Hepatology Communications最新文献

{"title":"Neutrophil extracellular traps induce intrahepatic thrombotic tendency and liver damage in cholestatic liver disease.","authors":"Muxin Yu, Xiaowen Li, Long Xu, Chuwei Zheng, Weiwei Pan, Hui Chen, Xiaoyu Liu, Xianshan Zhang, Jinming Zhang","doi":"10.1097/HC9.0000000000000513","DOIUrl":"10.1097/HC9.0000000000000513","url":null,"abstract":"<p><strong>Background: </strong>Cholestatic liver diseases induce local and systemic hypercoagulation, with neutrophil extracellular traps (NETs) serving as major drivers. These NETs have been linked to decreased liver function in patients with obstructive jaundice. However, the impact of NETs on liver hypercoagulation in cholestatic liver disease remains unknown.</p><p><strong>Methods: </strong>We utilized bile duct ligation to create experimental mice and analyzed NETs formation in the liver. Fibrin deposition, tissue factor expression, and inflammation in the liver were visualized through western blot and immunohistochemical techniques. LSECs were incubated with isolated NETs, and we detected endothelial procoagulant activity using coagulation protein production assays and measuring endothelial permeability. In both in vivo and in vitro settings, DNase I was applied to clarify the effect of NETs on intrahepatic hypercoagulability, hepatotoxicity, LSEC, and macrophage activation or injury.</p><p><strong>Results: </strong>Bile duct ligation mice exhibited significantly increased levels of NETs in liver tissue, accompanied by neutrophil infiltration, tissue necrosis, fibrin deposition, and thrombophilia compared to sham mice. Notably, NETs resulted in phosphatidylserine and tissue factor exposure on LSEC, enhancing coagulation Factor Xa and thrombin production. The enhanced procoagulant activity could be reversed by degrading NETs with DNase I. Additionally, NETs-induced permeability changes in LSECs, characterized by increased VE-cadherin expression and F-actin retraction, which could be rescued by DNase I. Meanwhile, NET formation is associated with KC activation and the formation of inflammatory factors.</p><p><strong>Conclusions: </strong>NETs promote intrahepatic activation of coagulation and inflammation, leading to liver tissue injury. Strategies targeting NET formation may offer a potential therapeutic approach for treating cholestatic liver disease.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889003","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":"ICIs in hepatocellular carcinoma: A comprehensive analysis of path forward for multimodal treatment strategies.","authors":"Shixuan Peng, Qisheng Chen, Yongjun Wu","doi":"10.1097/HC9.0000000000000509","DOIUrl":"10.1097/HC9.0000000000000509","url":null,"abstract":"","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889028","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":"Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy.","authors":"Paul R Burchard, Luis I Ruffolo, Nicholas A Ullman, Benjamin S Dale, Yatee A Dave, Bailey K Hilty, Jian Ye, Mary Georger, Rachel Jewell, Christine Miller, Luis De Las Casas, Wolfgang Jarolimek, Lara Perryman, Matthew M Byrne, Anthony Loria, Chelsea Marin, Mariana Chávez Villa, Jen Jen Yeh, Brian A Belt, David C Linehan, Roberto Hernandez-Alejandro","doi":"10.1097/HC9.0000000000000502","DOIUrl":"10.1097/HC9.0000000000000502","url":null,"abstract":"<p><strong>Background: </strong>Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA.</p><p><strong>Methods: </strong>Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays.</p><p><strong>Results: </strong>All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy.</p><p><strong>Conclusions: </strong>CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889004","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":"Transcriptomic profiling of intermediate cell carcinoma of the liver.","authors":"Byungchan Jang, So Mee Kwon, Jang Hyun Kim, Jung Mo Kim, Taek Chung, Jeong Eun Yoo, Haeryoung Kim, Julien Calderaro, Hyun Goo Woo, Young Nyun Park","doi":"10.1097/HC9.0000000000000505","DOIUrl":"10.1097/HC9.0000000000000505","url":null,"abstract":"<p><strong>Background: </strong>Intermediate cell carcinoma (Int-CA) is a rare and enigmatic primary liver cancer characterized by uniform tumor cells exhibiting mixed features of both HCC and intrahepatic cholangiocarcinoma. Despite the unique pathological features of int-CA, its molecular characteristics remain unclear yet.</p><p><strong>Methods: </strong>RNA sequencing and whole genome sequencing profiling were performed on int-CA tumors and compared with those of HCC and intrahepatic cholangiocarcinoma.</p><p><strong>Results: </strong>Int-CAs unveiled a distinct and intermediate transcriptomic feature that is strikingly different from both HCC and intrahepatic cholangiocarcinoma. The marked abundance of splicing events leading to intron retention emerged as a signature feature of int-CA, along with a prominent expression of Notch signaling. Further exploration revealed that METTL16 was suppressed within int-CA, showing a DNA copy number-dependent transcriptional deregulation. Notably, experimental investigations confirmed that METTL16 suppression facilitated invasive tumor characteristics through the activation of the Notch signaling cascade.</p><p><strong>Conclusions: </strong>Our results provide a molecular landscape of int-CA featured by METTL16 suppression and frequent intron retention events, which may play pivotal roles in the acquisition of the aggressive phenotype of Int-CA.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889005","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":"Immuno-targeting the ectopic phosphorylation sites of PDGFRA generated by MAN2A1-FER fusion in HCC.","authors":"Muhamuda Kader, Yan-Ping Yu, Silvia Liu, Jian-Hua Luo","doi":"10.1097/HC9.0000000000000511","DOIUrl":"10.1097/HC9.0000000000000511","url":null,"abstract":"<p><strong>Background: </strong>HCC is one of the most lethal cancers for humans. Mannosidase alpha class 2A member 1 (MAN2A1)-FER is one of the most frequent oncogenic fusion genes in HCC. In this report, we showed that MAN2A1-FER ectopically phosphorylated the extracellular domains of PDGFRA, MET, AXL, and N-cadherin. The ectopic phosphorylation of these transmembrane proteins led to the activation of their kinase activities and initiated the activation cascades of their downstream signaling molecules.</p><p><strong>Methods: </strong>A panel of mouse monoclonal antibodies was developed to recognize the ectopic phosphorylation sites of PDGFRA.</p><p><strong>Results and conclusions: </strong>The analyses showed that these antibodies bound to the specific phosphotyrosine epitopes in the extracellular domain of PDGFRA with high affinity and specificity. The treatment of MAN2A1-FER-positive cancer HUH7 with one of the antibodies called 2-3B-G8 led to the deactivation of cell growth signaling pathways and cell growth arrest while having minimal impact on HUH7ko cells where MAN2A1-FER expression was disrupted. The treatment of 2-3B-G8 antibody also led to a large number of cell deaths of MAN2A1-FER-positive cancer cells such as HUH7, HEPG2, SNU449, etc., while the same treatment had no impact on HUH7ko cells. When severe combined immunodeficiency mice xenografted with HEPG2 or HUH7 were treated with monomethyl auristatin E-conjugated 2-3B-G8 antibody, it slowed the progression of tumor growth, eliminated the metastasis, and reduced the mortality, in comparison with the controls. Targeting the cancer-specific ectopic phosphorylation sites of PDGFRA induced by MAN2A1-FER may hold promise as an effective treatment for liver cancer.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855350","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}

{"title":"Digital therapeutics lead to clinically significant body weight loss in patients with metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis.","authors":"Somaya Albhaisi, Justin Tondt, John Cyrus, Vernon M Chinchilli, David E Conroy, Jonathan G Stine","doi":"10.1097/HC9.0000000000000499","DOIUrl":"10.1097/HC9.0000000000000499","url":null,"abstract":"<p><strong>Background: </strong>Most patients with metabolic dysfunction-associated steatotic liver disease are unable to achieve clinically significant body weight loss with traditional in-person approaches. Digital therapeutic (DTx)-delivered interventions offer promise to remove barriers to weight loss success inherent to traditional resource-heavy in-person programs and at a population level, but their efficacy remains relatively unknown.</p><p><strong>Methods: </strong>Published studies were identified through May 2023 by searching the following electronic databases: PubMed and Embase (Ovid). DTx intervention was compared to standard of care. The primary outcome was a change in body weight. Secondary outcomes included clinically significant body weight loss (≥5%) and change in liver enzymes.</p><p><strong>Results: </strong>Eight studies comprising 1001 patients met inclusion criteria (mean age: 47 y; body mass index: 33.2 kg/m2). The overall rate of clinically significant body weight loss was 33%, with DTx lifestyle interventions ranging from 4 to 24 months in length. DTx lifestyle intervention achieved statistically significant body weight loss (absolute change -3.4 kg, 95% CI: -4.8 to -2.0 kg, p < 0.01, relative change -3.9%, 95% CI: -6.6 to -1.3, p < 0.01) as well as clinically significant body weight loss of ≥5% (risk ratio: 3.0, 95% CI: 1.7-5.5, p < 0.01) compared to standard of care. This was seen alongside improvement in liver enzymes.</p><p><strong>Conclusions: </strong>DTx-delivered lifestyle intervention programs lead to greater amounts of body weight loss than traditional in-person lifestyle counseling. These results further support the role of DTx in delivering lifestyle intervention programs to patients with metabolic dysfunction-associated steatotic liver disease and suggest that this scalable intervention offers promise to benefit the billions of patients worldwide with this condition.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855349","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}

{"title":"Long-term HBV infection of engineered cultures of induced pluripotent stem cell-derived hepatocytes.","authors":"Yang Yuan, Vedant V Bodke, Christine Lin, Shang Gao, Jalees Rehman, Jisu Li, Salman R Khetani","doi":"10.1097/HC9.0000000000000506","DOIUrl":"10.1097/HC9.0000000000000506","url":null,"abstract":"<p><strong>Background: </strong>HBV infects ~257 million people and can cause hepatocellular carcinoma. Since current drugs are not curative, novel therapies are needed. HBV infects chimpanzee and human livers. However, chimpanzee studies are severely restricted and cost-prohibitive, while transgenic/chimeric mouse models that circumvent the species barrier lack natural HBV infection and disease progression. Thus, in vitro human models of HBV infection are useful in addressing the above limitations. Induced pluripotent stem cell-derived hepatocyte-like cells mitigate the supply limitations of primary human hepatocytes and the abnormal proliferation/functions of hepatoma cell lines. However, variable infection across donors, deficient drug metabolism capacity, and/or low throughput limit iHep utility for drug development.</p><p><strong>Methods: </strong>We developed an optimal pipeline using combinations of small molecules, Janus kinase inhibitor, and 3',5'-cAMP to infect iHep-containing micropatterned co-cultures (iMPCC) with stromal fibroblasts within 96-well plates with serum-derived HBV and cell culture-derived HBV (cHBV). Polyethylene glycol was necessary for cell-derived HBV but not for serum-derived HBV infection.</p><p><strong>Results: </strong>Unlike iHep monocultures, iMPCCs created from 3 iHep donors could sustain HBV infection for 2+ weeks. Infected iMPCCs maintained high levels of differentiated functions, including drug metabolism capacity. HBV antigen secretion and gene expression patterns in infected iMPCCs in pathways such as fatty acid metabolism and cholesterol biosynthesis were comparable to primary human hepatocyte-MPCCs. Furthermore, iMPCCs could help elucidate the effects of interferons and direct-acting antiviral drugs on the HBV lifecycle and any hepatotoxicity; iMPCC response to compounds was similar to primary human hepatocyte-MPCCs.</p><p><strong>Conclusions: </strong>The iMPCC platform can enable the development of safe and efficacious drugs against HBV and ultimately help elucidate genotype-phenotype relationships in HBV pathogenesis.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855351","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}

{"title":"B cells expressing mutated IGHV1-69-encoded antigen receptors related to virus neutralization show lymphoma-like transcriptomes in patients with chronic HCV infection.","authors":"Christoph Schultheiß, Edith Willscher, Lisa Paschold, Christin Ackermann, Moritz Escher, Rebekka Scholz, Maximilian Knapp, Jana Lützkendorf, Lutz P Müller, Julian Schulze Zur Wiesch, Mascha Binder","doi":"10.1097/HC9.0000000000000503","DOIUrl":"10.1097/HC9.0000000000000503","url":null,"abstract":"<p><strong>Background: </strong>Chronic HCV infection leads to a complex interplay with adaptive immune cells that may result in B cell dyscrasias like cryoglobulinemia or lymphoma. While direct-acting antiviral therapy has decreased the incidence of severe liver damage, its effect on extrahepatic HCV manifestations such as B cell dyscrasias is still unclear.</p><p><strong>Methods: </strong>We sequenced B cell receptor (BCR) repertoires in patients with chronic HCV mono-infection and patients with HCV with a sustained virological response (SVR) after direct-acting antiviral therapy. This data set was mined for highly neutralizing HCV antibodies and compared to a diffuse large B cell lymphoma data set. The TKO model was used to test the signaling strength of selected B-BCRs in vitro. Single-cell RNA sequencing of chronic HCV and HCV SVR samples was performed to analyze the transcriptome of B cells with HCV-neutralizing antigen receptors.</p><p><strong>Results: </strong>We identified a B cell fingerprint with high richness and somatic hypermutation in patients with chronic HCV and SVR. Convergence to specific immunoglobulin genes produced high-connectivity complementarity-determining region 3 networks. In addition, we observed that IGHV1-69 CDR1 and FR3 mutations characterizing highly neutralizing HCV antibodies corresponded to recurrent point mutations found in clonotypic BCRs of high-grade lymphomas. These BCRs did not show autonomous signaling but a lower activation threshold in an in vitro cell model for the assessment of BCR signaling strength. Single-cell RNA sequencing revealed that B cells carrying these point mutations showed a persisting oncogenic transcriptome signature with dysregulation in signaling nodes such as CARD11, MALT1, RelB, MAPK, and NFAT.</p><p><strong>Conclusions: </strong>We provide evidence that lymphoma-like cells derive from the anti-HCV immune response. In many patients, these cells persist for years after SVR and can be interpreted as a mechanistic basis for HCV-related B cell dyscrasias and increased lymphoma risk even beyond viral elimination.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855348","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}

{"title":"Validation of MELD3.0 in 2 centers from different continents.","authors":"Marta Tejedor, José María Bellón, Margarita Fernández de la Varga, Peregrina Peralta, Eva Montalvá, Nazia Selzner, Marina Berenguer","doi":"10.1097/HC9.0000000000000504","DOIUrl":"10.1097/HC9.0000000000000504","url":null,"abstract":"<p><strong>Background: </strong>MELD3.0 has been proposed to stratify patients on the liver transplant waiting list (WL) to reduce the historical disadvantage of women in accessing liver transplant. Our aim was to validate MELD3.0 in 2 unique populations.</p><p><strong>Methods: </strong>This study is a 2-center retrospective cohort study from Toronto, Canada, and Valencia, Spain, of all adults added to the liver transplant WL between 2015 and 2019. Listing indications whose short-term survival outcome is not adequately captured by the MELD score were excluded. All patients analyzed had a minimum follow-up of 3 months after inclusion in the WL.</p><p><strong>Results: </strong>Six hundred nineteen patients were included; 61% were male, with a mean age of 56 years. Mean MELD at inclusion was 18.00 ± 6.88, Model for End-Stage Liver Disease Sodium (MELDNa) 19.78 ± 7.00, and MELD3.0 20.25 ± 7.22. AUC to predict 90-day mortality on the WL was 0.879 (95% CI: 0.820, 0.939) for MELD, 0.921 (95% CI: 0.876, 0.967) for MELDNa, and 0.930 (95% CI: 0.888, 0.973) for MELD3.0. MELDNa and MELD3.0 were better predictors than MELD (p = 0.055 and p = 0.024, respectively), but MELD3.0 was not statistically superior to MELDNa (p = 0.144). The same was true when stratified by sex, although the difference between MELD3.0 and MELD was only significant for women (p = 0.032), while no statistical significance was found in either sex when compared with MELDNa. In women, AUC was 0.835 (95% CI: 0.744, 0.926) for MELD, 0.873 (95% CI: 0.785, 0.961) for MELDNa, and 0.886 (95% CI: 0.803, 0.970) for MELD3.0; differences for the comparison between AUC in women versus men for all 3 scores were nonsignificant. Compared to MELD, MELD3.0 was able to reclassify 146 patients (24%), the majority of whom belonged to the MELD 10-19 interval. Compared to MELDNa, it reclassified 68 patients (11%), most of them in the MELDNa 20-29 category.</p><p><strong>Conclusions: </strong>MELD3.0 has been validated in centers with significant heterogeneity and offers the highest mortality prediction for women on the WL without disadvantaging men. However, in these cohorts, it was not superior to MELDNa.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855374","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}

{"title":"A plasma peptidomic signature reveals extracellular matrix remodeling and predicts prognosis in alcohol-associated hepatitis.","authors":"Khaled Sayed, Christine E Dolin, Daniel W Wilkey, Jiang Li, Toshifumi Sato, Juliane I Beier, Josepmaria Argemi, Vatsalya Vatsalya, Craig J McClain, Ramon Bataller, Abdus S Wahed, Michael L Merchant, Panayiotis V Benos, Gavin E Arteel","doi":"10.1097/HC9.0000000000000510","DOIUrl":"10.1097/HC9.0000000000000510","url":null,"abstract":"<p><strong>Background: </strong>Alcohol-associated hepatitis (AH) is plagued with high mortality and difficulty in identifying at-risk patients. The extracellular matrix undergoes significant remodeling during inflammatory liver injury and could potentially be used for mortality prediction.</p><p><strong>Methods: </strong>EDTA plasma samples were collected from patients with AH (n = 62); Model for End-Stage Liver Disease score defined AH severity as moderate (12-20; n = 28) and severe (>20; n = 34). The peptidome data were collected by high resolution, high mass accuracy UPLC-MS. Univariate and multivariate analyses identified differentially abundant peptides, which were used for Gene Ontology, parent protein matrisomal composition, and protease involvement. Machine-learning methods were used to develop mortality predictors.</p><p><strong>Results: </strong>Analysis of plasma peptides from patients with AH and healthy controls identified over 1600 significant peptide features corresponding to 130 proteins. These were enriched for extracellular matrix fragments in AH samples, likely related to the turnover of hepatic-derived proteins. Analysis of moderate versus severe AH peptidomes was dominated by changes in peptides from collagen 1A1 and fibrinogen A proteins. The dominant proteases for the AH peptidome spectrum appear to be CAPN1 and MMP12. Causal graphical modeling identified 3 peptides directly linked to 90-day mortality in >90% of the learned graphs. These peptides improved the accuracy of mortality prediction over the Model for End-Stage Liver Disease score and were used to create a clinically applicable mortality prediction assay.</p><p><strong>Conclusions: </strong>A signature based on plasma peptidome is a novel, noninvasive method for prognosis stratification in patients with AH. Our results could also lead to new mechanistic and/or surrogate biomarkers to identify new AH mechanisms.</p>","PeriodicalId":12978,"journal":{"name":"Hepatology Communications","volume":"8 8","pages":""},"PeriodicalIF":5.6,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855347","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}