Gastroenterology Report最新文献

Distal malignant biliary obstruction (dMBO) is a common complication of advanced malignancies, particularly pancreatic cancer and biliary tract cancer, requiring biliary drainage to relieve symptoms. Endoscopic drainage using self-expandable metal stents (SEMS) is widely preferred due to improved long-term patency compared with plastic stents. However, the choice between fully covered SEMS (FCSEMS) and uncovered SEMS (UCSEMS) remains controversial, primarily due to migration risks associated with FCSEMS. Recent advances in stent design, such as anchoring flaps, flared ends, and anti-migration coatings, have been developed to improve FCSEMS stability. Additionally, techniques incorporating double-pigtail plastic stents as internal or external anchors have demonstrated significant reductions in migration rates. This review examines the current literature and evaluates various anti-migration strategies for FCSEMS, highlighting the clinical efficacy and challenges associated with each approach. Understanding these innovations is crucial for optimizing stent selection and improving patient outcomes in dMBO.

Background: Ulcerative colitis (UC) is a chronic disease that induces colon tissue damage. Previous studies have shown the clinical benefit of New Baitouweng Decoction (NBD). Here, we aimed to investigate the effects of NBD on dextran sodium sulfate (DSS)-induced UC and the underlying mechanisms in a mouse model.

Methods: UC was induced in mice by using DSS for 7 days. The efficacy of NBD was determined by analysing the pathological appearance and the expression of inflammatory factors and tight junction proteins. 16S rDNA sequencing was used to describe the gut microbiota. Gas chromatography-mass spectrometry was employed to quantify bile acid (BA) levels. Spearman's correlation analysis was conducted to determine the relationship between gut microbiota composition and BA profiles. Western blot was used to detect the amounts of farnesoid X receptor (FXR), Nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3), caspase-1, and cleaved caspase-1.

Results: NBD reduced the disease activity index scores, ameliorated colonic pathological damage, inhibited colon inflammation, and repaired the intestinal barrier. In addition, 16S rDNA sequencing showed that NBD enhanced the relative abundance of beneficial bacteria such as Lactobacillus and Akkermansia, known to be involved in fecal BA metabolism. Furthermore, BA metabolomics analysis indicated that NBD elevated the concentrations of lithocholic acid and deoxycholic acid, thereby linking to the activation of the FXR pathway to inhibit NLRP3-mediated inflammation. Inhibiting FXR activation by using Z-guggulsterone impeded the protective function of NBD in DSS-induced UC.

Conclusion: NBD had a therapeutic effect on DSS-induced UC in a mouse model by regulating the gut microbiota, BAs, and subsequent FXR-NLRP3 pathway for decreasing the release of pro-inflammatory factors and repairing the intestinal barrier to preserve the equilibrium.

Dysregulation of bone morphogenetic protein 6 (BMP6) is found to be associated with gastric cancer development. Here, we further explored the functions of BMP6 in gastric cancer cell malignant behaviors, ferroptosis, and doxorubicin sensitivity and the mechanism driving BMP6 dysregulation. BMP6 mRNA detection was performed by quantitative polymerase chain reaction, and protein expression was tested by immunoblotting and immunohistochemistry. Subcutaneous xenograft studies were used to analyze in vivo effects. Cell growth was evaluated by CCK-8 and EdU assays. Cell invasiveness and motility were tested by transwell assay. Cell apoptosis was detected by flow cytometry. Cell ferroptosis was assessed by detecting related markers. Cytotoxicity assay was used to evaluate doxorubicin sensitivity. The relationship of the E3 ubiquitin ligase SMURF1 with BMP6 protein was predicted by UbiBrowser algorithm and verified by co-immunoprecipitation experiment and stability analysis. BMP6 expression was downregulated in gastric cancer, and its overexpression acted for in vitro suppression of gastric cancer cell growth, invasiveness, and migration. Increased BMP6 expression sensitized gastric cancer cells to doxorubicin therapy and enhanced cell ferroptosis. Mechanistically, SMURF1 mediated the ubiquitination and degradation of BMP6. Moreover, BMP6 reduction reversed sh-SMURF1-driven in vitro alterations of cell phenotypes and ferroptosis and in vivo enhancement of doxorubicin efficacy. Our study indicates that SMURF1-mediated BMP6 ubiquitination underlies the underexpression of BMP6 in gastric cancer. BMP6 upregulation induces gastric cancer cell ferroptosis and sensitizes cells to doxorubicin therapy. Our findings provide a therapeutic strategy in gastric cancer.

Background: Colorectal cancer (CRC) is one of the most lethal malignancies worldwide. Early diagnosis is critical in CRC treatment. More convenient and accurate biomarkers for early diagnosis are needed. However, whether circular RNAs (circRNAs) participate in colorectal tumorigenesis and their role in early diagnosis of CRC remain unknown.

Methods: We investigated the deregulated circRNAs and CRC-specific blood exosomal circRNAs in the Gene Expression Omnibus database and exoRBase. Functional assays were performed to evaluate the effects of hsa_circ_0004771 (circNRIP1) on proliferation and tumorigenesis both in vitro and in vivo. RNA pull-down, proteomic analysis, and RNA immunoprecipitation-polymerase chain reaction were performed to explore the underlying biological functions of circNRIP1 in CRC tumorigenesis.

Results: circNRIP1 was significantly downregulated in tumor tissues and increased in the blood exosomes of CRC patients. Knockdown of circNRIP1 significantly promoted CRC-cell proliferation and colony-forming ability in vitro and increased the tumor-formation ability in the xenograft mouse model. Mechanistically, circNRIP1 interacted with the K homology_1/2 domain of IGF2BP1 and blocked its m⁶A reader activity, and further reduced the stability of NACC1 mRNA and inhibited colorectal tumorigenesis.

Conclusions: circNRIP1 is an important tumor suppressor in CRC tumorigenesis and blood exosomal circNRIP1 could be an early diagnostic biomarker for CRC.

Background: Trend analysis in infection-related malignancy of the liver is still limited. We aimed to evaluate the incidence trend in hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA), and primary hepatic lymphoma (PHL) in the USA during 2000-2019.

Method: In this population-level study, cases of HCC, iCCA, cHCC-CCA, and PHL from the Surveillance, Epidemiology, and End Results (SEER) registries during 2000-2019 were included. The average annual percentage change (AAPC) in 2000-2019 was computed to describe the age-adjusted incidence trends for each disease and was stratified by demographic and geographic variables.

Results: HCC and iCCA incidence increased from 5.51 (per 100,000 persons) to 8.83 and 0.92 to 1.94 during 2000-2019, respectively, whereas cHCC-CCA and PHL incidence plateaued at ∼0.04 and ∼0.10, respectively. The AAPCs of HCC, iCCA, cHCC-CCA, and PHL were 2.5% (95% confidence interval [CI], 2.2% to 2.8%), 3.9% (95% CI, 2.1% to 5.7%), 0.4% (95% CI, -1.1% to 1.9%), and 0.2% (95% CI, -0.9% to 1.3%), respectively. The HCC incidence patterns differed between age groups, with a decreased trend for young adults (AAPC, -1.1% [95% CI, -2.2% to -0.1%]) and the fastest increase trend for elderly people (AAPC, 3.2% [95% CI, 2.8%-3.5%]). For iCCA, the incidence significantly increased for all age and race/ethnicity subgroups. The incidence trends in cHCC-CCA and PHL plateaued for the general population and all subgroups. Geographic disparities were found for HCC, with the highest proportion in Alaska Natives (91.6%) and the lowest proportion in Iowa (77.5%).

Conclusions: Although the incidence of infection-related malignancies of the liver increased in the USA during 2000-2019, a plateaued trend was observed for HCC during 2010-2019, especially for young adults. Racial/ethnic differences and geographic diversity remain. Systematic screening and prevention are highly requested.

Background: Pancreatic angiosarcoma is a rare and highly aggressive tumor originating from lymphatic or vascular endothelial cells, with poor prognosis and few effective treatments. In this study, we aimed to characterize the tumor ecosystem of metastatic pancreatic angiosarcoma, along with its potential treatment strategies.

Methods: Single-cell RNA-sequencing and bioinformatics analysis were performed on samples obtained from one patient, including at total of 16,841 cells from pancreatic angiosarcoma liver metastasis and adjacent normal liver tissue.

Results: Pancreatic angiosarcoma cells exhibited marked upregulation of nuclear factor kappa-B (NF-κB), hypoxia-inducible factor 1 (HIF-1), and myelocytomatosis oncogene (MYC) proto-oncogene signaling pathways, while presenting limited upregulation of actionable therapeutic targets except for cyclin-dependent kinase 4 (CDK4) and epidermal growth factor receptor. Several immune checkpoint genes, including cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), programmed cell death protein 1 (PDCD1), and cluster of differentiation 86 (CD86), were upregulated in tumor-infiltrating T cells, natural killer (NK) cells, and myeloid cells. Furthermore, intercellular interaction profiling demonstrated enhanced activity of the programmed death-ligand 1 (PD-L1) and CD86 signaling pathways within the tumor microenvironment. The gene-set scores of T/NK-cell exhaustion, regulatory T cell, and macrophage angiogenesis were significantly higher in tumor tissues compared with adjacent normal tissues. However, the phagocytosis scores of macrophages within the tumor-infiltrating region were significantly lower than those in the adjacent normal tissues.

Conclusions: Our findings outlined an immunosuppressive and angiogenic tumor ecosystem in pancreatic angiosarcoma liver metastasis, suggesting that pancreatic angiosarcoma may be insensitive to most targeted therapies. Conversely, immunotherapies targeting LAG3, PD-L1, and CD86 (e.g. isatuximab, Opdualag, and abatacept) and anti-angiogenic agents may be therapeutically effective and worthy of subsequent exploration.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed to replace the term of non-alcoholic fatty liver disease (NAFLD). To investigate the effect of MASLD on liver fibrosis and validate the clinical utility of MASLD criteria, differences in disease severity and clinical outcomes between MASLD and NAFLD were compared in a biopsy-proven pediatric cohort. The retrospective clinical data of 427 children with biopsy-proven steatotic liver between 2010 and 2021 were consecutively collected and categorized into three distinct subgroups of MASLD-only, NAFLD-only, and MASLD-NAFLD according to the diagnostic guidelines. Patients with MASLD-only and MASLD-NAFLD had more features of metabolic disorders, with higher level of triglycerides but lower level of high-density lipoprotein cholesterol than NAFLD-only. The proportion of significant fibrosis was highest in MASLD-only patients (68.0%), followed by those with MASLD-NAFLD and NAFLD-only (43.3% and 19.4%, respectively; P < 0.001). More steatohepatitis was presented in MASLD-NAFLD group than the other two groups (66.1% vs 30.8% vs 22.6%, P < 0.001). Multivariate regression revealed that children with MASLD-only had 5.8-fold greater risk of significant fibrosis than those with NAFLD-only (P = 0.001). After a median follow-up of 83 months, 14 of 427 patients developed clinical outcomes. Kaplan-Meier curves indicated no difference in the cumulative incidence of clinical events between the groups (log-rank, P = 0.073). Children in MASLD group tended to have concomitant with severe liver fibrosis and related metabolic diseases compared to those with NAFLD-only in pediatric cohort. Thus, the redefinition of MASLD may improve the detection of children with severe disease that need early intervention.