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Background Helicobacter pylori infection is a well-recognized cause of gastric diseases, including chronic gastritis, peptic ulcer, and gastric cancer. Vacuolating cytotoxin-A (VacA) and cytotoxin-associated gene A protein (CagA) play a role in the pathogenesis of H. pylori-related gastric diseases. Also, extragastric disorders are frequent morbid complications in patients with H. pylori infection. However, the direct pathologic implication of these virulence factors in extragastric manifestations remains unclear. Our hypothesis in the present study is that VacA and CagA released by H. pylori in the gastric mucosa leak into the systemic circulation, and therefore they can be measured in serum. Results Sixty-two subjects were enrolled. They were allocated into the H. pylori-positive and H. pylori-negative groups. VacA and CagA were measured by immunoassays. The serum levels of VacA and CagA above an upper limit cut-off (mean plus two standard deviations of the mean in patients without H. pylori infection) were considered positive for antigen circulating level. Five out of 25 H. pylori-positive patients were positive for both serum VacA and serum CagA. The serum levels of VacA and CagA were significantly correlated with the serum levels of anti- H. pylori antibody and interleukin-12p70 among all H. pylori-positive and H. pylori-negative patients. Conclusions This study suggests that spill-over of VacA and CagA antigens in the systemic circulation may occur in some patients with H. pylori infection. Keywords: Vacuolating cytotoxin A (VacA), Cytotoxin-associated gene A (CagA), Helicobacter pylori, Cytokine, Systemic circulation, Extragastric disease, Author(s): Ichiro Imoto[sup.1], Satoko Oka[sup.1], Masaki Katsurahara[sup.3], Misaki Nakamura[sup.3], Taro Yasuma[sup.2], Junko Akada[sup.4], Corina N. D'Alessandro-Gabazza[sup.2], Masaaki Toda[sup.2], Noriyuki Horiki[sup.3], Esteban C. Gabazza[sup.2] and Yoshio Yamaoka[sup.4,5] Introduction Helicobacter pylori (H. [...]

Background The natural protoberberine jatrorrhizine (JA) is reported to have several medicinal properties and a significant effect on the gut microbiota of mice. The regulation of gut microbiota is generally known to play an important role in the intestinal mucosal immune response to ulcerative colitis (UC). However, whether JA can be used in the treatment of UC is still unclear. Our study aimed to investigate the underlying therapeutic effects and mechanisms of JA in treating colitis. Results Compared with the DSS-induced colitis model group, the JA + DSS treated group had more significant improvements in weight loss, disease activity index score, colon length shortening, and pathological inflammation. 16s rRNA sequencing analysis showed that JA treatment protected colitis mice against DSS-induced disturbance of gut microbiota. At the phylum level, reductions in Deferribacteres and Proteobacteria were observed in the JA-treated group; At the genus level, the JA-treated group showed an increased relative abundance of Akkermansia and decreased abundance of Escherichia-Shigella, Desulfovibrio, Mucispirillum, etc. Network pharmacology was then used to screen out five drug-disease target genes (NOS2, ESR1, CALM1, CALM2, CALM3). Transcriptomics analysis further validated that the NOS2 expression was significantly reduced in colon tissue of JA-administered mice compared with DSS control mice. Additionally, analysis of correlation suggested that NOS2 expression was negatively correlated with the relative abundance of AKKermansia and positively correlated with Desulfovibrio, Rikenella. Conclusion JA alleviates ulcerative colitis via regulating gut microbiota and NOS2 expression. Keywords: Jatrorrhizine, Colitis, Gut microbiota, 16s rRNA, Network pharmacology, Transcriptome sequencing, Author(s): Jia Ling Zhang[sup.1,2], Min Na Zhang[sup.2], Hong Gang Wang[sup.2], Xiao Zhong Yang[sup.2] and Cheng Gong Yu[sup.1] Introduction With the increasing incidence and prevalence of inflammatory bowel disease (IBD), IBD [...]

Three inherited autosomal dominant conditions--BRCA-related hereditary breast and ovarian cancer (HBOC), Lynch syndrome (LS) and familial hypercholesterolemia (FH)--have been termed the Centers for Disease Control and Prevention Tier 1 (CDCT1) genetic conditions, for which early identification and intervention have a meaningful potential for clinical actionability and a positive impact on public health.sup.1. In typical medical practice, genetic testing for these conditions is based on personal or family history, ethnic background or other demographic characteristics.sup.2. In this study of a cohort of 26,906 participants in the Healthy Nevada Project (HNP), we first evaluated whether population screening could efficiently identify carriers of these genetic conditions and, second, we evaluated the impact of genetic risk on health outcomes for these participants. We found a 1.33% combined carrier rate for pathogenic and likely pathogenic (P/LP) genetic variants for HBOC, LS and FH. Of these carriers, 21.9% of participants had clinically relevant disease, among whom 70% had been diagnosed with relevant disease before age 65. Moreover, 90% of the risk carriers had not been previously identified, and less than 19.8% of these had documentation in their medical records of inherited genetic disease risk, including family history. In a direct follow-up survey with all carriers, only 25.2% of individuals reported a family history of relevant disease. Our experience with the HNP suggests that genetic screening in patients could identify at-risk carriers, who would not be otherwise identified in routine care. Screening for a set of autosomal-dominant genetic conditions in a large, unselected cohort of individuals uncovers carriers who were missed by routine medical care, demonstrating the utility of broad genetic screening., Author(s): J. J. Grzymski [sup.1] [sup.2] , G. Elhanan [sup.2] , J. A. Morales Rosado [sup.3] [sup.4] , E. Smith [sup.2] , K. A. Schlauch [sup.2] , R. Read [sup.2] [...]

The monkey parasite Plasmodium knowlesi was discovered to be a common cause of malaria in humans in 2004, initially from investigations in the Kapit division of Sarawak state, Malaysian Borneo [...]

Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene.sup.1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations. Analysis of genomic data from more than 60,000 cancer samples uncovers frequent multiple driver mutations in individual oncogenes, which confer enhanced oncogenicity in combination., Author(s): Yuki Saito [sup.1] [sup.2] , Junji Koya [sup.1] , Mitsugu Araki [sup.3] , Yasunori Kogure [sup.1] , Sumito Shingaki [sup.1] , Mariko Tabata [sup.1] [sup.4] , Marni B. McClure [...]

Mycobacterium tuberculosis (M. tuberculosis) has coevolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identification of the full complement by which host immunity is inhibited. Perturbation of host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV, lymphocytic choriomeningitis virus (LCMV), and schistosomiasis to evade host immunity. Here, we evaluated the DNA methylation status of patients with tuberculosis (TB) and their asymptomatic household contacts and found that the patients with TB have DNA hypermethylation of the IL-2/STAT5, TNF/NF-[kappa]B, and IFN-[gamma] signaling pathways. We performed methylation- sensitive restriction enzyme-quantitative PCR (MSRE-qPCR) and observed that multiple genes of the IL-12/IFN-[gamma] signaling pathway (IL12B, IL12RB2, TYK2, IFNGR1, JAK1, and JAK2) were hypermethylated in patients with TB. The DNA hypermethylation of these pathways was associated with decreased immune responsiveness with decreased mitogen-induced upregulation of IFN-[gamma], TNF, IL-6, CXCL9, CXCL10, and IL-1 p production. The DNA hypermethylation of the IL-12/IFN-[gamma] pathway was associated with decreased IFN-[gamma]-induced gene expression and decreased IL-12-inducible upregulation of IFN-[gamma]. This study demonstrates that immune cells from patients with TB are characterized by DNA hypermethylation of genes critical to mycobacterial immunity resulting in decreased mycobacteria-specific and nonspecific immune responsiveness., Introduction Tuberculosis (TB) continues to be a global problem, with 10 million cases and over 1 million deaths each year (1). Anti-TB therapy (ATT) requires 6 months of antibiotics, despite [...]