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The coronary artery calcification (CAC) is clinically considered as one of the important predictors of atherosclerosis. Several studies have confirmed that endothelin-1(ET-1) plays an important role in the process of atherosclerosis formation. The aim of this study was to investigate whether big ET-1 is associated with CAC.A total of 510 consecutively admitted patients from February 2011 to May 2012 in Fu Wai Hospital were analyzed. All patients had received coronary computed tomography angiography and then divided into two groups based on the results of coronary artery calcium score (CACS). The clinical characteristics including traditional and calcification-related risk factors were collected and plasma big ET-1 level was measured by ELISA. Patients with CAC had significantly elevated big ET-1 level compared with those without CAC (0.5 ± 0.4 vs. 0.2 ± 0.2, P0 and the highest tertile of big ET-1 (P

BACKGROUND: Both coronary artery disease (CAD) and diabetes mellitus (DM) are associated with inflammation. However, whether and which leukocytes can predict the presence and extent of CAD in patients with DM has not been investigated. The aim of the present study was to examine the association of leukocyte and its subsets counts with the severity of CAD in patients with DM. METHODS AND FINDINGS: Three hundred and seventy-three diabetic patients who were scheduled for coronary angiography due to typical stable angina pectoris were enrolled in this study. They were classified into the three groups according to tertiles of Gensini score (GS, low group 28, n=121). The relationship between the leukocyte and its subsets counts with the severity of CAD were evaluated. The data indicated that there were significant correlations between leukocyte and neutrophil counts with GS (r=0.154 and 0.156, respectively, all P28 points) was 5.0 × 10(9) cells/L in diabetic patients.

The association of B7-1/CD28 between antigen presenting cells (APCs) and T-cells provides a second signal to proliferate and activate T-cell immunity at the induction phase. Many reports indicate that tumor cells transfected with B7-1 induced augmented antitumor immunity at the induction phase by mimicking APC function; however, the function of B7-1 on antitumor immunity at the effector phase is unknown. Here, we report direct evidence of enhanced T-cell antitumor immunity at the effector phase by the B7-1 molecule. Our experiments in vivo and in vitro indicated that reactivity of antigen-specific monoclonal and polyclonal T-cell effectors against a Lass5 epitope presented by RMA-S cells is increased when the cells expressed B7-1. Use of either anti-B7-1 or anti-CD28 antibodies to block the B7-1/CD28 association reduced reactivity of the T effectors against B7-1 positive RMA-S cells. Transfection of Lass5 cDNA into or pulse of Lass5 peptide onto B7-1 positive RMA-S cells overcomes the requirement of the B7-1/CD28 signal for T effector response. To our knowledge, the data offers, for the first time, strong evidence that supports the requirement of B7-1/CD28 secondary signal at the effector phase of antitumor T-cell immunity being dependent on the density of an antigenic peptide.

BACKGROUND: Glycated hemoglobin (HbA1c) predicts clinical cardiovascular disease or cardiovascular mortality. However, the relationship between HbA1c and myocardial injury following elective percutaneous coronary intervention (PCI) in patients with type 2 diabetes mellitus (DM) has not been investigated. OBJECTIVES: The study sought to assess the relationship between HbA1c and myocardial injury following elective PCI in patients with type 2 DM. METHODS: We studied a cohort of consecutive 994 diabetic patients with coronary artery disease (CAD) undergoing elective PCI. Periprocedural myocardial injury was evaluated by analysis of troponin I (cTnI). The association between preprocedural HbA1c levels and the peak values of cTnI within 24 hours after PCI was evaluated. RESULTS: Peak postprocedural cTnI > 1×upper limit of normal (ULN), >3×ULN and >5×ULN were detected in 543 (54.6%), 337 (33.9%) and 245 (24.6%) respectively. In the multivariate model, higher HbA1c levels were associated with less risk of postprocedural cTnI >1×ULN (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76-0.95; P = 0.005). There was a trend that higher HbA1c levels were associated with less risk of postprocedural cTnI >3×ULN (OR, 0.90; 95% CI, 0.81-1.02; P = 0.088). HbA1c was not associated with the risk of postprocedural cTnI elevation above 5×ULN (OR, 0.95; 95% CI, 0.84-1.08; P = 0.411). CONCLUSIONS: The present study provided the first line of evidence that higher preprocedural HbA1c levels were associated with less risk of myocardial injury following elective PCI in diabetic patients.

Human prostate tumor vaccine and gene therapy trials using ex vivo methods to prime dendritic cells (DCs) with prostate specific membrane antigen (PSMA) have been somewhat successful, but to date the lengthy ex vivo manipulation of DCs has limited the widespread clinical utility of this approach. Our goal was to improve upon cancer vaccination with tumor antigens by delivering PSMA via a CD40-targeted adenovirus vector directly to DCs as an efficient means for activation and antigen presentation to T-cells. To test this approach, we developed a mouse model of prostate cancer by generating clonal derivatives of the mouse RM-1 prostate cancer cell line expressing human PSMA (RM-1-PSMA cells). To maximize antigen presentation in target cells, both MHC class I and TAP protein expression was induced in RM-1 cells by transduction with an Ad vector expressing interferon-gamma (Ad5-IFNγ). Administering DCs infected ex vivo with CD40-targeted Ad5-huPSMA, as well as direct intraperitoneal injection of the vector, resulted in high levels of tumor-specific CTL responses against RM-1-PSMA cells pretreated with Ad5-IFNγ as target cells. CD40 targeting significantly improved the therapeutic antitumor efficacy of Ad5-huPSMA encoding PSMA when combined with Ad5-IFNγ in the RM-1-PSMA model. These results suggest that a CD-targeted adenovirus delivering PSMA may be effective clinically for prostate cancer immunotherapy.

OBJECTIVE: The G-403A polymorphism in RANTES gene may be involved in the development of coronary artery disease (CAD) through increasing RANTES-mediated leukocyte trafficking and activation. However, studies investigating the relationship between G-403A polymorphism and CAD yielded contradictory and inconclusive results. In order to shed some light on these inconsistent findings, a meta analysis was performed to clarify the role of G-403A polymorphism of RANTES gene in the susceptibility of CAD. METHODS: A systemic literature search of PubMed and EMBASE was conducted from their inception to March 23, 2012, to retrieve related studies. In addition, Conference Proceedings Citation Index-Science was searched, authors of relevant studies were contacted, and reference lists of the included studies and their related citations in PubMed were reviewed for additional pertinent studies. RESULTS: A total of 8 eligible studies were identified, with a total of 4252 CAD cases and 2150 controls. There was no evidence of significant association between G-403A polymorphism and CAD risk in any genetic model or pairwise comparisons (additive model: OR = 1.046, 95% CI = 0.883-1.239, I(2) = 65.9%; recessive model: OR = 1.140, 95% CI = 0.774-1.678, I(2) = 53.1%; dominant model: OR = 1.000, 95% CI = 0.820-1.21), I(2) = 62.6%; AA vs GG: OR = 1.141, 95% CI = 0.734-1.773, I(2) = 61.2%; GA vs GG: OR = 0.993, 95% CI = 0.800-1.232, I(2) = 64.6%). Subgroup analysis and meta regression indicated that ethnicity and genotyping method accounted for the significant heterogeneity among studies. In the stratified analysis by ethnic group, G-403A polymorphism was found to be associated with increased CAD risk in Caucasian population whereas its protective role was observed in Asian population in some but not all comparisons. CONCLUSION: Data from the current meta-analysis do not support the existence of a relationship between G-403A polymorphism and the development of CAD, and large sample size study employing unified genotyping method is needed to further evaluate the influence of G-403A polymorphism on susceptibility of CAD.

Tumors deficient in expression of the transporter associated with antigen processing (TAP) usually fail to induce T-cell-mediated immunity and are resistant to T-cell lysis. However, we have found that introduction of the B7.1 gene into TAP-negative (TAP(-)) or TAP1-transfected (TAP1(+)) murine lung carcinoma CMT.64 cells can augment the capacity of the cells to induce a protective immune response against wild-type tumor cells. Differences in the strength of the protective immune responses were observed between TAP(-) and TAP1(+) B7.1 expressing CMT.64 cells depending on the doses of gamma-irradiated cell immunization. While mice immunized with either high or low dose of B7.1-expressing TAP1(+) cells rejected TAP(-) tumors, only high dose immunization with B7.1-expressing TAP(-) cells resulted in tumor rejection. The induced protective immunity was T-cell dependent as demonstrated by dramatically reduced antitumor immunity in mice depleted of CD8 or CD4 cells. Augmentation of T-cell mediated immune response against TAP(-) tumor cells was also observed in a virally infected tumor cell system. When mice were immunized with a high dose of gamma-irradiated CMT.64 cells infected with vaccinia viruses carrying B7.1 and/or TAP1 genes, we found that the cells co-expressing B7.1 and TAP1, but not those expressing B7.1 alone, induced protective immunity against CMT.64 cells. In addition, inoculation with live tumor cells transfected with several different gene(s) revealed that only B7.1- and TAP1-coexpressing tumor cells significantly decreased tumorigenicity. These results indicate that B7.1-provoked antitumor immunity against TAP(-) cancer is facilitated by TAP1-expression, and thus both genes should be considered for cancer therapy in the future.

The transporter associated with antigen processing (TAP) and the major histocompatibility complex class I (MHC-I), two important components of the MHC-I antigen presentation pathway, are often deficient in tumor cells. The restoration of their expression has been shown to restore the antigenicity and immunogenicity of tumor cells. However, it is unclear whether TAP and MHC-I expression in tumor cells can affect the induction phase of the T cell response. To address this issue, we expressed viral antigens in tumors that are either deficient or proficient in TAP and MHC-I expression. The relative efficiency of direct immunization or immunization through cross-presentation in promoting adaptive T cell responses was compared. The results demonstrated that stimulation of animals with TAP and MHC-I proficient tumor cells generated antigen specific T cells with greater killing activities than those of TAP and MHC-I deficient tumor cells. This discrepancy was traced to differences in the ability of dendritic cells (DCs) to access and sample different antigen reservoirs in TAP and MHC-I proficient versus deficient cells and thereby stimulate adaptive immune responses through the process of cross-presentation. In addition, our data suggest that the increased activity of T cells is caused by the enhanced DC uptake and utilization of MHC-I/peptide complexes from the proficient cells as an additional source of processed antigen. Furthermore, we demonstrate that immune-escape and metastasis are promoted in the absence of this DC 'arming' mechanism. Physiologically, this novel form of DC antigen sampling resembles trogocytosis, and acts to enhance T cell priming and increase the efficacy of adaptive immune responses against tumors and infectious pathogens.

Regorafenib is an oral small-molecule multi kinase inhibitor. Recently, several clinical trials have revealed that regorafenib has an anti-tumor activity in gastric cancer. However, only part of patients benefit from regorafenib, and the mechanisms of regorafenib's anti-tumor effect need further demonstrating. In this study, we would assess the potential anti-tumor effects and the underlying mechanisms of regorafenib in gastric cancer cells, and explore novel biomarkers for patients selecting of regorafenib.The anti-tumor effects of regorafenib on gastric cancer cells were analyzed via cell proliferation and invasion. The underlying mechanisms were demonstrated using molecular biology techniques.We found that regorafenib inhibited cell proliferation and invasion at the concentration of 20μmol/L and in a dose dependent manner. The anti-tumor effects of regorafenib related to the decreased expression of CXCR4, and elevated expression and activation of CXCR4 could reverse the inhibition effect of regorafenib on gastric cancer cells. Further studies revealed that regorafenib reduced the transcriptional activity of Wnt/β-Catenin pathway and led to decreased expression of Wnt pathway target genes, while overexpression and activation of CXCR4 could attenuate the inhibition effect of regorafenib on Wnt/β-Catenin pathway.Our findings demonstrated that regorafenib effectively inhibited cell proliferation and invasion of gastric cancer cells via decreasing the expression of CXCR4 and further reducing the transcriptional activity of Wnt/β-Catenin pathway.

Metastasis of tumor cells occurs through lymphatic vessels, blood vessels and transcoelomic spreading. Growing evidence from in vivo and in vitro studies has indicated that tumor lymphangiogenesis facilitates metastasis. However, the regulation of lymphangiogenesis in colon cancer remains unclear. The aims of this study were to identify key miRNAs in colon cancer lymphangiogenesis and to investigate its target and mechanism.miRNA microarray analysis was conducted to identify miRNAs in human lymphatic endothelial cells (HLECs) that were regulated by co-cultured human colon cancer cells. Gain- and loss-of-function studies were performed to determine the function of miR-27a, a top hint, on lymphangiogenesis and migration in HLECs. Furthermore, bioinformatics prediction and experimental validation were performed to identify miR-27a target genes in lymphangiogenesis.We found that expression of miR-27a in HLECs was induced by co-culturing with colon cancer cells. Over-expression of miR-27a in HLECs enhanced lymphatic tube formation and migration, whereas inhibition of miR-27a reduced lymphatic tube formation and migration. Luciferase reporter assays showed that miR-27a directly targeted SMAD4, a pivotal component of the TGF-β pathway. In addition, gain-of-function and loss-of-function experiments showed that SMAD4 negatively regulated the length of lymphatic vessels formed by HLECs and migration.Our data indicated that colon cancer cell induced the expression of miR-27a in HLECs, which promoted lymphangiogenesis by targeting SMAD4. Our finding implicated miR-27a as a potential target for new anticancer therapies in colon cancer.

Prunus is an economically important genus well-known for cherries, plums, almonds, and peaches. The genus can be divided into three major groups based on inflorescence structure and ploidy levels: (1) the diploid solitary-flower group (subg. Prunus, Amygdalus and Emplectocladus); (2) the diploid corymbose group (subg. Cerasus); and (3) the polyploid racemose group (subg. Padus, subg. Laurocerasus, and the Maddenia group). The plastid phylogeny suggests three major clades within Prunus: Prunus-Amygdalus-Emplectocladus, Cerasus, and Laurocerasus-Padus-Maddenia, while nuclear ITS trees resolve Laurocerasus-Padus-Maddenia as a paraphyletic group. In this study, we employed sequences of the nuclear loci At103, ITS and s6pdh to explore the origins and evolution of the racemose group. Two copies of the At103 gene were identified in Prunus. One copy is found in Prunus species with solitary and corymbose inflorescences as well as those with racemose inflorescences, while the second copy (II) is present only in taxa with racemose inflorescences. The copy I sequences suggest that all racemose species form a paraphyletic group composed of four clades, each of which is definable by morphology and geography. The tree from the combined At103 and ITS sequences and the tree based on the single gene s6pdh had similar general topologies to the tree based on the copy I sequences of At103, with the combined At103-ITS tree showing stronger support in most clades. The nuclear At103, ITS and s6pdh data in conjunction with the plastid data are consistent with the hypothesis that multiple independent allopolyploidy events contributed to the origins of the racemose group. A widespread species or lineage may have served as the maternal parent for multiple hybridizations involving several paternal lineages. This hypothesis of the complex evolutionary history of the racemose group in Prunus reflects a major step forward in our understanding of diversification of the genus and has important implications for the interpretation of its phylogeny, evolution, and classification.

The loss of microRNA-122 (miR-122) expression is strongly associated with increased invasion and metastasis, and poor prognosis of hepatocellular carcinoma (HCC), however, the underlying mechanisms remain poorly understood. In the present study, we observed that miR-122 over-expression in HCC cell lines Sk-hep-1 and Bel-7402 triggered the mesenchymal-epithelial transition (MET), as demonstrated by epithelial-like morphological changes, up-regulated epithelial proteins (E-cadherin, ZO-1, α-catenin, occludin, BVES, and MST4), and down-regulated mesenchymal proteins (vimentin and fibronectin). The over-expression of miRNA-122 also caused cytoskeleton disruption, RhoA/Rock pathway inactivation, enhanced cell adhesion, and suppression of migration and invasion of Sk-hep-1 and Bel-7402 cells, whereas, these effects could be reversed through miR-122 inhibition. Additional studies demonstrated that the inhibition of wild-type RhoA function induced MET and inhibited cell migration and invasion, while RhoA over-expression reversed miR-122-induced MET and inhibition of migration and invasion of HCC cells, suggesting that miR-122 induced MET and suppressed the migration and invasion of HCC cells by targeting RhoA. Moreover, our results demonstrated that HNF4α up-regulated its target gene miR-122 that subsequently induced MET and inhibited cell migration and invasion, whereas miR-122 inhibition reversed these HNF4α-induced phenotypes. These results revealed functional and mechanistic links among the tumor suppressors HNF4α, miR-122, and RhoA in EMT and invasive and metastatic phenotypes of HCC. Taken together, our study provides the first evidence that the HNF4α/miR-122/RhoA axis negatively regulates EMT and the migration and invasion of HCC cells.

BACKGROUND: Osteosarcoma is the most common primary bone cancer in growing adolescents and young adults. The prognostic role of C-reactive protein (CRP) in patients with osteosarcoma is not fully investigated. The purpose of this study is to perform a meta-analysis and literature review on the role of CRP in osteosarcoma and to assess the potential role of serum CRP as a prognostic factor for patients with osteosarcoma. METHODS: A detailed literature search was made in Medline for related research publications written in English. Methodological quality of the studies was also evaluated. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, risk ratio (RR) and corresponding confidence intervals (CIs) were calculated and summarized respectively. RESULTS: Final analysis of 397 patients from 2 eligible studies was performed. Combined RR of CRP expression suggested that the raised serum CRP level had an adverse prognostic effect on overall survival of patients with osteosarcoma (n = 397 in 2 studies; RR = 0.35; 95% CI: 0.18-0.68; p = 0.002). In the uni- and multivariate survival analysis, response rate and CRP levels were the only independent prognostic variables. CONCLUSIONS: The results of this meta-analysis suggest that CRP expression confers a worse prognosis in patients with osteosarcoma. Large prospective studies are necessary to provide solid data to confirm the prognostic significance of CRP.