Variations in Prkdc and susceptibility to benzene-induced toxicity in mice.

Benzene, a carcinogen that induces chromosomal breaks, is strongly associated with leukemias in humans. Possible genetic determinants of benzene susceptibility include proteins involved in repair of benzene-induced DNA damage. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), encoded by Prkdc, is one such protein. DNA-PKcs is involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Here we compared the toxic effects of benzene on mice (C57BL/6 and 129/Sv) homozygous for the wild-type Prkdc allele and mice (129/SvJ) homozygous for a Prkdc functional polymorphism that leads to diminished DNA-PK activity and enhanced apoptosis in response to radiation-induced damage. Male and female mice were exposed to 0, 10, 50, or 100 ppm benzene for 6 h/d, 5 d/week for 2 weeks. Male mice were more susceptible to benzene toxicity compared with females. Hematotoxicity was evident in all male mice but was not seen in female mice. We observed similar, large increases in both micronucleated erythrocyte populations in all male mice. Female mice had smaller but significant increases in micronucleated cells. The p53-dependent response was induced in all strains and genders of mice following benzene exposure, as indicated by an increase in p21 mRNA levels in bone marrow that frequently corresponded with cell cycle arrest in G2/M. Prkdc does not appear to be a significant genetic susceptibility factor for acute benzene toxicity. Moreover, the role of NHEJ, mediated by DNA-PK, in restoring genomic integrity following benzene-induced DSB remains equivocal.     

细胞色素P450 3A4基因多态性及与肝癌易感性研究

目的 探讨细胞色素P450 3A4(CYP3A4)基因的多态性与肝癌的关系。方法 应用聚合酶链反应（PCR）、变性梯度凝胶电泳（DGGE）、单链构象多态（SSCP）和DNA测序技术，对84例肝癌患者和144例健康对照的CYP3A4基因的多态性进行了研究。结果 通过对CYP3A4基因10个外显子的检测，发现2例肝癌患者的第7外显子第15742位核苷酸发生了A→G转换，使得第183位氨基酸残基由天冬酰胺转变为丝氨酸；发现第10内含子存在一单核苷酸多态，表现第20338位核苷酸发生了G→A转换。病例组G／G、G／A和A／A基因型频率分别为59.52％,36.90%和3.58%；对照组则为59.72%，33.33%和6.95％。两组比较没有统计学差异。结论 CYP3A4基因可能高度保守，虽有突变，但属罕见。     

Polymorphisms in the glutathione S-transferase class mu and theta genes interact and increase susceptibility to lung cancer in minority populations (Texas, United States)

The genes coding for separate isoforms of both the human glutathioneS-transferase class mu and class theta enzymes (GSTM1and GSTT1) arepolymorphic with a variable ethnic distribution. These enzymes detoxifyreactive epoxides, including carcinogens produced by tobacco smoke. Becauseof this, the null polymorphism in the GSTM1 gene (coding for the glutathioneS-transferase class mu enzyme) has been studied widely as a possible sourceof inherited susceptibility to smoking-related lung cancer. The more recentlydescribed null polymorphism in the GSTT1 gene also could contribute to anincreased risk of smoking-related lung cancer. As the incidence of lungcancer is known to differ by ethnicity, we have conducted a case-controlstudy in the United States of 108 African-Americans (Blacks) and 60Mexican-Americans (Hispanics) with lung cancer and 132 African-American(Black) and 146 Mexican-American (Hispanic) controls to investigate theassociation of the GSTT1 and GSTM1 polymorphi sms with lung cancer inminority populations. In the unadjusted data, there was a borderlinesignificant association of the GSTM1 null polymorphism with lung cancer inMexican-Americans (odds ratio [OR] = 1.8, 95 percent confidence interval [CI]= 1.0-3.3 ) that was not observed in African-Americans. The GSTT1 nullpolymorphism also had a higher prevalence in cases than controls in bothracial/ethnic groups, but this increase was not statistically significant.When the data were analyzed using logistic regression controlling for age,gender, race, and smoking, no significant association of either trait withlung cancer was observed, with ORs for both traits of approximately 1.3.However, when the prevalence of individuals who were null for bothpolymorphisms was compared by case status, a significant interaction wasobserved. Logistic regression models showed the OR for the association oflung cancer and the presence of both null polymorphisms compared with one(either GSTT1 or GSTM1) or no null genotype to be 2.9 (P < 0.04). Theseresults suggest that there may be carcinogenic intermediates in cigarettesmoke that are substrates for both the GSTT1 and GSTM1 enzymes, and that lungcancer risk is increased more than additively for individuals who have bothGSTT1 and GSTM1 null polymorphisms.     

Azoxymethane-induced colon tumors and aberrant crypt foci in mice of different genetic susceptibility

Azoxymethane (AOM) is an organotropic colon carcinogen that is commonly used to induce colon tumors in rodents. Unlike its parent compound, 1,2-dimethylhydrazine (DMH), a tumor susceptibility phenotype in inbred mice with respect to AOM has not been established. Thus, this study was undertaken to determine whether genetic susceptibility extends to this carcinogen. SWR/J, A/J (both susceptible to DMH carcinogenesis) and AKR/J (resistant) mice were treated with 10 mg/kg AOM i.p. once a week for 8 weeks. Twenty-five weeks after the initial injection, tumor yield was determined. With a single exception, only SWR/J and A/J mice developed tumors, with a distribution that was limited to the distal colon (16.3±1.1 and 36.4±2.4, respectively). The formation of aberrant crypt foci (ACF), putative preneoplastic lesions, was also assessed in whole-mount colons using Methylene Blue staining. Consistent with tumor multiplicity, the total number of ACF was highest in A/J mice, followed by SWR/J mice. In addition, A/J mice had a significantly greater number of large ACF (five or more crypts per foci) than the other strains. Despite the absence of colon tumors, however, AKR/J mice did develop a significant number of ACF. This finding suggests that ACF in resistant mice are persistent but do not progress to tumors.     

肿瘤患者合并肺部念珠菌感染药敏测定研究

采用ＲＰＭＩ１６４０及ＦＤＡ抗生素３号两种培养基的微量稀释法对肿瘤患者合并肺感染分离出５１株念珠菌进行药敏对比测定。结果显示二性霉素Ｂ在两种培养基中均具有非常好的抗菌活性，敏感率均为９８．０％，其次酮康唑也显示出良好的抗菌活性，敏感率均为９４．１％。相比之下，在ＲＰＭＩ培养基中伊曲康唑和氟康唑的敏感性稍差，敏感率分别为９２．２％和９０．２％，但在ＦＤＡ抗生素３号培养基中，伊曲康唑和氟康唑敏感性明显下降，敏感率分别为７０．６％和６６．７％。为此我们建议抗真菌药敏试验，尤其是咪唑类药物应该选用ＮＣＣＬＳ推荐的ＲＰＭＩ１６４０培养基做药敏试验     

应用DHPLC技术分析错配修复基因(hMLH1)T1151A多态与胃肠道肿瘤的遗传易感性

目的了解中国人hMLH1基因T1151A多态与胃肠道肿瘤的遗传易感性.方法采用病例对照研究设计,提取233例大肠癌(结,直肠癌)患者,273例胃癌患者和268例健康人外周血细胞的基因组DNA.PCR扩增hMLH1基因T1151A多态所在第12外显子的部分DNA片段(217 bp),变性高效液相色谱(DHPLC)检测,DNA测序验证,比较分析T1151A基因型在胃肠道肿瘤的分布.结果正常人群中T1151A多态T/A基因型频率为6.34%,其等位基因A频率为3.28%,在大肠癌患者和胃癌患者中T/A基因型频率与正常人群相比存在显著性差异,分别为11.6%(P=0.039)和12.1%(P=0.021),尤其在＜45岁的大肠癌患者和＜50岁的胃癌患者中,等位基因A频率与正常人群相比差异更为显著,分别为10.66%(P=0.002)和11.27%(P=0.001).结论T1151A作为中国人hMLH1基因上的一个多态位点,可能是中国人大肠癌和胃癌遗传易感因素,可作为中国人胃及大肠肿瘤、尤其是低龄胃及大肠肿瘤高危人群筛选的侯选指标.     

142例患儿应用抗菌药物的调查分析

目的：了解本院儿科抗菌药使用情况，以提高抗菌药物应用的合理性。方法：随机抽查，本院儿科住院患者病历142份，统计每种抗菌药的应用例数，应用天数。药品总消耗量，并按例数排序，统计联合用药情况。结果：本院儿科抗菌药使用率98．50％，其中联用两种药者54例，联用3种药者5例，共涉及6类15种抗菌药。结论：我院儿科住院患者抗菌药使用率较高，新型抗菌药应用广泛，合理用药有待改进。     

支原体耐药性与抗菌药消耗量相关性研究

目的：了解支原体耐药性与抗生素消耗量之间的相关性。方法：对112份解脲支原体阳性标本进行9种抗菌药敏感性试验，统计2002～2003年有关药物的消耗量，分析解脲支原体耐药率与相应药品消耗量之间的关系。结果：多因素逐步回归分析表明上年度相关药物成人剂型的消耗量是有显著性意义的相关因素（r=0．858，F=16.778，P〈0．01）。结论：支原体的耐药率主要与上一年度的相关药物消耗量相关。     

肺炎链球菌对抗菌药物的耐药性分析

目的 :调查肺炎链球菌对青霉素等抗菌药物的耐药性 ,并进行初步分析。方法 :采用肉汤微量稀释法测定肺炎链球菌对常用抗菌药物的耐药性。结果 :统计分析 5年中痰标本分离的 16 0株肺炎链球菌对常用的 8种抗菌药物的耐药性 ,结果显示对头孢噻肟耐药率最低 ,对红霉素耐药率最高。结论 :肺炎链球菌的耐药性有逐年增加的趋势 ,其中耐青霉素肺炎链球菌 (PRP)的耐药性同时也有逐年增加的趋势。     

海洋岩虫抗菌肽筛选及抗癌活性的初步研究

将岩虫匀浆液经反相浓缩、凝胶过滤和亲和柱层析获得活性组分，在体外用MTS／PMS(氮兰四唑盐／吩嗪硫酸甲酯)方法筛选抗菌肽，再分别用MTS／PMS方法和ELISA—AFP(甲胎蛋白)方法检测其对人肝癌细胞株HepG2增殖、AFP分泌及对正常大鼠成骨细胞株MC3T3-E1增殖的影响。结果表明，纯化的岩虫抗菌肽为组成型碱性蛋白(MW8．1kDa，pI8．6)，不同浓度抗菌肽对肝癌细胞增殖和AFP的分泌均有抑制作用，抑制作用大小与抗菌肽浓度呈正相关性；对正常成骨细胞未见明显的抑制和杀伤作用。