乙肝病毒与原发性肝癌的相关风险研究

为了解慢性乙型肝炎病毒感染与原发性肝癌的关系,本文采用回顾性研究方法对 328 例原发性肝癌病人与同期收治的 340 例非肝癌的其他消化道肿瘤病人的乙型肝炎病毒感染血清标志物(HBV M)及肝功能检测结果进行对比分析。结果显示肝癌组乙肝表面抗原(HBsAg)阳性率(63.11%)显著高于非肝癌组(消化道其他肿瘤对照组)(11.47%)。肝癌组慢性乙型肝炎病毒感染“HBsAg、抗-HBe 和抗-HBc 三者均表达为阳性者”(37.2%)显著高于“HBsAg、HBeAg 和抗-HBc 三者均表达为阳性者”(6.4%)。肝功能检测结果,“HBsAg、HBeAg 和抗-HBc三者均表达为阳性组”与“HBsAg、HBeAg 和抗-HBc 三者均表达为阳性组”比较无显著性差异(P>0.05),而肝癌组与非肝癌组比较,肝癌组肝损害显著高于非肝癌组(P<0.01)。表明慢性乙型肝炎病毒感染在原发性肝癌病因学中起着十分重要的作用,“HBsAg、抗-HBe 和抗-HBc 三者均表达为阳性者”是原发性肝癌的高危人群。     

乙肝病毒与原发性肝癌的相关风险研究

为了解慢性乙型肝炎病毒感染与原发性肝癌的关系,本文采用回顾性研究方法对328例原发性肝癌病人与同期收治的340例非肝癌的其他消化道肿瘤病人的乙型肝炎病毒感染血清标志物(HBV M)及肝功能检测结果进行对比分析.结果显示肝癌组乙肝表面抗原(HBsAg)阳性率(63.11%)显著高于非肝癌组(消化道其他肿瘤对照组)(11.47%).肝癌组慢性乙型肝炎病毒感染"HBsAg、抗-HBe和抗-HBc三者均表达为阳性者"(37.2%)显著高于"HBsAg、HBeAg和抗-HBc三者均表达为阳性者"(6.4%).肝功能检测结果,"HBsAg、HBeAg和抗-HBc三者均表达为阳性组"与"HBsAg、HBeAg和抗-HBc三者均表达为阳性组"比较无显著性差异(P＞0.05),而肝癌组与非肝癌组比较,肝癌组肝损害显著高于非肝癌组(P＜0.01).表明慢性乙型肝炎病毒感染在原发性肝癌病因学中起着十分重要的作用,"HBsAg、抗-HBe和抗-HBc三者均表达为阳性者"是原发性肝癌的高危人群.     

乙型肝炎病毒X基因诱导的细胞基因表达与肝细胞肝癌

乙型肝炎病毒X基因与原发性肝癌的发生密切相关,其编码的蛋白质(HBxAg)具有的反式激活功能,可通过结合细胞核内的转录因子和改变细胞质内信号转导途径而激活宿主基因的转录及调控细胞凋亡等。研究发现,用HBx基因转染HepG2细胞,有10个细胞基因有表达差异,其中8个基因表达增强,2个基因表达减弱。已经证明,HBx诱发的这种高水平表达的细胞基因产物及其相应的抗体常存在于肝癌发生之前的乙型肝炎患者血清中,而且这些细胞蛋白及其相应抗体的出现早于甲胎蛋白几个月,甚至一年以上。提示,这些指标有可能用于原发性肝癌的筛查和早期诊断,成为原发性肝癌颈警、早期诊断和疗效评估的新指标。     

四省观察点人群中血清乙型肝炎病毒表面抗原消长趋势调查

本文以前瞻性血清流行病学方法调查了人群中血清HBsAg消长趋势。观察了3 096名HBV易感者,其人年总感染率为7.0％;HBsAg人年阳转率为0.68％,两者之比为10.3:1.0。HBsAg阳转者中51.2％发生在0～3岁时期。调查了772例HBsAg携带者,其人年标化阴转率为2.01％,阴转者主要发生在10～29岁和50岁以上年龄组,占总阴转数的66.7％。以人群HBsAg阴转率加上因自然死亡而损失的HBsAg携带率和人群中HBsAg年增长率进行分析计算,得出HBsAg在观察点人群中的消长状况是呈上升趋势,即年增加率为0.370％,年减少率为0.264％。     

自身免疫性甲状腺功能紊乱孕妇血清TPOAb 检测的临床价值

目的:探讨血清甲状腺过氧化物酶抗体(TPOAb)对于患有自身免疫性甲状腺功能紊乱的孕妇的临床诊断价值。方法:筛选2009年9月至2013年1月我院收治的205例孕妇,其中甲状腺功能紊乱孕妇55例(紊乱组),非甲状腺功能紊乱孕妇150例(非紊乱组);非紊乱组中,年龄30岁的高龄孕妇50例(高龄组),年龄≤30岁的孕妇100例(正常组)。采用化学发光法,测定所有孕妇血清中游离甲状腺三碘原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺激素(TSH)和TPOAb水平。结果:紊乱组患者血清中TSH、TPOAb及TPOAb阳性率水平显著高于非紊乱组,且存在统计学意义(均P0.05),而两组患者血清中FT3和FT4水平无统计学意义(均P0.05);高龄组和正常组血清中TSH、FT3、FT4及TPOAb水平均无统计学意义(均P0.05);与TSH正常组相比,TSH异常组中约有超过半数TPOAb表现为阳性,有统计学意义(P0.05);孕妇体内的TSH水平正常与否,均有出现TPOAb阳性的可能,在TSH水平较高(4.67 m IU/L)中,TPOAb阳性概率更高。结论:TSH、FT3、FT4水平正常而TPOAb呈阳性的孕妇依然存在自身免疫性甲状腺功能紊乱的可能性,监测TPOAb的水平对于妊娠期孕妇功能紊乱的诊断与治疗具有重要意义。     

HBV X基因在大肠杆菌中高效表达及血清抗X抗体检测

本文分别用大肠杆菌(E．Coli的Lpp启动子和M13噬菌体的geneⅡ启动子表达了分子量约为17 kDa的HBx蛋白,并以抗合成x多肽抗血清和抗x融合蛋白抗血清对该重组蛋白进行了分析鉴定(用ELISA法和Western印迹法),然后用重组x蛋白检测肝病病人血清中抗x抗体。我们采用一种改进的ELISA方法检测了212份血清标本,结果表明：肝硬化、慢活肝、肝癌、慢迁肝和急性乙型肝炎病人血清中抗x抗体阳性率分别为49．3％,47．6％、37．8％,29．6％和40．0％,高滴度的抗体主要存在于肝硬化和慢活肝病人血清中。     

人原发性肝细胞肝癌中丙型肝炎病毒C_（33c）抗原及HBxAg的分布及意义

作者应用抗ＨＣＶＮＳ３区Ｃ３３ｃ抗原２Ｂ６株单克隆抗体和抗ＨＢｘＡｇ多克隆抗体,采用ＡＢＣ法对１０２例人原发性肝细胞肝癌（ＰＨＣ）组织进行了ＨＣＶ及ＨＢＶ抗原定位研究。ＨＣＶＣ３。抗原及ＨＢｘＡｇ在ＰＨＣ中的阳性检出率分别是８１．４％及７４．５％,Ｃ３３ｃ抗原或ＨＢｘＡｇ阳性占所检病例９４．１％,相同病例二者同时阳性为６１．８％。１０２例ＰＨＣ中５０例有癌旁肝组织,其Ｃ３３ｃ抗原和ＨＢｘＡｇ的阳性检出率分别是６２％和９２％。ＨＣＶＣ３３ｃ抗原定位于肝癌细胞的胞浆内,胞核未见阳性信号。Ｃ３３ｃ抗原阳性细胞在ＰＨＣ中呈散在、局灶分布为主,在癌旁肝组织呈弥漫分布为主。本文结果提示ＨＣＶ感染在ＰＨＣ的发生中可能起重要作用。     

乙型肝炎病毒DNA在患者血清及肝组织中存在状态的研究

对29例肝炎,1例尸检肝组织和血清中乙型肝炎病毒的DNA(HBV DNA)进行了研究,发现HBsAg( )/HBeAg( )患者中,有9/17(52.94％)血清HBV DNA阳性;HBsAg( )/抗-HBe( )患者中,2/6(33.33％)也为阳性。从30例肝组织中提取DNA经琼脂糖电泳,Southern吸印转移及分子杂交试验结果表明,27例HBV DNA阳性,全部有游离型HBV DNA。27例中有5例经用标记pBR322探针杂交排除非特异杂交带后,在高分子量区有HBV DNA特异的杂交带,提示有HBV DNA整合。     

肝癌组织中SOCS-3 mRNA的表达

目的:探讨人肝癌组织中细胞因子信号转导抑制因子-3(SOCS-3)的表达.方法:应用RT-PCR法测定8例人正常肝组织、10例肝硬化组织及10例肝癌组织中SOCS-3 mRNA的表达.结果:与正常肝组织和肝硬化相比较,肝癌组织SOCS-3 mRNA的表达明显降低(P<0.05).肝硬化组织与正常肝组织SOCS-3 mRNA的表达无明显差异(P>0.05).结论:SOCS-3表达下降与肝癌的发生、发展密切相关.     

Current pathogenetic and molecular concepts in viral liver carcinogenesis

Hepatocellular carcinoma (HCC) is one of the most frequent malignancies in humans and in most cases a consequence of chronic infection of the liver by hepatotropic viruses (Hepatitis B Virus (HBV) and possibly Hepatitis C Virus (HCV)). Formation of HCC results from a stepwise process involving different preneoplastic lesions that reflect multiple genetic events, like protooncogene activation, tumor suppressor gene inactivation, and growth factor overor reexpression. Recent investigations have gained new insights into how these factors are activated and may interact. In addition, improved knowledge of the molecular biology of HBV has led to better understanding of its pleiotropic effects on induction and progression in hepatocarcinogenesis     

Hepatitis viruses and hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is among the most frequent malignancies worldwide. Hepatitis viruses, such as the hepatitis B virus (HBV) and hepatitis C virus (HCV) are undoubtedly listed in the etiology of HCC. Studies show that, in the near future, viral hepatitis will carry increasing weight in the etiology of HCC. This review briefly discusses the known carcinogenic effects of HBV and HCV in the light of experimental and human studies. The data show that viral proteins may directly interfere with gene products responsible for cell proliferation and cell growth. Many other signal transduction cascades may be affected as well. Direct integration of HBV viral sequences into the host genome increases the genomic instability. The genomic imbalance allows the development and survival of malignant clones bearing defected genomic information. HBV and HCV infection induces indirect and direct mechanisms through cellular damage, increased regeneration and cell proliferation, therefore enhancing the development of HCC.     

Advances in Research on Hepatitis B Virus DNA Integration

Since HBV DNA integration was discovered for the first time in 1980, various methods have been used to detect and study it, such as Southern Blot, in situ hybridization, polymerase chain reaction and so on. HBV DNA integration is thought to be random on the whole although some hot spots of integration were described by some researchers, one of which might be the repetitive sequences of the genomic DNA. Besides, DNA damage, especially double-strand breaks could promote HBV DNA integration into host genome. HBV DNA integration into cells may damage the stability of the genome, cause DNA rearrangement, promote DNA deletion and induce the formation of HCC.     

Advances in research on hepatitis B virus DNA integration

Since HBV DNA integration was discovered for the first time in 1980, various methods have been used to detect and study it, such as Southern Blot, in situ hybridization, polymerase chain reaction and so on. HBV DNA integration is thought to be random on the whole although some hot spots of integration were described by some researchers, one of which might be the repetitive sequences of the genomic DNA. Besides, DNA damage, especially double-strand breaks could promote HBV DNA integration into host genome. HBV DNA integration into cells may damage the stability of the genome, cause DNA rearrangement, promote DNA deletion and induce the formation of HCC.     

肝癌组织中HBV核心基因启动子突变的研究

为深入了解乙肝病毒 (HBV)致癌机理 ,用套式PCR对广西 14例血清HBVDNA阳性的原发性肝癌患者癌组织、10例乙型病毒性肝炎患者血清及 10例乙肝病毒无症状携带者血清HBV核心基因启动子进行扩增 ,阳性者用Sanger氏双脱氧法做序列分析 ,发现肝癌组织 10例PCR阳性 ,阳性率 71.4 % ,所有PCR阳性标本的整合体均有乙肝病毒核心基因启动子双突变序列 (nt 176 2A→T ,176 4G→A) ,并且在其周围各序列都有不同部位的点突变 ,标本C14核苷酸的缺失突变高达10个。乙肝患者 6例PCR阳性 ,其中 3例乙肝病毒核心基因启动子发生双突变。无症状携带者中 4例PCR阳性 ,其中仅 1例发生双突变。结果提示乙肝病毒核心基因启动子双突变在肝癌患者中较常见 ,肝炎患者次之 ,无症状携带者居最后。     

Stereotactic body radiation therapy in hepatocellular carcinoma: Optimal treatment strategies based on liver segmentation and functional hepatic reserve

AimTo discuss current dosage for stereotactic body radiation therapy (SBRT) in hepatocellular carcinoma (HCC) patients and suggest alternative treatment strategies according to liver segmentation as defined by the Couinaud classification.BackgroundSBRT is a safe and effective alternative treatment for HCC patients who are unable to undergo liver ablation/resection. However, the SBRT fractionation schemes and treatment planning strategies are not well established.Materials and methodsIn this article, the latest developments and key findings from research studies exploring the efficacy of SBRT fractionation schemes for treatment of HCC are reviewed. Patients’ characteristics, fractionation schemes, treatment outcomes and toxicities were compiled. Special attention was focused on SBRT fractionation approaches that take into consideration liver segmentation according to the Couinaud classification and functional hepatic reserve based on Child–Pugh (CP) liver cirrhosis classification.ResultsThe most common SBRT fractionation schemes for HCC were 3 × 10–20 Gy, 4–6 × 8–10 Gy, and 10 × 5–5.5 Gy. Based on previous SBRT studies, and in consideration of tumor size and CP classification, we proposed 3 × 15–25 Gy for patients with tumor size <3 cm and adequate liver reserve (CP-A score 5), 5 × 10–12 Gy for patients with tumor sizes between 3 and 5 cm or inadequate liver reserve (CP-A score 6), and 10 × 5–5.5 Gy for patients with tumor size >5 cm or CP-B score.ConclusionsTreatment schemes in SBRT for HCC vary according to liver segmentation and functional hepatic reserve. Further prospective studies may be necessary to identify the optimal dose of SBRT for HCC.     

Proteomic analysis of liver tissue from HBx‐transgenic mice at early stages of hepatocarcinogenesis

The hepatitis B virus X‐protein (HBx), a multifunctional viral regulator, participates in the viral life cycle and in the development of hepatocellular carcinoma (HCC). We previously reported a high incidence of HCC in transgenic mice expressing HBx. In this study, proteomic analysis was performed to identify proteins that may be involved in hepatocarcinogenesis and/or that could be utilized as early detection biomarkers for HCC. Proteins from the liver tissue of HBx‐transgenic mice at early stages of carcinogenesis (dysplasia and hepatocellular adenoma) were separated by 2‐DE, and quantitative changes were analyzed. A total of 22 spots displaying significant quantitative changes were identified using LC‐MS/MS. In particular, several proteins involved in glucose and fatty acid metabolism, such as mitochondrial 3‐ketoacyl‐CoA thiolase, intestinal fatty acid‐binding protein 2 and cytoplasmic malate dehydrogenase, were differentially expressed, implying that significant metabolic alterations occurred during the early stages of hepatocarcinogenesis. The results of this proteomic analysis provide insights into the mechanism of HBx‐mediated hepatocarcinogenesis. Additionally, this study identifies possible therapeutic targets for HCC diagnosis and novel drug development for treatment of the disease.     

Low serum interleukin-6 levels as a predictive marker of recurrence in patients with hepatitis B virus related hepatocellular carcinoma who underwent curative treatment

BackgroundWe aimed to investigate the use of novel serum biomarkers for predicting the recurrence and survival of patients with hepatitis B virus (HBV)-related early hepatocellular carcinoma (HCC) after hepatic resection or radiofrequency ablation (RFA).MethodsOne hundred and five patients with HBV-related HCC, who fulfilled the Milan criteria without vascular invasion and underwent hepatic resection or RFA, were followed-up for a median duration of 52 months. Pretreatment serum concentrations of 16 cytokines including interleukin-6 (IL-6) were measured by using a Luminex 200 system. The measured serum cytokines and several clinical factors were analyzed retrospectively.ResultsUnivariate analysis showed that patients with lower pretreatment serum levels of IL-10, IL-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α had significantly shorter disease-free survival (DFS) than those with higher levels. Multivariate analysis revealed that a low serum IL-6 level (⩽33.00 pg/mL; hazard ratio [HR] = 5.39; 95% confidence interval [CI] = 1.27–22.93; P = 0.022), low platelet count (<100 × 10⁹/L; HR = 2.23; 95% CI = 1.28–3.89; P = 0.005), and low serum albumin level (⩽3.5 g/L; HR = 2.26; 95% CI = 1.28–3.97; P = 0.005) had a negative prognostic impact on DFS. In the analysis for overall survival, a low serum platelet level (<100 × 10⁹/L; HR = 2.80; 95% CI = 1.31–5.99; P = 0.008) and multiple tumor (⩾2; HR = 4.05; 95% CI = 1.56–10.48; P = 0.004) showed a negative prognostic impact on the overall survival.ConclusionA low serum IL-6 level is, in addition to low platelet count and low serum albumin level, an independent prognostic factor for DFS in patients with HBV-related early HCC who underwent hepatic resection or RFA with curative intention.     

乙型肝炎血清标志模式与病毒载量的关系及意义

为探讨乙型肝炎 (以下简称乙肝 )血清标志模式与病毒载量的关系及临床意义 ,作者选择符合 2 0 0 0年《全国病毒性肝炎诊断标准》的慢性肝炎血清 1343份 ,分别用ELISA法、PCR ELISA法检测HB血清标志、HBV -DNA和 1896位点变异株。结果显示 :HBsAg阳性血清 10 97份 (81.6 8%、)HBsAg阴性血清 2 4 6份 (81.31% )。在HBsAg阳性血清中 ,HBsAg、HBeAg、抗 HBc(1 3 5 )阳性组 4 0 4份 (30 .l% ) ,HBV -DNA阳性 347份 (85 .89% ) ,DNA阳性值呈递增趋势 (10 4～ 10 6拷贝 /ml,各占 8.6 5 %、33.71%、5 3.6 1% ) ;而HBsAg、抗 HBe阳性组血清 6 0 6份 (45 .12 % ) ,DNA阳性值 10 5拷贝 /ml,占优势 (6 4 .18% )。在HBsAg阴性血清中 ,抗 HBs、抗 HBe、抗 HBc(2 4 5 )阳性组 2 32份 (17.2 7% ) ,DNA阳性占 7.32 % ,DNA阳性值递减由 10 4～ 10 6拷贝 /ml,各占 5 2 .9%、4 1.l%、5 .9%。结论 ,各血清标志模式中的病毒载量为HBsAg阳性组 >HBsAg阴性组 ,阳性组 1 3 5 >1 4 5 >l 5 >2 4 5。但 1 3 5阳性组中 14 %在界值以下 ,1 4 5阳性组中 1896位点自然变异达 78.6 % ,2 4 5阳性组中仍存在DNA+ 血清 ,以上提示在临床判定和治疗时要慎重对待(注 :l=HBsAg,2 =抗 HBs,3=HBeAg ,4 =抗 HBe ,5 =抗 HBc)