基因组学技术推动中医药精准医学研究现状分析与展望

中医药具有精准医学的核心"个体化诊断和治疗"要素。基因组学技术在中医药基于体质的精准预防、个体化诊断与药物、针灸治疗、药物复杂性、包括中医药干预人体微生物环境等方面已经有较多应用。这与精准医学通过分析人群基因信息、生活方式、环境因素等了解疾病发生发展机制、针对相关靶点开发药物的方法及目标相匹配。未来将在整合各组学技术、结合中医药自身特色等方面应用于中医药精准医学研究,为实现中医药现代化及精准治疗的目标提供助力。     

本体:生物医学大数据与精准医学研究的基础

在最近兴起的生物医学大数据和精准医学研究中,本体正发挥着不可替代的作用。但一大部分人对本体的定义、类型与应用比较混淆。这篇综述对这些问题进行了回答。具体而言,本体使用人和计算机都可以理解的术语及关系集来表述各种实体/概念以及它们之间关系。根据本体的作用,本体可分为三类:具有多关系模型的增强版控制术语集,反映某知识域的本体知识系统,和对元数据在语义上的约束与标准化的元数据本体。基于这些作用,本体被广泛地应用于生物医学数据的标准化、整合、检索与分析,已经知识的挖掘。当代本体学的研究发展迅速,我国刚刚起步,机遇与挑战并存。广泛地开展国内与国际有关本体的合作研究,将促进国内生物医学本体领域研究水平的整体提升,提高生物与临床科研大数据整合与精准医学研究的能力。     

精准医学与微生物感染——实施精准感染病学的探讨

2015年3月,习近平主席亲自指示科技部召开了国家首次精准医学战略专家座谈会。鉴于我国在病原微生物学、免疫学、疫苗学及感染病学中的成就,本文从病因和机体免疫应答方面分析了我国开展精准感染病学的优势并提出主要切入点。通过对免疫基因组学的研究,结合环境因素及生活习惯的综合研究,将对控制感染性疾病作出创新性贡献,这具有全球性的重要价值。     

精准医学基础研究与临床实践的回顾与展望

精准医学是健康卫生和医学科学的发展方向,是发展了一个多世纪的现代医学实践的升级版。本文研究了医学科研和医疗实践的发展趋势,从分子遗传、环境变迁及医疗信息管理等领域,分析和总结了影响精准医学发展的一些因素,提出了精准医学基础研究和临床实践的一些新思路,希望对精准医学的发展、医学科研实践及医疗卫生政策的制定产生积极的影响。     

转化医学研究与循证决策

<正>20世纪90年代,国际上开始注重转化医学的理念,其典型含义是将基础研究的成果转化为有效的临床治疗手段,强调从实验室到病床旁的连接,通常称之为"从实验台到病床旁".随着转化医学在医学研究中的重要性不断提升,其定义和内涵也在不断变化和丰富.有学者指出,转化医学的概念还有新的内涵,即"将研究结果、结论应用到日常健康保健工     

肿瘤异质性：精准医学需破解的难题

肿瘤异质性是恶性肿瘤的重要特征,表现为同一种恶性肿瘤不同患者个体之间或者同一患者体内不同部位肿瘤细胞间从基因型到表型上存在的差异.这种差异可表现为不同的遗传背景、不同的病理类型、不同的分化状态、不同的基因突变谱和转录组、蛋白质组表达谱等,体现了恶性肿瘤在演进过程中的高度复杂性和多样性.肿瘤异质性给肿瘤的治疗带来极大的困难,一直是肿瘤发生发展机制研究领域重要的科学问题.本文综述了肿瘤异质性的生物学特征及其可能的形成机制,并对"精准医学"时代如何针对肿瘤异质性设计更为有效的个性化治疗方案进行了思考.     

肿瘤精准医学知识数据库的设计与构建

目的:整合现有前沿的大量而分散的精准医学知识以形成系统完整的知识数据库,为个体组学数据的临床应用提供依据,旨在最终实现基于组学特征的精准用药推荐。方法:采用MySQL数据库管理系统构建数据库,从FDA伴随诊断、NCCN指南、My Cancer Genome、GDSC四大权威医学资源中手动收集精准用药知识,并将原始数据标准化、结构化后以统一的格式存储。结果:成功设计并构建了肿瘤精准医学知识库,目前共收录1 940条精准用药指导,涵盖了基因突变等14种不同类型的组学特征。结论:精准医学知识数据库收录了肿瘤分子组学特征和治疗策略的关联信息,可为临床上个体化治疗方案的制订提供参考依据。数据库的建立为精准医疗临床决策支持系统的开发奠定了基础。     

前病毒插入诱变与白血病发生的研究进展

慢性白血病病毒包括禽白血病增生症病毒、猫白血病病毒、牛白血病病毒、长臂猿白血病病毒和小鼠白血病病毒等,它们的基因组结构完整,具有病毒复制能力,但是序列内不含有癌基因,这是此类病毒的共同特点,其中以小鼠白血病病毒最具代表性。小鼠白血病病毒感染动物后可产生不同类型白血病,潜伏期较长（3－4个月）。小鼠白血病病毒诱发白血病机制较复杂,是一个由多因子参加、多阶段发展的过程。本文就小鼠白血病病毒前病毒插入诱发的淋巴细胞白血病和粒细胞白血病中,原癌基因激活及其作用机制进行综述。     

应用细菌内同源重组机制快速克隆腺病毒基因组的研究

A novel procedure was used for cloning large adenovirus genome fragment by the homologous recombination in E.coli strain BJ5183. The 11.2Kb downstream fragment of the CAV-2 strain YCA18 genome was cloned by homologous recombination, the 1029bp left end and the 970bp fight end of this fragment were separately amplified by PCR. They were then cloned into plasmid pPoly2 with direction from left fragment to fight fragment, obtaining a “rescue” plasmid pT615. The pT615 was liberalized by Hind Ⅲ and PstⅠ digestion and was cotransformed with the purified CAV-2 genome which was cut by BstBI into competent E.coli strain BJ5183. Recombinant plasmids harboring the 11.2Kb downstream fragment of CAV-2 genome were obtained after bacterial intermolecular homologous recombination. The recombinant efficiency of all E.coli strains tested was 78.3%. One of the recombinant plasmids, pT618, was further identified by enzyme digestion analysis and PCR amplification. The results showed the plasmids contained the 11.2kb fragment downstream the genome of CAV-2.     

Challenges in implementing individualized medicine illustrated by antimetabolite therapy of childhood acute lymphoblastic leukemia

Predicting the response to medical therapy and subsequently individualizing the treatment to increase efficacy or reduce toxicity has been a longstanding clinical goal. Not least within oncology, where many patients fail to be cured, and others are treated to or beyond the limit of acceptable toxicity, an individualized therapeutic approach is indicated. The mapping of the human genome and technological developments in DNA sequencing, gene expression profiling, and proteomics have raised the expectations for implementing genotype-phenotype data into the clinical decision process, but also multiplied the complex interaction of genetic and other laboratory parameters that can be used for therapy adjustments. Thus, with the advances in the laboratory techniques, post laboratory issues have become major obstacles for treatment individualization. Many of these challenges have been illustrated by studies involving childhood acute lymphoblastic leukemia (ALL), where each patient may receive up to 13 different anticancer agents over a period of 2-3 years. The challenges include i) addressing important, but low-frequency outcomes, ii) difficulties in interpreting the impact of single drug or single gene response data that often vary across treatment protocols, iii) combining disease and host genomics with outcome variations, and iv) physicians' reluctance in implementing potentially useful genotype and phenotype data into clinical practice, since unjustified downward or upward dose adjustments could increase the of risk of relapse or life-threatening complications. In this review we use childhood ALL therapy as a model and discuss these issues, and how they may be addressed.     

Prospects for translational regenerative medicine

Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea "from bench to bedside and back", and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit.     

Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia

Accumulating evidence support the notion that acute myeloid leukemia(AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells(LSC). Similar to their normal counterpart, hematopoietic stem cells(HSC), LSC possess selfrenewal capacity and are responsible for the continued growth and proliferation of the bulk of leukemia cells in the blood and bone marrow. It is believed that LSC are also the root cause for the treatment failure and relapse of AML because LSC are often resistant to chemotherapy. In the past decade, we have made significant advancement in identification and understanding the molecular biology of LSC, but it remains a daunting task to specifically targeting LSC, while sparing normalHSC. In this review, we will first provide a historical overview of the discovery of LSC, followed by a summary of identification and separation of LSC by either cell surface markers or functional assays. Next, the review will focus on the current, various strategies for eradicating LSC. Finally, we will highlight future directions and challenges ahead of our ultimate goal for the cure of AML by targeting LSC.     

Targeting leukemia stem cells: The new goal of therapy in adult acute myeloid leukemia

The most popular view of hematopoietic cell lineage organization is that of complex reactive or adaptative systems. Leukemia contains a subpopulation of cells that display characteristics of stem cells. These cells maintain tumor growth. The properties of leukemia stem cells indicate that current conventional chemotherapy, directed against the bulk of the tumor, will not be effective. Leukemia stem cells are quiescent and do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and thus contribute to treatment failure. New strategies are required that specifically target this malignant stem cell population.     

The combination of DNA methyltransferase inhibitor therapy and immunotherapy for acute myeloid leukemia

Acute myeloid leukemia (AML), the most common form of acute leukemia in adults, is characterized by abnormal proliferation and blocked maturation and differentiation of myeloid precursor cells. AML is an aggressive cancer that progresses rapidly without treatment. Therefore, effective treatment modalities should be implemented immediately after diagnosis. The mainstay of classical AML therapy has been chemotherapy, which is not suitable for relapsing or refractory patients, especially elderly patients. Among emerging novel therapeutic approaches for AML, epigenetic therapy and immunotherapy represent two exciting therapeutic developments. This review focuses on discussion of the therapeutic considerations for AML from the perspective of combination treatment, which incorporates both DNA methyltransferase inhibitor therapy, as one of the most promising epigenetic therapies, and immune checkpoint inhibitor or dendritic cell-based vaccination treatments, as examples of immunotherapy. Both challenges and rationale in the optimization of therapeutic approaches, as well as recent clinical trial developments, along this line are summarized.     

精准医疗与结核病

精准医疗概念的提出开启了一个医学新时代,且在世界范围内引起了一场科技竞争。精准医疗的实质包括精准诊断和精准治疗,其具体内容,结合各国实际情况各不相同。对中国而言,慢性传染病特别是结核病造成了严重疾病负担,应作为重点研究对象,实际上该领域中各种形式的精准医疗已然展开。精准医疗作为一种新的理念,贯穿于结核病的研究和治疗中,势必对人类结束结核病的肆虐和消除结核病作出重大贡献。     

Methylenetetrahydrofolate reductase gene polymorphisms contribute to acute myeloid leukemia and chronic myeloid leukemia susceptibilities: Evidence from meta-analyses

PurposeThe expression of methylenetetrahydrofolate reductase (MTHFR) is associated with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Most studies have linked the common functional C677T and A1298C polymorphisms of the MTHFR gene and susceptibility to AML and CML, but the results were not consistent. The aim of the present study was to derive a more precise estimation of the relationship.MethodsMeta-analyses assessing the association of MTHFR C677T and A1298C variations with AML and CML were conducted. Eligible articles were identified from the PubMed and EMBASE databases. All statistical analyses were conducted using Review Manager Software.Results10 and 10 studies were included in the meta-analysis about the role of C677T polymorphism on the AML and CML risks, respectively; 6 and 4 studies were included about the role of A1298C polymorphism on the AML and CML risks, respectively. Overall, both the C677T and A1298C polymorphisms were significantly associated with CML risk under the recessive model (P = 0.04, OR = 1.35, 95% CI = 1.02–1.79 for C677T and P = 0.003, OR = 2.17, 95% CI = 1.29–3.63 for A1298C). In addition, the risk of CML was higher in 1298CC genotype carriers than in 1298AA genotype carriers (P = 0.004, OR = 2.17, 95% = 1.28–3.69). Conversely, the overall data failed to indicate a significant association of C677T or A1298C polymorphisms with AML risk under any model.ConclusionsThe findings provide evidence that C677T and A1298C polymorphisms are risk factors for CML risk.     

Over-expression of FoxM1 is associated with adverse prognosis and FLT3-ITD in acute myeloid leukemia

Forkhead box M1 (FoxM1) drives cell cycle progression and the prevention of growth arrest and is over-expressed in many human malignancies. However, the characteristics of FoxM1 in acute myeloid leukemia (AML) are not clearly understood. We investigated the expression level of FoxM1 and analyzed the correlation of FoxM1 expression with AML patient characteristics and prognoses. Changes in FoxM1 expression were detected after MV4–11 cells, which have an internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 gene (FLT3-ITD), and control THP1 cells (encoding wild-type FLT3) were treated with the FLT3 receptor tyrosine kinase inhibitor AC220 (quizartinib) or FLT3 ligand (FL). Finally, we determined the apoptosis rates after the addition of the FoxM1 inhibitor thiostrepton (TST) to AML cells with or without FLT3-ITD. The expression of FoxM1 in AML patients was correlated with the presence of FLT3-ITD, genetic groups, and possibly overall survival. Inhibition of FLT3-ITD by AC220 down-regulated FoxM1 expression in MV4–11 cells, and stimulation of FLT3 by FL up-regulated FoxM1 expression in MV4–11 and THP1 cells. TST induced the apoptosis of MV4–11 and THP1 cells in a dose-dependent manner. Thus, FoxM1 is a potential prognostic marker and a promising therapeutic target in AML.