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HBx Facilitates Drug Resistance in Hepatocellular Carcinoma via CD133-regulated Self-renewal of Liver Cancer Stem Cells. HBx通过cd133调控的肝癌干细胞自我更新促进肝癌耐药
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-28 Epub Date: 2024-11-25 DOI: 10.14218/JCTH.2024.00259
Xiangshu Jin, Huijun Dong, Juan Wang, Guomin Ou, Xinyuan Lai, Xing Tian, Lei Wang, Hui Zhuang, Tong Li, Kuanhui Xiang

Background and aims: Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) tumorigenesis, drug resistance, and recurrence, although the underlying molecular mechanisms remain unclear. Recent studies suggest that HBV infection may be associated with liver cancer stem cells (LCSCs), but the exact mechanisms are yet to be resolved. In this study, we aimed to analyze the role of HBV infection in regulating the stemness of HCCs, which is closely linked to drug resistance.

Methods: Sphere formation assay and real-time Polymerase Chain Reaction quantification were used to isolate and confirm liver cancer stem cells. The inhibitory concentration values of sorafenib and regorafenib were calculated and compared using the Cell Counting Kit-8 assay. HBV infection was used to assess the effect of HBV replication on LCSC markers. Co-immunoprecipitation assay was performed to detect the interaction between CD133 and SRC. Furthermore, we utilized the CRISPR-Cas9 system to knockout CD133 expression in HepG2.2.15 cells.

Results: LCSCs derived from HCCs exhibited high expression of stem cell markers and demonstrated reduced sensitivity to sorafenib and regorafenib. HBV replication promoted both drug resistance and stemness in hepatoma cells and clinical samples. Overexpression of HBx protein in HepG2 cells upregulated the expression of CD133, EpCAM, and CD24, enhancing resistance to sorafenib and regorafenib. Knockout of CD133 expression using the CRISPR-Cas9 system significantly inhibited drug resistance to both sorafenib and regorafenib in HepG2.2.15 cells. Mechanistically, HBV replication promoted CD133 expression, which in turn interacted with the SRC/STAT3 signaling pathway.

Conclusions: Our data suggest that HBV replication enhances the stemness and drug resistance of HCC, providing a strong theoretical foundation for the development of targeted and efficient treatments for HBV-infected HCCs.

背景和目的:乙型肝炎病毒(HBV)感染有助于肝细胞癌(HCC)的发生、耐药和复发,尽管其潜在的分子机制尚不清楚。最近的研究表明HBV感染可能与肝癌干细胞(LCSCs)有关,但确切的机制尚不清楚。在本研究中,我们旨在分析HBV感染在调节与耐药密切相关的hcc的干性中的作用。方法:采用球形法和实时聚合酶链反应法分离和鉴定肝癌干细胞。使用细胞计数试剂盒-8法计算索拉非尼和瑞非尼的抑制浓度值并进行比较。HBV感染用于评估HBV复制对LCSC标志物的影响。采用免疫共沉淀法检测CD133与SRC的相互作用。此外,我们利用CRISPR-Cas9系统敲除HepG2.2.15细胞中的CD133表达。结果:来自hcc的LCSCs显示出干细胞标记物的高表达,并且对索拉非尼和瑞非尼的敏感性降低。HBV复制促进了肝癌细胞和临床样本的耐药和干细胞性。HepG2细胞中HBx蛋白的过表达上调了CD133、EpCAM和CD24的表达,增强了对索拉非尼和瑞非尼的耐药性。使用CRISPR-Cas9系统敲除CD133表达可显著抑制HepG2.2.15细胞对索拉非尼和瑞非尼的耐药。在机制上,HBV复制促进CD133表达,而CD133又与SRC/STAT3信号通路相互作用。结论:我们的数据表明HBV复制增强了HCC的干细胞性和耐药性,为开发针对HBV感染的HCC的靶向和高效治疗提供了强有力的理论基础。
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引用次数: 0
T-cell Receptor Repertoire Analysis in the Context of Transarterial Chemoembolization Synergy with Systemic Therapy for Hepatocellular Carcinoma. 肝细胞癌经动脉化疗栓塞与全身治疗协同作用下的t细胞受体库分析。
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-28 Epub Date: 2024-11-12 DOI: 10.14218/JCTH.2024.00238
Jie Li, Yuyuan Zhang, Luqi Hu, Heqing Ye, Xingli Yan, Xin Li, Yifan Li, Shuwen Ye, Bailu Wu, Zhen Li

T-cell receptor (TCR) sequencing provides a novel platform for insight into and characterization of intricate T-cell profiles, advancing the understanding of tumor immune heterogeneity. Recently, transarterial chemoembolization (TACE) combined with systemic therapy has become the recommended regimen for advanced hepatocellular carcinoma. The regulation of the immune microenvironment after TACE and its impact on tumor progression and recurrence has been a focus of research. By examining and tracking fluctuations in the TCR repertoire following combination treatment, novel perspectives on the modulation of the tumor microenvironment post-TACE and the underlying mechanisms governing tumor progression and recurrence can be gained. Clarifying the distinctive metrics and dynamic alterations of the TCR repertoire within the context of combination therapy is imperative for understanding the mechanisms of anti-tumor immunity, assessing efficacy, exploiting novel treatments, and further advancing precision oncology in the treatment of hepatocellular carcinoma. In this review, we initially summarized the fundamental characteristics of TCR repertoire and depicted immune microenvironment remodeling after TACE. Ultimately, we illustrated the prospective applications of TCR repertoires in TACE combined with systemic therapy.

t细胞受体(TCR)测序为深入了解和表征复杂的t细胞谱提供了一个新的平台,促进了对肿瘤免疫异质性的理解。近年来,经动脉化疗栓塞(TACE)联合全身治疗已成为晚期肝癌的推荐治疗方案。TACE术后免疫微环境的调控及其对肿瘤进展和复发的影响一直是研究的热点。通过检查和跟踪TCR库在联合治疗后的波动,可以获得关于tace后肿瘤微环境调节和肿瘤进展和复发的潜在机制的新视角。在联合治疗的背景下,明确TCR库的独特指标和动态变化对于理解抗肿瘤免疫机制、评估疗效、开发新的治疗方法以及进一步推进精确肿瘤学治疗肝细胞癌至关重要。在这篇综述中,我们初步总结了TCR库的基本特征,并描述了TACE后免疫微环境的重塑。最后,我们阐述了TCR谱在TACE联合全身治疗中的应用前景。
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引用次数: 0
Evaluation of Plasma Neurodegenerative Biomarkers for Diagnosing Minimal Hepatic Encephalopathy and Predicting Overt Hepatic Encephalopathy in Chinese Patients with Hepatic Cirrhosis. 中国肝硬化患者血浆神经退行性生物标记物诊断轻度肝性脑病和预测重度肝性脑病的评估
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-28 Epub Date: 2024-12-12 DOI: 10.14218/JCTH.2024.00413
Qiuyu Cheng, Yunhui Liu, Zhongyuan Yang, Meng Zhang, Tingting Liu, Yuxin Niu, Wei Liu, Lanyue Huang, Yuzhao Feng, Xiaoyun Zhang, Xiaoping Luo, Qin Ning, Tao Chen

Background and aims: The performance of neurodegenerative biomarkers-neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1)-in diagnosing minimal hepatic encephalopathy (MHE) has not been systematically evaluated, simultaneously, nor have their associations with the development of overt hepatic encephalopathy (OHE). This study aimed to evaluate the performance of plasma NfL, GFAP, tau, and UCHL1 in diagnosing MHE and predicting the development of OHE in Chinese patients with hepatic cirrhosis.

Methods: In this prospective study, 124 patients with hepatic cirrhosis were recruited. The Psychometric Hepatic Encephalopathy Score was used to diagnose MHE, and OHE development was observed during a 30-day follow-up period. Plasma levels of NfL, GFAP, tau, and UCHL1 were measured using the highly sensitive single-molecule array when MHE was diagnosed. Additionally, serum interleukin-6 (IL-6) levels and the model for end-stage liver disease (MELD) and MELD-Na scores were also measured.

Results: MHE was diagnosed in 57 (46.0%) patients. Patients with MHE had significantly higher plasma levels of NfL and GFAP (34.2 vs. 22.4 pg/mL and 173 vs. 97.6 pg/mL, respectively; both p < 0.001) and lower tau levels (8.4 vs. 11.6 pg/mL, p = 0.048) compared to those without MHE. Plasma NfL (odds ratios = 1.027, 95% confidence interval [CI]: 1.006-1.048; p = 0.013) and serum ammonia levels (odds ratios = 1.021, 95% CI: 1.006-1.036; p = 0.007) were independently associated with MHE occurrence. A combination of NfL, GFAP, tau, and UCHL1 was effective in diagnosing MHE in all cirrhotic patients (area under the receiver operating characteristic curve [hereinafter referred to as AUROC]: 0.748, 95% CI: 0.662-0.821), with an accuracy, sensitivity, and specificity of 71.0%, 71.9%, and 71.6%, respectively. In patients without previous OHE, the combination had an AUROC of 0.764 (95% CI: 0.673-0.840), with an accuracy, sensitivity, and specificity of 72.5%, 71.7%, and 73.0%, respectively. Furthermore, GFAP (hazard ratio (HR) = 1.003, 95% CI: 1.000-1.005; p = 0.044), IL-6 (HR = 1.003, 95% CI: 1.001-1.004; p < 0.001), and MELD score (HR = 1.139, 95% CI: 1.072-1.210; p < 0.001)-but not NfL, tau, and UCHL1-were identified as risk factors for 30-day OHE development.

Conclusions: The combination of plasma levels of NfL, GFAP, tau, and UCHL1 performs well in diagnosing MHE. Additionally, MELD score, IL-6, and GFAP appear to be significant predictors of OHE development in patients with hepatic cirrhosis.

背景和目的:神经退行性生物标志物——神经丝轻链(NfL)、胶质纤维酸性蛋白(GFAP)、tau和泛素羧基末端水解酶L1 (UCHL1)在诊断轻度肝性脑病(MHE)中的作用尚未得到系统评估,同时,它们与显性肝性脑病(OHE)的发展也没有相关性。本研究旨在评估血浆NfL、GFAP、tau和UCHL1在诊断中国肝硬化患者MHE和预测OHE发展中的作用。方法:在这项前瞻性研究中,124例肝硬化患者被招募。采用肝性脑病心理测量评分来诊断MHE,并在30天的随访期间观察OHE的发展情况。当诊断为MHE时,使用高灵敏度的单分子阵列测量血浆中NfL、GFAP、tau和UCHL1的水平。此外,还测量了血清白细胞介素-6 (IL-6)水平、终末期肝病模型(MELD)和MELD- na评分。结果:MHE确诊57例(46.0%)。MHE患者血浆中NfL和GFAP水平显著升高(分别为34.2 vs. 22.4 pg/mL和173 vs. 97.6 pg/mL);p < 0.001)和较低的tau水平(8.4 vs. 11.6 pg/mL, p = 0.048)。血浆NfL(优势比= 1.027,95%可信区间[CI]: 1.006-1.048;p = 0.013)和血清氨水平(优势比= 1.021,95% CI: 1.006-1.036;p = 0.007)与MHE的发生独立相关。联合应用NfL、GFAP、tau和UCHL1可有效诊断所有肝硬化患者的MHE(受试者工作特征曲线下面积[以下简称AUROC]: 0.748, 95% CI: 0.662-0.821),准确性、敏感性和特异性分别为71.0%、71.9%和71.6%。在既往无OHE的患者中,联合用药AUROC为0.764 (95% CI: 0.673-0.840),准确性、敏感性和特异性分别为72.5%、71.7%和73.0%。此外,GFAP(风险比(HR) = 1.003, 95% CI: 1.000-1.005;p = 0.044), IL-6 (HR = 1.003, 95% CI: 1.001 ~ 1.004;p < 0.001), MELD评分(HR = 1.139, 95% CI: 1.072 ~ 1.210;p < 0.001),但NfL、tau和uchl1未被确定为30天OHE发展的危险因素。结论:结合血浆中NfL、GFAP、tau和UCHL1水平对MHE有较好的诊断价值。此外,MELD评分、IL-6和GFAP似乎是肝硬化患者OHE发展的重要预测因素。
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引用次数: 0
ADAMTS13 Improves Hepatic Platelet Accumulation in Pyrrolizidine Alkaloids-induced Liver Injury. ADAMTS13促进吡咯利西定生物碱诱导的肝损伤中肝脏血小板聚集。
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-01-28 Epub Date: 2024-11-22 DOI: 10.14218/JCTH.2024.00233
Mingyan Ji, Yun Chen, Yifan Ma, Dongping Li, Jin Ren, Hongyue Jiang, Sinuo Chen, Xiaoqing Zeng, Hong Gao

Background and aims: Pyrrolizidine alkaloids (PAs), widely distributed in plants, are known to induce liver failure. Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury (PA-ILI). This study aimed to investigate the mechanisms underlying platelet accumulation in PA-ILI.

Methods: Cases of PA-ILI, non-PA-ILI, and control subjects were collected from patients hospitalized at Zhongshan Hospital, Fudan University (Shanghai, China) between 2012 and 2019. A mouse model of PA-ILI was established using monocrotaline administration. Liver RNA sequencing was performed, and gene interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database. Low-molecular-weight heparin and recombinant a disintegrin and metalloproteinase with a thrombospondin type I motif member 13 (ADAMTS13) were applied. The necrotic liver area, hepatic platelet accumulation, and von Willebrand factor (VWF) deposition were examined using hematoxylin and eosin staining and immunofluorescence assay.

Results: Hepatic platelet accumulation, necrotic area expansion, and increased VWF expression were observed in both PA-ILI patients and mice. The Search Tool for the Retrieval of Interacting Genes/Proteins database indicated that ADAMTS13 regulates VWF expression and was differentially expressed in the livers of PA-ILI mice. Plasma and hepatic ADAMTS13 levels were significantly downregulated in both PA-ILI patients and mice. Systemic administration of recombinant ADAMTS13 decreased hepatic platelet accumulation, downregulated VWF expression, and mitigated mouse hepatic necrosis.

Conclusions: Hepatic platelet accumulation in PA-ILI was confirmed in both patients and mice. Deficiency of ADAMTS13 plays a critical role in platelet accumulation in PA-ILI, suggesting that ADAMTS13 could be a potential therapeutic target for this condition.

背景与目的:吡咯利西啶生物碱(Pyrrolizidine alkaloids, PAs)广泛存在于植物中,可引起肝功能衰竭。肝血小板积累在pa诱导的肝损伤(PA-ILI)的进展过程中有报道。本研究旨在探讨PA-ILI中血小板积聚的机制。方法:收集复旦大学附属中山医院2012 - 2019年收治的PA-ILI病例、非PA-ILI病例和对照。采用单碱给药建立PA-ILI小鼠模型。进行肝脏RNA测序,使用Search Tool for Retrieval of Interacting Genes/Proteins在线数据库分析基因相互作用。应用低分子肝素和重组具有血小板反应蛋白I型基序成员13的崩解素和金属蛋白酶(ADAMTS13)。采用苏木精染色、伊红染色和免疫荧光法检测肝坏死面积、肝血小板积累和血管性血友病因子(VWF)沉积。结果:PA-ILI患者和小鼠肝脏均出现血小板聚集、坏死面积扩大、VWF表达升高。相互作用基因/蛋白数据库检索工具显示,ADAMTS13调节VWF的表达,并在PA-ILI小鼠肝脏中存在差异表达。PA-ILI患者和小鼠血浆和肝脏ADAMTS13水平均显著下调。重组ADAMTS13全身给药可减少肝脏血小板积累,下调VWF表达,减轻小鼠肝坏死。结论:PA-ILI患者和小鼠均有肝血小板积聚。ADAMTS13的缺乏在PA-ILI的血小板积累中起关键作用,表明ADAMTS13可能是这种疾病的潜在治疗靶点。
{"title":"ADAMTS13 Improves Hepatic Platelet Accumulation in Pyrrolizidine Alkaloids-induced Liver Injury.","authors":"Mingyan Ji, Yun Chen, Yifan Ma, Dongping Li, Jin Ren, Hongyue Jiang, Sinuo Chen, Xiaoqing Zeng, Hong Gao","doi":"10.14218/JCTH.2024.00233","DOIUrl":"10.14218/JCTH.2024.00233","url":null,"abstract":"<p><strong>Background and aims: </strong>Pyrrolizidine alkaloids (PAs), widely distributed in plants, are known to induce liver failure. Hepatic platelet accumulation has been reported during the progression of PA-induced liver injury (PA-ILI). This study aimed to investigate the mechanisms underlying platelet accumulation in PA-ILI.</p><p><strong>Methods: </strong>Cases of PA-ILI, non-PA-ILI, and control subjects were collected from patients hospitalized at Zhongshan Hospital, Fudan University (Shanghai, China) between 2012 and 2019. A mouse model of PA-ILI was established using monocrotaline administration. Liver RNA sequencing was performed, and gene interactions were analyzed using the Search Tool for the Retrieval of Interacting Genes/Proteins online database. Low-molecular-weight heparin and recombinant a disintegrin and metalloproteinase with a thrombospondin type I motif member 13 (ADAMTS13) were applied. The necrotic liver area, hepatic platelet accumulation, and von Willebrand factor (VWF) deposition were examined using hematoxylin and eosin staining and immunofluorescence assay.</p><p><strong>Results: </strong>Hepatic platelet accumulation, necrotic area expansion, and increased VWF expression were observed in both PA-ILI patients and mice. The Search Tool for the Retrieval of Interacting Genes/Proteins database indicated that ADAMTS13 regulates VWF expression and was differentially expressed in the livers of PA-ILI mice. Plasma and hepatic ADAMTS13 levels were significantly downregulated in both PA-ILI patients and mice. Systemic administration of recombinant ADAMTS13 decreased hepatic platelet accumulation, downregulated VWF expression, and mitigated mouse hepatic necrosis.</p><p><strong>Conclusions: </strong>Hepatic platelet accumulation in PA-ILI was confirmed in both patients and mice. Deficiency of ADAMTS13 plays a critical role in platelet accumulation in PA-ILI, suggesting that ADAMTS13 could be a potential therapeutic target for this condition.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 1","pages":"25-34"},"PeriodicalIF":3.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11712092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
The Imbalance of Homeostasis in Neutrophil Extracellular Traps is Associated with Portal Vein Thrombosis in Patients with Decompensated Cirrhosis. 失代偿期肝硬化患者门静脉血栓形成与中性粒细胞胞外陷阱内平衡失衡有关。
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-28 Epub Date: 2024-11-04 DOI: 10.14218/JCTH.2024.00165
Ming Han, Yujia Liu, Ying Cao, Yue Zhang, Yonghong Yan, Shuwei Deng, Xiaoxue Yuan, Huichun Xing, Yuan Huang, Liuluan Zhu

Background and aims: Portal vein thrombosis (PVT) is a challenging complication in liver cirrhosis, with no currently available sensitive diagnostic markers. This study aimed to investigate the potential of neutrophil extracellular traps (NETs) and Deoxyribonuclease (DNase) as diagnostic indicators for PVT in chronic hepatitis B (CHB)-related decompensated cirrhosis.

Methods: We analyzed 145 CHB-related decompensated cirrhosis patients from the Ditan study and 33 from the Changgung validation study, categorizing them based on PVT occurrence. Plasma samples were assessed for NET markers, including cell-free DNA (cfDNA) and histone-DNA complexes, along with DNase activity.

Results: PVT patients exhibited elevated levels of cfDNA and histone-DNA complexes, and reduced DNase activity. This pattern persisted regardless of hepatocellular carcinoma (HCC) status. Histone-DNA levels, DNase activity, and hemoglobin were identified as independent risk factors for PVT. Receiver operating characteristic curve analysis revealed that high histone-DNA levels may serve as a potential diagnostic marker for PVT, with an area under the curve of 0.8628 in the Ditan study and 0.7521 in the Changgung study. When combined with cfDNA and DNase activity, the area under the curve improved to 0.8774 in the Ditan study and 0.7975 in the Changgung study.

Conclusions: Imbalances in NET homeostasis are associated with PVT in CHB-related decompensated cirrhosis, including cases involving HCC. Histone-DNA complexes, a significant risk factor for PVT, show potential as a diagnostic marker for PVT in decompensated cirrhosis, particularly in HBV-related HCC.

背景和目的:门静脉血栓形成(PVT)是肝硬化中一种具有挑战性的并发症,目前尚无敏感的诊断标志物。本研究旨在探讨中性粒细胞胞外陷阱(NETs)和脱氧核糖核酸酶(DNase)作为慢性乙型肝炎(CHB)相关失代偿肝硬化PVT诊断指标的潜力。方法:我们分析了地坛研究中的145例chb相关失代偿性肝硬化患者和长庚验证研究中的33例患者,并根据PVT的发生对其进行了分类。评估血浆样本的NET标记物,包括无细胞DNA (cfDNA)和组蛋白-DNA复合物,以及DNA酶活性。结果:PVT患者表现出cfDNA和组蛋白dna复合物水平升高,dna酶活性降低。无论肝细胞癌(HCC)状态如何,这种模式都持续存在。组蛋白- dna水平、dna酶活性和血红蛋白被确定为PVT的独立危险因素。受体工作特征曲线分析显示,高组蛋白- dna水平可能是PVT的潜在诊断标志物,地坛研究的曲线下面积为0.8628,长宫研究的曲线下面积为0.7521。当结合cfDNA和DNase活性时,地滩研究的曲线下面积提高到0.8774,长宫研究的曲线下面积提高到0.7975。结论:在chb相关失代偿性肝硬化(包括HCC)中,NET稳态失衡与PVT相关。组蛋白- dna复合物是PVT的一个重要危险因素,在失代偿性肝硬化中,特别是在hbv相关的HCC中,显示出PVT的诊断标志物的潜力。
{"title":"The Imbalance of Homeostasis in Neutrophil Extracellular Traps is Associated with Portal Vein Thrombosis in Patients with Decompensated Cirrhosis.","authors":"Ming Han, Yujia Liu, Ying Cao, Yue Zhang, Yonghong Yan, Shuwei Deng, Xiaoxue Yuan, Huichun Xing, Yuan Huang, Liuluan Zhu","doi":"10.14218/JCTH.2024.00165","DOIUrl":"10.14218/JCTH.2024.00165","url":null,"abstract":"<p><strong>Background and aims: </strong>Portal vein thrombosis (PVT) is a challenging complication in liver cirrhosis, with no currently available sensitive diagnostic markers. This study aimed to investigate the potential of neutrophil extracellular traps (NETs) and Deoxyribonuclease (DNase) as diagnostic indicators for PVT in chronic hepatitis B (CHB)-related decompensated cirrhosis.</p><p><strong>Methods: </strong>We analyzed 145 CHB-related decompensated cirrhosis patients from the Ditan study and 33 from the Changgung validation study, categorizing them based on PVT occurrence. Plasma samples were assessed for NET markers, including cell-free DNA (cfDNA) and histone-DNA complexes, along with DNase activity.</p><p><strong>Results: </strong>PVT patients exhibited elevated levels of cfDNA and histone-DNA complexes, and reduced DNase activity. This pattern persisted regardless of hepatocellular carcinoma (HCC) status. Histone-DNA levels, DNase activity, and hemoglobin were identified as independent risk factors for PVT. Receiver operating characteristic curve analysis revealed that high histone-DNA levels may serve as a potential diagnostic marker for PVT, with an area under the curve of 0.8628 in the Ditan study and 0.7521 in the Changgung study. When combined with cfDNA and DNase activity, the area under the curve improved to 0.8774 in the Ditan study and 0.7975 in the Changgung study.</p><p><strong>Conclusions: </strong>Imbalances in NET homeostasis are associated with PVT in CHB-related decompensated cirrhosis, including cases involving HCC. Histone-DNA complexes, a significant risk factor for PVT, show potential as a diagnostic marker for PVT in decompensated cirrhosis, particularly in HBV-related HCC.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"12 12","pages":"1009-1019"},"PeriodicalIF":3.1,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
The Failure Rate of Liver Stiffness Measured by Vibration-controlled Transient Elastography in the United States and Relevant Factors. 美国振动控制瞬态弹性仪测量肝脏刚度的失效率及相关因素。
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-28 Epub Date: 2024-11-08 DOI: 10.14218/JCTH.2024.00261
Ruoqi Zhou, Jiyang Chen, Rui Huang, Yida Yang, Yu Shi
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引用次数: 0
Emerging Roles of High-mobility Group Box-1 in Liver Disease. 高迁移率组Box-1在肝脏疾病中的新作用
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-28 Epub Date: 2024-10-22 DOI: 10.14218/JCTH.2024.00317
Lu Wang, Zhiwei Dong, Yeqiong Zhang, Liang Peng

High-mobility group box-1 (HMGB1) is an architectural chromosomal protein with various roles depending on its cellular localization. Extracellular HMGB1 functions as a prototypical damage-associated molecular pattern that triggers inflammation and adaptive immune responses, mediated by specific cell surface receptors, including receptors for advanced glycation end products and toll-like receptors. Post-translational modifications of HMGB1 significantly impact various cellular processes that contribute to the pathogenesis of liver diseases. Recent studies have highlighted the close relationship between HMGB1 and the pathogenesis of acute liver injuries, including acetaminophen-induced liver injury, hepatic ischemia-reperfusion injury, and acute liver failure. In chronic liver diseases, HMGB1 plays a role in nonalcoholic fatty liver disease, alcohol-associated liver disease, liver fibrosis, and hepatocellular carcinoma. Targeting HMGB1 as a therapeutic approach, either by inhibiting its release or blocking its extracellular function, is a promising strategy for treating liver diseases. This review aimed to summarize the available evidence on HMGB1's role in liver disease, focusing on its multifaceted signaling pathways, impact on disease progression, and the translation of these findings into clinical interventions.

高迁移率组盒-1 (HMGB1)是一种染色体结构蛋白,根据其细胞定位具有多种作用。细胞外HMGB1是一种典型的损伤相关分子模式,可触发炎症和适应性免疫反应,由特定细胞表面受体介导,包括晚期糖基化终产物受体和toll样受体。HMGB1的翻译后修饰显著影响肝脏疾病发病机制的各种细胞过程。近年来的研究强调HMGB1与急性肝损伤的发病机制密切相关,包括对乙酰氨基酚性肝损伤、肝缺血再灌注损伤和急性肝衰竭。在慢性肝病中,HMGB1在非酒精性脂肪性肝病、酒精相关性肝病、肝纤维化和肝细胞癌中发挥作用。以HMGB1为靶点,通过抑制其释放或阻断其细胞外功能,是一种治疗肝脏疾病的有前景的策略。本综述旨在总结HMGB1在肝脏疾病中作用的现有证据,重点关注其多方面的信号通路、对疾病进展的影响,以及将这些发现转化为临床干预措施。
{"title":"Emerging Roles of High-mobility Group Box-1 in Liver Disease.","authors":"Lu Wang, Zhiwei Dong, Yeqiong Zhang, Liang Peng","doi":"10.14218/JCTH.2024.00317","DOIUrl":"10.14218/JCTH.2024.00317","url":null,"abstract":"<p><p>High-mobility group box-1 (HMGB1) is an architectural chromosomal protein with various roles depending on its cellular localization. Extracellular HMGB1 functions as a prototypical damage-associated molecular pattern that triggers inflammation and adaptive immune responses, mediated by specific cell surface receptors, including receptors for advanced glycation end products and toll-like receptors. Post-translational modifications of HMGB1 significantly impact various cellular processes that contribute to the pathogenesis of liver diseases. Recent studies have highlighted the close relationship between HMGB1 and the pathogenesis of acute liver injuries, including acetaminophen-induced liver injury, hepatic ischemia-reperfusion injury, and acute liver failure. In chronic liver diseases, HMGB1 plays a role in nonalcoholic fatty liver disease, alcohol-associated liver disease, liver fibrosis, and hepatocellular carcinoma. Targeting HMGB1 as a therapeutic approach, either by inhibiting its release or blocking its extracellular function, is a promising strategy for treating liver diseases. This review aimed to summarize the available evidence on HMGB1's role in liver disease, focusing on its multifaceted signaling pathways, impact on disease progression, and the translation of these findings into clinical interventions.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"12 12","pages":"1043-1056"},"PeriodicalIF":3.1,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
2024 Reviewer Acknowledgement. 2024审稿人致谢。
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-28 DOI: 10.14218/JCTH.2024.000RA
Editorial Office Of Journal Of Clinical And Translational Hepatology
{"title":"2024 Reviewer Acknowledgement.","authors":"Editorial Office Of Journal Of Clinical And Translational Hepatology","doi":"10.14218/JCTH.2024.000RA","DOIUrl":"https://doi.org/10.14218/JCTH.2024.000RA","url":null,"abstract":"","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"12 12","pages":"1070-1073"},"PeriodicalIF":3.1,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622205/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Exploring Circulating Tumor Cells: Detection Methods and Biomarkers for Clinical Evaluation in Hepatocellular Carcinoma. 探索循环肿瘤细胞:肝细胞癌临床评价的检测方法和生物标志物。
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-28 Epub Date: 2024-10-17 DOI: 10.14218/JCTH.2024.00230
Chin-Mu Hsu, Yi-Chang Liu, Jee-Fu Huang

Circulating tumor cells (CTCs), originating from primary neoplastic tissues, infiltrate blood vessels, migrate through the bloodstream, and establish secondary tumor foci. The detection of CTCs holds significant promise for early-stage identification, diagnostic precision, therapeutic monitoring, and prognostic evaluation. It offers a non-invasive approach and has broad clinical relevance in cancer management. This comprehensive review primarily focused on CTCs as biomarkers in the diagnostic, therapeutic, and prognostic surveillance of hepatocellular carcinoma, compared their correlation with key clinical parameters and the identification of gene characteristics. It also highlighted current methodologies in CTC detection. Despite approval by the U.S. Food and Drug Administration for select malignancies, the comprehensive integration of CTCs into routine clinical practice requires procedural standardization and a deeper understanding of the underlying molecular intricacies. The challenges in CTC detection, including limited quantity, technical impediments, and cellular heterogeneity, call for concerted and further investigational efforts to advance precision in cancer diagnostics and prognostication, thus realizing the objectives of precise and personalized medicine.

循环肿瘤细胞(ctc)起源于原发肿瘤组织,浸润血管,通过血液迁移,并建立继发肿瘤灶。ctc的检测对早期识别、诊断精度、治疗监测和预后评估具有重要意义。它提供了一种非侵入性的方法,在癌症管理中具有广泛的临床意义。这篇综合综述主要关注ctc作为肝细胞癌诊断、治疗和预后监测中的生物标志物,比较了它们与关键临床参数和基因特征鉴定的相关性。它还强调了目前检测反恐中心的方法。尽管美国食品和药物管理局(fda)已批准将ctc用于特定的恶性肿瘤,但将ctc全面整合到常规临床实践中需要程序标准化和对潜在分子复杂性的更深入了解。CTC检测面临的挑战,包括数量有限、技术障碍和细胞异质性,需要协调和进一步的研究努力,以提高癌症诊断和预测的准确性,从而实现精确和个性化医疗的目标。
{"title":"Exploring Circulating Tumor Cells: Detection Methods and Biomarkers for Clinical Evaluation in Hepatocellular Carcinoma.","authors":"Chin-Mu Hsu, Yi-Chang Liu, Jee-Fu Huang","doi":"10.14218/JCTH.2024.00230","DOIUrl":"10.14218/JCTH.2024.00230","url":null,"abstract":"<p><p>Circulating tumor cells (CTCs), originating from primary neoplastic tissues, infiltrate blood vessels, migrate through the bloodstream, and establish secondary tumor foci. The detection of CTCs holds significant promise for early-stage identification, diagnostic precision, therapeutic monitoring, and prognostic evaluation. It offers a non-invasive approach and has broad clinical relevance in cancer management. This comprehensive review primarily focused on CTCs as biomarkers in the diagnostic, therapeutic, and prognostic surveillance of hepatocellular carcinoma, compared their correlation with key clinical parameters and the identification of gene characteristics. It also highlighted current methodologies in CTC detection. Despite approval by the U.S. Food and Drug Administration for select malignancies, the comprehensive integration of CTCs into routine clinical practice requires procedural standardization and a deeper understanding of the underlying molecular intricacies. The challenges in CTC detection, including limited quantity, technical impediments, and cellular heterogeneity, call for concerted and further investigational efforts to advance precision in cancer diagnostics and prognostication, thus realizing the objectives of precise and personalized medicine.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"12 12","pages":"1020-1042"},"PeriodicalIF":3.1,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622199/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Ferroptosis and Intrinsic Drug-induced Liver Injury by Acetaminophen and Other Drugs: A Critical Evaluation and Historical Perspective. 对乙酰氨基酚和其他药物引起的铁下垂和内源性药物性肝损伤:一个关键的评估和历史观点。
IF 3.1 3区 医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2024-12-28 Epub Date: 2024-10-29 DOI: 10.14218/JCTH.2024.00324
Hartmut Jaeschke, Anup Ramachandran

Drug-induced hepatotoxicity is a significant clinical issue worldwide. Given the limited treatment options for these liver injuries, understanding the mechanisms and modes of cell death is crucial for identifying novel therapeutic targets. For the past 60 years, reactive oxygen species and iron-dependent lipid peroxidation (LPO) have been hypothesized to be involved in many models of acute drug-induced liver injury. However, this mechanism of toxicity was largely abandoned when apoptosis became the primary focus of cell death research. More recently, ferroptosis-a novel, non-apoptotic form of cell death-was identified in NRAS-mutant HT-1080 fibrosarcoma cells exposed to erastin and other NRLs. Ferroptosis is characterized by glutathione depletion and the impairment of glutathione peroxidase 4 activity, which hinders the detoxification of lipid hydroperoxides. These hydroperoxides then serve as substrates for iron-dependent LPO propagation. This cell death mechanism is now receiving widespread attention, extending well beyond its original identification in cancer research, including in the field of drug-induced liver injury. However, concerns arise when such mechanisms are applied across different cell types and disease states without sufficient validation. This review critically evaluated the historical evidence for iron-dependent LPO as a mechanism of drug-induced hepatotoxicity and explored how these earlier findings have led to the current concept of ferroptosis. Overall, the published data support the idea that multi-layered endogenous antioxidant defense mechanisms in the liver limit the occurrence of pathophysiologically relevant LPO under normal conditions. Only when these defense mechanisms are severely compromised does ferroptosis become a significant mode of drug-induced cell death.

药物性肝毒性是世界范围内一个重要的临床问题。鉴于这些肝损伤的治疗选择有限,了解细胞死亡的机制和模式对于确定新的治疗靶点至关重要。在过去的60年里,活性氧和铁依赖性脂质过氧化(LPO)被假设参与了许多急性药物性肝损伤模型。然而,随着细胞凋亡成为细胞死亡研究的主要焦点,这种毒性机制在很大程度上被抛弃了。最近,在暴露于erastin和其他NRLs的nras突变HT-1080纤维肉瘤细胞中发现了铁凋亡——一种新的、非凋亡的细胞死亡形式。铁下垂的特征是谷胱甘肽耗竭和谷胱甘肽过氧化物酶4活性受损,这阻碍了脂质氢过氧化物的解毒。然后这些氢过氧化物作为依赖铁的LPO繁殖的底物。这种细胞死亡机制现在受到广泛关注,远远超出了它在癌症研究中的最初发现,包括在药物性肝损伤领域。然而,当这些机制应用于不同的细胞类型和疾病状态时,没有足够的验证,就会引起关注。这篇综述批判性地评估了铁依赖性LPO作为药物性肝毒性机制的历史证据,并探讨了这些早期发现如何导致目前铁下垂的概念。总体而言,已发表的数据支持肝脏多层内源性抗氧化防御机制在正常情况下限制病理生理相关LPO发生的观点。只有当这些防御机制严重受损时,铁下垂才成为药物诱导细胞死亡的一种重要模式。
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Journal of Clinical and Translational Hepatology
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