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With the rising epidemic of obesity, metabolic syndrome, and type 2 diabetes mellitus in China, metabolic dysfunction-associated non-alcoholic fatty liver disease has become the most prevalent chronic liver disease. This condition frequently occurs in Chinese patients with alcoholic liver disease and chronic hepatitis B. To address the impending public health crisis of non-alcoholic fatty liver disease and its underlying metabolic issues, the Chinese Society of Hepatology and the Chinese Medical Association convened a panel of clinical experts to revise and update the "Guideline of prevention and treatment of non-alcoholic fatty liver disease (2018, China)". The new edition, titled "Guideline for the prevention and treatment of metabolic dysfunction-associated fatty liver disease (Version 2024)", offers comprehensive recommendations on key clinical issues, including screening and monitoring, diagnosis and evaluation, treatment, and follow-up for metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatotic liver disease. Metabolic dysfunction-associated fatty liver disease is now the preferred English term and is used interchangeably with metabolic dysfunction-associated steatotic liver disease. Additionally, the guideline emphasizes the importance of multidisciplinary collaboration among hepatologists and other specialists to manage cardiometabolic disorders and liver disease effectively., Competing Interests: JGF has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2013. YMN has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2022. JDJ and LW have been Executive Associate Editors of Journal of Clinical and Translational Hepatology since 2013. CS has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2020. JL has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2024. The other authors have no conflict of interests related to this publication., (© 2024 Authors.)

Bilirubin, the primary breakdown product of hemoproteins, particularly hemoglobin, plays a key role in the diagnosis, prognosis, and monitoring of liver diseases. In acute liver diseases, such as acute liver failure, drug-induced liver injury, and viral hepatitis, bilirubin serves as a biomarker reflecting the extent of hepatocyte loss and liver damage. Chronic liver diseases, including alcohol-related liver disease, chronic hepatitis C virus infection, metabolic dysfunction-associated fatty liver disease, and autoimmune liver diseases, are marked by persistent liver injury and inflammation. Bilirubin levels in chronic liver diseases provide insight into liver function, disease severity, and prognosis. As a versatile biomarker, bilirubin offers valuable information on the pathophysiology of liver diseases and aids in guiding clinical decision-making regarding the treatment of liver diseases and their complications. This review aimed to explore the multifunctional role of bilirubin in liver diseases by analyzing its biological functions beyond its role as a biomarker of liver damage., Competing Interests: XQ has been an Editorial Board Member of Journal of Clinical and Translational Hepatology since 2023, NMS has been an Associate Editor of Journal of Clinical and Translational Hepatology since 2021. The other authors have no conflict of interests related to this publication., (© 2024 Authors.)

Plastics, encompassing a wide range of polymeric materials, and their downstream products (micro- and nanoplastics, MNPs) are accumulating in the environment at an alarming rate, and they are linked to adverse human health outcomes. Considering that ingestion is a main source of MNPs exposure, the impact of plastics is particularly relevant towards intestinal inflammation and inflammatory bowel disease (IBD). However, the study of MNPs has been limited by obstacles relating to sample collection, preparation, and microplastics analysis based on optical microscopy and chemical analysis, which we detail in this review alongside potential solutions. We summarize available data on human exposure to MNPs and overall health outcomes, with particular focus on data pertaining to intestinal inflammation, microbiome perturbations, and related outcomes. We include ecologic perspectives, and human, in vitro, and animal model studies. We discuss the way forward in MNPs and IBD research, including knowledge gaps and future research., Competing Interests: Declaration of competing interest The corresponding author confirms on behalf of all authors that there have been no involvements that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated. MA reports consulting for Douglas Pharmaceutical. AV reports no conflict of interest. MP reports no conflict of interest. LSS reports no conflict of interest. RC reports no conflict of interest. MME reports no conflict of interest. KW reports no conflict of interest. JL reports no conflict of interest. TJ reports consulting for Ferring and Pfizer. IP reports no conflict of interest. JFC reports receiving research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, TiGenix,; and hold stock options in Intestinal Biotech Development. KHA reports no conflict of interest. JV reports no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Doublet chemotherapy with fluoropyrimidine (FP) and oxaliplatin (OX) plus bevacizumab (BEV) is a standard regimen for unresectable metastatic colorectal cancer (MCRC). However, the efficacy of adding OX to FP plus BEV (FP + BEV) remains unclear for older patients, a population for whom FP + BEV is standard. We aimed to confirm the superiority of adding OX to FP + BEV for this population., Methods: This open-label, randomized, phase III trial was conducted at 42 institutions in Japan. Patients with unresectable MCRC age 70-74 years with Eastern Cooperative Oncology Group performance status (ECOG-PS) 2 and those 75 years and older with ECOG-PS 0-2 were randomly assigned (1:1) to an FP + BEV arm or an OX addition (FP + BEV + OX) arm. Fluorouracil plus levofolinate calcium or capecitabine was declared before enrollment. The primary end point was progression-free survival (PFS). The study was registered in the Japan Registry of Clinical Trials (identifier: jRCTs031180145)., Results: Between September 2012 and March 2019, 251 patients were randomly assigned to the FP + BEV arm (n = 125) and the FP + BEV + OX arm (n = 126). The median age was 80 and 79 years in the respective arm. The median PFS was 9.4 months (95% CI, 8.3 to 10.3) in the FP + BEV arm and 10.0 months (9.0 to 11.2) in the FP + BEV + OX arm (hazard ratio [HR], 0.84 [90.5% CI, 0.67 to 1.04]; one-sided P = .086). The median overall survival was 21.3 months (18.7 to 24.3) in the FP + BEV arm and 19.7 months (15.5 to 25.5) in the FP + BEV + OX arm (HR, 1.05 [0.81 to 1.37]). The proportion of any grade ≥3 adverse events was higher in the FP + BEV + OX arm (52% v 69%). There was one treatment-related death in the FP + BEV arm and three in the FP + BEV + OX arm., Conclusion: No benefit of adding OX to FP + BEV as first-line treatment was demonstrated in older patients with MCRC. FP + BEV is recommended for this population.

Objective: To analyze the value of differential diagnosis of post-reflux swallow-induced peristaltic wave index (PSPWI) between esophageal diseases of gut-brain interaction (E-DGBI) and gastroesophageal reflux disease (GERD). Methods: The patients diagnosed as E-DGBI and GERD in the Department of Gastroenterology, Beijing Tsinghua Changguang Hospital from June 2016 to June 2018 were retrospectively included. The medical records, gastroscopy and 24-hour pH-intraluminal impedance monitoring reports were collected. According to clinical diagnosis, the patients were divided into E-DGBI group and GERD group. PSPWI, acid exposure time (AET), DeMeester score, total reflux times and mean nocturnal baseline impedance (MNBI) were compared between the both group. The receiver operating characteristic curve (ROC) of PSPWI, AET, total reflux times and MNBI was drawn to identify the sensitivity and specificity of E-DGBI and GERD. The cut-off values were calculated with Youden index and the area under the curve (AUC) was compared. Results: A total of 73 patients were included,including 36 males and 37 females, whose age [ M (Q 1 , Q 3 )] was 54.0 (42.6, 63.0) years. There were 39 cases in E-DGBI group and 34 cases in GERD group. The 24-h AET [0.5 (0.1, 1.6) vs 6.0 (3.6, 11.9)], DeMeester score [2.8 (1.1, 5.7) vs 20.4 (14.7, 47.4) score] and total reflux times [32.0 (19.0, 53.0) vs 66.0 (34.3, 96.0) times] were significantly higher in E-DGBI group than those in GERD group (all P : 0.827-0.963) in differentiating E-DGBI and GERD. The sensitivity was 94.1% and the specificity was 69.2%. There were no significant differences of AUC between PSPWI and AET or total reflux events (all P >0.05). But the AUC of PSPWI was higher than that of MNBI (AUC=0.749,95% P <0.001). According to ROC, with PSPWI>0.46 as the cut-off value, the AUC was 0.895 (95% CI : 0.827-0.963) in differentiating E-DGBI and GERD. The sensitivity was 94.1% and the specificity was 69.2%. There were no significant differences of AUC between PSPWI and AET or total reflux events (all P >0.05). But the AUC of PSPWI was higher than that of MNBI (AUC=0.749,95% CI :0.632-0.866, P =0.031). Conclusion: PSPWI can better distinguish E-DGBI from GERD.

Protection against blood-brain barrier (BBB) dysfunction is key to reduce the cerebral ischemia injury as its breakdown causes edema formation and extravasation of blood components and immune cells. The maintenance of BBB integrity requires the GSK-3β/β-catenin pathway activity. Naringenin (NAR), an effective monomer from Chinese herbal medicine, had potent protective effect on brain inflammatory and oxidative injury. However, whether NAR could protect the integrity of BBB during cerebral ischemia injury and the involvement of GSK-3β/β-catenin pathway in the beneficial effect of NAR was unknown. Therefore, mouse middle cerebral artery occlusion/reperfusion (IR) model was employed to answer these questions. NAR was intraperitoneally administrated once daily for 6 days immediately after IR with the dose of 10 mg/kg. BBB damage was evaluated with Evans blue. Protein levels of GSK-3β and β-catenin in vascular endothelial cells at penumbra were assessed with western blotting and immunofluorescence. The experimental data suggested that NAR improved neurological deficits, decreased the percentage of infarct volumes and neuronal apoptosis at 7d after IR. NAR improved BBB damage as evidenced by a lower permeability of Evans blue dye and upregulation of tight junction proteins such as zonula occludens-1(ZO-1), Occludin and Claudin-5. Importantly, GSK-3β/β-catenin pathway activity was related to the improvement of BBB integrity rendered by NAR. Our findings demonstrated that NAR might become a potential therapeutic drug for IR., Competing Interests: Declarations Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Ferroptosis and inflammation are involved in cancer progression. The aim of this study was to identify inflammation-associated ferroptosis regulators in hepatocellular carcinoma (HCC)., Methods: FerrDb database was searched for ferroptosis-related genes. RNA sequencing data and clinicopathologic information of HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. Weighted gene co-expression network analysis was applied to obtain the genes probably involved in inflammation-associated ferroptosis. Univariate Cox regression analysis was conducted to screen prognostic genes, and 10 machine learning algorithms were combined to find the optimal strategy to evaluate the prognosis of the patients based on the prognosis-related genes. The patients were divided into high risk group and low risk group, and the differentially expressed genes were obtained. Thymosin beta 4 X-linked (TMSB4X) was overexpressed or knocked down in HCC cell lines, and then qPCR, CCK-8, Transwell, flow cytometery assays were performed to detect the change of HCC cells' phenotypes, and Western blot was used to detect the change of ferroptosis markers., Results: 157 genes related to inflammation and ferroptosis in HCC were obtained by WGCNA. rLasso algorithm, with the highest C-index, screened out 29 hub genes, and this model showed good efficacy to predict the prognosis of HCC patients. The patients in high risk group and low risk groups showed distinct molecular characteristics. TMSB4X was the most important gene which dominated the classification, and it was highly expressed in HCC samples. TMSB4X promoted the viability, migration and invasion, and repressed ferroptosis of HCC cells., Conclusion: The risk model constructed based on the inflammation-associated ferroptosis regulators is effective to predict the clinical outcome of HCC patients. TMSB4X, involved in inflammation-associated ferroptosis, is a potential biomarker and therapeutic target for HCC., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Acute-on-chronic liver failure (ACLF) is characterized by rapid onset, rapid development and a high short-term mortality rate. Systemic inflammation exerts an effect on the disease progression of ACLF., Objectives: The purposes of this study were to explore the clinical significance that the inflammatory response has on the disease process of hepatitis B virus acute-on-chronic liver failure (HBV-ACLF) patients, to further compare the values of different inflammation-related biomarkers in the prognosis evaluation of HBV-ACLF patients, and to combine inflammatory-related markers to establish a new prediction model., Material and Methods: Baseline admission data and 90-day outcomes were collected from 247 patients who met the inclusion criteria. According to the 90-day survival situation, they were divided into a survival group and a death group. The differences in baseline data and inflammation levels between the 2 groups were compared. A regression model was used to analyze the risk factors for 90-day mortality and establish a new model., Results: The study found that the differences between the survival group and the death group were statistically significant in terms of age, total bilirubin (Tbil), prothrombin time (PT), international standardized ratio (INR), inflammation level, and model for end-stage liver disease (MELD) series scores (p < 0.05). The monocyte-to-lymphocyte ratio (MLR)-integrated iMELD model (MLR-iMELD) can effectively predict the 90-day survival rate of HBV-ACLF patients. The area under the receiver operating characteristic (ROC) curve (AUROC) of the new model was 0.792, and the best cutoff for predicting the prognosis of 90 days for patients was -0.33 (sensitivity 0.577 and specificity 0.898)., Conclusions: The higher the level of inflammation in patients with HBV-ACLF, the greater the risk of 90-day death. Compared with other inflammation-related markers, the MLR-iMELD model can better predict the 90-day survival rate of HBV-ACLF patients.

Background: Both lipid metabolism and cyclic RNAs (circRNAs) have been found to be involved in pancreatic adenocarcinoma (PAAD) progression, but the relationship between lipid metabolism and circRNAs remains unclear., Methods: The expression levels of miR-223-3p, circ&#95;0124346, and acyl-CoA synthetase long chain family member 3 (ACSL3) were determined through qRT-PCR and Western blot analysis. Cell proliferation was evaluated using the CCK-8 and EdU incorporation assays. Cholesterol (CH) and triglyceride (TG) levels were quantified using relevant kits. The relationships between miR-223-3p and circ&#95;0124346 or ACSL3 mRNA were examined by bioinformatics analysis, luciferase reporter, RNA-RNA pull-down, and RIP assays., Results: We observed a significant elevation in circ&#95;0124346 expression in both pancreatic adenocarcinoma (PAAD) tissues and cell lines, and its expression level was shown to be correlated with tumor size. Circ&#95;0124346 stimulated cell proliferation and facilitated lipid synthesis in PAAD cells. Additionally, we found that circ&#95;0124346 functioned as a sponge for miR-223-3p, preventing miR-223-3p's binding to the 3'-UTR of ACSL3 mRNA, which subsequently led to an elevation in ACSL3 expression and promoted lipid synthesis. Accordingly, circ&#95;0124346 knockdown resulted in a significant decrease in lipid synthesis and cell proliferation in PAAD cells, with partial reversal of these effects achieved via inhibiting miR-223-3p or overexpressing ACSL3., Conclusion: Our study demonstrated that circ&#95;0124346 regulates lipid metabolism in PAAD cells via the miR-223-3p/ACSL3 axis, suggesting that targeting circ&#95;0124346 may serve as a potential strategy for treating PAAD and assisting in its diagnosis., Competing Interests: Declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by the Ethics Committee of the Taizhou Central Hospital (Taizhou University Hospital) (approval no. 2021 K-11–13). Informed consent was obtained from all individual participants included in the study. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Lung cancer is a major cause of cancer-related deaths worldwide. It can be divided into 2 main types, namely non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Most patients with NSCLC are diagnosed at an advanced stage, and current treatments have limited success. Moreover, relapsing tumors that often appear after surgical or drug treatment are particularly difficult to treat. The existence of cancer stem cells (CSCs) has been proposed as a key factor contributing to the development of resistance to therapy, recurrence and metastasis. Targeting CSCs is a potential strategy for eradicating tumors. However, due to the tumor-type specificity and cellular plasticity, the real clinical application of lung cancer stem cells (LCSCs) has not been realized. This review details the existing phenotypic markers of LCSCs and the limitations of their identification and summarizes the roles of the tumor microenvironment (TME) and epithelial-mesenchymal transition (EMT) in the existence and maintenance of LCSCs, as well as the contribution and controversy of cellular plasticity theory on LCSCs. It is expected that future research on LCSCs can solve the present problems, and approaches targeting LCSCs may be applied in the clinic as soon as possible.

Background: Microsatellite instable (MSI) gastric cancers exhibit reduced lymph node (LN) metastasis and improved survival compared to microsatellite stable (MSS) counterparts. However, to our longstanding observation, clinical N-staging (cN) is frequently overestimated in MSI cases. The clinical implications and underlying mechanisms of this discrepancy warrant further investigation., Materials and Methods: We conducted a comprehensive review of clinicopathological data from a 141 MSI and 1119 MSS gastric cancer patients. Expression of vascular endothelial growth factor-C (VEGF-C) and its receptor VEGFR-3 were assessed using qPCR and immunohistochemistry. High-parameter flow cytometry was employed to analyze subsets of CD8+ T cells within the tumors., Results: Multivariate analysis revealed that MSI status was an independent prognostic factor, alongside the LN ratio and AJCC8 pathology staging. MSI gastric cancers exhibited a reduced LN ratio, particularly at advanced T-staging, compared to MSS counterparts, while maintaining an equivalent LN yield. Overestimation of cN by computed tomography preoperatively was frequent in MSI gastric cancers but was more commonly underestimated in MSS counterparts. VEGF-C and VEGFR-3 expression were lower in MSI tumors. MSI gastric cancers showed an increased total number of CD8+ T cells, albeit with a lower proportion of effector memory cells expressing CD45RA (EMRA) and CD8+ CXCR4+ T cells, compared to MSS counterparts., Conclusion: Frequent overestimation of clinical N-staging in MSI gastric cancers is associated with VEGF-C signaling and CD8+ T-cell dynamics and should be cautiously interpreted, as it might misguide therapeutic options., (© The Author(s) 2024. Published by Oxford University Press.)

Background: There is still controversy regarding the treatment strategy for moderate acute cholecystitis (AC). Percutaneous transhepatic gallbladder drainage (PTGBD) followed laparoscopic cholecystectomy (LC) has shown advantages compared to emergency LC (ELC). However, the results are controversial. Therefore, we conducted this updated meta-analysis to clarify this issue., Materials and Methods: A comprehensive literature search for relevant studies comparing the PTGBD + LC and ELC for moderate AC was performed. The statistical analysis was conducted using Stata., Results: A total of 14 studies were included. The pooled analysis revealed that PTGBD + LC group had a shorter operation time (SMD = -1.07, 95%CI = -1.19 to -0.95), lower amount of intraoperative bleeding (SMD = -0.93, 95%CI = -1.07 to -0.79), lower conversion rate (OR = 0.28, 95% CI = 0.17-0.44), lower postoperative complications (OR = 0.45, 95% CI = 0.23-0.88) shorter postoperative hospital stay (SMD = -1.20, 95%CI = -1.33 to -1.07), lower wound infection rate (OR = 0.41, 95%CI = 0.23-0.74) and higher hospitalization expenses (SMD = 1.13, 95%CI = 0.96 to 1.29) compared with ELC group. There was no significant difference in the incidence of bile leak, bile duct injury and total hospital stay., Conclusion: This meta-analysis suggested that PTGBD + LC has significant advantages over ELC for moderate AC patients, including lower surgical difficulty, lower conversion rate, fewer postoperative complications, and shorter hospital stay., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Aims: The pathological characteristics of lymphocyte infiltration in the hepatic portal tracts of patients with primary biliary cholangitis (PBC) remain unclear. Tertiary lymphoid structures (TLSs) are ectopic lymphoid tissues associated with the exacerbation of autoimmune reactions. Here, we evaluate the role of TLSs in PBC and investigate their potential therapeutic value., Methods: We recruited 75 patients with PBC and 53 control patients with liver biopsies who were followed more than 2 years. TLSs and their maturity were identified by the amount and spatial distribution of immune cells. Bulk RNA sequencing of liver was performed in PBC patients with different TLS maturity. The sphingosine-1-phosphate receptor (S1PRs) modulator FTY720 was administered to dnTGFβRII mice to assess the role of TLSs on cholangitis., Results: TLSs presented in 61.3% (46/75) of liver tissues from patients with PBC, including 26 patients with mature TLS (mTLS) and 20 patients with immature TLS (imTLS). The proportion of mTLS was higher in PBC compared with chronic hepatitis B and autoimmune hepatitis. PBC patients with mTLS exhibited the highest serum levels of biochemical indicators, immune globulin and proportions of liver cirrhosis. Gene sets for lymphocyte migration and chemokine signalling pathways were enriched in patients with PBC presenting with TLS. FTY720 inhibited TLS formation and relieved cholangitis and fibrosis in dnTGFβRII mice., Conclusion: TLSs are characteristics of lymphocyte accumulation in the portal tracts of PBC, of which the maturity of TLSs correlates with the inflammation and fibrosis of PBC. Targeting TLSs formation is a potential treatment of PBC., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Context: A Body Shape Index (ABSI) has been reported to have associations with cardiovascular risk factors. However, there is no information on the association between ABSI and incidence of cardiovascular events., Methods: We investigated the associations between ABSI and first major cardiovascular events (death from cardiovascular disease, nonfatal acute coronary syndrome, and nonfatal stroke) in 1857 subjects from the database of Flow-Mediated Dilation Japan registry and from Hiroshima University Vascular Function registry., Results: The areas under the curves of ABSI to predict the first major cardiovascular events were superior to BMI (men: P = .032, women: P = .015) and waist circumference in women (men: P = .078, women: P = .002). The subjects were divided into 2 groups based on the cutoff value of ABSI for predicting first major cardiovascular events: a low ABSI group (<0.0822 in men and <0.0814 in women) and a high ABSI group (≥0.0822 in men and ≥0.0814 in women). During a median follow-up period of 41.6 months, 56 subjects died (23 from cardiovascular causes), 16 had nonfatal acute coronary syndrome, and 14 had nonfatal stroke. The Kaplan-Meier curves for first major cardiovascular events were significantly different between the 2 groups (men, P < .001; women, P < .001). Multivariate analysis revealed that high ABSI remained an independent predictor of first major cardiovascular events (men: hazard ratio, 2.33; 95% CI, 1.07 to 5.06; P = .033; women: hazard ratio, 8.33; 95% CI, 1.06 to 65.49; P = .044)., Conclusion: High ABSI is independently associated with incidence of cardiovascular events. ABSI calculation should be performed for evaluation of risk of cardiovascular events., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Context: One of the major prognostic indices in neuroendocrine tumors (NETs) is Ki67 proliferation index., Objective: To identify optimal grading Ki67 cutoffs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs)., Methods: Multicenter retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at 5 European referral centers with a mean (±SD) follow-up time of 51.5 (±52.9) months, measuring rates of overall survival (OS) and event-free survival (EFS)., Results: Median age at baseline was 62.3 (range, 17-90) years; 252 (45.7%) patients were female. All SI-NETs were well-differentiated, with 326 being grade 1 (G1; 59.2%), 169 G2 (30.7%), and 8 G3 (1.5), while 48 tumors were unspecified grade (8.7%). The median Ki67 was 2% (range, 1%-70%). At baseline, 247 (44.8%) patients had distant metastases (stage IV), 217 locoregional disease (41.1%; stage III), while 29 (7.1%) and 25 (4.5%) presented at stages II and I, respectively. Median OS was 214.7 (95% CI, 152.7-276.6) months and median EFS was 79.8 (68.2-91.5) months. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (Ki67 5%-10% group: HR = 2.2 [95% CI, 1.15-4.31], P = .018 and Ki67 ≥ 10% group: HR = 5.11 [2.87-9.09], P < .001), age (HR = 1.07 [1.04-1.09], P < .001), Charlson Comorbidity Index (HR = 1.08 [1-1.16], P = .028), and TNM stage (HR = 1.79 [1.05-3.06], P = .034) were independent predictors for death. Pertinent EFS analysis confirmed the proposed modified histopathological Ki67 grading system (Ki67 ≥ 10% group: HR = 4.01 [2.6-6.37], P < .001) and age (HR = 1.04 [1.02-1.05], P < .001) as independent predictors for recurrence, progression, and/or death., Conclusion: Ki67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki67 cutoffs of 5% and 10% could be superior to predict differences in SI-NET patient survival outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

The P2X7 receptor, an ATP-gated ion channel which belongs to the P2X receptor family, plays critical roles in recognizing extracellular adenosine 5'-triphosphate (ATP) and is widely expressed in most tumor cells as well as inflammatory cells. Previously, the P2X7 receptor has been demonstrated to modulate the progression of various malignancies, including glioblastoma, pancreatic cancer, lung cancer, leukemia, and lymphoma. However, the biological function and prognostic values of P2X7 receptor in hepatocellular carcinoma remain to be determined. Here, we investigated the expression level of P2X7 receptor in patients with hepatocellular carcinoma. Then MTS and EdU assays were carried out to study the role of P2X7 receptor blockade in the proliferation of hepatocellular carcinoma cells. In addition, the underlying mechanism was further elucidated by bulk RNAseq. Compared to the control group, the P2X7 receptor was significantly up-regulated in the hepatocellular carcinoma group. Interestingly, A740003 and A438079, two selective antagonists at P2X7 receptor, significantly blocked Ca 2+ influx and decreased the proliferative rate of hepatocellular carcinoma cells. Furthermore, the expression level of chondroitin sulfate synthase 1 (CHSY1), an enzyme that mediates the polymerization step of chondroitin sulfate, was reduced by both A740003 and A438079. In conclusion, inhibition of the P2X7 receptor attenuated the proliferation of hepatocellular carcinoma cells, and this process was largely modulated by CHSY1. Thus, our findings reveal a previously unknown role for P2X7 receptor in the proliferation of hepatocellular carcinoma cells and imply that the P2X7 receptor may represent a new target for the treatment of hepatocellular carcinoma., Competing Interests: Declarations Ethical approval There’s no animal experiment in this study, so no need to approve the experimental animal ethics. Moreover, all the clinical patients data were downloaded from public databases, and the ethical approval were stated in the references or cited websites. Consent for publication All authors approved to publish the study in this journal. Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that presents significant treatment challenges due to its complexity, especially in terms of the various side effects that traditional medications may bring during the chronic course of the disease. Traditional Chinese medicine (TCM) has emerged as a promising complementary therapy for UC. Based on the latest research, our editorial explored the current issues and potential essential research directions for TCM in treating UC. We anticipate that future high-quality research will pave the way for the optimization of TCM formulas for UC and their broader global application., Competing Interests: Conflict-of-interest statement: All authors decare no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic PRF1 null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life-threatening immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin-deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe-immune cell interactions due to specific pathogen-free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a "wild" microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota ('PKO-Wildlings') and monitored them for signs of HLH. PKO-Wildlings survived long-term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO-Wildlings. Interestingly, after infection with LCMV, PKO-Wildlings developed an altered HLH pattern. This included lower IFN-γ serum levels along with improved IFN-γ-driven anemia, but more elevated levels of IL-17 and increased liver inflammation compared with PKO-SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host-microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Background: Although specific biomarkers for primary sclerosing cholangitis (PSC) are required, no such biomarkers have been identified. We previously reported that patients with PSC had anti-integrin αvβ6 autoantibodies at only two hospitals. In this study, we aimed to validate the accuracy of the autoantibodies in diagnosing PSC using the newly developed Anti-integrin αvβ6 enzyme-linked immunosorbent assay (ELISA) Kit, which enables quantitation and comparison of antibodies among different facilities., Methods: Overall, 81 patients with PSC in a Japanese PSC registry recruited from 17 medical centers and hospitals, and 358 controls were enrolled. We retrospectively assessed anti-integrin αvβ6 autoantibodies using the Anti-integrin αvβ6 ELISA Kit and in-house ELISA., Results: Anti-Integrin αvβ6 ELISA Kit and in-house ELISA exhibited a significant correlation (r = 0.97, P < 0.001). Anti-integrin αvβ6 autoantibodies were detected in 67 of 81 (82.7%) patients with PSC and 20 of 358 (5.6%) controls, resulting in a sensitivity of 82.7% and specificity of 94.4% for PSC, using the anti-integrin αvβ6 ELISA Kit. When focusing on the presence or absence of inflammatory bowel disease (IBD), the sensitivities for PSC with ulcerative colitis, Crohn's disease, unclassified-IBD, and without IBD were 97.8% (43/44), 100% (1/1), 80.0% (8/10), and 53.8% (7/13), respectively. Antibody concentrations were significantly higher in PSC patients without IBD than in controls (P < 0.001)., Conclusions: We validated that anti-integrin αvβ6 autoantibodies have high sensitivity and specificity for diagnosing PSC. This study provides further evidence that anti-integrin αvβ6 autoantibodies are a useful biomarker for diagnosing PSC., (© 2024. The Author(s).)

Drug-induced liver injury (DILI) is a major concern associated with the use of avacopan, a new therapeutic agent for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Here, we report a rare instance of liver biopsy performed for persistent liver injury following discontinuation of avacopan in an elderly woman with microscopic polyangiitis (MPA). The patient developed cholestatic liver injury after 2 months of avacopan therapy, which led to drug cessation. Despite the discontinuation of avacopan followed by supportive care, the liver enzyme levels remained elevated, necessitating liver biopsy. Histological examination revealed residual inflammation and focal necrosis around the portal vein, indicating ongoing liver injury despite avacopan withdrawal. This case report highlights the hepatotoxic potential of avacopan, the importance of vigilant liver function monitoring, and the value of liver biopsy in the chronic phase of avacopan-induced liver injury. Further research is required to elucidate avacopan hepatotoxicity mechanisms and identify potential risk factors for DILI in patients with AAV., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Esophageal cancer is the 6th most common cancer in terms of incidence and the 4th most common cause of mortality in China. Given the limited survival outcomes observed in patients with locally advanced disease managed exclusively with surgical intervention, postoperative treatment is critically important. This study sought to assess the prognostic value of total cholesterol (TC) levels and the prognostic nutritional index (PNI) in patients undergoing postoperative chemotherapy for esophageal cancer., Methods: A total of 101 patients who underwent postoesophagectomy chemotherapy were included in this retrospective analysis. PNI values for prechemotherapy were calculated for each patient [PNI = albumin + 5 × lymphocyte count] and TC. The optimal cutoff values for these indices were calculated from the receiver operating characteristic (ROC) curve. Patients were stratified into three groups on the basis of their PNI and TC levels. A novel nutritional prognostic index, termed the cholesterol-dependent nutritional prognostic index (CPNI), was developed on the basis of the PNI and TC. Univariate and multivariate Cox analyses were employed to determine the associations between each indicator and clinical outcomes., Results: The prechemotherapy PNI, TC level, and TNM stage became independent risk factors for OS (p < 0.05). Patients in the high PNI-high TC group had significantly improved DFS and OS compared with those in the low PNI-low TC group (p < 0.001) and had a lower early recurrence rate (P = 0.008). In contrast, patients with a high CPNI had a higher mortality rate., Conclusion: The prechemotherapy PNI combined with TC is an accurate and useful predictor of patient prognosis., Competing Interests: Declarations Ethics approval and consent to participate This study was performed in accordance with the principles of the Declaration of Helsinki. Approval was granted by the Clinical Research Ethics Committee, Zhongda Hospital, Southeast University, China, with approval number 2020ZDSYLL259-P01. Consent for publication The Clinical Research Ethics Committee of Zhongda Hospital, Southeast University, China waived the need for written informed consent because of the retrospective nature of this study. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The objective of the current study was to investigate the potential effects of syringin against dextran sulphate colitis (DSS)-induced ulcerative colitis (UC) in mice., Material and Methods: In vitro study was performed on the RAW 264.7 cells and cytokines and inflammatory level were estimated. The oxidative stress, inflammatory cytokines, apoptosis and inflammatory parameters were estimated. The mRNA expression and faecal samples were estimated in the colon tissue., Results: Syringin treatment enhanced the body weight, colon length and reduced the disease activity index (DAI), spleen index. Syringin treatment remarkably suppressed the level of nitric oxide (NO), myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) along with alteration of antioxidant parameters. Syringin treatment also altered level of cytokines in the serum and colon tissue; inflammatory parameters viz., platelet-activating factor (PAF), cyclooxygenase-2 (COX-2), prostaglandin (PGE 2 ), inducible nitric oxide synthetase (iNOS), nuclear factor κ-B (NF-κB); matrix metalloproteinases (MMP) level. Syringin significantly (p < 0.001) enhanced the level of nuclear factor erythroid 2-related factor (Nrf 2 ) and heme oxygenase-1 (HO-1). Syringin remarkably altered the relative abundance of gut microbiota like Firmicutes, Bacteroidetes, F/B ratio, Verrucomicrobia and Actinobacteria., Conclusion: Syringin exhibited the protective effect against DSS-induced UC in mice via alteration of NF-κB signalling pathway., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: This retrospective study aimed to investigate the role of an additional high mechanical index (MI) setting scan during the post-vascular phase (PVP) in detecting deep-seated hepatocellular carcinoma (HCC) lesions., Methods: A total of 805 confirmed HCCs, which underwent Sonazoid-based contrast-enhanced ultrasound (CEUS) between January 2014 and October 2021, were included. Low MI scan was initially employed for lesion detection during the PVP, followed by high MI scan. Propensity score matching (PSM) was utilized to address confounding variables., Results: Of the 805 study lesions, 668 were detected as perfusion defects at the initial low MI setting, while 137 remained undetected. Among these 137 undetected lesions, 77 were identified at the subsequent high MI setting, whereas 60 remained undetected. Lesions that were larger (18.69 ± 11.27 mm vs. 16.55 ± 7.42 mm, p = 0.006), more superficial (6.06 ± 2.41 cm vs. 7.40 ± 2.74 cm, p < 0.001), and hypoechoic (482/668 vs. 62/137, p < 0.001) were detectable at the initial low MI setting. Male patients benefited more from the additional high MI scan (63/97 vs. 14/40, p < 0.001). Lesions identified with additional high MI were larger (18.30 ± 8.76 mm vs. 14.30 ± 4.34 mm, p < 0.001) and deeper than undetected ones (8.48 ± 2.48 cm vs. 6.02 ± 2.43 cm, p < 0.001). After PSM, depth was shown to be an independent predictor in multivariate analysis (odds ratio: 1.557, 95% confidence interval: 1.249-1.941). The depth cutoff was 7.75 cm, with a sensitivity of 0.681, specificity of 0.851, and area under the curve of 0.774., Conclusions: The additional high MI setting scan during the PVP of Sonazoid-based CEUS leads to enhanced detection of deep-seated HCCs., Competing Interests: Declarations Conflict of interest The authors have no conflicts of interest to report. Ethical statements The study has received approval from the Institutional Review Board (No. F220200042), ensuring compliance with all relevant laws and the Declaration of Helsinki. Due to the retrospective nature of the study, the need for informed consent was waived., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Background and Aim: Endoscopic submucosal dissection (ESD) has become the treatment of choice for many superficial gastric neoplasms. Clinical outcomes are increasingly comparable between Japanese and Western series; however, data are lacking on the validity of risk stratification tools in Western cohorts. We aimed to evaluate clinical outcomes, explore risk stratification, and compare our data with published Western series., Methods: We conducted a retrospective, observational cohort study in a single tertiary referral center over a 13-year period. Primary outcomes were rates of en bloc, complete (R0) and curative resection. Secondary outcomes included adverse events, recurrence, metachronous lesions, eCura grades, and ESGE criteria. A comparative analysis was performed with existing published series from Western centers., Results: Totally 112 patients were included in the study cohort. 50.9% were male, 87.5% Caucasian, and median age was 75.5 years (IQR 14.3 years). Lesions were predominantly antral (36.6%) or body (35.7%); median size 20 mm (IQR 15 mm). Rates of en bloc, R0 resection, and curative resection were 96.4%, 89.3%, and 78.6% (identical between eCura and ESGE), respectively. Adverse events occurred in 5.8%, recurrence in 0%, and metachronous lesions in 9.9%. Our data compared favorably with a review existing Western series, which illustrates increasing adoption of ESD and stable outcomes over time., Conclusion: ESD represents a safe and effective method of treatment for gastric neoplasia in the Western setting. This study highlights the potential for excellent outcomes in a single center with a heterogeneous patient cohort and supports the use of eCura in guiding post procedural management., (© 2024 The Author(s). JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Hyperplastic polyps, which represent 30%-93% of all gastric epithelial polyps, are the second most common type of gastric polyps after fundic gland polyps. They were previously considered to have no risk of neoplastic transformation. Recently, an increasing number of cases of gastric hyperplastic polyps (GHPs) combined with neoplastic changes have been reported; however, the specific mechanism underlying their transformation has not been thoroughly explored., Aim: To investigate the clinical, endoscopic, and pathological characteristics of the neoplastic transformation of GHPs and explore the risk factors., Methods: A retrospective analysis was performed on 4010 cases of GHPs diagnosed by gastroscopy and pathological examination at the hospital from 2005 to 2021. In total, 3874, 119, and 17 cases were in the group without intraepithelial neoplasia (IN), with low-grade IN, and with high-grade IN, respectively. The data analysis examined the association of endoscopic and pathological features with risk factors for neoplastic transformation. Factors with significant differences were entered into univariate logistic regression, followed by multivariate logistic regression analysis., Results: Univariate analysis revealed diameter, multiple polyp presence, redness, rough surface, lobulation, erosion, Yamada classification, location, and gastric mucosa were risk factors for neoplastic transformation. Multivariate analysis showed that age > 65 years [odds ratio (OR) = 1.789; 95% confidence interval (CI): 1.227-2.609; P = 0.003], male sex (OR = 1.680; 95%CI: 1.158-2.438; P = 0.006), multiple polyps (OR = 1.851; 95%CI: 1.230-2.784; P = 0.003), pedunculated or semi-pedunculated shape (OR = 2.722; 95%CI: 1.689-4.388; P < 0.001), and polyp diameter were significantly associated with GHPs that demonstrated neoplastic transformation. Compared with chronic superficial gastritis, autoimmune gastritis, atrophic gastritis, and gastritis with IN were independent risk factors for neoplastic transformation [(OR = 2.672; 95%CI: 1.559-4.579; P < 0.001), (OR = 1.876; 95%CI: 1.134-3.103; P = 0.014), and (OR = 5.299; 95%CI: 3.173-8.849; P < 0.001), respectively]., Conclusion: Male sex, age > 65 years, multiple polyps, pedunculated or semi-pedunculated shape, polyp size > 1 cm, and specific background gastric mucosa are key indicators for predicting neoplastic transformation of GHPs., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Muscle cramps are common in patients with cirrhosis. Despite their prevalence and impact on health-related quality of life, there are no widely used clinical practice guidelines for management of muscle cramps in cirrhosis. The aim of this review was to critically evaluate current evidence regarding treatment of muscle cramps in cirrhosis., Methods: A systematic review using PubMed, MEDLINE (Ovid), Embase, and Scopus databases was performed on 30 June by two independent reviewers to identify randomised controlled trials (RCTs) reporting interventions for muscle cramps in cirrhotic patients., Results: Twelve RCTs evaluating 13 distinct interventions were identified. Baclofen, methocarbamol, orphenadrine, and taurine supplementation reduced cramp frequency, severity, and duration when compared to placebo. Human albumin, pregabalin, and quinidine reduced cramp frequency compared to placebo. Pickle juice reduced cramp severity compared to placebo. BCAA supplementation and calcium carbonate were found to reduce cramp frequency compared to baseline. Stretching demonstrated a signal towards reducing cramp severity and frequency, and meditation had a signal towards reducing severity only when compared to baseline. Electro-acupuncture was the only intervention which demonstrated no therapeutic effect. Pregabalin was the only agent associated with significant side effects that limited its use., Conclusion: Methocarbamol, orphenadrine, and taurine supplementation were found in placebo-controlled RCTs to be effective in reducing cramp frequency, severity, and duration in cirrhotic patients. All other interventions reported aside from electro-acupuncture demonstrated a positive impact on cramps. High-quality RCTs are needed to further investigate the use of these treatments in terms of comparative efficacy and safety., (© 2024 John Wiley & Sons Ltd.)

RNF43 and ZNRF3 are recognized as important regulators of Wnt/β-catenin signaling by maintaining Wnt-receptors at minimal essential levels. In various cancer types, particularly gastrointestinal tumors, mutations in these genes lead to abnormal Wnt-dependent activation of β-catenin signaling. However, recent findings implicate RNF43/ZNRF3 also in the regulation of other tumor-related proteins, including EGFR, BRAF, and the BMP-signaling pathway, which may have important implications for tumor biology. Additionally, we describe in detail how phosphorylation and ubiquitination may finetune RNF43 and ZNRF3 activity. We also address the variety of mutations observed in cancers and the mechanism through which they support tumor growth, and challenge the prevailing view that specific missense mutations in the R-spondin and RING domains may possess dominant-negative activity in contributing to tumor formation., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: During the peak of the epidemic, hospitalized patients frequently encountered significant health risks and potentially life-threatening circumstances, including uncertainty regarding treatment and the potential for complications., Objective: The present study aimed to explore the prevalence of post-traumatic stress disorder (PTSD) symptoms among hospitalized patients 3 months after discharge during the first peak of the epidemic, and the association of PTSD with disease-related characteristics., Design: A single-center and full-sample follow-up study was conducted on COVID-19 patients from the Optical Valley Branch of Maternal and Child Hospital of Hubei Province, Wuhan, China. Data were collected during their hospitalization and 3 months after discharge., Methods: PTSD symptoms were evaluated by primary care post-traumatic stress disorder (PC-PTSD), a total score of 3 or above was considered as clinically significant PTSD symptoms. Demographic and disease-related characteristics were collected to identify related associations with PTSD symptoms., Results: A total of 903 patients completed the follow-up survey, yielding a response rate of 63.5%. A total of 212 (23.5%) of the patients were positive in PC-PTSD screening. Univariate regression analysis identified several factors correlated with PTSD symptoms, including female gender, younger age, a lower body mass index (BMI), preexisting sleep problems, bereavement due to COVID-19, a severe clinical diagnosis, the presence of three or more clinical symptoms at disease onset, and residual respiratory symptoms after discharge. Notably, in the multivariate regression analysis, experiencing three or more clinical symptoms at onset emerged as a robust predictor of PTSD symptoms (OR = 2.09, 95% CI: 1.48-2.95). An intriguing finding was that patients who underwent radiological assessment post-discharge reported a higher incidence of PTSD symptoms, whereas those who underwent re-testing for IgG or IgM antibodies exhibited a lower prevalence of PTSD symptoms., Conclusion: Three months post-recovery, PTSD symptoms prevalence among COVID-19 patients was 23.5%. Those with three or more clinical symptoms at onset or residual respiratory symptoms post-discharge showed higher risk. These findings highlighted the long-term effect of COVID-19 on mental health, urging enhanced attention and interventions for survivors., (© The Author(s), 2024.)

Background: Ferroptosis, a form of cell death characterized by lipid peroxidation, plays a crucial role in tumor suppression, offering novel avenues for cancer therapy. Previous studies have indicated that high levels of cyclin-dependent kinase subunit 2 (CKS2) promote the progression of various cancers. However, the potential interplay between CKS2 and ferroptosis in colon cancer (CC) remains unclear., Methods: Bioinformatics and RNA-seq analyses were employed to study genes associated with the ferroptosis signaling pathway. CKS2 expression was evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). The in vitro and in vivo effects of CKS2 on CC cells were assessed through the CCK-8 assay, colony formation assay, propidium iodide (PI) staining, BODIPY staining, DCFH-DA staining, and animal experiments. Additionally, the impact of CKS2 on autophagy and glutathione (GSH) metabolism was investigated using a transmission electron microscope (TEM), immunofluorescence (IF) assays, WB experiments, and relevant assay kits., Results: CKS2 expression was elevated in CC, indicating a poor clinical outcome. Knockdown of CKS2 significantly enhanced Erastin-induced ferroptosis in CC cells, leading to reduced GSH metabolism. Conversely, CKS2 overexpression produced opposite effects. Mechanistically, CKS2-induced autophagy reinforced GSH metabolism, thereby increasing resistance to ferroptosis in CC cells. Furthermore, inhibiting CKS2 promoted tumor ferroptosis by downregulating GPX4 expression. Additionally, CKS2 knockdown effectively increased sorafenib-induced ferroptosis both in vitro and in vivo., Conclusion: CKS2 suppresses ferroptosis in CC by modulating GSH metabolism in both in vitro and in vivo settings. These findings offer new insights into targeting CKS2 for CC treatment and shed light on the mechanism of ferroptosis in CC., Competing Interests: Declarations Ethics approval and consent to participate The use of tissue samples was approved by the Ethics Committee of Taizhou Hospital, Wenzhou Medical University (approval number: KL20240457). And the animal study was approved by the Ethics Committee of Taizhou Hospital, Wenzhou Medical University (approval number: tzy-2024084). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Aggressive primary gastrointestinal non-Hodgkin lymphoma (PGINHL) is an uncommon and heterogeneous group of lymphoid malignancies, that differs from indolent lymphoma and has a high incidence of severe gastrointestinal complications (GICs)., Aim: To investigate and compare the clinicopathological characteristics, treatments and outcomes in the GICs and No-GICs group with aggressive PGINHL., Methods: This retrospective analysis was performed on aggressive PGINHL patients between January 2013 and December 2021 at our hospital. The independent influence factors of GICs were obtained by univariate and multivariate Logistic regression analysis, the selected variables significantly related to GICs were selected as the final predictors to construct nomogram. Kaplan-Meier curves further analyzed the survival of patients in GICs and No-GICs groups. Survival analysis of GICs group was performed using Cox regression., Results: We focused on 124 aggressive PGINHL cases, which had a relatively high incidence 48.4% (60/124 cases) of GICs, the most common histological type in GICs group was diffuse large B-cell lymphoma (DLBCL) ( n = 49, 81.7%). In the GICs group, small intestine was the most common anatomic site of lesion (43.3%), followed by large intestine (31.7%), and then stomach and esophagus (25.0%). Multivariate Logistic regression analysis showed that the independent risk factors for GICs were the small intestine [odd ratio (OR) = 3.33; 95% confidence interval (CI): 1.47-9.41; P = 0.009), aggressive B-cell (OR = 0.09; 95%CI: 0.01-0.83; P = 0.033), maximum tumor diameter (OR = 1.25; 95%CI: 1.07-1.47; P = 0.005), invaded deep serous layer (OR = 3.38; 95%CI: 1.24-9.19; P = 0.017). We developed a nomogram to predict risk of GICs in aggressive PGINHL patients based on independent risk factors. The value of area under curve calculated by receiver operating characteristic curve was 0.815, and calibration curve and decision curve analysis further indicated that the prediction effect was superior. The majority of patients with GICs were given combination therapy (chemotherapy combined with surgery or radiation). Event-free survival and overall survival in GICs group were no worse than those in the No-GICs group., Conclusion: The complication rate of GICs in patients with aggressive PGINHL was relatively high, particularly in PGI-DLBCL. The independent risk factors for GICs were the small intestine, PGI-TNKL, bulky tumor, and depth of invasion. A combination treatment, involving surgery, improved survival in the GICs group., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Enoyl coenzyme A hydratase 1 (ECH1) is a secreted protein implicated in numerous metabolic disorders, yet its role in the pathogenesis of atherosclerosis remains unclear. In this study, we found higher serum ECH1 levels in coronary artery disease (CAD) patients and apolipoprotein E (ApoE) -/- mice on a western diet for 12 weeks. In vivo, aorta and aortic sinus histological staining revealed that intraperitoneal injection of recombinant ECH1 reduced aortic lesions, inflammation, and macrophage infiltration in ApoE -/- mice. In vitro, incubating peritoneal macrophages with recombinant ECH1 protein reduced oxidized low-density lipoprotein uptake and increased macrophage migration. Mechanically, we observed that recombinant ECH1 incubation led to a reduction in the protein levels of scavenger receptor cluster of differentiation 36 (CD36) in primary macrophages through the promotion of CD36 protein degradation. Additionally, we found that chloroquine (CQ), a lysosomal inhibitor, mitigated this pro-degradation effect. Taken together, our findings provide unique evidence that ECH1 can attenuate the severity of atherosclerotic plaques, especially improving the stability of plaques, by decreasing macrophage infiltration. ECH1 demonstrates its protective effect by enhancing the lysosome-dependent degradation of CD36, suggesting its potential as a viable target for the prevention and treatment of atherosclerosis., Competing Interests: Declaration of Competing Interest none., (Copyright © 2024. Published by Elsevier Inc.)

The receptor tyrosine kinase encoded by the MET gene plays an important role in various cellular processes such as growth, survival, migration and angiogenesis, and its abnormal activation is closely related to the occurrence and development of various tumors. This article reviews the recent advances in diagnosis and treatment of MET-variant digestive tract tumors. In terms of diagnosis, the application of next-generation sequencing technology and liquid biopsy technology makes the detection of MET variants more accurate and efficient, providing a reliable basis for individualized treatment. In terms of treatment, MET inhibitors such as crizotinib and cabotinib have shown good efficacy in clinical trials. In addition, the combination of immunotherapy and MET inhibitors also demonstrated potential synergies, further improving the therapeutic effect. However, the complexity and heterogeneity of drug resistance mechanisms are still one of the difficulties in current research. In the future, it is necessary to further deepen the understanding of the mechanism of MET variation and explore new combination treatment strategies to improve the overall survival rate and quality of life of patients. The diagnosis and treatment of MET-variant digestive tract tumors are moving towards precision and individualization, and have broad application prospects., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Periampullary malignancies are uncommon and encompass a wide variety of tumors. Early and accurate biopsy-proven diagnosis is important because different malignancy subtypes warrant different management and treatment plans. We present a unique and rare case of periampullary lymphoma, initially presenting as acute pancreatitis., (© 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Background: Gastric cancer (GC) endangers the survival and prognosis of patients worldwide. Improving the prognosis of patients with early GC (EGC) is crucial to prolong their survival time., Aim: To analyze the effects of endoscopic submucosal dissection (ESD) on gastrointestinal function and nutritional status in patients with EGC., Methods: Eighty patients with EGC between January 2021 and January 2024 were divided according to different surgical protocol into following two groups: 42 patients who underwent ESD in the ESD group and 38 patients treated with endoscopic mucosal resection (EMR) in the EMR group. Two groups were compared in the operative indices, lesion resection rate, postoperative recovery of gastrointestinal function, nutritional status, and incidence of surgical complications., Results: The overall resection rate of the lesion in the ESD group was higher. The operative bleeding volume and operation time were higher and gastrointestinal ventilation time was shorter in the ESD group than those in the EMR group ( P < 0.05). The nutritional statuses of the two groups decreased after operation; however, the levels of albumin, prealbumin, hemoglobin, and transferrin were higher in the ESD group than in the EMR group ( P < 0.05). The post-operative pepsinogen (PG) I level in the ESD group was higher than that in the EMR group, and the PG II level was lower than that in the EMR group ( P < 0.05). The incidence of postoperative complications was compared between the two groups ( P > 0.05)., Conclusion: ESD can promote the immediate recovery of patient's postoperative gastrointestinal function, improve their nutritional level, and signifies its application in patients with EGC., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: No specific triglyceride-lowering therapy is recommended in patients with hypertriglyceridemia-associated acute pancreatitis (HTG-AP), primarily because of the lack of quality evidence. This study aimed to describe practice variations in triglyceride-lowering therapies for early HTG-AP patients and assess whether more rapid triglyceride decline is associated with improving organ failure., Methods: This is a multicentre, prospective cohort study recruiting HTG-AP patients with elevated plasma triglyceride (> 11.3 mmol/L) admitted within 72 h from the onset of symptoms. Patients were dichotomised on study day 3 into either target reaching (plasma triglyceride ≤ 5.65 mmol/L) or not. The primary outcome was organ failure-free days (OFFD) to 14 days of enrolment. The association between target-reaching and OFFD was modelled. Additionally, the slope in plasma triglyceride over the first three days in response to treatment was calculated, and its association with OFFD was assessed as a sensitivity analysis., Results: Among the 300 enrolled patients, 211 underwent exclusive medical treatment, and 89 underwent various blood purification therapies. Triglyceride levels were available in 230 patients on study day 3, among whom 122 (53.0%) had triglyceride levels of ≤ 5.65 mmol/l. The OFFD was not different between these patients and those in whom plasma triglyceride remained > 5.65 mmol/L [median (IQR): 13 (10-14) vs. 14 (10-14), p = 0.46], even after adjustment for potential confounders. For the decline slopes, there was no significant change in OFFD with a steeper decline slope [risk difference, - 0.088, 95% CI, - 0.334 to 0.158, p = 0.48]., Conclusions: Triglyceride-lowering therapies vary greatly across centres. More rapid triglyceride decline was not associated with improving incidence and duration of organ failure., Competing Interests: Declarations Ethics approval and consent to participate The study was approved by the ethics committee of Jinling Hospital (ethical number: 2020NZKY-016–01) and registered with the Chinese Clinical Trial Registry (ChiCTR2000039541). The local hospital ethics committees of all the participating sites also approved the trial. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Objectives: This study developed a deep learning radiomics (DLR) model utilizing baseline computed tomography enterography (CTE) to non-invasively predict stratified healing in Crohn's disease (CD) patients following infliximab (IFX) treatment., Methods: The study included 246 CD patients diagnosed at three hospitals. From the first two hospitals, 202 patients were randomly divided into a training cohort (n = 141) and a testing cohort (n = 61) in a 7:3 ratio. The remaining 44 patients from the third hospital served as the validation cohort. Radiomics and deep learning features were extracted from both the active lesion wall and mesenteric adipose tissue. The most valuable features were selected using univariate analysis and least absolute shrinkage and selection operator (LASSO) regression. Multivariate logistic regression was then employed to construct the radiomics, deep learning, and DLR models. Model performance was evaluated using receiver operating characteristic (ROC) curves., Results: The DLR model achieved an area under the ROC curve (AUC) of 0.948 (95% CI: 0.916-0.980), 0.889 (95% CI: 0.803-0.975), and 0.938 (95% CI: 0.868-1.000) in the training, testing, and validation cohorts, respectively in predicting mucosal healing (MH). Furthermore, the diagnostic performance of DLR model in predicting transmural healing (TH) was 0.856 (95% CI: 0.776-0.935)., Conclusions: We have developed a DLR model based on the radiomics and deep learning features of baseline CTE to predict stratified healing (MH and TH) in CD patients following IFX treatment with high accuracies in both testing and external cohorts., Critical Relevance Statement: The deep learning radiomics model developed in our study, along with the nomogram, can intuitively, accurately, and non-invasively predict stratified healing at baseline CT enterography., Key Points: Early prediction of mucosal and transmural healing in Crohn's Disease patients is beneficial for treatment planning. This model demonstrated excellent performance in predicting mucosal healing and had a diagnostic performance in predicting transmural healing of 0.856. CT enterography images of active lesion walls and mesenteric adipose tissue exhibit an association with stratified healing in Crohn's disease patients., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of three hospitals, and the need for written informed consent was waived. Consent for publication All authors declare no conflict of interest in the present study. Competing interests J.L. is an employee of GE Healthcare. The remaining authors declare that they have no competing interests., (© 2024. The Author(s).)

Purpose: To investigate the clinical value of dual-source dual-energy CT (dsDECT) quantitative parameters in evaluating hemodynamics and predicting high-risk gastroesophageal varices in cirrhotic patients., Methods: 98 consecutive patients were collected in this prospectively study and all patients underwent an abdominal triple-phase contrasted-enhanced examination with dsDECT. Iodine concentration (IC) and normalized iodine concentration (NIC) of the liver parenchyma, spleen parenchyma and aorta at different phases were recorded, and arterial iodine fraction (AIF), iodine washout rate (IWR), and extracellular volume (ECV) were calculated. Using upper gastrointestinal endoscopy as the reference standard, patients who met the inclusion and exclusion criteria were divided into groups with varices need treatment (VNT) and non-VNT. The clinical characteristics, traditional CT features and quantitative dsDECT parameters were compared between the VNT group and the non-VNT group using univariate analysis. The binary logistics analysis was used to build a model for diagnosing VNT. The receiver operating characteristic (ROC) curve was used for analysis and the DeLong test was used to compare different ROC curves., Results: Finally, 57 patients were included in this study. Univariate analysis showed statistically significant differences in NIC of the liver at the portal venous phase (NIC-L PVP ), IWR of the liver (IWR-L) and spleen volume between the VNT group and the non-VNT group (p < 0.05). The mixed-CT model was built by binary logistics analysis. The ROC curves of NIC-L PVP , IWR-L, spleen volume and the mixed-CT model were statistically significant (p < 0.05) for predicting VNT in cirrhotic patients, among which the area under the ROC curve of the mixed-CT model was the highest., Conclusion: Dual-source dual-energy CT has added clinical value in evaluating hepatic hemodynamics and diagnosing VNT in patients with liver cirrhosis., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Budd-Chiari syndrome (BCS) is an uncommon disease caused by hepatic venous outflow obstruction. They can result in centrilobular fibrosis, nodular regenerative hyperplasia and cirrhosis. Assessing liver fibrosis is crucial for determining the stage of BCS, predicting disease progression and guiding treatment decisions. Although this pathology has been known for decades, no useful grading system was assigned. This study aims to introduce a histologic fibrosis grading system for BCS patients., Methodology: All patients from 2017 to 2022 (Sanjay Gandhi Postgraduate Institute of Medical Sciences [SGPGIMS]), Lucknow diagnosed with BCS for whom liver biopsy was performed were included in the study. The Budd-Chiari syndrome-Hepatic Fibrosis system (BCS-HFS) was implemented to grade fibrosis. The fibrosis grade was compared with the fibrosis percentage area and a correlation was found with the hemodynamic variables (hepatic venous pressure gradient [HVPG]) and the prognostic scores., Results: There were 56 patients with BCS. The median age was 27 years, with a male-female ratio of 1.8:1. There was a significant difference in the fibrosis percentage, hemorrhage percentage and model for end-stage liver disease (MELD) score among the BCS-HFS grades (p < 0.05). There was a significant correlation between BCS-HFS and HVPG (ρ = 0.699, p < 0.001) and the MELD prognostic score (ρ = 0.474, p < 0.001)., Conclusion: BCS-HFS is applicable for grading fibrosis in BCS. It can help in uniform histopathology reporting and for further prospective and comparative studies., Competing Interests: Declarations Conflict of interest NN, RY, GP, ZH, CB, RV, NK and PM declare no competing interests. Ethical approval and consent to participate Not applicable. Consent for publication Yes. Informed consent Not applicable. Disclaimer The authors are solely responsible for the data and the contents of the paper. In no way, the Honorary Editor-in-Chief, Editorial Board Members, the Indian Society of Gastroenterology or the printer/publishers are responsible for the results/findings and content of this article., (© 2024. Indian Society of Gastroenterology.)

Background: The clinical course of esophagogastric varices (EGV) after sustained virological response (SVR) with direct-acting antiviral (DAA) therapy has not been clearly elucidated. The predictors for the worsening/improvement of EGV after SVR with DAA therapy were investigated., Methods: Of the cirrhosis patients who achieved SVR with DAA therapy, 328 patients who underwent endoscopic examinations both before and after DAA therapy were enrolled. The predictors of EGV worsening or improvement were investigated., Results: Multivariate analysis identified a history of ascites retention, albumin at baseline, and MELD score at baseline as independent factors that contributed to EGV exacerbation. On multivariate analysis, two factors, BMI and platelet count, were related to EGV improvement. An integrated scoring system was created using these risk factors with or without weighting according to each hazard ratio, and the patients were divided into three groups. A scoring system with weighting of each factor appeared to be more useful, with fewer intermediate patients and more cases classified into the low-risk and high-risk groups., Conclusion: Esophagogastric varices after SVR have a varied clinical course. Using this scoring system that can accurately predict EGV outcomes in clinical settings, it may be feasible to establish a risk-based EGV surveillance plan following SVR., Competing Interests: Declarations Conflict of interest The authors declare that they have no conflicts of interest (COI)., (© 2024. Japanese Society of Gastroenterology.)

Background: Our objective in this study was to evaluate the short-term clinical efficacy and safety of endoscopic cardiac mucosal ligation, a novel endoscopic procedure, in the treatment of gastroesophageal reflux disease (GERD)., Methods: Patients diagnosed with refractory GERD or recurrent patients due to drug withdrawal admitted to our hospital were recruited in this clinical trial. All GERD patients were treated with endoscopic cardiac mucosal ligation. Postoperatively, all patients received subsequent follow-ups for approximately four months to evaluate the efficacy and safety of this endoscopic procedure., Results: A total of 13 GERD patients were enrolled. Endoscopic cardiac mucosal ligation was successfully performed in all cases. Postoperatively, relevant symptoms were significantly alleviated in 10 patients (76.9%). The average Gastroesophageal Reflux Disease Questionnaire (GERD-Q) score in all participants significantly decreased from preoperative 10.0 ± 3.5 to postoperative 7.8 ± 2.9 ( p  = .022). The average GERD symptom questionnaire score was 27.0 ± 12.0 prior to surgery, which significantly decreased to 18.3 ± 7.5 postoperatively ( p  = .032). No severe postoperative complications were observed during subsequent follow-ups., Conclusions: Endoscopic cardiac mucosal ligation might be a novel effective and safe endoscopic procedure for GERD.

Extracellular vesicles (EVs) are involved in the progression of various diseases. Tumor cell-derived EVs (TEVs) are a particular concern, as they can induce fatty liver by promoting liver macrophages to secrete tumor necrosis factor (TNF), thus enhancing the toxicity of chemotherapy. Therefore, reducing pathogenic EV production is a potential strategy for treating EV-related diseases. However, there are currently no effective clinical reagents to obtain this purpose. In addition, EVs are also natural and ideal drug-delivery vehicles. Improving the delivery efficiency of EVs remains a challenge. Proton pump inhibitors (PPIs) have been demonstrated to promote cell uptake of EVs by inducing micropinocytosis. Here, we show that PPIs can accelerate TEV clearance, reduce TEV uptake by liver macrophages and decrease the mRNA expression of TNF in liver macrophages of tumor-bearing mice. Correspondingly, the fatty liver phenotypes are alleviated, and the tolerance to chemotherapy is improved in these mice. Furthermore, our findings indicate that PPIs facilitate the uptake of red blood cell-derived EVs (RBC-EVs) loaded with antisense oligonucleotides of Trim21 (Trim21-ASOs) by the liver macrophages of obesity. Consequently, the inhibition of macrophage inflammatory responses in obese mice mediated by RBC-EVs/Trim21-ASOs was further enhanced by PPIs, resulting in a more profound improvement in obesity and related metabolic disorders. In conclusion, our findings demonstrated that PPIs can effectively clear pathogenic EVs and enhance the delivery efficacy of EV vehicles, making them a highly promising clinical prospect., Competing Interests: Declarations Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)