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1
Soukup, Jiri, Lucie Gerykova, Anjali Rachelkar, Helena Hornychova, Michael Christian Bartos, Petr Krupa, Barbora Vitovcova, et al. "Diagnostic Utility of Immunohistochemical Detection of MEOX2, SOX11, INSM1 and EGFR in Gliomas." Diagnostics 13, no. 15 (July 31, 2023): 2546. http://dx.doi.org/10.3390/diagnostics13152546.
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Histological identification of dispersed glioma cells in small biopsies can be challenging, especially in tumours lacking the IDH1 R132H mutation or alterations in TP53. We postulated that immunohistochemical detection of proteins expressed preferentially in gliomas (EGFR, MEOX2, CD34) or during embryonal development (SOX11, INSM1) can be used to distinguish reactive gliosis from glioma. Tissue microarrays of 46 reactive glioses, 81 glioblastomas, 34 IDH1-mutant diffuse gliomas, and 23 gliomas of other types were analysed. Glial neoplasms were significantly more often (p < 0.001, χ2) positive for EGFR (34.1% vs. 0%), MEOX2 (49.3% vs. 2.3%), SOX11 (70.5% vs. 20.4%), and INSM1 (65.4% vs. 2.3%). In 94.3% (66/70) of the glioblastomas, the expression of at least two markers was observed, while no reactive gliosis showed coexpression of any of the proteins. Compared to IDH1-mutant tumours, glioblastomas showed significantly higher expression of EGFR, MEOX2, and CD34 and significantly lower positivity for SOX11. Non-diffuse gliomas were only rarely positive for any of the five markers tested. Our results indicate that immunohistochemical detection of EGFR, MEOX2, SOX11, and INSM1 can be useful for detection of glioblastoma cells in limited histological samples, especially when used in combination.
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Olaofe, O. O., B. A. Adewara, C. C. Okongwu, and E. E. Ewoye. "Case report: A case report of optic nerve glioma in a 5-year-old African girl." Research Journal of Health Sciences 12, no. 1 (February 12, 2024): 82–87. http://dx.doi.org/10.4314/rejhs.v12i1.10.
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Background: Optic nerve gliomas are rare tumors that constitute less than 5% of all pediatric central nervous system tumors.
Case Presentation: We present the case of a 5-year-old girl with complaints of progressive protrusion of the right eye and poor vision of 3 years duration who was referred to the ophthalmologist. Ophthalmological evaluation of the right eye revealed tearing, no perception of light, inferior dystopia, severe proptosis, and a firm non-tender orbital mass palpable posterior to the eyeball. The cranial CT-scan was suggestive of a right optic nerve glioma. Histology showed Optic Glioma with extensive proliferation of meningothelial cells.
Conclusion: Optic gliomas can be associated with extensive proliferation of meningothelial cells that can histologically mimic a meningioma. It is important to be cautious about making a diagnosis of meningioma for tumors in locations that are also characteristic of optic nerve gliomas especially in appropriate clinical settings.
French title: Rapport de cas : Un rapport de cas de gliome du nerf optique chez une fillette africaine de 5 ans Titre en cours - Gliome optique chez une fillette africaineContexte de l'étude : Les gliomes du nerf optique sont des tumeurs rares qui constituent moins de 5 % de toutes les tumeurs pédiatriques du système nerveux central.
Présentation de cas : Nous présentons le cas d'une fillette de 5 ans présentant des plaintes de protrusion progressive de l'œil droit et une mauvaise vision depuis 3 ans qui a été référée à l'ophtalmologiste. L'évaluation ophtalmologique de l'œil droit a révélé un larmoiement, une absence de perception de la lumière, une dystopie inférieure, une exophtalmie sévère et une masse orbitaire ferme et non douloureuse, palpable en arrière du globe oculaire. Le scanner crânien était évocateur d'un gliome du nerf optique droit. L'histologie montrait un gliome optique avec une prolifération étendue de cellules méningothéliales.
Conclusion : Les gliomes optiques peuvent être associés à une prolifération étendue de cellules méningothéliales pouvant mimer histologiquement un méningiome. Il est important d'être prudent avant de poser un diagnostic de méningiome pour des tumeurs situées dans des localisations également caractéristiques des gliomes du nerf optique, en particulier dans des contextes cliniques appropriés.
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Hewer, Ekkehard, Jaison Phour, Marielena Gutt-Will, Philippe Schucht, Matthias S. Dettmer, and Erik Vassella. "TERT Promoter Mutation Analysis to Distinguish Glioma From Gliosis." Journal of Neuropathology & Experimental Neurology 79, no. 4 (January 29, 2020): 430–36. http://dx.doi.org/10.1093/jnen/nlaa004.
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Abstract Among the most challenging diagnostic issues in surgical neuropathology is the distinction between scant infiltration by diffuse gliomas and reactive gliosis. The best documented ancillary marker to establish a definitive diagnosis of glioma in this setting is the identification of hotspot mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes, which is limited, however, by the low prevalence of these mutations in gliomas of elderly adults. Since telomerase reverse transcriptase (TERT) promoter mutations are present in the vast majority of IDH-wildtype diffuse gliomas, we hypothesized that combined analysis of IDH and TERT might overcome these limitations. For this purpose, we analyzed a series of non-neoplastic and neoplastic CNS samples for the prevalence of TERT hotspot mutations. TERT mutations were identified in none out of 58 (0%) reactive gliosis samples, and in 91 out of 117 (78%) IDH-wildtype gliomas. Based on a series of 200 consecutive diffuse gliomas, we found that IDH mutation analysis alone had a sensitivity of 28% (63% and 12%, respectively, in patients below and above age of 50) for detection of gliomas, whereas a combined analysis of IDH and TERT was 85% sensitive (87% and 84%, respectively, below and above age of 50). In sum, our findings suggest that TERT promoter mutation analysis contributes favorably to a molecular panel in cases equivocal for glioma versus gliosis on morphological grounds, especially in patients above age of 50, in which IDH analysis alone performs poorly.
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Park, Jong-Whi. "Metabolic Rewiring in Adult-Type Diffuse Gliomas." International Journal of Molecular Sciences 24, no. 8 (April 16, 2023): 7348. http://dx.doi.org/10.3390/ijms24087348.
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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.
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Xia, He-chun, Zhan-feng Niu, Hui Ma, Shuan-zhu Cao, Shao-cai Hao, Zhong-tao Liu, and Fan Wang. "Deregulated Expression of the Per1 and Per2 in Human Gliomas." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 37, no. 3 (May 2010): 365–70. http://dx.doi.org/10.1017/s031716710001026x.
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Background:Growing evidence shows that the deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored.Methods:Using reverse transcription polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, Per1 and Per2, in 33 gliomas.Results:In this study, out of 33 gliomas, 28 were Per1-positive, and 23 were Per2-positive. The expression levels of Per1 and Per2 in glioma cells were significantly different from the surrounding non-glioma cells (P<0.01). The difference in the expression rate of Per1 and Per2 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was insignificant (P>0.05). While there was no difference in the intensity of immunoactivity for Per2 between high-grade gliomas and low-grade gliomas (r=-0.330, P=0.061), the expression level of Per1 in highgrade gliomas was significantly lower than that in low-grade gliomas(r=-0.433, P=0.012).Conclusions:In this study, we found that the expression of Per1 and Per2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in Per1 and Per2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.
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Sánchez, Manuel Lisardo, Arturo Mangas, and Rafael Coveñas. "Glioma and Peptidergic Systems: Oncogenic and Anticancer Peptides." International Journal of Molecular Sciences 25, no. 14 (July 22, 2024): 7990. http://dx.doi.org/10.3390/ijms25147990.
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Glioma cells overexpress different peptide receptors that are useful for research, diagnosis, management, and treatment of the disease. Oncogenic peptides favor the proliferation, migration, and invasion of glioma cells, as well as angiogenesis, whereas anticancer peptides exert antiproliferative, antimigration, and anti-angiogenic effects against gliomas. Other peptides exert a dual effect on gliomas, that is, both proliferative and antiproliferative actions. Peptidergic systems are therapeutic targets, as peptide receptor antagonists/peptides or peptide receptor agonists can be administered to treat gliomas. Other anticancer strategies exerting beneficial effects against gliomas are discussed herein, and future research lines to be developed for gliomas are also suggested. Despite the large amount of data supporting the involvement of peptides in glioma progression, no anticancer drugs targeting peptidergic systems are currently available in clinical practice to treat gliomas.
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Kim, Junhyung, Min Woo Park, Young Joon Park, Ju Won Ahn, Jeong Min Sim, Suwan Kim, Jinhyung Heo, et al. "miR-542-3p Contributes to the HK2-Mediated High Glycolytic Phenotype in Human Glioma Cells." Genes 12, no. 5 (April 23, 2021): 633. http://dx.doi.org/10.3390/genes12050633.
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(1) Background: The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear; (2) Methods: We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis; (3) Results: We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database; (4) Conclusions: miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.
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Kim, Junhyung, Min Woo Park, Ju Won Ahn, Jeong Min Sim, Suwan Kim, Young Joon Park, Jinhyung Heo, et al. "TAMI-47. MIR-542-3P CONTRIBUTES TO THE HK2-MEDIATED HIGH GLYCOLYTIC PHENOTYPE IN HUMAN GLIOMA CELLS." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi208. http://dx.doi.org/10.1093/neuonc/noab196.830.
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Abstract BACKGROUND The elevation of glucose metabolism is linked to high-grade gliomas such as glioblastoma multiforme (GBM). The high glycolytic phenotype is associated with cellular proliferation and resistance to treatment with chemotherapeutic agents in GBM. MicroRNA-542-3p (miR-542-3p) has been implicated in several tumors including gliomas. However, the role of miR-542-3p in glucose metabolism in human gliomas remains unclear. METHODS We measured the levels of cellular proliferation in human glioma cells. We measured the glycolytic activity in miR-542-3p knockdown and over-expressed human glioma cells. We measured the levels of miR-542-3p and HK2 in glioma tissues from patients with low- and high-grade gliomas using imaging analysis. RESULTS We show that knockdown of miR-542-3p significantly suppressed cellular proliferation in human glioma cells. Knockdown of miR-542-3p suppressed HK2-induced glycolytic activity in human glioma cells. Consistently, over-expression of miR-542-3p increased HK2-induced glycolytic activity in human glioma cells. The levels of miR-542-3p and HK2 were significantly elevated in glioma tissues of patients with high-grade gliomas relative to that in low-grade gliomas. The elevation of HK2 levels in patients with high-grade gliomas were positively correlated with the high levels of miR-542-3p in GBM and low-grade gliomas (LGG) based on the datasets from the Cancer Genome Atlas (TCGA) database. Moreover, the high levels of miR-542-3p were associated with poor survival rate in the TCGA database. CONCLUSIONS miR-542-3p contributes to the HK2-mediated high glycolytic phenotype in human glioma cells.
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Amin, Samirkumar, Kevin Anderson, Beth Bourdreau, Emmanuel Martínez, Emre Kocakavuk, Kevin C. Johnson, Floris Barthel, et al. "GENE-57. COMPARATIVE MOLECULAR LIFE HISTORY OF SPONTANEOUS CANINE AND HUMAN GLIOMA." Neuro-Oncology 21, Supplement_6 (November 2019): vi110. http://dx.doi.org/10.1093/neuonc/noz175.459.
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Abstract Diffuse gliomas are the commonest of malignant brain tumors with high-grade tumors carrying dismal prognosis. Preclinical models have proven themselves as poor predictors of clinical efficacy, attributed to the lack of a comparable tumor microenvironment. Comparative genomics of canine and human gliomas provide an attractive alternative modality to identify conserved drivers and underlying mutational processes of glioma as well as evaluate life history tradeoffs related to tissue context and aging that can shape type and relative timing of drivers in gliomagenesis. We performed a comparative genomics analysis between whole genome-, exome-, transcriptome- and methylation-sequencing of 77 canine gliomas, and human pediatric (n=217) and adult gliomas (n=822). We found alterations in common with those in human pediatric and adult gliomas in the Tp53 and cell cycle pathways, receptor tyrosine kinase and Idh1 R132 mutations. Canine gliomas showed similarity to human pediatric gliomas in terms of lower mutational rates (0.2–0.29 per megabase), hotspot mutations and amplifications of Pdgfrα, and robust aneuploidy constrained within the syntenic regions of Pdgfrα and Myc, but also in the known pediatric drivers, Hist1 and Acvr1 genes. A mutational signature reflecting homologous repair defect was detected in canine and pediatric but not adult gliomas, potentially resulting in the observed higher rates of genomic instability. Canine gliomas in majority classified as pediatric tumors using a commonly used human brain methylation classifier (Capper et al. 2018) and cell-of-origin analysis by deconvoluting canine transcriptome using lineage-specific gene signatures. By providing a large canine glioma genomic-sequencing dataset and comparing it with human glioma, our study provides unique insights into glioma etiology and the chronology of glioma-causing somatic alterations. Further, our results effectively position preclinical models of spontaneous canine glioma for use in understanding glioma drivers, and evaluate novel therapies targeting aneuploidy, especially for pediatric brain tumors.
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Wirth, Thomas, Farizan Ahmad, Agnieszka Pacholska, Haritha Samaranayake, and Seppo Ylä-Herttuala. "The Syngeneic BT4C Rat Malignant Glioma is a Valuable Model to study Myelomonocytic cells in Tumors." Cancer Growth and Metastasis 5 (January 2012): CGM.S9314. http://dx.doi.org/10.4137/cgm.s9314.
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Background The impact of infiltrating macrophages on tumor progression in malignant gliomas has been studied extensively. However, there is a lack of animal models for studying the role of infiltrating macrophages in malignant gliomas. Material and methods: The BT4C rat malignant glioma model was characterized by immunohistochemical analysis of inflammatory cell types associated with the tumors. Results BT4C malignant gliomas are highly vascularized tumors with an infiltrative behavior. BT4C gliomas demonstrated a high infiltration rate of macrophages. Particularly, a CD68/VEGFR-1 positive subtype of macrophages was detected at the edges of malignant gliomas. Also, CD133 positive cells were located mainly at the infiltrative edges of gliomas, whereas VEGFR-2 was highly expressed throughout the malignant glioma. Conclusion The immunocompetent BT4C rat malignant glioma model shows features similar to its human counterpart, which makes it a valuable model to study the impact of tumor associated macrophages in the pathology of malignant gliomas.
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Gisina, Alisa, Irina Kholodenko, Yan Kim, Maxim Abakumov, Alexey Lupatov, and Konstantin Yarygin. "Glioma Stem Cells: Novel Data Obtained by Single-Cell Sequencing." International Journal of Molecular Sciences 23, no. 22 (November 17, 2022): 14224. http://dx.doi.org/10.3390/ijms232214224.
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Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the inter-tumoral heterogeneity of gliomas, resulting in the updated 2021 WHO classification of gliomas. Thorough understanding of inter-tumoral heterogeneity has already improved the prognosis and treatment outcomes of some types of gliomas. Currently, the challenge for researchers is to study the intratumoral cell heterogeneity of newly defined glioma subtypes. Cancer stem cells (CSCs) present in gliomas and many other tumors are an example of intratumoral heterogeneity of great importance. In this review, we discuss the modern concept of glioma stem cells and recent single-cell sequencing-driven progress in the research of intratumoral glioma cell heterogeneity. The particular emphasis was placed on the recently revealed variations of the cell composition of the subtypes of the adult-type diffuse gliomas, including astrocytoma, oligodendroglioma and glioblastoma. The novel data explain the inconsistencies in earlier glioma stem cell research and also provide insight into the development of more effective targeted therapy and the cell-based immunotherapy of gliomas. Separate sections are devoted to the description of single-cell sequencing approach and its role in the development of cell-based immunotherapies for glioma.
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Nguyen, Hoang Dong, Phedias Diamandis, Michelle S. Scott, and Maxime Richer. "Deciphering of Adult Glioma Vulnerabilities through Expression Pattern Analysis of GABA, Glutamate and Calcium Neurotransmitter Genes." Journal of Personalized Medicine 12, no. 4 (April 14, 2022): 633. http://dx.doi.org/10.3390/jpm12040633.
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Adult infiltrating gliomas are highly aggressive tumors of the central nervous system with a dismal prognosis despite intensive multimodal therapy (chemotherapy and/or radiotherapy). In this study, we studied the expression, methylation and interacting miRNA profiles of GABA-, glutamate- and calcium-related genes in 661 adult infiltrating gliomas available through the TCGA database. Neurotransmitter-based unsupervised clustering identified three established glioma molecular subgroups that parallel major World Health Organization glioma subclasses (IDH-wildtype astrocytomas, IDH-mutant astrocytomas, IDH-mutant oligodendroglioma). In addition, this analysis also defined a novel, neurotransmitter-related glioma subgroup (NT-1), mostly comprised of IDH-mutated gliomas and characterized by the overexpression of neurotransmitter-related genes. Lower expression of neurotransmission-related genes was correlated with increased aggressivity in hypomethylated IDH-wildtype tumors. There were also significant differences in the composition of the tumor inflammatory microenvironment between neurotransmission-based tumor categories, with lower estimated pools of M2-phenotype macrophages in NT-1 gliomas. This multi-omics analysis of the neurotransmission expression landscape of TCGA gliomas—which highlights the existence of neurotransmission-based glioma categories with different expression, epigenetic and inflammatory profiles—supports the existence of operational neurotransmitter signaling pathways in adult gliomas. These findings could shed new light on potential vulnerabilities to exploit in future glioma-targeting drug therapies.
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Ramina, Ricardo, Erasmo Barros Da Silva Júnior, Maurício Coelho Neto, Leonardo Gilmone Ruschel, and Felipe Andrés Constanzo Navarrette. "5-Aminolevulinic Acid–Protoporphyrin IX Fluorescence-Guided Surgery for CNS Tumors." JBNC - JORNAL BRASILEIRO DE NEUROCIRURGIA 27, no. 1 (March 16, 2018): 13–19. http://dx.doi.org/10.22290/jbnc.v27i1.783.
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Introduction: In the last two decades the 5-aminolevulinic acid (5-ALA) has been utilized in primary brain lesions and metastases surgery to aid the identification of tumor limits and infiltration. Objectives: In this retrospective study, we demonstrate our experience with the first 41 cases Latin America of surgical resection of central nervous system (CNS) lesions with 5-ALA. Methods: In 41 consecutive patients, we recorded age, sex, histopathological diagnosis, intraoperative 5-ALA fluorescence tumor response, 5-ALA post-resection resection grade through magnetic resonance image (MRI) and other concomitantintra-operative techniques utilized (transoperative imaging, awake surgery, electrophysiological stimulation and monitoring). Results: Twenty seven high-grade gliomas and 4 non-glial lesions were 5-ALA fluorescence positive; 6 low-grade gliomas, 1 high-grade glioma and a hippocampal gliosis were 5-ALA fluorescence negative. In one case of a low-grade glioma, the patient developed a cardiac arrhythmia, probably not related to 5-ALA administration, but the surgery was suspended. Conclusions: 5-ALA fluorescence-guided surgery is a safe and easy technique to be used, increasing tumor total gross resection in glioma cases, proving to be an invaluable neurosurgical tool for intracranial tumor surgery. There was no serious side effect in this series. This dye should be utilized in all cases of high-grade gliomas.
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Comba, Andrea, Patrick J. Dunn, Anna E. Argento, Padma Kadiyala, Maria Ventosa, Priti Patel, Daniel B. Zamler, et al. "Fyn tyrosine kinase, a downstream target of receptor tyrosine kinases, modulates antiglioma immune responses." Neuro-Oncology 22, no. 6 (January 17, 2020): 806–18. http://dx.doi.org/10.1093/neuonc/noaa006.
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Abstract Background High-grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. Fyn tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinase pathway and is overexpressed in human gliomas. Fyn’s role in vivo in glioma growth remains unknown. We investigated whether Fyn regulates glioma initiation, growth and invasion. Methods We evaluated the role of Fyn using genetically engineered mouse glioma models (GEMMs). We also generated Fyn knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (nonobese diabetic severe combined immunodeficient gamma mice [NSG], CD8−/−, CD4−/−). We analyzed molecular mechanism by RNA sequencing and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the Fyn knockdown glioma TME. Results We demonstrate that Fyn knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontology (GO) analysis of differentially expressed genes in wild-type versus Fyn knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG and CD8−/− and CD4−/− immune-deficient mice, Fyn knockdown gliomas failed to show differences in survival. These data suggest that the expression of Fyn in glioma cells reduces antiglioma immune activation. Examination of glioma immune infiltrates by flow cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells in the Fyn glioma TME. Conclusions Gliomas employ Fyn mediated mechanisms to enhance immune suppression and promote tumor progression. We propose that Fyn inhibition within glioma cells could improve the efficacy of antiglioma immunotherapies.
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Young Ji, So, Chae Eun Lee, Tamrin Chowdhury, Jin Wook Kim, and Chul-Kee Park. "SURG-05. EXPERIENCE PROFILING OF FLUORESCENCE-GUIDED SURGERY FOR GLIOMAS." Neuro-Oncology 21, Supplement_6 (November 2019): vi240—vi241. http://dx.doi.org/10.1093/neuonc/noz175.1006.
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Abstract Numerous studies reported a usefulness of 5-ALA fluorescence-guided surgery (FGS) in high grade gliomas. However, fluorescence pattern and intensity is variable among gliomas. In this study, we report our extensive experiences of FGS in various gliomas focusing on epidemiological data of fluorescence pattern. A total of 827 histologically proven glioma patients out of 900 brain tumor patients who had undergone FGS using 5-ALA during the period of 8.5 years between July 2010 and January 2019 were analyzed. Indication for FGS in glioma surgery harbored any evidence of possible high-grade foci at presumed gliomas in preoperative magnetic resonance images (MRI). Among the 827 gliomas, the number of cases corresponding to 2016 World Health Organization (WHO) grade IV, III, II, and I are 528 (58.7%), 193 (21.4%), 87 (9.7%) and 19 (2.1%), respectively. In terms of fluorescence rate, grade IV gliomas showed positive fluorescence in 95.4% of cases including strong intensity in 85.6%. Grade III gliomas showed fluorescence in about half of cases (55.0%), while 45.0% of cases did not show any fluorescence. Anaplastic oligodendroglioma had more positive rate (63.9%) than anaplastic astrocytoma (46.2%). Both grade II and I gliomas still showed positive fluorescence in about one-fourths of cases (24.1% and 26.3%, respectively). Among them ependymoma and pilocytic astrocytoma were fluorescence-prone tumors. This epidemiological data of 5-ALA fluorescence in various grades of gliomas provides fundamental reference to clinical application of FGS using 5-ALA in glioma surgery.
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Ogawa, Tomoya, Keisuke Miyake, Takeshi Fujimori, Daisuke Ogawa, Masaki Okada, Tetsuhiro Hatakeyama, Masanobu Okauchi, Atsushi Shindo, Masahiko Kawanishi, and Takashi Tamiya. "NI-15 THE USEFULNESS OF PET IMAGING IN MOLECULAR DIAGNOSIS OF GLIOMA." Neuro-Oncology Advances 1, Supplement_2 (December 2019): ii28. http://dx.doi.org/10.1093/noajnl/vdz039.127.
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Abstract OBJECTIVE After WHO 2016 Classification of Tumors of the Central Nervous System have published, molecular diagnosis became part of the diagnostic criteria. In this study, we investigated the correlation between PET images and molecular diagnosis of glioma. METHODS We performed retrospective review of newly diagnosed supratentorial glioma patients who preoperatively underwent all four PET examinations (18F-FDG, 11C-MET, 18F-FLT and 18F-FMISO) from April 2009 to March 2019. The standardized uptake value (SUV) from the accumulation of each PET tracers, TNR (tumor to contralateral normal tissue ratio) of 18F-FDG,11C-MET and 18F-FLT, TBR (tumor to blood values ratio) of 18F-FMISO were measured. We investigated the correlation between these PET images and molecular diagnosis of glioma. RESULTS Data from total of 79 patients which were 42 cases of IDH wild type glioblastoma, 2 cases of IDH mutated glioblastoma, 9 cases of IDH wild type astrocytoma, 13 cases of IDH mutated astrocytoma and 13 cases of IDH mutated and 1p/19q co-deleted oligodendroglioma were included in this study. Both TNR of 11C-MET(p<0.01) and 18F-FLT(p<0.01), and also TBR of 18F-FMISO(p<0.01) in IDH wild type gliomas showed significantly higher than IDH mutated gliomas. In WHO Gr2-3 gliomas, only TNR of 18F-FLT showed a significant difference between IDH wild type gliomas and IDH mutated gliomas(p<0.01). TNR of 18F-FLT(p<0.01) and TBR of 18F-FMISO(p<0.01) in 1p/19q co-deleted gliomas were significantly lower than gliomas without 1p/19q co-deletion, but there were no significant differences in WHO Gr2-3 gliomas. Among IDH mutated gliomas, TNR of 11C-MET in 1p/19q co-deleted gliomas showed significantly higher uptake than gliomas without 1p/19q co-deletion(p<0.05). CONCLUSION Preoperative PET evaluation of each PET tracers may be useful for the molecular diagnosis of glioma.
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Jiang, Chongming, Evelien Schaafsma, Yanding Zhao, Thinh Nguyen, Kenneth Zhu, and Chao Cheng. "Abstract LB528: A microglia associated gene signature predicts survival risk in glioma patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB528. http://dx.doi.org/10.1158/1538-7445.am2022-lb528.
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Abstract Background: Gliomas are common tumors that affect the brain and spinal cord. A complex tumor microenvironment is one of the leading reasons for a poor prognosis in glioma patients. Microglia, as part of the immune microenvironment of gliomas, may facilitate glioma growth and invasion. However, the correlation between the microglia abundance and glioma prognosis has not been clarified. Method: Our goal was to examine the relationship between microglia abundance and glioma prognosis. We analyzed the single-cell RNA sequences of human and mouse glioma cells to identify microglia marker genes. Then, we built a LASSO Cox regression model of microglia abundance signatures in gliomas. The Cancer Genome Atlas (TCGA) dataset (Low-grade gliomas, LGG) was used as the training cohort. The Repository of Molecular Brain Neoplasia Data (REMBRANDT) dataset and Chinese Glioma Genome Atlas (CGGA) dataset was used to validate the model as the validation cohorts. Findings: Overall survival was significantly lower in those with a high level of microglia infiltration. Additionally, we found that microglia could interact with the tumor microenvironment and genomic features of gliomas, making microglia abundance negatively associated with the prognosis of glioma patients. Microglia abundance was positively correlated with immune genes expression and immune-related pathways. By applying our LASSO Cox regression model to gliomas, we found that patients with high-risk scores had significantly shorter overall survival (OS) than those with low-risk scores. Conclusions: Taken together, our findings suggest that microglia abundance may be negatively associated with survival in gliomas. Based on the novel microglia abundance signatures, we developed a high accuracy LASSO Cox regression model. In this study, we demonstrated that the model accurately predicted the prognosis of glioma patients and could offer new therapeutic targets for microglial-directed therapies. Keywords: Gliomas; Microglia abundance; LASSO Cox regression; TCGA; Signature.- 1 - Citation Format: Chongming Jiang, Evelien Schaafsma, Yanding Zhao, Thinh Nguyen, Kenneth Zhu, Chao Cheng. A microglia associated gene signature predicts survival risk in glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB528.
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Nagashima, Yoshitaka, Yusuke Nishimura, Fumiharu Ohka, Kaoru Eguchi, Kosuke Aoki, Hiroshi Ito, Tomoya Nishii, et al. "Driver Genetic Mutations in Spinal Cord Gliomas Direct the Degree of Functional Impairment in Tumor-Associated Spinal Cord Injury." Cells 10, no. 10 (September 24, 2021): 2525. http://dx.doi.org/10.3390/cells10102525.
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Genetic analysis in glioma has been developed recently. Spinal cord glioma is less common than intracranial glioma. Thus, the clinical significance of genetic mutations in spinal cord gliomas remains unclear. Furthermore, because the spinal cord is an important communication channel between the brain and the rest of the body, increased attention should be paid to its functional prognosis. In this study, we investigated the functional prognosis and driver genetic mutations in eight patients with spinal cord gliomas (World Health Organization grade I, three cases; grade II, two cases; grade III/IV, three cases). IDH mutations were detected in all grade II cases and H3F3A mutations were detected in all grade III/IV cases. The functional status of grade I and II gliomas remained unchanged or improved 1 year after surgery, whereas grade III/IV gliomas remained unchanged or deteriorated. Spinal glioma progenitor cells with H3F3A mutations were associated with accelerated tumor-associated spinal cord injury, which led to functional impairment. Conversely, the presence of IDH mutations, which are rarely reported in spinal gliomas, indicated a relatively favorable functional prognosis.
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Fritah, S., A. Cano-Galiano, R. Toth, A. Hau, E. Martinez-Garcia, M. Allega, D. Sumpton, et al. "P02.18.B INTEGRATIVE OMICS ANALYSIS OF IDH1 MUTANT GLIOMA PATIENTS REVEALS ALTERATIONS IN BUTYRATE METABOLISM." Neuro-Oncology 25, Supplement_2 (September 1, 2023): ii33—ii34. http://dx.doi.org/10.1093/neuonc/noad137.103.
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Abstract BACKGROUND Mutations in isocitrate dehydrogenase (IDH) 1 or 2 define glioma classification and determine the biology of these tumors. Although IDH is an essential enzyme in the cellular metabolism, powerful genome-wide analyses focus mostly at the genetic and epigenetic levels, while differences between distinct glioma entities at the proteomics, metabolomics, and functional levels are still poorly understood. Here, we provide an integrative multi-omics analysis of glioma patients to reveal metabolomic vulnerabilities of gliomas stratified by IDH mutation. MATERIAL AND METHODS We performed a multi-omics analysis of two cohorts of glioma patients (n=28) stratified based on IDH mutation status. Molecular assessment included LC-MS analysis, EPIC DNA methylation arrays, RNA-seq/HTA array-based transcriptomics and label-free quantitative proteomics. In 13 patients 13C-glucose was injected prior to surgery and tumor and adjacent brain tissue was collected. Gut microbial profiling using 16S ribosomal RNA (rRNA) sequencing was performed in a separate cohort of 128 glioma patients and 24 healthy individuals. Additional validation was performed in isogenic glioma stem-like cultures with CRISPR knock-in of IDH mutation. RESULTS We show that several molecular layers collectively contribute to biological differences between IDH mutant and wild-type gliomas, with strongest differences observed at the DNA methylation level. IDH mutant gliomas present specific molecular features linked to tumor metabolism. We confirm previous findings on 2-HG, cysteine and de novo glutathione synthesis pathways, which are specifically altered in IDH mutant gliomas. We further identify butyrate metabolism as a novel pathway highly active in IDH mutant gliomas. Butyrate is a bacterial metabolite with multiple systemic effects that is normally synthesized in the gut. This is supported by our gut microbiota metagenomics analysis of glioma patients. Yet the detection of enzymes associated with butyrate metabolism in tumor tissue and cell lines suggests a differential/enhanced metabolic rewiring of the butyrate signaling in IDH mutant gliomas CONCLUSION Our data shows the importance of multiple molecular layers in shaping specific features of IDH mutant gliomas. We unravel an activated butyrate metabolism in IDH mutant gliomas that may underly a novel gut-brain axis in glioma patients.
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Jadus, Martin, Neil Hoa, Lisheng Ge, Yurii Kuznetsov, Alex McPherson, Andrew Cornforth, Nabil Ahmed, and Lawrence Lamb. "Gliomas display complex cell surface topographies that resist cytolytic lymphocytes but are reversed by using fascin siRNA (48.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 48.2. http://dx.doi.org/10.4049/jimmunol.186.supp.48.2.
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Abstract Gliomas are invasive cancers that resist all forms of attempted therapy, but immunotherapy has improved survival for some patients. We present evidence that another level of complexity may also contribute to lack of responses by the lymphocytes towards gliomas. Atomic force microscopy of four different glioma types: human U251 and rat T9 and F98 glioma cells, including freshly isolated human GBM neurosphere cultures (containing “stem cell-like cells’), revealed a complex surface topography with numerous microvilli and filopodia. These structures were not found on other cell types. Electron microscopy and immunofluorescence microscopy of glioma cells confirmed that microvilli are present. U251 cells with microvilli resisted the cytolytic actions of different human effector cells, (lymphokine-activated killer cells, γδ T cells, conventional cytolytic T lymphocytes, [CTL], and chimeric antigen receptor redirected T cells) better than their non-microvilli expressing counterparts. Killer cells released perforin which was detected within the glioma’s microvilli/ filopodia, indicating these structures can receive the cytolytic effector molecules, but cytotoxicity is suboptimal. Transfection of fascin siRNA into U251 cells prevented the microvilli from forming and allowed cytolytic cells to kill these adherent cells just as well as the non-attached glioma cells. These microvilli play multiple roles in glioma biology, such as invasion and resistance to lymphocyte-mediated killing.
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Yang, Jiaying, Yongjun Yao, Li Tong, Ziwei Zhu, Lei Wang, and Jinju Yang. "CD47 is highly expressed in gliomas and targeting CD47 is a promising therapeutic strategy." European Journal of Inflammation 19 (January 2021): 205873922110008. http://dx.doi.org/10.1177/20587392211000899.
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Gliomas are very malignant brain tumors that are difficult to treat. CD47 is an antiphagocytic molecule that binds to SIPRα on phagocytes. It is overexpressed on the plasma membranes of multiple human tumor cell types and is an important diagnostic and prognostic biomarker in many types of cancer. However, the association between CD47 protein expression in glioma tissue and clinicopathological stage has not been investigated in detail. A total of 80 surgical glioma specimens were stained with anti-CD47 antibody to assess the relationship between CD47 protein expression and clinicopathological stage of the glioma. Wound healing assays were performed to analyze the influence of CD47 on the migration and invasion of glioma cells, and near-infrared fluorescence localization assays in a U-87 MG-bearing xenograft model were used to determine the distribution of anti-CD47 antibody in vivo. MTT assays and administration of anti-CD47 to a U251-bearing xenograft model were used to analyze the inhibitory effects of the antibody on gliomas. CD47 expression was higher in high-grade gliomas than in low-grade gliomas, and high CD47 expression was positively correlated with histology and tumor clinicopathological stage. CD47 over-expression promoted the growth and motility of two glioma cell lines (U-87 MG and U251) and a laboratory-developed anti-CD47 antibody accumulated at the glioma site. Proliferation of U251 and U-87 MG cells was not significantly inhibited by the anti-CD47 antibody in vitro, but the antibody significantly inhibited U251 growth in vivo. It also enhanced inhibition capacity by Taxol. Our results suggest that CD47 plays a critical role in the progression of gliomas from stage I to IV and may be a potential target for the treatment of gliomas. CD47 appears to play a critical role in the progression of gliomas from stage I to IV and an anti-CD47 antibody prepared in the laboratory may inhibit the growth of gliomas.
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Surapaneni, Akhil, Vik Kohli, Yousuf Ahmed, Matthew Seghers, and John Kuo. "OPTC-3. Differential Synapse-Related Gene Expression Identifies Glioma Subtypes and Predicts Prognosis." Neuro-Oncology Advances 3, Supplement_2 (July 1, 2021): ii6. http://dx.doi.org/10.1093/noajnl/vdab070.024.
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Abstract Synaptic connectivity between gliomas and adjacent brain was recently implicated in tumorigenesis. However, the interaction of synapse-related genes (SRGs) with patient survival and with established clinical and molecular glioma subtypes merit further study in a large patient cohort. We characterized differential expression of SRGs in gliomas and investigated SRG expression as putative clinical biomarkers in a large glioma cohort. Expression of 1189 SRGs was interrogated via RNA sequencing analysis in 603 gliomas (LGG n=451, GBM n=152) of The Cancer Genome Atlas. SRG expression patterns partitioned gliomas into two clusters that were more distinctive than priorly identified glioma subtypes. The two glioma clusters showed significantly low (14.9 months) or high median survival (105.1 months; Hazard Ratio = 7.1, 95% CI: [5.32, 9.78], p = 1.29e-46 using a log-rank test). The high survival cluster showed overrepresentation of known pro-neural and neural subtypes and IDH-mutated gliomas (p<0.00001). The mesenchymal and classic GBMs and IDH-wild type gliomas were overrepresented in the low survival cluster (p < 0.00001). In addition, an Elastic Net Cox Regression model identified 34 SRGs whose expression significantly predicted differential survival and a prognostic Synapse Gene Score (SGS) was created. Using an accelerated failure time model, SGS predicted survival in the overall gliomas after adjusting for IDH-1 mutation (HR = 2.51, 95% CI: [2.27, 2.7496], p<0.00001), and in the IDH-1 mutant cohort after adjusting for 1p/19q co-deletion (HR = 2.05, 95% CI: [1.73, 2.37], p<0.00001). Our analysis shows that gliomas can be distinctively clustered by differential SRGs expression, suggesting that synapse-related proteins may contribute to tumorigenesis via multiple mechanisms. Furthermore, the potential utility of SRGs as clinical glioma biomarkers is supported by our creation of a prognostic SGS. Future studies elucidating interactions between tumorigenesis and synaptic mechanisms may reveal additional insights for glioma biology and therapeutic targeting.
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Javier, Rodrigo, and Craig Horbinski. "TAMI-48. THE KETOGENIC DIET IS INEFFECTIVE IN PRECLINICAL MODELS OF IDH1 WILD-TYPE AND IDH1 MUTANT GLIOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi208. http://dx.doi.org/10.1093/neuonc/noab196.831.
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Abstract Despite decades of intensive research, infiltrative gliomas are still usually lethal and challenging to treat. A subset of gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1mut), which disrupts cellular biochemistry; such gliomas are generally less aggressive than their IDH1 wild-type (IDH1wt) counterparts. Some preclinical studies have suggested that a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial against a variety of cancers, including gliomas. However, not all studies have shown promising results, and to date, no study has addressed the sensitivity of glioma cells to KD in the specific context of the endogenous IDH1mut metabolic landscape. The aim of the current study was to compare the effects of KD in preclinical models to IDH1wt versus IDH1mut gliomas. In vitro treatment of patient-derived IDH1wt and IDH1mut glioma cells with the ketone body β-hydroxybutyrate showed no significant effect on cell proliferation in a low glucose culture environment. Likewise, the in vivo flank growth rates of these patient-derived IDH1wt and IDH1mut glioma xenografts showed no significant difference when mice were fed KD versus regular diet (GBM12 p=0.98, GBM164 p=0.4, GBM196 p=0.11). Finally, KD had no effect on the survival of mice engrafted with isogenic Sleeping-Beauty transposase-engineered IDH1wt (median control survival 22 days versus treatment 23 days, p=0.23) or IDH1mut glioma cells (median control survival 26.5 days versus treatment 26 days, p=0.81). These data suggest that IDH1mut gliomas are not more responsive than IDH1wt gliomas to KD, and that clinical trials further exploring KD in this subset of glioma patients are probably not warranted.
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Huang, Ruiting, Ying Kong, Zhiqing Luo, and Quhuan Li. "LncRNA NDUFA6-DT: A Comprehensive Analysis of a Potential LncRNA Biomarker and Its Regulatory Mechanisms in Gliomas." Genes 15, no. 4 (April 11, 2024): 483. http://dx.doi.org/10.3390/genes15040483.
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Gliomas are the most prevalent primary malignant tumors affecting the brain, with high recurrence and mortality rates. Accurate diagnoses and effective treatment challenges persist, emphasizing the need for identifying new biomarkers to guide clinical decisions. Long noncoding RNAs (lncRNAs) hold potential as diagnostic and therapeutic biomarkers in cancer. However, only a limited subset of lncRNAs in gliomas have been explored. Therefore, this study aims to identify lncRNA signatures applicable to patients with gliomas across all grades and explore their clinical significance and potential biological mechanisms. Data used in this study were obtained from TCGA, CGGA, and GEO datasets to identify key lncRNA signatures in gliomas through differential and survival analyses and machine learning algorithms. We examined their associations with the clinical characteristics, gene mutations, diagnosis, and prognosis of gliomas. Functional enrichment analysis was employed to elucidate the potential biological mechanisms associated with these significant lncRNA signatures. We explored competing endogenous RNA (ceRNA) regulatory networks. We found that NDUFA6-DT emerged as a significant lncRNA signature in gliomas, with reduced NDUFA6-DT expression associated with a worse prognosis in gliomas. Nomogram analysis incorporating NDUFA6-DT expression levels exhibited excellent prognostic and predictive capabilities. Functional annotation suggested that NDUFA6-DT might influence immunological responses and synaptic transmission, potentially modifying glioma initiation and progression. The associated ceRNA network revealed the possible presence of the NDUFA6-DT-miR-455-3p-YWHAH/YWHAG axis in low-grade glioma (LGG) and glioblastoma multiforme (GBM), regulating the PI3K-AKT signaling pathway and influencing glioma cell survival and apoptosis. We believe that NDUFA6-DT is a novel lncRNA linked to glioma diagnosis and prognosis, potentially becoming a pivotal biomarker for glioma.
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Ikeno, Yuji. "Ethylnitrosourea-induced gliomas: a song in the attic?" Aging Pathobiology and Therapeutics 5, no. 2 (June 28, 2023): 48–51. http://dx.doi.org/10.31491/apt.2023.06.111.
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It is essential to seek the underlying molecular mechanisms of glioma development, and critical to discover interventions that reduce the incidence and attenuate the growth of gliomas using a well-established in vivo experimental model because glioma is clinically one of the most difficult malignant tumors to treat. Ethylnitrosourea (ENU)-induced glioma in the rat has been extensively utilized as an experimental brain tumor model since the mid-1960s, however, the scientific value of ENU-induced glioma has been underappreciated mainly due to the recent development of transgenic mouse glioma models. Because of the pathophysiological characteristics, which are similar to the high grade human malignant gliomas, ENU-induced glioma is an excellent in vivo model to: a) examine the cell origin, development, and pathophysiology of gliomas; b) investigate anti-tumor effects of calorie restriction (CR) and its underlying mechanisms; and c) discover new preventive and/or therapeutic interventions of glioma. Further exploration of genetic changes during initiation, malignant transformation of glial cells, and progression of glioma as well as CR’s anti-tumor effects on cellular processes using cutting edge technology, e.g., spatial transcriptomics, could provide more insight and a deeper understanding of the pathophysiology of gliomas.
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Bhatia, Aashim. "EPCT-20. TECHNICAL FEASIBILITY SODIUM (23NA) MRI OF PEDIATRIC GLIOMAS." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i51. http://dx.doi.org/10.1093/neuonc/noab090.206.
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Abstract Pediatric glioma response to novel targeted therapy can be heterogeneous on conventional proton (1H) MRI. Sodium concentration, as measured with 23Na MRI in adult brain tumors can provide complementary assessment of tumor proliferation to conventional MRI. However, 23Na MRI pediatric brain tumor studies are lacking. Determine the technical feasibility of performing sodium23Na MRI on pediatric glioma patients. Prospective study of an immunotherapy trial for newly diagnosed and recurrent gliomas (high-grade gliomas, low-grade gliomas, brainstem gliomas) in which participants were imaged with 23Na MRI at 3.0 Tesla. The participants (n=26, 14 males) with median age of 11 years (range = 4–23 years of age) were prospectively evaluated with sodium. 23Na MRI is technically feasible in the pediatric population and can distinguish different types of pediatric gliomas at baseline.
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Nguyen, Thanh Binh. "PREOPERATIVE DETERMINATION OF IDH STATUS AND GRADE IN GLIOMAS USING MRS." Neuro-Oncology Advances 5, Supplement_2 (July 1, 2023): i5. http://dx.doi.org/10.1093/noajnl/vdad071.019.
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Abstract PURPOSE To evaluate the diagnostic accuracy of preoperative MRS in the determination of the IDH status and grade in patients with newly diagnosed gliomas. METHODS MRS was performed using a regular PRESS sequence and a spectral editing sequence (MEGA-PRESS). Concentration of 2-HG was estimated from the subtracted spectra from the edited MRS sequence while NAA, choline and creatinine concentrations were obtained from the regular PRESS sequence. IDH mutation status was assessed by immunohistochemistry for all patients and additional next generation sequencing for all grade 2 and 3 gliomas. Differences in metabolite concentrations between IHD-mutant and wild-type gliomas and between gliomas of various grades were assessed using non parametric tests. TAreas under-the ROC curve (AUC) for different metabolites were calculated with IDH mutation status or glioma grade as the outcome. RESULTS There were 29 IDH-mutant gliomas and 52 wild-type gliomas. There was a significant difference in the NAA/Choline ratio among various glioma grades (P<0.05). The AUC for 2HG was 0.74 in the differentiation between IDH-mutant vs wild type gliomas. Using a 2-HG cut-off of >0.96 I.U., sensitivity was 59% and specificity was 90% for the identification of IDH-mutant gliomas. The AUC for the NAA/Choline ratio was 0.74 in the differentiation of high vs low grade gliomas. Using a NAA/Choline cut-off ≤0.53, sensitivity was 45% and specificity was 100% for identification of high grade gliomas. CONCLUSION Preoperative MRS can identify IDH-mutant gliomas and high grade gliomas with high specificity.
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Yu, Di, Qiuhui Xuan, Chaoqi Zhang, Chunxiu Hu, Yanli Li, Xinjie Zhao, Shasha Liu, et al. "Metabolic Alterations Related to Glioma Grading Based on Metabolomics and Lipidomics Analyses." Metabolites 10, no. 12 (November 24, 2020): 478. http://dx.doi.org/10.3390/metabo10120478.
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Gliomas are the most aggressive phenotypes of brain tumors and are classified into four grades according to the malignancy degree by the World Health Organization. Metabolic profiling can provide an overview of metabolic reprogramming at a specific stage of tumor initiation and development. Studies about metabolic alterations related to different grades of gliomas are helpful to understand the molecular mechanism for progression of glioma. In the current study, metabolomics and lipidomics analyses based on chromatography-mass spectrometry were performed on different grades of glioma tissues. Differential metabolites between glioma and para-tumor tissues were studied and used as the basis to explore metabolic alterations related to glioma grading. It was found that short-chain acylcarnitines were elevated, whereas lysophosphatidylethanolamines (LPEs) were decreased in high-grade gliomas. Furthermore, the gene expression of short/branched-chain acyl-coenzyme dehydrogenase (ACADSB), which is involved in fatty acid oxidation, was found down-regulated with glioma progression by analyzing related genes and pathways. In addition, LPE metabolism showed a significant difference among different grades of gliomas. These important metabolic pathways related to glioma progression may provide potential clues for further study on the mechanisms and treatment of glioma.
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Rahmartani, Ludi Dhyani, Michael Nathaniel Budiarso, Eka Susanto, Mohamad Yanuar Amal, Endang Nuryadi, and Kevin Gunawan. "EPID-08. PEDIATRIC GLIOMA IN INDONESIA: CLINICAL PROFILES AND OUTCOMES." Neuro-Oncology 26, Supplement_4 (June 18, 2024): 0. http://dx.doi.org/10.1093/neuonc/noae064.240.
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Abstract BACKGROUNDS Gliomas are the most common form of pediatric brain tumor. The primary obstacle to optimizing pediatric brain tumor health services, particularly in LMICs, is the lack of comprehensive epidemiological data. We aim to compile comprehensive data on pediatric gliomas, focusing on clinical profiles and outcomes within a national general hospital in Indonesia. METHODS A retrospective observational longitudinal study was performed at Cipto Mangunkusumo National General Hospital, focusing on glioma patients’ profiles and outcomes, registered under the pediatric CNS tumor service from January 2022 to December 2023. RESULTS Out of 50 suspected glioma patients, 28 patients (56%) underwent biopsy, 28% underwent other modalities (brainstem location), 12% were scheduled for surgery but had already died, 2% were in a watchful waiting mode, and 2% were scheduled for surgery but were lost to follow-up. Glioma-confirmed patients were predominantly female (57.1%), with a mean age of 7.11 ± 4.98. Low-grade gliomas predominated at 57.1%, a trend we attribute to Cipto Mangunkusumo’s status as a referral national hospital, where low-grade glioma cases may have been managed more frequently at lower-level hospitals. The majority of tumors were supratentorial (53.6%) compared to infratentorial (39.3%) and supra-infratentorial (7.1%). The most common symptoms were seizures (25%), followed by headaches (21.4%), disequilibrium (14.3%), and vomiting (10.7%). Moreover, the latter three symptoms exhibited a longer mean delay between symptom onset and medical consultation, potentially impacting prognosis. In the last follow-up, higher-grade gliomas demonstrated a significantly higher mortality rate at 28.6% compared to low-grade gliomas at 3.6% (P < 0.001). CONCLUSION Given the variable clinical characteristics of glioma tumors, these results underscore the urgent need for comprehensive epidemiological data on pediatric gliomas in Indonesia, particularly regarding prognosis-related factors. Such data could serve as a crucial step towards future research and clinical strategies aimed at improving outcomes for children with gliomas.
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Smith, Nataliya, Debra Saunders, Randy L. Jensen, and Rheal A. Towner. "Association of decreased levels of lipopolysaccharide-binding protein with OKN-007–induced regression of tumor growth in an F98 rat glioma model." Journal of Neurosurgery 133, no. 6 (December 2020): 1695–703. http://dx.doi.org/10.3171/2019.7.jns182435.
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OBJECTIVEHigh-grade gliomas, such as glioblastoma (GBM), are devastating tumors with a very poor prognosis. Previously the authors have found that the nitrone compound OKN-007 (OKlahoma Nitrone 007; or disodium 4-[(tert-butyl-imino) methyl] benzene-1,3-disulfonate N-oxide) is effective against high-grade gliomas in various GBM rodent and human xenograft models. The purpose of the present study was to assess the levels of the lipopolysaccharide-binding protein (LBP) in rodent gliomas treated with OKN-007 as well as determine the expression of LBP in human gliomas.METHODSMicroarray analysis was done to assess altered gene expression following OKN-007 administration in an F98 glioma model. An enzyme-linked immunosorbent assay was incorporated to assess LBP levels in glioma tissues, as well as blood serum, comparing results in OKN-007–treated and untreated tumor-bearing animals. Immunohistochemistry was used to assess LBP levels in varying grades of human glioma tissue sections.RESULTSUpon further assessment of gene expression fold changes in F98 gliomas in rats that received or did not receive OKN-007, it was found that the gene for LBP was significantly downregulated by OKN-007. Further investigation was done to see whether levels of LBP were affected by OKN-007 treatment in F98 gliomas. It was found that LBP could be detected not only in glioma tissue but also in blood serum of F98 glioma-bearing rats and that OKN-007 decreased the levels of LBP. It was also found that LBP levels are highly expressed in human high-grade glioma tissues.CONCLUSIONSLBP could potentially be used as a serum diagnostic marker of treatment response in high-grade gliomas.
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Kitano, Yotaro, Kosuke Aoki, Takao Yasui, Kazuya Motomura, Fumiharu Ohka, Kuniaki Tanahashi, Masaki Hirano, et al. "PATH-36. MACHINE LEARNING TO DETECT GLIOMAS IN URINE-BASED LIQUID BIOPSY." Neuro-Oncology 21, Supplement_6 (November 2019): vi151. http://dx.doi.org/10.1093/neuonc/noz175.632.
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Abstract BACKGROUND Diffuse gliomas are the most common primary malignant brain tumors, whose overall prognosis is quite dismal. Tumor-cell-secreted extracellular vesicles (EVs) participate in physiological and pathological processes and have potential applications to diagnostics of malignant tumors including diffuse gliomas. Because urine is less invasive to collect, development of early diagnosis based on urine EVs is eagerly awaited. In this study, we captured urine EVs of patients with gliomas efficiently with the nanowire device and compared expression profile of microRNAs (miRNAs) within urine EVs with that of healthy donors to identify diagnostic accuracy by a machine learning algorithm. METHODS 62 patients with diffuse gliomas, including 27 glioblastoma and 35 lower grade gliomas, and 100 healthy donors were analyzed, along with orthotopic transplant mouse model. Urinary EVs were obtained with the nanowire device which could collect EVs more efficiently than the conventional ultracentrifugation method (Yasui et.al., Science Adv.2017). Machine learning methods were performed to select the miRNAs which could distinguish patients with gliomas from healthy control. RESULTS More than 2400 miRNAs were obtained from all urine samples. We identified miRNA panels that provided high diagnostic accuracy of diffuse gliomas (92.5%). There were 440 miRNAs whose expression increased by more than 1.5 fold (p< 0.05) as compared to healthy donor samples (glioma-upregulated miRNAs), whereas the expression of 87 miRNAs decreased to less than 2/3-fold (p< 0.05) (glioma-downregulated miRNAs). Mouse miRNAs which were homologous to glioma-upregulated and -downregulated miRNAs showed significantly high and low level expressions, respectively, in glioma mouse models as compared to normal control mice, confirming the reliability of urine miRNA-based diagnosis. Furthermore, some of these glioma-upregulated miRNAs has been reported to be involved in tumor progression. CONCLUSIONS miRNAs obtained from urine could be biomarkers for detection of gliomas by machine learning and some of these could be associated with tumor progression.
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Hey, Grace, Rohan Rao, Ashley Carter, Akshay Reddy, Daisy Valle, Anjali Patel, Drashti Patel, Brandon Lucke-Wold, Daniel Pomeranz Krummel, and Soma Sengupta. "Ligand-Gated Ion Channels: Prognostic and Therapeutic Implications for Gliomas." Journal of Personalized Medicine 13, no. 5 (May 19, 2023): 853. http://dx.doi.org/10.3390/jpm13050853.
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Gliomas are common primary brain malignancies that remain difficult to treat due to their overall aggressiveness and heterogeneity. Although a variety of therapeutic strategies have been employed for the treatment of gliomas, there is increasing evidence that suggests ligand-gated ion channels (LGICs) can serve as a valuable biomarker and diagnostic tool in the pathogenesis of gliomas. Various LGICs, including P2X, SYT16, and PANX2, have the potential to become altered in the pathogenesis of glioma, which can disrupt the homeostatic activity of neurons, microglia, and astrocytes, further exacerbating the symptoms and progression of glioma. Consequently, LGICs, including purinoceptors, glutamate-gated receptors, and Cys-loop receptors, have been targeted in clinical trials for their potential therapeutic benefit in the diagnosis and treatment of gliomas. In this review, we discuss the role of LGICs in the pathogenesis of glioma, including genetic factors and the effect of altered LGIC activity on the biological functioning of neuronal cells. Additionally, we discuss current and emerging investigations regarding the use of LGICs as a clinical target and potential therapeutic for gliomas.
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Kwikima, Ugumba. "GLIOMA-04 BRIDGING THE GAP ON ADULT GLIOMA IMAGING, DIAGNOSIS AND FOLLOW UP IN SUB-SAHARAN AFRICA." Neuro-Oncology Advances 5, Supplement_4 (October 31, 2023): iv1. http://dx.doi.org/10.1093/noajnl/vdad121.003.
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Abstract Cerebral Gliomas are the most common and devastating primary brain tumors. Prior to 2016 WHO CNS tumor classification update, the grading of gliomas, mainly relied on histological features, including cellularity, nuclear atypia, mitotic activity, vascularity, and necrosis, observed on light microscopy with the aid of immunohistochemistry. A number of studies confirmed that diffuse gliomas demonstrates different growth pattern, clinical behavior, and prognostication based on their genomic alterations, these findings necessitated incorporation of molecular subtypes in glioma classification, and leads to 2016 WHO CNS tumors Classification update. Introduction of molecular criteria into the classification of gliomas has given rise to interesting, wide-ranging implications regarding glioma management. In the current classification, all diffuse gliomas have been grouped based on their growth pattern, clinical behavior, and specifically sharing of the mutational state of the gene that codes for isocitrate dehydrogenase (IDH) in its isoforms (IDH1 and IDH2). Regardless of grade, the first phase in glioma molecular characterization is IDH testing. Mutations in IDH1 and IDH2 are associated with significant increase in progression free survival and overall survival. Immunohistochemistry, Molecular subtyping, Both FISH and genetic sequencing have significant implications in gliomas management and clinical outcome, yet they are not available in our low resource settings. Advanced MRI techniques (DTI, MR Perfussion, MR Spectroscopy, and Functional MRI) have a significant impact in presurgical planning and follow up of glioma patients after surgery and chemo radiation treatment. Radiographic findings can bridge the gap on accurate glioma diagnosis in sub-Saharan Africa through predicting Glioma Molecular subtypes based on clinical presentation and utilizing conventional MRI as a radio genomic tool. Also to emphasis in the utilization of available advanced MRI techniques (DTI, MR Perfussion, and MR spectroscopy) for presurgical planning and follow up of patients after Glioma treatment.
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Pedersen, L. K. "P05.02.A 18F-FACBC PET/MRI in diagnostic assessment of gliomas." Neuro-Oncology 24, Supplement_2 (September 1, 2022): ii36. http://dx.doi.org/10.1093/neuonc/noac174.121.
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Abstract Background and Theory MRI and histopathological tissue sampling are routinely done as part of the diagnostic work-up of patients with glioma. MRI provides anatomical images with high resolution and excellent soft-tissue contrast. But this modality has limitations in identifying tumor grade, true tumor extension and differentiate viable tumor tissue from treatment induced changes. PET can provide quantitative information of cellular activity and metabolism, and may therefore have additional value compared to MRI alone. Objective The aim of this study was to find the sensitivity of [18F]FACBC PET in gliomas, and evaluate if PET imaging with this tracer can improve differentiation between low-and high-grade gliomas. Methods Patients with suspicion of primary (n=19) or recurrent gliomas (n=8) were recruited to this study from St. Olavs hospital, Trondheim University Hospital, Trondheim, and from the University Hospital of North Norway, Tromsø. PET acquisitions (30-45 min post injection) using the amino acid radiotracer [18F]FACBC (3 MBq/kg) were performed simultaneously to MRI acquisitions (T1 with and without contrast, FLAIR, and UTE for attenuation correction. The sensitivity of [18F]FACBC PET in glioma detection was assessed using histopathology as reference. Tumor-to-background ratios (TBRs) were compared to tumor subtype and grade to assess the diagnostic value of this tracer for glioma diagnostics. Results Histopathology revealed 2 WHO grade 1 gliomas (pilocytic astrocytoma n=1, pilocytic astrocytoma/ganglioglioma n=1), 7 WHO grade 2 gliomas(astrocytoma n=4, oligodendroglioma n=3), 7 WHO grade 3 gliomas(astrocytoma n=5, oligodendroglioma n=2) and 12 WHO grade 4 tumors(astrocytoma n=1, glioblastoma n=11). [18F]FACBC PET provided a sensitivity of 74.1% in the detection of gliomas. PET uptake was observed in all grade 4 tumors, 5/7 grade 3 tumors, 2/7 grade 2 tumors, and all grade 1 tumors. TBRpeak was high with a median value of 9.4 (range: 2.1-34.9) in PET positive tumors. Only tumors with a TBRpeak > 2.0 were detected with [18F]FACBC PET. TBRpeak was highest for grade 1 gliomas with a median value of 20.6, and increased significantly from grade 2 to grade 4 tumors with median values of 1.7 (grade 2), 6.2 (grade 3) and 12.4 (grade 4) (Kruskal-Wallis, p=0.001). Conclusion [18F]FACBC PET demonstrated high uptake in the majority of gliomas, and there was a clear tendency to higher uptake in the higher grade tumors. [18F]FACBC PET may be useful in the differentiation between glioms grades and subtypes. A future study using the same patient data will be performed to evaluate the assessment of [18F]FACBC PET in neurosurgical treatment planning. Image-localized biopsies from different regions of each tumor will be correlated to fused PET/MRI images to evaluate if [18F]FACBC PET can be used to guide surgical resection and to improve accuracy in histopathological tissue sampling.
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Mitsuka, Kentaro, Tomoyuki Kawataki, Eiji Satoh, Takayuki Asahara, Toru Horikoshi, and Hiroyuki Kinouchi. "Expression of Indoleamine 2,3-Dioxygenase and Correlation With Pathological Malignancy in Gliomas." Neurosurgery 72, no. 6 (February 19, 2013): 1031–39. http://dx.doi.org/10.1227/neu.0b013e31828cf945.
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Abstract BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catabolic enzyme involved in immune tolerance and tumor immune escape processes. Recently, IDO expression has been found to correlate with the prognosis of malignant tumors, but the implication of IDO in glioma progression remains unknown. OBJECTIVE: To investigate the relationship between IDO expression and histological malignancy in gliomas. METHODS: IDO expression was examined in a total of 75 surgical specimens obtained from 68 patients with glioma using immunohistochemical staining. The 75 specimens included 15 diffuse astrocytomas, 21 anaplastic astrocytomas, and 39 glioblastomas. Six of 39 glioblastomas were secondary glioblastomas, transforming from grade II or III gliomas that had been determined at the first surgery. IDO expression rate was compared in each histological grade, and patient survival was analyzed. RESULTS: Expression of IDO was found in 72 of 75 gliomas at varying intensities. Stronger expression of IDO was more likely to be observed in malignant gliomas compared with low-grade gliomas. IDO expression in the 6 cases of secondary glioblastoma was stronger than in the initial low-grade glioma. Survival analysis using the Kaplan-Meier method revealed that grade IV patients with strong IDO expression had significantly worse overall survival rates (P = .04) than patients with weak IDO expression. CONCLUSION: IDO is expressed more strongly in both primary and secondary glioblastoma tissue than low-grade glioma and may affect clinical outcome. If IDO promotes glioma cells to escape from the immune system, IDO may be a crucial therapeutic target for malignant gliomas.
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Javier, Rodrigo, Wenxia Wang, Michael Drumm, Kathleen McCortney, Jann N. Sarkaria, and Craig Horbinski. "The efficacy of an unrestricted cycling ketogenic diet in preclinical models of IDH wild-type and IDH mutant glioma." PLOS ONE 17, no. 2 (February 8, 2022): e0257725. http://dx.doi.org/10.1371/journal.pone.0257725.
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Infiltrative gliomas are the most common neoplasms arising in the brain, and remain largely incurable despite decades of research. A subset of these gliomas contains mutations in isocitrate dehydrogenase 1 (IDH1mut) or, less commonly, IDH2 (together called “IDHmut”). These mutations alter cellular biochemistry, and IDHmut gliomas are generally less aggressive than IDH wild-type (IDHwt) gliomas. Some preclinical studies and clinical trials have suggested that various forms of a ketogenic diet (KD), characterized by low-carbohydrate and high-fat content, may be beneficial in slowing glioma progression. However, adherence to a strict KD is difficult, and not all studies have shown promising results. Furthermore, no study has yet addressed whether IDHmut gliomas might be more sensitive to KD. The aim of the current study was to compare the effects of a unrestricted, cycling KD (weekly alternating between KD and standard diet) in preclinical models of IDHwt versus IDHmut gliomas. In vitro, simulating KD by treatment with the ketone body β-hydroxybutyrate had no effect on the proliferation of patient-derived IDHwt or IDHmut glioma cells, either in low or normal glucose conditions. Likewise, an unrestricted, cycling KD had no effect on the in vivo growth of patient-derived IDHwt or IDHmut gliomas, even though the cycling KD did result in persistently elevated circulating ketones. Furthermore, this KD conferred no survival benefit in mice engrafted with Sleeping-Beauty transposase-engineered IDHmut or IDHwt glioma. These data suggest that neither IDHwt nor IDHmut gliomas are particularly responsive to an unrestricted, cycling form of KD.
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Jang, Taichang, Binulal Sathy, Yi-Hua Hsu, Milton Merchant, Benjamin Recht, Chen Chang, and Lawrence Recht. "A distinct phenotypic change in gliomas at the time of magnetic resonance imaging detection." Journal of Neurosurgery 108, no. 4 (April 2008): 782–90. http://dx.doi.org/10.3171/jns/2008/108/4/0782.
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Object Although gliomas remain refractory to treatment, it is not clear whether this characteristic is fixed at the time of its origin or develops later. The authors have been using a model of neurocarcinogenesis to determine whether a time exists during a glioma's evolution during which it is detectable but still curable, thus providing a justification for exploring the clinical merits of an early detection and treatment strategy. The authors recently reported the presence of 2 distinct cellular subsets, 1 expressing nestin and the other both glial fibrillary acidic protein (GFAP) and osteopontin (OPN), within all examined gliomas that developed after in utero exposure to ethylnitrosourea. Methods In this study, the authors used magnetic resonance (MR) imaging to assess when these 2 subpopulations appeared during glioma evolution. Results Using T2-weighted and diffusion-weighted MR imaging, the authors observed that gliomas grew exponentially once detected at rates that were location-dependent. Despite large differences in growth rates, however, they determined by correlating histochemistry with imaging in a second series of animals, that all lesions initially detected on T2-weighted images contained both subsets of cells. In contrast, lesions containing only nestin-positive cells, which appeared on average 40 days before detection on MR images, were not detected. Conclusions The sequential appearance of first the nestin-positive cells followed several weeks later by those expressing GFAP/OPN suggests that all gliomas arise through common early steps in this model. Furthermore, the authors hypothesize that the expression of OPN, a molecule associated with cancer aggressiveness, at the time of T2-weighted detection signals a time during glioma development when the lesion becomes refractory to treatment.
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Funes, Pedro Tomás, Daniela Moggia, Diana Lidia Parma, Marcela Ferrer, Florencia Giliberto, and Irene Szijan. "Prognostic value of mutations in isocitrate dehydrogenase 1 (IDH1) and reverse telomerase transcriptase (TERT) in Argentine patients` gliomas." ARS MEDICA Revista de Ciencias Médicas 46, no. 1 (March 30, 2021): 12–19. http://dx.doi.org/10.11565/arsmed.v46i1.1768.
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Background and aim: Gliomas are the most common primary brain tumors, and they are classified according to their histopathological and genetic features. Tumorigenesis depends on alterations in different genes. The aim of this study was to identify mutations in IDH1 and TERT genes in gliomas of Argentine patients and to correlate them with clinical features. Methods. DNA was isolated from 19 biopsies with different glioma grades matched with blood samples. IDH1 and TERT mutations were identified by PCR amplification and sequencing. Results. Six out of seven patients with low-grade glioma (grade II) harbor IDH1 mutations, mainly without tumor growth and an overall survival of more than 12 months. Eleven out of twelve patients with high-grade gliomas (grade III/IV) showed wild type IDH1, mainly with tumor growth and shorter survival than low-grade gliomas. Mutated TERT promoter was present in 5 out of 11 high-grade gliomas, showing the prevalence of polymorphic C allele, whereas, low-grade gliomas showed mutated TERT in 1 out of 5 gliomas and a predominance of T allele. TERT and IDH1 mutations were mutually exclusive in most gliomas. Conclusions: Our results show that genetic tests provided more accurate diagnosis than histopathological analysis. Evolution of gliomas can be predicted primarily by the mutational status of IDH1 and secondarily by other markers, such as TERT mutational status, and the patient´s age.
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Miyata, Satsuki, Kaoru Tominaga, Eiji Sakashita, Masashi Urabe, Yoshiyuki Onuki, Akira Gomi, Takashi Yamaguchi, et al. "CBMS-05 COMPREHENSIVE METABOLOMIC ANALYSIS OF IDH1R132H CLINICAL GLIOMA SAMPLES REVEALS SUPPRESSION OF Β-OXIDATION DUE TO CARNITINE DEFICIENCY." Neuro-Oncology Advances 1, Supplement_2 (December 2019): ii6. http://dx.doi.org/10.1093/noajnl/vdz039.025.
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Abstract BACKGROUND Gliomas with isocitrate dehydrogenase 1 (IDH1) mutation have alterations in several enzyme activities, resulting in various metabolic changes. The aim of this study was to investigate the mechanism for the better prognosis of gliomas with IDH mutation by performing metabolomic analysis. METHODS To comprehensively understand the metabolic state of human gliomas, we analyzed clinical samples obtained from surgical resection of glioma patients (grades II-IV) with or without the IDH1 mutation, and compared them with U87 glioblastoma cells overexpressing IDH1 or IDH1R132H cDNA. We used capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry for these analyses. RESULTS In clinical samples of gliomas with IDH1 mutation, levels of 2-hydroxyglutarate (2HG) were significantly increased compared with gliomas without IDH mutation. Gliomas with IDH mutation also showed decreased 2-oxoglutarate and downstream intermediates in the tricarboxylic acid cycle and pathways involved in production of energy, amino acids, and nucleic acids. The marked difference in the metabolic profile in IDH mutant clinical glioma samples compared with that of mutant IDH expressing cells includes a decrease in β-oxidation due to acyl-carnitine and carnitine deficiencies. CONCLUSIONS These metabolic changes may explain the lower cell division observed in IDH mutant gliomas and may be one mechanism of the better prognosis in IDH mutant gliomas.
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McClellan, Brandon, Ali Dabaja, Kaushik Banerjee, Ziwen Zhu, Marcus Barissi, Paul Oh, Abraham Wei, Pedro Lowenstein, and Maria Castro. "IMMU-19. MUTANT ISOCITRATE DEHYDROGENASE 1 IN GLIOMA CAUSES A REDUCTION IN ADENOSINERGIC PATHWAY SIGNALING WITHIN THE TUMOR MICROENVIRONMENT." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v145. http://dx.doi.org/10.1093/neuonc/noad179.0551.
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Abstract Glioma is one of the most aggressive cancers and represents approximately 80% of malignant brain tumors. The majority of CNS World Health Organization (WHO) grades 2-3 gliomas and a subset of high-grade gliomas (CNS WHO grade 4) harbor mutated isocitrate dehydrogenase 1 (IDH1R132H; mIDH1). Mutant IDH1 results in the accumulation of 2-hydroxyglutarate (2HG) which elicits profound changes in the glioma transcriptome/biology. Consequently, mIDH1 glioma patients have a significantly increased median survival compared to wildtype IDH1 patients. Recent data from our lab showed that mIDH1 gliomas exhibit increased immune-reactivity of tumor-infiltrating immune cells. A critical pathway that mediates reduction of anti-tumor immune cell reactivity is the adenosinergic pathway (AP), which converts ATP into adenosine via the enzymes CD39 and CD73. Adenosine binds to adenosine receptors, A2AR and A2BR, on immune cells resulting in a decreased immunoreactivity. Although mIDH1 has been implicated in altering the AP, the extent to which the AP is affected by mIDH1 in gliomas is largely unknown. Here we used human and mouse mIDH1 glioma cells in vitro along with in vivo mIDH1 glioma mouse models to examine changes in the AP. Our results show reduced levels of the enzyme, CD73, on the surface of mIDH1 glioma cells, and the ATP concentration in the mIDH1 glioma cell growth media is lower than from wildtype IDH1 glioma cells. Additionally, we discovered that mIDH1 glioma-infiltrating macrophages have decreased expression of CD39 and A2AR compared to their wildtype IDH1 glioma counterparts. Taken together, these data suggest a reduction of the AP mediated-immune suppression in mIDH1 gliomas. Uncovering these differences in the AP provides novel insights on the use of AP inhibitors for glioma treatment, revealing whether the AP is a preferred target in specific glioma types based on the IDH1 mutation status.
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Gupta, Pravesh, Minghao Dang, Krishna Bojja, Tuan Tran M, Huma Shehwana, Carlos Kamiya-Matsuoka, Jianzhuo Li, et al. "IMMU-35. TRANSCRIPTIONALLY DEFINED IMMUNE CONTEXTURE IN HUMAN GLIOMAS AT SINGLE-CELL RESOLUTION." Neuro-Oncology 22, Supplement_2 (November 2020): ii112. http://dx.doi.org/10.1093/neuonc/noaa215.465.
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Abstract The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression and a comprehensive understanding of the glioma-centric immune cell repertoire beyond a priori cell types and/or states is uncharted. Consequently, we performed single-cell RNA-sequencing on ~123,000 tumor-derived immune cells from 17-pathologically stratified, IDH (isocitrate dehydrogenase)-differential primary, recurrent human gliomas, and non-glioma brains. Our analysis delineated predominant 34-myeloid cell clusters (~75%) over 28-lymphoid cell clusters (~25%) reflecting enormous heterogeneity within and across gliomas. The glioma immune diversity spanned functionally imprinted phagocytic, antigen-presenting, hypoxia, angiogenesis and, tumoricidal myeloid to classical cytotoxic lymphoid subpopulations. Specifically, IDH-mutant gliomas were enriched for brain-resident microglial subpopulations in contrast to enhanced bone barrow-derived infiltrates in IDH-wild type, especially in a recurrent setting. Microglia attrition in IDH-wild type -primary and -recurrent gliomas were concomitant with invading monocyte-derived cells with semblance to dendritic cell and macrophage/microglia like transcriptomic features. Additionally, microglial functional diversification was noted with disease severity and mostly converged to inflammatory states in IDH-wild type recurrent gliomas. Beyond dendritic cells, multiple antigen-presenting cellular states expanded with glioma severity especially in IDH-wild type primary and recurrent- gliomas. Furthermore, we noted differential microglia and dendritic cell inherent antigen presentation axis viz, osteopontin, and classical HLAs in IDH subtypes and, glioma-wide non-PD1 checkpoints associations in T cells like Galectin9 and Tim-3. As a general utility, our immune cell deconvolution approach with single-cell-matched bulk RNA sequencing data faithfully resolved 58-cell states which provides glioma specific immune reference for digital cytometry application to genomics datasets. Resultantly, we identified prognosticator immune cell-signatures from TCGA cohorts as one of many potential immune responsiveness applications of the curated signatures for basic and translational immune-genomics efforts. Thus, we not only provide an unprecedented insight of glioma TIME but also present an immune data resource that can be exploited to guide pragmatic glioma immunotherapy designs.
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Sears, Thomas, Michael Drumm, Wenxia Wang, and Craig Horbinski. "EXTH-28. ISOCITRATE DEHYDROGENASE MUTATIONS PREDICT SENSITIVITY TO HISTONE DEACETYLASE INHIBITION AND ENHANCED HISTONE ACETYLATION DYNAMICS ONLY IN THE CONTEXT OF GLIOMA." Neuro-Oncology 25, Supplement_5 (November 1, 2023): v229—v230. http://dx.doi.org/10.1093/neuonc/noad179.0881.
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Abstract Isocitrate dehydrogenase 1/2 mutations (IDHmut) define a subtype of glioma with profound epigenetic dysregulation through genomic hypermethylation. IDHmut gliomas are incurable and fatal, demonstrating new treatments are needed. These mutations are common in other solid tumors, including chondrosarcoma (CS) and intrahepatic cholangiocarcinoma (ICC). Histone deacetylase (HDAC) enzymes compose a class of epigenetic drug targets utilized clinically to treat cancer, but their potential against IDHmut gliomas has not been extensively studied. We previously showed that IDHmut glioma cultures exhibit pronounced sensitivity to the effects mediated by the FDA-approved HDAC inhibitor (HDACi) panobinostat. Here, we integrate proliferation and cytoxicity data to show that this effect is unique to gliomas. In the context of histone H3 acetylation (H3KAc), panobinostat increased H3KAc, on average, by 7.6-fold and 30.5-fold in IDHwt and IDHmut glioma cultures, respectively (p< 0.001). This difference in HDACi-mediated H3KAc based on IDH status was not significant for CS and ICC. IDHmut gliomas are more sensitive two other FDA-approved HDACis: belinostat and vorinostat. RNA-Seq analysis showed that panobinostat more greatly affected gene expression in IDHmut glioma cells, particularly in the context of gene downregulation. Similarly, H3KAc ChIP-Seq showed a decrease in promoter histone acetylation moreso in IDHmut glioma cultures treated with panobinostat: there is an average loss of 1,236 and 14,759 H3KAc peaks at gene promoters in IDHwt and IDHmut cultures, respectively. This suggests that IDHmut gliomas exhibit enhanced histone acetylation dynamics in response to HDACi. Furthermore, using a PDX glioma model, we show that only mice engrafted with IDHmut glioma exhibit a significant survival increase in response to the HDACi belinostat: median survival was extended by 14 days in IDHmut glioma-bearing mice (p= 0.01), whereas belinostat extended median survival by 4 days in IDHwt glioma-bearing mice (p= 0.11). These results suggest that HDACi may be an effective in treating IDHmut gliomas.
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Sears, Thomas K., Craig M. Horbinski, and Kevin D. Woolard. "IDH1 mutant glioma is preferentially sensitive to the HDAC inhibitor panobinostat." Journal of Neuro-Oncology 154, no. 2 (August 23, 2021): 159–70. http://dx.doi.org/10.1007/s11060-021-03829-0.
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Abstract Introduction A large subset of diffusely infiltrative gliomas contains a gain-of-function mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2mut) which produces 2-hydroxglutarate, an inhibitor of α-ketoglutarate-dependent DNA demethylases, thereby inducing widespread DNA and histone methylation. Because histone deacetylase (HDAC) enzymes are localized to methylated chromatin via methyl-binding domain proteins, IDH1/2mut gliomas may be more dependent on HDAC activity, and therefore may be more sensitive to HDAC inhibitors. Methods Six cultured patient-derived glioma cell lines, IDH1wt (n = 3) and IDH1mut (n = 3), were treated with an FDA-approved HDAC inhibitor, panobinostat. Cellular cytotoxicity and proliferation assays were conducted by flow cytometry. Histone modifications and cell signaling pathways were assessed using immunoblot and/or ELISA. Results IDH1mut gliomas exhibited marked upregulation of genes associated with the HDAC activity. Glioma cell cultures bearing IDH1mut were significantly more sensitive to the cytotoxic and antiproliferative effects of panobinostat, compared to IDH1wt glioma cells. Panobinostat caused a greater increase in acetylation of the histone residues H3K14, H3K18, and H3K27 in IDH1mut glioma cells. Another HDAC inhibitor, valproic acid, was also more effective against IDH1mut glioma cells. Conclusion These data suggest that IDH1mut gliomas may be preferentially sensitive to HDAC inhibitors. Further, IDH1mut glioma cultures showed enhanced accumulation of acetylated histone residues in response to panobinostat treatment, suggesting a direct epigenetic mechanism for this sensitivity. This provides a rationale for further exploration of HDAC inhibitors against IDH1mut gliomas.
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Watts, Colin, Alimu Dayimu, Tomasz Matys, Keyoumars Ashkan, Stephen Price, Michael D. Jenkinson, Gail Doughton, et al. "Refining the Intraoperative Identification of Suspected High-Grade Glioma Using a Surgical Fluorescence Biomarker: GALA BIDD Study Report." Journal of Personalized Medicine 13, no. 3 (March 13, 2023): 514. http://dx.doi.org/10.3390/jpm13030514.
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Background. Improving intraoperative accuracy with a validated surgical biomarker is important because identifying high-grade areas within a glioma will aid neurosurgical decision-making and sampling. Methods. We designed a multicentre, prospective surgical cohort study (GALA-BIDD) to validate the presence of visible fluorescence as a pragmatic intraoperative surgical biomarker of suspected high-grade disease within a tumour mass in patients undergoing 5-aminolevulinic acid (5-ALA) fluorescence-guided cytoreductive surgery. Results. A total of 106 patients with a suspected high-grade glioma or malignant transformation of a low-grade glioma were enrolled. Among the 99 patients who received 5-ALA, 89 patients were eligible to assess the correlation of fluorescence with diagnosis as per protocol. Of these 89, 81 patients had visible fluorescence at surgery, and 8 patients had no fluorescence. A total of 80 out of 81 fluorescent patients were diagnosed as high-grade gliomas on postoperative central review with 1 low-grade glioma case. Among the eight patients given 5-ALA who did not show any visible fluorescence, none were high-grade gliomas, and all were low-grade gliomas. Of the seven patients suspected radiologically of malignant transformation of low-grade gliomas and with visible fluorescence at surgery, six were diagnosed with high-grade gliomas, and one had no tissue collected. Conclusion. In patients where there is clinical suspicion, visible 5-ALA fluorescence has clinical utility as an intraoperative surgical biomarker of high-grade gliomas and can aid surgical decision-making and sampling. Further studies assessing the use of 5-ALA to assess malignant transformation in all diffuse gliomas may be valuable.
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Ajisebutu, Andrew, Farshad Nassiri, Justin Z. Wang, Yasin Mamatjan, Romina Nejad, Vikas Patil, Jeff Liu, et al. "METABOLOGENOMIC CHARACTERIZATION UNCOVERS HETEROGENEITY AMONG IDH MUTANT GLIOMAS." Neuro-Oncology Advances 5, Supplement_2 (July 1, 2023): i1. http://dx.doi.org/10.1093/noajnl/vdad071.001.
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Abstract Mutations in isocitrate dehydrogenase (IDH) enzymes are recognised to drive the molecular footprint of diffuse gliomas, and patients with IDH-mutant gliomas have overall favorable outcomes compared to patients with IDH wildtype tumors. Nonetheless, survival can vary widely even amongst patients with IDH-mutant tumors. A comprehensive metabologenomic characterization of IDH-mutant gliomas has not been performed to date. METHOD: Glioma samples from a cohort of 154 patients that underwent surgery at the UHN in Toronto, ON, underwent multiplatform molecular analysis, including metabolomic studies, genome- wide DNA methylation profiling and bulk RNA sequencing. A comprehensive, integrative analysis was performed, and validated through the use of an independent cohort derived from The Cancer Genome Atlas. RESULTS: We discovered a group of IDH-mutant gliomas with globally altered metabolism that highly resembled IDH wildtype tumors. Notably, these IDH-mutant gliomas with dysregulated metabolism were distinguished from their IDH-mutant counterparts by significantly shorter overall survival. The prognostic relevance of dysregulated metabolism complements, but was not wholly explained by canonically recognized prognostic classifications in IDH-mutant gliomas including 1p/19q codeletion, glioma CpG Island Hypermethylator (GCIMP) status and CDKN2A homozygous deletion. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles. CONCLUSION: Utilizing a cross-platform analysis we have uncovered a novel subtyping of IDH-mutant gliomas with dysregulated cellular metabolism with similar survival to IDH-wildtype tumors. The metabolic profile provides unique information on glioma phenotypes, which may can facilitate a more comprehensive understanding of glioma biology, and provide a window to target novel dependencies.
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Jaraíz-Rodríguez, Myriam, Rocío Talaverón, Laura García-Vicente, Sara G. Pelaz, Marta Domínguez-Prieto, Andrea Álvarez-Vázquez, Raquel Flores-Hernández, et al. "Connexin43 peptide, TAT-Cx43266–283, selectively targets glioma cells, impairs malignant growth, and enhances survival in mouse models in vivo." Neuro-Oncology 22, no. 4 (December 28, 2019): 493–504. http://dx.doi.org/10.1093/neuonc/noz243.
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Abstract Background Malignant gliomas are the most frequent primary brain tumors and remain among the most incurable cancers. Although the role of the gap junction protein, connexin43 (Cx43), has been deeply investigated in malignant gliomas, no compounds have been reported with the ability to recapitulate the tumor suppressor properties of this protein in in vivo glioma models. Methods TAT-Cx43266–283 a cell-penetrating peptide which mimics the effect of Cx43 on c-Src inhibition, was studied in orthotopic immunocompetent and immunosuppressed models of glioma. The effects of this peptide in brain cells were also analyzed. Results While glioma stem cell malignant features were strongly affected by TAT-Cx43266–283, these properties were not significantly modified in neurons and astrocytes. Intraperitoneally administered TAT-Cx43266–283 decreased the invasion of intracranial tumors generated by GL261 mouse glioma cells in immunocompetent mice. When human glioma stem cells were intracranially injected with TAT-Cx43266–283 into immunodeficient mice, there was reduced expression of the stemness markers nestin and Sox2 in human glioma cells at 7 days post-implantation. Consistent with the role of Sox2 as a transcription factor required for tumorigenicity, TAT-Cx43266–283 reduced the number and stemness of human glioma cells at 30 days post-implantation. Furthermore, TAT-Cx43266–283 enhanced the survival of immunocompetent mice bearing gliomas derived from murine glioma stem cells. Conclusion TAT-Cx43266–283 reduces the growth, invasion, and progression of malignant gliomas and enhances the survival of glioma-bearing mice without exerting toxicity in endogenous brain cells, which suggests that this peptide could be considered as a new clinical therapy for high-grade gliomas.
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Cheng, Quan, Anliu Tang, Zeyu Wang, Ning Fang, Zhuojing Zhang, Liyang Zhang, Chuntao Li, and Yu Zeng. "CALD1 Modulates Gliomas Progression via Facilitating Tumor Angiogenesis." Cancers 13, no. 11 (May 30, 2021): 2705. http://dx.doi.org/10.3390/cancers13112705.
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Angiogenesis is more prominent in anaplastic gliomas and glioblastoma (GBM) than that in pilocytic and diffuse gliomas. Caldesmon (CALD1) plays roles in cell adhesion, cytoskeletal organization, and vascularization. However, limited information is available on mechanisms underlying the effect of CALD1 on the microvascular facilitation and architecture in glioma. In this study, we explored the role of CALD1 in gliomas by integrating bulk RNA-seq analysis and single cell RNA-seq analysis. A positive correlation between CALD1 expression and the gliomas’ pathological grade was noticed, according to the samples from the TCGA and CGGA database. Moreover, higher CALD1 expression samples showed worse clinical outcomes than lower CALD1 expression samples. Biofunction prediction suggested that CALD1 may affect glioma progression through modulating tumor angiogenesis. The map of the tumor microenvironment also depicted that more stromal cells, such as endothelial cells and pericytes, infiltrated in high CALD1 expression samples. CALD1 was found to be remarkably upregulated in neoplastic cells and was involved in tumorigenic processes of gliomas in single cell sequencing analysis. Histology and immunofluorescence analysis also indicated that CALD1 associates with vessel architecture, resulting in glioma grade progression. In conclusion, the present study implies that CALD1 may serve as putative marker monitoring the progress of glioma.
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Gao, Huasong, Bin Yu, Yaohua Yan, Jianhong Shen, Sanhu Zhao, Jianhong Zhu, Wenxin Qin, and Yilu Gao. "Correlation of expression levels of ANXA2, PGAM1, and CALR with glioma grade and prognosis." Journal of Neurosurgery 118, no. 4 (April 2013): 846–53. http://dx.doi.org/10.3171/2012.9.jns112134.
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Object Biomarkers for the diagnosis and prognosis of gliomas are lacking. To elucidate new diagnostic and prognostic targets, a routine method is used to evaluate differences between the protein profile of normal and tumor cells. The object of the current study was to investigate novel differentially expressed proteins and their roles in gliomas. Methods Differences in the protein profile were compared using 2D polyacrylamide gel electrophoresis using C6 glioma cells and rat astrocytes. The mRNA and protein expression of ANXA2, PGAM1, and CALR were analyzed in glioma tissues and normal brain tissues. The expression of ANXA2 in the U87 glioma cell line was interrupted using short interfering RNA duplexes, and the role of ANXA2 in the migration and invasiveness of glioma cells was assessed. The expression of ANXA2, PGAM1, and CALR was examined further by immunohistochemical analysis using 130 glioma samples obtained in patients, and their prognostic roles in gliomas were evaluated using Kaplan-Meier and Cox regression analyses. Results Significantly higher expression levels of ANXA2 and PGAM1 and a lower level of CALR were found in glioma samples than in the normal brain samples. ANXA2, PGAM1, and CALR expression correlated with the grade and survival of patients with gliomas. Multivariate analysis further revealed that ANXA2 was an independent prognostic marker for glioma. After ANXA2 expression was suppressed using short interfering RNA, U87 cells had decreased migratory and invasive capabilities in vitro. Conclusions Protein expression alterations in ANXA2, PGAM1, and CALR were found in gliomas, and ANXA2 provided a novel prognostic value.
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Rao, Aparna, Xiaoran Zhang, Christopher Deibert, Paola Sette, Paola Grandi, and Nduka Amankulor. "IDH Mutant Gliomas Escape Natural Killer Cell Immune Surveillance by Downregulation of NKG2D Ligand Expression." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 142.11. http://dx.doi.org/10.4049/jimmunol.196.supp.142.11.
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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.
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Wang, Ziyan. "Analysis of the clinical display effect of imaging techniques on the staging of gliomas." Theoretical and Natural Science 17, no. 1 (December 4, 2023): 9–12. http://dx.doi.org/10.54254/2753-8818/17/20240622.
Full textAbstract:
Glioma is a primary intracranial malignant tumor, which is difficult to be cured and has the characteristics of easy recurrence and high mortality rate, therefore, it is of great clinical significance to accurately grade glioma before operation. Since biopsy of gliomas is relatively difficult and its accuracy cannot be guaranteed, imaging examination has become an important means of clinical grading of gliomas. This paper, through the literature analysis method, reviews the previous studies of applying imaging methods to grade gliomas in China and abroad and summarizes the main techniques of MRI and CT and their grading effects. Finally, this paper finds that MRI and CT can be used to grade gliomas alone, but both have limitations, while the combined application of MRI and CT has high sensitivity and specificity for the diagnosis and grading of gliomas, which makes up for their respective shortcomings, and is worthy of wide application.