IgG4-related disease is a rare, immune-mediated, multisystem fibroinflammatory condition. It is characterized by elevated serum IgG4 concentrations and tissue infiltration of IgG4-positive plasma cells with distinctive histopathological features, including storiform fibrosis and obliterative phlebitis. Gastroenterological involvement is diverse and represents a critical diagnostic consideration, encompassing the pancreas, bile ducts, liver, esophagus, stomach, and intestine. In this review, we summarize the current understanding of genetic susceptibility and environmental risk factors underlying this disease, and systematically describe the clinical presentations, histopathological characteristics, imaging findings, and serological profiles of each major gastroenterological manifestation. We further review evidence-based treatment regimens ranging from glucocorticoids and conventional immunosuppressants to emerging biologic therapies, discuss organ-specific therapeutic responses, and identify predictors of disease relapse along with long-term surveillance strategies. From a gastroenterologist's perspective, this review aims to provide a practical and integrated framework to facilitate early recognition, accurate differentiation from mimicking conditions such as pancreaticobiliary malignancies, and optimized long-term management of this complex yet treatable disease.
Autosomal dominant acute porphyrias are rare inherited disorders of haem biosynthesis characterised by accumulation of potentially neurotoxic porphyrin precursors and attacks of severe abdominal pain with autonomic and neuropsychiatric features. Disease severity ranges from asymptomatic individuals to those with recurrent, life-threatening attacks. The International Porphyria Network invited 34 acute porphyria specialists from 17 countries to form an expert panel. The invited group included clinicians from diverse specialities (ie, internal medicine, haematology, endocrinology, gastroenterology, hepatology, neurology, and biochemistry), together with laboratory scientists and patient representatives. The panel met online (in 2023-25) to develop 15 evidence-based recommendations with the use of the Grading of Recommendations, Assessment, Development, and Evaluations framework addressing attack prevention, management of sporadic and recurrent attacks, long-term follow-up, surveillance for primary liver cancer, and family screening. The guidelines support safe, consistent clinical care and improved outcomes, recognising global variation in resources and access to high-cost drugs, and highlighting priorities for future research.
Vaccine preventable infections (VPIs) contribute substantially to morbidity and mortality in solid organ transplant (SOT) recipients. Recent outbreaks and declining herd immunity have brought attention to optimizing vaccination pre and posttransplant, as many patients remain incompletely immunized at the time of transplant. This review summarizes modern evidence and evolving recommendations regarding live vaccination in SOT candidates and recipients. Vaccination coverage at the time of transplant remains suboptimal, although targeted interventions have shown improvements in uptake. Accumulating data, largely from pediatric liver and kidney SOT cohorts, support the safety and immunogenicity of posttransplant measles, mumps, rubella (MMR) and varicella (VAR) vaccination under defined clinical and immunologic criteria. These findings have informed updated guidance and clinical practice for select pediatric SOT recipients, and multicenter experience with posttransplant live vaccination continues to expand. Growing evidence suggests that live vaccine administration may be feasible in carefully selected pediatric SOT recipients and may reduce susceptibility to VPIs. Important knowledge gaps remain, particularly for adult SOT recipients, nonliver transplant populations, and other live vaccines. Further research and prospective studies are needed to better define safety, immunogenicity, and optimal vaccination timing in these populations.
Human albumin (HA) infusion is beneficial for the management of decompensated cirrhosis, but its mechanism remains unclear. This study aimed to evaluate the effect of HA infusion on systemic inflammation, oxidative stress, and prognosis in decompensated cirrhosis. In a cohort study, patients with acute decompensated cirrhosis were enrolled and categorized according to HA infusion. Serum interleukin (IL)-6, IL-10, tumor necrosis factor-alpha (TNF-α), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) levels were measured before and after treatment. We compared the one-year cumulative incidence of further decompensation between the two groups. In a meta-analysis, all relevant papers were systematically searched, and pooled using a random-effects model. In the cohort study, 55 patients were included, of whom 23 received HA infusion. HA infusion significantly reduced IL-6 (92.79 ± 144.14 vs. 66.99 ± 89.61, P = 0.031) and MDA (15.19 ± 8.44 vs. 11.05 ± 6.77, P = 0.006) levels, but increased GSH (135.76 ± 14.91 vs. 142.00 ± 19.69, P = 0.033) level. ∆IL-6 (-25.80 ± 64.28 vs. 1.83 ± 25.05, P = 0.013) and ∆TNF-α (-12.95 ± 28.91 vs. 1.82 ± 11.31, P = 0.037) were greater in the HA group than in the control group. One-year cumulative incidence of further decompensation was significantly lower in the HA group than in the control group (P = 0.036). HA infusion was an independent protective factor of further decompensation (sHR = 0.312, P = 0.02). In the meta-analysis, 7 papers with 457 patients were included. ∆IL-6, ∆TNF-α, and ∆MDA were greater in the HA group than in the control group, but the difference was not statistically significant. HA infusion may reduce the risk of further decompensation by improving systemic inflammation and oxidative stress in decompensated cirrhosis.
Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism presenting with acute liver failure, cirrhosis, or neurologic involvement. Liver transplantation (LT) is the definitive treatment; however, data remain limited, particularly from regions reliant on living donor LT (LDLT). We retrospectively analyzed a prospectively collected transplant database, identifying all patients (≥ 14 years) who underwent LT for WD between January 2001 and December 2023. Data on demographics, LT indications, disease characteristics, pre-transplant therapy, complications, and outcomes were collected. Survival was assessed using Kaplan-Meier methods, and neurologic outcomes from clinical documentation. Forty-one patients underwent LT for WD (median age: 23 years; 51.2% female). Ascites was present in 68.4%, encephalopathy in 32.4%, and hepatocellular carcinoma in 5.1%. Acute liver failure was the initial presentation in 17.9%. LDLT comprised 53.7%. Acute cellular rejection occurred in 29.7% but was manageable; no patient required re-transplantation. Neurologic involvement was present in 17.1%, with 71% improving post-LT. One-, five-, and ten-year survival rates were 94%, 94%, and 82%. LT for WD yields excellent long-term survival. Neurologic improvement occurred in most Neuro-Wilson patients, supporting LT even in neurologically affected cases. LDLT plays a crucial role in regions with limited deceased donors.
Post-endoscopic submucosal dissection (ESD) electrocoagulation syndrome (PEECS) is a known complication in colorectal laterally spreading tumors (LSTs), but its risk factors in elderly patients remain unclear. This study aimed to develop and validate a risk-stratification scoring system for PEECS in elderly ESD patients. A multicenter retrospective study (2020-2025) enrolled 506 elderly patients with colorectal LSTs undergoing ESD, randomly allocated to training (TC, n = 354) and validation (VC, n = 152) cohorts (7:3). Synthetic minority over-sampling technique (SMOTE) was used in the TC to identify risk factors and construct a predictive model, which was validated in the VC. The incidence of post-ESD PEECS was 8.1% (41 cases). After applying the SMOTE, multivariate analysis identified sex, lesion with fibrosis, and intraoperative bleeding as independent risk factors. The scoring system assigned: 1 point for female sex, 3 points for lesion with fibrosis, and 2 points for intraoperative bleeding. In the VC, the model demonstrated an area under the curve (AUC) of 0.921, with a specificity of 0.949 and an accuracy of 0.908. Following risk stratification, the low-risk group (0-4 points) showed a PEECS incidence of 10.1% in the TC and 5.1% in the VC, while the high-risk group (5-6 points) exhibited 94.5% in the TC and 53.3% in the VC. In elderly patients with colorectal LSTs undergoing ESD, female sex, fibrotic lesions, and intraoperative bleeding were identified as independent predictors of PEECS. The proposed scoring system demonstrated good discriminatory ability in both cohorts and may be useful for risk stratification in this population.
Accurate detection of KRAS codon mutations is essential for precision oncology in colorectal cancer (CRC), yet conventional liquid biopsy methods often lack sufficient sensitivity for rare ctDNA variants, particularly in early diseases. We developed a three-dimensional (3D) plasmonic KRAS microarray integrating blocked recombinase polymerase amplification with plasmon-enhanced fluorescence. Quencher-modified blocking probes suppress wild-type DNA while selectively enabling mutant signal amplification. A single primer-probe set per codon allows comprehensive detection of all substitutions within KRAS codons 12/13, 61, and 146. The platform achieved detection down to 1 fM by direct hybridization and 100 zM after blocked amplification, exceeding conventional PCR and next-generation sequencing sensitivity. Codon-level specificity was validated in CRC cell lines, with distinct signals for each mutation. Clinical analysis of 58 patients showed 100% concordance between tissue, plasma, and urine in mutation-positive malignant cases when sufficient input was available, indicating accurate reflection of tumor profiles. In benign tumors, detection was rare despite tissue mutations, likely due to limited ctDNA release.This plasmonic microarray enables ultra-sensitive, specific, and non-invasive detection, supporting early diagnosis, minimal residual disease monitoring, and longitudinal CRC management.
Magnetic resonance imaging (MRI) is the preferred staging modality in the evaluation of rectal cancer. We aimed to evaluate the accuracy of MRI among large rectal polyps referred for endoscopic resection. We analyzed consecutive patients who underwent MRI prior to endoscopic resection for rectal neoplasia. 44 patients with large rectal polyps (mean size 5.8 cm) underwent MRI prior to endoscopic resection. MRI categorized 24 (54.5%) lesions as T0/T1, 16 (36.4%) T2, and 4 (9.1%) T3. Final pathology demonstrated 5 (11.4%) adenomas, 21 (47.7%) high grade dysplasia, 5 (11.4%) intramucosal adenocarcinoma, 9 (20.5%) pT1 adenocarcinoma, and 4 (9.1%) pT2 adenocarcinoma. Findings were discordant in 21 (47.7%) patients (p < 0.01), where MRI over-staged 18 (40.9%) and under-staged 3 (6.8%) patients. We demonstrate that MRI over-stages over 40% (18/44) of large rectal polyps. MRI staging should be interpreted cautiously when considering endoscopic resection for large rectal polyps.
Lactate, an energy source and metabolic by-product, has been implicated in cancer progression, but its role in colorectal cancer (CRC) remains incompletely understood. This study investigated the clinical significance, biological effects, and transcriptomic responses of CRC cells to lactate. In human CRC specimens, lactate levels were positively associated with advanced clinical stage and poorer disease-free survival. Functional assays showed that lactate promoted malignant cellular behaviors in both SW480 and HCT116 cells, while pH-control experiments suggested that these effects were not merely due to extracellular acidification alone. RNA sequencing in SW480 cells identified 1,418 differentially expressed genes after lactate treatment. GO and KEGG analyses revealed alterations in multiple metabolic and signaling pathways. qRT-PCR validated the alterations of representative genes, including HK2, VEGFA, JUNB, CCNB1, MAPK4, and COX2. In addition, flow cytometry showed activation of NF-κB and HIF-1α signaling following lactate treatment, and pharmacological inhibition of either pathway significantly attenuated the lactate-induced malignant phenotypes. Together, these findings provide transcriptomic and functional evidence that lactate promotes malignant phenotypes in CRC cells and offer exploratory mechanistic insights into the involvement of NF-κB and HIF-1α signaling.
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Gastric cancer (GC) remains a prevalent malignancy with poor outcomes in advanced stages. This study investigated the anti-GC effect of Scoparone (SCO) and elucidated its underlying mechanism involving the PIN1/STING/TBK1/IRF3 signaling pathway. GC cell lines (AGS and HGC-27) were treated with increasing concentrations of SCO, and subsequent assessments of proliferation, migration, and invasion were performed using colony formation, EdU, wound healing, and Transwell assays. Mechanistically, molecular docking was performed to predict the binding between SCO and PIN1. and Western blot analysis was further employed to evaluate the phosphorylation levels of key proteins in the PIN1/STING/TBK1/IRF3 axis. While stable knockdown and overexpression models were established in vitro to validate the pivotal role of PIN1, a subcutaneous xenograft model in nude mice was utilized to independently assess the in vivo antitumor efficacy of SCO. Our results demonstrated that SCO concentration-dependently inhibited GC cell proliferation, migration, and invasion. Mechanistically, SCO downregulated PIN1 expression and promoted the phosphorylation of STING, TBK1, and IRF3. Notably, PIN1 knockdown recapitulated and enhanced SCO-mediated suppression of malignant phenotypes as well as activation of the STING/TBK1/IRF3 pathway, whereas PIN1 overexpression partially reversed these effects. In vivo, SCO significantly suppressed tumor growth through regulation of the PIN1/STING/TBK1/IRF3 pathway. Collectively, these findings elucidate a novel mechanism by which SCO suppresses GC progression via the PIN1/STING/TBK1/IRF3 axis, providing a preclinical rationale for developing SCO as a promising therapeutic candidate for GC.
The overexpression of the transcriptional enhanced associate domain (TEAD), which regulates gene transcription linked to cell growth, drives the proliferation in cases of hepatocellular carcinoma (HCC). In order to discover novel TEAD inhibitors that are more effective and have better efficacy and pharmacokinetic properties for treating HCC, this study employed a cyclization strategy to generate a novel indole-based scaffold of TEAD inhibitors. A comprehensive and systematic structure-activity relationship (SAR) analysis identified the most promising compound: LC-TD-05, a non-covalent, partial TEAD inhibitor with selective activity against TEAD1, TEAD2 and TEAD4, but reduced potency against TEAD3. LC-TD-05 exhibits good potency against TEAD1/2/4 (TEAD1 IC50 = 116.6 ± 21.7 nM, TEAD2 IC50 = 168.7 ± 17.1 nM, TEAD4 IC50 = 68.3 ± 18.2 nM), demonstrates favorable oral bioavailability (F = 53.7%), and exhibits significant anti-tumor activity in HCC LM3 models in vitro (LM3 cell IC50 = 248 ± 27.9 nM) and in vivo (TGI = 75%). Overall, this study provides a novel scaffold for TEAD inhibitors, enabling more effective interventions against HCC.
Neutrophil extracellular traps (NETs) play a critical role in amplifying intestinal inflammation in ulcerative colitis (UC). Clostridium butyricum (CB) has shown anti-inflammatory effects in gastrointestinal diseases; however, its impact on NETs formation and related molecular mechanisms remains unclear. UC was induced in C57BL/6 mice by DSS, followed by CB and/or PMA administration. Colonic injury was assessed by colon length measurement, histopathology, and histological scoring. NETs formation was determined by immunofluorescence staining of Ly6G and citrullinated histone H3 (Cit-H3), and serum myeloperoxidase (MPO)/Cit-H3 levels were quantified by ELISA. In vitro, NETs release was induced in neutrophils by PMA with or without CB supernatant (CBS) administration. RNA-seq and qRT-PCR/Western blot analyses were used to explore underlying signaling pathways. IL-17A knockdown via siRNA was conducted to validate mechanistic involvement. CB significantly alleviated DSS-induced colitis, evidenced by reduced colon shortening, lower colon mass, and improved mucosal architecture. CB markedly suppressed NETs formation in both colonic tissue and serum. Comparative transcriptomics indicated that CBS suppresses NETs formation primarily through modulation of the IL-17 signaling pathway. DSS-induced colitis and PMA stimulation markedly increased the expression of IL-17A, IL-17RA, and p-p65 and elevated pro-inflammatory cytokines (IL-1β and TNF-α), while reducing the anti-inflammatory cytokine IL-10. CB or CBS treatment significantly reversed these pathological changes in both colon tissues and neutrophils. Importantly, IL-17A knockdown significantly reduced PMA-induced activation of the IL-17A/IL-17RA/NF-κB, and CBS treatment further enhanced these inhibitory effects under IL-17A-deficient conditions. CB protects against DSS-induced colitis by suppressing IL-17A/IL-17RA/NF-κB-mediated NETs formation in neutrophils. IL-17A knockdown confirmed IL-17A as a critical upstream regulator of NETs, establishing the IL-17A-NETs axis as a central mechanistic target of CB.
Peptic ulcer disease (PUD) remains a significant public health concern globally, particularly in regions with high prevalence of risk factors such as Helicobacter pylori infection and Non-Steroidal Anti-Inflammatory Drug (NSAID) use. This study aimed to investigate the prevalence of PUD and its associated risk factors among hospitalized patients in a tertiary hospital in southwest Iran. A mixed-methods design was employed, including a comprehensive literature review, checklist development and validation via a modified Delphi process, a cross-sectional prevalence study, and a hospital-based case-control study. Data were collected from 43,324 patient records (2019-2023) at Abadan University Teaching Hospital. Risk factors were assessed using a validated 21-item checklist, and multivariate logistic regression was used to identify independent predictors of PUD. Among all admissions, 6,874 cases of PUD were identified, indicating a point prevalence of 15.9% (95% CI: 15.6-16.2). NSAID use (75.3%), H. pylori infection (70.1%), smoking (46.9%), and corticosteroid use (30.2%) were highly prevalent among PUD patients. Significant independent risk factors included age ≥ 60 years (AOR: 1.65), NSAID use (AOR: 2.58), H. pylori positivity (AOR: 2.41), smoking (AOR: 1.45), and ulcer size ≥ 5 mm (AOR: 2.19). Despite the high rate of NSAID use, only 26.4% received gastroprotective therapy. The findings underscore the high burden of PUD in hospitalized patients in southwest Iran, with modifiable risk factors such as NSAID use, H. pylori infection, and smoking playing a critical role. Targeted interventions, including Proton Pump Inhibitor (PPI) co-prescription, H. pylori eradication, and lifestyle modifications, are essential to reduce PUD incidence and its complications.
Ex vivo differentiation platforms have a long-standing history for studying dendritic cell (DC) ontogeny and function. Here, we present a protocol for differentiating bona fide DCs from murine bone marrow. We describe steps for bone marrow preparation, followed by ex vivo differentiation of DC subtypes resembling either lymphoid or mucosal tissue DC phenotypes. We then detail procedures for flow cytometric analysis and sorting strategies that facilitate phenotypic and functional studies of murine DC subtypes and/or their bone marrow progenitors. For complete details on the use and execution of this protocol, please refer to Amon et al.1.
BACKGROUND Kennedy disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare and incurable X-linked neuromuscular disorder mainly affecting men aged 30 to 60 years. Polymyositis can present similarly, but can be excluded by measuring muscle enzymes, performing muscle imaging, and electromyography. This report describes the case of a 52-year-old man with a 10-year history of progressive limb weakness due to Kennedy disease, established by genetic testing. CASE REPORT A 52-year-old man presented with a 10-year history of gradually progressive proximal limb weakness and persistently elevated creatine kinase levels ranging from 808-2300 U/L (normal 39-308 U/L). One year prior to this admission, the limb weakness had worsened, but initial electromyography, neuroimaging, and muscle biopsy showed no specific abnormalities. Despite a trial of immunosuppressive therapy due to suspected polymyositis, there was no clinical improvement. Neurological examination later revealed gynecomastia, proximal muscle atrophy, and bilateral tongue atrophy with tremor. Electromyography showed chronic neurogenic changes and reduced sensory nerve action potentials. Repeat expansion analysis identified a hemizygous pathogenic CAG repeat expansion in exon 1 of the androgen receptor gene using a short-read next-generation sequencing-based repeat detection algorithm (ExpansionHunter), with an estimated repeat number of 51 (range 50-53). At 6-month follow-up, the patient demonstrated mild progression of motor symptoms but remained functionally stable. CONCLUSIONS This report presents a rare case of Kennedy disease, initially diagnosed as polymyositis, and highlights the importance of follow-up with genetic testing when neurological and electromyography investigations are not typical for polymyositis. Early identification of Kennedy disease helps avoid unnecessary immunosuppressive treatments.
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Genetic polymorphisms of alcohol-metabolizing enzymes influence drinking behavior and susceptibility to alcohol-related liver disease (ALD). This study aimed to clarify the distribution of ALDH2 and ADH1B genotypes in liver transplant recipients with ALD, and to explore associations with post-transplant drinking behavior using a recipient-donor paired design. Twenty-four living donor liver transplant (LDLT) recipients with ALD, their corresponding living donors, and 50 healthy controls were analyzed. Single nucleotide polymorphisms of ALDH2 (rs671) and ADH1B (rs1229984) were determined by the Cycleave PCR method. Drinking behavior before and after transplantation was assessed by self-report and electronic health records. Post-transplant alcohol use was classified as habitual (≥ once per week) or occasional (< once per week). ALDH2 genotype distribution differed among three groups (p = 0.002), with enrichment of the ALDH2*1/*1 genotype in ALD recipients (92%). ADH1B genotype distribution also differed among groups (p = 0.041), although the effect size was modest. During a median follow-up of 5.3 years (range, 0.3-15.9 years), 11 recipients (45%) reported post-transplant alcohol use, including 5 habitual drinkers (20%). In an exploratory analysis, a non-significant trend toward higher rates of habitual drinking was observed among recipients who received grafts from donors with the ALDH2*1/*1 genotype compared with other genotypes (40% vs. 7%, p = 0.12). The ALDH2*1/*1 genotype was more prevalent among liver transplant recipients with alcohol-related cirrhosis than among donors or healthy controls, supporting a role of alcohol tolerance-related genetic background in progression to end-stage liver disease. Donor ALDH2 genotypes may also influence post-transplant drinking behavior in an exploratory manner.
This study aimed to investigate the relationship between admission serum lipase levels, prognostic clinical scoring systems, and in-hospital mortality in patients presenting to the emergency department with acute pancreatitis. This retrospective cohort study included 389 patients hospitalized with acute pancreatitis at a tertiary care center between 2021 and 2023. Demographic characteristics, clinical findings, laboratory parameters obtained at admission and at 48 h, and imaging findings were collected. Prognostic assessment was performed using the Ranson, APACHE II, BISAP, Glasgow-Imrie, HAPS, and CTSI scoring systems. Patients were categorized according to a predefined serum lipase cutoff of 600 U/L. The associations between serum lipase levels, prognostic score categories, and in-hospital mortality were analyzed, and the diagnostic performance of the lipase cutoff was evaluated. The overall in-hospital mortality rate was 3.9% (n = 15). Admission serum lipase levels were significantly associated with the Ranson score (p < 0.05) and several laboratory parameters. A serum lipase cutoff of 600 U/L identified patients with a Ranson score ≥ 3 with a sensitivity of 70.2% (95% CI: 60.4-78.8) and a specificity of 57.3% (95% CI: 51.2-63.2). Higher prognostic scores, including Ranson, BISAP, and APACHE II, were significantly associated with in-hospital mortality (p < 0.01). However, admission serum lipase levels were not significantly associated with in-hospital mortality. Admission serum lipase showed a limited association with selected prognostic indicators in acute pancreatitis but was not associated with in-hospital mortality. These findings suggest that serum lipase has limited value as a standalone prognostic marker and should be interpreted in conjunction with established clinical scoring systems. Further prospective studies are needed to better clarify its role in risk assessment.