Knowledge boosting: a graph-based integration approach with multi-omics data and genomic knowledge for cancer clinical outcome prediction

Objective Cancer can involve gene dysregulation via multiple mechanisms, so no single level of genomic data fully elucidates tumor behavior due to the presence of numerous genomic variations within or between levels in a biological system. We have previously proposed a graph-based integration approach that combines multi-omics data including copy number alteration, methylation, miRNA, and gene expression data for predicting clinical outcome in cancer. However, genomic features likely interact with other genomic features in complex signaling or regulatory networks, since cancer is caused by alterations in pathways or complete processes.Methods Here we propose a new graph-based framework for integrating multi-omics data and genomic knowledge to improve power in predicting clinical outcomes and elucidate interplay between different levels. To highlight the validity of our proposed framework, we used an ovarian cancer dataset from The Cancer Genome Atlas for predicting stage, grade, and survival outcomes.Results Integrating multi-omics data with genomic knowledge to construct pre-defined features resulted in higher performance in clinical outcome prediction and higher stability. For the grade outcome, the model with gene expression data produced an area under the receiver operating characteristic curve (AUC) of 0.7866. However, models of the integration with pathway, Gene Ontology, chromosomal gene set, and motif gene set consistently outperformed the model with genomic data only, attaining AUCs of 0.7873, 0.8433, 0.8254, and 0.8179, respectively.Conclusions Integrating multi-omics data and genomic knowledge to improve understanding of molecular pathogenesis and underlying biology in cancer should improve diagnostic and prognostic indicators and the effectiveness of therapies.     

一种从石蜡包埋组织中获取高质量基因组DNA的改良方法

目的:比较现有的DNA制备方法,建立一种从甲醛固定石蜡包埋组织(formalin-fixed paraffin-embedded tissues,FFPET)提取高质量基因组DNA的方法。方法:将传统基因组DNA提取方法与市场供应的DNA亲和层析柱结合在一起,以水浴脱腊法替代二甲苯脱腊法,设计一种改良的基因组DNA快速提取方法,从石蜡包埋宫颈癌组织标本提取基因组DNA,并用琼脂糖凝胶电泳法和聚合酶链式反应法进行鉴定。结果:改良的基因组DNA提取法整合了水浴脱蜡与DNA亲和层析柱的优点,从石蜡包埋宫颈癌组织中获得了高质量的基因组DNA,特别是能以很高的效率回收大于20 kb的基因组DNA大片段。结论:改良的基因组DNA提取方法简单快捷,是一种从石蜡包埋组织中回收高质量基因组DNA的有效途径。     

基于IBD谱和基因组结构的复杂疾病相关分子标记识别的新策略

Single nucleotidepolymorphism(SNP)isthemostwidespreadformofDNApolymorphisminhumangenome,thuspermittinglarge scaleandhigh densitygenome wideprofiling.SNPsaregenerallyconsideredtobeidealgeneticmarkersforgeneticinvestigations,astheyarecommon,stableandincreas…     

A DNA probe specific to pathogenic Entamoeba histolytica.

A DNA sequence, IE-gen1 (3.1 kb), was isolated from the pathogenic strain of E. histolytica NIH-200. IE-gen1 was identified by the subtractive hybridization of a genomic library to a cDNA probe prepared from NIH-200 trophozoites. The IE-gen1 probe specifically detected pathogenic E. histolytica in slot blots of genomic DNA and Northern blots, but not other Entamoeba species and additional human parasites. This genomic probe could detect with complete specificity DNA from about 10(3) organisms. The IE-gen1 probe could be related to highly specialized loci in pathogenic E. histolytica, and is likely to be a valuable DNA reagent for clinical diagnosis and epidemiological investigations.     

生物样本库信息管理系统的设计和实现

基于生物样本库的海量数据,使样本信息和资源共享利用困难。结合可视化信息管理数据库的采集,应用Web技术的数据检索、查询和管理,建立生物样本库信息管理系统的信息整合和共享平台。     

食源性致病菌基因组数据平台建设与展望

在信息科学飞速发展、测序技术不断完善的今天,食源性致病菌溯源研究有了全新的基于全基因组测序的技术方法和分析手段,从食源性致病菌基因组序列中可以获得更多的遗传信息来支持科研人员做研究,进而辅助管理人员做决策。在食品安全管控方面,系统性地整合基因组数据、元数据和配套模型,搭建食源性致病菌基因组数据平台是十分有必要的。以食源性致病菌基因组数据平台建设的需求与发展方向出发,细致梳理数据集成和关联模型中可能存在的问题与部署方向,能够为平台建设提供详细的实施蓝图。     

人源肿瘤异种移植模型（PDX）在精准肿瘤医学中的研究进展

癌症是由于物理、化学、病毒等致癌因子导致的原癌基因和抑癌基因突变从而引发的一系列异质性疾病的统称。尽管近年来高通量测序技术与靶向治疗取得了突破性的进展,但是临床转化研究的高失败率使得抗肿瘤药物的创新发展十分有限。人源肿瘤异种移植模型（patient-derived xenograft model,PDX模型）是指直接将病人的新鲜肿瘤组织移植到免疫缺陷小鼠上,依靠小鼠提供的环境生长的一种异种移植模型。这种模型保留了原代肿瘤的基质异质性、组织学特性、分子多样性以及微环境,为临床前药效的个性化筛选评估以及生物标志物的鉴定提供了有效的研发资源。PDX模型结合临床数据,基因组图谱以及药效数据可以增加药物特异性,应用于肿瘤患者个体化治疗,提高临床治疗成功率。本文就PDX模型研究进展进行综述,包括其在肿瘤新疗法中的应用、挑战性与局限性、以及在精准肿瘤医学中的应用前景。     

基因数据隐私问题及相关保护技术进展研究

分析基因组数据存在的隐私安全问题,详细阐述基因数据隐私保护相关技术、研究进展、技术不足之处等方面,为相关研究提供参考。     

An XML-based System for Synthesis of Data from Disparate Databases

Diverse data sets have become key building blocks of translational biomedical research. Data types captured and referenced by sophisticated research studies include high throughput genomic and proteomic data, laboratory data, data from imagery, and outcome data. In this paper, the authors present the application of an XML-based data management system to support integration of data from disparate data sources and large data sets. This system facilitates management of XML schemas and on-demand creation and management of XML databases that conform to these schemas. They illustrate the use of this system in an application for genotype–phenotype correlation analyses. This application implements a method of phenotype–genotype correlation based on phylogenetic optimization of large data sets of mouse SNPs and phenotypic data. The application workflow requires the management and integration of genomic information and phenotypic data from external data repositories and from the results of phenotype–genotype correlation analyses. Our implementation supports the process of carrying out a complex workflow that includes large-scale phylogenetic tree optimizations and application of Maddison's concentrated changes test to large phylogenetic tree data sets. The data management system also allows collaborators to share data in a uniform way and supports complex queries that target data sets.     

癌症基因组学相关数据管理与应用探析

目的：梳理美国癌症基因组图谱计划（The Cancer Genome Atlas,TCGA）相关数据的收集、整理、组织、共享及应用情况,为建立及完善国家级大型的开放癌症基因组学相关数据资源提供参考。方法：系统调研TCGA计划的数据管理相关机构工作流程、数据共享利用等方面的解决方案和最佳实践。 结果：TCGA计划通过多中心合作,建立了组织样本采集、处理、质量控制、序列测定、特征分析、数据共享与研究应用等全链条的癌症基因组图谱数据管理流程,从所属癌症、数据类型、处理水平等角度对数据进行精细分类,并针对汇总数据和个体数据分别采取开放存取和受控访问两种共享机制,研究者们利用其共享数据开展了相关癌症特征基因的突变、扩增和缺失、以及受影响的信号通路等多方面研究。 结论：癌症基因组图谱计划的实践探索可为大规模癌症基因组学相关研究计划的实施提供数据管理方面的经验借鉴与参考。     

Choosing blindly but wisely: differentially private solicitation of DNA datasets for disease marker discovery

Objective To propose a new approach to privacy preserving data selection, which helps the data users access human genomic datasets efficiently without undermining patients’ privacy.Methods Our idea is to let each data owner publish a set of differentially-private pilot data, on which a data user can test-run arbitrary association-test algorithms, including those not known to the data owner a priori. We developed a suite of new techniques, including a pilot-data generation approach that leverages the linkage disequilibrium in the human genome to preserve both the utility of the data and the privacy of the patients, and a utility evaluation method that helps the user assess the value of the real data from its pilot version with high confidence.Results We evaluated our approach on real human genomic data using four popular association tests. Our study shows that the proposed approach can help data users make the right choices in most cases.Conclusions Even though the pilot data cannot be directly used for scientific discovery, it provides a useful indication of which datasets are more likely to be useful to data users, who can therefore approach the appropriate data owners to gain access to the data.     

应用Southern 印迹杂交法检测转移基因在宿主细胞中的整合

目的　应用Southern印迹杂交法（Southernblot）证实转移基因整合至宿主细胞基因组DNA。方法　酚氯仿法提取基因转导的PA317/AIM及K562/AIM细胞基因组DNA,以聚合酶链反应（PCR）扩增转移基因片段;随机引物法标记     

剪切HCV RNA的HDV核酶的设计及活性测定

目的：探讨丁型肝炎病毒（Hepatitis D virus,HDV）核酶用于抗丙型肝炎病毒（Hepatitis C virus,HCV）基因治疗的可能性。方法：以HDV基因组核酶的假结样结构为基础,优化其茎IV区,改建基底物结合区,获得3种针对HCV RNA的HDV核酶RzC1、RzC2和RzC3。体外转录获取含HCV RNA5‘－非编码区（5‘-noncoding region,5‘-NCR）及部分C区在内的底物RNA（HCV RNA 5‘－NCR－C）,并进行5‘端放射性标记。在pH7.5、37℃、Mg^2 20mmol/L和去离子甲酰胺2.5mol/L等条件下,将核酶和底物按摩尔比100：1混合,在不同的时间点观察剪切百分率。结论：RzC1、RzC2对底物的剪切百分率随时间延长而递增,90min分别达24.9％、20.3％;未观察到RzC3有剪切活性。结论：经过结构构优化的HDV基因组核酶在合适的位点能够剪切异源性RNA分子HCV RNA。     

Genomic sovereignty and the African promise: mining the African genome for the benefit of Africa

Scientific interest in genomics in Africa is on the rise with a number of funding initiatives aimed specifically at supporting research in this area. Genomics research on material of African origin raises a number of important ethical issues. A prominent concern relates to sample export, which is increasingly seen by researchers and ethics committees across the continent as being problematic. The concept of genomic sovereignty proposes that unique patterns of genomic variation can be found in human populations, and that these are commercially, scientifically or symbolically valuable and in need of protection against exploitation. Although it is appealing as a response to increasing concerns regarding sample export, there are a number of important conceptual problems relating to the term. It is not clear, for instance, whether it is appropriate that ownership over human genomic samples should rest with national governments. Furthermore, ethnic groups in Africa are frequently spread across multiple nation states, and protection offered in one state may not prevent researchers from accessing the same group elsewhere. Lastly, scientific evidence suggests that the assumption that genomic data is unique for population groups is false. Although the frequency with which particular variants are found can differ between groups, such genes or variants per se are not unique to any population group. In this paper, the authors describe these concerns in detail and argue that the concept of genomic sovereignty alone may not be adequate to protect the genetic resources of people of African descent.     

红细胞CR1基因组密度多型性与免疫粘附肿瘤细胞能力的相关性

目的：研究不同人群用密度多性与红细胞免疫粘附肿瘤细胞能力的相关性,方法：采用ＰＣＲ加ＨｉｎｄⅢ酶切技术测定红细胞ＣＲ１基因组密度多型性（ＨＨ型、ＨＬ型、ＬＬ型）,采用肿瘤红细胞花环试验测定红细胞免疫粘附肿瘤细胞的能力。结果：在不同人群中,ＨＨ型红细胞免疫粘附肿瘤细胞的能力明显大于ＨＬ型红细胞,而ＨＬ型红细胞免疫粘附肿瘤细胞的能力明显大于ＬＬ型红细胞。结论：红细胞免疫附肿瘤细胞的能力与ＣＲ１基因且密     

梅毒螺旋体比较基因组学研究进展

梅毒螺旋体(Tp)是一种可以引起慢性和持续性梅毒感染的病原体。比较基因组学通过对不同个体基因组数据进行比较分析,揭示不同个体之间的相似性和差异性。本文通过比较Tp不同菌株以及Tp和其他致病性螺旋体之间的基因组数据,探讨Tp的致病机制。     

Research and applications: Identifying survival associated morphological features of triple negative breast cancer using multiple datasets

Background and objective

Biomarkers for subtyping triple negative breast cancer (TNBC) are needed given the absence of responsive therapy and relatively poor prediction of survival. Morphology of cancer tissues is widely used in clinical practice for stratifying cancer patients, while genomic data are highly effective to classify cancer patients into subgroups. Thus integration of both morphological and genomic data is a promising approach in discovering new biomarkers for cancer outcome prediction. Here we propose a workflow for analyzing histopathological images and integrate them with genomic data for discovering biomarkers for TNBC.

Materials and methods

We developed an image analysis workflow for extracting a large collection of morphological features and deployed the same on histological images from The Cancer Genome Atlas (TCGA) TNBC samples during the discovery phase (n=44). Strong correlations between salient morphological features and gene expression profiles from the same patients were identified. We then evaluated the same morphological features in predicting survival using a local TNBC cohort (n=143). We further tested the predictive power on patient prognosis of correlated gene clusters using two other public gene expression datasets.

Results and conclusion

Using TCGA data, we identified 48 pairs of significantly correlated morphological features and gene clusters; four morphological features were able to separate the local cohort with significantly different survival outcomes. Gene clusters correlated with these four morphological features further proved to be effective in predicting patient survival using multiple public gene expression datasets. These results suggest the efficacy of our workflow and demonstrate that integrative analysis holds promise for discovering biomarkers of complex diseases.     

全基因组测序用于宁夏羊种3型布鲁氏菌毒力基因筛选的研究

目的 从3株布鲁氏菌分离株的全基因组序列中筛选出可能导致脑损害的关键毒力基因,为后续筛选布鲁氏菌致脑损害毒力基因的研究奠定基础.方法 通过BCSP31PCR、传统生化实验对3株分离于布鲁氏菌病患者外周血中的布鲁氏菌进行鉴定分型.利用Illumina Hiseq2000平台对3株布鲁氏菌进行全基因组测序与比较基因组学分析,根据文献报道分析筛选出布鲁氏菌的经典毒力基因,通过检索NCBI核酸数据库查找出所选毒力基因的参考序列,利用所选参考序列分别与3株布鲁氏菌全基因组序列做BLAT比对分析.结果 3株布鲁氏菌经BCSP31PCR、传统生化实验鉴定为羊种3型;比较基因组分析显示3株布鲁氏菌与标准株参考序列的同源性比例均达到99.02％.BLAT比对分析发现所选毒力基因wbkA、pgm、hemolysin、hemolysin Ⅲ和Omp25在这3株布鲁氏菌全基因组序列中的比对分数均达到99％以上.结论 本研究所选取的3株羊种3型布鲁氏菌的全基因组中存在经典的毒力基因序列.     

人鼻咽癌DNA的转化活性

本文以鼻咽癌活检组织及CNE_1细胞株DNA为实验材料,用磷酸钙沉淀法转染了NIH/3T3 小鼠纤维母细胞、Rat-1 大鼠纤维母细胞和JB_6Cl_(41)小鼠上皮细胞,并以软琼脂培养法检测了转染后的MIH/3T3 细胞集落生成情况。实验表明:鼻咽癌及其CNE_1细胞DNA均可以诱发NIH/3T3细胞、Rat-1细胞转化,也可使NIH/3T3细胞获得在软琼脂上生长的能力,但不能使JB_6Cl_(41)细胞转化。本文还讨论了鼻咽癌及其CNE_1细胞DNA诱发的受体细胞转化与EB病毒感染间的关系,并对鼻咽癌转化基因的性质作了初步估计。