Identification of key genes and pathways associated with resting mast cells in meningioma.

BACKGROUND: To identify candidate key genes and pathways related to resting mast cells in meningioma and the underlying molecular mechanisms of meningioma. METHODS: Gene expression profiles of the used microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. GO and KEGG pathway enrichments of DEGs were analyzed using the ClusterProfiler package in R. The protein-protein interaction network (PPI), and TF-miRNA- mRNA co-expression networks were constructed. Further, the difference in immune infiltration was investigated using the CIBERSORT algorithm. RESULTS: A total of 1499 DEGs were identified between tumor and normal controls. The analysis of the immune cell infiltration landscape showed that the probability of distribution of memory B cells, regulatory T cells (Tregs), and resting mast cells in tumor samples were significantly higher than those in the controls. Moreover, through WGCNA analysis, the module related to resting mast cells contained 158 DEGs, and KEGG pathway analysis revealed that the DEGs were dominant in the TNF signaling pathway, cytokine-cytokine receptor interaction, and IL-17 signaling pathway. Survival analysis of hub genes related to resting mast cells showed that the risk model was constructed based on 9 key genes. The TF-miRNA- mRNA co-regulation network, including MYC-miR-145-5p, TNFAIP3-miR-29c-3p, and TNFAIP3-hsa-miR-335-3p, were obtained. Further, 36 nodes and 197 interactions in the PPI network were identified. CONCLUSION: The results of this study revealed candidate key genes, miRNAs, and pathways related to resting mast cells involved in meningioma development, providing potential therapeutic targets for meningioma treatment.

Potential Molecular Mechanism of TNF Superfamily-Related Genes in Glioblastoma Multiforme Based on Transcriptome and Epigenome.

Objective: This study aimed to investigate the molecular mechanism of tumor necrosis factor (TNF) superfamily-related genes and potential therapeutic drugs for glioblastoma multiforme (GBM) patients based on transcriptome and epigenome. Methods: Gene expression data, corresponding clinical data, and methylation data of GBM samples and normal samples in the TCGA-GBM and GTEx datasets were downloaded. The TNF-related genes were obtained, respectively, from two groups in the TCGA dataset. Then, the TNF-related differentially expressed genes (DEGs) were investigated between two groups, followed by enrichment analysis. Moreover, TNF superfamily-related gene expression and upstream methylation regulation were investigated to explore candidate genes and the prognostic model. Finally, the protein expression level of candidate genes was performed, followed by drug prediction analysis. Results: A total of 41 DEGs including 4 ligands, 18 receptors, and 19 downstream signaling molecules were revealed between two groups. These DEGs were mainly enriched in pathways like TNF signaling and functions like response to TNF. A total of 5 methylation site-regulated prognosis-related genes including TNF Receptor Superfamily Member (TNFRSF) 12A, TNFRSF11B, and CD40 were explored. The prognosis model constructed by 5 genes showed a well-prediction effect on the current dataset and verification dataset. Finally, drug prediction analysis showed that zoledronic acid (ZA)-TNFRSF11B was the unique drug-gene relation in both two databases. Conclusion: Methylation-driven gene TNFRSF12A might participate in the development of GBM via response to the TNF biological process and TNF signaling pathway and significantly associated with prognosis. ZA that targets TNFRSF11B expression might be a potential effective drug for clinical treatment of GBM.

Identification of potential biomarkers and candidate small molecule drugs in glioblastoma.

BACKGROUND AND AIMS: Glioblastoma (GBM) is a common and aggressive primary brain tumor, and the prognosis for GBM patients remains poor. This study aimed to identify the key genes associated with the development of GBM and provide new diagnostic and therapies for GBM. METHODS: Three microarray datasets (GSE111260, GSE103227, and GSE104267) were selected from Gene Expression Omnibus (GEO) database for integrated analysis. The differential expressed genes (DEGs) between GBM and normal tissues were identified. Then, prognosis-related DEGs were screened by survival analysis, followed by functional enrichment analysis. The protein-protein interaction (PPI) network was constructed to explore the hub genes associated with GBM. The mRNA and protein expression levels of hub genes were respectively validated in silico using The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) databases. Subsequently, the small molecule drugs of GBM were predicted by using Connectivity Map (CMAP) database. RESULTS: A total of 78 prognosis-related DEGs were identified, of which10 hub genes with higher degree were obtained by PPI analysis. The mRNA expression and protein expression levels of CETN2, MKI67, ARL13B, and SETDB1 were overexpressed in GBM tissues, while the expression levels of CALN1, ELAVL3, ADCY3, SYN2, SLC12A5, and SOD1 were down-regulated in GBM tissues. Additionally, these genes were significantly associated with the prognosis of GBM. We eventually predicted the 10 most vital small molecule drugs, which potentially imitate or reverse GBM carcinogenic status. Cycloserine and 11-deoxy-16,16-dimethylprostaglandin E2 might be considered as potential therapeutic drugs of GBM. CONCLUSIONS: Our study provided 10 key genes for diagnosis, prognosis, and therapy for GBM. These findings might contribute to a better comprehension of molecular mechanisms of GBM development, and provide new perspective for further GBM research. However, specific regulatory mechanism of these genes needed further elaboration.

Genomic landscape of the immune microenvironments of brain metastases in breast cancer.

BACKGROUND: This study was intended to investigate the genomic landscape of the immune microenvironments of brain metastases in breast cancer. METHODS: Three gene expression profile datasets (GSE76714, GSE125989 and GSE43837) of breast cancer with brain metastases were downloaded from Gene Expression Omnibus (GEO) database. After differential expression analysis, the tumor immune microenvironment and immune cell infiltration were analyzed. Then immune-related genes were identified, followed by function analysis, transcription factor (TF)-miRNA-mRNA co-regulatory network analysis, and survival analysis of metastatic recurrence. RESULTS: The present results showed that the tumor immune microenvironment in brain metastases was immunosuppressed compared with primary caner. Compared with primary cancer samples, the infiltration ratio of plasma cells in brain metastases samples was significantly higher, while the infiltration ratio of macrophages M2 cells in brain metastases samples was significantly lower. Total 42 immune-related genes were identified, such as THY1 and NEU2. CD1B, THY1 and DOCK2 were found to be implicated in the metastatic recurrence of breast cancer. CONCLUSIONS: Targeting macrophages or plasma cells may be new strategies for immunotherapy of breast cancer with brain metastases. THY1 and NEU2 may be potential therapeutic targets for breast cancer with brain metastases, and THY1, CD1B and DOCK2 may serve as potential prognostic markers for improvement of brain metastases survival.

Endothelin B receptor promotes the proliferation and immune escape of malignant gliomas.

PURPOSE: As a kind of difficult to cure tumour, malignant gliomas have attracted widespread attention. The proliferation and immune escape of tumour cells were closely related to the development of malignant gliomas. The aim of this study was to investigate the role of endothelin B receptor (NTBR) in gliomas. METHODS: RT-PCR was used to detect the expression of NTBR mRNA in glioma tissue and glioma cell lines. The expression of NTBR in glioma tissues was detected by immunohistochemistry. MTT assay was used to detect the viability of U87 cells after adding NTBR. Cell cloning assay was used to detect the cell proliferation ability. Western blot was used to detect the expression of TGF-ß and the expression of Treg after adding NTBR to U87. RESULT: The expression of NTBR in glioma tissues and cells was significantly higher than that in the control group by RT-PCR. After adding NTBR, cell proliferation of U87 was significantly enhanced and TGF-ß and Treg were significantly expressed. It was suggested that NTBR could contribute to tumour immune escape in glioma, and it was found that there was a positive correlation between NTBR expression and different stages in malignant gliomas. CONCLUSION: Endothelin B receptor can increase the proliferation of glioma cells and tumour immune escape. The expression of endothelin B is closely related to the clinical stage of glioma.

Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy.

Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy.

[Application of intraoperative magnetic resonance imaging and multimodal navigation in surgical resection of glioblastoma].

OBJECTIVE: To evaluate the efficacy of intraoperative magnetic resonance imaging (iMRI) and multimodal navigation in surgical resection of glioblastoma. METHODS: Between February 2009 and July 2010, 76 glioblastoma patients underwent surgical resection guided by iMRI and multimodal navigation. The cohort consisted of 43 male and 33 female patients, with a mean age of 49 years (range: 14-79 years). Rates of gross total resection (GTR) and extent of resection (EoR) were calculated at first and final iMRI scans.Pearson χ(2) test was used to compare the rates of GTR. RESULTS: iMRI and multimodal navigation were successfully implemented in all cases. Rates of GTR were misestimated by neurosurgeons in 24 cases (31.6%), which were confirmed by first iMRI. Total tumor resection were achieved in 20 cases (26.3%) as a result of iMRI scan, increasing the rates of gross total resection from 52.6% to 78.9% (χ(2) = 11.692, P = 0.001). Extent of resection in 28 patients who underwent further tumor resection were increased from 81.5% to 98.1%, leading to the overall extent of resection improved from 92.3% to 98.4%. At 3-month follow-up, 3 cases (3.9%) developed permanent neurologic deficits. The mean clinical follow-up was 15.6 months (range 3.0-45.0 months). The 2-year overall survival rate was 19.7%. The median progression-free survival of gross total resection group was 12 months (95% CI: 10.1-13.9 months), compared with 9 months (95%CI: 7.9-10.1 months) of the subtotal resection group (χ(2) = 4.756, P = 0.029). The overall survival of gross total resection group was 16 months (95% CI: 13.7-18.3 months), compared with 12 months (95% CI: 9.7-14.3 months) of the subtotal resection group (χ(2) = 7.885, P = 0.005). CONCLUSION: Combined with multimodal navigation, iMRI helps maximize surgical resection of glioblastoma, preserving neurological function while increasing progression-free survival and overall survival.

[Integration of metabolism images into multimodal neuronavigation for frameless stereotaxy].

OBJECTIVES: To evaluate the efficacy of integration of metabolism images into multimodal neuronavigation for frameless stereotactic biopsy. METHODS: From January to December 2012, 32 patients with brain lesions underwent frameless stereotactic biopsy guided by positron emission tomograph (PET) and proton magnetic resonance spectroscopy ((1)H-MRS)-based multimodal neuronavigation and intraoperative magnetic resonance imaging (iMRI). The cohort consisted of 16 male and 16 female patients, with a mean age of 45 years (range: 7 - 62 years). Biopsy targets were identified according to PET and (1)H-MRS. Biopsy was performed with Varioguide frameless biopsy system. Diagnostic yield and complications were assessed. RESULTS: Metabolism images-based multimodal neuronavigation and iMRI were successfully implemented in all cases. iMRI confirmed accuracy of biopsy targets. All the specimens obtained pathological diagnosis, the diagnostic yield was 100%. In 1 patient, iMRI found small hematoma (< 5 ml), surgical evacuation wasn't needed with intraoperative complication rate 3.1%. With the help of multimodal neuronavigation, no patients had new or worsened neurologic deficits. CONCLUSIONS: Integration of metabolism images into multimodal neuronavigation provide not only anatomical, but also metabolic and functional information for frameless stereotaxy, increasing diagnostic yield and avoiding postoperative neurologic deficits.

[Implementation of VarioGuide in stereotactic brain biopsy: a preliminary experience].

OBJECTIVE: To evaluate the clinical value of VarioGuide in stereotactic brain biopsy. METHODS: Fifteen patients with brain lesions underwent frameless stereotactic brain biopsy guided by VarioGuide and multimodal neuronavigation. Intraoperative magnetic resonance imaging (iMRI) was used to confirm the accuracy of biopsy. And the VarioGuide-related adverse events, operative duration, surgical outcomes and postoperative complications were recorded respectively. RESULTS: In all patients, VarioGuide and multimodal neuronavigation were successfully integrated into the biopsy procedure. No VarioGuide-related adverse events were reported. The mean operative duration was (65 ± 8) min. The biopsy accuracy was confirmed by iMRI in all cases. And the postoperative histological diagnostic rate was 100%. No mortality and morbidity occurred postoperatively. CONCLUSION: The combined approach of VarioGuide and multimodal neuronavigation is accurate, safe and efficient. It may improve the histological diagnostic rate without postoperative neurological deficits in stereotactic brain biopsy.

[Influences of high-field intraoperative magnetic resonance imaging on the extent of resection in low-grade gliomas].

OBJECTIVE: To evaluate the influences of high-field intraoperative magnetic resonance imaging (iMRI) on the extent of resection (EoR) in low-grade gliomas. METHODS: Fifty-nine patients with low-grade gliomas underwent microsurgeries under the guidance of high-field iMRI and functional neuro-navigation. The rates of gross total removal and EoR were recorded after initial and final iMRI scans and neurological performances were evaluated peri-operatively and at follow-up. RESULTS: iMRI and functional neuronavigation were successfully performed in all patients. Initial iMRI found that the rates of gross total removal were misestimated in 21 cases (35.6%). In 17 cases (28.8%), initial iMRI revealed resectable residual tumors and further resection achieved gross total removal in 8 cases (13.6%). iMRI boosted the level of EoR from 90% ± 15% to 94% ± 12% (P < 0.001) in all cases and from 78% ± 17% to 91% ± 12% in 17 cases undergoing further tumor resections. At 3-month follow-up, 2 cases (3.4%) developed neurological deficits. CONCLUSION: The combination of iMRI and functional neuronavigation helped maximize safe tumor resection in low-grade gliomas.