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Simple Summary: Advances in molecular techniques have significantly improved our understanding of glioblastoma in recent decades. Here, we describe the genetic mutations important in the pathogenesis, diagnosis, prognosis, and treatment of glioblastoma. We then describe novel diagnostic tools that allow for faster and less invasive diagnosis as well as monitoring of treatment response and disease recurrence. This summary will serve as a reference for the current state-of-the-art and future directions for glioblastoma treatment. Glioblastoma is the most common primary brain tumor in adult patients, and despite standard-of-care treatment, median survival has remained less than two years. Advances in our understanding of molecular mutations have led to changes in the diagnostic criteria of glioblastoma, with the WHO classification integrating important mutations into the grading system in 2021. We sought to review the basics of the important genetic mutations associated with glioblastoma, including known mechanisms and roles in disease pathogenesis/treatment. We also examined new advances in image processing as well as less invasive and noninvasive diagnostic tools that can aid in the diagnosis and surveillance of those undergoing treatment for glioblastoma. Our review is intended to serve as an overview of the current state-of-the-art in the diagnosis and management of glioblastoma. [ABSTRACT FROM AUTHOR]

Background: NADPH oxidase 4 (NOX4) plays an important role in metabolic reprogramming, epithelial-mesenchymal transition (EMT), and other cellular processes by strictly regulating intracellular ROS generation. However, there is a lack of analysis on the role of NOX4 in the tumor immune microenvironment and predictive value for prognosis and immunotherapy response in various tumor types., Methods: This study used data from the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), Tumor Immune Single-cell Hub (TISCH), Genotype-Tissue Expression (GTEx), cBioPortal, Tumor Immune Estimation Resource (TIMER 2.0), and ROC Plotter databases to analyze the expression, prognosis, biological function, immune cell infiltration, and genetic and epigenetic changes of NOX4 in various tumor types. Meanwhile, in vitro experiments were conducted to verify the role of NOX4 in the migration, invasion, proliferation, and apoptosis of glioblastoma (GBM)., Results: The findings indicated that NOX4 is upregulated in various types of cancer, accompanied by gene amplification, mutation, and deletion. The high expression of NOX4 is associated with poor prognosis in various cancers. Functional enrichment analysis showed that NOX4 is mainly enriched in immune and cancer progression pathways, such as angiogenesis, EMT, interferon response, inflammatory response. Immune cell infiltration analysis showed that high expression of NOX4 is associated with increased infiltration of cancer-associated fibroblasts (CAF) and macrophages. In vitro experiments showed that silencing NOX4 inhibits the proliferation, migration, and invasion of GBM and increases cell apoptosis., Conclusion: NOX4 can serve as a prognostic and immunotherapy response biomarker for various cancers and targeting NOX4 may be a feasible anti-tumor therapy and may have synergistic anti-tumor effects combined with immunotherapy., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We aimed to build a robust classifier for the MGMT methylation status of glioblastoma in multiparametric MRI. We focused on multi-habitat deep image descriptors as our basic focus. A subset of the BRATS 2021 MGMT methylation dataset containing both MGMT class labels and segmentation masks was used. A comprehensive mask fusion approach was developed to select relevant image crops of diseased tissue. These fusion masks, which were guided by multiple sequences, helped collect information from the regions that seem disease-free to radiologists in standard MRI sequences while harboring pathology. Integrating the information in different MRI sequences and leveraging the high entropic capacity of deep neural networks, we built a 3D ROI-based custom CNN classifier for the automatic prediction of MGMT methylation status of glioblastoma in multi-parametric MRI. Single sequence-based classifiers reached intermediate predictive performance with 0.65, 0.71, 0.77, and 0.82 accuracy for T1W, T2W, T1 contrast-enhanced, and FLAIR sequences, respectively. The multiparametric classifier using T1 contrast-enhanced and FLAIR images reached 0.88 accuracy. The accuracy of the four-input model that used all sequences was 0.81. The best model reached 0.90 ROC AUC value. Integrating human knowledge in the form of relevant target selection was a useful approach in MGMT methylation status prediction in MRI. Exploration of means to integrate radiology knowledge into the models and achieve human-machine collaboration may help to develop better models. MGMT methylation status of glioblastoma is an important prognostic marker and is also important for treatment decisions. The preoperative non-invasive predictive ability and the explanation tools of the developed model may help clinicians to better understand imaging phenotypes of MGMT methylation status of glial tumors., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Cell therapies, including tumor antigen-loaded dendritic cells used as therapeutic cancer vaccines, offer treatment options for patients with malignancies. We evaluated the feasibility, safety, immunogenicity, and clinical activity of adjuvant vaccination with Wilms' tumor protein (WT1) mRNA-electroporated autologous dendritic cells (WT1-mRNA/DC) in a single-arm phase I/II clinical study of patients with advanced solid tumors receiving standard therapy. Disease status and immune reactivity were evaluated after 8 weeks and 6 months. WT1-mRNA/DC vaccination was feasible in all patients, except one. Vaccination was well tolerated without evidence of systemic toxicity. The disease control rate and overall response rate among a total of 39 evaluable patients were 74.4% and 12.8%, respectively. Median overall survival (OS) was 43.7 months among 13 patients with glioblastoma multiforme, 41.9 months among 12 patients with metastatic breast cancer, and 48.8 months among 10 patients with malignant pleural mesothelioma, comparing favourably with historical controls reported in the literature. OS was longer in patients with stable disease at 8 weeks and disease control at 6 months versus patients without disease control at either time point. Disease control and higher OS were associated with antigen-specific type 1 CD4 + and/or CD8 + T-lymphocyte responses, mainly induced by WT1-mRNA/DC vaccination. Antigen-nonspecific type 2 CD8 + T-cell responses were common before WT1-mRNA/DC vaccination but did not show any association with clinical outcome. Collectively, these data indicate that WT1-mRNA/DC vaccination is feasible, safe, and immunogenic and shows clinical activity in patients with advanced solid tumors, suggesting that it has the potential to help improve their survival., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of the Antwerp University Hospital/University of Antwerp (EC 10/40/266) and the Belgian Federal Agency for Medicines and Health Products (FAGG 08 − 0005) and registered at ClinicalTrials.gov (NCT01291420) and EudraCT (2011-000547-24). The sponsor’s protocol code was CCRG 11 − 001. All participants provided informed written consent in accordance with the principles of the Declaration of Helsinki. Consent for publication: Not applicable. Competing interests: VFVT and ZNB are coinventors of a now-elapsed patent covering the messenger RNA electroporation technique (Improved Transfection of Eukaryotic Cells with Linear Polynucleotides by Electroporation, WO/2003/000907)., (© 2025. The Author(s).)

Glioblastoma (GBM) is the most malignant type of glioma with a very poor prognosis. N6-methyladenosine (m6A) is well-documented to be involved in GBM progression, and FTO is a demethylase. GSTO1 is also associated with tumor progression. This study aimed to investigate the impact of FTO and GSTO1 on GBM progression and the regulation of FTO on m6A modification of GSTO1. T98G cell phenotypes including proliferation and apoptosis were analyzed by cell counting kit 8, colony formation assay, and flow cytometry. The regulation of m6A methylation mediated by FTO was evaluated by methylated RNA immunoprecipitation, RNA immunoprecipitation, and dual-luciferase reporter assay. The results showed that FTO expression was downregulated in GBM. Overexpression of FTO inhibited cell proliferation and facilitated apoptosis in vitro. Additionally, GSTO1 expression was elevated in GBM, and knockdown of GSTO1 suppressed cell proliferation and promoted apoptosis and oxidative stress. Moreover, FTO inhibited m6A methylation of GSTO1 and reduced the stability of GSTO1. Overexpression of GSTO1 abrogated T98G cellular processes mediated by FTO. The in vivo experiments showed that FTO inhibited tumor growth by downregulating GSTO1 expression. In conclusion, FTO decelerates GBM progression by inducing apoptosis through suppressing m6A methylation of GSTO1., Competing Interests: Declarations. Ethics Approval and Consent to Participate: The Ethics Committee of Chun’an First People’s Hospital approved the implementation of this study.All patients provided written informed consent. All operating processes were performed in line with the principles of the Declaration of Helsinki. All animal experiments should comply with the ARRIVE guidelines. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Primary brain tumors that were the most severe and aggressive were called glioblastoma multiforme (GBM). Cancers are caused in part by aberrant expression of circular RNA. Often referred to as competitive endogenous RNA (ceRNA), circRNA molecules act as "miRNA sponges" in cells by decreasing the inhibitory impact of miRNA on their target genes and hence raising the expression levels of those genes. circRNA molecules are rich in miRNA binding sites. The discovery of more structurally diverse and GBM-related circRNAs has great promise for the use of GMB prognostic biomarkers and therapeutic targets, as well as for comprehending the molecular regulatory mechanisms of GBM. In this work, we present an overview of the circRNA expression patterns associated with GBM and offer a potential integrated electrochemical strategy for detecting circRNA with extreme sensitivity in the diagnosis of glioblastoma., Competing Interests: Declarations. Ethics Approval: Not applicable (this is a review paper). Consent for Publication: Not applicable (this is a review paper). Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

CRISPR/Cas9 (CRISPR, clustered regularly interspaced short palindromic repeats) gene editing technology represents great promise for treating glioblastoma (GBM) due to its potential to permanently eliminate tumor pathogenic genes. Unfortunately, delivering CRISPR to the GBM in a safe and effective manner is challenging. Herein, a glycosylated and cascade-responsive nanoparticle (GCNP) that can effectively cross the blood-brain barrier (BBB) and activate CRISPR/Cas9-based gene editing only in the GBM is designed. The GCNP possesses a cationic polyplex core and a glycosylated polymer layer that is capable of cascading response to low pH and high GSH concentration, so that the release of CRISPR/Cas9 only takes place after crossing the BBB and entering the GBM where the acidic tumor microenvironment and high concentration of glutathione (GSH) are present. By targeting the programmed death-ligand 1 (PD-L1) in GBM, GCNP effectively inhibited the tumor growth and greatly prolonged the survival time of GBM-bearing mice when combined with temozolomide (TMZ).

Glioblastoma (GBM), the most malignant primary brain tumor in adults, has poor prognosis irrespective of therapeutic advances due to its radio-resistance and infiltrative growth into brain tissue. The present study assessed functions and putative druggability of BRCA1-associated ATM activator 1 (BRAT1) as a crucial factor driving key aspects of GBM, including enhanced DNA damage response and tumor migration. By a stable depletion of BRAT1 in GBM and glioma stem-like (GSC) cell lines, we observed a delay in DNA double-strand break repair and increased sensitivity to radiation treatment, corroborated by in vitro and in vivo studies demonstrating impaired tumor growth and invasion. Proteomic and phosphoproteomic analyses further emphasize the role of BRAT1's cell migration and invasion capacity, with a notable proportion of downregulated proteins associated with these processes. In line with the genetic manipulation, we found that treatment with the BRAT1 inhibitor Curcusone D (CurD) significantly reduced GSC migration and invasion in an ex vivo slice culture model, particularly when combined with irradiation, resulting in a synergistic inhibition of tumor growth and infiltration. Our results reveal that BRAT1 contributes to GBM growth and invasion and suggest that therapeutic inhibition of BRAT1 with CurD or similar compounds might constitute a novel approach for anti-GBM directed treatments., Competing Interests: Declarations. Ethical approval: All animal procedures were conducted in accordance with a valid approval (FK-1116) by the Regierungspräsidium Darmstadt. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s).)

Background: Glioblastoma multiforme (GBM) is characterized by its cellular complexity, with a microenvironment consisting of diverse cell types, including oligodendrocyte precursor cells (OPCs) and neoplastic CD133 + radial glia-like cells. This study focuses on exploring the distinct cellular transitions in GBM, emphasizing the role of alternative polyadenylation (APA) in modulating microRNA-binding and post-transcriptional regulation., Results: Our research identified unique APA profiles that signify the transitional phases between neoplastic cells and OPCs, underscoring the importance of APA in cellular identity and transformation in GBM. A significant finding was the disconnection between differential APA events and gene expression alterations, indicating that APA operates as an independent regulatory mechanism. We also highlighted the specific genes in neoplastic cells and OPCs that lose microRNA-binding sites due to APA, which are crucial for maintaining stem cell characteristics and DNA repair, respectively. The constructed networks of microRNA-transcription factor-target genes provide insights into the cellular mechanisms influencing cancer cell survival and therapeutic resistance., Conclusions: This study elucidates the APA-driven regulatory framework within GBM, spotlighting its influence on cell state transitions and microRNA network dynamics. Our comprehensive analysis using single-cell RNA sequencing data to investigate the microRNA-binding sites altered by APA profiles offers a robust foundation for future research, presenting a novel approach to understanding and potentially targeting the complex molecular interplay in GBM., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors read and approved the final manuscript. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Almost all high-grade gliomas, particularly glioblastoma (GBM), are highly migratory and aggressive. Migrasomes are organelles produced by highly migratory cells capable of mediating intercellular communication. Thus, GBM cells may produce migrasomes during migration. However, it remains unclear whether migrasomes can influence GBM migration and invasion. In this study, we observed the presence and formation of migrasomes in GBM cells. We found that expression levels of key migrasome formation factor, tetraspanin 4 (TSPAN4), correlated positively with pathological grade and poor prognosis of GBM based on the databases and clinical samples analysis. Subsequently, we knocked down TSPAN4 and found that GBM cell migration and invasion were significantly inhibited due to the reduced formation of migrasomes. We further confirmed that migrasomes are enriched in extracellular matrix (ECM)-related proteins such as p21-activating kinase 4 (PAK4) and laminin alpha 4 (LAMA4). Our experimental results suggest that migrasomes promote GBM cells migration by releasing such proteins into the extracellular space. Overall, we identified migrasomes in GBM and the molecular mechanisms by which they regulate them, providing potential targets for treating GBM., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Glioblastoma (GBM) is highly malignant and grows rapidly, and there is currently a lack of effective treatments. Metabolism provides the basis for the occurrence and development of GBM. Pyruvate dehydrogenase A1 (PDHA1) is a key component in both the tricarboxylic acid cycle and glycolysis, playing an important role in the metabolic processes related to cancer, but its role in GBM remains unclear. Glioma associated mesenchymal stem cells (GaMSC) play a significant role in the development of glioma. This study aims to explore the relationship between GaMSC derived exosomes (GAMSC-EXO) and PDHA1, as well as the effects and mechanisms on GBM glucose metabolism. In this study, human GaMSC-derived exosomes were isolated and identified. The role of GAMSC-EXO in GBM proliferation, migration, invasion and glucose metabolism was investigated. The upstream miRNA of PDHA1 was predicted and the relationship between miR-21-5p and PDHA1 in GAMSC-EXO and its effect on GBM glucose metabolism was investigated. We found that GAMSCs promote GBM cell proliferation, migration, invasion and glycolysis by releasing exosomes. After inhibiting GBM glycolysis, GBM proliferation, migration and invasion abilities were weakened. MiR-21-5p in exosomes was identified as the miRNA that affects the above biological behaviors. Mechanismly, miR-21-5p directly binds to the mRNA of PDHA1 and downregulates its transcription, thereby promoting GBM glycolysis. Together, this study demonstrated that exosomal miR-21-5p from GAMSC promoted GBM proliferation, migration, invasion, and glycolysis by targeting PDHA1, which provided novel insights into the metabolic interactions between GAMSCs and GBM cells, emphasizing the importance of exosome-mediated communication in tumor progression., Competing Interests: Declarations. Ethics approval and consent: All animal protocols were conducted in accordance with the guidelines for the care and utilization of laboratory animals and the authorization (IACUC: S2448) from the Experimental Animals Centre of Tongji Medical College, Huazhong University of Science and Technology. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth., Methods: V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels., Results: Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes., Conclusions: V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by a local Ethic Committee (IRB#275/2013) and all patients signed an informed consent. Animal experiments were carried out in compliance with the institutional guidelines for the care and use of experimental animals (European Directive 2010/63/UE and the Italian law 26/2014), authorized by the Italian Ministry of Health and approved by the Animal Use and Care Committee of the University of Milan. Consent for publication: Not applicable. Competing interests: The Authors declare no potential conflicts of interest to disclose., (© 2025. The Author(s).)

The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase-wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.

Hypoxia is a common feature of glioblastoma (GBM). Circular RNAs (circRNAs) are identified as regulators in cancers. However, the role of circRNAs in GBM remains elusive. Here, circPLOD2a and circPLOD2b, spliced from the same parental gene PLOD2, are identified as hypoxia-responsive circRNAs. Overexpression of circPLOD2a and b enhance while knockdown inhibit GBM cell aggressiveness. The protein partners and downstream molecules were investigated by RNA-pulldown, mass spectrometry and RNA-seq. Mechanistically, HIF1α induces the expression of circPLOD2a and b, which competitively bind to HuR, causing a degradation of XIRP1 in vitro and in vivo. Clinical data demonstrate circPLOD2a and b are highly expressed in GBM negatively correlated with XIRP1, whose lower expression associates with higher glioma grade and worse prognosis. In conclusion, hypoxia-induced circPLOD2a and b are oncogenic regulators of tumour aggressiveness through attenuating the interaction between HuR and XIRP1 in glioblastoma cells and may be potential therapeutic targets for this disease., Competing Interests: Competing interests: The authors declare no competing interests. Ethics statement: The animal study was performed after receiving approval from the Institutional Animal Care and Use Committee of Hubei University of Medicine (approval number: 2023008). Informed consents were obtained from GBM patients for sample collection, and the study was approved by the Ethics Committee of Shiyan Taihe Hospital (approval number: 2023KS11)., (© 2025. The Author(s).)

Glioblastoma multiforme (GBM) is a devastating, aggressive primary brain tumor with poor patient outcomes and a five-year survival of less than 10%. Significant limitations to effective GBM treatment include poor drug delivery across the blood-brain barrier, drug resistance, and complex genetic tumor alterations. Gene therapy uses a mechanism different from other GBM therapies to reduce tumor growth and enhance antitumor immunity. This review article will provide an update on various viral and nonviral vectors, their DNA and RNA cargoes, and how they genetically modify tumor cells and evoke therapeutic responses to GBM. The article explores the oncolytic and immunogenic effects of gene therapy agents. It reviews promising DNA transgenes, RNA inhibitors, and vectors for anti-GBM therapy. The possible benefits of combining gene therapy with standard GBM treatments will also be covered.

Glioblastoma is the deadliest primary brain tumor, largely due to inevitable recurrence of the disease after treatment. While most recurrences are local, patients rarely present with a new discontiguous focus of glioblastoma. Little is currently known about the genetic profile of discontiguous recurrences. In our institutional database, we identified 22 patients with targeted exome sequencing of pairs of initial and recurrent IDH-wildtype glioblastoma. Recurrences were classified as contiguous or discontiguous based on the presence or absence of T2 FLAIR signal connection to the initial site of disease on MRI. Exome analysis revealed shared driver and passenger mutations between discontiguous recurrences and initial tumors, supporting a common origin. Discontiguous recurrences were more likely to be hypermutated compared to contiguous recurrences (p = 0.038). Analysis of 2 glioblastoma cases with discontiguous recurrence at a collaborating institution also exhibited hypermutation. In conclusion, discontiguous glioblastoma recurrences share a common origin with the initial tumor and are more likely to be hypermutated than contiguous recurrences., Competing Interests: Declarations. Ethics approval and consent to participate: Patients provided informed consent for research under an IRB approved protocol. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Long non-coding RNAs (lncRNAs) play a pivotal role in regulating gene expression and are critically involved in the progression of malignant brain tumors, including glioblastoma, medulloblastoma, and meningioma. These lncRNAs interact with microRNAs (miRNAs), proteins, and DNA, influencing key processes such as cell proliferation, migration, and invasion. This review highlights the multifaceted impact of lncRNA dysregulation on tumor progression and underscores their potential as therapeutic targets to enhance the efficacy of chemotherapy, radiotherapy, and immunotherapy. The insights provided offer new directions for advancing basic research and clinical applications in malignant brain tumors.

Glioblastoma multiforme (GBM) is the most malignant and common form of brain cancer in adults. The molecular mechanisms underlying GBM progression and resistance are complex and poorly understood. Circular RNAs (circRNAs) are a new class of non-coding RNAsformed by covalently closed loopstructures with no free ends. Their circular structure makes them more stable than linear RNA and resistant to exonuclease degradation. In recent years, they have received significant attention due to their diverse functions in gene regulation and their association with various diseases, including cancer. Therefore, understanding the functions and applications of circRNAs is critical to developing targeted therapeutic interventions and advancing the field of glioblastoma cancer research. In this review, we summarized the main functions of circRNAs and their potential applications in the diagnosis, prognosis and targeted therapy of GBM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Tumor treating fields (TTFields) use low-intensity, alternating electric fields to exert antitumor activity and have demonstrated efficacy against multiple cancers, including glioblastoma (GBM). Unfortunately, cancer cells inevitably develop resistance to TTFields, highlighting the need to elucidate the underlying mechanisms to develop approaches to induce durable responses. Using a gene network-based machine learning algorithm, we interrogated TTFields-resistant GBM cells and uncovered a regulatory axis anchored by the prostaglandin E2 receptor 3 (EP3) and the transcription factor zinc finger 488 (ZNF488). Mechanistically, TTFields induced EP3 upregulation and nuclear envelope localization, where it formed a complex with ZNF488 to induce resistance to TTFields by promoting self-renewal of glioma stem-like cells (GSC). Overexpression of EP3 and/or ZNF488 in TTFields-sensitive GSC conferred resistance and enhanced self-renewal, whereas expression of noninteracting mutants of these proteins abrogated the formation of the nuclear complex and prevented resistance. Inhibition of either partner in this protein complex in resistant GSC, including those freshly isolated from TTFields-resistant GBM tumors, resensitized cells to the cytotoxic effects of TTFields, concomitant with reduced self-renewal and in vivo tumorigenicity. Importantly, inhibition of EP3 in TTFields-sensitive GSC preemptively halted the development of resistance. The EP3-ZNF488 axis was significantly upregulated in TTFields-resistant GBM tumors, and coexpression of EP3 and ZNF488 in other cancers correlated with lower survival rates. Collectively, these results indicate that the nuclear EP3-ZNF488 axis is necessary and sufficient to establish TTFields resistance, underscoring the potential to target this axis to prevent or reverse resistance in GBM and possibly other cancers. Significance: The EP3-ZNF488 master regulatory axis in cancer stem-like cells drives resistance to treatments like tumor treating fields, opening avenues for developing strategies to enhance therapeutic efficacy., (©2024 American Association for Cancer Research.)

Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), while glutamine and tryptophan metabolism further contribute to the aggressive phenotype of GBM. These metabolic alterations impair immune cell function, leading to exhaustion and stress in CD8+ and CD4+ T cells while favoring immunosuppressive populations such as regulatory T cells (Tregs) and M2-like macrophages. Recent studies emphasize the role of slow-cycling GBM cells (SCCs), lipid-laden macrophages, and tumor-associated astrocytes (TAAs) in reshaping GBM's metabolic landscape and reinforcing immune evasion. Genetic mutations, including Isocitrate Dehydrogenase ( IDH ) mutations, Epidermal Growth Factor Receptor ( EGFR ) amplification, and Phosphotase and Tensin Homolog ( PTEN ) loss, further drive metabolic reprogramming and offer potential targets for therapy. Understanding the relationship between GBM metabolism and immune suppression is critical for overcoming therapeutic resistance. This review focuses on the role of metabolic rewiring in GBM, its impact on the immune microenvironment, and the potential of combining metabolic targeting with immunotherapy to improve clinical outcomes for GBM patients.

Glioblastoma multiforme (GBM) is the most prevalent, treatment-resistant, and fatal form of brain malignancy. It is characterized by genetic heterogeneity, and an infiltrative nature, and GBM treatment is highly challenging. Despite multimodal therapies, clinicians lack efficient prognostic and predictive markers. Therefore, new insights into GBM management are urgently needed to increase the chance of therapeutic success. Circulating miRNAs (miRs) are important regulators of cancer progression and are potentially useful for GBM diagnosis and treatment. This study investigated how miR-29a, miR-106a, and miR-200a affect the prognosis of GBM patients. This study was conducted on 25 GBM patients and 20 healthy volunteers as a control group. The expression levels of target miRs were analyzed pre- and post-treatment using qRT-PCR and evaluated in relation to both clinical GBM criteria and the patient's survival modes. The diagnostic efficacy of target miRs was assessed using the receiver operating characteristic (ROC) curve. MiRs levels showed significant differences among the enrolled participants. All investigated miRs were significantly elevated in GBM patients with non-frontal lesions. Only miR-200a showed a significant difference in GBM patients older than 60 years with a tumor size ≥ 5 mm. Regarding miR-106a, a significant difference was detected based on the surgical strategy and use of an Eastern Cooperative Oncology Group (ECOG) performance status equal to 2. For miR-29a, a significant upregulation was detected according to the surgical strategy. All post-treatment miRs levels in GBM patients were significantly downregulated. In conclusion, circulating miRs revealed a significant role in predicting GBM patient treatment outcomes providing valuable insights for personalized therapeutic strategies., Competing Interests: Declarations. Ethical approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki Guidelines. Approval was granted by the Research Ethics Committee (REC), Faculty of Medicine, Ain Shams University (Approval No. FWA 000017585). Written informed consent was obtained from all individual participants included in the study. Consent for publication: The authors affirm that human research participants provided informed consent for publication. All authors have read the manuscript in its final form and approved the publication. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The association of necrosis in tumors with poor prognosis implies a potential tumor-promoting role. However, the mechanisms underlying cell death in this context and how damaged tissue contributes to tumor progression remain unclear. Here, we identified p38 mitogen-activated protein kinases (p38 MAPK, a.k.a. p38) as a key player in promoting cell death and the inflammatory response to ischemic stress associated with necrotic tumors. We found that glioblastoma (GBM) cells expressing patient-derived Kirsten rat sarcoma (KRAS) or phosphoinositide-3-kinase (PI3K) active mutants showed enhanced cell death under ischemia-mimetic conditions in vitro and were more likely to develop into necrotic tumors in vivo. Cell death in both settings depended on p38, which is also required for tumor progression driven by KRAS or PI3K. Under ischemia-mimetic conditions, GBM cells undergo reactive oxygen species (ROS)-dependent cell death. Gene expression in these cells recapitulated multiple features observed in peri-necrotic tumors from patient GBM. Further studies showed the involvement of a positive feedback loop between the p38-MAPK-activated protein kinase 2 (MAPKAPK2, a.k.a. MK2) signaling axis and the unfolded protein response signaling components activating transcription factor 4 (ATF4) and inositol-requiring enzyme 1 (IRE1α) in driving ischemic tumor cell death. This signaling cascade was further potentiated by RAS or PI3K activation under ischemic conditions, contributing to the inflammatory gene expression response. Therefore, our study suggests that p38 could be targeted to relieve the inflammatory response in necrotic tumors and inhibit GBM progression., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Glioblastoma is a highly aggressive primary brain tumor with glioblastoma stem cells (GSCs) enforcing the intra-tumoral hierarchy. Plasma cells (PCs) are critical effectors of the B-lineage immune system, but their roles in glioblastoma remain largely unexplored. Here, we leverage single-cell RNA and B cell receptor sequencing of tumor-infiltrating B-lineage cells and reveal that PCs are aberrantly enriched in the glioblastoma-infiltrating B-lineage population, experience low level of somatic hypermutation, and are associated with poor prognosis. PCs secrete immunoglobulin G (IgG), which stimulates GSC proliferation via the IgG-FcγRIIA-AKT-mTOR axis. Disruption of IgG-FcγRIIA paracrine communication inhibits GSC proliferation and self-renewal. Glioblastoma-infiltrating PCs are recruited to GSC niches via CCL2-CCR2 chemokine program. GSCs further derive pro-proliferative signals from broadly utilized monoclonal antibody-based immune checkpoint inhibitors via FcγRIIA signaling. Our data generate an atlas of B-lineage cells in glioblastoma with a framework for combinatorial targeting of both tumor cell-intrinsic and microenvironmental dependencies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a poor prognosis despite aggressive therapy. Here, we hypothesized that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We find daily glucocorticoids promote or suppress GBM growth through glucocorticoid receptor (GR) signaling depending on time of day and the clock genes, Bmal1 and Cry. Blocking circadian signals, like vasoactive intestinal peptide or glucocorticoids, dramatically slows GBM growth and disease progression. Analysis of human GBM samples from The Cancer Genome Atlas (TCGA) shows that high GR expression significantly increases hazard of mortality. Finally, mouse and human GBM models have intrinsic circadian rhythms in clock gene expression in vitro and in vivo that entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We conclude that GBM entrains to the circadian circuit of the brain, modulating its growth through clock-controlled cues, like glucocorticoids., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The goal of the study was to spatially validate intratumoral subregions (tumor habitat) using physiologic magnetic resonance imaging (MRI) on the pathology of the isocitrate dehydrogenase (IDH)-wild-type whole-glioblastoma sample., Methods: Data from 20 patients (168 slides) were obtained from the Ivy Glioblastoma Atlas Project. On MRI, tumor habitats were defined using voxel-wise clustering of the apparent diffusion coefficient and cerebral blood volume maps for contrast-enhancing lesions (CEL) and non-enhancing lesions (NEL). On pathology slides, normalized areas of leading-edge, infiltrating tumor (IT), cellular tumor (CT), hypervascular lesion (CThypervascular), and perinecrotic lesion (CTperinecrotic) were obtained. Gross specimen was coregistered on MRI and correlation between pathology-MRI habitats was calculated. RNA sequencing of 67 samples was assessed using 4 Neftel subtypes and further correlated with pathology., Results: Six tumor habitats were identified: hypervascular, hypovascular cellular, and hypovascular hypocellular habitats for CEL and NEL. CT was correlated with hypovascular cellular habitat in CEL (r = 0.238, P = .005). IT was correlated with hypovascular cellular habitat in NEL (r = 0.294, P = .017). CThypervascular was correlated with hypervascular habitat in NEL (r = 0.195, P = .023). CTperinecrotic was correlated with imaging necrosis (r = 0.199, P = .005). Astrocyte-like subtypes were correlated with IT (r = 0.256, P < .001), while mesenchymal-like subtypes were correlated with CTperinecrotic area (r = 0.246, P < .001)., Conclusions: Pathologically matched tumor subregions were CT with hypovascular cellular habitat in CEL and infiltrative tumor with hypovascular cellular habitat in NEL. Identification of the most aggressive, as well as infiltrative tumor portion, can be achieved using noninvasive MRI tumor habitats., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Temozolomide kills cancer cells by forming O6-methylguanine (O6-MeG), which leads to cell cycle arrest and apoptosis. However, O6-MeG repair by O6-methylguanine-DNA methyltransferase (MGMT) contributes to drug resistance. Characterizing genomic profiles of O6-MeG could elucidate how O6-MeG accumulation is influenced by repair, but there are no methods to map genomic locations of O6-MeG. Here, we developed an immunoprecipitation- and polymerase-stalling-based method, termed O6-MeG-seq, to locate O6-MeG across the whole genome at single-nucleotide resolution. We analyzed O6-MeG formation and repair across sequence contexts and functional genomic regions in relation to MGMT expression in a glioblastoma-derived cell line. O6-MeG signatures were highly similar to mutational signatures from patients previously treated with temozolomide. Furthermore, MGMT did not preferentially repair O6-MeG with respect to sequence context, chromatin state or gene expression level, however, may protect oncogenes from mutations. Finally, we found an MGMT-independent strand bias in O6-MeG accumulation in highly expressed genes. These data provide high resolution insight on how O6-MeG formation and repair are impacted by genome structure and nucleotide sequence. Further, O6-MeG-seq is expected to enable future studies of DNA modification signatures as diagnostic markers for addressing drug resistance and preventing secondary cancers., (© The Author(s) 2025. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The presence of specific genetic mutations in patients with glioblastoma multiforme (GBM) is associated with improved survival outcomes. Disruption of the DNA damage response (DDR) pathway in tumor cells enhances the effectiveness of radiotherapy drugs, while increased mutational burden following tumor cell damage also facilitates the efficacy of immunotherapy. The ATRX gene, located on chromosome X, plays a crucial role in DDR. The aim of this research is to elucidate the correlation between ATRX mutations and GBM. Dataset obtained from TCGA-GBM were conducted an analysis on the genomic features, biological characteristics, immunopathological markers, and clinical prognosis of patients carrying ATRX mutations. Our findings revealed a significantly elevated level of microsatellite instability in individuals with ATRX mutants, along with significant alterations in the receptor-tyrosine kinase (RTK)-ras pathway among patients exhibiting combined ATRX mutations. TCGA-GBM patients with concurrent ATRX mutations exhibited sensitivity to 26 chemotherapeutic and anticancer drugs, which exerted their effects by modulating the DDR of tumor cells through highly correlated mechanisms involving the RTK-ras pathway. Additionally, we observed an enrichment of ATRX mutations in specific pathways associated with DDR among TCGA-GBM patients. Our model also demonstrated prolonged overall survival in patients carrying ATRX mutations, particularly showing strong predictive value for 3- and 5-year survival rates. Furthermore, additional protective factors such as younger age, female gender, combined IDH mutations, and TP53 mutations were identified. The results underscore the protective role and prognostic significance of ATRX mutations in GBM as a potential therapeutic target and biomarker for patient survival., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

Glioblastoma (GBM), the most prevalent primary malignant brain tumor, remains challenging to treat due to extensive inter- and intra-tumor heterogeneity. This variability demands combination treatments to improve therapeutic outcomes. A significant obstacle in treating GBM is the expression of O 6 -methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. This underscores the need for novel, more targeted therapies. Our study investigates the metabolic-epigenetic impact of combining SN-38, a novel topoisomerase inhibitor inducing DNA double-strand breaks, with rabusertib, a checkpoint kinase 1 inhibitor. We identified this synergistic combination through high-throughput drug screening across a panel of GBM cell lines using a cancer drug library combined with SN-38. A secondary metabolic screening with the PEDS algorithm demonstrated a synergistic modulation of purine, one-carbon, and redox metabolism. Furthermore, the combined treatment led to the significant depletion of epigenetically relevant metabolites such as 5-methyl-cytosine, acetyl-lysine, and trimethyl-lysine. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O 6 -methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by its ability to evade the immune system, hindering the efficacy of current immunotherapies. Recent research has highlighted the important role of immunosuppressive macrophages in the tumor microenvironment (TME) in driving this immune evasion. In this study, we are the first to identify THEMIS2 as a key regulator of tumor-associated macrophage (TAM)-mediated immunosuppression in GBM. We found that a high THEMIS2 expression is associated with poor patient outcomes and increased infiltration of immune cells, particularly macrophages. Functional analyses revealed THEMIS2 's critical involvement in immune-related pathways, including immune response activation, mononuclear cell differentiation, and the positive regulation of cytokine production. Additionally, single-cell RNA sequencing data demonstrated that macrophages with a high THEMIS2 expression were associated with increased phagocytosis, immune suppression, and enhanced tumor growth. These findings suggest that THEMIS2 could serve as both a prognostic marker and a therapeutic target for enhancing anti-tumor immunity in GBM.

Background: Glioblastoma (GBM) is a rare brain cancer with an exceptionally high mortality rate, which illustrates the pressing demand for more effective therapeutic options. Despite considerable research efforts on GBM, its underlying biological mechanisms remain unclear. Furthermore, none of the United States Food and Drug Administration (FDA) approved drugs used for GBM deliver satisfactory survival improvement., Methods: This study presents a novel computational pipeline by utilizing gene expression data analysis for GBM for drug repurposing to address the challenges in rare disease drug development, particularly focusing on GBM. The GBM Gene Expression Profile (GGEP) was constructed with multi-omics data to identify drugs with reversal gene expression to GGEP from the Integrated Network-Based Cellular Signatures (iLINCS) database., Results: We prioritized the candidates via hierarchical clustering of their expression signatures and quantification of their reversal strength by calculating two self-defined indices based on the GGEP genes' log2 foldchange (LFC) that the drug candidates could induce. Among five prioritized candidates, in-vitro experiments validated Clofarabine and Ciclopirox as highly efficacious in selectively targeting GBM cancer cells., Conclusions: The success of this study illustrated a promising avenue for accelerating drug development by uncovering underlying gene expression effect between drugs and diseases, which can be extended to other rare diseases and non-rare diseases., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors consent to the publication of this manuscript. Competing interests: The authors declare no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Extensive neovascularization is a hallmark of glioblastoma (GBM). In addition to supplying oxygen and nutrients, vascular endothelial cells provide trophic support to GBM cells via paracrine signaling. Here we report that Endocan (ESM1), an endothelial-secreted proteoglycan, confers enhanced proliferative, migratory, and angiogenic properties to GBM cells and regulates their spatial identity. Mechanistically, Endocan exerts at least part of its functions via direct binding and activation of the PDGFRA receptor. Subsequent downstream signaling enhances chromatin accessibility of the Myc promoter and upregulates Myc expression inducing stable phenotypic changes in GBM cells. Furthermore, Endocan confers radioprotection on GBM cells in vitro and in vivo. Inhibition of Endocan-PDGFRA signaling with ponatinib increases survival in the Esm1 wild-type but not in the Esm1 knock-out mouse GBM model. Our findings identify Endocan and its downstream signaling axis as a potential target to subdue GBM recurrence and highlight the importance of vascular-tumor interactions for GBM development., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Glioblastoma (GBM) is the most common malignant brain tumor, and has a low survival rate and a poor prognosis. Intensive studies of pathogenic mechanisms are essential for exploring therapeutic targets for GBM. In this study, the roles played by interferon-stimulated gene 15 (ISG15), HECT, RCC1-containing protein 5 (HERC5), and SERPINE1 mRNA binding protein 1 (SERBP1) in regulating GBM cell stemness were investigated. The real-time quantitative polymerase chain reaction (qPCR), western blotting (WB), and immunohistochemistry (IHC) were used to determine the expression levels of HERC5, ISG15, and SERBP1. Cell stemness was analyzed using a cell sphere formation assay. Colony formation and cell counting kit-8 (CCK-8) assays were performed to assess cell proliferation, Transwell assays used to evaluate cell migration and invasion, and flow cytometry was used to assess cell apoptosis after treatment with temozolomide. SERBP1 stability was assessed by a CHX chase assay. A co-immunoprecipitation (Co-IP) assay verified the binding of ISG15 and HERC5 onto SERBP1. Our results showed that HERC5 and ISG15 were highly expressed in GBM. HERC5 and ISG15 promoted the cell stemness of GBM, and increased cell proliferation, sphere formation, migration, invasion, and chemoresistance. Moreover, HERC5 and ISG15 played a synergistic role in promoting the cell stemness of GBM. We also found that HERC5/ISG15 promoted the stability of SERBP1, which also promoted the cell stemness of GBM. The tumor-promoting role of HERC5 and ISG15 was also confirmed in a subcutaneous xenograft tumor model. Collectively, HERC5/ISG15 was found to regulate GBM stemness and tumor progression by mediating SERBP1 protein stability. Our present study suggests a promising therapeutic target for GBM., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical Approval: All the patients have signed informed consent. This study was approved by the Ethical Committee of Henan Provincial People’s Hospital (No. 2020-107)., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glioblastoma (GBM) is the most common intracranial malignancy, but current treatment options are limited. Super-enhancers (SEs) have been found to drive the expression of key oncogenes in GBM. However, the role of SE-associated long non-coding RNAs (lncRNAs) in GBM remains poorly understood. Here, we screened for an up-regulated lncRNA-SLCO4A1-AS1 expressed in GBM by analyzing data from GSE54791, GSE4536 and TCGA. We systematically analyzed its relationship with clinical characteristics, prognosis, epigenetics, tumor microenvironment (TME), biological functions, and transcription factors. We found that SE-driven SLCO4A1-AS1 was significantly upregulated in GBM and correlated with poor prognosis. Knockdown of SLCO4A1-AS1 decreased glioma cell proliferation, invasive ability, self-renewal ability, and increased apoptosis. Epigenetic analysis revealed that SOX2 and SE could drive SLCO4A1-AS1 expression. In vitro experiments further demonstrated that GBM cells with high SLCO4A1-AS1 expression were more sensitive to VX-11e, and overexpression of SLCO4A1-AS1 could reverse the inhibitory effect of VX-11e on GBM cells. In conclusion, this study revealed that SE-driven SLCO4A1-AS1 may be a potential therapeutic target in GBM., Competing Interests: Competing interests: The authors declare no competing interests. Ethics declarations: All the protocols in our study were admitted by the Research Ethics Committee of Shandong University and the Ethics Committee of Qilu Hospital (Shandong, China) (SDULCLL2021-2-26). All experiments and analyses were performed under the guidance of corresponding protocols or guidelines., (© 2024. The Author(s).)

Targeting of diseased cells is one of the most urgently needed prerequisites for a next generation of potent pharmaceuticals. Different approaches pursued fail mainly due to a lack of specific surface markers. Developing an RNA-based methodology, we can now ensure precise cell targeting combined with selective expression of effector proteins for therapy, diagnostics or cell steering. The specific combination of the molecular properties of antisense technology and mRNA therapy with functional RNA secondary structures allowed us to develop selectively expressed RNA molecules for medical applications. These seRNAs remain inactive in non-target cells and induce translation by partial degradation only in preselected cell types of interest. Cell specificity and type of functionalization are easily adaptable based on a modular system. In proof-of-concept studies we use seRNAs as platform technology for highly selective cell targeting. We effectively treat breast tumor cell clusters in mixed cell systems and shrink early U87 glioblastoma cell clusters in the brain of male mice without detectable side effects. Our data open up potential avenues for various therapeutic applications., Competing Interests: Competing interests: The underlying technology is patent pending in the following countries with B.H. and H.B. as inventors: Australia (PCT-AU2018222453), Canada (PCT-CA 3,054,096), Eurasia (PCT-EA 201991828), Israel (PCT-IL 2018149740), Indonesia (PCT-IN 201917032813), Japan, (PCT-JP 2019-565615). The patent has already been granted in the Republic of Korea (PCT-KR 10-2019-7024525), the USA (PCT-US 16487,377), Europe (PCT-EP-18710763.6), and China (PCT-CN 201880012606.3). The patent is owned by the SRTD Biotech GmbH. B.H. and H.B. hold shares in this company. The remaining authors declare no competing interests., (© 2025. The Author(s).)

Background: Glioblastoma multiforme (GBM) exhibits a cellular hierarchy with a subpopulation of stem-like cells known as glioblastoma stem cells (GSCs) that drive tumor growth and contribute to treatment resistance. NAD(H) emerges as a crucial factor influencing GSC maintenance through its involvement in diverse biological processes, including mitochondrial fitness and DNA damage repair. However, how GSCs leverage metabolic adaptation to obtain survival advantage remains elusive., Methods: A multi-step process of machine learning algorithms was implemented to construct the glioma stemness-related score (GScore). Further in silico and patient tissue analyses validated the predictive ability of the GScore and identified a potential target, CYP3A5. Loss-of-function or gain-of-function genetic experiments were performed to assess the impact of CYP3A5 on the self-renewal and chemoresistance of GSCs both in vitro and in vivo. Mechanistic studies were conducted using nontargeted metabolomics, RNA-seq, seahorse, transmission electron microscopy, immunofluorescence, flow cytometry, ChIP‒qPCR, RT‒qPCR, western blotting, etc. The efficacy of pharmacological inhibitors of CYP3A5 was assessed in vivo., Results: Based on the proposed GScore, we identify a GSC target CYP3A5, which is highly expressed in GSCs and temozolomide (TMZ)-resistant GBM patients. This elevated expression of CYP3A5 is attributed to transcription factor STAT3 activated by EGFR signaling or TMZ treatment. Depletion of CYP3A5 impairs self-renewal and TMZ resistance of GSCs. Mechanistically, CYP3A5 maintains mitochondrial fitness to promote GSC metabolic adaption through the NAD⁺/NADH-SIRT1-PGC1α axis. Additionally, CYP3A5 enhances the activity of NAD-dependent enzyme PARP to augment DNA damage repair. Treatment with CYP3A5 inhibitor alone or together with TMZ effectively suppresses tumor growth in vivo., Conclusion: Together, this study suggests that GSCs activate STAT3 to upregulate CYP3A5 to fine-tune NAD⁺/NADH for the enhancement of mitochondrial functions and DNA damage repair, thereby fueling tumor stemness and conferring TMZ resistance, respectively. Thus, CYP3A5 represents a promising target for GBM treatment., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures performed using human tissues were approved by the Ethics Committee of the First Medical Center of Chinese PLA General Hospital (No. S2018-089). All animal experimental protocols were approved by the Institutional Animal Ethics and Welfare Committee of Tianjin Medical University (No. IRB2022-DWFL-069). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Minimally invasive molecular profiling using cell-free DNA (cfDNA) is increasingly important to the management of cancer patients; however, low sensitivity remains a major limitation, particularly for brain tumor patients. Transiently attenuating cfDNA clearance from the body-thereby, allowing more cfDNA to be sampled-has been proposed to improve the performance of liquid biopsy diagnostics. However, there is a paucity of clinical data on the effect of higher cfDNA recovery. Here, we investigated the impact of collecting greater quantities of cfDNA on circulating tumor DNA (ctDNA) sensitivity in the "low-shedding" cancer type glioblastoma by analyzing up to approximately 15-fold more plasma than routinely obtained clinically., Methods: We tested 70 plasma samples (median 17.0 mL, range 2.5-66.5) from 8 IDH-wild-type glioblastoma patients using an optimized version of the MAESTRO-Pool ctDNA assay. Results were compared with simulated single-blood-tube equivalents of cfDNA. ctDNA results were then compared with magnetic resonance imaging (MRI) and pathology assessments of true progression vs pseudoprogression in glioblastoma patients., Results: Larger cfDNA yields exhibited a doubling in ctDNA-positivity while achieving a median specificity of 99% and more precise ctDNA quantification. In 8 glioblastoma patients, ctDNA was detected in 88%, including at multiple timepoints in 6/7. In the setting of indeterminate progression by MRI, our data suggested that MAESTRO-Pool with large plasma volumes can help distinguish true glioblastoma progression from pseudoprogression., Conclusions: Our findings provide a proof-of-principle that most glioblastomas shed ctDNA into plasma and that greater ctDNA yields could help improve liquid biopsies for "low-shedding" cancer types such as glioblastoma., (© Association for Diagnostics & Laboratory Medicine 2025. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Glioblastoma multiforme (GBM) is one of the deadliest and most heterogeneous forms of brain cancer, characterized by its resistance to conventional therapies. Within GBM, a subpopulation of slow-cycling cells, often linked to quiescence and stemness, plays a crucial role in treatment resistance and tumor recurrence. This study aimed to identify novel biomarkers associated with these slow-cycling GBM cells., Methods: We utilized The Cancer Genome Atlas (TCGA)-GBM dataset and presented the reproducible bioinformatics analysis for our results., Results: Our analysis highlighted Membrane-Associated Protein 17 ( MAP17 ) as strongly associated with the slow-cycling phenotype. We found that the protein cargo MAP17 expression is related to mesenchymal signatures and stem cell-related pathways. Also, MAP17 was linked to a distinct metabolic profile, characterized by significant enrichment in pathways related to folate, zinc, and fatty acids. Moreover, the immune cell distribution analysis revealed that MAP17 correlates with key molecular immune processes, including interferon-gamma ( IFN-γ ) signaling and antigen presentation, as well as immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) and macrophages. MAP17 -high tumors also showed elevated expression of several immune checkpoint inhibitors, indicating an immunosuppressive microenvironment., Conclusion: These findings provide insight into the role of MAP17 in quiescence, stemness, and immune evasion, positioning it as a promising therapeutic target.

Background: Glioblastoma multiforme (GBM) is a common and highly aggressive brain tumor with a poor prognosis. However, the prognostic value of ferroptosis-related genes (FRGs) and their classification remains insufficiently studied., Objective: This study aims to explore the significance of ferroptosis classification and its risk model in GBM using multi-omics approaches and to evaluate its potential in prognostic assessment., Methods: Ferroptosis-related genes (FRGs) were retrieved from databases such as FerrDB. The TCGA-GBM and CGGA-GBM datasets were used as training and testing cohorts, respectively. Univariate Cox regression and LASSO regression analyses were performed to establish a risk model comprising five genes (OSMR, G0S2, IGFBP6, IGHG2, FMOD). A Meta-analysis of integrated TCGA and GTEx data was conducted to examine the differential expression of these genes between GBM and normal tissues. Key gene protein expression differences were analyzed using CPTAC and HPA databases. Single-cell RNA sequencing (scRNA-seq) analysis was employed to explore the cell type-specific distribution of these genes., Results: The five-gene risk model demonstrated significant prognostic value in GBM. Meta-analysis revealed distinct expression patterns of the identified genes between GBM and normal tissues. Protein expression analysis confirmed these differences. scRNA-seq analysis highlighted the diverse distribution of these genes across different cell types, offering insights into their biological roles., Conclusion: The ferroptosis-based risk model provides valuable prognostic insights into GBM and highlights potential therapeutic targets, emphasizing the biological significance of ferroptosis-related genes in tumor progression., (© 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The widespread use of wireless communication technologies has increased human exposure to radiofrequency electromagnetic fields (RF-EMFs). Considering the brain's close proximity to mobile phones and its entirely electrical transmission network, it emerges as the organ most profoundly impacted by the RF field. This study aims to investigate the potential effects of RF radiation on cell viability, apoptosis, and gene expressions in glioblastoma cells (U118-MG) at different exposure times (1, 24, and 48 h). To achieve this, we designed and implemented an in vitro RF exposure system operating at a frequency of 2.1 GHz, specifically for cell culture studies, with an average specific absorption rate (SAR) of 1.12 ± 0.18 W/kg determined through numerical dosimetry calculations. Results reveal a significant influence of a 48 h exposure to a 2.1 GHz RF field on U118-MG cell viability, gene expression, and the induction of caspase (CASP) dependent apoptosis. Notably, increased CASP3, CASP8, and CASP9 mRNA levels were observed after 24 and 48 h of RF treatment. However, only the 48 h RF exposure resulted in apoptotic cell death and a significant elevation in the BAX/BCL-2 ratio. This observed effect may be influenced by extended exposure durations surpassing the cell's doubling time. The increased BAX/BCL-2 ratio, which acts as a key switch for apoptosis, and the heterogeneous morphology of the astrocyte-derived U118-MG cell line may also play a role in this effect., (© 2025 Bioelectromagnetics Society.)

Glioma, a type of brain tumor, is influenced by mechanical forces in its microenvironment that affect cancer progression. However, our understanding of the contribution of compression and its associated mechanisms remains limited. The objective of the present study was to create an environment in which human brain glioma H4 cells experience pressure and thereby investigate the compressive mechanosensors and signaling pathways. Subsequent time‑lapse imaging and wound healing assays confirmed that 12 h of compression significantly increased cell migration, thereby linking compression with enhanced cell motility. Compression upregulated the expression of Piezo1, a mechanosensitive ion channel, and growth differentiation factor 15 (GDF15), a TGF‑β superfamily member. Knockdown experiments targeting PIEZO1 or GDF15 using small interfering RNA resulted in reduced cell motility, with Piezo1 regulating GDF15 expression. Compression also upregulated CTLA4, a critical immune checkpoint protein. The findings of the present study therefore suggest that compression enhances glioma progression by stimulating Piezo1, promoting GDF15 expression and increasing CTLA4 expression. Thus, these findings provide important insights into the influence of mechanical compression on glioma progression and highlight the involvement of the Piezo1‑GDF15 signaling pathway. Understanding tumor responses to mechanical forces in the brain microenvironment may guide the development of targeted therapeutic strategies to mitigate tumor progression and improve patient outcomes.

Background:  Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer. This study investigated the clinical predictive value of heat shock protein β1 (HSPB1) in patients with GBM., Methods:  A correlation was established between HSPB1 expression and GBM progression using data from The Cancer Genome Atlas (TCGA) dataset, Chinese Glioma Genome Atlas dataset, Gene Expression Omnibus dataset, and Human Protein Atlas database. A survival analysis was conducted and an HSPB1-based nomogram was constructed to evaluate the prognostic value of HSPB1 in patients with GBM., Results:  Based on TCGA data mining, we discovered that HSPB1 was significantly elevated in patients with GBM and may reflect their response to immunotherapy. In survival analysis, it appeared to have a predictive role in the prognosis of patients with GBM. Five signaling pathways were significantly enriched in the high HSPB1 expression phenotype according to the gene set enrichment analysis. In addition, a significant association was found between HSPB1 expression and immune checkpoints, tumor immune infiltration, tumor immune microenvironment, and immune cell markers in glioma. Overall, our results suggest that HSPB1 may regulate the function of immune cells, serve as a new immunotherapy target, and predict the response to immunotherapy in patients with GBM., Conclusion:  HSPB1 appears to serve as a potential predictor of the clinical prognosis and response to immunotherapy in patients with GBM. It may be possible to identify patients who are likely to benefit from immunotherapy by assessing the expression level of HSPB1., Competing Interests: None declared., (Thieme. All rights reserved.)

A glioblastoma (GBM) patient with a high tumor mutation burden (TMB-high) and mismatch repair deficiency (dMMR) exhibited a significant response to pembrolizumab, an immune checkpoint inhibitor (ICI), despite prior treatment with temozolomide (TMZ), known to induce hypermutation and potential resistance to ICIs. The rapid disease progression, indicated by 80% Ki67 positivity, was markedly countered by the positive outcome of pembrolizumab treatment. This case challenges traditional GBM treatment paradigms, demonstrating the potential of precision oncology in patients with significant TMB and dMMR, and underscores the importance of comprehensive genomic profiling in guiding clinical decisions in GBM management., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Glioblastoma IDH wild type (GBM IDH wt) has a poor prognosis and a strongly associated with inflammatory processes. Inflammatory molecules generate positive feedback with tumor cells fueling tumor growth as well as recruitment of immune cells that promote aggressiveness. Although the role of many inflammatory molecules is well known, there are many macromolecules, such as the S100A proteins, whose role is only now beginning to be established. Methods: Using RNA-seq, bioinformatics tools and a cohort of glioma patients to validate the results, we have analysed the inflammatory processes involved in glioma. Transcriptional profiles were also used to define biological processes of relevance to specific S100A proteins. Finally, we characterized the relevant immune populations with an IHC analysis and transcriptional profiling. Results: We have noted an increased expression of S100A in GBM IDH wt compared to gliomas IDH mutants. This allowed us to analyse the involvement of different members of the family, such as S100A9, A11 and A13 as possible regulators of inflammatory processes in the GBM-IDH wt microenvironment. Thus, we observed that S100A9 is located in hypoxic areas linked to the function of neutrophils, S100A11 is found in vascular areas associated with the function of perivascular pericytes and macrophages, and finally, S100A13 which is related to the dysfunction of microglia. Conclusion: Our findings define different functions for S100A9, A11 and A13 proteins that are associated with the architecture of the glioblastoma microenvironment and define its progression. Moreover, these alterations can be reversed by the RAGE inhibitor, Azeliragon which is in a phase I/II clinical trial NCT05635734., Competing Interests: Competing Interests: Steve G. Marcus is the CEO of Cantex Pharmaceuticals. All other authors declare they have no conflict of interest., (© The author(s).)

Background: Cancer-associated fibroblasts (CAFs) play important roles in tumor microenvironments. Pyrroline-5-carboxylate reductase 1 (PYCR1) is a potential cancer therapy target. This study aimed to explore the expression of PYCR1 in glioma-associated CAFs and analyze the effects of PYCR1 expression in CAFs on the proliferation of C6 glioma., Methods: A rat glioma model was induced by injecting C6 cells in the right caudate putamen via a microliter syringe. After 14 days, tumor tissues were collected, and the levels of COL1A1 and PYCR1 were measured by immunohistochemistry. The colocalization of fibroblast activation protein α (FAP) and PYCR1 in tissues was measured by double-immunofluorescence. The CAFs were labeled by FAP and isolated from the tumor tissues using a fluorescence-activated cell sorting (FACS) machine. The isolated CAFs were further separated into CAFs with different PYCR1 expressions using the FACS machine. CAFs with different PYCR1 expressions were respectively cocultured with C6 cells or MUVECs for 48h using a Transwell permeable support. The invasion and proliferation of C6 cells were measured using a Transwell assay and colony formation assay, and the angiogenesis of MUVECs was measured using a Tube formation assay. The expression of COL1A1 and PYCR1 proteins in C6 cells and VEGF-A and EGF proteins in MUVECs was measured by western blotting. PYCR1 silencing in C6 cells was induced by PYCR1 siRNA transfection, the effects of which on the proliferation of C6 cells were measured using a wound healing assay, a Transwell assay, and western blotting., Results: The PYCR1 and COL1A1 upregulation co-occurred in the rat glioma, and PYCR1 was expressed in CAFs. The CAF coculture enhanced the invasion and proliferation of C6 cells and the angiogenesis of MUVECs. Meanwhile, the levels of COL1A1 protein in C6 cells, and the levels of VEGF-A and EGF proteins in MUVECs were increased after CAF coculture. Moreover, the effects of CAF coculture were increased with PYCR1 expression in the CAF. Silencing PYCR1 suppressed the migration and invasion of C6 cells, and decreased the levels of COL1A1 and VEGF-A proteins in C6 cells., Conclusions: PYCR1 is expressed in glioma-associated CAFs, and promotes the proliferation of C6 cells and angiogenesis of MUVECs, suggesting that targeting PYCR1 may be a therapeutic strategy for glioma., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Background and Aim: Elevated lactate dehydrogenase (LDH), a marker of tumor aggressiveness and metabolic alterations, may predict treatment response and overall survival across various tumors. This study investigates the correlation between serum LDH levels and clinical outcomes in glioblastoma patients treated with radiotherapy (RT) and temozolomide (TMZ)., Materials and Methods: This retrospective study analysed patients with IDH wild-type glioblastoma (IDH-wt GB) treated at the Radiotherapy Department of Azienda Ospedaliero-Universitaria Senese from 2018 to 2023. Clinical data, including hematologic parameters (e.g., LDH), imaging (MRI), and MGMT promoter methylation status, were collected. All patients received RT and TMZ following the Stupp protocol. Serum LDH levels were measured one week before RT, and Radiological Response (RR) was assessed using RANO criteria. Overall survival (OS), progression-free survival (PFS), and RR were primary endpoints. Statistical analyses included Kaplan-Meier, Cox regression, and decision tree analysis for LDH cut-off determination., Results: In a cohort of 147 IDH wild-type glioblastoma patients treated with the Stupp protocol, the median OS was 14 months and median PFS was 8 months. Elevated baseline LDH levels were associated with significantly poorer outcomes, showing a median OS of 9 months versus 20 months and a median PFS of 6 months versus 13 months for lower LDH levels (p < 0.001 and p = 0.0001, respectively). LDH levels also correlated with RR (p = 0,001), Multivariate analysis confirmed high LDH as an independent predictor of worse OS (HR = 2.31) and PFS (HR = 2.60), suggesting its utility as a prognostic biomarker., Conclusions: Elevated LDH levels before starting the Stupp protocol are clinically significant as they predict poorer overall survival and progression-free survival in glioblastoma patients and worse RR. Incorporating LDH measurements into treatment planning can help identify patients at higher risk of poor outcomes, allowing for more tailored and potentially aggressive treatment strategies to improve management and therapeutic responses in glioblastoma., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Glioblastomas are aggressive brain tumors for which effective therapy is still lacking, resulting in dismal survival rates. These tumors display significant phenotypic plasticity, harboring diverse cell populations ranging from tumor core cells to dispersed, highly invasive cells. Neuron navigator 3 (NAV3), a microtubule-associated protein affecting microtubule growth and dynamics, is downregulated in various cancers, including glioblastoma, and has thus been considered a tumor suppressor. In this study, we challenge this designation and unveil distinct expression patterns of NAV3 across different invasion phenotypes. Using glioblastoma cell lines and patient-derived glioma stem-like cell cultures, we disclose an upregulation of NAV3 in invading glioblastoma cells, contrasting with its lower expression in cells residing in tumor spheroid cores. Furthermore, we establish an association between low and high NAV3 expression and the amoeboid and mesenchymal invasive phenotype, respectively, and demonstrate that overexpression of NAV3 directly stimulates glioblastoma invasive behavior in both 2D and 3D environments. Consistently, we observed increased NAV3 expression in cells migrating along blood vessels in mouse xenografts. Overall, our results shed light on the role of NAV3 in glioblastoma invasion, providing insights into this lethal aspect of glioblastoma behavior., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

The most common and aggressive brain cancer, glioblastoma, is characterized by hypoxia and poor survival. The pro-tumour transcription factor, hypoxia-inducible factor (HIF), is regulated via HIF-hydroxylases that require ascorbate as cofactor. Decreased HIF-hydroxylase activity triggers the hypoxic pathway driving cancer progression. Tissue ascorbate accumulates via the sodium-dependent vitamin C transporter-2 (SVCT2). We hypothesize that glioblastoma cells rely on SVCT2 for ascorbate accumulation, and that knockout of this transporter would disrupt the regulation of the hypoxic pathway by ascorbate. Ascorbate uptake was measured in glioblastoma cell lines (U87MG, U251MG, T98G) by high-performance liquid chromatography. CRISPR/Cas9 was used to knockout SVCT2. Cells were treated with cobalt chloride, desferrioxamine or 5% oxygen, with/without ascorbate, and key hypoxic pathway proteins were measured using Western blot analysis. Ascorbate uptake was cell line dependent, ranging from 1.7 to 11.0 nmol/10 6 cells. SVCT2-knockout cells accumulated 90%-95% less intracellular ascorbate than parental cells. The hypoxic pathway was induced by all three stimuli, and ascorbate reduced this induction. In the SVCT2-knockout cells, ascorbate had limited effect on the hypoxic pathway. This study verifies that intracellular ascorbate is required to suppress the hypoxic pathway. As patient survival is related to an activated hypoxic pathway, increasing intra-tumoral ascorbate may be of clinical interest., (© 2024 The Author(s). Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Background: Adult glioblastomas (GBMs) are associated with high recurrence and mortality. Personalized treatment based on molecular markers may help improve the prognosis. We aimed to evaluate whether apparent diffusion coefficient (ADC) histogram analysis can better predict MGMT and TERT molecular characteristics and to determine the prognostic relevance of genetic profile in patients with GBM., Materials and Methods: MRI, clinical, and pathological data of 79 patients with GBM were retrospectively collected. The ADC values based on histogram analysis were described using 10th percentile (p10), 90th percentile (p90), mean, median, minimum, maximum, skewness, kurtosis, and entropy. The independent-sample t test, linear correlation analysis, receiver operating characteristics (ROC) curve analysis, Kaplan-Meier analysis, and Cox proportional hazard regression were performed., Results: MGMT promoter methylation and TERT promoter mutation were detected in 53.2% and 44.3% of GBM patients, respectively. The ADC p10 in MGMT promoter unmethylated group was significantly lower than that in the MGMT promoter methylated group (p = 0.005). There were significant differences in ADC min , ADC p10 , ADC mean , and entropy between TERT promoter mutant and wild-type groups. Entropy showed the best diagnostic performance in differentiating between positive and negative TERT groups (AUC = 0.722, p = 0.001). Overall survival (OS) showed a positive correlation with ADC min . The TERT promoter mutation was the only independent prognostic factor for GBM., Conclusions: ADC histogram analysis may be a potential noninvasive biomarker for differentiating MGMT and TERT molecular markers and providing prognostic information for GBM patients., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Glioblastoma (GBM) is one of the most prevalent cancerous brain tumors. Former studies have reported that exosomes derived from M1-polarized macrophages (M1 exosomes) inhibit tumor occurrence and development through delivery of tumor suppressor genes. Also, microRNA-142-3p (miR-142-3p) has been verified to function as a tumor suppressor. GBM cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8), colony formation assay and 5-ethynyl-2'-deoxyuridine (EdU) assay; cell apoptosis was determined by flow cytometry analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Mechanism investigations were conducted for analyzing the molecular mechanism by which miR-142-3p and M1 exosomes affect GBM progression. Upregulation of miR-142-3p expression was detected in M1-polarized macrophages and M1 exosomes. M1 exosomes inhibit GBM cell proliferation and trigger cell apoptosis. Functionally, miR-142-3p silencing promotes the proliferation and inhibits the apoptosis of GBM cells treated with M1 exosomes. As for molecular mechanism, miR-142-3p inhibits GBM cell growth via targeting high-mobility group box 1 (HMGB1). In addition, miR-142-3p/HMGB1 axis affects GBM cell immune escape through modulation of programmed death-1/programmed death ligand-1 (PD-1/PD-L1) checkpoint. Our study demonstrated that exosomal miR-142-3p from M1-polarized macrophages suppresses cell growth and immune escape in GBM through regulating HMGB1-mediated PD-1/PD-L1 checkpoint., (© 2024 International Society for Neurochemistry.)

Core1 β1,3-galactosyltransferase (C1GALT1) is an essential glycotransferase controlling the elongation of GalNAc-type O-glycosylation and its altered expression contributes tumor progression in various cancers. However, the mechanism how C1GALT1 influences gliomas remains unclear. Here，our results from The Cancer Genome Atlas (TCGA) database, The Chinese Glioma Genome Atlas (CGGA) database and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database showed that the expression of C1GALT1 was increased in higher grade gliomas namely glioblastoma compared with low grade gliomas or non-tumor tissues and significantly associated with poor survival. Downregulation of C1GALT1 suppressed cell proliferation, invasion, and migration in glioma cell lines. Consistent with the result in vitro, C1GALT1 knockdown distinctly inhibited the weight and tumor growth in nude mice. Mechanistically, C1GALT1 knockdown decreased the level of terminal galactose O-glycosylation and phosphorylation on epidermal growth factor receptor (EGFR). Moreover, The AKT/ERK phosphorylation was attenuated in C1GALT1 knockdown cells. And C1GALT1 knockdown decreased the expression of cyclinD1, matrix metalloproteinase 9 (MMP9) through the AKT/ERK signaling pathway Furthermore, transcription factor SP1 which the expression was found to be associated the C1GALT1 expression could bind to the promoter of C1GALT1 gene and regulated its expression. In conclusion, our data show that C1GALT1 enhances the progression of glioma by regulated the O-glycosylation and phosphorylation of EGFR and the subsequent downstream AKT/ERK signaling pathway. Therefore, C1GALT1 represents a potential target for the diagnosis and treatment of glioma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)