Pub Date : 2024-11-13DOI: 10.1016/j.jhep.2024.11.010
Cyriac Abby Philips, Arif Hussain Theruvath, Aryalakshmi Sreemohan, John Menachery, Rosh Varghese
Section snippets
Authors’ contributions
CAP designed the study and wrote the manuscript, AHT and AL acquired, compiled, and analysed the data, JM and RV finalized the manuscript and made critical revisions, all authors accepted the final version of manuscript for submission.
Financial support
The authors received no financial support to produce this manuscript.
Declaration of Competing Interest
The authors declare no conflicts of interest that pertain to this work.
{"title":"Surrender to evidence: the futility of plasma exchange for severe liver disease and liver failure","authors":"Cyriac Abby Philips, Arif Hussain Theruvath, Aryalakshmi Sreemohan, John Menachery, Rosh Varghese","doi":"10.1016/j.jhep.2024.11.010","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.010","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Authors’ contributions</h2>CAP designed the study and wrote the manuscript, AHT and AL acquired, compiled, and analysed the data, JM and RV finalized the manuscript and made critical revisions, all authors accepted the final version of manuscript for submission.</section></section><section><section><h2>Financial support</h2>The authors received no financial support to produce this manuscript.</section></section><section><section><h2>Declaration of Competing Interest</h2>The authors declare no conflicts of interest that pertain to this work.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"62 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601393","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 : 2024-11-13DOI: 10.1016/j.jhep.2024.11.011
Emma Vanderschueren
Section snippets
Author contributions
Conceptualization, data curation, formal analysis and writing of the manuscript were performed by EV and WL.
Financial support
None.
Declaration of Competing Interest
WL serves as a consultant for Cook Medical, MRM Health, and CSL Behring, and has received speaker’s fees from Boston Scientific. No other conflicts of interest were withheld.
Acknowledgements
We wish to thank Prof. Antonio Colecchia for his assistance in providing additional data from the validation cohort.
作者贡献构思、数据整理、正式分析和手稿撰写由 EV 和 WL 完成。财务支持无。竞争利益声明WL 担任 Cook Medical、MRM Health 和 CSL Behring 的顾问，并从波士顿科学公司获得演讲费。没有隐瞒其他利益冲突。感谢 Antonio Colecchia 教授协助提供验证队列的其他数据。
{"title":"Non-invasive algorithms could outperform HVPG in selecting candidates for non-selective beta-blockers in cirrhosis","authors":"Emma Vanderschueren","doi":"10.1016/j.jhep.2024.11.011","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.011","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Author contributions</h2>Conceptualization, data curation, formal analysis and writing of the manuscript were performed by EV and WL.</section></section><section><section><h2>Financial support</h2>None.</section></section><section><section><h2>Declaration of Competing Interest</h2>WL serves as a consultant for Cook Medical, MRM Health, and CSL Behring, and has received speaker’s fees from Boston Scientific. No other conflicts of interest were withheld.</section></section><section><section><h2>Acknowledgements</h2>We wish to thank Prof. Antonio Colecchia for his assistance in providing additional data from the validation cohort.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"5 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601296","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}
This work was supported by the Medical and Health Research Project of Baoan District (No. 2023JD250), and the Key Specialties in Clinical Medicine of the People’s Hospital of Baoan Shenzhen(No. 8).
Declaration of Competing Interest
The authors declare no conflicts of interest that pertain to this work.
{"title":"Unlock AI-Safe-C score's potential at all levels: Improve methods and overcome barriers","authors":"Qin Guo, Hui Li, Chengshan Guo","doi":"10.1016/j.jhep.2024.11.012","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.012","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Authors contributions</h2>Qin Guo: Conceptualization, Writing – original draft; Hui Li: Conceptualization, Funding acquisition, Writing – review & editing; Chengshan Guo: Funding acquisition, Writing – review & editing.</section></section><section><section><h2>Financial support statement</h2>This work was supported by the Medical and Health Research Project of Baoan District (No. 2023JD250), and the Key Specialties in Clinical Medicine of the People’s Hospital of Baoan Shenzhen(No. 8).</section></section><section><section><h2>Declaration of Competing Interest</h2>The authors declare no conflicts of interest that pertain to this work.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"159 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601295","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 : 2024-11-12DOI: 10.1016/j.jhep.2024.10.047
Tatjana Schwarz, Johannes Ptok, Maximilian Damagnez, Christopher Menne, Elahe Salimi Alizei, Julia Lang-Meli, Michelle Maas, Daniel Habermann, Daniel Hoffmann, Julian Schulze zur Wiesch, Georg Lauer, Helenie Kefalakes, Markus Cornberg, Anke RM. Kraft, Smaranda Gliga, Hans H. Bock, Peter A. Horn, Mala K. Maini, Robert Thimme, Heiner Wedemeyer, Jörg Timm
Background & Aims
Immune responses by CD8 T cells are essential for control of HBV replication. Although selection of escape mutations in CD8 T cell epitopes has been previously described in HBV infection, its overall influence on HBV sequence diversity and correlation with markers of HBV replication remain unclear.
Methods
Whole-genome sequencing was applied to HBV isolates from 532 patients with chronic HBV infection and high-resolution HLA class I genotyping. Using a Bayesian model (HAMdetector) for Identification of HLA-associated mutational states (HAMs) the frequency and location of residues under CD8 T cell selection pressure were determined and the levels of adaptation of individual isolates were quantified.
Results
Using previously published thresholds for the identification of HAMs, a total of 295 residues showed evidence of CD8 T cell escape, the majority of which were located in previously unidentified epitopes. Interestingly, HAMs were highly enriched in the HBV core protein compared to all other proteins. When individual HBV isolates were compared, different levels of adaptation to HLA class I immune pressure were noted. The level of adaptation increased with patient age and correlated with markers of replication, with low levels of adaptation in HBeAg-positive infection. Furthermore, the levels of adaptation negatively correlated with HBV viral load and HBsAg levels, consistent with high levels of HLA class I-associated selection pressure in patients with low replication level.
Conclusions
HBV sequence diversity is shaped by HLA class I-associated selection pressure with the HBV core protein being a predominant target of selection. Importantly, different levels of adaptation to immune pressure were observed between HBV infection stages, which need to be considered in the context of T cell-based therapies.
Impact and implications
The immune response mediated by CD8 T cells plays a critical role in controlling HBV infection and shows promise for therapeutic strategies aimed at achieving a functional cure. This study demonstrates that mutational escape within CD8 T cell epitopes is common in HBV and represents a key factor in the failure of immune control. Notably, the HBV core protein emerges as the primary target of CD8 T cell selection pressure. Additionally, the observed correlation between HBV adaptation levels and viral replication markers indicates that CD8 T cell immunity may influence transitions between phases of chronic HBV infection.
背景& 目的CD8 T细胞的免疫反应是控制HBV复制的关键。方法对来自 532 例慢性 HBV 感染患者的 HBV 分离物进行了全基因组测序，并进行了高分辨率 HLA I 类基因分型。结果根据之前公布的 HAMs 鉴定阈值，共有 295 个残基显示出 CD8 T 细胞逃逸的证据，其中大部分位于之前未确定的表位。有趣的是，与所有其他蛋白相比，HBV 核心蛋白中的 HAMs 高度富集。在对单个 HBV 分离物进行比较时，发现它们对 HLA I 类免疫压力的适应程度不同。适应水平随患者年龄的增长而增加，并与复制标志物相关，HBeAg 阳性感染者的适应水平较低。此外，适应水平与 HBV 病毒载量和 HBsAg 水平呈负相关，这与低复制水平患者的高水平 HLA I 类相关选择压力一致。影响和意义CD8 T 细胞介导的免疫反应在控制 HBV 感染中发挥着关键作用，并为旨在实现功能性治愈的治疗策略带来了希望。这项研究表明，CD8 T 细胞表位的突变逃逸在 HBV 中很常见，是导致免疫控制失败的关键因素。值得注意的是，HBV 核心蛋白是 CD8 T 细胞选择压力的主要目标。此外，观察到的 HBV 适应水平与病毒复制标志物之间的相关性表明，CD8 T 细胞免疫可能会影响慢性 HBV 感染阶段之间的转换。
{"title":"HBV shows different levels of adaptation to HLA class I-associated selection pressure correlating with markers of replication","authors":"Tatjana Schwarz, Johannes Ptok, Maximilian Damagnez, Christopher Menne, Elahe Salimi Alizei, Julia Lang-Meli, Michelle Maas, Daniel Habermann, Daniel Hoffmann, Julian Schulze zur Wiesch, Georg Lauer, Helenie Kefalakes, Markus Cornberg, Anke RM. Kraft, Smaranda Gliga, Hans H. Bock, Peter A. Horn, Mala K. Maini, Robert Thimme, Heiner Wedemeyer, Jörg Timm","doi":"10.1016/j.jhep.2024.10.047","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.10.047","url":null,"abstract":"<h3>Background & Aims</h3>Immune responses by CD8 T cells are essential for control of HBV replication. Although selection of escape mutations in CD8 T cell epitopes has been previously described in HBV infection, its overall influence on HBV sequence diversity and correlation with markers of HBV replication remain unclear.<h3>Methods</h3>Whole-genome sequencing was applied to HBV isolates from 532 patients with chronic HBV infection and high-resolution HLA class I genotyping. Using a Bayesian model (HAMdetector) for Identification of HLA-associated mutational states (HAMs) the frequency and location of residues under CD8 T cell selection pressure were determined and the levels of adaptation of individual isolates were quantified.<h3>Results</h3>Using previously published thresholds for the identification of HAMs, a total of 295 residues showed evidence of CD8 T cell escape, the majority of which were located in previously unidentified epitopes. Interestingly, HAMs were highly enriched in the HBV core protein compared to all other proteins. When individual HBV isolates were compared, different levels of adaptation to HLA class I immune pressure were noted. The level of adaptation increased with patient age and correlated with markers of replication, with low levels of adaptation in HBeAg-positive infection. Furthermore, the levels of adaptation negatively correlated with HBV viral load and HBsAg levels, consistent with high levels of HLA class I-associated selection pressure in patients with low replication level.<h3>Conclusions</h3>HBV sequence diversity is shaped by HLA class I-associated selection pressure with the HBV core protein being a predominant target of selection. Importantly, different levels of adaptation to immune pressure were observed between HBV infection stages, which need to be considered in the context of T cell-based therapies.<h3>Impact and implications</h3>The immune response mediated by CD8 T cells plays a critical role in controlling HBV infection and shows promise for therapeutic strategies aimed at achieving a functional cure. This study demonstrates that mutational escape within CD8 T cell epitopes is common in HBV and represents a key factor in the failure of immune control. Notably, the HBV core protein emerges as the primary target of CD8 T cell selection pressure. Additionally, the observed correlation between HBV adaptation levels and viral replication markers indicates that CD8 T cell immunity may influence transitions between phases of chronic HBV infection.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"18 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601481","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 : 2024-11-10DOI: 10.1016/j.jhep.2024.10.043
Changhoon Yoo, Hyehyun Jeong, Jae Ho Jeong, Kyu-pyo Kim, Seonmin Lee, Baek-Yeol Ryoo, Dae Wook Hwang, Jae Hoon Lee, Deog-Bog Moon, Ki-Hun Kim, Sang Soo Lee, Tae Jun Song, Dongwook Oh, Myung Ah Lee, Hong Jae Chon, Ji Sung Lee, George Laliotis, Samuel Rivero-Hinojosa, Erik Spickard, Derrick Renner, Minetta C. Liu
Background & Aims
Surgery is the only curative therapeutic option for resectable extrahepatic cholangiocarcinoma (eCCA), but recurrence is common, and prognosis is poor. There is an unmet clinical need for improved decision-making regarding adjuvant chemotherapy (ACT). Here we evaluated the usefulness of monitoring longitudinal circulating tumor DNA (ctDNA) for minimal residual disease (MRD) in patients of the STAMP trial, which compares the efficacy of adjuvant capecitabine (CAP) versus gemcitabine plus cisplatin (GemCis).
Methods
Between July 2017 and November 2020, 101 patients were randomized 1:1 to receive GemCis (n=50) or CAP (n=51). Efficacy outcomes were analyzed with an extended follow-up of 19 months from the previous report. From a biomarker cohort of 89 patients, longitudinal plasma samples (n=254) were prospectively collected post-surgery before adjuvant chemotherapy (ACT), and on-ACT at 12 and 24 weeks from cycle 1 day 1 (C1D1). ctDNA was evaluated using a personalized, tumor-informed, 16-plex PCR-NGS assay and was correlated with clinical outcomes.
Results
In the extended follow-up analysis, median disease-free survival (DFS) and overall survival (OS) did not significantly differ between the CAP and GemCis groups. Significantly inferior DFS was associated with ctDNA-positivity before ACT (HR, 1.8; p=0.029), on-ACT at 12 weeks from C1D1 (HR, 7.72; p<0.001), on-ACT at 24 weeks from C1D1 (HR, 5.24; p<0.001), and anytime post-surgery (HR, 3.81; p<0.001). Analysis of pre-treatment to on-treatment ctDNA dynamics revealed that serially ctDNA-negative patients exhibited a significantly longer DFS compared to those with sustained ctDNA-positivity (HR, 6.7; p<0.001) or who turned ctDNA-positive (HR, 5.8; p<0.001).
Conclusion
In patients with resected eCCA, ctDNA status and dynamics predicted recurrence during adjuvant therapy, and may help optimize clinical decision-making.
Impact and implications
The findings from this study highlight the critical role of ctDNA as a prognostic biomarker and monitoring tool for patients with resected extrahepatic cholangiocarcinoma (eCCA). By demonstrating the superiority of ctDNA to predict disease recurrence compared to conventional biomarkers such as CA 19-9 and CEA, this study underscores its potential in guiding decision-making during adjuvant chemotherapy. These results may be crucial to refine post-surgical treatment strategies and improve patient outcomes. The practical application of ctDNA monitoring could lead to more personalized treatment approaches, enabling timely interventions based on minimal residual disease (MRD) status.
{"title":"Circulating tumor DNA status and dynamics predict recurrence in patients with resected extrahepatic cholangiocarcinoma","authors":"Changhoon Yoo, Hyehyun Jeong, Jae Ho Jeong, Kyu-pyo Kim, Seonmin Lee, Baek-Yeol Ryoo, Dae Wook Hwang, Jae Hoon Lee, Deog-Bog Moon, Ki-Hun Kim, Sang Soo Lee, Tae Jun Song, Dongwook Oh, Myung Ah Lee, Hong Jae Chon, Ji Sung Lee, George Laliotis, Samuel Rivero-Hinojosa, Erik Spickard, Derrick Renner, Minetta C. Liu","doi":"10.1016/j.jhep.2024.10.043","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.10.043","url":null,"abstract":"<h3>Background & Aims</h3>Surgery is the only curative therapeutic option for resectable extrahepatic cholangiocarcinoma (eCCA), but recurrence is common, and prognosis is poor. There is an unmet clinical need for improved decision-making regarding adjuvant chemotherapy (ACT). Here we evaluated the usefulness of monitoring longitudinal circulating tumor DNA (ctDNA) for minimal residual disease (MRD) in patients of the STAMP trial, which compares the efficacy of adjuvant capecitabine (CAP) versus gemcitabine plus cisplatin (GemCis).<h3>Methods</h3>Between July 2017 and November 2020, 101 patients were randomized 1:1 to receive GemCis (<em>n</em>=50) or CAP (<em>n</em>=51). Efficacy outcomes were analyzed with an extended follow-up of 19 months from the previous report. From a biomarker cohort of 89 patients, longitudinal plasma samples (<em>n</em>=254) were prospectively collected post-surgery before adjuvant chemotherapy (ACT), and on-ACT at 12 and 24 weeks from cycle 1 day 1 (C1D1). ctDNA was evaluated using a personalized, tumor-informed, 16-plex PCR-NGS assay and was correlated with clinical outcomes.<h3>Results</h3>In the extended follow-up analysis, median disease-free survival (DFS) and overall survival (OS) did not significantly differ between the CAP and GemCis groups. Significantly inferior DFS was associated with ctDNA-positivity before ACT (HR, 1.8; <em>p</em>=0.029), on-ACT at 12 weeks from C1D1 (HR, 7.72; <em>p</em><0.001), on-ACT at 24 weeks from C1D1 (HR, 5.24; <em>p</em><0.001), and anytime post-surgery (HR, 3.81; <em>p</em><0.001). Analysis of pre-treatment to on-treatment ctDNA dynamics revealed that serially ctDNA-negative patients exhibited a significantly longer DFS compared to those with sustained ctDNA-positivity (HR, 6.7; <em>p</em><0.001) or who turned ctDNA-positive (HR, 5.8; <em>p</em><0.001).<h3>Conclusion</h3>In patients with resected eCCA, ctDNA status and dynamics predicted recurrence during adjuvant therapy, and may help optimize clinical decision-making.<h3>Impact and implications</h3>The findings from this study highlight the critical role of ctDNA as a prognostic biomarker and monitoring tool for patients with resected extrahepatic cholangiocarcinoma (eCCA). By demonstrating the superiority of ctDNA to predict disease recurrence compared to conventional biomarkers such as CA 19-9 and CEA, this study underscores its potential in guiding decision-making during adjuvant chemotherapy. These results may be crucial to refine post-surgical treatment strategies and improve patient outcomes. The practical application of ctDNA monitoring could lead to more personalized treatment approaches, enabling timely interventions based on minimal residual disease (MRD) status.<h3>Clinical Trial Registration number</h3>NCT03079427","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"3 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596803","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 : 2024-11-08DOI: 10.1016/j.jhep.2024.11.004
Moon Haeng Hur, Jeong-Hoon Lee
Section snippets
Grant support
This work was supported by National IT Industry Promotion Agency grant funded by the Korea Ministry of Science and ICT (S0252-21-1001), Liver Research Foundation of Korea as part of Bio Future Strategies Research Project, and Seoul National University Hospital Research Fund (04-2019-3090).
Authors’ contributions
MH and JL both drafted and reviewed the letter equally
Declaration of Competing Interest
Moon Haeng Hur: Nothing to declare; Jeong-Hoon Lee: Jeong-Hoon Lee receives research grants from Yuhan Pharmaceuticals and GreenCross Cell, and lecture fees from Samil Pharmaceuticals, GreenCross Cell, Daewoong Pharmaceuticals, and Gilead Korea.
本研究得到了韩国科学和信息通信技术部资助的国家信息技术产业振兴院基金（S0252-21-1001）、作为生物未来战略研究项目一部分的韩国肝脏研究基金会以及首尔国立大学医院研究基金（04-2019-3090）的支持：Jeong-Hoon Lee 从 Yuhan Pharmaceuticals 和 GreenCross Cell 获得研究基金，并从 Samil Pharmaceuticals、GreenCross Cell、Daewoong Pharmaceuticals 和 Gilead Korea 获得讲课费。
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Pub Date : 2024-11-08DOI: 10.1016/j.jhep.2024.11.001
Dario Saltini, Alberto Zanetto, Filippo Schepis
Section snippets
Author contributions
concept and design: DS, AZ, FS; drafted the letter: DS, AZ, FS. All authors approved the final version of this letter.
Financial support
No financial support was received for this study.
Declaration of Competing Interest
FS has received lecture fees and research grant from W.L. Gore, Cook Medical and Echosens.
章节片段作者贡献：构思和设计：DS、AZ、FS；起草信件：所有作者均批准了本信件的最终版本。财务支持本研究未获得任何财务支持。竞争利益声明FS 从 W.L. Gore、Cook Medical 和 Echosens 获得了讲课费和研究基金。
{"title":"Sedoanalgesia during TIPS placement: hemodynamic and ethical issues","authors":"Dario Saltini, Alberto Zanetto, Filippo Schepis","doi":"10.1016/j.jhep.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.001","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Author contributions</h2>concept and design: DS, AZ, FS; drafted the letter: DS, AZ, FS. All authors approved the final version of this letter.</section></section><section><section><h2>Financial support</h2>No financial support was received for this study.</section></section><section><section><h2>Declaration of Competing Interest</h2>FS has received lecture fees and research grant from W.L. Gore, Cook Medical and Echosens.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"38 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597837","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 : 2024-11-08DOI: 10.1016/j.jhep.2024.10.044
Hyun Young Kim, Sara Brin Rosenthal, Xiao Liu, Charlene Miciano, Xiaomeng Hou, Michael Miller, Justin Buchanan, Olivier B. Poirion, Daisy Chilin-Fuentes, Cuijuan Han, Mojgan Housseini, Raquel Carvalho-Gontijo Weber, Sadatsugu Sakane, Wonseok Lee, Huayi Zhao, Karin Diggle, Sebastian Preissl, Christopher K. Glass, Bing Ren, Allen Wang, Tatiana Kisseleva
Background and aims
Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from Metabolic dysfunction-associated steatotic liver (MASL) to Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Activation of Hepatic Stellate Cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. We compared transcriptome and chromatin accessibility of human HSCs from NORMAL, MASL, and MASH livers at single cell resolution. We aimed to identify genes that are upregulated in activated HSCs and to determine which of these genes are key in the pathogenesis of MASH fibrosis.
Methods
18 human livers were profiled using single-nucleus (sn)RNA-seq and snATAC-seq. High priority targets were identified, then tested in 2D human HSC cultures, 3D human liver spheroids, and HSC-specific gene knockout mice.
Results
MASH-enriched activated (A) HSC subclusters are the major source of extracellular matrix proteins. We identified a set of concurrently upregulated and more accessible core genes (GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1) that drive activation of (A) HSC subclusters. Expression of these genes was regulated via crosstalk between lineage-specific (JUNB/AP1), cluster-specific (RUNX1/2) and signal-specific (FOXA1/2) transcription factors. The pathological relevance of the selected targets, such as SERPINE1 (PAI-1), was demonstrated using dsiRNA-based HSC-specific gene knockdown or pharmacological inhibition of PAI-1 in 3D human MASH liver spheroids, and HSC-specific Serpine1 knockout mice.
Conclusion
This study identified novel gene targets and regulatory mechanisms underlying activation of MASH fibrogenic HSCs and demonstrated that genetic or pharmacological inhibition of select genes suppressed liver fibrosis.
Impact and implications
Here we present snRNA-seq and snATAC-seq analysis of human HSCs from NORMAL, MASL, and MASH livers. We identified additional subclusters that were not detected by previous studies and characterized the mechanism by which HSCs activate in the MASH livers, including the transcriptional machinery that activates HSCs into myofibroblasts. For the first time, we described the pathogenic role of activated HSC-derived PAI-1 (a product of SERPINE1 gene) in the development of MASH liver fibrosis. Targeting of RUNX1/2-SERPINE1 axis may provide a novel strategy for treatment of liver fibrosis in patients.
{"title":"Multi-Modal Analysis of human Hepatic Stellate Cells identifies novel therapeutic targets for Metabolic Dysfunction-Associated Steatotic Liver Disease","authors":"Hyun Young Kim, Sara Brin Rosenthal, Xiao Liu, Charlene Miciano, Xiaomeng Hou, Michael Miller, Justin Buchanan, Olivier B. Poirion, Daisy Chilin-Fuentes, Cuijuan Han, Mojgan Housseini, Raquel Carvalho-Gontijo Weber, Sadatsugu Sakane, Wonseok Lee, Huayi Zhao, Karin Diggle, Sebastian Preissl, Christopher K. Glass, Bing Ren, Allen Wang, Tatiana Kisseleva","doi":"10.1016/j.jhep.2024.10.044","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.10.044","url":null,"abstract":"<h3>Background and aims</h3>Metabolic dysfunction-associated steatotic liver disease (MASLD) ranges from Metabolic dysfunction-associated steatotic liver (MASL) to Metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Activation of Hepatic Stellate Cells (HSCs) into fibrogenic myofibroblasts plays a critical role in the pathogenesis of MASH liver fibrosis. We compared transcriptome and chromatin accessibility of human HSCs from NORMAL, MASL, and MASH livers at single cell resolution. We aimed to identify genes that are upregulated in activated HSCs and to determine which of these genes are key in the pathogenesis of MASH fibrosis.<h3>Methods</h3>18 human livers were profiled using single-nucleus (sn)RNA-seq and snATAC-seq. High priority targets were identified, then tested in 2D human HSC cultures, 3D human liver spheroids, and HSC-specific gene knockout mice.<h3>Results</h3>MASH-enriched activated (A) HSC subclusters are the major source of extracellular matrix proteins. We identified a set of concurrently upregulated and more accessible core genes (<em>GAS7, SPON1, SERPINE1, LTBP2, KLF9, EFEMP1</em>) that drive activation of (A) HSC subclusters. Expression of these genes was regulated via crosstalk between lineage-specific (<em>JUNB/AP1</em>), cluster-specific (<em>RUNX1/2</em>) and signal-specific (<em>FOXA1/2</em>) transcription factors. The pathological relevance of the selected targets, such as <em>SERPINE1</em> (PAI-1), was demonstrated using dsiRNA-based HSC-specific gene knockdown or pharmacological inhibition of PAI-1 in 3D human MASH liver spheroids, and HSC-specific <em>Serpine1</em> knockout mice.<h3>Conclusion</h3>This study identified novel gene targets and regulatory mechanisms underlying activation of MASH fibrogenic HSCs and demonstrated that genetic or pharmacological inhibition of select genes suppressed liver fibrosis.<h3>Impact and implications</h3>Here we present snRNA-seq and snATAC-seq analysis of human HSCs from NORMAL, MASL, and MASH livers. We identified additional subclusters that were not detected by previous studies and characterized the mechanism by which HSCs activate in the MASH livers, including the transcriptional machinery that activates HSCs into myofibroblasts. For the first time, we described the pathogenic role of activated HSC-derived PAI-1 (a product of <em>SERPINE1</em> gene) in the development of MASH liver fibrosis. Targeting of <em>RUNX1/2-SERPINE1</em> axis may provide a novel strategy for treatment of liver fibrosis in patients.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"9 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596806","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":"Does MASH Co-Morbidity in CHB Truly Suppress Immune Function?","authors":"Zhigang Wei, Dan Shan, Chaojie Liang","doi":"10.1016/j.jhep.2024.11.002","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.11.002","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Author’s contributions</h2>Zhigang Wei: Study design & Manuscript Writing.Dan Shan and Chaojie Liang: Study design & Manuscript Revision.</section></section><section><section><h2>Declaration of Competing Interest</h2>We declare there is no any conflict of interest.</section></section><section><section><h2>Acknowledgements & Funding</h2>This work was supported by Shanxi Medical University Doctoral Start-up Fund (XD1802) and Shanxi Scholarship Council of China (20221852).</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"94 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596807","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":"Therapeutic plasma exchange in acute liver failure: Challenges in patient selection and optimal timing of intervention","authors":"Bikrant Bihari Lal, Seema Alam","doi":"10.1016/j.jhep.2024.10.036","DOIUrl":"https://doi.org/10.1016/j.jhep.2024.10.036","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Author’s contribution</h2>BBL prepared the first draft. SA critically reviewed and approved the final manuscript.</section></section><section><section><h2>Financial disclosure</h2>None</section></section><section><section><h2>Declaration of Competing Interest</h2>Bikrant Bihari Lal and Seema Alam declare no financial or non-financial conflict of interest.</section></section>","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":"16 1","pages":""},"PeriodicalIF":25.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597854","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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