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75 results on '"Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon"'

1. French recommendations for the diagnosis and management of lymphangioleiomyomatosis

Author: Vincent Cottin, Elodie Blanchard, Mallorie Kerjouan, Romain Lazor, Martine Reynaud-Gaubert, Camille Taille, Yurdagül Uzunhan, Lidwine Wemeau, Claire Andrejak, Dany Baud, Philippe Bonniaud, Pierre-Yves Brillet, Alain Calender, Lara Chalabreysse, Isabelle Court-Fortune, Nicolas Pierre Desbaillets, Gilbert Ferretti, Anne Guillemot, Laurane Hardelin, Marianne Kambouchner, Violette Leclerc, Mathieu Lederlin, Marie-Claire Malinge, Alain Mancel, Sylvain Marchand-Adam, Jean-Michel Maury, Jean-Marc Naccache, Mouhamad Nasser, Hilario Nunes, Gaële Pagnoux, Grégoire Prévot, Christine Rousset-Jablonski, Olivier Rouviere, Salim Si-Mohamed, Renaud Touraine, Julie Traclet, Ségolène Turquier, Stéphane Vagnarelli, Kaïs Ahmad, Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Assistance Publique - Hôpitaux de Marseille (APHM), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Plateforme F-CRIN, 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), Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, Hôpital Avicenne [AP-HP], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, EA3920 University of Burgundy Franche-Comté Besançon, Equipe CADIR (LNC - U1231), 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)-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), Laboratoire de Biologie Tissulaire et d'ingénierie Thérapeutique UMR 5305 (LBTI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Centre pour l'innovation en cancérologie de Lyon (CICLY), Université de Lyon-Université de Lyon, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Centre Hospitalier Universitaire [Grenoble] (CHU)
Subjects: Pulmonary and Respiratory Medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; BackgroundThe present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France.MethodsPractical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases.ResultsLymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications.ConclusionThese recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis.
Published: 2023

2. Phenotypic characterization of seven individuals with <scp>Marbach–Schaaf</scp> neurodevelopmental syndrome

Author: Felix Marbach, Beata S. Lipska‐Ziętkiewicz, Agata Knurowska, Vincent Michaud, Henri Margot, James Lespinasse, Frédéric Tran Mau Them, Christine Coubes, Joohyun Park, Sarah Grosch, Cristiana Roggia, Ute Grasshoff, Louisa Kalsner, Anne‐Sophie Denommé‐Pichon, Alexandra Afenjar, Bénédicte Héron, Boris Keren, Pilar Caro, Christian P. Schaaf, Heidelberg University, University of Gdańsk (UG), Medical University of Gdańsk, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], Centre Hospitalier Métropole Savoie [Chambéry], Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Tübingen, School of Medicine [University of Connecticut], University of Connecticut (UCONN), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Baylor College of Medicine (BCM), Baylor University, and Admin, Oskar
Subjects: Adult, Pain insensitivity, Autism Spectrum Disorder, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Global developmental delay, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Syndrome, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Cohort Studies, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Phenotype, Neurodevelopmental disorder, PRKAR1B, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Genetics, Protein kinase a complex, Animals, Humans, Genetics (clinical)
Abstract: International audience; We present the phenotypes of seven previously unreported patients with Marbach-Schaaf neurodevelopmental syndrome, all carrying the same recurrent heterozygous missense variant c.1003C>T (p.Arg335Trp) in PRKAR1B. Clinical features of this cohort include global developmental delay and reduced sensitivity to pain, as well as behavioral anomalies. Only one of the seven patients reported here was formally diagnosed with autism spectrum disorder (ASD), while ASD-like features were described in others, overall indicating a lower prevalence of ASD in Marbach-Schaaf neurodevelopmental syndrome than previously assumed. The clinical spectrum of the current cohort is similar to that reported in the initial publication, delineating a complex developmental disorder with behavioral and neurologic features. PRKAR1B encodes the regulatory subunit R1beta of the protein kinase A complex (PKA), and is expressed in the adult and embryonal central nervous system in humans. PKA is crucial to a plethora of cellular signaling pathways, and its composition of different regulatory and catalytic subunits is cell-type specific. We discuss potential molecular disease mechanisms underlying the patients' phenotypes with respect to the different known functions of PKA in neurons, and the phenotypes of existing R1beta-deficient animal models.
Published: 2022

3. A new cure model that corrects for increased risk of non-cancer death: analysis of reliability and robustness, and application to real-life data

Author: Botta, Laura, Goungounga, Juste, Capocaccia, Riccardo, Romain, Gaëlle, Colonna, Marc, Gatta, Gemma, Boussari, Olayidé, Jooste, Valérie, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Equipe EPICAD (LNC - U1231), 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)-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), Centre de Recherches sur l'Action Politique en Europe (ARENES), Université de Rennes (UR)-Institut d'Études Politiques [IEP] - Rennes-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Centre National de la Recherche Scientifique (CNRS), École des Hautes Études en Santé Publique [EHESP] (EHESP), Registre Bourguignon des Cancers Digestifs, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), The work was partially supported by the French Institut National du Cancer (INCa grant number 2018–178) and the European Union (Fonds Européen de Développement Regional: FEDER grant number BG0028239)., and Internationale
Subjects: Population-based data, Net survival, Cure model, Life tables, Epidemiology, [SDV]Life Sciences [q-bio], Health Informatics, Increased non-cancer mortality, Reliability, Robustness, Cancer
Abstract: Background Non-cancer mortality in cancer patients may be higher than overall mortality in the general population due to a combination of factors, such as long-term adverse effects of treatments, and genetic, environmental or lifestyle-related factors. If so, conventional indicators may underestimate net survival and cure fraction. Our aim was to propose and evaluate a mixture cure survival model that takes into account the increased risk of non-cancer death for cancer patients. Methods We assessed the performance of a corrected mixture cure survival model derived from a conventional mixture cure model to estimate the cure fraction, the survival of uncured patients, and the increased risk of non-cancer death in two settings of net survival estimation, grouped life-table data and individual patients’ data. We measured the model’s performance in terms of bias, standard deviation of the estimates and coverage rate, using an extensive simulation study. This study included reliability assessments through violation of some of the model’s assumptions. We also applied the models to colon cancer data from the FRANCIM network. Results When the assumptions were satisfied, the corrected cure model provided unbiased estimates of parameters expressing the increased risk of non-cancer death, the cure fraction, and net survival in uncured patients. No major difference was found when the model was applied to individual or grouped data. The absolute bias was Conclusions The present analysis supports the use of the corrected mixture cure model, with the inclusion of increased risk of non-cancer death for cancer patients to provide better estimates of indicators based on cancer survival. These are important to public health decision-making; they improve patients’ awareness and facilitate their return to normal life.
Published: 2023

4. Stepwise use of genomics and transcriptomics technologies increases diagnostic yield in Mendelian disorders

Author: Estelle Colin, Yannis Duffourd, Martin Chevarin, Emilie Tisserant, Simon Verdez, Julien Paccaud, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Julien Thevenon, Hana Safraou, Thomas Besnard, Alice Goldenberg, Benjamin Cogné, Bertrand Isidor, Julian Delanne, Arthur Sorlin, Sébastien Moutton, Mélanie Fradin, Christèle Dubourg, Magali Gorce, Dominique Bonneau, Salima El Chehadeh, François-Guillaume Debray, Martine Doco-Fenzy, Kevin Uguen, Nicolas Chatron, Bernard Aral, Nathalie Marle, Paul Kuentz, Anne Boland, Robert Olaso, Jean-François Deleuze, Damien Sanlaville, Patrick Callier, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Antonio Vitobello, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), 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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), 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)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, CHU Dijon, Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Institut du Thorax [Nantes], Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), 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 Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Hospices Civils de Lyon (HCL), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), the European Union through the FEDER programs (PERSONALISE), and the Burgundy-Franche Comté regional council (INTEGRA). The sequencing performed at the CNRGH was supported by the France Génomique National infrastructure, funded as part of the 'Investissements d’Avenir' program managed by the Agence Nationale pour la Recherche (contract ANR-10-INBS-09)., and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cell Biology, Developmental Biology
Abstract: Purpose: Multi-omics offer worthwhile and increasingly accessible technologies to diagnostic laboratories seeking potential second-tier strategies to help patients with unresolved rare diseases, especially patients clinically diagnosed with a rare OMIM (Online Mendelian Inheritance in Man) disease. However, no consensus exists regarding the optimal diagnostic care pathway to adopt after negative results with standard approaches.Methods: In 15 unsolved individuals clinically diagnosed with recognizable OMIM diseases but with negative or inconclusive first-line genetic results, we explored the utility of a multi-step approach using several novel omics technologies to establish a molecular diagnosis. Inclusion criteria included a clinical autosomal recessive disease diagnosis and single heterozygous pathogenic variant in the gene of interest identified by first-line analysis (60%–9/15) or a clinical diagnosis of an X-linked recessive or autosomal dominant disease with no causative variant identified (40%–6/15). We performed a multi-step analysis involving short-read genome sequencing (srGS) and complementary approaches such as mRNA sequencing (mRNA-seq), long-read genome sequencing (lrG), or optical genome mapping (oGM) selected according to the outcome of the GS analysis.Results: SrGS alone or in combination with additional genomic and/or transcriptomic technologies allowed us to resolve 87% of individuals by identifying single nucleotide variants/indels missed by first-line targeted tests, identifying variants affecting transcription, or structural variants sometimes requiring lrGS or oGM for their characterization.Conclusion: Hypothesis-driven implementation of combined omics technologies is particularly effective in identifying molecular etiologies. In this study, we detail our experience of the implementation of genomics and transcriptomics technologies in a pilot cohort of previously investigated patients with a typical clinical diagnosis without molecular etiology.
Published: 2023

5. Factors influencing access to specialised haematology units during acute myeloblastic leukaemia patient care: A population-based study in France

Author: Kueshivi Midodji Atsou, Bernard Rachet, Edouard Cornet, Marie‐Lorraine Chretien, Cédric Rossi, Laurent Remontet, Laurent Roche, Roch Giorgi, Sophie Gauthier, Stéphanie Girard, Johann Böckle, Stéphane Kroudia Wasse, Helene Rachou, Laila Bouzid, Jean‐Marc Poncet, Sébastien Orazio, Alain Monnereau, Xavier Troussard, Morgane Mounier, Marc Maynadie, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), London School of Hygiene and Tropical Medicine (LSHTM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-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), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des sciences de la santé publique [Marseille] (ISSPAM), Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] (BiosTIC ), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, Institut National Du Cancer, Admin, Oskar, Université Bourgogne Franche-Comté [COMUE] (UBFC), Service d'Hématologie Clinique (CHU de Dijon), Equipe SAPHIHR (LNC - U1231), 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)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Registre des hématopathies malignes de Côte d'Or (RHEMCO), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Registre des hémopathies malignes de Côte d'Or, EPICENE Team, Inserm U1219, Bordeaux Population Health Research Center, University of Bordeaux, F-33076 Bordeaux, France., Registre des hémopathies malignes de Basse-Normandie [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), and Institut National du Cancer, Grant/Award Number: Projet INCa- SHS- ESP, n°2018- 124
Subjects: [STAT]Statistics [stat], Population-based data, Cancer Research, Oncology, Care pathways, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Acute myeloblastic leukaemia, Logistic regression, Radiology, Nuclear Medicine and imaging, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, population- based data, [SHS]Humanities and Social Sciences, Specialised haematology unit access
Abstract: International audience; BACKGROUND: The excess mortality observed in Acute Myeloblastic Leukaemia (AML) patients, partly attributed to unequal access to curative treatments, could be linked to care pathways. METHODS: We included 1039 AML incident cases diagnosed between 2012-2016 from the 3 French blood cancer registries (3,625,400 inhabitants). We describe patients according to age, the medical entry unit and access to the specialised haematology unit (SHU) during follow-up. Multivariate logistic regression model was done to determine the association between covariables and access to SHU. A total of 713 patients (69%) had access to SHU during care. RESULTS: The most common care pathway concerned referral from the general practitioner to SHU, n = 459(44%). The univariate analysis observed a downward trend for the most deprived patients. Patients who consulted in SHU were younger (66 years vs. 83, p
Published: 2023

6. iPSCs derived from infertile men carrying complex genetic abnormalities can generate primordial germ-like cells

Author: Aurélie Mouka, Brahim Arkoun, Pauline Moison, Loïc Drévillon, Rafika Jarray, Sophie Brisset, Anne Mayeur, Jérôme Bouligand, Anne Boland-Auge, Jean-François Deleuze, Frank Yates, Thomas Lemonnier, Patrick Callier, Yannis Duffourd, Patrick Nitschke, Emmanuelle Ollivier, Arnaud Bourdin, John De Vos, Gabriel Livera, Gérard Tachdjian, Leïla Maouche-Chrétien, Lucie Tosca, AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Saclay, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Site de recherche intégrée en cancérologie (SiRIC CURAMUS), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sup'Biotech, Signalisation Hormonale, Physiopathologie Endocrinienne et Métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), 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), MORNET, Dominique, and Institut Universitaire de Cancérologie [Paris] (IUC)
Subjects: [SDV] Life Sciences [q-bio], Male, Multidisciplinary, Germ Cells, Erythroblasts, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Humans, Cell Differentiation, Azoospermia
Abstract: Despite increasing insight into the genetics of infertility, the developmental disease processes remain unclear due to the lack of adequate experimental models. The advent of induced pluripotent stem cell (iPSC) technology has provided a unique tool for in vitro disease modeling enabling major advances in our understanding of developmental disease processes. We report the full characterization of complex genetic abnormalities in two infertile patients with either azoospermia or XX male syndrome and we identify genes of potential interest implicated in their infertility. Using the erythroblasts of both patients, we generated primed iPSCs and converted them into a naive-like pluripotent state. Naive-iPSCs were then differentiated into primordial germ-like cells (PGC-LCs). The expression of early PGC marker genes SOX17, CD-38, NANOS3, c-KIT, TFAP2C, and D2-40, confirmed progression towards the early germline stage. Our results demonstrate that iPSCs from two infertile patients with significant genetic abnormalities are capable of efficient production of PGCs. Such in vitro model of infertility will certainly help identifying causative factors leading to early germ cells development failure and provide a valuable tool to explore novel therapeutic strategies.
Published: 2022

7. Impact on antimicrobial consumption of procalcitonin-guided antibiotic therapy for pneumonia/pneumonitis associated with aspiration in comatose mechanically ventilated patients: a multicenter, randomized controlled study

Author: Khaldoun Kuteifan, François Belon, Melanie Claveau, Pascal Andreu, Pierre Emmanuel Charles, Alexandra Monnier, Gokhan Bodur, Sébastien Pili Floury, Anne Florence Dureau, Jean Pierre Quenot, Antoine Poidevin, Yannick Brunin, Hamid Merdji, Marc Ginet, Hassene Rahmani, F. Claudé, Jonathan Paillot, Nicolas Belin, Jean-Christophe Navellou, Guillaume Besch, François Aptel, Gaël Piton, Mathilde Grandperrin, Fiona Ecarnot, Philippe Guiot, Antoine Studer, Joy Mootien, Raphaël Clere-Jehl, Claire Chaignat, Gilles Capellier, Julie Helms, Auguste Dargent, Cyrille Patry, Ferhat Meziani, Carmen Ionescu, Guylaine Labro, Gilles Blasco, Loïc Barrot, Marion Colnot, Marc Puyraveau, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier de Mulhouse, site du Hasenrain (Mulhouse), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Nouvel Hôpital Civil de Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Nanomédecine Régénérative (NanoRegMed), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Equipe LIPNESS (LNC - U1231) (LIPNESS), 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)-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), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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)-Université de Montpellier (UM), Monash University [Melbourne], PROPASPI (PROcalcitonin Pneumonia/pneumonitis Associated with ASPIration) trial investigators: Jean-Christophe Navellou, Claire Chaignat, Mathilde Grandperrin, Mélanie Claveau, Nicolas Belin, Cyrille Patry, Frédéric Claude, François Belon, Loïc Barrot, Marion Colnot, Guillaume Besch, Gilles Blasco, Marc Ginet, Yannick Brunin, Pascal Andreu, Auguste Dargent, Pierre Emmanuel Charles, Ferhat Meziani, Alexandra Monnier, Antoine Studer, Raphaël Clere-Jehl, Hassene Rahmani, Anne Florence Dureau, Antoine Poidevin, Joy Mootien, Gokhan Bodur, Carmen Ionescu, Philippe Guiot, and univOAK, Archive ouverte
Subjects: medicine.medical_treatment, Aspiration pneumonia, Critical Care and Intensive Care Medicine, Procalcitonin, law.invention, Chemical pneumonitis, law, medicine, Intensive care unit, Coma, Pneumonitis, Mechanical ventilation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, RC86-88.9, Research, Medical emergencies. Critical care. Intensive care. First aid, Pneumonia, medicine.disease, Aspiration, SAPS II, Anesthesia, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background In comatose patients receiving oro-tracheal intubation for mechanical ventilation (MV), the risk of aspiration is increased. Aspiration can lead to chemical pneumonitis (inflammatory reaction to the gastric contents), or aspiration pneumonia (infection caused by inhalation of microorganisms). Distinguishing between the two types is challenging. We tested the interest of using a decisional algorithm based on procalcitonin (PCT) values to guide initiation and discontinuation of antibiotic therapies in intubated patients. Methods The PROPASPI (PROcalcitonin Pneumonia/pneumonitis Associated with ASPIration) trial is a multicenter, prospective, randomized, controlled, single-blind, superiority study comparing two strategies: (1) an intervention group where threshold PCT values were used to guide initiation and discontinuation of antibiotics (PCT group); and (2) a control group, where antibiotic therapy was managed at the physician’s discretion. Patients aged 18 years or over, intubated for coma (Glasgow score ≤ 8), with MV initiated within 48 h after admission, were eligible. The primary endpoint was the duration of antibiotic treatment during the first 15 days after admission to the ICU. Results From 24/2/2015 to 28/8/2019, 1712 patients were intubated for coma in the 5 participating centers, of whom 166 were included in the study. Data from 159 were available for intention-to-treat analysis: 81 in the PCT group, and 78 in the control group. Overall, 67 patients (43%) received antibiotics in the intensive care unit (ICU); there was no significant difference between groups (37 (46%) vs 30 (40%) for PCT vs control, p = 0.432). The mean duration of antibiotic treatment during the first 15 days in the ICU was 2.7 ± 3.8 days; there was no significant difference between groups (3.0 ± 4.1 days vs 2.3 ± 3.4 days for PCT vs control, p = 0.311). The mean number of days under MV was significantly higher in the PCT group (3.7 ± 3.6 days) than in controls (2.7 ± 2.5 days, p = 0.033). The duration of ICU stay was also significantly longer in the PCT group: 6.4 ± 6.5 days vs 4.6 ± 3.5 days in the control group (p = 0.043). After adjustment for SAPS II score, the difference in length of stay and duration of mechanical ventilation between groups was no longer significant. Conclusion The use of PCT values to guide therapy, in comparison to the use of clinical, biological (apart from PCT) and radiological criteria, does not modify exposure to antibiotics in patients intubated for coma. Trial registration Clinicaltrials.gov Identifier NCT02862314.
Published: 2021

8. Heterozygous Variants in KDM4B Lead to Global Developmental Delay and Neuroanatomical Defects

Author: Cyril Goizet, Arthur Sorlin, Antonio Novelli, Christophe Philippe, Mathilde Nizon, Joan M. Stoler, Maria J. Guillen Sacoto, Marielle Alders, Grace Yoon, Binnaz Yalcin, Aurélien Trimouille, Anna R. Duncan, Valerie E. Vancollie, Emanuele Agolini, Lance H. Rodan, Monica H. Wojcik, Christopher J. Lelliott, Saskia M. Maas, Antonio Vitobello, Pankaj B. Agrawal, Ange Line Bruel, Laurence Faivre, Paolo Prontera, Stephan C. Collins, Teresa Santiago-Sim, Casie A. Genetti, Ann Seman, Jiahai Shi, Marieke F. van Dooren, Patricia Ellen Grant, Clinical Genetics, Boston Children's Hospital, Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), FHU TRANSLAD (CHU de Dijon), The Wellcome Trust Sanger Institute [Cambridge], City University of Hong Kong [Hong Kong] (CUHK), Bambino Gesù Children’s Hospital [Rome, Italy], Università degli Studi di Perugia = University of Perugia (UNIPG), GeneDx [Gaithersburg, MD, USA], Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre hospitalier universitaire de Nantes (CHU Nantes), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Amsterdam UMC - Amsterdam University Medical Center, Centre de référence des maladies rares des déficiences intellectuelles de causes rares (CHU Dijon) (CRMR des déficiences intellectuelles de causes rares), The Hospital for sick children [Toronto] (SickKids), Dupuis, Christine, Human Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, ACS - Pulmonary hypertension & thrombosis, Amsterdam Reproduction & Development (AR&D), Lelliott, Christopher [0000-0001-8087-4530], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Jumonji Domain-Containing Histone Demethylases, [SDV]Life Sciences [q-bio], Developmental Disabilities, Corpus callosum, Hippocampus, Epigenesis, Genetic, Histones, Mice, 0302 clinical medicine, Neurodevelopmental disorder, Polymicrogyria, Global developmental delay, Agenesis of the corpus callosum, Genetics (clinical), Brain, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], intellectual disability, Brain size, Female, dysmorphic hippocampi, Signal Transduction, Heterozygote, heterozygous variant, global developmental delay, Biology, Nervous System Malformations, Methylation, 03 medical and health sciences, Seizures, Report, KDM4B, Genetics, medicine, Animals, Humans, neurodevelopmental disorder, Dentate gyrus, Genetic Variation, JMJD2B, medicine.disease, 030104 developmental biology, agenesis of the corpus callosum, Neuroscience, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, Ventriculomegaly
Abstract: International audience; KDM4B is a lysine-specific demethylase with a preferential activity on H3K9 tri/di-methylation (H3K9me3/2)-modified histones. H3K9 tri/di-demethylation is an important epigenetic mechanism responsible for silencing of gene expression in animal development and cancer. However, the role of KDM4B on human development is still poorly characterized. Through international data sharing, we gathered a cohort of nine individuals with mono-allelic de novo or inherited variants in KDM4B. All individuals presented with dysmorphic features and global developmental delay (GDD) with language and motor skills most affected. Three individuals had a history of seizures, and four had anomalies on brain imaging ranging from agenesis of the corpus callosum with hydrocephalus to cystic formations, abnormal hippocampi, and polymicrogyria. In mice, lysine demethylase 4B is expressed during brain development with high levels in the hippocampus, a region important for learning and memory. To understand how KDM4B variants can lead to GDD in humans, we assessed the effect of KDM4B disruption on brain anatomy and behavior through an in vivo heterozygous mouse model (Kdm4b þ/À), focusing on neuroanatomical changes. In mutant mice, the total brain volume was significantly reduced with decreased size of the hippocampal dentate gyrus, partial agenesis of the corpus callosum, and ventriculomegaly. This report demonstrates that variants in KDM4B are associated with GDD/ intellectual disability and neuroanatomical defects. Our findings suggest that KDM4B variation leads to a chromatinopathy, broadening the spectrum of this group of Mendelian disorders caused by alterations in epigenetic machinery.
Published: 2020

9. Retrotransposon insertion as a novel mutational cause of spinal muscular atrophy

Author: Myriam Vezain, Christel Thauvin-Robinet, Yoann Vial, Sophie Coutant, Séverine Drunat, Jon Andoni Urtizberea, Anne Rolland, Agnès Jacquin-Piques, Séverine Fehrenbach, Gaël Nicolas, François Lecoquierre, Pascale Saugier-Veber, Julien, Sabine, Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Cancer and Brain Genomics (CBG), Université de Rouen Normandie (UNIROUEN), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier de Valence, Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Genetics, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Genetics (clinical)
Abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder resulting from biallelic alterations of the SMN1 gene: deletion, gene conversion or, in rare cases, intragenic variants. The disease severity is mainly influenced by the copy number of SMN2, a nearly identical gene, which produces only low amounts of full-length (FL) mRNA. Here we describe the first example of retrotransposon insertion as a pathogenic SMN1 mutational event. The 50-year-old patient is clinically affected by SMA type III with a diagnostic odyssey spanning nearly 30 years. Despite a mild disease course, he carries a single SMN2 copy. Using Exome Sequencing and Sanger sequencing, we characterized a SVA-F retrotransposon inserted in SMN1 intron 7. Using RT-PCR and RNASeq experiments on lymphoblastoid cell lines, we documented the dramatic decrease of FL transcript production in the patient compared to subjects with the same SMN1 and SMN2 copy number, thus validating the pathogenicity of this SVA insertion. We characterized the mutant FL-SMN1-SVA transcript and showed that it is subject to degradation by nonsense-mediated mRNA decay. The stability of the SMN-SVA protein may explain the mild course of the disease. This observation exemplifies the role of retrotransposons in human genetic disorders.
Published: 2022

10. The economic, medical and psychosocial consequences of whole genome sequencing for the genetic diagnosis of patients with intellectual disability: The DEFIDIAG study protocol

Author: Catherine Lejeune, Charley Robert-Viard, Nicolas Meunier-Beillard, Myriam Alice Borel, Léna Gourvès, Stéphanie Staraci, Anne-Laure Soilly, Francis Guillemin, Valerie Seror, Hamza Achit, Marion Bouctot, Marie-Laure Asensio, Anne-Sophie Briffaut, Christelle Delmas, Ange-Line Bruel, Alexia Benoit, Alban Simon, Bénédicte Gerard, Hamza Hadj Abdallah, Stanislas Lyonnet, Laurence Faivre, Christel Thauvin-Robinet, Sylvie Odent, Delphine Heron, Damien Sanlaville, Thierry Frebourg, Jean Muller, Yannis Duffourd, Anne Boland, Jean-François Deleuze, Hélène Espérou, Christine Binquet, Hélène Dollfus, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe EPICAD (LNC - U1231), 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)-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), Délégation à la recherche clinique et à l'innovation [CHU Dijon] (DRCI), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pôle de Recherche Clinique [Paris] (PRC), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), FHU TRANSLAD (CHU de Dijon), Equipe GAD (LNC - U1231), Institut de génétique médicale, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-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), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Rouen, Normandie Université (NU), 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), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), TheDEFIDIAG study is funded by grants from the French Ministry of Health in the framewok of the national French initiative for genomic medicine. Institut national de la santé et de la recherche médicale (Inserm) is the sponsor of the DEFDIAG study., COMBE, Isabelle, and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA)
Subjects: [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, micro-costing, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, genome sequencing, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, intellectual disability, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Molecular Medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, cost-effectiveness, Genetics (clinical), [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, qualitative stud
Abstract: Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1–3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS.Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses.Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France.Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)—identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361).Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).
Published: 2022

11. Understanding the new BRD4-related syndrome: Clinical and genomic delineation with an international cohort study

Author: Guillaume Jouret, Solveig Heide, Arthur Sorlin, Laurence Faivre, Sandra Chantot‐Bastaraud, Claire Beneteau, Marie Denis‐Musquer, Peter D. Turnpenny, Charles Coutton, Gaëlle Vieville, Julien Thevenon, Austin Larson, Florence Petit, Elise Boudry, Thomas Smol, Bruno Delobel, Bénédicte Duban‐Bedu, Chiara Fallerini, Francesca Mari, Caterina Lo Rizzo, Alessandra Renieri, Jean‐Hubert Caberg, Anne‐Sophie Denommé‐Pichon, Frédéric Tran Mau‐Them, Isabelle Maystadt, Thomas Courtin, Boris Keren, Linda Mouthon, Perrine Charles, Silvestre Cuinat, Bertrand Isidor, Philippe Theis, Christian Müller, Marizela Kulisic, Seval Türkmen, Daniel Stieber, Dominique Bourgeois, Emmanuel Scalais, Barbara Klink, Couvet, Sandrine, Laboratoire National de Santé [Luxembourg] (LNS), Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), UF de Génétique chromosomique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Laboratoire de Génétique Chromosomique [CHU de Grenoble], CHU Grenoble, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Università degli Studi di Siena = University of Siena (UNISI), Azienda Ospedaliera Universitaria Senese, Centre Hospitalier Universitaire de Liège (CHU-Liège), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre de Génétique Humaine [Charleroi, Belgium] (Institut de Pathologie et de Génétique), Institut de Pathologie et de Génétique, Charleroi, Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], and Centre Hospitalier de Luxembourg [Luxembourg] (CHL)
Subjects: MESH: Mutation, [SDV]Life Sciences [q-bio], Cell Cycle Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, NIPBL, BRD4-related syndrome, cohesinopathy, MESH: Cell Cycle Proteins, MESH: Pregnancy, Pregnancy, MESH: Child, De Lange Syndrome, Genetics, Humans, Child, Genetics (clinical), MESH: Humans, MESH: Genomics, Nuclear Proteins, MESH: Transcription Factors, Genomics, Cornelia de Lange syndrome, [SDV] Life Sciences [q-bio], Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, BRD4, Female, MESH: Female, MESH: Nuclear Proteins, MESH: De Lange Syndrome, Transcription Factors
Abstract: International audience; BRD4 is part of a multiprotein complex involved in loading the cohesin complex onto DNA, a fundamental process required for cohesin-mediated loop extrusion and formation of Topologically Associating Domains. Pathogenic variations in this complex have been associated with a growing number of syndromes, collectively known as cohesinopathies, the most classic being Cornelia de Lange syndrome. However, no cohort study has been conducted to delineate the clinical and molecular spectrum of BRD4-related disorder. We formed an international collaborative study, and collected 14 new patients, including two fetuses. We performed phenotype and genotype analysis, integrated prenatal findings from fetopathological examinations, phenotypes of pediatric patients and adults. We report the first cohort of patients with BRD4-related disorder and delineate the dysmorphic features at different ages. This work extends the phenotypic spectrum of cohesinopathies and characterize a new clinically relevant and recognizable pattern, distinguishable from the other cohesinopathies.
Published: 2022

12. Prognostic value of circulating tumour DNA in metastatic pancreatic cancer patients: post-hoc analyses of two clinical trials

Author: Aurélien de Reyniès, Claire Mulot, Laetitia Dahan, Jean-Baptiste Bachet, Shu-Fang Wang-Renault, Valérie Taly, Jean-Marc Phelip, Pierre Laurent-Puig, Daniel Pietrasz, Yves Rinaldi, Julien Taieb, Jerome Durand-Labrunie, Hélène Blons, Solene Doat, Mathilde Postel, Karine Le Malicot, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Cancer Research and Personalized Medicine - CARPEM [Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Timone [CHU - APHM] (TIMONE), Fédération Francophone de Cancérologie Digestive (FFCD), Equipe EPICAD (LNC - U1231), 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)-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), Epigenetec, Centre de Ressources Biologiques (CRB), Hôpital Européen [Fondation Ambroise Paré - Marseille], CHU Saint-Etienne, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), and TALY, Valerie
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Multivariate analysis, Post hoc, medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, Circulating Tumor DNA, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Metastatic pancreatic cancer, Biomarkers, Tumor, Humans, Medicine, Prospective Studies, Neoplasm Metastasis, Aged, Chemotherapy, Plasma samples, business.industry, Hazard ratio, DNA Methylation, Middle Aged, Metastatic Pancreatic Adenocarcinoma, Prognosis, Pancreatic Neoplasms, Survival Rate, Clinical trial, Mutation, Female, business
Abstract: International audience; Objective: The prognostication of metastatic pancreatic adenocarcinoma (mPDAC) patients remains uncertain, mainly based on carbohydrate antigen 19-9 (CA19-9), with limited utility. Circulating tumour DNA (ctDNA) has been suggested as a prognostic factor, but its added value has been poorly explored. The objective was to determine whether ctDNA is an independent factor for the prognostication of mPDAC.Design: Translational study based on two prospective collections of plasma samples of mPDAC patients naïve for chemotherapy. One used as a test series and the other as validation series coming from two randomised trials (Prodige 35 and Prodige 37). CtDNA was assessed by digital droplet PCR targeting two methylated markers (HOXD8 and POU4F1) according to a newly developed and validated method. Univariate and multivariate analyses were performed according to ctDNA status.Results: Of 372 plasma samples available, 354 patients were analyzed for survival. In the validation series, 145 of 255 patients were found ctDNA positive (56.8%), Median PFS and OS were 5.3 and 8.2 months in ctDNA-positive and 6.2 and 12.6 months in ctDNA-negative patients, respectively. ctDNA positivity was more often associated with young age, high CA19-9 level and neutrophils lymphocytes ratio. In multivariate analysis including these previous markers, ctDNA was confirmed as an independent prognostic marker for PFS (adjusted hazard ratio (HR) 1.5, CI 95% [1.03-2.18], p = 0.034) and OS (HR 1.62, CI 95% [1.05-2.5], p = 0.029).Conclusions: In this first ctDNA assessment in a large series of mPDAC derived from clinical trials, ctDNA was detectable in 56.8% of patients and confirmed as an independent prognostic marker.
Published: 2022

13. SEMA6B variants cause intellectual disability and alter dendritic spine density and axon guidance

Author: Amélie Cordovado, Martina Schaettin, Médéric Jeanne, Veranika Panasenkava, Anne-Sophie Denommé-Pichon, Boris Keren, Cyril Mignot, Martine Doco-Fenzy, Lance Rodan, Keri Ramsey, Vinodh Narayanan, Julie R Jones, Eloise J Prijoles, Wendy G Mitchell, Jillian R Ozmore, Kali Juliette, Erin Torti, Elizabeth A Normand, Leslie Granger, Andrea K Petersen, Margaret G Au, Juliann P Matheny, Chanika Phornphutkul, Mary-Kathryn Chambers, Joaquín-Alejandro Fernández-Ramos, Eduardo López-Laso, Michael C Kruer, Somayeh Bakhtiari, Marcella Zollino, Manuela Morleo, Giuseppe Marangi, Davide Mei, Tiziana Pisano, Renzo Guerrini, Raymond J Louie, Anna Childers, David B Everman, Betrand Isidor, Séverine Audebert-Bellanger, Sylvie Odent, Dominique Bonneau, Brigitte Gilbert-Dussardier, Richard Redon, Stéphane Bézieau, Frédéric Laumonnier, Esther T Stoeckli, Annick Toutain, Marie-Laure Vuillaume, Jonchère, Laurent, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Zürich [Zürich] = University of Zurich (UZH), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hémostase et Remodelage Vasculaire Post-Ischémie (HERVI - EA 3801), Université de Reims Champagne-Ardenne (URCA), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), The Translational Genomics Research Institute (TGen), The Greenwood Genetic Center, Keck School of Medicine [Los Angeles], University of Southern California (USC), Dartmouth Hitchcock Medical Center [Lebanon], Gillette Children's Specialty Healthcare [St Paul], GeneDx [Gaithersburg, MD, USA], Randall Children's Hospital [Portland], University of Kentucky (UK), Warren Alpert Medical School of Brown University, Rhode Island Hospital [Providence, RI, États-Unis], Instituto Maimonides de Investigación Biomédica de Cordoba (IMIBIC), Universidad de Córdoba = University of Córdoba [Córdoba]-Hospital Universitario Reina Sofía, Barrow Neurological Institute, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Università degli Studi di Firenze = University of Florence (UniFI), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), 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), Funding for HUGODIMS (Western France exome-based trio approach project to identifygenes involved in intellectual disability) was supported by a grant from the French Ministryof Health and from the Health Regional Agency from Poitou-Charentes [HUGODIMS, 2013,RC14_0107]. [A.C.] is a research student recipient of a grant from the University of Tours., Cordovado, Amélie, Schaettin, Martina, Jeanne, Médéric, Panasenkava, Veranika, Denommé-Pichon, Anne-Sophie, Keren, Bori, Mignot, Cyril, Doco-Fenzy, Martine, Rodan, Lance, Ramsey, Keri, Narayanan, Vinodh, Jones, Julie R, Prijoles, Eloise J, Mitchell, Wendy G, Ozmore, Jillian R, Juliette, Kali, Torti, Erin, Normand, Elizabeth A, Granger, Leslie, Petersen, Andrea K, Au, Margaret G, Matheny, Juliann P, Phornphutkul, Chanika, Chambers, Mary-Kathryn, Fernández-Ramos, Joaquín-Alejandro, López-Laso, Eduardo, Kruer, Michael C, Bakhtiari, Somayeh, Zollino, Marcella, Morleo, Manuela, Marangi, Giuseppe, Mei, Davide, Pisano, Tiziana, Guerrini, Renzo, Louie, Raymond J, Childers, Anna, Everman, David B, Isidor, Betrand, Audebert-Bellanger, Séverine, Odent, Sylvie, Bonneau, Dominique, Gilbert-Dussardier, Brigitte, Redon, Richard, Bézieau, Stéphane, Laumonnier, Frédéric, Stoeckli, Esther T, Toutain, Annick, and Vuillaume, Marie-Laure
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, Epilepsy, Dendritic Spines, [SDV]Life Sciences [q-bio], Intellectual disability, Chick Embryo, Semaphorins, [SDV.GEN] Life Sciences [q-bio]/Genetics, General Medicine, Settore MED/03 - GENETICA MEDICA, Axon Guidance, [SDV] Life Sciences [q-bio], HEK293 Cells, SEMA6B, Intellectual Disability, Genetics, Animals, Humans, Original Article, Molecular Biology, Genetics (clinical)
Abstract: Intellectual disability (ID) is a neurodevelopmental disorder frequently caused by monogenic defects. In this study, we collected 14 SEMA6B heterozygous variants in 16 unrelated patients referred for ID to different centers. Whereas, until now, SEMA6B variants have mainly been reported in patients with progressive myoclonic epilepsy, our study indicates that the clinical spectrum is wider and also includes non-syndromic ID without epilepsy or myoclonus. To assess the pathogenicity of these variants, selected mutated forms of Sema6b were overexpressed in Human Embryonic Kidney 293T (HEK293T) cells and in primary neuronal cultures. shRNAs targeting Sema6b were also used in neuronal cultures to measure the impact of the decreased Sema6b expression on morphogenesis and synaptogenesis. The overexpression of some variants leads to a subcellular mislocalization of SEMA6B protein in HEK293T cells and to a reduced spine density owing to loss of mature spines in neuronal cultures. Sema6b knockdown also impairs spine density and spine maturation. In addition, we conducted in vivo rescue experiments in chicken embryos with the selected mutated forms of Sema6b expressed in commissural neurons after knockdown of endogenous SEMA6B. We observed that expression of these variants in commissural neurons fails to rescue the normal axon pathway. In conclusion, identification of SEMA6B variants in patients presenting with an overlapping phenotype with ID and functional studies highlight the important role of SEMA6B in neuronal development, notably in spine formation and maturation and in axon guidance. This study adds SEMA6B to the list of ID-related genes.
Published: 2022

14. EPHA7 haploinsufficiency is associated with a neurodevelopmental disorder

Author: Jessica Assoumani, Morgane Plutino, Caroline Benech, Nathalie Marle, Houda Karmous-Benailly, Elise Boudry Labis, Sylvia Redon, Lionel Van Maldergem, Hala Nasser, Nathalie Couque, Myriam Rachid, Anne-Claude Tabet, Bérénice Schell, Aafke Engwerda, Mélanie Rama, Odile Boute, Céline Dupont, Conny M. A. van Ravenswaaij-Arts, Patrick Callier, Lyse Ruaud, Jonathan I. Levy, Paul Kuentz, Alain Verloes, Laurence Faivre, Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), University Medical Center Groningen [Groningen] (UMCG), Centre Hospitalier Universitaire de Nice (CHU Nice), EFS, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Lille, Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Institut de génétique médicale, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre d'Investigation Clinique de Besançon (Inserm CIC 1431), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This work has been generated within the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]., Clinical Cognitive Neuropsychiatry Research Program (CCNP), PODEUR, Sophie, and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC)
Subjects: Male, Microcephaly, [SDV]Life Sciences [q-bio], 6q16, 1 microdeletion, Inheritance Patterns, EPHA7, Haploinsufficiency, Biology, speech and language development, Neurodevelopmental disorder, Exome Sequencing, Genetics, medicine, Ephrin, Humans, Genetic Predisposition to Disease, microcephaly, Genetics (clinical), Genetic Association Studies, In Situ Hybridization, Fluorescence, Comparative Genomic Hybridization, 6q16.1 microdeletion, Erythropoietin-producing hepatocellular (Eph) receptor, Receptor, EphA7, medicine.disease, Penetrance, Phenotype, neurodevelopmental disorder, Pedigree, [SDV] Life Sciences [q-bio], Neurodevelopmental Disorders, intellectual disability, Mutation, Chromosomes, Human, Pair 6, Female
Abstract: International audience; Ephrin receptor and their ligands, the ephrins, are widely expressed in the developing brain. They are implicated in several developmental processes that are crucial for brain development. Deletions in genes encoding for members of the Eph/ephrin receptor family were reported in several neurodevelopmental disorders. The ephrin receptor A7 gene (EPHA7) encodes a member of ephrin receptor subfamily of the protein-tyrosine kinase family. EPHA7 plays a role in corticogenesis processes, determines brain size and shape, and is involved in development of the central nervous system. One patient only was reported so far with a de novo deletion encompassing EPHA7 in 6q16.1. We report 12 additional patients from nine unrelated pedigrees with similar deletions. The deletions were inherited in nine out of 12 patients, suggesting variable expressivity and incomplete penetrance. Four patients had tiny deletions involving only EPHA7, suggesting a critical role of EPHA7 in a neurodevelopmental disability phenotype. We provide further evidence for EPHA7 deletion as a risk factor for neurodevelopmental disorder and delineate its clinical phenotype.
Published: 2021

15. A GWAS in Latin Americans identifies novel face shape loci, implicating VPS13B and a Denisovan introgressed region in facial variation

Author: Tábita Hünemeier, Andres Ruiz-Linares, Samuel Canizales-Quinteros, Christel Thauvin-Robinet, Betty Bonfante, Juan Camilo Chacón-Duque, Laurence Duplomb, Charlotte Montillot, Sagnik Palmal, Javier Mendoza-Revilla, Justin Cotney, Laurence Faivre, Seth M. Weinberg, Victor Acuña-Alonzo, Emma Wentworth, Philip H. Jones, Claudia Jaramillo, Caroline Costedoat, Morgane Dubied, David J. Balding, Manfred Kayser, Pierre Faux, Francisco Rothhammer, Mirsha Sánchez-Quinto, Carla Gallo, Paola Everardo-Martínez, Macarena Fuentes-Guajardo, Evie Stergiakouli, Pirro G. Hysi, Ziyi Xiong, Giovanni Poletti, Ceferino Varón-González, Rodrigo Barquera, Maria Cátira Bortolini, Laurence J. Howe, Lauriane Poloni, Rolando González-José, Valeria Villegas, Malena Hurtado, Kaustubh Adhikari, William Arias, Vanessa Granja, Lavinia Schuler-Faccini, Virginia Ramallo, John R. Shaffer, Timothy C. Cox, Tim D. Spector, Gabriel Bedoya, Hugo Villamil-Ramírez, Caio Cesar Silva de Cerqueira, Fan Liu, Binnaz Yalcin, Jorge Gómez-Valdés, Nicolas Navarro, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL), Universidad Peruana Cayetano Heredia (UPCH), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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), University of Connecticut Health Center [Farmington], Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), University College of London [London] (UCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Universidad de Tarapaca, The Natural History Museum [London] (NHM), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], National School of Anthropology and History [Mexico City, Mexico] (NSAH), Max Planck Institute for the Science of Human History (MPI-SHH), Max-Planck-Gesellschaft, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Instituto Nacional de Medicina Genomica, Scientific Police of São Paulo State [Ourinhos, Brazil], Universidade de São Paulo = University of São Paulo (USP), Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Centro Nacional Patagónico (CENPAT), Beijing Genomics Institute [Shenzhen] (BGI), University of Chinese Academy of Sciences [Beijing] (UCAS), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Bristol [Bristol], King‘s College London, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Melbourne, University of Missouri [Kansas City] (UMKC), University of Missouri System, The Open University [Milton Keynes] (OU), Fudan University [Shanghai], Work leading to this publication was funded by grants from the National Natural Science Foundation of China (#31771393), the Scientific and Technology Committee of Shanghai Municipality (18490750300), the Ministry of Science and Technology of China (2020YFE0201600), the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01) and the 111 Project (B13016), the Leverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), the Excellence Initiative of Aix-Marseille University–A*MIDEX (a French 'Investissements d’Avenir' program), Universidad de Antioquia (CODI sostenibilidad de grupos 2013-2014 and MASO 2013-2014), Conselho Nacional de Desenvolvimento Científico e Tecnológico, Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Apoio a Núcleos de Excelência Program), Fundação de Aperfeiçoamento de Pessoal de Nível Superior, the National Institute of Dental and Craniofacial Research (R01-DE027023, U01-DE020078, R01-DE016148, and X01-HG007821), and a Santander Research and Scholarship Award. B.B. is supported by a doctoral scholarship from Ecole Doctorale 251 Aix-Marseille Université., ANR-11-IDEX-0001,Amidex,INITIATIVE D'EXCELLENCE AIX MARSEILLE UNIVERSITE(2011), Biogéosciences [UMR 6282] [Dijon] (BGS), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, École pratique des hautes études (EPHE), Laboratorios de Investigación y Desarrollo (LID), Unit of Human Evolutionary Genetics, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Department of Genetics and Genome Sciences, University of Connecticut (UCONN), Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and Environment, Department of Genetic Identification, Departamento de Tecnología Médica, Division of Vertebrates and Anthropology, Genética Molecular (GENMOL), Molecular Genetics Laboratory, National School of Anthropology and History, Department of Archaeogenetics [Jena] (DAG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Forensic Science, Universidad Nacional Autónoma de México (UNAM), Unidad de Genomica de Poblaciones Aplicada a la Salud, Universidad Nacional Autónoma de México (UNAM)-Instituto Nacional de Medicina Genomica, Scientific Police of São Paulo State, Departamento de Genética e Biologia Evolutiva, Universidade de São Paulo (USP), Departamento de Genética, Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS)-Instituto de Biociencias, Instituto Patagónico de Ciencias Sociales y Humanas, Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Key Laboratory of Genomic and Precision Medicine [Beijing, China], Beijing Genomics Institute [Shenzhen] (BGI)-University of Chinese Academy of Sciences [Beijing] (UCAS), Center for Craniofacial and Dental Genetics, University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Department of Human Genetics, Department of Anthropology, Medical Research Council Integrative Epidemiology Unit, University of the West of England [Bristol] (UWE Bristol), School of Oral and Dental Sciences, Department of Twin Research & Genetic Epidemiology, King's College London, Facultad de Medicina & Instituto de Alta Investigacion, Universidad de Tarapaca-Universidade de Chile, Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne-University of Melbourne, Department of Oral and Craniofacial Sciences, University of Missouri System-University of Missouri System, School of Mathematics and Statistics [Milton Keynes], Faculty of Science, Technology, Engineering and Mathematics [Milton Keynes], The Open University [Milton Keynes] (OU)-The Open University [Milton Keynes] (OU), State Key Laboratory of Genetics Engineering & MOE Key Laboratory of Contemporary Anthropology, Fudan University [Shanghai]-School of Life Sciences, Work leading to this publication was funded by grantsfrom the National Natural Science Foundation of China (#31771393), the Scientific andTechnology Committee of Shanghai Municipality (18490750300), the Ministry ofScience and Technology of China (2020YFE0201600), the Shanghai Municipal Scienceand Technology Major Project (2017SHZDZX01) and the 111 Project (B13016), theLeverhulme Trust (F/07 134/DF), BBSRC (BB/I021213/1), the Excellence Initiative ofAix-Marseille University–A*MIDEX (a French 'Investissements d’Avenir' program),Universidad de Antioquia (CODI sostenibilidad de grupos 2013-2014 and MASO 2013-2014), Conselho Nacional de Desenvolvimento Científico e Tecnológico,Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (Apoio a Núcleos deExcelência Program), Fundação de Aperfeiçoamento de Pessoal de Nível Superior, theNational Institute of Dental and Craniofacial Research (R01-DE027023, U01-DE020078,R01-DE016148, and X01-HG007821), and a Santander Research and Scholarship Award.B.B. is supported by a doctoral scholarship from Ecole Doctorale 251 Aix-MarseilleUniversité., and Genetic Identification
Subjects: haplotype, Latin Americans, [SDV]Life Sciences [q-bio], [SHS.ANTHRO-BIO]Humanities and Social Sciences/Biological anthropology, Vesicular Transport Proteins, Genome-wide association study, Genome-wide association studies, Regulatory sequences, purl.org/becyt/ford/1 [https], Mice, 0302 clinical medicine, Native Americans, single nucleotide polymorphism, GWAS, 10. No inequality, Two-dimensional profiles, Research Articles, Mammals, 0303 health sciences, Multidisciplinary, biology, adult, article, SciAdv r-articles, Genomic regions, Hispanic or Latino, craniofacial development, VPS13B, GENÉTICA, Phenotype, American Indian, regulatory sequence, HUMAN POPULATION, Research Article, Morphology, Latin americans, Genotype, animal experiment, introgression, Introgression, Polymorphism, Single Nucleotide, Homo denisovan, 03 medical and health sciences, male, Animals, Humans, controlled study, human, Craniofacial, Facial feature, purl.org/becyt/ford/1.6 [https], Denisovan, Gene, mouse, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, nonhuman, genome-wide association study, Haplotype, face, Human Genetics, Single nucleotide polymorphisms, biology.organism_classification, photography, thickness, purl.org/pe-repo/ocde/ford#3.01.02 [https], facies, DENOSIVAN HAPLOTYPE, Evolutionary biology, Anthropology, Face, 030217 neurology & neurosurgery, purl.org/pe-repo/ocde/ford#1.06.07 [https], Genome-Wide Association Study
Abstract: We carried out a genome-wide association study in Latin Americans and identified novel face morphology loci.., To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.
Published: 2021

16. Lemon Juice, Sesame Paste, and Autoclaving Influence Iron Bioavailability of Hummus: Assessment by an In Vitro Digestion/Caco-2 Cell Model

Author: Nicolas Sok, Maya Tueni, Philippe Cayot, Marie-Christine Chagnon, Jacqueline Maalouly, Nour Doumani, Isabelle Severin, Laurence Dahbi, Elias Bou-Maroun, Physico-Chimie de l'Aliment et du Vin (PCAV), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe NuTox (LNC - U1231) (NUTOX), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Faculty of Sciences II [Fanar, Lebanon], Dijon, Institut Agro, Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-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), Faculty of science II [Fanar], Lebanese University [Beirut] (LU), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, and 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)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon
Subjects: Food processing and formulation, Health (social science), 030309 nutrition & dietetics, Iron uptake by Caco-2 cells, Plant Science, lcsh:Chemical technology, Health Professions (miscellaneous), Microbiology, Article, law.invention, 03 medical and health sciences, 0404 agricultural biotechnology, Iron dialysis, Plant-based food, In vivo, law, [SDV.IDA]Life Sciences [q-bio]/Food engineering, lcsh:TP1-1185, Food science, 2. Zero hunger, 0303 health sciences, biology, Chemistry, Mediterranean and middle-eastern cuisine, Cell model, In vitro digestion, 04 agricultural and veterinary sciences, [SDV.IDA] Life Sciences [q-bio]/Food engineering, Hummus, 040401 food science, 3. Good health, Bioavailability, Ferritin, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Caco-2, biology.protein, Lemon juice, Atomic absorption spectroscopy, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Non-heme iron, Food Science
Abstract: Hummus, an iron-containing plant-based dish mainly made from chickpea pur&eacute, e, tahini, lemon juice and garlic, could be a valuable source of iron when bioavailable. Since the processing and formulation of food influence iron bioavailability, the present study investigated for the first time, their effects on hummus. Firstly, iron bioaccessibility was assessed on eight samples (prepared according to the screening Hadamard matrix) by in vitro digestion preceding iron dialysis. Then, iron bioavailability of four selected samples was estimated by the in vitro digestion/Caco-2 cell model. Total and dialyzable iron were determined by the atomic absorption spectrometry and ferritin formation was determined using an ELISA kit. Only autoclaving, among other processes, had a significant effect on iron bioaccessibility (+9.5, p &lt, 0.05). Lemon juice had the highest positive effect (+15.9, p &lt, 0.05). Consequently, the effect of its acidic components were investigated based on a full factorial 23 experimental design, no significant difference was detected. Garlic&rsquo, s effect was not significant, but tahini&rsquo, s effect was negative (&minus, 8.9, p &lt, 0.05). Despite the latter, hummus had a higher iron bioavailability than only cooked chickpeas (30.4 and 7.23 ng ferritin/mg protein, respectively). In conclusion, hummus may be a promising source of iron, further in vivo studies are needed for confirmation.
Published: 2020

17. Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD

Author: Gaetan Des Guetz, Thomas Aparicio, Denis Smith, Bruno Valenza, Nathalie Baize, Côme Lepage, Catherine Delbaldo, Denis Père Verge, Olivier Romano, Frédéric Pamoukdjian, Emmanuelle Norguet Monnereau, Anthony Dohan, Claire Falandry, L. Cany, Ariane Darut-Jouve, Christine Le Foll, Pascal Artru, Yves Rinaldi, Carole Monterymard, E. Maillard, Meher Ben Abdelghani, Faiza Khemissa Akouz, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinique Drévon, Service de hépato-gastro-entérologie - cancérologie digestive [CH de Perpignan], Centre Hospitalier Saint Jean de Perpignan, Fédération Francophone de la Cancérologie Digestive, FFCD, Service Biostatistiques et Informatique Médicale (CHU de Dijon) (DIM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Clinique Jean-Mermoz, Hôpital privé Jean Mermoz, Polyclinique Francheville, Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe Hospitalier Diaconesses Croix Saint-Simon, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), CRLCC Paul Strauss, IRCER - Axe 1 : procédés céramiques (IRCER-AXE1), Institut de Recherche sur les CERamiques (IRCER), Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut des Procédés Appliqués aux Matériaux (IPAM), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service de gastro-entérologie (Hôpital Européen de Marseille), Hôpital Européen [Fondation Ambroise Paré - Marseille], Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Institut de Cancérologie de Bourgogne, Hôpital privé Jean Mermoz [Lyon], Clinique Francheville [Périgueux], Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Intercommunal Fréjus - St Raphaël (CHI Fréjus - St Raphaël), Grand Hôpital de l'Est Francilien (GHEF), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], Hôpital Européen de Marseille (HEM), Service de Gastro entérologie [Hôpital Paris Saint-Joseph], Hôpital Paris Saint-Joseph, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Hôpital Cochin [AP-HP], Hôpital Dupuytren [CHU Limoges], Hôpital Avicenne [AP-HP], Equipe EPICAD (LNC - U1231), 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)-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), CCSD, Accord Elsevier, 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), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: medicine.medical_specialty, Colorectal cancer, Pyridines, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Adenocarcinoma, Gastroenterology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Quality of life, Regorafenib, Internal medicine, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Adverse effect, Chemotherapy, business.industry, Phenylurea Compounds, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Diarrhea, Oncology, chemistry, 030220 oncology & carcinogenesis, Toxicity, Quality of Life, Geriatrics and Gerontology, medicine.symptom, business, Colorectal Neoplasms
Abstract: International audience; BACKGROUND: Regorafenib significantly increases overall survival (OS) in patients with metastatic colorectal cancer previously treated but gives toxicities. OBJECTIVES: to assess the efficacy and safety of regorafenib at it's approved dose in the older population. PATIENTS AND METHODS: This multicenter single-arm phase II enrolled patients ≥70 years old after the failure of fluoropyrimidine-based chemotherapy, anti-VEGF, and anti-EGFR treatment. The primary endpoint was disease control rate (DCR) 2 months after initiation of regorafenib (160 mg/day, 3 weeks on/1 week off). RESULTS: Forty-three patients were enrolled, with a median age of 77 years. The 2 months DCR was 31.4% in the 35 evaluable patients. For the 42 patients that received at least one dose of regorafenib, median progression-free survival and OS were 2.2 and 7.5 months. The median time to autonomy degradation and quality of life degradation was 3.1 and 3.2 months, respectively. A grade 3-4 treatment-related adverse events was observed in 35/42 patients, notably: fatigue (45.2%), hand-foot skin reaction (19.0%), hypertension (21.4%), and diarrhea (7.1%). There is a trend to achieve DCR in patients ≤80 years and a trend to discontinue the study due to toxicity in patients with ECOG ≥1, over 80 years and with impaired baseline autonomy. CONCLUSION: Treatment with regorafenib in pretreated patients ≥70 years is feasible and demonstrate similar efficacy that was observed in previous studies in young patients. Fatigue is the most frequent severe adverse event. However, caution should be taken for older patients with ECOG ≥1, over 80 years, and with impaired baseline autonomy.
Published: 2020

18. Associations between cognitive performance and the rehabilitation, medical care and social support provided to French children with Prader-Willi syndrome

Author: Natacha Lehman, Didier Lacombe, Delphine Héron, Frédérique Debomy, Sylvie Manouvrier, Frédéric Huet, Patrick Edery, Laurence Faivre, Sylvie Odent, Myriam Mikaty, Jennifer Gallard, Sophie Chancenotte, Sandrine Vinault, Maïté Tauber, David Geneviève, Coralie Rastel, Nicole Philip, Christine Binquet, Mathieu Bordes, Alain Verloes, Jamal Ghoumid, Elodie Gautier, Christel Thauvin-Robinet, Emilie Schmitt, Jenny Cornaton, Marie Bournez, Nolwenn Jean, Catherine Lejeune, Delphine Minot, Alice Masurel, Pierre-Henri Roux-Levy, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux], CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence du Syndrome de Prader-Willi, CHU Toulouse [Toulouse], 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)-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), FHU TRANSLAD (CHU de Dijon), CHU Dijon, Hôpital de la Timone [CHU - APHM] (TIMONE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pôle Enfants [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and CCSD, Accord Elsevier
Subjects: Male, 0301 basic medicine, medicine.medical_treatment, Intellectual disability, MESH: Cognition, CBCL, 030105 genetics & heredity, Cognition, Multidisciplinary approach, MESH: Child, Medicine, Child, Genetics (clinical), Rehabilitation, MESH: Hormone Replacement Therapy, Neurological Rehabilitation, Neuropsychology, Wechsler Adult Intelligence Scale, General Medicine, 3. Good health, MESH: Young Adult, Child, Preschool, Education, Special, Female, France, Prader-Willi Syndrome, Occupational therapy, medicine.medical_specialty, Adolescent, Hormone Replacement Therapy, MESH: Social Support, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Young Adult, 03 medical and health sciences, Social support, MESH: Neurological Rehabilitation, Genetics, Humans, Psychiatry, MESH: Adolescent, MESH: Humans, business.industry, MESH: Child, Preschool, Social Support, medicine.disease, MESH: Male, MESH: France, Patient care management, 030104 developmental biology, MESH: Education, Special, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Prader-Willi Syndrome, business, MESH: Female
Abstract: International audience; Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with a characteristic behavioural phenotype. A multidisciplinary approach to care is required to prevent multiple medical complications in individuals affected by PWS. The aim of this study was to describe the rehabilitation, medical care, educational and social support provided to school-aged French PWS patients with varying neuropsychological profiles. Data were obtained from a French multicentre study that included patients aged 4-20 years with diverse genetic syndromes. Nineteen PWS subjects with a mean age of 9.2 years were included. The mean full-scale intellectual quotient (IQ) was 58 (Wechsler scale). There were frequent dissociations between verbal and performance IQ that were not associated with a specific profile. We also observed lower autonomy and communication scores (5.3 years and 5.9 years equivalent, respectively, Vineland scale), the absence of hyperactivity (Conners scale), and the presence of behavioural abnormalities (CBCL scale). Multidisciplinary medical supervision was generally coordinated by the paediatric endocrinologist and did not always include follow-up with all of the recommended specialists, in particular with a paediatric psychiatrist. Analysis of multidisciplinary rehabilitation conducted in public and private-sector establishment revealed failings in psychological support, occupational therapy and dietary follow-up. Regarding education, most children younger than 10 years were in normal schools, while older individuals were often cared for in medico-social institutions. In conclusion, children and adolescents with PWS generally received appropriate care. Though there have been considerable improvements in the management of children with PWS, reference centres should continue reinforcing the coordination of multidisciplinary supervision.
Published: 2020

19. Cost of exome analysis in patients with intellectual disability: a micro-costing study in a French setting

Author: Soilly, Al, Robert-Viard, C, Besse, C, Bruel, Al, Gerard, B, Boland, A, Piton, A, Duffourd, Y, Muller, J, Poë, C, Jouan, T, El Doueiri, S, Faivre, L, Bacq-Daian, D, Isidor, B, Genevieve, D, Odent, S, Philip, N, Doco-Fenzy, M, Lacombe, D, Asensio, Ml, Deleuze, Jf, Binquet, C, Thauvin-Robinet, C, Lejeune, C, Arpin, S, Blanchet, P, Blesson, S, Boute-Benejean, O, Busa, T, Colin, E, Coubes, C, Devillard, F, Edery, P, El Chehadeh, S, Fradin, M, Goldenberg, A, Guerrot, A-M, Herenger, Y, Houcinat, N, Jean-Marcais, N, Jouk, P., Lambert, L, Lavillaureix, A, Legendre, M, Leheup, B, Manouvrier, S, Mercier, S, Moutton, S, Nizon, M, Pasquier, L, Petit, F, Pinson, L, Poirsier, C, Pons, L, Putoux, A, Quelin, C, Renaud, M, Rossi, M, Sorlin, A, Spodenkiewicz, M, Thevenon, J, Toutain, A, Van-Gils, J, Vanlerberghe, C, Verloes, A, Vincent, M, Vincent-Delorme, C, Willems, M, Ziegler, A, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Recherche en Génomique Humaine (CNRGH), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, 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), FHU TRANSLAD (CHU de Dijon), and This study was funded by the French Ministry of Health as part of the 2015 Medico-Economic Research Program.
Subjects: Exome sequencing, MESH: France, MESH: Exome, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Cost analysis, Intellectual disability, Micro-costing, MESH: Intellectual Disability
Abstract: Background: With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers.Methods: A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed.Results: The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID.Conclusion: This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES.Trial registration: ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.
Published: 2023

20. Lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours: An international double-blind, placebo-controlled randomised phase II trial – Prodige 31 REMINET: An FFCD study

Author: Côme Lepage, Jean-Marc Phelip, Astrid Lievre, Karine Le-Malicot, Laetitia Dahan, David Tougeron, Christos Toumpanakis, Frédéric Di-Fiore, Catherine Lombard-Bohas, Ivan Borbath, Romain Coriat, Thierry Lecomte, Rosine Guimbaud, Caroline Petorin, Jean-Louis Legoux, Pierre Michel, Jean-Yves Scoazec, Denis Smith, Thomas Walter, 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), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Royal Free Hospital [London, UK], Communications Cellulaires et Différenciation (CCD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Cliniques Universitaires Saint-Luc [Bruxelles], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Amgen, Bristol-Myers Squibb, BMS, Bayer, Merck, Novartis, Roche, Celgene, Sandoz, Advanced Accelerator Applications, AAA, Agence Nationale de la Recherche, ANR: ANR-11-LABX-0021, Ligue Contre le Cancer, Servier, Ipsen, and ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011)
Subjects: Pancreatic Neoplasms, Clinical trial, Neuroendocrine Tumors, Cancer Research, Neuroendocrine tumours, Oncology, Duodeno-pancreatic, Maintenance, Non-resectable, Humans, [SDV.CAN]Life Sciences [q-bio]/Cancer, Somatostatin, Peptides, Cyclic
Abstract: International audience; Background: Following European guidelines, patients with aggressive metastatic or locally advanced, non-resectable, duodeno-pancreatic (DP) neuroendocrine tumours (NETs) should receive systemic combination chemotherapy until progression. Aggressive disease is defined as progressive and/or symptomatic metastases with or without significant hepatic invasion (>30–50%), and/or bone metastases. Methods: This academic randomised, double-blind, placebo-controlled phase II study aims to evaluate lanreotide autogel 120 mg (LAN) as maintenance treatment after at least 2 months of first-line treatment (L1) in aggressive G1-G2 DP-NET. Patients were randomly assigned in a 1:1 ratio to receive LAN or placebo (PBO), every 28 days, until progression or toxicity. The primary end-point was progression-free survival (PFS) at 6 months. Results: Among the 118 planned patients, 53 were included. Of these, 81.1% had a G2 tumour, and 90.6% had metastatic disease. L1 therapy consisted of chemotherapy (96.8%). Median duration of L1 was 4.6 months (range: 2.0–7.7). At the time of randomisation, 81.1% of patients had stable disease. Median follow-up was 27.0 months (95% CI: 19.5; 31.2). PFS at 6 months was 73.1% (90% CI: 55.3; 86.6) in LAN versus 54.2% (90% CI: 35.8; 71.8) in PBO. Median PFS was 19.4 months (95% CI: 7.6; 32.6) and 7.6 months (95% CI: 3.0; 9.0), respectively. Median overall survival was 41.9 months in PBO and was not reached in LAN. The toxicity profile was mainly grade 1–2 expected toxicities. Conclusions: The encouraging results of lanreotide autogel 120 mg as a maintenance treatment after L1 in aggressive G1/2 DP-NET should be confirmed. Trial registration: NCT02288377 (clinicaltrials.gov). © 2022 The Authors
Published: 2022

21. Discovering a new part of the phenotypic spectrum of Coffin-Siris syndrome in a fetal cohort

Author: Pleuntje J. van der Sluijs, Marieke Joosten, Caroline Alby, Tania Attié-Bitach, Kelly Gilmore, Christele Dubourg, Mélanie Fradin, Tianyun Wang, Evangeline C. Kurtz-Nelson, Kaitlyn P. Ahlers, Peer Arts, Christopher P. Barnett, Myla Ashfaq, Anwar Baban, Myrthe van den Born, Sarah Borrie, Tiffany Busa, Alicia Byrne, Miriam Carriero, Claudia Cesario, Karen Chong, Anna Maria Cueto-González, Jennifer C. Dempsey, Karin E.M. Diderich, Dan Doherty, Stense Farholt, Erica H. Gerkes, Svetlana Gorokhova, Lutgarde C.P. Govaerts, Pernille A. Gregersen, Scott E. Hickey, Mathilde Lefebvre, Francesca Mari, Jelena Martinovic, Hope Northrup, Melanie O’Leary, Kareesma Parbhoo, Sophie Patrier, Bernt Popp, Fernando Santos-Simarro, Corinna Stoltenburg, Christel Thauvin-Robinet, Elisabeth Thompson, Anneke T. Vulto-van Silfhout, Farah R. Zahir, Hamish S. Scott, Rachel K. Earl, Evan E. Eichler, Neeta L. Vora, Yael Wilnai, Jessica L. Giordano, Ronald J. Wapner, Jill A. Rosenfeld, Monique C. Haak, Gijs W.E. Santen, Leiden University Medical Center (LUMC), Universiteit Leiden, Erasmus University Medical Center [Rotterdam] (Erasmus MC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), CHU Rouen, Normandie Université (NU), Columbia University Medical Center (CUMC), Columbia University [New York], Baylor College of Medicine (BCM), Baylor University, This work was supported, in part, by grants from the National Institutes of Health (Grant No. R01 MH101221 [to E.E.E.]). E.E.E. is an investigator of the Howard Hughes Medical Institute.Sequencing and analysis for individual 30 was provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung, and Blood Institute (Grant Nos. UM1 HG008900 and R01 HG009141).Sequencing and analysis of cases 5 and 18 was funded by the National Institute of Child Human Development (Grant Nos. K23 HD088742 and R01 HD105868 [to N.L.V.])., Emergency Medicine, Clinical Genetics, van der Sluijs, Pleuntje J, Joosten, Marieke, Alby, Caroline, Attié-Bitach, Tania, Arts, Peer, Byrne, Alicia, Scott, Hamish S, and Santen, Gijs WE
Subjects: prenatal, genetic association, Chromosomal Proteins, Non-Histone, Micrognathism, SMARCB1, genetic vulnerability, Article, Fetal, SMARCA4, Intellectual Disability, Humans, Coffin-Siris syndrome, Abnormalities, Multiple, Genetic Association Studies, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], BAF-complex, SMARCB, ARID1A, ARID1B BAFopathy, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, abnormalities, Hand Deformities, Congenital, Neck
Abstract: Purpose: Genome-wide sequencing is increasingly being performed during pregnancy to identify the genetic cause of congenital anomalies. The interpretation of prenatally identified variants can be challenging and is hampered by our often limited knowledge of prenatal phenotypes. To better delineate the prenatal phenotype of Coffin-Siris syndrome (CSS), we collected clinical data from patients with a prenatal phenotype and a pathogenic variant in one of the CSS-associated genes. Methods: Clinical data was collected through an extensive web-based survey. Results: We included 44 patients with a variant in a CSS-associated gene and a prenatal phenotype; 9 of these patients have been reported before. Prenatal anomalies that were frequently observed in our cohort include hydrocephalus, agenesis of the corpus callosum, hypoplastic left heart syndrome, persistent left vena cava, diaphragmatic hernia, renal agenesis, and intrauterine growth restriction. Anal anomalies were frequently identified after birth in patients with ARID1A variants (6/14, 43%). Interestingly, pathogenic ARID1A variants were much more frequently identified in the current prenatal cohort (16/44, 36%) than in postnatal CSS cohorts (5%-9%). Conclusion: Our data shed new light on the prenatal phenotype of patients with pathogenic variants in CSS genes. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
Published: 2022

22. Liver transplantation for autoimmune hepatitis: Pre‐transplant does not predict the early post‐transplant outcome

Author: Yasmina Chouik, Claire Francoz, Eleonora De Martin, Olivier Guillaud, Armand Abergel, Mario Altieri, Louise Barbier, Camille Besch, Olivier Chazouillères, Filomena Conti, Christophe Corpechot, Sébastien Dharancy, François Durand, Christophe Duvoux, Jean Gugenheim, Jean Hardwigsen, Marie‐Noëlle Hilleret, Pauline Houssel‐Debry, Nassim Kamar, Anne Minello, Martine Neau‐Cransac, Georges‐Philippe Pageaux, Sylvie Radenne, Olivier Roux, Faouzi Saliba, Didier Samuel, Claire Vanlemmens, Marie‐Lorraine Woehl‐Jaegle, Vincent Leroy, Jean‐Charles Duclos‐Vallée, Jérôme Dumortier, Hospices Civils de Lyon (HCL), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Edouard Herriot [CHU - HCL], Clinique de la Sauvegarde [Lyon], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Les Hôptaux universitaires de Strasbourg (HUS), CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor [Créteil], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Pontchaillou [Rennes], 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 ), 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), Département de Néphrologie et Transplantation d'organes [CHU Toulouse], Pôle Urologie - Néphrologie - Dialyse - Transplantations - Brûlés - Chirurgie plastique - Explorations fonctionnelles et physiologiques [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), and Fondation Léon Bouchut
Subjects: early infection, MESH: Liver Transplantation, immunosuppression, MESH: Humans, Hepatology, MESH: Hepatitis, Autoimmune, fulminant hepatitis, MESH: Adult, MESH: Retrospective Studies, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, survival, sepsis, MESH: Massive Hepatic Necrosis, MESH: Female, MESH: Sepsis
Abstract: Background and aims: Autoimmune hepatitis (AIH) is a rare indication (
Published: 2023

23. Characterization of human oxidoreductases involved in aldehyde odorant metabolism

Author: Boichot, Valentin, Menetrier, Franck, Saliou, Jean-Michel, Lirussi, Frederic, Canon, Francis, Folia, Mireille, HEYDEL, Jean-Marie, Hummel, Thomas, Menzel, Susanne, Steinke, Maria, Hackenberg, Stephan, Schwartz, Mathieu, Neiers, F., Publica, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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), Université Bourgogne Franche-Comté [COMUE] (UBFC), Plateformes Lilloises en Biologie et Santé - UAR 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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Hospital Wuerzburg / Universitätsklinikum Würzburg, Fraunhofer Institute for Silicate Research (Fraunhofer ISC), Fraunhofer (Fraunhofer-Gesellschaft), Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Agence Nationale de la Recherche., ANR-18-CE92-0018,NAOMI,Métabolites olfactifs des molécules odorantes : caractérisation et fonction dans la perception olfactive(2018), ANR-20-CE21-0002,MACARON,Pellicule mucosal, flaveur, interaction & perception(2020), and ANR-22-CE21-0001,FLAMME,Métabolisme de la flaveur en bouche et modulation de la perception par les enzymes du microbiote oral(2022)
Subjects: Xenobiotics/metabolism, Multidisciplinary, Respiratory System, Oxidoreductases/metabolism, Odorants/analysis, Alcohol Oxidoreductases/metabolism, Odorant/genetics/metabolism, Alcohol Oxidoreductases, Smell/physiology, Respiratory System/metabolism, Odorants, Receptors, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Oxidoreductases, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Oxidoreductases are major enzymes of xenobiotic metabolism. Consequently, they are essential in the chemoprotection of the human body. Many xenobiotic metabolism enzymes have been shown to be involved in chemosensory tissue protection. Among them, some were additionally shown to be involved in chemosensory perception, acting in signal termination as well as in the generation of metabolites that change the activation pattern of chemosensory receptors. Oxidoreductases, especially aldehyde dehydrogenases and aldo–keto reductases, are the first barrier against aldehyde compounds, which include numerous odorants. Using a mass spectrometry approach, we characterized the most highly expressed members of these families in the human nasal mucus sampled in the olfactory vicinity. Their expression was also demonstrated using immunohistochemistry in human epitheliums sampled in the olfactory vicinity. Recombinant enzymes corresponding to three highly expressed human oxidoreductases (ALDH1A1, ALDH3A1, AKR1B10) were used to demonstrate the high enzymatic activity of these enzymes toward aldehyde odorants. The structure‒function relationship set based on the enzymatic parameters characterization of a series of aldehyde odorant compounds was supported by the X-ray structure resolution of human ALDH3A1 in complex with octanal.
Published: 2023

24. Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool

Author: Tran Mau-Them, Frédéric, Delanne, Julian, Denommé-Pichon, Anne-Sophie, Safraou, Hana, Bruel, Ange-Line, Vitobello, Antonio, Garde, Aurore, Nambot, Sophie, Bourgon, Nicolas, Racine, Caroline, Sorlin, Arthur, Moutton, Sébastien, Marle, Nathalie, Rousseau, Thierry, Sagot, Paul, Simon, Emmanuel, Vincent-Delorme, Catherine, Boute, Odile, Colson, Cindy, Petit, Florence, Legendre, Marine, Naudion, Sophie, Rooryck, Caroline, Prouteau, Clément, Colin, Estelle, Guichet, Agnès, Ziegler, Alban, Bonneau, Dominique, Morel, Godelieve, Fradin, Mélanie, Lavillaureix, Alinoé, Quelin, Chloé, Pasquier, Laurent, Odent, Sylvie, Vera, Gabriella, Goldenberg, Alice, Guerrot, Anne-Marie, Brehin, Anne-Claire, Putoux, Audrey, Attia, Jocelyne, Abel, Carine, Blanchet, Patricia, Wells, Constance F., Deiller, Caroline, Nizon, Mathilde, Mercier, Sandra, Vincent, Marie, Isidor, Bertrand, Amiel, Jeanne, Dard, Rodolphe, Godin, Manon, Gruchy, Nicolas, Jeanne, Médéric, Schaeffer, Elise, Maillard, Pierre-Yves, Payet, Frédérique, Jacquemont, Marie-Line, Francannet, Christine, Sigaudy, Sabine, Bergot, Marine, Tisserant, Emilie, Ascencio, Marie-Laure, Binquet, Christine, Duffourd, Yannis, Philippe, Christophe, Faivre, Laurence, Thauvin-Robinet, Christel, 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), Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), FHU TRANSLAD (CHU de Dijon), Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], Service de Gynécologie Obstétrique, Médecine Foetale et Stérilité Conjugale - Chirurgie Gynécologie et Oncologique [CHU de Dijon], Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Nord, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de référence Maladies Rares CLAD-Ouest [Rennes], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Service de Gynécologie et Obstétrique [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Génétique et Centre de Diagnostic Anténatal, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Equipe Maladies Génétiques de L'Enfant et de L'Adulte, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée [Montpellier], Centre de Référence Anomalies du Développement et Syndromes Malformatifs [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Centre de Référence Anomalies du Développement et Syndromes Malformatifs [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Thorax [Nantes], Embryology and genetics of human malformation, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Génétique Médicale et Clinique, Hôpital Necker-Enfants Malades, Unité Fonctionnelle de Génétique Médicale, Cytogénétique, Génétique Médicale et Biologie de La Reproduction, Centre Hospitalier Intercommunal Poissy-Saint-Germain-en-Laye, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, UMR 1253 IBrain Imagerie & Cerveau Equipe 2 : 'Neurogénomique & Physiopathologie neuronale' (NPN), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de Génétique Médicale, Pôle Femme, Mère, Enfants CHU de La Réunion-GH Sud Réunion-Saint-Pierre, Pôle Femme, Mère, Enfants, CHU de La Réunion-GH Sud Réunion-Saint-Pierre-CHU de La Réunion-GH Sud Réunion-Saint-Pierre, Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Unité de Génétique Clinique Prénatale, Département de Génétique Médicale, Hôpital de la Timone [CHU - APHM] (TIMONE)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), the European Union through the FEDER programs, and the AnDDI-Rares network for ES performed in this study.
Subjects: prenatal, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, chromosomal microarray, exome sequencing (ES), diagnostic yield, Genetics, Molecular Medicine, fetal, Genetics (clinical)
Abstract: Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%–10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US.Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel.Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV.Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.
Published: 2023

25. Executive functioning in adolescents and adults with Silver-Russell syndrome

Author: Mélissa Burgevin, Agnès Lacroix, Fanny Ollivier, Karine Bourdet, Régis Coutant, Bruno Donadille, Laurence Faivre, Sylvie Manouvrier-Hanu, Florence Petit, Christel Thauvin-Robinet, Annick Toutain, Irène Netchine, Sylvie Odent, Laboratoire de Psychologie : Cognition, Comportement, Communication (LP3C - EA1285), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Université de Rennes 2 (UR2)-Institut Brestois des Sciences de l'Homme et de la Société (IBSHS), Université de Brest (UBO), Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Nantes Université - UFR Lettres et Langages (Nantes Univ - UFR LL), Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Humanités, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], and Bretagne Atlantique Ambition, an endowment fund for research and innovation in Western France (http://www.baa-recherche.fr), financed the salary of MB's doctoral thesis (Agreement No. 150827).
Subjects: Multidisciplinary, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SCCO.PSYC]Cognitive science/Psychology
Abstract: International audience; Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by prenatal and postnatal growth retardation. The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Knowledge of the neuropsychological profile of SRS remains sparse and incomplete even if several difficulties related to attention and learning have been reported both in the literature and by patients with SRS. These difficulties could be the result of troubles in different cognitive domains, but also of executive dysfunction. Nevertheless, executive functioning has never been investigated, even though executive functions play an essential role in psychological development, and are extensively involved in daily life. The present study explored the executive functioning of individuals with SRS due to UPD(7)mat or 11p15 LOM. A battery of executive tasks assessing cognitive flexibility, inhibitory control, and working memory, together with a task assessing sustained attention, was administered to 19 individuals with SRS (13–39 years) and 19 healthy controls. The Behavior Rating Inventory of Executive Function was also completed by the participants’ families. The results showed that participants with SRS had similar performance (z-scores) to our controls, in a context of normal intellectual efficiency. Group comparisons with Bayesian statistics showed a single difference between the 11p15 LOM and control groups: the completion time for part A of the Trail Making Test appeared to be longer in the 11p15 LOM group than in the control group. However, at the clinical level, several participants with SRS had clinically significant scores on various measures of EFs. Thus, the cognitive phenotype of SRS did not appear to be characterized by executive dysfunction, but individuals with SRS could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder. These results provide new insights into the neuropsychological profile of individuals with SRS.
Published: 2023

26. Should we screen for colorectal cancer in people aged 75 and over? A systematic review - collaborative work of the French geriatric oncology society (SOFOG) and the French federation of digestive oncology (FFCD)

Author: Lydia, Guittet, Valérie, Quipourt, Thomas, Aparicio, Elisabeth, Carola, Jean-François, Seitz, Elena, Paillaud, Astrid, Lievre, Rabia, Boulahssass, Carole, Vitellius, Leila, Bengrine, Florence, Canoui-Poitrine, Sylvain, Manfredi, Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Marseille, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cancer Research and Personalized Medicine - CARPEM [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], IHFIH UPRES EA 3859, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, CHU Henri Mondor [Créteil], 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), and None
Subjects: Aged, 80 and over, Cancer Research, Harms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Colonoscopy, Comorbidity, Cost effectiveness, Life Expectancy, Acceptability, Oncology, Genetics, Humans, Mass Screening, Colorectal Neoplasms, Early Detection of Cancer, Simulation, Aged
Abstract: Background We have done a systematic literature review about CRC Screening over 75 years old in order to update knowledge and make recommendations. Methods PUBMED database was searched in October 2021 for articles published on CRC screening in the elderly, and generated 249 articles. Further searches were made to find articles on the acceptability, efficacy, and harms of screening in this population, together with the state of international guidelines. Results Most benefit-risk data on CRC screening in the over 75 s derived from simulation studies. Most guidelines recommend stopping cancer screening at the age of 75. In private health systems, extension of screening up to 80–85 years is, based on the life expectancy and the history of screening. Screening remains effective in populations without comorbidity given their better life-expectancy. Serious adverse events of colonoscopy increase with age and can outweigh the benefit of screening. The great majority of reviews concluded that screening between 75 and 85 years must be decided case by case. Conclusion The current literature does not allow Evidence-Based Medicine propositions for mass screening above 75 years old. As some subjects over 75 years may benefit from CRC screening, we discussed ways to introduce CRC screening in France in the 75–80 age group. IRB An institutional review board composed of members of the 2 learned societies (SOFOG and FFCD) defined the issues of interest, followed the evolution of the work and reviewed and validated the report.
Published: 2023

27. Impact of aldehyde dehydrogenases and aldo-keto reductases on human olfactory peri-receptor events

Author: Boichot, Valentin, Ménétrier, Franck, Saliou, Jean-Michel, Lirussi, Frédéric, Canon, Francis, Folia, Mireille, HEYDEL, Jean-Marie, Hummel, Thomas, Menzel, Suzanne, Steinke, Maria, Hackenberg, Stephan, Schwartz, Mathieu, Neiers, F., Julien, Sabine, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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), University of 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, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Hospital Wuerzburg / Universitätsklinikum Würzburg, Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), and Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH)
Subjects: [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, flavor, enzymes, aldehydes, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, human, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, metabolism
Abstract: International audience
Published: 2023

28. Effect of Obesity among Hospitalized Cancer Patients with or without COVID-19 on a National Level

Author: Jonathan Cottenet, Solène Tapia, Patrick Arveux, Alain Bernard, Tienhan Sandrine Dabakuyo-Yonli, Catherine Quantin, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université Bourgogne Franche-Comté [COMUE] (UBFC), Université de Lausanne = University of Lausanne (UNIL), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, 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), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), and HAL UVSQ, Équipe
Subjects: obesity, Cancer Research, SARS-CoV-2, COVID-19, [SDV.CAN]Life Sciences [q-bio]/Cancer, medico-administrative data, intensive care unit, mortality, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, tumor subtype, cancer, France
Abstract: International audience; Cancer and obesity are well-known prognostic factors in COVID-19. Our objective was to study the effect of obesity (and its severity) on the risk of intensive care unit (ICU) admission, severe complications, and in-hospital mortality, in a population of cancer patients hospitalized with or without COVID-19. All patients hospitalized in France for cancer from 1 March 2020 to 28 February 2022 were included from the French national administrative database. The effect of obesity was estimated in COVID-19 and in non-COVID-19 cancer patients using logistic and survival regressions, taking into account age, sex, comorbidities, and different types of cancer. Among the 992,899 cancer patients, we identified 53,090 patients with COVID-19 (5.35%), of which 3260 were obese (6.1%). After adjustment, for patients with or without COVID-19, there is an increased risk of ICU admission or severe complications in obese patients, regardless of the type of obesity. Regarding in-hospital mortality, there is no excess risk associated with overall obesity. However, massive obesity appears to be associated with an increased risk of in-hospital mortality, with a significantly stronger effect in solid cancer patients without COVID-19 and a significantly stronger effect in hematological cancer patients with COVID-19. This study showed that in France, among hospitalized patients with cancer and with or without COVID-19, increased vigilance is needed for obese patients, both in epidemic and non-epidemic periods. This vigilance should be further strengthened in patients with massive obesity for whom the risk of in-hospital mortality is higher, particularly in epidemic periods for patients with hematological cancers.
Published: 2022
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29. Subcutaneous Stromal Cells and Visceral Adipocyte Size Are Determinants of Metabolic Flexibility in Obesity and in Response to Weight Loss Surgery

Author: Séverine Ledoux, Nathalie Boulet, Chloé Belles, Alexia Zakaroff-Girard, Arnaud Bernard, Albéric Germain, Pauline Decaunes, Anaïs Briot, Jean Galitzky, Anne Bouloumié, AP-HP. Nord - Université Paris Cité, Université Paris Cité (UPCité), Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), 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), and boulet, nathalie
Subjects: lymphocytes, MESH: Humans, MESH: Hypertrophy, [SDV]Life Sciences [q-bio], fibrosis, hypertrophy, hyperplasia, adipogenesis, macrophages, Bariatric Surgery, Hypertrophy, General Medicine, [SDV] Life Sciences [q-bio], MESH: Insulin Resistance, Adipocytes, MESH: Obesity, Humans, MESH: Bariatric Surgery, Obesity, MESH: Stromal Cells, Insulin Resistance, Stromal Cells, MESH: Adipocytes
Abstract: International audience; Adipose tissue (AT) expansion either through hypertrophy or hyperplasia is determinant in the link between obesity and metabolic alteration. The present study aims to profile the unhealthy subcutaneous and visceral AT (SAT, VAT) expansion in obesity and in the outcomes of bariatric surgery (BS). The repartition of adipocytes according to diameter and the numbers of progenitor subtypes and immune cells of SAT and VAT from 161 obese patients were determined by cell imaging and flow cytometry, respectively. Associations with insulin resistance (IR) prior to BS as well as with the loss of excessive weight (EWL) and IR at 1 and 3 years post-BS were studied; prior to BS, SAT and VAT, unhealthy expansions are characterized by the accumulation of adipogenic progenitors and CD4+ T lymphocytes and by adipocyte hypertrophy and elevated macrophage numbers, respectively. Such SAT stromal profile and VAT adipocyte hypertrophy are associated with adverse BS outcomes. Finally, myofibrogenic progenitors are a common determinant of weight and IR trajectories post-BS; the study suggests that adipogenesis in SAT and adipocyte hypertrophy in VAT are common determinants of metabolic alterations with obesity and of the weight loss and metabolic response to bariatric surgery. The data open up new avenues to better understand and predict individual outcomes in response to changes in energy balance.
Published: 2022
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30. Missense variants in ANKRD11 cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Author: de Boer, Elke, Ockeloen, Charlotte, Kampen, Rosalie, Hampstead, Juliet, Dingemans, Alexander, Rots, Dmitrijs, Lütje, Lukas, Ashraf, Tazeen, Baker, Rachel, Barat-Houari, Mouna, Angle, Brad, Chatron, Nicolas, Denommé-Pichon, Anne-Sophie, Devinsky, Orrin, Dubourg, Christèle, Elmslie, Frances, Elloumi, Houda Zghal, Faivre, Laurence, Fitzgerald-Butt, Sarah, Geneviève, David, Goos, Jacqueline, Helm, Benjamin, Kini, Usha, Lasa-Aranzasti, Amaia, Lesca, Gaetan, Lynch, Sally, Mathijssen, Irene, Mcgowan, Ruth, Monaghan, Kristin, Odent, Sylvie, Pfundt, Rolph, Putoux, Audrey, van Reeuwijk, Jeroen, Santen, Gijs, Sasaki, Erina, Sorlin, Arthur, van der Spek, Peter, Stegmann, Alexander, Swagemakers, Sigrid, Valenzuela, Irene, Viora-Dupont, Eléonore, Vitobello, Antonio, Ware, Stephanie, Wéber, Mathys, Gilissen, Christian, Low, Karen, Fisher, Simon, Dingemans, Alexander J.M., Goos, Jacqueline A.C., Mathijssen, Irene M.J., Santen, Gijs W.E., Stegmann, Alexander P.A., Swagemakers, Sigrid M.A., Vissers, Lisenka E.L.M., Wong, Maggie M.K., Kleefstra, Tjitske, MUMC+: DA KG Lab Specialisten (9), RS: FHML non-thematic output, Pathology, Plastic and Reconstructive Surgery and Hand Surgery, Radboud University [Nijmegen], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft, This work was financially supported by Aspasia grants of the Dutch Research Council (015.014.036 to T.K. and 015.014.066 to L.E.L.M.V.), Netherlands Organization for Health Research and Development (91718310 to T.K.), and the Max Planck Society (M.M.K.W., S.E.F.). Individual 4 was sequenced at the Scottish Genomes Partnership. The Scottish Genomes Partnership was funded by the Chief Scientist Office of the Scottish Government Health Directorates (SGP/1) and the Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (https://www.deciphergenomics.org/), which is funded by Wellcome. See Deciphering Developmental Disorders study8 or https://www.ddduk.org/access.html for full acknowledgment., Institut Català de la Salut, [de Boer E, Dingemans AJM, Rots D] Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands. [Ockeloen CW] Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands. [Kampen RA] Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands. [Hampstead JE] Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands. Radboud Institute for Molecular Life Sciences, Radboudumc, Nijmegen, The Netherlands. [Lasa-Aranzasti A] Àrea de Genètica Clínica i Molecular, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Grup de Recerca en Medicina Genètica, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Neuroinformatics, Proteasome Endopeptidase Complex, [SDV]Life Sciences [q-bio], fenómenos genéticos::variación genética::mutación::mutación de sentido erróneo [FENÓMENOS Y PROCESOS], Mutation, Missense, Genotype-phenotype study, enfermedades musculoesqueléticas::enfermedades óseas::enfermedades óseas del desarrollo [ENFERMEDADES], Ossos - Malalties - Aspectes genètics, ANKRD11, All institutes and research themes of the Radboud University Medical Center, Missense variants, Intellectual Disability, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Genotype–phenotype study, Musculoskeletal Diseases::Bone Diseases::Bone Diseases, Developmental [DISEASES], Abnormalities, Multiple, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, Bone Diseases, Developmental, Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Stomatognathic System Abnormalities::Tooth Abnormalities [DISEASES], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Otros calificadores::Otros calificadores::/genética [Otros calificadores], Tooth Abnormalities, Neurodevelopmental disorders, Facies, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], KBG syndrome, Repressor Proteins, Anomalies cromosòmiques, Phenotype, enfermedades y anomalías neonatales congénitas y hereditarias::anomalías congénitas::anomalías del sistema estomatognático::anomalías dentarias [ENFERMEDADES], Genetic Phenomena::Genetic Variation::Mutation::Mutation, Missense [PHENOMENA AND PROCESSES], Chromosome Deletion, Dents - Malformacions - Aspectes genètics, Transcription Factors
Abstract: KBG syndrome; Missense variants; Neurodevelopmental disorders Síndrome KBG; Variants de missense; Trastorns del neurodesenvolupament Síndrome KBG; Variantes de missense; Trastornos del neurodesarrollo Purpose Although haploinsufficiency of ANKRD11 is among the most common genetic causes of neurodevelopmental disorders, the role of rare ANKRD11 missense variation remains unclear. We characterized clinical, molecular, and functional spectra of ANKRD11 missense variants. Methods We collected clinical information of individuals with ANKRD11 missense variants and evaluated phenotypic fit to KBG syndrome. We assessed pathogenicity of variants through in silico analyses and cell-based experiments. Results We identified 20 unique, mostly de novo, ANKRD11 missense variants in 29 individuals, presenting with syndromic neurodevelopmental disorders similar to KBG syndrome caused by ANKRD11 protein truncating variants or 16q24.3 microdeletions. Missense variants significantly clustered in repression domain 2 at the ANKRD11 C-terminus. Of the 10 functionally studied missense variants, 6 reduced ANKRD11 stability. One variant caused decreased proteasome degradation and loss of ANKRD11 transcriptional activity. Conclusion Our study indicates that pathogenic heterozygous ANKRD11 missense variants cause the clinically recognizable KBG syndrome. Disrupted transrepression capacity and reduced protein stability each independently lead to ANKRD11 loss-of-function, consistent with haploinsufficiency. This highlights the diagnostic relevance of ANKRD11 missense variants, but also poses diagnostic challenges because the KBG-associated phenotype may be mild and inherited pathogenic ANKRD11 (missense) variants are increasingly observed, warranting stringent variant classification and careful phenotyping.
Published: 2022

31. Characterization of Two Mouse Chd7 Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome

Author: Stephan C. Collins, Valerie E. Vancollie, Anna Mikhaleva, Christel Wagner, Rebecca Balz, Christopher J. Lelliott, Binnaz Yalcin, 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), Wellcome Trust Sanger Institute [Hinxton, UK], Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL)-Université de Lausanne = University of Lausanne (UNIL), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dupuis, Christine, Collins, Stephan C [0000-0002-1533-3380], Lelliott, Christopher J [0000-0001-8087-4530], Yalcin, Binnaz [0000-0002-1924-6807], and Apollo - University of Cambridge Repository
Subjects: CHARGE syndrome, [SDV]Life Sciences [q-bio], neurodevelopmental disorders, Organic Chemistry, DNA Helicases, Insulins, General Medicine, Catalysis, Computer Science Applications, Corpus Callosum, Inorganic Chemistry, [SDV] Life Sciences [q-bio], CHD7, DNA-Binding Proteins, Mice, Mutation, Animals, mouse models, dysgenesis of the corpus callosum, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract: International audience; CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred Chd7 model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in Chd7 to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms.
Published: 2022
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32. Trends in the relation between hyperglycemia correction and active Charcot neuroarthropathy: results from the EPICHAR study

Author: Dured Dardari, Sophie Schuldiner, Carole-Anne Julien, Georges Ha Van, Jocelyne M’Bemba, Muriel Bourgeon, Ariane Sultan, Marc Lepeut, Sylvie Grandperret-Vauthier, Florence Baudoux, Maud François, Sylvaine Clavel, Jacques Martini, Julien Vouillarmet, Paul Michon, Myriam Moret, Arnaud Monnier, Vaneva Chingan-Martino, Vincent Rigalleau, Isabelle Dumont, Laurence Kessler, Ionela Stifii, Benjamin Bouillet, Pierre Bonnin, Amal Lemoine, Enrique Da Costa Correia, Marie Martine Bonello Faraill, Marie Muller, Marie Cazaubiel, Mohammed Zakarya Zemmache, Agnes Hartemann, Laboratoire de Biologie de l'Exercice pour la Performance et la Santé (LBEPS), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Centre Hospitalier Sud Francilien, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de diabétologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Roubaix, Service de Génétique Biologique, Histologie Biologie du Développement et de la reproduction, Centre Hospitalier Régional universitaire Jean Minjoz (Service de Génétique Biologique, Histologie Biologie du Développement et de la reproduction, Centre Hospitalier Régional universitaire Jean Minjoz), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Hôtel-Dieu [Paris], Service Diabétologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hôpital Louis Pradel [CHU - HCL], CHU Pointe-à-Pitre/Abymes [Guadeloupe], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), 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), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Hôpital Lucien Hussel Vienne [Vienne, France] (HLHV), Centre Hospitalier de Vichy (CH Vichy), Hôpital Archet 2 [Nice] (CHU), Hôpital Michallon, Centre Hospitalier de Tourcoing, and BESPIM
Subjects: Male, HbA1c, MESH: Glycated Hemoglobin, Endocrinology, Diabetes and Metabolism, MESH: Diabetic Neuropathies / epidemiology, Cohort Studies, Diabetic Neuropathies, Diabetes complications, Diagnosis, MESH: Diabetes Mellitus, Type 2 / complications, Humans, Aged, MESH: Hyperglycemia / complications, Glycated Hemoglobin, MESH: Aged, MESH: Humans, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, MESH: Male, MESH: Middle aged, Diabetes Mellitus, Type 2, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Hyperglycemia, MESH: Cohort studies, Neuroarthropathy, Female, MESH: Female, MESH: Diabetic Neuropathies / etiology
Abstract: IntroductionThe pathophysiology of Charcot neuroarthropathy (CN) remains unclear. There are a number of hypotheses but these are not exclusive. In its clinical presentation, this complication intersects with the semiology of diabetic-induced neuropathy, such as peripheral hypervascularization and the appearance of arteriovenous shunt. The EPICHAR study is as yet an unpublished cohort of people living with diabetes complicated by CN (in active or chronic phase). Based on the findings of the EPICHAR study, this study aimed to investigate whether a reduction in the rate of hyperglycemia accompanies the onset of an active phase of CN.Research design and methodsHemoglobin A1c (HbA1c) levels were assessed 3 months (M3) and 6 months (M6) before the diagnosis of active CN (M0).Results103 patients living with diabetes and presenting active CN were included between January and December 2019 from the 31 centers participating in this study (30 in France and 1 in Belgium). The mean age of the participants was 60.2±12.2 years; the vast majority were men (71.8%) living with type 2 diabetes (75.5%). Mean HbA1c levels significantly declined between M6 (median 7.70; Q1, Q3: 7.00, 8.55) and M3 (median 7.65; Q1, Q3: 6.90, 8.50) (p=0.012), as well as between M6 and M0 (median 7.40; Q1, Q3: 6.50, 8.50) (p=0.014). No significant difference was found between M3 and M0 (p=0.072).ConclusionsA significant reduction in HbA1c levels seems to accompany the onset of the active phase of CN.Trial registration numberNCM03744039.
Published: 2022

33. French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis – 2021 update. Full-length version

Author: Vincent Cottin, Philippe Bonniaud, Jacques Cadranel, Bruno Crestani, Stéphane Jouneau, Sylvain Marchand-Adam, Hilario Nunes, Lidwine Wémeau-Stervinou, Emmanuel Bergot, Elodie Blanchard, Raphaël Borie, Arnaud Bourdin, Cécile Chenivesse, Annick Clément, Emmanuel Gomez, Anne Gondouin, Sandrine Hirschi, François Lebargy, Charles-Hugo Marquette, David Montani, Grégoire Prévot, Sébastien Quetant, Martine Reynaud-Gaubert, Mathieu Salaun, Olivier Sanchez, Bruno Trumbic, Karim Berkani, Pierre-Yves Brillet, Marion Campana, Lara Chalabreysse, Gérard Chatté, Didier Debieuvre, Gilbert Ferretti, Jean-Michel Fourrier, Nicolas Just, Marianne Kambouchner, Bertrand Legrand, Frédéric Le Guillou, Jean-Pierre Lhuillier, Anas Mehdaoui, Jean-Marc Naccache, Catherine Paganon, Martine Rémy-Jardin, Salim Si-Mohamed, Philippe Terrioux, Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM), 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), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Pneumologie Soins Intensifs, Appareillage Respiratoire [CHU de Dijon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Avicenne [AP-HP], Institut Coeur Poumon [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pessac, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), 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), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Nouvel Hôpital Civil de Strasbourg, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Pasteur [Nice] (CHU), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hypertension arterielle pulmonaire physiopathologie et innovation thérapeutique, Centre Chirurgical Marie Lannelongue (CCML)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Marseille, Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-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), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, Centre Hospitalier Régional d'Orléans (CHRO), Hospices Civils de Lyon (HCL), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Eure-Seine - Hôpital d'Evreux - Vernon (Evreux), Groupe Hospitalier Paris Saint-Joseph (hpsj), Services de Pneumologie, Exploration Fonctionnelle Respiratoire et Cardiologie (Hôpital Louis Pradel), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pulmonary and Respiratory Medicine, Biopsy, Biopsie, [SDV]Life Sciences [q-bio], Fibrose pulmonaire, Pneumopathie interstitielle commune, Interstitial lung disease, Common interstitial lung disease, Pneumopathie interstitielle diffuse, Pulmonary fibrosis
Abstract: National audience; BACKGROUND: Since the previous French guidelines were published in 2017, substantial additional knowledge about idiopathic pulmonary fibrosis has accumulated. METHODS: Under the auspices of the French-speaking Learned Society of Pulmonology and at the initiative of the coordinating reference center, practical guidelines for treatment of rare pulmonary diseases have been established. They were elaborated by groups of writers, reviewers and coordinators with the help of the OrphaLung network, as well as pulmonologists with varying practice modalities, radiologists, pathologists, a general practitioner, a head nurse, and a patients’ association. The method was developed according to rules entitled "Good clinical practice" in the overall framework of the "Guidelines for clinical practice" of the official French health authority (HAS), taking into account the results of an online vote using a Likert scale. RESULTS: After analysis of the literature, 54 recommendations were formulated, improved, and validated by the working groups. The recommendations covered a wide-ranging aspects of the disease and its treatment: epidemiology, diagnostic modalities, quality criteria and interpretation of chest CT, indication and modalities of lung biopsy, etiologic workup, approach to familial disease entailing indications and modalities of genetic testing, evaluation of possible functional impairments and prognosis, indications for and use of antifibrotic therapy, lung transplantation, symptom management, comorbidities and complications, treatment of chronic respiratory failure, diagnosis and management of acute exacerbations of fibrosis. CONCLUSION: These evidence-based guidelines are aimed at guiding the diagnosis and the management in clinical practice of idiopathic pulmonary fibrosis.
Published: 2022

34. OMIXCARE: OMICS technologies solved about 33% of the patients with heterogeneous rare neuro-developmental disorders and negative exome sequencing results and identified 13% additional candidate variants

Author: Estelle Colin, Yannis Duffourd, Emilie Tisserant, Raissa Relator, Ange-Line Bruel, Frédéric Tran Mau-Them, Anne-Sophie Denommé-Pichon, Hana Safraou, Julian Delanne, Nolwenn Jean-Marçais, Boris Keren, Bertrand Isidor, Marie Vincent, Cyril Mignot, Delphine Heron, Alexandra Afenjar, Solveig Heide, Anne Faudet, Perrine Charles, Sylvie Odent, Yvan Herenger, Arthur Sorlin, Sébastien Moutton, Jennifer Kerkhof, Haley McConkey, Martin Chevarin, Charlotte Poë, Victor Couturier, Valentin Bourgeois, Patrick Callier, Anne Boland, Robert Olaso, Christophe Philippe, Bekim Sadikovic, Christel Thauvin-Robinet, Laurence Faivre, Jean-François Deleuze, Antonio Vitobello, Jonchère, Laurent, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, Medical Genomics - - GENMED2010 - ANR-10-LABX-0013 - LABX - VALID, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), 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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), London Health Sciences Center (LHSC), CHU Dijon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Sorbonne Université (SU), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratory of Excellence GENMED [Paris] (Medical Genomics), University of Western Ontario (UWO), The study was performed within the framework of the GAD (Génétique des Anomalies du Développement) collection and approved by the appropriate institutional review board of Dijon University Hospital (DC2011-1332). This work was supported by grants from Dijon University Hospital, the ISITE-BFC (PIA ANR), the European Union through the FEDER programs (PERSONALISE), and the Burgundy-Franche-Compté regional council (INTEGRA). The sequencing platform at the CNRGH was supported by the France Génomique National infrastructure, funded as part of the 'Investissements d’Avenir' program, managed by the Agence Nationale pour la Recherche (contract ANR-10-INBS-09). The whole genome sequencing performed at the CNRGH was funded by the Laboratory of Excellence GENMED (Medical Genomics) Grant No. ANR-10-LABX-0013, managed by the National Research Agency (ANR) as part of the Investment for the Future program., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and ANR-10-LABX-0013,GENMED,Medical Genomics(2010)
Subjects: genome sequencing, DNA methylation analysis, [SDV.GEN]Life Sciences [q-bio]/Genetics, translational research, Cell Biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, transcriptome sequencing, undiagnosed neurodevelopmental diseases, Developmental Biology
Abstract: Purpose: Patients with rare or ultra-rare genetic diseases, which affect 350 million people worldwide, may experience a diagnostic odyssey. High-throughput sequencing leads to an etiological diagnosis in up to 50% of individuals with heterogeneous neurodevelopmental or malformation disorders. There is a growing interest in additional omics technologies in translational research settings to examine the remaining unsolved cases.Methods: We gathered 30 individuals with malformation syndromes and/or severe neurodevelopmental disorders with negative trio exome sequencing and array comparative genomic hybridization results through a multicenter project. We applied short-read genome sequencing, total RNA sequencing, and DNA methylation analysis, in that order, as complementary translational research tools for a molecular diagnosis.Results: The cohort was mainly composed of pediatric individuals with a median age of 13.7 years (4 years and 6 months to 35 years and 1 month). Genome sequencing alone identified at least one variant with a high level of evidence of pathogenicity in 8/30 individuals (26.7%) and at least a candidate disease-causing variant in 7/30 other individuals (23.3%). RNA-seq data in 23 individuals allowed two additional individuals (8.7%) to be diagnosed, confirming the implication of two pathogenic variants (8.7%), and excluding one candidate variant (4.3%). Finally, DNA methylation analysis confirmed one diagnosis identified by genome sequencing (Kabuki syndrome) and identified an episignature compatible with a BAFopathy in a patient with a clinical diagnosis of Coffin-Siris with negative genome and RNA-seq results in blood.Conclusion: Overall, our integrated genome, transcriptome, and DNA methylation analysis solved 10/30 (33.3%) cases and identified a strong candidate gene in 4/30 (13.3%) of the patients with rare neurodevelopmental disorders and negative exome sequencing results.
Published: 2022

35. Efficacy of donepezil for the treatment of oxaliplatin-induced peripheral neuropathy: DONEPEZOX, a protocol of a proof of concept, randomised, triple-blinded and multicentre trial

Author: Nicolas Kerckhove, David Tougeron, Côme Lepage, Denis Pezet, Karine Le Malicot, Manon Pelkowski, Bruno Pereira, David Balayssac, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Service de Pharmacologie Médicale [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Service de Chirurgie Digestive et Hépatobiliaire [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Fédération Francophone de Cancérologie Digestive (FFCD), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand, French Ministry of Health, National Institute of Cancer ('Institut National du Cancer (INCa) : Programme Hospitalier de Recherche Clinique Cancer', {20-082 PHRC-K], and Molé, Christine
Subjects: Chemotherapy-induced peripheral neuropathy, Cancer Research, Peripheral Nervous System Diseases, Pain, [SDV.CAN]Life Sciences [q-bio]/Cancer, Anticholinesterase, Oxaliplatin, Clinical Trials, Phase III as Topic, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Study protocol, Quality of Life, Genetics, Humans, Multicenter Studies as Topic, Donepezil, Randomized Controlled Trials as Topic
Abstract: Background The use of oxaliplatin in digestive tract cancers could induce severe peripheral neuropathy (OIPN) decreasing the quality of life of patients and survivors. There is currently, no univocal treatment for these peripheral neuropathies. Donepezil, a reversible inhibitor of cholinesterase, used to treat Alzheimer’s disease and dementia, is reported to have a good safety profile in humans, and preclinical data have provided initial evidence of its effectiveness in diminishing neuropathic symptoms and related comorbidities in OIPN animal models. Methods The DONEPEZOX trial will be a proof-of-concept, randomised, triple-blinded, and multicentre study. It will be the first clinical trial evaluating the efficacy and safety of donepezil for the management of OIPN. Adult cancer survivors with OIPN that report sensory neuropathy according to QLQ-CIPN20 sensory score (equivalence of a grade ≥ 2), at least 6 months after the end of an oxaliplatin-based chemotherapy will be included. Eighty patients will be randomly assigned to receive either donepezil or placebo over 16 weeks of treatment. The primary endpoint will be the rate of responders (neuropathic grade decreases according to the QLQ-CIPN20 sensory score) in the donepezil arm. The severity of OIPN will be assessed by the QLQ-CIPN20 sensory scale before and after 16 weeks of treatment. The comparison versus the placebo arm will be a secondary objective. The other secondary endpoints will be tolerance to donepezil, the severity and features of OIPN in each arm before and after treatment, related-comorbidities and quality of life. Fleming’s one-stage design will be used for sample size estimation. This design yields a type I error rate of 0.0417 and power of 91% for a responder rate of at least 30% in donepezil arm. A total of 80 randomized patients is planned. Discussion This study will allow, in the case of positive results, to initiate a phase 3 randomized and placebo-controlled (primary endpoint) clinical study to assess the therapeutic interest of donepezil to treat OIPN. Trial registration NCT05254639, clincialtrials.gov, Registered 24 February 2022.
Published: 2022

36. Quantitative Neuroanatomical Phenotyping of the Embryonic Mouse Brain

Author: Sylvie Nguyen, Meghna Kannan, Marion Gaborit, Stephan C. Collins, Binnaz Yalcin, Dupuis, Christine, 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), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Brain Diseases, brain morphology, standardized histology pipeline, General Immunology and Microbiology, neurodevelopmental disorders, [SDV]Life Sciences [q-bio], General Neuroscience, Histological Techniques, Brain, embryo development, Health Informatics, General Biochemistry, Genetics and Molecular Biology, [SDV] Life Sciences [q-bio], Mice, Neuroanatomy, Medical Laboratory Technology, Cerebellum, Animals, coronal and sagittal planes, General Pharmacology, Toxicology and Pharmaceutics
Abstract: Congenital neurodevelopmental anomalies are present from birth and are characterized by an abnormal development of one or more structures of the brain. Brain structural anomalies are highly comorbid with neurodevelopmental and neuropsychiatric disorders such as intellectual disability, autism spectrum disorders, epilepsy, and schizophrenia, and 80% are of genetic origin. We aim to address an important neurobiological question: How many genes regulate the normal anatomy of the brain during development. To do so, we developed a quantitative approach for the assessment of a total of 106 neuroanatomical parameters in mouse mutant embryos at embryonic day 18.5 across two planes commonly used in brain anatomical studies, the coronal and sagittal planes. In this article we describe the techniques we developed and explain why ultrastandardized procedures involving embryonic mouse brains are even more of prime importance for morphological phenotyping than adult mouse brains. We focus our analysis on brain size anomalies and on the most frequently altered brain regions including the cortex, corpus callosum, hippocampus, ventricles, caudate putamen, and cerebellum. Our protocols allow a standardized histology pipeline from embryonic mouse brain preparation to sectioning, staining, and scanning and neuroanatomical analyses at well-defined positions on the coronal and sagittal planes. Together, our protocols will help scientists in deciphering congenital neurodevelopmental anomalies and anatomical changes between groups of mouse embryos in health and genetic diseases. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Fixation and preparation of embryonic mouse brain samples Basic Protocol 2: Sectioning, staining, and scanning of embryonic mouse brain sections Basic Protocol 3: Coronal neuroanatomical measurements of embryonic mouse brain structures Basic Protocol 4: Sagittal neuroanatomical measurements of embryonic mouse brain structures.
Published: 2022

37. The Tumor Microenvironment Impairs Th1 IFNγ Secretion through Alternative Splicing Modifications of Irf1 Pre-mRNA

Author: Sophie Lemoine, Christophe Hibos, Joséphine Melin, Frédérique Végran, Antoine Bernard, Sandy Chevrier, Romain Mary, Romain Boidot, Etienne Viltard, Paul Peixoto, Etienne Humblin, Fanny Chalmin, François Ghiringhelli, Mélanie Bruchard, Lionel Apetoh, Corentin Richard, Eric Hervouet, Théo Accogli, 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), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Université de Bourgogne (UB), GenomiqueENS (Genomique ENS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-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)-Université de Montpellier (UM), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon] (ICMUB), Université de Bourgogne (UB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Thomas-Chollier, Morgane
Subjects: 0301 basic medicine, Gene isoform, Cancer Research, Tumor microenvironment, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Chemistry, Immunology, Alternative splicing, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell biology, 03 medical and health sciences, Splicing factor, 030104 developmental biology, 0302 clinical medicine, Immune system, IRF1, 030220 oncology & carcinogenesis, Precursor mRNA, Transcription factor
Abstract: It is clearly established that the immune system can affect cancer response to therapy. However, the influence of the tumor microenvironment (TME) on immune cells is not completely understood. In this respect, alternative splicing is increasingly described to affect the immune system. Here, we showed that the TME, via a TGFβ-dependent mechanism, increased alternative splicing events and induced the expression of an alternative isoform of the IRF1 transcription factor (IRF1Δ7) in Th1 cells. We found that the SFPQ splicing factor (splicing factor, proline- and glutamine-rich) was responsible for the IRF1Δ7 production. We also showed, in both mice and humans, that the IRF1 alternative isoform altered the full-length IRF1 transcriptional activity on the Il12rb1 promoter, resulting in decreased IFNγ secretion in Th1 cells. Thus, the IRF1Δ7 isoform was increased in the TME, and inhibiting IRF1Δ7 expression could potentiate Th1 antitumor responses.
Published: 2021

38. <scp>Skraban‐Deardorff</scp> syndrome: Six new cases of <scp> WDR 26 </scp> ‐related disease and expansion of the clinical phenotype

Author: Laurence Faivre, Varoona Bizaoui, Christèle Dubourg, Frédéric Tran Mau-Them, Wilfrid Carré, Amélie Piton, Sylvie Odent, Lionel Van Maldergem, Ange-Line Bruel, Laurent Pasquier, Marie Faoucher, Bénédicte Gérard, Mélanie Fradin, Alinoë Lavillaureix, Auriane Cospain, Florence Demurger, Jessica Assoumani, Elise Schaefer, Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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), FHU TRANSLAD (CHU de Dijon), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), and Chard-Hutchinson, Xavier
Subjects: Male, 0301 basic medicine, Proband, Pediatrics, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Skraban-Deardorff syndrome, Disease, 030105 genetics & heredity, Young Adult, 03 medical and health sciences, Intellectual disability, Genetics, medicine, WDR26, Humans, Abnormalities, Multiple, hypotonia, Ataxic Gait, Child, Genetics (clinical), Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Muscle biopsy, medicine.diagnostic_test, business.industry, Infant, Syndrome, medicine.disease, Gait, Hypotonia, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, 030104 developmental biology, speech therapy, intellectual disability, Child, Preschool, Mutation, Cohort, language development disorders, Female, medicine.symptom, business
Abstract: International audience; Skraban-Deardorff syndrome (a disease related to variations in the WDR26 gene; OMIM #617616) was first described in a cohort of 15 individuals in 2017. The syndrome comprises intellectual deficiency, severe speech impairment, ataxic gait, seizures, mild hypotonia with feeding difficulties during infancy, and dysmorphic features. Here, we report on six novel heterozygous de novo pathogenic variants in WDR26 in six probands. The patients’ phenotypes were consistent with original publication. One patient displayed marked hypotonia with an abnormal muscle biopsy; this finding warrants further investigation. Gait must be closely monitored, in order to highlight any musculoskeletal or neurological abnormalities and prompt further examinations. Speech therapy and alternative communication methods should be initiated early in the clinical follow-up, in order to improve language and oral eating and drinking.
Published: 2021

39. Novel role of the synaptic scaffold protein Dlgap4 in ventricular surface integrity and neuronal migration during cortical development

Author: Delfina M. Romero, Karine Poirier, Richard Belvindrah, Imane Moutkine, Anne Houllier, Anne-Gaëlle LeMoing, Florence Petit, Anne Boland, Stephan C. Collins, Mariano Soiza-Reilly, Binnaz Yalcin, Jamel Chelly, Jean-François Deleuze, Nadia Bahi-Buisson, Fiona Francis, Sorbonne Université (SU), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Cité (UPCité), 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), CHU Amiens-Picardie, Service de génétique clinique (CHU Lille), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Bourgogne-Franche Comté, Besançon, France, Universidad de Buenos Aires [Buenos Aires] (UBA), UNIVERSITY OF BOURGOGNE FRANCHE COMTE BESANCON FRA, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandre [Lille], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris-Saclay, 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), ANR-16-CE16-0011,DYNEINOPATHY,Mecanismes moléculaires et cellulaires des dyneinopathies(2016), and Francis, Fiona
Subjects: Cerebral Cortex, Mice, Knockout, Neurons, Multidisciplinary, [SDV]Life Sciences [q-bio], Neurogenesis, General Physics and Astronomy, Classical Lissencephalies and Subcortical Band Heterotopias, General Chemistry, General Biochemistry, Genetics and Molecular Biology, SAP90-PSD95 Associated Proteins, [SDV] Life Sciences [q-bio], Mice, Cell Movement, Animals, Humans
Abstract: Subcortical heterotopias are malformations associated with epilepsy and intellectual disability, characterized by the presence of ectopic neurons in the white matter. Mouse and human heterotopia mutations were identified in the microtubule-binding protein Echinoderm microtubule-associated protein-like 1, EML1. Further exploring pathological mechanisms, we identified a patient with an EML1-like phenotype and a novel genetic variation in DLGAP4. The protein belongs to a membrane-associated guanylate kinase family known to function in glutamate synapses. We showed that DLGAP4 is strongly expressed in the mouse ventricular zone (VZ) from early corticogenesis, and interacts with key VZ proteins including EML1. In utero electroporation of Dlgap4 knockdown (KD) and overexpression constructs revealed a ventricular surface phenotype including changes in progenitor cell dynamics, morphology, proliferation and neuronal migration defects. The Dlgap4 KD phenotype was rescued by wild-type but not mutant DLGAP4. Dlgap4 is required for the organization of radial glial cell adherens junction components and actin cytoskeleton dynamics at the apical domain, as well as during neuronal migration. Finally, Dlgap4 heterozygous knockout (KO) mice also show developmental defects in the dorsal telencephalon. We hence identify a synapse-related scaffold protein with pleiotropic functions, influencing the integrity of the developing cerebral cortex.
Published: 2022

40. Guidelines on enhanced recovery after cardiac surgery under cardiopulmonary bypass or off-pump

Author: Paul-Michel Mertes, Michel Kindo, Julien Amour, Christophe Baufreton, Lionel Camilleri, Thierry Caus, Didier Chatel, Bernard Cholley, Alain Curtil, Jean-Philippe Grimaud, Rémi Houel, Fehmi Kattou, Jean-Luc Fellahi, Catherine Guidon, Pierre-Grégoire Guinot, Guillaume Lebreton, Sandrine Marguerite, Alexandre Ouattara, Sophie Provenchère Fruithiot, Bertrand Rozec, Jean-Philippe Verhoye, André Vincentelli, Hélène Charbonneau, Les Hôpitaux Universitaires de Strasbourg (HUS), Nouvel Hôpital Civil de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Hôpital Privé Jacques Cartier [Massy], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Clermont-Ferrand, CHU Amiens-Picardie, Nouvelle Clinique de Tours Saint Gatien-Alliance [Tours] (CTSGA), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Clinique de la Sauvegarde [Lyon], Clinique Saint Augustin, Hôpital Saint-Joseph [Marseille], Institut Mutualiste de Montsouris (IMM), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), 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), Hôpital Pontchaillou, CHU Lille, Université de Lille, Clinique Pasteur [Toulouse], DESSAIVRE, Louise, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Innovations thérapeutiques en hémostase = Innovative Therapies in Haemostasis (IThEM - U1140), École Pratique des Hautes Études (EPHE), and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC)
Subjects: Adult, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cardiopulmonary Bypass, Critical Care, Coronary Artery Bypass, Off-Pump, off pump cardiac surgery, General Medicine, Cardiac surgery, Guidelines, Length of Stay, Critical Care and Intensive Care Medicine, Enhanced recovery after surgery (ERAS), Anesthesiology and Pain Medicine, Anesthesiology, Patient Satisfaction, Humans, Anesthesia, Cardiac Surgical Procedures, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objective: To provide recommendations for enhanced recovery after cardiac surgery (ERACS) based on a multimodal perioperative medicine approach in adult cardiac surgery patients with the aim of improving patient satisfaction, reducing postoperative mortality and morbidity, and reducing the length of hospital stay. Design: A consensus committee of 20 experts from the French Society of Anaesthesia and Intensive Care Medicine (Societe francaise d'anesthesie et de reanimation, SFAR) and the French Society of Thoracic and Cardiovascular Surgery (Societe francaise de chirurgie thoracique et cardio-vasculaire, SFCTCV) was convened. A formal conflict-of-interest policy was developed at the onset of the process and enforced throughout. The entire guideline process was conducted independently of any industry funding. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide the assessment of the quality of evidence. Methods: Six fields were defined: (1) selection of the patient pathway and its information; (2) preoperative management and rehabilitation; (3) anaesthesia and analgesia for cardiac surgery; (4) surgical strategy for cardiac surgery and bypass management; (5) patient blood management; and (6) postoperative enhanced recovery. For each field, the objective of the recommendations was to answer questions formulated according to the PICO model (Population, Intervention, Comparison, Outcome). Based on these questions, an extensive bibliographic search was carried out and analyses were performed using the GRADE approach. The recommendations were formulated according to the GRADE methodology and then voted on by all the experts according to the GRADE grid method. Results: The SFAR/SFCTCV guideline panel provided 33 recommendations on the management of patients undergoing cardiac surgery under cardiopulmonary bypass or off-pump. After three rounds of voting and several amendments, a strong agreement was reached for the 33 recommendations. Of these recommendations, 10 have a high level of evidence (7 GRADE 1+ and 3 GRADE 1-); 19 have a moderate level of evidence (15 GRADE 2+ and 4 GRADE 2-); and 4 are expert opinions. Finally, no recommendations were provided for 3 questions. Conclusions: Strong agreement existed among the experts to provide recommendations to optimise the complete perioperative management of patients undergoing cardiac surgery. (C) 2022 The Authors. Published by Elsevier Masson SAS on behalf of Societe francaise d'anesthesie et de reanimation (Sfar).
Published: 2022

41. NLRP6 negatively regulates type 2 immune responses in mice

Author: Pauline Chenuet, Quentin Marquant, Louis Fauconnier, Ali Youness, Manon Mellier, Tiffany Marchiol, Nathalie Rouxel, Yasmine Messaoud‐Nacer, Isabelle Maillet, Aurélie Ledru, Valérie F. J. Quesniaux, Bernhard Ryffel, William Horsnell, Frédérique Végran, Lionel Apetoh, Dieudonnée Togbe, Université d'Orléans, SCD, Artimmune SAS, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), University of Cape Town, Institute of Microbiology and Infection, University of Birmingham [Birmingham], 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), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Orléans, 2016-00110366/European funding in Région Centre-Val de Loire, EX0057560/European funding in Région Centre-Val de Loire, Conseil Départemental 45, Le Studium, Program ARD2020 Biomédicament, and CNRS
Subjects: Inflammasomes, Immunology, NLRP6, ILC2, Th2, Mice, Th2 Cells, inflammasome, GATA3, Immunology and Allergy, Animals, Nippostrongylus brasiliensis, birch pollen, Lymphocytes, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Mice, Knockout, Interleukin-18, Pneumonia, CD4+ T cells, Immunity, Innate, Cytokines, Th17, Nippostrongylus, allergic asthma, IL-18, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology
Abstract: International audience; Background: Inflammasomes are large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection. Following activation, inflammasomes trigger cell death and the release of biologically active forms of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome is required for IL-18 secretion by intestinal epithelial cells, macrophages, and T cells, contributing to homeostasis and self-defense against pathogenic microbes. However, the involvement of NLRP6 in type 2 lung inflammation remains elusive.Methods: Wild-type (WT) and Nlrp6−/− mice were used. Birch pollen extract (BPE)-induced allergic lung inflammation, eosinophil recruitment, Th2-related cytokine and chemokine production, airway hyperresponsiveness, and lung histopathology, Th2 cell differentiation, GATA3, and Th2 cytokines expression, were determined. Nippostrongylus brasiliensis (Nb) infection, worm count in intestine, type 2 innate lymphoid cell (ILC2), and Th2 cells in lungs were evaluated.Results: We demonstrate in Nlrp6−/− mice that a mixed Th2/Th17 immune responses prevailed following birch pollen challenge with increased eosinophils, ILC2, Th2, and Th17 cell induction and reduced IL-18 production. Nippostrongylus brasiliensis infected Nlrp6−/− mice featured enhanced early expulsion of the parasite due to enhanced type 2 immune responses compared to WT hosts. In vitro, NLRP6 repressed Th2 polarization, as shown by increased Th2 cytokines and higher expression of the transcription factor GATA3 in the absence of NLRP6. Exogenous IL-18 administration partially reduced the enhanced airways inflammation in Nlrp6−/− mice.Conclusions: In summary, our data identify NLRP6 as a negative regulator of type 2 immune responses.
Published: 2022

42. Ibrutinib Associated with Rituximab-Platinum Salt-Based Immunochemotherapy in B-Cell Lymphomas: Results of a Phase 1b-II Study of the LYSA Group

Author: Christophe Bonnet, Jehan Dupuis, Hervé Tilly, Thierry Lamy, Christophe Fruchart, Steven le Gouill, Catherine Thieblemont, Franck Morschhauser, Olivier Casasnovas, Krimo Bouabdallah, Hervé Ghesquieres, Eric Van Den Neste, Marc André, Guillaume Cartron, Gilles Salles, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service d'hématologie, Jonchère, Laurent, Centre Hospitalier Universitaire de Liège (CHU-Liège), Hôpital Henri Mondor, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CH Dunkerque, Institut Curie [Paris], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Lille, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), CHU Bordeaux [Bordeaux], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cliniques Universitaires Saint-Luc [Bruxelles], Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Weill Medical College of Cornell University [New York], Lymphoma Academic Research Organization (LYSARC), and Janssen Pharmaceutics
Subjects: relapsed, safety, Cancer Research, Oncology, refractory non-Hodgkin B-cell lymphoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, ibrutinib, relapsed/refractory non-Hodgkin B-cell lymphoma, R-DHAP, R-DHAOx, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: International audience; Simple Summary Patients with relapsing/refractory B-cell lymphoma who respond to a platinum salt-based salvage regimen can be cured after therapy intensification followed by autologous stem cell transplantation. The Bruton tyrosine kinase inhibitor ibrutinib, given alone or in association with other molecules, has proven effective in numerous B-cell lymphomas. The aim of the current study was to evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), with ibrutinib given based on a prespecified dose-escalation design. The concomitant combination of ibrutinib and R-DHAP resulted in limiting hematological, infectious, and renal toxicities. As a result, the maximum ibrutinib dose could not be administered. On the other hand, when the ibrutinib administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to the maximum prespecified dose but with relevant toxicities. Despite a strong rationale for combining ibrutinib with either R-DHAP or R-DHAP/Ox, this approach was limited by significant toxicities. In the post-rituximab era, patients with relapsed/refractory non-Hodgkin B-cell lymphoma (R/R B-NHL) responding to a platinum salt-based salvage regimen can potentially be cured after intensification followed by autologous stem cell transplantation, with the quality of the response to salvage predicting survival. The Bruton tyrosine kinase inhibitor ibrutinib, given as monotherapy or combined with other molecules, has proven effective in numerous B-cell lymphomas. To evaluate the safety of the combination of ibrutinib, rituximab, dexamethasone, and cytarabine with either cisplatin (R-DHAP) or oxaliplatin (R-DHAOx), we conducted a multicenter Phase 1b-II study in transplant-eligible R/R B-NHL patients, with ibrutinib given using a 3-by-3 dose-escalation design. The combination of R-DHAP and ibrutinib (given from Day 1 to Day 21 of each cycle) was associated with dose-limiting hematological, infectious, and renal toxicities, while we were unable to reach a dose to recommend for Phase II. R-DHAOx could only be combined with a daily dosage of 280 mg ibrutinib when administered continuously. R-DHAP combined with intermittent ibrutinib administration (from Day 5 to Day 18) was found to be highly toxic. On the other hand, when this administration schedule was combined with R-DHAOx, ibrutinib dosing could be increased up to 560 mg but with relevant toxicities. Despite a strong rationale for combining ibrutinib and R-DHAP/R-DHAOx, as both target lymphoma B-cells by different mechanisms, this approach was limited by significant toxicities.
Published: 2022
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43. Septic patients without obvious signs of infection at baseline are more likely to die in the ICU

Author: Francesco Campanelli, Agnès Soudry-Faure, Aurélie Avondo, Jean-Baptiste Roudaut, Jean-Pierre Quenot, Patrick Ray, Pierre-Emmanuel Charles, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Malbec, Odile
Subjects: Fever, Emergency department, [SDV]Life Sciences [q-bio], Intensive Care Unit, Prognosis, [SDV] Life Sciences [q-bio], Hospitalization, Intensive Care Units, Infectious Diseases, Sepsis, Humans, Hospital Mortality, Infection, Emergency Service, Hospital, Time-to-antibiotics, Retrospective Studies
Abstract: Objective Early identification of sepsis is mandatory. However, clinical presentation is sometimes misleading given the lack of infection signs. The objective of the study was to evaluate the impact on the 28-day mortality of the so-called “vague” presentation of sepsis. Design Single centre retrospective observational study. Setting One teaching hospital Intensive Care Unit. Subjects All the patients who presented at the Emergency Department (ED) and were thereafter admitted to the Intensive Care Unit (ICU) with a final diagnosis of sepsis were included in this retrospective observational three-year study. They were classified as having exhibited either “vague” or explicit presentation at the ED according to previously suggested criteria. Baseline characteristics, infection main features and sepsis management were compared. The impact of a vague presentation on 28-day mortality was then evaluated. Interventions None. Measurements and main results Among the 348 included patients, 103 (29.6%) had a vague sepsis presentation. Underlying chronic diseases were more likely in those patients [e.g., peripheral arterial occlusive disease: adjusted odd ratio (aOR) = 2.01, (1.08–3.77) 95% confidence interval (CI); p = 0.028], but organ failure was less likely at the ED [SOFA score value: 4.7 (3.2) vs. 5.2 (3.1), p = 0.09]. In contrast, 28-day mortality was higher in the vague presentation group (40.8% vs. 26.9%, p = 0.011), along with longer time-to-diagnosis [18 (31) vs. 4 (11) h, p p = 0.006]. Conclusions Almost one third of septic patient requiring ICU had a vague presentation at the ED. Despite an apparent lower level of severity when initially assessed, those patients had an increased risk of mortality that could not be fully explained by delayed diagnosis and management of sepsis.
Published: 2022

44. Biallelic variants in TRAPPC10 cause a microcephalic TRAPPopathy disorder in humans and mice

Author: Lettie E. Rawlins, Hashem Almousa, Shazia Khan, Stephan C. Collins, Miroslav P. Milev, Joseph Leslie, Djenann Saint-Dic, Valeed Khan, Ana Maria Hincapie, Jacob O. Day, Lucy McGavin, Christine Rowley, Gaurav V. Harlalka, Valerie E. Vancollie, Wasim Ahmad, Christopher J. Lelliott, Asma Gul, Binnaz Yalcin, Andrew H. Crosby, Michael Sacher, Emma L. Baple, Rawlins, Lettie E [0000-0002-6764-253X], Almousa, Hashem [0000-0003-2679-5350], Collins, Stephan C [0000-0002-1533-3380], Leslie, Joseph [0000-0003-0972-8818], Saint-Dic, Djenann [0000-0001-9328-7108], Khan, Valeed [0000-0002-3840-5439], Day, Jacob O [0000-0002-6020-510X], Harlalka, Gaurav V [0000-0001-8968-2447], Vancollie, Valerie E [0000-0003-1547-1975], Lelliott, Christopher J [0000-0001-8087-4530], Yalcin, Binnaz [0000-0002-1924-6807], Crosby, Andrew H [0000-0003-3667-9054], Sacher, Michael [0000-0003-2926-5064], Baple, Emma L [0000-0002-6637-3411], Apollo - University of Cambridge Repository, University of Exeter Medical School, University of Exeter, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Concordia University [Montreal], International Islamic University [Islamabad, Pakistan] (2IU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Rehman Medical Institute [Peshawar, Pakistan] (RMI), Plymouth University, University Hospitals Plymouth NHS Trust [Plymouth, UK] (UHP), The Wellcome Trust Sanger Institute [Cambridge], Rajarshi Shahu College of Pharmacy [Malvihir, Buldana, India] (RSCP), Quaid-i-Azam University (QAU), McGill University = Université McGill [Montréal, Canada], and Dupuis, Christine
Subjects: [SDV] Life Sciences [q-bio], Cancer Research, Mice, Phenotype, Neurodevelopmental Disorders, [SDV]Life Sciences [q-bio], Genetics, Microcephaly, Animals, Humans, Molecular Biology, Genetics (clinical), Ecology, Evolution, Behavior and Systematics
Abstract: The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice.
Published: 2022

45. Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Author: Aidin Foroutan, Sadegheh Haghshenas, Pratibha Bhai, Michael A. Levy, Jennifer Kerkhof, Haley McConkey, Marcello Niceta, Andrea Ciolfi, Lucia Pedace, Evelina Miele, David Genevieve, Solveig Heide, Mariëlle Alders, Giuseppe Zampino, Giuseppe Merla, Mélanie Fradin, Eric Bieth, Dominique Bonneau, Klaus Dieterich, Patricia Fergelot, Elise Schaefer, Laurence Faivre, Antonio Vitobello, Silvia Maitz, Rita Fischetto, Cristina Gervasini, Maria Piccione, Ingrid van de Laar, Marco Tartaglia, Bekim Sadikovic, Anne-Sophie Lebre, Foroutan A., Haghshenas S., Bhai P., Levy M.A., Kerkhof J., McConkey H., Niceta M., Ciolfi A., Pedace L., Miele E., Genevieve D., Heide S., Alders M., Zampino G., Merla G., Fradin M., Bieth E., Bonneau D., Dieterich K., Fergelot P., Schaefer E., Faivre L., Vitobello A., Maitz S., Fischetto R., Gervasini C., Piccione M., van de Laar I., Tartaglia M., Sadikovic B., Lebre A.-S., Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, University of Western Ontario (UWO), London Health Sciences Center (LHSC), IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Amsterdam UMC - Amsterdam University Medical Center, University of Amsterdam [Amsterdam] (UvA), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University of Naples Federico II = Università degli studi di Napoli Federico II, Fondazione Casa Sollievo della Sofferenza [San Giovanni Rotondo, Italy] (FC2S), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), 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), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), San Gerardo Hospital [Monza, Italy] (SGH), Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Università degli Studi di Milano = University of Milan (UNIMI), Università degli studi di Palermo - University of Palermo, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de génétique [Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Foroutan, A., Haghshenas, S., Bhai, P., Levy, M. A., Kerkhof, J., Mcconkey, H., Niceta, M., Ciolfi, A., Pedace, L., Miele, E., Genevieve, D., Heide, S., Alders, M., Zampino, G., Merla, G., Fradin, M., Bieth, E., Bonneau, D., Dieterich, K., Fergelot, P., Schaefer, E., Faivre, L., Vitobello, A., Maitz, S., Fischetto, R., Gervasini, C., Piccione, M., van de Laar, I., Tartaglia, M., Sadikovic, B., Lebre, A. -S., Martinez Rico, Clara, and Clinical Genetics
Subjects: Wiedemann–Steiner syndrome, QH301-705.5, Intellectual disability, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Catalysis, Inorganic Chemistry, KMT2A gene, Neurodevelopmental disorder, Growth Disorder, Abnormalities, Multiple, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Biology (General), Physical and Theoretical Chemistry, Episignature, QD1-999, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, Spectroscopy, DNA methylation, Organic Chemistry, Neurodevelopmental disorders, Craniofacial Abnormalitie, Epigenetic, Hypertrichosi, General Medicine, Facie, Computer Science Applications, Chemistry, epigenetics, episignature, intellectual disability, neurodevelopmental disorders, Phenotype, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Epigenetics, Human
Abstract: Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
Published: 2022

46. Leptin-Induced HLA-G Inhibits Myometrial Contraction and Differentiation

Author: Maeva Wendremaire, Tatiana E. Lopez, Marina Barrichon, Hang Zhang, Tarik Hadi, Xiang-Yang Ye, Fabrice Neiers, Marc Bardou, Paul Sagot, Carmen Garrido, Frédéric Lirussi, Julien, Sabine, 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), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hangzhou Normal University, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Centre d'Investigation Clinique 1432 (Dijon) - Module Plurithématique : Périnatalité Cancérologie Handicap et Ophtalmologie (CIC-P803), Université de Bourgogne (UB)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and The French Regional Council of Burgundy (Conseil Régional de Bourgogne, Grant AOI 2011 OBEDI).
Subjects: HLA-G Antigens, Leptin, myometrium, Infant, Newborn, General Medicine, differentiation, macrophage, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, leptin, labour, oxidative stress, Uterine Contraction, Tocolytic Agents, Pregnancy, Humans, Premature Birth, Female, Reactive Oxygen Species, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract: International audience; Maternal obesity is associated with a wide spectrum of labour disorders, including preterm birth. Leptin, a pro-inflammatory adipokine and a key factor of obesity, is suspected to play a major role in these disorders. OB-R, its receptor, is expressed on macrophages and myocytes, two cell types critical for labour onset. Macrophages secrete reactive oxygen species/pro-inflammatory cytokines, responsible for myometrial differentiation while myocytes control uterine contractions. In this study, we assessed the effect of leptin on myometrial contraction and differentiation using our validated co-culture model of human primary macrophages and myocytes. We demonstrated that leptin had a different effect on myocytes and macrophages depending on the dose. A low leptin concentration induced a tocolytic effect by preventing myocytes’ contraction, differentiation, and macrophage-induced ROS production. Additionally, leptin led to an increase in HLA-G expression, suggesting that the tocolytic effect of leptin may be driven by HLA-G, a tolerogenic molecule. Finally, we observed that recombinant HLA-G also prevented LPS-induced ROS production by macrophages. Altogether, these data provide a putative molecular mechanism by which leptin may induce immune tolerance and therefore interfere with labour-associated mechanisms. Therefore, HLA-G represents a potential innovative therapeutic target in the pharmacological management of preterm labour.
Published: 2022

47. Clinical outcomes after treatment with direct antiviral agents: beyond the virological response in patients with previous HCV-related decompensated cirrhosis

Author: Pageaux, G. (Georges-Philippe), Nzinga, C. (Clovis Lusivika), Ganne, N. (Nathalie), Samuel, D. (Didier), Dorival, C. (Céline), Zoulim, F. (Fabien), Cagnot, C. (Carole), Decaens, T. (Thomas), Thabut, D. (Dominique), Asselah, T. (Tarik), Mathurin, P. (Philippe), Habersetzer, F. (Francois), Bronowicki, J. (Jean-Pierre), Guyader, D. (Dominique), Rosa, I. (Isabelle), Leroy, V. (Vincent), Chazouilleres, O. (Olivier), de Ledinghen, V. (Victor), Bourliere, M. (Marc), Causse, X. (Xavier), Cales, P. (Paul), Metivier, S. (Sophie), Loustaud-Ratti, V. (Véronique), Riachi, G. (Ghassan), Alric, L. (Laurent), Gelu-Simeon, M. (Moana), Minello, A. (Anne), Gournay, J. (Jérôme), Geist, C. (Claire), Tran, A. (Albert), Abergel, A. (Armand), Portal, I. (Isabelle), d'Alteroche, L. (Louis), Raffi, F. (François), Fontaine, H. (Hélène), Carrat, F. (Fabrice), Pol, S. (Stanislas), Baumert, Thomas F., Doffoel, M. (Michel), Mutter, C. (Catherine), Simo-Noumbissie, P. (Pauline), Razi, E. (Esma), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génomique Fonctionnelle des Tumeurs Solides (U1162), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathogénèse et Traitement des Maladies du Foie, Hôpital Paul Brousse-Université Paris-Saclay, 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), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre 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 sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Physiopathologie des Maladies Inflammatoires de l'Intestin, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHI Créteil, Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Hôpital Saint-Joseph [Marseille], Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), CHU Toulouse [Toulouse], Ciblage individuel et prévention des risques de traitements immunosupresseurs et de la transplantation (IPPRITT), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Nutrition, Inflammation et axe Microbiote-Intestin-Cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), 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)-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), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie du système immunitaire (Inserm U1223), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), French ANRS CO22 Hepather Cohort: Delphine Bonnet, Virginie Payssan-Sicart, Chloe Pomes, François Bailly, Marjolaine Beaudoin, Dominique Giboz, Kerstin Hartig-Lavie, Marianne Maynard, Eric Billaud, David Boutoille, Morane Cavellec, Caroline Chevalier, Isabelle Hubert, Pierre Goepfert, Adrien Lannes, Françoise Lunel, Jérôme Boursier, Nathalie Boyer, Nathalie Giuily, Corinne Castelnau, Giovanna Scoazec, Aziza Chibah, Sylvie Keser, Karim Bonardi, Anaïs Vallet-Pichard, Philippe Sogni, Juliette Foucher, Jean-Baptiste Hiriart, Amandine Legendre, Faiza Chermak, Marie Irlès-Depé, Si Nafa Si Ahmed, Christelle Ansaldi, Nisserine Ben Amara, Valérie Oules, Jacqueline Dunette, Rodolphe Anty, Eve Gelsi, Régine Truchi, Elena Luckina, Nadia Messaoudi, Joseph Moussali, Barbara De Dieuleveult, Héloïse Goin, Damien Labarrière, Pascal Potier, Si Nafa Si Ahmed, Véronique Grando-Lemaire, Pierre Nahon, Séverine Brulé, Rym Monard, Caroline Jezequel, Audrey Brener, Anne Laligant, Aline Rabot, Isabelle Renard, Thomas F Baumert, Michel Dofföel, Catherine Mutter, Pauline Simo-Noumbissie, Esma Razi, Hélène Barraud, Mouni Bensenane, Abdelbasset Nani, Sarah Hassani-Nani, Marie-Albertine Bernard, Georges-Philippe Pageaux, Michael Bismuth, Ludovic Caillo, Stéphanie Faure, Marie Pierre Ripault, Christophe Bureau, Sarah Launay, Jean Marie Peron, Marie Angèle Robic, Léa Tarallo, Marine Faure, Bruno Froissart, Marie-Noelle Hilleret, Jean-Pierre Zarski, Odile Goria, Victorien Grard, Hélène Montialoux, Muriel François, Christian Ouedraogo, Christelle Pauleau, Anne Varault, Tony Andreani, Bénédicte Angoulevant, Azeline Chevance, Lawrence Serfaty, Teresa Antonini, Audrey Coilly, Jean-Charles Duclos Vallée, Mariagrazia Tateo, Corinne Bonny, Chanteranne Brigitte, Géraldine Lamblin, Léon Muti, Abdenour Babouri, Virginie Filipe, Camille Barrault, Laurent Costes, Hervé Hagège, Soraya Merbah, Paul Carrier, Maryline Debette-Gratien, Jérémie Jacques, Guillaume Lassailly, Florent Artu, Valérie Canva, Sébastien Dharancy, Alexandre Louvet, Marianne Latournerie, Marc Bardou, Thomas Mouillot, Yannick Bacq, Didier Barbereau, Charlotte Nicolas, Caroline Chevalier, Isabelle Archambeaud, Sarah Habes, Nisserine Ben Amara, Danièle Botta-Fridlund, Eric Saillard, Marie-Josée Lafrance, Carole Cagnot, Alpha Diallo, Lena Wadouachi, Ventzi Petrov-Sanchez, Douae Ammour, Loubna Ayour, Jaouad Benhida, Fabrice Carrat, Frederic Chau, Céline Dorival, Audrey Gilibert, Isabelle Goderel, Warda Hadi, Clovis Luzivika Nzinga, Grégory Pannetier, François Pinot, Odile Stahl, François Téloulé, Université de Rennes (UR)-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 Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), 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 ), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Jonchère, Laurent
Subjects: Liver Cirrhosis, medicine.medical_specialty, Carcinoma, Hepatocellular, Survival, Hepatocellular carcinoma, [SDV]Life Sciences [q-bio], Decompensated cirrhosis, Infectious and parasitic diseases, RC109-216, Hepacivirus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, complications, drug therapy, Gastroenterology, Antiviral Agents, Virological response, Internal medicine, Medicine, Humans, In patient, business.industry, Hepatitis C virus, Research, Liver Neoplasms, Hepatitis C, [SDV] Life Sciences [q-bio], Sustained virological response, Infectious Diseases, Direst-acting antiviral agents, therapeutic use, business, After treatment
Abstract: Background In HCV-infected patients with advanced liver disease, the direct antiviral agents-associated clinical benefits remain debated. We compared the clinical outcome of patients with a previous history of decompensated cirrhosis following treatment or not with direct antiviral agents from the French ANRS CO22 HEPATHER cohort. Methods We identified HCV patients who had experienced an episode of decompensated cirrhosis. Study outcomes were all-cause mortality, liver-related or non-liver-related deaths, hepatocellular carcinoma, liver transplantation. Secondary study outcomes were sustained virological response and its clinical benefits. Results 559 patients met the identification criteria, of which 483 received direct antiviral agents and 76 remained untreated after inclusion in the cohort. The median follow-up time was 39.7 (IQR: 22.7–51) months. After adjustment for multivariate analysis, exposure to direct antiviral agents was associated with a decrease in all-cause mortality (HR 0.45, 95% CI 0.24–0.84, p = 0.01) and non-liver-related death (HR 0.26, 95% CI 0.08–0.82, p = 0.02), and was not associated with liver-related death, decrease in hepatocellular carcinoma and need for liver transplantation. The sustained virological response was 88%. According to adjusted multivariable analysis, sustained virological response achievement was associated with a decrease in all-cause mortality (HR 0.29, 95% CI 0.15–0.54, p Conclusion Treatment with direct antiviral agents is associated with reduced risk for mortality. The sustained virological response was 88%. Thus, direct antiviral agents treatment should be considered for any patient with HCV-related decompensated cirrhosis. Trial registration: ClinicalTrials.gov registry number: NCT01953458.
Published: 2022

48. Cytoplasmic and Nuclear Functions of cIAP1

Author: Aymeric Zadoroznyj, Laurence Dubrez, Dubrez-Daloz, Laurence, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, and 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)
Subjects: Cell Nucleus, Cytoplasm, cell migration, NF-kappa B, Ubiquitination, [SDV.BBM.MN]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], Apoptosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Biochemistry, signaling pathways, NF-κB, Inhibitor of Apoptosis Proteins, IAPs, E2F1, [SDV.BBM.MN] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular Networks [q-bio.MN], [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], TNFα, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Molecular Biology, innate immunity, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Signal Transduction
Abstract: International audience; Cellular inhibitor of apoptosis 1 (cIAP1) is a cell signaling regulator of the IAP family. Through its E3-ubiquitine ligase activity, it has the ability to activate intracellular signaling pathways, modify signal transduction pathways by changing protein-protein interaction networks, and stop signal transduction by promoting the degradation of critical components of signaling pathways. Thus, cIAP1 appears to be a potent determinant of the response of cells, enabling their rapid adaptation to changing environmental conditions or intra- or extracellular stresses. It is expressed in almost all tissues, found in the cytoplasm, membrane and/or nucleus of cells. cIAP1 regulates innate immunity by controlling signaling pathways mediated by tumor necrosis factor receptor superfamily (TNFRs), some cytokine receptors and pattern recognition-receptors (PRRs). Although less documented, cIAP1 has also been involved in the regulation of cell migration and in the control of transcriptional programs.
Published: 2022

49. OncoSNIPE® Study Protocol, a study of molecular profiles associated with development of resistance in solid cancer patients

Author: Sébastien Vachenc, Jessica Gobbo, Sarah El Moujarrebe, Isabelle Desmoulins, Marine Gilabert, Michelle Beau-Faller, Emmanuel Mitry, Nicolas Girard, Aurélie Bertaut, Nelson Dusetti, Juan L. Iovanna, Rahima Yousfi, Fabien Pierrat, Roman Bruno, Adèle Cueff, Romain Boidot, Philippe Genne, Oncodesign [Dijon], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, 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), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Curie [Paris], 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), ACOBIOM, and Malbec, Odile
Subjects: Adult, Male, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Triple negative breast or Luminal Breast Cancer, Breast Neoplasms, Triple Negative Breast Neoplasms, Pancreatic ductal adenocarcinoma, Study Protocol, Immunological profile, Carcinoma, Non-Small-Cell Lung, Neoplasms, Biomarkers, Tumor, Genetics, Humans, RC254-282, Response Evaluation Criteria in Solid Tumors, Disease Resistance, Early/ late resistance marker, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Non small-cell lung cancer, Pancreatic Neoplasms, [SDV] Life Sciences [q-bio], Oncology, Drug Resistance, Neoplasm, NGS, Female, Carcinoma, Pancreatic Ductal
Abstract: Background Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment. Methods Multicentric, interventional study with the primary objective to identify early and / or late markers of resistance to treatment, in 600 adult patients with locally advanced or metastatic triple negative or Luminal B breast cancer, non-small-cell lung cancer or pancreatic ductal adenocarcinoma. Patients targeted in this study have all rapid progression of their pathology, making it possible to obtain models for evaluating markers of early and / or late responses over the 2-year period of follow-up, and thus provide the information necessary to understand resistance mechanisms. To explore the phenomena of resistance, during therapeutic response and / or progression of the pathology, we will use a multidisciplinary approach including high-throughput sequencing (Exome-seq and RNAseq), clinical data, medical images and immunological profile by ELISA. Patients will have long-term follow-up with different biological samples, at baseline (blood and biopsy) and at each tumoral evaluation or tumoral progression evaluated by medical imaging. Clinical data will be collected through a dedicated Case Report Form (CRF) and enriched by semantic extraction based on the French ConSoRe (Continuum Soins Recherche) initiative, a dedicated Semantic Clinical Data Warehouse (SCDW) to cancer. The study is sponsored by Oncodesign (Dijon, France) and is currently ongoing. Discussion The great diversity of intrinsic or acquired molecular mechanisms involved in resistance to treatment constitutes a real therapeutic issue. Improving understanding of mechanisms of resistance of cancer cells to anti-tumor treatments is therefore a major challenge. The OncoSNIPE cohort will lead to a better understanding of the mechanisms of resistance and will allow to explore new mechanisms of actions and to discover new therapeutic targets or strategies making it possible to circumvent the escape in different types of cancer. Trial registration Clinicaltrial.gov. Registered 16 September 2020, https://clinicaltrials.gov/ct2/show/NCT04548960?term=oncosnipe&draw=2&rank=1 and ANSM ID RCB 2017-A02018-45.
Published: 2022

50. Impact of Gender on the Characteristics of Patients with Idiopathic Pulmonary Fibrosis Included in the RaDiCo-ILD Cohort

Author: Sandrine Hirschi, Sonia Gueguen, M. Chevereau, Serge Amselem, Anne-Sophie Gamez, Martine Reynaud-Gaubert, Philippe Bonniaud, Dominique Israel-Biet, Annick Clement, I. Dufaure-Garé, Sylvain Marchand-Adam, Lidwine Wemeau-Stervinou, David Montani, Vincent Cottin, Jacques Cadranel, Hilario Nunes, Sébastien Quétant, Bruno Crestani, Stéphane Jouneau, Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], 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 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 Pontchaillou [Rennes], Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Thorax et Vaisseaux [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Strasbourg, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Lapeyronie [Montpellier] (CHU), CHU Trousseau [APHP], French National Research Agency under the 'cohorts' programme of the Investissements d'Avenir (Investments for the Future) French National Research Agency (ANR) [ANR-10-COHO-0003], ANR-10-COHO-0003,RADICO,Cohorte nationale maladies rares(2010), École pratique des hautes études (EPHE), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-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 )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Constitutif de Référence des Maladies Pulmonaires Rares [AP-HP Tenon], Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM)-Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM)-Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Tenon [AP-HP], UF de Génétique moléculaire [CHU Trousseau], Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Chard-Hutchinson, Xavier, and Cohortes - Cohorte nationale maladies rares - - RADICO2010 - ANR-10-COHO-0003 - COHO - VALID
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Vital capacity, Registry, [SDV]Life Sciences [q-bio], Idiopathic pulmonary fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Pulmonary function testing, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Internal medicine, medicine, Humans, 030212 general & internal medicine, Honeycombing, Idiopathic interstitial pneumonia, 10. No inequality, Emphysema, Patient characteristics, business.industry, Interstitial lung disease, Gender, respiratory system, medicine.disease, Confidence interval, 3. Good health, respiratory tract diseases, [SDV] Life Sciences [q-bio], 030228 respiratory system, Cohort, Quality of Life, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, France, business, Lung Diseases, Interstitial
Abstract: Background: There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes. Objectives: We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort – Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences. Methods: Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender. Results: The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George’s Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females. Conclusions: This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females.
Published: 2022

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