Blood and sputum protein biomarkers for chronic obstructive pulmonary disease (COPD)

ABSTRACT

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous set of disorders, characterized by airflow limitation, and reduced lung function. Despite increasing knowledge regarding its pathophysiology, there has been limited advancement in therapeutics and the current treatment strategy is symptom management and prevention of exacerbations.

Areas covered: Biomarkers represent important tools for the implementation of precision medicine. As fundamental molecules of all living processes, proteins could provide crucial information about how genes interact with the environment. Proteomics studies could act as important tools in identifying reliable biomarkers to enable a more precise therapeutic approach. In this review, we will explore the most promising blood and sputum protein biomarkers in COPD that have been consistently reported in the literature.

Expert commentary: Given the complexity of COPD, no single protein biomarker has been able to improve the outcomes of COPD patients. According to preliminary studies, precision medicine in COPD will likely require a combination of different proteins in a biomarker panel for clinical translation. With advancements in current mass spectrometry techniques, an enhancement in the identification of new biomarkers will be observed, and improvements in sequence database search can fill in potential gaps between biomarker discovery and patient care.     

蛋白质芯片在肿瘤血清标识物发现中的应用

蛋白质芯片是一种新型的高通量蛋白质组学技术,由于其具有高通量、微型化、可平行快速分析等优点,因此在肿瘤血清标识物发现研究方面具有广泛的应用前景。本文综述了蛋白质芯片的基本原理、类型及其在肿瘤血清标记物发现研究中的应用,将蛋白质芯片技术与传统的肿瘤标志物发现技术进行了比较,并对蛋白质芯片技术在肿瘤标识物发现研究上的进一步应用进行了展望。     

Targeted and Untargeted Proteomics Approaches in Biomarker Development

An enormous amount of research effort has been devoted to biomarker discovery and validation. With the completion of the human genome, proteomics is now playing an increasing role in this search for new and better biomarkers. Here, what leads to successful biomarker development is reviewed and how these features may be applied in the context of proteomic biomarker research is considered. The “fit‐for‐purpose” approach to biomarker development suggests that untargeted proteomic approaches may be better suited for early stages of biomarker discovery, while targeted approaches are preferred for validation and implementation. A systematic screening of published biomarker articles using MS‐based proteomics reveals that while both targeted and untargeted technologies are used in proteomic biomarker development, most researchers do not combine these approaches. i) The reasons for this discrepancy, (ii) how proteomic technologies can overcome technical challenges that seem to limit their translation into the clinic, and (iii) how MS can improve, complement, or replace existing clinically important assays in the future are discussed.     

Diagnostic and prognostic value of circular RNAs in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumour, which has posed a heavy health and financial burden worldwide. Due to limited symptoms at the early stage and the limitation in current biomarkers, HCC patients are usually diagnosed at the advanced stage with a pessimistic overall survival rate. Circular RNAs (circRNAs) are a subclass of single-stranded RNAs characterized by a covalently closed loop structure without 3’- or 5’-end. With advances in high-throughput sequencing technology and bioinformatics, accumulating studies have demonstrated the promotor or suppressor roles of circRNAs in the carcinogenesis, progression, and metastasis of HCC. Moreover, circRNAs are characteristic of higher abundance, stability and conservation compared with linear RNAs. Therefore, circRNAs have emerged as one of the most promising diagnostic and prognostic biomarkers for HCC with reliable accuracy, sensitivity and specificity. In this review, we briefly introduce the characteristics of circRNAs and summarize the roles of circRNAs in the biological procedures of HCC. Furthermore, we provide an overview on the potential diagnostic and prognostic value of circRNAs as biomarkers for patients with HCC. Finally, we discuss future perspectives of circRNAs in cancer research.     

Edge biomarkers for classification and prediction of phenotypes

In general, a disease manifests not from malfunction of individual molecules but from failure of the relevant system or network, which can be considered as a set of interactions or edges among molecules. Thus, instead of individual molecules, networks or edges are stable forms to reliably characterize complex diseases. This paper reviews both traditional node biomarkers and edge biomarkers, which have been newly proposed. These biomarkers are classified in terms of their contained information. In particular, we show that edge and network biomarkers provide novel ways of stably and reliably diagnosing the disease state of a sample. First, we categorize the biomarkers based on the information used in the learning and prediction steps. We then briefly introduce conventional node biomarkers, or molecular biomarkers without network information, and their computational approaches. The main focus of this paper is edge and network biomarkers, which exploit network information to improve the accuracy of diagnosis and prognosis. Moreover, by extracting both network and dynamic information from the data, we can develop dynamical network and edge biomarkers. These biomarkers not only diagnose the immediate pre-disease state but also detect the critical molecules or networks by which the biological system progresses from the healthy to the disease state. The identified critical molecules can be used as drug targets, and the critical state indicates the critical point of disease control. The paper also discusses representative biomarker-based methods.     

Cancer biomarker discovery and translation: proteomics and beyond

Introduction: Cancer is often diagnosed at late stages when the chance of cure is relatively low and although research initiatives in oncology discover many potential cancer biomarkers, few transition to clinical applications. This review addresses the current landscape of cancer biomarker discovery and translation with a focus on proteomics and beyond.

Areas covered: The review examines proteomic and genomic techniques for cancer biomarker detection and outlines advantages and challenges of integrating multiple omics approaches to achieve optimal sensitivity and address tumor heterogeneity. This discussion is based on a systematic literature review and direct participation in translational studies.

Expert commentary: Identifying aggressive cancers early on requires improved sensitivity and implementation of biomarkers representative of tumor heterogeneity. During the last decade of genomic and proteomic research, significant advancements have been made in next generation sequencing and mass spectrometry techniques. This in turn has led to a dramatic increase in identification of potential genomic and proteomic cancer biomarkers. However, limited successes have been shown with translation of these discoveries into clinical practice. We believe that the integration of these omics approaches is the most promising molecular tool for comprehensive cancer evaluation, early detection and transition to Precision Medicine in oncology.     

Serum CYR61 as a potential biomarker for the diagnosis of esophagogastric junction tumor

Background: Esophagogastric junction tumor (EGJ) is a rare but fatal disease with a rapid rising incidence worldwide in the late 20 years, and it lacks a convenient and safe method for diagnosis. The present study aimed to evaluate the potential of serum CYR61 as a biomarker for the diagnosis of EGJ tumor.Methods: Enzyme-linked immunosorbent assay (ELISA) was used to estimate CYR61 levels in sera of 152 EGJ tumor patients and 137 normal controls. Receiver operating characteristics (ROC) was carried out to evaluate the diagnostic accuracy. The Mann–Whitney’s U test was used to compare the difference of serum levels of CYR61 between groups. And chi-square tests were employed to estimate the correlation of the positive rate of serum CYR61 between/among subgroups.Results: Serum CYR61 levels were statistically lower in EGJ tumor and early-stage EGJ tumor patients than those in normal controls (P<0.0001). The sensitivity, specificity and the area under the curve (AUC) of this biomarker in EGJ tumor were 88.2%, 43.8% and 0.691, respectively, and those for early stage of EGJ tumor were 80.0%, 66.4% and 0.722, respectively. Analyses showed that there was no correlation between the clinical data and the levels of CYR61 (P>0.05).Conclusion: The present study showed that CYR61 might be a potential biomarker to assist the diagnosis of EGJ tumor.     

香溪河大型底栖动物群落结构季节动态

通过大型底栖动物的量化监测,对香溪河水系大型底栖动物季节动态进行研究.共采集大型底栖动物197种,隶属6纲68科,其中,四节蜉、高翔蜉、短尾石蝇为该水系优势类群,不同季节间大型底栖动物优势类群组成存在较大差异.大型底栖动物群落结构以冬季最为复杂,春、秋季次之,夏季相对简单.大型底栖动物功能摄食类群以集食者占优,其次为刮食者、捕食者和滤食者,撕食者丰度最小.典型对应分析表明,不同季节影响底栖动物群落结构的因子差异较大;夏季和秋季营养盐对底栖动物群落结构影响较大,水深对各季度大型底栖动物群落结构均有影响.     

Adrenomedullin Is a Diagnostic and Prognostic Biomarker for Acute Intracerebral Hemorrhage

Hemorrhagic stroke remains an important health challenge. Adrenomedullin (AM) is a vasoactive peptide with an important role in cardiovascular diseases, including stroke. Serum AM and nitrate–nitrite and S-nitroso compounds (NOx) levels were measured and compared between healthy volunteers (n = 50) and acute hemorrhagic stroke patients (n = 64). Blood samples were taken at admission (d0), 24 h later (d1), and after 7 days or at the time of hospital discharge (d7). Neurological severity (NIHSS) and functional prognosis (mRankin) were measured as clinical outcomes. AM levels were higher in stroke patients at all times when compared with healthy controls (p < 0.0001). A receiving operating characteristic curve analysis identified that AM levels at admission > 69.0 pg/mL had a great value as a diagnostic biomarker (area under the curve = 0.89, sensitivity = 80.0%, specificity = 100%). Furthermore, patients with a favorable outcome (NIHSS ≤ 3; mRankin ≤ 2) experienced an increase in AM levels from d0 to d1, and a decrease from d1 to d7, whereas patients with unfavorable outcome had no significant changes over time. NOx levels were lower in patients at d0 (p = 0.04) and d1 (p < 0.001) than in healthy controls. In conclusion, AM levels may constitute a new diagnostic and prognostic biomarker for this disease, and identify AM as a positive mediator for hemorrhagic stroke resolution.     

Application of proteomics to graft-versus-host disease: from biomarker discovery to potential clinical applications

Introduction: Graft-versus-host disease (GVHD) is a frequent and potentially life-threatening complication that occurs in many patients who undergo hematopoietic stem cell transplantation. In an effort to develop blood and tissue-based biochemical assays for GVHD diagnosis, high throughput proteomic platforms have been widely utilized for the identification and validation of disease biomarkers for both acute and chronic GVHD.

Areas covered: This article reviews biomarker research findings on acute and chronic GVHD ascertained by studying peripheral blood, urine and saliva that gives biological information on systemic or localized disease. While the primary focus of GVHD biomarker discovery has been on identification and validation of prognostic and predictive biomarkers that might allow stratification of disease risk, molecular biomarkers that might aid patient diagnosis and/or response to treatment have also been reported.

Expert commentary: Unbiased as well as targeted proteomic studies of acute and chronic GVHD have identified some distinguishing features of the two diseases especially the role of certain immune cell populations. A combination of patient risk stratification using panels of biomarkers and the application of novel targeted therapeutics should help to reduce the burden of GVHD, and hence improve the quality of life for patients following hematopoietic stem cell transplantation.     

The use of tumors in wild populations of fish to assess ecosystem health

Evidence has linked toxicants in aquatic systems with cancer in fish and population level effects on species. Thus some types of tumors may be useful monitors of ecosystem health, at least as affected by genotoxins and promoters. However, tumors caused by purely genetic mechanisms or by virus would not be good indicators. Only neoplasms which have chemicals as a portion of their etiology (either as initiators or promoters) would be useful in assessing ecosystem health. Lesions which may fit these criteria include liver neoplasms (both biliary and hepatic) and skin lesions in a variety of primarily benthic fishes, and neural lesions in various drum species and in butterfly fish species. Two studies purporting to demonstrate a lack of tumors in fish from polluted areas have been reexamined and found either to have insufficient data on vulnerable species or to actually support a tumor-pollution linkage. Thus certain lesions in vulnerable species or species groups may serve as a mechanism to assess one facet of ecosystem health.     

Highly upregulated in liver cancer (HULC): An update on its role in carcinogenesis

Highly upregulated in liver cancer (HULC) was initially recognized during the screening of a hepatocellular carcinoma (HCC)-specific gene library. Further studies demonstrated its aberrant upregulation in several other tumor types. The oncogenic roles of this long noncoding RNA (lncRNA) have been verified through expression studies as well as functional studies. Moreover, the results of knockdown experiments have indicated diminished carcinogenic effects of cancer cell line in nude mice following HULC silencing. More recent studies have shown that expression levels of this lncRNA might be used as diagnostic biomarkers in cancer patients. Moreover, mechanistical studies have revealed associations between HULC and two HCC-related viruses namely hepatitis B and C viruses. Taken together, HULC can be regarded as a therapeutic target not only for HCC but also for a variety of human malignancies. In the current review, we summarized the recent literature about the role of HULC in the carcinogenesis and its potential application in cancer diagnosis and prognosis.     

microRNA signatures in peripheral blood fail to detect acute cellular rejection after liver transplantation

Objective: We investigated whether microRNA signatures in whole blood samples are associated with acute cellular rejection (ACR) after liver transplantation.

Materials and methods: Blood samples were collected using Paxgene technology and analyzed by microarrays and quantitative real-time polymerase chain reaction (qRT-PCR).

Results: microRNA signatures failed to distinguish between 19 patients with ACR and 16 controls. Let-7b-5p and let-7c were upregulated in a subgroup of patients with ACR during the 6th and 7th postoperative days but failed in an independent validation of 20 patients.

Conclusion: microRNA signatures in whole blood processed by Paxgene technology are not suited for the detection of ACR after liver transplantation.     

循环血中microRNAs作为疾病标志物的研究进展

新近研究发现成熟的microRNA能够游离于细胞之外,稳定存在于循环血中,具备疾病分子生物标志物的某些优点,已在多种肿瘤和非肿瘤疾病的早期诊断和预后中显示了独特的价值,同时循环血中microRNA的功能研究也已开始。该文针对近两年循环血中microRNA标志物及功能研究的成果,对microRNA研究中的这一热点问题进行综述。     

Introduction to proteomics: tools for the new biology

Towards revolutionary biomarkers, a considerable amount of research funds and time have been dedicated to proteomics. Although the discovery of novel biomarkers at the dawn of proteomics was a promising development, only a few identified biomarkers seemed to be beneficial for cancer patients. We may need to approach this issue differently, instead of only extending the conventional approaches that have been used historically. The study of biomarkers is essentially a study of diseases and the biochemistry relating to peptide, protein and post-translational modifications is only a tool. A problem-oriented approach should be needed in biomarker development. Clinician participation in the study of biomarkers will lead to realistic, practical and interesting biomarker candidates, which justify the time and expense involved in validation studies. Although discussion in this article is focused on cancer biomarkers, it can generally be applied to biomarker studies for other diseases.     

A specific miRNA signature in the peripheral blood of glioblastoma patients

The prognosis of patients afflicted by glioblastoma remains poor. Biomarkers for the disease would be desirable in order to allow for an early detection of tumor progression or to indicate rapidly growing tumor subtypes requiring more intensive therapy. In this study, we investigated whether a blood-derived specific miRNA fingerprint can be defined in patients with glioblastoma. To this end, miRNA profiles from the blood of 20 patients with glioblastoma and 20 age- and sex-matched healthy controls were compared. Of 1158 tested miRNAs, 52 were significantly deregulated, as assessed by unadjusted Student's t-test at an alpha level of 0.05. Of these, two candidates, miR-128 (up-regulated) and miR-342-3p (down-regulated), remained significant after correcting for multiple testing by Benjamini-Hochberg adjustment with a p-value of 0.025. The altered expression of these two biomarkers was confirmed in a second cohort of glioblastoma patients and healthy controls by real-time PCR and validated for patients who had received neither radio- nor chemotherapy and for patients who had their glioblastomas resected more than 6 months ago. Moreover, using machine learning, a comprehensive miRNA signature was obtained that allowed for the discrimination between blood samples of glioblastoma patients and healthy controls with an accuracy of 81% [95% confidence interval (CI) 78-84%], specificity of 79% (95% CI 75-83%) and sensitivity of 83% (95% CI 71-85%). In summary, our proof-of-concept study demonstrates that blood-derived glioblastoma-associated characteristic miRNA fingerprints may be suitable biomarkers and warrant further exploration.     

Fluid shear stress modulates endothelial inflammation by targeting LIMS2

Mechanosensitive genes regulate multiple cardiovascular pathophysiological processes and disorders; however, the role of flow-sensitive genes in atherosclerosis is still unknown. In this study, we identify LIM Zinc Finger Domain Containing 2 (LIMS2) that acts as a mechanosensitive gene downregulated by disturbed flow (d-flow) both in human endothelial cells (ECs) in vitro and in mice in vivo. Mechanistically, d-flow suppresses LIMS2 expression, which leads to endothelial inflammation by upregulating typical inflammatory factors, VCAM-1, and ICAM-1 in human ECs. The findings indicate that LIMS2, the new flow-sensitive gene, may help us to find a new insight to explain how d-flow caused endothelial inflammation and provide a new therapeutic approach for atherosclerosis in the future.     

AGR2：一个新的癌症诊断标记

AGR2（anterior gradient．2）是一种分泌蛋白,广泛存在于前列腺、乳腺、肺和胰腺等腺体组织,并在这些腺体的肿瘤组织过量表达,与肿瘤细胞的存活、生长和转移相关。临床上,AGR2的表达与乳腺癌、前列腺癌、胰腺癌等癌症的发展和预后相关,被认为是一个很有前途的早期诊断和判定预后的标志性基因。该文就目前AGR2的研究现状,尤其是肿瘤相关的功能、机制和临床调查上的最新研究进展加以综述。