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Background: There has been great progress in the use of endoscopic ultrasound (EUS)-guided drainage in acute pancreatitis patients using a novel lumen-apposing metal stent (LAMS) in the last decade, but some patients experience bleeding. Our research analyzed the preprocedural risk factors for bleeding. Methods: From July 13, 2016 to June 23, 2021, we retrospectively analyzed all patients who received endoscopic drainage by the LAMS in our hospital. Univariate and multivariate statistical analyses were used to identify the independent risk factors. We plotted ROC curves based on the independent risk factors. Results: A total of 205 patients were analyzed and 5 patients were excluded. A total of 200 patients were included in our research. Thirty (15%) patients presented with bleeding. In the multivariate analysis, computed tomography severity index score (CTSI) score [odds ratio (OR), 2.66; 95% CI: 1.31–5.38; P= 0.007], positive blood cultures [odds ratio (OR), 5.35; 95% CI: 1.31–21.9; P= 0.02], and Acute Physiology and Chronic Health Evaluation II (APACHE II) score [odds ratio (OR), 1.14; 95% CI: 1. 01–1.29; P= 0.045] were associated with bleeding. The area under the ROC curve of the combined predictive indicator was 0.79. Conclusion: Bleeding in endoscopic drainage by the LAMS is significantly associated with the CTSI score, positive blood cultures, and APACHE II score. This result could help clinicians make more appropriate choices.

Background: The goal of this study was to compare the efficacy and safety of needle-knife fistulotomy (NKF) to that of conventional cannulation methods (CCMs) when used for primary biliary access in patients with duodenal papillary tumors. Methods: Consecutive patients who had duodenal papillary tumors and who underwent endoscopic retrograde cholangiopancreatography (ERCP) were retrospectively enrolled. Successful cannulation rates, cannulation and procedure times, and the prevalence of adverse events were compared between the NKF and CCM groups. Results: A total of 404 patients (NKF, n= 124; CCM, n= 280) with duodenal papillary tumors were included. The primary and overall cannulation rates were 92.1% (372/404) and 96.0% (388/404), respectively. Compared to CCMs, NKF was associated with a significantly higher successful cannulation rate (99.2% versus 88.9%, P< 0.001) and significantly lower cannulation times (2.1 ± 2.0 min versus 4.7 ± 5.2 min), procedure times (8.8 ± 3.8 min versus 12.9 ± 7.6 min), and unintentional pancreatic duct cannulation rates (1.6% versus 20%), with P< 0.001 for all. Overall adverse events occurred less frequently in the NKF group (3.2% versus 10.7%, P= 0.011). Of these adverse events, post-ERCP pancreatitis (PEP) was significantly lower in the NKF group than in the CCM group (1.6% versus 6.8%, P= 0.03). Bleeding and cholangitis rarely occurred with either cannulation method (0.8% versus 2.1%, P= 0.681, and 0.8% versus 1.7%, P= 0.671, respectively). Conclusion: NKF is a more effective and safer procedure than CCMs for patients with duodenal papillary tumors.

ABSTRACTEarly dysbiosis of the gut microbiota is associated with the severity of acute pancreatitis (AP), although the underlying mechanism is unclear. Here, we investigated the role of crosstalk between NLRP3 and the gut microbiota in the development of AP utilizing gut microbiota deficient mice, as well as NLRP3 knockout (KO) mouse models. Pancreatic damage and systemic inflammation were improved in antibiotic-treated (Abx) and germ-free (GF) mice, accompanied by weakened activity of the intestinal NLRP3 inflammasome. Interestingly, fecal microbiota transplantation (FMT) reactivated the intestinal NLRP3 inflammasome and exacerbated the disease in Abx and GF mice. Although the gut barrier in GF and Abx mice was disrupted, gut microbiota deficiency ameliorated the severity of AP, probably due to the reduction in bacterial translocation from the gut to the pancreas. The composition of the gut microbiota was significantly different between NLRP3 KO mice and wild-type (WT) mice at baseline, and there were alterations in response to the induction of AP. While a dramatic shift in the gut microbiota with overgrowth of Escherichia-Shigellawas observed in WT mice suffering from AP, there was no significant change in NLRP3 KO mice with or without AP, suggesting that NLRP3 deficiency counteracts AP-induced microbial disturbance. With a strengthened gut barrier and decreased systemic inflammation, NLRP3 KO mice showed less severe AP, as revealed by reduced pancreatic neutrophilic infiltration and necrosis. Taken together, these results identified the bidirectional modulation between the gut microbiota and NLRP3 in the progression of AP, which suggests the interplay of the host and microbiome during AP.

ABSTRACTHelicobacter pylori (H. pylori) infection is the strongest known risk factor for the development of gastric cancer. DNA damage response (DDR) and autophagy play key roles in tumorigenic transformation. However, it remains unclear how H. pylorimodulate DDR and autophagy in gastric carcinogenesis. Here we report that H. pyloriinfection promotes DNA damage via suppression of Rad51 expression through inhibition of autophagy and accumulation of p62 in gastric carcinogenesis. We find that H. pyloriactivated DNA damage pathway in concert with downregulation of repair protein Rad51 in gastric cells, C57BL/6 mice and Mongolian gerbils. In addition, autophagy was increased early and then decreased gradually during the duration of H. pyloriinfection in vitro in a CagA-dependent manner. Moreover, loss of autophagy led to promotion of DNA damage in H. pylori-infected cells. Furthermore, knockdown of autophagic substrate p62 upregulated Rad51 expression, and p62 promoted Rad51 ubiquitination via the direct interaction of its UBA domain. Finally, H. pyloriinfection was associated with elevated levels of p62 in gastric intestinal metaplasia and decreased levels of Rad51 in dysplasia compared to their H. pylori-counterparts. Our findings provide a novel mechanism into the linkage of H. pyloriinfection, autophagy, DNA damage and gastric tumorigenesis.

ABSTRACTH. pyloriinfection is the strongest known risk factor for gastric carcinoma. The activation of the yes-associated protein 1 (YAP) and β-catenin pathways has been associated with multiple tumor types. In this study, we investigated the crosstalk between the YAP and β-catenin pathways in H. pylori-associated gastric tumorigenesis. Immunohistochemical analysis of YAP and β-catenin expression was performed in human gastric cancer tissues. The small molecules Super-TDU and KYA1797K, pharmacological inhibitors of YAP and β-catenin, respectively, were used to investigate the role of these signaling pathways in H. pylori-induced gastric carcinogenesis in murine models of infection. The common downstream targets of YAP and β-catenin signaling were evaluated by RNA sequencing (RNA-seq). Western blot, immunofluorescence, luciferase, RT-PCR, immunoprecipitation, cell counting kit-8 (CCK8), EdU and spheroid assays were used. H. pyloriinfection promoted YAP and β-catenin nuclear accumulation and transcriptional activity in gastric epithelial cells and transgenic insulin–gastrin (INS-GAS) mice, whereas silencing of both YAP and β-catenin synergistically inhibited H. pylori-induced cell proliferation and expansion. In addition, YAP was found to directly interact with β-catenin and knockdown of YAP suppressed H. pylori-induced nuclear translocation of β-catenin. Moreover, downstream genes caudal-type homeobox 2 (CDX2), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and RuvB like AAA ATPase 1 (RUVBL1) were shared by both YAP and β-catenin signaling. Furthermore, treatment with the YAP inhibitor Super-TDU or β-catenin inhibitor KYA1797A significantly alleviated gastric inflammation and epithelial DNA damage in H. pylori-infected mice. Finally, the elevation of gastric YAP was positively correlated with β-catenin expression in human gastric cancer tissues. These findings indicate that YAP and β-catenin synergistically promote H. pylori-induced gastric carcinogenesis via their physical interaction and reveal that CDX2, LGR5 and RUVBL1 are the downstream genes shared by both the YAP and β-catenin signaling pathways, and potentially contribute to H. pyloripathogenesis.

•Previous epidemiological studies have suggested a link between Helicobacter pylori(H. pylori) infection and nonalcoholic fatty liver disease (NAFLD), yet animal studies are lacking to elucidate this association.•This study first illustrated the effect of H. pyloriinfection combined with different diet structure on NAFLD in the mice model.•The results showed that H. pyloriinfection is associated with NAFLD in C57BL/6 mice, which depends on the bacterial strain and diet structure.•The infection of H. pyloriSS1 instead of NCTC11637 in combination with high fat diet induced more severe liver steatosis. H. pyloriinfection may play a role in NAFLD development and further studies are needed to determine whether H. pylorieradication can improve NAFLD risk.

Previous studies have indicated that thalidomide may be effective in achieving clinical remission and response; however, there is a lack of studies on its effect in endoscopic remission. The aim of this study was to assess the efficacy and safety of thalidomide in inducing and maintaining endoscopic remission.

ABSTRACTInfection with parasitic nematodes, especially gastrointestinal geohelminths, affects hundreds of millions of people worldwide and thus poses a major risk to global health. The host mechanism of defense against enteric nematode infection remains to be fully understood, but it involves a polarized type 2 immunity leading to alterations in intestinal function that facilitate worm expulsion. We investigated the role of interleukin-25 (IL-25) in host protection against Heligmosomoides polygyrus bakeriinfection in mice. Our results showed that Il25and its receptor subunit, Il17rb, were upregulated during a primary infection and a secondary challenge infection with H. polygyrus bakeri. Genetic deletion of IL-25 (IL-25−/−) led to an attenuated type 2 cytokine response and increased worm fecundity in mice with a primary H. polygyrus bakeriinfection. In addition, the full spectrum of the host memory response against a secondary infection with H. polygyrus bakeriwas severely impaired in IL-25−/−mice, including delayed type 2 cytokine responses, an attenuated functional response of the intestinal smooth muscle and epithelium, diminished intestinal smooth muscle hypertrophy/hyperplasia, and impaired worm expulsion. Furthermore, exogenous administration of IL-25 restored the host protective memory response against H. polygyrus bakeriinfection in IL-25−/−mice. These data demonstrate that IL-25 is critical for host protective immunity against H. polygyrus bakeriinfection, highlighting its potential application as a therapeutic agent against parasitic nematode infection worldwide.

Tumor metastasis is not only a sign of disease severity but also a major factor causing treatment failure and cancer-related death. Therefore, studies on the molecular mechanisms of tumor metastasis are critical for the development of treatments and for the improvement of survival. The epithelial-mesenchymal transition (EMT) is an orderly, polygenic biological process that plays an important role in tumor cell invasion, metastasis and chemoresistance. The complex, multi-step process of EMT involves multiple regulatory mechanisms. Specifically, the PI3K/Akt signaling pathway can affect the EMT in a variety of ways to influence tumor aggressiveness. A better understanding of the regulatory mechanisms related to the EMT can provide a theoretical basis for the early prediction of tumor progression as well as targeted therapy.

All‐trans retinoic acid inhibits inflammatory responses of human ulcerative and murine colitis. IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL‐17‐producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RARα, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RARα or LE135 as the antagonist of RARα. Expressions of IL‐17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.‐treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL‐17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up‐regulated FOXP3 expression and down‐regulated IL‐17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA‐treated mice produced lower levels of proinflammatory cytokines (TNF‐α, IL‐1β, IL‐17) but more regulatory cytokines (IL‐10, TGF‐β) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS‐induced colitis in a dose‐dependent manner, as seen by improved body weight and colon inflammation. RA down‐regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment.