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Ji D.,Institute of Infectious Diseases and Liver Failure Research Center | Ji D.,Liver Fibrosis Diagnosis and Treatment Center | Liu Y.,Institute of Infectious Diseases and Liver Failure Research Center | Li L.,Institute of Infectious Diseases and Liver Failure Research Center | And 9 more authors.
Journal of Clinical Virology | Year: 2012

Background: It remains unclear whether hepatitis B virus (HBV) reverse-transcriptase (RT) rtL229 substitutions influence HBV drug resistance. Objective: The study was to investigate the association of HBV rtL229 substitutions with viral resistance to lamivudine (LAM). Study design: Entire HBV RT genes were amplified by nested PCR and sequenced from sera of 6000 nucleos(t)ide analog-experienced patients with chronic HBV infection. The incidence and clinic relevance of rtL229 substitutions were analyzed. Replication-competent viral amplicons which harbored HBV genomes of wild-type, rtM204I, or rtM204I in conjunction with various rtL229 substitutions (rtL229F/W/M/V) were constructed. The amplicons were transfected into HepG2 cells for phenotyping of replication capacity and susceptibility to nucleos(t)ide analogs. Results: The rtL229 substitutions were detected in 6.57% (394/6000) of patients. Individual substitution incidences were 2.77%, 0.97%, 0.83% and 0.55% for rtL229V, rtL229F, rtL229M and rtL229W, respectively. The incidence of rtL229 substitutions was significantly higher in LAM-experienced patients (341/4220, 8.1%) than in LAM-naïve patients (53/1780, 3.0%), and were independently associated with genotypic LAM resistance (77.9% vs. 21.2%, OR 8.806, 95%CI 6.345-12.223) and low viral replication (HBV DNA <1000. IU/mL) (4.60% vs. 24.2%, OR 0.478, 95%CI 0.254-0.898). Representative cases follow-up showed that rtL229F developed subsequent to rtM204I emergence during LAM treatment and regressed with rtM204I after LAM withdrawal. Functionally, rtL229F did not confer reduced susceptibility to LAM, but could restore replication capacity of rtM204I strain. Conclusion: The rtL229 substitutions were potentially associated with LAM resistance in Chinese patients and rtL229F had characteristics of a compensatory mutation of rtM204I mutant. © 2012 Elsevier B.V. Source


Li B.,Liver Fibrosis Diagnosis and Treatment Center | Ji Y.J.,Liver Disease Center for Military Staff | Shao Q.,Liver Fibrosis Diagnosis and Treatment Center | Zhu Z.,Hepatobiliary Surgery Center | And 3 more authors.
Experimental and Therapeutic Medicine | Year: 2015

The aim of the present study was to evaluate and compare the treatment efficacy and cost of two therapies, splenectomy and thrombopoietin, in order to optimize the treatment plans for patients with HCV-associated cirrhosis. A prospective randomized controlled trial was conducted on 69 patients with a platelet count <60,000/mm3 that were enrolled between 2009 and 2013, including 38 cases as the research group and 31 cases as the observed group. The study included two stages: A 4-week initial treatment and a 48-week antiviral treatment, during which a number of parameters were evaluated, including platelet count, liver stiffness measure, albumin, total bilirubin, alanine aminotranferase and treatment cost-effectiveness. Of the 38 patients, 21 underwent a splenectomy and their platelet counts increased to 60,000/mm3 after the 4-week initial treatment. The patients then started a 48-week P-R antiviral treatment, and 18 cases completed the treatment. In addition, 17/38 patients received thrombopoietin as a drug therapy. The platelet counts in 15 cases increased to >60,000/mm3 and the patients received antiviral treatment, among which 9 cases completed the second treatment stage. The expense of the splenectomy group treatment was higher compared with that received by the thrombopoietin group. The results of the present study indicated that splenectomy was more effective at increasing platelet count. More splenectomy patients completed the full course of antiviral treatment and presented a sustained virologic response, compared with the thrombopoietin group. Therefore, splenectomy may be more expensive compared with thrombopoietin; however, the improved efficacy suggests that on balance it is the preferable treatment option. © 2015, Spandidos Publications. All rights reserved. Source


Ji D.,Liver Fibrosis Diagnosis and Treatment Center | Shao Q.,Liver Fibrosis Diagnosis and Treatment Center | Han P.,Tumor Radiotherapy Center | Li F.,Liver Fibrosis Diagnosis and Treatment Center | And 6 more authors.
PLoS ONE | Year: 2014

Objective: To investigate the frequency and determinants of liver stiffness measurement (LSM) failure by means of FibroScan in "real-life" Chinese patients. Methods: A total of 38,464 "real-life" Chinese patients in 302 military hospital of China through the whole year of 2013, including asymptomatic carrier, chronic hepatitis B, chronic hepatitis C, liver cirrhosis (LC), alcoholic liver disease, autoimmune liver disease, hepatocellular carcinoma (HCC) and other, were enrolled, their clinical and biological parameters were retrospectively investigated. Liver fibrosis was evaluated by FibroScan detection. S probe (for children with height less than 1.20 m) and M probe (for adults) were used. LSM failure defined as zero valid shots (unsuccessful LSM), or the ratio of the interquartile range to the median of 10 measurements (IQR/M) greater than 0.30 plus median LSM greater or equal to 7.1 kPa (unreliable LSM). Results: LSM failure occurred in 3.34% of all examinations (1286 patients out of 38,464), among them, there were 958 cases (2.49%) with unsuccessful LSM, and 328 patients (0.85%) with unreliable LSM. Statistical analyses showed that LSM failure was independently associated with body mass index (BMI) greater than 30 kg/m2, female sex, age greater than 50 years, intercostal spaces (IS) less than 9 mm, decompensated liver cirrhosis and HCC patients. There were no significant differences among other diseases. By changing another skilled operator, success was achieved on 301 cases out of 1286, which reduced the failure rate to 2.56%, the decrease was significant (P<0.0001). Conclusions: The principal reasons of LSM failure are ascites, obesity and narrow of IS. The failure rates of HCC, decompensated LC, elder or female patients are higher. These results emphasize the need for adequate operator training, technological improvements and optimal criteria for specific patient subpopulations. © 2014 Ji et al. Source


Li B.,Liver Fibrosis Diagnosis and Treatment Center | Shao Q.,Liver Fibrosis Diagnosis and Treatment Center | Ji D.,Liver Fibrosis Diagnosis and Treatment Center | Li F.,Liver Fibrosis Diagnosis and Treatment Center | Chen G.,Liver Fibrosis Diagnosis and Treatment Center
Cellular Physiology and Biochemistry | Year: 2015

Background/Aims: Transplantation of mesenchymal stem cells (MSCs) has therapeutic effects on various diseases, while its effect on developing cirrhosis as well as the underlying mechanism remained largely unknown. Methods: Twenty C57BL/6 mice were randomly separated into 2 groups of ten each. One group received transplantation of MSCs, while the other group received saline as control. The mice then received intraperitoneal injection of carbon tetrachloride (CCl4) twice per week for 8 weeks to develop cirrhosis. After another 4 weeks, the levels of cirrhosis in these mice were evaluated by liver fibrosis area, portal pressure, sodium balance and excretion. Transcripts of transforming growth factor β 1 (TGFβ1) and bone morphogenic protein 7 (BMP7) in the mouse livers were quantified by RT-qPCR. BMP7-depleted MSCs were prepared and applied in this model, and compared to MSCs. Results: Liver fibrosis, portal hypertension and sodium retention that were developed by CCl4, were all significantly alleviated by MSCs transplantation, which decreased TGFβ1 levels and increased BMP7 levels in the injured liver. MSCs were found to express extremely high levels of BMP7. Knockdown of BMP7 in MSCs completely abolished the protective effect of MSCs against CCl4-induced cirrhosis. Conclusion: MSCs mitigate cirrhosis through their production of BMP7 against the fibrogenic effect of TGFβ1 in the injured liver. © 2015 S. Karger AG, Basel. Source


Ji D.,Liver Fibrosis Diagnosis and Treatment Center | Li B.,Liver Fibrosis Diagnosis and Treatment Center | Shao Q.,Liver Fibrosis Diagnosis and Treatment Center | Li F.,Liver Fibrosis Diagnosis and Treatment Center | And 2 more authors.
Cellular Physiology and Biochemistry | Year: 2015

Background/Aims: New strategies for the prevention and treatment of cirrhosis are urgently needed for improving therapeutic outcome. A role of microRNAs (miRNAs) in the pathogenesis of cirrhosis has been recently acknowledged, whereas the exact involved miRNAs as well as the associated molecular signaling pathways have not been determined. Specifically, the studies on the relationship between miR-22 and bone morphogenic protein 7 (BMP7) in the development of cirrhosis are lacking. Methods: We examined the correlation of the levels of miR-22 and bone morphogenic protein 7 (BMP7) in the liver biopsies from patients with cirrhosis. We examined overexpression or suppression of miR-22 on BMP7 in hepatocytes. We examined the binding of miR-22 to the 3'-UTR of BMP7 mRNA. Finally, in a carbon tetrachloride (CCl4)-induced cirrhosis model in mice, we gave mice adeno-associated viruses carrying antisense of miR-22, and examined its effects on BMP7 levels and the hallmarks of cirrhosis. Results: The levels of miR-22 and BMP7 in the liver biopsies from patients were strongly and inversely correlated. MiR-22 inhibited BMP7 expression in hepatocytes, through directly binding the 3'-UTR of BMP7 mRNA. Expression of antisense miR-22 significantly attenuated the levels of liver fibrosis, portal hypertension and sodium retention caused by CCl4, possibly through upregulation of BMP7. Conclusions: MiR-22 promotes the development of cirrhosis through BMP7 suppression. © 2015 S. Karger AG, Basel. Source

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