Gut最新文献

{"title":"Strengths and limitations of AlphaMissense in <i>CPA1</i> missense variant classification.","authors":"Ya-Hui Wang, Emmanuelle Masson, Zhuan Liao, Claude Férec, Wen-Bin Zou, Jian-Min Chen","doi":"10.1136/gutjnl-2024-332120","DOIUrl":"10.1136/gutjnl-2024-332120","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"e42"},"PeriodicalIF":23.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140109764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of mailed outreach and patient navigation to promote HCC screening process completion: a multicentre pragmatic randomised clinical trial.","authors":"Amit G Singal, Manasa Narasimman, Darine Daher, Sruthi Yekkaluri, Yan Liu, MinJae Lee, Vanessa Cerda, Aisha Khan, Karim Seif El Dahan, Jennifer Kramer, Purva Gopal, Caitlin Murphy, Ruben Hernaez","doi":"10.1136/gutjnl-2024-332508","DOIUrl":"10.1136/gutjnl-2024-332508","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is plagued by failures across the cancer care continuum, leading to frequent late-stage diagnoses and high mortality. We evaluated the effectiveness of mailed outreach invitations plus patient navigation to promote HCC screening process completion in patients with cirrhosis.</p><p><strong>Methods: </strong>Between April 2018 and September 2021, we conducted a multicentre pragmatic randomised clinical trial comparing mailed outreach plus patient navigation for HCC screening (n=1436) versus usual care with visit-based screening (n=1436) among patients with cirrhosis at three US health systems. Our primary outcome was screening process completion over a 36-month period, and our secondary outcome was the proportion of time covered (PTC) by screening. All patients were included in intention-to-screen analyses.</p><p><strong>Results: </strong>All 2872 participants (median age 61.3 years; 32.3% women) were included in intention-to-screen analyses. Screening process completion was observed in 6.6% (95% CI: 5.3% to 7.9%) of patients randomised to outreach and 3.3% (95% CI: 2.4% to 4.3%) of those randomised to usual care (OR 2.05, 95% CI: 1.44 to 2.92). The intervention increased HCC screening process completion across most subgroups including age, sex, race and ethnicity, Child-Turcotte-Pugh class and health system. PTC was also significantly higher in the outreach arm than usual care (mean 37.5% vs 28.2%; RR 1.33, 95% CI: 1.31 to 1.35). Despite screening underuse, most HCC in both arms were detected at an early stage.</p><p><strong>Conclusion: </strong>Mailed outreach plus navigation significantly increased HCC screening process completion versus usual care in patients with cirrhosis, with a consistent effect across most examined subgroups. However, screening completion remained suboptimal in both arms, underscoring a need for more intensive interventions.</p><p><strong>Trial registration number: </strong>NCT02582918.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"2037-2044"},"PeriodicalIF":6.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical outcomes of potential coeliac disease: a systematic review and meta-analysis.","authors":"Mohamed G Shiha, Annalisa Schiepatti, Stiliano Maimaris, NIcoletta Nandi, Hugo A Penny, David S Sanders","doi":"10.1136/gutjnl-2024-333110","DOIUrl":"10.1136/gutjnl-2024-333110","url":null,"abstract":"<p><strong>Objective: </strong>Potential coeliac disease (PCD) is characterised by positive serological and genetic markers of coeliac disease with architecturally preserved duodenal mucosa. The clinical outcomes and rates of progression to overt coeliac disease in patients with PCD remain uncertain. In this systematic review and meta-analysis, we aimed to evaluate the clinical outcomes of patients with PCD.</p><p><strong>Design: </strong>We searched Medline, Embase, Scopus and Cochrane Library from 1991 through May 2024 to identify studies evaluating the clinical outcomes of patients with PCD. The progression rates to villous atrophy, seroconversion and response to a gluten-free diet (GFD) were analysed. A random-effect meta-analysis was performed, and the results were reported as pooled proportions with 95% CIs.</p><p><strong>Results: </strong>Seventeen studies comprising 1010 patients with PCD were included in the final analyses. The pooled prevalence of PCD among patients with suspected coeliac disease was 16% (95% CI 10% to 22%). The duration of follow-up in most of the studies was at least 1 year, with follow-up periods within individual studies ranging from 5 months to 13 years. During follow-up, 33% (95% CI 18% to 48%; I²=96.4%) of patients with PCD on a gluten-containing diet developed villous atrophy, and 33% (95% CI 17% to 48%; I²=93.0%) had normalisation of serology. Among those who adhered to a GFD, 88% (95% CI 79% to 97%; I²=93.2%) reported symptomatic improvement.</p><p><strong>Conclusion: </strong>Almost a third of patients with PCD develop villous atrophy over time, whereas a similar proportion experience normalisation of serology despite a gluten-containing diet. Most symptomatic patients benefit from a GFD. These findings highlight the importance of structured follow-up and individualised management for patients with PCD.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1944-1952"},"PeriodicalIF":23.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141995646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD64⁺ fibroblast-targeted vilanterol and a STING agonist augment CLDN18.2 BiTEs efficacy against pancreatic cancer by reducing desmoplasia and enriching stem-like CD8⁺ T cells.","authors":"Tianxing Zhou, Xupeng Hou, Jingrui Yan, Lin Li, Yongjie Xie, Weiwei Bai, Wenna Jiang, Yiping Zou, Xueyang Li, Ziyun Liu, Zhaoyu Zhang, Bohang Xu, Guohua Mao, Yifei Wang, Song Gao, Xiuchao Wang, Tiansuo Zhao, Hongwei Wang, Hongxia Sun, Xiufeng Zhang, Jun Yu, Chongbiao Huang, Jing Liu, Jihui Hao","doi":"10.1136/gutjnl-2024-332371","DOIUrl":"10.1136/gutjnl-2024-332371","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study is to improve the efficacy of CLDN18.2/CD3 bispecific T-cell engagers (BiTEs) as a promising immunotherapy against pancreatic ductal adenocarcinoma (PDAC).</p><p><strong>Design: </strong>Humanised hCD34⁺/hCD3e⁺, Trp53^R172HKras^G12DPdx1-Cre (KPC), pancreas-specific Cldn18.2 knockout (KO), fibroblast-specific Fcgr1 KO and patient-derived xenograft/organoid mouse models were constructed. Flow cytometry, Masson staining, Cell Titer Glo assay, virtual drug screening, molecular docking and chromatin immunoprecipitation were conducted.</p><p><strong>Results: </strong>CLDN18.2 BiTEs effectively inhibited early tumour growth, but late-stage efficacy was significantly diminished. Mechanically, the Fc fragment of BiTEs interacted with CD64⁺ cancer-associated fibroblasts (CAFs) via activation of the SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A-α-SMA/collagen-I pathway, which enhanced desmoplasia and limited late-stage infiltration of T cells. Molecular docking analysis found that vilanterol suppressed BiTEs-induced phosphorylation of VAV2 (Y172) in CD64⁺ CAFs and weakened desmoplasia. Additionally, decreased cyclic guanosine-adenosine monophosphate synthase/stimulator of interferon genes (STING) activity reduced proliferation of TCF-1⁺PD-1⁺ stem-like CD8⁺ T cells, which limited late-stage effects of BiTEs. Finally, vilanterol and the STING agonist synergistically boosted the efficacy of BiTEs by inhibiting the activation of CD64⁺ CAFs and enriching proliferation of stem-like CD8⁺ T cells, resulting in sustained anti-tumour activity.</p><p><strong>Conclusion: </strong>Vilanterol plus the STING agonist sensitised PDAC to CLDN18.2 BiTEs and augmented efficacy as a potential novel strategy.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"1984-1998"},"PeriodicalIF":23.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to: short-chain fatty acids in patients with severe acute pancreatitis: friend or foe?","authors":"Christoph Ammer-Herrmenau, Albrecht Neesse","doi":"10.1136/gutjnl-2024-332236","DOIUrl":"10.1136/gutjnl-2024-332236","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"e39"},"PeriodicalIF":23.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endoscopic stratification of gastric intestinal metaplasia: where are we, where do we want to go and how do we get there?","authors":"Shailja C Shah, Mario Dinis-Ribeiro","doi":"10.1136/gutjnl-2024-333977","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333977","url":null,"abstract":"We appreciate the positive remarks from Quach and colleagues in response to our manuscript.1 2 The authors propose that endoscopic staging should replace non-targeted mapping biopsies in individuals at increased risk of harbouring gastric intestinal metaplasia (GIM), citing that endoscopic staging using the endoscopic grading of GIM (EGGIM) score (1) is a more resource-sensitive approach; (2) avoids the small added risk of biopsies; (3) can be performed effectively among adequately trained endoscopists; and (4) correlates with histological severity as measured via the operative link on gastric intestinal metaplasia assessment (OLGIM), at least based on a multicentre European study among trained endoscopists and external validation in a single-centre study from South Korea.3 4 Overall, we are conceptually aligned with the authors on these points. However, the theme of our article was a …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"95 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiomics of the intestine-liver-adipose axis in multiple studies unveils a consistent link of the gut microbiota and the antiviral response with systemic glucose metabolism.","authors":"Anna Castells-Nobau, José Maria Moreno-Navarrete, Lisset de la Vega-Correa, Irene Puig, Massimo Federici, Jiuwen Sun, Remy Burcelin, Laurence Guzylack-Piriou, Pierre Gourdy, Laurent Cazals, María Arnoriaga-Rodríguez, Gema Frühbeck, Luisa Maria Seoane, José López-Miranda, Francisco J Tinahones, Carlos Dieguez, Marc-Emmanuel Dumas, Vicente Pérez-Brocal, Andrés Moya, Nikolaos Perakakis, Geltrude Mingrone, Stefan Bornstein, Jose Ignacio Rodriguez Hermosa, Ernesto Castro, Jose Manuel Fernández-Real, Jordi Mayneris-Perxachs","doi":"10.1136/gutjnl-2024-332602","DOIUrl":"10.1136/gutjnl-2024-332602","url":null,"abstract":"<p><strong>Background: </strong>The microbiota is emerging as a key factor in the predisposition to insulin resistance and obesity.</p><p><strong>Objective: </strong>To understand the interplay among gut microbiota and insulin sensitivity in multiple tissues.</p><p><strong>Design: </strong>Integrative multiomics and multitissue approach across six studies, combining euglycaemic clamp measurements (used in four of the six studies) with other measurements of glucose metabolism and insulin resistance (glycated haemoglobin (HbA1c) and fasting glucose).</p><p><strong>Results: </strong>Several genera and species from the Proteobacteria phylum were consistently negatively associated with insulin sensitivity in four studies (ADIPOINST, n=15; IRONMET, n=121, FLORINASH, n=67 and FLOROMIDIA, n=24). Transcriptomic analysis of the jejunum, ileum and colon revealed T cell-related signatures positively linked to insulin sensitivity. Proteobacteria in the ileum and colon were positively associated with HbA1c but negatively with the number of T cells. Jejunal deoxycholic acid was negatively associated with insulin sensitivity. Transcriptomics of subcutaneous adipose tissue (ADIPOMIT, n=740) and visceral adipose tissue (VAT) (ADIPOINST, n=29) revealed T cell-related signatures linked to HbA1c and insulin sensitivity, respectively. VAT Proteobacteria were negatively associated with insulin sensitivity. Multiomics and multitissue integration in the ADIPOINST and FLORINASH studies linked faecal Proteobacteria with jejunal and liver deoxycholic acid, as well as jejunal, VAT and liver transcriptomic signatures involved in the actin cytoskeleton, insulin and T cell signalling. Fasting glucose was consistently linked to interferon-induced genes and antiviral responses in the intestine and VAT. Studies in <i>Drosophila melanogaster</i> validated these human insulin sensitivity-associated changes.</p><p><strong>Conclusion: </strong>These data provide comprehensive insights into the microbiome-gut-adipose-liver axis and its impact on systemic insulin action, suggesting potential therapeutic targets.Cite Now.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential microbial effects on microsatellite instability possibly drive divergence in colorectal cancer immunotherapy responses among different anatomical subsites.","authors":"Ruize Qu, Zhipeng Zhang, Wei Fu","doi":"10.1136/gutjnl-2024-334008","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334008","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quest for HBV functional cure: what have we learnt from silencing RNAs?","authors":"Norah Terrault, Anna S Lok","doi":"10.1136/gutjnl-2024-333763","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333763","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TPX2 serves as a novel target for expanding the utility of PARPi in pancreatic cancer through conferring synthetic lethality.","authors":"Mingming Xiao, Rong Tang, Haoqi Pan, Jing Yang, Xuhui Tong, He Xu, Yanmei Guo, Yalan Lei, Di Wu, Yubin Lei, Yamei Han, Zhilong Ma, Wei Wang, Jin Xu, Xianjun Yu, Si Shi","doi":"10.1136/gutjnl-2024-332782","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332782","url":null,"abstract":"<p><strong>Background: </strong>PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer.</p><p><strong>Objective: </strong>There is a significant unmet clinical need to broaden the utility of PARPi.</p><p><strong>Design: </strong>RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC‒MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses.</p><p><strong>Results: </strong>Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi.</p><p><strong>Conclusions: </strong>Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":""},"PeriodicalIF":23.0,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}