Prediction of regioselectivity and preferred order of metabolisms on CYP1A2-mediated reactions. Part 2: Solving substrate interactions of CYP1A2 with non-PAH substrates on the template system

In our previous paper (Drug Metabolism Parmacokinet 31: 363, 2016), a simulation system for ligand interactions of human CYP1A2 was developed using “Template” composed of hexagonal grids focusing on polyaromatic hydrocarbons (PAHs). The system has been expanded for the application of non-PAH chemicals including medical drugs, industrial chemicals and natural products in the present study. Additions of two Templates C and D around Ring C/E and Ring B, respectively, perpendicular each to Template A, offered the accommodation of non-PAH substrates. The size and shape of Templates C and D were defined from the reciprocal comparison of experimental data of ligands with simulation on Templates. The requirements of occupancies at Trigger region (Ring B) and at region of Facial-side Movement (Ring C) as well as Site of Oxidation were found to be mutual throughout CYP1A2 good substrates tested for over the 450 reactions, irrespective of their shapes and flexibilities. The CYP1A2 Template system was also verified with distinct types of poor substrates (47 chemicals) and inhibitors (37 inhibitors) and found to offer the information on probable structural causes. Present CYP1A2 Template system offers a unified evaluation of human CYP1A2 ligands, which aids for toxicological assessments as well as drug metabolism studies.     

性激素及其受体在食管癌高发区食管鳞癌发生发展过程中的作用

[目的]探讨性激素及其受体仵高发区食管鳞癌发生、分化、转移中的作用。[方法]采用放射免疫法（RIA）检测食管癌高发区林州原发性食管鳞癌患者44例和林州当地以及食管癌低发区同龄健康体检者各60人的血清性激素水平：采用免疫组化法（ABC）测定72例青年食管鳞癌患者（≤40岁）的手术切除标本ER表达状况。[结果]男性低发区健康人组、高发区健康人组和患者的血清雌激素水平分别为70．500±11．300pg／ml、54．684±18．159pg／ml、42．330±16．016pg／ml，女性低发区健康人组、高发区健康人组和患者的血清雌激素水平分别为87．010±13．910pg／ml、52．044±21．790pg/ml、32．998±19．339pg/ml，低发区健康人组的血清雌激素水平高于高发区健康人组和患者（男性的P值均为〈0．001，女性的P值分别为0．0183和〈0．001）：男性低发区健康人组、高发区健康人组和患者的血清雄激素水平分别为4．100±1．500ng／ml、5．485±2．485ng／ml、5．555±2．648ng/ml，女性低发区健康人组、高发区健康人组和患者的血清雄激素水平分别为0．618±0．076ng／ml、1．795±0．959ng／ml、1．985±0．990ng／ml，低发区健康人组的血清雄激素水平低于高发区健康人组和患者（男性的P值分别为0．0457和〈0．001，女性的P值均为〈0．001）。高发区青年食管鳞癌患者中，高、中、低分化者的ER阳性率分别为65％、54％、37％（P=0．0684），淋巴结有无转移者ER阳性碍夏分别为44％、58％（辟0．3450），侵及黏膜下层-肌层和纤维膜者的ER阳性率分别为42％、53％（P=0．5368），TNM分期处于I、Ⅱ期和Ⅲ期ER阳性率分别为66％和35％（P=0．0176）。[结论]食管癌高发区人群血清雌激素水平过低和雄激素水平过高及其比例改变可能是决定食管癌变和易感性的重要因素之一，结合性激素受体状态检测可能更有助于加深?     

食管癌淋巴结转移的蛋白质组学

目的:对河南省林州地区食管癌高发区食管鳞癌患者(食管癌组)和健康人血清(对照组)蛋白质组进行比较研究,确立食管癌的蛋白质指纹诊断模型,并筛选与食管癌淋巴结转移相关的蛋白质.方法:采用IMAC3芯片及表面增强激光解吸电离飞行时间质谱技术(SELDI-TOF-MS)检测61例食管癌患者和50例健康人血清,用Bio-Marker Wizard软件对芯片检测得到的蛋白质相对含量进行处理及方差分析.并对25例发生淋巴结转移的食管癌患者(转移组),36例无淋巴结转移患者(未转移组)与对照组进行了对比分析.结果:以相对分子质量(Mr)为9 439.58、6 627.21、2 867.65、4 494.08、7 762.68、6 835.32、4 095.94 7种蛋白质组建立的决策树模型,对食管癌测试的准确率、敏感度和特异度分别为85.6%、88.5%和82.0%.转移组、未转移组与对照组3组相比,有15种蛋白差异有统计学意义.其中转移组和未转移组相比有2种蛋白差异有统计学意义(Mr分别为11 742.48、9 294.44).结论:以上述7种蛋白质建立的诊断模型用于食管癌的诊断,具有较高灵敏度和特异度;筛选出2种与食管癌转移密切相关蛋白质,后者为进一步建立食管癌转移相关肿瘤标志物提供了重要线索.     

Amyloid precursor protein transgenic mouse models and Alzheimer's disease: Understanding the paradigms,limitations, and contributions

Transgenic (Tg) mice that overexpress mutant familial Alzheimer's disease (AD) amyloid precursor protein (APP) genes have contributed to an understanding of dementia pathology, and support the amyloid cascade hypothesis. Although many sophisticated mice APP models exist, none recapitulates AD cellular and behavioral pathology. The morphological resemblance to AD amyloidosis is impressive, but fundamental biophysical and biochemical properties of the APP/Aβ produced in Tg mice differ substantially from those of humans. The greater resilience of Tg mice in the presence of substantial Aβ burdens suggests that levels and forms deleterious to human neurons are not as noxious in these models. Transgenic mice were widely used for testing AD therapeutic agents, and demonstrated promising results. Unfortunately, clinical trials resulted in unforeseen adverse events or negative therapeutic outcomes. The disparity between success and failure is in part attributable to evolutionary divergence between humans and rodents. These observations suggest that the pathogenesis of AD is by far more intricate than can be explained by a straightforward accumulation of Aβ.     

Statistical challenges for genome-wide association studies of suicidality using family data

The etiology of suicide is complex in nature with both environmental and genetic causes that are extremely diverse. This extensive heterogeneity weakens the relationship between genotype and phenotype and as a result, we face many challenges when studying the genetic etiology of suicide. We are now in the midst of a genetics revolution, where genotyping costs are decreasing and genotyping speed is increasing at a fast rate, allowing genetic association studies to genotype thousands to millions of SNPs that cover the entire human genome. As such, genome-wide association studies (GWAS) are now the norm. In this article we address several statistical challenges that occur when studying the genetic etiology of suicidality in the age of the genetics revolution. These challenges include: (1) the large number of statistical tests; (2) complex phenotypes that are difficult to quantify; and (3) modest genetic effect sizes. We address these statistical issues in the context of family-based study designs. Specifically, we discuss several statistical extensions of family-based association tests (FBATs) that work to alleviate these challenges. As our intention is to describe how statistical methodology may work to identify disease variants for suicidality, we avoid the mathematical details of the methodologies presented.     

蜂毒素(Mel)对裸鼠骨肉瘤的抑制作用与影响肿瘤血管生成、细胞增殖和凋亡的关系

 目的 探讨蜂毒素(melittin,Mel)抑制骨肉瘤裸鼠移植瘤的作用机制。方法 用SD大鼠成骨肉瘤UMR-106细胞株建立骨肉瘤原位移植瘤裸鼠模型,将18只裸鼠随机等分为3组,生理盐水组、Mel组和顺铂组。观察各组裸鼠骨肉瘤的体积和体质量抑制率;应用免疫组织化学法检测各组裸鼠瘤体 CD31、CD105、PCNA 蛋白表达;应用TUNEL法检测肿瘤细胞凋亡;运用相关性分析法研究Mel抑制骨肉瘤血管生成与细胞增殖、凋亡的关系。结果 Mel组肿瘤体积和体质量抑制率分别为42.98%和39.03%,Mel能明显抑制CD31、CD105标记的血管生成密度,能明显抑制肿瘤细胞增殖,促进细胞凋亡,且Mel抑制肿瘤血管生成与细胞增殖呈正相关及与细胞凋亡呈负相关。结论 Mel具有抑制骨肉瘤裸鼠移植瘤生长的作用,其作用机制可能与其能够抑制肿瘤血管生成、诱导肿瘤细胞凋亡及抑制细胞增殖有关。