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1. Deciphering Brain Metastasis Stem Cell Properties From Colorectal Cancer Highlights Specific Stemness Signature and Shared Molecular FeaturesSummary

Author

Amandine Desette, Pierre-Olivier Guichet, Sheik Emambux, Konstantin Masliantsev, Ulrich Cortes, Birama Ndiaye, Serge Milin, Simon George, Mathieu Faigner, Julie Tisserand, Afsaneh Gaillard, Sébastien Brot, Michel Wager, David Tougeron, and Lucie Karayan-Tapon

Subjects
Cancer Stem Cells, Colorectal Cancer, Brain Metastases, Stemness Signature, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Brain metastases (BMs) from colorectal cancer (CRC) are associated with significant morbidity and mortality, with chemoresistance and short overall survival. Migrating cancer stem cells with the ability to initiate BM have been described in breast and lung cancers. In this study, we describe the identification and characterization of cancer stem cells in BM from CRC. Methods: Four brain metastasis stem cell lines from patients with colorectal cancer (BM-SC-CRC1 to BM-SC-CRC4) were obtained by mechanical dissociation of patient’s tumors and selection of cancer stem cells by appropriate culture conditions. BM-SC-CRCs were characterized in vitro by clonogenic and limiting-dilution assays, as well as immunofluorescence and Western blot analyses. In ovo, a chicken chorioallantoic membrane (CAM) model and in vivo, xenograft experiments using BALB/c-nude mice were realized. Finally, a whole exome and RNA sequencing analyses were performed. Results: BM-SC-CRC formed metaspheres and contained tumor-initiating cells with self-renewal properties. They expressed stem cell surface markers (CD44v6, CD44, and EpCAM) in serum-free medium and CRC markers (CK19, CK20 and CDX-2) in fetal bovine serum-enriched medium. The CAM model demonstrated their invasive and migratory capabilities. Moreover, mice intracranial xenotransplantation of BM-SC-CRCs adequately recapitulated the original patient BM phenotype. Finally, transcriptomic and genomic approaches showed a significant enrichment of invasiveness and specific stemness signatures and highlighted KMT2C as a potential candidate gene to potentially identify high-risk CRC patients. Conclusions: This original study represents the first step in CRC BM initiation and progression comprehension, and further investigation could open the way to new therapeutics avenues to improve patient prognosis.

Published
2023
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2. Dual MGMT inactivation by promoter hypermethylation and loss of the long arm of chromosome 10 in glioblastoma

Author

Sophie Richard, Gaëlle Tachon, Serge Milin, Michel Wager, and Lucie Karayan‐Tapon

Subjects
10q, comparative genomic hybridization, glioblastoma, loss of heterozygosity, MGMT, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Epigenetic inactivation of O6‐methylguanine‐methyltransferase (MGMT) gene by methylation of its promoter is predictive of Temozolomid (TMZ) response in glioblastoma (GBM). MGMT is located on chromosome 10q26 and the loss of chromosome 10q is observed in 70% of GBMs. In this study, we assessed the hypothesis that the dual inactivation of MGMT, by hypermethylation of MGMT promoter and by loss the long arm of chromosome 10 (10q), may confer greater sensitivity to TMZ. Methods A total of 149 tumor samples from patients diagnosed with GBM based on the WHO 2016 classification were included in this retrospective study between November 2016 and December 2018. Methylation status of MGMT promoter was evaluated by pyrosequencing and status of chromosome 10q was assessed by array comparative genomic hybridization. Results Glioblastoma patients with chromosome 10q loss associated with hypermethylation of MGMT promoter had significantly longer overall survival (OS) (P = .0024) and progression‐free survival (PFS) (P = .031). Indeed, median OS of patients with dual inactivation of MGMT was 21.5 months compared to 12 months and 8.1 months for groups with single MGMT inactivation by hypermethylation and by 10q loss, respectively. The group with no MGMT inactivation had 9.5 months OS. Moreover, all long‐term survivors with persistent response to TMZ treatment (OS ≥ 30 months) displayed dual inactivation of MGMT. Conclusions Our data suggest that the molecular subgroup characterized by the dual inactivation of MGMT receives greater benefit from TMZ treatment. The results of our study may be of immediate clinical interest since chromosome 10q status and methylation of MGMT promoter are commonly determined in routine practice.

Published
2020
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3. Targeted RNA‐sequencing assays: a step forward compared to FISH and IHC techniques?

Author

Gaëlle Tachon, Ulrich Cortes, Sophie Richard, Sébastien Martin, Serge Milin, Camille Evrard, Corinne Lamour, and Lucie Karayan‐Tapon

Subjects
cancer genetics, lung cancer, medical genetics, next‐generation sequencing, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Introduction ALK and ROS1 rearrangements are molecular targets of several tyrosine kinase inhibitors. RNA‐sequencing approaches are regarded as the new standard for fusion gene detection, representing an alternative to standard immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) techniques. Patients and Methods We aimed to compare two recent amplicon‐based RNA‐sequencing techniques: FusionPlex® Alk Ret Ros1 v2 Kit (Archer®) with FHS‐003Z‐12—Human Lung Cancer Panel (Qiagen®) and assessed the accuracy of the data for therapy management. Thirty‐seven formalin‐fixed paraffin‐embedded non‐small cell carcinoma (NSCC) lesions initially explored by IHC and FISH were selected for RNA‐sequencing analysis. Results Qiagen® and Archer® kits produced similar results and correctly identified 85.1% (23/27) and 81.5% (22/27) of IHC/FISH ALK‐ and ROS1‐positive samples, respectively, and 100% (6/6) of the negative samples. With regard to the ambiguous IHC‐positive/FISH‐negative cases, RNA‐sequencing confirmed 75% (3/4) of the FISH conclusion. Although not statistically significant, patients with common EML4‐ALK variants presented shorter overall survival and progression‐free survival compared with patients harboring rare variants. Conclusion Our findings assessed the implementation of RNA‐sequencing approaches to explore ALK and ROS1 rearrangements from formalin‐fixed paraffin‐embedded samples. We highlighted the similarities between Qiagen® and Archer® kits in terms of handling time, cost, and outcomes. We confirmed the feasibility of molecular testing in routine organization and its possible use not only as an alternative for standard IHC and FISH techniques, but as a supplementary technique helping to classify discrepant cases.

Published
2019
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4. MEOX2 Transcription Factor Is Involved in Survival and Adhesion of Glioma Stem-like Cells

Author

Gaëlle Tachon, Konstantin Masliantsev, Pierre Rivet, Amandine Desette, Serge Milin, Elise Gueret, Michel Wager, Lucie Karayan-Tapon, and Pierre-Olivier Guichet

Subjects
MEOX2, glioma stem-like cells, differentiation, ERK, CDH10, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The high expression of MEOX2 transcription factor is closely associated with poor overall survival in glioma. MEOX2 has recently been described as an interesting prognostic biomarker, especially for lower grade glioma. MEOX2 has never been studied in glioma stem-like cells (GSC), responsible for glioma recurrence. The aim of our study was to investigate the role of MEOX2 in GSC. Loss of function approach using siRNA was used to assess the impact of MEOX2 on GSC viability and stemness phenotype. MEOX2 was localized in the nucleus and its expression was heterogeneous between GSCs. MEOX2 expression depends on the methylation state of its promoter and is strongly associated with IDH mutations. MEOX2 is involved in cell proliferation and viability regulation through ERK/MAPK and PI3K/AKT pathways. MEOX2 loss of function correlated with GSC differentiation and acquisition of neuronal lineage characteristics. Besides, inhibition of MEOX2 is correlated with increased expression of CDH10 and decreased pFAK. In this study, we unraveled, for the first time, MEOX2 contribution to cell viability and proliferation through AKT/ERK pathway and its potential involvement in phenotype and adhesion properties of GSC.

Published
2021
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5. Tri-methylation of H3K79 is decreased in TGF-β1-induced epithelial-to-mesenchymal transition in lung cancer

Author

Emilie Evanno, Julie Godet, Nathalie Piccirilli, Joëlle Guilhot, Serge Milin, Jean Marc Gombert, Benoit Fouchaq, and Joëlle Roche

Subjects
Lung cancer, NSCLC, EMT, H3K79me3, DOT1L, PD-L1, Medicine, Genetics, QH426-470
Abstract

Abstract Background The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-β1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT. Results Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-β1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD-L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-β1-induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-β1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF-β1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin. Conclusion Histone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses.

Published
2017
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6. Trans ε viniferin decreases amyloid deposits and inflammation in a mouse transgenic Alzheimer model.

Author

Martial Caillaud, Jérôme Guillard, Damien Richard, Serge Milin, Damien Chassaing, Marc Paccalin, Guylène Page, and Agnès Rioux Bilan

Subjects
Medicine, Science
Abstract

As Alzheimer's disease (AD) induces several cellular and molecular damages, it could be interesting to use multi-target molecules for therapeutics. We previously published that trans ε-viniferin induced the disaggregation of Aβ42 peptide and inhibited the inflammatory response in primary cellular model of AD. Here, effects of this stilbenoid were evaluated in transgenic APPswePS1dE9 mice. We report that trans ε-viniferin could go through the blood brain barrier, reduces size and density of amyloid deposits and decreases reactivity of astrocytes and microglia, after a weekly intraperitoneal injection at 10 mg/kg from 3 to 6 months of age.

Published
2019
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7. New Antibody-Free Mass Spectrometry-Based Quantification Reveals That C9ORF72 Long Protein Isoform Is Reduced in the Frontal Cortex of Hexanucleotide-Repeat Expansion Carriers

Author

Arthur Viodé, Clémence Fournier, Agnès Camuzat, François Fenaille, NeuroCEB Brain Bank, Morwena Latouche, Fanny Elahi, Isabelle Le Ber, Christophe Junot, Foudil Lamari, Vincent Anquetil, François Becher, Franck Letournel, Anne Vital, Françoise Chapon, Catherine Godfraind, Claude-Alain Maurage, Vincent Deramecourt, David Meyronnet, Nathalie Streichenberger, André Maues de Paula, Valérie Rigau, Fanny Vandenbos-Burel, Charles Duyckaerts, Danielle Seilhean, Véronique Sazdovitch, Serge Milin, Dan Christian Chiforeanu, Annie Laquerrière, and Béatrice Lannes

Subjects
frontotemporal dementia (FTD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), C9ORF72, TDP-43, TDP43, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Frontotemporal dementia (FTD) is a fatal neurodegenerative disease characterized by behavioral and language disorders. The main genetic cause of FTD is an intronic hexanucleotide repeat expansion (G4C2)n in the C9ORF72 gene. A loss of function of the C9ORF72 protein associated with the allele-specific reduction of C9ORF72 expression is postulated to contribute to the disease pathogenesis. To better understand the contribution of the loss of function to the disease mechanism, we need to determine precisely the level of reduction in C9ORF72 long and short isoforms in brain tissue from patients with C9ORF72 mutations. In this study, we developed a sensitive and robust mass spectrometry (MS) method for quantifying C9ORF72 isoform levels in human brain tissue without requiring antibody or affinity reagent. An optimized workflow based on surfactant-aided protein extraction and pellet digestion was established for optimal recovery of the two isoforms in brain samples. Signature peptides, common or specific to the isoforms, were targeted in brain extracts by multiplex MS through the parallel reaction monitoring mode on a Quadrupole–Orbitrap high resolution mass spectrometer. The assay was successfully validated and subsequently applied to frontal cortex brain samples from a cohort of FTD patients with C9ORF72 mutations and neurologically normal controls without mutations. We showed that the C9ORF72 short isoform in the frontal cortices is below detection threshold in all tested individuals and the C9ORF72 long isoform is significantly decreased in C9ORF72 mutation carriers.

Published
2018
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8. Pathological and Molecular Characteristics of Colorectal Cancer with Brain Metastases

Author

Pauline Roussille, Gaelle Tachon, Claire Villalva, Serge Milin, Eric Frouin, Julie Godet, Antoine Berger, Sheik Emambux, Christos Petropoulos, Michel Wager, Lucie Karayan-Tapon, and David Tougeron

Subjects
brain metastases, colorectal cancer, KRAS mutation, PD-L1, tumor infiltrating lymphocytes, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Colorectal cancers (CRC) with brain metastases (BM) are scarcely described. The main objective of this study was to determine the molecular profile of CRC with BM. Methods: We included 82 CRC patients with BM. KRAS, NRAS, BRAF and mismatch repair (MMR) status were investigated on primary tumors (n = 82) and BM (n = 38). ALK, ROS1, cMET, HER-2, PD-1, PD-L1, CD3 and CD8 status were evaluated by immunohistochemistry, and when recommended, by fluorescence in situ hybridization. Results: In primary tumors, KRAS, NRAS and BRAF mutations were observed in 56%, 6%, and 6% of cases, respectively. No ROS1, ALK and cMET rearrangement was detected. Only one tumor presented HER-2 amplification. Molecular profiles were mostly concordant between BM and paired primary tumors, except for 9% of discordances for RAS mutation. CD3, CD8, PD-1 and PD-L1 expressions presented some discordance between primary tumors and BM. In multivariate analysis, multiple BM, lung metastases and PD-L1+ tumor were predictive of poor overall survival. Conclusions: CRCs with BM are associated with high frequency of RAS mutations and significant discordance for RAS mutational status between BM and paired primary tumors. Multiple BM, lung metastases and PD-L1+ have been identified as prognostic factors and can guide therapeutic decisions for CRC patients with BM.

Published
2018
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9. Dual MGMT inactivation by promoter hypermethylation and loss of the long arm of chromosome 10 in glioblastoma

Author

Michel Wager, Sophie Richard, Serge Milin, Lucie Karayan-Tapon, and Gaëlle Tachon

Subjects
Male, 0301 basic medicine, Cancer Research, Time Factors, Central Nervous System Neoplasms, Loss of heterozygosity, 0302 clinical medicine, Medicine, Promoter Regions, Genetic, DNA Modification Methylases, Original Research, Cancer Biology, Aged, 80 and over, High-Throughput Nucleotide Sequencing, Methylation, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 10q, Progression-Free Survival, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Female, loss of heterozygosity, Chromosome Deletion, MGMT, Adult, Adolescent, comparative genomic hybridization, lcsh:RC254-282, Young Adult, 03 medical and health sciences, Temozolomide, Humans, Radiology, Nuclear Medicine and imaging, Gene Silencing, Epigenetics, Antineoplastic Agents, Alkylating, Gene, neoplasms, Aged, Retrospective Studies, Analysis of Variance, Chromosomes, Human, Pair 10, business.industry, Tumor Suppressor Proteins, glioblastoma, Chromosome, DNA Methylation, medicine.disease, digestive system diseases, DNA Repair Enzymes, 030104 developmental biology, Cancer research, CpG Islands, business, Comparative genomic hybridization, Glioblastoma
Abstract

Background Epigenetic inactivation of O6‐methylguanine‐methyltransferase (MGMT) gene by methylation of its promoter is predictive of Temozolomid (TMZ) response in glioblastoma (GBM). MGMT is located on chromosome 10q26 and the loss of chromosome 10q is observed in 70% of GBMs. In this study, we assessed the hypothesis that the dual inactivation of MGMT, by hypermethylation of MGMT promoter and by loss the long arm of chromosome 10 (10q), may confer greater sensitivity to TMZ. Methods A total of 149 tumor samples from patients diagnosed with GBM based on the WHO 2016 classification were included in this retrospective study between November 2016 and December 2018. Methylation status of MGMT promoter was evaluated by pyrosequencing and status of chromosome 10q was assessed by array comparative genomic hybridization. Results Glioblastoma patients with chromosome 10q loss associated with hypermethylation of MGMT promoter had significantly longer overall survival (OS) (P = .0024) and progression‐free survival (PFS) (P = .031). Indeed, median OS of patients with dual inactivation of MGMT was 21.5 months compared to 12 months and 8.1 months for groups with single MGMT inactivation by hypermethylation and by 10q loss, respectively. The group with no MGMT inactivation had 9.5 months OS. Moreover, all long‐term survivors with persistent response to TMZ treatment (OS ≥ 30 months) displayed dual inactivation of MGMT. Conclusions Our data suggest that the molecular subgroup characterized by the dual inactivation of MGMT receives greater benefit from TMZ treatment. The results of our study may be of immediate clinical interest since chromosome 10q status and methylation of MGMT promoter are commonly determined in routine practice., MGMT can be inactivated by two mechanisms: methylation of promoter and chr10q loss. Dual inactivation of MGMT selected a population with greater benefit from TMZ. Patients with long‐term OS (>30months) presented dual inactivation of MGMT. Chr10q status and methylation of MGMT are commonly determined in routine practice.

Published
2020

10. New Insights into Expression of Hormonal Receptors by Meningiomas

Author

Serge Milin, Marie Flores, Pierre Ingrand, Tania Banor, Benoit Bataille, Lucie Karayan-Tapon, Adrien Simonneau, Sylvain Portet, Jonathan Bousquet, Université de Poitiers - Faculté de Médecine et de Pharmacie, Université de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de neurosciences expérimentales et cliniques (LNEC), and Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Pathology, medicine.medical_specialty, medicine.drug_class, [SDV]Life Sciences [q-bio], Estrogen receptor, Meningioma, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Progesterone receptor, otorhinolaryngologic diseases, medicine, Meningeal Neoplasms, Humans, neoplasms, Aged, Tissue microarray, business.industry, Cyproterone acetate, Middle Aged, Androgen, medicine.disease, nervous system diseases, Androgen receptor, Gene Expression Regulation, Neoplastic, chemistry, Receptors, Estrogen, Estrogen, Receptors, Androgen, 030220 oncology & carcinogenesis, Surgery, Female, Neurology (clinical), business, Receptors, Progesterone, 030217 neurology & neurosurgery
Abstract

Objective Meningiomas have a female predilection, which is even stronger for spinal than for intracranial meningiomas. The relationship between meningiomas and endogenous or exogenous sex hormones such as cyproterone acetate (CPA) is well documented, yet their underlying mechanism remains unknown. Clarification of the expression profile of hormonal receptors by meningiomas would help us to better understand their hormonal susceptibility. Methods We used tissue microarray and immunohistochemistry to determine the receptor status of the 3 main sex hormones: androgen (AR), estrogen, and progesterone (PR) in 30 intracranial meningiomas, 30 spinal meningiomas, and 30 meningiomas developed on CPA. Results AR status was positive in 73% of meningiomas in the intracranial group, 87% of meningiomas in the CPA group, and in all meningiomas in the spinal group. Estrogen status was positive in only 7% of meningiomas in the intracranial group and in only 3% of meningiomas in the CPA group but in 30% of meningiomas in the spinal group. PR status was positive in 90% of meningiomas in the intracranial group, in 97% of meningiomas in the CPA group, and in 87% of meningiomas in the spinal group. These specific hormonal receptor statuses based on immunoreactive score were reflected on staining intensities. Furthermore, AR and PR expression was correlated in each group. Conclusions Our study shows that intracranial meningiomas, spinal meningiomas, and meningiomas developed on CPA express specific hormonal receptor patterns. This result invites the scientific community to review the potential role of AR in the unbalanced sex ratio of meningiomas.

Published
2020

11. Tri-methylation of H3K79 is decreased in TGF-β1-induced epithelial-to-mesenchymal transition in lung cancer

Author

Julie Godet, Benoit Fouchaq, Nathalie Piccirilli, Serge Milin, Joelle Guilhot, Joëlle Roche, Emilie Evanno, Jean Marc Gombert, Eurofins-Cerep, Laboratoire de neurosciences expérimentales et cliniques (LNEC), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Poitiers, INSERM CIC 0802 (INSERM - CHU de Poitiers), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Université de Poitiers, Ecologie et biologie des interactions (EBI), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Pinet, Nicolas, and Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Lung Neoplasms, H3K79me3, lcsh:Medicine, NSCLC, Epigenesis, Genetic, Histones, Transforming Growth Factor beta, Histone methylation, Gene Regulatory Networks, NRP2, Genetics (clinical), Epigenetic treatment, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Chemistry, Histone deacetylase inhibitor, EMT, 3. Good health, Lung cancer, Reprogramming, PD-L1, Epithelial-Mesenchymal Transition, lcsh:QH426-470, medicine.drug_class, Down-Regulation, Methylation, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Humans, Epithelial–mesenchymal transition, Epigenetics, Molecular Biology, Cell Proliferation, A549 cell, Cell growth, Research, lcsh:R, DOT1L, Histone Deacetylase Inhibitors, lcsh:Genetics, 030104 developmental biology, A549 Cells, SEMA3C, Cancer research, Benzimidazoles, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology
Abstract

Background The epithelial-to-mesenchymal transition (EMT) enables epithelial cancer cells to acquire mesenchymal features and contributes to metastasis and resistance to treatment. This process involves epigenetic reprogramming for gene expression. We explored global histone modifications during TGF-β1-induced EMT in two non-small cell lung cancer (NSCLC) cell lines and tested different epigenetic treatment to modulate or partially reverse EMT. Results Loss of classical epithelial markers and gain of mesenchymal markers were verified in A549 and H358 cell lines during TGF-β1-induced EMT. In addition, we noticed increased expression of the axonal guidance protein semaphorin 3C (SEMA3C) and PD-L1 (programmed death-ligand 1) involved in the inhibition of the immune system, suggesting that both SEMA3C and PD-L1 could be the new markers of TGF-β1-induced EMT. H3K79me3 and H2BK120me1 were decreased in A549 and H358 cell lines after a 48-h TGF-β1 treatment, as well as H2BK120ac in A549 cells. However, decreased H3K79me3 was not associated with expression of the histone methyltransferase DOT1L. Furthermore, H3K79me3 was decreased in tumors compared in normal tissues and not associated with cell proliferation. Associations of histone deacetylase inhibitor (SAHA) with DOT1L inhibitors (EPZ5676 or SGC0946) or BET bromodomain inhibitor (PFI-1) were efficient to partially reverse TGF-β1 effects by decreasing expression of PD-L1, SEMA3C, and its receptor neuropilin-2 (NRP2) and by increasing epithelial markers such as E-cadherin. Conclusion Histone methylation was modified during EMT, and combination of epigenetic compounds with conventional or targeted chemotherapy might contribute to reduce metastasis and to enhance clinical responses. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0380-0) contains supplementary material, which is available to authorized users.

Published
2017

12. Natural course and prognosis of anaplastic gangliogliomas: a multicenter retrospective study of 43 cases from the French Brain Tumor Database

Author

Luc Bauchet, Eric Bord, Valérie Rigau, Johan Pallud, Bertrand Muckenstrum, Guillaume Gauchotte, Louis-Marie Terrier, Walid Farah, Patrick François, Isabelle Filipiak, Bertrand Debono, Phong Dam Hieu, Bernard Irthum, Audrey Rousseau, Pierre-Hugues Roche, Catherine Godfraind, Pierre-Jean Le Reste, Marie-Bernadette Delisle, Agnès Caille, Philippe Metellus, Stéphane Velut, Alain Czorny, Anne-Marie Bergemer-Fouquet, Philippe Menei, D. Liguoro, Michel Wager, Marie-Hélène Aubriot-Lorton, Emmanuel Mandonnet, Pascale Varlet, Jimmy Voirin, Serge Milin, Sonia Zouaoui, Kevin Janot, Ilyess Zemmoura, Hugues Loiseau, Jacques Guyotat, Marc Zanello, Philippe Cornu, Evelyne Emery, Aymeric Amelot, Vincent Lubrano, Guillaume Lot, Fabien Almairac, Dominique Figarella-Branger, Anne Vital, Emmanuelle Uro-Coste, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie Valrose (IBV), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de Pathologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurochirurgie [Brest], Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Service de neurochirurgie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Sérine protéases et physiopathologie de l'unité neurovasculaire, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie [CHU Dijon], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Neurochirurgie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurochirurgie, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Kastler Brossel (LKB (Lhomond)), Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de neurochirurgie [CHU Marseille], Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), 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 Mouvement Adaptation Cognition (MAC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Cellules souches leucémiques et thérapeuthiques, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université Sorbonne Paris Cité (USPC), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Archimedes Pharma®, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Centre National de la Recherche Scientifique (CNRS)-Université de Tours-Institut Français du Cheval et de l'Equitation [Saumur]-Institut National de la Recherche Agronomique (INRA), CIC 1415, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Francois Rabelais [Tours], Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie [Rouen], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Service de neurochirurgie [CHU de Dijon], Université Catholique de Louvain (UCL)-Clinique Saint-Luc, Service de Neurochirurgie [Clermont-Ferrand], CHU Clermont-Ferrand-Hôpital Gabriel Montpied, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-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)-École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), 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), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Département de Neurochirurgie [CHU Toulouse], Université Pierre et Marie Curie - Paris 6 (UPMC)-Fédération de recherche du Département de physique de l'Ecole Normale Supérieure - ENS Paris (FRDPENS), Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), 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), and Institut National de la Recherche Agronomique (INRA)-Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, Adolescent, Databases, Factual, [SDV]Life Sciences [q-bio], Clinical Investigations, Brain tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Ganglioglioma, cerebral malignancy, surgery, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Progression-free survival, Pathological, Survival rate, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Intracranial pressure, Brain Neoplasms, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Combined Modality Therapy, 3. Good health, Survival Rate, Oncology, 030220 oncology & carcinogenesis, Anaplastic Ganglioglioma, Disease Progression, Female, Neurology (clinical), Radiology, prognosis, business, 030217 neurology & neurosurgery, anaplastic ganglioglioma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

International audience; Background - Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods - Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results - Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions - We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

Published
2017

13. Supratentorial clear cell ependymomas with branching capillaries demonstrate characteristic clinicopathological features and pathological activation of nuclear factor-kappaB signaling

Author

Stephanie Theresa Jünger, Didier Scavarda, François Labrousse, Catherine Godfraind, Henri Sevestre, Philippe Metellus, Anne Jouvet, Carole Colin, Isabelle Quintin-Roue, Corinne Bouvier, Emeline Tabouret, Marie-Christine Machet, Felipe Andreiuolo, Emmanuèle Lechapt-Zalcman, Fabien Forest, André Maues De Paula, Anne Heitzmann, Torsten Pietsch, Serge Milin, Dominique Figarella-Branger, Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), University of Bonn, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de pathologie [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional d'Orléans (CHRO), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Amiens-Picardie, CHU Clermont-Ferrand, Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, Service de neurochirurgie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Universität Bonn = University of Bonn, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurochirurgie [CHU Marseille], and figarella-branger, dominique

Subjects
Ependymoma, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Cancer Research, Pathology, medicine.medical_specialty, intracranial, clear cell ependymomas, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Viral Oncogene, RelA, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Chromosome 19, Chromosome instability, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, NF kappa B, trisomy 19, Pathological, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Supratentorial Neoplasms, medicine.disease, 3. Good health, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Basic and Translational Investigations, Clinicopathological features, Neurology (clinical), 030217 neurology & neurosurgery, Clear cell
Abstract

International audience; Clear cell ependymoma is one of the 4 main histological subtypes of ependymomas defined by the World Health Organization (WHO) classification of tumors of the CNS. DNA methylation profiling can distinguish 4 subgroups of intracranial ependymomas, including supratentorial (ST) ependymomas with Yes-associated protein 1 fusion (YAP1), ST ependymomas with fusion of v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), posterior fossa ependymomas with balanced genome, and posterior fossa ependymomas with chromosomal instability. In addition, trisomy 19 is a genomic hallmark of ependymomas with rich branching capillaries. However, the relation of histological and molecular subtypes is unclear.

Published
2016

14. Kidney Diseases Associated With Monoclonal Immunoglobulin M-Secreting B-Cell Lymphoproliferative Disorders: A Case Series of 35 Patients

Author

Laure Ecotiere, Vincent Javaugue, Jean-Paul Fermand, Serge Milin, Antoine Thierry, Bertrand Arnulf, Sébastien Bender, Sophie Chauvet, Jean-Michel Goujon, Frank Bridoux, Christophe Sirac, Nathalie Quellard, Arnaud Jaccard, Guy Touchard, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), CHU Limoges, and Carrion, Claire

Subjects
Nephrology, Adult, Male, medicine.medical_specialty, Pathology, Amyloid, Lymphoma, B-Cell, Nephrotic Syndrome, [SDV.IMM] Life Sciences [q-bio]/Immunology, Glomerulonephritis, Membranoproliferative, Paraproteinemias, Gastroenterology, Nephropathy, Cohort Studies, Internal medicine, medicine, Humans, 10. No inequality, Aged, Retrospective Studies, Aged, 80 and over, B-Lymphocytes, business.industry, Acute kidney injury, Waldenstrom macroglobulinemia, Antibodies, Monoclonal, Amyloidosis, Acute Kidney Injury, Middle Aged, medicine.disease, Kidney Neoplasms, Lymphoproliferative Disorders, 3. Good health, IgM Monoclonal Gammopathy, Hematologic disease, Renal pathology, Immunoglobulin M, Nephritis, Interstitial, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Kidney Diseases, Waldenstrom Macroglobulinemia, business, Nephrotic syndrome
Abstract

International audience; BACKGROUND:Kidney diseases associated with immunoglobulin M (IgM) monoclonal gammopathy are poorly described, with few data for patient outcomes and renal response.STUDY DESIGN:Case series.SETTING & PARTICIPANTS:35 patients from 8 French departments of nephrology were retrospectively studied. Inclusion criteria were: (1) detectable serum monoclonal IgM, (2) estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 and/or proteinuria with protein excretion > 0.5g/d and/or microscopic hematuria, and (3) kidney biopsy showing monoclonal immunoglobulin deposits and/or lymphomatous B-cell renal infiltration. All patients received chemotherapy, including rituximab-based regimens in 8 cases.PREDICTORS:Patients were classified into 3 groups according to renal pathology: glomerular AL amyloidosis (group 1; n=11), nonamyloid glomerulopathies (group 2; n=15, including 9 patients with membranoproliferative glomerulonephritis), and tubulointerstitial nephropathies (group 3; n=9, including cast nephropathy in 5, light-chain Fanconi syndrome in 3, and isolated tumor infiltration in 1).OUTCOMES:Posttreatment hematologic response (≥50% reduction in serum monoclonal IgM and/or free light chain level) and renal response (≥50% reduction in 24-hour proteinuria or eGFR≥30mL/min/1.73m2 in patients with glomerular and tubulointerstitial disorders, respectively).RESULTS:Nephrotic syndrome was observed in 11 and 6 patients in groups 1 and 2, respectively. Patients in group 3 presented with acute kidney injury (n=7) and/or proximal tubular dysfunction (n=3). Waldenström macroglobulinemia was present in 26 patients (8, 12, and 6 in groups 1, 2, and 3, respectively). Significant lymphomatous interstitial infiltration was observed in 18 patients (4, 9, and 5 patients, respectively). Only 9 of 29 evaluable patients had systemic signs of symptomatic hematologic disease (2, 5, and 2, respectively). In groups 1, 2, and 3, respectively, hematologic response was achieved after first-line treatment in 3 of 9, 9 of 10, and 5 of 6 evaluable patients, while renal response occurred in 5 of 10, 9 of 15, and 5 of 8 evaluable patients.LIMITATIONS:Retrospective study; insufficient population to establish the impact of chemotherapy.CONCLUSIONS:IgM monoclonal gammopathy is associated with a wide spectrum of renal manifestations, with an under-recognized frequency of tubulointerstitial disorders.

Published
2015

15. A mesenchymal glioma stem cell profile is related to clinical outcome

Author

Ulrich Cortes, Flamant S, Anais Balbous, Claire Villalva, Serge Milin, Jean-Claude Chomel, Annelise Bennaceur-Griscelli, Joelle Guilhot, Michel Wager, Ali G. Turhan, Afsaneh Gaillard, Guilloteau K, Lucie Karayan-Tapon, Nathalie Sorel, Université de Poitiers - Faculté de Sciences fondamentales et appliquées, Université de Poitiers, Service de Cancérologie Biologique, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), and Centre Scientifique et Technique du Bâtiment (CSTB)

Subjects
Homeobox protein NANOG, Cancer Research, COL1A1, glioblastoma stem cells, [SDV]Life Sciences [q-bio], Mesenchymal stem cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease, Bioinformatics, Embryonic stem cell, survival, Neural stem cell, Gene expression profiling, IFITM1, mesenchymal profile, SOX2, Glioma, Cancer research, medicine, Original Article, Stem cell, Molecular Biology
Abstract

International audience; Recent studies have demonstrated a relationship between the expression of stem cell-associated genes and relapses in glioblastoma (GBM), suggesting a key role for tumor stem cells in this process. Although there is increasing interest in this field, glioma stem cells (GSCs) are still poorly characterized, their 'stemness' state and factors maintaining these properties remain largely unknown. We performed an expression profiling analysis of pluripotency in gliomaspheres derived from 11 patients. Comparative analysis between GSCs and H1 and H9 human embryonic stem cells as well as H9-derived neural stem cells indicates major variations in gene expression of pluripotency factors Nanog and OCT4, but a stable pattern for SOX2 suggesting its important function in maintaining pluripotency in GSCs. Our results also showed that all GSC lines have the capacity to commit to neural differentiation and express mesenchymal or endothelial differentiation markers. In addition, hierarchical clustering analysis revealed two groups of GSCs reflecting their heterogeneity and identified COL1A1 and IFITM1 as the most discriminating genes. Similar patterns have been observed in tumors from which gliomaspheres have been established. To determine whether this heterogeneity could be clinically relevant, the expression of both genes was further analyzed in an independent cohort of 30 patients with GBM and revealed strong correlation with overall survival. In vitro silencing of COL1A1 and IFTM1 confirmed the effect of these mesenchymal-associated genes on cell invasion and gliomasphere initiation. Our results indicate that COL1A1 and IFITM1 genes could be considered for use in stratifying patients with GBM into subgroups for risk of recurrence at diagnosis, as well as for prognostic and therapeutic evolution.

Published
2014

16. Prevention of the β-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures

Author

Serge Milin, Milena Morel, Bernard Fauconneau, Julien Couturier, Guylène Page, Faraj Terro, Raymond Pontcharraud, Marc Paccalin, Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Service de gériatrie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), 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), Service d'Histologie, cytologie, cytogénétique, biologie cellulaire [CHU Limoges], CHU Limoges, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Anatomie et de Cytologie Pathologiques [Poitiers], This study was supported by a grant from the Association France Alzheimer and by the French Ministry of Education and Research with a grant to the Research Unit GReViC, EA 3808 and by the Poitiers University Hospital., BMC, Ed., and Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-CHU Limoges

Subjects
MESH: Inflammation, MESH: Signal Transduction, Indoles, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Neurons, MESH: NF-kappa B, Apoptosis, lcsh:RC346-429, Mice, eIF-2 Kinase, 0302 clinical medicine, Annexin, MESH: Animals, Cells, Cultured, Neurons, MESH: Indoles, 0303 health sciences, MESH: Cytokines, Microglia, General Neuroscience, Imidazoles, NF-kappa B, Interleukin, MESH: Amyloid beta-Peptides, I-kappa B Kinase, MESH: Microglia, medicine.anatomical_structure, Neurology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, MESH: Imidazoles, Signal Transduction, MESH: Cells, Cultured, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Microscopy, Electron, Scanning, Immunology, Biology, MESH: eIF-2 Kinase, MESH: Coculture Techniques, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, MESH: I-kappa B Kinase, Protein kinase A, MESH: Mice, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, Inflammation, EIF-2 kinase, Amyloid beta-Peptides, MESH: Humans, Research, MESH: Apoptosis, I-Kappa-B Kinase, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Molecular biology, Protein kinase R, Coculture Techniques, Mice, Inbred C57BL, MESH: Astrocytes, Astrocytes, biology.protein, Microscopy, Electron, Scanning, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract

Background Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by β-amyloid (Aβ) peptides, the nuclear factor-kappa B (NF-κB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-κB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Aβ42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia. Methods Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Aβ neurotoxicity (72 h), co-cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1β, and IL-6 were assessed by ELISA. Levels of PT451-PKR and activation of IκB, NF-κB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of PT451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test Results In these co-cultures, PKR inhibition prevented Aβ42-induced activation of IκB and NF-κB, strongly decreased production and release of tumor necrosis factor (TNFα) and interleukin (IL)-1β, and limited apoptosis. Conclusion In spite of the complexity of the innate immune response, PKR inhibition could be an interesting anti-inflammatory strategy in AD.

Published
2011

17. Analysis of machine perfusion benefits in kidney grafts: a preclinical study

Author

N. Chatauret, Serge Milin, Frédéric Favreau, Michel Eugene, Benoit Barrou, Thierry Hauet, Raphael Thuillier, Nader Vaziri, Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Urologie et chirurgie de la transplantation, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de Biochimie [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), FLIRT, Fédération pour L'étude de l'Ischémie Reperfusion en Transplantation, IBISA, IBiSA, Service d'Urologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Funding sources: the Conseil Général de la Vienne, Région Poitou Charentes, the Banque Tarneaud, Poitiers, CHU de Poitiers and Inserm, the Société Francophone de Transplantation, the French Foundation of Transplantation., and BMC, Ed.

Subjects
Male, medicine.medical_specialty, Epithelial-Mesenchymal Transition, Swine, Urinary system, 030232 urology & nephrology, Urology, Renal function, lcsh:Medicine, 030230 surgery, Kidney, Risk Assessment, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Fibrosis, Transplantation Immunology, Medicine, Animals, Kidney transplantation, Medicine(all), Tissue Survival, Machine perfusion, Immunity, Cellular, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Biochemistry, Genetics and Molecular Biology(all), Research, lcsh:R, General Medicine, Organ Preservation, Recovery of Function, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Kidney Transplantation, Tissue Donors, Surgery, Transplantation, Perfusion, medicine.anatomical_structure, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Machine perfusion (MP) has potential benefits for marginal organs such as from deceased from cardiac death donors (DCD). However, there is still no consensus on MP benefits. We aimed to determine machine perfusion benefits on kidney grafts. Methods We evaluated kidney grafts preserved in ViaspanUW or KPS solutions either by CS or MP, in a DCD pig model (60 min warm ischemia + 24 h hypothermic preservation). Endpoints were: function recovery, quality of function during follow up (3 month), inflammation, fibrosis, animal survival. Results ViaspanUW-CS animals did not recover function, while in other groups early follow up showed similar values for kidney function. Alanine peptidase and β-NAG activities in the urine were higher in CS than in MP groups. Oxydative stress was lower in KPS-MP animals. Histology was improved by MP over CS. Survival was 0% in ViaspanUW-CS and 60% in other groups. Chronic inflammation, epithelial-to-mesenchymal transition and fibrosis were lowest in KPS-MP, followed by KPS-CS and ViaspanUW-MP. Conclusions With ViaspanUW, effects of MP are obvious as only MP kidney recovered function and allowed survival. With KPS, the benefits of MP over CS are not directly obvious in the early follow up period and only histological analysis, urinary tubular enzymes and red/ox status was discriminating. Chronic follow-up was more conclusive, with a clear superiority of MP over CS, independently of the solution used. KPS was proven superior to ViaspanUW in each preservation method in terms of function and outcome. In our pre-clinical animal model of DCD transplantation, MP offers critical benefits.

Published
2011

18. Direct Thrombin Inhibitor Prevents Delayed Graft Function in a Porcine Model of Renal Transplantation

Author

Emilie Manguy, Jean-Michel Goujon, Aude Belliard, Gérard Mauco, Sébastien Giraud, Raphael Thuillier, Laurent Macchi, William Hebrard, Thierry Hauet, Serge Milin, Cedric Nadeau, Ischémie - Reperfusion en transplatation rénale, Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Génétique Expérimentale en Productions Animales (GEPA), Institut National de la Recherche Agronomique (INRA), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Faculté de Médecine et de Pharmacie, Université officielle de Bukavu, Laboratoire d'hématologie, Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)

Subjects
Male, Benzylamines, Swine, [SDV]Life Sciences [q-bio], pig model transplantation, 030204 cardiovascular system & hematology, Pharmacology, 0302 clinical medicine, direct thrombin inhibitor, ischemia reperfusion injury, 0303 health sciences, Kidney, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, Antithrombin, Thrombin, 3. Good health, Mitochondria, Endothelial stem cell, medicine.anatomical_structure, Creatinine, Reperfusion Injury, Models, Animal, Partial Thromboplastin Time, medicine.symptom, medicine.drug, kidney preservation, Brain Death, Cell Survival, Renal function, Inflammation, Transplantation, Autologous, Renal Circulation, 03 medical and health sciences, medicine, Animals, Transplantation, Homologous, 030304 developmental biology, Transplantation, business.industry, graft function, Anticoagulants, Kidney Transplantation, Thromboelastography, Heart Arrest, Direct thrombin inhibitor, Immunology, Azetidines, business
Abstract

Chantier qualité GA; International audience; Background. Kidney transplantations from donors after cardiac arrest (DCA) are characterized by an increase in the occurrence of delayed graft function and primary nonfunction. In this study, Melagatran, a selective reversible direct thrombin inhibitor was used to limit renal injury in a DCA pig kidney transplantation model. Methods. We used a porcine model of DCA to study the effects of treatment with Melagatran in the peri-conservation period. Thromboelastography was used to check Melagatran antithrombin effect on in vitro clot formation. Reverse-transcriptase polymerase chain reaction was used to analyze the peripheral immune cells activation status. Renal function and morphologic study were performed at days 1 and 7. Finally, we analyzed the mechanisms of Melagatran protection on kidney microvasculature primary endothelial cells. Results. Prolongation of coagulation time (Ex-Tem) was observed 10 min after injection; however, Melagatran did not modulate increases of thrombin-antithrombin complexes following reperfusion. Melagatran significant treatment lowered the proinflammatory status of circulating immune cells. Animal's survival was increased in Melagatran-treated groups (9 of 10 in Melagatran groups vs. 4 of 10 in controls at day 7). Renal injury and inflammation were also significantly reduced in treated groups. We also demonstrated a direct protective effect of Melagatran against endothelial cell activation and inflammation in vitro. Conclusion. Direct thrombin inhibitor administration in the periconservation period improved graft outcome and reduced renal injury in a model of DCA.

Published
2009

19. A p38 mitogen-activated protein kinase inhibitor protects against renal damage in a non-heart-beating donor model

Author

Jean Michel Goujon, Vassilios Papadopoulos, Michel Eugene, Yuriyo Yamamoto, Thibault Desurmont, William Hebrard, Serge Milin, Frédéric Favreau, Emilie Manguy, Thierry Hauet, Carole Doucet, Gérard Mauco, Génétique Expérimentale en Productions Animales (GEPA), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration

Subjects
Male, medicine.medical_specialty, Pathology, Physiology, Angiogenesis, Pyridines, Swine, Urinary system, [SDV]Life Sciences [q-bio], Interleukin-1beta, 030232 urology & nephrology, Cold storage, p38 Mitogen-Activated Protein Kinases, Kidney Tubules, Proximal, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Renal fibrosis, Cell Adhesion, Animals, PIGS, Enzyme Inhibitors, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Tumor Necrosis Factor-alpha, TRANSPLANTATION, medicine.disease, Fibrosis, Kidney Transplantation, 3. Good health, [SDV] Life Sciences [q-bio], Vascular endothelial growth factor, Transplantation, Endocrinology, Receptors, Vascular Endothelial Growth Factor, chemistry, Reperfusion Injury, Tubulointerstitial fibrosis, Pyrazoles, Kidney Diseases, business, Kidney disease
Abstract

Ischemia-reperfusion injury is one of the central nonimmunologic processes involved in renal allograft dysfunction. Kidneys from non-heart beating donors (NHBD) exhibit higher rates of delayed graft function (DGF) than those from other donors. Primary nonfunction and DGF are the main barriers to the use of kidneys from NHBD. Using a pig model of NHBD transplantation, we studied the effect of FR167653 (a p38 MAP kinase inhibitor) on the recovery and reparation of kidneys exposed to both warm (WI: 1 h) and cold ischemia (24 h). Our results demonstrate that the addition of FR167653 increases the kinetics of proximal tubule cell regeneration after 60 min of WI. Hypoxia-inducible factor and vascular endothelial growth factor expression was also more important in FR167653-treated kidneys compared with those in nontreated groups. Also, expression of peripheral-type benzodiazepine receptor, involved in tissue repair, was increased in the FR167653-treated groups. At 3 mo, the protective effects of FR167653 were accompanied by a reduction of long-term inflammation process and tubulointerstitial fibrosis development associated with a limitation of ischemia-induced remodeling. This study suggests that such treatment may be useful in protocols aimed at improving the quality of renal transplants from NHBD. In addition, the beneficial role of FR167653 in limiting early injury is associated with secondary reduction in development of tubular atrophy and interstitial fibrosis which are together the hallmark of failing renal transplants. The more efficient effect was observed when FR167653 was added in combination before WI, during cold storage and reperfusion.

Published
2008

20. Long-term molecular efficacy and safety of imatinib in a patient with chronic myeloid leukaemia after renal transplantation

Author

Frank Bridoux, François Guilhot, Brigitte Dreyfus, Serge Milin, Ramzi Abou Ayache, Antoine Thierry, Guy Touchard, Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), 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), Service d'onco-hématologie et thérapie cellulaire, and Centre hospitalier universitaire de Poitiers (CHU Poitiers)

Subjects
Oncology, medicine.medical_specialty, MESH: Diabetic Nephropathies, 030232 urology & nephrology, MESH: Piperazines, Chronic myeloid leukaemia, MESH: Kidney Transplantation, 03 medical and health sciences, 0302 clinical medicine, Text mining, Internal medicine, medicine, MESH: Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Transplantation, MESH: Humans, MESH: Middle Aged, business.industry, MESH: Time Factors, Imatinib, 3. Good health, Term (time), MESH: Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Nephrology, MESH: Kidney Failure, Chronic, 030220 oncology & carcinogenesis, MESH: Pyrimidines, MESH: Antineoplastic Agents, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, MESH: Female, medicine.drug
Abstract

International audience

Published
2007

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