建立生物标记物束

各组跟踪时间轨迹的生物标记物可以帮助破解疾病,需要多种途径来鉴定和验证新的标记物。     

多发性硬化生物标记物的研究进展

多发性硬化(MS)是主要以中枢神经系统(CNS)白质脱髓鞘病变为主要特点的自身免疫性疾病。生物标记物是中枢神经系统自身免疫性疾病病因、诊断和预后的重要参考因素,因为他们可能反映遗传以及环境变化所引起的某些免疫反应的存在,性质和强度。因此生物标记有助于MS的早期诊断和鉴别诊断,指导治疗方案,推断MS疾病活动性,以及判断疗效。本文概述了多发性硬化领域当前的生物标记物研究状况及其相关的临床实践,并通过对三种具有较大潜力的生物标记物与病理的特异性、灵敏度、可靠性和临床实用工具进行分析,以确定最优化的治疗以防止致残,同时还可以对疾病修饰药物的有效性进行测试。     

急性肺损伤的生物标记物

急性呼吸窘迫综合征(ARDS)和急性肺损伤(ALI)多由低氧性呼吸衰竭引起,导致高通透性肺水肿,临床上有较高的发病率与死亡率。近十年来,针对血浆和支气管肺泡灌洗液中相关生物标记物的研究为探索急性肺损伤的病理生理机制指明了新的方向。个别生物标记物已在一些大型、多中心ARDS试验中得到证实。但迄今仍没有一个或一组生物标记物常规应用于临床。随着人类对ALI发病机制理解的进一步深入,或许不久的将来,生物标记物会真正应用于评估疾病的严重程度和预后。本文将概述近年来ALI相关生物标记物的研究进展。     

心衰生物标记物研究新进展

心力衰竭(心衰)是临床最常见的危重疾病之一,其致死率不低于某些癌症。随着现代医学进展,年龄依赖性死亡率明显下降,冠脉事件显著减少,患者生存时间延长,心衰患病率较前增加。针对心衰的研究不断更新,心衰的病理生理机制日益趋向完善,不仅仅涉及先前众所周知的心肌损伤或者心脏前后负荷增加,更多因素先后被发现参与心衰的发生、发展,包括神经内分泌机制、炎症反应,内分泌信号系统和生化因素等。伴随心衰病理生理过程产生了一系列的生物标记物,某些生物标记物在协助临床医生诊疗心衰患者方面发挥重要作用。具体包括神经激素类生物(例如:脑钠肽、氨基末端-pro BNP、心房钠尿肽前体中段、肾上腺髓质素前体中段和嗜铬素A),炎症因子类生物标记物(例如:CRP、IL-6和ST2),内分泌生物标志物(例如:脂联素、抵抗素、瘦素和醛固酮),其他生物标记物(包括:肌钙蛋白I/T、乳糖凝集素-3、胱氨酸蛋白酶抑制剂C、生长分化因子-15和基质金属蛋白酶)。生物标记物凭借其高度敏感性及特异性,在心衰的诊断、危险分层及评估预后等方面发挥重要作用。本文就心衰生物标记物最新研究进展做一综述。     

运动对2型糖尿病大鼠血清生物标记物时序性特征的代谢组分析

目的：分析2型糖尿病大鼠在运动干预不同时点的血清生物标记物组合特征。方法：100只SD大鼠,随机选取90只高糖高脂饲料喂养4周,40 mg/kg体重腹腔注射链脲佐菌素（STZ）造模,稳定1周后,71只大鼠成模。最后进入实验共81只大鼠。实施三个时点游泳运动干预（2周、4周和8周）。实验设计共分8组,具体如下：正常对照组（C₀组,n=10）;糖尿病模型对照组（DC₀组,n=10）;糖尿病模型对照2周组（DC₂组,n=10）;糖尿病模型对照4周组（DC₄组,n=10）;糖尿病模型对照8周组（DC₈组,n=9）;糖尿病运动干预2周组（DE₂组,n=11）;糖尿病运动干预4周组（DE₄组,n=10）;糖尿病运动干预8周组（DE₈组,n=11）。采用UPLC/Q-TOF MS技术对大鼠血清进行代谢组学检测,分析运动干预三个时点血清生物标记物的组合特征。结果：依据变化倍数大小排列组合,形成运动干预三个时点的血清生物标记物组合。这些血清生物标记物组合中,大部分差异性物质在不同时点同时出现,但变化倍数有明显不同。2周时点单甘油酸酯的变化倍数最明显,4周时点葡糖酸的变化倍数最明显,4~8周时点二十碳五烯酸、亚麻酸含量可回归至正常水平。结论：2型糖尿病大鼠运动干预不同时点血清生物标记物组合呈现出一定特征。二十碳五烯酸、亚麻酸是运动干预三个时点中上调显著的共同物质,单甘油酸酯、葡糖酸、丙基肉碱、精氨酸、1-磷酸鞘氨醇是三个时点中下调显著的共同物质。     

先灵葆雅公司的生物标记物搜索

先灵葆雅这家制药企业已在新加坡设立了一个生物标记物发现中心。     

生物标记物与精准医疗研究进展

自2015年精准医疗理念提出后,生物标记物与精准医疗愈加被人们重视。并被广泛应用于病毒、癌症等重大疾病的筛查与治疗研究中。新兴循环生物标记物的应用与开发,在HBV、HPV的检测和肿瘤的靶向药物治疗、细胞治疗、免疫抑制剂、癌症疫苗开发方向上都取得了重大成果。与传统的医疗方法相比,生物标记物为辅助精准医疗的检测治疗模式,无论是在研发还是治疗上都有着显著的优势。因此,综述了生物标记物与精准医疗的应用,并就最近的研究报告重点综述了生物标记物与精准医疗的最新研究进展。     

线粒体单体型与线粒体相关的人类疾病

线粒体是一种拥有自身遗传体系的半自主细胞器,它的遗传物质线粒体DNA(mitochondrial DNA,mt DNA)随着人类的迁移、隔离、进化而形成了广泛的线粒体基因组多态性,同一祖先所具有的一些相同mt DNA SNP位点的集合称为线粒体单体型.不同的线粒体单体型会在一定程度上影响线粒体功能,从而影响整个细胞的生长,并在某些情况下导致一些个体的病变,例如Leber遗传性视神经病变、母系遗传性耳聋、Ⅱ型糖尿病、帕金森以及各种癌症等复杂疾病.本文列举总结了几种线粒体相关疾病及其与线粒体单体型如A、B、D、F、G、H、J、K、M、N、T、U、Y及一些有特点的多态位点如G11778A、A1555G、T3394C、G10398A等的相关性.     

在医疗保健领域开发和使用生物标记物的政策性问题

描述了发展中的生物标记物所处的科学、产业、监管和医疗保健管理系统背景,指出了可能阻碍生物标记物研究、发现、发展、商业化及最终临床应用的一些障碍,聚焦了医疗保健中基于生物标记物的诊断方法和医学检验的应用,探索了生物标记物在改良药物开发中的应用。     

Urinary proteomic profiling for diagnostic bladder cancer biomarkers

The ability to detect and monitor bladder cancer in noninvasively obtained urine samples is a major goal. While a number of protein biomarkers have been identified and commercially developed, none have greatly improved the accuracy of sample evaluation over invasive cystoscopy. The ongoing development of high-throughput proteomic profiling technologies will facilitate the identification of molecular signatures that are associated with bladder disease. The appropriate use of these approaches has the potential to provide efficient biomarkers for the early detection and monitoring of recurrent bladder cancer. Identification of disease-associated proteins will also advance our knowledge of tumor biology, which, in turn, will enable development of targeted therapeutics aimed at reducing morbidity from bladder cancer. In this article, we focus on the accumulating proteomic signatures of urine in health and disease, and discuss expected future developments in this field of research.     

Discovery of laryngeal carcinoma by serum proteomic pattern analysis

Laryngeal carcinoma is the most common malignancy among head and neck tumors. The purpose of this study is to find biomarkers for laryngeal carcinoma in patient blood serum using the Surface Enhanced Laser Desorption/Ionization (SELDI) technique. Serum samples from 33 laryngeal carcinoma (12 cases of glottis, 18 of supraglottis and 3 of subglottis) patients and 31 age- and sex-matched healthy people were analyzed by SELDI-TOF on a ProteinChip reader, PBSII-C. Protein profiles were generated using WCX2 protein chips. Protein peak clustering and classification analyses were performed utilizing the Biomarker Wizard and Biomarker Pattern software packages, respectively. The results showed that sixteen peaks had significant difference between laryngeal cancer patients and healthy group, eight of which were up-regulated in the patient samples, and the others were down-regulated. Two protein peaks 8153 Da and 2035 Da were automatically chosen for the system training and development of a classification tree. The analysis yielded a correct percentage of 96.9% for patients and 96.7% for control. The results suggest that serum is a useful resource for the detection of specific biomarkers for laryngeal carcinoma. Proteinchip Array System was a useful tool for a high throughput screening of large-sized serum samples to discover potential biomarkers for carcinoma.     

Discovery of laryngeal carcinoma by serum proteomic pattern analysis

Laryngealcarcinomaisthemostcommonma-lignancyamongtheheadandneckcarcinomas.Theincidenceoflaryngealcanceraccountsforapproxi-mately5%ofmalignanttumorsinthepopulationofdevelopedcountries[1].Laryngealcarcinomahasthreesubtypes,whichincludesupraglottis,glottisandsub-glottis.Amongthem,glottisisthemostcommononeandaffectsmorethan50%ofallthelaryngealcancerpatients.Thoughlaryngoscopyisthemainstayforla-ryngealcancerdetectionbecauseofitsgeneralavail-ability,diagnosisisconfirmedbybiopsyofthepri-marylesion.E…     

Discovery of serum biomarkers of alcoholic fatty liver in a rodent model: C-reactive protein

Background  

Excessive consumption of alcohol contributes to alcoholic liver disease. Fatty liver is the early stage of alcohol-related liver disease. The aim of this study was to search for specific serological biomarkers of alcoholic fatty liver (AFL) compared to healthy controls, non-alcoholic fatty liver (NAFL) and liver fibrosis in a rodent model.     

Discovery of candidate serum proteomic and metabolomic biomarkers in ankylosing spondylitis

Ankylosing Spondylitis (AS) is a common inflammatory rheumatic disease with a predilection for the axial skeleton, affecting 0.2% of the population. Current diagnostic criteria rely on a composite of clinical and radiological changes, with a mean time to diagnosis of 5 to 10 years. In this study we employed nano liquid-chromatography mass spectrometry analysis to detect and quantify proteins and small compounds including endogenous peptides and metabolites in serum from 18 AS patients and nine healthy individuals. We identified a total of 316 proteins in serum, of which 22 showed significant up- or down-regulation (p < 0.05) in AS patients. Receiver operating characteristic analysis of combined levels of serum amyloid P component and inter-α-trypsin inhibitor heavy chain 1 revealed high diagnostic value for Ankylosing Spondylitis (area under the curve = 0.98). We also depleted individual sera of proteins to analyze endogenous peptides and metabolic compounds. We detected more than 7000 molecular features in patients and healthy individuals. Quantitative MS analysis revealed compound profiles that correlate with the clinical assessment of disease activity. One molecular feature identified as a Vitamin D3 metabolite-(23S,25R)-25-hydroxyvitamin D3 26,23-peroxylactone-was down-regulated in AS. The ratio of this vitamin D metabolite versus vitamin D binding protein serum levels was also altered in AS as compared with controls. These changes may contribute to pathological skeletal changes in AS. Our study is the first example of an integration of proteomic and metabolomic techniques to find new biomarker candidates for the diagnosis of Ankylosing Spondylitis.     

Breath biomarkers and non-alcoholic fatty liver disease: Preliminary observations

Breath biomarkers have the potential to offer information that is similar to conventional clinical tests or they are entirely unique. Preliminary data support the use of breath biomarkers in the study of liver disease, in particular non-alcoholic fatty liver disease (NAFLD). It was evaluated whether breath ethanol, ethane, sulfur compounds and acetone would be associated with hepatic histopathology amongst morbidly obese patients presenting for bariatric surgery. Breath samples were collected during a preoperative visit and compared with liver biopsies obtained during the surgery. A Student's two-tailed t-test was used to compare differences between the two groups. Linear regression was used to analyse associations between the concentrations of breath molecules and independent predictor variables. It was found that breath ethanol, ethane and acetone can be useful biomarkers in patients with NAFLD. In particular, breath ethanol can be associated with hepatic steatosis, and breath acetone can be associated with non-alcoholic steatohepatitis.     

人群变异的分子基础:从单核苷酸多态性到单氨基酸多态性

单核苷酸多态性可以划分为位于基因编码区的SNP和非编码区的SNP两大种类;而在基因编码区的SNP还可以进一步划分为两个亚类:不改变氨基酸序列的同义SNP和改变氨基酸序列的非同义SNP.显然,非同义SNP将导致氨基酸序列的改变,即形成单氨基酸多态性.基于蛋白质组学方法,对亚洲人群血浆样本中的SAP进行了系统研究,发现某一特定SAP在纯合人群和杂合人群中可能与生理或病理性状有着不同的关联.更为重要的是,近期有研究发现,在生物体中广泛存在着RNA序列与DNA序列不一致的现象.导致这种差异的主要原因是在转录水平上存在着规模化的RNA编辑(被称为RNA编辑组,RNA editome).该发现表明,个体拥有的SAP中可能有一部分与基因组SNP无关,而是源于RNA编辑组.进一步推论,可能在翻译水平上存在着不依赖DNA和RNA序列的全新的SAP.     

Identification of accessible human cancer biomarkers using ex vivo chemical proteomic strategies

One promising avenue towards the development of more selective, better anticancer drugs lies in the targeted delivery of bioactive compounds to the tumor environment by means of binding molecules specific for tumor-associated biomarkers. Eligibility of such markers for therapeutic ideally use three criteria: accessibility from the bloodstream; expression at sufficient level, and no (or much lower) expression in normal tissues. Most current discovery strategies (such as biomarker searching into body fluids) provide no clue as to whether proteins of interest are accessible, in human tissues, to suitable high-affinity ligands, such as systemically delivered monoclonal antibodies. To address this limitation, our group recently developed two methodologies based on chemical proteomic modifications, enabling the discovery of proteins accessible from the bloodstream and the extracellular space in human pathological tissues. In this review, we will discuss the potential benefits of these methodologies for the fast discovery of therapeutically valuable biomarkers.