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1. An equine iPSC-based phenotypic screening platform identifies pro- and anti-viral molecules against West Nile virus

Author: Marielle Cochet, François Piumi, Kamila Gorna, Noémie Berry, Gaëlle Gonzalez, Anne Danckaert, Nathalie Aulner, Odile Blanchet, Stéphan Zientara, Francesc Xavier Donadeu, Hélène Munier-Lehmann, Jennifer Richardson, Alexandra Benchoua, and Muriel Coulpier
Subjects: Equine, brain, neural progenitors, Flavivirus, antiviral, statin, Veterinary medicine, SF600-1100
Abstract: Abstract Outbreaks of West Nile virus (WNV) occur periodically, affecting both human and equine populations. There are no vaccines for humans, and those commercialised for horses do not have sufficient coverage. Specific antiviral treatments do not exist. Many drug discovery studies have been conducted, but since rodent or primate cell lines are normally used, results cannot always be transposed to horses. There is thus a need to develop relevant equine cellular models. Here, we used induced pluripotent stem cells to develop a new in vitro model of WNV-infected equine brain cells suitable for microplate assay, and assessed the cytotoxicity and antiviral activity of forty-one chemical compounds. We found that one nucleoside analog, 2′C-methylcytidine, blocked WNV infection in equine brain cells, whereas other compounds were either toxic or ineffective, despite some displaying anti-viral activity in human cell lines. We also revealed an unexpected proviral effect of statins in WNV-infected equine brain cells. Our results thus identify a potential lead for future drug development and underscore the importance of using a tissue- and species-relevant cellular model for assessing the activity of antiviral compounds.
Published: 2024
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2. Associations between perfluoroalkyl substances and the severity of non-alcoholic fatty liver disease

Author: Norma David, Jean-Philippe Antignac, Marine Roux, Philippe Marchand, Sophie Michalak, Fréderic Oberti, Isabelle Fouchard, Adrien Lannes, Odile Blanchet, Paul Cales, Etienne B. Blanc, Jérôme Boursier, and Clémence M. Canivet
Subjects: NAFLD, NASH, PFAS, PFHpA, Environmental sciences, GE1-350
Abstract: Background: Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide and the determinants driving its severity remain to be elucidated. Perfluoroalkyl substances (PFAS) are synthetic chemical compounds. They are used in commonplace products and persistent in water, soil and the human body. In vitro and animal studies suggest a pathogenic role for PFAS in metabolic diseases such as NAFLD. Objectives: We aimed to evaluate the association between NAFLD severity and serum PFAS concentrations in humans. Methods: One hundred biopsy-proven NAFLD patients were included with a well-balanced distribution between the different stages of severity: 25 patients with simple steatosis, 25 with early non-alcoholic steatohepatitis (NASH and F0–F1 fibrosis), 33 with fibrotic NASH (NASH and F2–F3 fibrosis), and 17 with cirrhotic NASH (NASH and F4 fibrosis). Liver histological features were evaluated according to the NASH Clinical Research Network classification. Seventeen PFAS were measured by high-performance liquid chromatography coupled with tandem mass spectrometry on serum samples stored at −80 °C. Results: The median age was 60 years, 61 % of patients were male, 46 % had diabetes and the median body mass index (BMI) was 32 kg/m2. Long-chain PFAS were associated with steatosis grade (p = 0.03). Among the nine PFAS detected in > 50 % of the patients, Perfluoro-n-heptanoic acid (PFHpA) showed significantly higher concentrations in grade 3 steatosis versus grade 1 (p = 0.02). Perfluoro-n-dodecanoic acid (PFDoA) concentrations were higher in patients with significant fibrosis (p = 0.04) and PFHpA in patients with advanced fibrosis (p = 0.02). The association between PFHpA and steatosis grade remained significant in multivariate analysis adjusted for age, gender, BMI, diabetes presence and dyslipidemia (p = 0.004). Discussion: Our study showed a significant association between PFHpA and liver steatosis in NAFLD. According to data available in the literature, PFHpA could be implicated in liver steatosis through β-oxidation and biosynthesis of fatty acids.
Published: 2023
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3. Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author: Julien Broséus, Sébastien Hergalant, Julia Vogt, Eugen Tausch, Markus Kreuz, Anja Mottok, Christof Schneider, Caroline Dartigeas, Damien Roos-Weil, Anne Quinquenel, Charline Moulin, German Ott, Odile Blanchet, Cécile Tomowiak, Grégory Lazarian, Pierre Rouyer, Emil Chteinberg, Stephan H. Bernhart, Olivier Tournilhac, Guillaume Gauchotte, Sandra Lomazzi, Elise Chapiro, Florence Nguyen-Khac, Céline Chery, Frédéric Davi, Mathilde Hunault, Rémi Houlgatte, Andreas Rosenwald, Alain Delmer, David Meyre, Marie-Christine Béné, Catherine Thieblemont, Peter Lichter, Ole Ammerpohl, Jean-Louis Guéant, ICGC MMML-Seq Consortium, Romain Guièze, José Ignacio Martin-Subero, Florence Cymbalista, Pierre Feugier, Reiner Siebert, and Stephan Stilgenbauer
Subjects: Science
Abstract: Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.
Published: 2023
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4. An immuno-lipidomic signature revealed by metabolomic and machine-learning approaches in labial salivary gland to diagnose primary Sjögren’s syndrome

Author: Geoffrey Urbanski, Floris Chabrun, Estelle Delattre, Carole Lacout, Brittany Davidson, Odile Blanchet, Juan Manuel Chao de la Barca, Gilles Simard, Christian Lavigne, and Pascal Reynier
Subjects: kynurenine, biomarker, metabolomics, Sjögren’s syndrome, sicca, salivary glands, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionAssessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren’s syndrome. Currently this relies on the histopathologic diagnosis of focal lymphocytic sialadenitis and computing a focus score by counting lym=phocyte foci. However, those lesions represent advanced stages of primary Sjögren’s syndrome, although earlier recognition of primary Sjögren’s syndrome and its effective treatment could prevent irreversible damage to labial salivary gland. This study aimed at finding early biomarkers of primary Sjögren’s syndrome in labial salivary gland combining metabolomics and machine-learning approaches.MethodsWe used a standardized targeted metabolomic approach involving high performance liquid chromatography coupled with mass spectrometry among newly diagnosed primary Sjögren’s syndrome (n=40) and non- primary Sjögren’s syndrome sicca (n=40) participants in a prospective cohort. A metabolic signature predictive of primary Sjögren’s syndrome status was explored using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the data set into training, validation, and test sets.ResultsAmong 126 metabolites accurately measured, we identified a discriminant signature composed of six metabolites with robust performances (ROC-AUC = 0.86) for predicting primary Sjögren’s syndrome status. This signature included the well-known immune-metabolite kynurenine and five phospholipids (LysoPC C28:0; PCaa C26:0; PCaaC30:2; PCae C30:1, and PCaeC30:2). It was split into two main components: the first including the phospholipids was related to the intensity of lymphocytic infiltrates in salivary glands, while the second represented by kynurenine was independently associated with the presence of anti-SSA antibodies in participant serum.ConclusionOur results reveal an immuno-lipidomic signature in labial salivary gland that accurately distinguishes early primary Sjögren’s syndrome from other causes of sicca symptoms.
Published: 2023
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5. Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Author: Mazigh Fares, Marielle Cochet-Bernoin, Gaëlle Gonzalez, Claudia N. Montero-Menei, Odile Blanchet, Alexandra Benchoua, Claire Boissart, Sylvie Lecollinet, Jennifer Richardson, Nadia Haddad, and Muriel Coulpier
Subjects: Neurotropic virus, Flavivirus, Tick-borne encephalitis virus, Central nervous system, Human neuronal/glial cells, Viral tropism, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background Tick-borne encephalitis virus (TBEV) is a member of the Flaviviridae family, Flavivirus genus, which includes several important human pathogens. It is responsible for neurological symptoms that may cause permanent disability or death, and, from a medical point of view, is the major arbovirus in Central/Northern Europe and North-Eastern Asia. TBEV tropism is critical for neuropathogenesis, yet little is known about the molecular mechanisms that govern the susceptibility of human brain cells to the virus. In this study, we sought to establish and characterize a new in vitro model of TBEV infection in the human brain and to decipher cell type-specific innate immunity and its relation to TBEV tropism and neuropathogenesis. Method Human neuronal/glial cells were differentiated from neural progenitor cells and infected with the TBEV-Hypr strain. Kinetics of infection, cellular tropism, and cellular responses, including innate immune responses, were characterized by measuring viral genome and viral titer, performing immunofluorescence, enumerating the different cellular types, and determining their rate of infection and by performing PCR array and qRT-PCR. The specific response of neurons and astrocytes was analyzed using the same approaches after enrichment of the neuronal/glial cultures for each cellular subtype. Results We showed that infection of human neuronal/glial cells mimicked three major hallmarks of TBEV infection in the human brain, namely, preferential neuronal tropism, neuronal death, and astrogliosis. We further showed that these cells conserved their capacity to mount an antiviral response against TBEV. TBEV-infected neuronal/glial cells, therefore, represented a highly relevant pathological model. By enriching the cultures for either neurons or astrocytes, we further demonstrated qualitative and quantitative differential innate immune responses in the two cell types that correlated with their particular susceptibility to TBEV. Conclusion Our results thus reveal that cell type-specific innate immunity is likely to contribute to shaping TBEV tropism for human brain cells. They describe a new in vitro model for in-depth study of TBEV-induced neuropathogenesis and improve our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells.
Published: 2020
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6. A Metabolomic Profile of Seminal Fluid in Extremely Severe Oligozoopermia Suggesting an Epididymal Involvement

Author: Orianne Serri, Magalie Boguenet, Juan Manuel Chao de la Barca, Pierre-Emmanuel Bouet, Hady El Hachem, Odile Blanchet, Pascal Reynier, and Pascale May-Panloup
Subjects: metabolomics, male infertility, azoospermia, seminal fluid, testicular dysfunction, epididymis, Microbiology, QR1-502
Abstract: Male infertility has increased in the last decade. Pathophysiologic mechanisms behind extreme oligospermia (EO) are not yet fully understood. In new “omics” approaches, metabolomic can offer new information and help elucidate these mechanisms. We performed a metabolomics study of the seminal fluid (SF) in order to understand the mechanisms implicated in EO. We realized a targeted quantitative analysis using high performance liquid chromatography and mass spectrometry to compare the SF metabolomic profile of 19 men with EO with that of 22 men with a history of vasectomy (V) and 20 men with normal semen parameters (C). A total of 114 metabolites were identified. We obtained a multivariate OPLS-DA model discriminating the three groups. Signatures show significantly higher levels of amino acids and polyamines in C group. The sum of polyunsaturated fatty acids and free carnitine progressively decrease between the three groups (C > EO > V) and sphingomyelins are significantly lower in V group. Our signature characterizing EO includes metabolites already linked to infertility in previous studies. The similarities between the signatures of the EO and V groups are clear evidence of epididymal dysfunction in the case of testicular damage. This study shows the complexity of the metabolomic dysfunction occurring in the SF of EO men and underlines the importance of metabolomics in understanding male infertility.
Published: 2022
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7. A Metabolomic Profiling of Intra-Uterine Growth Restriction in Placenta and Cord Blood Points to an Impairment of Lipid and Energetic Metabolism

Author: Juan Manuel Chao de la Barca, Floris Chabrun, Tiphaine Lefebvre, Ombeline Roche, Noémie Huetz, Odile Blanchet, Guillaume Legendre, Gilles Simard, Pascal Reynier, and Géraldine Gascoin
Subjects: cord blood, intra-uterine growth restriction, metabolomics, lipidomic, placenta, Biology (General), QH301-705.5
Abstract: (1) Background: Intrauterine growth restriction (IUGR) involves metabolic changes that may be responsible for an increased risk of metabolic and cardiovascular diseases in adulthood. Several metabolomic profiles have been reported in maternal blood and urine, amniotic fluid, cord blood and newborn urine, but the placenta has been poorly studied so far. (2) Methods: To decipher the origin of this metabolic reprogramming, we conducted a targeted metabolomics study replicated in two cohorts of placenta and one cohort of cord blood by measuring 188 metabolites by mass spectrometry. (3) Results: OPLS-DA multivariate analyses enabled clear discriminations between IUGR and controls, with good predictive capabilities and low overfitting in the two placental cohorts and in cord blood. A signature of 25 discriminating metabolites shared by both placental cohorts was identified. This signature points to sharp impairment of lipid and mitochondrial metabolism with an increased reliance on the creatine-phosphocreatine system by IUGR placentas. Increased placental insulin resistance and significant alteration of fatty acids oxidation, together with relatively higher phospholipase activity in IUGR placentas, were also highlighted. (4) Conclusions: Our results show a deep lipid and energetic remodeling in IUGR placentas that may have a lasting effect on the fetal metabolism.
Published: 2022
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8. A Tear Metabolomic Profile Showing Increased Ornithine Decarboxylase Activity and Spermine Synthesis in Thyroid-Associated Orbitopathy

Author: Benjamin Billiet, Juan Manuel Chao de la Barca, Marc Ferré, Jeanne Muller, Anaïs Vautier, Sophie Assad, Odile Blanchet, Lydie Tessier, Céline Wetterwald, Justine Faure, Geoffrey Urbanski, Gilles Simard, Delphine Mirebeau-Prunier, Patrice Rodien, Philippe Gohier, and Pascal Reynier
Subjects: Graves’ ophthalmopathy, metabolomics, ornithine decarboxylase, spermine, thyroid-associated orbitopathy, Medicine
Abstract: About half of patients with Graves’ disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves’ ophthalmopathy.
Published: 2022
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9. Data-Mining Approach on Transcriptomics and Methylomics Placental Analysis Highlights Genes in Fetal Growth Restriction

Author: Floris Chabrun, Noémie Huetz, Xavier Dieu, Guillaume Rousseau, Guillaume Bouzillé, Juan Manuel Chao de la Barca, Vincent Procaccio, Guy Lenaers, Odile Blanchet, Guillaume Legendre, Delphine Mirebeau-Prunier, Marc Cuggia, Philippe Guardiola, Pascal Reynier, and Geraldine Gascoin
Subjects: data mining, methylomics, intrauterine growth restriction, multi-omics, text-mining, transcriptomics, Genetics, QH426-470
Abstract: Intrauterine Growth Restriction (IUGR) affects 8% of newborns and increases morbidity and mortality for the offspring even during later stages of life. Single omics studies have evidenced epigenetic, genetic, and metabolic alterations in IUGR, but pathogenic mechanisms as a whole are not being fully understood. An in-depth strategy combining methylomics and transcriptomics analyses was performed on 36 placenta samples in a case-control study. Data-mining algorithms were used to combine the analysis of more than 1,200 genes found to be significantly expressed and/or methylated. We used an automated text-mining approach, using the bulk textual gene annotations of the discriminant genes. Machine learning models were then used to explore the phenotypic subgroups (premature birth, birth weight, and head circumference) associated with IUGR. Gene annotation clustering highlighted the alteration of cell signaling and proliferation, cytoskeleton and cellular structures, oxidative stress, protein turnover, muscle development, energy, and lipid metabolism with insulin resistance. Machine learning models showed a high capacity for predicting the sub-phenotypes associated with IUGR, allowing a better description of the IUGR pathophysiology as well as key genes involved.
Published: 2020
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10. Transcriptomic Studies Suggest a Coincident Role for Apoptosis and Pyroptosis but Not for Autophagic Neuronal Death in TBEV-Infected Human Neuronal/Glial Cells

Author: Mazigh Fares, Kamila Gorna, Noémie Berry, Marielle Cochet-Bernoin, François Piumi, Odile Blanchet, Nadia Haddad, Jennifer Richardson, and Muriel Coulpier
Subjects: central nervous system, flavivirus, neuronal death, pathological modeling, tick-borne encephalitis virus, TNF family members, Microbiology, QR1-502
Abstract: Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, Flavivirus genus, is responsible for neurological symptoms that may cause permanent disability or death. With an incidence on the rise, it is the major arbovirus affecting humans in Central/Northern Europe and North-Eastern Asia. Neuronal death is a critical feature of TBEV infection, yet little is known about the type of death and the molecular mechanisms involved. In this study, we used a recently established pathological model of TBEV infection based on human neuronal/glial cells differentiated from fetal neural progenitors and transcriptomic approaches to tackle this question. We confirmed the occurrence of apoptotic death in these cultures and further showed that genes involved in pyroptotic death were up-regulated, suggesting that this type of death also occurs in TBEV-infected human brain cells. On the contrary, no up-regulation of major autophagic genes was found. Furthermore, we demonstrated an up-regulation of a cluster of genes belonging to the extrinsic apoptotic pathway and revealed the cellular types expressing them. Our results suggest that neuronal death occurs by multiple mechanisms in TBEV-infected human neuronal/glial cells, thus providing a first insight into the molecular pathways that may be involved in neuronal death when the human brain is infected by TBEV.
Published: 2021
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11. A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

Author: Juan M. Chao de la Barca, Barnabé Rondet-Courbis, Marc Ferré, Jeanne Muller, Adrien Buisset, Stéphanie Leruez, Guillaume Plubeau, Thibaut Macé, Laurie Moureauzeau, Stéphanie Chupin, Lydie Tessier, Odile Blanchet, Guy Lenaers, Vincent Procaccio, Delphine Mirebeau-Prunier, Gilles Simard, Philippe Gohier, Dan Miléa, and Pascal Reynier
Subjects: age-related macular degeneration, lipidomics, metabolomics., Medicine
Abstract: To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients (n = 40, mean age = 81.1) compared to an age- and sex-matched control group (n = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini−Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (p-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria; proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency.
Published: 2020
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12. A Data Mining Metabolomics Exploration of Glaucoma

Author: Judith Kouassi Nzoughet, Khadidja Guehlouz, Stéphanie Leruez, Philippe Gohier, Cinzia Bocca, Jeanne Muller, Odile Blanchet, Dominique Bonneau, Gilles Simard, Dan Milea, Vincent Procaccio, Guy Lenaers, Juan M. Chao de la Barca, and Pascal Reynier
Subjects: data mining, metabolomics, mitochondrial dysfunction, optic neuropathy, primary open-angle glaucoma, Microbiology, QR1-502
Abstract: Glaucoma is an age related disease characterized by the progressive loss of retinal ganglion cells, which are the neurons that transduce the visual information from the retina to the brain. It is the leading cause of irreversible blindness worldwide. To gain further insights into primary open-angle glaucoma (POAG) pathophysiology, we performed a non-targeted metabolomics analysis on the plasma from POAG patients (n = 34) and age- and sex-matched controls (n = 30). We investigated the differential signature of POAG plasma compared to controls, using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). A data mining strategy, combining a filtering method with threshold criterion, a wrapper method with iterative selection, and an embedded method with penalization constraint, was used. These strategies are most often used separately in metabolomics studies, with each of them having their own limitations. We opted for a synergistic approach as a mean to unravel the most relevant metabolomics signature. We identified a set of nine metabolites, namely: nicotinamide, hypoxanthine, xanthine, and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline with decreased concentrations and N-acetyl-L-Leucine, arginine, RAC-glycerol 1-myristate, 1-oleoyl-RAC-glycerol, cystathionine with increased concentrations in POAG; the modification of nicotinamide, N-acetyl-L-Leucine, and arginine concentrations being the most discriminant. Our findings open up therapeutic perspectives for the diagnosis and treatment of POAG.
Published: 2020
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13. Imatinib Treatment of Chronic Myeloid Leukemia Reveals a Preexisting CALR-mutated Essential Thrombocythemia

Author: Anaïse Blouet, Marie-Christine Rousselet, Yannick Le Bris, Bénédicte Ribourtout, Anne Bouvier, Laurane Cottin, Rébecca Jouanneau-Courville, Odile Blanchet, Valérie Ugo, and Damien Luque Paz
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2018
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14. CD45RC Expression of Circulating CD8+ T Cells Predicts Acute Allograft Rejection: A Cohort Study of 128 Kidney Transplant Patients

Author: Marie Lemerle, Anne-Sophie Garnier, Martin Planchais, Benoit Brilland, Yves Delneste, Jean-François Subra, Odile Blanchet, Simon Blanchard, Anne Croue, Agnès Duveau, and Jean-François Augusto
Subjects: kidney transplantation, acute rejection, lymphocyte, CD45RC, Medicine
Abstract: Predictive biomarkers of acute rejection (AR) are lacking. Pre-transplant expression of CD45RC on blood CD8+ T cells has been shown to predict AR in kidney transplant (KT) patients. The objective of the present study was to study CD45RC expression in a large cohort of KT recipients exposed to modern immunosuppressive regimens. CD45RC expression on T cells was analyzed in 128 KT patients, where 31 patients developed AR, of which 24 were found to be T-cell mediated (TCMR). Pre-transplant CD4+ and CD8+ CR45RChigh T cell proportions were significantly higher in patients with AR. The frequency of CD45RChigh T cells was significantly associated with age at transplantation but was not significantly different according to gender, history of transplantation, pre-transplant immunization, and de novo donor specific anti-Human Leucocyte Antigen (HLA) antibody. Survival-free AR was significantly better in patients with CD8+ CD45RChigh T cells below 58.4% (p = 0.0005), but not different according to CD4+ T cells (p = 0.073). According to multivariate analysis, CD8+ CD45RChigh T cells above 58.4% increased the risk of AR 4-fold (HR 3.96, p = 0.003). Thus, pre-transplant CD45RC expression on CD8+ T cells predicted AR, mainly TCMR, in KT patients under modern immunosuppressive therapies. We suggest that CD45RC expression should be evaluated in a prospective study to validate its usefulness to quantify the pre-transplant risk of AR.
Published: 2019
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15. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial

Author: Christophe Willekens, Odile Blanchet, Aline Renneville, Pascale Cornillet-Lefebvre, Cécile Pautas, Romain Guieze, Norbert Ifrah, Hervé Dombret, Eric Jourdan, Claude Preudhomme, and Nicolas Boissel
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)×100 ≤ 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4-year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy.
Published: 2016
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16. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial

Author: Nicolas Boissel, Aline Renneville, Thibaut Leguay, Pascale Cornillet Lefebvre, Christian Recher, Thibaud Lecerf, Eric Delabesse, Céline Berthon, Odile Blanchet, Thomas Prebet, Cécile Pautas, Patrice Chevallier, Stéphane Leprêtre, Stéphane Girault, Caroline Bonmati, Romain Guièze, Chantal Himberlin, Edouard Randriamalala, Claude Preudhomme, Eric Jourdan, Hervé Dombret, and Norbert Ifrah
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18–60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12).
Published: 2015
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17. Prognostic impact of day 15 blast clearance in risk-adapted remission induction chemotherapy for younger patients with acute myeloid leukemia: long-term results of the multicenter prospective LAM-2001 trial by the GOELAMS study group

Author: Sarah Bertoli, Pierre Bories, Marie C. Béné, Sylvie Daliphard, Bruno Lioure, Arnaud Pigneux, Norbert Vey, Jacques Delaunay, Vincent Leymarie, Isabelle Luquet, Odile Blanchet, Pascale Cornillet-Lefebvre, Mathilde Hunault, Didier Bouscary, Nathalie Fegueux, Philippe Guardiola, François Dreyfus, Jean Luc Harousseau, Jean Yves Cahn, Norbert Ifrah, and Christian Récher
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Early response to chemotherapy has a major prognostic impact in acute myeloid leukemia patients treated with a double induction strategy. Less is known about patients treated with standard-dose cytarabine and anthracycline. We designed a risk-adapted remission induction regimen in which a second course of intermediate-dose cytarabine was delivered after standard “7+3” only if patients had 5% or more bone marrow blasts 15 days after chemotherapy initiation (d15-blasts). Of 823 included patients, 795 (96.6%) were evaluable. Five hundred and forty-five patients (68.6%) had less than 5% d15-blasts. Predictive factors for high d15-blasts were white blood cell count (P
Published: 2014
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18. TET2 mutations in secondary acute myeloid leukemias: a French retrospective study

Author: Olivier Kosmider, Eric Delabesse, Véronique Mansat-De Mas, Pascale Cornillet-Lefebvre, Odile Blanchet, Alain Delmer, Christian Recher, Sophie Raynaud, Didier Bouscary, Franck Viguié, Catherine Lacombe, Olivier A. Bernard, Norbert Ifrah, François Dreyfus, and Michaëla Fontenay
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Ten-eleven translocation 2 (TET2) mutations have been involved in myeloid malignancies. This retrospective study aims at evaluating the frequency and impact of TET2 mutations in 247 secondary acute myeloid leukemia cases referred to as myelodysplasia-related changes (n=201) or therapy-related (n=46) leukemias. Mutation of at least one copy of the TET2 gene was detected in 49 of 247 (19.8%) patients who presented with older age, higher hemoglobin level, higher neutrophil and monocyte counts, and lower platelet count. TET2 mutations were significantly less frequent in therapy-related (8.7%) than myelodysplasia-related changes (22.3%; P=0.035) leukemias and strongly associated with normal karyotype (P
Published: 2011
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19. La ligne rose

Author: Odile Blanchet, Bérénice Boccara, Sana Puis and Odile Blanchet, Bérénice Boccara, Sana Puis
Published: 2021

20. Relationship between comorbidities, mutational profile, and outcome after intensive chemotherapy in patients older than 60 years with acute myeloid leukemia: Assessment of different risk scores

Author: Amélie Bachelot, Anne Bouvier, Jérémie Riou, Sylvain Thepot, Aurélien Giltat, Christopher Nunes Gomes, Jérôme Paillassa, Rébecca Jouanneau‐Courville, Maxime Renard, Annaelle Beucher, Laurane Cottin, Margaux Wiber, Bénédicte Ribourtout, Franck Geneviève, Damien Luque Paz, Aline Tanguy‐Schmidt, Valérie Ugo, Mathilde Hunault‐Berger, Odile Blanchet, and Corentin Orvain
Subjects: Hematology
Published: 2023

21. Association between kinetic of anti-neutrophil cytoplasmic antibody (ANCA), renal survival and relapse risk in ANCA glomerulonephritis

Author: Clément Samoreau, Giorgina Barbara Piccoli, Cécile Martin, Philippe Gatault, Emeline Vinatier, Frank Bridoux, Jérémie Riou, Alice Desouche, Pierre Jourdain, Jean-Philippe Coindre, Samuel Wacrenier, Fanny Guibert, Nicolas Henry, Odile Blanchet, Anne Croué, Assia Djema, Lise-Marie Pouteau, Marie-Christine Copin, Céline Beauvillain, Jean-François Subra, Jean-François Augusto, and Benoit Brilland
Subjects: Transplantation, Nephrology
Abstract: Background Anti-neutrophil cytoplasmic antibody (ANCA) kinetic in ANCA-associated vasculitis with glomerulonephritis (AAV-GN) has been suggested to be associated with AAV relapse. Few studies have focused on its association with renal prognosis. Thus we aimed to investigate the relationship between ANCA specificity and the evolutive profile and renal outcomes. Methods This multicentric retrospective study included patients diagnosed with ANCA-GN since 1 January 2000. Patients without ANCA at diagnosis and with fewer than three ANCA determinations during follow-up were excluded. We analysed estimated glomerular filtration rate (eGFR) variation, renal-free survival and relapse-free survival according to three ANCA profiles (negative, recurrent and persistent) and to ANCA specificity [myeloperoxidase (MPO) or proteinase 3 (PR3)]. Results Over a follow-up of 56 months [interquartile range (IQR) 34–101], a median of 19 (IQR 13–25) ANCA determinations were performed for the 134 included patients. Patients with a recurrent/persistent ANCA profile had a lower relapse-free survival (P = .019) and tended to have a lower renal survival (P = .053) compared with those with a negative ANCA profile. Patients with a recurrent/persistent MPO-ANCA profile had the shortest renal survival (P = .015) and those with a recurrent/persistent PR3-ANCA profile had the worst relapse-free survival (P = .013) compared with other profiles. The negative ANCA profile was associated with a greater eGFR recovery. In multivariate regression analysis, it was an independent predictor of a 2-fold increase in eGFR at 2 years [odds ratio 6.79 (95% confidence interval 1.78–31.4), P = .008]). Conclusion ANCA kinetic after an ANCA-GN diagnosis is associated with outcomes. MPO-ANCA recurrence/persistence identifies patients with a lower potential of renal recovery and a higher risk of kidney failure, while PR3-ANCA recurrence/persistence identifies patients with a greater relapse risk. Thus ANCA kinetics may help identify patients with a smouldering disease.
Published: 2022

22. Kidney injury molecule 1 (KIM-1): a potential biomarker of acute kidney injury and tubulointerstitial injury in patients with ANCA-glomerulonephritis

Author: Benoît Brilland, Charlotte Boud'hors, Samuel Wacrenier, Simon Blanchard, Jérôme Cayon, Odile Blanchet, Giorgina Barbara Piccoli, Nicolas Henry, Assia Djema, Jean-Philippe Coindre, Pascale Jeannin, Yves Delneste, Marie-Christine Copin, and Jean-François Augusto
Subjects: Transplantation, Nephrology
Abstract: Background Kidney injury molecule 1 (KIM-1) is a transmembrane glycoprotein expressed by proximal tubular cells, recognized as an early, sensitive and specific urinary biomarker for kidney injury. Blood KIM-1 was recently associated with the severity of acute and chronic kidney damage but its value in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis with glomerulonephritis (ANCA-GN) has not been studied. Thus, we analyzed its expression at ANCA-GN diagnosis and its relationship with clinical presentation, kidney histopathology and early outcomes. Methods We assessed KIM-1 levels and other pro-inflammatory molecules (C-reactive protein, interleukin-6, tumor necrosis factor α, monocyte chemoattractant protein-1 and pentraxin 3) at ANCA-GN diagnosis and after 6 months in patients included in the Maine-Anjou registry, which gathers data patients from four French Nephrology Centers diagnosed since January 2000. Results Blood KIM-1 levels were assessed in 54 patients. Levels were elevated at diagnosis and decreased after induction remission therapy. KIM-1 was associated with the severity of renal injury at diagnosis and the need for kidney replacement therapy. In opposition to other pro-inflammatory molecules, KIM-1 correlated with the amount of acute tubular necrosis and interstitial fibrosis/tubular atrophy (IF/TA) on kidney biopsy, but not with interstitial infiltrate or with glomerular involvement. In multivariable analysis, elevated KIM-1 predicted initial estimated glomerular filtration rate (β = –19, 95% CI –31, –7.6, P = .002). Conclusion KIM-1 appears as a potential biomarker for acute kidney injury and for tubulointerstitial injury in ANCA-GN. Whether KIM-1 is only a surrogate marker or is a key immune player in ANCA-GN pathogenesis remain to be determined.
Published: 2023

23. Validation of the Blood Test MACK-3 for the Noninvasive Diagnosis of Fibrotic Nonalcoholic Steatohepatitis: An International Study With 1924 Patients

Author: Clémence M. Canivet, Ming-Hua Zheng, Sami Qadri, Luisa Vonghia, Kee-Huat Chuah, Charlotte Costentin, Jacob George, Angelo Armandi, Leon A. Adams, Naomi F. Lange, Odile Blanchet, Valérie Moal, Ramy Younes, Marine Roux, Wah-Kheong Chan, Nathalie Sturm, Mohammed Eslam, Elisabetta Bugianesi, Zhengyi Wang, Jean-François Dufour, Sven Francque, Hannele Yki-Järvinen, Kenneth I. Zheng, and Jérôme Boursier
Subjects: Hepatology, Gastroenterology
Published: 2023

24. Very short insertions in the FLT3 gene are of therapeutic significance in acute myeloid leukemia

Author: Norman, Abbou, Sara, Addakiri, Louis, Adje Missa, Lucille, Altounian, Chloé, Arfeuille, Amélie, Bachelot, Fanny, Baran-Marszak, Kildie, Barrial, Anne, Barthel, Martine, Becker, Emmanuel, Beillard, Graziella, Bernier, Annaëlle, Beucher, Odile, Blanchet, Pauline, Blateau, Julliane, Bloch, Lara, Boucher, Marie-Laure, Boulland, Anne, Bouvier, Simon, Bouzy, Claire, Bracquemart, Clotilde, Bravetti, Chantal, Brouzes, Patricia, Brugel, Serge, Carillo, Bruno, Cassinat, Hélène, Cave, Aurélie, Caye-Eude, Jean-Michel, Cayuela, Carole, Charlot, Aurélie, Chauveau, Sara, Chikhi, Lionel, Chollet, Jean-Claude, Chomel, Emmanuelle, Clappier, Alexis, Claudel, Pascale, Cornillet Lefebvre, Laurane, Cottin, Marie-Magdelaine, Coude, Vincent, Cussac, Bérangère, Dadone-Montaudie, Frédéric, Davi, Véronique, De Mas, Agathe, Debliquis, Matthieu, Decamp, Sabine, Defasque, Michaël, Degaud, Marlene, Dejean, Eric, Delabesse, Hervé, Delacour, Marie-Hélène, Delfau-Larue, Anne, Desmares, Marion, Divoux, Natacha, Doumbadze, Julie, Dremaux, Bernard, Drenou, Stéphanie, Dulucq, Coraline, Dumont, Manon, Duprat, Valérie, Duranton-Tanneur, Marie-Hélène, Estienne, Pascaline, Etancelin, Lisa, Faucheux, Laurène, Fenwarth, Carole, Fleury, Elise, Fournier, Chloé, Friedrich, Xavier, Fund, Nathalie, Gachard, Jean-Baptiste, Gaillard, Coralie, Giot, Valérie, Goncalves, Nathalie, Grardel, Brigitte, Gubler, Yacine, Haddad, Mehdi, Hage Sleiman, Sandrine, Hayette, Claire, Hirschauer, Sarah, Huet, Carole, Humbert, Antoine, Ittel, Sophie, Kaltenbach, Sébastien, Lachot, Sophy, Laibe, Grégory, Lazarian, Valoris, Le Brun, Christelle, Le Sciellour, Benjamin, Lebecque, Isabelle, Lemaire, Melchior, Le Mene, Christine, Lespinasse, Ludovic, Lhermitte, Laurence, Lode, Damien, Luque Paz, Cyril, Maingourd, Elsa, Maitre, Mansier, Olivier, Alice, Marceau-Renaut, Angelique, Marcon, Mélanie, Martin-Gourier, Christophe, Marzac, Claire, Mauduit, Lucie, Maurice, Audrey, Menard, Jean-Philippe, Merlio, Yannick, Miguet Laurent, Djamia, Mokrane, Nathalie, Monhoven, Marie-Joelle, Mozziconacci, Marc, Muller, Anne, Murati-Zeller, Dina, Naguib, Rajiv, Narayanin, Olivier, Nibourel, Pauline, Noyel, Jennifer, Osman, Cédric, Pastoret, Agathe, Paubel, Anne, Perdrix, Benjamin, Podvin, Benoit, Quilichini, Anna, Raimbault, Thimali, Ranaweera Arachchige, Noémie, Ravalet, Julie, Renard, Aline, Renneville, Florian, Renosi, Bénédicte, Ribourtout, David, Rizzo, Camille, Rottier, Léa, Ryffel, Ivan, Sloma, Brigitte, Soubeyran, Nathalie, Sorel, Marc, Spentchian, Assia, Taleb, Thomas, Tassin, Andrei, Tchirkov, Giulia, Tueur, Valérie, Ugo, Laurent, Vallat, Lauren, Veronese, Patrick, Villarese, Margaux, Wiber, Loria, Zalmaï, Tamburini, Jerome, Mouche, Sarah, Larrue, Clement, Duployez, Nicolas, Bidet, Audrey, Salotti, Auriane, Hirsch, Pierre, Rigolot, Lucie, Carras, Sylvain, Templé, Marie, Favale, Fabrizia, Flandrin-Gresta, Pascale, Le Bris, Yannick, Alary, Anne-Sophie, Mauvieux, Laurent, Tondeur, Sylvie, Delabesse, Eric, Delhommeau, François, Sujobert, Pierre, and Kosmider, Olivier
Published: 2023
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25. Tear metabolomics highlights new potential biomarkers for differentiating between Sjögren's syndrome and other causes of dry eye

Author: Odile Blanchet, Juan Manuel Chao de la Barca, Delphine Prunier-Mirebeau, Sophie Assad, Floris Chabrun, Christian Lavigne, Gilles Simard, Philippe Gohier, Geoffrey Urbanski, Pascal Reynier, and Guy Lenaers
Subjects: Oncology, medicine.medical_specialty, Population, Dry Eye Syndromes, chemistry.chemical_compound, Metabolomics, stomatognathic system, Sicca syndrome, Internal medicine, Humans, Medicine, Prospective Studies, education, Prospective cohort study, education.field_of_study, business.industry, eye diseases, stomatognathic diseases, Ophthalmology, Sjogren's Syndrome, chemistry, Biomarker (medicine), Tears, business, Biomarkers, PCAA
Abstract: Purpose The lacrimal exocrinopathy of primary Sjogren's syndrome (pSS) is one of the main causes of severe dry eye syndrome and a burden for patients. Early recognition and treatment could prevent irreversible damage to lacrimal glands. The aim of this study was to find biomarkers in tears, using metabolomics and data mining approaches, in patients with newly-diagnosed pSS compared to other causes of dry eye syndrome. Methods A prospective cohort of 40 pSS and 40 non-pSS Sicca patients with dryness was explored through a standardized targeted metabolomic approach using liquid chromatography coupled with mass spectrometry. A metabolomic signature predictive of the pSS status was sought out using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the studied population into training, validation and test sets. Results Among the 104 metabolites accurately measured in tears, we identified a discriminant signature composed of nine metabolites (two amino acids: serine, aspartate; one biogenic amine: dopamine; six lipids: Lysophosphatidylcholine C16:1, C18:1, C18:2, sphingomyelin C16:0 and C22:3, and the phoshatidylcholine diacyl PCaa C42:4), with robust performances (ROC-AUC = 0.83) for predicting the pSS status. Adjustment for age, sex and anti-SSA antibodies did not disrupt the link between the metabolomic signature and the pSS status. The non-lipidic components also remained specific for pSS regardless of the dryness severity. Conclusion Our results reveal a metabolomic signature for tears that distinguishes pSS from other dry eye syndromes and further highlight nine key metabolites of potential interest for early diagnosis and therapeutics of pSS.
Published: 2021

26. A Tear Metabolomic Profile Showing Increased Ornithine Decarboxylase Activity and Spermine Synthesis in Thyroid-Associated Orbitopathy

Author: Benjamin Billiet, Juan Manuel Chao de la Barca, Marc Ferré, Jeanne Muller, Anaïs Vautier, Sophie Assad, Odile Blanchet, Lydie Tessier, Céline Wetterwald, Justine Faure, Geoffrey Urbanski, Gilles Simard, Delphine Mirebeau-Prunier, Patrice Rodien, Philippe Gohier, and Pascal Reynier
Subjects: spermine, Graves’ ophthalmopathy, thyroid-associated orbitopathy, Medicine, ornithine decarboxylase, General Medicine, metabolomics, Article
Abstract: About half of patients with Graves’ disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves’ ophthalmopathy.
Published: 2021

27. Transcriptomic studies suggest a coincident role for apoptosis and pyroptosis but not for autophagic neuronal death in TBEV-infected human neuronal/glial cells

Author: Nadia Haddad, Jennifer Richardson, Odile Blanchet, Mazigh Fares, François Piumi, Kamila Gorna, Marielle Cochet-Bernoin, Muriel Coulpier, Noémie Berry, Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MRC - University of Glasgow Centre for Virus Research, Centre de Ressources Biologiques [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), PRES Université Nantes Angers Le Mans (UNAM), Biologie moléculaire et immunologie parasitaires et fongiques (BIPAR), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), INRAE, DIM MalInf, École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and École nationale vétérinaire d'Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé
Subjects: tick-borne encephalitis virus, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Central nervous system, Apoptosis, Biology, Microbiology, Encephalitis Viruses, Tick-Borne, TNF-Related Apoptosis-Inducing Ligand, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, flavivirus, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Virology, Pyroptosis, medicine, Humans, Progenitor cell, TNF family members, 030304 developmental biology, Neurons, MESH: Encephalitis Viruses, Tick-Borne, 0303 health sciences, Communication, Autophagy, regulated cell death, Human brain, biology.organism_classification, central nervous system, neuronal death, QR1-502, 3. Good health, Cell biology, Receptors, TNF-Related Apoptosis-Inducing Ligand, Flavivirus, Infectious Diseases, medicine.anatomical_structure, Astrocytes, pathological modeling, Neuroglia, 030217 neurology & neurosurgery
Abstract: International audience; Tick-borne encephalitis virus (TBEV), a member of the Flaviviridae family, Flavivirus genus, is responsible for neurological symptoms that may cause permanent disability or death. With an incidence on the rise, it is the major arbovirus affecting humans in Central/Northern Europe and North-Eastern Asia. Neuronal death is a critical feature of TBEV infection, yet little is known about the type of death and the molecular mechanisms involved. In this study, we used a recently established pathological model of TBEV infection based on human neuronal/glial cells differentiated from fetal neural progenitors and transcriptomic approaches to tackle this question. We confirmed the occurrence of apoptotic death in these cultures and further showed that genes involved in pyroptotic death were up-regulated, suggesting that this type of death also occurs in TBEV-infected human brain cells. On the contrary, no up-regulation of major autophagic genes was found. Furthermore, we demonstrated an up-regulation of a cluster of genes belonging to the extrinsic apoptotic pathway and revealed the cellular types expressing them. Our results suggest that neuronal death occurs by multiple mechanisms in TBEV-infected human neuronal/glial cells, thus providing a first insight into the molecular pathways that may be involved in neuronal death when the human brain is infected by TBEV.
Published: 2021

28. Clinical, biological, and molecular genetic features of Richter syndrome and prognostic significance: a study of the French Innovative Leukemia Organization

Author: Reiner Siebert, Anne Quinquenel, Romain Guieze, Catherine Thieblemont, Frederic Davi, Caroline Dartigeas, Sébastien Hergalant, Mathilde Hunault, Florence Cymbalista, Christof Schneider, Marie-Christine Béné, Cécile Tomowiak, Thomas Remen, Kamel Laribi, Damien Roos-Weil, Julien Broséus, Gregory Lazarian, Francis Guillemin, Odile Blanchet, Florian Bouclet, Elise Chapiro, Eugen Tausch, Stephan Stilgenbauer, Sandra Lomazzi, Florence Nguyen-Khac, Pierre Feugier, Charline Moulin, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre d'investigation clinique - Epidémiologie clinique [Nancy] (CIC-EC), Centre d'investigation clinique [Nancy] (CIC), Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Méthodologie Promotion Investigation [CHRU Nancy] (MPI), CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre Hospitalier Universitaire de Reims (CHU Reims), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Ulm - Ulm University [Ulm, Allemagne], Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Ressources Biologiques - [Nancy] (CRB Nancy), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hergalant, Sébastien, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Oncology, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.medical_specialty, Richter syndrome, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], 0303 health sciences, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Hematology, medicine.disease, Prognosis, Survival Analysis, 3. Good health, [STAT] Statistics [stat], [STAT]Statistics [stat], Leukemia, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Mutation, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, France, Lymphoma, Large B-Cell, Diffuse, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], business
Abstract: International audience
Published: 2021

29. Next generation sequencing redefines a triple negative essential thrombocythaemia as double‐positive with rare mutations on <scp>JAK</scp> 2 V617 and <scp>MPL</scp> W515 hotspots

Author: Corentin Orvain, Damien Luque Paz, Annaëlle Beucher, Anne Bouvier, Mathilde Hunault, Philippe Guardiola, Rébecca Jouanneau-Courville, Marie-Christine Rousselet, Irène Dobo, Valérie Ugo, Laurane Cottin, Odile Blanchet, and Mammoun Dib
Subjects: Genetics, business.industry, Double negative, Myeloproliferative disease, Hematology, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Rare mutations, Medicine, business, Triple negative, 030215 immunology
Published: 2019

30. The French glioblastoma biobank (FGB): a national clinicobiological database

Author: Jean-Michel Lemée, Anne Clavreul, Pierre Dubus, Chiara Villa, Gwenaelle Soulard, Philippe Menei, Anna Luisa Di Stefano, Odile BLANCHET, Francois Ducray, Pascale Fabbro-Peray, Karine Lacut, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Cancéropôle Grand Ouest, Ligue Contre le Cancer, 6298, Institut National Du Cancer, GSI IBiSA, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Neurosciences de Montpellier (INM), Aix Marseille Université (AMU), and Jonchère, Laurent
Subjects: Adult, Male, 0301 basic medicine, Standard of care, Databases, Factual, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, computer.software_genre, General Biochemistry, Genetics and Molecular Biology, Database, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Informed consent, Humans, Medicine, Primary Brain Tumors, Biological Specimen Banks, Biobank, Brain Neoplasms, Potential risk, business.industry, lcsh:R, Correction, Biological materials, General Medicine, Research needs, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Clinical data, Female, France, business, Glioblastoma, computer
Abstract: International audience; Background. Glioblastomas (GB) are the most common and lethal primary brain tumors. Significant progress has been made toward identifying potential risk factors for GB and diagnostic and prognostic biomarkers. However, the current standard of care for newly diagnosed GB, the Stupp protocol, has remained unchanged for over a decade. Large-scale translational programs based on a large clinicobiological database are required to improve our understanding of GB biology, potentially facilitating the development of personalized and specifically targeted therapies. With this goal in mind, a well-annotated clinicobiological database housing data and samples from GB patients has been set up in France: the French GB biobank (FGB).Methods. The biobank contains data and samples from adult GB patients from 24 centers in France providing written informed consent. Clinical and biomaterial data are stored in anonymized certified electronic case report forms. Biological samples (including frozen and formalin-fixed paraffin-embedded tumor tissues, blood samples, and hair) are conserved in certified biological resource centers or tumor tissue banks at each participating center.Results. Clinical data and biological materials have been collected for 1087 GB patients. A complete set of samples (tumor, blood and hair) is available for 66%, and at least one frozen tumor sample is available for 88% of the GB patients.ConclusionsThis large biobank is unique in Europe and can support the large-scale translational projects required to improve GB care. Additional biological materials, such as peritumoral brain zone and fecal samples, will be collected in the future, to respond to research needs.
Published: 2019

31. WT1 gene is overexpressed in myeloproliferative neoplasms, especially in myelofibrosis

Author: Anne Bouvier, Valérie Ugo, Anaïse Blouet, Alain Zannetti, Mathilde Hunault-Berger, Matgorzata Truchan-Graczyk, Jérémie Riou, Damien Luque Paz, Odile Blanchet, Laurane Cottin, Annaëlle Beucher, Corentin Orvain, Françoise Boyer, Rébecca Jouanneau-Courville, Bénédicte Ribourtout, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire d'Hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service des maladies du sang [CHU Angers], Hématologie clinique [CH Cholet], CH Cholet, Hématologie clinique [CH Saumur], Centre Hospitalier de Saumur - CH Saumur, UFR Santé [UNIV Angers], Université d'Angers (UA), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), This work is part of the French clinical and biological network of myeloproliferative neoplasms (FIMBANK) supported by a grant from the Institut National du Cancer (INCa BCB 2013)., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Adult, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Myelofibrosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, urologic and male genital diseases, Myeloproliferative neoplasms, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, hemic and lymphatic diseases, Gene expression, Humans, Medicine, RNA, Messenger, WT1 Proteins, Polycythemia Vera, Molecular Biology, Aged, Aged, 80 and over, Myeloproliferative Disorders, urogenital system, business.industry, Essential thrombocythemia, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Cell Biology, Hematology, Middle Aged, Allografts, medicine.disease, Minimal residual disease, female genital diseases and pregnancy complications, WT1, Transplantation, Leukemia, Myeloid, Acute, 030104 developmental biology, ROC Curve, Primary Myelofibrosis, Cancer research, Molecular Medicine, Stem cell, business, Thrombocythemia, Essential, 030215 immunology
Abstract: International audience; Classical Philadelphia-negative myeloproliferative neoplasms include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF). They are characterized by the presence of driver mutations of JAK2, CALR or MPL genes. Overexpression of WT1 is used as a marker of minimal residual disease in acute myeloid leukemia, especially after allogeneic stem cell transplantation (SCT). We investigated WT1 expression at diagnosis in 152 MPN patients and showed that the WT1 transcript was overexpressed in PMFs and PVs compared to controls. In particular, WT1 transcript levels were higher in PMF than in ET and PV. WT1 transcript levels were significantly increased during myelofibrotic transformation of ET or PV. Using multi-variate linear regression, high WT1 transcript levels in PMF were associated with age over 65, splenomegaly and thrombocytopenia. The ROC curve analysis showed that a level of WT1 transcript > 10 WT1 copies/10 4 ABL1 enabled the diagnosis of PMF with a specificity of 95.8% (PMF vs ET; ROC AUC = 0.91). In myelofibrosis, studying follow-ups of WT1 transcript showed that this marker is of interest after allogeneic SCT. These results demonstrate that WT1 overexpression is a simple marker of myelofibrosis in MPN and could be used during patient follow-up.
Published: 2019

32. Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial

Author: Norbert Ifrah, Hacene Zerazhi, Pierre-Yves Dumas, Norbert Vey, Isabelle Luquet, Denis Caillot, Marie-Christine Béné, Célestine Simand, Marie-Pierre Ledoux, Véronique Dorvaux, Yosr Hicheri, Anne Banos, Maria Pilar Gallego Hernanz, Chantal Himberlin, Odile Blanchet, Eric Delabesse, Catherine Humbrecht, Pascal Turlure, Arnaud Pigneux, Eric Jourdan, Jacques Delaunay, Didier Bouscary, Emmanuelle Tavernier, Christian Recher, Gaelle Guillerm, Mathilde Hunault-Berger, Romain Guieze, Martin Carre, Anne Bouvier, Jean-Pierre Marolleau, Claude Eric Bulabois, Pascale Cornillet-Lefebvre, Mario Ojeda-Uribe, Marc Bernard, Magda Alexis, Jean-François Hamel, Etienne Daguindau, Pierre Peterlin, Gabrielle Roth Guepin, Emmanuel Gyan, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital privé du Confluent [Nantes], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de Strasbourg Europe (ICANS), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire [Grenoble] (CHU), Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Reims (CHU Reims), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service des maladies du sang [Angers], CHU Pontchaillou [Rennes], Département d'Hématologie [CHU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier de la Côte Basque (CHCB), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional d'Orléans (CHRO), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Henri Duffaut (Avignon), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Ressources Biologiques [CHU Angers], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Oncology, Adult, Male, Risk, medicine.medical_specialty, NPM1, Adolescent, medicine.medical_treatment, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Phases of clinical research, Gene mutation, Disease-Free Survival, Cytogenetics, Young Adult, Internal medicine, hemic and lymphatic diseases, CEBPA, Medicine, Cluster Analysis, Humans, Chemotherapy, business.industry, Gene Expression Regulation, Leukemic, Gene Expression Profiling, Remission Induction, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, General Medicine, Middle Aged, Prognosis, Gemtuzumab, Transplantation, Leukemia, Myeloid, Acute, Karyotyping, Cytogenetic Analysis, Mutation, Female, business
Abstract: International audience; In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m(2) of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (
Published: 2021

33. Prognostic factors of metastatic neuroendocrine carcinoma under first-line treatment with platinum etoposide with a focus on NEC score and Rb expression: Results from the multicentre RBNEC study of the Groupe d'Etude des Tumeurs Endocrines (GTE) and the ENDOCAN-RENATEN network

Author: Matthieu Faron, Emmanuelle Leteurtre, S. Laboureau, Marie-Christine Rousselet, Christine Do Cao, Odile Blanchet, Igor Tauveron, Aude Marchal, Michel Ducreux, Arnaud Jannin, Valérie Hervieu, Guillaume Cadiot, Céline Gu, Eric Baudin, Caroline Petorin, Ségolène Hescot, Christina Kanaan, Juliette J. Zakeyh, Alice Durand, Julien Hadoux, Jean-Yves Scoazec, Thomas Walter, Vincent Hautefeuille, Denis Chatelain, and Clément Beaulaton
Subjects: 0301 basic medicine, Oncology, Thorax, Adult, Male, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Ubiquitin-Protein Ligases, Risk Assessment, Drug Administration Schedule, Carboplatin, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Biomarkers, Tumor, Humans, Neuroendocrine carcinoma, Stage (cooking), Etoposide, Aged, Retrospective Studies, Aged, 80 and over, Chemotherapy, business.industry, Not Otherwise Specified, Age Factors, Retrospective cohort study, Middle Aged, Prognosis, Immunohistochemistry, digestive system diseases, Progression-Free Survival, Carcinoma, Neuroendocrine, Retinoblastoma Binding Proteins, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Cisplatin, business, medicine.drug
Abstract: Neuroendocrine carcinomas (NECs) are aggressive malignant diseases. Platinum-etoposide (PE) combination is the standard first-line treatment, whatever the primary location. The NEC score and also retinoblastoma protein (Rb) status have been suggested to be predictive/prognostic factors in NEC. The primary objective of our multicentric retrospective study was to evaluate the prognostic relevance of the NEC score and Rb status, assessed by immunohistochemistry in PE-treated patients with metastatic NEC.Seven centres participated. The inclusion criteria were NEC, whatever the primary site, metastatic stage, first-line treatment with PE and tissue samples available. Rb status was determined centrally.We report multicentric data from 185 metastatic patients (37% women, median age 63). There were 108 small-cell NECs (SCNECs, 58.4%), 50 large-cell NECs (LCNECs, 27%) and 27 not otherwise specified NECs (nosNECs, 14.6%). The primary sites were the thorax (37%), gastroenteropancreatic sites (38%), unknown (15%) and other (9%). The mean Ki-67 index was 76% (range 20-100). Rb status was interpretable in 122 cases. Rb expression was lost in 74% of the cases: 84% of SCNEC vs. 60% and 63% of LCNEC and nosNEC, respectively (p = 0.016). Objective response was seen in 70% of SCNEC, 45% of LCNEC and 48% of nosNEC (p 0.001) and in 62% of Rb-negative tumours vs. 46% of Rb-positive tumours (p = 0.3). There was no difference in median progression-free survival or overall survival (OS) as per Rb status. Age, NEC score and response to chemotherapy were the main factors associated with OS in our cohort.In our series, Rb status had no prognostic impact in PE-treated metastatic patients with NEC, whereas age, NEC score and response to chemotherapy were the main factors associated with OS.
Published: 2021

34. A plasma metabolomic signature of Leber hereditary optic neuropathy showing taurine and nicotinamide deficiencies

Author: Victor Le Paih, Odile Blanchet, Patrizia Amati-Bonneau, Pascal Reynier, Guy Lenaers, Judith Kouassy Nzoughet, Juan Manuel Chao de la Barca, Dominique Bonneau, Daniela Géromin, Cinzia Bocca, Christophe Orssaud, Vincent Procaccio, Gilles Simard, Benoit Vedie, LENAERS, Guy, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: AcademicSubjects/SCI01140, Adult, Male, Niacinamide, Retinal Ganglion Cells, medicine.medical_specialty, Taurine, Adolescent, [SDV]Life Sciences [q-bio], Optic Atrophy, Hereditary, Leber, Mitochondrion, Biology, Retinal ganglion, DNA, Mitochondrial, Optic neuropathy, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Metabolomics, Internal medicine, Genetics, medicine, Choline, Humans, Molecular Biology, Genetics (clinical), 030304 developmental biology, Aged, 0303 health sciences, Electron Transport Complex I, Nicotinamide, General Medicine, Middle Aged, medicine.disease, Penetrance, Mitochondria, [SDV] Life Sciences [q-bio], Endocrinology, chemistry, Mutation, Metabolome, Female, General Article, 030217 neurology & neurosurgery
Abstract: Leber’s hereditary optic neuropathy (LHON) is the most common disorder due to mitochondrial DNA mutations and complex I deficiency. It is characterized by an acute vision loss, generally in young adults, with a higher penetrance in males. How complex I dysfunction induces the peculiar LHON clinical presentation remains an unanswered question. To gain an insight into this question, we carried out a non-targeted metabolomic investigation using the plasma of 18 LHON patients, during the chronic phase of the disease, comparing them to 18 healthy controls. A total of 500 metabolites were screened of which 156 were accurately detected. A supervised Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) highlighted a robust model for disease prediction with a Q2 (cum) of 55.5%, with a reliable performance during the permutation test (cross-validation analysis of variance, P-value = 5.02284e−05) and a good prediction of a test set (P = 0.05). This model highlighted 10 metabolites with variable importance in the projection (VIP) > 0.8. Univariate analyses revealed nine discriminating metabolites, six of which were the same as those found in the Orthogonal Projections to Latent Structures Discriminant Analysis model. In total, the 13 discriminating metabolites identified underlining dietary metabolites (nicotinamide, taurine, choline, 1-methylhistidine and hippurate), mitochondrial energetic substrates (acetoacetate, glutamate and fumarate) and purine metabolism (inosine). The decreased concentration of taurine and nicotinamide (vitamin B3) suggest interesting therapeutic targets, given their neuroprotective roles that have already been demonstrated for retinal ganglion cells. Our results show a reliable predictive metabolomic signature in the plasma of LHON patients and highlighted taurine and nicotinamide deficiencies.
Published: 2021

35. A placebo-controlled double blind trial of hydroxychloroquine in mild-to-moderate COVID-19

Author: Bruno Vielle, Olivier Robineau, Patrick Rispal, Caroline Lefeuvre, Sophie Boucher, Pierre-Marie Roy, Chadi Abbara, Sylvain Diamantis, Vincent Dubée, Astrid Darsonval, Emma d’Anglejean, Elsa Parot-Schinkel, Odile Blanchet, Isabelle Pellier, Marc-Antoine Custaud, Edouard Devaud, Thomas Guimard, and Alain Mercat
Subjects: medicine.medical_specialty, education.field_of_study, Randomization, business.industry, medicine.medical_treatment, Population, Hydroxychloroquine, medicine.disease, Placebo, Comorbidity, Internal medicine, Relative risk, Oxygen therapy, medicine, Clinical endpoint, education, business, medicine.drug
Abstract: BackgroundThe efficacy of hydroxychloroquine in coronavirus disease 2019 (COVID-19) remains controversial.MethodsWe conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: age ≥75 years, age between 60 and 74 years, and presence of at least one comorbidity, or need for supplemental oxygen (≤3 L/min). Eligible patients were randomized in a 1:1 ratio to receive either 800mg hydroxychloroquine on Day 0 followed by 400mg per day for 8 days or a placebo. The primary endpoint was a composite of death or tracheal intubation within 14 days following randomization. Secondary endpoints included mortality and clinical evolution at Day 14 and 28, viral shedding at Day 5 and 10.ResultsThe trial was stopped after 250 patients were included due to a slowdown of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years and 151 patients required oxygen therapy. The primary endpoint occurred in nine patients in the hydroxychloroquine group and eight patients in the placebo group (relative risk 1.12; 95% confidence interval 0.45– 2.80; P=0.82). No difference was observed between the two groups in any of the secondary endpoints.ConclusionIn this trial involving mainly older patients with mild-to-moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo.
Published: 2020

36. Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation

Author: Cedric Pastoret, Yves Delneste, Sylvain Thepot, Marie-Christine Rousselet, Damien Luque Paz, Jean-Marie Chrétien, Maxime Renard, Jean-Christophe Ianotto, Odile Blanchet, Mathilde Hunault-Berger, Jean-Claude Chomel, Anne Murati, Norbert Ifrah, Maria-Pilar Gallego-Hernanz, Isabelle Quintin-Roué, Laurane Cottin, Aurélie Chauveau, Jérémie Riou, Frédéric Courtier, Françoise Boyer, Corentin Orvain, Valérie Ugo, Emilie Cayssials, Rébecca Jouanneau-Courville, Eric Lippert, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire d'hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie clinique [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service des maladies du sang [CHU Angers], Laboratoire d'hématologie (Labo Hémato - BREST), Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), Université de Brest (UBO), Service de Cancérologie Biologique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d’Oncologie Hématologique et Thérapie Cellulaire [CHU Poitiers], Laboratoire d'Hematologie [CHU Pontchaillou, Rennes] (Pôle de Biologie), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Laboratoire d'Hématologie et Laboratoire d'Oncologie Moléculaire, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département de Pathologie Cellulaire et Tissulaire, Cellule de Gestion des Données et Evaluation (DRCI), Centre de Ressources Biologiques [CHU Angers], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], and Bernardo, Elizabeth
Subjects: Neuroblastoma RAS viral oncogene homolog, IDH1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Myeloproliferative Disorders, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Allele, Polycythemia Vera, Gene, 030304 developmental biology, 0303 health sciences, Mutation, Myeloid Neoplasia, Essential thrombocythemia, Genomics, Hematology, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Cancer research, Erratum, Thrombocythemia, Essential
Abstract: Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.
Published: 2020

37. Correction to: The French glioblastoma biobank (FGB): a national clinicobiological database

Author: Jean-Michel Lemée, Pierre Dubus, Bijan Ghaleh, Chiara Villa, Gwenaelle Soulard, Philippe Menei, Anna Luisa Di Stefano, Odile BLANCHET, Pascale Fabbro-Peray, and Karine Lacut
Subjects: Oncology, medicine.medical_specialty, business.industry, Research, lcsh:R, MEDLINE, Biological materials, lcsh:Medicine, General Medicine, medicine.disease, Biobank, General Biochemistry, Genetics and Molecular Biology, Database, Internal medicine, medicine, Clinical data, Glioblastoma, business
Abstract: Background Glioblastomas (GB) are the most common and lethal primary brain tumors. Significant progress has been made toward identifying potential risk factors for GB and diagnostic and prognostic biomarkers. However, the current standard of care for newly diagnosed GB, the Stupp protocol, has remained unchanged for over a decade. Large-scale translational programs based on a large clinicobiological database are required to improve our understanding of GB biology, potentially facilitating the development of personalized and specifically targeted therapies. With this goal in mind, a well-annotated clinicobiological database housing data and samples from GB patients has been set up in France: the French GB biobank (FGB). Methods The biobank contains data and samples from adult GB patients from 24 centers in France providing written informed consent. Clinical and biomaterial data are stored in anonymized certified electronic case report forms. Biological samples (including frozen and formalin-fixed paraffin-embedded tumor tissues, blood samples, and hair) are conserved in certified biological resource centers or tumor tissue banks at each participating center. Results Clinical data and biological materials have been collected for 1087 GB patients. A complete set of samples (tumor, blood and hair) is available for 66%, and at least one frozen tumor sample is available for 88% of the GB patients. Conclusions This large biobank is unique in Europe and can support the large-scale translational projects required to improve GB care. Additional biological materials, such as peritumoral brain zone and fecal samples, will be collected in the future, to respond to research needs.
Published: 2020

38. A Plasma Metabolomic Profiling of Exudative Age-Related Macular Degeneration Showing Carnosine and Mitochondrial Deficiencies

Author: Delphine Mirebeau-Prunier, Vincent Procaccio, Stéphanie Leruez, Adrien Buisset, Jeanne Muller, Lydie Tessier, Guy Lenaers, Dan Milea, Odile Blanchet, Pascal Reynier, Marc Ferré, Juan Manuel Chao de la Barca, Gilles Simard, Laurie Moureauzeau, Stéphanie Chupin, Thibaut Macé, Philippe Gohier, Barnabé Rondet-Courbis, Guillaume Plubeau, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Stress Oxydant et Pathologies Métaboliques (SOPAM), Rigshospitalet [Copenhagen], and Copenhagen University Hospital
Subjects: medicine.medical_specialty, genetic structures, [SDV]Life Sciences [q-bio], lcsh:Medicine, Carnosine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Mitochondrion, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Metabolomics, Valine, Internal medicine, Lipidomics, medicine, Carnitine, Proline, age-related macular degeneration, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, metabolomics, 2. Zero hunger, 0303 health sciences, business.industry, [SDV.BA]Life Sciences [q-bio]/Animal biology, lcsh:R, General Medicine, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Macular degeneration, medicine.disease, eye diseases, 3. Good health, Endocrinology, chemistry, 030221 ophthalmology & optometry, lipidomics, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, medicine.drug
Abstract: To determine the plasma metabolomic profile of exudative age-related macular degeneration (AMD), we performed a targeted metabolomics study on the plasma from patients (n = 40, mean age = 81.1) compared to an age- and sex-matched control group (n = 40, mean age = 81.8). All included patients had documented exudative AMD, causing significant visual loss (mean logMAR visual acuity = 0.63), compared to the control group. Patients and controls did not differ in terms of body mass index and co-morbidities. Among the 188 metabolites analyzed, 150 (79.8%) were accurately measured. The concentrations of 18 metabolites were significantly modified in the AMD group, but only six of them remained significantly different after Benjamini&ndash, Hochberg correction. Valine, lysine, carnitine, valerylcarnitine and proline were increased, while carnosine, a dipeptide disclosing anti-oxidant and anti-glycating properties, was, on average, reduced by 50% in AMD compared to controls. Moreover, carnosine was undetectable for 49% of AMD patients compared to 18% in the control group (p-value = 0.0035). Carnitine is involved in the transfer of fatty acids within the mitochondria, proline, lysine and valerylcarnitine are substrates for mitochondrial electrons transferring flavoproteins, and proline is one of the main metabolites supplying energy to the retina. Overall, our results reveal six new metabolites involved in the plasma metabolomic profile of exudative AMD, suggesting mitochondrial energetic impairments and carnosine deficiency.
Published: 2020

39. Hydroxychloroquine in mild-to-moderate coronavirus disease 2019: a placebo-controlled double blind trial

Author: Vincent Dubée, Pierre-Marie Roy, Bruno Vielle, Elsa Parot-Schinkel, Odile Blanchet, Astrid Darsonval, Caroline Lefeuvre, Chadi Abbara, Sophie Boucher, Edouard Devaud, Olivier Robineau, Patrick Rispal, Thomas Guimard, Emma d’Anglejean, Sylvain Diamantis, Marc-Antoine Custaud, Isabelle Pellier, Alain Mercat, Antoine Brangier, Philippe Codron, Jean Michel Lemée, Virginie Pichon, Robin Dhersin, Geoffrey Urbanski, Christian Lavigne, Roxane Courtois, Hélène Danielou, Jonathan Lebreton, Rémi Vatan, Nicolas Crochette, Jean-Baptiste Lainé, Lucia Perez, Sophie Blanchi, Hikombo Hitoto, Louis Bernard, François Maillot, Sylvain Marchand Adam, Jean-Philippe Talarmin, Emeline Gaigneux, Pauline Motte-Vincent, Marine Morrier, Dominique Merrien, Yves Bleher, Maxime Flori, Amélie Ducet-Boiffard, Orane Colin, Ronan Février, Pauline Thill, Macha Tetart, François Demaeght, Barthelemy Lafond-Desmurs, Maxime Pradier, Agnes Meybeck, Marjorie Picaud, Thierry Prazuck, Guillaume Chapelet, Agnès Rouaud, Paul Le Turnier, Simon Sunder, Aurélien Lorleac'h, Christophe Dollon, Antoine Jacquet, Francois Le Vely, Pierre Gazeau, Séverine Ansart, Hélène Roger, François Laterza, Rodolphe Buzelé, Fella Tahmi, Raphael Lepeule, Karine Lacombe, Bénédicte Lefebvre, Thomas Célarier, Amandine Gagneux-Brunon, Elisabeth Botelho-Nevers, Marc Bernard, Camille Garnier, Morgane Mourguet, Gregory Pugnet, Sara Vienne-Noyes, Guillaume Martin-Blondel, Pierre Delobel, Gaspard Grouteau, Alexa Debard, Laurent Guilleminault, Pauline Arias, Catherine Chakvetadze, Clara Flateau, Aude Kopp, Alain Putot, Jeremy Barben, Suzanne Mouries Martin, Valentine Nuss, Lionel Piroth, Yann-Erick Claessens, Veronique Hentgen, Martin Martinot, Maxime Bach-Bunner, Thomas Bonijoly, Simon Gravier, Jean-Marc Michel, Mathilde Andreu, Mélanie Roriz, Aurélie Baldolli, Julia Brochard, Olivier Grossi, Samuel Pineau, Josselin Brisset, Edouard Desvaux, Guillaume Gondran, Jean-François Faucher, Paul-Antoine Quesnel, Holy Bezanahary, Clément Danthu, Blandine Gutierrez, Kim Ly, Yannick Simonneau, Anne Cypierre, Pauline Pinet, Hélène Durox, Sophie Ducroix-Roubertou, Claire Genet, Guillaume Beraud, Gwenael Le Moal, Blandine Rammaert, Jean-Philippe Lanoix, Claire Andrejak, Cédric Joseph, Sandrine Soriot-Thomas, Robin Dhote, Sébastien Abad, Ruben Benainous, Jean-François Boitiaux, Guillaume Briend, Celine Gonfroy, Stanislas Harent, Aurore Lagrange, Alina Tone, Laura Wayenberg, Sophie Desoutter, Nicolas Ettahar, Thomas Gey, Vincent Leroy, Sacha Gaillard, Andrea Toma, Amaury Broussier, Sandrine Etienne, Yann Spivac, Benoit Martha, Nathalie Roch, Pierre Diaz, Danièle N’guyen Baranoff, Stanislas Rebaudet, François Jourda, Valérie Zeller, Boris Bienvenu, Arnaud Boyer, Marie Briet, Bertrand Guidet, Patrick Mismetti, Eric Vicaut, Olivier Sanchez, Philippe Girard, Antoine Elias, Francis Couturaud, Béatrice Gable, Sybille Lazareff, Loïc Carballido, Catherine Hue, Jean-Marie Chrétien, Adrien Goraguer, Lucie van Eeckhoutte, ATOMycA (CRCINA-ÉQUIPE 6), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pharmacie [CHU d'Angers], Laboratoire de virologie [CHU Angers], Département de Pharmacologie-Toxicologie [CHU Angers], Centre Hospitalier René Dubos [Pontoise], Centre Hospitalier Tourcoing, Service de Médecine Interne [Agen], Centre Hospitalier d'Agen, Centre Hospitalier Départemental Vendée (CHDV), Centre Hospitalier de Versailles André Mignot (CHV), Groupe Hospitalier Sud, Université d'Angers (UA), HYCOVID study group, HYCOVID investigators, Angers University Hospital, Cholet Hospital, Laval Hospital, Le Mans Hospital, Tours University Hospital, Quimper Hospital, La Roche sur Yon Hospital, Tourcoing Hospital, Orléans Hospital, Nantes University Hospital, Niort Hospital, Lorient Hospital, Brest University Hospital, Cherbourg Hospital, Saint-Brieuc Hospital, Créteil – APHP University Hospital, Saint-Antoine – APHP University Hospital, Saint-Etienne University Hospital, Toulouse University Hospital, Melun Hospital, Dijon University Hospital, Princesse Grace – Monaco Hospital, Versailles Hospital, Colmar Hospital, Agen-Nerac Hospital, Caen University Hospital, Saint-Nazaire Hospital, Nantes – Confluent Hospital, Limoges University Hospital, Poitiers University Hospital, Amiens University Hospital, Bobigny – APHP University Hospital, Cergy-Pontoise Hospital, Valencienne Hospital, Valencienne – Clinique Tessier Hospital, Henri-Mondor – APHP University Hospital, Chalon-sur-Saône Hospital, Marseille European Hospital, Auxerre Hospital, Diaconnesses Croix-Saint-Simon Hospital, Marseille – Saint Joseph Hospital, Composition of the HYCOVID management team, Steering committee, Independant data safety and monitoring board, Independent adjudication of clinical events committee, Study management Coordination, Data management., Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service des maladies infectieuses et tropicales [CHU Angers], and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Placebo, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, [SDV.CAN] Life Sciences [q-bio]/Cancer, law, Interquartile range, Intensive care, Internal medicine, medicine, Clinical endpoint, 030212 general & internal medicine, education, Severe acute respiratory syndrome coronavirus 2, education.field_of_study, Coronavirus disease 2019, business.industry, Hydroxychloroquine, General Medicine, Placebo-controlled, 3. Good health, Infectious Diseases, Relative risk, business, medicine.drug
Abstract: Objectives To determine whether hydroxychloroquine decreases the risk of adverse outcome in patients with mild to moderate coronavirus disease 2019 (COVID-19) at high risk of worsening. Methods We conducted a multicentre randomized double-blind placebo-controlled trial evaluating hydroxychloroquine in COVID-19 patients with at least one of the following risk factors for worsening: need for supplemental oxygen, age ≥75 years, age between 60 and 74 years and presence of at least one co-morbidity. Severely ill patients requiring oxygen therapy >3 L/min or intensive care were excluded. Eligible patients were randomized in a 1:1 ratio to receive either 800 mg hydroxychloroquine on day 0 followed by 400 mg per day for 8 days or a placebo. The primary end point was a composite of death or start of invasive mechanical ventilation within 14 days following randomization. Secondary end points included mortality and clinical evolution at days 14 and 28, and viral shedding at days 5 and 10. Results The trial was stopped after 250 patients were included because of a slowing down of the pandemic in France. The intention-to-treat population comprised 123 and 124 patients in the placebo and hydroxychloroquine groups, respectively. The median age was 77 years (interquartile range 58–86 years) and 151/250 (60.4%) patients required oxygen therapy. The primary end point occurred in 9/124 (7.3%) patients in the hydroxychloroquine group and 8/123 (6.5%) patients in the placebo group (relative risk 1.12; 95% CI 0.45–2.80). The rates of positive SARS-CoV-2 RT-PCR tests at days 5 and 10 were 72.8% (75/103) and 57.1% (52/91) in the hydroxychloroquine group, versus 73.0% (73/100) and 56.6% (47/83) in the placebo group, respectively. No difference was observed between the two groups in any of the other secondary end points. Conclusion In this underpowered trial involving mainly older patients with mild to moderate COVID-19, patients treated with hydroxychloroquine did not experience better clinical or virological outcomes than those receiving the placebo. Trial registration ClinicalTrials.gov Identifier: NCT04325893 ( https://clinicaltrials.gov/ct2/show/NCT04325893 ).
Published: 2020

40. Donor cell-derived acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplantation

Author: Sylvie François, Aline Schmidt, Mathilde Hunault-Berger, Odile Blanchet, Valérie Ugo, Anne Bouvier, Philippe Guardiola, Corentin Orvain, Annaëlle Beucher, Damien Luque Paz, Alexandre. Guérard, Franck Geneviève, Bénédicte Ribourtout, Bernardo, Elizabeth, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'hématologie (Labo Hémato - ANGERS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), Service des maladies du sang [CHU Angers], UFR Santé [UNIV Angers], Université d'Angers (UA), Service de Génomique Onco-Hématologique [CHU Angers], Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), We also thank the 'Ligue contre le cancer' for their support of research on acute myeloid leukemia at Angers Hospital., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Adult, Male, Acute promyelocytic leukemia, Donor cell, Transplantation Conditioning, Biopsy, bone marrow transplantation, medicine.medical_treatment, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematopoietic stem cell transplantation, acute myeloid leukemia, Donor lymphocyte infusion, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Leukemia, Promyelocytic, Acute, [SDV.CAN] Life Sciences [q-bio]/Cancer, Bone Marrow, medicine, Humans, Transplantation, Homologous, business.industry, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, General Medicine, Middle Aged, medicine.disease, Tissue Donors, 3. Good health, 030220 oncology & carcinogenesis, Immunology, Female, Complication, business, Biomarkers, 030215 immunology
Abstract: International audience; Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell-derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long-term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI.
Published: 2018

41. Quantitative chimerism in CD3-negative mononuclear cells predicts prognosis in acute myeloid leukemia patients after hematopoietic stem cell transplantation

Author: Sylvie François, Mathilde Hunault-Berger, Bénédicte Ribourtout, Yves Delneste, Alban Villate, Laurane Cottin, Sylvain Thepot, Aurélien Sutra Del Galy, Damien Luque Paz, Odile Blanchet, Marie-Hélène Estienne, Valérie Ugo, Jérémie Riou, Corentin Orvain, Norbert Ifrah, Aline Schmidt, Anne Bouvier, Annaëlle Beucher, Laboratoire d'Hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Innate immunity and Immunotherapy (CRCINA - Département INCIT - Equipe 7), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service des maladies du sang [Angers], PRES Université Nantes Angers Le Mans (UNAM), Department of Hematology, CHU, Angers, Laboratoire d'hématologie (Labo Hémato - BREST), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'hématologie, Centre de Recherche sur le Cancer Nantes-Angers (LUNAM), Université d'Angers (UA)-Université de Nantes (UN), Hematology Department, Université d'Angers (UA), Laboratoire d'hématologie (Labo Hémato - ANGERS), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, Neoplasm, Residual, CD3 Complex, medicine.medical_treatment, Cell, Hematopoietic stem cell transplantation, Disease, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, Major complication, ComputingMilieux_MISCELLANEOUS, biology, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, Middle Aged, Prognosis, 3. Good health, Survival Rate, [STAT]Statistics [stat], Leukemia, Myeloid, Acute, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Female, Adult, medicine.medical_specialty, Adolescent, CD3, Chimerism, Peripheral blood mononuclear cell, Young Adult, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, Humans, Transplantation, Homologous, WT1 Proteins, Aged, Retrospective Studies, business.industry, 030104 developmental biology, biology.protein, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract: Relapse is a major complication of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (SCT). The objective of our study was to evaluate chimerism monitoring on the CD3-negative mononuclear cells by RQ-PCR to predict relapse of patients allografted for AML and to compare its performance with WT1 quantification. A cohort of 100 patients undergoing allogenic SCT for AML was retrospectively analyzed in a single institution. Patients without complete chimerism, defined as less than 0.01% of recipient’s DNA in CD3-negative cells, had a significantly higher risk of relapse and a lower overall survival (p
Published: 2019

42. Pathological modeling of TBEV infection reveals differential innate immune responses in human neurons and astrocytes that correlate with their susceptibility to infection

Author: Muriel Coulpier, Claudia N. Montero-Menei, Mazigh Fares, Marielle Cochet-Bernoin, Jennifer Richardson, Nadia Haddad, Sylvie Lecollinet, Claire Boissart, Gaelle Gonzalez, Alexandra Benchoua, Odile Blanchet, MRC - University of Glasgow Centre for Virus Research, Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Biologie moléculaire et immunologie parasitaires et fongiques (BIPAR), École nationale vétérinaire d'Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), French National Institute for Agriculture, Food and the Environment (INRAE) DIM MalInf (Ile de France) Paris Institute of Technology for Life, Food, and Environmental Sciences (AgroParisTech), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), and École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé
Subjects: Cell type, Human neuronal/glial cells, Cell Culture Techniques, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC346-429, Encephalitis Viruses, Tick-Borne, Neurotropic virus, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Viral tropism, lcsh:Neurology. Diseases of the nervous system, Cells, Cultured, Tropism, 030304 developmental biology, Neurons, Innate immunity, 0303 health sciences, Innate immune system, biology, Research, Flavivirus, Human brain, biology.organism_classification, medicine.disease, Immunity, Innate, Neural stem cell, 3. Good health, Astrogliosis, Viral Tropism, medicine.anatomical_structure, Central nervous system, Astrocytes, Neuropathogenesis, Pathological modeling, Tick-borne encephalitis virus, Disease Susceptibility, Neuroscience, Encephalitis, Tick-Borne, 030217 neurology & neurosurgery
Abstract: Tick-borne encephalitis virus (TBEV) is a member of theFlaviviridaefamily,Flavivirusgenus, which includes several important human pathogens. It is responsible for neurological symptoms that may cause permanent disability or death, and, from a medical point of view, is the major arbovirus in Central/Northern Europe and North-eastern Asia. TBEV tropism is critical for neuropathogenesis, yet, little is known about the molecular mechanisms that govern the susceptibility of human brain cells to the virus. In this study, we sought to establish and characterize a newin vitromodel of TBEV infection in the human brain and to decipher cell type-specific innate immunity and its relation to TBEV tropism and neuropathogenesis. We showed that infection of neuronal/glial cultures derived from human fetal neural progenitor cells (hNPCs) mimicked three major hallmarks of TBEV infection in the human brain, namely, preferential neuronal tropism, neuronal death and astrogliosis. We also showed that these cells had conserved their capacity to build an antiviral response against TBEV. TBEV-infected neuronal/glial cells, therefore, represented a highly relevant pathological model. By enriching the cultures in either human neurons or astrocytes, we further demonstrated qualitative and quantitative differential innate immune responses in the two cell types that correlated with their particular susceptibility to TBEV. Our results thus reveal that cell type-specific innate immunity is likely to contribute to shaping TBEV tropism for human brain cells. They offer a newin vitromodel to further study TBEV-induced neuropathogenesis and improve our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells.Author summaryTick-borne encephalitis virus (TBEV), a neurotropicFlavivirusthat is responsible for encephalitis in humans, is of growing concern in Europe. Indeed, over the last two decades the number of reported cases has continuously increased and the virus has spread into new geographical areas. Whereas it is well established that neurons are the main target of TBEV in the human brain, the mechanisms that underlie this preferential tropism have not yet been elucidated. Here, we used neuronal/glial cells derived from human fetal neural progenitors to establish and characterize a newin vitropathological model that mimics major hallmarks of TBEV infectionin vivo; namely, neuronal tropism, neuronal death and astrogliosis. Using this highly relevant model, we showed that human neurons and astrocytes were both capable of developing an innate immune response against TBEV, but with dissimilar magnitudes that correlated with differential susceptibility to TBEV. Our results thus revealed that TBEV tropism for subsets of human brain cells is likely to depend on cell-type specific innate immunity. This improves our understanding of the mechanisms by which neurotropic viruses target and damage human brain cells and may help guide development of future therapies.
Published: 2019

43. No detection of atypical one-base deletion of CALR exon 9 with fragment analysis: A molecular trap to avoid

Author: Laurane Cottin, Odile Blanchet, Mathilde Hunault-Berger, Maxime Renard, Anne Bouvier, Aurelien Giltat, Damien Luque Paz, Corentin Orvain, Sandrine Lemoine, Valérie Ugo, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service des maladies du sang, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Fragment (computer graphics), business.industry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Computational biology, 030204 cardiovascular system & hematology, Trap (computing), 03 medical and health sciences, Exon, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, Molecular Medicine, Medicine, Base (exponentiation), No detection, business, Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

44. La ligne rose

Author: Odile Blanchet, Bérénice Boccara, Sana Puis, Odile Blanchet, Bérénice Boccara, and Sana Puis
Subjects: Nineteen twenties--Drama, Telephone operators--Drama
Abstract: Paris. Les Années folles. Trois opératrices de téléphone.Marthe se voit déjà vieille fille. Denise joue les oiseaux de nuit. Jeanne démarre une nouvelle vie. La rencontre des trois demoiselles fait des étincelles lorsqu'elles se mettent à créer un service inédit : donner du plaisir aux hommes, par le simple son de leurs voix. Leur entreprise florissante se retrouve au cœur de toutes les convoitises : un gangster opportuniste, des collègues trop curieuses, une police des mœurs sur le qui-vive... Les pièges seront multiples, mais à cœur vaillant rien d'impossible!
Published: 2021

45. Sequential mutational evaluation of CALR ‐mutated myeloproliferative neoplasms with thrombocytosis reveals an association between CALR allele burden evolution and disease progression

Author: Jean-Marie Chrétien, Odile Blanchet, Sophie Sadot-Lebouvier, Yves Delneste, Isabelle Quintin-Roué, Corentin Orvain, Olivier Mansier, Françoise Boyer, Barbara Burroni, Mathilde Hunault-Berger, Matgorzata Truchan-Graczyk, Damien Luque Paz, Maxime Renard, Marie-Christine Rousselet, Anne Murati, Jérémie Riou, Olivier Allangba, Laurane Cottin, Rébecca Jouanneau-Courville, Antoine Martin, Jean Christophe Ianotto, Valérie Ugo, Eric Lippert, Boullé, Christelle, Laboratoire d'hématologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service des maladies du sang [Angers], Département d'Hématologie Clinique (BREST - Hémato Clinique), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service des maladies du sang, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Université de Bordeaux (UB), Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [AP-HP Hôpital Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Pathologie Cellulaire et Tissulaire [Angers] (Laboratoire d’Histopathologie-Cytopathologie), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), Biochimie et Physiologie Moléculaire des Plantes (BPMP), Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematopoïèse et Cellules Souches (U362), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie Biologique, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), CHU Cochin [AP-HP], Université de Montpellier (UM)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche sur le Cancer Nantes-Angers (LUNAM), Université d'Angers (UA)-Université de Nantes (UN), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: Oncology, Adult, Male, allele burden, medicine.medical_specialty, Myeloid, Adolescent, myeloproliferative neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, In patient, Allele, Myelofibrosis, CALR, Alleles, Aged, Aged, 80 and over, Thrombocytosis, Myeloproliferative Disorders, business.industry, Disease progression, High-Throughput Nucleotide Sequencing, Hematology, Middle Aged, medicine.disease, Prognosis, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Mutation, Disease Progression, Female, next-generation sequencing, Bone marrow, business, Calreticulin, 030215 immunology
Abstract: International audience; In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring.
Published: 2019

46. Circulating PCSK9 levels are not associated with the severity of hepatic steatosis and NASH in a high-risk population

Author: Bertrand Cariou, Odile Blanchet, Matthieu Wargny, Sarra Smati, L. Arnaud, Matthieu Pichelin, Benjamin Bouillet, Luc Van Gaal, Sven Francque, Philippe Lefebvre, Jean-Michel Petit, Jérôme Boursier, Pierre-Henri Ducluzeau, Cédric Le May, Bart Staels, Adrien Lannes, Bruno Vergès, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Endocrinologie (CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Département d'hépatologie (CHU Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Gastroenterology and Hepatology (Antwerp University Hospital), Antwerp University Hospital [Edegem] (UZA), Department of Endocrinology, Diabetology and Metabolism (Antwerp University Hospital), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), LUNAM Université, F-49933 Angers, France, Plateforme PACeM (Plateforme d'Analyse Cellulaire et Moléculaire), SFR ICAT4208, F-49933 Angers, France., PACeM Angers, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Unité de recherche de l'institut du thorax (ITX-lab), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme d'Analyse Cellulaire et Moléculaire [SFR ICAT - UA] (PACEM), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA)-Université d'Angers (UA), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Male, Biopsy, Liver steatosis, Type 2 diabetes, 030204 cardiovascular system & hematology, Gastroenterology, Severity of Illness Index, PCSK9, 0302 clinical medicine, Fibrosis, Non-alcoholic Fatty Liver Disease, LDL-cholesterol, ComputingMilieux_MISCELLANEOUS, education.field_of_study, medicine.diagnostic_test, Middle Aged, Liver biopsy, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Magnetic Resonance Imaging, 3. Good health, Liver, Female, France, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, MRI, Adult, Risk, medicine.medical_specialty, Population, Liver fibrosis, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, education, Aged, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Hepatology, medicine.disease, Fatty Liver, 030104 developmental biology, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Linear Models, Human medicine, Steatosis, Steatohepatitis, business
Abstract: Background and aims: Some studies suggested that proprotein convertase subtilisin kexin type 9 (PCSK9) is linked to liver steatosis severity and non-alcoholic steatohepatitis (NASH). We aimed to assess whether circulating PCSK9 levels are associated with either liver fat content (LFC) or histological markers of NASH in high-risk patients. Methods: We present results from three cross-sectional studies from two French Hospitals: Dijon and Numevox (departments of Endocrinology) and Angers (department of Hepatology). Only patients without lipid-lowering therapy were included. All 132 patients had type 2 diabetes in Dijon, compared to 55/224 in Numevox (25%) and 39/122 in Angers (32%). LFC was assessed on MRI (Dijon and Numevox), and NASH lesion on liver biopsy (Angers). Additionally, we included mRNA results from 138 overweight patients of a Belgian Hospital (Antwerp). Results: While circulating levels of PCSK9 were positively correlated with total cholesterol, LDL-C, triglycerides and non-HDL-C in all 3 cohorts, no significant association was found between PCSK9 and transaminases. Furthermore, no association was found between plasma PCSK9 levels and LFC in both Numevox (beta(adjusted) = 0.71 +/- 1.33, p = 0.60) and Dijon (beta(adjusted) = 1.03 +/- 0.90, p = 0.25). There was no correlation between circulating PCSK9 and histological liver lesions: steatosis severity (beta(adjusted) = -3.95 +/- 2.75, p = 0.15), NASH activity score (beta(adjusted) = -0.31 +/- 0.17, p = 0.082), lobular (beta = -0.067 +/- 0.055, p = 0.22) or portal inflammation (beta = -0.088 +/- 0.079, p = 0.27), ballooning (beta = -0.025 +/- 0.065, p = 0.70) and fibrosis (beta = -0.17 +/- 0.11, p = 0.12). Finally, hepatic PCSK9 mRNA levels were not correlated with NASH histological severity. Conclusions: Circulating PCSK9 concentrations are not associated with the severity of liver steatosis or histological markers of NASH. These data are reassuring regarding the clinical use of PCSK9 inhibitors in cardiovascular diseases.
Published: 2018

47. Tear Metabogren : identification d’une signature métabolique lacrymale prédictive du syndrome de Sjögren primaire

Author: Odile Blanchet, Pascal Reynier, G. Urbanski, S. Assad, J.M. Chao de la Barca, Gilles Simard, Christian Lavigne, Floris Chabrun, and Philippe Gohier
Subjects: Gastroenterology, Internal Medicine
Abstract: Introduction Le diagnostic de syndrome de Sjogren primaire (pSS) repose sur des criteres de classification comprenant des tests fonctionnels temoignant d’une atteinte lacrymale evoluee. Or, limiter la destruction des glandes lacrymales est un enjeu majeur pour reduire la morbidite du pSS. Ainsi l’identification de metabolites lacrymaux precocement perturbes pourrait servir de biomarqueur diagnostique. Quelques etudes ont pu identifier de potentiels biomarqueurs du syndrome sec oculaire mais aucune n’etait specifique du pSS. Les objectifs de cette etude etaient de rechercher une signature metabolomique des larmes chez des patients presentant un pSS nouvellement diagnostique, en comparaison a des patients presentant un syndrome sec oculaire non lie au pSS, et d’evaluer les variations de cette signature metabolomique selon la severite du syndrome sec oculaire. Patients et methodes Nous avons compare les compositions en metabolites des larmes de 40 patients pSS a 40 patients controles presentant un syndrome sec, par une approche metabolomique ciblee (Kit Biocrates® AbsoluteIDQ p180) selon une technique couplant chromatographie en phase liquide et spectrometre de masse (HPLC-MS/MS). Les larmes etaient recueillies sur bandelettes de test de Schirmer. Le plan d’analyse statistique comportait une etape de selection de variables par regression logistique avec regularisation de type elastic-net, puis une grid search comparant regression logistique et random forest. L’association de la signature metabolomique et du statut pSS etait ensuite analysee selon la severite du syndrome sec mesuree par le test de Schirmer, l’Ocular staining score (OSS) et la presence d’une dysfonction meibomienne. Les analyses statistiques ont ete menees avec les logiciels R software et SPSS. Le projet TEAR METABOGREN a fait l’objet d’un soutien financier de la part de l’association francaise du syndrome de Gougerot-Sjogren (AFGS) et de la SNFMI. Resultats Parmi les 188 metabolites testes, nous avons mis en evidence une signature metabolomique composee de 9 metabolites : Serine, Asparagine, Phosphatidylcholine diacyl (PCaa) C42 :4, lysophosphatidylcholines (LysoPC) C18 :1, C18 :2, C16 :1 et Sphingomyelines (SM) C16 :0 et C22 :3. Les capacites predictives de la signature metabolomique etaient interessantes (ROC-AUC 0,83) et restaient specifiques du pSS apres ajustement sur l’âge, le sexe, la presence d’anticorps anti-SSA et la severite du syndrome sec (test de Schirmer, presence d’une dysfonction meibomienne, break-up time test). Seule la composante lipidique de la signature variait selon le score OSS (p = 0,015). Conclusion La signature metabolomique identifiee au sein des larmes de patients pSS, en comparaison a des patients avec d’autres causes de syndromes secs pourrait servir de biomarqueur lacrymal precoce du pSS et identifier des pistes physiopathologiques pour l’elaboration de traitements specifiques.
Published: 2020

48. Study of mitochondrial function in placental insufficiency

Author: Valérie Seegers, Geraldine Gascoin, Vincent Procaccio, Naïg Gueguen, Guillaume Legendre, Majida Cherif, Valérie Desquiret-Dumas, Salim Khiati, Tiphaine Lefebvre, Guillaume Geffroy, Ombeline Roche, Guy Lenaers, Odile Blanchet, Pascal Reynier, Laboratoire d'Ecologie Alpine (LECA ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CEntre de REcherches en MAthématiques de la DEcision (CEREMADE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Nantes Angers Le Mans (UNAM), and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: 0301 basic medicine, Adult, medicine.medical_specialty, Mitochondrial DNA, Placenta, [SDV]Life Sciences [q-bio], Respiratory chain, Placental insufficiency, Mitochondrion, DNA, Mitochondrial, Polymerase Chain Reaction, Preeclampsia, Electron Transport, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Pregnancy, Internal medicine, medicine, Humans, reproductive and urinary physiology, ComputingMilieux_MISCELLANEOUS, 030219 obstetrics & reproductive medicine, Fetal Growth Retardation, business.industry, Obstetrics and Gynecology, medicine.disease, Placental Insufficiency, Mitochondria, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Reproductive Medicine, Haplotypes, Case-Control Studies, embryonic structures, Female, business, Maternal Serum Screening Tests, Developmental Biology, Human mitochondrial DNA haplogroup
Abstract: Introduction It has been suggested that mitochondria play a crucial role in sustaining pregnancy and foetal growth. The aim of the study was to assess the influence of mitochondrial functions and genetics on placental insufficiency diseases. Methods A total of 115 patients were recruited, subdivided into 74 placenta samples and 41 maternal blood samples: placental insufficiency diseases including intra uterine growth restriction (IUGR) (n = 35), preeclampsia (PE) (n = 13), IUGR associated to PE (PER) (n = 25); and controls (n = 42). Haplogroups were determined for all patients. Eighty-six placenta samples were studied for quantitative and qualitative analyses of mtDNA: IUGR (n = 25), PE (n = 1), PER (n = 18) and controls (n = 42). Sixteen placenta samples were selected for functional analysis: IUGR (n = 6), PER (n = 2) and controls (n = 8). Results Mitochondrial DNA copy numbers and rearrangements and haplogroup distribution were not significantly altered in the patient group. Enzyme activity and expression of respiratory chain complexes were also comparable between both groups. Discussion Our results do not argue in favour of a mitochondrial involvement in placental insufficiency, suggesting that the glycolytic pathway may represent a key energetic source in placental insufficiency diseases.
Published: 2018

49. Imatinib Treatment of Chronic Myeloid Leukemia Reveals a Preexisting CALR-mutated Essential Thrombocythemia

Author: Anne Bouvier, Damien Luque Paz, Rébecca Jouanneau-Courville, Bénédicte Ribourtout, Laurane Cottin, Odile Blanchet, Anaïse Blouet, Valérie Ugo, Marie-Christine Rousselet, Yannick Le Bris, Service d'Oncologie Médicale [CH Cholet], Centre Hospitalier de Cholet (CHC), Laboratoire d’anatomopathologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), UFR Santé [UNIV Angers], Université d'Angers (UA), Laboratoire d'Hematologie [CHU Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), Laboratoire d'Hématologie Biologique (Hémato - ANGERS), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, business.industry, Essential thrombocythemia, lcsh:RC633-647.5, Myeloid leukemia, Case Report, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, lcsh:Diseases of the blood and blood-forming organs, medicine.disease, Imatinib treatment, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, Cancer research, Medicine, business, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2018

50. Concomitant CALR and LNK mutations leading to essential thrombocythemia with erythrocytosis

Author: Odile Blanchet, Mathilde Hunault, Diane K. Lambert, Anne Bouvier, Rébecca Jouanneau-Courville, Philippe Guardiola, Françoise Boyer, Valérie Ugo, Yves Delneste, Damien Luque Paz, Annaëlle Beucher, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire d'hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Université d'Angers (UA), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Service des maladies du sang [CHU Angers], Service de Génomique Onco-Hématologique [CHU Angers], Centre de Ressources Biologiques [CHU d'Angers] (CRB CHU d'Angers BB-0033-00038), This study is part of the clinical and biological database 'FIMBANK' project supported by a grant of the French National Cancer Institute (INCa-BCB-2013)., Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Male, LNK, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polycythemia, Essential thrombocythemia, Myeloproliferative neoplasms, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Genetic Predisposition to Disease, CALR, Molecular Biology, Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, business.industry, Intracellular Signaling Peptides and Proteins, Proteins, Cell Biology, Hematology, Janus Kinase 2, medicine.disease, Erythrocytosis, 3. Good health, 030220 oncology & carcinogenesis, Concomitant, Mutation, Cancer research, Molecular Medicine, Calreticulin, business, Thrombocythemia, Essential
Abstract: International audience; no abstract
Published: 2018

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