art%3a10.1007%2fs12010-013-0238-7

Serum Proteomics in Biomedical Research: A SystematicReview

Ai-hua Zhang & Hui Sun & Guang-li Yan & Ying Han & Xi-jun Wang

Received: 3 November 2012 /Accepted: 11 April 2013 /Published online: 23 April 2013# Springer Science+Business Media New York 2013

Abstract Proteins that are important indicators of physiological or pathological states maycontribute to the early diagnosis of disease, which may provide a basis for identifying theunderlying mechanism of disease development. Serum, contains an abundance of proteins,offers an easy and inexpensive approach for disease detection and possesses a high potentialto revolutionize the diagnostics. These differentially expressed proteins in serum havebecome an important role to monitoring the state for disease. Availability of emergingproteomic techniques gives optimism that serum can eventually be placed as a biomediumfor clinical diagnostics. Advancements have benefited biomarker research to the point whereserum is now recognized as an excellent diagnostic medium for the detection of disease.Comprehensive proteome of human serum fluid with high accuracy and availability has thepotential to open new doors for disease biomarker discovery and for disease diagnostics,providing insights useful for future study. Thus, this review presents an overview of thevalue of serum as a credible diagnostic tool, and we aim to summarize the proteomictechnologies currently used for global analysis of serum proteins and to elaborate on theapplication of serum proteomics to the discovery of disease biomarkers, and discuss some ofthe critical challenges and perspectives for this emerging field.

Keywords Proteomics . Serum . Proteins . Biomarkers . Disease diagnosis . System biology

AbbreviationsMALDI-TOF-MS Matrix-assisted laser desorption/ionization time-of-flight

mass spectrometryCXCL7 CXC chemokine ligand 7SELDI-TOF-MS Surface enhanced laser desorption/ionization time-of-flight

mass spectrometryTB TuberculosisPSA Prostate specific antigenPD Parkinson’s diseaseHCC Hepatocellular carcinoma

Appl Biochem Biotechnol (2013) 170:774–786DOI 10.1007/s12010-013-0238-7

A.-h. Zhang :H. Sun (*) : G.-l. Yan : Y. Han : X.-j. WangNational TCM Key Lab of Serum Pharmacochemistry, Key Lab of Chinmedomics, and HeilongjiangUniversity of Chinese Medicine, Key Pharmacometabolomics Platform of Chinese Medicines,Heping Road 24, Harbin 150040, Chinae-mail: [email protected]

CRC Colorectal cancerLC Laryngeal carcinoma

Introduction

Diseases are often discovered in an advanced stage because of the lack of specificbiomarkers. An early molecular diagnosis is therefore of vital importance in order toincrease the survival rate. Currently, the lack of an easy-to-use and inexpensivesampling method and lack of an accurate and portable platform to facilitate earlydisease detection are the major limitations and have seriously hampered the develop-ment of clinical diagnostics [1]. A good diagnostic method should have the charac-teristics of high sensitivity and specificity and meet the requirements of highthroughput, portability, and low cost for subsequent clinical application [2]. In mostcases, the earlier the disease is diagnosed, the more likely it is to be successfullycured or well controlled, may dramatically reduce the severity of its impact on thepatient’s life, or prevent and/or delay subsequent complications [3]. Today, the im-proved proteomic-discovered technologies are turning serum diagnostics into a clinicalreality [4, 5].

Biomarkers are biomolecules that is associated with an increased risk of the disease andserve as indicators of biological and pathological processes or physiological and pharma-cological responses to a drug treatment. Due to the clinical significance, the identification ofdisease biomarkers in serum holds great promise for personalized medicine, especially fordisease diagnosis and prognosis [6]. Human serum contains a large array of proteins; it is anattractive diagnostic fluid because it has several key advantages for disease diagnosis andprognosis, for example, minimum cost and easy sample collection and processing [7].Comprehensive analysis of human serum proteome may contribute to the understanding ofpathophysiology and provide a foundation for the recognition of potential biomarkers ofdisease [8, 9]. Proteomics is widely envisioned as playing a significant role in the translationof genomics to clinically useful applications, especially in the areas of diagnostics andprognostics. Serum proteomic analysis shows great potential as a useful diagnostic tool andcan facilitate monitoring of both disease progression and effects of therapeutic treatments.These advantages have ensured the widespread use of serum proteomics as a diagnostic toolin clinical practice, which will have enormous impact [10].

Most clinical chemistry tests available today rely on old technologies, and these tests areneither sensitive nor specific for any particular disease, and traditional markers only increasesignificantly after substantial disease injury [11]. Therefore, more sensitive markers ofdisease are eagerly needed, particularly, for the early detection of disease. Proteomics offerspotential advantages that classical diagnostic approaches do not, based on the followingdiscovery of a suite clinically relevant biomarker that are simultaneously affected by thedisease [12]. Recently, serum proteomics has demonstrated a great potential for biomarkerdiscovery and validation for various diseases [13, 14]. The future of this field will depend onfurther validation of disease specific biomarkers and their incorporation into state-of-the-art,the assay that is quantitative, specific, rapid, reliable, sensitive, robust, and cost effective forbroad implementation in diagnostic programs. In order to pave the way for theuniversal acceptance of proteomics as a clinically relevant diagnostic tool, we sum-marize the proteomic technologies currently used for global identification and quan-tification of serum proteins and elaborate the putative biomarkers discovered for avariety of human diseases.

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Properties of Serum as a Diagnostic Fluid

Serum as a primary carrier of small molecules in the body contains an enormous amount ofinformation, making it ideal for the early detection of a wide range of diseases. Serum as aclinical tool has a number of advantages over other biofluids [15]. It can be obtained in largesampling quantities, and repeat sampling is not a problem. The advantage and developmenthave dramatically advanced serum-based diagnostics. Human serum proteomics have prov-en to be a novel approach in the search for protein biomarkers for the detection of diseases[16]. Therefore, the analysis of serum proteomes emerges into a field of high interest withthe future goal to maintain and improve livestock productivity and welfare. Currently, serumproteome analysis represents an important field both for diagnosis and monitoring of variousdiseases [17–19].

Discovery of biomarkers has become a major focus of disease research, which holdspromising future for early detection, diagnosis, monitoring disease recurrence, and thera-peutic treatment efficacy to improve long-term survival of patients. Development of stan-dardized methods for collection and storage of patient samples together with standards fortransportation and handling of samples are needed. This requires knowledge about howsample processing affects proteome analyses, and thereby how nonbiological biased classi-fication errors are avoided. Insenser et al. had analyzed the impact of storage temperature onthe 2D-DIGE profile of human plasma [20]. 2D-DIGE and MS were used to identify thedifferences in the proteomic profiles of human plasma samples stored at either −30 or−80 °C for 18 months. Results showed that plasma collections stored at −30 °C, and notonly those stored at −80 °C, may be used for 2D-DIGE analyses without losing the essentialinformation about highly abundant proteins. This finding expands the applicability of 2D-DIGE to the study of human disease by permitting the analysis of human plasma samplesstored at temperatures between −30 and −80 °C. Candidate biomarkers are believed to existin very low concentrations and comprise less than 1 % of serum proteins and may be highlylabile as well. Therefore, it is imperative to isolate and enrich low-molecular-weight proteinsfrom complex mixtures for biomarker discovery.

A key challenge in clinics is the identification of sensitive and specific biomarkers for earlydetection, prognostic evaluation, and surveillance of disease. Proteome analysis using humanserum is a technological advancement that will enable the discovery of novel biomarkers andbiomarker patterns of various human diseases [21]. The proteomes of serum represent apotential gold mine of biological and diagnostic information, but challenges such as dynamicrange of protein concentration have hampered efforts to unlock this resource. Althoughproteome analysis using serum has potential in disease prevention, early diagnosis and treat-ment of diseases, and evaluation of pharmacotherapies, this technology is still in its infancy.Identification of reliable markers that could predict the development of disease in high-riskpopulations would allow for intervention strategies that may prevent evolution to definitedisease [22–24]. A compelling need exists for the development of technologies that facilitateand accelerate the discovery of novel protein biomarkers with therapeutic and diagnosticpotential. Thus, investigative studies about serum biomarker probably afford the best opportu-nity for the discovery of disease biomarkers.

Serum Diagnostics

People are aware of the importance of regular health check-ups; however, most diseases arenot diagnosed until morbid symptoms become apparent in the late phase. To overcome this

776 Appl Biochem Biotechnol (2013) 170:774–786

challenge, medical researchers are devoted to finding disease biomarkers that reveal a hiddenlethal threat before the disease becomes complicated. Fortunately, serum is a readilyaccessible and informative biofluid, making it ideal for the early detection of a wide rangeof diseases. Serum fluid being the “mirror of the body” is a perfect medium to be exploredfor health and disease surveillance. The translational applications and opportunities areenormous. Serum proteomics is the application of proteomic technologies to improve apatient’s clinical outcomes [25]. Since early treatment is associated with improved clinicalresults, it is therefore essential to identify new biomarkers with substantial predictive powerto reduce the serious manifestation [26, 27]. Indeed, considerable efforts and progress havebeen made over the last few years in the search for novel biomarkers.

As proteomic technologies continue to mature, serum proteomics have great potential forbiomarker research and clinical applications [28]. An ongoing challenge in proteomicscontinues to be the analysis of the serum proteome due to the vast number and complexityof proteins estimated to be present in this biofluid [29]. With advanced instrumentation anddeveloped refined analytical techniques, serum proteomics is widely envisioned as a usefuland powerful approach for biomarker discovery [30]. A highly promising first step for mostanalytical approaches of serum is to deplete as many proteins as possible. With new andhighly sensitive proteomic technologies, the lower level of analytes in serum is no longer alimitation. Recently, a large number of medically valuable analytes in serum are graduallyunveiled, and some of them represent biomarkers for different diseases including cancer,autoimmune diseases, viral diseases, bacterial diseases, cardiovascular diseases, and HIV[31–33]. Interest in serum proteomics as a tool for disease diagnosis and a myriad of otherapplications continues to expand at a rapid rate [34, 35]. The state-of-the-art of serumproteomics is in evolution, and a growing number of proteins will be investigated anddiscovered. Thus, serum-based diagnostics may offer a robust alternative for clinicians touse in the near future to make clinical decisions and predict posttreatment outcomes.

Serum Proteomics

Serum proteome is thought to represent a rich source of biomarkers for early stage diseasedetection. Such an approach should not only aid in improved diagnostics, but has alreadycontributed to the identification of complex signatures that may represent disease subgroups,early diagnostics, and facilitated the analysis of disease. Nevertheless, three major chal-lenges have hindered biomarker discovery: (a) candidate biomarkers exist at extremely lowconcentrations in serum; (b) high abundance resident proteins such as albumin mask the rarebiomarkers; (c) biomarkers are rapidly degraded by endogenous and exogenous proteinases[36]. Proteomic technologies have been used to analyze the serum protein composition ofserum qualitatively and quantitatively. Analysis of these key proteins has become animportant role to monitor the state of biological organisms and is a widely used diagnostictool for disease. Proteomics provides potential advantages that classical diagnostic ap-proaches do not, based on the following discovery of a suite of clinically relevant biomarkersthat are simultaneously affected by the disease [37]. In-depth analysis of the serum proteomeis fundamental to understanding the functions of serum proteins and to reveal diseasebiomarkers involved in different pathophysiological conditions, with the ultimate goal ofimproving patient diagnosis and prognosis.

Protein biomarkers provide the key diagnostic information for the detection of disease,risk of disease progression, and a patient’s likely response to drug therapy. Profiling of theproteins in serum from a disease population can potentially yield valuable clinical


parameters to be used for diagnosis and prognosis of the disease [38]. Proteome of wholeserum is highly susceptible to a variety of physiological and biochemical processes.Comprehensive proteome of human serum fluid with high accuracy and availability hasthe potential to open new doors for disease biomarker discovery and for disease diagnostics,providing insights useful for future study. Serum proteomic analysis utilizes high-throughputanalytical technique in order to assay thousands of serum proteins simultaneously. Differentproteomic tools such as 2D-PAGE, 2D-DIGE, SELDI-ToF-MS, protein arrays, iTRAQ, andMudPIT technology have been used for differential analysis of various serum biologicalsamples, to better understand the molecular basis of pathogenesis and the validation andcharacterization of disease-associated proteins [39, 40].

Nevertheless, serum proteomics is a field in rapid progression that has already developedbeyond initial criticism and is making its way toward important applications and discoveries.Specifically, there have been an increasing number of reports on the potential clinicalapplication of proteomics for early detection as well as risk assessment and managementof disease. In the future, serum proteomic applications in the disease field could identifyserum-based biomarkers that are predictors of disease presence or progression, and serumproteomics could help define the optimal targeted agent and effective dose for each patient’sdisease. These advances will allow improved new insights into disease etiology and inter-vention. Emerging as a promising biofocus, serum proteomics will drive serum analyses andoffer great benefits for public health in the long-term.

Recent and Potential Application to Human Disease Detection

Serum is an attractive medium for disease diagnosis because serum testing has several keyadvantages including minimum cost, easy sample collection and processing, and possessestremendous potential in clinical diagnostics. Serum proteomics is guaranteed to be an easy-to-use and powerful diagnostic tool for defining the onset, progression, and prognosis ofhuman diseases. As proteomic technologies continue to mature, serum proteomics canenhance the sensitivity and specificity of human disease detection and have great potentialfor biomarker research and clinical applications. The goal of these efforts is to identifyproteins that are uniquely correlated with a specific human disease in order to accuratelydiagnose and treat the malady.

Cancer has been the disease with the highest cause of death for a decade. This is partlydue to the lack of ideal tumor markers for early diagnosis, which causes cancer found at theadvanced stage where no curative treatment is available. Therefore, development of tumormarkers with higher sensitivity and specificity is waiting to emerge. Recent advances inserum proteomic technology made it possible to identify the low abundant proteins in theclinical samples, and thus extensive efforts are now attempted to search for the tumormarkers [41]. Majority of women with ovarian cancer that is the fifth leading cause ofcancer death in women have advanced stage disease at the time of diagnosis and a poor 5-year survival rate [42]. The only available biomarker is CA125, which has an unacceptablylow sensitivity and specificity for diagnostic use. Highly sensitive and specific tools tofurther optimize early diagnosis and treatment are needed. Hence, screening has beeninvestigated in the hopes of improving survival by diagnosing ovarian cancer at an earlierstage. Serum proteomics is a specific method for cancer diagnosis and provides facilities forthe readily reproducible and reliable detection of tumors in early stages [43]. To identify newproteins with potential diagnostic or prognostic value for the therapy of ovarian cancer,comparative proteomic analysis of serum from ovarian cancer patients and healthy women


were performed. Three proteins with differential abundance were found and identified bymass spectrometry: α-1-antitrypsin, apolipoprotein A-IV, and retinol-binding protein [44]. Ina training set analysis, the three most effective biomarkers exhibited 94 % sensitivity at 98 %specificity, CA125 alone produced 68 % sensitivity, and the combination increased sensi-tivity to 88 % [45].

Pancreatic cancer, as a highly malignant cancer and the fourth cause of cancer-relateddeath in world, is characterized by dismal prognosis, due to rapid disease progression, highlyinvasive tumor phenotype, and resistance to chemotherapy. A contributory factor to the pooroutcome is the lack of appropriate, sensitive, and specific biomarkers for early diagnosis;and despite significant advances in treatment of the disease during the past decade, thesurvival rate is little improved. Recently, accompanying the development of proteomictechnology, more and more potential biomarkers have appeared and are being reported[46]. Matsubara et al. had identified a significant decrease of the plasma CXC chemokineligand 7 (CXCL7) level in patients with pancreatic cancer, and combination of CA19-9 withCXCL7 improved the discriminatory power of the former for pancreatic cancer [47].Diagnosis of pancreatic cancer at an early stage is important for successful treatment andimproving the prognosis of patients. Serum samples were applied to strong anionic exchangechromatography protein chips for protein profiling by surface enhanced laser SELDI-TOF-MS to distinguish pancreatic cancer from noncancer [48]. Sixty-one protein peaks between2,000 and 30,000 m/z ratios were detected to establish multiple decision classification treesfor differentiating the known disease states. A sensitivity of 0.833 and a specificity of 1.000were obtained in distinguishing pancreatic cancer from healthy controls and benign pancre-atic diseases. These findings suggest that serum profiling may provide a new diagnosticoption for pancreatic cancer and facilitate early detection of the disease.

Currently, there are no early clinical biomarkers for breast cancer [49]. The discovery ofbreast cancer associated serum biomarkers is important for early diagnosis, disease mech-anism elucidation, and determination of treatment strategy for the disease. A serum prote-omic platform including high abundance protein depletion, lectin affinity fractionation, IEFseparation, and LC–MS analysis has been applied to discover breast cancer-associatedproteins [50]. The following candidates, thrombospondin-1 and 5, alpha-1B-glycoprotein,serum amyloid P-component, and tenascin-X, were selected as promising examples of theuse of this platform. This biomarker panel allows accurate discrimination between breastcancer and healthy individuals. In addition, it could distinguish subgroups of breast cancerbased on patterns of several specific biomarkers. Pietrowska’s study established a highpotential of MALDI-ToF-based analyses for the detection of dynamic changes in the serumproteome related to therapy of breast cancer patients, which revealed the potential applica-bility of serum proteome-patterns analyses in monitoring the toxicity of therapy [51].Pietrowska et al. have identified features of serum proteome patterns that were significantlydifferent between blood samples of healthy individuals and early stage breast cancer patients[52]. Further validation of biomarkers could potentially facilitate the early diagnosis ofbreast cancer as an aid to imaging diagnostics, and this has progressively led toward morepersonalized medicine in regard to treatment options.

Tuberculosis (TB) remains to be a major infectious disease throughout the world.However, there is no commercially available diagnostic test for this disease with acceptablesensitivity and specificity for routine laboratory use [53]. New diagnosis tests are urgentlyneeded to address the global TB burden and to improve control programs especially inresource-limited settings. One of the potential strategies in developing a new diagnosticmethod and in improving the TB vaccine involves the identification of novel antigeniccandidates [54]. The model of biomarkers constructed on the three biomarkers generated


excellent separation between the TB and control groups [55]. The sensitivity was 84.0 %,and the specificity was 86.0 %. Blind test data indicated a sensitivity of 80.0 % and aspecificity of 84.2 %. The data suggested a potential application of serum proteomics as aneffective technology to profile proteome; and with pattern analysis, a diagnostic modelcomprising of three potential biomarkers was indicated to differentiate people with TB andhealthy controls rapidly and precisely.

Prostate cancer is the most common cancer among men worldwide and is the secondleading cause of death. However, many men who develop a prostate tumor never exhibitsymptoms in the early stage of the disease or even before it spreads to other parts of thebody, such as bones and lymph nodes [56, 57]. Therefore, there is a large drive towardsserum proteomic biomarker discovery, and an underlying necessity to discover specificmarkers that may serve as molecular targets for clinically relevant prostate cancer areneeded. Current studies have revealed promising biomarkers for use in diagnosis, assess-ment of prognosis, and targeting treatment of prostate cancer [58, 59]. Proteomics-basedapproaches have the potential to provide more insight into the underlying molecularmechanisms of the disease and also hold great promise for biomarker discovery in prostatecancer [60]. Two proteins, pigment epithelium-derived factor and zinc-alpha2-glycoprotein,have undergone extensive validation in serum and tissue samples from the original cohortand also from a larger independent cohort of patients. Combination of biomarkers withclinical and demographic data has produced progress toward the goal of both optimalscreening and risk assessment. On the basis of serum proteomic analysis, four novelcandidates, follistatin, chemokine ligand 16, pentraxin 3, and spondin 2, were validated inthe serum of patients with and without prostate cancer [61]. The proteins presented may beuseful as diagnostic, prognostic, or predictive serological markers for prostate cancer. Theseresults illustrate the potential of serum proteomic platform that strives to bridge the gapbetween discovery and validation of biomarkers for the detection of prostate cancer and helpto explore disease from a new perspective.

Serum biomarkers for neurodegenerative diseases are essential to facilitate diseasediagnosis. Parkinson’s disease (PD) is a common disease which occurs in aged people withchronic, progressive, and degenerative character of the central nervous system. Until now,there is no effective treatment method in PD patients before they show obvious symptomsfor prevention and early diagnosis. In order to find out early disease biomarkers, two-dimensional liquid chromatography-tandem mass spectrometry coupled with iTRAQ label-ing was employed to quantitatively identify the differentially expressed proteins among thedifferent disease progress types of PD [62, 63]. It was found that the expression level of eightproteins which included serotransferrin and clusterin was increased by proteomic tech-niques. Those proteins may be associated with oxidative stress, mitochondrial dysfunction,abnormal protein aggregation, and inflammation. The expression level of apolipoprotein A-Idecreased, particularly in the early stage of PD patients. This protein regulated not only thelipid metabolism in the central nervous system, but also influenced the deposition process ofproteins which are involved in PD.

Hepatic cirrhosis is a life-threatening disease arising from different chronic liver disor-ders. Chronic hepatitis C is characterized by a highly variable clinical course, with at least20 % developing liver cirrhosis within 40 years [64]. Only liver biopsy allows a reliableevaluation of the course of hepatitis C by grading inflammation and staging fibrosis, andthus serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed.Recent evidence from serum proteomics indicates that MFAP-4 as the novel candidatebiomarker with high diagnostic accuracy for prediction of nondiseased liver versus cirrhosis[65]. Hepatocellular carcinoma (HCC) is the fifth most common cancer, and advanced


hepatic fibrosis is a major risk factor for HCC. Recent advancements in quantitative andlarge-scale proteomic methods could be used to optimize the clinical application of bio-markers [66]. Early diagnosis of HCC and assessment of the stage of hepatic fibrosis canalso contribute to more effective therapeutic interventions and an improve prognosis.Furthermore, advancements of proteomic techniques contribute not only to the discoveryof clinically useful biomarkers but also in clarifying the molecular mechanisms of diseasepathogenesis by using serum fluid.

Colorectal cancer (CRC) is the third most common cancer worldwide and has poorprognosis [67]. To identify the proteins involved in colorectal carcinogenesis, 2-DE andMALDI-TOF/TOF-based proteomic approach were employed to study the differentiallyexpressed proteins in tumor and adjacent nontumor tissue samples [68]. Of the sevensignificantly and consistently altered proteins identified, hnRNP A1 was one of the mostsignificantly altered proteins, and its overexpression was confirmed using RT-PCR andwestern blot analysis. The data suggested that hnRNP A1 may be a potential biomarkerfor early diagnosis, prognosis, and monitoring in the therapy of colorectal cancer. Theincidence of esophageal adenocarcinoma is increasing worldwide, but survival remainspoor. Neoadjuvant chemotherapy can improve survival, but prognostic and predictive bio-markers are required. Serum samples collected before and during the treatment of esopha-geal cancer and noncancer controls were analyzed by SELDI-TOF-MS [69]. Three peaks,confirmed as apolipoprotein A-I, serum amyloid A, and transthyretin, were associated byunivariate and multivariate analysis with disease-free survival and overall survival. Plasmaproteins can be detected prior to treatment for esophageal cancer that are associated withoutcome and merit testing as prognostic and predictive markers of response to guidechemotherapy in esophageal cancer. Serum protein fingerprint of patients with laryngealcarcinoma (LC) was to screen for protein molecules closely related to LC during the onsetand progression of the disease with SELDI-TOF-MS [70]. The findings suggest thatproteomic diagnostic model could distinguish LC patients from controls with a sensitivityof 92.1 % and a specificity of 91.9 %. The data suggested that proteomic technology couldbe used to screen proteins with altered expression levels in the serum of LC patients.

Serum proteomic approaches that could be used for identifying new biomarkers ingallbladder cancer may be potential molecular targets for early gallbladder cancer diagnos-tics and therapeutic applications [71]. Serum samples of endometrial carcinoma were firstdepleted of high-abundance proteins, labeled with iTRAQ, and then analyzed via two-dimensional liquid chromatography and tandem mass spectrometry [72]. Seven proteins,orosomucoid 1, haptoglobin, SERPINC 1, alpha-1-antichymotrypsin, apolipoprotein A-IV,inter-alpha-trypsin inhibitor heavy chain H4, and histidine-rich glycoprotein, were found, forthe first time, to be differentially expressed in atypical endometrial hyperplasia. Thedifferentially expressed proteins may serve as biomarkers in the diagnosis and follow-upof endometrial hyperplasia and endometrial carcinoma. Lung cancer is the leading cause ofcancer deaths worldwide. New diagnostics are needed to detect early stage lung cancerbecause it may be cured with surgery. In a study done by Ostroff et al., proteomic technologyhad identified and developed a 12-protein panel that discriminates lung cancer from controlswith 91 % sensitivity and 84 % specificity in cross-validated training and 89 % sensitivityand 83 % specificity in a separate verification set, with similar performance for early and latestage lung cancer [73]. It provides a solid foundation to develop tests sorely needed toidentify early stage lung cancer. The identification of serum biomarkers has lead to im-provements in the detection and diagnosis of disease, and combinations of these biomarkershave increased further their sensitivity and specificity [74]. Consequently, these studiesclearly demonstrated that serum contains proteomic signatures that may serve as biomarkers


for human diseases, and further studies are needed to fully assess the potential clinical valueof this biomarker candidate.

Concluding Remarks and Future Perspectives

Modern medicine has experienced a tremendous explosion in knowledge about disease path-ophysiology, gained largely from understanding the molecular biology of human disease.Recent advances in proteomics now allow for simultaneous identification and quantificationof thousands of unique proteins in serum biological fluid. In particular, proteomic studiesbenefits of serum have been used successfully to discover novel markers of a variety conditions.With the advantages of an easy and cost-effective diagnostic approach, serum shows highpotential for monitoring general health and disease, possess enormous translational values, andunparalleled opportunities for clinical applications. This article presents an update on the statusof serum diagnostics and delves into their applications to the discovery of biomarkers fordisease detection and therapeutic applications, with an emphasis on specific high-throughputbiomarkers. With advanced instrumentation and developed analytical techniques, proteomics iswidely envisioned as a useful and powerful approach for serum biomarker discovery.

Human serum proteomics has proven to be a novel approach in the search for proteinbiomarkers for detection of human diseases. Comprehensive analysis and identification of thehuman serum may contribute to the understanding of the pathophysiology and provide afoundation for the recognition of potential biomarkers of human disease. Moreover, the avenueof serum diagnostics incorporating proteomic findings will enable us to connect molecularanalytes to monitor therapies, therapeutic outcomes, and finally disease progression. Thisshould aid the diagnosis, improve stratification of therapy, and identify novel therapeutic targetsfor a variety of diseases, all of which will be essential for the development of personalized andpredictive medicine of the future. Future developments in the field of serum diagnostics canrevolutionize our approach to screening, risk assessment, and therapeutic management for arange of health conditions. We anticipate that in the near future, this approach will hopefullyallow more individualized treatment to be provided before an advanced stage.

Acknowledgments This work was supported by grants from the Key Program of the Natural ScienceFoundation of the State (Grant no. 90709019), the National Key Program on the Subject of Drug Innovation(Grant no. 2009ZX09502-005), the National Specific Program on the Subject of Public Welfare (Grant no.200807014), the National Program for Key Basic Research Projects in China (Grant no. 2005CB523406), andthe Foundation of Heilongjiang University of Chinese Medicine (Grant no. 201209).

Competing Financial Interests The authors declare no competing financial interests.

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