ALBERT

Description: Helicobacter pylori (H. pylori) infection is strongly associated with the development of gastric diseases but also with several extragastric diseases. The clinical outcomes caused by H. pylori infection are considered to be associated with a complex combination of host susceptibility, environmental factors and bacterial isolates. Infections involving H. pylori strains that possess the virulence factor CagA have a worse clinical outcome than those involving CagA-negative strains. It is remarkable that CagA-positive H. pylori increase the risk for gastric cancer over the risk associated with H. pylori infection alone. CagA behaves as a bacterial oncoprotein playing a key role in H. pylori-induced gastric cancer. Activation of oncogenic signaling pathways and inactivation of tumor suppressor pathways are two crucial events in the development of gastric cancer. CagA shows the ability to affect the expression or function of vital protein in oncogenic or tumor suppressor signaling pathways via several molecular mechanisms, such as direct binding or interaction, phosphorylation of vital signaling proteins and methylation of tumor suppressor genes. As a result, CagA continuously dysregulates of these signaling pathways and promotes tumorigenesis. Recent research has enriched our understanding of how CagA effects on these signaling pathways. This review summarizes the results of the most relevant studies, discusses the complex molecular mechanism involved and attempts to delineate the entire signaling pathway.

Description: Background: Identification of driver mutations among numerous genomic alternations remains a critical challenge to the elucidation of the underlying mechanisms of cancer. Because driver mutations by definition are associated with a greater number of cancer phenotypes compared to other mutations, we hypothesized that driver mutations could more easily be identified once the genotype-phenotype correlations are detected across tumor samples. Results: In this study, we describe a novel network analysis to identify the driver mutation through integrating both cancer genomes and transcriptomes. Our method successfully identified a significant genotype-phenotype change correlation in all six solid tumor types and revealed core modules that contain both significantly enriched somatic mutations and aberrant expression changes specific to tumor development. Moreover, we found that the majority of these core modules contained well known cancer driver mutations, and that their mutated genes tended to occur at hub genes with central regulatory roles. In these mutated genes, the majority were cancer-type specific and exhibited a closer relationship within the same cancer type rather than across cancer types. The remaining mutated genes that exist in multiple cancer types led to two cancer type clusters, one cluster consisted of three neural derived or related cancer types, and the other cluster consisted of two adenoma cancer types. Conclusions: Our approach can successfully identify the candidate drivers from the core modules. Comprehensive network analysis on the core modules potentially provides critical insights into convergent cancer development in different organs.

Description: Background: Reduced beta2-glycoprotein I (beta2-GPI) is a free thiol-containing form of beta2-GPI that displays a powerful effect in protecting endothelial cells from oxidative stress-induced cell death. The present study aims to investigate the effect of beta2-GPI or reduced beta2-GPI on ox-LDL-induced foam cell formation and on cell apoptosis and to determine the possible mechanisms. Methods: The RAW264.7 macrophage cell line was selected as the experimental material. Oil red O staining and cholesterol measurement were used to detect cholesterol accumulation qualitatively and quantitatively, respectively. Flow cytometry was used to detect cell apoptosis. Real-time quantitative PCR was used to detect the mRNA expression of the main proteins that are associated with the transport of cholesterol, such as CD36, SRB1, ABCA1 and ABCG1. Western blot analysis was used to detect the protein expression of certain apoptosis-related proteins, such as caspase-9, caspase-3, p38 MAPK/p-p38 MAPK and JNK/p-JNK. Results: Beta2-GPI or reduced beta2-GPI decreased ox-LDL-induced cholesterol accumulation (96.45 +/- 8.51 mug/mg protein vs. 114.35 +/- 10.38 mug/mg protein, p 〈 0.05;74.44 +/- 5.27 mug/mg protein vs. 114.35 +/- 10.38 mug/mg protein, p 〈 0.01) and cell apoptosis (30.00 +/- 5.10% vs. 38.70 +/- 7.76%, p 〈 0.05; 20.66 +/- 2.50% vs. 38.70 +/- 7.76%, p 〈 0.01), and there are significant differences between beta2-GPI and reduced beta2-GPI (p 〈 0.05). Reduced beta2-GPI decreased the ox-LDL-induced expression of CD36 mRNA and ABCA1 mRNA (p 〈 0.05), as well as CD36, cleaved caspase-9, cleaved caspase-3, p-p38 MAPK and p-JNK proteins (p 〈 0.05 or p 〈 0.01). Beta2-GPI did not significantly decrease the expression of ABCA1 mRNA and the p-p38 MAPK protein. Conclusions: Both beta2-GPI and reduced beta2-GPI inhibit ox-LDL-induced foam cell formation and cell apoptosis, and the latter exhibits a stronger inhibition effect. Both of these glycoproteins reduce the lipid intake of macrophages by downregulating CD36 as well as protein expression. Reduced beta2-GPI inhibits cell apoptosis by reducing the ox-LDL-induced phosphorylation of p38 MAPK and JNK, and the amount of cleaved caspase-3 and caspase-9. Beta2-GPI does not inhibit the ox-LDL-induced phosphorylation of p38 MAPK.

Description: Background: Mycoplasma hyopneumoniae is the causative agent of porcine enzootic pneumonia (EP), a mild, chronic pneumonia of swine. Despite presenting with low direct mortality, EP is responsible for major economic losses in the pig industry. To identify the virulence-associated determinants of M. hyopneumoniae, we determined the whole genome sequence of M. hyopneumoniae strain 168 and its attenuated high-passage strain 168-L and carried out comparative genomic analyses. Results: We performed the first comprehensive analysis of M. hyopneumoniae strain 168 and its attenuated strain and made a preliminary survey of coding sequences (CDSs) that may be related to virulence. The 168-L genome has a highly similar gene content and order to that of 168, but is 4,483 bp smaller because there are 60 insertions and 43 deletions in 168-L. Besides these indels, 227 single nucleotide variations (SNVs) were identified. We further investigated the variants that affected CDSs, and compared them to reported virulence determinants. Notably, almost all of the reported virulence determinants are included in these variants affected CDSs. In addition to variations previously described in mycoplasma adhesins (P97, P102, P146, P159, P216, and LppT), cell envelope proteins (P95), cell surface antigens (P36), secreted proteins and chaperone protein (DnaK), mutations in genes related to metabolism and growth may also contribute to the attenuated virulence in 168-L. Furthermore, many mutations were located in the previously described repeat motif, which may be of primary importance for virulence. Conclusions: We studied the virulence attenuation mechanism of M. hyopneumoniae by comparative genomic analysis of virulent strain 168 and its attenuated high-passage strain 168-L. Our findings provide a preliminary survey of CDSs that may be related to virulence. While these include reported virulence-related genes, other novel virulence determinants were also detected. This new information will form the foundation of future investigations into the pathogenesis of M. hyopneumoniae and facilitate the design of new vaccines.

Description: Background: An emerging data suggested a significant impact of statins on PCSK9 concentration, while the rapid impacts of other lipid-lowering drugs such as ezetimibe and xuezhikang alone or in combination on PCSK9 and lipid profile have not been assessed. This study aims to investigate whether an enhanced PCSK9 concentration by single or combined therapy of lipid-lowering drugs currently used precedes the changes of lipid profile in rats. Methods: Sixty-three rats were randomly divided into six groups and orally administrated with placebo (N = 13), ezetimibe 10 mg/kg daily, Xuezhikang 1200 mg/kg daily, ezetimibe 10 mg/kg plus Xuezhikang 1200 mg/kg daily, pitavastatin 10 mg/kg daily or pitavastatin 10 mg/kg plus ezetimibe 10 mg/kg daily for 3 days (N = 10 for each group respectively). Blood samples were obtained at day 3 after orally administration. Plasma PCSK9 levels were determined by ELISA and lipid profile were measured by enzymatic assay. Results: Ezetimibe, Xuezhikang and pitavastatin alone and Xuezhikang plus ezetimibe as well as pitavastatin plus ezetimibe increased PCSK9 levels by 124%, 56%, 111%, 63% and 204% respectively (p 〈 0.05 compared with placebo). However, Xuezhikang plus ezetimibe did not enhance greater PCSK9 levels compared to monotherapy. Ezetimibe and pitavastatin in combination induced higher PCSK9 levels than pitavastatin monotherapy or co-therapy with ezetimibe plus Xuezhikang. There was no significant difference between any groups with regard to lipid profile levels at day 3 (P 〉 0.05). Conclusions: Elevated PCSK9 concentration by ezetimibe, Xuezhikang and pitavastatin alone or in combination was found prior to the alterations of lipid profile in rats. Combination of Xuezhikang and ezetimibe significantly attenuated increase in PCSK9 compared to ezetimibe plus pitavastatin, suggesting that the former combination may be better than the latter in future clinical application.

Description: Background: Because of the short read length of high throughput sequencing data, assembly errors are introduced in genome assembly, which may have adverse impact to the downstream data analysis. Several tools have been developed to eliminate these errors by either 1) comparing the assembled sequences with some similar reference genome, or 2) analyzing paired-end reads aligned to the assembled sequences and determining inconsistent features alone mis-assembled sequences. However, the former approach cannot distinguish real structural variations between the target genome and the reference genome while the latter approach could have many false positive detections (correctly assembled sequence being considered as mis-assembled sequence). Results: We present misFinder, a tool that aims to identify the assembly errors with high accuracy in an unbiased way and correct these errors at their mis-assembled positions to improve the assembly accuracy for downstream analysis. It combines the information of reference (or close related reference) genome and aligned paired-end reads to the assembled sequence. Assembly errors and correct assemblies corresponding to structural variations can be detected by comparing the genome reference and assembled sequence. Different types of assembly errors can then be distinguished from the mis-assembled sequence by analyzing the aligned paired-end reads using multiple features derived from coverage and consistence of insert distance to obtain high confident error calls. Conclusions: We tested the performance of misFinder on both simulated and real paired-end reads data, and misFinder gave accurate error calls with only very few miscalls. And, we further compared misFinder with QUAST and REAPR. misFinder outperformed QUAST and REAPR by 1) identified more true positive mis-assemblies with very few false positives and false negatives, and 2) distinguished the correct assemblies corresponding to structural variations from mis-assembled sequence. misFinder can be freely downloaded from https://github.com/hitbio/misFinder.

Description: Diffuse large B-cell lymphoma (DLBCL) of leukemic phase is a rare clinical manifestation, but is highly prevalent with central nervous system involvement (CNSI). Little is known about this rare clinical observ...