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Corrigendum to ‘Predicting post-resection recurrence by integrating imaging-based surrogates of distinct vascular patterns of hepatocellular carcinoma’ (JHEP Reports 5 [2023] 100806) 通过整合肝细胞癌不同血管模式的成像替代物预测切除术后复发》(JHEP Reports 5 [2023] 100806)的更正
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.jhepr.2024.101059
Xiang-Pan Meng , Tian-Yu Tang , Yongping Zhou , Cong Xia , Tianyi Xia , Yibing Shi , Xueying Long , Yun Liang , Wenbo Xiao , Yuan-Cheng Wang , Xiangming Fang , Shenghong Ju
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引用次数: 0
Oxytocin alleviates liver fibrosis via hepatic macrophages 催产素通过肝巨噬细胞缓解肝纤维化
IF 8.3 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.jhepr.2024.101032
Xiangyu Zhai , Hao Zhang , Zhijia Xia , Mingkun Liu , Gang Du , Zhengchen Jiang , Huaxin Zhou , Dan Luo , Dandan Dou , Jingxin Li , Wei Wang , Xiaosong Li , Bin Jin

Background & Aims

Previous studies demonstrated oxytocin treatment effectiveness in reducing mortality and reversing liver fibrosis in mice. However, the underlying mechanism remains obscure, given the absence of oxytocin receptor expression in hepatic stellate cells, the primary liver fibrosis effector cells.

Methods

A comprehensive map of cell populations in fibrotic liver was generated using single-cell sequencing. The map enabled our study of the target cells of oxytocin action in the liver in more dimensions. Furthermore, we elucidated the mechanism of the oxytocin signaling system in hepatic macrophages using oxytocin receptor-specific knockout mice and liver fibrosis animal models.

Results

The carbon tetrachloride-induced hepatic fibrosis and bile duct ligation hepatic fibrosis mouse models demonstrated that oxytocin reversed hepatic fibrosis in mice. The mapped liver cell populations demonstrated that oxytocin promoted the phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. The phenotypic control of oxytocin signaling system activation on this phenotypic switch was validated using myeloid-specific oxytocin receptor knockout mice. Subsequent studies demonstrated that the calcium inward flow induced by oxytocin receptor activation activated the key orphan nuclear receptor NR4A1, which controls macrophage phenotypic switching. Specifically, calcium ions activated CREB, a key target regulator of NR4A1 expression.

Conclusions

The findings established hepatic macrophages as a hub responsible for the oxytocin-mediated alleviation of liver fibrosis. This study revealed a novel pathway where oxytocin regulates macrophage phenotype.

Impact and implications

Previous studies revealed for the first time the expression of oxytocin receptors in the liver. The present study shows that oxytocin reverses hepatic fibrosis and that hepatic macrophages are the central hub of oxytocin-mediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6high to Ly6Clow expression. The present study reveals a novel pathway by which oxytocin regulates macrophage phenotype. In addition, the potential applications of oxytocin and its analogues, as traditional drugs for clinical application, in the treatment of liver fibrosis deserve to be further explored.

背景& 目的先前的研究表明催产素治疗能有效降低小鼠死亡率并逆转肝纤维化。然而,由于肝星状细胞--主要的肝纤维化效应细胞--缺乏催产素受体表达,其基本机制仍不清楚。方法利用单细胞测序生成了纤维化肝脏中细胞群的综合图谱。该图谱使我们能够从更多维度研究催产素在肝脏中的作用靶细胞。此外,我们还利用催产素受体特异性敲除小鼠和肝纤维化动物模型,阐明了催产素信号系统在肝巨噬细胞中的作用机制。肝细胞群图谱显示,催产素可促进髓源性巨噬细胞的表型从 Ly6high 向 Ly6Clow 转换。利用髓系特异性催产素受体基因敲除小鼠验证了催产素信号系统激活对这种表型转换的表型控制。随后的研究表明,催产素受体激活诱导的钙离子内流激活了关键的孤儿核受体NR4A1,而NR4A1控制着巨噬细胞的表型转换。结论研究结果表明,肝巨噬细胞是催产素介导的肝纤维化缓解的枢纽。本研究揭示了催产素调节巨噬细胞表型的新途径。影响和意义之前的研究首次揭示了催产素受体在肝脏中的表达。本研究表明,催产素能逆转肝纤维化,而肝巨噬细胞是催产素介导的缓解肝纤维化的中心枢纽,它能促进肝巨噬细胞的表型转换,从 Ly6high 表达过渡到 Ly6Clow 表达。本研究揭示了催产素调节巨噬细胞表型的新途径。此外,催产素及其类似物作为临床应用的传统药物,在治疗肝纤维化方面的潜在应用值得进一步探讨。
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引用次数: 0
Glycogen synthase kinase 3 activity enhances liver inflammation in MASH 糖原合成酶激酶 3 的活性可增强 MASH 的肝脏炎症反应
IF 8.3 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.jhepr.2024.101073
Mireille Khoury , Qianqian Guo , Kunimaro Furuta , Cristina Correia , Chady Meroueh , Hyun Se Kim Lee , Khaled Warasnhe , Lucía Valenzuela-Pérez , Andrew P. Mazar , Iljung Kim , Yung-Kyun Noh , Heather Holmes , Michael F. Romero , Caroline R. Sussman , Kevin D. Pavelko , Shahidul Islam , Adebowale O. Bamidele , Petra Hirsova , Hu Li , Samar H. Ibrahim

Background & Aims

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by excessive circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to liver sinusoidal endothelial cells (LSECs) and transendothelial migration (TEM) are crucial in the inflammatory process. Under lipotoxic stress, LSECs develop a proinflammatory phenotype known as endotheliopathy. However, mediators of endotheliopathy remain unclear.

Methods

Primary mouse LSECs isolated from C57BL/6J mice fed chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH resulting from a choline-deficient high-fat diet (CDHFD) or FFC diet were also treated with two structurally distinct GSK3 inhibitors (LY2090314 and elraglusib [9-ING-41]).

Results

Integrated pathway analysis of the mouse LSEC proteome and transcriptome indicated that leukocyte TEM and focal adhesion were the major pathways altered in MASH. Kinome profiling of the LSEC phosphoproteome identified glycogen synthase kinase (GSK)-3β as the major kinase hub in MASH. GSK3β-activating phosphorylation was increased in primary human LSECs treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependent mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through the LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC- and CDHFD-fed mice, respectively. Immunophenotyping using cytometry by mass cytometry by time of flight of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib showed reduced infiltration of proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells.

Conclusion

GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and could serve as a potential therapeutic strategy for treating human MASH.

Impact and Implications

LSECs under lipotoxic stress in MASH develop a proinflammatory phenotype known as endotheliopathy, with obscure mediators and functional outcomes. The current study identified GSK3 as the major driver of LSEC endotheliopathy, examined its pathogenic role in myeloid cell-associated liver inflammation, and defined the therapeutic efficacy of pharmacological GSK3 inhibitors in murine MASH. This study provides preclinical data for the future investigation of GSK3 pharmacological inhibitors in human MASH. The results of this study are important to hepatologists, vascular biologists, and investigators studying the mechanisms of inflammatory liver dis

背景& 目的代谢功能障碍相关性脂肪性肝炎(MASH)的特点是循环中有毒脂质过多、肝脏脂肪变性和肝脏炎症。单核细胞粘附到肝窦状内皮细胞(LSECs)和跨内皮迁移(TEM)在炎症过程中至关重要。在脂毒性压力下,肝窦内皮细胞会形成一种促炎症表型,即内皮病变。方法对从喂食饲料或富含脂肪、果糖和胆固醇(FFC)的 MASH 诱导饮食的 C57BL/6J 小鼠体内分离出的原代小鼠 LSECs 进行多组学分析。结果小鼠LSEC蛋白质组和转录组的整合通路分析表明,白细胞TEM和病灶粘附是MASH改变的主要通路。LSEC磷酸蛋白组的激酶组分析确定糖原合酶激酶(GSK)-3β是MASH的主要激酶枢纽。在使用有毒脂质棕榈酸酯处理的原代人LSEC和人MASH中,GSK3β激活磷酸化增加。棕榈酸酯通过 GSK3 依赖性机制上调了 C-X-C motif 趋化因子配体 2、细胞内粘附分子 1 和磷酸化焦点粘附激酶的表达。同样,在脂毒性胁迫下,GSK3抑制剂降低了原代人中性粒细胞和THP-1单核细胞通过LSEC单层的粘附和跨内皮迁移能力。GSK3抑制剂LY2090314和elraglusib可分别改善FFC和CDHFD喂养小鼠的肝脏炎症、损伤和纤维化。使用埃拉格鲁西布治疗的 CDHFD 喂养小鼠肝内白细胞飞行时间质谱细胞计数法进行的免疫分型显示,促炎性单核细胞衍生巨噬细胞和单核细胞衍生树突状细胞的浸润减少。影响和意义LSECs 在 MASH 脂肪毒性应激下会形成一种促炎症表型,即内皮病变,其介质和功能结果不明显。目前的研究发现 GSK3 是 LSEC 内皮细胞病变的主要驱动因素,研究了 GSK3 在髓细胞相关肝脏炎症中的致病作用,并确定了 GSK3 药理抑制剂在小鼠 MASH 中的疗效。这项研究为今后研究 GSK3 药理抑制剂在人类 MASH 中的应用提供了临床前数据。这项研究的结果对于肝病学家、血管生物学家、研究炎症性肝病和MASH机制的研究人员以及对药物开发感兴趣的人来说非常重要。
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引用次数: 0
Erratum Regarding Previously Published Articles 关于以前发表的文章的勘误
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.jhepr.2024.101097
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引用次数: 0
Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma 全代谢组关联发现胆管癌患者血清中改变的代谢物和代谢途径
IF 8.3 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/j.jhepr.2024.101068
Linsey E. Jackson , Jennifer L. Tomlinson , Roberto Alva-Ruiz , Lindsey A. Gregory , Seul Kee Byeon , Amro M. Abdelrahman , Dong-Gi Mun , Caroline W. Grant , Zachary C. Fogarty , Chen Wang , Lewis R. Roberts , Rondell P. Graham , Mitesh J. Borad , Sumera I. Ilyas , Gregory J. Gores , Akhilesh Pandey , Arjun P. Athreya , Rory L. Smoot

Background & Aims

Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA.

Methods

Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case–control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels.

Results

Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA.

Conclusions

The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis.

Impact and implications

Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

背景& 目的代谢组学和脂质组学分析为深入了解新生物学提供了机会。胆管癌(CCA)仍然是一种致死率很高的癌症,对全身、靶向和免疫治疗方法的反应有限。本研究利用全球代谢组学和脂质组学平台,旨在发现和描述CCA患者的代谢组变异和相关通路失调。方法利用生物样本收集(包括消化系统疾病患者和正常对照组的样本),对213名CCA患者和98名健康对照组进行了全球血清代谢组学和脂质组学分析。CCA患者群包括肝内、肝周和远端CCA肿瘤。利用多变量线性回归的全代谢组关联研究进行了病例对照比较,随后进行了通路富集分析、CCA 亚型分析和疾病分期分析。结果 在区分 CCA 患者和对照组的 420 种代谢物中,半胱氨酸-谷胱甘肽二硫化物丰度的降低与 CCA 的关系最为密切。即使在血清胆红素水平升高、没有临床相关胆道梗阻的情况下,也能发现其他共轭胆汁酸种类的丰度增加。通路富集分析还揭示了 CCA 患者血清中咖啡因代谢和线粒体氧化还原相关通路的改变。这些探索性数据突显了 CCA 中的新型代谢通路,为今后针对这些通路进行治疗和开发用于诊断的精准生物标记物面板提供了支持。 影响和意义胆管癌(CCA)是一种致死率很高的肝胆癌,但治疗效果有限,因此需要更好地了解这种疾病的生物学特性。利用全球代谢组学和脂质组学平台,我们对 213 名 CCA 患者与健康对照组相比血清中的明显变化进行了表征。这项研究的结果阐明了 CCA 的新代谢途径。这些发现为改进疾病诊断和确定治疗设计的新靶点奠定了基础,使临床和研究领域的相关人员受益匪浅。
{"title":"Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma","authors":"Linsey E. Jackson ,&nbsp;Jennifer L. Tomlinson ,&nbsp;Roberto Alva-Ruiz ,&nbsp;Lindsey A. Gregory ,&nbsp;Seul Kee Byeon ,&nbsp;Amro M. Abdelrahman ,&nbsp;Dong-Gi Mun ,&nbsp;Caroline W. Grant ,&nbsp;Zachary C. Fogarty ,&nbsp;Chen Wang ,&nbsp;Lewis R. Roberts ,&nbsp;Rondell P. Graham ,&nbsp;Mitesh J. Borad ,&nbsp;Sumera I. Ilyas ,&nbsp;Gregory J. Gores ,&nbsp;Akhilesh Pandey ,&nbsp;Arjun P. Athreya ,&nbsp;Rory L. Smoot","doi":"10.1016/j.jhepr.2024.101068","DOIUrl":"10.1016/j.jhepr.2024.101068","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA.</p></div><div><h3>Methods</h3><p>Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case–control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels.</p></div><div><h3>Results</h3><p>Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA.</p></div><div><h3>Conclusions</h3><p>The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis.</p></div><div><h3>Impact and implications</h3><p>Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":8.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924000697/pdfft?md5=463262013cf7f20ac8c676890d1b802a&pid=1-s2.0-S2589555924000697-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140283580","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}
引用次数: 0
Copyright and information 版权和信息
IF 9.5 1区 医学 Q1 Medicine Pub Date : 2024-06-01 DOI: 10.1016/S2589-5559(24)00144-7
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引用次数: 0
A molecular standard for circulating HBV RNA detection and quantification assays in patients with chronic hepatitis B 慢性乙型肝炎患者循环 HBV RNA 检测和定量测定的分子标准
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-25 DOI: 10.1016/j.jhepr.2024.101124

Background & Aims

Circulating HBV RNAs have been proposed as a biomarker that reflects the transcriptional activity of covalently closed circular DNA (cccDNA) and may help to evaluate HBV treatment activity. Different research assays have been proposed and, although two PCR-based research use only investigational assays have been developed, the lack of standardized protocols represents an important limitation. Here we have designed and generated a stable clonal cell line producing an RNA-based standard for the calibration of PCR-based circulating HBV RNA assays.

Methods

HBV RNA-producing Huh7-derived stable cell lines were generated by transfecting pTriEX plasmids containing 1.1 unit length HBV DNA genomes carrying mutations in the catalytic site (YMAA mutation) and the TP domain (Y63F) of the polymerase, and the ε-loop of the pregenomic (pg)RNA (mutation A1G).

Results

The clonal cell line (Huh7-3D29), carrying a double YMAA and Y63F mutation, displayed, and maintained over several passages in culture, a high RNA secretion phenotype with negligible residual secreted HBV DNA. Density gradient centrifugation showed that most of the secreted HBV RNA from Huh7-3D29 cells was detected in naked capsid and virion-like particles and only a minority in small extracellular vescicles. Nanopore sequencing of 5’RACE products shows that the majority of the Huh7-3D29-secreted HBV RNAs start at the 5' end of pgRNA and pgRNA-derived spliced RNAs. Finally, Huh7-3D29 cells showed a high and up-scalable secreted RNA yield allowing 1,300 standard curves in 9 days from one flask.

Conclusion

We generated a clonal cell line that produces high quantities of HBV RNAs with very low quantities of contaminating HBV DNAs, representing a stable source of RNA standard for HBV RNA assay calibration.

Impact and implications:

Several investigational assays and two research use only assays have been developed to detect and quantify circulating HBV RNAs, an emerging biomarker of covalently closed circular DNA transcriptional activity and target engagement by new HBV treatments. The lack of a unique molecular standard for circulating HBV RNA quantification represents an important limitation. Here we describe the generation of a stable clonal cell line producing and secreting an RNA-based standard containing all the HBV RNA species found in HBV patients’ sera (e.g. pgRNA, HBx transcripts). This new RNA standard can be used to calibrate all PCR-based assays for circulating HBV RNA quantification to evaluate, in a non-invasive manner, the size of the transcriptionally active cccDNA pool and the activity of novel strategies aimed at curing HBV infection.

背景& 目的循环中的 HBV RNA 被认为是反映共价闭合环状 DNA(cccDNA)转录活性的生物标志物,可能有助于评估 HBV 治疗活性。目前已提出了不同的研究测定方法,尽管已开发出两种基于 PCR 的研究用测定方法,但缺乏标准化方案是一个重要的限制因素。在这里,我们设计并生成了一种稳定的克隆细胞系,它能产生一种基于 RNA 的标准,用于校准基于 PCR 的循环 HBV RNA 检测。结果携带 YMAA 和 Y63F 双突变的克隆细胞系(Huh7-3D29)在培养过程中表现出高 RNA 分泌表型,其分泌的 HBV DNA 残留量可忽略不计。密度梯度离心显示,Huh7-3D29 细胞分泌的大部分 HBV RNA 在裸盖体和病毒样颗粒中被检测到,只有少数在小的胞外囊泡中被检测到。5'RACE 产物的纳米孔测序显示,Huh7-3D29 细胞分泌的 HBV RNA 大部分以 pgRNA 和 pgRNA 衍生的剪接 RNA 的 5' 端为起始。最后,Huh7-3D29 细胞显示出很高且可升级的分泌 RNA 产量,一个烧瓶在 9 天内可生成 1,300 条标准曲线。结论:我们生成了一种克隆细胞系,它能产生大量 HBV RNA,同时污染的 HBV DNA 数量极低,是校准 HBV RNA 检测的稳定 RNA 标准来源。影响和意义:目前已开发出几种研究性检测方法和两种仅供研究使用的检测方法,用于检测和量化循环中的 HBV RNA,它是共价闭合环状 DNA 转录活性和 HBV 新疗法靶标参与的新兴生物标志物。循环 HBV RNA 定量缺乏独特的分子标准是一个重要的局限。在这里,我们描述了一种稳定克隆细胞系的产生和分泌,这种基于 RNA 的标准包含 HBV 患者血清中发现的所有 HBV RNA 类型(如 pgRNA、HBx 转录本)。这种新的 RNA 标准可用于校准所有基于 PCR 的循环 HBV RNA 定量检测方法,从而以非侵入性的方式评估具有转录活性的 cccDNA 池的大小以及旨在治愈 HBV 感染的新策略的活性。
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引用次数: 0
Successful hepatitis B and C screening in the health check-up in the German primary care setting 在德国基层医疗机构的健康体检中成功筛查乙型肝炎和丙型肝炎
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-24 DOI: 10.1016/j.jhepr.2024.101122

Background & Aims

A goal of the World Health Organization’s global hepatitis strategy is the elimination of chronic hepatitis C virus (HCV) infection by 2030. As part of its strategy, the Federal Joint Committee (Germany) decided to include hepatitis B and C screening in a preventive medical examination, which is performed at the primary care level in Germany. We investigated the results 1 year after implementation of screening between October 2021 and September 2022.

Methods

HBsAg/HBV DNA and anti-HCV/HCV RNA screenings were identified by billing categories in 286,192 individuals of 11 ambulatory healthcare centers.

Results

Compared to 30,106 HBsAg and 31,266 anti-HCV laboratory requisitions in the year 2018, the number of tests increased to 286,192 during the screening period. Compared to routine care, additional anti-HCV positive tests age dependently increased the tally by 98% (177 plus 170 positive cases in males) and 123% (96 plus 118 positive cases in females) in those aged 35-44 years up to 518% (17 plus 88 positive cases in males) and 514% (29 plus 149 positive cases in females) in those aged 75-84 years. Similar results were observed for HBsAg. Prevalences of HBsAg, anti-HCV and HCV RNA were 0.54%, 0.79% and 0.13%, respectively.

Conclusions

A structured hepatitis screening program at the primary care level has been successfully established and leads to age- and-sex-dependent large additional effects compared to routine care.

Impact and implications

Strategies to eliminate chronic hepatitis B and C virus infection are country specific and vary between clinical scenarios. Our analysis proves the efficacy of a screening program by primary care physicians compared to routine care in a low-prevalence country. This program should be accompanied by additional efforts in risk populations like people who inject drugs who are under-represented in the current screening approach.

背景& 目标世界卫生组织全球肝炎战略的目标是到 2030 年消除慢性丙型肝炎病毒 (HCV) 感染。作为该战略的一部分,联邦联合委员会(德国)决定将乙型肝炎和丙型肝炎筛查纳入预防性体检,该体检在德国的初级医疗机构进行。我们对 2021 年 10 月至 2022 年 9 月实施筛查 1 年后的结果进行了调查。方法根据 11 家非住院医疗中心 286192 人的账单类别确定了乙肝/丙肝 DNA 和抗-HCV/HCV RNA 筛查。结果与 2018 年的 30106 份 HBsAg 和 31266 份抗-HCV 实验室申请单相比,筛查期间的检测次数增加到 286192 次。与常规护理相比,额外的抗-HCV 阳性检测结果与年龄有关,在 35-44 岁人群中增加了 98%(男性 177 例加 170 例阳性病例)和 123%(女性 96 例加 118 例阳性病例),在 75-84 岁人群中增加了 518%(男性 17 例加 88 例阳性病例)和 514%(女性 29 例加 149 例阳性病例)。在 HBsAg 方面也观察到类似的结果。HBsAg、抗-HCV 和 HCV RNA 的患病率分别为 0.54%、0.79% 和 0.13%。影响和意义消除慢性乙型肝炎和丙型肝炎病毒感染的策略因国家而异,也因临床情况而异。我们的分析证明,在一个发病率较低的国家,与常规护理相比,由初级保健医生实施的筛查计划非常有效。在实施该计划的同时,还应在注射吸毒者等高危人群中开展更多工作,因为在目前的筛查方法中,注射吸毒者的比例较低。
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引用次数: 0
Cirrhotic Cardiomyopathy And Beyond: Underscoring The Interaction Between The Liver And The Heart 肝硬化性心肌病及其他:强调肝脏与心脏之间的相互作用
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-23 DOI: 10.1016/j.jhepr.2024.101114
Gerardo V. Lo Russo , Stefano Carugo , Lorenzo Ridola , Vincenzo Cardinale
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引用次数: 0
CD40 stimulation activates CD8+ T cells and controls HBV in CD4-depleted mice CD40 刺激可激活 CD8+ T 细胞并控制 CD4 缺失小鼠的 HBV
IF 9.5 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-05-21 DOI: 10.1016/j.jhepr.2024.101121

Background & Aims

HBV treatment is challenging due to the persistence of the covalently closed circular DNA replication pool, which remains unaffected by antiviral intervention. In this study, we determined whether targeting antigen-presenting cells via CD40 stimulation represents an appropriate therapeutic approach for achieving sustained HBV control in a mouse model of HBV replication.

Methods

Mice were transduced with an adeno-associated virus encoding the HBV genome (AAV-HBV) to initiate HBV replication and were administered agonistic CD40 antibody. CD4-depleting antibody was administered in addition to the CD40 antibody. Viral antigens in the blood were measured over time to determine HBV control. HBV-specific CD8+ T cells were quantified in the spleen and liver at the experimental endpoint.

Results

CD40 stimulation in CD4-depleted AAV-HBV mice resulted in the clearance of HBsAg and HBeAg, along with a reduction in liver HBV mRNA, contrasting with CD4-competent counterparts. CD8+ T cells were indispensable for CD40-mediated HBV control, determined by HBV persistence following their depletion. In CD4-replete mice, CD40 stimulation initially facilitated the expansion of HBV-specific CD8+ T cells, which subsequently could not control HBV. Finally, α-CD4/CD40 treatment reduced antigenemia and liver HBV mRNA levels in chronic AAV-HBV mice, with further enhancement through synergy with immunization by VSV-MHBs (vesicular stomatitis virus expressing middle HBsAg).

Conclusions

Our findings underscore the potential of CD40 stimulation as a targeted therapeutic strategy for achieving sustained HBV control and reveal a CD4+ T cell-dependent limitation on CD40-mediated antiviral efficacy.

Impact and implications:

Immunotherapy has the potential to overcome immune dysfunction in chronic HBV infection. Using a mouse model of HBV replication, this study shows that CD40 stimulation can induce sustained HBV control, which is dependent on CD8+ T cells and further enhanced by co-immunization. Unexpectedly, CD40-mediated HBV reduction was improved by the depletion of CD4+ cells. These findings suggest potential strategies for reversing HBV persistence in infected individuals.

背景& 目的由于共价闭合环状 DNA 复制池持续存在,且不受抗病毒干预的影响,因此 HBV 治疗具有挑战性。方法用编码 HBV 基因组的腺相关病毒(AAV-HBV)转导小鼠以启动 HBV 复制,并给小鼠注射激动剂 CD40 抗体。除 CD40 抗体外,还注射了 CD4 清除抗体。随时间推移测量血液中的病毒抗原,以确定 HBV 控制情况。结果CD40刺激CD4-depleted AAV-HBV小鼠可清除HBsAg和HBeAg,同时肝脏HBV mRNA减少,这与CD4-competent小鼠形成鲜明对比。CD8+T细胞是CD40介导的HBV控制不可或缺的细胞,这是由CD8+T细胞耗竭后HBV持续存在所决定的。在CD4缺失的小鼠中,CD40刺激最初促进了HBV特异性CD8+T细胞的扩增,但这些细胞随后无法控制HBV。最后,α-CD4/CD40 治疗降低了慢性 AAV-HBV 小鼠的抗原血症和肝脏 HBV mRNA 水平,通过与 VSV-MHBs(表达中型 HBsAg 的水泡性口炎病毒)免疫的协同作用进一步提高了抗原血症和肝脏 HBV mRNA 水平。影响和意义:免疫疗法有可能克服慢性 HBV 感染中的免疫功能障碍。这项研究利用小鼠 HBV 复制模型表明,CD40 刺激可诱导持续的 HBV 控制,这种控制依赖于 CD8+ T 细胞,并通过联合免疫进一步增强。出乎意料的是,CD40 介导的 HBV 减少可通过消耗 CD4+ 细胞得到改善。这些发现为逆转感染者体内的 HBV 持续存在提出了潜在的策略。
{"title":"CD40 stimulation activates CD8+ T cells and controls HBV in CD4-depleted mice","authors":"","doi":"10.1016/j.jhepr.2024.101121","DOIUrl":"10.1016/j.jhepr.2024.101121","url":null,"abstract":"<div><h3>Background &amp; Aims</h3><p>HBV treatment is challenging due to the persistence of the covalently closed circular DNA replication pool, which remains unaffected by antiviral intervention. In this study, we determined whether targeting antigen-presenting cells via CD40 stimulation represents an appropriate therapeutic approach for achieving sustained HBV control in a mouse model of HBV replication.</p></div><div><h3>Methods</h3><p>Mice were transduced with an adeno-associated virus encoding the HBV genome (AAV-HBV) to initiate HBV replication and were administered agonistic CD40 antibody. CD4-depleting antibody was administered in addition to the CD40 antibody. Viral antigens in the blood were measured over time to determine HBV control. HBV-specific CD8<sup>+</sup> T cells were quantified in the spleen and liver at the experimental endpoint.</p></div><div><h3>Results</h3><p>CD40 stimulation in CD4-depleted AAV-HBV mice resulted in the clearance of HBsAg and HBeAg, along with a reduction in liver HBV mRNA, contrasting with CD4-competent counterparts. CD8<sup>+</sup> T cells were indispensable for CD40-mediated HBV control, determined by HBV persistence following their depletion. In CD4-replete mice, CD40 stimulation initially facilitated the expansion of HBV-specific CD8<sup>+</sup> T cells, which subsequently could not control HBV. Finally, α-CD4/CD40 treatment reduced antigenemia and liver HBV mRNA levels in chronic AAV-HBV mice, with further enhancement through synergy with immunization by VSV-MHBs (vesicular stomatitis virus expressing middle HBsAg).</p></div><div><h3>Conclusions</h3><p>Our findings underscore the potential of CD40 stimulation as a targeted therapeutic strategy for achieving sustained HBV control and reveal a CD4<sup>+</sup> T cell-dependent limitation on CD40-mediated antiviral efficacy.</p></div><div><h3>Impact and implications:</h3><p>Immunotherapy has the potential to overcome immune dysfunction in chronic HBV infection. Using a mouse model of HBV replication, this study shows that CD40 stimulation can induce sustained HBV control, which is dependent on CD8<sup>+</sup> T cells and further enhanced by co-immunization. Unexpectedly, CD40-mediated HBV reduction was improved by the depletion of CD4<sup>+</sup> cells. These findings suggest potential strategies for reversing HBV persistence in infected individuals.</p></div>","PeriodicalId":14764,"journal":{"name":"JHEP Reports","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589555924001253/pdfft?md5=01d66927efccecddb4b1e98ea0e78954&pid=1-s2.0-S2589555924001253-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141132032","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}
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