Clinical and Molecular Hepatology最新文献

{"title":"Genomic biomarkers to predict response to atezolizumab plus bevacizumab immunotherapy in hepatocellular carcinoma: Insights from the IMbrave150 trial.","authors":"Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee","doi":"10.3350/cmh.2024.0333","DOIUrl":"10.3350/cmh.2024.0333","url":null,"abstract":"<p><strong>Background/aims: </strong>Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.</p><p><strong>Methods: </strong>Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full model. We further validated ISS10 in an independent HCC cohort treated with nivolumab plus ipilimumab.</p><p><strong>Results: </strong>The study identified a significant association between the ISS and treatment response. Among patients classified as high responders, those treated with the atezolizumab plus bevacizumab combination exhibited improved overall and progression-free survival as well as better objective response rate compared to those treated with sorafenib. We also observed a significant correlation between ISS10 and response to nivolumab plus ipilimumab treatment. Analysis of immune cell subpopulations revealed distinct characteristics associated with ISS subtypes. In particular, the ISS10 high subtype displayed a more favorable immune environment with higher proportions of antitumor macrophages and activated T-cells, potentially explaining its better response.</p><p><strong>Conclusion: </strong>Our study suggests that ISS and ISS10 are promising predictive biomarkers for enhanced therapeutic outcomes in HCC patients undergoing combination immunotherapy. These markers are crucial for refining patient stratification and personalized treatment approaches to advance the effectiveness of standard-of-care regimens.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"807-823"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747510","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":"KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression.","authors":"Young Hoon Jung, Yun Ji Lee, Tam Dao, Kyung Hee Jung, Junjie Yu, Ah-Reum Oh, Yelin Jeong, HyunJoon Gi, Young Un Kim, Dongryeol Ryu, Michele Carrer, Utpal B Pajvani, Sang Bae Lee, Soon-Sun Hong, KyeongJin Kim","doi":"10.3350/cmh.2024.0364","DOIUrl":"10.3350/cmh.2024.0364","url":null,"abstract":"<p><strong>Background/aims: </strong>Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression.</p><p><strong>Methods: </strong>We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo.</p><p><strong>Results: </strong>Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice.</p><p><strong>Conclusion: </strong>KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"895-913"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888658","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":"Perspective of the risk and molecular mechanisms of hepatocellular carcinoma after HCV eradication in the post-DAA era: Correspondence to editorial on \"Unmet needs in the post-direct-acting antivirals era: The risk and molecular mechanisms of hepatocellular carcinoma after hepatitis C virus eradication\".","authors":"Chung-Feng Huang, Manar Hijaze Awad, Meital Gal-Tanamy, Ming-Lung Yu","doi":"10.3350/cmh.2024.0472","DOIUrl":"10.3350/cmh.2024.0472","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"1023-1025"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466589","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":"Reply to correspondence on \"Novel role of MHC class II transactivator in hepatitis B virus replication and viral counteraction\".","authors":"Cho-Rong Lee, Sung-Gyoo Park","doi":"10.3350/cmh.2024.0572","DOIUrl":"10.3350/cmh.2024.0572","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"1053-1054"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540364/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141632825","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":"Elimination of viral hepatitis: How far are we?: Editorial on \"Core indicators related to the elimination of hepatitis B and C virus infection in South Korea: A nationwide study\".","authors":"Eun Ju Cho","doi":"10.3350/cmh.2024.0557","DOIUrl":"10.3350/cmh.2024.0557","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"663-664"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733683","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":"Deep learning assisted biomarker development in patients with chronic hepatitis B: Editorial on \"Prognostic role of computed tomography analysis using deep learning algorithm in patients with chronic hepatitis B viral infection\".","authors":"Yong Eun Chung","doi":"10.3350/cmh.2024.0563","DOIUrl":"10.3350/cmh.2024.0563","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"669-672"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747509","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":"Racial and ethnic disparities in metabolic dysfunction-associated steatotic liver disease outcomes: A call for culturally sensitive interventions: Editorial on \"Differences in liver and mortality outcomes of non-alcoholic fatty liver disease by race and ethnicity: A longitudinal real-world study\".","authors":"Jae Hyun Bae","doi":"10.3350/cmh.2024.0562","DOIUrl":"10.3350/cmh.2024.0562","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"665-668"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787423","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":"Metabolic dysfunction-associated fatty liver disease is a ubiquitous latent cofactor in viral- and alcoholic-related hepatocellular carcinoma: Editorial on \"Global prevalence of metabolic dysfunction-associated fatty liver disease-related hepatocellular carcinoma: A systematic review and meta-analysis\".","authors":"Toru Nakamura, Masahito Nakano, Tsubasa Tsutsumi, Keisuke Amano, Takumi Kawaguchi","doi":"10.3350/cmh.2024.0372","DOIUrl":"10.3350/cmh.2024.0372","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"705-708"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070629","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":"Incretin-based therapy in the management of metabolic dysfunction-associated steatotic liver disease (MASLD): one piece of the puzzle: Editorial on \"Comparison of glucagon-like peptide-1 receptor agonists and thiazolidinediones on treating nonalcoholic fatty liver disease: A network meta-analysis\".","authors":"Tian-Yi Ren, Mohammed Eslam, Jian-Gao Fan","doi":"10.3350/cmh.2024.0558","DOIUrl":"10.3350/cmh.2024.0558","url":null,"abstract":"","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"649-652"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747511","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":"DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease.","authors":"Amal Magdy, Hee-Jin Kim, Hanyong Go, Jun Min Lee, Hyun Ahm Sohn, Keeok Haam, Hyo-Jung Jung, Jong-Lyul Park, Taekyeong Yoo, Eun-Soo Kwon, Dong Hyeon Lee, Murim Choi, Keon Wook Kang, Won Kim, Mirang Kim","doi":"10.3350/cmh.2024.0229","DOIUrl":"10.3350/cmh.2024.0229","url":null,"abstract":"<p><strong>Background/aims: </strong>Blocking the complement system is a promising strategy to impede the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interplay between complement and MASLD remains to be elucidated. This comprehensive approach aimed to investigate the potential association between complement dysregulation and the histological severity of MASLD.</p><p><strong>Methods: </strong>Liver biopsy specimens were procured from a cohort comprising 106 Korean individuals, which included 31 controls, 17 with isolated steatosis, and 58 with metabolic dysfunction-associated steatohepatitis (MASH). Utilizing the Infinium Methylation EPIC array, thorough analysis of methylation alterations in 61 complement genes was conducted. The expression and methylation of nine complement genes in a murine MASH model were examined using quantitative RT-PCR and pyrosequencing.</p><p><strong>Results: </strong>Methylome and transcriptome analyses of liver biopsies revealed significant (P<0.05) hypermethylation and downregulation of C1R, C1S, C3, C6, C4BPA, and SERPING1, as well as hypomethylation (P<0.0005) and upregulation (P<0.05) of C5AR1, C7, and CD59, in association with the histological severity of MASLD. Furthermore, DNA methylation and the relative expression of nine complement genes in a MASH diet mouse model aligned with human data.</p><p><strong>Conclusion: </strong>Our research provides compelling evidence that epigenetic alterations in complement genes correlate with MASLD severity, offering valuable insights into the mechanisms driving MASLD progression, and suggests that inhibiting the function of certain complement proteins may be a promising strategy for managing MASLD.</p>","PeriodicalId":10275,"journal":{"name":"Clinical and Molecular Hepatology","volume":" ","pages":"824-844"},"PeriodicalIF":14.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757407","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}