Influence of SLC40A1 on Cytokine Interactions and Immune Infiltration in Glioblastoma.

Numerous studies have explored the various functions of Slc40a1 in cancer development. However, the role of Slc40a1 in primary glioblastoma requires further investigation. Initially, we observed that GBM patients with high Slc40a1 expression had a more favorable prognosis than those with low Slc40a1 expression, as evidenced by an analysis of the TIMER database. Subsequent analysis using the cancer genome atlas (TCGA) database enabled us to identify potential underlying mechanisms involved. Further analyses, including GO, KEGG, GSEA, immune infiltration, and correlation analyses, revealed that Slc40a1 primarily affected cytokine interactions, particularly with Ccl14 and Il18, resulting in changes in the immune microenvironment and ultimately leading to a better prognosis in GBM patients. We validated our findings by examining a tissue microarray with 180 samples and confirmed that GBM patients with high SLC40A1 protein expression exhibited more favorable prognostic outcomes than those with low SLC40A1 protein expression. Immunofluorescence analysis also revealed a significant correlation between SLC40A1 protein expression and the protein expression of IL18 and CCL14. These findings suggest that Slc40a1 may play a role in GBM pathogenesis by modulating the tumor immune microenvironment through the regulation of Il18 and Ccl14. Hence, targeting Slc40a1 might offer potential benefits for immunotherapeutic interventions and prognostic assessments in GBM patients.

A Modified Anterior Petrosectomy Approach for Resection of Petroclival Meningioma; with Management of Complications.

Due to deep location and for being adjacent to neurovascular structures, petroclival meningiomas (PCMs) are generally considered to be associated with a high rate of recurrence and cranial nerve deficits.1 This video presents a 49-year-old female patient reporting right trigeminal neuralgia for more than 1 year. The incidence of this symptom with PCMs is about 5%.2 According to the classification system proposed by Kawase et al.3 and Ichimura et al.,4 this is a tentorium type PCM. A modified anterior petrosectomy approach was adopted based on the tumor size and its origin. The case presentation, surgical technique, postoperative outcome are reviewed. The treatments to the intraoperative trochlear nerve injury and temporal bridging vein occlusion are displayed (Video 1). The patient gave verbal consent for participating in the procedure and surgical video.

M2 macrophage marker CHI3L2 could serve as a potential prognostic and immunological biomarker in glioma by integrated single-cell and bulk RNA-Seq analysis.

BACKGROUND: CHI3L2 plays a crucial role in multiple cancers, but its importance in glioma remains unclear. Hence, we comprehensively integrated bulk RNA-sequencing (RNA-seq), proteomics and single-cell RNA-seq (scRNA-seq) to determine the roles of CHI3L2 in gliomas. METHODS: Bulk RNA-seq, proteomics and scRNA-seq data of CHI3L2 in glioma were obtained from online databases. The quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) were conducted to verify the CHI3L2 expression. Then, univariate and multivariate Cox regression analyses, Norman charts and gene set enrichment analysis (GSEA) were performed. Finally, the associations between CHI3L2 and tumor immunity were explored. RESULTS: The expression of CHI3L2 was markedly higher in glioma cancers compared with normal tissues from analysis of the data of the Cancer Genome Atlas and Chinese Glioma Genome Atlas datasets and as verified by GSE4290, GSE50161, qRT-PCR and IHC results (p < 0.05). High expression of CHI3L2 suggested poor overall survival (OS) prognosis in gliomas (p < 0.05). CHI3L2 might also serve as an independent predictor of OS for gliomas (p < 0.05) and we also constructed a Norman chart to predict these patients' survival prognosis with good performance. GSEA analysis showed that CHI3L2 might be involved with eight pathways in gliomas. Regarding tumor immunity, CHI3L2 was found to be significantly involved with immune cell infiltration levels of low-grade glioma, the tumor immune microenvironment, immune checkpoints and immune cells in both low-grade glioma and glioblastoma (p < 0.05). Additionally, scRNA-seq data for CHI3L2 in glioma from the TISCH2 website showed that CHI3L2 is mainly expressed in astrocytes, endothelial cells, CD8+ T cells, mono/macrophage cells, etc. CONCLUSIONS: CHI3L2 presents prognostic and immunological values in glioma, providing novel therapeutic targets for glioma patients.

Prognosis and Immune Landscapes in Glioblastoma Based on Gene-Signature Related to Reactive-Oxygen-Species.

Glioblastoma (GBM) is the most malignant and aggressive primary brain tumor and is highly resistant to current therapeutic strategies. Previous studies have demonstrated that reactive oxygen species (ROS) play an important role in the regulation of signal transduction and immunosuppressive environment in GBM. To further study the role of ROS in prognosis, tumor micro-environment (TME) and immunotherapeutic response in GBM, an ROS-related nine-gene signature was constructed using the Lasso-Cox regression method and validated using three other datasets in our research, based on the hallmark ROS-pathway-related gene sets and the Cancer Genome Atlas GBM dataset. Differences in prognosis, TME scores, immune cell infiltration, immune checkpoint expression levels, and drug sensitivity between high-risk and low-risk subgroups were analyzed using R software. Collectively, our research uncovered a novel ROS-related prognostic model for primary GBM, which could prove to be a potential tool for clinical diagnosis of GBM, and help assess the immune and molecular characteristics of ROS in the tumorigenesis and immunosuppression of GBM. Our research also revealed that the expressions of ROS-related genes-HSPB1, LSP1, and PTX3-were closely related to the cell markers of tumor-associated macrophages (TAMs) and M2 macrophages validated by quantitative RT-PCR, suggesting them could be potential targets of immunotherapy for GBM.

Crucial Role of RLIP76 in Promoting Glycolysis and Tumorigenesis by Stabilization of HIF-1α in Glioma Cells Under Hypoxia.

Hypoxia is intimately associated with enhanced glycolysis in gliomas, and hypoxia-inducible factor 1α (HIF-1α) plays a critical role in this process. RLIP76 (Ral-interacting protein 76) functions as a multifunctional mediator and is aberrantly expressed in various malignant tumors, including glioma. However, the underlying mechanism of RLIP76 and HIF-1α in glioma glycolysis remains largely unclear. In the present study, we demonstrated that RLIP76 is a hypoxia-inducible molecule that contributes to facilitating glycolysis in glioma cells under hypoxic conditions. In addition, hypoxia-induced RLIP76 is a novel target of HIF-1α and enhances the two important HIF-1α-target glycolytic proteins glucose transporter type 1 (GLUT1) and lactate dehydrogenase A (LDHA) in hypoxia. Mechanistically, RLIP76 can directly bind to HIF-1α in the nucleus and regulate the stability of HIF-1α by alleviating HIF-1α ubiquitination and therefore activates GLUT1 and LDHA to accelerate glycolysis in hypoxia. Furthermore, the enhanced glycolysis is necessary for the role of RLIP76 to promote glioma development in vivo, confirming the ability of RLIP76 to regulate tumor cell glycolysis. Collectively, our results demonstrate a previously unappreciated function of RLIP76 in hypoxia-mediated glycolytic metabolism and implicate that RLIP76 might be a valuable therapeutic target for gliomas.

Magnetic covalent organic framework nanospheres-based miRNA biosensor for sensitive glioma detection.

Sensitive detection and accurate diagnosis/prognosis of glioma remain urgent challenges. Herein, dispersed magnetic covalent organic framework nanospheres (MCOF) with uniformed Fe3O4 nano-assembly as cores and high-crystalline COF as shells were prepared by monomer-mediated in-situ interface growth strategy. Based on the unique interaction between MCOF and hairpin DNA, a fluorescent signal amplified miRNA biosensor was constructed. It could realize the sensitive detection of miRNA-182 in different matrixes, where the detection limit, linearity range and determination coefficient (R2) in real blood samples reached 20 fM, 0.1 pM-10 pM and 0.991, respectively. Also, it possessed good stability and precision as observed from the low intra-day/inter-day RSD and high extraction recovery. As a result, it could quantify miRNA-182 in serum of glioma patients, the concentration of which was significantly higher than that of healthy people and obviously decreased after surgery. Finally, a proof-of-concept capillary chip system using this biosensor was proposed to realize the visualized detection of miRNA-182 in microsample. These findings suggest a robust way for sensitive detection and accurate diagnosis/prognosis of glioma.

Angiocentric glioma: A case report and review of the literature.

BACKGROUND: Angiocentric glioma (AG) is a rare, low-grade glioma with slow growth. In 2007, AG was first classified as a solid tumor according to the WHO classification of the central nervous system (WHO class I). The outcome and prognosis of most of the cases are very good, but a few cases with tumor metastasis and disease progression, even death, have been reported. We report a case and systematically analyze previous literature to increase our understanding of the disease and determine the factors that may affect disease progression to make prognostic judgments. CASE PRESENTATION: A young male patient complained of a 3-year history of epilepsy. Anti-epileptic drug treatment was ineffective. An imaging examination revealed a lesion in the left parietal cortex area. Thus, the lesion was completely resected. The pathological diagnosis was angiocentric glioma. During a follow-up of two years, the patient had epilepsy relief controlled by sodium valproate and a disease-free period. CONCLUSION: AG is an epilepsy-related low-grade glioma that heals after complete resection in most reported cases. However, few reported cases have had disease progression and death. This result may be due to the pathological complexity of the diseased tissue. In addition, AG is usually found to have an MYB-QKI rearrangement on genetic analysis. Due to the small number of reported cases and studies, our understanding and knowledge of this disease are still lacking. The potential malignant changes and prognostic factors need to be verified in more than clinical cases and basic research in the future.

Accurately Controlled Delivery of Temozolomide by Biocompatible UiO-66-NH2 Through Ultrasound to Enhance the Antitumor Efficacy and Attenuate the Toxicity for Treatment of Malignant Glioma.

BACKGROUND: Glioma is the most common and malignant primary brain tumour in adults and has a dismal prognosis. Temozolomide (TMZ) is the only clinical first-line chemotherapy drug for malignant glioma up to present. Due to poor aqueous solubility and toxic effects, TMZ is still inefficient and limited for clinical glioma treatment. METHODS: UiO-66-NH2 nanoparticle is a zirconium-based framework, constructed by Zr and 2-amino-1,4-benzenedicarboxylic acid (BDC-NH2) with octahedral microporous structure, which can be decomposed by the body into an ionic form to discharge. We prepared the nanoscale metal-organic framework (MOF) of UiO-66-NH2 to load TMZ for therapy of malignant glioma, TMZ is released from UiO-66-NH2 through a porous structure. The ultrasound accelerates its porous percolation and promotes the rapid dissolution of TMZ through low-frequency oscillations and cavitation effect. The biological safety and antitumor efficacy were evaluated both in vitro and in vivo. RESULTS: The prepared TMZ@MOF exhibited excellent biocompatibility and biosafety due to minimal drug leakage without ultrasound intervention. We further used the flank model of glioblastoma to verify the in vivo therapeutic effect. TMZ@UiO-66-NH2 nanocomposites could be well delivered to the tumour tissue, which led to local enrichment of the TMZ concentration. Furthermore, TMZ@UiO-66-NH2 nanocomposites under ultrasound demonstrated much more efficient inhibition for tumor growth than TMZ@UiO-66-NH2 nanocomposites and TMZ alone. Meanwhile, the bone marrow suppression side effects of TMZ were significantly reduced by TMZ@UiO-66-NH2 nanocomposites. CONCLUSION: In this work, TMZ@UiO-66-NH2 nanocomposites with ultrasound mediation could effectively improve the killing effect of malignant glioma and decrease TMZ-induced toxicity in normal tissues, demonstrating great potential for the delivery of TMZ in the clinical treatment of malignant gliomas.

Microglia-Specific Expression of HEXA and HEXB Leads to Poor Prognosis in Glioblastoma Patients.

Glioblastoma multiforme (GBM) is one of the deadliest cancers in brain. There have been few treatment advances for GBM despite increasing scientific understanding of this disease. ß-hexosaminidase (Hex) is an important enzyme system in human body, encoded by two genes, HEXA and HEXB, are closely related to central nervous system (CNS) diseases such as Sandhoff disease (SD) and Tay-Sachs disease (TSD). However, the expression pattern and function of HEXA and HEXB in GBM remains unclear. Here, we found that both the mRNA and protein expression levels of HEXA and HEXB were significantly upregulated in GBM patient samples. The results from single-cell RNA-sequencing (scRNA-seq) database and double immunostaining showed that HEXA and HEXB were specifically expressed in microglia in GBM patient samples. Furthermore, our in vitro experiments revealed that conditioned media from HEXA and HEXB knockdown-microglia cells could inhibit the proliferation and migration of GBM cells. Finally, according to survival analysis based on online database, higher expression of HEXA and HEXB was associated with poor prognosis in GBM patients. In conclusion, these results suggest that microglial HEXA and HEXB play fundamental role in GBM progression, and they will be potential biomarkers for GBM.

TIGIT-Fc Promotes Antitumor Immunity.

T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a checkpoint receptor that mediates both T-cell and natural killer (NK)-cell exhaustion in tumors. An Fc-TIGIT fusion protein was shown to induce an immune-tolerance effect in a previous report, but the relevance of the TIGIT-Fc protein to tumor immunity is unknown. Here, we found that TIGIT-Fc promotes, rather than suppresses, tumor immunity. TIGIT-Fc treatment promoted the effector function of CD8+ T and NK cells in several tumor-bearing mouse models. TIGIT-Fc treatment resulted in potent T cell- and NK cell-mediated tumor reactivity, sustained memory-induced immunity in tumor rechallenge models, enhanced therapeutic effects via an antibody against PD-L1, and induction of Th1 development in CD4+ T cells. TIGIT-Fc showed a potent antibody-dependent cell-mediated cytotoxicity effect but had no intrinsic effect on tumor cell development. Our findings elucidate the role of TIGIT-Fc in tumor immune reprogramming, suggesting that TIGIT-Fc treatment alone or in combination with other checkpoint receptor blockers is a promising anticancer therapeutic strategy.

Facile Interfacial Synthesis of Densely Spiky Gold Nano-Chestnuts With Full Spectral Absorption for Photothermal Therapy.

The gold nanostructure is regarded as the most promising photothermal agent due to its strong localized surface plasma resonance (LSPR) effect. In particular, the gold nanostructures with sharp spikes on the surface have higher optical signal enhancement, owing to the sharp tips drastically enhancing the intense nanoantenna effect. However, current approaches for the synthesis of spiky gold nanostructures are either costly, complicated, or uncontrollable. Herein, we report a novel strategy to synthesize gold nano-chestnuts (SGNCs) with sharp spikes as an excellent photothermal agent. The SGNCs were prepared by a facile one-pot interfacial synthetic method, and their controllable preparation mechanism was acquired. The SGNCs exhibited ideal full-spectrum absorption and showed excellent photothermal effect. They have a photothermal conversion efficiency (η) as high as 52.9%, which is much higher than traditional photothermal agents. The in vitro and in vivo results show that the SGNCs could efficiently ablate the tumor cells. Thus, the SGNCs have great potential in photothermal therapy applied in malignant tumors.

A novel lncRNA-LINC01116 regulates tumorigenesis of glioma by targeting VEGFA.

Brain glioma is the most common malignant tumor of the central nervous system, and one of the leading causes of death in patients with intracranial tumors. The clinical outcome of glioma is usually poor due to abundant vascularity, fast growth and susceptibility of invasion to normal brain tissues. Our microarray study showed that lncRNA-LINC01116 was significantly upregulated in glioma tissues and played an important role in cell proliferation, cycle, migration, invasion and angiogenesis. In addition, vascular endothelial growth factor (VEGFA) may be the major target genes in the downstream of lncRNA-LINC01116. Dual luciferase assay showed that LINC01116 and VEGFA both contained a miR-31-5p binding site, and LINC01116 could regulate the expression of VEGFA through competitive absorption of miR-31-5p. RNA immunoprecipitation indicated that LINC01116 and VEGFA were present in the miR-31-5p-RISC complex, and biotinylated miR-31-5p pull-down assay suggested that there was a competitive relationship between LINC01116 and VEGFA to bind with miR-31-5p. Collectively, our study has identified a novel lncRNA-LINC01116 and clarified the role and mechanism of LINC01116 in the tumorigenesis of glioma. LINC01116 may prove to be a potential target for the clinical diagnosis and treatment of glioma.

Differential Expression of Circular RNAs in Glioblastoma Multiforme and Its Correlation with Prognosis.

OBJECTIVE: The present study aimed to explore the expression profiles of circular RNAs (circRNAs) in glioblastoma multiforme (GBM) in an attempt to identify potential core genes in the pathogenesis of this tumor. METHODS: Differentially expressed circRNAs were screened between tumor tissues from five GBM patients and five normal brain samples using Illumina Hiseq. Bioinformatics analysis was used to analyze their potential function. CircBRAF was further detected in different WHO grades glioma tissues and normal brain tissues. Kaplan-Meier curves and multivariate Cox's analysis were used to analyze the association between circBRAF expression level and prognosis of glioma patients. RESULTS: A total of 1411 differentially expressed circRNAs were identified in GBM patients including 206 upregulated circRNAs and 1205 downregulated circRNAs. Differential expression of circRNAs was closely associated with the biological process and molecular function. The downregulated circRNAs were mainly associated with ErbB and Neurotrophin signaling pathways. Moreover, the expression level of circBRAF in normal brain tissues was significantly higher than that in glioma tissues (P<.001). CircBRAF was significantly lower in glioma patients with high pathological grade (WHO III & IV) than those with low grade (WHO I & II) (P<.001). Cox analysis revealed that high circBRAF expression was an independent biomarker for predicting good progression-free survival and overall survival in glioma patients (HR=0.413, 95% CI 0.201-0.849; HR=0.299, 95% CI 0.135-0.661; respectively). CONCLUSION: The present study identified a profile of dysregulated circRNAs in GBM. Bioinformatics analysis showed that dysregulated circRNAs might be associated with tumorigenesis and development of GBM. In addition, circBRAF could severe as a biomarker for predicting pathological grade and prognosis in glioma patients.

Clinical features and prognostic factors of WHO II and III adult spinal meningiomas: analysis of 25 cases in a single center.

Spinal World Health Organization (WHO) II and III meningiomas are relatively rare, and often associated with great clinical aggressiveness and poor overall survival. There are controversies over factors affecting the prognosis of this disease. The aim of this retrospective study was to evaluate factors that may affect the therapeutic outcome and prognosis of adult high-grade spinal meningiomas by reviewing the medical records of 25 patients who were surgically treated in our hospital between 2001 and 2014. Univariate and multivariate analyses were performed to identify prognostic variables relative to patient and tumor characteristics, and treatment modalities. All 25 patients (14 men and 11 women; mean age 46.6 ± 16.1 years) underwent surgical resection. Local recurrence was occurred in 13 (52.0 %) patients, and 10 (40.0 %) patients died during the follow-up periods. The 5-year recurrence rate was 60.0 % and the 5-year survival rate was 68.0 %. The results of statistical analysis suggested that Simpson resection grade and the number of involved segments were prognostic factors related to progression-free survival and that sex, age, preoperative Frankel score, the number of involved segments and WHO grade were closely correlated with survival. Furthermore, we confirmed that the number of involved segments was the major independent factor affecting recurrence of patients with adult spinal high-grade meningiomas, and that sex, age and WHO grade were prognostic factors affecting survival but not recurrence.

Analysis on therapeutic outcomes and prognostic factors of intracranial ependymoma: a report of 49 clinical cases in a single center.

Although intracranial ependymoma is relatively rare, it is often associated with great clinical aggressiveness and poor overall survival. There are controversies over factors affecting the prognosis of the disease. The aim of this retrospective study was to evaluate factors that may affect the therapeutic outcome and prognosis of intracranial ependymoma by reviewing the medical records of 49 patients who were surgically treated in our hospital between 2001 and 2014. Univariate and multivariate analyses were performed to identify prognostic variables relative to patient and tumor characteristics, and treatment modalities. All 49 patients (24 men and 25 women; mean age 27.6 years) underwent surgical resection, of whom 14 patients also underwent postoperative radiotherapy. Local recurrence was found in 15 (48.8 %) patients, and 22 (51.2 %) patients died during the follow-up periods. The 5-year recurrence rate was 65 % and the survival rate was 51 %. The results of statistical analysis suggested that preoperative extraventricular drainage and surgical resection extent were prognostic factors related to progression-free survival, and that age, surgical resection extent and histological grade were closely associated with survival. Interestingly, there was a significant correlation between the symptom of hydrocephalus and age (P = 0.010), and patients with a better clinical status (KPS ≥ 80) were significantly associated with a lower WHO grade (P = 0.007). In conclusion, we confirmed that surgical resection extent was the major independent factor affecting both recurrence and survival of patients with intracranial ependymoma, while age and WHO grade were prognostic factors affecting survival but not recurrence.