Combined Use of Three Machine Learning Modeling Methods to Develop a Ten-Gene Signature for the Diagnosis of Ventilator-Associated Pneumonia.

BACKGROUND This study aimed to use three modeling methods, logistic regression analysis, random forest analysis, and fully-connected neural network analysis, to develop a diagnostic gene signature for the diagnosis of ventilator-associated pneumonia (VAP). MATERIAL AND METHODS GSE30385 from the Gene Expression Omnibus (GEO) database identified differentially expressed genes (DEGs) associated with patients with VAP. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment identified the molecular functions of the DEGs. The least absolute shrinkage and selection operator (LASSO) regression analysis algorithm was used to select key genes. Three modeling methods, including logistic regression analysis, random forest analysis, and fully-connected neural network analysis, also known as also known as the feed-forward multi-layer perceptron (MLP), were used to identify the diagnostic gene signature for patients with VAP. RESULTS Sixty-six DEGs were identified for patients who had VAP (VAP+) and who did not have VAP (VAP-). Ten essential or feature genes were identified. Upregulated genes included matrix metallopeptidase 8 (MMP8), arginase 1 (ARG1), haptoglobin (HP), interleukin 18 receptor 1 (IL18R1), and NLR family apoptosis inhibitory protein (NAIP). Down-regulated genes included complement factor D (CFD), pleckstrin homology-like domain family A member 2 (PHLDA2), plasminogen activator, urokinase (PLAU), laminin subunit beta 3 (LAMB3), and dual-specificity phosphatase 2 (DUSP2). Logistic regression, random forest, and MLP analysis showed receiver operating characteristic (ROC) curve area under the curve (AUC) values of 0.85, 0.86, and 0.87, respectively. CONCLUSIONS Logistic regression analysis, random forest analysis, and MLP analysis identified a ten-gene signature for the diagnosis of VAP.

MiR-26a-5p Heightens Breast Cancer Cell Sensitivity to Paclitaxel via Targeting Flap Endonuclease 1.

OBJECTIVE: Flap endonuclease 1 (FEN1) has been confirmed to involve the drug resistance of multiple cancers including breast cancer. However, the effect of miRNA-mediated FEN1 on breast cancer cell resistance is still ambiguous and needs further research. METHODS: Firstly, we used GEPIA2 to predict the FEN1 expression in breast cancer. Next, we used quantitative real-time polymerase chain reaction (qRT-PCR) and western blot to evaluate the FEN1 level of cells. After parental cells or MDA-MB-231-paclitaxel (PTX) cells being transfected with or without siFEN1, the apoptosis, migration, and protein levels of FEN1, Bcl-2, and resistance-related genes were examined by flow cytometry, wound healing assay, and western blot, respectively. Then, the putative miRNA targeting FEN1 was predicted using StarBase V3.0, and further confirmed by qRT-PCR. The targeted binding of FEN1 to miR-26a-5p was detected by dual-luciferase reporter assay. After parental cells or MDA-MB-231-PTX cells being transfected with or without miR-26a-5p mimic, the apoptosis, migration, and protein levels of FEN1, Bcl-2, and resistance-related genes were tested again. RESULTS: FEN1 expression was enhanced in breast cancer and MDA-MB-231-PTX cells. The combined application of FEN1 knockdown and PTX enhanced apoptosis in MDA-MB-231-PTX cells but suppressed cell migration and expressions of FEN1, Bcl-2, and resistance-related genes. Then, we confirmed that FEN1 was targeted by miR-26a-5p. The combined application of miR-26a-5p mimic and PTX largely facilitated apoptosis in MDA-MB-231-PTX cells but restrained cell migration and expressions of FEN1, Bcl-2, and resistance-related genes. CONCLUSION: MiR-26a-5p contributes to the sensitivity of breast cancer cells to paclitaxel via restraining FEN1.

Impact of individualized pharmaceutical care on efficacy and safety of opioid-tolerant outpatients with cancer pain: a multicenter randomized controlled trial.

Background: Managing cancer pain is a growing challenge. Individualized pharmaceutical care is particularly important for opioid-tolerant outpatients due to variation in terms of their knowledge about pain, treatment adherence, and risk of experiencing inadequate analgesia and severe adverse events. This study aimed to determine the influence of individualized pharmaceutical care on outcomes in opioid-tolerant outpatients with cancer pain. Methods: A multicenter, open-label, randomized, controlled study was carried out. Opioid-tolerant outpatients experiencing chronic cancer pain and receiving sustained-release opioids were randomly assigned to the intervention group and the control group with a 1:1 ratio. The intervention group received individualized pharmaceutical care, while the control group received conventional care during 4-week period. The primary endpoint was medication adherence on the intention-to-treat (ITT) population. Secondary outcomes included the patients' knowledge of cancer pain and pain medications, pain score, frequency of breakthrough pain, quality of life (QoL) which were assessed on the ITT population. Adverse events were evaluated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 4.0 on the per-protocol (PP) population. Results: A total of 118 patients were enrolled, and 102 patients (51 in each group) completed the 30-day follow-up from six oncology centers in China. The proportion of patients adhering to opioid medication increased to similar levels in the two groups during the 4 weeks (P=0.149). The intervention group had a significantly lower pain score at 4 weeks compared to the control group (P=0.015), and the proportion of participants without breakthrough pain was significantly higher at 4 weeks than at baseline in the intervention group (P=0.029), but not in the control group (P=0.322). The two groups did not differ significantly in terms of QoL or adverse events. Conclusions: Our results suggest that individualized pharmaceutical care can markedly reduce patient-related problems and significantly improve pain control in opioid-tolerant outpatients. These findings validate the recommendations to include clinical pharmacists in the management of cancer pain. Trial Registration: ClinicalTrials.gov identifier: NCT03439904.

Ropivacaine suppresses tumor biological characteristics of human hepatocellular carcinoma via inhibiting IGF-1R/PI3K/AKT/mTOR signaling axis.

Ropivacaine, a common local anesthetic in the clinic, has anti-proliferative and pro-apoptotic effects in numerous cancers, however, the underlying regulatory mechanism of ropivacaine in hepatocellular carcinoma remains unclear. In the current study, human HepG2 cells were stimulated with different ropivacaine concentrations. Cell Counting Kit-8 assay, cell colony formation, and cell cycle were used to monitor cell viability. Cell apoptosis, migration, and invasion were determined by flow cytometry and transwell assays. Tumor xenograft experiments were performed to prove the anti-cancer effect of ropivacaine in vivo. A high dose of ropivacaine inhibited proliferation and promoted apoptosis of HepG2 cells in a dose-dependent manner. Ropivacaine challenge also arrested cells in the G2 phase, followed by a decline in the protein expression of cyclin D1 and cyclin-dependent kinase 2, and an increase in p27 levels in HepG2 cells. Additionally, different ropivacaine doses suppressed cell migration and invasion by upregulating E-cadherin expression and downregulating N-cadherin expression. Mechanically, ropivacaine challenge gradually restrained insulin-like growth factor-1 receptor (IGF-1 R) expression and the activities of phosphorylated-PI3K, AKT, and mTOR in HepG2 cells with increased ropivacaine doses. In the tumor xenograft experiment, ropivacaine was confirmed to inhibit tumor growth, accompanied by inhibition of the IGF-1 R/PI3K/AKT/mTOR signaling axis. In conclusion, ropivacaine suppressed tumor biological characteristics and promoted apoptosis, resulting in the suppression of hepatocellular carcinoma progression by targeting the IGF-1 R/PI3K/AKT/mTOR signaling pathway. It is possible that ropivacaine-mediated local anesthesia may be developed as a novel surgical adjuvant drug for treating hepatocellular carcinoma.

Smoking is a risk factor for postoperative ileus after radical resection in male patients.

ABSTRACT: Most smokers are males, and smoking has been indicated as a risk factor for many cancers as well as postoperative complications after cancer surgery. However, little is known about whether smoking is a risk factor for postoperative ileus (POI) after radical rectal cancer resection in males. The aim of this study was to assess whether smoking is a risk factor for POI after radical resection in male rectal cancer patients.Data of 1486 patients who underwent radical resection for rectal cancer were extracted from the clinical medical system in our hospital and were statistically analyzed. POI was defined as nausea, vomiting or pain, failure to have bowel function for more than 4 days postoperatively, and absence of a mechanical bowel obstruction.The rate of POI was 12.79%. Univariate analysis showed that patients in the POI group were more likely to have a history of smoking and drinking and receive intraperitoneal chemotherapy and had a larger intraperitoneal chemotherapy dosage. In the multivariable analysis, smoking remained significantly associated with a higher incidence of POI (OR 2.238, 95% CI [1.545-3.240], P = .000). The results also showed that patients who received postoperative patient-controlled intravenous analgesia had a lower incidence of POI.Male patients with a history of smoking who undergo elective radical resection for rectal cancer have an increased risk for POI complications.

Kaempferol attenuated cisplatin-induced cardiac injury via inhibiting STING/NF-κB-mediated inflammation.

Cardiovascular complications have been well documented as the downside to conventional cancer chemotherapy. As a notable side effect of cisplatin, cardiotoxicity represents a major obstacle to the successful treatment of cancer. It has been reported that kaempferol (KPF) possesses cardioprotective and anti-inflammatory qualities. However, the effect of KPF on cardiac damage caused by conventional cancer chemotherapy remains unclear. In this study, we clarified the protective effect of KPF on cisplatin-induced heart injury, and conducted in-depth research on the molecular mechanism underlying this effect. The results showed that KPF protected against cardiac dysfunction and injury induced by cisplatin in vivo. In H9c2 cells, KPF dramatically reduced cispaltin-induced apoptosis and inflammatory response by modulating STING/NF-κB pathway. In conclusion, these results showed that KPF had great potential in attenuating cisplatin-induced cardiac injury. Besides, greater emphasis should be placed in the future on natural active compounds containing KPF with anti-inflammatory effects for the treatment of these diseases.