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5,268 results on '"Heidelberg University Hospital [Heidelberg]"'

1. Perturbation-Based Treadmill Training to Prevent Unrecovered Falls in Geriatric Patients (TRAIL)

Author: Marienhospital Herne, University of Ulm, University of Konstanz, University Hospital RWTH Aachen University, Aachen, Germany., Robert Bosch-Krankenhaus Stuttgart, Heidelberg University Hospital, Heidelberg, Germany, and Prof. Dr. med. Tania Zieschang, Prof. Dr. med.
Published: 2024

2. Silent Brain Infarction After Endovascular Arch Procedures

Author: Fondation Hôpital Saint-Joseph, Universitätsklinikum Hamburg-Eppendorf, Vascular Surgical Research Group, Imperial College, London, UK, Sanger Heart and Vascular Institute, Charlotte, NC, Loyola University Medical Center, Maywood, IL, UAB School of Medicine, Birmingham, AL, Heidelberg University Hospital, Heidelberg, Germany, University Hospital of Freiburg, Freiburg, Germany, Stanford University, Massachusetts General Hospital, Baylor Research Hospital, Dallas, TX, Emory University Hospital, Atlanta, GA, University Hospital of Mainz, Mainz, Germany, Diakonie Hospital Jung-Stilling, Siegen, Germany, Mayo Clinic, Rochester, MN, Sentara Vascular/Eastern Virginia Medical School, Norfolk, VA, Maastricht University Medical Centre, Maastricht, Netherlands, I.R.C.C.S. Policlinico San Donato, San Donato Milanese, Italy, Memorial Care Long Beach Heart & Vascular Institute, Long Beach, CA, and Wolf Eilenberg, Professor Stephan Haulon, Proessor Tilo Kölbel
Published: 2020

3. Combined Targeting of Pathogenetic Mechanisms in Pancreatic Neuroendocrine Tumors Elicits Synergistic Antitumor Effects

Author: Gulde, Sebastian, Foscarini, Alessia, April-Monn, Simon L, Genio, Edoardo, Marangelo, Alessandro, Satam, Swapna, Helbling, Daniel, Falconi, Massimo, Toledo, Rodrigo A, Schrader, Jörg, Perren, Aurel, Marinoni, Ilaria, Pellegata, Natalia S, Institut Català de la Salut, [Gulde S, Satam S] Institute for Diabetes and Cancer, Helmholtz Zentrum München, Neuherberg, Germany. Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany. [Foscarini A, Genio E, Marangelo A] Institute for Diabetes and Cancer, Helmholtz Zentrum München, Neuherberg, Germany. Joint Heidelberg-IDC Translational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany. Department of Biology and Biotechnology 'L. Spallanzani', University of Pavia, Pavia, Italy. [April-Monn SL] Institute of Pathology, University of Bern, Bern, Switzerland. [Toledo RA] Gastrointestinal and Endocrine Tumors, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Cancer Research, neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::tumores neuroendocrinos [ENFERMEDADES], Therapeutics::Drug Therapy::Drug Therapy, Combination [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Medicaments antineoplàstics - Ús terapèutic, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antineoplásicos [COMPUESTOS QUÍMICOS Y DROGAS], 610 Medicine & health, Tumors neuroendocrins - Tractament, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Quimioteràpia combinada, Oncology, Buparlisib, Combination Therapy, Pancreatic Nets, Primary Human Tumoroids, Ribociclib, pancreatic NETs, buparlisib, ribociclib, combination therapy, primary human tumoroids, Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neuroendocrine Tumors [DISEASES], terapéutica::farmacoterapia::farmacoterapia combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], 570 Life sciences, biology, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents [CHEMICALS AND DRUGS], 610 Medizin und Gesundheit, 570 Biowissenschaften, Biologie
Abstract: Buparlisib; Combination therapy; Primary human tumoroids Buparlisib; Terapia de combinación; Tumoroides humanos primarios Buparlisib; Teràpia combinada; Tumoroides humans primaris Pancreatic neuroendocrine neoplasms (PanNENs) are the second most common malignancy of the pancreas. Surgery remains the only curative treatment for localized disease. For patients with inoperable advanced or metastatic disease, few targeted therapies are available, but their efficacy is unpredictable and variable. Exploiting prior knowledge on pathogenetic processes involved in PanNEN tumorigenesis, we tested buparlisib (PI3K inhibitor) and ribociclib (CDK4/6 inhibitor), as single agents or in combination, in different preclinical models. First, we used cell lines representative of well-differentiated (INS-1E, NT-3) and poorly differentiated (BON-1) PanNENs. The combination of buparlisib with ribociclib reduced the proliferation of 2D and 3D spheroid cultures more potently than the individual drugs. Buparlisib, but not ribociclib, induced apoptosis. The anti-proliferative activity of the drugs correlated with downstream target inhibition at mRNA and protein levels. We then tested the drugs on primary islet microtissues from a genetic PanNET animal model (Men1-defective mice) and from wild-type mice: the drug combination was effective against the former without altering islet cell physiology. Finally, we treated PanNET patient-derived islet-like 3D tumoroids: the combination of buparlisib with ribociclib was effective in three out of four samples. Combined targeting of PI3K and CDK4/6 is a promising strategy for PanNENs spanning various molecular and histo-pathological features. This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft-DFG) within the CRC/Transregio 205/2, project number 314061271-TRR 205 (to NSP); and by the Deutsche Krebshilfe (# 70113629 to NSP). Ilaria Marinoni was supported by Wilhelm Sander Stiftung (# 2017.073.2). Aurel Perren was supported by the Swiss Cancer Research Foundation (KFS-4227-08-2017).
Published: 2022
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4. Cellular development and evolution of the mammalian cerebellum

Author: Mari Sepp, Kevin Leiss, Ioannis Sarropoulos, Florent Murat, Konstantin Okonechnikov, Piyush Joshi, Evgeny Leushkin, Noe Mbengue, Céline Schneider, Julia Schmidt, Nils Trost, Lisa Spänig, Peter Giere, Philipp Khaitovich, Steven Lisgo, Miklós Palkovits, Lena M. Kutscher, Simon Anders, Margarida Cardoso-Moreira, Stefan M. Pfister, Henrik Kaessmann, Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany] (ZMBH), Universität Heidelberg [Heidelberg], Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), German Cancer Consortium [Heidelberg] (DKTK), Museum für Naturkunde [Berlin], Humboldt University of Berlin, Skolkovo Institute of Science and Technology [Moscow] (Skoltech), Semmelweis University [Budapest], Bioquant, The Francis Crick Institute [London], and Heidelberg University Hospital [Heidelberg]
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, nervous system, [SDV]Life Sciences [q-bio], Neocortex, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The expansion of the neocortex, one of the hallmarks of mammalian evolution1,2, was accompanied by an increase in the number of cerebellar neurons3. However, little is known about the evolution of the cellular programs underlying cerebellum development in mammals. In this study, we generated single-nucleus RNA-sequencing data for ∼400,000 cells to trace the development of the cerebellum from early neurogenesis to adulthood in human, mouse, and the marsupial opossum. Our cross-species analyses revealed that the cellular composition and differentiation dynamics throughout cerebellum development are largely conserved, except for human Purkinje cells. Global transcriptome profiles, conserved cell state markers, and gene expression trajectories across neuronal differentiation show that the cerebellar cell type-defining programs have been overall preserved for at least 160 million years. However, we also discovered differences. We identified 3,586 genes that either gained or lost expression in cerebellar cells in one of the species, and 541 genes that evolved new expression trajectories during neuronal differentiation. The potential functional relevance of these cross-species differences is highlighted by the diverged expression patterns of several human disease-associated genes. Altogether, our study reveals shared and lineage-specific programs governing the cellular development of the mammalian cerebellum, and expands our understanding of the evolution of mammalian organ development.
Published: 2021

5. Mapping pediatric brain tumors to their origins in the developing cerebellum

Author: Konstantin Okonechnikov, Piyush Joshi, Mari Sepp, Kevin Leiss, Ioannis Sarropoulos, Florent Murat, Martin Sill, Pengbo Beck, Kenneth Chun-Ho Chan, Andrey Korshunov, Felix Sahm, Maximilian Y. Deng, Dominik Sturm, John DeSisto, Andrew M. Donson, Nicholas K. Foreman, Adam L. Green, Giles Robinson, Brent A. Orr, Qingsong Gao, Emily Darrow, Jennifer L. Hadley, Paul A. Northcott, Johannes Gojo, Marina Ryzhova, Daisuke Kawauchi, Volker Hovestadt, Mariella G. Filbin, Andreas von Deimling, Marc Zuckermann, Kristian W. Pajtler, Marcel Kool, David T.W. Jones, Natalie Jäger, Lena M. Kutscher, Henrik Kaessmann, Stefan M. Pfister, Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), German Cancer Consortium [Heidelberg] (DKTK), Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany] (ZMBH), Universität Heidelberg [Heidelberg], Heidelberg University Hospital [Heidelberg], University of Colorado School of Medicine, Children’s Hospital Colorado, University of Colorado Anschutz [Aurora], St Jude Children's Research Hospital, Medizinische Universität Wien = Medical University of Vienna, NN Burdenko Neurosurgical Institute (NNBNI), National Institute of Neuroscience (NCNP), Dana-Farber Cancer Institute [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], and Princess Máxima Center for Pediatric Oncology [Utrecht, Pays-Bas]
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV]Life Sciences [q-bio], 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Understanding the cellular origins of childhood brain tumors is key for discovering novel tumor-specific therapeutic targets. Previous strategies mapping cellular origins typically involved comparing human tumors to murine embryonal tissues1,2, a potentially imperfect approach due to spatio-temporal gene expression differences between species3. Here we use an unprecedented single-nucleus atlas of the developing human cerebellum (Sepp, Leiss, et al) and extensive bulk and single-cell transcriptome tumor data to map their cellular origins with focus on three most common pediatric brain tumors – pilocytic astrocytoma, ependymoma, and medulloblastoma. Using custom bioinformatics approaches, we postulate the astroglial and glial lineages as the origins for posterior fossa ependymomas and radiation-induced gliomas (secondary tumors after medulloblastoma treatment), respectively. Moreover, we confirm that SHH, Group3 and Group4 medulloblastomas stem from granule cell/unipolar brush cell lineages, whereas we propose pilocytic astrocytoma to originate from the oligodendrocyte lineage. We also identify genes shared between the cerebellar lineage of origin and corresponding tumors, and genes that are tumor specific; both gene sets represent promising therapeutic targets. As a common feature among most cerebellar tumors, we observed compositional heterogeneity in terms of similarity to normal cells, suggesting that tumors arise from or differentiate into multiple points along the cerebellar “lineage of origin”.
Published: 2021

6. Unraveling Ewing Sarcoma Tumorigenesis Originating from Patient-Derived Mesenchymal Stem Cells

Author: Patrick Revy, Thomas G. P. Grunewald, Sandrine Grossetête, Mark J. Tomishima, Anna Sole, Isabelle Janoueix-Lerosey, Benjamin Renouf, Erika Brunet, Cécile Pierre-Eugène, Maxime Heintzé, Sophie Kaltenbach, Maria Jasin, Anne De Cian, Loelia Babin, Sakina Zaidi, Didier Surdez, Carine Giovannangeli, Olivier Delattre, Lucile Couronné, University of Zurich, Surdez, Didier, Brunet, Erika, Giovannangeli, Carine, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Memorial Sloane Kettering Cancer Center [New York], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], Heidelberg University Hospital [Heidelberg], Heidelberg University, and Universität Zürich [Zürich] = University of Zurich (UZH)
Subjects: Cancer Research, [SDV]Life Sciences [q-bio], medicine.disease_cause, Translocation, Genetic, Mice, 0302 clinical medicine, CDKN2A, 1306 Cancer Research, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, In Situ Hybridization, Fluorescence, Gene Editing, Gene Rearrangement, 0303 health sciences, Chromoplexy, [SDV] Life Sciences [q-bio], Cell Transformation, Neoplastic, Oncology, 030220 oncology & carcinogenesis, FLI1, Gene Targeting, Heterografts, 10046 Balgrist University Hospital, Swiss Spinal Cord Injury Center, 2730 Oncology, Sarcoma, Disease Susceptibility, 610 Medicine & health, Sarcoma, Ewing, Biology, Article, Immunophenotyping, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Epigenetics, 030304 developmental biology, Gene Expression Profiling, Mesenchymal stem cell, fungi, Computational Biology, Mesenchymal Stem Cells, medicine.disease, Disease Models, Animal, Mutation, Cancer research, CRISPR-Cas Systems, Carcinogenesis, Immortalised cell line, Biomarkers
Abstract: Ewing sarcoma is characterized by pathognomonic translocations, most frequently fusing EWSR1 with FLI1. An estimated 30% of Ewing sarcoma tumors also display genetic alterations in STAG2, TP53, or CDKN2A (SPC). Numerous attempts to develop relevant Ewing sarcoma models from primary human cells have been unsuccessful in faithfully recapitulating the phenotypic, transcriptomic, and epigenetic features of Ewing sarcoma. In this study, by engineering the t(11;22)(q24;q12) translocation together with a combination of SPC mutations, we generated a wide collection of immortalized cells (EWIma cells) tolerating EWSR1-FLI1 expression from primary mesenchymal stem cells (MSC) derived from a patient with Ewing sarcoma. Within this model, SPC alterations strongly favored Ewing sarcoma oncogenicity. Xenograft experiments with independent EWIma cells induced tumors and metastases in mice, which displayed bona fide features of Ewing sarcoma. EWIma cells presented balanced but also more complex translocation profiles mimicking chromoplexy, which is frequently observed in Ewing sarcoma and other cancers. Collectively, these results demonstrate that bone marrow–derived MSCs are a source of origin for Ewing sarcoma and also provide original experimental models to investigate Ewing sarcomagenesis. Significance: These findings demonstrate that Ewing sarcoma can originate from human bone-marrow–derived mesenchymal stem cells and that recurrent mutations support EWSR1-FLI1 translocation-mediated transformation.
Published: 2021

7. Notch1 switches progenitor competence in inducing medulloblastoma

Author: Matteo Gianesello, Tingting Zhang, Giuseppe Aiello, Francesca Gianno, Luca Tiberi, Francesco Antonica, Bassem A. Hassan, Felice Giangaspero, Konstantin Okonechnikov, Claudio Ballabio, Chiara Lago, Stefan M. Pfister, Marica Anderle, University of Trento [Trento], Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), 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), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Istituto Neurologico Mediterraneo (NEUROMED I.R.C.C.S.), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Università degli studi di Napoli Federico II, Heidelberg University Hospital [Heidelberg], 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), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)-University of Naples Federico II = Università degli studi di Napoli Federico II, and HAL-SU, Gestionnaire
Subjects: Poor prognosis, Cell of origin, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, Developmental Neuroscience, [SDV.CAN] Life Sciences [q-bio]/Cancer, SOX2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, neoplasms, Research Articles, Cancer, 030304 developmental biology, Progenitor, Medulloblastoma, 0303 health sciences, Mouse Cerebellum, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Multidisciplinary, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, SciAdv r-articles, medicine.disease, Molecular biology, nervous system diseases, 3. Good health, stomatognathic diseases, ASCL1, 030220 oncology & carcinogenesis, embryonic structures, cardiovascular system, Cancer research, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Pathway activity, Research Article, Proto-oncogene tyrosine-protein kinase Src
Abstract: Notch1 pathway activation is required for group 3 medulloblastoma initiation., The identity of the cell of origin is a key determinant of cancer subtype, progression, and prognosis. Group 3 medulloblastoma (MB) is a malignant childhood brain cancer with poor prognosis and few candidates as putative cell of origin. We overexpressed the group 3 MB genetic drivers MYC and Gfi1 in different candidate cells of origin in the postnatal mouse cerebellum. We found that S100b+ cells are competent to initiate group 3 MB, and we observed that S100b+ cells have higher levels of Notch1 pathway activity compared to Math1+ cells. We found that additional activation of Notch1 in Math1+ and Sox2+ cells was sufficient to induce group 3 MB upon MYC/Gfi1 expression. Together, our data suggest that the Notch1 pathway plays a critical role in group 3 MB initiation.
Published: 2021

8. Diffuse Glioneuronal tumour with Oligodendroglioma‐like features and Nuclear Clusters (DGONC) – a molecularly‐defined glioneuronal CNS tumour class displaying recurrent monosomy 14

Author: Martin U. Schuhmann, Till Milde, A. von Deimling, Matija Snuderl, Kathy Keyvani, Nada Jabado, Thorsten Pietsch, Eleonora Aronica, Olaf Witt, Christian Hartmann, David T.W. Jones, David Ellison, Felix Sahm, Martin Sill, Dominik Sturm, M Kool, M. Y. Deng, Damian Stichel, Matthias Preusser, Felice Giangaspero, K. von Hoff, M. Lauten, Christine Haberler, Ori Staszewski, Ulrich Schüller, Jonas Ecker, Pieter Wesseling, Christopher Dunham, Martin Ebinger, Jens Schittenhelm, Christel Herold-Mende, Hendrik Witt, Wolfgang Wick, Andrey Korshunov, Nicholas G. Gottardo, Dominique Figarella-Branger, Andrea Wittmann, M. Deckert, Stefan M. Pfister, Heidelberg University Hospital [Heidelberg], Tübingen University Hospital [Germany], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, Hôpital de la Timone [CHU - APHM] (TIMONE), Genome Analysis, Department of Pediatrics and Adolescent Medicine, University Freiburg, Freiburg, Institut d'écologie et des sciences de l'environnement de Paris (IEES), Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology, Massachusetts General Hospital [Boston], Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], VU University Medical Center [Amsterdam], RMIT Melbourne, Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), Department of Neuropathology, Institute of Pathology, Division of Paediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany, Institut d'écologie et des sciences de l'environnement de Paris (iEES), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Pathology, CCA - Cancer biology, Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA), ANS - Cellular & Molecular Mechanisms, APH - Aging & Later Life, and APH - Mental Health
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Histology, [SDV]Life Sciences [q-bio], Oligodendroglioma, Medizin, Biology, Pathology and Forensic Medicine, Central Nervous System Neoplasms, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Monosomy, Physiology (medical), medicine, Humans, Neurocytoma, ComputingMilieux_MISCELLANEOUS, Paediatric patients, Chromosomes, Human, Pair 14, Glioma, DNA Methylation, medicine.disease, 3. Good health, 030104 developmental biology, Neurology, chemistry, Homogeneous, DNA methylation, Female, Neurology (clinical), Who classification, Monosomy 14, 030217 neurology & neurosurgery, DNA, Clear cell
Abstract: Aims: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the ‘conumee’ package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.
Published: 2019

9. The molecular landscape of ETMR at diagnosis and relapse

Author: Olaf Witt, Maria Łastowska, Anna Darabi, Ulrich Schüller, Andreas von Deimling, Nada Jabado, Susanne Gröbner, David Sumerauer, Annie Huang, Sebastian M. Waszak, Martin Sill, Xiao-Nan Li, Andrey Korshunov, Julien Masliah-Planchon, Pablo Landgraf, David Ellison, Maria J. Gil-da-Costa, Alexander J.R. Bishop, Christin Schmidt, Pieter Wesseling, Sebastian Brabetz, Marc Remke, July Carolina Romero, Dominique Figarella-Branger, Peter Hauser, Simon Papillon-Cavanagh, Jennifer A. Chan, Felix Sahm, Benjamin Schwalm, Peter Lichter, Ivo Buchhalter, Stephan Wolf, Norman Mack, Matthias A. Karajannis, Till Milde, Jan Koster, Valérie Rigau, Monika Mauermann, Matija Snuderl, Franck Bourdeaut, Christine Haberler, Torsten Pietsch, Volker Hovestadt, Wiesława Grajkowska, Katja von Hoff, Felice Giangaspero, Marcel Kool, Emmanuelle Uro-Coste, Jan O. Korbel, Michael D. Taylor, Martin Hasselblatt, Tobias Rausch, Danny A. Zwijnenburg, Jonas Ecker, Brent A. Orr, David T.W. Jones, Jens Schittenhelm, Aparna Gorthi, Sonja Krausert, Sanda Alexandrescu, Sander Lambo, Jens Martin Hübner, Ben Ho, Stefan M. Pfister, Marina Ryzhova, German Cancer Consortium [Heidelberg] (DKTK), Department of Oncogenomics [Amsterdam, Pays-Bas], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Heidelberg University Hospital [Heidelberg], Division of Medical Genetics [Seattle], University of Washington [Seattle], Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Heidelberg, Germany, Department of Neuropathology, Institute of Pathology, RMIT Melbourne, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Service d'Anatomie Pathologique et de Neuropathologie [Hôpital de la Timone - CHU - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), VU University Medical Center [Amsterdam], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Pathologie cellulaire : aspects moléculaires et viraux / Pathologie et Virologie Moléculaire, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Department of Pathology, Massachusetts General Hospital [Boston], Department of Human Genetics , Department of Experimental Medicine, Radboud University Medical Center [Nijmegen], European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany., Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Pathology, CCA - Imaging and biomarkers, Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier (INM), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS), and Oncogenomics
Subjects: Ribonuclease III, 0301 basic medicine, Genome instability, medicine.medical_specialty, Somatic cell, [SDV]Life Sciences [q-bio], Disease, Poly(ADP-ribose) Polymerase Inhibitors, Polymorphism, Single Nucleotide, Article, DEAD-box RNA Helicases, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Recurrence, Chromosome instability, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Cisplatin, Multidisciplinary, biology, embryonal tumours, Topoisomerase, brain tumours, genomic landscape, Neoplasms, Germ Cell and Embryonal, 3. Good health, MicroRNAs, 030104 developmental biology, DNA Topoisomerases, Type I, 030220 oncology & carcinogenesis, multilayered rosettes, Mutation, biology.protein, Cancer research, Medical genetics, RNA, Long Noncoding, Poly(ADP-ribose) Polymerases, medicine.drug
Abstract: Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2–4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.
Published: 2019

10. SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue

Author: Frank Kirchhoff, Dominik Hotter, Daniel Sauter, Martine Peeters, Christine Goffinet, Oliver T. Fackler, Konstantin M. J. Sparrer, Zhong Yao, Birthe Trautz, Ahidjo Ayouba, Bengisu Akbil, Thomas Zillinger, Igor Stagljar, Christina M. Stürzel, Swetha Ananth, Vânia Passos, Dorota Kmiec, Institute of Molecular Virology [Ulm, Allemagne], Universitätsklinikum Ulm - University Hospital of Ulm, Department of Infectious Diseases, Integrative Virology [Heidelberg, Allemagne], Center for Integrative Infectious Diseases Research [Heidelberg, Allemagne] (CIID), Heidelberg University Hospital [Heidelberg]-Heidelberg University Hospital [Heidelberg], German Center for Infection Research, Partner Site Heidelberg [Allemagne] (DZIF), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Donnelly Centre [Toronto, ON, Canada], University of Toronto, Department of Biochemistry [University of Toronto], Department of Molecular Genetics [Toronto], Institute of Virology [Hannover], Hannover Medical School [Hannover] (MHH), Institute of Clinical Chemistry and Clinical Pharmacology [Bonn, Allemagne], University of Bonn, This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, European Project: 323035,EC:FP7:ERC,ERC-2012-ADG_20120314,ANTI-VIROME(2013), Bodescot, Myriam, A combined evolutionary and proteomics approach to the discovery, induction and application of antiviral immunity factors - ANTI-VIROME - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 323035 - VALID, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Universität Bonn = University of Bonn, and Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: 0301 basic medicine, RNA viruses, CD4-Positive T-Lymphocytes, viruses, Xenopus, Monkeys, Pathology and Laboratory Medicine, Virus Replication, Gene Products, nef, Virions, White Blood Cells, Database and Informatics Methods, Jurkat Cells, Immunodeficiency Viruses, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, lcsh:QH301-705.5, Cells, Cultured, Infectivity, Mammals, T Cells, CD28, Eukaryota, virus diseases, Transfection, 3. Good health, Cell biology, medicine.anatomical_structure, Infectious Diseases, Medical Microbiology, Viral Pathogens, Viruses, Vertebrates, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Simian Immunodeficiency Virus, Pathogens, Cellular Types, Sequence Analysis, Research Article, Primates, lcsh:Immunologic diseases. Allergy, Proteasome Endopeptidase Complex, Infectious Disease Control, [SDV.IMM] Life Sciences [q-bio]/Immunology, Bioinformatics, Lymphoid Tissue, T cell, Immune Cells, Immunology, Biology, Viral Structure, Colobus, Research and Analysis Methods, Microbiology, 03 medical and health sciences, Sequence Motif Analysis, Virology, Retroviruses, Old World monkeys, Genetics, medicine, Animals, Humans, Molecular Biology, Microbial Pathogens, Blood Cells, Lentivirus, Organisms, Actin remodeling, Biology and Life Sciences, HIV, Membrane Proteins, Cell Biology, biology.organism_classification, Viral Replication, 030104 developmental biology, HEK293 Cells, Viral replication, lcsh:Biology (General), Amniotes, Proteolysis, Tetherin, HIV-1, Parasitology, lcsh:RC581-607
Abstract: SERINC5 is a host restriction factor that impairs infectivity of HIV-1 and other primate lentiviruses and is counteracted by the viral accessory protein Nef. However, the importance of SERINC5 antagonism for viral replication and cytopathicity remained unclear. Here, we show that the Nef protein of the highly divergent SIVcol lineage infecting mantled guerezas (Colobus guereza) is a potent antagonist of SERINC5, although it lacks the CD4, CD3 and CD28 down-modulation activities exerted by other primate lentiviral Nefs. In addition, SIVcol Nefs decrease CXCR4 cell surface expression, suppress TCR-induced actin remodeling, and counteract Colobus but not human tetherin. Unlike HIV-1 Nef proteins, SIVcol Nef induces efficient proteasomal degradation of SERINC5 and counteracts orthologs from highly divergent vertebrate species, such as Xenopus frogs and zebrafish. A single Y86F mutation disrupts SERINC5 and tetherin antagonism but not CXCR4 down-modulation by SIVcol Nef, while mutation of a C-proximal di-leucine motif has the opposite effect. Unexpectedly, the Y86F change in SIVcol Nef had little if any effect on viral replication and CD4+ T cell depletion in preactivated human CD4+ T cells and in ex vivo infected lymphoid tissue. However, SIVcol Nef increased virion infectivity up to 10-fold and moderately increased viral replication in resting peripheral blood mononuclear cells (PBMCs) that were first infected with HIV-1 and activated three or six days later. In conclusion, SIVcol Nef lacks several activities that are conserved in other primate lentiviruses and utilizes a distinct proteasome-dependent mechanism to counteract SERINC5. Our finding that evolutionarily distinct SIVcol Nefs show potent anti-SERINC5 activity supports a relevant role of SERINC5 antagonism for viral fitness in vivo. Our results further suggest this Nef function is particularly important for virion infectivity under conditions of limited CD4+ T cell activation., Author summary The accessory protein Nef promotes primate lentiviral replication and enhances the pathogenicity of HIV-1 by mechanisms of immune evasion and enhancing viral infectivity and replication. Here, we show that the evolutionarily most isolated primate lentivirus SIVcol lacks several otherwise conserved Nef functions. Nevertheless, SIVcol Nef potently antagonizes SERINC5, a recently discovered inhibitor of viral infectivity, by down-modulating it from the cell surface and inducing its proteasomal degradation. We identified Y86 in SIVcol Nef as a key determinant of SERINC5 antagonism. Efficient counteraction of SERINC5 did not increase HIV-1 replication in preactivated CD4+ T cells and in ex vivo infected lymphoid tissue but had modest enhancing effects when resting PBMCs were first infected and activated six days later. Evolution of high anti-SERINC5 activity by SIVcol Nef supports a relevant role of this antagonism in vivo, for instance by enhancing virion infectivity under conditions of limited T cell activation.
Published: 2018

11. Zika virus epidemiology in Bolivia : A seroprevalence study in volunteer blood donors

Author: Xavier de Lamballerie, Thomas Jaenisch, Paola Mariela Saba Villarroel, Stéphane Priet, Laetitia Ninove, Boris Pastorino, Pierre Gallian, Elif Nurtop, Isabelle Leparc-Goffart, Jan Felix Drexler, Yelin Roca, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centro Nacional de Enfermedades Tropicales [Santa Cruz de la Sierra, Bolivia] (CENETROP), Institute of Virology [Berlin, Germany] (Charité), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Centre for Infection Research [Berlin, Germany] (DZIF - Charité), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Section Clinical Tropical Medicine [Heidelberg], Department of Infectious Diseases [Heidelberg, Germany], Heidelberg University Hospital [Heidelberg]-Heidelberg University Hospital [Heidelberg], Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), European Project: 734548,ZIKAlliance(2016), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Centre for Infection Research (DZIF), Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), European Union’s Horizon 2020 research and innovation programmes ZIKAlliance and EVAg under grant agreements No 734548 and 653316, Dubois Frid, Caroline, A global alliance for Zika virus control and prevention - ZIKAlliance - 2016-10-01 - 2019-09-30 - 734548 - VALID, and European Virus Archive goes global - EVAg - - H20202015-04-01 - 2019-03-31 - 653316 - VALID
Subjects: RNA viruses, Male, Volunteers, 0301 basic medicine, [SDV]Life Sciences [q-bio], Disease Vectors, Dengue virus, Pathology and Laboratory Medicine, medicine.disease_cause, Mosquitoes, Geographical locations, Zika virus, Dengue fever, Dengue, 0302 clinical medicine, Aedes aegypti, Aedes, Seroepidemiologic Studies, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Epidemiology, Medicine and Health Sciences, Mass Screening, Enzyme-linked immunoassays, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, Zika Virus Infection, lcsh:Public aspects of medicine, Eukaryota, Middle Aged, 3. Good health, Insects, [SDV] Life Sciences [q-bio], Infectious Diseases, Geography, Medical Microbiology, Viral Pathogens, Viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Pathogens, Chikungunya virus, Research Article, Adult, medicine.medical_specialty, Bolivia, lcsh:Arctic medicine. Tropical medicine, Arthropoda, Adolescent, lcsh:RC955-962, Alphaviruses, Immunology, 030231 tropical medicine, Mosquito Vectors, Research and Analysis Methods, Blood donors, Microbiology, Virus, Togaviruses, Young Adult, 03 medical and health sciences, Environmental health, parasitic diseases, medicine, Animals, Humans, Seroprevalence, Immunoassays, Microbial Pathogens, Biology and life sciences, Flaviviruses, Organisms, Public Health, Environmental and Occupational Health, Immunity, lcsh:RA1-1270, South America, biology.organism_classification, medicine.disease, Invertebrates, Insect Vectors, Health Care, Species Interactions, 030104 developmental biology, Immunologic Techniques, Chikungunya Fever, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, People and places
Abstract: Background Zika virus (ZIKV), was widely reported in Latin America and has been associated with neuropathologies, as microcephaly, but only few seroprevalence studies have been published to date. Our objective was to determine the seroprevalence amongst Bolivian blood donors and estimate the future potential circulation of the virus. Methodology A ZIKV seroprevalence study was conducted between December 2016 and April 2017 in 814 asymptomatic Bolivian volunteer blood donors residing in various eco-environments corresponding to contrasting entomological activities. It was based on detection of IgG to ZIKV using NS1 ELISA screening, followed by a seroneutralisation test in case of positive or equivocal ELISA result. Conclusions/Significance Analysis revealed that ZIKV circulation occurred in tropical areas (Beni: 39%; Santa Cruz de la Sierra: 21.5%) but not in highlands (~0% in Cochabamba, La Paz, Tarija). It was modulated by Aedes aegypti activity and the virus spread was not limited by previous immunity to dengue. Cases were geo-localised in a wide range of urban areas in Santa Cruz and Trinidad. No differences in seroprevalence related to gender or age-groups could be identified. It is concluded that ZIKV has been intensely circulating in the Beni region and has still a significant potential for propagating in the area of Santa Cruz., Author summary Zika virus (ZIKV) is a virus of African origin, transmitted by Aedes mosquitoes, and related to dengue and yellow fever virus. It was originally believed to be responsible for a mild febrile illness in Africa and South-east Asia. However, in recent years, ZIKV has been responsible for outbreaks in the Pacific Islands before massively spreading in Latin America and the Caribbean. On this occasion, ZIKV has unexpectedly been associated with non-vector transmission (i.e., sexual and mother-to-foetus transmission) and with severe complications such as foetal abnormalities (e.g. microcephaly) and Guillain-Barré syndromes. Little is known about the actual proportion of the populations infected by ZIKV in Latin America. Here, we report a seroprevalence data in this region, after studying 814 asymptomatic Bolivian volunteer blood donors residing in various eco-environments corresponding to contrasting entomological activities. We conclude that ZIKV has been circulating in Bolivian tropical areas but not in highlands, and that the epidemic has not been limited by previous immunity against dengue. Specific attention should be paid to the region of Santa Cruz, where the seroprevalence is still limited, but the density of Aedes aegypti populations makes plausible further spreading of the disease.
Published: 2018

12. Clinical validity assessment of genes frequently tested on intellectual disability/autism sequencing panels

Author: Erin Rooney Riggs, Taylor I. Bingaman, Carrie-Ann Barry, Andrea Behlmann, Krista Bluske, Bret Bostwick, Alison Bright, Chun-An Chen, Amanda R. Clause, Avinash V. Dharmadhikari, Mythily Ganapathi, Claudia Gonzaga-Jauregui, Andrew R. Grant, Madeline Y. Hughes, Se Rin Kim, Amanda Krause, Jun Liao, Aimé Lumaka, Michelle Mah, Caitlin M. Maloney, Shruthi Mohan, Ikeoluwa A. Osei-Owusu, Emma Reble, Olivia Rennie, Juliann M. Savatt, Hermela Shimelis, Rebecca K. Siegert, Tam P. Sneddon, Courtney Thaxton, Kelly A. Toner, Kien Trung Tran, Ryan Webb, Emma H. Wilcox, Jiani Yin, Xinming Zhuo, Masa Znidarsic, Christa Lese Martin, Catalina Betancur, Jacob A.S. Vorstman, David T. Miller, Christian P. Schaaf, Geisinger Autism & Developmental Medicine Institute [Danville, PA, USA] (ADMI), Drexel University, Invitae Corporation, Illumina, Baylor College of Medicine (BCM), Baylor University, Natera [San Carlos, CA, USA], Children’s Hospital Los Angeles [Los Angeles], Keck School of Medicine [Los Angeles], University of Southern California (USC), Columbia University Irving Medical Center (CUIMC), Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], New York Medical College (NYMC), University of Illinois [Chicago] (UIC), University of Illinois System, National Human Genome Research Institute (NHGRI), University of the Witwatersrand [Johannesburg] (WITS), Université de Liège, Trillium Health Partners - Mississauga Hospital [Mississauga, ON, Canada] (THP-MH), University of Washington [Seattle], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), St. Michael's Hospital, The Hospital for sick children [Toronto] (SickKids), Garvan Institute of medical research, Warren Alpert Medical School of Brown University, University of California [Los Angeles] (UCLA), University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Heidelberg University Hospital [Heidelberg], This work was supported by the National Human Genome Research Institute of the National Institutes of Health under award number U24HG006834., and Betancur, Catalina
Subjects: ClinGen, MESH: Humans, Autism Spectrum Disorder, Autism, MESH: Autism Spectrum Disorder* / genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Autism Spectrum Disorder* / diagnosis, MESH: Intellectual Disability* / diagnosis, MESH: Intellectual Disability* / genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Intellectual Disability, MESH: Autistic Disorder* / genetics, MESH: Autistic Disorder* / diagnosis, Humans, Autistic Disorder, MESH: Neurodevelopmental Disorders* / genetics, Genetics (clinical), Gene–disease validity
Abstract: International audience; Purpose: Neurodevelopmental disorders (NDDs), such as intellectual disability (ID) and autism spectrum disorder (ASD), exhibit genetic and phenotypic heterogeneity, making them difficult to differentiate without a molecular diagnosis. The Clinical Genome Resource Intellectual Disability/Autism Gene Curation Expert Panel (GCEP) uses systematic curation to distinguish ID/ASD genes that are appropriate for clinical testing (ie, with substantial evidence supporting their relationship to disease) from those that are not.Methods: Using the Clinical Genome Resource gene-disease validity curation framework, the ID/Autism GCEP classified genes frequently included on clinical ID/ASD testing panels as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship.Results: As of September 2021, 156 gene-disease pairs have been evaluated. Although most (75%) were determined to have definitive roles in NDDs, 22 (14%) genes evaluated had either Limited or Disputed evidence. Such genes are currently not recommended for use in clinical testing owing to the limited ability to assess the effect of identified variants.Conclusion: Our understanding of gene-disease relationships evolves over time; new relationships are discovered and previously-held conclusions may be questioned. Without periodic re-examination, inaccurate gene-disease claims may be perpetuated. The ID/Autism GCEP will continue to evaluate these claims to improve diagnosis and clinical care for NDDs.
Published: 2022

13. Sudden cardiac death while waiting: do we need the wearable cardioverter-defibrillator?

Author: Israel, Carsten, Staudacher, Ingo, Leclercq, Christophe, Botto, Giovanni Luca, Scherr, Daniel, Fach, Andreas, Duru, Firat, Zylla, Maura M, Katus, Hugo A, Thomas, Dierk, Children’s Center Bethel (EvkB), Heidelberg University Hospital [Heidelberg], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Medical University Graz, Universität Zürich [Zürich] = University of Zurich (UZH), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Projekt DEAL, University of Zurich, Thomas, Dierk, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Electric Countershock, 610 Medicine & health, Ventricular tachycardia, General Medicine, 2705 Cardiology and Cardiovascular Medicine, Implantable cardioverter-defibrillator, Defibrillators, Implantable, Wearable Electronic Devices, Sudden cardiac death, Myocardial infarction, Death, Sudden, Cardiac, 10209 Clinic for Cardiology, Humans, [SDV.IB]Life Sciences [q-bio]/Bioengineering, cardiovascular diseases, Wearable cardioverter-defibrillator, Cardiomyopathies, Cardiology and Cardiovascular Medicine, Defibrillators, Randomized Controlled Trials as Topic
Abstract: Sudden cardiac death (SCD) is the most frequent cause of cardiovascular death in industrialized nations. Patients with cardiomyopathy are at increased risk for SCD and may benefit from an implantable cardioverter-defibrillator (ICD). The risk of SCD is highest in the first months after myocardial infarction or first diagnosis of severe non-ischemic cardiomyopathy. On the other hand, left ventricular function may improve in a subset of patients to such an extent that an ICD might no longer be needed. To offer protection from a transient risk of SCD, the wearable cardioverter-defibrillator (WCD) is available. Results of the first randomized clinical trial investigating the role of the WCD after myocardial infarction were recently published. This review is intended to provide insight into data from the VEST trial, and to put these into perspective with studies and clinical experience. As a non-invasive, temporary therapy, the WCD may offer advantages over early ICD implantation. However, recent data demonstrate that patient compliance and education play a crucial role in this new concept of preventing SCD.
Published: 2022

14. Evolution of disability in spinocerebellar ataxias type 1, 2, 3, and 6

Author: Jacobi, Heike, Schaprian, Tamara, Beyersmann, Jan, Tezenas du Montcel, Sophie, Schmid, Matthias, Klockgether, Thomas, EUROSCA, Groups, RISCA Study, Heidelberg University Hospital [Heidelberg], Dendrite Differenciation Group [DZNE - Bonn], German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institute of Communications Engineering [Ulm] (INT - University of Ulm.), Universität Ulm - Ulm University [Ulm, Allemagne], Sorbonne Université (SU), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Bonn, Tezenas du Montcel, Sophie, and Universität Bonn = University of Bonn
Subjects: General Neuroscience, Disease Progression, Humans, Spinocerebellar Ataxias, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ddc:610, genetics [Spinocerebellar Ataxias], Neurology (clinical)
Abstract: International audience; Objective: The aim was to study the evolution of disability in spinocerebellar ataxias (SCAs) type 1, 2, 3, and 6 (SCA1, 2, 3, 6). Methods: We analyzed data of two longitudinal cohorts (RISCA, EUROSCA) which recruited ataxic and non-ataxic SCA1, SCA2, SCA3, and SCA6 mutation carriers. To study disability, we used a five-stage system for ataxia defined by walking ability (stages 0-3) and death (stage 4). Transitions were analyzed using a multi-state model with proportional transition hazards. Based on the hazard estimates, transition probabilities and the expected lengths of stay in each stage were calculated. We further studied the effect of sex and CAG repeat length on progression. Results: Data of 3138 visits in 677 participants were analyzed. Median SARA scores for SCA1, SCA2, SCA3, and SCA6 ranged from 1.5 (interquartile range [IQR] = 0.0-3.5) to 3.5 (IQR = 1.4-6.1) in stage 0, 11.5 (IQR = 9.6-14.0) to 13.8 (IQR = 11.0-16.0) in stage 1, 19.0 (IQR = 17.0-21.0) to 23.8 (IQR = 19.5-27.0) in stage 2, and 28.5 (IQR = 26.0-32.5) to 34.0 (IQR = 32.6-37.1) in stage 3. Modeling allowed to calculate the subtype-specific probability to be in a certain stage at a given age and duration of each stage. CAG repeat length was associated with faster progression in SCA1 (HR, 95% CI: 1.1, 1.1-1.2), SCA2 (1.2, 1.1-1.3), and SCA3 (1.1, 1.0-1.2). In SCA6, female sex was associated with faster progression (1.7, 1.1-2.6). Interpretation: Our data are important for counselling of patients, assessment of the relevance of outcome markers, and design of clinical trials.
Published: 2022

15. Criteria for preclinical models of cholangiocarcinoma:scientific and medical relevance

Author: Calvisi, Diego, Boulter, Luke, Vaquero, Javier, Saborowski, Anna, Fabris, Luca, Rodrigues, Pedro, Coulouarn, Cédric, Castro, Rui, Segatto, Oreste, Raggi, Chiara, van der Laan, Luc, Carpino, Guido, Goeppert, Benjamin, Roessler, Stephanie, Kendall, Timothy, Evert, Matthias, Gonzalez-Sanchez, Ester, Valle, Juan, Vogel, Arndt, Bridgewater, John, Borad, Mitesh, Gores, Gregory, Roberts, Lewis, Marin, Jose, Andersen, Jesper, Alvaro, Domenico, Forner, Alejandro, Banales, Jesus, Cardinale, Vincenzo, Macias, Rocio, Vicent, Silve, Chen, Xin, Braconi, Chiara, Verstegen, Monique, Fouassier, Laura, Scheiter, Alexander, Selaru, Florin, Evert, Katja, Utpatel, Kirsten, Broutier, Laura, Cadamuro, Massimiliano, Huch, Meritxell, Goldin, Robert, Gradilone, Sergio, Saito, Yoshimasa, University of Regensburg, University of Edinburgh, Instituto de Salud Carlos III [Madrid] (ISC), Hannover Medical School [Hannover] (MHH), Yale School of Medicine [New Haven, Connecticut] (YSM), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Universidade de Lisboa, Università degli Studi di Firenze = University of Florence (UniFI), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli Studi di Roma 'Foro Italico', Heidelberg University Hospital [Heidelberg], University of Barcelona, Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), The Christie NHS Foundation Trust [Manchester, Royaume-Uni], University of Manchester [Manchester], University College of London [London] (UCL), Mayo Clinic, Mayo Clinic [Rochester], Universidad de Salamanca, University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Glasgow, 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), The authors thank the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and the European H2020 COST Action CA18122. The authors also acknowledge the valuable contributions of the external advisory panel. C.C. is supported by Inserm, Université de Rennes 1 and by a grant from the French Ministry of Health and the French National Cancer Institute (PRT-K20-136), CHU Rennes, CLCC Eugène Marquis, Rennes. M.M.A.V. and L.J.W.v.d.L. are supported by Medical Delta Regenerative Medicine 4D (Generating complex tissues with stem cells and printing technology) and TKI-LSH grant EMC-LSH19002. S.R. is supported by the German Research Foundation (DFG, project no. 314905040 and no. 493697503) and by German Cancer Aid (Deutsche Krebshilfe, project no. 70113922). S.V. is supported by Ministerio de Ciencia, Innovación y Universidades, Convocatoria 2019 para incentivar la Incorporación Estable de Doctores (IED2019-001007-I), by FEDER/Ministerio de Ciencia, Innovación y Universidades – Agencia Estatal de Investigación (PID2020‐116344‐RB‐100) and by the Government of Navarra-Health Research Department (58, and 2018). J.V. is funded by Ministerio de Ciencia e Innovación, part of Agencia Estatal de Investigación (AEI), through the Retos Investigación grant number PID2019-108651RJ-I00/DOI 10.13039/501100011033. The authors thank CERCA Programme/Generalitat de Catalunya for institutional support. R.I.R.M. and J.J.G.M. are supported by Instituto de Salud Carlos III, Spain (PI20/00189, PI19/00819) co-funded by the European Union. L. Fouassier belongs to a team supported by the Fondation pour la Recherche Médicale (Equipe FRM 2020 no. EQU202003010517) and is supported by Inserm and Sorbonne Université, INCa and ITMO Cancer of Aviesan within the framework of the 2021–2030 Cancer Control Strategy, on funds administered by Inserm.
Subjects: Hepatology, [SDV]Life Sciences [q-bio], Gastroenterology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract: International audience; Cholangiocarcinoma (CCA) is a rare malignancy that develops at any point along the biliary tree. CCA has a poor prognosis, its clinical management remains challenging, and effective treatments are lacking. Therefore, preclinical research is of pivotal importance and necessary to acquire a deeper understanding of CCA and improve therapeutic outcomes. Preclinical research involves developing and managing complementary experimental models, from in vitro assays using primary cells or cell lines cultured in 2D or 3D to in vivo models with engrafted material, chemically induced CCA or genetically engineered models. All are valuable tools with well-defined advantages and limitations. The choice of a preclinical model is guided by the question(s) to be addressed; ideally, results should be recapitulated in independent approaches. In this Consensus Statement, a task force of 45 experts in CCA molecular and cellular biology and clinicians, including pathologists, from ten countries provides recommendations on the minimal criteria for preclinical models to provide a uniform approach. These recommendations are based on two rounds of questionnaires completed by 35 (first round) and 45 (second round) experts to reach a consensus with 13 statements. An agreement was defined when at least 90% of the participants voting anonymously agreed with a statement. The ultimate goal was to transfer basic laboratory research to the clinics through increased disease understanding and to develop clinical biomarkers and innovative therapies for patients with CCA.
Published: 2023

16. Advancing One Health:Updated core competencies

Author: Gabrielle Laing, Eleanor Duffy, Neil Anderson, Nicolas Antoine-Moussiaux, Maurizio Aragrande, Caetano Luiz Beber, John Berezowski, Elena Boriani, Massimo Canali, Luis Pedro Carmo, Ilias Chantziaras, Glen Cousquer, Daniele Meneghi, Ana Gloria Rodrigues Sanches da Fonseca, Julie Garnier, Martin Hitziger, Thomas Jaenisch, Hans Keune, Claire Lajaunie, Lorena Franco Martinez, Rebecca Maudling, Marie K. McIntyre, Barry J. McMahon, Alberto Munoz Prieto, Liza Rosenbaum Nielsen, Ranya Özçelik, John W.A. Rossen, Simon R. Rüegg, Sara Savić, Margarida Pires Simoes, Deborah J. Thomson, Laura Tomassone, Asta Tvarijonaviciute, Manuela Vilhena, Barbara Vogler, Barbara Häsler, Gabrielle Laing, Eleanor Duffy, Neil Anderson, Nicolas Antoine-Moussiaux, Maurizio Aragrande, Caetano Luiz Beber, John Berezowski, Elena Boriani, Massimo Canali, Luis Pedro Carmo, Ilias Chantziaras, Glen Cousquer, Daniele De Meneghi, Ana Gloria Rodrigues Sanches da Fonseca, Julie Garnier, Martin Hitziger, Thomas Jaenisch, Hans Keune, Claire Lajaunie, Lorena Franco Martinez, Rebecca Maudling, Marie K. McIntyre, Barry J. McMahon, Alberto Munoz Prieto, Liza Rosenbaum Nielsen, Ranya Özçelik, John W.A. Rossen, Simon R. Rüegg, Sara Savić, Margarida Pires Simoes, Deborah J. Thomson, Laura Tomassone, Asta Tvarijonaviciute, Manuela Vilhena, Barbara Vogler, Barbara Häsler, Université de Liège, University of Bologna/Università di Bologna, University of Bern, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Universiteit Gent = Ghent University (UGENT), Cités, Territoires, Environnement et Sociétés (CITERES), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Heidelberg University Hospital [Heidelberg], Research Institute for Nature and Forest (INBO), Laboratoire Population-Environnement-Développement (LPED), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), and NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
Subjects: workforce development, One Health, planetary health, ecohealth, education, integrated, systems thinking, interdisciplinary, transdisciplinary, workforce development, capacity building, education, capacity building, [SHS.EDU]Humanities and Social Sciences/Education, One Health Skill, systems thinking, Interdisciplinarity, planetary health, integrated, [SDE.ES]Environmental Sciences/Environmental and Society, Human, Animal, and Environmental Health, ecohealth, interdisciplinary, transdisciplinary, Human medicine, One Health
Abstract: One Health recognises the interdependence between the health of humans, animals, plants and the environment. With the increasing inclusion of One Health in multiple global health strategies, the One Health workforce must be prepared to protect and sustain the health and well-being of life on the planet. In this paper, a review of past and currently accepted One Health core competencies was conducted, with competence gaps identified. Here, the Network for Ecohealth and One Health (NEOH) propose updated core competencies designed to simplify what can be a complex area, grouping competencies into three main areas of: Skills; Values and Attitudes; and Knowledge and Awareness; with several layers underlying each. These are intentionally applicable to stakeholders from various sectors and across all levels to support capacity-building efforts within the One Health workforce. The updated competencies from NEOH can be used to evaluate and enhance current curricula, create new ones, or inform professional training programs at all levels, including students, university teaching staff, or government officials as well as continual professional development for frontline health practitioners and policy makers. The competencies are aligned with the new definition of One Health developed by the One Health High-Level Expert Panel (OHHLEP), and when supported by subjectspecific expertise, will deliver the transformation needed to prevent and respond to complex global challenges. One Health Impact Statement Within a rapidly changing global environment, the need for practitioners competent in integrated approaches to health has increased substantially. Narrow approaches may not only limit opportunities for global and local solutions but, initiatives that do not consider other disciplines or social, economic and cultural contexts, may result in unforeseen and detrimental consequences. In keeping with principles of One Health, the Network for Ecohealth and One Health (NEOH) competencies entail a collaborative effort between multiple disciplines and sectors. They focus on enabling practitioners, from any background, at any level or scale of involvement, to promote and support a transformation to integrated health approaches. The updated competencies can be layered with existing disciplinary competencies and used to evaluate and enhance current education curricula, create new ones, or inform professional training programs at all levels-including for students, teachers and government officials as well as continual professional development for frontline health practitioners and policymakers. The competencies outlined here are applicable to all professionals and disciplines who may contribute to One Health, and are complimentary to, not a replacement for, any discipline-specific competencies. We believe the NEOH competencies meet the need outlined by the Quadripartite’s (Food and Agriculture Organisation, United Nations Environment Programme, World Health Organisation, World Organisation for Animal Health) Joint Plan of Action on One Health which calls for cross-sectoral competencies.
Published: 2023

17. A versatile and interoperable computational framework for the analysis and modeling of COVID-19 disease mechanisms

Author: Niarakis, Anna, Ostaszewski, Marek, Mazein, Alexander, Kuperstein, Inna, Kutmon, Martina, Gillespie, Marc, Funahashi, Akira, Acencio, Marcio, Hemedan, Ahmed, Aichem, Michael, Klein, Karsten, Czauderna, Tobias, Burtscher, Felicia, Yamada, Takahiro, Hiki, Yusuke, Hiroi, Noriko, Hu, Finterly, Pham, Nhung, Ehrhart, Friederike, Willighagen, Egon, Valdeolivas, Alberto, Dugourd, Aurelien, Messina, Francesco, Esteban-Medina, Marina, Pena-Chilet, Maria, Rian, Kinza, Soliman, Sylvain, Aghamiri, Sara, Puniya, Bhanwar, Naldi, Aurelien, Helikar, Tomas, Singh, Vidisha, Farinas Fernandez, Marco, Bermudez, Viviam, Tsirvouli, Eirini, Montagud, Arnau, Noel, Vincent, Ponce de Leon, Miguel, Maier, Dieter, Bauch, Angela, Gyori, Benjamin, Bachman, John, Luna, Agustin, Pinero, Janet, Furlong, Laura, Balaur, Irina, Rougny, Adrien, Jarosz, Yohan, Overall, Rupert, Phair, Robert, Perfetto, Livia, Matthews, Lisa, Rex, Devasahayam, Orlic-Milacic, Marija, Monraz Gomez, Luis, de Meulder, Bertrand, Ravel, Jean, Jassal, Bijay, Satagopam, Venkata, Wu, Guanming, Golebiewski, Martin, Gawron, Piotr, Calzone, Laurence, Beckmann, Jacques, Evelo, Chris, d'Eustachio, Peter, Schreiber, Falk, Saez-Rodriguez, Julio, Dopazo, Joaquin, Kuiper, Martin, Valencia, Alfonso, Wolkenhauer, Olaf, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Computational systems biology and optimization (Lifeware), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay, University of Luxembourg [Luxembourg], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Maastricht Centre for Systems Biology [Maastricht] (MaCSBio), Maastricht University [Maastricht], Ontario Institute for Cancer Research [Canada] (OICR), Ontario Institute for Cancer Research, Keio University, Luxembourg Centre For Systems Biomedicine (LCSB), University of Konstanz, Hochschule Mittweida - University of Applied Sciences, Kanagawa Institute of Technology, Heidelberg University Hospital [Heidelberg], National Institute for Infectious Diseases 'Lazzaro Spallanzani', Hospital Universitario Virgen del Rocío [Sevilla], Biomedicine Institute of Sevilla [Seville, Spain], University of Nebraska–Lincoln, University of Nebraska System, Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU), Barcelona Supercomputing Center - Centro Nacional de Supercomputacion (BSC - CNS), Harvard Medical School [Boston] (HMS), Universitat Pompeu Fabra [Barcelona] (UPF), National Institute of Advanced Industrial Science and Technology (AIST), Humboldt University Of Berlin, Integrative Bioinformatics Inc [Mountain View], Department of Informatics and System Sciences (Sapienza University of Rome), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Yenepoya University, Janet Piñero, Laura I. Furlong: IMI2-JU grants, resources which are composed of financial contributions from the European Union’s Horizon 2020 Research and Innovation Programme and EFPIA [GA: 777365 eTRANSAFE], and the EU H2020 Programme [GA:964537 RISKHUNT3R], Project 001-P-001647—Valorisation of EGA for Industry and Society funded by the European Regional Development Fund (ERDF) and Generalitat de Catalunya, and Institute of Health Carlos III (project IMPaCT-Data, exp. IMP/00019), co-funded by the European Union, European Regional Development Fund (ERDF, 'A way to make Europe').
Subjects: SARS-CoV-2, disease maps, systems biology, dynamic models, systems medicine, large-scale community effort, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], mechanistic models
Abstract: The COVID-19 Disease Map project is a large-scale community effort uniting 277 scientists from 130 Institutions around the globe. We use high-quality, mechanistic content describing SARS-CoV-2-host interactions and develop interoperable bioinformatic pipelines for novel target identification and drug repurposing. Community-driven and highly interdisciplinary, the project is collaborative and supports community standards, open access, and the FAIR data principles. The coordination of community work allowed for an impressive step forward in building interfaces between Systems Biology tools and platforms. Our framework links key molecules highlighted from broad omics data analysis and computational modeling to dysregulated pathways in a cell-, tissue- or patient-specific manner. We also employ text mining and AI-assisted analysis to identify potential drugs and drug targets and use topological analysis to reveal interesting structural features of the map. The proposed framework is versatile and expandable, offering a significant upgrade in the arsenal used to understand virus-host interactions and other complex pathologies.
Published: 2022

18. Dengue expansion in Africa—Not recognized or not happening?

Author: Thomas, Jaenisch, Thomas, Junghanss, Bridget, Wills, Oliver J, Brady, Isabella, Eckerle, Andrew, Farlow, Simon I, Hay, Philip J, McCall, Jane P, Messina, Victor, Ofula, Amadou A, Sall, Anavaj, Sakuntabhai, Raman, Velayudhan, G R William, Wint, Herve, Zeller, Harold S, Margolis, Osman, Sankoh, Heidelberg University Hospital [Heidelberg], Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), University of Oxford [Oxford], Universitätsklinikum Bonn (UKB), Liverpool School of Tropical Medicine (LSTM), United States Army (U.S. Army), Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), European Centre for Disease Prevention and Control (ECDC), Centers for Disease Control and Prevention [San Juan], Centers for Disease Control and Prevention, International Network for the Demographic Evaluation of Populations and Their Health (INDEPTH Network), The expert conference on dengue in Africa in Accra, Ghana, was supported by European Union grant FP7-281803 IDAMS., Members of the Dengue in Africa Study Group: Thierry A. Ouedraogo (Nouna HDSS, Burkina Faso), Oliver J. Brady, Andrew Farlow, Simon I. Hay, Janey P. Messina, (Oxford University, Oxford, UK), Isabella Eckerle (University of Bonn Medical Centre, Bonn, Germany), Moses Gwamaka (Rufiji HDSS, Tanzania), Thomas Jaenisch, Thomas Junghanss (Heidelberg University Hospital, Heidelberg, Germany), Harold S. Margolis (Centers for Disease Control and Prevention, San Juan, Puerto Rico, USA), Philip J. McCall (Liverpool School of Tropical Medicine, Liverpool, UK), Abraham Oduro (Navrongo HDSS, Ghana), Victor Ofula (US Army Medical Research Unit–Kenya, Nairobi, Kenya), Osman Sankoh (INDEPTH Network, Accra, Ghana and University of the Witwatersrand, Johannesburg, South Africa), Anavaj Sakunthabhai (Institut Pasteur, Paris, France), Amadou A. Sall (Institut Pasteur, Dakar, Senegal), Herrmann Sorgho (Nanoro HDSS, Burkina Faso), Alfred Tiono (Sapone HDSS, Burkina Faso), Raman Velayudhan (World Health Organization, Geneva), Bridget Wills (Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam), G.R. William Wint (Environmental Research Group Limited, Oxford, UK), Hervé Zeller (European Centre for Disease Control and Prevention, Stockholm, Sweden)., European Project: 281803,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,IDAMS(2011), University of Oxford, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and European Centre for Disease Prevention and Control [Stockholm, Sweden] (ECDC)
Subjects: Economic growth, Mosquito Control, Endemic Diseases, Happening, lcsh:Medicine, MESH: Dengue, Dengue virus, MESH: Africa, medicine.disease_cause, Diagnostic tools, MESH: Dengue Virus, Dengue fever, Disease Outbreaks, disease burden, Health services, 0302 clinical medicine, expansion, Aedes, Health care, diagnostics, MESH: Animals, 030212 general & internal medicine, MESH: Incidence, MESH: Disease Outbreaks, MESH: Mosquito Control, Health Policy, Incidence, MESH: Aedes, Online Report, 3. Good health, Infectious Diseases, disease incidence, MESH: Endemic Diseases, MESH: Health Policy, epidemiology, policy, Microbiology (medical), Dengue Expansion in Africa—Not Recognized or Not Happening?, 030231 tropical medicine, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, parasitic diseases, medicine, Animals, Humans, lcsh:RC109-216, viruses, Health policy, MESH: Humans, dengue virus, business.industry, lcsh:R, medicine.disease, dengue, Africa, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Endemic diseases, business, vector
Abstract: Addressing this expansion is essential before control and prevention of dengue are implemented., An expert conference on Dengue in Africa was held in Accra, Ghana, in February 2013 to consider key questions regarding the possible expansion of dengue in Africa. Four key action points were highlighted to advance our understanding of the epidemiology of dengue in Africa. First, dengue diagnostic tools must be made more widely available in the healthcare setting in Africa. Second, representative data need to be collected across Africa to uncover the true burden of dengue. Third, established networks should collaborate to produce these types of data. Fourth, policy needs to be informed so the necessary steps can be taken to provide dengue vector control and health services.
Published: 2014

19. Plasmodium Gametocyte Inhibition Identified from a Natural-Product-Based Fragment Library

Author: Wesley C. Van Voorhis, Hoan Vu, Katherine T. Andrews, Marc Ronald Campitelli, Katharine R. Trenholme, Catherine Roullier, Ronald J. Quinn, Gregory J. Crowther, Tina S. Skinner-Adams, Donald L. Gardiner, Département Réseaux, Information, Multimédia (RIM-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Centre G2I, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Agriculture Flagship, Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Zentrum für Infektiologie [Heidelberg, Germany], Universität Heidelberg [Heidelberg]-Heidelberg University Hospital [Heidelberg], Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Universität Heidelberg [Heidelberg] = Heidelberg University-Heidelberg University Hospital [Heidelberg]
Subjects: Spectrometry, Mass, Electrospray Ionization, Recombinant Fusion Proteins, Plasmodium falciparum, Protozoan Proteins, Biology, 01 natural sciences, Biochemistry, Small Molecule Libraries, 03 medical and health sciences, chemistry.chemical_compound, Antimalarials, Lactones, Structure-Activity Relationship, Alkaloids, Piperidines, Gametocyte, Structure–activity relationship, [CHIM]Chemical Sciences, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Biological sciences, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Biological Products, Life Cycle Stages, Natural product, Dose-Response Relationship, Drug, 010405 organic chemistry, General Medicine, Azepines, biology.organism_classification, Plasmodium gametocyte, Enzyme assay, Heterocyclic Compounds, Bridged-Ring, 3. Good health, 0104 chemical sciences, Kinetics, chemistry, Immunology, biology.protein, Molecular Medicine, Deoxyuracil Nucleotides
Abstract: Fragment-based screening is commonly used to identify compounds with relatively weak but efficient localized binding to protein surfaces. We used mass spectrometry to study fragment-sized three-dimensional natural products. We identified seven securinine-related compounds binding to Plasmodium falciparum 2′-deoxyuridine 5′-triphosphate nucleotidohydrolase (PfdUTPase). Securinine bound allosterically to PfdUTPase, enhancing enzyme activity and inhibiting viability of both P. falciparum gametocyte (sexual) and blood (asexual) stage parasites. Our results provide a new insight into mechanisms that may be applicable to transmission-blocking agents.
Published: 2013

20. Dengue Research Funded by the European Commission-Scientific Strategies of Three European Dengue Research Consortia

Author: Axel Kroeger, Fernando Augusto Bozza, Gavin Screaton, Peter Byass, Joacim Rocklöv, Bernard Cazelles, Marco Vignuzzi, Simon Hay, Annelies Wilder-Smith, Bridget Wills, Kerstin Rosenberger, Jeremy Farrar, Gabriela Maron, Adriana Tami, Michael Schreiber, Ernesto T A Marques, Andrea Caprara, Eric Daudé, Section Clinical Tropical Medicine [Heidelberg], Department of Infectious Diseases [Heidelberg, Germany], Heidelberg University Hospital [Heidelberg]-Heidelberg University Hospital [Heidelberg], Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Public Health and Clinical Medicine, Umeå University, This work was supported by the IDAMS project (European Union 7th FP, grant 281803), the DENFREE project (European Union 7th FP, grant 282378), and the DengueTools project (European Union 7th FP, grant 282589)., IDAMS - International Research Consortium on Dengue Risk Assessment, Management, and Surveillance : Thomas Jaenisch, Thomas Junghanss, Kerstin Rosenberger, Jaswinder Kaur (Section Clinical Tropical Medicine, Heidelberg Universty Hospital), Simon Hay, Janey Messina, Adrian Hill (Oxford University), Bridget Wills, Cameron Simmons, Marcel Wolbers, Jeremy Farrar (Oxford University Clinical Research Unit, Vietnam), Phil McCall (Liverpool School of Tropical Medicine), Antonio Lanzavecchia, Federica Sallusto (Institute for Research in Biomedicine, Bellinzona, Switzerland), Axel Kroeger, Silvia Runge-Ranzinger (TDR-WHO), Lucy Lum (University of Malaya Medical Center), Ida Safitri (Gadja Madah University, Indonesia), Varun Kumar (Angkor Hospital for Children, Cambodia), Maria Guzman (Instituto Pedro Kouri, Cuba), Gabriela Maron, Ernesto Pleitess (Hospital National de Ninos Benjamin Bloom, San Salvador), Andrea Caprara, Bruno Benevides (State University of Ceara, Brazil), Willy Wint (Environmental Research Group Oxford Ltd.), Osman Sankoh (INDEPTH-Network, Ghana), Fleur Monasso (Red Cross/Red Crescent Climate Centre, The Netherlands), Adriana Tami (University of Carabobo, Venezuela), Ernesto T. A. Marques, Fernando A. Bozza (FIOCRUZ, Brazil), DENFREE - Dengue Research Framework for Resisting Epidemics in Europe : Anavaj Sakuntabhai, Richard Paul, Félix Rey, Anna-Bella Failloux, Marco Vignuzzi, Louis Lambrechts (Institut Pasteur, France), Gavin Screaton, Juthathip Mongkolsapaya (Imperial College, United Kingdom), Michael Schreiber, Rolf Horstmann (Bernard Nocht Institute, Germany), Pattamaporn Kittayapong, Pratap Singhasivanon, Sutee Yoksan (Mahidol University, Thailand), Philippe Buchy, Vincent Deubel (Institut Pasteur Cambodia, Cambodia), Xavier Rodó (Fundacio Institut Catala De Ciencies Del Clima, Spain), Eric Daude, Alain Vaguet (University of Rouen, France), Bernard Cazelles (CNRS, France), Nico Stollenwerk (Cmaf, Fundacao Da Faculdade De Ciencias Da Universidade De Lisboa, Portugal), Luísa Pereira (Instituto De Patologia E Imunologia Molecular Da Universidade Do Porto, Portugal), Timo Kanninen (Biocomputing Platforms Ltd Oy, Finland), Guido Krupp (Amptec Gmbh, Germany), Mark Thursz (Riotech Pharmaceticals Ltd, United Kingdom), María G. Guzmán (Instituto Pedro Kouri, Cuba), DengueTools - Innovative Tools and Strategies for the Surveillance and Control of Dengue : Annelies Wilder-Smith, Joacim Rocklöv, Peter Byass (Umeå University, Sweden), Paba Palihawadana, Hasitha Tissera (Epidemiological Unit, Ministry of Health, Sri Lanka), David Brooks (TwistDx Ltd, UK), Sazaly Abu Bakar (University of Malaya), Luke Alphey (Oxitec Ltd, UK), Pattamaporn Kittayapong (Mahidol University, Thailand), Steve Lindsay, James Logan (London School of Hygiene and Tropical Medicine, UK), Christoph Hatz, Andreas Neumayr (Swiss Tropical and Public Health Institute), Paul Reiter (Institut Pasteur, France), Yesim Tozan, Valérie R. Louis (Heidelberg University Hospital), Duane Gubler (Duke-NUS Graduate Medical School Singapore), Eduardo Massad (University of Sao Paolo), Antonio Tenorio (Instituto de Salud Carlos III), Christophe Lagneau, Grégory L'Ambert (Entente Inter-Départementale pour la Démoustication du littoral Mediterranéen), European Project: 281803,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,IDAMS(2011), European Project: 282378,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENFREE(2012), European Project: 282589,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENGUETOOLS(2011), Microbes in Health and Disease (MHD), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Medical Research Council (MRC)
Subjects: Economic growth, Biomedical Research, Infektionsmedicin, MESH: Dengue/prevention & control, Dengue virus, medicine.disease_cause, Dengue fever, Capital Financing, Dengue, IDAMS, 0302 clinical medicine, DENFREE, 030212 general & internal medicine, Chikungunya, MESH: Capital Financing, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), media_common, Disease surveillance, education.field_of_study, lcsh:Public aspects of medicine, Health Policy, Public Health, Global Health, Social Medicine and Epidemiology, 11 Medical And Health Sciences, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, epidemiology, MESH: Health Policy, DengueTools, Infectious Medicine, lcsh:Arctic medicine. Tropical medicine, lcsh:RC955-962, 030231 tropical medicine, Population, MESH: Dengue/epidemiology, Biology, 03 medical and health sciences, Tropical Medicine, MESH: Biomedical Research/trends, MESH: European Union, medicine, media_common.cataloged_instance, Humans, European Union, European union, education, Health policy, MESH: Humans, business.industry, Policy Platform, Public Health, Environmental and Occupational Health, International health, lcsh:RA1-1270, 06 Biological Sciences, medicine.disease, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, 13. Climate action, business
Abstract: Dengue is a major international public health concern and one of the most important arthropod-borne diseases [1]. Approximately 2.5 billion people—40% of the world's population, in over 100 countries—are at risk of dengue virus (DENV) infection [2]. In recent years the average annual incidence of dengue-related serious disease in many tropical counties has been rising dramatically, with the infection becoming endemic in areas where its occurrence was once sporadic [3]. The exponential increase over the last decade has been connected to societal changes, such as population growth and increasing urbanization [4]. In addition, it has been suggested that rising temperatures and global climate change may lead to the expansion of the range of major mosquito vectors into new areas, extension of the transmission season in current endemic areas, and increase in the mosquito species vectorial capacity [5]–[7]. Human migration (likely including infected hosts) and international travel are constantly introducing new vectors and pathogens into novel geographic areas [8]. For example, chikungunya virus was introduced into northeastern Italy in 2007, causing an outbreak with local transmission due to the presence of Aedes albopictus, a vector also capable of transmitting dengue virus [9]. In 2010, three authochthonous cases of dengue were reported in Europe, thereby highlighting the potential for global spread of this disease [10], [11]. The island of Madeira, where the mosquito vector Aedes aegypti is present, experienced a major dengue outbreak in the fall of 2012 [12], highlighting that the introduction of dengue to non-endemic areas is a real threat. Dengue has been neglected for many years. Major research gaps for dengue exist in the areas of epidemiology under changing climate conditions, clinical management, pathogenesis, vector control, surveillance and response, vaccines, drugs, and health policy research [13]. The European Commission (EC) launched a call under the Seventh Framework Programme with the title of “Comprehensive control of Dengue fever under changing climatic conditions” (http://ec.europa.eu/research/participants/portal/page/cooperation?callIdentifier=FP7-HEALTH-2011-single-stage). The focus of this call is summarized in Box 1. Within this framework, in 2011, the EC awarded a total of approximately €18 million to three consortia. The hosting institutions are Heidelberg University Hospital (Germany), the Institute Pasteur (Paris, France), and Umea University (Sweden). Each consortium has partners from countries with endemic and epidemic dengue. In total, the consortia comprise 38 partners from 21 countries, of which 11 are from Asia and Latin America, the current hotspots of dengue endemicity, and one from Africa (Figure 1). Figure 1 The world map of the three EU-funded dengue consortia. Box 1. European Commission Seventh Framework Programme FP7 Cooperation - Health HEALTH.2011.2.3.3-2: Comprehensive control of Dengue fever under changing climatic conditions. FP7-HEALTH-2011-single-stage Research should develop innovative tools for one or more of the following aspects: better diagnosis, surveillance, development of treatment, prevention and vaccination strategies, prevention, and/or prediction and prevention of the spread of dengue fever to previously uninfected regions (including Europe), in the context of climate change. Research may also include studies on the underlying pathogenesis with respect to viral and host factors that can predict disease severity and prepare for further development of new vaccines, antiviral compounds, and more targeted treatment schemes. Funding Scheme Specific International Cooperation Action (SICA) Collaborative Project (small- or medium-scale focused research project) target regions: Latin America and/or Asia. SICA aims to bring about the balanced participation of third countries in collaboration with European partners. Expected Impact Better tools, and the use thereof, for improved comprehensive control of dengue fever at a global level. Participation from both SICA target regions and Small and Medium Enterprises SMEs in the projects should help ensure innovation and exploitation of the results in this area/topic. The degree of such participation will be considered during the evaluation. Source: http://ec.europa.eu/research/health/infectious-diseases/emerging-epidemics/call-for-proposals_en.html The funding of such a large and complex research programme focusing on a single disease highlights the emphasis that the European Commission has put on dengue and its potential threat to Europe. In this paper, we present these three consortia and outline their scientific strategies and potential role within the international dengue research community.
Published: 2013

21. Strengthening Altitude Knowledge: A Delphi Study to Define Minimum Knowledge of Altitude Illness for Laypersons Traveling to High Altitude

Author: Remco R, Berendsen, Peter, Bärtsch, Buddha, Basnyat, Marc Moritz, Berger, Peter, Hackett, Andrew M, Luks, Jean-Paul, Richalet, Ken, Zafren, Bengt, Kayser, D R, Woods, Leiden University Medical Center (LUMC), Heidelberg University Hospital [Heidelberg], Oxford University Clinical Research Unit [Kathmandu], University of Duisburg-Essen, University of Colorado Anschutz [Aurora], University of Washington [Seattle], Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, Stanford University, Université de Lausanne = University of Lausanne (UNIL), STAK Plenary Group: J Anholm, P S Auerbach, B A Beidleman, K E Bloch, M Brodmann, H Brugger, M Burtscher, C Dehnert, L Dumont, M Faulhaber, R Fischer, H Gatterer, F Gekeler, C K Grissom, M P W Grocott, D Hillebrandt, B Honigman, C Imray, M S Koehle, G S Lipman, J A Loeppky, M Maggiorini, L G Moore, S R Muza, M Pun, R C Roach, C Sartori, U Scherrer, G Sikri, A W Subudhi, E R Swenson, A A Thompson, S Verges, D R Woods, SALAS, Danielle, STAK Plenary Group, Anholm, J., Auerbach, P.S., Beidleman, B.A., Bloch, K.E., Brodmann, M., Brugger, H., Burtscher, M., Dehnert, C., Dumont, L., Faulhaber, M., Fischer, R., Gatterer, H., Gekeler, F., Grissom, C.K., Grocott, MPW, Hillebrandt, D., Honigman, B., Imray, C., Koehle, M.S., Lipman, G.S., Loeppky, J.A., Maggiorini, M., Moore, L.G., Muza, S.R., Pun, M., Roach, R.C., Sartori, C., Scherrer, U., Sikri, G., Subudhi, A.W., Swenson, E.R., Thompson, A.A., Verges, S., and Woods, D.R.
Subjects: laypersons, education, Physiology, [SDV]Life Sciences [q-bio], Public Health, Environmental and Occupational Health, Medizin, altitude illness, General Medicine, trekking, Humans, Altitude Sickness/prevention & control, Altitude, Delphi Technique, Acute Disease, Brain Edema, acclimatization, acute mountain sickness, expeditions to high altitude, [SDV] Life Sciences [q-bio]
Abstract: International audience; Berendsen, Remco R., Peter Bärtsch, Buddha Basnyat, Marc Moritz Berger, Peter Hackett, Andrew M. Luks, Jean-Paul Richalet, Ken Zafren, Bengt Kayser, and the STAK Plenary Group. Strengthening altitude knowledge: a Delphi study to define minimum knowledge of altitude illness for laypersons traveling to high altitude. High Alt Med Biol. 00:000-000, 2022. Introduction: A lack of knowledge among laypersons about the hazards of high-altitude exposure contributes to morbidity and mortality from acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE) among high-altitude travelers. There are guidelines regarding the recognition, prevention, and treatment of acute-altitude illness for experts, but essential knowledge for laypersons traveling to high altitudes has not been defined. We sought expert consensus on the essential knowledge required for people planning to travel to high altitudes. Methods: The Delphi method was used. The panel consisted of two moderators, a core expert group and a plenary expert group. The moderators made a preliminary list of statements defining the desired minimum knowledge for laypersons traveling to high altitudes, based on the relevant literature. These preliminary statements were then reviewed, supplemented, and modified by a core expert group. A list of 33 statements was then presented to a plenary group of experts in successive rounds. Results: It took three rounds to reach a consensus. Of the 10 core experts invited, 7 completed all the rounds. Of the 76 plenary experts, 41 (54%) participated in Round 1, and of these 41 a total of 32 (78%) experts completed all three rounds. The final list contained 28 statements in 5 categories (altitude physiology, sleeping at altitude, AMS, HACE, and HAPE). This list represents an expert consensus on the desired minimum knowledge for laypersons planning high-altitude travel. Conclusion: Using the Delphi method, the STrengthening Altitude Knowledge initiative yielded a set of 28 statements representing essential learning objectives for laypersons who plan to travel to high altitudes. This list could be used to develop educational interventions.
Published: 2022

22. Le virus de la fièvre de la vallée du Rift et son étonnante protéine NSs

Author: Pierre-Yves Lozach, Psylvia Léger, Heidelberg University Hospital [Heidelberg], Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: 0303 health sciences, 03 medical and health sciences, Rift Valley fever virus, 030306 microbiology, viruses, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, General Medicine, Biology, Humanities, General Biochemistry, Genetics and Molecular Biology, 030304 developmental biology, 3. Good health
Abstract: International audience; Rift Valley Fever Virus (RVFV) is an emerging zoonotic pathogen transmitted to humans and livestock through mosquito bites, which was first isolated in Kenya in 1930. The virus is classified by the WHO among the pathogens for which there is an urgent need to develop research, diagnostics, and therapies. However, the efforts developed to control the virus remain limited, and the virus is not well characterized. In this article, we will introduce RVFV and then focus on its virulence factor, the nonstructural protein NSs. We will mainly discuss the ability of this viral protein to form amyloid-like fibrils and its implication in the neurotoxicity associated with RVFV infection.; Le virus de la fièvre de la vallée du Rift (VFVR) est un agent pathogène transmis à l’homme et au bétail par la piqûre de moustiques. Ce virus, découvert au Kenya en 1930, est considéré par l’Organisation mondiale de la santé comme présentant un risque important de provoquer de vastes épidémies. Les moyens dédiés à la lutte contre le VFVR restent toutefois particulièrement limités et le virus est mal connu. Dans cette Synthèse, nous nous attacherons à présenter ce virus avant de nous intéresser plus spécifiquement à son facteur de virulence, la protéine NSs. Nous discuterons la capacité de cette protéine virale à former des fibrilles de type amyloïde et son implication dans la neurotoxicité du virus chez les animaux infectés.
Published: 2021

23. A digital twin of liver predicts regeneration after drug-induced damage at the level of cell type orchestration

Author: Zhao, Jieling, Ghallab, Ahmed, Hassan, Reham, Dooley, Steven, Hengstler, Jan, Drasdo, Dirk, Leibniz Research Centre for Working Environment and Human Factors [Dortmund] (IFADO), Technische Universität Dortmund [Dortmund] (TU), SImulations en Médecine, BIOtechnologie et ToXicologie de systèmes multicellulaires (SIMBIOTX ), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Heidelberg University Hospital [Heidelberg], and ANR-16-RHUS-0005,iLite,iLite(2016)
Subjects: Tissue microarchitecture, Agent-based model, Digital liver twin, Liver regeneration, Liver lobule, Cell-cell signaling, DILI, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell types
Abstract: This communication presents a mathematical mechanism-based model of the regenerating liver after drug-induced pericentral lobule damage resolving tissue microarchitecture. The consequence of alternative hypotheses about the interplay of different cell types on regeneration were simulated. Regeneration dynamics has been quantified by the size of the damage-induced dead cell area, the hepatocyte density and the spatial-temporal profile of the different cell types. We use deviations of observed trajectories from simulated system to identify branching points, at which the systems behavior cannot be explained by the underlying set of hypotheses anymore. Our procedure reflects a successful strategy for generating a fully digital liver-twin that, among others, permits to test perturbations from the molecular up to the tissue scale. The model simulations are complementing current knowledge on liver regeneration by identifying gaps in mechanistic relationships and guiding the system towards the most informative (lacking) parameters that can be experimentally addressed.
Published: 2022

24. A Delphi consensus statement for digital surgery

Author: Kyle Lam, Michael D. Abràmoff, José M. Balibrea, Steven M. Bishop, Richard R. Brady, Rachael A. Callcut, Manish Chand, Justin W. Collins, Markus K. Diener, Matthias Eisenmann, Kelly Fermont, Manoel Galvao Neto, Gregory D. Hager, Robert J. Hinchliffe, Alan Horgan, Pierre Jannin, Alexander Langerman, Kartik Logishetty, Amit Mahadik, Lena Maier-Hein, Esteban Martín Antona, Pietro Mascagni, Ryan K. Mathew, Beat P. Müller-Stich, Thomas Neumuth, Felix Nickel, Adrian Park, Gianluca Pellino, Frank Rudzicz, Sam Shah, Mark Slack, Myles J. Smith, Naeem Soomro, Stefanie Speidel, Danail Stoyanov, Henry S. Tilney, Martin Wagner, Ara Darzi, James M. Kinross, Sanjay Purkayastha, Lam, Kyle [0000-0001-6407-4912], Abràmoff, Michael D [0000-0002-3490-0037], Fermont, Kelly [0000-0002-0733-8958], Neto, Manoel Galvao [0000-0003-4549-3606], Hager, Gregory D [0000-0002-6662-9763], Langerman, Alexander [0000-0003-0866-463X], Logishetty, Kartik [0000-0002-0469-9539], Mascagni, Pietro [0000-0001-7288-3023], Mathew, Ryan K [0000-0002-2609-9876], Neumuth, Thomas [0000-0001-6999-5024], Pellino, Gianluca [0000-0002-8322-6421], Shah, Sam [0000-0002-7743-8479], Wagner, Martin [0000-0002-9831-9110], Darzi, Ara [0000-0001-7815-7989], Kinross, James M [0000-0002-0427-7643], Purkayastha, Sanjay [0000-0003-0187-8328], Apollo - University of Cambridge Repository, Lam, Kyle, Abràmoff, Michael D, Balibrea, José M, Bishop, Steven M, Brady, Richard R, Callcut, Rachael A, Chand, Manish, Collins, Justin W, Diener, Markus K, Eisenmann, Matthia, Fermont, Kelly, Neto, Manoel Galvao, Hager, Gregory D, Hinchliffe, Robert J, Horgan, Alan, Jannin, Pierre, Langerman, Alexander, Logishetty, Kartik, Mahadik, Amit, Maier-Hein, Lena, Antona, Esteban Martín, Mascagni, Pietro, Mathew, Ryan K, Müller-Stich, Beat P, Neumuth, Thoma, Nickel, Felix, Park, Adrian, Pellino, Gianluca, Rudzicz, Frank, Shah, Sam, Slack, Mark, Smith, Myles J, Soomro, Naeem, Speidel, Stefanie, Stoyanov, Danail, Tilney, Henry S, Wagner, Martin, Darzi, Ara, Kinross, James M, Purkayastha, Sanjay, Imperial College London, University of Iowa [Iowa City], University College of London [London] (UCL), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Johns Hopkins University (JHU), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Heidelberg University Hospital [Heidelberg], Universität Leipzig, Johns Hopkins University School of Medicine [Baltimore], Infrastructure support for this research was provided by the NIHR Imperial Biomedical Research Centre (BRC). M.D.A. is supported in part by The Robert C. Watzke MD Professorship as well as Research to Prevent Blindness, Inc, New York, New York (unrestricted grant to the Department of Ophthalmology, and Visual Sciences, University of Iowa. M.E. receives funding from the Helmholtz Imaging Platform (HIP), a platform of the Helmholtz Incubator on Information and Data Science. R.J.H. receives funding from the Enid Linder Foundation & Royal College of Surgeons of England Chair in Trials in Surgery and is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol. L.M.H. receives funding from the Federal Ministry for Economic Affairs and Energy (projects OP4·1 and pAItient), Germany. B.P.M.S. and M.W. receive funding from the German Federal Ministry of Health within project 'Surgomics'. SS receives funding from the German Research Foundation (DFG) as part of Germany’s Excellence Strategy - EXC2050/1 - Project ID 390696704 - Cluster of Excellence 'Centre for Tactile Internet with Human-in-the-Loop' (CeTI), and Imperial College Healthcare NHS Trust- BRC Funding
Subjects: [SDV]Life Sciences [q-bio], education, 8.1 Organisation and delivery of services, Medicine (miscellaneous), Health Informatics, and research governance, 8.3 Policy, 7.3 Management and decision making, 7.1 Individual care needs, Health Information Management, Clinical Research, 8.3 Policy, ethics, and research governance, 692/700/3935, 692/700/1538, 692/700/565/545, Science & Technology, article, 42 Health Sciences, 4203 Health Services and Systems, ethics, Computer Science Applications, Health Care Sciences & Services, Management of diseases and conditions, Patient Safety, Generic health relevance, 8 Health and social care services research, Life Sciences & Biomedicine, 7 Management of diseases and conditions, Medical Informatics, Health and social care services research
Abstract: The use of digital technology is increasing rapidly across surgical specialities, yet there is no consensus for the term ‘digital surgery’. This is critical as digital health technologies present technical, governance, and legal challenges which are unique to the surgeon and surgical patient. We aim to define the term digital surgery and the ethical issues surrounding its clinical application, and to identify barriers and research goals for future practice. 38 international experts, across the fields of surgery, AI, industry, law, ethics and policy, participated in a four-round Delphi exercise. Issues were generated by an expert panel and public panel through a scoping questionnaire around key themes identified from the literature and voted upon in two subsequent questionnaire rounds. Consensus was defined if >70% of the panel deemed the statement important and
Published: 2022

25. Benefit of mechanical thrombectomy in acute ischemic stroke related to calcified cerebral embolus

Author: Téodor Grand, Cyril Dargazanli, Chrysanthi Papagiannaki, Agnetha Bruggeman, Christoph Maurer, Gregory Gascou, Cédric Fauche, Romain Bourcier, Guillaume Tessier, Raphaël Blanc, Malek Ben Machaa, Gaultier Marnat, Xavier Barreau, Julien Ognard, Jean-Christophe Gentric, Charlotte Barbier, Benjamin Gory, Christine Rodriguez, Grégoire Boulouis, François Eugène, Pierre Thouant, Frederic Ricolfi, Kevin Janot, Denis Herbreteau, Omer Faruk Eker, Matteo Cappucci, Tomas Dobrocky, Markus Möhlenbruch, Theo Demerath, Marios Psychogios, Sebastian Fischer, Alessandro Cianfoni, Charles Majoie, Bart Emmer, Henk Marquering, Rémi Valter, Stéphanie Lenck, Kévin Premat, Jonathan Cortese, Didier Dormont, Nader-Antoine Sourour, Eimad Shotar, Yves Samson, Frédéric Clarençon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Rouen, Normandie Université (NU), Amsterdam UMC - Amsterdam University Medical Center, Klinikum Augsburg, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre hospitalier universitaire de Nantes (CHU Nantes), Fondation Ophtalmologique Adolphe de Rothschild [Paris], CHU Bordeaux [Bordeaux], Service de Neuroradiologie [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Bern University Hospital [Berne] (Inselspital), Heidelberg University Hospital [Heidelberg], University of Freiburg [Freiburg], University Hospital Basel [Basel], Universitätsklinikum Knappschaftskrankenhaus = University Hospital Knappschaftskrankenhaus [Bochum], University of Lugano, CHU Henri Mondor [Créteil], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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)-Centre National de la Recherche Scientifique (CNRS), Radiology and Nuclear Medicine, ACS - Microcirculation, ANS - Neurovascular Disorders, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, ANS - Brain Imaging, and Radiology and nuclear medicine
Subjects: Adult, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain Ischemia, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, MESH: Thrombectomy, Radiology, Nuclear Medicine and imaging, Ischemic Stroke, Retrospective Studies, Thrombectomy, MESH: Treatment Outcome, MESH: Intracranial Embolism, MESH: Humans, Radiological and Ultrasound Technology, Clinical outcome, MESH: Brain Ischemia, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], MESH: Adult, MESH: Retrospective Studies, Calcified cerebral embolus, Treatment Outcome, Intracranial Embolism, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Reperfusion, Neurology (clinical), Mechanical thrombectomy, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, MESH: Ischemic Stroke
Abstract: Summary purpose: Mechanical thrombectomies (MT) in patients with large vessel occlusion (LVO) related to calcified cerebral embolus (CCE) have been reported, through small case series, being associated with low reperfusion rate and worse outcome, compared to regular MT. The purpose of the MASC (Mechanical Thrombectomy in Acute Ischemic Stroke Related to Calcified Cerebral Embolus) study was to evaluate the incidence of CCEs treated by MT and the effectiveness of MT in this indication. Methods: The MASC study is a retrospective multicentric (n = 37) national study gathering the cases of adult patients who underwent MT for acute ischemic stroke with LVO related to a CCE in France from January 2015 to November 2019. Reperfusion rate (mTICI ≥ 2B), complication rate and 90-day mRS were systematically collected. We then conducted a systematic review by searching for articles in PubMed, Cochrane Library, Embase and Google Scholar from January 2015 to March 2020. A meta-analysis was performed to estimate clinical outcome at 90 days, reperfusion rate and complications. Results: We gathered data from 35 patients. Reperfusion was obtained in 57% of the cases. Good clinical outcome was observed in 28% of the patients. The meta-analysis retrieved 136 patients. Reperfusion and good clinical outcome were obtained in 50% and 29% of the cases, respectively. Conclusion: The MASC study found worse angiographic and clinical outcomes compared to regular thrombectomies. Individual patient-based meta-analysis including the MASC findings shows a 50% reperfusion rate and a 29% of good clinical outcome.
Published: 2022

26. Dynamic risk assessment to improve quality of care in patients with atrial fibrillation

Author: Ursula Ravens, Bushra S. Ilyas, Ulrich Schotten, Isabelle C. Van Gelder, Christian G Meyer, Burcu Vardar, Elena Andreassi Marinelli, Moritz F. Sinner, Stephan Willems, Christophe Leclercq, Renate B. Schnabel, Doreen Haase, Larissa Fabritz, Dierk Thomas, Dobromir Dobrev, Mattias Wieloch, Jeff S. Healey, Emma Svennberg, Paul D. Ziegler, Christina Easter, Stefan H. Hohnloser, Gregory Y.H. Lip, Gerhard Hindricks, A. John Camm, Andreas Goette, Monika Stoll, Irina Savelieva, Tatjana S. Potpara, Guenter Breithardt, Stéphane N. Hatem, Karl Georg Häusler, Rüdiger Smolnik, Alice J Sitch, Reza Wakili, Jan Steffel, Helmut Pürerfellner, Winnie Chua, José L. Merino, Anthony W.S. Chan, Harry J.G.M. Crijns, Thomas Huebner, Paulus Kirchhof, Christina Dimopoulou, Thorsten Lewalter, Stef Zeemering, Kenneth M. Stein, Mirko De Melis, Eduard Guasch, Jordi Heijman, Dipak Kotecha, Lluís Mont, Jonas Oldgren, Michael Nabauer, Michiel Rienstra, Ingo Kutschka, Aaron Isaacs, Lars Eckardt, Hein Heidbuchel, Cardiovascular Centre (CVC), University of Birmingham [Birmingham], University Hospitals Birmingham [Birmingham, Royaume-Uni], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], University of Barcelona, University Hospital of Würzburg, University Hospital Hamburg-Eppendorf, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), University of Belgrade [Belgrade], University Medical Center Groningen [Groningen] (UMCG), Asklepios Klinik St. Georg, University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), University of London [London], Pfizer, Medtronic Inc [Minneapolis, MI, USA], European Society of Cardiology (ESC), University Hospital [Essen, Germany], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Population Health Research Institute [Hamilton, ON, Canada], Goethe-Universität Frankfurt am Main, University Hospital Göttingen, CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Liverpool, La Paz University Hospital, Universitat de Barcelona (UB), University-Hospital Munich-Großhadern [München], Uppsala University, Ordensklinikum Linz Elisabethinen, St George's, University of London, Universität Zürich [Zürich] = University of Zurich (UZH), Boston Scientific, Karolinska Institutet [Stockholm], Heidelberg University Hospital [Heidelberg], University of Groningen [Groningen], University Hospital Essen, SANOFI Recherche, University of Antwerp (UA), Leipzig University, EHRA, 633196, EU Horizon 2020, AFNet, AFNET, MUMC+: MA Cardiologie (9), Cardiologie, RS: Carim - H01 Clinical atrial fibrillation, Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Biochemie, RS: Carim - H08 Experimental atrial fibrillation, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Technology, Quality management, Rate control, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Medizin, 030204 cardiovascular system & hematology, 0302 clinical medicine, Risk Factors, 030212 general & internal medicine, Stroke, Research priorities, CATHETER ABLATION, ROADMAP, Integrated care, Atrial fibrillation, 3. Good health, OPPORTUNITIES, Treatment Outcome, Consensus statement, Screening, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Rhythm control, Cognitive function, Cardiology and Cardiovascular Medicine, Risk assessment, medicine.medical_specialty, Consensus, Catheter ablation, Heart failure, Outcomes, DIAGNOSIS, Risk Assessment, CLASSIFICATION, 03 medical and health sciences, Big data, Anticoagulation, FUTURE, Physiology (medical), medicine, MANAGEMENT, Humans, Intensive care medicine, Atrial cardiomyopathy, business.industry, Research, Bleeding, Quality of care, Anticoagulants, EHRA, medicine.disease, Lifestyle, AFNET, Comorbidity, PREVENTION, REDUCTION, Human medicine, business
Abstract: Aims The risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes. Methods and results This article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence. Conclusion The remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.
Published: 2021

27. The Human Formin FHOD1 Contains a Bipartite Structure of FH3 and GTPase-Binding Domains Required for Activation

Author: Antje Schulte, Bettina Stolp, Matthias Geyer, Olena Pylypenko, Alexey Rak, Oliver T. Fackler, André Schönichen, Motilité structurale, Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Department of Infectious Diseases, Integrative Virology [Heidelberg, Allemagne], Center for Integrative Infectious Diseases Research [Heidelberg, Allemagne] (CIID), Heidelberg University Hospital [Heidelberg]-Heidelberg University Hospital [Heidelberg], Group Physical Biochemistry, Center of Advanced European Studies and Research, and Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Fetal Proteins, Models, Molecular, PROTEINS, [SDV]Life Sciences [q-bio], Amino Acid Motifs, Molecular Sequence Data, Mutation, Missense, Formins, macromolecular substances, GTPase, Biology, Transfection, Models, Biological, GTP Phosphohydrolases, Mice, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, Animals, Humans, Amino Acid Sequence, Molecular Biology, Conserved Sequence, Actin, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Armadillo Domain Proteins, 0303 health sciences, Sequence Homology, Amino Acid, Nuclear Proteins, Actin remodeling, Protein Structure, Tertiary, Cell biology, Enzyme Activation, SIGNALING, Armadillo repeats, NIH 3T3 Cells, biology.protein, Profilin binding, MDia1, 030217 neurology & neurosurgery, Protein Binding, GTPase binding
Abstract: SummaryFormins induce the nucleation and polymerization of unbranched actin filaments. They share three homology domains required for profilin binding, actin polymerization, and regulation. Diaphanous-related formins (DRFs) are activated by GTPases of the Rho/Rac family, whose interaction with the N-terminal formin domain is thought to displace a C-terminal Diaphanous-autoregulatory domain (DAD). We have determined the structure of the N-terminal domains of FHOD1 consisting of a GTPase-binding domain (GBD) and the DAD-recognition domain FH3. In contrast to the formin mDia1, the FHOD1-GBD reveals a ubiquitin superfold as found similarly in c-Raf1 or PI3 kinase. This GBD is recruited by Rac and Ras GTPases in cells and plays an essential role for FHOD1-mediated actin remodeling. The FHOD1-FH3 domain is composed of five armadillo repeats, similarly to other formins. Mutation of one residue in the predicted DAD-interaction surface efficiently activates FHOD1 in cells. These results demonstrate that DRFs have evolved different molecular solutions to govern their autoregulation and GTPase specificity.
Published: 2008

28. Objective neurocognitive functioning and neurocognitive complaints in patients with high-grade glioma

Author: Martin J. van den Bent, Martin Klein, Andrew Bottomley, Wolfgang Wick, Jos W. R. Twisk, Jaap C. Reijneveld, A Josephine Drijver, Ahmed Idbaih, Madeline Pe, Ivan Caramanna, Neurology, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Vrije Universiteit Amsterdam [Amsterdam] (VU), European Organisation for Research and Treatment of Cancer [Bruxelles] (EORTC), European Cancer Organisation [Bruxelles] (ECCO), VU University Medical Center [Amsterdam], Erasmus University Medical Center [Rotterdam] (Erasmus MC), 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), Heidelberg University Hospital [Heidelberg], Clinical Neuropsychology, Medical psychology, Epidemiology and Data Science, APH - Health Behaviors & Chronic Diseases, APH - Methodology, CCA - Cancer Treatment and quality of life, Gestionnaire, HAL Sorbonne Université 5, Unité de recherche de l'institut du thorax (ITX-lab), 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], and 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)
Subjects: 0301 basic medicine, Male, Health Knowledge, Attitudes, Practice, Cancer Research, Cognition Disorders/etiology, Health-related quality of life, Neuropsychological Tests, Correlation, High-grade glioma, 0302 clinical medicine, Quality of life, Surveys and Questionnaires, Medicine, Practice, Brain Neoplasms, Health Knowledge, Cognition, Glioma, Middle Aged, Mental Status and Dementia Tests, Prognosis, humanities, 3. Good health, Europe, Oncology, 030220 oncology & carcinogenesis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Clinical psychology, Cognitive awareness, Concordance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Glioma/complications, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cognitive skill, business.industry, Cancer, medicine.disease, Clinical trial, Neurocognitive functioning, 030104 developmental biology, Cross-Sectional Studies, Brain Neoplasms/complications, Attitudes, Quality of Life, PROs, Cognition Disorders, business, Neurocognitive, Follow-Up Studies
Abstract: BACKGROUND: Neurocognitively impaired patients with brain tumour are presumed to have reduced cognitive awareness preventing them from adequately valuing and reporting their own functioning, for instance, when providing patient-reported outcomes (PROs) such as health-related quality of life instruments. In this cross-sectional study, we aimed at assessing the concordance of neurocognitive complaints (NCCs) and objective neurocognitive functioning (NCF) as a measure of cognitive awareness.METHODS: NCF was assessed using an internationally accepted clinical trial battery. NCC was assessed using the cognitive functioning questionnaire from the Medical Outcome Study (MOS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire cognitive functioning subscale. Patients were divided in cognitively impaired and unimpaired groups, based on their NCF performance. Pearson's correlation coefficients between NCF and NCCs were calculated. The same procedure was used to evaluate the correlation of NCF and QLQ-C30 CF subscale.RESULTS: Data from EORTC trials 26091 and 26101 were pooled into a data set of 546 patients. Twenty percent of patients could be characterised as unimpaired (109) and 80% as impaired (437). Impaired patients reported more cognitive complaints on the MOS scale than unimpaired patients. Correlations between NCF and NCCs were weak but significant for impaired patients and non-significant for unimpaired ones. Similar results were found for the correlation between NCF test performance and the QLQ-C30 CF subscale.CONCLUSION: Correlations between NCF test scores and complaints were weak but suggesting that neurocognitive impairment in patients with HGG does not preclude cognitive awareness. However, considering the findings of this study, we would suggest not to use PROs as a surrogate of performance-based neurocognitive evaluation.
Published: 2021

29. Spatial intratumoral heterogeneity of proliferation in immunohistochemical images of solid tumors

Author: Jäger, Dirk [Department of Medical Oncology, National Center for Tumor Diseases, German Cancer Research Center, Heidelberg 69120, Germany and National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg 69120 (Germany)]
Published: 2016
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30. Recovery of adhesion to chondroitin-4-sulphate in Plasmodium falciparum varCSA disruption mutants by antigenically similar PfEMP1 variants

Author: Andrews, Katherine, Pirrit, Lindsay, Przyborski, Jude, Sanchez, Cecilia, Sterkers, Yvon, Ricken, Sigrid, Wickert, Hannes, Lepolard, Catherine, Avril, Marion, Scherf, Artur, Gysin, Jürg, Lanzer, Michael, Zentrum für Infektiologie [Heidelberg, Germany], Universität Heidelberg [Heidelberg]-Heidelberg University Hospital [Heidelberg], Biologie des Interactions Hôte-Parasite - Biology of Host-Parasite Interactions, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Parasitologie Expérimentale, Université de la Méditerranée - Aix-Marseille 2-Biologie des Interactions Hôte-Parasite, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work was supported by the SFB 544 –‘Kontrolle Tropischer Infektionskrankheiten’, the European Commission (QLRT‐PL‐1999‐30109), the Ministère Français de la Recherche et de la Technologie (VIHPAL‐grant 2001), and the Forschungs‐Förderungsprogramm der Medizinischen Fakultät Heidelberg (ADPLAMM‐2001). KTA is supported by an Alexander von Humboldt Fellowship, LAP is supported by CNPq, Brazil., We are grateful to Alan Cowman for advice on transfection. Technical assistance was provided by Elisabeth Wilken, Kathrin Steigleder and Nicole Klatt., Universität Heidelberg [Heidelberg] = Heidelberg University-Heidelberg University Hospital [Heidelberg], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: CD36 Antigens, Erythrocytes, [SDV]Life Sciences [q-bio], Protozoan Proteins, MESH: Cricetinae, MESH: Flow Cytometry, MESH: Plasmodium falciparum/metabolism, MESH: Gene Targeting, Chondroitin ABC Lyase, MESH: Nucleotide Mapping, MESH: Cricetulus, MESH: Antigens, Protozoan/immunology, MESH: Reverse Transcriptase Polymerase Chain Reaction, Cricetinae, MESH: Animals, MESH: Plasmodium falciparum/immunology, Lung, Saimiri, MESH: Cell Adhesion/physiology, MESH: Plasmodium falciparum/genetics, Virulence, Reverse Transcriptase Polymerase Chain Reaction, Chondroitin Sulfates, MESH: Plasmodium falciparum/pathogenicity, Nucleotide Mapping, MESH: Malaria Vaccines, Flow Cytometry, Antigenic Variation, Phenotype, Gene Targeting, MESH: Antigens, Protozoan/metabolism, MESH: Chondroitin ABC Lyase/pharmacology, Protein Binding, MESH: Endothelium, Vascular/cytology, MESH: Protozoan Proteins/genetics, Plasmodium falciparum, Antigens, Protozoan, CHO Cells, MESH: Phenotype, MESH: Plasmodium falciparum/cytology, Transfection, MESH: Host-Parasite Interactions, MESH: Lung/cytology, MESH: CD36 Antigens/metabolism, Host-Parasite Interactions, MESH: Saimiri, MESH: Antigens, Protozoan/genetics, Cricetulus, MESH: CHO Cells, parasitic diseases, Malaria Vaccines, Cell Adhesion, MESH: Protein Binding, Animals, Humans, MESH: Virulence/genetics, MESH: Protozoan Proteins/metabolism, MESH: Humans, MESH: Transfection, MESH: Chondroitin Sulfates/metabolism, MESH: Protozoan Proteins/immunology, Endothelium, Vascular, MESH: Antigenic Variation/genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, MESH: Erythrocytes/parasitology
Abstract: International audience; Protection against maternal malaria has been associated with the acquisition of a specific antibody response that prevents adhesion of Plasmodium falciparum-infected erythrocytes to the glycosaminoglycan chondroitin-4-sulphate (CSA), which is present in the placental intervillous space. These antibodies are directed against variant forms of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) that mediate binding to CSA. We have generated insertional disruption mutants of the gene encoding the CSA-binding phenotype in the P. falciparum clone FCR3 (varCSA) to test the hypothesis that strategies targeting the parasite's determinant for this adhesive phenotype may prevent sequestration of infected erythrocytes in the placenta and hence the development of maternal malaria. The varCSA-disruption mutants were initially unable to adhere to CSA; however, they could recover the phenotype after repeated selection over CSA. We show that recovery of CSA binding is varCSA independent and mediated by the activation of a novel var variant. Importantly, the corresponding PfEMP1 protein reacts with a monoclonal antibody recognizing the DBL3 gamma domain of the varCSA gene product, indicating that the DBL3 gamma CSA-binding domains are conserved between these PfEMP1-binding variants. Our data support strategies exploring these conserved epitopes as vaccine candidates against maternal malaria.
Published: 2003

31. NSs amyloid formation is associated with the virulence of Rift Valley fever virus in mice

Author: Susann Kummer, Hans-Georg Kräusslich, Psylvia Léger, Steeve Boulant, Jana Koch, Pierre-Yves Lozach, Megan L. Stanifer, Qilin Xin, Michèle Bouloy, Robin Burk, Carmen Nussbaum-Krammer, Carole Tamietti, Marie Flamand, Karsten Richter, Eliana Nachman, Xavier Montagutelli, Heidelberg University Hospital [Heidelberg], Center for Molecular Biology - Zentrum für Molekulare Biologie [Heidelberg, Germany] (ZMBH), Universität Heidelberg [Heidelberg] = Heidelberg University, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique Moléculaire des Bunyavirus, Institut Pasteur [Paris] (IP), Génétique de la souris - Mouse Genetics, This work was supported by grants from CellNetworks Research Group funds, Heidelberg, and from the Deutsche Forschungsgemeinschaft (DFG, LO-2338/1-1 and LO-2338/3-1). It was also supported by a Chinese Scholarship Council fellowship to Q.X, Universität Heidelberg [Heidelberg], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), École pratique des hautes études (EPHE), and Institut Pasteur [Paris]
Subjects: 0301 basic medicine, Rift Valley Fever, General Physics and Astronomy, Protein aggregation, Viral Nonstructural Proteins, MESH: Virulence, Virulence factor, chemistry.chemical_compound, Mice, MESH: Chlorocebus aethiops, Chlorocebus aethiops, MESH: Rift Valley Fever, MESH: Microscopy, Confocal, MESH: Animals, lcsh:Science, Multidisciplinary, Microscopy, Confocal, MESH: Protein Aggregation, Pathological, Virulence, Virus structures, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, MESH: Microscopy, Electron, Transmission, MESH: Rift Valley fever virus, Thioflavin, Encephalitis, MESH: Cell Nucleus, Amyloid, MESH: Cell Line, Tumor, Virulence Factors, Prions, Science, MESH: Vero Cells, Amyloidogenic Proteins, macromolecular substances, Biology, Fibril, Protein Aggregation, Pathological, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Microscopy, Electron, Transmission, Cell Line, Tumor, mental disorders, medicine, Animals, Humans, Vero Cells, MESH: Mice, MESH: Virulence Factors, Cell Nucleus, MESH: Amyloid, MESH: Amyloidogenic Proteins, MESH: Humans, 030102 biochemistry & molecular biology, General Chemistry, medicine.disease, Rift Valley fever virus, Virology, 030104 developmental biology, chemistry, MESH: HeLa Cells, Vero cell, MESH: Viral Nonstructural Proteins, lcsh:Q, HeLa Cells
Abstract: Amyloid fibrils result from the aggregation of host cell-encoded proteins, many giving rise to specific human illnesses such as Alzheimer’s disease. Here we show that the major virulence factor of Rift Valley fever virus, the protein NSs, forms filamentous structures in the brain of mice and affects mortality. NSs assembles into nuclear and cytosolic disulfide bond-dependent fibrillary aggregates in infected cells. NSs structural arrangements exhibit characteristics typical for amyloids, such as an ultrastructure of 12 nm-width fibrils, a strong detergent resistance, and interactions with the amyloid-binding dye Thioflavin-S. The assembly dynamics of viral amyloid-like fibrils can be visualized in real-time. They form spontaneously and grow in an amyloid fashion within 5 hours. Together, our results demonstrate that viruses can encode amyloid-like fibril-forming proteins and have strong implications for future research on amyloid aggregation and toxicity in general., Rift Valley fever virus (RVFV) can cause severe diseases in humans, including encephalitis. Here the authors show that NSs, the major virulence factor of RVFV, is an amyloidogenic protein forming fibrils in infected mouse brains and causing increased mortality in mice.
Published: 2020

32. Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

Author: Ferdinand Althammer, Francoise Muscatelli, Valery Grinevich, Christian P. Schaaf, Georgia State University, University System of Georgia (USG), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Heidelberg [Heidelberg] = Heidelberg University, and Heidelberg University Hospital [Heidelberg]
Subjects: Arthrogryposis, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Oxytocin, Hypopituitarism, Craniofacial Abnormalities, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Research Design, Intellectual Disability, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Prader-Willi Syndrome, Biological Psychiatry, Administration, Intranasal
Abstract: The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.
Published: 2022

33. Surgical data science – from concepts toward clinical translation

Author: Hubertus Feussner, Swaroop Vedula, Ozanan R. Meireles, Nicolas Padoy, Carla M. Pugh, Russell H. Taylor, Duygu Sarikaya, Bernard Gibaud, Jan Goedeke, Pietro Mascagni, Pierre Jannin, Hirenkumar Nakawala, Toby Collins, Beat P. Müller-Stich, Teodor P. Grantcharov, Stamatia Giannarou, Ines Gockel, Gregory D. Hager, Dogu Teber, Doreen Heckmann-Nötzel, Justin W. Collins, Matthias Eisenmann, Lena Maier-Hein, Sinan Onogur, Anand Malpani, Frank Ückert, Hani J. Marcus, Germain Forestier, Luc Joyeux, Daniel R. Leff, Keno März, Daniel A. Hashimoto, Johannes Fallert, Thomas Neumuth, Minu D. Tizabi, Tobias Roß, Makoto Hashizume, Lars Mündermann, Kevin Cleary, Raphael Sznitman, Kyle Lam, Nassir Navab, Alexander Seitel, Martin Wagner, Amin Madani, Stefanie Speidel, Ron Kikinis, Adrian Park, Danail Stoyanov, Gabor Fichtinger, Hannes Kenngott, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Heidelberg University, Gazi University, Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Contre les Cancers de l'Appareil Digestif-European Institute of Telesurgery (IRCAD/EITS), Johns Hopkins University (JHU), La société Karl STORZ, Technische Universität München = Technical University of Munich (TUM), Imperial College London, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, Università degli studi di Verona = University of Verona (UNIVR), Johns Hopkins University School of Medicine [Baltimore], Stanford University School of Medicine [CA, USA], University College of London [London] (UCL), Sheikh Zayed Institute for Pediatric Surgical Innovation, Washington DC, Queen's University [Kingston, Canada], Institut de Recherche en Informatique Mathématiques Automatique Signal - IRIMAS - UR 7499 (IRIMAS), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA)), Monash university, University of Toronto, Kyushu University, Heidelberg University Hospital [Heidelberg], Harvard Medical School [Boston] (HMS), University of Bern, Universität Leipzig, University Hospital Leipzig, Ludwig-Maximilians-Universität München (LMU), Massachusetts General Hospital [Boston], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Baylor College of Medicine (BCM), Baylor University, University Health Network, UCL Institute of Neurology, Queen Square [London], Universität Karlsruhe (TH), University Hospital Hamburg-Eppendorf, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), National Center for Tumor Diseases [Dresden] (NCT), Technische Universität Dresden = Dresden University of Technology (TU Dresden)-German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Helmholtz-Zentrum Dresden-Rossendorf (HZDR), This work was supported by the European Research Council (ERC) starting grant COMBIOSCOPY under the New Horizon Framework Programme grant agreement [ERC-2015-StG-637960], the Helmholtz Imaging Platform (HIP), a platform of the Helmholtz Incubator on Information and Data Science, the NCT Heidelberg, BPI France (project CONDOR), the Johns Hopkins Science of Learning Institute Research Grant, the National Institutes of Health [NIDCR R01 DE025265, P41 EB015902, P41 EB015898, R01 CA235589], the Surgical Oncology Program of the National Center for Tumor Diseases (NCT) Heidelberg, KARL STORZ SE & Co. KG, the Royal Society (UF140290) and NIHR Imperial BRC (Biomedical Research Centre), the ERC - H2020 Autonomous Robotic Surgery (ARS) grant agreement [ERC-2016-ADG-742671], the Surgical Metrics Project - American College of Surgeons (National Society Contract), the Quantified Physician - 7-SIGMA Simulation Systems, Minnesota, MN (Industry Contract), the Tourniquet Master Training - DOD SBIR Phase IIb - Continuation Award [W81XWH-13-C-0021], the Ontology for Human Motion and Psychomotor Performance - Stanford University Media-X, Motion Analysis for Microvascular Anastomosis - University of Wisconsin (Academic Contract), the Precision Learning Initiative - American Medical Association (National Society Grant), Quantifying the Metrics of Surgical Mastery: An Exploration in Data Science (NIH) [R01DK123445], the Wellcome/EPSRC Centre for Interventional and Surgical Sciences (WEISS) [203145Z/16/Z], Engineering and Physical Sciences Research Council (EPSRC) [EP/P027938/1, EP/R004080/1, EP/P012841/1], the Royal Academy of Engineering Chair in Emerging Technologies, the St. Michael’s Hospital, the University of Toronto, the Grant-in-Aid for Scientific Research on Innovative Area from MEXT, Japan, the National Cancer Data Ecosystem, contract number 19X037Q under Task Order HHSN26100071 from NCI, the project ProteCT [BMBF 16SV8568], the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft) as part of Germany’s Excellence Strategy - EXC 2050/1 - Project ID 390696704 - Cluster of Excellence 'Centre for Tactile Internet with Human-in-the-Loop' (CeTI), the Canada Research Chair in Computer Integrated Surgery, Natural Sciences and Engineering Research Council of Canada, the ANR with grants ANR-16-CE33-0009 (project DeepSurg), ANR-10-IAHU-02 (IHU Strasbourg) and ANR-20-CHIA-0029-01 (Chair AI4ORSafety), and the Federal Ministry of Economics and Energy (BMWi) and the German Aerospace Center (DLR) within the OP 4.1 project [BMWI 01MT17001C]., ANR-16-CE33-0009,DeepSurg,Apprentissage Profond à partir de Vidéos Chirurgicales Multi-vues et Multimodales pour Faciliter la Gestion du Bloc Opératoire(2016), ANR-10-IAHU-0002,MIX-Surg,Institut de Chirurgie Mini-Invasive guidée par l'Image(2010), ANR-20-CHIA-0029,AI4ORSafety,Evaluation automatique des vues endoscopiques pour la validation des points de contrôle au bloc opératoire(2020), European Project: 637960,H2020,ERC-2014-STG,COMBIOSCOPY(2015), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Kyushu University [Fukuoka], Universität Leipzig [Leipzig], Institute of Neurology - UCL/Queen Square [London, UK] (IN-UCL-QS), 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), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Center for Tumor Diseases - Deutsches Krebsforschungszentrum [Heidelberg, Allemagne] (NCT / DKFZ), and Technische Universität Dresden = Dresden University of Technology (TU Dresden)
Subjects: FOS: Computer and information sciences, Computer Science - Machine Learning, Artificial intelligence, Surgical data science, Computer science, Computer Vision and Pattern Recognition (cs.CV), media_common.quotation_subject, Aucun, Delphi method, Computer Science - Computer Vision and Pattern Recognition, Health Informatics, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Field (computer science), Machine Learning (cs.LG), [SPI.AUTO]Engineering Sciences [physics]/Automatic, Machine Learning, 03 medical and health sciences, Computer Science - Computers and Society, 0302 clinical medicine, Computers and Society (cs.CY), Health care, FOS: Electrical engineering, electronic engineering, information engineering, Humans, Radiology, Nuclear Medicine and imaging, Quality (business), 030304 developmental biology, media_common, 0303 health sciences, Radiological and Ultrasound Technology, business.industry, Clinical translation, Image and Video Processing (eess.IV), Data Science, Deep learning, Electrical Engineering and Systems Science - Image and Video Processing, Computer aided surgery, Computer Graphics and Computer-Aided Design, Data science, 3. Good health, Current practice, 030220 oncology & carcinogenesis, Data analysis, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Computer Vision and Pattern Recognition, business, Data Annotation
Abstract: Recent developments in data science in general and machine learning in particular have transformed the way experts envision the future of surgery. Surgical Data Science (SDS) is a new research field that aims to improve the quality of interventional healthcare through the capture, organization, analysis and modeling of data. While an increasing number of data-driven approaches and clinical applications have been studied in the fields of radiological and clinical data science, translational success stories are still lacking in surgery. In this publication, we shed light on the underlying reasons and provide a roadmap for future advances in the field. Based on an international workshop involving leading researchers in the field of SDS, we review current practice, key achievements and initiatives as well as available standards and tools for a number of topics relevant to the field, namely (1) infrastructure for data acquisition, storage and access in the presence of regulatory constraints, (2) data annotation and sharing and (3) data analytics. We further complement this technical perspective with (4) a review of currently available SDS products and the translational progress from academia and (5) a roadmap for faster clinical translation and exploitation of the full potential of SDS, based on an international multi-round Delphi process.
Published: 2022

34. Oligosarcomas, IDH-mutant are distinct and aggressive

Author: Abigail K. Suwala, Marius Felix, Dennis Friedel, Damian Stichel, Daniel Schrimpf, Felix Hinz, Ekkehard Hewer, Leonille Schweizer, Hildegard Dohmen, Ute Pohl, Ori Staszewski, Andrey Korshunov, Marco Stein, Thidathip Wongsurawat, Pornsuk Cheunsuacchon, Sith Sathornsumetee, Christian Koelsche, Clinton Turner, Emilie Le Rhun, Angelika Mühlebner, Philippe Schucht, Koray Özduman, Takahiro Ono, Hiroaki Shimizu, Marco Prinz, Till Acker, Christel Herold-Mende, Tobias Kessler, Wolfgang Wick, David Capper, Pieter Wesseling, Felix Sahm, Andreas von Deimling, Christian Hartmann, David E. Reuss, Pathology, APH - Aging & Later Life, APH - Mental Health, ANS - Cellular & Molecular Mechanisms, Acibadem University Dspace, CCA - Cancer biology and immunology, Universität Heidelberg [Heidelberg] = Heidelberg University, University Hospital Freiburg, Heidelberg University Hospital [Heidelberg], NN Burdenko Neurosurgical Institute (NNBNI), Universität Zürich [Zürich] = University of Zurich (UZH), Bern University Hospital [Berne] (Inselspital), Heidelberg University, INSERM, Université de Lille, NN Burdenko Neurosurgical Institute [NNBNI], Universität Zürich [Zürich] = University of Zurich [UZH], and Bern University Hospital [Berne] [Inselspital]
Subjects: Male, [SDV]Life Sciences [q-bio], Subtype, 1p/19q, Codeletion, DNA methylation, Gliosarcoma, NF1, Oligodendroglioma, Oligosarcoma, Prognosis, SMA, TERT, TP53, Type, Variant, YAP1, 2.1 Biological and endogenous factors, Aetiology, 610 Medicine & health, Cancer, Brain Neoplasms, Sarcoma, Middle Aged, 1p, Isocitrate Dehydrogenase, Female, 19q, Adult, Pediatric Research Initiative, Clinical Sciences, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Rare Diseases, Clinical Research, Genetics, Humans, neoplasms, Aged, Original Paper, Neurology & Neurosurgery, Neurosciences, Brain Disorders, nervous system diseases, Brain Cancer, Mutation, Neurology (clinical)
Abstract: Oligodendrogliomas are defined at the molecular level by the presence of an IDH mutation and codeletion of chromosomal arms 1p and 19q. In the past, case reports and small studies described gliomas with sarcomatous features arising from oligodendrogliomas, so called oligosarcomas. Here, we report a series of 24 IDH-mutant oligosarcomas from 23 patients forming a distinct methylation class. The tumors were recurrences from prior oligodendrogliomas or developed de novo. Precursor tumors of 12 oligosarcomas were histologically and molecularly indistinguishable from conventional oligodendrogliomas. Oligosarcoma tumor cells were embedded in a dense network of reticulin fibers, frequently showing p53 accumulation, positivity for SMA and CALD1, loss of OLIG2 and gain of H3K27 trimethylation (H3K27me3) as compared to primary lesions. In 5 oligosarcomas no 1p/19q codeletion was detectable, although it was present in the primary lesions. Copy number neutral LOH was determined as underlying mechanism. Oligosarcomas harbored an increased chromosomal copy number variation load with frequent CDKN2A/B deletions. Proteomic profiling demonstrated oligosarcomas to be highly distinct from conventional CNS WHO grade 3 oligodendrogliomas with consistent evidence for a smooth muscle differentiation. Expression of several tumor suppressors was reduced with NF1 being lost frequently. In contrast, oncogenic YAP1 was aberrantly overexpressed in oligosarcomas. Panel sequencing revealed mutations in NF1 and TP53 along with IDH1/2 and TERT promoter mutations. Survival of patients was significantly poorer for oligosarcomas as first recurrence than for grade 3 oligodendrogliomas as first recurrence. These results establish oligosarcomas as a distinct group of IDH-mutant gliomas differing from conventional oligodendrogliomas on the histologic, epigenetic, proteomic, molecular and clinical level. The diagnosis can be based on the combined presence of (a) sarcomatous histology, (b) IDH-mutation and (c) TERT promoter mutation and/or 1p/19q codeletion, or, in unresolved cases, on its characteristic DNA methylation profile.
Published: 2022

35. Influence of early identification and therapy on long-term outcomes in early-onset MTHFR deficiency

Author: Yverneau, Mathilde, Leroux, Stéphanie, Imbard, Apolline, Gleich, Florian, Arion, Alina, Moreau, Caroline, Nassogne, Marie-Cécile, Szymanowski, Marie, Tardieu, Marine, Touati, Guy, Bueno, María, Chapman, Kimberly A, Chien, Yin-Hsiu, Huemer, Martina, Ješina, Pavel, Janssen, Mirian C H, Kölker, Stefan, Kožich, Viktor, Lavigne, Christian, Lund, Allan Meldgaard, Mochel, Fanny, Morris, Andrew, Pons, Mónica Ruiz, Porras-Hurtado, Gloria Liliana, Benoist, Jean-François, Damaj, Léna, Schiff, Manuel, E-HOD Consortium, CHU Pontchaillou [Rennes], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Heidelberg University Hospital [Heidelberg], Service de Pédiatrie Médicale [Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Université Catholique de Louvain = Catholic University of Louvain (UCL), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hospital Universitario Virgen del Rocío [Sevilla], Children’s National Health System [Washington, DC, USA], National Taiwan University [Taiwan] (NTU), University Children’s Hospital Zurich, Charles University [Prague] (CU), Radboud University Medical Center [Nijmegen], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Copenhagen University Hospital, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Manchester University NHS Foundation Trust (MFT), Hospital Universitario N.S. de Candelaria [Santa Cruz de Tenerife, Spain], Hôpital Robert Debré Paris, Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), European Union [739543], EU-project phase [2012 12 02], SOBI, Recordati Rare Disease Foundation, Aeglea, and Jonchère, Laurent
Subjects: newborn screening, [SDV]Life Sciences [q-bio], MTHFR deficiency, Infant, Newborn, neurodevelopmental outcome, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], digestive system diseases, [SDV] Life Sciences [q-bio], Cohort Studies, homocystinuria, Psychotic Disorders, EHOD, Muscle Spasticity, Genetics, Humans, remethylation defects, Homocystinuria, Homocysteine, Genetics (clinical), Methylenetetrahydrofolate Reductase (NADPH2), Retrospective Studies
Abstract: Contains fulltext : 286882.pdf (Publisher’s version ) (Closed access) MTHFR deficiency is a severe inborn error of metabolism leading to impairment of the remethylation of homocysteine to methionine. Neonatal and early-onset patients mostly exhibit a life-threatening acute neurologic deterioration. Furthermore, data on early-onset patients' long-term outcomes are scarce. The aims of this study were (1) to study and describe the clinical and laboratory parameters of early-onset MTHFR-deficient patients (i.e., ≤3 months of age) and (2) to identify predictive factors for severe neurodevelopmental outcomes in a cohort with early and late onset MTHFR-deficient patients. To this end, we conducted a retrospective, multicentric, international cohort study on 72 patients with MTHFR deficiency from 32 international metabolic centres. Characteristics of the 32 patients with early-onset MTHFR deficiency were described at time of diagnosis and at the last follow-up visit. Logistic regression analysis was used to identify predictive factors of severe neurodevelopmental outcome in a broader set of patients with early and non-early-onset MTHFR deficiency. The majority of early-onset MTHFR-deficient patients (n = 32) exhibited neurologic symptoms (76%) and feeding difficulties (70%) at time of diagnosis. At the last follow-up visit (median follow-up time of 8.1 years), 76% of treated early-onset patients (n = 29) exhibited a severe neurodevelopmental outcome. Among the whole study population of 64 patients, pre-symptomatic diagnosis was independently associated with a significantly better neurodevelopmental outcome (adjusted OR 0.004, [0.002-0.232]; p = 0.003). This study provides evidence for benefits of pre-symptomatic diagnosis and appropriate therapeutic management, highlighting the need for systematic newborn screening for MTHFR deficiency and pre-symptomatic treatment that may improve outcome.
Published: 2022

36. Biliary tract cancer:ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up ☆

Author: A. Vogel, J. Bridgewater, J. Edeline, R.K. Kelley, H.J. Klümpen, D. Malka, J.N. Primrose, L. Rimassa, A. Stenzinger, J.W. Valle, M. Ducreux, Internal medicine, Medical School of Hannover (MHH), University College of London [London] (UCL), CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Amsterdam [Amsterdam] (UvA), Amsterdam UMC - Amsterdam University Medical Center, Dynamique des cellules tumorales (UMR1279), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Mutualiste de Montsouris (IMM), University Hospital Southampton NHS Foundation Trust, Humanitas University [Milan] (Hunimed), Heidelberg University Hospital [Heidelberg], University of Manchester [Manchester], Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), and Jonchère, Laurent
Subjects: gallbladder cancer, [SDV] Life Sciences [q-bio], Oncology, treatment, [SDV.CAN] Life Sciences [q-bio]/Cancer, diagnosis, precision medicine, [SDV]Life Sciences [q-bio], follow-up, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, cholangiocarcinoma
Abstract: International audience; No abstract available
Published: 2022

37. Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVAglio ancillary study

Author: Carine Jiguet-Jiglaire, Sebastien Boissonneau, Emilie Denicolai, Victoria Hein, Romain Lasseur, Josep Garcia, Sylvie Romain, Romain Appay, Thomas Graillon, Warren Mason, Antoine F. Carpentier, Alba A. Brandes, L.’Houcine Ouafik, Wolfgang Wick, Ania Baaziz, Julien P. Gigan, Rafael J. Argüello, Dominique Figarella-Branger, Olivier Chinot, Emeline Tabouret, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), F. Hoffmann-La Roche [Basel], Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Département de Neurochirurgie [CHU Timone], Princess Margaret Hospital, University of Toronto, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), IRCCS Istituto delle Scienze Neurologiche di Bologna [Bologna, Italy], Ospedale Bellaria [Bologna, Italy], Hôpital Nord [CHU - APHM], Heidelberg University Hospital [Heidelberg], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), ANR-20-CE14-0028,Epic-ZeNITH,Epic-ZENITH : Un effort intégratif pour identifier les régulateurs du métabolisme et de l'épigénétique dans le cellules myéloïdes associées aux glioblastomes(2020), and ARGUELLO, Rafael
Subjects: Adult, Male, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Neutrophils, [SDV]Life Sciences [q-bio], Angiogenesis Inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, RC346-429, Aged, Brain Neoplasms, MMP9, Research, Middle Aged, body regions, Bevacizumab, Predictive biomarker, Treatment Outcome, Matrix Metalloproteinase 9, Matrix Metalloproteinase 2, Female, Neurology (clinical), Neurology. Diseases of the nervous system, Glioblastoma
Abstract: We previously identified matrix metalloproteinase 2 (MMP2) and MMP9 plasma levels as candidate biomarkers of bevacizumab activity in patients with recurrent glioblastoma. The aim of this study was to assess the predictive value of MMP2 and MMP9 in a randomized phase III trial in patients with newly diagnosed glioblastoma and to explore their tumor source. In this post hoc analysis of the AVAglio trial (AVAGlio/NCT00943826), plasma samples from 577 patients (bevacizumab, n = 283; placebo, n = 294) were analyzed for plasma MMP9 and MMP2 levels by enzyme-linked immunosorbent assay. A prospective local cohort of 38 patients with newly diagnosed glioblastoma was developed for analysis of tumor characteristics by magnetic resonance imaging and measurement of plasma and tumor levels of MMP9 and MMP2. In this AVAglio study, MMP9, but not MMP2, was correlated with bevacizumab efficacy. Patients with low MMP9 derived a significant 5.2-month overall survival (OS) benefit with bevacizumab (HR 0.51, 95% CI 0.34–0.76, p = 0.0009; median 13.6 vs. 18.8 months). In multivariate analysis, a significant interaction was seen between treatment and MMP9 (p = 0.03) for OS. In the local cohort, we showed that preoperative MMP9 plasma levels decreased after tumor resection and were correlated with tumor levels of MMP9 mRNA (p = 0.03). However, plasma MMP9 was not correlated with tumor size, invasive pattern, or angiogenesis. Using immunohistochemistry, we showed that MMP9 was expressed by inflammatory cells but not by tumor cells. After cell sorting, we showed that MMP9 was expressed by CD45+ immune cells. Finally, using flow cytometry, we showed that MMP9 was expressed by tumor-infiltrating neutrophils. In conclusion, circulating MMP9 is predictive of bevacizumab efficacy and is released by tumor-infiltrating neutrophils.
Published: 2022

38. European Stroke Organisation (ESO) guidelines on mobile stroke units for prehospital stroke management

Author: Silke Walter, Heinrich J Audebert, Aristeidis H Katsanos, Karianne Larsen, Simona Sacco, Thorsten Steiner, Guillaume Turc, Georgios Tsivgoulis, Martinez Rico, Clara, Saarland University Medical Center [Homburg, Germany] (SUMC), Berlin Institute of Health (BIH), Humboldt University Of Berlin, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], McMaster University [Hamilton, Ontario], National and Kapodistrian University of Athens (NKUA), University of Oslo (UiO), University of L'Aquila [Italy] (UNIVAQ), Heidelberg University Hospital [Heidelberg], Universitätsklinikum Frankfurt, GHU Paris Psychiatrie et Neurosciences, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), FHU NeuroVasc [Site Sainte-Anne, Paris] (GHU-PPN), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), and The University of Tennessee Health Science Center [Memphis] (UTHSC)
Subjects: thrombolysis, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Guidelines, prehospital, stroke, Mobile Stroke Unit, large vessel occlusion, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), cardiovascular diseases, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cardiology and Cardiovascular Medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The safety and efficacy of mobile stroke units (MSUs) in prehospital stroke management has recently been investigated in different clinical studies. MSUs are ambulances equipped with a CT scanner, point-of-care lab, telemedicine and are staffed with a stroke specialised medical team. This European Stroke Organisation (ESO) guideline provides an up-to-date evidence-based recommendation to assist decision-makers in their choice on using MSUs for prehospital management of suspected stroke, which includes patients with acute ischaemic stroke (AIS), intracranial haemorrhage (ICH) and stroke mimics. The guidelines were developed according to the ESO standard operating procedure and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and aggregated data meta-analyses of the literature, assessed the quality of the available evidence and made specific recommendations. Expert consensus statements are provided where sufficient evidence was not available to provide recommendations based on the GRADE approach. We found moderate evidence for suggesting MSU management for patients with suspected stroke. The patient group diagnosed with AIS shows an improvement of functional outcomes at 90 days, reduced onset to treatment times and increased proportion receiving IVT within 60 min from onset. MSU management might be beneficial for patients with ICH as MSU management was associated with a higher proportion of ICH patients being primarily transported to tertiary care stroke centres. No safety concerns (all-cause mortality, proportion of stroke mimics treated with IVT, symptomatic intracranial bleeding and major extracranial bleeding) could be identified for all patients managed with a MSU compared to conventional care. We suggest MSU management to improve prehospital management of suspected stroke patients.
Published: 2022

39. SARS‐CoV‐2 variants as super cell fusers: cause or consequence of COVID‐19 severity?

Author: Jana Koch, Pierre-Yves Lozach, Zina M Uckeley, Heidelberg University Hospital [Heidelberg], Department of Infectious Diseases/Virology [Heidelberg, Germany] (Cluster of Excellence CellNetworks), Universität Heidelberg [Heidelberg], Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, Cell, Alpha (ethology), Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Beta (finance), Molecular Biology, 030304 developmental biology, 0303 health sciences, Syncytium, General Immunology and Microbiology, General Neuroscience, Spike Protein, virus diseases, respiratory system, biochemical phenomena, metabolism, and nutrition, Virology, 3. Good health, respiratory tract diseases, medicine.anatomical_structure, 030217 neurology & neurosurgery
Abstract: International audience; The most severe forms of coronavirus disease 2019 (COVID-19) are often associated with the presence of syncytia in the lungs resulting from cell-cell fusion mediated by the SARS-CoV-2 spike protein. In this issue, Rajah and colleagues show that the SARS-CoV-2 alpha, beta, and delta variants promote enhanced syncytia formation as compared to the original strain.
Published: 2021

40. Fatal Neonatal DOLK-CDG as a Rare Form of Syndromic Ichthyosis

Author: Katalin Komlosi, Olivier Claris, Sophie Collardeau-Frachon, Julia Kopp, Ingrid Hausser, Juliette Mazereeuw-Hautier, Nathalie Jonca, Andreas D. Zimmer, Damien Sanlaville, Judith Fischer, University of Freiburg [Freiburg], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Heidelberg University Hospital [Heidelberg], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and CarMeN, laboratoire
Subjects: DOLK, [SDV]Life Sciences [q-bio], syndromic ichthyosis, Mendelian disorders of cornification, QH426-470, whole exome sequencing, [SDV] Life Sciences [q-bio], interest, or financial relationships that could be construed as a potential conflict of, Genetics, Molecular Medicine, Genetics (clinical), Original Research, congenital disorders of glycosylation
Abstract: Neonatal collodion baby or ichthyosis can pose a diagnostic challenge, and in many cases, only additional organ involvement or the course of the disease will help differentiate between non-syndromic and syndromic forms. Skin abnormalities are described in about 20% of the congenital disorders of glycosylation (CDG). Among those, some rare CDG forms constitute a special group among the syndromic ichthyoses and can initially misdirect the diagnosis towards non-syndromic genodermatosis. DOLK-CDG is such a rare subtype, resulting from a defect in dolichol kinase, in which the congenital skin phenotype (often ichthyosis) is later associated with variable extracutaneous features such as dilatative cardiomyopathy, epilepsy, microcephaly, visual impairment, and hypoglycemia and may lead to a fatal course. We report two neonatal cases of lethal ichthyosis from the same family, with distal digital constrictions and a progressive course leading to multi-organ failure and death. Postmortem trio whole-exome sequencing revealed the compound heterozygous variants NM_014908.3: c.1342G>A, p.(Gly448Arg) and NM_014908.3: c.1558A>G, p.(Thr520Ala) in the DOLK gene in the first affected child, which were confirmed in the affected sibling. Reduced staining with anti-α-Dystroglycan antibody was observed in frozen heart tissue of the second child as an expression of reduced O-mannosylation due to the dolichol kinase deficiency. In addition to the detailed dermatopathological changes, both cases presented hepatic and extrahepatic hemosiderosis on histological examination. Our patients represent an early and fatal form of DOLK-CDG with a striking presentation at birth resembling severe collodion baby. Both cases emphasize the phenotypic variability of glycosylation disorders and the importance to broaden the differential diagnosis of ichthyosis and to actively search for organ involvement in neonates with ichthyosis.
Published: 2021

41. Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage

Author: Martin Kaiser, Baldeep Wirk, Monika Engelhardt, Bruno Paiva, Laurent Garderet, S. Vincent Rajkumar, Maria-Victoria Mateos, Philippe Moreau, Carlos Fernández de Larrea, Robert A. Kyle, Jo Caers, Wilson I. Gonsalves, Hermann Einsele, Hartmut Goldschmidt, Giampaolo Merlini, Suzanne Lentzch, Ashraf Badros, Saad Z. Usmani, Joan Bladé, Pellegrino Musto, Fredrik Schjesvold, Pieter Sonneveld, Jesús F. San Miguel, Laura Rosiñol, Gösta Gahrton, Patrick Hayden, Enrique M. Ocio, Brian G.M. Durie, Sascha A. Tuchman, Universidad de Cantabria, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Mayo Clinic [Rochester], Clínica Universidad de Navarra [Pamplona], Freiburg University Medical Center, The Levine Cancer Institute, Université de Liège, University of Oslo (UiO), University of Pavia, Columbia University [New York], Hospital Universitario de Salamanca, Servicio de Haematologia, 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), Centre hospitalier universitaire de Nantes (CHU Nantes), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Maryland [Baltimore], Karolinska Institutet [Stockholm], Heidelberg University Hospital [Heidelberg], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University Hospital of Würzburg, Samuel Oschin Comprehensive Cancer Institute, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, The institute of cancer research [London], Instituto de Salud Carlos III, Ministerio de Sanidad (España), European Commission, Generalitat de Catalunya, and Hematology
Subjects: Male, Cell biology, medicine.medical_specialty, Plasma Cells, Myeloma, macromolecular substances, Disease, Plasma cell, Gastroenterology, Article, Leukemia, Plasma Cell, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Effective treatment, In patient, Cancer genetics, RC254-282, Multiple myeloma, Aged, Retrospective Studies, Plasma cell leukemia, business.industry, technology, industry, and agriculture, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hematology, Prognosis, equipment and supplies, musculoskeletal system, medicine.disease, Peripheral blood, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma., This work has been supported in part by grants from the Instituto de Salud Carlos III, Spanish Ministry of Health (FIS PI19/00669), Fondo Europeo de Desarrollo Regional (FEDER) and 2017SGR00792 (AGAUR; Generalitat de Catalunya).
Published: 2021

42. Investigating the limits of PET/CT imaging at very low true count rates and high random fractions in ion-beam therapy monitoring

Author: Parodi, Katia [Heidelberg Ion-Beam Therapy Center and Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg 69120, Germany and Department of Experimental Physics – Medical Physics, Ludwig-Maximilians-University, Munich 85748 (Germany)]
Published: 2015
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43. Rift Valley fever virus: a new avenue of research on the biological functions of amyloids?

Author: Ke Peng, Pierre-Yves Lozach, Chinese Academy of Agricultural Sciences (CAAS), Heidelberg University Hospital [Heidelberg], Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and CellNetworks (University Heidelberg)German Research Foundation (DFG)LO-2338/3-1INRAEIDEX-Impulsion 2020 (University of Lyon)
Subjects: emerging virus, 0303 health sciences, Rift Valley fever virus, NSs, fibril, viruses, 030302 biochemistry & molecular biology, amyloid, Biology, Rift Valley fever, Virology, 3. Good health, virulence, 03 medical and health sciences, arbovirus, parasitic diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 030304 developmental biology
Abstract: International audience; Rift Valley fever is a mosquito-borne viral zoonosis that was first discovered in the Great Rift Valley, Kenya, in 1930. Rift Valley fever virus (RVFV) primarily infects domestic animals and humans, with clinical outcomes ranging from self-limiting febrile illness to acute hepatitis and encephalitis. The virus left Africa a few decades ago, and there is a risk of introduction into southern Europe and Asia. From this perspective, we introduce RVFV and focus on the capacity of its virulence factor, the nonstructural protein NSs, to form amyloid-like fibrils. Here, we discuss the implications for the NSs biological function, the ability of RVFV to evade innate immunity, and RVFV virulence and neurotoxicity.
Published: 2021

44. Chromatin accessibility combined with enhancer clusters activation mediates heterogeneous response to dexamethasone in myeloma cells

Author: Loïc Campion, Catherine Guérin-Charbonnel, Stephane Minvielle, Victor Gaborit, Jennifer Derrien, Jérémie Bourdon, P. Moreau, Carl Herrmann, Nathalie Roi, Jonathan Cruard, Elise Douillard, Florence Magrangeas, Magali Devic, Jean-Baptiste Alberge, Frank Westermann, Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), 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), Laboratoire des Sciences du Numérique de Nantes (LS2N), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), University of Heidelberg, Medical Faculty, 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), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), and Bernardo, Elizabeth
Subjects: 0303 health sciences, Chemistry, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, 3. Good health, Cell biology, Chromatin, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, [SDV.CAN] Life Sciences [q-bio]/Cancer, Regulatory sequence, medicine, Binding site, Enhancer, Receptor, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Epigenomics
Abstract: Glucocorticoids (GC) effects occur through binding to the GC receptor (GR) which, once translocated to the nucleus, binds to GC response elements (GREs) to activate or repress target genes. Among GCs, dexamethasone (Dex) is widely used in treatment of multiple myeloma (MM), mainly in combination regimens. However, despite a definite benefit, all patients relapse. Moreover, while GC efficacy can be largely attributed to lymphocyte-specific apoptosis, its molecular basis remains elusive.To determine the functional role of GR binding in myeloma cells, we generated bulk and single cell multi-omic data and high-resolution contact maps of active enhancers and target genes. We show that a minority (6%) of GR binding sites are associated with enhancer activity gains and increased interaction loops. We find that enhancers contribute to regulate gene activity through combinatorial assembly of large stretches of enhancers and/or enhancer cliques. Furthermore, one enhancer, proximal to GR-responsive genes, is predominantly associated with increased chromatin accessibility and higher H3K27ac occupancy. Finally, we show that Dex exposure leads to co-accessibility changes between predominant enhancer and other regulatory regions of the interaction network. Notably, these epigenomic changes are associated with cell-to-cell transcriptional heterogeneity. As consequences, BIM critical for GR-induced apoptosis and CXCR4 protective from chemotherapy-induced apoptosis are rather upregulated in different cells.In summary, our work provides new insights into the molecular mechanisms involved in Dex escape.
Published: 2021

45. CLinical Assessment of WEB device in Ruptured aneurYSms (CLARYS): results of 1-month and 1-year assessment of rebleeding protection and clinical safety in a multicenter study

Author: Jildaz Caroff, Léon Ikka, S. Velasco, Georg Bohner, Xavier Barreau, Laurent Pierot, Werner Weber, Joachim Berkefeld, Hubert Desal, Sebastian Fischer, Ana Paula Narata, R. Bibi, Jean-Christophe Ferré, Denis Herbreteau, Jean-Yves Gauvrit, Anne-Christine Januel, Jan-Hendrik Buhk, Jens Fiehler, Vincent Costalat, Thomas Liebig, Markus A Möhlenbruch, Cristian Mihalea, Laurent Spelle, James V. Byrne, Romain Bourcier, Augustin Ozanne, Hélène Raoult, Vanessa Chalumeau, Richard du Mesnil de Rochemont, Lamiae Grimaldi, Jacques Moret, Christophe Cognard, Alessandra Biondi, Maxim Bester, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Saclay, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Département de Radiologie [CHU de Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Hôpital Pierre-Paul Riquet [Toulouse], CHU Toulouse [Toulouse], Hôpital Gui de Chauliac, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University-Hospital Munich-Großhadern [München], Centre hospitalier universitaire de Nantes (CHU Nantes), Heidelberg University Hospital [Heidelberg], Universitätsklinikum Frankfurt am Main [Germany], Goethe-Universität Frankfurt am Main, Ruhr University Bochum (RUB), Service de Neuroradiologie [Rennes], CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Asklepios Klinikum Uckermark GmbH, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Hôpital JeanMinjoz, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, John Radcliffe Hospital [Oxford University Hospital], Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Reims Champagne-Ardenne (URCA), Ferré, Jean-Christophe, Université de Rennes (UR), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: medicine.medical_specialty, Intraoperative Complication, Ruptured aneurysms, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, subarachnoid, Aneurysm, Ruptured, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Aneurysm, Modified Rankin Scale, Clinical endpoint, Medicine, Fluoroscopy, Humans, Prospective Studies, Adverse effect, device, intervention, Retrospective Studies, medicine.diagnostic_test, business.industry, Endovascular Procedures, Intracranial Aneurysm, General Medicine, Prostheses and Implants, medicine.disease, Embolization, Therapeutic, 3. Good health, Surgery, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Treatment Outcome, Multicenter study, aneurysm, Neurology (clinical), hemorrhage, business, 030217 neurology & neurosurgery
Abstract: BackgroundThe primary goal of the CLARYS study is to assess the protection against rebleeding when treating ruptured bifurcation aneurysms with the Woven EndoBridge (WEB) device.MethodsThe CLARYS study is a prospective, multicenter study conducted in 13 European centers. Patients with ruptured bifurcation aneurysms were consecutively included between February 2016 and September 2017. The primary endpoint was defined as the rebleeding rate of the target aneurysm treated with the WEB within 30 days postprocedure. Secondary endpoints included periprocedural and postprocedural adverse events, total procedure and fluoroscopy times, and modified Rankin Scale score at 1 month and 1 year.ResultsSixty patients with 60 ruptured bifurcation aneurysms to be treated with the WEB were included. A WEB device was successfully implanted in 93.3%. The rebleeding rate at 1 month and 1 year was 0%. The mean fluoroscopy time was 27.0 min. Twenty-three periprocedural complications were observed in 18 patients and resolved without sequelae in 16 patients. Two of these complications were attributed to the procedure and/or the use of the WEB, leading to a procedure/device-related intraoperative complication rate of 3.3%. Overall mortality at 1 month and 1 year was 1.7% and 3.8%, respectively and overall morbidity at 1 month and 1 year was 15% and 9.6%, respectively. WEB-related 1-month and 1-year morbidity and mortality was 0%.ConclusionsThe interim results of CLARYS show that the endovascular treatment of ruptured bifurcation aneurysms with the WEB is safe and effective and, in particular, provides effective protection against rebleeding. It may induce profound change in the endovascular management of ruptured bifurcation aneurysms.
Published: 2021

46. WE-D-BRF-04: Experimental Investigations On Ion Radiography with Beam Scanning Using a Range Telescope

Author: Parodi, K [Heidelberg University Hospital, Heidelberg (Germany)]
Published: 2014
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47. EANO guideline on the diagnosis and management of meningiomas

Author: Christian Mawrin, Felix Sahm, Emilie Le Rhun, Michael D. Jenkinson, Emanuel Houdart, Florence Lefranc, Michael Weller, Pantelis Stavrinou, Morten Lund-Johansen, David Nieuwenhuizen, Riccardo Soffietti, Kita Sallabanda, Giuseppe Minniti, Roland Goldbrunner, Matthias Preusser, Ghazaleh Tabatabai, Damien C. Weber, University of Zurich, Goldbrunner, Roland, INSERM, Université de Lille, University Hospital of Cologne [Cologne], Heidelberg University Hospital [Heidelberg], Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] [OVGU], Paul Scherrer Institute [PSI], Medizinische Universität Wien = Medical University of Vienna, Università degli Studi di Siena = University of Siena [UNISI], Hôpital Lariboisière, University hospital of Zurich [Zurich], Università degli studi di Torino = University of Turin [UNITO], Universität Zürich [Zürich] = University of Zurich [UZH], Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Paul Scherrer Institute (PSI), Università degli Studi di Siena = University of Siena (UNISI), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Università degli studi di Torino = University of Turin (UNITO), and Universität Zürich [Zürich] = University of Zurich (UZH)
Subjects: Vascular Endothelial Growth Factor A, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 610 Medicine & health, Guidelines, meningioma, Radiosurgery, Meningioma, surgery, 10180 Clinic for Neurosurgery, Pharmacotherapy, molecular pathology, Meningeal Neoplasms, medicine, Humans, 1306 Cancer Research, Medical diagnosis, Aged, neuropathology, Molecular pathology, business.industry, radiosurgery, Guideline, medicine.disease, Magnetic Resonance Imaging, 10040 Clinic for Neurology, Clinical trial, 2728 Neurology (clinical), Oncology, Radionuclide therapy, 2730 Oncology, Neurology (clinical), Radiology, business
Abstract: Meningiomas are the most common intracranial tumors. Yet, only few controlled clinical trials have been conducted to guide clinical decision making, resulting in variations of management approaches across countries and centers. However, recent advances in molecular genetics and clinical trial results help to refine the diagnostic and therapeutic approach to meningioma. Accordingly, the European Association of Neuro-Oncology (EANO) updated its recommendations for the diagnosis and treatment of meningiomas. A provisional diagnosis of meningioma is typically made by neuroimaging, mostly magnetic resonance imaging. Such provisional diagnoses may be made incidentally. Accordingly, a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. A surgical intervention with tissue, commonly with the goal of gross total resection, is required for the definitive diagnosis according to the WHO classification. A role for molecular profiling including gene panel sequencing and genomic methylation profiling is emerging. A gross total surgical resection including the involved dura is often curative. Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if the size or the vicinity of critical structures allows that, or with fractionated radiotherapy (RT). Treatment concepts combining surgery and radiosurgery or fractionated RT are increasingly used, although there remain controversies regard timing, type, and dosing of the various RT approaches. Radionuclide therapy targeting somatostatin receptors is an experimental approach, as are all approaches of systemic pharmacotherapy. The best albeit modest results with pharmacotherapy have been obtained with bevacizumab or multikinase inhibitors targeting vascular endothelial growth factor receptor, but no standard of care systemic treatment has been yet defined.
Published: 2021

48. EUREXIT? High time to consider the merits of European collaboration in child and adolescent psychiatry

Author: Veit Roessner, Maria Melchior, Giulia Signorini, Johannes Hebebrand, Bruno Falissard, Nanda Rommelse, Pieter J. Hoekstra, Michael Kaess, Carmen Moreno, Nadia Micali, Clinical Cognitive Neuropsychiatry Research Program (CCNP), University Hospital Essen, Université Paris Sud Orsay, University of Groningen [Groningen], University of Bern, Heidelberg University Hospital [Heidelberg], Equipe de Recherche en Epidémiologie Sociale [iPLesp] (ERES), 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), Université de Genève = University of Geneva (UNIGE), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Radboud University Medical Center [Nijmegen], Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro San Giovanni di Dio, Fatebenefratelli, Brescia (IRCCS), Università degli Studi di Brescia = University of Brescia (UniBs), and Gestionnaire, Hal Sorbonne Université
Subjects: medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], MEDLINE, 610 Medicine & health, ddc:616.89, Adolescent Psychiatry, Developmental and Educational Psychology, Child and adolescent psychiatry, medicine, Humans, ADHD, Family, Cooperative Behavior, Psychiatry, Child, Child Psychiatry, Patient Care Team, Patient care team, Mental Disorders, Research, General Medicine, [SDV] Life Sciences [q-bio], Europe, Psychiatry and Mental health, Adolescent psychiatry, Pediatrics, Perinatology and Child Health, Cooperative behavior, Psychology
Abstract: International audience
Published: 2019

49. Quantitative assessment of radionuclide production yields in in-beam and offline PET measurements at different proton irradiation facilities

Author: Julia Bauer, Meret Hildebrandt, Michael Baumgartl, Fine Fiedler, Charlotte Robert, Irène Buvat, Wolfgang Enghardt, Katia Parodi, Heidelberg University Hospital [Heidelberg], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Ludwig Maximilian University [Munich] (LMU), University hospital of Zurich [Zurich], Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institut Gustave Roussy (IGR), Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire d'Imagerie Translationnelle en Oncologie (LITO ), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Dresden = Dresden University of Technology (TU Dresden), and Buvat, Irène
Subjects: Radioisotopes, positron emitter production yield, Radiological and Ultrasound Technology, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Phantoms, Imaging, offline PET, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, particle therapy, in-beam PET, Positron Emission Tomography Computed Tomography, Positron-Emission Tomography, Proton Therapy, Radiology, Nuclear Medicine and imaging, Protons, in-vivo range verification
Abstract: Objective. Reliable radionuclide production yield data are a prerequisite for positron-emission-tomography (PET) based in vivo proton treatment verification. In this context, activation data acquired at two different treatment facilities with different imaging systems were analyzed to provide experimentally determined radionuclide yields in thick targets and were compared with each other to investigate the impact of the respective imaging technique. Approach. Homogeneous thick targets (PMMA, gelatine, and graphite) were irradiated with mono-energetic proton pencil-beams at two distinct energies. Material activation was measured (i) in-beam during and after beam delivery with a double-head prototype PET camera and (ii) offline shortly after beam delivery with a commercial full-ring PET/CT scanner. Integral as well as depth-resolved β +-emitter yields were determined for the dominant positron-emitting radionuclides 11C, 15O, 13N and (in-beam only) 10C. In-beam data were used to investigate the qualitative impact of different monitoring time schemes on activity depth profiles and their quantitative impact on count rates and total activity. Main results. Production yields measured with the in-beam camera were comparable to or higher compared to respective offline results. Depth profiles of radionuclide-specific yields obtained from the double-head camera showed qualitative differences to data acquired with the full-ring camera with a more convex profile shape. Considerable impact of the imaging timing scheme on the activity profile was observed for gelatine only with a range variation of up to 3.5 mm. Evaluation of the coincidence rate and the total number of observed events in the considered workflows confirmed a strongly decreasing rate in targets with a large oxygen fraction. Significance. The observed quantitative and qualitative differences between the datasets underline the importance of a thorough system commissioning. Due to the lack of reliable cross-section data, in-house phantom measurements are still considered a gold standard for careful characterization of the system response and to ensure a reliable beam range verification.
Published: 2022

50. An open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single doses of GSK2586881 in participants with pulmonary arterial hypertension

Author: Marc A. Simon, Kate Hanrott, David C. Budd, Fernando Torres, Ekkehard Grünig, Pilar Escribano‐Subias, Manuel L. Meseguer, Michael Halank, Christian Opitz, David A. Hall, Deborah Hewens, William M. Powley, Sarah Siederer, Andrew Bayliffe, Aili L. Lazaar, Anthony Cahn, Stephan Rosenkranz, Institut Català de la Salut, [Simon MA] Division of Cardiology, Department of Medicine, University of California, San Francisco, California, USA. [Hanrott K, Budd DC] Research and Development, Medicines Research Centre, GlaxoSmithKline plc., Stevenage, UK. [Torres F] UT Southwestern Medical Center, Dallas, Texas, USA. [Grünig E] Centre for Pulmonary Hypertension, Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital, Heidelberg, Germany. [Escribano-Subias P] CIBER‐CV Cardiology Department, Pulmonary Hypertension Unit, Hospital Universitario 12 de Octubre, Madrid, Spain. [Meseguer ML] Unitat de Pneumologia, Vall d'Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Pulmonary and Respiratory Medicine, Respiratory Tract Diseases::Lung Diseases::Hypertension, Pulmonary [DISEASES], enfermedades respiratorias::enfermedades pulmonares::hipertensión pulmonar [ENFERMEDADES], Farmacocinètica, Metabolism::Pharmacokinetics [PHENOMENA AND PROCESSES], Hipertensió pulmonar - Tractament, Avaluació de resultats (Assistència sanitària), Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Other subheadings::Other subheadings::/drug therapy [Other subheadings], Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], metabolismo::farmacocinética [FENÓMENOS Y PROCESOS]
Abstract: Arterial hypertension; Hemodynamics; Renin‐angiotensin system Hipertensión arterial; Hemodinámica; Sistema renina-angiotensina Hipertensió arterial; Hemodinàmica; Sistema renina-angiotensina Preclinical and early clinical studies suggest that angiotensin-converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin-converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi-center, open-label, exploratory, single-dose, dose-escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin-angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy (N = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1–7) and angiotensin (1–5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined.
Published: 2021

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