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Chinese expert consensus on the clinical application of molecular diagnostics in hepatobiliary cancers(2024 edition)

Ainiwaer AIZIER ; Cheng JIAMIN ; Lang REN ; Peng TAO ; Bi XINYU ; Lu YINYING

Liver Research.2024;8(4):195-206. doi:10.1016/j.livres.2024.11.005

Hepatocellular carcinoma(HCC)and biliary tract cancer(BTC)are significant health challenges in China because of their high prevalence and mortality rates.Advances in molecular diagnostics have opened new avenues for personalized treatment strategies.This consensus provides a comprehensive update on the clinical applications of molecular diagnostics in HCC and BTC and addresses the urgent need for personalized treatment strategies tailored to the Chinese population,emphasizing the importance of molecular markers in guiding targeted therapies and immunotherapies.By employing the Delphi method and the Grading of Recommendations Assessment,Development,and Evaluation system,the expert panel formulated evidence-based recommendations for the use of molecular diagnostics in the clinical management of HCC and BTC.Key molecular markers,such as isocitrate dehydrogenase(IDH)1 and 2,fibroblast growth factor receptor 2(FGFR2),BRAF V600E,human epidermal growth factor receptor 2(HER2),rearranged during transfection(RET),and neurotrophic tyrosine receptor kinase(NTRK),are highlighted for their roles in optimizing treatment regimens.The consensus also explores the signifi-cance of emerging biomarkers,such as tumor mutation burden and microsatellite instability,in pre-dicting responses to immune checkpoint inhibitors.The recommendations aim to enhance precision medicine approaches,improve patient outcomes,and foster the integration of molecular diagnostics into routine clinical practice.

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Chinese clinical practice guidelines for pediatric split liver transplantation

Fu BINSHENG ; Feng XIAO ; Liu JIANRONG ; Ren JIE ; Wang JIN ; Yi SHUHONG ; Yang YANG

Liver Research.2024;8(4):207-217. doi:10.1016/j.livres.2024.11.002

Liver transplantation is an effective treatment for end-stage liver disease in children,and its clinical efficacy has been validated.Split liver transplantation(SLT)can effectively expand the donor liver pool for children.SLT for children has unique clinical characteristics and principles.Establishing technical operation specifications for pediatric SLT plays a significant role in improving clinical efficacy.In this paper,clinical practice guidelines on pediatric SLT were established in the aspect of donor and donor liver evaluation,donor-recipient matching,and ductal segmentation and reconstruction of donor liver,aiming to standardize the technical process,optimize surgical operational details,minimize the risk of com-plications of SLT for children,further promoting the rapid development of pediatric SLT in China.

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Current status and new directions for hepatocellular carcinoma diagnosis

Jinqi TU ; Bo WANG ; Xiaoming WANG ; Kugeng HUO ; Wanting HU ; Rongli ZHANG ; Jinyao LI ; Shijie ZHU ; Qionglin LIANG ; Shuxin HAN

Liver Research.2024;8(4):218-236. doi:10.1016/j.livres.2024.12.001

Liver cancer ranks as the sixth most common cancer globally,with hepatocellular carcinoma(HCC)accounting for approximately 75％-85％of cases.Most patients present with moderately advanced disease,while those with advanced HCC face limited and ineffective treatment options.Despite diagnostic efforts,no ideal tumor marker exists to date,highlighting the urgent clinical need for improved early detection of HCC.A key research objective is the development of assays that target specific pathways involved in HCC progression.This review explores the pathological origin and development of HCC,providing insights into the mechanistic rationale,clinical statistics,and the advantages and limitations of commonly used diagnostic tumor markers.Additionally,it discusses the potential of emerging biomarkers for early diagnosis and offers a brief overview of relevant assay methodologies.This review aims to summarize existing markers and investigate new ones,providing a basis for subsequent research.

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Cigarette smoking and alcohol-related liver disease

Hui-Min LIN ; Jing-Rong ZHANG ; Meng-Xue LI ; Hui HOU ; Hua WANG ; Yan HUANG

Liver Research.2024;8(4):237-245. doi:10.1016/j.livres.2024.12.002

China is a major consumer of alcohol and tobacco.Tobacco and alcohol use are closely linked,with up to 90％of alcoholics having a history of tobacco use,and heavy smokers also tending to be alcoholics.Alcohol-related liver disease(ALD),one of the most common and serious complications of chronic alcohol intake,involving hepatic steatosis,hepatitis,hepatic fibrosis,cirrhosis and hepatocellular carci-noma(HCC),has become one of the globally prevalent chronic diseases.An increasing number of studies have focused on the association between smoking and ALD and explored the mechanisms involved.Clinical evidence suggests that smoking has a negative impact on the incidence and severity of fatty liver disease,progression of liver fibrosis,development of HCC,prognosis of patients with advanced liver disease,and alcohol-related liver transplant recipients.The underlying mechanisms are complex and involve different pathophysiological pathways,including free radical exposure,endoplasmic reticulum stress,insulin resistance,and oncogenic signaling.This review discusses the deleterious effects of smoking on ALD patients and the possible underlying mechanisms at several levels.It emphasizes the importance of discouraging smoking among ALD patients.Finally,the pathogenic role of electronic cigarettes,which have emerged in recent years,is discussed,calling for an emphasis on social missions for young people.

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Application of mesenchymal stem cells in liver fibrosis and regeneration

Zhenyu LIU ; Junkai REN ; Cheng QIU ; Ying WANG ; Tong ZHANG

Liver Research.2024;8(4):246-258. doi:10.1016/j.livres.2024.11.004

Liver transplantation remains the most effective treatment for end-stage liver disease(ESLD),but it is fraught with challenges such as immunosuppression,high risk and cost,and donor shortage.In recent years,stem cell transplantation has emerged as a promising new strategy for ESLD treatment,with mesenchymal stem cells(MSCs)gaining significant attention because of their unique properties.MSCs can regulate signaling pathways,including hepatocyte growth factor/c-Met,Wnt/beta(β)-catenin,Notch,transforming growth factor-β1/Smad,interleukin-6/Janus kinase/signal transducer and activator of transcription 3,and phosphatidylinositol 3-kinase/PDK/Akt,thereby influencing the progression of liver fibrosis and regeneration.As a promising stem cell type,MSCs offer numerous advantages in liver disease treatment,including low immunogenicity;ease of acquisition;unlimited proliferative ability;pluripotent differentiation potential;immunomodulatory function;and anti-inflammatory,antifibrotic,and anti-apoptotic biological characteristics.This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration.MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors,regulation of signaling pathways,and modulation of immune responses.MSCs have shown good therapeutic effects in preclinical and clinical studies,providing new strategies for liver disease treatment.However,challenges still exist in the clinical application of MSCs,including low differentiation efficiency and limited sources.This review provides a reference for MSC application in liver disease treatment.With the continuous progress in MSC research,MSCs are expected to achieve breakthroughs in liver disease treatment,thereby improving patient treatment outcomes.

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Growth differentiation factor 7 alleviates the proliferation and metastasis of hepatocellular carcinoma

Jianyong ZHUO ; Huigang LI ; Peiru ZHANG ; Chiyu HE ; Wei SHEN ; Xinyu YANG ; Zuyuan LIN ; Runzhou ZHUANG ; Xuyong WEI ; Shusen ZHENG ; Xiao XU ; Di LU

Liver Research.2024;8(4):259-268. doi:10.1016/j.livres.2024.09.006

Background and aims:Inflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma(HCC).However,the tumor-protective functions of growth differentiation factors(GDFs)in HCC are yet to be clarified.In this study,we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo ex-periments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC.Methods:The gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues.A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression.Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC.Results:The mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in para-tumors(P＜0.001).Kaplan-Meier analysis showed that decreased GDF7 expression in HCC was asso-ciated with worse overall survival(5-year rate:61.8％vs.27.5％,P＜0.001)and increased recurrence risk(P＜0.001).Multivariate Cox regression analysis demonstrated that low GDF7 expression,the presence of microvascular invasion,and elevated alpha-fetoprotein(AFP)levels were independent risk factors for tumor recurrence and poor survival.Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model.GDF7 knockdown promoted migration and invasion via epithelial-mesenchymal transition.Meanwhile,a negative correlation between JunB proto-oncogene(JUNB)and GDF7 was observed in HCC tissues.Modulating JUNB levels altered GDF7 protein expression.Conclusions:GDF7 is a potential biomarker for predicting superior outcomes in patients with HCC.GDF7 amplification is a potential therapeutic option for HCC.

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Kehuang capsule inhibits MAPK and AKT signaling pathways to mitigate CCl4-induced acute liver injury

Qinyu NI ; Jiacheng LIN ; Weifan HUANG ; Liu YANG ; Ran LI ; Tianzhi TU ; Guangfu HE ; Yueqiu GAO ; Xuehua SUN ; Xiaoni KONG ; Xiaojun ZHU

Liver Research.2024;8(4):269-281. doi:10.1016/j.livres.2024.11.006

Background and aims:Kehuang(KH)capsule is an herbal medical product approved for the treatment of liver diseases,including liver injury,in China.However,the mechanism is still unclear.This study aimed to elucidate the protective effects of KH capsule against carbon tetrachloride(CCl4)-induced acute liver injury(ALI)in a murine model.Methods:Mice were randomly divided into control,model(CCl4),CCl4+KH_Low and CCl4+KH_High group.Liver enzyme levels and histological changes were assessed to evaluate liver injury.Oxidative stress markers and inflammatory cell infiltration in liver tissues were measured.Additionally,network pharmacology was employed to explore the potential mechanisms of KH capsule.Results:KH capsule significantly reduced serum alanine aminotransferase(ALT)and aspartate amino-transferase(AST)levels,as well as the necrotic area in liver tissue.KH capsule also decreased the infil-tration of macrophages and neutrophils,thereby inhibiting the expression of interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α),and interleukin-1 beta(IL-1β).Furthermore,KH capsule decreased liver malondialdehyde(MDA)levels and increased superoxide dismutase(SOD)activity.The number of ter-minal deoxynucleotidyl transferase(TdT)-mediated dUTP nick-end labeling(TUNEL)-positive cells in liver tissue was also reduced.The expression of nuclear factor erythroid 2 related factor 2(Nrf2)and heme oxygenase-1(HO-1)proteins was significantly elevated,while the protein expression of cyto-chrome P450 2E1(CYP2E1)was significantly reduced.Mass spectrometry identified genistein,galangin,wogonin,skullcapflavone Ⅱ,and hispidulin as potential active ingredients of KH capsule.Network pharmacology analysis revealed enrichment in the mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT)signaling pathways.Western blot analysis confirmed that KH capsule suppressed AKT,extracellular signal-regulated kinase(ERK),and p38 signaling.Conclusions:These findings suggest that KH capsule could exert protective effects against CCl4-induced ALI,with the inhibition of MAPK and PI3K-AKT signaling pathways playing a crucial role in its mecha-nism of action.

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Single-cell and machine learning approaches uncover intrinsic immune-evasion genes in the prognosis of hepatocellular carcinoma

Jiani WANG ; Xiaopeng CHEN ; Donghao WU ; Changchang JIA ; Qinghai LIAN ; Yuhang PAN ; Jiumei YANG

Liver Research.2024;8(4):282-294. doi:10.1016/j.livres.2024.11.001

Background and aims:Hepatocellular carcinoma(HCC)is a tumor of high heterogeneity and complexity,which poses significant challenges to effective treatment and patient prognosis because of its immune evasion characteristics.To address these issues,single-cell technology and machine learning methods have emerged as a promising approach to identify genes associated with immune escape in HCC.This study aimed to develop a prognostic risk score model for HCC by identifying intrinsic immune-evasion genes(IIEGs)through single-cell technology and machine learning,providing insights into immune infiltration,enhancing predictive accuracy,and facilitating the development of more effective treatment strategies.Materials and methods:The study utilized data from The Cancer Genome Atlas database to analyze gene expression profiles and clinical data related to intrinsic immune evasion in patients with HCC.Various tools,including the Human Protein Atlas,cBioPortal,single-cell analysis,machine learning,and Kaplan-Meier plot,were used to analyze IIEGs.Functional enrichment analysis was conducted to explore po-tential mechanisms.In addition,the abundance of infiltrating cells in the tumor microenvironment was investigated using single-sample gene set enrichment analysis,CIBERSORT,xCELL,and tumor immu-nophenotype algorithms.The expression of glycosylphosphatidylinositol anchor attachment 1(GPAA1)was examined in the clinical sample of HCC by quantitative real-time polymerase chain reaction,Western blotting,and immunohistochemical staining.Results:Univariate Cox analysis identified 63 IIEGs associated with the prognosis of HCC.Using random forest,least absolute shrinkage and selection operator regression analysis,and support vector machine,a risk score model consisting of six IIEGs(carbamoyl-phosphate synthetase 2,aspartate transcarbamylase,and dihydroorotase(CAD),phosphatidylinositol glycan anchor biosynthesis class U(PIGU),endoplasmic reticulum membrane protein complex subunit 3(EMC3),centrosomal protein 55(CEP55),autophagy-related 10(ATG10),and GPAA1)developed,which was validated using 10 pairs of HCC and adjacent non-cancerous samples.Based on the calculated median risk score,HCC samples were categorized into high-and low-risk groups.The Kaplan-Meier curve analysis showed that the high-risk group had a worse prognosis compared with the low-risk group.Time-dependent receiver operating characteristic analysis demonstrated the accurate predictive capability of the risk score model for HCC prognosis.Furthermore,immune infiltration analysis showed a positive correlation between the risk score model and 40 immune checkpoint genes as well as Th2 cells.Conclusions:A prognostic risk score model was formulated by six IIEG signatures and showed promise in predicting the prognosis of patients diagnosed with HCC.The utilization of the IIEG risk score as a novel prognostic index,together with its significance as a valuable biomarker for immunotherapy in HCC,provides benefit for patients with HCC in determining therapeutic strategies for clinical application.

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Long-term efficacy and safety of tenofovir alafenamide,tenofovir disoproxil fumarate,and entecavir in treating hepatitis B virus-related acute-on-chronic liver failure:A 144-week data analysis

Yeqiong ZHANG ; Wenxiong XU ; Zhexuan DENG ; Lu WANG ; Xingrong ZHENG ; Xiang ZHU ; Xuejun LI ; Jianguo LI ; Xin SHU ; Jing LAI ; Liang PENG ; Chan XIE

Liver Research.2024;8(4):295-303. doi:10.1016/j.livres.2024.10.001

Background and aims:Antiviral therapy is essential for hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF).No data are available on the long-term prognosis or safety of tenofovir alafenamide(TAF),tenofovir disoproxil fumarate(TDF),or entecavir(ETV)in treating HBV-ACLF globally.This study was conducted to investigate the long-term efficacy and safety of the three nucleos(t)ide analogs in the treatment of HBV-ACLF.Methods:In this prospective,real-world cohort study,patients with HBV-ACLF were assigned to the TAF,TDF,and ETV groups.A total of 199 patients completed the 144-week follow-up.After propensity score matching(PSM),44 patients remained in each group for further analysis of survival status,incidence of hepatocellular carcinoma(HCC),virological response,and liver and renal function indicators.Results:In the original cohort,HCC developed in one patient in each group.No serious drug-related adverse events were observed.In the PSM cohort,the 144-week survival rates were 56.82％,75.00％,and 59.09％in the TAF,TDF,and ETV groups,respectively(P=0.118).When stratified into noncirrhosis and cirrhosis subgroups at baseline,the survival rate of the ETV group was slightly lower than that of the TAF and TDF group in noncirrhosis patients(P=0.338),and the survival rate of the TAF group was slightly lower than that of the TDF and ETV group in cirrhosis patients(P=0.052),but the differences were not statistically significant.The long-term overall survival rates in the TAF,TDF,and ETV groups were comparable.After 144 weeks,no significant difference in the virological response rate or liver or renal function indicators was found among the three groups,except for the level of aspartate amino-transferase,which was significantly higher in the TDF group than in the ETV group at week 144(P=0.001).Conclusions:There were no significant differences in the survival rate,incidence of HCC,efficacy or safety associated with the use of these three nucleos(t)ide analogs in treating HBV-ACLF.Trial registration:ClinicalTrials.gov NCT03920618.

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Bile acids and their receptors in hepatic immunity

Fiorucci STEFANO ; Marchianò SILVIA ; Distrutti ELEONORA ; Biagioli MICHELE

Liver Research.2025;9(1):1-16. doi:10.1016/j.livres.2025.01.005

Similarly to conventional steroids,bile acids function as signaling molecules,acting on a family of membrane and nuclear receptors.The best-characterized bile acid-regulated receptors are the farnesoid X receptor,activated by primary bile acids,and the G-protein-coupled bile acid receptor 1(also known as Takeda G protein-coupled receptor 5),which is activated by secondary bile acids,such as lithocholic acid(LCA)and deoxycholic acid.Both the farnesoid X receptor and G-protein-coupled bile acid receptor 1 are expressed in cells of innate immunity,monocytes/macrophages,and natural killer cells.Their activation in these cells provides counter-regulatory signals that are inhibitory in nature and attenuate inflam-mation.In recent years,however,it has been increasingly appreciated that bile acids biotransformations by intestinal microbiota result in the formation of chemically different secondary bile acids that potently regulate adaptive immunity.The 3-oxoLCA and isoalloLCA,two LCA derivatives,bind receptors such as the retinoic acid receptor-related orphan receptor gamma t(RORγt)and the vitamin D receptor(VDR)that are expressed only by lymphoid cells,extending the regulatory role of bile acids to T cells,including T-helper 17 cells and type 3 innate lymphoid cells(ILC3).In this novel conceptual framework,bile acids have emerged as one of the main components of the postbiota,the waste array of chemical mediators generated by the intestinal microbiota.Deciphering the interaction of these mediators with the immune system in the intestine and liver is a novel and fascinating area of bile acid renaissance.

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