Journal of Gastroenterology最新文献

Background: Gastric cancer (GC) remains one of the most lethal malignancies, primarily due to limited treatment efficacy and its strong metastatic potential. The identification of new molecular targets is therefore crucial for enhancing therapeutic strategies and improving clinical outcomes.

Methods: The expression of ITGA3 was investigated in clinical GC tissue samples, and its association with patient prognosis was evaluated. Both in vitro and in vivo assays were employed to investigate the functional role of ITGA3 in GC cell proliferation and invasion. To uncover the underlying molecular mechanisms, integrated proteomic and transcriptomic analyses were performed. Mechanistic validation was subsequently carried out using Western blotting, immunofluorescence, nuclear-cytoplasmic fractionation, dual-luciferase reporter, and chromatin immunoprecipitation (ChIP) assays.

Results: Elevated ITGA3 expression was strongly correlated with an unfavorable prognosis in GC patients. Functional studies revealed that ITGA3 promotes tumor cell proliferation and invasion. Multi-omics analyses revealed that ITGA3 modulates glutamine metabolism by regulating the amino acid transporter SLC1A5 and engages the JAK-STAT3 signaling pathway. Silencing ITGA3 significantly reduced STAT3 nuclear translocation, suppressing SLC1A5 transcription and decreasing glutamine uptake. Both dual-luciferase reporter and ChIP assays confirmed that STAT3 directly binds to the promoter region of SLC1A5.

Conclusions: ITGA3 acts as an oncogenic driver in GC by facilitating glutamine uptake via the STAT3-SLC1A5 signaling axis. These findings suggest that therapeutic targeting of this pathway could represent a promising approach for the clinical management of GC.

Background: Systemic chemotherapy with gemcitabine plus S-1 (GEM + S-1), GEM + CDDP plus S-1 (GEM + CDDP + S-1), or gemcitabine plus cisplatin (GEM + CDDP) is standard treatment for advanced biliary tract cancer (aBTC). We aimed to evaluate the efficacy and safety of combination chemotherapy in older patients with aBTC.

Methods: This multicenter prospective observational study (JON2104-B, UMIN000045156) included patients aged ≥ 70 years with aBTC. Inverse-probability weighting propensity-score analyses (IPW) were used to compare overall survival (OS) as the primary endpoint and progression-free survival (PFS) across treatment groups.

Results: This study included 305 patients between August 2021 and January 2023. Of them, 75, 131, 26, 52, and 10 received GEM + CDDP + S-1, GEM + CDDP, GEM + S-1, gemcitabine, and S-1; their median ages were 74, 75, 77.5, 80, and 80 years, and approximately 24%, 16.8%, 23.1%, 9.6%, and 0% had G-8 scores of > 14, respectively. GEM + CDDP had a safety profile comparable to that of GEM + CDDP + S-1 but was more toxic than gemcitabine. Per IPW, the hazard ratio (HR) for GEM + CDDP + S-1 versus GEM + CDDP was 0.80 for OS (95% confidence interval [CI], 0.55-1.17) and 0.55 for PFS (95% CI 0.38-0.80). The HR for GEM + CDDP versus gemcitabine was 0.74 for OS (95% CI 0.42-1.29) and 0.79 for PFS (95% CI 0.42-1.49).

Conclusions: GEM + CDDP + S-1 was associated with longer PFS without additional toxicity than GEM + CDDP for fit older patients. However, the OS for both were not statistically different. The efficacies of GEM + CDDP and gemcitabine for vulnerable older patients did not also differ significantly. These findings highlight the importance of vulnerability in patients with aBTC.

Background: Dietary fatty acids are involved in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). We examined the mechanism by which dietary fatty acid composition affects MASLD pathogenesis.

Methods: The MASLD mouse model was developed by feeding a high-fat diet (HFD) rich in palmitic acid (PA), trans-fatty acids (TFAs), or oleic acid (OA). For in vitro experiments, Hepa 1-6 cells were exposed to PA, elaidic acid (a representative TFA), and OA. Glycerol-3-phosphate acyltransferase 1 (GPAM) expression in Hepa 1-6 cells was manipulated using a plasmid encoding GPAM and GPAM-specific siRNAs. In addition, GPAM depletion in the liver of HFD-fed mice was achieved using a pH-sensitive multifunctional envelope-type nanodevice as a siRNA carrier. Liver specimens from patients with MASLD were also analyzed.

Results: The TFA group displayed higher serum alanine-aminotransferase and hepatic triglyceride content but lower serum fasting triglyceride and visceral adipose tissue (VAT) compared with that in the PA and OA groups. Hepatic GPAM expression in the TFA group was higher than in the PA group. Consistently, TFA-treated Hepa 1-6 cells showed a greater GPAM increase than that with OA and PA. GPAM-overexpressing Hepa 1-6 cells showed increased triglyceride accumulation, whereas GPAM-deficient cells failed to accumulate triglyceride. Hepatic GPAM knockdown in HFD-fed mice suppressed steatosis and increased VAT. Notably, hepatic GPAM gene expression was higher in patients with severe steatosis than in those with non-severe steatosis.

Conclusions: A TFA-rich HFD increased hepatic GPAM expression, exacerbated steatosis, and decreased VAT. Therefore, GPAM may regulate systemic fat accumulation in the body.

Metastatic liver tumors are more common than primary liver cancers and are the most common liver malignancies. Performing B-mode ultrasonography and contrast-enhanced computed tomography is generally necessary for the diagnosis of liver metastases. However, various modalities, including dynamic contrast-enhanced computed tomography and magnetic resonance imaging using liver-specific contrast agents such as gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid, fluorodeoxyglucose positron emission tomography, and a combination of positron emission tomography and computed tomography, are also used. Improvements in imaging technology have made the detection of small liver masses possible, and liver metastases are being diagnosed more frequently, both before and after primary tumor treatment. The diagnosis of liver metastasis is related to treatment, and the benefits of liver resection depend on the primary tumor. For colorectal cancer, resection of liver metastases is beneficial. However, resection is not recommended for pancreatic or biliary tract cancers.

Background and aims: Hepatitis B e antigen (HBeAg) seroclearance is crucial in the natural history of chronic hepatitis B (CHB). Little is known about the role of hepatitis B core-related antigen (HBcrAg) levels in predicting spontaneous HBeAg seroclearance.

Methods: This retrospective cohort study included 484 treatment-naïve HBeAg-positive CHB patients with an extended follow-up period at National Taiwan University Hospital. The primary endpoint was spontaneous seroclearance of HBeAg. The association between baseline HBcrAg levels and their kinetic patterns with spontaneous HBeAg seroclearance was assessed.

Results: Of 484 patients with a mean follow-up period of 7.80 years, 331 (68.4%) achieved spontaneous HBeAg seroclearance, corresponding to an annual rate of 8.76%. Lower baseline HBcrAg levels correlated with an increased likelihood of HBeAg seroclearance (log-rank P < .001). When HBcrAg kinetics were assessed based on baseline and year 3 levels, patients with HBcrAg levels persistently < 10⁵ KU/mL (HR: 2.66; 95% CI: 1.75-4.04) and those declining to < 10⁵ KU/mL (HR: 2.31; 95% CI: 1.50-3.55) had an increased likelihood of HBeAg seroclearance when compared to those with persistently high HBcrAg levels. This association remained statistically significant in multivariate analysis after adjusting for baseline viral factors. In addition, HBcrAg kinetics were consistently associated with HBeAg seroclearance in immune-tolerant patients.

Conclusions: HBcrAg < 10⁵ KU/mL, or a decline to this threshold, identified HBeAg-positive CHB patients with higher likelihood of spontaneous HBeAg seroclearance. Persistently high HBcrAg may indicate earlier CHB phases and inform management strategies.

Background: Carotegrast methyl is approved for treating patients with moderately active ulcerative colitis with inadequate response to 5-aminosalicylic acid agents. However, real-world evidence to guide optimal use is limited. This retrospective study aimed to characterise suitable patient profiles, identify biomarkers predictive of carotegrast methyl efficacy, and determine the appropriate timing for treatment evaluation.

Methods: We analysed data from 186 patients enrolled in a phase 3 trial of carotegrast methyl (96 carotegrast methyl, 90 placebo). We assessed biomarkers (leucine-rich α-2 glycoprotein, C-reactive protein, faecal calprotectin, and anti-integrin αvβ6 antibody titres) alongside clinical outcomes and assessed symptom diaries and maintenance therapies.

Results: Low disease activity at baseline (partial Mayo score ≤ 5) was associated with higher remission rates (56.1 vs. 33.3%). Anti-integrin αvβ6 antibody titres of < 44.6 U/mL at baseline predicted higher clinical remission rates (49.1 vs. 26.8%). Symptom improvement was detectable from week 2. Faecal calprotectin correlated with the endoscopic subscore at the end of treatment (ρ = 0.566); a faecal calprotectin level of < 387.5 µg/g predicted Mayo endoscopic subscore 0/1. Most patients maintained remission with oral 5-aminosalicylic acid alone; the 1-year maintenance rate was 56.5%.

Conclusions: Carotegrast methyl appears most effective in patients with moderately active ulcerative colitis with low disease activity, with week 2 and beyond as an appropriate time point for assessing efficacy. Anti-integrin αvβ6 antibody titre shows promise in predicting response to carotegrast methyl. Faecal calprotectin may serve as a non-invasive surrogate for evaluating endoscopic healing.

Background: Gastric cancer (GC) is a highly aggressive malignancy with limited therapeutic options and poor clinical outcomes. Aberrant regulation of the ubiquitin-proteasome system contributes to tumorigenesis by disrupting protein homeostasis and signal transduction. STAMBPL1, a JAMM family deubiquitinase (DUB) implicated in several cancers, remains poorly characterized in GC, and its mechanistic relevance to disease progression warrants investigation.

Methods: Transcriptomic analyses and clinical specimen profiling were conducted to assess STAMBPL1 expression and prognostic significance in GC. Functional effects were evaluated using in vitro assays, patient-derived organoids, and multiple mouse models. Mechanistic studies included mass spectrometry, co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis, and pharmacologic blockade of downstream signaling pathways.

Results: STAMBPL1 was significantly overexpressed in GC tissues and strongly associated with advanced T stage, distant metastasis, higher clinical stage, and unfavorable prognosis. Functionally, STAMBPL1 promotes GC cell proliferation, migration, invasion, and organoid growth in vitro, and drives subcutaneous tumor growth, peritoneal dissemination, and lung metastasis in vivo. Mechanistically, STAMBPL1 directly binds IQ-domain GTPase-activating protein 1 (IQGAP1), specifically catalyzing the removal of K48- and K63-linked ubiquitin chains at the 1368 lysine residue, thereby stabilizing IQGAP1 protein levels. Stabilized IQGAP1 subsequently activates the JAK2/STAT3 signaling axis, potentiating GC malignant progression. Notably, pharmacological blockade of JAK2 by AG490 markedly curtailed tumor progression and abrogated the oncogenic effects of STAMBPL1/IQGAP1, underscoring the functional dependency of this axis.

Conclusions: These findings identify STAMBPL1 as a novel oncogenic DUB that promotes GC progression through IQGAP1 stabilization and subsequent activation of JAK2/STAT3 signaling, providing a potential therapeutic target for GC.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas are bona fide cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC), which is the cancer type with the most dismal prognosis. Since IPMNs are detectable by imaging, they offer a rare window of opportunity for early intervention for PDAC development. Despite their clinical visibility, the molecular pathogenesis of IPMNs remained incompletely understood, and no effective non-surgical therapeutic strategies have been established to date. In the past few decades, however, substantial progress has been made in elucidating their molecular pathology. Next-generation sequencing technologies demonstrated the comprehensive genetic mutation profile of IPMNs in the early 2010s. Elucidation of these mutation profiles enabled the establishment of genetically engineered mouse models, successfully recapitulating the natural development of human IPMNs and their progression to invasive cancer. Rapid evolution of "omics" technologies in recent years has facilitated the application of mass spectrometry, single-cell sequencing and spatial transcriptomics to IPMNs, significantly advancing our understanding of their pathophysiology. These techniques elucidated the changes in transcriptome, proteome, metabolome, microbiome, and tumor microenvironment associated with IPMN development and progression. This review summarizes current insights into the molecular and cellular landscapes of IPMN tumorigenesis, with particular emphasis on the mechanisms driving malignant progression.

Background: Although impaired intestinal barrier function is implicated in type 2 diabetes (T2D), its direct in vivo assessment in humans remains challenging, limiting our understanding of the underlying mechanisms. We utilized a novel endoscopic real-time, in situ impedance measurement technique to investigate how hyperglycemia and the intestinal microbiota contribute to intestinal barrier dysfunction in T2D.

Methods: We validated this impedance-based approach against ex vivo transepithelial electrical resistance (TEER) (r = 0.64, p = 0.011) and applied it to 137 patients undergoing colonoscopy. A mechanistic study (22 T2D, 19 controls) analyzed mucosal microbiota, short-chain fatty acid (SCFA) levels, and tight junction protein gene expression. In vitro assays with Caco-2 monolayers evaluated Bacteroides vulgatus (B. vulgatus) supernatant and high-glucose exposure effects on TEER.

Results: Patients with T2D had significantly lower ileal impedance (20.9 Ω·cm²) compared to controls (24.2 Ω·cm²; p < 0.001). Lower Bacteroides abundance correlated with decreased SCFA biosynthesis gene expression and ZO-1 levels. B. vulgatus supernatant counteracted lipopolysaccharide-induced barrier disruption. High-glucose exposure reduced transepithelial electrical resistance (p < 0.05), indicating a direct detrimental effect. Impedance negatively correlated with HbA1c (r = - 0.49, p < 0.001), and metformin use was associated with preserved barrier function.

Conclusions: To our knowledge, this study provides the first direct, in situ evidence that intestinal barrier function is impaired in T2D, a condition associated with concurrent microbial and metabolic alterations. Our findings establish intestinal barrier dysfunction as a key pathophysiological feature of T2D, suggesting that interventions aimed at the intestinal barrier function may represent a novel therapeutic strategy.