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151 results on '"Borgel, A."'

1. A retrospective analysis of discordances between international normalized ratio (INR) self‐testing and INR laboratory testing in a pediatric patient population

Author

Damien Bonnet, Sofiane Taleb, Pauline Cannet, Fanny Bajolle, Joan Bitan, Alice Braems, Dominique Lasne, Delphine Borgel, and Annie Harroche

Subjects
Quality Control, endocrine system, medicine.medical_specialty, Multivariate analysis, Adolescent, Quality Assurance, Health Care, Clinical Biochemistry, Population, Laboratory testing, health services administration, Retrospective analysis, medicine, Humans, heterocyclic compounds, International Normalized Ratio, cardiovascular diseases, Child, education, Blood Coagulation, Retrospective Studies, education.field_of_study, business.industry, fungi, Biochemistry (medical), Infant, Newborn, Infant, Retrospective cohort study, Hematology, General Medicine, Odds ratio, Pediatric patient, Self-Testing, Point-of-Care Testing, Child, Preschool, Concomitant, Emergency medicine, Blood Coagulation Tests, business
Abstract

INTRODUCTION The lack of quality control procedures for home point-of-care (POC) international normalized ratio (INR) devices is a concern. Concomitant laboratory and POC INR testing may be proposed to overcome the lack of quality control. However, a difference between the POC INR and the laboratory INR is not necessarily due to failure of the POC device. This study aimed to identify variables associated with a significant deviation between the POC INR and the laboratory INR. METHODS Children included in this retrospective cohort study performed at least one concomitant laboratory and POC INRs. Clinical and laboratory variables were assessed for an association with significant deviation within pairs of INR. RESULTS A significant deviation was noted for 30 (15.3%) of the 196 pairs of INR measurements from 124 children. Relative to patients without deviations, patients with deviations were younger (odds ratio =0.91; P = .020), less experienced in the use of POC INR devices (odds ratio =0.89; P = .098), and more likely to have received an INR result from a laboratory using animal thromboplastin (odds ratio =2.81 vs. 0.37 for laboratories using human thromboplastin; P = .016). In a multivariate analysis, younger age and the laboratory's use of animal thromboplastin were associated with significant deviations. CONCLUSIONS Although most children had coherent pairs of INR values, the occurrence of deviations raises the question of the origin of the thromboplastin used in the laboratory and emphasizes the need to provide specific quality control procedures for POC INR devices.

Published
2021

2. Endothelial Dysfunction as a Component of Severe Acute Respiratory Syndrome Coronavirus 2–Related Multisystem Inflammatory Syndrome in Children With Shock

Author

Damien Bonnet, Marion Grimaud, François Angoulvant, Maximilien Desvages, Julie Toubiana, David M. Smadja, Mehdi Oualha, Charlyne Brakta, Delphine Borgel, Dominique Lasne, Judith Chareyre, Richard Chocron, Sylvain Renolleau, Aurélien Philippe, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Health data- and model- driven Knowledge Acquisition (HeKA), Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138))

Subjects
Male, Inotrope, [SDV]Life Sciences [q-bio], Online Brief Reports, shock, Critical Care and Intensive Care Medicine, Severity of Illness Index, Gastroenterology, Ventricular Function, Left, 0302 clinical medicine, Adrenal Cortex Hormones, Interquartile range, Vasoconstrictor Agents, Endothelial dysfunction, Child, endotheliopathy, Cardiogenic shock, Systemic Inflammatory Response Syndrome, Troponin, C-Reactive Protein, Distributive shock, Shock (circulatory), ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, medicine.symptom, severe acute respiratory syndrome coronavirus 2, medicine.medical_specialty, Cardiotonic Agents, Shock, Cardiogenic, Immunoglobulins, Intensive Care Units, Pediatric, Angiopoietin-2, 03 medical and health sciences, children, Internal medicine, Severity of illness, medicine, Humans, Lactic Acid, Retrospective Studies, multisystem inflammatory syndrome, Interleukin-6, SARS-CoV-2, business.industry, COVID-19, 030208 emergency & critical care medicine, medicine.disease, Respiration, Artificial, COVID-19 Drug Treatment, Systemic inflammatory response syndrome, 030228 respiratory system, business, Biomarkers
Abstract

Supplemental Digital Content is available in the text., TRIAL REGISTRATION: NCT04420468. OBJECTIVES: Severe acute respiratory syndrome coronavirus 2–related multisystem inflammatory syndrome in children is frequently associated with shock; endothelial involvement may be one of the underlying mechanisms. We sought to describe endothelial dysfunction during multisystem inflammatory syndrome in children with shock and then assess the relationship between the degree of endothelial involvement and the severity of shock. DESIGN: Observational study. SETTING: A PICU in a tertiary hospital. PATIENTS: Patients aged under 18 (n = 28) with severe acute respiratory syndrome coronavirus 2–related multisystem inflammatory syndrome in children and shock, according to the Centers for Disease Control and Prevention criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Correlations between endothelial marker levels and shock severity were assessed using Spearman coefficient. The median (interquartile range) age was 9 years (7.5–11.2 yr). Sixteen children presented with cardiogenic and distributive shock, 10 presented with cardiogenic shock only, and two presented with distributive shock only. The median left ventricular ejection fraction, troponin level, and lactate level were, respectively, 40% (35–45%), 261 ng/mL (131–390 ng/mL), and 3.2 mmol/L (2–4.2 mmol/L). Twenty-five children received inotropes and/or vasopressors; the median Vasoactive and Inotropic Score was 8 (5–28). Plasma levels of angiopoietin-2 (6,426 pg/mL [2,814–11,836 pg/mL]), sE-selectin (130,405 pg/mL [92,987–192,499 pg/mL]), von Willebrand factor antigen (344% [288–378%]), and the angiopoietin-2/angiopoietin-1 ratio (1.111 [0.472–1.524]) were elevated and significantly correlated with the Vasoactive and Inotropic Score (r = 0.45, p = 0.016; r = 0.53, p = 0.04; r = 0.46, p = 0.013; and r = 0.46, p = 0.012, respectively). CONCLUSIONS: Endothelial dysfunction is associated with severe acute respiratory syndrome coronavirus 2–related multisystem inflammatory syndrome in children with shock and may constitute one of the underlying mechanisms.

Published
2021

3. Non-inhibitory antibodies inducing increased emicizumab clearance in a severe hemophilia A inhibitor patient

Author

Ivan Peyron, Delphine Borgel, Dominique Lasne, Thibaud Sefiane, Peter J. Lenting, Caterina Casari, Maximilien Desvages, Stéphanie Chhun, Cécile Bally, Laurent Frenzel, and Annie Harroche

Subjects
Emicizumab, Factor VIII, business.industry, Hematology, Case Reports, Inhibitory antibodies, Antibodies, Monoclonal, Humanized, Hemophilia A, Kinetics, Immunology, Antibodies, Bispecific, Medicine, Humans, Severe haemophilia A, business
Published
2021

4. Anti-inflammatory Activity of the Protein Z-Dependent Protease Inhibitor

Author

François Saller, Julie Helms, Marc Vasse, Allan de Carvalho, Delphine Borgel, Ferhat Meziani, JL Diehl, Mahita Razanakolona, Elsa P. Bianchini, Cécile V. Denis, and Frédéric Adam

Subjects
0301 basic medicine, Chemokine, Lipopolysaccharide, Protein Z, Inflammation, 030204 cardiovascular system & hematology, CCL5, Proinflammatory cytokine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Diseases of the circulatory (Cardiovascular) system, biology, lipopolysaccharide, Interleukin, protein Z-dependent plasma protease inhibitor, Molecular biology, 030104 developmental biology, chemistry, RC666-701, proinflammatory cytokines, biology.protein, Original Article, Tumor necrosis factor alpha, medicine.symptom, monocytes
Abstract

The protein Z (PZ)-dependent plasma protease inhibitor (ZPI) is a glycoprotein that inhibits factor XIa and, in the presence of PZ, FXa. Recently, ZPI has been shown to be an acute-phase protein (APP). As usually APPs downregulate the harmful effects of inflammation, we tested whether ZPI could modulate the increase of cytokines observed in inflammatory states. We observed that recombinant human ZPI (rhZPI) significantly decreases the levels of interleukin (IL)-1, IL-6, and tumor necrosis factor- α (TNF-α) induced by lipopolysaccharide (LPS) in a whole blood model. This inhibitory effect was unaffected by the presence of PZ or heparin. A ZPI mutant within the reactive loop center ZPI (Y387A), lacking anticoagulant activity, still had an anti-inflammatory activity. Surprisingly, rhZPI did not inhibit the synthesis of IL-6 or TNF-α when purified monocytes were stimulated by LPS, whereas the inhibitory effect was evidenced when lymphocytes were added to monocytes. The requirement of lymphocytes could be due to the synthesis of CCL5 (RANTES), a chemokine mainly produced by activated lymphocytes which is induced by rhZPI, and which can reduce the production of proinflammatory cytokines in whole blood. Lastly, we observed that the intraperitoneal injection of rhZPI significantly decreased LPS-induced IL-6 and TNF-α production in mouse plasma.

Published
2021

5. SLC37A4-CDG: New biochemical insights for an emerging congenital disorder of glycosylation with major coagulopathy

Author

Tiffany Pascreau, Walid Haouari, Celia Raulet-Bussian, Annie Harroche, Arnaud Bruneel, Sophie Cholet, Bobby G. Ng, Sandrine Vuillaumier-Barrot, Hudson H. Freeze, Samra Lounis-Ouaras, Alexandre Raynor, François Fenaille, and Delphine Borgel

Subjects
Gene isoform, Glycosylation, Monosaccharide Transport Proteins, Clinical Biochemistry, Golgi Apparatus, Disease, Biology, Endoplasmic Reticulum, Bioinformatics, Biochemistry, Antiporters, Article, chemistry.chemical_compound, symbols.namesake, Congenital Disorders of Glycosylation, Polysaccharides, Coagulopathy, medicine, Humans, Endoplasmic reticulum, Biochemistry (medical), General Medicine, Golgi apparatus, medicine.disease, carbohydrates (lipids), chemistry, Proteoglycan, biology.protein, symbols, Congenital disorder of glycosylation
Abstract

SLC37A4-CDG is an emerging congenital disorder of glycosylation which is characterized by a dominant inheritance and a major coagulopathy originating from the liver. Recent studies took interest in the biochemical alterations found in this CDG and showed that they consisted of multiple glycosylation abnormalities, which result from mislocalization of the endoplasmic reticulum glucose-6-phosphate transporter and associated Golgi homeostasis defects. In this work, we highlight in six affected individuals abnormal patterns for various serum N-glycoproteins and bikunin proteoglycan isoforms, together with specific alterations of the mass spectra of endoglycosidase H-released serum N-glycans. Collectively, these data complement previous findings, help to better delineate SLC37A4-CDG and could present interest in diagnosing this disease.

Published
2021

6. Assessing bleeding risk in 18 children with Osteogenesis imperfecta

Author

Tiffany Pascreau, Marie-Clotilde Haguet, Valérie Nivet-Antoine, Agathe Boussaroque, Rémi Favier, Véronique Forin, Christilla Bachelot-Loza, Jean-Louis Beaudeux, Pauline Lallemant-Dudek, Dominique Lasne, Delphine Borgel, Valérie Cormier-Daire, Vasiliki Gkalea, Annie Harroche, Teddy Léguillier, Geneviève Baujat, Sophie Monnot, and Hélène Lapillonne

Subjects
Male, Pediatrics, medicine.medical_specialty, Platelet Function Tests, business.industry, Vascular disease, Infant, Hemorrhage, Hematology, Osteogenesis Imperfecta, medicine.disease, Platelet function test, Risk Factors, Osteogenesis imperfecta, Child, Preschool, medicine, Humans, Female, Child, business, Blood Coagulation
Published
2021

7. Clinical Evolution of Epithelial–Mesenchymal Transition in Human Carcinomas

Author

Li Chen, Rodrigo F. Chuaqui, Sarah B. Miller, Jyothi Subramanian, Larry Rubinstein, Robert J. Kinders, Andrea Regier Voth, Scott M. Lawrence, Apurva K. Srivastava, Tony Navas, Melinda G. Hollingshead, Shivaani Kummar, Hala R. Makhlouf, Katherine V. Ferry-Galow, James H. Doroshow, Ralph E. Parchment, Alice P. Chen, Deborah Wilsker, Mariam M. Konaté, Sergio Y. Alcoser, Suzanne Borgel, Tomas Vilimas, and Donald P. Bottaro

Subjects
Male, 0301 basic medicine, Cancer Research, Epithelial-Mesenchymal Transition, Indazoles, Paclitaxel, medicine.medical_treatment, Cell Plasticity, Vimentin, Article, Metastasis, Targeted therapy, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigens, CD, Cancer stem cell, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, medicine, Carcinoma, Animals, Humans, Epithelial–mesenchymal transition, beta Catenin, Cell Proliferation, Sulfonamides, biology, Cancer, Cadherins, medicine.disease, Xenograft Model Antitumor Assays, Pyrimidines, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer cell, Neoplastic Stem Cells, Cancer research, biology.protein, Female, Biopsy, Large-Core Needle
Abstract

The significance of the phenotypic plasticity afforded by epithelial–mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in the clinic. We evaluated epithelial–mesenchymal phenotypic characteristics across a range of tumor histologies using a validated, high-resolution digital microscopic immunofluorescence assay (IFA) that incorporates β-catenin detection and cellular morphology to delineate carcinoma cells from stromal fibroblasts and that quantitates the individual and colocalized expression of the epithelial marker E-cadherin (E) and the mesenchymal marker vimentin (V) at subcellular resolution (“EMT-IFA”). We report the discovery of β-catenin+ cancer cells that coexpress E-cadherin and vimentin in core-needle biopsies from patients with various advanced metastatic carcinomas, wherein these cells are transitioning between strongly epithelial and strongly mesenchymal-like phenotypes. Treatment of carcinoma models with anticancer drugs that differ in their mechanism of action (the tyrosine kinase inhibitor pazopanib in MKN45 gastric carcinoma xenografts and the combination of tubulin-targeting agent paclitaxel with the BCR-ABL inhibitor nilotinib in MDA-MB-468 breast cancer xenografts) caused changes in the tumor epithelial–mesenchymal character. Moreover, the appearance of partial EMT or mesenchymal-like carcinoma cells in MDA-MB-468 tumors treated with the paclitaxel–nilotinib combination resulted in upregulation of cancer stem cell (CSC) markers and susceptibility to FAK inhibitor. A metastatic prostate cancer patient treated with the PARP inhibitor talazoparib exhibited similar CSC marker upregulation. Therefore, the phenotypic plasticity conferred on carcinoma cells by EMT allows for rapid adaptation to cytotoxic or molecularly targeted therapy and could create a form of acquired drug resistance that is transient in nature. Significance: Despite the role of EMT in metastasis and drug resistance, no standardized assessment of EMT phenotypic heterogeneity in human carcinomas exists; the EMT-IFA allows for clinical monitoring of tumor adaptation to therapy.

Published
2020

8. Long-Term Follow-up Study after Lentiviral Hematopoietic Stem/Progenitor Cell Gene Therapy for Wiskott - Aldrich Syndrome

Author

Salima Hacein-Bey-Abina, Adeline Denis, Alexandre Kauskot, Elizabeth Macintyre, Jin Hua Xu-Bayford, Aurélie Gabrion, Guy Gorochov, Cécile Roudaut, Chantal Lagresle-Peyrou, Aoife M. Doto, Capucine Picard, Frédéric Adam, Felipe Suarez, Alessandra Magnani, Frederic D. Bushman, Alain Fischer, Rachel Petermann, Emma C. Morris, Sarah Abbas, Emmanuel Clave, Marianne Guisset, Chrystelle Abdo, Christine Rivat, Loïc Dupré, Amélie Trinquand, Reem Elfeky, Marina Cavazzana, Elisa Magrin, Despina Moshous, Claire Booth, Anne Galy, Emmanuelle Six, Antoine Toubert, Bobby Gaspar, Adrian J. Thrasher, Mélanie Guiot, Delphine Borgel, Michaela Semeraro, John K. Everett, Makoto Miyara, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM), Great Ormond Street Hospital for Children [London] (GOSH), Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Universitaire Ouest, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Hopital Saint-Louis [AP-HP] (AP-HP), Arthrites autoimmunes (AA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Transfusion Sanguine [Paris] (INTS), Service d'immuno-hématologie pédiatrique [CHU Necker], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
business.industry, Wiskott–Aldrich syndrome, Long term follow up, Genetic enhancement, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Haematopoiesis, Cancer research, Medicine, Progenitor cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency associated with thrombocytopenia, eczema, infectious, autoimmune complications, and lymphomas. Patients lacking an HLA-matched donor may benefit from an alternative therapeutic approach based on the infusion of autologous gene corrected CD34+ cells. We previously reported a non-randomised, open-label, phase 1/2 clinical study applying a lentiviral vector based gene therapy (GT) protocol in 7 paediatric patients with severe WAS (score ≥ 3/5) (S. Hacein-Bey Abina et al, JAMA 2015). One patient died 7 months after GT because of pre-existing severe opportunistic infections, as reported. Two additional patients have been treated since that initial report, with a follow-up of at least 4 years. We here present a comprehensive long-term study on 8 patients with a follow-up from 4 to 9 years (median 7.6). The safety and efficacy of the approach is thoroughly investigated, with a particular focus on the correction of thrombocytopenia and auto-immunity. A stable engraftment of genetically and functionally corrected lymphoid and myeloid cells was reached in all patients, with no serious treatment-associated adverse events or concerning clonal expansion. Corrected lymphoid cells displayed a selective advantage over time with increasing vector copy number (VCN) level. In turn, this led to (i) sustained expression of WAS protein (WASp) in the patients' cells and (ii) clinical resolution of severe eczema and susceptibility to recurrent infections. In line with these results, T-cell function was restored after GT, as shown by the recovery of immune synapse assembly and the normalization of naïve T cell numbers. The T-cell compartment was also reconstituted in the patient treated at the age of 30 years, suggesting that GT for WAS is a treatment option in adult patients. In parallel with the robustness of T-cell reconstitution a normalized B-cell compartment was observed after GT, as shown in particular by increasing levels of WASp + switched memory B cells over time and the age-matched levels of KRECs. Five patients out of 8 were able to discontinue Ig replacement therapy while achieving normal post-vaccination antibody titers. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. After GT, a few autoimmune manifestations were observed: the persistence of lower extremity vasculitis (P2, very severe prior to GT), the new occurrence of nephrotic syndrome (P9), and the presence of anti-platelet antibodies (P2, P4, P7). The levels of circulating autoantibodies detected before GT (including ANA and vasculitis-related autoantibodies) normalized after treatment. Following GT, platelets were found to express sub-normal levels of WASp and to only partially augment their size. Platelet function studies indicated a partial correction of the platelet compartment achieved by GT, which may be sufficient to prevent occurrence of the hemorrhagic symptoms typical of WAS. Our results suggest that lentiviral GT provides sustained clinical benefits for patients with WAS. Overall clinical remission was observed in our patients despite very severe disease scores before GT. More efficacious and more reliable transduction protocols and conditioning regimen are likely to further improve outcomes, particularly with regard to platelet recovery, where the advantages of intrinsic correction are less apparent. Disclosures Booth: Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana: Smart Immune: Other: co-founder.

Published
2021

10. The Proteolytic Inactivation of Protein Z-Dependent Protease Inhibitor by Neutrophil Elastase Might Promote the Procoagulant Activity of Neutrophil Extracellular Traps in Sepsis

Author

Luc de Chaisemartin, Cécile V. Denis, Mahita Razanakolona, Sylvie Chollet-Martin, Delphine Borgel, Ferhat Meziani, Julie Boisramé-Helms, Viviana Marin-Esteban, Roselyne Bironien, Fouzia Zouiti, Marc Vasse, Allan de Carvalho, Elsa P. Bianchini, Jean-Luc Diehl, Amélie Couteau-Chardon, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Les Hôpitaux Universitaires de Strasbourg (HUS), Université de Strasbourg (UNISTRA), Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Saclay, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cytokines, chimiokines et immunopathologie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpital Foch [Suresnes], Innovations thérapeutiques en hémostase (IThEM - U1140), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Fédération de Médecine Translationnelle de Strasbourg (FMTS), CHU Necker - Enfants Malades [AP-HP], Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and BIANCHINI, ELSA

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Proteolysis, Protein Z, Inflammation, Serpin, Extracellular Traps, ZPI, sepsis, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, elastase, Protease Inhibitors, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Serpins, SERPINA10, biology, medicine.diagnostic_test, Chemistry, Acute-phase protein, Anticoagulants, NETs, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Blood Proteins, Hematology, Neutrophil extracellular traps, Disseminated Intravascular Coagulation, Shock, Septic, Molecular biology, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Dacarbazine, 030104 developmental biology, Coagulation, inflammation, 030220 oncology & carcinogenesis, Neutrophil elastase, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, biology.protein, medicine.symptom, Leukocyte Elastase
Abstract

Septic shock is the archetypal clinical setting in which extensive crosstalk between inflammation and coagulation dysregulates the latter. The main anticoagulant systems are systematically impaired, depleted, and/or downregulated. Protein Z-dependent protease inhibitor (ZPI) is an anticoagulant serpin that not only targets coagulation factors Xa and XIa but also acts as an acute phase reactant whose plasma concentration rises in inflammatory settings. The objective of the present study was to assess the plasma ZPI antigen level in a cohort of patients suffering from septic shock with or without overt-disseminated intravascular coagulation (DIC). The plasma ZPI antigen level was approximately 2.5-fold higher in the patient group (n = 100; 38 with DIC and 62 without) than in healthy controls (n = 31). The elevation's magnitude did not appear to depend on the presence/absence of DIC. Furthermore, Western blots revealed the presence of cleaved ZPI in plasma from patients with severe sepsis, independently of the DIC status. In vitro, ZPI was proteolytically inactivated by purified neutrophil elastase (NE) and by NE on the surface of neutrophil extracellular traps (NETs). The electrophoretic pattern of ZPI after NE-catalyzed proteolysis was very similar to that resulting from the clotting process—suggesting that the cleaved ZPI observed in severe sepsis plasma is devoid of anticoagulant activity. Taken as a whole, our results (1) suggest that NE is involved in ZPI inactivation during sepsis, and (2) reveal a novel putative mechanism for the procoagulant activity of NETs in immunothrombosis.

Published
2021

11. A mutation in SLC37A4 causes a dominantly inherited congenital disorder of glycosylation characterized by liver dysfunction

Author

Michael Kulik, Deepti M. Warad, Nathalie Seta, Mathieu Fiore, Anne Dell, Sandrine Vuillaumier-Barrot, Zhi-Jie Xia, Tadahiro Kumagai, Hudson H. Freeze, François Fenaille, Katherine Mcgoogan, Kimiyo Raymond, Mindy Porterfield, Thierry Dupré, Marie-Christine Vergnes-Boiteux, Deborah A. Nickerson, Michael Tiemeyer, Sophie Cholet, Michael J. Bamshad, Caroline Michot, Arnaud Bruneel, Tiffany Pascreau, Heather Flanagan-Steet, Shannon M. Wagner, Stuart M. Haslam, Bobby G. Ng, Delphine Borgel, Paulina Sosicka, Stephen Dalton, Richard Steet, Yohann Huguenin, Annie Harroche, Sanford Burnham Prebys Medical Discovery Institute, Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP - Hôpital Bichat - Claude Bernard [Paris], University of Georgia [USA], University of Washington [Seattle], CHU Bordeaux [Bordeaux], Imperial College London, Nemours Children's Specialty Care, Jacksonville, FL., Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Mayo Clinic [Rochester], The Greenwood Genetic Center, INSERM UMR S1193, Fondation Maladies Rares (FMR) WES-20160717, Commissariat à l'Energie Atomique et aux Energies Alternatives, R01DK99551, ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
0301 basic medicine, Adult, Male, Glycosylation, Monosaccharide Transport Proteins, glycosylation, Phosphatase, Biology, medicine.disease_cause, Endoplasmic Reticulum, Antiporters, Article, coagulopathy, 03 medical and health sciences, symbols.namesake, chemistry.chemical_compound, 0302 clinical medicine, Congenital Disorders of Glycosylation, Mutant protein, Genetics, medicine, Humans, Child, Genetics (clinical), Genes, Dominant, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Glycogen, Golgi pH, Endoplasmic reticulum, Liver Diseases, congenital disordes of glycosylation, Infant, Newborn, Infant, Golgi apparatus, Fibroblasts, medicine.disease, Molecular biology, Pedigree, 030104 developmental biology, chemistry, Child, Preschool, symbols, Female, Congenital disorder of glycosylation, exome sequencing, 030217 neurology & neurosurgery
Abstract

International audience; SLC37A4 encodes an endoplasmic reticulum (ER)-localized multitransmembrane protein required for transporting glucose-6-phosphate (Glc-6P) into the ER. Once transported into the ER, Glc-6P is subsequently hydrolyzed by tissue-specific phosphatases to glucose and inorganic phosphate during times of glucose depletion. Pathogenic variants in SLC37A4 cause an established recessive disorder known as glycogen storage disorder 1b characterized by liver and kidney dysfunction with neutropenia. We report seven individuals who presented with liver dysfunction multifactorial coagulation deficiency and cardiac issues and were heterozygous for the same variant, c.1267C>T (p.Arg423*), in SLC37A4; the affected individuals were from four unrelated families. Serum samples from affected individuals showed profound accumulation of both high mannose and hybrid type N-glycans, while N-glycans in fibroblasts and undifferentiated iPSC were normal. Due to the liver-specific nature of this disorder, we generated a CRISPR base-edited hepatoma cell line harboring the c.1267C>T (p.Arg423*) variant. These cells replicated the secreted abnormalities seen in serum N-glycosylation, and a portion of the mutant protein appears to relocate to a distinct, non-Golgi compartment, possibly ER exit sites. These cells also show a gene dosage-dependent alteration in the Golgi morphology and reduced intraluminal pH that may account for the altered glycosylation. In summary, we identify a recurrent mutation in SLC37A4 that causes a dominantly inherited congenital disorder of glycosylation characterized by coagulopathy and liver dysfunction with abnormal serum N-glycans.

Published
2021

13. Elevated thrombin generation in patients with congenital disorder of glycosylation and combined coagulation factor deficiencies

Author

Arnaud Bruneel, Mercedes Serrano, Dominique Lasne, Nathalie Seta, Nathalie Boddaert, Elsa P. Bianchini, María Eugenia de la Morena-Barrio, Tiffany Pascreau, Delphine Borgel, Javier Corral, Vicente Vicente, Pascale de Lonlay, and Manoelle Kossorotoff

Subjects
Male, Paris, medicine.medical_specialty, Adolescent, Coagulation Protein Disorders, 030204 cardiovascular system & hematology, Thrombomodulin, Protein S, 03 medical and health sciences, Blood Coagulation Disorders, Inherited, Congenital Disorders of Glycosylation, 0302 clinical medicine, Thrombin, Internal medicine, Humans, Medicine, Genetic Predisposition to Disease, Child, Blood Coagulation, Retrospective Studies, Factor IX, biology, business.industry, Antithrombin, Hematology, medicine.disease, Phenotype, Endocrinology, Coagulation, Spain, Child, Preschool, biology.protein, Female, business, Congenital disorder of glycosylation, Protein C, medicine.drug
Abstract

Background Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors. Objective To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay. Method We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin. Results A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke-like episodes or thrombosis displayed this hypercoagulant phenotype. Conclusion A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events.

Published
2019

14. Long-term follow-up in PMM2-CDG: are we ready to start treatment trials?

Author

Arnaud Bruneel, Eric Bauchart, Peter Witters, Wouter Meersseman, Gert Matthijs, Delphine Borgel, David Cassiman, Eva Morava, Tiffany Pascreau, Lonlay Pascale de, Tomas Honzik, Sandrine Vuillaumier, Jaak Jaeken, Nathalie Seta, and Ruqaiah Altassan

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Pediatrics, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Antithrombin, 030105 genetics & heredity, medicine.disease, Clinical trial, 03 medical and health sciences, 030104 developmental biology, Thyroid-stimulating hormone, medicine, Thyroid function, Liver function tests, Strabismus, business, Congenital disorder of glycosylation, Genetics (clinical), Partial thromboplastin time, medicine.drug
Abstract

PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution. We performed data analysis on PMM2-CDG patients’ clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years. On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases. PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.

Published
2019

15. Reappearance of inhibitor in a tolerized patient with severe haemophilia A during FVIII‐free emicizumab therapy

Author

Delphine Borgel, Cécile Bally, Sébastien Lacroix-Desmazes, Sandrine Delignat, Dominique Lasne, Maximilien Desvages, Annie Harroche, Ladislas Capdevila, and Laurent Frenzel

Subjects
Emicizumab, business.industry, Fviii inhibitor, Immunology, Haemophilia A, Medicine, Severe haemophilia A, Hematology, General Medicine, business, medicine.disease, Genetics (clinical)
Published
2021

16. Serpins in Hemostasis as Therapeutic Targets for Bleeding or Thrombotic Disorders

Author

Elsa P. Bianchini, Claire Auditeau, Mahita Razanakolona, Marc Vasse, and Delphine Borgel

Subjects
0301 basic medicine, lcsh:Diseases of the circulatory (Cardiovascular) system, animal structures, medicine.medical_treatment, Mini Review, serpin (serine proteinase inhibitor), 030204 cardiovascular system & hematology, Serpin, Cardiovascular Medicine, protein Z-dependent protease inhibitor (ZPI), Bioinformatics, Fibrin, 03 medical and health sciences, 0302 clinical medicine, Fibrinolysis, medicine, antithrombin (AT), Serine protease, therapy, biology, business.industry, medicine.disease, Clot formation, Thrombosis, carbohydrates (lipids), 030104 developmental biology, Coagulation, plasminogen activator inhibitor 1 (PAI-1), lcsh:RC666-701, Hemostasis, embryonic structures, biology.protein, Cardiology and Cardiovascular Medicine, business, protease nexin I (PN-1)
Abstract

Bleeding and thrombotic disorders result from imbalances in coagulation or fibrinolysis, respectively. Inhibitors from the serine protease inhibitor (serpin) family have a key role in regulating these physiological events, and thus stand out as potential therapeutic targets for modulating fibrin clot formation or dismantling. Here, we review the diversity of serpin-targeting strategies in the area of hemostasis, and detail the suggested use of modified serpins and serpin inhibitors (ranging from small-molecule drugs to antibodies) to treat or prevent bleeding or thrombosis.

Published
2021

17. Long term outcome of MPI‐CDG patients on D‐mannose therapy

Author

Muriel Girard, Pascale de Lonlay, Arnaud Bruneel, Thierry Dupré, Lena Damaj, Dominique Debray, Monique Fabre, Karine Mention, Eric Bauchard, Dries Dobbelaere, Manuel Schiff, Nathalie Seta, Sandrine Vuillaumier-Barrot, Claire Douillard, Florence Lacaille, Stéphanie Torre, Delphine Borgel, Valérie A. McLin, Alice Kuster, 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), Université de Lille, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geneva University Hospitals and Geneva University, Hospital Bichat Paris, Mécanismes cellulaires et moléculaires de l'adaptation au stress et cancérogenèse (INSERM UMR1193), Université Paris-Saclay, and European Project: 643578,H2020,H2020-HCO-2014,E-Rare-3(2014)

Subjects
Liver Cirrhosis, Male, [SDV]Life Sciences [q-bio], diarrhea, Administration, Oral, Gastroenterology, Congenital Disorders of Glycosylation, Enteropathy, Portal hypertension, Child, Genetics (clinical), Venous Thrombosis, 0303 health sciences, ddc:618, 030305 genetics & heredity, Transferrin, portal hypertension, Thrombosis, 3. Good health, Venous thrombosis, Diarrhea, Treatment Outcome, Child, Preschool, Hypertension, Congenital hepatic fibrosis, Female, medicine.symptom, D-mannose, medicine.medical_specialty, Renal function, Hypoglycemia, Medication Adherence, 03 medical and health sciences, congenital disorder of glycosylation, Internal medicine, Genetics, medicine, congenital hepatic fibrosis, Humans, coagulation, Retrospective Studies, 030304 developmental biology, Coagulation, Mannose-6-Phosphate Isomerase, business.industry, Congenital disorder of glycosylation, Infant, medicine.disease, MPI-CDG, business, Mannose
Abstract

International audience; Mannose phosphate isomerase MPI-CDG (formerly CDG-1b) is a potentially fatal inherited metabolic disease which is readily treatable with oral D-mannose. We retrospectively reviewed long-term outcomes of patients with MPI-CDG, all but one of whom were treated with D-mannose. Clinical, biological, and histological data were reviewed at diagnosis and on D-mannose treatment. Nine patients were diagnosed with MPI-CDG at a median age of 3 months. The presenting symptoms were diarrhea (n = 9), hepatomegaly (n = 9), hypoglycemia (n = 8), and protein loosing enteropathy (n = 7). All patients survived except the untreated one who died at 2 years of age. Oral D-mannose was started in eight patients at a median age of 7 months (mean 38 months), with a median follow-up on treatment of 14 years 9 months (1.5-20 years). On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function. Poor compliance with D-mannose was correlated with recurrence of diarrhea, thrombosis, and abnormal biological parameters including coagulation factors and transferrin profiles. Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up. This study highlights (i) the efficacy and safety of D-mannose treatment with a median follow-up on treatment of almost 15 years (ii) the need for life-long treatment (iii) the risk of relapse with poor compliance, (iii) the importance of portal hypertension screening (iv) the need to be aware of venous and renal complications in adulthood.

Published
2020

18. Factor XII in PMM2-CDG patients: role of N-glycosylation in the secretion and function of the first element of the contact pathway

Author

Mercedes Serrano, Vanessa Roldán, Monika Pathak, María Eugenia de la Morena-Barrio, Alberto López-Lera, Javier Corral, Raquel López-Gálvez, Delphine Borgel, Jonas Emsley, Antonia Miñano, and Vicente Vicente

Subjects
0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Glycosylation, lcsh:Medicine, N-glycosylation, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Congenital Disorders of Glycosylation, 0302 clinical medicine, N-linked glycosylation, law, Internal medicine, medicine, Humans, Pharmacology (medical), Secretion, Angioedema, Genetics (clinical), chemistry.chemical_classification, Hemostasis, Factor XII, Chemistry, Research, lcsh:R, Antithrombin, General Medicine, medicine.disease, carbohydrates (lipids), 030104 developmental biology, Endocrinology, Phosphotransferases (Phosphomutases), Transferrin, Hereditary angioedema, Recombinant DNA, lipids (amino acids, peptides, and proteins), medicine.drug
Abstract

Background Congenital disorders of glycosylation (CDG) are rare diseases with impaired glycosylation and multiorgan disfunction, including hemostatic and inflammatory disorders. Factor XII (FXII), the first element of the contact phase, has an emerging role in hemostasia and inflammation. FXII deficiency protects against thrombosis and the p.Thr309Lys variant is involved in hereditary angioedema through the hyperreactivity caused by the associated defective O-glycosylation. We studied FXII in CDG aiming to supply further information of the glycosylation of this molecule, and its functional and clinical effects. Plasma FXII from 46 PMM2-CDG patients was evaluated by coagulometric and by Western Blot in basal conditions, treated with N-glycosydase F or activated by silica or dextran sulfate. A recombinant FXII expression model was used to validate the secretion and glycosylation of wild-type and variants targeting the two described FXII N-glycosylation sites (p.Asn230Lys; p.Asn414Lys) as well as the p.Thr309Lys variant. Results PMM2-CDG patients had normal FXII levels (117%) but high proportions of a form lacking N-glycosylation at Asn414. Recombinant FXII p.Asn230Lys, and p.Asn230Lys&p.Asn414Lys had impaired secretion and increased intracellular retention compared to wild-type, p.Thr309Lys and p.Asn414Lys variants. The hypoglycosylated form of PMM2-CDG activated similarly than FXII fully glycosylated. Accordingly, no PMM2-CDG had angioedema. FXII levels did not associate to vascular events, but hypoglycosylated FXII, like hypoglycosylated transferrin, antithrombin and FXI levels did it. Conclusions N-glycosylation at Asn230 is essential for FXII secretion. PMM2-CDG have high levels of FXII lacking N-glycosylation at Asn414, but this glycoform displays similar activation than fully glycosylated, explaining the absence of angioedema in CDG.

Published
2020

19. Added value of buccal cell FISH analysis in the diagnosis and management of Turner syndrome

Author

N Bourcigaux, A. Khodawardi, Jean-Pierre Siffroi, A. Graff, Sophie Christin-Maitre, Camille Vatier, M.C. Villy, A. Borgel, B. Donadille, H. Morel, Sorbonne Université (SU), Service d'Endocrinologie, diabétologie et endocrinologie de la reproduction [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique chromosomique [CHU Trousseau], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], and Couvet, Sandrine

Subjects
MESH: Mouth Mucosa, [SDV]Life Sciences [q-bio], Buccal swab, blood karyotype, Turner Syndrome, [SDV.GEN] Life Sciences [q-bio]/Genetics, Cohort Studies, 0302 clinical medicine, Turner syndrome, Medicine, X/46, Prospective Studies, MESH: Cohort Studies, Ovarian Neoplasms, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, Mosaicism, Rehabilitation, Obstetrics and Gynecology, [SDV] Life Sciences [q-bio], MESH: Ovarian Neoplasms, buccal cells FISH, Cohort, Female, MESH: Mosaicism, Cohort study, Adult, medicine.medical_specialty, MESH: Turner Syndrome, Urinary system, Gonadoblastoma, 030209 endocrinology & metabolism, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 03 medical and health sciences, Internal medicine, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, Mouth Mucosa, Turner’s syndrome, MESH: Adult, Buccal administration, medicine.disease, MESH: Prospective Studies, Reproductive Medicine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Skin biopsy, business, MESH: Female, X monosomy, XX mosaicism
Abstract

STUDY QUESTION Is there an added diagnosis value of buccal cell FISH analysis compared with blood lymphocyte chromosomal investigations in patients with Turner syndrome (TS)? SUMMARY ANSWER Buccal cell FISH analysis, a non-invasive technique, modified the chromosomal results obtained with the blood karyotype in 17 patients (12%) of our cohort. WHAT IS KNOWN ALREADY Few studies have evaluated buccal cell FISH analysis and compared them with blood karyotype in patients with TS. STUDY DESIGN, SIZE, DURATION A prospective, monocentric cohort study was conducted in a rare diseases centre (CMERC) between July 2017 and August 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In total, 142 adult patients with TS, and at least 5% 45,X cells in a previous blood karyotype, were recruited. All the patients’ files were included in the CEMARA database. This national database has been declared to the French data protection agency (CNIL approval number 1187326). In compliance with French law, consent regarding non-opposition to collect and use the data was obtained from each patient. A FISH analysis on a buccal smear was performed. MAIN RESULTS AND THE ROLE OF CHANCE The percentage of 45,X cells was identical between the two tissues in only 32.4% of cases. The discrepancy was higher than 41% for 12% of the cohort. The percentage of 45,X cells was higher in blood in 53 (37.3%) patients, and higher in buccal cells in 43 (30.3%) of cases. In 17 (12%) cases, the blood karyotype had to be reconsidered in regard to the buccal cell analysis. LIMITATIONS, REASONS FOR CAUTION It would have been interesting to evaluate karyotypes in cells from other tissues such as cells from skin biopsy or from the urinary tract and even from blood vessels or gonads in case of surgery and to compare them with each patient’s phenotype. However, most of the time, these tissues are not available. WIDER IMPLICATIONS OF THE FINDINGS Although blood lymphocyte karyotype remains the gold standard for the diagnosis of TS, buccal cell FISH analysis is an efficient tool to evaluate the global chromosomal constitution in these patients, thus allowing them to have better care and follow-up. For instance, identifying a Y chromosome can prevent the occurrence of a gonadoblastoma, as gonadectomy should be discussed. On the other hand, finding normal XX cells in a patient with a previous diagnosis of homogenous 45,X TS, may be psychologically helpful and relevant for gynaecological care. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was sought for the study. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A, N/A.

Published
2020

20. NAADP/SERCA3-Dependent Ca 2+ Stores Pathway Specifically Controls Early Autocrine ADP Secretion Potentiating Platelet Activation

Author

Cécile V. Denis, Frédéric Adam, Delphine Borgel, Regis Bobe, Jean-Philippe Rosa, Ziane Elaib, Miao Feng, Marijke Bryckaert, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, and BOBE, Regis

Subjects
0301 basic medicine, Physiology, Chemistry, [SDV]Life Sciences [q-bio], Endoplasmic reticulum, Cell, 030204 cardiovascular system & hematology, Adenosine, sarcoplasmic reticulum, Cell biology, [SDV] Life Sciences [q-bio], endoplasmic reticulum, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, adenosine, platelet activation, medicine, Secretion, Platelet activation, Cardiology and Cardiovascular Medicine, Autocrine signalling, Reticulum, medicine.drug
Abstract

Rationale: Ca 2+ signaling is a key and ubiquitous actor of cell organization and its modulation controls many cellular responses. SERCAs (sarco-endoplasmic reticulum Ca 2+ -ATPases) pump Ca 2+ into internal stores that play a major role in the cytosolic Ca 2+ concentration rise upon cell activation. Platelets exhibit 2 types of SERCAs, SERCA2b and SERCA3 (SERCA3 deficient mice), which may exert specific roles, yet ill-defined. We have recently shown that Ca 2+ mobilization from SERCA3-dependent stores was required for full platelet activation in weak stimulation conditions. Objective: To uncover the signaling mechanisms associated with Ca 2+ mobilization from SERCA3-dependent stores leading to ADP secretion. Methods and Results: Using platelets from wild-type or Serca3 -deficient mice, we demonstrated that an early (within 5–10 s following stimulation) secretion of ADP specifically dependent on SERCA3 stored Ca 2+ is exclusively mobilized by nicotinic acid adenosine dinucleotide-phosphate (NAADP): both Ca 2+ mobilization from SERCA3-dependent stores and primary ADP secretion are blocked by the NAADP receptor antagonist Ned-19, and reciprocally both are stimulated by permeant NAADP. In contrast, Ca 2+ mobilization from SERCA3-dependent stores and primary ADP secretion were unaffected by inhibition of the production of IP3 (inositol-1,4,5-trisphosphate) by phospholipase-C and accordingly were not stimulated by permeant IP3. Conclusions: Upon activation, an NAADP/SERCA3 Ca 2+ mobilization pathway initiates an early ADP secretion, potentiating platelet activation, and a secondary wave of ADP secretion driven by both an IP3/SERCA2b-dependent Ca 2+ stores pathway and the NAADP/SERCA3 pathway. This does not exclude that Ca 2+ mobilized from SERCA3 stores may also enhance platelet global reactivity to agonists. Because of its modulating effect on platelet activation, this NAADP-SERCA3 pathway may be a relevant target for anti-thrombotic therapy. Graphic Abstract: A graphic abstract is available for this article.

Published
2020

21. First heterozygous NOP10 mutation in familial pulmonary fibrosis

Author

Spyros Papiris, Effrosyni D. Manali, Ibrahima Ba, Lykourgos Kolilekas, Caroline Kannengiesser, Catherine Boileau, Claire Oudin, Isabelle Callebaut, Raphael Borie, Patrick Revy, Adrien Borgel, Elodie Lainey, Katerina Malagari, Aggeliki Haritou, Bruno Crestani, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)

Subjects
Pulmonary and Respiratory Medicine, 0303 health sciences, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease, Bioinformatics, 3. Good health, Telomere, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Pulmonary fibrosis, Mutation (genetic algorithm), medicine, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

We provide first evidence that a heterozygous NOP10 mutation (c.17A>G,p.Tyr6Cys) identified in a large family co-segregates with adult-onset familial PF and predisposes to short telomere syndrome (familial PF, liver, haematological diseases)http://bit.ly/2wvXsUd

Published
2020

22. Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation

Author

Łukasz Pawliński, Luis Aldámiz-Echevarría, Tomas Honzik, Arnaud Bruneel, Tiffany Pascreau, Dulce Quelhas, Klaus Mohnike, Joana Correia, Delphine Borgel, Eva Morava, Sandrine Vuillaumier-Barrot, Pascale de Lonlay, Beata Kieć-Wilk, Peter Witters, Silvia Radenkovic, Esmeralda Martins, María L. Couce, Annie Harroche, Anna Cechova, Muriel Girard, and Ruqaiah Altassan

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Glycosylation, Consensus, Mannose-6-Phosphate Isomerase, business.industry, Mannose phosphate isomerase, Protein losing enteropathy, Mannose, Disease Management, Disease, Bioinformatics, medicine.disease, Article, chemistry.chemical_compound, Congenital Disorders of Glycosylation, chemistry, Intellectual disability, Practice Guidelines as Topic, Genetics, Medicine, Humans, Differential diagnosis, business, Congenital disorder of glycosylation, Genetics (clinical)
Abstract

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

Published
2020

23. Diagnosis of Acquired Hemophilia A Must be Considered in Childhood: A Case Report

Author

Dominique Lasne, Harroche A, Delphine Borgel, Bally C, Rothschild R, and Tiffany Pascreau

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Cyanotic congenital heart disease, Hypoplastic aortic arch, Acquired hemophilia, Medicine, General Medicine, business, medicine.disease, Pulmonary hypertension, Pathophysiology
Published
2019

24. A 2.5-Year Within-Patient Evolution of Pseudomonas aeruginosa Isolates with In Vivo Acquisition of Ceftolozane-Tazobactam and Ceftazidime-Avibactam Resistance upon Treatment

Author

Rémy A. Bonnin, Agnès B Jousset, Adrien Borgel, Laurent Dortet, Thierry Naas, Thibaud Boulant, Aurélie Barrail-Tran, and Saoussen Oueslati

Subjects
Pharmacology, 0303 health sciences, Imipenem, 030306 microbiology, Pseudomonas aeruginosa, Ceftazidime, Single-nucleotide polymorphism, biochemical phenomena, metabolism, and nutrition, Biology, bacterial infections and mycoses, Ceftazidime/avibactam, medicine.disease_cause, Antimicrobial, Meropenem, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Infectious Diseases, In vivo, polycyclic compounds, medicine, bacteria, Pharmacology (medical), 030212 general & internal medicine, medicine.drug
Abstract

Ceftolozane-tazobactam is considered to be a last resort treatment for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa Although, resistance to this antimicrobial have been described in vitro, development of resistance in vivo was rarely reported. Here, we described the evolution of resistance to ceftolozane-tazobactam of P. aeruginosa isolates recovered from the same patient during recurrent infections over 2.5 years.Antimicrobial susceptibility testing results showed that 24 of the 27 P. aeruginosa isolates recovered from blood (n=18), wound (n=2), pulmonary sample (n=1), bile (n=2) and stools (n=4) of the same patient were susceptible to ceftolozane-tazobactam and ceftazidime-avibactam but resistant to ceftazidime, piperacillin-tazobactam, imipenem and meropenem. Three clinical isolates acquired resistance to ceftolozane-tazobactam and ceftazidime-avibactam along with a partial restoration of piperacillin-tazobactam and carbapenems susceptibilities. Whole genome sequencing analysis reveals that all isolates were clonally related (ST-111) with a median of 24.9 single nucleotide polymorphisms (SNPs) (range 8-48). The ceftolozane-tazobactam and ceftazidime-avibactam resistance was likely linked to the same G183D substitution in the chromosome-encoded cephalosporinase.Our results suggest resistance to ceftolozane-tazobactam in P. aeruginosa might occur in vivo upon treatment through amino-acid substitution in the intrinsic AmpC leading to ceftolozane-tazobactam and ceftazidime-avibactam resistance accompanied by re-sensitization to piperacillin-tazobactam and carbapenems.

Published
2019

25. Endothelial cell surface limits coagulation without modulating the antithrombin potency

Author

Béatrice Catieau, Sami Chtourou, Jean-Luc Plantier, Delphine Borgel, and Véronique Devos

Subjects
0301 basic medicine, Endothelial protein C receptor, Chemistry, Antithrombin, Endothelial Cells, Hematology, Heparin, 030204 cardiovascular system & hematology, Pharmacology, Antithrombins, In vitro, Endothelial stem cell, 03 medical and health sciences, Tissue factor, 030104 developmental biology, 0302 clinical medicine, medicine, Humans, Heparanase, Receptor, Blood Coagulation, medicine.drug
Abstract

Antithrombin (AT) binds in vitro and in vivo to endothelial cells through various receptors, including heparan sulphate glycosaminoglycan (HSPG) that could modulate the AT activity. A thrombin generation assay (TGA) was set up at the surface of HUVEC and HMVEC evaluating their participation in the coagulation-anticoagulation processes. TGA induced by 0.5 pM Tissue Factor was performed in normal or AT-deficient plasma spiked with various amounts of recombinant or plasma-derived AT (0, 0.1, 0.5 and 1.0 U/ml). To evaluate the role of HSPG or cellular anticoagulant receptors, cells were treated or not with heparin, a mix of heparanase I, II and III, a neutralizing anti-Endothelial Protein C Receptor (EPCR) or with an anti-Tissue Factor Pathway Inhibitor (TFPI) antibody. The presence of the cells diminished the TG in normal plasma and maintained anticoagulation in AT-deficient plasma. Spiking the AT-deficient plasma with different doses of AT demonstrated that the cells did not amplify the anticoagulant activity of AT. The recombinant AT binds the cells with a higher avidity than the plasma-derived one but this did not affect its anticoagulant potency. Moreover both bindings are independent of the HSPG. The antithrombotic activity kept in absence of AT was not inhibited by blocking antibodies directed against EPCR or TFPI. Our data did not reveal a major co-factor activity for AT from endothelial cells that could have been mediated by HSPG. In contrast, it reveals the presence of alternative anti-coagulant system(s) in two venous cell types that maintain an antithrombotic activity.

Published
2018

26. Kinesin-1 Is a New Actor Involved in Platelet Secretion and Thrombus Stability

Author

Gaël Ménasché, Olivier D. Christophe, Mathieu Kurowska, Marijke Bryckaert, Alain Fischer, Frédéric Adam, Jian-Dong Huang, Nicolas Goudin, Geneviève de Saint Basile, Jean-Claude Bordet, Delphine Borgel, Isabelle Munoz, Alexandre Kauskot, University College Cork (UCC), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hémostase, Inflammation et sepsis (EA 4609), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Department of Hematology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ménasché, Gaël, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), and Collège de France - Chaire Médecine expérimentale (A. Fischer)

Subjects
0301 basic medicine, Platelet Aggregation, blood platelets, [SDV]Life Sciences [q-bio], platelet secretion, Vesicular Transport Proteins, Kinesins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Platelet Factor 4, kinesin, rab27 GTP-Binding Proteins, Exocytosis, 03 medical and health sciences, Adenosine Triphosphate, Thrombin, medicine, Animals, Humans, Secretion, Platelet, Thrombus, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Mice, Knockout, Secretory Pathway, Chemistry, Secretory Vesicles, Thrombosis, Platelet Activation, medicine.disease, 3. Good health, Cell biology, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Disease Models, Animal, P-Selectin, 030104 developmental biology, Hemostasis, hemostasis, Dense granule, Cardiology and Cardiovascular Medicine, Megakaryocytes, Platelet factor 4, Signal Transduction, medicine.drug
Abstract

Objective— Platelet secretion is crucial for many physiological platelet responses. Even though several regulators of the fusion machinery for secretory granule exocytosis have been identified in platelets, the underlying mechanisms are not yet fully characterized. Approach and Results— By studying a mouse model (cKO [conditional knockout] Kif5b ) lacking Kif5b (kinesin-1 heavy chain) in its megakaryocytes and platelets, we evidenced unstable hemostasis characterized by an increase of blood loss associated to a marked tendency to rebleed in a tail-clip assay and thrombus instability in an in vivo thrombosis model. This instability was confirmed in vitro in a whole-blood perfusion assay under blood flow conditions. Aggregations induced by thrombin and collagen were also impaired in cKO Kif5b platelets. Furthermore, P-selectin exposure, PF4 (platelet factor 4) secretion, and ATP release after thrombin stimulation were impaired in cKO Kif5b platelets, highlighting the role of kinesin-1 in α-granule and dense granule secretion. Importantly, exogenous ADP rescued normal thrombin induced-aggregation in cKO Kif5b platelets, which indicates that impaired aggregation was because of defective release of ADP and dense granules. Last, we demonstrated that kinesin-1 interacts with the molecular machinery comprising the granule-associated Rab27 (Ras-related protein Rab-27) protein and the Slp4 (synaptotagmin-like protein 4/SYTL4) adaptor protein. Conclusions— Our results indicate that a kinesin-1–dependent process plays a role for platelet function by acting into the mechanism underlying α-granule and dense granule secretion.

Published
2018

27. Abstract 3015: Applications of immunohistochemistry in characterization of patient derived xenograft models

Author

Michelle M. Gottholm Ahalt, Kelly Benauer, Jesse Stottlemyer, Vishnuprabha Rahulkannan, Michelle Eugeni, James H. Doroshow, Gloryvee Rivera, Lindsay Dutko, Tiffanie Chase, Erin Cantu, Melinda G. Hollingshead, Yvonne A. Evrard, Biswajit Das, Suzanne Borgel, Mickey Williams, Emily Delaney, Shahanawaz Jiwani, Chris Karlovich, Howard Stotler, Chelsea McGlynn, and John Mark Carter

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Oncology, business.industry, medicine, Immunohistochemistry, business, Tumor xenograft
Abstract

Background: Well characterized patient derived xenograft models (PDX) are becoming the preferred pre-clinical tool in translational cancer research for biologic understanding of the disease, development of new treatments, and identifying potential therapy predictive and resistant biomarkers. Characterization of PDX models using a multi-omic approach is most desirable, however such efforts can be expensive and technically demanding. Immunohistochemistry (IHC) has become an indispensable ancillary tool in the accurate classification of tumor types, determination of cell of origin, identification of biologic properties like growth and metastatic potential, and evaluation for the presence/absence of therapeutic or prognostic biomarkers. Methods: 43 IHC assays were validated on the Leica Bond RX automated staining platform to identify common inconsistencies in PDX development including markers for classifying carcinomas, lymphomas, sarcomas, murine tumors, and theragnostic biomarkers. Rabbit antibodies are used rather than mouse antibodies to prevent non-specific staining of murine tissue. Results: 1. IHC evaluation of models within NCI's Patient Derived Models Repository (pdmr.cancer.gov) led to re-classification or sub-classification of 12 tumor models in accordance with WHO guidelines. 2. IHC evaluation of theragnostic markers in 8 breast cancer PDX models showed concordant results throughout passaging, suggesting stability of these biomarkers in our models. 3. We observe malignant transformation of murine or transplanted benign human tissue at a rate of 2.5%. On IHC analysis, 52% were human lymphomas, 20% were murine lymphomas, and 28% were other murine tumors. Conclusions: IHC is a rapid, cost-effective tool that can be used for accurate tumor classification, identifying subclonal outgrowth and tumor evolution, assessing stability of biomarkers and identifying malignant transformation of benign tissue. Funded by NCI Contract No. HHSN261200800001E ANTIBODYCLONEVENDORANTIBODYCLONEVENDORAndrogen Receptor[EPR1535(2)]abcamGATA3[EPR16651]abcamB-Catenin[E247]abcamGCDFP-15[EPR1582Y]abcamCD19polyclonalabcamGFAPpolyclonalDAKO/AgilentCD3polyclonalabcamHER2 ErbB2[SP3]abcamCD20[SP32]abcamKi-67[D2H10]Cell SignalingCD34[EP373Y]abcamKu80[EPR3468]abcamCD45polyclonalabcamMGMTMT3.1MilliporeCD56 (NCAM1)[EPR2566]abcamMitochondria Marker (Biotin)MTC02abcamCD68[EPR20545]abcamMyogenin[EPR4789]abcamCDX2[EPR2764Y]abcamNAPSIN A[EPR6252]abcamChromogranin A[SP12]abcamp63polyclonalGeneTexCK7 (purified)[EPR1619Y]abcamPD-1[EPR4877(2)]abcamCK19[EPR1580Y]abcamPD-L1 (CD274)RBT-PDL1LifeSpan BiosciencesCK20[EPR1622Y]abcamProgesterone Receptor[SP2]abcamCytokeratin wide spectrumpolyclonalabcamProstate Specific Antigen (PSA)[EP1588Y]abcamDesmin[Y66]abcamS100[EPR19013]abcamEBV LMP1[D24-G]abcamSmooth Muscle Actin (SMA)polyclonalabcamERG[EPR3864]abcamSynaptophysin[SP11]abcamEstrogen Receptor[SP1]abcamTTF1[SP141]abcamFOXP1monoclonalLifeSpan BiosciencesVimentin[EPR3776]abcamFOXP3(5H10L18)Invitrogen Citation Format: Lindsay Dutko, Gloryvee Rivera, Erin Cantu, Vishnuprabha Rahulkannan, Kelly Benauer, Tiffanie Chase, Emily Delaney, Jesse Stottlemyer, Chelsea McGlynn, Howard Stotler, John Carter, Suzanne Borgel, Michelle M. Gottholm Ahalt, Michelle Eugeni, Melinda Hollingshead, Yvonne Evrard, Chris Karlovich, Biswajit Das, Mickey Williams, James H. Doroshow, Shahanawaz Jiwani. Applications of immunohistochemistry in characterization of patient derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3015.

Published
2021

28. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Author

Dominique Martin-Coignard, Olivier Pincemaille, Claire de Barace, Nathalie Boddaert, Michel Polak, Tiffany Pascreau, Nathalie Seta, Christine Francannet, Gilles Morin, Valérie Cormier-Daire, François Labarthe, Manuel Schiff, Alexis Brice, Anaïs Brassier, Arnaud Bruneel, Patrick Edery, Alina Arion, Isabelle Fontan, Brigitte Chabrol, Cyril Gitiaux, Emmanuel de Maistre, Anne de Saint-Martin, Valérie Drouin-Garraud, Maud Bidet, Magali Barth, Catherine Bloch, Thierry Dupré, Céline Roda, Nathalie Bednarek, Sandrine Vuillaumier-Barrot, Marie-Chantal Chevalier, Géraldine Viot, François Feillet, Annick Toutain, Sylvie Lamoureux, Christel Thauvin-Robinet, Marie Hully, Delphine Borgel, Cyril Mignot, Nathalie Dorison, Bernard Echenne, Agathe Roubertie, Delphine Héron, Roger Buissonnière, Marie-Lorraine Monin, and Pascale de Lonlay

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Pericarditis, Congenital Disorders of Glycosylation, 0302 clinical medicine, Tubulopathy, Hydrops fetalis, Genetics, Humans, Medicine, Hypoalbuminemia, Child, Alleles, Genetic Association Studies, Genetics (clinical), business.industry, Infant, medicine.disease, Hypotonia, Phenotype, 030104 developmental biology, Amino Acid Substitution, Phosphotransferases (Phosphomutases), Inborn error of metabolism, Child, Preschool, Mutation, Female, medicine.symptom, business, Nephrotic syndrome, Congenital disorder of glycosylation, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. Objectives To better characterise the natural history of PMM2-CDG. Methods Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. Results The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. Conclusions PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Published
2017

29. Inflammation in deep vein thrombosis: a therapeutic target?

Author

François Saller, Delphine Borgel, Dominique Lasne, Tiffany Pascreau, and Elsa P. Bianchini

Subjects
medicine.medical_specialty, medicine.drug_class, Deep vein, Inflammation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Venous Thrombosis, business.industry, Anticoagulant, Hematology, Heparin, medicine.disease, Thrombosis, Pathophysiology, medicine.anatomical_structure, Coagulation, 030220 oncology & carcinogenesis, cardiovascular system, Cardiology, medicine.symptom, business, 030215 immunology, Post-thrombotic syndrome, medicine.drug
Abstract

Deep vein thrombosis is a common disease associated with a variety of complications including post-thrombotic syndrome as a late complication. It is now clear that in addition to classical deep vein thrombosis triggers such as blood flow disturbance, hypercoagulability, and vessel wall changes, inflammation has a key role in the pathophysiology of deep vein thrombosis, and there is a close relationship between inflammation and coagulation. As attested by changes in several plasma biomarkers, inflammation may have a significant role in the development of post-thrombotic syndrome. Here, we review the link between inflammation and deep vein thrombosis and thus the potential value of anti-inflammatory and/or anticoagulant drugs in the treatment of deep vein thrombosis and the prevention of post-thrombotic syndrome.

Published
2019

30. Die Inzidenz von intrakraniellen Blutungen und Frakturen der HWS bei geriatrischen Patienten nach Niedrigenergietrauma des Kopfes

Author

Brand, A, Fakler, J, Jarvers, JS, Borgel, J, Henkelmann, J, Heyde, CE, and Josten, C

Subjects
HWS Verletzung, SHT, ddc: 610, Intrakranielle Blutung, 610 Medical sciences, Medicine, geriatrischer Patient
Abstract

Fragestellung: Aufgrund einer weiterhin steigenden Anzahl an Patienten nach Sturz auf den Kopf unter oralen Antikoagulantien (OAK) hat sich die kombinierte Computertomographie (CT) des Schädels und der Halswirbelsäule (HWS) etabliert. Ziel dieser Studie war es den Zusammenhang blutgerinnungshemmender[zum vollständigen Text gelangen Sie über die oben angegebene URL], Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2019)

Published
2019
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31. TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Author

Michel Polak, Catherine Strassel, Fabienne Jabot-Hanin, Claude Besmond, Frédéric Tores, Patrick Nitschke, Christine Bole-Feysot, Athanasia Stoupa, Carsten Janke, Anita Luise Michel, François Lanza, Dominique Lasne, Arnold Munnich, Frédéric Adam, Juliane Léger, Alexandre Kauskot, Alain Schmitt, Kathiresan Natarajan, Sanjay Gawade, Gabor Szinnai, Aurore Carré, Delphine Borgel, Dulanjalee Kariyawasam, Raphael Scharfmann, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, UMR-S1176, Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion, Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Basel (Unibas), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Stress génotoxiques et cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie et Diabétologie Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Pancréas endocrine et diabète de l'enfant, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion (http://www.u949.inserm.fr/), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
0301 basic medicine, Medicine (General), Pathology, endocrine system diseases, Platelet Aggregation, [SDV]Life Sciences [q-bio], Physiology, Gene mutation, QH426-470, Mice, TUBB1, Tubulin, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Research Articles, Mice, Knockout, Hematology, TUBB1 Subject Categories Genetics, Thyroid, congenital hypothyroidism, Congenital hypothyroidism, 3. Good health, medicine.anatomical_structure, Thyroid Dysgenesis, Molecular Medicine, Research Article, Blood Platelets, endocrine system, medicine.medical_specialty, Protein family, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Gene Therapy & Genetic Disease, Thyroid dysgenesis, 03 medical and health sciences, R5-920, Internal medicine, Genetics, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Animals, Humans, Gene, Abnormal Platelet, macroplatelets, business.industry, mutations, medicine.disease, 030104 developmental biology, Mutation, Genetics, Gene Therapy & Genetic Disease, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Haematology
Abstract

The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.

Published
2019

32. Immunization and multiple sclerosis: Recommendations from the French Multiple Sclerosis Society

Author

C. Lebrun, S. Vukusic, V. Abadie, C. Achour, F. Ader, H. Alchaar, A. Alkhedr, F. Andreux, G. Androdias, R. Arjmand, B. Audoin, D. Audry, D. Aufauvre, C. Autreaux, X. Ayrignac, M. Bailbe, M. Benazet, C. Bensa, D. Bensmail, E. Berger, P. Bernady, Y. Bertagna, D. Biotti, A. Blanchard-Dauphin, J. Bonenfant, M. Bonnan, B. Bonnemain, F. Borgel, E. Botelho-Nevers, S. Boucly, B. Bourre, C. Boutière, P. Branger, D. Brassat, S. Bresch, V. Breuil, B. Brochet, H. Brugeilles, P. Bugnon, P. Cabre, J.-P. Camdessanché, C. Carra-Dalière, O. Casez, J.-M. Chamouard, B. Chassande, P. Chataignier, M. Chbicheb, A. Chenet, J. Ciron, P. Clavelou, M. Cohen, R. Colamarino, N. Collongues, I. Coman, P.-R. Corail, S. Courtois, M. Coustans, A. Creange, E. Creisson, N. Daluzeau, C. Davenas, J. De Seze, M. Debouverie, R. Depaz, N. Derache, L. Divio, X. Douay, C. Dulau, F. Durand-Dubief, G. Edan, Z. Elias, O. Fagniez, M. Faucher, J.-M. Faucheux, M. Fournier, A. Gagneux-Brunon, P. Gaida, P. Galli, P. Gallien, J. Gaudelus, D. Gault, A. Gayou, M. Genevray, A. Gentil, J. Gere, L. Gignoux, M. Giroux, P. Givron, O. Gout, J. Grimaud, A.-M. Guennoc, N. Hadhoum, P. Hautecoeur, O. Heinzlef, M. Jaeger, S. Jeannin, L. Kremer, A. Kwiatkowski, P. Labauge, C. Labeyrie, S. Lachaud, I. Laffont, C. Lanctin-Garcia, J. Lannoy, L. Lanotte, D. Laplaud, D. Latombe, M. Lauxerois, E. Le Page, C. Lebrun-Frenay, P. Lejeune, P. Lejoyeux, B. Lemonnier, E. Leray, C.-M. Loche, C. Louapre, C. Lubetzki, A. Maarouf, B. Mada, L. Magy, E. Maillart, E. Manchon, R. Marignier, P. Marque, G. Mathey, A. Maurousset, C. Mekies, M. Merienne, L. Michel, A.-M. Milor, X. Moisset, A. Montcuquet, T. Moreau, N. Morel, M. Moussa, J.-P. Naudillon, M. Normand, P. Olive, J.-C. Ouallet, O. Outteryck, C. Pacault, C. Papeix, I. Patry, D. Peaureaux, J. Pelletier, B. Pichon, S. Pittion, E. Planque, M.-C. Pouget, V. Pourcher, C. Radot, I. Robert, F. Rocher, A. Ruet, C. Saint-Val, J.-Y. Salle, A. Salmon, E. Sartori, S. Schaeffer, B. Stankhof, F. Taithe, E. Thouvenot, C. Tizon, A. Tourbah, P. Tourniaire, M. Vaillant, P. Vermersch, S. Vidil, A. Wahab, M.-H. Warter, S. Wiertlewski, B. Wiplosz, B. Wittwer, C. Zaenker, H. Zephir, Université Côte d'Azur (UCA), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hosp Civils Lyon, Serv Malad Infect, Lyon, France, Biogéosciences [UMR 6282] [Dijon] (BGS), Centre National de la Recherche Scientifique (CNRS)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Pontchaillou [Rennes], CHU Saint-Etienne, Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - AP-HM] (CEMEREM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Comité de Développement Horticole du Centre Val de Loire (CDHRC), Génétique, physiopathologie et ingénierie du tissu osseux (GéPITOS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Service d'Etudes du Comportement des Matériaux de Conditionnement (SECM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Galaxies, Etoiles, Physique, Instrumentation (GEPI), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Rennes] = Neurology [Rennes], Excitabilité nerveuse et thérapeutique (ENT), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-EA 4391, Service de Physiologie Explorations Fonctionnelles-Hôpital Henri Mondor, Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), RMN et optique : De la mesure au biomarqueur, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Combustion Research Facility, Sandia National Laboratories - Corporation, Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Kuriwa Observatory, Fondation Ophtalmologique Adolphe de Rothschild [Paris], Laboratoire de Mécanique, Modélisation et Procédés Propres (M2P2), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Euromov (EuroMov), Université de Montpellier (UM), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université Nice Sophia Antipolis - Faculté de Médecine (UNS UFR Médecine), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Recherche en Pharmaco-épidémiologie et Recours aux Soins (REPERES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP), École des Hautes Études en Santé Publique [EHESP] (EHESP), Département Méthodes quantitatives en santé publique (METIS), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire d'automatique et de génie des procédés (LAGEP), Université de Lyon-Université de Lyon-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Haras National Suisse, Centre Hospitalier Universitaire de Reims (CHU Reims), Center for health studies, Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Hospices Civils de Lyon, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Biogéosciences [UMR 6282] (BGS), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hôpital Henri Mondor-EA 4391, Service de Physiologie Explorations Fonctionnelles-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre d'Exploration Métabolique par Résonance Magnétique [Hôpital de la Timone - APHM] (CEMEREM), Comité de développement horticole de la région Centre-Val-de-Loire (CDHR CENTRE-VAL-DE-LOIRE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), Service de Neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Ecole Centrale de Lille-Institut supérieur de l'électronique et du numérique (ISEN)-Université de Valenciennes et du Hainaut-Cambrésis (UVHC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Université Polytechnique Hauts-de-France (UPHF), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Neurologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie, CHU Clermont-Ferrand, Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
medicine.medical_specialty, Vaccination schedule, MEDLINE, Scientific literature, Multiple sclerosis, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Risk Factors, Health care, Medicine, Humans, 030212 general & internal medicine, Immunization Schedule, Societies, Medical, Vaccines, business.industry, Risk of infection, Prevention, Vaccination, medicine.disease, 3. Good health, Neurology, Immunization, Family medicine, Evidence-Based Practice, Practice Guidelines as Topic, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), France, business, Infection, Vaccine, 030217 neurology & neurosurgery
Abstract

Objectives To establish recommendations on immunization for patients with multiple sclerosis (MS). Background Vaccines have been suspected in the past to trigger MS and relapses. With the extension of the immunoactive treatment arsenal, other concerns have been raised more recently about an increased risk of infection or a decreased effectiveness of immunization in immunosuppressed patients. Methods The French Group for Recommendations into Multiple Sclerosis (France4MS) performed a systematic search of papers in Medline and other university databases (January 1975–June 2018). The RAND/UCLA appropriateness method was chosen to review the scientific literature and to formalize the degree of agreement among experts on 5 clinical questions related to immunization and MS. Readers from the steering committee conducted a systematic analysis, wrote a critical synthesis and prepared a list of proposals that were evaluated by a rating group of 28 MS experts. The final version of the recommendations was finally reviewed by a reading group of 110 health care professionals and classified as appropriate, inappropriate or uncertain. Results Neurologists should verify the vaccination status as soon as MS is diagnosed and before disease-modifying treatments (DMTs) are introduced. The French vaccination schedule applies to MS patients and seasonal influenza vaccination is recommended. In the case of treatment-induced immunosuppression, MS patients should be informed about the risk of infection and the vaccination standards of the French High Council of Health should be applied. Live attenuated vaccines are contra-indicated in patients recently treated with immunosuppressive drugs, including corticosteroids; other vaccines can be proposed whatever the treatment, but their effectiveness may be partly reduced with some drugs. Conclusion Physicians and patients should be aware of the updated recommendations for immunizations of patients with MS.

Published
2019

33. Fulminant arterial vasculitis as an unusual complication of disseminated staphylococcal disease due to the emerging CC1 methicillin-susceptible Staphylococcus aureus clone: a case report

Author

Xavier Nassif, Alain Charbit, Delphine Borgel, Charles Vidal, Anne Jamet, Louise Galmiche, Florence Moulin, Capucine Picard, Olivier Lortholary, Julie Toubiana, Jean-Paul Mira, Department of Microbiology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatric Intensive Care Unit [Paris], Pathology Department [Paris], Department of Hematology [Paris], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Center for the Study of Primary Immunodeficiencies [Paris], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Medical Intensive Care Unit [Paris], Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Infectious Diseases and Tropical Medicine [Paris], Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Département de Pédiatrie et maladies infectieuses [CHU Necker], CHU Necker - Enfants Malades [AP-HP], 'Personal Protection Against Vectors' working group (PPAV), PPAV working group, Université Paris Descartes - Paris 5 (UPD5), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service de Réanimation Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Cochin [AP-HP], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], and Bodescot, Myriam

Subjects
Male, 0301 basic medicine, Fulminant, Cefotaxime, [SDV.GEN] Life Sciences [q-bio]/Genetics, medicine.disease_cause, Methicillin, 0302 clinical medicine, Medical microbiology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, Gangrene, Virulence, Clindamycin, Brain, Staphylococcal Infections, Magnetic Resonance Imaging, Shock, Septic, Anti-Bacterial Agents, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Staphylococcus aureus, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Vasculitis, medicine.medical_specialty, Adolescent, 030106 microbiology, Amputation, Surgical, lcsh:Infectious and parasitic diseases, Sepsis, 03 medical and health sciences, Case report, medicine, Genetic susceptibility, Humans, lcsh:RC109-216, Polymorphism, Leg, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, S. aureus, Immunology, Methicillin Susceptible Staphylococcus Aureus, business
Abstract

International audience; BACKGROUND:Staphylococcus aureus has emerged as a leading cause of invasive severe diseases with a high rate of morbidity and mortality worldwide. The wide spectrum of clinical manifestations and outcome observed in staphylococcal illness may be a consequence of both microbial factors and variability of the host immune response.CASE PRESENTATION:A 14-years old child developed limb ischemia with gangrene following S. aureus bloodstream infection. Histopathology revealed medium-sized arterial vasculitis. The causing strain belonged to the emerging clone CC1-MSSA and numerous pathogenesis-related genes were identified. Patient's genotyping revealed functional variants associated with severe infections. A combination of virulence and host factors might explain this unique severe form of staphylococcal disease.CONCLUSION:A combination of virulence and genetic host factors might explain this unique severe form of staphylococcal disease.

Published
2019

34. Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS

Author

Caroline Lavie, Fabien Rollot, Françoise Durand-Dubief, Romain Marignier, Iuliana Ionescu, Romain Casey, Thibault Moreau, Patricia Tourniaire, Michael Hutchinson, Marie Béatrice D’Hooghe, David-Axel Laplaud, Pierre Clavelou, Jérôme De Sèze, Marc Debouverie, David Brassat, Jean Pelletier, Christine Lebrun-Frenay, Emmanuelle Le Page, Giovanni Castelnovo, Eric Berger, Patrick Hautecoeur, Olivier Heinzlef, Luca Durelli, Marinella Clerico, Maria Trojano, Francesco Patti, Sandra Vukusic, A. Alpérovitch, H. Carton, M.B. d’Hooghe, O. Hommes, M. Hutchinson, P. Adeleine, A. Biron, P. Cortinovis-Tourniaire, J. Grimaud, M. Hours, T. Moreau, S. Vukusic, C. Confavreux, G. Chauplannaz, D. Latombe, M. Clanet, G. Lau, L. Rumbach, J.Y. Goas, F. Rouhart, A. Mazingue, E. Roullet, M. Madigand, P. Hautecoeur, P. Brunet, G. Edan, C. Allaire, G. Riffault, J. Leche, T. Benoit, C. Simonin, F. Ziegler, J.C. Baron, Y. Rivrain, R. Dumas, D. Loche, J.C. Bourrin, B. Huttin, B. Delisse, I. Gibert, C. Boulay, M. Verceletto, G. Durand, G. Bonneviot, R. Gil, M.A. Hedreville, C. Belair, R.J. Poitevin, J.L. Devoize, P. Wyremblewski, F. Delestre, A. Setiey, G. Comi, M. Filippi, A. Ghezzi, V. Martinelli, P. Rossi, M. Zaffaroni, M.R. Tola, M.P. Amato, C. Fioretti, G. Meucci, M. Inglese, G.L. Mancardi, D. Gambi, A. Thomas, M. Cavazzuti, A. Citterio, A. Heltberg, H.J. Hansen, O. Fernandez, F. Romero, T. Arbizu, J.J. Hernandez, C. De Andres de Frutos, D. Geffner Sclarky, Y. Aladro Benito, P. Reyes Yanes, M Aguilar, J.A. Burguera, R. Yaya, W. Bonakim Dib, D. Arzua-Mouronte, C.J.M. Sindic, R. Medaer, H. Roose, K.M.J. Geens, D. Guillaume, M. Van Zandycke, J. Janssens, M. Cornette, L. Mol, F. Weilbach, P. Flachenecker, H.P. Hartung, J. Haas, I. Tendolkar, E. Sindrn, H.W. Kölmel, D. Reichel, M. Rauch, S. Preuss, S. Poser, E. Mauch, S. Strausser-Fuchs, H. Kolleger, S. Hawkins, S.J.L. Howell, J.E. Rees, A. Thompson, M. Johnson, M. Boggild, R.P. Gregory, D. Bates, I. Bone, C. Polman, S. Frequin, P. Jongen, J. Correia de Sa, M.E. Rio, S. Huber, J. Lechner-Scott, L. Kappos, I. Ionescu, C. Cornu, M. El-Etr, E.E. Baulieu, M Schumacher, D.H. Miller, M. Pugeat, C. d’Archangues, J. Conard, J. Ménard, R. Sitruk-Ware, C. Pelissier, S. Dat, J. Belaïsch-Allard, N. Athéa, D. Büschsenschutz, O. Lyon-Caen, R. Gonsette, J.P. Boissel, P. Ffrench, F. Durand-Dubief, F. Cotton, C. Pachai, L. Bracoud, G. Androdias, R. Marignier, D.A. Laplaud, S. Wiertlewski, C. Lanctin-Garcia, G. Couvreur, G. Madinier, P. Clavelou, F. Taithe, D. Aufauvre, N. Guy, A. Ferrier, J. De Sèze, N. Collongues, M. Debouverie, F. Viala, D. Brassat, A. Gerdelat-Mas, P. Henry, J. Pelletier, A. Rico-Lamy, C. Lebrun-Frenay, E. Lepage, V. Deburghraeve, G. Castelnovo, E. Berger, M. Blondiau, O. Heinzlef, M. Coustans, C. Clerc, L. Rieu, M. Lauxerois, G. Hinzelin, J.C. Ouallet, D. Minier, P. Vion, N. Gromaire-Fayolle, N. Derache, E. Thouvenot, M. Sallansonnet-Froment, P. Tourniaire, L. Toureille, F. Borgel, B. Stankoff, C. Moroianu, A.M. Guennoc, C.L. Tournier-Gervason, S. Peysson, M. Trojano, F. Patti, E. D’Amico, L. Motti, L. Durelli, A. Tavella, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Observatoire Français de la Sclérose En Plaques [Lyon] (OFSEP), Service de neurologie fonctionnelle et d'épileptologie [Hôpital Pierre Wertheimer-HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie générale, vasculaire et dégénérative (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Henri Duffaut (Avignon), National MS Center Melsbroek, Vrije Universiteit Brussel [Bruxelles] (VUB), Vrije Universiteit Brussel (VUB), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Laboratoire de Neuroimagerie in Vivo (LNV), CHU Strasbourg-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Service de neurologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Maladies chroniques, santé perçue, et processus d'adaptation (APEMAC), Université de Lorraine (UL), Neurologie vasculaire, pathologie neuro-dégénérative et explorations fonctionnelles du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), 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), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Neurologie [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Università degli studi di Torino = University of Turin (UNITO), University of Catania [Italy], Hospices Civils de Lyon, Departement de Neurologie (HCL), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Protéines membranaires transductrices d'énergie (PMTE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut des Géosciences de l’Environnement (IGE), Institut de Recherche pour le Développement (IRD)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Environnement Ville Société (EVS), École normale supérieure - Lyon (ENS Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Lumière - Lyon 2 (UL2)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet [Saint-Étienne] (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Solvay (France), Laboratoire des Mécanismes et Transfert en Géologie (LMTG), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Institute of Evolutionary Biology, University of Edinburgh, Université de Lille, Sciences et Technologies, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation, interaction, activation et migration des sous-populations lymphocitaires humaines, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Motricité, interactions, performance EA 4334 / Movement - Interactions - Performance (MIP), Le Mans Université (UM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR des Sciences et Techniques des Activités Physiques et Sportives (UFR STAPS), Laboratoire Ecologie Fonctionnelle et Environnement (ECOLAB), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Université Fédérale Toulouse Midi-Pyrénées-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Laboratoire de Chimie Physique D'Orsay (LCPO), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), RMN et optique : De la mesure au biomarqueur, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Department of Neurology, CHU Lyon, Institut de Recherche de Chimie Paris (IRCP), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Hôpital de Hautepierre [Strasbourg], Laboratoire de Réactivité des Surfaces et des Interfaces (LRSI), Département de Physico-Chimie (DPC), CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction des Energies (ex-Direction de l'Energie Nucléaire) (CEA-DES (ex-DEN)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Empenn, Institut National de la Santé et de la Recherche Médicale (INSERM)-Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-SIGNAUX ET IMAGES NUMÉRIQUES, ROBOTIQUE (IRISA-D5), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), 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)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-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)-Université de Rennes 1 (UR1), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-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), Service de Neurologie [Rennes] = Neurology [Rennes], CHU Pontchaillou [Rennes], Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation pour l'Aide à la Recherche sur la Sclérose en Plaques, European Leukodystrophies Association, PHRC National, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pierre Wertheimer, Département de Neurologie, Laboratoire de Mathématiques (LAMA), Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Nottingham Scientific Limited, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Turin, Università degli studi di Torino (UNITO), University of Bari Aldo Moro (UNIBA), Department of Neurosciences, Università degli studi di Catania [Catania], Centre de recherche en neurosciences de Lyon (CRNL), Neuroépidémiologie, Institut de Physique du Globe de Paris (IPGP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Centre National de la Recherche Scientifique (CNRS), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut de Recherche pour le Développement (IRD)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École nationale supérieure d'architecture de Lyon (ENSAL)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École Nationale des Travaux Publics de l'État (ENTPE)-Université Jean Monnet [Saint-Étienne] (UJM)-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ministère de la Culture (MC), Université de Bretagne Sud (UBS)-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)-Université de Rennes (UNIV-RENNES)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-CentraleSupélec-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Bretagne Sud (UBS)-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)-Université de Rennes (UNIV-RENNES)-École normale supérieure - Rennes (ENS Rennes)-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lavie, Caroline, Rollot, Fabien, Durand-Dubief, Françoise, Marignier, Romain, Ionescu, Iuliana, Casey, Romain, Moreau, Thibault, Tourniaire, Patricia, Hutchinson, Michael, D’Hooghe, Marie Béatrice, Laplaud, David-Axel, Clavelou, Pierre, De Sèze, Jérôme, Debouverie, Marc, Brassat, David, Pelletier, Jean, Lebrun-Frenay, Christine, Le Page, Emmanuelle, Castelnovo, Giovanni, Berger, Eric, Hautecoeur, Patrick, Heinzlef, Olivier, Durelli, Luca, Clerico, Marinella, Trojano, Maria, Patti, Francesco, Vukusic, Sandra, on behalf of PRIMS and POPARTMUS, Investigator, Filippi, Massimo, Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Environnement, Ville, Société (EVS), École normale supérieure de Lyon (ENS de Lyon)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-École Nationale des Travaux Publics de l'État (ENTPE)-École nationale supérieure d'architecture de Lyon (ENSAL)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Neuroimagerie: méthodes et applications (Empenn), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Laboratoire de glaciologie et géophysique de l'environnement (LGGE), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire Motricité, Interactions, Performance, Université de Nantes (UN), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Ministère de la Culture (MC), Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), CEA-Direction de l'Energie Nucléaire (CEA-DEN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-CEA-Direction de l'Energie Nucléaire (CEA-DEN), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service de neurologie [Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service de Neurologie [CHU Besançon], Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Service de Neurologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Clinical sciences, Neuroprotection & Neuromodulation, and Neurology

Subjects
relapses, Neurology, [SDV]Life Sciences [q-bio], MESH: Pregnancy Complications / physiopathology, 0302 clinical medicine, MESH: Pregnancy, Anesthesia, Conduction, Recurrence, MESH: Anesthesia, Conduction / adverse effects, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, reproductive and urinary physiology, relapse, Postpartum Period, post-partum, MESH: Follow-Up Studies, MESH: Multiple Sclerosis / physiopathology, Obstetrical Analgesia, MESH: Multiple Sclerosis / chemically induced, Anesthesia, Female, pregnancy, Adult, medicine.medical_specialty, Clinical Neurology, Multiple sclerosis, MESH: Postpartum Period, 03 medical and health sciences, medicine, Humans, Multiple sclerosi, Post partum, Retrospective Studies, Pregnancy, MESH: Humans, MESH: Pregnancy Complications / chemically induced, business.industry, Neurotoxicity, MESH: Adult, MESH: Retrospective Studies, neuraxial analgesia, medicine.disease, MESH: Recurrence, Multiple sclerosis, neuraxial analgesia, post-partum, pregnancy, Pregnancy Complications, Increased risk, Neurology (clinical), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

Background: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. Objective: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. Methods: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992–1995 and 2005–2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. Results: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). Conclusion: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Published
2019

35. International clinical guidelines for the management of phosphomannomutase 2-congenital disorders of glycosylation: Diagnosis, treatment and follow up

Author

Tomas Honzik, Antonio F. Martinez, Federic Tort, David Cassiman, Joana Correia, Christian Thiel, Simone Funke, Mari Anne Vals, Carlota Pascoal, Hossein Moravej, Katrin Õunap, Rita Barone, Marlen Hutter, Małgorzata Seroczyńska, Hudson H. Freeze, Ruqaiah Altassan, María Eugenia de la Morena-Barrio, Anna Cechova, Kimiyo Raymond, Dulce Quelhas, Carlos Ferreira, Matthijs Gert, Delphine Borgel, Trinidad Hernández-Caselles, David Coman, Romain Péanne, Paula A. Videira, Renate Zeevaert, Dorinda Marques-da-Silva, Stephanie Grunewald, Nathalie Seta, Javier Corral, Muad Bidet, Rita Francisco, Mercedes Serrano, Jaak Jaeken, Peter Witters, Manuel Schiff, Thatjana Gardeitchik, Joy Lee, Peymaneh Sarkhail, Christina Lam, Agata Fiumara, Pascale de Lonlay, Tiffany Pascreau, Sandra Brasil, Muriel Girad, Eva Morava, Dirk Lefeber, Marc C. Patterson, Marisa Giros, Donna M. Krasnewich, Jolanta Sykut-Cegielska, and Vanessa dos Reis

Subjects
medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Glycosylation, Genetics, Genetics (clinical), business.industry, MEDLINE, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Guideline, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Congenital Disorders of Glycosylation, Diagnosis treatment, Multidisciplinary approach, Phosphotransferases (Phosphomutases), medicine, Humans, Presentation (obstetrics), Intensive care medicine, business, Clinical evaluation, Phosphomannomutase, Congenital disorder, Follow-Up Studies
Abstract

Contains fulltext : 203022.pdf (Publisher’s version ) (Closed access) Phosphomannomutase 2 (PMM2-CDG) is the most common congenital disorder of N-glycosylation and is caused by a deficient PMM2 activity. The clinical presentation and the onset of PMM2-CDG vary among affected individuals ranging from a severe antenatal presentation with multisystem involvement to mild adulthood presentation limited to minor neurological involvement. Management of affected patients requires a multidisciplinary approach. In this article, a systematic review of the literature on PMM2-CDG was conducted by a group of international experts in different aspects of CDG. Our managment guidelines were initiated based on the available evidence-based data and experts' opinions. This guideline mainly addresses the clinical evaluation of each system/organ involved in PMM2-CDG, and the recommended management approach. It is the first systematic review of current practices in PMM2-CDG and the first guidelines aiming at establishing a practical approach to the recognition, diagnosis and management of PMM2-CDG patients.

Published
2019

36. Pharmacodynamic Response of the MET/HGF Receptor to Small-Molecule Tyrosine Kinase Inhibitors Examined with Validated, Fit-for-Clinic Immunoassays

Author

Yvonne A. Evrard, Sonny Khin, Tony Navas, Ralph E. Parchment, Apurva K. Srivastava, Donald P. Bottaro, Melinda G. Hollingshead, Thomas D. Pfister, W. Marston Linehan, Suzanne Borgel, Jiuping Jay Ji, Jennifer Weiner, Robert J. Kinders, Joseph E. Tomaszewski, Yiping Zhang, and James H. Doroshow

Subjects
0301 basic medicine, Cancer Research, Indazoles, Indoles, Pyridines, Mice, Nude, Pharmacology, Article, Cell Line, Small Molecule Libraries, Pazopanib, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Crizotinib, Stomach Neoplasms, Cell Line, Tumor, medicine, Animals, Humans, Sulfones, Tivantinib, Carcinoma, Renal Cell, Protein Kinase Inhibitors, Immunoassay, Sulfonamides, business.industry, Proto-Oncogene Proteins c-met, Xenograft Model Antitumor Assays, Kidney Neoplasms, Blockade, HEK293 Cells, Pyrimidines, 030104 developmental biology, Oncology, chemistry, Mechanism of action, A549 Cells, 030220 oncology & carcinogenesis, Pharmacodynamics, Pyrazoles, Biomarker (medicine), medicine.symptom, business, HT29 Cells, Tyrosine kinase, medicine.drug
Abstract

Purpose: Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding of target pharmacodynamics, including molecular target engagement, mechanism of action, and duration of effect. Experimental Design: Sandwich immunoassays and specimen handling procedures were developed and validated for quantifying full-length MET and its key phosphospecies (pMET) in core tumor biopsies. MET was captured using an antibody to the extracellular domain and then probed using antibodies to its C-terminus (full-length) and epitopes containing pY1234/1235, pY1235, and pY1356. Using pMET:MET ratios as assay endpoints, MET inhibitor pharmacodynamics were characterized in MET-amplified and -compensated (VEGFR blockade) models. Results: By limiting cold ischemia time to less than two minutes, the pharmacodynamic effects of the MET inhibitors PHA665752 and PF02341066 (crizotinib) were quantifiable using core needle biopsies of human gastric carcinoma xenografts (GTL-16 and SNU5). One dose decreased pY1234/1235 MET:MET, pY1235-MET:MET, and pY1356-MET:MET ratios by 60% to 80% within 4 hours, but this effect was not fully sustained despite continued daily dosing. VEGFR blockade by pazopanib increased pY1235-MET:MET and pY1356-MET:MET ratios, which was reversed by tivantinib. Full-length MET was quantifiable in 5 of 5 core needle samples obtained from a resected hereditary papillary renal carcinoma, but the levels of pMET species were near the assay lower limit of quantitation. Conclusions: These validated immunoassays for pharmacodynamic biomarkers of MET signaling are suitable for studying MET responses in amplified cancers as well as compensatory responses to VEGFR blockade. Incorporating pharmacodynamic biomarker studies into clinical trials of MET inhibitors could provide critical proof of mechanism and proof of concept for the field. Clin Cancer Res; 22(14); 3683–94. ©2016 AACR.

Published
2016

37. Inactivated antithrombins as fondaparinux antidotes: a promising alternative to haemostatic agents as assessed in vitro in a thrombin-generation assay

Author

François Saller, Yasmine Bourti, Elsa P. Bianchini, Judicael Fazavana, Delphine Borgel, Dominique Lasne, and Marine Armand

Subjects
medicine.drug_mechanism_of_action, medicine.drug_class, Antidotes, Factor Xa Inhibitor, Factor VIIa, In Vitro Techniques, 030204 cardiovascular system & hematology, Pharmacology, Fondaparinux, Antithrombins, Hemostatics, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Thrombin, Polysaccharides, medicine, Humans, 030212 general & internal medicine, Dose-Response Relationship, Drug, Factor VII, Heparin, Chemistry, Antithrombin, Anticoagulant, Anticoagulants, Hematology, Heparin, Low-Molecular-Weight, 3. Good health, Anesthesia, Blood Chemical Analysis, Factor Xa Inhibitors, medicine.drug
Abstract

SummaryIn the absence of specific antidote to fondaparinux, two modified forms of antithrombin (AT), one recombinant inactive (ri-AT) and the other chemically inactivated (chi-AT), were designed to antagonise AT-mediated anticoagulants, e. g. heparins or fondaparinux. These inactive ATs were previously proven to effectively neutralise anticoagulant activity associated with heparin derivatives in vitro and in vivo, as assessed by direct measurement of anti-FXa activity. This study was undertaken to evaluate in vitro the effectivity of inactive ATs to reverse anticoagulation by heparin derivatives and to compare them with non-specific fondaparinux reversal agents, like recombinant-activated factor VII (rFVIIa) or activated prothrombin-complex concentrate (aPCC), in a thrombin-generation assay (TGA). Addition of fondaparinux (3 μg/ml) to normal plasma inhibited thrombin generation by prolonging lag time (LT) as much as 244 % and lowering endogenous thrombin potential (ETP) to 17 % of their control (normal plasma) values. Fondaparinux-anticoagulant activity was reversed by ri-AT and chi-AT, as reflected by the corrections of LT up to 117 % and 114 % of its control value, and ETP recovery to 78 % and 63 %, respectively. Unlike ri-AT that had no effect on thrombin generation in normal plasma, chi-AT retained anticoagulant activity that minimises its reversal capacity. However, both ATs were more effective than rFVIIa or aPCC at neutralising fondaparinux and, unlike non-specific antidotes, inactive ATs specifically reversed AT-mediated anticoagulant activities, as suggested by their absence of procoagulant activity in anticoagulant-free plasma.

Published
2016

38. Abstract 3554: Genomic landscape of acquired uniparental disomy in NCI PDMR patient derived xenograft models

Author

Li Chen, Yvonne A. Evrard, Michelle Eugeni, Kelly Benauer, Amanda Peach, Michelle M. Gottholm Ahalt, James H. Doroshow, Shahanawaz Jiwani, Biswajit Das, Chris Karlovich, John Carter, Candace Mallow, Tara Grinnage-Pulley, Lindsay Dutko, Tiffanie L. Miner, Sergio Y. Alcoser, Dianne L. Newton, Devynn Breen, Thomas Forbes, Emily Delaney, Alyssa K. Chapman, Marianne Radzyminski, Anna J. Lee Fong, Shannon Uzelac, Chelsea McGlynn, Tomas Vilimas, Brandie A. Fullmer, Luis E. Romero, Gloryvee Rivera, Suzanne Borgel, Robin D. Harrington, Justine N. McCutcheon, Rajesh Patidar, Jesse Stottlemyer, Vishnuprabha R. Kannan, Nikitha Nair, Erin Cantu, Peng Wang, Melinda G. Hollingshead, Kelsey A. Conley, and Paul Williams

Subjects
Cancer Research, Haplotype, Chromosome, Cancer, Biology, medicine.disease, Uniparental disomy, Loss of heterozygosity, Clear cell renal cell carcinoma, Oncology, Cancer research, Carcinoma, medicine, Exome sequencing
Abstract

Background: Acquired Uniparental Disomy (aUPD) is relatively common in cancer. Occurrence of aUPD is more frequent in some tumor histologies (e.g., serous ovarian, colorectal) and may be relevant for choice of therapy. The Patient-Derived Models Repository (PDMR; https://pdmr.cancer.gov) developed by The National Cancer Institute (NCI) includes patient-derived xenograft (PDX) models from multiple tumor histologies with different passages and lineages. The associated clinical annotation and genomic data make it possible to assess the prevalence of aUPD in the PDMR cohort and the stability of aUPD in different passages and lineages within a PDX model. Methods: High tumor purity in the PDX specimens (after removal of mouse reads representing the stroma) enabled highly accurate assessment of loss of heterozygosity (LOH). Variants called by GATK Haplotype caller from whole exome sequencing (WES) data were used to identify segments of homozygosity using BCFtools/RoH (runs of homozygosity). The RoH segments were then intersected with the bed file for chromosome arms to get %LOH at the arm level. If %LOH on a chromosome arm was >90%, we considered the sample to have aUPD at the arm level. WES was also used to look for associations between DNA damage repair (DDR) pathway alterations and aUPD. Results: We made the following observations: a) aUPD was observed most frequently in chr18q (75/427, 17.6%) and chr3p (69/427, 16%) of PDX models; b) aUPD was observed more frequently in certain tumor histologies, e.g., clear cell renal cell carcinoma (6/8), small cell lung cancer (3/4) and non-small cell lung cancer (25/38); c) extensive aUPD was observed in 4 PDMR models (>50% of evaluated chromosome arms in these models have aUPD); d) aUPD was not observed in some tumor histologies, i.e., synovial sarcoma, uterine endometrioid carcinoma; e) in the vast majority of PDMR models (>90%), aUPD is maintained faithfully across lineages and through multiple passaging; f) subclonal aUPD events were observed in some models across different lineages; g) significant enrichment of double strand DNA break repair (DSBR) pathway alterations was observed in PDMR models without aUPD (p=0.0007, Fisher's exact test) suggesting defects in DSBR are not associated with aUPD; and h) aUPD was rarely observed in MSI-high models (1/30) suggesting mutual exclusivity of mismatch repair (MMR) pathway defects and aUPD. Conclusion: We observed a relatively high frequency of UPD in the PDMR models (at least 1 arm of a chromosome). UPD was more frequently observed in specific chromosomal arms. The frequency of aUPD was higher in some tumor histologies and absent in others. aUPD was stably maintained across passages and lineages, although some heterogeneity was observed. Our data suggest aUPD is not associated with defects in DSBR and MMR pathways. Preclinical drug studies using NCI PDMR models may suggest appropriate therapeutic options for cancers with aUPD. Citation Format: Rajesh Patidar, Li Chen, Chris A. Karlovich, Biswajit Das, Yvonne A. Evrard, Tomas Vilimas, Justine N. McCutcheon, Amanda L. Peach, Nikitha V. Nair, Thomas D. Forbes, Brandie A. Fullmer, Anna J. Lee Fong, Luis E. Romero, Alyssa K. Chapman, Kelsey A. Conley, Robin D. Harrington, Shahanawaz S. Jiwani, Peng Wang, Michelle M. Gottholm Ahalt, Erin N. Cantu, Gloryvee Rivera, Lindsay M. Dutko, Kelly M. Benauer, Vishnuprabha R. Kannan, Suzanne D. Borgel, John P. Carter, Jesse M. Stottlemyer, Tiffanie L. Miner, Devynn R. Breen, Emily T. Delaney, Chelsea A. McGlynn, Candace N. Mallow, Marianne Radzyminski, Shannon N. Uzelac, Sergio Y. Alcoser, Tara L. Grinnage-Pulley, Michelle A. Eugeni, Dianne L. Newton, Melinda G. Hollingshead, Paul M. Williams, James H. Doroshow. Genomic landscape of acquired uniparental disomy in NCI PDMR patient derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3554.

Published
2020

39. Abstract 5056: Quality control efforts in a large-scale, preclinical trial of rare cancer PDXs by the National Cancer Institute's patient-derived models repository (NCI PDMR)

Author

John Carter, Dianne L. Newton, Shannon Uzelac, Gloryvee Rivera, Michael Mullendore, Malorie Morris, Abigail Walke, Lily Chen, Thomas Forbes, Kyle Georgius, Emily Delaney, Sergio . Y. Alcoser, Debbie Trail, Tom Walsh, Raymond Divelbiss, Tara Grinnage-Pulley, Shahanawaz Jiwani, Chris Karlovich, Yvonne A. Evrard, Lyndsay Dutko, Sierra Hoffman, Devynn Breen, Biswajit Das, Howard Stotler, Rajesh Patidar, Thomas Vilimas, Peng Wang, Justine Mills, Suzanne Borgel, Nicole Walters, Melinda G. Hollingshead, James Doroshow, Savanna Styers, Jesse Stottlemyer, Tiffanie Chase, Michelle M. Gottholm-Ahalt, Alice P. Chen, Kristen Cooley, and P. Mickey Williams

Subjects
Cancer Research, medicine.medical_specialty, Scale (ratio), business.industry, media_common.quotation_subject, Cancer, medicine.disease, Rare cancer, Oncology, Medicine, Quality (business), Medical physics, business, media_common
Abstract

The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) is performing a large-scale multi-year preclinical study with 39 PDX models of rare cancers (mesothelioma, MPNST, osteosarcoma, Merkel cell carcinoma, etc) treated with 56 novel therapeutic combinations in an exploratory, n-of-4 arm, study design. Combinations that show promising responses (e.g., regression or durable inhibition of tumor growth) will be repeated along with the single agent arms to determine if the response is driven by the combination or only one of the agents. In order to do this in a timely fashion, relatively speaking, the PDX tumors are serially passaged and each passage is treated with a set of 8 combinations plus relevant vehicle control(s) while in parallel enough PDXs are retained to be expanded for the next passage and drug set. Every serial passage undergoes several quality control assessments that serve as go/no-go criteria including pathology assessment, human:mouse DNA content assessment, and low pass whole genome sequencing to determine the average fraction of genome changed compared to the original donor material. If there is a QC failure, the PDX model is restarted from early passage cryo-material (passage 1-2). An additional quality control effort is to bookend the combination studies with the first set of agents to see if tumor response is similar across passages. To date, most of the models have demonstrated a high degree of stability, though a couple of models have moved toward murine content and have been restarted from early passage material so all drug combinations can be tested. DNA and RNA are retained from all passages so a full NGS evaluation can be performed at a later date. This effort has been ongoing for over a year and the first bookend studies are beginning to be tested to determine if response at first and last passage of the study are consistent with each other, given the constraints of the inherent heterogeneity of the models themselves. Single agent studies of drug combinations that demonstrated a response in 30%-50% of the models tested are also underway to determine which combinations have a more than additive effect compared to the single agents. Promising combinations will be moved forward to early phase clinical trials for these rare cancers. Funded by NCI Contract No. HHSN261200800001E Citation Format: Yvonne A. Evrard, Biswajit Das, Sergio Y. Alcoser, Suzanne Borgel, Devynn Breen, John Carter, Tiffanie Chase, Alice Chen, Lily Chen, Kristen Cooley, Emily Delaney, Raymond Divelbiss, Lyndsay Dutko, Thomas Forbes, Kyle Georgius, Michelle Gottholm-Ahalt, Tara Grinnage-Pulley, Sierra Hoffman, Chris Karlovich, Shahanawaz Jiwani, Justine Mills, Malorie Morris, Michael Mullendore, Dianne Newton, Rajesh Patidar, Gloryvee Rivera, Howard Stotler, Jesse Stottlemyer, Savanna Styers, Debbie Trail, Shannon Uzelac, Thomas Vilimas, Abigail Walke, Thomas Walsh, Nicole Walters, Peng Wang, P. Mickey Williams, Melinda Hollingshead, James H. Doroshow. Quality control efforts in a large-scale, preclinical trial of rare cancer PDXs by the National Cancer Institute's patient-derived models repository (NCI PDMR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5056.

Published
2020

40. Abstract 1961: Preclinical development of NSC-801845, a new cytidine analog, in comparative cell culture and xenograft studies with the clinical candidates T-dCyd and aza-T-dCyd

Author

Raymond Divelbiss, Melinda G. Hollingshead, Suzanne Borgel, Joel Morris, Kyle Georgius, Beverly A. Teicher, Donn G. Wishka, Howard Stotler, Jerry M. Collins, Lopez Omar D, and John Carter

Subjects
Cancer Research, Methyltransferase, business.industry, Cancer, Phases of clinical research, Cytidine, medicine.disease, chemistry.chemical_compound, Leukemia, Oncology, chemistry, Cell culture, In vivo, Carcinoma, Cancer research, Medicine, business
Abstract

Cytidine analogs remain an area of active drug discovery and development with four FDA approved drugs. DNMT1, a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes, is a major molecular target of these agents. In addition, DNMT1 has roles independent of its methyltransferase activity and DNMT1 knockout results in decreased cell viability preceded by events consistent with activation of DNA damage response. 4'-thio-2'-deoxycytidine (T-dCyd) and 5-aza-4'-thio-2'-deoxycytidine (aza-T-dCyd) are two cytidine analogs that deplete DNMT1 both in vitro and in vivo in tumor cells. T-dCyd and aza-T-dCyd are currently in Phase I clinical trial at The National Cancer Institute (T-dCyd (NCT02423057) and aza-T-dCyd (NCT03366116)). Herein NSC-801845, a new cytidine analog, is compared with T-dCyd and aza-T-dCyd in cell culture and mouse xenograft studies in HCT-116 human colon carcinoma, BL0382 human bladder carcinoma, OVCAR3 human ovarian carcinoma, NCI-H23 human NSCLC carcinoma, and HL-60 human leukemia. In a 7-day monolayer culture cytotoxicity experiment, NSC-801845 was more potent than T-dCyd and less potent than aza-T-dCyd. In the 5 cell lines listed, the IC50s for NSC-801845 ranged from 3.7 uM to 0.2 uM in the 7-day experiment. In xenograft studies, T-dCyd was the least effective of the three cytidine analogs. In three of five xenograft lines (HCT-116, HL-60 and BL-0382), NSC-801845 was more efficacious than aza-T-dCyd (administered at the MTD of 1.5 mg/kg, IP). Comparable activity was observed for these two agents against the NCI-H23 and OVCAR3 xenografts. In the HCT-116 study, NSC-801845 (dosed 10 mg/kg IP, QDx5 for 4 cycles), produced complete regression of the tumors in all mice with a response that proved durable out to 150 days. Similarly, complete tumor regression was observed in the HL-60 leukemia xenograft when mice were dosed with NSC-801845 (10 mg/kg IP, QDx5 for 3 cycles). In the BL-0382 bladder study, oral and IP dosing of NSC-801845 (8 mg/kg PO, QDx5 for 3 cycles; 8 mg/kg IP QDx5, QDx5 for 3 cycles) produced regressions that showed tumor regrowth 13-days post dosing. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E. NCI-Frederick is accredited by AAALACi and follows the Public Health Service Policy on the Care and Use of Laboratory Animals. These studies were conducted on an approved Institutional Animal Care and Use Committee approved protocol. Citation Format: Joel Morris, Donn Wishka, Omar Lopez, Beverly A. Teicher, Raymond Divelbiss, Suzanne Borgel, Kyle Georgius, John Carter, Howard Stotler, Jerry Collins, Melinda Hollingshead. Preclinical development of NSC-801845, a new cytidine analog, in comparative cell culture and xenograft studies with the clinical candidates T-dCyd and aza-T-dCyd [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1961.

Published
2020

41. 5065Platelet desialylation induced by high shear-stress mechanical circulatory support

Author

A Rauch, Alexandre Kauskot, Petrus Lenting, N Rousse, Bart Staels, E. Van Belle, S. Susen, Delphine Borgel, Christoph Nix, M Moussa, H Spillemaeker, André Vincentelli, Annabelle Dupont, F Vincent, and Cécile V. Denis

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Circulatory system, Cardiology, Medicine, Cardiology and Cardiovascular Medicine, business, High shear stress
Published
2018

42. Design and Synthesis of Tubulin and Histone Deacetylase Inhibitor Based on iso -Combretastatin A-4

Author

François Saller, Cyril Bauvais, Hsin-Ping Lin, Hazar Al-Mouhammad, Guillaume Bollot, Martin Souce, Diana Lamaa, Olivier Pamlard, Athena Kasselouri, Abdallah Hamze, Joëlle Dubois, Lena Zig, Mehdi Ouaissi, Delphine Borgel, Jean Feuillard, Hélène Levaique, Chantal Jayat-Vignoles, Mouad Alami, Jérôme Bignon, Karim Benihoud, Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Physico-Chimique, Centre National de la Recherche Scientifique (CNRS), Synsight, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Chimie Analytique Pharmaceutique - Faculté de Pharmacie (Lip(Sys)2), Université Paris-Sud - Paris 11 (UP11), Groupe de Chimie Analytique de Paris-Sud, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Hematology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), and Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, medicine.drug_class, Protein Conformation, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, macromolecular substances, Chemistry Techniques, Synthetic, 01 natural sciences, Histone Deacetylases, 03 medical and health sciences, chemistry.chemical_compound, Tubulin, Drug Discovery, Stilbenes, medicine, Tubulin polymerization, Humans, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Combretastatin A-4, biology, 010405 organic chemistry, Drug discovery, Histone deacetylase inhibitor, HDAC8, HCT116 Cells, 0104 chemical sciences, 3. Good health, Histone Deacetylase Inhibitors, 030104 developmental biology, chemistry, Biochemistry, Drug Design, biology.protein, Molecular Medicine, K562 Cells, Belinostat, K562 cells
Abstract

Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes ( isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity.

Published
2018

43. Pharmacokinetics of Enoxaparin After Renal Transplantation in Pediatric Patients

Author

Olivia Boyer, Saïk Urien, Dominique Lasne, Jean-Marc Treluyer, Rémi Salomon, Alice Damamme, Saoussen Krid, Marina Charbit, Pauline Krug, and Delphine Borgel

Subjects
Male, Pediatrics, medicine.medical_specialty, Adolescent, Renal function, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, 030225 pediatrics, Intensive care, medicine, Humans, Pharmacology (medical), Dosing, Enoxaparin, Child, Retrospective Studies, Pharmacology, Volume of distribution, Kidney, Creatinine, business.industry, Body Weight, Anticoagulants, Infant, Retrospective cohort study, Kidney Transplantation, Transplantation, medicine.anatomical_structure, chemistry, Child, Preschool, Female, business
Abstract

Enoxaparin is commonly used in the prevention of renal allograft vascular thrombosis but off-label in children, and no consensus exists regarding the optimal dosing and dose adjustment. In this retrospective study, 444 anti-Xa levels were obtained from 30 pediatric renal transplant recipients in order to investigate enoxaparin population pharmacokinetics. The main results were (1) 25% of children achieved the target anti-Xa activity 36 hours after initiation of treatment, (2) anti-Xa time courses were best described by a 1-compartment open model with first-order absorption, (3) body weight but not renal function was the sole covariate influencing clearance and volume of distribution, and (4) large between-subject and between-occasion variabilities in anti-Xa activity were observed. However, creatinine-based estimated glomerular filtration rate in the first post-renal transplantation hours may not reliably reflect the actual renal function of the children. Based on the final population model, a Bayesian-based program was developed in order to estimate the individual pharmacokinetic parameters on a single anti-Xa measurement, allowing determination of the next enoxaparin dose that will quickly achieve an appropriate anti-Xa activity (targeting 0.3-0.5 IU/mL) and anticoagulation. Finally, these results should help standardize practices that remain to date largely heterogeneous in pediatric intensive care units.

Published
2018

44. Inactivated antithombin as anticoagulant reversal in a rat model of cardiopulmonary bypass: a potent and potentially safer alternative to protamine

Author

Jean-Luc Plantier, Alexandre Sebestyen, Vincent Richard, Alexandre Fontayne, Toufik Abache, Fabien Doguet, Elsa P. Bianchini, Yasmine Bourti, Fabienne Tamion, Delphine Borgel, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Ingénierie des protéines de l'hémostase à potentiel thérapeutique, Université Paris-Sud - Paris 11 (UP11), LFB Biotechnologies, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Service de soins intensifs [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), LFB Biotechnologies [Lille, France], Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Department of Hematology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, and Brakenhielm, Ebba

Subjects
Male, 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine.medical_treatment, 030204 cardiovascular system & hematology, Pharmacology, heparin, law.invention, chemistry.chemical_compound, 0302 clinical medicine, law, Protamines, Antidote, biology, medicine.diagnostic_test, Anticoagulant, Antithrombin, Heparin Antagonists, Hematology, Heparin, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, antithrombin, [SDV.IMM]Life Sciences [q-bio]/Immunology, cardiopulmonary bypass, protamine, Histamine, medicine.drug, Partial thromboplastin time, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.drug_class, Antithrombins, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Cardiopulmonary bypass, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Rats, Wistar, Hemodynamics, Anticoagulants, Protamine, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 030104 developmental biology, chemistry, biology.protein, antidote
Abstract

International audience; Heparin anticoagulation followed by protamine reversal is commonly used in cardiopulmonary bypass (CPB). As an alternative to protamine, a recombinant inactive antithrombin (riAT) was designed as an antidote to heparin and was previously shown to be as potent as protamine in-vitro. In the present study, riAT was assessed for its ability to neutralize heparin after CPB in a rat model. After 60 min of CPB under heparin, rats received 5 mg/kg protamine, 37.5 mg/kg riAT or phosphate buffered saline (PBS) as placebo. Residual anticoagulant activity was assessed using the activated partial thromboplastin time assay before, and 10-30 min after reversion. Haemodynamic monitoring was performed and plasma histamine concentration was also measured. In this model, riAT appeared to be as efficient as protamine in neutralizing heparin. Ten minutes after injection, riAT and protamine both decreased heparin activity, to 1.8 AE 1.3 and 4.5 AE 1.4 u/ ml, respectively (23.1 AE 5.1 u/ml in placebo group). Furthermore, evolution of mean carotid arterial pressure, heart rate and plasma histamine levels was comparable in rats treated with PBS or riAT, while protamine exhibited haemodynamic side effects and increased histamine plasma concentration. Thus, riAT could represent an advantage over protamine in CPB because it efficiently reverses heparin activity without negative effects on haemodynamic parameters and plasma histamine level.

Published
2018

45. Novel antibody reagents for characterization of drug- and tumor microenvironment-induced changes in epithelial-mesenchymal transition and cancer stem cells

Author

Thomas D. Pfister, Gordon Whiteley, Naoko Takebe, Ralph E. Parchment, Tara Hiltke, Young Hoon Lee, Lynda Dieckman, Robert J. Kinders, James H. Doroshow, Amina Aziz, Melinda G. Hollingshead, Simona Colantonio, Richard G. Saul, Tony Navas, Joseph E. Tomaszewski, Sergio Y. Alcoser, Suzanne Borgel, Donald P. Bottaro, and Jan A. Kaczmarczyk

Subjects
0301 basic medicine, Lung Neoplasms, Physiology, lcsh:Medicine, Triple Negative Breast Neoplasms, Biochemistry, Epitope, Metastasis, 0302 clinical medicine, Spectrum Analysis Techniques, Fluorescence Microscopy, Carcinoma, Non-Small-Cell Lung, Immune Physiology, Tumor Microenvironment, Medicine and Health Sciences, AC133 Antigen, Gene Knock-In Techniques, Enzyme-Linked Immunoassays, lcsh:Science, Sulfonamides, Microscopy, Multidisciplinary, Immune System Proteins, biology, medicine.diagnostic_test, Chemistry, Hepatocyte Growth Factor, Antibodies, Monoclonal, Light Microscopy, Flow Cytometry, Recombinant Proteins, Precipitation Techniques, Phenotype, Spectrophotometry, 030220 oncology & carcinogenesis, Pyrazines, embryonic structures, Benzamides, Neoplastic Stem Cells, Immunohistochemistry, Female, Cytophotometry, Antibody, Research Article, Immunofluorescence Microscopy, Epithelial-Mesenchymal Transition, Imaging Techniques, Immunology, Antineoplastic Agents, Mice, Transgenic, Research and Analysis Methods, Antibodies, Flow cytometry, 03 medical and health sciences, Cancer stem cell, Cell Line, Tumor, Fluorescence Imaging, medicine, Animals, Humans, Immunoprecipitation, Epithelial–mesenchymal transition, Immunoassays, Immunohistochemistry Techniques, Tumor microenvironment, lcsh:R, Biology and Life Sciences, Proteins, medicine.disease, Xenograft Model Antitumor Assays, Histochemistry and Cytochemistry Techniques, 030104 developmental biology, Cancer research, biology.protein, Immunologic Techniques, lcsh:Q, Indicators and Reagents
Abstract

The presence of cancer stem cells (CSCs) and the induction of epithelial-to-mesenchymal transition (EMT) in tumors are associated with tumor aggressiveness, metastasis, drug resistance, and poor prognosis, necessitating the development of reagents for unambiguous detection of CSC- and EMT-associated proteins in tumor specimens. To this end, we generated novel antibodies to EMT- and CSC-associated proteins, including Goosecoid, Sox9, Slug, Snail, and CD133. Importantly, unlike several widely used antibodies to CD133, the anti-CD133 antibodies we generated recognize epitopes distal to known glycosylation sites, enabling analyses that are not confounded by differences in CD133 glycosylation. For all target proteins, we selected antibodies that yielded the expected target protein molecular weights by Western analysis and the correct subcellular localization patterns by immunofluorescence microscopy assay (IFA); binding selectivity was verified by immunoprecipitation−mass spectrometry and by immunohistochemistry and IFA peptide blocking experiments. Finally, we applied these reagents to assess modulation of the respective markers of EMT and CSCs in xenograft tumor models by IFA. We observed that the constitutive presence of human hepatocyte growth factor (hHGF) in the tumor microenvironment of H596 non-small cell lung cancer tumors implanted in homozygous hHGF knock-in transgenic mice induced a more mesenchymal-like tumor state (relative to the epithelial-like state when implanted in control SCID mice), as evidenced by the elevated expression of EMT-associated transcription factors detected by our novel antibodies. Similarly, our new anti-CD133 antibody enabled detection and quantitation of drug-induced reductions in CD133-positive tumor cells following treatment of SUM149PT triple-negative breast cancer xenograft models with the CSC/focal adhesion kinase (FAK) inhibitor VS-6063. Thus, our novel antibodies to CSC- and EMT-associated factors exhibit sufficient sensitivity and selectivity for immunofluorescence microscopy studies of these processes in preclinical xenograft tumor specimens and the potential for application with clinical samples.

Published
2018

46. An ADAM-10 dependent EPCR shedding links meningococcal interaction with endothelial cells to purpura fulminans

Author

Sandrine Bourdoulous, Hervé Lécuyer, Jean-Philippe Barnier, François Saller, Xavier Nassif, Soraya Matczak, Elsa P. Bianchini, Mathieu Coureuil, Zoé Virion, Delphine Borgel, Bodescot, Myriam, Recherche transnationale sur les maladies infectieuses humaines - Bacterial interaction with the microvasculature, a target for therapeutic intervention during septicaemia - - BactInfectERA2014 - ANR-14-IFEC-0006 - IFEC - VALID, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Service de Microbiologie Clinique [Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'Hématologie Biologique [Paris], This work was supported by an Agence Nationale de la Recherche grant (ANR-14-IFEC-0006-01 call ERANET INFECT-ERA 2014 - grant recipient SB), the grant program EMERGENCE from La Mairie de Paris (grant recipient MC) and a grant from the Meningitis Research Foundation (MRF 1602 - grant recipient XN). The laboratory of XN is supported by INSERM, CNRS, Université Paris Descartes, and the Fondation pour la Recherche Médicale (FRM DEQ20140329533)., ANR-14-IFEC-0006,BactInfectERA,Bacterial interaction with the microvasculature, a target for therapeutic intervention during septicaemia(2014), and Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Bacterial Diseases, 0301 basic medicine, Physiology, ADAM10, Meningococcal Disease, Molting, Cardiovascular Medicine, Neisseria meningitidis, Pathology and Laboratory Medicine, medicine.disease_cause, Biochemistry, Vascular Medicine, Epithelium, Bacterial Adhesion, ADAM10 Protein, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Small interfering RNAs, Biology (General), Cells, Cultured, Endothelial protein C receptor, Thrombin, Endothelial Protein C Receptor, Hematology, Bacterial Pathogens, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Nucleic acids, Endothelial stem cell, Infectious Diseases, medicine.anatomical_structure, Medical Microbiology, Cardiovascular Diseases, Purpura Fulminans, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cellular Types, Anatomy, Pathogens, Neisseria, Research Article, medicine.drug, Purpura fulminans, Endothelium, QH301-705.5, Immune Cells, Immunology, Antigen-Presenting Cells, Meningococcal disease, Microbiology, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Virology, Genetics, medicine, Humans, Non-coding RNA, Microbial Pathogens, Blood Coagulation, Molecular Biology, Bacteria, Coagulation Disorders, business.industry, Organisms, Biology and Life Sciences, Endothelial Cells, Proteins, Membrane Proteins, Epithelial Cells, Thrombosis, Cell Biology, RC581-607, medicine.disease, Gene regulation, Meningococcal Infections, Biological Tissue, 030104 developmental biology, Microvessels, RNA, Parasitology, Gene expression, Endothelium, Vascular, Amyloid Precursor Protein Secretases, Immunologic diseases. Allergy, Physiological Processes, business, Protein C
Abstract

Purpura fulminans is a deadly complication of Neisseria meningitidis infections due to extensive thrombosis of microvessels. Although a Disseminated Intra-vascular Coagulation syndrome (DIC) is frequently observed during Gram negative sepsis, it is rarely associated with extensive thrombosis like those observed during meningococcemia, suggesting that the meningococcus induces a specific dysregulation of coagulation. Another specific feature of N. meningitidis pathogenesis is its ability to colonize microvessels endothelial cells via type IV pili. Importantly, endothelial cells are key in controlling the coagulation cascade through the activation of the potent anticoagulant Protein C (PC) thanks to two endothelial cell receptors among which the Endothelial Protein C Receptor (EPCR). Considering that congenital or acquired deficiencies of PC are associated with purpura fulminans, we hypothesized that a defect in the activation of PC following meningococcal adhesion to microvessels is responsible for the thrombotic events observed during meningococcemia. Here we showed that the adhesion of N. meningitidis on endothelial cells results in a rapid and intense decrease of EPCR expression by inducing its cleavage in a process know as shedding. Using siRNA experiments and CRISPR/Cas9 genome edition we identified ADAM10 (A Disintegrin And Metalloproteinase-10) as the protease responsible for this shedding. Surprisingly, ADAM17, the only EPCR sheddase described so far, was not involved in this process. Finally, we showed that this ADAM10-mediated shedding of EPCR induced by the meningococcal interaction with endothelial cells was responsible for an impaired activation of Protein C. This work unveils for the first time a direct link between meningococcal adhesion to endothelial cells and a severe dysregulation of coagulation, and potentially identifies new therapeutic targets for meningococcal purpura fulminans., Author summary Neisseria meningitidis (meningococcus) is responsible for a severe syndrome called purpura fulminans in which the coagulation system is totally dysregulated, leading to an extensive occlusion of blood microvessels. The pathogenesis of this syndrome is still not understood. Here we show that the meningococcus, when adhering on the apical surface of endothelial cells, induces the activation of membranous protease named ADAM-10, which in turn hydrolyses a cellular receptor called EPCR. The latter is key for the activation of a circulating potent anticoagulant, the Protein C (PC). PC activation is then impaired following meningococcal adhesion on endothelial cells. This work unveils for the first time a specific dysregulation of coagulation induced by the meningococcus and potentially identifies new therapeutic targets for meningococcal purpura fulminans.

Published
2018

47. Clinical variability and probable founder effect in oculocutaneous albinism type 7

Author

Matthieu P. Robert, Christine Bodemer, Benoit Arveiler, Delphine Borgel, Eulalie Lasseaux, L. Bekel, Smail Hadj-Rabia, Charlotte Celerier, Pauline Bataille, Dominique Bremond-Gignac, Annie Harroche, Stéphanie Leclerc-Mercier, and Vincent Michaud

Subjects
medicine.medical_specialty, Genetics, medicine, Albinism, Biology, medicine.disease, Oculocutaneous albinism, Dermatology, Genetics (clinical), Founder effect
Published
2019

48. Thrombomodulin favors leukocyte microvesicle fibrinolytic activity, reduces NETosis and prevents septic shock-induced coagulopathy in rats

Author

Mélanie Burban, Pierrick Le Borgne, Raphaël Clere-Jehl, Lelia Grunebaum, Fatiha Zobairi, Delphine Borgel, Ferhat Meziani, Julie Helms, Elsa P. Bianchini, Jean-Luc Diehl, and Florence Toti

Subjects
0301 basic medicine, medicine.medical_treatment, 030204 cardiovascular system & hematology, Lung injury, Critical Care and Intensive Care Medicine, Thrombomodulin, DIC, 03 medical and health sciences, 0302 clinical medicine, Septic shock, Fibrinolysis, medicine, Coagulopathy, Disseminated intravascular coagulation, business.industry, Research, Microvesicle, lcsh:Medical emergencies. Critical care. Intensive care. First aid, NETosis, lcsh:RC86-88.9, medicine.disease, 030104 developmental biology, Hemostasis, Immunology, Immunothrombosis, business, Microvesicles
Abstract

Background Septic shock-induced disseminated intravascular coagulation is responsible for increased occurrence of multiple organ dysfunction and mortality. Immunothrombosis-induced coagulopathy may contribute to hypercoagulability. We aimed at determining whether recombinant human thrombomodulin (rhTM) could control exaggerated immunothrombosis by studying procoagulant responses, fibrinolysis activity borne by microvesicles (MVs) and NETosis in septic shock. Methods In a septic shock model after a cecal ligation and puncture-induced peritonitis (H0), rats were treated with rhTM or a placebo at H18, resuscitated and monitored during 4 h. At H22, blood was sampled to perform coagulation tests, to characterize MVs and to detect neutrophils extracellular traps (NETs). Lungs were stained with hematoxylin–eosin for inflammatory injury assessment. Results Coagulopathy was attenuated in rhTM-treated septic rats compared to placebo-treated rats, as attested by a significant decrease in procoagulant annexin A5+-MVs and plasma procoagulant activity of phospholipids and by a significant increase in antithrombin levels (84 ± 8 vs. 64 ± 6%, p

Published
2017

49. Inefficacy of ultrasound-guided local injections of autologous conditioned plasma for recent epicondylitis: results of a double-blind placebo-controlled randomized clinical trial with one-year follow-up

Author

Maxime Breban, B. Montalvan, Philippe Hardy, Delphine Borgel, Patrick Le Goux, and Shahnaz Klouche

Subjects
Male, medicine.medical_specialty, Time Factors, Visual analogue scale, medicine.medical_treatment, Placebo, Injections, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Rheumatology, Randomized controlled trial, law, medicine, Tennis elbow, Humans, Pharmacology (medical), Saline, Ultrasonography, Interventional, Retrospective Studies, 030222 orthopedics, Platelet-Rich Plasma, business.industry, Epicondylitis, Tennis Elbow, 030229 sport sciences, Middle Aged, medicine.disease, Extensor carpi radialis brevis muscle, Surgery, Treatment Outcome, Platelet-rich plasma, Female, business, Follow-Up Studies
Abstract

Objectives The aim was to assess the efficacy of two intra-tendinous injections of platelet-rich plasma (PRP) on epicondylitis of recent evolution (≤3 months). Methods Our study was a double-blind placebo-controlled randomized trial. Two US-guided injections of either PRP (autologous conditioned plasma) or saline solution were performed with an interval of 4 weeks. The exclusion criterion was previous CS infiltration. Patients were monitored by an independent evaluator blinded to treatment at baseline and 1, 3, 6 and 12 months of follow-up. The primary evaluation criterion was the relative improvement from baseline to 6 months in pain score on visual analog scale (0-10). Secondary criteria were the Roles-Maudsley score and the assessment of pain on isometric contraction of extensor carpi radialis brevis and extensor digitorum communis. Results Twenty-five patients were randomly assigned to each group. Three patients in each arm dropped out before 6 months. In both groups, the pain score [mean (s.d.)] decreased significantly between two consecutive visits from 6.8 (0.8) (PRP) and 7 (1) (saline) at baseline to 2.5 (1.6) and 1.6 (1.5) (PRP) and to 2.1 (1.6) and 1.8 (2.1) (saline) at 6 and 12 months, respectively. At 6 months, no statistically significant difference was found between groups for relative improvement in pain score [autologous conditioned plasma: -63.2 (22.4%); saline: -69.7 (25.1%); P = 0.24]. No significant difference was found for the secondary criteria. Conclusion Two US-guided PRP injections for epicondylitis of recent evolution were not more efficacious than saline injections, until 6- and 12-months follow-up. Trial registration ClinicalTrials.gov; https://clinicaltrials.gov/; NCT02378285.

Published
2015

50. A fast capillary electrophoresis method to assess the binding affinity of recombinant antithrombin toward heparin directly from cell culture supernatants

Author

François Saller, Anne-Lise Marie, Toufik Abache, Delphine Borgel, Rémi Urbain, Nguyet Thuy Tran, Myriam Taverna, Stéphane Pautus, Jean-Luc Plantier, and Elsa P. Bianchini

Subjects
Chromatography, Heparin, Chemistry, Clinical Biochemistry, HEK 293 cells, Kinetics, Cell Culture Techniques, Electrophoresis, Capillary, Pharmaceutical Science, Serpin, Binding constant, Antithrombins, Fluorescence spectroscopy, Analytical Chemistry, Spectrometry, Fluorescence, Capillary electrophoresis, Cell culture, Drug Discovery, medicine, Humans, Spectroscopy, medicine.drug
Abstract

With the aim to determine the binding affinity of a new generation of recombinant antithrombin (AT) toward heparin, we developed a dynamic equilibrium-affinity capillary electrophoresis (DE-ACE) method. This method allows the determination of an AT-heparin binding constant (Kd) directly from the cell culture supernatant used to produce the AT variants. Eight measurements per AT variant are sufficient to determine an accurate Kd (uncertainty ≤ 22%, regression coefficient ≥ 0.97), which is not significantly different from the value obtained from a higher number of measurements. Due to the relatively short time required to determine the Kd of one AT variant (2h), this method has the potential for being a low throughput screening method. The method was validated by analyzing five AT variants, whose Kd have been reported in the literature using fluorescence spectroscopy. Finally, the method was applied to estimate the Kd of one new AT variant and one AT conformer, a latent form, that exhibits a significant loss of affinity.

Published
2015

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