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不限 癌症 糖尿病 心血管疾病 精神/神经疾病 自身免疫性疾病 炎症及感染性疾病 代谢性疾病 呼吸系统疾病 其他
乳腺癌患者福音:新药奥拉帕尼获批上市,针对乳腺癌基因突变!

新闻乳腺癌患者福音:新药奥拉帕尼获批上市,针对乳腺癌基因突变!

美国食品和药物管理局批准了乳腺癌新药,旨在治疗与BRCA基因突变有关的乳腺癌。 这些突变基因,BRCA1和BRCA2,在2013年间首次崭露头角,当时女演员兼导演安吉莉娜·朱莉宣布她进行了预防性双乳房切除术。因为朱莉携带了BRCA1基因,这大大提高了女性患乳腺癌和卵巢癌的几率。 现在,FDA正在扩大批准lynparza(奥拉帕尼),针对与BRCA相关的乳腺癌。Lynparza是一组强大的新癌症药物,被称为PARP抑制剂,它是这类药物中第一个被批准用于预防乳腺癌的药物。PARP抑制剂已经被用来治疗晚期,BRCA突变的卵巢癌,现在治疗BRCA突变的特定类型的乳腺癌的疗效。 “这项研究证实了当前开发药物的范例,这种药物针对的是癌症的潜在遗传病因,通常是癌症类型”。根据FDA,BRCA基因突变是乳腺癌的遗传因素。该机构称,这些异常基因也与非遗传性乳腺肿瘤有关。 当功能正常时,BRCA实际上有助于修复受损细胞的DNA,防止肿瘤,但是当BRCA1和BRCA2出错时就会促进乳腺癌的形成。PARP抑制剂的药物如Lynparza可以干扰突变的BRCA乳腺细胞的功能,导致他们死亡,或者停止复制,从而减慢肿瘤生长。详情>>

2018-01-17 00:00:00

论文Crohn氏病和帕金森病的致病风险都和LRRK2基因功能相关

Crohn’s disease (CD), an inflammatory bowel disease, has a relatively high prevalence in Ashkenazi Jewish populations. Hui et al. conducted genome-wide association analysis in 2066 CD patients and 3633 healthy control individuals of Ashkenazi Jewish ancestry and identified two functional variants in the LRRK2 gene. The LRRK2 gene has been previously linked to the development of Parkinson’s disease (PD). The new LRRK2 variants conferred risk for CD (N2081D) or protection from CD (N551K/R1398H). Analysis of other variants within the LRRK2 locus in 24,570 individuals revealed similar genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The presence of shared LRRK2 alleles in CD and PD provides insight into disease mechanisms and potential treatments.展开>><<收起

Science Translational Medicine, 2018,10:eaai7795  0
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mRNA疗法——疫苗通向未来的大门

新闻mRNA疗法——疫苗通向未来的大门

本月4号,总部位于德国美因茨的生物技术公司BioNTech完成了2.7亿美元的“A轮”融资,旨在满足其庞大生产业务的快速增长。作为E11评为最有潜力的公司之一,BioNTech公司最主要的关注领域就是个体化的mRNA疗法。 过去的半年,先后有多项关于mRNA技术的交易完成。10月,礼来与CureVac公司签署了一项价值18亿美元的巨额交易,将共同开发了5种新型mRNA癌症疫苗;11月,CRISPR Therapeutics宣布投资CureVac开发Cas9 mRNA用于体内基因编辑。另一家mRNA研究公司Moderna也得到了大量投资者支持,开启了针对个性化癌症疫苗mRNA-4157的临床研究。 投资者高涨的热情表明mRNA疗法这个并不算新的技术(上世纪90年代已完成概念验证),随着技术的发展提高了其安全有效性,正进入新一轮的爆发期。目前mRNA药物研发基本呈现三足鼎立的态势(图1)。BioNTech、CureVac AG和Moderna三家公司占据了绝大部分在研管线。场上还有一些其他的公司和研究机构,也在努力发展自己的产品。 图1.主要mRNA疫苗研发公司及机构一览 mRNA疫苗是什么? 1990年,科学家将体外转录的信使RNA—mRNA注射入小鼠体内,通过检测发现其可在小鼠体内表达活性,产生相关蛋白且具有剂量依赖性。这种直接注射mRNA的方法能够通过表达特定蛋白,产生免疫反应,这就是mRNA疗法的雏形。 在随后的研究中,虽然动物实验表明了mRNA可以发挥类似疫苗的作用,达到治疗目的。但是受当时技术限制,在mRNA稳定性,药物递送,还有安全性等方面存在瓶颈,这种疗法逐渐趋冷,更多研究者转向DNA和替代蛋白领域。 时间进入21世纪,mRNA合成、修饰技术和递送技术的发展让mRNA疗法重返生物制药公司的视线。相比传统疫苗,mRNA的安全性更有优势,不会插入基因突变,可以被正常细胞降解,通过调节序列修饰和递送载体可以改变其半衰期等(图2)。更重要的是,传统疫苗对很多新型病毒有心无力,更别提像癌症这种严重威胁人类健康的疾病了。而mRNA的作用机理使它就像一本餐谱一样,只要你编好RNA序列,就可以将细胞变成小型的药物工厂,mRNA引导细胞自己产生特定蛋白发挥系统药效。   图2.传统疫苗、DNA疫苗和mRNA疫苗的若干区别 mRNA疫苗靠什么? 作用机理 mRNA参与DNA翻译和蛋白质生成的中间步骤。目前用于制造疫苗的有两种RNA,非复制型(non-replicating) mRNA和自我扩增型(self-amplifying) mRNA。传统mRNA疫苗编码的抗原包含5ʹ和3ʹ的未翻译区(UTRs),而自我扩增型RNA不仅能编码抗原,还有类似病毒复制过程的序列,使其可以在细胞内复制,提高蛋白表达量。 简单的说,体外转录RNA利用DNA模板和RNA聚合酶,包括T7、T3或Sp6噬菌体聚合酶,来制备具有蛋白质编码功能的开放阅读框(open reading frame)。这个阅读框两个重要组成部分分别是一个5’端的“帽子”结构和一条多聚A (poly A)的”尾巴“。除此之外,还有一段未翻译区,它可以提高复合物在转录时的稳定性,使人工制造的mRNA可以像成熟mRNA分子一样发挥转录组装作用。裸露的mRNA很容易被胞外核糖核酸酶催化降解,因此很多载体被用于提高mRNA摄取。一旦mRNA进入胞浆,细胞翻译机制就能在其引导下组装氨基酸序列,进行翻译后修饰并恰当的折叠形成功能性蛋白质。mRNA的这些药理特性使其在疫苗疗法领域具有无可比拟的优势。 新的技术 近年来,不同的mRNA疫苗平台在免疫原性和药效方面均取得巨大进展。RNA序列工程技术使得人工合成的mRNA比以前的翻译功能更好,高效低毒的载体能够显著提高抗原的体内表达,一些疫苗中还加入了新型佐剂。 1.对mRNA翻译和稳定性的优化 现有的mRNA修饰技术能够直接或间接的影响免疫应答,主要包括:合成”帽子“类似结构;在5’和3’ UTR区域增加可调控序列;修饰多聚A“尾巴”。这其中5’和3’ UTR区域序列的改进对于提高mRNA稳定性和蛋白表达至关重要,选择与tRNA同源的密码子可以提高mRNA的翻译能力。在生产中还可以利用分离和纯化技术来优化mRNA。 2.免疫原性的调节 图3中展示了树突细胞(dendritic cell, DC)对两种mRNA疫苗的免疫应答。外源mRNA能在体内产生免疫刺激,因为它能被细胞表面、核内体或胞质的免疫应答受体识别。根据治疗方法不同,这种免疫刺激也是有利有弊。有利的一面是它能够驱动DC成熟因子,进而激发T细胞和B细胞产生强烈的免疫应答。弊的一面是这种免疫感应也可能抑制抗原的表达,对免疫应答产生消极作用。其背后复杂机理尚不十分清楚,但是近些年相关研究也取得了一些进展。   图3.mRNA疫苗触发免疫应答过程,黄色基团代表RNA感应器,红色基团代表抗原,绿色基团代表DC成熟因子,红蓝色基团代表主要组织相容性复合体(MHC),图片右上方一个脂质纳米粒载体 (图片引自参考文献2) 研究发现mRNA的这种免疫刺激可以通过制备纯化,引入修饰性核苷,或者通过改变载体分子来改善。生产mRNA疫苗过程中的酶促反应会生成一些双键RNA的副产物,因为与病毒基因组和复制中间产物类似,双键RNA是一个潜在的病原体相关分子(PAMP),能够被很多细胞区室受体感应产生应激反应,最终导致翻译抑制和mRNA降解。用分析手段,对制备的mRNA进行纯化,可以减少双链副产物,防止不必要的免疫刺激。除了双链RNA杂质的影响,单链RNA本身也是一种PAMP,能够引起I型干扰素产生,通过引入自然核苷可以减少其产生,这些结果表明似乎经过纯化和修饰的mRNA在树突细胞中可明显提高蛋白表达量。但是也有研究表明,经过纯化,未修饰的mRNA能够在HeLa细胞中产生比修饰过的mRNA更多的蛋白质,这与上面的结果是相反的。结论就是不论是采用纯化还是修饰,都要根据靶点细胞不同而采用不同的组合策略和调控技术,只有这样才能发挥最好的药效。 3.mRNA递送方式的进展 上文提到过,裸露的mRNA直接进入体内会被降解,因此高效的mRNA递送是疫苗药效的保证。目前利用载体和直接注入这两种mRNA递送方式都在生产中使用。 利用载体将mRNA注入体内 常用载体包括树突细胞,鱼精蛋白,微质粒载体和高分子载体等。树突细胞是免疫系统最有潜力的抗原表达细胞。阳离子多肽鱼精蛋白已被证实可以保护mRNA免于被核糖核苷酶降解。但是同时也有数据表明它会降低蛋白的表达,这可能是由于mRNA和鱼精蛋白连接过于紧密造成的。阳离子脂质体和高分子,如树枝状高分子,已经在过去几年的mRNA给药途径中广泛运用,这也是借了小干扰RNA (siRNA)领域发展的东风。脂质纳米粒(LNPs)载体已经变成了mRNA疫苗最常用的载体之一。 直接将mRNA注入体内 常用皮内注射或节内注射方法,有报道称重复节内接种mRNA,由肿瘤相关的抗原来激发T细胞应答,可以提高患者的无进展生存期(PFS)。 物理递送方法 除了以上两种方法,还有使用物理方法mRNA的细胞膜穿透。比如电基因枪、电穿孔法等。物理方法的缺点是可能会引起细胞死亡。 mRNA疫苗能带来什么? mRNA疫苗目前有两大应用领域,传染性疾病和癌症(图4)。需要注意的是mRNA给药后的生物分布。比如装载mRNA的脂质纳米粒,静脉给药后主要分布在肝脏,这对于树突细胞的活化并不是最理想的。影响给药后生物分布的因素有载体与mRNA的比例,净电荷等。比如带正电荷的纳米粒主要靶向肺部,而带负电荷则主要靶向次级淋巴组织和骨髓。 图4.目前处于临床研究阶段的mRNA疫苗疾病分布 抗传染病的mRNA疫苗 发展预防性或治疗性疫苗来对抗传染性病原体,是遏制和预防流行病是最有效的手段。但是,过去的疫苗产品不能对抗像HIV、疱疹病毒或是呼吸道合胞病毒这些对人类健康造成巨大危害的病毒。除此之外,像2014-2016年先后爆发的埃博拉病毒和塞卡病毒这类突发病毒疾病,传统疫苗也排不上用场。因此,发展更有效的疫苗刻不容缓。 无数临床前的动物实验已经证明了mRNA疫苗对抗传染性病毒的药效。动物实验中安全性良好,其快速制备的特点也适用于传染病爆发的灵活应对,相对简单的生产工艺也便于质量控制。与蛋白免疫接种不同,mRNA疫苗能够引起强烈的CD4+或CD8+ 的T细胞应答。它们也与DNA免疫接种不同,在动物体内mRNA疫苗通过一两次低剂量接种就能够产生抗体。目前临床阶段开发的mRNA疫苗针对疾病包括HIV,流感病毒和狂犬病毒等。 抗肿瘤的mRNA疫苗 肿瘤疫苗和其他免疫疗法被认为是非常有前途的治疗恶性肿瘤的方法。肿瘤疫苗可以设计成靶向肿瘤细胞选择表达的相关抗原,比如,生长因子等。也可以靶向恶性肿瘤细胞突变产生的特有抗原。针对癌症的mRNA疫苗一般起治疗作用,而不是传统的预防作用,目的是促使细胞介导的应答,比如典型的T淋巴细胞应答,从而达到清除或者减少肿瘤细胞的目的,部分研发管线见图5。 1.以树突细胞为载体的mRNA肿瘤疫苗 从1996年研究人员通过实验证明树突细胞装载mRNA可以激发肿瘤抗原产生免疫应答起,到今天,相关临床研究已涵盖转移性前列腺癌、肺癌、肾细胞癌、脑癌、黑色素瘤、急性髓性白血病和胰腺癌等。现在研究人员还将树突细胞载mRNA疫苗与传统化疗药物或者免疫检查点抑制剂联用,其中的一项临床试验中,III-IV期黑色素瘤患者同时给予单克隆抗体Ipilimumab和载有黑色素瘤抗原相关mRNA的树突细胞注射剂,结果表明该疗法可以持续降低部分复发性或难治性黑色素瘤患者的肿瘤。   图5.BioNTech,CureVac AG和Moderna三家公司部分mRNA研发管线(来自公司官网) 2.直接注射的mRNA肿瘤疫苗 直接注射的给药途径包括皮内注射,肌肉注射,皮下注射和鼻内给药,还有一些非传统方式包括节内注射,静脉给药,经脾给药和肿瘤给药。不同的给药方式对于mRNA疫苗的药效有很大影响,总体来讲,由于裸露的mRNA易于降解,存在血清蛋白聚合,所以直接注射法并不常用。 mRNA疫苗的挑战与展望 另一种声音 关于mRNA疫苗副作用的声音一刻也没有停止过,虽然目前临床研究大都没有问题,但是确实也有一些副反应的例子出现,甚至包括一些严重的副作用,引起注射部位或全身反应。因此在相关临床试验中要格外注意像局部和全身炎症、药物的生物分布、免疫原的持续表达、刺激抗体的自激活,还有非原生核苷酸及载体引入的成分所具有的潜在毒性等。一部分研究者认为mRNA疫苗能够引起I型干扰素反应,不仅会引起炎症,还可能与自身免疫相关。另一个潜在风险是胞外RNA的引入,其能够增加内皮细胞的渗透性导致水肿;还能引起血液凝固和病理性血栓形成。因此在将mRNA疫苗用于人体或是开展大规模临床研究前,一定要进行严格的安全性评价。 除了潜在的副作用,一些临床研究结果还证明mRNA疫苗在人体中的药效比动物体内低的多。虽然这不是一个普遍存在的现象,但是也给研究人员提了醒,需要进一步研究动物与人对mRNA疫苗的应答差异,到底人体中哪条免疫通路最有效的?是否可以通过改变疫苗的免疫刺激表达来改善药效?这些都是需要解决的问题。  结论 当下的mRNA疗法真的可以用炙手可热来形容。早期临床前的大量研究数据为这一领域做足了铺垫。除了在流感、塞卡病毒和癌症治疗方面大放异彩,最近的研究还发现mRNA能够激活被动免疫功能。但是任何一项新技术,捧得太高终归不是一件好事情,人体药效的验证和临床副作用,任何一点得不到很好的解决都会让mRNA疫苗跌下神坛。mRNA疗法到底是”未来疫苗的大门“,还是”皇帝的新衣“?且让我们拭目以待。 参考文献: 1.mRNA疫苗研究进展及挑战,免疫学杂志。 2.mRNA vaccines——a new era in vaccinology, Nature Reviews. 3.BioNTech raises mammoth $270M A round, nearing $1B mark as investors continue a love affair with mRNA. Endpoints. 4.mRNA Vaccines: Disruptive Innovation in Vaccination.详情>>

2018-01-16 00:00:00

论文肝癌在中国的精确诊断和治疗

Liver cancer ranks the sixth in cancer incidence and the second in tumor related mortality worldwide, with over half of the new cases and deaths occur in China. Because of difficulties in early diagnosis, rapid progression and lack of targeted drugs, the survival rate of liver cancer is extremely low. The existence of extraordinary heterogeneity has greatly limited the progress in early detection, molecular classification and targeted therapy of live cancer, owing to its varied risk factors, genetic susceptibilities, morphological diversity and microenvironmental discrepancies. Based on the heterogeneity of individual patients, precision medicine brings a new dimension to cancer personalized diagnosis and more-targeted treatment, and even give us access to pre-clinical screening of tumors in high risk populations. The present review article will provide progresses in precision diagnosis, molecular classification, signaling disregulation, preclinical models and personalized treatment of liver cancer in China.展开>><<收起

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结直肠癌的新生物标记物

新闻结直肠癌的新生物标记物

Researchers from the University of Luxembourg found a new biomarker for colorectal cancer (CRC) that might improve therapy and survival rates of patients. Biomarkers are measurable biological indicators for a specific disease, such as changes in the amounts of certain proteins that occur in combination with certain illnesses. Such biomarkers help physicians to diagnose a condition, identify the disease stage, and determine a patient's risk for recurrence of the disease. This supports the doctor in choosing the best-fitting treatment plan. For colorectal cancer (CRC), early detection and classification is especially important, as, for example, not all Stage II patients benefit from chemotherapy. Especially identifying patients at risk for recurrence during the early course of the disease might help clinicians. However, there are still too few prognostic markers for colorectal cancer known so that too many patients still suffer needlessly from side effects of the chemotherapy without having real benefits. In a study supported by the Fondation Cancer and the Luxembourg National Research Fund (FNR), an interdisciplinary team composed of experimental and computational scientists from the Molecular Disease Mechanisms (MDM) group at the Life Sciences Research Unit of the University of Luxembourg has recently discovered a new promising biomarker for colorectal cancer. Especially in early stages, such markers might allow to classify patients into "high" and "low" risk group. Such a classification may help oncologists choosing the adequate treatment regimens for a given patient. "The strength of the study lies in the concerted effort and the interdisciplinary approaches, involving bioinformatics and state-of-the-art experimental techniques. Especially the financial support from the Fondation Cancer has been crucial for the successful completion of our biomarker projects," explains Dr. Elisabeth Letellier, principal investigator in the MDM group. Using a previously established meta-analysis of publicly available gene expression data, the research team identified the protein family "Myosin" and especially the protein "MYO5B" as potential prognostic marker in the context of CRC. Members of this family are recognised to play a major role in cellular trafficking and polarisation of cells and have recently been reported to be closely associated with several types of cancer. The meta-analysis as well as an independent patient cohort study revealed that the concentration of "MYO5B" decreases as the disease progresses. CRC patients with low "MYO5B" expression had significantly lower chances of disease- and metastasis-free survival. Altogether, the data collected from the Molecular Disease Mechanisms (MDM) group identify MYO5B as a powerful prognostic biomarker in CRC, especially in early stages (stages I and II), which might help stratifying patients with stage II for adjuvant chemotherapy. LSRU-team identifies new prognostic biomarkers for CRC "Together with our partners, we have been able to set up a high-quality tissue collection from colon cancer patients here in Luxembourg. Only the close collaboration with the Integrated Biobank of Luxembourg (IBBL), the Laboratoire National de Santé (LNS), the Centre d'Investigation et d'Épidémiologie Clinique (CIEC) and local hospitals, primarily the Centre Hospitalier Emile Mayrisch (CHEM), has allowed us to establish these important foundations for further colon cancer projects," says Prof. Dr. Serge Haan, Head of the MDM group. In this research project, the MDM group has analysed the value of a biomarker in a Luxembourgish colorectal cancer (CRC) collection. Indeed, they have established a CRC collection that includes tissue samples from patients. This collection is of high value as it allows, for example, the identification of new prognostic biomarkers for CRC as highlighted in the present project.详情>>

2018-01-15 00:00:00

论文微生物组指导的精准医疗

Summary Accumulating evidence indicates that dysregulation of microbiota-host interactions associates with various diseases, including inflammatory bowel diseases (IBDs), colorectal cancer, diabetes, and liver cirrhosis (1). Recently, research has generated paradigm shifts in concepts about the interactions between bacteria and cancer therapeutic drugs. For example, bacteria modulate the antitumor efficacy in preclinical models of various chemotherapies (2–4) and immunotherapeutic agents (5, 6). Conceptually, these findings suggest that bacteria-mediated interactions with the immune system are essential for optimal drug efficacy. However, there is limited information regarding the functional impact of the composition of the human microbiome and therapeutic outcomes in cancer patients. On pages 91, 97, and 104 of this issue, Routy et al. (7), Gopalakrishnan et al. (8), and Matson et al. (9), respectively, address this important issue and demonstrate that patients can be stratified into responders and nonresponders to immunotherapy on the basis of the composition of their intestinal microbiomes, suggesting that microbiota should be considered when assessing therapeutic intervention.展开>><<收起

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病毒样蛋白对认知和记忆至关重要

新闻病毒样蛋白对认知和记忆至关重要

A protein involved in cognition and storing long-term memories looks and acts like a protein from viruses. The protein, called Arc, has properties similar to those that viruses use for infecting host cells, and originated from a chance evolutionary event that occurred hundreds of millions of years ago. The prospect that virus-like proteins could be the basis for a novel form of cell-to-cell communication in the brain could change our understanding of how memories are made, according to Jason Shepherd, Ph.D., a neuroscientist at University of Utah Health and senior author of the study publishing in Cell on Jan. 11. Shepherd first suspected that something was different about Arc when his colleagues captured an image of the protein showing that Arc was assembling into large structures. With a shape that resembles a capsule from a lunar lander, these structures looked a lot like the retrovirus, HIV. "At the time, we didn't know much about the molecular function or evolutionary history of Arc," says Shepherd who has researched the protein for 15 years. "I had almost lost interest in the protein, to be honest. After seeing the capsids, we knew we were onto something interesting." The gap in research was not for want of an interesting subject. Prior work had shown that mice lacking Arc forgot things they had learned a mere 24 hours earlier. Further, their brains lacked plasticity. There is a window of time early in life when the brain is like a sponge, easily soaking up new knowledge and skills. Without Arc, the window never opens. Scientists had never considered that mechanisms responsible for acquiring knowledge could stem from foreign origins. Now, the work by Shepherd and his team has raised this intriguing possibility. A protein important for cognition and memory named Arc can encapsulates genetic material (polyhedron enveloping the ribbon-like strands) and delivers it to brain cells in a manner similar to the way in which viruses infect host cells. Credit: Chris Manfre Everything Old is New Again Seeing Arc's unusual propensity to form virus-like structures prompted Shepherd to scrutinize the protein sequence with a new set of eyes. He found that regions of the code were similar to that from viral capsids. An essential tool for viral infection, capsids carry virus' genetic information and deliver it from cell to cell in its victim. Given that Arc looks like a viral protein, Shepherd and his colleagues designed a set of experiments to test whether it also acts like one. They first determined that several copies of Arc self-assemble into hollow virus-like capsids and stash its own genetic material, in this case mRNA, inside them. When the scientists added the capsids to mouse brain cells, or neurons, growing in a dish, Arc transferred its genetic cargo into the cells. After viruses invade host cells, they emerge ready to infect once again. It appears that Arc works in a similar way. The scientists gathered Arc that had been released from mouse neurons and determined that the proteins and their cargo could be taken up by another set of neurons. Unlike for viruses, activating neurons mobilizes Arc, triggering the release of capsids. "We went into this line of research knowing that Arc was special in many ways, but when we discovered that Arc was able to mediate cell-to-cell transport of RNA, we were floored," says the study's lead author, postdoctoral fellow Elissa Pastuzyn, Ph.D. "No other non-viral protein that we know of acts in this way." When Lightning Strikes Twice The story of Arc's origin is relayed through the genomes of animals throughout evolutionary time. 350-400 million years ago, a chance occurrence struck four-limbed creatures that roamed the earth. An ancestor to retroviruses, called retrotransposons, inserted its genetic material into the animals' DNA. The event led to the mammalian Arc that we know today. The significance of such an event is hinted at by the fact that it happened more than once. An accompanying paper in the same issue of Cell shows that a version of Arc found in flies also looks and acts like a viral capsid. Vivian Budnik's lab at the University of Massachusetts shows that fly Arc transports RNA from neurons to muscles to control movement. Even though mammalian and fly Arc evolved from the same class of retrotransposons, the event in flies occurred about 150 million years later. "As an evolutionary biologist this is what is the most exciting to me," says co-author Cédric Feschotte, Ph.D. a professor at Cornell University. "The fact that it happened at least twice makes us think that it happened even more." Shepherd believes this could mean that it is advantageous to have this viral-inspired system in place, and it may represent a novel form of intercellular communication. This hypothesis remains to be tested in mammals. "Knowing what cargo Arc vesicles transport in living animals will be critical to understanding the function of this pathway," he says. Remember the unusual viral-like protein that you just learned about? It could be controlling your memory. More information: Cell (2018). DOI: 10.1016/j.cell.2017.12.024 , http://www.cell.com/cell/fulltext/S0092-8674(17)31504-0详情>>

2018-01-12 00:00:00
基因的改变会导致肥胖

新闻基因的改变会导致肥胖

Greenland is like many other countries struggling with overweight and obesity. Both environment and genetics play a role in development of obesity. However, it is not fully known which specific genes that are causing obesity. Researchers from the University of Copenhagen, among others, now appear to have found one of these genes. 'We have found a gene, ADCY3, which predisposes Greenlanders to obesity and diabetes when it is inactive. This appears to be unique to the Greenlandic population', says Associate Professor Niels Grarup from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen. In the study, which has just been published in the scientific journal Nature Genetics, the researchers have examined the genes of 5,000 Greenlanders, corresponding to around nine per cent of the entire population in Greenland. In 4.4 per cent of the test subjects this specific gene was inactive. The activity of the gene is important because everyone has two copies of all their genes. This means that the gene may be expressed in full, in part or not at all. In around four per cent of the Greenlanders the gene is only expressed in part. On average this increases their weight by two kilos, their waist circumference by two centimetres and their BMI by 1 unit compared to the rest of the population. And the risk of developing diabetes also increases when the gene is not fully active: 11 per cent of those where the gene is expressed in part suffer from diabetes; the figure is 43 per cent for those where the gene is not expressed at all. Around seven per cent of all Greenlanders in whom the gene is expressed in full have diabetes. 'We are pretty convinced that it is this Greenlandic gene that impacts on obesity and the risk of developing diabetes. Because in seven individuals the gene is not expressed at all, and this really causes problems. On average it increases their weight by 15 kilos, their waist circumference by 17 centimetres and their BMI by seven units, of course with some statistical uncertainties, as we are talking about a very small number of people', Professor Torben Hansen from the Novo Nordisk Foundation Center for Basic Metabolic Research at the University of Copenhagen explains. The conclusions of the study are further supported by previous research results, as tests on mice have shown that increasing the activity of the gene causes the mice to become slender and develop a well-functioning metabolism. Thus, they do not develop overweight and diabetes, even if they are given a fat diet. 'These findings pave the way for more studies of whether this knowledge can be used to develop new drugs, which may also be used elsewhere in the world. At any rate, we now have several clear indications that expression of this gene is closely connected with obesity and diabetes', Torben Hansen says. 'It may not sound significant that we have found seven Greenlanders in whom this gene is not expressed at all. But when we look at a group of 140,000 Europeans we are unable to find a single person in whom the gene is not expressed. This means that this is strongly over-represented in Greenland', Niels Grarup explains. The genetic variation may be over-represented in the Greenlandic population, because it genetically has been cut off and isolated from other populations for several thousands of years. In the future the researchers will explore the possible positive effects of activating the gene. The study is a collaboration also involving the University of Greenland, the Greenlandic health authorities, Science at the University of Copenhagen, the University of Southern Denmark and the Steno Diabetes Center Copenhagen. The study is funded by the Novo Nordisk Foundation, the Independent Research Fund Denmark, the Steno Diabetes Center Copenhagen, the Simon Fougner Hartmann Family Foundation, the Villum Foundation and the European Research Council.详情>>

2018-01-11 00:00:00

论文儿科肿瘤精准医疗

PURPOSE OF REVIEW: The current review describes recent advances and unique challenges in precision medicine for pediatric cancers and highlights clinical trials assessing the clinical impact of targeted therapy matched to molecular alterations identified by tumor profiling. RECENT FINDINGS: Multiple prospective clinical sequencing studies in pediatric oncology have been reported in the last 2 years. These studies demonstrated feasibility of sequencing in the clinic and revealed a rate of actionable variants that justifies the development of precision trials for childhood cancer. A number of precision medicine trials are recently completed, underway or in development and these will be reviewed herein, with a focus on highlighting aspects of precision medicine trial design relevant to pediatric oncology. SUMMARY: The primary results of the first round of pediatric precision oncology clinical trials will provide us with a greater understanding of the clinical impact of linking tumor profiling to selection of targeted therapies. The aggregation of sequencing and clinical data from these trials and the results of biologic investigations linked to these trials will drive further discoveries and broaden opportunities for precision medicine for children with cancer.展开>><<收起

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不同淀粉样蛋白可引起不同类型的阿尔茨海默症

新闻不同淀粉样蛋白可引起不同类型的阿尔茨海默症

An international team of researchers has found different disease type associations with distinct amyloid-beta prion strains in the brains of dead Alzheimer's patients. In their paper published in Proceedings of the National Academy of Sciences, the group describes their study of sliced brain fragments and what they learned about the nature of amyloid-beta prions. Prior research has found a connection between protein clumps in the brain and Alzheimer's disease. Prior research has also shown that the protein clumps are a mutant type of amyloid beta, which results in the growth of plaques in the brain. In this new effort, the researchers have found evidence indicating that there are distinct types of amyloid-beta prion strains which can be associated with different types of brain diseases. The study consisted of dissecting and studying the brains of 41 patients who had died of Alzheimer's disease. Slices of brain tissue were doused with a fluorescent dye known to bind to amyloid bindings. The researchers studied the samples with confocal spectral imaging. Doing so, the group reports, revealed different types of disease associations between unique amyloid-beta prion strains. The researchers also found evidence that suggested mutant amyloid-beta can take on the self-propagating structure of prions, in which they form more self-replicating prions. One of the goals of research surrounding Alzheimer's disease and other dementia ailments is to find a way to diagnose the particular ailment so that it can be treated with drugs or other therapies specifically designed for it. Currently, the only way to accurately diagnose Alzheimer's disease is to study the brain after a patient has died. The researchers with this new effort suggest their findings are a step toward this goal. They further suggest that probes of the future might be sensitive enough to distinguish the different strains they have seen in their work, which would allow doctors to design treatments specifically suited to individual patients. There is no cure for Alzheimer's disease, but there are drugs that can slow its progression—thus, if the disease could be diagnosed earlier, before obvious mental impairments present, treatment could begin earlier, giving patients more productive years. More information: Carlo Condello et al. Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1714966115 Abstract Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aβ deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT Aβ, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aβ40 fibrils into transgenic mice expressing only WT Aβ induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aβ40 prions induce a conformation of WT Aβ similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aβ prion conformations, which kinetically dominate the spread of prions in the brain. Journal reference: Proceedings of the National Academy of Sciences详情>>

2018-01-10 00:00:00