Prognostic value and immunological characteristics of a novel autophagy-related signature in pancreatic cancer.

Autophagy affects the development, progression, and prognosis of various cancers including pancreatic cancer. To develop an autophagy-related prognostic model of pancreatic cancer, we systematically analyzed gene expression profile from The Cancer Genome Atlas and Genotype-Tissue Expression. Ten autophagy-relevant genes with potential prognostic values were identified, based on which a prognostic model was constructed. We divided patients into a high- and a low-risk group with this model. Time-dependent receiver operating characteristic and Kaplan-Meier curves were conducted to evaluate the accuracy of the model. The Area Under Curvevalues of this model at 12, 18, and 24 months were 0.76, 0.73, and 0.78, respectively. The model was further validated in two Gene Expression Omnibus datasets. Gene set enrichment analysis and Cibersort were applied to analyze immune infiltration patterns and immune checkpoint blockade (ICB) molecules. The expression of ICB molecules, such as PD-L1 and PD1, presented significant correlation with the risk score. In conclusion, the risk score model established herein has been proved to be robust for evaluating the prognosis of pancreatic cancer and facilitate to improve the efficacy of ICB.

Activated polymorphonuclear leukocytes induce cardiomyocyte apoptosis and the protective effects of carvedilol.

Previous studies have shown that ischemia and reperfusion are potent stimuli for eliciting cardiomyocyte apoptosis, and that polymorphonuclear leukocytes (PMNs) are involved in the development of myocardial injury induced by ischemia and reperfusion. The present study examined whether PMN could directly induce cardiomyocyte apoptosis and, if so, it possible signal transduction pathways. In addition, we also investigated the effects of carvedilol, a potent antioxidant, on PMN-induced apoptosis. Cultured primary neonatal rat cardiomyocytes were exposed to PAF-activated PMNs at concentrations of 10(5), 3 x 10(5) and 10(6) cells/well for 48 h. Multiple detecting techniques, including electron microscopy, DNA gel electrophoresis. TUNEL assay and flow cytometry were used to identify myocyte apoptosis. All of these techniques demonstrated that activated PMNs directly induced cardiomyocyte apoptosis in a concentration-dependent manner, while unactivated PMNs showed no such effect. Activated PMN-induced apoptosis was partially inhibited by SB203580, a specific inhibitor of the p38-MAPK signaling system. Carvedilol (at a dose range of 1-10 mumol/l) significantly prevented activated PMN-induced cardiomyocyte apoptosis. These results suggest that PMNs, when activated, directly induce cardiomyocyte apoptosis and that the p38-MAPK signaling pathway might be involved in this process. Carvedilol may prevent PMN-induced apoptosis possibly because of its antioxidant properties.

Insulin-like growth factor I inhibits cardiomyocyte apoptosis and the underlying signal transduction pathways.

The effects of insulin-like growth factor I (IGF-I) on cardiomyocyte apoptosis induced by hypoxia in cultured neonatal rat cardiomyocyte were investigated. Primary neonatal rat cardiomyocytes were cultured in 95% N2-5% CO2 to imitate the in vivo hypoxic condition. Electron microscopic observation revealed a series of typical morphological changes characteristic of apoptosis in cardiomyocytes under the hypoxic condition. DNA gel electrophoresis showed DNA laddering in an ischemic duration-dependent manner. The hypoxia-induced cardiomyocyte apoptosis was also evidenced by flow cytometry and TUNEL assay. DNA gel electrophoresis showed that IGF-I in a dose range of 10(-9)-10(-7) mol/l could significantly prevent the hypoxia-induced cardiomyocyte apoptosis. The protective effects of IGF-I against hypoxia-induced apoptosis could also be verified by flow cytometry and TUNEL assay. A tyrosine kinase inhibitor (genistein), a MAPK inhibitor (PD-098059) and a P13 kinase inhibitor (wortmannin) could also suppress the antiapoptotic effects of IGF-I. These results suggest that IGF-I can directly alleviate the hypoxia-induced cardiomyocyte apoptosis and that the three kinase routes mentioned above may be involved in its signaling pathways.

[Effects of tetrahydroberberine on peripheral vascular dopamine DA1 and DA2 receptor subtypes].

OBJECTIVE: To study the effect of tetrahydroberberine (THB) on the peripheral vascular dopamine DA1 and DA2 receptors. METHOD: Using isolated vascular rings method. RESULT: THB(0.1-10 mumol.L-1) shifted the dose-response curves to the right in a nonparallel fashion and decreased the maximal response (Emax) of both the fenoldopam(FODA, a selective DA1 agonist)-induced and the propyl-butyl-dopamine(PBDA, a selective DA2 agonist)-induced vasorelaxation, showing a non-competitive antagonistic action. The pD'2 values of THB for FODA in the renal, pulmonary and mesenteric arteries were 5.29, 5.37 and 5.46, respectively, while for PBDA in the mesenteric and femoral arteries were 5.53 and 5.48, respectively. The potencies of this antagonistic action were weaker than those of SCH23390, a selective DA1 antagonist, domperidone, a selective DA2 antagonist and l-SPD, a mixed DA1/DA2 antagonist, domperidone, a selective DA2 antagonist and l-SPD, a mixed DA1/DA2 antagonist. CONCLUSION: THB is a mixed peripheral DA, and DA2 receptor antagonist similar to l-SPD.

Screening of serum autoantibodies to cardiac beta1-adrenoceptors and M2-muscarinic acetylcholine receptors in 408 healthy subjects of varying ages.

Autoantibodies to cardiac beta1-adrenoceptors and M2-muscarinic receptors have mainly been found in the sera of patients with idiopathic dilated cardiomyopathy (DCM). In order to elucidate the pathological significance of these autoantibodies in DCM, it is necessary to understand their characteristic distribution in a healthy population of different genders and ages. The peptides corresponding to the sequences of the second extracellular loops of the human beta1-adrenoceptor and M2-muscarinic receptors were therefore used as antigens to screen the sera of 408 healthy subjects of different ages (ranging from 0.5 to 85 years). Of 408 sera, 41 (10.0%) and 46 (11.3%) recognized the beta1-adrenoceptor and M2-muscarinic receptor peptides respectively. Of the positive sera for beta1-adrenoceptors and M2-muscarinic receptors, up to 63.4% and 56.5% had both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies respectively. The antibody titres of the positive sera of healthy subjects were all of a low level, with a geometric mean titre of 1:42+/-1.9 for anti-beta1-adrenoceptor antibodies and 1:51+/-1.7 for anti-M2-muscarinic receptor antibodies. The frequency of occurrence of autoantibodies to both receptors in the sera of healthy subjects increased significantly with age. In conclusion, the autoantibodies to beta1-adrenoceptors and M2-muscarinic receptors in the sera of healthy subjects are characterized by a low frequency of occurrence and low titre, with the frequency of occurrence increasing with age.