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1. Inducible deletion of skeletal muscle AMPKℵ 1 reveals that AMPK is required for nucleotide balance but 2 dispensable for muscle glucose uptake and fat oxidation during exercise

Author

Hingst, Janne, Kjøbsted, Rasmus, Birk, Jesper, Jørgensen, Nicolas, Larsen, Magnus, Kido, Kohei, Larsen, Jeppe, Kjeldsen, Sasha, Fentz, Joachim, Frøsig, Christian, Holm, Stephanie, Fritzen, Andreas, Dohlmann, Tine, Larsen, Steen, Foretz, Marc, Viollet, Benoit, Schjerling, Peter, Overby, Peter, Halling, Jens, Pilegaard, Henriette, Helsten, Ylva, Wojtaszewski, Jørgen, Viollet, Benoit, University of Copenhagen = Københavns Universitet (UCPH), Department of Nutrition, Exercise and Sports [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Medical University of Białystok (MUB), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Copenhagen = Københavns Universitet (KU), University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Medical University of Bialystok [Bialystok, Pologne], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
AMPK, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, exercise, glycogen, muscle metabolism, fat oxidation, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, glucose uptake
Abstract

International audience; Objective: Current evidence for AMPK-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to chronic lack of AMPK function. In an attempt to study the direct effect(s) of AMPK on muscle metabolism during exercise, we generated a new mouse model with inducible muscle-specific deletion of AMPKα catalytic subunits in adult mice.Methods: Tamoxifen-inducible and muscle-specific AMPKα1/α2 double KO mice (AMPKα imdKO) were generated using the Cre/loxP system with the Cre driven by the human skeletal muscle actin (HSA) promotor.Results: During treadmill running at the same relative exercise intensity, AMPKα imdKO mice showed greater depletion of muscle ATP, which was associated with accumulation of the deamination product IMP. Muscle-specific deletion of AMPKα in adult mice promptly reduced maximal running speed, muscle glycogen content and was associated with reduced expression of UGP2, a key component of the glycogen synthesis pathway. Muscle mitochondrial respiration, whole body substrate utilization as well as muscle glucose uptake and fatty acid (FA) oxidation during muscle contractile activity remained unaffected by muscle-specific deletion AMPKα subunits in adult mice.Conclusions: Inducible deletion of AMPKα subunits in adult mice reveals that AMPK is required for maintaining muscle ATP levels and nucleotide balance during exercise, but is dispensable for regulating muscle glucose uptake, FA oxidation and substrate utilization during exercise.

Published
2020

2. A 300 IR sublingual tablet is an effective, safe treatment for house dust mite-induced allergic rhinitis: An international, double-blind, placebo-controlled, randomized phase III clinical trial

Author

Krzysztof Kowal, Peter S. Creticos, Margitta Worm, Philippe Gevaert, Pascal Demoly, Frédéric de Blay, N. Nenasheva, Oliver Pfaar, Miguel Tortajada-Girbés, Carmen Vidal, Jonathan Corren, Thomas B. Casale, Giovanni Passalacqua, Peter Hellings, Martine Le Gall, Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Université de Montpellier (UM), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Johns Hopkins University School of Medicine [Baltimore], CHU Strasbourg, Universiteit Gent = Ghent University [Belgium] (UGENT), University Hospitals Leuven [Leuven], Medical University of Bialystok [Bialystok, Pologne], Stallergenes SA (Stallergenes), Stallergenes, Ospedale Policlinico San Martino [Genoa], University of Genoa (UNIGE), Philipps Universität Marburg, Dr Peset University Hospital, Universitat de València (UV), Complejo Hospitalario Universitario de Santiago de Compostela [Saint-Jacques-de-Compostelle, Espagne] (CHUS), Universidade de Santiago de Compostela [Spain] (USC ), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of South Florida [Tampa] (USF), Ear, Nose and Throat, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Epidemiology of Allergic and Respiratory Diseases Department [iPlesp] (EPAR), 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), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of California (UC), Universiteit Gent = Ghent University (UGENT), Medical University of Białystok (MUB), Ministry of Health of the Russian Federation (MHRF), Università degli studi di Genova = University of Genoa (UniGe), Philipps Universität Marburg = Philipps University of Marburg, and CERRAMON, Laura

Subjects
0301 basic medicine, Allergen immunotherapy, allergic rhinitis, allergy, house-dust mite, medication score, sublingual immunotherapy, symptom score, tablet, total combined score, Male, Allergy, International Cooperation, Severity of Illness Index, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Clinical endpoint, Immunology and Allergy, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, house dust mite, biology, Pyroglyphidae, 3. Good health, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology, Adult, medicine.medical_specialty, Adolescent, Drug-Related Side Effects and Adverse Reactions, Immunology, Placebo, 03 medical and health sciences, Young Adult, Double-Blind Method, Internal medicine, medicine, Animals, Humans, Antigens, Dermatophagoides, Asthma, House dust mite, Sublingual Immunotherapy, business.industry, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, biology.organism_classification, Placebo Effect, Rhinitis, Allergic, Clinical trial, 030104 developmental biology, 030228 respiratory system, Quality of Life, business
Abstract

Background: Allergic rhinitis induced by house dust mites (HDMs) is a highly prevalent but often underdiagnosed and undertreated/untreated chronic disease. It often has a negative impact on sleep, work, leisure activities, and health-related quality of life. Allergen immunotherapy is a proven, safe treatment for respiratory allergies. Objective: We sought to assess the efficacy and safety of a 300 index of reactivity (IR) sublingual tablet formulation of Dermatophagoides pteronyssinus:Dermatophagoides farinae 1:1 extract in adolescents (aged >_12) and adults with moderate to severe HDM-induced allergic rhinitis. Methods: In a phase III, international, double-blind, placebo controlled, randomized clinical trial, participants received approximately 12 months of treatment with placebo or the 300 IR tablet. The primary end point was the average total combined score during 4 weeks at the end of the treatment period. Results: A total of 1607 participants were randomized, and 1476 (including 555 [37.6%] with concomitant mild controlled asthma at inclusion) comprised the full analysis set. Over the primary evaluation period, the least squares mean average total combined score in the 300 IR group (3.62) was significantly lower (P Superscript/Subscript Available

Published
2019

3. Advantages and disadvantages of the use of the CSF Amyloid β (Aβ) 42/40 ratio in the diagnosis of Alzheimer’s Disease

Author

Markus Otto, Henrik Zetterberg, Piotr Lewczuk, Oskar Hansson, Sylvain Lehmann, Clinical Memory Research Unit [Malmö, Suède], Department of Clinical Sciences [Malmö, Suède], Lund University [Malmö, Suède]-Lund University [Malmö, Suède], Memory Clinic [Malmö, Suède], Skåne University Hospital [Malmö, Suède], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Neurology [Ulm, Allemagne], Universität Ulm - Ulm University [Ulm, Allemagne], Clinical Neurochemistry Laboratory [Göteborg, Suède], Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Neurodegenerative Disease [Londres, Royaume-Uni], Institute of Neurology [London], University College of London [London] (UCL)-University College of London [London] (UCL), UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Department of Psychiatry and Psychotherapy [Erlangen, Allemagne], Universitätsklinikum Erlangen [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Department of Neurodegeneration Diagnostics [Bialystok, Pologne], Medical University of Bialystok [Bialystok, Pologne], Lab for Clinical Neurochemistry and Neurochemical Dementia Diagnostics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Friedrich-Alexander Universität Erlangen-Nürnberg (FAU)-Universitätsklinikum Erlangen [Erlangen, Allemagne], Fujirebio Europe sponsored this paper, however, it had no influence on its factual content. PL was supported by the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement n° 115372, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution. OH has acquired research support (for the institution) from Roche, GE Healthcare, Biogen, AVID Radiopharmaceuticals, Fujirebio and Euroimmun. HZ’s research is supported by the Swedish Research Council, the European Research Council, the Knut and Alice Wallenberg Foundation, the Olav Thon Foundation, the UK Dementia Research Institute at UCL and Swedish State Support for Clinical Research (ALFGBG)., Lund University [Lund]-Lund University [Lund], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Medical University of Białystok (MUB), and Bodescot, Myriam

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Neurology, Amyloid β, Cognitive Neuroscience, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Diagnostic accuracy, Disease, Review, Aβ 42/40 ratio, Alzheimer's Disease, lcsh:RC346-429, lcsh:RC321-571, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medizinische Fakultät, Alzheimer Disease, Internal medicine, medicine, Dementia, Humans, ddc:610, Alzheimer’s Disease, Cognitive impairment, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Biochemical markers, lcsh:Neurology. Diseases of the nervous system, Cerebrospinal Fluid, Amyloid beta-Peptides, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Peptide Fragments, 030104 developmental biology, Aβ42/40 ratio, Neurology (clinical), business, 030217 neurology & neurosurgery, Amyloidβ Peptides, Biomarkers
Abstract

International audience; The cerebrospinal fluid (CSF) biochemical markers (biomarkers) Amyloidβ 42 (Aβ42), total Tau (T-tau) and Tau phosphorylated at threonine 181 (P-tau181) have proven diagnostic accuracy for mild cognitive impairment and dementia due to Alzheimer's Disease (AD). In an effort to improve the accuracy of an AD diagnosis, it is important to be able to distinguish between AD and other types of dementia (non-AD). The concentration ratio of Aβ42 to Aβ40 (Aβ42/40 Ratio) has been suggested to be superior to the concentration of Aβ42 alone when identifying patients with AD. This article reviews the available evidence on the use of the CSF Aβ42/40 ratio in the diagnosis of AD. Based on the body of evidence presented herein, it is the conclusion of the current working group that the CSF Aβ42/40 ratio, rather than the absolute value of CSF Aβ42, should be used when analysing CSF AD biomarkers to improve the percentage of appropriately diagnosed patients.

Published
2019

4. Real-world safety and effectiveness of ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin in hepatitis C virus genotype 1- and 4-infected patients with diverse comorbidities and comedications: A pooled analysis of post-marketing observational studies from 13 countries

Author

Mariem Charafeddine, Henning Kleine, Peter Ferenci, David Back, Suzanne Norris, Dominique Larrey, Eric Crown, Robert Flisiak, Manuela Curescu, Patrick K. Dorr, Suzanne Bourgeois, Mark Bondin, Peter Buggisch, Fiona Marra, Dept of internal medicine III, Medizinische Universität Wien = Medical University of Vienna, ZNA Stuivenberg, Institute for Interdisciplinary Medicine Hamburg, Department of Hepatology, St. James's Hospital, West University of Timișoara [Roumanie] (WUT), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University of Liverpool, AbbVie Deutschland GmbH & Co KG, Abbott GmbH & Co KG, Abbvie Inc. [North Chicago], Medical University of Bialystok [Bialystok, Pologne], and Funding informationAbbVie

Subjects
Cyclopropanes, Male, hepatitis C virus, Internationality, Sustained Virologic Response, [SDV]Life Sciences [q-bio], Hepacivirus, chemistry.chemical_compound, 0302 clinical medicine, drug‐drug interaction, 2-Naphthylamine, Anilides, Drug Interactions, 030212 general & internal medicine, Prospective Studies, Aged, 80 and over, education.field_of_study, Sulfonamides, Dasabuvir, Valine, real‐world evidence, Middle Aged, 3. Good health, comorbidity, Infectious Diseases, Tolerability, 030211 gastroenterology & hepatology, Drug Therapy, Combination, Female, Original Article, medicine.drug, Adult, medicine.medical_specialty, Macrocyclic Compounds, direct‐acting antiviral, Adolescent, Genotype, Proline, Lactams, Macrocyclic, Population, Antiviral Agents, 03 medical and health sciences, Young Adult, Virology, Internal medicine, Ribavirin, medicine, Humans, real-world evidence, education, Uracil, Aged, direct-acting antiviral, Ritonavir, Hepatology, business.industry, Original Articles, Hepatitis C, Chronic, Ombitasvir, Discontinuation, chemistry, Paritaprevir, Carbamates, business, drug-drug interaction
Abstract

International audience; Ombitasvir/paritaprevir/ritonavir ± dasabuvir ± ribavirin (OBV/PTV/r ± DSV ± RBV) regimens show high efficacy and good tolerability in clinical trials for chronic hepatitis C virus (HCV) genotypes (GT) 1 or 4. To evaluate whether these results translate to clinical practice, data were pooled from observational studies across 13 countries. Treatment‐naïve or ‐experienced patients, with or without cirrhosis, received OBV/PTV/r ± DSV ± RBV according to approved local labels and clinical practice. Sustained virologic response at post‐treatment Week 12 (SVR12), adverse events (AEs) and comedication management were assessed for patients initiating treatment before 1 June 2017. The safety population included 3850 patients who received ≥1 dose of study drug. The core population (N = 3808) further excluded patients with unknown GT or cirrhosis status, or who received off‐label treatment. Patients had HCV GT1a (n = 732; 19%), GT1b (n = 2619; 69%) or GT4 (n = 457; 12%). In 3546 patients with sufficient follow‐up data at post‐treatment Week 12, the SVR12 rate was 96% (n/N = 3401/3546 [95% CI 95.2‐96.5]). In patients with or without cirrhosis, SVR12 was comparable (96%). In patients with HCV GT1a, GT1b or GT4, SVR12 rates were 93%, 97% and 94%. In GT1b‐infected patients with planned treatment for 8 weeks, SVR12 was 96%. In patients with ≥1 comorbidity (67%), SVR12 was 95%. 58% of patients received ≥1 comedication, and there was minimal impact on SVR12 rates using comedications for peptic ulcers and gastro‐esophageal reflux disease, statins, antipsychotics or antiepileptics. Most comedications were maintained during treatment although 58% of patients changed their statin medication. AEs and serious AEs occurred in 26% and 3% of patients. Post‐baseline Grade 3‐4 laboratory abnormalities were rare (

Published
2018

5. Tumor stiffening reversion through collagen crosslinking inhibition improves T cell migration and anti-PD-1 treatment

Author

Alba Nicolas-Boluda, Javier Vaquero, Lene Vimeux, Thomas Guilbert, Sarah Barrin, Chahrazade Kantari-Mimoun, Matteo Ponzo, Gilles Renault, Piotr Deptula, Katarzyna Pogoda, Robert Bucki, Ilaria Cascone, José Courty, Laura Fouassier, Florence Gazeau, Emmanuel Donnadieu, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Matière et Systèmes Complexes (MSC (UMR_7057)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Bellvitge Biomedical Research Institute IDIBELL [Barcelona, Spain], Laboratoire de Physique des Plasmas (LPP), Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École polytechnique (X)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Croissance cellulaire, réparation et régénération tissulaires (CRRET), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Medical University of Białystok (MUB), Institute of Physics, Polish Academy of Sciences, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Courty, José, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CNRS UMR 7057 - Laboratoire Matières et Systèmes Complexes (MSC) (MSC), Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Medical University of Bialystok [Bialystok, Pologne], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)

Subjects
tumor, Mouse, cell migration, QH301-705.5, T-Lymphocytes, extracellular matrix, Science, Programmed Cell Death 1 Receptor, T lymphocytes, Immunoteràpia, T cells, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Cell Physiological Phenomena, Protein-Lysine 6-Oxidase, Mice, stiffness, Cell Movement, Tumor Microenvironment, Animals, Biology (General), Càncer, Immune Checkpoint Inhibitors, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Cancer Biology, Cancer, Neoplasms, Experimental, Mice, Inbred C57BL, Cèl·lules T, Medicine, Female, Collagen, immunotherapy, Immunotherapy, Research Article
Abstract

International audience; Only a fraction of cancer patients benefits from immune checkpoint inhibitors. This may be partly due to the dense extracellular matrix (ECM) that forms a barrier for T cells. Comparing five preclinical mouse tumor models with heterogeneous tumor microenvironments, we aimed to relate the rate of tumor stiffening with the remodeling of ECM architecture and to determine how these features affect intratumoral T cell migration. An ECM-targeted strategy, based on the inhibition of lysyl oxidase, was used. In vivo stiffness measurements were found to be strongly correlated with tumor growth and ECM crosslinking but negatively correlated with T cell migration. Interfering with collagen stabilization reduces ECM content and tumor stiffness leading to improved T cell migration and increased efficacy of anti-PD-1 blockade. This study highlights the rationale of mechanical characterizations in solid tumors to understand resistance to immunotherapy and of combining treatment strategies targeting the ECM with anti-PD-1 therapy.

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