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{"title":"Serum matrix metalloproteinase-7 (MMP-7): As good as it gets?","authors":"Mark Davenport","doi":"10.1097/HEP.0000000000000835","DOIUrl":"10.1097/HEP.0000000000000835","url":null,"abstract":"","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":13.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140026933","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":"Combined use of the CLivD score and FIB-4 for prediction of liver-related outcomes in the population.","authors":"Fredrik Åberg, Juho Asteljoki, Ville Männistö, Panu K Luukkonen","doi":"10.1097/HEP.0000000000000707","DOIUrl":"10.1097/HEP.0000000000000707","url":null,"abstract":"<p><strong>Background and aims: </strong>A need exists for effective and practical tools to identify individuals at increased risk of liver-related outcomes (LROs) within the general population.</p><p><strong>Approach and results: </strong>We externally validated the chronic liver disease (CLivD) score for LROs in the UK Biobank cohort. We also investigated the sequential combined use of CLivD and fibrosis-4 (FIB-4) scores. Our analysis included 369,832 adults without baseline liver disease and with available data for CLivD and FIB-4 computation. LROs reflecting compensated or decompensated liver cirrhosis or HCC were ascertained through linkages with electronic health care registries. Discriminatory performance and cumulative incidence were evaluated with competing-risk methodologies. Over a 10-year follow-up, time-dependent AUC values for LRO prediction were 0.80 for CLivD lab (including gamma-glutamyltransferase), 0.72 for CLivD non-lab (excluding laboratory values), and 0.75 for FIB-4. CLivD lab demonstrated AUC values exceeding 0.85 for liver-related death and severe alcohol-associated liver outcomes. The predictive performance of FIB-4 increased with rising CLivD scores; 10-year FIB-4 AUC values ranged from 0.60 within the minimal-risk CLivD subgroup to 0.81 within the high-risk CLivD subgroup. Moreover, in the minimal-risk CLivD subgroup, the cumulative incidence of LRO varied from 0.05% to 0.3% across low-to-high FIB-4 strata. In contrast, within the high-risk CLivD subgroup, the corresponding incidence ranged from 1.7% to 21.1% (up to 33% in individuals with FIB-4 >3.25).</p><p><strong>Conclusions: </strong>The CLivD score is a valid tool for LRO risk assessment and improves the predictive performance of FIB-4. The combined use of CLivD and FIB-4 identified a subgroup where 1 in 3 individuals developed LROs within 10 years.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11191041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138796769","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":"Impending HCC diagnosis in patients with cirrhosis after HCV cure features a natural killer cell signature.","authors":"Sophie Anna Engelskircher, Po-Chun Chen, Benedikt Strunz, Carlos Oltmanns, Tijana Ristic, Solomon Owusu Sekyere, Anke R M Kraft, Markus Cornberg, Thomas Wirth, Bernd Heinrich, Niklas K Björkström, Heiner Wedemeyer, Norman Woller","doi":"10.1097/HEP.0000000000000804","DOIUrl":"10.1097/HEP.0000000000000804","url":null,"abstract":"<p><strong>Background and aims: </strong>The risk of developing HCC in chronically infected patients with AQ2 HCV with liver cirrhosis is significantly elevated. This risk remains high even after a sustained virological response with direct-acting antivirals. To date, disease-associated signatures of NK cells indicating HCC development are unclear.</p><p><strong>Approach and results: </strong>This study investigated NK cell signatures and functions in 8 cohorts covering the time span of HCC development, diagnosis, and onset. In-depth analysis of NK cell profiles from patients with cirrhosis who developed HCC (HCV-HCC) after sustained virological response compared with those who remained tumor-free (HCV-noHCC) revealed increasingly dissimilar NK cell signatures over time. We identified expression patterns with persistently high frequencies of TIM-3 and CD38 on NK cells that were largely absent in healthy controls and were associated with a high probability of HCC development. Functional assays revealed that the NK cells had potent cytotoxic features. In contrast to HCV-HCC, the signature of HCV-noHCC converged with the signature found in healthy controls over time. Regarding tissue distribution, single-cell sequencing showed high frequencies of these cells in liver tissue and the invasive margin but markedly lower frequencies in tumors.</p><p><strong>Conclusions: </strong>We show that HCV-related HCC development has profound effects on the imprint of NK cells. Persistent co-expression of TIM-3hi and CD38 + on NK cells is an early indicator for HCV-related HCC development. We propose that the profiling of NK cells may be a rapid and valuable tool to assess the risk of HCC development in a timely manner in patients with cirrhosis after HCV cure.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11191062/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139929213","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":"Palladium(II)-Catalyzed Nondirected Late-Stage C(sp²)-H Deuteration of Heteroarenes Enabled Through a Multi-Substrate Screening Approach.","authors":"Jyotirmoy Dey, Simon Kaltenberger, Manuel van Gemmeren","doi":"10.1002/anie.202404421","DOIUrl":"10.1002/anie.202404421","url":null,"abstract":"<p><p>The importance of deuterium labelling in a variety of applications, ranging from mechanistic studies to drug-discovery, has spurred immense interest in the development of new methods for its efficient incorporation in organic, and especially in bioactive molecules. The five-membered heteroarenes at the center of this work are ubiquitous motifs in bioactive molecules and efficient methods for the deuterium labelling of these compounds are therefore highly desirable. However, the profound differences in chemical properties encountered between different heteroarenes hamper the development of a single set of broadly applicable reaction conditions, often necessitating a separate optimization campaign for a given type of heteroarene. In this study we describe the use of a multi-substrate screening approach to identify optimal reaction conditions for different classes of heteroarenes from a minimal number of screening reactions. Using this approach, four sets of complementary reaction conditions derived from our dual ligand-based palladium catalysts for nondirected C(sp²)-H activation were identified, that together enable the deuteration of structurally diverse heteroarenes, including bioactive molecules.</p>","PeriodicalId":125,"journal":{"name":"Angewandte Chemie International Edition","volume":null,"pages":null},"PeriodicalIF":16.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140173752","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Doory Kim.","authors":"","doi":"10.1002/anie.202408955","DOIUrl":"10.1002/anie.202408955","url":null,"abstract":"<p><p>\"The most exciting thing about my research is making something invisibly small visible, which makes me feel like I can make impossible things possible… My secret/not-so-secret passion is watching short-track speed skating…\" Find out more about Doory Kim in her Introducing… Profile.</p>","PeriodicalId":125,"journal":{"name":"Angewandte Chemie International Edition","volume":null,"pages":null},"PeriodicalIF":16.1,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Counter-gradient variation in gene expression between fish populations facilitates colonization of low-dissolved oxygen environments.","authors":"Janay A Fox, David A G A Hunt, Andrew P Hendry, Lauren J Chapman, Rowan D H Barrett","doi":"10.1111/mec.17419","DOIUrl":"10.1111/mec.17419","url":null,"abstract":"<p><p>The role of phenotypic plasticity during colonization remains unclear due to the shifting importance of plasticity across timescales. In the early stages of colonization, plasticity can facilitate persistence in a novel environment; but over evolutionary time, processes such as genetic assimilation may reduce variation in plastic traits such that species with a longer evolutionary history in an environment can show lower levels of plasticity than recent invaders. Therefore, comparing species in the early stages of colonization to long-established species provides a powerful approach for uncovering the role of phenotypic plasticity during different stages of colonization. We compared gene expression between low-dissolved oxygen (DO) and high-DO populations of two cyprinid fish: Enteromius apleurogramma, a species that has undergone a recent range expansion, and E. neumayeri, a long-established native species in the same region. We sampled tissue either immediately after capture from the field or after a 2-week acclimation under high-DO conditions, allowing us to test for both evolved and plastic differences in low-DO vs high-DO populations of each species. We found that most genes showing candidate-evolved differences in gene expression did not overlap with those showing plastic differences in gene expression. However, in the genes that did overlap, there was counter-gradient variation such that plastic and evolved gene expression responses were in opposite directions in both species. Additionally, E. apleurogramma had higher levels of plasticity and evolved divergence in gene expression between field populations. We suggest that the higher level of plasticity and counter-gradient variation may have allowed rapid genetic adaptation in E. apleurogramma and facilitated colonization. This study shows how counter-gradient variation may impact the colonization of divergent oxygen environments.</p>","PeriodicalId":210,"journal":{"name":"Molecular Ecology","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Retreatment of direct-acting antiviral failures with the current first-line regimens for patients with chronic hepatitis C.","authors":"Eiichi Ogawa","doi":"10.1111/apt.18041","DOIUrl":"10.1111/apt.18041","url":null,"abstract":"","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141329810","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":"Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis.","authors":"Andreas E Kremer, Marlyn J Mayo, Gideon M Hirschfield, Cynthia Levy, Christopher L Bowlus, David E Jones, Jeff D Johnson, Charles A McWherter, Yun-Jung Choi","doi":"10.1097/HEP.0000000000000728","DOIUrl":"10.1097/HEP.0000000000000728","url":null,"abstract":"<p><strong>Background and aims: </strong>Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar's antipruritic effects and IL-31 and bile acid levels in patients with PBC.</p><p><strong>Approach and results: </strong>IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS ( r = 0.54, p < 0.0001), and total ( r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p = 0.0003) and 10 mg (-52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids ( r = 0.63, p < 0.0001) in the seladelpar 10 mg group.</p><p><strong>Conclusions: </strong>Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar's antipruritic effects.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11191048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138796783","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":"Computational drug prediction in hepatoblastoma by integrating pan-cancer transcriptomics with pharmacological response.","authors":"Mario Failli, Salih Demir, Álvaro Del Río-Álvarez, Juan Carrillo-Reixach, Laura Royo, Montserrat Domingo-Sàbat, Margaret Childs, Rudolf Maibach, Rita Alaggio, Piotr Czauderna, Bruce Morland, Sophie Branchereau, Stefano Cairo, Roland Kappler, Carolina Armengol, Diego di Bernardo","doi":"10.1097/HEP.0000000000000601","DOIUrl":"10.1097/HEP.0000000000000601","url":null,"abstract":"<p><strong>Background and aims: </strong>Hepatoblastoma (HB) is the predominant form of pediatric liver cancer, though it remains exceptionally rare. While treatment outcomes for children with HB have improved, patients with advanced tumors face limited therapeutic choices. Additionally, survivors often suffer from long-term adverse effects due to treatment, including ototoxicity, cardiotoxicity, delayed growth, and secondary tumors. Consequently, there is a pressing need to identify new and effective therapeutic strategies for patients with HB. Computational methods to predict drug sensitivity from a tumor's transcriptome have been successfully applied for some common adult malignancies, but specific efforts in pediatric cancers are lacking because of the paucity of data.</p><p><strong>Approach and results: </strong>In this study, we used DrugSense to assess drug efficacy in patients with HB, particularly those with the aggressive C2 subtype associated with poor clinical outcomes. Our method relied on publicly available collections of pan-cancer transcriptional profiles and drug responses across 36 tumor types and 495 compounds. The drugs predicted to be most effective were experimentally validated using patient-derived xenograft models of HB grown in vitro and in vivo. We thus identified 2 cyclin-dependent kinase 9 inhibitors, alvocidib and dinaciclib as potent HB growth inhibitors for the high-risk C2 molecular subtype. We also found that in a cohort of 46 patients with HB, high cyclin-dependent kinase 9 tumor expression was significantly associated with poor prognosis.</p><p><strong>Conclusions: </strong>Our work proves the usefulness of computational methods trained on pan-cancer data sets to reposition drugs in rare pediatric cancers such as HB, and to help clinicians in choosing the best treatment options for their patients.</p>","PeriodicalId":177,"journal":{"name":"Hepatology","volume":null,"pages":null},"PeriodicalIF":12.9,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11185924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41110582","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":"Liver function and portal-systemic shunting quantified by the oral cholate challenge test and risk for large oesophageal varices.","authors":"Tarek Hassanein, Andrew P Keaveny, Parvez Mantry, Alastair D Smith, Michael P McRae, John Kittelson, Steve Helmke, Gregory T Everson","doi":"10.1111/apt.18054","DOIUrl":"10.1111/apt.18054","url":null,"abstract":"<p><strong>Background: </strong>The quantitative HepQuant SHUNT test of liver function and physiology generates a disease severity index (DSI) that correlates with risk for clinical complications, such as large oesophageal varices (LEVs). A derivative test, HepQuant DuO, generates an equivalent DSI and simplifies testing by requiring only oral administration of the test solution and two blood samples at 20 and 60 min.</p><p><strong>Aims: </strong>Since the DSIs measured from DuO and SHUNT are equivalent, we compared the diagnostic performance for large oesophageal varices (LEVs) between the DSIs measured from DuO and SHUNT tests.</p><p><strong>Methods: </strong>This study combined the data from two prospectively conducted US studies: HALT-C and SHUNT-V. A total of 455 subjects underwent both the SHUNT test and esophagogastroduodenoscopy (EGD).</p><p><strong>Results: </strong>DSI scores correlated with the probability of LEVs (p < 0.001) and demonstrated a stepwise increase from healthy lean controls without liver disease to subjects with chronic liver disease and no, small or large varices. Furthermore, a cutoff of DSI ≤ 18.3 from DuO had a sensitivity of 0.98 (missing only one case) and, if applied to the endoscopy (EGD) decision, would have prevented 188 EGDs (41.3%). The AUROC for DSI from DuO did not differ from that of the reference SHUNT test method (0.82 versus 0.81, p = 0.3500).</p><p><strong>Conclusions: </strong>DSI from HepQuant DuO links liver function and physiology to the risk of LEVs across a wide spectrum of patient characteristics, disease aetiologies and liver disease severity. DuO is minimally invasive, easy to administer, quantitative and may aid the decision to avoid or perform EGD for LEVs.</p>","PeriodicalId":121,"journal":{"name":"Alimentary Pharmacology & Therapeutics","volume":null,"pages":null},"PeriodicalIF":6.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080086","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}