Journal of Clinical and Translational Hepatology最新文献

{"title":"Oleanolic Acid Restores Drug Sensitivity in Sorafenib-resistant Hepatocellular Carcinoma: Evidence from <i>In Vitro</i> and <i>In Vivo</i> Studies.","authors":"Tongtong Li, Xuan Shen, Tao Zhang, Jiaheng Ren, Wang Wang, Didi Wang, Pengxia Zhang","doi":"10.14218/JCTH.2024.00369","DOIUrl":"10.14218/JCTH.2024.00369","url":null,"abstract":"<p><strong>Background and aims: </strong>Hepatocellular carcinoma (HCC) remains challenging to treat in advanced stages, primarily due to the development of resistance to sorafenib. There is an urgent need for novel therapeutic strategies to overcome this resistance. This study aimed to investigate the potential of oleanolic acid (OA), a natural hepatoprotective compound, in mitigating sorafenib resistance and elucidate its underlying molecular mechanisms.</p><p><strong>Methods: </strong>Sorafenib-resistant Huh7 and HepG2 cell lines were established to mimic the resistant phenotype. The effects of OA on these cells were evaluated by assessing cell invasion, migration, and sensitivity to sorafenib. Gene expression analysis was conducted to identify molecular changes induced by OA treatment, with a focus on <i>fabp3</i> expression.</p><p><strong>Results: </strong>Oleanolic acid significantly inhibited the invasive and migratory capabilities of sorafenib-resistant Huh7 and HepG2 cells (<i>p</i> < 0.01). Furthermore, OA treatment downregulated <i>fabp3</i> expression and restored the cells' sensitivity to sorafenib.</p><p><strong>Conclusions: </strong>Oleanolic acid shows promise as an adjunct therapy for overcoming sorafenib resistance in HCC. By reducing cell aggressiveness and restoring drug sensitivity, OA may enhance the therapeutic efficacy of current treatments for advanced HCC.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"469-483"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234305","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}

{"title":"Improved Discrimination and Predictive Ability of Novel Prognostic Scores for Long-term Mortality in Hospitalized Patients with Cirrhosis.","authors":"Sipu Wang, Gaoyue Guo, Han Wang, Xuqian Zhang, Wanting Yang, Jie Yang, Liping Wu, Chao Sun","doi":"10.14218/JCTH.2025.00004","DOIUrl":"10.14218/JCTH.2025.00004","url":null,"abstract":"<p><strong>Background and aims: </strong>Since the adoption of novel prognostic scores, such as the iterative model for end-stage liver disease (MELD 3.0) and the gender-equity model for liver allocation (GEMA), their utility has markedly expanded to diverse clinical scenarios. However, data concerning their prognostic value in more generalized cirrhotic populations are scarce. In this study, we aimed to elucidate the MELD 3.0/GEMA-Na for long-term mortality risk stratification and refine their usage scope.</p><p><strong>Methods: </strong>This study retrospectively reviewed 310 hospitalized patients with decompensated cirrhosis. Discrimination and stratification were compared between MELD 3.0/GEMA-Na and other scores. Validation was performed in another 120 subjects.</p><p><strong>Results: </strong>In the investigated cohort, the median MELD-Na, MELD 3.0, and GEMA-Na were 9 (7, 12), 12 (10, 17), and 12 (9, 17), respectively. Compared to their predecessors, both MELD 3.0 and GEMA-Na models exhibited consistently better discriminative ability, especially in relation to long-term mortality. This effect was more pronounced for GEMA-Na, which was the only score to present an area under the receiver operating characteristic curve greater than 0.8 up to two years (0.807). Statistical analysis indicated that a MELD 3.0 score of 18 and a GEMA-Na score of 20 were the most optimal cutoffs to rank the risk of death, both of which were independently associated with two-year all-cause transplant-free mortality (MELD 3.0: hazard ratio: 1.13, 95% confidence interval: 1.10, 1.17; GEMA-Na: hazard ratio: 1.12, 95% confidence interval: 1.10, 1.17, both <i>P</i> < 0.001). Similar findings were affirmed in the validation cohort.</p><p><strong>Conclusions: </strong>MELD 3.0 is superior to other MELD-based scores for long-term prognostication in hospitalized patients with cirrhosis, while GEMA-Na demonstrated even better accuracy and performance.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"484-492"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234224","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}

{"title":"Intestinal Depletion of TM6SF2 Exacerbates High-fat Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease through the Gut-liver Axis.","authors":"Li-Zhen Chen, Yu-Rong Wang, Zhen-Zhen Zhao, Shou-Lin Zhao, Cong-Cong Min, Yong-Ning Xin","doi":"10.14218/JCTH.2024.00407","DOIUrl":"10.14218/JCTH.2024.00407","url":null,"abstract":"<p><strong>Background and aims: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common form of chronic liver disease worldwide. This study aimed to explore the role of TM6SF2 in high-fat diet (HFD)-induced MASLD through the gut-liver axis.</p><p><strong>Methods: </strong>The TM6SF2 gut-specific knockout (TM6SF2 GKO) mouse was constructed using CRISPR/Cas9 technology. TM6SF2 GKO and wild-type (CON) mice were fed either a HFD or a control diet for 16 weeks to induce MASLD. Blood, liver, and intestinal lipid content, as well as gut microbiota and serum metabolites, were then analyzed.</p><p><strong>Results: </strong>TM6SF2 GKO mice fed an HFD showed elevated liver and intestinal lipid deposition compared to CON mice. The gut microbiota of HFD-fed TM6SF2 GKO mice exhibited a decreased Firmicutes/Bacteroidetes ratio compared to HFD-fed CON mice. The HFD also reduced the diversity and abundance of the microbiota and altered its composition.Aspartate aminotransferase, alanineaminotransferase, and total cholesterol levels were higher in HFD-fed TM6SF2 GKO mice compared to CON mice, while triglyceride levels were lower. Serum metabolite analysis revealed that HFD-fed TM6SF2 GKO mice had an increase in the expression of 17 metabolites (e.g., LPC [18:0/0-0]) and a decrease in 22 metabolites (e.g., benzene sulfate). The differential metabolites of LPC (18:0/0-0) may serve as HFD-fed TM6SF2 serum biomarkers, leading to MASLD exacerbation in GKO mice.</p><p><strong>Conclusions: </strong>TM6SF2 GKO aggravates liver lipid accumulation and liver injury in MASLD mice. TM6SF2 may play an important role in regulating intestinal flora and the progression of MASLD through the gut-liver axis.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"443-455"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234225","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}

{"title":"Investigation of HO-1 Regulation of Liver Fibrosis Related to Nonalcoholic Fatty Liver Disease Through the SIRT1/TGF-ß/Smad3 Pathway.","authors":"Mengjiao Sun, Xiaoqing Wu, Zhandong Lin, Congyue Zhang, Jiawei Cui, Yaoyao Mao, Yue Shi, Jiaming Zhang, Yuemin Nan","doi":"10.14218/JCTH.2024.00481","DOIUrl":"10.14218/JCTH.2024.00481","url":null,"abstract":"<p><strong>Background and aims: </strong>Heme oxygenase 1 (HO-1) has an influential yet insufficiently investigated effect on Sirtuin 1 (SIRT1), a histone deacetylase activated by nicotinamide adenine dinucleotide, which may impact the transforming growth factor-β (TGF-ß)/Smad3 pathway in nonalcoholic fatty liver disease (NAFLD)-related liver fibrosis. This study aimed to elucidate the regulation of NAFLD-related liver fibrosis induced by HO-1 through the SIRT1/TGF-ß/Smad3 pathway.</p><p><strong>Methods: </strong>HO-1 induction and inhibition were established in C57BL/6J mice fed a methionine- and choline-deficient (MCD) diet. Additionally, wild-type mice were fed either a normal diet or an MCD diet. Hematoxylin and eosin, Masson's trichrome, and Sirius Red staining were used to assess hepatic steatosis, inflammation, and fibrosis. <i>In vitro</i>, plasmid overexpression and small interfering RNA silencing of HO-1 were performed in LX-2 cells. Cell viability was assessed using the Cell Counting Kit-8, and apoptosis was evaluated via terminal deoxynucleotidyl transferase dUTP nick-end labeling and immunofluorescence. Flow cytometry was employed to assess apoptosis and reactive oxygen species production. Western blot and real-time quantitative reverse transcription polymerase chain reaction were used to analyze the mRNA and protein expression of genes related to HO-1, SIRT1, the TGF-ß signaling pathway, and fibrosis.</p><p><strong>Results: </strong>MCD-fed mice developed significant liver damage, including steatosis, inflammatory infiltration, and pericellular fibrosis. Zinc protoporphyrin treatment exacerbated these conditions. Corroborating these findings, silencing HO-1 in LX-2 cells increased the expression of fibrosis-related genes. Furthermore, HO-1 overexpression not only increased SIRT1 expression but also reduced the activity of key regulatory factors in the TGF-ß signaling pathway, suggesting a potential interaction between HO-1 and the SIRT1/TGF-ß pathway.</p><p><strong>Conclusions: </strong>HO-1 inhibits the activation of the TGF-ß/Smad3 pathway in NAFLD-related liver fibrosis through SIRT1. These findings provide insights into new therapeutic strategies for treating NAFLD-associated liver fibrosis.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"456-468"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234226","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}

{"title":"Molecular and Histological Profiles and Relevant Imaging Signatures of Intrahepatic Cholangiocarcinoma.","authors":"Huizhen Huang, Feng Chen","doi":"10.14218/JCTH.2024.00410","DOIUrl":"10.14218/JCTH.2024.00410","url":null,"abstract":"<p><p>Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent primary liver cancer, characterized by insidious onset and high malignancy. Many patients are diagnosed at an inoperable stage, and the effectiveness of chemotherapy and radiotherapy remains limited. This study aimed to provide a comprehensive review of the histological classification, genetic alterations, molecular subtypes, and corresponding imaging signatures of iCCA, highlighting its heterogeneity and offering insights into targeted therapy and personalized treatment. The heterogeneity of iCCA poses significant challenges to both targeted therapy and immunotherapy, necessitating in-depth exploration at the molecular and subtyping levels. Investigating genetic variations, signaling pathway alterations, and molecular subtypes can aid in patient stratification. Stratifying iCCA patients allows for more precise treatment selection, ultimately improving survival outcomes. Imaging, as a non-invasive tool, holds substantial potential for predicting subtypes and molecular profiles. It is possible to infer histological and molecular features from imaging, or to interpret imaging signatures in light of known histological and molecular data. This integrative approach, combining external imaging with internal molecular insights, fosters a comprehensive understanding of iCCA's characteristics and enhances clinical management.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"504-515"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234304","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}

{"title":"Ketamine Hepatotoxicity: An Underappreciated Cause of Liver Damage - Analysis by RUCAM.","authors":"Bianca Thakkar, George Y Wu","doi":"10.14218/JCTH.2024.00478","DOIUrl":"10.14218/JCTH.2024.00478","url":null,"abstract":"","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"524-531"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234227","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}

{"title":"Chinese Expert Consensus for the Management of Thrombocytopenia in Cirrhosis.","authors":"Xiaoyuan Xu, Yujuan Guan, Jinghang Xu, Song Yang, Yifan Han, Jidong Jia, Yuemin Nan, Lai Wei, Zhongping Duan, Hui Zhuang","doi":"10.14218/JCTH.2025.00105","DOIUrl":"10.14218/JCTH.2025.00105","url":null,"abstract":"<p><p>Thrombocytopenia in cirrhosis presents significant challenges in clinical practice. To help clinicians rapidly understand and standardize the diagnosis and treatment of this condition, the Liver Fibrosis, Cirrhosis, and Portal Hypertension Group under the Chinese Society of Hepatology, Chinese Medical Association, convened experts across relevant fields to formulate the <i>Expert Consensus for the Management of Thrombocytopenia in Cirrhosis</i>. This consensus aimed to provide evidence-based guidance for clinical diagnosis and treatment.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"516-523"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234223","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}

{"title":"The Role of Novel Immunomodulators in the Treatment of Autoimmune Hepatitis.","authors":"Jing Li, Huanhuan Wang, Jie Lin, Aili Wang, Shuiyin Miao, Huaie Liu","doi":"10.14218/JCTH.2025.00008","DOIUrl":"10.14218/JCTH.2025.00008","url":null,"abstract":"<p><p>Autoimmune hepatitis (AIH) is a chronic, progressive inflammatory liver disease characterized by autoimmune-mediated hepatic injury. Currently, glucocorticoid drugs, primarily prednisone, with or without azathioprine, are commonly recommended as first-line therapeutic agents in treatment guidelines by many scientific associations. However, the primary objective of treatment is to achieve a complete biochemical response, which is defined as the normalization of both transaminases and immunoglobulin G levels within six to twelve months. Ideally, this should also be accompanied by histological remission. Nevertheless, corticosteroid therapy is associated with significant adverse effects, potentially resulting in treatment discontinuation. In this context, it has become evident that standard treatment is inadequate for a proportion of patients, leading to the emergence of other treatment options and lines. Novel immunomodulatory agents, a class of drugs that regulate the body's immune functions, have been confirmed to possess properties that modulate immune balance and induce immune tolerance. In recent years, these agents have played an increasingly significant role in the clinical management of AIH. This article provided an in-depth review of recent advancements in the development of novel immunomodulators, including immune cell nucleic acid inhibitors, calmodulin phosphate inhibitors, mammalian target of rapamycin inhibitors, tumor necrosis factor-α inhibitors, interleukin-2, anti-CD20 monoclonal antibodies, and B cell-activating factor inhibitors, for the treatment of AIH.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 6","pages":"493-503"},"PeriodicalIF":3.1,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12134904/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234306","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}

{"title":"Hydronidone for the Treatment of Liver Fibrosis Associated with Chronic Hepatitis B: Protocol for a Phase 3 Randomized Trial.","authors":"Xiaobo Cai, Yin Qu, Wen Xie, Yanbin Wang, Mengyu Zhao, Ling Zhang, Ying Luo, Ping Yin, Jun Cheng, Lungen Lu","doi":"10.14218/JCTH.2024.00472","DOIUrl":"10.14218/JCTH.2024.00472","url":null,"abstract":"<p><strong>Background and aims: </strong>Liver fibrosis is a key process in the progression of chronic liver diseases. However, there are currently no drugs specifically designed to treat liver fibrosis. Our Phase 2 trial of hydronidone for the treatment of chronic hepatitis B (CHB)-associated liver fibrosis showed that adding hydronidone to entecavir resulted in significant reversal of liver fibrosis. To further evaluate the efficacy of a 270 mg/day dose of hydronidone for treating liver fibrosis associated with CHB, we conducted this Phase 3 trial.</p><p><strong>Methods: </strong>This is a 52-week, randomized (1:1), double-blind, placebo-controlled, multicenter, entecavir-based Phase 3 clinical study conducted at 44 study centers across China. Adult patients aged 18 to 65 years with significant liver fibrosis (defined as an Ishak score ≥ 3 on liver biopsy) associated with CHB were included.</p><p><strong>Results: </strong>The primary endpoint of the trial is to demonstrate the efficacy of fibrosis reversal, defined as a decrease in the Ishak stage score of liver fibrosis by ≥1 after 52 weeks of treatment, compared to baseline.</p><p><strong>Conclusions: </strong>The results of this trial are expected to further support the antifibrotic indication for this novel drug.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 5","pages":"361-366"},"PeriodicalIF":3.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093625","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}

{"title":"Beyond the Cure: Navigating Hepatocellular Risk and Surveillance after Hepatitis C Eradication in the Direct-acting Antiviral Era.","authors":"Chencheng Xie, Ashwani K Singal","doi":"10.14218/JCTH.2024.00499","DOIUrl":"10.14218/JCTH.2024.00499","url":null,"abstract":"<p><p>Direct-acting antivirals (DAAs) have dramatically changed the landscape of chronic hepatitis C virus (HCV) treatment and significantly reduced the risk of HCV-related hepatocellular carcinoma (HCC) after achieving sustained virologic response. However, the risk of HCC persists, particularly in patients with pre-treatment cirrhosis or fibrosis stage 3 (F3), even after DAA-induced viral eradication. While professional guidelines agree on the need for surveillance in cirrhotic patients, there is no consensus regarding surveillance for the pre-treatment F3 population following HCV eradication. The risk of HCC in the F3 population falls below the threshold for cost-effective surveillance. However, co-existing risk factors-such as diabetes, hepatic steatosis, alcohol use, advanced age, and elevated alpha-fetoprotein levels-may warrant reconsideration of HCC surveillance in this group. This underscores the need for an individualized, risk-based approach to HCC surveillance. This review provided a simplified algorithm to assist clinicians in managing patients with HCV after DAA-induced sustained virologic response.</p>","PeriodicalId":15484,"journal":{"name":"Journal of Clinical and Translational Hepatology","volume":"13 5","pages":"418-424"},"PeriodicalIF":3.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144093918","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}