BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy whose progression is tightly linked to the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), central regu...BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy whose progression is tightly linked to the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs), central regulatory components of the TME, foster HCC metastasis by mediating immune evasion and epithelial-mesenchymal transition (EMT). The underlying molecular mechanisms remain to be elucidated. Clarifying how TAM polarization intersects with EMT will provide a rational basis for targeted HCC therapies. METHODS: We integrated scRNA-seq and copy-number variation profiling to delineate TAM subpopulations. CellChat was employed to construct cell-cell communication networks and screen for pivotal TAM-EMT signals. Expression and prognostic relevance of key molecules were validated in the TCGA-LIHC cohort. qRT-PCR, WB, Transwell, CCK-8, and flow cytometry were used for functional characterization. RESULTS: scRNA-seq resolved eight major cell types, including T/NK cells, epithelial cells, macrophages, monocytes, endothelial cells, fibroblasts, B cells, and dendritic cells. Four TAM subpopulations were identified, among which M2-like macrophages dominated both primary and metastatic HCC lesions. Cell-cell communication analysis revealed that M2-like macrophages engaged epithelial cells via the SPP1-(ITGA5 + ITGB1) signaling. According to clinical data, the activity of this signaling correlated with poor prognosis in HCC patients. Functional assays confirmed that knocking down ITGA5 reversed M2 macrophage polarization and suppressed HCC cell proliferation, apoptosis resistance, migration, and invasion. CONCLUSIONS: ITGA5 is a master regulator of the pro-tumorigenic functions of TAMs. The SPP1-(ITGA5 + ITGB1) signaling represents a novel immunotherapeutic target in HCC. Targeting TAM polarization may reprogram the immunosuppressive microenvironment and improve patient outcomes.
PURPOSE: Food insecurity impacts health in a multifactorial fashion, but the relationship with bowel habits is poorly understood. We aimed to examine the association between food insecurity status and bowel habits in a l...PURPOSE: Food insecurity impacts health in a multifactorial fashion, but the relationship with bowel habits is poorly understood. We aimed to examine the association between food insecurity status and bowel habits in a large cohort of US adults. METHODS: We analyzed adults (age 20-59 years) who completed both the bowel habits questionnaire and the food security survey module in the National Health and Nutrition Examination Survey over a 6-year period from 2005 to 2010 (n = 9,637). Constipation and diarrhea were defined according to Bristol Stool Form Scale and/or stool frequency. Adjusted odds ratios (AORs) for the likelihood of constipation or diarrhea were estimated in a multinomial logistic model across levels of food security. RESULTS: Constipation and diarrhea were more prevalent among individuals with lower food security compared to those with full food security (constipation: 19.6% vs. 14.2%; diarrhea: 14.8% vs. 11.0%; both p < 0.0001). Very low food security was associated with nearly twice the odds of constipation (OR 1.90, 95% CI: 1.48-2.42) and 54% greater odds of diarrhea (OR 1.54, 95% CI: 1.22-1.93). After stepwise adjustments for demographic, BMI, and dietary factors, these associations persisted (constipation AOR: 1.39, 95% CI 1.06-1.83; diarrhea AOR: 1.27, 95% CI 1.00-1.61). Adjustment for depression attenuated the significance of this association (constipation AOR: 1.25, 95% CI 0.97-1.63; diarrhea AOR: 1.16, 95% CI 0.90-1.51), suggesting a potential mediating role. CONCLUSION: In a nationally representative sample of community-dwelling US adults, decreasing food security was associated with increased odds of constipation and diarrhea. However, when multivariable adjustment included depression, this impact was attenuated, suggesting that depression may confound this relationship.
Okuno M, Mukai T, Kataoka F
… +17 more, Iwata K, Tezuka R, Iwasa Y, Koizumi T, Shimojo K, Ohashi Y, Iwata S, Mita N, Maruta A, Uemura S, Ichikawa H, Yoshida K, Iwashita T, Tomita E, Yasuda I, Moriwaki H, Shimizu M
BACKGROUND AND AIMS: Various self-expandable metallic stents (SEMS) have been developed to improve the patency of patients with malignant distal biliary obstruction (MDBO). This retrospective study aimed to evaluate SEMS...BACKGROUND AND AIMS: Various self-expandable metallic stents (SEMS) have been developed to improve the patency of patients with malignant distal biliary obstruction (MDBO). This retrospective study aimed to evaluate SEMS characteristics associated with longer patency in initial SEMS placement for unresectable MDBO. METHODS: Patients with unresectable MDBO identified in databases from four medical centers were analyzed. Patient background, SEMS type, and time to recurrent biliary obstruction (TRBO) were analyzed. The extracted variables were subjected to propensity score matching (PSM) to reduce selection bias. RESULTS: Between 2010 and 2025, 780 patients with MDBO were identified, 501 of whom met the inclusion criteria. In the multivariate analysis, 12-mm bore size, laser-cut SEMS, and 8-cm length SEMS were identified as independent significant factors contributing to TRBO. To confirm the utility of three significant factors, PSM analysis was performed on each. A total of 126 patients with 12- and 10-mm bore-size SEMS, 34 patients with laser-cut and braided SEMS, and 169 patients with 8-cm and < 8-cm length SEMS were compared. The hazard ratio of the 12-mm bore size SEMS was 0.65 (95% CI 0.44-0.98, P = 0.037), laser-cut SEMS was 0.24 (95% CI 0.07-0.86, P = 0.029), and SEMS < 8-cm length was 0.68 (95% CI 0.47-0.99, P = 0.044). The stent occlusion rate was lower in the 12-mm SEMS group (16%) than in the 10-mm SEMS group (26%). No stent migration was observed in laser-cut SEMS. CONCLUSIONS: Because the choice of SEMS length depends on the patient's condition, a 12-mm bore size and laser-cut SEMS seem promising for SEMS selection. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov UMIN000058935.
PURPOSE: Although guidelines recommend early cholecystectomy (CCY) after ERCP for choledocholithiasis-associated cholangitis, surgery is frequently deferred, particularly in severe disease. We evaluated real-world outcom...PURPOSE: Although guidelines recommend early cholecystectomy (CCY) after ERCP for choledocholithiasis-associated cholangitis, surgery is frequently deferred, particularly in severe disease. We evaluated real-world outcomes and decision-making between same-admission versus deferred CCY to assess the impact of surgical delay. METHODS: We conducted a retrospective cohort study on patients with choledocholithiasis-associated cholangitis from 2011 to 2022. Primary outcomes were the occurrence of ≥ 1 recurrent biliary event (RBE) within one year, and 30-day mortality and readmissions. Secondary outcomes included operative complications, length of stay, and reasons for delay. Multivariable logistic regression adjusted for age, comorbidities, sex, and severity, with subgroup analyses for Grade III cholangitis. Kaplan-Meier survival analysis evaluated time to first RBE. RESULTS: Among 171 patients (mean [SD] age, 66.2 [19.1] years; 85 [49.7%] female), 94 (55%) had CCY deferred. Same-admission CCY was associated with lower odds of RBEs (aOR 0.01; 95% CI 0-0.08; p < 0.001) and 30-day readmission (1.3% vs. 13.8%; aOR 0.11; 95% CI 0.01-0.48; p = 0.0023), with similar complication rates and length of stay. Kaplan-Meier analysis confirmed superior RBE-free survival for same-admission CCY (log-rank p < 0.001). Among patients with Grade III cholangitis (n = 34), same-admission CCY reduced RBE rate (0% vs. 56.5%; p < 0.001) without increasing intraoperative or postoperative complications. Deferral was most often due to high surgical risk (21.3%), concurrent pathology (20.2%), or patient preference (14.9%). CONCLUSIONS: Same-admission CCY for choledocholithiasis-associated acute cholangitis reduced recurrence and 30-day readmission without increasing postoperative complications, mortality, or length of stay, including in Grade III cholangitis. These findings support same-admission CCY after clinical stabilization.
BACKGROUND: Current severe acute pancreatitis (SAP) murine models face significant limitations. The sodium taurocholate method consistently induces pancreatic necrosis but demands intricate surgical procedures, leading t...BACKGROUND: Current severe acute pancreatitis (SAP) murine models face significant limitations. The sodium taurocholate method consistently induces pancreatic necrosis but demands intricate surgical procedures, leading to high variability and infection risks. In contrast, the arginine approach causes acinar cell damage without fully mimicking clinical injury pathways. Furthermore, the caerulein-lipopolysaccharide (CAE-LPS) model, while operationally straightforward, fails to replicate persistent organ failure due to LPS's rapid clearance, thereby inadequately capturing the lethal trajectory observed in clinical SAP patients who succumb to the disease. AIMS: To address these gaps, we developed a SAP mouse model by integrating two key pathogenic mechanisms: trypsin-driven complement activation and sustained complement hyperactivation as drivers of multiple organ failure. METHODS: The SAP model was established by combining CAE-induced pancreatic injury with zymosan (ZYM)-mediated complement activation. Dosing and combination protocols were meticulously optimized and were followed by a comprehensive longitudinal analysis during the acute phase (0-12 days), with comparisons to the CAE-LPS model. RESULTS: The optimized protocol involved nine intraperitoneal CAE injections (100 μg/kg each) followed by a single ZYM dose (1000 mg/kg). This regimen triggered pancreatic necrosis, inflammatory infiltration, and multi-organ damage (liver, kidney, intestine). Notably, the model demonstrated sustained complement activation and a mortality pattern in non-survivors that more closely aligned with clinical SAP outcomes than the CAE-LPS model. CONCLUSION: This novel model offers a robust platform for advancing SAP research, bridging the divide between preclinical studies and clinical translation.
PURPOSE: Fecal calprotectin (FCAL) is an established biomarker for monitoring intestinal inflammation in inflammatory bowel disease. However, fecal sampling can be socially unacceptable and inconvenient. Urinary calprote...PURPOSE: Fecal calprotectin (FCAL) is an established biomarker for monitoring intestinal inflammation in inflammatory bowel disease. However, fecal sampling can be socially unacceptable and inconvenient. Urinary calprotectin (UCAL) could potentially be a suitable surrogate marker of FCAL. METHODS: Levels of FCAL and UCAL and C-reactive protein (CRP) were measured in samples from two different cohorts; a) in adults with active Crohn's disease (CD) receiving induction treatment with adalimumab and b) children with CD during early food re-introduction after successful treatment with exclusive enteral nutrition (EEN). In each cohort, participants were categorized based on their FCAL trajectories. Adults were classified as responders if FCAL decreased ≥ 50% after 12 weeks of treatment; otherwise, they were classified as non-responders. In children, a FCAL baseline rise > 100% during three weeks of food reintroduction, after EEN, was classified as having an FCAL increase. Children were classified as FCAL-stable if FCAL remained < 300 mg/kg throughout food reintroduction. FCAL, UCAL and CRP were also measured in healthy adults. RESULTS: A total of 364 paired stool and urine samples, and 100 blood samples were utilized from adults and children with CD. Changes in UCAL did not parallel changes in FCAL, neither in adults who were classed as FCAL responders after 12-weeks treatment with biologics, nor in pediatric patients who demonstrated an increase in FCAL, following completion of EEN and return to normal diet. UCAL did not correlate with either FCAL or CRP. CONCLUSIONS: Urinary calprotectin is not a useful biomarker of systemic or gut inflammation in patients with CD.