scholarly journals Starting from the Influence of Tobacco: AKR1C3 and COVID-19 Receptor ACE2 Are Potential Pprognostic Biomarkers for Brain Lower Grade Glioma, Evidence from Bioinformatics Analyses

2020 ◽  
Author(s):  
Heng-Yi Yang ◽  
Tian-Ni Mao
Keyword(s):  
Host Cells ◽  
Expression Level ◽  
Lower Grade ◽  
Cancer Type ◽  
Survival Curves ◽  
Hub Genes ◽  
Bioinformatics Analyses ◽  
Clinical Model ◽  
Lower Grade Glioma

Background: Coronavirus disease (COVID-19) related pneumonia is leaded by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which infects host cells through receptors named Angiotensin-converting enzyme 2 (ACE2). Smoking is thought to be related to poor disease prognosis, as a large amount of evidence highlights the negative effects of smoking on lung health and its causal relationship with various respiratory diseases. Methods: We first evaluated the role of ACE2 expression level with tobacco effect. And correlation analyses were used to identify the related genes of ACE2 both in smoker trait and human normal multi-tissues. After intersections, hub genes were later used to further GSEA and co-regulated mechanisms were explored by GeneMANIA. We used UALCAN to perform survival curves of pan-cancers included 33 types of cancers. New clinical model of top co-occurrence cancer type was constructed and validated. Results: Effected by cigarette smoking, the expression level of ACE2 expressed statistically upwards in current smokers compared with never smokers, upwards in groups after acute smoke exposed compared with normal control. But no strong evidence detected in third-hand smoke, as poor amounts of samples, only 4. A little trend of expressing upwards became in groups after third-hand smoke compared with groups after clean air exposing. 4 genes included PIR, ADH7, AKR1C2 and AKR1C3 were identified as ACE2 related genes in smoker trait and human normal multi-tissues. Then, we made the survival curves of pan-cancers in 4 genes. Brain lower grade glioma was the co-occurrence type as both ACE2, PIR and AKR1C3 had the significantly prognostic situation. Later, we made the new clinical prediction model as the C-index was 0.827 and the Area Under Curves (AUCs) of 1-year survival, 2-year survival and 3-year survival were 0.921(95%CI, 0.882-0.961), 0.911(95%CI, 0.860-0.962) and 0.878(95%CI, 0.818-0.939). In inner validation, the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.777(95%CI, 0.640-0.914), 0.916(95%CI, 0.842-0.990) and 0.888(95%CI, 0.768-1.000). In outer validation one, the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.764(95%CI, 0.672-0.856), 0.848(95%CI, 0.783-0.913) and 0.748(95%CI, 0.656-0.841). And in outer validation two the AUCs of 1-year survival, 2-year survival and 3-year survival were 0.740(95%CI, 0.654-0.826), 0.766(95%CI, 0.688-0.843) and 0.794(95%CI, 0.721-0.866). Conclusions: In our study, we compared the ACE2 expression level between smokers and non-smokers crowds and identified associated hub genes. Then we explored the further role of hub genes in tumor fields to identify the correlation and influence between the avoidable host factors such as smoking on COVID-19 contamination and tumor. ACE2 and AKR1C3 are potential prognostic genes for brain lower grade glioma, and we created the web dynamic nomogram and encapsulation app through validations.

The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued

Neurosurgery ◽  
2021 ◽  
Author(s):  
Peng Wang ◽  
Chen Luo ◽  
Peng-jie Hong ◽  
Wen-ting Rui ◽  
Shuai Wu
Keyword(s):  
Cox Regression ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
Lower Grade ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Lower Grade Glioma ◽  
Clinical Benefits

Abstract BACKGROUND While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

scholarly journals Association Between Tumor Mutation Burden and Prognosis in Lower-Grade Glioma: An Exploratory Study 

2021 ◽  
Author(s):  
Di Cao ◽  
Jun Wang ◽  
Yan Lin ◽  
Guangwei Li
Keyword(s):  
Immune Cell ◽  
Differential Expression Analysis ◽  
Cell Infiltration ◽  
Lower Grade ◽  
Immune Cell Infiltration ◽  
Hub Genes ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Lower Grade Glioma ◽  
Genome Atlas

Abstract Background: The therapeutic efficacy of immune checkpoint inhibitor therapy is highly influenced by tumor mutation burden (TMB). The relationship between TMB and prognosis in lower-grade glioma is still unclear. We aimed to explore the relationships and mechanisms between them in lower-grade glioma.Methods: We leveraged somatic mutation data from The Cancer Genome Atlas (TCGA). Clinical cases were divided into high- and low-TMB groups based on the median of TMB. Infiltrating immune cells were analyzed using CIBERSORT and differential expression analysis between the prognostic groups performed. The key genes were identified as intersecting between immune-related genes. Cox regression and survival analysis were performed on the intersecting genes. A total of 7 hub genes were identified. The effect of somatic copy number alterations (SCNA) of the hub genes on immune cell infiltration was analyzed using TIMER, which was used to determine the risk factors and immune infiltration status in LGG. Subsequently, based on hub genes, a TMB Prognosis Index (TMBPI) model was constructed to predict the risk in LGG patients. Besides, this model was validated using data from TCGA and Chinese Glioma Genome Atlas (CGGA).Results: High-TMB favored worse prognosis (P＜0.001) and macrophage infiltration was an independent risk factor (P＜0.001). In the high-TMB group (P=0.033, P=0.009), the proportion of macrophages M0 and M2 increased and monocytes decreased (P=0.006). Besides, the SCNA of the hub genes affected the level of immune cell infiltration by varying degrees among which IGF2BP3, NPNT, and PLA2G2A had a significant impact. The AUC of the ROC curve at 1-, 3- and 5-years were all above 0.74.Conclusions: This study implies that high-TMB correlated with unfavorable prognosis in lower-grade glioma. And high-TMB may have an impact on prognosis by changing tumor microenvironment, caused by the SCNAs of genes. The TMBPI model accurately predicted prognosis in LGG patients.

scholarly journals Tau: At the Interface Between Neurodegeneration and Cancer?

2020 ◽  
Author(s):  
Stéphanie Papin ◽  
Paolo Paganetti
Keyword(s):  
Meta Analysis ◽  
Expression Level ◽  
Cancer Type ◽  
Cancer Resistance ◽  
Tumor Cell Death ◽  
Microtubule Network ◽  
Related Disorder ◽  
P53 Signaling ◽  
Tau Expression

For its microtubule-binding properties, the expression level of the neurodegeneration-associated protein Tau is pondered as a potential modifier of cancer resistance to chemotherapy since decades. Indeed, Tau binds microtubules at the same site as taxanes, a class of chemotherapeutic drugs designed to stabilize the microtubule network in order to stall cell division and to induce tumor cell death. Whilst independent studies report the association between low Tau expression and superior taxane response, the data were refused by a meta-analysis, suggesting interference of other parameters. Unpredictably, Tau expression level was identified as a prognostic cancer marker, whereby its positive or negative predictive value for survival depended on the cancer type. With recent experimental evidence linking Tau to P53 signaling, DNA stability and protection and to the implication of Tau in cancer is strengthened. The identification of a role of Tau at the interface between two major aging-related disorder families, neurodegeneration and cancer, offers clues for the epidemiological observation inversely correlating these disorders. Elucidating how Tau is mechanistically implicated in cellular pathways common to these devastating illnesses may extend the Tau-targeting therapeutic opportunities to cancer.

scholarly journals NLGN3 Upregulates Expression of ADAM10 to Promote the Cleavage of NLGN3 via Activating the LYN Pathway in Human Gliomas

2021 ◽  
Vol 9 ◽  
Author(s):  
Ning-Ning Dang ◽  
Xiao-Bing Li ◽  
Mei Zhang ◽  
Chen Han ◽  
Xiao-Yong Fan ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Feedback Regulation ◽  
Feedback Mechanism ◽  
Therapeutic Window ◽  
Migration And Invasion ◽  
Lower Grade ◽  
Lower Grade Glioma ◽  
Glioma Growth ◽  
The Brain

The neuron derived synaptic adhesion molecular neuroligin-3 (NLGN3) plays an important role in glioma growth. While the role of autocrine NLGN3 in glioma has not been well-studied. The expression of NLGN3 in glioma was detected using immunohistochemistry. We further explored its function and regulatory mechanism in U251 and U87 cells with high expression of NLGN3. Knockdown of endogenous NLGN3 significantly reduced the proliferation, migration, and invasion of glioma cells and down-regulated the activity of the PI3K-AKT, ERK1/2, and LYN signaling pathways. In comparison, overexpression of NLGN3 yielded opposite results. Our results further demonstrate that LYN functions as a feedback mechanism to promote NLGN3 cleavage. This feedback regulation was achieved by upregulating the ADAM10 sheddase responsible for NLGN3 cleavage. Inhibition of ADAM10 suppressed the proliferation, migration, and invasion of glioma cells; oppositely, the expression of ADAM10 was correlated with a higher likelihood of lower grade glioma (LGG) in the brain. Our study demonstrates that glioma-derived NLGN3 promotes glioma progression by upregulating activity of LYN and ADAM10, which in turn promote NLGN3 cleavage to form a positive feedback loop. This pathway may open a potential therapeutic window for the treatment of human glioma.

scholarly journals Development and Verification of Glutamatergic Synapse-Associated Prognosis Signature for Lower-Grade Gliomas

2021 ◽  
Vol 14 ◽  
Author(s):  
Liguo Ye ◽  
Yang Xu ◽  
Ping Hu ◽  
Long Wang ◽  
Ji’an Yang ◽  
...  
Keyword(s):  
Risk Score ◽  
Cox Regression ◽  
Gene Set Enrichment Analysis ◽  
Normal Brain ◽  
Lower Grade ◽  
Glutamatergic Synapse ◽  
Hub Genes ◽  
Gene Set ◽  
Genome Atlas

Background: Lower-grade glioma (LGG) is the most common histology identified in gliomas, a heterogeneous tumor that may develop into high-grade malignant glioma that seriously shortens patient survival time. Recent studies reported that glutamatergic synapses might play an essential role in the progress of gliomas. However, the role of glutamatergic synapse-related biomarkers in LGG has not been systemically researched yet.Methods: The mRNA expression data of glioma and normal brain tissue were obtained from The Cancer Genome Atlas database and Genotype-Tissue Expression, respectively, and the Chinese Glioma Genome Atlas database was used as a validation set. Difference analysis was performed to evaluate the expression pattern of glutamatergic synapse-related genes (GSRGs) in LGG. The least absolute shrinkage and selection operator (LASSO) Cox regression was applied to construct the glutamatergic synapse-related risk signature (GSRS), and the risk score of each LGG sample was calculated based on the coefficients and expression value of selected GSRGs. Univariate and multivariate Cox regression analyses were used to investigate the prognostic value of risk score. Immunity profile and single-sample gene set enrichment analysis (ssGSEA) were performed to explore the association between risk score and the characters of tumor microenvironment in LGG. Gene set variation analysis (GSVA) was performed to investigate the potential pathways related to GSRS. The HPA database and real-time PCR were used to identify the expression of hub genes identified in GSRS.Results: A total of 22 genes of 39 GSRGs were found differentially expressed among normal and LGG samples. Through the LASSO algorithm, 14-genes GSRS constructed were associated with the prognosis and clinicopathological features of patients with LGG. Furthermore, the risk score level was significantly positively correlated with the infiltrating level of immunosuppressive cells, including M2 macrophages and regulatory T cells. GSVA identified a series of cancer-related pathways related to GSRS, such as P13K-AKT and P53 pathways. Moreover, ATAD1, NLGN2, OXTR, and TNR, hub genes identified in GSRS, were considered as potential prognostic biomarkers in LGG.Conclusion: A 14-genes GSRS was constructed and verified in this study. We provided a novel insight into the role of GSRS in LGG through a series of bioinformatics methods.

STEM-20. THE ROLE OF HUMAN BETA DEFENSINS IN THE CLONOGENICITY OF GLIOBLASTOMA MULTIFORME

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi25-vi25
Author(s):  
Peggy Harris ◽  
Amber Kerstetter-Fogle ◽  
Anthony Sloan ◽  
Alankrita Raghavan ◽  
Harry Hoffman ◽  
...  
Keyword(s):  
Median Overall Survival ◽  
Poor Response ◽  
Small Population ◽  
Response To Treatment ◽  
Lower Grade ◽  
Cancer Type ◽  
Mrna Levels ◽  
Self Renewal ◽  
Beta Defensins

Abstract INTRODUCTION Glioblastoma (GBM) is the most common primary malignant brain tumor with a median overall survival of 12-15months. GBM aggressiveness and poor response to treatment are often attributed to a small population of stem-like cells referred to as glioma stem cells (GSCs). Human Beta-Defensins (HBDs), a family of small molecules initially thought to function as anti-microbials, have been implicated in various cancers with functions that are cancer type specific, including proinflammatory and immunosuppressive roles. GOAL: This study aimed to elucidate HBDs expression in GSCs and differentiated gioma cells (DGSs). METHODS We identified HBD2 and HBD3 in glioma and GSCs and DGSs by immunofluorescence (IF) and immunohistochemistry (IHC). We also assessed the role HBD2/3 play in GBM oncogenesis by investigating their effects on the self-renewal capacity of GSCs. RESULTS HBD2 and HBD3 are found in both bulk tumor and GSCs by IHC and IF. Expression of HBD2 and HBD3 mRNA levels are elevated in GBM patient tissue in comparison to lower grade gliomas by 16.2 & 1.9 fold (respectively; p < 0.0001). Additionally, transcriptional expression of HBD2 and HBD3 are increased by 0.68 and 1.15 fold respectively in GSCs versus autologous DGCs (p < 0.05; p< 0.005 respectively), suggesting a role for HBD 2/3 in oncogenesis. Interestingly however, HBD2 and HBD3 pretreatment of GSC cell lines showed decreased self-renewal capacity by 34.2 and 66.4% (p < 0.001), determined by the reduced number of large neurospheres ( >250mm). CONCLUSIONS Our results demonstrate the presence of HBD2/3 in GBM samples by IHC and IF with increased HBD2/3 mRNA expression in GBM samples. Interestingly DGCs contain less HBD2/3 than their GCS counterparts, and clonogenicity assays demonstrate a decrease in oncogenesis, suggesting that HBD’s role in proliferation and clonogenicity of DGCs and GSCs may be context dependent, leading to additional questions and future studies.

scholarly journals Modulation of transcriptional activity in brain lower grade glioma by alternative splicing

2018 ◽  
Author(s):  
Jin Li ◽  
Yang Wang ◽  
Xianglian Meng ◽  
Hong Liang
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Alternative Splicing ◽  
Structural Features ◽  
Vital Role ◽  
Lower Grade ◽  
Exon Inclusion ◽  
Gene Transcriptional Regulation ◽  
Lower Grade Glioma

Proteins that modify the activity of transcription factor (TF), often called modulators, play a vital role in gene transcriptional regulation. Alternative splicing is a critical step of gene processing and it can modulate gene function by adding or removing certain protein domains, and therefore influences the activity of a protein. The objective of this study is to investigate the role of alternative splicing in modulating the transcriptional regulation in brain lower grade glioma (LGG), especially transcription factor ELK1, which is closely related to various diseases, including Alzheimer’s disease and down syndrome. Results showed that changes in the exon inclusion ratio of proteins APP and STK16 are associated with changes in the expression correlation between ELK1 and its targets. Meanwhile, the structural features of the two modulators are strongly associated with the pathological impact of exon inclusion. Our analysis suggests, protein in different splicing level could play different functions on transcription factors, hence induces multiple genes dysregulation.

scholarly journals Modulation of transcriptional activity in brain lower grade glioma by alternative splicing

2018 ◽  
Author(s):  
Jin Li ◽  
Yang Wang ◽  
Xianglian Meng ◽  
Hong Liang
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Alternative Splicing ◽  
Structural Features ◽  
Vital Role ◽  
Lower Grade ◽  
Exon Inclusion ◽  
Gene Transcriptional Regulation ◽  
Lower Grade Glioma

Proteins that modify the activity of transcription factor (TF), often called modulators, play a vital role in gene transcriptional regulation. Alternative splicing is a critical step of gene processing and it can modulate gene function by adding or removing certain protein domains, and therefore influences the activity of a protein. The objective of this study is to investigate the role of alternative splicing in modulating the transcriptional regulation in brain lower grade glioma (LGG), especially transcription factor ELK1, which is closely related to various diseases, including Alzheimer’s disease and down syndrome. Results showed that changes in the exon inclusion ratio of proteins APP and STK16 are associated with changes in the expression correlation between ELK1 and its targets. Meanwhile, the structural features of the two modulators are strongly associated with the pathological impact of exon inclusion. Our analysis suggests, protein in different splicing level could play different functions on transcription factors, hence induces multiple genes dysregulation.

scholarly journals Fam20C Overexpression Predicts Poor Outcomes and is a Diagnostic Biomarker in Lower-Grade Glioma

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Feng ◽  
Jinping Zhou ◽  
Lin Zhao ◽  
Xinpeng Wang ◽  
Danyu Ma ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Research Field ◽  
Gene Set Enrichment Analysis ◽  
Lower Grade ◽  
Kaplan Meier ◽  
Lower Grade Glioma ◽  
Poor Outcomes

Glioma is a relatively low aggressive brain tumor. Although the median survival time of patients for lower-grade glioma (LGG) was longer than that of patients for glioblastoma, the overall survival was still short. Therefore, it is urgent to find out more effective molecular prognostic markers. The role of the Fam20 kinase family in different tumors was an emerging research field. However, the biological function of Fam20C and its prognostic value in brain tumors have rarely been reported. This study aimed to evaluate the value of Fam20C as a potential prognostic marker for LGG. A total of 761 LGG samples (our cohort, TCGA and CGGA) were included to investigate the expression and role of Fam20C in LGG. We found that Fam20C was drastically overexpressed in LGG and was positively associated with its clinical progression. Kaplan-Meier analysis and a Cox regression model were employed to evaluate its prognostic value, and Fam20C was found as an independent risk factor in LGG patients. Gene set enrichment analysis also revealed the potential signaling pathways associated with Fam20C gene expression in LGG; these pathways were mainly enriched in extracellular matrix receptor interactions, cell adhesion, cell apoptosis, NOTCH signaling, cell cycle, etc. In summary, our findings provide insights for understanding the potential role of Fam20C and its application as a new prognostic biomarker for LGG.

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