SYMPOSIUM 2 : Chronic Hepatitis B Antiviral Therapy vs. Immune Modulation

( Qin Ning ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Hepatitis B virus (HBV) infection is a worldwide health problem. About a quarter of the world population, more than 2 billion people have been infected with HBV. Chronic HBV hepatitis (CHB) is an important risk factor for the development of liver cirrhosis and hepatocellular carcinoma. Nature course of CHB closely related with immune status. The persistent infection of HBV is now regarded as the result of inefficacy of both innate and adaptive immune response. Most information has been derived from data on the adaptive immune response, in which the roles of T cells and its regulation by T regulatory (Treg) cells have been elucidated. An increasing number of studies have suggested the importance of the components of innate immunity, such as macrophage, natural killer (NK) cell, natural killer T (NKT) cell and immune modulation molecules, in the pathogenesis of HBV infection. Sustained immune control was found associated with sustained off-antiviral therapy response, and the critical step towards HBsAg seroclearance. The immune control models among different nucleotide analogues, and interferon could be different. Better understanding the immune system before and post antiviral treatment shed light on improvement of treatment strategy. How to combine or sequential these agents to achieve an optimal treatment response need further investigation. The OSST study is one of the examples of these efforts.

T-SPOT.TB for Detection of Tuberculosis Infection among Hematological Malignancy Patients and Hematopoietic Stem Cell Transplant Recipients

Qin, Li-Li,Wang, Qin-Rong,Wang, Qian,Yao, Hong,Wen, Li-Jun,Wu, Li-Li,Ping, Na-Na,Xie, Jun-Dan,Chen, Mei-Yu,Chen, Su-Ning Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.12

The diagnosis of latent Mycobacterium tuberculosis infection (LTBI) is recommended in hematological malignancy patients and before hematopoietic stem cell transplantation (Guidelines for the prevention and management of infectious complications of solid organ transplantation, 2004). Compared to traditional methods such as tuberculin skin test (TST), T-SPOT.TB has been shown to be more specific. In the present study we enrolled 536 patients for whom T-SPOT.TB was performed, among which 295 patients also received the TST test. The agreement (79%) between T-SPOT.TB and TST was poor (x=0.274, P<0.001). The patients with positive T-SPOT.TB results numbered 62 (11.6%), in which only 20 (48.8%) of the 41 receiving the TST test had positive results. A majority of the patients with T-SPOT.TB positive results had some other evidence ofTB, such as TB history, clinical symptoms and an abnormal chest CT scan. Active TB was found in 9 patients, in which 2 had negative TST results. We followed up the patients and no one developed active TB. Our study suggested that the T-SPOT.TB may be more useful for screening LTBI and active TB in hematological malignancy patients and hematopoietic stem cell transplant recipients than the TST test.

Towards Hepatitis B Virus Cure and Immunology

( Qin Ning ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Currently, there are two main types of antiviral drugs approved in the treatment of chronic hepatitis B (CHB): nucleos(t)ide analogue with high barrier to resistance (i.e., entecavir and tenofovir), or pegylated interferon alpha.1 Currently majority of CHB patients require long-term or lifelong treatment dur to limited treatment options, thus there is a need for strategies toward an hepatitis B virus (HBV) cure. The definition of chronic hepatitis B cure includes 1) absolute or complete cure, which is defined by elimination of cccDNA, undetectable HBV DNA in serum and liver and off-therapy HBsAg loss 2) functional (immunological) cure, which is defined by HBsAg loss or seroconversion 3) disease cure, which is defined by no risk of disease progression to cirrhosis, liver failure or hepatocellular carcinoma (HCC).2 However, there are some obstacles for HBV cure. On the one hand, NAs do no directly affect the viral cccDNA or have significant effect on HBsAg level. On the other hand, HBV-specific T cells are exhausted in chronic infection and HBV has evolved mechanisms to evade both innate and adaptive immune responses.3 Combinations of potent NA with immunotherapeutic approaches are highly promising and should help to circumvent these obstacles in the future. In patients on long-term NA therapy, PegIFNα can be used as a ‘switch to’ or ‘add-on’ strategy. Several cohort studies, including OSST study, Endeavor study, Anchor study, New Switch Study, SWAP study in Asia and PEGAN Study, PEGON study, HERMES study in the West, have been carried on in either treatment naïve or NA suppressed CHB patients. In most of these studes with OSST as the first report, HBeAg seroconversion and/or HBsAg reductions or loss rates increase significantly in the combination/switch group.4 Based on these studies, a roadmap to clinical cure of CHB has been proposed5 and recently we launched the COST study to validate the roadmap and OCEAN study to follow up a long term outcome of these approaches. The novel antiviral therapies aim to cure HBV can be categorized into direct-acting antivirals and immunotherapeutic agents. The direct-acting antivirals include HBV entry inhibitors, drugs targeting cccDNA, siRNA or anti-sense oligonucleotides targeting viral transcripts, nucleocapsid assembly modulators, and approaches to inhibit HBsAg release in serum.6 Several potential mechanisms for restoration of immune responses have been suggested. Among them, Toll-like receptor agonists or specific antiviral cytokine delivery are supposed to work for restoration of innate immunity; inhibitors of negative checkpoint regulators, therapeutic vaccines, or autologous transfer of engineered HBV-specific T cells are supposed to work for restoration of adaptive immunity.5,7

Ni-NTA-COATED NANOWIRE MATERIALS FOR PROTEIN ENRICHMENT AND THE APPLICATION IN A MEDICAL DEVICE USED FOR BLOOD GLUCOSE DEGRADATION

QIN HU,YING QI LIU,NING LI,CHUN CHENG,SHUIGANG XU,NING WANG,WEI QIN,BEN ZHONG TANG 성균관대학교(자연과학캠퍼스) 성균나노과학기술원 2013 NANO Vol.8 No.3

A general and reliable method has been developed to functionalize either the iron oxide or the silicon nanowires (NWs) with nickel–nitriloacetic acid (Ni–NTA) complex, which was manufactured to manipulate His-tagged proteins and enzymes. The Ni–NTA-functionalized sea-urchin-shaped α-Fe2O3 NWs exhibit the superior protein purification efficiency and excellent stability in the form of dry powder. Application of this new nanotechnology in biomedical research field has been explored. A glucose degradation bio-matrix was made via the Ni–NTA-modified silicon NW-chips, which were conjugated with an enzyme essential to glycolysis. The glucose level in a simulated blood solution was found to be reduced from 14.4 mM to 9 mM after incubating the hexokinase I-functionalized silicon NW-chips for 12 h. These results suggest a possible way to build up a medical device using enzymes functionalized NW-chips for the removal of excess blood glucose.

HCV, Acute, LT : Hepatic Stellate Cells Modulate Functions of Tregs in IFNγ-mediated Hepatitis of Mice

( Qin Ning ),( Young Sun Lee ),( Hyon Seung Yi ),( Hyuk Soo Eun ),( Won Il Jeong ) 대한간학회 2013 춘·추계 학술대회 (KASL) Vol.2013 No.1

Background: Hepatic stellate cells (HSCs) perform important roles not only in liver fibrosis but also in inflammation by regulating activation or induction of immune cells and producing various chemokines and cytokines. Moreover, it has been reported that HSCs are also involved in the induction of regulatory T cells (Tregs). Therefore, we investigated the immune regulatory role of HSCs to Tregs in interferon γ (IFNγ)- mediated hepatitis of mice. Methods: To induce IFNγ-mediated hepatitis in mice, we injected concanavalin A (ConA) to mice through tail vein at dose of 12 μg/g. Mice were sacrificed at 0, 3, 12 and 24 hours after ConA treatment. In vitro experiment, isolated natural Tregs from lymph nodes and spleen were co-cultured with HSCs and then analyzed the FoxP3 expression and gene expressions. Results: After ConA treatment, liver injuries sharply increased a n d p e a k e d a t 2 4 h o u r s a n d t h e p o p u l a t i o n o CD4+CD25+FoxP3+ Tregs was also significantly increased. In addition, isolated HSCs after ConA treatment showed enhanced expressions of TGF-β and IL-10. In vitro co-culturing Tregs with HSCs, HSCs significantly up-regulated Foxp3 expression in Tregs compared to that of non-co-cultured Tregs. Moreover, levels of IL-10 and TGF-β at supernatant remarkably increased in the co-cultured group compared with those of Tregs or HSCs only cultured group. Conclusions: In ConA-induced hepatitis, HSCs might regulate the expression of FoxP3 in Tregs by producing cytokines such as IL-10 and TGF-β. Therefore, the regulation of function in HSCs could be a new therapeutic target for immune-mediated hepatitis.

Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell

Bao-Qin Liu,Hua-Qin Wang,Xin Meng,Chao Li,Yan-Yan Gao,Ning Li,Xiao-Fang Niu,Yifu Guan 생화학분자생물학회 2011 Experimental and molecular medicine Vol.43 No.9

Glucosamine, a naturally occurring amino monosaccharide,has been reported to play a role in the regulation of apoptosis more than half century. However the effect of glucosamine on tumor cells and the involved molecular mechanisms have not been thoroughly investigated. Glucosamine enters the hexosamine biosynthetic pathway (HBP) downstream of the rate-limiting step catalyzed by the GFAT (glutamine:fluctose-6-phosphate amidotransferase), providing UDPGlcNAc substrates for O-linked β-N-acetylglucosamine (O-GlcNAc) protein modification. Considering that O-GlcNAc modification of proteasome subunits inhibits its activity, we examined whether glucosamine induces growth inhibition via affecting proteasomal activity. In the present study, we found glucosamine inhibited proteasomal activity and the proliferation of ALVA41 prostate cancer cells. The inhibition of proteasomal activity results in the accumulation of ubiquitinated proteins, followed by induction of apoptosis. In addition, we demonstrated that glucosamine downregulated proteasome activator PA28γ and overexpression of PA28γ rescued the proteasomal activity and growth inhibition mediated by glucosamine. We further demonstrated that inhibition of O-GlcNAc abrogated PA28γ suppression induced by glucosamine. These findings suggest that glucosamine may inhibit growth of ALVA41 cancer cells through downregulation of PA28γ and inhibition of proteasomal activity via O-GlcNAc modification.

Glucosamine induces cell death $via$ proteasome inhibition in human ALVA41 prostate cancer cell

Liu, Bao-Qin,Meng, Xin,Li, Chao,Gao, Yan-Yan,Li, Ning,Niu, Xiao-Fang,Guan, Yifu,Wang, Hua-Qin Korean Society for Biochemistry and Molecular Bion 2011 Experimental and molecular medicine Vol.43 No.9

Glucosamine, a naturally occurring amino monosaccharide, has been reported to play a role in the regulation of apoptosis more than half century. However the effect of glucosamine on tumor cells and the involved molecular mechanisms have not been thoroughly investigated. Glucosamine enters the hexosamine biosynthetic pathway (HBP) downstream of the rate-limiting step catalyzed by the GFAT (glutamine:fluctose- 6-phosphate amidotransferase), providing UDP-GlcNAc substrates for O-linked ${\beta}$-N-acetylglucosamine (O-GlcNAc) protein modification. Considering that O-GlcNAc modification of proteasome subunits inhibits its activity, we examined whether glucosamine induces growth inhibition $via$ affecting proteasomal activity. In the present study, we found glucosamine inhibited proteasomal activity and the proliferation of ALVA41 prostate cancer cells. The inhibition of proteasomal activity results in the accumulation of ubiquitinated proteins, followed by induction of apoptosis. In addition, we demonstrated that glucosamine downregulated proteasome activator $PA28{\gamma}$ and overexpression of $PA28{\gamma}$ rescued the proteasomal activity and growth inhibition mediated by glucosamine. We further demonstrated that inhibition of O-GlcNAc abrogated $PA28{\gamma}$ suppression induced by glucosamine. These findings suggest that glucosamine may inhibit growth of ALVA41 cancer cells through downregulation of $PA28{\gamma}$ and inhibition of proteasomal activity via O-GlcNAc modification.

The CCND1 G870A Gene Polymorphism and Brain Tumor Risk: a Meta-analysis

Qin, Ling-Yan,Zhao, Li-Gang,Chen, Xu,Li, Ping,Yang, Zheng,Mo, Wu-Ning Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.8

Background: In recent years, numerous studies have been performed to investigate the CCND1 G870A gene polymorphism impact on brain tumors susceptibility. Unfortunately, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of any association. Materials and Methods: We conducted a search in PubMed, Embase and CNKI covering all published papers up to November, 2013. Odds ratios (ORs) and their 95% confidence intervals (95%CIs) were applied to assess associations. Results: A total of 6 publications including 9 case-control studies met the inclusion criteria. The pooled ORs for the total included studies showed significant association among comparison A vs G (OR= 1.246, 95%CI= 1.092-1.423, p= 0.001), homozygote comparison AA vs GG (OR= 1.566, 95%CI= 1.194-2.054, p= 0.001), heterozygote comparison AG vs GG (OR= 1.290, 95%CI= 0.934-1.782, p= 0.122), dominant model AA/GA vs GG (OR= 1.381, 95%CI= 1.048-1.821, p= 0.022) and recessive model AA vs GA/GG (OR= 1.323, 95%CI= 1.057-1.657, p= 0.015) especially in glioma. Conclusions: CCND1 G870A polymorphism may increase brain tumor risk, especially for gliomas. However, more primary large scale and well-designed studies are still required to evaluate the interaction of CCND1 G870A polymorphism with brain tumor risk.

Association Between the XRCC3 Thr241Met Polymorphism and Cervical Cancer Risk: a Meta-analysis

Qin, Ling-Yan,Chen, Xu,Li, Ping,Yang, Zheng,Mo, Wu-Ning Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.11

Background: Numerous epidemiological studies have been conducted to evaluate the association between variants of the DNA repair gene XRCC3 and cancer risk. Here we focused on one XRCC3 polymorphism and development of cervical cancer, performing a meta-analysis. Methods: The pooled association between the XRCC3 Thr241Met polymorphism and cervical cancer risk was assessed by odds ratios (ORs) and their 95% confidence intervals (95%CIs). Results: A total of 5 case-control studies met the inclusion criteria. The pooled ORs for the total included studies showed no association among homozygotes TT vs. CC: OR=1.93, 95%CI=0.68-5.49, P=0.22; dominant model TT+TC vs. CC: OR=1.37, 95%CI=0.90-2.06, P=0.14; and recessive model TT vs. TC+CC: OR=1.76, 95%CI=0.68-4.55, P=0.25, but might be a slight risk factor for cervical cancer in heterozygote contrast TT vs. CT: OR= 1.33, 95%CI=1.04-1.71, P=0.02. In subgroup analysis, significant associations were found for Asians under all genetic models. Conclusions: Our meta-analysis suggested the XRCC3 Thr241Met polymorphism might not act as a cervical cancer risk factor overall. However, in subgroup analysis, a significant association was found in Asians under all genetic models. The association should be studied with a larger, stratified population, especially for Asians.

The CCND1 G870A Gene Polymorphism and Leukemia or Non-Hodgkin Lymphoma Risk: a Meta-analysis

Qin, Ling-Yan,Zhao, Li-Gang,Chen, Xu,Yang, Zheng,Mo, Wu-Ning Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.16

In recent years, mounting evidence has indicated that the CCND1 G870A gene polymorphism, which impacts the mitotic cell cycle, may influence leukemia or non-Hodgkin lymphoma risk. Unfortunately, the previous results were inconsistent. Therefore, a meta-analysis was performed to obtain a more precise estimation of any association. We conducted a search in PubMed, Embase and CNKI covering all published papers up to March, 2014. A total of 9 publications including 10 case-control studies met the inclusion criteria. Odds ratios (ORs) and their 95% confidence intervals (95%CIs) were applied to assess association. The pooled ORs showed significant association in non-Hodgkin lymphoma (comparison A vs G: OR= 1.114, 95%CI=1.053-1.179, p=0.000; homozygote comparison AA vs GG: OR=1.245, 95%CI=1.110-1.396, p=0.000; heterozygote comparison AG vs GG: OR=1.095, 95%CI=1.000-1.199, p=0.05; dominant model AA/GA vs GG: OR=1.137, 95%CI=1.043-1.239, p=0.003; and recessive model AA vs GA/GG: OR=1.177, 95%CI=1.066-1.301, p=0.001). However, there was no association between the CCND1 G870A polymorphism and leukemia risk. In conclusion, the CCND1 G870A polymorphism may increase risk of non-Hodgkin lymphoma, but not leukemia. However, more primary large scale and well-designed studies are still required to evaluate the interaction of CCND1 G870A polymorphism with leukemia and non-Hodgkin lymphoma risk.