{"title":"Enhancing the Understanding of Obesity and Liver Health: Addressing Lifestyle, Socio-economic and Ethnic Disparities","authors":"Zeping Chen, Lincheng Duan, Changhu Sun","doi":"10.1111/liv.70035","DOIUrl":"https://doi.org/10.1111/liv.70035","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G protein-coupled receptors (GPCRs) are important potential drug targets for the treatment of metabolic disorders. The D2 dopamine receptor (DRD2), a GPCR receptor, is a member of the dopamine receptor family. However, the role of DRD2 in regulating lipid metabolism, especially in hepatic steatosis, is unclear.
Methods
Eight-week male mice were fed HFHC/MCD to induce the MASH model. AAV2/8 containing the TBG promoter was used to knock down and overexpress DRD2 in mouse liver. Co-immunoprecipitation, Western lotting, immunofluorescence, and immunohistochemistry were used to investigate the mechanisms and screen DRD2 antagonists.
Results
The study found that activation of PKC leads to the elevation and internalisation of DRD2 in a high-fat environment. Knockdown of DRD2 in mouse liver can effectively interfere with the progression of MASH, while overexpression of DRD2 significantly aggravates the process of MASH. The study on the mechanism of DRD2 regulating lipid metabolism found that the internalisation of DRD2 could lead to dephosphorylation of pAKT (T308) by binding to β-arrestin2 and pAKT, thereby inducing ubiquitin-dependent degradation of AMPK and exacerbating steatosis. L-741626, a DRD2 antagonist, was found to interfere with the internalisation of DRD2 in a high-fat environment. It has been shown that L-741626 can treat MASH by regulating the AKT-AMPK signalling axis in vitro and in vivo.
Conclusions
In conclusion, this study demonstrated that internalisation of DRD2 in a high-fat environment aggravated MASH progression through the AKT-AMPK signalling axis. Furthermore, L-741626, as a DRD2 antagonist, has the potential to treat MASH.
{"title":"DRD2-Mediated AMPK Ubiquitination Regulates the Occurrence of Hepatic Steatosis","authors":"Peng Ma, Hao Ou, Junze Cai, Yuanli Zhang, Yu Ou","doi":"10.1111/liv.70053","DOIUrl":"https://doi.org/10.1111/liv.70053","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background & Aims</h3>\u0000 \u0000 <p>G protein-coupled receptors (GPCRs) are important potential drug targets for the treatment of metabolic disorders. The D2 dopamine receptor (DRD2), a GPCR receptor, is a member of the dopamine receptor family. However, the role of DRD2 in regulating lipid metabolism, especially in hepatic steatosis, is unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Eight-week male mice were fed HFHC/MCD to induce the MASH model. AAV2/8 containing the TBG promoter was used to knock down and overexpress DRD2 in mouse liver. Co-immunoprecipitation, Western lotting, immunofluorescence, and immunohistochemistry were used to investigate the mechanisms and screen DRD2 antagonists.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study found that activation of PKC leads to the elevation and internalisation of DRD2 in a high-fat environment. Knockdown of DRD2 in mouse liver can effectively interfere with the progression of MASH, while overexpression of DRD2 significantly aggravates the process of MASH. The study on the mechanism of DRD2 regulating lipid metabolism found that the internalisation of DRD2 could lead to dephosphorylation of pAKT (T308) by binding to β-arrestin2 and pAKT, thereby inducing ubiquitin-dependent degradation of AMPK and exacerbating steatosis. L-741626, a DRD2 antagonist, was found to interfere with the internalisation of DRD2 in a high-fat environment. It has been shown that L-741626 can treat MASH by regulating the AKT-AMPK signalling axis in vitro and in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In conclusion, this study demonstrated that internalisation of DRD2 in a high-fat environment aggravated MASH progression through the AKT-AMPK signalling axis. Furthermore, L-741626, as a DRD2 antagonist, has the potential to treat MASH.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Steatotic liver disease (SLD) associated with insulin resistance (IR) and the metabolic syndrome (‘IR-SLD’) increases the risk of liver disease, type 2 diabetes and cardiovascular disease (CVD). SLD associated with the PNPLA3 I148M variant (‘PNPLA3-SLD’) also predisposes individuals to liver disease but protects against type 2 diabetes and CVD. Although in real life the two causes of SLD commonly co-exist, the opposite effects of ‘IR-SLD’ and ‘PNPLA3-SLD’ on CVD and liver disease suggest their pathogenesis differs.
Methods and Results
This review summarises human data comparing the effects of ‘IR-SLD’ and ‘PNPLA3-SLD’ on the human liver lipidome, hepatic handling of fatty acids, pathways of intrahepatocellular triglyceride synthesis, circulating lipids and lipoproteins and adipose tissue inflammation. We also discuss how steatosis in PNPLA3 I148M carriers leads to defects in mitochondrial function.
{"title":"Function of PNPLA3 I148M—Lessons From In Vivo Studies in Humans","authors":"Hannele Yki-Järvinen, Panu K. Luukkonen","doi":"10.1111/liv.70047","DOIUrl":"https://doi.org/10.1111/liv.70047","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Steatotic liver disease (SLD) associated with insulin resistance (IR) and the metabolic syndrome (‘IR-SLD’) increases the risk of liver disease, type 2 diabetes and cardiovascular disease (CVD). SLD associated with the PNPLA3 I148M variant (‘PNPLA3-SLD’) also predisposes individuals to liver disease but protects against type 2 diabetes and CVD. Although in real life the two causes of SLD commonly co-exist, the opposite effects of ‘IR-SLD’ and ‘PNPLA3-SLD’ on CVD and liver disease suggest their pathogenesis differs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>This review summarises human data comparing the effects of ‘IR-SLD’ and ‘PNPLA3-SLD’ on the human liver lipidome, hepatic handling of fatty acids, pathways of intrahepatocellular triglyceride synthesis, circulating lipids and lipoproteins and adipose tissue inflammation. We also discuss how steatosis in PNPLA3 I148M carriers leads to defects in mitochondrial function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pingping Sun, Haiyan Xu, Chengfeng Guo, Lei Yang, Xiaojing Zhang, Bing Lu, Lei Chen, Jianfei Huang
Background
Transmembrane (TMEM) proteins are involved in fundamental biological processes such as material transport and signal transduction. TMEM115 is a member of the TMEM protein family, but its significance in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigate the clinical predictive significance and potential functions of TMEM115 in HCC.
Methods
Bioinformatics was used to investigate TMEM115 mRNA expression and immune infiltration score. Through multiplex immunohistochemistry analysis, we assessed its protein expression and association with HCC patient clinical features, prognosis and immune cell infiltration in HCC. Through in vitro and in vivo experiments, we evaluated the biological functions of TMEM115 in HCC cells and its impact on the immune microenvironment.
Results
TMEM115 mRNA and protein levels were significantly higher in HCC tissues compared to paracancerous liver tissues. Its protein expression correlated with clinical characteristics and overall survival in HCC patients. In HCC tissues, higher TMEM115 protein expression corresponded to lower proportions of CD66b+ neutrophils and CD8+ T cells and a higher proportion of CD4+ T cells. Furthermore, patients with low TMEM115 expression displayed higher programmed cell death ligand-1 and lower lymphocyte activation gene 3 protein expression. Functionally, TMEM115 knockdown inhibited the proliferation, migration and invasion of HCC cells. In orthotopic models, TMEM115 knockdown inhibited the growth of HCC and affected the infiltration of immune cells.
Conclusions
Our findings show TMEM115 as a promising prognostic indicator for HCC and hold promise in predicting responses to immune therapy, emphasising its potential clinical relevance and intricate involvement in the immune microenvironment of HCC.
{"title":"TMEM115 as an Oncogenic and Immunological Biomarker in Hepatocellular Carcinoma","authors":"Pingping Sun, Haiyan Xu, Chengfeng Guo, Lei Yang, Xiaojing Zhang, Bing Lu, Lei Chen, Jianfei Huang","doi":"10.1111/liv.70048","DOIUrl":"https://doi.org/10.1111/liv.70048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Transmembrane (TMEM) proteins are involved in fundamental biological processes such as material transport and signal transduction. TMEM115 is a member of the TMEM protein family, but its significance in hepatocellular carcinoma (HCC) remains unclear. In this study, we investigate the clinical predictive significance and potential functions of TMEM115 in HCC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Bioinformatics was used to investigate TMEM115 mRNA expression and immune infiltration score. Through multiplex immunohistochemistry analysis, we assessed its protein expression and association with HCC patient clinical features, prognosis and immune cell infiltration in HCC. Through in vitro and in vivo experiments, we evaluated the biological functions of TMEM115 in HCC cells and its impact on the immune microenvironment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>TMEM115 mRNA and protein levels were significantly higher in HCC tissues compared to paracancerous liver tissues. Its protein expression correlated with clinical characteristics and overall survival in HCC patients. In HCC tissues, higher TMEM115 protein expression corresponded to lower proportions of CD66b<sup>+</sup> neutrophils and CD8<sup>+</sup> T cells and a higher proportion of CD4<sup>+</sup> T cells. Furthermore, patients with low TMEM115 expression displayed higher programmed cell death ligand-1 and lower lymphocyte activation gene 3 protein expression. Functionally, TMEM115 knockdown inhibited the proliferation, migration and invasion of HCC cells. In orthotopic models, TMEM115 knockdown inhibited the growth of HCC and affected the infiltration of immune cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our findings show TMEM115 as a promising prognostic indicator for HCC and hold promise in predicting responses to immune therapy, emphasising its potential clinical relevance and intricate involvement in the immune microenvironment of HCC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nidhi Sharma, Yogesh Chandra, Sai Balaji Andugulapati
Background and Purpose
Hepatic sinusoidal obstruction syndrome (HSOS) is a rare liver disorder with potentially life-threatening consequences for colorectal chemotherapy and haematopoietic stem cell transplant recipients. MALT1 (mucous-associated lymphoid tissue lymphoma translocation protein-1) is a protein that plays a key role in the production of inflammatory cytokines, ischemia, atherosclerosis, apoptosis and thromboinflammation; however, its role in HSOS is largely unknown. We aimed to investigate the effect of MALT-1 inhibition in in vitro and in vivo models of HSOS.
Experimental Approach
Two mouse models (FOLFOX challenge in immunocompetent and immunocompromised mice) were used to investigate the therapeutic benefits of the MALT-1 inhibitor (MI-2) in vivo. HHSEC, HLEC and RAW-264.7 cells served as in vitro models. HSOS-responsible genes, marker levels and downstream signalling were examined using quantitative real-time PCR, western blot, immunocytochemistry and immunohistochemistry analysis.
Key Results
In the current investigation, MI-2 significantly reduced FOLFOX-induced HSOS in both mouse models by inhibiting the occlusion of sinusoids, RBC extravasation and bridging fibrosis in liver sections. MI-2 treatment also dramatically reduced specific SOS markers (vWF, VEGF, ephrin, bilirubin and PECAM) and other inflammatory markers. Mechanistic investigation in in vitro models using macrophages, sinusoidal and endothelial cells demonstrated that MI-2 treatment significantly diminished the inflammatory marker levels/expression by lowering ROS production. In addition to the pharmacological approach, siRNA-mediated MALT1 suppression remarkably reduced chemokine and cytokine marker expression in sinusoidal cells.
Conclusions and Implications
Thus, our findings demonstrate that MALT1 suppression dramatically reduces FOLFOX-induced inflammatory and fibrotic conditions by modulating the NF-κB activation, paving the way for innovative HSOS therapy approaches.
{"title":"Inhibition of MALT1 Protease Attenuates Hepatic Sinusoidal Obstruction Syndrome by Modulating NRF2/HO1 and NF-κB Pathway","authors":"Nidhi Sharma, Yogesh Chandra, Sai Balaji Andugulapati","doi":"10.1111/liv.70050","DOIUrl":"https://doi.org/10.1111/liv.70050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Purpose</h3>\u0000 \u0000 <p>Hepatic sinusoidal obstruction syndrome (HSOS) is a rare liver disorder with potentially life-threatening consequences for colorectal chemotherapy and haematopoietic stem cell transplant recipients. MALT1 (mucous-associated lymphoid tissue lymphoma translocation protein-1) is a protein that plays a key role in the production of inflammatory cytokines, ischemia, atherosclerosis, apoptosis and thromboinflammation; however, its role in HSOS is largely unknown. We aimed to investigate the effect of MALT-1 inhibition in in vitro and in vivo models of HSOS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Experimental Approach</h3>\u0000 \u0000 <p>Two mouse models (FOLFOX challenge in immunocompetent and immunocompromised mice) were used to investigate the therapeutic benefits of the MALT-1 inhibitor (MI-2) in vivo. HHSEC, HLEC and RAW-264.7 cells served as in vitro models. HSOS-responsible genes, marker levels and downstream signalling were examined using quantitative real-time PCR, western blot, immunocytochemistry and immunohistochemistry analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Results</h3>\u0000 \u0000 <p>In the current investigation, MI-2 significantly reduced FOLFOX-induced HSOS in both mouse models by inhibiting the occlusion of sinusoids, RBC extravasation and bridging fibrosis in liver sections. MI-2 treatment also dramatically reduced specific SOS markers (vWF, VEGF, ephrin, bilirubin and PECAM) and other inflammatory markers. Mechanistic investigation in in vitro models using macrophages, sinusoidal and endothelial cells demonstrated that MI-2 treatment significantly diminished the inflammatory marker levels/expression by lowering ROS production. In addition to the pharmacological approach, siRNA-mediated MALT1 suppression remarkably reduced chemokine and cytokine marker expression in sinusoidal cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions and Implications</h3>\u0000 \u0000 <p>Thus, our findings demonstrate that MALT1 suppression dramatically reduces FOLFOX-induced inflammatory and fibrotic conditions by modulating the NF-κB activation, paving the way for innovative HSOS therapy approaches.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143564860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tingting Li, Chenyang Fu, Zhongzheng Tang, Changkun Li, Duanyi Hua, Bei Liu, Zheying Tao, Jie Yang, Li Zhang, Tingting Cheng, Shujie Wang, Guang Ning, Yanyun Gu
Background and Aims
The farnesoid X receptor (FXR) is an attractive pharmaceutical target for metabolic dysfunction-associated steatotic liver disease (MASLD). However, its tissue-specific roles in energy metabolism remain controversial, hindering the development of effective therapies. To address this, new approaches are required.
Methods
A novel mouse model was developed to facilitate the re-expression of endogenous FXR in specific tissues on a global FXR-null background. Liver-specific and gut-specific FXR re-expression models were generated. Mice were subjected to a high-fat diet (HFD) for 12 weeks, after which metabolic indices, bile acid (BA) profiles, and gut microbiota composition were analysed. Antibiotic treatment was used to mimic germ-free conditions.
Results
The resistance of FXR-null mice to MASLD and most HFD-induced metabolic disorders, including increased body weight, adiposity, hepatic triglyceride (TG) accumulation, and hyperglycemia, was reversed by liver, but not gut, FXR re-expression. Gut FXR re-expression restored the increased intestinal TG absorption in FXR-null mice by limiting 12OH BA synthesis and inhibiting intestinal microsomal triglyceride transfer protein (MTTP). Moreover, gut FXR activity was essential for gut microbiota-driven promotion of diet-induced obesity (DIO) and MASLD.
Conclusions
Our study overcomes the limitations of traditional tissue-specific knockout models, providing a more comprehensive understanding of FXR's complex roles in metabolic homeostasis, encouraging the development of organ-specific FXR targeting strategy.
{"title":"Disentangling Organ-Specific Roles of Farnesoid X Receptor in Bile Acid and Glucolipid Metabolism","authors":"Tingting Li, Chenyang Fu, Zhongzheng Tang, Changkun Li, Duanyi Hua, Bei Liu, Zheying Tao, Jie Yang, Li Zhang, Tingting Cheng, Shujie Wang, Guang Ning, Yanyun Gu","doi":"10.1111/liv.70027","DOIUrl":"https://doi.org/10.1111/liv.70027","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>The farnesoid X receptor (FXR) is an attractive pharmaceutical target for metabolic dysfunction-associated steatotic liver disease (MASLD). However, its tissue-specific roles in energy metabolism remain controversial, hindering the development of effective therapies. To address this, new approaches are required.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A novel mouse model was developed to facilitate the re-expression of endogenous FXR in specific tissues on a global FXR-null background. Liver-specific and gut-specific FXR re-expression models were generated. Mice were subjected to a high-fat diet (HFD) for 12 weeks, after which metabolic indices, bile acid (BA) profiles, and gut microbiota composition were analysed. Antibiotic treatment was used to mimic germ-free conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The resistance of FXR-null mice to MASLD and most HFD-induced metabolic disorders, including increased body weight, adiposity, hepatic triglyceride (TG) accumulation, and hyperglycemia, was reversed by liver, but not gut, FXR re-expression. Gut FXR re-expression restored the increased intestinal TG absorption in FXR-null mice by limiting 12OH BA synthesis and inhibiting intestinal microsomal triglyceride transfer protein (MTTP). Moreover, gut FXR activity was essential for gut microbiota-driven promotion of diet-induced obesity (DIO) and MASLD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study overcomes the limitations of traditional tissue-specific knockout models, providing a more comprehensive understanding of FXR's complex roles in metabolic homeostasis, encouraging the development of organ-specific FXR targeting strategy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Precision in Diagnosis of Liver Fibrosis in MASLD: Machine Learning-Based Scores May Be More Accurate Than Conventional NITs","authors":"R. Soliman, A. Helmy, G. Shiha","doi":"10.1111/liv.70039","DOIUrl":"https://doi.org/10.1111/liv.70039","url":null,"abstract":"","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Arechederra, Emil Bik, Carla Rojo, Jasmin Elurbide, María Elizalde, Beata Kruk, Maciej Krasnodębski, Jan Pertkiewicz, Sławomir Kozieł, Michał Grąt, Joanna Raszeja-Wyszomirska, Maria Rullan, Gorka Alkorta-Aranburu, Daniel Oyón, Maite G. Fernández-Barrena, Lena S. Candels, Andrzej Białek, Łukasz Krupa, Kai M. Schneider, Jesús Urman, Pavel Strnad, Christian Trautwein, Piotr Milkiewicz, Marcin Krawczyk, Matías A. Ávila, Carmen Berasain
Background
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by inflammation and fibrosis of the bile ducts, conferring an increased risk of cholangiocarcinoma (CCA). However, detecting CCA early in PSC patients remains challenging due to the limited sensitivity of conventional diagnostic methods, including imaging or bile duct brush cytology during endoscopic retrograde cholangiopancreatography (ERCP). This study aims to evaluate the potential of bile cell-free DNA (cfDNA) mutational analysis, termed the Bilemut assay, as a tool for CCA detection in PSC patients.
Methods
Sixty-three PSC patients undergoing ERCP due to biliary strictures were prospectively recruited. Bile samples were collected, and cfDNA was extracted and analysed using the Oncomine Pan-Cancer Cell-Free assay. Twenty healthy liver donors were included for comparison. Samples with a mutant allele frequency (MAF) ≥ 0.1% were considered positive. Correlations between mutational status and clinical characteristics were assessed.
Results
cfDNA mutational analysis was successful in all bile samples. Mutations predominantly in KRAS, GNAS, and TP53 were detected in 36.5% (23/63) of PSC patients, compared to 10% (2/20) of healthy donors (p = 0.0269). The clinical characteristics of Bilemut-positive and -negative patients were comparable, though there was a trend towards a lower prevalence of inflammatory bowel disease in the Bilemut-positive group. Among PSC patients diagnosed with CCA during follow-up, 75% were Bilemut-positive, suggesting an association between mutational status and malignancy risk.
Conclusions
Mutational analysis of cfDNA obtained from bile collected from PSC patients undergoing ERCP is feasible. Implementing the Bilemut assay may help identify patients needing closer surveillance and further imaging studies.
{"title":"Mutational Analysis of Bile Cell-Free DNA in Primary Sclerosing Cholangitis: A Pilot Study","authors":"Maria Arechederra, Emil Bik, Carla Rojo, Jasmin Elurbide, María Elizalde, Beata Kruk, Maciej Krasnodębski, Jan Pertkiewicz, Sławomir Kozieł, Michał Grąt, Joanna Raszeja-Wyszomirska, Maria Rullan, Gorka Alkorta-Aranburu, Daniel Oyón, Maite G. Fernández-Barrena, Lena S. Candels, Andrzej Białek, Łukasz Krupa, Kai M. Schneider, Jesús Urman, Pavel Strnad, Christian Trautwein, Piotr Milkiewicz, Marcin Krawczyk, Matías A. Ávila, Carmen Berasain","doi":"10.1111/liv.70049","DOIUrl":"https://doi.org/10.1111/liv.70049","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Primary sclerosing cholangitis (PSC) is a chronic liver disease characterised by inflammation and fibrosis of the bile ducts, conferring an increased risk of cholangiocarcinoma (CCA). However, detecting CCA early in PSC patients remains challenging due to the limited sensitivity of conventional diagnostic methods, including imaging or bile duct brush cytology during endoscopic retrograde cholangiopancreatography (ERCP). This study aims to evaluate the potential of bile cell-free DNA (cfDNA) mutational analysis, termed the Bilemut assay, as a tool for CCA detection in PSC patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Sixty-three PSC patients undergoing ERCP due to biliary strictures were prospectively recruited. Bile samples were collected, and cfDNA was extracted and analysed using the Oncomine Pan-Cancer Cell-Free assay. Twenty healthy liver donors were included for comparison. Samples with a mutant allele frequency (MAF) ≥ 0.1% were considered positive. Correlations between mutational status and clinical characteristics were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>cfDNA mutational analysis was successful in all bile samples. Mutations predominantly in <i>KRAS</i>, <i>GNAS</i>, and <i>TP53</i> were detected in 36.5% (23/63) of PSC patients, compared to 10% (2/20) of healthy donors (<i>p</i> = 0.0269). The clinical characteristics of Bilemut-positive and -negative patients were comparable, though there was a trend towards a lower prevalence of inflammatory bowel disease in the Bilemut-positive group. Among PSC patients diagnosed with CCA during follow-up, 75% were Bilemut-positive, suggesting an association between mutational status and malignancy risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Mutational analysis of cfDNA obtained from bile collected from PSC patients undergoing ERCP is feasible. Implementing the Bilemut assay may help identify patients needing closer surveillance and further imaging studies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Randomised controlled trials (RCTs) have historically underrepresented female, racial and ethnic minorities across various fields. This systematic review and meta-analysis aims to examine the global distribution, reporting and participation of diverse groups based on sex, race and ethnicity in trials focused on metabolic dysfunction-associated steatohepatitis (MASH).
Methods
PubMed and Cochrane Library databases were systematically searched for MASH RCTs (through December 13, 2024) that included any pharmacotherapy as an intervention arm. RCTs were qualitatively reviewed to assess their global distribution and reporting of populations. A meta-analysis of proportions was performed using a generalised linear mixed model.
Results
One hudred and nine studies were identified, reporting data from 112 RCTs and 19 516 MASH participants. Of the 49 countries that conducted trials, 34 were high-income countries (69.4%). Sex, race and ethnicity were reported in 111 (99.1%), 69 (61.6%) and 56 (50.0%) of the 112 RCTs, respectively, with reporting improving in recent years. We found no reporting of sexual and gender minorities. The pooled proportions of female, White, Asian, Black and Hispanic/Latino groups were 54.23% (95% confidence interval [CI]: 51.31–57.12), 87.63% (95% CI: 85.37–89.58), 4.95% (95% CI: 3.42–7.10), 2.27% (95% CI: 1.89–2.71) and 31.42% (95% CI: 26.61–36.66), respectively. Meta-regressions showed a trend toward more female, White and Hispanic/Latino participants in RCTs over time.
Conclusions
Although female and Hispanic/Latino representation has increased over time, racial minorities are underrepresented in MASH trials. These data provide an overview of participant representation in MASH trials and call for collaborative efforts among researchers, sponsors, regulators and other relevant stakeholders to improve diversity in these trials.
{"title":"Representation of Sex, Race and Ethnicity in MASH Randomised Controlled Trials: A Systematic Review and Meta-Analysis","authors":"Matheus Souza, Lubna Al-Sharif, Ivanna Diaz, Samira Mohamad Khalil, Xiu-He Lv, Alessandro Mantovani, Cristiane Alves Villela-Nogueira","doi":"10.1111/liv.70029","DOIUrl":"https://doi.org/10.1111/liv.70029","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background and Aims</h3>\u0000 \u0000 <p>Randomised controlled trials (RCTs) have historically underrepresented female, racial and ethnic minorities across various fields. This systematic review and meta-analysis aims to examine the global distribution, reporting and participation of diverse groups based on sex, race and ethnicity in trials focused on metabolic dysfunction-associated steatohepatitis (MASH).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>PubMed and Cochrane Library databases were systematically searched for MASH RCTs (through December 13, 2024) that included any pharmacotherapy as an intervention arm. RCTs were qualitatively reviewed to assess their global distribution and reporting of populations. A meta-analysis of proportions was performed using a generalised linear mixed model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>One hudred and nine studies were identified, reporting data from 112 RCTs and 19 516 MASH participants. Of the 49 countries that conducted trials, 34 were high-income countries (69.4%). Sex, race and ethnicity were reported in 111 (99.1%), 69 (61.6%) and 56 (50.0%) of the 112 RCTs, respectively, with reporting improving in recent years. We found no reporting of sexual and gender minorities. The pooled proportions of female, White, Asian, Black and Hispanic/Latino groups were 54.23% (95% confidence interval [CI]: 51.31–57.12), 87.63% (95% CI: 85.37–89.58), 4.95% (95% CI: 3.42–7.10), 2.27% (95% CI: 1.89–2.71) and 31.42% (95% CI: 26.61–36.66), respectively. Meta-regressions showed a trend toward more female, White and Hispanic/Latino participants in RCTs over time.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Although female and Hispanic/Latino representation has increased over time, racial minorities are underrepresented in MASH trials. These data provide an overview of participant representation in MASH trials and call for collaborative efforts among researchers, sponsors, regulators and other relevant stakeholders to improve diversity in these trials.</p>\u0000 </section>\u0000 </div>","PeriodicalId":18101,"journal":{"name":"Liver International","volume":"45 4","pages":""},"PeriodicalIF":6.0,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/liv.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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