M6A-Related Long Non-Coding RNA Displays Utility in Predicting Prognosis, Portraying the Tumor Immune Microenvironment and Guiding Immunotherapy in Pancreatic Ductal Adenocarcinoma.

N6-methyladenosine (m6A) lncRNA plays a pivotal role in cancer. However, little is known about its role in pancreatic ductal adenocarcinoma (PDAC) and its tumor immune microenvironment (TIME). Based on The Cancer Genome Atlas (TCGA) cohort, m6A-related lncRNAs (m6A-lncRNA) with prognostic value were filtered using Pearson analysis and univariate Cox regression analysis. Distinct m6A-lncRNA subtypes were divided using unsupervised consensus clustering. Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to establish an m6A-lncRNA-based risk score signature. The CIBERSORT and ESTIMATE algorithms were employed to analyze the TIME. The expression pattern of TRAF3IP2-AS1 was examined using qRT-PCR. The influence of TRAF3IP2-AS1 knockdown on cell proliferation was estimated by performing CCK8, EdU and colony-formation assays. Flow cytometry was applied to measure the effect of TRAF3IP2-AS1 knockdown on cell cycle and apoptosis. The in vivo anti-tumor effect of TRAF3IP2-AS1 was validated in a tumor-bearing mouse model. Two m6A-lncRNA subtypes with different TIME features were clarified. A risk score signature was constructed as a prognostic predictor based on m6A-lncRNAs. The risk score also correlated with TIME characterization, which facilitated immunotherapy. Finally, the m6A-lncRNA TRAF3IP2-AS1 was proved to be a tumor suppressor in PDAC. We comprehensively demonstrated m6A-lncRNAs to be useful tools for prognosis prediction, TIME depiction and immunotherapeutic guidance in PDAC.

Fibroblast Common Serum Response Signature-Related Classification Affects the Tumour Microenvironment and Predicts Prognosis in Bladder Cancer.

Abnormal oncogenic signatures provide important clues regarding cancer prognosis and treatment. We analysed the variations in 189 oncogenic signature gene sets between normal and tumourous tissues from The Cancer Genome Atlas (TCGA) and found that the "CSR_LATE_UP" signature was the most upregulated oncogenic signature gene set in bladder cancer. Next, we developed a common serum response (CSR) risk score (CRS) model based on fibroblast CSR genes and systematically analysed the correlations of these genes or the CRSs with survival, previously reported molecular subtypes, clinicopathological features, cancer signalling pathways, chemotherapeutic responses, and the tumour microenvironment using TCGA and validation cohorts. The CRS could predict the malignant phenotype, chemotherapeutic efficacy, immune invasion, and disease prognosis. Inflammatory signalling pathways (e.g., inflammatory response, TNFA signalling via NFƘB, IFNα response, and IL2-STAT5 signalling) were markedly upregulated in patients with high CRS. Notably, the CSR-related gene ANLN was positively correlated with CD8+ immune cell infiltration, PD-L1 expression, and sensitivity to PD-L1 inhibitors and could thus provide guidance for clinical immunotherapy. This study highlights the crucial role of the CSR signature in bladder cancer and provides a CRS model for accurate predictions of the disease prognosis and chemotherapy and immunotherapy responses.

The neutrophil-lymphocyte ratio: A promising predictor of mortality in coronary care unit patients - A cohort study.

BACKGROUND: Severe inflammation causes poor outcomes in coronary care unit (CCU) patients. The neutrophil-lymphocyte ratio (NLR), a biomarker used to monitor inflammation and the immune response, can predict a poor prognosis in various diseases. However, it remains unclear whether the NLR is associated with all-cause mortality in CCU patients. This study investigated the association between the NLR and CCU outcomes. METHODS: Clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database, which contains health data for over 50,000 patients. The primary outcome was 30-day mortality and the secondary outcome was 90-day mortality. Cox proportional hazard models were used to reveal the associations between NLR and outcomes. Multivariate analyses were used to control for confounders. RESULTS: We enrolled 3563 CCU patients. For 30-day mortality, the hazard ratio (HR) (95% confidence interval [CI]) for the second (NLR 4.80-10.08) and the third (NLR ≥ 10.09) tertiles were 1.57 (1.24, 1.97) and 2.76 (2.23, 3.41), respectively, compared to the first tertile (NLR < 4.80). In the model adjusted for multiple confounders, the fifth quintile (NLR ≥ 14.17) showed a slightly lower mortality risk [HR (95% CI) 1.44 (1.07, 1.94)] compared to the fourth (NLR 8.82-14.16) [HR (95% CI) 1.55 (1.15, 2.10)]. A similar trend was observed for 90-day mortality. The interactions between the acute kidney injury, respiratory failure, and pneumonia subgroups and 30-day mortality were significant. CONCLUSIONS: The NLR was an independent predictor of 30- and 90-day mortality for CCU patients. The NLR is a promising clinical biomarker as an integrated, readily available predictor of CCU mortality.

RNA sequencing revealing the role of AMP-activated protein kinase signaling in mice myocardial ischemia reperfusion injury.

Long non-coding RNAs (lncRNA) and circular RNAs (circRNA) that sponge miRNAs could indirectly regulate gene expression, contributing to certain biological processes. This study aimed to investigate the role of non-coding RNAs in the pathogenesis of myocardial ischemia reperfusion-injury (MIRI). MIRI in male C57B/6J mice was induced by left anterior descending coronary artery ligation occlusion for 30 min, and 4 h of reperfusion. RNA sequencing was performed to obtain the mRNA and non-coding RNA expression profiles of the MIRI and sham groups. Bioinformatic methods were used to analyze the co-expression RNAs, miRNA binding sites and competitive endogenous RNA (ceRNA) pairs. Differentially expressed RNAs were identified with a cutoff fold change > 2 and p < 0.05. A total of 64 mRNAs were upregulated and 98 mRNAs were downregulated, and 10 lncRNAs were upregulated and 10 lncRNAs were downregulated. All altered (p < 0.05) mRNAs were selected for gene ontology and pathway analysis. The AMP-activated protein kinase (AMPK) signaling pathway was enriched in the downregulated genes, and the activation of AMPK was confirmed by western blotting. The lncRNA co-expression network and ceRNA network base on genes in AMPK signaling pathway were then constructed, revealing that ENSMUST00000147762.7 and TUCP_000184 might be key regulators in MIRI induced AMPK activation. The expression levels of AMPK signaling-related RNAs and those involved in the ceRNA network were validated using qRT-PCR. Overall, this study identified potential new targets on AMPK signaling in MIRI.

LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma.

Multiple myeloma (MM), the second most common hematologic malignancy, is an incurable disease characterized by the accumulation of malignant plasma cells within the bone marrow. Though great progresses have been made in understanding the mechanisms of MM, metabolic plasticity and drug resistance remain largely unknown. In this study, we found lncRNA Protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) is highly expressed in MM and is associated with the survival rate of MM patients. PDIA3P regulates MM growth and drug resistance through Glucose 6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Mechanistically, we revealed that PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, stimulating G6PD expression and PPP flux. Our study identified PDIA3P as a novel c-Myc interacting lncRNA and elucidated crucial roles for PDIA3P in metabolic regulation of MM, providing a potential therapeutic target for MM patients.