Letteratura scientifica selezionata sul tema "Diffuse glioma"
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Articoli di riviste sul tema "Diffuse glioma"
1
Park, Jong-Whi. "Metabolic Rewiring in Adult-Type Diffuse Gliomas". International Journal of Molecular Sciences 24, n. 8 (16 aprile 2023): 7348. http://dx.doi.org/10.3390/ijms24087348.
Testo completoAbstract (sommario):
Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma’s complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.
2
Wong, Shu Chyi, Muhamad Noor Alfarizal Kamarudin e Rakesh Naidu. "Anticancer Mechanism of Flavonoids on High-Grade Adult-Type Diffuse Gliomas". Nutrients 15, n. 4 (4 febbraio 2023): 797. http://dx.doi.org/10.3390/nu15040797.
Testo completoAbstract (sommario):
High-grade adult-type diffuse gliomas are the most common and deadliest malignant adult tumors of the central nervous system. Despite the advancements in the multimodality treatment of high-grade adult-type diffuse gliomas, the five-year survival rates still remain poor. The biggest challenge in treating high-grade adult-type diffuse gliomas is the intra-tumor heterogeneity feature of the glioma tumors. Introducing dietary flavonoids to the current high-grade adult-type diffuse glioma treatment strategies is crucial to overcome this challenge, as flavonoids can target several molecular targets. This review discusses the anticancer mechanism of flavonoids (quercetin, rutin, chrysin, apigenin, naringenin, silibinin, EGCG, genistein, biochanin A and C3G) through targeting molecules associated with high-grade adult-type diffuse glioma cell proliferation, apoptosis, oxidative stress, cell cycle arrest, migration, invasion, autophagy and DNA repair. In addition, the common molecules targeted by the flavonoids such as Bax, Bcl-2, MMP-2, MMP-9, caspase-8, caspase-3, p53, p38, Erk, JNK, p38, beclin-1 and LC3B were also discussed. Moreover, the clinical relevance of flavonoid molecular targets in high-grade adult-type diffuse gliomas is discussed with comparison to small molecules inhibitors: ralimetinib, AMG232, marimastat, hydroxychloroquine and chloroquine. Despite the positive pre-clinical results, further investigations in clinical studies are warranted to substantiate the efficacy and safety of the use of flavonoids on high-grade adult-type diffuse glioma patients.
3
Rao, Aparna, Xiaoran Zhang, Christopher Deibert, Paola Sette, Paola Grandi e Nduka Amankulor. "IDH Mutant Gliomas Escape Natural Killer Cell Immune Surveillance by Downregulation of NKG2D Ligand Expression". Journal of Immunology 196, n. 1_Supplement (1 maggio 2016): 142.11. http://dx.doi.org/10.4049/jimmunol.196.supp.142.11.
Testo completoAbstract (sommario):
Abstract Background Diffuse gliomas are fatal primary brain tumors that are poorly immunogenic. The basis for insufficient anti-tumor immunity in diffuse gliomas is not understood. Mutations in isocitrate dehydrogenases (IDH1 and IDH2) promote diffuse glioma formation through epigenetic reprogramming of a number of genes, including immune-related genes. Here, we identify epigenetic dysregulation of natural killer (NK) cell ligand genes as significant contributors to immune escape in glioma. Methods We analyzed the TCGA database for immune gene expression patterns in IDH mutant or wild-type gliomas and identified differentially expressed immune genes. NKG2D ligands expression levels and NK cell-mediated lysis were measured in patient-derived glioma stem cells and in genetically engineered astrocytes. Finally, we assessed the impact of hypomethylating agent Decitabine as a potential NK cell sensitizing agent in IDH mutant cells. Results All IDH mutant glioma stem-like cell lines exhibited significantly lower expression of NKG2D ligands compared with IDH wild-type cells. Consistent with these findings, IDH mutant glioma cells and astrocytes were resistant to NK cell-mediated lysis. The hypomethylating agent Decitabine increased NKG2D ligand expression, and restored NK- mediated lysis of IDH mutant cells in an NKG2D-dependent manner. Conclusions IDH mutant glioma cells acquire resistance to NK cells through epigenetic silencing of NKG2D ligands ULBP1 and ULPB3. Decitabine-mediated hypomethylation restores ULBP1 and ULBP3 expression in IDH mutant glioma cells and may provide a clinically useful method to sensitize IDH mutant gliomas to NK cell-mediated immune surveillance in patients with IDH mutated diffuse gliomas.
4
Barron, Tara, Belgin Yalçın, Aaron Mochizuki, Evan Cantor, Kiarash Shamardani, Dana Tlais, Andrea Franson et al. "CNSC-01. GABAERGIC NEURON-TO-GLIOMA SYNAPSES IN DIFFUSE MIDLINE GLIOMAS". Neuro-Oncology 25, Supplement_1 (1 giugno 2023): i11. http://dx.doi.org/10.1093/neuonc/noad073.044.
Testo completoAbstract (sommario):
Abstract High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling and direct neuron-to-glioma synapses. Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric and adult high-grade gliomas, but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology, in vivo optogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation, we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam – a positive allosteric modulator of GABAA receptors commonly administered to children with DMG for nausea or anxiety - increases GABAA receptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAA receptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and DMG cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context.
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Nguyen, Anthony V., Jose M. Soto, Sarah-Marie Gonzalez, Jennifer Murillo, Eric R. Trumble, Frank Y. Shan e Jason H. Huang. "H3G34-Mutant Gliomas—A Review of Molecular Pathogenesis and Therapeutic Options". Biomedicines 11, n. 7 (15 luglio 2023): 2002. http://dx.doi.org/10.3390/biomedicines11072002.
Testo completoAbstract (sommario):
The 2021 World Health Organization Classification of Tumors of the Central Nervous System reflected advances in understanding of the roles of oncohistones in gliomagenesis with the introduction of the H3.3-G34R/V mutant glioma to the already recognized H3-K27M altered glioma, which represent the diagnoses of pediatric-type diffuse hemispheric glioma and diffuse midline glioma, respectively. Despite advances in research regarding these disease entities, the prognosis remains poor. While many studies and clinical trials focus on H3-K27M-altered-glioma patients, those with H3.3-G34R/V mutant gliomas represent a particularly understudied population. Thus, we sought to review the current knowledge regarding the molecular mechanisms underpinning the gliomagenesis of H3.3-G34R/V mutant gliomas and the diagnosis, treatment, long-term outcomes, and possible future therapeutics.
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Nuechterlein, Nicholas, e Patrick Cimino. "PATH-24. COPY NUMBER ALTERATIONS IN NOTCH PATHWAY GENES ARE PROGNOSTIC IN A SUBSET OF DIFFUSE ASTROCYTIC GLIOMAS". Neuro-Oncology 23, Supplement_6 (2 novembre 2021): vi120. http://dx.doi.org/10.1093/neuonc/noab196.476.
Testo completoAbstract (sommario):
Abstract Inactivating mutations in NOTCH1 occur in many cancer types and are frequently observed in IDH-mutant, 1p/19q-codeleted oligodendroglioma. Although the role of NOTCH1 as a tumor suppressor in diffuse glioma has become appreciated in human tissue and small animal models, the spectrum of inactivating mutations in Notch pathway genes in diffuse astrocytic gliomas has not been well described. To address this, we queried the TCGA lower-grade glioma and glioblastoma datasets to establish the extent of inactivation of Notch pathway genes, specifically by cataloging single nucleotide variants and those with copy number loss or deletion. Key alteration frequencies were found to be similar in two-independent glioma cohorts (Col, MSK). Notch pathway genes with inactivating alterations (overwhelmingly copy number loss) were present in 77% of TCGA diffuse gliomas. Across all diffuse gliomas, DLL3 loss was the most common alteration (TCGA 31%). For IDH-mutant diffuse astrocytic gliomas, JAG2 loss was the most common alteration (TCGA 23.0%, Col 35%, MSK 27%). DLL1 loss and MAML1 loss were mutually exclusive (p< 0.001) in TCGA IDH-mutant astrocytomas with a combined frequency of 39% (Col 47%, MSK 56%). The presence of any alteration in the top 10 altered Notch pathway genes indicated a shorter progression-free survival (p = 0.028) for TCGA IDH-mutant diffuse astrocytomas. For IDH-wildtype diffuse astrocytic gliomas, EP300 loss was the most common inactivating alteration (TCGA 35.4%, Col 49%, MSK 38%). EP300 loss, DLL1 loss, DLL4 loss were mutually exclusive (p = 0.006) in TCGA IDH-wildtype diffuse astrocytic gliomas with a combined frequency of 61% (Col 72%, MSK 66%). The presence of alterations in any of these three genes indicated a decreased overall survival (p = 0.045) in TCGA IDH-wildtype diffuse astrocytic gliomas. Overall, loss of differential Notch pathway genes has prognostic implications in both IDH-wildtype and IDH-mutant diffuse astrocytic gliomas.
7
Campos Paiva, Aline, João Luiz Vitorino Araujo, Guilherme Brasileiro de Aguiar, Gabriel Rezende Batistella, Marcos Maldaum e José Esteves veiga. "SURG-11. NEOADJUVANT CHEMOTHERAPY FOR DIFFUSE GLIOMAS: A FEASIBLE OPTION?" Neuro-Oncology 22, Supplement_2 (novembre 2020): ii205. http://dx.doi.org/10.1093/neuonc/noaa215.858.
Testo completoAbstract (sommario):
Abstract BACKGROUND Diffuse gliomas are slow-growing tumors with predilection for deep and eloquent structures such as supplementary motor area and insula. They can reach huge dimensions which is a surgical challenging. OBJECTIVE Describe indications and limitations of neoadjuvant chemotherapy for diffuse gliomas. METHODS Systematic review was performed in November/2019 using Pubmed, Bireme and Cochrane databases. The following combinations were used: “Chemotherapy” AND “neoadjuvant” AND “diffuse glioma”, “Chemotherapy” AND “neoadjuvant” AND “low grade glioma”, “Chemotherapy” AND “preoperative” AND “diffuse glioma”, “Neoadjuvant” AND “Chemotherapy” AND “temozolomide” AND “diffuse glioma”. RESULTS After carefully analysis, 7 papers were selected. They had mixed surgical interventions and used different drugs. In general, it was observed that neoadjuvant Temozolomide for Oligodendrogliomas 1p19q codeleted with MGMT methylation had better response than other molecular groups. Tumor reduction was significant. CONCLUSIONS Quality of life is a main goal in neurooncology. Tumor reduction using chemotherapy is a promising therapeutic. Surgery, especially in eloquent areas, could remove more tumors with less morbidity. Recent publications are using this approach with good outcomes, however further studies with more patients and uniformization are required to stablish this approach.
8
Soni, Vaishali Walke, Deepti Joshi, Tanya Sharma, Adesh Shrivastava e Amit Agrawal. "The spectrum of microvascular patterns in adult diffuse glioma and their correlation with tumor grade". Journal of Pathology and Translational Medicine 58, n. 3 (15 maggio 2024): 127–33. http://dx.doi.org/10.4132/jptm.2024.03.11.
Testo completoAbstract (sommario):
Background: Primary brain tumors constitute the leading cause of cancer-related mortality. Among them, adult diffuse gliomas are the most common type, affecting the cerebral hemispheres and displaying a diffuse infiltrative pattern of growth in the surrounding neuropil that accounts for about 80% of all primary intracranial tumors. The hallmark feature of gliomas is blood vessel proliferation, which plays an important role in tumor growth, tumor biological behavior, and disease outcome. High-grade gliomas exhibit increased vascularity, the worst prognosis, and lower survival rates. Several angiogenic receptors and factors are upregulated in glioblastomas and stimulate angiogenesis signaling pathways by means of activating oncogenes and/or down-regulating tumor-suppressor genes. Existing literature has emphasized that different microvascular patterns (MVPs) are displayed in different subtypes of adult diffuse gliomas. Methods: We examined the distribution and biological characteristics of different MVPs in 50 patients with adult diffuse gliomas. Haematoxylin and eosin staining results, along with periodic acid–Schiff and CD34 dual-stained sections, were examined to assess the vascular patterns and correlate with different grades of diffuse glioma. Results: The present observational study on adult diffuse glioma evaluated tumor grade and MVPs. Microvascular sprouting was the most common pattern, while a bizarre pattern (type 2) was associated with the presence of a high-grade glioma. Vascular mimicry was observed in 6% of cases, all of which were grade 4 gliomas. Conclusions: This study supplements the role of neo-angiogenesis and aberrant vasculature patterns in the grading and progression of adult diffuse gliomas, which can be future targets for planning treatment strategies.
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Dellaretti, Marcos, Nicolas Reyns, Gustavo Touzet, François Dubois, Sebastião Gusmão, Júlio Leonardo Barbosa Pereira e Serge Blond. "Diffuse brainstem glioma: prognostic factors". Journal of Neurosurgery 117, n. 5 (novembre 2012): 810–14. http://dx.doi.org/10.3171/2012.7.jns111992.
Testo completoAbstract (sommario):
Object Brainstem gliomas were regarded as a single entity prior to the advent of MRI; however, several studies investigating MRI have recognized that these lesions are a heterogeneous group, and certain subgroups have a better prognosis for long-term survival. The aim of this study was to conduct a retrospective analysis of prognostic factors of patients with brainstem gliomas confirmed by histopathological diagnosis, particularly regarding assessment of whether histological grade, age, and MRI findings are prognostic factors for patient survival. Methods The study evaluated 100 patients diagnosed with brainstem glioma. There were 63 adults (40 men and 23 women; age range 18–75 years, mean 41 years) and 37 children (19 boys and 18 girls; age range 2–12 years, mean 6.9 years). Results The mean overall survival of this population, measured from the date of biopsy, was 57 months for diffuse low-grade glioma and 13.8 months for diffuse high-grade glioma (p < 0.001). The mean survival among patients with nonenhancing contrast lesions on MRI was 54.2 months, whereas for patients with enhancing lesions, it was 21.7 months (p < 0.001). Comparisons between the Kaplan-Meier survival curves of adults and children revealed similar median survival periods of 25 and 16 months, respectively (p > 0.05). The multivariate analysis (Cox proportional hazards regression) revealed that only histological grade was a significant prognostic factor (p < 0.001). Conclusions The study revealed that histological grade and MRI features were significant prognostic factors for survival in these patients, but in multivariate analysis, only histological grade remained a significant factor.
10
Sarangi, Sasmit, e Eric Wong. "HOUT-05. COMPARING OUTCOMES OF ADULT DIFFUSE MIDLINE GLIOMAS TO GLIOBLASTOMA (GBM) IN YOUNG PATIENTS". Neuro-Oncology 21, Supplement_6 (novembre 2019): vi112—vi113. http://dx.doi.org/10.1093/neuonc/noz175.470.
Testo completoAbstract (sommario):
Abstract Diffuse midline gliomas are a diagnostic entity with astrocytic tumors in a midline location and in the pediatric age group they have been associated with poor outcomes. There is ongoing debate if adults with diffuse midline gliomas also have a poor prognosis particularly as complete surgical resection is often not achievable in these patients. One of the limitations of looking at case-series based outcomes with these patients is that the incidence of these tumors has a skew towards younger patients and recent case-series with observed better than expected outcomes, might be subject to influence from this parameter. To better compare outcomes of these patients we reviewed our institutional tumor registry to identify 31 patients with diffuse midline gliomas from January 2010 to December 2017. We also identified a contemporaneous consecutive series of 46 patients of age ≤ 55 with a diagnosis of GBM, as the control group for comparison. Both groups were comparable in median age (53 vs 50), gender distribution and median Karnofsky Performance Status (80 vs 90). But fewer resections were performed on diffuse midline gliomas (35.5% vs 80%). Our results indicate that patients with a diffuse midline glioma have a higher likelihood of a poorer outcome with a median overall survival of 52 vs 91 weeks in the control. The hazard ratio for death in the diffuse midline glioma cohort as compared to the control was 1.68 (95% CI – 0.97–2.91, log-rank P value = 0.038). The 2-year survival rate was also lower in the diffuse midline glioma with 22.6% vs 39.1% in the control. This poorer outcome could be related to the slightly lower median performance status or the lack of complete resection in diffuse midline glioma patients. Additional analysis is being planned to genetically differentiate these patients and identify possible prognostic indicators.
Tesi sul tema "Diffuse glioma"
1
Konnully, Augustus Meera Bessy. "Characterization of cellular heterogeneity in Diffuse Low Grade Glioma". Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT038.
Testo completoAbstract (sommario):
Les gliomes diffus de bas grade (DLGG) sont des tumeurs gliales de grade II qui affectent principalement les jeunes adultes. Elles sont caractérisées par une croissance lente et une activité mitotique réduite. Cependant, ces tumeurs diffusent et envahissent le cerveau sain via les vaisseaux sanguins et les fibres nerveuses. Après plusieurs années de croissance lente, ces tumeurs peuvent évoluer vers des glioblastomes, des tumeurs cérébrales très agressives dont la survie médiane moyenne est alors de 12 à 15 mois après le diagnostic. La caractérisation cellulaire des DLGG est encore limitée ce qui nuit à la recherche d’un traitement à un stade précoce. Dans ma thèse de doctorat, je me suis focalisée sur la caractérisation de 'hétérogénéité cellulaire des DLGG mutés pour IDH1. En effectuant une analyse d'immunofluorescence sur des astrocytomes et oligodendrogliomes de grade II, j'ai identifié deux sous-populations cellulaires largement non chevauchantes et exprimant respectivement les facteurs de transcription SOX9 et OLIG1. Ces cellules s’apparentent à des cellules de type astrocytaire et oligodendrocytaire et expriment des marqueurs moléculaires distincts. Les cellules SOX9 expriment APOE, KCNN3, CRYAB et ID4, tandis que les cellules OLIG1 expriment préfentiellement PDGFRA, SOX8, MASH1 et SOX4. Par ailleurs, j’ai montré que les cellules SOX9 présentent une activation particulière des voies de signalisation, notamment Notch, BMP et leurs cibles en aval. Pour étudier le rôle de la voie de signalisation Notch dans la formation de ces 2 sous-populations tumorales, j'ai purifié par tri magnétique les cellules tumorales à partir d'échantillons de gliomes fraîchement réséqués et j'ai surexprimé le domaine intracellulaire Notch (NICD), une forme active de Notch. J’ai ainsi montré que cette activation augmentait l’expression des marqueurs cellulaires associés aux cellules SOX9+ et une baisse de ceux associés aux cellules OLIG1+. J'ai ensuite étendu ces analyses à une lignée cellulaire anaplasique dérivée d'un patient et mutée pour IDH1. Ces résultats indiquent un rôle clé de la signalisation Notch dans la régulation de la plasticité des cellules tumorales. Des expériences similaires pour étudier l'activation de la signalisation BMP (bone morphogenetic protein) n'ont pas montré d'effet notable sur la plasticité. Néanmoins, le traitement des cellules par des membres de la famille BMP a fortement augmenté l’expression de CRYAB, un marqueur associé à SOX9, et a diminué l’expression de OLIG1 et OLIG2. En conclusion, j'ai identifié deux sous-populations tumorales non chevauchantes dans des gliomes diffus de bas grade et j'ai démontré le rôle déterminant de la voie de signalisation Notch dans leur formation. Ces résultats permettront de mieux comprendre l'hétérogénéité tumorale dans les DLGG et de concevoir de nouvelles stratégies thérapeutiques contre ces tumeursDiffuse Low-Grade Gliomas (DLGG) are WHO grade II glial tumors affecting younger adults. They are characterized as silent, slow growing tumors with fewer mitotic activities. However, they diffuse and invade the healthy brain via blood vessels and nerve fibers. These, over a period of years develop to malignant Glioblastoma, aggressive brain tumors where patients have an average medial survival of 12-15 months after diagnosis. Ill-defined phenotypic and cellular diversity of DLGG poses serious limitation to treatment and prevention at the early stage.In my PhD thesis, I aimed to address this limitation by characterizing the cellular heterogeneity in IDH1-mutated DLGG. By performing immunofluorescence analysis on grade II astrocytoma and oligodendroglioma, I have identified two largely non-overlapping cellular subpopulations expressing SOX9 and OLIG1 transcription factors, which represent astrocyte-like and oligodendrocyte-like cells, respectively. Upon further investigation, I have shown that these subpopulations express distinct molecular markers. Sox9 cells are associated with APOE, KCNN3, CRYAB and ID4, while Olig1 cells showed strong correlation with the expression of PDGFRA, SOX8, MASH1, and SOX4. In addition, the sox9 cells show a particular activation of signaling pathways including Notch, BMP and their downstream targets.To ascertain the role of Notch signaling in regulating the formation of these tumoral subpopulations, I used magnetic sorting of tumor cells from freshly resected glioma samples and overexpressed Notch Intracellular Domain (NICD), an active form of Notch. Increased Notch activation resulted in an upregulation of Sox9- and downregulation of Olig1-associated cell markers. I have then extended these analyses on one anaplastic IDH1 mutated patient derived cell line which reproduced similar gene expression profile confirming the robustness of the role of Notch signaling in regulating the plasticity of the cells. Parallel experiments performed by activation of Bone Morphogenetic Protein (BMP) signaling on IDH1 mutated cell line did not show a prominent effect on the plasticity. Nevertheless, BMP signal activation highly upregulated CRYAB, a SOX9 related marker and downregulated OLIG1 and OLIG2.In conclusion, I have identified two non-overlapping tumor subpopulations in diffuse low-grade gliomas and demonstrated the deterministic role of Notch signaling pathway in their formation. I believe that these findings would aid in better understanding tumoral heterogeneity in DLGG and be extended in designing new therapeutic strategies against these tumors
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Furnish, Robin. "Evaluating Immune Modulatory Therapeutic Strategies for Diffuse Intrinsic Pontine Glioma". University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595849080346532.
Testo completo
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Trisolini, Elena. "Targeted molecular characterization of adult midline and circumscribed gliomas for the identification of new potential targets for personalized therapy". Doctoral thesis, Università del Piemonte Orientale, 2020. http://hdl.handle.net/11579/114872.
Testo completoAbstract (sommario):
Diffuse midline gliomas (MLG) are primary brain tumours arising from thalamus, hypothalamus, brainstem, cerebellum or spinal cord, mainly occurring in children. In adults, less than 10% of diffuse gliomas arises in midline structures and recent works suggested that this subset of tumours
may present with phenotypic and molecular characteristics differing from both pediatric MLG and adult supratentorial gliomas.
Circumscribed gliomas (CG) are low-grade tumours but may progress to anaplasia. They have lower genetic complexity than diffuse gliomas and could be better candidate for targeted therapies, when complete surgical resection is not feasible.
Unravelling the genomic landscape of MLG and CG will better define the prognostic value of molecular biomarkers and identify new therapeutic strategies that could improve patient care. Adult patients with diagnosis of MLG and CG were retrospectively identified from «Maggiore della
Carità» Hospital and GH Pitié-Salpêtrière (Paris). Mutation analysis was performed by Sanger sequencing of the major hot-spots: IDH1, IDH2, H3F3A, HIST1H3B, FGFR1, TERT promoter. FISH analyses of NTRK1-2-3 rearrangements were performed by break-apart probes on tissue
microarray of MLG cases. We identified 116 (French) and 47 (Italian) patients. The two cohorts showed a lower percentage of
H3F3A mutations (20% vs 33%), the mutation was not associated to a worse prognosis. FGFR1 mutations were identified in 18% of cases and are restricted to MLG. NTRKs analysis in the Italian cohort showed NTRK1 translocations in 15% of cases.
We reported a high rate of FGFR1 mutations in optic nerve pilocytic astrocitomas and the presence of alternative BRAF activating mutations (Thr599_Val600insThr and Val600_Lys601>Glu). Our finding of frequent and potentially targetable FGFR1 and BRAF mutations and NTRK1
translocations have important therapeutical implications in the current context of clinical trials, and further reinforces the need for molecular analyses.
4
Ben, Abdallah Mériem. "Un modèle de l'évolution des gliomes diffus de bas grade sous chimiothérapie". Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0215/document.
Testo completoAbstract (sommario):
Les gliomes diffus de bas grade sont des tumeurs cérébrales des jeunes adultes. Dans cette thèse, nous nous intéressons à la segmentation et à la modélisation de ces tumeurs. Dans la première partie du manuscrit, nous étudions la segmentation des gliomes diffus de bas grade à base de différentes méthodes manuelles et semi-automatiques. La délimitation de ces tumeurs peut être problématique en raison de leur caractère très infiltrant et inhomogène. En pratique clinique, le suivi des gliomes diffus de bas grade repose sur l'estimation du volume tumoral, soit par une segmentation suivie d'une reconstruction logicielle, soit par la méthode des trois diamètres. Pour la segmentation, elle est manuelle et est exécutée par des praticiens sur des IRM en pondération FLAIR ou T2. La méthode des trois diamètres est rapide mais s'avère difficile à implémenter dans le cas de gliomes diffus de bas grade très infiltrants ou en post-traitement. La solution par segmentation manuelle et reconstruction logicielle du volume est chronophage mais demeure plus précise en comparaison de la méthode des trois diamètres. Nous étudions ici la reproductibilité de la segmentation manuelle avec le logiciel OsiriX en réalisant un test subjectif dans le Living Lab PROMETEE de TELECOM Nancy. Les résultats de cette étude montrent que ni la spécialité du praticien ni le nombre d’années d’expérience ne semblent impacter significativement la qualité de la segmentation. Nous comparons par ailleurs les résultats obtenus à ceux d'un deuxième test où nous appliquons la méthode des trois diamètres. Enfin, nous explorons deux algorithmes de segmentation semi-automatique basés, respectivement, sur les contours actifs et sur la méthode des level set. Même si la segmentation automatique semble être une voie prometteuse, nous recommandons aujourd’hui l’utilisation de la segmentation manuelle du fait notamment du caractère diffus des gliomes de bas grade qui rend le contour complexe à délimiter. La seconde partie du manuscrit est consacrée à la modélisation des gliomes diffus de bas grade eux-mêmes ou, plus exactement, à la modélisation de l'évolution du diamètre tumoral en phase de chimiothérapie. La prise en charge thérapeutique des patients atteints de ces tumeurs inclut en effet souvent une chimiothérapie. Pour ce travail, nous nous intéressons à la chimiothérapie par Témozolomide en première ligne de traitement. Une fois le traitement entamé, les praticiens aimeraient déterminer l'instant optimal d'arrêt de traitement. Nous proposons une modélisation statistique du diamètre tumoral sous chimiothérapie. Cette modélisation s'appuie sur des modèles de régression linéaire et exponentielle. Elle permet de prédire le diamètre tumoral à partir d'un jeu de données d'apprentissage et d'alerter le clinicien sur l'état d'évolution du diamètre sous traitement. Nous espérons que ces modèles pourront un jour être utilisés comme un outil dans la planification de la chimiothérapie en milieu cliniqueDiffuse low-grade gliomas are brain tumors of young adults. In this thesis, we focus on the segmentation and on the modeling of these tumors. In the first part of the manuscript, we study the segmentation of diffuse low-grade gliomas based on different manual and semi-automatic methods. The delineation of these tumors can be problematic because of their very infiltrating and inhomogeneous nature. In clinical practice, the monitoring of diffuse low-grade gliomas is based on the estimation of tumor volume, obtained either through a segmentation followed by a software reconstruction or through the three diameters method. As for the segmentation, it is manual and it is performed by practitioners on FLAIR-weighted or T2-weighted MRI.The three diameters approach is fast but it is difficult to implement in the case of highly infiltrating diffuse low grade gliomas or after a treatment. The manual segmentation and software-based volume reconstruction solution is time-consuming but it remains more accurate in comparison with the three diameters method. We investigate in this work the reproducibility of the manual segmentation with the OsiriX software by performing a subjective test in the Living Lab PROMETEE in TELECOM Nancy. The results of this study show that neither the practitioners' specialty nor their number of years of experience seem to have a significant impact on the quality of the segmentation. We also compare the results to those of a second test where we apply the three diameters method. Finally, we explore two semi-automatic segmentation algorithms which are, respectively, based on active contours and on the level set method. Even if automatic segmentation seems to be a promising avenue, we recommend for now the use of manual segmentation because of the diffuse nature of low-grade gliomas, which makes the tumor's contours complex to delineate. The second part of the manuscript is dedicated to the modeling of diffuse low-grade gliomas themselves or, to be more precise, to the modeling of the evolution of the tumor's diameter during chemotherapy. The therapeutic management of patients with these tumors often includes indeed chemotherapy. For this work, we focus on Temozolomide chemotherapy in first-line treatment. After the beginning of the treatment, the practitioners would like to determine the optimum time of discontinuation. We propose a statistical modeling of tumor diameter under chemotherapy. This modeling is based on linear and exponential regression models. It can predict the tumor diameter from a set of training dataset and can alert the clinician on the state of change in diameter under treatment. We hope that these models will, eventually, be used as a tool in the planning of chemotherapy in a clinical environment
5
Fromm, Jan. "Investigating the expression and role of chloride ion channels in diffuse intrinsic pontine glioma". Thesis, Fromm, Jan (2021) Investigating the expression and role of chloride ion channels in diffuse intrinsic pontine glioma. Honours thesis, Murdoch University, 2021. https://researchrepository.murdoch.edu.au/id/eprint/63626/.
Testo completoAbstract (sommario):
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive type of glial brain tumour found in the pons region of the brainstem. DIPG accounts for about 10% of childhood central nervous system tumours and the prognosis for these children is poor. Resistance to radiation, the only current available therapy for DIPG, is one of the biggest challenges. This resistance could be due to the plasticity of DIPG cells, allowing them to rapidly adapt in response to different conditions. Preliminary RNA sequencing analyses of patient tumours identified the expression of ion channel genes including the GABA family. It is known that ion channels regulate tumour plasticity in other cancers and as such we aimed to investigate and characterise the role of ion channels in DIPG. This study aimed to validate the mRNA and protein expression of the GABA-A receptors associated with ligand-gated chloride channels, in DIPG patient-derived cell lines. The results of the study validated mRNA expression of the GABA-A receptor subunits using semi-quantitative and quantitative RT-PCR. Protein expression of three of the most highly expressed subunits (GABRA2, GABRA4, and GABRA5) was also demonstrated using western blotting and immunocytochemistry. Furthermore, a drug screen and titration showed that some GABA-A receptor modulators significantly inhibited proliferation of DIPG cells. This work confirmed that GABA-A subunits are expressed in DIPG cells and that blocking these ion channels inhibits DIPG cell proliferation. These findings form the foundation for future studies that will investigate GABA-A receptor drugs as potential treatments for DIPG using preclinical models.
6
Andreiuolo, Felipe. "Target in context : molecular pathology of pediatric ependymoma and high grade glioma". Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00913042.
Testo completoAbstract (sommario):
Biomarkers for the classification, clinical management and prognosis of pediatric brain tumors (ependymoma and high grade glioma, (HGG)) are lacking. To address this, biomarkers were developed and explored in view of classification, prognostication, target identification and prediction of the efficacy of treatment for patients with such tumors.We show that overexpression of neuronal markers distinguishes supratentorial from infratentorial ependymoma, and among the former higher immunoexpression of neurofilament 70 (NEFL) is correlated with better progression free survival (PFS). Tenascin-C (TNC) is significantly overexpressed in infratentorial ependymoma. A multi-institutional European ependymoma collaboration group was established and analyses were performed in a pediatric cohort of 250 patients, where immunohistochemistry (IHC) for TNC showed to be a robust marker of poor overall survival (OS) and PFS, particularly among children under 3 years, this being further validated in an independent cohort. Techniques and scoring performed in different laboratories were highly reproducible. IHC for NEFL and TNC could be used for prognostication of pediatric ependymoma.The analysis of putative predictive markers for the response to targeted therapies in pediatric HGG in the setting of a clinical trial with the anti-EGFR agent erlotinib was performed by IHC and fluorescent in situ hybridization. The frequent loss of PTEN in diffuse intrinsic pontine glioma (DIPG) and the confirmation of the biological singularity of the certain subgroups (expressing EGFR, displaying oligodendroglial differentiation) which seem to be associated with better response to erlotinib have helped our group to establish the design of the next Phase III protocol for this disease at our institution. We report mutations in PI3KCA constituting the first identification of oncogene mutations in some DIPG, which further highlight their biological heterogeneity. Further studies are needed to define the interaction between PTEN loss, EGFR overexpression, oligodendroglial differentiation, PI3KCA mutations and other recent findings such as PDGFRA/MET gains/amplification and TP53 mutations in these heterogeneous lesions and their relationship to the outcome of patients under new targeted therapies for this largely fatal disease.This thesis has allowed us to explore the molecular pathology in the context of biology and clinical setting of pediatric brain tumors.
7
Ben, Abdallah Mériem. "Un modèle de l'évolution des gliomes diffus de bas grade sous chimiothérapie". Electronic Thesis or Diss., Université de Lorraine, 2016. http://www.theses.fr/2016LORR0215.
Testo completoAbstract (sommario):
Les gliomes diffus de bas grade sont des tumeurs cérébrales des jeunes adultes. Dans cette thèse, nous nous intéressons à la segmentation et à la modélisation de ces tumeurs. Dans la première partie du manuscrit, nous étudions la segmentation des gliomes diffus de bas grade à base de différentes méthodes manuelles et semi-automatiques. La délimitation de ces tumeurs peut être problématique en raison de leur caractère très infiltrant et inhomogène. En pratique clinique, le suivi des gliomes diffus de bas grade repose sur l'estimation du volume tumoral, soit par une segmentation suivie d'une reconstruction logicielle, soit par la méthode des trois diamètres. Pour la segmentation, elle est manuelle et est exécutée par des praticiens sur des IRM en pondération FLAIR ou T2. La méthode des trois diamètres est rapide mais s'avère difficile à implémenter dans le cas de gliomes diffus de bas grade très infiltrants ou en post-traitement. La solution par segmentation manuelle et reconstruction logicielle du volume est chronophage mais demeure plus précise en comparaison de la méthode des trois diamètres. Nous étudions ici la reproductibilité de la segmentation manuelle avec le logiciel OsiriX en réalisant un test subjectif dans le Living Lab PROMETEE de TELECOM Nancy. Les résultats de cette étude montrent que ni la spécialité du praticien ni le nombre d’années d’expérience ne semblent impacter significativement la qualité de la segmentation. Nous comparons par ailleurs les résultats obtenus à ceux d'un deuxième test où nous appliquons la méthode des trois diamètres. Enfin, nous explorons deux algorithmes de segmentation semi-automatique basés, respectivement, sur les contours actifs et sur la méthode des level set. Même si la segmentation automatique semble être une voie prometteuse, nous recommandons aujourd’hui l’utilisation de la segmentation manuelle du fait notamment du caractère diffus des gliomes de bas grade qui rend le contour complexe à délimiter. La seconde partie du manuscrit est consacrée à la modélisation des gliomes diffus de bas grade eux-mêmes ou, plus exactement, à la modélisation de l'évolution du diamètre tumoral en phase de chimiothérapie. La prise en charge thérapeutique des patients atteints de ces tumeurs inclut en effet souvent une chimiothérapie. Pour ce travail, nous nous intéressons à la chimiothérapie par Témozolomide en première ligne de traitement. Une fois le traitement entamé, les praticiens aimeraient déterminer l'instant optimal d'arrêt de traitement. Nous proposons une modélisation statistique du diamètre tumoral sous chimiothérapie. Cette modélisation s'appuie sur des modèles de régression linéaire et exponentielle. Elle permet de prédire le diamètre tumoral à partir d'un jeu de données d'apprentissage et d'alerter le clinicien sur l'état d'évolution du diamètre sous traitement. Nous espérons que ces modèles pourront un jour être utilisés comme un outil dans la planification de la chimiothérapie en milieu cliniqueDiffuse low-grade gliomas are brain tumors of young adults. In this thesis, we focus on the segmentation and on the modeling of these tumors. In the first part of the manuscript, we study the segmentation of diffuse low-grade gliomas based on different manual and semi-automatic methods. The delineation of these tumors can be problematic because of their very infiltrating and inhomogeneous nature. In clinical practice, the monitoring of diffuse low-grade gliomas is based on the estimation of tumor volume, obtained either through a segmentation followed by a software reconstruction or through the three diameters method. As for the segmentation, it is manual and it is performed by practitioners on FLAIR-weighted or T2-weighted MRI.The three diameters approach is fast but it is difficult to implement in the case of highly infiltrating diffuse low grade gliomas or after a treatment. The manual segmentation and software-based volume reconstruction solution is time-consuming but it remains more accurate in comparison with the three diameters method. We investigate in this work the reproducibility of the manual segmentation with the OsiriX software by performing a subjective test in the Living Lab PROMETEE in TELECOM Nancy. The results of this study show that neither the practitioners' specialty nor their number of years of experience seem to have a significant impact on the quality of the segmentation. We also compare the results to those of a second test where we apply the three diameters method. Finally, we explore two semi-automatic segmentation algorithms which are, respectively, based on active contours and on the level set method. Even if automatic segmentation seems to be a promising avenue, we recommend for now the use of manual segmentation because of the diffuse nature of low-grade gliomas, which makes the tumor's contours complex to delineate. The second part of the manuscript is dedicated to the modeling of diffuse low-grade gliomas themselves or, to be more precise, to the modeling of the evolution of the tumor's diameter during chemotherapy. The therapeutic management of patients with these tumors often includes indeed chemotherapy. For this work, we focus on Temozolomide chemotherapy in first-line treatment. After the beginning of the treatment, the practitioners would like to determine the optimum time of discontinuation. We propose a statistical modeling of tumor diameter under chemotherapy. This modeling is based on linear and exponential regression models. It can predict the tumor diameter from a set of training dataset and can alert the clinician on the state of change in diameter under treatment. We hope that these models will, eventually, be used as a tool in the planning of chemotherapy in a clinical environment
8
Khalid, Fahad. "Magnetic Resonance Imaging and Genomic Mutation in Diffuse Intrinsic Pontine Glioma : Machine Learning Approaches for a Comprehensive Analysis". Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPAST006.
Testo completoAbstract (sommario):
Le diagnostic du gliome infiltrant du tronc cérébral (GITC) chez les enfants est l'un des plus éprouvants en oncologie pédiatrique. Malgré de nombreux essais cliniques explorant divers traitements, le pronostic reste sombre, la plupart des patients succombant entre 9 et 11 mois après le diagnostic. Les mutations génétiques clé associées au GITC incluent H3K27M, ACVR1 et TP53. Chaque mutation a des caractéristiques distinctes, poussant les médecins à suggérer des thérapies personnalisées, soulignant l'importance d'une détection précise des mutations pour guider le traitement. Situées dans la région cruciale du tronc cérébral, les tumeurs GITC présentent des risques significatifs liés à la biopsie en raison de potentiels dommages neurologiques. L'IRM est une méthode indispensable pour le diagnostic de ces tumeurs, évaluant leur extension et permettant de mesurer l'évolution de la maladie au cours de la thérapie. Une prédiction des mutations, combinée à l'identification des patients survivant plus de deux ans, pourrait améliorer la thérapie proposée à ces patients. Dans ce contexte, la radiomique transforme les images en vastes sources de données, extrayant des caractéristiques comme la forme et la texture pour aider à la prise de décision. L'objectif de cette thèse est de prédire les principales mutations génétiques et d'identifier les survivants à long terme, en mettant l'accent sur la normalisation des images et l'applicabilité des modèles radiomiques. Notre étude a utilisé une base de données rétrospective de l'Institut Gustave Roussy, comprenant les données IRM de 80 patients et leurs données cliniques respectives. Les données d'IRM ont mis en évidence des problèmes pour les études radiomiques, tels que l'inhomogénéité du champ de biais et l'effet "scanner". Pour répondre à ces défis, un pipeline de normalisation d'images IRM a été mis en place, et les caractéristiques radiomiques ont été harmonisées par la méthode ComBat. Pour faire face au problème de modalités manquantes dans l'ensemble de données, une stratégie multi-modèles a été employée, conduisant à 16 modèles distincts reposant sur diverses combinaisons de caractéristiques radiomiques et cliniques. Cette approche a ensuite été rationalisée en une méthode multimodale, réduisant le nombre de modèles à cinq, après une phase de sélection de caractéristiques indépendantes. Les résultats de l'approche multimodale se sont avérés être prometteurs. Cette stratégie multimodale a été essentielle pour identifier les patients survivant plus de deux ans et a été complétée par l'approche ICARE pour une analyse de survie détailléeThe diagnosis of diffuse intrinsic pontine glioma (DIPG) in children stands as one of the most harrowing within pediatric oncology. Despite numerous clinical trials exploring various treatments, the prognosis remains bleak, with most patients succumbing between 9 to 11 months post-diagnosis. Key gene mutations linked to DIPG include H3K27M, ACVR1, and TP53. Each mutation has distinct characteristics, leading physicians to suggest tailored therapies, underscoring the importance of accurate mutation detection in guiding treatment. Located in the crucial region of the brainstem, the pons, DIPG tumors pose significant biopsy risks due to potential neurological damage. Hence, MRI could become a primordial diagnostic tool for these tumors, assessing their spread and gauging therapy responses. Its use to predict accurate gene mutation, and identify long-term survivors, could enhance patient care significantly. Within this framework, radiomics transforms images into vast data sources, extracting features like shape and texture to aid decision-making. The objective of this thesis is to refine mutation prediction and pinpoint long-term survivors, emphasizing image normalization and the applicability of radiomic models. Our study utilized a retrospective database from Gustave Roussy Institute, encompassing 80 patients MRI data and their respective clinical data. These MRI images highlighted issues in radiomic studies, such as bias field inhomogeneity and the "scanner effect". To address these challenges, a dedicated MR image normalization pipeline was implemented, and radiomic features underwent ComBat harmonization. Given the dataset's missing modalities, a multi-model strategy was employed, leading to 16 distinct models based on various radiomic and clinical feature combinations. This approach was then streamlined into a multi-modal method, reducing the number of models to five. The results from the ensemble of these models proved to be the most promising. This multi-modal strategy incorporated a feature selection phase, pinpointing the most pertinent features. Additionally, this method was applied to identify long-term survivors and was complemented by the ICARE framework for a nuanced survival analysis output
9
Laurenge-Leprince, Alice. "Impact of D-2HG on the Tumor Microenvironment of IDH-mutated Gliomas". Electronic Thesis or Diss., université Paris-Saclay, 2024. https://theses.hal.science/tel-04905906.
Testo completoAbstract (sommario):
Contexte : Les gliomes diffus sont les tumeurs primitives malignes du système nerveux central les plus fréquentes. Certains présentent une mutation du gène codant pour l'isocitrate déshydrogénase 1 ou 2 (IDH) qui leur confère la néo-activité de transformer l'alpha-cétoglutarate (α-KG) produit par l'enzyme non mutée en D-2hydroxyglutarate (D-2HG). L'accumulation de cet oncométabolite entraîne l'inhibition compétitive des dioxygénases dépendantes de l'α-KG, incluant la famille TET (Ten Eleven Translocase) des ADN hydroxylases, et les JmjC/KMDs histone déméthylases, qui conduit elle-même à l'hyperméthylation des histones et de l'ADN des cellules tumorales. Les macrophages et microglies associés aux tumeurs (TAMs) sont des cellules myéloïdes très abondantes dans les gliomes, dont le phénotype et la réponse immunitaire sont déterminés par l'ontogenèse et le microenvironnement. Les TAMs présentent des caractéristiques différentes en fonction du statut IDH du gliome, mais les mécanismes de régulation sous-jacents restent largement méconnus. Le D-2HG relargué dans le microenvironnement par les cellules de gliomes IDH-mutants (IDH-m) pourrait influencer le phénotype et la fonction de ces TAMs. Nous avons émis l'hypothèse que le D-2HG pourrait modifier l'épigénome des TAMs, comme dans le cas des cellules tumorales.Matériel et méthodes : Nous avons comparé le méthylome (puce EPIC de méthylation) et le transcriptome des TAMs (CD11B+ isolés par tri cellulaire activé par magnétisme) de 25 gliomes IDH-m et 11 gliomes IDH-wildtype (IDH-wt), ainsi que de tissu cérébral contrôle non tumoral. Pour déterminer les effets directs du D-2HG sur la microglie, nous avons mis au point des cultures primaires de microglie humaine obtenues à partir d'une chirurgie de gliome ou d'épilepsie. Nous avons d'abord dosé le D-2HG dans la microglie traitée par D-2HG par spectrométrie de masse par chromatographie en phase liquide (LC-MS) afin d'évaluer l'entrée du métabolite dans ces cellules, et avons évalué l'activité enzymatique de TET. Nous avons exposé ou non des cellules microgliales au D-2HG pendant 14 jours et analysé leur méthylome et leur transcriptome. Les ratios de 5mC/5hmC ont été analysés à une résolution de base unique. Nous avons évalué la réponse transcriptomique et la respiration mitochondriale après stimulation au LPS de la microglie pré-traitée par D-2HG. Enfin, nous avons analysé par snRNA-seq le transcriptome microglial d'un échantillon apparié de gliome IDH-m avant et après traitement par l'inhibiteur d'IDH-m ivosidenib, qui diminue les concentrations intratumorales de D-2HG.Résultats : Nous montrons que les cellules myéloïdes CD11B+ des gliomes IDH-m humains présentent une hyperméthylation de l'ADN principalement au niveau des enhancers. Cette hyperméthylation est liée à une diminution de l'expression des gènes impliqués dans les réponses inflammatoires et le métabolisme glycolytique, et à l'inactivation des facteurs de transcription qui régulent la réponse microgliale aux stimuli environnementaux. L'exposition prolongée de la microglie primaire humaine au D-2HG inhibe l'oxydation de 5mC médiée par TET, ce qui entraîne une accumulation réduite des niveaux globaux de 5hmC. Nous avons observé des rapports 5mC/5hmC élevés, en particulier au niveau d'enhancers spécifiquement actifs dans ces cellules. Conformément à la modulation des enhancers, la microglie traitée au D-2HG présente une capacité pro-inflammatoire réduite et une augmentation de la phosphorylation oxydative. À l'inverse, la diminution des niveaux de D-2HG après traitement par ivosidenib chez un patient atteint de gliome IDH-m est associée à la restauration de l'expression génique liée à l'activation microgliale.Conclusion : Nos résultats fournissent une base mécanistique de l'état hyporéactif de la microglie dans les gliomes IDH-m et élargissent le concept selon lequel les oncométabolites peuvent perturber la fonction des cellules immunitaires du microenvironnement tumoralBackground: Diffuse gliomas are the most common primary malignant tumors of the central nervous system. A subset of these tumors harbors mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH), which confer a neo-activity that converts alpha-ketoglutarate (α-KG) produced by the wildtype enzyme into D-2-hydroxyglutarate (D-2HG). The accumulation of this oncometabolite competitively inhibits α-KG-dependent dioxygenases, including the TET (Ten Eleven Translocase) family of DNA hydroxylases and the JmjC/KDM family of histone demethylases. This ultimately leads to hypermethylation of both histones and DNA in tumor cells. Tumor-associated macrophages and microglia (TAMs) are abundant myeloid cells in gliomas, with their phenotype and immune responses shaped by ontogeny and the tumor microenvironment. The characteristics of TAMs differ depending on the IDH status of the glioma, yet the regulatory mechanisms underlying these differences remain poorly understood. D-2HG released by IDH-mutant (IDH-m) glioma cells into the microenvironment may affect the phenotype and function of TAMs. We hypothesized that D-2HG may influence the epigenome of TAMs, as in the case of tumor cells.Materials and Methods: We compared the bulk DNA methylome (Methylation EPIC array) and transcriptome of TAMs (CD11B+ cells purified via magnetic-activated cell sorting) from 25 IDH-mutant (IDH-m) and 11 IDH-wildtype (IDH-wt) gliomas, as well as control tissues. To experimentally assess the direct effects of D-2HG, the oncometabolite produced and released by IDH-m glioma cells, we used primary cultures of human microglial cells obtained from glioma or epilepsy surgeries. We first measured D-2HG levels in D-2HG-treated microglia using liquid chromatography-mass spectrometry (LC-MS) to confirm metabolite uptake, and evaluated TET enzymatic activity. Bona fide IDH-m and IDH-wt cells were used as external controls. Microglia were exposed to D-2HG for 14 days, after which we analyzed their DNA methylome and transcriptome. Ratios of 5mC/5hmC were examined at single-base resolution. We evaluated the transcriptomic response and the mitochrondrial respiration after LPS stimulation of microglia pre-treated with D-2HG. Lastly, we performed single-nuclei RNA sequencing (snRNA-seq) on microglial cells from a paired IDH-m glioma sample, before and after treatment with the IDH-m inhibitor ivosidenib, known to reduce intratumoral D-2HG levels.Results: Our analysis revealed that CD11B+ myeloid cells in human IDH-m gliomas exhibit DNA hypermethylation predominantly at distal enhancers. This hypermethylation is associated with decreased expression of genes involved in inflammatory responses and glycolytic metabolism, as well as the inactivation of transcription factors critical for microglial response to environmental stimuli. Prolonged exposure of primary human microglia to D-2HG inhibited TET-mediated 5mC oxidation, leading to reduced global 5hmC accumulation. High 5mC/5hmC ratios were particularly prominent at lineage-specific enhancers. Consistent with this altered enhancer landscape, D-2HG-treated microglia demonstrated diminished proinflammatory capacity and enhanced oxidative phosphorylation. Conversely, depletion of D-2HG following ivosidenib treatment in an IDH-m glioma patient was associated with the restoration of microglial gene expression related to activation.Conclusion: Our findings provide mechanistic insight into the hyporesponsive state of microglia in IDH-m gliomas and support the concept that oncometabolites, such as D-2HG, can disrupt the function of immune cells in the tumor microenvironment
10
Herbet, Guillaume. "Vers un modèle à double voie dynamique et hodotopique de l'organisation anatomo-fonctionnelle de la mentalisation : étude par cartographie cérébrale multimodale chez les patients porteurs d'un gliome diffus de bas-grade". Thesis, Montpellier 1, 2014. http://www.theses.fr/2014MON1T004/document.
Testo completoAbstract (sommario):
Comprendre comment le cerveau humain engendre les formes les plus élaborées de comportements est profondément lié à nos connaissances générales sur son organisation anatomique et fonctionnelle. Jusqu'à récemment encore, on pensait que les fonctions cognitives n'étaient rien d'autre que le sous-produit de l'activité neurale de régions corticales discrètes et hyper-fonctionnalisées. Les découvertes majeures obtenues ces dix dernières années dans le champ de la neuro-imagerie, et plus particulièrement de la connectomique, invitent cependant à complexifier nos représentations sur les liens qu'entretiennent structures et fonctions cérébrales. Le cerveau semble en effet être organisé en systèmes neurocognitifs complexes, hautement distribués et plastiques. C'est dans cet esprit qu'a été réalisé ce travail de thèse dont l'ambition première a été de repenser les modèles actuels de la cognition sociale, et en particulier ceux ayant trait à la fonction de mentalisation, à travers l'étude comportementale des patients porteurs d'un gliome diffus de bas-grade. Cette tumeur neurologique rare constitue un excellent modèle physiopathologique en vue du démasquage des structures maîtresses des systèmes cognitifs complexes, en ce qu'elle induit des phénomènes majeurs de réorganisation fonctionnelle, et s'infiltre préférentiellement le long de la connectivité axonale associative. Des corrélations anatomo-cliniques ont été réalisées suivant une approche topologique classique (analyse de groupe en régions d'intérêt, cartographie voxel-based lesion-symptom, stimulation électrique corticale intra-opératoire) mais également hodologique (degré de déconnection des faisceaux d'association, stimulation électrique de la connectivité axonale). Les résultats principaux de nos différents travaux nous permettent de jeter les premières bases d'un modèle à double voie dynamique (plastique) et hodotopique (contraint par la réalité anatomique) de l'organisation anatomo-fonctionnelle des processus de mentalisation. Spécifiquement, une voie dorsale, interconnectant le aires corticales fronto-pariétales « miroirs » via le système périsylvien de substance blanche associative (faisceau arqué et faisceau longitudinal supérieur latéral), sous-tendrait les processus perceptifs de « bas-niveau » nécessaires à l'identification préréflexive des états mentaux ; une voie cingulo-médiane, interconnectant les régions préfrontales médiales et rostro-cingulaires aux régions pariétales postérieures médiales via le faisceau cingulaire, sous-tendrait les processus de «haut-niveau » nécessaires aux inférences mentalistiques conscientes. Ces découvertes constituent une avancée substantielle en neurosciences sociales, ont des implications importantes pour la prise en charge clinique des patients, et peuvent permettre de mieux comprendre certaines psychopathologies caractérisées à la fois par un trouble de la mentalisation et des anomalies structurales de la connectivité associative (troubles du spectre autistique)Understanding how the brain produces sophisticated behaviours strongly depends of our knowledge on its anatomical and functional organization. Until recently, it was believed that high-level cognition was merely the by-product of the neural activity of discrete and highly specialized cortical areas. Major findings obtained in the past decade from neuroimaging, particularly from the field of connectomics, prompt now researchers to revise drastically their conceptions about the links between brain structures and functions. The brain seems indeed organized in complex, highly distributed and plastic neurocognitive networks. This is in this state of mind that our work has been carried out. Its foremost ambition was to rethink actuals models of social cognition, especially mentalizing, through the behavioural study of patients harbouring a diffuse low-grade glioma. Because this rare neurological tumour induces major functional reorganization phenomena and migrates preferentially along axonal associative connectivity, it constitutes an excellent pathophysiological model for unmasking the core structures subserving complex cognitive systems. Anatomo-clinical correlations were conducted according to both a classical topological approach (region of interest analyses, voxel-based lesion-symptom mapping, intraoperative cortical electrostimulation) and a hodological approach (degree of disconnection of associative white matter fasciculi, intraoperative axonal connectivity mapping). The main results of our different studies enable us to lay the foundation of a dynamic (plastic) and hodotopical (connectivity) dual-stream model of mentalizing. Specifically, a dorsal stream, interconnecting mirror frontoparietal areas via the perisylvian network (arcuate fasciculus and lateral superior longitudinal fasciculus), may subserve low-level perceptual processes required in rapid and pre-reflective identification of mental states; a cingulo-medial stream, interconnecting medial prefrontal and rostro-cingulated areas with medial posterior parietal areas via the cingulum, may subserve higher-level processes required in reflective mentalistic inferences. These original findings represents a great step in social neuroscience, have major implications in clinical practice, and opens new opportunities in understanding certain pathological conditions characterized by both mentalizing deficits and aberrant structural connectivity (e.g. autism spectrum disorders)
Libri sul tema "Diffuse glioma"
1
Duffau, Hugues, a cura di. Diffuse Low-Grade Gliomas in Adults. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-55466-2.
Testo completo
2
Duffau, Hugues, a cura di. Diffuse Low-Grade Gliomas in Adults. London: Springer London, 2013. http://dx.doi.org/10.1007/978-1-4471-2213-5.
Testo completo
3
Weller, Michael, Michael Brada, Tai-Tong Wong e Michael A. Vogelbaum. Astrocytic tumours: diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, and gliomatosis cerebri. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199651870.003.0003.
Testo completoAbstract (sommario):
Astrocytic gliomas are primary brain tumours thought to originate from neural stem or progenitor cells. They are assigned grades II, III, or IV by the World Health Organization according to degree of malignancy as defined by histology. The following molecular markers are increasingly used for diagnostic subclassification or clinical decision-making: 1p/19q co-deletion status, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and isocitrate dehydrogenase 1 and 2 mutation status. Extent of resection is a favourable prognostic factor, but surgery is never curative. Radiotherapy prolongs progression-free survival across all astrocytic glioma entities. Alkylating agent chemotherapy is an active treatment in particular for patients with MGMT promoter-methylated tumours. Anti-angiogenic therapies have failed to improve survival, and the current focus of major clinical trials is on novel targeted agents or on immunotherapy.
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Kleihues, Paul, Elisabeth Rushing e Hiroko Ohgaki. The 2016 revision of the WHO classification of tumours of the central nervous system. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199651870.003.0001.
Testo completoAbstract (sommario):
The revised fourth edition of the WHO classification of Tumours of the Central Nervous System, published in 2016, comprises several newly recognized tumour entities, and a significant restructuring of the classification, mainly based on genetic profiling. Glioblastomas are now classified into two major types. Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (primary glioblastoma IDH-wildtype) develops rapidly de novo without a recognizable precursor lesion. IDH-mutant glioblastoma (secondary glioblastoma IDH-mutant) develops more slowly through malignant progression from diffuse or anaplastic astrocytoma. Medulloblastomas are now defined by combining histological patterns (classic, desmoplastic/nodular, extensive nodularity, anaplastic) and genetic hallmarks (WNT-activated; SHH-activated, TP53-mutant; SHH-activated, TP53-wildtype; non-WNT/non-SHH). Other newly recognized tumour entities include diffuse midline glioma, H3 K27M-mutant; ependymoma, RELA fusion-positive; and embryonal tumour with multilayered rosettes. The new classification is a significant step forward and will facilitate the development of novel targeted therapies of brain tumours.
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Duffau, Hugues. Diffuse Low-Grade Gliomas in Adults. Springer, 2018.
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Duffau, Hugues. Diffuse Low-Grade Gliomas in Adults. Springer, 2017.
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Schroeder, Kristin, e Oren Becher. Pontine Gliomas. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199937837.003.0138.
Testo completoAbstract (sommario):
Pontine gliomas-also known as diffuse intrinsic pontine gliomas (DIPG)-primarily occur in children and typically present subacutely with a combination of cranial nerve palsies associated with long track signs including hyper-reflexia in the legs, positive Babinski responses, and cerebellar signs. On imaging they typically appear as intrinsic mass lesions within the pons. Treatment with radiation can prolong the course of from months to years but the tumors are rarely curable. Chemotherapy combined with radiation therapy targeted at specific signaling pathways has shown only modest impact on survival.
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Diffuse Lowgrade Gliomas In Adults Natural History Interaction With The Brain And New Individualized Therapeutic Strategies. Springer London Ltd, 2013.
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A new diffusely infiltrating glioma mouse model reveals neuronal alterations in the brain tumor microenvironment. [New York, N.Y.?]: [publisher not identified], 2018.
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Duffau, Hugues. Diffuse Low-Grade Gliomas in Adults: Natural History, Interaction with the Brain, and New Individualized Therapeutic Strategies. Springer, 2013.
Cerca il testo completoCapitoli di libri sul tema "Diffuse glioma"
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Noureldine, Mohammad Hassan A., Nir Shimony e George I. Jallo. "Diffuse Midline Glioma – Diffuse Intrinsic Pontine Glioma". In Brainstem Tumors, 159–93. Cham: Springer International Publishing, 2020. http://dx.doi.org/10.1007/978-3-030-38774-7_8.
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Liu, Dongyou. "Chordoid Glioma, Angiocentric Glioma, and Diffuse Midline Glioma". In Tumors and Cancers, 31–36. Boca Raton : Taylor & Francis, 2018. | Series: Pocket guides to biomedical sciences | “A CRC title, part of the Taylor & Francis imprint, a member of the Taylor & Francis Group, the academic division of T&F Informa plc.”: CRC Press, 2017. http://dx.doi.org/10.1201/9781315120522-6.
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Vanan, Magimairajan Issai, Vivek Mehta e David D. Eisenstat. "Diffuse Intrinsic Pontine Glioma". In Pediatric Neuro-oncology, 117–26. New York, NY: Springer New York, 2015. http://dx.doi.org/10.1007/978-1-4939-1541-5_11.
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Vanan, Magimairajan Issai, Craig Erker, Vivek Mehta, Cynthia Hawkins e David D. Eisenstat. "Diffuse Midline Glioma-Pons". In Pediatric Neuro-oncology, 185–201. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-031-62017-1_11.
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Morrison, Melanie A., e Adam D. Waldman. "Imaging Markers of Lower-Grade Diffuse Glioma". In Glioma Imaging, 139–59. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-27359-0_9.
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Karajannis, Matthias A., Matija Snuderl, Brian K. Yeh, Michael F. Walsh, Rajan Jain, Nikhil A. Sahasrabudhe e Jeffrey H. Wisoff. "High-Grade Glioma, Including Diffuse Intrinsic Pontine Glioma". In Brain Tumors in Children, 193–221. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-43205-2_9.
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McNeill, Katharine, Kenneth Aldape e Howard A. Fine. "Adult High-Grade (Diffuse) Glioma". In Molecular Pathology Library, 77–93. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1830-0_6.
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De Witt Hamer, Philip C., Emmanuel Mandonnet e Hugues Duffau. "Resection Probability Maps of Glioma". In Diffuse Low-Grade Gliomas in Adults, 665–83. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-55466-2_32.
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Cesselli, Daniela, Antonio Paolo Beltrami, Anja Pucer, Evgenia Bourkoula, Tamara Ius, Marco Vindigni, Miran Skrap e Carlo Alberto Beltrami. "Human Low-Grade Glioma Cultures". In Diffuse Low-Grade Gliomas in Adults, 137–63. London: Springer London, 2013. http://dx.doi.org/10.1007/978-1-4471-2213-5_10.
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Pope, Whitney B., e Kevin Spitler. "Molecular Imaging of Diffuse Low Grade Glioma". In Diffuse Low-Grade Gliomas in Adults, 173–95. Cham: Springer International Publishing, 2017. http://dx.doi.org/10.1007/978-3-319-55466-2_10.
Testo completoAtti di convegni sul tema "Diffuse glioma"
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Giannoni, Luca, Camilla Bonaudo, Marta Marradi, Alessandro Della Puppa e Francesco S. Pavone. "Optical characterisation and study of ex vivo glioma tissue for hyperspectral imaging during neurosurgery". In Diffuse Optical Spectroscopy and Imaging, a cura di Davide Contini, Yoko Hoshi e Thomas D. O'Sullivan. SPIE, 2023. http://dx.doi.org/10.1117/12.2670854.
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Ryall, Scott T., Robert Siddaway, Arun Ramani, Andrei Turinsky, Michael Brudno e Cynthia Hawkins. "Abstract 1184: Clonal evolution of diffuse intrinsic pontine glioma". In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1184.
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Tolson, Hannah. "Abstract 466: Epigenetic drug profiling in diffuse intrinsic pontine glioma". In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-466.
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Ben Abdallah, Meriem, Marie Blonski, Sophie Wantz-Mezieres, Yann Gaudeau, Luc Taillandier e Jean-Marie Moureaux. "Predictive models for diffuse low-grade glioma patients under chemotherapy". In 2016 38th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). IEEE, 2016. http://dx.doi.org/10.1109/embc.2016.7591692.
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Becher, Oren Josh. "Abstract IA22: Developing improved diffuse intrinsic pontine glioma mouse models". In Abstracts: AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.brain15-ia22.
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Diaz, Alexander K., Gang Wu, Barbara S. Paugh, Yongjin Li, Xiaoyan Zhu, Sherri Rankin, Chunxu Qu et al. "Abstract PR03: The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma". In Abstracts: AACR Special Conference: Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; November 3-6, 2013; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.pedcan-pr03.
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Ferris, Sarah F., Rachel K. Surowiec, Carlos Espinoza e Stefanie Galban. "Abstract 6152: Characterizing cancer stem cells in diffuse intrinsic pontine glioma". In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-6152.
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Yadavilli, Sridevi, Madhuri Kambhampati, Oren J. Becher, Tobey MacDonald, Ravi Bellamkonda, Roger J. Paker e Javad Nazarian. "Abstract 5004: NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-5004.
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Grasso, Catherine S. "Abstract LB-B06: Functionally defined therapeutic targets in diffuse intrinsic pontine glioma". In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; November 5-9, 2015; Boston, MA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1535-7163.targ-15-lb-b06.
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Saratsis, Amanda, Sridevi Yadavilli, Madhuri Kambhampati, Eric Raabe, Suresh Magge e Javad Nazarian. "Abstract C30: Four dimensional molecular analysis of pediatric diffuse intrinsic pontine glioma". In Abstracts: Third AACR International Conference on Frontiers in Basic Cancer Research - September 18-22, 2013; National Harbor, MD. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.fbcr13-c30.
Testo completoRapporti di organizzazioni sul tema "Diffuse glioma"
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Becher, Oren, e Alex Chung. Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool. Fort Belvoir, VA: Defense Technical Information Center, settembre 2012. http://dx.doi.org/10.21236/ada569511.
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Becher, Oren. Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool. Fort Belvoir, VA: Defense Technical Information Center, novembre 2014. http://dx.doi.org/10.21236/ada620002.
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