MiR-130b attenuates vascular inflammation via negatively regulating tumor progression locus 2 (Tpl2) expression

Endothelial cell (EC) activation and dysfunction have been linked to a wide variety of vascular inflammatory diseases. However, the role of microRNAs in EC activation and inflammation remains largely unknown. In this study, we found that miR-130b was significantly decreased in human umbilical vein endothelial cells (HUVECs) after lipopolysaccharides (LPS) treatment. Forced expression of miR-130b inhibited the LPS-induced activation of extracellular signal-regulated kinase (ERK) and the inflammatory genes expression, such as interleukin (IL)-6 and tumor necrosis factor alpha (TNF-α). Furthermore, we identified that tumor progression locus 2 (Tpl2) is a direct target of miR-130b. Finally, in vivo overexpression of miR-130b via miR-130b agomir attenuates acute lung vascular inflammation in the LPS-induced sepsis mouse model. Taken together, our data demonstrated that miR-130b represses vascular inflammation via targeting Tpl2, suggesting that miR-130b mimics might be a promising therapeutic strategy for treatment of vascular inflammatory diseases.     

Predictive role of the overexpression for CXCR4, C-Met,and VEGF-C among breast cancer patients: A meta-analysis

BackgroundThe overexpression of CXCR4, C-Met and VEGF-C present widely in breast tumors, they may be markers of resistance to treatment. However, the studies are still controversial. Thus, this meta-analysis aims to research the relationship between the overexpression of CXCR4, C-Met, VEGF-C and clinical prognosis among breast cancer patients.MethodsPubMed and EMBASE databases were searched for eligible literature. The outcomes of interest were progression-free survival (PFS), relapse-free survival (RFS) and overall survival (OS). All tests of statistical significance were two sided.ResultsA total of 7830 patients from 28 eligible studies were assessed. The overexpression of the CXCR4 and C-Met both implied significantly worse PFS compared with normal expression [HR = 2.56, 95% CI = 1.34–4.91, P = 0.005; and HR = 1.63 95% CI = 1.20–2.22, P = 0.002]. Meanwhile, if patients had high expression of CXCR4, they would have worse OS [HR = 2.56 95% CI = 1.52–4.31, P = 0.000]. However, the overexpression of C-Met did not relate to OS for breast cancer patients [HR = 1.16, 95% CI = 0.69–1.95, P = 0.570]. Meanwhile, no statistically significant different was observed with respect to PFS and OS between VEGF-C overexpression and normal expression [HR = 0.99, 95% CI = 0.64–1.52, P = 0.968; and HR = 0.76, 95% CI = 0.43–1.33, P = 0.333].ConclusionsOur meta-analysis showed that CXCR4 and C-Met were efficient prognostic factors for breast cancer. Nevertheless, highly expressing VEGF-C was not related to progression-free survival and overall survival. Due to the small samples and insufficient date, further studies should be conducted to clarify the association between the overexpression of CXCR4 or C-Met or VEGF-C and the prognosis about breast cancer patients.     

Pronounced effect of hapten binding on thermal stability of an anti-(4-hydroxy-3-nitrophenyl)acetyl antibody possessing a glycine residue at position 95 of the heavy chain

Immune response to T-cell-dependent antigens is highly dynamic; several B-cell clones responsible for antibody production appear alternately during immunization. It was previously shown that at least two-types of antibodies are secreted after immunization with (4-hydroxy-3-nitrophenyl)acetyl (NP); one has Tyr and another has Gly at position 95 of the heavy chain (referred to as Tyr95- and Gly95-type). The former appeared at an early stage, while the latter appeared at a late stage, i.e., after secondary immunization, although Fv domains of these antibodies were encoded by same genes of variable heavy and light chains. We examined whether any biophysical properties of antigen-combing sites relate to this shift in B-cell clones by preparing single-chain Fv (scFv). Thermodynamic and kinetic parameters of the interaction of scFv with various haptens are in accordance with those of intact antibodies, indicating that scFvs are appropriate models for the study on structure and function of antibodies. Next, we measured thermal stability of scFvs using differential scanning calorimetry and found that the apparent melting temperature of free Tyr95-type was 64–66 °C,while that of Gly95-type was 47–48 °C, indicating that the latter was highly unstable. However, Gly95-type greatly gained thermal stability because of hapten binding. We discussed the relationship between thermal stability resulted by hapten binding and dynamism of antibody response during immunization.     

Carcinogenicity of acrylamide in B6C3F1 mice and F344/N rats from a 2-year drinking water exposure

Acrylamide is a component of roasted coffee and certain baked and fried carbohydrate-rich foods prepared at high temperatures. We have assessed the carcinogenicity of acrylamide in male and female B6C3F₁ mice and F344/N rats administered 0, 0.0875, 0.175, 0.35, or 0.70 mM acrylamide in the drinking water ad libitum for 2 years. Acrylamide caused significant dose-related decreasing trends in the body weights of F344/N rats. Acrylamide administration resulted in significant dose-related decreasing trends in survival in both sexes of B6C3F₁ mice and in female F344/N rats. Histopathological analyses indicated significant dose-related increases in Harderian gland and lung tumors in male and female B6C3F₁ mice. Male B6C3F₁ mice also had a significantly increased incidence of forestomach tumors, while female B6C3F₁ mice had significant dose-related increases in mammary gland, ovary, and skin tumors. In male and female F344/N rats, there were significant increases in thyroid tumors. Male F344/N rats also had significant dose-related increases in testes, heart, and pancreas tumors, while female F344 rats demonstrated significant increases in clitoral gland, mammary gland, oral cavity, and skin tumors. These results, combined with previous mechanistic studies, provide strong support for the concept that acrylamide is activated to a carcinogen through metabolism to glycidamide.     

Nucleus classification in histology images using message passing network

Identification of nuclear components in the histology landscape is an important step towards developing computational pathology tools for the profiling of tumor micro-environment. Most existing methods for the identification of such components are limited in scope due to heterogeneous nature of the nuclei. Graph-based methods offer a natural way to formulate the nucleus classification problem to incorporate both appearance and geometric locations of the nuclei. The main challenge is to define models that can handle such an unstructured domain. Current approaches focus on learning better features and then employ well-known classifiers for identifying distinct nuclear phenotypes. In contrast, we propose a message passing network that is a fully learnable framework build on classical network flow formulation. Based on physical interaction of the nuclei, a nearest neighbor graph is constructed such that the nodes represent the nuclei centroids. For each edge and node, appearance and geometric features are computed which are then used for the construction of messages utilized for diffusing contextual information to the neighboring nodes. Such an algorithm can infer global information over an entire network and predict biologically meaningful nuclear communities. We show that learning such communities improves the performance of nucleus classification task in histology images. The proposed algorithm can be used as a component in existing state-of-the-art methods resulting in improved nucleus classification performance across four different publicly available datasets.     

A trivalent vaccine candidate against hepatitis E virus,norovirus, and astrovirus

Hepatitis E virus (HEV), norovirus (NoV), and astrovirus (AstV) are enterically-transmitted viral pathogens causing epidemic or endemic hepatitis (HEV) and gastroenteritis (NoV and AstV) respectively in humans, leading to significant morbidity and mortality worldwide. While a recombinant subunit vaccine against HEVs is available in China, there is no commercial vaccine or antiviral against NoV or AstV. We report here our development of a trivalent vaccine against the three viral pathogens through our new polymer vaccine technology. All HEV, NoV, and AstV are non-enveloped RNA viruses covered by a protein capsid, featuring surface protruding (P) proteins that are responsible for virus–host interaction. These dimeric P proteins elicit neutralizing antibody and are good targets for subunit vaccine development. The trivalent subunit vaccine was developed by fusion of the dimeric P domains of the three viruses together that formed tetramers. This trivalent vaccine elicited significantly higher antibody responses in mice against all three P domains than those induced by a mixture of the three free P domains (mixed vaccine). Furthermore, the post-immune antisera of the trivalent vaccine showed significantly higher neutralizing titers against HEV infection in cell culture and higher blocking activity against NoV binding to HBGA ligands than those of the post-immune sera of the mixed vaccine. Thus, the trivalent vaccine is a promising vaccine candidate against HEV, NoV, and AstV.