Chronic hepatitis B is a global health problem. The clinical outcomes of chronic hepatitis B infection include asymptomatic carrier state, chronic hepatitis(CH), liver cirrhosis(LC), and hepatocellular carcinoma(HCC)....Chronic hepatitis B is a global health problem. The clinical outcomes of chronic hepatitis B infection include asymptomatic carrier state, chronic hepatitis(CH), liver cirrhosis(LC), and hepatocellular carcinoma(HCC). Because of the spontaneous error rate inherent to viral reverse transcriptase, the hepatitis B virus(HBV) genome evolves during the course of infection under the antiviral pressure of host immunity. The clinical significance of pre-S/S variants has become increasingly recognized in patients with chronic HBV infection. Pre-S/S variants are often identified in hepatitis B carriers with CH, LC, and HCC, which suggests that these naturally occurring pre-S/S variants may contribute to the development of progressive liver damage and hepatocarcinogenesis. This paper reviews the function of the pre-S/S region along with recent findings related to the role of pre-S/S variants in liver diseases. According to the mutation type, five pre-S/S variants have been identified: pre-S deletion, pre-S point mutation, pre-S1 splice variant, C-terminus S point mutation, and pre-S/S nonsense mutation. Their associations with HBV genotype and the possible pathogenesis of pre-S/S variants are discussed. Different pre-S/S variants cause liver diseases through different mechanisms. Most cause the intracellular retention of HBV envelope proteins and induction of endoplasmic reticulum stress, which results in liver diseases. Pre-S/S variants should be routinely determined in HBV carriers to help identify individuals who may be at a high risk of less favorable liver disease progression. Additional investigations are required to explore the molecular mechanisms of the pre-S/S variants involved in the pathogenesis of each stage of liver disease.展开更多
AIM: To design and construct an exogenous multiple epitope of helper T lymphocytes (HTL), and to evaluate its effect on anti-HBs response through DNA immunization. METHODS: Artificial HTL epitope, PADRE and four other...AIM: To design and construct an exogenous multiple epitope of helper T lymphocytes (HTL), and to evaluate its effect on anti-HBs response through DNA immunization. METHODS: Artificial HTL epitope, PADRE and four other HTL epitopes from different proteins were linked together using splicing by overlap extension to generate exogenous multiple epitopes of HTL, MTE5. pcMTE5 and pcHB were generated by cloning MTE5 and fragments of HBV pre-S2/S gene into mammalian expression plasmid pcDNA3. Four chimeric plasmids were constructed by cloning MTE5 into the region of pre-S2 gene (Barn HI), 5' terminal of S gene (HincII, Xba I) and 3' terminal of S gene (Acc I) of pcHB respectively. BALB/c mice were used in DNA immunization of the recombinant plasmids. Anti-HBs was detected using Abbott IMx AUSAB test kits.RESULTS: The sequences of MTE5 and the 6 constructs ofrecombinant plasmids were confirmed to be correct by DNA sequencing. The anti-HBs response of the coinoculation of pcHB and pcMTE5 was much higher than that of the inoculation of pcHB only (136.7+69.1 mIU/mL vs 27.6+17.3 mIU/mL, P<0.01, t =-6.56). Among the 4 chimeric plasmids, only the plasmid in which MTE5 was inserted into the pre-S2 region had good anti-HBs response (57.54±7.68 mIU/mL), and had no significant difference compared with those of pcHB and the co-inoculation of pcHB and pcMTE5. CONCLUSION: Exogenous multiple epitopes of HTL had immune enhancement when they were co-inoculated with pre-S2/S gene or inoculated in the chimeric form at a proper site of pre-S2/S gene of HBV. It might suggest that it was possible to improve hepatitis B vaccine using exogenous multiple epitopes of HTL. The antibody responses were very low using DNA immunization in the study. Thus, the immune enhancement effect of exogenous multiple epitopes of HTL has to be confirmed and the effect on overcoming the drawback of the polymorphism of HLA II antigens should also be evaluated after these chimeric plasmids are expressed in mammalian cell lines.展开更多
目的探讨乙型肝炎病毒(hepatitis B virus,HBV)前S/S区氨基酸位点的变异与肝硬化发生发展的潜在关联,为进一步理解HBV变异在疾病进展中的作用及开发针对性治疗策略提供科学依据。方法2018—2022年于甘肃省武威肿瘤医院纳入慢性乙型肝炎(...目的探讨乙型肝炎病毒(hepatitis B virus,HBV)前S/S区氨基酸位点的变异与肝硬化发生发展的潜在关联,为进一步理解HBV变异在疾病进展中的作用及开发针对性治疗策略提供科学依据。方法2018—2022年于甘肃省武威肿瘤医院纳入慢性乙型肝炎(chronic hepatitis B,CHB)感染者建立专病队列,共纳入乙型肝炎表面抗原(hepati-tis B surface antigen,HBsAg)阳性患者3882人。随访至2022年12月31日,对患者血清样本的HBV前S/S区进行二代测序(next-generation sequencing,NGS),将序列进行翻译与基因分型后得到C基因型,并将肝硬化与非肝硬化患者按年龄(±5岁)与性别进行1∶1匹配后,计算氨基酸突变率与香农熵。构建稀疏逻辑回归(sparse logistic regression,SLR)模型,分析乙型肝炎相关肝硬化患者病毒前S/S区氨基酸的特征。结果测序完整的C基因型患者196人,其中肝硬化22人,非肝硬化174人。年龄(±5岁)与性别的1∶1匹配分析后,得到肝硬化组和非肝硬化组各20人。非肝硬化组中接受抗病毒治疗的患者比例高于肝硬化组,差异有统计学意义(χ^(2)=4.912,P<0.05)。肝硬化组前S1区的平均突变频率及香农熵均高于非肝硬化组,差异有统计学意义(Z=3.793、3.057,P<0.05)。共发现8个氨基酸位点的突变频率在2组间差异有统计学意义,有6个是有效突变位点。其中,T68、G73、M120和G318位点突变频率肝硬化组高于非肝硬化组(Z=2.029、2.191、2.299、2.029,P<0.05),而T84、L267、L283和N380位点则相反(Z=2.380、2.056、2.353、2.462,P<0.05)。建立的SLR模型筛选出第380个位点(即N380位点)的突变频率为最高贡献度指标(Z=2.462,P<0.05),其余指标的贡献度虽排在前10,但2组间差异无统计学意义。结论HBV前S/S区氨基酸位点的改变可能影响肝硬化的发展,即前S1区氨基酸突变频率越高肝硬化就越有可能发生;SLR模型的应用为肝硬化预测及精准治疗提供了新的方向。展开更多
Let R be a ring and S a class of R-modules. S-superfluous epimorphisms and S-essential monomorphisms are introduced and studied in this article. As applications, some new characterizations of von Neumann regular rings...Let R be a ring and S a class of R-modules. S-superfluous epimorphisms and S-essential monomorphisms are introduced and studied in this article. As applications, some new characterizations of von Neumann regular rings and perfect rings are given. Finally, these notions are also used to study minimal homomorphisms.展开更多
基金Supported by the grant from the National Science Council(NSC 96-2320-B-030-004-MY3),Executive Yuan,Taiwan
文摘Chronic hepatitis B is a global health problem. The clinical outcomes of chronic hepatitis B infection include asymptomatic carrier state, chronic hepatitis(CH), liver cirrhosis(LC), and hepatocellular carcinoma(HCC). Because of the spontaneous error rate inherent to viral reverse transcriptase, the hepatitis B virus(HBV) genome evolves during the course of infection under the antiviral pressure of host immunity. The clinical significance of pre-S/S variants has become increasingly recognized in patients with chronic HBV infection. Pre-S/S variants are often identified in hepatitis B carriers with CH, LC, and HCC, which suggests that these naturally occurring pre-S/S variants may contribute to the development of progressive liver damage and hepatocarcinogenesis. This paper reviews the function of the pre-S/S region along with recent findings related to the role of pre-S/S variants in liver diseases. According to the mutation type, five pre-S/S variants have been identified: pre-S deletion, pre-S point mutation, pre-S1 splice variant, C-terminus S point mutation, and pre-S/S nonsense mutation. Their associations with HBV genotype and the possible pathogenesis of pre-S/S variants are discussed. Different pre-S/S variants cause liver diseases through different mechanisms. Most cause the intracellular retention of HBV envelope proteins and induction of endoplasmic reticulum stress, which results in liver diseases. Pre-S/S variants should be routinely determined in HBV carriers to help identify individuals who may be at a high risk of less favorable liver disease progression. Additional investigations are required to explore the molecular mechanisms of the pre-S/S variants involved in the pathogenesis of each stage of liver disease.
基金Supported by the National Natural Science Foundation of China,NO.39970677 and the Science Foundation of Guangdong Province,NO.99M04801G
文摘AIM: To design and construct an exogenous multiple epitope of helper T lymphocytes (HTL), and to evaluate its effect on anti-HBs response through DNA immunization. METHODS: Artificial HTL epitope, PADRE and four other HTL epitopes from different proteins were linked together using splicing by overlap extension to generate exogenous multiple epitopes of HTL, MTE5. pcMTE5 and pcHB were generated by cloning MTE5 and fragments of HBV pre-S2/S gene into mammalian expression plasmid pcDNA3. Four chimeric plasmids were constructed by cloning MTE5 into the region of pre-S2 gene (Barn HI), 5' terminal of S gene (HincII, Xba I) and 3' terminal of S gene (Acc I) of pcHB respectively. BALB/c mice were used in DNA immunization of the recombinant plasmids. Anti-HBs was detected using Abbott IMx AUSAB test kits.RESULTS: The sequences of MTE5 and the 6 constructs ofrecombinant plasmids were confirmed to be correct by DNA sequencing. The anti-HBs response of the coinoculation of pcHB and pcMTE5 was much higher than that of the inoculation of pcHB only (136.7+69.1 mIU/mL vs 27.6+17.3 mIU/mL, P<0.01, t =-6.56). Among the 4 chimeric plasmids, only the plasmid in which MTE5 was inserted into the pre-S2 region had good anti-HBs response (57.54±7.68 mIU/mL), and had no significant difference compared with those of pcHB and the co-inoculation of pcHB and pcMTE5. CONCLUSION: Exogenous multiple epitopes of HTL had immune enhancement when they were co-inoculated with pre-S2/S gene or inoculated in the chimeric form at a proper site of pre-S2/S gene of HBV. It might suggest that it was possible to improve hepatitis B vaccine using exogenous multiple epitopes of HTL. The antibody responses were very low using DNA immunization in the study. Thus, the immune enhancement effect of exogenous multiple epitopes of HTL has to be confirmed and the effect on overcoming the drawback of the polymorphism of HLA II antigens should also be evaluated after these chimeric plasmids are expressed in mammalian cell lines.
基金Supported by Specialized Research Fund for the Doctoral Program of Higher Education (20050284015)National Natural Science Foundation of China (10771096)
文摘Let R be a ring and S a class of R-modules. S-superfluous epimorphisms and S-essential monomorphisms are introduced and studied in this article. As applications, some new characterizations of von Neumann regular rings and perfect rings are given. Finally, these notions are also used to study minimal homomorphisms.
