Dendritic cells (DCs) mediate host immune responses to gut microbes and play critical roles in inflammatory bowel disease. In this study, we examined the role of TGF-β signaling in DCs in colonic ...homeostasis. CD11c-cre Tgfbr2(fl/fl) mice developed spontaneous colitis, and CD11c-cre Tgfbr2(fl/+) mice exhibited susceptibility to dextran sulfate sodium-induced colitis. Colitis in these mice was characterized by goblet cell depletion and dysbiosis caused by Enterobacteriaceae enrichment. Wild-type mice gavaged with Enterobacteriaceae from CD11c-cre Tgfbr2(fl/fl) mice feces showed severe colitis after dextran sulfate sodium treatment, whereas those treated with Notch inhibitor exhibited attenuated colonic injury with increased goblet cell numbers, thickened mucus layer, and fewer fecal Enterobacteriaceae Wild-type mice transplanted with CD11c-cre Tgfbr2(fl/fl) bone marrow developed colitis showing increased Jagged1 and Jagged2 in DCs, increased Hes1 levels in epithelium, and goblet cell depletion. These findings suggest that TGF-β signaling in DCs regulates intestinal homeostasis by modulating epithelial cell differentiation and fecal microbiota.
The prevalence of Helicobacter pylori (H. pylori) has decreased during several decades due to improvements in the sanitary environment in Japan. Consequently, a relative increase in the incidence of ...H. pylori-uninfected gastric cancer is expected. We analyzed the trends in H. pylori-uninfected gastric cancer. Two hundred fifty-eight patients with gastric cancer were retrospectively analyzed. The study was divided into four periods: 2008–2011 (first period), 2012–2014 (second period), 2015–2017 (third period), and 2018–2021 (fourth period). The status of H. pylori infection was divided into four categories: uninfected, successful eradication, spontaneous eradication, and persistent infection. Gastric mucosal atrophy was divided into six grades according to the Kimura–Takemoto classification. The proportion of H. pylori infections significantly changed over the study period (p = 0.007). In particular, the rate of H. pylori-uninfected gastric cancer tended to increase over time (0%, 2.9%, 4.9%, and 13.4% in the first, second, third, and fourth periods, respectively; p = 0.0013). The rate of no atrophy (C-0) in gastric cancer tended to increase over time (0%, 2.9%, 4.9%, and 11.0% in the first, second, third, and fourth periods, respectively; p = 0.0046). In conclusion, the rate of H. pylori-uninfected gastric cancer without gastric atrophy tended to increase over time.
Objective
The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics.
Methods
...Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver.
Results
Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver.
Conclusions
Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females.
Abstract
Intestinal crypts are maintained by long-lived intestinal stem cells (ISCs) which reside near the base of glands. Above the ISC pool, there are short-lived progenitors that can supply ...lineage-specific differentiated cell types into the villus. Notch and Wnt pathways play a key role for determining the stem/progenitor cell function and their cell fate, and regulating cancer development in the gastrointestine. Although it has been well established that ISCs are a major origin of intestinal cancer, it remains unknown whether intestinal progenitor population can give rise to cancer. We use Mist1-CreERT mice and induce Notch and Wnt activation by mating with LSL-Notch1-IC mice and/or Apc flox mice. We found that a bHLH transcriptional factor Mist1 is expressed in Paneth cells (Lysozyme+CD24high) as well as short-lived secretory progenitors (Lysozyme-CD24low) in the intestine. Mist1+ secretory progenitors are radio- and chemo-resistant, but do not show stem cell interconversion even after intestinal injury or Lgr5 ablation. However, aberrant Notch activation changes Mist1+ cells to Lgr5+ long-lived enterocyte progenitors, with loss of secretory lineage differentiation. Mist1+CD24low progenitor population can form intestinal organoids with Notch activation in vitro. Mist1+ secretory progenitors can give rise to intestinal cancer by simultaneous Notch and Wnt activation by loss of Apc gene, while loss of Apc in Mist1 lineage alone does not develop cancer. In the colon, Mist1 marks colonic secterory progenitors that become to lineage trace and can be a cancer-initiating cell after Notch activation or DSS-induced colonic injury. These results provide the clear evidence of cellular plasticity dependent on Notch signaling in the gut, and suggest short-lived progenitors as another cellular origin of cancer besides ISC pool.
Citation Format: Yoku Hayakawa, Kosuke Sakitani, Woosook Kim, Yagnesh Tailor, Karan Nagar, Kazuhiko Koike, Samuel Asfaha, Timothy C. Wang. Mist1+ secretory progenitor cells can give rise to cancer in the intestine and colon. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 912.
BACKGROUNDAccurate diagnosis of the depth of gastric cancer invasion is crucial in clinical practice. The diagnosis of gastric cancer depth is often made using endoscopic characteristics of the tumor ...and its margins; however, evaluating invasion depth based on endoscopic background gastritis remains unclear. AIMTo investigate predicting submucosal invasion using the endoscopy-based Kyoto classification of gastritis. METHODSPatients with gastric cancer detected on esophagogastroduodenoscopy at Toyoshima Endoscopy Clinic were enrolled. We analyzed the effects of patient and tumor characteristics, including age, sex, body mass index, surveillance endoscopy within 2 years, current Helicobacter pylori infection, the Kyoto classification, and Lauren's tumor type, on submucosal tumor invasion and curative endoscopic resection. The Kyoto classification included atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness. Atrophy was characterized by non-reddish and low mucosa. Intestinal metaplasia was detected as patchy whitish or grayish-white flat elevations, forming an irregular uneven surface. An enlarged fold referred to a fold width ≥ 5 mm in the greater curvature of the corpus. Nodularity was characterized by goosebump-like multiple nodules in the antrum. Diffuse redness was characterized by uniform reddish non-atrophic mucosa in the greater curvature of the corpus. RESULTSA total of 266 gastric cancer patients (mean age, 66.7 years; male sex, 58.6%; mean body mass index, 22.8 kg/m2) were enrolled. Ninety-three patients underwent esophagogastroduodenoscopy for surveillance within 2 years, and 140 had current Helicobacter pylori infection. The mean Kyoto score was 4.54. Fifty-eight cancers were diffuse-type, and 87 cancers had invaded the submucosa. Multivariate analysis revealed that low body mass index (odds ratio 0.88, P = 0.02), no surveillance esophagogastroduodenoscopy within 2 years (odds ratio 0.15, P < 0.001), endoscopic enlarged folds of gastritis (odds ratio 3.39, P = 0.001), and Lauren's diffuse-type (odds ratio 5.09, P < 0.001) were independently associated with submucosal invasion. Similar results were obtained with curative endoscopic resection. Among cancer patients with enlarged folds, severely enlarged folds (width ≥ 10 mm) were more related to submucosal invasion than mildly enlarged folds (width 5-9 mm, P < 0.001). CONCLUSIONEnlarged folds of gastritis were associated with submucosal invasion. Endoscopic observation of background gastritis as well as the lesion itself may help diagnose the depth of cancer invasion.
PDF
