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


Abstract Key challenges for human genetics, precision medicine and evolutionary biology include deciphering the regulatory code of gene expression and understanding the transcriptional effects of genome variation. However, this is extremely difficult because of the enormous scale of the noncoding mutation space. We developed a deep learning–based framework, ExPecto, that can accurately predict, ab initio from a DNA sequence, the tissue-specific transcriptional effects of mutations, including those that are rare or that have not been observed. We prioritized causal variants within disease- or trait-associated loci from all publicly available genome-wide association studies and experimentally validated predictions for four immune-related diseases. By exploiting the scalability of ExPecto, we characterized the regulatory mutation space for human RNA polymerase II–transcribed genes by in silico saturation mutagenesis and profiled > 140 million promoter-proximal mutations. This enables probing of evolutionary constraints on gene expression and ab initio prediction of mutation disease effects, making ExPecto an end-to-end computational framework for the in silico prediction of expression and disease risk.展开>><<收起

Mutation burden predicts benefit of PD-1-treated NSCLC

新闻Mutation burden predicts benefit of PD-1-treated NSCLC

An elevated tumor mutational burden (TMB) in the blood has now demonstrated its potential as a reliable clinical biomarker for predicting the clinical efficacy of the checkpoint inhibitor Tecentriq (atezolizumab, Roche Holding AG) in treating patients with advanced non-small-cell lung cancer (NSCLC), a Sino-U.S. study has shown. "This is the first time a validated blood TMB (bTMB) assay has been shown that it may predict the clinical efficacy of a checkpoint inhibitor," said David Shames, principal scientist in the department of Oncology Biomarker Development at Roche subsidiary Genentech Inc. in South San Francisco. Shames co-led the study with David Gandara, professor and director of the Thoracic Oncology Program at University of California Davis Comprehensive Cancer Center, Sacramento, and Tony Mok, a professor in the Department of Clinical Oncology at The Chinese University of Hong Kong. In patients with previously treated, advanced second-line and higher NSCLC, an overall survival (OS) benefit has been observed in patients treated with the checkpoint inhibitors Tecentriq or Opdivo (nivolumab, Bristol-Myers Squibb Co.). "Checkpoint inhibitors are antibodies targeting programmed death-ligand 1 (PD-L1) or programmed death 1 (PD-1). These proteins regulate an immune checkpoint, which typically guards against autoimmunity by inducing apoptosis of antigen-specific T cells in lymph nodes and inhibiting it in regulatory T cells," explained Shames. "In cancer, tumor cells express or induce expression of PD-L1 on neighboring T cells, thereby preventing the immune system from recognizing the tumor, which is an example of immune evasion by tumor cells." Checkpoint inhibition "with anti-PD-L1/PD-1 antibodies reverses this immunosuppressive regulatory process," Shames told BioWorld. "Checkpoint inhibitors appear to be more effective than doublet chemotherapy in patients who are positive for PD-L1 by immunohistochemistry and/or TMB, while in combination with chemotherapy, they seem to be more effective than chemotherapy alone in most NSCLC patients," he said. While PD-L1 testing is required prior to checkpoint inhibitor monotherapy as front-line NSCLC treatment, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging, with around 30 percent of NSCLC patients having inadequate tissue for testing at diagnosis. "Initially, physicians are interested in obtaining a pathological diagnosis to rule in/out lung cancer, but because many patients present with co-morbidities and tend to be frail, physicians select less invasive procedures such as bronchoscopy. Such procedures are useful for diagnosing lung cancer, but often yield insufficient material for molecular testing," noted Shames. Furthermore, "historically, it wasn't necessary to obtain substantial tissue, as there weren't any medicines available requiring a molecular diagnosis. This has changed in recent years in the U.S., but in many countries it remains the standard of care to use minimally invasive procedures, which also frequently produce insufficient material." An unmet medical need therefore exists for diagnostic approaches that do not require tissue biopsies, in order to identify those patients who may benefit from novel immunotherapies like checkpoint inhibitors. In their new study reported Aug. 2, 2018, in Nature Medicine, the authors described a novel, technically robust, blood-based assay to measure bTMB that obviates tissue-based approaches. "The investigational bTMB assay uses next-generation gene sequencing to evaluate the number of mutations detectable in a patient's blood plasma. It is quite simple to use at the point of care, as it only requires a simple blood draw – the equivalent of two standard vials of blood," said Shames. "The plasma is then shipped to [U.S. genomic testing company] Foundation Medicine in Cambridge, Massachusetts, where circulating tumor DNA is extracted, sequenced and subjected to bioinformatic analysis. "We have made numerous adaptations to standard protocols in upstream processing to improve the assay's sensitivity, specificity and reproducibility," said Shames. Using a retrospective analysis of the large randomized OAK and POPLAR trials as test and validation studies, respectively, the researchers showed the bTMB assay reproducibly identified patients with second-line and higher NSCLCs who would derive significant improvements in progression-free survival (PFS) from atezolizumab. Measuring bTMB was shown collectively to be feasible, with a cut-point of >/= 16 reproducibly identifying patients who would obtain an increased PFS benefit in those receiving atezolizumab compared to patients receiving single-agent docetaxel chemotherapy. "The cut-point of >/=16 was derived by evaluating the specificity and sensitivity of the assay at a range of cut-offs and then evaluating the best technical cut-offs in the POPLAR trial," Shames said. "In POPLAR, there was a 35 percent reduction in the risk of disease progression for bTMB-positives compared to the intent-to-treat (ITT) population, whereas in OAK, the reduction in risk of disease progression for bTMB-positives was 30 percent versus the ITT group." Although additional work is needed to better understand the dynamics and biology of bTMB and its relevance to indications beyond NSCLC, the study findings suggest the future potential application of that assay to the molecular diagnostic and therapeutic algorithms for patients who have progressed on first-line therapy for advanced NSCLC. "We are currently evaluating the performance of the bTMB assay in two prospective studies, which will hopefully validate the platform," Shames said. "We are also evaluating approaches to improve the assay's efficiency from a cost and turnaround time perspective and are interested in identifying other areas where such an assay might be useful in improving patient outcomes."详情>>

2018-08-15 00:00:00


多基因控制的复杂性状对于生物适应环境和人工选择有着重要意义,其中包含了众多有着巨大科学价值和经济价值的性状,高产性状就是一种典型的多基因控制的复杂性状。 来自南京大学生命科学学院的研究人员发表了题为“Identifying a large number of high-yield genes in rice by pedigree analysis, whole-genome sequencing, andCRISPR-Cas9gene knockout”的文章,通过系谱分析,全基因组测序和CRISPR-Cas9基因敲除鉴定出了水稻高产相关基因,提供了一种有效的探索复杂性状相关基因的方法。 这一研究成果公布在PNAS杂志上,由田大成教授领导完成,第一作者为黄驹和李婧。 多基因控制的复杂性状对于生物适应环境和人工选择有着重要意义,其中包含了众多有着巨大科学价值和经济价值的性状,高产性状就是一种典型的多基因控制的复杂性状。但是由于在复杂性状中,基因控制方式较为复杂,单个基因可能只有较小的表型效应,解析复杂性状的控制基因一直是比较困难的。 田大成课题组以水稻“绿色革命”中的关键品种“奇迹稻”IR8的系谱为主要研究材料,对IR8的亲本和后代等主要品种进行全基因组测序,鉴定出有28个基因组片段在杂交和选育过程中不断地受到强烈的人工选择,在IR8所有后代始终得到继承。 系谱结构与受选择基因鉴定流程图 研究人员在进一步结合群体遗传学数据的基础上,从这些片段中筛选出可能与高产性状相关的129个基因位点。在这些基因位点中,有6个为已报道功能的基因,其中包括绿色革命的关键基因sd1。 为了对其余123个功能未知基因进行功能验证,他们随机挑选出了57个进行CRISPR-Cas9敲除或敲低实验,结果表明这些基因中有较高比例具有必须功能或能影响与水稻产量相关的性状,许多基因敲除后表现出了明显的株高降低,而这也正是绿色革命中的关键性状。此外敲除突变体还表现出了生育期、育性、穗型等多种与水稻产量密切相关的表型变化。 总而言之,这项研究鉴定出了大量水稻高产相关基因,提供了一种有效的探索复杂性状相关基因的方法。详情>>

2018-08-15 00:00:00
Novel Method Allows Researchers to Precisely Engineer and Monitor Protein Function

新闻Novel Method Allows Researchers to Precisely Engineer and Monitor Protein Function

Boston College chemists have developed a new, bacteria-derived technology to incorporate non-canonical amino acids into proteins of a broad class of organisms, including humans. [Cell Chemical Biology] Boston College chemists say they have developed a technology to precisely incorporate a range of useful non-canonical amino acids into proteins made in eukaryotes. The team’s goal was to create a new method to engineer and monitor protein functions as a way of expanding the scientific understanding of the processes that guide protein functions in our cells. Their study (“Resurrecting the Bacterial Tyrosyl-tRNA Synthetase/tRNA Pair for Expanding the Genetic Code of Both E. coli and Eukaryotes”) appears in Cell Chemical Biology.   “The bacteria-derived tyrosyl-tRNA synthetase (TyrRS)/tRNA pair was first used for unnatural amino acid (Uaa) mutagenesis in eukaryotic cells over 15 years ago. It provides an ideal platform to genetically encode numerous useful Uaas in eukaryotes. However, this pair has been engineered to charge only a small collection of Uaas to date. Development of Uaa-selective variants of this pair has been limited by technical challenges associated with a yeast-based directed evolution platform, which is currently required to alter its substrate specificity,” write the investigators. “Here we overcome this limitation by enabling its directed evolution in an engineered strain of E. coli (ATMY), where the endogenous TyrRS/tRNA pair has been functionally replaced with an archaeal counterpart. The facile E. coli-based selection system enabled rapid engineering of this pair to develop variants that selectively incorporate various Uaas, including p-boronophenylalanine, into proteins expressed in mammalian cells as well as in the ATMY strain of E. coli.” According to Abhishek Chatterjee, Ph.D., assistant professor of chemistry, and lead on the project, the researchers were surprised by the facility of the new approach. "Creating this novel E. coli strain required substituting its native aminoacyl-tRNA synthetase/tRNA pair with a counterpart from a different organism, which we anticipated would be very difficult," he says. "But it turned out to be quite feasible. That opens up this complete technology. "Thousands of proteins are encoded in the genome that make us who we are, but we know very little about that process. In human cells, there are roughly 20,000 protein-coding genes. What they are doing and how they are doing it remains difficult to study. One of the major problems is that if you want to know what they are doing, you have to spy on them. You need to attach a probe that can report back on what is going on."   Introducing such probes has proven difficult, as the process often damages the target protein.   "The idea is that we can introduce a new building block into proteins that nature does not have—beyond the 20 canonical amino acids that nature uses," Dr. Chatterjee says. "If we can do that, we have the ability to very specifically introduce a wide variety of non-natural functionalities into any site of virtually any protein."   The immediate benefit would be to assist researchers who are still unraveling the mysteries of cell biology and protein function.   "You could create a protein with a non-canonical amino acid into any chosen site, load it with probes that are very tiny and give out an optical signal that tells where it is going,” continues Dr. Chatterjee. “It could allow you to manipulate how the protein is working. You could introduce limits, so whatever the protein is doing, it can't do anymore. And you could remove the probe by using an external signal such as light. This technology opens up numerous new ways one can start to probe and engineer protein function, which would be very challenging otherwise."详情>>

2018-08-07 00:00:00
这家公司用机器人生产个性化癌症疫苗 估值70亿美元

新闻这家公司用机器人生产个性化癌症疫苗 估值70亿美元

7月25日消息,据《连线》网站报道,生产个性化的癌症疫苗需要一批机器人来完成。波士顿生物科技公司Moderna Therapeutics正在涉足这一领域,目前其估值达到70亿美元。 20世纪90年代初,当梅丽莎·摩尔(Melissa Moore)捣鼓RNA(核糖核酸)时,这位年轻的生物化学家得小心翼翼地用微量移液管构建基因分子,一次只能构建几个。在诺贝尔奖得主菲尔·夏普(Phil Sharp)位于麻省理工学院(MIT)的实验室里,可能需要数天时间才能做几滴RNA。RNA可将细胞的遗传源代码运送到蛋白质制造机器里。她没有想到,近三十年后,她会离开学术界,去一家公司工作,而这家公司一次就能制造出20升的RNA。 摩尔在Moderna Therapeutics公司负责RNA研究。根据行业研究机构CB Insights的数据,该公司估值约70亿美元,是世界上最有价值的私营医疗公司之一。这家总部位于波士顿的生物技术公司是少数几家开发技术利用信使RNA?(mRNA)将人类自身细胞变成制药工厂的公司之一。这些指令串可以促使病人的身体产生诸如抗癌化学物质、心脏修复蛋白或抗病毒抗体的东西。摩尔说:“一旦你了解了如何在需要的地方获得这些药物,你就可以改变序列,非常快速地制造出一种新药。这是我们的能力的一种彻底突变。” 也许是这样,但Moderna的研发在它成立8年后仍然处于初期阶段。该公司在头两年秘密运营,因而早早就给人一种神秘的印象。《自然生物技术》(Nature Biotechnology)的编辑曾一度诟病该公司——以及包括陷入困境的Theranoa在内的其他生物科技公司——在公开研究工作方面做得不够。 直到最近一年半,随着Moderna将几种候选药物投入到临床试验中,它才开始公开露面,并最终发表了一些有关其正在开发的技术细节的论文。随着这些试验的展开——目前有10项,未来还将展开另外11项——Moderna也扩大了它的基地。上周,该公司新开了一个占地20万平方英尺、耗资1.1亿美元的制造工厂,该工厂将为其试验和临床前研究团队提供所需的所有mRNA,至少目前是这样。 Moderna的首席执行官、新网站负责人斯蒂芬·哈宾(Stephen Harbin)坦言,公司距离生产商业化产品还有数年时间。 新制造工厂 本月早些时候,当英格兰队仍有机会问鼎世界杯的时候,这个穿着牛仔靴的英国人给《连线》展示了Moderna的新基地。哈宾解释了穿制服、戴着手套、戴着发网的科学家们会如何穿过这座大楼的五个有荧光照明的临床洁净室。在新基地7月17日启用时,他们在打造Moderna的第一批正式的GMP(药品生产质量管理规范)mRNA。 在第一个房间里,大型的不锈钢机器将一组被称为核苷酸的基因构建块的数字序列转化成环状的DNA质粒。在第二个房间里,酶将该DNA转化成mRNA链。在第三个房间里,mRNA?被涂上脂质纳米颗粒,以借此进入细胞。 最后也是最重要的一个房间位于建筑的中央,处于封闭的无菌区内。要到达那里,员工们必须穿上双层的工作服和手套,慢慢移动,这样就不会激起任何可能从空气过滤器上滑下来的微生物。在这里防止污染是至关重要的。mRNA在这里被储存到小瓶中,然后随小瓶被带到最终的目的地。 在临床洁净室后面,在哈宾说外人不得进入的一处区域里,工人们仍然在修整Moderna的“舞厅”。该公司计划今年晚些时候在那里安装一些冰箱大小的定制机器人,用于生产个性化的癌症疫苗。除了Moderna为治疗传染病、心血管疾病和罕见疾病而成立的项目以外,也许没有什么比设计一次性抗癌药物更能引起人们的关注了。十年前,成本问题让这一切不可想象;据Moderna总裁史蒂芬·霍格(Steven Hoge)称,在人工劳动方面,为一个病人生产一种药物的成本与为100万名病人生产一种药物的成本是一样的。但是自动化技术和先进的测序技术正在改变这一点。 “我们将能够生产出以很不同的方式治疗不同人身上的疾病的药物,等于把人类这一因素从这一过程中剔除。”霍格今年早些时候在接受《连线》采访时表示,“不是说‘哦,这是适合你的颜色’,而是‘不,我们为你发明了这种颜色。’” 个性化治疗 与其他尝试这种做法的公司一样,Moderna也开始利用癌症患者的两个基因特征进行个性化治疗。一个来自肿瘤组织的小颗粒,一个来自他们的小瓶血液。通过比较二者,算法会查找出导致癌症的突变。另一个算法根据那些突变生成一份包含20种蛋白质靶点的清单,它预测这些蛋白质靶点将教导病人的免疫系统来攻击肿瘤。不过,另一个算法会设计核苷酸链,然后Moderna独特的自动化机器将其整合到mRNA药物。人类工作者负责在工作站监视整个过程,并进行质量控制检查,但是大体上机器承担大部分的工作。 去年秋天,Moderna与默克公司(Merck)合作,开始了实体肿瘤的临床试验;第一个病人在感恩节前接受了个体化治疗。那些疫苗正在与默克公司的免疫治疗药物Keytruda联合进行测试,该药物用于削弱癌症避开免疫系统的能力。 这是一种合作策略,至少Moderna的一些竞争对手也在采用这种策略,大家都希望能率先将产品推出市场。总部位于德国的BioNTech公司已经开始携手它的合作伙伴Genentech,共同展开在患有多种肿瘤的患者身上进行个体化癌症疫苗治疗的第二阶段试验。早在2011年,该公司就获得了首个GMP?授权。同样位于德国的CureVac公司在2006年建立了全球首家针对mRNA的GMP生产工厂。目前,该公司正在建设第三家和第四家工厂,到2020年,它的产能将增加30倍。它有三个抗癌疫苗项目目前正在临床试验当中。 会被Crispr技术淘汰? 一些行业分析人士说,基于mRNA的癌症疫苗缺乏进展,应当引起投资者的担忧。德国的生物技术顾问德克·豪塞克(Dirk Haussecker)已经将注意力转向了诸如Crispr基因编辑的新技术,他认为这种技术将会淘汰包括个体化癌症治疗在内的大多数mRNA应用。 密歇根大学RNA生物医学中心主任尼尔斯·沃尔特(Nils Walter)则没那么悲观。他认为,基于RNA的疗法的推行时机终于成熟了,Moderna、CureVac和BioNTech等公司可能将走在最前面。但他警告说,关于这些潜在疗法的生物学原理,还有很多东西有待研究。“如果你想越过疫苗,你必须开始担心那个mRNA在做什么,因为它可以逃到身体的其他部位。”他说,“例如,你给肌肉注射,它却神奇地出现在血液里。” 但他表示,梅丽莎·摩尔的加入毫无疑问将有助于Moderna解决这些问题。她之前供职于马萨诸塞大学医学院RNA治疗研究所,备受尊崇。沃尔特说,借助摩尔的科学才干,也许他们就能发现潜在的瓶颈,坦率地对待它们,并快速地克服它们。毕竟,她已经开发了许多被该领域广泛使用的RNA技术。在与Moderna的流程创新团队的一次会议上,摩尔意识到,他们使用的是她30年前还是博士后的时候发明的一种技术。她后来找出了当年的老旧的实验室笔记本给他们看。 随着Moderna步入新的篇章,她或许还能帮助他们撕掉神秘的标签。摩尔说,她的团队即将发表一篇论文,证明他们能够通过设计关闭mRNA,使得它们只能在Moderna所希望的细胞中表达蛋白质,比如癌细胞。他们也已经准备展开更多的研究来设计得mRNA能够在人体内存在更长的时间,这对于治疗需要终生服用药物的遗传性疾病将有重大的意义。相关论证也将会公开发表。详情>>

2018-07-26 00:00:00


一种非常复杂的治疗一些乳腺癌和卵巢癌的方法就是使用一类叫做PARP抑制剂的药物。PARP抑制剂旨在利用让发生某些突变的肿瘤特别致命的缺陷。然而,这种靶向癌症治疗方法有时会失败,科学家们迫切地想要知道其中的原因。 如今,在一项新的研究中,美国洛克菲勒大学的Titia de Lange教授及其团队对这种耐药性机制提供了新的认识,并且为抵抗这种耐药性提供了新的希望。他们发现了由基因BRCA1发生的错误引发的一些癌症逃避旨在杀死它们的定制药物的分子机制。这一发现也挑战了之前针对这些PARP抑制剂成功地或未能给患者带来益处的机制作出的猜测。相关研究结果于2018年7月18日在线发表在Nature期刊上,论文标题为“53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in”。 图片来自Laboratory of Cell Biology and Genetics at The Rockefeller University。 他们的发现有助于解释为什么某些癌症会对PARP抑制剂作出反应,而其他癌症却没有---这种认识最终可能有助于改善对患者的治疗。 缺陷和机会 专家们预测今年将有大约288000例乳腺癌和卵巢癌新确诊病例。这些癌症的很大一部分是由人类基因组中的两个最臭名昭着的基因--- BRCA1和BRCA2---发生的有害错误引起的。 据估计,作为这项新研究主题的BRCA1突变会导致女性到80岁时患上乳腺癌的几率大约为72%,患上卵巢癌的几率为44%。 这两个基因都是肿瘤抑制基因,这意味着它们在正常情形下有助于保持身体无癌症。它们编码的蛋白在正确地修复沿着DNA分子的长度在某处发生的切割---一种被称作双链断裂(double-strand break, DSB)的事件---中起着重要的作用,这是因为它起着切断DNA螺旋的两条链的作用。在缺乏BRCA基因的情形下,断裂的DNA不能被正确地修复,从而产生能够导致癌症的突变。 近年来,开发被称作PARP抑制剂的新药使得阻止这些遗传缺陷转化为癌症成为可能。这些药物促使双链断裂形成;缺乏BRCA的肿瘤细胞因无法正确地修复这些断裂而死亡。 然而,一些本应对PARP抑制剂敏感的肿瘤却没有作出反应。科学家们认为这种失败的原因有很多,而de Lange团队特别关注与BRCA1癌症耐药性相关的罪魁祸首。 近十年来,科学家们已知道一种被称作53BP1的蛋白的缺失使得缺乏BRCA1的细胞有可能克服它们的内在缺陷并正确地修复双链断裂。在PARP抑制剂治疗期间或之后,一些肿瘤细胞在在发生导致53BP1丢失的突变后茁壮生长,这就能够导致这种耐药性产生。不过,人们仍不清除为何丢失这种蛋白会这些癌细胞带来如此致命的优势。 一种不同的机制 为了准备修复发生断裂的DNA分子,首先需要切断双螺旋DNA的一条链。人们之前猜测53BP1会阻止这种切断。按照这种思维,一旦53BP1丢失,那么缺乏BRCA1的细胞就会突然获得修复DNA断裂的能力。 在实验中,de Lange团队证实53BP1发挥着不同的作用。这些研究人员发现53BP1反而有助于通过重写从这些松散的DNA链中切下的DNA片段来抵消这种切断过程。 在经过PARP抑制剂治疗的BRCA1缺陷癌症中,53BP1的这种重写功能导致错误的DNA修复和癌细胞死亡。然而,其中的一些癌细胞因失去53BP1而成功地逃避治疗。de Lange团队的这项研究解释了仅这种变化如何让它们存活下去。 de Lange实验室研究生Zachary Mirman说,“总体而言,这种对53BP1功能及其在耐药性中的作用的新认识为改进PARP抑制剂治疗奠定了基础。”这些研究人员说,这些改进可能包括开展筛查测试以便确定哪种肿瘤对PARP抑制剂作出产生最好的反应,或确定哪些其他的药物应该或不应该与PARP抑制剂一起联合使用。 参考资料: Zachary Mirman, Francisca Lottersberger, Hiroyuki Takai et al. 53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in. Nature, Published online: 18 July 2018, doi:10.1038/s41586-018-0324-7.详情>>

2018-07-20 00:00:00


浙江大学转化医学院的一间实验室里,科学家用近红外激光照射乳腺癌小鼠。3分钟后,等候在肿瘤部位的“药匣子”打开,抗肿瘤药物快速均匀地渗透到肿瘤深层组织。4小时后,肿瘤细胞陆续凋亡。 这是浙江大学医学院附属第二医院、转化医学研究院的周民团队构建出的一种“抗癌纳米材料多级载药系统”,可令肿瘤药物向肿瘤组织深层递送,明显抑制恶性肿瘤的转移。该研究成果日前发表在国际知名学术期刊《先进功能材料》杂志上。 研究人员表示,当前一些被证明对肿瘤确有效果的药物在临床使用上有较大局限,比如药物总是“跑太快”“跑不远”。“一般情况下,不到24小时,药物就会被代谢出体外,药效发挥的时间很短,真正跑到肿瘤里去的药物很少,所以需要持续用药。”周民介绍,团队最新设计的多级载药系统,让抗癌药物降低代谢速度,并能渗透到常规抗癌药进入不了的肿瘤深层组织。 肿瘤细胞周围分布着丰富的血管,但血管生长往往跟不上肿瘤细胞分裂的速度,导致肿瘤细胞深层没有血管分布。传统的抗癌药物分子要通过血管才能到达肿瘤细胞,没有血管,意味着药物也到达不了。这是当前肿瘤药物研发的重大挑战之一。 周民团队对一种广谱型抗癌药阿霉素进行了改造,让多个阿霉素小分子形成一个聚合球。通过这个设计,药物的“个头”变大了,一定程度延长了药物在机体内停留的时间。 此外,药物递送系统被设计成一个光控的“药匣子”,只有在特定波长的光的激发下,搭载在聚合球上的抗癌分子才会释放扩散。实验中,课题组选用了800纳米波长的近红外光,这种光线最多能穿透5厘米左右的生物组织。在光照下,纳米球“解体”为超小尺寸的纳米点和抗癌分子,在肿瘤组织内部快速渗透。 进一步实验表明,该多级载药系统不但可以高效地摧毁肿瘤细胞,同时还可以显着抑制肿瘤干细胞的生长,抑制肿瘤转移的发生。由于具有较好的肿瘤集聚能力,该系统可以显着降低抗肿瘤药物的心脏和系统毒性,具有较高的临床转化前景。但该治疗方法想要应用于临床,仍需要大量的试验。详情>>

2018-07-16 00:00:00


Heart failure is known to be more common in certain families, but whether this familial transition is caused by genetic or lifestyle factors is not understood. By studying adoptees in relation to both their biological parents and adoptive parents, a new population study in Sweden has found that genetic heritage is the dominant factor when it comes to heart failure in these families. "The results of our study do not mean that a person's lifestyle is insignificant to their risk of heart failure, but they indicate that hereditary factors are behind 26 percent of all cases of heart failure in Sweden," explains Magnus Lindgren, specialist in family medicine and doctoral student at Lund University, who led the study. Magnus Lindgren and his research colleagues studied Swedish-born adoptees, whom they linked to both their biological parents and their adoptive parents through the Swedish multigenerational register. A total of 21,643 adoptees, all born between 1942 and 1990, were tracked, along with their parents, between 1964 and 2015 with regard to the incidence of heart failure as recorded in hospital registers in the Swedish National Patient Register. The study found the risk of heart failure in adoptees who had at least one biological parent with heart failure to be 45 percent higher than in a control group with no biological parent suffering from heart failure. On the other hand, there was no increased risk in individuals with adoptive parents with heart failure, compared with the equivalent control group. "The study's design enabled us to look at the overall effect of hereditary factors for heart failure. Heart failure often depends on a combination of several risk factors, whose collective effects are otherwise difficult to study," said Magnus Lindgren. "By mapping the underlying genetic factors for heart failure, we hope our results will contribute to the development of better diagnostics and new therapies." "The occurrence of heart failure in a biological parent is a risk factor for heart failure, and physicians should, where applicable, ask patients about heredity. It is important information when deciding whether further investigation is needed," concludes Magnus Lindgren.详情>>

2018-07-16 00:00:00


Abstract Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types1,2,3,4. Patients and tumours may respond unpredictably to immunotherapy partly owing to heterogeneity of the immune composition and phenotypic profiles of tumour-infiltrating lymphocytes (TILs) within individual tumours and between patients5,6. Although there is evidence that tumour-mutation-derived neoantigen-specific T cells play a role in tumour control2,4,7,8,9,10, in most cases the antigen specificities of phenotypically diverse tumour-infiltrating T cells are largely unknown. Here we show that human lung and colorectal cancer CD8+ TILs can not only be specific for tumour antigens (for example, neoantigens), but also recognize a wide range of epitopes unrelated to cancer (such as those from Epstein–Barr virus, human cytomegalovirus or influenza virus). We found that these bystander CD8+ TILs have diverse phenotypes that overlap with tumour-specific cells, but lack CD39 expression. In colorectal and lung tumours, the absence of CD39 in CD8+ TILs defines populations that lack hallmarks of chronic antigen stimulation at the tumour site, supporting their classification as bystanders. Expression of CD39 varied markedly between patients, with some patients having predominantly CD39− CD8+ TILs. Furthermore, frequencies of CD39 expression among CD8+ TILs correlated with several important clinical parameters, such as the mutation status of lung tumour epidermal growth factor receptors. Our results demonstrate that not all tumour-infiltrating T cells are specific for tumour antigens, and suggest that measuring CD39 expression could be a straightforward way to quantify or isolate bystander T cells.展开>><<收起



Objectives Reports of the prognostic significance of ALK-rearrangement in resected non-small cell lung cancer (NSCLC) have been contradictory. We aimed to determine the prognosis of early-stage ALK-positive lung cancers relative to KRAS- and EGFR-mutant lung cancers. Material and methods We reviewed medical records of patients with resected NSCLC harboring an ALK rearrangement (n = 29) or a driver mutation in EGFR (n = 255) or KRAS (n = 480). Recurrence-free survival (RFS) was estimated for each genotype with the differences reported as a hazard ratio (HR). Results Among the 764 patients, 555 (73%), 101 (13%), and 108 (14%) had stage I, II, and III NSCLC, respectively. ALK-positive patients were distributed across all stages: 10 (34%) stage I, 6 (21%) stage II, and 13 (45%) stage III. Median RFS was not reached for EGFR-mutant patients, 24.3 months (95%CI 11.4–65.3) for ALK-positive patients, and 72.9 months (95%CI 59.7 to undefined) for KRAS-mutant patients. When adjusted for stage, ALK-positive NSCLC remained associated with worse RFS compared to EGFR-mutant (HR 1.8, 95%CI: 1.1-3.1), but not when compared to KRAS-mutant (HR 1.3, 95%CI: 0.8-2.1) NSCLC. Conclusions In this large series of resected NSCLC, ALK rearrangements were associated with a trend toward inferior disease outcomes compared to other clinically relevant genomic subsets. These data support the need for clinical trials evaluating use of ALK inhibitors among ALK-positive patients with localized or locally-advanced disease.展开>><<收起