180 results on '"David Castel"'
Search Results
2. VRK3 depletion induces cell cycle arrest and metabolic reprogramming of pontine diffuse midline glioma - H3K27 altered cells
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Virginie Menez, Thomas Kergrohen, Tal Shasha, Claudia Silva-Evangelista, Ludivine Le Dret, Lucie Auffret, Chloé Subecz, Manon Lancien, Yassine Ajlil, Irma Segoviano Vilchis, Kévin Beccaria, Thomas Blauwblomme, Estelle Oberlin, Jacques Grill, David Castel, and Marie-Anne Debily
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VRK3 ,diffuse midline glioma H3 K27-altered ,oxidative phosphorylation (OXPHOS) ,cell cycle arrest ,pediatric glioma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-H3K27M cell fitness. Gene expression studies after VRK3 knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG following VRK3 knockdown. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations, e.g. with the mitochondrial ClpP protease activator ONC201.
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- 2023
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3. NF2 and ZFTA evaluation in the diagnostic algorithm of pediatric posterior fossa ependymoma with H3K27ME3 retained expression
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Arnault Tauziède-Espariat, Yassine Ajlil, Marie-Anne Debily, David Castel, Jacques Grill, Stéphanie Puget, Lauren Hasty, Fabrice Chrétien, Alice Métais, Volodia Dangouloff-Ros, Nathalie Boddaert, and Pascale Varlet
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2023
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4. Pediatric high-grade glioma MYCN is frequently associated with Li-Fraumeni syndrome
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Léa Guerrini-Rousseau, Arnault Tauziède-Espariat, David Castel, Etienne Rouleau, Philipp Sievers, Raphaël Saffroy, Kévin Beccaria, Thomas Blauwblomme, Lauren Hasty, Franck Bourdeaut, Jacques Grill, Pascale Varlet, and Marie-Anne Debily
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2023
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5. Mucosal transcriptomics highlight lncRNAs implicated in ulcerative colitis, Crohn’s disease, and celiac disease
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Tzipi Braun, Katya E. Sosnovski, Amnon Amir, Marina BenShoshan, Kelli L. VanDussen, Rebekah Karns, Nina Levhar, Haya Abbas-Egbariya, Rotem Hadar, Gilat Efroni, David Castel, Camila Avivi, Michael J. Rosen, Anne M. Grifiths, Thomas D. Walters, David R. Mack, Brendan M. Boyle, Syed Asad Ali, Sean R. Moore, Melanie Schirmer, Ramnik J. Xavier, Subra Kugathasan, Anil G. Jegga, Batya Weiss, Chen Mayer, Iris Barshack, Shomron Ben-Horin, Igor Ulitsky, Anthony Beucher, Jorge Ferrer, Jeffrey S. Hyams, Lee A. Denson, and Yael Haberman
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Gastroenterology ,Medicine - Abstract
Ulcerative colitis (UC), Crohn’s disease (CD), and celiac disease are prevalent intestinal inflammatory disorders with nonsatisfactory therapeutic interventions. Analyzing patient data-driven cohorts can highlight disease pathways and new targets for interventions. Long noncoding RNAs (lncRNAs) are attractive candidates, since they are readily targetable by RNA therapeutics, show relative cell-specific expression, and play key cellular functions. Uniformly analyzing gut mucosal transcriptomics from 696 subjects, we have highlighted lncRNA expression along the gastrointestinal (GI) tract, demonstrating that, in control samples, lncRNAs have a more location-specific expression in comparison with protein-coding genes. We defined dysregulation of lncRNAs in treatment-naive UC, CD, and celiac diseases using independent test and validation cohorts. Using the Predicting Response to Standardized Pediatric Colitis Therapy (PROTECT) inception UC cohort, we defined and prioritized lncRNA linked with UC severity and prospective outcomes, and we highlighted lncRNAs linked with gut microbes previously implicated in mucosal homeostasis. HNF1A-AS1 lncRNA was reduced in all 3 conditions and was further reduced in more severe UC form. Similarly, the reduction of HNF1A-AS1 ortholog in mice gut epithelia showed higher sensitivity to dextran sodium sulfate–induced colitis, which was coupled with alteration in the gut microbial community. These analyses highlight prioritized dysregulated lncRNAs that can guide future preclinical studies for testing them as potential targets.
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- 2023
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6. Intraoperative abobotulinumtoxinA alleviates pain after surgery and improves general wellness in a translational animal model
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Sylvie Cornet, Denis Carré, Lorenzo Limana, David Castel, Sigal Meilin, Ron Horne, Laurent Pons, Steven Evans, Stephane Lezmi, and Mikhail Kalinichev
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Medicine ,Science - Abstract
Abstract Pain after surgery remains a significant healthcare challenge. Here, abobotulinumtoxinA (aboBoNT-A, DYSPORT) was assessed in a post-surgical pain model in pigs. Full-skin-muscle incision and retraction surgery on the lower back was followed by intradermal injections of either aboBoNT-A (100, 200, or 400 U/pig), vehicle (saline), or wound infiltration of extended-release bupivacaine. We assessed mechanical sensitivity, distress behaviors, latency to approach the investigator, and wound inflammation/healing for 5–6 days post-surgery. We followed with immunohistochemical analyses of total and cleaved synaptosomal-associated protein 25 kD (SNAP25), glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor protein-1(Iba1), calcitonin gene-related peptide (CGRP) and substance P (SP) in the skin, dorsal root ganglia (DRG) and the spinal cord of 400 U aboBoNT-A- and saline-treated animals. At Day 1, partial reversal of mechanical allodynia in aboBoNT-A groups was followed by a full reversal from Day 3. Reduced distress and normalized approaching responses were observed with aboBoNT-A from 6 h post-surgery. Bupivacaine reversed mechanical allodynia for 24 h after surgery but did not affect distress or approaching responses. In aboBoNT-A-treated animals cleaved SNAP25 was absent in the skin and DRG, but present in the ipsilateral dorsal horn of the spinal cord. In aboBoNT-A- versus saline-treated animals there were significant reductions in GFAP and Iba1 in the spinal cord, but no changes in CGRP and SP. Analgesic efficacy of aboBoNT-A appears to be mediated by its activity on spinal neurons, microglia and astrocytes. Clinical investigation to support the use of aboBoNT-A as an analgesic drug for post-surgical pain, is warranted.
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- 2022
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7. Posterior fossa ependymoma H3 K27-mutant: an integrated radiological and histomolecular tumor analysis
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Cassandra Mariet, David Castel, Jacques Grill, Raphaël Saffroy, Volodia Dangouloff-Ros, Nathalie Boddaert, Francisco Llamas-Guttierrez, Céline Chappé, Stéphanie Puget, Lauren Hasty, Fabrice Chrétien, Alice Métais, Pascale Varlet, and Arnault Tauziède-Espariat
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Posterior fossa ,Ependymoma ,Histones ,DNA-methylation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Posterior fossa group A ependymomas (EPN_PFA) are characterized by a loss of H3 K27 trimethylation due to either EZHIP overexpression or H3 p.K27M mutation, similar to H3 K27-altered diffuse midline gliomas (DMG), but in reverse proportions. Very little data is available in the literature concerning H3 K27M-mutant EPN_PFA. Here, we retrospectively studied a series of nine pediatric tumors initially diagnosed as H3 K27M-mutant EPN_PFA to compare them to EZHIP-overexpressing EPN_PFA in terms of radiology, follow-up, histopathology, and molecular biology (including DNA-methylation profiling). Seven tumors clustered within EPN_PFA by DNA-methylation analysis and t-distributed stochastic neighbor embedding. Among the two remaining cases, one was reclassified as a DMG and the last was unclassified. H3 K27M-mutant EPN_PFA cases were significantly older than their counterparts with an EZHIP overexpression. Radiological and histopathological central review of our seven H3 K27M-mutant EPN_PFA cases found them to be similar to their counterparts with an EZHIP overexpression. Sequencing analyses revealed HIST1H3B (n = 2), HIST1H3C (n = 2), H3F3A (n = 1), and HIST1H3D (n = 1) K27M mutations (no sequencing analysis available for the last case which was immunopositive for H3K27M). Consequently, HIST1H3C/D mutations are more frequently observed in EPN_PFA than in classic pontine DMG, H3K27-mutant. Overall survival and event-free survival of EZHIP-overexpressing and H3 K27M-mutant EPN_PFA were similar. After surgery and radiation therapy, 5/7 patients were alive at the end of the follow-up. In summary, the diagnosis of EPN_PFA must include tumor location, growth pattern, Olig2 expression, and DNA-methylation profiling before it can be differentiated from DMG, H3 K27-altered.
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- 2022
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8. Disseminated diffuse midline gliomas, H3K27-altered mimicking diffuse leptomeningeal glioneuronal tumors: a diagnostical challenge!
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Arnault Tauziède-Espariat, Aurore Siegfried, Emmanuelle Uro-Coste, Yvan Nicaise, David Castel, Annick Sevely, Marion Gambart, Sergio Boetto, Lauren Hasty, Alice Métais, Fabrice Chrétien, Joseph Benzakoun, Stéphanie Puget, Jacques Grill, Volodia Dangouloff-Ros, Nathalie Boddaert, Azadeh Ebrahimi, Pascale Varlet, and the RENOCLIP-LOC Network
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2022
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9. The dural angioleiomyoma harbors frequent GJA4 mutation and a distinct DNA methylation profile
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Arnault Tauziède-Espariat, Thibaut Pierre, Michel Wassef, David Castel, Florence Riant, Jacques Grill, Alexandre Roux, Johan Pallud, Edouard Dezamis, Damien Bresson, Sandro Benichi, Thomas Blauwblomme, Djallel Benzohra, Guillaume Gauchotte, Celso Pouget, Sophie Colnat-Coulbois, Karima Mokhtari, Corinne Balleyguier, Frédérique Larousserie, Volodia Dangouloff-Ros, Nathalie Boddaert, Marie-Anne Debily, Lauren Hasty, Marc Polivka, Homa Adle-Biassette, Alice Métais, Emmanuèle Lechapt, Fabrice Chrétien, Felix Sahm, Philipp Sievers, Pascale Varlet, and the RENOCLIP-LOC
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Dural angioleiomyoma ,GJA4 ,DNA methylation profile ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract The International Society for the Study of Vascular Anomalies (ISSVA) has defined four vascular lesions in the central nervous system (CNS): arteriovenous malformations, cavernous angiomas (also known as cerebral cavernous malformations), venous malformations, and telangiectasias. From a retrospective central radiological and histopathological review of 202 CNS vascular lesions, we identified three cases of unclassified vascular lesions. Interestingly, they shared the same radiological and histopathological features evoking the cavernous subtype of angioleiomyomas described in the soft tissue. We grouped them together with four additional similar cases from our clinicopathological network and performed combined molecular analyses. In addition, cases were compared with a cohort of 5 soft tissue angioleiomyomas. Three out 6 CNS lesions presented the same p.Gly41Cys GJA4 mutation recently reported in hepatic hemangiomas and cutaneous venous malformations and found in 4/5 soft tissue angioleiomyomas of our cohort with available data. Most DNA methylation profiles were not classifiable using the CNS brain tumor (version 12.5), and sarcoma (version 12.2) classifiers. However, using unsupervised t-SNE analysis and hierarchical clustering analysis, 5 of the 6 lesions grouped together and formed a distinct epigenetic group, separated from the clusters of soft tissue angioleiomyomas, other vascular tumors, inflammatory myofibroblastic tumors and meningiomas. Our extensive literature review identified several cases similar to these lesions, with a wide variety of denominations. Based on radiological and histomolecular findings, we suggest the new terminology of “dural angioleiomyomas” (DALM) to designate these lesions characterized by a distinct DNA methylation pattern and frequent GJA4 mutations.
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- 2022
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10. The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of 'CNS tumors with BCOR internal tandem duplication'
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Arnault Tauziède-Espariat, Gaëlle Pierron, Aurore Siegfried, Delphine Guillemot, Emmanuelle Uro-Coste, Yvan Nicaise, David Castel, Isabelle Catalaa, Delphine Larrieu-Ciron, Patrick Chaynes, Amaury de Barros, Julien Nicolau, Albane Gareton, Emmanuèle Lechapt, Fabrice Chrétien, Franck Bourdeaut, François Doz, Yassine Bouchoucha, Jacques Grill, Kévin Beccaria, Nathalie Boddaert, Raphaël Saffroy, Mélanie Pagès, and Pascale Varlet
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2020
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11. Transcriptomic and epigenetic profiling of ‘diffuse midline gliomas, H3 K27M-mutant’ discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location
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David Castel, Cathy Philippe, Thomas Kergrohen, Martin Sill, Jane Merlevede, Emilie Barret, Stéphanie Puget, Christian Sainte-Rose, Christof M. Kramm, Chris Jones, Pascale Varlet, Stefan M. Pfister, Jacques Grill, David T. W. Jones, and Marie-Anne Debily
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Pediatric high-grade glioma ,Diffuse midline glioma ,H3 K27M-mutant ,Diffuse intrinsic pontine glioma ,Epigenetics ,DNA methylation profiling ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail. Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG. Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization. These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones. H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.
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- 2018
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12. A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value
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Natacha Entz-Werlé, Laetitia Poidevin, Petr V. Nazarov, Olivier Poch, Benoit Lhermitte, Marie Pierre Chenard, Hélène Burckel, Eric Guérin, Quentin Fuchs, David Castel, Georges Noel, Laurence Choulier, Monique Dontenwill, and Eric Van Dyck
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pediatric high-grade gliomas ,DNA damage repair ,prognostic clustering ,PARP1 ,XRCC1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response pathways that operate in pHGGs and the vulnerabilities that these pathways might expose, we sought to identify and characterize a specific DNA repair and cell-cycle gene expression signature of pHGGs. Methods: Transcriptomic analyses were performed to identify a DNA repair and cell-cycle gene expression signature able to discriminate pHGGs (n = 6) from low-grade gliomas (n = 10). This signature was compared to related signatures already established. We used the pHGG signature to explore already transcriptomic datasets of DIPGs and sus-tentorial pHGGs. Finally, we examined the expression of key proteins of the pHGG signature in 21 pHGG diagnostic samples and nine paired relapses. Functional inhibition of one DNA repair factor was carried out in four patients who derived H3.3 K27M mutant cell lines. Results: We identified a 28-gene expression signature of DNA repair and cell cycle that clustered pHGGs cohorts, in particular sus-tentorial locations, in two groups. Differential protein expression levels of PARP1 and XRCC1 were associated to TP53 mutations and TOP2A amplification and linked significantly to the more radioresistant pHGGs displaying the worst outcome. Using patient-derived cell lines, we showed that the PARP-1/XRCC1 expression balance might be correlated with resistance to PARP1 inhibition. Conclusion: We provide evidence that PARP1 overexpression, associated to XRCC1 expression, TP53 mutations, and TOP2A amplification, is a new theranostic and potential therapeutic target.
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- 2021
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13. Human-like cutaneous neuropathologies associated with a porcine model of peripheral neuritis: A translational platform for neuropathic pain
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Frank L. Rice, David Castel, Elizabeth Ruggiero, Marilyn Dockum, George Houk, Itai Sabbag, Phillip J. Albrecht, and Sigal Meilin
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Despite enormous investment in research and development of novel treatments, there remains a lack of predictable, effective, and safe therapeutics for human chronic neuropathic pain (NP) afflictions. NP continues to increase among the population and treatments remain a major unmet public health care need. In recent years, numerous costly (time and money) failures have occurred attempting to translate successful animal pain model results, typically using rodents, to human clinical trials. These continued failures point to the essential need for better animal models of human pain conditions. To address this challenge, we have previously developed a peripheral neuritis trauma (PNT) model of chronic pain induced by a proximal sciatic nerve irritation in pigs, which have a body size, metabolism, skin structure, and cutaneous innervation more similar to humans. Here, we set out to determine the extent that the PNT model presents with cutaneous neuropathologies consistent with those associated with human chronic NP afflictions. Exactly as is performed in human skin biopsies, extensive quantitative multi-molecular immunofluorescence analyses of porcine skin biopsies were performed to assess cutaneous innervation and skin structure. ChemoMorphometric Analysis (CMA) results demonstrated a significant reduction in small caliber intraepidermal nerve fiber (IENF) innervation, altered dermal vascular innervation, and aberrant analgesic/algesic neurochemical properties among epidermal keratinocytes, which are implicated in modulating sensory innervation. These comprehensive pathologic changes very closely resemble those observed from CMA of human skin biopsies collected from NP afflictions. The results indicate that the porcine PNT model is more appropriate for translational NP research compared with commonly utilized rodent models. Because the PNT model creates cutaneous innervation and keratinocyte immunolabeling alterations consistent with human NP conditions, use of this animal model for NP testing and treatment response characteristics will likely provide more realistic results to direct successful translation to humans. Keywords: Animal model, IENF density, PGP9.5, CGRP, ET-1 receptors, NaV, Immunolabeling
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- 2019
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14. Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification.
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Felipe Andreiuolo, Gwénaël Le Teuff, Mohamed Amine Bayar, John-Paul Kilday, Torsten Pietsch, André O von Bueren, Hendrik Witt, Andrey Korshunov, Piergiorgio Modena, Stefan M Pfister, Mélanie Pagès, David Castel, Felice Giangaspero, Leila Chimelli, Pascale Varlet, Stefan Rutkowski, Didier Frappaz, Maura Massimino, Richard Grundy, Jacques Grill, and SIOP Ependymoma Biology Working Group BIOMECA (BIOlogical Markers for Ependymomas in Children and Adolescents)
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Medicine ,Science - Abstract
Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths.This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed.Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group.Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.
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- 2017
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15. Correction: Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.
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Michal Yalon, Liron Tuval-Kochen, David Castel, Itai Moshe, Inbal Mazal, Osher Cohen, Camila Avivi, Kineret Rosenblatt, Sarit Aviel-Ronen, Ginette Schiby, Joachim Yahalom, Ninette Amariglio, Raphael Pfeffer, Yaacov R Lawrence, Amos Toren, Gideon Rechavi, and Shoshana Paglin
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Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0155711.].
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- 2016
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16. Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations.
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Michal Yalon, Liron Tuval-Kochen, David Castel, Itai Moshe, Inbal Mazal, Osher Cohen, Camila Avivi, Kineret Rosenblatt, Sarit Aviel-Ronen, Ginette Schiby, Joachim Yahalom, Ninette Amariglio, Raphael Pfeffer, Yaacov Lawrence, Amos Toren, Gideon Rechavi, and Shoshana Paglin
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Medicine ,Science - Abstract
Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi), become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi)). Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG)-a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF) 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors.
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- 2016
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17. Data from TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)
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David Castel, Marie-Anne Debily, Jacques Grill, Stéphanie Puget, Nathalie Boddaert, Kevin Beccaria, Pascale Varlet, Stéphanie Bolle, Michele Mondini, Thomas Kergrohen, Romain Brusini, Jane Merlevede, Gwénaël Le Teuff, Emilie Barret, María-Jesús Lobón-Iglesias, Cláudia C.S. Evangelista, and Coralie Werbrouck
- Abstract
Purpose:Diffuse intrinsic pontine gliomas (DIPG) are the most severe pediatric brain tumors. Although accepted as the standard therapeutic, radiotherapy is only efficient transiently and not even in every patient. The goal of the study was to identify the underlying molecular determinants of response to radiotherapy in DIPG.Experimental Design:We assessed in vitro response to ionizing radiations in 13 different DIPG cellular models derived from treatment-naïve stereotactic biopsies reflecting the genotype variability encountered in patients at diagnosis and correlated it to their principal molecular alterations. Clinical and radiologic response to radiotherapy of a large cohort of 73 DIPG was analyzed according to their genotype. Using a kinome-wide synthetic lethality RNAi screen, we further identified target genes that can sensitize DIPG cells to ionizing radiations.Results:We uncover TP53 mutation as the main driver of increased radioresistance and validated this finding in four isogenic pairs of TP53WT DIPG cells with or without TP53 knockdown. In an integrated clinical, radiological, and molecular study, we show that TP53MUT DIPG patients respond less to irradiation, relapse earlier after radiotherapy, and have a worse prognosis than their TP53WT counterparts. Finally, a kinome-wide synthetic lethality RNAi screen identifies CHK1 as a potential target, whose inhibition increases response to radiation specifically in TP53MUT cells.Conclusions:Here, we demonstrate that TP53 mutations are driving DIPG radioresistance both in patients and corresponding cellular models. We suggest alternative treatment strategies to mitigate radioresistance with CHK1 inhibitors. These findings will allow to consequently refine radiotherapy schedules in DIPG.
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- 2023
18. Supplementary Figures from TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)
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David Castel, Marie-Anne Debily, Jacques Grill, Stéphanie Puget, Nathalie Boddaert, Kevin Beccaria, Pascale Varlet, Stéphanie Bolle, Michele Mondini, Thomas Kergrohen, Romain Brusini, Jane Merlevede, Gwénaël Le Teuff, Emilie Barret, María-Jesús Lobón-Iglesias, Cláudia C.S. Evangelista, and Coralie Werbrouck
- Abstract
All supplementary figures in one PDF
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- 2023
19. Supplementary Figure Legends from TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)
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David Castel, Marie-Anne Debily, Jacques Grill, Stéphanie Puget, Nathalie Boddaert, Kevin Beccaria, Pascale Varlet, Stéphanie Bolle, Michele Mondini, Thomas Kergrohen, Romain Brusini, Jane Merlevede, Gwénaël Le Teuff, Emilie Barret, María-Jesús Lobón-Iglesias, Cláudia C.S. Evangelista, and Coralie Werbrouck
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Supplementary Figure Legends
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- 2023
20. Supplementary Tables from TP53 Pathway Alterations Drive Radioresistance in Diffuse Intrinsic Pontine Gliomas (DIPG)
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David Castel, Marie-Anne Debily, Jacques Grill, Stéphanie Puget, Nathalie Boddaert, Kevin Beccaria, Pascale Varlet, Stéphanie Bolle, Michele Mondini, Thomas Kergrohen, Romain Brusini, Jane Merlevede, Gwénaël Le Teuff, Emilie Barret, María-Jesús Lobón-Iglesias, Cláudia C.S. Evangelista, and Coralie Werbrouck
- Abstract
Supplementary Tables
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- 2023
21. VRK3 depletion induces cell cycle arrest and metabolic reprogramming of Pontine Diffuse Midline Glioma (DMG)-K27 altered cells
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Virginie Menez, Thomas Kergrohen, Tal Shasha, Claudia Silva-Evangelista, Ludivine Ledret, Lucie Auffret, Chloé Subecz, Manon Lancien, Yassine Ajlil, Kévin Beccaria, Thomas Blauwblomme, Estelle Oberlin, Jacques Grill, David Castel, and Marie-Anne Debily
- Abstract
We previously identified VRK3 as a specific vulnerability in DMG-H3K27M cells in a synthetic lethality screen targeting the whole kinome. The aim of the present study was to elucidate the mechanisms by which VRK3 depletion impact DMG-K27M cell fitness. Gene expression studies afterVRK3knockdown emphasized the inhibition of genes involved in G1/S transition of the cell cycle resulting in growth arrest in G1. Additionally, a massive modulation of genes involved in chromosome segregation was observed, concomitantly with a reduction in the level of phosphorylation of serine 10 and serine 28 of histone H3 supporting the regulation of chromatin condensation during cell division. This last effect could be partly due to a concomitant decrease of the chromatin kinase VRK1 in DMG followingVRK3knock-down. Furthermore, a metabolic switch specific to VRK3 function was observed towards increased oxidative phosphorylation without change in mitochondria content, that we hypothesized would represent a cell rescue mechanism. This study further explored the vulnerability of DMG-H3K27M cells to VRK3 depletion suggesting potential therapeutic combinations,e.g.with the mitochondrial ClpP protease activator ONC201.
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- 2023
22. Pediatric high-grade glioma MYCN is frequently associated with Li-Fraumeni syndrome
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Léa Guerrini-Rousseau, Arnault Tauziède-Espariat, David Castel, Etienne Rouleau, Philipp Sievers, Raphaël Saffroy, Kévin Beccaria, Thomas Blauwblomme, Lauren Hasty, Franck Bourdeaut, Jacques Grill, Pascale Varlet, and Marie-Anne Debily
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Cellular and Molecular Neuroscience ,Neurology (clinical) ,Pathology and Forensic Medicine - Published
- 2022
23. Radiogenomics of diffuse intrinsic pontine gliomas (DIPGs): correlation of histological and biological characteristics with multimodal MRI features
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Christelle Dufour, Thomas Blauwblomme, Jacques Grill, David Castel, D. Grevent, Christophe Deroulers, Nathalie Boddaert, Monica Zilbovicius, Yvonne Purcell, Stéphanie Puget, Ana Saitovitch, Volodia Dangouloff-Ros, Pascale Varlet, Raphael Levy, Marie-Anne Debily, Kevin Beccaria, Cathy Philippe, Raphael Calmon, and Charles-Joris Roux
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medicine.medical_specialty ,Pathology ,medicine.diagnostic_test ,business.industry ,Radiogenomics ,Microvascular Density ,Blood volume ,Perfusion scanning ,General Medicine ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Cerebral blood flow ,030220 oncology & carcinogenesis ,Biopsy ,medicine ,Effective diffusion coefficient ,Radiology, Nuclear Medicine and imaging ,Radiology ,business ,Perfusion - Abstract
The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics. Twenty-seven treatment-naive children with histopathologically confirmed DIPG H3K27M mutant were prospectively included. MRI performed prior to biopsy included multi-b-value diffusion-weighted imaging, ASL, and dynamic susceptibility contrast (DSC) perfusion imaging. The ADC and cerebral blood flow (CBF) and blood volume (CBV) were measured at the biopsy site. We assessed quantitative histological data, including microvascular density, nuclear density, and H3K27M-positive nuclear density. Gene expression profiling was also assessed in the samples. We compared imaging and histopathological data according to histone subgroup. We correlated MRI quantitative data with histological data and gene expression. H3.1K27M mutated tumors showed higher ADC values (median 3151 μm2/s vs 1741 μm2/s, p = 0.003), and lower perfusion values (DSC-rCBF median 0.71 vs 1.43, p = 0.002, and DSC-rCBV median 1.00 vs 1.71, p = 0.02) than H3.3K27M ones. They had similar microvascular and nuclear density, but lower H3K27M-positive nuclear density (p = 0.007). The DSC-rCBV was positively correlated to the H3K27M-positive nuclear density (rho = 0.74, p = 0.02). ADC values were not correlated with nuclear density nor perfusion values with microvascular density. The expression of gated channel activity–related genes tended to be inversely correlated with ADC values and positively correlated with DSC perfusion. H3.1K27M mutated tumors have higher ADC and lower perfusion values than H3.3K27M ones, without direct correlation with microvascular or nuclear density. This may be due to tissular edema possibly related to gated channel activity–related gene expression. • H3.1K27M mutant DIPG had higher apparent diffusion coefficient (p = 0.003), lower α (p = 0.048), and lower relative cerebral blood volume (p = 0.02) than H3.3K27M mutant DIPG at their biopsy sites. • Biopsy samples obtained within the tumor’s enhancing portion showed higher microvascular density (p = 0.03) than samples obtained outside the tumor’s enhancing portion, but similar H3K27M-positive nuclear density (p = 0.84). • Relative cerebral blood volume measured at the biopsy site was significantly correlated with H3K27M-positive nuclear density (rho = 0.74, p = 0.02).
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- 2021
24. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR
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Dominik Sturm, Andrey Korshunov, Andreas von Deimling, Brigitte Bison, Ales Vicha, Matija Snuderl, Nada Jabado, David Castel, Damian Stichel, Lenka Krskova, Jacques Grill, David T.W. Jones, Daniel Schrimpf, Felix Sahm, Arie Perry, Michal Zapotocky, Pieter Wesseling, Olaf Witt, Marie-Anne Debily, Stefan M. Pfister, Wolfgang Wick, David E. Reuss, Thomas S. Jacques, Jürgen Hench, Philipp Sievers, Patrick N. Harter, Guido Reifenberger, Stephan Frank, David A. Solomon, Christof M. Kramm, Martin Sill, Chris Jones, Pathology, and CCA - Cancer biology and immunology
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Cancer Research ,medicine.disease_cause ,pediatric-type high-grade glioma ,Histones ,0302 clinical medicine ,Thalamus ,Missense mutation ,Epidermal growth factor receptor ,Child ,Cancer ,Pediatric ,0303 health sciences ,Mutation ,biology ,Brain Neoplasms ,Astrocytoma ,Glioma ,3. Good health ,ErbB Receptors ,Oncology ,030220 oncology & carcinogenesis ,DNA methylation ,K27me3 ,H3 K27M mutation ,Pediatric Cancer ,Oncology and Carcinogenesis ,03 medical and health sciences ,Rare Diseases ,medicine ,Genetics ,Humans ,EGFR Gene Amplification ,Oncology & Carcinogenesis ,erbB-1 ,030304 developmental biology ,H3 K27M Mutation ,(bi)thalamic ,Neurosciences ,Genes, erbB-1 ,DNA Methylation ,medicine.disease ,Brain Disorders ,Brain Cancer ,Genes ,Cancer research ,biology.protein ,Neurology (clinical) ,EGFR mutation ,Fast-Track Article - Abstract
Background Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern. Methods Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas. Results EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations. Conclusions Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
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- 2021
25. A comprehensive evaluation of normalization methods for Illumina high-throughput RNA sequencing data analysis.
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Marie-Agnès Dillies, Andrea Rau, Julie Aubert, Christelle Hennequet-Antier, Marine Jeanmougin, Nicolas Servant, Céline Keime, Guillemette Marot, David Castel, Jordi Estelle, Gregory Guernec, Bernd Jagla, Luc Jouneau, Denis Laloë, Caroline Le Gall, Brigitte Schaeffer, Stéphane Le Crom, Mickaël Guedj, and Florence Jaffrézic
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- 2013
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26. Modeling the Interaction between the Microenvironment and Tumor Cells in Brain Tumors
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Tatsuya Kozaki, Claudia Pasqualini, Marco Bruschi, Jacques Grill, Veronique Minard-Colin, Florent Ginhoux, David Castel, and Thi Hai Hoa Nguyen
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0301 basic medicine ,Stromal cell ,Microglia ,Brain Neoplasms ,Tumor biology ,General Neuroscience ,medicine.medical_treatment ,Brain ,Tumor cells ,Immunotherapy ,Models, Theoretical ,Biology ,Extracellular matrix ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Cancer cell ,Tumor Microenvironment ,medicine ,Cancer research ,Animals ,Humans ,Macrophage ,030217 neurology & neurosurgery - Abstract
Despite considerable recent advances in understanding and treating many other cancers, malignant brain tumors remain associated with low survival or severe long-term sequelae. Limited progress, including development of immunotherapies, relates in part to difficulties in accurately reproducing brain microenvironment with current preclinical models. The cellular interactions among resident microglia, recruited tumor-associated macrophages, stromal cells, glial cells, neurons, and cancer cells and how they affect tumor growth or behavior are emerging, yet many questions remain. The role of the blood-brain barrier, extracellular matrix components, and heterogeneity among tumor types and within different regions of a single tumor further complicate the matter. Here, we focus on brain microenvironment features impacted by tumor biology. We also discuss limits of current preclinical models and how complementary models, such as humanized animals and organoids, will allow deeper mechanistic insights on cancer biology, allowing for more efficient testing of therapeutic strategies, including immunotherapy, for brain cancers.
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- 2020
27. The EP300:BCOR fusion extends the genetic alteration spectrum defining the new tumoral entity of 'CNS tumors with BCOR internal tandem duplication'
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Nathalie Boddaert, Fabrice Chrétien, Raphaël Saffroy, Gaëlle Pierron, Yvan Nicaise, Amaury De Barros, Emmanuelle Uro-Coste, Delphine Larrieu-Ciron, David Castel, Julien Nicolau, Yassine Bouchoucha, Kevin Beccaria, Arnault Tauziède-Espariat, I. Catalaa, Patrick Chaynes, Jacques Grill, Emmanuèle Lechapt, Albane Gareton, Aurore Siegfried, Pascale Varlet, François Doz, Mélanie Pagès, Franck Bourdeaut, and Delphine Guillemot
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business.industry ,Genetic Alteration ,Internal tandem duplication ,Computational biology ,Biology ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Text mining ,Neurology (clinical) ,CNS TUMORS ,EP300 ,business ,Letter to the Editor ,lcsh:Neurology. Diseases of the nervous system - Published
- 2020
28. Analgesic Activity of AbobotulinumtoxinA in Postoperative Pain Models in the Pig is Driven by the Route of Administration: New Highlights on the Mechanism of Action
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Stephane Lezmi, Sylvie Cornet, Denis Carré, Franck Theo, Elie Altman, Clement Levin, David Castel, Sigal Meilin, Ron Horne, Jeong Rih, and Mikhail Kalinichev
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Toxicology - Published
- 2022
29. The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts
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Raphaël Saffroy, Jacques Grill, Mélanie Pagès, Volodia Dangouloff-Ros, Albane Gareton, Arnault Tauziède-Espariat, Stéphanie Puget, Fabrice Chrétien, Alexandre Roux, David Castel, Pascale Varlet, Nathalie Boddaert, Emmanuèle Lechapt, and M-A Debily
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Male ,Pathology ,medicine.medical_specialty ,Adolescent ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Text mining ,Gene duplication ,Brain Stem Neoplasms ,Humans ,Medicine ,Child ,Letter to the Editor ,lcsh:Neurology. Diseases of the nervous system ,N-Myc Proto-Oncogene Protein ,business.industry ,Gene Amplification ,Infant ,Supratentorial Neoplasms ,Glioma ,Methylation ,DNA Methylation ,Class (biology) ,Child, Preschool ,Radiological weapon ,DNA methylation ,Female ,Neurology (clinical) ,business - Published
- 2020
30. Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation
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Nathalie Boddaert, Stéphanie Puget, Chris Jones, David T.W. Jones, David Castel, Arnault Tauziède-Espariat, Thomas Blauwblomme, Marie-Anne Debily, Thomas Kergrohen, Samia Ghermaoui, Kevin Beccaria, Stefan M. Pfister, Alan Mackay, Christof M. Kramm, Jacques Grill, Emmanuèle Lechapt, and Pascale Varlet
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H3 K27M Mutation ,biology ,business.industry ,Wild type ,Pathology and Forensic Medicine ,Cellular and Molecular Neuroscience ,Histone H3 ,Text mining ,Cancer research ,biology.protein ,Medicine ,Neurology (clinical) ,business ,PRC2 - Published
- 2020
31. Rapid and Sensitive Drug Quantification in Tissue Sections Using Matrix Assisted Laser Desorption Ionization-Ion Mobility-Mass Spectrometry Profiling
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Walter E. Haefeli, Alexander Muck, Ludivine Le Dret, Marius Majewsky, Stefan M. Pfister, Britta Statz, Jürgen Burhenne, Sonja Krausert, David Castel, Julia Benzel, Margaux Fresnais, and Rémi Longuespée
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Anthelmintics ,Detection limit ,Time Factors ,Chromatography ,Chemistry ,Ion-mobility spectrometry ,010401 analytical chemistry ,Mice, Nude ,010402 general chemistry ,Mass spectrometry ,01 natural sciences ,0104 chemical sciences ,Mebendazole ,Matrix-assisted laser desorption/ionization ,Electrophoresis ,Structural Biology ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Desorption ,Ionization ,Ion Mobility Spectrometry ,Animals ,Tissue Distribution ,Sample preparation ,Spectroscopy - Abstract
Ion mobility spectrometry (IMS) represents a considerable asset for analytics of complex samples as it allows for rapid mass spectrometric separation of compounds. IMS is even more useful for the separation of isobaric compounds when classical separation methods such as liquid chromatography or electrophoresis cannot be used, e.g., during matrix-assisted laser desorption/ionization (MALDI) analyses of biological surfaces. In the present study, we proved the usefulness of IMS for pharmacological applications of MALDI analyses on tissue sections. To illustrate our proof-of-concept, we used the anthelmintic drug mebendazole (MBZ) as a model. Using this exemplary drug, we demonstrated the possibility of using ion mobility to discriminate a drug in tissues from the biological background that masked its signal at low concentrations. In this proof-of-concept, the IMS mode together with the use of a profiling approach for sample preparation enabled quantification of the model drug MBZ from tissue sections in the concentration range 5 to 5,000 ng/g and with a limit of detection of 1 ng/g of tissue, within 2 h. This study highlights the importance of IMS as a separation method for on-surface quantification of drugs in tissue sections.
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- 2020
32. Deciphering the genetic and epigenetic landscape of pediatric bithalamic tumors
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Raphaël Saffroy, Lauren Hasty, Guillaume Gauchotte, Philipp Sievers, Marie-Anne Debily, Ellen Wahler, Nathalie Boddaert, Fabrice Chrétien, Stéphanie Puget, Alexandre Roux, Emmanuèle Lechapt, Pascale Varlet, Volodia Dangouloff-Ros, Arnault Tauziède-Espariat, David Castel, and Jacques Grill
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Epigenomics ,Brain Neoplasms ,General Neuroscience ,Immunohistochemistry ,Humans ,Neurology (clinical) ,Epigenetics ,Glioma ,Biology ,Bioinformatics ,Child ,Pathology and Forensic Medicine ,Epigenesis, Genetic - Abstract
Pediatric bithalamic gliomas encompass several histomolecular tumoral types from benign to malignant and underlines the central role of a comprehensive neuropathological review, including immunohistochemistry, genetic, and epigenetic analyses, to achieve an accurate diagnosis.
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- 2021
33. HGG-49. Gliomatosis cerebri in children: A collaborative report from the European Society for Pediatric Oncology (SIOPE)
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Gunther Nussbaumer, Martin Benesch, Gerrit H Gielen, David Castel, Jacques Grill, Marta M Alonso Roldán, Manila Antonelli, Simon Bailey, Joshua N Baugh, Veronica Biassoni, Andrea Carai, Niclas Colditz, Giovanni Stefania Colefati, Selim Corbacioglu, Shauna Crampsie, Natacha Entz-Werle, Matthias Eyrich, Michael C Frühwald, Maria Luisa Garrè, Nicolas U Gerber, Felice Giangaspero, Maria João Gil-da-Costa, Yura Grabovska, Norbert Graf, Darren Hargrave, Peter Hauser, Marion Hoffmann, Esther Hulleman, Sandra Jacobs, Michael Karremann, Antonis Kattamis, Rejin Kebudi, Rolf-Dieter Kortmann, Robert Kwiecien, Alan Mackay, Maura Massimino, Evelina Miele, Angela Mastronuzzi, Giovanni Morana, Claudia M Noack, Virve Pentikainen, Thomas Perwein, Stefan M Pfister, Torsten Pietsch, Kleoniki Roka, Sabrina Rossi, Stefan Rutkowski, Elisabetta Schiavello, Jaroslav Štěrba, Dominik Sturm, David Sumerauer, Sara Temelso, Dannis van Vuurden, Pascale Varlet, Sophie E M Veldhuijzen van Zanten, Maria Vinci, André O von Bueren, Monika Warmuth-Metz, Pieter Wesseling, Maria Wiese, Johannes E A Wolff, Josef Zamecnik, David T W Jones, Brigitte Bison, Andrés Morales La Madrid, Chris Jones, and Christof M Kramm
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
BACKGROUND: Gliomatosis cerebri (GC), a radiologically defined diffusely infiltrating glioma, is no longer considered a distinct entity since the 2016 WHO classification for tumors of the CNS. Due to its rarity and dismal prognosis treatment recommendations in children remain ambiguous. Using central neuroradiological review, we performed a multi-institutional, retrospective study of GC providing comprehensive radiological, clinical, and (epi)genetic characterization. RESULTS: We included 104 patients between 1-19 years. Within a median follow-up of 15.5 months (range, 2.3-138.8), 93 patients (89.4 %) had died, 4 (3.8 %) were lost to follow-up and 7 (6.8 %) were alive with stable/progressive disease. Median progression-free- (PFS) and overall survival (OS) were 8.6 months (interquartile range, 4.3-14.0) and 15.5 months (10.9-27.7), respectively. Former WHO grading correlated significantly with median OS: WHO °II: 47.8 months (25.2-55.7); WHO °III: 15.9 months (11.4-26.3); WHO °IV: 10.4 months (8.8-14.4) (p
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- 2022
34. Loss of the H4 lysine methyltransferase KMT5B drives tumorigenic phenotypes by depleting H3K27me3 at loci otherwise retained in H3K27M mutant DIPG cells
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Yura Grabovska, Sara Temelso, Chris Jones, Valeria Molinari, Jyoti S. Choudhary, Alan Mackay, Mara Vinci, Ketty Kessler, Lu Yu, Mariella G. Filbin, Andrea Sottoriva, Haider Tari, Ilon Liu, Erika Yara-Romero, David Castel, and Anna Burford
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Histone ,Methyltransferase ,biology ,DNA repair ,Mutant ,medicine ,biology.protein ,H3K4me3 ,Carcinogenesis ,medicine.disease_cause ,Phenotype ,Chromatin ,Cell biology - Abstract
SUMMARYDIPG are characterised by histone H3K27M mutations, resulting in global loss of the repressive mark H3K27me3, although certain key loci are retained. We recently identified subclonal loss-of-function mutations in the H4 lysine methyltransferase KMT5B to be associated with enhanced invasion/migration, but the mechanism by which this occurred was unclear. Here we use integrated ChIP-seq, ATAC-seq and RNA-seq on patient-derived, subclonal and CRISPR-Cas9-KD DIPG cells to show that loss of KMT5B/C causes depletion of these retained H3K27me3 loci via changes in chromatin accessibility, causing a raft of transcriptional changes which promote tumorigenesis. De-repression occurred at bivalent loci marked by H3K4me3, driving increased transcriptional heterogeneity and elevated gene expression associated with increased invasion, abrogated DNA repair and mesenchymal transition, along with a markedly altered secretome. These data suggest a previously unrecognised trans-histone (H4/H3) interaction in DIPG cells with a potentially profound effect on their diffusely infiltrating phenotype.
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- 2021
35. Characterization of arterial stenosis and elasticity by analysis of high-frequency pressure wave components.
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Zehava Ovadia-Blechman, Shmuel Einav, Uri Zaretsky, David Castel, and Michael Eldar
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- 2003
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36. Intraoperatively Administered AbobotulinumtoxinA Alleviates Pain After Surgery and Improves General Wellness in a Pig Model
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Stephane Lezmi, Sylvie Cornet, Denis Carré, David Castel, Sigal Meilin, Ron Horne, and Mikhail Kalinichev
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Toxicology - Published
- 2022
37. A DNA Repair and Cell Cycle Gene Expression Signature in Pediatric High-Grade Gliomas: Prognostic and Therapeutic Value
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Eric Guérin, Hélène Burckel, Georges Noël, Benoit Lhermitte, Quentin Fuchs, David Castel, Marie Pierre Chenard, Olivier Poch, Eric Van Dyck, Laetitia Poidevin, Laurence Choulier, Monique Dontenwill, Petr V. Nazarov, Natacha Entz-Werle, Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CRBS - Centre de Recherche en Biomédecine de Strasbourg (Inserm UMS38/UNISTRA), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Institute of Health (LIH), Institut de Cancérologie de Strasbourg Europe (ICANS), Université de Strasbourg (UNISTRA), UNICANCER, CRLCC Paul Strauss, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Centre National de la Recherche Scientifique (CNRS)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Biomédecine de Strasbourg (CRBS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), and univOAK, Archive ouverte
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[INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI] ,0301 basic medicine ,Cancer Research ,pediatric high-grade gliomas ,DNA damage repair ,prognostic clustering ,PARP1 ,XRCC1 ,DNA repair ,DNA damage ,Biology ,Article ,[INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI] ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Radioresistance ,Gene expression ,RC254-282 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell cycle ,Cell Cycle Gene ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research - Abstract
Simple Summary Pediatric high-grade gliomas are incurable brain tumors for which there is a critical need for new therapeutic strategies as well as treatment-predictive biomarkers. This study examined the expression of DNA repair and cell cycle genes in pediatric high-grade gliomas with distinct driving mutations. The aim is to propose a novel classification of these tumors based on sub-groups exposing therapeutic vulnerabilities. Several DNA repair factors were identified that might become new diagnostic markers. Abstract Background: Pediatric high-grade gliomas (pHGGs) are the leading cause of mortality in pediatric neuro-oncology, displaying frequent resistance to standard therapies. Profiling DNA repair and cell cycle gene expression has recently been proposed as a strategy to classify adult glioblastomas. To improve our understanding of the DNA damage response pathways that operate in pHGGs and the vulnerabilities that these pathways might expose, we sought to identify and characterize a specific DNA repair and cell-cycle gene expression signature of pHGGs. Methods: Transcriptomic analyses were performed to identify a DNA repair and cell-cycle gene expression signature able to discriminate pHGGs (n = 6) from low-grade gliomas (n = 10). This signature was compared to related signatures already established. We used the pHGG signature to explore already transcriptomic datasets of DIPGs and sus-tentorial pHGGs. Finally, we examined the expression of key proteins of the pHGG signature in 21 pHGG diagnostic samples and nine paired relapses. Functional inhibition of one DNA repair factor was carried out in four patients who derived H3.3 K27M mutant cell lines. Results: We identified a 28-gene expression signature of DNA repair and cell cycle that clustered pHGGs cohorts, in particular sus-tentorial locations, in two groups. Differential protein expression levels of PARP1 and XRCC1 were associated to TP53 mutations and TOP2A amplification and linked significantly to the more radioresistant pHGGs displaying the worst outcome. Using patient-derived cell lines, we showed that the PARP-1/XRCC1 expression balance might be correlated with resistance to PARP1 inhibition. Conclusion: We provide evidence that PARP1 overexpression, associated to XRCC1 expression, TP53 mutations, and TOP2A amplification, is a new theranostic and potential therapeutic target.
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- 2021
38. Copy-number alterations reshape the classification of diffuse intrinsic pontine gliomas. First exome sequencing results of the BIOMEDE trial
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Moussa A, Cécile Faure-Conter, Picot S, Sabourin-Cousin M, Stéphanie Puget, Anne-Isabelle Bertozzi, Lechapt-Zalcman E, Emilie Barret, M-A Debily, Arnault Tauziède-Espariat, Klas Blomgren, Jacques Grill, Gilles Vassal, Natacha Entz-Werle, De Carli E, Karsten Nysom, Pascale Varlet, Thomas Kergrohen, Kevin Beccaria, Chappe C, Ghermaoui S, David Castel, Le Teuff G, and P. Leblond
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Oncology ,medicine.medical_specialty ,Mutation ,Everolimus ,business.industry ,DNA repair ,Precision medicine ,medicine.disease_cause ,Dasatinib ,Internal medicine ,medicine ,Erlotinib ,business ,PI3K/AKT/mTOR pathway ,Exome sequencing ,medicine.drug - Abstract
Diffuse intrinsic pontine gliomas (DIPG) is an incurable neoplasm occurring mainly in children for which no progress was made in the last decades. The randomized phase II BIOMEDE trial compared three drugs (everolimus, dasatinib, erlotinib) combined with irradiation. The present report describes whole exome sequencing (WES) results for the first 100 patients randomized.Copy-number-Alteration (CNA) unsupervised clustering identified four groups with different outcomes and biology. This classification improved prognostication compared to models based on known biomarkers (Histone H3 and TP53 mutations). The cluster presenting complex genomic rearrangements was associated with significantly worse outcome and TP53 dysfunction. Mutation and CNA signatures confirmed the frequent alteration in DNA repair machinery. With respect to potential targetable pathways, PI3K/AKT/mTOR activation occurred in all the samples through multiples mechanisms. In conclusion, WES at diagnosis was feasible in most patients and provides a better patient stratification and theranostic information for precision medicine.
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- 2021
39. An integrative radiological, histopathological and molecular analysis of pediatric pontine histone-wildtype glioma with MYCN amplification (HGG-MYCN)
- Author
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Emmanuèle Lechapt, Volodia Dangouloff-Ros, Klas Blomgren, Jacques Grill, Arnault Tauziède-Espariat, Nathalie Boddaert, M-A Debily, Magnus Sabel, Albane Gareton, Pascale Varlet, David Castel, and Stéphanie Puget
- Subjects
biology ,business.industry ,Wild type ,medicine.disease ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Molecular analysis ,Cellular and Molecular Neuroscience ,Text mining ,Histone ,Glioma ,Mycn amplification ,Cancer research ,medicine ,biology.protein ,Neurology (clinical) ,business ,Letter to the Editor ,lcsh:Neurology. Diseases of the nervous system - Published
- 2019
40. Non-thermal focused ultrasound induced reversible reduction of essential tremor in a rat model
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Dianne Daniels, Shirley Sharabi, Yael Mardor, Itay Rachmilevich, Sagi Harnof, Zion Zivli, Javier Grinfeld, Alexander Volovick, Yoav Levy, Talia Amar, David Guez, and David Castel
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Male ,medicine.medical_specialty ,Movement disorders ,Focused ultrasound ,Ultrasonic Therapy ,medicine.medical_treatment ,Rat model ,Isppa ,Biophysics ,Harmaline ,050105 experimental psychology ,lcsh:RC321-571 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Intensity spatial peak pulse average ,Internal medicine ,Animals ,Medicine ,0501 psychology and cognitive sciences ,Kinetic tremor ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Reduction (orthopedic surgery) ,FUS ,Essential tremor ,business.industry ,General Neuroscience ,05 social sciences ,medicine.disease ,Neuromodulation (medicine) ,Rats ,nervous system diseases ,chemistry ,Medulla oblongata ,Cardiology ,Neurology (clinical) ,medicine.symptom ,business ,ET ,030217 neurology & neurosurgery - Abstract
Background: Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. With drug treatment only partially efficient, new treatments are being developed. Objectives: The goal of this study was to demonstrate the feasibility of non-thermal focused-ultrasound (FUS) to induce tremor-suppression in an ET rat model. Methods: Harmaline-induced tremor rats were treated with FUS along the inferior olivary (IO) system. EMG was recorded continuously during treatment in order to quantify FUS-induced tremor suppression. T2-weighted MRI was performed immediately following treatment and periodically thereafter. Results: FUS treatment at an intensity of 27.2 W/cm2 (Isppa) induced significant reduction of tremor in 12 out of 13 ET rats. Tremor frequency was reduced from 6.2 ± 2.8 to 2 ± 1 Hz, p
- Published
- 2019
41. EPCO-03. GLIOMA ONCOGENESIS IN THE CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD) SYNDROME
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Laurence Brugières, Jacques Grill, Nadim Hamzaoui, Martine Muleris, Tiphaine Adam de Beaumais, Odile Cabaret, Philippe Denizeau, Franck Bourdeaut, David Castel, Jane Merlevede, Felipe Andreiuolo, Chrystelle Colas, Cécile Faure-Conter, Stéphanie Puget, Pascale Varlet, Thomas Blauwblomme, Etienne Rouleau, Léa Guerrini-Rousseau, Marie-Anne Debily, and Kevin Beccaria
- Subjects
Cancer Research ,business.industry ,Cancer ,26th Annual Meeting & Education Day of the Society for Neuro-Oncology ,medicine.disease ,medicine.disease_cause ,Oncology ,Glioma ,medicine ,Cancer research ,MISMATCH REPAIR DEFICIENCY ,DNA mismatch repair ,Neurology (clinical) ,Carcinogenesis ,business ,Exome sequencing ,Protein overexpression ,Glioblastoma - Abstract
PURPOSE Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40NS SNV/Mb, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
- Published
- 2021
42. HGG-41. Glioma oncogenesis in the constitutional mismatch repair deficiency (CMMRD) syndrome
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Lea Guerrini-Rousseau, Jane Merlevede, Philippe Denizeau, Felipe Andrejuolo, Pascale Varlet, Stephanie Puget, Kevin Beccaria, Thomas Blauwblomme, Odile Cabaret, Nadim Hamzaoui, Franck Bourdeaut, Cecile Faure-Conter, Martine Muleris, Chrystelle Colas, Tiphaine Adam de Beaumais, David Castel, Etienne Rouleau, Laurence Brugieres, Jacques Grill, and Marie-Anne Debily
- Subjects
Cancer Research ,Oncology ,Neurology (clinical) - Abstract
PURPOSE: Constitutional Mismatch Repair Deficiency (CMMRD) is a cancer predisposition due to bi-allelic mutations in one of the four main mismatch repair (MMR) genes (PMS2, MSH2, MSH6 or MLH1) associated with early onset of cancers, especially glioblastomas (GBM). Our aim was to decipher the molecular specificities of gliomas occurring in this context. METHODS: A comprehensive analysis of clinical, histopathological and genomic data (whole exome sequencing) was performed for 12 children with a CMMRD for which we had available frozen brain tumor material (10 GBM and 2 anaplastic astrocytomas). RESULTS: Eight patients harbored an ultra-mutated phenotype with more than 100 somatic non synonymous (NS) SNV/Mb. No correlation was observed between the number of mutation and sex, age, overall survival or mutated MMR gene. POLE and POLD1 exonuclease domain driver somatic mutations were described for eight and one patients respectively. The 4/12 tumors without POLE somatic mutation did not show the classical ultra-hypermutation pattern. All patients with POLE mutation had already more than 20 NS SNV/Mb (median 40, [range 23-114]) suggesting that the hypermutation phenomenon started before the appearance of the somatic POLE mutation. The mutational signatures of the tumors, dominated by the MMR signatures, were not modified after the onset of the POLE mutation when analyzing the different mutation bursts. Specific recurrent somatic mutations were observed in SETD2 (9/12), TP53 (9/12), NF1 (9/12), EPHB2 (8/12), and DICER1 (7/12). Only half of the tumors overexpressed PDL1 by immunohistochemistry and this overexpression was not associated with a higher tumor mutation burden. CONCLUSION: CMMRD-associated gliomas have a specific oncogenesis that does not trigger usual pathways and mutations seen in sporadic pediatric or adult GBM. Frequent alterations in other pathways (e.g. MAPK or DNA-PK pathway) may suggests the use of other targeted therapies aside from PD1 inhibitors.
- Published
- 2022
43. The dark matter of diffuse intrinsic pontine gliomas: an update
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Alexandre Plessier, Ludivine Le Dret, Stéphanie Puget, David Castel, Kevin Beccaria, Marie-Anne Debily, Jacques Grill, and Pascale Varlet
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business.industry ,Health Policy ,Dark matter ,03 medical and health sciences ,0302 clinical medicine ,health services administration ,030220 oncology & carcinogenesis ,Radioresistance ,Pediatric oncology ,Cancer research ,Medicine ,Pharmacology (medical) ,business ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,030217 neurology & neurosurgery - Abstract
Introduction: DIPG represents the biggest therapeutic challenge in pediatric oncology and in neuro-oncology. Knowledge about its biology has dramatically increased in the last 5 years, but we are s...
- Published
- 2018
44. Diagnostics of pediatric supratentorial RELA ependymomas: integration of information from histopathology, genetics, DNA methylation and imaging
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Kristian W. Pajtler, S. Puget, Stephanie Picot, Jacques Grill, Marcel Kool, Marie-Anne Debily, Felipe Andreiuolo, Christian Sainte-Rose, David Castel, Torsten Pietsch, Arnault Tauziède-Espariat, Nathalie Boddaert, Mélanie Pagès, Fabrice Chrétien, David Capper, Stefan M. Pfister, and Pascale Varlet
- Subjects
Male ,0301 basic medicine ,Ependymoma ,Pathology ,medicine.medical_specialty ,YAP1 ,Malignancy ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,FISH ,C11orf95‐RELA ,medicine ,Humans ,Child ,In Situ Hybridization, Fluorescence ,Research Articles ,Brain Neoplasms ,business.industry ,General Neuroscience ,NF-kappa B ,Transcription Factor RelA ,Infant ,Proteins ,Supratentorial Neoplasms ,Methylation ,DNA Methylation ,Subependymoma ,medicine.disease ,Immunohistochemistry ,subependymoma ,030104 developmental biology ,HGNET ,Child, Preschool ,DNA methylation ,Female ,Histopathology ,Neurology (clinical) ,Differential diagnosis ,business ,Supratentorial Ependymoma ,030217 neurology & neurosurgery ,Research Article - Abstract
Ependymoma with RELA fusion has been defined as a novel entity of the revised World Health Organization 2016 classification of tumors of the central nervous system (CNS), characterized by fusion transcripts of the RELA gene and consequent pathological activation of the NFkB pathway. These tumors represent the majority of supratentorial ependymomas in children. The validation of diagnostic tools to identify this clinically relevant ependymoma entity is essential. Here, we have used interphase fluorescent in situ hybridization (FISH) for C11orf95 and RELA, immunohistochemistry (IHC) for p65‐RelA and the recently developed DNA methylation‐based classification besides conventional histopathology, and compared the precision of the methods in 40 supratentorial pediatric brain tumors diagnosed as ependymomas in the past years. Reverse transcription PCR (RT‐PCR) and RNA sequencing were performed to explore discordant cases. Furthermore, we integrated imaging and clinical features as additional layers of information. The concordance between nuclear RelA expression by IHC and RELA FISH was 100%. Concordance between IHC and DNA methylation profiling, and between FISH and DNA methylation profiling was also high (96.4% and 95.2%, respectively). Thirty‐four out of 40 (85%) cases were confirmed by integrated diagnoses as ependymal tumors, including 22 RELA‐fused ependymomas (71% of ependymal tumors), two YAP1‐fused ependymomas (6%), six non‐RELA/non‐YAP1 ependymomas (18%) and four ependymal/subependymal mixed tumors (12%). Ependymal/subependymal mixed tumors had an excellent clinical outcome despite the presence of histopathological signs of malignancy, suggesting that these tumors should not be diagnosed as classic ependymomas. DNA methylation profiling helped in the differential diagnosis of RELA‐fused ependymomas. IHC and FISH, which are available in the majority of pathology laboratories, are valuable tools to identify RELA‐fused ependymomas.
- Published
- 2018
45. International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma
- Author
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John Caird, Stephanie Francis, Rachid Drissi, Chris Jones, Anahid Ehteda, Maria Vinci, Cynthia Hawkins, Jordan R. Hansford, Darach Crimmins, Alexander Plessier, Dannis G. van Vuurden, Tim Hassall, Danielle Upton, Bing Liu, David Castel, Jane Pears, Jane Cryan, Michael Farrell, Louise E. Ludlow, Esther Hulleman, Diana Carvalho, Michelle Monje, Chelsea Mayoh, Michaël H. Meel, Maria Tsoli, Jacques Grill, Andrea Carai, Maryam Fouladi, Maria Kirby, David S. Ziegler, Angela Mastronuzzi, Nicholas G. Gottardo, Han Shen, Laura Franshaw, Pediatric surgery, and CCA - Cancer biology and immunology
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Cell Survival ,Brain Stem Neoplasm ,Autopsy ,Histones ,Mice ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Internal medicine ,Glioma ,Neurosphere ,Biopsy ,medicine ,Brainstem glioma ,Animals ,Brain Stem Neoplasms ,Humans ,Cells, Cultured ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,medicine.disease ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Neurology ,030220 oncology & carcinogenesis ,Mutation ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Purpose: Diffuse intrinsic pontine glioma is the most aggressive form of high grade glioma in children with no effective therapies. There have been no improvements in survival in part due poor understanding of underlying biology, and lack of representative in vitro and in vivo models. Recently, it has been found feasible to use both biopsy and autopsy tumors to generate cultures and xenograft models. Methods: To further model development, we evaluated the collective international experience from 8 collaborating centers to develop DIPG pre-clinical models from patient-derived autopsies and biopsies. Univariate and multivariate analysis was performed to determine key factors associated with the success of in vitro and in vivo PDX development. Results: In vitro cultures were successfully established from 57% of samples (84.2% of biopsies and 38.2% of autopsies). Samples transferred in DMEM media were more likely to establish successful culture than those transported in Hibernate A. In vitro cultures were more successful from biopsies (84.2%) compared with autopsies (38.2%) and as monolayer on laminin-coated plates than as neurospheres. Primary cultures successfully established from autopsy samples were more likely to engraft in animal models than cultures established from biopsies (86.7% vs. 47.4%). Collectively, tumor engraftment was more successful when DIPG samples were directly implanted in mice (68%), rather than after culturing (40.7%). Conclusion: This multi-center study provides valuable information on the success rate of establishing patient-derived pre-clinical models of DIPG. The results can lead to further optimization of DIPG model development and ultimately assist in the investigation of new therapies for this aggressive pediatric brain tumor.
- Published
- 2018
46. Radiogenomics of diffuse intrinsic pontine gliomas (DIPGs): correlation of histological and biological characteristics with multimodal MRI features
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Raphaël, Calmon, Volodia, Dangouloff-Ros, Pascale, Varlet, Christophe, Deroulers, Cathy, Philippe, Marie-Anne, Debily, David, Castel, Kevin, Beccaria, Thomas, Blauwblomme, David, Grevent, Raphael, Levy, Charles-Joris, Roux, Yvonne, Purcell, Ana, Saitovitch, Monica, Zilbovicius, Christelle, Dufour, Stéphanie, Puget, Jacques, Grill, and Nathalie, Boddaert
- Subjects
Histones ,Brain Neoplasms ,Diffuse Intrinsic Pontine Glioma ,Brain Stem Neoplasms ,Humans ,Glioma ,Child ,Magnetic Resonance Imaging - Abstract
The diffuse intrinsic pontine gliomas (DIPGs) are now defined by the type of histone H3 mutated at lysine 27. We aimed to correlate the multimodal MRI features of DIPGs, H3K27M mutant, with their histological and molecular characteristics.Twenty-seven treatment-naïve children with histopathologically confirmed DIPG H3K27M mutant were prospectively included. MRI performed prior to biopsy included multi-b-value diffusion-weighted imaging, ASL, and dynamic susceptibility contrast (DSC) perfusion imaging. The ADC and cerebral blood flow (CBF) and blood volume (CBV) were measured at the biopsy site. We assessed quantitative histological data, including microvascular density, nuclear density, and H3K27M-positive nuclear density. Gene expression profiling was also assessed in the samples. We compared imaging and histopathological data according to histone subgroup. We correlated MRI quantitative data with histological data and gene expression.H3.1K27M mutated tumors showed higher ADC values (median 3151 μmH3.1K27M mutated tumors have higher ADC and lower perfusion values than H3.3K27M ones, without direct correlation with microvascular or nuclear density. This may be due to tissular edema possibly related to gated channel activity-related gene expression.• H3.1K27M mutant DIPG had higher apparent diffusion coefficient (p = 0.003), lower α (p = 0.048), and lower relative cerebral blood volume (p = 0.02) than H3.3K27M mutant DIPG at their biopsy sites. • Biopsy samples obtained within the tumor's enhancing portion showed higher microvascular density (p = 0.03) than samples obtained outside the tumor's enhancing portion, but similar H3K27M-positive nuclear density (p = 0.84). • Relative cerebral blood volume measured at the biopsy site was significantly correlated with H3K27M-positive nuclear density (rho = 0.74, p = 0.02).
- Published
- 2020
47. Staging of Orthodontic Tooth Movement in Clear Aligner Treatment: Macro-Staging and Micro-Staging—A Narrative Review
- Author
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David Martínez-Lozano, David Castellanos-Andrés, and Alberto-José López-Jiménez
- Subjects
clear aligners ,staging ,orthodontics tooth movement ,macro-staging ,micro-staging ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Aims: This review aims to analyze the multiple factors affecting the staging of the orthodontic tooth movement during clear aligner treatment and to provide an efficient work methodology in this regard during digital treatment planning. Materials and Methods: A literature search was conducted on electronic databases (Pubmed, Scopus, Google Scholar and CNKI). The results of the present study have been divided into several sections: (1) definition and concept of staging, (2) basic principles of clear aligners, (3) macro-staging, (4) micro-staging, and (5) limitations. Results: The terminology of macro-staging and micro-staging proposed in this paper aims to be a first step towards a more detailed analysis of staging. The macro-staging constitutes the general biomechanics of movements that need to be prioritized to meet the objectives of the treatment plan. It provides a comprehensive view of the movements occurring in each dental arch. The micro-staging constitutes the biomechanics of movements for each individual tooth. This involves studying the movements in the different planes of space in which each tooth is programmed, deciding if they are compatible, and having strategies to create space to avoid lack of expression. Conclusions: Further studies should focus on exploring different staging approaches to address similar malocclusions to determine which are the most effective and applicable to clinical practice.
- Published
- 2024
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48. High-Resolution Ultrasound Platform for Infant Meningitis Detection: An In Vitro Demonstration
- Author
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Manuel Navarrete, David Castells-Rufas, Hassane Baghdad Kichou, Guillermo Navarro-Patron, Javier Jimenez, and Jordi Carrabina
- Subjects
ultrasound ,white blood cells ,high resolution ,detection ,microscopy ,cerebrospinal fluid ,Chemical technology ,TP1-1185 - Abstract
Infant meningitis remains a severe burden on global health, particularly for young infants. Traditional ultrasound imaging techniques are limited in spatial resolution to visualize white blood cells (WBCs) in the cerebrospinal fluid (CSF), which is considered a well-established marker for meningitis detection. This work presents a novel platform that uses high-resolution ultrasound to detect the backscatter signals from microscopic CSF WBCs through the anterior fontanelle of neonates and young infants. The whole system was built around a custom probe that allows for a 20 MHz focused transducer to be mechanically controlled to map the area of interest in the CSF. Data processing can be performed internally in the device without the need to extract the images for further analysis. The in vitro feasibility of the proposed solution was evaluated in imaging 7 μm particle suspensions at different concentrations relevant to meningitis diagnosis ranging from 7- to 646-particles (pp)/μL. The experimental tests were conducted from a simple setup using a sample container to a more realistic setup based on an anatomical phantom of the neonatal head. The results show high-quality images, where 7 μm particles can be resolved for the different concentrations.
- Published
- 2024
- Full Text
- View/download PDF
49. EZHIP is a specific diagnostic biomarker for posterior fossa ependymomas, group PFA and diffuse midline gliomas H3-WT with EZHIP overexpression
- Author
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Marie-Anne Debily, Fabrice Chrétien, Mélanie Pagès, Arnault Tauziède-Espariat, Albane Gareton, Felipe Andreiuolo, Antin C, Jacques Grill, David Castel, Emmanuèle Lechapt, Olivier Ayrault, Pascale Varlet, Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), and Olivier, AYRAULT
- Subjects
Pathology ,medicine.medical_specialty ,Neurology ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Oligodendroglioma ,Posterior fossa ,Infratentorial Neoplasms ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Astrocytoma ,Sensitivity and Specificity ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Histones ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Text mining ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Medicine ,Diagnostic biomarker ,Humans ,Letter to the Editor ,lcsh:Neurology. Diseases of the nervous system ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Oncogene Proteins ,0303 health sciences ,business.industry ,Brain Neoplasms ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Glioma ,Ependymoma ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Neurology (clinical) ,business ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
International audience
- Published
- 2020
50. Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation
- Author
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David, Castel, Thomas, Kergrohen, Arnault, Tauziède-Espariat, Alan, Mackay, Samia, Ghermaoui, Emmanuèle, Lechapt, Stefan M, Pfister, Christof M, Kramm, Nathalie, Boddaert, Thomas, Blauwblomme, Stéphanie, Puget, Kévin, Beccaria, Chris, Jones, David T W, Jones, Pascale, Varlet, Jacques, Grill, and Marie-Anne, Debily
- Subjects
Histones ,Oncogene Proteins ,Glutamates ,Brain Neoplasms ,Mutation ,Humans ,Glioma ,Transcription Factors - Published
- 2019
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