Targeting PAK4 reverses cisplatin resistance in NSCLC by modulating ER stress.

Chemoresistance poses a significant impediment to effective treatments for non-small-cell lung cancer (NSCLC). P21-activated kinase 4 (PAK4) has been implicated in NSCLC progression by invasion and migration. However, the involvement of PAK4 in cisplatin resistance is not clear. Here, we presented a comprehensive investigation into the involvement of PAK4 in cisplatin resistance within NSCLC. Our study revealed enhanced PAK4 expression in both cisplatin-resistant NSCLC tumors and cell lines. Notably, PAK4 silencing led to a remarkable enhancement in the chemosensitivity of cisplatin-resistant NSCLC cells. Cisplatin evoked endoplasmic reticulum stress in NSCLC. Furthermore, inhibition of PAK4 demonstrated the potential to sensitize resistant tumor cells through modulating endoplasmic reticulum stress. Mechanistically, we unveiled that the suppression of the MEK1-GRP78 signaling pathway results in the sensitization of NSCLC cells to cisplatin after PAK4 knockdown. Our findings establish PAK4 as a promising therapeutic target for addressing chemoresistance in NSCLC, potentially opening new avenues for enhancing treatment efficacy and patient outcomes.

Development of a prognostic nomogram based on an eight-gene signature for esophageal squamous cell carcinoma by weighted gene co-expression network analysis (WGCNA).

Background: Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignant tumor. This study aims to develop a robust prognostic model for ESCC. Methods: Expression profiles of ESCC were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Co-expressed modules were constructed by weighted gene co-expression network analysis (WGCNA). Differentially expressed genes (DEGs) between ESCC and normal samples were identified with the screening criteria of adjusted P value <0.05 and log |fold change (FC)| >1. After univariate and multivariate Cox regression analysis, an 8-gene module was constructed. A receiver operating characteristic (ROC) curve for overall survival (OS) was used to assess the prediction efficacy of the risk score. A nomogram was developed based on the risk score, age, gender, and stage for 1-, 2- and 3-year survival. The potential biological functions and pathways of the 8 genes were predicted using the Metascape database. Results: The 2 ESCC-related co-expression modules were built via WGCNA. Among all DEGs, 55 survival-related genes were identified for ESCC. Based on these genes, an 8-gene module was constructed, composed of CFAP53, FCGR2A, FCGR3A, GNGT1, IGF2, LINC01524, MAGEA3, and MAGEA6. The area under the curve (AUC) was 0.961, suggesting that the risk score could effectively predict the OS of patients with ESCC. Furthermore, the nomogram exhibited high accuracy in predicting the survival rate of ESCC patients at 1, 2, and 3 years. These genes were mainly involved in ESCC-related pathways such as extracellular matrix organization, collagen formation, and blood vessel development. Conclusions: Our nomogram based on the 8-gene risk score could be a reliable prognostic tool for ESCC.

miR-203a-3p-DNMT3B feedback loop facilitates non-small cell lung cancer progression.

It has been reported that microRNA-203a-3p (miR-203a-3p) modulates cell proliferation, migration and invasion in a variety of cancer cell types. However, little is known about its role in lung cancer progression. The present study found that miR-203a-3p was downregulated in non-small cell lung cancer (NSCLC) cell lines and tissues. Overexpression of miR-203a-3p inhibits NSCLC cell proliferation, migration and invasion, and promotes cellular apoptosis in vitro. Restoration of miR-203a-3p expression in A549 and NCI-H520 cells enhances their chemosensitivity. Further experiments showed that DNA methyltransferase 3B (DNMT3B) was a direct target of miR-203a-3p. In addition, the present results revealed that promoter hypermethylation was the potential mechanism responsible for low miR-203a-3p expression in NSCLC. Notably, feedback regulation between miR-203a-3p and DNMT3B was observed in NSCLC. Moreover, Overexpression of miR-203a-3p reduces tumor growth in vivo. In summary, the present study has identified an miR-203a-3p-DNMT3B feedback loop that facilitates NSCLC progression.

A novel cuproptosis-related prognostic lncRNA signature and lncRNA MIR31HG/miR-193a-3p/TNFRSF21 regulatory axis in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) remains the most common subtype of lung malignancy. Cuproptosis is a newly identified cell death which could regulate tumor cell proliferation and progression. Long non-coding RNAs (lncRNAs) are key molecules and potential biomarkers for diagnosing and treating various diseases. However, the effects of cuproptosis-related lncRNAs on LUAD are still unclear. In our study, 7 cuproptosis-related lncRNAs were selected to establish a prognostic model using univariate Cox regression analysis, LASSO algorithm, and multivariate analysis. Furthermore, we evaluated AC008764.2, AL022323.1, ELN-AS1, and LINC00578, which were identified as protective lncRNAs, while AL031667.3, AL606489.1, and MIR31HG were identified as risk lncRNAs. The risk score calculated by the prognostic model proved to be an effective independent factor compared with other clinical features by Cox regression analyses [univariate analysis: hazard ratio (HR) = 1.065, 95% confidence interval (CI) = 1.043-1.087, P < 0.001; multivariate analysis: HR = 1.067, 95% CI = 1.044-1.091, P < 0.001]. In addition, both analyses (ROC and nomogram) were used to corroborate the accuracy and reliability of this signature. The correlation between cuproptosis-related lncRNAs and immune microenvironment was elucidated, where 7 immune cells and 8 immune-correlated pathways were found to be differentially expressed between two risk groups. Furthermore, our results also identified and verified the ceRNA of cuproptosis-related lncRNA MIR31HG/miR-193a-3p/TNFRSF21 regulatory axis using bioinformatics tools. MIR31HG was highly expressed in LUAD specimens and some LUAD cell lines. Inhibition of MIR31HG clearly reduced the proliferation, migration, and invasion of the LUAD cells. MIR31HG showed oncogenic features via sponging miR-193a-3p and tended to positively regulate TNFRSF21 expression. In a word, lncRNA MIR31HG acts as an oncogene in LUAD by targeting miR-193a-3p to modulate TNFRSF21, which may be beneficial to the gene therapy of LUAD.

The mitochondrial genome of the land snail Camaenella platyodon (Pfeiffer, 1846) (Stylommatophora, Camaenidae).

The complete mitochondrial genome (mitogenome) of Chinese endemic snail Camaenella platyodon (Pfeiffer, 1846) has been sequenced and annotated in this study. The entire circular genome is 13,985 bp in size and represents the third camaenid mt genome, with 2 ribosomal RNA genes, 22 transfer RNA genes, 13 protein-coding genes. All of genes are divided into two groups, including 24 genes on the majority coding strand (J strand) and others on the minority coding strand (N strand). Phylogenetic analysis of 13 protein-coding genes suggests that C. platyodon is closely related to the species in family Camaenidae.

Preoperative plasma leptin levels predict delirium in elderly patients after hip fracture surgery.

Leptin is considered to be a modulator of the immune response. Hypoleptinemia increases the risk for Alzheimer's disease and vascular dementia. The present study aimed to investigate the ability of plasma leptin level to predict delirium in elderly patients after hip fracture surgery. Postoperative delirium (pod) was evaluated using the Confusion Assessment Method. Prolonged postoperative delirium (ppod) was defined as delirium lasting more than 4 weeks. Plasma leptin levels of 186 elderly patients and 186 elderly controls were measured by an enzyme-linked immunosorbent assay. Plasma leptin level was substantially lower in patients than in controls (4.6±2.2ng/ml vs. 7.5±1.8ng/ml, P<0.001). It was identified as an independent predictor for pod [odds ratio, 0.385; 95% confidence interval (CI), 0.286-0.517; P<0.001] and ppod (odds ratio, 0.283; 95% CI, 0.152-0.527; P<0.001) using a multivariate analysis, and had high area under receiver operating characteristic curve for pod [area under curve (AUC), 0.850; 95% CI, 0.790-0.898] and ppod (AUC, 0.890; 95% CI, 0.836-0.931). The predictive value of leptin was markedly bigger than that of age for pod (AUC, 0.705; 95% CI, 0.634-0.770; P=0.002) and ppod (AUC, 0.713; 95% CI, 0.642-0.777; P=0.019). In a combined logistic-regression model, leptin improved the AUC of age to 0.890 (95% CI, 0.836-0.931) (P<0.001) for pod and 0.910 (95% CI, 0.860-0.947) (P=0.005) for ppod. Thus, preoperative plasma leptin level may be a useful, complementary tool to predict delirium and also prolonged delirium in elderly patients after hip fracture surgery.