistance Publique - Hôpitaux de Marseille (APHM), 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), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Néphrologie [CHU Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'investigation clinique [Nancy] (CIC), Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bicêtre, Hôpital Pasteur [Nice] (CHU), CHU Bordeaux [Bordeaux], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 ), Centre hospitalier universitaire de Nantes (CHU Nantes), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université d'Angers (UA), Université de Caen Normandie (UNICAEN), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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 Toulouse (UT), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-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 )
Subjects: 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Immunosuppression Therapy, law.invention, chemistry.chemical_compound, 0302 clinical medicine, MESH: Aged, 80 and over, law, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, Kidney transplantation, ComputingMilieux_MISCELLANEOUS, education.field_of_study, MESH: France / epidemiology, immunosuppression, Mortality rate, Immunosuppression, MESH: Kidney Transplantation / mortality, Intensive care unit, 3. Good health, Nephrology, MESH: Young Adult, Covid-19, medicine.medical_specialty, MESH: COVID-19 / complications, MESH: Postoperative Complications / virology, Population, kidney transplantation, Article, 03 medical and health sciences, Tocilizumab, Internal medicine, Diabetes mellitus, education, MESH: Pandemics / statistics & numerical data, business.industry, Retrospective cohort study, MESH: Adult, MESH: Retrospective Studies, medicine.disease, MESH: Deprescriptions, mortality, 030104 developmental biology, chemistry, prognosis, business, MESH: Female
Abstract: Notwithstanding the ongoing coronavirus disease-2019 (Covid-19) pandemic, information on its clinical presentation and prognosis in recipients of a kidney transplant remain scanty. The aim of this registry-based observational study was to explore characteristics and clinical outcomes of recipients of kidney transplants included in the French nationwide Registry of Solid Organ Transplant Recipients with Covid-19. Covid-19 was diagnosed in symptomatic patients who had a positive PCR assay for SARS-CoV-2 or having typical lung lesions on imaging. Clinical and laboratory characteristics, management of immunosuppression, treatment for Covid-19, and clinical outcomes (hospitalization, admission to intensive care unit, mechanical ventilation, or death) were recorded. Risk factors for severe disease or death were determined. Of the 279 patients, 243 were admitted to hospital and 36 were managed at home. The median age of hospitalized patients was 61.6 years; most had comorbidities (hypertension, 90.1%; overweight, 63.8%; diabetes, 41.3%; cardiovascular disease, 36.2%). Fever, cough, dyspnea, and diarrhea were the most common symptoms on admission. Laboratory findings revealed mild inflammation frequently accompanied by lymphopenia. Immunosuppressive drugs were generally withdrawn (calcineurin inhibitors: 28.7%; antimetabolites: 70.8%). Treatment was mainly based on hydroxychloroquine (24.7%), antiviral drugs (7.8%), and tocilizumab (5.3%). Severe Covid-19 occurred in 106 patients (46%). Forty-three hospitalized patients died (30-day mortality 22.8%). Multivariable analysis identified overweight, fever, and dyspnea as independent risk factors for severe disease, whereas age over 60 years, cardiovascular disease, and dyspnea were independently associated with mortality. Thus, Covid-19 in recipients of kidney transplants portends a high mortality rate. Proper management of immunosuppression and tailored treatment of this population remain challenging., Graphical abstract
Published: 2020

192. Generation of the induced pluripotent stem cell line UHOMi002-A from peripheral blood mononuclear cells of a healthy male donor

Author: Mathieu, Fieldes, Engi, Ahmed, Chloé, Bourguignon, Joffrey, Mianné, Mélanie, Martin, Cécile, Arnould, Isabelle, Vachier, Said, Assou, John, De Vos, Arnaud, Bourdin, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), MORNET, Dominique, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Male, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Karyotype, Cell Differentiation, Cellular Reprogramming, [SDV] Life Sciences [q-bio], lcsh:Biology (General), Leukocytes, Mononuclear, Humans, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Transcription Factors
Abstract: Human pluripotent stem cells (hiPSC) are highly valuable tools to model lung development and chronic bronchial diseases. We generated a hiPSC line from a highly characterized 40-year-old healthy male nonsmoking donor. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using integration-free Sendai Virus. The cell line had normal karyotype, expressed pluripotency hallmarks, and differentiated into the three primary germ layers. The reported UHOMi002-A iPSC line may be used as a control to model lung development, study human chronic bronchial diseases and drug testing.
Published: 2020

193. Sénothérapies

Author: Jean-Marc Brondello, Damien Veret, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Senescence, 0303 health sciences, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Cell, Longevity, Cellular senescence, General Medicine, Biology, Phenotype, General Biochemistry, Genetics and Molecular Biology, 3. Good health, Tissue Degeneration, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Ageing, medicine, Epigenetics, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract: International audience; Bien que la sénescence cellulaire joue un rôle essentiel dans le développent embryonnaire, la cicatrisation ou l’hémostase, il est maintenant également démontré qu’elle est à l’origine de nombreux processus dégénératifs qui caractérisent le vieillissement. Cette sénescence est induite en réponse à divers stress ou stimulus inappropriés, conduisant à un arrêt de la prolifération et des adaptations géniques, épigénétiques, métaboliques, structurelles et fonctionnelles. Ces cellules sénescentes, lorsqu’elles ne sont pas éliminées, favorisent la propagation de leur phénotype de proche en proche dans le tissu environnant, par l’établissement d’un profil sécrétoire spécifique. Éliminer ou bloquer l’action de ces cellules par des agents dits sénothérapeutiques pourrait prévenir la dégénérescence tissulaire et améliorer la longévité en bonne santé. Nous nous proposons dans cette revue de présenter les dernières avancées et applications développées en sénothérapie et discuterons les résultats très prometteurs des premiers essais cliniques chez l’homme.
Published: 2020

194. Sénothérapies: Avancées et nouvelles perspectives cliniques

Author: Veret, Damien, Brondello, Jean-Marc, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Bien que la sénescence cellulaire joue un rôle essentiel dans le développent embryonnaire, la cicatrisation ou l’hémostase, il est maintenant également démontré qu’elle est à l’origine de nombreux processus dégénératifs qui caractérisent le vieillissement. Cette sénescence est induite en réponse à divers stress ou stimulus inappropriés, conduisant à un arrêt de la prolifération et des adaptations géniques, épigénétiques, métaboliques, structurelles et fonctionnelles. Ces cellules sénescentes, lorsqu’elles ne sont pas éliminées, favorisent la propagation de leur phénotype de proche en proche dans le tissu environnant, par l’établissement d’un profil sécrétoire spécifique. Éliminer ou bloquer l’action de ces cellules par des agents dits sénothérapeutiques pourrait prévenir la dégénérescence tissulaire et améliorer la longévité en bonne santé. Nous nous proposons dans cette revue de présenter les dernières avancées et applications développées en sénothérapie et discuterons les résultats très prometteurs des premiers essais cliniques chez l’homme.
Published: 2020

195. [Dental stem cells: myth or hope in neuroregenerative medicine?]

Author: Dimassi, Syrine, Relaño-Ginés, Aroa, Hirtz, Christophe, Lehmann, Sylvain, Deville de Périère, Dominique, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), and Herrada, Anthony
Subjects: MESH: Cell Differentiation, MESH: Neural Stem Cells, MESH: Nerve Regeneration, MESH: Humans, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Tooth, Neurodegenerative diseases, Cellular therapy, Maladies neurodégénératives, MESH: Stem Cells, MESH: Neurodegenerative Diseases, MESH: Neurogenesis, Cellules souches dentaires, Dental stem cells, MESH: Regenerative Medicine, Mesenchymal stem cells, MESH: Animals, MESH: Tissue Culture Techniques, Cellules souches mésenchymateuses, MESH: Stem Cell Transplantation, MESH: Tissue Banks, Thérapie cellulaire, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The use of dental stem cells has raised many hopes in the development of new treatments for neurodegenerative diseases. According to current statistics, about 1 in 6 people in the world would be affected by a neurological disease. This number continues to increase as the world's population ages, making neurodegenerative diseases probably the one of the major challenges of public health in the 21st century. Neurodegenerative diseases are characterized mainly by a progressive loss of cognitive abilities and patient autonomy related to loss and degeneration of neurons in brain structures. Unfortunately, today, the only treatments available for this type of disease do only relieve the symptoms, they do not treat them, and few clinical trials have been truly convincing to date. Hence, hope lies for these diseases in the development of other therapeutic approaches. As such, dental stem cells could be a promising area of research because of their rapid growth, their great capacity for differentiation into different types of cells (among neuronal ones for some of them) and how easy they can be obtained, without raising ethical issues as for example for embryonic stem cells., L’utilisation des cellules souches dentaires a fait naître de nombreux espoirs dans le développement de nouveaux traitements destinés aux maladies neurodégénératives. Si l’on se réfère aux statistiques actuelles, environ 1 personne sur 6 dans le monde serait atteinte par une maladie neurologique. Ce nombre ne cesse d’augmenter au fur et à mesure que la population mondiale vieillit, faisant des maladies neurodégénératives probablement l’un des principaux défis de la santé publique du XXIe siècle. Les maladies neurodégénératives se caractérisent principalement par une perte progressive des facultés cognitives et de l’autonomie des patients liée à une perte et une dégénérescence des neurones des structures cérébrales. Malheureusement, force est de constater que les seuls traitements disponibles actuellement pour ce type de pathologies ne font que soulager les symptômes et non les traiter et que peu d’essais cliniques à ce jour ont été véritablement probants. L’espoir réside donc pour ces maladies neurodégénératives dans le développement de nouvelles approches thérapeutiques. Les cellules souches dentaires pourraient constituer une nouvelle voie de recherche en thérapie cellulaire, de par leur croissance rapide, leur grande capacité de différenciation en différents types cellulaires (y compris en cellules neuronales pour certaines) et la facilité avec laquelle elles peuvent être obtenues sans soulever de problèmes d’éthique comme par exemple pour les cellules souches embryonnaires.
Published: 2020

196. Revisiting the cardiovascular risk of hydroxychloroquine in RA

Author: Guillaume Padern, Yves-Marie Pers, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Herrada, Anthony, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Time Factors, MESH: Hydroxychloroquine, Azithromycin, Arthritis, Rheumatoid, 0302 clinical medicine, Anti-Infective Agents, Cardiac toxicity, Medicine, MESH: COVID-19, News & Views, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, MESH: Arthritis, Rheumatoid, Anti-Bacterial Agents, 3. Good health, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cardiovascular Diseases, MESH: Heart Disease Risk Factors, Rheumatoid arthritis, Drug Therapy, Combination, Drug therapy, Safety, Hydroxychloroquine, medicine.drug, 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MESH: Anti-Infective Agents, Antimalarials, 03 medical and health sciences, Rheumatology, Internal medicine, MESH: Anti-Bacterial Agents, MESH: Azithromycin, Humans, MESH: SARS-CoV-2, 030203 arthritis & rheumatology, MESH: Humans, MESH: Sulfasalazine, SARS-CoV-2, business.industry, Adverse effects, MESH: Safety, MESH: Time Factors, COVID-19, MESH: Cardiovascular Diseases, medicine.disease, bacterial infections and mycoses, MESH: Antimalarials, COVID-19 Drug Treatment, Sulfasalazine, MESH: Drug Therapy, Combination, 030104 developmental biology, Heart Disease Risk Factors, business
Abstract: International audience; Cardiac toxicity can be induced by hydroxychloroquine, especially when used in combination with azithromycin. Interest in hydroxychloroquine and azithromycin as potential therapies for COVID-19 has renewed concerns about the possible cardiovascular risk these drugs present to patients with rheumatoid arthritis.
Published: 2020

197. FTO-mediated cytoplasmic $m6Am$ demethylation adjusts stem-like properties in colorectal cancer cell

Author: Amandine Bastide, Armelle Choquet, Sebastien Relier, Eric Rivals, Julie Pannequin, Jean-Jacques Vasseur, F. Boissière, Jérôme Vialaret, Francoise Macari, Evelyne Crapez, Emmanuelle Samalin, Amandine Amalric, Julie Ripoll, Françoise Debart, Alexandre David, Christophe Hirtz, Hélène Guillorit, Aurore Attina, Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cancer de Montpellier (ICM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, education.field_of_study, Colorectal cancer, Cell, Population, Cancer, Translation (biology), Biology, medicine.disease, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Cancer stem cell, 030220 oncology & carcinogenesis, Demethylase activity, medicine, Cancer research, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], education, 030304 developmental biology
Abstract: Cancer stem cells (CSCs) are a small but critical cell population for cancer biology since they display inherent resistance to standard therapies and give rise to metastases. Despite accruing evidence establishing a link between deregulation of epitranscriptome-related players and tumorigenic process, the role of messenger RNA (mRNA) modifications dynamic in the regulation of CSC properties remains poorly understood. Here, we show that the cytoplasmic pool of fat mass and obesity-associated protein (FTO) impedes CSC abilities in colorectal cancer through its m6Am(N6,2’-O-dimethyladenosine) demethylase activity. While m6Amis strategically located next to the m7G-mRNA cap, its biological function is not well understood and has not been addressed in cancer. Low FTO expression in patient-derived cell lines elevates m6Amlevel in mRNA which results in enhancedin vivotumorigenicity and chemoresistance. Inhibition of the nuclear m6Ammethyltransferase, PCIF1/CAPAM, partially reverses this phenotype. FTO-mediated regulation of m6Ammarking constitutes a novel, reversible pathway controlling CSC abilities that does not involve transcriptome remodeling, but could fine-tune translation efficiency of selected m6Ammarked transcripts. Altogether, our findings bring to light the first biological function of the m6Ammodification and its potential adverse consequences for colorectal cancer management.
Published: 2020

198. Liver venous deprivation versus portal vein embolization before major hepatectomy: future liver remnant volumetric and functional changes

Author: Fabrizio Panaro, Emmanuel Deshayes, Christophe Cassinotto, M A Pierredon-Foulongne, Boris Guiu, Serge Aho-Glele, Lauranne Piron, François-Régis Souche, Astrid Herrerro, François Quenet, Ali Belgour, Margaux Hermida, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cancer de Montpellier (ICM), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'épidémiologie et d'hygiène hospitalières (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Herrada, Anthony, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: medicine.medical_specialty, Cirrhosis, Portal vein embolization (PVE), medicine.medical_treatment, Urology, 030230 surgery, liver venous deprivation (LVD), 03 medical and health sciences, 0302 clinical medicine, hepatectomy, medicine, Major complication, Embolization, resection, Vein, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, mebrofenin, medicine.disease, Klatskin tumor, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Portal vein embolization, Original Article, Hepatectomy, business, Major hepatectomy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background: We previously showed that embolization of portal inflow and hepatic vein (HV) outflow (liver venous deprivation, LVD) promotes future liver remnant (FLR) volume (FLR-V) and function (FLR-F) gain. Here, we compared FLR-V and FLR-F changes after portal vein embolization (PVE) and LVD.Methods: This study included all patients referred for liver preparation before major hepatectomy over 26 months. Exclusion criteria were: unavailable baseline/follow-up imaging, cirrhosis, Klatskin tumor, two-stage hepatectomy. 99mTc-mebrofenin SPECT-CT was performed at baseline and at day 7, 14 and 21 after PVE or LVD. FLR-V and FLR-F variations were compared using multivariate generalized linear mixed models (joint modelling) with/without missing data imputation.Results: Baseline FLR-F was lower in the LVD (n=29) than PVE group (n=22) (P
Published: 2020

199. Description of neurotoxicity in a series of patients treated with CAR T-cell therapy

Author: Lila Sirven-Villaros, Sylvain Lamure, Thomas Gastinne, Florent Wallet, Antoine F. Carpentier, Benoit Tessoulin, David Laplaud, Claire Simard, Catherine Belin, Elie Azoulay, Adrien Paix, Catherine Thieblemont, Perrine Devic, Guillaume Cartron, Renata Ursu, Laura Platon, Xavier Ayrignac, Emmanuel Bachy, Colette Berger, Amélie Dos Santos, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Radiothérapie de Bobigny, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), and Hopital Saint-Louis [AP-HP] (AP-HP)
Subjects: CAR-T cell therapy, Adult, Male, medicine.medical_specialty, Lymphoma, B-Cell, Lymphoma, medicine.medical_treatment, Receptors, Antigen, T-Cell, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunotherapy, Adoptive, Severity of Illness Index, Article, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Neurotoxicity syndromes, Internal medicine, Severity of illness, Neurotoxicity, medicine, Humans, Prospective Studies, lcsh:Science, Prospective cohort study, Survival analysis, Aged, 030304 developmental biology, 0303 health sciences, Multidisciplinary, business.industry, lcsh:R, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Immunotherapy, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Cytokine release syndrome, C-Reactive Protein, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Female, business
Abstract: Chimeric antigen receptor-modified T (CAR T) cell therapy is a highly promising treatment for haematological malignancies but is frequently associated with cytokine release syndrome and neurotoxicity. Between July 2018 and July 2019, all patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma were followed-up longitudinally to describe neurological symptoms and their evolution over time. Four different French centres participated and 84 patients (median age 59 years, 31% females) were included. Neurotoxicity, defined as the presence of at least one neurological symptom appearing after treatment infusion, was reported in 43% of the patients. The median time to onset was 7 days after infusion with a median duration of 6 days. More than half of the patients (64%) had grade 1–2 severity and 34% had grade 3–4. CRS was observed in 80% of all patients. The most frequent neurological symptoms were cognitive signs, being severe in 36%, and were equally distributed between language disorders and cognitive disorders without language impairment. Non-pyramidal motor disorders, severe in 11%, were reported in 42% of the patients. Elevation of C-reactive protein (CRP) within 4 days after treatment was significantly correlated with the occurrence of grade 3–4 neurotoxicity. Although sometimes severe, neurotoxicity was almost always reversible. The efficacy of steroids and antiepileptic drugs remains unproven in the management of neurotoxicity. Neurotoxicity associated with CAR T-cell therapies occurs in more than 40% of patients. The clinical pattern is heterogeneous but cognitive disorders (not limited to language disorders) and, to a minor degree, non-pyramidal motor disorders, appeared as a signature of severe neurotoxicity.
Published: 2020

200. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long‐term outcome

Author: Rima Nabbout, Patrick Berquin, Sylvie Odent, Mathieu Kuchenbuch, Gwenaël Le Guyader, Marieke F. van Dooren, Jamel Chelly, Edor Kabashi, Melanie Jennesson, Giulia Barcia, Cyril Mignot, Tayeb Sekhara, Alexandra Afenjar, Marlène Rio, Anne Rolland, Claude Besmond, Andrés Rodríguez-Sacristán Cascajo, Gaetano Terrone, Isabelle Marey, Boris Keren, Alice Goldenberg, A.S. Lebre, Heather C Mefford, Gaetan Lesca, Anne de Saint Martin, Susanna Negrin, Nathalie Dorison, Hélène Maurey, Agnès Guët, David Geneviève, Marie Claire Y. de Wit, Jeremy L. Freeman, Pierre Meyer, Thierry Billette de Villemeur, Ingrid E. Scheffer, Katherine B. Howell, Anca Nica, Raphael Levy, Martino Montomoli, Renzo Guerrini, Elena Parrini, Candace T. Myers, Bertrand Isidor, Alice Poisson, Marion Gérard, Salima El Chehadeh, Lynette G. Sadleir, Julien Durigneux, Pascal Vrielynck, Amy L Schneider, Emmanuel Scalais, Laurence Hubert, Sophie Dupont, Vesna Brankovic, Damien Lederer, Hervé Isnard, Delphine Breuillard, Claire Bar, Alberto Danieli, Diane Doummar, Arnold Munnich, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Institut NeuroMyoGène (INMG), 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), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Centre for the Diagnosis and management of genetic psychiatric disorders [Bron] (GénoPsy), Centre Hospitalier le Vinatier [Bron], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Rouen, Normandie Université (NU), CHU Amiens-Picardie, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pitié-Salpêtrière [AP-HP], FP7 Ideas: European Research Council, National Health and Medical Research Council, Health Research Council of New Zealand, ANR‐10-IAHU‐01, Agence Nationale de la Recherche, Fondation Bettencourt Schueller, 602531, Seventh Framework Programme, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Lyon-Université de Lyon-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)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR‐10IAHU‐01, Agence Nationale de la Recherche, Clinical Genetics, Neurology, and Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Time Factors, Adolescent, autism spectrum disorders, [SDV]Life Sciences [q-bio], Encephalopathy, Severe epilepsy, Imaging data, Cohort Studies, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Shab Potassium Channels, drug-resistant epilepsy, Intellectual disability, medicine, Missense mutation, Humans, In patient, developmental and epileptic encephalopathy, Child, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Brain Diseases, sudden unexpected death in epilepsy, developmental encephalopathy, business.industry, Genetic Variation, Infant, Cognition, Electroencephalography, medicine.disease, potassium channels, 3. Good health, 030104 developmental biology, Treatment Outcome, Neurology, Child, Preschool, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association “KCNB1 France.” Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the longterm outcome in patients older than 12 years from our series and from literature. Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
Published: 2020

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