Author: "CIBER de Enfermedades Raras (CIBERER)" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"CIBER de Enfermedades Raras (CIBERER)"' showing total 550 results

Start Over Author "CIBER de Enfermedades Raras (CIBERER)"

550 results on '"CIBER de Enfermedades Raras (CIBERER)"'

1. Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Author: Daniel R. Barnes, Matti A. Rookus, Lesley McGuffog, Goska Leslie, Thea M. Mooij, Joe Dennis, Nasim Mavaddat, Julian Adlard, Munaza Ahmed, Kristiina Aittomäki, Nadine Andrieu, Irene L. Andrulis, Norbert Arnold, Banu K. Arun, Jacopo Azzollini, Judith Balmaña, Rosa B. Barkardottir, Daniel Barrowdale, Javier Benitez, Pascaline Berthet, Katarzyna Białkowska, Amie M. Blanco, Marinus J. Blok, Bernardo Bonanni, Susanne E. Boonen, Åke Borg, Aniko Bozsik, Angela R. Bradbury, Paul Brennan, Carole Brewer, Joan Brunet, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Lise Lotte Christensen, Wendy K. Chung, Kathleen B.M. Claes, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Antonis Antoniou, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D. Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-ren Ong, Lucy Side, Aoife O’Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Mary B. Daly, Miguel de la Hoya, Robin de Putter, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Cecilia M. Dorfling, Martine Dumont, Bent Ejlertsen, Christoph Engel, Lenka Foretova, Florentia Fostira, Michael Friedlander, Eitan Friedman, Patricia A. Ganz, Judy Garber, Andrea Gehrig, Anne-Marie Gerdes, Paul Gesta, Gord Glendon, Andrew K. Godwin, David E. Goldgar, Anna González-Neira, Mark H. Greene, Daphne Gschwantler-Kaulich, Eric Hahnen, Ute Hamann, Julia Hentschel, Frans B.L. Hogervorst, Maartje J. Hooning, Judit Horvath, Chunling Hu, Peter J. Hulick, Evgeny N. Imyanitov, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Catherine Noguès, Claudine Isaacs, Angel Izquierdo, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Esther M. John, Vijai Joseph, Beth Y. Karlan, Karin Kast, Torben A. Kruse, Ava Kwong, Yael Laitman, Conxi Lazaro, Jenny Lester, Fabienne Lesueur, Annelie Liljegren, Jennifer T. Loud, Jan Lubiński, Phuong L. Mai, Siranoush Manoukian, Hanne E.J. Meijers-Heijboer, Alfons Meindl, Arjen R. Mensenkamp, Austin Miller, Marco Montagna, Semanti Mukherjee, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Dieter Niederacher, Finn Cilius Nielsen, Liene Nikitina-Zake, Edith Olah, Olufunmilayo I. Olopade, Ana Osorio, Claus-Eric Ott, Laura Papi, Sue K. Park, Michael T. Parsons, Inge Sokilde Pedersen, Bernard Peissel, Ana Peixoto, Paolo Peterlongo, Georg Pfeiler, Karolina Prajzendanc, Miquel Angel Pujana, Paolo Radice, Juliane Ramser, Susan J. Ramus, Johanna Rantala, Gad Rennert, Harvey A. Risch, Mark Robson, Karina Rønlund, Ritu Salani, Leigha Senter, Payal D. Shah, Priyanka Sharma, Lucy E. Side, Christian F. Singer, Thomas P. Slavin, Penny Soucy, Melissa C. Southey, Amanda B. Spurdle, Doris Steinemann, Zoe Steinsnyder, Christian Sutter, Yen Yen Tan, Manuel R. Teixeira, Soo Hwang Teo, Darcy L. Thull, Silvia Tognazzo, Amanda E. Toland, Alison H. Trainer, Nadine Tung, Elizabeth J. van Rensburg, Ana Vega, Jeroen Vierstraete, Gabriel Wagner, Shan Wang-Gohrke, Barbara Wappenschmidt, Jeffrey N. Weitzel, Siddhartha Yadav, Xin Yang, Drakoulis Yannoukakos, Dario Zimbalatti, Kenneth Offit, Mads Thomassen, Fergus J. Couch, Rita K. Schmutzler, Jacques Simard, Douglas F. Easton, Antonis C. Antoniou, Pediatric surgery, Human genetics, CCA - Cancer biology and immunology, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), Apollo - University of Cambridge Repository, University of Cambridge [UK] (CAM), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Chapel Allerton Hospital, Great Ormond Street Hospital for Children [London] (GOSH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Mount Sinai Hospital [Toronto, Canada] (MSH), University of Toronto (University of Toronto), Christian-Albrechts University of Kiel, The University of Texas M.D. Anderson Cancer Center [Houston], Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Landspitali National University Hospital of Iceland, University of Iceland [Reykjavik], CIBER de Enfermedades Raras (CIBERER), Spanish National Cancer Research Center (CNIO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Pomeranian Medical University [Szczecin] (PUM), University of California (UC), Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], European Institute of Oncology IRCCS [Milan, Italy] (EIO), Zealand University Hospital [Roskilde, Denmark], Lund University [Lund], National Institute of Oncology [Budapest, Hungary], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Royal Devon & Exeter Hospital, Exeter, UK, Catalan Institute of Oncology [Barcelone, Espagne], Huntsman Cancer Institute [Salt Lake City], University of Utah, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Pisa University Hospital, Peter MacCallum Cancer Centre [Melbourne, Australie], University of Melbourne, Aarhus University Hospital, Columbia University [New York], Ghent University Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Sheffield Children's NHS Foundation Trust, Fox Chase Cancer Center, Queen Elizabeth University Hospital (Glasgow), Centre hospitalier universitaire de Nantes (CHU Nantes), Leiden University Medical Center (LUMC), Beckman Research Institute of the City of Hope, Abramson Cancer Center, University of Pretoria [South Africa], Centre Hospitalier Universitaire de Québec Research Center [Canada], Royal Marsden NHS Foundation Trust, Copenhagen University Hospital, Leipzig University, University of Manchester [Manchester], Manchester Academic Health Science Centre (MAHSC), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Masaryk Memorial Cancer Institute (MMCI), Institute of Nuclear and Radiological Sciences and Technology, Energy and Safety (INRASTES), National Center for Scientific Research 'Demokritos' (NCSR), NHMRC Clinical Trials Centre [Camperdown NSW 2050, Australie], Chaim Sheba Medical Center, Tel Aviv University (TAU), Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), Dana-Farber Cancer Institute [Boston], University of Würzburg, Rigshospitalet [Copenhagen], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Hospices Civils de Lyon (HCL), University of Kansas [Kansas City], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Medizinische Universität Wien = Medical University of Vienna, University of Cologne, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Lancashire NHS Foundation Trust, University Hospital Leipzig, Department of Medical Oncology, Family Cancer Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Mayo Clinic, NorthShore University HealthSystem [Evanston, IL, USA], The University of Chicago Medicine [Chicago], N. N. Petrov Institute of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Guy's and St Thomas' NHS Foundation Trust [London, UK], Peter MacCallum Cancer Center, East Melbourne, Peter MacCallum Cancer Center, Vilnius University [Vilnius], The State Scientific Research Institute Nature Research Centre, Vilnius, Lithuania, Stanford University School of Medicine [CA, USA], Memorial Sloane Kettering Cancer Center [New York], Cedars-Sinai Medical Center, Technische Universität Dresden = Dresden University of Technology (TU Dresden), University Medical Center [Utrecht], Odense University Hospital [Odense, Denmark], The Hong Kong Hereditary Breast Cancer Family Registry, The University of Hong Kong (HKU), Hong Kong Sanatorium and Hospital [Hong Kong] (HKSH), Equipe de prévention et épidémiologie génétique, Centre Léon Bérard [Lyon], 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), David Geffen School of Medicine [Los Angeles], Fondation MINES ParisTech, Karolinska Institutet [Stockholm], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Amsterdam UMC - Amsterdam University Medical Center, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Radboud University Medical Center [Nijmegen], Roswell Park Cancer Institute [Buffalo], Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], University of Toronto, University Health Network, University Hospital Düsseldorf, Latvian Biomedical Research and Study Centre [Rīga], 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 Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), University of Chicago, Birmingham Women's and Children's NHS Foundation Trust, Cambridge University Hospitals - NHS (CUH), Charité Campus Virchow-Klinikum (CVK), Università degli Studi di Firenze = University of Florence (UniFI), Seoul National University College of Medicine [Séoul, Corée du Sud] (SNUCM), Seoul National University [Seoul] (SNU), QIMR Berghofer Medical Research Institute, Aalborg University [Denmark] (AAU), IRCCS Istituto Nazionale dei Tumori [Milano], Instituto Português de Oncologia do Porto / Portuguese Oncology Institute of Porto (IPO Porto), IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Klinikum rechts der Isar [Munich, Germany], University of New South Wales [Sydney] (UNSW), Garvan Institute of medical research, Technion Faculty of Medicine [Haifa, Israel], Yale School of Medicine [New Haven, Connecticut] (YSM), Vejle Hospital [Danemark], Ohio State University [Columbus] (OSU), Centre de lutte contre le cancer Paul-Strauss, Institut de Cancérologie de Strasbourg Europe (ICANS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Kansas Medical Center [Kansas City, KS, USA], Princess Anne Hospital, City of Hope Comprehensive Cancer Center [Duarte], Monash University [Clayton], Cancer Council Victoria [Melbourne, VIC, Australia], Hannover Medical School [Hannover] (MHH), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Heidelberg University Hospital [Heidelberg], Institute of Biomedical Sciences Abel Salazar - ICBAS [Porto, Portugal], Malaysia and University Malaya Cancer Research Institute, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), McGill University = Université McGill [Montréal, Canada], Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), Instituto de Investigaciones Sanitarias, Universidade de Santiago de Compostela [Spain] (USC ), Universiteit Gent = Ghent University (UGENT), Oxford University Hospitals NHS Trust, University of Oxford, Universitätsklinikum Ulm - University Hospital of Ulm, University Hospital of Cologne [Cologne], Mayo Clinic [Rochester], Collaborators : Pascaline Berthet, Chrystelle Colas, Marie-Agnès Collonge-Rame, Capucine Delnatte, Laurence Faivre, Sophie Giraud, Christine Lasset, Véronique Mari, Noura Mebirouk, Emmanuelle Mouret-Fourme, Hélène Schuster, Dominique Stoppa-Lyonnet, Julian Adlard, Munaza Ahmed, Antonis Antoniou, Daniel Barrowdale, Paul Brennan, Carole Brewer, Jackie Cook, Rosemarie Davidson, Douglas Easton, Ros Eeles, D Gareth Evans, Debra Frost, Helen Hanson, Louise Izatt, Kai-Ren Ong, Lucy Side, Aoife O'Shaughnessy-Kirwan, Marc Tischkowitz, Lisa Walker, Georgia Chenevix-Trench, Kelly-Anne Phillips, Amanda Spurdle, Marinus Blok, Peter Devilee, Frans Hogervorst, Maartje Hooning, Marco Koudijs, Arjen Mensenkamp, Hanne Meijers-Heijboer, Matti Rookus, Klaartje van Engelen, Nadine Andrieu, Catherine Noguès, Dupuis, Christine, Institut Català de la Salut, [Barnes DR, McGuffog L, Leslie G, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Rookus MA, Mooij TM] The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands. [Balmaña J] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Barnes, Daniel [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI), Medical Oncology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, University of Helsinki, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Pomeranian Medical University, University of California, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], University of Leipzig [Leipzig, Allemagne], Masaryk Memorial Cancer Institute (RECAMO), Tel Aviv University [Tel Aviv], University of California-University of California, University of Münster, Amsterdam UMC, Technical University of Munich (TUM), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Garvan Institute of Medical Research [Sydney, Australia], Yale University School of Medicine, Vejle Hospital, University of Kansas Medical Center [Lawrence], Université Paris Descartes (Paris 5), University of Malaya [Kuala Lumpur, Malaisie], Universiteit Gent = Ghent University [Belgium] (UGENT), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Oncology, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], [SDV]Life Sciences [q-bio], Càncer d'ovari, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], MODIFIERS, Diàtesi, SUSCEPTIBILITY, Carcinoma, Ovarian Epithelial, PRS, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Medicine and Health Sciences, Medicine, Genetics(clinical), genetics, Prospective Studies, Prospective cohort study, skin and connective tissue diseases, Genetics (clinical), Ovarian Neoplasms, education.field_of_study, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], BRCA1 Protein, Hazard ratio, Absolute risk reduction, 1184 Genetics, developmental biology, physiology, article, ASSOCIATION, neoplasias::neoplasias::neoplasias por localización::neoplasias de las glándulas endocrinas::neoplasias ováricas::carcinoma epitelial de ovario [ENFERMEDADES], ddc, 3. Good health, [SDV] Life Sciences [q-bio], ovarian cancer, 030220 oncology & carcinogenesis, Female, Cohort study, medicine.medical_specialty, Heterozygote, Population, 3122 Cancers, Single-nucleotide polymorphism, Breast Neoplasms, MUTATION CARRIERS, Ovaris - Càncer - Aspectes genètics, Càncer de mama, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, Ovarian cancer, BRCA1/2, Internal medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], BRCA2 Protein, IDENTIFICATION, business.industry, Neoplasms::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms::Carcinoma, Ovarian Epithelial [DISEASES], Retrospective cohort study, ALLELES, medicine.disease, BRCA1, BRCA2, MODEL, PATHOLOGY, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, 3111 Biomedicine, business
Abstract: Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
Published: 2020

2. In utero and childhood exposure to tobacco smoke and multi-layer molecular signatures in children

Author: Sandra Andrusaityte, Léa Maitre, Eva Borràs, Martine Vrijheid, Carlos Ruiz-Arenas, Kristine B. Gutzkow, Maribel Casas, Mariona Bustamante, Marta Vives-Usano, Chung-Ho E Lau, Carles Hernandez-Ferrer, Juan R. González, Leda Chatzi, Xavier Estivill, Rémy Slama, Inés Quintela, Regina Grazuleviciene, Oliver Robinson, Marina Vafeiadi, Angel Carracedo, Solène Cadiou, Muireann Coen, Eduard Sabidó, Johanna Lepeule, Alexandros P. Siskos, Gillian Santorelli, Dan Mason, Per E. Schwarze, Eulàlia Martí, Hector C. Keun, Medical Research Council (MRC), Commission of the European Communities, BARBAGALLO, Maïlys, Advancing Tools for Human Early Lifecourse Exposome Research and Translation - ATHLETE - - H20202020-01-01 - 2024-12-31 - 874583 - VALID, Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona Institute of Science and Technology (BIST), Vytautas Magnus University - Vytauto Didziojo Universitetas (VDU), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), CIBER de Enfermedades Raras (CIBERER), University of Southern California (USC), AstraZeneca [Cambridge, UK], Imperial College London, L’Hospitalet de Llobregat [Barcelona, Spain], Norwegian Institute of Public Health [Oslo] (NIPH), 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), Bradford Institute for Health Research [Bradford, UK], Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), Universidade de Santiago de Compostela [Spain] (USC ), University of Crete [Heraklion] (UOC), Universitat de Barcelona (UB), European Project: 874583,H2020,H2020-EU.3.1.2.,ATHLETE(2020), and Bradford Institute for Health Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK (BIHR)
Subjects: Male, [SDV]Life Sciences [q-bio], ADN, Physiology, lcsh:Medicine, Tobacco smoke, 0302 clinical medicine, Secondhand smoke, Pregnancy, Gene expression, Medicine, 030212 general & internal medicine, Child, Children, 11 Medical and Health Sciences, DNA methylation, General Medicine, Methylation, Molecular phenotypes, Tobacco smoking, 3. Good health, [SDV] Life Sciences [q-bio], In utero, Child, Preschool, Prenatal Exposure Delayed Effects, Female, Hàbit de fumar en l'embaràs, Transcription, Research Article, Exposome, Adolescent, Omics, 03 medical and health sciences, General & Internal Medicine, Humans, Metabolomics, Gene, miRNA, business.industry, lcsh:R, Infant, Newborn, Infant, DNA, medicine.disease, [SDE.ES]Environmental Sciences/Environmental and Society, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Tobacco Smoke Pollution, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDE.ES] Environmental Sciences/Environmental and Society, Smoking in pregnancy, business, 030217 neurology & neurosurgery, Biomarkers
Abstract: Background: The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. Methods: We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. Results: Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. Conclusion: In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis. The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007-206) under grant agreement no. 308333 (the HELIX project); and the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (the ATHLETE project). BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The RHEA project was financially supported by European projects and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN (MTM2015-68140-R) and Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech), and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I+D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.
Published: 2020

3. Evolution of tyrosinemia type 1 disease in patients treated with nitisinone in Spain

Author: Luis Aldámiz-Echevarría, Paula Sánchez-Pintos, Elena Martín-Hernández, María A. Bueno, Carmen Díaz-Fernández, Victor Navas, Camila García-Volpe, Isidro Vitoria, Luis Peña-Quintana, Felix Sánchez-Valverde, Iria Roca, Guillem Pintos, Encarna López-Ruzafa, María L. Couce, David Gil, Tomás Hernández, [Couce ML, Sánchez-Pintos P] Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, S. Neonatology, Department of Pediatrics, Clínico Universitario de Santiago de Compostela, Spain. CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain. [Aldámiz-Echevarría L] Unit of Metabolism, Department of Pediatrics, Hospital de Cruces, Baracaldo, Spain. Group of Metabolism, Biocruces Health Research Institute, Baracaldo, Spain. CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. [Vitoria I] Unit of Metabolopathies, Hospital Universitario La Fe, Valencia, Spain. [Navas V] Pediatric Gastroenterology and Nutrition Unit Hospital Carlos Haya, Málaga, Spain. [Martín-Hernández E] Unit of Mitochondrial and Congenital Metabolic Diseases, Hospital 12 de Octubre, Madrid, Spain. [Pintos G] Unitat de Malalties Minoritàries, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Pediatrics, Delayed Diagnosis, Tiroide - Malalties, Nitisinone, Ciclohexà, therapeutic use, Disease, 0302 clinical medicine, heterocyclic compounds, 030212 general & internal medicine, Enzyme Inhibitors, Child, enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::alteraciones congénitas del metabolismo::enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::alteraciones congénitas del metabolismo::enfermedades cerebrales metabólicas congénitas::tirosinemias [ENFERMEDADES], ambiente y salud pública::salud pública::medidas epidemiológicas::demografía::estado de salud::calidad de vida [ATENCIÓN DE SALUD], Tyrosinemias, musculoskeletal, neural, and ocular physiology, Follow up studies, General Medicine, musculoskeletal system, Prognosis, Hereditary tyrosinemia, tubulopathy, Qualitat de vida, 030220 oncology & carcinogenesis, cardiovascular system, Female, Kidney Diseases, Needs Assessment, Research Article, medicine.drug, Adult, medicine.medical_specialty, phenotype, Time to treatment, Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Alicyclic::Cycloparaffins::Cyclohexanes::Cyclohexanones [CHEMICALS AND DRUGS], Observational Study, severe liver dysfunction, Time-to-Treatment, Tyrosinemia, 03 medical and health sciences, Neonatal Screening, nephrocalcinosis, medicine, Humans, In patient, Cognitive Dysfunction, Obesity, Retrospective Studies, uso terapéutico, business.industry, Cyclohexanones, Infant, Newborn, Retrospective cohort study, complicaciones, medicine.disease, Environment and Public Health::Public Health::Epidemiologic Measurements::Demography::Health Status::Quality of Life [HEALTH CARE], complications, Spain, Nitrobenzoates, Quality of Life, Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Metabolism, Inborn Errors::Amino Acid Metabolism, Inborn Errors::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Metabolism, Inborn Errors::Tyrosinemias [DISEASES], business, tyrosine, compuestos orgánicos::hidrocarburos::hidrocarburos cíclicos::hidrocarburos alicíclicos::cicloparafinas::ciclohexanos::ciclohexanonas [COMPUESTOS QUÍMICOS Y DROGAS], Follow-Up Studies
Abstract: Nephrocalcinosis; Phenotype; Severe liver dysfunction Nefrocalcinosis; Fenotipo; Disfunción hepática grave Nefrocalcinosi; Fenotip; Disfunció hepàtica greu Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 ± 4.9 and 10.6 ± 5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P < .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma.Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 ± 4.43 vs 24.30 ± 6.10; P = .08) and those with good pharmacological adherence (21.19 ± 4.68 vs 28.58 ± 213.79).intellectual quotient was ≥85 in all NBS- and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure.Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554-1 G>T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.
Published: 2019

4. BRCA1 Circos: a visualisation resource for functional analysis of missense variants

Author: Jhuraney, A., Velkova, A., Johnson, R.C., Kessing, B., Carvalho, R.S., Whiley, P., Spurdle, A.B., Vreeswijk, M.P.G., Caputo, S.M., Millot, G.A., Vega, A., Coquelle, N., Galli, A., Eccles, D., Blok, M.J., Pal, T., Luijt, R.B. van der, Pena, M.S., Neuhausen, S.L., Donenberg, T., Machackova, E., Thomas, S., Vallee, M., Couch, F.J., Tavtigian, S.V., Glover, J.N.M., Carvalho, M.A., Brody, L.C., Sharan, S.K., Monteiro, A.N., ENIGMA Evidence-Based Network, University of South Florida [Tampa] (USF), H. Lee Moffitt Cancer Center and Research Institute, National Human Genome Research Institute (NHGRI), Frederick National Laboratory for Cancer Research (FNLCR), Instituto Nacional de Câncer [Rio de Janeiro, Brésil], Instituto Federal de Educação, Ciência e Tecnologia de São Paulo (IFSP), QIMR Berghofer Medical Research Institute, Leiden University Medical Center (LUMC), Institut Curie [Paris], Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), University of Alberta, Instituto di fisiologia clinica, University of Southampton, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University Medical Center [Utrecht], CIBER de Enfermedades Raras (CIBERER), Beckman Research Institute of the City of Hope, University of Miami Leonard M. Miller School of Medicine (UMMSM), Masaryk Memorial Cancer Institute (RECAMO), Salisbury District Hospital, International Agency for Cancer Research (IACR), Mayo Clinic [Rochester], University of Utah School of Medicine [Salt Lake City], National Cancer Institute Frederick, This work was funded by H. Lee Moffitt Cancer Center Foundation (Milesfor Moffitt), and the US National Cancer Institute. The ENIGMA consortium is funded by a supplement to NIH RO1 award CA116167, The authors would like to sincerely thank Tyra Wolfsberg and Suiyuan Zhang for helping with webpage development and all individuals and families who have generously donated their time, samples and information to facilitate research on the predisposition factors of breast and ovarian cancer, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - Oncology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Targeted Gynaecologic Oncology (TARGON)
Subjects: [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Datasets as Topic, LIGASE ACTIVITY, MUTATION-POSITIVE FAMILIES, Databases, Genetic, SEQUENCE VARIANTS, Missense mutation, Genetics(clinical), MESH: Datasets as Topic, Molecular genetics, MESH: DNA Mutational Analysis, Non-U.S. Gov't, skin and connective tissue diseases, Genetics (clinical), MESH: Databases, Genetic, Ovarian Neoplasms, Genetics, education.field_of_study, medicine.diagnostic_test, MESH: Genetic Testing, BRCA1 Protein, Research Support, Non-U.S. Gov't, UNKNOWN CLINICAL-SIGNIFICANCE, MESH: Genetic Predisposition to Disease, BREAST-CANCER RISK, RING-DOMAIN, 3. Good health, MESH: Ovarian Neoplasms, MESH: Internet, UNCERTAIN SIGNIFICANCE, Medical genetics, Female, MESH: Computer Graphics, MESH: Computational Biology, medicine.medical_specialty, Population, Mutation, Missense, Breast Neoplasms, Biology, Research Support, OVARIAN-CANCER, N.I.H, MESH: Software, Germline mutation, Research Support, N.I.H., Extramural, GENETIC-ANALYSIS, Journal Article, Cancer Genetics, Computer Graphics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Ligase activity, Clinical genetics, NEGATIVE WOMEN, education, Genetic testing, MESH: BRCA1 Protein, Internet, MESH: Mutation, Missense, MESH: Humans, Cancer: breast, Extramural, Computational Biology, BRCA1, Database Management Systems, MESH: Female, Software, MESH: Breast Neoplasms, MESH: Database Management Systems
Abstract: BACKGROUND: Inactivating germline mutations in the tumour suppressor gene BRCA1 are associated with a significantly increased risk of developing breast and ovarian cancer. A large number (>1500) of unique BRCA1 variants have been identified in the population and can be classified as pathogenic, non-pathogenic or as variants of unknown significance (VUS). Many VUS are rare missense variants leading to single amino acid changes. Their impact on protein function cannot be directly inferred from sequence information, precluding assessment of their pathogenicity. Thus, functional assays are critical to assess the impact of these VUS on protein activity. BRCA1 is a multifunctional protein and different assays have been used to assess the impact of variants on different biochemical activities and biological processes.METHODS AND RESULTS: To facilitate VUS analysis, we have developed a visualisation resource that compiles and displays functional data on all documented BRCA1 missense variants. BRCA1 Circos is a web-based visualisation tool based on the freely available Circos software package. The BRCA1 Circos web tool (http://research.nhgri.nih.gov/bic/circos/) aggregates data from all published BRCA1 missense variants for functional studies, harmonises their results and presents various functionalities to search and interpret individual-level functional information for each BRCA1 missense variant.CONCLUSIONS: This research visualisation tool will serve as a quick one-stop publically available reference for all the BRCA1 missense variants that have been functionally assessed. It will facilitate meta-analysis of functional data and improve assessment of pathogenicity of VUS.
Published: 2015

5. Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome

Author: Michael Schön, Pablo Lapunzina, Julián Nevado, Teresa Mattina, Cecilia Gunnarsson, Kinga Hadzsiev, Chiara Verpelli, Thomas Bourgeron, Sarah Jesse, Conny M.A. van Ravenswaaij-Arts, Raoul C. Hennekam, General Paediatrics, APH - Quality of Care, Universität Ulm - Ulm University [Ulm, Allemagne], Hospital Universitario La Paz, CIBER de Enfermedades Raras (CIBERER), University of Catania [Italy], Linköping University (LIU), University of Pecs, Istituto di Neuroscienze - Institute of Neuroscience [Milan, Italy] (CNR), Università degli Studi di Milano = University of Milan (UNIMI)-Consiglio Nazionale delle Ricerche [Milano] (CNR), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Groningen [Groningen], VU University Medical Center [Amsterdam], This study has been supported by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) represented by Klea Vyshka. Funding was also obtained from the European Union’s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP N° 825575., and This publication has been supported by the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA). ERN-ITHACA is partly co-funded by the Health Program of the European Union. We thank for the comprehensive help of Klea Vyshka from ERN-ITHACA. We thank the American guideline consortium for discussions and support.
Subjects: Genotype-phenotype correlation, 22q13 deletion syndrome, Clinical trials, SHANK3, Genetics, Natural history, Phelan-McDermid syndrome, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], PMS, General Medicine, Genetics (clinical)
Abstract: International audience; Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2–33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.
Published: 2023

6. Large scale genomic reorganization of topological domains at the HoxD locus

Author: Daan Noordermeer, Pierre J. Fabre, Lucille Lopez-Delisle, Benjamin H. Mormann, Leonardo Beccari, Marion Leleu, Denis Duboule, School of Life Sciences [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Dynamique de la Chromatine (CHRODY), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Neurobiologia Molecular Celular y del desarrollo, Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autonoma de Madrid (UAM)-CIBER de Enfermedades Raras (CIBERER), Chaire internationale Évolution des génomes et développement, Collège de France (CdF (institution)), Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Consejo Superior de Investigaciones Científicas [Spain] (CSIC)-Centro de Biologia Molecular Severo Ochoa (CBMSO)-CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), and Collège de France - Chaire internationale Évolution des génomes et développement
Subjects: 0301 basic medicine, Chromatin Immunoprecipitation, Genomic Islands, Transcription, Genetic, lcsh:QH426-470, [SDV]Life Sciences [q-bio], Locus (genetics), Regulatory Sequences, Nucleic Acid, Biology, Topology, Chromosome conformation capture, Mice, 03 medical and health sciences, Chromatin organization, Animals, Hox gene, Enhancer, lcsh:QH301-705.5, In Situ Hybridization, Fluorescence, Limb development, Gene Rearrangement, Topologically associating domains, Research, Genes, Homeobox, High-Throughput Nucleotide Sequencing, Genomics, TAD, Gene rearrangement, CTCF, Hox, Gene regulation, Chromatin, lcsh:Genetics, Enhancer Elements, Genetic, 030104 developmental biology, lcsh:Biology (General), Genetic Loci, Multigene Family, Chromatin immunoprecipitation, Regulatory landscape
Abstract: Background The transcriptional activation of HoxD genes during mammalian limb development involves dynamic interactions with two topologically associating domains (TADs) flanking the HoxD cluster. In particular, the activation of the most posterior HoxD genes in developing digits is controlled by regulatory elements located in the centromeric TAD (C-DOM) through long-range contacts. Results To assess the structure–function relationships underlying such interactions, we measured compaction levels and TAD discreteness using a combination of chromosome conformation capture (4C-seq) and DNA FISH. We assessed the robustness of the TAD architecture by using a series of genomic deletions and inversions that impact the integrity of this chromatin domain and that remodel long-range contacts. We report multi-partite associations between HoxD genes and up to three enhancers. We find that the loss of native chromatin topology leads to the remodeling of TAD structure following distinct parameters. Conclusions Our results reveal that the recomposition of TAD architectures after large genomic re-arrangements is dependent on a boundary-selection mechanism in which CTCF mediates the gating of long-range contacts in combination with genomic distance and sequence specificity. Accordingly, the building of a recomposed TAD at this locus depends on distinct functional and constitutive parameters. Electronic supplementary material The online version of this article (doi:10.1186/s13059-017-1278-z) contains supplementary material, which is available to authorized users.
Published: 2017
Full Text: View/download PDF

7. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author: Lim, Elaine T., Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S., Zhang, Xiaochang, D'Gama, Alissa M., Kim, Sonia N., Hill, Robert Sean, Goldberg, Arthur P., Poultney, Christopher, Minshew, Nancy J., Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J., Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M., Weiss, Lauren A., Fromer, Menachem, Chiocchetti, Andreas G., Freitag, Christine M., Church, George M., Scherer, Stephen W., Buxbaum, Joseph D., Walsh, Christopher A, Aleksic, B, Anney, R, Barbosa, M, Barrett, J, Betancur, C, Bishop, S, Brusco, A, Buxbaum, Jd, Carracedo, A, Chiocchetti, Ag, Chung, Bhy, Cook, E, Coon, H, Cutler, Dj, Daly, M, De Rubeis, S, Doan, R, Fernández-Prieto, M, Ferrero, Gb, Freitag, Cm, Fromer, M, Gargus, J, Geschwind, D, Gill, M, Gómez-Guerrero, L, Hansen-Kiss, E, He, X, Herman, G, Hertz-Picciotto, I, Hultman, C, Iliadou, B, Ionita-Laza, I, Jugessur, A, Knudsen, Gp, Kolevzon, A, Kosmicki, J, Kushima, I, Lee, Sl, Lehner, T, Lennertz, S, Lim, E, Maciel, P, Magnus, P, Manoach, D, Minshew, N, Morrow, E, Mulle, J, Neale, B, Ozaki, N, Palotie, A, Parellada, M, Passos-Bueno, Mr, Pericak-Vance, M, Persico, A, Pessah, I, Reichenberg, A, Reichert, J, Renieri, A, Robinson, E, Samocha, K, Sanders, S, Sandin, S, Santangelo, Sl, Satterstrom, K, Schafer, C, Schellenberg, G, Scherer, S, Senthil, G, Silva, M, Singh, T, Siper, Pm, Soares, G, Stevens, C, Stoltenberg, C, Surén, P, Sutcliffe, Js, Szatmari, P, Tassone, F, Thurm, A, Walsh, C, Weiss, L, Werling, D, Willsey, J, Xu, X, Yu, Tw, Yuen, R, Zwick, Me., Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard University [Cambridge], Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Nagoya University, Hospital General Universitario 'Gregorio Marañón' [Madrid], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Universidade de Santiago de Compostela [Spain] (USC ), CIBER de Enfermedades Raras (CIBERER), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), King Abdulaziz University, Karolinska Institutet [Stockholm], University of California [San Francisco] (UCSF), University of California, Goethe-University Frankfurt am Main, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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 Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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), The Hospital for sick children [Toronto] (SickKids), University of Toronto, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Autism Sequencing Consortium: Branko Aleksic, Richard Anney, Mafalda Barbosa, Jeffrey Barrett, Catalina Betancur, Somer Bishop, Alfredo Brusco, Joseph D Buxbaum, Angel Carracedo, Andreas G Chiocchetti, Brian H Y Chung, Edwin Cook, Hilary Coon, David J Cutler, Mark Daly, Silvia De Rubeis, Ryan Doan, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M Freitag, Menachem Fromer, Jay Gargus, Dan Geschwind, Michael Gill, Lorena Gómez-Guerrero, Emily Hansen-Kiss, Xin He, Gail Herman, Irva Hertz-Picciotto, Christina Hultman, Bozenna Iliadou, Iuliana Ionita-Laza, Anil Jugessur, Gun Peggy Knudsen, Alexander Kolevzon, Jack Kosmicki, Itaru Kushima, S L Lee, Thomas Lehner, Savannah Lennertz, Elaine Lim, Patricia Maciel, Per Magnus, Dara Manoach, Nancy Minshew, Eric Morrow, Jennifer Mulle, Benjamin Neale, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio Persico, Isaac Pessah, Avi Reichenberg, Jennifer Reichert, Alessandra Renieri, Elise Robinson, Kaitlin Samocha, Stephan Sanders, Sven Sandin, Susan L Santangelo, Kyle Satterstrom, Chad Schafer, Gerry Schellenberg, Stephen Scherer, Geetha Senthil, Marisol Silva, Tarjinder Singh, Paige M Siper, Gabriela Soares, Christine Stevens, Camilla Stoltenberg, Pål Surén, James S Sutcliffe, Peter Szatmari, Flora Tassone, Audrey Thurm, Christopher Walsh, Lauren Weiss, Donna Werling, Jeremy Willsey, Xinyi Xu, Timothy W Yu, Ryan Yuen, Michael E Zwick., University of California [San Francisco] (UC San Francisco), University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Betancur, Catalina
Subjects: 0301 basic medicine, Proband, Nonsynonymous substitution, Autism Spectrum Disorder, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Humans, Mosaicism, Mutation, Missense, Zygote, Neuroscience (all), Mutation, Missense, Epigenetics of autism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, Article, 03 medical and health sciences, Genetic variation, mental disorders, Databases, Genetic, medicine, Missense mutation, Heritability of autism, MESH: Genetic Variation, MESH: Databases, Genetic, Genetics, MESH: Autism Spectrum Disorder, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, General Neuroscience, MESH: Genetic Predisposition to Disease, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, MESH: Zygote, MESH: Mosaicism
Abstract: International audience; We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.
Published: 2017

8. Diagnostic workup of childhood interstitial lung disease

Author: Nathan, Nadia, Griese, Matthias, Michel, Katarzyna, Carlens, Julia, Gilbert, Carlee, Emiralioglu, Nagehan, Torrent-Vernetta, Alba, Marczak, Honorata, Willemse, Brigitte, Delestrain, Céline, Epaud, Ralph, Universitat Autònoma de Barcelona, Institut Català de la Salut, [Nathan N] AP-HP, Sorbonne Université, Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Armand Trousseau Hospital, Paris, France. Sorbonne Université, Inserm Laboratory of Childhood Genetic Diseases, Armand Trousseau Hospital, Paris, France. [Griese M, Michel K] Department of Paediatric Pneumology, Dr von Hauner Children’s Hospital, German Centre for Lung Research, University of Munich, Munich, Germany. [Carlens J] Clinic for Pediatric Pneumology, Hannover Medical School, Hannover, Germany. [Gilbert C] Institute of Population Health, University of Liverpool, Liverpool, UK. [Emiralioglu N] Department of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, Ankara, Turkey. [Torrent-Vernetta A] Unitat de Pneumologia Pediàtrica i Fibrosi Quística, Servei de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, Vall d'Hebron Barcelona Hospital Campus, Service de Pneumologie pédiatrique [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), Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [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], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Dr von Hauner Children's Hospital [Munich, Germany], Ludwig-Maximilians-Universität München (LMU), Hannover Medical School [Hannover] (MHH), University of Liverpool, Hacettepe University = Hacettepe Üniversitesi, Faculty of Medicine [Hacettepe University], Universitat Autònoma de Barcelona (UAB), CIBER de Enfermedades Raras (CIBERER), Medical University of Warsaw - Poland, University of Groningen [Groningen], Centre Hospitalier Intercommunal de Créteil (CHIC), 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), and Couvet, Sandrine
Subjects: Pulmonary and Respiratory Medicine, Rentada broncoalveolar, técnicas de investigación::irrigación terapéutica::lavado broncoalveolar [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Respiratory Tract Diseases::Lung Diseases::Lung Diseases, Interstitial [DISEASES], diagnóstico::técnicas y procedimientos diagnósticos::diagnóstico por imagen [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Otros calificadores::/diagnóstico [Otros calificadores], Investigative Techniques::Therapeutic Irrigation::Bronchoalveolar Lavage [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Persons::Age Groups::Child [NAMED GROUPS], [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Imaging [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], enfermedades respiratorias::enfermedades pulmonares::enfermedades pulmonares intersticiales [ENFERMEDADES], Pulmons - Càncer - Diagnòstic, Other subheadings::/diagnosis [Other subheadings], [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Infants, Imatgeria per al diagnòstic
Abstract: Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of "undefined chILD" is stressed. Childhood interstitial lung diseases are rare and severe diseases. A stepwise approach to an aetiological diagnosis includes specific investigations performed in expert centres. The term "undefined chILD" must be regularly reassessed
Published: 2023

9. First evidence of <scp> SOX2 </scp> mutations in Peters' anomaly: Lessons from molecular screening of 95 patients

Author: Bertrand Chesneau, Marion Aubert‐Mucca, Félix Fremont, Jacmine Pechmeja, Vincent Soler, Bertrand Isidor, Mathilde Nizon, Hélène Dollfus, Josseline Kaplan, Lucas Fares‐Taie, Jean‐Michel Rozet, Tiffany Busa, Didier Lacombe, Sophie Naudion, Jeanne Amiel, Marlène Rio, Tania Attie‐Bitach, Cécile Lesage, Dominique Thouvenin, Sylvie Odent, Godelieve Morel, Catherine Vincent‐Delorme, Odile Boute, Clémence Vanlerberghe, Anne Dieux, Simon Boussion, Laurence Faivre, Lucile Pinson, Fanny Laffargue, Gwenaël Le Guyader, Guylène Le Meur, Fabienne Prieur, Victor Lambert, Beatrice Laudier, Edouard Cottereau, Carmen Ayuso, Marta Corton‐Pérez, Laurence Bouneau, Cédric Le Caignec, Véronique Gaston, Claire Jeanton‐Scaramouche, Delphine Dupin‐Deguine, Patrick Calvas, Nicolas Chassaing, Julie Plaisancié, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut des Jeunes Aveugles [Toulouse] (IJA), Clinique rive gauche, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Lille, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional d'Orléans (CHRO), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CIBER de Enfermedades Raras (CIBERER), Universidad Autónoma de Madrid (UAM), Toulouse Neuro Imaging Center (ToNIC), 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)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), French National Research AgencyFrench National Research Agency (ANR) [ANR-10-COHO-0003], and ANR-10-COHO-0003,RADICO,Cohorte nationale maladies rares(2010)
Subjects: Comparative Genomic Hybridization, [SDV.GEN]Life Sciences [q-bio]/Genetics, DNA Copy Number Variations, SOXB1 Transcription Factors, Peters' anomaly, [SDV]Life Sciences [q-bio], CNV, SOX2, eye diseases, PAX6, Corneal Opacity, microphthalmia, Anterior Eye Segment, Mutation, B3GLCT, Genetics, Humans, anterior segment dysgenesis, FOXE3, Eye Abnormalities, PITX3, Genetics (clinical)
Abstract: International audience; Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.
Published: 2022

10. Reliability of extracellular contrast versus gadoxetic acid in assessing small liver lesions using liver imaging reporting and data system v.2018 and European association for the study of the liver criteria

Author: Jordi Rimola, Víctor Sapena, Giuseppe Brancatelli, Anna Darnell, Laura Forzenigo, Aline Mähringer‐Kunz, Anita Paisant, Matteo Renzulli, Wolfgang Schima, Sylvain Terraz, Carlos Valls, Mathilde Wagner, Carmen Ayuso, Valerie Vilgrain, Maria Reig, Maxime Ronot, Rimola J, Sapena V, Brancatelli G, Darnell A, Forzenigo L, Mähringer-Kunz A, Paisant A, Renzulli M, Schima W, Terraz S, Valls C, Wagner M, Ayuso C, Vilgrain V, Reig M, Ronot M, Radiology, Hospital Clinic, Universitat de Barcelona (UB), Istituto Nazionale di Geofisica e di Oceanografia Sperimentale (OGS), Département de Radiologie [CHU de Rennes], Université de Rennes (UR), Geneva University Hospital (HUG), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'imagerie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad Autónoma de Madrid (UAM), CIBER de Enfermedades Raras (CIBERER), Hôpital Beaujon, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Hôpital Beaujon [AP-HP], and Université Paris Cité (UPCité)
Subjects: Carcinoma, Hepatocellular, Hepatology, [SDV]Life Sciences [q-bio], Liver Neoplasms, Contrast Media, Reproducibility of Results, Hepatocellular Carcinoma, liver, Magnetic Resonance Imaging, Sensitivity and Specificity, Humans, Data Systems, Prospective Studies, Retrospective Studies
Abstract: Background & aims: The diagnostic accuracy of Liver Imaging Reporting and Data System (LI-RADS) v.2018 and European Association for the Study of the Liver (EASL) criteria for the diagnosis of HCC have been widely evaluated, but their reliability should be investigated. We aimed to assess and compare the reliability of LI-RADS v.2018 and EASL criteria for the diagnosis of HCC using MRI with extracellular contrast agents (ECAs) and gadoxetic acid (GA) and determine the effect of ancillary features on LI-RADS reliability. Approach & results: Ten readers reviewed MRI studies of 92 focal liver lesions measuring
Published: 2022

11. Structural and Genomic Evolution of RRNPPA Systems and Their Pheromone Signaling

Author: Felipe-Ruiz, Alonso, Marina, Alberto, Rocha, Eduardo, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia e Innovación (España), Generalitat Valenciana, Fondation pour la Recherche Médicale, Agence Nationale de la Recherche (France), Ministerio de Universidades (España), Marina, Alberto, Instituto de biomedicina [Valencia] (IBV), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), CIBER de Enfermedades Raras (CIBERER), Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by grants BIO2016-78571-P and PID2019-108541GB-I00 from the Spanish Government (Ministerio de Economía y Competitividad y Ministerio de Ciencia e Innovación) and PROMETEO/2020/012 from the Valencian Government to A.M. and grants EQU201903007835 (Equipe FRM (Fondation pour la Recherche Médicale)), Laboratoire d′Excellence IBEID Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID) and PIA/ANR-16-CONV-0005 (Inception project from Agence Nationale pour la Recherche) to E.P.C.R. A.F.-R. received an FPU predoctoral fellowship from the Spanish Ministry of Universities with identifier FPU19/00433., We thank Elena Cabello Yeves for her help performing the Kruskal-Wallis analysis on peptide length and Eugen Pfeifer for data on Phage-plasmids., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016)
Subjects: Quorum sensing, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, TPR domain, RRNPPA family, Transcription factors, Peptide pheromone, Signal transduction
Abstract: 18 páginas, 6 figuras, 4 tablas., In Firmicutes, important processes such as competence development, sporulation, virulence, and biofilm formation are regulated by cytoplasmic quorum sensing (QS) receptors of the RRNPPA family using peptide-based communication. Although these systems regulate important processes in a variety of bacteria, their origin and diversification are poorly understood. Here, we integrate structural, genomic, and phylogenetic evidence to shed light on RRNPPA protein origin and diversification. The family is constituted by seven different subfamilies with different domain architectures and functions. Among these, three were found in Lactobacillales (Rgg, ComR, and PrgX) and four in Bacillales (AimR, NprR, PlcR, and Rap). The patterns of presence and the phylogeny of these proteins show that subfamilies diversified a long time ago, resulting in key structural and functional differences. The concordance between the distribution of subfamilies and the bacterial phylogeny was somewhat unexpected, since many of the subfamilies are very abundant in mobile genetic elements, such as phages, plasmids, and phage-plasmids. The existence of diverse propeptide architectures raises intriguing questions about their export and maturation. It also suggests the existence of diverse roles for the RRNPPA systems. Some systems encode multiple pheromones on the same propeptide or multiple similar propeptides, suggesting that they act as "chatterers." Many others lack pheromone genes and may be "eavesdroppers." Interestingly, AimR systems without associated propeptide genes were particularly abundant in chromosomal regions not classed as prophages, suggesting that either the bacterium or other mobile elements are eavesdropping on phage activity. IMPORTANCE Quorum sensing (QS) is a mechanism of bacterial communication, coordinating important decisions depending on bacterial population. QS regulates important processes not only in bacterial behavior but also in genetic mobile elements and host-guest interactions. In Firmicutes, the most important family of QS receptors is the RRNPPA family. Despite the importance of such systems in microbiology, we know little about RRNPPA origin and diversification. In this work, the combination of sequence analysis and structural biology allowed us to identify a very large number of novel systems but also to class of them in functional families and thereby study of their origin and functional diversification. Moreover, peptide pheromone analysis revealed new and intriguing mechanisms of communication, such as "eavesdropper" systems which only listen for the pheromone and "chatterers" that take control of the communication in their microenvironment., This work was supported by grants BIO2016-78571-P and PID2019-108541GB-I00 from the Spanish Government (Ministerio de Economía y Competitividad y Ministerio de Ciencia e Innovación) and PROMETEO/2020/012 from the Valencian Government to A.M. and grants EQU201903007835 (Equipe FRM (Fondation pour la Recherche Médicale)), Laboratoire d9Excellence IBEID Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID) and PIA/ANR-16-CONV-0005 (Inception project from Agence Nationale pour la Recherche) to E.P.C.R. A.F.-R. received an FPU predoctoral fellowship from the Spanish Ministry of Universities with identifier FPU19/00433.
Published: 2022

12. Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology

Author: María del Carmen Ortuño-Costela, Victoria Cerrada, Ana Moreno-Izquierdo, Inés García-Consuegra, Camille Laberthonnière, Mégane Delourme, Rafael Garesse, Joaquín Arenas, Carla Fuster García, Gema García García, José María Millán, Frédérique Magdinier, María Esther Gallardo, Instituto de Salud Carlos III, Ministerio de Cultura y Deporte (España), Association Française contre les Myopathies, Aix-Marseille Université, Institut des Maladies Rares (France), Hospital Universitario 12 de Octubre [Madrid], Universidad Autónoma de Madrid (UAM), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIBER de Enfermedades Raras (CIBERER), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Technology, McArdle disease, Isogenic control, Induced Pluripotent Stem Cells, iPSCs, Gene editing, Read-through drugs, Catalysis, PYGM, Inorganic Chemistry, Humans, Physical and Theoretical Chemistry, CRISPR/Cas9, Molecular Biology, Skeletal muscle differentiation, Spectroscopy, [SDV.GEN]Life Sciences [q-bio]/Genetics, Organic Chemistry, General Medicine, Computer Science Applications, Disease modelling, Glycogen Storage Disease Type V, Glycogen Phosphorylase, Muscle Form, disease modelling, skeletal muscle differentiation, gene editing, isogenic control, read-through drugs, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Glycogen
Abstract: McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity., This work has been funded by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (ISCIII): PI15/00484, CP16/00046 and PI18/00151 to MEG and PI17/02052 to JA (co-funded by European Regional Development Fund “A way to make Europe”); PI21/00162 and CPII21/00011 co-funded by the European Union to MEG. MdCOC receives grant support from the ‘Ministerio de Educación, Cultura y Deporte’ (FPU16/03895), ‘Fundación para la Investigación Biomédica Hospital 12 de Octubre’ (2022/0065, i+12-AY20220114-1) and EMBO Grant 8917. CL and MD were recipient of a fellowship from the French Ministry of Education. The work in FM’s laboratory was funded by “Association Française contre les Myopathies” (AFM; TRIM-RD and MoThARD) and from the Excellence Initiative of Aix-Marseille University-A*Midex, a French “investissement d’avenir programme” AMX-19-IET-007 through the Marseille Maladies Rares (MarMaRa) Institute (phD fellowship to CL).
Published: 2022

13. The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview

Author: Angels García-Cazorla, Fanny Mochel, Jean-Marie Saudubray, Foudil Lamari, Department of Neurology, CIBERER, CIBER de Enfermedades Raras (CIBERER)-CIBER de Enfermedades Raras (CIBERER)-Hospital de Sant Joan de Deu, Barcelona, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Administateur, HAL Sorbonne Université
Subjects: Pathology, peripheral neuropathy, Neurodegeneration with brain iron accumulation, Lipomatosis, Leber Congenital Amaurosis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Macular Degeneration, 0302 clinical medicine, chondrodysplasia, Stargardt Disease, Genetics (clinical), neurodegeneration with brain iron accumulation, Hypertriglyceridemia, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Ichthyosis, hepatic steatosis, Liver Diseases, Peripheral Nervous System Diseases, Neurodegenerative Diseases, Lipids, 3. Good health, Phenotype, Retinal Dystrophies, Retinitis Pigmentosa, medicine.medical_specialty, spastic paraplegia, Jaundice, inborn errors of metabolism, Lipid Metabolism, Inborn Errors, 03 medical and health sciences, Retinitis pigmentosa, Genetics, medicine, Humans, retinal dystrophy, phospholipids, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bone Diseases, Developmental, business.industry, Spastic Paraplegia, Hereditary, Complex lipids, medicine.disease, Stargardt disease, Fatty Liver, Peripheral neuropathy, Dysplasia, Paraparesis, Spastic, Ataxia, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Over one hundred diseases related to inherited defects of complex lipids synthesis and remodeling are now reported. Most of them were described within the last 5 years. New descriptions and phenotypes are expanding rapidly. While the associated clinical phenotype is currently difficult to outline, with only a few patients identified, it appears that all organs and systems may be affected. The main clinical presentations can be divided into (1) Diseases affecting the central and peripheral nervous system. Complex lipid synthesis disorders produce prominent motor manifestations due to upper and/or lower motoneuron degeneration. Motor signs are often complex, associated with other neurological and extra-neurological signs. Three neurological phenotypes, spastic paraparesis, neurodegeneration with brain iron accumulation and peripheral neuropathies, deserve special attention. Many apparently well clinically defined syndromes are not distinct entities, but rather clusters on a continuous spectrum, like for the PNPLA6-associated diseases, extending from Boucher-Neuhauser syndrome via Gordon Holmes syndrome to spastic ataxia and pure hereditary spastic paraplegia; (2) Muscular/cardiac presentations; (3) Skin symptoms mostly represented by syndromic (neurocutaneous) and non syndromic ichthyosis; (4) Retinal dystrophies with syndromic and non syndromic retinitis pigmentosa, Leber congenital amaurosis, cone rod dystrophy, Stargardt disease; (5) Congenital bone dysplasia and segmental overgrowth disorders with congenital lipomatosis; (6) Liver presentations characterized mainly by transient neonatal cholestatic jaundice and non alcoholic liver steatosis with hypertriglyceridemia; and (7) Renal and immune presentations. Lipidomics and molecular functional studies could help to elucidate the mechanism(s) of dominant versus recessive inheritance observed for the same gene in a growing number of these disorders.
Published: 2014

14. Molecular testing for fragile X: Analysis of 5062 tests from 1105 fragile X families - Performed in 12 clinical laboratories in Spain

Author: María-Teresa Calvo, Elizabet Pintado, Yolanda de Diego-Otero, Jordi Rosell, G. Glover, Francisco Martínez, María-Antonia Ramos-Arroyo, Montserrat Milà, Carmen Ayuso, Isabel Fernandez-Carvajal, Miriam Guitart, Concepción Hernández-Chico, Maria-Isabel Tejada, Feliciano J. Ramos, Hiart Maortua, Ministerio de Sanidad, Servicios Sociales e Igualdad (España), Asociación Girmogen (España), [Tejada,MI, and Maortua,H] Laboratorio de Genetica Molecular, Servicio de Genética, Hospital Universitario Cruces, BioCruces Health Research Institute, GCV-CIBER de Enfermedades Raras (CIBERER-ISCIII), Barakaldo, Bizkaia, Spain. [Glover,G] Unidad de Genetica Molecular, Centro de Bioquímica y Genetica Clínica, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain. [Martínez,F] Unidad de Genetica, Hospital Universitario La Fe, Valencia, Spain. [Guitart,M] Laboratorio de Genetica, UDIAT-Centre Diagnóstic, Corporaciò Sanitária Parc Taulí, Institut Universitari UAB, Sabadell, Barcelona, Spain. [Diego-Otero,Y de] Unidad de Gestion Clínica de Salud Mental, Hospital Regional Universitario de Malaga, Instituto de Investigacion Biomédica de Málaga (IBIMA), Málaga, Spain. [Fernández-Carvajal] Instituto de Biología y Genetica Molecular (IBGM), Universidad de Valladolid, CSIC, Valladolid, Spain. [Ramos,FJ] Consulta de Genetica Clínica, Servicio de Pediatría, Hospital Clínico Universitario Lozano Blesa, Facultad de Medicina, Universidad de Zaragoza, GCV-CIBER de Enfermedades Raras (CIBERER-ISCIII), Zaragoza, Spain. [Hernández-Chico,C] Servicio de Genetica, Hospital Ramón y Cajal, Madrid, Spain. [Pintado,E] Servicio de Biología Molecular, Hospital Virgen Macarena y Universidad de Sevilla, Sevilla, Spain. [Rosell,J] Servicio de Genetica, Hospital Universitari Son Espases, GCV-CIBER de Enfermedades Raras (CIBERER-ISCIII), Palma de Mallorca, Illes Balears, Spain. [Calvo,MT] Unidad de Genetica Médica, Hospital Universitario Miguel Servet, Zaragoza, Spain. [Ayuso,C] Servicio de Genetica, IIS-Hospital Universitario Fundacion Jiménez Díaz (IIS-FJD, UAM), CIBER de Enfermedades Raras (CIBERER-ISCIII), Madrid, Spain. [Ramos-Arroyo,MA] Servicio de Genetica, Complejo Hospitalario de Navarra, Pamplona, Spain. [Milà,M] Servicio de Bioquímica y Genetica Molecular, Hospital Clinic, IDIBAPS, CIBER de Enfermedades Raras (CIBERER-ISCIII), Barcelona, Spain.
Subjects: Male, alelos, Síndrome del cromosoma X frágil, Fragile x, sistema de registros, humanos, España, adolescente, lcsh:Medicine, ComputingMilieux_LEGALASPECTSOFCOMPUTING, frecuencia génica, Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Gene Frequency, Intellectual disability, Registries, Child, Full mutation, mediana edad, síndrome del cromosoma X frágil, Geographicals::Geographic Locations::Europe::Spain [Medical Subject Headings], Genetics, Named Groups::Persons::Age Groups::Child::Child, Preschool [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Testing [Medical Subject Headings], General Medicine, adulto, Middle Aged, Fragile X syndrome, Child, Preschool, Named Groups::Persons::Age Groups::Adolescent [Medical Subject Headings], Female, Sistema de registros, Named Groups::Persons::Age Groups::Infant [Medical Subject Headings], Alelos, Pruebas genéticas, Research Article, Adult, Adolescent, Article Subject, Offspring, Genetic counseling, Check Tags::Male [Medical Subject Headings], Biology, Named Groups::Persons::Age Groups::Infant::Infant, Newborn [Medical Subject Headings], General Biochemistry, Genetics and Molecular Biology, Named Groups::Persons::Age Groups::Adult [Medical Subject Headings], medicine, Humans, Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital Abnormalities::Chromosome Disorders::Sex Chromosome Disorders::Fragile X Syndrome [Medical Subject Headings], pruebas genéticas, Genetic Testing, Allele, Alleles, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Alleles [Medical Subject Headings], Named Groups::Persons::Age Groups::Child [Medical Subject Headings], lactante, General Immunology and Microbiology, lcsh:R, Infant, Newborn, Infant, medicine.disease, Frecuencia génica, Check Tags::Female [Medical Subject Headings], Spain, Fragile X Syndrome, Data_GENERAL, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Registries [Medical Subject Headings], Klinefelter syndrome, Phenomena and Processes::Genetic Phenomena::Gene Frequency [Medical Subject Headings]
Abstract: This is an open access article distributed under the Creative Commons Attribution License.-- et al., Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of < 59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling. © 2014 María-Isabel Tejada et al., Thanks are due to the agreements between GIRMOGEN and the Real Patronato sobre Discapacidad of the Spain’s Ministry for Health, Social Services and Equality (Spain) to carry out this study.
Published: 2014

15. Loss of seryl-tRNA synthetase ( SARS1 ) causes complex spastic paraplegia and cellular senescence

Author: Edgard Verdura, Bruno Senger, Miquel Raspall-Chaure, Agatha Schlüter, Nathalie Launay, Montserrat Ruiz, Carlos Casasnovas, Agustí Rodriguez-Palmero, Alfons Macaya, Hubert Dominique Becker, Aurora Pujol, Génétique et Physiopathologie des Maladies Cérébro-Vasculaires (U1161 / UMR_S 1161), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitat Autònoma de Barcelona (UAB), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Pediatrics Department, Hospital Universitari Germans Trias I Pujol, Architecture et réactivité de l'ARN (ARN), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Neurometabolic Diseases Laboratory [Barcelona, Spain], Centre for Biomedical Research on Rare Diseases [Barcelona, Spain] (CIBERER), Hospital Sant Joan de Déu [Barcelona], Institució Catalana de Recerca i Estudis Avançats (ICREA), Institut Català de la Salut, [Verdura E, Schlüter A, Launay N, Ruiz M] Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, 08908, Barcelona, Catalonia, Spain. Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. [Senger B] Université de Strasbourg 1, Strasbourg, France. [Raspall-Chaure M] Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Macaya A] Grup de Recerca en Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: nervous system diseases, Paraplegia - Aspectes genètics, Sequence analysis, RNA, pediatrics, sequence analysis, Otros calificadores::Otros calificadores::/genética [Otros calificadores], neurology, [SDV]Life Sciences [q-bio], Cell Physiological Phenomena::Cellular Senescence [PHENOMENA AND PROCESSES], genetic research, Nervous system diseases, Pediatrics, Nervous System Diseases::Neurologic Manifestations::Paralysis::Paraplegia [DISEASES], enfermedades del sistema nervioso::manifestaciones neurológicas::parálisis::paraplejía [ENFERMEDADES], Neurology, Other subheadings::Other subheadings::/genetics [Other subheadings], Genetics, RNA, fenómenos fisiológicos celulares::senescencia celular [FENÓMENOS Y PROCESOS], Cèl·lules - Envelliment, Genetic research, Genetics (clinical)
Abstract: Genetic research; Nervous system diseases; Pediatrics Investigación genética; Enfermedades del sistema nervioso; Pediatría Recerca genètica; Malalties del sistema nerviós; Pediatria Background Aminoacyl-tRNA synthetases (ARS) are key enzymes catalysing the first reactions in protein synthesis, with increasingly recognised pleiotropic roles in tumourgenesis, angiogenesis, immune response and lifespan. Germline mutations in several ARS genes have been associated with both recessive and dominant neurological diseases. Recently, patients affected with microcephaly, intellectual disability and ataxia harbouring biallelic variants in the seryl-tRNA synthetase encoded by seryl-tRNA synthetase 1 (SARS1) were reported. Methods We used exome sequencing to identify the causal variant in a patient affected by complex spastic paraplegia with ataxia, intellectual disability, developmental delay and seizures, but without microcephaly. Complementation and serylation assays using patient’s fibroblasts and an Saccharomyces cerevisiae model were performed to examine this variant’s pathogenicity. Results A de novo splice site deletion in SARS1 was identified in our patient, resulting in a 5-amino acid in-frame insertion near its active site. Complementation assays in S. cerevisiae and serylation assays in both yeast strains and patient fibroblasts proved a loss-of-function, dominant negative effect. Fibroblasts showed an abnormal cell shape, arrested division and increased beta-galactosidase staining along with a senescence-associated secretory phenotype (raised interleukin-6, p21, p16 and p53 levels). Conclusion We refine the phenotypic spectrum and modes of inheritance of a newly described, ultrarare neurodevelopmental disorder, while unveiling the role of SARS1 as a regulator of cell growth, division and senescence. This study was supported by grants from the Undiagnosed Rare Disease programme URD-Cat (SLT002/16/00174) from the Generalitat de Catalunya, the Center for Biomedical Research on Rare Diseases (CIBERER) (ACCI19-759), the ASL-HSP France and the Hesperia Foundation to AP. This study was also funded by the Instituto de Salud Carlos III and ‘Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, una manera de hacer Europa’ (FIS PI20/00758) to CC and ‘La Marató de TV3’ Foundation (202006-30) to CC and AP. This study was also funded by Instituto de Salud Carlos III (Sara Borrell programme, CD19/00221) to EV, the Spanish Ministerio de Economia, Industria y Competividad (Juan de la Cierva programme FJCI-2016-28811) to EV, and the Center for Biomedical Research on Rare Diseases (CIBERER) to MR and NL. This study was supported by the French National Programme Investissement d’Avenir administered by the ‘Agence National de la Recherche’ (ANR), ‘MitoCross’ Laboratory of Excellence (Labex), funded as ANR-10-IDEX-0002-02, the University of Strasbourg and CNRS (to HB, BS). The CERCA Programme/Generalitat de Catalunya provided institutional support. AP is member of the Undiagnosed Disease Network International (UDNI).
Published: 2022

16. The Transcription Factor Encyclopedia

Author: Yusuf, Dimas, Butland, Stefanie L., Swanson, Magdalena I., Bolotin, Eugene, Ticoll, Amy, Cheung, Warren A., Zhang, Xiao Yu Cindy, Dickman, Christopher T. D., Fulton, Debra L., Lim, Jonathan S., Schnabl, Jake M., Ramos, Oscar H. P., Vasseur-Cognet, Mireille, de Leeuw, Charles N., Simpson, Elizabeth M., Ryffel, Gerhart U., Lam, Eric W.-F., Kist, Ralf, Wilson, Miranda S. C., Marco-Ferreres, Raquel, Brosens, Jan J., Beccari, Leonardo L., Bovolenta, Paola, Benayoun, Bérénice A., Monteiro, Lara J, Schwenen, Helma D C, Grontved, Lars, Wederell, Elizabeth, Mandrup, Susanne, Veitia, Reiner A, Chakravarthy, Harini, Hoodless, Pamela A., Mancarelli, M Michela, Torbett, Bruce E, Banham, Alison H, Reddy, Sekhar P, Cullum, Rebecca L, Liedtke, Michaela, Tschan, Mario P, Vaz, Michelle, Rizzino, Angie, Zannini, Mariastella, Frietze, Seth, Farnham, Peggy J, Eijkelenboom, Astrid, Brown, Philip J, Laperrière, David, Leprince, Dominique, de Cristofaro, Tiziana, Prince, Kelly L, Putker, Marrit, del Peso, Luis, Camenisch, Gieri, Wenger, Roland H, Mikula, Michal, Rozendaal, Marieke, Mader, Sylvie, Ostrowski, Jerzy, Rhodes, Simon J, Van Rechem, Capucine, Boulay, Gaylor, Olechnowicz, Sam W Z, Breslin, Mary B, Lan, Michael S, Nanan, Kyster K, Wegner, Michael, Hou, Juan, Mullen, Rachel D, Colvin, Stephanie C, Noy, Peter John, Webb, Carol F, Witek, Matthew E, Ferrell, Scott, Daniel, Juliet M, Park, Jason, Waldman, Scott A, Peet, Daniel J, Taggart, Michael, Jayaraman, Padma-Sheela, Karrich, Julien J, Blom, Bianca, Vesuna, Farhad, O'Geen, Henriette, Sun, Yunfu, Gronostajski, Richard M, Woodcroft, Mark W, Hough, Margaret R, Chen, Edwin, Europe-Finner, G Nicholas, Karolczak-Bayatti, Magdalena, Bailey, Jarrod, Hankinson, Oliver, Raman, Venu, LeBrun, David P, Biswal, Shyam, Harvey, Christopher J, DeBruyne, Jason P, Hogenesch, John B, Hevner, Robert F, Héligon, Christophe, Luo, Xin M, Blank, Marissa Cathleen, Millen, Kathleen Joyce, Sharlin, David S, Forrest, Douglas, Dahlman-Wright, Karin, Zhao, Chunyan, Mishima, Yuriko, Sinha, Satrajit, Chakrabarti, Rumela, Portales-Casamar, Elodie, Sladek, Frances M, Bradley, Philip H, Wasserman, Wyeth W, Cindy Zhang, Xiao, Department of Medical Genetics, Faculty of Medicine-Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia (UBC), Evaluation and Research Services, Fraser Health Authority, Children's Hospital Oakland, Oakland Research Institute, Computational Biology Program, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Department of Bioinformatics, Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia (UBC), Department of Biology, University of Western Ontario (UWO), Genetics Program, Department of Cell Biology and Neuroscience [Riverside] (CBNS), University of California [Riverside] (UC Riverside), University of California (UC)-University of California (UC), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut für Zellbiologie, Universität Duisburg-Essen [Essen]-Universitätsklinikum Essen, Department of Surgery and Cancer, Imperial College London-Division of Cancer, Centre for Oral Health Research, Newcastle University [Newcastle]-Medical School-School of Dental Sciences, Department of Development and Differentiation, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), Division of Reproductive Health, University of Warwick [Coventry]-Warwick Medical School, University of Warwick [Coventry], Neurobiologia Molecular Celular y del desarrollo, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry and Molecular Biology, University of Southern Denmark (SDU), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-Provincial Health Services Authority, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Department of Molecular Experimental Medicine, The Scripps Research Institute [La Jolla, San Diego], Departments of Molecular and Experimental Medicine and Immunology and Microbial Sciences (MEM 131), Nuffield Department of Clinical Laboratory Sciences, University of Oxford- John Radcliffe Hospital [Oxford University Hospital]-Oxford NIHR Biomedical Research Centre, Department of Pediatrics, College of Medicine-Department of pediatrics-University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Division of Hematology [Stanford], Stanford Medicine, Stanford University-Stanford University, Department of Medicine, University of Bern, Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine [Baltimore]-Johns Hopkins University School of Medicine [Baltimore]-Johns Hopkins University School of Medicine, Institute of Experimental Endocrinology and Oncology (IEOS), Consiglio Nazionale delle Ricerche (CNR), University of Southern California (USC)-Norris Comprehensive Cancer Center, Department of Molecular Cancer Research, University Medical Center [Utrecht]-Utrecht University [Utrecht], University of Oxford- John Radcliffe Hospital [Oxford University Hospital]-Medical Sciences Division, Molecular Targeting in Breast Cancer research unit, Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indiana University System-Indiana University System, Department of Physiological Chemistry, Department of Biochemistry, Universidad Autónoma de Madrid (UAM)-School of Medicine, Institute of Physiology, Universität Zürich [Zürich] = University of Zurich (UZH)-Zurich Center for Integrative Human Physiology, Department of Oncological Genetics, Institute of Oncology-Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC)-Medical Center of Postgraduate Education [Warsaw] (MCPE), Indiana University [Bloomington], Indiana University System-Indiana University System-School of Science, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston]-Cancer Center, University of Adelaide-School of Molecular and Biomedical Science, Department of Pediatrics and Biochemistry and Molecular Biology, Louisiana State University (LSU)-Research Institute for Children-Children's Hospital at New Orleans, Departments of Pediatrics and Genetics, Department of Pathology and Molecular Medicine, Queen's University [Kingston, Canada]-Queen's Cancer Research Institute, School of Medicine [Erlangen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Institut fuer Biochemie-Emil-Fischer-Zentrum, Department of Molecular Biology and Biochemistry, University Indianapolis-Indiana University School of Medicine, Department of Immunity and Infection, School of Medical and Dental Sciences-University of Birmingham [Birmingham], Immunobiology and Cancer Program, Oklahoma Medical Research Foundation (OMRF), Radiation Oncology, Department of Pharmacology and Experimental Therapeutics-Jefferson University Hospitals, Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center (OUHSC), McMaster University [Hamilton, Ontario], School of Medicine, Johns Hopkins University (JHU), Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University-Jefferson Medical College, Discipline of Biochemistry, Institute of Cellular Medicine, Newcastle University [Newcastle]-Faculty of Medicine-Medical School, Department of Immunity and Immunology, Department of Cell Biology and Histology, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA)-Center for Immunology Amsterdam, Division of Cancer Imaging Research, Johns Hopkins University (JHU)-School of Medicine-Department of Radiology, Genome Center [UC Davis], University of California [Davis] (UC Davis), School of Biological Sciences [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), Department of Biochemistry and Developmental Genomics Group, University at Buffalo [SUNY] (SUNY Buffalo), State University of New York (SUNY)-State University of New York (SUNY)-Center of Excellence in Bioinformatics and Life Sciences, Department of Molecular and Cellular Biology, University of Toronto-Sunnybrook Health Sciences Centre-Department of Laboratory Medicine and Pathobiology, Faculty of Medical Sciences, Newcastle University [Newcastle]-Medical School-Institute of Cellular Medicine, Department of Pathology and Laboratory Medicine, University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Radiology and Oncology, Johns Hopkins University (JHU)-School of Medicine, Department of Environmental Health Sciences, Johns Hopkins University (JHU)-Johns Hopkins Bloomberg School of Public Health [Baltimore], Department of Pharmacology and Toxicology, Neuroscience Institute-Morehouse School of Medicine, Department of Pharmacology, University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Department of Neurological Surgery, University of Washington [Seattle]-Seattle Children's Research Institute, Faculty of Biology and Medicine, Université de Lausanne = University of Lausanne (UNIL)-Center for Integrated Genomics, Department of Biomedical Sciences and Pathobiology, Virginia Polytechnic Institute and State University [Blacksburg]-Virginia-Maryland College of Veterinary Medicine, Department of Molecular Genetics and Cell Biology, University of Illinois [Chicago] (UIC), Center for Integrative Brain Research, University of Washington [Seattle], Clinical Endocrinology Branch, National Institutes of Health (NIH)-National Institute of Diabetes, Digestive, and Kidney Disorders, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], State University of New York (SUNY)-State University of New York (SUNY), BMC, Ed., Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-Universitätsklinikum Essen, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), UAM. Departamento de Bioquímica, Faculty of Medicine-Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia ( UBC ), Fred Hutchinson Cancer Research Center [Seattle] ( FHCRC ) -Public Health Sciences Division, Child and Family Research Institute-Centre for Molecular Medicine and Therapeutics-University of British Columbia ( UBC ), University of Western Ontario ( UWO ), Department of Cell Biology and Neuroscience [Riverside] ( CBNS ), University of California [Riverside] ( UCR ), Service d'Ingénierie Moléculaire des Protéines ( SIMOPRO ), Département Médicaments et Technologies pour la Santé ( DMTS ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), CIBER de Enfermedades Raras (CIBERER)-Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ) -Centro de Biologia Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ) -Centro de Biologia Molecular Severo Ochoa (CBMSO)-CIBER de Enfermedades Raras (CIBERER), Service de Pathologies moléculaire et cellulaire, Institut Jacques Monod ( IJM ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), UNIVERSITY OF SOUTHERN DENMARK, BC Cancer Agency ( BCCRC ) -Provincial Health Services Authority, Scripps Research Institute, Departments of Molecular and Experimental Medicine and Immunology and Microbial Sciences ( MEM 131 ), University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-Oxford NIHR Biomedical Research Centre, College of Medicine-Department of pediatrics-University of Illinois at Chicago ( UIC ), Department of Medicine/Hematology, Stanford University School of Medicine, Institute of Experimental Endocrinology and Oncology ( IEOS ), CNR - National Research Council, University of Southern California ( USC ) -Norris Comprehensive Cancer Center, Utrecht University [Utrecht]-University Medical Center Utrecht, University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-Medical Sciences Division, Université de Montréal-Institute for Research in Immunology and Cancer, Institut de biologie de Lille - IBL ( IBLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Lille, Droit et Santé, Utrecht University [Utrecht]-University Medical Centre Utrecht, Universidad Autonoma de Madrid ( UAM ) -School of Medicine, University of Zürich [Zürich] ( UZH ) -Zurich Center for Integrative Human Physiology, Institute of Oncology-Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology ( MCMCC ) -Medical Center of Postgraduate Education [Warsaw] ( MCPE ), Indiana University [Bloomington]-School of Science, Harvard Medical School [Boston] ( HMS ) -Cancer Center-Massachusetts General Hospital, Louisiana State University Health Sciences Center-Research Institute for Children-Children's Hospital at New Orleans, Queen's University [Kingston]-Queen's Cancer Research Institute, Institut fuer Biochemie-Emil-Fischer-Zentrum-Friedrich-Alexander Universitaet Erlangen-Nuernberg, Indiana University School of Medicine-University Indianapolis, Oklahoma Medical Research Foundation, Department of Pharmacology and Experimental Therapeutics-Jefferson University Hospital, University of Oklahoma Health Sciences Center ( OUHSC ), Johns Hopkins University ( JHU ), Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ) -Center for Immunology Amsterdam, Johns Hopkins University ( JHU ) -School of Medicine-Department of Radiology, University of California at Davis, Division of Biological Sciences [San Diego], University of California [San Diego] ( UC San Diego ), State University of New York at Buffalo ( SUNY Buffalo ) -Center of Excellence in Bioinformatics and Life Sciences, University of California at Los Angeles [Los Angeles] ( UCLA ) -David Geffen School of Medicine, Johns Hopkins University ( JHU ) -School of Medicine, Johns Hopkins University ( JHU ) -Johns Hopkins Bloomberg School of Public Health, University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Lausanne-Center for Integrated Genomics, Virginia Polytechnic Institute and State University [Blacksburg]-VA-MD Regional College of Veterinary Medicine, University of Illinois at Chicago ( UIC ), State University of New York at Buffalo ( SUNY Buffalo ) -University of Buffalo School of Medicine and Biomedical Sciences, University of California [Riverside] (UCR), University of California-University of California, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC)-CIBER de Enfermedades Raras (CIBERER), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Johns Hopkins University School of Medicine-The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine [Baltimore]-Johns Hopkins University School of Medicine [Baltimore], Utrecht University [Utrecht]-University Medical Center [Utrecht], Universidad Autonoma de Madrid (UAM)-School of Medicine, Cancer Center-Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Emil-Fischer-Zentrum-Institut fuer Biochemie, School of Molecular and Biomedical Science-University of Adelaide, School of Medicine-Department of Radiology-Johns Hopkins University (JHU), University of California-University of California-David Geffen School of Medicine [Los Angeles], Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), University of Pennsylvania [Philadelphia], Université de Lausanne (UNIL)-Center for Integrated Genomics, AII - Amsterdam institute for Infection and Immunity, and Cell Biology and Histology
Subjects: Encyclopedias as Topic, INFORMATION, WIKI, Transcription, Genetic, 05 Environmental Sciences, Medizin, [SDV.GEN] Life Sciences [q-bio]/Genetics, Automate Content, Web API, ANNOTATION, Mini review, Mice, 0302 clinical medicine, Portable Document Format, GENETICS & HEREDITY, Databases, Protein, Informática, 0303 health sciences, PROTEIN DATA-BANK, Application programming interface, BIOTECHNOLOGY & APPLIED MICROBIOLOGY, MENDELIAN-INHERITANCE, ddc:57, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 030220 oncology & carcinogenesis, Application Programming Interface, Encyclopedia, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], The Internet, Transcription (software), Transcription, Life Sciences & Biomedicine, KNOWLEDGEBASE, Medicina, DATABASE, Bioinformatics, Biology, Medizinische Fakultät » Universitätsklinikum Essen » Institut für Zellbiologie (Tumorforschung), World Wide Web, Access to Information, 03 medical and health sciences, Databases, Genetic, Protein Data Bank, ddc:570, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ddc:61, Animals, Humans, ddc:610, MeSH Term, Transcription factor, 030304 developmental biology, Internet, 08 Information And Computing Sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, GENE-REGULATION, business.industry, Protein, Computational Biology, 06 Biological Sciences, Compendium, EVOLUTION, Rats, Evolutionary biology, UPDATE, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Software, Transcription Factors
Abstract: Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
Published: 2012

17. Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology

Author: Ferdinand Dhombres, Patricia Morgan, Bimal P. Chaudhari, Isabel Filges, Teresa N. Sparks, Pablo Lapunzina, Tony Roscioli, Umber Agarwal, Shagun Aggarwal, Claire Beneteau, Pilar Cacheiro, Leigh C. Carmody, Sophie Collardeau‐Frachon, Esther A. Dempsey, Andreas Dufke, Michael Henri Duyzend, Mirna el Ghosh, Jessica L. Giordano, Ragnhild Glad, Ieva Grinfelde, Dominic G. Iliescu, Markus S. Ladewig, Monica C. Munoz‐Torres, Marzia Pollazzon, Francesca Clementina Radio, Carlota Rodo, Raquel Gouveia Silva, Damian Smedley, Jagadish Chandrabose Sundaramurthi, Sabrina Toro, Irene Valenzuela, Nicole A. Vasilevsky, Ronald J. Wapner, Roni Zemet, Melissa A Haendel, Peter N. Robinson, Institut Català de la Salut, [Dhombres F] Sorbonne University, GRC26, INSERM, Limics, Armand Trousseau Hospital, Fetal Medicine Department, APHP, Paris, France. [Morgan P] American College of Medical Genetics and Genomics, Newborn Screening Translational Research Network, Bethesda, USA. [Chaudhari BP] Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, USA. [Filges I] University Hospital Basel and University of Basel, Medical Genetics, Basel, Switzerland. [Sparks TN] Department of Obstetrics, Gynecology, & Reproductive Sciences, University of California, San Francisco, California, USA. [Lapunzina P] CIBERER and Hospital Universitario La Paz, INGEMM-Institute of Medical and Molecular Genetics, Madrid, Spain. [Rodo C] Grup de Recerca en Medicina Materna i Fetal, Vall d'Hebron Hospital Universitari, Barcelona, Spain. [Valenzuela I] Àrea de Genètica Clínica i Molecular, Vall d'Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, American College of Medical Genetics and Genomics [Bethesda, MD, USA] (ACM2G), Nationwide Children's Hospital, University Hospital Basel [Basel], University of Basel (Unibas), University of California [San Francisco] (UC San Francisco), University of California (UC), CIBER de Enfermedades Raras (CIBERER), Hospital Universitario La Paz, University of New South Wales [Canberra Campus] (UNSW), Liverpool Women's NHS Foundation Trust, Nizam's Institute of Medical Sciences (NIMS), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Queen Mary University of London (QMUL), The Jackson Laboratory [Bar Harbor] (JAX), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Société Française de Foetopathologie [Paris] (SOFFOET), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), St George's, University of London, University of Tübingen, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Columbia University Irving Medical Center (CUIMC), University Hospital of North Norway [Tromsø] (UNN), Children's Clinical University Hospital [Riga, Latvia] (CCUH), University of Medicine and Pharmacy of Craiova, Saarland University Hospital (UKS), University of Colorado Anschutz [Aurora], AUSL di Reggio Emilia Istituto di Ricerca a Carattere Clinico Scientifico [Reggio Emilia, Italie], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Vall d'Hebron University Hospital [Barcelona], Hospital de Santa Maria [Lisboa], Centro Hospitalar Universitário Lisboa Norte [Lisbon, Portugal] (CHULN), Baylor College of Medicine (BCM), Baylor University, and CarMeN, laboratoire
Subjects: prenatal phenotyping, [SDV]Life Sciences [q-bio], Placenta, Clinical Sciences, Diagnòstic prenatal, fetal pathology, Reproductive health and childbirth, afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::enfermedades raras [ENFERMEDADES], Rare Diseases, Pregnancy, Clinical Research, Exome Sequencing, Genetics, Humans, Genetics (clinical), Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Techniques, Obstetrical and Gynecological::Prenatal Diagnosis [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Pediatric, Genetics & Heredity, diagnóstico::técnicas y procedimientos diagnósticos::técnicas diagnósticas obstétricas y ginecológicas::diagnóstico prenatal [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], screening and diagnosis, prenatal diagnosis, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Rare Diseases [DISEASES], Prevention, Human Genome, Infant, Newborn, Computational Biology, Infant, Perinatal Period - Conditions Originating in Perinatal Period, Newborn, 4.1 Discovery and preclinical testing of markers and technologies, [SDV] Life Sciences [q-bio], Fenotip, Detection, Phenotype, Good Health and Well Being, Neurological, Genetic Phenomena::Phenotype [PHENOMENA AND PROCESSES], GA4GH Phenopacket, Congenital Structural Anomalies, Female, Hpo, HPO, Malalties rares, fenómenos genéticos::fenotipo [FENÓMENOS Y PROCESOS], human phenotype ontology
Abstract: Human phenotype ontology; Prenatal diagnosis; Prenatal phenotyping Ontología del fenotipo humano; Diagnóstico prenatal; Fenotipado prenatal Ontologia del fenotip humà; Diagnòstic prenatal; Fenotipat prenatal Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care. European Commission; National Human Genome Research Institute; NIH Office of the Director; The European Union's EIT-Health Innovation Program bp2020-2022, Grant/Award Numbers: #211015, #20062; NIH Office of the Director (OD), the European Union's Horizon 2020 research and innovation program, Grant/Award Number: 779257; NHGRI, Grant/Award Numbers: 2R24OD011883-05A1, 1U24HG011449-01A1
Published: 2022

18. Guía clínica de atención a menores transexuales, transgéneros y de género diverso

Author: Amadora Moral-Martos, Julio Guerrero-Fernández, Marcelino Gómez-Balaguer, Itxaso Rica Echevarría, Ariadna Campos-Martorell, María Jesús Chueca-Guindulain, Emilio García García, Raúl Hoyos-Gurrea, Diego López de Lara, Juan Pedro López-Siguero, José María Martos Tello, Cristina Mora Palma, Isolina Riaño Galán, Diego Yeste Fernández, Institut Català de la Salut, [Moral-Martos A] Unitat d’Endocrinologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Grupo de Identidad y Diferenciación sexual de la Sociedad Española de Endocrinología y Nutrición (GIDSEEN). Equipo de Pediatría Territorial Garraf, Institut Català de la Salut (ICS), Barcelona, Spain. [Guerrero-Fernández J] Servicio de Endocrinología Pediátrica, Hospital Infantil La Paz, Madrid, Spain. [Gómez-Balaguer M] Unidad de Identidad de Género, Servicio de Endocrinología y Nutrición, Hospital Universitario Doctor Peset, Valencia, Spain, Grupo de Identidad y Diferenciación sexual de la Sociedad Española de Endocrinología y Nutrición (GIDSEEN). [Rica Echevarría I] Endocrinología Pediátrica, Hospital Universitario de Cruces, Barakaldo, Bizkaia, España, UIG Osakidetza, Biocruces-Bizkaia, GIDSEEN, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). [Campos-Martorell A, Yeste Fernández D] Unitat d’Endocrinologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBER de Enfermedades Raras (CIBERER) ISCIII, EndoERN, Barcelona, Spain. [Chueca-Guindulain MJ] Sección de Endocrinología Pediátrica, Complejo Hospitalario de Navarra, Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Navarra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, Persons::Sexual and Gender Minorities::Transgender Persons [NAMED GROUPS], Behavior and Behavior Mechanisms::Behavior::Sexual Behavior::Sexuality::Transsexualism [PSYCHIATRY AND PSYCHOLOGY], Disforia de género, Adolescent, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Terapia hormonal cruzada, Bloqueo puberal, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Transgender Persons, Gender-affirming hormonal treatment, No binario, Gender incongruence, Transgèneres, Management of Technology and Innovation, Gender identity, Hormone cross therapy, Incongruencia de género, Puberty suppression, Humans, Gender Dysphoria, Non-binary, trastornos mentales::disfunciones sexuales psicológicas::disforia de género [PSIQUIATRÍA Y PSICOLOGÍA], Transsexualitat, personas::minorías sexuales y de género::personas transgénero [DENOMINACIONES DE GRUPOS], Gender Identity, Mental Disorders::Sexual Dysfunctions, Psychological::Gender Dysphoria [PSYCHIATRY AND PSYCHOLOGY], conducta y mecanismos de la conducta::conducta::conducta sexual::sexualidad::transexualismo [PSIQUIATRÍA Y PSICOLOGÍA], Pubertal blockade, Transgénero, Disfòria de gènere - Tractament, Minors, Fertilidad, Fertility, Supresión de la pubertad, Practice Guidelines as Topic, Identidad de género, Transgender, Terapia hormonal de afirmación de género, Female, Transsexualism
Abstract: Transgénero; Terapia hormonal cruzada; Identidad de género Transgender; Hormone cross therapy; Gender identity Transgènere; Teràpia hormonal creuada; Identitat de gènere Some people, including minors, have a gender identity that does not correspond to the sex assigned at birth. They are known as trans* people, which is an umbrella term that encompasses transgender, transsexual, and other identities not conforming to the assigned gender. Healthcare units for trans* minors require multidisciplinary working, undertaken by personnel expert in gender identity, enabling, when requested, interventions for the minor and their social–familial environment, in an individualized and flexible way during the gender affirmation path. This service model also includes hormonal treatments tailored as much as possible to the individual's needs, beyond the dichotomic goals of a traditional binary model. This guide addresses the general aspects of professional care of trans* minors and presents the current evidence-based protocol of hormonal treatments for trans* and non-binary adolescents. In addition, it details key aspects related to expected body changes and their possible side effects, as well as prior counselling about fertility preservation. Algunas personas, también las menores de edad, tienen una identidad de género que no se corresponde con el sexo asignado al nacer. Se les conoce como personas trans*, que es el término paraguas que engloba transgénero, transexual y otras identidades no conformes con el género asignado. Las unidades de asistencia sanitaria a menores trans* requieren un trabajo multidisciplinario, realizado por personal experto en identidad de género, que permita, cuando así lo soliciten, intervenciones para el menor y su entorno sociofamiliar, de forma individualizada y flexible durante el camino de afirmación de género. Este modelo de servicio también incluye tratamientos hormonales adaptados en la medida de lo posible a las necesidades del individuo, más allá de los objetivos dicotómicos de un modelo binario tradicional. Esta guía aborda los aspectos generales de la atención profesional de menores trans* y presenta el protocolo actual basado en evidencia de tratamientos hormonales para adolescentes trans* y no binarios. Además, detalla aspectos clave relacionados con los cambios corporales esperados y sus posibles efectos secundarios, así como el asesoramiento previo sobre preservación de la fertilidad.
Published: 2022

19. Development of whole-genome multiplex assays and construction of an integrated genetic map using SSR markers in Senegalese sole

Author: Israel Guerrero-Cózar, María Jesús Zamorano, Pedro Seoane, Cathaysa Pérez-García, Fernando Cruz, M. Gonzalo Claros, Hicham Benzekri, Manuel Manchado, Marta Gut, Juan José García Sánchez, [Guerrero-Cózar,I, Manchado,M] IFAPA Centro El Toruño, Junta de Andalucía, El Puerto de Santa María, Cádiz, Spain. [Perez-Garcia,C, Zamorano,MJ] Aquaculture Research Group (GIA), IU-ECOAQUA, Universidad de Las Palmas de Gran Canaria, Telde, Spain. [Benzekri,H, Seoane,P, Claros,MG] Department of Molecular Biology and Biochemistry, Universidad de Málaga, Málaga, Spain. [Sánchez,JJ] Instituto Nacional de Toxicología Y Ciencias Forenses (INT), La Laguna, Sta. Cruz de Tenerife, Spain. [Cruz,F, Gut,M] CNAG‑CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [Claros,MG] CIBER de Enfermedades Raras (CIBERER), Málaga, Spain. [Claros,MG] Institute of Biomedical Research in Málaga (IBIMA), IBIMA-RARE, Málaga, Spain. [Claros,MG] Instituto de Hortofruticultura Subtropical Y Mediterránea (IHSM-UMA-CSIC), Málaga, Spain. [Manchado,M] 'Crecimiento Azul', Centro IFAPA El Toruño, Unidad Asociada Al CSIC', El Puerto de Sta. María, Spain., and This study was funded by project RTA2017-00054-C03-01, RTA2017-00054-C03-02 and RTA2017-00054-C03-03 funded from MCIU/AEI/FEDER, UE. IGC is funded by a predoctoral fellowship from INIA.
Subjects: 0106 biological sciences, 0301 basic medicine, Genetic Linkage, Multiplex polymerase chain reaction, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Pedigree [Medical Subject Headings], Llenguados, 01 natural sciences, Genome, Organisms::Eukaryota::Animals [Medical Subject Headings], Multiplex, Phylogeny, Multidisciplinary, Mapeo cromosómico, Contig, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Fishes::Flatfishes [Medical Subject Headings], Femenino, Chromosome Mapping, food and beverages, Sintenía, Pedigree, Flatfishes, Microsatellite, Medicine, Female, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Chromosome Mapping::Physical Chromosome Mapping [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Tandem Repeat Sequences::Microsatellite Repeats [Medical Subject Headings], Science, Computational biology, Biology, Variación genética, 010603 evolutionary biology, Synteny, Article, 03 medical and health sciences, Phenomena and Processes::Genetic Phenomena::Genetic Linkage [Medical Subject Headings], Linaje, Reacción en cadena de la polimerasa multiplex, Animals, Genetic variation, Genotyping, Genoma, Animal breeding, Genetic diversity, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Genetic Association Studies::Genome-Wide Association Study [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Sequence Homology::Sequence Homology, Nucleic Acid::Synteny [Medical Subject Headings], Genòmica, 030104 developmental biology, Genetic marker, Phenomena and Processes::Genetic Phenomena::Phylogeny [Medical Subject Headings], Genetic markers, Peces planos, Genètica, Genome-Wide Association Study, Microsatellite Repeats
Abstract: The Senegalese sole (Solea senegalensis) is an economically important flatfish species. In this study, a genome draft was analyzed to identify microsatellite (SSR) markers for whole-genome genotyping. A subset of 224 contigs containing SSRs were preselected and validated by using a de novo female hybrid assembly. Overall, the SSR density in the genome was 886.7 markers per megabase of genomic sequences and the dinucleotide motif was the most abundant (52.4%). In silico comparison identified a set of 108 SSRs (with di-, tetra- or pentanucleotide motifs) widely distributed in the genome and suitable for primer design. A total of 106 markers were structured in thirteen multiplex PCR assays (with up to 10-plex) and the amplification conditions were optimized with a high-quality score. Main genetic diversity statistics and genotyping reliability were assessed. A subset of 40 high polymorphic markers were selected to optimize four supermultiplex PCRs (with up to 11-plex) for pedigree analysis. Theoretical exclusion probabilities and real parentage allocation tests using parent-offspring information confirmed their robustness and effectiveness for parental assignment. These new SSR markers were combined with previously published SSRs (in total 229 makers) to construct a new and improved integrated genetic map containing 21 linkage groups that matched with the expected number of chromosomes. Synteny analysis with respect to C. semilaevis provided new clues on chromosome evolution in flatfish and the formation of metacentric and submetacentric chromosomes in Senegalese sole. This study was funded by project RTA2017-00054-C03-01, RTA2017-00054-C03-02 and RTA2017-00054-C03-03 funded from MCIU/AEI/FEDER, UE. IGC is funded by a predoctoral fellowship from INIA
Published: 2020

20. A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection

Author: Andreakos, Evangelos, Abel, Laurent, Vinh, Donald C., Kaja, Elżbieta, Drolet, Beth A., Zhang, Qian, O’Farrelly, Cliona, Novelli, Giuseppe, Rodríguez-Gallego, Carlos, Haerynck, Filomeen, Prando, Carolina, Pujol, Aurora, Bastard, Paul, Biggs, Catherine M., Bigio, Benedetta, Boisson, Bertrand, Bolze, Alexandre, Bondarenko, Anastasiia, Brodin, Petter, Chakravorty, Samya, Christodoulou, John, Cobat, Aurelié, Condino-Neto, Antonio, Constantinescu, Stefan N., Feldman, Hagit Baris, Fellay, Jacques, Flores, Carlos, Halwani, Rabih, Jouanguy, Emmanuelle, Lau, Yu-Lung, Meyts, Isabelle, Mogensen, Trine H., Okada, Satoshi, Okamoto, Keisuke, Ozcelik, Tayfun, Pan-Hammarström, Qiang, Diego, Rebeca Pérez de, Planas, Anna M., Puel, Anne, Quintana-Murci, Lluis, Renia, Laurent, Resnick, Igor, Sediva, Anna, Shcherbina, Anna, Slaby, Ondrej, Tancevski, Ivan, Turvey, Stuart E., Uddin, K. M. Furkan, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Zhang, Shen-Ying, Su, Helen C., Casanova, Jean-Laurent, Spaan, András N., Biomedical Research Foundation of the Academy of Athens (BRFAA), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Department of Medecine [Montréal], McGill University = Université McGill [Montréal, Canada], University of Wisconsin-Madison, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Trinity College Dublin, University of Rome Tor Vergata, Hospital Universitario de Gran Canaria Dr Negrin, Universidad de las Palmas de Gran Canaria (ULPGC), Ghent University Hospital, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Institució Catalana de Recerca i Estudis Avançats (ICREA), CIBER de Enfermedades Raras (CIBERER), University of British Columbia (UBC), Karolinska Institutet [Stockholm], Emory University [Atlanta, GA], University of Melbourne, Universidade de São Paulo = University of São Paulo (USP), Université Catholique de Louvain = Catholic University of Louvain (UCL), Tel Aviv University (TAU), School of Life Sciences [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), University of Sharjah (UoS), Department of Paediatrics and Adolescent Medicine [HKU], The University of Hong Kong (HKU), University Hospitals Leuven [Leuven], Department of Microbiology, Immunology and Transplantation [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Aarhus University Hospital, Hiroshima University, Tokyo Medical and Dental University [Japan] (TMDU), Bilkent University [Ankara], Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Agency for science, technology and research [Singapore] (A*STAR), Nanyang Technological University [Singapour], Faculty of Medicine [Brno] (MED / MUNI), Masaryk University [Brno] (MUNI), Leopold Franzens Universität Innsbruck - University of Innsbruck, University of Amsterdam [Amsterdam] (UvA), Adam Mickiewicz University in Poznań (UAM), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), University Medical Center [Utrecht], The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS-COV05, the Fondation du Souffle, the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. E.A. is supported by research grants from the European Commission’s Horizon 2020 research and innovation program (IMMUNAID, grant no. 779295, CURE, grant no. 767015 and TO_AITION grant no. 848146) and the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). C.O.F. is supported in part by the Science Foundation Ireland COVID-19 Program. G.N. is supported by a grant awarded to Regione Lazio (Research Group Projects 2020) no. A0375-2020-36663, GecoBiomark. A.P. is supported in part by the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342) and the CERCA Program/Generalitat de Catalunya. H.S. is supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. A.S. is supported in part by the European Union’s Horizon 2020 research and innovation program (Marie Sklodowska-Curie grant no. 789645)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), Özçelik, Tayfun, Department of Public Health and Cell Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy, Université Paris Cité, Equipe HAL, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé - - GENCOVID2020 - ANR-20-COVI-0003 - COVID-19 - VALID, National Institutes of Health (US), National Center for Advancing Translational Sciences (US), National Human Genome Research Institute (US), Fisher Center for Alzheimer's Research Foundation, Meyer Foundation, Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Pershing Square Foundation, Institut National de la Santé et de la Recherche Médicale (France), Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, Université de Paris, European Commission, Hellenic Foundation for Research and Innovation, Science Foundation Ireland, Regione Lazio, Generalitat de Catalunya, and National Institute of Allergy and Infectious Diseases (US)
Subjects: Tuberculosis, autoantibodies, Immunology, Plasmodium vivax, restriction, Disease, Asymptomatic, Risk Assessment, Chemokine receptor, Genetic Heterogeneity, Immunity, Risk Factors, il28b, medicine, Immunology and Allergy, Animals, Humans, PLASMODIUM, Genetic Predisposition to Disease, Disease Resistance, Genetics, biology, Transmission (medicine), SARS-CoV-2, transmission, Autoantibody, COVID-19, virus diseases, deficiency, Protective Factors, hiv-1 infection, biology.organism_classification, medicine.disease, immunity, Phenotype, tuberculosis, Settore MED/03, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Viral infection, Host-Pathogen Interactions, Perspective, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Infection, individuals, inborn-errors
Abstract: SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection., The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS-COV05, the Fondation du Souffle, the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. E.A. is supported by research grants from the European Commission’s Horizon 2020 research and innovation program (IMMUNAID, grant no. 779295, CURE, grant no. 767015 and TO_AITION grant no. 848146) and the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). C.O.F. is supported in part by the Science Foundation Ireland COVID-19 Program. G.N. is supported by a grant awarded to Regione Lazio (Research Group Projects 2020) no. A0375-2020-36663, GecoBiomark. A.P. is supported in part by the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342) and the CERCA Program/Generalitat de Catalunya. H.S. is supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. A.S. is supported in part by the European Union’s Horizon 2020 research and innovation program (Marie Sklodowska-Curie grant no. 789645).
Published: 2022

21. Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry

Author: Neil Lawrence, Irina Bacila, Jeremy Dawson, Jillian Bryce, Salma R. Ali, Erica L. T. van den Akker, Tânia A. S. S. Bachega, Federico Baronio, Niels H. Birkebæk, Walter Bonfig, Hedi C. van der Grinten, Eduardo C. Costa, Liat de Vries, Heba Elsedfy, Ayla Güven, Sabine Hannema, Violeta Iotova, Hetty J. van der Kamp, María Clemente, Corina R. Lichiardopol, Tatjana Milenkovic, Uta Neumann, Ana Nordenström, Şukran Poyrazoğlu, Ursina Probst‐Scheidegger, Luisa De Sanctis, Rieko Tadokoro‐Cuccaro, Ajay Thankamony, Ana Vieites, Zehra Yavaş, Syed Faisal Ahmed, Nils Krone, Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development, Institut Català de la Salut, [Lawrence N] Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK. Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK. [Bacila I] Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK. [Dawson J] Institute of Work Psychology, Management School, University of Sheffield, Sheffield, UK. School of Health and Related Research, University of Sheffield, Sheffield, UK. [Bryce J] Office for Rare Conditions, Royal Hospital for Children & Queen Elizabeth University Hospital, Glasgow, UK. Office for Rare Conditions, Royal Hospital for Children & Queen Elizabeth University Hospital, Glasgow, UK. [Ali SR] Office for Rare Conditions, Royal Hospital for Children & Queen Elizabeth University Hospital, Glasgow, UK. Office for Rare Conditions, Royal Hospital for Children & Queen Elizabeth University Hospital, Glasgow, UK. Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK. [van den Akker ELT] Department of Pediatric Endocrinology, Sophia Children's Hospital, Erasmus Medical Centre, Rotterdam, the Netherlands. [Clemente M] Servei d’Endocrinologia Pediàtrica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. CIBER de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Lawrence, Neil [0000-0002-7686-6172], Bonfig, Walter [0000-0002-6797-7604], Hannema, Sabine [0000-0002-8996-0993], Neumann, Uta [0000-0003-3892-0577], Nordenström, Ana [0000-0003-0405-3401], Faisal Ahmed, Syed [0000-0003-0689-5549], Krone, Nils [0000-0002-3402-4727], Apollo - University of Cambridge Repository, and Amsterdam Reproduction & Development (AR&D)
Subjects: compuestos policíclicos::compuestos con anillos de fusión::esteroides::pregnanos::pregnenos::pregnenodionas::hidrocortisona [COMPUESTOS QUÍMICOS Y DROGAS], Male, Endocrinology, Diabetes and Metabolism, Malalties congènites - Tractament, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Other subheadings::Other subheadings::/drug therapy [Other subheadings], biomarkers, congenital adrenal hyperplasia, hydrocortisone, linear mixed-effects models, Endocrinology, SDG 3 - Good Health and Well-being, Humans, Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Adrenal Hyperplasia, Congenital [DISEASES], Other subheadings::/therapeutic use [Other subheadings], Registries, Child, Progesterone, Retrospective Studies, Hidrocortisona - Ús terapèutic, Adrenal Hyperplasia, Congenital, Otros calificadores::/uso terapéutico [Otros calificadores], 17-alpha-Hydroxyprogesterone, Androstenedione, Polycyclic Compounds::Fused-Ring Compounds::Steroids::Pregnanes::Pregnenes::Pregnenediones::Hydrocortisone [CHEMICALS AND DRUGS], Child, Preschool, Female, enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades genéticas congénitas::hiperplasia suprarrenal congénita [ENFERMEDADES], Hiperplàsia - Tractament
Abstract: Funder: European Society for Paediatric Endocrinology Research Unit, OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.
Published: 2022

22. Reflections in bioethics key to the document Clinical guidelines for the care of transsexual, transgender and diverse gender minors. Authors reply

Author: Amadora Moral-Martos, Marcelino Gómez-Balaguer, Isolina Riaño Galán, Diego Yeste Fernández, Institut Català de la Salut, [Moral-Martos A] Unitat d’Endocrinologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Equipo de Pediatría Territorial Garraf, Institut Català de la Salut (ICS), Barcelona, Spain. [Gómez-Balaguer M] Unidad de Identidad de Género, Servicio de Endocrinología y Nutrición, Hospital Universitario Doctor Peset, Grupo de Identidad y Diferenciación sexual de la Sociedad Española de Endocrinología y Nutrición (GIDSEEN), Valencia, Spain. [Riaño Galán I] Endocrinología Pediátrica, AGC de Pediatría, Hospital Universitario Central de Asturias, IUOPA-Departamento de Medicina-ISPA, Universidad de Oviedo, CIBER de Epidemiología y Salud Pública, Oviedo, Spain. [Yeste Fernández D] Unitat d’Endocrinologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, CIBER de Enfermedades Raras (CIBERER), ISCIII, EndoERN, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Persons::Sexual and Gender Minorities::Transgender Persons [NAMED GROUPS], personas::minorías sexuales y de género::personas transgénero [DENOMINACIONES DE GRUPOS], Transgèneres, Pediatrics, Perinatology and Child Health, Presa de decisions, Minories sexuals, Psychological Phenomena::Mental Processes::Thinking::Decision Making [PSYCHIATRY AND PSYCHOLOGY], fenómenos psicológicos::procesos mentales::pensamiento::toma de decisión [PSIQUIATRÍA Y PSICOLOGÍA]
Abstract: Menores transexuales; Género diverso Menors transsexuals; Gènere divers Transsexual minors; Diverse gender
Published: 2022

23. Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders

Author: Delaby, Constance, Alcolea, Daniel, Carmona Iragui, María, Illán-Gala, Ignacio, Morenas Rodríguez, Estrella, Barroeta, Isabel, Altuna-Azkargorta, Miren, Estellés, T., Santos-Santos, M., Turon-Sans, J., Muñoz, L., Ribosa-Nogué, Roser, Sala-Matavera, I., Sánchez-Saudinós, María Belén, Subirana, A., Videla Toro, Laura, Benejam, Bessy, Sirisi Dolcet, Sonia, Lehmann, S., Belbin, Olivia, Clarimón, Jordi, Blesa, Rafael, Pagonabarraga Mora, Javier, Rojas-Garcia, Ricard, Fortea, Juan, Lleó, Alberto, Universitat Autònoma de Barcelona, 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), Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona (UAB), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Ludwig-Maximilians-Universität München (LMU), CIBER de Enfermedades Raras (CIBERER), and Salvy-Córdoba, Nathalie
Subjects: 0301 basic medicine, Male, Pathology, Neurology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurodegenerative Diseases, Cohort Studies, 0302 clinical medicine, Cerebrospinal fluid, Neurofilament Proteins, MESH: Early Diagnosis, Medicine, Amyotrophic lateral sclerosis, MESH: Neurofilament Proteins, MESH: Cohort Studies, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], MESH: Aged, Multidisciplinary, Neurodegeneration, Neurodegenerative Diseases, MESH: Follow-Up Studies, Disease Progression, Female, MESH: Disease Progression, Alzheimer's disease, Frontotemporal dementia, medicine.medical_specialty, Science, Neuroaxonal Dystrophies, Article, Progressive supranuclear palsy, 03 medical and health sciences, mental disorders, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Aged, MESH: Humans, business.industry, Dementia with Lewy bodies, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, MESH: Neuroaxonal Dystrophies, MESH: Male, 030104 developmental biology, Early Diagnosis, MESH: Biomarkers, business, MESH: Female, 030217 neurology & neurosurgery, Biomarkers, Follow-Up Studies
Abstract: Altres ajuts: "Marató TV3" grant (20141210, 044412, 20143710). Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases.
Published: 2020

24. Fasentin diminishes endothelial cell proliferation, differentiation and invasion in a glucose metabolism-independent manner

Author: Ana R. Quesada, Beatriz Martínez-Poveda, Miguel Ángel Medina, Manuel Marí-Beffa, MÂª Carmen Ocaña, [Ocaña,MC, Martínez-Poveda,B, Quesada,AR, Medina,MÁ] Universidad de Málaga, Andalucía Tech, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Málaga, Spain. [Ocaña,MC, Medina,MÁ] IBIMA (Biomedical Research Institute of Málaga), Málaga, Spain. [Marí-Beffa,M] Universidad de Málaga, Andalucía Tech, Departamento de Biología Celular, Genética y Fisiología, Facultad de Ciencias, Málaga, Spain. [Quesada,AR, Medina,MÁ] CIBER de Enfermedades Raras (CIBERER), Málaga, Spain., and Mª Carmen Ocaña is recipient of a predoctoral FPU grant from the Spanish Ministry of Education, Culture and Sport. This work was supported by grants PID2019-105010RB-100 (MINECO and FEDER), UMA18-FEDERJA-220 (Andalusian Government and FEDER) and funds from group BIO 267 (Andalusian Government), as well as funds from 'Plan Propio de Investigación y Transferencia (Universidad de Málaga). The 'CIBER de Enfermedades Raras' is an initiative from the ISCIII (Spain).
Subjects: Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation [Medical Subject Headings], Angiogenesis, Pyridines, Endothelial cells, Glucose uptake, Cellular differentiation, Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose [Medical Subject Headings], lcsh:Medicine, Chick Embryo, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyridines [Medical Subject Headings], Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Movement [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Neovascularization, Cell Movement, Phenomena and Processes::Circulatory and Respiratory Physiological Phenomena::Cardiovascular Physiological Phenomena::Cardiovascular Physiological Processes::Neovascularization, Physiologic [Medical Subject Headings], Organisms::Eukaryota::Animals [Medical Subject Headings], Anilides, lcsh:Science, Anilidas, Cell proliferation, Cells, Cultured, Anatomy::Cells::Epithelial Cells::Endothelial Cells::Human Umbilical Vein Endothelial Cells [Medical Subject Headings], Tube formation, Multidisciplinary, Chemistry, Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Growth::Cell Growth Processes::Cell Proliferation [Medical Subject Headings], Cell Differentiation, Anatomy::Animal Structures::Embryo, Nonmammalian::Chick Embryo [Medical Subject Headings], Cell biology, Endothelial stem cell, MCF-7 Cells, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::MCF-7 Cells [Medical Subject Headings], medicine.symptom, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Artiodactyla::Ruminants::Cattle [Medical Subject Headings], Proliferación celular, Neovascularization, Physiologic, Article, Target identification, medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, Chemicals and Drugs::Organic Chemicals::Amides::Anilides [Medical Subject Headings], Cell Proliferation, Cell growth, lcsh:R, Células endoteliales, Glucose, Anatomy::Cells::Cells, Cultured [Medical Subject Headings], Glucosa, Cancer cell, Cattle, lcsh:Q, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::HeLa Cells [Medical Subject Headings], Tumour angiogenesis, HeLa Cells
Abstract: The synthetic compound fasentin has been described as a modulator of GLUT-1 and GLUT-4 transporters, thus inhibiting glucose uptake in some cancer cells. Endothelial glucose metabolism has been recently connected to angiogenesis and it is now an emerging topic in scientific research. Indeed, certain compounds with a known effect on glucose metabolism have also been shown to inhibit angiogenesis. In this work we tested the capability of fasentin to modulate angiogenesis in vitro and in vivo. We show that fasentin inhibited tube formation in endothelial cells by a mechanism that involves a negative effect on endothelial cell proliferation and invasion, without affecting other steps related to the angiogenic process. However, fasentin barely decreased glucose uptake in human dermal microvascular endothelial cells and the GLUT-1 inhibitor STF-31 failed to inhibit tube formation in these cells. Therefore, this modulatory capacity on endothelial cells function exerted by fasentin is most likely independent of a modulation of glucose metabolism. Taken together, our results show a novel biological activity of fasentin, which could be evaluated for its utility in cancer and other angiogenesis-dependent diseases.
Published: 2020

25. European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 1. epidemiology, diagnostics and prevention

Author: Stratigos, Alexander J, Garbe, Claus, Dessinioti, Clio, Lebbe, Celeste, Bataille, Veronique, Bastholt, Lars, Dreno, Brigitte, Fargnoli, Maria Concetta, Forsea, Ana Maria, Frenard, Cecille, Harwood, Catherine Α, Hauschild, Axel, Hoeller, Christoph, Kandolf-Sekulovic, Lidija, Kaufmann, R, Kelleners-Smeets, Nicole Wj, Malvehy, Josep, Del Marmol, Veronique, Middleton, Mark R, Moreno-Ramirez, David, Pellecani, Giovanni, Peris, Ketty, Saiag, Philippe, van den Beuken-van Everdingen, Marieke H J, Vieira, Ricardo, Zalaudek, Iris, Eggermont, Alexander M M, Grob, Jean-Jacques, European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC), National and Kapodistrian University of Athens (NKUA), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), North & East Hertfordshire NHS Trust [Northwood, UK], Odense University Hospital (OUH), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), University of L'Aquila [Italy] (UNIVAQ), University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Queen Mary University of London (QMUL), Kiel University, Medizinische Universität Wien = Medical University of Vienna, Military Medical Academy [Belgrade, Serbia] (2MA), Frankfurt University Hospital, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III [Madrid] (ISC), Université libre de Bruxelles (ULB), Hôpital Erasme [Bruxelles], University of Oxford, Hospital Universitario Virgen Macarena [Sevilla, Spain] (HUVM), University - Hospital of Modena and Reggio Emilia [Modena, Italy], Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], University Veterinary Hospital [Coimbra, Portugal], Università degli studi di Trieste = University of Trieste, Princess Máxima Center for Pediatric Oncology, Assistance Publique - Hôpitaux de Marseille (APHM), Aix Marseille Université (AMU), Novartis Les Laboratories Pierre Fabre Sanofi Bristol-Myers Squibb, BMS Pfizer Amgen Roche LEO Pharma Research Foundation Cilag Merck Meso Scale Diagnostics, MSD Genentech, The guidelines were supported by grants from the EADO for the guideline meetings. The authors did this work on a voluntary basis and did not receive any honorarium or reimbursements. Guidelines development group members stated their conflicts of interest in the relevant section., Dr. Stratigos reports personal fees and/or research support from Novartis , Roche , BMS , Abbvie , Sanofi , Regeneron , Genesis Pharma , outside the submitted work. Dr. Garbe reports personal fees from Amgen , personal fees from MSD , grants and personal fees from Novartis , grants and personal fees from NeraCare, grants and personal fees from BMS , personal fees from Pierre Fabre , personal fees from Philogen, grants and personal fees from Roche , grants and personal fees from Sanofi , outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb , personal fees from MSD , personal fees from Novartis , personal fees from Amgen , grants and personal fees from Roche , personal fees from Avantis Medical Systems, personal fees from Pierre Fabre , personal fees from Pfizer , personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis , personal fees from Merck MSD , outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS , Roche , Novartis , Pierre-Fabre, Astra Zeneca, InCyte, MSD / Merck , Bayer . Dr. Dréno reports grants and personal fees from BMS , personal fees from MSD , grants and personal fees from Roche , grants and personal fees from Fabre, grants and personal fees from Sanofi , outside the submitted work. Dr. Fargnoli reports grants and personal fees from Almirall, grants and personal fees from Leo Pharma, personal fees from Janssen, grants and personal fees from Novartis , personal fees from Lilly , grants and personal fees from Sanofi , personal fees from UCB , grants and personal fees from Abbvie , personal fees from Celgene , personal fees from Pierre Fabre , grants and personal fees from Galderma , personal fees from Mylan, personal fees from Medac Pharma, personal fees from Roche , personal fees from Sun Pharma , outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis , Leo Pharma, Solartium, Pierre-Fabre, outside the submitted work. Dr. Frenard has nothing to disclose. Dr. Harwood reports institutional research grants and honoraria from Sanofi , Novartis , Merck , Pfizer , Galderma , MEDA, Almirall, Pellepharm, Leo Pharma, CERIES. Dr. Hauschild reports honoraria and/or research grants from: Almirall, BMS , Roche , Novartis , Pierre-Fabre, Sunpharma, MerckSerono, SanofiAventis, Regeneron , MSD / Merck , Philogen, OncoSec outside the submitted work. Dr. Hoeller reports grants and personal fees from Amgen , personal fees from BMS , personal fees from MSD , personal fees from Novartis , personal fees from Pierre Fabre , personal fees from Roche , personal fees from Sanofi , personal fees from Incyte, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers’ honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from: AbbVie , Amgen , Biontech, BMS , Celgene , Galderma , Janssen, Leo, Lilly , Merck , MSD , Novartis , Pierre Fabre , Pfizer , Regeneron , Roche , Wyeth . Advisory Board and Honoraria from Merz, Roche, Novartis. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development, other from Janssen-Cilag, other from AbbVie , other from Galderma , outside the submitted work. Dr. Malvehy reports research grants from Almirall, ISDIN, Leo Pharma, Galderma , GSK , Cantabria, participation in advisory board meetings for Almirall, Sunpharma, BMS , Roche , Novartis , Pierre-Fabre. Dr. del Marmol reports personal fees from MSD , from BMS , personal fees from Sanofi , grants and personal fees from ABVIE, grants from Jansen, outside the submitted work. Dr. Middleton reports personal fees and/or grants from Amgen , Roche , Astrazeneca, GSK , Novartis , Immunocore, BMS , Eisai and Merck . Institutional funding from Millennium, Vertex, Pfizer , Regeneron , TCBiopharma, BiolineRx, Replimune, outside the submitted work. Dr. Moreno-Ramírez has nothing to disclose. Dr. Pellecani reports grants from university of modena and reggio emilia, during the conduct of the study, grants from novartis, grants and personal fees from almirall, grants from leo pharma, from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie , Almirall, Biogen Celgene , Lilly , Galderma , Leo Pharma, Novartis , Roche , Sanofi , Sun Pharma , Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen , Bristol-Myers Squibb , MSD , Merck-Serono, Novartis , Pfizer , Roche- Genentech , Pierre Fabre , and Sanofi , outside the submitted work. Dr. van den Beuken-van Everdingen has nothing to disclose. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi , Sun Pharma , Novartis , Galderma , Roche , Celgene , Almirall, Leofarma, Mylan, Difa Cooper, Cieffe Labs, La Roche Posay, Pierre Fabre . Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for Biocad, BioInvent, Bristol Myers Squibb ( BMS ), CatalYm, Ellipses, Glaxo Smith Kline ( GSK ), HalioDX, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme ( MSD ), Novartis , Pfizer , Polynoma, Regeneron , Sanofi , Sellas, SkylineDx. Dr. Grob reports personal fees for advisory board and as speaker from Amgen , Roche , GSK , Novartis , BMS , Pierre fabre, Merck , Sanofi , Merck , Pfizer outside the submitted work., European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC), HAL UVSQ, Équipe, Dermatologie, MUMC+: MA Dermatologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, RS: MHeNs - R3 - Neuroscience, MUMC+: TPZ Palliatieve Zorg (9), Stratigos, A. J., Garbe, C., Dessinioti, C., Lebbe, C., Bataille, V., Bastholt, L., Dreno, B., Fargnoli, M. C., Forsea, A. M., Frenard, C., Harwood, C. Alpha., Hauschild, A., Hoeller, C., Kandolf-Sekulovic, L., Kaufmann, R., Kelleners-Smeets, N. W., Malvehy, J., del Marmol, V., Middleton, M. R., Moreno-Ramirez, D., Pellecani, G., Peris, K., Saiag, P., van den Beuken-van Everdingen, M. H. J., Vieira, R., Zalaudek, I., Eggermont, A. M. M., Grob, J. -J., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Cancer Research, Skin Neoplasms, Staging, Medical Oncology, Palpation, Imaging, Low-risk, 0302 clinical medicine, Protective Clothing, Metastatic cSCC, Positron Emission Tomography Computed Tomography, Diagnosis, Epidemiology, Societies, Medical, AMERICAN JOINT COMMITTEE, Skin, Ultrasonography, Invasive cutaneous squamous cell carcinoma, medicine.diagnostic_test, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, High-risk common primary cSCC, RANDOMIZED CONTROLLED-TRIAL, Prognosis, Magnetic Resonance Imaging, 3. Good health, LYMPH-NODE BIOPSY, Oncology, 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Sunlight, Settore MED/35 - MALATTIE CUTANEE E VENEREE, Diagnosi, medicine.medical_specialty, Consensus, Prognosi, Sentinel lymph node, Locally advanced Cscc, Prevention, Dermatology, Humans, Lymph Nodes, Neoplasm Staging, Patient Education as Topic, Risk Assessment, Sunscreening Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Physical examination, PERINEURAL INVASION, 03 medical and health sciences, BASAL-CELL, [SDV.CAN] Life Sciences [q-bio]/Cancer, Medical, Biopsy, medicine, CANCER PREVENTION, ORGAN TRANSPLANT RECIPIENTS, business.industry, Carcinoma, Cancer, Magnetic resonance imaging, Guideline, medicine.disease, Cancérologie, HIGH-RISK, 030104 developmental biology, Squamous Cell, SUN PROTECTION, Societies, business
Abstract: Invasive cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in the white populations, accounting for 20% of all cutaneous malignancies. Factors implicated in cSCC etiopathogenesis include ultraviolet radiation exposure and chronic photoaging, age, male sex, immunosuppression, smoking and genetic factors. A collaboration of multidisciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organisation of Research and Treatment of Cancer (EORTC) was formed to update recommendations on cSCC classification, diagnosis, risk stratification, staging and prevention, based on current literature, staging systems and expert consensus. Common cSCCs are typically indolent tumors, and most have a good prognosis with 5-year cure rates of greater than 90%, and a low rate of metastases (, SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

26. The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder

Author: Kumble, Smitha, Levy, Amanda, Punetha, Jaya, Gao, Hua, Ah Mew, Nicholas, Anyane-Yeboa, Kwame, Benke, Paul, Berger, Sara, Bjerglund, Lise, Campos-Xavier, Belinda, Ciliberto, Michael, Cohen, Julie, Comi, Anne, Curry, Cynthia, Damaj, Lena, Denommé-Pichon, Anne-Sophie, Emrick, Lisa, Faivre, Laurence, Fasano, Mary Beth, Fiévet, Alice, Finkel, Richard, García-Miñaúr, Sixto, Gerard, Amanda, Gomez-Puertas, Paulino, Guillen Sacoto, Maria, Hoffman, Trevor, Howard, Lillian, Iglesias, Alejandro, Izumi, Kosuke, Larson, Austin, Leiber, Anja, Lozano, Reymundo, Marcos-Alcalde, Iñigo, Mintz, Cassie, Mullegama, Sureni, Møller, Rikke, Odent, Sylvie, Oppermann, Henry, Ostergaard, Elsebet, Pacio-Míguez, Marta, Palomares-Bralo, Maria, Parikh, Sumit, Paulson, Anna, Platzer, Konrad, Posey, Jennifer, Potocki, Lorraine, Revah-Politi, Anya, Rio, Marlene, Ritter, Alyssa, Robinson, Scott, Rosenfeld, Jill, Santos-Simarro, Fernando, Anyane‐Yeboa, Kwame, Campos‐Xavier, Belinda, Denommé‐Pichon, Anne‐Sophie, García‐Miñaúr, Sixto, Gomez‐Puertas, Paulino, Marcos‐Alcalde, Iñigo, Pacio‐Míguez, Marta, Palomares‐Bralo, Maria, Revah‐Politi, Anya, Santos‐Simarro, Fernando, Sombra, Sérgio Sousa, Wéber, Mathys, Xie, Yili, Chung, Wendy K., Brown, Natasha, Tümer, Zeynep, Murdoch Children's Research Institute (MCRI), Copenhagen University Hospital, Baylor College of Medicine (BCM), Baylor University, Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Pontchaillou [Rennes], Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Institut Gustave Roussy (IGR), 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), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CIBER de Enfermedades Raras (CIBERER), GeneDx [Gaithersburg, MD, USA], Columbia University Irving Medical Center (CUIMC), University of Melbourne, University of Copenhagen = Københavns Universitet (KU), Spanish Ministry of Science / State Research Agency projects. Grant Numbers: DTS20-00024, RTC-2017-6494-1, RTI2018-094434-B-I00 SFARI and JPB Foundation, Raregenomics network, financed by the Consejería de Educación de la C. de Madrid. Grant Number: S2017 / BMD-3721, European Comission JPIAMR projects CONNECT and AEPIC, National Center for Advancing Translational Sciences, National Institutes of Health. Grant Number: UL1TR001873, National Human Genome Research Institute (NHGRI) and National Heart, Lung, and Blood Institute (NHLBI). Grant Number: UM1 HG006542 Undiagnosed Diseases Network, European Social Fund, Rashid Family Fund, NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director. Grant Number: U01HG007709, ISCIII, Ministerio de Ciencia e Innovación. Grant Number: PI19/01681, Baylor Hopkins Center for Mendelian Genomics. Grant Numbers: NHGRI K08 HG008986, NHGRI/NLHBI UM1 HG006542, Centro Portugal Regional Operational Programme (CENTRO 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Grant Number: CENTRO-01-0247-FEDER-017800, Département de biologie et pathologie médicales [Gustave Roussy], 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 ), and University of Copenhagen = Københavns Universitet (UCPH)
Subjects: Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Dwarfism, Biology, Bioinformatics, Weight Gain, Short stature, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Neuroimaging, Seizures, variable expressivity, Intellectual disability, Genetics, medicine, Missense mutation, Humans, QRICH1, hypotonia, Genetics (clinical), 030304 developmental biology, 0303 health sciences, medicine.disease, Hypotonia, short stature, Scoliosis, variant, Autism spectrum disorder, Neurodevelopmental Disorders, intellectual disability, Muscle Hypotonia, medicine.symptom, 030217 neurology & neurosurgery
Abstract: De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability. The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum (ER) stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n=38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/intellectual disability (71%), non-specific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity. This article is protected by copyright. All rights reserved.
Published: 2021

27. Chromosome anchoring in Senegalese sole (Solea senegalensis) reveals sex-associated markers and genome rearrangements in flatfish

Author: M. Gonzalo Claros, Concha Berbel, Manuel Manchado, Juan F. Martinez-Blanch, Jèssica Gómez-Garrido, Israel Guerrero-Cózar, Pierre-Alexandre Gagnaire, Tyler Alioto, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Guerrero-Cózar, Israel, Gómez-Garrido, Jèssica, Berbel, Concha, Martinez-Blanch, Juan F., Alioto, Tyler, Claros, M. Gonzalo, Gagnaire, Pierre-Alexandre, Manchado, Manuel, [Guerrero-Cózar,I, Berbel,C, Manchado,M] IFAPA Centro El Toruño, Junta de Andalucía, Puerto de Santa María, Cádiz, Spain. [Gomez-Garrido,J, Alioto,T] CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [Martinez-Blanch,JF] Biopolis S.L.-ADM, Parc Cientifc Universidad De Valencia, Paterna, Spain. [Alioto,T] Universitat Pompeu Fabra (UPF), Barcelona, Spain. [Claros,MG] Department of Molecular Biology and Biochemistry, Universidad de Málaga, Málaga, Spain. [Claros,MG] CIBER de Enfermedades Raras (CIBERER), Málaga, Spain. [Claros,MG] Institute of Biomedical Research in Málaga (IBIMA), IBIMA-RARE, Málaga, Spain. [Claros,MG] Instituto de Hortofruticultura Subtropical Y Mediterránea (IHSM-UMA-CSIC), Málaga, Spain. [Gagnaire,PA] ISEM, Univ Montpellier, CNRS, EPHE, IRD, Montpellier, France. [Manchado,M] Crecimiento Azul, Centro IFAPA El Toruño, Unidad Asociada al CSIC, El Puerto de Santa María, Spain., and This study was funded by project RTA2017-00054-C03-01 and RTA2017-00054-C03-funded from MCIU/AEI/FEDER, UE and cofunded 80% by Programa Operativo FEDER de Andalucía 2014-2020, project PP.AVA.AVA201601.9 SOLEALGAE. Moreover, the study has received funding from EU H2020 research and innovation program under grant agreement 817992 ERANET-BLUEBIO COFUND project PCI2020-111994 BestBrood/AEI/10.13039/501100011033. IGC is funded by a predoctoral fellowship from INIA. This work would not have been possible without the computer resources and the technical support provided by the Plataforma Andaluza de Bioinformática of the University of Málaga and CNAG. We acknowledge the support of the Spanish Ministry of Science, Innovation and Universities to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya, the Spanish Ministry of Science and Innovation through the Instituto de Salud Carlos III, Generalitat de Catalunya through Departament de Salut and Departament d’Empresa i Coneixement and co-fnancing with funds from the European Regional Development Fund by the Spanish Ministry of Science and Innovation corresponding to the Programa Operativo FEDER Plurirregional de España (POPE) 2014-2020 and by the Secretaria d’Universitats i Recerca, Departament d’Empresa i Coneixe ment of the Generalitat de Catalunya corresponding to the Programa Operatiu FEDER de Catalunya 2014-20.
Subjects: Male, Genetic Linkage, Genome-wide association study, Genome, 0302 clinical medicine, Organisms::Eukaryota::Animals [Medical Subject Headings], Diferenciación sexual, Ligamiento genético, Genetics, Gene Rearrangement, 0303 health sciences, Multidisciplinary, Contig, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Fishes::Flatfishes [Medical Subject Headings], [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Genomics, Penetrance, Repeticiones de microsatélite, Fatfish, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Base Sequence::Repetitive Sequences, Nucleic Acid::Tandem Repeat Sequences::Microsatellite Repeats [Medical Subject Headings], Flatfishes, Medicine, Sex, Female, Heterogametic sex, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Sex Determination Processes [Medical Subject Headings], Science, Check Tags::Male [Medical Subject Headings], Locus (genetics), Biology, Chromosome, Article, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome [Medical Subject Headings], 03 medical and health sciences, Genetic linkage, Phenomena and Processes::Genetic Phenomena::Genetic Linkage [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Rearrangement [Medical Subject Headings], Animals, Genoma, 030304 developmental biology, Animal breeding, Cromosomas, Sex Determination Processes, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Genes, Check Tags::Female [Medical Subject Headings], 030217 neurology & neurosurgery, Genome-Wide Association Study, Microsatellite Repeats
Abstract: The integration of physical and high-density genetic maps is a very useful approach to achieve chromosome-level genome assemblies. Here, the genome of a male Senegalese sole (Solea senegalensis) was de novo assembled and the contigs were anchored to a high-quality genetic map for chromosome-level scaffolding. Hybrid assembled genome was 609.3 Mb long and contained 3403 contigs with a N50 of 513 kb. The linkage map was constructed using 16,287 informative SNPs derived from ddRAD sequencing in 327 sole individuals from five families. Markers were assigned to 21 linkage groups with an average number of 21.9 markers per megabase. The anchoring of the physical to the genetic map positioned 1563 contigs into 21 pseudo-chromosomes covering 548.6 Mb. Comparison of genetic and physical distances indicated that the average genome-wide recombination rate was 0.23 cM/Mb and the female-to-male ratio 1.49 (female map length: 2,698.4 cM, male: 2,036.6 cM). Genomic recombination landscapes were different between sexes with crossovers mainly concentrated toward the telomeres in males while they were more uniformly distributed in females. A GWAS analysis using seven families identified 30 significant sex-associated SNP markers located in linkage group 18. The follicle-stimulating hormone receptor appeared as the most promising locus associated with sex within a region with very low recombination rates. An incomplete penetrance of sex markers with males as the heterogametic sex was determined. An interspecific comparison with other Pleuronectiformes genomes identified a high sequence similarity between homologous chromosomes, and several chromosomal rearrangements including a lineage-specific Robertsonian fusion in S. senegalensis. This study was funded by project RTA2017-00054-C03-01 and RTA2017-00054-C03-funded from MCIU/AEI/FEDER, UE and cofunded 80% by Programa Operativo FEDER de Andalucía 2014-2020, project PP.AVA.AVA201601.9 SOLEALGAE. Moreover, the study has received funding from EU H2020 research and innovation program under grant agreement 817992 ERANET-BLUEBIO COFUND project PCI2020-111994 BestBrood/AEI/10.13039/501100011033. IGC is funded by a predoctoral fellowship from INIA. This work would not have been possible without the computer resources and the technical support provided by the Plataforma Andaluza de Bioinformática of the University of Málaga and CNAG.
Published: 2021

28. Miniaturized Electrochemical Sensors to Monitor Fetal Hypoxia and Acidosis in a Pregnant Sheep Model

Author: Mònica Mir, Nicole Picard-Hagen, Samuel Dulay, Miriam Illa, Eduard Gratacós, Lourdes Rivas, Sergio Berdún, Josep Samitier, Laura Pla, Elisenda Eixarch, Hospital Sant Joan de Déu [Barcelona], Institut de Recerca Pediàtrica Hospital Sant Joan de Déu [Barcelona, Spain], Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III [Madrid] (ISC)-ministerio de ciencia e innovacion, Institute for Bioengineering of Catalonia [Barcelona] (IBEC), Universitat Autònoma de Barcelona (UAB), Exposition, Perturbation Endocrino-métabolique et Reproduction (ToxAlim-EXPER), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), CIBER de Enfermedades Raras (CIBERER), and This research was funded by CELLEX FOUNDATION. This work was financially supported by The Cellex Foundation and the Agencia de Gestio d'Ajuts Universitaris i de Recerca (Grant 2017 SGR 1531). Additionally, E.E. has received support from the Departament de Salut (Grant SLT008/18/00156). The Nanobioengineering group at the Institute of Bioengineering of Catalonia (IBEC) has received support from the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (No. 2017 SGR 1079) and is part of the CERCA Programme/Generalitat de Catalunya and is supported by the Severo Ochoa programme of the Spanish Ministry of Science and Competitiveness (Grant SEV-2014-0425 (2015-2019)). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. L.R. would also like to acknowledge her support within the BEST Postdoctoral Programme, funded by the European Commission under Horizon 2020's Marie Sklodowska-Curie Actions COFUND scheme (Grant Agreement No. 712754).
Subjects: QH301-705.5, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Hemodynamics, Fetal monitoring, Hindlimb, General Biochemistry, Genetics and Molecular Biology, Article, Asphyxia, 03 medical and health sciences, 0302 clinical medicine, Prenatal medicine, medicine, Umbilical Cord Occlusion, Biology (General), Acidosis, umbilical cord occlusion, Asfíxia, Fetus, 030219 obstetrics & reproductive medicine, business.industry, Medicina prenatal, electrochemical sensors, Skeletal muscle, medicine.disease, high-risk pregnancies, Monitoratge fetal, Perinatal asphyxia, Fetal hypoxia, medicine.anatomical_structure, sense organs, medicine.symptom, business, continuous monitoring of acid-base status, 030217 neurology & neurosurgery, Biomedical engineering
Abstract: Perinatal asphyxia is a major cause of severe brain damage and death. For its prenatal identification, Doppler ultrasound has been used as a surrogate marker of fetal hypoxia. However, Doppler evaluation cannot be performed continuously. We have evaluated the performance of a miniaturized multiparametric sensor aiming to evaluate tissular oxygen and pH changes continuously in an umbilical cord occlusion (UCO) sheep model. The electrochemical sensors were inserted in fetal hindlimb skeletal muscle and electrochemical signals were recorded. Fetal hemodynamic changes and metabolic status were also monitored during the experiment. Additionally, histological assessment of the tissue surrounding the sensors was performed. Both electrochemical sensors detected the pO2 and pH changes induced by the UCO and these changes were correlated with hemodynamic parameters as well as with pH and oxygen content in the blood. Finally, histological assessment revealed no signs of alteration on the same day of insertion. This study provides the first evidence showing the application of miniaturized multiparametric electrochemical sensors detecting changes in oxygen and pH in skeletal muscular tissue in a fetal sheep model., This research was funded by CELLEX FOUNDATION. This work was financially supported by The Cellex Foundation and the Agència de Gestió d’Ajuts Universitaris i de Recerca (Grant 2017 SGR 1531). Additionally, E.E. has received support from the Departament de Salut (Grant SLT008/18/00156). The Nanobioengineering group at the Institute of Bioengineering of Catalonia (IBEC) has received support from the Commission for Universities and Research of the Department of Innovation, Universities, and Enterprise of the Generalitat de Catalunya (No. 2017 SGR 1079) and is part of the CERCA Programme / Generalitat de Catalunya and is supported by the Severo Ochoa programme of the Spanish Ministry of Science and Competitiveness (Grant SEV-2014-0425 (2015–2019)). CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008–2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. L.R. would also like to acknowledge her support within the BEST Postdoctoral Programme, funded by the European Commission under Horizon 2020’s Marie Skłodowska-Curie Actions COFUND scheme (Grant Agreement No. 712754).
Published: 2021

29. Endoglin Is an endothelial housekeeper against inflammation: insight in ECFC-related permeability through LIMK/cofilin pathway

Author: Elisa, Rossi, Alexandre, Kauskot, François, Saller, Elisa, Frezza, Sonia, Poirault-Chassac, Anna, Lokajczyk, Pierre, Bourdoncle, Bruno, Saubaméa, Pascale, Gaussem, Miguel, Pericacho, Regis, Bobe, Christilla, Bachelot-Loza, Samuela, Pasquali, Carmelo, Bernabeu, David M, Smadja, Promex Stiftung Fur Die Forschung, Université de Paris, Institut National de la Santé et de la Recherche Médicale (France), Rossi, Elisa, Kauskot. Alexander, Saller, François, Frezza, Elisa, Saubaméa, Bruno, Gaussem, Pascale, Pericacho, Miguel, Bobe, Regis, Bachelot-Loza, Christilla, Pasquali, Samuela, Bernabéu, Carmelo, Smadja, David M., Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Universidad de Salamanca, Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBER de Enfermedades Raras (CIBERER), Rossi, Elisa [0000-0002-0570-6104], Kauskot. Alexander [0000-0002-4064-8114], Saller, François [0000-0001-5255-2630], Frezza, Elisa [0000-0003-0122-7859], Saubaméa, Bruno [0000-0002-6218-0460], Gaussem, Pascale [0000-0002-9139-2147], Pericacho, Miguel [0000-0003-0226-482X], Bobe, Regis [0000-0002-8225-9117], Bachelot-Loza, Christilla [0000-0002-6264-902X ], Pasquali, Samuela [0000-0003-1487-0894], Bernabéu, Carmelo [0000-0002-1563-6162], and Smadja, David M. [0000-0001-7731-9202]
Subjects: Inflammation, Cell Membrane Permeability, Neovascularization, Pathologic, QH301-705.5, [SDV]Life Sciences [q-bio], Endoglin, Endothelial Cells, Lim Kinases, macromolecular substances, Article, Mice, Chemistry, Actin Depolymerizing Factors, Cofilin, HHT1, ECFC, TNFα, Animals, Biology (General), QD1-999
Abstract: Endoglin (Eng) is an endothelial cell (EC) transmembrane glycoprotein involved in adhesion and angiogenesis. Eng mutations result in vessel abnormalities as observed in hereditary hemorrhagic telangiectasia of type 1. The role of Eng was investigated in endothelial functions and permeability under inflammatory conditions, focusing on the actin dynamic signaling pathway. Endothelial Colony-Forming Cells (ECFC) from human cord blood and mouse lung/aortic EC (MLEC, MAEC) from Eng+/+ and Eng+/− mice were used. ECFC silenced for Eng with Eng-siRNA and ctr-siRNA were used to test tubulogenesis and permeability +/− TNFα and +/− LIM kinase inhibitors (LIMKi). In silico modeling of TNFα–Eng interactions was carried out from PDB IDs 5HZW and 5HZV. Calcium ions (Ca2+) flux was studied by Oregon Green 488 in epifluorescence microscopy. Levels of cofilin phosphorylation and tubulin post-translational modifications were evaluated by Western blot. F-actin and actin–tubulin distribution/co-localization were evaluated in cells by confocal microscopy. Eng silencing in ECFCs resulted in a decrease of cell sprouting by 50 ± 15% (p &lt, 0.05) and an increase in pseudo-tube width (41 ± 4.5%, p &lt, 0.001) compared to control. Upon TNFα stimulation, ECFC Eng–siRNA displayed a significant higher permeability compared to ctr-siRNA (p &lt, 0.01), which is associated to a higher Ca2+ mobilization (p &lt, 0.01). Computational analysis suggested that Eng mitigated TNFα activity. F-actin polymerization was significantly increased in ECFC Eng-siRNA, MAEC+/−, and MLEC+/− compared to controls (p &lt, 0.001, p &lt, 0.01, and p &lt, 0.01, respectively) as well as actin/tubulin distribution (p &lt, 0.01). Furthermore, the inactive form of cofilin (P-cofilin at Ser3) was significantly decreased by 36.7 ± 4.8% in ECFC Eng-siRNA compared to ctr-siRNA (p &lt, 0.001). Interestingly, LIMKi reproduced the absence of Eng on TNFα-induced ECFC-increased permeability. Our data suggest that Eng plays a critical role in the homeostasis regulation of endothelial cells under inflammatory conditions (TNFα), and loss of Eng influences ECFC-related permeability through the LIMK/cofilin/actin rearrangement-signaling pathway.
Published: 2021

30. Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa

Author: Guylène Le Meur, Susanne Roosing, Panagiotis I. Sergouniotis, Marta Corton, Sandro Banfi, Graeme C.M. Black, Ivan Conte, Hélène Naacke, Carmen Ayuso, Christian Hamel, Almudena Avila-Fernandez, Agnès Muller, Guillaume Olivier, Daniela Intartaglia, Claire-Marie Dhaenens, Gaël Manes, Sanne K Verbakel, Jeroen Klevering, Isabelle Meunier, Béatrice Bocquet, Carel B. Hoyng, Agathe Roubertie, Audrey Sénéchal, Xavier Zanlonghi, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universidad Autónoma de Madrid (UAM), CIBER de Enfermedades Raras (CIBERER), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Radboud University Medical Center [Nijmegen], Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Centre hospitalier universitaire de Nantes (CHU Nantes), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique Saint-Joseph Angoulême (CSJA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], University of Naples Federico II = Università degli studi di Napoli Federico II, Clinique Jules-Vernes [Nantes], Hôpital Gui de Chauliac [Montpellier], Michel-Avella, Amandine, Olivier, Guillaume, Corton, Marta, Intartaglia, Daniela, Verbakel, Sanne K, Sergouniotis, Panagiotis I, Le Meur, Guylène, Dhaenens, Claire-Marie, Naacke, Hélène, Avila-Fernández, Almudena, Hoyng, Carel B, Klevering, Jeroen, Bocquet, Béatrice, Roubertie, Agathe, Sénéchal, Audrey, Banfi, Sandro, Muller, Agnè, Hamel, Christian L, Black, Graeme C, Conte, Ivan, Roosing, Susanne, Zanlonghi, Xavier, Ayuso, Carmen, Meunier, Isabelle, and Manes, Gaël
Subjects: 0301 basic medicine, MESH: Extracellular Matrix Proteins, sequence analysis, [SDV]Life Sciences [q-bio], eye disease, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Benign concentric annular macular dystrophy, MESH: Eye Proteins, Missense mutation, genetics, Genetics (clinical), Exome sequencing, Genetics, MESH: Aged, MESH: Exome, MESH: Middle Aged, medicine.diagnostic_test, MESH: Retina, MESH: Genetic Predisposition to Disease, [SDV] Life Sciences [q-bio], MESH: Proteoglycans, MESH: Mutation, Sequence analysis, MESH: Pedigree, MESH: Arthrogryposis, Vitelliform macular dystrophy, Biology, MESH: Phenotype, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, MESH: Whole Exome Sequencing, Retinitis pigmentosa, medicine, MESH: Macular Degeneration, MESH: Genes, Recessive, Genetic testing, MESH: Humans, Genetic heterogeneity, eye diseases, MESH: Retrospective Studies, medicine.disease, MESH: Male, ophthalmology, 030104 developmental biology, 030221 ophthalmology & optometry, MESH: Retinitis Pigmentosa, genetic, MESH: Inheritance Patterns, MESH: Female
Abstract: BackgroundInherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.MethodsExome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role.ResultsExome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.ConclusionThis study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.
Published: 2021

31. Building the Future Therapies for Down Syndrome: The Third International Conference of the T21 Research Society

Author: Anna Vazquez, Eric D. Hamlett, Sébastien Malinge, Yann Herault, Frances K. Wiseman, Bradley T. Christian, Laura del Hoyo Soriano, Patricia A Shaw, Floriana Costanzo, John D. Crispino, Eugenio Barone, Jean Maurice Delabar, Renata Bartesaghi, Alain D. Dekker, Juan Fortea Ormaechea, Véronique Brault, Marzia Perluigi, Peter Paul De Deyn, Mara Dierssen, Elizabeth M. C. Fisher, Tarik F. Haydar, Lisa M. Jacola, Marie-Claude Potier, Stephanie L. Sherman, Anita Bhattacharyya, Leonard J Abbeduto, William C. Mobley, Maria Florencia Iulita, Andre Strydom, Maria Carmona-Iragui, María Martínez de Lagrán, Jorge Busciglio, Pablo Helguera, Anna J. Esbensen, Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Enfermedades Raras (CIBERER), 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), Instituto de Investigación Médica Mercedes y Martín Ferreyra [Córdoba] (INIMEC), Universidad Nacional de Córdoba [Argentina]-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), University of Wisconsin-Madison, Universitat Autònoma de Barcelona (UAB), Fundació Catalana de Síndrome de Down [Barcelona], University College of London [London] (UCL), University of California [San Diego] (UC San Diego), University of California, Cincinnati Children's Hospital Medical Center, St Jude Children's Research Hospital, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Medical University of South Carolina [Charleston] (MUSC), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Université de Montréal (UdeM), McGill University = Université McGill [Montréal, Canada], Northwestern University [Evanston], Telethon KIDS Institute, The University of Western Australia (UWA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Bambino Gesù Children’s Hospital [Rome, Italy], University of Bologna, University of Groningen [Groningen], University of Antwerp (UA), Boston University [Boston] (BU), Emory University [Atlanta, GA], King‘s College London, and Molecular Neuroscience and Ageing Research (MOLAR)
Subjects: BIOMARKER, Down syndrome, media_common.quotation_subject, Intellectual and Developmental Disabilities (IDD), [SDV]Life Sciences [q-bio], Clinical Sciences, Intellectual disability, Disease, Mouse models, s disease, 03 medical and health sciences, Presentation, Trisomy 21 Research Society, medicine, Genetics, 2.1 Biological and endogenous factors, Language impairment, Alzheimer&#8217, Genetics (clinical), 030304 developmental biology, media_common, Cancer, 0303 health sciences, Scientific organization, 030305 genetics & heredity, Neurodevelopmental disorders, Neurosciences, Cognition, ADULTS, Alzheimer's disease, medicine.disease, biomarkers, down syndrome, intellectual disability, language impairment, mouse models, neurodevelopmental disorders, trisomy 21 Research Society, DYSFUNCTION, 3. Good health, Brain Disorders, Syndrome Conferences, Symposia or Workshops, ALZHEIMERS-DISEASE, GENE DOSAGE, Engineering ethics, Human medicine, Trisomy, Psychology, Biomarkers
Abstract: International audience; Research focused on Down syndrome has increased in the last several years to advance understanding of the consequences of trisomy 21 (T21) on molecular and cellular processes and, ultimately, on individuals with Down syndrome. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. The Third International Conference of T21RS, held June 6–9, 2019, in Barcelona, Spain, brought together 429 scientists, families, and industry representatives to share the latest discoveries on underlying cellular and molecular mechanisms of T21, define cognitive and behavioral challenges and better understand comorbidities associated with Down syndrome, including Alzheimer’s disease and leukemia. Presentation of cutting-edge results in neuroscience, neurology, model systems, psychology, cancer, biomarkers and molecular and pharmacological therapeutic approaches demonstrate the compelling interest and continuing advancement in all aspects of understanding and ameliorating conditions associated with T21.
Published: 2021

32. Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome

Author: Tomer Illouz, Arya Biragyn, Maria Florencia Iulita, Lisi Flores-Aguilar, Mara Dierssen, Ilario De Toma, Stylianos E. Antonarakis, Eugene Yu, Yann Herault, Marie-Claude Potier, Alexandra Botté, Randall Roper, Benjamin Sredni, Jacqueline London, William Mobley, Andre Strydom, Eitan Okun, Bar-Ilan University [Israël], National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Universitat Autònoma de Barcelona (UAB), Hospital de la Santa Creu i Sant Pau, McGill University = Université McGill [Montréal, Canada], CIBER de Enfermedades Raras (CIBERER), Geneva University Hospital (HUG), State University of New York (SUNY), 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), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of California [San Francisco] (UCSF), University of California, King‘s College London, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California [San Francisco] (UC San Francisco), University of California (UC), and Gestionnaire, HAL Sorbonne Université 5
Subjects: 0301 basic medicine, Adult, Risk, Down syndrome, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Population, Immunology, Disease, Review, Respiratory tract infections, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Animals, Humans, Immunology and Allergy, Respiratory system, education, education.field_of_study, business.industry, SARS-CoV-2, Respiratory disease, COVID-19, Pneumonia, Immune dysregulation, RC581-607, medicine.disease, Orthomyxoviridae, 3. Good health, Respiratory Syncytial Viruses, Hospitalization, 030104 developmental biology, Virus Diseases, Immune System, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interferon, Immunologic diseases. Allergy, business, 030217 neurology & neurosurgery
Abstract: International audience; The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.
Published: 2021
Full Text: View/download PDF

33. MicroRNAs Targeting HIF-2α, VEGFR1 and/or VEGFR2 as Potential Predictive Biomarkers for VEGFR Tyrosine Kinase and HIF-2α Inhibitors in Metastatic Clear-Cell Renal Cell Carcinoma

Author: Benoit Beuselinck, Maarten Albersen, Annouschka Laenen, Annelies Verbiest, Jessica Zucman-Rossi, Lisa Kinget, Gabrielle Couchy, Cristina Rodríguez-Antona, Marcella Baldewijns, Sylvie Job, Osvaldo Graña-Castro, Eduard Roussel, Lucía Inglada-Pérez, Aurélien de Reyniès, University Hospitals Leuven [Leuven], CIBER de Enfermedades Raras (CIBERER), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Gestionnaire, Hal Sorbonne Université, and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, Cancer Research, TUMORIGENICITY, Angiogenesis, [SDV]Life Sciences [q-bio], MIR-221, EXPRESSION LEVELS, 0302 clinical medicine, Renal cell carcinoma, SUPPRESSES, miR-34c-5p, RC254-282, miR-3529-3p, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, HIF-2α, ENHANCE, miR-221-3p, CANCER, 3. Good health, microRNAs, [SDV] Life Sciences [q-bio], VEGFR2, Oncology, 030220 oncology & carcinogenesis, cardiovascular system, Tyrosine kinase, Life Sciences & Biomedicine, renal cell carcinoma, miR-222-3p, SUNITINIB, Article, 03 medical and health sciences, microRNA, medicine, Gene, Loss function, Science & Technology, miR-223-3p, business.industry, Retrospective cohort study, medicine.disease, miR-185-5p, Clear cell renal cell carcinoma, 030104 developmental biology, DISCOVERY, ENDOTHELIAL GROWTH-FACTOR, Cancer research, business, HIF-2 alpha, RESISTANCE
Abstract: Simple Summary Metastatic clear-cell renal cell carcinoma is characterized by heightened angiogenesis through increased expression of HIF-2α and VEGFR2. VEGFR tyrosine kinase inhibitors are a cornerstone of metastatic clear-cell renal cell carcinoma treatment, and new treatments targeting HIF-2α are currently under investigation. However, clinically useful biomarkers that can predict response to these treatments are lacking. MicroRNAs are small RNA molecules that interfere with gene translation. In this study, we identified four microRNAs that potentially interfere with the translation of VEGFR1 and/or VEGFR2 and are associated with tumor shrinkage and progression-free survival upon treatment with VEGFR-TKIs. These microRNAs might be predictive of response to VEGFR-TKIs. Moreover, we identified three microRNAs associated with HIF-2α expression and with tumor shrinkage and progression-free survival upon treatment with VEGFR-TKIs. These three microRNAs might be able to predict response not only to treatment with VEGFR-TKIs but possibly also to treatment with the upcoming HIF-2α inhibitor belzutifan. Abstract Metastatic clear-cell renal cell carcinoma (m-ccRCC) is characterized by increased hypoxia-induced factor (HIF)-2α and vascular endothelial growth factor receptor (VEGFR)-dependent angiogenesis through loss of function of the von Hippel–Lindau protein. VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) are a cornerstone of m-ccRCC treatment, and new treatments targeting HIF-2α are currently under investigation. However, predictive biomarkers for these treatments are lacking. In this retrospective cohort study including 109 patients treated with VEGFR-targeted therapies as first-line treatment, we aimed to study the possible predictive function of microRNAs (miRNAs) targeting HIF-2α, VEGFR1 and VEGFR2. We selected miRNAs inversely correlated with HIF-2α, VEGFR1 and/or VEGFR2 expression and with predicted target sites in the respective genes and subsequently studied their impact on therapeutic outcomes. We identified four miRNAs (miR-34c-5p, miR-221-3p, miR-222-3p and miR-3529-3p) inversely correlated with VEGFR1 and/or VEGFR2 expression and associated with tumor shrinkage and progression-free survival (PFS) upon treatment with VEGFR-TKIs, highlighting the potential predictive value of these miRNAs. Moreover, we identified three miRNAs (miR-185-5p, miR-223-3p and miR-3529-3p) inversely correlated with HIF-2α expression and associated with tumor shrinkage and PFS upon treatment with VEGFR-TKIs. These three miRNAs can have a predictive value not only upon treatment with VEGFR-TKIs but possibly also upon treatment with the upcoming HIF-2α inhibitor belzutifan.
Published: 2021

34. Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug-Induced Acute Urticaria/Angioedema

Author: Raquel Jurado-Escobar, Inmaculada Doña, José Triano-Cornejo, James R. Perkins, Natalia Pérez-Sánchez, Almudena Testera-Montes, Marina Labella, Joan Bartra, José J. Laguna, Miguel Estravís, José A. G. Agúndez, María J. Torres, José A. Cornejo-García, [Jurado-Escobar,R, Doña,I, Triano-Cornejo,J, Torres,MJ, Cornejo-García,JA] Allergy Research Group, Instituto De Investigación Biomédica De Málaga-IBIMA, Malaga, Spain. [Jurado-Escobar,R, Torres,MJ] Departamento De Medicina, Universidad De Málaga, Malaga, Spain. [Doña,I, Pérez-Sánchez,N, Testera-Montes,A, Labella,M, Torres,MJ] Allergy Unit, Hospital Regional Universitario De Málaga, Malaga, Spain. [Doña,I, Bartra,J, Laguna,JJ, Estravis,M, Agúndez,JAG, Cornejo-García,JA] ARADyAL Network, Instituto De Salud Carlos III, Madrid, Spain. [Perkins,JR] Department of Molecular Biology and Biochemistry, University of Malaga, Malaga, Spain. [Perkins,JR] CIBER De Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain. [Perkins,JR] The Biomedical Research Institute of Malaga (IBIMA), Malaga, Spain. [Bartra,J] Allergy Section, Pneumology Department, Hospital Clinic, Universitat De Barcelona, Barcelona, Spain. [Laguna,JJ] Allergy Unit, Allergo-Anaesthesia Unit, Hospital Central De La Cruz Roja, Faculty of Medicine, Alfonso X El Sabio University, Madrid, Spain. [Estravis,M] Instituto De Investigación Biomédica De Salamanca (IBSAL), Salamanca, Spain. [Agúndez,JAG] Institute of Molecular Pathology Biomarkers, UEx, Cáceres, Spain. [Torres,MJ] Nanostructures for Diagnosing and Treatment of Allergic Diseases Laboratory, Andalusian Center for Nanomedicine and Biotechnology-BIONAND, Malaga, Spain., and This work was supported by Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Science and Innovation), co-founded by Fondo Europeo de Desarrollo Regional-FEDER for Research Projects (PI17/ 01593, PI18/00540, and PI20/01540), GR18145 from Junta de Extremadura, the Thematic Networks and Co-operative Research
Subjects: 0301 basic medicine, Polimorfismo Genético, Single-nucleotide polymorphism, RM1-950, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antirheumatic Agents [Medical Subject Headings], 03 medical and health sciences, 0302 clinical medicine, Phospholipase A2, Cytosolic phospholipase A2, Genetic variation, arachidomic acid, medicine, Pharmacology (medical), Phenomena and Processes::Chemical Phenomena::Chemical Processes::Hydrolysis [Medical Subject Headings], cytosolic phospholipase A2, skin and connective tissue diseases, Gene, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Multienzyme Complexes::Prostaglandin-Endoperoxide Synthases [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Carboxylic Ester Hydrolases::Phospholipases::Phospholipases A::Phospholipases A2 [Medical Subject Headings], Ácido araquidónico, Original Research, Pharmacology, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], biology, Angioedema, business.industry, urticaria/angioedema, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Arachidonic Acids::Arachidonic Acid [Medical Subject Headings], Diseases::Cardiovascular Diseases::Vascular Diseases::Angioedema [Medical Subject Headings], Angioneurotic oedema, NSAID cross-hypersensitivity, PLA2G4A, 030104 developmental biology, Arachidomic acid, 030220 oncology & carcinogenesis, Immunology, Fosfolipasas A2 grupo IV, biology.protein, Cyclooxygenase, Therapeutics. Pharmacology, medicine.symptom, Urticaria/angioedema, business, polymorphisms, Polymorphisms
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity reactions, probably due to their high consumption worldwide. The most frequent type of NSAID hypersensitivity is NSAID cross-hypersensitivity, in which patients react to NSAIDs from different chemical groups in the absence of a specific immunological response. The underlying mechanism of NSAID cross-hypersensitivity has been linked to cyclooxygenase (COX)-1 inhibition causing an imbalance in the arachidonic acid pathway. Despite NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype, most studies have focused on NSAID-exacerbated respiratory disease. As NSAID cross-hypersensitivity reactions are idiosyncratic, only appearing in some subjects, it is believed that individual susceptibility is under the influence of genetic factors. Although associations with polymorphisms in genes from the AA pathway have been described, no previous study has evaluated the potential role of cytosolic phospholipase A2 (cPLA2) variants. This enzyme catalyzes the initial hydrolysis of membrane phospholipids to release AA, which can be subsequently metabolized into eicosanoids. Here, we analyzed for the first time the overall genetic variation in the cPLA2 gene (PLA2G4A) in NIUA patients. For this purpose, a set of tagging single nucleotide polymorphisms (tagSNPs) in PLA2G4A were selected using data from Europeans subjects in the 1,000 Genomes Project, and genotyped with the iPlex Sequenom MassArray technology. Two independent populations, each comprising NIUA patients and NSAID-tolerant controls, were recruited in Spain, for the purposes of discovery and replication, comprising a total of 1,128 individuals. Fifty-eight tagSNPs were successfully genotyped in the discovery cohort, of which four were significantly associated with NIUA after Bonferroni correction (rs2049963, rs2064471, rs12088010, and rs12746200). These polymorphisms were then genotyped in the replication cohort: rs2049963 was associated with increased risk for NIUA after Bonferroni correction under the dominant and additive models, whereas rs12088010 and rs12746200 were protective under these two inheritance models. Our results suggest a role for PLA2G4A polymorphisms in NIUA. However, further studies are required to replicate our findings, elucidate the mechanistic role, and evaluate the participation of PLA2G4A variants in other phenotypes induced by NSAID cross-hypersensitivity.
Published: 2021

35. Genetic Estimates for Growth and Shape-Related Traits in the Flatfish Senegalese Sole

Author: Israel Guerrero-Cózar, Concha Berbel, Elena Espinosa, Manuel Gonzalo Claros, Ricardo Zerolo, Eduardo Jiménez-Fernández, Manuel Manchado, [Guerrero-Cozar,I, Berbel,C, Manchado,M] IFAPA Centro El Toruño, Junta de Andalucía, El Puerto de Santa María Cádiz, Spain. [Jimenez-Fernandez,E] Free Radical Research Group, Centre for Health Sciences, University of the Highlands and Islands, UK. [Espinosa,E, Claros,MG] Molecular Biology and Biochemistry Department, University of Málaga, Málaga, Spain. [Claros,MG] CIBER de Enfermedades Raras (CIBERER), Málaga, Spain. [Claros,MG] Institute of Biomedical Research in Málaga (IBIMA), IBIMA-RARE, Málaga, Spain. [Claros,MG] Instituto de Hortofruticultura Subtropical y Mediterránea (IHSM-UMA-CSIC), Málaga, Spain. [Zerolo,R] CUPIMAR, San Fernando, Cádiz, Spain. [Manchado,M] 'Crecimiento Azul', Centro IFAPA El Toruño, Unidad Asociada al CSIC, El Puerto de Sta. María, Spain., and This research was funded by MCIU/AEI/FEDER, UE, grant numbers RTA2017-00054-C03- 01 and RTA2017-00054-C03-03. Moreover, this research was funded by the EU H2020 research and innovation program under grant agreement 817992 ERANET-BLUEBIO COFUND project PCI2020-111994 'BestBrood'. IGC is funded by a predoctoral fellowship from INIA.
Subjects: Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Acuicultura, Anatomy::Animal Structures::Animal Fins [Medical Subject Headings], Body height, Peduncle (anatomy), Veterinary medicine, growth, Productos pesqueros, Production cycle, Growth, Biology, Breeding, Variación genética, Cruzamiento, shape, Crecimiento, Article, Forma de la célula, genetic estimates, 03 medical and health sciences, Animal science, Flatfish, Technology and Food and Beverages::Technology, Industry, and Agriculture::Agriculture::Aquaculture [Medical Subject Headings], SF600-1100, Organisms::Eukaryota::Animals [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development [Medical Subject Headings], Solea senegalensis, 030304 developmental biology, Phenomena and Processes::Biological Phenomena [Medical Subject Headings], 0303 health sciences, General Veterinary, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Fishes::Flatfishes [Medical Subject Headings], Fish fin, Shape, 04 agricultural and veterinary sciences, Genetic estimates, biology.organism_classification, QL1-991, breeding, Animales, 040102 fisheries, 0401 agriculture, forestry, and fisheries, %22">Fish , Animal Science and Zoology, Phenomena and Processes::Genetic Phenomena::Genetic Variation [Medical Subject Headings], Zoology, Senegalese sole, Peces planos
Abstract: Shape quality is very important in flatfish aquaculture due to the impact on commercialization. The Senegalese sole (Solea senegalensis) is a valuable flatfish with a highly elliptic body that slightly changes with age and size, and it is prone to accumulating malformations during the production cycle. The present study aims to investigate the genetic parameters of two growth traits (weight and standard length) and six shape quality predictors (ellipticity, three body heights (body height at the pectoral fin base [BHP], body maximum height [BMH] and caudal peduncle height [CPH]) and two ratios (BMH/BHP and BMH/CPH)). These traits were measured before the on-growing stage (age ~400 days (d)) and at harvest (~800 d). Phenotypic data, heritabilities and genetic and phenotypic correlations between the traits are presented and discussed. High or very high heritabilities (0.433–0.774) were found for growth traits, body heights and ellipticity and they were higher at 400 than 800 d. In contrast, the ratios of BMH/BHP and BMH/CPH were less heritable (0.144–0.306). Positive and very high (&gt, 0.95) correlations between growth traits and the three heights were found and decreased with age. In contrast, ellipticity had negative and medium-high genetic correlations with growth traits and heights, indicating fish selected for bigger size would also become rounder. The ratio of BMH/CPH showed low genetic correlations with all traits and provided complementary information to ellipticity for a better fitting to the expected lanceolate body morphology of sole. The genetic correlations for all traits at both ages were very high, indicating that selection before entering the growth-out stage in recirculation aquaculture systems is recommended to accelerate genetic gains.
Published: 2021
Full Text: View/download PDF

36. Decoding Neuromuscular Disorders Using Phenotypic Clusters Obtained From Co-Occurrence Networks

Author: Elena Díaz-Santiago, M. Gonzalo Claros, Raquel Yahyaoui, Yolanda de Diego-Otero, Rocío Calvo, Janet Hoenicka, Francesc Palau, Juan A. G. Ranea, James R. Perkins, [Díaz-Santiago,E, Claros,MG, Ranea,JAG, Perkins,JR] Department of Molecular Biology and Biochemistry, Universidad de Málaga, Málaga, Spain. [Claros,MG, Hoenicka,J, Palau,F, Perkins,JR] CIBER de Enfermedades Raras (CIBERER), Madrid, Spain. [Claros,MG, Yahyaoui,R, de Diego-Otero,Y, Calvo,R, Perkins,JR] Institute of Biomedical Research in Malaga (IBIMA), IBIMA-RARE, Málaga, Spain. [Claros,MG] Institute for Mediterranean and Subtropical Horticulture 'La Mayora' (IHSM-UMA-CSIC), Málaga, Spain, [Yahyaoui,R, Calvo,R] Laboratory of Metabolopathies and Neonatal Screening, Málaga Regional University Hospital, Málaga, Spain. [Hoenicka,J, Palau,F] Sant Joan de Déu Hospital and Research Institute, Barcelona, Spain. [Palau,F] Hospital Clínic and University of Barcelona School of Medicine and Health Sciences, Barcelona, Spain., The study was funded by grants from the Andalusian Government (Junta de Andalucia) with European Regional Development Fund (UMA18-FEDERJA-102), the Ramón Areces foundation, which funds project for the investigation of rare disease (National call for research on life and material sciences, XIX edition), the Spanish Ministry of Science and Innovation with European Regional Development Fund PID2019-108096RB-C21, and and the Ramón y Cajal I3 projects through the Research Plan of the University of Malaga (Ayudas del I Plan Propio).
Subjects: Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology::Systems Biology [Medical Subject Headings], phenotype, QH301-705.5, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genetic Research::Gene Ontology [Medical Subject Headings], Systems biology, rare disease, Computational biology, Biology, neuromuscular disorders, Information Science::Information Science::Medical Informatics::Medical Informatics Applications::Information Systems::Databases as Topic::Databases, Factual::Databases, Genetic [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Rare Diseases [Medical Subject Headings], Biochemistry, Genetics and Molecular Biology (miscellaneous), Biochemistry, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnosis, Differential [Medical Subject Headings], co-occurrence analysis, Human Phenotype Ontology, Phenomena and Processes::Genetic Phenomena::Inheritance Patterns::Genetic Pleiotropy [Medical Subject Headings], Molecular Biosciences, KEGG, Biology (General), cluster, Gene, Molecular Biology, network analysis, Original Research, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases Nitrogenous Group Acceptor::Creatine Kinase [Medical Subject Headings], Cell specific, Enfermedades raras, Common framework, Phenotype, Cluster, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Azoles::Imidazoles::Creatinine [Medical Subject Headings], Network analysis, Co-occurrence analysis, Rare disease, Fenotipo, Co-occurrence networks, Neuromuscular disorders
Abstract: Neuromuscular disorders (NMDs) represent an important subset of rare diseases associated with elevated morbidity and mortality whose diagnosis can take years. Here we present a novel approach using systems biology to produce functionally-coherent phenotype clusters that provide insight into the cellular functions and phenotypic patterns underlying NMDs, using the Human Phenotype Ontology as a common framework. Gene and phenotype information was obtained for 424 NMDs in OMIM and 126 NMDs in Orphanet, and 335 and 216 phenotypes were identified as typical for NMDs, respectively. ‘Elevated serum creatine kinase’ was the most specific to NMDs, in agreement with the clinical test of elevated serum creatinine kinase that is conducted on NMD patients. The approach to obtain co-occurring NMD phenotypes was validated based on co-mention in PubMed abstracts. A total of 231 (OMIM) and 150 (Orphanet) clusters of highly connected co-occurrent NMD phenotypes were obtained. In parallel, a tripartite network based on phenotypes, diseases and genes was used to associate NMD phenotypes with functions, an approach also validated by literature co-mention, with KEGG pathways showing proportionally higher overlap than Gene Ontology and Reactome. Phenotype-function pairs were crossed with the co-occurrent NMD phenotype clusters to obtain 40 (OMIM) and 72 (Orphanet) functionally coherent phenotype clusters. As expected, many of these overlapped with known diseases and confirmed existing knowledge. Other clusters revealed interesting new findings, indicating informative phenotypes for differential diagnosis, providing deeper knowledge of NMDs, and pointing towards specific cell dysfunction caused by pleiotropic genes. This work is an example of reproducible research that i) can help better understand NMDs and support their diagnosis by providing a new tool that exploits existing information to obtain novel clusters of functionally-related phenotypes, and ii) takes us another step towards personalised medicine for NMDs.
Published: 2021

37. Discovery of common and rare genetic risk variants for colorectal cancer

Author: Charles M. Connolly, Deborah A. Nickerson, Jian Gong, Sébastien Küry, Barbara Pardini, Brent W. Zanke, Andrea Gsur, Jochen Hampe, Coral Arnau-Collell, M. Henar Alonso, Elio Riboli, Annika Lindblom, Ulrike Peters, Gad Rennert, Tabitha A. Harrison, Lori C. Sakoda, Caroline McNeil, Flavio Lejbkowicz, Hyun Min Kang, David J. Hunter, Martha L. Slattery, Miguel Rodríguez-Barranco, Christina Bamia, Satu Männistö, Timothy J. Key, W. James Gauderman, Gonçalo R. Abecasis, Sanford D. Markowitz, Laurence N. Kolonel, Mark A. Jenkins, Yi Lin, Robin Myte, Hedy S. Rennert, Neil Murphy, Antonia Trichopoulou, Christopher I. Li, Ross L. Prentice, Sai Chen, Stephanie J. Weinstein, Kristin E. Anderson, Hua Ling, Mitul Shah, Philipp Hofer, Wen Yi Huang, Sergi Castellví-Bel, Susanna C. Larsson, Maria Dolores Chirlaque, Wei Zheng, Stephanie L. Schmit, Cecelia A. Laurie, Soo-Chin Lee, David Forman, Andrea N. Burnett-Hartman, Giovanna Masala, Sarah C. Nelson, Michael O. Woods, Charles Kooperberg, Qing Zhang, Sonja I. Berndt, Christopher S. Carlson, Katja Butterbach, Hyeong Rok Kim, Rebecca D. Jackson, David Van Den Berg, Michael C. Bassik, Amanda J. Cross, Sushma S. Thomas, Clemens Schafmayer, Anna H. Wu, Douglas F. Easton, Robert W. Haile, Ludmila Vodickova, Graham G. Giles, Yu Ru Su, Jenny Chang-Claude, Lorena Moreno, Peter C. Scacheri, Stefanie Brezina, Min-Ho Shin, Steven Gallinger, Bethany Van Guelpen, Daniel D. Buchanan, Roger L. Milne, Stephen J. Chanock, Tin Louie, Tameka Shelford, Emily White, Kala Visvanathan, Loic Le Marchand, Veronika Vymetalkova, Roxann G. Ingersoll, Temitope O. Keku, Stephanie A. Bien, Fredrick R. Schumacher, Wan-Ling Hsu, Amanda E. Toland, John S. Grove, Noralane M. Lindor, Faye Elliott, Leon Raskin, Heather Hampel, Joshua D. Smith, Vicente Martín, David V. Conti, Sjoerd G. Elias, Henk J. van Kranen, Manish Gala, Daniela Seminara, Syed H.E. Zaidi, Suzanne M. Leal, Tilman Kühn, Korbinian Weigl, Marc J. Gunter, Cornelia M. Ulrich, Peyton Greenside, Victor Moreno, John D. Potter, Michael Hoffmeister, Eric J. Jacobs, Catherine M. Tangen, Jihyoun Jeon, Fränzel J.B. Van Duijnhoven, Andrew T. Chan, Stephen B. Gruber, John A. Baron, Alicja Wolk, Edith J. M. Feskens, Demetrius Albanes, Amit Joshi, Bette J. Caan, Polly A. Newcomb, Stéphane Bézieau, Elizabeth M. Gillanders, Anshul Kundaje, Elizabeth A. Platz, Michael Wainberg, Sun-Seog Kweon, C. Roland Wolf, Gemma Ibáñez-Sanz, Shuji Ogino, Emiko Kobayashi, Richard B. Hayes, Patrick S. Parfrey, Katarina Cuk, Stephen N. Thibodeau, Kenneth Offit, David Duggan, Sophia Harlid, Pavel Vodicka, Juergen Boehm, Christa Stegmaier, Jeroen R. Huyghe, Joseph Vijai, Sang-Hee Cho, Elizabeth W. Pugh, Rachel Pearlman, Alessio Naccarati, Marilena Melas, Graham Casey, Jane Romm, Stephan Buch, Phyllis J. Goodman, Albert de la Chapelle, John L. Hopper, Zsofia K. Stadler, Corinne E. Joshu, Liesel M. FitzGerald, Wolfgang Lieb, Aung Ko Win, Keith R. Curtis, Hermann Brenner, Christopher K. Edlund, Li Hsu, Conghui Qu, Peter T. Campbell, Robert E. Schoen, Heiner Boeing, D. Timothy Bishop, Kimberly F. Doheny, Sabina Sieri, Barbara L. Banbury, Mathieu Lemire, Jane C. Figueiredo, Gregory Idos, Katerina Shulman, Thomas J. Hudson, Melissa C. Southey, Duncan C. Thomas, Paul D.P. Pharoah, Mila Pinchev, Vittorio Perduca, Rocky Fischer, Volker Arndt, William M. Grady, Nasa Sinnott-Armstrong, N. Charlotte Onland-Moret, David M. Levine, Li Li, Dallas R. English, Health Research Board - Ireland, Department of Medical Genetics, HMNC Brain Health, Case Western Reserve University [Cleveland], National Cancer Institute, NIH, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Division of Cancer Epidemiology, Cancer Genome Project, The Wellcome Trust Sanger Institute [Cambridge], Division of Signaling Biology, Ontario Cancer Institute, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), National Institute of Standards and Technology [Gaithersburg] (NIST), Ohio State University [Columbus] (OSU), Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Epidemiology Centre, Cancer Council Victoria, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Division of Public Health Sciences, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Northern and Yorkshire Cancer Registry and Information Service, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), University of Melbourne, Nutrition and Metabolism Section, International Agency for Cancer Research (IACR), Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, London School of Hygiene and Tropical Medicine (LSHTM), Fraunhofer Institute for Manufacturing Engineering and Automation (Fraunhofer IPA), Fraunhofer (Fraunhofer-Gesellschaft), Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne-Centre for Molecular, Melbourne School of Population Health, Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Department of Statistics, Penn State University, University of Pennsylvania [Philadelphia], Tata Memorial Centre, Cancer Epidemiology Unit, University of Oxford [Oxford], Thermo Fisher Scientific, Thermo Fisher Scientific Inc., Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, National University Health System, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Ontario Institute for Cancer Research [Canada] (OICR), Ontario Institute for Cancer Research, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Dell-EMC, Molecular and Nutritional Epidemiology Unit (ISPO), Cancer Research and Prevention Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Department of Pathology, Brigham and Women's Hospital [Boston], University Medical Center [Utrecht], Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Department of Oncology, Department of Epidemiology and Biostatistics, Imperial College London, Department of Visceral and Thoracic Surgery [Kiel, Germany], University Hospital Schleswig-Holstein [Kiel, Germany], Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Department of Laboratory Medicine and Department of Pathology, Mayo Clinic College of Medicine, Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], Department of Medical Biosciences and Pathology, Umeå University, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Dundee Technopole, CXR Biosciences Ltd, Karolinska Institutet [Stockholm], CINTRA / SEEE Nanyang Technological University, Nanyang Technological University [Singapour], Center for Astrophysical Sciences [Baltimore], Johns Hopkins University (JHU), Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology (MIT), Department of Preventive Medicine, University of Southern California (USC), Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Medstar Research Institute, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Internal Medicine, Epidemiology, Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Wageningen University and Research Centre [Wageningen] (WUR), Mount Sinai Hospital (MSH), Fraunhofer Institute for Manufacturing Engineering and Automation [Stuttgart] (IPA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Czech Academy of Sciences [Prague] (ASCR), Huyghe, Jeroen R [0000-0001-6027-9806], Harrison, Tabitha A [0000-0002-4173-7530], Chen, Sai [0000-0003-3106-5643], Schmit, Stephanie L [0000-0001-5931-1194], Jeon, Jihyoun [0000-0001-7003-3412], Schumacher, Fredrick R [0000-0002-3073-7463], Nelson, Sarah C [0000-0002-2109-6465], Sinnott-Armstrong, Nasa A [0000-0003-4490-0601], Alonso, M Henar [0000-0003-0285-5451], Arndt, Volker [0000-0001-9320-8684], Bézieau, Stéphane [0000-0003-0095-1319], Bishop, D Timothy [0000-0002-8752-8785], Brezina, Stefanie [0000-0001-5238-6900], Buchanan, Daniel D [0000-0003-2225-6675], Chanock, Stephen J [0000-0002-2324-3393], de la Chapelle, Albert [0000-0001-9345-9248], Easton, Douglas F [0000-0003-2444-3247], Hampe, Jochen [0000-0002-2421-6127], Hayes, Richard B [0000-0002-0918-661X], Hofer, Philipp [0000-0003-2550-6019], Huang, Wen-Yi [0000-0002-4440-3368], Hudson, Thomas J [0000-0002-1376-4849], Jacobs, Eric J [0000-0002-8458-7659], Jenkins, Mark A [0000-0002-8964-6160], Joshi, Amit D [0000-0001-7581-6934], Küry, Sébastien [0000-0001-5497-0465], Larsson, Susanna C [0000-0003-0118-0341], Laurie, Cecelia A [0000-0001-6569-2501], Martín, Vicente [0000-0003-0552-2804], Masala, Giovanna [0000-0002-5758-9069], Milne, Roger L [0000-0001-5764-7268], Naccarati, Alessio [0000-0001-5774-0905], Newcomb, Polly A [0000-0001-8786-0043], Pardini, Barbara [0000-0001-9571-4257], Perduca, Vittorio [0000-0003-0339-0473], Pharoah, Paul DP [0000-0001-8494-732X], Raskin, Leon [0000-0003-1195-7214], Rennert, Gad [0000-0002-8512-068X], Shin, Min-Ho [0000-0002-2217-5624], Toland, Amanda E [0000-0002-0271-1792], Vijai, Joseph [0000-0002-7933-151X], Weigl, Korbinian [0000-0003-4453-2036], Win, Aung Ko [0000-0002-2794-5261], Wolk, Alicja [0000-0001-7387-6845], Zheng, Wei [0000-0003-1226-070X], Bassik, Michael C [0000-0001-5185-8427], Moreno, Victor [0000-0002-2818-5487], Peters, Ulrike [0000-0001-5666-9318], and Apollo - University of Cambridge Repository
Subjects: Male, Nutrition and Disease, Colorectal cancer, IDENTIFIES 6, Genome-wide association study, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Genotype, ComputingMilieux_MISCELLANEOUS, Avaluació del risc per la salut, Genetics & Heredity, Genetics, 0303 health sciences, COLON-CANCER, 11 Medical And Health Sciences, Middle Aged, 3. Good health, Medical genetics, Female, RNA, Long Noncoding, Colorectal Neoplasms, Life Sciences & Biomedicine, Signal Transduction, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, Article, Health risk assessment, 03 medical and health sciences, QUALITY-CONTROL, Càncer colorectal, Journal Article, medicine, Life Science, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, VLAG, Aged, 030304 developmental biology, Global Nutrition, [SDV.GEN]Life Sciences [q-bio]/Genetics, Wereldvoeding, Science & Technology, ORGAN SIZE, MUTATIONS, Haplotype, Case-control study, 06 Biological Sciences, medicine.disease, Genetic architecture, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human genome, LYSOPHOSPHATIDIC ACID, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract: To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P, Reporting Summary. Further information on experimental design is available in the Life Sciences Reporting Summary linked to this article.
Published: 2018

38. DLG4-related synaptopathy: a new rare brain disorder

Author: Edgard Verdura, Alex MacKenzie, Rolph Pfundt, Tobias B. Haack, Ange Line Bruel, Paulino Gómez-Puertas, Anna C.E. Hurst, Bert B.A. de Vries, Stella A. de Man, Maria Johansson Soller, Bregje W.M. van Bon, Elisabeth Sarrazin, Agustí Rodríguez-Palmero, Stephan Waldmüller, Melanie O’Leary, Anne Sophie Denommé-Pichon, Bitten Schönewolf-Greulich, Joseph T. Shieh, V. A. Bjerregaard, Vahid Bahrambeigi, Malin Kvarnung, Agatha Schlüter, Anne Marie Bisgaard, Ingrid M.B.H. van de Laar, Elisa Giorgio, Lars Feuk, Mieke M. van Haelst, Thomas D. Challman, Ineke van de Burgt, Sulagna Kushary, Simone F. Reiter, David B. Everman, Zeynep Tümer, Giorgia Mandrile, Conny M. A. van Ravenswaaij-Arts, Charles Shaw-Smith, Juliane Hoyer, Chad R. Haldeman-Englert, Lotte Kleinendorst, Bryce A. Mendelsohn, Anna Lindstrand, Christine Coubes, Gea Beunders, Sixto García-Miñaur, Antonio Vitobello, Melissa Maria Boerrigter, Alysia Kern Lovgren, Anya Revah-Politi, Carlos E. Prada, Bertrand Isidor, Elena Repnikova, Stephanie Spranger, Esmée van Drie, Frédéric Tran Mau-Them, Zohra Shad, Ben Pode-Shakked, Aurora Pujol, Christiane Zweier, Bjørn Ivar Haukanes, David Gómez-Andrés, Kathleen A. Leppig, Marta Pacio-Míguez, Motti Shohat, Yuval Landau, Benjamin Cogné, Frances Elmslie, Kimberly A. Aldinger, Anita Rauch, Juliann M. Savatt, Nicolas Gruchy, Sharon Whiting, William B. Dobyns, Thomas J. Dye, Sebastien Moutton, Heidi Thiese, Setareh Moghadasi, Iñigo Marcos-Alcalde, Jenny Morton, Sumit Parikh, María Palomares-Bralo, Stéphanie Arpin, Tracy S. Gertler, Meredith J. Ross, Bernt Popp, Amelie J. Müller, Claudia A. L. Ruivenkamp, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Hospital Universitario Germans Trias I Pujol, Vall d'Hebron University Hospital [Barcelona], Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Department of Molecular and Human Genetics (Baylor College of Medicine), Baylor College of Medecine, Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical Genetics, Human Genetics, Graduate School, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ARD - Amsterdam Reproduction and Development, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], 030105 genetics & heredity, Biology, 03 medical and health sciences, Intellectual Disability, Intellectual disability, medicine, Missense mutation, Humans, Global developmental delay, Exome, Genetics (clinical), Genetics, Brain Diseases, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Brain, medicine.disease, 030104 developmental biology, Phenotype, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Autism spectrum disorder, Neurodevelopmental Disorders, Synaptopathy, DLG4, Postsynaptic density, Disks Large Homolog 4 Protein
Abstract: Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
Published: 2021

39. Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease

Author: Moore, Ursula, Gordish, Heather, Diaz-Manera, Jordi, James, Meredith K, Mayhew, Anna G, Guglieri, Michela, Fernandez-Torron, Roberto, Rufibach, Laura E, Feng, Jia, Blamire, Andrew M, Carlier, Pierre G, Spuler, Simone, Day, John W, Jones, Kristi J, Bharucha-Goebel, Diana X, Salort-Campana, Emmanuelle, Pestronk, Alan, Walter, Maggie C, Paradas, Carmen, Stojkovic, Tanya, Mori-Yoshimura, Madoka, Bravver, Elena, Pegoraro, Elena, Lowes, Linda Pax, Mendell, Jerry R, Bushby, Kate, Straub, Volker, Jain COS Consortium, Newcastle University [Newcastle], Georgetown University [Washington] (GU), CIBER de Enfermedades Raras (CIBERER), Hospital de la Santa Creu i Sant Pau, 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), Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, The University of Sydney, National Institutes of Health [Bethesda] (NIH), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Ludwig-Maximilians-Universität München (LMU), Hospital Universitario Virgen del Rocío [Sevilla], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Padova = University of Padua (Unipd), Abigail Wexner Research Institute, Nationwide Children's Hospital, Centre de référence des maladies rares neuromusculaires, 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), Universita degli Studi di Padova, Jain Foundation, and International Centre for Genomic Medicine in Neuromuscular Diseases
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Disease, Clinical trials methodology, 0302 clinical medicine, [185] Muscle disease, Child, Genetics (clinical), Muscle disease, Muscle Weakness, medicine.diagnostic_test, [21] Clinical trials methodology, Anatomy, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Limb girdle weakness, Muscular Atrophy, Phenotype, Neurology, Child, Preschool, Disease Progression, Female, Function and Dysfunction of the Nervous System, Cohort study, Adult, Dysferlinopathy, Miyoshi myopathy, Adolescent, [54] Cohort study, Lower limb weakness, [16] Clinical neurology examination, 03 medical and health sciences, Young Adult, medicine, Humans, Clinical neurology examination, [176] All neuromuscular disease, business.industry, Infant, Newborn, Infant, Magnetic resonance imaging, medicine.disease, Clinical trial, Distal Myopathies, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, Pediatrics, Perinatology and Child Health, Neurology (clinical), business, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, All neuromuscular disease
Abstract: The Jain COS Consortium., This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments., The estimated $4 million USD needed to fund this study was provided by the Jain Foundation. Volker Straub was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1.
Published: 2021

40. Variability of multi-omics profiles in a population-based child cohort

Author: Chung-Ho E Lau, Léa Maitre, Barbara Heude, Maribel Casas, Juan R. González, John Wright, Marta Gallego-Paüls, Martine Vrijheid, Angel Carracedo, Muireann Coen, Regina Grazuleviciene, Alexandros P. Siskos, Carles Hernandez-Ferrer, Xavier Basagaña, Jose Barrera-Gómez, Jose Urquiza, Eduard Sabidó, Hector C. Keun, Leda Chatzi, Rémy Slama, Xavier Estivill, Carlos Ruiz-Arenas, Mariona Bustamante, Marta Vives-Usano, Eva Borràs, Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Universitat Pompeu Fabra [Barcelona] (UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona Institute of Science and Technology (BIST), Imperial College London, Bradford Teaching Hospitals NHS Foundation Trust [Bradford, UK] (BTHFT), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Grenoble Alpes (UGA), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Vytautas Magnus University - Vytauto Didziojo Universitetas (VDU), University of Southern California (USC), CIBER de Enfermedades Raras (CIBERER), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), AstraZeneca [Cambridge, UK], Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría, Malbec, Odile, 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), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Instituto de Investigación Sanitaria de Santiago de Compostela / Health Research Institute of Santiago de Compostela (IDIS), and Commission of the European Communities
Subjects: 0301 basic medicine, European community, [SDV]Life Sciences [q-bio], mRNA, Library science, Population based, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Environmental risk, General & Internal Medicine, Humans, Medicine, Metabolomics, Social science research, Variability, Child, Children, 11 Medical and Health Sciences, miRNA, Multi-omics, DNA methylation, business.industry, General Medicine, language.human_language, 3. Good health, [SDV] Life Sciences [q-bio], MicroRNAs, Exposome, Cross-Sectional Studies, 030104 developmental biology, Diabetes Mellitus, Type 2, 030220 oncology & carcinogenesis, language, Multi omics, Christian ministry, Catalan, Cross-omics, business, Population study, Research Article, Omics technologies
Abstract: Background: Multiple omics technologies are increasingly applied to detect early, subtle molecular responses to environmental stressors for future disease risk prevention. However, there is an urgent need for further evaluation of stability and variability of omics profiles in healthy individuals, especially during childhood. Methods: We aimed to estimate intra-, inter-individual and cohort variability of multi-omics profiles (blood DNA methylation, gene expression, miRNA, proteins and serum and urine metabolites) measured 6 months apart in 156 healthy children from five European countries. We further performed a multi-omics network analysis to establish clusters of co-varying omics features and assessed the contribution of key variables (including biological traits and sample collection parameters) to omics variability. Results: All omics displayed a large range of intra- and inter-individual variability depending on each omics feature, although all presented a highest median intra-individual variability. DNA methylation was the most stable profile (median 37.6% inter-individual variability) while gene expression was the least stable (6.6%). Among the least stable features, we identified 1% cross-omics co-variation between CpGs and metabolites (e.g. glucose and CpGs related to obesity and type 2 diabetes). Explanatory variables, including age and body mass index (BMI), explained up to 9% of serum metabolite variability. Conclusions: Methylation and targeted serum metabolomics are the most reliable omics to implement in single time-point measurements in large cross-sectional studies. In the case of metabolomics, sample collection and individual traits (e.g. BMI) are important parameters to control for improved comparability, at the study design or analysis stage. This study will be valuable for the design and interpretation of epidemiological studies that aim to link omics signatures to disease, environmental exposures, or both The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project) and the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project). Additionally, BiB received core infrastructure funding from the Wellcome Trust (WT101597MA) and a joint grant from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1). INMA data collections were supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV.2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV- 1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV.2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011- 2014; “Rhea Plus”: Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012-15). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I+D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science and Innovation and State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program. MV-U and CR-A were supported by a FI fellowship from the Catalan Government (FI-DGR 2015 and #016FI_B 00272). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (MS16/00128). LM is funded by a Juan de la Cierva-Incorporación fellowship (IJC2018-035394-I) awarded by the Spanish Ministerio de Economía, Industria y Competitividad SI
Published: 2021
Full Text: View/download PDF

41. Identification of PITX3 mutations in individuals with various ocular developmental defects

Author: Caroline Michot, Julie Plaisancié, Marta Corton, Edouard Cottereau, Julian Delanne, Nicolas Chassaing, Nicola K. Ragge, Jacmine Pechmeja, Celia Zazo Seco, P Calvas, Tatiana Lupasco, Carmen Ayuso, Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale [Toulouse], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'Ophtalmologie [Hopital Purpan - Toulouse], 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), Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CIBER de Enfermedades Raras (CIBERER), Oxford Brookes University, Birmingham Women’s and Children’s Hospitals NHS Foundation Trust, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, CARBILLET, Véronique, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d'Ophtalmologie [CHU Toulouse], Pôle Céphalique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: 0301 basic medicine, Male, genetic structures, MESH: Congenital Abnormalities / pathology, medicine.disease_cause, Microphthalmia, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Peters anomaly, Microphthalmos, PITX3, Eye Abnormalities, Child, Genetics (clinical), MESH: Heterozygote, Genetics, Sanger sequencing, MESH: Aged, MESH: Microphthalmos / pathology, Mutation, MESH: Infant, Newborn, sclereocornea, MESH: Congenital Abnormalities / genetics, MESH: Infant, 3. Good health, Pedigree, Child, Preschool, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Congenital cataracts, symbols, Female, Heterozygote, MESH: Mutation, Adolescent, MESH: Pedigree, Biology, MESH: Transcription Factors / genetics, Cataract, Congenital Abnormalities, 03 medical and health sciences, symbols.namesake, Cataracts, Anterior segment mesenchymal disorder, medicine, Humans, MESH: Homeodomain Proteins / genetics, Aged, MESH: Adolescent, Homeodomain Proteins, Anophthalmia, MESH: Humans, Genetic heterogeneity, MESH: Child, Preschool, MESH: Microphthalmos / genetics, Infant, Newborn, MESH: Eye Abnormalities / pathology, Infant, MESH: Cataract / pathology, medicine.disease, MESH: Male, eye diseases, Ophthalmology, 030104 developmental biology, MESH: Cataract / genetics, MESH: Eye Abnormalities / genetics, Pediatrics, Perinatology and Child Health, Eye development, sense organs, MESH: Female, Transcription Factors
Abstract: Background: Congenital cataract displays large phenotypic (syndromic and isolated cataracts) and genetic heterogeneity. Mutations in several transcription factors involved in eye development, like PITX3, have been associated with congenital cataracts and anterior segment mesenchymal disorders. Materials and methods: Targeted sequencing of 187 genes involved in ocular development was performed in 96 patients with mainly anophthalmia and microphthalmia. Additionally, Sanger sequencing analysis of PITX3 was performed on a second cohort of 32 index cases with congenital cataract and Peters anomaly and/or sclereocornea. Results: We described five families with four different PITX3 mutations, two of which were novel. In Family 1, the heterozygous recurrent c.640_656dup (p.Gly220Profs*95) mutation cosegregated with eye anomalies ranging from congenital cataract to Peters anomaly. In Family 2, the novel c.669del [p.(Leu225Trpfs*84)] mutation cosegregated with dominantly inherited eye anomalies ranging from posterior embryotoxon to congenital cataract in heterozygous carriers and congenital sclereocornea and cataract in a patient homozygous for this mutation. In Family 3, we identified the recurrent heterozygous c.640_656dup (p.Gly220Profs*95) mutation segregating with congenital cataract. In Family 4, the de novo c.582del [p.(Ile194Metfs*115)] mutation was identified in a patient with congenital cataract, microphthalmia, developmental delay and autism. In Family 5, the c.38G>A (p.Ser13Asn) mutation segregated dominantly in a family with Peters anomaly, which is a novel phenotype associated with the c.38G>A variant compared with the previously reported isolated congenital cataract. Conclusions: Our study unveils different phenotypes associated with known and novel mutations in PITX3, which will improve the genetic counselling of patients and their families.
Published: 2021
Full Text: View/download PDF

42. A novel hypomorphic splice variant in EIF2B5 gene is associated with mild ovarioleukodystrophy

Author: Gérald Le Gac, Isabelle Gourlaouen, Carlos Casasnovas, Stéphane Fourcade, Agatha Schlüter, Aurora Pujol, Agustí Rodríguez-Palmero, Chandran Ka, Montserrat Ruiz, Edgard Verdura, Ricardo Lobato, Juan José Martínez, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), CIBER de Enfermedades Raras (CIBERER), 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), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hospital Universitario Infanta Sofía, Institut Brestois Santé Agro Matière (IBSAM), Institució Catalana de Recerca i Estudis Avançats (ICREA), and PODEUR, Sophie
Subjects: 0301 basic medicine, Adult, [SDV]Life Sciences [q-bio], Neurosciences. Biological psychiatry. Neuropsychiatry, medicine.disease_cause, Ovary diseases, 03 medical and health sciences, 0302 clinical medicine, Diagnòstic, Leukoencephalopathies, Diagnosis, Exome Sequencing, Intronic Mutation, Medicine, Humans, Ovarian Diseases, Allele, RC346-429, Gene, Research Articles, Genetics, Malalties de l'ovari, Mutation, business.industry, General Neuroscience, Alternative splicing, Phenotype, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Eukaryotic Initiation Factor-2B, 030104 developmental biology, RNA splicing, Female, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, Research Article, Minigene, RC321-571
Abstract: Objective: To identify the genetic cause in an adult ovarioleukodystrophy patient resistant to diagnosis. Methods: We applied whole-exome sequencing (WES) to a vanishing white matter disease patient associated with premature ovarian failure at 26 years of age. We functionally tested an intronic variant by RT-PCR on patient's peripheral blood mononuclear cells (PBMC) and by minigene splicing assay. Results: WES analysis identified two novel variants in theEIF2B5gene: c.725A > G (p.Tyr242Cys) and an intronic noncanonical mutation (c.1156 + 13G>A). This intronic mutation resulted into generation of various isoforms both in patient's PBMC and in the minigene splicing assay, showing that similar to 20% residual wild-type isoform is still expressed by the intronic-mutated allele alone, concordant with an hypomorphic effect of this variant. Conclusion: We report two novel variants inEIF2B5, one of them a noncanonical intronic splice variant, located at a +13 intronic position. This position is mutated only in 0.05% of ClinVar intronic mutations described so far. Furthermore, we illustrate how minigene splicing assay may be advantageous when validating splice-altering variants, in this case highlighting the coexistence of wild-type and mutated forms, probably explaining this patient's milder, late-onset phenotype.
Published: 2020

43. Melanocortin-1 receptor (MC1R) genotypes do not correlate with size in two cohorts of medium-to-giant congenital melanocytic nevi Institutional affiliations

Author: Calbet-Llopart, Neus, Pascini-Garrigos, Mirella, Tell-Martí, Gemma, Potrony, Miriam, Martins da Silva, Vanessa, Barreiro, Alicia, Puig, Susana, Captier, Guillaume, James, Isabelle, Degardin, Nathalie, Carrera, Cristina, Malvehy, Josep, Etchevers, Heather, Puig-Butillé, Joan, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), CIBER de Enfermedades Raras (CIBERER), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Clinique du Val d'Ouest, 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), and Gall, Valérie
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, inherited variants, phenotype, Congenital melanocytic nevi or nevus, population, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, melanocortin 1 receptor (MC1R) gene, Giant Congenital Melanocytic Nevus (GCMN), nevogenesis, cutaneous lesion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: Congenital melanocytic nevi (CMN) are cutaneous malformations whose prevalence is inversely correlated with projected adult size. CMN are caused by somatic mutations, but epidemiological studies suggest that germline genetic factors may influence CMN development. In CMN patients from the U.K., genetic variants in the MC1R gene, such as p.V92M and loss-of-function variants, have been previously associated with larger CMN. We analyzed the association of MC1R variants with CMN characteristics in 113 medium-to-giant CMN patients from Spain and from a distinct cohort of 53 patients from France, Norway, Canada and the U.S. These cohorts were similar at the clinical and phenotypical level, except for the number of nevi per patient. We found that the p.V92M or loss-of-function MC1R variants either alone or in combination did not correlate with CMN size, in contrast to the U.K. CMN patients. An additional case-control analysis with 259 unaffected Spanish individuals, showed a higher frequency of MC1R compound heterozygous or homozygous variant genotypes in Spanish CMN patients compared to the control population (15.9% vs. 9.3%; P=0.075). Altogether, this study suggests that MC1R variants are not associated with CMN size in these non-U.K. cohorts. Additional studies are required to define the potential role of MC1R as a risk factor in CMN development.
Published: 2020

44. Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment

Author: Delgado-Martín, Belén, Medina, Miguel Ángel, [Delgado-Martín,B, Medina,MA] Department of Molecular Biology and Biochemistry Faculty of Sciences, University of Málaga Málaga, Spain. [Medina,MA] IBIMA (Biomedical Research Institute of Málaga) Málaga, Spain. [Medina,MA] CIBER de Enfermedades Raras (CIBERER) Málaga, Spain., and This work received funds from grants PID2019-105010RB-I00 (Spanish Ministry of Science, Innovation and Universities), UMA18-FEDERJA-220 (Andalusian Government and FEDER), group BIO 267 (Andalusian Government), as well as 'Plan Propio de Investigación y Transferencia' (U. Málaga). The 'CIBER de Enfermedades Raras' is an initiative from the ISCIII (Spain).
Subjects: Health Care::Health Care Economics and Organizations::Organizations::International Agencies::United Nations::World Health Organization [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Molecular Biology [Medical Subject Headings], Cancer therapy, Patient stratification, Diagnóstico, Terapéutica, Diseases::Neoplasms::Neoplasms by Site::Nervous System Neoplasms::Central Nervous System Neoplasms::Brain Neoplasms [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Combined Modality Therapy::Chemotherapy, Adjuvant [Medical Subject Headings], Chemicals and Drugs::Pharmaceutical Preparations [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Neoplasias, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Neoplasms, Neuroepithelial::Glioma [Medical Subject Headings], Preparaciones farmacéuticas, Encéfalo, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Glandular and Epithelial::Neoplasms, Neuroepithelial::Glioma::Astrocytoma::Glioblastoma [Medical Subject Headings], Glioblastoma, Diagnostics
Abstract: Gliomas are the most common primary brain tumors in adults. They arise in the glial tissue and primarily occur in the brain. Low-grade tumors of World Health Organization (WHO) grade II tend to progress to high-grade gliomas of WHO grade III and, eventually, glioblastoma of WHO grade IV, which is the most common and deadly glioma, with a median survival of 12-15 months after final diagnosis. Knowledge of the molecular biology and genetics of glioblastoma has increased significantly in the past few years, giving rise to classification methods that can help in management and stratification of glioblastoma patients. However, glioblastoma remains an incurable disease. Glioblastoma cells have acquired genetic and metabolic adaptations in order to sustain tumor growth and progression, including changes in energetic metabolism, invasive capacity, migration, and angiogenesis, that make it very difficult to find suitable therapeutic targets and to develop effective drugs. The current standard of care for glioblastoma patients is surgery followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide. Although progress in glioblastoma therapies in recent years has been more limited than in other tumors, numerous drugs and targets are being proposed and many clinical trials are underway to develop effective subtype-specific treatments. Yes
Published: 2020

45. Physical activity and risks of breast and colorectal cancer : a Mendelian randomisation analysis

Author: Michael O. Woods, Fränzel J.B. van Duijnhoven, Tilman Kühn, Graham G. Giles, Temitope O. Keku, Konstantinos K. Tsilidis, Andrew T. Chan, Mingyang Song, Michael Hoffmeister, Gad Rennert, Tabitha A. Harrison, Anna H. Wu, Kenneth Offit, Mark A. Jenkins, Elizabeth A Platz, Sabina Sieri, Noralane M Lindor, John D. Potter, D Timothy Bishop, Barbara L. Banbury, Anne M. May, Sonja I. Berndt, José María Huerta, Antonia Trichopoulou, Paul D.P. Pharoah, Niki Dimou, Christopher I. Li, Roger L. Milne, Marc J. Gunter, Hermann Brenner, Martha L. Slattery, Catherine M. Tangen, Gianluca Severi, Richard M. Martin, Nabila Kazmi, Ruth C. Travis, Sanford D. Markowitz, Jeroen R. Huyghe, Heather Hampel, Ulrike Peters, John L. Hopper, Brigid M. Lynch, Krasimira Aleksandrova, Alicja Wolk, Merete Ellingjord-Dale, Li Li, Bethany Van Guelpen, Sergi Castellví-Bel, Edward Giovannucci, Steven J Gallinger, Annika Lindblom, Cornelia M. Ulrich, Stephen B. Gruber, Stephanie L. Schmit, Jenny Chang-Claude, Lorena Moreno, Victor Moreno, Nikos Papadimitriou, Stephen N. Thibodeau, Elio Riboli, Sophia Harlid, Polly A. Newcomb, Pavel Vodicka, Demetrius Albanes, Bas Bueno-de-Mesquita, Maria J. Sánchez, Sarah J Lewis, Timothy Robinson, Daniel D Buchanan, Loic Le Marchand, Carlo La Vecchia, Robert E Schoen, Neil Murphy, Giovanna Masala, Evelyn M. Monninkhof, Jane C. Figueiredo, Andrea Gsur, Jochen Hampe, Vittorio Perduca, Li Hsu, Emily White, Peter T. Campbell, School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, University of Bristol [Bristol], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Department of Epidemiology, German Institute of Human Nutrition, Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment [Bilthoven] (RIVM), The Cancer, Ageing and Somatic Mutation Programme [Cambridgeshire, UK], The Wellcome Trust Sanger Institute [Cambridge], Division of Cancer Epidemiology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), University of Melbourne, Harvard School of Public Health, Department of Internal Medicine, Epidemiology, Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Medical Department 1 [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Ohio State University [Columbus] (OSU), FESTO, Universität Stuttgart [Stuttgart], Centre for MEGA Epidemiology, The University of Melbourne, Victoria, Australia, CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Medical Genetics, HMNC Brain Health, Department of Clinical Sciences and Community Health [Milan, Italy], Università degli Studi di Milano [Milano] (UNIMI), University of Hawai‘i [Mānoa] (UHM), Chinese Center for Disease Control and Prevention, Department of Clinical Genetics, Karolinska University Hospital [Stockholm], Mayo Clinic, Case Western Reserve University [Cleveland], Cancer Risk Factors and LifeStyle Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Julius Center for Health Sciences and Primary Care, University Medical Center [Utrecht], Cancer Epidemiology Centre, Cancer Council Victoria, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Memorial Sloane Kettering Cancer Center [New York], Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Department of Oncology, University of Cambridge [UK] (CAM), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, School of Public Health [London, UK] (Faculty of Medicine), Andalusian School of Public Health [Granada], Istituto Nazionale dei Tumori, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Mayo Clinic [Rochester], University of Oxford [Oxford], WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens]-University of Athens Medical School [Athens], Helmholtz Centre for Ocean Research [Kiel] (GEOMAR), Department of Medical Biosciences and Pathology, Umeå University, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Karolinska Institutet [Stockholm], Nutrition and Metabolism Section, International Agency for Research on Cancer, [Papadimitriou,N, Dimou,N, Gunter,MJ, Murphy,N] Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France. [Tsilidis,KK] Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. [Tsilidis,KK, Ellingjord-Dale,M, Riboli,E] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. [Banbury,B, Harrison,TA, Hsu,L, Huyghe,JR, Li,CI, Newcomb,PA, Potter,JD, White,E, Peters,U] Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. [Martin,RM, Kazmi,N] MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. [Martin,RM, Lewis,SJ, Robinson,TM] Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK. [Martin,RM] National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK. [Albanes,D, Berndt,SI] Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MA, USA. [Aleksandrova,K] German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Nuthetal, Germany. [Bishop,DT] Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. [Brenner,H, Hoffmeister,M] Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. [Brenner,H] Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. [Brenner,H] German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. [Buchanan,DD, Giles,GG, Hopper,JL, Jenkins,MA, Lynch,B, Milne,R] Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia. [Buchanan,DD] Colorectal Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia. [Buchanan,DD] Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC, Australia [Bueno-de-Mesquita,B] Former senior scientist, Dept. for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), BA Bilthoven, Netherlands. [Bueno-de-Mesquita,B] Former associate professor, Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, Netherlands. [Bueno-de-Mesquita,B] ormer visiting professor, Dept. of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, St Mary’s Campus, Norfolk Place, London, London, UK. [Bueno-de-Mesquita,B] Former academic Icon / visiting professor, Dept. of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Pantai Valley, Kuala Lumpur, Malaysia. [Campbell,PT] Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA. [Castellví-Bel,S, Moreno,L] Gastroenterology Department, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain. [Chan,AT, Song,M] Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [Chan,AT, Song,M] Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. [Chang-Claude,J, Kühn,T] Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [Chang-Claude,J] University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany. [Figueiredo,JC] Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. [Figueiredo,JC] Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. [Gallinger,SJ] Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada. [Giles,GG, Milne,R] Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia. [Giovannucci,E, Song,M] Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. [Giovannucci,E, Song,M] Department of Nutrition, T.H. H, Chan School of Public Health, Boston, MA, USA. [Giovannucci,E] Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA. [Gruber,SB, Schmit,SL] Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. [Gsur,A] Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria. [Hampe,J] Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany. [Hampel,H] Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. [Harlid,S] Department of Radiation Sciences, Oncology, Umea University, Umea, Sweden. [Hopper,JL] Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea. [Hsu,L] Department of Biostatistics, University of Washington, Seattle, WA, USA. [Huerta,JM, Moreno,V, Sánchez,MJ] CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. [Huerta,JM] Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain. [Keku,TO] Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA. [La Vecchia,C, Trichopoulou,A] Hellenic Health Foundation, Athens, Greece. [La Vecchia,C] Dept. of Clinical Sciences and Community Health, Università degli Studi di Milano, Milano, Italy. [Le Marchand,L] University of Hawaii Cancer Center, Honolulu, HI, USA. [Li,L] Department of Family Medicine, University of Virginia, Charlottesville, VA, USA. [Lindblom,A] Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. [Lindblom,A] Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. [Lindor,NM] Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA. [Lynch,B] Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. [Markowitz,SD] Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, Cleveland, OH, USA. [Masala,G] Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy. [May,AM, Monninkhof,E] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, GA UTRECHT, Netherlands. [Milne,R] Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia. [Moreno,V] Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain. [Moreno,V] Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. [Newcomb,PA] School of Public Health, University of Washington, Seattle, WA, USA. [Offit,K] Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. [Offit,K] Department of Medicine, Weill Cornell Medical College, New York, NY, USA. [Perduca,V, Severi,G] CESP, Fac. de médecine - Univ. ParisSud, Fac. de médecine - UVSQ I, Université Paris-Saclay, Villejuif, France. [Perduca,V, Severi,G] Gustave Roussy, Villejuif, France. [Perduca,V] Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France. [Pharoah,PDP] Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Platz,EA] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. [Rennert,G] Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel. [Rennert,G] 7Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. [Rennert,G] Clalit National Cancer Control Center, Haifa, Israel. [Sánchez,MJ] Andalusian School of Public Health, Biomedical Research Institute ibs.GRANADA, University of Granada, Granada, Spain. [Schmit,SL] Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. [Schoen,RE] Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. [Sieri,S] Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Slattery,ML] Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. [Tangen,CM] SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. [Thibodeau,SN] Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. [Travis,RC] Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. [Ulrich,CM] Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA. [van Duijnhoven,FJB] Division of Human Nutrition, Wageningen University and Research, Wageningen, Netherlands. [Van Guelpen,B] Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden. [Van Guelpen,B] Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden. [Vodicka,P] Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic. [Vodicka,P] Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic. [Vodicka,P] Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic. [White,E, Peters,U] Department of Epidemiology, University of Washington, Seattle, WA, USA. [Wolk,A] Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. [Woods,MO] Memorial University of Newfoundland, Discipline of Genetics, St. John’s, Canada. [Wu,AH] University of Southern California, Preventative Medicine, Los Angeles, CA, USA., This work was supported by the National Cancer Institute, the International Agency for Research on Cancer and a Cancer Research UK program grant (C18281/A19169 to RMM, SJL & NK). RMM was supported by the National Institute for Health Research (NIHR) Bristol Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The funding sources for BCAC, CCFR, GECCO, and CORECT consortia are presented in detail in the appendix in the Supplementary material., Tsilidis, Konstantinos K [0000-0002-8452-8472], Martin, Richard M [0000-0002-7992-7719], Lewis, Sarah J [0000-0003-4311-6890], Robinson, Timothy M [0000-0003-0933-646X], Timothy Bishop, D [0000-0002-8752-8785], Buchanan, Daniel D [0000-0003-2225-6675], Chan, Andrew T [0000-0001-7284-6767], Giles, Graham G [0000-0003-4946-9099], Gsur, Andrea [0000-0002-9795-1528], Hampe, Jochen [0000-0002-2421-6127], Hampel, Heather [0000-0001-7558-9794], Harlid, Sophia [0000-0001-8540-6891], Harrison, Tabitha A [0000-0002-4173-7530], María Huerta, José [0000-0002-9637-3869], Huyghe, Jeroen R [0000-0001-6027-9806], Jenkins, Mark A [0000-0002-8964-6160], La Vecchia, Carlo [0000-0003-1441-897X], Masala, Giovanna [0000-0002-5758-9069], Milne, Roger [0000-0001-5764-7268], Moreno, Victor [0000-0002-2818-5487], Newcomb, Polly A [0000-0001-8786-0043], Perduca, Vittorio [0000-0003-0339-0473], Pharoah, Paul D P [0000-0001-8494-732X], Potter, John D [0000-0001-5439-1500], Rennert, Gad [0000-0002-8512-068X], Riboli, Elio [0000-0001-6795-6080], Schmit, Stephanie L [0000-0001-5931-1194], Schoen, Robert E [0000-0001-7153-2766], Van Guelpen, Bethany [0000-0002-9692-101X], Wolk, Alicja [0000-0001-7387-6845], Peters, Ulrike [0000-0001-5666-9318], Murphy, Neil [0000-0003-3347-8249], Apollo - University of Cambridge Repository, Tsilidis, Konstantinos K. [0000-0002-8452-8472], Martin, Richard M. [0000-0002-7992-7719], Lewis, Sarah J. [0000-0003-4311-6890], Timothy Bishop, D. [0000-0002-8752-8785], Buchanan, Daniel D. [0000-0003-2225-6675], Chan, Andrew T. [0000-0001-7284-6767], Giles, Graham G. [0000-0003-4946-9099], Harrison, Tabitha A. [0000-0002-4173-7530], Huyghe, Jeroen R. [0000-0001-6027-9806], Jenkins, Mark A. [0000-0002-8964-6160], Newcomb, Polly A. [0000-0001-8786-0043], Pharoah, Paul D. P. [0000-0001-8494-732X], Potter, John D. [0000-0001-5439-1500], Schmit, Stephanie L. [0000-0001-5931-1194], Schoen, Robert E. [0000-0001-7153-2766], and Pharoah, Paul DP [0000-0001-8494-732X]
Subjects: Oncology, Epidemiology, Colorectal cancer, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Accelerometry [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Molecular Epidemiology::Mendelian Randomization Analysis [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Breast cancer, Epidemiology of cancer, Accelerometry, Odds Ratio, lcsh:Science, skin and connective tissue diseases, Cancer genetics, ComputingMilieux_MISCELLANEOUS, Cancer, 0303 health sciences, Biobank, 3. Good health, 030220 oncology & carcinogenesis, ICEP, Factores de riesgo, medicine.medical_specialty, Science, 631/67/2324, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms::Colorectal Neoplasms, Hereditary Nonpolyposis [Medical Subject Headings], Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Càncer colorectal, Anthropology, Education, Sociology and Social Phenomena::Human Activities::Exercise [Medical Subject Headings], Humans, Epidemiologia, Exercise, VLAG, Cancer och onkologi, 45, 631/67/1347, Odds ratio, Mendelian Randomization Analysis, medicine.disease, Colorectal Neoplasms/genetics, 030104 developmental biology, Analyses, Risk factors, Check Tags::Female [Medical Subject Headings], Cancer and Oncology, lcsh:Q, Breast neoplasms, 0301 basic medicine, 631/67/1504/1885, Nutrition and Disease, General Physics and Astronomy, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Risk Factors, Neoplasias colorrectales, Voeding en Ziekte, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Odds Ratio [Medical Subject Headings], Multidisciplinary, article, Public Health, Global Health, Social Medicine and Epidemiology, Polymorphism, Single Nucleotide/genetics, Ejercicio físico, Neoplasias de la mama, Female, Colorectal Neoplasms, 631/67, 141, Breast Neoplasms, 45/23, Polymorphism, Single Nucleotide, Colorectal neoplasms, Càncer de mama, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], Cancer epidemiology, 631/67/68, Internal medicine, Mendelian randomization, medicine, Journal Article, Life Science, Genetic Predisposition to Disease, Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms [Medical Subject Headings], 030304 developmental biology, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], business.industry, General Chemistry, Physical fitness, Confidence interval, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Condició física
Abstract: Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI), International Agency for Research on Cancer, Cancer Research UK C18281/A19169, National Institute for Health Research (NIHR)
Published: 2020

46. European interdisciplinary guideline on invasive squamous cell carcinoma of the skin: Part 2. Treatment

Author: Stratigos, Alexander J, Garbe, Claus, Dessinioti, Clio, Lebbe, Celeste, Bataille, Veronique, Bastholt, Lars, Dreno, Brigitte, Concetta Fargnoli, Maria, Forsea, Ana M, Frenard, Cecille, Harwood, Catherine A, Hauschild, Axel, Hoeller, Christoph, Kandolf-Sekulovic, Lidija, Kaufmann, Roland, Kelleners-Smeets, Nicole W J, Malvehy, Josep, Del Marmol, Veronique, Middleton, Mark R, Moreno-Ramirez, David, Pellecani, Giovanni, Peris, Ketty, Saiag, Philippe, van den Beuken-van Everdingen, Marieke H J, Vieira, Ricardo, Zalaudek, Iris, Eggermont, Alexander M M, Grob, Jean-Jacques, European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC), HAL UVSQ, Équipe, National and Kapodistrian University of Athens (NKUA), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), North & East Hertfordshire NHS Trust [Northwood, UK], Odense University Hospital (OUH), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), University of L'Aquila [Italy] (UNIVAQ), University of Bucharest (UniBuc), Queen Mary University of London (QMUL), Kiel University, Medizinische Universität Wien = Medical University of Vienna, Military Medical Academy [Belgrade, Serbia] (2MA), Frankfurt University Hospital, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), CIBER de Enfermedades Raras (CIBERER), Université libre de Bruxelles (ULB), University of Oxford, Hospital Universitario Virgen Macarena [Sevilla, Spain] (HUVM), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Coimbra Hospital and Universitary Centre [Coimbra, Portugal] (CHUC), Università degli studi di Trieste = University of Trieste, Princess Máxima Center for Pediatric Oncology, Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM), Amgen Bristol-Myers Squibb, BMS Pfizer AstraZeneca GlaxoSmithKline, GSK Merck Novartis Roche Sanofi AbbVie Meso Scale Diagnostics, MSD Merck Sharp and Dohme, MSD DUSA Pharmaceuticals Les Laboratories Pierre Fabre Cilag LEO Pharma Research Foundation, The development of the current set of guideline was supported solely by funds of the EADO which were used to mainly support the consensus meeting.Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, AbbVie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis, grants and personal fees from NeraCare, grants and personal fees from BMS, personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb, personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche, personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis, personal fees from Merck MSD, outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS, Roche, Novartis, Pierre Fabre, AstraZeneca, Incyte, MSD/Merck, Bayer. Dr. Dr?no reports grants and personal fees from BMS, personal fees from MSD, grants and personal fees from Roche, grants and personal fees from Fabre, grants and personal fees from Sanofi, outside the submitted work. Dr. Fargnoli reports grants and personal fees from Almirall, grants and personal fees from Leo Pharma, personal fees from Janssen, grants and personal fees from Novartis, personal fees from Lilly, grants and personal fees from Sanofi, personal fees from UCB, grants and personal fees from AbbVie, personal fees from Celgene, personal fees from Pierre Fabre, grants and personal fees from Galderma, personal fees from Mylan, personal fees from Medac Pharma, personal fees from Roche, personal fees from Sun Pharma, outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis, Leo Pharma, Solartium, Pierre Fabre, outside the submitted work. Dr. Frenard has nothing to disclose. Dr. Harwood reports institutional research grants and honoraria from Sanofi, Novartis, Merck, Pfizer, Galderma, Meda, Almirall, PellePharm, Leo Pharma, Ceries. Dr. Hauschild reports honoraria and/or research grants from Almirall, BMS, Roche, Novartis, Pierre Fabre, Sun Pharma, Merck Serono, Sanofi-Aventis, Regeneron, MSD/Merck, Philogen, OncoSec outside the submitted work. Dr. Hoeller reports grants and personal fees from Amgen, personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Roche, personal fees from Sanofi, personal fees from Incyte, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers? honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from AbbVie, Amgen, Biontech, BMS, Celgene, Galderma, Janssen, Leo, Lilly, Merck, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Roche, Wyeth. Advisory board and honoraria from Merz, Roche, Novartis. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development, other from Janssen-Cilag, other from AbbVie, other from Galderma, outside the submitted work. Dr. Malvehy reports research grants from Almirall, ISDIN, Leo Pharma, Galderma, GSK, Cantabria, participation in advisory board meetings for Almirall, Sun Pharma, BMS, Roche, Novartis, Pierre Fabre. Dr. del Marmol reports personal fees from MSD, from BMS, personal fees from Sanofi, grants and personal fees from AbbVie, grants from Janssen, outside the submitted work. Dr. Middleton reports personal fees and/or grants from Amgen, Roche, AstraZeneca, GSK, Novartis, Immunocore, BMS, Eisai and Merck. Institutional funding from Millennium, Vertex, Pfizer, Regeneron, TC Biopharm, BioLineRx, Replimune, outside the submitted work. Dr. Moreno-Ram?rez has nothing to disclose. Dr. Pellecani reports grants from university of Modena and Reggio Emilia, during the conduct of the study, grants from Novartis, grants and personal fees from Almirall, grants from Leo Pharma, from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie, Almirall, Biogen Celgene, Lilly, Galderma, Leo Pharma, Novartis, Roche, Sanofi, Sun Pharma, Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen, Bristol-Myers Squibb, MSD, Merck Serono, Novartis, Pfizer, Roche-Genentech, Pierre Fabre, and Sanofi, outside the submitted work. Dr. van den Beuken-van Everdingen has nothing to disclose. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi, Sun Pharma, Novartis, Galderma, Roche, Celgene, Almirall, Leo Pharma, Mylan, Difa Cooper, Cieffe Labs, La Roche Posay, Pierre Fabre. Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for BIOCAD, BioInvent, Bristol-Myers Squibb (BMS), CatalYm, Ellipses, GlaxoSmithKline (GSK), HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, SELLAS, SkylineDx. Dr. Grob reports personal fees for advisory board and as speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre Fabre, Merck, Sanofi, Merck, Pfizer outside the submitted work., Dr. Stratigos reports personal fees and/or research support from Novartis, Roche, BMS, AbbVie, Sanofi, Regeneron, Genesis Pharma, outside the submitted work. Dr. Garbe reports personal fees from Amgen, personal fees from MSD, grants and personal fees from Novartis , grants and personal fees from NeraCare , grants and personal fees from BMS , personal fees from Pierre Fabre, personal fees from Philogen, grants and personal fees from Roche , grants and personal fees from Sanofi , outside the submitted work. Dr. Dessinioti has nothing to disclose. Dr. Lebbe reports grants and personal fees from Bristol-Myers Squibb , personal fees from MSD, personal fees from Novartis, personal fees from Amgen, grants and personal fees from Roche , personal fees from Avantis Medical Systems, personal fees from Pierre Fabre, personal fees from Pfizer, personal fees from Incyte, outside the submitted work. Dr. Bataille reports personal fees from Novartis, personal fees from Merck MSD, outside the submitted work. Dr. Bastholt reports personal fees for advisory board activity: BMS, Roche, Novartis, Pierre Fabre, AstraZeneca, Incyte, MSD/Merck, Bayer. Dr. Dréno reports grants and personal fees from BMS , personal fees from MSD, grants and personal fees from Roche , grants and personal fees from Fabre , grants and personal fees from Sanofi , outside the submitted work. Dr. Fargnoli reports grants and personal fees from Almirall , grants and personal fees from Leo Pharma , personal fees from Janssen, grants and personal fees from Novartis , personal fees from Lilly, grants and personal fees from Sanofi , personal fees from UCB, grants and personal fees from AbbVie , personal fees from Celgene, personal fees from Pierre Fabre, grants and personal fees from Galderma , personal fees from Mylan, personal fees from Medac Pharma, personal fees from Roche, personal fees from Sun Pharma, outside the submitted work. Dr. Forsea reports scientific consultant/speaker fee from Novartis, Leo Pharma, Solartium, Pierre Fabre, outside the submitted work. Dr. Frenard has nothing to disclose. Dr. Harwood reports institutional research grants and honoraria from Sanofi , Novartis , Merck , Pfizer , Galderma , Meda , Almirall , PellePharm , Leo Pharma , Ceries . Dr. Hauschild reports honoraria and/or research grants from Almirall , BMS , Roche , Novartis , Pierre Fabre , Sun Pharma , Merck Serono , Sanofi-Aventis , Regeneron , MSD/Merck , Philogen , OncoSec outside the submitted work. Dr. Hoeller reports grants and personal fees from Amgen , personal fees from BMS, personal fees from MSD, personal fees from Novartis, personal fees from Pierre Fabre, personal fees from Roche, personal fees from Sanofi, personal fees from Incyte, outside the submitted work. Dr. Kandolf-Sekulovic reports speakers’ honoraria for Roche, Novartis, MSD, BMS, Janssen outside the submitted work. Dr. Kaufmann reports institutional research grants (clinical trials) from AbbVie , Amgen , Biontech , BMS , Celgene , Galderma , Janssen , Leo , Lilly , Merck , MSD , Novartis , Pierre Fabre , Pfizer , Regeneron , Roche , Wyeth . Advisory board and honoraria from Merz, Roche, Novartis. Dr. Kelleners-Smeets reports grants from Netherlands Organization for Health Research and Development , other from Janssen-Cilag, other from AbbVie, other from Galderma, outside the submitted work. Dr. Malvehy reports research grants from Almirall , ISDIN , Leo Pharma , Galderma , GSK , Cantabria, participation in advisory board meetings for Almirall, Sun Pharma, BMS, Roche, Novartis, Pierre Fabre. Dr. del Marmol reports personal fees from MSD, from BMS, personal fees from Sanofi, grants and personal fees from AbbVie, grants from Janssen , outside the submitted work. Dr. Middleton reports personal fees and/or grants from Amgen , Roche , AstraZeneca , GSK , Novartis , Immunocore , BMS , Eisai and Merck . Institutional funding from Millennium , Vertex , Pfizer , Regeneron , TC Biopharm , BioLineRx , Replimune , outside the submitted work. Dr. Moreno-Ramírez has nothing to disclose. Dr. Pellecani reports grants from university of Modena and Reggio Emilia , during the conduct of the study, grants from Novartis , grants and personal fees from Almirall , grants from Leo Pharma , from null, outside the submitted work. Dr. Peris reports honoraria for advisory board and grants from AbbVie , Almirall , Biogen Celgene , Lilly , Galderma , Leo Pharma , Novartis , Roche , Sanofi , Sun Pharma , Sandoz outside the submitted work. Dr. Saiag reports honoraria for advisory board and grants from Amgen , Bristol-Myers Squibb , MSD , Merck Serono , Novartis , Pfizer , Roche-Genentech , Pierre Fabre , and Sanofi , outside the submitted work. Dr. van den Beuken-van Everdingen has nothing to disclose. Dr. Vieira has nothing to disclose. Dr. Zalaudek reports honoraria and advisory board and grants from Sanofi , Sun Pharma , Novartis , Galderma , Roche , Celgene , Almirall , Leo Pharma , Mylan , Difa Cooper , Cieffe Labs , La Roche Posay , Pierre Fabre . Dr. Eggermont reports over the last 5 years personal fees as a consultant advisor for BIOCAD, BioInvent, Bristol-Myers Squibb (BMS), CatalYm, Ellipses, GlaxoSmithKline (GSK), HalioDx, Incyte, IO Biotech, ISA Pharmaceuticals, Merck Sharpe & Dohme (MSD), Novartis, Pfizer, Polynoma, Regeneron, Sanofi, SELLAS, SkylineDx. Dr. Grob reports personal fees for advisory board and as speaker from Amgen, Roche, GSK, Novartis, BMS, Pierre Fabre, Merck, Sanofi, Merck, Pfizer outside the submitted work., European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization for Research and Treatment of Cancer (EORTC), Stratigos, A. J., Garbe, C., Dessinioti, C., Lebbe, C., Bataille, V., Bastholt, L., Dreno, B., Concetta Fargnoli, M., Forsea, A. M., Frenard, C., Harwood, C. A., Hauschild, A., Hoeller, C., Kandolf-Sekulovic, L., Kaufmann, R., Kelleners-Smeets, N. W. J., Malvehy, J., del Marmol, V., Middleton, M. R., Moreno-Ramirez, D., Pellecani, G., Peris, K., Saiag, P., van den Beuken-van Everdingen, M. H. J., Vieira, R., Zalaudek, I., Eggermont, A. M. M., Grob, J. -J., Dermatologie, MUMC+: MA Dermatologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, RS: MHeNs - R3 - Neuroscience, Anesthesiologie, MUMC+: MA Anesthesiologie (9), and MUMC+: TPZ Palliatieve Zorg (9)
Subjects: 0301 basic medicine, Oncology, Cancer Research, Skin Neoplasms, medicine.medical_treatment, Dermatologic Surgical Procedures, Aftercare, Anti-PD-1 antibody, Cemiplimab, Chemotherapy, Cutaneous squamous cell carcinoma, EGFR inhibitors, Follow-up, Locally advanced, Metastatic, Radiotherapy, Surgical excision, Treatment, Medical Oncology, Metastasis, METASTATIC CUTANEOUS HEAD, 0302 clinical medicine, Antineoplastic Agents, Immunological, Quality of life, IN-TRANSIT METASTASIS, Monoclonal, ADJUVANT RADIOTHERAPY, Lymph node, Humanized, Societies, Medical, Skin, Cetuximab, Palliative Care, Margins of Excision, Chemoradiotherapy, 3. Good health, EGFR inhibitor, Dissection, medicine.anatomical_structure, Immunological, 030220 oncology & carcinogenesis, PHASE-II, Carcinoma, Squamous Cell, Sunlight, Settore MED/35 - MALATTIE CUTANEE E VENEREE, medicine.drug, medicine.medical_specialty, Consensus, Clinical Decision-Making, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, CERVICAL LYMPH-NODES, Dermatology, Antibodies, Monoclonal, Humanized, ELECTIVE NECK DISSECTION, Antibodies, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Patient Education as Topic, Internal medicine, Humans, Lymph Node Excision, Lymph Nodes, Neoplasm Staging, Patient Care Team, Medical, medicine, ORGAN TRANSPLANT RECIPIENTS, business.industry, Carcinoma, Guideline, medicine.disease, Cancérologie, Radiation therapy, 030104 developmental biology, Squamous Cell, INTERFERON-ALPHA, business, GROWTH-FACTOR RECEPTOR, Societies, INTRALESIONAL METHOTREXATE
Abstract: In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on management and be provided with best supportive care to optimise symptom management and improve quality of life. Frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2020

47. Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses

Author: Elio Riboli, Jochen Hampe, Ruth C. Travis, Andrea N. Burnett-Hartman, Anna H. Wu, Steven Gallinger, Stephen B. Gruber, Christopher I. Li, Bethany Van Guelpen, Kala Visvanathan, Loic Le Marchand, Veronika Vymetalkova, Demetrius Albanes, Jeroen R. Huyghe, Lori C. Sakoda, Jennifer Ose, Daniel D. Buchanan, Kenneth Offit, D. Timothy Bishop, John D. Potter, Sonja I. Berndt, Neil Murphy, Vittorio Perduca, Roger L. Milne, Niki Dimou, Marc J. Gunter, Ulrike Peters, Wen Yi Huang, Sergi Castellví-Bel, Graham Casey, Robert E. Schoen, Martha L. Slattery, Kathryn E. Bradbury, Albert de la Chapelle, Temitope O. Keku, Andrea Gsur, Wei Zheng, Gad Rennert, Hermann Brenner, Tabitha A. Harrison, Claudia Agnoli, Fränzel J.B. Van Duijnhoven, Sabina Rinaldi, Catherine M. Tangen, Jane C. Figueiredo, Ludmila Vodickova, Andrew T. Chan, Tilman Kühn, Hansong Wang, Mingyang Song, Sun-Seog Kweon, Annika Lindblom, Amanda I. Phipps, Cornelia M. Ulrich, Victor Moreno, Mark A. Jenkins, Li Hsu, Emily White, Conghui Qu, Peter T. Campbell, Stéphane Bézieau, Nikos Papadimitriou, Michael O. Woods, Jelena Bešević, Polly A. Newcomb, Pavel Vodicka, Heather Hampel, Barbara L. Banbury, Amanda J. Cross, Robert Carreras-Torres, Alicja Wolk, Graham G. Giles, Michael Hoffmeister, Elizabeth A. Platz, N. Charlotte Onland-Moret, Dallas R. English, Li Li, Jenny Chang-Claude, Vicente Martín, Richard M. Martin, María Dolores Chirlaque, Konstantinos K. Tsilidis, Clemens Schafmayer, Shuji Ogino, Nutrition and Metabolism Section, International Agency for Research on Cancer, Centre international de Recherche sur le Cancer (CIRC), School of Public Health - Department of Epidemiology and Biostatistics, Imperial College London, Nuffield Department of Population Health - Cancer Epidemiology Unit, University of Oxford [Oxford], International Agency for Cancer Research (IACR), School of Public Health [London, UK] (Faculty of Medicine), Candiolo Cancer Institute (IRCCS), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Division of Cancer Epidemiology and Genetics [Bethesda, MD, États-Unis], National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Interactions récepteurs ligands en immunocancérologie et immunopathologie, IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), St. James's University Hospital, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University Medical Center [Utrecht], The Cancer, Ageing and Somatic Mutation Programme [Cambridgeshire, UK], The Wellcome Trust Sanger Institute [Cambridge], Department of Preventive Medicine, University of Southern California (USC), Division of Cancer Epidemiology, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), Ohio State University [Columbus] (OSU), Cancer Epidemiology Centre, Cancer Council Victoria, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), University of Melbourne, Department of Internal Medicine, Epidemiology, Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Medical Department 1 [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), FESTO, Universität Stuttgart [Stuttgart], Division of Cancer Epidemiology and Genetics, Department of Medical Genetics, HMNC Brain Health, University of Hawai‘i [Mānoa] (UHM), Chinese Center for Disease Control and Prevention, Department of Clinical Genetics, Karolinska University Hospital [Stockholm], Dell-EMC, Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Memorial Sloane Kettering Cancer Center [New York], Department of Pathology, Brigham and Women's Hospital [Boston], 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, Institut Gustave Roussy (IGR), Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Department of Visceral and Thoracic Surgery [Kiel, Germany], University Hospital Schleswig-Holstein [Kiel, Germany], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Helmholtz Centre for Ocean Research [Kiel] (GEOMAR), Department of Medical Biosciences and Pathology, Umeå University, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Karolinska Institutet [Stockholm], and Center for Astrophysical Sciences [Baltimore]
Subjects: Oncology, Male, Nutrition and Disease, Colorectal cancer, BMI, body mass index, PLASMA-INSULIN, IGFBP3, IGF1, insulin-like growth factor 1, Genome-wide association study, GWAS, genome-wide association studies, MR-PRESSO, Mendelian Randomization Pleiotropy RESidual Sum and Outlier, FACTOR (IGF)-I, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Insulina, Medicine, Insulin, GWAS, Registries, Insulin-Like Growth Factor I, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, ICC, intraclass correlation coefficient, Incidence, Hazard ratio, MR, Mendelian randomization, Gastroenterology, MEN, SNP, single nucleotide polymorphism, Middle Aged, SERUM-LEVELS, 3. Good health, IGF-I, CRC, 030220 oncology & carcinogenesis, CRP, C-reactive protein, Female, Colorectal Neoplasms, Life Sciences & Biomedicine, Medical Genetics, REGRESSION DILUTION, Signal Transduction, medicine.medical_specialty, HbA1c, glycolated hemoglobin, FACTOR-I, Polymorphism, Single Nucleotide, Risk Assessment, Article, C-PEPTIDE, 03 medical and health sciences, Sex Factors, Insulin-Like Growth Factor II, Càncer colorectal, Internal medicine, COLON, Mendelian randomization, Biomarkers, Tumor, Journal Article, Humans, IGFBP3, insulin-like growth factor binding protein 3, 030304 developmental biology, Aged, VLAG, Medicinsk genetik, Cancer och onkologi, Science & Technology, Gastroenterology & Hepatology, Hepatology, business.industry, Case-control study, Cancer, IGFBP-3, 1103 Clinical Sciences, Odds ratio, Mendelian Randomization Analysis, medicine.disease, HR, hazard ratio, United Kingdom, CI, confidence interval, OR, odds ratio, Insulin-Like Growth Factor Binding Protein 3, Case-Control Studies, Cancer and Oncology, SHBG, sex hormone binding globulin, 1114 Paediatrics and Reproductive Medicine, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, SD, standard deviation, 1109 Neurosciences, Follow-Up Studies
Abstract: Background & Aims Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. Methods Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) Results After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12; P = 3.3 × 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18; P = 4.2 × 10–5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. Conclusions In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis., Graphical abstract
Published: 2020

48. Rimeporide as a ﬁrst- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Author: Joana Domingos, Delphine Labolle, Teresa Gidaro, Francesco Muntoni, Florence Porte Thomé, Camilla Johansson, Stefano C. Previtali, Jordi Díaz-Manera, Pietro Spitali, Julian Gray, Mirko Signorelli, Stephanie Carnesecchi, Jacqueline Pitchforth, Alberto Zambon, Cristina Al-Khalili Szigyarto, Pascale Roux-Lombard, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospital de la Santa Creu i Sant Pau, CIBER de Enfermedades Raras (CIBERER), Université de Genève (UNIGE), Geneva University Hospital (HUG), Leiden University Medical Center (LUMC), Royal Institute of Technology [Stockholm] (KTH ), Science for Life Laboratory [Solna], University College of London [London] (UCL), 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), Université de Genève = University of Geneva (UNIGE), and Universiteit Leiden
Subjects: Male, 0301 basic medicine, musculoskeletal diseases, Cardiomyopathy, Duchenne muscular dystrophy, Administration, Oral, Pharmacokinetic, Duchenne Muscular Dystrophy, Pharmacology, ddc:616.07, Models, Biological, Drug Administration Schedule, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, Rimeporide, medicine, Humans, In patient, Child, Muscle, Skeletal, NHE-1, ComputingMethodologies_COMPUTERGRAPHICS, ddc:616, Sodium-Hydrogen Exchanger 1, business.industry, medicine.disease, Pathophysiology, 3. Good health, Europe, Muscular Dystrophy, Duchenne, Treatment Outcome, 030104 developmental biology, Neuromuscular Agents, chemistry, 030220 oncology & carcinogenesis, Pharmacodynamics, Heart failure, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Safety, business
Abstract: Graphical abstract, Rimeporide, a ﬁrst-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide’s anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6–11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.
Published: 2020

49. Absence of p.R50X Pygm read-through in McArdle disease cellular models

Author: Tarrasó, Guillermo, Real-Martinez, Alberto, Parés, Marta, Romero-Cortadellas, Lídia, Puigros, Laura, Moya Borrego, Laura, de Luna Salva, Noemí, Brull, Astrid, Martín, Miguel Angel, Arenas, Joaquín, Lucia, Alejandro, Andreu, Antoni L., Barquinero, Jordi, Vissing, John, Krag, Thomas, Pinós Figueras, Tomàs, Universitat Autònoma de Barcelona, Universitat Autònoma de Barcelona (UAB), CIBER de Enfermedades Raras (CIBERER), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), University of Copenhagen = Københavns Universitet (KU), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Centre de Recherche en Myologie, University of Copenhagen = Københavns Universitet (UCPH), and Gestionnaire, Hal Sorbonne Université
Subjects: 0301 basic medicine, Medicine (miscellaneous), lcsh:Medicine, Cellular models, medicine.disease_cause, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immunology and Microbiology (miscellaneous), Metabolic myopathy, Metabolismo, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Biología molecular, Premature termination codon, Transfection, Stop codon, 3. Good health, metabolic myopathy, Glycogen Phosphorylase, Muscle Form, Enfermedad, Research Article, lcsh:RB1-214, McArdle disease, read-through, Neuroscience (miscellaneous), Context (language use), Biology, General Biochemistry, Genetics and Molecular Biology, mcardle disease, 03 medical and health sciences, Glycogen phosphorylase, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:Pathology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, lcsh:R, Intron, premature termination codon, Read-through, Molecular biology, Enfermedades, Ataluren, Disease Models, Animal, 030104 developmental biology, HEK293 Cells, chemistry, Glycogen Storage Disease Type V, cellular models, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, HeLa Cells
Abstract: McArdle disease is an autosomal recessive disorder caused by the absence of muscle glycogen phosphorylase, which leads to blocked muscle glycogen breakdown. We used three different cellular models to evaluate the efficiency of different read-through agents (including amlexanox, Ataluren, RTC13 and G418) in McArdle disease. The first model consisted of HeLa cells transfected with two different GFP-PYGM constructs presenting the Pygm p.R50X mutation (GFP-PYGM p.R50X and PYGM Ex1-GFP p.R50X). The second cellular model was based on the creation of HEK293T cell lines stably expressing the PYGM Ex1-GFP p.R50X construct. As these plasmids encode murine Pygm cDNA without any intron sequence, their transfection in cells would allow for analysis of the efficacy of read-through agents with no concomitant nonsense-mediated decay interference. The third model consisted of skeletal muscle cultures derived from the McArdle mouse model (knock-in for the p.R50X mutation in the Pygm gene). We found no evidence of read-through at detectable levels in any of the models evaluated. We performed a literature search and compared the premature termination codon context sequences with reported positive and negative read-through induction, identifying a potential role for nucleotide positions −9, −8, −3, −2, +13 and +14 (the first nucleotide of the stop codon is assigned as +1). The Pygm p.R50X mutation presents TGA as a stop codon, G nucleotides at positions −1 and −9, and a C nucleotide at −3, which potentially generate a good context for read-through induction, counteracted by the presence of C at −2 and its absence at +4., Summary: Here, we evaluated the efficiency of different read-through agents in McArdle disease cell culture models, revealing that read-through compounds do not restore full-length muscle glycogen phosphorylase.
Published: 2020

50. Ethanol-Induced Changes in Brain of Transgenic Mice Overexpressing DYRK1A

Author: Nathalie Janel, Marta Fructuoso, María Martínez de Lagrán, Mara Dierssen, Yu Chen Gu, Nadim Kassis, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CIBER de Enfermedades Raras (CIBERER), and Universitat Politècnica de Catalunya [Barcelona] (UPC)
Subjects: 0301 basic medicine, Genetically modified mouse, EXPRESSION, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Neuroscience (miscellaneous), Mice, Transgenic, ALCOHOL, Neurotransmission, Protein Serine-Threonine Kinases, Choice Behavior, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Glutamatergic, Mice, GLUTAMATE, DOPAMINE, 0302 clinical medicine, TARGETS, Internal medicine, medicine, Animals, Ethanol metabolism, Receptor, Liver injury, Neurons, DECREASES, Ethanol, Chemistry, Glutamate Decarboxylase, Glutamate receptor, SEROTONIN, Brain, CONSUMPTION, MOUSE MODEL, Protein-Tyrosine Kinases, medicine.disease, GENE, 3. Good health, 030104 developmental biology, Endocrinology, Neurology, Synapses, Disks Large Homolog 4 Protein, 030217 neurology & neurosurgery
Abstract: International audience; Alcoholism is a chronic relapsing disorder defined by loss of control over excessive consumption of ethanol despite damaging effects on the liver and brain. We previously showed that the overexpression in mice of Dyrk1A (TgDyrk1A, for dual-specificity tyrosine (Y) phosphorylation-regulated kinase 1A) reduces the severity of alcohol mediated liver injury. Ethanol consumption has also been associated with increased brain glutamate concentration that led to therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Interestingly, mice overexpressing Dyrk1A (TgDyrk1A mice) present a reduction of glutamatergic brain transmission, which we propose could be protective against alcohol intake. To answer this question, we investigated the ethanol preference in TgDyrk1A mice using a two-bottle choice paradigm. TgDyrk1A mice showed a non-significant decrease of voluntary ethanol intake and ethanol preference compared with wild-type mice. At the peripheral level, mice overexpressing Dyrk1A show lower ethanol plasma levels, indicating a faster ethanol metabolism. At the end of the protocol, lasting 21 days, brains were extracted for protein analysis. Ethanol reduced levels of the synaptic protein PSD-95 and increased the glutamate decarboxylase GAD65, specifically in the cortex of TgDyrk1A mice. Our results suggest that overexpression of DYRK1A may cause different ethanol-induced changes in the brain.
Published: 2020

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Region

Database

Publisher

550 results on '"CIBER de Enfermedades Raras (CIBERER)"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources