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Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although rigorous efforts identified the presence of ‘cancer stem cells (CSCs)’ in PDAC and molecular markers for them, stem cell dynamics in vivo have not been clearly demonstrated. Here we focused on Doublecortin-like kinase 1 (Dclk1), known as a CSC marker of PDAC. Using genetic lineage tracing with a dual-recombinase system and live imaging, we showed that Dclk1 + tumor cells continuously provided progeny cells within pancreatic intraepithelial neoplasia, primary and metastatic PDAC, and PDAC-derived spheroids in vivo and in vitro. Furthermore, genes associated with CSC and epithelial mesenchymal transition were enriched in mouse Dclk1 + and human DCLK1-high PDAC cells. Thus, we provided direct functional evidence for the stem cell activity of Dclk1 + cells in vivo, revealing the essential roles of Dclk1 + cells in expansion of pancreatic neoplasia in all progressive stages.

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.

Inactivating mutations of Arid1a, a subunit of the Switch/sucrose nonfermentable chromatin remodeling complex, have been reported in multiple human cancers. Intestinal deletion of Arid1a has been reported to induce colorectal cancer in mice; however, its functional role in intestinal homeostasis remains unclear. We investigated the functional role of Arid1a in intestinal homeostasis in mice. We found that intestinal deletion of Arid1a results in loss of intestinal stem cells (ISCs), decreased Paneth and goblet cells, disorganized crypt-villous structures, and increased apoptosis in adult mice. Spheroids did not develop from intestinal epithelial cells deficient for Arid1a. Lineage-tracing experiments revealed that Arid1a deletion in Lgr5⁺ ISCs leads to impaired self-renewal of Lgr5⁺ ISCs but does not perturb intestinal homeostasis. The Wnt signaling pathway, including Wnt agonists, receptors, and target genes, was strikingly down-regulated in Arid1a-deficient intestines. We found that Arid1a directly binds to the Sox9 promoter to support its expression. Remarkably, overexpression of Sox9 in intestinal epithelial cells abrogated the above phenotypes, although Sox9 overexpression in intestinal epithelial cells did not restore the expression levels of Wnt agonist and receptor genes. Furthermore, Sox9 overexpression permitted development of spheroids from Arid1a-deficient intestinal epithelial cells. In addition, deletion of Arid1a concomitant with Sox9 overexpression in Lgr5⁺ ISCs restores self-renewal in Arid1a-deleted Lgr5⁺ ISCs. These results indicate that Arid1a is indispensable for the maintenance of ISCs and intestinal homeostasis in mice. Mechanistically, this is mainly mediated by Sox9. Our data provide insights into the molecular mechanisms underlying maintenance of ISCs and intestinal homeostasis.

ObjectiveNardilysin (NRDC), a zinc peptidase, exhibits multiple localisation-dependent functions including as an enhancer of ectodomain shedding in the extracellular space and a transcriptional coregulator in the nucleus. In this study, we investigated its functional role in exocrine pancreatic development, homeostasis and the formation of pancreatic ductal adenocarcinoma (PDA).DesignWe analysed Ptf1a-Cre; Nrdcflox/flox mice to investigate the impact of Nrdc deletion. Pancreatic acinar cells were isolated from Nrdcflox/flox mice and infected with adenovirus expressing Cre recombinase to examine the impact of Nrdc inactivation. Global gene expression in Nrdc-cKO pancreas was analysed compared with wild-type pancreas by microarray analysis. We also analysed Ptf1a-Cre; KrasG12D; Nrdcflox/flox mice to investigate the impact of Nrdc deletion in the context of oncogenic Kras. A total of 51 human samples of pancreatic intraepithelial lesions (PanIN) and PDA were examined by immunohistochemistry for NRDC.ResultsWe found that pancreatic deletion of Nrdc leads to spontaneous chronic pancreatitis concomitant with acinar-to-ductal conversion, increased apoptosis and atrophic pancreas in mice. Acinar-to-ductal conversion was observed mainly through a non-cell autonomous mechanism, and the expression of several chemokines was significantly increased in Nrdc-null pancreatic acinar cells. Furthermore, pancreatic deletion of Nrdc dramatically accelerated KrasG12D -driven PanIN and subsequent PDA formation in mice. These data demonstrate a previously unappreciated anti-inflammatory and tumour suppressive functions of Nrdc in the pancreas in mice. Finally, absence of NRDC expression was observed in a subset of human PanIN and PDA.ConclusionNrdc inhibits pancreatitis and suppresses PDA initiation in mice.

Nonalcoholic steatohepatitis (NASH) is an inflammatory form of nonalcoholic fatty liver disease that progresses to liver cirrhosis. It is still unknown how only limited patients with fatty liver develop NASH. Tumor necrosis factor (TNF)-α is one of the key molecules in initiating the vicious circle of inflammations. Nardilysin (N-arginine dibasic convertase; Nrd1), a zinc metalloendopeptidase of the M16 family, enhances ectodomain shedding of TNF-α, resulting in the activation of inflammatory responses. In this study, we aimed to examine the role of Nrd1 in the development of NASH. Nrd1+/+ and Nrd1-/- mice were fed a control choline-supplemented amino acid-defined (CSAA) diet or a choline-deficient amino acid-defined (CDAA) diet. Fatty deposits were accumulated in the livers of both Nrd1+/+ and Nrd1-/- mice by the administration of the CSAA or CDAA diets, although the amount of liver triglyceride in Nrd1-/- mice was lower than that in Nrd1+/+ mice. Serum alanine aminotransferase levels were increased in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. mRNA expression of inflammatory cytokines were decreased in Nrd1-/- mice than in Nrd1+/+ mice fed the CDAA diet. While TNF-α protein was detected in both Nrd1+/+ and Nrd1-/- mouse livers fed the CDAA diet, secretion of TNF-α in Nrd1-/- mice was significantly less than that in Nrd1+/+ mice, indicating the decreased TNF-α shedding in Nrd1-/- mouse liver. Notably, fibrotic changes of the liver, accompanied by the increase of fibrogenic markers, were observed in Nrd1+/+ mice but not in Nrd1-/- mice fed the CDAA diet. Similar to the CDAA diet, fibrotic changes were not observed in Nrd1-/- mice fed a high-fat diet. Thus, deletion of nardilysin prevents the development of diet-induced steatohepatitis and liver fibrogenesis. Nardilysin could be an attractive target for anti-inflammatory therapy against NASH.

Background The eCura system is a widely used risk-scoring model for predicting lymph node metastasis (LNM) after non-curative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), but its external validation is limited. Recently, the W-eCura score, a modified version, was proposed. We aimed to validate the eCura system and compare its discriminatory performance with the W-eCura score. Methods A multicenter retrospective study was conducted using data from 19 Japanese institutions. The patients who underwent ESD for EGC followed by gastrectomy with lymph node dissection were included. The predictive performance of the eCura system, including calibration and discrimination, was evaluated and its discrimination was compared with the W-eCura score. Results Among 901 eligible patients, 65 cases (7.2%) showed LNM. The eCura system demonstrated good calibration, with a calibration-in-the-large of −0.008 (95% confidence interval [CI] −0.024–0.010), an observed-to-expected ratio of 0.905 (95% CI 0.707–1.121), and a calibration slope of 0.975 (95% CI 0.692–1.257). Discrimination was also good, with a C-statistic of 0.741 (95% CI 0.676–0.806). In patients evaluable for both systems, the C-statistics for the eCura system and W-eCura score were 0.745 (95% CI 0.675–0.816) and 0.750 (95% CI 0.684–0.817), respectively, showing no significant difference ( P  = 0.547). Conclusions The eCura system was validated as a reliable tool for predicting LNM following ESD in real-world clinical settings.

Background Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers. Methods We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort ( N  = 185) and a validation cohort ( N  = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort. Results The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%). Conclusions We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer.

Chronic inflammation contributes to a wide variety of human disorders. In the stomach, longstanding gastritis often results in structural alterations in the gastric mucosa, including metaplastic changes and gastric cancers. Therefore, it is important to elucidate factors that are involved in gastric inflammation. Nardilysin (N-arginine dibasic convertase; Nrdc) is a metalloendopeptidase of the M16 family that promotes ectodomain shedding of the precursor forms of various growth factors and cytokines by enhancing the protease activities of a disintegrin and metalloproteinase (ADAM) proteins. Here, we have demonstrated that Nrdc crucially regulates gastric inflammation caused by Helicobacter felis infection or forced expression of prostaglandin E 2 in K19-C2mE mice. Metaplastic changes following gastric inflammation were suppressed by the deletion of Nrdc . Furthremore, the deletion of Nrdc significantly suppressed N -methyl- N -nitrosourea (MNU)-induced gastric tumorigenesis in the murine stomach. These data may lead to a global therapeutic approach against various gastric disorders by targeting Nrdc.

The intravenous formulation for supplementing iron currently available in Japan requires frequent administration. In contrast, ferric carboxymaltose (FCM) can improve iron-deficiency anemia (IDA) with only a small number of administrations; however, its efficacy and safety have not been established in Japanese patients. In this randomized, open-label study, we verified the noninferiority of FCM to saccharated ferric oxide (SFO) in Japanese patients with IDA due to hypermenorrhea, with the mean change from baseline to the highest observed hemoglobin level as the primary endpoint. Two hundred and thirty-eight eligible subjects (119 in FCM group, 119 in SFO group) were administered the investigational medicinal product and included in the analysis. The adjusted mean change from baseline to the highest observed hemoglobin level (95% CI) was 3.90 g/dL (3.77, 4.04) in the FCM group and 4.05 g/dL (3.92, 4.19) in the SFO group, and the difference between the groups (95% CI) was − 0.15 g/dL (− 0.35, 0.04). The noninferiority of FCM was verified. Incidence of adverse events was < 60% in both groups, and no significant difference was observed between the treatment groups. These results indicate that FCM can be a new, well-tolerated, and rapid treatment option for Japanese patients with IDA.

Osteoporosis has become a worldwide public health problem, in part due to the fact that it increases the risk of fragility hip fractures (FHFs). The epidemiological assessment of FHFs is critical for their prevention; however, datasets for FHFs in Japan remain scarce. This was a multicenter, prospective, observational study in the northern district of Kyushu Island. Inclusion criteria were age > 60 years with a diagnosis of FHF and acquisition of clinical data by an electronic data capture system. Of 1294 registered patients, 1146 enrolled in the study. Nearly one third of patients (31.8%) had a history of previous fragility fractures. The percentage of patients receiving osteoporosis treatment on admission was 21.5%. Almost all patients underwent surgical treatment (99.1%), though fewer than 30% had surgery within 48 h after hospitalization. Bone mineral density (BMD) was evaluated during hospitalization in only 50.4% of patients. The rate of osteoporosis treatment increased from 21.5% on admission to 39.3% during hospitalization. The main reasons that prescribers did not administer osteoporosis treatment during hospitalization were forgetfulness (28.4%) and clinical judgment (13.6%). Age and female ratio were significantly higher in patients with previous FHFs than in those without. There was a significant difference in the rate of osteoporosis treatment or L-spine BMD values in patients with or without previous FHFs on admission. In conclusion, this study confirmed that the evaluation and treatment of osteoporosis and FHFs is still suboptimal in Japan, even in urban districts.