Gene mutation‐based and specific therapies in precision medicine

Precision medicine has been initiated and gains more and more attention from preclinical and clinical scientists. A number of key elements or critical parts in precision medicine have been described and emphasized to establish a systems understanding of precision medicine. The principle of precision medicine is to treat patients on the basis of genetic alterations after gene mutations are identified, although questions and challenges still remain before clinical application. Therapeutic strategies of precision medicine should be considered according to gene mutation, after biological and functional mechanisms of mutated gene expression or epigenetics, or the correspondent protein, are clearly validated. It is time to explore and develop a strategy to target and correct mutated genes by direct elimination, restoration, correction or repair of mutated sequences/genes. Nevertheless, there are still numerous challenges to integrating widespread genomic testing into individual cancer therapies and into decision making for one or another treatment. There are wide‐ranging and complex issues to be solved before precision medicine becomes clinical reality. Thus, the precision medicine can be considered as an extension and part of clinical and translational medicine, a new alternative of clinical therapies and strategies, and have an important impact on disease cures and patient prognoses.     

Abandoning personalization to get to precision in the pharmacotherapy of depression

Effectiveness studies and analyses of naturalistic cohorts demonstrate that many patients with major depressive disorder do not experience symptomatic remission with antidepressant treatments. In an effort to better match patients with effective treatments, numerous investigations of predictors or moderators of treatment response have been reported over the past five decades, including clinical features as well as biological measures. However, none of these have entered routine clinical practice; instead, clinicians typically personalize treatment on the basis of patient preferences as well as their own. Here, we review the reasons why it has been challenging to identify and deploy treatment‐specific predictors of response, and suggest strategies that may be required to achieve true precision in the pharmacotherapy of depression. We emphasize the need for changes in how depression care is delivered, measured, and used to inform future practice.     

解决法医学问题的新工具：微生物群落

生物痕迹往往成为刑事侦查案件中的突破口,比如在涉及个人识别、嫌疑人追踪或者死亡时间(postmortem interval,PMI)等法医学问题上,生物源性证据往往发挥着至关重要的作用。目前,许多传统的法医学方法仍在沿用,但研究者们试图发现新的法医学工具,以此来弥补传统方法的不足或者为法医学实践增加新的思路和方法。得益于测序技术的发展,研究者们发现机体内外的微生物数量要远远超过细胞的数量,它们在地点溯源、个人识别、死亡时间的推断、生物犯罪及环境保护等方面均有着不小的应用价值。本文对这方面的研究进展进行了介绍。     

Designing precision medicine trials to yield a greater population impact

Traditionally, a clinical trial is conducted comparing treatment to standard care for all patients. However, it could be inefficient given patients’ heterogeneous responses to treatments, and rapid advances in the molecular understanding of diseases have made biomarker-based clinical trials increasingly popular. We propose a new targeted clinical trial design, termed as Max-Impact design, which selects the appropriate subpopulation for a clinical trial and aims to optimize population impact once the trial is completed. The proposed design not only gains insights on the patients who would be included in the trial but also considers the benefit to the excluded patients. We develop novel algorithms to construct enrollment rules for optimizing population impact, which are fairly general and can be applied to various types of outcomes. Simulation studies and a data example from the SWOG Cancer Research Network demonstrate the competitive performance of our proposed method compared to traditional untargeted and targeted designs.     

Navigating conflicts of justice in the use of race and ethnicity in precision medicine

Given the sordid history of injustices linking genetics to race and ethnicity, considerations of justice are central to ensuring the responsible development of precision medicine programmes around the world. While considerations of justice may be in tension with other areas of concern, such as scientific value or privacy, there are also tensions between different aspects of justice. This paper focuses on three particular aspects of justice relevant to this precision medicine: social justice, distributive justice and human rights. We describe the implications of each for the use of race and ethnicity in precision medicine, and also how they intersect and potentially conflict with each another. By attending to these intersections, we aim to enrich and add nuance to debates over how best to proceed with precision medicine initiatives.     

Clinical proteomics-driven precision medicine for targeted cancer therapy: current overview and future perspectives

Cancer is a common disease that is a leading cause of death worldwide. Currently, early detection and novel therapeutic strategies are urgently needed for more effective management of cancer. Importantly, protein profiling using clinical proteomic strategies, with spectacular sensitivity and precision, offer excellent promise for the identification of potential biomarkers that would direct the development of targeted therapeutic anticancer drugs for precision medicine. In particular, clinical sample sources, including tumor tissues and body fluids (blood, feces, urine and saliva), have been widely investigated using modern high-throughput mass spectrometry-based proteomic approaches combined with bioinformatic analysis, to pursue the possibilities of precision medicine for targeted cancer therapy. Discussed in this review are the current advantages and limitations of clinical proteomics, the available strategies of clinical proteomics for the management of precision medicine, as well as the challenges and future perspectives of clinical proteomics-driven precision medicine for targeted cancer therapy.     

Whole genomes: the foundation of new biology and medicine

Our genomic DNA sequence provides a unique glimpse of the provenance and evolution of our species, the migration of peoples, and the causation of disease. Understanding the genome may help resolve previously unanswerable questions, including perhaps which human characteristics are innate or acquired. Such an understanding will make it possible to study how genomic DNA sequence varies among populations and among individuals, including the role of such variation in the pathogenesis of important illnesses and responses to pharmaceuticals. The study of the genome and the associated proteomics of free-living organisms will eventually make it possible to localize and annotate every human gene, as well as the regulatory elements that control the timing, organ-site specificity, extent of gene expression, protein levels, and post-translational modifications. For any given physiological process, we will have a new paradigm for addressing its evolution, development, function, and mechanism.     

急性缺血性卒中患者肠道菌群与中医证候类型的关系初探

观察缺血性卒中后不同中医证候类型患者肠道菌群的组成与结构,寻找不同证候类型与肠道菌群之间的关系,并初步探索各中医证候类型可能存在的特征菌属。

本研究共纳入首发急性缺血性卒中患者17名,并基于缺血性中风证候要素诊断量表与中风病中医诊断标准对患者进行中医证候类型分类,依次分为痰热腑实风痰上扰组、风痰瘀血痹阻脉络组、肝阳暴亢风火上扰组、气虚血瘀组、阴虚风动组。同时选择同期的健康体检者5名作为对照组。分别记录研究对象基本信息,采集粪便样本运用16S rRNA基因高通量测序技术对患者粪便样本中肠道菌群进行OTUs（operational taxonomic units）聚类,并根据结果进行多样性分析和差异性分析。

急性缺血性卒中不同中医证候类型患者与健康体检者在年龄和BMI上差异均无统计学意义（均P＞0.05）。各组对象肠道菌群Chao指数和Shannon指数差异均无统计学意义（均P＞0.05）。痰热腑实风痰上扰组患者独有菌属高达133种;对照组次之,达127种;而阴虚风动组、风痰瘀血痹阻脉络组、肝阳暴亢风火上扰组、气虚血瘀组的独有菌属数量依次为94种、32种、18种、8种。痰热腑实风痰上扰组患者的特征菌属为Anaerotruncus,气虚血瘀组的特征菌属为Megasphaera（巨球菌属）,阴虚风动组的特征菌属为Pyramidobacter。

本研究初步显示不同中医证候类型的急性缺血性卒中患者与健康人群有着不同的肠道菌群构成,各证型患者肠道菌群丰度与多样性无显著差异。急性缺血性卒中患者中医证候类型与肠道菌群的组成存在相关性,其中痰热腑实风痰上扰证患者与其他各证患者之间菌群组成差异最大,其特征菌属为Anaerotruncus。

     

古代病原微生物基因组的研究进展

古代病原微生物基因组研究对病理学、微生物学、考古学等领域均具有重要的价值。在过去的十年里,高通量测序和靶向富集技术的发展和应用使古代微生物基因组的获取成为可能,通过对古代人群样本中获取的宏基因组进行筛查,使得引发古代疫情的相关病原体的基因组得以重建,为研究人类传染病的起源、传播和演化提供了一个独特的窗口。在当今全球化的背景下,新发及再发传染性疾病的出现频率促使我们回顾过去,以便更好地了解现代病原菌出现和古代病原菌重新出现的过程和生态环境。在这篇文章中,我们总结了近十年古代病原微生物基因组水平的研究进展,并提出了这项研究所面临的挑战以及未来的研究前景和方向。     

Toward next-generation sequencing of mitochondrial genomes — Focus on parasitic worms of animals and biotechnological implications

Helminths (worms) include parasitic nematodes (roundworms) and platyhelminths (flatworms). These worms are abundant, and many of them are of agricultural, aquacultural, veterinary and medical importance and cause substantial socioeconomic losses worldwide. The genetic characterization of parasitic nematodes using advanced molecular tools is central to the diagnosis of infections and the control of parasitism. The accurate analysis of genetic variation also underpins studies of their taxonomy, epidemiology and evolutionary history. Although the nuclear genome contains suitable genetic markers (e.g., in ribosomal DNA) for the identification of many species, the large size and high variability of the mt genome consistently provides a rich source of such markers for informative systematic and epidemiological studies both within and among species. There is significant value in establishing a practical platform for the rapid sequencing, annotation and analysis of mt genomic datasets to underpin such fundamental and applied studies of parasitic worms (= helminths). In the last decade, there have been some important advances in the mt genomics of helminths, but next-generation sequencing (NGS) technologies now provide opportunities for high throughput sequencing, assembly and annotation. In this article, we provide a background on mt genomics, cover technological challenges and recent advances, and provide a perspective on future mt genome research of parasitic helminths and its fundamental scientific and biotechnological implications.     

Sequencing and comparative analyses of Aegilops tauschii chromosome arm 3DS reveal rapid evolution of Triticeae genomes

Bread wheat (Triticum aestivum, AABBDD) is an allohexaploid species derived from two rounds of interspecific hybridizations. A high-quality genome sequence assembly of diploid Aegilops tauschii, the donor of the wheat D genome, will provide a useful platform to study polyploid wheat evolution. A combined approach of BAC pooling and next-generation sequencing technology was employed to sequence the minimum tiling path (MTP) of 3176 BAC clones from the short arm of Ae. tauschii chromosome 3 (At3DS). The final assembly of 135 super-scaffolds with an N50 of 4.2 Mb was used to build a 247-Mb pseudomolecule with a total of 2222 predicted protein-coding genes. Compared with the orthologous regions of rice, Brachypodium, and sorghum, At3DS contains 38.67% more genes. In comparison to At3DS, the short arm sequence of wheat chromosome 3B (Ta3BS) is 95-Mb large in size, which is primarily due to the expansion of the non-centromeric region, suggesting that transposable element (TE) bursts in Ta3B likely occurred there. Also, the size increase is accompanied by a proportional increase in gene number in Ta3BS. We found that in the sequence of short arm of wheat chromosome 3D (Ta3DS), there was only less than 0.27% gene loss compared to At3DS. Our study reveals divergent evolution of grass genomes and provides new insights into sequence changes in the polyploid wheat genome.     

Proteomics and personalized medicine: a focus on kidney disease

ABSTRACT

Introduction: Inter-individual variability in response to drug treatment has induced an increased demand for decisions via personalize medicine. Also, the contribution of proteomics to the era of personalized medicine would seem to be vital in improving therapeutic outcomes.

Areas covered: We review validated biomarkers discovered by proteomics techniques and their use in personalized medicine with the focus on kidney diseases. We discuss this topic with a special emphasis on recent publications and relevant initiatives and depict some limitations that remain for personalized medicine.

Expert opinion: The development of highly accurate biomarkers is essential for optimizing the management of kidney diseases. Various biomarkers of kidney diseases have been identified using proteomic techniques. However, only a few of these biomarkers showed the potential to be used in clinical practice concerning personalized medicine. Therefore, it becomes evident that the combination of multiple biomarkers confers higher accuracy and the ability to depict complex pathophysiological conditions, a prerequisite for personalized treatment. CKD273, a multimarker panel for early CKD detection may serve as a first example for personalized medicine in nephrology. Based on this successful example, proteomics is expected to develop into the key technology to guide personalized intervention.     

高通量测序技术及其在微生物学研究中的应用

20世纪70年代发明的核酸测序技术为基因组学及其相关学科的发展做出了巨大贡献,本世纪初发展的以Illumina公司的HiSeq 2000,ABI公司的SOLID,和Roche公司的454技术为代表的高通量测序技术又为基因组学的发展注入了新活力.本文在阐述这些技术的基础上,着重讨论了新一代测序技术在微生物领域中的应用.