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青年科学家周虎:研究蛋白质组学 助力精准医疗

新闻青年科学家周虎:研究蛋白质组学 助力精准医疗

中国科学院上海药物研究所研究员、质谱技术服务部负责人周虎,原是个计算机爱好者,却在“机缘巧合”下做了生物学研究。他从事基于质谱的蛋白质组学研究,这一领域未来有望助力精准医疗。 何为蛋白质组学?周虎解释,通俗来讲,过去人们在研究蛋白质时,像“钓鱼”似的,一个蛋白一个蛋白地挨个研究;而现在用蛋白质组学技术研究蛋白质,就像“撒网捕鱼”,捞起来就是一网“鱼”,是对生物体内、细胞内所有蛋白质的研究,内容包括:蛋白质的具体位置、量的变化、蛋白修饰、相互作用等等。 周虎希望研究能朝着应用方向迈进,一是利用蛋白质作为工具,搭建从发现靶标到研究药物机制的快速通道,与经典的药物研究手段实现互补。 二则,将研究与临床结合,利用蛋白质组学对病人进行个性化用药的指导,助力精准医疗。他解释,现在都是先病后治,将来,如果能利用蛋白质组学提供的蛋白质层面信息,建立大数据库,就可以未病先防,“比如,不到医院就知道这个人有糖尿病前兆,去控制饮食、加强运动;而不是等到生病,才提供治疗手段。” 周虎出生于湖南,1997年开始走上科学的道路。“那时候本想报考计算机系,却误打误撞进了南开大学生物系。”没想到这一“偶遇”让他从此爱上了生物学基础研究,并在这条道路上越走越远。 2001年大学毕业后,他来到中国科学院生物化学与细胞生物学研究所攻读博士。毕业后,他赴加拿大渥太华大学系统生物学研究所开展博士后研究工作,在蛋白质组学研究领域进一步深造。2012年,他回国,到了中国科学院上海药物研究所。之所以回来,周虎说,“不忘初心吧,出国前我就感觉中国国内蛋白质组学很快会迎来它的第二个高潮,而我想在当中做个‘弄潮儿’。” 那时,中国国内早已开始蛋白组学研究,比如中国科学院生物化学与细胞生物学研究所在上世纪90年代中期就开始研究这一领域了;上海药物研究所是“后起之秀”,从零起步、刚刚开始,但有其独特资源,希望为国家蛋白质组学研究队伍添砖加瓦。 周虎介绍,蛋白质组学好比一种工具,上海药物研究所有肥沃的有机小分子土壤,更容易让研究“生根发芽”,以寻找药物的靶标或作用机制。 周虎在实验室 郑莹莹 摄 周虎具体开展的是有机小分子和生物大分子的相互作用以及转化医学相关的蛋白质组学研究。“单纯做蛋白质组学,像是在煮纯的咖啡;而做小分子、大分子相互作用的蛋白质组学,相当于学科交叉,有点像往咖啡里加伴侣,风味独具。”他说。 尽管在时间上是“第二梯队”,但从无到有,从有到强,中国科学院上海药物研究所的蛋白质组学研究越来越有显示度。周虎的课题组6年来在国际学术刊物上发表SCI(美国《科学引文索引》)收录论文40余篇。 在周虎看来,一个研究方法的开发,如果单纯是为了发文章,没有太大意义,还是希望这些东西能够真正应用起来。“有句俗话,是骡子是马,拉出来遛遛。你做的技术也好,方法也罢,都要拿到实践中去检验”,周虎说。他认为,关键要看课题组的研究能不能用到临床相关的药物研制中去,真正让公众受益。 这些年,中国在科技领域出现了一批“国际领跑者”,周虎坦言,他的研究团队还处于从跟跑向并跑发展的阶段。关于“跟跑”,他有着自己的理解,“别人已经做过的事情,我们从无到有,肯定要先‘跟跑’,不会走就先跑,那是无稽之谈。首先得跟跑学习,然后才能实现并跑,乃至领跑。” 国际上,蛋白质组学相关研究体系正在建立,周虎希望自己的课题组未来也能参与其中,“首先得成为研究上的player(参与者),而后才能参与规则制定。”(完)详情>>

2018-12-11 00:00:00
一文看懂基因检测和精准医学领域八大最新进展(第6期)

新闻一文看懂基因检测和精准医学领域八大最新进展(第6期)

1. Illumina拟12亿美元收购Pacific Biosciences,进军长读测序市场 11月1日,基因测序领域两大公司Illumina和Pacific Biosciences宣布达成协议,Illumina公司将以12亿美元的价格收购Pacific Biosciences。这一强强联手将有机结合Illumina公司的短读(short read)测序技术和Pacific Biosciences公司的长读(long-read)测序技术,让基因组测序结果更为精准。Pacific Biosciences公司的长读测序技术将帮助完成特定基因测序项目,包括de novo测序和对高度同源的基因组区域的测序。长读测序市场据估计到2022年将增长至25亿美元。Pacific Biosciences公司最新的Sequel SMRT技术与Illumina公司基础设施的结合,将提高生物发现速度和临床洞见的产生。 2. 23andMe又一款直面消费者测试获批,评估药物代谢影响 10月31日,美国FDA批准23andMe公司开发的个人基因组服务药物遗传学报告(Personal Genome Service Pharmacogenetic Reports)检测产品上市,可作为直接面向消费者(direct-to-consumer)的测试,提供与患者代谢特定药物相关的基因变异信息。FDA批准这一测试用于检测多个基因中的33种变异。药物遗传学是了解基因在患者对药物反应中起到什么作用的学科。23andMe公司开发的个人基因组服务测试通过分析由消费者自行采集的唾液样本中的DNA,报告患者是否携带某些基因变异或者特定基因,影响对特定药物的代谢能力。FDA对这一检测的审评表明,23andMe提供的数据证明了该测试的准确性和可重复性,而且消费者能够理解测试的说明和报告结果。 3. FDA批准NIH资助的遗传数据库,推动可靠和有益的基因检测的开发 12月4日,FDA正式承认了一个公共数据库,其中包含相关基因,遗传变异及其与疾病关系的数据。该数据库是临床基因组资源(ClinGen)联盟的ClinGen专家策划的人类基因数据(ClinGen Expert Curated Human Genetic Data),由美国国立卫生研究院(NIH)资助。FDA认为,这个数据库将“促进检测开发人员,包括使用二代测序技术的检测开发人员,依据数据库的信息来验证他们的检测的有效性,而不是用自己生成信息。” 承认ClinGen联盟的数据库作为支持临床有效性的科学证据的来源,意味着基因检测的开发人员所使用的免费数据有可靠保障。同时,开发人员也不需要向FDA证明数据库的可靠性,该数据库中可用于支持基因突变与特定疾病之间关系的数据和信息,都属于承认范围。 4. GRAIL宣布计划启动SUMMIT研究,支持早期癌症血液检测开发 12月4日,专注于癌症早期检测的GRAIL公司,宣布计划于2019年初启动SUMMIT研究。这是一项前瞻性、观察性、纵向的队列研究,旨在招募约50,000名年龄在50至77岁,且在入组时未被诊断出患有癌症的男性和女性。该研究将评估使用二代测序(NGS)技术检测多种癌症类型(包括肺癌)的研究性血液检测能力。大约一半的受试者将是由于吸烟史严重而患肺癌和其他癌症的高风险人群,另一半将是根据吸烟史判断不具有癌症高风险的人。SUMMIT研究将支持GRAIL公司的血液检测产品的开发,以便在多样化人群中早期发现多种类型的癌症。SUMMIT将在英国进行,并与英国伦敦大学学院(UCL)和UCL医院国家健康服务信托基金会(UCLH)合作。肺癌联盟(LCA)是一家位于华盛顿特区的非营利组织,也是SUMMIT的研究合作伙伴。它将为研究设计提供指导。 5. 药明明码收购GMI,将承担爱尔兰国家级全基因组测序项目 10月27日,药明明码(WuXi NextCODE)宣布完成对爱尔兰基因组医学公司Genomics Medicine Ireland(GMI)的收购,后者将成为药明明码爱尔兰子公司。该投资是药明明码总投资4亿美元的爱尔兰国家级别精准医疗计划的核心组成部分。同时,药明明码正式公布一项重要计划:公司将在爱尔兰打造世界一流的优质数据库,推动基因驱动的新药发现,开发领先的精准医疗模型,以惠及爱尔兰全国民众。GMI计划招募约10%的爱尔兰居民,并将重点招募迫切需要更好治疗方案的病患,进行个人全基因组测序,并获取有关详细的医疗和健康数据。这些深度优质数据与爱尔兰人口同质化较高的基因特征相结合,将切实为医药和生物技术公司提供对新药开发真正具有独特价值的机会。 6. 液体活检获重大突破!“验血”就可以找到癌症病变,还能区分癌症类型! 近日,顶尖学术期刊《自然》在线发表一项研究成果,一支联合团队开发的一种新方法,能通过简单的“验血”,找到只属于癌症的DNA特征。由于这种技术的灵敏度极高,我们甚至可以只用几纳克DNA,就分辨出癌症的类型。科学家们通过检测循环肿瘤DNA(ctDNA),再加上表观遗传学指标来实现这一点。不同的组织,不同的癌症,都会在DNA上留下不同的甲基化修饰。科学家们通过分析甲基化的变化,能对循环肿瘤DNA进行有效检测。而为了解决cfDNA总体水平不高的难题,他们又对流程进行了优化,使用免疫沉淀技术,辅以高通量测序进行分析。科学家们指出,这种技术能有效使富含CpG(常见甲基化修饰位点)的区域得到富集,从而提高检测效率。 这种技术已经在胰腺癌上得以验证。研究获得了24名早期胰腺癌患者的血浆cfDNA,并使用另外24名健康人的样本作为对照。在两组样本之间,研究一共找到了14716个不同的甲基化修饰区域,得到不同修饰的CpG的数目高达45173。研究人员指出,这些数据足以表明,我们能够通过这种技术找到来自肿瘤的DNA。在胰腺癌诊断上取得成功之后,科学家们又开始评估这种技术在肺癌、白血病、乳腺癌、膀胱癌等癌症中的应用价值。利用机器学习技术,他们开发的一款算法能够以很高的准确度去区分这些癌症。 科学家们指出,这款技术还需要更多独立数据的验证。但对cfDNA甲基化进行分析,有望带来一种非侵入性、低成本、灵敏度高的早期癌症检测手段,造福患者。 7. Illumina推出新的基因分型阵列,参与美国NIH精准医学计划的基因检测 Illumina宣布推出一种新型高密度基因分型阵列——Infinium™全球多样性阵列。这个新阵列将支持由美国国立卫生研究院(NIH)资助和领导的全美研究计划(All of Us Research Program)。该计划旨在收集美国一百万以上居民的基因数据,包括历史上研究不足的群体,以加速人类疾病研究和改善健康状况。 Illumina提供新的Infinium™全球多样性阵列,将为该计划在全美的三个基因组中心免费处理100万个样本。新阵列是一种高密度芯片,可以进行基因分型。该计划的目标是覆盖更多人群,并将结果反馈给参与者,例如携带ACMG-59基因和关键药物基因组学突变的人。某些基因突变可能与威胁生命健康的疾病有关,比如家族性高胆固醇血症、乳腺癌和卵巢癌。 8. Natera在SABCS上公布液体活检最新数据,提早2年预测乳腺癌复发 12月6日,一家非侵入性基因检测和游离细胞DNA分析领域的领导者Natera,公布了两项研究的数据。在2018年圣安东尼奥乳腺癌研讨会(SABCS)上,该公司展示了Signatera(RUO,仅限研究用途)循环肿瘤DNA(ctDNA)检测产品在临床复发前两年检测分子残留病(MRD)以及预测乳腺癌治疗反应的能力。两项乳腺癌研究均包括不同患者亚型:HER2阳性,激素受体阳性和三阴性。 I-SPY 2研究:在接受新辅助治疗的82名高危早期乳腺癌患者队列中,新辅助治疗期间可测量的ctDNA从阳性到阴性的变化预示了治疗反应,而新辅助治疗后如未能清除ctDNA,则与不良临床结果相关(p<0.001)。成像检测表明,ctDNA水平也与肿瘤负荷相关(p<0.01)。 Leicester/Imperial研究:在49名接受辅助治疗的乳腺癌患者队列中,Signatera(RUO)在临床或放射性检测前检测到分子残留病,提前期最高可达两年(中位数为8.9个月;范围为0.5-24.0个月)。总体而言,Signatera(RUO)检测到临床复发的敏感性为89%,特异性为100%。详情>>

2018-12-11 00:00:00
科学家发现与肠癌有关的40个基因突变

新闻科学家发现与肠癌有关的40个基因突变

最近发表在Nature Genetics上的最全面的全基因组关联研究(GWAS)结果发现了40种新的与结肠癌的风险增加有关的遗传变异。 由Fred Hutchinson癌症研究中心的一个研究小组领导的这项研究同时确定了第一种罕见的散发性结直肠癌保种。总之,这些发现对于创建个性化筛查策略和更好地为结直肠癌的药物开发提供了重要的信息。 这些研究结果也阐明了研究作者在药物开发中所谓的“错失机会”。作者认为,使用GWAS结果为癌症药物开发提供信息可以提高药物开发成功率,甚至可以为高风险人群提供化学预防药物。 “使用GWAS结果为抗癌药物的靶点发现提供了很大的潜力。对于2型糖尿病和心脏病等疾病,GWAS方法推动了新生物学和潜在药物靶点的发现,”该研究的作者,Jeroen Huyghe博士解释说:“迄今为止,对癌症治疗新目标的研究主要集中在癌症细胞的分子特征上。我们认为使用GWAS方法为结直肠癌的药物开发提供了一个巨大的机会。” Huyghe解释说:“大规模的全基因组测序研究已经发现了数百种尚未系统检查与疾病相关的遗传变异。我们的研究充分利用了Haplotype Reference Consortium面板的可用性,该面板是来自超过32,000个个体的序列数据的群体参考面板。通过将该策略与定制设计的基因分型芯片相结合,我们能够稳健地识别罕见的变异关联信号以及涉及低频变种的多个附加信号。“ 之前针对结直肠癌风险的GWAS仅考察了常见的遗传变异。相比之下,这项研究涉及超过2,000个人的全基因组测序,旨在检查罕见遗传变异对结直肠癌风险的贡献。 “通过这项研究,我们已经将已知数量的结直肠癌风险变种带到了近100个,”该研究的共同第一作者,Fred Hutch的遗传流行病学家Tabitha Harrison说。 “接下来,我们将研究人群扩大到包括来自不同种族背景的人。这将使我们更全面地了解整个人口的风险。” 资讯出处:Study discovers 40 new genetic variants associated with colorectal cancer risk 原始出处:Jeroen R. Huyghe et al, Discovery of common and rare genetic risk variants for colorectal cancer, Nature Genetics (2018). DOI: 10.1038/s41588-018-0286-6详情>>

2018-12-07 00:00:00
新的基因洞察力可帮助治疗罕见的衰弱性心肺病

新闻新的基因洞察力可帮助治疗罕见的衰弱性心肺病

The largest study of genetic variation in patients with pulmonary arterial hypertension has associated two important genes with the disease. In collaboration with institutes from Europe and Northern America, researchers from Imperial College London have conducted the largest genetic analysis to date of 2,000 patients with pulmonary arterial hypertension (PAH) and identified associations with two genes. PAH is a rare form of pulmonary hypertension that affects the blood vessels in the lungs, causing high blood pressure that can lead to heart failure. The disease is often fatal and, on average, patients survive 5-6 years after diagnosis. Sufferers feel breathless and tired, with symptoms worsening during exercise. The research is the first to demonstrate that variations in the SOX17 gene and the HLA-DPB1 gene were associated with PAH. Insight into the genetic mechanisms behind this life-threatening disease could help inform treatments and identify new therapeutic targets. Common genetic variation PAH can be related to other conditions such as congenital heart problems, connective tissue disease, and HIV but for many sufferers, PAH is either inherited (HPAH) or arises for no known reason, which is known as idiopathic PAH (IPAH). Around 1,500 people in the UK have either HPAH or IPAH and 10 per cent of sufferers die each year. PAH affects more women than men, typically in their 30s and 40s. Previous research has identified some of the rare genetic mutations behind inherited PAH, but little is known about the common genetic variation responsible for smaller differences between patients and the variation in their response to treatments. Current treatments include medicines to help prevent blood clots, diuretics and specialist treatments to relax the arteries in the lungs. Published in The Lancet Respiratory Medicine, the study aggregated data from four international cohorts from Europe and North America on patients with heritable or idiopathic PAH. UK data was from the National Institute for Health Research BioResource (NIHR BioResource) - Rare Diseases and the British Heart Foundation Pulmonary Arterial Hypertension (BHFPAH) study. The analysis took a genome-wide association (GWAS) approach, which examined millions of common variants covering the genome. The research identified three genetic signals associated with PAH: two of these were next to the SOX17 gene in the region that 'loops back' to regulate the levels of SOX17 and the third signal was within the HLA-DPB1 gene. Lead author and British Heart Foundation Intermediate Basic Science Fellow Dr. Christopher Rhodes from Imperial's Department of Medicine, said: "This is the first study at the scale required to look at how common genetic variations influence PAH, which could help us understand variations in how the disease presents itself and how patients respond to treatments. "We were very lucky to pool data with our collaborators as this has provided us with a large enough sample to study these more subtle genetic variations in a statistically meaningful way. Out of the 23,000 genes in the whole genome we have found that PAH has significant associations with two genes, SOX17 and HLA-DPB1, providing strong evidence that these genes play an important role in PAH. This opens up exciting possibilities for future research into new therapies." Susceptibility and disease progression SOX17 is instrumental in the development of the endothelial cells that line the arteries in the lung, indicating it could be associated with the structural changes that make patients susceptible to PAH. Previous research has shown that rare genetic variation in SOX17 can cause heritable PAH. The other gene identified by the study, HLA-DPB1, is involved in controlling the immune response and plays a role in disease progression. The analysis identified different variations or alleles of HLA-DPB1 within PAH patients and found that the number of years that patients survived after diagnosis depended on which versions were active. About 5 per cent of patients have two copies of the C allele of HLA-DPB1 and on average they survived 13.5 years, whereas the majority of patients (69 per cent) have two copies of the T allele and survived on average 7 years. One of the variations of HLA-DPB1 identified in the study has also been linked with susceptibility to lung diseases caused by exposure to hard metals such as berylliosis. Professor Martin Wilkins, a senior author and Head of the Department of Medicine at Imperial College London, said: "This study represents the enormous efforts of an international collaboration and the generous participation of many patients, making it the largest genetic study of PAH to date. The findings raise the importance of including the genotype as a factor when interpreting the results of clinical studies, as it may be that some patients deteriorate at a rate determined by their genotype, rather than at a rate determined by a new treatment. "The discovery of a common variant that operates through a gene, SOX17, that is mutated in a few patients with the disease suggests that SOX17 may be more commonly involved in pulmonary hypertension than previously thought. This has implications for the development of new treatments that might come from further work on SOX17." Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation said: "PAH is a rare but devastating condition which usually strikes people in the prime of their life. "This is scientific collaboration at its best. This international team has made real gains in our understanding of PAH by identifying two important genes which contribute to its development, laying the essential groundwork we need to develop new treatments in future."详情>>

2018-12-07 00:00:00
致命的制动失败:结肠中的肿瘤发生

新闻致命的制动失败:结肠中的肿瘤发生

Two genes normally work together to suppress the development of colon cancer. Their combined loss favors tumorigenesis and stimulates the formation of metastases. Colon cancers can be successfully treated by surgical resection if the illness is already diagnosed after the appearance of the primary tumor. However, when the disease progresses further, the metastatic tumors that arise are the most frequent cause of death in patients with this type of cancer. An understanding of the molecular mechanisms that drive the process of metastasis in such patients is therefore crucial to efforts to improve survival rates. Tumorigenesis in the colon essentially results from the loss of function of specific tumor suppressor genes. These genes code for factors that serve as brakes to tumor growth by controlling the rate of cell division and survival in the epithelium in this region of the gastrointestinal tract. In addition, p53 and miR-34a inhibit migration and invasion of tumor cells and thereby prevent the formation of metastases. A team led by Heiko Hermeking, Professor of Experimental and Molecular Pathology at LMU, has found that in the 50% of cases in which metastases develop, the genes that code for the protein p53 and the microRNA miR-34a are inactivated. In order to trace the consequences of this twofold inactivation, they inactivated these genes in a mouse model for colon cancer, and identified signal pathways which could potentially serve as effective drug targets for the treatment of the disease. Their findings appear in the journal Gastroenterology. The study reveals that "the combined loss of both genes is associated with an upsurge in the frequency and size of colon tumors, and a increase in their propensity to invade surrounding tissues and seed metastases," says Heiko Hermeking. These findings demonstrate that the two genes normally function as suppressors of colon tumorigenesis. Indeed, Hermeking and his colleagues show that they act together to inhibit the activation of signal pathways which promote the survival and stimulate the invasiveness of tumor cells. Thus the microRNA miR-34a inhibits the production of the protein IL-6R. IL-6R is a cell-surface receptor that is activated by binding of the cytokine interleukin 6 (IL-6), which is synthesized and released by cells nearby the tumor (the so-called tumor stroma). The interaction between the two proteins activates what is called an epithelial-to-mesenchymal transition (EMT). The EMT transforms epithelial cells, which normally adhere to each other to form planar cell sheets, into mobile mesenchymal cells that are the primary mediators of metastasis formation. Furthermore, simultaneous loss of p53 and miR-34a activates the production of the protein PAI1, which in turn stimulates growth of primary tumors and also their invasion. In their experimental mouse model, the LMU researchers were able to show that therapeutic inactivation of the IL-6R/STAT3 and the PAI1 signaling pathways inhibits tumor growth and formation of metastases in colon cancers that have lost p53 and miR-34a function. The results of the study indicate that the IL-6R/STAT3 and PAI1 signaling pathways offer promising targets for the development of new drugs for the treatment of advanced colon cancer in patients. They plan to investigate this possibility further in upcoming studies. The researchers also analyzed the genetic and expression profiles of 628 cases of colon cancerrepresented in online databases, and subjected tissue samples obtained from 61 patients to immunohistochemical investigation. The results of these analyses suggest that the findings made in their preclinical mouse model are in fact transferable to humans.详情>>

2018-12-05 00:00:00
让你想吃多少吃多少的基因有望防止肥胖

新闻让你想吃多少吃多少的基因有望防止肥胖

It sounds too good to be true, but a novel approach that might allow you to eat as much food as you want without gaining weight could be a reality in the near future. When a single gene known as RCAN1 was removed in mice and they were fed a high fat diet, they failed to gain weight, even after gorging on high fat foods for prolonged periods. The international team behind the study are hopeful a similar approach that inhibits this gene will also be effective with humans to combat obesity and serious diseases like diabetes. Led by Professor Damien Keating at Flinders University, the study used a huge genetic screen in rodents to identify novel genetic candidates that may cause obesity, potentially paving the way for new drug therapies. "We know a lot of people struggle to lose weight or even control their weight for a number of different reasons. The findings in this study could mean developing a pill which would target the function of RCAN1 and may result in weight loss," Professor Keating says. Obesity is a major global health epidemic, resulting in increased risk of serious diseases like type 2 diabetes, and heart disease, but avenues for effective therapeutic treatments are lacking. Professor Keating says blocking RCAN1 helps to transform unhealthy white fat into healthy brown fat, presenting a potential treatment method in the fight against obesity. "We have already developed a series of drugs that target the protein that this gene makes, and we are now in the process of testing them to see if they inhibit RCAN1 and whether they might represent potential new anti-obesity drugs," "In light of our results, the drugs we are developing to target RCAN1 would burn more calories while people are resting. It means the body would store less fat without the need for a person to reduce food consumption or exercise more." Two thirds of Australian adults and a quarter of children are either overweight or obese, and the statistics are just as concerning in Britain and the US. "We looked at a variety of different diets with various timespans from eight weeks up to six months, and in every case we saw health improvements in the absence of the RCAN1 gene." The researchers say these findings open up a potentially simple treatment but further studies are required to determine if they translate the same results to humans. "Our research is focused on understanding how cells send signals to each other and how this impacts health and the spread of disease". "We really want to pursue this, it's exciting and we have research funding from the Australian government through the National Health and Medical Research Council to continue to explore viable options. These results show we can potentially make a real difference in the fight again obesity."详情>>

medicalxpress
2018-12-05 00:00:00

论文基因诊断对未确诊疾病的影响

BACKGROUND Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.)展开>><<收起

N Engl J Med 2018; 379:2131-2139  0
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研究者发现与痴呆相关的基因

新闻研究者发现与痴呆相关的基因

A UCLA-led research team has identified genetic processes involved in the neurodegeneration that occurs in dementia—an important step on the path toward developing therapies that could slow or halt the course of the disease. The findings appear Dec. 3 in the journal Nature Medicine. The researchers discovered two major groups of genes involved in mutations that result in an overproduction of a protein called tau, a hallmark of the progressive loss of neurons seen in major forms of dementia. The study was largely done in mouse models of dementia, although the researchers performed additional experiments that indicated the same genetic process occurs in human brains. Armed with that knowledge, the team searched a large database of the genetic effects of experimental drugs to identify those that might alter this loss of neurons, or neurodegeneration. In human cell cultures, the researchers showed that the use of these molecules interfered with neurodegeneration. "Our study is the most comprehensive published effort to date to identify the source of neurodegeneration across species and provides an important roadmap for the development of potentially effective new drugs for Alzheimer's disease and other dementia," said senior author Dr. Daniel Geschwind, a professor of neurology and psychiatry who holds the Gordon and Virginia MacDonald Distinguished Chair in Human Genetics at the David Geffen School of Medicine at UCLA. More than 5 million people in the United States have Alzheimer's disease or related dementias; that number is projected to nearly triple by 2060, according to the U.S. Centers for Disease Control and Prevention. There is currently no treatment that can alter the course of neurodegeneration-associated dementia.  Although scientists have identified genes associated with dementia risk, there is little understanding of how those genes contribute to the cascade of events that lead brain cells to die. The research team sought to solve that puzzle through an approach known as "systems biology," which applies powerful genomic and analytic tools to studying the genome holistically, taking into account the complex interactions of the thousands of genes and the cells and proteins they produce. The researchers used systems biology to identify genetic processes in a mutation that results in the overproduction of tau in frontotemporal dementia, a form of early-onset dementia. A similar process also has been shown to play an important role in Alzheimer's disease and another form of dementia known as supranuclear palsy, which affects both movement and cognition. Geschwind's team hypothesized that a reason why research with mouse models of dementia often fails to produce results translatable to humans is that most mouse studies have relied on a single inbred strain. To increase the likelihood that their findings would have broader implications, the researchers studied the mutation caused by frontotemporal dementia in three genetically distinct strains of mice. The team looked at the genetic activity occurring in different parts of and points of time in a degenerating brain. In the study, two gene clusters were found to be associated with neurodegeneration across all three mouse models and in the susceptible regions of the brain. "There is still a significant amount of work that needs to be done to develop drugs that could be effectively used in humans against these targets, but this is an encouraging step," said Geschwind, who also serves as co-director of the Center for Neurobehavioral Genetics at the Semel Institute for Neuroscience and Human Behavior at UCLA, and senior associate dean and associate vice chancellor of precision medicine at UCLA Health. More information: Identification of evolutionarily conserved gene networks mediating neurodegenerative dementia, Nature Medicine (2018). DOI: 10.1038/s41591-018-0223-3 , https://www.nature.com/articles/s41591-018-0223-3详情>>

2018-12-04 00:00:00
与结直肠癌风险相关的40个新基因变体

新闻与结直肠癌风险相关的40个新基因变体

The most comprehensive genome-wide association study, or GWAS, of colorectal cancer risk to date, published today in Nature Genetics, has discovered 40 new genetic variants and validated 55 previously identified variants that signal an increased risk of colon cancer. The study, led by a team of investigators at Fred Hutchinson Cancer Research Center, also has identified the first rare protective variant for sporadic colorectal cancer. Sporadic colorectal cancers have no known familial syndrome and account for the vast majority of colorectal cancer cases. Together, these findings are a significant step toward creating personalized screening strategies and better informing drug development for colorectal cancer. "A study of this magnitude was only possible through collaboration with our partners from institutions around the world," said Dr. Ulrike "Riki" Peters, associate director of the Public Health Sciences Division at Fred Hutch and recipient of Fred Hutch's 40th Anniversary Endowed Chair. "Understanding the genetic architecture of colorectal cancer will revolutionize how we assess risk and treatment for this disease, which is the second most deadly cancer in U.S." In 2009, Peters initiated and has since led the Genetics and Epidemiology of Colorectal Cancer Consortium, the world's largest molecular genetic consortium for colorectal cancer. These findings also illuminate what the study authors call "a missed opportunity" in drug development. The study identified several loci, the physical location of the gene on a chromosome, near proposed drug targets and genes in pathways not previously known to be causally linked to colorectal cancer. Using GWAS results to inform cancer drug development, the authors believe, could improve the drug-development success rate and even lead to chemoprevention drugs for high-risk individuals. "There's great potential in using GWAS results to inform target discovery for anti-cancer drugs. For diseases like type 2 diabetes and heart disease, the GWAS approach drives the discovery of new biology and potential drug targets," explained Dr. Jeroen Huyghe, who co-led the study's statistical genetic analysis and is a staff scientist at Fred Hutch. "To date, the search for new targets for cancer therapy has been limited to focus primarily on the molecular characteristics of cancer cells. We think there is a huge opportunity in using the GWAS approach to inform drug development for colorectal cancer." Researchers from more than 130 different institutions contributed to this study, many by sharing data and biospecimens that allowed the team to analyze the genomes of more than 125,000 individuals, of which there were 58,131 colorectal cancer cases and 38,296 control participants who had not developed the disease. The number of participants in this study is nearly double that of previous analyses of this type. "Large-scale whole-genome sequencing studies have discovered millions of genetic variants that have yet to be examined systematically for association with disease," Huyghe explained. "Our research capitalized on the availability of the Haplotype Reference Consortium panel, a population reference panel of sequence data from more than 32,000 individuals. By coupling this strategy with a custom-designed genotyping chip, we were able to robustly identify a rare variant association signal and multiple additional signals involving lower-frequency variants." Previous GWAS for colorectal cancer risk only looked at common genetic variants. In contrast, this study involved whole-genome sequencing of more than 2,000 individuals and was designed to examine the contribution of rare genetic variants to colorectal cancer risk. "With this study, we've brought the known number of risk variants for colorectal cancer to nearly 100," said Tabitha Harrison, a shared first author of the study and a genetic epidemiologist at Fred Hutch. "Next, we're broadening the study population to include people from diverse ethnic backgrounds. This will give us a more complete understanding of risk across the entire population." The study authors acknowledge a bias in the study sample, of which 91 percent were people of European descent. "It is critically important that we increase diversity in our future studies because premature use of these findings to inform screening guidelines could exacerbate existing racial disparities in colorectal cancer screening and survival rates," cautioned Dr. Stephanie Bien, a shared first author of the study and staff scientist at Fred Hutch. Genetic variants occur from differences in our DNA. Most variants are believed to be benign, some are known to be associated with various diseases and the significance of many others are unknown. While individual genetic variants have little impact on disease risk, several combined variants can become clinically relevant, and this could have an impact on future personalized screening recommendations. "Individuals with genetic risks in the top decile could benefit from earlier screening by colonoscopy," said Dr. Li Hsu, a biostatistician at Fred Hutch and the lead biostatistician in the consortium. To evaluate a person's full risk profile, genetic risk factors need to be combined with other epidemiological factors, such as diet, weight and exercise. In some cases, a low genetic risk score could be skewed by unhealthy lifestyle factors to yield a high overall risk profile. This type of work is currently conducted by the team, which not only collected genetic data from all studies, but also harmonized many clinical and lifestyle risk factors across more than 70 studies. Furthermore, the research team believes there may be hundreds of other genetic variants contributing to colorectal cancer risk that have yet to be identified.详情>>

2018-12-04 00:00:00

论文检测儿童LDL-高胆固醇血症的新方法:德国的Fr1dolin试验

Background and aims Lipid disorders are often detected very late, particularly in affected young children. We evaluated the feasibility of a screening for LDL-hypercholesterolemia (highLDL) among toddlers and preschoolers. Methods Population-based screening has been offered to all children (2–6 years) living in the State of Lower Saxony, Germany, with capillary blood sampling for detection of elevated LDL-cholesterol (LDL-C ≥ 135 mg/dL). Positive results were confirmed by a second measurement. Follow-up in specialized centers, including disease specific counselling and extended diagnostics, as well as evaluation of psychological distress of the parents, is carried out longitudinally. Results Up to March 2018, 5656 children have participated in the screening program. 5069/5656 children have completed the screening for highLDL (52.0% boys; median age: 4.0 years [Interquartile range, IQR 3.0–5.1]; mother age: 35 years [IQR 31–38]; father's age: 37 years; [IQR 33–42]). HighLDL was identified in 112 children (2.2%; 40.2% boys; LDL-C 157.6 ± 29.5 mg/dL, mean ± SD). In the total cohort, parents stated in 40.9% of the cases a positive family history for hyperlipidemia and in 29.9% a premature cardiovascular event. Children with highLDL had more often both risk factors in their family history; however, in 37% of them none of these factors were reported. Conclusions The first results of the screening program showed its feasibility and revealed high prevalence of highLDL in the general population. Furthermore, a large proportion of families of affected children were not aware about their lipid disorders.展开>><<收起

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