Pub Date : 2024-09-24DOI: 10.1136/gutjnl-2024-333222
Maximilian Joseph Brol, Ali Canbay, Jonel Trebicka
Alcohol-associated hepatitis (AH) is the acute deterioration of alcohol-related liver disease (ArLD) with rapid onset or worsening of jaundice, which, in severe cases, may transition to acute-on-chronic liver failure (ACLF) with extremely high short-term mortality, increasing with the number and severity of hepatic and extra-hepatic organ dysfunction. Systemic inflammation is a hallmark, driving acute decompensation (AD) towards ACLF. Diagnosis and treatment are insufficient and challenging, especially due to the complex, multifactorial and as yet not fully understood pathogenesis. In patients with AH, this inflammation is characterised by increased levels of circulating and hepatic neutrophils, which are essential immune cells responsible for pathogen defence. However, the exact role of neutrophils in AH remains controversial, with ongoing debate over whether their hyperactivation exacerbates liver damage or helps to resolve the disease. Current treatment for AH primarily relies on steroids, but their use is restricted in cases of bacterial infections. Consequently, there is a clinical need to better understand the mechanisms underlying AH and the associated organ dysfunction. Moreover, early detection and treatment of bacterial infections are critical to improve patient outcomes. These challenges, coupled with its rising prevalence in Germany and other Western countries, highlight a significant gap in patient care.1 Chronic alcohol consumption is associated with gut dysbiosis, leading to alterations in the composition of bacteria, viruses and fungi. Several bacterial metabolites were identified to foster liver disease progression. Among them, cytolysin, an endotoxin secreted by Enterococcus faecalis, is associated with higher hepatic inflammation and higher short-term mortality in patients with AH.2 …
{"title":"Alcohol-associated hepatitis: a neutrophile disease?","authors":"Maximilian Joseph Brol, Ali Canbay, Jonel Trebicka","doi":"10.1136/gutjnl-2024-333222","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333222","url":null,"abstract":"Alcohol-associated hepatitis (AH) is the acute deterioration of alcohol-related liver disease (ArLD) with rapid onset or worsening of jaundice, which, in severe cases, may transition to acute-on-chronic liver failure (ACLF) with extremely high short-term mortality, increasing with the number and severity of hepatic and extra-hepatic organ dysfunction. Systemic inflammation is a hallmark, driving acute decompensation (AD) towards ACLF. Diagnosis and treatment are insufficient and challenging, especially due to the complex, multifactorial and as yet not fully understood pathogenesis. In patients with AH, this inflammation is characterised by increased levels of circulating and hepatic neutrophils, which are essential immune cells responsible for pathogen defence. However, the exact role of neutrophils in AH remains controversial, with ongoing debate over whether their hyperactivation exacerbates liver damage or helps to resolve the disease. Current treatment for AH primarily relies on steroids, but their use is restricted in cases of bacterial infections. Consequently, there is a clinical need to better understand the mechanisms underlying AH and the associated organ dysfunction. Moreover, early detection and treatment of bacterial infections are critical to improve patient outcomes. These challenges, coupled with its rising prevalence in Germany and other Western countries, highlight a significant gap in patient care.1 Chronic alcohol consumption is associated with gut dysbiosis, leading to alterations in the composition of bacteria, viruses and fungi. Several bacterial metabolites were identified to foster liver disease progression. Among them, cytolysin, an endotoxin secreted by Enterococcus faecalis, is associated with higher hepatic inflammation and higher short-term mortality in patients with AH.2 …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317592","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}
Pub Date : 2024-09-19DOI: 10.1136/gutjnl-2024-333773
Duc Trong Quach,Toru Hiyama,Gwang Ha Kim,Takuji Gotoda,Kentaro Sugano
{"title":"Rethinking routine mapping biopsies in gastric intestinal metaplasia: justification for endoscopic stratification.","authors":"Duc Trong Quach,Toru Hiyama,Gwang Ha Kim,Takuji Gotoda,Kentaro Sugano","doi":"10.1136/gutjnl-2024-333773","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333773","url":null,"abstract":"","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275218","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}
Pub Date : 2024-09-18DOI: 10.1136/gutjnl-2024-333426
Jaime Bosch
I read with pleasure the paper by Zhou et al 1 analysing the long-term clinical outcomes and changes in liver elastography associated with statin usage in patients with metabolic-associated steatotic liver disease (MASLD). This is a population-based study of 7988 patients selected from a total of 17 849 MASLD patients seen in 16 centres in Europe, America and Asia and who had also transient elastography measurements of liver stiffness (LSM). The final cohort included patients >18 years that had at least two LSM, a controlled attenuation parameter denoting steatosis (over ≥248 dB/m), a prolonged follow-up (over 1 year, median 4.6 years), and no other cause of liver disease or excessive alcohol intake. Usage of statins was defined as the consistent use of statins on most days for more than 1 month within a year, which occurred in 3233 patients (40.4%). Patients were considered to have compensated advanced chronic liver disease (cACLD) if the first LSM was >10 kPa, which occurred in 17.2%. The primary outcome was a composite of all-cause death and liver-related events (LREs) (developing cirrhosis decompensation, hepatocellular carcinoma (HCC) or liver-related mortality). In addition, a secondary outcome was the change in LSM, categorised as progression, regression or stable based on observing or not changes in LSM of at least 20% or crossing the threshold of 10 kPa. The authors did Cox regression analysis for examining the association between statin …
{"title":"Statins for MAFLD/MASH: another brick in the wall while waiting for final answers","authors":"Jaime Bosch","doi":"10.1136/gutjnl-2024-333426","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333426","url":null,"abstract":"I read with pleasure the paper by Zhou et al 1 analysing the long-term clinical outcomes and changes in liver elastography associated with statin usage in patients with metabolic-associated steatotic liver disease (MASLD). This is a population-based study of 7988 patients selected from a total of 17 849 MASLD patients seen in 16 centres in Europe, America and Asia and who had also transient elastography measurements of liver stiffness (LSM). The final cohort included patients >18 years that had at least two LSM, a controlled attenuation parameter denoting steatosis (over ≥248 dB/m), a prolonged follow-up (over 1 year, median 4.6 years), and no other cause of liver disease or excessive alcohol intake. Usage of statins was defined as the consistent use of statins on most days for more than 1 month within a year, which occurred in 3233 patients (40.4%). Patients were considered to have compensated advanced chronic liver disease (cACLD) if the first LSM was >10 kPa, which occurred in 17.2%. The primary outcome was a composite of all-cause death and liver-related events (LREs) (developing cirrhosis decompensation, hepatocellular carcinoma (HCC) or liver-related mortality). In addition, a secondary outcome was the change in LSM, categorised as progression, regression or stable based on observing or not changes in LSM of at least 20% or crossing the threshold of 10 kPa. The authors did Cox regression analysis for examining the association between statin …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245449","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}
Pub Date : 2024-09-18DOI: 10.1136/gutjnl-2024-333263
Alexander Zipprich, Ruben Hernaez
International guidelines recommend that primary prophylaxis of varices in patients with cirrhosis be either non-selective beta-blockers (NSBBs) or variceal band ligation (VBL). These recommendations are based on studies that include both compensated and decompensated patients. Notably, the European Association for the Study of the Liver 2018 guidelines recognise a gap in the efficacy of NSBB therapy for patients with decompensated cirrhosis.1 The Baveno guidelines recommend preventing further decompensation in patients with ascites and high-risk varices (large varices >5 mm, or with red spot signs, or Child-Pugh-Turcotte (CPT-C)), with traditional NSBBs or carvedilol preferred over VBL.2 The American Association for the Study of Liver Diseases guidelines support NSBBs or VBL for large high-risk varices.3 However, a recent systematic review with network meta-analysis indicated that VBL is associated with higher risks of complications and mortality compared with NSBBs.4 The supporting evidence for these recommendations is limited, and it remains unclear whether the same treatment options or combination therapies are more effective in decompensated cirrhosis (CPT B or C). In Gut , Tevethia et al report the results of the CAVARLY trial.5 The study compared carvedilol, VBL and a combination of both for preventing the first variceal bleed in patients with CPT- B/C cirrhosis (up to C-13) and high-risk oesophageal varices (>5 mm or <5 mm with red signs). The authors excluded patients with contraindications to carvedilol, hepatocellular carcinoma, portal vein thrombosis, platelet count <30 000 per µL, those on therapeutic anticoagulation, or with previous VBL or transjugular intrahepatic portosystemic shunt (TIPS). They enrolled 330 patients (110 for each arm) …
{"title":"High-risk varices in patients with Child-Pugh-Turcotte B and C: consider band ligation with carvedilol for preventing first variceal bleeding, especially in patients with MASLD-associated cirrhosis","authors":"Alexander Zipprich, Ruben Hernaez","doi":"10.1136/gutjnl-2024-333263","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333263","url":null,"abstract":"International guidelines recommend that primary prophylaxis of varices in patients with cirrhosis be either non-selective beta-blockers (NSBBs) or variceal band ligation (VBL). These recommendations are based on studies that include both compensated and decompensated patients. Notably, the European Association for the Study of the Liver 2018 guidelines recognise a gap in the efficacy of NSBB therapy for patients with decompensated cirrhosis.1 The Baveno guidelines recommend preventing further decompensation in patients with ascites and high-risk varices (large varices >5 mm, or with red spot signs, or Child-Pugh-Turcotte (CPT-C)), with traditional NSBBs or carvedilol preferred over VBL.2 The American Association for the Study of Liver Diseases guidelines support NSBBs or VBL for large high-risk varices.3 However, a recent systematic review with network meta-analysis indicated that VBL is associated with higher risks of complications and mortality compared with NSBBs.4 The supporting evidence for these recommendations is limited, and it remains unclear whether the same treatment options or combination therapies are more effective in decompensated cirrhosis (CPT B or C). In Gut , Tevethia et al report the results of the CAVARLY trial.5 The study compared carvedilol, VBL and a combination of both for preventing the first variceal bleed in patients with CPT- B/C cirrhosis (up to C-13) and high-risk oesophageal varices (>5 mm or <5 mm with red signs). The authors excluded patients with contraindications to carvedilol, hepatocellular carcinoma, portal vein thrombosis, platelet count <30 000 per µL, those on therapeutic anticoagulation, or with previous VBL or transjugular intrahepatic portosystemic shunt (TIPS). They enrolled 330 patients (110 for each arm) …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245448","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}
Pub Date : 2024-09-18DOI: 10.1136/gutjnl-2024-333684
David Y Graham, Yi-Chia Lee
Recently, Gut published a review of guidelines for the management of gastric intestinal metaplasia (GIM) with the goal of promoting harmonisation of the guidelines regarding indications for endoscopic screening for gastric cancer and GIM detection/staging, metrics for high-quality endoscopy and non-endoscopic interventions for gastric cancer prevention in patients with GIM.1 GIM is not a disease per se but rather is a reparative response to gastric mucosal injury that may be present, at least temporarily, as part of healing such as of an ulcer.2 Clinically, widespread GIM is best considered a manifestation of healing of another disease, typically Helicobacter pylori infection or autoimmune gastritis. When present in autoimmune gastritis, GIM has no malignant potential and is potentially completely reversible.3 In contrast, when associated with chronic H. pylori infection, GIM is typically permanent and, at most, minimally reversible.4 The underlying H. pylori -induced inflammation is carcinogenic. H. pylori -related GIM is a manifestation of the duration, extent and severity of an H. pylori infection which, in turn, is related to the risk of gastric cancer. Because GIM is easily recognised and reflects the extent and severity of the infection, it is a valuable surrogate for the risk of developing gastric cancer. This has given GIM a role in the determination of an individual’s cancer risk. However, because GIM is neither a disease nor a cause of cancer, eradication of gastric cancer should focus on the eradication of the cause, that is, H. pylori infections. The population …
{"title":"Commentary on: the management of patients with gastric intestinal metaplasia","authors":"David Y Graham, Yi-Chia Lee","doi":"10.1136/gutjnl-2024-333684","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333684","url":null,"abstract":"Recently, Gut published a review of guidelines for the management of gastric intestinal metaplasia (GIM) with the goal of promoting harmonisation of the guidelines regarding indications for endoscopic screening for gastric cancer and GIM detection/staging, metrics for high-quality endoscopy and non-endoscopic interventions for gastric cancer prevention in patients with GIM.1 GIM is not a disease per se but rather is a reparative response to gastric mucosal injury that may be present, at least temporarily, as part of healing such as of an ulcer.2 Clinically, widespread GIM is best considered a manifestation of healing of another disease, typically Helicobacter pylori infection or autoimmune gastritis. When present in autoimmune gastritis, GIM has no malignant potential and is potentially completely reversible.3 In contrast, when associated with chronic H. pylori infection, GIM is typically permanent and, at most, minimally reversible.4 The underlying H. pylori -induced inflammation is carcinogenic. H. pylori -related GIM is a manifestation of the duration, extent and severity of an H. pylori infection which, in turn, is related to the risk of gastric cancer. Because GIM is easily recognised and reflects the extent and severity of the infection, it is a valuable surrogate for the risk of developing gastric cancer. This has given GIM a role in the determination of an individual’s cancer risk. However, because GIM is neither a disease nor a cause of cancer, eradication of gastric cancer should focus on the eradication of the cause, that is, H. pylori infections. The population …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245450","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}
Pub Date : 2024-09-17DOI: 10.1136/gutjnl-2024-333490
Veronique Van der Voort, Cesare Hassan, Alessandro Repici, Romain Legros, Mathieu Pioche, Jérémie Jacques
We read with great interest the study by O’Sullivan et al ,1 examining the technical and procedural outcomes of Cold Endoscopic Mucosal Resection (C-EMR) versus Hot EMR (H-EMR). We congratulate the authors for conducting this important research, which adds valuable information to the body of knowledge guiding our choice of the optimal treatment modality for large, benign colorectal polyps. However, we would like to address several points. First, readers should be aware that this study focuses on a highly selected group of large non-pedunculated colon polyps (LNPCPs) as only 20% of referred lesions during the study period of 4 years met the inclusion criteria, being flat lesions of 15–50 mm, without macronodule, depressed area or optical suspicion of submucosal invasive cancer (SMIC). Despite this selection, 2.2% unrecognised SMIC was found, …
{"title":"Cold EMR, hot EMR or ESD for large benign adenoma: not one size fits all","authors":"Veronique Van der Voort, Cesare Hassan, Alessandro Repici, Romain Legros, Mathieu Pioche, Jérémie Jacques","doi":"10.1136/gutjnl-2024-333490","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333490","url":null,"abstract":"We read with great interest the study by O’Sullivan et al ,1 examining the technical and procedural outcomes of Cold Endoscopic Mucosal Resection (C-EMR) versus Hot EMR (H-EMR). We congratulate the authors for conducting this important research, which adds valuable information to the body of knowledge guiding our choice of the optimal treatment modality for large, benign colorectal polyps. However, we would like to address several points. First, readers should be aware that this study focuses on a highly selected group of large non-pedunculated colon polyps (LNPCPs) as only 20% of referred lesions during the study period of 4 years met the inclusion criteria, being flat lesions of 15–50 mm, without macronodule, depressed area or optical suspicion of submucosal invasive cancer (SMIC). Despite this selection, 2.2% unrecognised SMIC was found, …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236841","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}
Pub Date : 2024-09-13DOI: 10.1136/gutjnl-2024-332412
Yuki Makino, Kimal I Rajapakshe, Benson Chellakkan Selvanesan, Takashi Okumura, Kenjiro Date, Prasanta Dutta, Lotfi Abou-Elkacem, Akiko Sagara, Jimin Min, Marta Sans, Nathaniel Yee, Megan J Siemann, Jose Enriquez, Paytience Smith, Pratip Bhattacharya, Michael Kim, Merve Dede, Traver Hart, Anirban Maitra, Fredrik Ivar Thege
Background Oncogenic ‘hotspot’ mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D and Gnas R201C co-expression in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice ( ‘Kras;Gnas ’ mice) caused development of cystic lesions recapitulating IPMNs. Objective We aim to unveil the consequences of mutant Gnas R201C expression on phenotype, transcriptomic profile and genomic dependencies. Design We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the ‘Kras;Gnas ’ autochthonous model and tumour-derived cell lines ( Kras;Gnas cells), where Gnas R201C expression is inducible. A genome-wide CRISPR/ Cas 9 screen was conducted to identify potential vulnerabilities in KrasG12D;GnasR201C co-expressing cells. Results Induction of Gnas R201C—and resulting G(s)alpha signalling—leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in Kras G12D; Gnas R201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on Gnas R201C induction. Induction of Gnas R201C made Kras G12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on Gnas R201C induction. Conclusion Multiple orthogonal approaches demonstrate that Kras G12D and Gnas R201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs. Data are available in a public, open access repository. Bulk RNA-seq, single-cell RNA-seq and spatial transcriptomic datasets generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE275406.
{"title":"Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal papillary mucinous neoplasms of the pancreas","authors":"Yuki Makino, Kimal I Rajapakshe, Benson Chellakkan Selvanesan, Takashi Okumura, Kenjiro Date, Prasanta Dutta, Lotfi Abou-Elkacem, Akiko Sagara, Jimin Min, Marta Sans, Nathaniel Yee, Megan J Siemann, Jose Enriquez, Paytience Smith, Pratip Bhattacharya, Michael Kim, Merve Dede, Traver Hart, Anirban Maitra, Fredrik Ivar Thege","doi":"10.1136/gutjnl-2024-332412","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332412","url":null,"abstract":"Background Oncogenic ‘hotspot’ mutations of KRAS and GNAS are two major driver alterations in intraductal papillary mucinous neoplasms (IPMNs), which are bona fide precursors to pancreatic ductal adenocarcinoma. We previously reported that pancreas-specific Kras G12D and Gnas R201C co-expression in p48Cre; KrasLSL-G12D; Rosa26LSL-rtTA; Tg (TetO-GnasR201C) mice ( ‘Kras;Gnas ’ mice) caused development of cystic lesions recapitulating IPMNs. Objective We aim to unveil the consequences of mutant Gnas R201C expression on phenotype, transcriptomic profile and genomic dependencies. Design We performed multimodal transcriptional profiling (bulk RNA sequencing, single-cell RNA sequencing and spatial transcriptomics) in the ‘Kras;Gnas ’ autochthonous model and tumour-derived cell lines ( Kras;Gnas cells), where Gnas R201C expression is inducible. A genome-wide CRISPR/ Cas 9 screen was conducted to identify potential vulnerabilities in KrasG12D;GnasR201C co-expressing cells. Results Induction of Gnas R201C—and resulting G(s)alpha signalling—leads to the emergence of a gene signature of gastric (pyloric type) metaplasia in pancreatic neoplastic epithelial cells. CRISPR screening identified the synthetic essentiality of glycolysis-related genes Gpi1 and Slc2a1 in Kras G12D; Gnas R201C co-expressing cells. Real-time metabolic analyses in Kras;Gnas cells and autochthonous Kras;Gnas model confirmed enhanced glycolysis on Gnas R201C induction. Induction of Gnas R201C made Kras G12D expressing cells more dependent on glycolysis for their survival. Protein kinase A-dependent phosphorylation of the glycolytic intermediate enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was a driver of increased glycolysis on Gnas R201C induction. Conclusion Multiple orthogonal approaches demonstrate that Kras G12D and Gnas R201C co-expression results in a gene signature of gastric pyloric metaplasia and glycolytic dependency during IPMN pathogenesis. The observed metabolic reprogramming may provide a potential target for therapeutics and interception of IPMNs. Data are available in a public, open access repository. Bulk RNA-seq, single-cell RNA-seq and spatial transcriptomic datasets generated in this study have been deposited in the NCBI Gene Expression Omnibus (GEO) database under accession number GSE275406.","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231345","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}
Pub Date : 2024-09-12DOI: 10.1136/gutjnl-2024-333026
Lung Yi Mak, Christine I Wooddell, Oliver Lenz, Thomas Schluep, James Hamilton, Heather L Davis, Xianhua Mao, Wai-Kay Seto, Michael Biermer, Man-Fung Yuen
Background and aims RNA interference has been extensively explored in patients with chronic hepatitis B (CHB) infection. We aimed to characterise the long-term efficacy of small interfering RNA (siRNA) on hepatitis B surface antigen (HBsAg) suppression. Methods We prospectively followed up participants with CHB who received siRNA, either ARC-520 or JNJ-73763989 (JNJ-3989), in combination with nucleoside analogue (NUC) in our centre. Participants enrolled included 15 receiving 4 monthly injections of ARC-520, 38 receiving 3 injections of JNJ-3989 at 1, 2 or 4 weekly intervals and 5 receiving placebo in previous clinical trials. Serial blood sampling was performed according to the original protocols and on completion every 24 weeks until last follow-up (LFU) with mean duration of 52.5 months. Results Among the 53 NUC+siRNA-treated participants (mean age 46.8, baseline HBsAg 3.08 log, 83% previously on NUC, 34% hepatitis B e antigen+), the proportion of patients achieving HBsAg seroclearance or <100 IU/mL at LFU was 1.9% and 32.1%, respectively, compared with 0% and 0% for placebo. Among siRNA-recipients, 48.5% and 5.0% of those with HBsAg <100 IU/mL and >100 IU/mL at nadir or ≤24 weeks from last dose could maintain or achieve HBsAg <100 IU/mL at LFU, respectively. Compared with placebo recipients, siRNA-recipients demonstrated faster overall annual decline of HBsAg (0.08 vs 0.21 log IU/mL/year) contributed predominantly by changes in the first year. Age was negatively correlated with HBsAg reduction at LFU (r=−0.427, p=0.001). Conclusion Short-duration siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years in some participants. All data relevant to the study are included in the article or uploaded as online supplemental information.
{"title":"Long-term hepatitis B surface antigen response after finite treatment of ARC-520 or JNJ-3989","authors":"Lung Yi Mak, Christine I Wooddell, Oliver Lenz, Thomas Schluep, James Hamilton, Heather L Davis, Xianhua Mao, Wai-Kay Seto, Michael Biermer, Man-Fung Yuen","doi":"10.1136/gutjnl-2024-333026","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333026","url":null,"abstract":"Background and aims RNA interference has been extensively explored in patients with chronic hepatitis B (CHB) infection. We aimed to characterise the long-term efficacy of small interfering RNA (siRNA) on hepatitis B surface antigen (HBsAg) suppression. Methods We prospectively followed up participants with CHB who received siRNA, either ARC-520 or JNJ-73763989 (JNJ-3989), in combination with nucleoside analogue (NUC) in our centre. Participants enrolled included 15 receiving 4 monthly injections of ARC-520, 38 receiving 3 injections of JNJ-3989 at 1, 2 or 4 weekly intervals and 5 receiving placebo in previous clinical trials. Serial blood sampling was performed according to the original protocols and on completion every 24 weeks until last follow-up (LFU) with mean duration of 52.5 months. Results Among the 53 NUC+siRNA-treated participants (mean age 46.8, baseline HBsAg 3.08 log, 83% previously on NUC, 34% hepatitis B e antigen+), the proportion of patients achieving HBsAg seroclearance or <100 IU/mL at LFU was 1.9% and 32.1%, respectively, compared with 0% and 0% for placebo. Among siRNA-recipients, 48.5% and 5.0% of those with HBsAg <100 IU/mL and >100 IU/mL at nadir or ≤24 weeks from last dose could maintain or achieve HBsAg <100 IU/mL at LFU, respectively. Compared with placebo recipients, siRNA-recipients demonstrated faster overall annual decline of HBsAg (0.08 vs 0.21 log IU/mL/year) contributed predominantly by changes in the first year. Age was negatively correlated with HBsAg reduction at LFU (r=−0.427, p=0.001). Conclusion Short-duration siRNA treatment suppressed HBsAg expression with a prolonged effect for up to 6 years in some participants. All data relevant to the study are included in the article or uploaded as online supplemental information.","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174962","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}
Pub Date : 2024-09-11DOI: 10.1136/gutjnl-2024-332504
Giorgos Bamias, Paola Menghini, Theresa T Pizarro, Fabio Cominelli
TNF-like cytokine 1A (TL1A) and its functional receptor, death-domain receptor 3 (DR3), are members of the TNF and TNFR superfamilies, respectively, with recognised roles in regulating innate and adaptive immune responses; additional existence of a decoy receptor, DcR3, indicates a tightly regulated cytokine system. The significance of TL1A:DR3 signalling in the pathogenesis of inflammatory bowel disease (IBD) is supported by several converging lines of evidence.To provide a comprehensive understanding of what is currently known regarding the TL1A/DR3 system in the context of IBD.TL1A and DR3 are expressed by cellular subsets with important roles for the initiation and maintenance of intestinal inflammation, serving as potent universal costimulators of effector immune responses, indicating their participation in the pathogenesis of IBD. Recent evidence also supports a homoeostatic role for TL1A:DR3 via regulation of Tregs and innate lymphoid cells. TL1A and DR3 are also expressed by stromal cells and may contribute to inflammation-induced or inflammation-independent intestinal fibrogenesis. Finally, discovery of genetic polymorphisms with functional consequences may allow for patient stratification, including differential responses to TL1A-targeted therapeutics.TL1A:DR3 signalling plays a central and multifaceted role in the immunological pathways that underlie intestinal inflammation, such as that observed in IBD. Such evidence provides the foundation for developing pharmaceutical approaches targeting this ligand-receptor pair in IBD.
{"title":"Targeting TL1A and DR3: the new frontier of anti-cytokine therapy in IBD","authors":"Giorgos Bamias, Paola Menghini, Theresa T Pizarro, Fabio Cominelli","doi":"10.1136/gutjnl-2024-332504","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-332504","url":null,"abstract":"TNF-like cytokine 1A (TL1A) and its functional receptor, death-domain receptor 3 (DR3), are members of the TNF and TNFR superfamilies, respectively, with recognised roles in regulating innate and adaptive immune responses; additional existence of a decoy receptor, DcR3, indicates a tightly regulated cytokine system. The significance of TL1A:DR3 signalling in the pathogenesis of inflammatory bowel disease (IBD) is supported by several converging lines of evidence.To provide a comprehensive understanding of what is currently known regarding the TL1A/DR3 system in the context of IBD.TL1A and DR3 are expressed by cellular subsets with important roles for the initiation and maintenance of intestinal inflammation, serving as potent universal costimulators of effector immune responses, indicating their participation in the pathogenesis of IBD. Recent evidence also supports a homoeostatic role for TL1A:DR3 via regulation of Tregs and innate lymphoid cells. TL1A and DR3 are also expressed by stromal cells and may contribute to inflammation-induced or inflammation-independent intestinal fibrogenesis. Finally, discovery of genetic polymorphisms with functional consequences may allow for patient stratification, including differential responses to TL1A-targeted therapeutics.TL1A:DR3 signalling plays a central and multifaceted role in the immunological pathways that underlie intestinal inflammation, such as that observed in IBD. Such evidence provides the foundation for developing pharmaceutical approaches targeting this ligand-receptor pair in IBD.","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170852","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}
Recently, we were intrigued by a recent study by Montironi et al ,1 in which they discovered that an inflamed subclass in hepatocellular carcinoma (HCC) patients is associated with a response to immunotherapy. The authors used a 20-gene signature to distinguish these patients and further found different immune infiltration between inflamed and non-inflamed class at the bulk level. We commend the authors for undertaking this study, which holds significant clinical implications. We also observed that Li et al 2 have validated the predictive value of inflamed class in two additional RNA-seq datasets from patients who received anti-PD1 therapy. However, the use of combination immunotherapy, which includes dual immune checkpoint inhibitors or is combined with anti-VEGF agents, has become a growing trend in HCC.3–6 Here, we first performed unsupervised clustering on the RNA-seq data from 289 patients enrolled in the GO30140 Ph1b and IMbrave150 PhIII trials who received a combination of anti-PD-L1 and anti-VEGF therapy7 (figure 1). The results indicated that the subclass (C1), which exhibited high expression of genes associated with B/plasma cells and fibroblasts, had a higher inflamed-class score and better therapeutic efficacy (figure 1B–D). The performance of inflamed-class gene signature in predicting combination therapy response showed anarea under …
{"title":"Extending inflamed-class signature to predict immune checkpoint inhibitor-based combination therapy in hepatocellular carcinoma","authors":"Wenhua You, Chupeng Hu, Mengya Zhao, Yuhan Zhang, Jinying Lu, Yedi Huang, Ling Li, Yun Chen","doi":"10.1136/gutjnl-2024-333375","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333375","url":null,"abstract":"Recently, we were intrigued by a recent study by Montironi et al ,1 in which they discovered that an inflamed subclass in hepatocellular carcinoma (HCC) patients is associated with a response to immunotherapy. The authors used a 20-gene signature to distinguish these patients and further found different immune infiltration between inflamed and non-inflamed class at the bulk level. We commend the authors for undertaking this study, which holds significant clinical implications. We also observed that Li et al 2 have validated the predictive value of inflamed class in two additional RNA-seq datasets from patients who received anti-PD1 therapy. However, the use of combination immunotherapy, which includes dual immune checkpoint inhibitors or is combined with anti-VEGF agents, has become a growing trend in HCC.3–6 Here, we first performed unsupervised clustering on the RNA-seq data from 289 patients enrolled in the GO30140 Ph1b and IMbrave150 PhIII trials who received a combination of anti-PD-L1 and anti-VEGF therapy7 (figure 1). The results indicated that the subclass (C1), which exhibited high expression of genes associated with B/plasma cells and fibroblasts, had a higher inflamed-class score and better therapeutic efficacy (figure 1B–D). The performance of inflamed-class gene signature in predicting combination therapy response showed anarea under …","PeriodicalId":12825,"journal":{"name":"Gut","volume":null,"pages":null},"PeriodicalIF":24.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170853","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}
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