Search

Background and Aim: The APAGE Position Statements aimed to provide guidance to healthcare practitioners on clinical practices aligned with climate sustainability., Methods: A taskforce convened by APAGE proposed provisional statements. Twenty-two gastroenterologists from the Asian Pacific region participated in online voting and consensus was assessed through an anonymized and iterative Delphi process., Results: There were five sections that addressed the rationale for climate action, the importance of adopting principles of waste management, clinical practice, gastrointestinal endoscopy, and issues related to advocacy and research. Sixteen statements achieved consensus and included the following: 1. APAGE recommends adopting prompt measures to reduce the carbon footprint of clinical practice due to the importance of climate action and its health cobenefits. 5. APAGE recommends adherence to professional clinical guidelines to optimize clinical care delivery in gastroenterology and hepatology to avoid the environmental impact of unnecessary procedures and tests. 8. APAGE recommends an emphasis on health promotion, disease prevention, and appropriate screening and surveillance, when resources are available, to reduce the environmental impact of managing more advanced diseases that require more intensive resources. 12. APAGE recommends that technological advances in endoscopic imaging and artificial intelligence, when available, be used to improve the precision of endoscopic diagnosis to reduce the risk of missed lesions and need for unnecessary biopsies. 13. APAGE recommends against the routine use of single-use endoscopes., Conclusion: The position statements provide guidance to healthcare practitioners on clinical practices in gastroenterology, hepatology, and endoscopy that promote climate sustainability., (© 2025 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: To investigate the prevalence and risk factors of psychological symptoms and quality of life (QoL) in early patients with inflammatory bowel disease (IBD)., Methods: From September 2021 to May 2022, a unified questionnaire was developed to collect clinical data from early patients with IBD from 42 tertiary care hospitals. The influencing factors of psychological symptoms and poor QoL are screened by logistic regression analysis for constructing model in predicting poor QoL. The consistency index, receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the model., Results: A total of 939 early patients with IBD were surveyed, Among them, 20.3% exhibited anxiety, 21.7% had depression, 57.3% experienced sleep disturbance, and 41.9% reported poor QoL. The factors influencing psychological symptoms varied between ulcerative colitis (UC) and Crohn's disease (CD) patients. The QoL was primarily affected by disease activity, income level and depression. The AUC value of the model in the training group was 0.781 (95% CI: 0.748-0.814). The calibration diagram of the model closely matched the ideal curve. Compared to other prediction models, our model showed superior predictive capability, with NRI and IDI values of 0.324 (95%CI:0.196-0.4513) and 0.026 (95%CI:0.014-0.038), respectively. DCA indicated that the nomogram model could provide clinical benefits., Conclusion: Early patients with IBD exhibit a high prevalence of psychological symptoms and poor QoL. The nomogram prediction model we constructed demonstrates high accuracy and performance in predicting QoL in early patients with IBD., Competing Interests: Declarations Ethics approval and consent to participate The study complies with the Declaration of Helsinki. The study was approved by the Institutional Review Board of Renmin Hospital of Wuhan University, and informed consent was obtained from all patients. The clinical research Ethics Review approval number of Renmin Hospital of Wuhan University was WDRY2022-K150. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The lack of clear definition and classification for "moderate ulcerative colitis (UC)" creates ambiguity regarding the suitability of step-up versus top-down treatment approaches. In this paper, experts address crucial gaps in assessing and managing moderate UC. The Asia-Pacific, Middle East, and Africa Inflammatory Bowel Disease Coalition comprised 24 experts who convened to share, discuss and vote electronically on management recommendations for moderate UC. Experts emphasized that the goal of treating UC is to attain clinical, biomarker, and endoscopic remission using cost-effective strategies such as 5-aminosalicylates (5-ASAs), well-tolerated therapy that can be optimized to improve outcomes. Experts agreed that 5-ASA therapy could be optimized by maximizing dosage (4 g/day for induction of remission), combining oral and topical administration, extending treatment duration beyond 8 weeks, and enhancing patient adherence through personalized counselling and reduced pill burden. Treatment escalation should ideally be reserved for patients with predictors of aggressive disease or those who do not respond to 5-ASA optimization. Premature treatment escalation to advanced therapies (including biologics and oral small molecules) may have long-term health and financial consequences. This paper provides consensus-based expert recommendations and a treatment algorithm, based on current evidence and practices, to assist decision-making in real-world settings.

Background and Aims: Whether the natural course of ulcerative colitis (UC) in mainland China is similar or different from that in Western countries is unknown, and data on it is limited. We aimed to provide a comprehensive description of the natural course of UC in China and compare it with Western UC patients., Methods: Based on a prospective Chinese nationwide registry of consecutive patients with inflammatory bowel diseases, the medical treatments and natural history of UC were described in detail, including disease extension, surgery, and neoplasia. The Cox regression model was used to identify factors associated with poor outcomes., Results: A total of 1081 UC patients were included with a median follow-up duration of 5.3 years. The overall cumulative exposure was 99.1% to 5-aminosalicylic acids, 52.1% to corticosteroids, 25.6% to immunomodulators, and 15.4% to biologics. Disease extent at diagnosis was proctitis in 26.9%, left-sided colitis in 34.8%, and extensive colitis in 38.3%. Of 667 patients with proctitis and left-sided colitis, 380 (57.0%) experienced disease extent progression. A total of 58 (5.4%) UC patients underwent colectomy, demonstrating cumulative proportions of surgery at 1, 5, and 10 years after diagnosis of 0.6%, 3.4%, and 8.2%, respectively. In addition, 23 (2.1%) UC patients were diagnosed with neoplasia, demonstrating cumulative proportions of neoplasia at 1, 5, and 10 years after diagnosis of 0.5%, 1.0%, and 3.5%, respectively., Conclusions: Chinese UC patients had similar cumulative proportions of exposure to IBD-specific treatments but a lower surgical rate than patients in Western countries, indicating a different natural course, and close monitoring needs for UC in China. However, these results must be confirmed in population-based studies because the hospital-based cohort in our study might lead to selection bias., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Objectives: The aim of this study is to assess the risk factors associated with thrombotic events in obstetric antiphospholipid syndrome (OAPS) patients and to develop a predictive model specifically tailored to predict the risk of postpartum thrombosis in OAPS patients without prior thrombotic events. This research seeks to enhance clinician's awareness regarding the postpartum care and monitoring of OAPS patients., Methods: A retrospective study was conducted at the First Affiliated Hospital of the Fourth Military Medical University including 269 consecutive inpatients diagnosed with antiphospholipid syndrome (APS) from July 1, 2008 to July 31, 2022. All participants met the 2006 Sydney APS classification criteria or the "non-criteria OAPS classification". Out of 98 candidate clinical and laboratory parameters considered, 40 potential variables were selected for analysis based on expert opinion. The logistic regression mode with the Least Absolute Shrinkage and Selection Operator (LASSO) were used to identify optimal predictive characteristics. All samples were included in the model building and a nomogram was generated based on these characteristics. The differentiation, calibration, and clinical utility of the predictive model were evaluated using the area under the curve (AUC), calibration curve, and decision curve analysis. The model was also validated by a 1000 bootstrap tests., Results: 126 patients with OAPS were enrolled, and a total of 89 OAPS patients who had never experienced thrombosis were retrospectively analyzed. After 3 years follow-up, 32.58% of the patients (29/89) developed thrombosis. In order to create, LASSO logistic regression identified three optimal variables: the platelet count less than 125×109/L, more than one positive aPLs (antiphospholipid antibody), and the use of low molecular weight heparin (LMWH) or low dose aspirin (LDA) after delivery. A predictive model was conducted using these three predictive indicators for patients with OAPS who experience thrombosis for the first-time. This prediction model has good distinction, good calibration, and fair clinical practicality., Conclusion: Our model has good predictive ability in assessing the risk of thrombosis in patients with OAPS without prior thrombotic events. This model is easy to predict, has good discriminability and calibration, and can be utilized as a routine tool for thrombus screening in OAPS patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao, Zheng, Wang, Jia, Wan, Han, Zheng, Liu, Zheng, Wu and Zhu.)

Upadacitinib is an oral new selective JAK1 inhibitor that has been approved for treating adult patients with moderately to severely active ulcerative colitis. However, a growing number of studies are needed on the effectiveness of upadacitinib in the treatment of acute severe ulcerative colitis. This study was mainly aimed to describe the clinical and endoscopic effectiveness of upadacitinib 45 mg in Chinese acute severe ulcerative colitis patients following eight weeks of treatment. In this study, we examined all patients with acute severe ulcerative colitis from Xijing IBD Center, Xi'an, China, with acute severe ulcerative colitis. All patients were initially given oral upadacitinib 45 mg. Clinical indicators, C-reactive protein, and erythrocyte sedimentation rates were collected. Clinical response and clinical remission were assessed using modified Mayo. Endoscopic evaluation was performed carried out using the Mayo Endoscopic Score and Ulcerative colitis endoscopic index of severity score. A total of 14 patients who received upadacitinib were included in the study period. All patients exhibited a clinical response to 45 mg upadacitinib initially. All patients completed the 8-week induction. The clinical remission rate was 28.6% after eight weeks. Two patients revealed endoscopic remission at 14.3%. The pathology improved in 50.0% of patients. The 8-week surgical resection rate was 7.1%, with the 16-week surgical resection rate being 14.3%. Adverse events included herpes simplex virus infection and increased thrombin time. The results of our study support the short-term effectiveness and safety of upadacitinib in acute severe ulcerative colitis, providing new choices for patients' treatment. However, more extended investigation needs to be performed on the long-term effectiveness and safety., (© 2024. The Author(s).)

Importance: The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown., Objective: To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis., Design, Setting, and Participants: Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab., Interventions: For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks., Main Outcomes and Measures: The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial., Results: Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups., Conclusion and Relevance: Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up., Trial Registration: ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135.

Background & Aims: Current prognostic models for patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) are not extensively validated and widely accepted. We aimed to develop and validate a continuous model incorporating tumor burden and biology for individual survival prediction and risk stratification., Methods: Overall, 4,377 treatment-naive candidates for whom TACE was recommended, from 39 centers in five countries, were enrolled and divided into training, internal validation, and two external validation datasets. The novel model was developed using a Cox multivariable regression analysis and compared with our original 6-and-12 model (the largest tumor size [ts, centimetres] + tumor number [tn]) and other available models in terms of predictive accuracy., Results: The proposed model, named the '6-and-12 model 2.0', was generated as 'ts + tn + 1.5×log 10 alpha-fetoprotein (AFP)', showed good discrimination (C-index 0.674) and calibration (Hosmer-Lemeshow test p  = 0.147), and outperformed current existing models. An easy-to-use stratification was proposed according to the different AFP levels (≤100, 100-400, 400-2,000, 2,000-10,000, 10,000-40,000, and >40,000 ng/ml) along with the corresponding tumor burden cutoffs (8/14, 7/13, 6/12, 5/11, 4/10, and any tumor burden); that is, if the AFP level was 400-2,000 ng/ml, the stratification should be low-(≤6)/intermediate-(6-12)/high-risk (>12) strata. Hence, it could divide the patients into three distinct risk categories with a median overall survival of 45.0 (95% CI, 40.1-49.9), 30.0 (95% CI, 26.1-33.9), and 15.4 (95% CI, 13.4-17.4) months ( p <0.001) from low-risk to high-risk strata, respectively. These findings were confirmed in validation and subgroup analyses., Conclusions: The 6-and-12 model 2.0 significantly improved individual outcome predictions and better stratified the candidates recommended for TACE; thus, this model could be used in both clinical practice and trial design., Impact and Implications: In this international multicentre study, we developed and internally and externally validated a novel outcome prediction model for candidates with HCC who would be ideal for TACE. The model, called the 6-and-12 model 2.0, was based on 4,377 patients from 39 centers in five countries. The model offers individualized outcome prediction, outperforming the original 6-and-12 model score and other existing metrics across all datasets and subsets. Based on different levels of alpha-fetoprotein (AFP) and corresponding cut-offs of tumor burden, patients could be stratified into three risk strata with significantly different survival prognoses, which could provide a referential framework to control study heterogeneity and define the target population in future trial designs., Competing Interests: AV: consulting fees (AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, and Terumo); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events [AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, Bristol Myers Squibb, BTG, Daichi-Sankyo, EISAI, GSK, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Jiangsu Hengrui Medicines; MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, and Terumo]; support for attending meetings and/or travel (Roche, MSD, and Astellas); participation on a data safety monitoring board or advisory board (AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, BTG, Daichi-Sankyo, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, Sirtex, Tahio, and Terumo). RK: grants or contracts from any entity (German Federal Ministry of Research & Education and DFG – German Research Foundation); consulting fees (Boston Scientific, Bristol Myers Squibb, Guerbet, Roche, and Sirtex); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events (Astra Zeneca, BTG, Eisai, Guerbet, Ipsen, Roche, Siemens, Sirtex, MSD Sharp & Dohme); participation on a data safety monitoring board or advisory board (ABC HCC Trial); leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid (European Society of Radiology, Chair of the Audit and Standards Subcommittee – unpaid; and Eurosafe Imaging, Steering Committee - unpaid); JWC: grants or contracts from any entity (educational grant from Guerbet); DB: grants or contracts from any entity (German Research Foundation and Dr Rolf M. Schwiete Stiftung); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Falk Foundation and Gore); support for attending meetings and/or travel (Gilead Science and Abbvie); X.A.: grants or contracts from any entity (Servier and Ipsen); consulting fees (Bayer and Ipsen); payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (Gilead, Servier); support for attending meetings and/or travel (Roche and Gilead); the other authors have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Despite the success of immunotherapy in treating hepatocellular carcinoma (HCC), HCC remains a severe threat to health. Here, a crucial transcription factor, SOX12, is revealed that induces the immunosuppression of liver tumor microenvironment. Overexpressing SOX12 in HCC syngeneic models increases intratumoral regulatory T-cell (Treg) infiltration, decreases CD8 + T-cell infiltration, and hastens HCC metastasis. Hepatocyte-specific SOX12 knockout attenuates DEN/CCl 4 -induced HCC progression and metastasis, whereas hepatocyte-specific SOX12 knock-in accelerates these effects. Mechanistically, SOX12 transcriptionally activates C-C motif chemokine ligand 22 (CCL22) expression to promote the recruitment and suppressive activity of Tregs. Moreover, SOX12 transcriptionally upregulates CD274 expression to suppress CD8 + T-cell infiltration. Either knockdown of CCL22 or PD-L1 dampens SOX12-mediated HCC metastasis. Blocking of CC chemokine receptor 4 (CCR4), a receptor for CCL22, by inhibitor C-021 or Treg-specific knockout of CCR4 inhibits SOX12-mediated HCC metastasis. Transforming growth factor-β1 (TGF-β1)/TGFβR1-Smad2/3/4 is identified as a key upstream signaling for SOX12 overexpression in HCC cells. Combining C-021 or TGFβR1 inhibitor galunisertib with anti-PD-L1 exhibits an enhanced antitumor effect in two HCC models. Collectively, the findings demonstrate that SOX12 contributes to HCC immunosuppression through the CCL22/CCR4-Treg and PD-L1-CD8 + T axes. Blocking of CCR4 or TGFβR1 improves the efficacy of anti-PD-L1 in SOX12-mediated HCC., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The biophysical properties of the extracellular matrix (ECM) play a pivotal role in modulating cancer progression via cell-ECM interactions. However, the biophysical properties specific to gastric cancer (GC) remain largely unexplored. Pertinently, GC ECM shows significantly heterogeneous metamorphoses, such as matrix stiffening and intricate restructuring. By combining collagen I and alginate, this study designs an in vitro biomimetic hydrogel platform to independently modulate matrix stiffness and structure across a physiological stiffness spectrum while preserving consistent collagen concentration and fiber topography. With this platform, this study assesses the impacts of matrix biophysical properties on cell proliferation, migration, invasion, and other pivotal dynamics of AGS. The findings spotlight a compelling interplay between matrix stiffness and structure, influencing both cellular responses and ECM remodeling. Furthermore, this investigation into the integrin/actin-collagen interplay reinforces the central role of integrins in mediating cell-ECM interactions, reciprocally sculpting cell conduct, and ECM adaptation. Collectively, this study reveals a previously unidentified role of ECM biophysical properties in GC malignant potential and provides insight into the bidirectional mechanical cell-ECM interactions, which may facilitate the development of novel therapeutic horizons., (© 2024 Wiley‐VCH GmbH.)

Purpose: Impaired quality of life (QOL) is common in patients with inflammatory bowel disease (IBD). A tool to more quickly identify IBD patients at high risk of impaired QOL improves opportunities for earlier intervention and improves long-term prognosis. The purpose of this study was to use a machine learning (ML) approach to develop risk stratification models for evaluating IBD-related QOL impairments., Patients and Methods: An online questionnaire was used to collect clinical data on 2478 IBD patients from 42 hospitals distributed across 22 provinces in China from September 2021 to May 2022. Eight ML models used to predict the risk of IBD-related QOL impairments were developed and validated. Model performance was evaluated using a set of indexes and the best ML model was explained using a Local Interpretable Model-Agnostic Explanations (LIME) algorithm., Results: The support vector machine (SVM) classifier algorithm-based model outperformed other ML models with an area under the receiver operating characteristic curve (AUC) and an accuracy of 0.80 and 0.71, respectively. The feature importance calculated by the SVM classifier algorithm revealed that glucocorticoid use, anxiety, abdominal pain, sleep disorders, and more severe disease contributed to a higher risk of impaired QOL, while longer disease course and the use of biological agents and immunosuppressants were associated with a lower risk., Conclusion: An ML approach for assessing IBD-related QOL impairments is feasible and effective. This mechanism is a promising tool for gastroenterologists to identify IBD patients at high risk of impaired QOL., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhen et al.)

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC., (© 2024. The Author(s).)

Background & Aims: Hepatocellular carcinoma (HCC) is characterized by an immune-suppressive microenvironment, which contributes to tumor progression, metastasis, and immunotherapy resistance. Identification of HCC-intrinsic factors regulating the immunosuppressive microenvironment is urgently needed. Here, we aimed to elucidate the role of SYR-Related High-Mobility Group Box 18 (SOX18) in inducing immunosuppression and to validate novel combination strategies for SOX18-mediated HCC progression and metastasis., Methods: The role of SOX18 in HCC was investigated in orthotopic allografts and diethylinitrosamine/carbon tetrachloride-induced spontaneous models by using murine cell lines, adeno-associated virus 8, and hepatocyte-specific knockin and knockout mice. The immune cellular composition in the HCC microenvironment was evaluated by flow cytometry and immunofluorescence., Results: SOX18 overexpression promoted the infiltration of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) while diminishing cytotoxic T cells to facilitate HCC progression and metastasis in cell-derived allografts and chemically induced HCC models. Mechanistically, transforming growth factor-beta 1 (TGF-β1) upregulated SOX18 expression by activating the Smad2/3 complex. SOX18 transactivated chemokine (C-X-C motif) ligand 12 (CXCL12) and programmed death ligand 1 (PD-L1) to induce the immunosuppressive microenvironment. CXCL12 knockdown significantly attenuated SOX18-induced TAMs and Tregs accumulation and HCC dissemination. Antagonism of chemokine receptor 4 (CXCR4), the cognate receptor of CXCL12, or selective knockout of CXCR4 in TAMs or Tregs likewise abolished SOX18-mediated effects. TGFβR1 inhibitor Vactosertib or CXCR4 inhibitor AMD3100 in combination with anti-PD-L1 dramatically inhibited SOX18-mediated HCC progression and metastasis., Conclusions: SOX18 promoted the accumulation of immunosuppressive TAMs and Tregs in the microenvironment by transactivating CXCL12 and PD-L1. CXCR4 inhibitor or TGFβR1 inhibitor in synergy with anti-PD-L1 represented a promising combination strategy to suppress HCC progression and metastasis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Targeted therapy is crucial for advanced colorectal cancer (CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs, existing standard molecular pathological detection systems and therapeutic strategies can no longer meet the requirements for careful management of patients with advanced CRC. Thus, rare genetic variations require diagnosis and targeted therapy in clinical practice. Rare gene mutations, amplifications, and rearrangements are usually associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare genetic variations, in genes including erb-b2 receptor tyrosine kinase 2 (ERBB2), B-Raf proto-oncogene, serine/threonine kinase (BRAF), ALK receptor tyrosine kinase/ROS proto-oncogene 1, receptor tyrosine kinase (ALK/ROS1), neurotrophic receptor tyrosine kinases (NTRKs), ret proto-oncogene (RET), fibroblast growth factor receptor 2 (FGFR2), and epidermal growth factor receptor (EGFR), to enhance understanding and identify more accurate personalized treatments for patients with rare genetic variations., Competing Interests: No potential conflicts of interest are disclosed., (Copyright: © 2024, The Authors.)

Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8 + T cells. Tumor cells outcompete CD8 + T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8 + T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8 + T cells and increases the efficacy of cancer therapies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To explore the impact of common gastrointestinal (GI) symptoms on psychological symptoms, sleep quality, and quality of life in patients with inflammatory bowel disease (IBD)., Methods: A unified questionnaire was developed to collect clinical data on the mental psychology and quality of life of IBD patients from 42 hospitals in 22 provinces in P. R. China from September 2021 to May 2022. The general clinical characteristics, psychological symptoms, sleep quality, and quality of life of IBD patients with different numbers of GI symptoms were analyzed by descriptive statistical analysis., Results: A total of 2,478 IBD patients were finally analysed in this study, including 365 without GI symptoms (14.7%), 752 with single symptoms (30.4%), 841 with double symptoms (33.9%), and 520 with three symptoms (21.0%). Compared with patients without GI symptoms, patients with only simple abdominalgia or diarrhea or hematochezia showed significantly higher levels of anxiety and depression and worse quality of life (all P  <   0.05). Compared with asymptomatic patients, patients with double symptoms (e.g. abdominalgia plus hematochezia, diarrhea plus hematochezia, abdominalgia plus diarrhea) and patients with three symptoms (abdominalgia, diarrhea, and hematochezia) showed significantly higher levels of anxiety and depression and worse sleep quality and quality of life (all P  <   0.05)., Conclusion: Compared with IBD patients without gastrointestinal symptoms, patients with gastrointestinal symptoms were more likely to experience anxiety, depression, sleep disturbances, and poorer quality of life., Competing Interests: The authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Aims: To investigate the current situation of mental psychology and quality of life (QoL) in patients with inflammatory bowel disease (IBD) in China, and analyze the influencing factors., Methods: A unified questionnaire was developed to collect clinical data on IBD patients from 42 hospitals in 22 provinces from September 2021 to May 2022. Multivariate Logistic regression analysis was conducted, and independent influencing factors were screened out to construct nomogram. The consistency index (C-index), receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), calibration curve, and decision curve analysis (DCA) were used to evaluate the discrimination, accuracy, and clinical utility of the nomogram model., Results: A total of 2478 IBD patients were surveyed, including 1371 patients with ulcerative colitis (UC) and 1107 patients with Crohn's disease (CD). Among them, 25.5%, 29.7%, 60.2%, and 37.7% of IBD patients had anxiety, depression, sleep disturbance and poor QoL, respectively. The proportion of anxiety, depression, and poor QoL in UC patients was significantly higher than that in CD patients (all p < 0.05), but there was no difference in sleep disturbance between them (p = 0.737). Female, higher disease activity and the first visit were independent risk factors for anxiety, depression and sleep disturbance in IBD patients (all p < 0.05). The first visit, higher disease activity, abdominal pain and diarrhea symptoms, anxiety, depression and sleep disturbance were independent risk factors for the poor QoL of patients (all p < 0.05). The AUC value of the nomogram prediction model for predicting poor QoL was 0.773 (95% CI: 0.754-0.792). The calibration diagram of the model showed that the calibration curve fit well with the ideal curve, and DCA showed that the nomogram model could bring clinical benefits., Conclusion: IBD patients have higher anxiety, depression, and sleep disturbance, which affect their QoL. The nomogram prediction model we constructed has high accuracy and performance when predicting QoL., (© 2024 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: The use of artificial intelligence (AI) can revolutionize health care, but this raises risk concerns. It is therefore crucial to understand how clinicians trust and accept AI technology. Gastroenterology, by its nature of being an image-based and intervention-heavy specialty, is an area where AI-assisted diagnosis and management can be applied extensively., Objective: This study aimed to study how gastroenterologists or gastrointestinal surgeons accept and trust the use of AI in computer-aided detection (CADe), computer-aided characterization (CADx), and computer-aided intervention (CADi) of colorectal polyps in colonoscopy., Methods: We conducted a web-based questionnaire from November 2022 to January 2023, involving 5 countries or areas in the Asia-Pacific region. The questionnaire included variables such as background and demography of users; intention to use AI, perceived risk; acceptance; and trust in AI-assisted detection, characterization, and intervention. We presented participants with 3 AI scenarios related to colonoscopy and the management of colorectal polyps. These scenarios reflect existing AI applications in colonoscopy, namely the detection of polyps (CADe), characterization of polyps (CADx), and AI-assisted polypectomy (CADi)., Results: In total, 165 gastroenterologists and gastrointestinal surgeons responded to a web-based survey using the structured questionnaire designed by experts in medical communications. Participants had a mean age of 44 (SD 9.65) years, were mostly male (n=116, 70.3%), and mostly worked in publicly funded hospitals (n=110, 66.67%). Participants reported relatively high exposure to AI, with 111 (67.27%) reporting having used AI for clinical diagnosis or treatment of digestive diseases. Gastroenterologists are highly interested to use AI in diagnosis but show different levels of reservations in risk prediction and acceptance of AI. Most participants (n=112, 72.72%) also expressed interest to use AI in their future practice. CADe was accepted by 83.03% (n=137) of respondents, CADx was accepted by 78.79% (n=130), and CADi was accepted by 72.12% (n=119). CADe and CADx were trusted by 85.45% (n=141) of respondents and CADi was trusted by 72.12% (n=119). There were no application-specific differences in risk perceptions, but more experienced clinicians gave lesser risk ratings., Conclusions: Gastroenterologists reported overall high acceptance and trust levels of using AI-assisted colonoscopy in the management of colorectal polyps. However, this level of trust depends on the application scenario. Moreover, the relationship among risk perception, acceptance, and trust in using AI in gastroenterology practice is not straightforward., (©Wilson WB Goh, Kendrick YA Chia, Max FK Cheung, Kalya M Kee, May O Lwin, Peter J Schulz, Minhu Chen, Kaichun Wu, Simon SM Ng, Rashid Lui, Tiing Leong Ang, Khay Guan Yeoh, Han-mo Chiu, Deng-chyang Wu, Joseph JY Sung. Originally published in JMIR AI (https://ai.jmir.org), 07.03.2024.)

Background: Baseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests., Materials and Methods: This was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters., Results: The Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy ( P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63)., Conclusion: The dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lu, Fang, Yu, Gao, Wang, Pan, Han, Yan, Xie, Yao, Yang, Zheng, Hong, Li, Li, Shang, Wu, Ji and Nie.)

Background: Recurrence following radical resection in patients with stage IB gastric cancer (GC) is not uncommon. However, whether postoperative adjuvant chemotherapy could reduce the risk of recurrence in stage IB GC remains contentious., Methods: We collected data on 2110 consecutive patients with pathologic stage IB (T1N1M0 or T2N0M0) GC who were admitted to 8 hospitals in China from 2009 to 2018. The survival of patients who received adjuvant chemotherapy was compared with that of postoperative observation patients using propensity score matching (PSM). Two survival prediction models were constructed to estimate the predicted net survival gain attributable to adjuvant chemotherapy., Findings: Of the 2110 patients, 1344 received adjuvant chemotherapy and 766 received postoperative observation. Following the 1-to-1 matching, PSM yielded 637 matched pairs. Among matched pairs, adjuvant chemotherapy was not associated with improved survival compared with postoperative observation (OS: hazard ratio [HR], 0.72; 95% CI, 0.52-1.00; DFS: HR, 0.91; 95% CI, 0.64-1.29). Interestingly, in the subgroup analysis, reduced mortality after adjuvant chemotherapy was observed in the subgroups with elevated serum CA19-9 (HR, 0.22; 95% CI, 0.08-0.57; P  = 0.001 for multiplicative interaction), positive lymphovascular invasion (HR, 0.32; 95% CI, 0.17-0.62; P  < 0.001 for multiplicative interaction), or positive lymph nodes (HR, 0.17; 95% CI, 0.07-0.38; P  < 0.001 for multiplicative interaction). The survival prediction models mainly based on variables associated with chemotherapy benefits in the subgroup analysis demonstrated good calibration and discrimination, with relatively high C-indexes. The C-indexes for OS were 0.74 for patients treated with adjuvant chemotherapy and 0.70 for patients treated with postoperative observation. Two nomograms were built from the models that can calculate individualized estimates of expected net survival gain attributable to adjuvant chemotherapy., Interpretation: In this cohort study, pathologic stage IB alone was not associated with survival benefits from adjuvant chemotherapy compared with postoperative observation in patients with early-stage GC. High-risk clinicopathologic features should be considered simultaneously when evaluating patients with stage IB GC for adjuvant chemotherapy., Funding: National Natural Science Foundation of China; the National Key R&D Program of China., Competing Interests: We declare no competing interests., (© 2024 The Authors.)

Ulcerative colitis (UC), a chronic and nonspecific inflammatory disease of the intestine, has become a prevalent global health concern. This guideline aims to equip clinicians and caregivers with effective strategies for the treatment and management of adult UC patients using traditional Chinese medicine (TCM). The guideline systematically evaluated contemporary evidence through the Grading of Recommendations Assessment, Development, and Evaluation framework. Additionally, it incorporated insights from ancient Chinese medical sources, employing the evidence grading method found in traditional TCM literature. The development process involved collaboration with multidisciplinary experts and included input from patients with UC. The guideline, based on a comprehensive review of available evidence, present 40 recommendations. They offer a condensed overview of TCM's role in understanding the pathogenesis, diagnosis, and treatment of UC, along with an assessment of the efficacy of various TCM-based treatments. TCM exhibits promising outcomes in the treatment of UC. However, to establish its efficacy conclusively, further high-quality clinical studies on TCM for UC are essential., (© 2023 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Escherichia coli LF82 (LF82) is associated with Crohn's disease. The simplicity and genetic maneuverability of honeybees' gut microbiota make them suitable for studying host-microbe interactions. To understand the interaction between LF82 and host gut, LF82 was used to infect germ-free honeybees (Apis mellifera) orally. We found that LF82 successfully colonized the gut and shortened the lifespan of germ-free bees. LF82 altered the gut structure and significantly increased gut permeability. RT-qPCR showed that LF82 infection activated anti-infective immune pathways and upregulated the mRNAs levels of antimicrobial peptides in the gut of germ-free bees. The gut transcriptome showed that LF82 significantly upregulated genes involved in Notch signaling, adhesion junctions, and Toll and Imd signaling pathways and downregulated genes involved in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, protein digestion and absorption, and tyrosine metabolism. In conclusion, the human-derived enteropathogenic bacterium LF82 can successfully colonize the gut of germ-free honeybees and cause enteritis-like changes, which provides an ideal model organism for revealing the pathogenesis of bacterial-associated diseases., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Aims: RNA splicing is an essential step in regulating the gene posttranscriptional expression. Serine/arginine-rich splicing factors (SRSFs) are splicing regulators with vital roles in various tumors. Nevertheless, the expression patterns and functions of SRSFs in hepatocellular carcinoma (HCC) are not fully understood., Methods: Flow cytometry and immunofluorescent staining were used to determine the CD8 + T cell infiltration. Orthotopic HCC model, lung metastasis model, DEN/CCl 4 model, Srsf10 △hep model, and Srsf10 HepOE model were established to evaluate the role of SRSF10 in HCC and the efficacy of combination treatment., Results: SRSF10 was one of the most survival-relevant genes among SRSF members and was an independent prognostic factor for HCC. SRSF10 facilitated HCC growth and metastasis by suppressing CD8 + T cell infiltration. Mechanistically, SRSF10 down-regulated the p53 protein by preventing the exon 6 skipping (exon 7 in mouse) mediated degradation of MDM4 transcript, thus inhibiting CD8 + T cell infiltration. Elimination of CD8 + T cells or overexpression of MDM4 removed the inhibitory role of SRSF10 knockdown in HCC growth and metastasis. SRSF10 also inhibited the IFNα/γ signaling pathway and promoted the HIF1α-mediated up-regulation of PD-L1 in HCC. Hepatocyte-specific SRSF10 deficiency alleviated the DEN/CCl 4 -induced HCC progression and metastasis, whereas hepatocyte-specific SRSF10 overexpression deteriorated these effects. Finally, SRSF10 knockdown enhanced the anti-PD-L1-mediated anti-tumor activity., Conclusions: SRSF10 promoted HCC growth and metastasis by repressing CD8 + T cell infiltration mediated by the MDM4-p53 axis. Furthermore, SRSF10 suppressed the IFNα/γ signaling pathway and induced the HIF1α signal mediated PD-L1 up-regulation. Targeting SRSF10 combined with anti-PD-L1 therapy showed promising efficacy., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The incidence of inflammatory bowel disease (IBD) is rapidly increasing in China, a vast country with significant geographical differences. The socioeconomic status of Eastern China is significantly higher than that of Western China., Objectives: This study aimed to describe the geographical heterogeneity in the characteristics and management of patients with IBD in both Eastern and Western China., Design: This was a multicenter, cross-sectional study., Methods: Patients with IBD with ages ⩾18 years up to 18 January 2023 were included in the analysis from the Chinese database for IBD. Logistic regression was used to identify risk factors associated with surgeries among patients with IBD., Results: Among 8305 patients with IBD, the ratio of ulcerative colitis (UC) to Crohn's disease (CD) was 4.13 and 0.33 in Western and Eastern China, respectively. The median age at diagnosis of UC and CD was 40.69 and 28.58 years, respectively. There was a male predominance among patients with UC (54.3%) and CD (68.0%). The two regions exhibited a similar distribution of disease locations in UC. However, Western China had a higher proportion of L2 involvement (30.0% versus 19.1%) and more advanced disease behavior (B2 and B3) (48.8% versus 39.8%) than Eastern China. Patients with IBD in Western China received more 5-aminosalicylic acid and corticosteroids and fewer immunomodulators and biologicals. In terms of surgical risk, Eastern China [ versus Western China, odds ratios (OR): 5.36, 95% confidence intervals (CI): 2.96-9.68] was associated with a higher risk of surgery in UC, while Western China ( versus Eastern China, OR: 3.39, 95% CI: 2.37-4.86) was associated with a higher risk of surgery in CD., Conclusion: Geographical heterogeneity exists in the disease characteristics and management of IBD in Eastern and Western China. These findings have the potential to guide the formulation of location-specific strategies aimed at enhancing the long-term outcomes of patients with IBD., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Patients with inflammatory bowel disease (IBD) have a high risk for colorectal cancer (CRC). This cancer type, which is strongly associated with chronic inflammation, is called colitis-associated CRC (CAC). Understanding the molecular pathogenesis of CAC is crucial to identify biomarkers necessary for early diagnosis and more effective treatment directions. The accumulation of immune cells and inflammatory factors, which constitute a complex chronic inflammatory environment in the intestinal mucosa, may cause oxidative stress or DNA damage to the epithelial cells, leading to CAC development and progression. An important feature of CAC is genetic instability, which includes chromosome instability, microsatellite instability, hypermethylation, and changes in noncoding RNAs. Furthermore, the intestinal microbiota and metabolites have a great impact on IBD and CAC. By clarifying immune, genetic, intestinal microecology, and other related pathogenesis, CAC may be more predictable and treatable., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alternative splicing regulates gene expression and functional diversity and is often dysregulated in human cancers. Here, we discovered that the long noncoding RNA (lncRNA) MIR99AHG regulated alternative splicing to alter the activity of a chromatin remodeler and promote metastatic behaviors in colorectal cancer (CRC). MIR99AHG was abundant in invasive CRC cells and metastatic tumors from patients and promoted motility and invasion in cultured CRC cells. MIR99AHG bound to and stabilized the RNA splicing factor PTBP1, and this complex increased cassette exon inclusion in the mRNA encoding the chromatin remodeling gene SMARCA1 . Specifically, MIR99AHG altered the nature of PTBP1 binding to the splice sites on intron 12 of SMARCA1 pre-mRNA, thereby triggering a splicing switch from skipping to including exon 13 to produce the long isoform, SMARCA1-L. SMARCA1, but not SMARCA1-L, suppressed invadopodia formation, cell migration, and invasion. Analysis of CRC samples revealed that the abundance of MIR99AHG transcript positively correlated with that of SMARCA1-L mRNA and PTBP1 protein and with poor prognosis in patients with CRC. Furthermore, TGF-β1 secretion from cancer-associated fibroblasts increased MIR99AHG expression in CRC cells. Our findings identify an lncRNA that is induced by cues from the tumor microenvironment and that interacts with PTBP1 to regulate alternative splicing, potentially providing a therapeutic target and predictive biomarker for metastatic CRC.

Background: Better predictors of patients with stage II/III gastric cancer (GC) most likely to benefit from adjuvant chemotherapy are urgently needed. This study aimed to assess the ability of CDX2 and mucin markers to predict prognosis and fluorouracil-based adjuvant chemotherapy benefits., Methods: CDX2 and mucin protein expressions were examined by immunohistochemistry and compared with survival and adjuvant chemotherapy benefits in a prospective evaluation cohort of 782 stage II/III GC patients. Then, the main findings were validated in an independent validation cohort (n = 386) and an external mRNA sequencing dataset (ACRG cohort, n = 193)., Results: In the evaluation cohort, CDX2, CD10, MUC2, MUC5AC, and MUC6 expressions were observed in 59.7%, 26.7%, 27.6%, 55.1%, and 57.7% of patients, respectively. However, only the expression of CDX2 was found to be associated with adjuvant chemotherapy benefits. Most importantly, CDX2-negative patients had a poorer prognosis when treated with surgery only, while the prognosis of CDX2-negative and CDX2-positive patients was similar when receiving postoperative adjuvant chemotherapy. Further analysis revealed that patients with CDX2 negative tumors benefited from chemotherapy (5-year overall survival rates: 60.0% with chemotherapy vs. 23.2% with surgery-only, p < 0.001), whereas patients with CDX2 positive tumors did not (p interaction  = 0.004). Consistent results were obtained in the validation and ACRG cohorts., Conclusions: Negative expression of CDX2 is an independent risk factor for survival in stage II/III GC, but subsequent adjuvant chemotherapy is able to compensate for this unfavorable effect. Therefore, active chemotherapy is more urgent for patients with negative CDX2 expression than for patients with positive CDX2 expression., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Metastasis is a major cause of HCC-related deaths with no effective pharmacotherapies. Chronic inflammation promotes HCC dissemination, however, its underlying mechanisms are not fully understood. Here, we investigated the role of Krüppel-like factor 7 (KLF7) in inflammation-provoked HCC metastasis and proposed therapeutic strategies for KLF7-positive patients. Methods: The expression of KLF7 in human HCC specimens were examined by immunohistochemistry and quantitative real-time PCR. The luciferase reporter assays and chromatin immunoprecipitation assays were conducted to explore the transcriptional regulation related to KLF7. Orthotopic xenograft models and DEN/CCl 4 -induced HCC models were established to evaluate HCC progression and metastasis. Results: KLF7 overexpression promotes HCC metastasis through transactivating toll-like receptor 4 (TLR4) and protein tyrosine kinase 2 (PTK2) expression. High mobility group box 1 (HMGB1) upregulates KLF7 expression through the TLR4/advanced glycosylation end-product specific receptor (RAGE)-PI3K-AKT-NF-κB pathway, forming an HMGB1-KLF7-TLR4 positive feedback loop. The HMGB1-KLF7-TLR4/PTK2 axis is gradually activated during the progression of inflammation-HCC transition. Genetic depletion of KLF7 impedes HMGB1-mediated HCC progression and metastasis. The combined application of TLR4 inhibitor TAK-242 and PTK2 inhibitor defactinib alleviates HCC progression and metastasis induced by the HMGB1-KLF7 axis. In human HCCs, KLF7 expression is positively correlated with cytoplasmic HMGB1, p-p65, TLR4, and PTK2 levels, and patients positively co-expressing HMGB1/KLF7, p-p65/KLF7, KLF7/TLR4 or KLF7/PTK2 exhibit the worst prognosis. Conclusions: HMGB1-induced KLF7 overexpression facilitates HCC progression and metastasis by upregulating TLR4 and PTK2. Genetic ablation of KLF7 via AAV gene therapy and combined blockade of TLR4 and PTK2 represents promising therapy strategies for KLF7-positive HCC patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Screening for colorectal cancer (CRC) is effective in reducing CRC related mortality. Current screening methods include endoscopy based and biomarker based approaches. This guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society of Digestive Endoscopy (APSDE), developed in response to the increasing use of, and accumulating supportive evidence for the role of, non-invasive biomarkers for the diagnosis of CRC and its precursor lesions. A systematic review of 678 publications and a two stage Delphi consensus process involving 16 clinicians in various disciplines was undertaken to develop 32 evidence based and expert opinion based recommendations for the use of faecal immunochemical tests, faecal based tumour biomarkers or microbial biomarkers, and blood based tumour biomarkers for the detection of CRC and adenoma. Comprehensive up-to-date guidance is provided on indications, patient selection and strengths and limitations of each screening tool. Future research to inform clinical applications are discussed alongside objective measurement of research priorities. This joint APAGE-APSDE practice guideline is intended to provide an up-to-date guide to assist clinicians worldwide in utilising non-invasive biomarkers for CRC screening; it has particular salience for clinicians in the Asia-Pacific region., Competing Interests: Competing interests: FKLC is Board Member of CUHK Medical Centre. He is a co-founder, non-executive Board Chairman and shareholder of GenieBiome Ltd. He receives patent royalties through his affiliated institutions. He has received fees as an advisor and honoraria as a speaker for Eisai Co. Ltd., AstraZeneca, Pfizer Inc., Takeda Pharmaceutical Co., and Takeda (China) Holdings Co. Ltd. MCSW is the honorary medical advisor of GenieBiome. He is an advisory committee member of Pfizer, external expert of GlaxoSmithKline, a member of the advisory board of AstraZeneca and has been paid consultancy fees for providing advice on research. ATC is a member of the AGA Governing Board and has received grant funding from Freenome for a colorectal cancer screening study. HM-C is the principal investigator, Taiwan CRC Screening Program, Asian Chair of WEO CRC screening committee and secretary general of the Gastroenterological Society of Taiwan (GEST), received research funding from Volition Rx, Eiken Chemical and Aether AI, and lecture honorarium from Olympus, Fuji and Eiken Chemical. JEE has served on clinical advisory boards for Paion, has served on the clinical advisory board and has share options in Satisfai Health and reports speaker fees from Falk, Jannsen and Medtronic. He was also part of the British Society of Gastroenterology guideline working group for 'Faecal immunochemical testing (FIT) in patients with signs or symptoms of suspected colorectal cancer (CRC)'. He is funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the National Health Service, the NIHR or the Department of Health. KW has served as an advisory board member for BioChain (Beijing), Ferring, Janssen, Takeda and Abbvie, and a speaker for BioChain (Beijing), Ferring, Janssen, Abbvie, Everest and Takeda. He is named inventor of patent applications held by the FMMU and BioChain (Beijing) that cover the diagnostic use of ctDNA related to gastrointestinal cancers. SCN has served as an advisory board member for Pfizer, Ferring, Janssen, and Abbvie and received honoraria as a speaker for Ferring, Tillotts, Menarini, Janssen, Abbvie, and Takeda. SCN has received research grants through her affiliated institutions from Olympus, Ferring, and Abbvie. SCN is a scientific co-founder and shareholder of GenieBiome Ltd. SCN receives patent royalties through her affiliated institutions., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Accumulating evidence indicates that gut microbiota closely correlates with the tumorigenesis of digestive system cancers (DSCs). However, whether the causality between gut microbiota and DSCs exists is unknown. Genome-wide association study (GWAS) summary statistics for gut microbiota and DSCs and the bidirectional two-sample Mendelian randomization (MR) analysis were utilized to assess the causality between gut microbiota and DSCs. Sensitivity analyses were performed to evaluate the robustness of our results. We found that the genus Eggerthella (OR = 0.464, 95%CI: 0.27 to 0.796, p = 0.005) was negatively associated with the risk of gastric cancer. The genetically predicted genus Lachnospiraceae FCS020 group (OR = 0.607, 95%CI: 0.439 to 0.84, p = 0.003) correlated with a lower risk of colorectal cancer, and genus Turicibacter (OR = 0.271, 95%CI: 0.109 to 0.676, p = 0.005) was a protective factor for liver cancer. In the reverse MR, DSCs regulated the relative abundance of specific strains of gut microbiota. We comprehensively screened the association between gut microbiota and DSCs using a bidirectional two-sample MR analysis and identified the causality between several microbial taxa and DSCs. Our discoveries are beneficial for the development of novel microbial markers and microbiota-modifying therapeutics for DSC patients.

Objective: To explore the correlation between disease activity and anxiety, depression, sleep quality, and quality of life in patients with inflammatory bowel disease (IBD)., Methods: The disease activity of IBD patients was evaluated by 66 gastroenterologists from 42 hospitals in 22 provinces in China from September 2021 to May 2022. Anxiety, depression, sleep quality and quality of life of IBD patients were investigated and statistically analyzed by different scales, including Generalized Anxiety Disorder 7-item Scale (GAD-7), Patient Health Questionnaire-9 (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), and Inflammatory Bowel Disease Quality-of-Life Questionnaire (IBD-Q)., Results: A total of 2478 IBD patients were included, of which 1532 (61.8%) were in active stage and 946 (38.2%) were in remission. The proportions of active IBD with anxiety, depression, sleep disturbance, and poor quality of life were 29.5%, 29.7%, 71.1%, and 50.1%, respectively, while the proportions of remission IBD with anxiety, depression, sleep disturbance, and poor quality of life were 19.1%, 24.4%, 69.3%, and 17.4%, respectively. IBD patients who also had anxiety, depression, sleep disturbances and poor quality of life had 80 cases (8.46%) in remission and 114 cases (7.44%) in active stage, with 54 cases (9.18%) in mild activity, 51 cases (6.95%) in moderate activity and 9 cases (4.49%) in severe activity. IBD patients with different disease activity levels differed in GAD-7 scores, PHQ-9 scores, PSQI scores, and IBD-Q scores (all P <0.001). In IBD patients, anxiety, depression, and sleep disturbance, which interact with each other, can further aggravate their disease activity (all P <0.001)., Conclusion: Anxiety, depression, sleep disturbances, and quality of life are strongly correlated with disease activity in IBD patients, and IBD patients with psychological disturbances are most often in the active stage and have a poor quality of life., Competing Interests: The authors have no conflicts of interest to declare in this work., (© 2023 Yu et al.)

Background: Human epidermal growth factor receptor 2 (HER2) is a well-developed therapeutic target in breast and gastric cancer (GC). However, the impact of HER2 on survival and benefit from fluorouracil-based adjuvant chemotherapy remains unclear in patients with GC., Materials and Methods: This multicenter cohort study involved 5622 consecutive stage II/III GC patients. HER2 expression was assessed prospectively via immunohistochemistry (IHC). The staining intensity was graded on a scale of 0 to 3+. An IHC score of 2+or 3+was defined as high expression, and a score of 3+was defined as overexpression., Results: HER2 overexpression was independently associated with a lower 5-year overall survival (OS) in stage II [hazard ratio (HR), 2.10; 95% CI: 1.41-3.11], but not in stage III GC (HR, 1.00; 95% CI, 0.82-1.20). Further analysis revealed that stage II patients with high HER2 expression showed a poorer response to chemotherapy than stage II patients with low HER2 expression ( Pinteraction =0.024). The HRs for 5-year OS were 0.51 (95% CI, 0.38-0.70) for stage II patients with low HER2 expression, 0.58 (95% CI, 0.51-0.66) for stage III patients with low HER2 expression, 1.13 (95% CI, 0.61-2.09) for stage II patients with high HER2 expression, and 0.47 (95% CI, 0.36-0.61) for stage III patients with high HER2 expression., Conclusions: Fluorouracil-based adjuvant chemotherapy is insufficient for stage II GC patients with high HER2 expression, indicating that prospective trials are required to validate alternative HER2-targeted adjuvant therapies in the individuals above., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: This study aimed to determine the prevalence and risk factors for poor sleep quality in inflammatory bowel disease (IBD) patients., Methods: 2,478 IBD patients were enrolled to investigate their sleep quality using the Pittsburgh sleep quality index (PSQI). Clinical and psychological characteristics were collected to explore the risk factors for poor sleep quality. A hurdle model was conducted to predict poor sleep quality based on the risk factors. Among this hurdle model, the logistic regression model was used to determine risk factors of the presence of poor sleep quality, and the zero-inflated negative binomial model was employed to identify risk factors of the severity of poor sleep quality., Results: In this study, 1,491 (60.17%) IBD patients had poor sleep quality, and the proportion in the older group was higher than younger group (64.89% vs. 58.27%, p  = 0.003). According to multivariable logistic regression, age (OR, 1.011; 95% CI [1.002,1.020]; p  = 0.014), Patient Health Questionnaire-9 (PHQ-9) score (OR, 1.263; 95% CI [1.228,1.300]; p  < 0.001), systemic (OR, 0.906; 95% CI [0.867,0.946]; p  < 0.001) and emotional performance (OR, 1.023; 95% CI [1.005,1.043]; p  = 0.015) were risk factors of the presence of poor sleep quality. The area under the curve (AUC) of the prediction model was 0.808. According to zero-truncated negative binomial regression, age (RR, 1.004; 95% CI [1.002,1.005]; p  < 0.001) and PHQ-9 score (RR, 1.027; 95% CI [1.021,1.032]; p  < 0.001) were risk factors of the severity of poor sleep quality., Conclusion: The prevalence of poor sleep quality among the older group in IBD patients was relatively high. Old age and depressive mood are risk factors for both the presence and severity of poor sleep quality., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zeng, Liu, Zhang, An, Liu, Jiang, Shi, Wu and Dong.)

Objective: To explore the gender differences in the psychological symptoms, sleep quality, and quality of life of patients with inflammatory bowel disease (IBD)., Methods: A unified questionnaire was developed to collect clinical data on the psychology and quality of life of IBD patients from 42 hospitals in 22 provinces in China from September 2021 to May 2022. The general clinical characteristics, psychological symptoms, sleep quality, and quality of life of IBD patients of different genders were analyzed via a descriptive statistical analysis. A multivariate logistic regression analysis was conducted, and independent influencing factors were screened to construct a nomogram to predict the quality of life. The consistency index (C-index), receiver operating characteristic (ROC) curve, area under the ROC curve (AUC), and calibration curve were used to evaluate the discrimination and accuracy of the nomogram model. Decision curve analysis (DCA) was used to evaluate the clinical utility., Results: A total of 2478 IBD patients (1371 patients with ulcerative colitis (UC) and 1107 patients with Crohn's disease (CD)) were investigated, including 1547 males (62.4%) and 931 females (37.6%). The proportion of anxiety in females was significantly higher than in males (IBD: 30.5% vs. 22.4%, p < 0.001; UC: 32.4% vs. 25.1%, p = 0.003; CD: 26.8% vs. 19.9%, p = 0.013), and there were differences in the severity of anxiety between the genders (IBD: p < 0.001; UC: p < 0.001; CD: p = 0.050). The proportion of depression in females was higher than in males (IBD: 33.1% vs. 27.7%, p = 0.005; UC: 34.4% vs. 28.9%, p = 0.031; CD: 30.6% vs. 26.6%, p = 0.184), and there were differences in the severity of depression between the genders (IBD: p = 0.004; UC: p = 0.022; CD: p = 0.312). The proportion suffering from sleep disturbances among females was slightly higher than among males (IBD: 63.2% vs. 58.4%, p = 0.018; UC: 63.4% vs. 58.1%, p = 0.047; CD: 62.7% vs. 58.6%, p = 0.210), and the proportion of females with a poor quality of life was higher than that of males (IBD: 41.8% vs. 35.2%, p = 0.001; UC: 45.1% vs. 39.8%, p = 0.049; CD: 35.4% vs. 30.8%, p = 0.141). The AUC values of the female and male nomogram prediction models for predicting poor quality of life were 0.770 (95% CI: 0.7391-0.7998) and 0.771 (95% CI: 0.7466-0.7952), respectively. The calibration diagrams of the two models showed that the calibration curves fitted well with the ideal curve, and the DCA that showed nomogram models could bring clinical benefits., Conclusions: There were significant gender differences in the psychological symptoms, sleep quality, and quality of life of IBD patients, suggesting that females need more psychological support. In addition, a nomogram model with high accuracy and performance was constructed to predict the quality of life of IBD patients of different genders, which is helpful for the timely clinical formulation of personalized intervention plans that can improve the prognosis of patients and save medical costs.

Background: Metastasis accounts for the high lethality of colorectal cancer (CRC) patients. Unfortunately, the molecular mechanism manipulating metastasis in CRC is still elusive. Here, we investigated the function of E74-like factor 4 (ELF4), an ETS family member, in facilitating CRC progression. Methods: The expression of ELF4 in human CRC samples and CRC cell lines was determined by quantitative real-time PCR, immunohistochemistry and immunoblotting. The migratory and invasive phenotypes of CRC cells were evaluated by in vitro transwell assays and in vivo metastatic models. The RNA sequencing was used to explore the downstream targets of ELF4. The luciferase reporter assays and chromatin immunoprecipitation assays were used to ascertain the transcriptional regulation related to ELF4. Results: We found elevated ELF4 was positively correlated with distant metastasis, advanced AJCC stages, and dismal outcomes in CRC patients. ELF4 expression was also an independent predictor of poor prognosis. Overexpression of ELF4 boosted CRC metastasis via transactivating its downstream target genes, fibroblast growth factor receptor 4 (FGFR4) and SRC proto-oncogene, non-receptor tyrosine kinase, SRC . Fibroblast growth factor 19 (FGF19) upregulated ELF4 expression through the ERK1/2/SP1 axis. Clinically, ELF4 expression had a positive correlation with FGF19, FGFR4 and SRC, and CRC patients who positively coexpressed FGF19/ELF4, ELF4/FGFR4, or ELF4/SRC exhibited the worst clinical outcomes. Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis. Conclusions: We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Cuproptosis is a newly defined form of cell death, whether cuproptosis involved in hepatocellular carcinoma (HCC) remains elusive. Method: We obtained patients' RNA expression data and follow-up information from University of California Santa Cruz (UCSC) and The Cancer Genome Atlas (TCGA). We analyzed the mRNA level of Cuproptosis-related genes (CRGs) and performed univariate Cox analysis. Liver hepatocellular carcinoma (LIHC) was chosen for further investigation. Real-Time quantitative PCR (RT-qPCR), Western blotting (WB), Immunohistochemical (IHC), and Transwell assays were used to determine expression patterns and functions of CRGs in LIHC. Next, we identified CRGs-related lncRNAs (CRLs) and differentially expressed CRLs between HCC and normal cases. Univariate Cox analysis, least absolute shrinkage selection operator (LASSO) analysis and Cox regression analysis were used to construct the prognostic model. Univariate and multivariate Cox analysis was used to assess whether the risk model can act as an independent risk factor of overall survival duration. Different risk groups performed immune correlation analysis, tumor mutation burden (TMB), and Gene Set Enrichment Analysis (GSEA) analysis were performed in different risk groups. Finally, we assessed the performance of the predictive model in drug sensitivity. Results: CRGs expression levels have significant differences between tumor and normal tissues. High expression of Dihydrolipoamide S-Acetyltransferase ( DLAT ) correlated to metastasis of HCC cells and indicated poor prognosis for HCC patients. Our prognostic model consisted of four cuproptosis-related lncRNA (AC011476.3, AC026412.3, NRAV, MKLN1-AS). The prognostic model performed well in predicting survival rates. The results from Cox regression analysis suggested that risk score can serve as an independent prognostic element for survival durations. Survival analysis revealed that low risk patients have extended survival periods compared with those with high risk. The results of the immune analysis indicated that risk score has a positive correlation with B cell and CD4 + T cell Th2, while has a negative relationship with endothelial cell and hematopoietic cells. Besides, immune checkpoint genes have higher expression folds in the high-risk set than in the low-risk set. The high-risk group had higher rates of genetic mutation than the low-risk set while having a shorter survival time. GSEA revealed the signaling pathways enriched in the high-risk group were mostly immune-related, while metabolic-related pathways were enriched in the low-risk group. Drugs sensitivity analysis indicated that our model has the ability to predict the efficacy of clinical treatment. Conclusion: The Cuproptosis-related lncRNAs prognostic formula is a novel predictor of HCC patients' prognosis and drug sensitivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Sun, Feng, Chen, Ji, Xie, Huang, Chen, Zhang, Nie, Fan, Wu and Xia.)

Background: The correlation and difference in T-cell phenotypes between peripheral blood lymphocytes (PBLs) and the tumor immune microenvironment (TIME) in patients with gastric cancer (GC) is not clear. We aimed to characterize the phenotypes of CD8 + T cells in tumor infiltrating lymphocytes (TILs) and PBLs in patients with different outcomes and to establish a useful survival prediction model., Methods: Multiplex immunofluorescence staining and flow cytometry were used to detect the expression of inhibitory molecules (IMs) and active markers (AMs) in CD8 + TILs and PBLs, respectively. The role of these parameters in the 3-year prognosis was assessed by receiver operating characteristic analysis. Then, we divided patients into two TIME clusters (TIME-A/B) and two PBL clusters (PBL-A/B) by unsupervised hierarchical clustering based on the results of multivariate analysis, and used the Kaplan-Meier method to analyze the difference in prognosis between each group. Finally, we constructed and compared three survival prediction models based on Cox regression analysis, and further validated the efficiency and accuracy in the internal and external cohorts., Results: The percentage of PD-1 + CD8 + TILs, TIM-3 + CD8 + TILs, PD-L1 + CD8 + TILs, and PD-L1 + CD8 + PBLs and the density of PD-L1 + CD8 + TILs were independent risk factors, while the percentage of TIM-3 + CD8 + PBLs was an independent protective factor. The patients in the TIME-B group showed a worse 3-year overall survival (OS) (HR: 3.256, 95% CI 1.318-8.043, P = 0.006), with a higher density of PD-L1 + CD8 + TILs (P < 0.001) and percentage of PD-1 + CD8 + TILs (P = 0.017) and PD-L1 + CD8 + TILs (P < 0.001) compared to the TIME-A group. The patients in the PBL-B group showed higher positivity for PD-L1 + CD8 + PBLs (P = 0.042), LAG-3 + CD8 + PBLs (P < 0.001), TIM-3 + CD8 + PBLs (P = 0.003), PD-L1 + CD4 + PBLs (P = 0.001), and LAG-3 + CD4 + PBLs (P < 0.001) and poorer 3-year OS (HR: 0.124, 95% CI 0.017-0.929, P = 0.015) than those in the PBL-A group. In our three survival prediction models, Model 3, which was based on the percentage of TIM-3 + CD8 + PBLs, PD-L1 + CD8 + TILs and PD-1 + CD8 + TILs, showed the best sensitivity (0.950, 0.914), specificity (0.852, 0.857) and accuracy (κ = 0.787, P < 0.001; κ = 0.771, P < 0.001) in the internal and external cohorts, respectively., Conclusion: We established a comprehensive and robust survival prediction model based on the T-cell phenotype in the TIME and PBLs for GC prognosis., (© 2023. The Author(s).)

The accurate assessment of lymph node metastasis (LNM) in patients with early gastric cancer is critical to the selection of the most appropriate surgical treatment. This study aims to develop an optimal LNM prediction model using different methods, including nomogram, Decision Tree, Naive Bayes, and deep learning methods. In this study, we included two independent datasets: the gastrectomy set (n=3158) and the endoscopic submucosal dissection (ESD) set (n=323). The nomogram, Decision Tree, Naive Bayes, and fully convolutional neural networks (FCNN) models were established based on logistic regression analysis of the development set. The predictive power of the LNM prediction models was revealed by time-dependent receiver operating characteristic (ROC) curves and calibration plots. We then used the ESD set as an external cohort to evaluate the models' performance. In the gastrectomy set, multivariate analysis showed that gender (P=0.008), year when diagnosed (2006-2010 year, P=0.265; 2011-2015 year, P=0.001; and 2016-2020 year, P<0.001, respectively), tumor size (2-4 cm, P=0.001; and ≥4 cm, P<0.001, respectively), tumor grade (poorly-moderately, P=0.016; moderately, P<0.001; well-moderately, P<0.001; and well, P<0.001, respectively), vascular invasion (P<0.001), and pT stage (P<0.001) were independent risk factors for LNM in early gastric cancer. The area under the curve (AUC) for the validation set using the nomogram, Decision Tree, Naive Bayes, and FCNN models were 0.78, 0.76, 0.77, and 0.79, respectively. In conclusion, our multi-cohort study systematically investigated different LNM prediction methods for patients with early gastric cancer. These models were validated and shown to be reliable with AUC>0.76 for all. Specifically, the FCNN model showed the most accurate prediction of LNM risks in early gastric cancer patients with AUC=0.79. Based on the FCNN model, patients with LNM rates of >4.77% are strong candidates for gastrectomy rather than ESD surgery., Competing Interests: None., (AJCR Copyright © 2023.)

The Asia-Pacific region has the largest number of cases of colorectal cancer (CRC) and one of the highest levels of mortality due to this condition in the world. Since the publishing of two consensus recommendations in 2008 and 2015, significant advancements have been made in our knowledge of epidemiology, pathology and the natural history of the adenoma-carcinoma progression. Based on the most updated epidemiological and clinical studies in this region, considering literature from international studies, and adopting the modified Delphi process, the Asia-Pacific Working Group on Colorectal Cancer Screening has updated and revised their recommendations on (1) screening methods and preferred strategies; (2) age for starting and terminating screening for CRC; (3) screening for individuals with a family history of CRC or advanced adenoma; (4) surveillance for those with adenomas; (5) screening and surveillance for sessile serrated lesions and (6) quality assurance of screening programmes. Thirteen countries/regions in the Asia-Pacific region were represented in this exercise. International advisors from North America and Europe were invited to participate., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with inflammatory bowel disease (IBD) are often accompanied with some cognitive impairment, but the mechanism is unclear. By orally exposing honeybees ( Apis mellifera ) to IBD-associated Escherichia coli LF82 (LF82), and non-pathogenic Escherichia coli MG1655 (MG1655) as the normal strain, we investigated whether and how LF82 induces enteritis-like manifestations and cognitive behavioral modifications in honeybees using multiparametric analysis. LF82 significantly increased gut permeability, impaired learning and memory ability in olfactory proboscis extension response conditioning, and shortened the lifespan of honeybees. Compared to MG1655, LF82 reduced the levels of tryptophan metabolism pathway substances in the honeybee gut. LF82 also upregulated genes involved in immune and apoptosis-related pathways and downregulated genes involved in G protein-coupled receptors in the honeybee brain. In conclusion, LF82 can induce enteritis-like manifestations and cognition impairment through gut metabolites and brain transcriptome alteration in honeybees. Honeybees can serve as a novel potential model to study the microbiota-gut-brain interaction in IBD condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chang, Chen, Zhong, Li, Wu, Zheng and Yang.)

Background: Distinguishing Crohn's disease (CD) and intestinal Behçet's disease (BD) is difficult in clinical practice., Aim: To evaluate the ability of CT enterography (CTE) to enhance the diagnostic value of endoscopy in differentiating CD from intestinal BD and to establish differential diagnosis models., Methods: A total of 113 patients with CD and 70 patients with intestinal BD from seven tertiary inflammatory bowel disease centers were enrolled. The univariate and multivariate analyses were used by SAS software version 9.2. Three differential scoring models based on the multivariate analysis of endoscopic features alone (model 1), endoscopic features combined with clinical symptoms (model 2), and endoscopic features combined with clinical symptoms and CTE (model 3) were established., Results: The results showed that model 2 increased the efficacy of model 1 in differential diagnosis and model 3 had the highest accuracy of 84.15% at a cutoff value of two points. The scoring of model 3 was as follows: genital ulcer (-3 points), skin lesions (-3 points), oval ulcer (-2 points), longitudinal ulcer (1 point), number of ulcers > 5 (3 points), inflammatory polyps (2 points), mucosal severe enhancement (2 points), and fibrofatty proliferation (1 point)., Conclusion: Clinical symptoms and CTE increased the ability of endoscopy to differentiate CD from intestinal BD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Zhang, Liu, Han, Guo, Lai, Tan, Wang, Chen, Gao, Ran, Liu, Wu, Cao and Qian.)

Diet can impact on gut health and disease by modulating intestinal stem cells (ISCs). However, it is largely unknown if and how the ISC niche responds to diet and influences ISC function. Here, we demonstrate that Lepr + mesenchymal cells (MCs) surrounding intestinal crypts sense diet change and provide a novel niche signal to maintain ISC and progenitor cell proliferation. The abundance of these MCs increases upon administration of a high-fat diet (HFD) but dramatically decreases upon fasting. Depletion of Lepr + MCs resulted in fewer intestinal stem/progenitor cells, compromised the architecture of crypt-villus axis and impaired intestinal regeneration. Furthermore, we showed that IGF1 secreted by Lepr + MCs is an important effector that promotes proliferation of ISCs and progenitor cells in the intestinal crypt. We conclude that Lepr + MCs sense diet alterations and, in turn, modulate intestinal stem/progenitor cell function via a stromal IGF1-epithelial IGF1R axis. These findings reveal that Lepr + MCs are important mediators linking systemic diet changes to local ISC function and might serve as a novel therapeutic target for gut diseases., (© 2022. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.)

Background: Inflammatory bowel disease (IBD) is a complex chronic disorder characterized by systemic inflammation, which may cause abnormal state of coagulation, resulting in cardiac events. This study aimed to investigate the incidences and risks of cardiac events in patients with IBD in China., Methods: A retrospective cohort study was performed comprising 1435 patients with IBD from 12 IBD centers in China. Cases were matched with 1588 eligible participants without IBD from 12 medical centers according to age, sex, and laboratory parameters., Results: Patients with IBD in China exhibited significantly higher incidences of ischemic heart disease (IHD; coronary heart disease included) but lower frequencies of right bundle branch block and premature contraction than those of matched controls. The risk of IHD increased in patients with IBD, peaking at the age of 18-35 years. Female patients with IBD were more likely to experience IHD than male patients. The C-reactive protein (CRP) levels and neutrophil count in the peripheral blood were positively related with the risk of IHD among patients with Crohn's disease, whereas plasma fibrinogen levels were negatively related with the risk of IHD both in patients with Crohn's disease and ulcerative colitis., Conclusions: The risk of IHD is increased in patients with IBD, especially in young female patients with IBD when compared with matched non-IBD subjects. The CRP and plasma fibrinogen levels and neutrophil count in the peripheral blood may be potential predictors associated with the occurrence of IHD in patients with IBD. The study's findings have significant implications for the management and prevention of cardiac events in patients with IBD., (© The Author(s) 2021. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with ulcerative colitis (UC) are at an increased risk of developing Clostridioides difficile infection (CDI), which in turn leads to poor outcomes. The gut microbial structure and metabolites in patients with UC and CDI have been scarcely studied. We hypothesized that CDI changes the gut microbiota and metabolites of patients with UC., Materials and Methods: This study included 89 patients: 30 healthy controls (HC group), 29 with UC alone (UCN group), and 30 with UC and CDI (UCP group). None of the participants has been exposed to antibiotic treatments during the 3 months before stool collection. Stool samples were analyzed using 16S rRNA gene sequencing of the V3-V4 region and gas chromatography tandem time-of-flight mass spectrometry., Results: The UCN group displayed lower diversity and richness in gut microbiota and a higher relative abundance of the phylum Proteobacteria than the HC group. There were no significant differences between the UCN and UCP groups in the α-diversity indices. The UCP group contained a higher relative abundance of the genera Clostridium sensu stricto , Clostridium XI, Aggregatibacter , and Haemophilus , and a lower relative abundance of genera Clostridium XIVb and Citrobacter than the UCN group. In the UCP group, the increased metabolites included putrescine, maltose, 4-hydroxybenzoic acid, 4-hydroxybutyrate, and aminomalonic acid. Spearman's correlation analysis revealed that these increased metabolites negatively correlated with Clostridium XlVb and positively correlated with the four enriched genera. However, the correlations between hemoglobin and metabolites were contrary to the correlations between erythrocyte sedimentation rate and high-sensitivity C-reactive protein and metabolites., Conclusion: Our study identified 11 differential genera and 16 perturbed metabolites in patients with UC and CDI compared to those with UC alone. These findings may guide the design of research on potential mechanisms and specific treatments for CDI in patients with UC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wan, Zhang, He, Tian, Lin, Liu, Li, Chen, Han, Liang, Shi, Wang, Zhou, Cao, Liu and Wu.)

Background: Ulcerative colitis (UC) is a chronic lifelong disease. The disease extent of UC can progress over time. This study aimed to assess whether cumulative inflammatory burden (CIB) is associated with disease extension in distal UC (proctitis [E1] and left-sided colitis [E2]) patients, and to develop a quantified indicator of CIB., Methods: In this retrospective study based on a prospective registry, distal UC patients receiving colonoscopies in Xijing Hospital (Xi'an, China) from January 2000 to May 2019 were studied. We developed a new score, namely the time-adjusted average Mayo endoscopic score (TA-MES), calculated as dividing the sum of the cumulative average MES over a period of surveillance time by the length of the endoscopic examination interval, to quantify the CIB. Cox regression was used to identify other potential risk factors., Results: A total of 295 UC patients were followed for 1,487.02 patient-years. Among them, 140 patients (47.5%) experienced disease extension. Multivariate analysis showed that the TA-MES was significantly associated with disease extension in E1 (hazard ratio [HR], 2.90; 95% confidence interval [CI], 1.58-5.33, P  =   0.001) and E2 (HR, 1.89; 95% CI, 1.16-3.09, P  =   0.011) patients. Other risk factors included hemoglobin of <90 g/L and appendiceal skip inflammation; the protective factors included age, E2 at diagnosis, former smoking, and 5-aminosalicylic acid dose. Otherwise, MES at diagnosis, maximal MES, and mean MES failed to estimate the risk of disease extension., Conclusion: TA-MES is a good quantified indicator of CIB and is independently associated with increased disease extension in distal UC patients. Whether the dynamic multiple scoring system could be used as a risk factor in other chronic relapsing-remitting diseases is a direction for future research., (© The Author(s) 2022. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University.)

Background: Differential diagnosis of Crohn's disease (CD) and ulcerative primary intestinal lymphoma (UPIL) is a tough problem in clinical practice., Aims: Our study identified key differences between CD and UPIL patients and aimed to further establish a scoring model for differential diagnosis., Methods: A total of 91 CD and 50 UPIL patients from 9 tertiary inflammatory bowel disease centers were included. Univariate and multivariate analyses were used to determine significant markers for differentiating CD and UPIL. A differential scoring model was established by logistic regression analysis., Results: The differential model was based on clinical symptoms, endoscopic and imaging features that were assigned different scores: intestinal bleeding (-2 points), extraintestinal manifestation (2 points), segmental lesions (1 point), cobblestone sign (2 points), homogeneous enhancement (-1 point), mild enhancement (-1 point), engorged vasa recta (1 point). A total score of ≥1 point indicates CD, otherwise UPIL was indicated. This model produced an accuracy of 83.66% and an area under the ROC curve of 0.947. The area under the ROC curve for validation using the 10-fold validation method was 0.901., Conclusion: This study provided a convenient and useful model to differentiate CD from UPIL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Zhang, Liu, Tan, Guo, Gao, Feng, Wu, Cao, Ran, Liu, Hu, Zhu, Lai, Wang, Han and Qian.)

Background/aims: The incidence and prevalence of inflammatory bowel disease (IBD) is rising in Asia recently. The study aimed to obtain a comprehensive understanding of the current status of drug therapy and monitoring for IBD in Asia., Methods: A questionnaire investigation on drug therapy and monitoring for IBD was conducted right before the 6th Annual Meeting of Asian Organization for Crohn's & Colitis. Questionnaires were provided to Asian physicians to fill out via emails between March and May 2018., Results: In total, responses of 166 physicians from 129 medical centers were included for analysis. Among the surveyed regions, the most average number of IBD specialist gastroenterologists and nurses was 4.8 per center in Taiwan and 2.5 per center in Mainland China, respectively. 5-Aminosalicylic acid/sulfasalazine (99.4%) was the most preferred first-line choice for mild-moderate ulcerative colitis (UC), meanwhile corticosteroid (83.7%) was widely applied for severe UC. The first-line medication for Crohn's disease (CD) markedly varied as corticosteroid (68.1%) was the most favored in Mainland China, Japan, and South Korea, followed by infliximab (52.4%) and azathioprine (47.0%). Step-up strategy was preferred in mild-moderate UC (96.4%), while 51.8% of the physicians selected top-down treatment for CD. Only 25.9% and 17.5% of the physicians could test blood concentration of infliximab and antibody to infliximab in their hospitals, respectively., Conclusions: The current status of drug therapy and monitoring for IBD in Asia possesses commonalities as well as differences. Asian recommendations, IBD specialist teams and practice of therapeutic drug monitoring are required to improve IBD management in Asia.

De novo and acquired resistance are major impediments to the efficacy of conventional and targeted cancer therapy. In unselected gastric cancer (GC) patients with advanced disease, trials combining chemotherapy and an anti-EGFR monoclonal antibody have been largely unsuccessful. In an effort to identify biomarkers of resistance so as to better select patients for such trials, we screened the secretome of chemotherapy-treated human GC cell lines. We found that levels of CGA, the α-subunit of glycoprotein hormones, were markedly increased in the conditioned media of chemoresistant GC cells, and CGA immunoreactivity was enhanced in GC tissues that progressed on chemotherapy. CGA levels in plasma increased in GC patients who received chemotherapy, and this increase was correlated with reduced responsiveness to chemotherapy and poor survival. Mechanistically, secreted CGA was found to bind to EGFR and activate EGFR signaling, thereby conferring a survival advantage to GC cells. N-glycosylation of CGA at Asn52 and Asn78 is required for its stability, secretion, and interaction with EGFR. GATA2 was found to activate CGA transcription, whose increase, in turn, induced the expression and phosphorylation of GATA2 in an EGFR-dependent manner, forming a positive feedback circuit that was initiated by GATA2 autoregulation upon sublethal exposure to chemotherapy. Based on this circuit, combination strategies involving anti-EGFR therapies or targeting CGA with microRNAs (miR-708-3p and miR-761) restored chemotherapy sensitivity. These findings identify a clinically actionable CGA/EGFR/GATA2 circuit and highlight CGA as a predictive biomarker and therapeutic target in chemoresistant GC.