JHEP Reports最新文献

{"title":"Decreasing interleukin-6 levels after TIPS predict outcomes in decompensated cirrhosis","authors":"Andrea Kornfehl ,&nbsp;Anja Tiede ,&nbsp;Paul Hemetsberger ,&nbsp;Julia Kappel ,&nbsp;Theresa Müllner-Bucsics ,&nbsp;Lena Stockhoff ,&nbsp;Hannah Rieland ,&nbsp;Lukas Reider ,&nbsp;Nina Dominik ,&nbsp;Georg Kramer ,&nbsp;Michael Trauner ,&nbsp;Mattias Mandorfer ,&nbsp;Christine Falk ,&nbsp;Benjamin Maasoumy ,&nbsp;Thomas Reiberger ,&nbsp;Lukas Hartl","doi":"10.1016/j.jhepr.2024.101308","DOIUrl":"10.1016/j.jhepr.2024.101308","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Transjugular intrahepatic portosystemic shunt (TIPS) effectively treats complications of cirrhosis. Systemic inflammation (SI) is linked to acute-on-chronic liver failure (ACLF) and liver-related death. We aimed to assess the trajectory and clinical impact of SI parameters after TIPS implantation.</div></div><div><h3>Methods</h3><div>Consecutive patients undergoing elective implantation of covered TIPS for recurrent/refractory ascites or portal-hypertensive bleeding at the Medical University Vienna (NCT03409263; n = 58) and at the Hannover Medical School (NCT04801290, n = 51) were included. IL-6 was assessed at baseline (BL), 3 months (M3) and up to 6 (M6; Hannover cohort) or 9 months (M9; Vienna cohort) of follow-up; C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) were assessed in the Vienna cohort only.</div></div><div><h3>Results</h3><div>In 109 patients (66.1% male, median age 57 years) receiving TIPS mainly (72.4%) by indication ascites the median BL IL-6 levels were 10.5 pg/ml; and 41.3% (n = 45/109) patients exhibiting IL-6 ≥14 pg/ml. From BL to M3, IL-6 decreased in 63.8% (n = 37/58; Vienna cohort) and in 68.6% (n = 35/51; Hannover cohort) of patients, respectively. Similar rates of decreases were observed also for CRP (in 62.1%) and for LBP (in 77.4%). A considerable IL-6 reduction (≥50% of baseline) was noted in 41 (37.6%) patients during follow-up. Competing risk regression in the combined cohort adjusted for age, albumin, and model for end-stage liver disease revealed that IL-6 decrease at M3 was an independently protective factor for the development of ACLF (adjusted subdistribution hazard ratio [asHR]: 0.26; 95% CI: 0.09–0.77; <em>p</em> = 0.016) and liver-related death (asHR: 0.26; 95% CI: 0.07–0.95; <em>p</em> = 0.042).</div></div><div><h3>Conclusions</h3><div>TIPS leads to a sustained reduction of SI and bacterial translocation in patients with decompensated cirrhosis. Decreasing IL-6 levels three months after TIPS implantation indicate a lower risk of ACLF and liver-related death in patients with cirrhosis.</div></div><div><h3>Impact and implications:</h3><div>Systemic inflammation is a major driver of disease progression in patients with decompensated advanced chronic liver disease (dACLD). This study demonstrates that systemic inflammation (<em>i.e.</em> interleukin-6 [IL-6]) effectively and sustainedly decreases after transjugular intrahepatic portosystemic shunt (TIPS) implantation. A decrease of IL-6 3 months after TIPS implantation is a protective factor for acute-on-chronic liver failure and liver-related death. Thus, our results suggest that TIPS reduces systemic inflammation in a clinically meaningful way.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 4","pages":"Article 101308"},"PeriodicalIF":9.5,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551067","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":"Identification of a cancer stem cell-like subpopulation that promotes HCC metastasis","authors":"Chunyuan Yang ,&nbsp;Yang Li ,&nbsp;Zhaohai Wang ,&nbsp;Hui Shan ,&nbsp;Guangze Zhang ,&nbsp;Xiangyan Meng ,&nbsp;Guangxi Wang ,&nbsp;Zhiyuan Hou ,&nbsp;Xuyang Zhao ,&nbsp;Xin Zhang ,&nbsp;Anhang Liu ,&nbsp;Yuntao Bing ,&nbsp;Guanglin Lei ,&nbsp;Yan Jin ,&nbsp;Jianyuan Luo ,&nbsp;Limei Guo ,&nbsp;Yuxin Yin","doi":"10.1016/j.jhepr.2024.101302","DOIUrl":"10.1016/j.jhepr.2024.101302","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Cancer stem cells (CSCs) are well-established drivers of tumorigenesis, but their role in regulating tumor metastasis remains poorly understood. Here, we report the identification and characterization of a cluster of metastasis-promoting CSC-like cells in hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>CSC-like cells in HCC were identified through the analysis of single cell RNA-sequencing data from 19 HCC samples. The stemness and invasive characteristics of these cells were evaluated using bioinformatical analyses of nine clinical cohorts and experimental validations. Spatial transcriptomics sequencing of 12 HCC samples revealed the cellular interactions between the CSC-like cells and tumor microenvironments, which were validated through gene co-expression analyses and immunohistochemistry. Finally, signaling pathway blockade was used to assess the potential clinical application of CSC-like cells.</div></div><div><h3>Results</h3><div>Through comprehensive analyses of single cell RNA-sequencing data from 19 patients with HCC and spatial transcriptomics data from 12 patients with HCC, a metastasis-promoting CSC-like subpopulation was identified. These CSC-like cells expressed high levels of epithelial–mesenchymal transition genes and were associated with poor prognosis of HCC. Histologically, CSC-like cells were enriched in highly aggressive tumors, especially in intrahepatic disseminated foci, where they interacted with immune cells. Functionally, CSC-like cells induced macrophage M2 polarization and T cell exhaustion through the ICAM1 signaling pathway, forming immunosuppressive microenvironments. Downregulation of ICAM1 expression in CSC-like cells suppressed macrophage M2-polarization and T cell exhaustion, thereby reversing antitumor immune effects.</div></div><div><h3>Conclusions</h3><div>Our study identified a metastasis-promoting CSC subpopulation, providing a potential perspective for CSC-targeted therapies in HCC.</div></div><div><h3>Impact and implications</h3><div>The heterogeneity of CSCs in HCC has been identified, yet the identification and characterization of metastasis-promoting CSC subpopulations remain unexplored. Here, we identified a CSC-like tumor cell subpopulation that promotes HCC metastasis by increasing cell invasiveness and suppressing antitumor immune responses via the ICAM1 signaling pathway. Our study uncovers novel mechanisms of HCC metastasis from the perspective of CSCs, and proposes potential tumor therapeutic strategies by inhibiting cellular interactions between CSC-like cells and immune cells.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 5","pages":"Article 101302"},"PeriodicalIF":9.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143748545","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 phenotyping of patients with MASLD upon high-intensity interval training","authors":"Veera Houttu ,&nbsp;Ulrika Boulund ,&nbsp;Marian Troelstra ,&nbsp;Susanne Csader ,&nbsp;Daniela Stols-Gonçalves ,&nbsp;Anne Linde Mak ,&nbsp;Anne-Marieke van Dijk ,&nbsp;Julia Bouts ,&nbsp;Maaike Winkelmeijer ,&nbsp;Xanthe Verdoes ,&nbsp;Sandra van den Berg-Faay ,&nbsp;Donne Lek ,&nbsp;Ted Ronteltap ,&nbsp;Ferdinand de Haan ,&nbsp;Harald Jorstad ,&nbsp;Ville Männistö ,&nbsp;Kai Savonen ,&nbsp;Heikki Pentikäinen ,&nbsp;Kati Hanhineva ,&nbsp;Ambrin Farizah Babu ,&nbsp;Adriaan Georgius Holleboom","doi":"10.1016/j.jhepr.2024.101289","DOIUrl":"10.1016/j.jhepr.2024.101289","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Exercise is a key component of lifestyle management in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but neither its therapeutic effect on the active stage of the disease, that is metabolic dysfunction-associated steatohepatitis (MASH) nor the mediating mechanisms have been characterized. Therefore, we performed multi-omic phenotyping of patients with MASLD-MASH on an exercise program.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Fifteen patients with MASLD conducted high-intensity interval training (HIIT) combined with home-based training for 12 weeks. MASLD was evaluated using histology, transient elastography, and multiparametric magnetic resonance imaging (MRI) before and after the intervention. Change in maximal oxygen consumption (VO&lt;sub&gt;2max&lt;/sub&gt;) and MRI-determined liver fat were compared with a control group of patients with MASLD (n = 22). RNA sequencing was performed on liver, muscle, and fat biopsies of patients in the exercise group. Stool was analyzed by shotgun metagenomics and untargeted metabolomics was performed on plasma, urine, adipose, and stool.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;HIIT increased VO&lt;sub&gt;2max&lt;/sub&gt; by 10.1% and improved mitochondrial metabolism in skeletal muscle, indicating improved cardiorespiratory fitness and adherence. VO&lt;sub&gt;2max&lt;/sub&gt; increased significantly in the exercise group compared with controls. Histologically, no reduction in steatosis, MASH, or liver fibrosis was observed; however, transient elastography tended to improve. MRI-determined liver fat did not change in the exercise group compared with controls. HIIT induced changes in mRNA expression of genes related to beiging of adipose tissue and fibrogenesis in liver. In addition, specific gut microbial taxa and metabolites changed.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;HIIT increased cardiorespiratory fitness and induced beneficial gene expression changes in muscle, adipose tissue, and liver, but without translation into histological improvement of MASLD. Longer exercise intervention trials are warranted to validate or refute current recommendations for exercise as a cornerstone treatment for MASLD-MASH.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;Despite exercise being considered as a key component of lifestyle management for steatotic liver disease, neither the clinical effects nor the mechanisms involved are completely understood. We show that a high-intensity interval training (HIIT) program in 15 patients with metabolic dysfunction-associated steatotic liver disease (MASLD) improved cardiorespiratory fitness, compared with 22 control patients with MASLD who did not participate in an exercise program, however, it did not improve MASLD. HIIT induced a positive effect on fat tissue and muscle metabolism which was accompanied with changes in certain gut bacteria and metabolites in blood and urine. These findings improve our understanding of the effects of exerci","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101289"},"PeriodicalIF":9.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437463","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":"Unraveling the immune-activated tumor microenvironment correlated with clinical response to atezolizumab plus bevacizumab in advanced HCC","authors":"Jinyeong Lim ,&nbsp;Myung Ji Goh ,&nbsp;Byeong Geun Song ,&nbsp;Dong Hyun Sinn ,&nbsp;Wonseok Kang ,&nbsp;Geum-Youn Gwak ,&nbsp;Moon Seok Choi ,&nbsp;Joon Hyeok Lee ,&nbsp;Dong Ik Cha ,&nbsp;Kyowon Gu ,&nbsp;Sang Yun Ha ,&nbsp;Inwoo Hwang ,&nbsp;Woong-Yang Park ,&nbsp;Yong-Han Paik","doi":"10.1016/j.jhepr.2024.101304","DOIUrl":"10.1016/j.jhepr.2024.101304","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Despite atezolizumab plus bevacizumab being a standard treatment for advanced hepatocellular carcinoma (HCC), a significant proportion of patients do not achieve durable benefit. This study aimed to identify predictive biomarkers for this therapy by investigating the role of immune activation within the tumor microenvironment (TME).</div></div><div><h3>Methods</h3><div>We characterized the intratumoral TME of patients with advanced HCC treated with atezolizumab plus bevacizumab using single cell transcriptomics on pretreatment tumor biopsies from 12 patients. To complement and support these findings, we integrated our single cell data with publicly available bulk RNA-sequencing data from independent clinical trial cohorts.</div></div><div><h3>Results</h3><div>Patients who responded to combination therapy with atezolizumab plus bevacizumab demonstrated an immune-activated TME, marked by enhanced cytotoxicity and a tumor-specific T cell response. These patients also exhibited an increased proportion of inflammatory cytokine-enriched tumor-associated macrophage clusters with stronger interactions with T cells, an increased population of conventional dendritic cells, and activated antigen-presenting function in tumor endothelial cells. When publicly available bulk RNA-sequencing data from independent clinical trial cohorts were analyzed, these immune activation features were associated with improved progression-free survival (median 10.8 months, 95% CI: 7.3–not reached versus 5.5 months, 95% CI: 4.0–6.7; <em>p</em> &lt;0.001).</div></div><div><h3>Conclusions</h3><div>These findings suggest that the existence of an activated immune TME before treatment is crucial for a favorable clinical response in patients with HCC treated with atezolizumab plus bevacizumab.</div></div><div><h3>Impact and implications:</h3><div>Only a subset of patients with HCC benefit from combination therapy with atezolizumab plus bevacizumab, limiting its clinical utility. In this study, we used single cell RNA analysis to identify TME features associated with a clinical response to this therapy. Our findings suggest that a pre-existing immune-activated TME is crucial for predicting the response to atezolizumab plus bevacizumab. Specifically, features such as enhanced T cell cytotoxicity, inflammatory cytokine-enriched macrophage clusters, active antigen presentation in endothelial cells, and an increased presence of dendritic cells may aid patient selection and inform therapeutic strategies.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 4","pages":"Article 101304"},"PeriodicalIF":9.5,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551064","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":"CPEB4 modulates liver cancer progression by translationally regulating hepcidin expression and sensitivity to ferroptosis","authors":"M. Eugenia Delgado ,&nbsp;Salvador Naranjo-Suarez ,&nbsp;Marta Ramírez-Pedraza ,&nbsp;Beatriz I. Cárdenas ,&nbsp;Carmen Gallardo-Martínez ,&nbsp;Alexandra Balvey ,&nbsp;Eulalia Belloc ,&nbsp;Judit Martín ,&nbsp;Mark Boyle ,&nbsp;Raúl Méndez ,&nbsp;Mercedes Fernandez","doi":"10.1016/j.jhepr.2024.101296","DOIUrl":"10.1016/j.jhepr.2024.101296","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background &amp; Aims&lt;/h3&gt;&lt;div&gt;Liver cancer is a significant global health issue, with its incidence rising in parallel with the obesity epidemic. The limited therapeutic options available emphasize the need for a better understanding of the molecular pathways involved in its pathogenesis. While much of the previous research has focused on transcriptional changes, this study examines translational alterations, specifically the role of cytoplasmic polyadenylation element binding protein 4 (CPEB4), a key regulator of translation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We analyzed publicly available patient databases and conducted studies using human and mouse liver cancer cells, xenograft and allograft models, mouse models of high-fat diet-related liver cancer, and CPEB4 knockout and knockdown mice and cell lines.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Patient data analysis (n = 87) showed a strong correlation between low CPEB4 levels and reduced survival rates (&lt;em&gt;p&lt;/em&gt; &lt;0.001). In mouse models of diet-induced liver cancer (n = 10–15 per group), both systemic and hepatocyte-specific CPEB4 knockout mice exhibited significantly increased tumor burden compared with wild-type controls (&lt;em&gt;p&lt;/em&gt; &lt;0.05). &lt;em&gt;In vitro&lt;/em&gt; studies using human and murine liver cancer cells (n = 3 biological replicates) demonstrated reduced sensitivity to ferroptosis upon CPEB4 depletion when induced by erastin or RSL3 (&lt;em&gt;p&lt;/em&gt; &lt;0.01). Mechanistically, CPEB4 deficiency suppressed hepcidin expression, leading to elevated ferroportin levels, decreased intracellular iron accumulation, and reduced lipid peroxidation (&lt;em&gt;p&lt;/em&gt; &lt;0.05).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;This study uncovers a novel CPEB4-dependent mechanism linking translational control to liver cancer progression and ferroptosis regulation. Therapeutic strategies targeting CPEB4-mediated pathways hold promise for advancing treatment options in liver cancer.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Impact and implications:&lt;/h3&gt;&lt;div&gt;This study addresses the pressing need for improved therapies in liver cancer, particularly given its increasing prevalence linked to obesity and metabolic-associated fatty liver disease. By uncovering the role of the RNA-binding protein cytoplasmic polyadenylation element binding protein 4 (CPEB4) in modulating iron regulation and cancer cell sensitivity to ferroptosis, our research highlights a new translational mechanism with potential therapeutic relevance. These findings are particularly significant for clinicians, researchers, and policymakers focused on advancing targeted treatments for hepatocellular carcinoma. If further validated in human clinical studies, targeting CPEB4-mediated pathways could help develop treatments that enhance cancer cell susceptibility to ferroptosis, offering a promising strategy for improving outcomes in patients with advanced liver cancer. Limitations of the study include the need for further clinical validation to confirm these preclinica","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101296"},"PeriodicalIF":9.5,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143182323","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":"Comparing methods for plasma HDV RNA quantification in bulevirtide-treated and untreated patients with HDV","authors":"Maria Paola Anolli ,&nbsp;Sara Uceda Renteria ,&nbsp;Elisabetta Degasperi ,&nbsp;Floriana Facchetti ,&nbsp;Dana Sambarino ,&nbsp;Marta Borghi ,&nbsp;Riccardo Perbellini ,&nbsp;Roberta Soffredini ,&nbsp;Sara Monico ,&nbsp;Annapaola Callegaro ,&nbsp;Pietro Lampertico","doi":"10.1016/j.jhepr.2024.101299","DOIUrl":"10.1016/j.jhepr.2024.101299","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Accurate HDV RNA quantification is crucial for diagnosis and management of chronic hepatitis delta (CHD), yet a significant variability between assays exists. We compared three methods to quantify HDV RNA levels in untreated and bulevirtide (BLV)-treated patients with CHD.</div></div><div><h3>Methods</h3><div>Frozen plasma from untreated and BLV-treated patients with CHD were tested in a single-center retrospective study using three different assays: Robogene 2.0 HDV RNA Quantification Kit 2.0 (Roboscreen GmbH; limit of detection [LOD] 6 IU/ml on 7500 Fast Real-Time PCR System [Applied Biosystem]), EurobioPlex HDV PCR quantitative kit (Eurobio Scientific; LOD 100 IU/m) on CFX96™ real-time PCR detection system [Bio-Rad]), and AltoStar HDV RT-PCR RUO Kit 1.5 (Altona Diagnostics; estimated LOD &lt;10 IU/ml) on the AltoStar®AM16.</div></div><div><h3>Results</h3><div>Overall, 431 plasma samples from 130 patients with CHD (69 untreated and 61 BLV-treated) were studied. Compared with Robogene 2.0, EurobioPlex reported higher HDV RNA levels (3.78 [0.70–7.99] <em>vs</em>. 4.69 [2.00–8.19] log IU/ml, <em>p</em> &lt;0.0001), with viremia higher than &gt;0.5 log in 160 (69%). Likewise, HDV RNA levels were higher with AltoStar than with Robogene 2.0 (3.32 [0.70–7.37] <em>vs</em>. 3.91 [0.19–7.54] log IU/ml, <em>p</em> &lt;0.0001), with AltoStar reporting HDV RNA levels &gt;0.5 log in 127 (52%). Although virological response rates (≥2 log decline <em>vs.</em> baseline) at Weeks 24 (Robogene 2.0 <em>vs.</em> EurobioPlex and AltoStar) and 48 (Robogene 2.0 <em>vs.</em> AltoStar) were similar across assays, rates of HDV RNA undetectability significantly differed between the three assays at Weeks 24 and 72 (<em>p</em> = 0.003 and <em>p</em> = 0.02, respectively).</div></div><div><h3>Conclusions</h3><div>HDV RNA levels quantified by EurobioPlex and AltoStar were 1 and 0.5 logs higher than those quantified by Robogene 2.0, respectively. HDV RNA undetectability rates during BLV treatment were assay-dependent.</div></div><div><h3>Impact and implications:</h3><div>Management and diagnosis of chronic hepatitis delta (CHD) require standardized tests for HDV RNA quantification. Quantification of HDV RNA is significantly influenced by the quantification method, with EurobioPlex detecting approximatively 1 log and AltoStar 0.5 log IU/ml more than Robogene 2.0, respectively. The HDV RNA undetectability rates during BLV monotherapy significantly differed among assays. These findings are of clinical relevance as patients who achieve negative viremia during BLV monotherapy might be entitled to stop therapy successfully.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101299"},"PeriodicalIF":9.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143437356","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":"Non-invasive assessment of portal hypertension: Liver stiffness and beyond","authors":"Mattias Mandorfer ,&nbsp;Juan G. Abraldes ,&nbsp;Annalisa Berzigotti","doi":"10.1016/j.jhepr.2024.101300","DOIUrl":"10.1016/j.jhepr.2024.101300","url":null,"abstract":"<div><div>Portal hypertension (PH) leads to life-threatening clinical manifestations such as bleeding from gastro-oesophageal varices, ascites and its complications, and portosystemic encephalopathy. It can develop because of advanced chronic liver disease (ACLD) or due to rarer causes such as vascular liver disease. Reference standard methods to assess PH in ACLD include the measurement of hepatic venous pressure gradient and endoscopy, which have limitations due to their high resource utilisation and invasiveness. Non-invasive tests (NITs) have entered clinical practice and allow invasive procedures to be reserved for patients with indeterminate findings on NITs or for specific clinical questions. In this review, we present an update on the role of NITs, and in particular ultrasound elastography, to diagnose PH in ACLD and vascular liver disease, and to stratify the risk of liver-related events. We also provide insights into the open research questions and design of studies in this field.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101300"},"PeriodicalIF":9.5,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402720","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":"Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome","authors":"Fabien Robert ,&nbsp;Feriel Benchenouf ,&nbsp;My Ngoc Ha ,&nbsp;Alessandra Cuomo ,&nbsp;Mina Ottaviani ,&nbsp;Maxime Surbier ,&nbsp;Raphaël Thuillet ,&nbsp;Corinne Normand ,&nbsp;Florent Dumont ,&nbsp;Céline Verstuyft ,&nbsp;Frederic Fiore ,&nbsp;Frederic Guinut ,&nbsp;Marc Humbert ,&nbsp;Audrey Coilly ,&nbsp;Emmanuel Gonzales ,&nbsp;Olivier Sitbon ,&nbsp;Ly Tu ,&nbsp;Christophe Guignabert ,&nbsp;Laurent Savale","doi":"10.1016/j.jhepr.2024.101297","DOIUrl":"10.1016/j.jhepr.2024.101297","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Hepatopulmonary syndrome (HPS) results from portal hypertension, with or without cirrhosis, and is marked by pulmonary vascular dilations leading to severe hypoxemia. Although placental growth factor (PlGF) is important for vascular growth and endothelial function, its role in HPS is unclear. This study investigated the involvement of PlGF in experimental models of HPS and in patients.</div></div><div><h3>Methods</h3><div>Circulating PlGF levels were measured in 64 controls and 137 patients with liver disease, with or without HPS. Two rat models, common bile duct ligation (CBDL) and long-term partial portal vein ligation (PPVL), were used. <em>Plgf</em>-knockout (<em>Plgf</em>^{<em>–</em>/–}) rats were generated using CRISPR-Cas9. Lung RNA-sequencing analysis was performed in the CBDL model. The effects of PlGF on endothelial nitric oxide synthase (eNOS) activity in human pulmonary microvascular endothelial cells were also investigated.</div></div><div><h3>Results</h3><div>Circulating PlGF levels were significantly higher in patients with cirrhosis compared with healthy controls (29.4 ± 1.2 <em>vs.</em> 20.2 ± 0.8 pg/ml, <em>p</em> &lt;0.0001), but no difference were found between patients with and without HPS. PlGF levels were not elevated in patients with extrahepatic portal hypertension. In <em>Plgf</em>^–/– rats, there was a protective effect against CBDL-induced HPS, whereas PPVL-induced HPS severity remained unchanged. RNA sequencing coupled with ingenuity pathway analysis identified significant interactions between PlGF and pulmonary eNOS activity. Following CBDL, <em>Plgf</em>^–/– rats showed decreased pulmonary eNOS activity and reduced circulating nitric oxide metabolites. <em>In vitro</em>, PlGF stimulation enhanced eNOS activity in human pulmonary microvascular endothelial cells, whereas PlGF knockdown led to a decrease.</div></div><div><h3>Conclusions</h3><div>These findings indicate that PlGF aggravates cirrhosis-induced HPS through modulation of pulmonary eNOS activity, and is not involved in HPS from extrahepatic portal hypertension.</div></div><div><h3>Impact and implications:</h3><div>This study identified PlGF as a significant contributor to the exacerbation of HPS associated with cirrhosis, through its regulation of pulmonary nitric oxide production. Our findings demonstrated that PlGF deficiency mitigates the severity of both cirrhosis and HPS in the CBDL model, highlighting its potential as a therapeutic target in cirrhosis-induced HPS. Notably, this protective effect was absent in the PPVL model, which induces HPS associated with portal hypertension without cirrhosis. These results open avenues for novel pharmacological interventions aiming to improve outcomes for patients with cirrhosis-induced HPS.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101297"},"PeriodicalIF":9.5,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143180628","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":"Evaluation of prognostic scores in patients with HCC undergoing first-line immunotherapy with atezolizumab and bevacizumab","authors":"Simon Johannes Gairing ,&nbsp;Philipp Mildenberger ,&nbsp;Jennifer Gile ,&nbsp;Fabian Artusa ,&nbsp;Bernhard Scheiner ,&nbsp;Catherine Leyh ,&nbsp;Sabine Lieb ,&nbsp;Friedrich Sinner ,&nbsp;Vincent Jörg ,&nbsp;Thorben Fruendt ,&nbsp;Vera Himmelsbach ,&nbsp;Nada Abedin ,&nbsp;Cennet Sahin ,&nbsp;Katrin Böttcher ,&nbsp;Jasmin Schuhbaur ,&nbsp;Simon Labuhn ,&nbsp;James Korolewicz ,&nbsp;Claudia A.M. Fulgenzi ,&nbsp;Antonio D'Alessio ,&nbsp;Valentina Zanuso ,&nbsp;Friedrich Foerster","doi":"10.1016/j.jhepr.2024.101295","DOIUrl":"10.1016/j.jhepr.2024.101295","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><div>Immunotherapy with atezolizumab and bevacizumab (a + b) has improved the prognosis of patients with unresectable hepatocellular carcinoma (HCC). However, the outcome for individual patients is highly variable. This study aimed to (i) develop and validate a prognostic prediction model to estimate individual prognosis and (ii) compare it with established models.</div></div><div><h3>Methods</h3><div>In this multicenter retrospective study, patients with HCC undergoing first-line immunotherapy with a + b from 24 centers (Europe, USA) were included. Statistical analysis and reporting followed the TRIPOD guidelines. The primary objective was overall survival (OS). A Cox model was developed and externally validated.</div></div><div><h3>Results</h3><div>In total, 683 patients were included (training: 526, validation: 157). The C-reactive protein, albumin, bilirubin, lymphocytes, ECOG performance status, and extrahepatic spread (CABLE score) remained significantly associated with OS in Cox regression analysis. In the training set, the CABLE score had a higher discriminatory accuracy relative to ALBI, EZ-ALBI, mALBI, CRAFITY, PNI, NLR, PLR, and GPS (time-dependent AUC 0.79 and C-index 0.75 (95% CI 0.71–0.78) at 12 months). In the external validation set, the discriminatory performance of the CABLE score was comparable to ALBI, EZ-ALBI, and mALBI, but on average higher than PNI, CRAFITY, NLR, PLR, and GPS. In patients with Child-Pugh A, the CABLE score outperformed ALBI, EZ-ALBI, and mALBI in the first 9 months. We provide a web-based calculator for the CABLE score to allow estimation of individual prognosis for these patients (<span><span>http://shiny.imbei.uni-mainz.de:3838/CABLE_Score/</span><svg><path></path></svg></span>).</div></div><div><h3>Conclusions</h3><div>The CABLE score shows good discriminatory performance in assessing the individual prognosis of patients undergoing first-line immunotherapy with a + b. Further validation studies are needed to investigate its performance compared with the ALBI score, in particular in subgroup analysis.</div></div><div><h3>Impact and implications:</h3><div>The CABLE score allows estimation of the prognosis of patients with unresectable hepatocellular carcinoma undergoing first-line immunotherapy with atezolizumab and bevacizumab at an individual level using our web-based calculator. This feature, as well as the evaluation of the score’s added benefit through an extensive comparison with other established scores, can inform clinicians on their significance and may guide clinical decision-making in the context of a malignant disease where the prognosis has become highly variable. Further large validation studies are needed to investigate the incremental value of the CABLE score compared with the ALBI score, in particular in subgroups such as patients designated as Child-Pugh A.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101295"},"PeriodicalIF":9.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143444431","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":"Monitoring of hepatitis E virus infection and replication by functional tagging of the ORF2 protein","authors":"Maliki Ankavay ,&nbsp;Nathalie Da Silva ,&nbsp;Angela Pollán ,&nbsp;Noémie Oechslin ,&nbsp;Katja Dinkelborg ,&nbsp;Patrick Behrendt ,&nbsp;Darius Moradpour ,&nbsp;Jérôme Gouttenoire","doi":"10.1016/j.jhepr.2024.101293","DOIUrl":"10.1016/j.jhepr.2024.101293","url":null,"abstract":"<div><h3>Background and Aims</h3><div>Hepatitis E virus (HEV) infection is a leading cause of acute hepatitis worldwide. Understanding of the mechanisms underlying productive HEV infection remains incomplete and would benefit from technological advances improving current model systems.</div></div><div><h3>Methods</h3><div>We exploited transposon-mediated random insertion and selection of viable clones to identify sites in the HEV open reading frame 2 (ORF2) protein, corresponding to the viral capsid, allowing for the insertion of reporter sequences in a functional context.</div></div><div><h3>Results</h3><div>Short sequence insertions (5 amino acids) were tolerated at four distinct sites in the C-terminal region of the ORF2 protein, without significantly affecting viral capsid expression and subcellular localization as well as virus production. Full-length HEV genomes harboring larger sequence insertions such as an HA epitope tag, a highly sensitive miniaturized luciferase reporter (HiBiT) or a split GFP at these sites conserved their ability to produce infectious virus, with about a 1-log decrease in viral titers. Findings were confirmed in two different HEV genotype 3 clones. In addition, we demonstrate that HiBiT-tagged HEV, offering rapid and several-log amplitude detection, can be used for the evaluation of antiviral drugs and neutralizing antibodies.</div></div><div><h3>Conclusions</h3><div>We describe a convenient, quantitative and potentially scalable system for the monitoring of HEV infection and replication in tissue culture.</div></div><div><h3>Impact and implications:</h3><div>Hepatitis E virus infection is one of the most frequent causes of acute hepatitis and jaundice worldwide. As treatment options are limited and a vaccine is not universally available, the development of molecular tools to facilitate the identification of new therapeutic strategies is crucial. Based on a screening approach to identify viable insertion sites in the viral genome, we describe a versatile system for preparing recombinant viruses harboring split-reporter tags, <em>i.e.</em> luciferase and GFP. Proof-of-concept experiments revealed that convenient and quantitative monitoring of viral infection and replication is possible with this system, allowing for the evaluation of antiviral drugs and neutralizing antibodies.</div></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":"7 3","pages":"Article 101293"},"PeriodicalIF":9.5,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143182324","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}