Objective To observe the effects of vitamin E(VE) on the changes of the intercellular adhesion molecule-1(ICAM-1)and free radicals in ischemic-reperfused myocardium(MIR) of diabetic rats Method The diabetic rat model was established by i.p.streptozotocin injection.Four weeks later,MIR models were established,and 30 rats were divided into three groups with each group 10 rats(sham group,MIR group and VE group).The ICAM-1 protein expressions were evaluated by immunocytochemistry.The contents of malonialdehyde(MDA) in serum and myocardial tissues were detected.The activities of superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px) in serum and myocardial tissues were measured.The activities of Na+,K+-ATPase,Mg++-ATPase,Ca++-ATPase in myocardial mitochondria were measured.Results Compared with sham group,the activities of Na+,K+-ATPase,Mg++-ATPase,Ca++-ATPase in myocardial mitochondria were decreased,the contents of MDA in serum and myocardium increased,the levels of SOD and GSH-Px in serum and myocardium decreased,and the levels of ICAM-1 in myocardium increased significantly in MIR group.Compared with MIR group,the activities of Na+,K+-ATPase,Mg++-ATPase in myocardial mitochondria were increased,the levels of MDA in serum andmyocardium decreased the activities of SOD and GSH-Px in serum and myocardium increased,and the levels of ICAM-1 in myocardium decreased significantly in VE group.Conclusion VE could relieve myocardial ischemic reperfusion injury and the damage of lipid peroxidation and free radical induced by MIR in diabetic rats,and this effect was mediated by reduction of the expression of ICAM-1 protein.

Objective:To investigate the value of programmed death-1（PD-1） expression on the T lymphocytes for the prognosis of septic patients.Methods:From September 2017 to May 2019, septic patients were included in Department of Intensive Care Unit at 6 hospitals. The PD-1 expression on T cells were measured by flow cytometry. Logistic regression was conducted to analyze independent risk factors related to death within 28 days，and receiver operating characteristic curve(ROC) was conducted to evaluate the prognostic value of PD-1 expression on T cells in septic patients.Results:A total of 64 septic patients were enrolled to this study，including 32 survivors and 32 deaths. The PD-1 expression on T cells in the death group was significantly higher than that in the surviving group ( P<0.05). Correlation analysis showed that the percentages of PD-1 +/CD3 +T cells and PD-1 +/CD8 +T cells were positively correlated with procalciton in ( r=0.313, P =0.015； r=0.375, P=0.003), logistic regression analysis showed that the percentages of PD-1 +/CD3 +，PD-1 +/CD4 +，PD-1 +/CD8 +T cells were independent risk factors for the death of sepsis patients. The percentage of PD-1 +/CD3 +T cell was 3.63%, with AUC 0.842, sensitivity to predict the mortality 96.43% and specificity 59.38%, ( P<0.000 1). The percentage of PD-1 +/CD4 +T cell was 4.65%, with AUC 0.847, sensitivity 96.43%, specificity 62.50%，( P<0.000 1). The percentage of PD-1 +/CD8 +T cell was 3.91%, with AUC 0.771, sensitivity 64.29%, specificity 81.25%，( P=0.000 3). Conclusions:The T cell PD-1 expression is an independent risk factor to predict the 28-day mortality in septic patients. Combining the proportions of PD-1 +/CD3 +, PD-1 +/CD4 +and PD-1 +/CD8 +T cells may further enhance the predictive value for death.

Various c-mesenchymal-to-epithelial transition (c-MET) inhibitors are effective in the treatment of non-small cell lung cancer; however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras (PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC₅₀ values and achieved picomolar DC₅₀ values and >99% of maximum degradation (D_max) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15 dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion. Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^Y1230H and c-MET^D1228N mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.