Isolation of mucosa-associated microbiota dysbiosis in the ascending colon in hepatitis C virus post-sustained virologic response cirrhotic patients

BackgroundAchieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients.MethodsWe collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR.ResultsIn the post-SVR group, the microbial β-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients.ConclusionIn patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon

Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple steps. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophages and monocytes and their potential roles in lung metastasis and measures to combat lung metastasis by targeting these populations

Changes of circulating tumor cells expressing CD90 and EpCAM in early-phase of atezolizumab and bevacizumab for hepatocellular carcinoma

Circulating tumor cells (CTCs) are noninvasive biomarkers that can indicate the therapeutic response and prognosis. The study aimed to investigate the cellular characteristics of CTCs focusing on monitoring during atezolizumab and bevacizumab (Atezo-Bev) therapy in patients with hepatocellular carcinoma (HCC). Peripheral blood samples were collected from 10 healthy controls and 40 patients with HCC. CTCs enriched using RosetteSep™ Human CD45 depletion cocktail were analyzed by multiparametric flow cytometry. CTC isolation was based on PanCK(+)CD45(−) cells, and CTCs exhibiting markers CD90, CD133, EpCAM, or vimentin. The total number of CTCs and the number of CTCs expressing CD90, CD133, EpCAM, and vimentin were correlated with the BCLC stage of HCC. The change in total CTC count accurately reflected the initial response to Atezo-Bev therapy. The numbers and mean fluorescence intensity of the CTC subsets expressing CD90 and EpCAM molecules decreased in patients with partial response/stable disease, and increased in patients with progressive disease and were markedly correlated with overall survival. CD90(+) and EpCAM(+) CTCs may be candidate biomarkers for the early prediction of the treatment response and the overall survival of patients with HCC receiving Atezo-Bev therapy

Lung Macrophages: Multifunctional Regulator Cells for Metastatic Cells

金沢大学がん進展制御研究所Metastasis is responsible for most of the cancer-associated deaths and proceeds through multiple steps. Several lines of evidence have established an indispensable involvement of macrophages present at the primary tumor sites in various steps of metastasis, from primary tumor growth to its intravasation into circulation. The lungs encompass a large, dense vascular area and, therefore, are vulnerable to metastasis, particularly, hematogenous ones arising from various types of neoplasms. Lung tissues constitutively contain several types of tissue-resident macrophages and circulating monocytes to counteract potentially harmful exogenous materials, which directly reach through the airway. Recent advances have provided an insight into the ontogenetic, phenotypic, and functional heterogeneity of these lung macrophage and monocyte populations, under resting and inflammatory conditions. In this review, we discuss the ontogeny, trafficking dynamics, and functions of these pulmonary macrophages and monocytes and their potential roles in lung metastasis and measures to combat lung metastasis by targeting these populations. © 2018 by the authors. Licensee MDPI, Basel, Switzerland.Acknowledgments: This work is supported partially by Research Program on the Innovative Development and Application for New Drugs for Hepatitis B (17fk0310116h0001) from the Japan Agency for Medical Research and Development (AMED) (N.M., Y.N.) and Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University (N.M., Y.N.)

Daily Usage of Proton Pump Inhibitors May Reduce the Severity of Critical Upper Gastrointestinal Bleeding in Elderly Patients

Introduction. We retrospectively examined the relationship between daily proton pump inhibitor (PPI) use and severity of upper gastrointestinal bleeding (UGIB), mainly in the elderly. Methods. We included 97 patients with nonvariceal UGIB diagnosed at our hospital from January 2012 to October 2017. Bleeding severity was assessed using the shock index (SI) and estimated bleeding volume; 49 patients met the criterion for the mild group and 48 for the moderate/severe group. The effect of PPI use on bleeding severity was compared between the groups. The relationships of PPI use and dose with the clinical symptoms of UGIB were also analyzed. Results. Among the 97 patients, 17 (17.5%) habitually used PPIs. The rate of habitual PPI use was significantly higher in the mild group, indicating as an independent factor contributing to a reduction in the severity of UGIB in a multiple logistic regression analysis (30.6% vs. 4.2%; OR 10.147; 95% CI 2.174–47.358, P<0.01). When analyzing data for a subgroup of patients older than 75 years, we found the protective PPI effect to be even higher in the mild UGIB group than in the moderate/severe group (37.0% vs. 5.6%; OR 10.000; 95% CI 1.150–86.951, P<0.05). Conversely, we found no association between PPI prescription and UGIB symptoms in patients younger than 75 years. The mean estimated bleeding volume and SI in the 17 habitual PPI users were both significantly less than those among the 80 nonhabitual users, respectively (P<0.05). The proportion of patients with mild UGIB was similar between the low- and high-dose PPI users. Conclusions. Particularly in elderly patients with nonvariceal UGIB, habitual PPI use can alleviate the clinical symptoms of UGIB by suppressing the volume of bleeding, regardless of the adapted dose of PPIs