Molecular subtype identification and prognosis stratification by a immunogenic cell death-related gene expression signature in colorectal cancer.

OBJECTIVES: This study intended to develop a new immunogenic cell death (ICD)-related prognostic signature for colorectal cancer (CRC) patients. RESEARCH DESIGN AND METHODS: The Non-Negative Matrix Factorization (NMF) algorithm was adopted to cluster tumor samples based on ICD gene expression to obtain ICD-related subtypes. Survival analysis and immune microenvironment analysis were conducted among different subtypes. Regression analysis was used to construct the model. Based on riskscore median, cancer patients were classified into high and low risk groups, and independent prognostic ability of the model was analyzed. The CIBERSORT algorithm was adopted to determine the immune infiltration level of both groups. RESULTS: We analyzed the differential genes between cluster 4 and cluster 1-3 and obtained 12 genes with the best prognostic features finally (NLGN1, SLC30A3, C3orf20, ADAD2, ATOH1, ATP6V1B1, KCNQ2, MUCL3, RGCC, CLEC17A, COL6A5, and INSL4). In addition, patients with lower risk had higher levels of infiltration of most immune cells, lower Tumor Immune Dysfunction and Exclusion (TIDE) level and higher immunophenscore (IPS) level than those with higher risk. CONCLUSIONS: This study constructed and validated the ICD feature signature predicting CRC prognosis and provide a reference criteria for guiding the prognosis and immunotherapy of CRC cancer patients.

Developing a RiskS-core Model based on Angiogenesis-related lncRNAs for Colon Adenocarcinoma Prognostic Prediction.

AIM: We screened key angiogenesis-related lncRNAs based on colon adenocarcinoma (COAD) to construct a RiskS-core model for predicting COAD prognosis and help reveal the pathogenesis of the COAD as well as optimize clinical treatment. BACKGROUND: Regulatory roles of lncRNAs in tumor progression and prognosis have been confirmed, but few studies have probed into the role of angiogenesis-related lncRNAs in COAD. OBJECTIVE: To identify key angiogenesis-related lncRNAs and build a RiskS-core model to predict the survival probability of COAD patients and help optimize clinical treatment. METHODS: Sample data were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The HALLMARK pathway score in the samples was calculated using the single sample gene set enrichment analysis (ssGSEA) method. LncRNAs associated with angiogenesis were filtered by an integrated pipeline algorithm. LncRNA-based subtypes were classified by ConsensusClusterPlus and then compared with other established subtypes. A RiskS-core model was created based on univariate Cox, least absolute shrinkage and selection operator (LASSO) regression and stepwise regression analysis. The Kaplan-Meier curve was drawn by applying R package survival. The time-dependent ROC curves were drawn by the timeROC package. Finally, immunotherapy benefits and drug sensitivity were analyzed using tumor immune dysfunction and exclusion (TIDE) software and pRRophetic package. RESULTS: Pathway analysis showed that the angiogenesis pathway was a risk factor affecting the prognosis of COAD patients. A total of 66 lncRNAs associated with angiogenesis were screened, and three molecular subtypes (S1, S2, S3) were obtained. The prognosis of S1 and S2 was better than that of S3. Compared with the existing subtypes, the S3 subtype was significantly different from the other two subtypes. Immunoassay showed that immune cell scores of the S2 subtype were lower than those of the S1 and S3 subtypes, which also had the highest TIDE scores. We recruited 8 key lncRNAs to develop a RiskS-core model. The high RiskS-core group with inferior survival and higher TIDE scores was predicted to benefit limitedly from immunotherapy, but it may be more sensitive to chemotherapeutics. A nomogram designed by RiskS-core signature and other clinicopathological characteristics shed light on rational predictive power for COAD treatment. CONCLUSION: We constructed a RiskS-core model based on angiogenesis-related lncRNAs, which could serve as potential prognostic predictors for COAD patients and may offer clues for the intervention of anti-angiogenic application. Our results may help evaluate the prognosis of COAD and provide better treatment strategies.

Antiaging effects of simvastatin on vascular endothelial cells.

The anti-inflammatory, antioxidative, and antiarteriosclerosis activities of simvastatin along with its protective effects on the endothelium suggest that it may also have antiaging effects. The aim of this study was to investigate the antiaging effects of simvastatin as well as its effects on sirtuin 1 (SIRT1) expression in endothelial cells. Aged rats and human umbilical vein endothelial cells were treated with simvastatin in the presence and absence of oxidized low-density lipoprotein (OX-LDL). Aortic ß-galactosidase staining was undertaken to determine senescence, and SIRT1 protein expression was evaluated using Western blot analysis. After simvastatin therapy, arterial endothelial cell aging was significantly reduced, and SIRT1 expression was significantly increased. The OX-LDL significantly accelerated the senescence of umbilical vein endothelial cells and decreased SIRT1 expression. The OX-LDL-induced downregulation of SIRT1 was blocked by simvastatin. Simvastatin treatment also reduced umbilical vein endothelial cell aging and increased SIRT1 expression.

Mimecan is involved in aortic hypertrophy induced by sinoaortic denervation in rats.

This study was designed to investigate whether mimecan was involved in aortic hypertrophy induced by sinoaortic denervation in rats. 8 weeks after sinoaortic denervation, when compared to sham-operated rats, sinoaortic denervated rats exhibited aortic hypertrophy and down-regulation of mimecan. Through classic univariate correlation analysis, it was found that mimecan mRNA was negatively related to extent of aortic hypertrophy. Treatment of primary cultured vascular smooth muscle cells with the Ang II (1 µM), which was found locally increased in the aortae of sinoaortic denervated rats, resulted in a reduction of mimecan expression. In vitro, knockdown of mimecan in vascular smooth muscle cells promoted cell proliferation induced by 15% of fetal bovine serum or Ang II (1 µM). We concluded that down-regulation of mimecan was involved in aortic hypertrophy induced by sinoaortic denervation in rats.