31 results on '"Humez S"'
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2. Fibrose pulmonaire idiopathique : recherche modèle désespérément
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Hennion, N., primary, Chenivesse, C., additional, Humez, S., additional, Gottrand, F., additional, Desseyn, J.-L., additional, and Gouyer, V., additional
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- 2024
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3. Prise en charge diagnostique et thérapeutique du mésothéliome pleural en 2024
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Scherpereel, A., Venissac, N., Humez, S., Ulmer, L., Locatelli-Sanchez, M., Brosseau, S., Dhalluin, X., Nunes, D., Gounant, V., Lantuejoul, S., and Zalcman, G.
- Abstract
Le mésothéliome pleural (MP) est un cancer assez rare, classiquement secondaire à une exposition antérieure à l’amiante. Son pronostic reste globalement mauvais, sans traitement curatif validé à ce jour. La thoracoscopie avec biopsies pleurales (± une symphyse pleurale d’emblée) est l’examen diagnostique clé. La chirurgie, intégrée à un traitement multimodal et d’indication très restreinte à des patients hyper-sélectionnés, est à nouveau remise en cause récemment. En première ligne de traitement, la chimiothérapie standard à base de pemetrexed et sels de platine a vu son efficacité améliorée par l’association avec le bevacizumab. Mais elle est concurrencée par la double immunothérapie Nivolumab + Ipilimumab particulièrement dans les formes non-épithélioïdes, et bientôt peut-être par des associations chimiothérapie + immunothérapie. Aucun traitement standard n’est validé en deuxième ligne ou plus, même si les anticorps anti-PD-1 /PD-L1 ± anti-CTLA-4 ont aussi montré des résultats intéressants en essais cliniques de phase II et III. La recherche de nouveaux traitements, stratégies et biomarqueurs est donc cruciale et l’inclusion des patients en essai clinique fortement encouragée. D’autres immunothérapies seules ou en combinaison avec des traitements standards et/ou thérapies ciblées, des stratégies multimodales sont actuellement évaluées. En France, le réseau national INCades centres experts pour la prise en charge du MP « NETMESO » vise à proposer une prise en charge optimale à tout patient systématiquement discuté en RCP régionale (± nationale) dédiée, et à stimuler la recherche clinique et translationnelle en collaboration avec ses partenaires dont les associations de patients.
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- 2024
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4. Développement et caractérisation d’un modèle de fibrose pulmonaire idiopathique et recherche de nouvelles cibles thérapeutiques
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Hennion, N., Humez, S., Gottrand, F., Desseyn, J.L., and Gouyer, V.
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- 2024
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5. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, DʼHooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
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- 2016
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6. Erratum: A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, D'Hooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
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- 2016
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7. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
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Laurent, C., Burnouf, S., Ferry, B., Batalha, Vânia, Coelho, Joana E, Baqi, Y., Malik, E., Mariciniak, E., Parrot, S., Van der Jeugd, A., Faivre, E., Flaten, V., Ledent, C., D'Hooge, R., Sergeant, N., Hamdane, M., Humez, S., Müller, C. E., Lopes, Luisa V., Buée, L., Blum, D., and Repositório da Universidade de Lisboa
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Receptor, Adenosine A2A ,Long-Term Synaptic Depression ,Glutamic Acid ,Biologie moléculaire ,Mice, Transgenic ,tau Proteins ,Hippocampus ,Adenosine A2 Receptor Antagonists ,Tissue Culture Techniques ,Disease Models, Animal ,Tauopathies ,Alzheimer Disease ,Xanthines ,Animals ,Humans ,RNA, Messenger ,Phosphorylation ,Cognition Disorders ,Sciences cognitives ,gamma-Aminobutyric Acid ,Psychiatrie - Abstract
© 2016 Macmillan Publishers Limited All rights reserved. This work is licensed under a Creative Commons Attribution- NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/, Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies., This work was supported by grants from France Alzheimer (to DB) and LECMA/Alzheimer Forschung Initiative (to DB and CEM). DB and LVL got a Égide/Pessoa program EU exchange grant. Our laboratory is also supported by the LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), Inserm, CNRS, Université Lille 2, Lille Métropole Communauté Urbaine, Région Nord/Pas-de-Calais, FEDER, DN2M, ANR (ADONTAGE and ADORATAU, to DB) and FUI MEDIALZ. We thank the animal facility of IMPRT-IFR114 and M Besegher, I Brion, D Cappe, R Dehaynin, J Devassine, Y Lepage, C Meunier and D Taillieu for transgenic mouse production and animal care, as well as M Basquin, D Demeyer, S Eddarkaoui, H Obriot and M Schneider for support. CL holds a doctoral grant from Lille 2 University, and SB from Région Nord Pas de Calais and CHRU de Lille. VF holds a grant from Région Nord-Pas-de-Calais and Inserm. EF holds a post-doctoral grant from Région Nord-Pas-de-Calais (DN2M). LVL is an Investigator FCT (Fundação para a Ciência e Tecnologia, Portugal).
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- 2016
8. Erratum: A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
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Laurent, C, primary, Burnouf, S, additional, Ferry, B, additional, Batalha, V L, additional, Coelho, J E, additional, Baqi, Y, additional, Malik, E, additional, Mariciniak, E, additional, Parrot, S, additional, Van der Jeugd, A, additional, Faivre, E, additional, Flaten, V, additional, Ledent, C, additional, D'Hooge, R, additional, Sergeant, N, additional, Hamdane, M, additional, Humez, S, additional, Müller, C E, additional, Lopes, L V, additional, Buée, L, additional, and Blum, D, additional
- Published
- 2015
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9. A2A adenosine receptor deletion is protective in a mouse model of Tauopathy
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Laurent, C, primary, Burnouf, S, additional, Ferry, B, additional, Batalha, V L, additional, Coelho, J E, additional, Baqi, Y, additional, Malik, E, additional, Mariciniak, E, additional, Parrot, S, additional, Van der Jeugd, A, additional, Faivre, E, additional, Flaten, V, additional, Ledent, C, additional, D'Hooge, R, additional, Sergeant, N, additional, Hamdane, M, additional, Humez, S, additional, Müller, C E, additional, Lopes, L V, additional, Buée, L, additional, and Blum, D, additional
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- 2014
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10. A2Aadenosine receptor deletion is protective in a mouse model of Tauopathy
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, D'Hooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
- Abstract
Consumption of caffeine, a non-selective adenosine A2Areceptor (A2AR) antagonist, reduces the risk of developing Alzheimer’s disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2Areceptors as important molecular targets to consider against AD and Tauopathies.
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- 2016
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11. Erratum: A2Aadenosine receptor deletion is protective in a mouse model of Tauopathy
- Author
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Laurent, C, Burnouf, S, Ferry, B, Batalha, V L, Coelho, J E, Baqi, Y, Malik, E, Mariciniak, E, Parrot, S, Van der Jeugd, A, Faivre, E, Flaten, V, Ledent, C, D'Hooge, R, Sergeant, N, Hamdane, M, Humez, S, Müller, C E, Lopes, L V, Buée, L, and Blum, D
- Abstract
Correction to: Molecular Psychiatry advance online publication, 2 December 2014; doi:10.1038/mp.2014.151 Following publication of this paper, the authors noticed that the eighth author’s name was misspelled. The author’s name should have been listed as E Marciniak.
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- 2016
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12. [Idiopathic pulmonary fibrosis: Desperately seeking a model].
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Hennion N, Chenivesse C, Humez S, Gottrand F, Desseyn JL, and Gouyer V
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- Animals, Humans, Idiopathic Pulmonary Fibrosis diagnosis, Idiopathic Pulmonary Fibrosis therapy
- Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease of which the origin and development mechanisms remain unknown. The few available pharmacological treatments can only slow the progression of the disease. The development of curative treatments is hampered by the absence of experimental models that can mimic the specific pathophysiological mechanisms of IPF. The aim of this mini-review is to provide an overview of the most commonly used experimental animal models in the study of IPF and to underline the urgent need to seek out new, more satisfactory models., (Copyright © 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.)
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- 2024
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13. Histo-Molecular Factors of Response to Combined Chemotherapy and Immunotherapy in Non-Small Cell Lung Cancers.
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Marchal M, Leroy V, Behal H, Dansin E, Paris N, Bordier S, Humez S, Escande F, Gauvain C, and Cortot AB
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- Humans, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins genetics, Mutation, Receptor Protein-Tyrosine Kinases genetics, ErbB Receptors genetics, Biomarkers, Immunotherapy, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics
- Abstract
Background: Chemo-immunotherapy (CIT) is the standard of care for advanced non-small cell lung cancer (NSCLC), but the impact of routinely available histo-molecular biomarkers on its efficacy has not yet been fully assessed., Objective: The purpose of this multicenter study was to evaluate the clinical activity of CIT according to oncogenic drivers, STK11 and TP53 mutations, and MET overexpression., Patients and Methods: Patients receiving CIT for advanced NSCLC with available comprehensive molecular profile were included. The primary endpoint was progression-free survival (PFS), adjusted on main confounding factors, and secondary endpoints were overall survival (OS) and objective response rate., Results: Among the 195 patients included between September 2018 and October 2021, 88 (41%) had a KRAS mutation, 16 (8.2%) an EGFR mutation or an ALK, ROS1, or RET rearrangement, 11 (5.6%) a BRAF mutation, 6 (3.1%) a MET exon 14 mutation or MET amplification, and 5 (2.6%) a HER2 mutation. Seventy-seven patients (39.5%) had none of these alterations. The median PFS was 6.4 months (95% CI 5.3-7.3). Per subgroup, the median PFS was 7.1 months (5.4-8.9) for KRAS, 5.5 months (2.5-15.3) for EGFR/ALK/ROS1/RET, 12.9 months (2.6-not reached [NR]) for BRAF, 1.5 months (0.6-NR) for MET, 3.9 months (2.6-NR) for HER2, and 5.6 months (4.7-7.8) for patients without any oncogenic alteration. No difference in PFS was observed between the KRAS, BRAF, EGFR/ALK/ROS1/RET, and no-driver subgroups. STK11 mutations were associated with poor PFS (HR 1.59 [95% CI 1.01-2.51]) whereas TP53 mutations had no impact. MET overexpression was associated with longer PFS (HR 0.59 [95% CI 0.35-0.99])., Conclusion: This study suggests that the efficacy of combining pembrolizumab with pemetrexed and platinum-based chemotherapy differs according to the histo-molecular biomarkers, which may help to identify patients liable to benefit from CIT., (© 2023. The Author(s).)
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- 2023
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14. MET exon 14 skipping mutation is a hepatocyte growth factor (HGF)-dependent oncogenic driver in vitro and in humanised HGF knock-in mice.
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Fernandes M, Hoggard B, Jamme P, Paget S, Truong MJ, Grégoire V, Vinchent A, Descarpentries C, Morabito A, Stanislovas J, Farage E, Meneboo JP, Sebda S, Bouchekioua-Bouzaghou K, Nollet M, Humez S, Perera T, Fromme P, Grumolato L, Figeac M, Copin MC, Tulasne D, Cortot AB, Kermorgant S, and Kherrouche Z
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- Humans, Exons, Hepatocyte Growth Factor genetics, Hepatocyte Growth Factor metabolism, Mutation genetics, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met metabolism, Animals, Mice, Carcinoma, Non-Small-Cell Lung pathology, Lung Neoplasms pathology
- Abstract
Exon skipping mutations of the MET receptor tyrosine kinase (METex14), increasingly reported in cancers, occur in 3-4% of non-small-cell lung cancer (NSCLC). Only 50% of patients have a beneficial response to treatment with MET-tyrosine kinase inhibitors (TKIs), underlying the need to understand the mechanism of METex14 oncogenicity and sensitivity to TKIs. Whether METex14 is a driver mutation and whether it requires hepatocyte growth factor (HGF) for its oncogenicity in a range of in vitro functions and in vivo has not been fully elucidated from previous preclinical models. Using CRISPR/Cas9, we developed a METex14/WT isogenic model in nontransformed human lung cells and report that the METex14 single alteration was sufficient to drive MET-dependent in vitro anchorage-independent survival and motility and in vivo tumorigenesis, sensitising tumours to MET-TKIs. However, we also show that human HGF (hHGF) is required, as demonstrated in vivo using a humanised HGF knock-in strain of mice and further detected in tumour cells of METex14 NSCLC patient samples. Our results also suggest that METex14 oncogenicity is not a consequence of an escape from degradation in our cell model. Thus, we developed a valuable model for preclinical studies and present results that have potential clinical implication., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
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- 2023
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15. Pursuit or discontinuation of anti-PD1 after 2 years of treatment in long-term responder patients with non-small cell lung cancer.
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Ardin C, Humez S, Leroy V, Ampere A, Bordier S, Escande F, Turlotte A, Stoven L, Nunes D, Cortot A, and Gauvain C
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Background: The optimal duration of immune checkpoint inhibitor (ICI) treatment for patients with advanced non-small cell lung cancer (NSCLC) remains to be determined. Treatment durations in cornerstone phase 3 clinical trials vary between a fixed 2-year duration and pursuit until disease progression. Clinical practices may thus differ according to the attending physician., Objectives: Here we provide real-world data about treatment decisions at 2 years, with subsequent clinical outcomes., Design and Methods: This multicentric observational study included patients with advanced NSCLC whose disease was controlled after 2 years of pembrolizumab or nivolumab. The primary outcome was the decision to discontinue ICI treatment or not, along with factors motivating this decision. Secondary outcomes included progression-free survival (PFS) (according to treatment continuation or not) and adverse events., Results: A total of 91 patients were included, of which 60 (66%) had been pre-treated. The programmed death-ligand 1 expression level was ⩾50% in 43 patients (47%). In 61 patients (67%), ICI was continued after 2 years of treatment. This decision was significantly associated with the care center ( p < 0.001) but neither with the tumor response at 2 years, as evaluated by CT scan or PET scan, nor with clinical status, immune-related adverse events, or previous locally treated oligo-progressive disease under ICI. Two years after the 2-year decision, PFS was 68.5%, [95% confidence interval (CI) (53.3-88.0)] in the 'ICI discontinuation' group and 64.1% [95% CI (51.9-79.2)] in the 'ICI pursuit' group; hazard ratio for relapse was 1.14 [95% CI (0.54-2.30), p = 0.77]. The overall survival rate at 24 months after discontinuation was 89.2% [95% CI (78.4-100)] for the 'discontinuation' group and 93.1% [95% CI (85.8-100)] for the 'pursuit' group. Given insufficient power, overall survival could not be compared., Conclusion: The decision to continue ICI or not after 2 years of treatment depends mainly on the care center and does not seem to impact survival. Larger, randomized data sets are required to confirm this result., Competing Interests: AC reports grants to institution from Meck and Roche; consulting fees from Novartis; honoraria from Sanofi, Pfizer, Novartis, Takeda, Amgen; payment for expert testimony from Pfizer, Takeda, Novartis, Janssen, Roche, Abbvie; support for attending meetings and/or travel from Novartis and Takeda; consulting or advisory role with Novartis and InhaTarget. CG declares receiving support for attending meetings and/or travel from Pfizer and Novartis. The other authors declare that there is no conflict of interest., (© The Author(s), 2023.)
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- 2023
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16. Mammalian Brain Ca 2+ Channel Activity Transplanted into Xenopus laevis Oocytes.
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Rousset M, Humez S, Laurent C, Buée L, Blum D, Cens T, Vignes M, and Charnet P
- Abstract
Several mutations on neuronal voltage-gated Ca
2+ channels (VGCC) have been shown to cause neurological disorders and contribute to the initiation of epileptic seizures, migraines, or cerebellar degeneration. Analysis of the functional consequences of these mutations mainly uses heterologously expressed mutated channels or transgenic mice which mimic these pathologies, since direct electrophysiological approaches on brain samples are not easily feasible. We demonstrate that mammalian voltage-gated Ca2+ channels from membrane preparation can be microtransplanted into Xenopus oocytes and can conserve their activity. This method, originally described to study the alteration of GABA receptors in human brain samples, allows the recording of the activity of membrane receptors and channels with their native post-translational processing, membrane environment, and regulatory subunits. The use of hippocampal, cerebellar, or cardiac membrane preparation displayed different efficacy for transplanted Ca2+ channel activity. This technique, now extended to the recording of Ca2+ channel activity, may therefore be useful in order to analyze the calcium signature of membrane preparations from unfixed human brain samples or normal and transgenic mice.- Published
- 2022
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17. Early Renal Recovery after the First Flare of Pauci-Immune Glomerulonephritis.
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Zaworski J, Gnemmi V, Bataille P, Hachulla E, Glowacki F, Gibier JB, Daroux M, Ratsimbazafy A, Bitton L, Humez S, Guincestre T, Béhal H, Azar R, Hoffmann M, Cardon G, Bourdon F, Lemoine C, Auxenfant E, Copin MC, Vandenbussche C, and Quéméneur T
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- Antibodies, Antineutrophil Cytoplasmic, Female, Humans, Kidney, Male, Retrospective Studies, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Glomerulonephritis diagnosis
- Abstract
Introduction: Renal involvement is a severe manifestation of antineutrophil cytoplasmic antibody-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after the first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in the eGFR between diagnosis and the follow-up at 3 months (ΔeGFRM0-M3)., Methods: This was a retrospective study over the period 2003-2018 of incident patients in the Nord-Pas-de-Calais (France). The primary outcome was the ΔeGFRM0-M3., Results: One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs. 28 ± 26 mL/min/1.73 m2, p < 0.001), with a ΔeGFRM0-M3 of 12 ± 19 mL/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs. 40 ± 24 mL/min/1.73 m2, p = 0.003). The factors significantly associated with the ΔeGFRM0-M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in the eGFR was 2.90 ± 0.06 mL/min/1.73 m2 for every 10-point gain in the percentage of cellular crescents., Conclusions: Early renal recovery after the first flare of pauci-immune glomerulonephritis occurred mainly in the first 3 months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery., (© 2022 S. Karger AG, Basel.)
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- 2022
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18. Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.
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Meiller C, Montagne F, Hirsch TZ, Caruso S, de Wolf J, Bayard Q, Assié JB, Meunier L, Blum Y, Quetel L, Gibault L, Pintilie E, Badoual C, Humez S, Galateau-Sallé F, Copin MC, Letouzé E, Scherpereel A, Zucman-Rossi J, Le Pimpec-Barthes F, Jaurand MC, and Jean D
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- Biopsy, Computational Biology methods, DNA Mutational Analysis methods, Disease Management, Disease Susceptibility, Gene Expression Profiling, Genetic Heterogeneity, High-Throughput Nucleotide Sequencing, Humans, Mesothelioma, Malignant diagnosis, Mesothelioma, Malignant metabolism, Molecular Diagnostic Techniques, Molecular Sequence Annotation, Mutation, Pleural Neoplasms diagnosis, Pleural Neoplasms metabolism, Precision Medicine methods, Precision Medicine standards, Prognosis, Tumor Microenvironment genetics, Exome Sequencing, Biomarkers, Tumor, Mesothelioma, Malignant etiology, Pleural Neoplasms etiology
- Abstract
Background: Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples., Methods: Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed., Results: Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients., Conclusions: This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine., (© 2021. The Author(s).)
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- 2021
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19. [Renal granulomatous nephritis: Histopathological point of view].
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Gnemmi V, Gibier JB, Humez S, Copin MC, and Glowacki F
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- Granuloma etiology, Histiocytes, Humans, Kidney, Nephritis, Interstitial diagnosis, Nephritis, Interstitial etiology, Sarcoidosis diagnosis
- Abstract
Granulomatous interstitial nephritis (NIG) is a rare form of interstitial nephritis that can be related to acute or chronic clinical presentation. NIG is characterized by granulomas located to the renal interstitium and composed of either epithelioid histiocytes with giant cells and/or of foreign body reaction. The symptoms are unspecific and associate varying degrees of renal failure with abnormal urinanalysis. Extra-renal signs may point to systemic disease. Pathological examination from kidney percutaneous biopsy or surgical resection is required to assert NIG diagnosis and to guide the etiological research. The main causes of NIG are sarcoidosis, drug reactions, mycobacterial infections and crystalline nephropathies. Sarcoidosis is characterized by non-necrotic and well-formed giant cell epithelioid interstitial granulomas. Drug reactions have less well-defined granulomas with inconstant eosinophils. The presence of caseous necrosis within giant cell and epithelioid granulomas leads to infectious NIG diagnosis (tuberculosis and fungal infection). Identification of crystals within foreign body reaction can be improved by polarized light study. Xanthogranulomatous pyelonephritis and malakoplakia are rarer causes of NIG characterized by patches of histiocytes associated with inconstant giant cells. Differential diagnoses of NIG are represented by granulomatous reactions centered on glomeruli and vessels (vasculitis and emboli of cholesterol crystals). Less than 10% of NIG are idiopathic. The prognosis and the treatment vary according to the cause. The factors of poor renal prognosis are chronic irreversible tubulo-interstitial injury (tubular atrophy and interstitial fibrosis)., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
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- 2021
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20. Paraffin Immunofluorescence Increases Light-Chain Detection in Extra-Renal Light Chain Amyloidosis and Other Light-Chain-Associated Diseases.
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Gibier JB, Perbet R, Lopez B, Colombat M, Dubois R, Humez S, Terriou L, Copin MC, and Gnemmi V
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- Amyloid, Amyloidosis pathology, Cohort Studies, Fluorescent Antibody Technique, Frozen Sections, Humans, Immunohistochemistry, Kidney pathology, Kidney Diseases pathology, Mass Spectrometry, Paraffin, Prospective Studies, Retrospective Studies, Amyloidosis diagnosis, Kidney Diseases diagnosis
- Abstract
Context.—: Distinguishing the different types of amyloid is clinically important because treatments and outcomes are different. Mass spectrometry is the new gold standard for amyloid typing, but it is costly and not widely available. Therefore, immunolabeling remains the first step in identifying the most common types of amyloidosis. In amyloid subtyping, direct immunofluorescence works well when applied to frozen sections, but immunohistochemistry on formalin-fixed, paraffin-embedded material often yields poor results, particularly for light chain amyloidosis. Recently, paraffin immunofluorescence has been described as a valuable salvage technique in renal pathology when frozen sections are not available but it has not been evaluated for extra-renal diseases., Objectives.—: To evaluate the use of paraffin immunofluorescence for light-chain detection in extra-renal amyloidosis and other light-chain-associated diseases., Design.—: First, we compared the staining intensity of both light chains between paraffin immunofluorescence and immunohistochemistry on a retrospective cohort of 28 cases of amyloidosis that have been previously typed. Then, we studied the role of paraffin immunofluorescence as an addition to our classical immunohistochemistry panel for amyloidosis typing., Results.—: In the retrospective cohort, we found that paraffin immunofluorescence outperformed immunohistochemistry for light-chain detection. Then, in the prospective part of the study, we showed that the proportion of correctly classified cases increased from 50% to 71.9% with the adjunction of second-intention paraffin immunofluorescence to the immunohistochemistry procedure., Conclusions.—: We therefore view paraffin immunofluorescence as a significant addition to the routine workflow for detection of light-chain-related diseases., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2021 College of American Pathologists.)
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- 2021
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21. Specific Genomic Alterations in High-Grade Pulmonary Neuroendocrine Tumours with Carcinoid Morphology.
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Cros J, Théou-Anton N, Gounant V, Nicolle R, Reyes C, Humez S, Hescot S, Thomas de Montpréville V, Guyétant S, Scoazec JY, Guyard A, de Mestier L, Brosseau S, Mordant P, Castier Y, Gentien D, Ruszniewski P, Zalcman G, Couvelard A, and Cazes A
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Genomics, Humans, Male, Middle Aged, Mutation, Neoplasm Grading, Carcinoid Tumor genetics, Carcinoid Tumor pathology, Carcinoma, Neuroendocrine genetics, Carcinoma, Neuroendocrine pathology, Lung Neoplasms genetics, Lung Neoplasms pathology
- Abstract
Introduction: High-grade lung neuroendocrine tumours with carcinoid morphology have been recently reported; they may represent the thoracic counterparts of grade 3 digestive neuroendocrine tumours. We aimed to study their genetic landscape including analysis of tumoral heterogeneity., Methods: Eleven patients with high-grade (>20% Ki-67 and/or >10 mitoses) lung neuroendocrine tumours with a carcinoid morphology were included. We analysed copy number variations, somatic mutations, and protein expression in 16 tumour samples (2 samples were available for 5 patients allowing us to study spatial and temporal heterogeneity)., Results: Genomic patterns were heterogeneous ranging from "quiet" to tetraploid, heavily rearranged genomes. Oncogene mutations were rare and most genetic alterations targeted tumour suppressor genes. Chromosomes 11 (7/11), 3 (6/11), 13 (4/11), and 6-17 (3/11) were the most frequently lost. Altered tumour suppressor genes were common to both carcinoids and neuroendocrine carcinomas, involving different pathways including chromatin remodelling (KMT2A, ARID1A, SETD2, SMARCA2, BAP1, PBRM1, KAT6A), DNA repair (MEN1, POLQ, ATR, MLH1, ATM), cell cycle (RB1, TP53, CDKN2A), cell adhesion (LATS2, CTNNB1, GSK3B) and metabolism (VHL). Comparative spatial/temporal analyses confirmed that these tumours emerged from clones of lower aggressivity but revealed that they were genetically heterogeneous accumulating "neuroendocrine carcinoma-like" genetic alterations through progression such as TP53/RB1 alterations., Conclusion: These data confirm the importance of chromatin remodelling genes in pulmonary carcinoids and highlight the potential role of TP53 and RB1 to drive the transformation in more aggressive high-grade tumours., (© 2020 S. Karger AG, Basel.)
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- 2021
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22. CXCL13 is expressed in various haematological disorders other than angioimmunoblastic T-cell lymphoma.
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de Mestral SG, Dubois R, Gibier JB, Humez S, Lefèvre G, Morschhauser F, and Copin MC
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- Aged, Female, Hematologic Diseases pathology, Humans, Lymph Nodes pathology, Male, Middle Aged, Skin pathology, Chemokine CXCL13 metabolism, Hematologic Diseases metabolism, Lymph Nodes metabolism, Skin metabolism
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- 2020
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23. Tubulointerstitial damage and interstitial immune cell phenotypes are useful predictors for renal survival and relapse in antineutrophil cytoplasmic antibody-associated vasculitis.
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Bitton L, Vandenbussche C, Wayolle N, Gibier JB, Cordonnier C, Verine J, Humez S, Bataille P, Lenain R, Ramdane N, Azar R, Mac Namara E, Hatron PY, Maurage CA, Perrais M, Frimat M, Vanhille P, Glowacki F, Buob D, Copin MC, Quéméneur T, and Gnemmi V
- Subjects
- Antibodies, Antineutrophil Cytoplasmic, Humans, Kidney pathology, Kidney Tubules immunology, Kidney Tubules pathology, Phenotype, Recurrence, Retrospective Studies, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis immunology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis pathology, Kidney Failure, Chronic immunology, Kidney Failure, Chronic pathology
- Abstract
The aims of this study were to determine whether tubulointerstitial damage in the form of interstitial fibrosis/tubular atrophy and total interstitial inflammation predicted progression to end stage renal disease (ESRD) and/or renal relapse (RR) in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). One hundred thirteen patients with AAV from six French centers with an index biopsy performed between 2003 and 2013 were included. Histological assessments using the AAV glomerular classification and the kidney allograft Banff classification were performed on pathological review. Biopsy tissues were also investigated by CD3, CD20, CD68, CD163, FOXP3 and RORγt immunohistochemical staining. Competing risks models were calculated. Of the 113 patients, 26 (23.0%) died during follow-up and 29 (25.6%) developed ESRD. Among the 94 patients who achieved remission by the end of induction therapy without developing ESRD, 26 (27.6%) experienced RR. The two independent prognostic factors for ESRD were the estimated glomerular filtration rate at presentation (HR 0.35; 95% CI 0.23-0.51; P < 0.0001) and IF/TA > 25% (HR 2.27; 95% CI 1.18-4.37; P = 0.014). When the distribution of interstitial immune cell phenotypes was included in a second multivariable model, the organization of lymphocytic infiltrates was also an independent predictor of ESRD (HR 2.86; 95% CI 1.35-6.1, P = 0.006). The independent risk factors for RR were a higher CD3/CD20 ratio (HR 1.39; 95% CI 1.05-1.85; P = 0.02) and the presence of RORγt positive cells (HR 2.70; 95% CI 1.11-6.54; P = 0.02). Our results highlight the prognostic value of initial histological evaluations in AAV. Measurements of tubulointerstitial damage and interstitial immune cell phenotype distributions should be considered to improve risk assessments for ESRD and RR.
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- 2020
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24. Does the medical autopsy still have a place in the current diagnostic process? A 6-year retrospective study in two French University hospitals.
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Humez S, Delteil C, Maurage CA, Torrents J, Capuani C, Tuchtan L, and Piercecchi MD
- Abstract
Medical autopsies have been in considerable decline for several decades, in France and worldwide. We aimed to determine whether a medical autopsy still currently has a role to play in diagnosis, by analyzing its performance and diagnostic limitations. This dual-centre retrospective descriptive study included all medical autopsies performed in the university hospitals of Lille and Marseille, France, between January 2007 and December 2012. Autopsies of fetuses or stillborn infants, or those related to sudden infant deaths and research protocols were excluded. 412 medical autopsies were included. The male:female ratio was 1.5:1 and mean age was 27.3 years. Half of all autopsies were pediatric. Regarding anatomical region and/or injury mechanism, a clinical diagnosis was suggested in 52.2% of cases, an autopsy diagnosis in 55.6% and a microscopic diagnosis in 81.8%. There was very low agreement between the clinician's suggested diagnosis and the final diagnosis, both for organ specific diseases and cause of death. Agreement was moderate between autopsy diagnoses and microscopic diagnoses for organ specific diseases and low for cause of death. From our findings we concluded that an autopsy associated with microscopic examination was still valuable in diagnosing cause of death. Microscopic examination was indispensable to determine certain causes of death.
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- 2019
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25. Histological dating of subarachnoid hemorrhage and retinal hemorrhage in infants.
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Delteil C, Kolopp M, Capuani C, Humez S, Boucekine M, Leonetti G, Torrents J, Tuchtan L, and Piercecchi MD
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- Blood Platelets pathology, Child Abuse, Child, Preschool, Collagen metabolism, Erythrocytes pathology, Female, Fibrin metabolism, Fibroblasts pathology, Forensic Pathology, Humans, Infant, Infant, Newborn, Lymphocytes pathology, Macrophages pathology, Male, Neovascularization, Physiologic, Retina pathology, Retrospective Studies, Sclerosis pathology, Postmortem Changes, Retinal Hemorrhage pathology, Subarachnoid Hemorrhage pathology
- Abstract
Background: Dating the traumatic event is usually done on subdural hematoma (SDH). After infant deaths due to Abusive head trauma (AHT) without SDH available, the magistrates still ask experts to date the traumatic event. To do so, the expert only has tools based on adult series of AHT. We aimed to develop a subarachnoid hemorrhage (SAH) and retinal hemorrhage (RH) dating system applicable to infants aged under 3 years., Methods and Results: We studied a retrospective multicenter collection of 235 infants who died between the ages of 0 and 36 months, diagnosed with SAH and/or RH by forensic pathological examination and with known posttraumatic interval (PTI). Two pathologists assessed blindly and independently 12histomorphological features in 83 infants (35 girls, 48 boys) whose median age was 3.8 months. For SAH, histopathological changes were significantly correlated with PTI for the appearance of red blood cells, of fibrino-plaquetted organization, the quantity of lymphocytes and macrophages and the presence or absence of siderophages, collagen and fibroblast formation and presence or absence of neovascularization. For RH, histopathological changes were significantly correlated with PTI for the appearance of red blood cells, the presence or absence of siderophages and sclerosis of the retina., Conclusion: Our HAS dating system improves the precision and reliability of forensic pathological expert examination of AHT, when SDH are not available, for age estimation in infants. The study of RH histomorphological changes does not allow for reliable dating., (Copyright © 2019 Elsevier B.V. All rights reserved.)
- Published
- 2019
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26. Histological dating of subdural hematoma in infants.
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Delteil C, Humez S, Boucekine M, Jouvet A, Hedouin V, Fanton L, Leonetti G, Tuchtan L, and Piercecchi MD
- Subjects
- Bilirubin metabolism, Child, Preschool, Collagen metabolism, Dura Mater metabolism, Dura Mater pathology, Erythrocytes metabolism, Female, Fibrin metabolism, Fibroblasts metabolism, Humans, Infant, Infant, Newborn, Intracranial Thrombosis metabolism, Intracranial Thrombosis pathology, Lymphocytes metabolism, Macrophages metabolism, Male, Neovascularization, Pathologic, Postmortem Changes, Reticulin metabolism, Retrospective Studies, Forensic Pathology methods, Hematoma, Subdural pathology
- Abstract
Background: After infant deaths due to non-accidental head injury (NAHI) with subdural hematoma (SDH), the magistrates ask experts to date the traumatic event. To do so, the expert only has tools based on adult series of NAHI. We aimed to develop an SDH dating system applicable to infants aged under 3 years., Methods and Results: We studied a retrospective multicenter collection of 235 infants who died between the ages of 0 and 36 months, diagnosed with SDH by forensic pathological examination and with known posttraumatic interval (PTI). Two pathologists assessed blindly and independently 12 histomorphological criteria relating to the clot and 14 relating to the dura mater in 73 victims (31 girls, 42 boys) whose median age was 3.8 months. Histopathological changes were significantly correlated with PTI for the appearance of red blood cells (RBCs) and the presence or absence of siderophages, and regarding the dura mater, the quantity of lymphocytes, macrophages, and siderophages; presence or absence of hematoidin deposits; collagen and fibroblast formation; neomembrane thickness; and presence or absence of neovascularization. Dating systems for SDH in adults are not applicable to infants. Notably, neomembrane of organized connective tissue is formed earlier in infants than in adults., Conclusion: Our dating system improves the precision and reliability of forensic pathological expert examination of NAHI, particularly for age estimation of SDH in infants. However, the expert can only define a time interval. Histopathology is indispensable to detect repetitive trauma.
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- 2019
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27. Tau deletion promotes brain insulin resistance.
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Marciniak E, Leboucher A, Caron E, Ahmed T, Tailleux A, Dumont J, Issad T, Gerhardt E, Pagesy P, Vileno M, Bournonville C, Hamdane M, Bantubungi K, Lancel S, Demeyer D, Eddarkaoui S, Vallez E, Vieau D, Humez S, Faivre E, Grenier-Boley B, Outeiro TF, Staels B, Amouyel P, Balschun D, Buee L, and Blum D
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- Animals, Brain physiology, Cognitive Dysfunction etiology, Haplotypes, Hippocampus physiology, Humans, Insulin physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Brain metabolism, Insulin Resistance, tau Proteins physiology
- Abstract
The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients., (© 2017 Marciniak et al.)
- Published
- 2017
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28. The mechanism of the keyhole lesion reassessed: An experimental approach.
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Delannoy Y, Colard T, Le Garff E, Humez S, Gosset D, and Hedouin V
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- Aged, Cadaver, Forensic Pathology, Head Injuries, Penetrating diagnostic imaging, Humans, Imaging, Three-Dimensional, Male, Skull Fractures diagnostic imaging, Wounds, Gunshot diagnostic imaging, X-Ray Microtomography, Forensic Ballistics methods, Head Injuries, Penetrating pathology, Skull Fractures pathology, Wounds, Gunshot pathology
- Abstract
The initial description of the keyhole defect was detailed as a peculiar gunshot entrance wound in the cranial vault due to firearm discharge in a tangential path. This injury may be described in two parts: a rounded section with inner table beveling and a triangular section with outer table beveling. We report a case of a gunshot skull wound "keyhole" shaped, appeared to have been made perpendicularly to the bone. Performing an experimental study on cranial bones with shots made perpendicularly to the skull approved this hypothesis, and bone injuries were then architecturally characterised using high-resolution micro computed tomography. The singular link between the tangential gunshot path and the keyhole pattern has been refuted several times, and some authors have hypothesised that there is an important role for concentric fractures that occur far away from the initial impact point of the bullet. Micro computed tomography analysis of the bone showed these keyhole defect features with a particular high description. Then, the whole pattern has a spider-web effect, and these concentric fractures could explain the keyhole pattern even in a perpendicular gunshot path., (Copyright © 2015 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)
- Published
- 2016
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29. The Chemokine MIP-1α/CCL3 impairs mouse hippocampal synaptic transmission, plasticity and memory.
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Marciniak E, Faivre E, Dutar P, Alves Pires C, Demeyer D, Caillierez R, Laloux C, Buée L, Blum D, and Humez S
- Subjects
- Animals, Chemokine CCL3 metabolism, Male, Mice, Neurotransmitter Agents metabolism, Chemokine CCL3 pharmacology, Hippocampus metabolism, Long-Term Potentiation drug effects, Long-Term Synaptic Depression drug effects, Memory drug effects, Neurotransmitter Agents pharmacology, Synaptic Transmission drug effects
- Abstract
Chemokines are signaling molecules playing an important role in immune regulations. They are also thought to regulate brain development, neurogenesis and neuroendocrine functions. While chemokine upsurge has been associated with conditions characterized with cognitive impairments, their ability to modulate synaptic plasticity remains ill-defined. In the present study, we specifically evaluated the effects of MIP1-α/CCL3 towards hippocampal synaptic transmission, plasticity and spatial memory. We found that CCL3 (50 ng/ml) significantly reduced basal synaptic transmission at the Schaffer collateral-CA1 synapse without affecting NMDAR-mediated field potentials. This effect was ascribed to post-synaptic regulations, as CCL3 did not impact paired-pulse facilitation. While CCL3 did not modulate long-term depression (LTD), it significantly impaired long-term potentiation (LTP), an effect abolished by Maraviroc, a CCR5 specific antagonist. In addition, sub-chronic intracerebroventricular (icv) injections of CCL3 also impair LTP. In accordance with these electrophysiological findings, we demonstrated that the icv injection of CCL3 in mouse significantly impaired spatial memory abilities and long-term memory measured using the two-step Y-maze and passive avoidance tasks. These effects of CCL3 on memory were inhibited by Maraviroc. Altogether, these data suggest that the chemokine CCL3 is an hippocampal neuromodulator able to regulate synaptic plasticity mechanisms involved in learning and memory functions.
- Published
- 2015
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30. [Cardiac fibroma: A rare cause of sudden child death].
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Humez S, Gibier JB, Recher M, Leteurtre S, Leroy X, and Devisme L
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- Calcinosis pathology, Cardiomegaly etiology, Child, Preschool, Diagnosis, Differential, Fibroma complications, Fibroma diagnosis, Heart Neoplasms complications, Heart Neoplasms diagnosis, Humans, Male, Rhabdomyoma diagnosis, Death, Sudden, Cardiac etiology, Fibroma pathology, Heart Neoplasms pathology
- Abstract
We report the case of a 3-year-old child who died from the consequences of a cardio-respiratory arrest despite reanimation procedures. Echocardiography and magnetic resonance imaging (MRI) revealed a mass of the free wall of the left ventricle. Autopsy confirmed the existence of a solitary myocardial tumor, well-circumscribed, firm, with a whitish and trabeculated cut surface. Histologically, the tumor consisted of bundles of spindle-shaped and regular cells mingling with collagen and elastic fibers, insinuating themselves between myocytes in periphery. Calcifications were present. After immunohistochemistry, the cells were highlighted by anti-actin smooth muscle antibody; but they were not highlighted by anti-desmin, anti-β catenin and anti-Ki67 antibodies. The diagnosis of cardiac fibroma was made. The primary cardiac tumors of child are rare and usually benign. They are essentially represented by rhabdomyoma and fibroma. Cardiac fibroma mostly occurs during the first year of life. It can be revealed by cardiac insufficiency, arrhythmia, chest pain or sudden death., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
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31. Prefibrillar Tau oligomers alter the nucleic acid protective function of Tau in hippocampal neurons in vivo.
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Violet M, Chauderlier A, Delattre L, Tardivel M, Chouala MS, Sultan A, Marciniak E, Humez S, Binder L, Kayed R, Lefebvre B, Bonnefoy E, Buée L, and Galas MC
- Subjects
- Animals, Cell Death drug effects, Cell Death physiology, Cell Nucleus drug effects, Cell Nucleus metabolism, Cell Nucleus pathology, Cytoplasm drug effects, Cytoplasm metabolism, Cytoplasm pathology, DNA Breaks drug effects, Disease Models, Animal, Female, Fever drug therapy, Fever metabolism, Fever pathology, Hippocampus drug effects, Hippocampus pathology, Humans, Methylene Blue pharmacology, Mice, Transgenic, Neurons drug effects, Neurons pathology, Neuroprotective Agents pharmacology, Oxidative Stress drug effects, Oxidative Stress physiology, Protein Multimerization drug effects, Protein Multimerization physiology, RNA metabolism, Tauopathies drug therapy, Tauopathies pathology, Hippocampus metabolism, Neurons metabolism, Tauopathies metabolism, tau Proteins metabolism
- Abstract
The accumulation of DNA and RNA oxidative damage is observed in cortical and hippocampal neurons from Alzheimer's disease (AD) brains at early stages of pathology. We recently reported that Tau is a key nuclear player in the protection of neuronal nucleic acid integrity in vivo under physiological conditions and hyperthermia, a strong inducer of oxidative stress. In a mouse model of tauopathy (THY-Tau22), we demonstrate that hyperthermia selectively induces nucleic acid oxidative damage and nucleic acid strand breaks in the nucleus and cytoplasm of hippocampal neurons that display early Tau phosphorylation but no Tau fibrils. Nucleic acid-damaged neurons were exclusively immunoreactive for prefibrillar Tau oligomers. A similar association between prefibrillar Tau oligomers and nucleic acid oxidative damage was observed in AD brains. Pretreatment with Methylene Blue (MB), a Tau aggregation inhibitor and a redox cycler, reduced hyperthermia-induced Tau oligomerization as well as nucleic acid damage. This study clearly highlights the existence of an early and critical time frame for hyperthermia-induced Tau oligomerization, which most likely occurs through increased oxidative stress, and nucleic acid vulnerability during the progression of Tau pathology. These results suggest that at early stages of AD, Tau oligomerization triggers the loss of the nucleic acid protective function of monomeric Tau. This study highlights the existence of a short therapeutic window in which to prevent the formation of pathological forms of Tau and their harmful consequences on nucleic acid integrity during the progression of Tau pathology., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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