Publications by authors named "Junqi Niu"

195 Publications

A conserved pathway of transdifferentiation in murine Kupffer cells.

Eur J Immunol 2021 Jul 29. Epub 2021 Jul 29.

Department of Laboratory Medicine and Pathology, University of Washington, Seattle, USA.

Abundant long-lived liver-resident macrophages, termed Kupffer cells, are activated during chronic liver injury. They secrete both pro-inflammatory and pro-fibrotic cytokines, which act on hepatic stellate cells causing their trans-differentiation into myofibroblasts that deposit collagen. In other tissues, wound-associated macrophages go further, and transdifferentiate into fibrocytes, secreting collagen themselves. We tested Kupffer cells for this property in two experimental models: mixed non-parenchymal cell culture, and precision-cut liver slice culture. Using the Emr1-Cre transgene as a driver and the RiboTag transgene as a reporter, we found that Kupffer cells undergo transdifferentiation under these circumstances. Over time, they lose the expression of both Kupffer cell-specific and macrophage-specific genes and the transcription factors that control their expression, and they begin to express multiple genes and proteins characteristic of either myofibroblasts or tissue fibroblasts. These effects were strongly conserved between non-parenchymal cell culture and liver tissue slice culture, arguing that such transdifferentiation is a conserved function of Kupffer cells. We conclude that in addition to supporting fibrosis through an action on stellate cells, Kupffer cells also participate in liver fibrosis through trans-differentiation into fibrocytes. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/eji.202049124DOI Listing
July 2021

Safety, tolerability, and pharmacokinetics of the novel hepatitis B virus capsid assembly modulator GST-HG141 in healthy Chinese subjects: a first-in-human single- and multiple-dose escalation trial.

Antimicrob Agents Chemother 2021 Jul 19:AAC0122021. Epub 2021 Jul 19.

Fujian Cosunter Pharmaceutical Co., Ltd., Fuzhou, China.

Hepatitis B virus capsid assembly modulators (HBV CAMs) are promising, clinically validated therapeutic agents for the treatment of chronic hepatitis B (CHB). The safety, tolerability, and pharmacokinetic (PK) profiles of GST-HG141, a novel HBV CAM, were evaluated in healthy Chinese volunteers. This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (50, 100, 200, 300, 400, or 500 mg) study comprising a food-effect investigation (300 mg), and a multiple-ascending-dose (MAD) (100 or 200 mg BID) study. GST-HG141 reached the maximum plasma concentration (C) at 1.25-3.00 h (median T). The exposure exhibited a linear increase, while the mean half-life (t) ranged from 13.096 h to 22.121 h. The exposure of GST-HG141 (300 mg) was higher after food intake by about 2.4-fold. In the MAD study, steady-state was reached at around day 5, and the mean trough steady-state concentrations were 423 and 588 ng/mL for 50 and 100mg cohorts, respectively. The ratios of GST-HG141 accumulation were <1.5. GST-HG141 was well tolerated in healthy Chinese subjects. The rates of adverse events (AEs) in the GST-HG141 cohort did not differ from those of the placebo cohort. GST-HG141 was tolerated in healthy Chinese subjects. The safety and PK profiles of GST-HG141 support the further evaluation of its efficacy in individuals with CHB.
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http://dx.doi.org/10.1128/AAC.01220-21DOI Listing
July 2021

A randomized dose-escalation study on the safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics of a novel recombinant human albumin in healthy subjects.

Eur J Pharm Sci 2021 Jul 3;165:105923. Epub 2021 Jul 3.

Department of Hepatology, First Hospital, Jilin University, Changchun, 130021, Jilin, China. Electronic address:

Objective: Recombinant human albumin (rHA) is an alternative to human serum albumin (HSA) for treating ascites in cirrhosis patients. This study was to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics/pharmacodynamics (PK/PD) of rHA in healthy subjects to guide the design for further clinical trials.

Methods: Healthy subjects aged 18-55 years were enrolled in this double-blinded, first-in-human, placebo-controlled single ascending dose (SAD) (1.25, 5, 10, 20, or 30g) and positive-controlled multiple-dose study (3-day treatment of 10g/day for three cycles every three weeks). The safety was assessed by adverse events (AEs). Antibodies (IgE and IgD) and cytokines were analyzed for immunogenicity. Serum albumin levels and changes in plasma colloid osmotic pressure (PCOP) and hematocrit (HCT) were measured for PK/PD analysis.

Results: rHA was well tolerated as all AEs were assessed as mild or moderate. No severe allergy or difference in the incidence of AEs was observed among the different cohorts in the SAD study or in the different cycles in the multiple-dose study. The incidence of AEs was similar for the rHA and HSA cohort. Antibodies or cytokines showed no changes after drug administration. As expected, serum albumin levels and PCOP increases, and HCT ratio decreases were dose-related with significant differences (p < 0.01). No differences were observed between rHA and HSA.

Conclusion: rHA is safe and well-tolerated in healthy Chinese subjects. rHA and HSA exhibited similar safety, tolerability, and PK/PD profiles. The results support further evaluation of rHA treatment in cirrhotic patients with ascites. The clinical trial registration numbers are CTR20191221 (http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml).
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http://dx.doi.org/10.1016/j.ejps.2021.105923DOI Listing
July 2021

Association of central obesity with hepatocellular carcinoma in patients with chronic hepatitis B receiving antiviral therapy.

Aliment Pharmacol Ther 2021 Aug 22;54(3):329-338. Epub 2021 Jun 22.

Guangzhou, China.

Background: Obesity is typically associated with metabolic dysfunction, but its impact on hepatocellular carcinoma (HCC) remains unclear in patients with chronic hepatitis B (CHB).

Aim: To study the effect of obesity on HCC development in patients with CHB receiving antiviral therapy.

Methods: We included patients from a Chinese multicentre, prospective, observational, treated CHB cohort in this study. General obesity was evaluated by body-mass index (BMI). Central obesity was evaluated by waist circumference, waist-to-hip ratio and waist-to-height ratio.

Results: A total of 5754 nucleos(t)ide analogue treated patients were enrolled in the analysis. The 5-year cumulative incidence of HCC was 2.9%. Waist-to-height ratio performed better in predicting HCC development than BMI, waist circumference or waist-to-hip ratio. Patients with central obesity (defined as waist-to-height ratio >0.5) had significantly higher 5-year incidence of HCC than those without central obesity in the overall population (3.9% vs 2.1%, hazard ratio [HR]: 2.06, P = 0.0001) and 745 propensity score matched pairs (4.7% vs 2.3%, HR: 2.04, P = 0.026), respectively. Besides cirrhosis status and aMAP HCC risk score, central obesity was also independently associated with HCC risk (HR: 1.63, P = 0.013). Waist-to-height ratio gain within 1 year was associated with a significantly higher HCC risk with an adjusted HR value of 1.88 (95% confidence interval: 1.12-3.13, P = 0.017).

Conclusions: Central obesity, evaluated by the waist-to-height ratio, was associated with a twofold increase in HCC risk among CHB patients receiving antiviral treatment, highlighting the important role of abnormal metabolic function in the progression of liver disease.
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http://dx.doi.org/10.1111/apt.16469DOI Listing
August 2021

[Retracted] miR‑154 targeting ZEB2 in hepatocellular carcinoma functions as a potential tumor suppressor.

Oncol Rep 2021 Aug 16;46(2). Epub 2021 Jun 16.

Department of Hepatology, The First Hospital, jilin University, Changchun, jilin 130021, P.R. China.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that certain of the western blotting data shown in Fig. 3C, 4D, 5A and 6D bore unexpected similarities to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to , the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in 34: 3272‑3279, 2015; DOI: 10.3892/or.2015.4321].
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http://dx.doi.org/10.3892/or.2021.8113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218308PMC
August 2021

A new nairo-like virus associated with human febrile illness in China.

Emerg Microbes Infect 2021 Dec;10(1):1200-1208

Department of Emerging Infectious Diseases, The First Hospital of Jilin University, Changchun, People's Republic of China.

Several nairo-like viruses have been discovered in ticks in recent years, but their relevance to public health remains unknown. Here, we found a patient who had a history of tick bite and suffered from a febrile illness was infected with a previously discovered RNA virus, Beiji nairovirus (BJNV), in the nairo-like virus group of the order . We isolated the virus by cell culture assay. BJNV could induce cytopathic effects in the baby hamster kidney and human hepatocellular carcinoma cells. Negative-stain electron microscopy revealed enveloped and spherical viral particles, morphologically similar to those of nairoviruses. We identified 67 patients as BJNV infection in 2017-2018. The median age of patients was 48 years (interquartile range 41-53 years); the median incubation period was 7 days (interquartile range 3-12 days). Most patients were men (70%), and a few (10%) had underlying diseases. Common symptoms of infected patients included fever (100%), headache (99%), depression (63%), coma (63%), and fatigue (54%), myalgia or arthralgia (45%); two (3%) patients became critically ill and one died. BJNV could cause growth retardation, viremia and histopathological changes in infected suckling mice. BJNV was also detected in sheep, cattle, and multiple tick species. These findings demonstrated that the newly discovered nairo-like virus may be associated with a febrile illness, with the potential vectors of ticks and reservoirs of sheep and cattle, highlighting its public health significance and necessity of further investigation in the tick-endemic areas worldwide.
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http://dx.doi.org/10.1080/22221751.2021.1936197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212832PMC
December 2021

Liver sinusoidal endothelial cells are implicated in multiple fibrotic mechanisms.

Mol Biol Rep 2021 Mar 17;48(3):2803-2815. Epub 2021 Mar 17.

Department of Hepatology, The First Hospital of Jilin University, NO. 71, Xinmin Street, Changchun, 130021, Jilin, China.

Chronic liver diseases are attributed to liver injury. Development of fibrosis from chronic liver diseases is a dynamic process that involves multiple molecular and cellular processes. As the first to be impacted by injury, liver sinusoidal endothelial cells (LSECs) are involved in the pathogenesis of liver diseases caused by a variety of etiologies. Moreover, capillarization of LSECs has been recognized as an important event in the development of chronic liver diseases and fibrosis. Studies have reported that various cytokines (such as vascular endothelial growth factor, transforming growth factor-β), and pathways (such as hedgehog, and Notch), as well as epigenetic and metabolic factors are involved in the development of LSEC-mediated liver fibrosis. This review describes the complexity and plasticity of LSECs in fibrotic liver diseases from several perspectives, including the cross-talk between LSECs and other intra-hepatic cells. Moreover, it summarizes the mechanisms of several kinds of LSECs-targeting anti-fibrosis chemicals, and provides a theoretical basis for future studies.
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http://dx.doi.org/10.1007/s11033-021-06269-1DOI Listing
March 2021

Src homolog and collagen homolog1 isoforms in acute and chronic liver injuries.

Life Sci 2021 May 1;273:119302. Epub 2021 Mar 1.

Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address:

Src homolog and collagen homolog (SHC) proteins are adaptor proteins bound to cell surface receptors that play an important role in signal transduction and related diseases. As an important member of the SHC protein family, SHC1 regulates cell proliferation and apoptosis, reactive oxygen species (ROS) production, and oxidative stress. Three isomeric proteins namely, p46shc, p52shc, and p66shc, are produced from the same SHC1 gene locus. All the three proteins are found in the liver, and are widely expressed in various hepatic cells. SHC1 has been proven to be associated with acute and chronic liver injuries of different etiologies, and plays important roles in liver fibrosis and hepatocellular carcinoma (HCC). Therefore, this review summarizes recent studies that discuss and explore the role of SHC1 in the occurrence and progression of liver diseases. We also provide a theoretical basis for future studies.
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http://dx.doi.org/10.1016/j.lfs.2021.119302DOI Listing
May 2021

Seraprevir and sofosbuvir for treatment of chronic hepatitis C virus infection: A single-arm, open-label, phase 3 trial.

J Gastroenterol Hepatol 2021 Jan 24. Epub 2021 Jan 24.

Cirrhosis Department, Zhengzhou Sixth Municipal People's Hospital, Zhengzhou, China.

Background And Aim: This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis.

Methods: Treatment-naive or interferon-experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12).

Results: Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post-treatment course and 3 discontinued follow-up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention.

Conclusions: The all-oral, ribavirin-free regimen of seraprevir and sofosbuvir is an effective and well-tolerated treatment option for Chinese patients mono-infected with HCV, including those with a history of interferon treatment.
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http://dx.doi.org/10.1111/jgh.15412DOI Listing
January 2021

Neutrophil-to-Lymphocyte Ratio and Albumin: New Serum Biomarkers to Predict the Prognosis of Male Alcoholic Cirrhosis Patients.

Biomed Res Int 2020 21;2020:7268459. Epub 2020 Dec 21.

Department of Hepatology, First Hospital of Jilin University, Xinmin Street, No. 71, Changchun, Jilin Province 130021, China.

Background And Aims: Alcohol-associated liver disease is exhibiting an increasing disease burden. In terms of pathogenesis, inflammation is closely related to alcohol-induced liver injury. The neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory biomarker. Here, we aim to evaluate the role of the NLR and other biomarkers in predicting short-term mortality in alcoholic cirrhotic patients.

Methods: This was a retrospective study that included 459 male alcoholic cirrhosis patients. Among them, 345 patients completed follow-up. Based on their 30-day mortality information, patients were separated into surviving and nonsurviving groups. Demographic, clinical, and biochemical features were collected for further analysis. Logistic regression was used to identify factors associated with short-term mortality, and receiver operating characteristic (ROC) curve analysis was used to establish the predictive value of these factors.

Results: The prognostic scores were significantly higher in the nonsurviving group than in the surviving group: NLR: 5.5 vs. 3.2 ( < 0.001), model for end-stage liver disease (MELD): 15.4 vs. 7.9 ( < 0.001), Maddrey's discriminant function (MDF): 39.8 vs. 12.7 ( < 0.001), and the integrated MELD (i-MELD): 37.9 vs. 28.4 ( < 0.001). Logistic regression demonstrated that albumin (ALB), NLR, and i-MELD values were significantly correlated with patient death in 30 days. On ROC analysis, the diagnostic accuracy for 30-day mortality of the NLR (area under the ROC curve (AUROC) of 0.72, < 0.001) was similar to that of the MELD or i-MELD (AUROCs of 0.71 and 0.74, respectively, < 0.001). The new biomarker, NLA, calculated as 100 × NLR/ALB, had the best prognostic value. The cutoff values of the NLR and NLA for predicting 30-day mortality were 4.2 and 19.6, respectively.

Conclusions: The NLR and its related biomarker NLA are simple and robust predictors of 30-day mortality in alcoholic cirrhosis patients.
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http://dx.doi.org/10.1155/2020/7268459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769654PMC
December 2020

Serum HBV RNA correlated with intrahepatic cccDNA more strongly than other HBV markers during peg-interferon treatment.

Virol J 2021 01 6;18(1). Epub 2021 Jan 6.

Department of Hepatology, The First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, Jilin Province, China.

Background: Serum hepatitis B virus RNA (HBV RNA) has been reported to be a surrogate marker of intrahepatic cccDNA during nucleos(t)ide analogs therapy. However, in HBeAg-positive patients treated with peg-interferon (peg-IFN), whether HBV RNA is superior to other HBV markers in reflecting cccDNA profile is still unclear.

Methods: Serum HBV RNA, HBcrAg, HBV DNA, and HBsAg were longitudinally assessed among 30 HBeAg-positive patients during 48-week peg-IFN treatment. Besides, intrahepatic cccDNA was detected at baseline and week 48 respectively. Then, the individual correlations between HBV RNA, HBcrAg, HBV DNA, HBsAg, and cccDNA were statistically analyzed.

Results: HBV RNA levels decreased more rapidly in patients with HBeAg seroconversion than those without HBeAg seroconversion. Among all patients, cccDNA correlated better with HBV RNA than with HBcrAg, HBV DNA, and HBsAg at baseline. After 48 weeks peg-IFN treatment, cccDNA still correlated more strongly with HBV RNA than other HBV markers. Further analysis indicated that in patients with HBeAg seroconversion cccDNA strongly correlated with HBV RNA and HBcrAg, whereas not correlate with HBV DNA and HBsAg. While in patients without HBeAg seroconversion, cccDNA highly correlated with HBV RNA and HBV DNA, moderately correlated with HBcrAg, and not correlated with HBsAg.

Conclusion: Compared to HBcrAg, HBV DNA, and HBsAg, serum HBV RNA correlated more strongly with intrahepatic cccDNA levels before and after 48-week peg-IFN treatment. The level of serum HBV RNA may be a superior surrogate marker in reflecting the intrahepatic cccDNA profile in HBeAg-positive patients during peg-IFN treatment. Trial registration ClinicalTrials, NCT03546530. Registered 1 January 2015. https://clinicaltrials.gov/ct2/results?cond=&term=NCT03546530 .
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http://dx.doi.org/10.1186/s12985-020-01471-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789711PMC
January 2021

Safety, pharmacokinetics and pharmacodynamics of TQ-A3334, an oral toll-like receptor 7 agonist in healthy individuals.

Expert Opin Investig Drugs 2021 Mar 13;30(3):263-269. Epub 2021 Jan 13.

Phase I Clinical Research Center, the First Hospital of Jilin University, Jilin, China.

Background & Aims: TQ-A3334, a selective, oral toll-like receptor (TLR)-7 agonist, is being developed to treat chronic hepatitis B (CHB). This study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TQ-A3334 in healthy participants.

Research Design And Methods: The effects of a single-ascending dose of TQ-A3334 (0.2-1.8 mg) combined with food (1.2 mg) were evaluated in 48 healthy participants.

Results: No serious adverse events or discontinuations occurred in the study. The most common adverse reactions were lymphocyte count decreased and headache, which were generally consistent with IFN-α exposure and the mechanism of action of a TLR7 agonist. TQ-A3334 was rapidly absorbed, with a time to maximum plasma concentration of 0.42-0.5 h. Systemic exposure (C and AUC) to TQ-A3334 increased with a slight saturation proportion to dose. Food reduced the exposure of TQ-A3334. The concentrations of MCP-1, , and were observed to be slightly dose-dependent, ranging from 1.0 to 1.8 mg TQ-A3334.

Conclusions: Oral doses of 0.2-1.8 mg appeared to be safe and tolerated. PD activity was seen at doses ranging from 1.0 to 1.8 mg, indicating its possible future use to treat CHB.

Trial Registration: The trial is registered at the Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20182248).
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http://dx.doi.org/10.1080/13543784.2021.1873275DOI Listing
March 2021

Timing of DAA Initiation After Curative Treatment and Its Relationship with the Recurrence of HCV-Related HCC.

J Hepatocell Carcinoma 2020 1;7:347-360. Epub 2020 Dec 1.

Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin 130021, People's Republic of China.

Hepatitis C virus infection is a major cause of chronic hepatitis, leading to cirrhosis and hepatocellular carcinoma (HCC). Many studies agree that interferon (IFN)-based antiviral therapy can reduce the risk of HCC recurrence in patients with chronic hepatitis C who have achieved a sustained virological response (SVR). The recent introduction of direct-acting antivirals (DAA) has resulted in excitingly high SVR rates. However, as an IFN-free regimen, DAAs only exert antiviral activity without an immune response. The benefit of DAA-based regimens for HCC recurrence in patients with cirrhosis and following successful curative treatment remains controversial. Additionally, the time span between curative-intent therapy and the DAA regimen is an independent risk factor for HCC recurrence, irrespective of the DAA response. HCC patients who are eligible for potentially curative therapy by liver resection or ablation should defer DAA therapy; however, the accurate timing remains unclear. In this study, we reviewed the timing of DAA initiation after curative treatment and its effect on the recurrence of related HCC.
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http://dx.doi.org/10.2147/JHC.S279657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720283PMC
December 2020

Randomised clinical trial: safety, efficacy and pharmacokinetics of HS-10234 versus tenofovir for the treatment of chronic hepatitis B infection.

Aliment Pharmacol Ther 2021 01 28;53(2):243-252. Epub 2020 Nov 28.

Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China.

Background: HS-10234 is a novel prodrug of tenofovir developed to increase anti-viral potency and to reduce systemic toxicities.

Aims: To evaluate the tolerability, pharmacokinetics and anti-viral efficacy of HS-10234 in patients with chronic hepatitis B (CHB) infection METHODS: Treatment-naïve subjects with non-cirrhotic CHB were divided into three groups (n = 12/group) and randomised within each group to receive 10, 25 or 40 mg of HS-10234, or 300 mg of tenofovir disoproxil fumarate (TDF) once a day for 28 days.

Results: Among 36 enrolled subjects, 33.3% were hepatitis B e antigen-negative with a mean hepatitis B virus (HBV) DNA level of 6.32-7.42 log  IU/mL. Nephrotoxicity and serious adverse events were not observed; all adverse events were mild or moderate and non-specific. The mean reductions in serum HBV DNA after 28 days were -2.70, -2.89, -2.72 and -3.04 log  IU/mL for treatment with 10, 25 or 40 mg HS-10234, and 300 mg TDF, respectively. HS-10234 and its metabolite TFV showed linear, dose-proportional pharmacokinetics. The concentrations of active TFV-DP in peripheral blood mononuclear cells were higher (approximately 2- to 11-fold increase) and TFV in plasma were lower (approximately 4.5- to 25-fold reduction) in subjects taking HS-10234 than those in the TDF group.

Conclusions: HS-10234 was well tolerated during a 4-week course. TDF and HS-10234 had comparable potency in inhibiting HBV replication. A daily dose of 10-25 mg of HS-10234 is recommended for CHB treatment. (Chinese Drug Trial Identifier: CTR20161077).
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http://dx.doi.org/10.1111/apt.16196DOI Listing
January 2021

Liver failure in pregnancy: a review of 25 cases.

J Obstet Gynaecol 2020 Nov 26:1-6. Epub 2020 Nov 26.

Department of Obstetrics, The First Hospital of Jilin University, Changchun, Jilin, China.

We retrospectively reviewed the medical records from 25 pregnant women with liver failure from May 2009 to July 2019. Data describing clinical symptoms and manifestations, routine blood analyses, coagulation, and liver and kidney function were extracted. Swansea criteria were assessed to identify variables with prognostic significance for maternal mortality. The results showed that acute fatty liver was the primary cause of liver failure and 8 (88.89%) patients died within 7 days. Swansea diagnostic criteria for assessing the severity of liver failure were consistent with Chinese guidelines and were more systematic and convenient. The incidence of postpartum haemorrhage was 76%, and the velocity of bleeding was approximately 600 mL per hour. Increased Swansea score, hepatic encephalopathy and decreased PWR were important prognostic indicators for mortality. Recovery during the 7 days postpartum period was an important determinant of maternal outcomes.Impact statement Liver failure in pregnant women is a rare but potentially devastating disease with a high rate of short-term morbidity and mortality. There are limited reports about clinical predictors of maternal-foetal outcomes and the dilemmas faced in the term of delivery. The incidence of postpartum haemorrhage was 76% in pregnant women with liver failure, but the velocity of bleeding was approximately 600 mL per hour. Our study revealed the Swansea score and the ratio of hepatic encephalopathy were significantly higher and platelet-to-white blood cell ratio (PWR) was lower in women who died compared to those who survived. During treatment period, 8 (88.89%) patients died within 7 days. Swansea score, hepatic encephalopathy and PWR were important prognostic indicators for mortality in pregnant women with liver failure. Recovery during the 7 days postpartum period was an important determinant of maternal outcomes. Our findings may prompt researchers to conduct a large multicentre study to evaluate the prognostic indicators for mortality in pregnant women with liver failure.
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http://dx.doi.org/10.1080/01443615.2020.1824214DOI Listing
November 2020

Tolvaptan therapy of Chinese cirrhotic patients with ascites after insufficient diuretic routine medication responses: a phase III clinical trial.

BMC Gastroenterol 2020 Nov 19;20(1):391. Epub 2020 Nov 19.

School of Medicine Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, No. 145, Middle Shandong Road, Shanghai, 200001, China.

Background: To determine the safety and efficacy of different doses of tolvaptan for treating Chinese cirrhotic patients with or without hyponatraemia who still had ascites after routine therapy with diuretics.

Methods: In the present placebo-controlled, randomized, double-blinded, multicentre clinical trial, patients with cirrhotic ascites who failed to adequately respond to a combination of an aldosterone antagonist plus an orally administered loop diuretic were randomly placed at a 4:2:1 ratio into 3 groups [the 15 mg/day tolvaptan group (N = 301), 7.5 mg/day tolvaptan group (N = 153) and placebo group (N = 76)] for 7 days of treatment. The effects and safety were evaluated on days 4 and 7. A change in body weight from baseline on day 7 of treatment was the primary endpoint.

Results: The administration of 7.5 or 15 mg/day tolvaptan significantly decreased body weight from baseline on day 7 of treatment compared to that with placebo treatment (P = 0.026; P = 0.001). For the secondary endpoints, changes in abdominal circumference from baseline and improvements in ascites were markedly different in the treatment groups and the placebo group on day 7 (P = 0.05, P = 0.002 and P = 0.037, P = 0.003), but there was no difference between the 7.5 mg/day and 15 mg/day dosage groups. The 24-h cumulative urine volume was higher in the 7.5 mg/day and 15 mg/day tolvaptan groups than the placebo group (P = 0.002, P < 0.001) and was greater in the 15 mg/day tolvaptan group than the 7.5 mg/day tolvaptan group (P = 0.004). Sodium serum concentrations were higher in patients with hyponatraemia after tolvaptan treatment, with no significant difference between the two dosage groups. The incidence of serious adverse drug reactions was not different between the groups (P = 0.543).

Conclusions: Tolvaptan treatment at 7.5 mg per day might be a good therapeutic choice for Chinese cirrhotic patients with ascites who did not achieve satisfactory clinical responses to previous treatment regimens with combination therapy with an aldosterone antagonist and an orally administered loop diuretic.

Trial Registration: NCT01349348. Retrospectively registered May 2011.
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http://dx.doi.org/10.1186/s12876-020-01536-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678173PMC
November 2020

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects.

Front Pharmacol 2020 8;11:01329. Epub 2020 Oct 8.

Phase I Clinical Research Center, The First Hospital of Jilin University, Jilin, China.

Objective: This study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects.

Methods: This is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva was administered to the subjects, who were followed up for 134 days.

Results: Similar PK properties as those of Xgeva were exhibited by QL1206. When compared to QL1206 with Xgeva, the 90% confidence intervals of the ratios for C, AUC, and AUC were observed to be within 80-125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva groups, respectively.

Conclusion: Similar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva. The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva were found to be similar.
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http://dx.doi.org/10.3389/fphar.2020.01329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580200PMC
October 2020

Validation of the GALAD Model and Establishment of GAAP Model for Diagnosis of Hepatocellular Carcinoma in Chinese Patients.

J Hepatocell Carcinoma 2020 23;7:219-232. Epub 2020 Oct 23.

Department of Hepatology, First Hospital of Jilin University, Changchun, Jilin Province 130021, People's Republic of China.

Purpose: GALAD is a statistical model for estimating the likelihood of having hepatocellular carcinoma (HCC) based on gender, age, AFP, AFP-L3, and PIVKA-II. We aimed to assess its performance and build new models in China, where hepatitis B virus (HBV) is the leading etiology of HCC.

Patients And Methods: We built the GALAD-C model with the same five variables in GALAD, and the GAAP model with gender, age, AFP, and PIVKA-II, using logistic regression based on 242 patients with HCC and 283 patients with chronic liver disease (CLD). We also collected 50 patients with other malignant liver tumors (OMTs) and 50 healthy controls (HCs). A test dataset (169 patients with HCC and 139 with CLD) was used to test the performance of GAAP.

Results: The GALAD-C and GAAP models achieved comparable performance (area under the receiver operating characteristic curve [AUC], 0.922 vs 0.914), and both were superior to GALAD, PIVKA-II, AFP, and AFP-L3% (AUCs, 0.891, 0.869, 0.750, and 0.711) for discrimination of HCC from CLD for the entire dataset. The AUCs of the GALAD, GALAD-C and GAAP models were excellent for the hepatitis C virus (HCV) subgroup (0.939, 0.958 and 0.954), and for discrimination HCC from HCs (0.988, 0.982, and 0.979), but were relatively lower for the HBV subgroup (0.855, 0.904, and 0.894), and for HCC within Milan Criteria (0.810, 0.841, and 0.840). They were not superior to AFP (0.873) for discrimination of HCC from OMT (0.873, 0.809, and 0.823). GAAP achieved an AUC of 0.922 in the test dataset.

Conclusion: GALAD was excellent for discrimination of HCC from CLD in the HCV subgroup of a cohort of Chinese patients. The GAAP and GALAD-C models achieved better performance compared with GALAD. These three models exhibited better performance in patients with an HCV etiology than those with HBV.
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http://dx.doi.org/10.2147/JHC.S271790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591054PMC
October 2020

Coblopasvir and sofosbuvir for treatment of chronic hepatitis C virus infection in China: A single-arm, open-label, phase 3 trial.

Liver Int 2020 11 13;40(11):2685-2693. Epub 2020 Oct 13.

Department of Hepatology, the First Hospital of Jilin University, Changchun, China.

Background & Aim: An affordable, pangenotypic regimen remains as an unmet medical need for chronic hepatitis C patients in China. This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of coblopasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic hepatitis C virus (HCV) infection.

Methods: Treatment-naïve and interferon-experienced adult patients, including those with advanced fibrosis (F3) or compensated cirrhosis (F4), were treated with a universal, combinational regimen of coblopasvir 60 mg and sofosbuvir 400 mg, once daily, for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12).

Results: Overall, 371 patients (men, 51%; age, 47 ± 11 years; genotype 1a < 1%, 1b 48%, 2a 26%, 3a 6%, 3b 7% and 6 12%) were enrolled from 19 sites. Fifty-one patients (14%) had F3, 39 patients (11%) had F4 and 39 patients (11%) were interferon experienced. The overall SVR12 was 97% (95% CI, [94%, 98%]) for the full analysis set and was equal to or above 90% for all predefined subsets. Ten patients (3%) experienced virological relapse and two patients did not complete follow-up. No adverse events (AEs) occurred at a frequency ≥5%, and the most often reported AEs (≥1%) were neutropenia and fatigue. The majority of AEs were mild to moderate and transient without specific medical intervention.

Conclusions: The universal, pangenotypic combo of coblopasvir plus sofosbuvir is an efficacious and safe treatment for Chinese patients monoinfected with HCV of genotype 1, 2, 3 and 6, including those with compensated cirrhosis.

Lay Summary: The regimen of coblopasvir and sofosbuvir is a safe and effective treatment for Chinese patients with genotype 1, 2, 3 and 6 HCV infection, including those with compensated cirrhosis. Therefore, this regimen would be a novel choice of treatment for this patient population.
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http://dx.doi.org/10.1111/liv.14633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702130PMC
November 2020

The long-term outcomes of deceased-donor liver transplantation for primary biliary cirrhosis: a two-center study in China.

PeerJ 2020 19;8:e9563. Epub 2020 Aug 19.

Department of Hepatology, First Hospital, Jilin University, Changchun, China.

Background & Aims: Factors that influence the outcomes after deceased-donor liver transplantation (DDLT) for primary biliary cirrhosis (PBC) are not well known. We aimed to clarify these effects on the outcomes after DDLT.

Methods: We retrospectively analyzed patients with PBC who underwent DDLT from March 2006 to July 2018 at the organ transplantation center of the First Hospital of Jilin University and the First Central Hospital of Tianjin. Changes in liver function were assessed posttransplantation. Recurrence, survival rate, and complications were recorded at follow-up. The effect of liver transplantation on survival and recurrence was evaluated using univariate and/or multivariate Cox regression analyses.

Results: In total, 69 patients with PBC undergoing DDLT were included in this study. At 4 weeks posttransplant, all liver function tests were normal. During a median follow-up time of 32 months, 5-year overall survival and recurrence rates were estimated as 95.1% and 21.8%, respectively. A recipient aspartate aminotransferase-to-platelet ratio index (APRI) greater than 2 was negatively associated with survival ( = 0.0018). Multivariate regression analysis demonstrated that age younger than 48 years was an independent risk factor for recurrent PBC in recipients undergoing liver transplantation (hazard ratio 0.028, 95% confidence interval 0.01-0.71,  = 0.03). Posttransplant infections (62%) and biliary tract complications (26%) were the most common complications.

Conclusion: Liver transplantation is an effective treatment for patients with PBC. Liver function normalizes by 4 weeks posttransplant. Although posttransplant survival rate is high, recurrence is possible. To some extent, survival rate and recurrence rate can be predicted by APRI and age, respectively.
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http://dx.doi.org/10.7717/peerj.9563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443077PMC
August 2020

High hepatitis C virus cure rates with approved interferon-free direct-acting antivirals among diverse mainland Chinese patients including genotypes 3a and 3b.

J Gastroenterol Hepatol 2021 Mar 5;36(3):767-774. Epub 2020 Aug 5.

Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA.

Background And Aim: Globally, China has the highest chronic hepatitis C (CHC) burden, but its real-world direct-acting antiviral (DAA) data are limited. Our aim is to investigate the real-world outcome of China Food and Drug Administration-approved DAA therapies across mainland China including those with genotype (GT) 3.

Methods: The REAL-C is a multinational real-world interferon-free DAA-treated CHC registry of several mainland China and other Asian centers. We evaluated the sustained virological response rate 12 weeks after end of treatment (SVR12), adverse events, and treatment effect on liver function and fibrosis (fibrosis-4 index).

Results: We analyzed 859 DAA-treated CHC patients (6/1/2017-5/30/2019) from 12 mainland China centers (three municipalities and nine provinces): median age 52, 49.9% male, 33.1% cirrhosis, 95% treatment naïve, and 2.5% HBsAg . The most common GT was GT1b (523, 62.2%), followed by GT2a (156, 18.5%), GT3b (74, 8.8%), GT3a (41, 4.9%), and GT6 (37, 4.4%). SVR12 rates were 98.0% overall (95% confidence interval 96.9-98.8%), 98.1% for GT1b, 96.8% GT2a, 100% GT3a, 97.3% GT3b, and 100% GT6. Baseline cirrhosis and male sex but not prior treatment history, renal dysfunction, age, and GTs were associated with SVR12. For both cirrhotic and non-cirrhotic patients, there were significant improvement in liver function tests, alpha fetoprotein, and fibrosis-4 index with SVR12. Serious adverse events were rare (1.1%) with only nine patients discontinuing therapy prematurely and anemia being the most common adverse event (13.1%, mostly with ribavirin).

Conclusions: In real-world Chinese patients with diverse GTs, Chinese Food and Drug Administration-approved interferon-free DAAs were well tolerated, provided high cure rates (98.0% overall) including GT3a/3b, and led to improvement of liver function.
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http://dx.doi.org/10.1111/jgh.15192DOI Listing
March 2021

Efficacy of a combination of HBV RNA and HBeAg in predicting HBeAg seroconversion in patients treated with entecavir for 144 weeks.

Int J Infect Dis 2020 Oct 25;99:171-178. Epub 2020 Jul 25.

Department of Hepatology, the First Hospital of Jilin University, Changchun, China. Electronic address:

Background: In some previous studies, serum hepatitis B virus RNA (HBV RNA) was proposed as an HBV viral marker during therapy. However, the dynamic change of HBV RNA, the correlation of HBV RNA with cccDNA, and the combination of HBV RNA with known HBV markers in predicting entecavir (ETV) treatment outcome in the same cohort are rarely reported.

Methods: A total of 111 HBeAg-positive patients were enrolled in our study. The dynamic changes of serum HBV RNA and the correlation of HBV RNA with other HBV markers were investigated in the early treatment period of 144-week ETV treatment. Intrahepatic cccDNA was detected at baseline and week 48. Receiver operating characteristic analyses were used to identify HBV RNA levels associated with HBeAg seroconversion.

Results: The serum HBV RNA levels decreased more rapidly in patients with HBeAg seroconversion than those without HBeAg seroconversion. The levels of HBV RNA decreased slower compared with the serum HBV DNA, irrespective of whether the patients achieved HBeAg seroconversion or not. Although the serum HBV RNA was positively correlated with cccDNA at baseline among all patients, no significant correlation was observed in the patients with HBeAg seroconversion at week 48 (r=0.094, P=0.588). The area under the receiver operating characteristic (AUROC) of HBV RNA and HBeAg at week 24 was 0.754 and 0.800, respectively. The AUROC of the HBV RNA and HBeAg combination had a higher value (AUROC=0.821).

Conclusions: The level of HBV RNA at week 24 was a powerful predictor of HBeAg seroconversion in HBeAg-positive patients after 144-week ETV treatment, while the combination of HBV RNA and HBeAg was superior to HBV RNA alone in predicting HBeAg seroconversion.
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http://dx.doi.org/10.1016/j.ijid.2020.07.031DOI Listing
October 2020

aMAP risk score predicts hepatocellular carcinoma development in patients with chronic hepatitis.

J Hepatol 2020 12 21;73(6):1368-1378. Epub 2020 Jul 21.

Department of Infectious Diseases, First Hospital of Shanxi Medical University, Taiyuan, China.

Background & Aims: Hepatocellular carcinoma (HCC) is the leading cause of death in patients with chronic hepatitis. In this international collaboration, we sought to develop a global universal HCC risk score to predict the HCC development for patients with chronic hepatitis.

Methods: A total of 17,374 patients, comprising 10,578 treated Asian patients with chronic hepatitis B (CHB), 2,510 treated Caucasian patients with CHB, 3,566 treated patients with hepatitis C virus (including 2,489 patients with cirrhosis achieving a sustained virological response) and 720 patients with non-viral hepatitis (NVH) from 11 international prospective observational cohorts or randomised controlled trials, were divided into a training cohort (3,688 Asian patients with CHB) and 9 validation cohorts with different aetiologies and ethnicities (n = 13,686).

Results: We developed an HCC risk score, called the aMAP score (ranging from 0 to 100), that involves only age, male, albumin-bilirubin and platelets. This metric performed excellently in assessing HCC risk not only in patients with hepatitis of different aetiologies, but also in those with different ethnicities (C-index: 0.82-0.87). Cut-off values of 50 and 60 were best for discriminating HCC risk. The 3- or 5-year cumulative incidences of HCC were 0-0.8%, 1.5-4.8%, and 8.1-19.9% in the low- (n = 7,413, 43.6%), medium- (n = 6,529, 38.4%), and high-risk (n = 3,044, 17.9%) groups, respectively. The cut-off value of 50 was associated with a sensitivity of 85.7-100% and a negative predictive value of 99.3-100%. The cut-off value of 60 resulted in a specificity of 56.6-95.8% and a positive predictive value of 6.6-15.7%.

Conclusions: This objective, simple, reliable risk score based on 5 common parameters accurately predicted HCC development, regardless of aetiology and ethnicity, which could help to establish a risk score-guided HCC surveillance strategy worldwide.

Lay Summary: In this international collaboration, we developed and externally validated a simple, objective and accurate prognostic tool (called the aMAP score), that involves only age, male, albumin-bilirubin and platelets. The aMAP score (ranged from 0 to 100) satisfactorily predicted the risk of hepatocellular carcinoma (HCC) development among over 17,000 patients with viral and non-viral hepatitis from 11 global prospective studies. Our findings show that the aMAP score had excellent discrimination and calibration in assessing the 5-year HCC risk among all the cohorts irrespective of aetiology and ethnicity.
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http://dx.doi.org/10.1016/j.jhep.2020.07.025DOI Listing
December 2020

High prevalence of Clonorchis sinensis infections and coinfection with hepatitis virus in riverside villages in northeast China.

Sci Rep 2020 07 16;10(1):11749. Epub 2020 Jul 16.

Department of Hepatology, The First Hospital of Jilin University, Jilin University, No. 71 Xinmin Street, Changchun, 130021, China.

In China, the prevalence of Clonorchis sinensis (C. sinensis) infections is only evaluated at the provincial level by national sampling surveys, and data from villages and counties are still lacking. In this study, we conducted a cross-sectional survey in 10 villages located along the Lalin River in northeast China. Clonorchiasis was diagnosed using a modified Kato-Katz method that detects the C. sinensis egg in stools. A total of 3,068 persons were screened and 2,911 were recruited for the study. Overall, the prevalence of C. sinensis infection was 29.3%. Among 175 participants who were cured after antiparasitic treatment, 54 (30.86%) were re-infected in this survey. After calibration of potential confounders, male gender, occupation as a farmer, smoking, and occasionally or frequently eating raw fish were independent risk factors for C. sinensis infection. The results of laboratory examinations in the C. sinensis/hepatitis B or C virus co-infection group were similar to those in the hepatitis B or C virus mono-infection groups. In conclusion, C. sinensis is highly endemic in villages along the Lalin River, and the primary route of infection is the consumption of raw freshwater fish. Co-infection with C. sinensis did't aggravate the clinical manifestations of viral hepatitis in this cross-sectional study.
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http://dx.doi.org/10.1038/s41598-020-68684-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366707PMC
July 2020

Antiviral Activity and Pharmacokinetics of the Hepatitis B Virus (HBV) Capsid Assembly Modulator GLS4 in Patients With Chronic HBV Infection.

Clin Infect Dis 2021 Jul;73(2):175-182

Department of Hepatology, The First Hospital of Jilin University, Jilin, China.

Background: GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator (class I) that can inhibit HBV replication by interfering with the assembly and disassembly of HBV nucleocapsid. Here, we evaluated its antiviral activity, pharmacokinetics, and tolerability in a double-blind, randomized, parallel, entecavir-controlled study.

Methods: Twenty-four patients with chronic HBV were randomized to receive a 28-day course of GLS4 (120 or 240 mg) and ritonavir (100 mg) combination (cohorts A and B, respectively) or entecavir treatment (cohort C) at a 1:1:1 ratio. Patients were followed up for 40 days in a phase 1b study.

Results: The GLS4/ritonavir combination was a tolerated combination for the treatment of chronic HBV infection. A total of 2, 3, and 3 subjects presented with alanine aminotransferase flare in cohorts A, B, and C, respectively. This contributed to the withdrawal of 1, 2, and 1 patient from cohorts A, B, and C, respectively. The mean Ctrough of GLS4 was 205-218 ng/mL, which was approximately 3.7-3.9 times the 90% effective concentration (55.8 ng/mL), with a lower accumulation (accumulation rate, 1.1-2.0). In cohorts A, B, and C, the mean declines in HBV DNA after 28 days of treatment were -1.42, -2.13, and -3.5 log10 IU/mL; in hepatitis B surface antigen were -0.06, -0.14, and -0.33 log10 IU/mL; in pregenomic RNA were -0.75, -1.78, and -0.96 log10 copies/mL; and in hepatitis B core antigen were -0.23, -0.5, and -0.44 log10 U/mL, respectively.

Conclusions: Treatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection.

Clinical Trials Registration: Chinese Clinical Trial Registry; CTR20160068. http://www.chinadrugtrials.org.cn.
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http://dx.doi.org/10.1093/cid/ciaa961DOI Listing
July 2021

The deubiquitinase USP44 promotes Treg function during inflammation by preventing FOXP3 degradation.

EMBO Rep 2020 09 9;21(9):e50308. Epub 2020 Jul 9.

Department of Pulmonary and Critical Care Medicine, Institute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The transcription factor forkhead box P3 (FOXP3) is essential for the development of regulatory T cells (Tregs) and their function in immune homeostasis. Previous studies have shown that in natural Tregs (nTregs), FOXP3 can be regulated by polyubiquitination and deubiquitination. However, the molecular players active in this pathway, especially those modulating FOXP3 by deubiquitination in the distinct induced Treg (iTreg) lineage, remain unclear. Here, we identify the ubiquitin-specific peptidase 44 (USP44) as a novel deubiquitinase for FOXP3. USP44 interacts with and stabilizes FOXP3 by removing K48-linked ubiquitin modifications. Notably, TGF-β induces USP44 expression during iTreg differentiation. USP44 co-operates with USP7 to stabilize and deubiquitinate FOXP3. Tregs genetically lacking USP44 are less effective than their wild-type counterparts, both in vitro and in multiple in vivo models of inflammatory disease and cancer. These findings suggest that USP44 plays an important role in the post-translational regulation of Treg function and is thus a potential therapeutic target for tolerance-breaking anti-cancer immunotherapy.
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http://dx.doi.org/10.15252/embr.202050308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507386PMC
September 2020

Profiles of COVID-19 clinical trials in the Chinese Clinical Trial Registry.

Emerg Microbes Infect 2020 Dec;9(1):1695-1701

Neurology Department, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, People's Republic of China.

The COVID-19 pandemic has caused a global public health crisis. There is a pressing need for evidence-based interventions to address the devastating clinical and public health effects of the COVID-19 pandemic. The Chinese scientists supported by private and government resources have adopted extensive efforts to identify effective drugs against the virus. To date, a large number of clinical trials addressing various aspects of COVID19 have been registered in the Chinese Clinical Trial Registry (ChiCTR), including more than 200 interventional studies. Under such an urgent circumstance, the scope and quality of these clinical studies vary significantly. Hence, this review aims to make a comprehensive analysis on the profiles of COVID-19 clinical trials registered in the ChiCTR, including a wide range of characteristics. Our findings will provide a useful summary on these clinical studies since most of these studies will encounter major challenges from the design to completion. It will be a long road for the outcomes of these studies to be published and international collaboration will help the ultimate goals of developing new vaccines and anti-viral drugs.
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http://dx.doi.org/10.1080/22221751.2020.1791736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473047PMC
December 2020

A Novel Approach To Display Structural Proteins of Hepatitis C Virus Quasispecies in Patients Reveals a Key Role of E2 HVR1 in Viral Evolution.

J Virol 2020 08 17;94(17). Epub 2020 Aug 17.

CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

Hepatitis C virus (HCV) infection remains a major worldwide health problem despite development of highly effective direct-acting antivirals. HCV rapidly evolves upon acute infection and generates multiple viral variants (quasispecies), leading to immune evasion and persistent viral infection. Identification of epitopes of broadly neutralizing anti-HCV antibodies (nAbs) is critical to guide HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on -complementation of viral structural proteins. The HCV genome (JFH1 strain) lacking the structural protein-coding sequence can be efficiently rescued by ectopic expression of core-E1-E2-p7-NS2 (core-NS2) or core-E1-E2-p7 (core-p7) in , leading to production of single-round infectious virions designated HCVΔS. JFH1-based HCVΔS can be also rescued by expressing core-NS2 of other HCV genotypes, rendering it an efficient tool to display the structural proteins of HCV strains of interests. Furthermore, we successfully rescued HCVΔS with structural proteins from clinical isolates. Multiple viral structural proteins with different sensitivities to nAbs were identified from a same patient serum, demonstrating the genetic diversity of HCV quasispecies Interestingly, the structural protein-coding sequences of highly divergent viral quasispecies from the same patient can be clustered based on their hypervariable region 1 (HVR1) in viral envelope protein E2, which critically dictates the sensitivity to neutralizing antibodies. In summary, we developed a novel reverse genetics system that efficiently displays viral structural proteins from HCV clinical isolates, and analysis of quasispecies from the same patient using this system demonstrated that E2 HVR1 is the major determinant of viral evolution A cell culture model that can recapitulate the diversity of HCV quasispecies in patients is important for analysis of neutralizing epitopes and HCV vaccine development. In this study, we developed a new reverse genetics system for HCV infection based on -complementation of viral structural proteins (HCVΔS). This system can be used to display structural proteins of HCV strains of multiple genotypes as well as clinical isolates. By using this system, we showed that multiple different HCV structural proteins from a same patient were displayed on HCVΔS. Interestingly, these variant structural proteins within the same patient can be classified according to the sequence of HVR1in E2, which dictates viral sensitivity to nAbs and viral evolution Our work provided a new tool to study highly divergent HCV quasispecies and shed light on underlying mechanisms driving HCV evolution.
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http://dx.doi.org/10.1128/JVI.00622-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431814PMC
August 2020

Author Correction: Role of HDAC9-FoxO1 Axis in the Transcriptional Program Associated with Hepatic Gluconeogenesis.

Sci Rep 2020 May 28;10(1):8989. Epub 2020 May 28.

Jiangsu Province Key Lab of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, 210029, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-66085-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253407PMC
May 2020

IL-33 Inhibits Hepatitis B Virus through Its Receptor ST2 in Hydrodynamic HBV Mouse Model.

Mediators Inflamm 2020 28;2020:1403163. Epub 2020 Apr 28.

Department of Hepatology, The First Hospital of Jilin University, Jilin University, 71 XinMin Street, Changchun, Jilin Province 130021, China.

Interleukin-33 has been demonstrated to be associated with liver damage. However, its potential value in hepatitis B virus (HBV) infection remains unknown. This study was designed to investigate the role of IL-33 in hydrodynamic HBV mouse model. Different doses of IL-33 were used to treat HBV wild-type, ST2 knockout, CD8+ T depletion, NK depletion C57BL/6 mice and C.B-17 SCID and nod SCID mouse, respectively. The concentrations of HBV DNA, HBsAg, HBeAg, and molecules related to liver function were detected in the collected serum at different time points from model mice. Intrahepatic HBcAg was visualized by immunohistochemical staining of liver tissues. , hepG2 cells were transfected with pAAV-HBV 1.2, then treated with IL-33. The results showed that IL-33 significantly reduced HBV DNA and HBsAg in a dose-dependent manner in HBV wild-type mice. However, in the IL-33 specific receptor ST2 knockout mice, their antiviral effects could not be exerted. Through immunodeficient animal models and immune cell depletion mouse model, we found that IL-33 could not play antiviral effects without NK cells. Moreover, IL-33 could reduce the levels of HBsAg and HBeAg in the supernatant of HBV-transfected hepG2 cells . Our study revealed that IL-33 could inhibit HBV through ST2 receptor in the HBV mouse model, and this effect can be impaired without NK cell. Additionally, IL-33 had the direct anti-HBV effect , indicating that IL-33 could be a potent inducer of HBV clearance and a promising drug candidate.
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http://dx.doi.org/10.1155/2020/1403163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204199PMC
July 2021
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