Gefitinib metabolism-related lncRNAs for the prediction of prognosis, tumor microenvironment and drug sensitivity in lung adenocarcinoma.

The complete compound of gefitinib is effective in the treatment of lung adenocarcinoma. However, the effect on lung adenocarcinoma (LUAD) during its catabolism has not yet been elucidated. We carried out this study to examine the predictive value of gefitinib metabolism-related long noncoding RNAs (GMLncs) in LUAD patients. To filter GMLncs and create a prognostic model, we employed Pearson correlation, Lasso, univariate Cox, and multivariate Cox analysis. We combined risk scores and clinical features to create nomograms for better application in clinical settings. According to the constructed prognostic model, we performed GO/KEGG and GSEA enrichment analysis, tumor immune microenvironment analysis, immune evasion and immunotherapy analysis, somatic cell mutation analysis, drug sensitivity analysis, IMvigor210 immunotherapy validation, stem cell index analysis and real-time quantitative PCR (RT-qPCR) analysis. We built a predictive model with 9 GMLncs, which showed good predictive performance in validation and training sets. The calibration curve demonstrated excellent agreement between the expected and observed survival rates, for which the predictive performance was better than that of the nomogram without a risk score. The metabolism of gefitinib is related to the cytochrome P450 pathway and lipid metabolism pathway, and may be one of the causes of gefitinib resistance, according to analyses from the Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Immunological evasion and immunotherapy analysis revealed that the likelihood of immune evasion increased with risk score. Tumor microenvironment analysis found most immune cells at higher concentrations in the low-risk group. Drug sensitivity analysis found 23 sensitive drugs. Twenty-one of these drugs exhibited heightened sensitivity in the high-risk group. RT-qPCR analysis validated the characteristics of 9 GMlncs. The predictive model and nomogram that we constructed have good application value in evaluating the prognosis of patients and guiding clinical treatment.

miR-140-3p enhances cisplatin sensitivity and attenuates stem cell-like properties through repressing Wnt/ß-catenin signaling in lung adenocarcinoma cells.

Lung adenocarcinoma (LUAD) is the most predominant subtype of non-small cell lung cancer (NSCLC) that is experiencing the fastest growth rate in incidence. Chemoresistance and the presence of cancer stem cells are considered to be the main obstacles preventing the successful treatment of patients with NSCLC, the molecular mechanism of which remains poorly understood. The present study aimed to investigate the effects of microRNA (miR)-140-3p on cisplatin sensitivity and stem cell-like properties of LUAD cells. Analysis of publicly available data demonstrated that miR-140-3p expression was downregulated in LUAD, and positively associated with the overall survival rate of patients. In addition, transfection with the miR-140-3p mimic reduced LUAD cell viability and induced apoptosis following treatment with cisplatin whilst decreasing stem cell-like properties. miR-140-3p overexpression was also found to attenuate cisplatin resistance and reduce stem cell-like properties in LUAD cells by suppressing Wnt/ß-catenin signaling, all of which were reversed by the overexpression of ß-catenin. Taken together, results of the present study suggest miR-140-3p to be an effective therapeutic strategy for patients with LUAD.

Proteomic analysis of the immunosuppressive effects of mesenchymal stem cells in a rat heart transplantation model.

BACKGROUND: Some reports suggest mesenchymal stem cells (MSCs) have immunosuppressive properties. However, conflicting evidence regarding the role of MSCs has emerged. OBJECTIVES: To gain a better understanding of the immunosuppressive properties of mesenchymal stem cells (MSCs) in a rat heart transplantation model. MATERIAL AND METHODS: MSCs were obtained from the femoral and tibial bone marrow of Sprague-Dawley rats and cultured. Heart-transplanted rats were allocated into a MSC-treated group and 2 control groups. On postoperative day 7, 1 rat was sacrificed and the pathological changes of heart tissues were assessed. Serum proteomic spectra were generated by surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS: Rat MSCs displayed the typical spindle-shaped morphology in culture and significantly prolonged the graft survival up to 33.25 ± 2.54 days compared with controls (19.75 ± 1.56 and 11.16 ± 1.34 days, respectively). Pathological analysis showed the inflammatory cell infiltration in the MSC-treated group was significantly reduced. SELDI analysis showed that 5 protein/peptide peaks with M/Z 1272.33, 1986.65, 2323.42, 5375.59 and 12968.11 were up-regulated in the MSC-treated group (P < 0.001). CONCLUSIONS: Donor-derived MSCs clearly alleviate acute rejection following heart transplantation in rats and significantly prolong the isograft survival time.

TFPI-2 methylation predicts poor prognosis in non-small cell lung cancer.

BACKGROUND: Methylation of human tissue factor pathway inhibitor-2 (TFPI-2) gene has been detected in several types of cancer, including non-small cell lung cancer (NSCLC). However, an association between the methylation status of TFPI-2 gene and prognosis has not yet been investigated. METHODS: Methylation of TFPI-2 gene was examined in a consecutive series of 133 non-metastatic NSCLC patients using methylation-specific PCR (MSP). Univariate and multivariate analyses were conducted to investigate the association between clinical variables and overall survival time. RESULTS: Methylation of TFPI-2 gene was detected in 36 of 133 patients (27.1%). Of these 36 patients, seventeen individuals (47.2%) carried stage III tumors. The 5-year disease free survival rate among patients carrying methylated TFPI-2 tumors was significantly lower as compared to those with unmethylated TFPI-2 tumors (35.5% versus 6.1%, P<0.0001). Moreover, methylation of TFPI-2 gene was found to be an independent prognostic factor for poor overall survival based on multivariate analysis models (P=0.013), as was age >62 years old (P<0.0001) and TNM stage of disease (P<0.0001). CONCLUSIONS: The results of the present study suggest that methylation of TFPI-2 gene is an independent factor for an unfavorable prognosis in patients with NSCLC.