Nanoparticles for efficient drug delivery and drug resistance in glioma: New perspectives.

Gliomas are the most common primary tumors of the central nervous system, with glioblastoma multiforme (GBM) having the highest incidence, and their therapeutic efficacy depends primarily on the extent of surgical resection and the efficacy of postoperative chemotherapy. The role of the intracranial blood-brain barrier and the occurrence of the drug-resistant gene O6-methylguanine-DNA methyltransferase have greatly limited the efficacy of chemotherapeutic agents in patients with GBM and made it difficult to achieve the expected clinical response. In recent years, the rapid development of nanotechnology has brought new hope for the treatment of tumors. Nanoparticles (NPs) have shown great potential in tumor therapy due to their unique properties such as light, heat, electromagnetic effects, and passive targeting. Furthermore, NPs can effectively load chemotherapeutic drugs, significantly reduce the side effects of chemotherapeutic drugs, and improve chemotherapeutic efficacy, showing great potential in the chemotherapy of glioma. In this article, we reviewed the mechanisms of glioma drug resistance, the physicochemical properties of NPs, and recent advances in NPs in glioma chemotherapy resistance. We aimed to provide new perspectives on the clinical treatment of glioma.

A biosensor for D-2-hydroxyglutarate in frozen sections and intraoperative assessment of IDH mutation status.

The oncometabolite D-2-hydroxyglutarate (D-2-HG) has emerged as a valuable biomarker in tumors with isocitrate dehydrogenase (IDH) mutations. Efficient detection methods are required and rapid intraoperative determination of D-2-HG remains a huge challenge. Herein, D-2-HG dehydrogenase from Achromobacter xylosoxidans (AX-D2HGDH) was found to have high substrate specificity. AX-D2HGDH dehydrogenizes D-2-HG and reduces flavin adenine dinucleotide (FAD) bound to the enzyme. Interestingly, the dye resazurin can be taken as another substrate to restore FAD. AX-D2HGDH thus catalyzes a bisubstrate and biproduct reaction: the dehydrogenation of D-2-HG to 2-ketoglutarate and simultaneous reduction of non-fluorescent resazurin to highly fluorescent resorufin. According to steady-state analysis, a ping-pong bi-bi mechanism has been concluded. The Km values for resazurin and D-2-HG were determined as 0.56 µM and 10.93 µM, respectively, suggesting high affinity to both substrates. On the basis, taking AX-D2HGDH and resazurin as recognition and fluorescence transducing element, a D-2-HG biosensor (HGAXR) has been constructed. HGAXR exhibits high sensitivity, accuracy and specificity for D-2-HG in different biological samples. With the aid of HGAXR and the matched low-cost palm-size detecting device, D-2-HG levels in frozen sections of resected brain tumor tissues can be measured in a direct, simple and accurate manner with a fast detection (1-3 min). As the technique of frozen section is familiar to surgeons and pathologists, HGAXR and the portable device can be easily integrated into the current workflow, having potential to provide rapid intraoperative pathology for IDH mutation status and guide decision-making during surgery.

Establishment and validation of a novel integrin-based prognostic gene signature that sub-classifies gliomas and effectively predicts immunosuppressive microenvironment.

The integrin family members play a key role in cancer immunomodulation and prognosis. We comprehensively analyzed the expression patterns and clinical significance of integrin family-related genes in gliomas. A total of 2293 gliomas from the Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Gliovis platform were enrolled for analyses. Twenty-six integrin coding genes showed different expression patterns between glioma and normal brain tissues. We screened an integrin family-related gene signature (ITGA5, ITGA9, ITGAE, ITGB7 and ITGB8) that showed independent prognostic value and sub-classified gliomas into different prognostic and molecular clusters, further composed an integrin-based risk score model associated with glioma malignant clinical features, overall survival (OS), and immune microenvironment alterations. Besides, glioma patients with high-risk scores showed chemotherapeutic resistance and more immune cells infiltration as well as high immune checkpoints expression. Concurrently, we also revealed that high-risk score group presented resistance to T cell-mediated cancer killing process and lower rates of response to immune checkpoint blockade (ICB) treatment. In conclusion, our study identified a valuable integrin gene signature that predicted gliomas OS effectively, and sub-classified them into different phenotypes and accompanied with immunological changes, possibly acted as a biomarker for ICB treatment.

Angiogenesis-Related Gene Signature-Derived Risk Score for Glioblastoma: Prospects for Predicting Prognosis and Immune Heterogeneity in Glioblastoma.

Background: Glioblastoma multiforme (GBM) is the most common malignant tumor in the central nervous system with poor prognosis and unsatisfactory therapeutic efficacy. Considering the high correlation between tumors and angiogenesis, we attempted to construct a more effective model with angiogenesis-related genes (ARGs) to better predict therapeutic response and prognosis. Methods: The ARG datasets were downloaded from the NCBI-Gene and Molecular Signatures Database. The gene expression data and clinical information were obtained from TCGA and CGGA databases. The differentially expressed angiogenesis-related genes (DE-ARGs) were screened with the R package "DESeq2". Univariate Cox proportional hazards regression analysis was used to screen for ARGs related to overall survival. The redundant ARGs were removed by least absolute shrinkage and selection operator (LASSO) regression analysis. Based on the gene signature of DE-ARGs, a risk score model was established, and its effectiveness was estimated through Kaplan-Meier analysis, ROC analysis, etc. Results: A total of 626 DE-ARGs were explored between GBM and normal samples; 31 genes were identified as key DE-ARGs. Then, the risk score of ARG signature was established. Patients with high-risk score had poor survival outcomes. It was proved that the risk score could predict some medical treatments' response, such as temozolomide chemotherapy, radiotherapy, and immunotherapy. Besides, the risk score could serve as a promising prognostic predictor. Three key prognostic genes (PLAUR, ITGA5, and FMOD) were selected and further discussed. Conclusion: The angiogenesis-related gene signature-derived risk score is a promising predictor of prognosis and treatment response in GBM and will help in making appropriate therapeutic strategies.

Identification of a five-gene signature deriving from the vacuolar ATPase (V-ATPase) sub-classifies gliomas and decides prognoses and immune microenvironment alterations.

Aberrant expression of coding genes of the V-ATPase subunits has been reported in glioma patients that can activate oncogenic pathways and result in worse prognosis. However, the predictive effect of a single gene is not specific or sensitive enough. In this study, by using a series of bioinformatics analyses, we identified five coding genes (ATP6V1C2, ATP6V1G2, TCIRG1, ATP6AP1 and ATP6AP2) of the V-ATPase that were related to glioma patient prognosis. Based on the expression of these genes, glioma patients were sub-classified into different prognosis clusters, of which C1 cluster performed better prognosis; however, C2 cluster showed more malignant phenotypes with oncogenic and immune-related pathway activation. The single-cell RNA-seq data revealed that ATP6AP1, ATP6AP2, ATP6V1G2 and TCIRG1 might be cell-type potential markers. Copy number variation and DNA promoter methylation potentially regulate these five gene expressions. A risk score model consisted of these five genes effectively predicted glioma prognosis and was fully validated by six independent datasets. The risk scores also showed a positive correlation with immune checkpoint expression. Importantly, glioma patients with high-risk scores presented resistance to traditional treatment. We also revealed that more inhibitory immune cells infiltration and higher rates of "non-response" to immune checkpoint blockade (ICB) treatment in the high-risk score group. In conclusion, our study identified a five-gene signature from the V-ATPase that could sub-classify gliomas into different phenotypes and their abnormal expression was regulated by distinct mechanisms and accompanied with immune microenvironment alterations potentially act as a biomarker for ICB treatment.

T cell immune regulator 1 is a prognostic marker associated with immune infiltration in glioblastoma multiforme.

Glioma is the most common primary brain tumor and glioblastoma multiforme (GBM) is the most malignant brain glioma with the worst prognosis. T cell immune regulator 1 (TCIRG1) constitutes the V0a3 subunit of vacuolar ATPase (V-ATPase), and the function of V-ATPase in malignant tumors, such as breast cancer, melanoma and hepatocellular carcinoma, has been reported. However, the effect of the TCIRG1 subunit on GBM remains to be fully elucidated. mRNA levels of TCIRG1 in different cancer types and the corresponding normal tissues were extracted from the Oncomine and Tumor Immune Estimation Resource (TIMER) databases. The Gene Expression Omnibus (access number: GSE16011), the Chinese Glioma Genome Atlas and The Cancer Genome Atlas were used to investigate the mRNA level of TCIRG1 in glioma. Protein level validation in glioma was performed using western blotting. The Database for Annotation, Visualization and Integrated Discovery was used to analyze Gene Ontology (GO) categories for genes correlated with TCIRG1 in GBM. Protein-protein interaction (PPI) networks and module analyses were performed using Cytoscape software and the MCODE plugin. The correlation between tumor immune cell infiltration and TCIRG1 expression was explored using the TIMER database. Additionally, the correlation between TCIRG1 and the gene signature of immune infiltration was explored through TIMER and Gene Expression Profiling Interactive Analysis. External validation of TCIRG1 expression according to immune signatures in GBM was performed using the GSE16011 dataset with the GlioVis online tool. It was found that TCIRG1 expression was increased in GBM and numerous malignant tumors and may serve as a biomarker of the mesenchymal subtype of GBM. GO category analysis of positively correlated genes revealed that TCIRG1 was correlated with the immune response in GBM. PPI network and module analyses also supported the potential function of TCIRG1 in the local immune response. The expression of TCIRG1 was associated with various immune markers. It was therefore speculated that TCIRG1 is associated with glioma malignancy and may be a marker of unfavorable prognosis in patients with GBM, and it could be regarded as a prognostic biomarker and an indicator of immune infiltration in GBM.

Thrombospondin-1 is a prognostic biomarker and is correlated with tumor immune microenvironment in glioblastoma.

Glioblastoma (GBM) is the most common malignant brain tumor and the most aggressive type of glioma, characterized by strong invasive potential and rapid recurrence despite severe treatment methods, such as maximal tumor resection followed by chemotherapy and radiotherapy. Thrombospondin-1 (THBS1) was first discovered in platelets and subsequent studies have indicated its functions in the development of several cancers, including breast cancer, melanoma, gastric cancer, cervical cancer and GBM. However, to the best of our knowledge, the expression profiles of THBS1 in GBM subtypes remain unknown, and the underlying mechanism by which THBS1 expression is regulated, and its effect on the local immune response in GBM, remains unclear. The present study used public datasets from The Cancer Genome Atlas, the Chinese Glioma Genome Atlas, the Gene Expression Omnibus, the Ivy Glioblastoma Atlas Project, Tumor Immune Estimation Resource, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data and the Human Protein Atlas to investigate the prognostic value of THBS1 and its expression profiles, as well as its correlation with the local immune response in GBM. The results demonstrated that THBS1 was a biomarker of the pathological malignancy of glioma, and predicted the mesenchymal subtype of GBM. Furthermore, DNA methylation of THBS1 may be an important mechanism by which THBS1 expression is regulated in GBM. The hypomethylation or overexpression of THBS1 predicted an unfavorable prognosis in patients with GBM. Additionally, THBS1 was correlated with immune and inflammatory responses in GBM. Thus, the findings of the present study provide insight into the potential value of THBS1 in the treatment of GBM.

Serine Incorporator 2 (SERINC2) Expression Predicts an Unfavorable Prognosis of Low-Grade Glioma (LGG): Evidence from Bioinformatics Analysis.

Serine Incorporator 2 (SERINC2) is a transmembrane protein that incorporates serine into membrane lipids. The function of SERINC2 in tumors has been reported, but the role of SERINC2 in gliomas is not fully understood. RNA-sequencing data from The Cancer Genome Atlas (TCGA) (530 cases of low-grade glioma (LGG) and 173 cases of glioblastoma multiforme (GBM)) and microarray data from Gene Expression Omnibus (GEO) (Accession No. GSE16011, 284 cases gliomas were included) were acquired. Bioinformatics analysis was performed as the primary method to examine the function of SERINC2 and its correlated genes in glioma. SERINC2 was highly expressed in GBM compared with LGG and normal brain tissues. Elevated SERINC2 expression predicted shorter 5-, 10-, and 15-year overall survival (OS) of LGG patients and isocitrate dehydrogenase-1 (IDH-1) mutation-type LGG patients but had no effect on the OS of GBM patients. Cox regression analysis showed that SERINC2 was an independent factor in LGG OS. Methylation analysis found that 13 CpG methylation sites (methylation450k) correlated with SERINC2 expression in LGG. The mRNA expression level of SERINC2 was significant lower in the DNA deletion group than in the intact and amplification groups. A total of 390 copositive and 244 conegative correlation genes with SERINC2 were obtained from LGG in TCGA-LGG and GSE16011. Gene ontology (GO) category and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the copositive correlation genes were primarily enriched in the mitotic process and cell cycle. Combining the results from the protein-protein interaction (PPI) network of SERINC2 correlation genes and CytoHubba led to the selection of 10 hub genes (CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE). OncoLnc analysis confirmed that high expression levels of these hub genes were associated with poor OS in LGG. Our results suggested that aberrant SERINC2 expression existed in glioma and that its expression might be a potential prognostic marker in LGG patients. CDC20, FN1, AURKB, AURKA, KIF2C, BIRC5, CCNB2, UBE2C, CCNA2, and CENPE may be potential biomarkers and therapeutic targets for LGG.

Systematic identification of lncRNA-based prognostic biomarkers for glioblastoma.

Glioblastoma (GBM), a primary malignant tumor of the central nervous system, has a very poor prognosis. Analysis of global GBM samples has revealed a variety of long non-coding RNAs (lncRNAs) associated with prognosis; nevertheless, there remains a lack of accurate prognostic markers. Using RNA-Seq, methylation, copy number variation (CNV), mutation and clinical follow-up data for GBM patients from The Cancer Genome Atlas, we performed univariate analysis, multi-cluster analysis, differential analysis of different subtypes of lncRNA and coding genes, weighted gene co-expression network analyses, gene set enrichment analysis, Kyoto Encyclopedia of Genes and Genomes analysis, Gene Ontology analysis, and lncRNA CNV analyses. Our analyses yielded five lncRNAs closely related to survival and prognosis for GBM. To verify the predictive role of these five lncRNAs on the prognosis of GBM patients, the corresponding RNA-seq data from Chinese Glioma Genome Atlas were downloaded and analyzed, and comparable results were obtained. The role of one lncRNA LINC00152 has been observed previously; the others are novel findings. Expression of these lncRNAs could become effective predictors of survival and potential prognostic biomarkers for patients with GBM.

Clinical Application of Multimodal Neuronavigation System in Neuroendoscope-Assisted Skull Base Chordoma Resection.

Skull base chordoma is a rare tumor arising from embryonic remnants of the notochord with invasive potential. Due to the destruction of osseous landmarks and invasion of surrounding structures, surgical resection is challenging. The authors explored the clinical value of a multimodal neuronavigation system in skull base chordoma resection using a neuroendoscope. Between January 2012 and January 2016, the authors utilized neuroendoscopy to excise skull base chordoma in 93 patients. The authors performed 45 operations assisted by multimodal neuronavigation (neuronavigation group) and 48 without intraoperative imaging guidance (control group). In the control group, 35 patients (73%) underwent gross total resection. In the neuronavigation group, all patients underwent gross total resection without radiographically identified bleeding. Only 1 patient (2%) in the neuronavigation group showed a temporary reduction in vision, which improved after symptomatic treatment. In contrast, there were 4 patients (8%) with postoperative complication, including 2 patients with intracranial hematoma and 2 with neurological deficits. Complication rates were higher than the neuronavigation group. In the follow-up period, 2 patients in the control group with subtotal resection had recurrence within 24 months, but without extracranial metastases. The multimodal neuronavigation system could contribute intraoperative real-time guidance for spatial relationships between lesions and adjacent neurovascular structures, as well as eroded and distorted anatomical landmarks through multiple image fusion and 3-dimensional reconstruction. It significantly improves surgical outcome and provides a new insight into the management of skull base chordomas.

Intraoperative electrocorticography-guided microsurgical management for patients with onset of supratentorial neoplasms manifesting as epilepsy: a review of 65 cases.

AIM: We reviewed the surgical procedures guided by intraoperative electrocorticography and outcome of 65 patients with onset of supratentorial neoplasms manifesting as epilepsy. METHOD: Clinical data were obtained for 65 patients with supratentorial neoplasms who received surgery, with the aid of intraoperative electrocorticography to screen epileptogenic foci before and after removal of neoplasms, and depth electrodes when needed. According to electrocorticography findings, appropriate surgical procedures were performed to treat the epileptogenic foci. In the control group, 72 patients received simple lesionectomy. Postoperative seizure outcomes were documented and analysed retrospectively. RESULTS: In the case group, 33 patients received lesionectomy only, while the other 32 patients underwent intraoperative electrocorticography-guided tailored epilepsy surgery. In total, 57 patients (87.7%) in the case group and 38 patients (52.8%) in the control group were seizure-free (Engel Class I). Comparing outcomes of patients with temporal lesions between the two groups, 80.0% patients (12/15) in the case group and 20.0% (3/15) in the control group were seizure-free. Furthermore, comparing the seizure outcomes of patients who finally underwent tailored epilepsy surgery and simple lesionectomy (33 after electrocorticography and 72 without electrocorticography), intraoperative electrocorticography-guided tailored epilepsy surgery demonstrated superiority over lesionectomy (Engel Class I; 87.5% vs. 63.8%, respectively). CONCLUSIONS: Electrocorticography plays an important role in the localisation of epileptogenic foci and evaluation of the effects of microsurgical procedures intraoperatively. Isolated lesionectomy is not usually sufficient for better postoperative seizure outcome. In addition, for patients with temporal tumours, especially in the non-dominant hemisphere, a more aggressive strategy, such as an anterior temporal lobectomy, is recommended.