栀子苷、胆酸及其配伍干预脑缺血全基因表达谱的比较研究

目的比较脑缺血后清开灵主要组分栀子苷、胆酸及其配伍对基因表达谱的影响。方法建立全脑缺血再灌注小鼠模型,分为栀子苷组、胆酸组、栀子苷 胆酸组。一步法抽提小鼠脑组织的总RNA,Cy3/Cy5标记,16463个小鼠脑oligo片段芯片检测全基因组表达谱,每组重复实验669次。Genespring分析显著变化基因,GO原则分类,层次聚类分析全基因组表达谱信息。结果栀子苷组、胆酸组、栀子苷 胆酸组所致差异表达基因数分别为95、86、102,其中上调63、48、56个,下调32、38、45个基因,共同调节基因19个。3组差异基因集中在代谢和信号转导相关基因方面。重叠基因数栀子苷 胆酸组与胆酸组(30个)多于栀子苷 胆酸组与栀子苷组(25个),前两者及早反应基因如Pip92表达相似,后两者则在炎症相关因子,如NFκB、Irf5、IL-1β、TNF-α、IL-6、IFN-γ等表达雷同;聚类分析发现栀子苷组表达谱较胆酸组更接近栀子苷 胆酸组;实时定量PCR结果与芯片结果一致。结论①虽然栀子苷组、胆酸组与栀子苷 胆酸组存在共同的调节基因,但栀子苷组偏重于对炎症相关因子,特别是对NFκB、Irf5等炎症介导因子的调控;而胆酸组对Pip92等凋亡前功能基因的调节较为突出;②重叠基因数与聚类分析结果的不一致提示基因分析不能仅局限在差异数量上,而应该深入分析基因功能和组分的关系。     

基因网络的构建方法及应用

基因网络是一种描述基因表达水平现象的模型,从实验数据来构建模型的研究越来越普遍.近几年来相继提出了几种基于基因表达数据构建基因调节网络的方法,其中包括聚类技术、布尔型网络、线性非线性模型、贝叶斯网络模型和微分模型方程等.本文综述了重建基因网络的模型和方法,比较了不同模型的优缺点,并对该领域存在的问题进行了分析.     

Incorporating covariates in mapping heterogeneous traits: a hierarchical model using empirical Bayes estimation

Complex genetic traits are inherently heterogeneous, i.e., they may be caused by different genes, or non-genetic factors, in different individuals. So, for mapping genes responsible for these diseases using linkage analysis, heterogeneity must be accounted for in the model. Heterogeneity across different families can be modeled using a mixture distribution by letting each family have its own heterogeneity parameter denoting the probability that its disease-causing gene is linked to the marker map under consideration. A substantial gain in power is expected if covariates that can discriminate between the families of linked and unlinked types are incorporated in this modeling framework. To this end, we propose a hierarchical Bayesian model, in which the families are grouped according to various (categorized) levels of covariate(s). The heterogeneity parameters of families within each group are assigned a common prior, whose parameters are further assigned hyper-priors. The hyper-parameters are obtained by utilizing the empirical Bayes estimates. We also address related issues such as evaluating whether the covariate(s) under consideration are informative and grouping of families. We compare the proposed approach with one that does not utilize covariates and show that our approach leads to considerable gains in power to detect linkage and in precision of interval estimates through various simulation scenarios. An application to the asthma datasets of Genetic Analysis Workshop 12 also illustrates this gain in a real data analysis. Additionally, we compare the performances of microsatellite markers and single nucleotide polymorphisms for our approach and find that the latter clearly outperforms the former.     

Genomic clustering analysis identifies molecular subtypes of thymic epithelial tumors independent of World Health Organization histologic type

Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line’s gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.     

Geographic and Socioeconomic Disparity of Gastric Cancer Patients in Canada

Gastric cancer is the 5th most common malignancy worldwide, representing ~5–10% of all new cancer cases. Although its incidence is declining, it is estimated that 1 in 98 Canadians will develop gastric cancer in their lifetime. The epidemiology and distribution of gastric cancer throughout Canada, however, remains poorly understood. A retrospective analysis of demographic data across Canada between 1992 and 2010 was performed using 2 population-based cancer registries. The incidence of gastric cancer was examined at the levels of provinces, cities, and postal codes. In addition, 43,955 patients were diagnosed with gastric cancer in Canada between 1992 and 2010; 66% were male and the average age of diagnosis was 68.4 years. The age-adjusted incidence rate was 5.07 cases per 100,000 individuals per year. The incidence decreased over the study period by 30%. High incidence rates were identified in rural areas of Newfoundland and Labrador, New Brunswick, and Quebec. Our study found a significant association between gastric cancer incidence rates and lower socioeconomic status, as well as Hispanic ethnicity. This is the first study to provide a comprehensive analysis of the incidence of gastric carcinoma in Canada, identifying high-risk populations that may benefit from increased primary and secondary prevention.     

Glycoprotein Ib–IX-mediated activation of integrin αIIbβ3: effects of receptor clustering and von Willebrand factor adhesion

Summary. The interaction between the platelet glycoprotein (GP) Ib–IX complex and von Willebrand factor (VWF) initiates both hemostasis and pathological thrombosis. This interaction is not only the first adhesive event of platelets at sites of vessel injury, but also facilitates fibrinogen binding to α_IIbβ₃, which subsequently results in platelet aggregation. Since it has been suggested that GP Ib–IX clustering may promote platelet activation, we investigated the effect of such clustering on both VWF–GP Ib–IX and fibrinogen–α_IIbβ₃ bonds using optical tweezers. In our system, fusion of tandem repeats of FK506‐binding protein (FKBP) to the cytoplasmic tail of the GP IX subunit of the GP Ib–IX complex allowed subsequent receptor clustering within the plasma membrane by the bivalent, cell‐permeant small molecule ligand AP20187. We measured binding forces between polystyrene beads coated with either plasma‐derived VWF or the VWF A1 domain and GP Ib–IX(FKBP)₂, and those between fibrinogen‐coated beads and α_IIbβ₃ expressed on Chinese hamster ovary cells. The minimal detachment force between GP Ib–IX(FKBP)₂ and A1 or plasma‐derived VWF doubled after AP20187 was added. The binding force between immobilized fibrinogen and α_IIbβ₃ was not changed by the clustering agent; however, the strength of single fibrinogen–α_IIbβ₃ bonds increased significantly after ligation of GP Ib–IX(FKBP)₂ by A1. These results demonstrate that GP Ib–IX clustering increases the overall strength of its interaction with VWF. Furthermore, signals from GP Ib–IX can activate α_IIbβ₃, thereby increasing the strength of its interaction with fibrinogen.     

A two-step approach for mining patient treatment pathways in administrative healthcare databases

Clustering electronic medical records allows the discovery of information on healthcare practices. Entries in such medical records are usually composed of a succession of diagnostics or therapeutic steps. The corresponding processes are complex and heterogeneous since they depend on medical knowledge integrating clinical guidelines, the physician's individual experience, and patient data and conditions. To analyze such data, we are first proposing to cluster medical visits, consultations, and hospital stays into homogeneous groups, and then to construct higher-level patient treatment pathways over these different groups. These pathways are then also clustered to distill typical pathways, enabling interpretation of clusters by experts. This approach is evaluated on a real-world administrative database of elderly people in Québec suffering from heart failures.     

湖北省随州市一起成人百日咳传播导致家庭聚集性发病的调查报告

近年来许多国家出现了百日咳重现,且主要发病人群出现新的特征。2016年湖北省随州市主动监测到一起百日咳家庭聚集性发病,一个家庭5人中有4人被感染,出现续发病例,为随州市首次发现成人百日咳病例,为研究其流行病学特征,特开展调查。     

时间-空间相关成像技术对胎儿室间隔缺损应用的研究

目的:探索时间-空间相关成像(STIC)技术对胎儿室间隔缺损(VSD)三维成像的方法及临床应用价值。方法:获取25例存在VSD的胎儿心脏容积数据,分别应用表面成像、多平面成像、玻璃体成像及反转成像方法进行分析。观察缺损部位、形态特征,统计各种成像模式对VSD的显示率。结果:表面成像:对VSD的显示率为88%,22例膜周部缺损均表现为室间隔上段出现大小不一的孔洞,边缘较清晰,形态多为不对称圆形或椭圆形,少数呈狭长的裂隙状;可见VSD形态在心动周期不同时相内有所改变。3例肌部VSD在该模式下均未显示。多平面成像:可以在B平面及C平面同时显示缺损的矢状面和横断面,显示率分别为88%及80%。3例肌部VSD未显示。玻璃体成像:VSD显示率为96%,22例显示膜周部VSD见断端及穿隔血流信号。2例肌部VSD见一细小的分流束穿隔,1例肌部缺损未能显示分流。反转成像:VSD显示率为96%。3例为室间隔肌部缺损,其中2例可显示;22例膜周部VSD均显示。结论:表面成像可再现VSD的立体形态,并能动态观察缺损面积在心动周期中的变化。多平面成像可获得二维超声所难于显示的VSD矢状面及横断面,从多角度观察VSD的形态大小。玻璃体成像及反转成像能直观地显示VSD与分流束的空间分布,对于肌部小缺损的显示优于其他三维成像方法。但目前各种成像模式所成VSD的三维图像仍显粗糙,距离临床诊断需求尚有较大差距。