HCV core protein inhibits polarization and activity of both M1 and M2 macrophages through the TLR2 signaling pathway

Hepatitis C virus (HCV) establishes persistent infection in most infected patients, and eventually causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma in some patients. Monocytes and macrophages provide the first line of defense against pathogens, but their roles in HCV infection remains unclear. We have reported that HCV core protein (HCVc) manipulates human blood-derived dendritic cell development. In the present study, we tested whether HCVc affects human blood-derived monocyte differentiating into macrophages. Results showed that HCVc inhibits monocyte differentiation to either M1 or M2 macrophages through TLR2, associated with impaired STATs signaling pathway. Moreover, HCVc inhibits phagocytosis activity of M1 and M2 macrophages, M1 macrophage-induced autologous and allogeneic CD4+ T cell activation, but promotes M2 macrophage-induced autologous and allogeneic CD4+ T cell activation. In conclusion, HCVc inhibits monocyte-derived macrophage polarization via TLR2 signaling, leading to dysfunctions of both M1 and M2 macrophages in chronic HCV infected patients. This may contribute to the mechanism of HCV persistent infection, and suggest that blockade of HCVc might be a novel therapeutic approach to treating HCV infection

Extracting Credible Dependencies for Averaged One-Dependence Estimator Analysis

Of the numerous proposals to improve the accuracy of naive Bayes (NB) by weakening the conditional independence assumption, averaged one-dependence estimator (AODE) demonstrates remarkable zero-one loss performance. However, indiscriminate superparent attributes will bring both considerable computational cost and negative effect on classification accuracy. In this paper, to extract the most credible dependencies we present a new type of seminaive Bayesian operation, which selects superparent attributes by building maximum weighted spanning tree and removes highly correlated children attributes by functional dependency and canonical cover analysis. Our extensive experimental comparison on UCI data sets shows that this operation efficiently identifies possible superparent attributes at training time and eliminates redundant children attributes at classification time

Synergistic antitumor effects of endostar in combination with oxaliplatin via inhibition of HIF and CXCR4 in the colorectal cell line SW1116.

Combination treatment with endostar, a novel modified endostatin, and cytotoxic chemotherapies showed a survival benefit in Chinese clinical trials. However, the exact mechanism for this synergism remains unclear. In this study, we report for the first time that the chemokine receptor CXCR4 and the hypoxia-inducible transcription factors (HIF)-1α and HIF-2α are involved in these synergistic antitumor effects in human colorectal cancer SW1116 cells in vitro when endostar treatment is combined with the cytotoxic drug oxaliplatin. Under normoxia, we demonstrate that endostar and oxaliplatin treatments synergize to inhibit SW1116 cell proliferation, Matrigel adhesion and invasion by reduction of CXCR4 expression. Consistently, these antitumor abilities of endostar and oxaliplatin were markedly reduced by silencing of CXCR4 in SW1116 cells. Under low oxygen conditions (hypoxia, 1% oxygen), enhanced proliferation of SW1116 cells exposed to oxaliplatin was observed due to the emergence of drug resistance. Strikingly, endostar overcame oxaliplatin-resistance, most likely as a consequence of reduced HIF-2α and CXCR4 levels. CXCR4, is only dependent on HIF-2α, which promotes more aggressive phenotype and more significant for oxaliplatin resistance in SW1116 cells. Our data not only provide clues to aid understanding of the mechanism of the synergism of endostar and chemotherapy under either normoxia or hypoxia, but also suggests a new strategy of combination endostar and chemotherapy treatments which might potentiate therapeutic efficacies and/or counteract chemotherapy resistance

National Clinical Skills Competition: an effective simulation-based method to improve undergraduate medical education in China

Background: The National Clinical Skills Competition has been held in China for 5 consecutive years since 2010 to promote undergraduate education reform and improve the teaching quality. The effects of the simulation-based competition will be analyzed in this study. Methods: Participation in the competitions and the compilation of the questions used in the competition finals are summarized, and the influence and guidance quality are further analyzed. Through the nationwide distribution of questionnaires in medical colleges, the effects of the simulation-based competition on promoting undergraduate medical education reform were evaluated. Results: The results show that approximately 450 students from more than 110 colleges (accounting for 81% of colleges providing undergraduate clinical medical education in China) participated in the competition each year. The knowledge, skills, and attitudes were comprehensively evaluated by simulation-based assessment. Eight hundred and eighty copies of the questionnaires were distributed to 110 participating medical schools in 2015. In total, 752 valid responses were received across 95 schools. The majority of the interviewees agreed or strongly agreed that competition promoted the adoption of advanced educational principles (76.8%), updated the curriculum model and instructional methods (79.8%), strengthened faculty development (84.0%), improved educational resources (82.1%), and benefited all students (53.4%). Conclusions: The National Clinical Skills Competition is widely accepted in China. It has effectively promoted the reform and development of undergraduate medical education in China

Anti-Tumor Effects of an Oncolytic Adenovirus Expressing Hemagglutinin-Neuraminidase of Newcastle Disease Virus in Vitro and in Vivo

Oncolytic virotherapy has been an attractive drug platform for targeted therapy of cancer over the past few years. Viral vectors can be used to target and lyse cancer cells, but achieving good efficacy and specificity with this treatment approach is a major challenge. Here, we assessed the ability of a novel dual-specific anti-tumor oncolytic adenovirus, expressing the hemagglutinin-neuraminidase (HN) gene from the Newcastle disease virus under the human telomerase reverse transcriptase (hTERT) promoter (Ad-hTERTp-E1a-HN), to inhibit esophageal cancer EC-109 cells in culture and to reduce tumor burden in xenografted BALB/c nude mice. In vitro, infection with Ad-hTERT-E1a-HN could inhibit the growth of EC-109 cells significantly and also protect normal human liver cell line L02 from growth suppression in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Ad-hTERT-E1a-HN also effectively and selectively decreased the sialic acid level on EC-109 cells, but not on L02 cells. Furthermore, Ad-hTERT-E1a-HN was shown to induce the apoptosis pathway via acridine orange and ethidium bromide staining (AO/EB staining), increase reactive oxygen species (ROS), reduce mitochondrial membrane potential and release cytochrome c. In vivo, xenografted BALB/c nude mice were treated via intratumoral or intravenous injections of Ad-hTERT-E1a-HN. Although both treatments showed an obvious suppression in tumor volume, only Ad-hTERT-E1a-HN delivered via intratumoral injection elicited a complete response to treatment. These results reinforced previous findings and highlighted the potential therapeutic application of Ad-hTERT-E1a-HN for treatment of esophageal cancer in clinical trials

CXCR4 is hypoxia inducible, but only the target gene of HIF-2α.

<p>(<b>A</b>) Western blots of whole cell lysates for HIF-1α, HIF-2α and CXCR4 expression under hypoxic condition, demonstrating hypoxia increases CXCR4 abundance. (<b>B</b>) Western blots of SW1116 cells expressing shHIF-1α and shHIF-2α. The cells were treated with 1 mM DMOG for 4 h. Proliferation (<b>C</b>) and Matrigel invasion assay (<b>D</b>) were conducted in hypoxia. **<i>p</i><0.01/***<i>p</i><0.001 versus control; ⁺<i>p</i><0.05/⁺⁺<i>p</i><0.01 versus HIF-1α control, demonstrating both HIF-1α and HIF-2α contribute to SW1116 cells survival and invasion, whereas HIF-2α inhibited proliferation and invasion to a greater extent than HIF-1α.</p