他莫昔芬诱发的非酒精性脂肪性肝病的研究进展

他莫昔芬是治疗激素受体阳性乳腺癌的一种抗雌激素类药物,被广泛地应用于临床.国内外的许多临床研究和动物实验已经证实他莫昔芬可以诱发非酒精性脂肪性肝病.全文主要对他莫昔芬的治疗现状及其诱发的非酒精性脂肪性肝病的流行病学、发病机制、诊断、预测因素、对乳腺癌预后的影响以及预防和管理进行系统全面的综述.     

非酒精性脂肪性肝病相关肝细胞癌发病机制研究进展北大核心

非酒精性脂肪性肝病(NAFLD)正逐渐成为肝细胞癌(HCC)的主要病因。到2030年,NAFLD相关肝癌的年发病率预计将增加45%~130%。尽管NAFLD已成为严重的全球健康威胁,但NAFLD相关HCC的分子机制仍不清楚,需要进一步探索,而NAFLD在HCC中的作用应该引起足够的关注。本文综述了NAFLD相关HCC流行病学最新进展,阐述了遗传易感性、肠道微生物群、代谢紊乱和免疫机制在促进NAFLD进展为HCC进程中的作用机制最新进展,为认识NAFLD相关HCC的现状和发病机制奠定基础。     

非酒精性脂肪性肝病与消化道肿瘤的相关研究进展

非酒精性脂肪性肝病（NAFLD）是代谢综合征的肝脏表现,易合并心脑血管疾病、内分泌疾病、慢性肾脏病、阻塞性睡眠呼吸暂停综合征、骨质疏松症等肝外疾病,近年来众多研究发现NAFLD患者多种肝外恶性肿瘤患病率增高,并以消化道肿瘤患病率最高,本文就NAFLD与消化道肿瘤的相关研究进展及其可能的分子机制进行综述。     

化合物治疗非酒精性脂肪肝病相关肝细胞癌的研究进展

目前非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)已成为全球健康的严重威胁,将成为肝细胞癌(hepatocellular carcinoma, HCC)的主要诱导因素,并最终导致NAFLD相关的HCC的发生。但目前为止,其具体分子机制仍不完全清楚。现越来越多的研究关注着化合物在NAFLD和NAFLD相关的HCC中的应用。因此本文在简要回顾了NAFLD相关HCC发病和进展可能机制的最新研究基础上,进行总结和整理化合物对NAFLD相关肝细胞癌治疗的最新进展,并将这部分药物分为以下五种作用机制：抗炎、抗氧化、调节脂质代谢、调节肠道菌群和抑制肝纤维化,以期为今后NAFLD相关HCC的治疗和预防提供有价值的信息。     

三苯氧胺与脂肪性肝病

三苯氧胺用于雌激素受体阳性乳腺癌患者的内分泌治疗效果肯定,但长期应用可诱发脂肪性肝病.其机制包括药物聚集于肝细胞线粒体、脂肪酸氧化异常、雌激素拮抗作用等.对服用三苯氧胺的乳腺癌患者需定期监测肝功能、血脂、超声及CT等.可选择托瑞米芬、芳香化酶抑制剂替代治疗及应用降脂药物等进行防治.     

三苯氧胺与脂肪性肝病

三苯氧胺用于雌激素受体阳性乳腺癌患者的内分泌治疗效果肯定,但长期应用可诱发脂肪性肝病。其机制包括药物聚集于肝细胞线粒体、脂肪酸氧化异常、雌激素拮抗作用等。对服用三苯氧胺的乳腺癌患者需定期监测肝功能、血脂、超声及CT等。可选择托瑞米芬、芳香化酶抑制剂替代治疗及应用降脂药物等进行防治。     

食管癌治疗敏感基因单核苷酸多态性

研究显示食管癌治疗过程中表现的个体差异与遗传多态性有密切关系.已证实顺铂及5氟尿嘧啶(5-FU)代谢相关基因、凋亡及血管生成相关基因单核苷酸多态性与食管癌治疗敏感性密切相关.     

胃癌相关易感基因单核苷酸多态性研究进展

胃癌具有一定程度的遗传易感性,可能与人群中存在基因多态性有关.近来,胃癌易感性与基因单核苷酸多态性的相关性研究逐渐增加并取得长足进展,目前研究的基因包括细胞增殖基因、酶基因、癌基因与抑癌基因等.     

PTEN基因单核苷酸多态性与肺癌易感性的关系

目的:探讨中国汉族人群PTEN基因多态性与肺癌的关系.方法:应用PCR-RFLP方法对77个中国北方汉族肺癌患者及104个健康人检测单核苷酸多态性(SNP)rs2537343和rs701848位点的基因型.结果:基因型频率分析均符合Hardy-Weinberg平衡;病例对照分析显示rs2735343与肺癌相关,而rs701848与肺癌不相关,单倍体型分析表明rs2735343-rs701848单倍体型与肺癌不相关.结论:PTEN与中国汉族人群肺癌密切相关:rs2735343的等位基因分布与肺癌具有相关性,可能通过调节 PTEN基因的表达影响疾病的发生.     

食管鳞癌易感基因的单核苷酸多态性

我国人群个体食管鳞状细胞癌(ESCC)易感因素主要为易感基因某些位点的变异.其中某些基因位点参与了DNA损伤、修复过程,某些与抑癌基因、代谢酶、微量元素、吸烟等因素相关.这些易感基因位点上的单核苷酸多态性与ESCC的发生密切相关.     

Renin-Angiotensin System Single Nucleotide Polymorphisms Are Associated with Bladder Cancer Risk

The renin-angiotensin system (RAS), besides being a major regulator of blood pressure, is also involved in tumor angiogenesis. Emerging evidence suggests a correlation between the use of pharmacologic RAS inhibitors and a delay in urothelial bladder cancer (BC) progression. However, it is unknown whether RAS gene variants may predispose to the development of BC. This study examined the association of RAS single nucleotide polymorphisms (SNPs) including AT1R rs5186, AT2R rs11091046, REN rs12750834, ANG rs4762, and ANG rs699 with the risk of developing non-invasive BC. Peripheral blood samples from 73 patients with T1 urothelial BC (66 men, seven women) and an equal number of healthy subjects (control group) were collected. The TT genotype of the REN rs12750834 SNP (OR: 2.8 [1.3–6.05], p = 0.008) and to a lesser extent the presence of the T allele (OR: 2.3 [1.2–4.48], p = 0.01) conferred a higher risk of BC. The highest risk for BC within SNP carriers of the RAS system was associated with the presence of the CC genotype (OR: 17.6 [7.5–41.35], p < 0.001) and C allele (OR: 17.7 [8.8–35.9], p < 0.001) of the ANG rs699 SNP. The presence of the AT2R rs11091046 SNP, particularly the AA genotype, was associated with a protective effect against developing BC (OR: 0.268 [0.126–057], p < 0.001). In conclusion, these results support the clinical utility of RAS gene SNPs AT2R rs11091046, REN rs12750834, and ANG rs699 in the genetic cancer risk assessment of patients and families with BC.     

核苷酸切除修复系统基因多态性与淋巴造血系统肿瘤药物治疗反应的研究进展

核苷酸切除修复途径是细胞内最主要、最灵活的DNA修复方式.单核苷酸多态性(single nucleotide polymorphisms,SNPs)是人类第三代分子遗传标志物,反映了个体表型、疾病易感性以及对药物、环境等影响因素反应的差异.淋巴造血系统肿瘤是一种多基因遗传疾病,涉及到多个遗传易感基因的相互作用.全文就NER基因多态性与淋巴造血系统肿瘤药物反应性密切关联的相关基因进展作一综述.     

非酒精性脂肪肝对免疫检查点抑制剂治疗肝细胞癌疗效的影响及机制研究进展

近年来,非酒精性脂肪肝合并肝细胞癌的患者数量逐渐上升,免疫治疗在晚期肝细胞癌的治疗中扮演着越来越重要的角色。既往研究发现非酒精性脂肪肝可以影响肝细胞癌免疫治疗的疗效,但机制不清,可能与这些因素相关：非酒精性脂肪肝中CD8⁺PD-1⁺T细胞增多导致肝脏细胞增殖能力缺陷;锌指蛋白64激活CSF1抑制抗肿瘤免疫;PCSK9下调LDLR水平抑制肿瘤微环境中CD8⁺T细胞免疫应答;免疫应答的缺失导致肝损伤等。研究发现联合使用仑伐替尼、PKCa抑制剂、PCSK9蛋白的抑制、铁死亡诱导剂、HIF2a小分子抑制剂可以改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂的疗效。本文就非酒精性脂肪肝对肝脏免疫微环境和肝细胞癌免疫检查点抑制剂疗效的影响和机制,以及如何改善非酒精性脂肪肝相关肝细胞癌免疫检查点抑制剂疗效的研究进行综述。     

XRCC1单核苷酸多态性与鼻咽癌患者晚期放射性损伤的相关性

目的分析XRCC1 Codon399单核苷酸多态性与鼻咽癌患者正常组织晚期放射性损伤的相关性。方法经病理学检查确诊的60例鼻咽癌患者,放疗前提取全血基因组DNA,进行PCR扩增及LDP连接检测反应扩增,得出XRCC1 Codon399的3种基因型。随访至放疗结束后3个月,对晚期放射性损伤进行评价,比较XRCC1 Codon399不同基因型与正常组织晚期放射性损伤的相关性。结果 60例患者中,XRCC1 Codon399 Gln/Gln基因型6例,Arg/Gln基因型21例,Arg/Arg基因型33例,不同性别之间无明显差异。Gln/Gln基因型者1、2、3级皮肤晚期放射性损伤发生率分别为33.3%、66.7%、0,Arg/Gln基因型者为52.4%、42.9%、4.7%,Arg/Arg基因型者为63.6%、36.4%、0;Gln/Gln基因型患者1、2、3级皮下组织晚期放射性损伤发生率分别为33.3%、66.7%、0,Arg/Gln基因型者为38.1%、57.2%、4.7%,Arg/Arg基因型者为42.4%、57.6%、0;Gln/Gln基因型患者1、2、3级黏膜晚期放射性损伤发生率分别为100.0%、0、0,Arg/Gln基因型者分别为80.9%、14.3%4.7%,Arg/Arg基因型者分别为93.9%、6.1%、0;Gln/Gln基因型患者1、2、3级涎腺晚期放射性损伤发生率分别为100.0%、0、0,Arg/Gln基因型者分别为80.9%、14.3%、4.7%,Arg/Arg基因型者分别为93.9%、6.1%、0。经统计分析,不同基因型患者间晚期放射性损伤发生率无明显差异（P〉0.05）。结论 XRCC1 Co-don399单核苷酸多态性与鼻咽癌患者皮肤、皮下组织、黏膜、涎腺晚期放射性损伤程度无明显相关性,尚不能将其应用于对鼻咽癌患者正常组织晚期放射性损伤程度的预测。     

Non-alcoholic Fatty Liver Disease (NAFLD) and Significant Hepatic Fibrosis Defined by Non-invasive Assessment in Patients with Type 2 Diabetes

Background: Non-alcoholic fatty liver disease (NAFLD), the most common liver problem in diabetes, is arisk factor for liver cancer. Diabetes, high body mass index (BMI) and old age can all contribute to NAFLDprogression. Transient elastography (TE) is used for non-invasive fibrosis assessment. Objectives: To identifythe prevalence of NAFLD and significant hepatic fibrosis in diabetic patients and to assess associated factors.Materials and Methods: One hundred and forty-one diabetic and 60 normal subjects were screened. Fatty liverwas diagnosed when increased hepatic echogenicity and vascular blunting were detected by ultrasonography.Liver stiffness measurement (LSM) representing hepatic fibrosis was assessed by TE. LSM ≥7 kPa was used todefine significant hepatic fibrosis. Results: Four cases were excluded due to positive hepatitis B viral markersand failed TE. Diabetic patients had higher BMI, systolic blood pressure, waist circumference and fasting glucoselevels than normal subjects. Fatty liver was diagnosed in 82 (60.7%) diabetic patients but in none of the normalgroup. BMI (OR: 1.31; 95%CI: 1.02-1.69; p=0.038) and alanine aminotransferase (ALT)(OR: 1.14; 95%CI:1.05-1.23; p=0.002) were associated with NAFLD. Diabetic patients with NAFLD had higher LSM than thosewithout [5.99 (2.4) vs 4.76 (2.7) kPa, p=0.005)]. Significant hepatic fibrosis was more common in diabetic patientsthan in normal subjects [22 (16.1%) vs 1 (1.7%), p=0.002]. Aspartate aminotransferase (AST)(OR: 1.24; 95%CI:1.07-1.42; p=0.003) was associated with significant hepatic fibrosis. Conclusions: Sixty and sixteen percent ofdiabetic patients were found to have NAFLD and significant hepatic fibrosis. High BMI and ALT levels are thepredictors of NAFLD, and elevated AST level is associated with significant hepatic fibrosis.     

XRCC1 单核苷酸多态性预测晚期NSCLC铂类药物化疗的敏感性

 目的 研究XRCC1单核苷酸多态性与晚期非小细胞肺癌（nowsmallcelllungcancer，NSCLC）对以顺铂（cisplatin，DDP）或卡铂（carDoplatin，CBP）为基础药物的化疗敏感性的关系。方法 经病理学确诊的晚期NSCLC患者97例，采用DDP或CBP为基础药物的方案化疗，3个周期后进行疗效评价。以聚合酶链反应（PCR）结合限制性片段长度多态性（RFLP）检测RiCelArg194Trp和Arg399G1n基因型，并比较基因型与化疗敏感性的关系。结果 （1）携带RiCel194Arg／Trp的患者有效率高于携带Arg／Arg、Trp／Trp基因型的患者（P〈0．05）；携带至少一个Trp等位基因基因型患者的化疗敏感性是携带Arg／Arg基因型的3．4倍（OR=3．39，95％，CI=1．3248．70，P〈0.05）。（2）携带RiCel399Arg／Arg、Arg／G1n、Gin／Gin基因型患者的有效率分别为36．4％、22．9％、28．6％，差异无统计学意义（P〉0.05）。尚未发现RiCelArg194Trp和Arg399Gln基因多态性存在联合作用。结论 XRCClArg194Trp单核苷酸多态性可能与晚期NSCLC对铂类药物的化疗敏感性相关。     

Association Between Single Nucleotide Polymorphisms in the XRCC1 Gene and Susceptibility to Prostate Cancer in Chinese Men

Background: Prostate cancer (Pca) is one of the most common complex and polygenic diseases in men. TheX-ray repair complementing group 1 gene (XRCC1) is an important candidate in the pathogenesis of Pca. Thepurpose of this study was to evaluate the association between single nucleotide polymorphisms in the XRCC1gene and susceptibility to Pca. Materials and Methods: XRCC1 gene polymorphisms and associations withsusceptibility to Pca were investigated in 193 prostate patients and 188 cancer-free Chinese men. Results: Thec.910A>G variant in the exon9 of XRCC1 gene could be detected by polymerase chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) and DNA sequencing methods. Significantly increased susceptibility toprostate cancer was noted in the homozygote comparison (GG versus AA: OR=2.95, 95% CI 1.46-5.42, χ2=12.36,P=0.001), heterozygote comparison (AG versus AA: OR=1.76, 95% CI 1.12-2.51, χ2=4.04, P=0.045), dominantmodel (GG/AG versus AA: OR=1.93, 95% CI 1.19-2.97, χ2=9.12, P=0.003), recessive model (GG versus AG+AA:OR=2.17, 95% CI 1.33-4.06, χ2=8.86, P=0.003) and with allele contrast (G versus A: OR=1.89, 95% CI 1.56-2.42,χ2=14.67, P<0.000). Conclusions: These findings suggest that the c.910A>G polymorphism of the XRCC1 geneis associated with susceptibility to Pca in Chinese men, the G-allele conferring higher risk.     

肝硬化及肝癌p53基因突变的实验研究

目的 :研究肝硬化及肝癌p53基因的突变情况。方法 :选择 80例肝硬化、肝癌标本 ,分别以PCR SSCP法 ,双链DNA序列测定法研究其p53基因外显子的突变情况及突变位点。结果 :62例肝癌标本p53总突变率为 19 4 % ,其中 ,早、中、晚期突变率分别为 10 5%、15 0 %、35 0 % ;18例肝硬化标本p53总突变率为 5 6% ;第 7外显子的突变发生在 2 4 9位密码子第 3号碱基上 ,为G :C→T :A的颠换突变 ;第 8外显子的突变发生在 2 73位密码子第 1号碱基上 ,为C :G→T :A的转换突变。结论 :p53基因突变发生在肝细胞发生形态学改变之初 ,随着肝癌的进展逐渐积累 ,突变率呈上升趋势 ,故p53基因突变很可能是启动癌变过程的重要因素之一。