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Background Alzheimer’s disease (AD) and glioblastoma are the most common and devastating diseases in the neurology and neurosurgery departments, respectively. Our previous research reports that the AD-related protein Presenilin1 represses cell proliferation by inhibiting the Wnt/β-catenin pathway in glioblastoma. However, the function of Presenilin1 and the underlying mechanism need to be further investigated. Methods The correlations of two genes were conducted on the R2 microarray platform and CGGA. Wound healing, Transwell assays and glioblastoma transplantation were performed to detect invasion ability. Phalloidin staining was employed to show cell morphology. Proximity ligation assays and protein docking assays were employed to detect two protein locations. We also employed western blotting to detect protein expression. Results We found that Presenilin1 clearly repressed the migration, invasion and mesenchymal transition of glioblastoma cells. Intriguingly, we observed that the expression of Presenilin1 was positively correlated with Sortilin, which is identified as a pro-invasion molecule in glioma. Furthermore, Presenilin1 interacted with Sortilin at the transmembrane domain and repressed Sortilin expression by cleaving it in glioblastoma cells. First, we found that Sortilin introduced the function of Presenilin1 in phosphorylating β-catenin and repressing invasion in glioblastoma cells. Last, Presenilin1 stimulation sharply suppressed the invasion and mesenchymal transition of glioblastoma in mouse subcutaneous and intracranial transplantation models. Conclusions Our study reveals that Sortilin mediates the regulation of β-catenin by Presenilin1 and transduces the anti-invasive function of Presenilin1, which may provide novel therapeutic targets for glioblastoma treatment.

Aims Tumor electric fields therapy (TTFields) is emerging as a novel anti‐cancer physiotherapy. Despite recent breakthroughs of TTFields in glioma treatment, the average survival time for glioblastoma patients with TTFields is, Primary tumor cells prepared from 20 patients were treated with the tumor electric field treatment system (TEFTS). The impact of genetic background on cell responses to TEFTS were evaluated. Cell volume, cell number and cell proliferation were measured after TEFT at different frequencies (100, 150, 180, 200, 220 kHz). A transwell system was used to evaluate the influence of TEFT on the invasiveness of primary cells. The therapeutic effect and safety of random sequence electric field therapy in tumor‐bearing rats were assessed by calculating tumor size and survival time and by evaluating other immunobiological and blood parameters. Twelve types of primary tumor cells with different genetic traits were all sensitive to electric field treatment. After sensitive frequency treatment, the volume of primary cells significantly increased compared to control group, while the proliferation and invasiveness of tumor cells were inhibited. The optimal frequencies among all 20 types of primary cells were divided into different categories: 30% of them had the optimal frequency of 180 kHz; 25% of them had the optimal frequency of 200 kHz; 15% of them had the optimal frequency of 150 kHz, and 30% of them had the optimal frequency of 220 kHz. Two cases were not sensitive to 200 kHz. The therapy with random sequence electric field output significantly reduced tumor size and elongated survival time of tumor‐bearing rats compared to the fixed sequence TEFT, while increased the incidence of dermatological side effects.

Resection of high-grade glioma with sodium fluorescein can improve the resection rate of the glioma and improve survival. However, it is unclear whether the yellow fluorescence boundary of the high-grade glioma is consistent with the actual boundary of the tumor. This study explores the yellow fluorescence boundary and the actual tumor boundary in high-grade glioma surgery.This is a retrospective analysis of 10 patients with high-grade gliomas who underwent tumor visualization with sodium fluorescein. After staining of the tumor, random selections of both developed and non-developed yellow fluorescent border tissue at the fluorescence chromogenic boundary were made, followed by pathological examination. Claudin-5, an important component of the tight connections between vascular endothelial cells, was assessed by immunohistochemistry and qRT-PCR in the tumor and surrounding tissues in order to determine the tumor cell content of the tissue, blood-brain barrier damage, and vascular proliferation. The yellow fluorescence boundary was compared with the actual tumor boundary and the results analyzed.Tumor cells were still detected outside the yellow fluorescence boundary during high-grade glioma surgery (There is a difference between the yellow fluorescence boundary and the actual boundary of the tumor in high-grade glioma, and there are glioma cell infiltrations in the brain tissue of the undeveloped yellow fluorescent border. To ensure patient recovery and function, it is recommended that tumor resection be expanded based on yellow fluorescence visualization. Claudin-5 is overall up-regulated in high-grade gliomas, but some Claudin-5 expression is disconnected. This Claudin-5 expression pattern may be related to the development of yellow fluorescence.

Glioblastoma (GBM) is a prevalent and highly lethal form of glioma, with rapid tumor progression and frequent recurrence. Excessive outgrowth of pericytes in GBM governs the ecology of the perivascular niche, but their function in mediating chemoresistance has not been fully explored. Herein, we uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. We found that increased pericyte proportion correlates with accelerated tumor recurrence and worse prognosis. Genetic depletion of pericytes in GBM xenografts enhances TMZ-induced cytotoxicity and prolongs survival of tumor-bearing mice. Mechanistically, C-C motif chemokine ligand 5 (CCL5) secreted by pericytes activates C-C motif chemokine receptor 5 (CCR5) on GBM cells to enable DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-mediated DDR upon TMZ treatment. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ. GBM patient-derived xenografts with high CCL5 expression benefit from combined treatment with TMZ and MVC. Our study reveals the role of pericytes as an extrinsic stimulator potentiating DDR signaling in GBM cells and suggests that targeting CCL5-CCR5 signaling could be an effective therapeutic strategy to improve chemotherapeutic efficacy against GBM.

To investigate the performance of multi-parametric magnetic resonance imaging (MRI) for glioma grading.Seventy consecutive patients with histopathologically confirmed glioma were retrospectively evaluated by conventional MRI, dynamic susceptibility-weighted contrast-enhanced, multiple diffusion-weighted imaging signal models including mono-exponential, bi-exponential, stretched exponential, and diffusion kurtosis imaging. One-way analysis of variance and independent-samples t test were used to compare the MR parameter values between low and high grades as well as among all grades of glioma. Receiver operating characteristic analysis, Spearman's correlation analysis, and binary logistic regression analysis were used to assess their diagnostic performance.The diagnostic performance (the optimal thresholds, area under the receiver operating characteristic curve, sensitivity, and specificity) was achieved with normalized relative cerebral blood flow (rCBV) (2.240 ml/100 g, 0.844, 87.8%, and 75.9%, respectively), mean kurtosis (MK) (0.471, 0.873, 92.7%, and 79.3%), and water molecular diffusion heterogeneity index (α) (1.064, 0.847, 79.3% and 78.0%) for glioma grading. There were positive correlations between rCBV and MK and the tumor grades and negative correlations between α and the tumor grades (p0.01). The parameter of α yielded a diagnostic accuracy of 85.3%, the combination of MK and α yielded a diagnostic accuracy of 89.7%, while the combination of rCBV, MK, and α were more accurate (94.2%) in predicting tumor grade.The most accurate parameters were rCBV, MK, and α in dynamic susceptibility-weighted contrast, diffusion kurtosis imaging, and Multi-b diffusion-weighted imaging for glioma grading, respectively. Multiparametric MRI can increase the accuracy of glioma grading.

Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are typical causes of developmental delay and refractory epilepsy. G‐protein‐coupled receptor 30 (GPR30) is a specific estrogen receptor that is critical in neurodevelopment, neuroinflammation, and neuronal excitability, suggesting that it plays a potential role in the epilepsy of patients with FCDIIb and TSC. Therefore, we investigated the role of GPR30 in patients with FCDIIb and TSC. We found that the expression of GPR30 and its downstream protein kinase A (PKA) pathway were decreased and negatively correlated with seizure frequency in female patients with FCDIIb and TSC, but not in male patients. GPR30 was widely distributed in neurons, astrocytes, and microglia, and its downregulation was especially notable in microglia. The GPR30 agonist G‐1 increased the expression of PKA and p‐PKA in cultured cortical neurons, and the GPR30 antagonist G‐15 exhibited the opposite effects of G‐1. The NF‐κB signaling pathway was also activated in the specimens of female patients with FCDIIb and TSC, and was regulated by G‐1 and G‐15 in cultured cortical neurons. We also found that GPR30 regulated cortical neuronal excitability by altering the frequency of spontaneous excitatory postsynaptic currents and the expression of NR2A/B. Further, the relationship between GPR30 and glycometabolism was evaluated by analyzing the correlations between GPR30 and 18F‐FDG PET‐CT values (standardized uptake values, SUVs). Positive correlations between GPR30 and SUVs were found in female patients, but not in male patients. Intriguingly, GPR30 expression and SUVs were significantly decreased in the epileptogenic tubers of female TSC patients, and ROC curves indicated that SUVs could predict the localization of epileptogenic tubers. Taken together, our results suggest a potential protective effect of GPR30 in the epileptogenesis of female patients with FCDIIb and TSC.

Epilepsy is a highly prevalent and drug-refractory neurological disorder characterized by spontaneous recurrent seizures. Estrogen is identified to be proconvulsant and lowers the seizure threshold of female epilepsy. Estrogen receptor β (ERβ) has been proposed to mediate neuroprotection in epilepsy, although the underlying mechanism remains unknown. Rationale: In this study, we investigated the role of ERβ in the epileptogenesis of female temporal lobe epilepsy (TLE). Methods: Immunohistochemistry, immunofluorescence, western blots, Golgi staining, 1H MRS and whole-cell patch-clamp were used to evaluate ERβ expression, pathological changes, and synaptic excitation /inhibition (E/I) balance in female TLE patients and ovariectomized (OVX) chronic epileptic mice. Electroencephalogram (EEG) recordings were recorded to evaluate the epileptic susceptibility in OVX WT and ERβ-/- mice. And high-throughput RNA-sequence was performed to identify differential expression genes (DEGs) which can elucidate the potential mechanism of ERβ regulating the seizure susceptibility. Results: ERβ expression was decreased in the brains of female TLE patients and OVX chronic epileptic mice. ERβ deletion enhanced seizure susceptibility and exacerbated the imbalance of synaptic E/I in hippocampal CA1 area of OVX epileptic mice. In line with these observations, RNA-sequence data further identified glutamine ligase (GLUL) as the target of ERβ involved in regulating synaptic E/I in CA1. Furthermore, ERβ agonist WAY-200070 markedly suppressed epileptic phenotypes and normalized GLUL expression in CA1 region of kainic acid (KA) induced OVX chronic epileptic model. Conclusions: Our data provide novel insight into the pathogenesis of female TLE, and indicate ERβ provides a new therapeutic strategy for female TLE patients.

Tumour-associated macrophages (TAMs) abundantly infiltrate high-grade gliomas and orchestrate immune response, but their diversity in isocitrate dehydrogenase (IDH)-differential grade 4 gliomas remains largely unknown. This study aimed to dissect the transcriptional states, spatial distribution, and clinicopathological significance of distinct monocyte-derived TAM (Mo-TAM) and microglia-derived TAM (Mg-TAM) clusters across glioblastoma-IDH-wild type and astrocytoma-IDH-mutant-grade 4 (Astro-IDH-mut-G4). Single-cell RNA sequencing was performed on four cases of human glioblastoma and three cases of Astro-IDH-mut-G4. Cell clustering, single-cell regulatory network inference, and gene set enrichment analysis were performed to characterize the functional states of myeloid clusters. The spatial distribution of TAM subsets was determined in human glioma tissues using multiplex immunostaining. The prognostic value of different TAM-cluster specific gene sets was evaluated in the TCGA glioma cohort. Profiling and unbiased clustering of 24,227 myeloid cells from glioblastoma and Astro-IDH-mut-G4 identified nine myeloid cell clusters including monocytes, six Mo/Mg-TAM subsets, dendritic cells, and proliferative myeloid clusters. Different Mo/Mg-TAM clusters manifest functional and transcriptional diversity controlled by specific regulons. Multiplex immunostaining of subset-specific markers identified spatial enrichment of distinct TAM clusters at peri-vascular/necrotic areas in tumour parenchyma or at the tumour-brain interface. Glioblastoma harboured a substantially higher number of monocytes and Mo-TAM-inflammatory clusters, whereas Astro-IDH-mut-G4 had a higher proportion of TAM subsets mediating antigen presentation. Glioblastomas with a higher proportion of monocytes exhibited a mesenchymal signature, increased angiogenesis, and worse patient outcome. Our findings provide insight into myeloid cell diversity and its clinical relevance in IDH-differential grade 4 gliomas, and may serve as a resource for immunotherapy development. © 2022 The Pathological Society of Great Britain and Ireland.

Glioblastoma (GBM) has limited therapeutic options. DNA repair mechanisms contribute GBM cells to escape therapies and re-establish tumor growth. Multiple studies have shown that POLD2 plays a critical role in DNA replication, DNA repair and genomic stability. We demonstrate for the first time that POLD2 is highly expressed in human glioma specimens and that expression correlates with poor patient survival. siRNA or shRNA POLD2 inhibited GBM cell proliferation, cell cycle progression, invasiveness, sensitized GBM cells to chemo/radiation-induced cell death and reversed the cytoprotective effects of EGFR signaling. Conversely, forced POLD2 expression was found to induce GBM cell proliferation, colony formation, invasiveness and chemo/radiation resistance. POLD2 expression associated with stem-like cell subsets (CD133(+) and SSEA-1(+) cells) and positively correlated with So×2 expression in clinical specimens. Its expression was induced by So×2 and inhibited by the forced differentiation of GBM neurospheres. shRNA-POLD2 modestly inhibited GBM neurosphere-derived orthotopic xenografts growth, when combined with radiation, dramatically inhibited xenograft growth in a cooperative fashion. These novel findings identify POLD2 as a new potential therapeutic target for enhancing GBM response to current standard of care therapeutics.

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by hamartomas in multiple organ systems. The TSC1 and TSC2 genes have been identified as the genetic basis of TSC. Two gene tests were used for definitive genetic diagnosis. In our study, the case of a Chinese pediatric patient with seizures, hypomelanotic macules, hyperpigmented patches, multiple parenchymal lesions in the ventricle, and developmental retardation is detailed. Whole-genome sequencing (WGS) and multiplex ligation-dependent probe amplification (MLPA) were employed to detect genetic variations and copy number variations of TSC1 and TSC2. A novel heterozygous nonsense mutation in the TSC2 gene (c.3751A>T, p.Lys1251Ter) was identified in a Chinese pediatric patient suffering from TSC, whose unaffected parents did not carry this mutation. The mutation was classified as “pathogenic” according to the American College of Medical Genetics (ACMG) guidelines. WGS was carried out to definitively diagnose and detect variations in the exon and noncoding region of the gene and copy number variations in the whole genome simultaneously. For diseases with complex genetic mechanisms, WGS as the first-line test can be efficient and cost-effective for clinical diagnosis.

Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.

NUSAP1, which is a microtubule-associated protein involved in mitosis, plays essential roles in diverse biological processes, especially in cancer biology. In this study, NUSAP1 was found to be overexpressed in GBM tissues in a grade-dependent manner compared with normal brain tissues. NUSAP1 was also highly expressed in GBM patients, dead patients, and GBM cells. In addition, NUSAP1 was found to participate in cell proliferation, apoptosis, and DNA damage in GBM cells. Ataxia telangiectasia and Rad3-related protein (ATR) are a primary sensor of DNA damage, and ATR is also a promising target in cancer therapy. Here, we found that NUSAP1 positively regulated the expression of ATR. Mechanistically, NUSAP1 suppressed the ubiquitin-dependent proteolysis of ATR. The SAP (SAF-A/B, Acinus, and PIAS) domain is a common motif of many SUMO (small ubiquitin-like modifier) E3 ligases, and this domain is involved in substrate recognition and ligase activity. This study further demonstrated that the SAP domain of NUSAP1 promoted the sumoylation of ATR, and thereby antagonized the ubiquitination of ATR. These results suggest that NUSAP1 stabilizes ATR by sumoylation. Moreover, NUSAP1 potentiated chemotherapeutic resistance to temozolomide (TMZ) and doxorubicin (DOX) through its SAP domain. Overall, this study indicates that NUSAP1 is a promising therapeutic target in GBM.

Objectives: To explore the clinical surgical methods for the treatment of tensile effusion in postoperative cavity after glioma resection. Methods: Clinical data of 26 cases of tensile effusion in postoperative cavity after glioma resection were analyzed retrospectively. All 26 patients underwent surgical treatment, including 16 cases who underwent puncture and drainage (P&D), and 10 cases who underwent craniotomy decompression (CD). Among the cases of P&D, postoperative cavity in 7 cases were punctured through the burr hole for creating the skull flap for intraoperative resection of glioma, and postoperative cavities in 9 cases were punctured through a burr hole for the dura mater suspended under the skull flap. Glasgow Coma Scale (GCS) was used to evaluate the consciousness status of the two groups of patients before and after surgery. Moreover, time of operation, intraoperative blood loss, postoperative hospital duration, and postoperative complications were also adopted for evaluation of the merits of the two methods for treatment of tensile effusion in postoperative cavity after glioma resection. Results: The consciousness of the patients in both groups improved within 24 hours after the operation, and there were no death cases. In the P&D group, the GCS score within 24 hours after surgery was (14.38±0.20), the time of operation time was (7.81±0.64) mins, intraoperative blood loss was (6.25±0.56) ml, and postoperative hospital duration was (6.69±0.54) days. There were 3 cases with postoperative complications (1 case of puncture tract hemorrhage, 1 case of subdural hematoma and 1 case of intracranial infection) in the P&D group. All of the puncture tract hemorrhage and subdural hematoma did not require surgical treatment, and the intracranial infection was cured after antibiotic treatment and lumbar puncture for cerebrospinal fluid replacement. In the CD group, the GCS score within 24 hours after surgery was (13.70±0.21), the time of operation was (124.10±8.96) mins, intraoperative blood loss was (260±30.55) ml, and postoperative hospital duration was (11.30±0.60) days. There were 2 cases with postoperative complications (both of them were with subdural hematoma), none of which required surgical treatment. The GCS score, time of operation, intraoperative blood loss and postoperative hospital duration in the P&D group were better than those in the CD group (P < 0.05). There was no significant difference in the incidence of postoperative complications between the two groups (P >0.05). Conclusion: The P&D and CD for tensile effusion in postoperative cavity after glioma resection can both achieve ideal results, but P&D in line with the concept of micro-invasive neurosurgery was better than CD in terms of postoperative GCS score within 24 hours, duration of operative, intraoperative blood loss, and postoperative hospital duration.

Rationale: Around 10%-20% patients with glioblastoma (GBM) are diagnosed with more than one tumor lesions or multifocal GBM (mGBM). However, the understanding on genetic, DNA methylomic, and transcriptomic characteristics of mGBM is still limited. Methods: In this study, we collected nine tumor foci from three mGBM patients followed by whole genome sequencing, whole genome bisulfite sequencing, RNA sequencing, and immunohistochemistry. The data were further examined using public GBM databases and GBM cell line. Results: Analysis on genetic data confirmed common features of GBM, including gain of chr.7 and loss of chr.10, loss of critical tumor suppressors, high frequency of PDGFA and EGFR amplification. Through profiling DNA methylome of individual tumor foci, we found that promoter methylation status of genes involved in detection of chemical stimulus, immune response, and Hippo/YAP1 pathway was significantly changed in mGBM. Although both CNV and promoter methylation alteration were involved in heterogeneity of different tumor foci from same patients, more CNV events than promoter hypomethylation events were shared by different tumor foci, implying CNV were relatively earlier than promoter methylation alteration during evolution of different tumor foci from same mGBM. Moreover, different tumor foci from same mGBM assumed different molecular subtypes and mesenchymal subtype was prevalent in mGBM, which might explain the worse prognosis of mGBM than single GBM. Interestingly, we noticed that LIF and CCL2 was tightly correlated with mesenchymal subtype tumor focus in mGBM and predicted poor survival of GBM patients. Treatment with LIF and CCL2 produced mesenchymal-like transcriptome in GBM cells. Conclusions: Together, our work herein comprehensively profiled multi-omics features of mGBM and emphasized that components of extracellular microenvironment, such as LIF and CCL2, contributed to the evolution and prognosis of tumor foci in mGBM patients.

Lipopolysaccharide-induced tumor necrosis factor alpha factor (LITAF), also called p53-induced gene 7 (PIG7), was identified as a transcription factor that activates transcription of proinflammatory cytokines in macrophages in response to lipopolysaccharide (LPS). Previous studies have identified LITAF as a potential tumor suppressor in several neoplasms, including prostate cancer, B-NHL, acute myeloid leukemia, and pancreatic cancer. However, the expression and function of LITAF in human glioma remain unexplained. The present study aimed to analyze the regulation of LITAF in gliomas. Data from The Cancer Genome Atlas (TCGA) database revealed that LITAF mRNA expression in glioma tissues was higher than that in normal brain tissues, and lower LITAF expression in gliomas showed a good prognosis in patients who received radiotherapy, by Kaplan-Meier analysis. In our collected specimens, however, LITAF showed low expression in glioma tissues compared to that in the normal brain tissue. Proliferation and apoptosis of glioma cells were not affected by knockdown or overexpression of LITAF in glioma U251, U373, and U87 cells, but LITAF was able to enhance the radiosensitivity of glioma cells. Furthermore, we found that LITAF enhanced radiosensitivity via FoxO1 and its specific downstream targets BIM, TRAIL, and FASLG. Taken together, our present results demonstrate that LITAF expression is decreased in glioma tissues and might enhance radiosensitivity of glioma cells via upregulation of the FoxO1 pathway.

Introduction: Brain glioma is the most common type of primary malignancy in the central nervous system (CNS), with high recurrence and mortality rate, especially glioblastoma (GBM). Recent evidence suggests a role for many long noncoding RNAs (lncRNAs) in the pathogenesis, proliferation, apoptosis, metastasis, and chemotherapeutic resistance of cancer cells. Although the functions of some lncRNAs in the occurrence and development of gliomas have been confirmed, detailed mechanisms of action are lacking. Furthermore, the biological roles of many other lncRNAs in glioma have not been reported at all. Methods: In this study, we identified a novel lncRNA, UBE2R2-AS1, which was dramatically downregulated in glioma compared with normal tissue, by performing microarray detection of six pairs of glioma samples and adjacent normal tissues. In vitro experiments demonstrated that UBE2R2-AS1 regulated glioma cell proliferation, apoptosis, and migration. Results: UBE2R2-AS1 acted as a competing endogenous RNA (ceRNA) to target Toll-like receptor 4 (TLR4) mRNA by binding to miR-877-3p. Furthermore, lncRNA UBE2R2-AS1 suppressed glioblastoma cell growth, migration, and invasion, as well as promoting cell apoptosis by targeting miR-877-3p/TLR4 directly. Conclusion: This information regarding UBE2R2-AS1 and its glioma-related molecular mechanisms will aid the future identification of new lncRNA-directed diagnostics and drug-targeting therapies.

Our previous study showed that the lncRNA UBE2R2-AS1 inhibits the growth and invasion of glioma cells and promotes apoptosis through the miR-877-3p/TLR4 pathway. In this study, it was further found that the expression of UBE2R2-AS1 in glioma tissues was decreased significantly, and gradually decreased with increasing clinical stage. Chi-square analysis showed that the expression of UBE2R2-AS1 was significantly correlated with the WHO stage of tumor and epilepsy. Using Kaplan-Meier univariate survival analysis, it was found that the expression of UBE2R2-AS1 correlated positively with the overall survival of patients with glioma, while multiple Cox regression analysis showed that the expression of UBE2R2-AS1 correlated positively with the overall survival of patients with glioma as a protective factor for glioma prognosis. The analysis of data from TCGA also showed that patients with high UBE2R2-AS1 levels or low miR-877-3p expression were more likely to have good survival outcomes. Further construction of a glioma xenograft model in nude mice showed that UBE2R2-AS1 overexpression inhibited the growth of tumors, and the inhibition of miR-877-3p expression had a similar effect. Simultaneous UBE2R2-AS1 overexpression and miR-877-3p inhibition further decreased the growth rate of tumors in nude mice. Taken together, the results of our study suggest that UBE2R2-AS1 is an important tumor suppressor gene in glioma, which may be a good marker and treatment target for the clinical detection of glioma.

Glioma is the most common primary malignant tumor of the central nervous system and has a poor prognosis. Therefore, exploring the key molecular targets is a new opportunity for basic research and clinical treatment of glioma. Previous studies found that circRNA-hsa_circ_0073237 was upregulated in gliomas. Our further analyses of the biological function and molecular mechanism of hsa_circ_0073237 showed that hsa_circ_0073237 was also upregulated in glioma cell lines and could combine with miR-345 to inhibit its expression. miR-345 was downregulated in glioma tissues and cells, and targeted to regulate the expression of hepatoma-derived growth factor (HDGF), while HDGF expression was enhanced in glioma. Hsa_circ_0073237 promoted the expression of HDGF in glioma cells by adsorbing miR-345. Hsa_circ_0073237 siRNA, miR-345, and HDGF siRNA effectively inhibited cell viability and invasion and promoted cell apoptosis. When expression of hsa_circ_0073237 and miR-345 was inhibited simultaneously, cell viability, apoptosis, and invasion did not change significantly; however, after transfection with HDGF overexpression vector, the effects of hsa_circ_0073237 siRNA and miR-345 on glioma cell viability, apoptosis, and invasion were obviously reversed. Further construction of glioma xenograft models in nude mice confirmed that the introduction of miR-345 in vivo effectively inhibited tumor growth, significantly reduced tumor diameter and weight, and obviously decreased the expression of HDGF. Therefore, hsa_circ_0073237 can regulate the biological functions of glioma cells through miR-345/HDGF, thereby affecting the progression of tumors, indicating that the hsa_circ_0073237/miR-345/HDGF pathway may be a key target for the treatment of glioma.

Background Multifocal glioblastoma is a rare type of glioblastoma with worse prognosis. In this article, we aimed to report two cases of classical multifocal glioblastoma. Case presentation In case 1, a 47-year-old male presented with dizziness, and once had a sudden loss of consciousness accompanied by convulsion of limbs. Contrast-enhanced MRI showed multiple lesions with heterogeneously ring-enhanced characters in the left hemisphere, diagnosed as multifocal glioblastoma. He underwent a craniotomy of all lesions, concurrent radiotherapy and chemotherapy as well as additional chemotherapy of temozolomide. After 2 cycles, repeat MRI showed that the new lesions already occurred and progressed. Eventually, he abandoned the chemotherapy after the 2 cycles and died 1 year later. In case 2, a 71-year-old male presented with a history of headache, left limb weakness, and numbness. Discontinuous convulsion of limbs once occurred. Contrast-enhanced MRI showed multiple lesions located in the right hemisphere, diagnosed as multifocal glioblastoma. He underwent a right frontoparietal craniotomy of the main lesion. Hemorrhage of the residual tumor and pulmonary artery embolism occurred synchronously. Eventually, his family decided not to pursue any further treatment and opted for hospice care and he passed away within 11 days of surgery. Conclusions We reported two cases of typical multifocal glioblastoma. Valid diagnosis is crucial; then, resection of multiple lesions and canonical radio-chemotherapy probably bring survival benefits.

Multiple glioblastoma multiforme (GBM) is classified as multifocal and multicentric GBM according to whether there is communication between the lesions. Multiple GBM is more genetically heterogeneous, aggressive and resistant to chemoradiotherapy than unifocal GBM, and has a worse prognosis. There is no international consensus on the treatment of multiple GBM. This review discusses some paradigms of multiple GBM and focuses on the heterogeneity spread pathway, imaging diagnosis, pathology, molecular characterization and prognosis of multifocal and multicentric GBM. Several promising therapeutic methods of multiple GBM are also recommended.

Background High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation. This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas. Methods U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, tumor cell spheroid growth, and colony formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. Temozolomide (TMZ)-insensitive cell lines were induced by long-term TMZ treatment, and cells with stem cell characteristics were enriched with stem cell culture medium. The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction, and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections. Via inoculating U87 cells subcutaneously, glioma xenograft models in nude mice were established for drug experiments. Patient survival data were analyzed using the Kaplan–Meier method. Results Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest. Bortezomib also significantly inhibited the spheroid growth, colony formation, and stem-like cell proliferation of U251 and U87 cells. When administrated in combination, bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo. Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1 (FOXM1) and its target gene Survivin. The FOXM1–Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients. Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor prognosis in glioma patients. Conclusions Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy, probably via down-regulating the FOXM1–Survivin axis. Bortezomib might be a promising agent for treating malignant glioma, alone or in combination with TMZ.

Background Temporal lobe epilepsy (TLE) is the most common intractable epilepsy in adults, and elucidation of the underlying pathological mechanisms is needed. Voltage-gated chloride channels (ClC) play diverse physiological roles in neurons. However, less is known regarding their functions in the epilepogenesis of TLE. Methods ClC-mediated current and the spontaneous inhibitory synaptic currents (sIPSC) in hippocampal neurons of epileptic lesions were investigated by electrophysiological recording. The EEG data were analyzed by Z-scored wavelet and Fourier transformations. The expression of ClC-3, a member of ClC gene family, was detected by immunostaining and western blot. Findings ClC-mediated current was increased in the hippocampal neurons of chronic TLE mice. Application of chloride channel blockers, NPPB (5-Nitro-2- [3-phenylpropylamino] benzoic acid) and DIDS (4,4’-Diisothiocyanato-2,2’-stilbenedisulfonic acid disodium salt) reduced ClC-mediated current and increased inhibitory synaptic transmission in TLE mice. NPPB and DIDS reduced the seizure frequency and the average absolute power of ictal high-frequency oscillations (HFOs, 80-500 Hz) in TLE mice. In addition, both drugs induced outwardly rectified currents, which might be tonic inhibitory currents in the hippocampal neurons of TLE patients. Furthermore, the expression of ClC-3 was increased in the hippocampus of TLE mice and patients and positively correlated with both the absolute power and number of ictal HFOs per seizure in the sclerotic hippocampus. Interpretation These data suggest that ClC participate in the epilepogenetic process of TLE and the inhibition of ClC may have anti-epileptic effect. Funding This work was supported by National Natural Science Foundation of China (No. 81601143, No. 81771217).

The current study investigated the effect of pyrrolidine dithiocarbamate (PDTC) on the proliferation, apoptosis, cell cycle and sensitivity to temozolomide (TMZ) of the U251 glioma cell line. Proliferation, apoptosis and cell cycle analysis of U251 cells following treatment with PDTC and TMZ was determined by an MTT assay and flow cytometry, respectively. The mRNA and protein expression levels of O-6-methylguanine-DNA methyltransferase (MGMT), B-cell lymphoma extra-large (BCL-XL) and survivin were further determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting analysis. The results revealed that treatment with TMZ, PDTC and TMZ + PDTC significantly inhibited cell proliferation, induced apoptosis and contributed to cell cycle arrest in U251 cells. A combination of PDTC and TMZ induced the highest rates of proliferation inhibition and apoptosis. PDTC treatment markedly reduced the expression levels of MGMT, BCL-XL and survivin. The expression levels of MGMT and BCL-XL, were significantly upregulated by TMZ but not by combination treatment of TMZ and PDTC. The results of the present study suggest that treatment with PDTC inhibits cell proliferation, induces apoptosis and cell cycle arrest, and enhances sensitivity to TMZ in U251 cells, which is partly induced by downregulation of MGMT and BCL-XL.

Epithelial-mesenchymal transformation(EMT) is a coordinated process in which polarized epithelial cells are induced to lose adhesion from the basement membrane and obtain the properties of mesenchymal cells, including invasion and metastasis. It has been proved that EMT greatly contributes to the invasion and therapeutic resistance of various solid human cancers. However, the role of EMT in brain glioma has not yet been fully clarified. So in this review, we mainly elaborate the latest progression about the related regulatory transcription factors, key signaling pathways and microRNAs (miRNAs) of EMT in gliomas.

Purpose Despite recent advances in multimodal treatments, the prognosis of patients with glioblastoma multiforme (GBM) remains poor. The aim of this study was to evaluate the efficacy of moderately hypofractionated simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) combined with temozolomide (TMZ) for the postoperative treatment of GBM. Materials and methods From February 2012 to February 2018, 80 patients with newly diagnosed and histologically confirmed GBM in our institute were reviewed retrospectively. All patients underwent complete resection or partial resection surgery and then received hypofractionated SIB-IMRT with concomitant TMZ followed by adjuvant TMZ. A total dose of 64 Gy over 27 fractions was delivered to the gross tumor volume (GTV), clinical target volume 1 (CTV1) received 60 Gy over 27 fractions, and CTV2 received 54 Gy over 27 fractions. The progression-free survival (PFS) and overall survival (OS) rates and the toxicities were evaluated. Prognostic factors were analyzed using univariate and multivariate Cox models. Results The median follow-up was 16 months (range, 5~72 months). The median PFS was 15 months, and the 1-, 2-, and 3-year PFS rates were 56.0, 27.6, and 19.5%, respectively. The median OS was 21 months, and the 1-, 2-, 3-, and 5-year OS rates were 77.6, 41.6, 32.8, and 13.4%, respectively. The toxicities were mild and acceptable. Age, KPS scores and the total number of TMZ cycles were significant factors influencing patient survival. Conclusion Moderately hypofractionated SIB-IMRT combined with TMZ is a feasible and safe treatment option with mild toxicity and good PFS and OS.

Background Circadian rhythm has a significant correlation with the occurrence and development of many diseases. Studies have shown that the anesthetic agent propofol can alter the rhythms of body temperature and activity in rats. Methods U2OS cells and ex vivo liver tissue were treated with different concentration of propofol, followed by recording the oscillation of the circadian clock. And two month-old mice were exposed to propofol (10mg/kg and 20mg/kg) or vehicle, detecting the expression of the clock genes. Results The results showed that propofol reduced the amplitude and lengthened the period of Per2 oscillation. Treatment with 10 mg/kg propofol significantly increased the expression of D-box binding PAR BZIP transcription factor (Dbp) and clock circadian regulator (Clock) in the liver. Treatment with 20 mg/kg propofol significantly decreased expression of cryptochrome circadian regulator 1 (Cry1), Dbp, nuclear receptor subfamily 1 group D member 1 (Nr1d1) and Clock and significantly increased the hypoxia signaling pathway genes hypoxia inducible factor 1 subunit alpha (Hif-1α), Egl-9 family hypoxia inducible factors Egln1, Egln2 and Egln3 in the hypothalamus. Conclusion The above results indicate that the general anesthetic propofol can change the circadian clock of ex vivo and in vivo mammalian liver tissues.

Introduction: Brain glioma is the most common type of primary malignancy in the central nervous system (CNS), with high recurrence and mortality rate, especially glioblastoma (GBM). Recent evidence suggests a role for many long noncoding RNAs (lncRNAs) in the pathogenesis, proliferation, apoptosis, metastasis, and chemotherapeutic resistance of cancer cells. Although the functions of some lncRNAs in the occurrence and development of gliomas have been confirmed, detailed mechanisms of action are lacking. Furthermore, the biological roles of many other lncRNAs in glioma have not been reported at all. Methods: In this study, we identified a novel lncRNA, UBE2R2-AS1, which was dramatically downregulated in glioma compared with normal tissue, by performing microarray detection of six pairs of glioma samples and adjacent normal tissues. In vitro experiments demonstrated that UBE2R2-AS1 regulated glioma cell proliferation, apoptosis, and migration. Results: UBE2R2-AS1 acted as a competing endogenous RNA (ceRNA) to target Toll-like receptor 4 (TLR4) mRNA by binding to miR-877-3p. Furthermore, lncRNA UBE2R2-AS1 suppressed glioblastoma cell growth, migration, and invasion, as well as promoting cell apoptosis by targeting miR-877-3p/TLR4 directly. Conclusion: This information regarding UBE2R2-AS1 and its glioma-related molecular mechanisms will aid the future identification of new lncRNA-directed diagnostics and drug-targeting therapies.

The Chinese Glioma Cooperative Group (CGCG) Guideline Panel for adult diffuse gliomas provided recommendations for diagnostic and therapeutic procedures. The Panel covered all fields of expertise in neuro-oncology, i.e. neurosurgeons, neurologists, neuropathologists, neuroradiologists, radiation and medical oncologists and clinical trial experts. The task made clearer and more transparent choices about outcomes considered most relevant through searching the references considered most relevant and evaluating their value. The scientific evidence of papers collected from the literature was evaluated and graded based on the Oxford Centre for Evidence-based Medicine Levels of Evidence and recommendations were given accordingly. The recommendations will provide a framework and assurance for the strategy of diagnostic and therapeutic measures to reduce complications from unnecessary treatment and cost. The guideline should serve as an application for all professionals involved in the management of patients with adult diffuse glioma and also as a source of knowledge for insurance companies and other institutions involved in the cost regulation of cancer care in China.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long‐term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients.

Glioblastomas (GBMs) are classified into isocitrate dehydrogenase (IDH) mutant (IDHMT) and wild-type (IDHWT) subtypes, and each is associated with distinct tumor behavior and prognosis. The present study aimed to investigate differentially expressed long non-coding (lnc)RNAs and mRNAs between IDHMT and IDHWT GBMs, as well as to explore the interaction and potential functions of these RNAs. A total of 132 GBM samples with RNA profiling data (10 IDHMT and 122 IDHWT cases) were obtained from The Cancer Genome Atlas, and 62/78 and 142/219 up/downregulated lncRNAs and mRNAs between IDHMT and IDHWT GBMs were identified, respectively. Multivariate Cox analysis of the dysregulated lncRNAs/mRNAs identified three-lncRNA and fifteen-mRNA signatures with independent prognostic value, indicating that these RNAs may serve roles in determining distinct tumor behaviors and prognosis of patients with IDHMT/WT GBMs. Functional analysis of the three lncRNAs revealed that they were primarily associated with cell stemness or differentiation. Pearson's correlation analysis revealed that the protective lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AC068643.1","term_id":"7711219","term_text":"AC068643.1"}}AC068643.1 was significantly positively correlated with two key bone morphogenetic protein (BMP) signaling-associated mRNAs, Bone morphogenetic protein 2 (BMP2) and Myostatin (MSTN), from the 15 mRNAs. Further in vitro studies demonstrated that BMP2 and MSTN directly stimulated {"type":"entrez-nucleotide","attrs":{"text":"AC068643.1","term_id":"7711219","term_text":"AC068643.1"}}AC068643.1 expression. In conclusion, the present study identified a BMP signaling pathway-regulated lncRNA {"type":"entrez-nucleotide","attrs":{"text":"AC068643.1","term_id":"7711219","term_text":"AC068643.1"}}AC068643.1, which may contribute to the different tumor behaviors observed between IDHMT and IDHWT GBMs.

Early invasive growth along specific anatomical structures, especially the white matter tract, is regarded as one of the main causes of poor therapeutic outcome of people with gliomas. We show that some glioma stem cells (GSCs) are preferentially located along white matter tracts, which exhibit a demyelinated phenotype, at the invasive frontier of glioma tissues. These GSCs are CD133+Notch1+, whereas the nerve fibers express the Notch ligand Jagged1. The Notch-induced transcription factor Sox9 promotes the transcription of SOX2 and the methylation level of the NOTCH1 promoter is attenuated by the upregulation of SOX2 to reinforce NOTCH1 expression in GSCs. This positive-feedback loop in a cohort of glioma subjects is correlated with a poor prognosis. Inhibition of Notch signaling attenuates the white-matter-tract tropism of GSCs. These findings provide evidence indicating that the NOTCH1-SOX2 positive-feedback loop controls GSC invasion along white matter tracts.

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified as one of the earliest events in gliomagenesis, occurring in over 70% of low grade gliomas and are present in the vast majority of secondary glioblastoma (GBM) that develop from these low-grade lesions. The aim of this study was to investigate whether the IDH1 R132H mutation influences the expression of oncogenic miR-20a and shed light on the underlying molecular mechanisms. The findings of the current study demonstrate presence of the IDH1 R132H mutation in primary human glioblastoma cell lines with upregulated HIF-1α expression, downregulating c-MYC activity and resulting in a consequential decrease in miR-20a, which is responsible for cell proliferation and resistance to standard temozolomide treatment. Elucidating the mechanism of oncogenic miR-20a activity introduces its role among well-established signaling pathways (i.e. HIF/c-MYC) and may be a meaningful prognostic biomarker or target for novel therapies among patients with IDH1-mutant glioma.

Aberrant expression of miR-206 has been repeatedly found and demonstrated to play crucial roles in cancers. However, the role of miR-206 in brain glioma remains unclear. To address this issue, we detected miR-206 expression of 60 gliomas and 18 normal peritumor tissues, and found that miR-206 is significantly down-regulated in gliomas. Further in silico analysis of 198 glioma samples from the Chinese Glioma Genome Atlas (CGGA) indicated that miR-206 is significantly down-regulated in high grade gliomas and that miR-206 predicts favorable patients’ prognosis. Notably, we found that miR-206 expression is negatively correlated with Ki-67 staining, indicating a proliferative inhibition of miR-206 in gliomas. To explore the crucial role of miR-206 in gliomas, we constructed miR-206 stably overexpressed LN229 glioma cell lines and found that the proliferation is significantly inhibited. Through flow cytometry (FCM) analyses, we found that the apoptotic rate is increased and the cell cycle is arrested in LN229 cells after overexpression of miR-206. Bioinformatic analysis, qPCR, western blot and luciferase assay indicated that the Forkhead Box Protein 1 (FOXP1) is a direct target of miR-206 in gliomas. Overexpression of FOXP1 could partially rescue the proliferative inhibition in the miR-206 stably overexpressed LN229 cells. In summary, our results suggest that miR-206 might function as a tumor suppressor of gliomas by inhibition of proliferation and could serve as a promising candidate for therapeutic applications in glioma by targeting FOXP1.