Endoscopic retrograde cholangiopancreatography (ERCP) remains the gold standard for Common bile duct (CBD) stone management, yet biliary cannulation challenges persist in some cases. There are limited data on primary Insulation-tipped (IT) knife precut for the biliary cannulation. Our aim was to investigate the efficacy and safety of IT nano knife-assisted primary precut in comparison to conventional cannulation for biliary access for the first time. This multicenter randomized controlled trial compared the efficacy and safety of primary IT knife nano-assisted precut sphincterotomy (group A) versus conventional cannulation (group B) in 340 patients with choledocholithiasis. Outcomes included initial/overall biliary cannulation success, procedural time, and adverse events (AEs). Group A demonstrated superior initial cannulation success compared to group B (85.9

Background and Objectives:Various lumen-apposing metal stents (LAMSs) were used for pancreatic fluid collection (PFC) drainage for many years. The structural design of LAMS needs to be improved to reduce the occurrence of adverse events. This trial assessed the efficacy and safety of a novel modified LAMS for the drainage of PFCs. Methods:This open-label, multicenter, prospective trial was done at 11 tertiary care hospitals. This study enrolled patients (18-75 years old) with confirmed diagnosis of PFC with cyst diameter no less than 6 cm. Novel LAMS (Micro-Tech Co, Ltd, Nanjing, China) was used. The primary end point was the 1-month postoperative drainage success rate. The secondary end points were technical success rate and adverse events. This study is registered with Chictr.org.cn, ChiCTR2000039955. Results:Between December 9, 2020, and December 27, 2021, 100 patients with PFC were assessed for eligibility, and 94 patients met the criteria and agreed to participate in the trial. The median size of PFC cyst was 11.23 ± 3.84 cm. The drainage success rate was 90.48% (95% CI, 83.6%-97.3%) and achieved the prespecified target value of 75% (P < 0.0001). In subgroup analysis, the clinical success rates of pancreatic pseudocyst (PPC) and walled-off necrosis (WON) were 95.45% and 85%, respectively (P = 0.143). The overall technical success rate was 98.94%. Postoperative early adverse events occurred in 57 (60.64%) of 94 patients, and late adverse events were encountered in 16 (17.02%) of 94 patients. The overall rate of serious adverse event (bleeding-related death) was 2.13% (2/94). Patients with WON had a significantly higher rate of early adverse events compared to those with PPC (77.78% vs. 44.90%, P = 0.001). Conclusions:The novel LAMS used in this trial was technically feasible, efficient, and safe for the treatment of PFCs. Comparable with WON, the usage of LAMS in PPC achieved a high drainage success rate and acceptable adverse events.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by early metastasis and poor prognosis. Here, we demonstrate that aldehyde dehydrogenase 1A3 (ALDH1A3) regulates PDAC lung tropism through an epigenetic-axon guidance axis. RNA sequencing analysis of clinical samples revealed that PDAC lung recurrence is associated with basal-like features and involves retinol metabolism and axon guidance pathways. Mechanistically, ALDH1A3 promotes acetyl-CoA production, enhancing histone H3 (H3K9/K14) acetylation at promoters of axon guidance receptors PLXNB1 and NRP1 to activate their transcription. Consequently, PDAC cells become sensitized to ligands SEMA4D and SEMA3A, which are abundantly expressed in lung epithelial cells. The resulting SEMA4D-PLXNB1 and SEMA3A-NRP1 signaling axes drive early metastatic colonization in the lung. Our findings reveal a regulatory circuit underlying PDAC organotropism and suggest potential therapeutic strategies against metastasis.

Objective Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by immune dysregulation and persistent inflammation. Mesenchymal stem cell (MSC) therapy shows promise but is limited by low homing efficiency. This study aimed to investigate whether berberine (BBR) pretreatment enhances the homing capacity and therapeutic efficacy of dental pulp MSCs (DP-MSCs) in IBD, and to clarify the role of the CXCR4/SDF-1 signaling pathway in immunomodulation. Methods Human dental pulp mesenchymal stem cells were isolated and identified. Through in vitro screening experiments (berberine, curcumin, quercetin, and liquiritigenin), 2 μmol/L BBR was determined to be the optimal pretreatment concentration (verified by CCK-8 and apoptosis experiments).A TNBS-induced mouse IBD model was established,and mice were randomized into Control,TNBS,TNBS+DP-MSC,TNBS+BBR-pretreated DP-MSC(BBR-DPMSC) groups,the DP-MSC + AMD3100 group, and the BBR-DPMSC+AMD3100 group.(n = 6/group). DP-MSCs or BBR-DPMSCs were administered via tail vein injection.AMD3100(CXCR4 pathway blocker) was administered by intraperitoneal injection.The intestinal inflammation and immune regulatory effects were evaluated by colon length measurement, disease activity index (DAI) score, HE staining and pathological score, and ELISA (IL-1β,IL-6,IL-10,TGF-β,SDF-1,CXCR4). In vivo live imaging assessed DP-MSC homing. Transwell assays and CXCR4 inhibitor AMD3100 were used to verify the CXCR4/SDF-1 pathway. Results In vitro screening demonstrated that berberine had the best pro-proliferative and anti-apoptotic effects on DP-MSCs among the four natural compounds (P < 0.01). In the IBD mouse model, compared with the untreated DP-MSCs, BBR-DPMSCs alleviated colonic shortening, reduced DAI scores, decreased intestinal mucosal damage and inflammatory cell infiltration, and regulated cytokine levels: lowering serum IL-1β and IL-6, and increasing anti-inflammatory factors IL-10 and TGF-β.Live imaging demonstrated that berberine significantly enhanced the homing efficiency of DP-MSCs to the injured intestine. In the TNBS model, SDF-1 was mainly highly expressed in the intestinal tissue, forming a specific chemotactic gradient. Transwell experiments confirmed that berberine promoted the migration of DP-MSCs in an SDF-1 concentration-dependent manner. Meanwhile, BBR could up-regulate the expression of CXCR4 in DP-MSCs. After blocking the CXCR4/SDF-1 pathway with AMD3100, the homing enhancement effect and therapeutic effect of the BBR-DP-MSC group were significantly decreased. Conclusion BBR pretreatment enhances the intestinal homing capacity of DP-MSCs via activating the CXCR4/SDF-1 signaling pathway, and exerts synergistic anti-inflammatory effects by upregulating IL-10 and TGF-β secretion, ultimately improving the therapeutic efficacy in IBD. This study provides a novel strategy for optimizing MSC-based immunotherapy of IBD by combining natural compounds with stem cells.

Background: Eosinophilic esophageal myositis (EoEM) involves eosinophilic infiltration of muscle layers but spares the epithelium, differing from eosinophilic esophagitis (EoE). EoEM is rare and underrecognized, with challenges in diagnosis and treatment. Objectives: To compare the clinical, endoscopic, pathological, and manometric characteristics of EoEM with mucosal-predominant and muscle-predominant EoE, and to elucidate differences and interconnections between these conditions. Design: Retrospective cohort study with literature review. Methods: The retrospective study included patients diagnosed with mucosal-predominant EoE ( n = 21), muscle-predominant EoE ( n = 6), and EoEM ( n = 7) at Nanjing Drum Tower Hospital from 2019 to 2024, along with a review of EoEM cases reported in the literature ( n = 11). Muscle thickness was measured using endoscopic ultrasonography and computed tomography (CT). High-resolution esophageal manometry was performed to evaluate esophageal motility and diagnose motility disorders according to the Chicago Classification v4.0 criteria. Clinical, endoscopic, pathological, manometric, and treatment data were analyzed. Results: EoEM patients were older and had more severe dysphagia, food impaction, and weight loss. Endoscopic findings revealed a distinct corkscrew-like appearance and luminal compression without typical mucosal inflammation. High immunoglobulin E (IgE) may be a marker of EoEM. Compared with muscle-predominant EoE, EoEM patients had higher maximum distal contractile integral values and a higher frequency of Jackhammer esophagus, although they exhibited similar muscle thickness. EoEM patients resisted proton pump inhibitors but responded favorably to oral steroids and Per-Oral Endoscopic Myotomy (POEM). Conclusion: EoEM is characterized by severe esophageal motility dysfunction. Muscle biopsy should be considered in patients with frequent dysphagia, motility disorders, and high serum IgE levels. Oral steroids and POEM effectively relieve symptoms.

[This corrects the article DOI: 10.3892/ol.2021.12973.].

Objective To evaluate the auxiliary diagnostic value of metabolic indicators and tumor markers combined with imaging in liver metastasis from pancreatic cancer,and to construct a nomogram model to improve diagnostic accuracy of radiologically indeterminate lesions.Methods A total of 255 patients with pancreatic cancer confirmed at Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School between January 2019 and August 2025 were retrospectively enrolled,including 46 patients with liver metastasis and 209 without.All cases were randomly divided into a training set(n=177,34 with liver metastasis)and a validation set(n=78,12 with liver metastasis)at a ratio of 7∶3.Clinical information,including CT/MRI imaging and routine laboratory data[lipid profile,glycated hemoglobin(HbA1C),tumor markers,liver enzymes],was collected.Independent associated factors were identified in the training set through logistic regression analysis,and a combined nomogram model integrating these factors with imaging information was constructed,and its performance was assessed in both sets using ROC analysis,calibration,and decision curve analysis.Results Patients with liver metastasis had significantly higher levels of low-density lipoprotein cholesterol(LDL-C),HbA1C,lactate dehydrogenase(LDH),as well as higher proportion of patients with carcinoembryonic antigen(CEA)＞10 ng/mL and CA125＞30.2 u/mL compared with those without metastasis(P＜0.05).Multivariate analysis of the training set identified that elevated LDL-C(OR=2.449,95％CI:1.085-5.525,P=0.031),elevated HbA1C(OR=1.625,95％CI:1.107-2.384,P=0.013),and CA125＞30.2 u/mL(OR=3.540,95％CI:1.006-12.450,P=0.049)were independent predictors of liver metastasis.The nomogram incorporating these factors and imaging information demonstrated excellent performance in the training set[area under the curve(AUC)=0.961,95％CI:0.907-1.000;sensitivity 89.9％,specificity 94.4％],and outperformed imaging alone(AUC=0.806).In the validation set,the model achieved an AUC of 0.907(95％CI:0.779-1.000),with sensitivity of 77.8％and specificity of 95.8％.Calibration curves indicated good agreement between predicted and observed outcomes,and decision curve analysis confirmed that the nomogram model provided a higher net clinical benefit across a wider range of threshold values.Conclusion Elevated LDL-C,HbA1C,and CA125＞30.2 u/mL are significantly associated with liver metastasis in pancreatic cancer.A nomogram model integrating these indicators with imaging findings can markedly improve diagnostic accuracy,particularly in patients with atypical imaging results or limited pathological sampling.

Hypoxia triggers PYGB to regulate ER stress to alter malignancy of CCA in vitro.

Tissue-resident memory T cells (TRM cells) have been shown to play an instrumental role in driving the onset and relapse of inflammatory bowel diseases (IBD). However, the underlying mechanism of TRM cells differentiation and its regulation in intestines remain to be unveiled. Mothers against decapentaplegic homolog 3 (SMAD3) is translocated from nucleus to membrane and activated in response to transforming growth factor beta (TGF-β), which is a key cytokine in the process of TRM cells polarization. Cysteine palmitoylation (S-palmitoylation) is a post-translational modification catalyzed by the DHHC family, regulating protein membrane associations. Genes associated with the classic SMAD3 signaling pathway, along with most genes in the DHHC family, were upregulated in TRM cells. Our study demonstrated that SMAD3 underwent reversible S-palmitoylation on Cys31 by DHHC6, leading to SMAD3 endomembrane recruitment and its subsequent colocalization with TGF-β receptor I (TGF-βRI) under TRM polarization conditions. The membrane recruitment of SMAD3 activated SMAD3 and subsequently upregulated the expression of its target genes, inducing the differentiation of TRM cells. In contrast, perturbation in DHHC6-induced palmitoylation with MYD-4 inhibited TRM cells differentiation and alleviated colitis in IBD model mice. Our work provides an example how the immune responses are regulated through the S-palmitoylation-dependent SMAD3 signaling in TRM cells differentiation and reveals protein S-palmitoylation as a potential target in IBD treatment, which could be of greater application considering the wide involvement of protein S-palmitoylation in the signal transduction in mammalian cells. The differentiation of TRM cells is promoted through TGF-β/SMAD3 pathway. The palmitoylation of SMAD3 on Cys31 by DHHC6 drives the membrane localization, the phosphorylation and the activation of SMAD3 under TRM polarization conditions. Inhibiting the differentiation of TRM cells by blocking palmitoylation of SMAD3 ameliorates colitis.

Gastric cancer remains a global health concern with high incidence and mortality rates. Accurate preoperative prediction of lymph node (LN) metastasis is crucial for staging, treatment planning, and prognosis. This study introduces a novel 3D end-to-end lymph node metastasis multi-task learning network (LMML-net) designed to predict LN metastasis across multiple nodal stations in gastric cancer. We analyzed a cohort of 293 patients who underwent gastrectomy with LN dissection. Preoperative CT scans, conducted within two weeks before surgery, were utilized. The LMML-net integrates tumor segmentation and LN metastasis prediction, employing a 3D attention-unet for tumor segmentation and a multi-task learning approach to address metastasis at different nodal stations. LMML-net demonstrated robust predictive performance, achieving AUCs of 0.813, 0.820, and 0.805 for total LN metastasis in training, testing, and validating cohorts, respectively. Notably, the model effectively addressed challenges posed by early gastric cancer and exhibited satisfactory results across various nodal stations. Visualization through GradCam highlighted significant contributions of both tumor and connective tissue areas to the predictions, enhancing the model’s interpretability. The LMML-net exhibits strong predictive capabilities for LN metastasis across multiple stations in gastric cancer, including cases of early-stage disease. This innovative approach holds promise for guiding personalized preoperative treatments and surgical planning, potentially improving patient outcomes in gastric cancer management. Code and models will be available at: https://github.com/yangzhi028/LMML-net.

As a highly malignant tumor, pancreatic adenocarcinoma (PAAD) has nonspecific symptoms and a poor prognosis. Previous studies have demonstrated that perineural invasion (PNI) and neurotrophic factors (NFs) play essential roles in PAAD. Nevertheless, the prognostic significance and functions of NF-related genes (NFRGs) in PAAD remain unclear. In this research, we conducted an intersection analysis utilizing differentially expressed genes (DEGs) found in the TCGA-PAAD cohort along with NFRGs from the Genecard. Using machine learning (ML) techniques, including LASSO regression, SVM-RFE and random forest algorithms, we developed a highly accurate prognostic model centered on NFRGs, ultimately pinpointing BCL11A as the crucial prognostic NFRG. Via analysis of the TCGA cohort, immunohistochemistry of 20 pairs of clinical samples and western blot of PAAD cell lines, BCL11A was found to be low-expressed in PAAD and associated with a poor prognosis. Experiments conducted both in vitro and in vivo revealed that the increased expression of BCL11A suppressed tumor growth and triggered apoptosis through endoplasmic reticulum (ER) stress. Moreover, immune infiltration analysis found increased CD8+ T cells in the BCL11Ahigh group. Flow cytometry demonstrated that overexpression of BCL11A in vivo promoted intratumoral CD8+ T cell infiltration and activation, and increased PD-L1 expression. Our study confirmed BCL11A as a potential biomarker of clinical prognosis, immune infiltration, and neural-tumor interactions in PAAD, and might provide new insights for diagnosis and treatment of this tumor.

Background:The precancerous lesion of colorectal cancer (CRC), colorectal sessile serrated lesion (SSL), takes an average of 15 years to germinate from no cell dysplasia to CRC, and 2 years for SSL with dysplasia (SSL-D). To date, the impacts of endoscopic and pathological features of SSL and SSL-D on the development of dysplasia remain unclear. In this study, we explored these impacts, striving to provide reference for its classification, detection, and diagnosis. Methods:Retrospectively, a cross-sectional analysis was conducted to compare 414 SSL and 59 SSL-D, which had been diagnosed under colonoscopy in the Affiliated Drum Tower Hospital of Nanjing University. Results:A total of 454 participants were enrolled with a mean age of 58.43±13.94 years and a male-to-female ratio of 0.91:1. There were significant differences between the SSL and SSL-D groups in the gender distribution (P=0.044). The proportion of patients with hypertension (33.33% vs. 17.13%, P=0.004) was higher in the SSL-D group. Significantly higher indexes in lipid metabolism were observed in the SSL-D group. SSL-D had a greater number of lesions ≥10 mm (86.44% vs. 57.00%, P<0.001), 0-IIa morphology (55.93% vs. 41.55%, P=0.049), and kermesinus surface (22.03% vs. 7.49%, P<0.001). Conclusions:Female SSL patients with a history of hypertension are more prone to developing into dysplasia, whereas morphological discriminations between SSL and SSL-D are vague. Lipid metabolism might have certain impact on the germination of SSL to SSL-D. Studies with larger sample sizes are warranted.

Berberine has been reported as a safe and effective pharmacological agent to reduce colorectal adenoma recurrence after polypectomy. This retrospective cohort study is an extended follow-up of a previous clinical trial (NCT02226185) during the post-treatment observational phase. We aim to evaluate the long-term protective effects of berberine on adenoma recurrence. Among 895 patients who finished the previous 2-year randomized trial, we recruited 781 patients at 7 clinical centers across 6 provinces in China. The primary outcome is adenoma recurrence. Between December 29, 2018, and October 10, 2024, 648 patients underwent at least one colonoscopy during the follow-up. The protective effects of berberine persist for at least 6 years after treatment cessation, with lower adenoma recurrence rate (34.7% vs. 52.1%) and lower neoplasm occurrence rate (63.4% vs. 71.0%). Berberine may serve as a potential long-term preventive agent against adenoma recurrence after polypectomy.

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide and in recent years its incidence is increasing rapidly in China, which constitutes a major public health burden. Almost 90% of CRC cases develop from precursor adenomatous polyps, through a series of genetic changes known as adenoma-carcinoma sequence during at least 10 years. Detection and removal of colorectal adenoma (CRA) could reduce CRC mortality risk by colonoscopy, but the recurrence rate is high. Our previous RCT study (NCT02226185) found that oral Berberine (BBR), a natural isoquinoline alkaloid extracted from the Chinese herb Coptis chinensis for 2 years significantly reduced recurrence after endoscopic removal of CRA (RR 0.77, 95% CI 0.66-0.91; p=0.001). The study recruited 895 participants who had undergone complete polypectomy within 6 months in seven hospital centers across six provinces in China between Nov 14, 2014, and Dec 30, 2016. Participants were randomly assigned (1:1) to receive BBR (0·3 g twice daily) or placebo tablets via block randomization for 2 years. After the end of randomized treatment, we continued this Follow-up Study to track adenoma recurrence for an average of 6 years till Sep 30, 2024. Besides 114 participants lost to follow up, we obtained follow-up information for 781 participants, 648 of whom underwent at least one colonoscopy after the end of study treatment and were included in this analysis. Mantel-Haenszel test was used to compute relative risks (RRs) and 95% confidence intervals (CIs) for the effect of BBR on risk of adenoma recurrence. Cox proportional-hazards model and Andersen-Gill model were used to analyze multi-recurrence by time. The study is registered with ClinicalTrials.gov, number NCT06629051. During the average 6 years follow up, we found that participants in the BBR group still had a substantially and statistically significantly lower risk of CRA than those in the placebo group (34.7% versus 52.1%; adjusted RR = 0.639, 95% CI = 0.508 to 0.785, P<0.001) and a reduction in risk of any neoplasm including inflammatory polyps, serrated lesions and colorectal cancer (adjusted RR = 0.874, 95% CI = 0.775 to 0.983, P = 0.022). Meanwhile the risk of non-advanced CRA in BBR group was lower than that in placebo group (adjusted RR = 0.634, 95% CI = 0.497 to 0.790, P<0.001). The incidence of adenoma recurrence was significantly lower in participants receiving BBR (HR= 0.601; 95% CI = 0.473-0.765; P<0.001). And in every year after treatment ended, the risk of adenoma recurrence in BBR group was lower than placebo group for all RRs<1.0 but some of which were not statistically significant. Generally, the protective effect of berberine on risk of colorectal recurrence extends up to 6 years after cessation of active treatment, even in the absence of continued supplementation.