Chinese Hepatolgy

Phase Ⅰ study of HLA-halfmatched allogeneic natural killer cells therapy in patients with hepatocellular carcinoma

XIE Yun-bo, ZHANG Ji-yuan, YANG Tao, JIN Lei, WANG Song-shan, LIAN Fang, QU Rui, MA Xiao-fen, SHI Ming, DUAN Hai-feng, WANG Fu-sheng.

2017, 22(7): 581-584.

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Objective To investigate the safety of allogeneic natural killer (NK) cells transfusion in patients with hepatocellular carcinoma (HCC).Methods Four patients with HCC after operation or chemotherapy were enrolled in this study, and received transfusion of NK cells derived from their immediate family. Numeric, phenotypic and functional characteristics of the NK cells cultured in vitro were observed. Moreover, liver function, kidney function, coagulation time test, blood routine and serum tumor markers of patients were measured at baseline and at week 4 and 12 after the transfusion, respectively.Results About 2~5×10⁹ mononuclear cells were collected from 50~80 mL peripheral blood of donors, in which NK cells accounted for 49%~83%. The cytolytic assay showed that cultured NK cells could kill HepG2 cells in a dose-dependent manner, and the cytotoxicity of NK cells were further enhanced by interleukin-2. After transfusion, no patients showed occurrence of graft-vs-host disease (GVHD) or significant changes in liver, kidney and heart functions. Two patients had transient body temperature rising and relieved by themselves.Conclusion Histocompatibility antigens (HLA) half matched allogeneic NK cell transfusion therapy in HCC patients is safe and tolerable.

Clinical phenotype analysis on the mutation of HJV E3D gene in 3 Chinese families with hereditary hemochromatosis

ZHANG Wei, LV Ting-xia, LI Yan-meng, WANG Xiao-ming, ZHAO Xin-yan, WANG Yu, XU An-jian, LI Xiao-jin, HUANG Jian, OU Xiao-juan

2017, 22(7): 585-589.

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Objective To investigate the relationship between HJV E3D variation and clinical phenotype from 3 Chinese families with hereditary hemochromatosis (HH).Methods To exclude secondary causes of iron overload and clinically diagnose HH, medical history, iron studies, liver function test, magnetic resonance imaging of liver and liver biopsy were performed in 3 probands from the 3 families. Blood samples of the 3 probands and their families were collected for genomic DNA extraction, and then subjected for sequence analysis on mutations of common HH-related genes (HFE, HAMP, HJV, TFR2 and SLC40A1) was performed.Results Three probands of HH were manifested with obvious iron overload, and 2 members from 2 families also showed iron overload. Additionally, 2 probands carried other HH-related genes besides HJV E3D.Conclusion HJV E3D might be the hotspot mutation of Chinese patient with HH. Its combination with other HH-related mutations may be necessary for emergency of HH. Moreover, the prevalence of HH increases with advanced age in male.

Clinical effectiveness of 7-year entecavir treatment on nucleoside analogues -na ve or-experienced patients with chronic hepatitis B

SUN Zhen-guang, LIU Ke-hui, CAO Zhu-jun, CHEN Rong, LIU Yun-ye, LAI Rong-tao, GUO Qing, XIE Qing, WANG Hui

2017, 22(7): 590-593.

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Objective To investigate the efficacy, safety and drug resistance of entecavir (ETV) in nucleoside analogues (NA)-na ve or NA-experienced chronic hepatitis B (CHB) patients. Methods Eighty-seven CHB outpatients treated with ETV monotherapy in our department was retrospectively analyzed, whose liver function, hepatitis B virus (HBV) DNA, hepatitis B surface antigen (HBsAg) quantitation, hepatitis B e antigen (HBeAg) loss and drug resistance were recorded.Results Among the 87 patients, 32 (37%) were NA-na ve and 55 (63%) were NA-experienced. Following at least 3.5 years of ETV monotherapy, the 7-year cumulative virological response rate (62%) was significantly lower in lamivudine (LAM)-experienced patients than NA-na ve (100%) or adefovir (ADV)-experienced (97%) patients. In contrast, 7-year cumulative drug resistance rate in LAM-experienced (38%) patients was significantly higher than that in NA-na ve (3%) and ADV-experienced patients (3%). Seven-year cumulative HBeAg loss rate was higher in NA-na ve patients (47%) than that in ADV-experienced (45%) and LAM-experienced (20%) patients. Additionally, 2 patients in ADV-experienced group achieved HBsAg loss. In all patients, HBeAg-negative patients had higher virological response rate than HBeAg-positive patients (91% vs. 89%, P=0.012). In NA-na ve patients, HBeAg-negative patients also showed a higher early virological response rate than HBeAg-positive patients (P=0.001), while their cumulative virological response rates were both 100%. The early persistent virological response rate of NA-na ve patients were higher than those of ADV-experienced and LAM-experienced patients (P<0.001).Conclusion ETV monotherapy in NA-na ve and ADV-experienced patients showed satisfactory long-term efficacy, safety and low resistance. However, there was still a high risk of ETV-resistance in LAM-experienced patients.

Functional status of dendritic cells induced by different hepatitis B virus antigen in chronic hepatitis B patients

XIE Li-ping, LIN Tao-fa, ZHU Ling-ling, WANG Shao-yang

2017, 22(7): 594-596.

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Objective To investigate the functional changes of dendritic cells (DC) from chronic hepatitis B (CHB) patients upon stimulation of different hepatitis B virus antigen and treated with antiviral drugs.Methods Monocytes, isolated from peripheral blood mononuclear cells (PBMC) in 17 CHB patients, were induced into mature DC with hepatitis B core antigen (HBcAg), hepatitis B surface antigen (HBsAg), and HBcAg combination with HBsAg, respectively. Co-stimulatory molecules on DC surface, including CD1a, CD80, CD83 and human leukocyte antigen DR (HLA-DR), were analyzed using flow cytometry. The functions of DC were evaluated using allogeneic mixed lymphocyte reaction assay.Results Compared with those in HBsAg-induced DC, levels of CD1a, CD80, CD83 and HLA-DR were higher on DC induced by HBcAg alone, as well as HBsAg combination with HBcAg (HLA-DR: 85.12±1.55 vs. 98.37±1.27 vs. 99.21±1.33; CD1a: 15.69±2.46 vs. 16.25±2.33 vs. 42.20±1.10; CD80: 71.88±6.38 vs. 80.74±3.23 vs. 94.70±2.77; CD83: 32.64±2.77 vs. 42.55±2.88 vs. 44.16±1.89). The mixed lymphocyte reaction ability of DC showed the similar pattern (HBV DNA+: 7.29±0.17 vs. 7.99±0.43 vs. 8.56±0.31; HBV DNA-: 7.48±0.30 vs. 8.22±0.41 vs. 8.78±0.31). After anti-viral therapy, functional status of DC, such as co-stimulatory molecules expression and the mixed lymphocyte reaction ability, were improved more obviously than those at baseline (HLA-DR:99.21±1.33 vs. 99.82±2.67;CD1a:42.20±1.10 vs. 71.33±5.89;CD80:94.70±2.77 vs. 96.42±3.56;CD83:44.16±1.89 vs. 68.34±2.11).Conclusion The dysfunction of DC as the important phagocytes from CHB patients might be improved and recovered through combined induction with HBsAg and HBcAg, which could be further relived after anti-viral therapy. It provides a effective and potential therapy for CHB.

The effects of ghrelin on hepatic oxidative stress and Akt/GSK3β signaling pathway in high-fat diet-fed rats

LI Wen-song, CHEN Li-yan, BI Man-ru, YAN Bing-zhu, KANG Lan, YANG Peng-fei, WANG Xiao-ren, YANG Bao-shan.

2017, 22(7): 597-601.

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Objective To investigate the effect of ghrelin on hepatic oxidative stress and Akt/GSK3β signaling pathway in rats fed with high-fat diet.Methods Male Wistar rats were randomly divided into normal control (NC) group, high-fat diet (HFD) group and ghrelin group (n=10 per group). Rats in NC group were fed with normal diet, while rats in both HFD and ghrelin group were fed with HFD for 6 weeks. Then, rats in NC group and HFD group were treated with saline for 4 weeks, while rats in ghrelin group were injected with ghrelin twice intraperitoneally at dose of 60 μg/kg for 4 weeks. At the end of the experiment, serum levels of alanine aminotransferase (ALT), triglycerides (TG) and total cholesterol (TC) were detected, and superoxide dismutase (SOD) and malondialdehyde (MDA) in liver homogenate were analyzed. Expressions of Akt and GSK3β mRNA in liver were detected using real-time PCR (RT-PCR). Results Wet weight of liver, serum TG and TC in HFD group were obviously higher than those in ghrelin group (P<0.05). Compared with those in HFD group, SOD level was higher (P<0.05) while MDA level was slightly lower (P>0.05) in ghrelin group. Ghrelin treatment enhanced the expression of Akt (P>0.05) and GSK3β (P<0.05).Conclusion Ghrelin could reduce hepatic oxidative stress in HFD-fed rats, which might be related to its effect on Akt/GSK3β pathway.

Hepatitis C virus core protein induces activation of hepatic stellate cell by down-regulation of silent information regulator 1

SUN Li-jie, SHI Yu-guang, ZHANG Xiao-yu, SHU Meng-ni, CHEN Mo-yang, YU Jian-wu.

2017, 22(7): 602-604.

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Objective To investigate the effects of hepatitis C virus (HCV) core protein on expression of silent information regulator 1 (SIRT1) and activation of hepatic stellate cells (HSC). Methods HSC (LX-2 cells) were co-cultured with HepG2 cells or HCV core protein-positive HepG2 cells. Activity, mRNA and protein expressions of SIRT1 in LX-2 cells were detected using scintillation counter, real time-PCR (RT-PCR) and western blot, respectively. Expressions of phosphorylated adenosine monophosphate activated protein kinase (p-AMPK), adiponectin receptor 2 (AdipoR2) and transforming growth factor β1 (TGF-β1) were measured using western blot. Levels of collagen Ⅳ (ColⅣ), procollagen Ⅲ peptide (PⅢNP), hyaluronan (HA) and laminin (LN) in the supernatant were measured using enzyme-linked immunosorbent assay (ELISA). The quantitative data was analyzed using t-test.Results Compared with LX-2 cells co-cultured with HepG2 cells, the activity (0.4±0.1 vs. 1.0±0.2, t=6.573, P<0.01), mRNA (0.3±0.1 vs. 1.0±0.3, t=5.422, P<0.01) and protein expressions (0.4±0.1 vs. 0.8±0.2, t=4.382, P<0.01) of SIRT1 were both reduced in LX-2 cells co-cultured with HCV core-positive HepG2 cells. In LX-2 cells co-cultured with HCV core-positive HepG2 cells, the expression levels of p-AMPK protein (0.3±0.1 vs. 0.8±0.2, t=5.477, P<0.01) and AdipoR2 protein (0.4±0.1 vs. 0.8±0.2, t=4.382, P<0.01) were decreased comparing with those in LX-2 cells co-cultured with HepG2 cells, while TGF-β1 protein expression (2.3±0.5 vs 0.8±0.2, t=6.823, P<0.01) was increased. Moreover, the levels of ColⅣ, PⅢNP, HA and LN in the supernatant were increased in LX-2 cells co-cultured with HCV core-positive HepG2 cells. SIRT1 activator resveratrol decreased the expression of TGF-β1 protein.Conclusion HCV core protein might decrease the expression of AdipoR2 and increase the expression of TGF-β1 through down-regulating the activity and expression of SIRT1, and ultimately cause the activation of HSC.

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