Decision system for extent of resection in WHO grade 3 gliomas: a Chinese Glioma Genome Atlas database analysis.

BACKGROUND: Extensive surgical resection has been found to be associated with longer survival in patients with gliomas, but the interactive prognostic value of molecular pathology of the surgical resection is unclear. This study evaluated the impact of molecular pathology and clinical characteristics on the surgical benefit in WHO grade 3 IDH-mutant gliomas. METHODS: Clinical and pathological information of 246 patients with WHO grade 3 IDH-mutant gliomas were collected from the Chinese Glioma Genome Atlas database (2006-2020). The role of the extent of resection on overall survival, stratified by molecular pathology and clinical characteristics, was investigated. We then assessed prognostic factors using a univariate log-rank test and multivariate Cox proportional hazards model in the subgroups. RESULTS: The extent of resection was an independent prognostic factor in the entire cohort, even when adjusted for molecular pathology. Gross total resection was found to be associated with longer survival in all patients and in the astrocytoma group but not in the oligodendroglioma group. Compared with subtotal resections, gross total resections resulted in a longer survival time for astrocytoma patients aged ≤ 45 years. However, there was no survival benefit from total resection in patients with astrocytoma aged > 45 years. CONCLUSIONS: Extensive resection benefits only a proportion of patients with WHO grade 3 IDH-mutant gliomas. Younger patients with astrocytomas had survival benefits from extensive resection. In addition to clinical characteristics (especially age), molecular pathology impacted prognosis in patients with gliomas. Our findings provide guiding information to neurosurgeons while planning surgeries.

[Alcohol extract of root and root bark of Toddalia asiatica alleviates CIA in rats through anti-inflammatory and proapoptotic effects].

This study aims to investigate the therapeutic effect of alcohol extract of root and root bark of Toddalia asiatica(TAAE) on collagen-induced arthritis(CIA) in rats through phosphatidylinoinosidine-3 kinase/protein kinase B(PI3K/Akt) signaling pathway. To be specific, CIA was induced in rats, and then the rats were treated(oral, daily) with TAAE and Tripterygium Glycoside Tablets(TGT), respectively. The swelling degree of the hind leg joints was scored weekly. After 35 days of administration, the histopathological changes were observed based on hematoxylin and eosin(HE) staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the levels of cytokines [tumor necrosis factor-α(TNF-α), interleukin(IL)-6)]. Terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL) staining was performed to detect the apoptosis of synoviocytes in rats. Western blot was used to detect the expression levels of apoptosis-related proteins B-cell lymphoma 2(Bcl-2)-associated X(Bax), Bcl-2, and caspase-3 and pathway-related proteins phosphoinositide 3-kinase(PI3K), phosphorylated(p)-PI3K, protein kinase B(Akt), and p-Akt. RT-qPCR was conducted to examine the mRNA levels of Bax, Bcl-2, caspase-3, TNF-α, IL-6, and IL-1ß and pathway-related proteins PI3K, p-PI3K, Akt, and p-Akt. TAAE can alleviate the joint swelling in CIA rats, reduce serum levels of inflammatory cytokines, improve synovial histopathological changes, promote apoptosis of synoviocytes, and inhibit synovial inflammation. In addition, RT-qPCR and Western blot results showed that TAAE up-regulated the level of Bax, down-regulated the level of Bcl-2, and activated caspase-3 to promote apoptosis in synoviocytes. TAAE effectively down-regulated the protein levels of p-PI3K and p-Akt. In this study, TAAE shows therapeutic effect on CIA in rats and reduces the inflammation. The mechanism is that it suppresses PI3K/Akt signaling pathway and promotes synoviocyte apoptosis. Overall, this study provides a new clue for the research on the anti-inflammatory mechanism of TAAE and lays a theoretical basis for the better clinical application of TAAE in the treatment of inflammatory and autoimmune diseases.

Molecular subtype impacts surgical resection in low-grade gliomas: A Chinese Glioma Genome Atlas database analysis.

Surgeons have considered extending the resection margins for better outcomes in gliomas, but have not considered molecular pathology. We investigated the impact of molecular pathology on the surgical benefit in gliomas. Herein, we collected the clinical and pathological information of 449 patients with glioma from the Chinese Glioma Genome Atlas database, and enrolled those who underwent surgical resection. We measured the impact of the extent of resection on survival time in subgroups classified by clinical characteristics. We found that gross total resection (GTR) was associated with longer survival times in the entire cohort, and each of the three molecular subtypes. Even after age stratification, there was no survival benefit from GTR in those with a Karnofsky performance score (KPS) ≤ 80. In patients aged >45 years with a KPS >80, extensive resection resulted in longer survival times in isocitrate dehydrogenase-mutated astrocytomas. Additionally, GTR was associated with longer overall survival times in patients aged ≤45 years with a KPS >80. In conclusion, extensive resection does not always prolong survival in patients with glioma. Along with clinical characteristics, molecular pathology positively impacts survival in gliomas. Neurosurgeons may consider our findings when planning surgery in the future.

A Potential Prognostic Gene Signature for Predicting Survival for Glioblastoma Patients.

OBJECTIVE: This study aimed to screen prognostic gene signature of glioblastoma (GBM) to construct prognostic model. METHODS: Based on the GBM information in the Cancer Genome Atlas (TCGA, training set), prognostic genes (Set X) were screened by Cox regression. Then, the optimized prognostic gene signature (Set Y) was further screened by the Cox-Proportional Hazards (Cox-PH). Next, two prognostic models were constructed: model A was based on the Set Y; model B was based on part of the Set X. The samples were divided into low- and high-risk groups according to the median prognosis index (PI). GBM datasets in Gene Expression Ominous (GEO, GSE13041) and Chinese Glioma Genome Atlas (CGGA) were used as the testing datasets to confirm the prognostic models constructed based on TCGA. RESULTS: We identified that the prognostic 14-gene signature was significantly associated with the overall survival (OS) in the TCGA. In model A, patients in high- and low-risk groups showed the significantly different OS (P = 7.47 × 10-9, area under curve (AUC) 0.995) and the prognostic ability were also confirmed in testing sets (P=0.0098 and 0.037). The model B in training set was significant but failed in testing sets. CONCLUSION: The prognostic model which was constructed based on the prognostic 14-gene signature presented a high predictive ability for GBM. The 14-gene signature may have clinical implications in the subclassification of GBM.

Gene expression microarray analysis reveals prognostic markers of survival in high grade astrocytomas.

OBJECTIVE: High grade astrocytoma (HGA) as an aggressive brain tumor, is always correlated with poor prognosis. In this paper, we aimed to explore the genetic prognostic biomarkers for HGA. METHODS: The genome-wide expression profile of 26 brain tumor samples obtained from 26 patients with HGA was downloaded from Gene Expression Omnibus. The risk genes for prognosis of HGA were identified and verified by the data in TCGA database. Protein-protein interaction (PPI) network of risk factor genes was constructed and significant module was screened. Function and pathway annotations were performed for risk genes and drug target genes were further analyzed. RESULTS: A total of 598 genes were identified as significant risk genes for prognosis, such as checkpoint kinase 1, potassium inwardly-rectifying channel, subfamily J, member 6, leukocyte receptor tyrosine kinase and uncharacterized LOC283887. All risk genes for prognosis of HGA were significantly enriched in cell cycle, mitotic as well as mitotic anaphase. While the genes in the network module mainly participated in functions such as cell cycle, mitotic cell cycle and cell cycle process. Moreover, the genes in the network module mainly participated in the pathways such as cell cycle and cell cycle, mitotic. Drug target analysis showed that seven genes were recorded in Drugbank database, and there were as many as 32 drug records of CHEK1. CONCLUSION: The prognostic effect of CHEK1 was validated based on the expression profile data of 615 low-grade glioma and glioblastoma samples. We proposed CHEK1 as prognostic biomarker for HGA. Our work might provide the candidate target for HGA therapy.

Gene expression profiles reveal key genes for early diagnosis and treatment of adamantinomatous craniopharyngioma.

Adamantinomatous craniopharyngioma (ACP) is an aggressive brain tumor that occurs predominantly in the pediatric population. Conventional diagnosis method and standard therapy cannot treat ACPs effectively. In this paper, we aimed to identify key genes for ACP early diagnosis and treatment. Datasets GSE94349 and GSE68015 were obtained from Gene Expression Omnibus database. Consensus clustering was applied to discover the gene clusters in the expression data of GSE94349 and functional enrichment analysis was performed on gene set in each cluster. The protein-protein interaction (PPI) network was built by the Search Tool for the Retrieval of Interacting Genes, and hubs were selected. Support vector machine (SVM) model was built based on the signature genes identified from enrichment analysis and PPI network. Dataset GSE94349 was used for training and testing, and GSE68015 was used for validation. Besides, RT-qPCR analysis was performed to analyze the expression of signature genes in ACP samples compared with normal controls. Seven gene clusters were discovered in the differentially expressed genes identified from GSE94349 dataset. Enrichment analysis of each cluster identified 25 pathways that highly associated with ACP. PPI network was built and 46 hubs were determined. Twenty-five pathway-related genes that overlapped with the hubs in PPI network were used as signatures to establish the SVM diagnosis model for ACP. The prediction accuracy of SVM model for training, testing, and validation data were 94, 85, and 74%, respectively. The expression of CDH1, CCL2, ITGA2, COL8A1, COL6A2, and COL6A3 were significantly upregulated in ACP tumor samples, while CAMK2A, RIMS1, NEFL, SYT1, and STX1A were significantly downregulated, which were consistent with the differentially expressed gene analysis. SVM model is a promising classification tool for screening and early diagnosis of ACP. The ACP-related pathways and signature genes will advance our knowledge of ACP pathogenesis and benefit the therapy improvement.

Bioinformatic analysis of gene expression profiles of pituitary gonadotroph adenomas.

The aim of the present study was to identify genes, microRNAs (miRNAs/miRs) or pathways associated with the development of pituitary gonadotroph adenomas. The array data of GSE23207, which included 16 samples of multiple endocrine neoplasia-associated rat pituitary homozygous mutations and 5 pituitary tissue samples from healthy rats, were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were analyzed prior to functional enrichment analysis and protein-protein interaction (PPI) network construction. miRNAs associated with DEGs were predicted, and an miRNA-target regulatory network was constructed. A total of 187 upregulated and 370 downregulated DEGs were identified in the pituitary gonadotroph adenoma group compared with the healthy (control) group. Cyclin-dependent kinase (Cdk) 1 exhibited the highest degree in the PPI network. The upregulated DEGs were predominately enriched in 'neuroactive ligand-receptor interaction' pathway, and downregulated DEGs were mainly enriched in 'cell cycle'. The DEGs in module were predominately enriched in the 'cell cycle', whereas DEGs in module b and c were enriched in 'neuroactive ligand-receptor interaction'. miR-374, -153, -145 and -33 were identified as important miRNAs in the regulation of the DEGs. Cdk1, cyclin (Ccn) A2, Ccnb1, 'cell cycle' and 'neuroactive ligand-receptor interaction' pathways may serve important roles in the development of pituitary gonadotroph adenomas; Ccna2 and Ccnb1 may contribute to this development via an effect on the 'cell cycle' pathway. Furthermore, miR-374 and -145 may contribute to the development of pituitary gonadotroph adenomas via regulation of the expression of target genes.

Serum microRNA-376 family as diagnostic and prognostic markers in human gliomas.

BACKGROUND: MicroRNA (miR)-376 family play crucial roles in cancer formation and progression. OBJECTIVE: To investigate expression patterns of circulating miR-376 members in glioma patients, and to explore their diagnostic and prognostic values. METHODS: Expression of miR-376 members in serum samples from 100 glioma patients and 50 healthy controls were detected by quantitative real-time PCR. RESULTS: Serum miR-376a, miR-376b and miR-376c in glioma patients were significantly lower than those in healthy controls (all P< 0.05). Their expression could efficiently distinguish the glioma patients from healthy controls according to the receiver operating characteristic (ROC) analysis [for miR-376a, the area under ROC curve (AUC) = 0.872, the optimal cut-off value = 1.95, the sensitivity = 81.0% and the specificity = 82.0%; for miR-376b, AUC = 0.890, the optimal cut-off value = 2.07, the sensitivity = 82.0% and the specificity = 78.0%; for miR-376c, AUC = 0.837, the optimal cut-off value = 2.12, the sensitivity = 90.0% and the specificity = 70.0%; all P<0. 001]. Decreased expression of miR-376a, miR-376b and miR-376c in patients' sera were significantly associated with advanced WHO grade (all P< 0.01) and low KPS (all P< 0.05). Kaplan-Meier and Cox regression analyses showed that low miR-376a, miR-376b and miR-376c expression, and high grade were all independent factors predicting poor outcome of glioma patients. Notably, subgroup analyses showed that serum miR-376a, miR-376b and miR-376c levels had more significant prognostic values in patients with high grade gliomas than those with low grade gliomas. CONCLUSIONS: Aberrant expression of the miR-376 family may be involved into tumorigenesis and tumor progression of human gliomas. Circulating miR-376a, miR-376b and miR-376c may be promising non-invasive biomarkers for diagnosis and prognosis in glioma patients.