Survival Of Glioblastoma Multiforme Patients Research Articles

STAT1 mediated downregulation of the tumor suppressor gene PDCD4, is driven by the atypical cadherin FAT1, in glioblastoma

STAT1 (Signal Transducer and Activator of Transcription 1), belongs to the STAT protein family, essential for cytokine signaling. It has been reported to have either context dependent oncogenic or tumor suppressor roles in different tumors. Earlier, we demonstrated that Glioblastoma multiforme (GBMs) overexpressing FAT1, an atypical cadherin, had poorer outcomes. Overexpressed FAT1 promotes pro-tumorigenic inflammation, migration/invasion by downregulating tumor suppressor gene, PDCD4. Here, we demonstrate that STAT1 is a novel mediator downstream to FAT1, in downregulating PDCD4 in GBMs. In-silico analysis of GBM databases as well as q-PCR analysis in resected GBM tumors showed positive correlation between STAT1 and FAT1 mRNA levels. Kaplan-Meier analysis showed poorer survival of GBM patients having high FAT1 and STAT1 expression. SiRNA-mediated knockdown of FAT1 decreased STAT1 and increased PDCD4 expression in glioblastoma cells (LN229 and U87MG). Knockdown of STAT1 alone resulted in increased PDCD4 expression. In silico analysis of the PDCD4 promoter revealed four putative STAT1 binding sites (Site1-Site4). ChIP assay confirmed the binding of STAT1 to site1. ChIP-PCR revealed decrease in the binding of STAT1 on the PDCD4 promoter after FAT1 knockdown. Site directed mutagenesis of Site1 resulted in increased PDCD4 luciferase activity, substantiating STAT1 mediated PDCD4 inhibition. EMSA confirmed STAT1 binding to the Site 1 sequence. STAT1 knockdown led to decreased expression of pro-inflammatory cytokines and EMT markers, and reduced migration/invasion of GBM cells. This study therefore identifies STAT1 as a novel downstream mediator of FAT1, promoting pro-tumorigenic activity in GBM, by suppressing PDCD4 expression.

Identification of Novel Molecular and Clinical Biomarkers of Survival in Glioblastoma Multiforme Patients: A Study Based on The Cancer Genome Atlas Data.

Glioblastoma multiforme (GBM) is the most prevalent type of brain tumour; although advancements in treatment have been made, the median survival time for GBM patients has persisted at 15 months. This study is aimed at investigating the genetic alterations and clinical features of GBM patients to find predictors of survival. GBM patients' methylation and gene expression data along with clinical information from TCGA were retrieved. The most overrepresented pathways were identified independently for each omics dataset. From the genes found in at least 30% of these pathways, one gene that was identified in both sets was further examined using the Kaplan-Meier method for survival analysis. Additionally, three groups of patients who started radio and chemotherapy at different times were identified, and the influence of these variations in treatment modality on patient survival was evaluated. Four pathways that seemed to negatively impact survival and two with the opposite effect were identified. The methylation status of PRKCB was highlighted as a potential novel biomarker for patient survival. The study also found that treatment with chemotherapy prior to radiotherapy can have a significant impact on patient survival, which could lead to improvements in clinical management and therapeutic approaches for GBM patients.

Repurposing of Zika virus live-attenuated vaccine (ZIKV-LAV) strains as oncolytic viruses targeting human glioblastoma multiforme cells

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer affecting the adult population. Median overall survival for GBM patients is poor (15 months), primarily due to high rates of tumour recurrence and the paucity of treatment options. Oncolytic virotherapy is a promising treatment alternative for GBM patients, where engineered viruses selectively infect and eradicate cancer cells by inducing cell lysis and eliciting robust anti-tumour immune response. In this study, we evaluated the oncolytic potency of live-attenuated vaccine strains of Zika virus (ZIKV-LAV) against human GBM cells in vitro. Our findings revealed that Axl and integrin αvβ5 function as cellular receptors mediating ZIKV-LAV infection in GBM cells. ZIKV-LAV strains productively infected and lysed human GBM cells but not primary endothelia and terminally differentiated neurons. Upon infection, ZIKV-LAV mediated GBM cell death via apoptosis and pyroptosis. This is the first in-depth molecular dissection of how oncolytic ZIKV infects and induces death in tumour cells.

Prognostic marker CXCL5 in glioblastoma polyformis and its mechanism of immune invasion

Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a poor prognosis. Therefore, the correlative molecular markers and molecular mechanisms should be explored to assess the occurrence and treatment of glioma.WB and qPCR assays were used to detect the expression of CXCL5 in human GBM tissues. The relationship between CXCL5 expression and clinicopathological features was evaluated using logistic regression analysis, Wilcoxon symbolic rank test, and Kruskal–Wallis test. Univariate, multivariate Cox regression and Kaplan–Meier methods were used to assess CXCL5 and other prognostic factors of GBM. Gene set enrichment analysis (GSEA) was used to identify pathways associated with CXCL5. The correlation between CXCL5 and tumor immunoinfiltration was investigated using single sample gene set enrichment analysis (ssGSEA) of TCGA data. Cell experiments and mouse subcutaneous transplanted tumor models were used to evaluate the role of CXCL5 in GBM. WB, qPCR, immunofluorescence, and immunohistochemical assays showed that CXCL5 expression was increased in human GBM tissues. Furthermore, high CXCL5 expression was closely related to poor disease-specific survival and overall survival of GBM patients. The ssGSEA suggested that CXCL5 is closely related to the cell cycle and immune response through PPAR signaling pathway. GSEA also showed that CXCL5 expression was positively correlated with macrophage cell infiltration level and negatively correlated with cytotoxic cell infiltration level. CXCL5 may be associated with the prognosis and immunoinfiltration of GBM.

Comprehensive somatic mutational analysis in glioblastoma: Implications for precision medicine approaches.

Glioblastoma multiforme (GBM), a malignant neoplasm originating from glial cells, remains challenging to treat despite the current standard treatment approach that involves maximal safe surgical resection, radiotherapy, and adjuvant temozolomide chemotherapy. This underscores the critical need to identify new molecular targets for improved therapeutic interventions. The current study aimed to explore the somatic mutations and potential therapeutic targets in GBM using somatic mutational information from four distinct GBM datasets including CGGA, TCGA, CPTAC and MAYO-PDX. The analysis included the evaluation of whole exome sequencing (WES) of GBM datasets, tumor mutation burden assessment, survival analysis, drug sensitivity prediction, and examination of domain-specific amino acid changes. The results identified the top ten commonly altered genes in the aforementioned GBM datasets and patients with mutations in OBSCN and AHNAK2 alone or in combination had a more favorable overall survival (OS). Also, the study identified potential drug sensitivity patterns in GBM patients with mutations in OBSCN and AHNAK2, and evaluated the impact of amino acid changes in specific protein domains on the survival of GBM patients. These findings provide important insights into the genetic alterations and somatic interactions in GBM, which could have implications for the development of new therapeutic strategies for this aggressive malignancy.

Comparison of MRI radiomics-based machine learning survival models in predicting prognosis of glioblastoma multiforme

ObjectiveTo compare the performance of radiomics-based machine learning survival models in predicting the prognosis of glioblastoma multiforme (GBM) patients.Methods131 GBM patients were included in our study. The traditional Cox proportional-hazards (CoxPH) model and four machine learning models (SurvivalTree, Random survival forest (RSF), DeepSurv, DeepHit) were constructed, and the performance of the five models was evaluated using the C-index.ResultsAfter the screening, 1792 radiomics features were obtained. Seven radiomics features with the strongest relationship with prognosis were obtained following the application of the least absolute shrinkage and selection operator (LASSO) regression. The CoxPH model demonstrated that age (HR = 1.576, p = 0.037), Karnofsky performance status (KPS) score (HR = 1.890, p = 0.006), radiomics risk score (HR = 3.497, p = 0.001), and radiomics risk level (HR = 1.572, p = 0.043) were associated with poorer prognosis. The DeepSurv model performed the best among the five models, obtaining C-index of 0.882 and 0.732 for the training and test set, respectively. The performances of the other four models were lower: CoxPH (0.663 training set / 0.635 test set), SurvivalTree (0.702/0.655), RSF (0.735/0.667), DeepHit (0.608/0.560).ConclusionThis study confirmed the superior performance of deep learning algorithms based on radiomics relative to the traditional method in predicting the overall survival of GBM patients; specifically, the DeepSurv model showed the best predictive ability.

The genes significantly associated with an improved prognosis and long-term survival of glioblastoma.

Glioblastoma multiforme (GBM) is the most devastating brain tumor with less than 5% of patients surviving 5 years following diagnosis. Many studies have focused on the genetics of GBM with the aim of improving the prognosis of GBM patients. We investigated specific genes whose expressions are significantly related to both the length of the overall survival and the progression-free survival in patients with GBM. We obtained data for 12,042 gene mRNA expressions in 525 GBM tissues from the Cancer Genome Atlas (TCGA) database. Among those genes, we identified independent genes significantly associated with the prognosis of GBM. Receiver operating characteristic (ROC) curve analysis was performed to determine the genes significant for predicting the long-term survival of patients with GBM. Bioinformatics analysis was also performed for the significant genes. We identified 33 independent genes whose expressions were significantly associated with the prognosis of 525 patients with GBM. Among them, the expressions of five genes were independently associated with an improved prognosis of GBM, and the expressions of 28 genes were independently related to a poorer prognosis of GBM. The expressions of the ADAM22, ATP5C1, RAC3, SHANK1, AEBP1, C1RL, CHL1, CHST2, EFEMP2, and PGCP genes were either positively or negatively related to the long-term survival of GBM patients. Using a large-scale and open database, we found genes significantly associated with both the prognosis and long-term survival of patients with GBM. We believe that our findings may contribute to improving the understanding of the mechanisms underlying GBM.

MODL-38. DEFINING THE ROLE OF DAAM2 R414W MUTATION IN GLIOMAGENESIS AND GBM GROWTH

Abstract Each year in the United States, more than 13,000 people are diagnosed with glioblastoma multiforme (GBM), and more than 10,000 are estimated to succumb to the disease, making GBM the most common and lethal primary adult brain tumor. Despite advancing therapies, GBM patient survival has not improved over the decades, so it is critical to better understand glioma etiology. The majority of GBM cases arise from a sporadic accumulation of somatic mutations, but approximately 5-10% of gliomas are classified as “familial”, occurring clustered with hereditary cancer predispositions. These familial gliomas are caused by germline mutations inherited from parent to offspring, and only a few of these mutations have been directly linked to the development of GBM. We recently discovered five germline mutations in Daam2 (Dishevelled associated activator of morphogenesis 2) from GBM patients with a history of familial glioma. To examine the role of these mutations in GBM, we overexpressed these mutations in patient-derived GBM cells, which were then orthotopically xenografted into immunodeficient mice. We identified that one of these mutations, Daam2-R414W, promotes tumor cell proliferation both in vitro and in vivo. To further understand the role of the Daam2-R414W mutation in GBM, we generated a knock-in immunocompetent mouse model that harbors the Daam2-R414W mutation. In these mutant mice, we found increased proliferation of glial progenitor cells in the subventricular zone compared to Daam2 wildtype mice, suggesting the potential of the Daam2-R414W mutation to influence glial progenitor expansion to stimulate glioma initiation. Future experiments aim to answer whether this mutation promotes GBM growth in an immunocompetent model and to decipher the mechanism relating the Daam2-R414W mutation to GBM pathology. These studies will shed light on the repercussions of a human developmental gene variant and its potential to disrupt normal cellular machinery to promote malignancy and GBM development.

Systematic integration of m6A regulators and autophagy-related genes in combination with long non-coding RNAs predicts survival in glioblastoma multiforme

Glioblastoma multiforme (GBM) is probably the only tumor in which a unique epigenetic alteration, namely methylation of the MGMT gene, possesses direct clinical relevance. Now with the emergence of aberrant N6 methyladenosine (m6A) modifications (the most common epigenetic modification of mRNA, closely linked to the autophagy process) in cancer, the epi-transcriptomic landscape of GBM pathobiology has been expanded. Considering this, herein, we systematically analyzed m6A regulators, assessed their correlation with autophagy-related genes (ATG), and established a long non-coding RNAs (lncRNA)-dependent prognostic signature (m6A-autophagy-lncRNAs) for GBM. Our analysis identified a novel signature of five long non-coding RNAs (lncRNAs: ITGA6-AS1, AC124248.1, NFYC-AS1, AC025171.1, and AC005229.3) associated with survival of GBM patients, and four among them clearly showed cancer-associated potential. We further validated and confirmed the altered expression of two lncRNAs (AC124248.1, AC005229.3) in GBM associated clinical samples using RT-PCR. Concerning the prognostic ability, the obtained signature determined high-/low-risk groups in GBM patients and showed sensitivity to anticancer drugs. Collectively, the m6A-autophagy-lncRNAs signature presented in the study is clinically relevant and is the first attempt to systematically predict the potential interaction between the three key determinants (m6A, autophagy, lncRNA) in cancer, particularly in GBM.

A Preliminary Study Indicating Improvement in the Median Survival Time of Glioblastoma Multiforme Patients by the Application of Deuterium Depletion in Combination with Conventional Therapy.

Glioblastoma multiforme (GBM) and malignant gliomas are the most common primary malignant brain tumors. Temozolomide (TMZ) chemotherapy plus radiation therapy (RT), admi-mistered after debulking surgery, increased the median survival time (MST) from 12.1 months with RT alone merely to 14.6 months, respectively. In this study, the actions of deuterium-depleted water (DDW) on the survival of GBM patients who also received conventional therapies was investigated. Without changing the conventional treatment, the daily fluid intake of the patients was wholly replaced with DDW in 1.5-2 L per day volume to reduce the D concentration in their bodies. The primary endpoint was the MST. The 55 patients involved in this study, who received conventional treatment and consumed DDW, showed a longer MST (30 months) compared to the historical control (12.1-14.6 months). There was a massive difference between the two genders in the calculated MST values; it was 25 months in the male subgroup (n = 33) and 42 months in the female subgroup (n = 22), respectively. The MST was 27 months without TMZ treatment (38 patients) and 42 months in the TMZ-treated group (17 patients), respectively. For the selected 31 patients, who consumed DDW in the correct way in addition to their conventional treatments, their MST was calculated as 30 months. Within this group, the 20 subjects who had relapsed before DDW treatment had 30 months of MST, but in those 10 subjects who were in remission when DDW treatment started, their MST was 47 months. In the subgroup of patients who began their DDW treatment parallel with radiotherapy, their MST was again 47 months, and it was 25 months when their DDW treatment was started at 8 weeks or later after the completion of radiotherapy. Altogether, these survival times were substantially prolonged compared to the prospective clinical data of patients with primary GBM. Consequently, if conventional therapies are supplemented with D depletion, better survival can be achieved in the advanced stage of GBM than with the known targeted or combination therapies. Application of DDW is recommended in all stages of the disease before surgery and in parallel with radiotherapy, and repeated DDW courses are advised when remission has been achieved.

The application of cannabidiol in the treatment of glioblastoma

Glioblastoma multiforme (GBM), a high-grade astrocytoma, is an incurable brain tumor associated with genetic heterogeneity and dysregulated signaling pathways. As alternations of the endocannabinoid system have been demonstrated in GBM cells, the substances affecting its key elements may potentially inhibit tumor progression. Preclinical models indicate that CBD inhibits GBM tumor growth by inhibiting cellular proliferation, migration, and invasion but also promotes autophagy and apoptosis of tumor cells. Moreover, clinical trials indicate the safety and positive results regarding the survival of GBM patients upon cannabinoids treatment. Nevertheless, more human clinical trials with large sample sizes are urgently needed to implement cannabinoids, including CBD, into standard GBM treatment.

TMEM2 induces epithelial-mesenchymal transition and promotes resistance to temozolomide in GBM cells

Glioblastoma multiforme (GBM) is the most common intracranial malignant tumor and is notorious for its poor prognosis. An important element in the short overall survival of GBM patients is the lack of understanding the pathogenesis and progression of tumor and deficiency biomarkers that can be used for early diagnosis and therapeutic sensitivity monitoring. Studies have shown that transmembrane protein 2 (TMEM2) is participated in tumorigenesis of various human tumors, including rectal and breast cancers. Although Qiuyi Jiang et al. have reported that TMEM2 combined with IDH1/2 and 1p19q can predict the survival time of glioma patients based on bioinformatics, its expression and biological role of glioma remain unclear. In our study, we investigated the effect of TMEM2 expression level on glioma malignancy in public datasets and an independent internal dataset. We revealed TEMM2 expression was higher in GBM tissues than in non-tumor brain tissues (NBT). Moreover, the increase in TMEM2 expression level was closely related to tumor malignancy. The survival analysis showed that TMEM2 high expression reduces survival time in all glioma patients, including GBM and LGG patients. Subsequent experiments demonstrated that knockdown TMEM2 inhibited proliferation of GBM cells. In addition, we analyzed TMEM2 mRNA levels in different GBM subtypes, and demonstrated that TMEM2 expression was upregulated in mesenchymal subtype. Meanwhile, bioinformatics analysis and transwell assay indicated that knockdown TMEM2 suppressed epithelial-mesenchymal transition (EMT) in GBM. Importantly, Kaplan–Meier analysis demonstrated that TMEM2 high expression reduced the treatment response to TMZ in GBM patients. Knockdown of TMEM2 alone did not reduce apoptosis GBM cells, but significant apoptotic cells were observed in the group treated with additional TMZ. These studies may contribute to improving the accuracy of early diagnosis and evaluating the effectiveness of TMZ treatment in GBM patients.

Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma

Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.

Surprising Long Term Survival in Glioblastoma Patients Treated with Cannabidiol

Glioblastoma multiforme (GBM) is one of the most deadly tumors; even with aggressive radiochemotherapy, mean survival rates are only around 14 to 16 months post diagnose. Here we present the follow-up of 15 patients with GBM that have received concomitant cannabidiol (CBD) in addition to standard therapy, and that have been reported in details two years ago. The survival time of patients is presented together with prognostic factors such as age at diagnose, molecular markers and dose of CBD. The actual median survival time is 28 months, the arithmetic mean is 30.9 months, therefore about three to five times longer than expected. When comparing the group of patients surviving less than 28 months with those who lived longer, we found that all subjects who received a low dose of CBD (200mg per day) were in the group surviving less than 28 months. Apart from the daily dose of CBD, no striking difference was observed for other prognostic factors. It is concluded that CBD contributed to the long term survival of GBM patients, and that this effect depends on the dose.

Proteomic analysis predicts anti-angiogenic resistance in recurred glioblastoma

BackgroundRecurrence is common in glioblastoma multiforme (GBM) because of the infiltrative, residual cells in the tumor margin. Standard therapy for GBM consists of surgical resection followed by chemotherapy and radiotherapy, but the median survival of GBM patients remains poor (~ 1.5 years). For recurrent GBM, anti-angiogenic treatment is one of the common treatment approaches. However, current anti-angiogenic treatment modalities are not satisfactory because of the resistance to anti-angiogenic agents in some patients. Therefore, we sought to identify novel prognostic biomarkers that can predict the therapeutic response to anti-angiogenic agents in patients with recurrent glioblastoma.MethodsWe selected patients with recurrent GBM who were treated with anti-angiogenic agents and classified them into responders and non-responders to anti-angiogenic therapy. Then, we performed proteomic analysis using liquid-chromatography mass spectrometry (LC–MS) with formalin-fixed paraffin-embedded (FFPE) tissues obtained from surgical specimens. We conducted a gene-ontology (GO) analysis based on protein abundance in the responder and non-responder groups. Based on the LC–MS and GO analysis results, we identified potential predictive biomarkers for anti-angiogenic therapy and validated them in recurrent glioblastoma patients.ResultsIn the mass spectrometry-based approach, 4957 unique proteins were quantified with high confidence across clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic patterns (n = 269 proteins) between responders and non-responders. The GO term enrichment analysis revealed a cluster of genes related to immune cell-related pathways (e.g., TMEM173, FADD, CD99) in the responder group, whereas the non-responder group had a high expression of genes related to nuclear replisome (POLD) and damaged DNA binding (ERCC2). Immunohistochemistry of these biomarkers showed that the expression levels of TMEM173 and FADD were significantly associated with the overall survival and progression-free survival of patients with recurrent GBM.ConclusionsThe candidate biomarkers identified in our protein analysis may be useful for predicting the clinical response to anti-angiogenic agents in patients with recurred GBM.

Comprehensive analysis of the prognosis and immune infiltrates for the BET protein family reveals the significance of BRD4 in glioblastoma multiforme.

Background: Glioblastoma multiforme (GBM) is the most common and invasive primary central nervous system tumor. The prognosis after surgery, radiation and chemotherapy is very poor. Bromodomain (BRD) proteins have been identified in oncogenic rearrangements, and play a key role in the development of multiple cancers. However, the relationship between BET proteins and prognosis of GBM are still worth exploring, and the distinct functions of BET proteins and tumor immunology in GBM have not been fully elucidated. Therefore, it is particularly important to develop effective biomarkers to predict the prognosis of GBM patients. Methods: Metascape, David, Kaplan-Meier Plotter, Oncomine, GEPIA, TCGA, TIMER, and LinkedOmics databases were used to assess the expression and prognosis for BET proteins in GBM. ROC analysis of risk model was established to identify the correlation between BET genes and overall survival in GBM patients. TIMER and GEPIA databases were used to comprehensively investigate the correlation between BET genes and tumor immune infiltration cells. Moreover, the image of immunohistochemistry staining of BET proteins in normal tissue and tumor tissue were retrived from the HPA database. In addition, differential analysis and pathway enrichment analysis of BRD4 gene expression profile were also carried out. Finally, immune-fluorescence and Western blot were used to clarify the expression of BRD4 in GBM cells. Results: Bioinformatics analysis showed that the expression levels of BET genes in GBM may play an important role in oncogenesis. Specifically, bioinformatic and immunohistochemistry analysis showed that BRD4 protein was more highly expressed in tumor tissues than that in normal tissues. The high expression of BRD4 was associated with poor prognosis in GBM. The expression of BET genes were closely related to the immune checkpoint in GBM. The correlation effect of BRD4 was significantly higher than other BET genes, which represented negative correlation with immune checkpoint. The expression of BRD4 was positively associated with tumor purity, and negatively associated with immune infiltration abundance of macrophage, neutrophil and CD8+ T-cell, respectively. Cox analysis showed that the model had good survival prediction and prognosis discrimination ability. In addition, the expression levels of BRD4 protein was significantly higher in U-251MGcells than that in normal cells, which was consistent with the results of bioinformatics data. Conclusion: This study implied that BRD4 could be hopeful prognostic biomarker in GBM. The increased expression of BRD4 may act as a molecular marker to identify GBM patients with high-risk subgroups. BRD4 may be a valuable prognostic biomarker, and a potential target of precision therapy against GBM.

ALKBH5-PYCR2 Positive Feedback Loop Promotes Proneural-Mesenchymal Transition Via Proline Synthesis In GBM.

AlkB homolog 5, RNA demethylase (ALKBH5) is abnormally highly expressed in glioblastoma multiforme (GBM) and is negatively correlated with overall survival in GBM patients. In this study, we found a new mechanism that ALKBH5 and pyrroline-5-carboxylate reductase 2 (PYCR2) formed a positive feedback loop involved in proline synthesis in GBM. ALKBH5 promoted PYCR2 expression and PYCR2-mediated proline synthesis; while PYCR2 promoted ALKBH5 expression through the AMPK/mTOR pathway in GBM cells. In addition, ALKBH5 and PYCR2 promoted GBM cell proliferation, migration, and invasion, as well as proneural-mesenchymal transition (PMT). Furthermore, proline rescued AMPK/mTOR activation and PMT after silencing PYCR2 expression. Our findings reveal an ALKBH5-PYCR2 axis linked to proline metabolism, which plays an important role in promoting PMT in GBM cells and may be a promising therapeutic pathway for GBM.

Development of a novel angiogenesis-related lncRNA signature to predict the prognosis and immunotherapy of glioblastoma multiforme.

Long noncoding RNA (lncRNA) can regulate tumorigenesis, angiogenesis, proliferation, and other tumor biological behaviors, and is closely related to the growth and progression of glioma. The purpose of this research was to investigate the role of angiogenesis-related lncRNA in the prognosis and immunotherapy of glioblastoma multiforme (GBM). Differential analysis was carried out to acquire angiogenesis-related differentially expressed lncRNAs (AR-DElncRNAs). The AR-DElncRNAs were then subjected to univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses to construct a prognostic model. Based on the median risk score, patients were classified into high-risk and low-risk groups. Kaplan-Meier survival analysis was conducted to estimate the prognostic value of the prognostic model. In addition, a nomogram was built to predict individual survival probabilities by combining clinicopathological characteristics and a prognostic model. Furthermore, immune infiltration, immunotherapy, and drug sensitivity analyses were administered to investigate the differences between the high- and low-risk groups. We identified 3 lncRNAs (DGCR5, PRKAG2-AS1, and ACAP2-IT1) that were significantly associated with the survival of GBM patients from the 255 AR-DElncRNAs based on univariate Cox and LASSO analyses. Then, a prognostic model was structured according to these 3 lncRNAs, from which we found that high-risk GBM patients had a worse prognosis than that of low-risk patients. Moreover, the risk score was determined to be an independent prognostic factor [hazard ratio (HR) =1.444; 95% confidence interval (CI): 1.014-2.057; P<0.05]. The immune microenvironment analysis revealed that the immune score, stromal score, and Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) score were significantly higher in the high-risk group than in the low-risk group. Neutrophils, macrophages, immature dendritic cells (iDCs), natural killer (NK) CD56dim cells, activated DCs (aDCs), and uncharacterized cells were different in the high- and low-risk groups. In addition, the high-risk group had a stronger sensitivity to immunotherapy. Furthermore, the sensitivity of 28 potential chemotherapeutic drugs differed significantly between the high- and low-risk groups. A novel angiogenesis-related lncRNA signature could be used to predict the prognosis and treatment of GBM.

QOL-13. THE ROLE OF EPILEPSY IN ELDERLY PATIENTS WITH GLIOBLASTOMA: AN AUSTRIAN MULTICENTER ANALYSIS

Abstract BACKGROUND With an aging population, acquisition of a better understanding of prognostic factors in elderly patients with Glioblastoma multiforme (GBM) is of utmost importance. Epileptic seizures have been found to correlate with improved overall survival (OS) in low-grade gliomas; however, the impact of epilepsy in GBM patients on outcome parameters is poorly defined. This study aims at specifically evaluating the impact of epilepsy in elderly GBM patients. Material &amp; METHODS Two Austrian academic neurosurgical centers retrospectively analyzed all elderly (≥ 65 years) GBM patients with de-novo tumors, who underwent surgery between 09/2006 and 07/2021. Epidemiological, histopathological and survival data were gained from patients’ electronic charts and screened for presence of epilepsy preoperatively or during follow-up. Tumor volume was assessed using standardized software. RESULTS 391 patients (55% males, 45% females) with a median age at surgery of 73 years (IqR 68.5-77.5) were analyzed. The mean predicted OS was 12.4 months (CI95% 10.9-14.0). Mean follow-up was 10.4 months (CI95% 9.1-11.6) in our cohort. Median tumor volume amounted to 26.47 cm3 (IqR 12.65-43.49). 95 patients (24%) suffered from preoperative epilepsy. 17 (18%) patients showed epilepsy after tumor resection. Four patients (1.0%) showed a worsening of already preoperatively diagnosed seizures. Patients with lower tumor volumes experienced significantly more often seizures compared to patients with larger tumors, p&amp;lt; 0.001. Survival did not correlate with preoperative epilepsy (p &amp;gt; 0.05). However, Cox-regression revealed that multifocal tumor location (HR=1.777, p=0.025) and thalamic involvement (HR=11.121, p=0.030) influenced OS. Surgery-associated complications shortened OS significantly (HR=1.945 [CI95% 1,296-2,916], p=0.025). CONCLUSION Even though epilepsy was not found to directly impact survival in elderly GBM patients, we found that surgery led to epilepsy freedom in a significant proportion of our patient cohort, thereby potentially leading to improved QoL. Greatest focus should be set on avoiding any surgery-associated deficits, since these severely influence the OS.

Peroxidase-mimicking TA-VOx nanobranches for enhanced photothermal/chemodynamic therapy of glioma by inhibiting the expression of HSP60

Glioblastoma multiforme (GBM) is the most prevalent malignant brain tumor. It expresses high levels of heat shock protein (HSP60), which is associated with poor prognosis. Chemodynamic therapy (CDT) can be improved by photothermal therapy (PTT) and facilitate tumor eradication. Therefore, it is necessary to develop novel agents that synergize with the tumor killing effects of PTT/CDT by downregulating HSP60. Based on The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases and clinical cases, this study determined that HSP60 was upregulated and associated with reduced overall survival (OS) in GBM patients. Herein, TA-VOx nanobranches (TA-VOx NBs) were successfully synthesized by a one-step self-assembly procedure, which had excellent photothermal conversion characteristics and improved peroxidase-mimicking activity at elevated temperatures. Moreover, TA-VOx NBs can degrade to VO2+ in a slightly acidic tumor microenvironment. In vitro and in vivo studies showed that TA-VOx NBs synergized with PTT/CDT and improved glioma eradication under 808 nm irradiation due to the heat-induced ROS generation and the inhibition of HSP60. Furthermore, TA-VOx NBs were rapidly cleared by the kidney and showed good biosafety. Combined with the ease of fabrication, this is a promising nanomaterial that can be introduced for clinical translation in cancer therapy.