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临床与转化肝病杂志（英文版）
临床与转化肝病杂志（英文版）

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临床与转化肝病杂志（英文版）/Journal Journal of Clinical and Translational Hepatology
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    Development of a Widely Applicable and Simple Prognostic Score for Patients with Acute-on-chronic Liver Failure

    Zhenjun YuYu ZhangYuhan LiFeng Zhou...
    867-878页
    查看更多>>摘要：Background and Aims: Acute-on-chronic liver failure (ACLF) tends to progress rapidly with high short-term mor-tality. We aimed to create a widely applicable, simple prog-nostic (WASP) score for ACLF patients. Methods: A retro-spective cohort of ACLF cases recruited from three centers in China were divided into training and validation sets to de-velop the new score. A prospective longitudinal cohort was recruited for further validation. Results: A total of 541 cas-es were included in the training set, and seven independent ACLF prognostic factors were screened to construct a new quantitative WASP-ACLF table. In the validation set of 671 cases, WASP-ACLF showed better predictive ability for 28-day and 90-day mortality than the currently used prognos-tic scores at baseline, day 3, week 1, and week 2. The pre-dictive efficacy and clinical validity of the model improved over time. Patients were assigned to low-, intermediate-, and high-risk groups by their WASP-ACLF scores. Compared with the other two groups, intermediate-risk patients had a more uncertain prognosis, with a 90-day mortality of 44.4–50.6％. Sequential assessments at weeks 1 and 2 found the 90-day mortality of intermediate-risk groups was <20％ for patients with a ≥2 point decrease in WASP-ACLF and was up to 56％ for patients with a ≥2 points increase. Similar re-sults were observed in prospective data. Conclusions: The new ACLF prognostic score was simple, widely applicable, and had good predictive efficacy. Continuous assessments and trend of change in WASP-ACLF need to be considered, especially for intermediate-risk patients.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普

    Regulatory Effect of JAK2/STAT3 on the Immune Function of Endotoxin-tolerant Dendritic Cells and its Involvement in Acute Liver Failure

    Yukai ChenChaochen HouNaibin YangYanyan Yang...
    879-890页
    查看更多>>摘要：Background and Aims: Acute liver failure (ALF) is a poten-tially fatal clinical syndrome with no effective treatment. This study aimed to explore the role of Janus kinase 2/signal trans-ducer and activator of transcription 3 (JAK2/STAT3) pathway in modulating the phenotype and immune function of en-dotoxin-tolerant dendritic cells (ETDCs). In addition, we ex-plored the use of EDTCs in an experimental model of ALF and investigated the associated mechanisms. Methods: In the in vitro experiment, ETDCs were transfected with adenovirus to induce SOCS1+/+ETDCs and SOCS1−/−ETDCs. Thereafter, costimulatory molecules and mixed lymphocyte reaction were assessed. Experimental mice were randomly divided into nor-mal control, ALF, ALF+mock-ETDCs, ALF+SOCS1+/+ETDCs, ALF+AG490, and ALF+AG490+SOCS1+/+ETDCs groups. We examined the therapeutic effect of adoptive cellular immuno-therapy by tail-vein injection of target ETDCs 12 h before ALF modeling. AG490, a JAK2/STAT3 inhibitor, was used in the in vivo experiment to further explore the protective mechanism of SOCS1+/+ETDCs. Results: Compared with control ETDCs, SOCS1+/+ETDCs had lower expression of costimulatory mol-ecules, weaker allostimulatory ability, lower levels of IL-6 and TNF-α expression and higher IL-10 secretion. SOCS1−/−ETDCs showed the opposite results. In the in vivo experiments, the ALF+SOCS1+/+ETDCs and ALF+AG490+SOCS1+/+ETDCs groups showed less pathological damage and suppressed activation of JAK2/STAT3 pathway. The changes were more pronounced in the ALF+AG490+SOCS1+/+ETDCs group. In-fusion of SOCS1+/+ETDCs had a protective effect against ALF possibly via inhibition of JAK2 and STAT3 phosphorylation. Conclusions: The SOCS1 gene had an important role in in-duction of endotoxin tolerance. SOCS1+/+ETDCs alleviated lipopolysaccharide/D-galactosamine-induced ALF by down-regulating the JAK2/STAT3 signaling pathway.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普

    A Prognostic Nomogram for Hepatocellular Carcinoma Based on Wound Healing and Immune Checkpoint Genes

    Beiyuan HuXiaotian ShenWei QinLan Zhang...
    891-900页
    查看更多>>摘要：Background and Aims: Wound healing and tumor progres-sion share some common biological features; however, how variations in wound healing patterns affect hepatocellular carcinoma (HCC) prognosis remains unclear. Methods: We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas (TCGA) and the Internation-al Cancer Genome Consortium (ICGC) and correlated them with immune infiltration and the expression levels of immune checkpoint genes. A risk score, which we named the "heal. immune" score, was established via stepwise Cox estima-tion. We constructed a nomogram based on age, sex, TNM stage, and heal.immune score and explored its predictive value for HCC prognosis. Seventy-four clinical patients were enrolled in this study, and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an in-dependent validation group. Results: We identified two dis-tinct wound healing patterns in HCC. The biological processes of healing cluster 1 (C1) are related to metabolism, while those of healing cluster 2 (C2) are related to the inflamma-tory response and immune cell accumulation. A total of 565 wound healing-related genes (based on Gene Ontology) and 25 immune checkpoint genes were considered. By analyz-ing differentially expressed genes and implementing a step-wise Cox estimation analysis, six genes with p values less than 0.02 in a multivariate Cox estimation were chosen as the "heal.immune" gene set (FCER1G, PLAT, ITGA5, CCNB1, CD86 and CD40). The "heal.immune" gene set, as an OS risk factor, was further validated in Fudan cohort. We constructed a nomogram to predict the 1-, 3- and 5-year overall survival (OS) in the TCGA cohort. The area under curve vales of the receiver characteristic operator curves were 0.82, 0.76 and 0.73 in the training group and 0.84, 0.76 and 0.72 in the test group. Conclusions: We established a prognostic nomogram based on the heal.immune gene signature, which includes six wound healing- and immunity-related genes. This nomogram accurately predicts the OS of HCC patients.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普

    Establishment of a Prognostic Model for Hepatocellular Carcinoma Based on Bioinformatics and the Role of NR6A1 in the Progression of HCC

    Zhong-Hua LinJie ZhangLi-Kun ZhuangYong-Ning Xin...
    901-912页
    查看更多>>摘要：Background and Aims: Generally acceptable prognostic models for hepatocellular carcinoma (HCC) are not avail-able. This study aimed to establish a prognostic model for HCC by identifying immune-related differentially expressed genes (IR-DEGs) and to investigate the potential role of NR6A1 in the progression of HCC. Methods: Bioinformat-ics analysis using The Cancer Genome Atlas and ImmPort databases was used to identify IR-DEGs. Lasso Cox re-gression and multivariate Cox regression analysis were used to establish a prognostic model of HCC. Kaplan-Meier analysis and the receiver operating characteristic (ROC) curves were used to evaluate the performance of the prog-nostic model, which was further verified in the Interna-tional Cancer Genome Consortium (ICGC) database. Gene set enrichment analysis was used to explore the potential pathways of NR6A1. Cell counting kit 8, colony formation, wound healing, and Transwell migration assays using Huh7 cells, and tumor formation models in nude mice were con-ducted. Results: A prognostic model established based on ten identified IR-DEGs including HSPA4, FABP6, MAPT, NDRG1, APLN, IL17D, LHB, SPP1, GLP1R, and NR6A1, ef-fectively predicted the prognosis of HCC patients, was con-firmed by the ROC curves and verified in ICGC database. NR6A1 expression was significantly up-regulated in HCC patients, and NR6A1 was significantly associated with a low survival rate. Gene set enrichment analysis showed the enrichment of cell cycle, mTOR, WNT, and ERBB sign-aling pathways in patients with high NR6A1 expression. NR6A1 promoted cell proliferation, invasiveness, migra-tion, and malignant tumor formation and growth in vitro and in vivo. Conclusions: An effective prognostic model for HCC, based on a novel signature of 10 immune-related genes, was established. NR6A1 was up-regulated in HCC and was associated with a poor prognosis of HCC. NR6A1 promoted cell proliferation, migration, and growth of HCC, most likely through the cell cycle, mTOR, WNT, and ERBB signaling pathways.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普

    Upregulation of TMCO3 Promoting Tumor Progression and Contributing to the Poor Prognosis of Hepatocellular Carcinoma

    Tianxing DaiLinsen YeMingbin DengGuozhen Lin...
    913-924页
    查看更多>>摘要：Background and Aims: TMCO3, a member of the monova-lent cation:proton antiporter-2 family, has been annotated as a Na+/H+ antiporter, but its pathophysiological role is still unclear. We aimed to investigate the expression pro-file, prognostic significance, and oncogenic role of TMCO3 in hepatocellular carcinoma (HCC). Methods: Bioinformatic analyses were conducted using transcriptome data from pub-lic databases to determine the expression, prognosis, and functional enrichment of TMCO3 in HCC. TMCO3 expression was further validated in an independent HCC cohort from our institution. The oncogenic role of TMCO3 in HCC was evaluated using in vitro and in vivo experiments. Results: The upregulated expression of TMCO3 was identified and verified in multiple HCC cohorts, and worse overall survival and recurrence-free survival were observed in patients with high TMCO3 expression. The overexpression and knockdown of TMCO3 could affect the proliferation and metastasis of HCC cells, which might be associated with the p53-induced cell cycle regulation and epithelial-mesenchymal transition, respectively. Notably, significant correlations were found be- tween dysregulated TMCO3 and various antitumor agents. Its role in sorafenib sensitivity was further identified by in vitro experiments and the potential mechanism might be related to the regulation of apoptosis. Positive correlations were also identified between upregulation of TMCO3 and the increased infiltration of various immune cells and the elevated expression of multiple immune checkpoint genes in HCC. Conclusions: Upregulated TMCO3 could act as an on- cogenic mediator and promote sorafenib resistance in HCC, providing a potential therapeutic target for HCC treatment.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普

    A Novel mRNA Signature Related to Immunity to Predict Survival and Immunotherapy Response in Hepatocellular Carcinoma

    Chenhao ZhouJialei WengYuan GaoChunxiao Liu...
    925-938页
    查看更多>>摘要：Background and Aims: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the incidence and mortality rates are increasing. Given the limited treat-ments of HCC and promising application of immunotherapy for cancer, we aimed to identify an immune-related prog-nostic signature that can predict overall survival (OS) rates and immunotherapy response in HCC. Methods: The initial signature development was conducted using a training data-set from the Cancer Genome Atlas followed by independent internal and external validations from that resource and the Gene Expression Omnibus. A signature based nomogram was generated using multivariate Cox regression analysis. The associations of signature score with tumor immune phenotype and response to immunotherapy were analyzed using single-sample gene set enrichment analysis and tu-mor immune dysfunction and exclusion algorithm. A cohort from Zhongshan Hospital was employed to verify the pre- dictive robustness of the signature regarding prognostic risk and immunotherapy response. Results: The prognostic sig-nature, IGSHCC, consisting of 22 immune-related genes, had independent prognostic ability, with training and validation cohorts. Also, IGSHCC stratified HCC patients with different outcomes in subgroups. The prognostic accuracy of IGSHCC was better than three reported prognostic signatures. The IGSHCC-based nomogram had high accuracy and significant clinical benefits in predicting 3- and 5-year OS. IGSHCC re-flected distinct immunosuppressive phenotypes in low- and high-score groups. Patients with low IGSHCC scores were more likely than those with high scores to benefit from im-munotherapy. Conclusions: IGSHCC predicted HCC prog-nosis and response to immunotherapy, and contributed to individualized clinical management.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普

    Reactive Oxygen Species and Oxidative Stress in the Pathogenesis of MAFLD

    Kathleen ClareJohn F.DillonPaul N.Brennan
    939-946页
    查看更多>>摘要：The pathogenesis of metabolic-associated fatty liver dis-ease (MAFLD) is complex and thought to be dependent on multiple parallel hits on a background of genetic suscep-tibility. The evidence suggests that MAFLD progression is a dynamic two-way process relating to repetitive bouts of metabolic stress and inflammation interspersed with endog-enous anti-inflammatory reparative responses. In MAFLD, excessive hepatic lipid accumulation causes the produc-tion of lipotoxins that induce mitochondrial dysfunction, endoplasmic reticular stress, and over production of reac-tive oxygen species (ROS). Models of MAFLD show marked disruption of mitochondrial function and reduced oxidative capacitance with impact on cellular processes including mi-tophagy, oxidative phosphorylation, and mitochondrial bio-genesis. In excess, ROS modify insulin and innate immune signaling and alter the expression and activity of essential enzymes involved in lipid homeostasis. ROS can also cause direct damage to intracellular structures causing hepatocyte injury and death. In select cases, the use of anti-oxidants and ROS scavengers have been shown to diminish the pro-apoptopic effects of fatty acids. Given this link, endogenous anti-oxidant pathways have been a target of interest, with Nrf2 activation showing a reduction in oxidative stress and inflammation in models of MAFLD. Thyroid hormone recep-tor β (THRβ) agonists and nuclear peroxisome proliferation-activated receptor (PPAR) family have also gained interest in reducing hepatic lipotoxicity and restoring hepatic func-tion in models of MAFLD. Unfortunately, the true interplay between the clinical and molecular components of MAFLD progression remain only partly understood. Most recently, multiomics-based strategies are being adopted for hypoth-esis-free analysis of the molecular changes in MAFLD. Tran-scriptome profiling maps the unique genotype-phenotype associations in MAFLD and with various single-cell tran- scriptome-based projects underway, there is hope of novel physiological insights to MAFLD progression and uncover therapeutic targets.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普

    Pregnancy and Metabolic-associated Fatty Liver Disease: A Clinical Update

    Sherouk FoudaMadhu Mathew VennikandamJoseph M.PappachanCornelius J.Fernandez...
    947-954页
    查看更多>>摘要：The intricate relationship between metabolic-associated fatty liver disease (MAFLD) and maternal complications has rapid- ly become a significant health threat in pregnant women. The presence of MAFLD in pregnancy increases the maternal risk of metabolic complications and comorbidities for both moth- er and baby. The preexistence or development of MAFLD in pregnancy is a complex multifactorial disorder that can lead to further complications for mother and baby. Therefore, as pregnant women are severely underrepresented in clinical research, there is a great need for a fair inclusion of this group in clinical trials. This review aims to explore the ef- fects of MAFLD during pregnancy in the context of maternal complications and outcomes and explore the effects of preg- nancy on the development and progression of MAFLD within the context of maternal obesity, altered metabolic profiles, gestational diabetes and altered hormonal profiles. We also addressed potential implications for the presence of MAFLD during pregnancy and its management in the clinical setting.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Hepatocellular Carcinoma in Non-alcoholic Fatty Liver Disease: Current Progresses and Challenges

    Yu-Xian TengSi XiePing-Ping GuoZhu-Jian Deng...
    955-964页
    查看更多>>摘要：The rising global prevalence of metabolic diseases has in-creased the prevalence of non-alcoholic fatty liver disease (NAFLD), leading to an increase in cases of NAFLD-related hepatocellular carcinoma (HCC). To provide an updated liter-ature review detailing epidemiology, risk factors, pathogenic pathways, and treatment strategies linked to NAFLD-related HCC, we conducted a literature search on PubMed from its inception to December 31, 2021. About 25％ of the glob-al population suffers from NAFLD. The annual incidence of HCC among NAFLD patients is approximately 1.8 per 1,000 person-years. Older age, male sex, metabolic comorbidi-ties, unhealthy lifestyle habits (such as smoking and alcohol consumption), physical inactivity, genetic susceptibility, liver fibrosis, and degree of cirrhosis in NAFLD patients are impor-tant risk factors for NAFLD-related HCC. Therefore, low-calo-rie diet, moderate-intensity exercise, treatment of metabolic comorbidities, and cessation of smoking and alcohol are the main measures to prevent NAFLD-related HCC. In addition, all patients with advanced NAFLD-related fibrosis or cirrho-sis should be screened for HCC. Immune suppression disor-ders and changes in the liver microenvironment may be the main pathogenesis of NAFLD-related HCC. Hepatic resection, liver transplantation, ablation, transarterial chemoemboliza-tion, radiotherapy, targeted drugs, and immune checkpoint inhibitors are used to treat NAFLD-related HCC. Lenvatinib treatment may lead to better overall survival, while immune checkpoint inhibitors may lead to worse overall survival. Giv-en the specific risk factors for NAFLD-related HCC, primary prevention is key. Moreover, the same treatment may dif- fer substantially in efficacy against NAFLD-related HCC than against HCC of other etiologies.
      原文链接:
    • NETL
    • NSTL
    • 万方数据

    Pharmacotherapy for Non-alcoholic Fatty Liver Disease Associated with Diabetes Mellitus Type 2

    Emmanouil S.KoulliasJohn Koskinas
    965-971页
    查看更多>>摘要：Non-alcoholic fatty liver disease (NAFLD) and diabetes mel-litus type 2 commonly coexist as a manifestation of meta-bolic syndrome. The presence of diabetes promotes the pro-gression of simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis, and the presence of NAFLD increases the risk of diabetic complications. This coexistence affects a large part of the population, imposing a great burden on health care systems worldwide. Apart from diet modification and exercise, recent advances in the pharmacotherapy of diabetes offer new prospects regarding liver steatosis and steatohepatitis improvement, enriching the existing algo-rithm and supporting a multifaceted approach to diabetic patients with fatty liver disease. These agents mainly in-clude members of the families of glucagon-like peptide-1 analogues and the sodium-glucose co-transporter-2 inhibi-tors. In addition, agents acting on more than one receptor simultaneously are presently under study, in an attempt to further enhance our available options.
      原文链接:
    • NETL
    • NSTL
    • 万方数据
    • 维普