Applying the en-bloc technique in corpus callosum glioblastoma surgery contributes to maximal resection and better prognosis: a retrospective study.

BACKGROUND: Corpus callosum glioblastoma (ccGBM) is a specific type of GBM and has worse outcomes than other non-ccGBMs. We sought to identify whether en-bloc resection of ccGBMs based on T2-FLAIR imaging contributes to clinical outcomes and can achieve a satisfactory balance between maximal resection and preservation of neurological function. METHODS: A total of 106 adult ccGBM patients (including astrocytoma, WHO grade 4, IDH mutation, and glioblastoma) were obtained from the Department of Neurosurgery in Nanfang Hospital between January 2008 and December 2018. The clinical data, including gender, age, symptoms, location of tumor, involvement of eloquent areas, extent of resection (EOR), pre- and postoperative Karnofsky Performance Status (KPS) scales, and National Institute of Health stroke scale (NIHSS) scores were collected. Propensity score matching (PSM) analysis was applied to control the confounders for analyzing the relationship between the en-bloc technique and EOR, and the change in the postoperative KPS scales and NIHSS scores. RESULTS: Applying the en-bloc technique did not negatively affect the postoperative KPS scales compared to no-en-bloc resection (P = 0.851 for PSM analysis) but had a positive effect on preserving or improving the postoperative NIHSS scores (P = 0.004 for PSM analysis). A positive correlation between EOR and the en-bloc technique was identified (r = 0.483, P < 0.001; r = 0.720, P < 0.001 for PSM analysis), indicating that applying the en-bloc technique could contribute to enlarged maximal resection. Further survival analysis confirmed that applying the en-bloc technique and achieving supramaximal resection could significantly prolong OS and PFS, and multivariate analysis suggested that tumor location, pathology, EOR and the en-bloc technique could be regarded as independent prognostic indicators for OS in patients with ccGBMs, and pathology, EOR and the en-bloc technique were independently correlated with patient's PFS. Interestingly, the en-bloc technique also provided a marked reduction in the risk of tumor recurrence compared with the no-en-bloc technique in tumors undergoing TR, indicating that the essential role of the en-bloc technique in ccGBM surgery (HR: 0.712; 95% CI: 0.535-0.947; P = 0.02). CONCLUSIONS: The en-bloc technique could contribute to achieving an enlarged maximal resection and could significantly prolong overall survival and progression-free survival in patients with ccGBMs.

Supramaximal resection based on en-bloc technique reduces tumor burden and prolongs survival in primary supratentorial lobar glioblastoma.

PURPOSE: Resection beyond the contrast-enhanced zone contributed to reduce tumor burden and prolong survival in glioblastomas. The optimal extent of resection (EOR) and how to achieve it are worthy of continuous investigation for obtaining a satisfactory balance between maximal resection and the preservation of neurological function. METHODS: A total of 340 adult supratentorial lobar glioblastomas (included astrocytoma, WHO 4, IDH mutation and glioblastoma) were retrospectively evaluated. The clinical data, EOR, technique of resection, postoperative complications, overall survival (OS) and progression-free survival (PFS) were assessed by univariate, multivariate and propensity score matched analysis. Histological staining was performed to comprehend the effect of the membranous structures and the cell distribution in tumoral and peritumoral regions. RESULTS: Supramaximal resection (SMR) was confirmed as resection with 100% EORCE and > 50% EORnCE in glioblastomas by Cox proportional hazards model. Histological results showed SMR reduced the cell density of surgical edge compared to total resection. En-bloc technique based on membranous structures, which had blocking effect on tumoral invasion, contributed to achieve SMR. Moreover, applying en-bloc technique and achieving SMR did not additionally deteriorate neurological function and had similarly effects on the improvement of neurological function. Multivariate analysis confirmed that IDH1 status, technique of resection and EOR were independently correlated with PFS, and > 64 years old, IDH1 status, technique of resection, EOR and preoperative NIHSS were independently correlated with OS. CONCLUSIONS: Applying en-bloc technique and achieving SMR, which could reduce tumor burden and did not increase additional complications, both had remarkedly positive effects on clinical outcomes in patients with primary supratentorial lobar glioblastomas.

Molecular mechanism by which CDCP1 promotes proneural-mesenchymal transformation in primary glioblastoma.

BACKGROUND: Compared with the proneural (PN) subtype of glioblastoma (GBM), the mesenchymal (MES) subtype is more invasive and immune evasive and is closely related to poor prognosis. Here, we used transcriptome data and experimental evidence to indicate that CUB domain-containing protein 1 (CDCP1) is a novel regulator that facilitates the transformation of PN-GBM to MES-GBM. METHODS: The mRNA expression data of CDCP1 in glioma were collected from the TCGA, CGGA and GEO databases, and in vitro experiments verified CDCP1 expression in glioma tissue samples. Independent prognostic analysis revealed the correlation of the CDCP1 expression level and patient survival. Bioinformatics analysis and experiments verified the biological function of CDCP1. Multivariate proportional hazards models and a PPI network were used to select key genes. A prognostic risk model for predicting the survival of glioma patients was constructed based on the selected genes. RESULTS: The results showed that the expression of CDCP1 increased with increasing tumor grade and that the overexpression of CDCP1 correlated with a poor prognosis. CDCP1 was highly expressed in MES-GBM but weakly expressed in PN-GBM. The risk model (considering CDCP1 combined with CD44 and ITGAM expression) could represent a tool for predicting survival and prognosis in glioma patients. CONCLUSIONS: Our study indicates that CDCP1 plays an important role in facilitating the transformation of PN-GBM to MES-GBM.

Recycling of SLC38A1 to the plasma membrane by DSCR3 promotes acquired temozolomide resistance in glioblastoma.

PURPOSE: Glioblastoma multiforme (GBM) is a primary brain tumor with devastating prognosis. Although the O6-methylguanine-DNA methyltransferase (MGMT) leads to inherent temozolomide (TMZ) resistance, approximately half of GBMs were sufficient to confer acquired TMZ resistance, which express low levels of MGMT. The purpose of this study was to investigate the underlying mechanisms of the acquired TMZ resistance in MGMT-deficient GBM. METHODS: The function of Down syndrome critical region protein 3 (DSCR3) on MGMT-deficient GBM was investigated in vitro and in an orthotopic brain tumor model in mice. Purification of plasma membrane proteins by membrane-cytoplasmic separation and subsequent label free-based quantitative proteomics were used to identified potential protein partners for DSCR3. Immunofluorescence was performed to show the reverse transport of solute carrier family 38 member 1 (SLC38A1) mediated by DSCR3. RESULTS: DSCR3 is upregulated in MGMT-deficient GBM cells during TMZ treatment. Both DSCR3 and SLC38A1 were highly expressed in recurrent GBM patients. Silencing DSCR3 or SLC38A1 expression can increase TMZ sensitivity in MGMT-deficient GBM cells. Combination of proteomics and in vitro experiments show that DSCR3 directly binds internalized SLC38A1 to mediate its sorting into recycling pathway, which maintains the abundance on plasma membrane and enhances uptake of glutamine in MGMT-deficient GBM cells. CONCLUSIONS: DSCR3 is a crucial regulator of acquired TMZ resistance in MGMT-deficient GBM. The DSCR3-dependent recycling of SLC38A1 maintains its abundance on plasma membrane, leading to tumor progression and acquired TMZ resistance in MGMT-deficient GBM.

Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in a glioblastoma patient with secondary osteosarcoma: case report and genetic characterization.

BACKGROUND: The incidence of osteosarcoma as a secondary neoplasm in glioblastoma patient is extremely rare. The genetic characteristic still remains unclear until now. CASE DESCRIPTION: We reported a 47-year-old female patient with multiple intracranial disseminations and infiltrations (splenium of the corpus callosum and lateral ventricular wall) of a rapid progressive glioblastoma underwent occipital craniotomy and total resection of all the enhancing lesions. Whole-exome sequencing and pathological examination revealed glioblastoma, IDH1 wild type, PTEN deficient, TERT mutated, NF1mutated, MGMT unmethylated. After surgery, the patient received combined therapeutic regimen of TTFields (tumor-treating fields) plus pembrolizumab plus temozolomide and TTFields plus everolimus, which displayed significant clinical benefits. During the combined therapeutic course, an extremely rare secondary malignant neoplasm occurred, femur MR and pathological detection of biopsy tissue demonstrated osteosarcoma. The result of whole-exome sequencing revealed 7 germline mutated genes (EPAS1, SETD2, MSH3, BMPR1A, ERCC4, CDH1, AR). Bioinformatic analysis showed the two germline mutations (MSH3 and ERCC4) induced deficiency in the DNA repair machinery, which resulting in the accumulation of mutations and may generate neoantigens contributing to the development of a secondary osteosarcoma in this case. CONCLUSION: Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in this case. Germline MSH3 and ERCC4 mutation may induce a secondary osteosarcoma in glioblastoma patients.

Establishment of age group classification for risk stratification in glioma patients.

BACKGROUND: Age is associated with the prognosis of glioma patients, but there is no uniform standard of age-group classification to evaluate the prognosis of glioma patients. In this study, we aimed to establish an age group classification for risk stratification in glioma patients. METHODS: 1502 patients diagnosed with gliomas at Nanfang Hospital between 2000 and 2018 were enrolled. The WHO grade of glioma was used as a dependent variable to evaluate the effect of age on risk stratification. The evaluation model was established by logistic regression, and the Akaike information criterion (AIC) value of the model was used to determine the optimal cutoff points for age-classification. The differences in gender, WHO grade, pathological subtype, tumor cell differentiation, tumor size, tumor location, and molecular markers between different age groups were analyzed. The molecular markers included GFAP, EMA, MGMT, P53, NeuN, Oligo2, EGFR, VEGF, IDH1, Ki-67, PR, CD3, H3K27M, TS, and 1p/19q status. RESULTS: The proportion of men with glioma was higher than that of women with glioma (58.3% vs 41.7%). Analysis of age showed that appropriate classifications of age group were 0-14 years old (pediatric group), 15-47 years old (youth group), 48-63 years old (middle-aged group), and ≥ 64 years old (elderly group).The proportions of glioblastoma and large tumor size (4-6 cm) increased with age (p = 0.000, p = 0.018, respectively). Analysis of the pathological molecular markers across the four age groups showed that the proportion of patients with larger than 10% area of Ki-67 expression or positive PR expression increased with age (p = 0.000, p = 0.017, respectively). CONCLUSIONS: Appropriate classifications of the age group for risk stratification are 0-14 years old (pediatric group), 15-47 years old (young group), 48-63 years old (middle age group) and ≥ 64 years old (elderly group). This age group classification is effective in evaluating the risk of glioblastoma in glioma patients.

Acquired temozolomide resistance in MGMT-deficient glioblastoma cells is associated with regulation of DNA repair by DHC2.

The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma.

Quantitative Proteomics Analysis Reveals Nuclear Perturbation in Human Glioma U87 Cells treated with Temozolomide.

Glioblastoma (GBM) is the most malignant and aggressive glioma, which has a very poor prognosis. Temozolomide (TMZ) is still a first-line treatment, but resistance is inevitable even in MGMT-deficient glioblastoma cells. The aims of this study were to comprehend the effect of TMZ on nucleus and the underlying mechanism of acquired TMZ resistance in MGMT-deficient GBM. We show the changes of nuclear proteome in the MGMT-deficient GBM U87 cells treated with TMZ for 1 week. Label-free-based quantitative proteomics were used to investigate nuclear protein abundance change. Subsequently, gene ontology function annotation, KEGG pathway analysis, protein-protein interaction (PPI) network construction analysis of DAPs, and immunofluorescence were applied to validate the quality of proteomics. In total, 457 (455 gene products) significant DAPs were identified, of which 327 were up-regulated and 128 were down-regulated. Bioinformatics analysis uncovered RAD50, MRE11, UBR5, MSH2, MSH6, DDB1, DDB2, RPA1, RBX1, CUL4A, and CUL4B mainly enriched in DNA damage repair related pathway and constituted a protein-protein interaction network. Ribosomal proteins were down-regulated. Cells were in a stress-responsive state, while the entire metabolic level was lowered. SIGNIFICANCE OF THE STUDY: In U87 cell treated with TMZ for 1 week, which resulted in DNA damage, we found various proteins dysregulated in the nucleus. Some proteins related to the DNA damage repair pathway were up-regulated, and there was a strong interaction. We believe this is the potential clues of chemotherapy resistance in tumour cells. These proteins can be used as indicators of tumour resistance screening in the future.

Overexpression of COX7A2 is associated with a good prognosis in patients with glioma.

Cytochrome c oxidase subunit 7A2 (COX7A2) is a nuclear-encoded polypeptide involved in assembly and regulation of cytochrome c oxidase (COX). Changes in the respiratory chain as big complex are known to be associated with cancer, but little research has been performed to discover COX7A2 as a prognostic marker in glioma. In the present study, we investigated COX7A2 expression and its prognostic significance in glioma. Glioma surgical tissue samples were taken from 126 patients who had been followed up from 4 to 51 months. Immunohistochemistry were used to test COX7A2 expression in the 126 tumor samples. Eighty-six of 126 (68.3%) paraffin-embedded glioma biopsies showed high expression of COX7A2. Statistical analysis displayed that there was significant difference of COX7A2 expression level in patients categorized according to WHO classification. Kaplan-Meier survival analysis revealed that patients with higher COX7A2 expression had longer overall survival time and better prognosis. R2: microarray analysis based on Tumor Glioma French 284 database, Tumor Glioblastoma TCGA 540 database, and Tumor Glioma Kawaguchi 50 database testified that high expression of COX7A2 is associated with a good prognosis in patients with glioma. Multivariate analysis showed that COX7A2 high expression was an independent prognostic indicator for survival. Our results suggest that COX7A2 could be served as a valuable prognostic marker of glioma.

miR-1268a regulates ABCC1 expression to mediate temozolomide resistance in glioblastoma.

INTRODUCTION: Temozolomide (TMZ) is the preferred chemotherapeutic drug approved for the Glioblastoma multiforme (GBM) treatment. However, resistance to TMZ is the most intractable challenge for treatment of GBM. Screening of miRNAs is becoming a novel strategy to reveal underlying mechanism of drug-resistance of human tumors. MATERIALS AND METHODS: We conducted RNA sequencing (RNA-seq) for GBM cells treated continuously with TMZ 1 or 2 week or not. Bioinformatic analysis was used to predict targets of these altered miRNAs. Subsequently, we studied the potential role of miR-1268a in TMZ-resistance of GBM cells. RESULTS: Expression levels of 55 miRNAs were identified altering both after 1 and 2 weeks TMZ treatment. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to illuminate the biological implication and related pathways of predicted target genes. We showed that miR-1268a was downregulated after TMZ treatment and targeted ABCC1/MRP1, a membrane transporter contributing to drug resistance, using dual-luciferase assay. Furthermore, we confirmed overexpression of miR-1268a inhibited protein translation of ABCC1 and restored upregulated expression of ABCC1 due to TMZ. Inversely, knockdown of miR-1268a increased ABCC1 at protein level and enhanced upregulation of ABCC1 with TMZ treatment. In addition, our data indicated that miR-1268a enhanced TMZ sensitivity in GBM cells. CONCLUSION: Through RNA-seq analysis, we discovered miR-1268a and elucidated its role in modulating TMZ-resistance of GBM cells by targeting ABCC1.

Patient-derived organoids in human cancer: a platform for fundamental research and precision medicine.

Cancer is associated with a high degree of heterogeneity, encompassing both inter- and intra-tumor heterogeneity, along with considerable variability in clinical response to common treatments across patients. Conventional models for tumor research, such as in vitro cell cultures and in vivo animal models, demonstrate significant limitations that fall short of satisfying the research requisites. Patient-derived tumor organoids, which recapitulate the structures, specific functions, molecular characteristics, genomics alterations and expression profiles of primary tumors. They have been efficaciously implemented in illness portrayal, mechanism exploration, high-throughput drug screening and assessment, discovery of innovative therapeutic targets and potential compounds, and customized treatment regimen for cancer patients. In contrast to conventional models, tumor organoids offer an intuitive, dependable, and efficient in vitro research model by conserving the phenotypic, genetic diversity, and mutational attributes of the originating tumor. Nevertheless, the organoid technology also confronts the bottlenecks and challenges, such as how to comprehensively reflect intra-tumor heterogeneity, tumor microenvironment, tumor angiogenesis, reduce research costs, and establish standardized construction processes while retaining reliability. This review extensively examines the use of tumor organoid techniques in fundamental research and precision medicine. It emphasizes the importance of patient-derived tumor organoid biobanks for drug development, screening, safety evaluation, and personalized medicine. Additionally, it evaluates the application of organoid technology as an experimental tumor model to better understand the molecular mechanisms of tumor. The intent of this review is to explicate the significance of tumor organoids in cancer research and to present new avenues for the future of tumor research.

Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder.

Depression is a major contributor to poor global health and disability, with a recently increasing incidence. Although drug therapy is commonly used to treat depression, conventional antidepressant drugs have several disadvantages, including slow onset, low response rates and severe adverse effects. Therefore, developing effective therapies for depression remains challenging. Although various aetiological theories of depression exist, the underlying mechanisms of depression are complex, and further research is crucial. Moreover, oxidative stress (OS)-induced lipid peroxidation has been demonstrated to trigger ferroptosis. Both OS and ferroptosis are pivotal mechanisms implicated in the pathogenesis of neurological disorders, and investigation of the mediators involved in these processes has emerged as a prominent and active research direction. One previous study revealed that regulatory proteins involved in ferroptosis are implicated in the pathogenesis of depression, and antidepressant drugs could reverse depressive symptoms by inhibiting ferroptosis in vivo, suggesting an important role of ferroptosis in the pathogenesis of depression. Hence, our current comprehensive review offers an up-to-date perspective on the intricate mechanisms involved, specifically concerning ferroptosis and OS in the context of depression, along with promising prospects for using molecular mediators to target ferroptosis. We delineate the key targets of molecular mediators involved in OS and ferroptosis implicated in depression, most notably reactive oxygen species and iron overload. Considering the pivotal role of OS-induced ferroptosis in the pathogenesis of neurological disorders, delving deeper into the underlying subsequent mechanisms will contribute significantly to the identification of novel therapeutic targets for depression.

Albumin-bound paclitaxel augment temozolomide treatment sensitivity of glioblastoma cells by disrupting DNA damage repair and promoting ferroptosis.

BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma (GBM) patients has been limited by resistance in the clinic. Currently, there are no clinically proven therapeutic options available to restore TMZ treatment sensitivity. Here, we investigated the potential of albumin-bound paclitaxel (ABX), a novel microtubule targeting agent, in sensitizing GBM cells to TMZ and elucidated its underlying molecular mechanism. METHODS: A series of in vivo and in vitro experiments based on two GBM cell lines and two primary GBM cells were designed to evaluate the efficacy of ABX in sensitizing GBM cells to TMZ. Further proteomic analysis and validation experiments were performed to explore the underlying molecular mechanism. Finally, the efficacy and mechanism were validated in GBM patients derived organoids (PDOs) models. RESULTS: ABX exhibited a synergistic inhibitory effect on GBM cells when combined with TMZ in vitro. Combination treatment of TMZ and ABX was highly effective in suppressing GBM progression and significantly prolonged the survival oforthotopic xenograft nude mice, with negligible side effects. Further proteomic analysis and experimental validation demonstrated that the combined treatment of ABX and TMZ can induce sustained DNA damage by disrupting XPC and ERCC1 expression and nuclear localization. Additionally, the combination treatment can enhance ferroptosis through regulating HOXM1 and GPX4 expression. Preclinical drug-sensitivity testing based on GBM PDOs models confirmed that combination therapy was significantly more effective than conventional TMZ monotherapy. CONCLUSION: Our findings suggest that ABX has the potential to enhance TMZ treatment sensitivity in GBM, which provides a promising therapeutic strategy for GBM patients.

Nucleo-cytoplasmic shuttling of 14-3-3 epsilon carrying hnRNP C promotes autophagy.

Translocation of 14-3-3 protein epsilon (14-3-3ε) was found to be involved in Triptolide (Tp)-induced inhibition of colorectal cancer (CRC) cell proliferation. However, the form of cell death induced by 14-3-3ε translocation and mechanisms underlying this effect remain unclear. This study employed label-free LC-MS/MS to identify 14-3-3ε-associated proteins in CRC cells treated with or without Tp. Our results confirmed that heterogeneous nuclear ribonucleoproteins C1/C2 (hnRNP C) were exported out of the nucleus by 14-3-3ε and degraded by ubiquitination. The nucleo-cytoplasmic shuttling of 14-3-3ε carrying hnRNP C mediated Tp-induced proliferation inhibition, cell cycle arrest and autophagic processes. These findings have broad implications for our understanding of 14-3-3ε function, provide an explanation for the mechanism of nucleo-cytoplasmic shuttling of hnRNP C and provide new insights into the complex regulation of autophagy.

IKBIP, a novel glioblastoma biomarker, maintains abnormal proliferation of tumor cells by inhibiting the ubiquitination and degradation of CDK4.

Sustained proliferative signaling is a crucial hallmark and therapeutic target in glioblastoma (GBM); however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. In this study, I kappa B kinase interacting protein (IKBIP) was identified to be correlated with the progression of GBM by analysis of The Cancer Genome Atlas (TCGA) data. TCGA database analysis indicated that higher IKBIP expression was associated with high tumor grade and poor prognosis in GBM patients, and these correlations were subsequently validated in clinical samples. IKBIP knockdown induced G1/S arrest by blocking the Cyclin D1/CDK4/CDK6/CDK2 pathway. Our results showed that IKBIP may bind directly to CDK4, a key cell cycle checkpoint protein, and prevent its ubiquitination-mediated degradation in GBM cells. An in vivo study confirmed that IKBIP knockdown strongly suppressed cell proliferation and tumor growth and prolonged survival in a mouse xenograft model established with human GBM cells. In conclusion, IKBIP functions as a novel driver of GBM by binding and stabilizing the CDK4 protein. IKBIP could be a potential therapeutic target in GBM.

A Four-Gene Panel for the Prediction of Prognosis and Immune Cell Enrichment in Gliomas.

BACKGROUNDS: Gliomas is a deadly disease without effective therapy. Although immunotherapy has provided novel choices for glioma treatment, the curative efficacy is unsatisfactory due to the complex immune micro-environment and the heterogeneity of the disease. Therefore, it is urgent to identify effective biomarkers and therapeutic targets. METHODS: Overall survival, gene ontology (GO), Kyoto Encyclopedia of Genes, and Genomes (KEGG) enrichment analysis, Gene Set Enrichment Analysis (GSEA) and immune infiltration were analyzed by bioinformatics software with The Cancer Genome Atlas (TCGA) database. RESULTS: Based on the TCGA database and protein-protein interaction (PPI) analysis revealed a four-gene panels [DNA topoisomerase II alpha (TOP2A); ribonucleotide reductase regulatory subunit M2 (RRM2); kinesin family member 20 A (KIF20A) and DLG associated protein 5 (DLGAP5)], which correlated with poor prognosis, including overall survival (OS), disease specific survival (DSS) and progress free interval (PFI), mitosis, cell cycle, Th2 cells and macrophages enrichment. The four-gene panels correlates with the biomarkers of Th2 cells, macrophages tumor-associated macrophages (TAMs) and the immune checkpoint molecules in gliomas. CONCLUSION: The four-gene panels represented a novel prognostic indicator and potential therapeutic target for the treatment of glioma. In addition, the four-gene panels might contribute to enhance the efficacy of immunotherapy in glioma.

Identification of Necroptosis-related Molecular Subtypes and Construction of Necroptosis-related Gene Signature for Glioblastoma Multiforme.

Background Necroptosis is a highly regulated and genetically controlled process, and therefore, attention has been paid to the exact effects of this disorder on a variety of diseases, including cancer. An in-depth understanding of the key regulatory factors and molecular events that trigger necroptosis can not only identify patients at risk of cancer development but can also help to develop new treatment strategies. Aims This study aimed to increase understanding of the complex role of necroptosis in glioblastoma multiforme (GBM) and provide a new perspective and reference for accurate prediction of clinical outcomes and gene-targeted therapy in patients with GBM. The objective of this study was to analyze the gene expression profile of necroptosis regulatory factors in glioblastoma multiforme (GBM) and establish a necroptosis regulatory factor-based GBM classification and prognostic gene signature to recognize the multifaceted impact of necroptosis on GBM. Method The necroptosis score of the glioblastoma multiforme (GBM) sample in TCGA was calculated by ssGSEA, and the correlation between each gene and the necroptosis score was calculated. Based on necroptosis score-related genes, unsupervised consensus clustering was employed to classify patients. The prognosis, tumor microenvironment (TME), genomic changes, biological signal pathways and gene expression differences among clusters were analyzed. The gene signature of GBM was constructed by Cox and LASSO regression analysis of differentially expressed genes (DEGs). Result Based on 34 necroptosis score-related genes, GBM was divided into two clusters with different overall survival (OS) and TME. A necroptosis-related gene signature (NRGS) containing 8 genes was developed, which could stratify the risk of GBM in both the training set and verification set and had good prognostic value. NRGS and age were both independent prognostic indicators of GBM, and a nomogram developed by the integration of both of them showed a better predictive effect than traditional clinical features. Conclusion In this study, patients from public data sets were divided into two clusters and the unique TME and molecular characteristics of each cluster were described. Furthermore, an NRGS was constructed to effectively and independently predict the survival outcome of GBM, which provides some insights for the implementation of personalized precision medicine in clinical practice.

Exercise Intervention as a Therapy in Patients with Diabetes Mellitus and Sarcopenia: A Meta-Analysis.

INTRODUCTION: Sarcopenia is defined as a progressive and generalized muscle disorder that involves accelerated loss of muscle mass and impaired function. It is believed to influence the ability to carry out daily activities, muscle strength, and physical capacity in the elderly. Studies have shown that sarcopenia has been implicated as both a cause and a consequence of diabetes mellitus. In this analysis, we aimed to systematically show the impact of exercise intervention as a therapy for patients with diabetes mellitus and sarcopenia. METHODS: Electronic databases, including PubMed, EMBASE, Web of Science, and the Cochrane database, were searched from November to December 2021 for publications based on exercise intervention in patients with sarcopenia. After the selection of studies for this analysis, patients with diabetes mellitus were retrieved. Since dichotomous data including mean and standard deviation were reported, weighted mean difference (MD) with 95% confidence intervals (CI) were used to represent the data following analysis. RESULTS: A total of 431 participants with diabetes mellitus and sarcopenia were included in this meta-analysis. A statistical analysis was carried out on patients with diabetes mellitus who were assigned to the exercise intervention group. Our analysis showed that "sit-to-stand test" and "timed up and go" were significantly in favor of exercise intervention: MD -1.57, 95% confidence interval (CI) -2.26 to -0.87 (P = 0.0001) versus MD -0.61, 95% CI -1.21 to -0.01 (P = 0.05), respectively. Handgrip strength, walking speed and leg strength were also assessed. Another statistical analysis was carried out, this time on patients with diabetes mellitus and sarcopenia who were not assigned to an exercise intervention. The results showed no significant difference among sit-to-stand test, timed up and go, handgrip strength, and leg strength. CONCLUSION: Exercise intervention significantly improved the time taken to stand up from a sitting position, and to "stand up and go" in patients with diabetes mellitus and sarcopenia. Therefore, exercise intervention should be considered a relevant therapy for such patients.

Pleomorphic xanthoastrocytoma, anaplastic pleomorphic xanthoastrocytoma, and epithelioid glioblastoma: Case series with clinical characteristics, molecular features and progression relationship.

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA), anaplastic pleomorphic xanthoastrocytoma (A-PXA), and epithelioid glioblastoma (E-GBM) show overlapping features. However, little is known about their clinical characteristics, molecular features and relationship with progression. METHODS: Fourteen patients diagnosed at Nanfang Hospital from 2016 to 2019 were enroled, including eleven PXA patients, two A-PXA patients, and one E-GBM patient. All tumour tissue samples of the fourteen patients were examined by immunohistochemical staining (MGMT, VEGF, BRAF-V600E, etc.). RESULTS: The mean age of 13 patients with PXA or A-PXA was 25.4 years; twelve of these patients had tumours at supratentorial regions. VEGF positivity was detected in the tumour samples of 13 patients, MGMT positivity in 10 patients, and BRAF-V600E positivity in 7 patients. The recurrent tumour tissue of the patient with E-GBM arising from A-PXA was screened to detect 11 glioma markers (MGMT, BRAF-V600E, etc.) and chromosome 1p/19q by next-generation sequencing (NGS). For the tumour sample of the E-GBM patient who survived for up to 11 years after the fourth resection, BRAF V600E was wild type in the sample obtained from the first surgery, while it was mutant in the second, third, and fourth surgeries. In contrast, the promoter status of MGMT in the four surgeries was unmethylated. The NGS results showed that the mutation frequencies of BRAF V600E in the second, third and fourth surgeries were 14.06%, 9.13% and 48.29%, respectively. CONCLUSIONS: Collectively, the results suggest that patients with A-PXA may relapse multiple times and eventually progress to E-GBM with the BRAF-V600E mutation.

Classification of unilateral thalamic gliomas predicts tumor resection and patient's survival: a single center retrospective study.

BACKGROUND: To propose our classification about unilateral thalamic gliomas, and to describe relationship between the classification and clinical characteristics including symptoms, surgical approaches and survival, which should contribute to the treatment and the prognostic prediction of unilateral thalamic gliomas. METHODS: A total of 66 adult unilateral thalamic glioma patients with pathologic confirmation between January 2010 and December 2018 were retrospectively investigated. RESULTS: Unilateral thalamic gliomas could be divided into quadrigeminal cistern and ventricle extension type (Type Q), lateral type (Type L) and anterior type (Type A) according to tumor location, extensive polarity and location of ipsilateral posterior limb of internal capsule. Each subtype of QLA classification could match with one kind of corresponding approach. Preoperative symptoms including headache, dyskinesia, aphasia, hydrocephalus and KPS scores, and pathological features including H3K27M mutation and P53 expression were correlated with QLA classification. Further analysis confirmed that Type Q tumors had a higher rate of total resection and a significantly longer survival time compared to Type L and Type A tumors, with similar improved and deteriorated rates of symptoms. Univariate and multivariate analysis demonstrated QLA classification was remarkedly associated with overall survival and could be considered as an independent prognostic factor in patients with unilateral thalamic gliomas. CONCLUSIONS: Unilateral thalamic glioma could be divided into 3 subtypes by imaging characteristics, symptoms and survival. QLA classification could predict tumor resection and the prognosis and could contribute to the planning of therapeutic strategy in patients with unilateral thalamic gliomas.