Browsing by Author "Gao, Shan"

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    Chronic hepatitis B carriers with acute on chronic liver failure show increased HBV surface gene mutations, including immune escape variants
    (2017-10-24) Gao, Shan; Joshi, Shivali S; Osiowy, Carla; Chen, Y.; Coffin, Carla S; Duan, Z-P.
    Abstract Background The pathogenesis of acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) is not well understood. The aim of this study was to investigate whether there is an association between HBV polymerase (P)/overlapping surface (S) gene and basal core promoter (BCP)/precore (PC) variants and development of ACLF in CHB. Methods Two CHB patient cohorts were compared: (i) ACLF (N = 12) (11/12 M, median age 52 yrs., 5/9 genotype C, 6/12 HBeAg+), (ii) 27 treatment native CHB carriers (15/27 M, median age 44 yrs., 9 genotype B, 10 genotype C, 1 genotype A, 5 genotype D, 2 genotype E). Clonal sequencing of PCR-amplified HBV P/S and BCP/PC gene fragments was done and HBV diversity, frequency of immune escape (IE) and drug resistance (DR) mutations and mutations in BCP/PC gene (G1896A and A1762T/G1764A), were compared between each group. Results Our data showed the incidence of IE and clusters of mutations in the HBV S region was significantly greater in ACLF patients vs. treatment naïve CHB patients (p < 0.05). Additionally, a significantly higher frequency of G1896A and A1762T/G1764A mutations were found in HBeAg negative than in ACLF patients (p < 0.0001). Conclusion In our study, ACLF was not associated with a specific genomic mutation. However, higher frequency of IE mutations along with various mutations clustering in the HBV S region could contribute to or be an outcome of ACLF in CHB infection. (words 226).
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    Compartmental Hepatitis B Virus (HBV) Evolution, Replication and Infectivity in vivo and ex vivo
    (2017) Gao, Shan; Coffin, Carla S; Lee, Samuel S.; Duan, Zhongping; Van Marle, Guido; van der Meer, Frank
    Hepatitis B Virus (HBV) is classically considered a hepatotropic virus, however, the presence of different HBV genomic molecules in lymphoid cells and tissues support its lymphotropic nature. Our previous studies showed that HBV evolved in a compartment- and disease phase-specific fashion. However, the effect of nucleos/tide analogue (NA) therapy on HBV evolution and replication in different compartments (i.e., liver, plasma and peripheral blood mononuclear cell (PBMC)) is unknown, as well as the replicative competence and infectious capacity of PBMC-derived HBV. We hypothesize that HBV replicating in lymphoid cells is infectious, and the HBV evolves in PBMC and/or plasma in chronic hepatitis B (CHB) patients under the influence of NA therapy or host immune pressure (i.e., fulminant hepatitis B). The study on HBV replication and genetic evolution in PBMC, liver and plasma of CHB patients under NA therapy revealed the HBV evolution varied between three compartments both before and after treatment. NA had little effect on HBV cccDNA level and persistence of mRNA in PBMC. The study on HBV genetic features in CHB carriers with acute-on-chronic liver failure (ACLF) revealed the frequent immune escape mutations with clusters of surface gene variants possibly associated with development of fulminant hepatitis B. Mitogen stimulation in PBMC of CHB patients revealed presence of replicating HBV, which can be upregulated in PBMC and exhibited infectious capacity to HepaRG cells in vitro. In summary, our data suggests potent NAs have little effect on HBV cccDNA in liver and PBMC, which highlights the need for continued suppressive antiviral therapy. The HBV evolution varied between different compartments in CHB patients under NA therapy. Distinct variants in HBV surface gene were found to be associated with HBV fulminant hepatitis. Moreover, HBV residing in lymphoid cells is increased after mitogen stimulation of PBMC and infectious to a hepatocyte cell line. The study furthers our understanding of HBV lymphotropism, role on viral persistence and the pathogenesis of chronic hepatitis B.
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    Enterolactone has stronger effects than enterodiol on ovarian cancer
    (2017-07-24) Liu, Huidi; Liu, Jianrui; Wang, Siwen; Zeng, Zheng; Li, Ting; Liu, Yongfang; Mastriani, Emilio; Li, Qing-Hai; Bao, Hong-Xia; Zhou, Yu-Jie; Wang, Xiaoyu; Hu, Sijing; Gao, Shan; Qi, Yingying; Shen, Zhihang; Wang, Hongyue; Yu, Miao; Gao, Tingting; Johnston, Randal N; Liu, Shu-Lin
    Abstract Background Ovarian cancer is one of the three leading gynecological malignancies, characterized by insidious growth, highly frequent metastasis, and quick development of drug resistance. As a result, this disease has low 5-year survival rates. Estrogen receptor inhibitors were commonly used for the treatment, but only 7% to 18% of patients respond to anti-estrogen therapies. Therefore, more effective therapies to inhibit estrogen-related tumors are urgently needed. Recently, phytoestrogens, such as lignans with estrogen-like biological activities, have attracted attention for their potential effects in the prevention or treatment of estrogen-related diseases. Enterodiol (END) and enterolactone (ENL) are mammalian lignans, which can reduce the risk of various cancers. However, the effects of END and ENL on ovarian cancer are not adequately documented. Methods We used in vitro assays on the ES-2 cell line to evaluate the inhibiting effects of END and ENL on ovarian cancer cell proliferation, invasion and migration ability and in vivo xenograft experiments on nude mice to validate the anticancer effects of END and ENL. Results The in vitro assays demonstrated that high-dose END and ENL could obviously inhibit ovarian malignant properties, including cancerous proliferation, invasion, and metastasis. Compared to END, ENL behaved in a better time-dose dependent manner on the cancer cells. The in vivo experiments showed that END (1 mg/kg), ENL (1 mg/kg) and ENL (0.1 mg/kg) suppressed tumor markedly, and there were statistically significant differences between the experimental and control groups in tumor weight and volume. Compared to END, which have serious side effects to the animals at high concentration such as 1 mg/kg, ENL had higher anticancer activities and less side effects in the animals than END at the same concentrations, so it would be a better candidate for drug development. Conclusion END and ENL both have potent inhibitory effects on ovarian cancer but ENL possesses a more effective anti-cancer capability and less side effects than END. Findings in this work provide novel insights into ovarian cancer therapeutics with phytoestrogens and encourage their clinical applications.
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    Hepatitis B Virus (HBV) Variants in Untreated and Tenofovir Treated Chronic Hepatitis B (CHB) Patients during Pregnancy and Post-Partum Follow-Up
    (PLoS One, 2015-10-16) Virine, Boris; Osiowy, Carla; Gao, Shan; Wang, Tong; Castillo, Eliana; Martin, Steven R.; Lee, Samuel S.; Simmonds, Kimberley; van Marle, Guido; Coffin, Carla
    BACKGROUND: Chronic hepatitis B (CHB) is a dynamic disease that may be affected by immune changes in pregnancy. Guidelines suggest consideration of nucleos/tide analogs (NA), i.e., tenofovir, (TDF) in highly viremic mothers to reduce vertical transmission risk. HBV variability affects CHB outcome, but little is known about HBV genetic changes in pregnancy due to immune or NA selection. OBJECTIVES: To evaluate HBV diversity in NA treated or untreated pregnant vs. post-partum CHB carriers. STUDY DESIGN: In plasma collected from 21 mothers (7 matching pre/post-partum), HBV serological tests, genotype and viral load were assayed. The HBV pre-surface (S) /S overlapping polymerase (P) (N = 20), pre-core (C) /C (N = 11) and/or full genome PCR amplicons (N = 3) underwent clonal sequence analysis. RESULTS: The median age was 31 y, 71% Asian, 68% genotype B or C, 33% HBV eAg+, 5 received TDF (median HBV DNA 8.5 log IU/ml). In untreated mothers, median antepartum vs. post-partum ALT was 21 vs. 24 U/L and HBV DNA was 2.7 vs. 2.4 log(10) IU/ml. ALT and/or HBV DNA flares occurred during pregnant and/or post-partum period in 47% (10/21). Clonal sequencing antepartum showed the presence of minor "a determinant" and/or vaccine escape mutants (VEM) but drug resistant variants were infrequent. Analysis of pregnant vs. post-partum samples showed different HBV variants and viral diversity. CONCLUSIONS: Differences in immune and/or by NA selective pressures during pregnancy may affect HBV evolution during pregnancy. The presence of minor VEM warrant infant follow-up.