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1. The Spontaneous Autoimmune Neuromyopathy in ICOSL−/− NOD Mice Is CD4+ T-Cell and Interferon-γ Dependent

Author: Briet, Claire, Bourdenet, Gwladys, Rogner, Ute, Becourt, Chantal, Tardivel, Isabelle, Drouot, Laurent, Arnoult, Christophe, Do Rego, Jean-Claude, Prévôt, Nicolas, Massaad, Charbel, Boyer, Olivier, Boitard, Christian, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Polymères Biopolymères Surfaces (PBS), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Service Commun d'Analyse Comportementale (SCAC), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developmental Immunology [Oxford, UK] (Department of Paediatrics), The Weatherall Institute of Molecular Medicine, University of Oxford-University of Oxford, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), This work was funded by AFM grant (myoAID—application number 17643), FRM grant (Fondation pour la Recherche Médicale—FDM20081114737), and 'Association pour la Recherche sur le Diabète' (ARD) grant., Bos, Mireille, Centre National de la Recherche Scientifique (CNRS), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices ( PANTHER ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Polymères Biopolymères Surfaces ( PBS ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ), Service Commun d'Analyse Comportementale ( SCAC ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institute for Research and Innovation in Biomedicine ( IRIB ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Developmental Immunology [Oxford, UK] ( Department of Paediatrics ), University of Oxford [Oxford]-University of Oxford [Oxford]-University of Oxford [U.K.], Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU), University of Oxford [Oxford]-University of Oxford [Oxford], Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford [Oxford]-The Weatherall Institute of Molecular Medicine, University of Oxford [Oxford], 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), Immunologie, génétique et traitement des maladies métaboliques et du diabète (UMR_S 561), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Centre de recherches en ethnomusicologie (CREM), Laboratoire d'ethnologie et de sociologie comparative (LESC), Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Nanterre (UPN)-Centre National de la Recherche Scientifique (CNRS), Stéroïdes et système nerveux : physiopathologie moléculaire et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), MITOVASC institute and CARFI facility, UMR CNRS 6015, INSERM U1083, University of Angers, Angers, France., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: type 1 diabetes, [SDV]Life Sciences [q-bio], Immunology, autoimmunity, ICOS, costimulation, ICOSL, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.IMM]Life Sciences [q-bio]/Immunology, neuropathy, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS, myopathy
Abstract: International audience; Abrogation of ICOS/ICOS ligand (ICOSL) costimulation prevents the onset of diabetes in the non-obese diabetic (NOD) mouse but, remarkably, yields to the development of a spontaneous autoimmune neuromyopathy. At the pathological level, ICOSL −/− NOD mice show stronger protection from insulitis than their ICOS −/− counterparts. Also, the ICOSL −/− NOD model carries a limited C57BL/6 region containing the Icosl nul mutation, but, in contrast to ICOS −/− NOD mice, no gene variant previously reported as associated to NOD diabetes. Therefore, we aimed at providing a detailed characterization of the ICOSL −/− NOD model. The phenotype observed in ICOSL −/− NOD mice is globally similar to that observed in ICOS −/− and ICOS −/− ICOSL −/− double-knockout NOD mice, manifested by a progressive locomotor disability rst affecting the front paws as observed by catwalk analysis and a decrease in grip test performance. The pathology remains limited to peripheral nerve and striated muscle. The muscle disease is characterized by myoober necrosis/regeneration and an innammatory innltrate composed of CD4 + T-cells, CD8 + T-cells, and myeloid cells, resembling human myositis. Autoimmune neuromyopa-thy can be transferred to NOD.scid recipients by CD4 + but not by CD8 + T-cells isolated from 40-week-old female ICOSL −/− NOD mice. The predominant role of CD4 + T-cells is further demonstrated by the observation that neuromyopathy does not develop in CIITA −/− ICOSL −/− NOD in contrast to β2microglobulin −/− ICOSL −/− NOD mice. Also, the cytokine proole of CD4 + T-cells innltrating muscle and nerve of ICOSL −/− NOD mice is biased toward a Th1 pattern. Finally, adoptive transfer experiments show that diabetes development requires expression of ICOSL, in contrast to neuromyopathy. Altogether, the deviation of autoimmunity from the pancreas to skeletal muscles in the absence of ICOS/ICOSL signaling in NOD mice is strictly dependent on CD4 + T-cells, leads to myoober necrosis and regeneration. It provides the rst mouse model of spontaneous autoimmune myopathy akin to human myositis.
Published: 2017
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2. Clinical features, therapeutic choice and response by phototype in psoriasis: analysis of the French PsoBioTeq cohort

Author: Salle-Siri, Romain, Tubach, Florence, Arlegui, Hugo, Curmin, Raphaëlle, Viguier, Manuelle, Beylot-Barry, Marie, Dupuy, Alain, Bénéton, Nathalie, Joly, Pascal, de Rycke, Yann, Jullien, Denis, Mahé, Emmanuel, Paul, Carle, Richard, Marie‐aleth, Bachelez, Hervé, Zago, Marilyn, Chosidow, Olivier, Sbidian, Emilie, Hôpital Henri Mondor, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Robert Debré, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre Hospitalier Le Mans (CH Le Mans), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre Hospitalier Victor Dupouy, Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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)-Centre National de la Recherche Scientifique (CNRS), CHU Marseille, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CIC - CHU Henri Mondor, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; BACKGROUND: Little is known about phototype and the response to systemic treatment in psoriasis. OBJECTIVE: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype. METHODS: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on PASI 90 and DLQI 0/1. RESULTS: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I-II, III-IV and V-VI groups, respectively. The V-VI group had a higher initial DLQI, more frequently initiated ustekinumab. Patients in the phototype V-VI group maintained the first sequence of biologic as the other phototype groups, even though the proportion of patients reaching the PASI 90 and DLQI 0/1 at 12 months was lower in this group than other groups. CONCLUSION: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. Phototype V-VI group less frequently switched treatments than did the other groups when the response was not efficient.
Published: 2023
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3. Throughout in vitro first spermatogenic wave: Next-generation sequencing gene expression patterns of fresh and cryopreserved prepubertal mice testicular tissue explants

Author: Dumont, Ludovic, Lopez-Maestre, Hélène, Chalmel, Frédéric, Huber, Louise, Rives-Feraille, Aurélie, Moutard, Laura, Bateux, Frédérique, Rondanino, Christine, Rives, Nathalie, Neuroendocrine, Endocrine and Germinal Differentiation Communication (NorDic), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut de recherche en santé, environnement et travail (Irset), 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 ), CHU Rouen, Normandie Université (NU), and ANR-21-CE14-0068,sc-SpermInVitro,Exploration de la maturation in vitro du tissu testiculaire prépubère frais ou décongelé par approche ' single cell '(2021)
Subjects: mice, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], transcriptomic, RNA-Seq, testis, cryopreservation, in vitro spermatogenesis
Abstract: IntroductionSuitable cryopreservation procedures of pre-pubertal testicular tissue associated with efficient culture conditions are crucial in the fields of fertility preservation and restoration. In vitro spermatogenesis remains a challenging technical procedure to undergo a complete spermatogenesis.The number of haploid cells and more specifically the spermatic yield produced in vitro in mice is still extremely low compared to age-matched in vivo controls and this procedure has never yet been successfully transferred to humans.MethodsTo evaluate the impact of in vitro culture and freezing procedure, pre-pubertal testicular mice testes were directly cultured until day 4 (D4), D16 and D30 or cryopreserved by controlled slow freezing then cultured until D30. Testes composed of a panel of 6.5 dpp (days postpartum), 10.5 dpp, 22.5 dpp, and 36.5 dpp mice were used as in vivo controls. Testicular tissues were assessed by histological (HES) and immunofluorescence (stimulated by retinoic acid gene 8, STRA8) analyses. Moreover, a detailed transcriptome evaluation study has been carried out to study the gene expression patterns throughout the first in vitro spermatogenic wave.ResultsTranscriptomic analyses reveal that cultured tissues expression profiles are almost comparable between D16 and D30; highlighting an abnormal kinetic throughout the second half of the first spermatogenesis during in vitro cultures. In addition, testicular explants have shown dysregulation of their transcriptomic profile compared to controls with genes related to inflammation response, insulin-like growth factor and genes involved in steroidogenesis.DiscussionThe present work first shows that cryopreservation had very little impact on gene expression in testicular tissue, either directly after thawing or after 30 days in culture. Transcriptomic analysis of testis tissue samples is highly informative due to the large number of expressed genes and identified isoforms. This study provides a very valuable basis for future studies concerning in vitro spermatogenesis in mice.
Published: 2023
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4. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

Author: Anne Rovelet-Lecrux, Sebastien Feuillette, Laetitia Miguel, Catherine Schramm, Ségolène Pernet, Olivier Quenez, Isabelle Ségalas-Milazzo, Laure Guilhaudis, Stéphane Rousseau, Gaëtan Riou, Thierry Frébourg, Dominique Campion, Gaël Nicolas, Magalie Lecourtois, 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), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut de Chimie Organique Fine (IRCOF), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), and Rovelet Lecrux, Anne
Subjects: Mutation, Missense, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Maturation defects, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Alzheimer Disease, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RC346-429, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, LDL-Receptor Related Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, iPSC, Trafficking, Research, Membrane Transport Proteins, Alzheimer's disease, SorLA, HEK293 Cells, Neurology (clinical), Neurology. Diseases of the nervous system, Alzheimer’s disease, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.
Published: 2021
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5. Immunomonitoring of patients treated with CAR-T cells for hematological malignancy: guidelines from the CARTi group and the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)

Author: Pauline Varlet, Christophe Ferrand, Marie-Thérèse Rubio, Claude Lemarie, Marina Deschamps, Alexis Cuffel, Amélie Guihot, Florence Morin, Ibrahim Yakoub-Agha, Caroline Ballot, Guillaume Martinroche, Vincent Allain, Sophie Servais, Jacques Foguenne, Kathleen Schmit, Federico Simonetta, Anne Huynh, Sophie Caillat Zucman, Edouard Forcade, Jean-Baptiste Latouche, Stéphanie Nguyen, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Etablissement Français du Sang Hauts-de-France - Normandie (EFS Hauts-de-France - Normandie), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Liège (CHU-Liège), CHU Bordeaux [Bordeaux], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-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), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Hôpital de la Conception - APHM] (CIC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Université de Genève = University of Geneva (UNIGE), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Bone marrow transplantation, business.industry, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Context (language use), Hematology, General Medicine, Immunotherapy, Cell therapy, Clinical trial, Apheresis, Immune system, Internal medicine, Toxicity, medicine, Radiology, Nuclear Medicine and imaging, business, ComputingMilieux_MISCELLANEOUS
Abstract: CAR-T cells represent a new anti-tumor immunotherapy which has shown its clinical efficacy in B-cell malignancies. The results of clinical trials carried out in this context have shown that certain immunological characteristics of patients before (at the time of apheresis) and after the administration of the treatment, or of the CAR-T cells themselves, are correlated with the response to the treatment or to its toxicity. However, to date, there are no recommendations on the immunological monitoring of patients treated in real life. The objectives of this workshop were to determine, based on data from the literature and the experience of the centers, the immunological analyses to be carried out in patients treated with CAR-T cells. The recommendations relate to the characterization of the patient's immune cells at the time of apheresis, the characterization of the injected CAR-T cells, as well as the monitoring of the CAR-T cells and other parameters of immune reconstitution in the patient after administration of the treatment. Harmonization of practices will allow clinical-biological correlation studies to be carried out in patients treated in real life with the aim of identifying factors predictive of response and toxicity. Such data could have a major medico-economic impact by making it possible to identify the patients who will optimally benefit from these expensive treatments.
Published: 2021
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6. Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study

Author: Mohamad Mohty, Didier Blaise, Régis Peffault de Latour, Myriam Labopin, Jean Henri Bourhis, Benedicte Bruno, Patrice Ceballos, Marie Detrait, Virginie Gandemer, Anne Huynh, Faezeh Izadifar-Legrand, Charlotte Jubert, Hélène Labussière-Wallet, Delphine Lebon, Sébastien Maury, Catherine Paillard, Cécile Pochon, Cecile Renard, Fanny Rialland, Pascale Schneider, Anne Sirvent, Kobby Asubonteng, Gwennaëlle Guindeuil, Ibrahim Yakoub-Agha, Jean-Hugues Dalle, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Lapeyronie [Montpellier] (CHU), Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe hospitalier Pellegrin, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Centre d'Investigation Clinique [CHU Clermont-Ferrand] (CIC 1405), Institut National de la Santé et de la Recherche Médicale (INSERM)-Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service d'Oncologie Pédiatrique [CHRU Nancy], Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Jazz Pharmaceuticals, Inc, Jazz Pharmaceuticals [Lyon], 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), Hôpital Robert Debré Paris, Hôpital Robert Debré, and Jazz Pharmaceuticals
Subjects: Transplantation, Haematopoietic stem cells, Hematology, Drug therapy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin
Published: 2022
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7. IgG N-glycosylation from Patients with Pemphigus Treated with Rituximab

Author: Guillaume Font, Marie-Laure Walet-Balieu, Marie Petit, Carole Burel, Maud Maho-Vaillant, Vivien Hébert, Philippe Chan, Manuel Fréret, Olivier Boyer, Pascal Joly, Sébastien Calbo, Muriel Bardor, Marie-Laure Golinski, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Glycobiologie et Matrice Extracellulaire Végétale (Glyco-MEV), Normandie Université (NU)-Normandie Université (NU), Plate-forme de Protéomique PISSARO, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Biochemistry & Molecular Biology, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, glycosylation, IgG, Medicine (miscellaneous), N-glycans, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Research & Experimental Medicine, FC-GAMMA-RIII, General Biochemistry, Genetics and Molecular Biology, DISEASE, rituximab, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], SIALYLATION LEVELS, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BV]Life Sciences [q-bio]/Vegetal Biology, pemphigus, N-glycome, sialic acid, Pharmacology & Pharmacy, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BDD]Life Sciences [q-bio]/Development Biology, SIALIC-ACID, Science & Technology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BV.PEP]Life Sciences [q-bio]/Vegetal Biology/Phytopathology and phytopharmacy, RHEUMATOID-ARTHRITIS, GALACTOSYLATION, OLIGOSACCHARIDES, [SDV.BV.AP]Life Sciences [q-bio]/Vegetal Biology/Plant breeding, Medicine, Research & Experimental, B-CELLS, ANTIBODIES, AUTOANTIBODIES, Life Sciences & Biomedicine
Abstract: Pemphigus is a life-threatening auto-immune blistering disease of the skin and mucous membrane that is caused by the production of auto-antibodies (auto-Abs) directed against adhesion proteins: desmoglein 1 and 3. We demonstrated in the "Ritux3" trial, the high efficacy of rituximab, an anti-CD20 recombinant monoclonal antibody, as the first-line treatment for pemphigus. However, 25% of patients relapsed during the six-month period after rituximab treatment. These early relapses were associated with a lower decrease in anti-desmoglein auto-Abs after the initial cycle of rituximab. The N-glycosylation of immunoglobulin-G (IgG) can affect their affinity for Fc receptors and their serum half-life. We hypothesized that the extended half-life of Abs could be related to modifications of IgG N-glycans. The IgG N-glycome from pemphigus patients and its evolution under rituximab treatment were analyzed. Pemphigus patients presented a different IgG N-glycome than healthy donors, with less galactosylated, sialylated N-glycans, as well as a lower level of N-glycans bearing an additional N-acetylglucosamine. IgG N-glycome from patients who achieved clinical remission was not different to the one observed at baseline. Moreover, our study did not identify the N-glycans profile as discriminating between relapsing and non-relapsing patients. We report that pemphigus patients present a specific IgG N-glycome. The changes observed in these patients could be a biomarker of autoimmunity susceptibility rather than a sign of inflammation. ispartof: BIOMEDICINES vol:10 issue:8 ispartof: location:Switzerland status: published
Published: 2022
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8. Association between inflammation, angiopoietins, and disease severity in critically ill COVID-19 patients: a prospective study

Author: Youssef Bennis, Saïd Kamel, Pierre Gauthier, Gwladys Bourdenet, Osama Abou-Arab, Brigitte Gubler, Hervé Dupont, Yazine Mahjoub, Cédric Boudot, Christophe Beyls, Université d'Amiens, CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université de Picardie Jules Verne (UPJV), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [CHU d'Amiens-Picardie], and DESSAIVRE, Louise
Subjects: Male, medicine.medical_specialty, ARDS, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], Critical Illness, Inflammation, Severity of Illness Index, Angiopoietin, Internal medicine, Correspondence, medicine, Humans, Prospective Studies, Prospective cohort study, Interleukin 6, ComputingMilieux_MISCELLANEOUS, Aged, biology, business.industry, angiopoietin, interleukin-6, COVID-19, Angiopoietins, Middle Aged, medicine.disease, cytokines, [SDV] Life Sciences [q-bio], Anesthesiology and Pain Medicine, inflammation, biology.protein, biomarker, Biomarker (medicine), Female, Inflammation Mediators, medicine.symptom, business, Biomarkers
Abstract: International audience
Published: 2021
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9. Impact of Childhood Onset Psoriasis on Addictive Behaviours, Socioeconomic and Educational Data in Adulthood

Author: Emmanuel, Mahé, Florence, Tubach, Denis, Jullien, Diep, Tran, Carle, Paul, Marie, Beylot-Barry, Alain, Dupuy, Manuelle, Viguier, Marie-Aleth, Richard, Emilie, Sbidian, Nathalie, Beneton, Pascal, Joly, Olivier, Chosidow, Hervé, Bachelez, Centre Hospitalier Victor Dupouy, Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Hospices Civils de Lyon (HCL), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-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], Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC), Université de Reims Champagne-Ardenne (URCA), CHU Marseille, Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Le Mans (CH Le Mans), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), French Ministry of Health [PHRC AOM 09 195], French Drugs Agency (ANSM), AbbVie, Janssen, MSD France, Pfizer, Departement a la Recherche Clinique et au Developpement (DRCD), Assistance Publique-Hopitaux de Paris, French Society of Dermatology (Societe Francaise de Dermatologie), Groupe de Recherche sur le Psoriasis, Jonchère, Laurent, 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), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, socioeconomic data, alcohol, [SDV]Life Sciences [q-bio], Dermatology, General Medicine, psoriasis, tobacco, Behavior, Addictive, [SDV] Life Sciences [q-bio], Cross-Sectional Studies, educational level, Socioeconomic Factors, children, adolescent, Educational Status, Humans, Prospective Studies, Child
Abstract: International audience; Paediatric psoriasis has been associated with school absenteeism, limitation of physical activities, psychiatric disorders and, in the longer term, with sexual dysfunction and addictions. This raises the hypothesis that childhood onset psoriasis may affect patients' educational development, and further social and professional outcomes. This study evaluated the relationship between childhood onset psoriasis and patients' educational and socioeconomic characteristics, and the development of addictions in adulthood. This cross-sectional ancillary study captured patients' characteristics at baseline in the French PSOBIOTEQ registry. Data in adulthood included: educational (baccalaureate) and socioeconomic (working activity) groups, smoking status (self-reporting of being a current smoker vs past smoker or non-smoker), alcohol consumption (defined as at least 1 glass of alcoholic beverage per day), and living conditions (alone/family/social institutions; child at home). A total of 1,960 patients were included, of whom 26.2% had childhood onset psoriasis. In multivariate analyses, childhood onset psoriasis was associated with smoker status (p = 0.02). No association was observed with educational level, working activity, living conditions, or alcohol consumption. This study provides reassuring data overall with regard to the impact of childhood onset psoriasis on major social outcomes. Evidence for some association with addictive behaviours paves the way for larger prospective studies assessing in depth the social and educational impact of this disease.
Published: 2022
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10. The Ρ2Χ7 receptor : a new target in inflation and cancer

Author: Demeules, Melanie, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université, Sahil Adriouch, and STAR, ABES
Subjects: Inflammation, Tumor, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Nanobodies, P2X7, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cancer
Abstract: P2X7 receptor is an ATP-sensitive cation channel expressed on the surface of various immune cells, in particular monocytes, macrophages and Tregs. P2X7 plays a central role in inflammation due to its ability to activate the NLRP3 inflammasome and to release IL-1β and IL-18. Its prolonged activation leads to the formation of a non-selective macropore allowing the entry of molecules up to 900 Da and leads to cell death. It is also expressed by tumour cells, however its role in cancer is still complex. To study the modulation of P2X7 in inflammation and cancer, we developed the AAVnano methodology. We tested several nanobody-based constructs and different formats allowing us to select a specific P2X7 antagonist (13A7-hcAb) and a P2X7 potentiator (14D5-dimHLE) modulating the activity of this receptor in the long term. We confirmed this methodology in acute and chronic colon inflammation in a DSS model. Blocking P2X7 decreased the clinical score while potentiating it increased the score. In the tumor context, we used subcutaneous syngeneic transplant and demonstrated that inhibiting P2X7 reduces tumor volume when the tumor expresses this receptor. Stimulation of P2X7 in combination with immunogenic death-inducing chemotherapy resulted in enhanced antitumor immune responses, reduced tumor volume and improved animal survival. We also tested the combination of 14D5-dimHLE with other AAVnano targeting PD-L1 (PD-L1-dimHLE), CD73 (CD73-dimHLE) or both (CD73/PD-L1-HLE) in two tumor models. The combination of 14D5-dimHLE with the PD-L1-dimHLE results in reduced tumor volume and improved animal survival. The CD73/PD-L1-HLE bispecific alone or in combination with 14D5-dimHLE construct was able to reduce the tumor volume of the animals to a greater extent., Le récepteur P2X7 est un canal cationique sensible à l’ATP. Il est exprimé à la surface de diverses cellules immunitaires, en particulier les monocytes, les macrophages et les Tregs. P2X7 joue un rôle central dans l’inflammation en raison de sa capacité à activer l’inflammasome NLRP3 et à libérer de l’IL-1β et de l'IL-18. Son activation prolongée conduit à la formation d’un macropore non sélectif permettant l’entrée de molécules allant jusqu’à 900 Da et entrainant la mort cellulaire. Il est également exprimé par les cellules tumorales, cependant son rôle dans le cancer reste complexe. Afin d’étudier la modulation de P2X7 dans l’inflammation et le cancer, nous avons mis au point la méthodologie AAVnano. Nous avons testé plusieurs constructions basées sur des nanobodies sous différents formats afin de sélectionner un antagoniste spécifique de P2X7 (13A7-hcAb) et un potentialisateur de P2X7 (14D5-dimHLE) modulant à long terme l’activité de ce récepteur. Nous avons validé cette méthodologie dans l’inflammation aiguë et chronique du colon dans un modèle DSS. Bloquer P2X7 permettait de diminuer le score clinique tandis que le potentialiser augmentait ce score. Dans le contexte tumoral, nous avons utilisé des greffes syngéniques ectopiques sous-cutanées. Nous avons démontré qu’inhiber P2X7 permettait de réduire le volume tumoral quand la tumeur l’exprime. La potentialisation de P2X7 en combinaison avec une chimiothérapie induisant la mort immunogénique permet de stimuler les réponses immunitaires antitumorales, de diminuer le volume tumoral et d’améliorer la survie des animaux. Nous avons également combiné 14D5-dimHLE avec d’autres AAVnano ciblant PD-L1 (PD-L1-dimHLE), CD73 (CD73-dimHLE) ou les deux (CD73/PD-L1-HLE) dans deux modèles tumoraux. La combinaison de 14D5-dimHLE avec PD-L1-dimHLE a montré des effets bénéfiques sur le volume tumoral et la survie des animaux. Pour finir, la construction bispécifique CD73/PD-L1-HLE seule ou en combinaison avec 14D5-dimHLE permettait de diminuer de façon plus importante le volume tumoral des animaux.
Published: 2022

11. AA amyloidosis complicating cryopyrin-associated periodic syndrome: a study of 86 cases including 23 French patients and systematic review

Author: François Rodrigues, Laurence Cuisset, Bérangère Cador-Rousseau, Irina Giurgea, Benedicte Neven, David Buob, Pierre Quartier, Eric Hachulla, Thierry Lequerré, Gérard Cam, Guilaine Boursier, Valérie Hervieu, Gilles Grateau, Sophie Georgin-Lavialle, Service de Médecine Interne = Hôpital de jour de médecine [CHU Tenon], CHU Tenon [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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de Référence des Maladies Auto-Immunes Systémiques Rares du Nord et Nord-Ouest de France (CeRAINO), 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), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CH de Saint-Malo [Broussais], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [CHU Tenon] (CeréMAIA), Hôpital Edouard Herriot [Lyon], Hospices Civils de Lyon (HCL)-Groupement Hospitalier Centre [Lyon], Sorbonne Université (SU), Couvet, Sandrine, Maladies génétiques d'expression pédiatrique (U933), Groupe de recherche clinique Amylose AA Sorbonne Université (GRC 28 - GRAASU), Hôpital Edouard Herriot [CHU - HCL], and Hospices Civils de Lyon (HCL)
Subjects: Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Amyloidosis, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Cryopyrin-Associated Periodic Syndromes, Cryopyrin associated periodic syndrome (CAPS), [SDV] Life Sciences [q-bio], IL1 inhibitors, Rheumatology, NLRP3, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, NLR Family, Pyrin Domain-Containing 3 Protein, Mutation, AA amyloidosis, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Pharmacology (medical), Retrospective Studies, Interleukin-1
Abstract: Objective Cryopyrin-associated periodic syndrome (CAPS) is a rare but treatable inherited autoinflammatory condition including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS) and chronic infantile neurologic cutaneous articular syndrome (CINCA). Our objective was to describe the main features of CAPS AA amyloidosis (AA-CAPS) associated and the efficacy of IL-1 inhibitors in this indication. Methods Retrospective study in France associated with a systematic literature review. Results Eighty-six patients were identified: 23 new French cases and 63 from the literature, with a median age at amyloidosis diagnosis of 39 years old. CAPS subtypes were MWS (n = 62), FCAS (n = 9), frontier forms between MWS and FCAS (n = 12) and between CINCA and MWS (n = 3). NLRP3 had been sequenced in 60 patients (70%) and the most frequent mutation was R260W (60%). Three AA-CAPS patients displayed somatic NLRP3 mutations. Death occurred in 35 patients (41%), none of whom having ever received IL-1 inhibitors. Twenty-eight patients (33%) received IL-1 inhibitors, with a >50% decrease in proteinuria in 89% of cases. Conclusion AA amyloidosis can occur in nearly all CAPS subtypes. IL-1 inhibitors are effective, underlining the necessity of an early diagnosis of CAPS in order to start this treatment as soon as possible among AA-CAPS patients.
Published: 2022
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12. Evolution of Drug Survival with Biological Agents and Apremilast Between 2012 and 2018 in Patients with Psoriasis from the PsoBioTeq Cohort

Author: Olivier Chosidow, Hervé Bachelez, Thomas Bettuzzi, Marie Beylot-Barry, Pascal Joly, Alain Dupuy, Florence Tubach, Emmanuel Mahé, Nathalie Beneton, Manuelle Viguier, Marie-Aleth Richard, Denis Jullien, Hugo Arlegui, Emilie Sbidian, Carle Paul, CHU Henri Mondor [Créteil], Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), 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), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Victor Dupouy, Centre Hospitalier Le Mans (CH Le Mans), Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Pontchaillou, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), AOM 09 195, Amgen, Pfizer, Novartis, AbbVie, Meso Scale Diagnostics, MSD, Novartis Pharma, Janssen Pharmaceuticals, MSD France, Ministère des Affaires Sociales et de la Santé, Société Française de Dermatologie et de Pathologie Sexuellement Transmissible, SFD: JMD/MDM/177-11, NCT01617018, Agence Nationale de Sécurité du Médicament et des Produits de Santé, ANSM, LEO Pharma Research Foundation, Assistance publique-Hôpitaux de Paris, Jonchère, Laurent, CHU Henri Mondor, Centre de Pharmacoépidémiologie de l'AP-HP (Cephepi), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, [SDV]Life Sciences [q-bio], Dermatology, Biological Factors, Primary outcome, drug survival, Psoriasis, Internal medicine, apre-milast, medicine, Humans, Biological Products, treatment, business.industry, Proportional hazards model, Hazard ratio, General Medicine, psoriasis, Middle Aged, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.disease, Thalidomide, Drug survival, [SDV] Life Sciences [q-bio], Antirheumatic Agents, Cohort, Observational study, Female, Apremilast, business, biologic, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.drug
Abstract: International audience; Drug survival reflects treatment effectiveness and safety in real life. There is limited data on the variation of drug survival with the availability of systemic treatments with additional biological disease-modifying antirheumatic drugs (bDMARDs) or synthetic disease-modifying antirheumatic drugs (sDMARDs). The aim of this study was to determine whether the increasing number of available systemic treatments for psoriasis affects drug survival over time. Patients were selected from the PsoBioTeq cohort, a French prospective observational cohort enrolling patients with moderate to severe psoriasis. All patients initiating a first bDMARD or sDMARD were included. The primary outcome was comparison of drug survival over time. A multivariate Cox proportional hazard ratio model was computed. A total of 1,866 patients were included; 739 females (39%), median age 47 years. In the multivariate Cox model, no association was found between the calendar year of initiation and drug survival (hazard ratio) over-lapping from 0.80 (0.42–1.52) to 1.17 (0.64–2.17), p = 0.633). In conclusion, drug survival in psoriasis is not affected by the year of initiation.
Published: 2022
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13. Αnalysis of antigen-specific Β and T lymphοcytes response in pemphigus patients treated with rituximab

Author: Hébert, Vivien, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université, Pascal Joly, and STAR, ABES
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Rémission prolongée, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Tfh DSG3-specific Tfr, BAFF-R, Rechutes, Tfr anti-DSG3, Facteurs prédictifs, Anti-DSG3, Tfh anti-DSG3, Complete remission, BAFF, IgG DSG3-specific, Rituximab, Reclapses sustained, Pemphigus, Predictive factors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, IgG anti-DSG3
Abstract: The first-line treatment for moderate to severe forms of pemphigus vulgaris (PV) is RTX, a chimeric anti-CD20 monoclonal Ac, combined with short-term oral corticosteroid therapy. Despite the formidable efficacy of this combination, a significant relapse rate persists, mainly in the first year.First, we determined prognostic factors for relapse in patients treated with RTX. The presence of at least one of the following criteria: PDAI ≥ 45 at diagnosis and/or the presence of anti-DSG1 Ac ≥ 20IU/mL and/or anti-DSG3 Ac ≥ 130IU/mL between months 3 and 6 predicted short-term relapse with a PPV of 50% and an NPV of 94%.Next, longitudinal transcriptomic analysis of 33 genes of interest showed that autoreactive B cells initially exhibited a proinflammatory profile compared with nonautoreactive B cells, marked by overexpression of 3 genes encoding the cytokines IL-1β, IL-12p35, and IL-23p19 as well as the gene for IRF5. Surprisingly, rituximab induced few change in gene expression, with the exception of IL-1β and CD27 both "down-regulated." The decreased expression of the memory marker CD27 was confirmed by cytometry, and correlated with clinical improvement.Subsequently, we studied the cytokine BAFF and its receptor BAFF-R. We showed that basal serum BAFF levels were higher in pemphigus patients than in healthy donors and especially in relapsing patients. RTX resulted in increased BAFF levels associated with decreased transcriptomic and cytometric expression of BAFF-R in both non-autoreactive and autoreactive B cells. CS allowed a transient decrease in BAFF followed by a re-ascension upon decay below a threshold of 20mg/d, with no change in BAFF-R expression. Thus, the activation of autoreactive B cells at the onset of pemphigus could be related to the presence of high serum BAFF levels and the decrease in BAFF-R expression would delay the return of memory B cells. Conversely, incomplete B-cell depletion and persistent BAFF-R expression associated with BAFF re-ascension could explain relapses in patients treated with CS.In another work, we studied the distribution and evolution of anti-DSG3 IgG subclasses in patients with PV and correlated their distribution and pathogenicity in vitro with the clinical course of the patients, before and after CS alone or associated with RTX. We confirmed the majority presence of anti-DSG3 IgG4 in patients, with an association with another subclass in 1/4 of the cases. RTX reduced the diversity of subclasses. The presence of ≥2 anti-DSG3 IgG subclasses at diagnosis was associated with an increased risk of relapse. Our pathogenicity tests emphasized the importance of anti-DSG3 IgG4 concentration, mainly when it was the only isotype found. On the contrary, in patients with both IgG3 and IgG4 at diagnosis and only IgG4 in remission, purified IgG3 was able to induce acantholysis while purified IgG3 residues were not.Finally, we studied the impact of RTX on the frequency, polarization and activation of DSG3-specific follicular helper (Tfh) and regulatory (Tfr) T cells. At diagnosis, we showed that the phenotypes of the patients' autoreactive and non-autoreactive Tfh were different with a predominance of Tfh1* and Tfh17 phenotypes in the autoreactive Tfh and, on the contrary, an underrepresented Tfh2 phenotype. RTX had no effect on Tfh polarization. We then demonstrated the emergence of an Ag-specific Tfr population after RTX use. Furthermore, these Tfr significantly overexpressed the surface activation markers PD1, ICOS and CD25., Le traitement de 1ère intention des formes modérée à sévère de pemphigus vulgaire (PV) est le RTX, un Ac monoclonal chimérique anti-CD20, associé à une corticothérapie orale de courte durée. Malgré l’efficacité redoutable de cette association, un taux de rechutes important persiste, principalement la 1ère année.D’abord, nous avons déterminé des facteurs pronostiques de rechute chez les patients traités par RTX. La présence d’au moins un des critères suivants : PDAI ≥ 45 au diagnostic et/ou la présence d’Ac anti-DSG1 ≥ 20UI/mL et/ou anti-DSG3 ≥ 130UI/mL entre le 3ème et le 6ème mois permettait de prédire une rechute à court terme avec une VPP de 50% et une VPN de 94%.Ensuite, une analyse transcriptomique longitudinale sur 33 gènes d’intérêt a montré que les LB autoréactifs présentaient initialement un profil pro-inflammatoire par rapport aux LB non auto-réactifs, marquée par la surexpression de 3 gènes codant pour les cytokines IL-1β, IL-12p35 et IL-23p19 ainsi que pour le gène de l’IRF5. Étonnamment, le rituximab n’induisait que peu de changement d’expression génique, à l'exception de l’IL-1β et du CD27 tous deux « down-régulés ». La diminution d’expression du marqueur mémoire CD27 était confirmée en cytométrie, et corrélée à l’amélioration clinique.Par la suite, nous avons étudié la cytokine BAFF et son récepteur BAFF-R. Nous avons montré que les taux sériques basaux de BAFF étaient plus élevés chez les patients atteints de pemphigus que chez les donneurs sains et plus particulièrement chez les rechuteurs. Le rituximab entraînait une augmentation des taux de BAFF associée à une diminution d’expression transcriptomique et cytométrique de BAFF-R à la fois sur les LB non-autoréactifs et autoréactifs. La CS permettait une diminution transitoire de BAFF suivie d’une ré-ascension lors de la décroissance sous un seuil de 20mg/j, sans modification de l’expression de BAFF-R. Ainsi, l'activation des LB autoréactifs au début du pemphigus pourrait être liée à la présence de taux sériques élevés de BAFF et la diminution de l'expression du BAFF-R retarderait le retour de cellules B mémoires. Inversement, la déplétion incomplète des cellules B et l'expression persistante de BAFF-R associées à une ré ascension de BAFF pourraient expliquer les rechutes chez les patients traités par CS.Dans un autre travail, nous avons étudié la distribution et l'évolution des sous-classes d'IgG anti-DSG3 chez les patients atteints de PV et corrélé leur distribution et leur pathogénicité in vitro avec l'évolution clinique des patients, avant et après CS seule ou associée au RTX. Nous avons confirmé la présence majoritaire d’IgG4 anti-DSG3 chez les patients, avec une association à une autre sous-classe dans 1/4 des cas. Le RTX permettait de réduire la diversité des sous-classes. La présence de ≥2 sous-classes d'IgG anti-DSG3 au diagnostic était liée à un risque accru de rechute. Nos tests de pathogénicité ont souligné l’importance de la concentration en IgG4 anti-DSG3, principalement lorsqu’il s’agit du seul isotype retrouvé. Au contraire, dans le cas de patients présentant à la fois des IgG3 et des IgG4 au diagnostic et uniquement des IgG4 en rémission, les IgG3 purifiées ont été capables d'induire une acantholyse alors que les résidus purifiés d'IgG3 ne l'étaient pas. nfin, nous avons étudié l’impact du RTX sur la fréquence, la polarisation et l’activation des LT folliculaires helper (Tfh) et régulateurs (Tfr) spécifiques de la DSG3. Au diagnostic, nous avons montré que les phénotypes des Tfh autoréactifs et non autoréactifs des patients étaient différents avec une prédominance des phénotypes Tfh1* et Tfh17 dans les Tfh autoréactifs et, au contraire, un phénotype Tfh2 sous-représenté. Le RTX n'avait aucun effet sur la polarisation des Tfh. Nous avons ensuite démontré l'émergence d'une population Tfr spécifique de l'Ag après l'utilisation de RTX. De plus, ces Tfr surexprimaient significativement les marqueurs d'activation de surface PD1, ICOS et CD25.
Published: 2021

14. Inter-center comparison of good manufacturing practices-compliant stromal vascular fraction and proposal for release acceptance criteria: a review of 364 productions

Author: Camille Giverne, Greta Minonzio, Julie Veran, Giulio Rusconi, Françoise Dignat-George, Pauline François, Dominique Casanova, Luca Mariotta, Fanny Grimaud, Florence Sabatier, Jeremy Magalon, Luc Lyonnet, Laurent Giraudo, Guy Magalon, Baptiste Bertrand, Chloé Dumoulin, Laurent Arnaud, Gianni Soldati, Audrey Cras, Centre d'Investigation Clinique [Hôpital de la Conception - APHM] (CIC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), 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), Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Swiss Stem Cell Foundation (SSCF), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), 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), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], and Remedex
Subjects: Medicine (General), Stromal cell, Cell Survival, Stromal vascular fraction, Cell subset distribution, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Adipose tissue, QD415-436, Biochemistry, Biochemistry, Genetics and Molecular Biology (miscellaneous), Flow cytometry, Andrology, R5-920, Advanced therapy medicinal product, medicine, Distribution (pharmacology), Viability assay, Retrospective Studies, medicine.diagnostic_test, business.industry, Research, Endothelial Cells, Cell Biology, Microbiological quality, GMP production, Molecular Medicine, Stromal Cells, Stem cell, business
Abstract: Background Even though the manufacturing processes of the stromal vascular fraction for clinical use are performed in compliance with the good manufacturing practices applying to advanced therapy medicinal products, specifications related to stromal vascular fraction quality remain poorly defined. We analyzed stromal vascular fraction clinical batches from two independent good manufacturing practices-compliant manufacturing facilities, the Swiss Stem Cell Foundation (SSCF) and Marseille University Hospitals (AP-HM), with the goal of defining appropriate and harmonized release acceptance criteria. Methods This retrospective analysis reviewed the biological characteristics of 364 batches of clinical-grade stromal vascular fraction. Collected data included cell viability, recovery yield, cell subset distribution of stromal vascular fraction, and microbiological quality. Results Stromal vascular fraction from SSCF cohort demonstrated a higher viability (89.33% ± 4.30%) and recovery yield (2.54 × 105 ± 1.22 × 105 viable nucleated cells (VNCs) per mL of adipose tissue) than stromal vascular fraction from AP-HM (84.20% ± 5.96% and 2.25 × 105 ± 1.11 × 105 VNCs per mL). AP-HM batches were significantly less contaminated (95.71% of sterile batches versus 74.15% for SSCF batches). The cell subset distribution was significantly different (higher proportion of endothelial cells and lower proportion of leukocytes and pericytes in SSCF cohort). Conclusions Both centers agreed that a good manufacturing practices-compliant stromal vascular fraction batch should exert a viability equal or superior to 80%, a minimum recovery yield of 1.50 × 105 VNCs per mL of adipose tissue, a proportion of adipose-derived stromal cells at least equal to 20%, and a proportion of leukocytes under 50%. In addition, a multiparameter gating strategy for stromal vascular fraction analysis is proposed.
Published: 2021
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15. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

Author: Sébastien Feuillette, Segalas-Milazzo I, Catherine Schramm, Dominique Campion, Anne Rovelet-Lecrux, Laetitia Miguel, Magalie Lecourtois, Pernet S, Gaëtan Riou, Gaël Nicolas, Thierry Frebourg, Stéphane Rousseau, Guilhaudis L, 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), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER)
Subjects: 0303 health sciences, iPSC, Endosome, Endoplasmic reticulum, [SDV]Life Sciences [q-bio], HEK 293 cells, SORL1, maturation defects, Biology, medicine.disease, Phenotype, Cell biology, 03 medical and health sciences, SorLA, 0302 clinical medicine, trafficking, medicine, Missense mutation, Secretion, Alzheimer's disease, Alzheimer’s disease, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 71 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variations (R332W, S577P, and R654W) and two maturation-competent variations (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variations on SorLA protein indicated that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.
Published: 2021

16. Viral exanthema in the Americas during the SARS‐CoV‐2 pandemic infection: dengue or COVID‐19?

Author: Geoffrey Grotta, Stéphanie Guyomard, Nadège Cordel, Cécile Herrmann-Storck, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut Pasteur de la Guadeloupe, Réseau International des Instituts Pasteur (RIIP), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BONIZEC, Sandrine
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Dermatology, Dengue fever, Dengue, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Correspondence, Pandemic, Humans, Medicine, Pandemics, ComputingMilieux_MISCELLANEOUS, SARS-CoV-2, business.industry, COVID-19, Exanthema, medicine.disease, Virology, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Americas, business
Abstract: International audience
Published: 2021
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17. Assessment of adherence to disease-modifying anti-rheumatic drugs in rheumatoid arthritis

Author: Sophie Pouplin, Rémi Varin, Clélia Monchablon, Olivier Vittecoq, Thierry Lequerré, Henri Gondé, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Disease, Medication Adherence, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Diabetes mellitus, Internal medicine, medicine, Humans, In patient, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Aged, 030203 arthritis & rheumatology, business.industry, Anti rheumatic drugs, General Medicine, Middle Aged, medicine.disease, 3. Good health, Medication possession ratio, Cross-Sectional Studies, Antirheumatic Agents, Concomitant, Rheumatoid arthritis, Female, Self Report, business
Abstract: This work aimed to assess treatment adherence in rheumatoid arthritis patients with several tools and to identify factors associated with poor adherence.Between February and December 2015, 183 patients were included in this cross-sectional study. A homemade 23-item self-questionnaire was filled by patients during an outpatient consultation or a day hospitalization stay. Morisky Medication Adherence Scale (MMAS)-4, MMAS-8 and Girerd scores were extracted from this homemade questionnaire. Medication possession ratio (MPR) was then calculated. For identification of factors associated with nonadherence, patients were divided in two groups according to MMAS-8 results differentiating patients with good or bad adherence to treatments.Of the 183 patients, 59% received a combination of biologic and conventional synthetic disease-modifying drugs, 22% a biological treatment alone, and 19% a conventional DMARD alone. Respectively, 3%, 10%, and 7% were considered as low adherent according to MMAS-4, MMAS-8, and Girerd scores. MPR was calculated for 84/183 patients; 23% were low adherent. The need for a help in preparing the drugs (p = 0.05; OR = 6.12; 95% CI: 0.86 to 268.90) and concomitant diabetes (p0.001; OR = 0.045, 95% CI: 0.001 to 0.299) was higher in patients with good adherence. Presence of a patient's relative reminding to take medications was associated with low adherence (p = 0.002; OR = 4.32, 95% CI: 1.41 to 13.11).This study highlighted the difficulty of assessing treatment adherence in rheumatoid arthritis patients despite four different tools. Objective measures by MPR indicated a higher proportion of poor adherent patients than self-questionnaires.Key Points• Proportion of patients considered as low adherent ranged from 3 to 27% according to the method of evaluation.• The use of a pillbox and/or the preparation of drugs by a patient's relative was associated with good adherence.• The presence of a patient's relative reminding to take medication was associated with low adherence.
Published: 2019
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18. Pemphigus

Author: Schmidt, Enno, Kasperkiewicz, Michael, Joly, Pascal, Department of Dermatology, Rouen University Hospital, Centre de référence des maladies bulleuses autoimmunes, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), and Université de Rouen Normandie (UNIROUEN)
Subjects: 0303 health sciences, Desmoglein 1, Enzyme-Linked Immunosorbent Assay, General Medicine, 030207 dermatology & venereal diseases, 03 medical and health sciences, Treatment Outcome, 0302 clinical medicine, Adrenal Cortex Hormones, Immunoglobulin G, Azathioprine, Humans, Rituximab, Immunosuppressive Agents, Pemphigus, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, 030304 developmental biology
Abstract: Pemphigus consists of a group of rare and severe autoimmune blistering diseases mediated by pathogenic autoantibodies mainly directed against two desmosomal adhesion proteins, desmoglein (Dsg)1 and Dsg3 (also known as DG1 and DG3), which are present in the skin and surface-close mucosae. The binding of autoantibodies to Dsg proteins induces a separation of neighbouring keratinocytes, in a process known as acantholysis. The two main pemphigus variants are pemphigus vulgaris, which often originates with painful oral erosions, and pemphigus foliaceus, which is characterised by exclusive skin lesions. Pemphigus is diagnosed on the basis of either IgG or complement component 3 deposits (or both) at the keratinocyte cell membrane, detected by direct immunofluorescence microscopy of a perilesional biopsy, with serum anti-Dsg1 or anti-Dsg3 antibodies (or both) detected by ELISA. Corticosteroids are the therapeutic mainstay, which have recently been complemented by the anti-CD20 antibody rituximab in moderate and severe disease. Rituximab induces complete remission off therapy in 90% of patients, despite rapid tapering of corticosteroids, thus allowing for a major corticosteroid-sparing effect and a halved number of adverse events related to corticosteroids.
Published: 2019
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19. Feedback on the use of three surgical sealants for preventing prolonged air leak after robot-assisted anatomical lung resection

Author: Charles Hervouët, André Gillibert, Marc Laurent, Rémi Varin, Benjamin Bottet, Constance Le Gac, Henri Gondé, Jean-Marc Baste, Matthieu Sarsam, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Pharmacie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)
Subjects: Pulmonary and Respiratory Medicine, Univariate analysis, medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], Sealant, Robotic Surgical Procedures, Retrospective cohort study, Odds ratio, 030204 cardiovascular system & hematology, humanities, 3. Good health, Surgery, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Cardiothoracic surgery, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, Lung resection, Complication, business, ComputingMilieux_MISCELLANEOUS
Abstract: Background: Prolonged air leak (PAL) is the most common complication after lung resection. Several surgical sealants have been developed to reduce PAL, including fibrin-based (FS), polyethylene glycol-based (PEGS) and polyglycolic acid-based (PGAS) sealants. In this work we report our experience of surgical sealant use after robot-assisted lung resection. Methods: A 7-year retrospective study was conducted, including patients who had robot-assisted lobectomy or segmentectomy. Data were collected using a prospective national database. The use of surgical sealants was recorded in traceability sheets. Results: PAL occurred in 60 of the 299 patients included. American Society of Anesthesiologists score (ASA) and index of prolonged air leak (IPAL) were higher for patients with sealants. In this group, operative time, chest drain duration and length of stay were significantly longer. PAL occurrence was significantly associated to sealant in univariate analysis (Odds ratio =1.88, 95% CI: 1.07 to 3.36, P=0.03) but the association was slightly decreased when adjusting on IPAL and ASA score (Odds ratio =1.70, 95% CI: 0.94 to 3.10, P=0.08). Comparing sealants, more segmentectomies were performed in patients with PGAS (P=0.0013) and their operative time was shorter (P=0.0002). PAL occurrences were not different. Length of stay (P=0.0045) and operative time (P=0.0002) were longer in patients with PEGS who had more postoperative complications (P=0.024). Conclusions: This study did not identify a positive effect of surgical sealants for preventing PAL. However it highlighted the need to rationalize their use.
Published: 2019
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20. Facteurs prédictifs de réponses dans la polyarthrite rhumatoïde

Author: Pascal Rottenberg, Céline Derambure, Thierry Lequerré, Pascal Cosette, Olivier Vittecoq, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Polymères Biopolymères Surfaces (PBS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Plate-forme de Protéomique PISSARO, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 030203 arthritis & rheumatology, 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, [SDV]Life Sciences [q-bio], 030304 developmental biology, 3. Good health
Abstract: Resume L’accroissement du nombre de molecules disponibles pour le traitement de la polyarthrite rhumatoide incite les rhumatologues a identifier et valider des biomarqueurs de reponse ou biomarqueurs theranostiques, capables de predire la reponse aux traitements, prealablement a toute exposition. Cette demarche s’inscrit dans le contexte de medecine personnalisee afin de traiter efficacement un patient donne et a un instant donne. Les anticorps anti-peptides citrullines, les facteurs rhumatoides et la signature interferon sont les biomarqueurs les plus robustes et valides parmi tous ceux identifies. Les matrices utilisant des parametres cliniques ou biologiques, diagnostiques ou pronostiques, semblent pertinentes pour definir un traitement a l’echelon individuel. Par ailleurs, le developpement des approches a grande echelle sans a priori, comme la genomique fonctionnelle ou la metabolomique, representent une voie de recherche tout a fait prometteuse, bien que la replication des resultats reste difficile. La complexite de la reponse therapeutique chez un meme patient et la variabilite interindividuelle incitent a identifier des combinaisons de biomarqueurs plutot qu’un seul biomarqueur. L’objectif de cette revue est de faire le point sur les differentes approches utilisees pour identifier des biomarqueurs theranostiques et de recenser l’ensemble des biomarqueurs disponibles en discutant de leur performance en pratique clinique. Cependant, le nombre de biomarqueurs actuellement utilisables en pratique quotidienne reste tres limite.
Published: 2019
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21. The relapsing polychondritis damage index (RPDAM): Development of a disease-specific damage score for relapsing polychondritis

Author: Jean Sibilia, Robert Lebovics, Lorenzo Dagna, Tyng Yu Chuah, Camille Francès, Aman Sharma, Kong Kok Ooi, Noboru Suzuki, Jacques-Eric Gottenberg, Laurent Arnaud, Alexandre Belot, Stanford L. Peng, David D'Cruz, François Chasset, Laura Damian, Ricard Cervera, Gerard Espinosa, Ronald F van Vollenhoven, Debashish Danda, Isabelle Marie, Guillaume Moulis, Philippe Mertz, Toshio Tanaka, Eugene J. Kucharz, David Jayne, Immunorhumathologie moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Autoinflammatory Diseases Clinical Unit (Department of Autoimmune Diseases Working Group of Adult Rare Diseases), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universita Vita Salute San Raffaele (UniSR), Universitatea Babeş-Bolyai [Cluj-Napoca], Christian Medical College & Hospital, Service de Médecine Interne [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], JSW Jaigarh Port Ltd, JSW Infrastructure Ltd, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Laboratoire Géomatériaux (DGCB-LGM), École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS), Clinical Immunology and Rheumatology, AII - Inflammatory diseases, AMS - Ageing & Morbidty, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Hôpital de Hautepierre [Strasbourg], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Barcelona Centre for International Health Research, Hospital Clinic (CRESIB), Universitat de Barcelona (UB), Singapore General Hospital, Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Christian Medical College, Guy's Hospital [London], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Cambridge [UK] (CAM), Yong Loo Lin School of Medicine [Singapore], Medical University of Silesia (SUM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Bois-Guillaume, Swedish Medical Center [Seattle, WA, USA], PGIMER, Chandigarh, St. Marianna University, Kawasaki, Osaka University [Osaka], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Jayne, David [0000-0002-1712-0637], Apollo - University of Cambridge Repository, Service de Médecine Interne [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Mertz, Philippe, Belot, Alexandre, Cervera, Ricard, Chuah, Tyng Yu, Dagna, Lorenzo, Damian, Laura, Danda, Debashish, D'Cruz, David, Espinosa, Gerard, Frances, Camille, Jayne, David, Ooi, Kong Kok, Kucharz, Eugene J, Lebovics, Robert, Marie, Isabelle, Moulis, Guillaume, Peng, Stanford, Sharma, Aman, Suzuki, Noboru, Tanaka, Toshio, Van Vollenhoven, Ronald, Sibilia, Jean, Gottenberg, Jacques Eric, Chasset, Françoi, Arnaud, Laurent, Medical University of Silesia, and School of Pharmacy
Subjects: Disease specific, Adult, Male, Pediatrics, medicine.medical_specialty, Autoinflammatory disease, Scoring system, Consensus, Internationality, Delphi Technique, Relapsing polychondritis, [SDV]Life Sciences [q-bio], Autoinflammatory diseases, Delphi method, Risk Assessment, Severity of Illness Index, Cohort Studies, 03 medical and health sciences, Disability Evaluation, 0302 clinical medicine, Sex Factors, Rheumatology, Severity of illness, medicine, Humans, In patient, 030212 general & internal medicine, Polychondritis, Relapsing, Expert Testimony, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, business.industry, Age Factors, Reproducibility of Results, Middle Aged, medicine.disease, 3. Good health, Clinical trial, Damage Index, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, Cohort study
Abstract: International audience; Objectives: Relapsing polychondritis is a rare, multi-systemic and inflammatory condition of unknown origin. We currently lack a core set of measures to assess and follow damage in patients suffering from this condition. Our primary aim was to derive a disease-specific damage measuring tool for relapsing polychondritis, the Relapsing Polychondritis Damage Index (RPDAM).Methods: We performed an international 4-round multicenter Delphi study during which experts were asked to rate the relevance of potential damage items for relapsing polychondritis (141 items were obtained from a literature review and 12 from expert suggestion), using a Likert Scale. The selection of items for each subsequent round was based on the median rating of each item.Results: Twenty-four experts from 11 nationalities participated in round 1 and 22 in rounds 2, 3 and 4. From the initial 153 potential damage items, 44 items were selected during round 1, 30 items during round 2 and 16 during round 3. During round 4, we refined the index to a total of 17 items referring to ear nose and throat, eye, respiratory, cardiovascular and hematological systems as well as to treatment-related specific damage items.Conclusion: We have developed by international consensus a scoring system to assess damage in patients with relapsing polychondritis. Following its validation, the RPDAM may contribute to improve the care of patients suffering from this rare condition as well as to standardize data collection for future clinical trials.
Published: 2019
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22. Adipose tissue-derived stromal vascular fraction for treating hands of patients with systemic sclerosis: a multicentre randomized trial Autologous AD-SVF versus placebo in systemic sclerosis

Author: Elisabeth Jouve, Chloé Dumoulin, David Bocara, Audrey Cras, Olivier Boyer, Françoise Dignat-George, Julie Brunet, Ygal Benhamou, Isabelle Auquit-Auckbur, Cécile Philandrianos, Nicolas Schleinitz, Veronique Bourgarel, Dominique Casanova, Camille Giverne, Stéphanie Mallet, Rosanna Ferreira, Yves-Marie Pers, Aurélie Daumas, Brigitte Granel, Joseph Château, Florence Sabatier, Hervé Levesque, Maxime Abellan Lopez, Jérôme Larghero, Jean-Robert Harlé, Laurent Arnaud, Jeremy Magalon, Guy Magalon, J. Veran, Arnaud Hot, L. Giraudo, Alexandra Giuliani, Dominique Farge, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), 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), Centre d'Investigation Clinique [Hôpital de la Conception - APHM] (CIC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital Nord [CHU - APHM], Assistance Publique - Hôpitaux de Marseille (APHM), CHU Rouen, Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), McGill University = Université McGill [Montréal, Canada], Service de Médecine Interne [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital privé Jean Mermoz [Lyon], Hôpital Edouard Herriot [CHU - HCL], and Hospices Civils de Lyon (HCL)
Subjects: medicine.medical_specialty, Population, Adipose tissue, Placebo, Scleroderma, law.invention, Rheumatology, Randomized controlled trial, law, Fibrosis, Internal medicine, CHFS, medicine, Humans, Pharmacology (medical), education, education.field_of_study, Scleroderma, Systemic, Stromal Vascular Fraction, business.industry, Stromal vascular fraction, medicine.disease, Hand, Autologous adipose tissue-derived stromal vascular fraction, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Adipose Tissue, Regenerative medicine, Systemic sclerosis, business, Cochin Hand Function Scale
Abstract: Objective To assess the superiority of adipose tissue-derived stromal vascular fraction (AD-SVF) injection into the fingers vs placebo in reducing hand disability in systemic sclerosis (SSc) patients. Methods We performed a double-blind, multicentre, phase II trial from October 2015 to January 2018 in France. SSc patients with a Cochin Hand Function Scale (CHFS) ≥20/90 were randomized 1:1 to receive injection of AD-SVF or placebo. AD-SVF was obtained using the automated processing Celution 800/CRS system. The placebo was lactated Ringer’s solution. The primary efficacy end point was the change of the CHFS score from baseline to 3 months. Secondary efficacy endpoints included the CHFS score at 6 months, hand function, vasculopathy, hand pain, skin fibrosis, sensitivity of the finger pulps, Scleroderma Health Assessment Questionnaire, patients and physician satisfaction, and safety. Results Forty patients were randomized. The AD-SVF and placebo groups were comparable for age, sex ratio, disease duration, skin fibrosis of the hands and main cause of hand disability. After 3 months’ follow-up, hand function significantly improved in both groups with no between-group difference of CHFS (mean change of −9.2 [12.2] in the AD-SVF group vs −7.6 [13.2] in the placebo group). At 6 months, hand function improved in both groups. Conclusion This study showed an improvement of hand function in both groups over time, with no superiority of the AD-SVF. Considering the limits of this trial, studies on a larger population of patients with homogeneous phenotype and hand handicap should be encouraged to accurately assess the benefit of AD-SVF therapy. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT02558543. Registered on September 24, 2015.
Published: 2021
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23. Out‐of‐pocket expenditures in France to manage psoriasis in adult patients: results from an observational, cross‐sectional, non‐comparative, multicentre study

Author: Richard, M.‐a., Paul, C., de Pouvourville, G., Jullien, D., Mahe, E., Bachelez, H., Seneschal, J., Misery, L., Aubert, R., Reguiai, Z., Shourick, J., Taieb, C., Joly, P., Ezzedine, K., Essec Business School, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Victor Dupouy, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Laboratoire sur les interactions Epithéliums Neurones (LIEN), Université de Brest (UBO), Département de Dermatologie [CHU de Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Toulouse [Toulouse], European Market Maintenance Assessment [Fontenay-sous-Bois] (EMMA ), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Mondor], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Subjects: vitiligo, Mesures adjuvantes, MESH: Interferon-gamma, Associated measures, MESH: Long-Term Care, MESH: Skin, interferon-γ, MESH: Melanocytes, MESH: Physicians, MESH: Surveys and Questionnaires, skin and connective tissue diseases, Prescriber, Systemic glucocorticoid therapy, MESH: Humans, MESH: Long Term Adverse Effects, MESH: Middle Aged, integumentary system, Corticothérapies systémiques, pathogenesis, MESH: Polypharmacy, cytotoxic CD8+ T cells, targeted therapies, MESH: Keratinocytes, MESH: Male, Prescripteur, MESH: Practice Patterns, Physicians', MESH: Specialization, MESH: Vitiligo, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: International audience; Vitiligo is the most common depigmenting disorder affecting 0.1%-2% of the population worldwide. The characteristic white patches result from the selective loss of melanocytes. Sustained recent efforts have resulted in a detailed understanding of the genetic architecture of vitiligo. About 80% of vitiligo risk is attributable to genetic factors; and the rest (20%) is attributable to the environment. Over the past decade, substantial progress has been made in our understanding of the pathogenesis of vitiligo which is now clearly classified as an autoimmune disease. Melanocytes from patients with vitiligo are more susceptible to oxidative stress which begets the release of exosomes and inflammatory cytokines that will lead to activation of the innate immune response and subsequently to adaptive immune response through activation of autoreactive cytotoxic CD8+ T cells. These produce interferon-γ (IFN-γ) which promotes disease progression through IFN-γ-induced chemokine secretion from surrounding keratinocytes to further recruit T cells to the skin through a positive feedback loop. CD8 tissue-resident memory T cells are in turn responsible for long-term maintenance and potential relapse of vitiligo in human patients through cytokine-mediated recruitment of T cells from the circulation. This review summarizes the current knowledge on vitiligo and attempt to give an overview of the future in vitiligo treatment.
Published: 2021
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24. TRIM33 gene somatic mutations identified by next generation sequencing in neoplasms of patients with anti-TIF1γ positive cancer-associated dermatomyositis

Author: Cordel, Nadège, Derambure, Céline, Coutant, Sophie, Mariette, Xavier, Jullien, Denis, Debarbieux, Sébastien, Chosidow, Olivier, Meyer, Alain, Bessis, Didier, Joly, Pascal, Mathian, Alexis, Levesque, Hervé, Sabourin, Jean-Christophe, Tournier, Isabelle, Boyer, Olivier, Amoura, Zahir, Aouizerate, Jessie, Benveniste, Olivier, Brocheriou, Isabelle, Dechelotte, Benoît, Graveleau, Julie, Guerzider, Pascale, Isaac, Sylvie, Kanitakis, Jean, Lannes, Béatrice, Lazure, Thierry, Rigau, Valérie, Sibilia, Jean, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Henri Mondor, Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Strasbourg, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], CHU Rouen, Normandie Université (NU), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), 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], Service de Médecine Interne [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Institut des Neurosciences de Montpellier (INM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Myositis and muscle disease, Male, Somatic cell, DNA Mutational Analysis, Disease, Gene mutation, MESH: Dermatomyositis, 0302 clinical medicine, Neoplasms, Medicine, Pharmacology (medical), MESH: Neoplasms, MESH: DNA Mutational Analysis, MESH: High-Throughput Nucleotide Sequencing, Skin, MESH: Aged, MESH: DNA, High-Throughput Nucleotide Sequencing, Zinc Fingers, MESH: Transcription Factors, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Muscle, Female, MESH: Mutation, DNA sequencing, Dermatomyositis, 03 medical and health sciences, Rheumatology, Genetics, MESH: Zinc Fingers, Humans, Gene, Aged, 030203 arthritis & rheumatology, MESH: Humans, Neoplasia, business.industry, Cancer, DNA, medicine.disease, TRIM33, MESH: Male, 030104 developmental biology, Mutation, Cancer research, business, MESH: Female, Transcription Factors
Abstract: Objective To deep sequence the TRIM33 gene in tumours from patients with cancer-associated anti-TIF1γ autoantibody-positive dermatomyositis (DM) as TRIM33 somatic mutations in tumours may trigger this auto-immune disease. Methods Next generation sequencing of tumour DNA samples from patients with cancer-associated anti-TIF1γ autoantibody-positive DM. Fourteen tumours from 13 anti-TIF1γ autoantibody-positive DM individuals were sequenced along with two control tumours from non-DM individuals. Results Fourteen probable somatic variants from four tumours were identified in the TRIM33 gene. Conclusion These results are in accordance with the previous report of Pinal-Fernandez et al. and support the hypothesis of a role of TRIM33 gene mutations in the pathophysiology of anti-TIF1γ autoantibody-positive DM.
Published: 2021
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25. First-Line Biologic Therapy and Obesity in Moderate-to-Severe Psoriasis: Results from the Prospective Multicenter Cohort Psobioteq

Author: Carle Paul, Alain Dupuy, Pascal Joly, Caroline Giboin, Denis Jullien, Manuelle Viguier, Emilie Sbidian, Hervé Bachelez, Florence Assan, Hugo Arlegui, Olivier Chosidow, Emmanuel Mahé, Marie Beylot-Barry, Nathalie Beneton, and Psobioteq, Florence Tubach, Marie-Aleth Richard, Hôpital Henri Mondor, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Robert Debré, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre Hospitalier Le Mans (CH Le Mans), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Victor Dupouy, Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Marseille, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Hopital Saint-Louis [AP-HP] (AP-HP), Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), French Ministry of Health [PHRC AOM 09 195], French National Agency for the Safety of Medicines and Health Products (ANSM), Abbvie, MSD France, Janssen Johnson and Johnson USA Janssen Biotech Inc, Pfizer Pfizer, Departement a la Recherche Clinique et au Developpement (DRCD - Department for Clinical Research and Development), Assistance Publique - Hopitaux de Paris (Paris Hospitals), French Society of Dermatology, Psoriasis Research Group, Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Dermatology, Antibodies, Monoclonal, Humanized, Body Mass Index, Etanercept, Cohort Studies, Interquartile range, Drug survival, Internal medicine, Psoriasis, Ustekinumab, Adalimumab, medicine, Humans, Cumulative incidence, Obesity, Psobioteq, 2. Zero hunger, business.industry, Patient Selection, Middle Aged, medicine.disease, Infliximab, 3. Good health, Discontinuation, Biological Therapy, Methotrexate, Female, Dermatologic Agents, France, business, Body mass index, medicine.drug, Biologic therapy
Abstract: Background: Obesity is associated with an increased risk of psoriasis. Objective: In this study, we examined whether body mass index (BMI) is taken into account when choosing first-line biologic therapy for psoriasis. Methods: In this cohort study, we compared obese (BMI ≥30 kg/m2) and non-obese patients for the first-line biologic therapy prescribed, its survival, reasons for discontinuation, therapy optimization, co-prescription of methotrexate and factors associated with long drug survival. Results: A total of 931 patients were included: 594 (64%) were male, median age was 46 years (interquartile range 36–56). The most-prescribed biologic agents as first-line treatment were adalimumab (ADA; 42.7%), ustekinumab (UST; 29.9%) and etanercept (ETA; 22.9%); only frequency of infliximab (IFX) prescription differed between groups. Drug survival was significantly shorter for obese than non-obese patients ( p < 2.10–4) and was worse for obese than non-obese patients for UST ( p = 0.009) and ETA ( p = 0.02), with no difference for ADA ( p = 0.11). The main reason for discontinuation was primary inefficacy (62%), which was more frequent in obese than non-obese patients. The cumulative incidence of optimization did not significantly differ between the groups, except for ADA (SHR 1.91, 95% CI [1.23–2.96], p = 0.005). On multivariate analysis, risk of discontinuation was associated with only ETA as first-line biologic therapy (HR 1.51, 95% CI 1.04–2.19). Conclusion: This study highlighted the lack of difference in prescription of first-line biologic treatment, except for IFX, between obese and non-obese patients presenting moderate-to-severe psoriasis. Drug survival in obese patients is shorter, mainly because of inefficacy, than in non-obese patients. This highlights the need for targeted pharmacological studies in obese individuals to find optimal administration schemes.
Published: 2021
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26. Anti-Carbamylated Fibrinogen Antibodies Might Be Associated With a Specific Rheumatoid Phenotype and Include a Subset Recognizing In Vivo Epitopes of Its gamma Chain One of Which Is Not Cross Reactive With Anti-Citrullinated Protein Antibodies

Author: Brevet, Pauline, Lattard, Claire, Guillou, Clement, Rottenberg, Pascal, Fardellone, Patrice, Le-Loet, Xavier, Lequerre, Thierry, Cosette, Pascal, Boyer, Olivier, Freret, Manuel, Vittecoq, Olivier, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Pharmacie [CHU Rouen], Plate-forme de Protéomique PISSARO, Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Polymères Biopolymères Surfaces (PBS), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, and DESSAIVRE, Louise
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], skin and connective tissue diseases
Abstract: International audience; To identify the targets recognized by anti-carbamylated protein antibodies (anti-CarP) in patients with early Rheumatoid Arthritis (RA), to study the cross-reactivity between anti-CarP and anti-citrullinated protein antibodies (ACPA) and to evaluate their prognostic value. 331 patients (184 RA and 147 other rheumatisms) from the Very Early Arthritis (VErA) French cohort were analyzed. We performed mass spectrometry analysis of RA sera displaying anti-CarP activity and epitope mapping of the carbamylated fibrinogen gamma chain to identify immunodominant peptides. The specificity of these targets was studied using competition assays with the major antigens recognized by ACPA. The prognostic value of anti-carbamylated fibrinogen IgG antibodies (ACa-Fib IgG) was compared to that of anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-CarP using an in-house ELISA. Besides the alpha chain, the gamma chain of fibrinogen, particularly one immunodominant epitope that has a specific reactivity, was identified as a circulating carbamylated target in sera. The prevalence of ACa-Fib was 37% at baseline and 10.9% for anti-CCP-negative RA. In anti-CCP-negative patients, ACa-Fib positivity was associated with a more inflammatory and erosive disease at baseline but not with rapid radiological progression, which remains strongly related to anti-CCP antibodies. Fibrinogen seems to be one of the antigens recognized in vivo by the anti-CarP response, particularly 2 epitopes of the gamma chain, one of which is not cross reactive with ACPA. This specificity might be associated with a distinct clinical phenotype since ACa-Fib IgG were shown to be linked to systemic inflammation in very early RA but not to rapid radiological progression.
Published: 2021
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27. Longitudinal study of antibodies in pemphigus

Author: Petit, Marie, STAR, ABES, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université, and Pascal Joly
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Mass spectrometry, IgG, Répertoire, Desmogléine, N-glycosylation, Pathogénicité, Spectrométrie de masse, Corticoids, Pathogenicity, Auto-anticorps, Corticostéroïdes, Desmogleins, Pemphigus, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Autoantibodies
Abstract: Recognizing skin adhesion proteins called desmogleins 1 and 3. The pathogenicity of the pemphigus antibodies has been demonstrated by the observation of neonatal pemphigus in newborns of mothers with pemphigus and by passive transfer experiments in mice. Nevertheless, in a previous clinical study, we detected the presence of autoantibodies in some patients in complete remission. This observation is surprising since one would expect these patients to relapse. To understand this phenomenon, we studied longitudinally the pathogenicity of immunoglobulin G and anti-desmoglein 3 immunoglobulin G, which are the autoantibodies most frequently found in patients after treatment. Various phenomena may be responsible for changes in the pathogenicity of antibodies such as their repertoire or N-glycosylation. Studies have shown that the pathogenicity of anti-desmoglein-3 immunoglobulin G is dependent on the recognized epitope. Furthermore, in many autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, changes in N-glycosylation of immunoglobulin G and autoantibodies have been identified, indicating a link between N-glycosylation and antibody pathogenicity.To test our hypothesis of non-pathogenicity of antibodies in patients in remission, we studied the N-glycosylation of serum immunoglobulin G. First, we linked antibody pathogenicity to its N-glycosylation in vitro. Digestion of the anti-desmoglein 3 monoclonal antibody AK23 or patients’ immunoglobulin G with neuraminidase to remove sialic acids results in a decrease in their pathogenic activity. Then, pathogenicity and N-glycosylation of circulating immunoglobulin G were analyzed longitudinally in corticosteroid-treated patients who maintained high titers of anti-desmoglein 3 immunoglobulin G throughout the study, even when in clinical remission. We show that antibody pathogenicity is not always associated with the clinical status of patients. Indeed, a good correlation between clinical status and immunoglobulin G pathogenicity is observed at early time points (active phase and 6 months after treatment), while the persistence of in vitro IgG pathogenic activity during the course of the disease even in patients in clinical remission seems to be predictive of relapse. A particular N-glycosylation profile is observed in patients compared to healthy donors. However, this profile is not related to the clinical status of the patients since it is preserved over time even when the patients are in remission. In conclusion, the pathogenic properties of IgG do not seem to be due to variations in the N-glycans present on IgG during the course of pemphigus.As autoantibodies are responsible for the clinical symptoms of the disease, the second part of this thesis is focused on the study of anti-desmoglein 3 immunoglobulin G. Their pathogenicity was tested longitudinally, at the same time as for serum immunoglobulin G, and a correlation was observed with the clinical status. Moreover, the pathogenicity of these autoantibodies also allows anticipating of the appearance of clinical symptoms., Le pemphigus est une maladie auto-immune associée à la présence d’auto-anticorps pathogènes reconnaissant des protéines d'adhésion de la peau appelées desmogléines 1 et 3. Le caractère pathogène des anticorps a été démontré par l’observation de pemphigus néonataux chez des nouveaux nés dont la mère était atteinte de pemphigus et par des expériences de transfert passif chez la souris. Néanmoins, lors d’une précédente étude clinique menée par le laboratoire, la présence d’auto-anticorps a été détectée chez certains patients en rémission complète. Pour comprendre ce phénomène, nous avons étudié longitudinalement la pathogénicité des immunoglobulines G et des immunoglobulines G anti-desmogléine 3, qui sont les auto-anticorps les plus fréquemment présents chez les patients après traitement. Divers phénomènes peuvent être à l’origine de modifications de la pathogénicité des anticorps tels que leur répertoire ou leur N-glycosylation. En effet, des études ont démontré que la pathogénicité des immunoglobulines G anti-desmogléine 3 était dépendante de l’épitope reconnu. De plus, dans un grand nombre de maladies auto-immunes telles que la polyarthrite rhumatoïde ou le lupus systémique érythémateux, des modifications de la N-glycosylation des immunoglobulines G et des auto-anticorps ont été identifiées, indiquant un lien entre la N-glycosylation et la pathogénicité des anticorps.Pour tester notre hypothèse d’absence de pathogénicité des anticorps chez les patients en rémission, nous avons étudié la N-glycosylation des immunoglobulines G sériques. Tout d’abord, nous avons établi un lien entre la pathogénicité des anticorps et leur N-glycosylation in vitro. La digestion de l’anticorps monoclonal anti-desmogléine 3 AK23 ou des immunoglobulines G de patients par la neuraminidase afin de retirer les acides sialiques entraine une diminution de leur activité pathogène. Puis, la pathogénicité et la N-glycosylation des immunoglobulines G circulantes ont été analysées longitudinalement chez des patients traités par corticostéroïdes qui maintenaient des titres élevés d'immunoglobuline G anti-desmogléine 3 tout au long de l’étude, même lorsqu'ils étaient en rémission clinique. Nous montrons que la pathogénicité des anticorps n'est pas toujours associée à l'état clinique des patients. En effet, une bonne corrélation entre le statut clinique et la pathogénicité des immunoglobulines G est observée aux temps précoces (phase active et 6 mois après traitement), tandis que la persistance d'une activité pathogène des IgG in vitro au cours de l'évolution même chez les patients en rémission clinique semble être prédictif de la rechute. Un profil particulier de N-glycosylation est observé chez les patients comparés aux donneurs sains. Néanmoins ce profil n’est pas lié au statut clinique des patients puisqu’il est conservé au cours du temps même quand les patients sont en rémission. En conclusion, les propriétés pathogènes des IgG ne semblent pas être dues à des variations des N-glycanes présents sur les IgG au cours de l'évolution du pemphigus.Les auto-anticorps étant responsables des symptômes cliniques de la maladie, la deuxième partie de cette thèse est focalisée sur l’étude des immunoglobulines G anti-desmogléine 3. Leur pathogénicité a été testée longitudinalement, aux mêmes temps que pour les immunoglobulines G sériques, et une corrélation a été observée avec le statut clinique. De plus, la pathogénicité de ces auto-anticorps permet également d’anticiper l’apparition de symptômes cliniques.
Published: 2021

28. Longitudinal Pathogenic Properties and N-Glycosylation Profile of Antibodies from Patients with Pemphigus after Corticosteroid Treatment

Author: Petit, Marie, Walet-Balieu, Marie-Laure, Schapman, Damien, Golinski, Marie-Laure, Burel, Carole, Barray, Marion, Drouot, Laurent, Maho-Vaillant, Maud, Hébert, Vivien, Boyer, Olivier, Bardor, Muriel, Joly, Pascal, Calbo, Sébastien, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Glycobiologie et Matrice Extracellulaire Végétale (Glyco-MEV), Normandie Université (NU)-Normandie Université (NU), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Lehner, Arnaud
Subjects: integumentary system, QH301-705.5, autoantibodies, glycans, pemphigus, pathogenic, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Biology (General), [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, skin and connective tissue diseases, Article
Abstract: Pemphigus vulgaris is an autoimmune disease that occurs due to pathogenic autoantibodies that recognize the following epidermal adhesion proteins: desmogleins. Systemic corticosteroids usually decrease the titers of anti-desmoglein autoantibodies and improve patients’ conditions. Since modifications of IgG N-glycosylation have been described in some autoimmune diseases, we hypothesized that changes in the pathogenic activity of pemphigus IgG could be related to changes in their N-glycosylation profile. The purpose of this study was to assess, longitudinally, the pathogenicity of pemphigus serum IgG and their N-glycosylation profile during phases of disease activity and clinical remission. The pathogenic activity of serum IgG was measured in vitro on immortalized keratinocytes, by immunofluorescence and dissociation assays, and IgG N-glycans were analyzed by mass spectrometry. We showed (i) a correlation between pemphigus clinical activity and the pathogenicity of serum IgG at baseline and at month 6, while the persistence of the in vitro pathogenic activity of IgG during its evolution, even in patients in clinical remission, seemed to be predictive of relapse, (ii) that modifications of the N-glycan structure were altered the in vitro pathogenicity of patients’ autoantibodies, (iii) that the pathogenic properties of pemphigus IgG did not appear to be related to the disparity in IgG N-glycans during the course of pemphigus.
Published: 2021
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29. Étude longitudinale des anticorps dans le pemphigus

Author: Petit, Marie, STAR, ABES, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université, and Pascal Joly
Subjects: [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, [SDV.SA] Life Sciences [q-bio]/Agricultural sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Mass spectrometry, IgG, Répertoire, Desmogléine, N-glycosylation, Pathogénicité, Spectrométrie de masse, Corticoids, Pathogenicity, Auto-anticorps, Corticostéroïdes, Desmogleins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Pemphigus, Autoantibodies
Abstract: Recognizing skin adhesion proteins called desmogleins 1 and 3. The pathogenicity of the pemphigus antibodies has been demonstrated by the observation of neonatal pemphigus in newborns of mothers with pemphigus and by passive transfer experiments in mice. Nevertheless, in a previous clinical study, we detected the presence of autoantibodies in some patients in complete remission. This observation is surprising since one would expect these patients to relapse. To understand this phenomenon, we studied longitudinally the pathogenicity of immunoglobulin G and anti-desmoglein 3 immunoglobulin G, which are the autoantibodies most frequently found in patients after treatment. Various phenomena may be responsible for changes in the pathogenicity of antibodies such as their repertoire or N-glycosylation. Studies have shown that the pathogenicity of anti-desmoglein-3 immunoglobulin G is dependent on the recognized epitope. Furthermore, in many autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, changes in N-glycosylation of immunoglobulin G and autoantibodies have been identified, indicating a link between N-glycosylation and antibody pathogenicity.To test our hypothesis of non-pathogenicity of antibodies in patients in remission, we studied the N-glycosylation of serum immunoglobulin G. First, we linked antibody pathogenicity to its N-glycosylation in vitro. Digestion of the anti-desmoglein 3 monoclonal antibody AK23 or patients’ immunoglobulin G with neuraminidase to remove sialic acids results in a decrease in their pathogenic activity. Then, pathogenicity and N-glycosylation of circulating immunoglobulin G were analyzed longitudinally in corticosteroid-treated patients who maintained high titers of anti-desmoglein 3 immunoglobulin G throughout the study, even when in clinical remission. We show that antibody pathogenicity is not always associated with the clinical status of patients. Indeed, a good correlation between clinical status and immunoglobulin G pathogenicity is observed at early time points (active phase and 6 months after treatment), while the persistence of in vitro IgG pathogenic activity during the course of the disease even in patients in clinical remission seems to be predictive of relapse. A particular N-glycosylation profile is observed in patients compared to healthy donors. However, this profile is not related to the clinical status of the patients since it is preserved over time even when the patients are in remission. In conclusion, the pathogenic properties of IgG do not seem to be due to variations in the N-glycans present on IgG during the course of pemphigus.As autoantibodies are responsible for the clinical symptoms of the disease, the second part of this thesis is focused on the study of anti-desmoglein 3 immunoglobulin G. Their pathogenicity was tested longitudinally, at the same time as for serum immunoglobulin G, and a correlation was observed with the clinical status. Moreover, the pathogenicity of these autoantibodies also allows anticipating of the appearance of clinical symptoms., Le pemphigus est une maladie auto-immune associée à la présence d’auto-anticorps pathogènes reconnaissant des protéines d'adhésion de la peau appelées desmogléines 1 et 3. Le caractère pathogène des anticorps a été démontré par l’observation de pemphigus néonataux chez des nouveaux nés dont la mère était atteinte de pemphigus et par des expériences de transfert passif chez la souris. Néanmoins, lors d’une précédente étude clinique menée par le laboratoire, la présence d’auto-anticorps a été détectée chez certains patients en rémission complète. Pour comprendre ce phénomène, nous avons étudié longitudinalement la pathogénicité des immunoglobulines G et des immunoglobulines G anti-desmogléine 3, qui sont les auto-anticorps les plus fréquemment présents chez les patients après traitement. Divers phénomènes peuvent être à l’origine de modifications de la pathogénicité des anticorps tels que leur répertoire ou leur N-glycosylation. En effet, des études ont démontré que la pathogénicité des immunoglobulines G anti-desmogléine 3 était dépendante de l’épitope reconnu. De plus, dans un grand nombre de maladies auto-immunes telles que la polyarthrite rhumatoïde ou le lupus systémique érythémateux, des modifications de la N-glycosylation des immunoglobulines G et des auto-anticorps ont été identifiées, indiquant un lien entre la N-glycosylation et la pathogénicité des anticorps.Pour tester notre hypothèse d’absence de pathogénicité des anticorps chez les patients en rémission, nous avons étudié la N-glycosylation des immunoglobulines G sériques. Tout d’abord, nous avons établi un lien entre la pathogénicité des anticorps et leur N-glycosylation in vitro. La digestion de l’anticorps monoclonal anti-desmogléine 3 AK23 ou des immunoglobulines G de patients par la neuraminidase afin de retirer les acides sialiques entraine une diminution de leur activité pathogène. Puis, la pathogénicité et la N-glycosylation des immunoglobulines G circulantes ont été analysées longitudinalement chez des patients traités par corticostéroïdes qui maintenaient des titres élevés d'immunoglobuline G anti-desmogléine 3 tout au long de l’étude, même lorsqu'ils étaient en rémission clinique. Nous montrons que la pathogénicité des anticorps n'est pas toujours associée à l'état clinique des patients. En effet, une bonne corrélation entre le statut clinique et la pathogénicité des immunoglobulines G est observée aux temps précoces (phase active et 6 mois après traitement), tandis que la persistance d'une activité pathogène des IgG in vitro au cours de l'évolution même chez les patients en rémission clinique semble être prédictif de la rechute. Un profil particulier de N-glycosylation est observé chez les patients comparés aux donneurs sains. Néanmoins ce profil n’est pas lié au statut clinique des patients puisqu’il est conservé au cours du temps même quand les patients sont en rémission. En conclusion, les propriétés pathogènes des IgG ne semblent pas être dues à des variations des N-glycanes présents sur les IgG au cours de l'évolution du pemphigus.Les auto-anticorps étant responsables des symptômes cliniques de la maladie, la deuxième partie de cette thèse est focalisée sur l’étude des immunoglobulines G anti-desmogléine 3. Leur pathogénicité a été testée longitudinalement, aux mêmes temps que pour les immunoglobulines G sériques, et une corrélation a été observée avec le statut clinique. De plus, la pathogénicité de ces auto-anticorps permet également d’anticiper l’apparition de symptômes cliniques.
Published: 2021

30. Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network

Author: Gabriel Ichim, Benjamin Gibert, Sahil Adriouch, Catherine Brenner, Nathalie Davoust, Solange Desagher, David Devos, Svetlana Dokudovskaya, Laurence Dubrez, Jérôme Estaquier, Germain Gillet, Isabelle Guénal, Philippe P. Juin, Guido Kroemer, Patrick Legembre, Romain Levayer, Stéphen Manon, Patrick Mehlen, Olivier Meurette, Olivier Micheau, Bernard Mignotte, Florence Nguyen-Khac, Nikolay Popgeorgiev, Jean-Luc Poyet, Muriel Priault, Jean-Ehrland Ricci, Franck B. Riquet, Santos A. Susin, Magali Suzanne, Pierre Vacher, Ludivine Walter, Bertrand Mollereau, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques (METSY), Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hospices Civils de Lyon (HCL), Laboratoire de génétique et biologie cellulaire (LGBC), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Cellules Souches et Développement / Stem Cells and Development, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Universiteit Gent = Ghent University (UGENT), Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 (PhLAM), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Mignotte, Bernard, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), École Pratique des Hautes Études (EPHE), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
Subjects: NF-KAPPA-B, ANTICANCER CHEMOTHERAPY, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biochemistry, necrosis, SIGNALING PATHWAYS, COMPENSATORY PROLIFERATION, NEURONAL APOPTOSIS, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Medicine and Health Sciences, Animals, Humans, cancer, TARGETING AAC-11, IMMUNE-RESPONSE, CANCER-CELLS, Caenorhabditis elegans, Molecular Biology, CHRONIC LYMPHOCYTIC-LEUKEMIA, APOPTOSIS-INDUCING LIGAND, apoptosis, Biology and Life Sciences, cell death
Abstract: International audience; Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy.
Published: 2022
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31. Maladies bulleuses auto-immunes en 2020 : des progrès aux paradoxes

Author: Pascal Joly, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier
Subjects: 030203 arthritis & rheumatology, [SDV] Life Sciences [q-bio], 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, business.industry, [SDV]Life Sciences [q-bio], Immunology, MEDLINE, Medicine, Dermatology, business, Auto immune
Published: 2020
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32. Flow cytometry: An accurate tool for screening P2RX7 modulators

Author: Sahil Adriouch, Nicolas Renault, Valérie Vouret-Craviari, Nathalie Jouy, Audrey Hottin, Régis Millet, Xavier Dezitter, Hélène Bauderlique-Le Roy, Thierry Idziorek, Amélie Barczyk, 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), Plateformes Lilloises en Biologie et Santé - UMS 2014 - US 41 (PLBS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut National Du Cancer, University of Lille, Idziorek, Thierry, Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Imaging flow cytometry, 0303 health sciences, Histology, medicine.diagnostic_test, Chemistry, Cell Biology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Pathology and Forensic Medicine, Flow cytometry, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, Biomedical engineering
Abstract: International audience; The P2X purinergic receptor 7 (P2RX7) is a poorly selective ATP‐gated ion channel. Although P2RX7 binds ATP with relatively low affinity, prolonged activation can lead to nonselective membrane pore formation. Indeed, brief exposure to ATP triggers a rapid Ca2+ influx, whereas prolonged exposure to high ATP concentrations results in the passage of larger organic molecules. P2RX7 is involved in the physiopathology of a number of diseases and has notably emerged as a potential therapeutic target in inflammation, neuropathic pain, Alzheimer's disease, and cancer—prompting growing interest in the synthesis of novel P2RX7 modulators and the development of reliable, stringent screening methods. In the present study, we developed methods based on conventional flow cytometry, imaging flow cytometry and spectral flow cytometry and used them to measure P2RX7's activity upon activation by 3'‐O‐(4‐benzoyl)benzoyl ATP. We also demonstrated the use of the highly sensitive DNA‐intercalating dye TO‐PRO‐3 to determine P2RX7's large pore activity. The simultaneous quantification of calcium influx (Fluo‐3 AM), large pore opening (TO‐PRO‐3), and viability (propidium iodide) is a very efficient method for low‐ to medium‐throughput screening of P2RX7 modulators. Agonist and antagonist potencies can be accurately evaluated. Spectral cytometry notably enabled us to assay several biological activities while correcting for the intrinsic fluorescence of the screened compounds—otherwise a well‐known limitation of fluorescence‐based screening. Hence, spectral cytometry appears to be a useful, novel tool for drug candidate screening.
Published: 2020
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33. Impact de la réticulation à la génipine sur les propriétés biophysiques d'un hydrogel d'acide hyaluronique pour la culture en trois dimensions

Author: Bonnesoeur, Sarah, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université, and Jean-Pierre Vannier
Subjects: Collagène de type III et IV, Acide hyaluronique, 3D tumor model, Genipin, Modèle 3D, Génipine, Hydrogels, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Collagen type III and type IV, Hyaluronan
Abstract: Three-dimensional (3D) biomimetic cell culture platforms offer more realisticmicroenvironments that cells naturally experience in vivo. We developed a tunable hyaluronan(HA)-based hydrogels that could easily be modified to mimic healthy or malignant extracellularmatrices (ECMs). For that, we pre-functionalized our hydrogels with an adhesive polypeptide(poly-l-lysine, PLL) or ECM proteins (type III and type IV collagens), naturally present intumorous tissues, and next, we tuned their stiffness by crosslinking with gradual concentrationsof genipin (GnP). Then, we thoroughly characterized our substrates before testing them withglioblastoma, breast cancer cells and thereafter with endothelial cells and hematopoietic stemcells. Overall, our hydrogels exhibited (a) increasing stiffness with GnP concentration for everypre-functionalization and (b) efficient enzyme resistance with PLL treatment, and also withtype IV collagen but to a lesser extent. While PLL-treated hydrogels were not favorable to theculture of any glioblastoma cell lines, they enhanced the proliferation of breast cancer cells ina stiffness-dependent manner. Contrary to type III collagen, type IV collagen pre-treatedhydrogels supported the proliferation of glioblastoma cells. The as-desired HA-based 3Dtumor-like models we developed may provide a useful platform for the study of various cancercells by simply tuning their biochemical composition and their mechanical properties.; La culture en trois dimensions permet de reproduire dans une certaine mesure lemicroenvironnement dans lequel évoluent les cellules in vivo. Nous avons développé unhydrogel d’acide hyaluronique (AH) dont les caractéristiques sont aisément modifiables afind’imiter les matrices extracellulaires (MEC) saines ou malignes. Pour cela, nous avons traiténos hydrogels avec un polypeptide adhésif (poly-L-lysine, PLL) ou des protéines de la MEC(collagènes de type III et IV) qui sont naturellement présentes dans les tissus. Ensuite, nousavons modifié la rigidité des hydrogels en les réticulant avec concentrations croissantes degénipine (GnP). Chaque condition de réticulation a été caractérisée mécaniquement avant d’êtreutilisée en culture avec des cellules de glioblastomes, de cancer du sein, puis avec des cellulesendothéliales et des cellules souches hématopoïétiques. Dans l'ensemble, nos hydrogelsprésentaient (a) une rigidité croissante avec la concentration de GnP pour chaque traitement et(b) une résistance enzymatique efficace avec le traitement PLL, ainsi qu'avec le collagène detype IV, mais dans une moindre mesure. Alors que le traitement à la PLL n'était pas favorableà la culture de lignées de glioblastomes, il améliorait la prolifération des cellules cancéreusesdu sein proportionnellement au degré de réticulation. Contrairement au collagène de type III,les hydrogels traités au collagène de type IV soutenaient la prolifération des cellules deglioblastome. Le modèle 3D que nous avons développé peut servir de plateforme pour l'étudede diverses cellules cancéreuses en ajustant simplement sa composition biochimique et sespropriétés mécaniques.
Published: 2020

34. Comparison of different modes of antibiotic delivery on gut microbiota depletion efficiency and body composition in mouse

Author: Gaëtan Riou, D. Ribet, Moïse Coëffier, Pierre Déchelotte, Pauline Tirelle, Jonathan Breton, Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de nutrition [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), douville, sabine, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Rouen, and Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN)
Subjects: Microbiology (medical), Escherichia, Intestinal microbiota, medicine.drug_class, Antibiotics, lcsh:QR1-502, Administration, Oral, Gut microbiota, Gut flora, Microbiology, lcsh:Microbiology, Mouse model, Feces, Mice, 03 medical and health sciences, Fecal bacteria, Ampicillin, medicine, Animals, 030304 developmental biology, 0303 health sciences, Gut microbiome, Antifungals, Bacteria, biology, 030306 microbiology, Fungi, Neomycin, medicine.disease, biology.organism_classification, Intestinal microbiome, Anti-Bacterial Agents, Gastrointestinal Microbiome, 3. Good health, Mice, Inbred C57BL, Metronidazole, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Body Composition, Dysbiosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Research Article, medicine.drug
Abstract: Background The use of animal models with depleted intestinal microbiota has recently increased thanks to the huge interest in the potential role of these micro-organisms in human health. In particular, depletion of gut bacteria using antibiotics has recently become popular as it represents a low cost and easy alternative to germ-free animals. Various regimens of antibiotics are used in the literature, which differ in composition, dose, length of treatment and mode of administration. In order to help investigators in choosing the most appropriate protocol for their studies, we compared here three modes of antibiotic delivery to deplete gut bacteria in C57Bl/6 mice. We delivered one of the most frequently used combination of antibiotics (a mix of ampicillin, neomycin, metronidazole and vancomycin) either ad libitum in drinking water or by oral gavage once or twice per day. Results We quantified the global bacterial density, as well as the abundance of specific bacterial and fungal taxa, in mouse feces in response to antibiotics exposure. We observed that oral gavage once a day with antibiotics is not a reliable method as it occasionally triggers hyperproliferation of bacteria belonging to the Escherichia/Shigella taxon and leads, as a consequence, to a moderate decrease in fecal bacterial density. Antibiotics delivery by oral gavage twice a day or in drinking water induces in contrast a robust and consistent depletion of mouse fecal bacteria, as soon as 4 days of treatment, and is associated with an increase in fecal moisture content. Extending exposure to antibiotics beyond 7 days does not improve total bacteria depletion efficiency and promotes fungal overgrowth. We show in addition that all tested protocols impact neither gut microbiota recolonization efficiency, 1 or 2 weeks after the stop of antibiotics, nor mice body composition after 1 week of treatment. Conclusions Our study provides key experimental data and highlights important parameters to consider before selecting an appropriate protocol for antibiotic-mediated depletion of gut bacteria, in order to optimize the accuracy and the reproducibility of results and to facilitate comparison between studies.
Published: 2020
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35. Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction

Author: Anaïs Dumesnil, Sylvanie Renet, Sylvain Fraineau, Nathalie Pizzinat, Kari Alitalo, Jean-Paul Henry, Mahmoud Houssari, David Godefroy, Sahil Adriouch, Youssef Anouar, Ebba Brakenhielm, Paul Mulder, Riikka Kivelä, Vincent Richard, Damien Schapman, Karthik Amudhala Hemanthakumar, Gaëtan Riou, Inès Boukhalfa, Julie Rondeaux, Virginie Tardif, Mathilde Bizou, Institut National de la Santé et de la Recherche Médicale (INSERM), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wihuri Research Institute [Helsinki, Finland], Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Différenciation et communication neuronale et neuroendocrine (DC2N), Plate-Forme de Recherche en Imagerie Cellulaire de Haute-Normandie (PRIMACEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-High-tech Research Infrastructures for Life Sciences (HeRacLeS), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Lebon, Alexis, Kivelä Lab, Faculty of Medicine, Research Programs Unit, University of Helsinki, CAN-PRO - Translational Cancer Medicine Program, HUSLAB, Translational Cancer Biology (TCB) Research Programme, and Kari Alitalo / Principal Investigator
Subjects: CD4-Positive T-Lymphocytes, Male, STIMULATION, Time Factors, [SDV]Life Sciences [q-bio], Vascular Endothelial Growth Factor C, Cell, Myocardial Infarction, heart failure, VEGF-C, CD8-Positive T-Lymphocytes, 030204 cardiovascular system & hematology, Ventricular Function, Left, ACTIVATION, 0302 clinical medicine, VESSELS, Interferon, Myocardial infarction, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, interferon, Dependovirus, macrophages, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Lymphangiogenesis, lymphangiogenesis, Lymphatic system, medicine.anatomical_structure, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, Signal Transduction, medicine.drug, Genetic Vectors, Inflammation, DENDRITIC CELLS, Interferon-gamma, 03 medical and health sciences, Immune system, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Animals, Rats, Wistar, Lymphatic Vessels, 030304 developmental biology, REPAIR, business.industry, Myocardium, INFLAMMATORY RESPONSE, Genetic Therapy, Recovery of Function, Vascular Endothelial Growth Factor Receptor-3, medicine.disease, Mice, Inbred C57BL, Disease Models, Animal, inflammation, 3121 General medicine, internal medicine and other clinical medicine, Heart failure, Immunology, T-CELLS, 3111 Biomedicine, business
Abstract: Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI). We investigated the effects of gene therapy to modulate cardiac lymphangiogenesis post-MI in rodents. Second, we determined the impact of cardiac-infiltrating T cells on lymphatic remodeling in the heart. Approach and Results: Comparing adenoviral versus adeno-associated viral gene delivery in mice, we found that only sustained VEGF (vascular endothelial growth factor)-C C156S therapy, achieved by adeno-associated viral vectors, increased cardiac lymphangiogenesis, and led to reduced cardiac inflammation and dysfunction by 3 weeks post-MI. Conversely, inhibition of VEGF-C/-D signaling, through adeno-associated viral delivery of soluble VEGFR3 (vascular endothelial growth factor receptor 3), limited infarct lymphangiogenesis. Unexpectedly, this treatment improved cardiac function post-MI in both mice and rats, linked to reduced infarct thinning due to acute suppression of T-cell infiltration. Finally, using pharmacological, genetic, and antibody-mediated prevention of cardiac T-cell recruitment in mice, we discovered that both CD4 + and CD8 + T cells potently suppress, in part through interferon-γ, cardiac lymphangiogenesis post-MI. Conclusions: We show that resolution of cardiac inflammation after MI may be accelerated by therapeutic lymphangiogenesis based on adeno-associated viral gene delivery of VEGF-C C156S . Conversely, our work uncovers a major negative role of cardiac-recruited T cells on lymphatic remodeling. Our results give new insight into the interconnection between immune cells and lymphatics in orchestration of cardiac repair after injury.
Published: 2020
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36. Mapping of proteomic profile and effect of the spongy layer in the human amniotic membrane

Author: Marc Muraine, Olivier Boyer, Parvin Nazari Hashemi, Aurélie Bisson, Julie Gueudry, Fanny Chaventre, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Banque Normande de Cornées [CHU Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Laboratoire d'immunologie et biothérapies [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'ophtalmologie [Rouen], Normandie Université (NU)-Hôpital Charles-Nicolle, VILLIER, Venceslas, Hôpital Charles Nicolle [Rouen]-CHU Rouen, and Hôpital Charles-Nicolle-CHU Rouen
Subjects: Proteomics, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biomedical Engineering, Amniotic membrane, Inflammation, Umbilical cord, Biomaterials, Andrology, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Placenta, medicine, Spongy layer, Humans, Amnion, 030222 orthopedics, Transplantation, Proteomic Profile, Labor, Obstetric, Chemistry, Tumor Necrosis Factor-alpha, Growth factor, Cell Biology, Delivery, Obstetric, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cytokine, Mapping, 030221 ophthalmology & optometry, Intercellular Signaling Peptides and Proteins, Tumor necrosis factor alpha, Female, medicine.symptom, Inflammation Mediators, Wound healing
Abstract: International audience; The graft of human amniotic membrane (HAM) contributes to the healing of corneal perforating ulcers and so to save a large number of eyes suffering of severe chemical burns. This biological material is used for the treatment of ocular surface diseases because of its capacity to reduce inflammation and promote a quicker wound healing. For clinical use, the HAM is denuded from its spongy layer, but this layer can be an important source of growth factors which promote re-epithelialization. The aim of our study is to provide a general view of protein expression of the HAM and the spongy layer and therefore to determine if the spongy layer and/or a specific part of HAM have a beneficial role in the process of wound healing in patients with corneal ulcers. For this study, human placentas were obtained from healthy women after vaginal delivery or caesarean section after signing the consent form. Mapping of protein expression is done by dividing the placenta in 2 equal parts, one with spongy layer and another without (conventional HAM). Each part is also divided in 3 zones depending on the distance from the umbilical cord. The proteomic analysis was done by ELISA, targeting growth factors (EGF, HGF, KGF, NGF and TGF-beta1) and pro inflammatory cytokine TNF-α in the HAM without spongy layer and in the spongy layer. In this study we observed significant difference in the total amount of protein extract between the different donors. We do not observe a significant difference in the growth factor level between the conventional HAM and the spongy layer. No variation was observed in the expression of HGF, KGF and NGF in different zone of HAM and neither between conventional HAM and spongy layer in each zone. (*p value < 0.05, **p value
Published: 2020
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37. Lack of association between chilblains outbreak and severe acute respiratory syndrome coronavirus 2: Histologic and serologic findings from a new immunoassay

Author: Vivien Hébert, Fabienne Jouen, Anne Bénédicte Duval-Modeste, Olivier Boyer, Laurent Drouot, Lucie Cellier, Benoit Veber, Pascal Joly, Véronique Lemée, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire de virologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Département de microbiologie : Bactério, Virologie, Parasito, Hygiène, Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, and CCSD, Accord Elsevier
Subjects: Adult, Male, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Adolescent, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Pneumonia, Viral, Dermatology, Article, Serology, 030207 dermatology & venereal diseases, 03 medical and health sciences, Betacoronavirus, Young Adult, 0302 clinical medicine, COVID-19 Testing, Bias, medicine, Humans, 030212 general & internal medicine, Chilblains, Pandemics, Skin, Immunoassay, medicine.diagnostic_test, business.industry, Clinical Laboratory Techniques, SARS-CoV-2, Outbreak, COVID-19, medicine.disease, [SDV] Life Sciences [q-bio], Pneumonia, Immunology, Female, business, Coronavirus Infections
Published: 2020
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38. Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts

Author: Katarzyna Wozniak, Catherine Prost-Squarcioni, Savaş Yayli, Branka Marinović, Donna A. Culton, Michael Hertl, Guiseppe Cianchini, Snejina Vassileva, Dedee F. Murrell, Aikaterini Patsatsi, Marwah A. Saleh, Sergei A. Grando, Pilar Iranzo, Dimitrios Ioannides, Annette Czernik, Aimee S. Payne, Claudio Feliciani, Johann W. Bauer, Francis Palisson, Luca Borradori, Jun Yamagami, Valeria Aoki, Karen E. Harman, Soner Uzun, Hideyuki Ujiie, Philippe Bernard, M. Peter Marinkovich, Daniel Mimouni, Richard Groves, Enno Schmidt, Cezary Kowalewski, Russell P. Hall, Pascal Joly, Hana Jedličková, John J. Zone, Neil J. Korman, Kossara Drenovska, Soo Chan Kim, Julia S. Lehman, Sharon Baum, Masayuki Amagai, Frédéric Caux, Adela R. Cardones, José M. Mascaró, Takashi Hashimoto, Victoria P. Werth, Emanual Michael Maverakis, Animesh A. Sinha, David P. Fivenson, Marcel F. Jonkman, Hiroshi Shimizu, Rüdiger Eming, Sandra Pena, Ron J. Feldman, Detlef Zillikens, Luis A. Diaz, Ayşe Akman-Karakaş, Maryam Daneshpazhooh, Centre Hospitalier Universitaire de Reims (CHU Reims), Immuno-Régulation dans les Maladies Auto-Immunes Inflammatoires et le Cancer - EA 7509 (IRMAIC), Université de Reims Champagne-Ardenne (URCA), Service de dermatologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), INSERM U1234, OSA (XLIM-OSA), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Universität Bern [Bern], Immunodermatologie, Cytokines, Cancer - EA 7319 (ICA), Service de dermatologie [Avicenne], Hôpital Avicenne-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13), Service de dermatologie [Paris], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Akdeniz University, St. John's Institute of Dermatology, London School of Medicine, Stanford University [Stanford], Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Stanford University
Subjects: Standardization, Delphi Technique, [SDV]Life Sciences [q-bio], Delphi method, Severity of Illness Index, 030207 dermatology & venereal diseases, 0302 clinical medicine, Medicine, CD20 inhibitor, guidelines, skin and connective tissue diseases, health care economics and organizations, computer.programming_language, Majority opinion, integumentary system, treatment, Academies and Institutes, Treatment options, Plasmapheresis, Combined Modality Therapy, 3. Good health, consensus, pemphigus foliaceus, pemphigus vulgaris, Europe, 030220 oncology & carcinogenesis, Combination, Practice Guidelines as Topic, Administration, Intravenous, Rituximab, Venereology, Consensus, Clinical Sciences, education, 610 Medicine & health, Dermatology, Article, 03 medical and health sciences, Drug Therapy, Humans, Immunologic Factors, Generalizability theory, CD20, Antigens, Glucocorticoids, Medical education, business.industry, Dermatology & Venereal Diseases, business, computer, Delphi, Pemphigus, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background-Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. Objective-We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. Methods-A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. Results-The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. Limitations-Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. Conclusions-We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus. Keywords CD20 inhibitor; consensus; guidelines; pemphigus foliaceus; pemphigus vulgaris; treatment Pemphigus encompasses a spectrum of rare mucocutaneous bullous diseases that are autoimmune in origin. Because of the rarity of these diseases, it can take patients months before their pemphigus is diagnosed, during which time many are treated for other blistering diseases. 1,2 Even once the diagnosis has been made, treatment regimens can vary greatly, as
Published: 2020
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39. Impact of genipin crosslinking on hyaluronan hydrogels as tumor-like models : biophysical properties and 3D cell culture

Author: Bonnesoeur, Sarah, STAR, ABES, Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université, and Jean-Pierre Vannier
Subjects: Collagène de type III et IV, Acide hyaluronique, 3D tumor model, Genipin, Modèle 3D, Génipine, Hydrogels, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Collagen type III and type IV, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Hyaluronan
Abstract: Three-dimensional (3D) biomimetic cell culture platforms offer more realisticmicroenvironments that cells naturally experience in vivo. We developed a tunable hyaluronan(HA)-based hydrogels that could easily be modified to mimic healthy or malignant extracellularmatrices (ECMs). For that, we pre-functionalized our hydrogels with an adhesive polypeptide(poly-l-lysine, PLL) or ECM proteins (type III and type IV collagens), naturally present intumorous tissues, and next, we tuned their stiffness by crosslinking with gradual concentrationsof genipin (GnP). Then, we thoroughly characterized our substrates before testing them withglioblastoma, breast cancer cells and thereafter with endothelial cells and hematopoietic stemcells. Overall, our hydrogels exhibited (a) increasing stiffness with GnP concentration for everypre-functionalization and (b) efficient enzyme resistance with PLL treatment, and also withtype IV collagen but to a lesser extent. While PLL-treated hydrogels were not favorable to theculture of any glioblastoma cell lines, they enhanced the proliferation of breast cancer cells ina stiffness-dependent manner. Contrary to type III collagen, type IV collagen pre-treatedhydrogels supported the proliferation of glioblastoma cells. The as-desired HA-based 3Dtumor-like models we developed may provide a useful platform for the study of various cancercells by simply tuning their biochemical composition and their mechanical properties., La culture en trois dimensions permet de reproduire dans une certaine mesure lemicroenvironnement dans lequel évoluent les cellules in vivo. Nous avons développé unhydrogel d’acide hyaluronique (AH) dont les caractéristiques sont aisément modifiables afind’imiter les matrices extracellulaires (MEC) saines ou malignes. Pour cela, nous avons traiténos hydrogels avec un polypeptide adhésif (poly-L-lysine, PLL) ou des protéines de la MEC(collagènes de type III et IV) qui sont naturellement présentes dans les tissus. Ensuite, nousavons modifié la rigidité des hydrogels en les réticulant avec concentrations croissantes degénipine (GnP). Chaque condition de réticulation a été caractérisée mécaniquement avant d’êtreutilisée en culture avec des cellules de glioblastomes, de cancer du sein, puis avec des cellulesendothéliales et des cellules souches hématopoïétiques. Dans l'ensemble, nos hydrogelsprésentaient (a) une rigidité croissante avec la concentration de GnP pour chaque traitement et(b) une résistance enzymatique efficace avec le traitement PLL, ainsi qu'avec le collagène detype IV, mais dans une moindre mesure. Alors que le traitement à la PLL n'était pas favorableà la culture de lignées de glioblastomes, il améliorait la prolifération des cellules cancéreusesdu sein proportionnellement au degré de réticulation. Contrairement au collagène de type III,les hydrogels traités au collagène de type IV soutenaient la prolifération des cellules deglioblastome. Le modèle 3D que nous avons développé peut servir de plateforme pour l'étudede diverses cellules cancéreuses en ajustant simplement sa composition biochimique et sespropriétés mécaniques.
Published: 2020

40. Uptake of Pineal Gland Visible on 18F-DOPA PET/CT With Last Generation of SiPM PET/CT

Author: Pierre Vera, Olivier Humbert, Sébastien Hapdey, Aude Marie-Cardine, Pierre Decazes, Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), Laboratoire d'Electronique, d'Informatique et d'Image [EA 7508] (Le2i), Université de Technologie de Belfort-Montbeliard (UTBM)-Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Hôpital Charles Nicolle [Rouen], Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), and ANR-19-P3IA-0002,3IA@cote d'azur,3IA Côte d'Azur(2019)
Subjects: Movement disorders, Adolescent, [SDV]Life Sciences [q-bio], Partial volume, Astrocytoma, Pineal Gland, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Pineal gland, 0302 clinical medicine, Silicon photomultiplier, Positron Emission Tomography Computed Tomography, Medicine, Humans, Radiology, Nuclear Medicine and imaging, ComputingMilieux_MISCELLANEOUS, PET-CT, Pilocytic astrocytoma, business.industry, Biological Transport, General Medicine, medicine.disease, Dihydroxyphenylalanine, 18f dopa, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, business, Nuclear medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, DOPA decarboxylase activity
Abstract: A 17-year-old girl underwent an F-DOPA brain PET/CT on a new high-resolution digital SiPM PET/CT (Vision600 Siemens) to explore a suspicion of recurrence of a pilocytic astrocytoma. This study showed a local recurrence, but a second intense focal uptake was visible above, more intense than striata. On fused MRI, this was the pineal gland considered as physiological. This physiological uptake, due to a pineal DOPA decarboxylase activity, has also been observed with this PET system in other patients with F-DOPA to explore movement disorders. New high-resolution PET can show uptake of small structures by being less dependent to partial volume effect.
Published: 2020
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41. Drug resistance‑related sunitinib sequestration in autophagolysosomes of endothelial cells

Author: Wu, Shuang, Huang, Limin, Shen, Rong, Bernard‑Cacciarella, Melanie, Zhou, Pei, Hu, Chaoquan, Di Benedetto, Melanie, Janin, Anne, Bousquet, Guilhem, Li, Hong, He, Zhixu, Lu, He, Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Sichuan University [Chengdu] (SCU), Zhengzhou University, Guizhou Provincial People's Hospital [Guizhou, P.R. China], Shanghai Jiao Tong University [Shanghai], Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Guizhou Medical University (贵州医科大学), This study was supported by the China Scholarship Council. LH is supported by the Science and Technology Department of Guizhou Province (grant nos. J-2015-2088 and Qian-P-Ren-2017-5611), the Guiyang Municipal Science and Technology Bureau (grant nos. 20141001-62 and Zhukehetong-2017-5-1) and the National Natural Science Foundation of China (grant nos. 81660451, 31860325 and 31460312)., Ratajczak, Philippe, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Université Sorbonne Paris Nord
Subjects: tyrosine kinase receptor inhibitor, autophagy, drug resistance, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Autophagosomes, Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Articles, endothelial cells, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, [SDV.TOX] Life Sciences [q-bio]/Toxicology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Sunitinib, lysosomal drug sequestration, Humans, Lysosomes, Cells, Cultured, Cell Proliferation
Abstract: International audience; Our previous study demonstrated that the tyrosine kinase receptor inhibitor sunitinib induces acquired drug resistance in endothelial cells. The present study explored the role of lysosomal sequestration of sunitinib in the acquisition of drug resistance in human microcapillary endothelial HMEC‑1 cells. Resistance was induced by escalating concentrations of sunitinib and a shift in IC50 from 12.8 to >20 µM was detected. The results of time‑lapse fluorescence microscopy illustrated an instantaneous emergence of fluorescent vesicles in living cells once sunitinib was added. Most of these vesicles emerged in the juxtanuclear area, and exhibited the characteristics of growing autophagosomes and lysosomes. The vesicles were identified as autophagosomes and lysosomes because they co‑located with the lysosomal tracers Lyso‑ER and Lyso‑NIR, and the protein markers lysosomal‑associated membrane protein 1 (LAMP‑1) and microtubule‑associated protein 1A/1B‑light chain 3 (LC3). The results of western blotting demonstrated that sunitinib induced upregulation of LAMP‑1 and LC3‑II, and downregulation of sequestosome 1/p62, indicating the activation of autophagy. Bafilomycin A1, which suppresses lysosomal acidification, completely blocked sunitinib sequestration; however, chloroquine, which blocks lysosomal fusion with autophagosomes, exhibited no effect. Notably, bafilomycin A1 and chloroquine significantly counterbalanced HMEC‑1 drug‑resistance. These results provided evidence for autophagy‑flux‑associated sunitinib lysosomal sequestration in endothelial cells, leading to isolation of the drug from the cytoplasm; a key process involved in the development of drug resistance during antiangiogenic therapy. These data supported the notion that inhibiting autophagy may be a potential strategy to prevent drug sequestration and resistance to antiangiogenic therapy.
Published: 2020
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42. Gene expression regulated by abatacept associated with methotrexate and correlation with disease activity in rheumatoid arthritis

Author: Gaelle Dzangue-Tchoupou, Olivier Vittecoq, Céline Derambure, Maria Antonietta D'Agostino, Thierry Lequerré, Bodescot, Myriam, 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), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Service de Rhumatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Ambroise Paré [AP-HP], Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), The APPRAISE trial was funded by Bristol-Myers Squibb and this ancillary study was funded by Bristol-Myers Squibb which was involved in the design of the study as well as in the collection of clinical data and biological samples, in the interpretation of data, in the writing of this manuscript and in the decision to submit the manuscript for publication. This does not alter our adherence to PLOS ONE policies on sharing data and materials., and Hôpital Charles Nicolle [Rouen]-CHU Rouen
Subjects: Male, 0301 basic medicine, Oncology, Cell signaling, Settore MED/16 - REUMATOLOGIA, Gene Expression, Arthritis, Apoptosis, Signal transduction, medicine.disease_cause, Biochemistry, Autoimmunity, Arthritis, Rheumatoid, White Blood Cells, 0302 clinical medicine, Animal Cells, Rheumatoid, Medicine and Health Sciences, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Multidisciplinary, TCR signaling cascade, Cell Death, T Cells, Signaling cascades, CD28, Middle Aged, C-Reactive Proteins, medicine.anatomical_structure, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cell Processes, Antirheumatic Agents, Rheumatoid arthritis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Cellular Types, Research Article, medicine.drug, musculoskeletal diseases, medicine.medical_specialty, Science, Immune Cells, T cell, Immunology, Motor Proteins, Cytotoxic T cells, Rheumatoid Arthritis, Autoimmune Diseases, Abatacept, 03 medical and health sciences, Rheumatology, Molecular Motors, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Humans, 030203 arthritis & rheumatology, Blood Cells, business.industry, Biology and Life Sciences, Proteins, Cell Biology, medicine.disease, Methotrexate, 030104 developmental biology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Clinical Immunology, Clinical Medicine, Transcriptome, business, CD80
Abstract: International audience; Objectives: Abatacept acts as a competitive inhibitor of the CD28/(CD80/86) costimulation signal required for T cell activation. Mechanisms of action of abatacept have not been fully investigated. The objective of this study was to provide detailed insight into the mode of action of Abatacept based on gene expression data. Methods: In this ancillary study from the APPRAISE trial, we investigated the global molecular effects of Abatacept in whole blood samples collected prospectively in biologic naive rheumatoid arthritis patients (n = 19) at baseline and 6 months after the initiation of Abatacept therapy concomitant with methotrexate. Whole human genome microarrays (4x44K) were performed on both baseline and 6-month samples from responders and non-responders patients categorized according to EULAR criteria. T-test with Benjamini-Hochberg correction was performed to identify significant gene expression changes. Gene Ontology and Single Experiment Analysis tools allowed us to highlight specific biological mechanisms involved in methotrexate/Abatacept. Results: In methotrexate/Abatacept responders, 672 genes were significantly (q
Published: 2020
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43. Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France

Author: Eliane Gluckman, Yves Bertrand, Karima Yakouben, Isabelle Thuret, Charlotte Jubert, Bénédicte Neven, Felipe Suarez, F. Bernaudin, Sébastien Maury, Catherine Paillard, Patrick Lutz, Société Française de Greffe de Moelle et de Thérapie Cellulaire, Jacques-Olivier Bay, Catherine Poirot, M. Kuentz, Claire Galambrun, Dominique Bories, Marie Robin, Jean-Paul Vernant, Pierre Rohrlich, Gérard Socié, Nicole Raus, Corinne Pondarré, Jean-Hugues Dalle, Régis Peffault de Latour, Jean-Pierre Vannier, Nathalie Dhedin, Centre Hospitalier Intercommunal de Créteil (CHIC), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Hôpital 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), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hospices Civils de Lyon (HCL), CHI Créteil, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'hématologie clinique, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Nice (CHU Nice), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hématologie moléculaire [CHU Mondor], CHU Henri Mondor, Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hématologie et immunologie pédiatrique, Hospices Civils de Lyon (HCL)-CHU Lyon-Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL)-Hôpital Femme-Mère-Enfant (HFME), Hôpital Civil, Hopital Civil, Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Service de Greffe de Moelle - Unité AJA, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinical Research Unit, Biology of Reproduction Unit, Paris, France, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Hemolytic anemia, medicine.medical_specialty, Transplantation Conditioning, Anemia, [SDV]Life Sciences [q-bio], Graft vs Host Disease, Anemia, Sickle Cell, Gastroenterology, Chimerism, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Progression-free survival, Red Cell Biology & its Disorders, ComputingMilieux_MISCELLANEOUS, Aged, business.industry, Siblings, Hazard ratio, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Sickle cell anemia, Progression-Free Survival, 3. Good health, Transplantation, Fertility, 030220 oncology & carcinogenesis, France, business, Busulfan, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology, medicine.drug
Abstract: Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG)]. Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells 15 years (hazard ratio=4.37; P=0.002) and lower (5-15 vs. 20 mg/kg) ATG dose (hazard ratio=4.55; P=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells
Published: 2020
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44. Epidemiological changes in cutaneous lymphomas: an analysis of 8593 patients from the French Cutaneous Lymphoma Registry

Author: Nicolas Franck, E. Maubec, Gaëlle Quéreux, Caroline Ram-Wolff, Philippe Courville, Laurence Lamant, Olivier Dereure, G. Dobos, Isabelle Templier, Florent Grange, Saskia Ingen-Housz-Oro, Jacques Rouanet, Martine Bagot, N. Josselin, O. Augereau, Stéphane Barete, Serge Boulinguez, Isabelle Moulonguet, Marisa Battistella, Nicolas Ortonne, Anne Durlach, A. Carlotti, Pascal Joly, S. Taix, Sophie Dalac, Michel D'Incan, F. Franck, Laurent Mortier, A. de Masson, Marie Beylot-Barry, Charlée Nardin, Jacqueline Rivet, M.-D. Vignon-Pennamen, Laurence Michel, Liliane Laroche, Anne Pham-Ledard, Romain Dubois, T. Petrella, Béatrice Vergier, Florent Amatore, Service de Dermatologie [AP-HP Hôpital Saint-Louis], 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), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service de dermatologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Service de Dermatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hôpital Cochin [AP-HP], Centre hospitalier de Cahors, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Dermatologie (CHU de Dijon), Service de Dermatologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Département de Pathologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Claude Huriez [Lille], CHU Lille, Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de dermatologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, CHU Grenoble, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Cahors, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC)
Subjects: medicine.medical_specialty, Mycosis fungoides, Heterogeneous group, business.industry, Incidence (epidemiology), [SDV]Life Sciences [q-bio], CBCL, Retrospective cohort study, Dermatology, medicine.disease, Cutaneous lymphoma, 3. Good health, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Male patient, Epidemiology, medicine, business, ComputingMilieux_MISCELLANEOUS
Abstract: Background Primary cutaneous lymphomas (PCLs) are a heterogeneous group of T-cell (CTCL) and B-cell (CBCL) malignancies. Little is known about their epidemiology at initial presentation in Europe and about potential changes over time. Objectives The aim of this retrospective study was to analyse the frequency of PCLs in the French Cutaneous Lymphoma Registry (GFELC) and to describe the demography of patients. Methods Patients with a centrally validated diagnosis of primary PCL, diagnosed between 2005 and 2019, were included. Results The calculated incidence was unprecedently high at 1·06 per 100 000 person-years. The number of included patients increased yearly. Most PCL subtypes were more frequent in male patients, diagnosed at a median age of 60 years. The relative frequency of rare CTCL remained stable, the proportion of classical mycosis fungoides (MF) decreased, and the frequency of its variants (e.g. folliculotropic MF) increased. Similar patterns were observed for CBCL; for example, the proportion of marginal-zone CBCL increased over time. Conclusions Changes in PCL frequencies may be explained by the emergence of new diagnostic criteria and better description of the entities in the most recent PCL classification. Moreover, we propose that an algorithm should be developed to confirm the diagnosis of PCL by central validation of the cases.
Published: 2020
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45. Recurring acute urticaria and abdominal pain: Consider a diagnosis of alpha-galactose anaphylaxis

Author: Pascal Joly, O. Bauvin, A.F. Deschamps Huvier, Florence Tetart, J. Martinet, Laboratoire de microbiologie et génétique moléculaires (LMGM), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Abdominal pain, medicine.medical_specialty, Allergy, Meat, Anaphylaxie, Urticaria, education, Viande, Alpha (ethology), Dermatology, Immunoglobulin E, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Animals, Humans, Medicine, 030212 general & internal medicine, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Tique, Anaphylaxis, Acute urticaria, biology, business.industry, Galactose, food and beverages, Middle Aged, medicine.disease, Abdominal Pain, 3. Good health, Urticaire, 030220 oncology & carcinogenesis, Pork meat, Etiology, biology.protein, Alpha-galactose, Female, medicine.symptom, business, Food Hypersensitivity, Tick
Abstract: Summary Background Food urticaria is common and generally benign, and it may be of viral or idiopathic aetiology. A food origin of the allergy is frequently sought but rarely found. Mammalian meat anaphylaxis, or alpha-galactose (α-gal) anaphylaxis, is a rare and recently discovered entity. Patients and methods Herein, we report a case of alpha-galactose (α-gal) anaphylaxis in a 60-year-old woman presenting four episodes of acute urticaria with signs of anaphylaxis occurring a few hours after meals containing mammalian meat (beef meat, pork meat and offal). The diagnosis was confirmed by a positive gelatine prick-test and the presence of α-gal IgE. Discussion In the event of acute urticaria associated with systemic symptoms, in particular gastrointestinal signs, allergy to α-galactose should be considered.
Published: 2018
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46. Aortic involvement in relapsing polychondritis

Author: Maelle Le Besnerais, Jonathan Boutemy, Laurent Arnaud, Hervé Levesque, Zahir Amoura, Isabelle Marie, Boris Bienvenu, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Laboratoire Géomatériaux (DGCB-LGM), École Nationale des Travaux Publics de l'État (ENTPE)-Centre National de la Recherche Scientifique (CNRS), Service de médecine interne [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), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Médecine Interne [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Computed Tomography Angiography, [SDV]Life Sciences [q-bio], Comorbidity, 030204 cardiovascular system & hematology, Risk Assessment, Severity of Illness Index, Cohort Studies, 03 medical and health sciences, Aortic aneurysm, 0302 clinical medicine, Aneurysm, Rheumatology, Predictive Value of Tests, medicine.artery, Ectasia, Prevalence, medicine, Humans, Polychondritis, Relapsing, ComputingMilieux_MISCELLANEOUS, Aortitis, Relapsing polychondritis, Aged, Retrospective Studies, 030203 arthritis & rheumatology, Academic Medical Centers, Aorta, medicine.diagnostic_test, business.industry, Abdominal aorta, Middle Aged, Prognosis, medicine.disease, 3. Good health, Surgery, Survival Rate, Erythrocyte sedimentation rate, cardiovascular system, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, business, Aortic Aneurysm, Abdominal, Dilatation, Pathologic
Abstract: Objective To assess prevalence of aortic involvement in relapsing polychondritis (RP) patients; to evaluate clinical features and long-term outcome of RP patients exhibiting aortitis, aortic ectasia and/or aneurysm. Methods One hundred and seventy-two RP patients underwent aortic computed tomography (CT)-scan; they were seen in 3 medical centers. Results Eleven patients (6.4%) had aortic involvement, occurring within a median time of 2 years after RP diagnosis. CT-scan showed isolated aortitis ( n = 2); the 9 other patients exhibited: aortitis and aortic aneurysm ( n = 2) or ectasia ( n = 1), isolated aortic aneurysm ( n = 4) or ectasia ( n = 2); aortic localizations were as follows: thoracic ( n = 6), abdominal ( n = 2), thoracic and abdominal ( n = 4) aorta. Patients exhibited: resolution ( n = 3) improvement ( n = 3), stabilization ( n = 4) or deterioration ( n = 1) of aortic localization. Five patients experienced recurrence of aortic localization; one patient died of aortic abdominal aneurysm rupture. Predictive factors of death related to aortic complications were: aortitis on CT-scan, higher median levels of erythrocyte sedimentation rate. Predictive parameters of aortic relapses were: aortitis on CT-scan and involvement of the abdominal aorta. Conclusions This study underlines that aortic involvement is severe in RP. Furthermore, we suggest that RP patients exhibiting poor prognostic factors, including panaortitis and higher values of ESR, may require more aggressive therapy.
Published: 2018
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47. The impact of smoking on rheumatoid arthritis outcomes

Author: Thierry Lequerré, Laetitia Richard, Olivier Vittecoq, Christopher Banse, Service de rhumatologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), and Normandie Université (NU)-Normandie Université (NU)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Arthritis, Risk Assessment, Severity of Illness Index, Arthritis, Rheumatoid, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Severity of illness, medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030203 arthritis & rheumatology, business.industry, Smoking, Disease progression, Joint bone, Middle Aged, Prognosis, medicine.disease, Response to treatment, 3. Good health, Radiography, Treatment Outcome, 030104 developmental biology, Antirheumatic Agents, Rheumatoid arthritis, Disease Progression, Physical therapy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Smoking cessation, Female, Smoking Cessation, Dose reduction, business
Abstract: Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 10 janvier 2018
Published: 2018
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48. Impact of collaborative pharmaceutical care on in-patients’ medication safety: study protocol for a stepped wedge cluster randomized trial (MEDREV study)

Author: Géraldine Leguelinel-Blache, Christel Castelli, Clarisse Roux-Marson, Sophie Bouvet, Sandrine Andrieu, Philippe Cestac, Rémy Collomp, Paul Landais, Bertrice Loulière, Christelle Mouchoux, Rémi Varin, Benoit Allenet, MEDREV Working Group, Pierrick Bedouch, Jean-Marie Kinowski, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Université de Montpellier (UM), BESPIM, 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), Institut du Vieillissement, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Departement /u563 : Oncogenèse, Signalisation et Innovation thérapeutique, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Claudius Regaud, Centre Hospitalier Universitaire de Nice, Hopital de Nice, Micro-Environnement et Régulation Cellulaire Intégrée (MERCI), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Techniques pour l'Evaluation et la Modélisation des Actions de la Santé (TIMC-IMAG-ThEMAS), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Biostatistique, Epidémiologie clinique, Santé Publique Innovation et Méthodologie [CHU Nîmes] (BESPIM), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)-Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nice (CHU Nice), Hôpital des Charpennes [CHU - HCL], Hospices Civils de Lyon (HCL), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and roussel, pascale
Subjects: Male, Health Knowledge, Attitudes, Practice, Time Factors, [SDV]Life Sciences [q-bio], Hospital pharmacist, Psychological intervention, Medicine (miscellaneous), Collaborative Care, [SHS.PSY]Humanities and Social Sciences/Psychology, Inappropriate Prescribing, Pharmacists, 030226 pharmacology & pharmacy, law.invention, Hospitals, University, Study Protocol, 0302 clinical medicine, Randomized controlled trial, law, Risk Factors, Health care, Medicine, Multicenter Studies as Topic, Pharmacology (medical), Drug Interactions, 030212 general & internal medicine, Cluster randomised controlled trial, Hospital pharmacy, Cooperative Behavior, Drug safety, Randomized Controlled Trials as Topic, lcsh:R5-920, 3. Good health, [SDV] Life Sciences [q-bio], Female, Medical emergency, Hospitalpharmacist, France, Patient Safety, Pharmacy Service, Hospital, lcsh:Medicine (General), Medication review, Drug-Related Side Effects and Adverse Reactions, Attitude of Health Personnel, Medication Therapy Management, [SHS.EDU]Humanities and Social Sciences/Education, Risk Assessment, 03 medical and health sciences, Pharmaceutical care, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Drug-related problem, Humans, Aged, Patient Care Team, Inpatients, business.industry, medicine.disease, Clinical pharmacy, Medication reconciliation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Interdisciplinary Communication, business, Stepped wedge study
Abstract: Background Clinical pharmaceutical care has long played an important role in the improvement of healthcare safety. Pharmaceutical care is a collaborative care approach, implicating all the actors of the medication circuit in order to prevent and correct drug-related problems that can lead to adverse drug events. The collaborative pharmaceutical care performed during patients’ hospitalization requires two mutually reinforcing activities: medication reconciliation and medication review. Until now, the impact of the association of these two activities has not been clearly studied. Methods This is a multicentric stepped wedge randomized study involving six care units from six French University Hospitals (each unit corresponding to a cluster) over seven consecutive 14-day periods. Each hospital unit will start with a control period and switch to an experimental period after a randomized number of 14-day periods. Patients aged at least 65 years hospitalized in one of the participating care units and having given their consent to be called for a 30-day and 90-day follow-up can be enrolled. For each 14-day period, 15 patients will be recruited in each care unit to obtain a total of 630 patients enrolled in all centers. Patients with a hospital stay of more than 21 days will be excluded. During the control period, there will be no clinical pharmacist in the care unit, whereas during the experimental period a clinical pharmacist will perform medication reconciliation and review with the healthcare team. The primary outcome will assess the impact of collaborative pharmaceutical care on preventable medication error rate. The secondary outcomes will evaluate the clinical impact of the strategy, the acceptance rate of pharmaceutical interventions, the induced and avoided costs of the strategy (cost-consequence analysis), and the healthcare team’s satisfaction. Discussion This study will assess the impact of collaborative pharmaceutical care associating medication reconciliation and review at patient admission to hospital in terms of preventable medication error rate and costs. This activity will prevent and correct medication errors arising earlier in the hospitalization. Trial registration ClinicalTrials.gov, NCT02598115. Registered on 4 November 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2412-7) contains supplementary material, which is available to authorized users.
Published: 2018
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49. Linear IgA bullous dermatosis treated with rituximab

Author: Pascal Joly, Myriam Lecuyer, Vivien Hébert, C. Pinard, Laurine Sacre, CHU Rouen, Normandie Université (NU), Service de dermatologie [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, Linear IgA bullous dermatosis, Case Report, Dermatology, 030207 dermatology & venereal diseases, 03 medical and health sciences, rituximab, 0302 clinical medicine, LABD, Linear IgA bullous dermatosis, medicine, MMF, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, business.industry, mycophenolate mofetil, medicine.disease, autoimmune blistering disease, LABD, Rituximab, MMF, mycophenolate mofetil, linear IgA bullous dermatosis, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, medicine.drug
Abstract: International audience
Published: 2019
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50. Two Tumors in 1: What Should be the Therapeutic Target? Pediatric Germ Cell Tumor With Somatic Malignant Transformation

Author: Daniel Orbach, Marie Pierre Castex, Anguella Ghanem, Brice Fresneau, Amandine Bertrand, Cecile Dumesnil, Cecile Faure Conter, Estelle Thebaud, Frédérique Dijoud, Angélique Rome, Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Service d'oncologie pédiatrique [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Anatomie Pathologique, Groupement Hospitalier Est, Hospices Civils de Lyon, CHU Rouen, Normandie Université (NU), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Allergologie et d'Immunologie [CHRU Toulouse], CHRU Toulouse, and Institut Curie [Paris]
Subjects: Male, Oncology, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Malignant transformation, 03 medical and health sciences, 0302 clinical medicine, Papillary adenocarcinoma, Internal medicine, Parametrium, medicine, Humans, Child, Survival rate, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, business.industry, Infant, Mediastinum, Hematology, Neoplasms, Germ Cell and Embryonal, medicine.disease, Survival Rate, Leukemia, Cell Transformation, Neoplastic, Treatment Outcome, medicine.anatomical_structure, Child, Preschool, Surgical Procedures, Operative, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, Germ cell tumors, Teratoma, business
Abstract: Background Germ cell tumors with somatic malignant transformation (GCT with SMT) are rare in children and poorly described. Data are missing to determine if therapies should target the GCT, the SMT compound, or both simultaneously. Patients and methods A retrospective national study was conducted in the Societe Francaise des cancers de l'Enfant (SFCE) Centers. Medical records from patients aged 0 to 18 years diagnosed with GCT with SMT between 2000 and 2015 were analyzed. Any stages and primary sites were considered as well as synchronous and metachronous cases. Results Fifteen patients were identified. Thirteen patients had synchronous GCT with SMT. In the latter cases, primaries were ovary (5), mediastinum (3), pineal gland (3), sacrococcyx (1), and parametrium (1). SMT histologies were central primitive neuroectodermal tumor (5), embryonal rhabdomyosarcomas (3) or thyroid papillary adenocarcinoma, leukemia, poorly differentiated carcinoma, mixed sarcomas, and miscellaneous histology (1 case each). Chemotherapy was targeted against the GCT (3), the SMT (6), or both components (3). The last patient received surgery exclusively. Partial or complete response to chemotherapy was observed in 5/10 assessable cases: 2/3 patients treated with GCT-dedicated chemotherapy, 3/6 patients treated with SMT-dedicated therapy, and 0/1 treated with combined therapy. In addition, 2 patients with mediastinal GCT primary had metachronous SMT, with acute myeloid leukemia and thyroid papillary adenocarcinoma, 8 months and 8 years, respectively, after the diagnoses of GCT. Two patients (1 synchronous and 1 metachronous) were cured with surgery exclusively. At the end of follow-up, 6 patients died of their disease including all 4 with postsurgical macroscopic residue. Conclusions GCT with SMT constitutes a very rare entity in children and adolescents. Surgical removal of the tumor is the cornerstone of the treatment and might be sufficient in selected cases. In the remaining cases, the best management is still unknown and should take into account both components and their respective chemosensitivity. Long-term surveillance is advised for patient with unresected teratoma as late transformation can occur.
Published: 2017
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