Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.

Metformin is used as a first-line therapy for type 2 diabetes, with reports of its usefulness for the prevention and control of several types of cancers. This study investigated the effects of metformin on hepatocellular carcinoma (HCC). The human HCC cell lines HepG2 and PLC/PRF/5 were cultured and treated with metformin or 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of adenosine monophosphate (AMP)-activated protein kinase. Changes in cell viability and cell cycle distribution were evaluated by MTT and flow cytometry, respectively. Apoptosis was assessed by fluorescent-dye staining. An HCC model was established in 6- to 8-week-old BALB/c-nu mice by subcutaneous injection of PLC/PRF/5 cells. After 1 week, mice were treated intragastrically with metformin or vehicle. Tumor xenograft tissues were examined using immunohistochemistry for evaluation of the the expression of cyclin D1, p21CIP and p27KIP. HCC cells and tissues from the in vitro and in vivo experiments, respectively, were subjected to protein extraction and western blotting. We found that metformin treatment reduced HCC cell viability in a dose-dependent manner similar to AICAR treatment. In addition, metformin treatment induced HCC cell cycle arrest at G1/G0 phase and apoptosis. Intragastric treatment of the mouse PLC/PRF/5 cell xenograft model with metformin showed that metformin not only blocked tumor progression, but also reduced tumor morbidity. Treatment with metformin upregulated the expression of p21CIP and p27KIP, but downregulated cyclin D1 levels, both in vitro and in vivo. Metformin treatment also upregulated the expression of phosphorylated AMPK protein in xenograft tissues. These findings indicate that metformin warrants further evaluation as a novel therapeutic and preventive strategy against HCC.

Previous studies have suggested that metformin, a biguanide family member widely used as an oral antidiabetic drug, may inhibit proliferation and induce apoptosis in certain types of cancer cell. However, the molecular mechanisms underlying metformin-associated anticancer effects, and in particular antimetastatic effects, remain to be fully understood. The present study assessed the efficacy of metformin in inhibiting the migration and invasion of the esophageal carcinoma cell line EC109, and evaluated the effect of metformin on the protein kinase B (AKT) signaling pathway. EC109 cells were treated with 0, 5, 10 or 20 mM metformin during the logarithmic growth phase. A Transwell assay and western blot analysis revealed that metformin inhibited the migration and invasion of EC109 cells, nuclear factor-κB activation, matrix metallopeptidase 9 and N-cadherin expression in a phosphorylated-AKT dependent manner. These results suggested that metformin inhibits the migration and invasion of human esophageal carcinoma cells by suppressing AKT phosphorylation and regulating the expression of migration- and invasion-associated genes.

Al x Cr 0.4 CuFe 0.4 MnNi (x ¼ 0, 0.1, 0.2, 0.3, 0.4) high entropy alloys (HEAs) were prepared by coppermold casting. The effects of Al were investigated on the microstructure, tensile properties and oxidation behavior of these HEAs. It was shown that the addition of Al resulted in the formation of BCC and ordered BCC phases. The compositional heterogeneity between dendrites and interdendrites was alleviated when the content of Al was small. The mechanical properties of HEAs have been remarkably improved by the addition of Al. Considering the low cost and good mechanical properties, this kind of HEAs is rather competitive among HEAs for engineering application as structural materials. In this work, it was also shown that the oxidation resistance of current HEAs was significantly improved by the addition of Al.

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BackgroundThis study aimed to evaluate the association between the glucose-to-lymphocyte ratio (GLR) and in-hospital mortality in intensive care unit (ICUs) patients with sepsis.MethodsThis is a retrospective cohort study. Patients with sepsis from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database had their baseline data and in-hospital prognosis retrieved. Multivariable Cox regression analyses were applied to calculate adjusted hazard ratios (HR) with 95% confidence intervals (CI). Survival curves were plotted, and subgroup analyses were stratified by relevant covariates. To address the non-linearity relationship, curve fitting and a threshold effect analysis were performed.ResultsOf the 23,901 patients, 10,118 patients with sepsis were included. The overall in-hospital mortality rate was 17.1% (1,726/10,118). Adjusted for confounding factors in the multivariable Cox regression analysis models, when GLR was used as a categorical variable, patients in the highest GLR quartile had increased in-hospital mortality compared to patients in the lowest GLR quartile (HR = 1.26, 95% CI: 1.15–1.38). When GLR was used as a continuous variable, each unit increase in GLR was associated with a 2% increase in the prevalence of in-hospital mortality (adjusted HR = 1.02, 95% CI: 1.01–1.03, p = 0.001). Stratified analyses indicated that the correlation between the GLR and in-hospital mortality was stable. The non-linear relationship between GLR and in-hospital mortality was explored in a dose-dependent manner. In-hospital mortality increased by 67% (aHR = 1.67, 95% CI: 1.45–1.92) for every unit GLR increase. When GLR was beyond 1.68, in-hospital mortality did not significantly change (aHR: 1.04, 95% CI: 0.92–1.18).ConclusionThere is a non-linear relationship between GLR and in-hospital mortality in intensive care patients with sepsis. A higher GLR in ICU patients is associated with in-hospital mortality in the United States. However, further research is needed to confirm the findings.

BackgroundThis study aimed to investigate the relationship between the blood urea nitrogen to serum albumin ratio (BAR) and in-hospital mortality in patients with sepsis.Materials and methodsThis is a retrospective cohort study. All septic patient data for the study were obtained from the intensive care unit of Beth Israel Deaconess Medical Center. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using multivariable Cox regression analyses. Survival curves were plotted and subgroup analyses were stratified by relevant covariates.ResultsAmong 23,901 patients, 13,464 with sepsis were included. The overall in-hospital mortality rate was 18.9% (2550/13464). After adjustment for confounding factors, patients in the highest BAR quartile had an increased risk of sepsis death than those in the lowest BAR quartile (HR: 1.42, 95% CI: 1.3–1.55), using BAR as a categorical variable. When BAR was presented as a continuous variable, the prevalence of in-hospital sepsis-related death increased by 8% (adjusted HR: 1.08, 95% CI: 1.07–1.1, P < 0.001) for each 5-unit increase in BAR, irrespective of confounders. Stratified analyses indicated age interactions (P < 0.001), and the correlation between BAR and the probability of dying due to sepsis was stable.ConclusionBAR was significantly associated with in-hospital mortality in intensive care patients with sepsis. A higher BAR in patients with sepsis is associated with a worse prognosis in the ICU in the USA. However, further research is required to confirm this finding.

e effect of metformin on human esophageal normal and carcinoma cells remains poorly understood. We aim to investigate the different antiproliferation effects and underlying distinct molecular mechanisms between these two types of cells. Human esophageal squamous cell carcinoma cell line, EC109, and normal esophageal epithelial cell line, HEEC, were used in the experiment. e cell survival rate was determined by cell counting kit-8 (CCK-8). Cell apoptosis was analyzed by flow cytometry. e mRNA and protein levels of signal transducer and activator of transcription 3 (Stat3) were detected by real-time quantitative PCR and western blot. Interleukin-6 (IL-6) was added to activate Stat3. e level of intracellular reactive oxygen species (ROS) was assessed by a DCFH-DA fluorescent probe. Metformin had more significant inhibitory effects on cell proliferation in EC109 cells than HEECs. Metformin induced apoptosis of EC109 cells in a dose-dependent manner instead of HEECs. e expression of Stat3 in both mRNA and protein levels was higher in EC109 cells than HEECs. Further study revealed that metformin may attenuate the phosphorylation of the Stat3 and the Bcl-2 expression, which was restored by IL-6 partly in EC109 cells but not HEECs. On the contrary, metformin increased the level of ROS in both the cell lines, but this intracellular ROS variation had no effect on apoptosis. Metformin has different functional roles on the apoptosis in esophageal carcinoma cells and normal esophageal cells. erefore, the Stat3/Bcl-2 pathway-mediated apoptosis underlies the cell-type-specific drug sensitivity, suggesting metformin possesses a therapeutic activity and selectivity on esophageal cancer.