Glioma Pathogenesis Research Articles

CNSC-30. DETERMINING THE REGULATION AND FUNCTION OF ANGPT1 HIGH-GRADE GLIOMAS

Abstract Angiopoietin-1 (Angpt1) is a secreted protein that promotes angiogenesis and vascular stability in development and certain disease states through activation of the Tie2 receptor. However, little is known about its regulation and function in brain tumors. Angpt1 is upregulated in glial brain tumors, including high-grade gliomas and ependymomas. We find Angpt1 is expressed by specific cell populations within gliomas, along with non-tumor reactive astrocytes and perivascular mural cells. Leveraging an in vivo brain tumor modeling system we have generated glioma models to investigate how tumor cell state impacts Angpt1 expression, along with creating Angpt1 knock-out models. We find that Angpt1 expression is increased when glioma models are biased towards a more astrocytic and/or mesenchymal state, mirroring developmental expression patterns. Ongoing studies utilizing these models are being used to determine the mechanisms that regulate the dynamic expression of Angpt1 and its function in glioma pathogenesis, including tumor angiogenesis and blood-brain barrier function.

TMOD-21. MOUSE MODEL TO CONDITIONALLY EXPRESS A DIFFUSE MIDLINE GLIOMA DERIVED MUTATION IN THE ONCOGENIC PHOSPHATASE PPM1D

Abstract Diffuse Midline Gliomas (DMGs) are incurable brain tumors of children and adults, and there is an urgent need for new therapeutic approaches. Their location within critical areas of the brain precludes complete surgical removal. While current treatment mainly relies on radiation therapy, its efficacy remains palliative. DMGs commonly harbor truncating mutations in the Mn2+/Mg2+-dependent protein phosphatase 1D (PPM1D), leading to a gain-of-function in PPM1D by enhancing protein stability and activity. Thus, investigating PPM1D protein expression and its regulatory mechanisms is crucial for understanding its oncogenic role and identifying therapeutic targets. To address this, we developed a Ppm1d-loxP-exon6-loxP-exon6-E518X-tag mouse allele (Ppm1d-FL). This allele allows conditional expression of DMG-derived truncating mutations from the endogenous Ppm1d locus when the loxP sites are recombined in the presence of Cre recombinase. Tosimulate primary gliomas, we utilized the RCAS/tv-a retrovirus system and Cre/loxP recombination platforms. Mouse pups were injected with RCAS retroviruses bearing oncogenic platelet-derived growth factor B, Cre recombinase, and luciferase reporter genes into the brainstem. We confirmed that Cre leads to expected recombination of Ppm1d-FL, leading to expression of DMG-derived truncated Ppm1d-E518X-Tag mRNA. We examined tumor-free survival data, which indicates accelerated tumor formation with Ppm1d-FL compared to littermate controls with wildtype Ppm1d. The tumors demonstrated expression of molecular biomarkers commonly found in DMGs. Single-cell RNA sequencing has identified pathways activated or inactivated upon Ppm1d mutation. These data shed light on the complex interplay between PPM1D mutations and glioma pathogenesis and may guide the design of therapies that target PPM1D molecular pathways.

EPCO-49. SEX-SPECIFIC CHROMATIN REMODELING DRIVES TUMORIGENESIS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most prevalent primary malignant brain cancer and has higher incidence and lower survival in males compared to females. The SWI/SNF chromatin remodeling complexes, including canonical BAF (cBAF), polybromo-associated BAF (PBAF), and non-canonical BAF (ncBAF), play a critical role in multiple cancers including gliomas. However, their role in gliomagenesis and progression remains largely unknown. We analyzed 18 human glioma specimens for BAF complex mRNA expression by CNS WHO grade and used these data to guide CRISPRi knockdown of BAF components in syngeneic murine male and female GBM astrocytes. BAF complex knockdown revealed marked sex-specific differences in proliferation. Specifically, Smarce1 or Smarcb1 knockdown (cBAF & PBAF) resulted in increased growth in male astrocytes but decreased growth in females. Brd7 (PBAF) knockdown enhanced growth in both sexes, while Brd9 (ncBAF) had minimal impact. We utilized extreme limiting dilution analysis (ELDA) to assess the clonogenic potential of GBM cells with depleted BAF components. Notably, cells with BRD7 knockdown displayed enhanced sphere-forming capacity in both male and female cells. Male cells with Smarce1or Smarcb1 knockdown showed increased clonogenic frequency, whereas females with Smarce1 knockdown had a marked reduction in sphere formation. Brd9 knockdown did not affect the sphere-forming capacity in male or female cells, in part due to compensatory plasticity of an alternate BAF complex. Epitranscriptomic analysis is ongoing and demonstrates sex-specific differences in chromatin accessibility and downstream gene expression programs based on BAF complex knockdown. Immunoprecipitation coupled with mass spectrometry was performed to elucidate the structure and assembly of the BAF complex in GBM cells. Understanding sex-specific mechanisms of BAF chromatin remodeling complex in glioma pathogenesis may yield critical insights for the development of precision therapeutics that have the potential to improve patient outcomes.

DNAR-06. EPITRANSCRIPTOMIC TRNA MODIFICATIONS TARGETING ADENOSINE (A) AT POSITION 37 IN GBM

Abstract GBM stands as the most aggressive brain tumor in adults. The median overall survival is less than 2 years despite conventional treatments. Recent advancements in DNA analysis have delineated the molecular characteristics of gliomas, leading to revisions in the WHO classification based on DNA profiles. However, the role of RNA modifications, epitranscriptomics, remains poorly understood in glioma. In this study, we underscore the significance of tRNA modifications targeting adenosine at position 37 in GBM. Transfer RNA isopentenyl transferase 1 (TRIT1) is identified as an isopentenyl transferase catalyzing the conversion of A into i6A at position 37 of tRNA, a nucleotide adjacent to the anticodon region. Additionally, i6A is further modified to 2-methylthio i6A (ms2i6A) by cyclin-dependent kinase 5 regulatory subunit associated-protein 1 (CDK5RAP1) within mitochondrial tRNA. Analysis of TCGA data reveals elevated TRIT1 mRNA expression levels in GBM compared to non-tumor samples. Furthermore, a low expression group of TRIT1 in gliomas demonstrates improved survival outcomes according to data from the CGGA, implicating TRIT1 in glioma progression. Functional assays involving TRIT1 knockdown in human GBM cell lines result in decreased cell viability, indicating its functional significance. Moreover, our data suggest that this phenotype may be mediated through translational control of selenoprotein W (SEPW1) via tRNA^(Ser)Sec modification. GO analysis of TRIT1 and SEPW1 in TCGA data further supports this proposed mechanism. At position 37 of tRNA, we also found that CDK5RAP1 in mitochondrial tRNAs is indispensable for sustaining glioblastoma initiating cell (GIC)-related traits. CDK5RAP1 maintains the self-renewal capacity, undifferentiated state, and tumorigenic potential of GICs, independent of translational control of mitochondrial proteins. Notably, CDK5RAP1 abrogates the antitumor effect of i6A by converting i6A to ms2i6A and shields GICs from excessive autophagy triggered by i6A. This work underscores the critical role of tRNA modifications in glioma pathogenesis. We will report these findings alongside RNA modification profile data and clinical data from glioma patients.

EPCO-04. H3F3A K27M MUTATION DRIVES A REPRESSIVE TRANSCRIPTOME VIA REDUCED SERINE 31 PHOSPHORYLATION BY MODULATING CHROMATIN ACCESSIBILITY, INDEPENDENT OF H3K27ME3 IN DIFFUSE MIDLINE GLIOMA

Abstract Heterozygous H3.3 K27M mutations are central to the pathogenesis of diffuse midline gliomas (DMG), causing a global reduction in H3K27 trimethylation (H3K27me3) and subsequent epigenetic dysregulation. H3.3 contains a unique Serine 31 (S31) phosphorylation site crucial for mitotic checkpoint regulation. In DMG cells, reduced mitotic S31 phosphorylation correlates with chromosomal instability and aneuploidy. Using a mouse model, we demonstrate that both H3.3K27M and H3.3S31A mutations promote high-grade glioma development, whereas wild-type H3.3 does not. Importantly, S31A, which maintains normal K27me, suggests that S31 phosphorylation loss alone is oncogenic. The H3.3K27M mutation disrupts epigenetic regulation by inhibiting the Polycomb Repressive Complex 2 (PRC2), leading to decreased H3K27me3 and unintended gene induction. Concurrently, K27M exerts a compensatory repressive effect on the transcriptome, mediated by reduced S31 phosphorylation, independent of PRC2 activity. Using CRISPR-engineered isogenic DMG cells and analyzing the transcriptome and chromatin accessibility with RNA-seq and ATAC-seq, we found that the K27M mutation produces a balanced gene expression profile, while PRC2 loss primarily leads to gene induction. Notably, cells with S31A mutations also maintain this balanced profile, linking the PRC2-independent effect of K27M to reduced S31 phosphorylation. Conversely, cells with wild-type K27 but S31A mutation show a repressive genomic state, evidenced by an up/down gene ratio of 0.75, owing to functional PRC2. We further show that the genes uniquely dysregulated by K27M or S31A, independent of PRC2, overlap significantly, with dysregulated genes displaying altered chromatin accessibility. This suggests that the effect of K27M and S31A mutations on gene regulation is primarily due to changes in chromatin state. This complex interplay points to targeting K27M-associated pathways, particularly S31 phosphorylation, as a promising therapeutic avenue in DMG, a malignancy with fewer effective treatments and dismal prognosis.

EPCO-41. THE NUCLEOSOME REMODELING AND DEACETYLASE COMPLEX UNDERLIES SELECTIVE DEPENDENCY IN H3 G34-MUTANT DIFFUSE HEMISPHERIC GLIOMA

Abstract Pediatric-type diffuse high-grade gliomas are fatal central nervous system malignancies of childhood. Recurrent mutations in histone H3.3 at amino acid 34 (glycine to arginine/valine) are a defining molecular feature of diffuse hemispheric glioma, H3 G34-mutant (H3 G34-mutant DHG), which arises preferentially in adolescents and young adults. Single-nuclei sequencing of age and anatomically matched H3 wild-type and H3 G34-mutant primary patient tumors identified aberrant neuronal-like transcriptional programs enriched for signatures of cortical interneurons derived from the medial ganglionic eminence. The extent to which these molecular signatures reflect cancer dependencies in H3 G34-mutant DHG is poorly understood. To identify transcriptional vulnerabilities governing cellular state and underlying developmental lineage, we performed CRISPR screening targeting the DNA-binding domains of 1,427 proteins in H3 G34-mutant DHG (n=6) and H3 K27-altered diffuse midline glioma (DMG) (n=3). Through these efforts, we identified developmentally relevant transcription factor vulnerabilities corresponding to neuronal and oligodendrocyte precursor cell-like hierarchies comprising H3 G34-mutant DHG and H3 K27-altered DMG cellular states, respectively. Intriguingly, we also identified multiple members of the nucleosome remodeling and deacetylase (NuRD) complex as selective dependencies in H3 G34-DHG compared to H3 K27-altered DMG and 32 other cancer cell line models screened using the same DNA-binding domain library. Genetic perturbation of the holo-NuRD structural subunit MBD3 conferred an upregulation of genes involved in neuronal differentiation and synapse formation consistent with NuRD-mediated modulation of the aberrant neuronal-like cell hierarchy observed in H3 G34-mutant DHG. To therapeutically target NuRD-associated class I HDAC activity, patient-derived H3 G34-mutant DHG cell lines were treated with quisinostat, a highly potent class I and II HDAC inhibitor. Pharmacologic inhibition of HDAC activity was sufficient to impair cell growth in vitro. Ongoing experiments are evaluating dependencies in vivo. Our results may suggest a differential requirement for chromatin repressive complex dysregulation in the pathogenesis of oncohistone-mutant pediatric-type diffuse high-grade gliomas.

Study of Molecular Markers in Glioma and Their Association with Clinicopathological Features.

Central nervous system tumors are a major cause of morbidity and mortality worldwide. The most prevalent type of primary brain tumor is glioma. The exploration of significant genetic, epigenetic, and transcriptional abnormalities has not only improved our understanding of glioma pathogenesis but has also revealed that these molecular alterations can serve as useful diagnostic markers for more precise classification and are linked to better treatment response and prognosis. Hence, incorporating molecular markers into routine tumor classification is a major priority in modern glioma diagnostics. The aim is to assess the mutation status of isocitrate dehydrogenase (IDH)-1, alpha-thalassemia/mental retardation syndrome X-linked (ATRX), and tumor protein 53 in glioma, and look for their association with various clinicopathological features. A single-center prospective cohort study, where all biopsies of glioma (January 2019 to July 2020) were evaluated, and immunohistochemistry was performed to assess the expression of IDH-1, ATRX, p53, and Ki-67 index. The data were analyzed using IBM SPSS-24 software. Immunohistochemistry was performed in 123 consecutive cases of glioma. IDH-1 mutation was noted in 54 (43.9%) cases and these patients frequently presented with "seizures" (P = 0.006). The expression was maximum in World Health Organization (WHO) grade 2 tumors (65.4%) (P < 0.001), with the highest frequency in oligodendrogliomas (100% in WHO grade 2 and 3). Furthermore, these tumors showed lower proliferative indices (P = 0.001). ATRX mutation was noted in 59 (48%) and p53 overexpression was noted in 76 (61.8%) cases. These mutations were significantly associated with astrocytic phenotype (P = 0.03). Molecular characterization of glioma is an important step in modern glioma diagnostics and immunohistochemistry can play an important role. IDH-1 mutation is commonly observed in adults, frontal lobe location, patients presenting with seizures, and WHO grade 2 tumors with the highest frequencies in oligodendrogliomas. ATRX and p53 can be used as surrogate markers for tumors of astrocytic lineage.

Complement C1S is a potential prognostic biomarker and associated with M2 macrophage infiltration in gliomas: From bioinformatics to comprehensive experimental validation

Glioma is the most common malignant tumor of the central nervous system, and the ability of traditional clinical treatment to prolong the survival of glioma patients is limited. A substantial body of evidence underscores the pivotal role of the immune system in eradicating malignant cells and impeding tumor metastasis. Consequently, tumor immunotherapy has become a promising avenue to address the clinical conundrum faced by glioma patients. The complement system is a natural immune system that is an important line of defense in the immune response. C1S plays a key role in activating the classical complement system. Nevertheless, few studies have focused on the role of C1S in glioma tumorigenesis and progression. In this study, we demonstrated that C1S was upregulated in GBM (Grade IV) and low-grade gliomas (LGG, Grade II-III) by combining glioma cohorts from multiple public databases with our internal independent cohorts and that increased C1S expression levels predict a poor prognosis for gliomas. Cox regression analysis identified C1S as an important prognostic indicator for glioma patients. In addition, gene functional enrichment analysis demonstrated that C1S was involved in cellular immunity, T-cell activation, macrophage differentiation, and cell proliferation. Further experiments demonstrated that C1S facilitates tumor cell proliferation, cell migration and intracranial tumor growth in nude mice. More importantly, we evaluated the role of C1S in immune infiltration. These results suggested that C1S was closely related to a variety of immune cell types in glioma, especially M2 macrophages. Our findings were further validated via glioma tissue microarray immunohistochemical analysis and an M2 macrophage infiltration assay. Together, these findings revealed the underlying critical role of C1S in glioma tumorigenesis, progression, and the tumor immune microenvironment, contributing to further understanding of glioma pathogenesis and guiding immunotherapy.

Bibliometric and visualization analysis in the field of epigenetics and glioma (2009-2024).

Glioma represents the most prevalent primary malignant tumor in the central nervous system, a deeper understanding of the underlying molecular mechanisms driving glioma is imperative for guiding future treatment strategies. Emerging evidence has implicated a close relationship between glioma development and epigenetic regulation. However, there remains a significant lack of comprehensive summaries in this domain. This study aims to analyze epigenetic publications pertaining to gliomas from 2009 to 2024 using bibliometric methods, consolidate the extant research, and delineate future prospects for investigation in this critical area. For the purpose of this study, publications spanning the years 2009 to 2024 were extracted from the esteemed Web of Science Core Collection (WoSCC) database. Utilizing advanced visualization tools such as CiteSpace and VOSviewer, comprehensive data pertaining to various aspects including countries, authors, author co-citations, countries/regions, institutions, journals, cited literature, and keywords were systematically visualized and analyzed. A thorough analysis was conducted on a comprehensive dataset consisting of 858 publications, which unveiled a discernible trend of steady annual growth in research output within this specific field. The nations of the United States, China, and Germany emerged as the foremost contributors to this research domain. It is noteworthy that von Deimling A and the Helmholtz Association were distinguished as prominent authors and institutions, respectively, in this corpus of literature. A rigorous keyword search and subsequent co-occurrence analysis were executed, ultimately leading to the identification of seven distinct clusters: "epigenetic regulation", "DNA repair", "DNA methylation", "brain tumors", "diffuse midline glioma (DMG)", "U-87 MG" and "epigenomics". Furthermore, an intricate cluster analysis revealed that the primary foci of research within this field were centered around the exploration of glioma pathogenesis and the development of corresponding treatment strategies. This article underscores the prevailing trends and hotspots in glioma epigenetics, offering invaluable insights that can guide future research endeavors. The investigation of epigenetic mechanisms primarily centers on DNA modification, non-coding RNAs (ncRNAs), and histone modification. Furthermore, the pursuit of overcoming temozolomide (TMZ) resistance and the exploration of diverse emerging therapeutic strategies have emerged as pivotal avenues for future research within the field of glioma epigenetics.

Association between Fat-Soluble Vitamin Metabolic Process and Glioma Progression.

Although multimodality therapy has recently advanced, patients with glioblastoma, one of the most aggressive and deadly types of central nervous system cancer, have a very poor prognosis and rare long-term survival. Vitamins are essential organic nutrients that play a pivotal role in maintaining homeostasis, and various studies have demonstrated the implication of vitamins in the pathophysiology of gliomas. Herein, we aimed to investigate the association of the vitamin metabolic pathway and the corresponding candidate genes for the malignancy, aggressiveness, and poor prognosis of gliomas using The Cancer Genome Atlas database of patients with gliomas. We demonstrated that fat-soluble vitamin metabolic processes are prominently associated with glioma grade, molecular biomarkers, molecular subtypes, and clinical outcomes. Moreover, we identified the key genes related to the fat-soluble metabolic pathway in gliomas using differentially expressed gene analysis. Among them, the expression of the vitamin K epoxide reductase complex subunit 1 (VKORC1), encoding VKOR essential for the vitamin K-dependent γ-carboxylation of target proteins, was prominently associated with not only malignancy, aggressiveness, and poor prognosis of gliomas but also the representative signal pathways related to glioma pathogenesis. Moreover, the inactivation of Vkorc1 by RNA interference decreased the proliferation and migration potential of glioma cells in vitro. Collectively, these findings reveal the pivotal role of fat-soluble vitamin and vitamin K metabolic processes in the pathophysiology of gliomas, thereby identifying a potential target for drug development for the treatment of malignant gliomas.

M6A RNA METHYLATION AS A THERAPEUTIC TARGET IN HIGH GRADE GLIOMA

Abstract AIMS High grade glioma (HGG) is a devastating brain cancer that has poor prognostic outcomes. Very recently, the field of epitranscriptome has emerged as a novel druggable target for multiple diseases, including cancers. In the present study, we sought to investigate the functional importance of N6-methyladenosine (m6A) RNA methylation in the pathogenesis and drug resistance of paediatric and adult high grade glioma. METHOD To identify the expression of key m6A effectors, RT-qPCR and immunofluorescence were undertaken in patient derived HGG cell lines, primary low passage HGG cells and human tissues. The expression of these effectors was modified using siRNA-mediated knockdown and small molecules to identify their effects on key transcription factors. The consequences of modification on the ability of the cells to form neurospheres and invade was also assessed. Developing chemotherapy-resistant cell lines is undertaking to assess the effect of m6A RNA levels on the ability of HGG cells to adapt to environmental changes. Measuring the level of m6A-modified transcripts were achieved by developing LC-MS/MS and MeRIP (methylated RNA immunoprecipitation) qPCR techniques. RESULTS We found that key m6A effectors such as methyltransferase like 3 (METTL3), Wilms tumor 1-associating protein (WTAP) and fat mass and obesity-associated (FTO) are expressed at significantly higher level in paediatric and adult HGG models than in control at both gene and protein levels. Furthermore, these effectors regulate the expression of key transcription factors in self-renewal, cell cycle regulation and tumorigenesis. siRNA-mediated depletion of m6A effectors and inhibition of METTL3 using small molecules such as STM2457 and STM3006 reduce the capacity of cells to form neurospheres and invade as well as improving the sensitivity of HGG cells to chemotherapeutic agents. CONCLUSION Our findings suggest that m6A effectors are potential pro-oncogenic factors that, if druggable, will represent an advanced avenue in HGG therapy.

Congress of Neurological Surgeons systematic review and evidence‑based guidelines on the management of recurrent diffuse low-grade glioma: update.

Target population These recommendations apply to adult patients with recurrent WHO grade 2 infiltrative diffuse glioma (oligodendroglioma, astrocytoma).Questions and Recommendations:Imaging Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, do advanced imaging techniques using magnetic resonance spectroscopy, perfusion weighted imaging, diffusion weighted imaging or PET provide superior assessment of tumor recurrence and histologic progression compared to standard MRI neuroimaging?Recommendation Level III: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, advanced imaging techniques using magnetic resonance spectroscopy, perfusion weighted imaging, diffusion weighted imaging or PET are suggested for identification of tumor recurrence or histologic progression.Pathology Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, is molecular testing for IDH-1, IDH-2, and TP53 Mutations and MGMT promotor methylation mutation warranted for predicting survival and formulating treatment recommendations?Recommendation Level III: It is suggested that IDH mutation status be determined for diagnostic purposes. TP53 mutations occur early in WHO grade 2 diffuse glioma pathogenesis, remain stable, and are not suggested as a marker of predisposition to malignant transformation at recurrence or other measures of prognosis. Assessment of MGMT status is suggested as an adjunct to assessing prognosis. Assessment of CDK2NA status is suggested since this is associated with malignant progression of WHO grade 2 diffuse gliomas.Q2: In adult patients with suspected recurrence of histologically proven WHO Grade 2 diffuse glioma, is testing of proliferation indices (MIB-1 and/or BUdR) warranted for predicting survival and formulating treatment recommendations?Recommendation Level III: It is suggested that proliferative indices (MIB-1 or BUdR) be measured in WHO grade 2 diffuse glioma as higher proliferation indices are associated with increased likelihood of recurrence and shorter progression free and overall survival.Chemotherapy Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, does addition of temozolomide (TMZ), other cytotoxic agents or targeted agents to their treatment regimen improve PFS and/or OS?Recommendation Level III: Temozolomide is suggested in the therapy of recurrent WHO grade 2 diffuse glioma as it may improve clinical symptoms. PCV is suggested in the therapy of WHO grade 2 diffuse glioma at recurrence as it may improve clinical symptoms with the strongest evidence being for oligodendrogliomas. TMZ is suggested as the initial choice for recurrent WHO grade 2 diffuse glioma. Carboplatin is not suggested as there is no significant benefit from carboplatin as single agent therapy for recurrent WHO grade 2 diffuse gliomas. There is insufficient evidence to make any recommendations regarding other agents in the management of recurrent WHO grade 2 diffuse glioma.Radiotherapy Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, does addition of radiotherapy to treatment regimen improve PFS and/or OS?Recommendation Level III: Radiation is suggested at recurrence if there was no previous radiation treatment. Q2: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma after previous radiotherapy, does addition of re-irradiation or proton therapy to the treatment regimen improve PFS and/or OS?Recommendation Level III: It is suggested that re-irradiation be considered in the setting of WHO grade 2 diffuse glioma recurrence as it may provide benefit in PFS and OS.Surgery Q1: In adult patients with suspected recurrence of histologically proven WHO grade 2 diffuse glioma, does surgical resection improve PFS and/or OS?. There is insufficient evidence to make any new specific recommendations regarding the value of surgery or extent of resection in relationship to survival for recurrent WHO grade 2 diffuse glioma.

Deciphering the role of heat shock protein HSPA1L: biomarker discovery and prognostic insights in Parkinson's disease and glioma

BackgroundHeat shock proteins (HSPs) play a critical role in cellular stress responses and have been implicated in numerous diseases, including Parkinson's disease (PD) and various cancers. Understanding the differential expression and functional implications of HSPs in these conditions is crucial for identifying potential therapeutic targets and biomarkers for diagnosis and prognosis. MethodsWe utilized combined datasets (GSE6613 and GSE72267) to identify and analyze the heat shock-related genes differentially expressed in PD. Gene Set Variation Analysis (GSVA) was performed to explore functional profiles, while LASSO regression was employed to screen potential PD biomarkers. In glioma, prognostic value, immune infiltration, and pathway enrichment associated with HSPA1L gene expression were assessed via Kaplan-Meier plots, ssGSEA, and enrichment analyses. ResultsIn PD, we identified 17 differentially expressed HSPs. Enrichment analysis revealed significant pathways related to protein homeostasis and cellular stress responses. LASSO regression pinpointed 12 genes, including HSPA1L, as significant markers for PD, with nomogram and calibration plots indicating predictive accuracy. Stratification based on HSPA1L expression in PD highlighted differentially active biological processes, immune responses, and metabolic disruptions. In the pan-cancer analysis, HSPA1L showed variable expression across cancer types and a significant correlation with patient survival and immune infiltration. In glioma, low HSPA1L expression was associated with worse overall survival, distinct immune infiltration patterns, and altered pathway activities. ConclusionThis integrative study reveals the substantial role of HSPs, especially HSPA1L, in the pathogenesis and prognosis of PD and glioma. Our findings offer new perspectives on the molecular mechanisms underlying these diseases and propose HSPA1L as a potential prognostic biomarker and a target for therapeutic intervention.

Immunohistochemical investigation of SOX2 expression in Iraqi patients with high-grade glioma

Background. Gliomas, particularly high-grade gliomas, are aggressive brain tumors with poor prognosis. Sex-determining region Y-box 2 (SOX2) is a transcription factor responsible for stem cell maintenance and differentiation and has been implicated in glioma progression and recurrence. The present study investigated SOX2 expression in Iraqi patients with high-grade glioma and assessed its potential as a diagnostic and prognostic biomarker. Methods. Sixty-four paraffin-embedded samples from the Neurological Hospital in Baghdad were analyzed, including 34 high-grade glioma cases (21 males and 13 females) and 13 benign controls (10 males and 3 females). Immunohistochemical staining for SOX2 was performed, and staining levels were categorized using a scoring system. Statistical analyses were conducted to evaluate differences in SOX2 expression between genders and between patient and control groups. Results. There were highly significant differences in SOX2 expression between patients and controls (p ≤0.01). However, no significant difference was observed between male and female patients (p ≤0.01). Additionally, there were significant differences in SOX2 expression distribution between genders, with p-values of 0.0022 for males and 0.0061 for females. The highest distribution percentages for males were at scores 2 and 3, with values of 38.10 and 47.62%, respectively. In contrast, females had distribution ratios only at scores 2 and 3, with values of 30.77 and 69.23%, respectively. Conclusion. SOX2 is highly expressed in high-grade gliomas, supporting its potential as a diagnostic and prognostic marker. Future studies with larger cohorts and detailed sex-specific analyses are needed to elucidate SOX2's role in glioma pathogenesis and its potential as a therapeutic target.

Emerging Role of the Slit/Roundabout (Robo) Signaling Pathway in Glioma Pathogenesis and Potential Therapeutic Options

Gliomas represent the most common primary Central Nervous System (CNS) tumors, characterized by increased heterogeneity, dysregulated intracellular signaling, extremely invasive properties, and a dismal prognosis. They are generally resistant to existing therapies and only a few molecular targeting options are currently available. In search of signal transduction pathways with a potential impact in glioma growth and immunotherapy, the Slit guidance ligands (Slits) and their Roundabout (Robo) family of receptors have been revealed as key regulators of tumor cells and their microenvironment. Recent evidence indicates the implication of the Slit/Robo signaling pathway in inflammation, cell migration, angiogenesis, and immune cell infiltration of gliomas, suppressing or promoting the expression of pivotal proteins, such as cell adhesion molecules, matrix metalloproteinases, interleukins, angiogenic growth factors, and immune checkpoints. Herein, we discuss recent data on the significant implication of the Slit/Robo signaling pathway in glioma pathology along with the respective targeting options, including immunotherapy, monoclonal antibody therapy, and protein expression modifiers.

Machine learning-based discovery of UPP1 as a key oncogene in tumorigenesis and immune escape in gliomas.

Gliomas are the most common and aggressive type of primary brain tumor, with a poor prognosis despite current treatment approaches. Understanding the molecular mechanisms underlying glioma development and progression is critical for improving therapies and patient outcomes. The current study comprehensively analyzed large-scale single-cell RNA sequencing and bulk RNA sequencing of glioma samples. By utilizing a series of advanced computational methods, this integrative approach identified the gene UPP1 (Uridine Phosphorylase 1) as a novel driver of glioma tumorigenesis and immune evasion. High levels of UPP1 were linked to poor survival rates in patients. Functional experiments demonstrated that UPP1 promotes tumor cell proliferation and invasion and suppresses anti-tumor immune responses. Moreover, UPP1 was found to be an effective predictor of mutation patterns, drug response, immunotherapy effectiveness, and immune characteristics. These findings highlight the power of combining diverse machine learning methods to identify valuable clinical markers involved in glioma pathogenesis. Identifying UPP1 as a tumor growth and immune escape driver may be a promising therapeutic target for this devastating disease.

Gender-specific microbial signatures in saliva: Unveiling the association between the oral microbiome and the pathogenesis of glioma

The intricate interplay between the human oral microbiome and systemic health is increasingly being recognized, particularly in the context of central nervous system pathologies such as glioblastoma. In this study, we aimed to elucidate gender-specific differences in the salivary microbiome of glioma patients by utilizing 16S rRNA sequencing data from publicly available salivary microbiome datasets. We conducted comprehensive bioinformatics analysis, encompassing quality control, noise reduction, species classification, and microbial community composition analysis at various taxonomic levels. Machine learning algorithms were employed to identify microbial signatures associated with glioma. When compared to healthy controls, our analysis revealed distinct differences in the salivary microbiota of glioma patients. Notably, the genera Leptotrichia and Atopobium exhibited significant variations in abundance between genders. Leptotrichia was prevalent in healthy females but exhibited a reduced abundance in female glioma patients. In contrast, Atopobium was more abundant in male glioma patients. These findings suggest that hormonal influences might play a role in shaping the salivary microbiome and its association with glioma. We utilized a combination of LASSO-logistic regression and random forest models for feature selection, and identified key microbial features that differentiated glioma patients from healthy controls. We developed a diagnostic model with high predictive accuracy and area under the curve and principal component analysis metrics confirmed its robustness. The analysis of microbial markers, including Atopobium and Leptotrichia, highlighted the potential of the salivary microbiota as a non-invasive biomarker for the diagnosis and prognosis of glioma. Our findings highlight significant gender-specific disparities in the salivary microbiome of patients with glioma, offering new insights into the pathogenesis of glioma and paving the way for innovative diagnostic and therapeutic strategies. The use of saliva as a diagnostic fluid, given its ease of collection and non-invasive nature, holds immense promise for monitoring systemic health and the trajectory of disease. Future research should focus on investigating the underlying mechanisms by which the salivary microbiome influences the development of glioma and identifying potential microbiome-targeted therapies to enhance the management of glioma.

Exploring the multifaceted role of key lncRNA in glioma: From genetic expression to clinical implications and immunotherapy potential

BackgroundLong non-coding RNAs (lncRNAs) are implicated in a variety of regulatory functions within tumors, yet their specific roles in glioma remain underexplored. MethodsWe extracted glioma patient data from The Cancer Genome Atlas and UCSC Xena database for analysis using R, focusing on genomic characterization, biological enrichment, immune evaluation, and the development of a predictive model employing machine learning techniques. Additionally, we conducted cell culture and proliferation assays. ResultsOur analysis revealed that the lncRNA SLC16A1-AS1 plays a pivotal role in glioma pathogenesis and prognosis. We observed that abnormal expression of SLC16A1-AS1 varied with tumor grade, IDH mutation status, and histological type, correlating with worse survival outcomes. Genomically, SLC16A1-AS1 was associated with Tumor Mutational Burden and other prognostic biomarkers. The expression of this lncRNA was also linked to the activation of critical biological pathways and appeared to modulate the immune microenvironment, enhancing the presence of immune cells and checkpoints, which may be predictive of immunotherapy outcomes. Our predictive model, constructed from genes associated with SLC16A1-AS1, accurately forecasted glioma prognosis, strongly correlating with survival and treatment responses. In vitro experiments further demonstrated that SLC16A1-AS1 significantly influences glioma cell proliferation, invasion, and migration, underscoring its role in tumor aggression and its potential as a therapeutic target. ConclusionsThis study underscores the significant influence of SLC16A1-AS1 on glioma progression and prognosis, with its expression correlating with tumor traits and immune responses. The findings highlight the potential of targeting SLC16A1-AS1 in therapeutic strategies aimed at mitigating glioma aggressiveness.

Immunosuppressive MDSC and Treg signatures predict prognosis and therapeutic response in glioma

Glioma, a complex and aggressive brain tumor, is characterized by dysregulated immune responses within the tumor microenvironment (TME). We conducted a comprehensive analysis to elucidate the roles of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) in glioma progression and their impact on the immune landscape. Using transcriptome data, we stratified glioma samples based on MDSC and Treg levels, revealing significant differences in patient survival probabilities. LASSO regression identified a gene panel associated with glioma prognosis, yielding a patient-specific risk score. Multivariate Cox regression confirmed the risk score’s correlation with overall survival. An ISS (immune suppressive score) system assessed the immune landscape’s impact on glioma progression and therapeutic response. Functional validation showed MDSC and Treg infiltration’s relevance in glioma progression and immune modulation. Hub genes in the black module, including CCL2, LINC01503, CXCL8, CLEC2B, TIMP1, and RGS2, were identified through MCODE analysis. RGS2 expression correlated with immune cell populations and varied in glioma cells. This study sheds light on MDSCs’ and Tregs’ roles in glioma pathogenesis, suggesting their potential as prognostic biomarkers and therapeutic targets for personalized immunotherapeutic strategies in glioma treatment.

Nanocarriers for the treatment of glioblastoma multiforme: A succinct review of conventional and repositioned drugs in the last decade.

Glioblastoma multiforme is a very combative and threatening type of cancer. The standard course of treatment involves excising the tumor surgically, then administering chemotherapy and radiation therapy. Because of the presence of the blood-brain barrier and the unique characteristics of the tumor microenvironment, chemotherapy is extremely difficult and has a high incidence of relapse. With their capacity to precisely target and transport therapeutic medications to the tumor while overcoming the challenges provided by invasive and infiltrative gliomas, nanocarriers offer a potentially beneficial treatment option for gliomas. Drug repositioning or, in other words, finding novel therapeutic uses for medications that have received approval for previous uses has also recently emerged to provide alternative treatments for many diseases, with glioblastoma being among them. In this article, our goal is to shed light on the pathogenesis of glioma and summarize the proposed treatment approaches in the last decade, highlighting how combining repositioned drugs and nanocarriers technology can reduce drug resistance and improve therapeutic efficacy in primary glioma.