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1. Comparative outcomes of extracorporeal membrane oxygenation for COVID-19 delivered in experienced European centres during successive SARS-CoV-2 variant outbreaks (ECMO-SURGES): an international, multicentre, retrospective cohort study

Author: Matthieu Schmidt, David Hajage, Micha Landoll, Benjamin Pequignot, Elise Langouet, Matthieu Amalric, Armand Mekontso-Dessap, Luis Chiscano-Camon, Katy Surman, Dylan Finnerty, Patricia Santa-Teresa, Antonio Arcadipane, Pablo Millán, Roberto Roncon-Albuquerque, Aaron Blandino-Ortiz, Pablo Blanco-Schweizer, Pilar Ricart, Ricardo Gimeno-Costa, Carlos Luis Albacete, Philip Fortuna, Peter Schellongowski, Dieter Dauwe, Hadrien Winiszewski, Antoine Kimmoun, Bruno Levy, Greet Hermans, Giacomo Grasselli, Guillaume Lebreton, Christophe Guervilly, Gennaro Martucci, Christian Karagiannidis, Jordi Riera, Alain Combes, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de cardiologie [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), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), 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), Pharmacoépidémiologie et évaluation des soins [iPLesp] (PEPITES), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Universität Witten Herdecke, Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CHU Marseille, IMRB - 'Biomechanics and Respiratory Apparatus' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Groupe de recherche clinique CARMAS (Cardiovascular and Respiratory Manifestations of Acute lung injury and Sepsis) (CARMAS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-CHU Henri Mondor [Créteil], Vall d'Hebron University Hospital [Barcelona], Royal Papworth Hospital [Cambridge, UK] (RPH), Hospital General Universitario 'Gregorio Marañón' [Madrid], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT), Universidad Loyola Andalucía = Loyola University Andalucía, Hospital de São João [Porto], Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), Rio Hortega University Hospital (Hospital Universitario Río Hortega) [Valladolid, Spain] (RHUH), Germans Trias i Pujol University Hospital [Badalona, Barcelona, Spain] (GTPUH), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Hospital Clínico Universitario Virgen de la Arrixaca = University Hospital Virgen de la Arrixaca [Murcia], Centro Hospitalar de Lisboa Central E.P.E, Medizinische Universität Wien = Medical University of Vienna, University Hospitals Leuven [Leuven], Service d'anesthésie et soins intensifs [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Marqueurs pronostiques et facteurs de régulations des pathologies cardiaques et vasculaires - UFC ( UR 3920) (PCVP / CARDIO), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), and Vall d’Hebron Research Institute (VHIR)
Subjects: Pulmonary and Respiratory Medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases
Abstract: International audience
Published: 2023

2. PECATI: A Multicentric, Open-Label, Single-Arm Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab and Lenvatinib in Pretreated B3-Thymoma and Thymic Carcinoma Patients

Author: Laurence Bigay-Game, Miguel Sampayo, Nicolas Girard, Laurent Greillier, Benjamin Besse, Javier de Castro, Jordi Remon, Sophie Cousin, R. Bernabé, Oscar Juan, Joaquin Mosquera, Silvia Novello, Centro Integral Oncologico Clara Campal, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut Curie [Paris], Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Università degli studi di Torino = University of Turin (UNITO), Hospital Universitario La Paz, Service de pneumologie [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hospital Universitario Virgen del Rocío [Sevilla], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Nord [CHU - APHM], Institut Bergonié [Bordeaux], UNICANCER, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Institut Gustave Roussy (IGR), and Université Paris-Saclay
Subjects: Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Thymoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Second-line, Pembrolizumab, Antibodies, Monoclonal, Humanized, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Immunotherapy, Lenvatinib, Pembrolizumab, Second-line, Thymic epithelial tumors, chemistry.chemical_compound, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Lenvatinib, Humans, Medicine, Thymic epithelial tumors, Lung cancer, Survival rate, Thymic carcinoma, business.industry, Phenylurea Compounds, Standard treatment, Cancer, Thymus Neoplasms, medicine.disease, chemistry, Quinolines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunotherapy, business
Abstract: International audience; Thymic epithelial tumors are rare neoplastic proliferations of thymic epithelial cells. The aggressiveness of these malignancies increases as higher is the histologic subtype, being thymic carcinoma the most aggressive subtype, with a greater tendency to metastatic spread. In metastatic setting, there is no standard treatment after progression on platinum-based chemotherapy. In this scenario, monotherapy treatment either with lenvatinib, a multi-tyrosine kinase inhibitor with antiangiogenic properties, or pembrolizumab, an immune-checkpoint inhibitor, has reported clinical activity. Potential combination of both agents may have synergistic activity as reported in other cancer types. PECATI trial is a single-arm, investigator-initiated phase II study aiming to assess the activity and safety of the combination of lenvatinib and pembrolizumab in 43 patients with advanced B3-thymoma or thymic carcinoma who progressed on or after at least one previous line of platinum-based chemotherapy. The primary endpoint of the trial is 5-month progression-free survival rate and the secondary endpoints include overall response rate, duration of response, and overall survival.
Published: 2022

3. An ESPGHAN Position Paper on the Use of Low-FODMAP Diet in Pediatric Gastroenterology

Author: Thomassen, R A, Luque, V, Assa, A, Borrelli, O, Broekaert, I, Dolinsek, J, Martin-de-Carpi, J, Mas, E, Miele, E, Norsa, L, Ribes-Koninckx, C, Saccomani, M Deganello, Thomson, M, Tzivinikos, C, Verduci, E, Bronsky, J, Haiden, N, Köglmeier, J, de Koning, B, Benninga, M A, Pediatrics, Paediatric Gastroenterology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), Oslo University Hospital [Oslo], Universitat Rovira i Virgili, The Hebrew University of Jerusalem (HUJ), Great Ormond Street Hospital for Children [London] (GOSH), University Hospital of Cologne [Cologne], University of Maribor, University of Barcelona, Institut de Recherche en Santé Digestive (IRSD ), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Naples Federico II = Università degli studi di Napoli Federico II, ASST Papa Giovanni XXIII [Bergamo, Italy], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Inst Invest Sanitaria La FE, Sheffield Children's NHS Foundation Trust, Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Università degli Studi di Milano = University of Milan (UNIMI), University Hospital Motol [Prague], Medizinische Universität Wien = Medical University of Vienna, Erasmus University Rotterdam, University of Amsterdam [Amsterdam] (UvA), SEGUIN, Nathalie, Thomassen, R A, Luque, V, Assa, A, Borrelli, O, Broekaert, I, Dolinsek, J, Martin-de-Carpi, J, Mas, E, Miele, E, Norsa, L, Ribes-Koninckx, C, Saccomani, M Deganello, Thomson, M, Tzivinikos, C, Verduci, E, Bronsky, J, Haiden, N, Köglmeier, J, de Koning, B, and Benninga, M A
Subjects: IRRITABLE-BOWEL-SYNDROME, Oligosaccharides, CHILDREN, Disaccharides, POLYOLS DIET, CLINICAL-TRIAL, Irritable Bowel Syndrome, Diet, Carbohydrate-Restricted, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, QUALITY-OF-LIFE, MANAGEMENT, Humans, Settore MED/49 - Scienze Tecniche Dietetiche Applicate, REDUCES SYMPTOMS, Child, Settore MED/38 - Pediatria Generale e Specialistica, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Monosaccharides, Gastroenterology, RANDOMIZED CONTROLLED-TRIAL, Diet, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Fermentation, Pediatrics, Perinatology and Child Health, LOW FERMENTABLE OLIGOSACCHARIDES, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, CELIAC GLUTEN SENSITIVITY, Systematic Reviews as Topic
Abstract: OBJECTIVES: Excluding oligo-, di-, monosaccharides and polyols (FODMAPs) from the diet is increasingly being used to treat children with gastrointestinal complaints. The aim of this position paper is to review the available evidence on the safety and efficacy of its use in children and provide expert guidance regarding practical aspects in case its use is considered. METHODS: Members of the Gastroenterology Committee, the Nutrition Committee and the Allied Health Professionals Committee of the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) contributed to this position paper. Clinical questions regarding initiation, introduction, duration, weaning, monitoring, professional guidance, safety and risks of the diet are addressed. A systematic literature search was performed from 2005 to May 2021 using PubMed, MEDLINE and Cochrane Database of Systematic Reviews. In the absence of evidence, recommendations reflect the expert opinion of the authors. RESULTS: The systematic literature search revealed that the low-FODMAP diet has not been comprehensively studied in children. Indications and contraindications of the use of the diet in different pediatric gastroenterological conditions are discussed and practical recommendations are formulated. CONCLUSIONS: There is scarce evidence to support the use of a low-FODMAP diet in children with Irritable Bowel Syndrome and no evidence to recommend its use in other gastrointestinal diseases and complaints in children. Awareness of how and when to use the diet is crucial, as a restrictive diet may impact nutritional adequacy and/or promote distorted eating in vulnerable subjects. The present manuscript provides practical safety tips to be applied when the low-FODMAP diet is considered in children.
Published: 2022

4. First-line Nivolumab + Ipilimumab + Chemo in Patients With Advanced NSCLC and Brain Metastases: Results From CheckMate 9LA

Author: Carbone, D., Ciuleanu, T., Cobo, M., Schenker, M., Zurawski, B., Menezes, J., Richardet, E., Bennouna, J., Felip, E., Juan-Vidal, O., Alexandru, A., Sakai, H., de La Mora Jimenez, E., Paz-Ares, L., Reck, M., John, T., Hu, N., Zhang, X., Tran, P., Grootendorst, D.J., Lu, S., The Ohio State University Press, The Oncology Institute 'Prof. Dr. Ion Chiricuţă' [Cluj-Napoca, Romania] (TOI), Virgen de la Victoria University Hospital, SF Nectarie Oncology Center [Craiova, Romania], Ambulatorium Chemioterapii [Bydgoszcz, Poland] (AC), Hospital Nossa Senhora Da Conceição [Porto Alegre, Brazil] (HNSDC), Instituto Oncológico De Córdoba [Córdoba, Argentina] (IODC), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Vall d'Hebron University Hospital [Barcelona], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Institute of Oncology Prof. Dr. Alexandru Trestioreanu (IOB), Saitama Cancer Center [Saitama, Japan] (S2C), Universidad de Guadalajara, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), German Center for Lung Research, Austin Hospital [Melbourne], Austin Health, Bristol-Myers Squibb [Princeton], Shanghai Jiaotong University, and Bernardo, Elizabeth
Subjects: [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

5. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update

Author: X. Zhang, Michael Schenker, Shunyuan Lu, Arnaud Scherpereel, Maurice Pérol, A. Lingua, Manuel Cobo, S. Marimuthu, Tudor-Eliade Ciuleanu, Arteid Memaj, Eduardo Richardet, O. Juan-Vidal, F. Reyes, David P. Carbone, B. Zurawski, A. Alexandru, Phuong Tran, Hiroshi Sakai, Jaafar Bennouna, Martin Reck, Enriqueta Felip, Thomas John, Juliana Janoski de Menezes, Pierre-Jean Souquet, C. Martin, Luis Paz-Ares, P. De Marchi, German Center for Lung Research, Institutul oncologic Prof Dr Ion Chiricuta [Cluj-Napoca, Romania], Instituto de Investigación Biomédica [Malaga, Spain] (IBIMA), SF Nectarie Oncology Center [Craiova, Romania], Ambulatorium Chemioterapii [Bydgoszcz, Poland] (AC), Hospital Nossa Senhora Da Conceição [Porto Alegre, Brazil] (HNSDC), Instituto Oncológico De Córdoba [Córdoba, Argentina] (IODC), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Vall d'Hebron University Hospital [Barcelona], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Oncology Institute of Bucharest Professor Doctor Alexandru Trestioreanu [Bucharest, Romania] (OIB), Saitama Cancer Center [Saitama, Japan] (S2C), Instituto Medico Rio Cuarto SA [Córdoba, Argentina] (IMRC), Fundacion Arturo Lopez Perez [Santiago, Metropolitana, Chile] (FALP), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Barretos Cancer Hospital [São Paulo, Brazil] (BCH), Instituto Alexander Fleming [Buenos Aires, Argentina] (IAF), Centre Léon Bérard [Lyon], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Shanghai Jiaotong University, Hospital Universitario 12 de Octubre [Madrid], Ohio State University [Columbus] (OSU), Bristol-Myers Squibb [Princeton], Austin Hospital [Melbourne], Austin Health, Bernardo, Elizabeth, Institut Català de la Salut, [Reck M] Department of Thoracic Oncology, Airway Research Center North, German Center for Lung Research, LungClinic, Grosshansdorf, Germany. [Ciuleanu TE] Department of Oncology, Institutul Oncologic Prof Dr Ion Chiricuta and UMF Iuliu Hatieganu, Cluj-Napoca, Romania. [Cobo M] Department of Medical Oncology, Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain. [Schenker M] Department of Oncology, SF Nectarie Oncology Center, Craiova, Romania. [Zurawski B] Department of Clinical Oncology, Ambulatorium Chemioterapii, Bydgoszcz, Poland. [Menezes J] Department of Oncology, Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil. [Felip E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Other subheadings::Other subheadings::/drug therapy [Other subheadings], NSCLC, Quimioteràpia combinada, nivolumab, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Carcinoma, Non-Small-Cell Lung, Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, first-line, ipilimumab, Lung cancer, Adverse effect, NSCLC, dual immunotherapy, first-line, ipilimumab, nivolumab, Original Research, Chemotherapy, business.industry, Hazard ratio, terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES], neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES], medicine.disease, Confidence interval, Discontinuation, Nivolumab, dual immunotherapy, Neoplasm Recurrence, Local, business, Corrigendum, Pulmons - Càncer - Tractament, medicine.drug
Abstract: Background To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up. Patients and methods Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs. Results With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation. Conclusions With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer., Highlights • Nivolumab + ipilimumab + two cycles of chemotherapy (chemo) significantly prolonged survival versus chemo in first-line advanced NSCLC. • At 2 years, overall survival benefits were durable with nivolumab + ipilimumab + chemo versus chemo. • Benefits of nivolumab + ipilimumab + chemo were seen across most patient subgroups, including by PD-L1 and histology. • Discontinuing nivolumab + ipilimumab + chemo due to treatment-related AEs did not negatively impact long-term benefits. • Nivolumab + ipilimumab + two cycles of chemo is an efficacious first-line treatment option for advanced non-oncogene-driven NSCLC.
Published: 2021

6. Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS)

Author: Luca S. Belli, Christophe Duvoux, Thierry Artzner, William Bernal, Sara Conti, Paolo A. Cortesi, Sophie-Caroline Sacleux, George-Philippe Pageaux, Sylvie Radenne, Jonel Trebicka, Javier Fernandez, Giovanni Perricone, Salvatore Piano, Silvio Nadalin, Maria C. Morelli, Silvia Martini, Wojciech G. Polak, Krzysztof Zieniewicz, Christian Toso, Marina Berenguer, Claudia Iegri, Federica Invernizzi, Riccardo Volpes, Vincent Karam, René Adam, François Faitot, Liane Rabinovich, Faouzi Saliba, Lucy Meunier, Mickael Lesurtel, Frank E. Uschner, Costantino Fondevila, Baptiste Michard, Audrey Coilly, Magdalena Meszaros, Domitille Poinsot, Andreas Schnitzbauer, Luciano G. De Carlis, Roberto Fumagalli, Paolo Angeli, Vincente Arroyo, Rajiv Jalan, Raffaella Viganò, Chiara Mazzarelli, Andrea Lauterio, Alessandro Giacomoni, Francesca Donato, Pietro Lampertico, Luisa Pasulo, Stefano Fagiuoli, Michele Colledan, Maria Cristina Morelli, Giovanni Vitale, Damiano Patrono, Renato Romagnoli, Antonio Ottobrelli, Ioannis Petridis, Umberto Cillo, Giacomo Germani, Patrizia Burra, Philippe Bachellier, Pietro Addeo, Camille Besch, Francoise Faitot, Sophie Caroline Sacleux, Saliba Faouzi, Rene Adam, Didier Samuel, Celine Guichon, Stéfanie Faure, Josè Ursic-Bedoya, Jorde Colmenero, David Toapanta, María Hernández-Tejero, Carmen Vinaixa, Caroline den Hoed, Jubi E. de Haan, Andrea Della Penna, Frank Erhard Uschner, Martin Welker, Stefan Zeuzem, Wolf Bechstein, Nicolas Goossens, Joanna Raszeja-Wyszomirska, Dev Katarey, Banwari Agarwal, Surgery, Internal Medicine, Gastroenterology & Hepatology, Intensive Care, ASST Great Metropolitan Niguarda / ASST Grande Ospedale Metropolitano Niguarda [Milan, Italia], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital de Hautepierre [Strasbourg], King‘s College London, Ospedale Multimedica Sesto San Giovanni, Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Centre Hépato-Biliaire [Hôpital Paul Brousse] (CHB), Hôpital Paul Brousse-Assistance Publique - Hôpitaux de Paris, Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département d'Hépato-Gastroentérologie et de Transplantation Hépatique [CHU Saint-Eloi], Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Service d'Hépatologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Goethe-University Frankfurt am Main, European Foundation for Study of Chronic Liver Failure [Barcelona] (EF CLIF), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Azienda Ospedale Università di Padova = Hospital-University of Padua (AOUP), Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Azienda Ospedaliero-Universitaria di Bologna, Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Medical University of Warsaw - Poland, Geneva University Hospitals and Geneva University, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Hospital Papa Giovanni XXIII (Hosp P Giovanni XXIII), Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT), Pôle des Pathologies Digestives Hépatiques et Transplantation [Hôpital Hautepierre-Strasbourg], Department of Physiopatology and Transplantation, University of Milan (DEPT), Università degli Studi di Milano = University of Milan (UNIMI), Ospedale S. Giovanni Battista-Molinette, Azienda Ospedaliera di Padova, Università degli Studi di Padova = University of Padua (Unipd), Hospital Clinic i Provincial de Barcelona (SCReN), University College London Hospitals (UCLH), Belli, L, Duvoux, C, Artzner, T, Bernal, W, Conti, S, Cortesi, P, Sacleux, S, Pageaux, G, Radenne, S, Trebicka, J, Fernandez, J, Perricone, G, Piano, S, Nadalin, S, Morelli, M, Martini, S, Polak, W, Zieniewicz, K, Toso, C, Berenguer, M, Iegri, C, Invernizzi, F, Volpes, R, Karam, V, Adam, R, Faitot, F, Rabinovich, L, Saliba, F, Meunier, L, Lesurtel, M, Uschner, F, Fondevila, C, Michard, B, Coilly, A, Meszaros, M, Poinsot, D, Schnitzbauer, A, De Carlis, L, Fumagalli, R, Angeli, P, Arroyo, V, Jalan, R, Fagiuoli, S, Goossens, Nicolas, and Salvy-Córdoba, Nathalie
Subjects: Male, 0301 basic medicine, Multi-drug resistant organisms, medicine.medical_treatment, Waiting list, Salvage therapy, Liver transplantation, Severity of Illness Index, MESH: Proportional Hazards Models, Cohort Studies, 0302 clinical medicine, MESH: Risk Factors, Risk Factors, Medicine, MESH: Cohort Studies, Acute-on-Chronic Liver Failure, MESH: Aged, High rate, MESH: Middle Aged, ddc:617, Hazard ratio, MESH: Acute-On-Chronic Liver Failure, Middle Aged, Prognosis, Predictive factors, Italy, Female, 030211 gastroenterology & hepatology, Adult, MESH: Liver Transplantation, medicine.medical_specialty, MESH: Prognosis, 03 medical and health sciences, MESH: Severity of Illness Index, Internal medicine, Humans, Acute on chronic liver failure, Renal replacement therapy, Aged, Proportional Hazards Models, Retrospective Studies, MESH: Humans, Hepatology, business.industry, MESH: Italy, MESH: Adult, MESH: Retrospective Studies, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Retrospective cohort study, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Multi-drug resistant organism, MESH: Male, 030104 developmental biology, Predictive factor, business, MESH: Female
Abstract: Background & Aims: Liver transplantation (LT) has been proposed as an effective salvage therapy even for the sickest patients with acute-on-chronic liver failure (ACLF). This large collaborative study was designed to assess the current clinical practice and outcomes of patients with ACLF who are wait-listed for LT in Europe. Methods: This was a retrospective study including 308 consecutive patients with ACLF, listed in 20 centres across 8 European countries, from January 2018 to June 2019. Results: A total of 2,677 patients received a LT: 1,216 (45.4%) for decompensated cirrhosis. Of these, 234 (19.2%) had ACLF at LT: 58 (4.8%) had ACLF-1, 78 (6.4%) had ACLF-2, and 98 (8.1%) had ACLF-3. Wide variations were observed amongst countries: France and Germany had high rates of ACLF-2/3 (27-41%); Italy, Switzerland, Poland and the Netherlands had medium rates (9-15%); and the United Kingdom and Spain had low rates (3-5%) (p 4 mmol/L (hazard ratio [HR] 3.14; 95% CI 1.37-7.19), recent infection from multidrug resistant organisms (HR 3.67; 95% CI 1.63-8.28), and renal replacement therapy (HR 2.74; 95% CI 1.37-5.51) were independent predictors of post-LT mortality. During the same period, 74 patients with ACLF died on the waiting list. In an intention-to-treat analysis, 1-year survival of patients with ACLF on the LT waiting list was 73% for ACLF-1 or-2 and 50% for ACLF-3. Conclusion: The results reveal wide variations in the listing of patients with ACLF in Europe despite favourable post-LT survival. Risk factors for mortality were identified, enabling a more pre-cise prognostic assessment of patients with ACLF. Lay summary: Acute-on-chronic liver failure (ACLF) is a severe clinical condition for which liver transplantation is an effective therapeutic option. This study has demonstrated that in Europe, referral and access to liver transplantation (LT) for patients with ACLF needs to be harmonised to avoid inequities. Post-LT survival for patients with ACLF was >80% after 1 year and some factors have been identified to help select patients with favourable outcomes. (C) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All reserved.
Published: 2021

7. Lactobacillus supports Clostridiales to restrict gut colonization by multidrug-resistant Enterobacteriaceae

Author: Ana Djukovic, María José Garzón, Cécile Canlet, Vitor Cabral, Rym Lalaoui, Marc García-Garcerá, Julia Rechenberger, Marie Tremblay-Franco, Iván Peñaranda, Leonor Puchades-Carrasco, Antonio Pineda-Lucena, Eva María González-Barberá, Miguel Salavert, José Luis López-Hontangas, Miguel Á. Sanz, Jaime Sanz, Bernhard Kuster, Jean-Marc Rolain, Laurent Debrauwer, Karina B. Xavier, Joao B. Xavier, Carles Ubeda, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Metatoul AXIOM (E20 ), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Instituto Gulbenkian de Ciência [Oeiras] (IGC), Fundação Calouste Gulbenkian, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Université de Lausanne = University of Lausanne (UNIL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Instituto de Investigación Sanitaria de Aragón [Zaragoza] (IIS Aragón), Universidad de Navarra [Pamplona] (UNAV), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Instituto de Salud Carlos III [Madrid] (ISC), Memorial Sloan-Kettering Cancer Institute, Memorial Sloane Kettering Cancer Center [New York], C.U. was supported by the InfectERA-ERANET-Acciones complementarias grant [PCIN-2015-094] from the Spanish Ministerio de Economia y Competitividad and the 7th Research framework program from EU, grants from Conselleria d'Innovacio, Universitats, Ciencia i Societat Digital [AICO/2019/266, CIPROM/2021/053] and a grant from the Spanish MICINN [PID2020-120292RB-I00]. A.D. was supported by a Boehringer Ingelheim Fonds travel grant, and with J.B.X. by grant R01 AI137269/AI/NIAID from the US National Institutes of Health. B.K. was supported by the BMBF FloraStopMRE grant [031L0089]. V.C. was supported by an European Commission grant [MSCA-IF-2018-843183]. J.S. was supported by an InfectERA-ERANET-Acciones complementarias de programacion conjunta internacional grant (AC15/00070) and Proyectos de Investigacion en Salud del Instituto Carlos III (PI18/00280). K.B.X. was supported by FundacAo para a Ciencia e a Tecnologia grant (InfectERA/0004/2015). J.M.R. was supported by ANR FloraStopInfectMRE project., Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), 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), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-ToxAlim (ToxAlim), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), and LESUR, Hélène
Subjects: Clostridiales, Multidisciplinary, [SDV]Life Sciences [q-bio], General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology, Anti-Bacterial Agents, [SDV] Life Sciences [q-bio], Butyrates, Lactobacillus, Mice, Enterobacteriaceae, Animals, Prospective Studies
Abstract: Infections by multidrug-resistant Enterobacteriaceae (MRE) are life-threatening to patients. The intestinal microbiome protects against MRE colonization, but antibiotics cause collateral damage to commensals and open the way to colonization and subsequent infection. Despite the significance of this problem, the specific commensals and mechanisms that restrict MRE colonization remain largely unknown. Here, by performing a multi-omic prospective study of hospitalized patients combined with mice experiments, we find that Lactobacillus is key, though not sufficient, to restrict MRE gut colonization. Lactobacillus rhamnosus and murinus increase the levels of Clostridiales bacteria, which induces a hostile environment for MRE growth through increased butyrate levels and reduced nutrient sources. This mechanism of colonization resistance, an interaction between Lactobacillus spp. and Clostridiales involving cooperation between microbiota members, is conserved in mice and patients. These results stress the importance of exploiting microbiome interactions for developing effective probiotics that prevent infections in hospitalized patients.
Published: 2021

8. An ESPGHAN Position Paper on the Use of Breath Testing in Paediatric Gastroenterology

Author: Rut Ann Thomassen, Jernej Dolinsek, Carmen Ribes-Koninckx, Erasmo Miele, Christos Tzivinikos, Corina Pienar, Javier Martín-de-Carpi, Emmanuel Mas, Marc A. Benninga, Osvaldo Borrelli, Ilse Broekaert, Mike Thomson, University Hospital of Cologne [Cologne], Great Ormond Street Hospital for Children [London] (GOSH), University medical centre Maribor (UKC Maribor), Hospital Sant Joan de Déu [Barcelona], Institut de Recherche en Santé Digestive (IRSD ), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 'Federico II' University of Naples Medical School, Victor Babeş University of Medicine and Pharmacy (UMFT), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Oslo University Hospital [Oslo], Sheffield Children's NHS Foundation Trust, Al Jalila Children's Specialty Hospital, VU University Medical Center [Amsterdam], SEGUIN, Nathalie, Broekaert, Ilse Julia, Borrelli, Osvaldo, Dolinsek, Jernej, Martin-de-Carpi, Javier, Mas, Emmanuel, Miele, Erasmo, Pienar, Corina, Ribes-Koninckx, Carmen, Thomassen, Rut, Thomson, Mike, Tzivinikos, Christo, Benninga, Marc, and Hospital Universitari i Politècnic La Fe
Subjects: medicine.medical_specialty, Malabsorption, Consensus, Carbohydrate malabsorption, 030309 nutrition & dietetics, MEDLINE, carbohydrate malabsorption, small intestinal bacterial overgrowth, Helicobacter pylori infection, Helicobacter Infections, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, children, Internal medicine, Small intestinal bacterial overgrowth, medicine, breath testing, Humans, Intensive care medicine, Exocrine pancreatic insufficiency, Child, Children, 0303 health sciences, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Fat malabsorption, Breath testing, Systematic review, Breath Tests, Pediatrics, Perinatology and Child Health, Position paper, 030211 gastroenterology & hepatology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Systematic Reviews as Topic
Abstract: International audience; Objectives: Given a lack of a systematic approach to the use of breath testing in paediatric patients, the aim of this position paper is to provide expert guidance regarding the indications for its use and practical considerations to optimise its utility and safety. Methods: Nine clinical questions regarding methodology, interpretation, and specific indications of breath testing and treatment of carbohydrate malabsorption were addressed by members of the Gastroenterology Committee (GIC) of the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). A systematic literature search was performed from 1983 to 2020 using PubMed, the MEDLINE and Cochrane Database of Systematic Reviews. Grading of Recommendations, Assessment, Development, and Evaluation was applied to evaluate the outcomes. During a consensus meeting, all recommendations were discussed and finalised. In the absence of evidence from randomised controlled trials, recommendations reflect the expert opinion of the authors. Results: A total of 22 recommendations were voted on using the nominal voting technique. At first, recommendations on prerequisites and preparation for as well as on interpretation of breath tests are given. Then, recommendations on the usefulness of H2-lactose breath testing, H2-fructose breath testing as well as of breath tests for other types of carbohydrate malabsorption are provided. Furthermore, breath testing is recommended to diagnose small intestinal bacterial overgrowth (SIBO), to control for success of Helicobacter pylori eradication therapy and to diagnose and monitor therapy of exocrine pancreatic insufficiency, but not to estimate oro-caecal transit time (OCTT) or to diagnose and follow-up on celiac disease. Conclusions: Breath tests are frequently used in paediatric gastroenterology mainly assessing carbohydrate malabsorption, but also in the diagnosis of small intestinal overgrowth, fat malabsorption, H. pylori infection as well as for measuring gastrointestinal transit times. Interpretation of the results can be challenging and in addition, pertinent symptoms should be considered to evaluate clinical tolerance.
Published: 2021

9. Drug clearance in neonates : a combination of population pharmacokinetic modelling and machine learning approaches to improve individual prediction

Author: Yue-E Wu, Alison H. Thomson, Yi Zheng, José Esteban Peris, Lo Yl, Bernd Meibohm, Edmund V. Capparelli, Wei Zhao, John N. van den Anker, Irja Lutsar, Hai-Yan Shi, Hai-Yan Xu, Xiao Li, Stéphanie Leroux, Karel Allegaert, Evelyne Jacqz-Aigrain, Bo Hao Tang, Yue Zhou, Xin Huang, Xiaoling Wang, Bao-Ping Xu, Bu-Fan Yao, Jacobus Burggraaf, Nicolas Simon, A.-Dong Shen, Chen Kou, Guo-Xiang Hao, Efthymios Manolis, Tian-You Wang, Remedios Marques, Valérie Biran, Jumpei Saito, Zheng Guan, Wen-Qi Wang, Shandong University, Leiden University Medical Center (LUMC), Universiteit Leiden, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), European Medicines Agency [Amsterdam, Pays-Bas] (EMA), Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Shandong Jiaotong University [Jinan], Capital University of Medical Sciences [Beijing] (CUMS), University of Strathclyde [Glasgow], University of California [San Diego] (UC San Diego), University of California (UC), Hôpital Robert Debré, 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), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), The University of Tennessee Health Science Center [Memphis] (UTHSC), University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Universitat de València (UV), University of Tartu, National Center for Child Health and Development [Tokyo], Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Georgetown University [Washington] (GU), University Children's Hospital [Basel, Switzerland]], and Malbec, Odile
Subjects: SELECTION, 0301 basic medicine, RM, BIG DATA, AZLOCILLIN, Metabolic Clearance Rate, [SDV]Life Sciences [q-bio], education, 030106 microbiology, Population, Drug Elimination Routes, Body weight, Machine learning, computer.software_genre, Models, Biological, 030226 pharmacology & pharmacy, CLASSIFICATION, Machine Learning, 03 medical and health sciences, 0302 clinical medicine, Text mining, Pharmacokinetics, Vancomycin, REGRESSION, Covariate, Humans, Medicine, Pharmacology (medical), CROSS-VALIDATION, Combined method, Pharmacology, education.field_of_study, PRETERM, business.industry, Infant, Newborn, CEFEPIME, DOSING OPTIMIZATION, [SDV] Life Sciences [q-bio], YOUNG, Artificial intelligence, business, computer, Clearance, Predictive methods
Abstract: International audience; Background Population pharmacokinetic evaluations have been widely used in neonatal pharmacokinetic studies, while machine learning has become a popular approach to solving complex problems in the current era of big data. Objective The aim of this proof-of-concept study was to evaluate whether combining population pharmacokinetic and machine learning approaches could provide a more accurate prediction of the clearance of renally eliminated drugs in individual neonates. Methods Six drugs that are primarily eliminated by the kidneys were selected (vancomycin, latamoxef, cefepime, azlocillin, ceftazidime, and amoxicillin) as 'proof of concept' compounds. Individual estimates of clearance obtained from population pharmacokinetic models were used as reference clearances, and diverse machine learning methods and nested cross-validation were adopted and evaluated against these reference clearances. The predictive performance of these combined methods was compared with the performance of two other predictive methods: a covariate-based maturation model and a postmenstrual age and body weight scaling model. Relative error was used to evaluate the different methods. Results The extra tree regressor was selected as the best-fit machine learning method. Using the combined method, more than 95% of predictions for all six drugs had a relative error of < 50% and the mean relative error was reduced by an average of 44.3% and 71.3% compared with the other two predictive methods. Conclusion A combined population pharmacokinetic and machine learning approach provided improved predictions of individual clearances of renally cleared drugs in neonates. For a new patient treated in clinical practice, individual clearance can be predicted a priori using our model code combined with demographic data. Bo-Hao Tang and Zheng Guan contributed equally to this work.
Published: 2021

10. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA

Author: Phuong Tran, Aurella Alexandru, S. Marimuthu, Tudor-Eliade Ciuleanu, Hiroshi Sakai, Manuel Cobo, Luis Paz-Ares, Michael Schenker, Jaafar Bennouna, Arnaud Scherpereel, Arteid Memaj, Enriqueta Felip, O. Juan-Vidal, David P. Carbone, B. Zurawski, Thomas John, Eduardo Richardet, Juliana Janoski de Menezes, Shun Lu, Martin Reck, German Center for Lung Research, Institutul oncologic Prof Dr Ion Chiricuta [Cluj-Napoca, Romania], Instituto de Investigación Biomédica [Malaga, Spain] (IBIMA), SF Nectarie Oncology Center [Craiova, Romania], Ambulatorium Chemioterapii [Bydgoszcz, Poland] (AC), Hospital Nossa Senhora Da Conceição [Porto Alegre, Brazil] (HNSDC), Instituto Oncológico De Córdoba [Córdoba, Argentina] (IODC), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Vall d'Hebron University Hospital [Barcelona], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Oncology Institute of Bucharest Professor Doctor Alexandru Trestioreanu [Bucharest, Romania] (OIB), Saitama Cancer Center [Saitama, Japan] (S2C), Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Shanghai Jiaotong University, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Ohio State University [Columbus] (OSU), Bristol-Myers Squibb [Princeton], Bristol Myers Squibb [Springfield, PA, USA] (BMS), Austin Hospital [Melbourne], Austin Health, and Bernardo, Elizabeth
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, First line, Checkmate, non-small cell lung cancer (NSCLC), Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, stomatognathic diseases, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, hemic and lymphatic diseases, medicine, Overall survival, In patient, Nivolumab, business, neoplasms, medicine.drug
Abstract: 9000 Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. [Table: see text]
Published: 2021

11. Drugs in Focus: The Use of Racecadotril in Paediatric Gastrointestinal Disease

Author: Emmanuel Mas, Ilse Broekaert, Erasmo Miele, Christos Tzivinikos, Jernej Dolinsek, Carmen Ribes-Koninckx, Marc A. Benninga, Corina Pienar, Rut Anne Thomassen, Nikhil Thapar, Rok Orel, Mike Thomson, Victor Babeş University of Medicine and Pharmacy (UMFT), Emma Children’s Hospital Academic Medical Centre, University Hospital of Cologne, University medical centre Maribor (UKC Maribor), Institut de Recherche en Santé Digestive (IRSD ), 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-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Università degli studi di Napoli Federico II, University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Hospital Universitario y Politécnico La Fe, Oslo University Hospital [Oslo], NHS Foundation Trust, Al Jalila Children's Specialty Hospital, UCL Great Ormond Street Institute of Child Health [London, UK], Great Ormond Street Hospital, Partenaires INRAE, Queensland Children's Hospital, Pienar, Corina, Benninga, Marc A, Broekaert, Ilse J, Dolinsek, Jernej, Mas, Emmanuel, Miele, Erasmo, Orel, Rok, Ribes-Koninckx, Carmen, Thomassen, Rut-Anne, Thomson, Mike, Tzivinikos, Christo, Thapar, Nikhil, Paediatric Gastroenterology, AGEM - Digestive immunity, AGEM - Re-generation and cancer of the digestive system, Amsterdam Reproduction & Development (AR&D), ProdInra, Migration, University of Naples Federico II = Università degli studi di Napoli Federico II, and Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe
Subjects: Diarrhea, Drug, Thiorphan, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Gastrointestinal Diseases, medicine.drug_class, media_common.quotation_subject, medicine.medical_treatment, Pharmacology, Racecadotril, 03 medical and health sciences, 0302 clinical medicine, adjuvant, 030225 pediatrics, Antidiarrhoeal, medicine, Humans, Antidiarrheals, Child, Adverse effect, Neprilysin, media_common, racecadotril, business.industry, digestive, oral, and skin physiology, Gastroenterology, medicine.disease, Small intestine, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, medicine.anatomical_structure, Pharmaceutical Preparations, Gastrointestinal disease, Pediatrics, Perinatology and Child Health, 030211 gastroenterology & hepatology, business, gastroenteritis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Adjuvant, medicine.drug
Abstract: International audience; Acute diarrhoea is a leading cause of morbidity and mortality in the paediatric population. Racecadotril is an antisecretory drug recommended as an adjuvant anti-diarrhoeal treatment.In the small bowel, the enzyme neutral endopeptidase (NEP) inhibits the action of enkephalins, which prevent water and electrolyte hypersecretion. By inhibiting NEP, racecadotril allows enkephalins to exhibit their antisecretory effects. Consequently, racecadotril reduces the secretion of water and electrolytes in the small intestine, without having an effect on intestinal motility. No serious adverse events related to racecadotril have been reported.Racecadotril has proven its efficacy as an adjuvant anti-diarrhoeal drug with a good safety profile. Its addition to oral rehydration solution (ORS) appears clinically beneficial and potentially leads to health care savings.
Published: 2020

12. A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials

Author: Jean-Didier, Lemaréchal, Maciej, Jedynak, Lena, Trebaul, Anthony, Boyer, François, Tadel, Manik, Bhattacharjee, Pierre, Deman, Viateur, Tuyisenge, Leila, Ayoubian, Etienne, Hugues, Blandine, Chanteloup-Forêt, Carole, Saubat, Raouf, Zouglech, Gina Catalina, Reyes Mejia, Sébastien, Tourbier, Patric, Hagmann, Claude, Adam, Carmen, Barba, Fabrice, Bartolomei, Thomas, Blauwblomme, Jonathan, Curot, François, Dubeau, Stefano, Francione, Mercedes, Garcés, Edouard, Hirsch, Elizabeth, Landré, Sinclair, Liu, Louis, Maillard, Eeva-Liisa, Metsähonkala, Ioana, Mindruta, Anca, Nica, Martin, Pail, Ana Maria, Petrescu, Sylvain, Rheims, Rodrigo, Rocamora, Andreas, Schulze-Bonhage, William, Szurhaj, Delphine, Taussig, Antonio, Valentin, Haixiang, Wang, Philippe, Kahane, Nathalie, George, Olivier, David, Elisa, Nacci, 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), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Le Centre de Magnétoencéphalographie et d'Electroencéphalographie [CHU Pitié-Salpêtrière] (MEG-EEG), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-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), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Service de neurochirurgie pédiatrique [CHU Necker], 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 de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], Hospital Universitario y Politécnico La Fe [Valencia, Spain], CHU Strasbourg, Centre Hospitalier Sainte Anne [Paris], Jinan University [Guangzhou], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University Emergency Hospital [Bucharest], Laboratoire Traitement du Signal et de l'Image (LTSI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University Hospital Brno, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IMIM-Hospital del Mar, Generalitat de Catalunya, Freiburg University Medical Center, CHU Lille, Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Tsinghua University [Beijing] (THU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Firenze = University of Florence (UniFI), Centre de recherche cerveau et cognition (CERCO UMR5549), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-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), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), The research leading to these results has received funding from the European Research Councilunder the European Union's Seventh Framework Programme (FP/2007-2013)/ERC GrantAgreement no. 616268 F-TRACT, the European Union’s Horizon 2020 FrameworkProgramme for Research and Innovation under Specific Grant Agreement No. 785907 and945539 (Human Brain Project SGA2 and SGA3), and from the French 'Investissementsd’avenir' programme under grant numbers ANR-11-INBS-0006 and ANR-10-IAIHU-06. PHwas supported by Swiss National Science Foundation grant #CRSII5_170873, ANR-11-INBS-0006,FLI,France Life Imaging(2011), European Project: 616268,EC:FP7:ERC,ERC-2013-CoG,F-TRACT(2014), European Project: 785907,H2020,HBP SGA2(2018), European Project: 945539,H2020,H2020-SGA-FETFLAG-HBP-2019,HBP SGA3(2020), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Toulouse Mind & Brain Institut (TMBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Gestionnaire, Hal Sorbonne Université, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, Functional Brain Tractography - F-TRACT - - EC:FP7:ERC2014-08-01 - 2019-07-31 - 616268 - VALID, Human Brain Project Specific Grant Agreement 2 - HBP SGA2 - - H20202018-04-01 - 2020-03-31 - 785907 - VALID, and Human Brain Project Specific Grant Agreement 3 - HBP SGA3 - - H20202020-01-01 - 2023-09-30 - 945539 - VALID
Subjects: neural mass models, 0303 health sciences, Brain Mapping, Epilepsy, cortico-cortical evoked potential, Brain, Bayes Theorem, Electric Stimulation, dynamic causal modelling, 03 medical and health sciences, 0302 clinical medicine, axonal conduction delay, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], synaptic time constant, Evoked Potentials, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (
Published: 2021

13. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial

Author: Pierre-Jean Souquet, David P. Carbone, Michael Schenker, Shun Lu, S. Meadows-Shropshire, A. Alexandru, Pamela Salman, Hiroshi Sakai, Jaafar Bennouna, Maurice Pérol, Enriqueta Felip, Alejo Lingua, J. Yan, Juliana Janoski de Menezes, B. Zurawski, Martin Reck, Arnaud Scherpereel, C. Martin, Eduardo Richardet, Abderrahim Oukessou, Tudor-Eliade Ciuleanu, Manuel Cobo, O. Juan-Vidal, Pedro Rafael Martins De Marchi, Thomas John, Luis Paz-Ares, Shruti Agrawal, Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), The Oncology Institute 'Prof. Dr. Ion Chiricuţă' [Cluj-Napoca, Romania] (TOI), Instituto de Investigación Biomédica [Malaga, Spain] (IBIMA), SF Nectarie Oncology Center [Craiova, Romania], Ambulatorium Chemioterapii [Bydgoszcz, Poland] (AC), Hospital Nossa Senhora Da Conceição [Porto Alegre, Brazil] (HNSDC), Instituto Oncológico De Córdoba [Córdoba, Argentina] (IODC), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre hospitalier universitaire de Nantes (CHU Nantes), Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Hospital Universitario La Fe [Valencia, Spain] (HU), Oncology Institute of Bucharest Professor Doctor Alexandru Trestioreanu [Bucharest, Romania] (OIB), Saitama Cancer Center [Saitama, Japan] (S2C), Instituto Medico Rio Cuarto SA [Córdoba, Argentina] (IMRC), Fundacion Arturo Lopez Perez [Santiago, Metropolitana, Chile] (FALP), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Barretos Cancer Hospital [São Paulo, Brazil], Instituto Alexander Fleming [Buenos Aires, Argentina] (IAF), Centre Léon Bérard [Lyon], Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Lille, CHU Lille, Shanghai Jiao Tong University [Shanghai], Austin Hospital [Melbourne], Austin Health, Ohio State University [Columbus] (OSU), Bristol-Myers Squibb [Princeton], German Center for Lung Research, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, and Bernardo, Elizabeth
Subjects: Male, medicine.medical_specialty, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neutropenia, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Aged, Neoplasm Staging, business.industry, Hazard ratio, Middle Aged, medicine.disease, Interim analysis, 3. Good health, respiratory tract diseases, Regimen, Nivolumab, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, business, Febrile neutropenia, medicine.drug
Abstract: Erratum in Correction to Lancet Oncol 2021; 22: 198-211. [No authors listed] Lancet Oncol. 2021 Mar;22(3):e92. doi: 10.1016/S1470-2045(21)00082-6. PMID: 33662299 No abstract available.; International audience; Background: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit.Methods: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706.Findings: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.Interpretation: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC.Funding: Bristol Myers Squibb.
Published: 2021

14. Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder

Author: Erica E. Davis, Xenia Latypova, Damien Lederer, LaDonna Immken, Bertrand Isidor, Carmen Orellana, Nicolette S. den Hollander, Shannon Bell, Francisco Martínez, Alice Molle, Oluwadamilare A. Adebambo, Thomas Besnard, Dmitriy Niyazov, Anne Claude Tabet, Marie Deprez, Kamran Moradkhani, Alfonso Caro, Sandra Mercier, Solène Conrad, Philippe M. Campeau, Xiang-Jiao Yang, Christelle Retière, Nicholas Katsanis, Marie Vincent, Kirsty McWalter, Jill A. Rosenfeld, Raymond J. Louie, Stéphane Bézieau, Cynthia Fourgeux, Sharon F. Suchy, Jagdeep S. Walia, Mónica Roselló, Cédric Le Caignec, Emmelien Aten, Jeremie Poschmann, Benjamin Cogné, Peter Kannu, Miranda Splitt, Pawel Stankiewicz, Yline Capri, Catherine Willem, Tahir N. Khan, Justine Rousseau, Sébastien Küry, Jonathan I. Levy, Roger E. Stevenson, Centre hospitalier universitaire de Nantes (CHU Nantes), Duke University Medical Center, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hospital Universitario y Politécnico La Fe [Valencia, Spain], Ochsner Medical Center [New Orleans, Louisiana, USA], Institut de Pathologie et Génétique [Gosselies] (I.P.G.), Hôpital Robert Debré, The Hospital for sick children [Toronto] (SickKids), Leiden University Medical Center (LUMC), Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Kingston General Health Research Institute [Kingston, ON, Canada] (KGHRI), Dell Children's Medical Group [Austin, TX, USA] (DCMG), Baylor College of Medicine (BCM), Baylor University, GeneDx [Gaithersburg, MD, USA], The Greenwood Genetic Center, Centre Hospitalier Universitaire Sainte-Justine [Montréal, QC, Canada] (CHU Sainte-Justine), EFS Centre-Pays de la Loire [Nantes], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), LabEX IGO Immunothérapie Grand Ouest, McGill University = Université McGill [Montréal, Canada], Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Medical School [Chicago], Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, CHU Sainte Justine [Montréal], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), and RETIERE, Christelle
Subjects: Male, Models, Molecular, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Haploinsufficiency, medicine.disease_cause, Histones, 0302 clinical medicine, HDAC, Intellectual disability, Child, Zebrafish, Genetics (clinical), Exome sequencing, Genetics, 0303 health sciences, Mutation, HDAC, SIN3A, SINB, acetylation, autism, epigenetics, intellectual disability, mutation, transcription, zebrafish, Syndrome, Middle Aged, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], intellectual disability, Child, Preschool, Larva, Female, transcription, Adolescent, DNA Copy Number Variations, autism, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Histone Deacetylases, Frameshift mutation, Young Adult, 03 medical and health sciences, Report, medicine, Animals, Humans, Epigenetics, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, SIN3A, acetylation, epigenetics, Infant, Zebrafish Proteins, SINB, biology.organism_classification, medicine.disease, zebrafish, Repressor Proteins, Histone deacetylase, mutation, 030217 neurology & neurosurgery
Abstract: International audience; Proteins involved in transcriptional regulation harbor a demonstrated enrichment of mutations in neurodevelopmental disorders. The Sin3 (Swi-independent 3)/histone deacetylase (HDAC) complex plays a central role in histone deacetylation and transcriptional repression. Among the two vertebrate paralogs encoding the Sin3 complex, SIN3A variants cause syndromic intellectual disability, but the clinical consequences of SIN3B haploinsufficiency in humans are uncharacterized. Here, we describe a syndrome hallmarked by intellectual disability, developmental delay, and dysmorphic facial features with variably penetrant autism spectrum disorder, congenital malformations, corpus callosum defects, and impaired growth caused by disruptive SIN3B variants. Using chromosomal microarray or exome sequencing, and through international data sharing efforts, we identified nine individuals with heterozygous SIN3B deletion or single-nucleotide variants. Five individuals harbor heterozygous deletions encompassing SIN3B that reside within a $230 kb minimal region of overlap on 19p13.11, two individuals have a rare nonsynonymous substitution, and two individuals have a single-nucleotide deletion that results in a frameshift and predicted premature termination codon. To test the relevance of SIN3B impairment to measurable aspects of the human phenotype, we disrupted the orthologous zebrafish locus by genome editing and transient suppression. The mutant and morphant larvae display altered craniofacial patterning, commissural axon defects, and reduced body length supportive of an essential role for Sin3 function in growth and patterning of anterior structures. To investigate further the molecular consequences of SIN3B variants, we quantified genome-wide enhancer and promoter activity states by using H3K27ac ChIP-seq. We show that, similar to SIN3A mutations, SIN3B disruption causes hyperacetylation of a subset of enhancers and promoters in peripheral blood mononuclear cells. Together, these data demonstrate that SIN3B haploinsufficiency leads to a hitherto unknown intellectual disability/autism syndrome, uncover a crucial role of SIN3B in the central nervous system, and define the epigenetic landscape associated with Sin3 complex impairment.
Published: 2021

15. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

Author: F. Le Calvez-Kelm, John K. Field, Nicolas Girard, Ernst-Jan M. Speel, Marie Brevet, Lynnette Fernandez-Cuesta, Jean-François Deleuze, Nicolas Lemaitre, Noémie Leblay, Sandrine Boyault, Marius Lund-Iversen, Gabriella Sozzi, Véronique Hofman, Sylvie Lantuejoul, Lucia Anna Muscarella, Paolo Graziano, Alex Soltermann, Matthieu Foll, Amelie Chabrier, Robert Olaso, A. Ferrari, Anne Boland, Paul Hofman, Luca Roz, Behnoush Abedi-Ardekani, Janine Altmüller, Tiffany M. Delhomme, Akram Ghantous, Christophe Caux, Jules L. Derks, Giuseppe Pelosi, Vincent Meyer, Anne-Marie C. Dingemans, Juan Sandoval, Jean-Michel Vignaud, Jelena Stojsic, Catherine Voegele, Geoffroy Durand, James D. McKay, Peter Nuernberg, Cyrille Cuenin, Nicolas Alcala, L. Moonen, Hector Hernandez-Vargas, Ugo Pastorino, Theo Giffon, O.T. Brustugun, L. Mangiante, Mauro Papotti, Philippe Lorimier, Anne-Claire Toffart, Prudence A. Russell, Aurélie A G Gabriel, Zdenko Herceg, A. S. Sertier, Joachim H. Clement, M. Milione, Joerg Saenger, Luka Brcic, Stéphanie Lacomme, V. Thomas de Montpreville, A. Viari, Marco Volante, Elisabeth Brambilla, Gavin M. Wright, Cécile Blanc-Fournier, David Hervás, N. Le Stang, H. Popper, Françoise Galateau-Sallé, Centre international de Recherche sur le Cancer (CIRC), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Fondation Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Centre for Molecular Medicine Cologne [Cologne] (CMMC), University Hospital of Cologne [Cologne], School for Oncology and Developmental Biology [Maastricht] (GROW), Maastricht University [Maastricht]-Maastricht University Medical Centre (MUMC), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de pneumologie [Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), Institute of Pathology and Molecular Pathology [Zurich], Department Hematology and Medical Oncology [Jena], Jena University Hospital [Jena], Central Clinic Bad Berka, Department of Molecular and Clinical Cancer Medicine [Liverpool], University of Liverpool, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), University of Melbourne, IRCCS Istituto Nazionale dei Tumori [Milano], Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Oslo University Hospital [Oslo], Centre Chirurgical Marie Lannelongue (CCML), Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), University Hospital Graz, Clinical Center of Serbia (KCS), Equipe de recherche européenne en algorithmique et biologie formelle et expérimentale (ERABLE), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Università degli Studi di Milano = University of Milan (UNIMI), Università degli studi di Torino = University of Turin (UNITO), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitari i Politècnic La Fe, Synergie Lyon Cancer [Lyon], UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre chirurgical Marie Lannelongue, University of Milan, University of Turin, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Promovendi ODB, Pulmonologie, RS: GROW - R2 - Basic and Translational Cancer Biology, MUMC+: MA Med Staf Spec Longziekten (9), and Pathologie
Subjects: 0301 basic medicine, Oncology, Male, Lung Neoplasms, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Datasets as Topic, 02 engineering and technology, Neuroendocrine tumors, Machine Learning, PATHWAY, Cancer genomics, lcsh:Science, Lung, Aged, 80 and over, Comparative Genomic Hybridization, Multidisciplinary, Intracellular Signaling Peptides and Proteins, Genomics, Middle Aged, 021001 nanoscience & nanotechnology, Prognosis, 3. Good health, Neuroendocrine Carcinomas, Survival Rate, medicine.anatomical_structure, Female, Non small cell, HEALTH, Technology Platforms, 0210 nano-technology, Adult, EXPRESSION, medicine.medical_specialty, Adolescent, Science, CELL LUNG-CANCER, Nerve Tissue Proteins, Carcinoid Tumor, DENDRITIC CELLS, General Biochemistry, Genetics and Molecular Biology, Article, Small-cell lung cancer, CLASSIFICATION, 03 medical and health sciences, Young Adult, Internal medicine, Overall survival, medicine, Carcinoma, Biomarkers, Tumor, Humans, Survival rate, Aged, Homeodomain Proteins, IDENTIFICATION, business.industry, MUTATIONS, Membrane Proteins, General Chemistry, medicine.disease, Small Cell Lung Carcinoma, 030104 developmental biology, DISCOVERY, Carcinoma, Large Cell, lcsh:Q, business, NEUROENDOCRINE TUMORS, Comparative genomic hybridization
Abstract: The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms., The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Here, Alcala and colleagues present a multi-omics analysis of these tumours, revealing distinct molecular and prognostic subgroups.
Published: 2019

16. Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells

Author: Hadjer Miloudi, Patricia Pérez-Galán, Oliver Weigert, Gaël Roué, Alejandra Sanjuan-Pla, Vanina Rodriguez, Régis Lavigne, Jean-Michel Picquenot, Sophie Bustany, Anna Esteve-Arenys, Pablo Menendez, Alexandra Moros, Bénédicte Marcq, Simon C. Body, Guergana Tchakarska, Emmanuelle Com, Brigitte Sola, Anna Vidal-Crespo, Clara Recasens-Zorzo, Ramon Mangues, Fabrice Jardin, Isolda Casanova, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Proteomics Core Facility (Protim), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®, lnstitut d’Investigacions Biomèdica San Pau (IIB Sant Pau), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), University of Barcelona, University Hospital of the Ludwig-Maximilians University, Hospital Universitario y Politécnico La Fe, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Sola, Brigitte, Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®, and Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe
Subjects: 0301 basic medicine, Male, Proteomics, Cytoplasm, Cyclin D, Cyclin A, Cyclin B, lcsh:Medicine, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Lymphoma, Mantle-Cell, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Mice, 0302 clinical medicine, Cytosol, Cell Movement, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Cyclin D1, Neoplasm Metastasis, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Multidisciplinary, biology, Cell migration, Middle Aged, 3. Good health, Cell biology, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Female, Adult, Active Transport, Cell Nucleus, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine, Animals, Humans, Neoplasm Invasiveness, Aged, Cell Nucleus, lcsh:R, medicine.disease, 030104 developmental biology, biology.protein, Cancer research, Mantle cell lymphoma, lcsh:Q, Cyclin A2
Abstract: Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. The cell functions of cyclin D1 depend on its partners and/or subcellular distribution, resulting in different oncogenic properties. We observed the accumulation of cyclin D1 in the cytoplasm of a subset of MCL cell lines and primary cells. In primary cells, this cytoplasmic distribution was correlated with a more frequent blastoid phenotype. We performed immunoprecipitation assays and mass spectrometry on enriched cytosolic fractions from two cell lines. The cyclin D1 interactome was found to include several factors involved in adhesion, migration and invasion. We found that the accumulation of cyclin D1 in the cytoplasm was associated with higher levels of migration and invasiveness. We also showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Our data reveal a role of cytoplasmic cyclin D1 in the control of MCL cell migration and invasion, and as a true operator of MCL pathogenesis.
Published: 2017

17. Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

Author: Evelyne Jacqz-Aigrain, Johannes N. van den Anker, Alison H. Thomson, Stéphanie Leroux, Hidefumi Nakamura, Karel Allegaert, Remedios Marques, Edmund V. Capparelli, Irja Lutsar, Bernd Meibohm, Nicolas Simon, Jumpei Saito, Valérie Biran, Mike Sharland, José Esteban Peris, Wei Zhao, Lo Yl, Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Strathclyde [Glasgow], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University of California [San Diego] (UC San Diego), University of California, Hôpital Robert Debré, 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), University of Tenessee [USA], University of Malaya [Kuala Lumpur, Malaisie], University Hospital La Fe, Valencia, Universitat de València (UV), University of Tartu, National Center for Child Health and Development [Tokyo], Glasgow Royal Infirmary, St George's Hospital, University of California (UC), University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, HAL AMU, Administrateur, and Pediatric Surgery
Subjects: 0301 basic medicine, Pediatrics, vancomycin, infusion procedures, 0302 clinical medicine, newborn, Medicine, Pharmacology (medical), Randomized Controlled Trials as Topic, education.field_of_study, Maintenance dose, Anti-Bacterial Agents, 3. Good health, Infectious Diseases, drug maintenance dose, Research Design, Area Under Curve, Data Interpretation, Statistical, creatinine tests, Vancomycin, Monte Carlo Method, medicine.drug, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, Gestational Age, Microbial Sensitivity Tests, Loading dose, RS, 03 medical and health sciences, Pharmacokinetics, drug loading dose, 030225 pediatrics, Humans, steady state, education, Pharmacology, Dose-Response Relationship, Drug, business.industry, Body Weight, Infant, Newborn, Postmenstrual Age, infant, NONMEM, Regimen, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, regimen, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, serum
Abstract: Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates. Results A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if 89% of the treated patients. Conclusions The results of a population meta-analysis of vancomycin data have been used to develop a new dosing regimen for neonatal use and to assist in the design of the model-based, multinational European trial, NeoVanc.
Published: 2019

18. Detection of plasmid-mediated colistin resistance, mcr-1 gene, in Escherichia coli isolated from high-risk patients with acute leukemia in Spain

Author: Miguel A. Sanz, Laurent Debrauwer, Ana Djukovic, Rym Lalaoui, Jaime Sanz, Eva María González-Barberá, Carles Ubeda, Sofiane Bakour, Karina B. Xavier, Jose Luis López-Hontangas, Jean-Marc Rolain, Bernhard Kuster, Miguel Salavert, Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), Hospital Universitari i Politècnic La Fe, Universidad Carlos III de Madrid [Madrid] (UC3M), Instituto Gulbenkian de Ciência [Oeiras] (IGC), Fundação Calouste Gulbenkian, Technical University of Munich (TUM), Technische Universität München [München] (TUM), Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), 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-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CIBER de Epidemiología y Salud Pública (CIBERESP), ANR FloraStopInfectMRE project, InfecERA-ERANET-Acciones complementarias [PCIN-2015-094], IHU Mediterranee Infection, Marseille, France, French Government [10-IAHU-03], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-MetaToul-MetaboHUB, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, MetaToul AXIOM (E20), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan)
Subjects: 0301 basic medicine, Microbiology (medical), medicine.drug_class, 030106 microbiology, Antibiotics, Colistin resistance, Microbial Sensitivity Tests, Biology, medicine.disease_cause, beta-Lactamases, Microbiology, Leukemic patients, 03 medical and health sciences, Minimum inhibitory concentration, 0302 clinical medicine, Plasmid, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Resistance, Bacterial, medicine, Escherichia coli, Humans, Pharmacology (medical), [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, 030212 general & internal medicine, Escherichia coli Infections, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Leukemia, Colistin, Escherichia coli Proteins, Middle Aged, biology.organism_classification, Enterobacteriaceae, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Anti-Bacterial Agents, Infectious Diseases, Spain, Colistin resistance, Escherichia coli, Leukemic patients, Spain, mcr-1 gene, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Multilocus sequence typing, mcr-1 gene, MCR-1, hormones, hormone substitutes, and hormone antagonists, medicine.drug, Plasmids
Abstract: Background: Bacterial infections in immunocompromised patients are associated with a high mortality and morbidity rate. In this high-risk group, the presence of multidrug-resistant (MDR) bacteria, particularly bacteria that harbor a transferable antibiotic resistance gene, complicates the management of bacterial infections. In this study, we investigated the presence of the transferable colistin resistance mcr genes in patients with leukemia in Spain. Methods: 217 fecal samples collected in 2013-2015 from 56 patients with acute leukemia and colonized with MDR Enterobacteriaceae strains, were screened on September 2017 for the presence of the colistin resistance mcr genes (mcr-1 to -5) by multiplex PCR. mcr positive strains selected on LBJMR and Mac-Conkey supplemented with colistin (2 mu g/ml) media were phenotypically and molecularly characterized by antimicrobial susceptibility testing, minimum inhibitory concentration, multilocus sequence typing and plasmid characterization. Results: Among 217 fecal samples, 5 samples collected from 3 patients were positive for the presence of the mcr-1 colistin-resistance gene. Four Escherichia coli strains were isolated and exhibited resistance to colistin with MIC = 4 mu g/ml. Other genes conferring the resistance to beta-lactam antibiotics have also been identified in mcr-1 positive strains, including bla(TEM-206) and bla(TEM-98). Three different sequence types were identified, including ST1196, ST140 and ST10. Plasmid characterization allowed us to detect the mcr-1 colistin resistance gene on conjugative IncP plasmid type. Conclusion: To the best of our knowledge, we have identified the mcr-1 gene for the first time in leukemia patients in Spain. In light of these results, strictmeasures have been implemented to prevent its dissemination. (c) 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Published: 2019

19. Low-density lipoprotein receptor-deficient hepatocytes differentiated from induced pluripotent stem cells allow familial hypercholesterolemia modeling, CRISPR/Cas-mediated genetic correction, and productive hepatitis C virus infection

Author: Eric Bruckert, Jean-Marie Heslan, E. Luce, Laia Tolosa, Samir Saheb, Arielle R. Rosenberg, Anne Dubart-Kupperschmitt, María José Gómez-Lechón, Angélique Fourrier, Jérôme Caron, Tuan Huy Nguyen, Maxime Villaret, Anne Weber, Véronique Pène, Physiopathogenèse et Traitement des Maladies du Foie [Villejuif], Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie de l'hépatite C (EA 4474), Université Paris Descartes - Paris 5 (UPD5), Unidad de Hepatología Experimental [Valencia, Spain], Hospital Universitari La Fe, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], 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), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MESR (French Ministry for Education and Research),Fondation pour la Recherche Médicale (FDT20160435349),DHU Hepatinov,French Society for Hematology (SFH), Fondation pour la Recherche Médicale (FDT20160435349),Région Ile de France/DIM Biothérapies,Nantes Métropole and the Pays de la Loire Region., ANR-10-RFCS-0004,Liv-iPS,Modélisation et approches thérapeutiques de maladies génétiques hépatiques à l'aide de cellules iPS spécifiques de patients(2010), European Project: 278152,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,INNOVALIV(2011), Le Bihan, Sylvie, Recherche finalisée sur les cellules souches - Modélisation et approches thérapeutiques de maladies génétiques hépatiques à l'aide de cellules iPS spécifiques de patients - - Liv-iPS2010 - ANR-10-RFCS-0004 - RFCS - VALID, Innovative strategies to generate human hepatocytes for treatment ofmetabolic Liver diseases: Tools for personalized cell therapy - INNOVALIV - - EC:FP7:HEALTH2011-12-01 - 2014-11-30 - 278152 - VALID, Physiopathogénèse et Traitement des Maladies du Foie, Hôpital Paul Brousse-Université Paris-Saclay, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Genetic enhancement, Medicine (miscellaneous), Hepacivirus, Familial hypercholesterolemia, medicine.disease_cause, Cell therapy, 0302 clinical medicine, lcsh:QD415-436, Promoter Regions, Genetic, Induced pluripotent stem cell, Gene Editing, lcsh:R5-920, Cell models, Cell Differentiation, Cardiovascular disease, Hepatitis C, 3. Good health, [SDV] Life Sciences [q-bio], Cholesterol, Phenotype, 030220 oncology & carcinogenesis, Molecular Medicine, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Stem cell, lcsh:Medicine (General), Apolipoprotein A-II, Plasmids, Sterol Regulatory Element Binding Protein 2, Genome editing, Hepatitis C virus, Induced Pluripotent Stem Cells, Biology, Antiviral Agents, Biochemistry, Genetics and Molecular Biology (miscellaneous), Virus, lcsh:Biochemistry, Hyperlipoproteinemia Type II, 03 medical and health sciences, Gene therapy, medicine, Humans, Research, Cell Biology, medicine.disease, Personalized medicine, Molecular biology, 030104 developmental biology, Receptors, LDL, LDL receptor, Hepatocytes, CRISPR-Cas Systems, Sofosbuvir, Lipoprotein
Abstract: Background Familial hypercholesterolemia type IIA (FH) is due to mutations in the low-density lipoprotein receptor (LDLR) resulting in elevated levels of low-density lipoprotein cholesterol (LDL-c) in plasma and in premature cardiovascular diseases. As hepatocytes are the only cells capable of metabolizing cholesterol, they are therefore the target cells for cell/gene therapy approaches in the treatment of lipid metabolism disorders. Furthermore, the LDLR has been reported to be involved in hepatitis C virus (HCV) entry into hepatocytes; however, its role in the virus infection cycle is still disputed. Methods We generated induced pluripotent stem cells (iPSCs) from a homozygous LDLR-null FH-patient (FH-iPSCs). We constructed a correction cassette bearing LDLR cDNA under the control of human hepatic apolipoprotein A2 promoter that targets the adeno-associated virus integration site AAVS1. We differentiated both FH-iPSCs and corrected FH-iPSCs (corr-FH-iPSCs) into hepatocytes to study statin-mediated regulation of genes involved in cholesterol metabolism. Upon HCV particle inoculation, viral replication and production were quantified in these cells. Results We showed that FH-iPSCs displayed the disease phenotype. Using homologous recombination mediated by the CRISPR/Cas9 system, FH-iPSCs were genetically corrected by the targeted integration of a correction cassette at the AAVS1 locus. Both FH-iPSCs and corr-FH-iPSCs were then differentiated into functional polarized hepatocytes using a stepwise differentiation approach (FH-iHeps and corr-FH-iHeps). The correct insertion and expression of the correction cassette resulted in restoration of LDLR expression and function (LDL-c uptake) in corr-FH-iHeps. We next demonstrated that pravastatin treatment increased the expression of genes involved in cholesterol metabolism in both cell models. Moreover, LDLR expression and function were also enhanced in corr-FH-iHeps after pravastatin treatment. Finally, we demonstrated that both FH-iHeps and corr-FH-iHeps were as permissive to viral infection as primary human hepatocytes but that virus production in FH-iHeps was significantly decreased compared to corr-FH-iHeps, suggesting a role of the LDLR in HCV morphogenesis. Conclusions Our work provides the first LDLR-null FH cell model and its corrected counterpart to study the regulation of cholesterol metabolism and host determinants of HCV life cycle, and a platform to screen drugs for treating dyslipidemia and HCV infection. Electronic supplementary material The online version of this article (10.1186/s13287-019-1342-6) contains supplementary material, which is available to authorized users.
Published: 2019

20. Challenges in Clinical Metaproteomics Highlighted by the Analysis of Acute Leukemia Patients with Gut Colonization by Multidrug-Resistant Enterobacteriaceae

Author: Rechenberger, Julia, Samaras, Patroklos, Jarzab, Anna, Behr, Juergen, Frejno, Martin, Djukovic, Ana, Sanz, Jaime, González-Barberá, Eva, Salavert, Miguel, López-Hontangas, Jose Luis, Xavier, Karina, Debrauwer, Laurent, Rolain, Jean-Marc, Sanz, Miguel, Garcia-Garcerà, Marc, Wilhelm, Mathias, Ubeda, Carles, Kuster, Bernhard, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), Hospital Universitari i Politècnic La Fe, Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Gulbenkian de Ciência [Oeiras] (IGC), Fundação Calouste Gulbenkian, Analyse de Xénobiotiques, Identification, Métabolisme (E20 Metatoul-AXIOM), ToxAlim (ToxAlim), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), 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-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Université de Lausanne (UNIL), CIBER in Epidemiology and Public Health, BMBF FloraStopMRE grant [031L0089], Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-MetaToul-MetaboHUB, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, MetaToul AXIOM (E20), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Lausanne = University of Lausanne (UNIL)
Subjects: [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, human gut microbiome, data analysis, lcsh:QR1-502, multi-omics, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, lcsh:Microbiology, Article, proteomics, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, clinical proteomics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, mass spectrometry, metaproteome, multidrug-resistant Enterobacteriaceae, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract: International audience; The microbiome has a strong impact on human health and disease and is, therefore, increasingly studied in a clinical context. Metaproteomics is also attracting considerable attention, and such data can be efficiently generated today owing to improvements in mass spectrometry-based proteomics. As we will discuss in this study, there are still major challenges notably in data analysis that need to be overcome. Here, we analyzed 212 fecal samples from 56 hospitalized acute leukemia patients with multidrug-resistant Enterobactericeae (MRE) gut colonization using metagenomics and metaproteomics. This is one of the largest clinical metaproteomic studies to date, and the first metaproteomic study addressing the gut microbiome in MRE colonized acute leukemia patients. Based on this substantial data set, we discuss major current limitations in clinical metaproteomic data analysis to provide guidance to researchers in the field. Notably, the results show that public metagenome databases are incomplete and that sample-specific metagenomes improve results. Furthermore, biological variation is tremendous which challenges clinical study designs and argues that longitudinal measurements of individual patients are a valuable future addition to the analysis of patient cohorts.
Published: 2019

21. Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey

Author: Pau Montesinos, J McKendrick, Arnaud Pigneux, Heather Wieffer, Monika Brüggemann, Anja K. Pownell, Ze Cong, Xinke Zhang, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Instituto de Salud Carlos III [Madrid] (ISC), Amgen Inc, PRMA Consulting [Hampshire, UK] (Linea House), University of Technology Sydney (UTS), Universitätsklinikum Schleswig-Holstein, Amgen Inc., Bodescot, Myriam, and Hospital Universitario La Fe, Valencia
Subjects: Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Neoplasm, Residual, Subsequent Relapse, Cross-sectional study, Lymphoblastic Leukemia, Clinical Decision-Making, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Induction therapy, hemic and lymphatic diseases, MRD testing, Genetics, Medicine, Humans, In patient, Oncology & Carcinogenesis, Internet, business.industry, Minimal residual disease, Consolidation Chemotherapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Test (assessment), Europe, body regions, Cross-Sectional Studies, Oncology, 030220 oncology & carcinogenesis, Health Care Surveys, Cross-sectional survey, Female, business, ALL, 030215 immunology, Research Article
Abstract: Background In acute lymphoblastic leukemia (ALL), the presence of minimal residual disease (MRD) after induction/consolidation chemotherapy is a strong prognostic factor for subsequent relapse and mortality. Accordingly, European clinical guidelines and protocols recommend testing patients who achieve a complete hematological remission (CR) for MRD for the purpose of risk stratification. The aim of this study was to provide quantitative information regarding real-world clinical practice for MRD testing in five European countries. Methods A web-based survey was conducted in March/April 2017 in France, Germany, Italy, Spain, and the UK. The survey was developed after consultation with specialist clinicians and a review of published literature. Eligible clinicians (20 per country; 23 in Spain) were board-certified in hemato-oncology or hematology, had at least five years’ experience in their current role after training, had treated at least two patients with B-cell precursor ALL in the 12 months before the survey or at least five patients in the last five years, and had experience of testing for MRD in clinical practice. Results MRD testing is now standard practice in the treatment of adult ALL across the five European countries, with common use of recent treatment protocols which specify testing. Respondents estimated that, among clinicians in their country who conduct MRD testing, 73% of patients in first CR (CR1) and 63% of patients in second or later CR (CR2+) are tested for MRD. The median time point reported as most commonly used for the first MRD test, to establish risk status and to determine a treatment plan was four weeks after the start of induction therapy. The timing and frequency of tests is similar across countries. An average of four or five post-CR1 tests per patient in the 12 months after the first MRD test were reported across countries. Conclusions This comprehensive study of MRD testing patterns shows consistent practice across France, Germany, Italy, Spain, and the UK with respect to the timing and frequency of MRD testing, aligning with use of national protocols. MRD testing is used in clinical practice also in patients who reach CR2 + . Electronic supplementary material The online version of this article (10.1186/s12885-018-5002-5) contains supplementary material, which is available to authorized users.
Published: 2018

22. J Acquir Immune Defic Syndr

Author: Daniel Gillor, Lars P. Ryder, Rodolphe Thiébaut, Luuk Gras, Santiago Moreno, Marie Helleberg, Peter Reiss, Michael S. Saag, Margaret T May, Jonathan A C Sterne, Ferdinand W. N. M. Wit, Janet Tate, Niels Obel, Frank de Wolf, Ronald B. Geskus, Colette Smith, José M. Miró, Jodie L. Guest, Dominique Costagliola, Suzanne M Ingle, Matthias Cavassini, Antonella dʼArminio Monforte, Heidi M. Crane, Marta Montero, Timothy R. Sterling, Leah Shepherd, Viviane D. Lima, Christoph Stephan, Adam Trickey, Armin Rieger, John Gill, Antiretroviral Therapy Cohort Collaboration (ART-CC), Stichting HIV Monitoring [Amsterdam], Universiteit van Amsterdam (UvA), University of Bristol [Bristol], University of Copenhagen = Københavns Universitet (KU), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Emory University School of Medicine, Emory University [Atlanta, GA], University of Calgary, University of Washington [Seattle], British Columbia Centre for Excellence in HIV/AIDS [Vancouver], University of British Columbia (UBC), University of Milan, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), University of Barcelona, Hospital Universitario Ramón y Cajal [Madrid], Universidad de Alcalá - University of Alcalá (UAH), Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, University College of London [London] (UCL), Yale University School of Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), University of Vienna [Vienna], Universität zu Köln, Université de Lausanne (UNIL), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Hospital Universitari i Politècnic La Fe, University of Amsterdam [Amsterdam] (UvA), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], Imperial College London, Public Health Service of Amsterdam, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Yale School of Medicine [New Haven, Connecticut] (YSM), Universität zu Köln = University of Cologne, Université de Lausanne = University of Lausanne (UNIL), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Oxford, Gestionnaire, Hal Sorbonne Université, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Université de Bordeaux (UB), Graduate School, AII - Infectious diseases, APH - Global Health, APH - Methodology, Global Health, and APH - Aging & Later Life
Subjects: CD8 ratio [CD4], Male, Oncology, Cross-sectional study, CD4:CD8 ratio, [SDV]Life Sciences [q-bio], Cell, Human immunodeficiency virus (HIV), CD4-CD8 Ratio, CD4 cell count, HIV Infections, CD8-Positive T-Lymphocytes, 030312 virology, medicine.disease_cause, MORPH3Eus, Pharmacology (medical), Longitudinal Studies, Young adult, Cd4 cell count, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Clinical Science, Middle Aged, Viral Load, SISTM, 3. Good health, Antiretroviral therapy, [SDV] Life Sciences [q-bio], Infectious Diseases, medicine.anatomical_structure, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, Coll_IDLIC, Adult, medicine.medical_specialty, Adolescent, Anti-HIV Agents, CD8 cell count, antiretroviral therapy, Young Adult, 03 medical and health sciences, Age, Internal medicine, medicine, Coll_ART-CC, Humans, Lymphocyte Count, Anti-HIV Agents/therapeutic use, CD4 Lymphocyte Count, Cross-Sectional Studies, HIV Infections/drug therapy, HIV-1, Viral Load/drug effects, business.industry, HIV, age, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, CD8, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Supplemental Digital Content is Available in the Text., Background: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. Methods: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. Results: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with
Published: 2018

23. Single- or double-unit UCBT following RIC in adults with AL: a report from Eurocord, the ALWP and the CTIWP of the EBMT

Author: Annalisa Ruggeri, Jan J. Cornelissen, Eliane Gluckman, Patrice Chevallier, Mohamad Mohty, Bipin N. Savani, Guillermo Sanz, Frédéric Baron, Didier Blaise, Myriam Labopin, Eefke Petersen, Arnon Nagler, Eric Beohou, Department of Hematology [Liege, Belgium], CHU Sart Tilman [Liege, Belgium]-Université de Liège, Eurocord [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hématologie [Marseille], Centre de Lutte contre le Cancer-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Service d'Hématologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Servicio de Hematologia [Valencia, Spain], Hospital Universitari i Politècnic La Fe, Department of Hematology [Utrecht, The Netherlands] (UMCU), University Medical Center [Utrecht], Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], France Monacord [Monaco], Centre Scientifique de Monaco (CSM), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Division of Hematology and Bone Marrow Transplantation [Ramat-Gan, Israel], The Chaim Sheba Medical Center at Tel hashomer, no source, Université de Liège-CHU Sart Tilman [Liege, Belgium], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre de Lutte contre le Cancer, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, BMC, BMC, and Hematology
Subjects: Oncology, Male, Cancer Research, Transplantation Conditioning, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Single, Graft vs Host Disease, Hematopoietic stem cell transplantation, 0302 clinical medicine, AML, Medicine, 10. No inequality, Reduced-intensity, Univariate analysis, Hematology, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, lcsh:Diseases of the blood and blood-forming organs, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Fetal Blood, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Cord Blood Stem Cell Transplantation, Adult, medicine.medical_specialty, Adolescent, Double, lcsh:RC254-282, 03 medical and health sciences, Young Adult, Unrelated cord blood, Internal medicine, Humans, Molecular Biology, Aged, Retrospective Studies, Transplantation, Neutrophil Engraftment, business.industry, lcsh:RC633-647.5, Research, Retrospective cohort study, Surgery, UCB, Neoplasm Recurrence, Local, business, ALL, 030215 immunology
Abstract: Background The feasibility of cord blood transplantation (CBT) in adults is limited by the relatively low number of hematopoietic stem/progenitor cells contained in one single CB unit. The infusion of two CB units from different partially HLA-matched donors (double CBT) is frequently performed in patients who lack a sufficiently rich single CB unit. Methods We compared CBT outcomes in patients given single or double CBT following reduced-intensity conditioning (RIC) in a retrospective multicenter registry-based study. Inclusion criteria included adult (≥18 years) patients, acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), complete remission (CR) at the time of transplantation, first single (with a cryopreserved TNC ≥ 2.5 × 107/kg) or double CBT between 2004 and 2014, and RIC conditioning. Results Data from 534 patients with AML (n = 408) or ALL (n = 126) receiving a first single (n = 172) or double (n = 362) CBT were included in the analyses. In univariate analysis, in comparison to patients transplanted with a single CB, double CB recipients had a similar incidence of neutrophil engraftment but a suggestion for a higher incidence of grade II–IV acute GVHD (36 versus 28%, P = 0.08). In multivariate analyses, in comparison to single CBT recipients, double CBT patients had a comparable incidence of relapse (HR = 0.9, P = 0.5) and of nonrelapse mortality (HR = 0.8, P = 0.3), as well as comparable overall (HR = 0.8, P = 0.17), leukemia-free (HR = 0.8, P = 0.2) and GVHD-free, relapse-free (HR = 1.0, P = 0.3) survival. Conclusions These data failed to demonstrate better transplantation outcomes in adult patients receiving double CBT in comparison to those receiving single CBT with adequate TNC after RIC. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0497-9) contains supplementary material, which is available to authorized users.
Published: 2017

24. RENEB–Running the European Network of biological dosimetry and physical retrospective dosimetry

Author: Kulka, U., Abend, M., Ainsbury, E., Badie, C., Barquinero, J.F., Barrios, L., Beinke, C., Bortolin, E., Cucu, A., De Amicis, A., Domínguez, I., Fattibene, P., Frøvig, A.M., Gregoire, E., Guogyte, K., Hadjidekova, V., Jaworska, A., Kriehuber, R., Lindholm, C., Lloyd, D., Lumniczky, K., Lyng, F., Meschini, R., Mörtl, S., Della Monaca, S., Monteiro Gil, O., Montoro, A., Moquet, J., Moreno, M., Oestreicher, U., Palitti, F., Pantelias, G., Patrono, C., Piqueret-Stephan, L., Port, M., Prieto, M.J., Quintens, R., Ricoul, M., Romm, H., Roy, L., Sáfrány, G., Sabatier, L., Sebastià, N., Sommer, S., Terzoudi, G., Testa, A., Thierens, H., Turai, I., Trompier, F., Valente, M., Vaz, P., Voisin, P., Vral, A., Woda, C., Zafiropoulos, D., Wojcik, A., Bundesamt für Strahlenschutz (BfS), Bundeswehr Institute of Radiobiology, Universität Ulm - Ulm University [Ulm, Allemagne], Centre for Radiation, Chemical and Environmental Hazards, Public Health England [London], Universitat Autònoma de Barcelona (UAB), Istituto Superiore di Sanita` (ISS), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Radiation and Nuclear Safety Authority [Helsinki] (STUK), National center for public health [Hungary], Hospital Universitario y Politécnico La Fe, University of Tuscia, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile (ENEA), Universiteit Gent = Ghent University [Belgium] (UGENT), Helmholtz-Zentrum München (HZM), Stockholm University, Seventh Framework Programme, Bundesamt für Strahlenschutz - Federal Office for Radiation Protection (BfS), Istituto Superiore di Sanità (ISS), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Università degli studi della Tuscia [Viterbo], Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile = Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Universiteit Gent = Ghent University (UGENT), and Helmholtz Zentrum München = German Research Center for Environmental Health
Subjects: [SDV]Life Sciences [q-bio]
Abstract: International audience; Purpose: A European network was initiated in 2012 by 23 partners from 16 European countries with the aim to significantly increase individualized dose reconstruction in case of large-scale radiological emergency scenarios. Results: The network was built on three complementary pillars: (1) an operational basis with seven biological and physical dosimetric assays in ready-to-use mode, (2) a basis for education, training and quality assurance, and (3) a basis for further network development regarding new techniques and members. Techniques for individual dose estimation based on biological samples and/or inert personalized devices as mobile phones or smart phones were optimized to support rapid categorization of many potential victims according to the received dose to the blood or personal devices. Communication and cross-border collaboration were also standardized. To assure long-term sustainability of the network, cooperation with national and international emergency preparedness organizations was initiated and links to radiation protection and research platforms have been developed. A legal framework, based on a Memorandum of Understanding, was established and signed by 27 organizations by the end of 2015. Conclusions: RENEB is a European Network of biological and physical-retrospective dosimetry, with the capacity and capability to perform large-scale rapid individualized dose estimation. Specialized to handle large numbers of samples, RENEB is able to contribute to radiological emergency preparedness and wider large-scale research projects. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published: 2017

25. RENEB accident simulation exercise

Author: Brzozowska, B., Ainsbury, E., Baert, A.E., Beaton-Green, L., Barrios, L., Barquinero, J.F., Bassinet, C., Beinke, C., Benedek, A., Beukes, P., Bortolin, E., Buraczewska, I., Burbidge, C.I., de Amicis, A., de Angelis, C., Della Monaca, S., Depuydt, J., de Sanctis, S., Dobos, K., Domene, M.M., Domínguez, I., Facco, E., Fattibene, P., Frenzel, M., Monteiro Gil, O., Gonon, G., Gregoire, E., Gruel, G., Hadjidekova, V., Hatzi, V.I., Hristova, R., Jaworska, A., Kis, E., Kowalska, M., Kulka, U., Lista, F., Lumniczky, K., Martínez-López, W., Meschini, R., Mörtl, S., Moquet, J., Noditi, M., Oestreicher, U., Orta Vázquez, M.L., Palma, V., Pantelias, G., Montoro Pastor, A., Patrono, C., Piqueret-Stephan, L., Quattrini, M.C., Regalbuto, E., Ricoul, M., Roch-Lefevre, S., Roy, L., Sabatier, L., Sarchiapone, L., Sebastià, N., Sommer, S., Sun, M., Suto, Y., Terzoudi, G., Trompier, F., Vral, A., Wilkins, R., Zafiropoulos, D., Wieser, A., Woda, C., Wojcik, A., Istituto Superiore di Sanita` (ISS), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Bundesamt für Strahlenschutz (BfS), National center for public health [Hungary], Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hospital Universitario y Politécnico La Fe, Public Health England [London], Universiteit Gent = Ghent University [Belgium] (UGENT), Helmholtz-Zentrum München (HZM), Stockholm University, University of Warsaw (UW), Universitat Autònoma de Barcelona (UAB), Bundeswehr Institute of Radiobiology, Universität Ulm - Ulm University [Ulm, Allemagne], Seventh Framework Programme, Istituto Superiore di Sanità (ISS), Bundesamt für Strahlenschutz - Federal Office for Radiation Protection (BfS), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Universiteit Gent = Ghent University (UGENT), and Helmholtz Zentrum München = German Research Center for Environmental Health
Subjects: RENEB network, Safety Management, [SDV]Life Sciences [q-bio], Radiobiology, Biology and Life Sciences, Disaster Planning, Reneb Network, Accident Simulation, Radiobiological Event, Europe, radiobiological event, Radiation Monitoring, Medicine and Health Sciences, accident simulation, Triage, Radioactive Hazard Release
Abstract: International audience; Purpose: The RENEB accident exercise was carried out in order to train the RENEB participants in coordinating and managing potentially large data sets that would be generated in case of a major radiological event. Materials and methods: Each participant was offered the possibility to activate the network by sending an alerting email about a simulated radiation emergency. The same participant had to collect, compile and report capacity, triage categorization and exposure scenario results obtained from all other participants. The exercise was performed over 27 weeks and involved the network consisting of 28 institutes: 21 RENEB members, four candidates and three non-RENEB partners. Results: The duration of a single exercise never exceeded 10 days, while the response from the assisting laboratories never came later than within half a day. During each week of the exercise, around 4500 samples were reported by all service laboratories (SL) to be examined and 54 scenarios were coherently estimated by all laboratories (the standard deviation from the mean of all SL answers for a given scenario category and a set of data was not larger than 3 patient codes). Conclusions: Each participant received training in both the role of a reference laboratory (activating the network) and of a service laboratory (responding to an activation request). The procedures in the case of radiological event were successfully established and tested. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published: 2017

26. Capabilities of the RENEB network for research and large scale radiological and nuclear emergency situations

Author: Monteiro Gil, Octavia, Pedro Vaz, Romm, Horst, Angelis, Cinzia, Antunes, Ana Catarina, Barquinero, Joan-Francesc, Beinke, Christina, Bortolin, Emanuela, Burbidge, Christopher Ian, Cucu, Alexandra, Della Monaca, Sara, Domene, Mercedes Moreno, Fattibene, Paola, Gregoire, Eric, Hadjidekova, Valeria, Kulka, Ulrike, Lindholm, Carita, Meschini, Roberta, M Kacher, Radhia, Moquet, Jayne, Oestreicher, Ursula, Palitti, Fabrizio, Pantelias, Gabriel, Montoro Pastor, Alegria, Popescu, Irina-Anca, Quattrini, Maria Cristina, Ricoul, Michelle, Rothkamm, Kai, Sabatier, Laure, Sebastia, Natividad, Sommer, Sylwester, Terzoudi, Georgia, Testa, Antonella, Trompier, Francois, Vral, Anne, Istituto Superiore di Sanita` (ISS), Bundeswehr Institute of Radiobiology, Universität Ulm - Ulm University [Ulm, Allemagne], Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Bundesamt für Strahlenschutz (BfS), Radiation and Nuclear Safety Authority [Helsinki] (STUK), University of Tuscia, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre for Radiation, Chemical and Environmental Hazards, Public Health England [London], Hospital Universitario y Politécnico La Fe, Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile (ENEA), Universiteit Gent = Ghent University [Belgium] (UGENT), Seventh Framework Programme, Istituto Superiore di Sanità (ISS), Bundesamt für Strahlenschutz - Federal Office for Radiation Protection (BfS), Università degli studi della Tuscia [Viterbo], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile = Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), and Universiteit Gent = Ghent University (UGENT)
Subjects: BIODOSIMETRY RENEB, Safety Management, Biomedical Research, [SDV]Life Sciences [q-bio], questionnaire/survey, Radiobiology, Biology and Life Sciences, Biodosimetry, Disaster Planning, emergency preparedness, capacity of laboratory response, radiological accident/emergency, Europe, Radiation Protection, EUROPEAN NETWORK, Radiation Monitoring, Models, Organizational, Radioactive Hazard Release
Abstract: International audience; Purpose: To identify and assess, among the participants in the RENEB (Realizing the European Network of Biodosimetry) project, the emergency preparedness, response capabilities and resources that can be deployed in the event of a radiological or nuclear accident/incident affecting a large number of individuals. These capabilities include available biodosimetry techniques, infrastructure, human resources (existing trained staff), financial and organizational resources (including the role of national contact points and their articulation with other stakeholders in emergency response) as well as robust quality control/assurance systems. Materials and methods: A survey was prepared and sent to the RENEB partners in order to acquire information about the existing, operational techniques and infrastructure in the laboratories of the different RENEB countries and to assess the capacity of response in the event of radiological or nuclear accident involving mass casualties. The survey focused on several main areas: laboratory’s general information, country and staff involved in biological and physical dosimetry; retrospective assays used, the number of assays available per laboratory and other information related to biodosimetry and emergency preparedness. Following technical intercomparisons amongst RENEB members, an update of the survey was performed one year later concerning the staff and the available assays. Conclusions: The analysis of RENEB questionnaires allowed a detailed assessment of existing capacity of the RENEB network to respond to nuclear and radiological emergencies. This highlighted the key importance of international cooperation in order to guarantee an effective and timely response in the event of radiological or nuclear accidents involving a considerable number of casualties. The deployment of the scientific and technical capabilities existing within the RENEB network members seems mandatory, to help other countries with less or no capacity for biological or physical dosimetry, or countries overwhelmed in case of a radiological or nuclear accident involving a large number of individuals. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Published: 2017

27. Web based scoring is useful for validation and harmonisation of scoring criteria within RENEB

Author: Romm, H., Ainsbury, E.A., Barquinero, J.F., Barrios, L., Beinke, C., Cucu, A., Domene, M.M., Filippi, S., Monteiro Gil, O., Gregoire, E., Hadjidekova, V., Hatzi, V., Lindholm, C., M´kacher, R., Montoro, A., Moquet, J., Noditi, M., Oestreicher, U., Palitti, F., Pantelias, G., Prieto, M.J., Popescu, I., Rothkamm, K., Sebastià, N., Sommer, S., Terzoudi, G., Testa, A., Wojcik, A., University of Tuscia, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), National Centre for Scientific Research Demokritos, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hospital Universitario y Politécnico La Fe, Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile (ENEA), European Commission, EC 295513, Università degli studi della Tuscia [Viterbo], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, and Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile = Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA)
Subjects: Internet, [SDV]Life Sciences [q-bio], Web based scoring, Reproducibility of Results, Radiation Exposure, biological dosimetry, Sensitivity and Specificity, Europe, radiation, Radiation Monitoring, Cytogenetic Analysis, Humans, Biological Assay, Lymphocytes, biodosimetry network, Laboratories, dicentric assay
Abstract: International audience; Purpose To establish a training data set of digital images and to investigate the scoring criteria and dose assessment of the dicentric assay within the European network of biodosimetry (RENEB), a web based scoring inter-comparison was undertaken by 17 RENEB partners. Materials and methods Two sets of 50 high resolution images were uploaded onto the RENEB website. One set included metaphases after a moderate exposure (1.3 Gy) and the other set consisted of metaphases after a high dose exposure (3.5 Gy). The laboratories used their own calibration curves for estimating doses based on observed aberration frequencies. Results The dose estimations and 95% confidence limits were compared to the actual doses and the corresponding z-values were satisfactory for the majority; only the dose estimations from two laboratories were too low or too high. The coefficients of variation were 17.6% for the moderate and 11.2% for the high dose. Metaphases with controversial results could be identified for training purposes. Conclusions Overall, the web based scoring of the two galleries by the 17 laboratories produced very good results. Application of web based scoring for the dicentric assay may therefore be a relevant strategy for an operational biodosimetry assistance network. © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor and Francis Group.
Published: 2017

28. Integration of new biological and physical retrospective dosimetry methods into EU emergency response plans - joint RENEB and EURADOS inter-laboratory comparisons

Author: Elizabeth, Ainsbury, Christophe, Badie, Stephen, Barnard, Grainne, Manning, Jayne, Moquet, Michael, Abend, Ana Catarina, Antunes, Lleonard, Barrios, Celine, Bassinet, Christina, Beinke, Emanuela, Bortolin, Lily, Bossin, Clare, Bricknell, Kamil, Brzoska, Iwona, Buraczewska, Carlos Huertas, Castaño, Zina, Čemusová, Maria, Christiansson, Santiago Mateos, Cordero, Guillaume, Cosler, Sara Della, Monaca, François, Desangles, Michael, Discher, Inmaculada, Dominguez, Sven, Doucha-Senf, Jon, Eakins, Paola, Fattibene, Silvia, Filippi, Monika, Frenzel, Dimka, Georgieva, Eric, Gregoire, Kamile, Guogyte, Valeria, Hadjidekova, Ljubomira, Hadjiiska, Rositsa, Hristova, Maria, Karakosta, Enikő, Kis, Ralf, Kriehuber, Jungil, Lee, David, Lloyd, Katalin, Lumniczky, Fiona, Lyng, Ellina, Macaeva, Matthaeus, Majewski, S, Vanda Martins, Stephen W S, McKeever, Aidan, Meade, Dinesh, Medipally, Roberta, Meschini, Radhia, M'kacher, Octávia Monteiro, Gil, Alegria, Montero, Mercedes, Moreno, Mihaela, Noditi, Ursula, Oestreicher, Dominik, Oskamp, Fabrizio, Palitti, Valentina, Palma, Gabriel, Pantelias, Jerome, Pateux, Clarice, Patrono, Gaetano, Pepe, Matthias, Port, María Jesús, Prieto, Maria Cristina, Quattrini, Roel, Quintens, Michelle, Ricoul, Laurence, Roy, Laure, Sabatier, Natividad, Sebastià, Sergey, Sholom, Sylwester, Sommer, Albena, Staynova, Sonja, Strunz, Georgia, Terzoudi, Antonella, Testa, Francois, Trompier, Marco, Valente, Olivier Van, Hoey, Ivan, Veronese, Andrzej, Wojcik, Clemens, Woda, Public Health England [London], Centre for Radiation, Chemical and Environmental Hazards, Bundeswehr Institute of Radiobiology, Universität Ulm - Ulm University [Ulm, Allemagne], Universitat Autònoma de Barcelona (UAB), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Istituto Superiore di Sanita` (ISS), Istituto Superiore di Sanita [Rome], University of Salzburg, University of Tuscia, National center for public health [Hungary], Oklahoma State University [Stillwater], Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hospital Universitario y Politécnico La Fe, Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile (ENEA), Institut de Recherche Biomédicale des Armées (IRBA), Università degli Studi di Milano [Milano] (UNIMI), Stockholm University, Helmholtz-Zentrum München (HZM), European Commission, Istituto Superiore di Sanità (ISS), Università degli studi della Tuscia [Viterbo], Oklahoma State University [Stillwater] (OSU), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Agenzia Nazionale per le nuove Tecnologie, l’energia e lo sviluppo economico sostenibile = Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Università degli Studi di Milano = University of Milan (UNIMI), and Helmholtz Zentrum München = German Research Center for Environmental Health
Subjects: Safety Management, [SDV]Life Sciences [q-bio], TELOMERE, Disaster Planning, radiation accidents, Sensitivity and Specificity, physical retrospective dosimetry, Radiation Monitoring, TOOL, European Union, DICENTRIC CHROMOSOMES, NETWORK, Retrospective Studies, GENE-EXPRESSION, SPECTROSCOPY, Biodosimetry, RENEB, Reproducibility of Results, Biology and Life Sciences, TRIAGE, IN-VITRO, Radiation Exposure, Systems Integration, PERIPHERAL-BLOOD LYMPHOCYTES, Biological Assay, IONIZING-RADIATION, Laboratories
Abstract: International audience; Purpose: RENEB, ‘Realising the European Network of Biodosimetry and Physical Retrospective Dosimetry,’ is a network for research and emergency response mutual assistance in biodosimetry within the EU. Within this extremely active network, a number of new dosimetry methods have recently been proposed or developed. There is a requirement to test and/or validate these candidate techniques and inter-comparison exercises are a well-established method for such validation. Materials and methods: The authors present details of inter-comparisons of four such new methods: dicentric chromosome analysis including telomere and centromere staining; the gene expression assay carried out in whole blood; Raman spectroscopy on blood lymphocytes, and detection of radiation-induced thermoluminescent signals in glass screens taken from mobile phones. Results: In general the results show good agreement between the laboratories and methods within the expected levels of uncertainty, and thus demonstrate that there is a lot of potential for each of the candidate techniques. Conclusions: Further work is required before the new methods can be included within the suite of reliable dosimetry methods for use by RENEB partners and others in routine and emergency response scenarios. © 2016 Crown Copyright. Published by Informa UK Limited, trading as Taylor & Francis Group.
Published: 2017

29. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

Author: Robert J. Wilkinson, James E. Bower, Liliana K. Rutaihwa, W. Henry Boom, Matthias Egger, Philip Noel Suffys, Elisabeth Sanchez-Padilla, Linda Gail-Bekker, Sebastien Gagneux, Issam Alani, Marie Ballif, Kathleen D. Eisenach, Jennifer L. Guthrie, Ana Gil-Brusola, Eddie M. Wampande, Willy Ssengooba, Nyanda E. Ntinginya, Rita Macedo, Petras Stakenas, Bijaya Malla, Adwoa Asante-Poku, Stefan Niemann, Lynsey Stewart-Isherwood, Mireia Coscolla, Perpetual Wangui Ndung'u, Florian Gehre, Daniela Maria Cirillo, E. Jane Carter, Sidra Ezidio Gonçalves Vasconcellos, Moses Joloba, Midori Kato-Maeda, Indira Basu, Andrea Rachow, Bouke C. de Jong, Serej D. Ley, Andrej Trauner, Hans-Peter Beck, Jackson Thomas, Dorothy Yeboah-Manu, Qingyun Liu, Tao Luo, Francesca Barletta, Véronique Penlap Beng, Janet A. M. Fyfe, Anastasia Koch, Margarida Saraiva, Sven Hoffner, Daniela Brites, Sahal Al-Hajoj, Griselda Tudo Vilanova, Maria Globan, Qian Gao, Helmi Mardassi, Maryline Bonnet, Philip Supply, Iñaki Comas, Valeriu Crudu, Girts Skenders, Francine Ntoumi, Frances B. Jamieson, Olga Domnica Moldovan, Leïla Jeljeli, Gunturu Revathi, Milagros Moreno, Suriya Akter, Sonia Borrell, Kadri Toit, Matthias Frank, Michael Hoelscher, Lameck Diero, Daiva Bakonyte, David Stucki, Lukas Fenner, Larissa Otero, Roland Diel, University of Basel (Unibas), Swiss Tropical Institute, Swiss Tropical and Public Health Institute [Basel], Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research, Borstel Site, Institute of Social and Preventive Medicine [Bern] (ISPM), Universität Bern [Bern], Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), Key Laboratory of Medical Molecular Virology of the Ministries of Education and Health, Institutes of Biomedical Sciences and Institute of Medical Microbiology, Fudan University, Laboratory of Infection and Immunity, School of Basic Medical Science, West China Center of Medical Sciences, Sichuan University [Chengdu] (SCU), University of California at San Francisco, University of California [San Francisco] (UCSF), University of California-University of California, School of Medicine, Laboratorio Nacional de Saude Publica, Hospital Nossa Senhora da Paz, Servei de Microbiologia, Hospital Clínic–ISGlobal, Barcelona, Victorian Infectious Diseases Reference Laboratory, Public Health Ontario - Santé publique Ontario, Noguchi Memorial Institute for Medical Research [Accra, Ghana] (NMIMR), University of Ghana, Makerere University College of Health Sciences, Department of Global Health, University of Amsterdam [Amsterdam] (UvA), Department of Molecular Biology and Microbiology, Case Western Reserve University [Cleveland], Lab Plus, Auckland City Hospital, ICVS/3B's—PT Government Associate Laboratory, Braga, Molecular Biology Applied to Mycobacteria / Biologia Molecular Aplicada a Micobactérias [Rio de Janeiro], Instituto Oswaldo Cruz / Oswaldo Cruz Institute [Rio de Janeiro] (IOC), Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institute of Infectious Disease and Molecular Medicine, and Department of Clinical Laboratory Sciences, University of Cape Town, Department of Medicine, Imperial College London, Francis Crick Institute Mill Hill Laboratory, London, Papua New Guinea Institute of Medical Research (PNG-IMR), Institute of Tropical Medicine [Antwerp] (ITM), Tartu University Hospital United Laboratories, Mycobacteriology, Epicentre [Paris] [Médecins Sans Frontières], Institute of Tropical Medicine and Infectious Diseases (ITROMID), Jomo Kenyatta University of Agriculture and Technology (JKUAT), Nairobi, Department of Microbiology, University Hospital La Fe, Valencia, University of Tübingen [Germany], Fondation Congolaise pour la Recherche Médicale, Université Marien Gouabi, Brazzaville, University of Yaoundé [Cameroun], University of Arkansas for Medical Sciences (UAMS), Department of Medical Laboratory Technology, Faculty of Medical Technology, Baghdad, Department of Pathology, Aga Khan University Hospital (AKUH), Nairobi, Medical Research Council, Fajara, Right to Care and the Clinical HIV Research Unit, University of the Witwatersrand [Johannesburg] (WITS), Division of Infectious Diseases and Tropical Medicine = Abteilung für infektions und tropenmedizin [Munich, Germany], Klinikum der Universität [München]-Ludwig-Maximilians-Universität München (LMU), National Institute of Medical Research, Mbeya Medical Research Centre (NIMR-MMRC), Mbeya, Emerging Bacterial Pathogen Unit, San Raffaele Scientific Institute, WHO Supranational TB Reference Laboratory, Department of Microbiology, Public Health Agency of Sweden, Department of Immunology and Cell Biology, Institute of Biotechnology, Vilnius University [Vilnius], Institute for Epidemiology, Schleswig-Holstein University Hospital, Kiel, Marius Nasta Institute of Pneumology, Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Instituto de Medicina Tropical Alexander von Humboldt, Molecular Epidemiology Unit–Tuberculosis, Instituto de Medicina Tropical 'Alexander von Humboldt' (IMT AvH), Universidad Peruana Cayetano Heredia (UPCH)-Universidad Peruana Cayetano Heredia (UPCH), Warren Alpert Medical School of Brown University, Moi University School of Medicine, Eldoret, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), CIBER Epidemiology and Public Health, Madrid, [et. al.], Universidade do Minho, Wellcome Trust, Universität Bern [Bern] (UNIBE), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Victorian Infectious Diseases Reference Laboratory [Melbourne, Australia] (VIDRL), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Ludwig-Maximilians-Universität München (LMU)-Klinikum der Universität [München], King Faisal Specialist Hospital and Research Centre (KFSH & RC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: 0301 basic medicine, Infecções Respiratórias, [SDV]Life Sciences [q-bio], Generalist and specialist species, Global Health, ANTIGENIC VARIATION, Polymorphism, Genetic/genetics, POPULATION, ComputingMilieux_MISCELLANEOUS, Genetics & Heredity, education.field_of_study, RESISTANT TUBERCULOSIS, Human migration, Ecology, 11 Medical And Health Sciences, Genomics, SOUTH-AFRICA, 3. Good health, Mycobacterium tuberculosis/classification/genetics/isolation & purification, Phylogeography, GENETIC DIVERSITY, Life Sciences & Biomedicine, DNA, Bacterial, Lineage (genetic), Genotype, Niche, Population, Tuberculosis/genetics/microbiology, Biology, Article, Host Specificity, 03 medical and health sciences, HIV-INFECTION, Genetics, Humans, Tuberculosis, DNA, Bacterial/analysis, education, Ecological niche, PATHOGENS, Science & Technology, Polymorphism, Genetic, Obligate, business.industry, Mycobacterium tuberculosis, 06 Biological Sciences, biology.organism_classification, PAPUA-NEW-GUINEA, EVOLUTION, Genomics/methods, 030104 developmental biology, Evolutionary biology, business, GENOMIC DIVERSITY, purl.org/pe-repo/ocde/ford#1.06.07 [https], Developmental Biology, Mycobacterium
Abstract: Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration., We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.).
Published: 2016

30. Transplantation of hESC-derived hepatocytes protects mice from liver injury

Author: Tolosa L, Caron J, Hannoun Z, Antoni M, López S, Burks D, Castell JV, Weber A, Gomez-Lechon MJ, Dubart-Kupperschmitt A, Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Unidad de Hepatología Experimental, Hospital Universitari La Fe, Hepatinov (DHU), Université Paris-Sud - Paris 11 (UP11)-Centre Hépato-Biliaire Paul Brousse, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III [Madrid] (ISC), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, and BMC, BMC
Subjects: [SDV] Life Sciences [q-bio], Transplantation, Preclinical animal model, [SDV]Life Sciences [q-bio], Human embryonic stem cells (hESCs), Directed differentiation, Hepatocytes, Liver injury, Cell therapy
Abstract: Background: Hepatic cell therapy has become a viable alternative to liver transplantation for life-threatening liver diseases. However, the supply of human hepatocytes is limited due to the shortage of suitable donor organs required to isolate high-quality cells. Human pluripotent stem cells reflect a potential renewable source for generating functional hepatocytes. However, most differentiation protocols use undefined matrices or factors of animal origin; as such, the resulting hepatocytes are not Good Manufacturing Practice compliant. Moreover, the preclinical studies employed to assess safety and function of human embryonic stem cell (hESC)-derived hepatocytes are generally limited to immunodeficient mice. In the present study, we evaluate the generation of hepatocytes under defined conditions using a European hESC line (VAL9) which was derived under animal-free conditions. The function capacity of VAL9-derived hepatocytes was assessed by transplantation into mice with acetaminophen-induced acute liver failure, a clinically relevant model. Methods: We developed a protocol that successfully differentiates hESCs into bipotent hepatic progenitors under defined conditions, without the use of chromatin modifiers such as dimethyl sulphoxide. These progenitors can be cryopreserved and are able to generate both committed precursors of cholangiocytes and neonate-like hepatocytes. Results: Thirty days post-differentiation, hESCs expressed hepatocyte-specific markers such as asialoglycoprotein receptor and hepatic nuclear factors including HNF4 alpha. The cells exhibited properties of mature hepatocytes such as urea secretion and UGT1A1 and cytochrome P450 activities. When transplanted into mice with acetaminophen-induced acute liver failure, a model of liver damage, the VAL9-derived hepatocytes efficiently engrafted and proliferated, repopulating up to 10 % of the liver. In these transplanted livers, we observed a significant decrease of liver transaminases and found no evidence of tumourigenicity. Thus, VAL9-derived hepatocytes were able to rescue hepatic function in acetaminophen-treated animals. Conclusions: Our study reveals an efficient protocol for differentiating VAL9 hESCs to neonatal hepatocytes which are then able to repopulate livers in vivo without tumour induction. The human hepatocytes are able to rescue liver function in mice with acetaminophen-induced acute toxicity. These results provide proof-of-concept that replacement therapies using hESC-derived hepatocytes are effective for treating liver diseases.
Published: 2015

31. Unrelated cord blood transplantation for adult patients with acute myeloid leukemia: higher incidence of acute graft-versus-host disease and lower survival in male patients transplanted with female unrelated cord blood--a report from Eurocord, the Acute Leukemia Working Party, and the Cord Blood Committee of the Cellular Therapy and Immunobiology Working Party of the European Group for Blood and Marrow Transplantation

Author: Baron, Frédéric, Labopin, Myriam, Ruggeri, Annalisa, Mohty, Mohamad, Sanz, Guillermo, Milpied, Noel, Bacigalupo, Andrea, Rambaldi, Alessandro, Bonifazi, Francesca, Bosi, Alberto, Sierra, Jorge, Yakoub-Agha, Ibrahim, Ribera, Jose-Maria, Gluckman, Eliane, Nagler, Arnon, Universitat Autònoma de Barcelona, Service d'Hématologie, Université de Liège-CHU Sart-Tilman, Centre International des greffes [CHU Saint-Antoine] (EBMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Eurocord, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Servicio de Hematologia, Hospital Universitari i Politècnic La Fe, Service d'Hématologie et Thérapie Cellulaire, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Department of Haematology II, Ospedale San Martino, Hematology and Bone Marrow Transplant Unit, Azienda Ospedaliera Papa Giovanni XXIII, Institute of Hematology and Medical, Oncology L and A Seràgnoli, Policlinico S. Orsola - Malpighi, Bone Marrow Transplant Unit (BMT), Azienda Ospedaliera Careggi, Hematology Department, Hospital de la Santa Creu i Sant Pau, Unités d'Activité Médicale [Lille] (UAM), Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Jose Carreras Research Institute, Hospital Universitari Germans Trias i Pujol, France Monacord, Centre Scientifique de Monaco (CSM), Division of Hematology and Bone Marrow Transplantation, The Chaim Sheba Medical Center at Tel hashomer, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, BMC, BMC, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut Universitaire d'Hématologie (IUH), and Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Male, Cancer Research, [SDV]Life Sciences [q-bio], GVHD, Graft vs Host Disease, Blood Donors, 0302 clinical medicine, AML, Risk Factors, hemic and lymphatic diseases, Medicine, 0303 health sciences, Acute leukemia, Hematology, Incidence, Hazard ratio, Middle Aged, 3. Good health, Europe, Survival Rate, [SDV] Life Sciences [q-bio], Leukemia, surgical procedures, operative, Oncology, Leukemia, Myeloid, 030220 oncology & carcinogenesis, Cord blood, Acute Disease, Female, Cord Blood Stem Cell Transplantation, Adult, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Young Adult, Sex Factors, Unrelated cord blood, Sang fetal, Internal medicine, Humans, Survival rate, Molecular Biology, 030304 developmental biology, Aged, Retrospective Studies, Transplantation, business.industry, Research, medicine.disease, Survival Analysis, Surgery, Multivariate Analysis, business
Abstract: Background In the setting of allogeneic human leukocyte antigen (HLA)-matched bone marrow transplantation, transplanting male patients with grafts from female donors has been associated with a higher incidence of graft-versus-host disease (GVHD) and of nonrelapse mortality (NRM). The aim of the current analysis was to compare transplantation outcomes in male patients given female unrelated cord blood (UCB) versus other gender combinations. Patients and methods Data from 552 consecutive patients with acute myeloid leukemia (AML) given a single UCB transplantation between 2000 and 2014 were included. Results In comparison with other gender combination, male patients given female UCB (n = 131) had a trend for a higher incidence of grades II–IV acute GVHD (33 versus 25 %, P = 0.08), a trend for a higher incidence of NRM (41 versus 33 %, P = 0.06), and a lower leukemia-free (LFS, 30 versus 41 %, P = 0.01) and overall survival (OS, 33 versus 45 %, P = 0.008). In multivariate analyses, taking into consideration all patients for which data on HLA-matching and cell dose transplanted were fully available (n = 363), male patients transplanted with a female UCB had a trend for a higher incidence of grade III–IV acute GVHD (hazard ratio (HR) = 2.0, P = 0.06), a trend for a higher NRM (HR = 1.5, P = 0.06), and a worse LFS (HR = 1.4, P = 0.04) and OS (HR = 1.3, P = 0.06). Conclusions Our data suggest that male patients transplanted with female UCB might have higher risk of acute GVHD and of NRM leading to worse LFS and OS. These results should be confirmed in other large cohorts of patients before used for determining the choice of an UCB unit. Electronic supplementary material The online version of this article (doi:10.1186/s13045-015-0207-4) contains supplementary material, which is available to authorized users.
Published: 2015

32. Human neonatal hepatocyte transplantation induces long-term rescue of unconjugated hyperbilirubinemia in the Gunn rat

Author: Anne Myara, Eugenia Pareja, Laia Tolosa, José V. Castell, María José Gómez-Lechón, Silvia López, María Teresa Donato, Tuan Huy Nguyen, Unidad de Hepatología Experimental [Valencia, Spain], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Unidad de Cirugia Hepatobiliopancreatica y Transplante Hepatico [Valencia, Spain], Hospital La Fe [Valencia, Spain], Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Departamento de Bioquımica y Biologıa Molecular [Valencia, Spain] (Facultad de Medicina), Universidad de Valencia, Service de Biologie [GH Saint-Joseph - APHP], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Funding was provided by the European Union (INNOVALIV, FP7-HEALTH-2011 number 278152) and Generalitat Valenciana(Conselleria de Educacion GV2014/116). Laia Tolosa was a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness., European Project: 278152,HEALTH,FP7-HEALTH-2011-two-stage,INNOVALIV(2011), Hospital Universitari La Fe, Le Bihan, Sylvie, and Innovative strategies to generate human hepatocytes for treatment of metabolic Liver diseases: Tools for personalized cell therapy - INNOVALIV - - HEALTH2011-12-01 - 2014-11-30 - 278152 - VALID
Subjects: Male, medicine.medical_specialty, Glucuronosyltransferase, Bilirubin, medicine.medical_treatment, Rats, Gunn, Liver transplantation, chemistry.chemical_compound, Internal medicine, medicine, Animals, Humans, Progenitor cell, Unconjugated hyperbilirubinemia, Aged, Cell Proliferation, Crigler-Najjar Syndrome, Aged, 80 and over, Transplantation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hepatology, biology, business.industry, Infant, Newborn, Middle Aged, Gunn rat, Propranolol, Liver regeneration, 3. Good health, Liver Regeneration, Endocrinology, chemistry, Liver, Immunology, biology.protein, Hepatocytes, Surgery, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Crigler-Najjar type 1 disease is a rare inherited metabolic disease characterized by high levels of unconjugated bilirubin due to the complete absence of hepatic uridine diphosphoglucuronate-glucuronosyltransferase activity. Hepatocyte transplantation (HT) has been proposed as an alternative treatment for Crigler-Najjar syndrome, but it is still limited by the quality and the low engraftment and repopulation ability of the cells used. Because of their attachment capability and expression of adhesion molecules as well as the higher proportion of hepatic progenitor cells, neonatal hepatocytes may have an advantage over adult cells. Adult or neonatal hepatocytes were transplanted into Gunn rats, a model for Crigler-Najjar disease. Engraftment and repopulation were studied and compared by immunofluorescence (IF). Additionally, the serum bilirubin levels, the presence of bilirubin conjugates in rat serum, and the expression of uridine diphosphate glucuronosyltransferase 1 family polypeptide A1 (UGT1A1) in rat liver samples were also analyzed. Here we show that neonatal HT results in long-term correction in Gunn rats. In comparison with adult cells, neonatal cells showed better engraftment and repopulation capability 3 days and 6 months after transplantation, respectively. Bilirubinemia decreased in the transplanted animals during the whole experimental follow-up (6 months). Bilirubin conjugates were also present in the serum of the transplanted animals. Western blots and IF confirmed the presence and expression of UGT1A1 in the liver. This work is the first to demonstrate the advantage of using neonatal hepatocytes for the treatment of Crigler-Najjar in vivo.
Published: 2014

33. Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa

Author: Marcela Mena, Carmen Ayuso, María González del Pozo, Christina Zeitz, Joaquín Dopazo, Montserrat Baiget, Mai M. Abd El-Aziz, Shomi S. Bhattacharya, José M. Millán, Juan Ignacio Pieras, Karin W. Littink, Salud Borrego, Guillermo Antiñolo, Javier Santoyo, Isabelle Audo, Isabel Barragan, Instituto de Salud Carlos III, Junta de Andalucía, Centro de Investigación Biomédica en Red Enfermedades Raras (España), Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío [Sevilla], Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIBER de Enfermedades Raras (CIBERER), Departamento de Bioinformática y Genómica, Centro de Investigación Principe Felipe, Departamento de Genética, Servei de Genética, Hospital de la Santa Creu i Sant Pau, Unidad de Genética, Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, UCL-Institute of Ophthalmology, Institut de la Vision, 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), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Department of Molecular Genetics, Institute of Ophthalmology, Department of Human Genetics, Radboud University Medical Center [Nijmegen], The Rotterdam Eye Hospital, Celular Therapy and Regenerative Medicine, CABIMER, and Hospital Universitari La Fe
Subjects: Male, DNA Mutational Analysis, medicine.disease_cause, 0302 clinical medicine, EYS, Drosophila Proteins, Copy-number variation, Genetics (clinical), Genetics, 0303 health sciences, Mutation, recurrent mutation, functional domain, Life Sciences, Pedigree, 3. Good health, Retinitis pigmentosa, Female, Retinitis Pigmentosa, Retinal Dystrophies, Spanish population, Recurrent mutation, Molecular Sequence Data, Mutation in Brief, Genes, Recessive, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Functional domain, Evolution, Molecular, 03 medical and health sciences, Genetic variation, medicine, Animals, Humans, Amino Acid Sequence, Eye Proteins, Gene, 030304 developmental biology, Genetic Variation, medicine.disease, Protein Structure, Tertiary, Spain, Structural Homology, Protein, Case-Control Studies, 030221 ophthalmology & optometry, Human genome
Abstract: 29 páginas, 4 figuras, 3 tablas.-- et al., Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene (EYS) encoding an ortholog of Drosophila spacemaker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28) are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain. Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study., This study was funded by PN de I+D+I 2008- 2011, Instituto de Salud Carlos III (ISCIII) -Subdirección General de Evaluación y Fomento de la Investigación, Fondo de Investigación Sanitaria (PI081131), Spain; Consejería de Salud (PI-0334/2007), Consejería de Innovación, Ciencia y Empresa (PI08-CTS-03687), Junta de Andalucía, Spain; El Centro de Investigación Biomédica en Red de Enfermedades Raras is an initiative of the Instituto de Salud Carlos III. J.I. P. was supported by Fondo de Investigación Sanitaria and M. G-dP by Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain. The research of K.W.L. was funded by the Stichting Wetenschappelijk Onderzoek Oogziekenhuis Prof. Dr. H.J. Flieringa, Rotterdam. Contract grant sponsor: Fondo de Investigación Sanitaria, Spain; Consejería de Salud; Consejería de Innovación, Ciencia y Empresa; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER). Contract grant number: PI081131, PI-0334/2007, PI08-CTS-03687
Published: 2010

34. Regenerative cell therapy for the treatment of hyperbilirubinemic Gunn rats with fresh and frozen human induced pluripotent stem cells‐derived hepatic stem cells

Author: Anne Myara, Delphine Garnier, Angélique Fourrier, Frédéric Delbos, Tuan Huy Nguyen, Linh Trinh Thi Thuy, François Petit, Ignacio Anegon, Sophie Laplanche, María José Gómez-Lechón, Philippe Labrune, Séverine Ménoret, Laia Tolosa, Camille Collet, Ludovic Vallier, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN), GoLiver Therapeutics [UNIV Nantes] (Institut de Recherche en Santé), Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Plate-forme de 'transgénèse immunophénomique du rat' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Service de Biologie [GH Saint-Joseph - APHP], Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de génétique moléculaire [Hôpital Antoine Béclère - APHP], AP-HP - Hôpital Antoine Béclère [Clamart], Unidad de Hepatología Experimental [Valencia, Spain], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique [Hôpital Antoine Béclère - APHP (CRMR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge [UK] (CAM), 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), European Union, Grant/Award Number: 278152, IHU‐Cesti, Grant/Award Number: ANR-10-IBHU-005, French Agence Nationale pour la Recherche, Grant/Award Number: ANR-14-CE16-0026-StemHepTher, Labex IGO, Grant/Award Number: ANR-11-LABX-0016-01, ERC, ANR-10-IBHU-0005,CESTI (TSI-IHU),Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU)(2010), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), ANR-14-CE16-0026,StemHepTher,Validation pré-clinique des hépatocytes dérivés de cellules souches pluripotentes pour la biothérapie hépatique(2014), European Project: 278152,HEALTH,FP7-HEALTH-2011-two-stage,INNOVALIV(2011), Vallier, Ludovic [0000-0002-3848-2602], Apollo - University of Cambridge Repository, Hospital Universitari La Fe, 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), Le Bihan, Sylvie, Instituts Hospitalo-Universitaires B - Centre Européen des Sciences de la Transplantation et de l'Immunothérapie (TSI-IHU) - - CESTI (TSI-IHU)2010 - ANR-10-IBHU-0005 - IBHU - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Appel à projets générique - Validation pré-clinique des hépatocytes dérivés de cellules souches pluripotentes pour la biothérapie hépatique - - StemHepTher2014 - ANR-14-CE16-0026 - Appel à projets générique - VALID, and Innovative strategies to generate human hepatocytes for treatment of metabolic Liver diseases: Tools for personalized cell therapy - INNOVALIV - - HEALTH2011-12-01 - 2014-11-30 - 278152 - VALID
Subjects: 0301 basic medicine, induced pluripotent stem cells, [SDV]Life Sciences [q-bio], Rats, Gunn, Transplantation, Heterologous, Immunology, Cell- and Tissue-Based Therapy, regenerative medicine, 030230 surgery, Biology, Regenerative medicine, Cell therapy, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, In vivo, Animals, Humans, Induced pluripotent stem cell, Cells, Cultured, Hyperbilirubinemia, Cryopreservation, Transplantation, Matrigel, Crigler-Najjar syndrome, Gunn rats, Cell Differentiation, Rats, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, Liver, Hepatocytes, Hepatic stellate cell, Stem cell, hepatocyte-like cells, Stem Cell Transplantation
Abstract: International audience; Pluripotent stem cells have been investigated as a renewable source of therapeutic hepatic cells, in order to overcome the lack of transplantable donor hepatocytes. Whereas different studies were able to correct hepatic defects in animal models, they focused on the most mature phenotype of hepatocyte-like cells (HLCs) derived from pluripotent stem cells and needed freshly prepared cells, which limits clinical applications of HLCs. Here, we report the production of hepatic stem cells (pHSCs) from human-induced pluripotent stem cells (hiPSCs) in xeno-free, feeder-free, and chemically defined conditions using as extracellular matrix a recombinant laminin instead of Matrigel, an undefined animal-derived matrix. Freshly prepared and frozen pHSCs were transplanted via splenic injection in Gunn rats, the animal model for Crigler-Najjar syndrome. Following cell transplantation and daily immunosuppression treatment, bilirubinemia was significantly decreased (around 30% decrease, P < .05) and remained stable throughout the 6-month study. The transplanted pHSCs underwent maturation in vivo to restore the deficient metabolic hepatic function (bilirubin glucuronidation by UGT1A1). In conclusion, we demonstrate for the first time the differentiation of hiPSCs into pHSCs that (a) are produced using a differentiation protocol compatible with Good Manufacturing Practices, (b) can be frozen, and (c) are sufficient to demonstrate in vivo therapeutic efficacy to significantly lower hyperbilirubinemia in a model of inherited liver disease, despite their immature phenotype. Thus, our approach provides major advances toward future clinical applications and would facilitate cell therapy manufacturing from human pluripotent stem cells.
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35. The association between dermoscopic features and BRAF mutational status in cutaneous melanoma: Significance of the blue-white veil.

Author: Armengot-Carbó M, Nagore E, García-Casado Z, and Botella-Estrada R
Subjects: Adult, Aged, Confidence Intervals, Cross-Sectional Studies, DNA Mutational Analysis, Dermoscopy, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Odds Ratio, Predictive Value of Tests, Prognosis, Prospective Studies, Proto-Oncogene Mas, Risk Assessment, Melanoma diagnosis, Melanoma genetics, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms diagnosis, Skin Neoplasms genetics
Abstract: Background: The genetic basis of melanoma affects its clinicopathologic characteristics and increasingly influences its management. B-Raf proto-oncogene, serine/threonine kinase gene (BRAF)-mutated melanoma may present with specific dermoscopic features., Objectives: To identify the dermoscopic features associated with BRAF mutation in cutaneous melanoma and to evaluate a model capable of predicting BRAF mutations on the basis of dermoscopic and clinicopathologic features that are easily accessible in normal clinical practice., Methods: A prospective, cross-sectional, observational, and descriptive study was performed. A total of 93 cutaneous melanomas with dermoscopic images from 93 patients were included. BRAF mutational status was determined by genetic analysis using 2 methods: cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems, Pleasanton, CA) and Sanger sequencing. Clinicopathologic data were collected; dermoscopic images were analyzed by 2 independent blind observers., Results: Blue-white veil in dermoscopy was significantly associated with BRAF mutations (odds ratio, 4.3; 95% confidence interval, 1.6-11.5; P = .003). Patients with BRAF-mutated melanomas were significantly younger than those with wild-type melanomas (odds ratio, 0.96; 95% confidence interval, 0.93-0.99; P = .008). On the basis of these 2 variables, it was possible to predict BRAF mutational status in melanoma with 73% accuracy., Limitations: Histologic data were obtained from pathology reports. The accuracy of the predictive model has not been tested with a new data set., Conclusions: Blue-white veil in dermoscopy is associated with BRAF mutations in cutaneous melanoma., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)
Published: 2018
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35 results on '"Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe"'

1. Comparative outcomes of extracorporeal membrane oxygenation for COVID-19 delivered in experienced European centres during successive SARS-CoV-2 variant outbreaks (ECMO-SURGES): an international, multicentre, retrospective cohort study

2. PECATI: A Multicentric, Open-Label, Single-Arm Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab and Lenvatinib in Pretreated B3-Thymoma and Thymic Carcinoma Patients

3. An ESPGHAN Position Paper on the Use of Low-FODMAP Diet in Pediatric Gastroenterology

4. First-line Nivolumab + Ipilimumab + Chemo in Patients With Advanced NSCLC and Brain Metastases: Results From CheckMate 9LA

5. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update

6. Liver transplantation for patients with acute-on-chronic liver failure (ACLF) in Europe: Results of the ELITA/EF-CLIF collaborative study (ECLIS)

7. Lactobacillus supports Clostridiales to restrict gut colonization by multidrug-resistant Enterobacteriaceae

8. An ESPGHAN Position Paper on the Use of Breath Testing in Paediatric Gastroenterology

9. Drug clearance in neonates : a combination of population pharmacokinetic modelling and machine learning approaches to improve individual prediction

10. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA

11. Drugs in Focus: The Use of Racecadotril in Paediatric Gastrointestinal Disease

12. A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials

13. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial

14. Haploinsufficiency of the Sin3/HDAC corepressor complex member SIN3B causes a syndromic intellectual disability/autism spectrum disorder

15. Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids

16. Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells

17. Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants

18. Detection of plasmid-mediated colistin resistance, mcr-1 gene, in Escherichia coli isolated from high-risk patients with acute leukemia in Spain

19. Low-density lipoprotein receptor-deficient hepatocytes differentiated from induced pluripotent stem cells allow familial hypercholesterolemia modeling, CRISPR/Cas-mediated genetic correction, and productive hepatitis C virus infection

20. Challenges in Clinical Metaproteomics Highlighted by the Analysis of Acute Leukemia Patients with Gut Colonization by Multidrug-Resistant Enterobacteriaceae

21. Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey

22. J Acquir Immune Defic Syndr

23. Single- or double-unit UCBT following RIC in adults with AL: a report from Eurocord, the ALWP and the CTIWP of the EBMT

24. RENEB–Running the European Network of biological dosimetry and physical retrospective dosimetry

25. RENEB accident simulation exercise

26. Capabilities of the RENEB network for research and large scale radiological and nuclear emergency situations

27. Web based scoring is useful for validation and harmonisation of scoring criteria within RENEB

28. Integration of new biological and physical retrospective dosimetry methods into EU emergency response plans - joint RENEB and EURADOS inter-laboratory comparisons

29. Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

30. Transplantation of hESC-derived hepatocytes protects mice from liver injury

32. Human neonatal hepatocyte transplantation induces long-term rescue of unconjugated hyperbilirubinemia in the Gunn rat

33. Mutation spectrum of EYS in Spanish patients with autosomal recessive retinitis pigmentosa

34. Regenerative cell therapy for the treatment of hyperbilirubinemic Gunn rats with fresh and frozen human induced pluripotent stem cells‐derived hepatic stem cells

35. The association between dermoscopic features and BRAF mutational status in cutaneous melanoma: Significance of the blue-white veil.

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