Influences of point defects on electron transport of two-dimensional gep semiconductor device.

The quantum transport properties of defective two-dimensional (2D) GeP semiconductor nanodevice consisting of typical point defects, such as antisite defect, substitutional defect, and Schottky defect, have been studied by using density functional theory combined with non-equilibrium Green's function calculation. The antisite defect has indistinctive influences on electron transport. However, both substitutional and Schottky defect have introduced promising defect state at the Fermi level, indicating the possibility of improvement on the carrier transport. Our quantitative quantum transport calculations ofI-Vbbehavior have revealed that the electrical characters are enhanced. Moreover, the P atom vacancy could induce significant negative differential resistance phenomenon, and the physical mechanism is unveiled by detailed analysis. The transfer characteristic properties could be prominently improved by substitutional defect and vacancy defect. Most importantly, we have proposed a computational design of GeP-based electronic device with improved electrical performance by introducing vacancy defect. Our findings could be helpful to the practical application of novel 2D GeP semiconductor nanodevice in future.

Efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitor versus chemotherapy for advanced lung cancer: A meta-analysis.

BACKGROUND: This meta-analysis was performed to compare efficacy and tolerability between antiprogrammed cell death (PD-1)/programmed cell death-ligand-1 (PD-L1) + anticytotoxic T-lymphocyte-associated protein-4 (CTLA-4) treatment and chemotherapy in advanced lung cancer. METHODS: Cochrane Library, Embase, and PubMed databases were searched for potential articles. The fixed-effect model or random-effect model was adopted for pooled analysis based on the I2 and P-value. RESULTS: Six articles with 1338 patients were identified and subjected to meta-analysis. Compared with chemotherapy, anti-PD-1/PD-L1 + anti-CTLA-4 treatment could significantly improve the overall survival (hazard ratio [HR] = 0.78, 95%confidence interval [CI]: 0.71-0.84, P = .21) and progression-free survival (HR = 0.77, 95%CI: 0.71-0.83, P = .30) of advanced lung cancer patients. Moreover, there was no obvious difference in the incidence of 3 to 4 adverse events (AEs) serious adverse reactions (HR = 1.35, 95%CI: 0.66-2.74, P < .00001) between the 2 treatment groups, but the incidence rates of AEs leading to discontinuation (HR = 2.56, 95%CI: 1.53-4.30, P < .00001) and AEs leading to death (HR = 2.10, 95%CI: 1.21-3.63, P = .20) were higher. Furthermore, no remarkable differences in objective response rate (HR = 1.31, 95%CI: 0.97-1.77, P = .02) were observed between the 2 groups. CONCLUSION: Our meta-analysis revealed that PD-1/PD-L1 inhibitors plus CTLA-4 inhibitor could markedly improve the endpoint outcomes of patients compared with chemotherapy alone, and did not significantly increase the serious adverse reactions. Thus, it can serve as a new treatment strategy for advanced lung cancer.

Runt-related transcription factor 2 influences cell adhesion-mediated drug resistance and cell proliferation in B-cell non-Hodgkin's lymphoma and multiple myeloma.

Several lines of evidence show that RUNX2 as a transcription factor is closely involved in carcinogenesis in a variety of human cancers. Cell adhesion-mediated drug resistance (CAM-DR) is an important part of the mechanism underlying drug resistance in hematological tumors. In this study, we investigated the biological function of RUNX2 in B-cell Non-Hodgkin's lymphoma (B-NHL) and multiple myeloma (MM). We assessed the expression of RUNX2 in suspension and adhesion model by western blot in B-NHL and MM. Adhesion assay, flow cytometry and CCK-8 were utilized to examine the role and mechanism of RUNX2 in CAM-DR and proliferation in B-NHL and MM. RUNX2 was highly expressed in adherent B-NHL and MM cells compared to suspension cells, and knockdown the expression of RUNX2 could reverse CAM-DR. Besides, RUNX2 could promote the proliferation of B-NHL and MM cells. Furthermore, RUNX2 participated the process of CAM-DR and proliferation by regulating the AKT/GSK-3ß pathway. Developing RUNX2 inhibitor may be a possible strategy for drug resistance.

C­type natriuretic peptide prevents angiotensin II­induced atrial connexin 40 and 43 dysregulation by activating AMP­activated kinase signaling.

C­type natriuretic peptide (CNP), from the family of natriuretic peptides (NPs), has been shown to induce antihypertrophic and antifibrotic effects in cardiomyocytes. However, the roles of CNP in the atrial dysregulation of connexin (Cx)40 and Cx43 remain to be elucidated. The present study aimed to investigate the effects of CNP on angiotensin (Ang) II­induced Cx40 and Cx43 dysregulation in isolated perfused beating rat left atria. A rat isolated perfused beating atrial model was used and the protein levels were determined via western blotting. Ang II significantly upregulated NF­κB, activator protein­1, transforming growth factor­ß1 (TGF­ß1), collagen I and matrix metalloproteinase 2, leading to atrial fibrosis, and downregulated expression of Cx40 and Cx43. The changes in Cx40 and Cx43 induced by Ang II were abolished by CNP through upregulation of phosphorylated AMP­activated kinase a1 (AMPK) and downregulation of TGF­ß1. The effects of CNP on AMPK and TGF­ß1 levels were inhibited by KT5823 and pertussis toxin, inhibitors of protein kinase G (PKG) and NP receptor type C (NPR­C), respectively. Thus, CNP can prevent Ang II­induced dysregulation of Cx40 and Cx43 through activation of AMPK via the CNP­PKG and CNP­NPR­C pathways in isolated beating rat atria. The present findings suggested that CNP may be therapeutically useful for clinical conditions involving cardiac dysregulation of Cx expression­related diseases.

Expression of TRIM28 correlates with proliferation and Bortezomib-induced apoptosis in B-cell non-Hodgkin lymphoma.

Tripartite motif containing 28 (TRIM28) as a transcriptional co-repressor has been reported playing a role in regulating DNA damage response (DDR), cell differentiation, immune response, and tumorigenesis. The present study was performed to explore the biological function and clinical significance of TRIM28 in B-cell non-Hodgkin lymphoma (B-NHL). Results of the study displayed that high expression of TRIM28 was positively associated with the poorer survival of B-NHL patients as an independent prognostic factor. In addition, TRIM28 could promote the B-NHL cells proliferation through modulating cell cycle progression. The change of cyclinA, P21, and PCNA expression after TRIM28 expression modified further illustrated the mechanism in which TRIM28 participated in cell proliferation progression. Moreover, inhibition TRIM28 expression in B-NHL cells enhanced the sensibility to Bortezomib by regulating p53-mediated apoptosis pathway. Taken together, the present study showed that TRIM28 functions as a tumor promoter in B-NHL and may be a novel target for drug resistance to Bortezomib.

MAPK and PI3K pathways regulate hypoxia-induced atrial natriuretic peptide secretion by controlling HIF-1 alpha expression in beating rabbit atria.

Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways are pivotal and intensively studied signaling pathways in hypoxic conditions. However, the roles of MAPK and PI3K in the regulation of hypoxia-induced atrial natriuretic peptide (ANP) secretion are not well understood. The purpose of the present study was to investigate the mechanism by which the MAPK/ERK (extracellular signal-regulated kinase) and PI3K signaling pathways regulate the acute hypoxia-induced ANP secretion in isolated beating rabbit atria. An acute hypoxic perfused beating rabbit atrial model was used. The ANP levels in the atrial perfusates were measured by radioimmunoassay, and the hypoxia-inducible factor-1α (HIF-1α) mRNA and protein levels in the atrial tissue were determined by RT-PCR and Western blot. Acute hypoxia significantly increased ANP secretion and HIF-1α mRNA and protein levels. Hypoxia-induced ANP secretion was markedly attenuated by the HIF-1α inhibitors, rotenone (0.5µmol/L) and CAY10585 (10µmol/L), concomitantly with downregulation of the hypoxia-induced HIF-1α mRNA and protein levels. PD098059 (30µmol/L) and LY294002 (30µmol/L), inhibitors of MAPK and PI3K, markedly abolished the hypoxia-induced ANP secretion and atrial HIF-1α mRNA and protein levels. The hypoxia-suppressed atrial dynamics were significantly attenuated by PD098059 and LY294002. Acute hypoxia in isolated perfused beating rabbit atria, markedly increased ANP secretion through HIF-1α upregulation, which was regulated by the MAPK/ERK and PI3K pathways. ANP appears to be part of the protective program regulated by HIF-1α in the response to acute hypoxic conditions.

Ouabain stimulates atrial natriuretic peptide secretion via the endothelin-1/ET(B) receptor-mediated pathway in beating rabbit atria.

AIMS: Ouabain has been reported to increase the secretion of atrial natriuretic peptide (ANP) in vitro. However, the mechanism by which ouabain increases ANP secretion is not well known. Therefore, the purpose of the present study was to investigate the underlying mechanism of ouabain-stimulated ANP secretion. MAIN METHODS: A perfused beating rabbit atrial model was used. The ANP and ET-1 levels in the atrial perfusates were measured by radioimmunoassays. KEY FINDINGS: Ouabain (1.0, 3.0 and 6.0 µmol/L) significantly increased atrial ANP secretion in a dose-dependent manner, while the endothelin (ET)-1 levels were increased by the higher doses (3.0 and 6.0 µmol/L) of ouabain. Ouabain-increased atrial ET-1 release was blocked by PD98059 (30.0 µmol/L), an inhibitor of mitogen-activated protein kinase (MAPK). Nifedipine (1.0 µmol/L), an inhibitor of L-type Ca(2+) channels, completely abolished ouabain-increased ANP secretion without changing the ouabain-induced atrial dynamics. KB-R7943 (3.0 µmol/L), an inhibitor of Na(+)-Ca(2+) exchangers, completely blocked the effects of ouabain-increased atrial dynamics, but did not modulate ouabain-increased ANP secretion. ET-1 significantly stimulated atrial ANP release in a dose-dependent manner. The effects of ET-1 and ouabain on ANP secretion were completely blocked by BQ788 (0.3 µmol/L), an inhibitor of ET-1 type B (ET(B)) receptors, but not by BQ123 (0.3 µM), an inhibitor of ET-1 type A receptors. Ouabain-increased atrial ANP secretion was blocked by PD98059 and indomethacin (30.0 µmol/L), an inhibitor of cyclooxygenase. SIGNIFICANCE: Ouabain significantly stimulated atrial ANP secretion via an ET-1-ET(B) receptor-mediated pathway involving MAPK signaling pathway activation and prostaglandin formation.

The ethical Kampo formulation Sho-seiryu-to (TJ-19) prevents bleomycin-induced pulmonary fibrosis in rats.

The effects of Sho-seiryu-to (TJ-19), an ethical Kampo formulation, on bleomycin (BLM)-induced pulmonary fibrosis in rats was examined. Pulmonary fibrosis was induced by intratracheal instillation of a single dose of BLM (5 mg/kg). The TJ-19 used consisted of at least 21 constituents, as determined by three-dimensional HPLC analysis, and was administered orally twice a day at a dose of 1.5 g/kg until the end of the study period. Changes in general appearance and body weight were monitored. Twenty-eight days after BLM instillation, the animals were sacrificed and the study parameters were measured. TJ-19 attenuated the loss in body weight, increase in lung/body weight ratio and concentration of hydroxyproline and malondialdehyde in the lung tissues induced by BLM administration. TJ-19 also prevented BLM-induced fibrotic changes in the lung histology. These protective effects of TJ-19 were observed when administration was started 1 week before and simultaneously with the instillation of BLM. These results suggest that TJ-19 has prophylactic potential against BLM-induced pulmonary fibrosis, and may therefore be a promising drug candidate and medicinal resource for preventing BLM-induced and idiopathic pulmonary fibrosis.