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。     

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。     

炎症标记物与缺血性中风预后评价

缺血性中风触发的炎症反应是一个级联放大过程,不仅可直接对缺血脑组织造成继发性损伤,还可通过与其他病理生理通路的相互影响、相互促进,共同对缺血后脑组织造成不可逆损伤。因此,采用炎症标记物对脑缺血损伤及其预后进行评价,具有重要临床意义。临床研究发现,多炎症标记物法用于缺血性中风的诊治和预后评价比单炎症标记物法更全面、更准确,故更具明显优势。综述脑缺血引发的炎症机制、脑缺血所致炎症通路与其他病理生理通路( 如氧化应激、细胞凋亡和兴奋性毒性) 的关联以及炎症标记物在缺血性中风预后评价中的应用。     

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。     

蚯蚓生物标记物在土壤生态风险评价中的应用

蚯蚓在土壤中行使了很多重要的生态功能,蚯蚓生物标记物常用作土壤污染风险评价研究。这篇综述的目的是探讨当前蚯蚓生物标记物研究是否可以应用到实际的土壤污染风险评价。1)讨论了蚯蚓生物标记物在土壤污染风险评价体系中的重要性,认为它是化学分析方法的有益补充,可以提供更为全面和客观的土壤污染信息;2)综述了相关研究中所使用的蚯蚓类型,土壤类型和生物标记物类型,及其它试验设计要素和最后结果的变异,认为目前蚯蚓生物标记物研究以实验室基础研究为主,筛选出了大量的生物标记物,一定程度上揭示了生物标记物的对各类典型污染物及其组合的应答机制;同时也认为,未来的蚯蚓生物标记物研究应该重点探讨将其应用到实际的土壤污染风险评价中的可行性及如何应用;3)目前不同研究之间从试验设计到结果都具有很大的变异,难以通过综合比较获得完全可靠的具有实践意义的结论和成果,因此,有必要通过建立标准化的蚯蚓生物标记物研究方法,推动生物标记物的研究工作;4)提出了蚯蚓生物标记物研究方法标准化的具体建议,推荐了蚯蚓生物标记物走向实际应用所需要解决的问题。     

基于蛋白质组学的糖尿病相关生物标记物发现

近年来,随着生活水平的提高和生活方式的转变,我国糖尿病的发病率呈快速上升趋势。然而,目前对糖尿病的发生发展机制仍缺乏系统了解。最近本课题组结合多种蛋白质组学技术对糖尿病的发生发展过程进行研究,发现在大鼠2型糖尿病的发生发展过程中,肝脏线粒体的多个代谢通路蛋白质表达及其修饰发生改变。在人群研究中发现,单氨基酸多态性与肥胖以及糖尿病的发展密切相关。此外,还发现了一些潜在糖尿病相关生物标志物,如载脂蛋白C-I、Ficolin-3等。这些研究有助于完善对糖尿病发病机制的认识,同时也为防治糖尿病提供新的思路与方向。     

生物分子的纳米粒子标记和检测技术

生物分子的标记和检测一直是生物分析领域的重要内容 .近年来 ,纳米材料与生物检测技术的结合 ,使得生物分子的检测有了重要的发展 ,这一交叉学科现已成为生物分析领域最具活力的研究方向 .对近期出现的新型纳米粒子标记物的性质、检测原理、特点和应用进行了评述 ,并分析了用该标记物进行分析的可能发展方向     

诱导多能干细胞技术在药物研发领域中的前景

由于基础研究环境和临床环境之间存在的转化差异,使得药物在临床阶段取得成功仍然具有挑战性。诱导多能干(iPS)细胞的诞生为药物研发领域带来了新的希望,使研究者能在体外人性化各种药理学和毒理学模型。人iPS衍生细胞的可获得性,特别是可以定向分化成特定的功能性细胞、组织和器官,一方面为疾病机制研究与细胞治疗提供了全新的途径。另一方面,转化研究中的生物标记物提供了评估临床前基础研究环境和临床环境下毒理学及药理学影响的可衡量的指标,而iPS细胞给生物标记物的研究带来了全新的思路。从转化研究的角度概述了基于iPS细胞药物发现的现行策略,阐明了iPS细胞的潜力以及生物标志物在药物发现和发展整个过程中的作用,突出在该领域有待改进的地方,以期为进一步相关性研究提供一定参考,为新药研发提供新的思路与方法。     

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。     

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。     

Development of a Novel Heart Failure Risk Tool: The Barcelona Bio-Heart Failure Risk Calculator (BCN Bio-HF Calculator)

Background

A combination of clinical and routine laboratory data with biomarkers reflecting different pathophysiological pathways may help to refine risk stratification in heart failure (HF). A novel calculator (BCN Bio-HF calculator) incorporating N-terminal pro B-type natriuretic peptide (NT-proBNP, a marker of myocardial stretch), high-sensitivity cardiac troponin T (hs-cTnT, a marker of myocyte injury), and high-sensitivity soluble ST2 (ST2), (reflective of myocardial fibrosis and remodeling) was developed.

Methods

Model performance was evaluated using discrimination, calibration, and reclassification tools for 1-, 2-, and 3-year mortality. Ten-fold cross-validation with 1000 bootstrapping was used.

Results

The BCN Bio-HF calculator was derived from 864 consecutive outpatients (72% men) with mean age 68.2±12 years (73%/27% New York Heart Association (NYHA) class I-II/III-IV, LVEF 36%, ischemic etiology 52.2%) and followed for a median of 3.4 years (305 deaths). After an initial evaluation of 23 variables, eight independent models were developed. The variables included in these models were age, sex, NYHA functional class, left ventricular ejection fraction, serum sodium, estimated glomerular filtration rate, hemoglobin, loop diuretic dose, β-blocker, Angiotensin converting enzyme inhibitor/Angiotensin-2 receptor blocker and statin treatments, and hs-cTnT, ST2, and NT-proBNP levels. The calculator may run with the availability of none, one, two, or the three biomarkers. The calculated risk of death was significantly changed by additive biomarker data. The average C-statistic in cross-validation analysis was 0.79.

Conclusions

A new HF risk-calculator that incorporates available biomarkers reflecting different pathophysiological pathways better allowed individual prediction of death at 1, 2, and 3 years.     

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.     

Biomarkers in heart failure with preserved ejection fraction

Biomarkers are widely used and studied in heart failure. Most studies have described the utility and performance of biomarkers in sub-studies of randomised clinical trials, where the vast majority of the patients suffered from heart failure with reduced ejection fraction (HFrEF), and not with preserved ejection fraction (HFpEF). As a result, there is a scarcity of data describing the levels, dynamics, clinical and biochemical correlates, and biology of biomarkers in patients suffering from HFpEF, whereas HFpEF is in fact a very frequent clinical entity. This article discusses the value of different biomarkers in HFpEF. We describe various aspects of natriuretic peptide measurements in HFpEF patients, with a focus on diagnosis, prognosis and the risk prediction of developing heart failure. Further, we will discuss several emerging biomarkers such as galectin-3 and suppression of tumorigenicity 2, and recently discovered ones such as growth differentiation factor-15 and syndecan-1.     

Scoring approach based on fish biomarkers applied to French river monitoring

The aim was to apply a multimarker scoring approach as complementary to freshwater monitoring programmes carried out by the Water Agency Adour-Garonne. Fish (chub, barbel and trout) were collected in 11 sites in rivers in south-west France. Five biomarkers of response were measured either in muscle or brain for acetylcholinesterase (AChE) and in liver for glutathione S-transferase, catalase and 7-ethoxyresorufine O-deethylase. As a result of multivariate analysis, sites were clearly discriminated mainly by 7-ethoxyresorufine O-deethylase and acetylcholinesterase activities. According to the scoring approach, a multimarker pollution index was calculated for each sampling site as the sum of the response index of the five measured biomarkers (pollution index). Sorting was established by ranging the sites from lightly to highly contaminated locations.     

Scoring approach based on fish biomarkers applied to French river monitoring

The aim was to apply a multimarker scoring approach as complementary to freshwater monitoring programmes carried out by the Water Agency Adour–Garonne. Fish (chub, barbel and trout) were collected in 11 sites in rivers in south-west France. Five biomarkers of response were measured either in muscle or brain for acetylcholinesterase (AChE) and in liver for glutathione S-transferase, catalase and 7-ethoxyresorufine O-deethylase. As a result of multivariate analysis, sites were clearly discriminated mainly by 7-ethoxyresorufine O-deethylase and acetylcholinesterase activities. According to the scoring approach, a multimarker pollution index was calculated for each sampling site as the sum of the response index of the five measured biomarkers (pollution index). Sorting was established by ranging the sites from lightly to highly contaminated locations.     

Proteome analysis in cardiovascular pathophysiology using Dahl rat model

Dahl salt-sensitive (DS) and salt-resistant (DR) inbred rat strains represent a well established animal model for cardiovascular research. Upon prolonged administration of high-salt-containing diet, DS rats develop systemic hypertension, and as a consequence they develop left ventricular hypertrophy, followed by heart failure. The aim of this work was to explore whether this animal model is suitable to identify biomarkers that characterize defined stages of cardiac pathophysiological conditions. The work had to be performed in two stages: in the first part proteomic differences that are attributable to the two separate rat lines (DS and DR) had to be established, and in the second part the process of development of heart failure due to feeding the rats with high-salt-containing diet has to be monitored. This work describes the results of the first stage, with the outcome of protein expression profiles of left ventricular tissues of DS and DR rats kept under low salt diet. Substantial extent of quantitative and qualitative expression differences between both strains of Dahl rats in heart tissue was detected. Using Principal Component Analysis, Linear Discriminant Analysis and other statistical means we have established sets of differentially expressed proteins, candidates for further molecular analysis of the heart failure mechanisms.     

Sarcoplasmic reticulum Ca-ATPase-phospholamban interactions and dilated cardiomyopathy

Dilated cardiomyopathy is a disease of the heart muscle resulting from a diverse array of conditions that damages the heart and impairs myocardial function. Heart failure occurs when the heart is unable to pump blood at a rate which can accommodate the heart muscle's metabolic requirements. Several signaling pathways have been shown to be involved in the induction of cardiac disease and heart failure. Many of these pathways are linked to cardiac sarcoplasmic reticulum (SR) Ca cycling directly or indirectly. A large body of evidence points to the central role of abnormal Ca handling by SR proteins, Ca-ATPase pump (SERCA2a) and phospholamban (PLN), in pathophysiological heart conditions, compromising the contractile state of the cardiomyocytes. This review summarizes studies which highlight the key role of these two SR proteins in the regulation of cardiac function, the significance of SERCA2a-PLN interactions using transgenic approaches, and the recent discoveries of human PLN mutations leading to disease states. Finally, we will discuss extrapolation of experimental paradigms generated in animal models to the human condition.     

Sensitization of cardiac vagal afferent reflexes at the sensory receptor level: an overview

The gain or sensitivity of reflexes originating in cardiac sensory receptors with vagal afferent pathways is highly dynamic. This modulation is usually attributed to central nervous system or efferent mechanisms. This paper briefly reviews evidence that modulation of reflexes originating in the heart can also occur at the sensory or afferent level. Five examples are cited: calcium antagonists, cardiac glycosides, arginine vasopressin, atrial natriuretic peptides, and changes in dietary sodium. These examples emphasize the role of ionic and humoral factors in regulation of cardiac vagal afferent function. This concept of sensory modulation of cardiac vagal afferents has implications for cardiovascular pharmacology and for pathophysiological states such as heart failure and hypertension.     

Integrative analysis of competing endogenous RNA networks reveals the functional lncRNAs in heart failure

Heart failure has become one of the top causes of death worldwide. It is increasing evidence that lncRNAs play important roles in the pathology processes of multiple cardiovascular diseases. Additionally, lncRNAs can function as ceRNAs by sponging miRNAs to affect the expression level of mRNAs, implicating in numerous biological processes. However, the functional roles and regulatory mechanisms of lncRNAs in heart failure are still unclear. In our study, we constructed a heart failure‐related lncRNA‐mRNA network by integrating probe re‐annotation pipeline and miRNA‐target interactions. Firstly, some lncRNAs that had the central topological features were found in the heart failure‐related lncRNA‐mRNA network. Then, the lncRNA‐associated functional modules were identified from the network, using bidirectional hierarchical clustering. Some lncRNAs that involved in modules were demonstrated to be enriched in many heart failure‐related pathways. To investigate the role of lncRNA‐associated ceRNA crosstalks in certain disease or physiological status, we further identified the lncRNA‐associated dysregulated ceRNA interactions. And we also performed a random walk algorithm to identify more heart failure‐related lncRNAs. All these lncRNAs were verified to show a strong diagnosis power for heart failure. These results will help us to understand the mechanism of lncRNAs in heart failure and provide novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets.