Search

Enhanced de novo lipogenesis mediated by sterol regulatory element-binding proteins (SREBPs) is thought to be involved in nonalcoholic steatohepatitis (NASH) pathogenesis. In this study, we assessed the impact of SREBP inhibition on NASH and liver cancer development in murine models. Unexpectedly, SREBP inhibition via deletion of the SREBP cleavage-activating protein (SCAP) in the liver exacerbated liver injury, fibrosis, and carcinogenesis despite markedly reduced hepatic steatosis. These phenotypes were ameliorated by restoring SREBP function. Transcriptome and lipidome analyses revealed that SCAP/SREBP pathway inhibition altered the fatty acid (FA) composition of phosphatidylcholines due to both impaired FA synthesis and disorganized FA incorporation into phosphatidylcholine via lysophosphatidylcholine acyltransferase 3 (LPCAT3) downregulation, which led to endoplasmic reticulum (ER) stress and hepatocyte injury. Supplementation with phosphatidylcholines significantly improved liver injury and ER stress induced by SCAP deletion. The activity of the SCAP/ SREBP/LPCAT3 axis was found to be inversely associated with liver fibrosis severity in human NASH. SREBP inhibition also cooperated with impaired autophagy to trigger liver injury. Thus, excessively strong and broad lipogenesis inhibition was counterproductive for NASH therapy; this will have important clinical implications in NASH treatment., Introduction Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic steatosis, inflammation, hepatocellular injury, and fibrosis, which lead to progression of [...]

Background and Aim: Convolutional neural network (CNN) systems that automatically detect abnormalities from small‐bowel capsule endoscopy (SBCE) images are still experimental, and no studies have directly compared the clinical usefulness of different systems. We compared endoscopist readings using an existing and a novel CNN system in a real‐world SBCE setting. Methods: Thirty‐six complete SBCE videos, including 43 abnormal lesions (18 mucosal breaks, 8 angioectasia, and 17 protruding lesions), were retrospectively prepared. Three reading processes were compared: (A) endoscopist readings without CNN screening, (B) endoscopist readings after an existing CNN screening, and (C) endoscopist readings after a novel CNN screening. Results: The mean number of small‐bowel images was 14 747 per patient. Among these images, existing and novel CNN systems automatically captured 24.3% and 9.4% of the images, respectively. In this process, both systems extracted all 43 abnormal lesions. Next, we focused on the clinical usefulness. The detection rates of abnormalities by trainee endoscopists were not significantly different across the three processes: A, 77%; B, 67%; and C, 79%. The mean reading time of the trainees was the shortest during process C (10.1 min per patient), followed by processes B (23.1 min per patient) and A (33.6 min per patient). The mean psychological stress score while reading videos (scale, 1–5) was the lowest in process C (1.8) but was not significantly different between processes B (2.8) and A (3.2). Conclusions: Our novel CNN system significantly reduced endoscopist reading time and psychological stress while maintaining the detectability of abnormalities. CNN performance directly affects clinical utility and should be carefully assessed. [ABSTRACT FROM AUTHOR]

Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. Kras activation and Pten deletion are observed in intestinal‐type gastric cancer, and Cdh1 mutation is associated with diffuse‐type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a Tff1‐Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomach, Tff1‐Cre‐mediated recombination was most evident in the pit lineage in the corpus and in entire antral glands; recombination was also observed in a few gastric chief and parietal cells. Outside the stomach, recombination was patchy throughout the intestines, and particularly frequently in the duodenum (Brunner glands), cecum, and proximal colon. In the stomachs of Tff1‐Cre;LSL‐KrasG12D mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue‐positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide‐expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Corpus‐derived organoids from Tff1‐Cre;LSL‐KrasG12D mice exhibited accelerated growth and abnormal differentiation with a loss of chief and parietal cell markers. Tff1‐Cre;Ptenflox/flox mice displayed similar changes to those seen in Tff1‐Cre;LSL‐KrasG12D mice, both with aberrant ERK activation within 3 months. In contrast, Tff1‐Cre;Cdh1flox/flox mice initially showed signet ring‐like cells that were rapidly lost with disruption of the mucosal surface, and later developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in Tff1‐Cre;Cdh1flox/flox mice was completely replaced by squamous epithelium which expanded from the forestomach. Tff1‐Cre mice offer an additional useful tool for studying gastric carcinogenesis both in vivo and in vitro. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the association between proton pump inhibitor (PPI) use and the incidence of intestinal Behçet disease (BD) in patients with BD., Methods: A retrospective cohort study was conducted at The University of Tokyo Hospital, including patients with BD diagnosed between April 2005 and November 2023. Cox models and Kaplan-Meier analyses were used to evaluate hazard ratios (HRs) and cumulative incidence of intestinal BD, respectively. Secondary analyses were performed to assess the duration and dose-response relationship of PPI use., Results: Among 194 patients with BD, 25.3% developed intestinal BD during a mean follow-up of 12 years. PPI users had a significantly higher incidence of intestinal BD compared to nonusers (adjusted HR 2.48, 95% CI 1.38-4.47, P = 0.002), with a confirmed duration/dose-dependent relationship. The cumulative incidence of intestinal BD was markedly elevated in PPI users (log-rank P < 0.001). The result was similar to that in the propensity score-matched cohort., Conclusion: This study demonstrates a significant association between PPI use and increased incidence of intestinal BD in patients with BD. Caution in prescribing PPIs for patients with BD is warranted due to the potential risk of severe complications associated with intestinal BD.

Background & Aims: Peribiliary glands (PBGs), clusters of epithelial cells residing in the submucosal compartment of extrahepatic bile ducts, have been suggested as biliary epithelial stem/progenitor cell niche; however, evidence to support this claim is limited because of a lack of PBG-specific markers. We therefore sought to identify PBG-specific markers to investigate the potential role of PBGs as stem/progenitor cell niches, as well as an origin of cancer., Methods: We examined the expression pattern of the Wnt target gene Axin2 in extrahepatic bile ducts. We then applied lineage tracing to investigate whether Axin2-expressing cells from PBGs contribute to biliary regeneration and carcinogenesis using Axin2-Cre ERT mice., Results: Wnt signaling activation, marked by Axin2, was limited to PBGs located in the periampullary region. Lineage tracing showed that Axin2-expressing periampullary PBG cells are capable of self-renewal and supplying new biliary epithelial cells (BECs) to the luminal surface. Additionally, the expression pattern of Axin2 and the mature ductal cell marker CK19 were mutually exclusive in periampullary region, and fate tracing of CK19 + luminal surface BECs showed gradual replacement by CK19 - cells, further supporting the continuous replenishment of new BECs from PBGs to the luminal surface. We also found that Wnt signal enhancer R-spondin3 secreted from Myh11-expressing stromal cells, corresponding to human sphincter of Oddi, maintained the periampullary Wnt signal-activating niche. Notably, introduction of PTEN deletion into Axin2 + PBG cells, but not CK19 + luminal surface BECs, induced ampullary carcinoma whose development was suppressed by Wnt inhibitor., Conclusion: A specific cell population receiving Wnt-activating signal in periampullary PBGs functions as biliary epithelial stem/progenitor cells and also the cellular origin of ampullary carcinoma., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

During human gastric carcinogenesis, intestinal metaplasia is frequently seen in the atrophic stomach. In mice, a distinct type of metaplasia known as spasmolytic polypeptide-expressing metaplasia (SPEM) is found in several inflammatory and genetically engineered models. Given the diversity of long- and short-term models of mouse SPEM, it remains unclear whether all models have a shared or distinct molecular mechanism. The origin of SPEM in mice is presently under debate. It is postulated that stem or progenitor cells acquire genetic alterations that then supply metaplastic cell clones, whereas the possibility of transdifferentiation or dedifferentiation from mature gastric chief cells has also been suggested. In this study, we report that loss of chief cells was sufficient to induce short-term regenerative SPEM-like lesions that originated from chief cell precursors in the gastric neck region. Furthermore, Lgr5 + mature chief cells failed to contribute to both short- and long-term metaplasia, whereas isthmus stem and progenitor cells efficiently contributed to long-term metaplasia. Interestingly, multiple administrations of high-dose pulsed tamoxifen induced expansion of Lgr5 expression and Lgr5-CreERT recombination within the isthmus progenitors apart from basal chief cells. Thus we conclude that short-term SPEM represents a regenerative process arising from neck progenitors following chief cell loss, whereas true long-term SPEM originates from isthmus progenitors. Mature gastric chief cells may be dispensable for SPEM development. NEW & NOTEWORTHY Recently, dedifferentiation ability in gastric chief cells during metaplasia development has been proposed. Our findings reveal that lesions that were thought to be acute metaplasia in fact represent normal regeneration supplied from neck lineage and that isthmus stem/progenitors are more responsible for sustained metaplastic changes. Cellular plasticity in gastric chief cells may be more limited than recently highlighted.