A combined risk model for the multi-encompassing identification of heterogeneities of prognoses, biological pathway variations and immune states for sepsis patients.

BACKGROUND: Sepsis is a highly heterogeneous syndrome with stratified severity levels and immune states. Even in patients with similar clinical appearances, the underlying signal transduction pathways are significantly different. To identify the heterogeneities of sepsis from multiple angles, we aimed to establish a combined risk model including the molecular risk score for rapid mortality prediction, pathway risk score for the identification of biological pathway variations, and immunity risk score for guidance with immune-modulation therapy. METHODS: We systematically searched and screened the mRNA expression profiles of patients with sepsis in the Gene Expression Omnibus public database. The screened datasets were divided into a training cohort and a validation cohort. In the training cohort, authentic prognostic predictor characteristics (differentially expressed mRNAs, pathway activity variations and immune cells) were screened for model construction through bioinformatics analysis and univariate Cox regression, and a P value less than 0.05 of univariate Cox regression on 28-day mortality was set as the cut-off value. The combined risk model was finally established by the decision tree algorithm. In the validation cohort, the model performance was assessed and validated by C statistics and the area under the receiver operating characteristic curve (AUC). Additionally, the current models were further compared in clinical value with traditional indicators, including procalcitonin (PCT) and interleukin-8 (IL-8). RESULTS: Datasets from two sepsis cohort studies with a total of 585 consecutive sepsis patients admitted to two intensive care units were downloaded as the training cohort (n = 479) and external validation cohort (n = 106). In the training cohort, 15 molecules, 20 pathways and 4 immune cells were eventually enrolled in model construction. These prognostic factors mainly reflected hypoxia, cellular injury, metabolic disorders and immune dysregulation in sepsis patients. In the validation cohort, the AUCs of the molecular model, pathway model, immune model, and combined model were 0.81, 0.82, 0.62 and 0.873, respectively. The AUCs of the traditional biomarkers (PCT and IL-8) were 0.565 and 0.585, respectively. The survival analysis indicated that patients in the high-risk group identified by models in the current study had a poor prognosis (P < 0.05). The above results indicated that the models in this study are all superior to the traditional biomarkers for the predicting the prognosis of sepsis patients. Furthermore, the current study provides some therapeutic recommendations for patients with high risk scores identified by the three submodels. CONCLUSIONS: In summary, the present study provides opportunities for bedside tests that could quantitatively and rapidly measure heterogeneous prognosis, underlying biological pathway variations and immune dysfunction in sepsis patients. Further therapeutic recommendations for patients with high risk scores could improve the therapeutic system for sepsis.

miR-874 inhibits gastric cancer cell proliferation by targeting SPAG9.

BACKGROUND: microRNAs (miRNAs) play essential roles in the development and progression of gastric cancer (GC). Although aberrant miR-874 expression has been reported in various human cancers, its role in GC remains obscure. METHODS: miR-874 expression was assessed by real-time quantitative polymerase chain reaction (RT-qPCR) in 62 matched GC and adjacent normal tissues, as well as in GC cell lines and immortalized human gastric epithelial cells. CCK8 assay, colony formation assay, and flow cytometry were used to assess the role of miR-874 in GC cell proliferation and apoptosis in vitro. Additionally, to determine the effects of miR-874 on GC cell proliferation and apoptosis in vivo, BALB/c nude mice were injected with GC cells transfected with a miR-874 mimic. The role of miR-874 in SPAG9 expression was assessed by luciferase assay, Western blotting, and RT-qPCR. RESULTS: miR-874 was downregulated in GC cell lines and tissues. miR-874 overexpression in GC cells led to inhibition of cell proliferation and induction of apoptosis. Moreover, SPAG9 was identified as a direct miR-874 target, the expression of which was suppressed by miR-874. SPAG9 overexpression markedly promoted GC cell proliferation. CONCLUSIONS: miR-874 inhibited cell proliferation and induced apoptosis in GC cells. SPAG9 downregulation was crucial for the tumor-suppressive effects of miR-874. Hence, the miR-874/SPAG9 axis could serve as a novel therapeutic target in GC.

miR-7641 depletion suppresses proliferation of gastric cancer cells by targeting ARID1A.

Gastric cancer (GC) is lethal and there is an urgent need for improved understanding of this disease. Recent studies have reported that microRNAs (miRNAs) play increasingly important roles in the regulation of GC. In this study, we explored the target genes and effects of miR-7641 in GC. Our data showed that high miR-7641 expression was associated with low expression of ARID1A in GC tissue. miR-7641 expression promoted GC cell proliferation and colony formation. Luciferase reporter assay results confirmed that ARID1A was a target gene of miR-7641. Furthermore, downregulation of ARID1A expression caused a significant increase in GC cell proliferation. In vivo depletion of miR-7641 reduced tumor volume and weight and increased ARID1A and Ki67 expression as well as a decreased terminal-deoxynucleotidyl transferase-mediated nick end labeling in mouse tumor tissues. Conversely, ARID1A silencing reversed the suppressive effects of miR-7641 inhibitors on GC cells. Overall, these findings indicate that miR-7641 is a promising novel prognostic biomarker of GC and may represent a novel target for clinical management of GC.

Activation of ERK1/2 and Akt is associated with cisplatin resistance in human lung cancer cells.

Cisplatin is widely used for the treatment of solid tumours including small cell lung cancers, but its success is often compromised by relapse and resistance to further treatment. Extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt are two major cell survival pathways that are upregulated and activated in lung cancer tissues. Phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt) can be further stimulated by chemotherapeutics in cancer cells. Although individually targeting the ERK1/2 or Akt pathway has been reported to sensitize cancer cells to therapy, the effect of concurrently blocking these two pathways on the sensitivity of lung cancer cells to cisplatin has not been investigated. In the present study, we aimed to determine whether the ERK1/2 and Akt pathways contribute to cisplatin resistance in human small cell lung cancer A549 cells. The results showed that cisplatin activates p-ERK1/2 and p-Akt in A549 cells. Blockade of either of these pathways with chemical inhibitors moderately sensitized A549 cells to cisplatin-induced apoptosis and reduced cell viability. Strikingly, concurrent inhibition of p-ERK1/2 and p-Akt significantly potentiated cisplatin cytotoxicity in vitro and in vivo. The sensitization of A549 cells to cisplatin cytotoxicity induced by p-Akt inhibition was mediated by the upregulation of PUMA, whereas that induced by p-ERK1/2 inhibition occurred by Bcl-2 downregulation. These data indicate that the cooperative effects of p-ERK1/2 and p-Akt on attenuating cisplatin cytotoxicity are mediated by PUMA and Bcl-2 regulation, and concurrently blocking these pathways may be an effective strategy for improving the efficacy of cisplatin as anticancer treatment.