Screening and validation of serum protein biomarkers for early postmenopausal osteoporosis diagnosis.

PubMed

Wang, Long; Hu, Ya-Qian; Zhao, Zhuo-Jie; Zhang, Hong-Yang; Gao, Bo; Lu, Wei-Guang; Xu, Xiao-Long; Lin, Xi-Sheng; Wang, Jin-Peng; Jie, Qiang; Luo, Zhuo-Jing; Yang, Liu

2017-12-01

Postmenopausal osteoporosis is one of the most prominent worldwide public health problems and the morbidity is increasing with the aging population. It has been demonstrated that early diagnosis and intervention delay the disease progression and improve the outcome. Therefore, searching for biomarkers that are able to identify postmenopausal women at high risk for developing osteoporosis is an effective way to improve the quality of life of patients, and alleviate social and economic burdens. In the present study, a protein array was used to identify potential biomarkers. The bone mineral densities of 10 rats were dynamically measured in an ovariectomized model by micro‑computed tomography assessment, and the early stage of osteoporosis was defined. Through the protein array‑based screening, the expression levels of six serum protein biomarkers in ovariectomized rats were observed to alter at the initiation stage of the postmenopausal osteoporosis. Fractalkine, tissue inhibitor of metalloproteinases‑1 and monocyte chemotactic protein‑1 were finally demonstrated to be increased in the serum of eight enrolled postmenopausal osteoporosis patients using ELISA assay and were correlated with the severity of progressive bone loss. These biomarkers may be explored as potential early biomarkers to readily evaluate and diagnose postmenopausal osteoporosis in the clinic.

Enrichment of serum biomarkers by magnetic metal-organic framework composites.

PubMed

Wei, Ji-Ping; Wang, Heng; Luo, Tao; Zhou, Zhi-Jiang; Huang, Yan-Feng; Qiao, Bin

2017-03-01

Highly efficient extraction of peptides from serum is critical for finding serum biomarkers using mass spectrometry, which still remains a great challenge. Currently, a bottom-up proteomics approach has been applied to discover serum biomarkers. However, the approach was labor intensive, time and cost consuming, and cannot meet the requirements for clinical application. In this work, Fe 3 O 4 /C@MIL-100 composites were synthesized to efficiently capture peptides from microwave-assisted formic acid digests of BSA and human serum prior to MALDI-TOF MS analysis. Fe 3 O 4 /C@MIL-100 composites exhibited size-selective adsorption performance, thus providing a rapid and convenient approach to enrich low-abundance peptides. Notably, the peptides' mass fingerprinting of serum digestions between type 2 diabetes mellitus (T2DM) and healthy persons were distinguishable, which indicated the potential ability of this technique for T2DM diagnosis and rapid biomarker discovery. Graphical Abstract Efficient extraction and identification of serum biomarkers using Fe 3 O 4 /C@MIL-100 composites from acid hydrolysate.

Serum Immunoproteomics Combined With Pathological Reassessment of Surgical Specimens Identifies TCP-1ζ Autoantibody as a Potential Biomarker in Thyroid Neoplasia.

PubMed

Belousov, Pavel V; Bogolyubova, Apollinariya V; Kim, Yan S; Abrosimov, Alexander Y; Kopylov, Arthur T; Tvardovskiy, Andrey A; Lanshchakov, Kirill V; Sazykin, Alexei Y; Dvinskikh, Nina Y; Bobrovskaya, Yana I; Selivanova, Lilia S; Shilov, Evgeniy S; Schwartz, Anton M; Shebzukhov, Yuriy V; Severskaia, Natalya V; Vanushko, Vladimir E; Moshkovskii, Sergei A; Nedospasov, Sergei A; Kuprash, Dmitry V

2015-09-01

Current methods of preoperative diagnostics frequently fail to discriminate between benign and malignant thyroid neoplasms. In encapsulated follicular-patterned tumors (EnFPT), this discrimination is challenging even using histopathological analysis. Autoantibody response against tumor-associated antigens is a well-documented phenomenon with prominent diagnostic potential; however, autoantigenicity of thyroid tumors remains poorly explored. Objectives were exploration of tumor-associated antigen repertoire of thyroid tumors and identification of candidate autoantibody biomarkers capable of discrimination between benign and malignant thyroid neoplasms. Proteins isolated from FTC-133 cells were subjected to two-dimensional Western blotting using pooled serum samples of patients originally diagnosed with either papillary thyroid carcinoma (PTC) or EnFPT represented by apparently benign follicular thyroid adenomas, as well as healthy individuals. Immunoreactive proteins were identified using liquid chromatography-tandem mass-spectrometry. Pathological reassessment of EnFPT was performed applying nonconservative criteria for capsular invasion and significance of focal PTC nuclear changes (PTC-NCs). Recombinant T-complex protein 1 subunitζ (TCP-1ζ) was used to examine an expanded serum sample set of patients with various thyroid neoplasms (n = 89) for TCP-1ζ autoantibodies. All patients were included in tertiary referral centers. A protein demonstrating a distinct pattern of EnFPT-specific seroreactivity was identified as TCP-1ζ protein. A subsequent search for clinicopathological correlates of TCP-1ζ seroreactivity revealed nonclassical capsular invasion or focal PTC-NC in all TCP-1ζ antibody-positive cases. Further studies in an expanded sample set confirmed the specificity of TCP-1ζ autoantibodies to malignant EnFPT. We identified TCP-1ζ autoantibodies as a potential biomarker for presurgical discrimination between benign and malignant encapsulated follicular

Serum Metabolomics to Identify the Liver Disease-Specific Biomarkers for the Progression of Hepatitis to Hepatocellular Carcinoma

NASA Astrophysics Data System (ADS)

Gao, Rong; Cheng, Jianhua; Fan, Chunlei; Shi, Xiaofeng; Cao, Yuan; Sun, Bo; Ding, Huiguo; Hu, Chengjin; Dong, Fangting; Yan, Xianzhong

2015-12-01

Hepatocellular carcinoma (HCC) is a common malignancy that has region specific etiologies. Unfortunately, 85% of cases of HCC are diagnosed at an advanced stage. Reliable biomarkers for the early diagnosis of HCC are urgently required to reduced mortality and therapeutic expenditure. We established a non-targeted gas chromatography-time of flight-mass spectrometry (GC-TOFMS) metabolomics method in conjunction with Random Forests (RF) analysis based on 201 serum samples from healthy controls (NC), hepatitis B virus (HBV), liver cirrhosis (LC) and HCC patients to explore the metabolic characteristics in the progression of hepatocellular carcinogenesis. Ultimately, 15 metabolites were identified intimately associated with the process. Phenylalanine, malic acid and 5-methoxytryptamine for HBV vs. NC, palmitic acid for LC vs. HBV, and asparagine and β-glutamate for HCC vs. LC were screened as the liver disease-specific potential biomarkers with an excellent discriminant performance. All the metabolic perturbations in these liver diseases are associated with pathways for energy metabolism, macromolecular synthesis, and maintaining the redox balance to protect tumor cells from oxidative stress.

Serum periostin: a novel biomarker for asthma management.

PubMed

Matsumoto, Hisako

2014-06-01

Chronic airway inflammation and remodeling are fundamental features of asthma. Even with adequate inhaled corticosteroid (ICS) treatment, there are still patients who exhibit Th2/eosinophilic inflammation and develop airflow limitation, a functional consequence of airway remodeling. There are few biomarkers that are applicable in the clinical setting that reflect refractory Th2/eosinophilic inflammation and remodeling of the asthmatic airways. Therefore, establishing such biomarkers is essential for managing patients who suffer from these conditions. This review addresses the importance of serum periostin measurements by describing observations made in a KiHAC multicenter cohort with periostin used as a marker of pulmonary function decline and refractory Th2/eosinophilic inflammation in patients with asthma receiving long-term ICS treatment. Furthermore, serum periostin could be a companion diagnostic for targeted therapy against refractory Th2/eosinophilic inflammation. Finally, the distinct characteristics of serum periostin as compared to conventional biomarkers are addressed.

Serum amyloid A as a prognostic marker in melanoma identified by proteomic profiling.

PubMed

Findeisen, Peter; Zapatka, Marc; Peccerella, Teresa; Matzk, Heike; Neumaier, Michael; Schadendorf, Dirk; Ugurel, Selma

2009-05-01

Currently known prognostic serum biomarkers of melanoma are powerful in metastatic disease, but weak in early-stage patients. This study was aimed to identify new prognostic biomarkers of melanoma by serum mass spectrometry (MS) proteomic profiling, and to validate candidates compared with established markers. Two independent sets of serum samples from 596 melanoma patients were investigated. The first set (stage I = 102; stage IV = 95) was analyzed by matrix assisted laser desorption and ionization time of flight (MALDI TOF) MS for biomarkers differentiating between stage I and IV. In the second set (stage I = 98; stage II = 91; stage III = 87; stage IV = 103), the serum concentrations of the candidate marker serum amyloid A (SAA) and the known biomarkers S100B, lactate dehydrogenase, and C reactive protein (CRP) were measured using immunoassays. MALDI TOF MS revealed a peak at m/z 11.680 differentiating between stage I and IV, which could be identified as SAA. High peak intensities at m/z 11.680 correlated with poor survival. In univariate analysis, SAA was a strong prognostic marker in stage I to III (P = .043) and stage IV (P = .000083) patients. Combination of SAA and CRP increased the prognostic impact to P = .011 in early-stage (I to III) patients. Multivariate analysis revealed sex, stage, tumor load, S100B, SAA, and CRP as independent prognostic factors, with an interaction between SAA and CRP. In stage I to III patients, SAA combined with CRP was superior to S100B in predicting patients' progression-free and overall survival. SAA combined with CRP might be used as prognostic serological biomarkers in early-stage melanoma patients, helping to discriminate low-risk patients from high-risk patients needing adjuvant treatment.

Serum inflammatory biomarkers and clinical outcomes of COPD exacerbation caused by different pathogens.

PubMed

Kawamatawong, Theerasuk; Apiwattanaporn, Apitch; Siricharoonwong, Warisara

2017-01-01

COPD exacerbation is characterized by worsening of symptoms, warranting change in treatment. Systemic and airway inflammation play roles in the pathogenesis of COPD exacerbation. We hypothesized whether increased serum inflammatory biomarkers are associated with the clinical outcomes of COPD exacerbation caused by different infectious pathogens. COPD patients with exacerbation were recruited from a hospital emergency department during 2014-2015. Serum procalcitonin (PCT) and C-reactive protein (CRP) were measured. Dyspnea, eosinopenia, consolidation, acidemia, and atrial fibrillation (DECAF) score was calculated for predicting mortality. Multiplex polymerase chain reaction was carried out for respiratory viral assay from nasopharyngeal swabs, and sputum bacterial culture was also performed. Hospital mortality, invasive mechanical ventilation requirement, and length of hospital stay (LOS) were evaluated, and their associations with clinical characteristics, DECAF score, and serum biomarkers were examined. A total of 62 COPD patients were enrolled. These patients were classified as Global Initiative for Obstructive Lung Disease (GOLD) stage 2, 3, and 4 in 12.9%, 6.4%, and 80.7% of cases, respectively. Isolated bacterial exacerbation was recovered in 30.6% of exacerbation episodes: Klebsiella pneumoniae was the most commonly identified bacteria. Viral pathogens and coinfections were noted in 9.6% and 16.1% of exacerbated patients, respectively. Influenza was the most commonly detected viral pathogen. Serum biomarkers and DECAF score for viruses, bacteria, coinfection, and noninfectious causes of exacerbations were similar. Neither DECAF score nor serum biomarkers were able to differentiate patients with and without mortality or requiring mechanical ventilation. Increased serum PCT was noted in patients with LOS ≥7 days when compared with those with LOS <7 days (0.38 ng/mL vs 0.1 ng/mL; P =0.035). Increased serum PCT is associated with longer LOS in COPD exacerbation

Utilization of metabonomics to identify serum biomarkers in murine H22 hepatocarcinoma and deduce antitumor mechanism of Rhizoma Paridis saponins.

PubMed

Qiu, Peiyu; Man, Shuli; Yang, He; Fan, Wei; Yu, Peng; Gao, Wenyuan

2016-08-25

Murine H22 hepatocarcinoma model is so popular to be used for the preclinical anticancer candidate's evaluation. However, the metabolic biomarkers of this model were not identified. Meanwhile, Rhizoma Paridis saponins (RPS) as natural products have been found to show strong antitumor activity, while its anti-cancer mechanism is not clear. To search for potential metabolite biomarkers of this model, serum metabonomics approach was applied to detect the variation of metabolite biomarkers and the related metabolism genes and signaling pathway were used to deduce the antitumor mechanisms of RPS. As a result, ten serum metabolites were identified in twenty-four mice including healthy mice, non-treated cancer mice, RPS-treated cancer mice and RPS-treated healthy mice. RPS significantly decreased tumor weight correlates to down-regulating lactate, acetate, N-acetyl amino acid and glutamine signals (p < 0.05), which were marked metabolites screened according to the very important person (VIP), loading plot and receiver operating characteristic curve (ROC) tests. For the analysis of metabolic enzyme related genes, RPS reversed the aerobic glycolysis through activating tumor suppressor p53 and PTEN, and suppressed FASN to inhibit lipogenesis. What's more, RPS repressed Myc and GLS expression and decreased glutamine level. The regulating PI3K/Akt/mTOR and HIF-1α/Myc/Ras networks also participated in these metabolic changes. Taken together, RPS suppressed ATP product made the tumor growth slow, which indicated a good anti-cancer effect and new angle for understanding the mechanism of RPS. In conclusion, this study demonstrated that the utility of (1)H NMR metabolic profiles taken together with tumor weight and viscera index was a promising screening tool for evaluating the antitumor effect of candidates. In addition, RPS was a potent anticancer agent through inhibiting cancer cellular metabolism to suppress proliferation in hepatoma H22 tumor murine, which promoted the

Integrating multiple ‘omics’ analyses identifies serological protein biomarkers for preeclampsia

PubMed Central

2013-01-01

Background Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-’omics’ based discovery approach. Methods Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment. Results In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively. Conclusions Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE. PMID:24195779

Evaluation of a Serum Lung Cancer Biomarker Panel.

PubMed

Mazzone, Peter J; Wang, Xiao-Feng; Han, Xiaozhen; Choi, Humberto; Seeley, Meredith; Scherer, Richard; Doseeva, Victoria

2018-01-01

A panel of 3 serum proteins and 1 autoantibody has been developed to assist with the detection of lung cancer. We aimed to validate the accuracy of the biomarker panel in an independent test set and explore the impact of adding a fourth serum protein to the panel, as well as the impact of combining molecular and clinical variables. The training set of serum samples was purchased from commercially available biorepositories. The testing set was from a biorepository at the Cleveland Clinic. All lung cancer and control subjects were >50 years old and had smoked a minimum of 20 pack-years. A panel of biomarkers including CEA (carcinoembryonic antigen), CYFRA21-1 (cytokeratin-19 fragment 21-1), CA125 (carbohydrate antigen 125), HGF (hepatocyte growth factor), and NY-ESO-1 (New York esophageal cancer-1 antibody) was measured using immunoassay techniques. The multiple of the median method, multivariate logistic regression, and random forest modeling was used to analyze the results. The training set consisted of 604 patient samples (268 with lung cancer and 336 controls) and the testing set of 400 patient samples (155 with lung cancer and 245 controls). With a threshold established from the training set, the sensitivity and specificity of both the 4- and 5-biomarker panels on the testing set was 49% and 96%, respectively. Models built on the testing set using only clinical variables had an area under the receiver operating characteristic curve of 0.68, using the biomarker panel 0.81 and by combining clinical and biomarker variables 0.86. This study validates the accuracy of a panel of proteins and an autoantibody in a population relevant to lung cancer detection and suggests a benefit to combining clinical features with the biomarker results.

Evaluation of a Serum Lung Cancer Biomarker Panel

PubMed Central

Mazzone, Peter J; Wang, Xiao-Feng; Han, Xiaozhen; Choi, Humberto; Seeley, Meredith; Scherer, Richard; Doseeva, Victoria

2018-01-01

Background: A panel of 3 serum proteins and 1 autoantibody has been developed to assist with the detection of lung cancer. We aimed to validate the accuracy of the biomarker panel in an independent test set and explore the impact of adding a fourth serum protein to the panel, as well as the impact of combining molecular and clinical variables. Methods: The training set of serum samples was purchased from commercially available biorepositories. The testing set was from a biorepository at the Cleveland Clinic. All lung cancer and control subjects were >50 years old and had smoked a minimum of 20 pack-years. A panel of biomarkers including CEA (carcinoembryonic antigen), CYFRA21-1 (cytokeratin-19 fragment 21-1), CA125 (carbohydrate antigen 125), HGF (hepatocyte growth factor), and NY-ESO-1 (New York esophageal cancer-1 antibody) was measured using immunoassay techniques. The multiple of the median method, multivariate logistic regression, and random forest modeling was used to analyze the results. Results: The training set consisted of 604 patient samples (268 with lung cancer and 336 controls) and the testing set of 400 patient samples (155 with lung cancer and 245 controls). With a threshold established from the training set, the sensitivity and specificity of both the 4- and 5-biomarker panels on the testing set was 49% and 96%, respectively. Models built on the testing set using only clinical variables had an area under the receiver operating characteristic curve of 0.68, using the biomarker panel 0.81 and by combining clinical and biomarker variables 0.86. Conclusions: This study validates the accuracy of a panel of proteins and an autoantibody in a population relevant to lung cancer detection and suggests a benefit to combining clinical features with the biomarker results. PMID:29371783

Deciphering systemic lupus erythematosus-associated serum biomarkers reflecting apoptosis and disease activity.

PubMed

Delfani, P; Sturfelt, G; Gullstrand, B; Carlsson, A; Kassandra, M; Borrebaeck, C A K; Bengtsson, A A; Wingren, C

2017-04-01

Systemic lupus erythematosus (SLE) is a severe chronic inflammatory autoimmune connective tissue disease. Despite major efforts, SLE remains a poorly understood disease with unpredictable course, unknown etiology and complex pathogenesis. Apoptosis combined with deficiency in clearing apoptotic cells is an important etiopathogenic event in SLE, which could contribute to the increased load of potential autoantigen(s); however, the lack of disease-specific protein signatures deciphering SLE and the underlying biological processes is striking and represents a key limitation. In this retrospective pilot study, we explored the immune system as a specific sensor for disease, in order to advance our understanding of SLE. To this end, we determined multiplexed serum protein expression profiles of crude SLE serum samples, using antibody microarrays. The aim was to identify differential immunoprofiles, or snapshots of the immune response modulated by the disease, reflecting apoptosis, a key process in the etiology of SLE and disease activity. The results showed that multiplexed panels of SLE-associated serum biomarkers could be decoded, in particular reflecting disease activity, but potentially the apoptosis process as well. While the former biomarkers could display a potential future use for prognosis, the latter biomarkers might help shed further light on the apoptosis process taking place in SLE.

Identification of candidate diagnostic serum biomarkers for Kawasaki disease using proteomic analysis

PubMed Central

Kimura, Yayoi; Yanagimachi, Masakatsu; Ino, Yoko; Aketagawa, Mao; Matsuo, Michie; Okayama, Akiko; Shimizu, Hiroyuki; Oba, Kunihiro; Morioka, Ichiro; Imagawa, Tomoyuki; Kaneko, Tetsuji; Yokota, Shumpei; Hirano, Hisashi; Mori, Masaaki

2017-01-01

Kawasaki disease (KD) is a systemic vasculitis and childhood febrile disease that can lead to cardiovascular complications. The diagnosis of KD depends on its clinical features, and thus it is sometimes difficult to make a definitive diagnosis. In order to identify diagnostic serum biomarkers for KD, we explored serum KD-related proteins, which differentially expressed during the acute and recovery phases of two patients by mass spectrometry (MS). We identified a total of 1,879 proteins by MS-based proteomic analysis. The levels of three of these proteins, namely lipopolysaccharide-binding protein (LBP), leucine-rich alpha-2-glycoprotein (LRG1), and angiotensinogen (AGT), were higher in acute phase patients. In contrast, the level of retinol-binding protein 4 (RBP4) was decreased. To confirm the usefulness of these proteins as biomarkers, we analyzed a total of 270 samples, including those collected from 55 patients with acute phase KD, by using western blot analysis and microarray enzyme-linked immunosorbent assays (ELISAs). Over the course of this experiment, we determined that the expression level of these proteins changes specifically in the acute phase of KD, rather than the recovery phase of KD or other febrile illness. Thus, LRG1 could be used as biomarkers to facilitate KD diagnosis based on clinical features. PMID:28262744

Discovery of serum biomarkers predicting development of a subsequent depressive episode in social anxiety disorder.

PubMed

Gottschalk, M G; Cooper, J D; Chan, M K; Bot, M; Penninx, B W J H; Bahn, S

2015-08-01

Although social anxiety disorder (SAD) is strongly associated with the subsequent development of a depressive disorder (major depressive disorder or dysthymia), no underlying biological risk factors are known. We aimed to identify biomarkers which predict depressive episodes in SAD patients over a 2-year follow-up period. One hundred sixty-five multiplexed immunoassay analytes were investigated in blood serum of 143 SAD patients without co-morbid depressive disorders, recruited within the Netherlands Study of Depression and Anxiety (NESDA). Predictive performance of identified biomarkers, clinical variables and self-report inventories was assessed using receiver operating characteristics curves (ROC) and represented by the area under the ROC curve (AUC). Stepwise logistic regression resulted in the selection of four serum analytes (AXL receptor tyrosine kinase, vascular cell adhesion molecule 1, vitronectin, collagen IV) and four additional variables (Inventory of Depressive Symptomatology, Beck Anxiety Inventory somatic subscale, depressive disorder lifetime diagnosis, BMI) as optimal set of patient parameters. When combined, an AUC of 0.86 was achieved for the identification of SAD individuals who later developed a depressive disorder. Throughout our analyses, biomarkers yielded superior discriminative performance compared to clinical variables and self-report inventories alone. We report the discovery of a serum marker panel with good predictive performance to identify SAD individuals prone to develop subsequent depressive episodes in a naturalistic cohort design. Furthermore, we emphasise the importance to combine biological markers, clinical variables and self-report inventories for disease course predictions in psychiatry. Following replication in independent cohorts, validated biomarkers could help to identify SAD patients at risk of developing a depressive disorder, thus facilitating early intervention. Copyright © 2015 Elsevier Inc. All rights reserved.

Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma

PubMed Central

Chauhan, Ranjit; Lahiri, Nivedita

2016-01-01

Hepatocellular carcinoma (HCC), one of the leading causes of cancer deaths in the world, is offering a challenge to human beings, with the current modes of treatment being a palliative approach. Lack of proper curative or preventive treatment methods encouraged extensive research around the world with an aim to detect a vaccine or therapeutic target biomolecule that could lead to development of a drug or vaccine against HCC. Biomarkers or biological disease markers have emerged as a potential tool as drug/vaccine targets, as they can accurately diagnose, predict, and even prevent the diseases. Biomarker expression in tissue, serum, plasma, or urine can detect tumor in very early stages of its development and monitor the cancer progression and also the effect of therapeutic interventions. Biomarker discoveries are driven by advanced techniques, such as proteomics, transcriptomics, whole genome sequencing, micro- and micro-RNA arrays, and translational clinics. In this review, an overview of the potential of tissue- and serum-associated HCC biomarkers as diagnostic, prognostic, and therapeutic targets for drug development is presented. In addition, we highlight recently developed micro-RNA, long noncoding RNA biomarkers, and single-nucleotide changes, which may be used independently or as complementary biomarkers. These active investigations going on around the world aimed at conquering HCC might show a bright light in the near future. PMID:27398029

Serum Metabolite Biomarkers Discriminate Healthy Smokers from COPD Smokers

PubMed Central

Chen, Qiuying; Deeb, Ruba S.; Ma, Yuliang; Staudt, Michelle R.; Crystal, Ronald G.; Gross, Steven S.

2015-01-01

COPD (chronic obstructive pulmonary disease) is defined by a fixed expiratory airflow obstruction associated with disordered airways and alveolar destruction. COPD is caused by cigarette smoking and is the third greatest cause of mortality in the US. Forced expiratory volume in 1 second (FEV1) is the only validated clinical marker of COPD, but it correlates poorly with clinical features and is not sensitive enough to predict the early onset of disease. Using LC/MS global untargeted metabolite profiling of serum samples from a well-defined cohort of healthy smokers (n = 37), COPD smokers (n = 41) and non-smokers (n = 37), we sought to discover serum metabolic markers with known and/or unknown molecular identities that are associated with early-onset COPD. A total of 1,181 distinct molecular ions were detected in 95% of sera from all study subjects and 23 were found to be differentially-expressed in COPD-smokers vs. healthy-smokers. These 23 putative biomarkers were differentially-correlated with lung function parameters and used to generate a COPD prediction model possessing 87.8% sensitivity and 86.5% specificity. In an independent validation set, this model correctly predicted COPD in 8/10 individuals. These serum biomarkers included myoinositol, glycerophopshoinositol, fumarate, cysteinesulfonic acid, a modified version of fibrinogen peptide B (mFBP), and three doubly-charged peptides with undefined sequence that significantly and positively correlate with mFBP levels. Together, elevated levels of serum mFBP and additional disease-associated biomarkers point to a role for chronic inflammation, thrombosis, and oxidative stress in remodeling of the COPD airways. Serum metabolite biomarkers offer a promising and accessible window for recognition of early-stage COPD. PMID:26674646

Detection of cancer biomarkers in serum using a hybrid mechanical and optoplasmonic nanosensor

NASA Astrophysics Data System (ADS)

Kosaka, P. M.; Pini, V.; Ruz, J. J.; da Silva, R. A.; González, M. U.; Ramos, D.; Calleja, M.; Tamayo, J.

2014-12-01

Blood contains a range of protein biomarkers that could be used in the early detection of disease. To achieve this, however, requires sensors capable of detecting (with high reproducibility) biomarkers at concentrations one million times lower than the concentration of the other blood proteins. Here, we show that a sandwich assay that combines mechanical and optoplasmonic transduction can detect cancer biomarkers in serum at ultralow concentrations. A biomarker is first recognized by a surface-anchored antibody and then by an antibody in solution that identifies a free region of the captured biomarker. This second antibody is tethered to a gold nanoparticle that acts as a mass and plasmonic label; the two signatures are detected by means of a silicon cantilever that serves as a mechanical resonator for ‘weighing’ the mass of the captured nanoparticles and as an optical cavity that boosts the plasmonic signal from the nanoparticles. The capabilities of the approach are illustrated with two cancer biomarkers: the carcinoembryonic antigen and the prostate specific antigen, which are currently in clinical use for the diagnosis, monitoring and prognosis of colon and prostate cancer, respectively. A detection limit of 1 × 10-16 g ml-1 in serum is achieved with both biomarkers, which is at least seven orders of magnitude lower than that achieved in routine clinical practice. Moreover, the rate of false positives and false negatives at this concentration is extremely low, ˜10-4.

Use of ProteinChip technology for identifying biomarkers of parasitic diseases: the example of porcine cysticercosis (Taenia solium).

PubMed

Deckers, N; Dorny, P; Kanobana, K; Vercruysse, J; Gonzalez, A E; Ward, B; Ndao, M

2008-12-01

Taenia solium cysticercosis is a significant public health problem in endemic countries. The current serodiagnostic techniques are not able to differentiate between infections with viable cysts and infections with degenerated cysts. The objectives of this study were to identify specific novel biomarkers of these different disease stages in the serum of experimentally infected pigs using ProteinChip technology (Bio-Rad) and to validate these biomarkers by analyzing serum samples from naturally infected pigs. In the experimental sample set 30 discriminating biomarkers (p<0.05) were found, 13 specific for the viable phenotype, 9 specific for the degenerated phenotype and 8 specific for the infected phenotype (either viable or degenerated cysts). Only 3 of these biomarkers were also significant in the field samples; however, the peak profiles were not consistent among the two sample sets. Five biomarkers discovered in the sera from experimentally infected pigs were identified as clusterin, lecithin-cholesterol acyltransferase, vitronectin, haptoglobin and apolipoprotein A-I.

Comparison of statistical methods for detection of serum lipid biomarkers for mesothelioma and asbestos exposure.

PubMed

Xu, Rengyi; Mesaros, Clementina; Weng, Liwei; Snyder, Nathaniel W; Vachani, Anil; Blair, Ian A; Hwang, Wei-Ting

2017-07-01

We compared three statistical methods in selecting a panel of serum lipid biomarkers for mesothelioma and asbestos exposure. Serum samples from mesothelioma, asbestos-exposed subjects and controls (40 per group) were analyzed. Three variable selection methods were considered: top-ranked predictors from univariate model, stepwise and least absolute shrinkage and selection operator. Crossed-validated area under the receiver operating characteristic curve was used to compare the prediction performance. Lipids with high crossed-validated area under the curve were identified. Lipid with mass-to-charge ratio of 372.31 was selected by all three methods comparing mesothelioma versus control. Lipids with mass-to-charge ratio of 1464.80 and 329.21 were selected by two models for asbestos exposure versus control. Different methods selected a similar set of serum lipids. Combining candidate biomarkers can improve prediction.

Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects

PubMed Central

Nam, H W; Karpyak, V M; Hinton, D J; Geske, J R; Ho, A M C; Prieto, M L; Biernacka, J M; Frye, M A; Weinshilboum, R M; Choi, D-S

2015-01-01

Acamprosate has been widely used since the Food and Drug Administration approved the medication for treatment of alcohol use disorders (AUDs) in 2004. Although the detailed molecular mechanism of acamprosate remains unclear, it has been largely known that acamprosate inhibits glutamate action in the brain. However, AUD is a complex and heterogeneous disorder. Thus, biomarkers are required to prescribe this medication to patients who will have the highest likelihood of responding positively. To identify pharmacometabolomic biomarkers of acamprosate response, we utilized serum samples from 120 alcohol-dependent subjects, including 71 responders (maintained continuous abstinence) and 49 non-responders (any alcohol use) during 12 weeks of acamprosate treatment. Notably, baseline serum glutamate levels were significantly higher in responders compared with non-responders. Importantly, serum glutamate levels of responders are normalized after acamprosate treatment, whereas there was no significant glutamate change in non-responders. Subsequent functional studies in animal models revealed that, in the absence of alcohol, acamprosate activates glutamine synthetase, which synthesizes glutamine from glutamate and ammonia. These results suggest that acamprosate reduces serum glutamate levels for those who have elevated baseline serum glutamate levels among responders. Taken together, our findings demonstrate that elevated baseline serum glutamate levels are a potential biomarker associated with positive acamprosate response, which is an important step towards development of a personalized approach to treatment for AUD. PMID:26285131

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

PubMed

Hathout, Yetrib; Brody, Edward; Clemens, Paula R; Cripe, Linda; DeLisle, Robert Kirk; Furlong, Pat; Gordish-Dressman, Heather; Hache, Lauren; Henricson, Erik; Hoffman, Eric P; Kobayashi, Yvonne Monique; Lorts, Angela; Mah, Jean K; McDonald, Craig; Mehler, Bob; Nelson, Sally; Nikrad, Malti; Singer, Britta; Steele, Fintan; Sterling, David; Sweeney, H Lee; Williams, Steve; Gold, Larry

2015-06-09

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

Low levels of serum serotonin and amino acids identified in migraine patients.

PubMed

Ren, Caixia; Liu, Jia; Zhou, Juntuo; Liang, Hui; Wang, Yayun; Sun, Yinping; Ma, Bin; Yin, Yuxin

2018-02-05

Migraine is a highly disabling primary headache associated with a high socioeconomic burden and a generally high prevalence. The clinical management of migraine remains a challenge. This study was undertaken to identify potential serum biomarkers of migraine. Using Liquid Chromatography coupled to Mass Spectrometry (LC-MS), the metabolomic profile of migraine was compared with healthy individuals. Principal component analysis (PCA) and Orthogonal partial least squares-discriminant analysis (orthoPLS-DA) showed the metabolomic profile of migraine is distinguishable from controls. Volcano plot analysis identified 10 serum metabolites significantly decreased during migraine. One of these was serotonin, and the other 9 were amino acids. Pathway analysis and enrichment analysis showed tryptophan metabolism (serotonin metabolism), arginine and proline metabolism, and aminoacyl-tRNA biosynthesis are the three most prominently altered pathways in migraine. ROC curve analysis indicated Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine are potential sensitive and specific biomarkers for migraine. Our results show Glycyl-l-proline, N-Methyl-dl-Alanine and l-Methionine may be as specific or more specific for migraine than serotonin which is the traditional biomarker of migraine. We propose that therapeutic manipulation of these metabolites or metabolic pathways may be helpful in the prevention and treatment of migraine. Copyright © 2018 Elsevier Inc. All rights reserved.

New serum biomarkers for prostate cancer diagnosis

PubMed Central

Chadha, Kailash C.; Miller, Austin; Nair, Bindukumar B.; Schwartz, Stanley A.; Trump, Donald L.; Underwood, Willie

2014-01-01

Background Prostate-specific antigen (PSA) is currently used as a biomarker for diagnosis and management of prostate cancer (CaP). However, PSA typically lacks the sensitivity and specificity desired of a diagnostic marker. Objective The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign versus malignant prostate disease and/or localized CaP versus metastatic CaP. Methods Concurrent measurements of circulating interleukin-8 (IL-8), Tumor necrosis factor-α (TNF-α) and soluble tumor necrosis factor-α receptors 1 (sTNFR1) were obtained from four groups of men: (1) Controls (2) with elevated prostate-specific antigen with a negative prostate biopsy (elPSA_negBx) (3) with clinically localized CaP and (4) with castration resistant prostate cancer. Results TNF-α Area under the receiver operating characteristic curve (AUC = 0.93) and sTNFR1 (AUC = 0.97) were strong predictors of elPSA_negBx (vs. CaP). The best predictor of elPSA_negBx vs CaP was sTNFR1 and IL-8 combined (AUC = 0.997). The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC = 0.992) and PSA (AUC = 0.963) levels. Conclusions The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in the larger cohort is warranted. PMID:25593898

Serum metabolome biomarkers associate low-level environmental perfluorinated compound exposure with oxidative /nitrosative stress in humans.

PubMed

Wang, Xiaofei; Liu, Liangpo; Zhang, Weibing; Zhang, Jie; Du, Xiaoyan; Huang, Qingyu; Tian, Meiping; Shen, Heqing

2017-10-01

Previous in vivo and in vitro studies have linked perfluorinated compound (PFC) exposure with metabolic interruption, but the inter-species difference and high treatment doses usually make the results difficult to be extrapolated to humans directly. The best strategy for identifying the metabolic interruption may be to establish the direct correlations between monitored PFCs data and metabolic data on human samples. In this study, serum metabolome data and PFC concentrations were acquired for a Chinese adult male cohort. The most abundant PFCs are PFOA and PFOS with concentration medians 7.56 and 12.78 nM, respectively; in together they count around 81.6% of the total PFCs. PFC concentration-related serum metabolic profile changes and the related metabolic biomarkers were explored by using partial least squares-discriminant analysis (PLS-DA). Respectively taking PFOS, PFOA and total PFC as the classifiers, serum metabolome can be differentiated between the lowest dose group (1st quartile PFCs) and the highest PFC dose group (4th quartile PFCs). Ten potential PFC biomarkers were identified, mainly involving in pollutant detoxification, antioxidation and nitric oxide (NO) signal pathways. These suggested that low-level environmental PFC exposure has significantly adverse impacts on glutathione (GSH) cycle, Krebs cycle, nitric oxide (NO) generation and purine oxidation in humans. To the best of our knowledge, this is the first report investigating the association of environmental PFC exposure with human serum metabolome alteration. Given the important biological functions of the identified biomarkers, we suggest that PFC could increase the metabolism syndromes risk including diabetes and cardiovascular diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Novel Serum Biomarkers Detected by Protein Array in Polycystic Ovary Syndrome with Low Progesterone Level.

PubMed

Zheng, Qin; Zhou, Feifei; Cui, Xinyuan; Liu, Mulin; Li, Yulin; Liu, Shuai; Tan, Jichun; Yan, Qiu

2018-01-01

Polycystic ovary syndrome (PCOS), characterized by female infertility and metabolic abnormalities, is one of the most common endocrine disorders. The etiology of PCOS remains unknown. The comprehensive analysis of protein alterations in PCOS patients is meaningful for identifying diagnostic biomarkers of PCOS. Here, we explored the clinical value of serum proteins as novel biomarkers to detect PCOS with low progesterone level. A total of 43 patients with PCOS and 30 healthy women were enrolled. Protein array was used to detect the variations of serum proteins between PCOS patients and healthy women. The level of five serum proteins was further confirmed by ELISA and western blot. The human ovarian granulosa cells (KGN) was cultured to examine the underlying mechanism of PCOS. CCK8 assay and western blot were carried out to evaluate the alterations in proliferative ability, TUNEL assay and DAPI staining to detect the apoptosis of KGN cells. Among the 507 proteins, we identified 76 differentially expressed serum proteins (≧1.5 fold), with 40 elevated and 36 decreased proteins. Moreover, 47 proteins were newly reported in PCOS. The alterations in the five significantly decreased proteins (EREG, inhibin βA, IDE, PDGF-D and KNG1) were further confirmed by ELISA and western blot. The level of these proteins were directly associated with the low progesterone, and the expression could be upregulated by progesterone. EREG and inhibin βA also promoted the proliferation and inhibited the apoptosis of ovarian granulosa cells. The study highlights that serum proteins are differentially expressed in PCOS patients and healthy women, and EREG and inhibin βA levels are upregulated by progesterone, which are correlated with ovarian functions. The study suggests that EREG and inhibin βA may be applied as novel potential biomarkers for PCOS with low progesterone level. © 2018 The Author(s). Published by S. Karger AG, Basel.

HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients.

PubMed

Napolitano, Andrea; Antoine, Daniel J; Pellegrini, Laura; Baumann, Francine; Pagano, Ian; Pastorino, Sandra; Goparaju, Chandra M; Prokrym, Kirill; Canino, Claudia; Pass, Harvey I; Carbone, Michele; Yang, Haining

2016-06-15

To determine whether serum levels of high mobility group box protein 1 (HMGB1) could differentiate malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Hyperacetylated and nonacetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from malignant mesothelioma patients (n = 22), individuals with verified chronic asbestos exposure (n = 20), patients with benign pleural effusions (n = 13) or malignant pleural effusions not due to malignant mesothelioma (n = 25), and healthy controls (n = 20). Blood levels of previously proposed malignant mesothelioma biomarkers fibulin-3, mesothelin, and osteopontin were also measured in nonhealthy individuals. HMGB1 serum levels reliably distinguished malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in malignant mesothelioma patients and asbestos-exposed individuals compared with healthy controls. Hyperacetylated HMGB1 was significantly higher in malignant mesothelioma patients compared with asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/mL, the sensitivity and specificity of serum hyperacetylated HMGB1 in differentiating malignant mesothelioma patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating malignant mesothelioma patients from patients with cytologically benign or malignant non-mesothelioma pleural effusion. Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyperacetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these

Urine and serum microRNA-1 as novel biomarkers for myocardial injury in open-heart surgeries with cardiopulmonary bypass.

PubMed

Zhou, Xian; Mao, Anqiong; Wang, Xiaobin; Duan, Xiaoxia; Yao, Yi; Zhang, Chunxiang

2013-01-01

MicroRNA-1 (miR-1) is a cardio-specific/enriched microRNA. Our recent studies have revealed that serum and urine miR-1 could be a novel sensitive biomarker for acute myocardial infarction. Open-heart surgeries with cardiopulmonary bypass (CPB) are often accompanied with surgery injury and CPB-associated injury on the hearts. However, the association of miR-1 and these intra-operative and post-operative cardiac injures is unknown. The objective of this study was to test the hypothesis that urine and serum miR-1 might be a novel biomarker for myocardial injuries in open-heart surgeries with CPB. Serum and urine miR-1 levels in 20 patients with elective mitral valve surgery were measured at pre-surgery, pre-CPB, 60 min post-CBP, and 24h post-CBP. Serum cardiac troponin-I (cTnI) was used as a positive control biomarker for cardiac injury. Compared with these in pre-operative and pre-CPB groups, the levels of miR-1 in serum and urine from patients after open-heart surgeries and CPB were significant increased at all observed time points. A similar pattern of serum cTnI levels and their strong positive correlation with miR-1 levels were identified in these patients. The results suggest that serum and urine miR-1 may be a novel sensitive biomarker for myocardial injury in open-heart surgeries with CPB.

Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery--a prospective cohort study.

PubMed

Haase-Fielitz, Anja; Bellomo, Rinaldo; Devarajan, Prasad; Story, David; Matalanis, George; Dragun, Duska; Haase, Michael

2009-02-01

To compare the value of novel with conventional serum biomarkers in the prediction of acute kidney injury (AKI) in adult cardiac surgical patients according to preoperative renal function. Single-center, prospective observational study. Tertiary hospital. One hundred adult cardiac surgical patients. We measured concentrations of plasma neutrophil gelatinase-associated lipocalin (NGAL), and serum cystatin C, and creatinine and urea at baseline, on arrival in the intensive care unit (ICU) and at 24 hours postoperatively. We assessed such biomarkers in relation to the development of AKI (>50% increase in creatinine from baseline) and to a composite end point (need for renal replacement therapy and in-hospital mortality). We defined an area under the receiver operating characteristic curve of 0.60-0.69 as poor, 0.70-0.79 as fair, 0.80-0.89 as good, and 0.90-1.00 as excellent in terms of predictive value. On arrival in ICU, plasma NGAL and serum cystatin C were of good predictive value, but creatinine and urea were of poor predictive value. After exclusion of patients with preoperative renal impairment (estimated glomerular filtration rate <60 mL/min), the predictive performance for AKI of all renal biomarkers on arrival in ICU remained unchanged except for cystatin C, which was of fair value in such patients. At 24 hours postoperatively, all renal biomarkers were of good predictive value. On arrival in ICU, novel biomarkers were superior to conventional biomarkers (p < 0.05). Plasma NGAL (p = 0.015) and serum cystatin C (p = 0.007) were independent predictors of AKI and of excellent value in the prediction of the composite end point. Early postoperative measurement of plasma NGAL was of good value in identifying patients who developed AKI after adult cardiac surgery. Plasma NGAL and serum cystatin C were superior to conventional biomarkers in the prediction of AKI and were also of prognostic value in this setting.

Preclinical Alterations in the Serum of COL(IV)A3(-)/(-) Mice as Early Biomarkers of Alport Syndrome.

PubMed

Muckova, Petra; Wendler, Sindy; Rubel, Diana; Büchler, Rita; Alert, Mandy; Gross, Oliver; Rhode, Heidrun

2015-12-04

The efficiency of the inhibition of the angiotensin converting enzyme, the most widely used therapy for the Alport syndrome, depends on the onset of the therapy-the earlier the better. Hence, early progressive biomarkers are urgently required to allow for preclinical diagnosis, an early start of possible therapy as well as the monitoring of this therapy. In the present study, an improved comprehensive and precise proteomic approach has been applied to the serum of juvenile Alport-mice, nontreated and treated, and wild-type controls of various ages to search for biomarkers. With a total of 2542 stringently altered proteins, the serum composition clearly shows a dependency on age, that is, stage, and therapy. Initially, the serum constituents indicate an enhanced extracellular matrix remodeling, cell damage, and the production of particular acute phase proteins. A panel of 15 potential biomarker candidates has been identified. In later stages, renal filtration failure and systemic acute phase reaction determine the composition of the serum; an effect that is well-known for manifested human Alport syndrome. With a small number of mouse urine samples, for example, the proteomic results for gelsolin could be verified using ELISA. Once verified in man, these early biomarkers would allow for a sensitive and specific diagnosis of the Alport syndrome in children as well as facilitate the monitoring of a possible therapy.

International Team Identifies Biomarker for Scleroderma

MedlinePlus

... Identifies Biomarker for Scleroderma Spotlight on Research International Team Identifies Biomarker for Scleroderma By Kirstie Saltsman, Ph. ... suggests it stems from immune system malfunction. The team chose to focus on immune cells called plasmacytoid ...

Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study.

PubMed

Kirino, Yohei; Kawaguchi, Yasushi; Tada, Yoshifumi; Tsukamoto, Hiroshi; Ota, Toshiyuki; Iwamoto, Masahiro; Takahashi, Hiroki; Nagasawa, Kohei; Takei, Shuji; Horiuchi, Takahiko; Ichida, Hisae; Minota, Seiji; Ueda, Atsuhisa; Ohta, Akihide; Ishigatsubo, Yoshiaki

2018-01-11

Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive

Global analysis of serum microRNAs as potential biomarkers for lung adenocarcinoma.

PubMed

Rani, Sweta; Gately, Kathy; Crown, John; O'Byrne, Ken; O'Driscoll, Lorraine

2013-12-01

Early diagnosis and the ability to predict the most relevant treatment option for individuals is essential to improve clinical outcomes for non-small cell lung cancer (NSCLC) patients. Adenocarcinoma (ADC), a subtype of NSCLC, is the single biggest cancer killer and therefore an urgent need to identify minimally invasive biomarkers to enable early diagnosis. Recent studies, by ourselves and others, indicate that circulating miRNAs have potential as biomarkers. Here we applied global profiling approaches in serum from patients with ADC of the lung to explore if miRNAs have potential as diagnostic biomarkers. This study involved RNA isolation from 80 sera specimens including those from ADC patients (equal numbers of stages 1, 2, 3, and 4) and age- and gender-matched controls (n = 40 each). Six hundred and sixty-seven miRNAs were co-analyzed in these specimens using TaqMan low density arrays and qPCR validation using individual miRNAs. Overall, approximately 390 and 370 miRNAs were detected in ADC and control sera, respectively. A group of 6 miRNAs, miR-30c-1* (AUC = 0.74; P<0.002), miR-616* (AUC = 0.71; P = 0.001), miR-146b-3p (AUC = 0.82; P<0.0001), miR-566 (AUC = 0.80; P<0.0001), miR-550 (AUC = 0.72; P = 0.0006), and miR-939 (AUC = 0.82; P<0.0001) was found to be present at substantially higher levels in ADC compared with control sera. Conversely, miR-339-5p and miR-656 were detected at substantially lower levels in ADC sera (co-analysis resulting in AUC = 0.6; P = 0.02). Differences in miRNA profile identified support circulating miRNAs having potential as diagnostic biomarkers for ADC. More extensive studies of ADC and control serum specimens are warranted to independently validate the potential clinical relevance of these miRNAs as minimally invasive biomarkers for ADC.

Serum miR-300 as a diagnostic and prognostic biomarker in osteosarcoma.

PubMed

Liu, Jian-Dong; Xin, Qun; Tao, Chun-Sheng; Sun, Pei-Feng; Xu, Peng; Wu, Bing; Qu, Liang; Li, Shu-Zhong

2016-11-01

In order to determine whether microRNA (miR)-300 is a diagnostic and prognostic biomarker in osteosarcoma, the miR-300 levels in serum of 114 osteosarcoma patients and 114 healthy controls were compared, followed by serum analysis of the differences between the pre-operative and post-operative sera of these osteosarcoma patients. It was observed that the concentration levels of miR-300 in the serum of osteosarcoma patients was significantly higher than those in the serum of healthy controls (P<0.01). Furthermore, the concentration levels of miR-300 in the post-operative serum were significantly reduced when compared with the pre-operative serum levels (P<0.001). High miR-300 levels in serum correlated significantly with clinical stage, distant metastasis and poor survival of osteosarcoma patients. Notably, serum miR-300 was an independent prognostic marker for osteosarcoma. In conclusion, our results suggested that serum miR-300 may be a potential and useful noninvasive biomarker for the early detection of osteosarcoma.

Serum miR-300 as a diagnostic and prognostic biomarker in osteosarcoma

PubMed Central

Liu, Jian-Dong; Xin, Qun; Tao, Chun-Sheng; Sun, Pei-Feng; Xu, Peng; Wu, Bing; Qu, Liang; Li, Shu-Zhong

2016-01-01

In order to determine whether microRNA (miR)-300 is a diagnostic and prognostic biomarker in osteosarcoma, the miR-300 levels in serum of 114 osteosarcoma patients and 114 healthy controls were compared, followed by serum analysis of the differences between the pre-operative and post-operative sera of these osteosarcoma patients. It was observed that the concentration levels of miR-300 in the serum of osteosarcoma patients was significantly higher than those in the serum of healthy controls (P<0.01). Furthermore, the concentration levels of miR-300 in the post-operative serum were significantly reduced when compared with the pre-operative serum levels (P<0.001). High miR-300 levels in serum correlated significantly with clinical stage, distant metastasis and poor survival of osteosarcoma patients. Notably, serum miR-300 was an independent prognostic marker for osteosarcoma. In conclusion, our results suggested that serum miR-300 may be a potential and useful noninvasive biomarker for the early detection of osteosarcoma. PMID:27895748

Characterization of serum microRNAs profile of PCOS and identification of novel non-invasive biomarkers.

PubMed

Long, Wei; Zhao, Chun; Ji, Chenbo; Ding, Hongjuan; Cui, Yugui; Guo, Xirong; Shen, Rong; Liu, Jiayin

2014-01-01

Polycystic ovary syndrome (PCOS), the most common endocrinopathy in women of reproductive age, is characterized by polycystic ovaries, chronic anovulation, hyperandrogenism and insulin resistance. Despite the high prevalence of hyperandrogenemia, a definitive endocrine marker for PCOS has so far not been identified. Circulating miRNAs have recently been shown to serve as diagnostic/prognostic biomarkers in patients with cancers. Our current study focused on the altered expression of serum miRNAs and their correlation with PCOS. We systematically used the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays to identify and validate the expression of serum miRNAs of PCOS patients. The expression levels of three miRNAs (miR-222, miR-146a and miR-30c) were significantly increased in PCOS patients with respect to the controls in our discovery evaluation and followed validation. The area under the receiver operating characteristic (ROC) curve (AUC) is 0.799, 0.706, and 0.688, respectively. The combination of the three miRNAs using multiple logistic regression analysis showed a larger AUC (0.852) that was more efficient for the diagnosis of PCOS. In addition, logistic binary regression analyses show miR-222 is positively associated with serum insulin, while miR-146a is negatively associated with serum testosterone. Furthermore, bioinformatics analysis indicated that the predicted targets function of the three miRNAs mainly involved in the metastasis, cell cycle, apoptosis and endocrine. Serum miRNAs are differentially expressed between PCOS patients and controls. We identified and validated a class of three serum miRNAs that could act as novel non-invasive biomarkers for diagnosis of PCOS. These miRNAs may be involved in the pathogenesis of PCOS. © 2014 S. Karger AG, Basel.

Bio-logic analysis of injury biomarker patterns in human serum samples.

PubMed

Zhou, Jian; Halámek, Jan; Bocharova, Vera; Wang, Joseph; Katz, Evgeny

2011-01-15

Digital biosensor systems analyzing biomarkers characteristic of liver injury (LI), soft tissue injury (STI) and abdominal trauma (ABT) were developed and optimized for their performance in serum solutions spiked with injury biomarkers in order to mimic real medical samples. The systems produced 'Alert'-type optical output signals in the form of "YES-NO" separated by a threshold value. The new approach aims at the reliable detection of injury biomarkers for making autonomous decisions towards timely therapeutic interventions, particularly in conditions when a hospital treatment is not possible. The enzyme-catalyzed reactions performing Boolean AND/NAND logic operations in the presence of different combinations of the injury biomarkers allowed high-fidelity biosensing. Robustness of the systems was confirmed by their operation in serum solutions, representing the first example of chemically performed logic analysis of biological fluids and a step closer towards practical biomedical applications of enzyme-logic bioassays. Copyright © 2010 Elsevier B.V. All rights reserved.

Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy

PubMed Central

Burch, Peter M.; Pogoryelova, Oksana; Goldstein, Richard; Bennett, Donald; Guglieri, Michela; Straub, Volker; Bushby, Kate; Lochmüller, Hanns; Morris, Carl

2015-01-01

Abstract Background: Identifying translatable, non-invasive biomarkers of muscular dystrophy that better reflect the disease pathology than those currently available would aid the development of new therapies, the monitoring of disease progression and the response to therapy. Objective: The goal of this study was to evaluate a panel of serum protein biomarkers with the potential to specifically detect skeletal muscle injury. Method: Serum concentrations of skeletal troponin I (sTnI), myosin light chain 3 (Myl3), fatty acid binding protein 3 (FABP3) and muscle-type creatine kinase (CKM) proteins were measured in 74 Duchenne muscular dystrophy (DMD), 38 Becker muscular dystrophy (BMD) and 49 Limb-girdle muscular dystrophy type 2B (LGMD2B) patients and 32 healthy controls. Results: All four proteins were significantly elevated in the serum of these three muscular dystrophy patient populations when compared to healthy controls, but, interestingly, displayed different profiles depending on the type of muscular dystrophy. Additionally, the effects of patient age, ambulatory status, cardiac function and treatment status on the serum concentrations of the proteins were investigated. Statistical analysis revealed correlations between the serum concentrations and certain clinical endpoints including forced vital capacity in DMD patients and the time to walk ten meters in LGMD2B patients. Serum concentrations of these proteins were also elevated in two preclinical models of muscular dystrophy, the mdx mouse and the golden-retriever muscular dystrophy dog. Conclusions: These proteins, therefore, are potential muscular dystrophy biomarkers for monitoring disease progression and therapeutic response in both preclinical and clinical studies. PMID:26870665

Serum decoy receptor 3, a potential new biomarker for sepsis.

PubMed

Hou, Yan-Qiang; Xu, Ping; Zhang, Mei; Han, Deping; Peng, Liang; Liang, Dong-Yu; Yang, Shanmin; Zhang, Zhenhuan; Hong, Jinsheng; Lou, Xiao-Li; Zhang, Lurong; Kim, Sunghee

2012-04-11

Sepsis, a common deadly systemic infection caused by a variety of pathogens, has some clinical symptoms similar to the systemic inflammatory response syndrome (SIRS), a whole-body non-infectious inflammatory reaction to severe insults, such as burn, trauma, hypotensive shock and so on. Treatment of sepsis depends mainly on anti-microbial, while remedy for SIRS might require steroids that could possibly enhance the spread of microbes. Unfortunately, it is very difficult to distinguish these two completely different serious conditions without blood culture, which takes days to grow and identify causative pathogens. We examined a biomarker, serum decoy receptor 3 (DcR3), was evaluated for its utility in the differential diagnosis between sepsis and SIRS. Serum DcR3 level in 118 healthy controls, 24 sepsis patients and 43 SIRS patients, was quantitatively measured by enzyme-linked immunosorbent assay (ELISA). The serum DcR3 was significantly increased in sepsis patients compared with SIRS patients and healthy controls (6.11±2.58 ng/ml vs 2.62±1.46 ng/ml, and 0.91±0.56 ng/ml, respectively, p<0.001). The areas under the receiver operating characteristic curve of DcR3 for the normal vs. SIRS, normal vs. sepsis and SIRS vs. sepsis were 0.910 (0.870-0.950), 0.992 (0.984-1.000) and 0.896 (0.820-0.973), respectively. In addition, the DcR3 exhibited a positive correlation coefficient with APACHE II score, a most commonly used index for the severity of sepsis (r=0.556, p=0.005). The serum DcR3 has a potential to serve as a new biomarker for sepsis with its high specificity and sensitivity. Copyright © 2012 Elsevier B.V. All rights reserved.

Chronic hepatitis C virus infection: Serum biomarkers in predicting liver damage

PubMed Central

Valva, Pamela; Ríos, Daniela A; De Matteo, Elena; Preciado, Maria V

2016-01-01

Currently, a major clinical challenge in the management of the increasing number of hepatitis C virus (HCV) infected patients is determining the best means for evaluating liver impairment. Prognosis and treatment of chronic hepatitis C (CHC) are partly dependent on the assessment of histological activity, namely cell necrosis and inflammation, and the degree of liver fibrosis. These parameters can be provided by liver biopsy; however, in addition to the risks related to an invasive procedure, liver biopsy has been associated with sampling error mostly due to suboptimal biopsy size. To avoid these pitfalls, several markers have been proposed as non-invasive alternatives for the diagnosis of liver damage. Distinct approaches among the currently available non-invasive methods are (1) the physical ones based on imaging techniques; and (2) the biological ones based on serum biomarkers. In this review, we discuss these approaches with special focus on currently available non-invasive serum markers. We will discuss: (1) class I serum biomarkers individually and as combined panels, particularly those that mirror the metabolism of liver extracellular matrix turnover and/or fibrogenic cell changes; (2) class II biomarkers that are indirect serum markers and are based on the evaluation of common functional alterations in the liver; and (3) biomarkers of liver cell death, since hepatocyte apoptosis plays a significant role in the pathogenesis of HCV infection. We highlight in this review the evidence behind the use of these markers and assess the diagnostic accuracy as well as advantages, limitations, and application in clinical practice of each test for predicting liver damage in CHC. PMID:26819506

Serum Glutamine Levels as a Potential Diagnostic Biomarker in Sepsis following Surgery for Peritonitis.

PubMed

Yang, Chun-Ju; Huang, Ting-Shuo; Lee, Tung-Liang; Yang, Kang-Chung; Yuan, Shin-Sheng; Lu, Ruey-Hwa; Hsieh, Chung-Ho; Shyu, Yu-Chiau

2017-12-31

Few diagnostic biomarkers for sepsis after emergency peritonitis surgery are available to clinicians, and, thus, it is important to develop new biomarkers for patients undergoing this procedure. We investigated whether serum glutamine and selenium levels could be diagnostic biomarkers of sepsis in individuals recovering from emergency peritonitis surgery. From February 2012 to March 2013, patients who had peritonitis diagnosed at the emergency department and underwent emergency surgery were screened for eligibility. Serum glutamine and selenium levels were obtained at pre-operative, post-operative and recovery time points. The average level of pre-operation serum glutamine was significantly different from that on the recovery day (0.317 ± 0.168 vs. 0.532 ± 0.155 mM, P < 0.001); moreover, serum glutamine levels were unaffected by surgery. Selenium levels were significantly lower on the day of surgery than they were at recovery (106.6 ± 36.39 vs. 130.68 ± 56.98 ng/mL, P = 0.013); no significant difference was found between pre-operation and recovery selenium levels. Unlike selenium, glutamine could be a sepsis biomarker for individuals with peritonitis. We recommend including glutamine as a biomarker for sepsis severity assessment in addition to the commonly used clinical indicators.

The Choice of Euthanasia Method Affects Metabolic Serum Biomarkers.

PubMed

Pierozan, Paula; Jernerén, Fredrik; Ransome, Yusuf; Karlsson, Oskar

2017-08-01

The impact of euthanasia methods on endocrine and metabolic parameters in rodent tissues and biological fluids is highly relevant for the accuracy and reliability of the data collected. However, few studies concerning this issue are found in the literature. We compared the effects of three euthanasia methods currently used in animal experimentation (i.e. decapitation, CO 2 inhalation and pentobarbital injection) on the serum levels of corticosterone, insulin, glucose, triglycerides, cholesterol and a range of free fatty acids in rats. The corticosterone and insulin levels were not significantly affected by the euthanasia protocol used. However, euthanasia by an overdose of pentobarbital (120 mg/kg intraperitoneal injection) increased the serum levels of glucose, and decreased cholesterol, stearic and arachidonic acids levels compared with euthanasia by CO 2 inhalation and decapitation. CO 2 inhalation appears to increase the serum levels of triglycerides, while euthanasia by decapitation induced no individual discrepant biomarker level. We conclude that choice of the euthanasia methods is critical for the reliability of serum biomarkers and indicate the importance of selecting adequate euthanasia methods for metabolic analysis in rodents. Decapitation without anaesthesia may be the most adequate method of euthanasia when taking both animal welfare and data quality in consideration. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

The Choice of Euthanasia Method Affects Metabolic Serum Biomarkers

PubMed Central

Pierozan, Paula; Jernerén, Fredrik; Ransome, Yusuf; Karlsson, Oskar

2018-01-01

The impact of euthanasia methods on endocrine and metabolic parameters in rodent tissues and biological fluids is highly relevant for the accuracy and reliability of the data collected. However, few studies concerning this issue are found in the literature. We compared the effects of three euthanasia methods currently used in animal experimentation (i.e. decapitation, CO2 inhalation and pentobarbital injection) on the serum levels of corticosterone, insulin, glucose, triglycerides, cholesterol and a range of free fatty acids in rats. The corticosterone and insulin levels were not significantly affected by the euthanasia protocol used. However, euthanasia by an overdose of pentobarbital (120 mg/kg intraperitoneal injection) increased the serum levels of glucose, and decreased cholesterol, stearic and arachidonic acids levels compared with euthanasia by CO2 inhalation and decapitation. CO2 inhalation appears to increase the serum levels of triglycerides, while euthanasia by decapitation induced no individual discrepant biomarker level. We conclude that choice of the euthanasia methods is critical for the reliability of serum biomarkers and indicate the importance of selecting adequate euthanasia methods for metabolic analysis in rodents. Decapitation without anaesthesia may be the most adequate method of euthanasia when taking both animal welfare and data quality in consideration. PMID:28244216

Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma

PubMed Central

Arakawa, Noriaki; Kobayashi, Hiroshi; Yonemoto, Naohiro; Masuishi, Yusuke; Ino, Yoko; Shigetomi, Hiroshi; Furukawa, Naoto; Ohtake, Norihisa; Miyagi, Yohei; Hirahara, Fumiki; Hirano, Hisashi; Miyagi, Etsuko

2016-01-01

Background There is currently no reliable serum biomarker for ovarian clear cell carcinoma (CCC), a highly lethal histological subtype of epithelial ovarian cancer (EOC). Previously, using a proteome-based approach, we identified tissue factor pathway inhibitor 2 (TFPI2) as a candidate serum biomarker for CCC. In this study, we sought to evaluate the clinical diagnostic performance of TFPI2 in preoperative prediction of CCC. Methods Serum TFPI2 levels were measured in serum samples from a retrospective training set consisting of patients with benign and borderline ovarian tumors, EOC subtypes, and uterine diseases. Via receiver operating characteristic (ROC) analyses, we compared the diagnostic performance of TFPI2 with that of CA125 in discrimination of patients with ovarian CCC from other patient groups. The observed diagnostic performances were examined in a prospective validation set. Results The 268-patient training set included 29 patients with ovarian CCC. Unlike CA125, which was also elevated in patients with endometriosis and several EOC subtypes, serum TFPI2 levels were specifically elevated only in ovarian CCC patients, consistent with the mRNA expression pattern in tumor tissues. The area under the ROC curve (AUC) of serum TFPI2 was obviously higher than that of CA125 for discrimination of CCC from other ovarian diseases (AUC = 0.891 versus 0.595). Applying a cut-off value of 280 pg/mL, TFPI2 could distinguish early-stage (FIGO I and II) CCC from endometriosis with 72.2% sensitivity, 93.3% specificity, and 88.8% accuracy. Similar results were confirmed in an independent 156-patient prospective validation set. Conclusions TFPI2 is a useful serum biomarker for preoperative clinical diagnosis of CCC. PMID:27798689

Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma.

PubMed

Arakawa, Noriaki; Kobayashi, Hiroshi; Yonemoto, Naohiro; Masuishi, Yusuke; Ino, Yoko; Shigetomi, Hiroshi; Furukawa, Naoto; Ohtake, Norihisa; Miyagi, Yohei; Hirahara, Fumiki; Hirano, Hisashi; Miyagi, Etsuko

2016-01-01

There is currently no reliable serum biomarker for ovarian clear cell carcinoma (CCC), a highly lethal histological subtype of epithelial ovarian cancer (EOC). Previously, using a proteome-based approach, we identified tissue factor pathway inhibitor 2 (TFPI2) as a candidate serum biomarker for CCC. In this study, we sought to evaluate the clinical diagnostic performance of TFPI2 in preoperative prediction of CCC. Serum TFPI2 levels were measured in serum samples from a retrospective training set consisting of patients with benign and borderline ovarian tumors, EOC subtypes, and uterine diseases. Via receiver operating characteristic (ROC) analyses, we compared the diagnostic performance of TFPI2 with that of CA125 in discrimination of patients with ovarian CCC from other patient groups. The observed diagnostic performances were examined in a prospective validation set. The 268-patient training set included 29 patients with ovarian CCC. Unlike CA125, which was also elevated in patients with endometriosis and several EOC subtypes, serum TFPI2 levels were specifically elevated only in ovarian CCC patients, consistent with the mRNA expression pattern in tumor tissues. The area under the ROC curve (AUC) of serum TFPI2 was obviously higher than that of CA125 for discrimination of CCC from other ovarian diseases (AUC = 0.891 versus 0.595). Applying a cut-off value of 280 pg/mL, TFPI2 could distinguish early-stage (FIGO I and II) CCC from endometriosis with 72.2% sensitivity, 93.3% specificity, and 88.8% accuracy. Similar results were confirmed in an independent 156-patient prospective validation set. TFPI2 is a useful serum biomarker for preoperative clinical diagnosis of CCC.

Least absolute shrinkage and selection operator type methods for the identification of serum biomarkers of overweight and obesity: simulation and application.

PubMed

Vasquez, Monica M; Hu, Chengcheng; Roe, Denise J; Chen, Zhao; Halonen, Marilyn; Guerra, Stefano

2016-11-14

The study of circulating biomarkers and their association with disease outcomes has become progressively complex due to advances in the measurement of these biomarkers through multiplex technologies. The Least Absolute Shrinkage and Selection Operator (LASSO) is a data analysis method that may be utilized for biomarker selection in these high dimensional data. However, it is unclear which LASSO-type method is preferable when considering data scenarios that may be present in serum biomarker research, such as high correlation between biomarkers, weak associations with the outcome, and sparse number of true signals. The goal of this study was to compare the LASSO to five LASSO-type methods given these scenarios. A simulation study was performed to compare the LASSO, Adaptive LASSO, Elastic Net, Iterated LASSO, Bootstrap-Enhanced LASSO, and Weighted Fusion for the binary logistic regression model. The simulation study was designed to reflect the data structure of the population-based Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD), specifically the sample size (N = 1000 for total population, 500 for sub-analyses), correlation of biomarkers (0.20, 0.50, 0.80), prevalence of overweight (40%) and obese (12%) outcomes, and the association of outcomes with standardized serum biomarker concentrations (log-odds ratio = 0.05-1.75). Each LASSO-type method was then applied to the TESAOD data of 306 overweight, 66 obese, and 463 normal-weight subjects with a panel of 86 serum biomarkers. Based on the simulation study, no method had an overall superior performance. The Weighted Fusion correctly identified more true signals, but incorrectly included more noise variables. The LASSO and Elastic Net correctly identified many true signals and excluded more noise variables. In the application study, biomarkers of overweight and obesity selected by all methods were Adiponectin, Apolipoprotein H, Calcitonin, CD14, Complement 3, C-reactive protein, Ferritin

Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports

PubMed Central

Zetterberg, Henrik; Tegner, Yelverton; Blennow, Kaj

2017-01-01

Objective: To evaluate whether the axonal protein neurofilament light (NFL) in serum is a sensitive biomarker to detect subtle brain injury or concussion in contact sports athletes. Methods: Two prospective cohort studies involving (1) 14 Swedish amateur boxers who underwent fluid biomarker assessments at 7–10 days after bout and after 3 months of rest from boxing and (2) 35 Swedish professional hockey players who underwent blood biomarker assessment at 1, 12, 36, and 144 hours after concussion and when the players returned to play were performed. Fourteen healthy nonathletic controls and 12 athletic controls were also enrolled. Serum NFL was measured using ultrasensitive single molecule array technology. Results: Serum NFL concentrations were increased in boxers 7–10 days after bout as compared to the levels after 3 months rest as well as compared with controls (p = 0.0007 and p < 0.0001, respectively). NFL decreased following 3 months of rest, but was still higher than in controls (p < 0.0001). Boxers who received many (>15) hits to the head or were groggy after bout had higher concentrations of serum NFL as compared to those who received fewer hits to the head (p = 0.0023). Serum NFL increased over time in hockey players, and the levels returned to normal at return to play. Importantly, serum NFL could separate players with rapidly resolving postconcussion symptoms (PCS) from those with prolonged PCS. Conclusions: The results from these 2 independent cohort studies suggest that serum NFL is a highly sensitive biomarker for concussion. PMID:28404801

A cross sectional study of two independent cohorts identifies serum biomarkers for facioscapulohumeral muscular dystrophy (FSHD)

PubMed Central

Petek, Lisa M.; Rickard, Amanda M.; Budech, Christopher; Poliachik, Sandra L.; Shaw, Dennis; Ferguson, Mark R.; Tawil, Rabi; Friedman, Seth D.; Miller, Daniel G.

2016-01-01

Measuring the severity and progression of facioscapulohumeral muscular dystrophy (FSHD) is particularly challenging because muscle weakness progresses over long periods of time and can be sporadic. Biomarkers are essential for measuring disease burden and testing treatment strategies. We utilized the sensitive, specific, high-throughput SomaLogic proteomics platform of 1129 proteins to identify proteins with levels that correlate with FSHD severity in a cross-sectional study of two independent cohorts. We discovered biomarkers that correlate with clinical severity and disease burden measured by magnetic resonance imaging. Sixty-eight proteins in the Rochester cohort (n = 48) and 51 proteins in the Seattle cohort (n = 30) had significantly different levels in FSHD-affected individuals when compared with controls (p-value ≤ .005). A subset of these varied by at least 1.5 fold and four biomarkers were significantly elevated in both cohorts. Levels of creatine kinase MM and MB isoforms, carbonic anhydrase III, and troponin I type 2 reliably predicted the disease state and correlated with disease severity. Other novel biomarkers were also discovered that may reveal mechanisms of disease pathology. Assessing the levels of these biomarkers during clinical trials may add significance to other measures of quantifying disease progression or regression. PMID:27185459

Biomarkers intersect with the exposome

PubMed Central

Rappaport, Stephen M.

2016-01-01

The exposome concept promotes use of omic tools for discovering biomarkers of exposure and biomarkers of disease in studies of diseased and healthy populations. A two-stage scheme is presented for profiling omic features in serum to discover molecular biomarkers and then for applying these biomarkers in follow-up studies. The initial component, referred to as an exposome-wide-association study (EWAS), employs metabolomics and proteomics to interrogate the serum exposome and, ultimately, to identify, validate and differentiate biomarkers of exposure and biomarkers of disease. Follow-up studies employ knowledge-driven designs to explore disease causality, prevention, diagnosis, prognosis and treatment. PMID:22672124

The Use of Breast Magnetic Resonance Imaging Parameters to Identify Possible Signaling Pathways of a Serum Biomarker, HE4.

PubMed

Durur-Karakaya, Afak; Durur-Subasi, Irmak; Karaman, Adem; Akcay, Mufide Nuran; Palabiyik, Saziye Sezin; Erdemci, Burak; Alper, Fatih; Acemoglu, Hamit

2016-01-01

This study aimed to investigate the relationship between breast magnetic resonance imaging (MRI) parameters; clinical features such as age, tumor diameter, N, T, and TNM stages; and serum human epididymis protein 4 (HE4) levels in patients with breast carcinoma and use this as a means of estimating possible signaling pathways of the biomarker, HE4. Thirty-seven patients with breast cancer were evaluated by breast MRI and serum HE4 levels before therapy. Correlations between parameters including age, tumor diameter T and N, dynamic curve type, enhancement ratio (ER), slope washin (S-WI), time to peak (TTP), slope washout (S-WO), and the serum level of HE4 were investigated statistically. Human epididymis protein 4 levels of early and advanced stage of disease were also compared statistically. Breast MRI parameters showed correlation to serum HE4 levels and correlations were statistically significant. Of these MRI parameters, S-WI had higher correlation coefficient than the others. Human epididymis protein 4 levels were not statistically different in early and advanced stage of disease. High correlation with MRI parameters related to neoangiogenesis may indicate signaling pathway of HE4.

Effects of extracorporeal shock wave therapy and polysulfated glycosaminoglycan treatment on subchondral bone, serum biomarkers, and synovial fluid biomarkers in horses with induced osteoarthritis.

PubMed

Kawcak, Chris E; Frisbie, David D; McIlwraith, C Wayne

2011-06-01

To evaluate effects of extracorporeal shock wave therapy (ESWT) and polysulfated glycosaminoglycan treatment (PSGAGT) on subchondral bone (SCB), serum biomarkers, and synovial fluid biomarkers in horses with induced osteoarthritis. 24 healthy 2- to 3-year-old horses. An osteochondral fragment was created on the distal aspect of the radial carpal bone in 1 middle carpal joint of each horse. Horses were randomly allocated to receive local application of ESWT (days 14 and 28; n = 8), PSGAGT (IM, q 4 d for 28 days; 8), or a sham ESWT probe (placebo; days 14 and 28; 8). Serum biomarkers were measured every 7 days, and synovial fluid biomarkers were measured every 14 days. Bone density was measured by use of computed tomography on days 0 and 70, and microdamage and bone formation variables were compared among groups at the end of the study (day 70). There was no significant effect of ESWT or PSGAGT on any bone variable. Serum osteocalcin concentration was significantly greater in horses that received ESWT, compared with placebo-treated horses, and serum concentration of the C-terminal telopeptide of type I collagen was significantly higher in horses that received ESWT, compared with placebo- and PSGAG-treated horses. Concentrations of the synovial fluid epitope CS846 were significantly higher in joints with osteoarthritis treated with ESWT CONCLUSIONS AND CLINICAL RELEVANCE: Treatment of osteoarthritis with ESWT had no effect on SCB but did induce increases in serum biomarkers indicative of bone remodeling. Treatment of osteoarthritis with PSGAG had no effect on SCB or biomarkers.

Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1.

PubMed

Cluzeau, Celine V M; Watkins-Chow, Dawn E; Fu, Rao; Borate, Bhavesh; Yanjanin, Nicole; Dail, Michelle K; Davidson, Cristin D; Walkley, Steven U; Ory, Daniel S; Wassif, Christopher A; Pavan, William J; Porter, Forbes D

2012-08-15

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1(-/-) survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.

Identification of serum biomarkers in dogs naturally infected with Babesia canis canis using a proteomic approach

PubMed Central

2014-01-01

Background Canine babesiosis is a tick-borne disease that is caused by the haemoprotozoan parasites of the genus Babesia. There are limited data on serum proteomics in dogs, and none of the effect of babesiosis on the serum proteome. The aim of this study was to identify the potential serum biomarkers of babesiosis using proteomic techniques in order to increase our understanding about disease pathogenesis. Results Serum samples were collected from 25 dogs of various breeds and sex with naturally occurring babesiosis caused by B. canis canis. Blood was collected on the day of admission (day 0), and subsequently on the 1st and 6th day of treatment. Two-dimensional electrophoresis (2DE) of pooled serum samples of dogs with naturally occurring babesiosis (day 0, day 1 and day 6) and healthy dogs were run in triplicate. 2DE image analysis showed 64 differentially expressed spots with p ≤ 0.05 and 49 spots with fold change ≥2. Six selected spots were excised manually and subjected to trypsin digest prior to identification by electrospray ionisation mass spectrometry on an Amazon ion trap tandem mass spectrometry (MS/MS). Mass spectrometry data was processed using Data Analysis software and the automated Matrix Science Mascot Daemon server. Protein identifications were assigned using the Mascot search engine to interrogate protein sequences in the NCBI Genbank database. A number of differentially expressed serum proteins involved in inflammation mediated acute phase response, complement and coagulation cascades, apolipoproteins and vitamin D metabolism pathway were identified in dogs with babesiosis. Conclusions Our findings confirmed two dominant pathogenic mechanisms of babesiosis, haemolysis and acute phase response. These results may provide possible serum biomarker candidates for clinical monitoring of babesiosis and this study could serve as the basis for further proteomic investigations in canine babesiosis. PMID:24885808

Clinical significance of the serum biomarker index detection in children with Henoch-Schonlein purpura.

PubMed

Purevdorj, Narangerel; Mu, Yun; Gu, Yajun; Zheng, Fang; Wang, Ran; Yu, Jinwei; Sun, Xuguo

2018-02-01

To explore a panel of serum biomarkers for laboratory diagnosis of pediatric Henoch-Schönlein purpura (HSP). The blood white blood cells (WBC) and serum levels of serum amyloid A (SAA), interleukin 6 (IL-6), immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin E (IgE), C-reactive protein (CRP), complement component 3 (C3), complement component 4 (C4), and ASO (anti-streptolysin O) were detected in 127 patients with Henoch-Schonlein purpura (HSP), 110 cases of septicemia patients, and 121 healthy volunteers. The diagnostic ability of biomarkers selected from HSP and septicemia patients was analyzed by ROC curve. By designing the calculation model, the biomarker index was calculated for laboratory diagnosis of HSP and differential diagnosis between HSP and septicemia. The levels of serum WBC, CRP, IL-6 and SAA in the septicemia patients were significantly higher than those in the control group (p<0.05). Compared with the healthy individuals, serum levels of WBC, CRP, IL-6, SAA, IgA and IgM were significantly increased in patients with HSP (p<0.05). The area under the curve (AUC) of SAA, IgA, IgM, WBC, IL-6, and CRP in the patients with HSP was 0.964, 0.855, 0.849, 0.787, 0.765, and 0.622, respectively. The values of SAA, IgA, IgM, WBC, IL-6, and CRP in septicemia patients were 0.700, 0.428, 0.689, 0.682, 0.891, and 0.853, respectively. Biomarker index=SAA+IgA/4000+IgM/4000×0.4CRPmean valueCRPi . The biomarker index in HSP patients was significantly higher than that of the healthy controls. However, the biomarker index in septicemia patients was significantly lower than the control. The biomarker index of HSP patients is higher than that of the control group. While in the infectious disease represented by septicemia, it is decreased. The detection of biomarker index could exclude the interference of infection as the auxiliary examination to HSP patients. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by

Identification of suitable reference gene and biomarkers of serum miRNAs for osteoporosis

PubMed Central

Chen, Jian; Li, Kai; Pang, Qianqian; Yang, Chao; Zhang, Hongyu; Wu, Feng; Cao, Hongqing; Liu, Hongju; Wan, Yumin; Xia, Weibo; Wang, Jinfu; Dai, Zhongquan; Li, Yinghui

2016-01-01

Our objective was to identify suitable reference genes in serum miRNA for normalization and screen potential new biomarkers for osteoporosis diagnosis by a systematic study. Two types of osteoporosis models were used like as mechanical unloading and estrogen deficiency. Through a large-scale screening using microarray, qPCR validation and statistical algorithms, we first identified miR-25-3p as a suitable reference gene for both type of osteoporosis, which also showed stability during the differentiation processes of osteoblast and osteoclast. Then 15 serum miRNAs with differential expression in OVX rats were identified by microarray and qPCR validation. We further detected these 15 miRNAs in postmenopausal women and bedrest rhesus monkeys and evaluated their diagnostic value by ROC analysis. Among these miRNAs, miR-30b-5p was significantly down-regulated in postmenopausal women with osteopenia or osteoporosis; miR-103-3p, miR-142-3p, miR-328-3p were only significantly decreased in osteoporosis. They all showed positive correlations with BMD. Except miR328-3p, the other three miRNAs were also declined in the rhesus monkeys after long-duration bedrest. Their AUC values (all >0.75) proved the diagnostic potential. Our results provided a reliable normalization reference gene and verified a group of circulating miRNAs as non-invasive biomarkers in the detection of postmenopausal- and mechanical unloading- osteoporosis. PMID:27821865

Isomer-specific profiling of N-glycans derived from human serum for potential biomarker discovery in pancreatic cancer.

PubMed

Liu, Yufei; Wang, Chang; Wang, Ran; Wu, Yike; Zhang, Liang; Liu, Bi-Feng; Cheng, Liming; Liu, Xin

2018-06-15

Glycosylation is one of the most important post-translational modifications of protein. Recently, global profiling of human serum glycomics has become a noninvasive method for cancer-related biomarker discovery and many studies have focused on compositional glycan profiling. In contrast, structure-specific glycan profiling may provide more potential biomarkers with higher specificity than compositional profiling. In this work, N-glycans released from human serum were neutralized with methylamine and reduced by ammonia-borane complex prior to profiling using nanoLC-ESI-MS with porous graphitized carbon (PGC) and relative abundances of over 280 isomers were compared between pancreatic cancer (PC) cases (n = 32) and healthy controls (n = 32). Statistical analysis identified 25 specific-isomeric biomarkers with significant differences (p-value < 0.05). ROC and PCA analysis were performed to assess the potential biomarkers which were identified as being significantly altered in cancer. The AUCs of the significantly changed specific-isomers were ranging from 0.712 to 0.949. In addition, with the combination of all potential biomarkers, a higher AUC of 0.976 with sensitivity (93.5%) and specificity (90.6%) was obtained. Overall, the proposed strategy coupled to relative quantitative analysis of isomeric glycans make it possible to discover new biomarkers for the diagnosis of PC. Pancreatic cancer (PC) has a poor prognosis with a five-year survival rate <5%. Therefore, a strategy for accurate diagnosis of PC is indeed required. In this paper, a dual-derivatized strategy for structure-specific glycan profiling has been used and according to our best knowledge, this is the first application of this strategy for PC biomarker discovery, in which the separation, identification and relative quantification of isomeric glycans can be simultaneously obtained. In addition, by in-depth analysis of isomeric glycans, the full description of the stereo- and region- diversity

On the identification of biomarkers for non-small cell lung cancer in serum and pleural effusion.

PubMed

Rodríguez-Piñeiro, A M; Blanco-Prieto, S; Sánchez-Otero, N; Rodríguez-Berrocal, F J; de la Cadena, M Páez

2010-06-16

The current imperative need for new biomarkers of non-small cell lung cancer (NSCLC) prompted us to compare the proteome of serum and pleural effusion samples from cancer patients with those with benign lung diseases as pneumonia or tuberculosis. Samples were prefractionated through affinity chromatography prior to 2D-DIGE to detect proteins with altered expression in cancer patients. Overall, we identified more potential biomarkers in pleural effusion, which is closer to the affected organ, than in serum. Nevertheless, in both cases principal component analysis demonstrated that the pattern of significantly altered proteins discriminates between disease groups. The biomarker candidates comprise proteins increased in malignant pleural effusions as gelsolin and the metalloproteinase inhibitor 2, and others with lower levels as S100-A8 and S100-A9. The most interesting protein was the pigment epithelium-derived factor (PEDF), which is related to angiogenesis inhibition, and was significantly overexpressed both in serum and pleural effusion from NSCLC patients. More than 12 PEDF isoforms were specifically immunodetected in both fluids in 2-D blots, most of them overexpressed in NSCLC. Thus, further validation would be ideally directed to quantify individual PEDF isoforms, as it may be only one or some of them the ones altered in the cancer process. Copyright 2010 Elsevier B.V. All rights reserved.

Reproducibility of biomarkers in induced sputum and in serum from chronic smokers.

PubMed

Zuiker, Rob G J A; Kamerling, Ingrid M C; Morelli, Nicoletta; Calderon, Cesar; Boot, J Diderik; de Kam, Marieke; Diamant, Zuzana; Burggraaf, Jacobus; Cohen, Adam F

2015-08-01

Soluble inflammatory markers obtained from non-invasive airway sampling such as induced sputum may be useful biomarkers for targeted pharmaceutical interventions. However, before these soluble markers can be used as potential targets, their variability and reproducibility need to be established in distinct study populations. This study aimed to assess the reproducibility of biomarkers obtained from induced sputum and serum in chronic smokers and non-smokers. Sputum and serum samples were obtained from 16 healthy non-smokers and 16 asymptomatic chronic smokers (for both groups: 8M/8F, 30-52 years, FEV1 ≥80% pred.; ≥10 pack years for the smokers) on 2 separate visits 4-10 days apart. Soluble markers in serum and sputum were analysed by ELISA. The differences between smokers vs non-smokers were analysed with a t-test and variability was assessed on log-transformed data by a mixed model ANOVA. Analysable sputum samples could be obtained from all 32 subjects. In both study populations neutrophils and macrophages were the predominant cell types. Serum Pulmonary Surfactant Associated Protein D had favourable reproducibility criteria for reliability ratio (0.99), intra-subject coefficient of variation (11.2%) and the Bland Altman limits of agreement. Furthermore, chronic smokers, compared to non-smokers, had significantly higher sputum concentrations of IL-8 (1094.6 pg/mL vs 460.8 pg/mL, p = 0.006)), and higher serum concentrations of Pulmonary Surfactant Associated Protein D (110.9 pg/mL vs 64.7 pg/mL, p = 0.019), and lower concentrations of Serum Amyloid A (1352.4 pg/mL vs 2297.5 pg/mL, p = 0.022). Serum Pulmonary Surfactant Associated Protein D proved to be a biomarker that fulfilled the criteria for reproducibility in both study groups. Copyright © 2015 Elsevier Ltd. All rights reserved.

Assessment of Serum Biomarkers in Rats After Exposure to Pesticides of Different Chemical Classes

EPA Science Inventory

There is increasing emphasis on the use of biomarkers of adverse outcomes in safety assessment and translational research. We evaluated serum biomarkers and targeted metabolite profiles after exposure to pesticides (permethrin, deltamethrin, imidacloprid, carbaryl, triadimefon...

Serum Squamous Cell Carcinoma Antigen in Psoriasis: A Potential Quantitative Biomarker for Disease Severity.

PubMed

Sun, Ziwen; Shi, Xiaomin; Wang, Yun; Zhao, Yi

2018-06-05

An objective and quantitative method to evaluate psoriasis severity is important for practice and research in the precision care of psoriasis. We aimed to explore serum biomarkers quantitatively in association with disease severity and treatment response in psoriasis patients, with serum squamous cell carcinoma antigen (SCCA) evaluated in this pilot study. 15 psoriasis patients were treated with adalimumab. At different visits before and after treatment, quantitative body surface area (qBSA) was obtained from standardized digital body images of the patients, and the psoriasis area severity index (PASI) was also monitored. SCCA were detected by using microparticle enzyme immunoassay. The serum biomarkers were also tested in healthy volunteers as normal controls. Receiver-operating characteristic (ROC) curve analysis was used to explore the optimal cutoff point of SCCA to differentiate mild and moderate-to-severe psoriasis. The serum SCCA level in the psoriasis group was significantly higher (p < 0.05) than in the normal control group. After treatment, the serum SCCA levels were significantly decreased (p < 0.05). The SCCA level was well correlated with PASI and qBSA. In ROC analysis, when taking PASI = 10 or qBSA = 10% as the threshold, an optimal cutoff point of SCCA was found at 2.0 ng/mL with the highest Youden index. Serum SCCA might be a useful quantitative biomarker for psoriasis disease severity. © 2018 S. Karger AG, Basel.

Endometrial cancer risk prediction including serum-based biomarkers: results from the EPIC cohort.

PubMed

Fortner, Renée T; Hüsing, Anika; Kühn, Tilman; Konar, Meric; Overvad, Kim; Tjønneland, Anne; Hansen, Louise; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Fournier, Agnès; Boeing, Heiner; Trichopoulou, Antonia; Benetou, Vasiliki; Orfanos, Philippos; Masala, Giovanna; Agnoli, Claudia; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Bueno-de-Mesquita, H B As; Peeters, Petra H M; Weiderpass, Elisabete; Gram, Inger T; Gavrilyuk, Oxana; Quirós, J Ramón; Maria Huerta, José; Ardanaz, Eva; Larrañaga, Nerea; Lujan-Barroso, Leila; Sánchez-Cantalejo, Emilio; Butt, Salma Tunå; Borgquist, Signe; Idahl, Annika; Lundin, Eva; Khaw, Kay-Tee; Allen, Naomi E; Rinaldi, Sabina; Dossus, Laure; Gunter, Marc; Merritt, Melissa A; Tzoulaki, Ioanna; Riboli, Elio; Kaaks, Rudolf

2017-03-15

Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination. © 2016 UICC.

Serum miR-146a and miR-223 as potential new biomarkers for sepsis.

PubMed

Wang, Jia-feng; Yu, Man-li; Yu, Guang; Bian, Jin-jun; Deng, Xiao-ming; Wan, Xiao-jian; Zhu, Ke-ming

2010-03-26

Current biomarkers cannot completely distinguish sepsis from systemic inflammatory response syndrome (SIRS) caused by other non-infectious diseases. Circulating microRNAs (miRNAs) are promising biomarkers for several diseases, but their correlation with sepsis is not totally clarified. Seven miRNAs related to inflammation or infection were included in the present study. Serum miRNA expression was investigated in 50 patients diagnosed with sepsis, 30 patients with SIRS and 20 healthy controls to evaluate the diagnostic and prognostic value. Expression levels of serum miRNAs were determined by quantitative PCR using the Qiagen miScript system. Serum CRP and IL-6 levels were determined by enzyme linked immunosorbent assay. Serum miR-146a and miR-223 were significantly reduced in septic patients compared with SIRS patients and healthy controls. The areas under the receiver operating characteristic curve of miR-146a, miR-223 and IL-6 were 0.858, 0.804 and 0.785, respectively. Serum miR-146a and miR-223 might serve as new biomarkers for sepsis with high specificity and sensitivity. (ClinicalTrials.gov number, NCT00862290.). Copyright (c) 2010 Elsevier Inc. All rights reserved.

High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orwoll, Eric S.; Wiedrick, Jack; Jacobs, Jon

The biological perturbations associated with incident mortality are not well elucidated, and there are limited biomarkers for the prediction of mortality. We used a novel high throughput proteomics approach to identify serum peptides and proteins associated with 5 year mortality in community dwelling men age >65 years who participated in a longitudinal observational study of musculoskeletal aging (Osteoporotic Fractures in Men: MrOS). In a discovery phase, serum specimens collected at baseline in 2473 men were analyzed using liquid chromatography-ion mobility-mass spectrometry, and incident mortality in the subsequent 5 years was ascertained by tri-annual questionnaire. Rigorous statistical methods were utilized tomore » identify 56 peptides (31 proteins) that were associated with 5-year mortality. In an independent replication phase, selected reaction monitoring was used to examine 21 of those peptides in baseline serum from 750 additional men; 81% of those peptides remained significantly associated with mortality. Mortality-associated proteins included a variety involved in inflammation or complement activation; several have been previously linked to mortality (e.g. C reactive protein, alpha 1-antichymotrypsin) and others are not previously known to be associated with mortality. Other novel proteins of interest included pregnancy-associated plasma protein, VE cadherin, leucine-rich α-2 glycoprotein 1, vinculin, vitronectin, mast/stem cell growth factor receptor and Saa4. A panel of peptides improved the predictive value of a commonly used clinical predictor of mortality. Overall, these results suggest that complex inflammatory pathways, and proteins in other pathways, are linked to 5-year mortality risk. This work may serve to identify novel biomarkers for near term mortality.« less

Serum biomarkers for the early diagnosis of TIA: The MIND-TIA study protocol.

PubMed

Dolmans, L Servaas; Rutten, Frans H; El Bartelink, Marie-Louise; Seppenwoolde, Gerdien; van Delft, Sanne; Kappelle, L Jaap; Hoes, Arno W

2015-07-28

A Transient Ischaemic Attack (TIA) bears a high risk of a subsequent ischaemic stroke. Adequate diagnosis of a TIA should be followed immediately by the start of appropriate preventive therapy, including antiplatelets. The diagnosis of a TIA based on symptoms and signs only is notoriously difficult and biomarkers of brain ischaemia might improve the recognition, and target management and prognosis of TIA patients. Our aim is to quantify the added diagnostic value of serum biomarkers of brain ischaemia in patients suspected of TIA. a cross-sectional diagnostic accuracy study with an additional six month follow-up period. 350 patients suspected of TIA in the primary care setting. Patients suspected of a TIA will be recruited by at least 200 general practitioners (GPs) in the catchment area of seven TIA outpatient clinics willing to participate in the study. In all patients a blood sample will be drawn as soon as possible after the patient has contacted the GP, but at least within 72 h after onset of symptoms. Participants will be referred by the GP to the regional TIA outpatient clinic for additional investigations, including brain imaging. The 'definite' diagnosis (reference standard) will be made by a panel consisting of three experienced neurologists who will use all available diagnostic information and the clinical information obtained during the outpatient clinic assessment, and a six month follow-up period. The diagnostic accuracy, and value in addition to signs and symptoms of candidate serum biomarkers will be assessed in terms of discrimination with C statistics, and calibration with plots. We aim to include 350 suspected cases, with 250 patients with indeed definite TIA (or minor stroke) according to the panel. We hope to find novel biomarkers that will enable a rapid and accurate diagnosis of TIA. This would largely improve the management and prognosis of such patients. ClinicalTrials.gov Identifier NCT01954329.

Serum Leptin Is a Biomarker of Malnutrition in Decompensated Cirrhosis

PubMed Central

Rachakonda, Vikrant; Borhani, Amir A.; Dunn, Michael A.; Andrzejewski, Margaret; Martin, Kelly; Behari, Jaideep

2016-01-01

Background and Aims Malnutrition is a leading cause of morbidity and mortality in cirrhosis. There is no consensus as to the optimal approach for identifying malnutrition in end-stage liver disease. The aim of this study was to measure biochemical, serologic, hormonal, radiographic, and anthropometric features in a cohort of hospitalized cirrhotic patients to characterize biomarkers for identification of malnutrition. Design In this prospective observational cohort study, 52 hospitalized cirrhotic patients were classified as malnourished (42.3%) or nourished (57.7%) based on mid-arm muscle circumference < 23 cm and dominant handgrip strength < 30 kg. Anthropometric measurements were obtained. Appetite was assessed using the Simplified Nutrition Appetite Questionnaire (SNAQ) score. Fasting levels of serum adipokines, cytokines, and hormones were determined using Luminex assays. Logistic regression analysis was used to determine features independently associated with malnutrition. Results Subjects with and without malnutrition differed in several key features of metabolic phenotype including wet and dry BMI, skeletal muscle index, visceral fat index and HOMA-IR. Serum leptin levels were lower and INR was higher in malnourished subjects. Serum leptin was significantly correlated with HOMA-IR, wet and dry BMI, mid-arm muscle circumference, skeletal muscle index, and visceral fat index. Logistic regression analysis revealed that INR and log-transformed leptin were independently associated with malnutrition. Conclusions Low serum leptin and elevated INR are associated with malnutrition in hospitalized patients with end-stage liver disease. PMID:27583675

Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.

PubMed

Sharapova, T; Devanarayan, V; LeRoy, B; Liguori, M J; Blomme, E; Buck, W; Maher, J

2016-01-01

MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. © The Author(s) 2015.

Serum microRNA biomarker identification in a residential cohort with elevated polychlorinated biphenyl exposures

EPA Science Inventory

Exposure to liver toxicants can result in or exacerbate fatty liver disease. Recent evidence suggests that serum-derived microRNAs (miRs) may improve identification of chemical-induced fatty liver disease relative to traditional protein-based biomarkers alone. Historical serum sa...

Urinary metabolomics analysis identifies key biomarkers of different stages of nonalcoholic fatty liver disease

PubMed Central

Dong, Shu; Zhan, Zong-Ying; Cao, Hong-Yan; Wu, Chao; Bian, Yan-Qin; Li, Jian-Yuan; Cheng, Gen-Hong; Liu, Ping; Sun, Ming-Yu

2017-01-01

AIM To identify a panel of biomarkers that can distinguish between non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and explore molecular mechanism involved in the process of developing NASH from NAFLD. METHODS Biomarkers may differ during stages of NAFLD. Urine and blood were obtained from non-diabetic subjects with NAFLD and steatosis, with normal liver function (n = 33), from patients with NASH, with abnormal liver function (n = 45), and from healthy age and sex-matched controls (n = 30). Samples were subjected to metabolomic analysis to identify potential non-invasive biomarkers. Differences in urinary metabolic profiles were analyzed using liquid chromatography tandem mass spectrometry with principal component analysis and partial least squares-discriminate analysis. RESULTS Compared with NAFLD patients, patients with NASH had abnormal liver function and high serum lipid concentrations. Urinary metabonomics found differences in 31 metabolites between these two groups, including differences in nucleic acids and amino acids. Pathway analysis based on overlapping metabolites showed that pathways of energy and amino acid metabolism, as well as the pentose phosphate pathway, were closely associated with pathological processes in NAFLD and NASH. CONCLUSION These findings suggested that a panel of biomarkers could distinguish between NAFLD and NASH, and could help to determine the molecular mechanism involved in the process of developing NASH from NAFLD. Urinary biomarkers may be diagnostic in these patients and could be used to assess responses to therapeutic interventions. PMID:28487615

New serum biomarkers for detection of tuberculosis using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry.

PubMed

Liu, Ji-Yan; Jin, Lei; Zhao, Meng-Yuan; Zhang, Xin; Liu, Chi-Bo; Zhang, Yu-Xiang; Li, Fu-Jian; Zhou, Jian-Min; Wang, Hua-Jun; Li, Ji-Cheng

2011-10-01

New technologies for the early detection of tuberculosis (TB) are urgently needed. Pathological changes within an organ might be reflected in proteomic patterns in serum. The aim of the present study was to screen for the potential protein biomarkers in serum for the diagnosis of TB using proteomic fingerprint technology. Proteomic fingerprint technology combining protein chips with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to profile the serum proteins from 50 patients with TB, 25 patients with lung disease other than TB, and 25 healthy volunteers. The protein fingerprint expression of all the serum samples and the resulting profiles between TB and control groups were analyzed with the Biomarker Wizard system. A total of 30 discriminating m/z peaks were detected that were related to TB (p<0.01). The model of biomarkers constructed by the Biomarker Patterns Software based on the three biomarkers (2024, 8007, and 8598 Da) generated excellent separation between the TB and control groups. The sensitivity was 84.0% and the specificity was 86.0%. Blind test data indicated a sensitivity of 80.0% and a specificity of 84.2%. The data suggested a potential application of SELDI-TOF MS as an effective technology to profile serum proteome, and with pattern analysis, a diagnostic model comprising three potential biomarkers was indicated to differentiate people with TB and healthy controls rapidly and precisely.

Serum VEGFR-3 as a potential biomarker in psoriasis.

PubMed

Hong, Xia; Jiang, Shan; Marmolejo, Nancy; Vangipuram, Ramya; Ramos-Rojas, Elmira; Yuan, Yulin; Lin, Zuan-Tao; Li, Yaxi; Qiu, Jingyi; Xing, Yikun; Haley, Christopher; Tyring, Stephen K; Wu, Tianfu

2018-06-29

To discover novel biomarkers of psoriasis, a target-specific antibody array screening of serum samples from psoriasis patients was initially performed. The results revealed that Vascular endothelial growth factor receptor 3 (VEGFR-3) was significantly elevated in the sera of psoriasis patients, compared to healthy controls. Next, ELISA validation studies in a larger cohort of psoriasis patients (N=73) were conducted which confirmed that serum VEGFR-3 was indeed significantly increased in patients with psoriasis compared to healthy controls (P < 0.001). Furthermore, Receiver operating characteristic (ROC) curve analysis demonstrated that serum VEGFR-3 exhibited potential in distinguishing healthy controls from psoriasis patients: Area Under the Curve (AUC) = 0.85, P < 0.001. In addition, serum levels of VEGFR-3 were correlated with Psoriasis Area Severity Index (PASI) scores (R = 0.32, P = 0.008) in psoriasis patients. Interestingly, serum VEGFR-3 levels were significantly elevated in psoriatic arthritis compared to non-psoriatic arthritis (P = 0.026). A pilot longitudinal study demonstrated that serum levels of VEGFR-3 could reflect disease progression in psoriasis. Collectively, serum VEGFR-3 may have a clinical value in monitoring disease activity of psoriasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study.

PubMed

Larkin, S E T; Johnston, H E; Jackson, T R; Jamieson, D G; Roumeliotis, T I; Mockridge, C I; Michael, A; Manousopoulou, A; Papachristou, E K; Brown, M D; Clarke, N W; Pandha, H; Aukim-Hastie, C L; Cragg, M S; Garbis, S D; Townsend, P A

2016-10-25

Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease. We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa. We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an 'interactome' with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-κB and IL6. Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.

MicroRNAs as serum biomarkers for periodontitis.

PubMed

Tomofuji, Takaaki; Yoneda, Toshiki; Machida, Tatsuya; Ekuni, Daisuke; Azuma, Tetsuji; Kataoka, Kota; Maruyama, Takayuki; Morita, Manabu

2016-05-01

Studies demonstrated that periodontitis modulates microRNA (miRNAs) expression rates in periodontal tissue. However, the relationship between periodontitis and miRNAs profile in circulation remains unclear. In this study, we investigated the effects of periodontitis on serum miRNAs profile in a rat model. Male Wistar rats (n = 32, 8 weeks old) were divided into four groups of eight rats each. The control groups received no treatment for 2 or 4 weeks. In the other two groups, periodontitis was ligature induced for 2 or 4 weeks. Serum miRNAs expression profiles of each group were compared. Ligation around teeth induced periodontal inflammation at 2 weeks and periodontal tissue destruction at 4 weeks. Microarray results showed that 25 miRNAs were expressed with a <0.5 or >2 difference between the control and periodontitis groups at 4 weeks. Results of real-time PCR revealed that the periodontitis group up-regulated expression rates of serum miR-207 and miR-495 at 2 weeks, and miR-376b-3p at 4 weeks (p < 0.05). Serum miRNAs (miR-207, miR-495, and miR-376b-3p) could be valuable biomarkers for periodontitis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Combined serum and EPS-urine proteomic analysis using iTRAQ technology for discovery of potential prostate cancer biomarkers.

PubMed

Zhang, Mo; Chen, Lizhu; Yuan, Zhengwei; Yang, Zeyu; Li, Yue; Shan, Liping; Yin, Bo; Fei, Xiang; Miao, Jianing; Song, Yongsheng

2016-11-01

Prostate cancer (PCa) is one of the most common malignant tumors and a major cause of cancer-related death for men worldwide. The aim of our study was to identify potential non-invasive serum and expressed prostatic secretion (EPS)-urine biomarkers for accurate diagnosis of PCa. Here, we performed a combined isobaric tags for relative and absolute quantification (iTRAQ) proteomic analysis to compare protein profiles using pooled serum and EPS-urine samples from 4 groups of patients: benign prostate hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN), localized PCa and metastatic PCa. The differentially expressed proteins were rigorously selected and further validated in a large and independent cohort using classical ELISA and Western blot assays. Finally, we established a multiplex biomarker panel consisting of 3 proteins (serum PF4V1, PSA, and urinary CRISP3) with an excellent diagnostic capacity to differentiate PCa from BPH [area under the receiver operating characteristic curve (AUC) of 0.941], which showed an evidently greater discriminatory ability than PSA alone (AUC, 0.757) (P<0.001). Importantly, even when PSA level was in the gray zone (4-10 ng/mL), a combination of PF4V1 and CRISP3 could achieve a relatively high diagnostic efficacy (AUC, 0.895). Furthermore, their combination also had the potential to distinguish PCa from HGPIN (AUC, 0.934). Our results demonstrated that the combined application of serum and EPS-urine biomarkers can improve the diagnosis of PCa and provide a new prospect for non-invasive PCa detection.

A Multiplexed Serum Biomarker Immunoassay Panel Discriminates Clinical Lung Cancer Patients from High-Risk Individuals Found to be Cancer-Free by CT Screening

PubMed Central

Bigbee, William L.; Gopalakrishnan, Vanathi; Weissfeld, Joel L.; Wilson, David O.; Dacic, Sanja; Lokshin, Anna E.; Siegfried, Jill M.

2012-01-01

Introduction Clinical decision-making in the setting of CT screening could benefit from accessible biomarkers that help predict the level of lung cancer risk in high-risk individuals with indeterminate pulmonary nodules. Methods To identify candidate serum biomarkers, we measured 70 cancer-related proteins by Luminex xMAP® multiplexed immunoassays in a training set of sera from 56 patients with biopsy-proven primary non small cell lung cancer and 56 age-, sex- and smoking-matched CT-screened controls. Results We identified a panel of 10 serum biomarkers – prolactin, transthyretin, thrombospondin-1, E-selectin, C-C motif chemokine 5, macrophage migration inhibitory factor, plasminogen activator inhibitor, receptor tyrosine-protein kinase, Cyfra 21.1, and serum amyloid A – that distinguished lung cancer from controls with an estimated balanced accuracy (average of sensitivity and specificity) of 76.0%±3.8% from 20-fold internal cross-validation. We then iteratively evaluated this model in independent test and verification case/control studies confirming the initial classification performance of the panel. The classification performance of the 10-biomarker panel was also analytically validated using ELISAs in a second independent case/control population further validating the robustness of the panel. Conclusions The performance of this 10-biomarker panel based model was 77.1% sensitivity/76.2% specificity in cross-validation in the expanded training set, 73.3% sensitivity/93.3% specificity (balanced accuracy 83.3%) in the blinded verification set with the best discriminative performance in Stage I/II cases: 85% sensitivity (balanced accuracy 89.2%). Importantly, the rate of misclassification of CT-screened controls was not different in most control subgroups with or without airflow obstruction or emphysema or pulmonary nodules. These biomarkers have potential to aid in the early detection of lung cancer and more accurate interpretation of indeterminate pulmonary

Paired Serum and Urine Concentrations of Biomarkers of Diethyl Phthalate, Methyl Paraben, and Triclosan in Rats

PubMed Central

Teitelbaum, Susan L.; Li, Qian; Lambertini, Luca; Belpoggi, Fiorella; Manservisi, Fabiana; Falcioni, Laura; Bua, Luciano; Silva, Manori J.; Ye, Xiaoyun; Calafat, Antonia M.; Chen, Jia

2015-01-01

Background Exposure to environmental chemicals, including phthalates and phenols such as parabens and triclosan, is ubiquitous within the U.S. general population. Objective This proof-of-concept rodent study examined the relationship between oral doses of three widely used personal care product ingredients [diethyl phthalate (DEP), methyl paraben (MPB), and triclosan] and urine and serum concentrations of their respective biomarkers. Methods Using female Sprague-Dawley rats, we carried out two rounds of experiments with oral gavage doses selected in accordance with no observed adverse effect levels (NOAELs) derived from previous studies: 1,735 (DEP), 1,050 (MPB), 50 (triclosan) mg/kg/day. Administered doses ranged from 0.005 to 173 mg/kg/day, 10–100,000 times below the NOAEL for each chemical. Controls for the MPB and triclosan experiments were animals treated with olive oil (vehicle) only; controls for the DEP serum experiments were animals treated with the lowest doses of MPB and triclosan. Doses were administered for 5 days with five rats in each treatment group. Urine and blood serum, collected on the last day of exposure, were analyzed for biomarkers. Relationships between oral dose and biomarker concentrations were assessed using linear regression. Results Biomarkers were detected in all control urine samples at parts-per-billion levels, suggesting a low endemic environmental exposure to the three chemicals that could not be controlled even with all of the precautionary measures undertaken. Among the exposed animals, urinary concentrations of all three biomarkers were orders of magnitude higher than those in serum. A consistently positive linear relationship between oral dose and urinary concentration was observed (R2 > 0.80); this relationship was inconsistent in serum. Conclusions Our study highlights the importance of carefully considering the oral dose used in animal experiments and provides useful information in selecting doses for future studies

Serum biomarkers of oxidative stress in dogs with idiopathic inflammatory bowel disease.

PubMed

Rubio, C P; Martínez-Subiela, S; Hernández-Ruiz, J; Tvarijonaviciute, A; Cerón, J J; Allenspach, K

2017-03-01

The objective of this work was to study and compare a panel of various serum biomarkers evaluating both the antioxidant response and oxidative damage in dogs with idiopathic inflammatory bowel disease (IBD). Eighteen dogs with IBD and 20 healthy dogs were enrolled in the study. Trolox equivalent antioxidant capacity (TEAC), cupric reducing antioxidant capacity (CUPRAC), ferric reducing ability of the plasma (FRAP), total thiol concentrations, and paraoxonase 1 (PON1) activity were evaluated in serum to determine antioxidant response. To evaluate oxidative status, ferrous oxidation-xylenol orange (FOX), thiobarbituric acid reactive substances (TBARS) and reactive oxygen species production (ROS) concentrations in serum were determined. Mean concentrations of all antioxidant biomarkers analyzed, with exception of FRAP, were significantly lower (P < 0.0001) in the sera of dogs with IBD than in healthy dogs. The oxidant markers studied were significantly higher (P < 0.0001) in sera of dogs with IBD than in healthy dogs. These findings support the hypothesis that oxidative stress could play an important role in the pathogenesis of canine IBD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serum quantitative proteomic analysis reveals potential zinc-associated biomarkers for nonbacterial prostatitis.

PubMed

Yang, Xiaoli; Li, Hongtao; Zhang, Chengdong; Lin, Zhidi; Zhang, Xinhua; Zhang, Youjie; Yu, Yanbao; Liu, Kun; Li, Muyan; Zhang, Yuening; Lv, Wenxin; Xie, Yuanliang; Lu, Zheng; Wu, Chunlei; Teng, Ruobing; Lu, Shaoming; He, Min; Mo, Zengnan

2015-10-01

Prostatitis is one of the most common urological problems afflicting adult men. The etiology and pathogenesis of nonbacterial prostatitis, which accounts for 90-95% of cases, is largely unknown. As serum proteins often indicate the overall pathologic status of patients, we hypothesized that protein biomarkers of prostatitis might be identified by comparing the serum proteomes of patients with and without nonbacterial prostatitis. All untreated samples were collected from subjects attending the Fangchenggang Area Male Health and Examination Survey (FAMHES). We profiled pooled serum samples from four carefully selected groups of patients (n = 10/group) representing the various categories of nonbacterial prostatitis (IIIa, IIIb, and IV) and matched healthy controls using a mass spectrometry-based 4-plex iTRAQ proteomic approach. More than 160 samples were validated by ELISA. Overall, 69 proteins were identified. Among them, 42, 52, and 37 proteins were identified with differential expression in Category IIIa, IIIb, and IV prostatitis, respectively. The 19 common proteins were related to immunity and defense, ion binding, transport, and proteolysis. Two zinc-binding proteins, superoxide dismutase 3 (SOD3), and carbonic anhydrase I (CA1), were significantly higher in all types of prostatitis than in the control. A receiver operating characteristic curve estimated sensitivities of 50.4 and 68.1% and specificities of 92.1 and 83.8% for CA1 and SOD3, respectively, in detecting nonbacterial prostatitis. The serum CA1 concentration was inversely correlated to the zinc concentration in expressed-prostatic secretions. Our findings suggest that SOD3 and CA1 are potential diagnostic markers of nonbacterial prostatitis, although further large-scale studies are required. The molecular profiles of nonbacterial prostatitis pathogenesis may lay a foundation for discovery of new therapies. © 2015 Wiley Periodicals, Inc.

Biomarkers identified from serum proteomic analysis for the differential diagnosis of systemic lupus erythematosus.

PubMed

Kazemipour, N; Qazizadeh, H; Sepehrimanesh, M; Salimi, S

2015-05-01

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that involves different organs. Its most important feature is the production of specific autoantibodies against nuclear or cytoplasmic antigens. Proteomic analysis of serum, as one of the most readily available body fluids, can be used as a method for clarifying the pathogenesis of SLE. In this study the serum proteome of 13 patients with SLE was evaluated and compared with seven healthy control participants. A specific kit was used to remove high-abundance proteins. After depletion, the protein expression patterns created by two-dimensional gel electrophoresis (2-DE) and MALDI-TOF/TOF-MS were used to identify disease-associated proteins. We found differential expression of 15 protein spots, including seven up-regulated and eight down-regulated proteins in SLE samples, in comparison with healthy participants. These spots were identified by MALDI-TOF/TOF-MS and classified into three groups include keratins, apolipoproteins and albumin, and individual proteins such as transthyretin, haptoglobin and prothrombin. These findings can help to clarify the pathophysiology and mechanism of SLE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Serum MicroRNAs as Potential Biomarkers for Early Diagnosis of Hepatitis C Virus-Related Hepatocellular Carcinoma in Egyptian Patients

PubMed Central

Motawi, Tarek K.; Shaker, Olfat G.; El-Maraghy, Shohda A.; Senousy, Mahmoud A.

2015-01-01

Circulating microRNAs are deregulated in liver fibrosis and hepatocellular carcinoma (HCC) and are candidate biomarkers. This study investigated the potential of serum microRNAs; miR-19a, miR-296, miR-130a, miR-195, miR-192, miR-34a, and miR-146a as early diagnostic biomarkers for hepatitis C virus (HCV)-related HCC. As how these microRNAs change during liver fibrosis progression is not clear, we explored their serum levels during fibrosis progression in HCV-associated chronic liver disease (CLD) and if they could serve as non-invasive biomarkers for fibrosis progression to HCC. 112 Egyptian HCV-HCC patients, 125 non-malignant HCV-CLD patients, and 42 healthy controls were included. CLD patients were subdivided according to Metavir fibrosis-scoring. Serum microRNAs were measured by qRT-PCR custom array. Serum microRNAs were deregulated in HCC versus controls, and except miR-130a, they were differentially expressed between HCC and CLD or late fibrosis (F3-F4) subgroup. Serum microRNAs were not significantly different between individual fibrosis-stages or between F1-F2 (early/moderate fibrosis) and F3-F4. Only miR-19a was significantly downregulated from liver fibrosis (F1-F3) to cirrhosis (F4) to HCC. Individual microRNAs discriminated HCC from controls, and except miR-130a, they distinguished HCC from CLD or F3-F4 patients by receiver-operating-characteristic analysis. Multivariate logistic analysis revealed a panel of four microRNAs (miR-19a, miR-195, miR-192, and miR-146a) with high diagnostic accuracy for HCC (AUC = 0.946). The microRNA panel also discriminated HCC from controls (AUC = 0.949), CLD (AUC = 0.945), and F3-F4 (AUC = 0.955). Studied microRNAs were positively correlated in HCC group. miR-19a and miR-34a were correlated with portal vein thrombosis and HCC staging scores, respectively. In conclusion, studied microRNAs, but not miR-130a, could serve as potential early biomarkers for HCC in high-risk groups, with miR-19a as a biomarker for liver fibrosis

Serum Concentrations of New Predictive Cardiovascular Disease Biomarkers in Mexican Women Exposed to Lead.

PubMed

Ochoa-Martínez, Ángeles C; Cardona-Lozano, Elvia D; Carrizales-Yáñez, Leticia; Pérez-Maldonado, Iván N

2018-02-01

The purpose of this study was to evaluate lead exposure and its relationship with serum levels of predictive CVD biomarkers [asymmetric dimethylarginine (ADMA), adipocyte fatty acid-binding protein (FABP4), adiponectin, and chemerin] in women living in San Luis Potosi, Mexico. A mean blood lead level (BLL) of 11.5 ± 9.00 μg/dL (mean ± standard deviation) was found after all blood samples were analyzed. Regarding serum predictive CVD biomarkers, mean serum level of 0.68 ± 0.38 μmol/L, 20.5 ± 16.5 ng/mL, 12.5 ± 3.30 μg/mL, and 255 ± 130 ng/mL were found for ADMA, FABP4, adiponectin, and chemerin, respectively. Simple significant associations (Pearson´s correlations) between BLL and ADMA (r = 0.17; p = 0.04) and FABP4 (r = 0.23; p = 0.03) were found. Furthermore, a multivariate linear regression model showed that BLL was a significant predictor of serum ADMA (β = 0.06; p = 0.001) and FABP4 (β = 1.75; p = 0.0004) concentrations after adjusting by confounders. For serum chemerin and adiponectin levels, no associations were found with BLL. In conclusion, high serum ADMA and FABP4 (predictive CVD biomarkers) levels were found in women exposed to lead. Consequently, this research can be used as a point of departure for the prevention of CVD events in populations living in sites environmentally impacted with lead.

Serum anti-Helicobacter pylori immunoglobulin G titer correlates with grade of histological gastritis, mucosal bacterial density, and levels of serum biomarkers.

PubMed

Tu, Huakang; Sun, Liping; Dong, Xiao; Gong, Yuehua; Xu, Qian; Jing, Jingjing; Yuan, Yuan

2014-03-01

OBJECTIVE. Clinical implications of serum anti-Helicobacter pylori immunoglobulin G (IgG) titer were unclear. This study investigated the associations of serum anti-H. pylori IgG titer with grade of histological gastritis, mucosal bacterial density and levels of serum biomarkers, including pepsinogen (PG) I, PGII, PGI/II ratio and gastrin-17. MATERIAL AND METHODS. Study participants were from a screening program in northern China. Serum anti-H. pylori IgG measurements were available for 5922 patients with superficial gastritis. Serum anti-H. pylori IgG titer and serum biomarkers were measured using ELISA, and gastric biopsies were evaluated using standardized criteria. RESULTS. In patients with mild, moderate or severe superficial gastritis, the mean serum anti-H. pylori IgG titers were 17.3, 33.4 and 54.4 EIU (p for trend < 0.0001), respectively. As mucosal H. pylori density score increased from 0 to 3, the mean serum anti-H. pylori IgG titers also increased from 24.7 to 44.8 EIU (p for trend < 0.0001). Serum anti-H. pylori IgG titer was associated positively with serum PGI, PGII and gastrin-17 concentrations and negatively with PGI/II ratio, and the association was the strongest for PGII. The mean PGII concentration of the patients in the highest quartile of IgG titer was twice the mean concentration of the patients in the lowest quartile (17.2 vs. 8.6 EIU, p < 0.0001). CONCLUSIONS. Our results suggest that serum anti-H. pylori IgG titer was associated positively with grade of histological gastritis, mucosal bacterial density and concentrations of serum PGI, PGII and gastrin-17, and negatively with PGI/II ratio.

Serum Osteopontin as a Novel Biomarker for Muscle Regeneration in Duchenne Muscular Dystrophy.

PubMed

Kuraoka, Mutsuki; Kimura, En; Nagata, Tetsuya; Okada, Takashi; Aoki, Yoshitsugu; Tachimori, Hisateru; Yonemoto, Naohiro; Imamura, Michihiro; Takeda, Shin'ichi

2016-05-01

Duchenne muscular dystrophy is a lethal X-linked muscle disorder. We have already reported that osteopontin (OPN), an inflammatory cytokine and myogenic factor, is expressed in the early dystrophic phase in canine X-linked muscular dystrophy in Japan, a dystrophic dog model. To further explore the possibility of OPN as a new biomarker for disease activity in Duchenne muscular dystrophy, we monitored serum OPN levels in dystrophic and wild-type dogs at different ages and compared the levels to other serum markers, such as serum creatine kinase, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1. Serum OPN levels in the dystrophic dogs were significantly elevated compared with those in wild-type dogs before and 1 hour after a cesarean section birth and at the age of 3 months. The serum OPN level was significantly correlated with the phenotypic severity of dystrophic dogs at the period corresponding to the onset of muscle weakness, whereas other serum markers including creatine kinase were not. Immunohistologically, OPN was up-regulated in infiltrating macrophages and developmental myosin heavy chain-positive regenerating muscle fibers in the dystrophic dogs, whereas serum OPN was highly elevated. OPN expression was also observed during the synergic muscle regeneration process induced by cardiotoxin injection. In conclusion, OPN is a promising biomarker for muscle regeneration in dystrophic dogs and can be applicable to boys with Duchenne muscular dystrophy. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Identifying novel biomarkers in sarcoidosis using genome-based approaches

PubMed Central

Knox, Kenneth S.; Garcia, Joe G.N.

2015-01-01

Synopsis We briefly review conventional biomarkers used clinically to 1) support a diagnosis and 2) monitor disease progression in patients with sarcoidosis. We describe potential new biomarkers identified by genome-wide screening and the approaches to discover these biomarkers. PMID:26593137

Relationship between lean body mass and serum renal biomarkers in healthy dogs.

PubMed

Hall, Jean A; Yerramilli, Maha; Obare, Edward; Yerramilli, Murthy; Melendez, Lynda D; Jewell, Dennis E

2015-01-01

Symmetric dimethylarginine (SDMA) is an accurate and precise biomarker for estimating glomerular filtration rate (GFR) in humans and cats. Serum creatinine (sCr) also correlates with GFR, but has limitations as a biomarker of renal function because nonrenal factors can influence its concentration. Differences in lean body mass (LBM) influence sCr, but not serum SDMA concentrations. Forty-one healthy Beagles, mean age 9.9 years (range: 3.1-14.8 years), were studied over a 6 month period. Serum biomarkers of renal function were measured prospectively at baseline, and 1, 3, and 6 months. SDMA concentrations were measured by liquid chromatography-mass spectroscopy and sCr concentrations by enzymatic colorimetry. Body composition was determined by dual energy x-ray absorptiometry. LBM (P < .001) and age (P = .006) were significant explanatory variables for sCr concentration (R(2) = 0.38), but not SDMA concentration. Time on food was the only significant explanatory variable for SDMA concentration (R(2) = 0.49). SDMA concentrations decreased across time (P < .001). LBM was affected by sex (males > females; P = .02). Mature adult dogs (<8 years) had greater LBM compared with geriatric dogs (≥8 years; P < .001). sCr concentrations, but not SDMA concentrations, are influenced by LBM, which limits sCr utility as a biomarker for monitoring renal function in dogs with decreased LBM. Reductions in LBM can lower sCr concentration and overestimate GFR. SDMA concentrations, but not sCr concentrations were influenced by time on food. SDMA could have clinical advantages over sCr in monitoring response to nutritional interventions. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Seminal plasma and serum fertility biomarkers in dromedary camels (Camelus dromedarius).

PubMed

Waheed, M M; Ghoneim, I M; Alhaider, A K

2015-03-01

Eight healthy fertile (control) and 11 infertile male dromedaries were used to investigate whether specific seminal plasma and serum fertility biomarkers could be related to their in vivo fertility. Eight fertility biomarkers and testosterone were determined in both seminal plasma and serum of all studied camels during the rutting season using commercial kits. Results revealed a significant (P < 0.01) difference in semen parameters between the control and infertile camels. There was a significant (P < 0.01) difference between the control and infertile dromedaries in seminal plasma glutathione peroxidase (GPx) activity (15.04 ± 1.14 vs. 4.55 ± 0.96 nmol/min/mL, respectively) and both phospholipase A2 (sPLA2; 50.66 ± 6.28 vs. 23.56 ± 4.29 pg/mL, respectively) and testosterone concentrations (732.14 ± 57.12 vs. 396.36 ± 79.34 pg/mL, respectively). A significant (P < 0.05) difference was found between the control and infertile camels in seminal plasma concentrations of osteopontin, cysteine-rich secretory protein 3 (CRISP3), and prostaglandin D synthase (lipocalcin-type). There was a significant (P < 0.01) difference between the fertile and infertile camels in serum GPx activity 67.81 ± 12.41 vs. 21.31 ± 4.63 nmol/min/mL, respectively) and both testosterone (599.57 ± 110.90 vs. 176.09 ± 24.05 pg/mL, respectively) and clusterin concentrations (137.29 ± 14.15 vs. 253.00 ± 17.14 ng/mL, respectively). A significant (P < 0.05) difference existed between the control and infertile male dromedaries in serum concentrations of sPLA2, CRISP3, malonialdehyde, and insulinlike growth factor 1. In conclusion, CRISP3, sPLA2, GPx, and testosterone are fertility-associated biomarkers in both seminal plasma and serum of dromedary camels. Seminal plasma osteopontin is positively correlated and prostaglandin D synthase (lipocalcin-type) is negatively correlated with camels' fertility. Serum malonialdehyde, insulinlike growth factor 1

Serum proteomic MRM identify peptide ions of transferrin as new fibrosis markers in chronic hepatitis B.

PubMed

Xu, Ming-Yi; Qu, Ying; Jia, Xiao-Fang; Wang, Mei-Ling; Liu, Heng; Wang, Xing-Peng; Zhang, Li-Jun; Lu, Lun-Gen

2013-09-01

Because of the limitations of liver biopsy, reliable non-invasive serum biomarkers of liver fibrosis are needed. The aim of this study was to identify such markers by the use of serum proteomics in chronic hepatitis B (CHB). Two-dimensional gel electrophoresis (2-DE) was used to identify differentially expressed protein spots in sera from 40 CHB patients [20 with mild fibrosis (S0-S1) and 20 with severe fibrosis (S3-S4)]. Mass spectrometry (MS) based multiple reaction monitoring (MRM) was used to quantify peptide ions of differential protein spots in another set of sera from 86 CHB patients with different liver fibrosis (S0-S4). Seven differentially expressed protein spots were found by 2-DE. Fourteen peptide ions of seven target protein spots were quantified by MS-based MRM. Summed peak areas ratio (SPAR) values of peptide ions from protein spot 1, 4 and 8, identified as apo serum transferrin, complement component C3c and transferrin, were significantly different from non-fibrosis (S0) to fibrosis stage 4. AUROCs of models established by peptide ions (protein spot 1, 4, 8) and model consisting of a combination of all ions were 0.848∼0.966 (S2-S4 versus S0-S1) and 0.785∼0.875 (S3-S4 versus S0-S2). Only the peptide ions model of transferrin had better sensitivity and specificity for predicting fibrosis stages than did aspartate aminotransferase-to-platelet ratio index (APRI), FIB-4 and Forn's index. Serum peptide ions of transferrin, detected by proteomic MRM, are new and promising biomarkers for staging liver fibrosis in CHB patients. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Identification of potential serum peptide biomarkers of biliary tract cancer using MALDI MS profiling

PubMed Central

2014-01-01

Background The aim of this discovery study was the identification of peptide serum biomarkers for detecting biliary tract cancer (BTC) using samples from healthy volunteers and benign cases of biliary disease as control groups. This work was based on the hypothesis that cancer-specific exopeptidases exist and that their activities in serum can generate cancer-predictive peptide fragments from circulating proteins during coagulation. Methods This case control study used a semi-automated platform incorporating polypeptide extraction linked to matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) to profile 92 patient serum samples. Predictive models were generated to test a validation serum set from BTC cases and healthy volunteers. Results Several peptide peaks were found that could significantly differentiate BTC patients from healthy controls and benign biliary disease. A predictive model resulted in a sensitivity of 100% and a specificity of 93.8% in detecting BTC in the validation set, whilst another model gave a sensitivity of 79.5% and a specificity of 83.9% in discriminating BTC from benign biliary disease samples in the training set. Discriminatory peaks were identified by tandem MS as fragments of abundant clotting proteins. Conclusions Serum MALDI MS peptide signatures can accurately discriminate patients with BTC from healthy volunteers. PMID:24495412

Serum DHCR24 Auto-antibody as a new Biomarker for Progression of Hepatitis C

PubMed Central

Ezzikouri, Sayeh; Kimura, Kiminori; Sunagozaka, Hajime; Kaneko, Shuichi; Inoue, Kazuaki; Nishimura, Tomohiro; Hishima, Tsunekazu; Kohara, Michinori; Tsukiyama-Kohara, Kyoko

2015-01-01

Background New biomarkers are needed to identify the stage of hepatitis C virus (HCV)-infected diseases in order to reduce the mortality rates. Herein, we investigated whether serum 3β-hydroxysterol Δ24-reductase antibody (DHCR24 Ab) may serve as a prognostic marker for hepatitis C infection progression to hepatocellular carcinoma (HCC). Methods Serum DHCR24 Abs from 395 HCV-positive patients, including 133 chronic hepatitis (CHC), 85 liver cirrhosis (LCC), and 177 HCC (HCC-C) patients; 232 hepatitis B virus (HBV)-positive patients, including 103 chronic hepatitis (CHB), 56 liver cirrhosis (LCB), and 73 HCC (HCC-B) patients; and 24 healthy controls, were measured using enzyme-linked immunosorbent assay. Results The serum DHCR24 Ab levels were significantly higher in patients with CHC than in healthy controls, in LCC than in CHC, and in LCC than in HCC-C (P < 0.0001 for all). The concentration of serum DHCR24 Ab in HCC-B patients showed no significant difference compared to CHB and LCB patients (P = 0.1247). The DHCR24 Ab levels were significantly higher in early HCC-C than CHC or LCC patients and in late HCC-C compared to early HCC-C patients. The sensitivity of the DHCR24 Ab for HCC-C detection (70.6%) was higher than that of alpha-fetoprotein (AFP; 54.8%) and protein induced by vitamin K absence or antagonist-II (PIVKA-II; 42 · 5%). Moreover, DHCR24 was up-regulated in HCV-positive, but not HBV-positive tissues or HBV-negative, HCV-negative HCC specimens. Conclusions DHCR24 auto-antibody represents a potential noninvasive biomarker for HCV-related liver disease and may facilitate the diagnosis of PIVKA-II and AFP-negative HCC. PMID:26288822

Conjugated bile acids in gallbladder bile and serum as potential biomarkers for cholesterol polyps and adenomatous polyps.

PubMed

Zhao, Mei-Fen; Huang, Peng; Ge, Chun-Lin; Sun, Tao; Ma, Zhi-Gang; Ye, Fei-Fei

2016-02-28

To identify conjugated bile acids in gallbladder bile and serum as possible biomarkers for cholesterol polyps (CPs) and adenomatous polyps (APs). Gallbladder bile samples and serum samples were collected from 18 patients with CPs (CP group), 9 patients with APs (AP group), and 20 patients with gallstones (control group) from March to November, 2013. High performance liquid chromatography (HPLC) assay with ultraviolent detection was used to detect the concentration of 8 conjugated bile acids (glycocholic acid, GCA; taurocholic acid, TCA; glycochenodeoxycholic acid, GCDCA; taurochenodeoxycholic acid, TCDCA; glycodeoxycholic acid, GDCA; taurodeoxycholic acid, TDCA; taurolithocholic acid, TLCA; tauroursodeoxycholic acid, TUDCA) in bile samples and serum samples. The diagnostic efficacy of serum GCA, GCDCA and TCDCA was evaluated. These 8 conjugated bile acids in gallbladder bile and serum were completely identified within 10 minutes with good linearity (correlation coefficient: R>0.9900; linearity range: 3.91-500 µg/mL). Among these conjugated bile acids, the levels of gallbladder bile GCDCA and TCDCA in the CP group were significantly higher than those in the AP group (p<0.05). Furthermore, serum GCDCA and TCDCA as well as GCA were significantly higher in the AP group than the CP group (p<0.05). Serum GCDCA alone (≤12 µg/mL) had relatively better diagnostic efficacy than the other conjugated bile acids. The levels of serum GCA, GCDCA and TCDCA may be valuable for differentiation of APs and CPs.

Biomarkers of One-Carbon Metabolism Are Associated with Biomarkers of Inflammation in Women123

PubMed Central

Abbenhardt, Clare; Miller, Joshua W.; Song, Xiaoling; Brown, Elissa C.; Cheng, Ting-Yuan David; Wener, Mark H.; Zheng, Yingye; Toriola, Adetunji T.; Neuhouser, Marian L.; Beresford, Shirley A. A.; Makar, Karen W.; Bailey, Lynn B.; Maneval, David R.; Green, Ralph; Manson, JoAnn E.; Van Horn, Linda; Ulrich, Cornelia M.

2014-01-01

Folate-mediated one-carbon metabolism is essential for DNA synthesis, repair, and methylation. Perturbations in one-carbon metabolism have been implicated in increased risk of some cancers and may also affect inflammatory processes. We investigated these interrelated pathways to understand their relation. The objective was to explore associations between inflammation and biomarkers of nutritional status and one-carbon metabolism. In a cross-sectional study in 1976 women selected from the Women’s Health Initiative Observational Study, plasma vitamin B-6 [pyridoxal-5′-phosphate (PLP)], plasma vitamin B-12, plasma folate, and RBC folate were measured as nutritional biomarkers; serum C-reactive protein (CRP) and serum amyloid A (SAA) were measured as biomarkers of inflammation; and homocysteine and cysteine were measured as integrated biomarkers of one-carbon metabolism. Student’s t, chi-square, and Spearman rank correlations, along with multiple linear regressions, were used to explore relations between biomarkers; additionally, we tested stratification by folic acid fortification period and multivitamin use. With the use of univariate analysis, plasma PLP was the only nutritional biomarker that was modestly significantly correlated with serum CRP and SAA (ρ = −0.22 and −0.12, respectively; P < 0.0001). Homocysteine (μmol/L) showed significant inverse correlations with all nutritional biomarkers (ranging from ρ = −0.30 to ρ = −0.46; all P < 0.0001). With the use of multiple linear regression, plasma PLP, RBC folate, homocysteine, and cysteine were identified as independent predictors of CRP; and PLP, vitamin B-12, RBC folate, and homocysteine were identified as predictors of SAA. When stratified by folic acid fortification period, nutrition-homocysteine correlations were generally weaker in the postfortification period, whereas associations between plasma PLP and serum CRP increased. Biomarkers of inflammation are associated with PLP, RBC folate, and

Predictive Biomarkers for Asthma Therapy.

PubMed

Medrek, Sarah K; Parulekar, Amit D; Hanania, Nicola A

2017-09-19

Asthma is a heterogeneous disease characterized by multiple phenotypes. Treatment of patients with severe disease can be challenging. Predictive biomarkers are measurable characteristics that reflect the underlying pathophysiology of asthma and can identify patients that are likely to respond to a given therapy. This review discusses current knowledge regarding predictive biomarkers in asthma. Recent trials evaluating biologic therapies targeting IgE, IL-5, IL-13, and IL-4 have utilized predictive biomarkers to identify patients who might benefit from treatment. Other work has suggested that using composite biomarkers may offer enhanced predictive capabilities in tailoring asthma therapy. Multiple biomarkers including sputum eosinophil count, blood eosinophil count, fractional concentration of nitric oxide in exhaled breath (FeNO), and serum periostin have been used to identify which patients will respond to targeted asthma medications. Further work is needed to integrate predictive biomarkers into clinical practice.

Serum Metabolomic Profiling in Acute Alcoholic Hepatitis Identifies Multiple Dysregulated Pathways

PubMed Central

Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit; Bell, Lauren N.; Cooper, Sara; Malik, Shahid; Behari, Jaideep

2014-01-01

Background and Objectives While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. Methods This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Results Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Conclusion Severe AAH is

A serum glycomics approach to breast cancer biomarkers.

PubMed

Kirmiz, Crystal; Li, Bensheng; An, Hyun Joo; Clowers, Brian H; Chew, Helen K; Lam, Kit S; Ferrige, Anthony; Alecio, Robert; Borowsky, Alexander D; Sulaimon, Shola; Lebrilla, Carlito B; Miyamoto, Suzanne

2007-01-01

Because the glycosylation of proteins is known to change in tumor cells during the development of breast cancer, a glycomics approach is used here to find relevant biomarkers of breast cancer. These glycosylation changes are known to correlate with increasing tumor burden and poor prognosis. Current antibody-based immunochemical tests for cancer biomarkers of ovarian (CA125), breast (CA27.29 or CA15-3), pancreatic, gastric, colonic, and carcinoma (CA19-9) target highly glycosylated mucin proteins. However, these tests lack the specificity and sensitivity for use in early detection. This glycomics approach to find glycan biomarkers of breast cancer involves chemically cleaving oligosaccharides (glycans) from glycosylated proteins that are shed or secreted by breast cancer tumor cell lines. The resulting free glycan species are analyzed by MALDI-FT-ICR MS. Further structural analysis of the glycans can be performed in FTMS through the use of tandem mass spectrometry with infrared multiphoton dissociation. Glycan profiles were generated for each cell line and compared. These methods were then used to analyze sera obtained from a mouse model of breast cancer and a small number of serum samples obtained from human patients diagnosed with breast cancer or patients with no known history of breast cancer. In addition to the glycosylation changes detected in mice as mouse mammary tumors developed, glycosylation profiles were found to be sufficiently different to distinguish patients with cancer from those without. Although the small number of patient samples analyzed so far is inadequate to make any legitimate claims at this time, these promising but very preliminary results suggest that glycan profiles may contain distinct glycan biomarkers that may correspond to glycan "signatures of cancer."

Identifying biomarkers for asthma diagnosis using targeted metabolomics approaches.

PubMed

Checkley, William; Deza, Maria P; Klawitter, Jost; Romero, Karina M; Klawitter, Jelena; Pollard, Suzanne L; Wise, Robert A; Christians, Uwe; Hansel, Nadia N

2016-12-01

The diagnosis of asthma in children is challenging and relies on a combination of clinical factors and biomarkers including methacholine challenge, lung function, bronchodilator responsiveness, and presence of airway inflammation. No single test is diagnostic. We sought to identify a pattern of inflammatory biomarkers that was unique to asthma using a targeted metabolomics approach combined with data science methods. We conducted a nested case-control study of 100 children living in a peri-urban community in Lima, Peru. We defined cases as children with current asthma, and controls as children with no prior history of asthma and normal lung function. We further categorized enrollment following a factorial design to enroll equal numbers of children as either overweight or not. We obtained a fasting venous blood sample to characterize a comprehensive panel of targeted markers using a metabolomics approach based on high performance liquid chromatography-mass spectrometry. A statistical comparison of targeted metabolites between children with asthma (n = 50) and healthy controls (n = 49) revealed distinct patterns in relative concentrations of several metabolites: children with asthma had approximately 40-50% lower relative concentrations of ascorbic acid, 2-isopropylmalic acid, shikimate-3-phosphate, and 6-phospho-d-gluconate when compared to children without asthma, and 70% lower relative concentrations of reduced glutathione (all p < 0.001 after Bonferroni correction). Moreover, a combination of 2-isopropylmalic acid and betaine strongly discriminated between children with asthma (2-isopropylmalic acid ≤ 13 077 normalized counts/second) and controls (2-isopropylmalic acid > 13 077 normalized counts/second and betaine ≤ 16 47 121 normalized counts/second). By using a metabolomics approach applied to serum, we were able to discriminate between children with and without asthma by revealing different metabolic patterns. These results suggest that

Exosomal Fetuin-A identified by proteomics: a novel urinary biomarker for detecting acute kidney injury

PubMed Central

Zhou, Hua; Pisitkun, Trairak; Aponte, Angel; Yuen, Peter S.T.; Hoffert, Jason D.; Yasuda, Hideo; Hu, Xuzhen; Chawla, Lakhmir; Shen, Rong-Fong; Knepper, Mark A.; Star., Robert A.

2008-01-01

Urinary exosomes containing apical membrane and intracellular fluid are normally secreted into the urine from all nephron segments, and may carry protein markers of renal dysfunction and structural injury. We aimed to discover biomarkers in urinary exosomes to detect acute kidney injury (AKI) which has a high mortality and morbidity. Animals were injected intravenously with cisplatin. Urinary exosomes were isolated by differential centrifugation. Protein changes were evaluated by two-dimensional difference in gel electrophoresis and changed proteins were identified by MALDI-TOF-TOF or LC-MS/MS. The identified candidate biomarkers were validated by western blotting in individual urine samples from rats subjected to cisplatin injection; bilateral ischemia and reperfusion (I/R); volume depletion (VD); and ICU patients with and without AKI. We identified 18 proteins that were increased and 9 proteins that were decreased 8 hr after cisplatin. Most of the candidates could not be validated by western blotting. However, exosomal Fetuin-A increased 52.5-fold at day 2 (1 day before serum creatinine increase and tubule damage) and remained elevated 51.5-fold at day 5 (peak renal injury) after cisplatin injection. By immuno-electron microscopy and elution studies, Fetuin-A was located inside urinary exosomes. Urinary Fetuin-A was increased 31.6-fold in the early phase (2~8hr) of ischemia/reperfusion, but not in prerenal azotemia. Urinary exosomal Fetuin-A also increased in three ICU patients with AKI compared to the patients without AKI. We conclude that 1) Proteomic analysis of urinary exosomes can provide biomarker candidates for the diagnosis of AKI; 2) Urinary Fetuin-A might be a predictive biomarker of structural renal injury. PMID:17021608

Semi-automated literature mining to identify putative biomarkers of disease from multiple biofluids

PubMed Central

2014-01-01

Background Computational methods for mining of biomedical literature can be useful in augmenting manual searches of the literature using keywords for disease-specific biomarker discovery from biofluids. In this work, we develop and apply a semi-automated literature mining method to mine abstracts obtained from PubMed to discover putative biomarkers of breast and lung cancers in specific biofluids. Methodology A positive set of abstracts was defined by the terms ‘breast cancer’ and ‘lung cancer’ in conjunction with 14 separate ‘biofluids’ (bile, blood, breastmilk, cerebrospinal fluid, mucus, plasma, saliva, semen, serum, synovial fluid, stool, sweat, tears, and urine), while a negative set of abstracts was defined by the terms ‘(biofluid) NOT breast cancer’ or ‘(biofluid) NOT lung cancer.’ More than 5.3 million total abstracts were obtained from PubMed and examined for biomarker-disease-biofluid associations (34,296 positive and 2,653,396 negative for breast cancer; 28,355 positive and 2,595,034 negative for lung cancer). Biological entities such as genes and proteins were tagged using ABNER, and processed using Python scripts to produce a list of putative biomarkers. Z-scores were calculated, ranked, and used to determine significance of putative biomarkers found. Manual verification of relevant abstracts was performed to assess our method’s performance. Results Biofluid-specific markers were identified from the literature, assigned relevance scores based on frequency of occurrence, and validated using known biomarker lists and/or databases for lung and breast cancer [NCBI’s On-line Mendelian Inheritance in Man (OMIM), Cancer Gene annotation server for cancer genomics (CAGE), NCBI’s Genes & Disease, NCI’s Early Detection Research Network (EDRN), and others]. The specificity of each marker for a given biofluid was calculated, and the performance of our semi-automated literature mining method assessed for breast and lung cancer

MRM for the verification of cancer biomarker proteins: recent applications to human plasma and serum.

PubMed

Chambers, Andrew G; Percy, Andrew J; Simon, Romain; Borchers, Christoph H

2014-04-01

Accurate cancer biomarkers are needed for early detection, disease classification, prediction of therapeutic response and monitoring treatment. While there appears to be no shortage of candidate biomarker proteins, a major bottleneck in the biomarker pipeline continues to be their verification by enzyme linked immunosorbent assays. Multiple reaction monitoring (MRM), also known as selected reaction monitoring, is a targeted mass spectrometry approach to protein quantitation and is emerging to bridge the gap between biomarker discovery and clinical validation. Highly multiplexed MRM assays are readily configured and enable simultaneous verification of large numbers of candidates facilitating the development of biomarker panels which can increase specificity. This review focuses on recent applications of MRM to the analysis of plasma and serum from cancer patients for biomarker verification. The current status of this approach is discussed along with future directions for targeted mass spectrometry in clinical biomarker validation.

Cross-platform method for identifying candidate network biomarkers for prostate cancer.

PubMed

Jin, G; Zhou, X; Cui, K; Zhang, X-S; Chen, L; Wong, S T C

2009-11-01

Discovering biomarkers using mass spectrometry (MS) and microarray expression profiles is a promising strategy in molecular diagnosis. Here, the authors proposed a new pipeline for biomarker discovery that integrates disease information for proteins and genes, expression profiles in both genomic and proteomic levels, and protein-protein interactions (PPIs) to discover high confidence network biomarkers. Using this pipeline, a total of 474 molecules (genes and proteins) related to prostate cancer were identified and a prostate-cancer-related network (PCRN) was derived from the integrative information. Thus, a set of candidate network biomarkers were identified from multiple expression profiles composed by eight microarray datasets and one proteomics dataset. The network biomarkers with PPIs can accurately distinguish the prostate patients from the normal ones, which potentially provide more reliable hits of biomarker candidates than conventional biomarker discovery methods.

Serial serum alkaline phosphatase as an early biomarker for osteopenia of prematurity.

PubMed

Abdallah, Enas A A; Said, Reem N; Mosallam, Dalia S; Moawad, Eman M I; Kamal, Naglaa M; Fathallah, Mohammed G E-D

2016-09-01

Metabolic bone disease of prematurity is a condition characterized by reduction in bone mineral content (osteopenia). It is a problem faced by very low birth weight (VLBW) infants because of lack of fetal mineralization during the last trimester. Our aim was to assess serum alkaline phosphatase (ALP) level as an early biomarker for osteopenia in premature infants and to estimate an optimal cutoff value of serum ALP at which osteopenia is detected radiologically in premature newborns.This prospective study was conducted on a cohort of 120 newborn infants of both sex of ≤34 weeks' gestational age and <1500 g birth weight. Two blood samples, from each infant on at least 2 consecutive weeks, were reported for calcium, phosphorus, and ALP. Evidence of osteopenia was evaluated radiologically by performing wrist/knee x-ray.Sixteen infants (13.3%) had evidence of osteopenia in x-ray, whereas 104 infants (86.7%) were nonosteopenic and all the osteopenic infants were <1000-g birth weight. Birth weight and gestational age were significantly inversely related to serum ALP levels. Both samples showed statistically significantly higher mean ALP level in osteopenic than nonosteopenics (P < 0.001, and P < 0.001 respectively). There was no constant value of serum ALP related to radiologic evidence of osteopenia. However, the optimal cutoff value of serum ALP at which osteopenia is detected is 500 IU/L with 100% sensitivity and 80.77% specificity.High levels of ALP can be considered a reliable biomarker to predict the status of bone mineralization and the need for radiological evaluation in premature infants particularly those <1000-g birth weight and <32 weeks' gestation.

Exploration of potential biomarkers and related biological pathways for PCB exposure in maternal and cord serum: A pilot birth cohort study in Chiba, Japan.

PubMed

Eguchi, Akifumi; Sakurai, Kenichi; Watanabe, Masahiro; Mori, Chisato

2017-05-01

Polychlorinated biphenyls (PCBs) have been associated with adverse human reproductive and fetal developmental measures or outcomes because of their endocrine-disrupting effects; however, the biological mechanisms of adverse effects of PCB exposure in humans are not currently well established. In this study, we aimed to identify the biological pathways and potential biomarkers of PCB exposure in maternal and umbilical cord serum using a hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) metabolomics platform. The median concentration of total PCBs in maternal (n=93) and cord serum (n=93) were 350 and 70pgg -1 wet wt, respectively. PCB levels in maternal and fetal serum from the Chiba Study of Mother and Children's Health (C-MACH) cohort are comparable to those of earlier cohort studies conducted in Japan, the USA, and European countries. We used the random forest model with the metabolome profile to predict exposure levels of PCB (first quartile [Q1] and fourth quartile [Q4]) for pregnant women and fetuses. In the prediction model for classification of Q1 versus Q4 (area-under-curve [AUC]: pregnant women=0.812 and fetuses=0.919), citraconic acid level in maternal serum and ethanolamine, p-hydroxybenzoate, and purine levels in cord serum had >0.70 AUC values. These candidate biomarkers and metabolite included in composited models were related to glutathione and amino acid metabolism in maternal serum and the amino acid metabolism and ubiquinone and other terpenoid-quinone biosynthesis in cord serum (FDR <0.10), indicating disruption of metabolic pathways by PCB exposure in pregnant women and fetuses. These results showed that metabolome analysis might be useful to explore potential biomarkers and related biological pathways for PCB exposure. Thus, more detailed studies are needed to verify sensitivity of the biomarkers and clarify the biochemical changes resulting from PCB exposure. Copyright © 2017 The Authors. Published by Elsevier Ltd

Serum Antibody Biomarkers for ASD

DTIC Science & Technology

2015-10-01

autism blood biomarker. In addition, we have identified two new proteins that are linked to ASD. 15. SUBJECT TERMS ASD, autism spectrum disorders . TD...4 8. Appendices…………………………………………………………. 5 3 Introduction: Autism spectrum disorder (ASD) is a neurodevelopmental disorder ...immune responses in young children with autism spectrum disorders : their relationship to gastrointestinal symptoms and dietary intervention

Blood biomarker for Parkinson disease: peptoids

PubMed Central

Yazdani, Umar; Zaman, Sayed; Hynan, Linda S; Brown, L Steven; Dewey, Richard B; Karp, David; German, Dwight C

2016-01-01

Parkinson disease (PD) is the second most common neurodegenerative disease. Because dopaminergic neuronal loss begins years before motor symptoms appear, a biomarker for the early identification of the disease is critical for the study of putative neuroprotective therapies. Brain imaging of the nigrostriatal dopamine system has been used as a biomarker for early disease along with cerebrospinal fluid analysis of α-synuclein, but a less costly and relatively non-invasive biomarker would be optimal. We sought to identify an antibody biomarker in the blood of PD patients using a combinatorial peptoid library approach. We examined serum samples from 75 PD patients, 25 de novo PD patients, and 104 normal control subjects in the NINDS Parkinson’s Disease Biomarker Program. We identified a peptoid, PD2, which binds significantly higher levels of IgG3 antibody in PD versus control subjects (P<0.0001) and is 68% accurate in identifying PD. The PD2 peptoid is 84% accurate in identifying de novo PD. Also, IgG3 levels are significantly higher in PD versus control serum (P<0.001). Finally, PD2 levels are positively correlated with the United Parkinson’s Disease Rating Scale score (r=0.457, P<0001), a marker of disease severity. The PD2 peptoid may be useful for the early-stage identification of PD, and serve as an indicator of disease severity. Additional studies are needed to validate this PD biomarker. PMID:27812535

Multiplexing of miniaturized planar antibody arrays for serum protein profiling--a biomarker discovery in SLE nephritis.

PubMed

Petersson, Linn; Dexlin-Mellby, Linda; Bengtsson, Anders A; Sturfelt, Gunnar; Borrebaeck, Carl A K; Wingren, Christer

2014-06-07

In the quest to decipher disease-associated biomarkers, miniaturized and multiplexed antibody arrays may play a central role in generating protein expression profiles, or protein maps, of crude serum samples. In this conceptual study, we explored a novel, 4-times larger pen design, enabling us to, in a unique manner, simultaneously print 48 different reagents (antibodies) as individual 78.5 μm(2) (10 μm in diameter) sized spots at a density of 38,000 spots cm(-2) using dip-pen nanolithography technology. The antibody array set-up was interfaced with a high-resolution fluorescent-based scanner for sensitive sensing. The performance and applicability of this novel 48-plex recombinant antibody array platform design was demonstrated in a first clinical application targeting SLE nephritis, a severe chronic autoimmune connective tissue disorder, as the model disease. To this end, crude, directly biotinylated serum samples were targeted. The results showed that the miniaturized and multiplexed array platform displayed adequate performance, and that SLE-associated serum biomarker panels reflecting the disease process could be deciphered, outlining the use of miniaturized antibody arrays for disease proteomics and biomarker discovery.

Biomarkers identified by urinary metabonomics for noninvasive diagnosis of nutritional rickets.

PubMed

Wang, Maoqing; Yang, Xue; Ren, Lihong; Li, Songtao; He, Xuan; Wu, Xiaoyan; Liu, Tingting; Lin, Liqun; Li, Ying; Sun, Changhao

2014-09-05

Nutritional rickets is a worldwide public health problem; however, the current diagnostic methods retain shortcomings for accurate diagnosis of nutritional rickets. To identify urinary biomarkers associated with nutritional rickets and establish a noninvasive diagnosis method, urinary metabonomics analysis by ultra-performance liquid chromatography/quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis were employed to investigate the metabolic alterations associated with nutritional rickets in 200 children with or without nutritional rickets. The pathophysiological changes and pathogenesis of nutritional rickets were illustrated by the identified biomarkers. By urinary metabolic profiling, 31 biomarkers of nutritional rickets were identified and five candidate biomarkers for clinical diagnosis were screened and identified by quantitative analysis and receiver operating curve analysis. Urinary levels of five candidate biomarkers were measured using mass spectrometry or commercial kits. In the validation step, the combination of phosphate and sebacic acid was able to give a noninvasive and accurate diagnostic with high sensitivity (94.0%) and specificity (71.2%). Furthermore, on the basis of the pathway analysis of biomarkers, our urinary metabonomics analysis gives new insight into the pathogenesis and pathophysiology of nutritional rickets.

Possibilities and limitations of 2DE-based analyses for identifying low-abundant tumor markers in human serum and plasma.

PubMed

Strohkamp, Sarah; Gemoll, Timo; Habermann, Jens K

2016-10-01

Hallmarks of malignancy can be monitored by protein signatures in serum or plasma. The current challenge in cancer research is the identification of clinically reliable protein biomarkers for diagnostic and prognostic purposes. A widely used and powerful technique to screen tumor markers is two-dimensional gel electrophoresis (2DE). This review provides an overview of 2DE functionality with its advantages and drawbacks as well as a current literature overview of gel-based cancer biomarker discovery in serum/plasma. In this context, 11 of the 12 studies reviewed here identified at least one of eight classical serum or high-abundant proteins (HAPs). Expression levels of those proteins are regulated by a vast variety of different physiological, metabolic and immunological stimuli leading to a questionable application as cancer-specific markers. Misinterpretation of HAPs as tumor markers might be caused by either the experimental setup or the technical and analytical potential in gel-based serum or plasma proteomics to detect low-abundant proteins, or a combination thereof. Additionally, based on currently available technology we propose an optimized experimental workflow to allow detecting cancer-specific protein markers of low abundance in future 2DE studies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Multiplatform serum metabolic phenotyping combined with pathway mapping to identify biochemical differences in smokers.

PubMed

Kaluarachchi, Manuja R; Boulangé, Claire L; Garcia-Perez, Isabel; Lindon, John C; Minet, Emmanuel F

2016-10-01

Determining perturbed biochemical functions associated with tobacco smoking should be helpful for establishing causal relationships between exposure and adverse events. A multiplatform comparison of serum of smokers (n = 55) and never-smokers (n = 57) using nuclear magnetic resonance spectroscopy, UPLC-MS and statistical modeling revealed clustering of the classes, distinguished by metabolic biomarkers. The identified metabolites were subjected to metabolic pathway enrichment, modeling adverse biological events using available databases. Perturbation of metabolites involved in chronic obstructive pulmonary disease, cardiovascular diseases and cancer were identified and discussed. Combining multiplatform metabolic phenotyping with knowledge-based mapping gives mechanistic insights into disease development, which can be applied to next-generation tobacco and nicotine products for comparative risk assessment.

Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers

PubMed Central

Sereno, José; Nunes, Sara; Rodrigues-Santos, Paulo; Rocha-Pereira, Petronila; Fernandes, João; Teixeira, Frederico; Reis, Flávio

2014-01-01

Protocols of conversion from cyclosporin A (CsA) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κ β, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to SRL. PMID:24971338

Utility of salivary biomarkers for demonstrating acute myocardial infarction.

PubMed

Miller, C S; Foley, J D; Floriano, P N; Christodoulides, N; Ebersole, J L; Campbell, C L; Bailey, A L; Rose, B G; Kinane, D F; Novak, M J; McDevitt, J T; Ding, X; Kryscio, R J

2014-07-01

The comparative utility of serum and saliva as diagnostic fluids for identifying biomarkers of acute myocardial infarction (AMI) was investigated. The goal was to determine if salivary biomarkers could facilitate a screening diagnosis of AMI, especially in cases of non-ST elevation MI (NSTEMI), since these cases are not readily identified by electrocardiogram (ECG). Serum and unstimulated whole saliva (UWS) collected from 92 AMI patients within 48 hours of chest pain onset and 105 asymptomatic healthy control individuals were assayed for 13 proteins relevant to cardiovascular disease, by Beadlyte technology (Luminex(®)) and enzyme immunoassays. Data were analyzed with concentration cut-points, ECG findings, logistic regression (LR) (adjusted for matching for age, gender, race, smoking, number of teeth, and oral health status), and classification and regression tree (CART) analysis. A sensitivity analysis was conducted by repetition of the CART analysis in 58 cases and 58 controls, each matched by age and gender. Serum biomarkers demonstrated AMI sensitivity and specificity superior to that of saliva, as determined by LR and CART. The predominant discriminators in serum by LR were troponin I (TnI), B-type natriuretic peptide (BNP), and creatine kinase-MB (CK-MB), and TnI and BNP by CART. In saliva, LR identified C-reactive protein (CRP) as the biomarker most predictive of AMI. A combination of smoking tobacco, UWS CRP, CK-MB, sCD40 ligand, gender, and number of teeth identified AMI in the CART decision trees. When ECG findings, salivary biomarkers, and confounders were included, AMI was predicted with 80.0% sensitivity and 100% specificity. These analyses support the potential utility of salivary biomarker measurements used with ECG for the identification of AMI. Thus, saliva-based tests may provide additional diagnostic screening information in the clinical course for patients suspected of having an AMI. © International & American Associations for Dental Research.

Protein and microRNA biomarkers from lavage, urine, and serum in military personnel evaluated for dyspnea

PubMed Central

2014-01-01

Background We have identified candidate protein and microRNA (miRNA) biomarkers for dyspnea by studying serum, lavage fluid, and urine from military personnel who reported serious respiratory symptoms after they were deployed to Iraq or Afghanistan. Methods Forty-seven soldiers with the complaint of dyspnea who enrolled in the STudy of Active Duty Military Personnel for Environmental Dust Exposure (STAMPEDE) underwent comprehensive pulmonary evaluations at the San Antonio Military Medical Center. The evaluation included fiber-optic bronchoscopy with bronchoalveolar lavage. The clinical findings from the STAMPEDE subjects pointed to seven general underlying diagnoses or findings including airway hyperreactivity, asthma, low diffusivity of carbon monoxide, and abnormal cell counts. The largest category was undiagnosed. As an exploratory study, not a classification study, we profiled proteins or miRNAs in lavage fluid, serum, or urine in this group to look for any underlying molecular patterns that might lead to biomarkers. Proteins in lavage fluid and urine were identified by accurate mass tag (database-driven) proteomics methods while miRNAs were profiled by a hybridization assay applied to serum, urine, and lavage fluid. Results Over seventy differentially expressed proteins were reliably identified both from lavage and from urine in forty-eight dyspnea subjects compared to fifteen controls with no known lung disorder. Six of these proteins were detected both in urine and lavage. One group of subjects was distinguished from controls by expressing a characteristic group of proteins. A related group of dyspnea subjects expressed a unique group of miRNAs that included one miRNA that was differentially overexpressed in all three fluids studied. The levels of several miRNAs also showed modest but direct associations with several standard clinical measures of lung health such as forced vital capacity or gas exchange efficiency. Conclusions Candidate proteins and mi

Protein and microRNA biomarkers from lavage, urine, and serum in military personnel evaluated for dyspnea.

PubMed

Brown, Joseph N; Brewer, Heather M; Nicora, Carrie D; Weitz, Karl K; Morris, Michael J; Skabelund, Andrew J; Adkins, Joshua N; Smith, Richard D; Cho, Ji-Hoon; Gelinas, Richard

2014-10-05

We have identified candidate protein and microRNA (miRNA) biomarkers for dyspnea by studying serum, lavage fluid, and urine from military personnel who reported serious respiratory symptoms after they were deployed to Iraq or Afghanistan. Forty-seven soldiers with the complaint of dyspnea who enrolled in the STudy of Active Duty Military Personnel for Environmental Dust Exposure (STAMPEDE) underwent comprehensive pulmonary evaluations at the San Antonio Military Medical Center. The evaluation included fiber-optic bronchoscopy with bronchoalveolar lavage. The clinical findings from the STAMPEDE subjects pointed to seven general underlying diagnoses or findings including airway hyperreactivity, asthma, low diffusivity of carbon monoxide, and abnormal cell counts. The largest category was undiagnosed. As an exploratory study, not a classification study, we profiled proteins or miRNAs in lavage fluid, serum, or urine in this group to look for any underlying molecular patterns that might lead to biomarkers. Proteins in lavage fluid and urine were identified by accurate mass tag (database-driven) proteomics methods while miRNAs were profiled by a hybridization assay applied to serum, urine, and lavage fluid. Over seventy differentially expressed proteins were reliably identified both from lavage and from urine in forty-eight dyspnea subjects compared to fifteen controls with no known lung disorder. Six of these proteins were detected both in urine and lavage. One group of subjects was distinguished from controls by expressing a characteristic group of proteins. A related group of dyspnea subjects expressed a unique group of miRNAs that included one miRNA that was differentially overexpressed in all three fluids studied. The levels of several miRNAs also showed modest but direct associations with several standard clinical measures of lung health such as forced vital capacity or gas exchange efficiency. Candidate proteins and miRNAs associated with the general diagnosis of

Protein and microRNA biomarkers from lavage, urine, and serum in military personnel evaluated for dyspnea

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brown, Joseph N.; Brewer, Heather M.; Nicora, Carrie D.

Background: We have identified candidate protein and microRNA (miRNA) biomarkers for dyspnea by studying serum, lavage fluid, and urine from military personnel who reported serious respiratory symptoms after they were deployed to Iraq or Afghanistan. Methods: Forty-seven soldiers with the complaint of dyspnea who enrolled in the STudy of Active Duty Military Personnel for Environmental Dust Exposure (STAMPEDE) underwent comprehensive pulmonary evaluations at the San Antonio Military Medical Center. The evaluation included fiber-optic bronchoscopy with bronchoalveolar lavage. The clinical findings from the STAMPEDE subjects pointed to seven general underlying diagnoses or findings including airway hyperreactivity, asthma, low diffusivity of carbonmore » monoxide, and abnormal cell counts. The largest category was undiagnosed. As an exploratory study, not a classification study, we profiled proteins or miRNAs in lavage fluid, serum, or urine in this group to look for any underlying molecular patterns that might lead to biomarkers. Proteins in lavage fluid and urine were identified by accurate mass tag (database-driven) proteomics methods while miRNAs were profiled by a hybridization assay applied to serum, urine, and lavage fluid. Results: Over seventy differentially expressed proteins were reliably identified both from lavage and from urine in forty-eight dyspnea subjects compared to fifteen controls with no known lung disorder. Six of these proteins were detected both in urine and lavage. One group of subjects was distinguished from controls by expressing a characteristic group of proteins. A related group of dyspnea subjects expressed a unique group of miRNAs that included one miRNA that was differentially overexpressed in all three fluids studied. The levels of several miRNAs also showed modest but direct associations with several standard clinical measures of lung health such as forced vital capacity or gas exchange efficiency. Conclusions: Candidate proteins

Protein and microRNA biomarkers from lavage, urine, and serum in military personnel evaluated for dyspnea

DOE PAGES

Brown, Joseph N.; Brewer, Heather M.; Nicora, Carrie D.; ...

2014-10-05

Background: We have identified candidate protein and microRNA (miRNA) biomarkers for dyspnea by studying serum, lavage fluid, and urine from military personnel who reported serious respiratory symptoms after they were deployed to Iraq or Afghanistan. Methods: Forty-seven soldiers with the complaint of dyspnea who enrolled in the STudy of Active Duty Military Personnel for Environmental Dust Exposure (STAMPEDE) underwent comprehensive pulmonary evaluations at the San Antonio Military Medical Center. The evaluation included fiber-optic bronchoscopy with bronchoalveolar lavage. The clinical findings from the STAMPEDE subjects pointed to seven general underlying diagnoses or findings including airway hyperreactivity, asthma, low diffusivity of carbonmore » monoxide, and abnormal cell counts. The largest category was undiagnosed. As an exploratory study, not a classification study, we profiled proteins or miRNAs in lavage fluid, serum, or urine in this group to look for any underlying molecular patterns that might lead to biomarkers. Proteins in lavage fluid and urine were identified by accurate mass tag (database-driven) proteomics methods while miRNAs were profiled by a hybridization assay applied to serum, urine, and lavage fluid. Results: Over seventy differentially expressed proteins were reliably identified both from lavage and from urine in forty-eight dyspnea subjects compared to fifteen controls with no known lung disorder. Six of these proteins were detected both in urine and lavage. One group of subjects was distinguished from controls by expressing a characteristic group of proteins. A related group of dyspnea subjects expressed a unique group of miRNAs that included one miRNA that was differentially overexpressed in all three fluids studied. The levels of several miRNAs also showed modest but direct associations with several standard clinical measures of lung health such as forced vital capacity or gas exchange efficiency. Conclusions: Candidate proteins

Search for breast cancer biomarkers in fractionated serum samples by protein profiling with SELDI-TOF MS.

PubMed

Opstal-van Winden, Annemieke W J; Beijnen, Jos H; Loof, Arnoud; van Heerde, Waander L; Vermeulen, Roel; Peeters, Petra H M; van Gils, Carla H

2012-01-01

Many high-abundant acute phase reactants have been previously detected as potential breast cancer biomar-kers. However, they are unlikely to be specific for breast cancer. Cancer-specific biomarkers are thought to be among the lower abundant proteins. We aimed to detect lower abundant discriminating proteins by performing serum fractionation by strong anion exchange chromatography preceding protein profiling with SELDI-TOF MS. In a pilot study, we tested the different fractions resulting from fractionation, on several array types. Fraction 3 on IMAC30 and Fraction 6 on Q10 yielded the most discriminative proteins and were used for serum protein profiling of 73 incident breast cancer cases and 73 matched controls. Eight peaks showed statistically significantly different intensities between cases and controls (P⧁0.05), and had less than 10% chance to be a false-positive finding. Seven of these were tentatively identified as apolipoprotein C-II (m/z 8,909), oxidized apolipoprotein C-II (m/z 8,925), apolipoprotein C-III (m/z 8,746), fragment of coagulation factor XIIIa (m/z 3,959), heterodimer of apolipoprotein A-I and apolipoprotein A-II (m/z 45,435), hemoglobin B-chain (m/z 15,915), and post-translational modified hemoglobin (m/z 15,346). By extensive serum fractionation, we detected many more proteins than in previous studies without fractionation. However, discriminating proteins were still high abundant. Results indicate that either lower abundant proteins are less distinctive, or more rigorous fractionation and selective protein depletion, or a more sensitive assay, are needed to detect lower abundant discriminative proteins. © 2012 Wiley Periodicals, Inc.

Serum Proteomic Changes after Randomized Prolonged Erythropoietin Treatment and/or Endurance Training: Detection of Novel Biomarkers

PubMed Central

Christensen, Britt; Ludvigsen, Maja; Nellemann, Birgitte; Kopchick, John J.; Honoré, Bent; Jørgensen, Jens Otto L.

2015-01-01

Introduction Despite implementation of the biological passport to detect erythropoietin abuse, a need for additional biomarkers remains. We used a proteomic approach to identify novel serum biomarkers of prolonged erythropoiesis-stimulating agent (ESA) exposure (Darbepoietin-α) and/or aerobic training. Trial Design Thirty-six healthy young males were randomly assigned to the following groups: Sedentary-placebo (n = 9), Sedentary-ESA (n = 9), Training-placebo (n = 10), or Training-ESA (n = 8). They were treated with placebo/Darbepoietin-α subcutaneously once/week for 10 weeks followed by a 3-week washout period. Training consisted of supervised biking 3/week for 13 weeks at the highest possible intensity. Serum was collected at baseline, week 3 (high dose Darbepoietin-α), week 10 (reduced dose Darbepoietin-α), and after a 3-week washout period. Methods Serum proteins were separated according to charge and molecular mass (2D-gel electrophoresis). The identity of proteins from spots exhibiting altered intensity was determined by mass spectrometry. Results Six protein spots changed in response to Darbepoietin-α treatment. Comparing all 4 experimental groups, two protein spots (serotransferrin and haptoglobin/haptoglobin related protein) showed a significant response to Darbepoietin-α treatment. The haptoglobin/haptoglobin related protein spot showed a significantly lower intensity in all subjects in the training-ESA group during the treatment period and increased during the washout period. Conclusion An isoform of haptoglobin/haptoglobin related protein could be a new anti-doping marker and merits further research. Trial Registration ClinicalTrials.gov NCT01320449 PMID:25679398

Reevaluating cathepsin D as a biomarker for breast cancer: serum activity levels versus histopathology.

PubMed

Abbott, Daniel E; Margaryan, Naira V; Jeruss, Jacqueline S; Khan, Seema; Kaklamani, Virginia; Winchester, David J; Hansen, Nora; Rademaker, Alfred; Khalkhali-Ellis, Zhila; Hendrix, Mary J C

2010-01-01

Cathepsin D is a lysosomal hydrolase involved in intra- and extracellular proteolysis. This enzyme is aberrantly produced and processed in malignancy, and most notably is over-secreted into the tumor cell microenvironment. This hyper-secretion may lead to excessive degradation of the extracellular matrix, and contribute to tumor progression and metastases. These phenomena have been established in vitro, and there is evidence that Cathepsin D is similarly dysregulated in human breast cancer patients. Because breast cancer lacks an effective screening or surveillance biomarker, here we address the hypothesis that serum Cathepsin D activity may be useful to assess the presence or progression of breast cancer in females. While representative histologic sections from various disease-specific cohorts confirm previous findings that increased Cathepsin D production and secretion correlate with tumor progression, we report no difference in serum Cathepsin D activity between patients who are disease free, patients with pre-invasive or limited invasive disease, and patients with metastatic disease. Furthermore, in patients with known metastatic disease, there were no clinical variables associated with significantly different serum Cathepsin D activity. However, the immunohistochemical localization of Cathepsin D expression in histopathologic sections from breast cancer patients correlates with disease progression. Based on the serum results, and in contradistinction to Cathepsin D localization in breast cancer tissues, our findings support using Cathepsin D as a reliable histopathology biomarker for disease progression, but not for serum screening.

Identification of low-abundance cancer biomarker candidate TIMP1 from serum with lectin fractionation and peptide affinity enrichment by ultrahigh-resolution mass spectrometry.

PubMed

Ahn, Yeong Hee; Kim, Kwang Hoe; Shin, Park Min; Ji, Eun Sun; Kim, Hoguen; Yoo, Jong Shin

2012-02-07

As investigating a proteolytic target peptide originating from the tissue inhibitor of metalloproteinase 1 (TIMP1) known to be aberrantly glycosylated in patients with colorectal cancer (CRC), we first confirmed that TIMP1 is to be a CRC biomarker candidate in human serum. For this, we utilized matrix-assisted laser desorption/ionization (MALDI) Fourier transform ion cyclotron resonance (FTICR) mass spectrometry (MS) showing ultrahigh-resolution and high mass accuracy. This investigation used phytohemagglutinin-L(4) (L-PHA) lectin, which shows binding affinity to the β-1,6-N-acetylglucosamine moiety of N-linked glycan on a protein, to compare fractionated aberrant protein glycoforms from both noncancerous control and CRC serum. Each lectin-captured fraction containing aberrant glycoforms of TIMP1 was digested by trypsin, resulting in the tryptic target peptide, representative of the serum glycoprotein TIMP1. The resulting target peptide was enriched using a stable isotope standard and capture by the antipeptide antibody (SISCAPA) technique and analyzed by a 15 T MALDI FTICR mass spectrometer with high mass accuracy (Δ < 0.5 ppm to the theoretical mass value of the target peptide). Since exact measurement of multiplex isotopic peaks of the target peptide could be accomplished by virtue of high mass resolution (Rs > 400,000), robust identification of the target peptide is only achievable with 15 T FTICR MS. Also, MALDI data obtained in this study showed that the L-PHA-captured glycoforms of TIMP1 were measured in the pooled CRC serum with about 5 times higher abundance than that in the noncancerous serum, and were further proved by MRM mass analysis. These results confirm that TIMP1 in human serum is a potent CRC biomarker candidate, demonstrating that ultrahigh-resolution MS can be a powerful tool toward identifying and verifying potential protein biomarker candidates. © 2011 American Chemical Society

Utility of a non-invasive serum biomarker panel for diagnosis and monitoring of eosinophilic esophagitis: A prospective study

PubMed Central

Dellon, Evan S.; Rusin, Spencer; Gebhart, Jessica H.; Covey, Shannon; Higgins, Leana L.; Beitia, RoseMary; Speck, Olga; Woodward, Kimberly; Woosley, John T.; Shaheen, Nicholas J.

2015-01-01

Objectives Non-invasive biomarkers would be valuable for diagnosis and monitoring of eosinophilic esophagitis (EoE). The aim of this study was to determine the utility of a panel of serum biomarkers for the diagnosis and management of EoE. Methods We conducted a prospective cohort study of consecutive adults undergoing outpatient EGD. Incident cases of EoE were diagnosed per consensus guidelines; controls had GERD or dysphagia and did not meet EoE criteria. EoE cases were treated with topical steroids and had repeat endoscopy. Pre- and post-treatment serum samples were analyzed in a blinded fashion for: IL-4, IL-5, IL-6, IL-9, IL-13, TGF-α, TGF-β, TNF-α, eotaxin-1, -2, and -3, TSLP, major basic protein (MBP), and eosinophil-derived neurotoxin (EDN). Cases and controls were compared at baseline, and pre- and post-treatment assays were compared in cases. Results A total of 61 incident EoE cases and 87 controls were enrolled; 51 EoE cases had post-treatment serum analyzed. There were no significant differences in any of the biomarkers between EoE cases and controls at baseline. IL-13 and eotaxin-3 for cases and controls were 85 ±160 vs 43 ±161 pg/mL (p=0.12), and 41 ±159 vs 21 ±73 (p=0.30). There were no significant differences in assay values among cases before and after treatment. There were also no differences after stratification by atopic status or treatment response. Conclusions A panel of inflammatory factors known to be associated with EoE pathogenesis were not increased in the serum, nor were they responsive to therapy. None of these biomarkers are likely candidates for a serum test for EoE. Histologic analysis for diagnosis and management of EoE continues to be necessary, and novel, less invasive, biomarkers are needed. PMID:25781367

Automated analysis of immunohistochemistry images identifies candidate location biomarkers for cancers.

PubMed

Kumar, Aparna; Rao, Arvind; Bhavani, Santosh; Newberg, Justin Y; Murphy, Robert F

2014-12-23

Molecular biomarkers are changes measured in biological samples that reflect disease states. Such markers can help clinicians identify types of cancer or stages of progression, and they can guide in tailoring specific therapies. Many efforts to identify biomarkers consider genes that mutate between normal and cancerous tissues or changes in protein or RNA expression levels. Here we define location biomarkers, proteins that undergo changes in subcellular location that are indicative of disease. To discover such biomarkers, we have developed an automated pipeline to compare the subcellular location of proteins between two sets of immunohistochemistry images. We used the pipeline to compare images of healthy and tumor tissue from the Human Protein Atlas, ranking hundreds of proteins in breast, liver, prostate, and bladder based on how much their location was estimated to have changed. The performance of the system was evaluated by determining whether proteins previously known to change location in tumors were ranked highly. We present a number of candidate location biomarkers for each tissue, and identify biochemical pathways that are enriched in proteins that change location. The analysis technology is anticipated to be useful not only for discovering new location biomarkers but also for enabling automated analysis of biomarker distributions as an aid to determining diagnosis.

A protocol for identifying suitable biomarkers to assess fish health: A systematic review

PubMed Central

2017-01-01

Background Biomarkers have been used extensively to provide the connection between external levels of contaminant exposure, internal levels of tissue contamination, and early adverse effects in organisms. Objectives To present a three-step protocol for identifying suitable biomarkers to assess fish health in coastal and marine ecosystems, using Gladstone Harbour (Australia) as a case study. Methods Prior to applying our protocol, clear working definitions for biomarkers were developed to ensure consistency with the global literature on fish health assessment. First, contaminants of concern were identified based on the presence of point and diffuse sources of pollution and available monitoring data for the ecosystem of interest. Second, suitable fish species were identified using fisheries dependent and independent data, and prioritised based on potential pathways of exposure to the contaminants of concern. Finally, a systematic and critical literature review was conducted on the use of biomarkers to assess the health of fish exposed to the contaminants of concern. Results/Discussion We present clear working definitions for bioaccumulation markers, biomarkers of exposure, biomarkers of effect and biomarkers of susceptibility. Based on emission and concentration information, seven metals were identified as contaminants of concern for Gladstone Harbour. Twenty out of 232 fish species were abundant enough to be potentially suitable for biomarker studies; five of these were prioritised based on potential pathways of exposure and susceptibility to metals. The literature search on biomarkers yielded 5,035 articles, of which 151met the inclusion criteria. Based on our review, the most suitable biomarkers include bioaccumulation markers, biomarkers of exposure (CYP1A, EROD, SOD, LPOX, HSP, MT, DNA strand breaks, micronuclei, apoptosis), and biomarkers of effect (histopathology, TAG:ST). Conclusion Our protocol outlines a clear pathway to identify suitable biomarkers to

Serum biomarkers are similar in Churg-Strauss syndrome and hypereosinophilic syndrome.

PubMed

Khoury, P; Zagallo, P; Talar-Williams, C; Santos, C S; Dinerman, E; Holland, N C; Klion, A D

2012-09-01

Churg-Strauss syndrome (CSS) and hypereosinophilic syndrome (HES) overlap considerably in clinical presentation. A reliable means of distinguishing between these groups of patients is needed, especially in the setting of glucocorticoid therapy. A retrospective chart review of 276 adult subjects referred for evaluation of eosinophilia > 1500/μl was performed, and subjects with a documented secondary cause of eosinophilia or a PDGFR -positive myeloproliferative neoplasm were excluded. The remaining subjects were assessed for the presence of American College of Rheumatology (ACR) criteria. Laboratory and clinical parameters were compared between subjects with biopsy-proven vasculitis (CSS; n = 8), ≥4 ACR criteria (probable CSS; n = 21), HES with asthma and/or sinusitis without other CSS-defining criteria (HESwAS; n = 20), HES without asthma or sinusitis (HES; n = 18), and normal controls (n = 8). Serum biomarkers reported to be associated with CSS were measured using standard techniques. There were no differences between the subjects with definite or probable CSS or HES with respect to age, gender, or maintenance steroid dose. Serum CCL17, IL-8, and eotaxin levels were significantly increased in eosinophilic subjects as compared to normal controls, but were similar between the eosinophilic groups. Serum CCL17 correlated with eosinophil count (P < 0.0001, r = 0.73), but not with prednisone dose. In patients with a history of asthma and sinusitis, distinguishing between ANCA-negative CSS and PDGFR-negative HES is difficult because of significant overlap in clinical presentation and biomarker profiles. Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Serum biomarkers are similar in Churg-Strauss syndrome and hypereosinophilic syndrome

PubMed Central

Khoury, Paneez; Zagallo, Patricia; Talar-Williams, Cheryl; Santos, Carlo S.; Dinerman, Ellen; Holland, Nicole C.; Klion, Amy D.

2012-01-01

Rationale Churg-Strauss syndrome (CSS) and hypereosinophilic syndrome (HES) overlap considerably in clinical presentation. A reliable means of distinguishing between these groups of patients is needed, especially in the setting of glucocorticoid therapy. Methods A retrospective chart review of 276 adult subjects referred for evaluation of eosinophilia >1500/μl was performed, and subjects with a documented secondary cause of eosinophilia or a PDGFR-positive myeloproliferative neoplasm were excluded. The remaining subjects were assessed for the presence of American College of Rheumatology (ACR) criteria. Laboratory and clinical parameters were compared between subjects with biopsy-proven vasculitis (CSS; n=8), ≥4 ACR criteria (probable CSS; n=21), HES with asthma and/or sinusitis without other CSS-defining criteria (HESwAS; n=20), HES without asthma or sinusitis (HES; n=18), and normal controls (n=8). Serum biomarkers reported to be associated with CSS were measured using standard techniques. Results There were no differences between the subjects with definite or probable CSS or HES with respect to age, gender, or maintenance steroid dose. Serum CCL17, IL-8 and eotaxin levels were significantly increased in eosinophilic subjects as compared to normal controls, but were similar between the eosinophilic groups. Serum CCL17 correlated with eosinophil count (p<0.0001, r=0.73), but not with prednisone dose. Conclusions In patients with a history of asthma and sinusitis, distinguishing between ANCA-negative CSS and PDGFR-negative HES is difficult due to significant overlap in clinical presentation and biomarker profiles. PMID:22775568

Strategies to design clinical studies to identify predictive biomarkers in cancer research.

PubMed

Perez-Gracia, Jose Luis; Sanmamed, Miguel F; Bosch, Ana; Patiño-Garcia, Ana; Schalper, Kurt A; Segura, Victor; Bellmunt, Joaquim; Tabernero, Josep; Sweeney, Christopher J; Choueiri, Toni K; Martín, Miguel; Fusco, Juan Pablo; Rodriguez-Ruiz, Maria Esperanza; Calvo, Alfonso; Prior, Celia; Paz-Ares, Luis; Pio, Ruben; Gonzalez-Billalabeitia, Enrique; Gonzalez Hernandez, Alvaro; Páez, David; Piulats, Jose María; Gurpide, Alfonso; Andueza, Mapi; de Velasco, Guillermo; Pazo, Roberto; Grande, Enrique; Nicolas, Pilar; Abad-Santos, Francisco; Garcia-Donas, Jesus; Castellano, Daniel; Pajares, María J; Suarez, Cristina; Colomer, Ramon; Montuenga, Luis M; Melero, Ignacio

2017-02-01

The discovery of reliable biomarkers to predict efficacy and toxicity of anticancer drugs remains one of the key challenges in cancer research. Despite its relevance, no efficient study designs to identify promising candidate biomarkers have been established. This has led to the proliferation of a myriad of exploratory studies using dissimilar strategies, most of which fail to identify any promising targets and are seldom validated. The lack of a proper methodology also determines that many anti-cancer drugs are developed below their potential, due to failure to identify predictive biomarkers. While some drugs will be systematically administered to many patients who will not benefit from them, leading to unnecessary toxicities and costs, others will never reach registration due to our inability to identify the specific patient population in which they are active. Despite these drawbacks, a limited number of outstanding predictive biomarkers have been successfully identified and validated, and have changed the standard practice of oncology. In this manuscript, a multidisciplinary panel reviews how those key biomarkers were identified and, based on those experiences, proposes a methodological framework-the DESIGN guidelines-to standardize the clinical design of biomarker identification studies and to develop future research in this pivotal field. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Metabolomics-Based Discovery of Small Molecule Biomarkers in Serum Associated with Dengue Virus Infections and Disease Outcomes

PubMed Central

Voge, Natalia V.; Perera, Rushika; Mahapatra, Sebabrata; Gresh, Lionel; Balmaseda, Angel; Loroño-Pino, María A.; Hopf-Jannasch, Amber S.; Belisle, John T.; Harris, Eva; Blair, Carol D.; Beaty, Barry J.

2016-01-01

Background Epidemic dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) are overwhelming public health capacity for diagnosis and clinical care of dengue patients throughout the tropical and subtropical world. The ability to predict severe dengue disease outcomes (DHF/DSS) using acute phase clinical specimens would be of enormous value to physicians and health care workers for appropriate triaging of patients for clinical management. Advances in the field of metabolomics and analytic software provide new opportunities to identify host small molecule biomarkers (SMBs) in acute phase clinical specimens that differentiate dengue disease outcomes. Methodology/Principal Findings Exploratory metabolomic studies were conducted to characterize the serum metabolome of patients who experienced different dengue disease outcomes. Serum samples from dengue patients from Nicaragua and Mexico were retrospectively obtained, and hydrophilic interaction liquid chromatography (HILIC)-mass spectrometry (MS) identified small molecule metabolites that were associated with and statistically differentiated DHF/DSS, DF, and non-dengue (ND) diagnosis groups. In the Nicaraguan samples, 191 metabolites differentiated DF from ND outcomes and 83 differentiated DHF/DSS and DF outcomes. In the Mexican samples, 306 metabolites differentiated DF from ND and 37 differentiated DHF/DSS and DF outcomes. The structural identities of 13 metabolites were confirmed using tandem mass spectrometry (MS/MS). Metabolomic analysis of serum samples from patients diagnosed as DF who progressed to DHF/DSS identified 65 metabolites that predicted dengue disease outcomes. Differential perturbation of the serum metabolome was demonstrated following infection with different DENV serotypes and following primary and secondary DENV infections. Conclusions/Significance These results provide proof-of-concept that a metabolomics approach can be used to identify metabolites or SMBs in serum

Overlap of proteomics biomarkers between women with pre-eclampsia and PCOS: a systematic review and biomarker database integration

PubMed Central

Khan, Gulafshana Hafeez; Galazis, Nicolas; Docheva, Nikolina; Layfield, Robert; Atiomo, William

2015-01-01

STUDY QUESTION Do any proteomic biomarkers previously identified for pre-eclampsia (PE) overlap with those identified in women with polycystic ovary syndrome (PCOS). SUMMARY ANSWER Five previously identified proteomic biomarkers were found to be common in women with PE and PCOS when compared with controls. WHAT IS KNOWN ALREADY Various studies have indicated an association between PCOS and PE; however, the pathophysiological mechanisms supporting this association are not known. STUDY DESIGN, SIZE, DURATION A systematic review and update of our PCOS proteomic biomarker database was performed, along with a parallel review of PE biomarkers. The study included papers from 1980 to December 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS In all the studies analysed, there were a total of 1423 patients and controls. The number of proteomic biomarkers that were catalogued for PE was 192. MAIN RESULTS AND THE ROLE OF CHANCE Five proteomic biomarkers were shown to be differentially expressed in women with PE and PCOS when compared with controls: transferrin, fibrinogen α, β and γ chain variants, kininogen-1, annexin 2 and peroxiredoxin 2. In PE, the biomarkers were identified in serum, plasma and placenta and in PCOS, the biomarkers were identified in serum, follicular fluid, and ovarian and omental biopsies. LIMITATIONS, REASONS FOR CAUTION The techniques employed to detect proteomics have limited ability in identifying proteins that are of low abundance, some of which may have a diagnostic potential. The sample sizes and number of biomarkers identified from these studies do not exclude the risk of false positives, a limitation of all biomarker studies. The biomarkers common to PE and PCOS were identified from proteomic analyses of different tissues. WIDER IMPLICATIONS OF THE FINDINGS This data amalgamation of the proteomic studies in PE and in PCOS, for the first time, discovered a panel of five biomarkers for PE which are common to women with PCOS, including transferrin

Biomarker identification and pathway analysis of preeclampsia based on serum metabolomics.

PubMed

Chen, Tingting; He, Ping; Tan, Yong; Xu, Dongying

2017-03-25

Preeclampsia presents serious risk of both maternal and fetal morbidity and mortality. Biomarkers for the detection of preeclampsia are critical for risk assessment and targeted intervention. The goal of this study is to screen potential biomarkers for the diagnosis of preeclampsia and to illuminate the pathogenesis of preeclampsia development based on the differential expression network. Two groups of subjects, including healthy pregnant women, subjects with preeclampsia, were recruited for this study. The metabolic profiles of all of the subjects' serum were obtained by liquid chromatography quadruple time-of-flight mass spectrometry. Correlation between metabolites was analyzed by bioinformatics technique. Results showed that the PC(14:0/00), proline betaine and proline were potential sensitive and specific biomarkers for preeclampsia diagnosis and prognosis. Perturbation of corresponding biological pathways, such as iNOS signaling, nitric oxide signaling in the cardiovascular system, mitochondrial dysfunction were responsible for the pathogenesis of preeclampsia. This study indicated that the metabolic profiling had a good clinical significance in the diagnosis of preeclampsia as well as in the study of its pathogenesis. Copyright © 2017 Elsevier Inc. All rights reserved.

Serum S100B Represents a New Biomarker for Mood Disorders

PubMed Central

Schroeter, Matthias L.; Sacher, Julia; Steiner, Johann; Schoenknecht, Peter; Mueller, Karsten

2013-01-01

Recently, mood disorders have been discussed to be characterized by glial pathology. The protein S100B, a growth and differentiation factor, is located in, and may actively be released by astro- and oligodendrocytes. This protein is easily assessed in human serum and provides a useful parameter for glial activation or injury. Here, we review studies investigating the glial marker S100B in serum of patients with mood disorders. Studies consistently show that S100B is elevated in mood disorders; more strongly in major depressive than bipolar disorder. Consistent with the glial hypothesis of mood disorders, serum S100B levels interact with age with higher levels in elderly depressed subjects. Successful antidepressive treatment has been associated with serum S100B reduction in major depression, whereas there is no evidence of treatment effects in mania. In contrast to the glial marker S100B, the neuronal marker protein neuron-specific enolase is unaltered in mood disorders. Recently, serum S100B has been linked to specific imaging parameters in the human white matter suggesting a role for S100B as an oligodendrocytic marker protein. In sum, serum S100B can be regarded as a promising in vivo biomarker for mood disorders deepening the understanding of the pathogenesis and plasticity-changes in these disorders. Future longitudinal studies combining serum S100B with other cell-specific serum parameters and multimodal imaging are warranted to further explore this serum protein in the development, monitoring and treatment of mood disorders. PMID:23701298

Identifying biomarkers of dietary patterns by using metabolomics123

PubMed Central

Derkach, Andriy; Reedy, Jill; Subar, Amy F; Sampson, Joshua N; Albanes, Demetrius; Gu, Fangyi; Kontto, Jukka; Lassale, Camille; Liao, Linda M; Männistö, Satu; Mondul, Alison M; Weinstein, Stephanie J; Irwin, Melinda L; Mayne, Susan T; Stolzenberg-Solomon, Rachael

2017-01-01

Background: Healthy dietary patterns that conform to national dietary guidelines are related to lower chronic disease incidence and longer life span. However, the precise mechanisms involved are unclear. Identifying biomarkers of dietary patterns may provide tools to validate diet quality measurement and determine underlying metabolic pathways influenced by diet quality. Objective: The objective of this study was to examine the correlation of 4 diet quality indexes [the Healthy Eating Index (HEI) 2010, the Alternate Mediterranean Diet Score (aMED), the WHO Healthy Diet Indicator (HDI), and the Baltic Sea Diet (BSD)] with serum metabolites. Design: We evaluated dietary patterns and metabolites in male Finnish smokers (n = 1336) from 5 nested case-control studies within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Participants completed a validated food-frequency questionnaire and provided a fasting serum sample before study randomization (1985–1988). Metabolites were measured with the use of mass spectrometry. We analyzed cross-sectional partial correlations of 1316 metabolites with 4 diet quality indexes, adjusting for age, body mass index, smoking, energy intake, education, and physical activity. We pooled estimates across studies with the use of fixed-effects meta-analysis with Bonferroni correction for multiple comparisons, and conducted metabolic pathway analyses. Results: The HEI-2010, aMED, HDI, and BSD were associated with 23, 46, 23, and 33 metabolites, respectively (17, 21, 11, and 10 metabolites, respectively, were chemically identified; r-range: −0.30 to 0.20; P = 6 × 10−15 to 8 × 10−6). Food-based diet indexes (HEI-2010, aMED, and BSD) were associated with metabolites correlated with most components used to score adherence (e.g., fruit, vegetables, whole grains, fish, and unsaturated fat). HDI correlated with metabolites related to polyunsaturated fat and fiber components, but not other macro- or micronutrients (e

Brain, blood, cerebrospinal fluid, and serum biomarkers in schizophrenia.

PubMed

Mohammadi, Alireza; Rashidi, Ehsan; Amooeian, Vahid Ghasem

2018-04-13

Over the last decade, finding a reliable biomarker for the early detection of schizophrenia (Scz) has been a topic of interest. The main goal of the current review is to provide a comprehensive view of the brain, blood, cerebrospinal fluid (CSF), and serum biomarkers of Scz disease. Imaging studies have demonstrated that the volumes of the corpus callosum, thalamus, hippocampal formation, subiculum, parahippocampal gyrus, superior temporal gyrus, prefrontal and orbitofrontal cortices, and amygdala-hippocampal complex were reduced in patients diagnosed with Scz. It has been revealed that the levels of interleukin 1β (IL-1β), IL-6, IL-8, and TNF-α were increased in patients with Scz. Decreased mRNA levels of brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), neurotrophin-3 (NT-3), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) genes have also been reported in Scz patients. Genes with known strong relationships with this disease include BDNF, catechol-O-methyltransferase (COMT), regulator of G-protein signaling 4 (RGS4), dystrobrevin-binding protein 1 (DTNBP1), neuregulin 1 (NRG1), Reelin (RELN), Selenium-binding protein 1 (SELENBP1), glutamic acid decarboxylase 67 (GAD 67), and disrupted in schizophrenia 1 (DISC1). The levels of dopamine, tyrosine hydroxylase (TH), serotonin or 5-hydroxytryptamine (5-HT) receptor 1A and B (5-HTR1A and 5-HTR1B), and 5-HT1B were significantly increased in Scz patients, while the levels of gamma-aminobutyric acid (GABA), 5-HT transporter (5-HTT), and 5-HT receptor 2A (5-HTR2A) were decreased. The increased levels of SELENBP1 and Glycogen synthase kinase 3 subunit α (GSK3α) genes in contrast with reduced levels of B-cell translocation gene 1 (BTG1), human leukocyte antigen DRB1 (HLA-DRB1), heterogeneous nuclear ribonucleoprotein A3 (HNRPA3), and serine/arginine-rich splicing factor 1 (SFRS1) genes have also been reported. This review covers various dysregulation of

Early serum biomarker networks in infants with distinct retinochoroidal lesion status of congenital toxoplasmosis.

PubMed

de Araújo, Thádia Evelyn; Coelho-Dos-Reis, Jordana Grazziela; Béla, Samantha Ribeiro; Carneiro, Ana Carolina Aguiar Vasconcelos; Machado, Anderson Silva; Cardoso, Ludmila Melo; Ribeiro, Ágata Lopes; Dias, Michelle Hallais França; Queiroz Andrade, Gláucia Manzan; Vasconcelos-Santos, Daniel Vitor; Januário, José Nélio; Teixeira-Carvalho, Andréa; Vitor, Ricardo Wagner Almeida; Ferro, Eloisa Amália Vieira; Martins-Filho, Olindo Assis

2017-07-01

The present study characterized the early changes in the serum chemokines/cytokine signatures and networks in infants with congenital-toxoplasmosis/(TOXO) as compared to non-infected-controls/(NI). TOXO were subgrouped according to the retinochoroidal lesion status as no-lesion/(NL), active-lesion/(ARL), active/cicatricial-lesion/(ACRL) and cicatricial-lesion/(CRL). The results showed that TOXO display prominent chemokine production mediated by IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10 and RANTES/CCL5. Additionally, TOXO is accompanied by mixed proinflammatory/regulatory cytokine pattern mediated by IL-6, IFN-γ, IL-4, IL-5 and IL-10. While TNF appears as a putative biomarker for NL and IFN-γ/IL-5 as immunological features for ARL, IL-10 emerges as a relevant mediator in ACRL/CRL. IL-8/CXCL8 and IP-10/CXCL10 are broad-spectrum indicators of ocular disease, whereas TNF is a NL biomarker, IFN-γ and MIG/CXCL9 point out to ARL; and IL-10 is highlighted as a genuine serum biomarker of ACRL/CRL. The network analysis demonstrated a broad chemokine/cytokine crosstalk with divergences in the molecular signatures in patients with different ocular lesions during congenital toxoplasmosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Serum factors and clinical characteristics associated with serum E-Screen activity

PubMed Central

Wang, Jue; Trentham-Dietz, Amy; Hemming, Jocelyn D. C.; Hedman, Curtis J.; Sprague, Brian L.

2013-01-01

Background The E-Screen bioassay can measure the mitogenicity of human serum and thus may be useful as a biomarker in epidemiologic studies of breast cancer. While the assay’s MCF-7 cells are known to proliferate in response to estrogen, the specific determinants of variation in E-Screen activity in human serum samples are poorly understood. We sought to identify serum molecules and patient characteristics associated with serum E-Screen activity among postmenopausal women. Methods Postmenopausal women (N=219) aged 55–70 with no history of postmenopausal hormone use or breast cancer completed a questionnaire and provided a blood sample. Serum was analyzed for E-Screen activity and a variety of molecules including sex hormones, growth factors, and environmental chemicals. Stepwise selection procedures were used to identify correlates of E-Screen activity. Results Serum samples from all women had detectable E-Screen activity, with a median estradiol equivalents value of 0.027 ng/mL and interquartile range of 0.018–0.036 ng/mL. In the final multivariable-adjusted model, serum E-Screen activity was positively associated with serum estradiol, estrone, IGFBP-3, and testosterone levels (p<0.05), as well as body mass index (p=0.03). Serum E-Screen activity was lower among women with higher SHBG (p<0.0001) and progesterone levels (p=0.03). Conclusion Serum E-Screen activity varies according to levels of endogenous estrogens and other serum molecules. Obesity appears to confer additional serum mitogenicity beyond its impact on the measured hormones and growth factors. Impact By capturing mitogenicity due to a variety of patient and serum factors, the E-Screen may provide advantages for use as a biomarker in breast cancer studies. PMID:23588007

Identifying module biomarkers from gastric cancer by differential correlation network

PubMed Central

Liu, Xiaoping; Chang, Xiao

2016-01-01

Gastric cancer (stomach cancer) is a severe disease caused by dysregulation of many functionally correlated genes or pathways instead of the mutation of individual genes. Systematic identification of gastric cancer biomarkers can provide insights into the mechanisms underlying this deadly disease and help in the development of new drugs. In this paper, we present a novel network-based approach to predict module biomarkers of gastric cancer that can effectively distinguish the disease from normal samples. Specifically, by assuming that gastric cancer has mainly resulted from dysfunction of biomolecular networks rather than individual genes in an organism, the genes in the module biomarkers are potentially related to gastric cancer. Finally, we identified a module biomarker with 27 genes, and by comparing the module biomarker with known gastric cancer biomarkers, we found that our module biomarker exhibited a greater ability to diagnose the samples with gastric cancer. PMID:27703371

Prospective evaluation of 64 serum autoantibodies as biomarkers for early detection of colorectal cancer in a true screening setting.

PubMed

Chen, Hongda; Werner, Simone; Butt, Julia; Zörnig, Inka; Knebel, Phillip; Michel, Angelika; Eichmüller, Stefan B; Jäger, Dirk; Waterboer, Tim; Pawlita, Michael; Brenner, Hermann

2016-03-29

Novel blood-based screening tests are strongly desirable for early detection of colorectal cancer (CRC). We aimed to identify and evaluate autoantibodies against tumor-associated antigens as biomarkers for early detection of CRC. 380 clinically identified CRC patients and samples of participants with selected findings from a cohort of screening colonoscopy participants in 2005-2013 (N=6826) were included in this analysis. Sixty-four serum autoantibody markers were measured by multiplex bead-based serological assays. A two-step approach with selection of biomarkers in a training set, and validation of findings in a validation set, the latter exclusively including participants from the screening setting, was applied. Anti-MAGEA4 exhibited the highest sensitivity for detecting early stage CRC and advanced adenoma. Multi-marker combinations substantially increased sensitivity at the price of a moderate loss of specificity. Anti-TP53, anti-IMPDH2, anti-MDM2 and anti-MAGEA4 were consistently included in the best-performing 4-, 5-, and 6-marker combinations. This four-marker panel yielded a sensitivity of 26% (95% CI, 13-45%) for early stage CRC at a specificity of 90% (95% CI, 83-94%) in the validation set. Notably, it also detected 20% (95% CI, 13-29%) of advanced adenomas. Taken together, the identified biomarkers could contribute to the development of a useful multi-marker blood-based test for CRC early detection.

Prostate Cancer Associated Lipid Signatures in Serum Studied by ESI-Tandem Mass Spectrometryas Potential New Biomarkers.

PubMed

Duscharla, Divya; Bhumireddy, Sudarshana Reddy; Lakshetti, Sridhar; Pospisil, Heike; Murthy, P V L N; Walther, Reinhard; Sripadi, Prabhakar; Ummanni, Ramesh

2016-01-01

Prostate cancer (PCa) is one amongst the most common cancersin western men. Incidence rate ofPCa is on the rise worldwide. The present study deals with theserum lipidome profiling of patients diagnosed with PCa to identify potential new biomarkers. We employed ESI-MS/MS and GC-MS for identification of significantly altered lipids in cancer patient's serum compared to controls. Lipidomic data revealed 24 lipids are significantly altered in cancer patinet's serum (n = 18) compared to normal (n = 18) with no history of PCa. By using hierarchical clustering and principal component analysis (PCA) we could clearly separate cancer patients from control group. Correlation and partition analysis along with Formal Concept Analysis (FCA) have identified that PC (39:6) and FA (22:3) could classify samples with higher certainty. Both the lipids, PC (39:6) and FA (22:3) could influence the cataloging of patients with 100% sensitivity (all 18 control samples are classified correctly) and 77.7% specificity (of 18 tumor samples 4 samples are misclassified) with p-value of 1.612×10-6 in Fischer's exact test. Further, we performed GC-MS to denote fatty acids altered in PCa patients and found that alpha-linolenic acid (ALA) levels are altered in PCa. We also performed an in vitro proliferation assay to determine the effect of ALA in survival of classical human PCa cell lines LNCaP and PC3. We hereby report that the altered lipids PC (39:6) and FA (22:3) offer a new set of biomarkers in addition to the existing diagnostic tests that could significantly improve sensitivity and specificity in PCa diagnosis.

Prostate Cancer Associated Lipid Signatures in Serum Studied by ESI-Tandem Mass Spectrometryas Potential New Biomarkers

PubMed Central

Duscharla, Divya; Bhumireddy, Sudarshana Reddy; Lakshetti, Sridhar; Pospisil, Heike; Murthy, P. V. L. N.; Walther, Reinhard; Sripadi, Prabhakar; Ummanni, Ramesh

2016-01-01

Prostate cancer (PCa) is one amongst the most common cancersin western men. Incidence rate ofPCa is on the rise worldwide. The present study deals with theserum lipidome profiling of patients diagnosed with PCa to identify potential new biomarkers. We employed ESI-MS/MS and GC-MS for identification of significantly altered lipids in cancer patient’s serum compared to controls. Lipidomic data revealed 24 lipids are significantly altered in cancer patinet’s serum (n = 18) compared to normal (n = 18) with no history of PCa. By using hierarchical clustering and principal component analysis (PCA) we could clearly separate cancer patients from control group. Correlation and partition analysis along with Formal Concept Analysis (FCA) have identified that PC (39:6) and FA (22:3) could classify samples with higher certainty. Both the lipids, PC (39:6) and FA (22:3) could influence the cataloging of patients with 100% sensitivity (all 18 control samples are classified correctly) and 77.7% specificity (of 18 tumor samples 4 samples are misclassified) with p-value of 1.612×10−6 in Fischer’s exact test. Further, we performed GC-MS to denote fatty acids altered in PCa patients and found that alpha-linolenic acid (ALA) levels are altered in PCa. We also performed an in vitro proliferation assay to determine the effect of ALA in survival of classical human PCa cell lines LNCaP and PC3. We hereby report that the altered lipids PC (39:6) and FA (22:3) offer a new set of biomarkers in addition to the existing diagnostic tests that could significantly improve sensitivity and specificity in PCa diagnosis. PMID:26958841

Assessment of serum biomarkers in rats after exposure to pesticides of different chemical classes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moser, Virginia C., E-mail: Moser.ginger@epa.gov; Stewart, Nicholas; Freeborn, Danielle L.

There is increasing emphasis on the use of biomarkers of adverse outcomes in safety assessment and translational research. We evaluated serum biomarkers and targeted metabolite profiles after exposure to pesticides (permethrin, deltamethrin, imidacloprid, carbaryl, triadimefon, fipronil) with different neurotoxic actions. Adult male Long–Evans rats were evaluated after single exposure to vehicle or one of two doses of each pesticide at the time of peak effect. The doses were selected to produce similar magnitude of behavioral effects across chemicals. Serum or plasma was analyzed using commercial cytokine/protein panels and targeted metabolomics. Additional studies of fipronil used lower doses (lacking behavioral effects),more » singly or for 14 days, and included additional markers of exposure and biological activity. Biomarker profiles varied in the number of altered analytes and patterns of change across pesticide classes, and discriminant analysis could separate treatment groups from control. Low doses of fipronil produced greater effects when given for 14 days compared to a single dose. Changes in thyroid hormones and relative amounts of fipronil and its sulfone metabolite also differed between the dosing regimens. Most cytokine changes reflected alterations in inflammatory responses, hormone levels, and products of phospholipid, fatty acid, and amino acid metabolism. These findings demonstrate distinct blood-based analyte profiles across pesticide classes, dose levels, and exposure duration. These results show promise for detailed analyses of these biomarkers and their linkages to biological pathways. - Highlights: • Pesticides typical of different classes produced distinct patterns of change in biomarker panels. • Based on the panels used, alterations suggest impacts on immune, metabolism, and homeostasis functions. • Some changes may reflect actions on neurotransmitter systems involved in immune modulation. • Fipronil effects on thyroid and

Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis.

PubMed

Yang, Xinyu; Lin, Ke; Ni, Shanmin; Wang, Jianmin; Tian, Qingqing; Chen, Huaijun; Brown, Matthew A; Zheng, Kaidi; Zhai, Weitao; Sun, Li; Jin, Shengwei; Wang, Jianguang

2017-11-22

Our previous proteomic study indicated that connective tissue growth factor (CTGF) may be a potential biomarker for rheumatoid arthritis (RA) diagnosis. The aim was to assess the performance of CTGF as a biomarker of RA. Serum and synovial fluid CTGF was detected using a direct high sensitivity sandwich ELISA kit. Serum CTGF levels were tested for discriminatory capacity and optimal assay cutoffs determined in a training cohort of 98 cases of RA with 103 healthy controls. The assay performance was then validated in a further cohort of 572 patients (with RA (n = 217), ankylosing spondylitis (n = 92), gout (n = 74), osteoarthritis (n = 52), systemic lupus erythematosus (n = 72), or primary Sjögren's syndrome (pSS) (n = 65)). Significant elevation of synovial fluid CTGF concentration was found in RA patients, demonstrating excellent diagnostic ability to predict RA (area under the curve (AUC) = 0.97). Similar results were found in serum CTGF detection. At the optimal cutoff value 88.66 pg/mL, the sensitivity, specificity, and the AUC was 0.86, 0.92, and 0.92, respectively, in the training cohort. Similar performance was observed in the validation cohort, with sensitivity, specificity, positive likelihood, and negative likelihood of 0.82, 0.91, 5.74, and 0.12, respectively. Stronger discriminatory capacity was seen with the combination of CTGF and anti-citrullinated protein antibody (ACPA) (AUC = 0.96) than with either ACPA or rheumatoid factor (RF) alone (AUC = 0.80 or 0.79, respectively). The discriminatory performance of serum CTGF was consistent across all inflammatory conditions tested (AUC >0.92 in all cases), with the sole exception of pSS. Serum CTGF did not vary with symptom duration or disease activity. Serum CTGF is a promising diagnostic biomarker for RA, with performance in the current study better than either ACPA or RF.

Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas

PubMed Central

2014-01-01

Background Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers. Methods We searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas. Results FLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients’ sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC. Conclusions The present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study

Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis

PubMed Central

Lizio, Andrea; Maestri, Eleonora; Sansone, Valeria Ada; Mora, Gabriele; Miller, Robert G.; Appel, Stanley H.; Chiò, Adriano

2017-01-01

Importance Various factors have been proposed as possible candidates associated with the prognosis of amyotrophic lateral sclerosis (ALS); however, there is still no consensus on which biomarkers are reliable prognostic factors. C-reactive protein (CRP) is a biomarker of the inflammatory response that shows significant prognostic value for several diseases. Objective To examine the prognostic significance of CRP in ALS. Design, Setting, and Participants Patients’ serum CRP levels were evaluated from January 1, 2009, to June 30, 2015, in a large cohort of patients with ALS observed by an Italian tertiary multidisciplinary center. Results were replicated in an independent cohort obtained from a population-based registry of patients with ALS. A post hoc analysis was performed of the phase 2 trial of NP001 to determine whether stratification by levels of CRP improves differentiation of responders and nonresponders to the drug. Main Outcomes and Measures Serum CRP levels from the first examination were recorded to assess their effect on disease progression and survival. Results A total of 394 patients with ALS (168 women and 226 men; mean [SD] age at diagnosis, 60.18 [13.60] years) were observed in a tertiary multidisciplinary center, and the analysis was replicated in an independent cohort of 116 patients with ALS (50 women and 66 men; mean [SD] age at diagnosis, 67.00 [10.74] years) identified through a regional population-based registry. Serum CRP levels in the 394 patients with ALS correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale–Revised, at first evaluation (r = –0.14818; P = .004), and with patient survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P = .007). Similar results were found in the independent cohort (hazard ratio, 1.044; 95% CI, 1.016-1.056; P ≤ .001). Moreover, a post hoc analysis of the phase 2 trial of NP001 using the same CRP threshold showed that patients with

Utility of circulating serum miRNAs as biomarkers of early cartilage degeneration in animal models of post-traumatic osteoarthritis and inflammatory arthritis.

PubMed

Kung, L H W; Zaki, S; Ravi, V; Rowley, L; Smith, M M; Bell, K M; Bateman, J F; Little, C B

2017-03-01

The purpose of this study was to determine if serum microRNA (miRNA) signatures were biomarkers of early cartilage degeneration in preclinical mouse models of post-traumatic osteoarthritis (OA) and inflammatory arthritis. Cartilage degeneration was induced in 10-12 week old male C57BL6 mice by destabilization of the medial meniscus (DMM) or intra-articular injection of methylated-bovine-serum-albumin (AIA), with sham-operated or saline-injected control animals (n = 6/treatment/time). Total serum RNA and knee joints were isolated at 1, 4 and 16 weeks post-induction. Cartilage degeneration was scored histologically. Serum miRNA expression profiling was performed using Agilent microarrays and validated by qPCR. DMM-operated and AIA mice had characteristic cartilage degeneration (proteoglycan loss, chondrocyte hypertrophy, structural damage), that increased significantly with time compared with controls, and with distinct temporal differences between arthritis models. However, expression profiling revealed no statistically significant dysregulation of serum miRNAs between AIA vs saline-injected or DMM vs sham-operated control mice at the critical early disease stages. The inability to detect DMM or AIA serum miRNA signatures compared with controls was not due to the insensitivity of the expression profiling approach since significant changes were observed in miRNA expression between the arthritis models and between time points. While distinct patterns of progressive cartilage degradation were induced in the arthritis models, we were unable to identify any serum miRNAs that were significantly dysregulated in early stages of disease compared with controls. This suggests circulating serum miRNAs may not be useful as cartilage biomarkers in distinguishing the early or progressive stages of arthritis cartilage degeneration. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Diagnostic value of lactate, procalcitonin, ferritin, serum-C-reactive protein, and other biomarkers in bacterial and viral meningitis

PubMed Central

Sanaei Dashti, Anahita; Alizadeh, Shekoofan; Karimi, Abdullah; Khalifeh, Masoomeh; Shoja, Seyed Abdolmajid

2017-01-01

Abstract There are many difficulties distinguishing bacterial from viral meningitis that could be reasonably solved using biomarkers. The aim of this study was to evaluate lactate, procalcitonin (PCT), ferritin, serum-CRP (C-reactive protein), and other known biomarkers in differentiating bacterial meningitis from viral meningitis in children. All children aged 28 days to 14 years with suspected meningitis who were admitted to Mofid Children's Hospital, Tehran, between October 2012 and November 2013, were enrolled in this prospective cross-sectional study. Children were divided into 2 groups of bacterial and viral meningitis, based on the results of cerebrospinal fluid (CSF) culture, polymerase chain reaction, and cytochemical profile. Diagnostic values of CSF parameters (ferritin, PCT, absolute neutrophil count [ANC], white blood cell count, and lactate) and serum parameters (PCT, ferritin, CRP, and erythrocyte sedimentation rate [ESR]) were evaluated. Among 50 patients with meningitis, 12 were diagnosed with bacterial meningitis. Concentrations of all markers were significantly different between bacterial and viral meningitis, except for serum (P = .389) and CSF (P = .136) PCT. The best rates of area under the receiver operating characteristic (ROC) curve (AUC) were achieved by lactate (AUC = 0.923) and serum-CRP (AUC = 0.889). The best negative predictive values (NPV) for bacterial meningitis were attained by ANC (100%) and lactate (97.1%). The results of our study suggest that ferritin and PCT are not strong predictive biomarkers. A combination of low CSF lactate, ANC, ESR, and serum-CRP could reasonably rule out the bacterial meningitis. PMID:28858084

Anti-p-benzoquinone antibody level as a prospective biomarker to identify smokers at risk for COPD.

PubMed

Banerjee, Santanu; Bhattacharyya, Parthasarathi; Mitra, Subhra; Kundu, Somenath; Panda, Samiran; Chatterjee, Indu B

2017-01-01

Identification of smokers having predisposition to COPD is important for early intervention to reduce the huge global burden of the disease. Using a guinea pig model, we have shown that p -benzoquinone ( p -BQ) derived from cigarette smoke (CS) in the lung is a causative factor for CS-induced emphysema. p -BQ is also derived from CS in smokers and it elicits the production of anti- p -BQ antibody in humans. We therefore hypothesized that anti- p -BQ antibody might have a protective role against COPD and could be used as a predictive biomarker for COPD in smokers. The objective of this study was to compare the serum anti- p -BQ antibody level between smokers with and without COPD for the evaluation of the hypothesis. Serum anti- p -BQ antibody concentrations of current male smokers with (n=227) or without (n=308) COPD were measured by an indirect enzyme-linked immunoabsorbent assay (ELISA) developed in our laboratory. COPD was diagnosed by spirometry according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. A significant difference was observed in the serum anti- p -BQ antibody level between smokers with and without COPD (Mann-Whitney U -test =4,632.5, P =0.000). Receiver operating characteristic (ROC) curve analysis indicated that the ELISA had significant precision (area under the curve [AUC] =0.934, 95% confidence interval [CI]: 0.913-0.935) for identifying smokers with COPD from their low antibody level. The antibody cutoff value of 29.4 mg/dL was constructed from the ROC coordinates to estimate the risk for COPD in smokers. While 90.3% of smokers with COPD had a low antibody value (≤29.4 mg/dL), the majority (86.4%) of smokers without COPD had a high antibody value (≤29.4 mg/dL); 13.6% of current smokers without COPD having an antibody level below this cutoff value (odds ratio [OR] =59.3, 95% CI: 34.15-101.99) were considered to be at risk for COPD. Our results indicate that serum anti- p -BQ antibody level may be used as a

The Temporal Pattern of Changes in Serum Biomarker Levels Reveals Complex and Dynamically Changing Pathologies after Exposure to a Single Low-Intensity Blast in Mice

PubMed Central

Ahmed, Farid; Plantman, Stefan; Cernak, Ibolja; Agoston, Denes V.

2015-01-01

Time-dependent changes in blood-based protein biomarkers can help identify the ­pathological processes in blast-induced traumatic brain injury (bTBI), assess injury severity, and monitor disease progression. We obtained blood from control and injured mice (exposed to a single, low-intensity blast) at 2-h, 1-day, 1–week, and 1-month post-injury. We then determined the serum levels of biomarkers related to metabolism (4-HNE, HIF-1α, ceruloplasmin), vascular function (AQP1, AQP4, VEGF, vWF, Flk-1), inflammation (OPN, CINC1, fibrinogen, MIP-1a, OX-44, p38, MMP-8, MCP-1 CCR5, CRP, galectin-1), cell adhesion and the extracellular matrix (integrin α6, TIMP1, TIMP4, Ncad, connexin-43), and axonal (NF-H, Tau), neuronal (NSE, CK-BB) and glial damage (GFAP, S100β, MBP) at various post-injury time points. Our findings indicate that the exposure to a single, low-intensity blast results in metabolic and vascular changes, altered cell adhesion, and axonal and neuronal injury in the mouse model of bTBI. Interestingly, serum levels of several inflammatory and astroglial markers were either unchanged or elevated only during the acute and subacute phases of injury. Conversely, serum levels of the majority of biomarkers related to metabolic and vascular functions, cell adhesion, as well as neuronal and axonal damage remained elevated at the termination of the experiment (1 month), indicating long-term systemic and cerebral alterations due to blast. Our findings show that the exposure to a single, low-intensity blast induces complex pathological processes with distinct temporal profiles. Hence, monitoring serum biomarker levels at various post-injury time points may provide enhanced diagnostics in blast-related neurological and multi-system deficits. PMID:26124743

Evaluation of pretreatment serum interleukin-6 and tumour necrosis factor alpha as a potential biomarker for recurrence in patients with oral squamous cell carcinoma.

PubMed

Skrinjar, Ivana; Brailo, Vlaho; Vidovic-Juras, Danica; Vucicevic-Boras, Vanja; Milenovic, Aleksandar

2015-07-01

Oral squamous cell carcinoma (OSCC) constitutes 3 percent of all cancers with predominant occurrence in middle aged and elderly males. Tumour recurrence worsens disease prognosis and decreases quality of life in patients with OSCC. Proinflammatory cytokines such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF-α) have been suggested to play a certain role in variety of tumours. The aim of this study was to investigate the relationship of pretreatment serum IL-6 and TNF-α levels on tumour recurrence in patients with OSCC in order to identify potential biomarkers for the early detection of disease recurrence. The patients with newly diagnosed OSCC were treated and followed from the first visit from November 2006 until January 2008. Serum IL-6 and TNF-α concentrations were measured. The records of the patients were re-examined in July 2012 and data were recorded about cancer characteristics and tumour recurrence. Disease free survival was analyzed by Kaplan-Meier survival curves, log rank test and Cox proportional hazards regression. Serum IL-6 was shown as an independent risk factor for tumour recurrence. Pretreatment serum IL-6 concentration may be a useful biomarker for identification of OSCC patients with increased risk of the disease recurrence.

Prediagnostic serum levels of inflammatory biomarkers are correlated with future development of lung and esophageal cancer

PubMed Central

Keeley, Brieze R; Islami, Farhad; Pourshams, Akram; Poustchi, Hossein; Pak, Jamie S; Brennan, Paul; Khademi, Hooman; Genden, Eric M; Abnet, Christian C; Dawsey, Sanford M; Boffetta, Paolo; Malekzadeh, Reza; Sikora, Andrew G

2014-01-01

This study tests the hypothesis that prediagnostic serum levels of 20 cancer-associated inflammatory biomarkers correlate directly with future development of head and neck, esophageal, and lung cancers in a high-risk prospective cohort. This is a nested case–control pilot study of subjects enrolled in the Golestan Cohort Study, an ongoing epidemiologic project assessing cancer trends in Golestan, Iran. We measured a panel of 20 21cytokines, chemokines, and inflammatory molecules using Luminex technology in serum samples collected 2 or more years before cancer diagnosis in 78 aerodigestive cancer cases and 81 controls. Data was analyzed using Wilcoxon rank sum test, odds ratios, receiver operating characteristic areas of discrimination, and multivariate analysis. Biomarkers were profoundly and globally elevated in future esophageal and lung cancer patients compared to controls. Odds ratios were significant for association between several biomarkers and future development of esophageal cancer, including interleukin-1Rα (IL-1Ra; 35.9), interferon α2 (IFN-a2; 34.0), fibroblast growth factor-2 (FGF-2; 17.4), and granulocyte/macrophage colony-stimulating factor (GM-CSF; 17.4). The same pattern was observed among future lung cancer cases for G-CSF (27.7), GM-CSF (13.3), and tumor necrosis factor-α (TNF-a; 8.6). By contrast, the majority of biomarkers studied showed no significant correlation with future head and neck cancer development. This study provides the first direct evidence that multiple inflammatory biomarkers are coordinately elevated in future lung and esophageal cancer patients 2 or more years before cancer diagnosis. PMID:25040886

Expression and Regulatory Network Analysis of miR-140-3p, a New Potential Serum Biomarker for Autism Spectrum Disorder

PubMed Central

Cirnigliaro, Matilde; Barbagallo, Cristina; Gulisano, Mariangela; Domini, Carla N.; Barone, Rita; Barbagallo, Davide; Ragusa, Marco; Di Pietro, Cinzia; Rizzo, Renata; Purrello, Michele

2017-01-01

Given its prevalence and social impact, Autism Spectrum Disorder (ASD) is drawing much interest. Molecular basis of ASD is heterogeneous and only partially known. Many factors, including disorders comorbid with ASD, like TS (Tourette Syndrome), complicate ASD behavior-based diagnosis and make it vulnerable to bias. To further investigate ASD etiology and to identify potential biomarkers to support its precise diagnosis, we used TaqMan Low Density Array technology to profile serum miRNAs from ASD, TS, and TS+ASD patients, and unaffected controls (NCs). Through validation assays in 30 ASD, 24 TS, and 25 TS+ASD patients and 25 NCs, we demonstrated that miR-140-3p is upregulated in ASD vs.: NC, TS, and TS+ASD (Tukey's test, p-values = 0.03, = 0.01, < 0.0001, respectively). ΔCt values for miR-140-3p and YGTSS (Yale Global Tic Severity Scale) scores are positively correlated (Spearman r = 0.33; Benjamini-Hochberg p = 0.008) and show a linear relationship (p = 0.002). Network functional analysis showed that nodes controlled by miR-140-3p, especially CD38 and NRIP1 which are its validated targets, are involved in processes convergingly dysregulated in ASD, such as synaptic plasticity, immune response, and chromatin binding. Biomarker analysis proved that serum miR-140-3p can discriminate among: (1) ASD and NC (Area under the ROC curve, AUC: 0.70; sensitivity: 63.33%; specificity: 68%); (2) ASD and TS (AUC: 0.72; sensitivity: 66.66%; specificity: 70.83%); (3) ASD and TS+ASD (AUC: 0.78; sensitivity: 73.33%; specificity: 76%). Characterization of miR-140-3p network would contribute to further clarify ASD etiology. Serum miR-140-3p could represent a potential non-invasive biomarker for ASD, easy to test through liquid biopsy. PMID:28848387

Protein biomarkers identify patients unlikely to benefit from primary prevention implantable cardioverter defibrillators: findings from the Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSE-ICD).

PubMed

Cheng, Alan; Zhang, Yiyi; Blasco-Colmenares, Elena; Dalal, Darshan; Butcher, Barbara; Norgard, Sanaz; Eldadah, Zayd; Ellenbogen, Kenneth A; Dickfeld, Timm; Spragg, David D; Marine, Joseph E; Guallar, Eliseo; Tomaselli, Gordon F

2014-12-01

Primary prevention implantable cardioverter defibrillators (ICDs) reduce all-cause mortality, but the benefits are heterogeneous. Current risk stratification based on left ventricular ejection fraction has limited discrimination power. We hypothesize that biomarkers for inflammation, neurohumoral activation, and cardiac injury can predict appropriate shocks and all-cause mortality in patients with primary prevention ICDs. The Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSe-ICD) enrolled 1189 patients with systolic heart failure who underwent ICD implantation for primary prevention of sudden cardiac death. The primary end point was an ICD shock for adjudicated ventricular tachyarrhythmia. The secondary end point was all-cause mortality. After a median follow-up of 4.0 years, 137 subjects experienced an appropriate ICD shock and 343 participants died (incidence rates of 3.2 and 5.8 per 100 person-years, respectively). In multivariable-adjusted models, higher interleukin-6 levels increased the risk of appropriate ICD shocks. In contrast, C-reactive protein, interleukin-6, tumor necrosis factor-α receptor II, pro-brain natriuretic peptide (pro-BNP), and cardiac troponin T showed significant linear trends for increased risk of all-cause mortality across quartiles. A score combining these 5 biomarkers identified patients who were much more likely to die than to receive an appropriate shock from the ICD. An increase in serum biomarkers of inflammation, neurohumoral activation, and myocardial injury increased the risk for death but poorly predicted the likelihood of an ICD shock. These findings highlight the potential importance of serum-based biomarkers in identifying patients who are unlikely to benefit from primary prevention ICDs. clinicaltrials.gov; Unique Identifier: NCT00733590. © 2014 American Heart Association, Inc.

A proteomic analysis identifies candidate early biomarkers to predict ovarian hyperstimulation syndrome in polycystic ovarian syndrome patients.

PubMed

Wu, Lan; Sun, Yazhou; Wan, Jun; Luan, Ting; Cheng, Qing; Tan, Yong

2017-07-01

Ovarian hyperstimulation syndrome (OHSS) is a potentially life‑threatening, iatrogenic complication that occurs during assisted reproduction. Polycystic ovarian syndrome (PCOS) significantly increases the risk of OHSS during controlled ovarian stimulation. Therefore, a more effective early prediction technique is required in PCOS patients. Quantitative proteomic analysis of serum proteins indicates the potential diagnostic value for disease. In the present study, the authors revealed the differentially expressed proteins in OHSS patients with PCOS as new diagnostic biomarkers. The promising proteins obtained from liquid chromatography‑mass spectrometry were subjected to ELISA and western blotting assay for further confirmation. A total of 57 proteins were identified with significant difference, of which 29 proteins were upregulated and 28 proteins were downregulated in OHSS patients. Haptoglobin, fibrinogen and lipoprotein lipase were selected as candidate biomarkers. Receiver operating characteristic curve analysis demonstrated all three proteins may have potential as biomarkers to discriminate OHSS in PCOS patients. Haptoglobin, fibrinogen and lipoprotein lipase have never been reported as a predictive marker of OHSS in PCOS patients, and their potential roles in OHSS occurrence deserve further studies. The proteomic results reported in the present study may gain deeper insights into the pathophysiology of OHSS.

Prospective evaluation of 64 serum autoantibodies as biomarkers for early detection of colorectal cancer in a true screening setting

PubMed Central

Chen, Hongda; Werner, Simone; Butt, Julia; Zörnig, Inka; Knebel, Phillip; Michel, Angelika; Eichmüller, Stefan B.; Jäger, Dirk; Waterboer, Tim; Pawlita, Michael; Brenner, Hermann

2016-01-01

Novel blood-based screening tests are strongly desirable for early detection of colorectal cancer (CRC). We aimed to identify and evaluate autoantibodies against tumor-associated antigens as biomarkers for early detection of CRC. 380 clinically identified CRC patients and samples of participants with selected findings from a cohort of screening colonoscopy participants in 2005–2013 (N=6826) were included in this analysis. Sixty-four serum autoantibody markers were measured by multiplex bead-based serological assays. A two-step approach with selection of biomarkers in a training set, and validation of findings in a validation set, the latter exclusively including participants from the screening setting, was applied. Anti-MAGEA4 exhibited the highest sensitivity for detecting early stage CRC and advanced adenoma. Multi-marker combinations substantially increased sensitivity at the price of a moderate loss of specificity. Anti-TP53, anti-IMPDH2, anti-MDM2 and anti-MAGEA4 were consistently included in the best-performing 4-, 5-, and 6-marker combinations. This four-marker panel yielded a sensitivity of 26% (95% CI, 13–45%) for early stage CRC at a specificity of 90% (95% CI, 83–94%) in the validation set. Notably, it also detected 20% (95% CI, 13–29%) of advanced adenomas. Taken together, the identified biomarkers could contribute to the development of a useful multi-marker blood-based test for CRC early detection. PMID:26909861

Identifying FGA peptides as nasopharyngeal carcinoma-associated biomarkers by magnetic beads.

PubMed

Tao, Ya-Lan; Li, Yan; Gao, Jin; Liu, Zhi-Gang; Tu, Zi-Wei; Li, Guo; Xu, Bing-Qing; Niu, Dao-Li; Jiang, Chang-Bin; Yi, Wei; Li, Zhi-Qiang; Li, Jing; Wang, Yi-Ming; Cheng, Zhi-Bin; Liu, Qiao-Dan; Bai, Li; Zhang, Chun; Zhang, Jing-Yu; Zeng, Mu-Sheng; Xia, Yun-Fei

2012-07-01

Early diagnosis and treatment is known to improve prognosis for nasopharyngeal carcinoma (NPC). The study determined the specific peptide profiles by comparing the serum differences between NPC patients and healthy controls, and provided the basis for the diagnostic model and identification of specific biomarkers of NPC. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) can be used to detect the molecular mass of peptides. Mass spectra of peptides were generated after extracting and purification of 40 NPC samples in the training set, 21 in the single center validation set and 99 in the multicenter validation set using weak cationic-exchanger magnetic beads. The spectra were analyzed statistically using FlexAnalysis™ and ClinProt™ bioinformatics software. The four most significant peaks were selected out to train a genetic algorithm model to diagnose NPC. The diagnostic sensitivity and specificity were 100% and 100% in the training set, 90.5% and 88.9% in the single center validation set, 91.9% and 83.3% in the multicenter validation set, and the false positive rate (FPR) and false negative rate (FNR) were obviously lower in the NPC group (FPR, 16.7%; FNR, 8.1%) than in the other cancer group (FPR, 39%; FNR, 61%), respectively. So, the diagnostic model including four peptides can be suitable for NPC but not for other cancers. FGA peptide fragments identified may serve as tumor-associated biomarkers for NPC. Copyright © 2012 Wiley Periodicals, Inc.

Autoantibody signatures as biomarkers to distinguish prostate cancer from benign prostatic hyperplasia in patients with increased serum prostate specific antigen.

PubMed

O'Rourke, Dennis J; DiJohnson, Daniel A; Caiazzo, Robert J; Nelson, James C; Ure, David; O'Leary, Michael P; Richie, Jerome P; Liu, Brian C-S

2012-03-22

Serum prostate specific antigen (PSA) concentrations lack the specificity to differentiate prostate cancer from benign prostate hyperplasia (BPH), resulting in unnecessary biopsies. We identified 5 autoantibody signatures to specific cancer targets which might be able to differentiate prostate cancer from BPH in patients with increased serum PSA. To identify autoantibody signatures as biomarkers, a native antigen reverse capture microarray platform was used. Briefly, well-characterized monoclonal antibodies were arrayed onto nanoparticle slides to capture native antigens from prostate cancer cells. Prostate cancer patient serum samples (n=41) and BPH patient samples (collected starting at the time of initial diagnosis) with a mean follow-up of 6.56 y without the diagnosis of cancer (n=39) were obtained. One hundred micrograms of IgGs were purified and labeled with a Cy3 dye and incubated on the arrays. The arrays were scanned for fluorescence and the intensity was quantified. Receiver operating characteristic curves were produced and the area under the curve (AUC) was determined. Using our microarray platform, we identified autoantibody signatures capable of distinguishing between prostate cancer and BPH. The top 5 autoantibody signatures were TARDBP, TLN1, PARK7, LEDGF/PSIP1, and CALD1. Combining these signatures resulted in an AUC of 0.95 (sensitivity of 95% at 80% specificity) compared to AUC of 0.5 for serum concentration PSA (sensitivity of 12.2% at 80% specificity). Our preliminary results showed that we were able to identify specific autoantibody signatures that can differentiate prostate cancer from BPH, and may result in the reduction of unnecessary biopsies in patients with increased serum PSA. Copyright © 2011 Elsevier B.V. All rights reserved.

Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker

PubMed Central

Ray, Partha; Rialon-Guevara, Kristy L.; Veras, Emanuela; Sullenger, Bruce A.; White, Rebekah R.

2012-01-01

Most cases of pancreatic cancer are not diagnosed until they are no longer curable with surgery. Therefore, it is critical to develop a sensitive, preferably noninvasive, method for detecting the disease at an earlier stage. In order to identify biomarkers for pancreatic cancer, we devised an in vitro positive/negative selection strategy to identify RNA ligands (aptamers) that could detect structural differences between the secretomes of pancreatic cancer and non-cancerous cells. Using this molecular recognition approach, we identified an aptamer (M9-5) that differentially bound conditioned media from cancerous and non-cancerous human pancreatic cell lines. This aptamer further discriminated between the sera of pancreatic cancer patients and healthy volunteers with high sensitivity and specificity. We utilized biochemical purification methods and mass-spectrometric analysis to identify the M9-5 target as cyclophilin B (CypB). This molecular recognition–based strategy simultaneously identified CypB as a serum biomarker and generated a new reagent to recognize it in body fluids. Moreover, this approach should be generalizable to other diseases and complementary to traditional approaches that focus on differences in expression level between samples. Finally, we suggest that the aptamer we identified has the potential to serve as a tool for the early detection of pancreatic cancer. PMID:22484812

Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker.

PubMed

Ray, Partha; Rialon-Guevara, Kristy L; Veras, Emanuela; Sullenger, Bruce A; White, Rebekah R

2012-05-01

Most cases of pancreatic cancer are not diagnosed until they are no longer curable with surgery. Therefore, it is critical to develop a sensitive, preferably noninvasive, method for detecting the disease at an earlier stage. In order to identify biomarkers for pancreatic cancer, we devised an in vitro positive/negative selection strategy to identify RNA ligands (aptamers) that could detect structural differences between the secretomes of pancreatic cancer and non-cancerous cells. Using this molecular recognition approach, we identified an aptamer (M9-5) that differentially bound conditioned media from cancerous and non-cancerous human pancreatic cell lines. This aptamer further discriminated between the sera of pancreatic cancer patients and healthy volunteers with high sensitivity and specificity. We utilized biochemical purification methods and mass-spectrometric analysis to identify the M9-5 target as cyclophilin B (CypB). This molecular recognition-based strategy simultaneously identified CypB as a serum biomarker and generated a new reagent to recognize it in body fluids. Moreover, this approach should be generalizable to other diseases and complementary to traditional approaches that focus on differences in expression level between samples. Finally, we suggest that the aptamer we identified has the potential to serve as a tool for the early detection of pancreatic cancer.

Comparison of Magnetic Resonance Imaging and Serum Biomarkers for Detection of Human Pluripotent Stem Cell-Derived Teratomas.

PubMed

Riegler, Johannes; Ebert, Antje; Qin, Xulei; Shen, Qi; Wang, Mouer; Ameen, Mohamed; Kodo, Kazuki; Ong, Sang-Ging; Lee, Won Hee; Lee, Grace; Neofytou, Evgenios; Gold, Joseph D; Connolly, Andrew J; Wu, Joseph C

2016-02-09

The use of cells derived from pluripotent stem cells (PSCs) for regenerative therapies confers a considerable risk for neoplastic growth and teratoma formation. Preclinical and clinical assessment of such therapies will require suitable monitoring strategies to understand and mitigate these risks. Here we generated human-induced pluripotent stem cells (iPSCs), selected clones that continued to express reprogramming factors after differentiation into cardiomyocytes, and transplanted these cardiomyocytes into immunocompromised rat hearts post-myocardial infarction. We compared magnetic resonance imaging (MRI), cardiac ultrasound, and serum biomarkers for their ability to delineate teratoma formation and growth. MRI enabled the detection of teratomas with a volume >8 mm(3). A combination of three plasma biomarkers (CEA, AFP, and HCG) was able to detect teratomas with a volume >17 mm(3) and with a sensitivity of more than 87%. Based on our findings, a combination of serum biomarkers with MRI screening may offer the highest sensitivity for teratoma detection and tracking. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Prognostic biomarkers in osteoarthritis

PubMed Central

Attur, Mukundan; Krasnokutsky-Samuels, Svetlana; Samuels, Jonathan; Abramson, Steven B.

2013-01-01

Purpose of review Identification of patients at risk for incident disease or disease progression in osteoarthritis remains challenging, as radiography is an insensitive reflection of molecular changes that presage cartilage and bone abnormalities. Thus there is a widely appreciated need for biochemical and imaging biomarkers. We describe recent developments with such biomarkers to identify osteoarthritis patients who are at risk for disease progression. Recent findings The biochemical markers currently under evaluation include anabolic, catabolic, and inflammatory molecules representing diverse biological pathways. A few promising cartilage and bone degradation and synthesis biomarkers are in various stages of development, awaiting further validation in larger populations. A number of studies have shown elevated expression levels of inflammatory biomarkers, both locally (synovial fluid) and systemically (serum and plasma). These chemical biomarkers are under evaluation in combination with imaging biomarkers to predict early onset and the burden of disease. Summary Prognostic biomarkers may be used in clinical knee osteoarthritis to identify subgroups in whom the disease progresses at different rates. This could facilitate our understanding of the pathogenesis and allow us to differentiate phenotypes within a heterogeneous knee osteoarthritis population. Ultimately, such findings may help facilitate the development of disease-modifying osteoarthritis drugs (DMOADs). PMID:23169101

Serum human epididymis secretory protein 4 as a potential biomarker of renal fibrosis in kidney transplantation recipients.

PubMed

Luo, Jinmei; Wang, Fen; Wan, Jianxin; Ye, Zhuangjian; Huang, Chumei; Cai, Yuesu; Liu, Min; Wu, Ben-Quan; Li, Laisheng

2018-05-05

Renal fibrosis remains an important cause of kidney allograft failure. The objective of this study was to evaluate the performance of serum human epididymis secretory protein 4 (HE4) as a biomarker for renal fibrosis in kidney transplant recipients. A total of 103 kidney transplantation patients were enrolled in this study, and serum HE4 concentrations were detected using the chemiluminescent microparticle immunoassay. Renal biopsy was carried out, and histological findings were assessed by immunohistochemistry. Median serum HE4 concentrations were significantly increased in kidney transplant recipients (186.2 pmol/l, interquartile range [IQR] 125.6-300.2) compared with control subjects (34.3 pmol/l, IQR 30.4-42.3, p < 0.0001). Meanwhile, serum HE4 concentrations were significantly increased along with disease severity (p < 0.0001). In addition, we found serum HE4 concentrations to be strongly correlated with the severity of fibrosis (IF/TA 0, 1, 2, and 3: 114.3, 179.0, 197.8, and 467.8 pmol/l, respectively; p < 0.0001) and serum HE4 concentrations significantly correlated with HE4 tissue expression concentrations in renal biopsy. Serum HE4 was increased in kidney transplant recipients with decreased kidney function and renal fibrosis and was correlated with the severity of the disease, suggesting that HE4 has the potential to be used as a novel clinical biomarker for evaluating kidney function and predicting renal fibrosis in kidney transplant recipients. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of Mud-Bath Therapy on Serum Biomarkers in Patients with Knee Osteoarthritis: Results from a Randomized Controlled Trial.

PubMed

Pascarelli, Nicola A; Cheleschi, Sara; Bacaro, Giovanni; Guidelli, Giacomo M; Galeazzi, Mauro; Fioravanti, Antonella

2016-01-01

Balneotherapy is one of the most commonly used non-pharmacological approaches for osteoarthritis (OA). Recent data indicate that some biomarkers could be useful to predict OA progression and to assess therapeutic response. To evaluate the effects of mud-bath therapy on serum biomarkers in patients with knee OA. The study group comprised 103 patients with primary symptomatic bilateral knee OA who were randomly assigned to receive a cycle of mud-bath therapy over a period of 2 weeks or to continue their standard therapy alone. Clinical and biochemical parameters were assessed at baseline and after 2 weeks. Clinical assessments included global pain score on a visual analogue scale (VAS) and the Western Ontario and McMaster Universities Index (WOMAC) subscores for knee OA. Cartilage oligomeric matrix protein (COMP), C-terminal cross-linked telopeptide type II collagen (CTX-II), myeloperoxidase (MPO) and high sensitivity C-reactive protein (hsCRP) serum levels were assessed by ELISA. At the end of mud-bath therapy we observed a statistically significant improvement in VAS and WOMAC subscores. Serum levels of COMP, MPO and hsCRP did not show any significant modification in either group, while a significant increase (P < 0.001) in CTX-II serum levels was observed in the mud-bath group after the treatment. A cycle of mud-bath therapy added to the usual treatment had a beneficial effect on pain and function in patients with knee OA. The evaluation of serum biomarkers showed a significant increase of CTX-II only, perhaps due to an increase of cartilage turnover induced by thermal stress.

Serum Nutritional Biomarkers and Their Associations with Sleep among US Adults in Recent National Surveys

PubMed Central

Beydoun, May A.; Gamaldo, Alyssa A.; Canas, Jose A.; Beydoun, Hind A.; Shah, Mauli T.; McNeely, Jessica M.; Zonderman, Alan B.

2014-01-01

Background The associations between nutritional biomarkers and measures of sleep quantity and quality remain unclear. Methods Cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) 2005–2006 were used. We selected 2,459 adults aged 20–85, with complete data on key variables. Five sleep measures were constructed as primary outcomes: (A) Sleep duration; (B) Sleep disorder; (C) Three factors obtained from factor analysis of 15 items and labeled as “Poor sleep-related daytime dysfunction” (Factor 1), “Sleepiness” (Factor 2) and “Sleep disturbance” (Factor 3). Main exposures were serum concentrations of key nutrients, namely retinol, retinyl esters, carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lutein+zeaxanthin, lycopene), folate, vitamin B-12, total homocysteine (tHcy), vitamin C, 25-hydroxyvitamin D (25(OH)D) and vitamin E. Main analyses consisted of multiple linear, logistic and multinomial logit models. Results Among key findings, independent inverse associations were found between serum vitamin B-12 and sleep duration, 25(OH)D and sleepiness (as well as insomnia), and between folate and sleep disturbance. Serum total carotenoids concentration was linked to higher odds of short sleep duration (i.e. 5–6 h per night) compared to normal sleep duration (7–8 h per night). Conclusions A few of the selected serum nutritional biomarkers were associated with sleep quantity and quality. Longitudinal studies are needed to ascertain temporality and assess putative causal relationships. PMID:25137304

The extracellular domain of Her2 in serum as a biomarker of breast cancer.

PubMed

Perrier, Alexandre; Gligorov, Joseph; Lefèvre, Guillaume; Boissan, Mathieu

2018-02-28

Breast cancer is a major health problem worldwide. In ~15% of breast cancers, the epidermal growth factor receptor HER2, a transmembrane protein, is overexpressed. This HER2 overexpression is associated with an aggressive form of the disease and a poor clinical prognosis. The extracellular domain (ECD) of HER2 is released into the blood by a proteolytic mechanism known as "ECD shedding". This proteolytic shedding leaves a constitutively active truncated receptor in the membrane that is 10-100-fold more oncogenic than the full-length receptor and promotes the growth and survival of cancer cells. Shedding of the HER2 ECD is increased during metastasis: whereas 15% of primary breast cancer patients have elevated levels of serum HER2 ECD (sHER2 ECD), the levels reach 45% in patients with metastatic disease. Thus, sHER2 ECD has been proposed as a promising biomarker for cancer recurrence and for monitoring the disease status of patients overexpressing HER2. Nevertheless, in 2016, the American Society of Clinical Oncology advises clinicians not to use soluble HER2 levels to guide their choice of adjuvant therapy for patients with HER2-positive breast cancer, because the evidence was considered not strong enough. Currently, biomarkers such as carcinoembryonic antigen and cancer antigen 15-3 are widely used to monitor metastatic breast cancer disease even if the level of evidence of clinical impact of this monitoring is poor. In this article, we review the evidence that sHER2 ECD might be used in some situations as a biomarker for breast cancer. Although this serum biomarker will not replace the direct measurement of tumor HER2 status for diagnosis of early-stage tumors; it might be especially useful in metastatic disease for prognosis, as an indicator of cancer progression and of therapy response, particularly to anti-HER2 therapies. Owing to these data, sHER2 ECD should be considered as a promising biomarker to detect cancer recurrence and metastasis.

Perspective on Clinical Application of Biomarkers in AKI

PubMed Central

Mansour, Sherry G.

2017-01-01

Several biomarkers of renal injury have been identified but the utility of these biomarkers is largely confined to research studies, whereas widespread clinical applicability is limited. This is partly because the use of serum creatinine as the comparator has several limitations and restricts the full interpretation of biomarker performance. To highlight the potential for clinical application of biomarkers, the most pertinent biomarker data are summarized here, using clinically relevant scenarios in which biomarkers could assist with diagnostic and management dilemmas. The paradigms proposed in this review aim to enhance the clinical diagnosis, management, and prognosis of AKI through the combined use of available clinical markers and novel inflammatory, injury, and repair biomarkers. PMID:28220028

Proteome screening of pleural effusions identifies galectin 1 as a diagnostic biomarker and highlights several prognostic biomarkers for malignant mesothelioma.

PubMed

Mundt, Filip; Johansson, Henrik J; Forshed, Jenny; Arslan, Sertaç; Metintas, Muzaffer; Dobra, Katalin; Lehtiö, Janne; Hjerpe, Anders

2014-03-01

Malignant mesothelioma is an aggressive asbestos-induced cancer, and affected patients have a median survival of approximately one year after diagnosis. It is often difficult to reach a conclusive diagnosis, and ancillary measurements of soluble biomarkers could increase diagnostic accuracy. Unfortunately, few soluble mesothelioma biomarkers are suitable for clinical application. Here we screened the effusion proteomes of mesothelioma and lung adenocarcinoma patients to identify novel soluble mesothelioma biomarkers. We performed quantitative mass-spectrometry-based proteomics using isobaric tags for quantification and used narrow-range immobilized pH gradient/high-resolution isoelectric focusing (pH 4-4.25) prior to analysis by means of nano liquid chromatography coupled to MS/MS. More than 1,300 proteins were identified in pleural effusions from patients with malignant mesothelioma (n = 6), lung adenocarcinoma (n = 6), or benign mesotheliosis (n = 7). Data are available via ProteomeXchange with identifier PXD000531. The identified proteins included a set of known mesothelioma markers and proteins that regulate hallmarks of cancer such as invasion, angiogenesis, and immune evasion, plus several new candidate proteins. Seven candidates (aldo-keto reductase 1B10, apolipoprotein C-I, galectin 1, myosin-VIIb, superoxide dismutase 2, tenascin C, and thrombospondin 1) were validated by enzyme-linked immunosorbent assays in a larger group of patients with mesothelioma (n = 37) or metastatic carcinomas (n = 25) and in effusions from patients with benign, reactive conditions (n = 16). Galectin 1 was identified as overexpressed in effusions from lung adenocarcinoma relative to mesothelioma and was validated as an excellent predictor for metastatic carcinomas against malignant mesothelioma. Galectin 1, aldo-keto reductase 1B10, and apolipoprotein C-I were all identified as potential prognostic biomarkers for malignant mesothelioma. This analysis of the effusion proteome

Serum biomarkers in young adult and aged Brown Norway (BN) rats following episodic (weekly) ozone exposure

EPA Science Inventory

Ozone (03) is an air pollutant that is associated with cardiovascular and respiratory diseases. Older adults are considered to be particularly susceptible to oxidant air pollutants such as 03. Serum biomarkers are being sought that would lead to better predictions of susceptibili...

Using Serological Proteome Analysis to Identify Serum Anti-Nucleophosmin 1 Autoantibody as a Potential Biomarker in European-American and African-American Patients With Prostate Cancer.

PubMed

Dai, Liping; Li, Jitian; Xing, Mengtao; Sanchez, Tino W; Casiano, Carlos A; Zhang, Jian-Ying

2016-11-01

The prostate-specific antigen (PSA) testing has been widely implemented for the early detection and management of prostate cancer (PCa). However, the lack of specificity has led to overdiagnosis, resulting in many possibly unnecessary biopsies and overtreatment. Therefore, novel serological biomarkers with high sensitivity and specificity are of vital importance needed to complement PSA testing in the early diagnosis and effective management of PCa. This is particularly critical in the context of PCa health disparities, where early detection and management could help reduce the disproportionately high PCa mortality observed in African-American men. Previous studies have demonstrated that sera from patients with PCa contain autoantibodies that react with tumor-associated antigens (TAAs). The serological proteome analysis (SERPA) approach was used to identify tumor-associated antigens (TAAs) of PCa. In evaluation study, the level of anti-NPM1 antibody was examined in sera from test cohort, validation cohort, as well as European-American (EA) and African-American (AA) men with PCa by using immunoassay. Nucleophosmin 1 (NPM1) as a 33 kDa TAA in PCa was identified and characterized by SERPA approach. Anti-NPM1 antibody level in PCa was higher than in benign prostatic hyperplasia (BPH) patients and healthy individuals. Receiver operating characteristic (ROC) curve analysis showed similar high diagnostic value for PCa in the test cohort (area under the curve (AUC):0.860) and validation cohort (AUC: 0.822) to differentiate from normal individuals and BPH. Interestingly, AUC values were significantly higher for AA PCa patients. When considering concurrent serum measurements of anti-NPM1 antibody and PSA, 97.1% PCa patients at early stage were identified correctly, while 69.2% BPH patients who had elevated PSA levels were found to be anti-NPM1 negative. Additionally, anti-NPM1 antibody levels in PCa patients at early stage significantly increased after surgery treatment

Quantification of NS1 dengue biomarker in serum via optomagnetic nanocluster detection

NASA Astrophysics Data System (ADS)

Antunes, Paula; Watterson, Daniel; Parmvi, Mattias; Burger, Robert; Boisen, Anja; Young, Paul; Cooper, Matthew A.; Hansen, Mikkel F.; Ranzoni, Andrea; Donolato, Marco

2015-11-01

Dengue is a tropical vector-borne disease without cure or vaccine that progressively spreads into regions with temperate climates. Diagnostic tools amenable to resource-limited settings would be highly valuable for epidemiologic control and containment during outbreaks. Here, we present a novel low-cost automated biosensing platform for detection of dengue fever biomarker NS1 and demonstrate it on NS1 spiked in human serum. Magnetic nanoparticles (MNPs) are coated with high-affinity monoclonal antibodies against NS1 via bio-orthogonal Cu-free ‘click’ chemistry on an anti-fouling surface molecular architecture. The presence of the target antigen NS1 triggers MNP agglutination and the formation of nanoclusters with rapid kinetics enhanced by external magnetic actuation. The amount and size of the nanoclusters correlate with the target concentration and can be quantified using an optomagnetic readout method. The resulting automated dengue fever assay takes just 8 minutes, requires 6 μL of serum sample and shows a limit of detection of 25 ng/mL with an upper detection range of 20000 ng/mL. The technology holds a great potential to be applied to NS1 detection in patient samples. As the assay is implemented on a low-cost microfluidic disc the platform is suited for further expansion to multiplexed detection of a wide panel of biomarkers.

MD-miniRNA could be a more accurate biomarker for prostate cancer screening compared with serum prostate-specific antigen level.

PubMed

Xue, Dong; Zhou, Cui-Xing; Shi, Yun-Bo; Lu, Hao; He, Xiao-Zhou

2015-05-01

Prostate cancer and prostatic hyperplasia detection remains a great challenge, lacking of effective non-invasive and specific diagnostic biomarkers. In the current study, we aimed to identify the relative expression of plasma MD-miniRNA and its diagnostic performance in differentiating prostate cancer and prostatic hyperplasia patients from healthy controls, compared with serum prostate-specific antigen (PSA) level. All of the clinical participants (63 prostate cancer patients, 32 prostatic hyperplasia patients, and 50 healthy controls) were obtained from the Third Affiliated Hospital of Suzhou University in China between January 2013 and April 2014. Clinical characteristics were well matched. Plasma samples were extracted to test the relative expression of MD-miniRNA using the method of qRT-PCR. SPSS 22.0 statistical software package was used to analyze the data and GraphPad Prism 6.0 was used to generate the graphs. Relativity expression of plasma MD-miniRNA was significantly upregulated in prostate cancer, compared with prostatic hyperplasia patients and healthy controls. Serum PSA level revealed similar differences among these groups. MD-miniRNA presented a relatively high diagnostic accuracy with AUC of 0.86 (95 % CI 0.80-0.93) in differentiating prostate cancer patients from healthy controls. Simultaneously, MD-miniRNA was able to discriminate prostate cancer patients from prostatic hyperplasia controls with AUC of 0.79 (95 % CI 0.70-0.88). In addition, MD-miniRNA displayed a better diagnostic performance than PSA level. However, the panel of these two biomarkers revealed the best diagnostic performance, compared with either single biomarker. Results of this study showed that plasma MD-miniRNA could serve as a promising and noninvasive biomarker for diagnosing prostate cancer. Further large-scale studies are needed to confirm its clinical diagnosis accuracy.

Biomarkers of systemic lupus erythematosus identified using mass spectrometry-based proteomics: a systematic review.

PubMed

Nicolaou, Orthodoxia; Kousios, Andreas; Hadjisavvas, Andreas; Lauwerys, Bernard; Sokratous, Kleitos; Kyriacou, Kyriacos

2017-05-01

Advances in mass spectrometry technologies have created new opportunities for discovering novel protein biomarkers in systemic lupus erythematosus (SLE). We performed a systematic review of published reports on proteomic biomarkers identified in SLE patients using mass spectrometry-based proteomics and highlight their potential disease association and clinical utility. Two electronic databases, MEDLINE and EMBASE, were systematically searched up to July 2015. The methodological quality of studies included in the review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Twenty-five studies were included in the review, identifying 241 SLE candidate proteomic biomarkers related to various aspects of the disease including disease diagnosis and activity or pinpointing specific organ involvement. Furthermore, 13 of the 25 studies validated their results for a selected number of biomarkers in an independent cohort, resulting in the validation of 28 candidate biomarkers. It is noteworthy that 11 candidate biomarkers were identified in more than one study. A significant number of potential proteomic biomarkers that are related to a number of aspects of SLE have been identified using mass spectrometry proteomic approaches. However, further studies are required to assess the utility of these biomarkers in routine clinical practice. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Serum YKL-40 as a potential biomarker of inflammation in psoriasis.

PubMed

Baran, Anna; Myśliwiec, Hanna; Szterling-Jaworowska, Malgorzata; Kiluk, Paulina; Świderska, Magdalena; Flisiak, Iwona

2018-02-01

YKL-40 is an inflammatory glycoprotein associated with atherosclerosis, cardiovascular disease, diabetes or metabolic syndrome which are common comorbidities in psoriasis. The aim of the study was to assess serum YKL-40 level in psoriasis and elucidate possible associations with disease activity, inflammatory or metabolic parameters and treatment. A total of 37 individuals with active plaque-type psoriasis and 15 healthy controls were enrolled. Blood samples were collected before and after 2 weeks of therapy. Serum YKL-40 concentrations were evaluated by enzyme-linked immunosorbent assay (ELISA). The results were correlated with Psoriasis Area and Severity Index (PASI), body mass index (BMI), inflammatory and biochemical markers, lipid profile and topical therapy. Median YKL-40 serum levels were significantly increased in psoriatic patients in comparison to the controls (p < .0001). No significant correlations between investigated protein and metabolic parameters as BMI (p = .19), glucose (p = .32) nor lipids levels were found. Significant positive relation with CRP (p = .003) or alanine aminotransferase (p = .04) and no correlation with PASI (p = .2) were noted. Serum YKL-40 level remained unchanged (p = .5) after topical treatment, despite clinical improvement. YKL-40 might be a biomarker of psoriasis and inflammation in psoriatic patients, but not a reliable indicator of metabolic conditions, severity of psoriasis nor efficacy of the treatment.

Decreased serum 5-oxoproline in TB patients is associated with pathological damage of the lung.

PubMed

Che, Nanying; Cheng, Jianhua; Li, Haijing; Zhang, Zhiguo; Zhang, Xuxia; Ding, Zhixin; Dong, Fangting; Li, Chuanyou

2013-08-23

Tuberculosis (TB) is a serious world-wide health problem, causing millions of deaths every year. Metabolomics is a relatively new approach to identify disease specific biomarkers. However, there is little information available on metabolite biomarkers in TB. In this study, we used gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS) to identify serum metabolite biomarkers associated with the active state of TB. Potential biomarkers were selected by comparing serum metabolites in 10 healthy donors with 10TB patients, and in 6TB patients before and after treatment. Selected biomarkers were then validated using a larger population of samples from 120 healthy donors and 120TB patients derived from different clinical backgrounds The 5-oxoproline level was consistently low in patients with active TB. Further validation in larger population of clinical samples showed that 5-oxoproline was associated with pathological damage of the lung but not with age, sex, or bacterial burden in TB patients. Serum 5-oxoproline may be a useful biomarker for active TB and pathological damage of the lung. Copyright © 2013 Elsevier B.V. All rights reserved.

Proteomic evaluation of sheep serum proteins

PubMed Central

2012-01-01

Background The applications of proteomic strategies to ovine medicine remain limited. The definition of serum proteome may be a good tool to identify useful protein biomarkers for recognising sub-clinical conditions and overt disease in sheep. Findings from bovine species are often directly translated for use in ovine medicine. In order to characterize normal protein patterns and improve knowledge of molecular species-specific characteristics, we generated a two-dimensional reference map of sheep serum. The possible application of this approach was tested by analysing serum protein patterns in ewes with mild broncho-pulmonary disease, which is very common in sheep and in the peripartum period which is a stressful time, with a high incidence of infectious and parasitic diseases. Results This study generated the first reference 2-DE maps of sheep serum. Overall, 250 protein spots were analyzed, and 138 identified. Compared with healthy sheep, serum protein profiles of animals with rhino-tracheo-bronchitis showed a significant decrease in protein spots identified as transthyretin, apolipoprotein A1 and a significant increase in spots identified as haptoglobin, endopin 1b and alpha1B glycoprotein. In the peripartum period, haptoglobin, alpha-1-acid glycoprotein, apolipoprotein A1 levels rose, while transthyretin content dropped. Conclusions This study describes applications of proteomics in putative biomarker discovery for early diagnosis as well as for monitoring the physiological and metabolic situations critical for ovine welfare. PMID:22630135

Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study.

PubMed

de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E; Oliveira, Michelli F; Chaillon, Antoine; de Pereira, Ana Paula; Cunha, Ana Paula; Zonta, Marise; Bents, Joao França; Raboni, Sonia M; Smith, Davey; Letendre, Scott; Ellis, Ronald J

2017-06-01

Despite the effective suppression of viremia with antiretroviral therapy, HIV can still replicate in the central nervous system (CNS). This was a longitudinal study of the cerebrospinal fluid (CSF) and serum dynamics of several biomarkers related to inflammation, the blood-brain barrier, neuronal injury, and IgG intrathecal synthesis in serial samples of CSF and serum from a patient infected with HIV-1 subtype C with CNS compartmentalization.The phylogenetic analyses of plasma and CSF samples in an acute phase using next-generation sequencing and F-statistics analysis of C2-V3 haplotypes revealed distinct compartmentalized CSF viruses in paired CSF and peripheral blood mononuclear cell samples. The CSF biomarker analysis in this patient showed that symptomatic CSF escape is accompanied by CNS inflammation, high levels of cell and humoral immune biomarkers, CNS barrier dysfunction, and an increase in neuronal injury biomarkers with demyelization. Independent and isolated HIV replication can occur in the CNS, even in HIV-1 subtype C, leading to compartmentalization and development of quasispecies distinct from the peripheral plasma. These immunological aspects of the HIV CNS escape have not been described previously. To our knowledge, this is the first report of CNS HIV escape and compartmentalization in HIV-1 subtype C.

Anti-p-benzoquinone antibody level as a prospective biomarker to identify smokers at risk for COPD

PubMed Central

Banerjee, Santanu; Bhattacharyya, Parthasarathi; Mitra, Subhra; Kundu, Somenath; Panda, Samiran; Chatterjee, Indu B

2017-01-01

Background and objective Identification of smokers having predisposition to COPD is important for early intervention to reduce the huge global burden of the disease. Using a guinea pig model, we have shown that p-benzoquinone (p-BQ) derived from cigarette smoke (CS) in the lung is a causative factor for CS-induced emphysema. p-BQ is also derived from CS in smokers and it elicits the production of anti-p-BQ antibody in humans. We therefore hypothesized that anti-p-BQ antibody might have a protective role against COPD and could be used as a predictive biomarker for COPD in smokers. The objective of this study was to compare the serum anti-p-BQ antibody level between smokers with and without COPD for the evaluation of the hypothesis. Methods Serum anti-p-BQ antibody concentrations of current male smokers with (n=227) or without (n=308) COPD were measured by an indirect enzyme-linked immunoabsorbent assay (ELISA) developed in our laboratory. COPD was diagnosed by spirometry according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Results and discussion A significant difference was observed in the serum anti-p-BQ antibody level between smokers with and without COPD (Mann–Whitney U-test =4,632.5, P=0.000). Receiver operating characteristic (ROC) curve analysis indicated that the ELISA had significant precision (area under the curve [AUC] =0.934, 95% confidence interval [CI]: 0.913–0.935) for identifying smokers with COPD from their low antibody level. The antibody cutoff value of 29.4 mg/dL was constructed from the ROC coordinates to estimate the risk for COPD in smokers. While 90.3% of smokers with COPD had a low antibody value (≤29.4 mg/dL), the majority (86.4%) of smokers without COPD had a high antibody value (≤29.4 mg/dL); 13.6% of current smokers without COPD having an antibody level below this cutoff value (odds ratio [OR] =59.3, 95% CI: 34.15–101.99) were considered to be at risk for COPD. Conclusion and future directions

Altered serum microRNAs as biomarkers for the early diagnosis of pulmonary tuberculosis infection

PubMed Central

2012-01-01

Background Pulmonary tuberculosis (TB) is a highly lethal infectious disease and early diagnosis of TB is critical for the control of disease progression. The objective of this study was to profile a panel of serum microRNAs (miRNAs) as potential biomarkers for the early diagnosis of pulmonary TB infection. Methods Using TaqMan Low-Density Array (TLDA) analysis followed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) validation, expression levels of miRNAs in serum samples from 30 patients with active tuberculosis and 60 patients with Bordetella pertussis (BP), varicella-zoster virus (VZV) and enterovirus (EV) were analyzed. Results The Low-Density Array data showed that 97 miRNAs were differentially expressed in pulmonary TB patient sera compared with healthy controls (90 up-regulated and 7 down-regulated). Following qRT-PCR confirmation and receiver operational curve (ROC) analysis, three miRNAs (miR-361-5p, miR-889 and miR-576-3p) were shown to distinguish TB infected patients from healthy controls and other microbial infections with moderate sensitivity and specificity (area under curve (AUC) value range, 0.711-0.848). Multiple logistic regression analysis of a combination of these three miRNAs showed an enhanced ability to discriminate between these two groups with an AUC value of 0.863. Conclusions Our study suggests that altered levels of serum miRNAs have great potential to serve as non-invasive biomarkers for early detection of pulmonary TB infection. PMID:23272999

Serum proteomic analysis reveals potential serum biomarkers for occupational medicamentosa-like dermatitis caused by trichloroethylene.

PubMed

Huang, Peiwu; Ren, Xiaohu; Huang, Zhijun; Yang, Xifei; Hong, Wenxu; Zhang, Yanfang; Zhang, Hang; Liu, Wei; Huang, Haiyan; Huang, Xinfeng; Wu, Desheng; Yang, Linqing; Tang, Haiyan; Zhou, Li; Li, Xuan; Liu, Jianjun

2014-08-17

Trichloroethylene (TCE) is an industrial solvent with widespread occupational exposure and also a major environmental contaminant. Occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) is an autoimmune disease and it has become one major hazard in China. In this study, sera from 3 healthy controls and 3 OMLDT patients at different disease stages were used for a screening study by 2D-DIGE and MALDI-TOF-MS/MS. Eight proteins including transthyretin (TTR), retinol binding protein 4 (RBP4), haptoglobin, clusterin, serum amyloid A protein (SAA), apolipoprotein A-I, apolipoprotein C-III and apolipoprotein C-II were found to be significantly altered among the healthy, acute-stage, healing-stage and healed-stage groups. Specifically, the altered expression of TTR, RBP4 and haptoglobin were further validated by Western blot analysis and ELISA. Our data not only suggested that TTR, RBP4 and haptoglobin could serve as potential serum biomarkers of OMLDT, but also indicated that measurement of TTR, RBP4 and haptoglobin or their combination could help aid in the diagnosis, monitoring the progression and therapy of the disease. Copyright © 2014. Published by Elsevier Ireland Ltd.

Copeptin as a serum biomarker of febrile seizures.

PubMed

Stöcklin, Benjamin; Fouzas, Sotirios; Schillinger, Paula; Cayir, Sevgi; Skendaj, Roswitha; Ramser, Michel; Weber, Peter; Wellmann, Sven

2015-01-01

Accurate diagnosis of febrile seizures in children presenting after paroxysmal episodes associated with fever, is hampered by the lack of objective postictal biomarkers. The aim of our study was to investigate whether FS are associated with increased levels of serum copeptin, a robust marker of arginine vasopressin secretion. This was a prospective emergency-setting cross-sectional study of 161 children between six months and five years of age. Of these, 83 were diagnosed with febrile seizures, 69 had a febrile infection without seizures and nine had epileptic seizures not triggered by infection. Serum copeptin and prolactin levels were measured in addition to standard clinical, neurophysiological, and laboratory assessment. NCT01884766. Circulating copeptin was significantly higher in children with febrile seizures (median [interquartile range] 18.9 pmol/L [8.5-36.6]) compared to febrile controls (5.6 pmol/L [4.1-9.4]; p < 0.001), with no differences between febrile and epileptic seizures (21.4 pmol/L [16.1-46.6]; p = 0.728). In a multivariable regression model, seizures were the major determinant of serum copeptin (beta 0.509; p < 0.001), independently of clinical and baseline laboratory indices. The area under the receiver operating curve for copeptin was 0.824 (95% CI 0.753-0.881), significantly higher compared to prolactin (0.667 [0.585-0.742]; p < 0.001). The diagnostic accuracy of copeptin increased with decreasing time elapsed since the convulsive event (at 120 min: 0.879 [0.806-0.932] and at <60 min: 0.975 [0.913-0.997]). Circulating copeptin has high diagnostic accuracy in febrile seizures and may be a useful adjunct for accurately diagnosing postictal states in the emergency setting.

Mycothiol acetyltransferase (Rv0819) of Mycobacterium tuberculosis is a potential biomarker for direct diagnosis of tuberculosis using patient serum specimens.

PubMed

Zeitoun, H; Bahey-El-Din, M; Kassem, M A; Aboushleib, H M

2017-12-01

Mycobacterium tuberculosis infection constitutes a global threat that results in significant morbidity and mortality worldwide. Efficient and early diagnosis of tuberculosis (TB) is of paramount importance for successful treatment. The aim of the current study is to investigate the mycobacterial mycothiol acetyltransferase Rv0819 as a potential novel biomarker for the diagnosis of active TB infection. The gene encoding Rv0819 was cloned and successfully expressed in Escherichia coli. The recombinant Rv0819 was purified using metal affinity chromatography and was used to raise murine polyclonal antibodies against Rv0819. The raised antibodies were employed for direct detection of Rv0819 in patient serum samples using dot blot assay and competitive enzyme-linked immunosorbent assay (ELISA). Serum samples were obtained from 68 confirmed new TB patients and 35 healthy volunteers as negative controls. The dot blot assay showed sensitivity of 64·7% and specificity of 100%, whereas the competitive ELISA assay showed lower sensitivity (54·4%) and specificity (88·57%). The overall sensitivity of the combined results of the two tests was found to be 89·7%. Overall, the mycobacterial Rv0819 is a potential TB serum biomarker that can be exploited, in combination with other TB biomarkers, for efficient and reliable diagnosis of active TB infection. The early and accurate diagnosis of tuberculosis infection is of paramount importance for initiating treatment and avoiding clinical complications. Most current diagnostic tests have poor sensitivity and/or specificity and in many cases they are too expensive for routine diagnostic testing in resource-limited settings. In the current study, we examined a novel mycobacterial serum biomarker, namely mycothiol acetyltransferase Rv0819. The antigen was detectable in serum specimens of a significant number of tuberculosis patients. This article proves the importance of Rv0819 and paves the way towards its future use as a useful

miR-210 inhibits trophoblast invasion and is a serum biomarker for preeclampsia.

PubMed

Anton, Lauren; Olarerin-George, Anthony O; Schwartz, Nadav; Srinivas, Sindhu; Bastek, Jamie; Hogenesch, John B; Elovitz, Michal A

2013-11-01

Preeclampsia is characterized by hypertension and proteinuria in pregnant women. Its exact cause is unknown. Preeclampsia increases the risk of maternal and fetal morbidity and mortality. Although delivery, often premature, is the only known cure, early targeted interventions may improve maternal and fetal outcomes. Successful intervention requires a better understanding of the molecular etiology of preeclampsia and the development of accurate methods to predict women at risk. To this end, we tested the role of miR-210, a miRNA up-regulated in preeclamptic placentas, in first-trimester extravillous trophoblasts. miR-210 overexpression reduced trophoblast invasion, a process necessary for uteroplacental perfusion, in an extracellular signal-regulated kinase/mitogen-activated protein kinase-dependent manner. Conversely, miR-210 inhibition promoted invasion. Furthermore, given that the placenta secretes miRNAs into the maternal circulation, we tested if serum expression of miR-210 was associated with the disease. We measured miR-210 expression in two clinical studies: a case-control study and a prospective cohort study. Serum miR-210 expression was significantly associated with a diagnosis of preeclampsia (P = 0.007, area under the receiver operator curves = 0.81) and was predictive of the disease, even months before clinical diagnosis (P < 0.0001, area under the receiver operator curve = 0.89). Hence, we conclude that aberrant expression of miR-210 may contribute to trophoblast function and that miR-210 is a novel predictive serum biomarker for preeclampsia that can help in identifying at-risk women for monitoring and treatment. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Serum levels of adiponectin and leptin as biomarkers of proteinuria in lupus nephritis.

PubMed

Diaz-Rizo, Valeria; Bonilla-Lara, David; Gonzalez-Lopez, Laura; Sanchez-Mosco, Dalia; Fajardo-Robledo, Nicte S; Perez-Guerrero, Edsaul E; Rodriguez-Jimenez, N Alejandra; Saldaña-Cruz, A Miriam; Vazquez-Villegas, M Luisa; Gomez-Bañuelos, Eduardo; Vazquez-Del Mercado, Monica; Cardona-Muñoz, E German; Cardona-Muller, David; Trujillo, Xochitl; Huerta, Miguel; Salazar-Paramo, Mario; Gamez-Nava, Jorge I

2017-01-01

There are controversial results about the role of serum leptin and adiponectin levels as biomarkers of the severity of proteinuria in lupus nephritis. The aim of this study was to evaluate the relationship between serum leptin and adiponectin levels with severity of proteinuria secondary to lupus nephritis (LN). In a cross-sectional study, 103 women with systemic lupus erythematosus (SLE) were evaluated for kidney involvement. We compared 30 SLE patients with LN, all of them with proteinuria, versus 73 SLE patients without renal involvement (no LN). A comprehensive set of clinical and laboratory variables was assessed, including serum levels of leptin and adiponectin by ELISA. Multivariate analyses were used to adjust for potential confounders associated with proteinuria in LN. We found higher adiponectin levels in the LN group compared with the no LN group (20.4 ± 10.3 vs 15.6 ± 7.8 μg/mL; p = 0.02), whereas no differences were observed in leptin levels (33.3 ± 31.4 vs 22.5 ± 25.5 ng/mL; p = 0.07). Severity of proteinuria correlated with an increase in adiponectin levels (r = 0.31; p = 0.001), but no correlation was observed with leptin. Adiponectin levels were not related to anti-dsDNA or anti-nucleosome antibodies. In the logistic regression, adiponectin levels were associated with a high risk of proteinuria in SLE (OR = 1.06; 95% CI 1.01-1.12; p = 0.02). Instead, leptin was not associated with LN. These findings indicate that adiponectin levels are useful markers associated with proteinuria in LN. Further longitudinal studies are required to identify if these levels are predictive of renal relapse.

Serum Cystatin C as an Early Diagnostic Biomarker of Diabetic Kidney Disease in Type 2 Diabetic Patients.

PubMed

Qamar, Ayesha; Hayat, Asma; Ahmad, Tariq Mahmood; Khan, Alamgir; Hasnat, Mohammad Najam Ul; Tahir, Sufyan

2018-04-01

To determine the diagnostic accuracy and cut-off values of serum cystatin C as early diagnostic biomarker of diabetic kidney disease. Cross-sectional analytical study. Department of Pathology, Army Medical College, Rawalpindi in collaboration with Endocrinology Department, Military Hospital (MH), Rawalpindi from November 2015 to November 2016. One hundred and nineteen diagnosed patients of type 2 diabetes mellitus were enrolled in the study from the outpatient Endocrinology Department of the MH Rawalpindi. Fifty disease-free controls were also included. Fasting blood samples of the patients and controls were analysed for creatinine by Jaffé's kinetic method and estimated GFR was calculated using MDRD-based equation for GFR. Serum cystatin C was estimated by quantitative turbidimetric method. Serum cystatin C was higher in the diabetic group (mean = 1.022 ±0.33 mg/dl) as compared to the control group (mean = 0.63 ±0.14 mg/dl). ROC curve analysis, keeping less than 60 ml/min/1.73 m2 GFR (CKD-MDRD based) as reference value of the stat variable/gold standard; revealed an area under the curve of 0.914 (95% CI 0.85-0.98) and at optimal sensitivity of 88.2% and specificity of 84.8% the established cut-off of serum cystatin C was 1.26 mg/L. Cystatin C is an accurate biomarker of diabetic kidney disease with good sensitivity and specificity.

Potential metabolomic biomarkers for reliable diagnosis of Behcet's disease using gas chromatography/ time-of-flight-mass spectrometry.

PubMed

Ahn, Joong Kyong; Kim, Jungyeon; Hwang, Jiwon; Song, Juhwan; Kim, Kyoung Heon; Cha, Hoon-Suk

2018-05-01

Although many diagnostic criteria of Behcet's disease (BD) have been developed and revised by experts, diagnosing BD is still complicated and challenging. No metabolomic studies on serum have been attempted to improve the diagnosis and to identify potential biomarkers of BD. The purposes of this study were to investigate distinctive metabolic changes in serum samples of BD patients and to identify metabolic candidate biomarkers for reliable diagnosis of BD using the metabolomics platform. Metabolomic profiling of 90 serum samples from 45 BD patients and 45 healthy controls (HCs) were performed via gas chromatography with time-of-flight mass spectrometry (GC/TOF-MS) with multivariate statistical analyses. A total of 104 metabolites were identified from samples. The serum metabolite profiles obtained from GC/TOF-MS analysis can distinguish BD patients from HC group in discovery set. The variation values of the partial least squared-discrimination analysis (PLS-DA) model are R 2 X of 0.246, R 2 Y of 0.913 and Q 2 of 0.852, respectively, indicating strong explanation and prediction capabilities of the model. A panel of five metabolic biomarkers, namely, decanoic acid, fructose, tagatose, linoleic acid and oleic acid were selected and adequately validated as putative biomarkers of BD (sensitivity 100%, specificity 97.1%, area under the curve 0.998) in the discovery set and independent set. The PLS_DA model showed clear discrimination of BD and HC groups by the five metabolic biomarkers in independent set. This is the first report on characteristic metabolic profiles and potential metabolite biomarkers in serum for reliable diagnosis of BD using GC/TOF-MS. Copyright © 2017. Published by Elsevier SAS.

Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy.

PubMed

Goede, V; Coutelle, O; Neuneier, J; Reinacher-Schick, A; Schnell, R; Koslowsky, T C; Weihrauch, M R; Cremer, B; Kashkar, H; Odenthal, M; Augustin, H G; Schmiegel, W; Hallek, M; Hacker, U T

2010-10-26

The combination of chemotherapy with the vascular endothelial growth factor (VEGF) antibody bevacizumab is a standard of care in advanced colorectal cancer (CRC). However, biomarkers predicting outcome of bevacizumab-containing treatment are lacking. As angiopoietin-2 (Ang-2) is a key regulator of vascular remodelling in concert with VEGF, we investigated its role as a biomarker in metastatic CRC. Serum Ang-2 levels were measured in 33 healthy volunteers and 90 patients with CRC. Of these, 34 had metastatic disease and received bevacizumab-containing therapy. To determine the tissue of origin of Ang-2, quantitative real-time PCR was performed on microdissected cryosections of human CRC and in a murine xenograft model of CRC using species-specific amplification. Ang-2 originated from the stromal compartment of CRC tissues. Serum Ang-2 levels were significantly elevated in patients with metastatic CRC compared with healthy controls. Amongst patients receiving bevacizumab-containing treatment, low pre-therapeutic serum Ang-2 levels were associated with a significant better response rate (82 vs 31%; P<0.01), a prolonged median progression-free survival (14.1 vs 8.5 months; P<0.01) and a reduction of 91% in the hazard of death (P<0.05). Serum Ang-2 is a candidate biomarker for outcome of patients with metastatic CRC treated with bevacizumab-containing therapy, and it should be further validated to customise combined chemotherapeutic and anti-angiogenic treatment.

Imperfect Gold Standards for Kidney Injury Biomarker Evaluation

PubMed Central

Betensky, Rebecca A.; Emerson, Sarah C.; Bonventre, Joseph V.

2012-01-01

Clinicians have used serum creatinine in diagnostic testing for acute kidney injury for decades, despite its imperfect sensitivity and specificity. Novel tubular injury biomarkers may revolutionize the diagnosis of acute kidney injury; however, even if a novel tubular injury biomarker is 100% sensitive and 100% specific, it may appear inaccurate when using serum creatinine as the gold standard. Acute kidney injury, as defined by serum creatinine, may not reflect tubular injury, and the absence of changes in serum creatinine does not assure the absence of tubular injury. In general, the apparent diagnostic performance of a biomarker depends not only on its ability to detect injury, but also on disease prevalence and the sensitivity and specificity of the imperfect gold standard. Assuming that, at a certain cutoff value, serum creatinine is 80% sensitive and 90% specific and disease prevalence is 10%, a new perfect biomarker with a true 100% sensitivity may seem to have only 47% sensitivity compared with serum creatinine as the gold standard. Minimizing misclassification by using more strict criteria to diagnose acute kidney injury will reduce the error when evaluating the performance of a biomarker under investigation. Apparent diagnostic errors using a new biomarker may be a reflection of errors in the imperfect gold standard itself, rather than poor performance of the biomarker. The results of this study suggest that small changes in serum creatinine alone should not be used to define acute kidney injury in biomarker or interventional studies. PMID:22021710

Exosomal microRNA profiling to identify hypoxia-related biomarkers in prostate cancer

PubMed Central

Panigrahi, Gati K.; Ramteke, Anand; Birks, Diane; Abouzeid Ali, Hamdy E.; Venkataraman, Sujatha; Agarwal, Chapla; Vibhakar, Rajeev; Miller, Lance D.; Agarwal, Rajesh; Abd Elmageed, Zakaria Y.; Deep, Gagan

2018-01-01

Hypoxia and expression of hypoxia-related biomarkers are associated with disease progression and treatment failure in prostate cancer (PCa). We have reported that exosomes (nanovesicles of 30-150 nm in diameter) secreted by human PCa cells under hypoxia promote invasiveness and stemness in naïve PCa cells. Here, we identified the unique microRNAs (miRNAs) loaded in exosomes secreted by PCa cells under hypoxia. Using TaqMan® array microRNA cards, we analyzed the miRNA profile in exosomes secreted by human PCa LNCaP cells under hypoxic (ExoHypoxic) and normoxic (ExoNormoxic) conditions. We identified 292 miRNAs loaded in both ExoHypoxic and ExoNormoxic. The top 11 miRNAs with significantly higher level in ExoHypoxic compared to ExoNormoxic were miR-517a, miR-204, miR-885, miR-143, miR-335, miR-127, miR-542, miR-433, miR-451, miR-92a and miR-181a; and top nine miRNA with significantly lower expression level in ExoHypoxic compared to ExoNormoxic were miR-521, miR-27a, miR-324, miR-579, miR-502, miR-222, miR-135b, miR-146a and miR-491. Importantly, the two differentially expressed miRNAs miR-885 (increased expression) and miR-521 (decreased expression) showed similar expression pattern in exosomes isolated from the serum of PCa patients compared to healthy individuals. Additionally, miR-204 and miR-222 displayed correlated expression patterns in prostate tumors (Pearson R = 0.66, p < 0.0001) by The Cancer Genome Atlas (TCGA) prostate adenocarcinoma (PRAD) genomic dataset analysis. Overall, the present study identified unique miRNAs with differential expression in exosomes secreted from hypoxic PCa cells and suggests their potential usefulness as a biomarker of hypoxia in PCa patients. PMID:29568403

Targeted metabolomics: new insights into pathobiology of retained placenta in dairy cows and potential risk biomarkers.

PubMed

Dervishi, E; Zhang, G; Mandal, R; Wishart, D S; Ametaj, B N

2018-05-01

A targeted quantitative metabolomics approach was used to study temporal changes of serum metabolites in cows that normally released their fetal membranes and those that retained the placenta. We identified and measured serum concentrations of 128 metabolites including amino acids, acylcarnitines, biogenic amines, glycerophospholipids, sphingolipids and hexose at -8 and -4 weeks before parturition, during the week of retained placenta (RP) diagnosis, and at +4 and +8 weeks after parturition. In addition, we aimed at identifying metabolite signatures of pre-RP in the serum that might be used as predictive biomarkers for risk of developing RP in dairy cows. Results revealed major alterations in the metabolite fingerprints of pre-RP cows starting as early as -8 weeks before parturition and continuing as far as +8 weeks after calving. Biomarker candidates found in this study are mainly biomarkers of inflammation which might not be specific to RP. Therefore, the relevance of serum Lys, Orn, acetylornithine, lysophophatidylcholine LysoPC a C28:0, Asp, Leu and Ile as potential serum biomarkers for prediction of risk of RP in dairy cows will have to be tested in the future. In addition, lower concentrations of LysoPCs, Trp, and higher kynurenine in the serum during prepartum and the week of occurrence of RP suggest involvement of inflammation in the pathobiology of RP.

Accurate Quantification of Cardiovascular Biomarkers in Serum Using Protein Standard Absolute Quantification (PSAQ™) and Selected Reaction Monitoring*

PubMed Central

Huillet, Céline; Adrait, Annie; Lebert, Dorothée; Picard, Guillaume; Trauchessec, Mathieu; Louwagie, Mathilde; Dupuis, Alain; Hittinger, Luc; Ghaleh, Bijan; Le Corvoisier, Philippe; Jaquinod, Michel; Garin, Jérôme; Bruley, Christophe; Brun, Virginie

2012-01-01

Development of new biomarkers needs to be significantly accelerated to improve diagnostic, prognostic, and toxicity monitoring as well as therapeutic follow-up. Biomarker evaluation is the main bottleneck in this development process. Selected Reaction Monitoring (SRM) combined with stable isotope dilution has emerged as a promising option to speed this step, particularly because of its multiplexing capacities. However, analytical variabilities because of upstream sample handling or incomplete trypsin digestion still need to be resolved. In 2007, we developed the PSAQ™ method (Protein Standard Absolute Quantification), which uses full-length isotope-labeled protein standards to quantify target proteins. In the present study we used clinically validated cardiovascular biomarkers (LDH-B, CKMB, myoglobin, and troponin I) to demonstrate that the combination of PSAQ and SRM (PSAQ-SRM) allows highly accurate biomarker quantification in serum samples. A multiplex PSAQ-SRM assay was used to quantify these biomarkers in clinical samples from myocardial infarction patients. Good correlation between PSAQ-SRM and ELISA assay results was found and demonstrated the consistency between these analytical approaches. Thus, PSAQ-SRM has the capacity to improve both accuracy and reproducibility in protein analysis. This will be a major contribution to efficient biomarker development strategies. PMID:22080464

Prioritization of biomarker targets in human umbilical cord blood: identification of proteins in infant blood serving as validated biomarkers in adults.

PubMed

Hansmeier, Nicole; Chao, Tzu-Chiao; Goldman, Lynn R; Witter, Frank R; Halden, Rolf U

2012-05-01

Early diagnosis represents one of the best lines of defense in the fight against a wide array of human diseases. Umbilical cord blood (UCB) is one of the first easily available diagnostic biofluids and can inform about the health status of newborns. However, compared with adult blood, its diagnostic potential remains largely untapped. Our goal was to accelerate biomarker research on UCB by exploring its detectable protein content and providing a priority list of potential biomarkers based on known proteins involved in disease pathways. We explored cord blood serum proteins by profiling a UCB pool of 12 neonates with different backgrounds using a combination of isoelectric focusing and liquid chromatography coupled with matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) and by comparing results with information contained in metabolic and disease databases available for adult blood. A total of 1,210 UCB proteins were identified with a protein-level false discovery rate of ~ 5% as estimated by naïve target-decoy and MAYU approaches, signifying a 6-fold increase in the number of UCB proteins described to date. Identified proteins correspond to 138 different metabolic and disease pathways and provide a platform of mechanistically linked biomarker candidates for tracking disruptions in cellular processes. Moreover, among the identified proteins, 38 were found to be approved biomarkers for adult blood. The results of this study advance current knowledge of the human cord blood serum proteome. They showcase the potential of UCB as a diagnostic medium for assessing infant health by detection and identification of candidate biomarkers for known disease pathways using a global, nontargeted approach. These biomarkers may inform about mechanisms of exposure-disease relationships. Furthermore, biomarkers approved by the U.S. Food and Drug Administration for screening in adult blood were detected in UCB and represent high-priority targets for

Multiplexed Immunoassay Panel Identifies Novel CSF Biomarkers for Alzheimer's Disease Diagnosis and Prognosis

PubMed Central

Craig-Schapiro, Rebecca; Kuhn, Max; Xiong, Chengjie; Pickering, Eve H.; Liu, Jingxia; Misko, Thomas P.; Perrin, Richard J.; Bales, Kelly R.; Soares, Holly; Fagan, Anne M.; Holtzman, David M.

2011-01-01

Background Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ∼10–15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Aβ42, tau, p-tau181). Methods and Findings Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-α, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Aβ42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Aβ42, and age. Conclusions/Significance Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best

Use of a Combination Biomarker Algorithm To Identify Medical Intensive Care Unit Patients with Suspected Sepsis at Very Low Likelihood of Bacterial Infection

PubMed Central

Nachamkin, Irving; Coffin, Susan E.; Gerber, Jeffrey S.; Fuchs, Barry; Garrigan, Charles; Han, Xiaoyan; Bilker, Warren B.; Wise, Jacqueleen; Tolomeo, Pam; Lautenbach, Ebbing

2015-01-01

Sepsis remains a diagnostic challenge in the intensive care unit (ICU), and the use of biomarkers may help in differentiating bacterial sepsis from other causes of systemic inflammatory syndrome (SIRS). The goal of this study was to assess test characteristics of a number of biomarkers for identifying ICU patients with a very low likelihood of bacterial sepsis. A prospective cohort study was conducted in a medical ICU of a university hospital. Immunocompetent patients with presumed bacterial sepsis were consecutively enrolled from January 2012 to May 2013. Concentrations of nine biomarkers (α-2 macroglobulin, C-reactive protein [CRP], ferritin, fibrinogen, haptoglobin, procalcitonin [PCT], serum amyloid A, serum amyloid P, and tissue plasminogen activator) were determined at baseline and at 24 h, 48 h, and 72 h after enrollment. Performance characteristics were calculated for various combinations of biomarkers for discrimination of bacterial sepsis from other causes of SIRS. Seventy patients were included during the study period; 31 (44%) had bacterial sepsis, and 39 (56%) had other causes of SIRS. PCT and CRP values were significantly higher at all measured time points in patients with bacterial sepsis. A number of combinations of PCT and CRP, using various cutoff values and measurement time points, demonstrated high negative predictive values (81.1% to 85.7%) and specificities (63.2% to 79.5%) for diagnosing bacterial sepsis. Combinations of PCT and CRP demonstrated a high ability to discriminate bacterial sepsis from other causes of SIRS in medical ICU patients. Future studies should focus on the use of these algorithms to improve antibiotic use in the ICU setting. PMID:26239984

Mechanistic Biomarkers in Acetaminophen-induced Hepatotoxicity and Acute Liver Failure: From Preclinical Models to Patients

PubMed Central

McGill, Mitchell R.; Jaeschke, Hartmut

2015-01-01

SUMMARY Introduction Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models to humans. Areas covered We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermdiates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury. Expert Opinion Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis, and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets. PMID:24836926

A CONCISE PANEL OF BIOMARKERS IDENTIFIES NEUROCOGNITIVE FUNCTIONING CHANGES IN HIV-INFECTED INDIVIDUALS

PubMed Central

Marcotte, Thomas D.; Deutsch, Reena; Michael, Benedict Daniel; Franklin, Donald; Cookson, Debra Rosario; Bharti, Ajay R.; Grant, Igor; Letendre, Scott L.

2013-01-01

Background Neurocognitive (NC) impairment (NCI) occurs commonly in people living with HIV. Despite substantial effort, no biomarkers have been sufficiently validated for diagnosis and prognosis of NCI in the clinic. The goal of this project was to identify diagnostic or prognostic biomarkers for NCI in a comprehensively characterized HIV cohort. Methods Multidisciplinary case review selected 98 HIV-infected individuals and categorized them into four NC groups using normative data: stably normal (SN), stably impaired (SI), worsening (Wo), or improving (Im). All subjects underwent comprehensive NC testing, phlebotomy, and lumbar puncture at two timepoints separated by a median of 6.2 months. Eight biomarkers were measured in CSF and blood by immunoassay. Results were analyzed using mixed model linear regression and staged recursive partitioning. Results At the first visit, subjects were mostly middle-aged (median 45) white (58%) men (84%) who had AIDS (70%). Of the 73% who took antiretroviral therapy (ART), 54% had HIV RNA levels below 50 c/mL in plasma. Mixed model linear regression identified that only MCP-1 in CSF was associated with neurocognitive change group. Recursive partitioning models aimed at diagnosis (i.e., correctly classifying neurocognitive status at the first visit) were complex and required most biomarkers to achieve misclassification limits. In contrast, prognostic models were more efficient. A combination of three biomarkers (sCD14, MCP-1, SDF-1α) correctly classified 82% of Wo and SN subjects, including 88% of SN subjects. A combination of two biomarkers (MCP-1, TNF-α) correctly classified 81% of Im and SI subjects, including 100% of SI subjects. Conclusions This analysis of well-characterized individuals identified concise panels of biomarkers associated with NC change. Across all analyses, the two most frequently identified biomarkers were sCD14 and MCP-1, indicators of monocyte/macrophage activation. While the panels differed depending on

Favorable modulation of benign breast tissue and serum risk biomarkers is associated with > 10 % weight loss in postmenopausal women.

PubMed

Fabian, Carol J; Kimler, Bruce F; Donnelly, Joseph E; Sullivan, Debra K; Klemp, Jennifer R; Petroff, Brian K; Phillips, Teresa A; Metheny, Trina; Aversman, Sonya; Yeh, Hung-Wen; Zalles, Carola M; Mills, Gordon B; Hursting, Stephen D

2013-11-01

We conducted a phase II feasibility study of a 6-month behavioral weight loss intervention in postmenopausal overweight and obese women at increased risk for breast cancer and the effects of weight loss on anthropomorphic, blood, and benign breast tissue biomarkers. 67 women were screened by random peri-areolar fine-needle aspiration, 27 were registered and 24 participated in the interventional phase. The 24 biomarker evaluable women had a median baseline BMI of 34.2 kg/m(2) and lost a median of 11 % of their initial weight. Significant tissue biomarker modulation after the 6-month intervention was noted for Ki-67 (if restricted to the 15 women with any Ki-67 at baseline, p = 0.041), adiponectin to leptin ratio (p = 0.003); and cyclin B1 (p = 0.001), phosphorylated retinoblastoma (p = 0.005), and ribosomal S6 (p = 0.004) proteins. Favorable modulation for serum markers was observed for sex hormone-binding globulin (p < 0.001), bioavailable estradiol (p < 0.001), bioavailable testosterone (p = 0.033), insulin (p = 0.018), adiponectin (p = 0.001), leptin (p < 0.001), the adiponectin to leptin ratio (p < 0.001), C-reactive protein (p = 0.002), and hepatocyte growth factor (p = 0.011). When subdivided by <10 or >10 % weight loss, change in percent total body and android (visceral) fat, physical activity, and the majority of the serum and tissue biomarkers were significantly modulated only for women with >10 % weight loss from baseline. Some factors such as serum PAI-1 and breast tissue pS2 (estrogen-inducible gene) mRNA were not significantly modulated overall but were when considering only those with >10 % weight loss. In conclusion, a median weight loss of 11 % over 6 months resulted in favorable modulation of a number of anthropomorphic, breast tissue and serum risk and mechanistic markers. Weight loss of 10 % or more should likely be the goal for breast cancer risk reduction studies in obese women.

ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1)

PubMed Central

Kunde, Dale A.; Taylor, Robyn L.; Pyecroft, Stephen B.; Sohal, Sukhwinder Singh; Snow, Elizabeth T.

2017-01-01

Devil Facial Tumour 1 (DFT1) is one of two transmissible neoplasms of Tasmanian devils (Sarcophilus harrisii) predominantly affecting their facial regions. DFT1’s cellular origin is that of Schwann cell lineage where lesions are evident macroscopically late in the disease. Conversely, the pre-clinical timeframe from cellular transmission to appearance of DFT1 remains uncertain demonstrating the importance of an effective pre-clinical biomarker. We show that ERBB3, a marker expressed normally by the developing neural crest and Schwann cells, is immunohistohemically expressed by DFT1, therefore the potential of ERBB3 as a biomarker was explored. Under the hypothesis that serum ERBB3 levels may increase as DFT1 invades local and distant tissues our pilot study determined serum ERBB3 levels in normal Tasmanian devils and Tasmanian devils with DFT1. Compared to the baseline serum ERBB3 levels in unaffected Tasmanian devils, Tasmanian devils with DFT1 showed significant elevation of serum ERBB3 levels. Interestingly Tasmanian devils with cutaneous lymphoma (CL) also showed elevation of serum ERBB3 levels when compared to the baseline serum levels of Tasmanian devils without DFT1. Thus, elevated serum ERBB3 levels in otherwise healthy looking devils could predict possible DFT1 or CL in captive or wild devil populations and would have implications on the management, welfare and survival of Tasmanian devils. ERBB3 is also a therapeutic target and therefore the potential exists to consider modes of administration that may eradicate DFT1 from the wild. PMID:28591206

Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer.

PubMed

Wang, Ying-Nai; Lee, Heng-Huan; Chou, Chao-Kai; Yang, Wen-Hao; Wei, Yongkun; Chen, Chun-Te; Yao, Jun; Hsu, Jennifer L; Zhu, Cihui; Ying, Haoqiang; Ye, Yuanqing; Wang, Wei-Jan; Lim, Seung-Oe; Xia, Weiya; Ko, How-Wen; Liu, Xiuping; Liu, Chang-Gong; Wu, Xifeng; Wang, Huamin; Li, Donghui; Prakash, Laura R; Katz, Matthew H; Kang, Yaan; Kim, Michael; Fleming, Jason B; Fogelman, David; Javle, Milind; Maitra, Anirban; Hung, Mien-Chie

2018-04-09

Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families. Copyright © 2018 Elsevier Inc. All rights reserved.

Computational analysis identifies putative prognostic biomarkers of pathological scarring in skin wounds.

PubMed

Nagaraja, Sridevi; Chen, Lin; DiPietro, Luisa A; Reifman, Jaques; Mitrophanov, Alexander Y

2018-02-20

Pathological scarring in wounds is a prevalent clinical outcome with limited prognostic options. The objective of this study was to investigate whether cellular signaling proteins could be used as prognostic biomarkers of pathological scarring in traumatic skin wounds. We used our previously developed and validated computational model of injury-initiated wound healing to simulate the time courses for platelets, 6 cell types, and 21 proteins involved in the inflammatory and proliferative phases of wound healing. Next, we analysed thousands of simulated wound-healing scenarios to identify those that resulted in pathological (i.e., excessive) scarring. Then, we identified candidate proteins that were elevated (or decreased) at the early stages of wound healing in those simulations and could therefore serve as predictive biomarkers of pathological scarring outcomes. Finally, we performed logistic regression analysis and calculated the area under the receiver operating characteristic curve to quantitatively assess the predictive accuracy of the model-identified putative biomarkers. We identified three proteins (interleukin-10, tissue inhibitor of matrix metalloproteinase-1, and fibronectin) whose levels were elevated in pathological scars as early as 2 weeks post-wounding and could predict a pathological scarring outcome occurring 40 days after wounding with 80% accuracy. Our method for predicting putative prognostic wound-outcome biomarkers may serve as an effective means to guide the identification of proteins predictive of pathological scarring.

Influence of Long-Distance Bicycle Riding on Serum/Urinary Biomarkers of Prostate Cancer

PubMed Central

Heger, Zbynek; Gumulec, Jaromir; Ondrak, Ales; Skoda, Jan; Zitka, Zdenek; Cernei, Natalia; Masarik, Michal; Zitka, Ondrej; Adam, Vojtech

2016-01-01

Herein, we present a study focused on the determination of the influence of long-distance (53 km) bicycle riding on levels of chosen biochemical urinary and serum prostate cancer (PCa) biomarkers total prostate-specific antigen (tPSA), free PSA (fPSA) and sarcosine. Fourteen healthy participants with no evidence of prostate diseases, in the age range from 49–57 years with a median of 52 years, underwent physical exercise (mean race time of 150 ± 20 min, elevation increase of 472 m) and pre- and post-ride blood/urine sampling. It was found that bicycle riding resulted in elevated serum uric acid (p = 0.001, median 271.76 vs. 308.44 µmol/L pre- and post-ride, respectively), lactate (p = 0.01, median 2.98 vs. 4.8 mmol/L) and C-reactive protein (p = 0.01, 0.0–0.01 mg/L). It is noteworthy that our work supports the studies demonstrating an increased PSA after mechanical manipulation of the prostate. The subjects exhibited either significantly higher post-ride tPSA (p = 0.002, median 0.69 vs. 1.1 ng/mL pre- and post-ride, respectively) and fPSA (p = 0.028, median 0.25 vs. 0.35 ng/mL). Contrary to that, sarcosine levels were not significantly affected by physical exercise (p = 0.20, median 1.64 vs. 1.92 µmol/mL for serum sarcosine, and p = 0.15, median 0.02 µmol/mmol of creatinine vs. 0.01 µmol/mmol of creatinine for urinary sarcosine). Taken together, our pilot study provides the first evidence that the potential biomarker of PCa—sarcosine does not have a drawback by means of a bicycle riding-induced false positivity, as was shown in the case of PSA. PMID:26999116

The Potential Biomarkers to Identify the Development of Steatosis in Hyperuricemia

PubMed Central

He, Xiaojuan; Lu, Cheng; He, Bing; Niu, Xuyan; Xiao, Cheng; Xu, Gang; Bian, Zhaoxiang; Zu, Xianpeng; Zhang, Ge; Zhang, Weidong; Lu, Aiping

2016-01-01

Hyperuricemia (HU) often progresses to combine with non-alcoholic fatty liver disease (NAFLD) in the clinical scenario, which further exacerbates metabolic disorders; early detection of biomarkers, if obtained during the HU progression, may be beneficial for preventing its combination with NAFLD. This study aimed to decipher the biomarkers and mechanisms of the development of steatosis in HU. Four groups of subjects undergoing health screening, including healthy subjects, subjects with HU, subjects with HU combined with NAFLD (HU+NAFLD) and subjects with HU initially and then with HU+NAFLD one year later (HU→HU+NAFLD), were recruited in this study. The metabolic profiles of all subjects’ serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry. The metabolomic data from subjects with HU and HU+NAFLD were compared, and the biomarkers for the progression from HU to HU+NAFLD were predicted. The metabolomic data from HU→HU+NAFLD subjects were collected for further verification. The results showed that the progression was associated with disturbances of phospholipase metabolism, purine nucleotide degradation and Liver X receptor/retinoic X receptor activation as characterized by up-regulated phosphatidic acid, cholesterol ester (18:0) and down-regulated inosine. These metabolic alterations may be at least partially responsible for the development of steatosis in HU. This study provides a new paradigm for better understanding and further prevention of disease progression. PMID:26890003

Correlation of spleen metabolism assessed by 18F-FDG PET with serum interleukin-2 receptor levels and other biomarkers in patients with untreated sarcoidosis.

PubMed

Kalkanis, Alexandros; Kalkanis, Dimitrios; Drougas, Dimitrios; Vavougios, George D; Datseris, Ioannis; Judson, Marc A; Georgiou, Evangelos

2016-03-01

The objective of our study was to assess the possible relationship between splenic F-18-fluorodeoxyglucose (18F-FDG) uptake and other established biochemical markers of sarcoidosis activity. Thirty treatment-naive sarcoidosis patients were prospectively enrolled in this study. They underwent biochemical laboratory tests, including serum interleukin-2 receptor (sIL-2R), serum C-reactive protein, serum angiotensin-I converting enzyme, and 24-h urine calcium levels, and a whole-body combined 18F-FDG PET/computed tomography (PET/CT) scan as a part of an ongoing study at our institute. These biomarkers were statistically compared in these patients. A statistically significant linear dependence was detected between sIL-2R and log-transformed spleen-average standard uptake value (SUV avg) (R2=0.488, P<0.0001) and log-transformed spleen-maximum standard uptake value (SUV max) (R2=0.490, P<0.0001). sIL-2R levels and splenic size correlated linearly (Pearson's r=0.373, P=0.042). Multivariate linear regression analysis revealed that this correlation remained significant after age and sex adjustment (β=0.001, SE=0.001, P=0.024). No statistically significant associations were detected between (a) any two serum biomarkers or (b) between spleen-SUV measurements and any serum biomarker other than sIL-2R. Our analysis revealed an association between sIL-2R levels and spleen 18F-FDG uptake and size, whereas all other serum biomarkers were not significantly associated with each other or with PET 18F-FDG uptake. Our results suggest that splenic inflammation may be related to the systemic inflammatory response in sarcoidosis that may be associated with elevated sIL-2R levels.

Assessment of aflatoxin exposure using serum and urinary biomarkers in São Paulo, Brazil: A pilot study.

PubMed

Jager, Alessandra V; Tonin, Fernando G; Baptista, Gabriela Z; Souto, Pollyana C M C; Oliveira, Carlos A F

2016-05-01

The aim of this study was to evaluate the human exposure of individuals from Pirassununga, Brazil, to dietary aflatoxins B1 (AFB1) and M1 (AFM1) by determination of serum AFB1-lysine and urinary aflatoxin biomarkers (AFM1 and AFB1-N(7)-guanine). The participants were recruited among employees from a Campus of the University of São Paulo, which provided food samples from their homes, as well as serum and urine samples four times every three months, from June 2011 until March 2012. The probable daily intake (PDI) of aflatoxin was estimated by using the results from analysis of food products collected by the time of samples collection, and data from a 24-hour dietary recall questionnaire. Analyses of AFB1 and AFM1 in food samples were conducted by high-performance liquid chromatography with fluorescence detection. Biomarkers in serum and urine were determined by tandem mass spectrometry. AFB1 and AFM1 were detected in 38 samples of cereals (28%, N=136) and 31 milk products (36%, N=86), respectively. AFB1-lysine and AFB1-N(7)-guanine and were not detected in serum or urine samples, respectively. However, AFM1 was found in 74 urine samples (65%), at mean levels in the 4 sampling times ranging from 0.37±0.23 to 1.70±2.88pg/mg creatinine. The mean PDI varied among different sampling times, ranging from 0.09±0.09 to 1.35±5.98ng/kg body weight/day. A modest though significant correlation (r=0.45; p=0.03; N=23) was found for the first time in Brazil between the AFM1 concentration in urine and the PDI for total aflatoxins (AFB1+AFM1) in sampling 1 (June 2011). Urinary AFM1 was confirmed as very sensitive for monitoring the human exposure to dietary aflatoxin. Further studies using serum and urinary biomarkers are needed to estimate the aflatoxin exposure of populations in higher risk areas in Brazil. Copyright © 2015 Elsevier GmbH. All rights reserved.

Serum miR-206 and other muscle-specific microRNAs as non-invasive biomarkers for Duchenne muscular dystrophy.

PubMed

Hu, Jun; Kong, Min; Ye, Yuanzhen; Hong, Siqi; Cheng, Li; Jiang, Li

2014-06-01

Creatine kinase has been utilized as a diagnostic marker for Duchenne muscular dystrophy (DMD), but it correlates less well with the DMD pathological progression. In this study, we hypothesized that muscle-specific microRNAs (miR-1, -133, and -206) in serum may be useful for monitoring the DMD pathological progression, and explored the possibility of these miRNAs as potential non-invasive biomarkers for the disease. By using real-time quantitative reverse transcription-polymerase chain reaction in a randomized and controlled trial, we detected that miR-1, -133, and -206 were significantly over-expressed in the serum of 39 children with DMD (up to 3.20 ± 1.20, 2(-ΔΔCt) ): almost 2- to 4-fold enriched in comparison to samples from the healthy controls (less than 1.15 ± 0.34, 2(-ΔΔCt) ). To determine whether these miRNAs were related to the clinical features of children with DMD, we analyzed the associations compared to creatine kinase. There were very good inverse correlations between the levels of these miRNAs, especially miR-206, and functional performances: high levels corresponded to low muscle strength, muscle function, and quality of life. Moreover, by receiver operating characteristic curves analyses, we revealed that these miRNAs, especially miR-206, were able to discriminate DMD from controls. Thus, miR-206 and other muscle-specific miRNAs in serum are useful for monitoring the DMD pathological progression, and hence as potential non-invasive biomarkers for the disease. There has been a long-standing need for reliable, non-invasive biomarkers for Duchenne muscular dystrophy (DMD). We found that the levels of muscle-specific microRNAs, especially miR-206, in the serum of DMD were 2- to 4-fold higher than in the controls. High levels corresponded to low muscle strength, muscle function, and quality of life (QoL). These miRNAs were able to discriminate DMD from controls by receiver operating characteristic (ROC) curves analyses. Thus, miR-206 and other

Serum sphinganine and the sphinganine to sphingosine ratio as a biomarker of dietary fumonisins during chronic exposure in ducks.

PubMed

Tran, S T; Tardieu, D; Auvergne, A; Bailly, J D; Babilé, R; Durand, S; Benard, G; Guerre, P

2006-03-10

Sphinganine concentration (Sa) and sphinganine to sphingosine ratio (Sa/So) are sensitive biomarkers of fumonisin B1 (FB1) exposure in animals and have been proposed to reveal FB1 exposure in humans. They correlate with liver and kidney toxicity and often precede signs of toxicity. However, the use of Sa and Sa/So is confusing during chronic exposure. Indeed, some authors report altered sphingolipids metabolism, whereas others fail to demonstrate significant effect. The aim of this study was to investigate the kinetics of Sa and Sa/So in the serum of ducks over a 77-day exposure to 0, 2, 8, 32 and 128 mg FB1/kg feeds. Serum biochemistry was also investigated to reveal hepatotoxicity. The results obtained indicate that the kinetics of sphingolipids and serum biochemistry are closely linked with the duration of the exposure. After a strong and rapid increase Sa and Sa/So decrease then stabilize. The lowest investigated dose able to determine a detectable effect is 2 mg/kg feeds, the Sa/So ratio being the most sensitive biomarker of FB1 exposure.

Serum levels of adiponectin and leptin as biomarkers of proteinuria in lupus nephritis

PubMed Central

Sanchez-Mosco, Dalia; Fajardo-Robledo, Nicte S.; Perez-Guerrero, Edsaul E.; Rodriguez-Jimenez, N. Alejandra; Saldaña-Cruz, A. Miriam; Vazquez-Villegas, M. Luisa; Gomez-Bañuelos, Eduardo; Vazquez-Del Mercado, Monica; Cardona-Muñoz, E. German; Cardona-Muller, David; Trujillo, Xochitl; Huerta, Miguel; Salazar-Paramo, Mario

2017-01-01

Introduction There are controversial results about the role of serum leptin and adiponectin levels as biomarkers of the severity of proteinuria in lupus nephritis. Objective The aim of this study was to evaluate the relationship between serum leptin and adiponectin levels with severity of proteinuria secondary to lupus nephritis (LN). Methods In a cross-sectional study, 103 women with systemic lupus erythematosus (SLE) were evaluated for kidney involvement. We compared 30 SLE patients with LN, all of them with proteinuria, versus 73 SLE patients without renal involvement (no LN). A comprehensive set of clinical and laboratory variables was assessed, including serum levels of leptin and adiponectin by ELISA. Multivariate analyses were used to adjust for potential confounders associated with proteinuria in LN. Results We found higher adiponectin levels in the LN group compared with the no LN group (20.4 ± 10.3 vs 15.6 ± 7.8 μg/mL; p = 0.02), whereas no differences were observed in leptin levels (33.3 ± 31.4 vs 22.5 ± 25.5 ng/mL; p = 0.07). Severity of proteinuria correlated with an increase in adiponectin levels (r = 0.31; p = 0.001), but no correlation was observed with leptin. Adiponectin levels were not related to anti-dsDNA or anti-nucleosome antibodies. In the logistic regression, adiponectin levels were associated with a high risk of proteinuria in SLE (OR = 1.06; 95% CI 1.01–1.12; p = 0.02). Instead, leptin was not associated with LN. Conclusion These findings indicate that adiponectin levels are useful markers associated with proteinuria in LN. Further longitudinal studies are required to identify if these levels are predictive of renal relapse. PMID:28898254

Evaluation of Serum Vascular Adhesion Protein-1 as a Potential Biomarker in Thyroid Cancer

PubMed Central

Zhao, Pengxin; Zhang, Kaili

2016-01-01

Vascular adhesion protein-1 (VAP-1) is a glycoprotein that mediates tissue-selective lymphocyte adhesion. The prognostic value of VAP-1 has been determined in gastric cancer. The aim of this study was to evaluate the changes and the predictive value of serum VAP-1 in patients with thyroid cancer. A total of 126 patients with thyroid nodules and 53 healthy controls participated in this study. The patients were further divided into subgroup 1 (69 cases with benign thyroid nodules) and subgroup 2 (57 cases with thyroid cancer). Serum VAP-1 was measured by time-resolved immunofluorometric assay. Diagnostic value of presurgical VAP-1 for thyroid cancer was conducted by receiver operating characteristic (ROC) curves. Serum levels of VAP-1 were significantly lower in thyroid cancer group than in healthy control and benign thyroid nodule groups. VAP-1 concentrations negatively correlated with serum thyroglobulin (Tg) levels in thyroid cancer patients (r = −0.81; p < 0.001). The optimum cut-off value of VAP-1 was 456.6 ng/mL with a 77.4% specificity and 66.7% sensitivity for thyroid cancer diagnosis. Serum VAP-1 decreased in thyroid cancer patients and VAP-1 could be a potential useful adjunct biomarker in the diagnosis of thyroid cancer. PMID:27446209

Identification of Tetranectin as a Potential Biomarker for Metastatic Oral Cancer

PubMed Central

Arellano-Garcia, Martha E.; Li, Roger; Liu, Xiaojun; Xie, Yongming; Yan, Xiaofei; Loo, Joseph A.; Hu, Shen

2010-01-01

Lymph node involvement is the most important predictor of survival rates in patients with oral squamous cell carcinoma (OSCC). A biomarker that can indicate lymph node metastasis would be valuable to classify patients with OSCC for optimal treatment. In this study, we have performed a serum proteomic analysis of OSCC using 2-D gel electrophoresis and liquid chromatography/tandem mass spectrometry. One of the down-regulated proteins in OSCC was identified as tetranectin, which is a protein encoded by the CLEC3B gene (C-type lectin domain family 3, member B). We further tested the protein level in serum and saliva from patients with lymph-node metastatic and primary OSCC. Tetranectin was found significantly under-expressed in both serum and saliva of metastatic OSCC compared to primary OSCC. Our results suggest that serum or saliva tetranectin may serve as a potential biomarker for metastatic OSCC. Other candidate serum biomarkers for OSCC included superoxide dismutase, ficolin 2, CD-5 antigen-like protein, RalA binding protein 1, plasma retinol-binding protein and transthyretin. Their clinical utility for OSCC detection remains to be further tested in cancer patients. PMID:20957082

Comparing metabolite profiles of habitual diet in serum and urine123

PubMed Central

Playdon, Mary C; Sampson, Joshua N; Cross, Amanda J; Sinha, Rashmi; Guertin, Kristin A; Moy, Kristin A; Rothman, Nathaniel; Irwin, Melinda L; Mayne, Susan T; Stolzenberg-Solomon, Rachael; Moore, Steven C

2016-01-01

Background: Diet plays an important role in chronic disease etiology, but some diet-disease associations remain inconclusive because of methodologic limitations in dietary assessment. Metabolomics is a novel method for identifying objective dietary biomarkers, although it is unclear what dietary information is captured from metabolites found in serum compared with urine. Objective: We compared metabolite profiles of habitual diet measured from serum with those measured from urine. Design: We first estimated correlations between consumption of 56 foods, beverages, and supplements assessed by a food-frequency questionnaire, with 676 serum and 848 urine metabolites identified by untargeted liquid chromatography mass spectrometry, ultra-high performance liquid chromatography tandem mass spectrometry, and gas chromatography mass spectrometry in a colon adenoma case–control study (n = 125 cases and 128 controls) while adjusting for age, sex, smoking, fasting, case-control status, body mass index, physical activity, education, and caloric intake. We controlled for multiple comparisons with the use of a false discovery rate of <0.1. Next, we created serum and urine multiple-metabolite models to predict food intake with the use of 10-fold crossvalidation least absolute shrinkage and selection operator regression for 80% of the data; predicted values were created in the remaining 20%. Finally, we compared predicted values with estimates obtained from self-reported intake for metabolites measured in serum and urine. Results: We identified metabolites associated with 46 of 56 dietary items; 417 urine and 105 serum metabolites were correlated with ≥1 food, beverage, or supplement. More metabolites in urine (n = 154) than in serum (n = 39) were associated uniquely with one food. We found previously unreported metabolite associations with leafy green vegetables, sugar-sweetened beverages, citrus, added sugar, red meat, shellfish, desserts, and wine. Prediction of dietary

Mining the Immune Cell Proteome to Identify Ovarian Cancer-Specific Biomarkers

DTIC Science & Technology

2012-03-01

data and are in the process of identifying gene signatures that can be used as biomarkers for the identification of ovarian cancer-specific biomarkers...groups. The groups showed significant difference in age as well as gestational age, which is expected when considering the disease process . Isolation of...MUC4 in intracellular signaling.32 Oligosaccharides attached to the extracellular domains of mucins have also been shown to interact with different

Increased Kappa/Lambda Hybrid Antibody in Serum Is a Novel Biomarker Related to Disease Activity and Inflammation in Rheumatoid Arthritis.

PubMed

Yi, Lang; Hao, Mingju; Lu, Tian; Lin, Guigao; Chen, Lida; Gao, Ming; Fan, Gaowei; Zhang, Dong; Wang, Guojing; Yang, Xin; Li, Yulong; Zhang, Kuo; Zhang, Rui; Han, Yanxi; Wang, Lunan; Li, Jinming

2016-01-01

The κ/λ hybrid antibodies in normal human serum were reported recently, but their clinical relevance has not yet been explored. Rheumatoid arthritis (RA) is one of the major joint diseases, and the early diagnosis and treatment of RA remain a challenge. Here, we developed a double-sandwich enzyme-linked immunosorbent assay system to quantify relative serum κ/λ hybrid antibody levels in RA patients, osteoarthritis (OA) patients, and healthy controls (HC) in order to assess their potential use as a serological biomarker of early disease and clinical activity and to preliminarily investigate their immunomodulatory roles in RA. Surprisingly, we found that κ/λ hybrid antibody was markedly increased in both early and established RA. Serum κ/λ hybrid antibody levels were significantly correlated with clinical indexes and inflammatory markers in RA. Further analysis showed a positive correlation between κ/λ hybrid antibody levels and the 28-joint disease activity score (DAS28). In conclusion, serum κ/λ hybrid antibodies in RA were identified for the first time. High levels of κ/λ hybrid antibody may be a useful tool in distinguishing early RA from OA and HC. We suggest κ/λ hybrid antibody as a marker for disease activity. The increased κ/λ hybrid antibodies were associated with inflammatory conditions in RA.

Increased Kappa/Lambda Hybrid Antibody in Serum Is a Novel Biomarker Related to Disease Activity and Inflammation in Rheumatoid Arthritis

PubMed Central

Yi, Lang; Hao, Mingju; Lu, Tian; Lin, Guigao; Chen, Lida; Gao, Ming; Fan, Gaowei; Zhang, Dong; Wang, Guojing; Yang, Xin; Li, Yulong; Zhang, Kuo; Zhang, Rui; Han, Yanxi; Wang, Lunan; Li, Jinming

2016-01-01

The κ/λ hybrid antibodies in normal human serum were reported recently, but their clinical relevance has not yet been explored. Rheumatoid arthritis (RA) is one of the major joint diseases, and the early diagnosis and treatment of RA remain a challenge. Here, we developed a double-sandwich enzyme-linked immunosorbent assay system to quantify relative serum κ/λ hybrid antibody levels in RA patients, osteoarthritis (OA) patients, and healthy controls (HC) in order to assess their potential use as a serological biomarker of early disease and clinical activity and to preliminarily investigate their immunomodulatory roles in RA. Surprisingly, we found that κ/λ hybrid antibody was markedly increased in both early and established RA. Serum κ/λ hybrid antibody levels were significantly correlated with clinical indexes and inflammatory markers in RA. Further analysis showed a positive correlation between κ/λ hybrid antibody levels and the 28-joint disease activity score (DAS28). In conclusion, serum κ/λ hybrid antibodies in RA were identified for the first time. High levels of κ/λ hybrid antibody may be a useful tool in distinguishing early RA from OA and HC. We suggest κ/λ hybrid antibody as a marker for disease activity. The increased κ/λ hybrid antibodies were associated with inflammatory conditions in RA. PMID:27143816

Vasorin is a potential serum biomarker and drug target of hepatocarcinoma screened by subtractive-EMSA-SELEX to clinic patient serum.

PubMed

Li, Shaohua; Li, Hui; Yang, Xiqin; Wang, Wei; Huang, Aixue; Li, Jie; Qin, Xingliang; Li, Fei; Lu, Guanyi; Ding, Hongmei; Su, Xueting; Hou, Lvbin; Xia, Wei; Shi, Ming; Zhang, Hongwen; Zhao, Qiang; Dong, Jie; Ge, Xingfeng; Sun, Leqiao; Bai, Chenjun; Wang, Chaonan; Shen, Xuelian; Fang, Tao; Wang, Fusheng; Zhang, Heqiu; Shao, Ningsheng

2015-04-30

We report a new biomarker of hepatocarcinoma, vasorin (VASN), screened by a subtractive EMSA-SELEX strategy from AFP negative serum of hepatocellular carcinoma (HCC) patients with extrahepatic metastases. VASN was verified to be highly expressed in sera of 100 cases of HCC patients compared with 97 cases of normal persons and 129 cases of hepatitis patients. Further validation by Q-PCR,IFA and Western blot showed higher expression of VASN at mRNA and protein levels in HCC cell lines and HCC tissues than in normal controls. RNA interference and forced overexpression assays verified that VASN promotes cell proliferation and migration and inhibits apoptosis. Down-regulation of microRNA miR145 and miR146a is an important mechanism leading to high expression of VASN. As a membrane protein and/or as free protein, VASN may be an effective target for biological treatment of liver cancer and is a potential biomarker for HCC diagnosis. Small molecular nucleotides targeting VASN are promising biological therapies to HCC.

Diagnostic value of lactate, procalcitonin, ferritin, serum-C-reactive protein, and other biomarkers in bacterial and viral meningitis: A cross-sectional study.

PubMed

Sanaei Dashti, Anahita; Alizadeh, Shekoofan; Karimi, Abdullah; Khalifeh, Masoomeh; Shoja, Seyed Abdolmajid

2017-09-01

There are many difficulties distinguishing bacterial from viral meningitis that could be reasonably solved using biomarkers. The aim of this study was to evaluate lactate, procalcitonin (PCT), ferritin, serum-CRP (C-reactive protein), and other known biomarkers in differentiating bacterial meningitis from viral meningitis in children.All children aged 28 days to 14 years with suspected meningitis who were admitted to Mofid Children's Hospital, Tehran, between October 2012 and November 2013, were enrolled in this prospective cross-sectional study. Children were divided into 2 groups of bacterial and viral meningitis, based on the results of cerebrospinal fluid (CSF) culture, polymerase chain reaction, and cytochemical profile. Diagnostic values of CSF parameters (ferritin, PCT, absolute neutrophil count [ANC], white blood cell count, and lactate) and serum parameters (PCT, ferritin, CRP, and erythrocyte sedimentation rate [ESR]) were evaluated.Among 50 patients with meningitis, 12 were diagnosed with bacterial meningitis. Concentrations of all markers were significantly different between bacterial and viral meningitis, except for serum (P = .389) and CSF (P = .136) PCT. The best rates of area under the receiver operating characteristic (ROC) curve (AUC) were achieved by lactate (AUC = 0.923) and serum-CRP (AUC = 0.889). The best negative predictive values (NPV) for bacterial meningitis were attained by ANC (100%) and lactate (97.1%).The results of our study suggest that ferritin and PCT are not strong predictive biomarkers. A combination of low CSF lactate, ANC, ESR, and serum-CRP could reasonably rule out the bacterial meningitis.

Immunological signature of the different clinical stages of the HTLV-1 infection: establishing serum biomarkers for HTLV-1-associated disease morbidity.

PubMed

Starling, Ana Lúcia Borges; Coelho-Dos-Reis, Jordana Grazziela Alves; Peruhype-Magalhães, Vanessa; Pascoal-Xavier, Marcelo Antônio; Gonçalves, Denise Utsch; Béla, Samantha Ribeiro; Lambertucci, José Roberto; Labanca, Ludimila; Souza Pereira, Silvio Roberto; Teixeira-Carvalho, Andréa; Ribas, João Gabriel; Trindade, Bruno Caetano; Faccioli, Lucia Helena; Carneiro-Proietti, Anna Bárbara Freitas; Martins-Filho, Olindo Assis

2015-01-01

This study aimed at establishing the immunological signature and an algorithm for clinical management of the different clinical stages of the HTLV-1-infection based on serum biomarkers. A panel of serum biomarkers was evaluated by four sets of innovative/non-conventional data analysis approaches in samples from 87 HTLV-1 patients: asymptomatic carriers (AC), putative HTLV-1 associated myelopathy/tropical spastic paraparesis (pHAM/TSP) and HAM/TSP. The analysis of cumulative curves and molecular signatures pointed out that HAM/TSP presented a pro-inflammatory profile mediated by CXCL10/LTB-4/IL-6/TNF-α/IFN-γ, counterbalanced by IL-4/IL-10. The analysis of biomarker networks showed that AC presented a strongly intertwined pro-inflammatory/regulatory net with IL-4/IL-10 playing a central role, while HAM/TSP exhibited overall immune response toward a predominant pro-inflammatory profile. At last, the classification and regression trees proposed for clinical practice allowed for the construction of an algorithm to discriminate AC, pHAM and HAM/TSP patients with the elected biomarkers: IFN-γ, TNF-α, IL-10, IL-6, IL-4 and CysLT. These findings reveal a complex interaction among chemokine/leukotriene/cytokine in HTLV-1 infection and suggest the use of the selected but combined biomarkers for the follow-up/diagnosis of disease morbidity of HTLV-1-infected individuals.

Use of a Combination Biomarker Algorithm To Identify Medical Intensive Care Unit Patients with Suspected Sepsis at Very Low Likelihood of Bacterial Infection.

PubMed

Han, Jennifer H; Nachamkin, Irving; Coffin, Susan E; Gerber, Jeffrey S; Fuchs, Barry; Garrigan, Charles; Han, Xiaoyan; Bilker, Warren B; Wise, Jacqueleen; Tolomeo, Pam; Lautenbach, Ebbing

2015-10-01

Sepsis remains a diagnostic challenge in the intensive care unit (ICU), and the use of biomarkers may help in differentiating bacterial sepsis from other causes of systemic inflammatory syndrome (SIRS). The goal of this study was to assess test characteristics of a number of biomarkers for identifying ICU patients with a very low likelihood of bacterial sepsis. A prospective cohort study was conducted in a medical ICU of a university hospital. Immunocompetent patients with presumed bacterial sepsis were consecutively enrolled from January 2012 to May 2013. Concentrations of nine biomarkers (α-2 macroglobulin, C-reactive protein [CRP], ferritin, fibrinogen, haptoglobin, procalcitonin [PCT], serum amyloid A, serum amyloid P, and tissue plasminogen activator) were determined at baseline and at 24 h, 48 h, and 72 h after enrollment. Performance characteristics were calculated for various combinations of biomarkers for discrimination of bacterial sepsis from other causes of SIRS. Seventy patients were included during the study period; 31 (44%) had bacterial sepsis, and 39 (56%) had other causes of SIRS. PCT and CRP values were significantly higher at all measured time points in patients with bacterial sepsis. A number of combinations of PCT and CRP, using various cutoff values and measurement time points, demonstrated high negative predictive values (81.1% to 85.7%) and specificities (63.2% to 79.5%) for diagnosing bacterial sepsis. Combinations of PCT and CRP demonstrated a high ability to discriminate bacterial sepsis from other causes of SIRS in medical ICU patients. Future studies should focus on the use of these algorithms to improve antibiotic use in the ICU setting. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Serum VEGF-C levels as a candidate biomarker of hypervolemia in chronic kidney disease

PubMed Central

Sahutoglu, Tuncay; Sakaci, Tamer; Hasbal, Nuri B.; Ahbap, Elbis; Kara, Ekrem; Sumerkan, Mutlu C.; Sevinc, Mustafa; Akgol, Cuneyt; Koc, Yener; Basturk, Taner; Unsal, Abdulkadir

2017-01-01

Abstract Attaining and maintaining optimal “dry weight” is one of the principal goals during maintenance hemodialysis (MHD). Recent studies have shown a close relationship between Na+ load and serum vascular endothelial growth factor-C (VEGF-C) levels; thus, we aimed to investigate the role of VEGF-C as a candidate biomarker of hypervolemia. Physical examination, basic laboratory tests, N-terminal pro b-type natriuretic peptide (NT-ProBNP), echocardiography, and bioimpedance spectroscopy data of 3 groups of study subjects (euvolemic MHD patients, healthy controls, and hypervolemic chronic kidney disease [CKD] patients) were analyzed. Research data for MHD patients were obtained both before the first and after the last hemodialysis (HD) sessions of the week. Data of 10 subjects from each study groups were included in the analysis. Serum VEGF-C levels were significantly higher in hypervolemic CKD versus in MHD patients both before the first and after the last HD sessions (P = .004 and P = .000, respectively). Healthy controls had serum VEGF-C levels similar to and higher than MHD patients before the first and after the last HD sessions of the week (P = .327 and P = .021, respectively). VEGF-C levels were correlated with bioimpedance spectroscopy results (r2 0.659, P = .000) and edema (r2 0.494, P =0.006), but not with ejection fraction (EF) (r2 −0.251, P = .134), blood pressures (systolic r2 0.037, P = 0.824, diastolic r2 −0.067, P = .691), and NT-ProBNP (r2 −0.047, P = .773). These findings suggest that serum VEGF-C levels could be a potential new biomarker of hypervolemia. The lack of correlation between VEGF-C and EF may hold a promise to eliminate this common confounder. Further studies are needed to define the clinical utility of VEGF-C in volume management. PMID:28471955

[Establishment of novel biomarkers for Personalized medication for atopic dermatitis].

PubMed

Ohta, Shoichiro; Taniguchi, Kazuto; Arima, Kazuhiko; Suzuki, Shoichi; Shiraishi, Hiroshi; Masuoka, Miho; Izuhara, Kenji

2013-03-01

To diagnose atopic dermatitis (AD), an appearance of eczema examined by experienced dermatologists is required. Therefore, biomarkers to diagnose AD or to reflect the severity of AD would be of a great use for non-specialists in the clinic or hospitals. We can apply such a biomarker for realization of personalized medicine for AD in the future. Interleukin-4 (IL-4) and IL-13 have been known to play important roles in the pathogenesis of allergic diseases including AD. In addition to these, we previously identified SCCA1, SCCA2, and periostin as IL-4/IL-13-inducible genes. We recently established ELISA systems to measure serum levels of SCCA1, SCCA2, and periostin and evaluated their usefulness in the treatment of AD patients. Serum SCCA1 and SCCA2 are up-regulated in AD patients and can distinguish AD patients from non-atopic controls, and their serum levels reflect eczema grades. Periostin concentration is also elevated in the serum of AD patients. These results demonstrate that SCCA1, SCCA2, and periostin might be promising biomarkers for personalized medicine in allergic diseases including AD.

An integrated proteomics and metabolomics approach for defining oncofetal biomarkers in the colorectal cancer.

PubMed

Ma, Yanlei; Zhang, Peng; Wang, Feng; Liu, Weijie; Yang, Jianjun; Qin, Huanlong

2012-04-01

The present study was designed to search for potential diagnostic biomarkers in the serum of colorectal cancer (CRC). CRC is the third most common cancer worldwide, and its prognosis is poor at early stages. A panel of novel biomarkers is urgently needed for early diagnosis of CRC. An integrated proteomics and metabolomics approach was performed to define oncofetal biomarkers in CRC by protein and metabolite profiling of serum samples from CRC patients, healthy control adults, and fetus. The differentially expressed proteins were identified by a 2-D DIGE (2-Dimensional Difference Gel Electrophoresis) coupled with a Finnigan LTQ-based proteomics approach. Meanwhile, the serum metabolome was analyzed using gas chromatography-mass spectrometry integrated with a commercial mass spectral library for peak identification. Of the 28 identified proteins and the 34 analyzed metabolites, only 5 protein spots and 6 metabolites were significantly increased or decreased in both CRC and fetal serum groups compared with the healthy adult group. Data from supervised predictive models allowed a separation of 93.5% of CRC patients from the healthy controls using the 6 metabolites. Finally, correlation analysis was applied to establish quantitative linkages between the 5 individual metabolite 3-hydroxybutyric acid, L-valine, L-threonine, 1-deoxyglucose, and glycine and the 5 individual proteins MACF1, APOH, A2M, IGL@, and VDB. Furthermore, 10 potential oncofetal biomarkers were characterized and their potential for CRC diagnosis was validated. The integrated approach we developed will promote the translation of biomarkers with clinical value into routine clinical practice.

Serum miRNAs miR-23a, 206, and 499 as Potential Biomarkers for Skeletal Muscle Atrophy

PubMed Central

Wang, Jing; He, Jian; Li, Wenjiong; Li, Jinglong; Chen, Shengju; Zhang, Peng; Liu, Hongju

2017-01-01

Muscle biopsy has long been expected to be replaced by noninvasive biomarkers with diagnostic value and prognostic applications for muscle atrophy. Growing evidence suggests that circulating microRNAs (miRNAs) could act as biomarkers for numerous pathophysiological statuses. In the present study, our results showed that the serum levels of six muscle-specific miRNAs (miR-1/23a/133/206/208b/499) were all elevated in unloading induced mice. The medium levels of these six muscle-specific miRNAs were all elevated in starvation induced atrophic C2C12 myotubes. Moreover, the serum levels of miR-23a/206/499 were induced in participants after 45 days of head-down bed rest (HDBR). The levels of miR-23a/206/499 were positively correlated with the ratio of soleus volume loss in HDBR participants, indicating that they might represent the process of muscle loss. In conclusion, our results demonstrated that circulating miRNAs could serve as useful biochemical and molecular indicators for muscle atrophy diagnosis and disease progression. PMID:29214178

A multi-analyte serum test for the detection of non-small cell lung cancer

PubMed Central

Farlow, E C; Vercillo, M S; Coon, J S; Basu, S; Kim, A W; Faber, L P; Warren, W H; Bonomi, P; Liptay, M J; Borgia, J A

2010-01-01

Background: In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer. Methods: Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort. Results: A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients. Conclusions: Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various ‘high-risk' individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions. PMID:20859284

Off surface matrix based on-chip electrochemical biosensor platform for protein biomarker detection in undiluted serum.

PubMed

Arya, Sunil K; Kongsuphol, Patthara; Park, Mi Kyoung

2017-06-15

The manuscript describes a concept of using off surface matrix modified with capturing biomolecule for on-chip electrochemical biosensing. 3D matrix made by laser engraving of polymethyl methacrylate (PMMA) sheet as off surface matrix was integrated in very close vicinity of the electrode surface. Laser engraving and holes in PMMA along with spacing from surface provide fluidic channel and incubation chamber. Covalent binding of capturing biomolecule (anti-TNF-α antibody) on off-surface matrix was achieved via azide group activity of 4-fluoro-3-nitro-azidobenzene (FNAB), which act as cross-linker and further covalently binds to anti-TNF-α antibody via thermal reaction. Anti-TNF-α/FNAB/PMMA matrix was then integrated over comb structured gold electrode array based sensor chip. Separate surface modification followed by integration of sensor helped to prevent the sensor chip surface from fouling during functionalization. Nonspecific binding was prevented using starting block T20 (PBS). Results for estimating protein biomarker (TNF-α) in undiluted serum using Anti-TNF-α/FNAB/PMMA/Au reveal that system can detect TNF-α in 100pg/ml to 100ng/ml range with high sensitivity of 119nA/(ng/ml), with negligible interference from serum proteins and other cytokines. Thus, use of off surface matrix may provide the opportunity to electrochemically sense biomarkers sensitively to ng/ml range with negligible nonspecific binding and false signal in undiluted serum. Copyright © 2016 Elsevier B.V. All rights reserved.

Metabonomics identifies serum metabolite markers of colorectal cancer.

PubMed

Tan, Binbin; Qiu, Yunping; Zou, Xia; Chen, Tianlu; Xie, Guoxiang; Cheng, Yu; Dong, Taotao; Zhao, Linjing; Feng, Bo; Hu, Xiaofang; Xu, Lisa X; Zhao, Aihua; Zhang, Menghui; Cai, Guoxiang; Cai, Sanjun; Zhou, Zhanxiang; Zheng, Minhua; Zhang, Yan; Jia, Wei

2013-06-07

Recent studies suggest that biofluid-based metabonomics may identify metabolite markers promising for colorectal cancer (CRC) diagnosis. We report here a follow-up replication study, after a previous CRC metabonomics study, aiming to identify a distinct serum metabolic signature of CRC with diagnostic potential. Serum metabolites from newly diagnosed CRC patients (N = 101) and healthy subjects (N = 102) were profiled using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) and ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS). Differential metabolites were identified with statistical tests of orthogonal partial least-squares-discriminant analysis (VIP > 1) and the Mann-Whitney U test (p < 0.05). With a total of 249 annotated serum metabolites, we were able to differentiate CRC patients from the healthy controls using an orthogonal partial least-squares-discriminant analysis (OPLS-DA) in a learning sample set of 62 CRC patients and 62 matched healthy controls. This established model was able to correctly assign the rest of the samples to the CRC or control groups in a validation set of 39 CRC patients and 40 healthy controls. Consistent with our findings from the previous study, we observed a distinct metabolic signature in CRC patients including tricarboxylic acid (TCA) cycle, urea cycle, glutamine, fatty acids, and gut flora metabolism. Our results demonstrated that a panel of serum metabolite markers is of great potential as a noninvasive diagnostic method for the detection of CRC.

Imaging Biomarkers for Adult Medulloblastomas: Genetic Entities May Be Identified by Their MR Imaging Radiophenotype.

PubMed

Keil, V C; Warmuth-Metz, M; Reh, C; Enkirch, S J; Reinert, C; Beier, D; Jones, D T W; Pietsch, T; Schild, H H; Hattingen, E; Hau, P

2017-10-01

The occurrence of medulloblastomas in adults is rare; nevertheless, these tumors can be subdivided into genetic and histologic entities each having distinct prognoses. This study aimed to identify MR imaging biomarkers to classify these entities and to uncover differences in MR imaging biomarkers identified in pediatric medulloblastomas. Eligible preoperative MRIs from 28 patients (11 women; 22-53 years of age) of the Multicenter Pilot-study for the Therapy of Medulloblastoma of Adults (NOA-7) cohort were assessed by 3 experienced neuroradiologists. Lesions and perifocal edema were volumetrized and multiparametrically evaluated for classic morphologic characteristics, location, hydrocephalus, and Chang criteria. To identify MR imaging biomarkers, we correlated genetic entities sonic hedgehog ( SHH ) TP53 wild type, wingless ( WNT ), and non -WNT/ non -SHH medulloblastomas (in adults, Group 4), and histologic entities were correlated with the imaging criteria. These MR imaging biomarkers were compared with corresponding data from a pediatric study. There were 19 SHH TP53 wild type (69%), 4 WNT -activated (14%), and 5 Group 4 (17%) medulloblastomas. Six potential MR imaging biomarkers were identified, 3 of which, hydrocephalus ( P = .03), intraventricular macrometastases ( P = .02), and hemorrhage ( P = .04), when combined, could identify WNT medulloblastoma with 100% sensitivity and 88.3% specificity (95% CI, 39.8%-100.0% and 62.6%-95.3%). WNT -activated nuclear β-catenin accumulating medulloblastomas were smaller than the other entities (95% CI, 5.2-22.3 cm 3 versus 35.1-47.6 cm 3 ; P = .03). Hemorrhage was exclusively present in non -WNT/ non -SHH medulloblastomas ( P = .04; n = 2/5). MR imaging biomarkers were all discordant from those identified in the pediatric cohort. Desmoplastic/nodular medulloblastomas were more rarely in contact with the fourth ventricle (4/15 versus 7/13; P = .04). MR imaging biomarkers can help distinguish histologic and genetic

DJ-1 is a reliable serum biomarker for discriminating high-risk endometrial cancer.

PubMed

Di Cello, Annalisa; Di Sanzo, Maddalena; Perrone, Francesca Marta; Santamaria, Gianluca; Rania, Erika; Angotti, Elvira; Venturella, Roberta; Mancuso, Serafina; Zullo, Fulvio; Cuda, Giovanni; Costanzo, Francesco

2017-06-01

New reliable approaches to stratify patients with endometrial cancer into risk categories are highly needed. We have recently demonstrated that DJ-1 is overexpressed in endometrial cancer, showing significantly higher levels both in serum and tissue of patients with high-risk endometrial cancer compared with low-risk endometrial cancer. In this experimental study, we further extended our observation, evaluating the role of DJ-1 as an accurate serum biomarker for high-risk endometrial cancer. A total of 101 endometrial cancer patients and 44 healthy subjects were prospectively recruited. DJ-1 serum levels were evaluated comparing cases and controls and, among endometrial cancer patients, between high- and low-risk patients. The results demonstrate that DJ-1 levels are significantly higher in cases versus controls and in high- versus low-risk patients. The receiver operating characteristic curve analysis shows that DJ-1 has a very good diagnostic accuracy in discriminating endometrial cancer patients versus controls and an excellent accuracy in distinguishing, among endometrial cancer patients, low- from high-risk cases. DJ-1 sensitivity and specificity are the highest when high- and low-risk patients are compared, reaching the value of 95% and 99%, respectively. Moreover, DJ-1 serum levels seem to be correlated with worsening of the endometrial cancer grade and histotype, making it a reliable tool in the preoperative decision-making process.

Prioritization of Biomarker Targets in Human Umbilical Cord Blood: Identification of Proteins in Infant Blood Serving as Validated Biomarkers in Adults

PubMed Central

Hansmeier, Nicole; Chao, Tzu-Chiao; Goldman, Lynn R.; Witter, Frank R.

2012-01-01

Background: Early diagnosis represents one of the best lines of defense in the fight against a wide array of human diseases. Umbilical cord blood (UCB) is one of the first easily available diagnostic biofluids and can inform about the health status of newborns. However, compared with adult blood, its diagnostic potential remains largely untapped. Objectives: Our goal was to accelerate biomarker research on UCB by exploring its detectable protein content and providing a priority list of potential biomarkers based on known proteins involved in disease pathways. Methods: We explored cord blood serum proteins by profiling a UCB pool of 12 neonates with different backgrounds using a combination of isoelectric focusing and liquid chromatography coupled with matrix-assisted laser desorption/ionization tandem mass spectrometry (MALDI-MS/MS) and by comparing results with information contained in metabolic and disease databases available for adult blood. Results: A total of 1,210 UCB proteins were identified with a protein-level false discovery rate of ~ 5% as estimated by naïve target-decoy and MAYU approaches, signifying a 6-fold increase in the number of UCB proteins described to date. Identified proteins correspond to 138 different metabolic and disease pathways and provide a platform of mechanistically linked biomarker candidates for tracking disruptions in cellular processes. Moreover, among the identified proteins, 38 were found to be approved biomarkers for adult blood. Conclusions: The results of this study advance current knowledge of the human cord blood serum proteome. They showcase the potential of UCB as a diagnostic medium for assessing infant health by detection and identification of candidate biomarkers for known disease pathways using a global, nontargeted approach. These biomarkers may inform about mechanisms of exposure–disease relationships. Furthermore, biomarkers approved by the U.S. Food and Drug Administration for screening in adult blood were

Serum vitamin C and other biomarkers differ by genotype of phase 2 enzyme genes GSTM1 and GSTT1123

PubMed Central

Shaikh, Nishat; Jensen, Christopher D; Volberg, Vitaly; Holland, Nina

2011-01-01

Background: Glutathione S-transferases (GSTs) detoxify environmental chemicals and are involved in oxidative stress pathways. Deletion polymorphisms affect enzyme activities and have been associated with risk of disease. Objective: The objective was to clarify whether biomarkers of oxidation, antioxidation, inflammation, and nutritional factors differ by GST genotype in healthy adults. Design: Subjects (n = 383) consisted of nonsmokers and nonusers of antiinflammatory drugs and antioxidant vitamin supplements. Deletion polymorphisms of GSTM1 and GSTT1 were genotyped. F2-isoprostanes, malondialdehyde, C-reactive protein, serum vitamin C, carotenoids, tocopherols, and other nutritional factors were assessed. Results: The concentration of serum vitamin C was higher in persons with the inactive GSTM1-0 genotype (P = 0.006). This relation was unchanged after adjustment for age, sex, BMI, or dietary vitamin C. F2-isoprostanes and malondialdehyde were lower in the GSTM1-0 and GSTT1-0 groups, respectively, but significance was lost after control for serum vitamin C. The dual deletion, GSTM1-0/GSTT1-0 (n = 37), was associated with higher serum iron and total and LDL-cholesterol concentrations (all P < 0.01) and lower malondialdehyde concentrations, which persisted after adjustment for age, sex, BMI, and serum vitamin C. Carotenoids and α- and γ-tocopherols were not associated with either genotype. Conclusions: Oxidative stress and inflammation biomarkers differ by GST genotype, but serum vitamin C appears to be the most consistent factor. Examination of other relevant genes may be needed to understand the concentration and function of ascorbic acid in the GST enzyme system. This trial is registered at clinicaltrials.gov as NCT00079963. PMID:21813807

Apolipoprotein C-II Is a Potential Serum Biomarker as a Prognostic Factor of Locally Advanced Cervical Cancer After Chemoradiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harima, Yoko, E-mail: harima@takii.kmu.ac.jp; Ikeda, Koshi; Utsunomiya, Keita

Purpose: To determine pretreatment serum protein levels for generally applicable measurement to predict chemoradiation treatment outcomes in patients with locally advanced squamous cell cervical carcinoma (CC). Methods and Materials: In a screening study, measurements were conducted twice. At first, 6 serum samples from CC patients (3 with no evidence of disease [NED] and 3 with cancer-caused death [CD]) and 2 from healthy controls were tested. Next, 12 serum samples from different CC patients (8 NED, 4 CD) and 4 from healthy controls were examined. Subsequently, 28 different CC patients (18 NED, 10 CD) and 9 controls were analyzed in themore » validation study. Protein chips were treated with the sample sera, and the serum protein pattern was detected by surface-enhanced laser desorption and ionization–time-of-flight mass spectrometry (SELDI-TOF MS). Then, single MS-based peptide mass fingerprinting (PMF) and tandem MS (MS/MS)-based peptide/protein identification methods, were used to identify protein corresponding to the detected peak. And then, turbidimetric assay was used to measure the levels of a protein that indicated the best match with this peptide peak. Results: The same peak 8918 m/z was identified in both screening studies. Neither the screening study nor the validation study had significant differences in the appearance of this peak in the controls and NED. However, the intensity of the peak in CD was significantly lower than that of controls and NED in both pilot studies (P=.02, P=.04) and validation study (P=.01, P=.001). The protein indicated the best match with this peptide peak at 8918 m/z was identified as apolipoprotein C-II (ApoC-II) using PMF and MS/MS methods. Turbidimetric assay showed that the mean serum levels of ApoC-II tended to decrease in CD group when compared with NED group (P=.078). Conclusion: ApoC-II could be used as a biomarker for detection in predicting and estimating the radiation treatment outcome of patients with CC.« less

Identification of serum miRNAs by nano-quantum dots microarray as diagnostic biomarkers for early detection of non-small cell lung cancer.

PubMed

Fan, Lihong; Qi, Huiwei; Teng, Junliang; Su, Bo; Chen, Hao; Wang, Changhui; Xia, Qing

2016-06-01

Circulating microRNAs (miRNAs) are potential noninvasive biomarkers for cancer detection. We used preoperative serum samples from non-small cell lung cancer (NSCLC) patients and healthy controls to investigate whether serum levels of candidate miRNAs could be used as diagnostic biomarkers in patients with resectable NSCLC and whether they were associated with clinicopathologic characteristics. We initially detected expression of 12 miRNAs using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) in preoperative serum samples of 94 NSCLC patients and 58 healthy controls. We further validated our results using the fluorescence quantum dots liquid bead array for differentially expressed miRNAs in serum samples of 70 NSCLC patients and 54 healthy controls. Receiver operating characteristic (ROC) analysis was performed to select the best diagnostic miRNA cutoff value. A predictive model of miRNAs for NSCLC was derived by multivariate logistic regression. We found that five serum miRNAs (miR-16-5p, miR-17b-5p, miR-19-3p, miR-20a-5p, and miR-92-3p) were significantly downregulated in NSCLC, while miR-15b-5p was significantly upregulated (p < 0.05). Multivariate logistic regression analysis revealed that miR-15b-5p, miR-16-5p, and miR-20a-5p expression were independent diagnostic factors for the identification of patients with NSCLC after adjustment for patient's age and sex. In addition, the expression of serum miR-106-5p was higher in stage I than in stages IIa-IIIb, and no significant association was observed between expression of miRNAs and other variables including pathological type, tumor size, and lymph nodes status. Six serum miRNAs could potentially serve as noninvasive diagnostic biomarkers for resectable NSCLC. The predictive model combining miR-15b-5p, miR-16-5p, and miR-20a-5p was the best diagnostic approach.

Serum miRNAs as Biomarkers for the Diagnosis and Prognosis of Thyroid Cancer: A Comprehensive Review of the Literature.

PubMed

Mahmoudian-Sani, Mohammad-Reza; Mehri-Ghahfarrokhi, Ameneh; Asadi-Samani, Majid; Mobini, Gholam-Reza

2017-07-01

Thyroid cancer is the most common endocrine malignancy and accounts for 1% of cancers. In recent years, there has been much interest in the feasibility of using miRNAs or miRNA panels as biomarkers for the diagnosis of thyroid cancer. miRNAs are noncoding RNAs with 21-23 nucleotides that are highly conserved during evolution. They have been proposed as regulators of gene expression, apoptosis, cancer, and cell growth and differentiation. The Directory of Open Access Journals (DOAJ), Google Scholar, PubMed (NLM), LISTA (EBSCO), and Web of Science were searched. The serum level of miRNAs (miRNA-375, 34a, 145b, 221, 222, 155, Let-7, 181b) can be used as molecular markers for the diagnosis and prognosis of thyroid cancer in the serum samples of patients with thyroid glands. Given that most common methods for the screening of thyroid cancer cannot detect the disease in its early stages, identifying miRNAs that are released in the bloodstream during the gradual progression of the disease is considered a key method in the early diagnosis of thyroid cancers.

Serum 6-Bromotryptophan Levels Identified as a Risk Factor for CKD Progression.

PubMed

Tin, Adrienne; Nadkarni, Girish; Evans, Anne M; Winkler, Cheryl A; Bottinger, Erwin; Rebholz, Casey M; Sarnak, Mark J; Inker, Lesley A; Levey, Andrew S; Lipkowitz, Michael S; Appel, Lawrence J; Arking, Dan E; Coresh, Josef; Grams, Morgan E

2018-05-18

Background Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with APOL1 risk alleles-genetic variants associated with CKD risk commonly present in persons of African descent-may reveal novel markers of CKD progression relevant to other populations. Methods We evaluated associations between the number of APOL1 risk alleles and 760 serum metabolites identified via untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) ( n =588; Bonferroni significance threshold P <6.5×10 -5 ) and replicated findings in 678 black participants with CKD in Bio Me , an electronic medical record-linked biobank. We tested the metabolite association with CKD progression in AASK, Bio Me , and the Modification of Diet in Renal Disease (MDRD) Study. Results One metabolite, 6-bromotryptophan, was significant in AASK ( P =4.7×10 -5 ) and replicated in Bio Me ( P =5.7×10 -3 ) participants, with lower levels associated with more APOL1 risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and Bio Me participants and in white participants in the MDRD Study, independent of demographics and clinical characteristics, including baseline GFR (adjusted hazard ratio per two-fold higher 6-bromotryptophan level, AASK, 0.76; 95% confidence interval [95% CI], 0.64 to 0.91; Bio Me , 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the APOL1 risk alleles and 6-bromotryptophan was not significant. The identity of 6-bromotryptophan was confirmed in experiments comparing its molecular signature with that of authentic standards of other bromotryptophan isomers. Conclusions Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression. Copyright © 2018 by the American Society of Nephrology.

Serum Irisin Predicts Mortality Risk in Acute Heart Failure Patients.

PubMed

Shen, Shutong; Gao, Rongrong; Bei, Yihua; Li, Jin; Zhang, Haifeng; Zhou, Yanli; Yao, Wenming; Xu, Dongjie; Zhou, Fang; Jin, Mengchao; Wei, Siqi; Wang, Kai; Xu, Xuejuan; Li, Yongqin; Xiao, Junjie; Li, Xinli

2017-01-01

Irisin is a peptide hormone cleaved from a plasma membrane protein fibronectin type III domain containing protein 5 (FNDC5). Emerging studies have indicated association between serum irisin and many major chronic diseases including cardiovascular diseases. However, the role of serum irisin as a predictor for mortality risk in acute heart failure (AHF) patients is not clear. AHF patients were enrolled and serum was collected at the admission and all patients were followed up for 1 year. Enzyme-linked immunosorbent assay was used to measure serum irisin levels. To explore predictors for AHF mortality, the univariate and multivariate logistic regression analysis, and receiver-operator characteristic (ROC) curve analysis were used. To determine the role of serum irisin levels in predicting survival, Kaplan-Meier survival analysis was used. In this study, 161 AHF patients were enrolled and serum irisin level was found to be significantly higher in patients deceased in 1-year follow-up. The univariate logistic regression analysis identified 18 variables associated with all-cause mortality in AHF patients, while the multivariate logistic regression analysis identified 2 variables namely blood urea nitrogen and serum irisin. ROC curve analysis indicated that blood urea nitrogen and the most commonly used biomarker, NT-pro-BNP, displayed poor prognostic value for AHF (AUCs ≤ 0.700) compared to serum irisin (AUC = 0.753). Kaplan-Meier survival analysis demonstrated that AHF patients with higher serum irisin had significantly higher mortality (P<0.001). Collectively, our study identified serum irisin as a predictive biomarker for 1-year all-cause mortality in AHF patients though large multicenter studies are highly needed. © 2017 The Author(s). Published by S. Karger AG, Basel.

Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease

PubMed Central

Zetterberg, Henrik; Mattsson, Niklas; Johansson, Per; Minthon, Lennart; Blennow, Kaj; Olsson, Mattias

2015-01-01

Objective: To compare the diagnostic accuracy of CSF biomarkers and amyloid PET for diagnosing early-stage Alzheimer disease (AD). Methods: From the prospective, longitudinal BioFINDER study, we included 122 healthy elderly and 34 patients with mild cognitive impairment who developed AD dementia within 3 years (MCI-AD). β-Amyloid (Aβ) deposition in 9 brain regions was examined with [18F]-flutemetamol PET. CSF was analyzed with INNOTEST and EUROIMMUN ELISAs. The results were replicated in 146 controls and 64 patients with MCI-AD from the Alzheimer's Disease Neuroimaging Initiative study. Results: The best CSF measures for identifying MCI-AD were Aβ42/total tau (t-tau) and Aβ42/hyperphosphorylated tau (p-tau) (area under the curve [AUC] 0.93–0.94). The best PET measures performed similarly (AUC 0.92–0.93; anterior cingulate, posterior cingulate/precuneus, and global neocortical uptake). CSF Aβ42/t-tau and Aβ42/p-tau performed better than CSF Aβ42 and Aβ42/40 (AUC difference 0.03–0.12, p < 0.05). Using nonoptimized cutoffs, CSF Aβ42/t-tau had the highest accuracy of all CSF/PET biomarkers (sensitivity 97%, specificity 83%). The combination of CSF and PET was not better than using either biomarker separately. Conclusions: Amyloid PET and CSF biomarkers can identify early AD with high accuracy. There were no differences between the best CSF and PET measures and no improvement when combining them. Regional PET measures were not better than assessing the global Aβ deposition. The results were replicated in an independent cohort using another CSF assay and PET tracer. The choice between CSF and amyloid PET biomarkers for identifying early AD can be based on availability, costs, and doctor/patient preferences since both have equally high diagnostic accuracy. Classification of evidence: This study provides Class III evidence that amyloid PET and CSF biomarkers identify early-stage AD equally accurately. PMID:26354982

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury.

PubMed

Robinson, Shenandoah; Winer, Jesse L; Berkner, Justin; Chan, Lindsay A S; Denson, Jesse L; Maxwell, Jessie R; Yang, Yirong; Sillerud, Laurel O; Tasker, Robert C; Meehan, William P; Mannix, Rebekah; Jantzie, Lauren L

2016-06-01

OBJECTIVE Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes. METHODS With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1-4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13-28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction. RESULTS Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst-like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0

Proteomics as a Tool for Biomarker Discovery

PubMed Central

Kohn, Elise C.; Azad, Nilofer; Annunziata, Christina; Dhamoon, Amit S.; Whiteley, Gordon

2007-01-01

Novel technologies are now being advanced for the purpose of identification and validation of new disease biomarkers. A reliable and useful clinical biomarker must a) come from a readily attainable source, such as blood or urine, b) have sufficient sensitivity to correctly identify affected individuals, c) have sufficient specificity to avoid incorrect labeling of unaffected persons, and d) result in a notable benefit for the patient through intervention, such as survival or life quality improvement. Despite these critical descriptors, the few available FDA-approved biomarkers for cancer do not completely fit this definition and their benefits are limited to a small number of cancers. Ovarian cancer exemplifies the need for a diagnostic biomarker of early stage disease. Symptoms are present but not specific to the disease, delaying diagnosis until an advanced and generally incurable stage in over 70% of affected women. As such, diagnostic intervention in the form of oopherectomy can be performed in the appropriate at-risk population if identified such as with a new accurate, sensitive, and specific biomarker. If early stage disease is identified, the requirement for survival and life quality improvement will be met. One of the new technologies applied to biomarker discovery is tour-de-force analysis of serum peptides and proteins. Optimization of mass spectrometry techniques coupled with advanced bioinformatics approaches has yielded informative biomarker signatures discriminating presence of cancer from unaffected in multiple studies from different groups. Validation and randomized outcome studies are needed to determine the true value of these new biomarkers in early diagnosis, and improved survival and quality of life. PMID:18057524

MFAP4: a candidate biomarker for hepatic and pulmonary fibrosis?

PubMed

Mölleken, Christian; Poschmann, Gereon; Bonella, Francesco; Costabel, Ulrich; Sitek, Barbara; Stühler, Kai; Meyer, Helmut E; Schmiegel, Wolff H; Marcussen, Niels; Helmer, Michael; Nielsen, Ole; Hansen, Søren; Schlosser, Anders; Holmskov, Uffe; Sorensen, Grith Lykke

2016-03-29

Several comparable mechanisms have been identified for hepatic and pulmonary fibrosis. The human microfibrillar associated glycoprotein 4 (MFAP4), produced by activated myofibroblasts, is a ubiquitous protein playing a potential role in extracellular matrix (ECM) turnover and was recently identified as biomarker for hepatic fibrosis in hepatitis C patients. The current study aimed to evaluate serum levels of MFAP4 in patients with pulmonary fibrosis in order to test its potential as biomarker in clinical practice. A further aim was to determine whether MFAP4 deficiency in mice affects the formation of pulmonary fibrosis in the bleomycin model of lung fibrosis. 91 patients with idiopathic pulmonary fibrosis (IPF), 23 with hypersensitivity pneumonitis (HP) and 31 healthy subjects were studied. In the mouse model, C57BL/6 Mfap4+/+ and Mfap4-/- mice between 6-8 weeks of age were studied. Serum levels of MFAP4 were measured by ELISA in patients and in mice. Surfactant protein D (SP-D) and LDH were measured as comparison biomarkers in patients with pulmonary fibrosis. Morphometric assessment and the Sircol kit were used to determine the amount of collagen in the lung tissue in the mouse model. Serum levels of MFAP4 were not elevated in lung fibrosis - neither in the patients with IPF or HP nor in the animal model. Furthermore no significant correlations with pulmonary function tests of IPF patients could be found for MFAP4. MFAP4 levels were increased in BAL of bleomycin treated mice with pulmonary fibrosis. MFAP4 is not elevated in sera of patients with pulmonary fibrosis or bleomycin treated mice with pulmonary fibrosis. This may be due to different pathogenic mechanisms of liver and lung fibrogenesis. MFAP4 seems to be useful as serum biomarker for hepatic but not for lung fibrosis.

Periostin and CA242 as potential diagnostic serum biomarkers complementing CA19.9 in detecting pancreatic cancer.

PubMed

Dong, Dong; Jia, Li; Zhang, Lufang; Ma, Na; Zhang, Aimin; Zhou, Yunli; Ren, Li

2018-06-26

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with few biomarkers to guide treatment options. Carbohydrate antigen 19.9 (CA19.9), the mainly used biomarker for PDAC, is not sensitive and specific enough for the detection of the disease. This study was aimed to evaluate serum periostin (POSTN) and CA242 as potential diagnostic biomarkers complementing CA19.9 in detecting pancreatic cancer. Blood samples were from 362 participants, including 213 patients with different stages of PDAC, 75 patients with benign pancreatic disease and 74 healthy individuals. All samples were randomly divided into training set and validation set. CA19.9, CA242, POSTN, as well as carcinoembryonic antigen (CEA), were measured by ELISA or automated immunoassay. The receiver operating curve (ROC) analysis revealed that the performances of CA19.9 in the validation group were improved by the marker panel composed of CA19.9, POSTN and CA242, to discriminate early-stage PDAC not only from healthy controls (AUC CA 19.9 = 0.94 vs. AUC CA 19.9 + POSTN + CA 242 = 0.98, P < 0.05) but also from benign conditions (AUC CA 19.9 = 0.87 vs. AUC CA 19.9 + POSTN + CA 242 = 0.90, P < 0.05). In addition, POSTN retained significant diagnostic capabilities to distinguish PDAC CA19.9-negative from healthy controls (AUC POSTN = 0.87) as well as from benign conditions (AUC POSTN = 0.84) in the whole set. This study suggested that POSTN and CA242 are potential diagnostic serum biomarkers complementing CA19.9 in detecting early pancreatic cancer. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Vasorin is a potential serum biomarker and drug target of hepatocarcinoma screened by subtractive-EMSA-SELEX to clinic patient serum

PubMed Central

Wang, Wei; Huang, Aixue; Li, Jie; Qin, Xingliang; Li, Fei; Lu, Guanyi; Ding, Hongmei; Su, Xueting; Hou, Lvbin; Xia, Wei; Shi, Ming; Zhang, Hongwen; Zhao, Qiang; Dong, Jie; Ge, Xingfeng; Sun, Leqiao; Bai, Chenjun; Wang, Chaonan; Shen, Xuelian; Fang, Tao; Wang, Fusheng; Zhang, Heqiu; Shao, Ningsheng

2015-01-01

We report a new biomarker of hepatocarcinoma, vasorin (VASN), screened by a subtractive EMSA-SELEX strategy from AFP negative serum of hepatocellular carcinoma (HCC) patients with extrahepatic metastases. VASN was verified to be highly expressed in sera of 100 cases of HCC patients compared with 97 cases of normal persons and 129 cases of hepatitis patients. Further validation by Q-PCR, IFA and Western blot showed higher expression of VASN at mRNA and protein levels in HCC cell lines and HCC tissues than in normal controls. RNA interference and forced overexpression assays verified that VASN promotes cell proliferation and migration and inhibits apoptosis. Down-regulation of microRNA miR145 and miR146a is an important mechanism leading to high expression of VASN. Conclusion: As a membrane protein and/or as free protein, VASN may be an effective target for biological treatment of liver cancer and is a potential biomarker for HCC diagnosis. Small molecular nucleotides targeting VASN are promising biological therapies to HCC. PMID:25826090

Resting and post-exercise serum biomarkers of cardiac and skeletal muscle damage in adolescent runners.

PubMed

Nie, J; Tong, T K; George, K; Fu, F H; Lin, H; Shi, Q

2011-10-01

This study examined the response of serum biomarkers of cardiac and skeletal muscle damage at rest and after a routine workout of 21 km run in 12 male adolescent (16.2±0.6 years) long-distance runners. Biomarkers of cardiac [troponins (cTnT, cTnI), creatine kinase MB mass (CK-Mbmass)] and skeletal muscle [creatine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hydroxybutyrate dehydrogenase (HBD)] damage were assayed at rest, 2, 4 and 24 h post-exercise. At rest, cTnT and cTnI were not detectable; however, CK, CK-MBmass, AST, ALT and HBD were above corresponding clinical cut-off values. Post-exercise significant elevations above rest were observed for all biomarkers, except ALT, 2 and 4 h following the run, and remained elevated in cTnI, CK, CK-MBmass, LDH and AST 24 h post-workout. A significant increase in data points above clinical cut-off values from rest to post-exercise was reported for cTnT, cTnI and CK at 2 and 4 h, and in cTnI and CK 24 h post-exercise. In conclusion, a 21 km run in adolescent runners increased post-exercise biomarkers of cardiac and skeletal muscle damage. © 2010 John Wiley & Sons A/S.

Potential Role of Serum and Urinary Biomarkers in Diagnosis and Prognosis of Diabetic Nephropathy.

PubMed

Campion, Carole G; Sanchez-Ferras, Oraly; Batchu, Sri N

2017-01-01

Diabetic nephropathy (DN) is a progressive kidney disease caused by alterations in kidney architecture and function, and constitutes one of the leading causes of end-stage renal disease (ESRD). The purpose of this review is to summarize the state of the art of the DN-biomarker field with a focus on the new strategies that enhance the sensitivity of biomarkers to predict patients who will develop DN or are at risk of progressing to ESRD. In this review, we provide a description of the pathophysiology of DN and propose a panel of novel putative biomarkers associated with DN pathophysiology that have been increasingly investigated for diagnosis, to predict disease progression or to provide efficient personal treatment. We performed a review of the literature with PubMed and Google Scholar to collect baseline data about the pathophysiology of DN and biomarkers associated. We focused our research on new and emerging biomarkers of DN. In this review, we summarized the critical signaling pathways and biological processes involved in DN and highlighted the pathogenic mediators of this disease. We next proposed a large review of the major advances that have been made in identifying new biomarkers which are more sensitive and reliable compared with currently used biomarkers. This includes information about emergent biomarkers such as functional noncoding RNAs, microRNAs, long noncoding RNAs, exosomes, and microparticles. Despite intensive strategies and constant investigation, no current single treatment has been able to reverse or at least mitigate the progression of DN, or reduce the morbidity and mortality associated with this disease. Major difficulties probably come from the renal disease being heterogeneous among the patients. Expanding the proteomics screening, including oxidative stress and inflammatory markers, along with metabolomics approaches may further improve the prognostic value and help in identifying the patients with diabetes who are at high risk of

Effects of the Dietary Detoxification Program on Serum γ-glutamyltransferase, Anthropometric Data and Metabolic Biomarkers in Adults.

PubMed

Kim, Ju Ah; Kim, Jin Young; Kang, Seung Wan

2016-09-01

Persistent Organic Pollutants (POPs) are well-known environmental contaminants which are associated with chronic diseases. As foods are the major sources of human exposure to toxic pollutants, we developed an integrated dietary and education program to eliminate the chemical toxin throughout the human body. The present study evaluated effects of the dietary detoxification program on serum γ -glutamyltransferase (GGT), anthropometric data and metabolic biomarkers in adults. Single-armed, pre-post study was conducted from June 2013 to June 2015 at a health examination center and a public health center in Seoul, Korea. Sixty eight subjects (mean age of 52.4 years) were recruited. Subjects participated 20 hours' dietary education sessions. On-line coaching with SNS was performed to enhance participants' proper protocol compliance. Physical and laboratory examinations were assessed at week 0 and 3. Changes of the serum GGT were correlated with reductions of the body fat percentage (r = .379, p = .001), body fat mass (r = .435, p = .000) and fasting blood glucose (r = .423, p = .000). Serum GGT, weight, body fat percentage, body fat mass, waist circumference, LDL-cholesterol, HDL-cholesterol, triglyceride, total cholesterol, and blood pressure of all participants were reduced with statistical significance in 3 weeks. In metabolic syndrome group, total cholesterol (p = .049), fasting blood glucose (p = .002), and systolic blood pressure (p = .001) were significantly reduced comparison to non-metabolic syndrome group. This dietary detoxification program might decrease serum GGT which indicated the overall toxic burden in the body. Anthropometric data and metabolic biomarkers were improved. The integrated dietary and education detoxification program seemed to be a protective intervention for elimination of toxicants from the body.

Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet.

PubMed

Kim, Sung-Eun; Choo, Jinsil; Yoon, Joon; Chu, Jae Ryang; Bae, Yun Jung; Lee, Seungyeoun; Park, Taesung; Sung, Mi-Kyung

2017-01-01

Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn's disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories) or high-fat diet (HFD, 45% of fat calories) for 8 weeks. Serum concentrations of insulin, insulin-like growth factor-1 (IGF-1), leptin, and adiponectin were measured as obesity-related phenotypic markers. Genome-wide gene expression profiles of colon tissue were determined, followed by statistical analyses to detect differentially expressed and serum phenotype-associated genes. HFD-fed mice showed higher serum concentrations of leptin (P < 0.001) and insulin (P < 0.01) than those in the ND group, whereas serum IGF-1 and adiponectin concentrations did not differ between the two dietary groups. Among differentially expressed genes affected by HFD, 135, 128, 110, and 341 genes were associated with serum levels of leptin, insulin, IGF-1, and adiponectin, respectively. We identified 17 leptin-associated genes and 4 insulin-associated genes that inversely responded to HFD and ND. Among these, leptin-associated Peli3 (Pellino E3 ubiquitin protein ligase family member 3), Creb1 (cAMP responsive element binding protein 1), and Enpp2 (ectonucleotide pyrophosphatase/phosphodiesterase 2, autotaxin) and insulin-associated Centg1 (AGAP2, ArfGAP with GTPase domain) are reported to play a role either in obesity or colonic diseases. mRNA expression of these genes was validated by RT-qPCR. Our data suggest Peli3, Creb1, Enpp2, and Centg1 as potential early biomarker candidates for obesity-induced pathophysiological changes in the colon. Future studies verifying the function of these candidates are needed for

Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet

PubMed Central

Yoon, Joon; Chu, Jae Ryang; Bae, Yun Jung; Lee, Seungyeoun; Park, Taesung; Sung, Mi-Kyung

2017-01-01

Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn’s disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories) or high-fat diet (HFD, 45% of fat calories) for 8 weeks. Serum concentrations of insulin, insulin-like growth factor-1 (IGF-1), leptin, and adiponectin were measured as obesity-related phenotypic markers. Genome-wide gene expression profiles of colon tissue were determined, followed by statistical analyses to detect differentially expressed and serum phenotype-associated genes. HFD-fed mice showed higher serum concentrations of leptin (P < 0.001) and insulin (P < 0.01) than those in the ND group, whereas serum IGF-1 and adiponectin concentrations did not differ between the two dietary groups. Among differentially expressed genes affected by HFD, 135, 128, 110, and 341 genes were associated with serum levels of leptin, insulin, IGF-1, and adiponectin, respectively. We identified 17 leptin-associated genes and 4 insulin-associated genes that inversely responded to HFD and ND. Among these, leptin-associated Peli3 (Pellino E3 ubiquitin protein ligase family member 3), Creb1 (cAMP responsive element binding protein 1), and Enpp2 (ectonucleotide pyrophosphatase/phosphodiesterase 2, autotaxin) and insulin-associated Centg1 (AGAP2, ArfGAP with GTPase domain) are reported to play a role either in obesity or colonic diseases. mRNA expression of these genes was validated by RT-qPCR. Our data suggest Peli3, Creb1, Enpp2, and Centg1 as potential early biomarker candidates for obesity-induced pathophysiological changes in the colon. Future studies verifying the function of these candidates are needed

Glycoblotting method allows for rapid and efficient glycome profiling of human Alzheimer's disease brain, serum and cerebrospinal fluid towards potential biomarker discovery.

PubMed

Gizaw, Solomon T; Ohashi, Tetsu; Tanaka, Masakazu; Hinou, Hiroshi; Nishimura, Shin-Ichiro

2016-08-01

Understanding of the significance of posttranslational glycosylation in Alzheimer's disease (AD) is of growing importance for the investigation of the pathogenesis of AD as well as discovery research of the disease-specific serum biomarkers. We designed a standard protocol for the glycoblotting combined with MALDI-TOFMS to perform rapid and quantitative profiling of the glycan parts of glycoproteins (N-glycans) and glycosphingolipids (GSLs) using human AD's post-mortem samples such as brain tissues (dissected cerebral cortices such as frontal, parietal, occipital, and temporal domains), serum and cerebrospinal fluid (CSF). The structural profiles of the major N-glycans released from glycoproteins and the total expression levels of the glycans were found to be mostly similar between the brain tissues of the AD patients and those of the normal control group. In contrast, the expression levels of the serum and CSF protein N-glycans such as bisect-type and multiply branched glycoforms were increased significantly in AD patient group. In addition, the levels of some gangliosides such as GM1, GM2 and GM3 appeared to alter in the AD patient brain and serum samples when compared with the normal control groups. Alteration of the expression levels of major N- and GSL-glycans in human brain tissues, serum and CSF of AD patients can be monitored quantitatively by means of the glycoblotting-based standard protocols. The changes in the expression levels of the glycans derived from the human post-mortem samples uncovered by the standardized glycoblotting method provides potential serum biomarkers in central nervous system disorders and can contribute to the insight into the molecular mechanisms in the pathogenesis of neurodegenerative diseases and future drug discovery. Most importantly, the present preliminary trials using human post-mortem samples of AD patients suggest that large-scale serum glycomics cohort by means of various-types of human AD patients as well as the normal

Serum Vascular Endothelial Growth Factor (VEGF) as a Biomarker for Disease Activity in Lupus Nephritis.

PubMed

Ghazali, Wan Syamimee Wan; Iberahim, Rahimah; Ashari, Noor Suryani Mohd

2017-10-01

Previous studies have shown that serum VEGF levels were elevated in patients with active systemic lupus erythematosus (SLE), especially in those with lupus nephritis (LN). In this case control study, we aimed to compare serum levels of VEGF in SLE patients between LN, non-LN and healthy participants to determine the association between serum VEGF levels and the activity and histological classes of lupus nephritis. Blood samples were obtained from 92 SLE patients (46 LN and 46 non-LN) and 26 controls. Data were collected from medical records. Serum VEGF assays were performed by specific, enzyme-linked immunosorbent assay kits (ELISA). Laboratory investigations included urinalysis, urine protein-creatinine ratio, serum creatinine, albumin and VEGF levels. Blood pressure, renal biopsy result and treatment were recorded. LN activity was evaluated using the renal subscale of the British Isles Lupus Assessment Group (rBILAG, 2004). The rBILAG measures blood pressure (diastolic and systolic), urine protein, serum creatinine, calculated glomerular filtration rate (GFR), presence of active urinary sediments and histological evidence of active nephritis. Serum VEGF was elevated in SLE patients with LN compared with the non-LN group and healthy controls. The levels found were significantly higher in the sera of patients with active nephritis compared to those with quiescent nephritis ( P = 0.024). The study did not find a statistically significant relationship between serum VEGF levels and histological classes of LN. There was no significant difference of serum VEGF level between LN and non-LN SLE groups and between the non-LN group and healthy controls. However, there were increased levels of serum VEGF in the LN group, especially in patients with active nephritis as compared to quiescent nephritis group. This reflects the role of VEGF in the pathogenesis of lupus nephritis, however the clinical potential of this biomarker needs further study.

Biomarkers of World Trade Center Particulate Matter Exposure: Physiology of distal airway and blood biomarkers that predict FEV1 decline

PubMed Central

Weiden, Michael D.; Kwon, Sophia; Caraher, Erin; Berger, Kenneth I.; Reibman, Joan; Rom, William N.; Prezant, David J.; Nolan, Anna

2016-01-01

Biomarkers can be important predictors of disease severity and progression. The intense exposure to particulates and other toxins from the destruction of the World Trade Center (WTC) overwhelmed the lung’s normal protective barriers. The Fire Department of New York (FDNY) cohort not only had baseline pre-exposure lung function measures but also had serum samples banked soon after their WTC exposure. This well phenotyped group of highly exposed first responders is an ideal cohort for biomarker discovery and eventual validation. Disease progression was heterogeneous in this group in that some individuals subsequently developed abnormal lung function while others recovered. Airflow obstruction predominated in WTC exposed patients who were symptomatic. Multiple independent disease pathways may cause this abnormal FEV1 after irritant exposure. WTC exposure activates one or more of these pathways causing abnormal FEV1 in an individual. Our hypothesis was that serum biomarkers expressed within 6 months after World Trade Center (WTC) exposure reflect active disease pathways and predict subsequent development or protection from abnormal FEV1biomarkers of WTC-LI. We have identified biomarkers of Inflammation, metabolic derangement, protease/antiprotease balance and vascular injury expressed in serum within 6 months of WTC exposure that were predictive of their FEV1 up to 7 years after their WTC exposure. Predicting future risk of airway injury after particulate exposures can focus monitoring and early treatment on a subset of patients in greatest need of these services. PMID:26024341

Serum biomarkers of Burkholderia mallei infection elucidated by proteomic imaging of skin and lung abscesses.

PubMed

Glaros, Trevor G; Blancett, Candace D; Bell, Todd M; Natesan, Mohan; Ulrich, Robert G

2015-01-01

The bacterium Burkholderia mallei is the etiological agent of glanders, a highly contagious, often fatal zoonotic infectious disease that is also a biodefense concern. Clinical laboratory assays that analyze blood or other biological fluids are the highest priority because these specimens can be collected with minimal risk to the patient. However, progress in developing sensitive assays for monitoring B. mallei infection is hampered by a shortage of useful biomarkers. Reasoning that there should be a strong correlation between the proteomes of infected tissues and circulating serum, we employed imaging mass spectrometry (IMS) of thin-sectioned tissues from Chlorocebus aethiops (African green) monkeys infected with B. mallei to localize host and pathogen proteins that were associated with abscesses. Using laser-capture microdissection of specific regions identified by IMS and histology within the tissue sections, a more extensive proteomic analysis was performed by a technique that combined the physical separation capabilities of liquid chromatography (LC) with the sensitive mass analysis capabilities of mass spectrometry (LC-MS/MS). By examining standard formalin-fixed, paraffin-embedded tissue sections, this strategy resulted in the identification of several proteins that were associated with lung and skin abscesses, including the host protein calprotectin and the pathogen protein GroEL. Elevated levels of calprotectin detected by ELISA and antibody responses to GroEL, measured by a microarray of the bacterial proteome, were subsequently detected in the sera of C. aethiops, Macaca mulatta, and Macaca fascicularis primates infected with B. mallei. Our results demonstrate that a combination of multidimensional MS analysis of traditional histology specimens with high-content protein microarrays can be used to discover lead pairs of host-pathogen biomarkers of infection that are identifiable in biological fluids.

Biomarkers of gluten sensitivity in patients with non-affective psychosis: a meta-analysis.

PubMed

Lachance, Laura R; McKenzie, Kwame

2014-02-01

Dohan first proposed that there may be an association between gluten sensitivity and schizophrenia in the 1950s. Since then, this association has been measured using several different serum biomarkers of gluten sensitivity. At this point, it is unclear which serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia. However, evidence suggests that the immune response in this group is different from the immune response to gluten found in patients with Celiac disease. A systematic literature review was performed to identify all original articles that measured biomarkers of gluten sensitivity in patients with schizophrenia and non-affective psychoses compared to a control group. Three databases were used: Ovid MEDLINE, Psych INFO, and Embase, dating back to 1946. Forward tracking and backward tracking were undertaken on retrieved papers. A meta-analysis was performed of specific biomarkers and reported according to MOOSE guidelines. 17 relevant original articles were identified, and 12 met criteria for the meta-analysis. Five biomarkers of gluten sensitivity were found to be significantly elevated in patients with non-affective psychoses compared to controls. The pooled odds ratio and 95% confidence intervals were Anti-Gliadin IgG OR=2.31 [1.16, 4.58], Anti-Gliadin IgA OR=2.57 [1.13, 5.82], Anti-TTG2 IgA OR=5.86 [2.88, 11.95], Anti-Gliadin (unspecified isotype) OR=7.68 [2.07, 28.42], and Anti-Wheat OR=2.74 [1.06, 7.08]. Four biomarkers for gluten sensitivity, Anti-EMA IgA, Anti-TTG2 IgG, Anti-DGP IgG, and Anti-Gluten were not found to be associated with schizophrenia. Not all serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia. However, the specific immune response to gluten in this population differs from that found in patients with Celiac disease. Copyright © 2013 Elsevier B.V. All rights reserved.

Identifying cut points for biomarker defined subset effects in clinical trials with survival endpoints.

PubMed

He, Pei

2014-07-01

The advancements in biotechnology and genetics lead to an increasing research interest in personalized medicine, where a patient's genetic profile or biological traits contribute to choosing the most effective treatment for the patient. The process starts with finding a specific biomarker among all possible candidates that can best predict the treatment effect. After a biomarker is chosen, identifying a cut point of the biomarker value that splits the patients into treatment effective and non-effective subgroups becomes an important scientific problem. Numerous methods have been proposed to validate the predictive marker and select the appropriate cut points either prospectively or retrospectively using clinical trial data. In trials with survival outcomes, the current practice applies an interaction testing procedure and chooses the cut point that minimizes the p-values for the tests. Such method assumes independence between the baseline hazard and biomarker value. In reality, however, this assumption is often violated, as the chosen biomarker might also be prognostic in addition to its predictive nature for treatment effect. In this paper we propose a block-wise estimation and a sequential testing approach to identify the cut point in biomarkers that can group the patients into subsets based on their distinct treatment outcomes without assuming independence between the biomarker and baseline hazard. Numerical results based on simulated survival data show that the proposed method could pinpoint accurately the cut points in biomarker values that separate the patient subpopulations into subgroups with distinctive treatment outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

Biology and Biomarkers for Wound Healing.

PubMed

Lindley, Linsey E; Stojadinovic, Olivera; Pastar, Irena; Tomic-Canic, Marjana

2016-09-01

As the population grows older, the incidence and prevalence of conditions that lead to a predisposition for poor wound healing also increase. Ultimately, this increase in nonhealing wounds has led to significant morbidity and mortality with subsequent huge economic ramifications. Therefore, understanding specific molecular mechanisms underlying aberrant wound healing is of great importance. It has and will continue to be the leading pathway to the discovery of therapeutic targets, as well as diagnostic molecular biomarkers. Biomarkers may help identify and stratify subsets of nonhealing patients for whom biomarker-guided approaches may aid in healing. A series of literature searches were performed using Medline, PubMed, Cochrane Library, and Internet searches. Currently, biomarkers are being identified using biomaterials sourced locally from human wounds and/or systemically using high-throughput "omics" modalities (genomic, proteomic, lipidomic, and metabolomic analysis). In this review, we highlight the current status of clinically applicable biomarkers and propose multiple steps in validation and implementation spectrum, including those measured in tissue specimens, for example, β-catenin and c-myc, wound fluid, matrix metalloproteinases and interleukins, swabs, wound microbiota, and serum, for example, procalcitonin and matrix metalloproteinases. Identification of numerous potential biomarkers using different avenues of sample collection and molecular approaches is currently underway. A focus on simplicity and consistent implementation of these biomarkers, as well as an emphasis on efficacious follow-up therapeutics, is necessary for transition of this technology to clinically feasible point-of-care applications.

Identifying Subgroups of Tinnitus Using Novel Resting State fMRI Biomarkers and Cluster Analysis

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-2-0032 TITLE: Identifying Subgroups of Tinnitus Using Novel Resting State fMRI Biomarkers and Cluster Analysis PRINCIPAL...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Identifying Subgroups of Tinnitus Using Novel Resting State fMRI Biomarkers and Cluster Analysis 5b...Public Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The subject of the project is FY14 PRMRP Topic Area – Tinnitus . The broad

Identifying protein biomarkers in predicting disease severity of dengue virus infection using immune-related protein microarray.

PubMed

Soe, Hui Jen; Yong, Yean K; Al-Obaidi, Mazen M Jamil; Raju, Chandramathi Samudi; Gudimella, Ranganath; Manikam, Rishya; Sekaran, Shamala Devi

2018-02-01

Dengue virus is one of the most widespread flaviviruses that re-emerged throughout recent decades. The progression from mild dengue to severe dengue (SD) with the complications such as vascular leakage and hemorrhage increases the fatality rate of dengue. The pathophysiology of SD is not entirely clear. To investigate potential biomarkers that are suggestive of pathogenesis of SD, a small panel of serum samples selected from 1 healthy individual, 2 dengue patients without warning signs (DWS-), 2 dengue patients with warning signs (DWS+), and 5 patients with SD were subjected to a pilot analysis using Sengenics Immunome protein array. The overall fold changes of protein expressions and clustering heat map revealed that PFKFB4, TPM1, PDCL3, and PTPN20A were elevated among patients with SD. Differential expression analysis identified that 29 proteins were differentially elevated greater than 2-fold in SD groups than DWS- and DWS+. From the 29 candidate proteins, pathways enrichment analysis also identified insulin signaling and cytoskeleton pathways were involved in SD, suggesting that the insulin pathway may play a pivotal role in the pathogenesis of SD.

Glycosylation Changes in Serum Proteins Identify Patients with Pancreatic Cancer.

PubMed

Drabik, Anna; Bodzon-Kulakowska, Anna; Suder, Piotr; Silberring, Jerzy; Kulig, Jan; Sierzega, Marek

2017-04-07

After more than a decade of biomarker discovery using advanced proteomic and genomic approaches, very few biomarkers have been involved in clinical diagnostics. Most candidate biomarkers are focused on the protein component. Targeting post-translational modifications (PTMs) in combination with protein sequences will provide superior diagnostic information with regards to sensitivity and specificity. Glycosylation is one of the most common and functionally important PTMs. It plays a central role in many biological processes, including protein folding, host-pathogen interactions, immune response, and inflammation. Cancer-associated aberrant glycosylation has been identified in various types of cancer. Expression of cancer-specific glycan epitopes represents an excellent opportunity for diagnostics and potentially specific detection of tumors. Here, we report four proteins (LIFR, CE350, VP13A, HPT) found in sera from pancreatic cancer patients carrying aberrant glycan structures as compared to those of controls.

Prediagnostic Serum Biomarkers as Early Detection Tools for Pancreatic Cancer in a Large Prospective Cohort Study

PubMed Central

Nolen, Brian M.; Brand, Randall E.; Prosser, Denise; Velikokhatnaya, Liudmila; Allen, Peter J.; Zeh, Herbert J.; Grizzle, William E.; Lomakin, Aleksey; Lokshin, Anna E.

2014-01-01

Background The clinical management of pancreatic cancer is severely hampered by the absence of effective screening tools. Methods Sixty-seven biomarkers were evaluated in prediagnostic sera obtained from cases of pancreatic cancer enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Results The panel of CA 19-9, OPN, and OPG, identified in a prior retrospective study, was not effective. CA 19-9, CEA, NSE, bHCG, CEACAM1 and PRL were significantly altered in sera obtained from cases greater than 1 year prior to diagnosis. Levels of CA 19-9, CA 125, CEA, PRL, and IL-8 were negatively associated with time to diagnosis. A training/validation study using alternate halves of the PLCO set failed to identify a biomarker panel with significantly improved performance over CA 19-9 alone. When the entire PLCO set was used for training at a specificity (SP) of 95%, a panel of CA 19-9, CEA, and Cyfra 21-1 provided significantly elevated sensitivity (SN) levels of 32.4% and 29.7% in samples collected <1 and >1 year prior to diagnosis, respectively, compared to SN levels of 25.7% and 17.2% for CA 19-9 alone. Conclusions Most biomarkers identified in previously conducted case/control studies are ineffective in prediagnostic samples, however several biomarkers were identified as significantly altered up to 35 months prior to diagnosis. Two newly derived biomarker combinations offered advantage over CA 19-9 alone in terms of SN, particularly in samples collected >1 year prior to diagnosis. However, the efficacy of biomarker-based tools remains limited at present. Several biomarkers demonstrated significant velocity related to time to diagnosis, an observation which may offer considerable potential for enhancements in early detection. PMID:24747429

Serum Albumin and Body Weight as Biomarkers for the Antemortem Identification of Bone and Gastrointestinal Disease in the Common Marmoset

PubMed Central

Baxter, Victoria K.; Shaw, Gillian C.; Sotuyo, Nathaniel P.; Carlson, Cathy S.; Olson, Erik J.; Zink, M. Christine; Mankowski, Joseph L.; Adams, Robert J.

2013-01-01

The increasing use of the common marmoset (Callithrix jacchus) in research makes it important to diagnose spontaneous disease that may confound experimental studies. Bone disease and gastrointestinal disease are two major causes of morbidity and mortality in captive marmosets, but currently no effective antemortem tests are available to identify affected animals prior to the terminal stage of disease. In this study we propose that bone disease and gastrointestinal disease are associated disease entities in marmosets and aim to establish the efficacy of several economical antemortem tests in identifying and predicting disease. Tissues from marmosets were examined to define affected animals and unaffected controls. Complete blood count, serum chemistry values, body weight, quantitative radiographs, and tissue-specific biochemical markers were evaluated as candidate biomarkers for disease. Bone and gastrointestinal disease were associated, with marmosets being over seven times more likely to have either concurrent bone and gastrointestinal disease or neither disease as opposed to lesions in only one organ system. When used in tandem, serum albumin <3.5 g/dL and body weight <325 g identified 100% of the marmosets affected with concurrent bone and gastrointestinal disease. Progressive body weight loss of 0.05% of peak body weight per day predicted which marmosets would develop disease prior to the terminal stage. Bone tissue-specific tests, such as quantitative analysis of radiographs and serum parathyroid hormone levels, were effective for distinguishing between marmosets with bone disease and those without. These results provide an avenue for making informed decisions regarding the removal of affected marmosets from studies in a timely manner, preserving the integrity of research results. PMID:24324827

Cancer biomarker detection in serum samples using surface plasmon resonance and quartz crystal microbalance sensors with nanoparticle signal amplification.

PubMed

Uludag, Yildiz; Tothill, Ibtisam E

2012-07-17

Early detection of cancer is vital for the successful treatment of the disease. Hence, a rapid and sensitive diagnosis is essential before the cancer is spread out to the other body organs. Here we describe the development of a point-of-care immunosensor for the detection of the cancer biomarker (total prostate-specific antigen, tPSA) using surface plasmon resonance (SPR) and quartz crystal microbalance (QCM) sensor platforms in human serum samples. K(D) of the antibody used toward PSA was calculated as 9.46 × 10(-10) M, indicating high affinity of the antibody used in developing the assay. By performing a sandwich assay using antibody-modified nanoparticles concentrations of 2.3 ng mL(-1) (Au, 20 nm) and 0.29 ng mL(-1) (8.5 pM) (Au, 40 nm) tPSA in 75% human serum were detected using the developed assay on an SPR sensor chip. The SPR sensor results were found to be comparable to that achieved using a QCM sensor platform, indicating that both systems can be applied for disease biomarkers screening. The clinical applicability of the developed immunoassay can therefore be successfully applied to patient's serum samples. This demonstrates the high potential of the developed sensor devices as platforms for clinical prostate cancer diagnosis and prognosis.

Use of on-line supercritical fluid extraction-supercritical fluid chromatography/tandem mass spectrometry to analyze disease biomarkers in dried serum spots compared with serum analysis using liquid chromatography/tandem mass spectrometry.

PubMed

Suzuki, Makoto; Nishiumi, Shin; Kobayashi, Takashi; Sakai, Arata; Iwata, Yosuke; Uchikata, Takato; Izumi, Yoshihiro; Azuma, Takeshi; Bamba, Takeshi; Yoshida, Masaru

2017-05-30

The analytical stability and throughput of biomarker assays based on dried serum spots (DSS) are strongly dependent on the extraction process and determination method. In the present study, an on-line system based on supercritical fluid extraction-supercritical fluid chromatography coupled with tandem mass spectrometry (SFE-SFC/MS/MS) was established for analyzing the levels of disease biomarkers in DSS. The chromatographic conditions were investigated using the ODS-EP, diol, and SIL-100A columns. Then, we optimized the SFE-SFC/MS/MS method using the diol column, focusing on candidate biomarkers of oral, colorectal, and pancreatic cancer that were identified using liquid chromatography (LC)/MS/MS. By using this system, four hydrophilic metabolites and 17 hydrophobic metabolites were simultaneously detected within 15 min. In an experiment involving clinical samples, PC 16:0-18:2/16:1-18:1 exhibited 93.8% sensitivity and 64.3% specificity, whereas PC 17:1-18:1/17:0-18:2 showed 81.3% sensitivity and 92.9% specificity for detecting oral cancer. In addition, assessments of the creatine levels demonstrated 92.3% sensitivity and 78.6% specificity for detecting colorectal cancer. The results of this study indicate that our method has great potential for clinical diagnosis and would be suitable for large-scale screening. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

The diagnostic effect of serum miR-196b as biomarker in colorectal cancer

PubMed Central

Xu, Chunjie; Gu, Lei

2017-01-01

The microRNA, miR-196b, serves a role in normal cell differentiation, proliferation and tumorigenesis of different types of cancer. The aim of the present study was to explore the serum expression of miR-196b in colorectal cancer (CRC) and its correlation with clinicopathological features. Sera samples were obtained from 103 patients with CRC, 51 patients with colorectal adenoma (Ad) and 100 healthy individuals for the present study. The serum expression of miR-196b in sera samples of the three cohorts was detected using reverse transcription-quantitative polymerase chain reaction. The diagnostic value of miR-196b in the serum of the patients with CRC was evaluated by receiver operating characteristic (ROC) curve and survival analysis, using the Kaplan-Meier method, which was performed with the data from a 5-year follow-up. The expression of miR-196b in the serum of patients with CRC was significantly higher compared with that in Ad patients or healthy individuals (all P<0.001), and the overexpression of serum miR-196b was clearly associated with lymph node invasion, differentiation, and the tumor-lymph nodes-metastasis stage (all P<0.05). ROC curve analysis demonstrated that, comparing patients with CRC with healthy individuals, the area under the curve of serum miR-196b was 0.8135, and its specificity and sensitivity were 63 and 87.38%, respectively, at a diagnostic threshold of −4.785. Patients with CRC of miR-196b-high status had shorter overall survival and disease-free survival rates compared with those of miR-196b-low status. In conclusion, the results of the present study demonstrated that serum miR-196b is upregulated in CRC, and may have an application as a diagnostic and prognostic biomarker for patients with CRC. PMID:28123705

Correlation of serum MMP3 and other biomarkers with clinical outcomes in patients with ankylosing spondylitis: A pilot study

USDA-ARS?s Scientific Manuscript database

The studies aimed to assess a set of biomarkers for their correlations with disease activity/severity of patients with ankylosing spondylitis (AS). A total of 24 AS patients were treated with etanercept and prospectively followed for 12 weeks. Serum levels of TNF-alpha, IFN-gamma, TGF-beta, IL6, IL1...

Delayed Imatinib Treatment for Acute Spinal Cord Injury: Functional Recovery and Serum Biomarkers

PubMed Central

Finn, Anja; Hao, Jingxia; Wellfelt, Katrin; Josephson, Anna; Svensson, Camilla I.; Wiesenfeld-Hallin, Zsuzsanna; Eriksson, Ulf; Abrams, Mathew

2015-01-01

Abstract With no currently available drug treatment for spinal cord injury, there is a need for additional therapeutic candidates. We took the approach of repositioning existing pharmacological agents to serve as acute treatments for spinal cord injury and previously found imatinib to have positive effects on locomotor and bladder function in experimental spinal cord injury when administered immediately after the injury. However, for imatinib to have translational value, it needs to have sustained beneficial effects with delayed initiation of treatment, as well. Here, we show that imatinib improves hind limb locomotion and bladder recovery when initiation of treatment was delayed until 4 h after injury and that bladder function was improved with a delay of up to 24 h. The treatment did not induce hypersensitivity. Instead, imatinib-treated animals were generally less hypersensitive to either thermal or mechanical stimuli, compared with controls. In an effort to provide potential biomarkers, we found serum levels of three cytokines/chemokines—monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-3α, and keratinocyte chemoattractant/growth-regulated oncogene (interleukin 8)—to increase over time with imatinib treatment and to be significantly higher in injured imatinib-treated animals than in controls during the early treatment period. This correlated to macrophage activation and autofluorescence in lymphoid organs. At the site of injury in the spinal cord, macrophage activation was instead reduced by imatinib treatment. Our data strengthen the case for clinical trials of imatinib by showing that initiation of treatment can be delayed and by identifying serum cytokines that may serve as candidate markers of effective imatinib doses. PMID:25914996

Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury.

PubMed

Moledina, Dennis G; Hall, Isaac E; Thiessen-Philbrook, Heather; Reese, Peter P; Weng, Francis L; Schröppel, Bernd; Doshi, Mona D; Wilson, F Perry; Coca, Steven G; Parikh, Chirag R

2017-12-01

The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown. Cross-sectional analysis from multicenter prospective cohort. Hospitalized deceased kidney donors on whom kidney biopsies were performed at the time of organ procurement for histologic evaluation. (1) AKI diagnosed by change in Scr concentration during donor hospitalization and (2) concentrations of urinary biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], liver-type fatty acid-binding protein [L-FABP], interleukin 18 [IL-18], and kidney injury molecule 1 [KIM-1]) measured at organ procurement. Histologic acute tubular injury. Of 581 donors, 98 (17%) had mild acute tubular injury and 57 (10%) had severe acute tubular injury. Overall, Scr-based AKI had poor diagnostic performance for identifying histologic acute tubular injury and 49% of donors with severe acute tubular injury did not have AKI. The area under the receiver operating characteristic curve (AUROC) of change in Scr concentration for diagnosing severe acute tubular injury was 0.58 (95% CI, 0.49-0.67) and for any acute tubular injury was 0.52 (95% CI, 0.45-0.58). Compared with Scr concentration, NGAL concentration demonstrated higher AUROC for diagnosing both severe acute tubular injury (0.67; 95% CI, 0.60-0.74; P=0.03) and any acute tubular injury (0.60; 95% CI, 0.55-0.66; P=0.005). In donors who did not have Scr-based AKI, NGAL concentrations were higher with increasing severities of acute tubular injury (subclinical AKI). However, compared with Scr concentration, AUROCs for acute tubular injury diagnosis were not significantly higher for urinary L

Can Serum Neutrophil-to-Lymphocyte Ratio Be a Predictive Biomarker to Help Differentiate Active Chronic Otitis Media From Inactive Chronic Otitis Media?

PubMed

Tansuker, Hasan Deniz; Eroğlu, Sinan; Yenigün, Alper; Taşkin, Ümit; Oktay, Mehmet Faruk

2017-05-01

The authors' aim was to investigate whether serum neutrophil to lymphocyte ratio might be used as a predictive biomarker to help differentiate active from inactive chronic otitis media (COM). Two hundred fifty-nine patients having inactive COM received tympanoplasty without mastoidectomy and were identified as Group 1. On the other hand, 254 patients having active COM received tympanoplasty with mastoidectomy and were identified as Group 2. Routine hemogram tests were performed preoperatively for both the groups. By performing a chart review, white blood cell count, red blood cell count, hemoglobin, hematocrit, platelet, and mean platelet volume values were compared between the groups in an age-matched and sex-matched manner. A total of 513 COM patients with age range of 7 to 65 years were included in the study. Two hundred seventy-five patients (53.6%) were male, 238 were (46.4%) female. Preoperatively both serum neutrophil and lymphocyte counts were significantly higher in Group 2 (P = 0.015 and P = 0.004, respectively). However, the neutrophil-to-lymphocyte ratios between the groups were not significantly different (P = 0.511). No statistically significant differences were identified from preoperative neutrophil-to-lymphocyte ratios between patients having active COM and inactive COM. Level NA.

Biomarkers of Alzheimer’s Disease Among Mexican Americans

PubMed Central

O’Bryant, Sid E.; Xiao, Guanghua; Edwards, Melissa; Devous, Michael; Gupta, Veer Bala; Martins, Ralph; Zhang, Fan; Barber, Robert

2013-01-01

Background Mexican Americans are the fastest aging segment of the U.S. population yet little scientific literature exists regarding the Alzheimer disease (AD) among this segment of the population. The extant literature suggests that biomarkers of AD will vary according to race/ethnicity though no prior work has explicitly studied this possibility. The aim of this study was to create a serum-based biomarker profile of AD among Mexican American. Methods Data were analyzed from 363 Mexican American participants (49 AD and 314 normal controls) enrolled in the Texas Alzheimer’s Research & Care Consortium (TARCC). Non-fasting serum samples were analyzed using a luminex-based multi-plex platform. A biomarker profile was generated using random forest analyses. Results The biomarker profile of AD among Mexican Americans was different from prior work from non-Hispanic populations with regards to the variable importance plots. In fact, many of the top markers were related to metabolic factors (e.g. FABP, GLP-1, CD40, pancreatic polypeptide, insulin-like-growth factor, and insulin). The biomarker profile was a significant classifier of AD status yielding an area under the receiver operating characteristic curve (AUC), sensitivity (SN) and specificity (SP) of 0.77, 0.92 and 0.64, respectively. Combining biomarkers with clinical variables yielded a better balance of SN and SP. Conclusion The biomarker profile for AD among Mexican American cases is significantly different from that previously identified among non-Hispanic cases from many large-scale studies. This is the first study to explicitly examine and provide support for blood-based biomarkers of AD among Mexican Americans. Areas for future research are highlighted. PMID:23313927

An Automated Microfluidic Assay for Photonic Crystal Enhanced Detection and Analysis of an Antiviral Antibody Cancer Biomarker in Serum

DOE PAGES

Race, Caitlin M.; Kwon, Lydia E.; Foreman, Myles T.; ...

2017-11-24

Here, we report on the implementation of an automated platform for detecting the presence of an antibody biomarker for human papillomavirus-associated oropharyngeal cancer from a single droplet of serum, in which a nanostructured photonic crystal surface is used to amplify the output of a fluorescence-linked immunosorbent assay. The platform is comprised of a microfluidic cartridge with integrated photonic crystal chips that interfaces with an assay instrument that automates the introduction of reagents, wash steps, and surface drying. Upon assay completion, the cartridge interfaces with a custom laser-scanning instrument that couples light into the photonic crystal at the optimal resonance conditionmore » for fluorescence enhancement. The instrument is used to measure the fluorescence intensity values of microarray spots corresponding to the biomarkers of interest, in addition to several experimental controls that verify correct functioning of the assay protocol. In this work, we report both dose-response characterization of the system using anti-E7 antibody introduced at known concentrations into serum and characterization of a set of clinical samples from which results were compared with a conventional enzyme-linked immunosorbent assay (ELISA) performed in microplate format. Finally, the demonstrated capability represents a simple, rapid, automated, and high-sensitivity method for multiplexed detection of protein biomarkers from a low-volume test sample.« less

An Automated Microfluidic Assay for Photonic Crystal Enhanced Detection and Analysis of an Antiviral Antibody Cancer Biomarker in Serum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Race, Caitlin M.; Kwon, Lydia E.; Foreman, Myles T.

Here, we report on the implementation of an automated platform for detecting the presence of an antibody biomarker for human papillomavirus-associated oropharyngeal cancer from a single droplet of serum, in which a nanostructured photonic crystal surface is used to amplify the output of a fluorescence-linked immunosorbent assay. The platform is comprised of a microfluidic cartridge with integrated photonic crystal chips that interfaces with an assay instrument that automates the introduction of reagents, wash steps, and surface drying. Upon assay completion, the cartridge interfaces with a custom laser-scanning instrument that couples light into the photonic crystal at the optimal resonance conditionmore » for fluorescence enhancement. The instrument is used to measure the fluorescence intensity values of microarray spots corresponding to the biomarkers of interest, in addition to several experimental controls that verify correct functioning of the assay protocol. In this work, we report both dose-response characterization of the system using anti-E7 antibody introduced at known concentrations into serum and characterization of a set of clinical samples from which results were compared with a conventional enzyme-linked immunosorbent assay (ELISA) performed in microplate format. Finally, the demonstrated capability represents a simple, rapid, automated, and high-sensitivity method for multiplexed detection of protein biomarkers from a low-volume test sample.« less

Serum insulin-like growth factor-1 (IGF-1) during CF pulmonary exacerbation: trends and biomarker correlations.

PubMed

Gifford, A H; Nymon, A B; Ashare, A

2014-04-01

Cystic fibrosis (CF) is characterized by low circulating levels of insulin-like growth factor-1 (IGF-1), a hormone produced by the liver that governs anabolism and influences immune cell function. Because treatment of CF pulmonary exacerbation (CFPE) often improves body weight and lung function, we questioned whether serum IGF-1 trends were emblematic of these responses. Initially, we compared serum levels between healthy adults with CF and controls of similar age. We then measured serum IGF-1 throughout the CFPE cycle. We also investigated correlations among IGF-1 and other serum biomarkers during CFPE. Anthopometric, spirometric, and demographic data were collected. Serum IGF-1 concentrations were measured by ELISA. CF subjects in their usual state of health had lower serum IGF-1 levels than controls. Serum IGF-1 concentrations fell significantly from baseline at the beginning of CFPE. Treatment with intravenous antibiotics was associated with significant improvement in serum IGF-1 levels, body mass index (BMI), and percent-predicted forced expiratory volume in 1 sec (FEV1 %). At early and late CFPE, serum IGF-1 was directly correlated with FEV1 %, serum iron, hemoglobin concentration, and transferrin saturation (TSAT) and indirectly correlated with alpha-1-antitrypsin. This study not only supports the paradigm that CF is characterized by IGF-1 deficiency but also that trends in lung function, nutritional status, and serum IGF-1 are related. Improvements in all three parameters after antibiotics for CFPE likely highlight the connection between lung function and nutritional status in CF. Close correlations among IGF-1 and iron-related hematologic parameters suggest that IGF-1 may participate in CF iron homeostasis, another process that is known to be influenced by CFPE. © 2013 Wiley Periodicals, Inc.

Serum C-reactive protein as a diagnostic biomarker in dogs with bacterial respiratory diseases.

PubMed

Viitanen, S J; Laurila, H P; Lilja-Maula, L I; Melamies, M A; Rantala, M; Rajamäki, M M

2014-01-01

C-reactive protein (CRP) is a major acute-phase protein in dogs. Serum concentrations are low in healthy animals, but increase rapidly after inflammatory stimuli. The aim of the study was to investigate CRP concentrations in various respiratory diseases of dogs and to determine if CRP can be used as a biomarker in the diagnosis of bacterial respiratory diseases. A total of 106 privately owned dogs with respiratory diseases (17 with bacterial tracheobronchitis [BTB], 20 with chronic bronchitis [CB], 20 with eosinophilic bronchopneumopathy [EBP], 12 with canine idiopathic pulmonary fibrosis [CIPF], 15 with cardiogenic pulmonary edema [CPE], and 22 with bacterial pneumonia [BP]) and 72 healthy controls. The study was conducted as a prospective cross-sectional observational study. CRP was measured in serum samples. Diagnosis was confirmed by clinical and laboratory findings, diagnostic imaging, and selected diagnostic methods such as cytological and microbiological analysis of respiratory samples, echocardiography, and histopathology. Dogs with BP had significantly higher CRP concentrations (median, 121 mg/L; interquartile range, 68-178 mg/L) than dogs with BTB (23, 15-38, P = .0003), CB (13, 8-14, P < .0001), EBP (5, 5-15, P < .0001), CIPF (17, 10-20, P < .0001), or CPE (19, 13-32, P < .0001) and healthy controls (14, 8-20, P < .0001). Dogs with BTB had significantly higher CRP concentrations than dogs with CB (P = .001) or EBP (P < .0001) and healthy controls (P = .029). These results indicate that CRP has potential for use as an additional biomarker, especially in the diagnostics of BP. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Three novel serum biomarkers, miR-1, miR-133a, and miR-206 for Limb-girdle muscular dystrophy, Facioscapulohumeral muscular dystrophy, and Becker muscular dystrophy.

PubMed

Matsuzaka, Yasunari; Kishi, Soichiro; Aoki, Yoshitsugu; Komaki, Hirofumi; Oya, Yasushi; Takeda, Shin-Ichi; Hashido, Kazuo

2014-11-01

Muscular dystrophies are a clinically and genetically heterogeneous group of inherited myogenic disorders. In clinical tests for these diseases, creatine kinase (CK) is generally used as diagnostic blood-based biomarker. However, because CK levels can be altered by various other factors, such as vigorous exercise, etc., false positive is observed. Therefore, three microRNAs (miRNAs), miR-1, miR-133a, and miR-206, were previously reported as alternative biomarkers for duchenne muscular dystrophy (DMD). However, no alternative biomarkers have been established for the other muscular dystrophies. We, therefore, evaluated whether these miR-1, miR-133a, and miR-206 can be used as powerful biomarkers using the serum from muscular dystrophy patients including DMD, myotonic dystrophy 1 (DM1), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), becker muscular dystrophy (BMD), and distal myopathy with rimmed vacuoles (DMRV) by qualitative polymerase chain reaction (PCR) amplification assay. Statistical analysis indicated that all these miRNA levels in serum represented no significant differences between all muscle disorders examined in this study and controls by Bonferroni correction. However, some of these indicated significant differences without correction for testing multiple diseases (P < 0.05). The median values of miR-1 levels in the serum of patients with LGMD, FSHD, and BMD were approximately 5.5, 3.3 and 1.7 compared to that in controls, 0.68, respectively. Similarly, those of miR-133a and miR-206 levels in the serum of BMD patients were about 2.5 and 2.1 compared to those in controls, 1.03 and 1.32, respectively. Taken together, our data demonstrate that levels of miR-1, miR-133a, and miR-206 in serum of BMD and miR-1 in sera of LGMD and FSHD patients showed no significant differences compared with those of controls by Bonferroni correction. However, the results might need increase in sample sizes to evaluate these three miRNAs as

Targeted Metabolomics Identifies Pharmacodynamic Biomarkers for BIO 300 Mitigation of Radiation-Induced Lung Injury.

PubMed

Jones, Jace W; Jackson, Isabel L; Vujaskovic, Zeljko; Kaytor, Michael D; Kane, Maureen A

2017-12-01

Biomarkers serve a number of purposes during drug development including defining the natural history of injury/disease, serving as a secondary endpoint or trigger for intervention, and/or aiding in the selection of an effective dose in humans. BIO 300 is a patent-protected pharmaceutical formulation of nanoparticles of synthetic genistein being developed by Humanetics Corporation. The primary goal of this metabolomic discovery experiment was to identify biomarkers that correlate with radiation-induced lung injury and BIO 300 efficacy for mitigating tissue damage based upon the primary endpoint of survival. High-throughput targeted metabolomics of lung tissue from male C57L/J mice exposed to 12.5 Gy whole thorax lung irradiation, treated daily with 400 mg/kg BIO 300 for either 2 weeks or 6 weeks starting 24 h post radiation exposure, were assayed at 180 d post-radiation to identify potential biomarkers. A panel of lung metabolites that are responsive to radiation and able to distinguish an efficacious treatment schedule of BIO 300 from a non-efficacious treatment schedule in terms of 180 d survival were identified. These metabolites represent potential biomarkers that could be further validated for use in drug development of BIO 300 and in the translation of dose from animal to human.

Associations between serum ghrelin and knee symptoms, joint structures and cartilage or bone biomarkers in patients with knee osteoarthritis.

PubMed

Wu, J; Wang, K; Xu, J; Ruan, G; Zhu, Q; Cai, J; Ren, J; Zheng, S; Zhu, Z; Otahal, P; Ding, C

2017-09-01

The roles of ghrelin in knee osteoarthritis (OA) are unclear. This study aimed to examine cross-sectional associations of ghrelin with knee symptoms, joint structures and cartilage or bone biomarkers in patients with knee OA. This study included 146 patients with symptomatic knee OA. Serum levels of ghrelin and cartilage or bone biomarkers including cartilage oligomeric matrix protein (COMP), cross linked C-telopeptide of type I collagen (CTXI), cross linked N-telopeptide of type I collagen (NTXI), N-terminal procollagen III propeptide (PIIINP), and matrix metalloproteinase (MMP)-3, 10, 13 were measured using Enzyme-linked immunosorbent assay (ELISA). Knee symptoms were assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Infrapatellar fat pad (IPFP) volume, IPFP signal intensity alternation, cartilage defects, bone marrow lesions (BMLs) and effusion-synovitis were assessed using the (MRI). Osteophytes and joint space narrowing (JSN) were assessed using the Osteoarthritis Research Society International atlas. After adjustment for potential confounders, ghrelin quartiles were positively associated with knee symptoms including pain, stiffness, dysfunction and total score (quartile 4 vs 1: β 24.19, 95% CI 8.13-40.25). Ghrelin quartiles were also significantly associated with increased IPFP signal intensity alteration (quartile 4 vs 1: OR 3.57, 95% CI 1.55-8.25) and NTXI, PIIINP, MMP3 and MMP13. Ghrelin was not significantly associated with other joint structures and biomarkers. Serum levels of ghrelin were significantly associated with increased knee symptoms, IPFP signal intensity alteration and serum levels of MMP3, MMP13, NTXI and PIIINP, suggesting that ghrelin may have a role to play in knee OA. Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Biology and Biomarkers for Wound Healing

PubMed Central

Lindley, Linsey E.; Stojadinovic, Olivera; Pastar, Irena; Tomic-Canic, Marjana

2016-01-01

Background As the population grows older, the incidence and prevalence of conditions which lead to a predisposition for poor wound healing also increases. Ultimately, this increase in non-healing wounds has led to significant morbidity and mortality with subsequent huge economic ramifications. Therefore, understanding specific molecular mechanisms underlying aberrant wound healing is of great importance. It has, and will continue to be the leading pathway to the discovery of therapeutic targets as well as diagnostic molecular biomarkers. Biomarkers may help identify and stratify subsets of non-healing patients for whom biomarker-guided approaches may aid in healing. Methods A series of literature searches were performed using Medline, PubMed, Cochrane Library, and Internet searches. Results Currently, biomarkers are being identified using biomaterials sourced locally, from human wounds and/or systemically using systematic high-throughput “omics” modalities (genomic, proteomic, lipidomic, metabolomic analysis). In this review we highlight the current status of clinically applicable biomarkers and propose multiple steps in validation and implementation spectrum including those measured in tissue specimens e.g. β-catenin and c-myc, wound fluid e.g. MMP’s and interleukins, swabs e.g. wound microbiota and serum e.g. procalcitonin and MMP’s. Conclusions Identification of numerous potential biomarkers utilizing different avenues of sample collection and molecular approaches is currently underway. A focus on simplicity, and consistent implementation of these biomarkers as well as an emphasis on efficacious follow-up therapeutics is necessary for transition of this technology to clinically feasible point-of-care applications. PMID:27556760

Myelin protein zero and its antibody in serum as biomarkers of n-hexane-induced peripheral neuropathy and neurotoxicity effects.

PubMed

Jia, Xiaowei; Liu, Qingjun; Zhang, Yanshu; Dai, Yufei; Duan, Huawei; Bin, Ping; Niu, Yong; Liu, Jie; Zhong, Liuzhen; Guo, Jisheng; Liu, Xiaofeng; Zheng, Yuxin

2014-01-01

Chronic exposure to n-hexane can lead to peripheral neuropathy that no effective treatment regimen could be applied presently. This study investigated whether myelin protein zero (P0) protein and its antibody could be used to distinguish n-hexane intoxication and protect workers from peripheral neuropathy. We compared P0 protein and its antibody among three levels of n-hexane-exposed groups, which included 18 patients with n-hexane-induced peripheral neuropathy as case group, 120 n-hexane-exposed workers as n-hexaneexposed control group, and 147 non-hexane-exposed participants used as control group. ELISA method was applied to detect P0 protein and its antibody. P0 protein in serum was significantly higher in the case group and n-hexane-exposed control group in comparison with the control group (P < 0.01). Compared with the n-hexane-exposed control group, the case group also had significant increase of P0 protein (P < 0.01). After 6 months therapy, P0 protein was observed to decrease significantly in the case group (P < 0.01). The P0 antibody in serum was significantly higher in the n-hexane-exposed control group than in the control group (P < 0.01), but not significantly different between cases and controls. P0 antibodies in serum may be a short-term effect biomarker for n-hexane exposure. P0 protein in serum may be an early effective biomarker for peripheral nerve neuropathy and its biological limit value needs investigation in the future study.

Nonclinical evaluation of the serum pharmacodynamic biomarkers HGF and shed MET following dosing with the anti-MET monovalent monoclonal antibody onartuzumab.

PubMed

Mai, Elaine; Zheng, Zhong; Chen, Youjun; Peng, Jing; Severin, Christophe; Filvaroff, Ellen; Romero, Mally; Mallet, William; Kaur, Surinder; Gelzleichter, Thomas; Nijem, Ihsan; Merchant, Mark; Young, Judy C

2014-02-01

Onartuzumab, a humanized, monovalent monoclonal anti-MET antibody, antagonizes MET signaling by inhibiting binding of its ligand, hepatocyte growth factor (HGF). We investigated the effects of onartuzumab on cell-associated and circulating (shed) MET (sMET) and circulating HGF in vitro and nonclinically to determine their utility as pharmacodynamic biomarkers for onartuzumab. Effects of onartuzumab on cell-associated MET were assessed by flow cytometry and immunofluorescence. sMET and HGF were measured in cell supernatants and in serum or plasma from multiple species (mouse, cynomolgus monkey, and human) using plate-based immunoassays. Unlike bivalent anti-MET antibodies, onartuzumab stably associates with MET on the surface of cells without inducing MET internalization or shedding. Onartuzumab delayed the clearance of human xenograft tumor-produced sMET from the circulation of mice, and endogenous sMET in cynomolgus monkeys. In mice harboring MET-expressing xenograft tumors, in the absence of onartuzumab, levels of human sMET correlated with tumor size, and may be predictive of MET-expressing tumor burden. Because binding of sMET to onartuzumab in circulation resulted in increasing sMET serum concentrations due to reduced clearance, this likely renders sMET unsuitable as a pharmacodynamic biomarker for onartuzumab. There was no observed effect of onartuzumab on circulating HGF levels in xenograft tumor-bearing mice or endogenous HGF in cynomolgus monkeys. Although sMET and HGF may serve as predictive biomarkers for MET therapeutics, these data do not support their use as pharmacodynamic biomarkers for onartuzumab.

Genomic analysis, cytokine expression, and microRNA profiling reveal biomarkers of human dietary zinc depletion and homeostasis.

PubMed

Ryu, Moon-Suhn; Langkamp-Henken, Bobbi; Chang, Shou-Mei; Shankar, Meena N; Cousins, Robert J

2011-12-27

Implementation of zinc interventions for subjects suspected of being zinc-deficient is a global need, but is limited due to the absence of reliable biomarkers. To discover molecular signatures of human zinc deficiency, a combination of transcriptome, cytokine, and microRNA analyses was applied to a dietary zinc depletion/repletion protocol with young male human subjects. Concomitant with a decrease in serum zinc concentration, changes in buccal and blood gene transcripts related to zinc homeostasis occurred with zinc depletion. Microarray analyses of whole blood RNA revealed zinc-responsive genes, particularly, those associated with cell cycle regulation and immunity. Responses of potential signature genes of dietary zinc depletion were further assessed by quantitative real-time PCR. The diagnostic properties of specific serum microRNAs for dietary zinc deficiency were identified by acute responses to zinc depletion, which were reversible by subsequent zinc repletion. Depression of immune-stimulated TNFα secretion by blood cells was observed after low zinc consumption and may serve as a functional biomarker. Our findings introduce numerous novel candidate biomarkers for dietary zinc status assessment using a variety of contemporary technologies and which identify changes that occur prior to or with greater sensitivity than the serum zinc concentration which represents the current zinc status assessment marker. In addition, the results of gene network analysis reveal potential clinical outcomes attributable to suboptimal zinc intake including immune function defects and predisposition to cancer. These demonstrate through a controlled depletion/repletion dietary protocol that the illusive zinc biomarker(s) can be identified and applied to assessment and intervention strategies.

Serum Levels of Toxic AGEs (TAGE) May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases.

PubMed

Takeuchi, Masayoshi

2016-06-07

Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE)), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer's disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD.

Serum Levels of Toxic AGEs (TAGE) May Be a Promising Novel Biomarker for the Onset/Progression of Lifestyle-Related Diseases

PubMed Central

Takeuchi, Masayoshi

2016-01-01

Advanced glycation end-products (AGEs) generated with aging or in the presence of diabetes mellitus, particularly AGEs derived from the glucose/fructose metabolism intermediate glyceraldehyde (Glycer-AGEs; termed toxic AGEs (TAGE)), were recently shown to be closely involved in the onset/progression of diabetic vascular complications via the receptor for AGEs (RAGE). TAGE also contribute to various diseases, such as cardiovascular disease; nonalcoholic steatohepatitis; cancer; Alzheimer’s disease, and; infertility. This suggests the necessity of minimizing the influence of the TAGE-RAGE axis in order to prevent the onset/progression of lifestyle-related diseases (LSRD) and establish therapeutic strategies. Changes in serum TAGE levels are closely associated with LSRD related to overeating, a lack of exercise, or excessive ingestion of sugars/dietary AGEs. We also showed that serum TAGE levels, but not those of hemoglobin A1c, glucose-derived AGEs, or Nε-(carboxymethyl)lysine, have potential as a biomarker for predicting the progression of atherosclerosis and future cardiovascular events. We herein introduce the usefulness of serum TAGE levels as a biomarker for the prevention/early diagnosis of LSRD and the evaluation of the efficacy of treatments; we discuss whether dietary AGE/sugar intake restrictions reduce the generation/accumulation of TAGE, thereby preventing the onset/progression of LSRD. PMID:27338481

Salivary Biomarkers, Oral Inflammation, and Functional Status in Patients With Heart Failure.

PubMed

Dekker, Rebecca L; Lennie, Terry A; Moser, Debra K; Miller, Craig S; Ebersole, Jeffrey L; Chung, Misook L; Campbell, Charles L; Bailey, Alison; Tovar, Elizabeth G

2017-03-01

To describe correlations and agreement between salivary and serum B-type natriuretic peptide (BNP), C-reactive protein (CRP), interleukin (IL)-6, and IL-10 and determine which biomarkers predict worse functional class in patients with heart failure (HF). Serum and saliva were collected from 75 hospitalized patients with HF (57 ± 12 years, 43% female, New York Heart Association [NYHA] Classes I [4%], II [43%], and III [53%]). Oral inflammation was rated as good, fair, or poor. Spearman's ρ and Bland-Altman were used to determine correlations and agreement of the salivary and serum forms of each biomarker. Logistic regressions were used to determine which biomarkers predicted worse NYHA functional class, controlling for depression, body mass index, smoking, and oral inflammation. Median biomarker concentrations were as follows: BNP (serum 361 pg/ml, saliva 9 pg/ml), CRP (serum 13 ng/ml, saliva 25.6 ng/ml), IL-6 (serum 19.3 pg/ml, saliva 10.5 pg/ml), and IL-10 (serum 64.1 pg/ml, saliva 4.7 pg/ml). There was a moderate-to-strong correlation for serum-salivary CRP, weak correlation for serum-salivary IL-6, and no correlations for serum-salivary BNP and IL-10. The Bland-Altman test showed good salivary-serum agreement for all biomarkers, but as serum concentrations rose, salivary measures underestimated serum levels. Visible oral inflammation was the only predictor of worse NYHA class.

Proteoglycan 4 is a diagnostic biomarker for COPD.

PubMed

Lee, Kang-Yun; Chuang, Hsiao-Chi; Chen, Tzu-Tao; Liu, Wen-Te; Su, Chien-Ling; Feng, Po-Hao; Chiang, Ling-Ling; Bien, Mauo-Ying; Ho, Shu-Chuan

2015-01-01

The measurement of C-reactive protein (CRP) to confirm the stability of COPD has been reported. However, CRP is a systemic inflammatory biomarker that is related to many other diseases. The objective of this study is to discover a diagnostic biomarker for COPD. Sixty-one subjects with COPD and 15 healthy controls (10 healthy non-smokers and 5 smokers) were recruited for a 1-year follow-up study. Data regarding the 1-year acute exacerbation frequency and changes in lung function were collected. CRP and the identified biomarkers were assessed in the validation COPD cohort patients and healthy subjects. Receiver operating characteristic values of CRP and the identified biomarkers were determined. A validation COPD cohort was used to reexamine the identified biomarker. Correlation of the biomarker with 1-year lung function decline was determined. Proteoglycan 4 (PRG4) was identified as a biomarker in COPD. The serum concentrations of PRG4 in COPD Global initiative for chronic Obstructive Lung Disease (GOLD) stages 1+2 and 3+4 were 10.29 ng/mL and 13.20 ng/mL, respectively; 4.99 ng/mL for healthy controls (P<0.05); and 4.49 ng/mL for healthy smokers (P<0.05). PRG4 was more sensitive and specific than CRP for confirming COPD severity and acute exacerbation frequency. There was no correlation between CRP and PRG4 levels, and PRG4 was negatively correlated with the 1-year change in predicted forced vital capacity percent (R (2)=0.91, P=0.013). PRG4 may be a biomarker for identification of severity in COPD. It was related to the 1-year forced vital capacity decline in COPD patients.

Using non-invasive biomarkers to identify hepatic fibrosis in people with type 2 diabetes mellitus: the Edinburgh type 2 diabetes study.

PubMed

Morling, Joanne R; Fallowfield, Jonathan A; Guha, Indra N; Nee, Lisa D; Glancy, Stephen; Williamson, Rachel M; Robertson, Christine M; Strachan, Mark W J; Price, Jackie F

2014-02-01

It is difficult to determine the different stages of non-alcoholic fatty liver disease without the use of invasive liver biopsy. In this study we investigated five non-invasive biomarkers used previously to detect hepatic fibrosis and determined the level of agreement between them in order to inform future research. In the Edinburgh Type 2 Diabetes Study, a population-based cohort aged 60-74 years with type 2 diabetes, 831 participants underwent ultrasound assessment for fatty liver and had serum aspartate aminotransferase to alanine aminotransferase ratio (AST/ALT), aspartate to platelet ratio index (APRI), European Liver Fibrosis panel (ELF), Fibrosis-4 Score (FIB4) and liver stiffness measurement (LSM) measured. Literature based cut-offs yielded marked differences in the proportions of the cohort with probable liver fibrosis in the full cohort. Agreement between the top 5% of the distribution for each biomarker pair was poor. APRI and FIB4 had the best positive agreement at 76.4%, but agreement for all of the other serum biomarker pairs was between 18% and 34%. Agreement with LSM was poor (9-16%). We found poor correlation between the five biomarkers of liver fibrosis studied. Using the top 5% of each biomarker resulted in good agreement on the absence of advanced liver disease but poor agreement on the presence of advanced disease. Further work is required to validate these markers against liver biopsy and to determine their predictive value for clinical liver-related endpoints, in a range of different low and high risk population groups.

Biomarkers in Prodromal Parkinson Disease: a Qualitative Review.

PubMed

Cooper, Christine A; Chahine, Lama M

2016-11-01

Over the past several years, the concept of prodromal Parkinson disease (PD) has been increasingly recognized. This term refers to individuals who do not fulfill motor diagnostic criteria for PD, but who have clinical, genetic, or biomarker characteristics suggesting risk of developing PD in the future. Clinical diagnosis of prodromal PD has low specificity, prompting the need for objective biomarkers with higher specificity. In this qualitative review, we discuss objectively defined putative biomarkers for PD and prodromal PD. We searched Pubmed and Embase for articles pertaining to objective biomarkers for PD and their application in prodromal cohorts. Articles were selected based on relevance and methodology. Objective biomarkers of demonstrated utility in prodromal PD include ligand-based imaging and transcranial sonography. Development of serum, cerebrospinal fluid, and tissue-based biomarkers is underway, but their application in prodromal PD has yet to meaningfully occur. Combining objective biomarkers with clinical or genetic prodromal features increases the sensitivity and specificity for identifying prodromal PD. Several objective biomarkers for prodromal PD show promise but require further study, including their application to and validation in prodromal cohorts followed longitudinally. Accurate identification of prodromal PD will likely require a multimodal approach. (JINS, 2016, 22, 956-967).

A fast and reproducible method for albumin isolation and depletion from serum and cerebrospinal fluid.

PubMed

Holewinski, Ronald J; Jin, Zhicheng; Powell, Matthew J; Maust, Matthew D; Van Eyk, Jennifer E

2013-03-01

Analysis of serum and plasma proteomes is a common approach for biomarker discovery, and the removal of high-abundant proteins, such as albumin and immunoglobins, is usually the first step in the analysis. However, albumin binds peptides and proteins, which raises concerns as to how the removal of albumin could impact the outcome of the biomarker study while ignoring the possibility that this could be a biomarker subproteome itself. The first goal of this study was to test a new commercially available affinity capture reagent from Protea Biosciences and to compare the efficiency and reproducibility to four other commercially available albumin depletion methods. The second goal of this study was to determine if there is a highly efficient albumin depletion/isolation system that minimizes sample handling and would be suitable for large numbers of samples. Two of the methods tested (Sigma and ProteaPrep) showed an albumin depletion efficiency of 97% or greater for both serum and cerebrospinal fluid (CSF). Isolated serum and CSF albuminomes from ProteaPrep spin columns were analyzed directly by LC-MS/MS, identifying 128 serum (45 not previously reported) and 94 CSF albuminome proteins (17 unique to the CSF albuminome). Serum albuminome was also isolated using Vivapure anti-HSA columns for comparison, identifying 105 proteins, 81 of which overlapped with the ProteaPrep method. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Discriminant biomarkers of acute respiratory distress syndrome associated to H1N1 influenza identified by metabolomics HPLC-QTOF-MS/MS platform.

PubMed

Ferrarini, Alessia; Righetti, Laura; Martínez, Ma Paz; Fernández-López, Mariano; Mastrangelo, Annalaura; Horcajada, Juan P; Betbesé, Antoni; Esteban, Andrés; Ordóñez, Jordi; Gea, Joaquín; Cabello, Jesús Ruiz; Pellati, Federica; Lorente, José A; Nin, Nicolás; Rupérez, Francisco J

2017-09-01

Acute respiratory distress syndrome (ARDS) is a serious complication of influenza A (H1N1) virus infection. Its pathogenesis is unknown and biomarkers are lacking. Untargeted metabolomics allows the analysis of the whole metabolome in a biological compartment, identifying patterns associated with specific conditions. We hypothesized that LC-MS could help identify discriminant metabolites able to define the metabolic alterations occurring in patients with influenza A (H1N1) virus infection that developed ARDS. Serum samples from patients diagnosed with 2009 influenza A (H1N1) virus infection with (n = 25) or without (n = 32) ARDS were obtained on the day of hospital admission and analyzed by LC-MS/MS. Metabolite identification was determined by MS/MS analysis and analysis of standards. The specificity of the patterns identified was confirmed in patients without 2009 influenza A(H1N1) virus pneumonia (15 without and 17 with ARDS). Twenty-three candidate biomarkers were found to be significantly different between the two groups, including lysophospholipids and sphingolipids related to inflammation; bile acids, tryptophan metabolites, and thyroxine, related to the metabolism of the gut microflora. Confirmation results demonstrated the specificity of major alterations occurring in ARDS patients with influenza A (H1N1) virus infection. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Serum Protein KNG1, APOC3, and PON1 as Potential Biomarkers for Yin-Deficiency-Heat Syndrome.

PubMed

Liu, Changming; Mao, Liangen; Ping, Zepeng; Jiang, Tingting; Wang, Chong; Chen, Zhongliang; Li, Zhongjie; Li, Jicheng

2016-01-01

Yin-deficiency-heat (YDH) syndrome is a concept in Traditional Chinese Medicine (TCM) for describing subhealth status. However, there are few efficient diagnostic methods available for confirming YDH syndrome. To explore the novel method for diagnosing YDH syndrome, we applied iTRAQ to observe the serum protein profiles in YDH syndrome rats and confirmed protein levels by ELISA. A total of 92 differentially expressed proteins (63 upregulated proteins and 29 downregulated proteins), which were mainly involved in complement and coagulation cascades and glucose metabolism pathway, were identified by the proteomic experiments. Kininogen 1 (KNG1) was significantly increased ( p < 0.0001), while apolipoprotein C-III (APOC3, p < 0.005) and paraoxonase 1 (PON1, p < 0.001) were significantly decreased in the serum of YDH syndrome rats. The combination of KNG1, APOC3, and PON1 constituted a diagnostic model with 100.0% sensitivity and 85.0% specificity. The results indicated that KNG1, APOC3, and PON1 may act as potential biomarkers for diagnosing YDH syndrome. KNG1 may regulate cytokines and chemokines release in YDH syndrome, and the low levels of PON1 and APOC3 may increase oxidative stress and lipolysis in YDH syndrome, respectively. Our work provides a novel method for YDH syndrome diagnosis and also provides valuable experimental basis to understand the molecular mechanism of YDH syndrome.

Serum paraoxonase-1 as biomarker for improved diagnosis of fatty liver in dairy cows.

PubMed

Farid, Ayman Samir; Honkawa, Kazuyuki; Fath, Eman Mohamed; Nonaka, Nariaki; Horii, Yoichiro

2013-04-11

Fatty liver is a major metabolic disorder in dairy cows and is believed to result in major economic losses in dairy farming due to decreased health status, reproductive performance and fertility. Currently, the definitive means for diagnosing fatty liver is determining the fat content of hepatic tissue by liver biopsy, which is an invasive and costly procedure, making it poorly suited to dairy farms. Therefore, the key aim of this study was to investigate the measurement of serum paraoxonase-1 (PON1), an enzyme exclusively synthesized by the liver, as a sensitive noninvasive biomarker for diagnosis of fatty liver in dairy cows. A comparative cohort study using serum specimens from Holstein-Friesian dairy cows (46 healthy and 46 fatty liver cases) was conducted. Serum PON1 (paraoxonase, lactonase and arylesterase) activity and other biochemical and hematological parameters were measured. We found that serum PON1 activity was lower (P<0.001) in cows suffering from fatty liver. The area under the receiver operating characteristic curve (AUC-ROC) of PON1 activity for diagnosis of fatty liver was 0.973-0.989 [95% confidence interval (CI) 0.941, 1.000] which was higher than the AUC-ROC of aspartate aminotransferase (AST), lecithin-cholesterol acyltransferase (LCAT), alkaline phosphatase (ALP), non-esterified fatty acids (NEFA), beta-hydroxybutyrate (BHBA), total cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL). We found that adding serum PON1 measurement to different batteries of serum diagnostic panels showed a combination of high sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (+LR), negative likelihood ratio (-LR), diagnostic odd ratio (DOR) and overall diagnostic accuracy in diagnosing fatty liver. The present results indicate that addition of serum PON1 activity measurement to the biochemical profile could improve the diagnosis of fatty liver in dairy cows, which would

Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea.

PubMed

Mesarwi, Omar A; Shin, Mi-Kyung; Drager, Luciano F; Bevans-Fonti, Shannon; Jun, Jonathan C; Putcha, Nirupama; Torbenson, Michael S; Pedrosa, Rodrigo P; Lorenzi-Filho, Geraldo; Steele, Kimberley E; Schweitzer, Michael A; Magnuson, Thomas H; Lidor, Anne O; Schwartz, Alan R; Polotsky, Vsevolod Y

2015-10-01

Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis. Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing. A separate group with severe OSA had serum LOX measured before and after 3 mo of CPAP or no therapy, as did age-matched controls. LOX expression and secretion were measured in mouse hepatocytes following exposure to hypoxia. The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School. In the bariatric cohort, the apnea-hypopnea index was higher in patients with hepatic fibrosis than in those without fibrosis (42.7 ± 30.2 events/h, versus 16.2 ± 15.5 events/h; P = 0.002), as was serum LOX (84.64 ± 29.71 ng/mL, versus 45.46 ± 17.16 ng/mL; P < 0.001). In the sleep clinic sample, patients with severe OSA had higher baseline LOX than healthy controls (70.75 ng/mL versus 52.36 ng/mL, P = 0.046), and serum LOX decreased in patients with OSA on CPAP (mean decrease 20.49 ng/mL) but not in untreated patients (mean decrease 0.19 ng/mL). Hypoxic mouse hepatocytes demonstrated 5.9-fold increased LOX transcription (P = 0.046), and enhanced LOX protein secretion. The hypoxic stress of obstructive sleep apnea may increase circulating lysyl oxidase (LOX) levels. LOX may serve as a biomarker of liver fibrosis in patients with severe obesity and nonalcoholic fatty liver disease. © 2015 Associated Professional Sleep Societies, LLC.

Sepsis and identification of reliable biomarkers for postoperative period prognosis.

PubMed

Siloşi, Cristian Adrian; Siloşi, Isabela; Pădureanu, Vlad; Bogdan, Maria; Mogoantă, Stelian Ştefăniţă; Ciurea, Marius Eugen; Cojocaru, Manole; Boldeanu, Lidia; Avrămescu, Carmen Silvia; Boldeanu, Mihail Virgil; Popa, Dragoş George

2018-01-01

Sepsis is currently defined as the presence of organ dysfunction occurring as the result of a disturbed host response to a serious infection. Sepsis is one of the most common diseases, which cause mortality and a considerable absorber of healthcare resources. Despite progress in technology and improving knowledge of pathophysiology, the disease mechanism is still poorly understood. At present, diagnosis is based on non-specific physiological criteria and on the late identification of the pathogen. For these reasons, the diagnosis may be uncertain, treatment delayed or an immunomodulatory therapy cannot be established. An early and reliable diagnosis is essential to achieve better outcomes on disease progression. The host response to infection involves hundreds of many mediators of which have been proposed as biomarkers. There is a need for new diagnostic approaches for sepsis, new sepsis biomarkers that can aid in diagnosis, therapeutic decision and monitoring of the response to therapy. The differentiation of sepsis from non-infectious systemic inflammatory response syndrome is difficult, and the search for a highly accurate biomarker of sepsis has become one important objective of the medicine. The goal of our review is to summarize the recent advances on the most commonly studied serum biomarkers, evaluated in clinical and experimental studies, for early diagnosis of sepsis and their informative value in diagnosis, prognosis, or response to therapy. In this context, we have tracked the clinical utility of measuring serum biomarkers, such as procalcitonin, pro- and anti-inflammatory cytokines, C-reactive protein, leptin and their combinations. Currently, has not been identified an ideal biomarker to aid in the diagnosis of sepsis. It is hoped that the discovery of new serum markers, as well as their combinations, will serve for the diagnosis and prognosis of sepsis.

Quantitative label-free proteomic analysis of human urine to identify novel candidate protein biomarkers for schistosomiasis.

PubMed

Onile, Olugbenga Samson; Calder, Bridget; Soares, Nelson C; Anumudu, Chiaka I; Blackburn, Jonathan M

2017-11-01

Schistosomiasis is a chronic neglected tropical disease that is characterized by continued inflammatory challenges to the exposed population and it has been established as a possible risk factor in the aetiology of bladder cancer. Improved diagnosis of schistosomiasis and its associated pathology is possible through mass spectrometry to identify biomarkers among the infected population, which will influence early detection of the disease and its subtle morbidity. A high-throughput proteomic approach was used to analyse human urine samples for 49 volunteers from Eggua, a schistosomiasis endemic community in South-West, Nigeria. The individuals were previously screened for Schistosoma haematobium and structural bladder pathologies via microscopy and ultrasonography respectively. Samples were categorised into schistosomiasis, schistosomiasis with bladder pathology, bladder pathology, and a normal healthy control group. These samples were analysed to identify potential protein biomarkers. A total of 1306 proteins and 9701 unique peptides were observed in this study (FDR = 0.01). Fifty-four human proteins were found to be potential biomarkers for schistosomiasis and bladder pathologies due to schistosomiasis by label-free quantitative comparison between groups. Thirty-six (36) parasite-derived potential biomarkers were also identified, which include some existing putative schistosomiasis biomarkers that have been previously reported. Some of these proteins include Elongation factor 1 alpha, phosphopyruvate hydratase, histone H4 and heat shock proteins (HSP 60, HSP 70). These findings provide an in-depth analysis of potential schistosoma and human host protein biomarkers for diagnosis of chronic schistosomiasis caused by Schistosoma haematobium and its pathogenesis.

Comparison of serum, EDTA plasma and P100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the SPIROMICS study.

PubMed

O'Neal, Wanda K; Anderson, Wayne; Basta, Patricia V; Carretta, Elizabeth E; Doerschuk, Claire M; Barr, R Graham; Bleecker, Eugene R; Christenson, Stephanie A; Curtis, Jeffrey L; Han, Meilan K; Hansel, Nadia N; Kanner, Richard E; Kleerup, Eric C; Martinez, Fernando J; Miller, Bruce E; Peters, Stephen P; Rennard, Stephen I; Scholand, Mary Beth; Tal-Singer, Ruth; Woodruff, Prescott G; Couper, David J; Davis, Sonia M

2014-01-08

As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100). 105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform (Myriad-RBM) were evaluated in duplicate from the three sample types from 24 subjects. The reliability coefficient and the coefficient of variation (CV) were calculated. The performance of each analyte and mean analyte levels were evaluated across sample types. 20% of analytes were not consistently detectable in any sample type. Higher reliability and/or smaller CV were determined for 12 analytes in EDTA plasma compared to serum, and for 11 analytes in serum compared to EDTA plasma. While reliability measures were similar for EDTA plasma and P100 plasma for a majority of analytes, CV was modestly increased in P100 plasma for eight analytes. Each analyte within a multiplex produced independent measurement characteristics, complicating selection of sample type for individual multiplexes. There were notable detectability and measurability differences between serum and plasma. Multiplexing may not be ideal if large reliability differences exist across analytes measured within the multiplex, especially if values differ based on sample type. For some analytes, the large CV should be considered during experimental design, and the use of duplicate and/or triplicate samples may be necessary. These results should prove useful for studies evaluating selection of samples for evaluation of

Comparison of serum, EDTA plasma and P100 plasma for luminex-based biomarker multiplex assays in patients with chronic obstructive pulmonary disease in the SPIROMICS study

PubMed Central

2014-01-01

Background As a part of the longitudinal Chronic Obstructive Pulmonary Disease (COPD) study, Subpopulations and Intermediate Outcome Measures in COPD study (SPIROMICS), blood samples are being collected from 3200 subjects with the goal of identifying blood biomarkers for sub-phenotyping patients and predicting disease progression. To determine the most reliable sample type for measuring specific blood analytes in the cohort, a pilot study was performed from a subset of 24 subjects comparing serum, Ethylenediaminetetraacetic acid (EDTA) plasma, and EDTA plasma with proteinase inhibitors (P100™). Methods 105 analytes, chosen for potential relevance to COPD, arranged in 12 multiplex and one simplex platform (Myriad-RBM) were evaluated in duplicate from the three sample types from 24 subjects. The reliability coefficient and the coefficient of variation (CV) were calculated. The performance of each analyte and mean analyte levels were evaluated across sample types. Results 20% of analytes were not consistently detectable in any sample type. Higher reliability and/or smaller CV were determined for 12 analytes in EDTA plasma compared to serum, and for 11 analytes in serum compared to EDTA plasma. While reliability measures were similar for EDTA plasma and P100 plasma for a majority of analytes, CV was modestly increased in P100 plasma for eight analytes. Each analyte within a multiplex produced independent measurement characteristics, complicating selection of sample type for individual multiplexes. Conclusions There were notable detectability and measurability differences between serum and plasma. Multiplexing may not be ideal if large reliability differences exist across analytes measured within the multiplex, especially if values differ based on sample type. For some analytes, the large CV should be considered during experimental design, and the use of duplicate and/or triplicate samples may be necessary. These results should prove useful for studies evaluating

Development of a multi-biomarker disease activity test for rheumatoid arthritis.

PubMed

Centola, Michael; Cavet, Guy; Shen, Yijing; Ramanujan, Saroja; Knowlton, Nicholas; Swan, Kathryn A; Turner, Mary; Sutton, Chris; Smith, Dustin R; Haney, Douglas J; Chernoff, David; Hesterberg, Lyndal K; Carulli, John P; Taylor, Peter C; Shadick, Nancy A; Weinblatt, Michael E; Curtis, Jeffrey R

2013-01-01

Disease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment. To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis. Candidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein [DAS28-CRP], a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing. 130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities. We followed a stepwise approach to

Identifying Exosome-Derived MicroRNAs as Candidate Biomarkers of Frailty.

PubMed

Ipson, B R; Fletcher, M B; Espinoza, S E; Fisher, A L

2018-01-01

Frailty is a geriatric syndrome associated with progressive physical decline and significantly increases risk for falls, disability, hospitalizations, and death. However, much remains unknown regarding the biological mechanisms that contribute to aging and frailty, and to date, there are no clinically used prognostic or diagnostic molecular biomarkers. The present study profiled exosome-derived microRNAs isolated from the plasma of young, robust older, and frail older individuals and identified eight miRNAs that are uniquely enriched in frailty: miR-10a-3p, miR-92a-3p, miR-185-3p, miR-194-5p, miR-326, miR-532-5p, miR-576-5p, and miR-760. Furthermore, since exosomes can deliver miRNAs to alter cellular activity and behavior, these miRNAs may also provide insights into the biological mechanisms underlying frailty; KEGG analysis of their target genes revealed multiple pathways implicated in aging and age-related processes. Although further validation and research studies are warranted, our study identified eight novel candidate biomarkers of frailty that may help to elucidate the multifactorial pathogenesis of frailty.

Salivary Biomarkers, Oral Inflammation, and Functional Status in Patients With Heart Failure

PubMed Central

Dekker, Rebecca L.; Lennie, Terry A.; Moser, Debra K.; Miller, Craig S.; Ebersole, Jeffrey L.; Chung, Misook L.; Campbell, Charles L.; Bailey, Alison; Tovar, Elizabeth G.

2016-01-01

Aims: To describe correlations and agreement between salivary and serum B-type natriuretic peptide (BNP), C-reactive protein (CRP), interleukin (IL)-6, and IL-10 and determine which biomarkers predict worse functional class in patients with heart failure (HF). Methods: Serum and saliva were collected from 75 hospitalized patients with HF (57 ± 12 years, 43% female, New York Heart Association [NYHA] Classes I [4%], II [43%], and III [53%]). Oral inflammation was rated as good, fair, or poor. Spearman’s ρ and Bland–Altman were used to determine correlations and agreement of the salivary and serum forms of each biomarker. Logistic regressions were used to determine which biomarkers predicted worse NYHA functional class, controlling for depression, body mass index, smoking, and oral inflammation. Results: Median biomarker concentrations were as follows: BNP (serum 361 pg/ml, saliva 9 pg/ml), CRP (serum 13 ng/ml, saliva 25.6 ng/ml), IL-6 (serum 19.3 pg/ml, saliva 10.5 pg/ml), and IL-10 (serum 64.1 pg/ml, saliva 4.7 pg/ml). There was a moderate-to-strong correlation for serum–salivary CRP, weak correlation for serum–salivary IL-6, and no correlations for serum–salivary BNP and IL-10. The Bland–Altman test showed good salivary–serum agreement for all biomarkers, but as serum concentrations rose, salivary measures underestimated serum levels. Visible oral inflammation was the only predictor of worse NYHA class. PMID:27605566

Changes to serum sample tube and processing methodology does not cause Intra-Individual [corrected] variation in automated whole serum N-glycan profiling in health and disease.

PubMed

Ventham, Nicholas T; Gardner, Richard A; Kennedy, Nicholas A; Shubhakar, Archana; Kalla, Rahul; Nimmo, Elaine R; Fernandes, Daryl L; Satsangi, Jack; Spencer, Daniel I R

2015-01-01

Serum N-glycans have been identified as putative biomarkers for numerous diseases. The impact of different serum sample tubes and processing methods on N-glycan analysis has received relatively little attention. This study aimed to determine the effect of different sample tubes and processing methods on the whole serum N-glycan profile in both health and disease. A secondary objective was to describe a robot automated N-glycan release, labeling and cleanup process for use in a biomarker discovery system. 25 patients with active and quiescent inflammatory bowel disease and controls had three different serum sample tubes taken at the same draw. Two different processing methods were used for three types of tube (with and without gel-separation medium). Samples were randomised and processed in a blinded fashion. Whole serum N-glycan release, 2-aminobenzamide labeling and cleanup was automated using a Hamilton Microlab STARlet Liquid Handling robot. Samples were analysed using a hydrophilic interaction liquid chromatography/ethylene bridged hybrid(BEH) column on an ultra-high performance liquid chromatography instrument. Data were analysed quantitatively by pairwise correlation and hierarchical clustering using the area under each chromatogram peak. Qualitatively, a blinded assessor attempted to match chromatograms to each individual. There was small intra-individual variation in serum N-glycan profiles from samples collected using different sample processing methods. Intra-individual correlation coefficients were between 0.99 and 1. Unsupervised hierarchical clustering and principal coordinate analyses accurately matched samples from the same individual. Qualitative analysis demonstrated good chromatogram overlay and a blinded assessor was able to accurately match individuals based on chromatogram profile, regardless of disease status. The three different serum sample tubes processed using the described methods cause minimal inter-individual variation in serum whole N

The prognostic significance of circulating serum amyloid A and CXC chemokine ligand 4 in osteosarcoma.

PubMed

Flores, Ricardo J; Kelly, Aaron J; Li, Yiting; Chen, Xiang; McGee, Colin; Krailo, Mark; Barkauskas, Donald A; Hicks, John; Man, Tsz-Kwong

2017-12-01

Osteosarcoma (OS) is the most common pediatric bone cancer.  Despite advances in treatment regimens, the survival rate remains 60-70%.  There is an urgent need to identify prognostic biomarkers, so that targeted therapies can be developed to improve the outcome. Our laboratory has previously identified that circulating serum amyloid A (SAA) and CXC chemokine ligand 4 (CXCL4) are upregulated in patients with OS.  In this study, we tested if they could be used as prognostic biomarkers.  We used enzyme-linked immunosorbent assays to measure their concentrations in serum samples (n = 233) and immunohistochemistry to examine their expressions in primary tumors (n = 37).  Prognostic significance of the serum concentrations and tumor expressions of the biomarkers was then evaluated. Patients with "high SAA" and "low CXCL4" circulating levels at diagnosis significantly correlated with a worse outcome (HR = 1.68, P = 0.014), which was independent of the metastatic status.  These patients also exhibited a significantly higher rate of poor histologic response to chemotherapy.  Furthermore, low tumor expression of CXCL4 correlated with poor survival (HR = 3.57, P = 0.005). Our results demonstrate that circulating SAA and CXCL4 may serve as prognostic biomarkers in OS.  Targeting CXCL4 has been reported, suggesting that it may be exploited as a therapeutic target in OS. © 2017 Wiley Periodicals, Inc.

The Prognostic Significance of Circulating Serum Amyloid A and CXC Chemokine Ligand 4 in Osteosarcoma

PubMed Central

Flores, Ricardo J.; Kelly, Aaron J.; Li, Yiting; Chen, Xiang; McGee, Colin; Krailo, Mark; Barkauskas, Donald A.; Hicks, John; Man, Tsz-Kwong

2017-01-01

BACKGROUND Osteosarcoma is the most common pediatric bone cancer. Despite advances in treatment regimens, the survival rate remains 60–70%. There is an urgent need to identify prognostic biomarkers, so that targeted therapies can be developed to improve the outcome. PROCEDURE Our lab has previously identified that circulating Serum Amyloid A (SAA) and CXC Chemokine Ligand 4 (CXCL4) are upregulated in patients with osteosarcoma. In this study, we tested if they could be used as prognostic biomarkers. We used ELISAs to measure their concentrations in serum samples (n = 233), and immunohistochemistry to examine expressions in primary tumors (n = 37). Prognostic significance of the serum concentrations and tumor expressions of the biomarkers was then evaluated. RESULTS Patients with “High SAA” and “Low CXCL4” circulating levels at diagnosis significantly correlated with a worse outcome (HR = 1.68, p = 0.014), which was independent of the metastatic status. These patients also exhibited a significantly higher rate of poor histological response to chemotherapy. Furthermore, low tumor expression of CXCL4 correlated with poor survival (HR = 3.57, p = 0.005). CONCLUSIONS Our results demonstrate that circulating SAA and CXCL4 may serve as prognostic biomarkers in osteosarcoma. Targeting CXCL4 has been reported, suggesting that it may be exploited as a therapeutic target in osteosarcoma. PMID:28544777

Identification of serum analytes and metabolites associated with aerobic capacity

USDA-ARS?s Scientific Manuscript database

Studies aimed at identifying serum markers of cellular metabolism (biomarkers) that are associated at baseline with aerobic capacity (V02 max) in young, healthy individuals have yet to be reported. Therefore, the goal of the present study was to use the standard chemistry screen and untargeted mass ...

Detection of Serum microRNAs From Department of Defense Serum Repository

PubMed Central

Woeller, Collynn F.; Thatcher, Thomas H.; Van Twisk, Daniel; Pollock, Stephen J.; Croasdell, Amanda; Kim, Nina; Hopke, Philip K.; Xia, Xiaoyan; Thakar, Juilee; Mallon, COL Timothy M.; Utell, Mark J.; Phipps, Richard P.

2017-01-01

Objective The aim of this study was to investigate whether serum samples from the Department of Defense Serum Repository (DoDSR) are of sufficient quality to detect microRNAs (miRNAs), cytokines, immunoglobulin E (IgE), and polycyclic aromatic hydrocarbons (PAHs). Methods MiRNAs were isolated and quantified by polymerase chain reaction (PCR) array. Cytokines and chemokines related to inflammation were measured using multiplex immunoassays. Cotinine and IgE were detected by enzyme-linked immunoassay (ELISA) and PAHs were detected by Liquid Chromatography/Mass Spectroscopy. Results We detected miRNAs, cytokines, IgE, and PAHs with high sensitivity. Eleven of 30 samples tested positive for cotinine suggesting tobacco exposure. Significant associations between serum cotinine, cytokine, IgE, PAHs, and miRNA were discovered. Conclusion We successfully quantified over 200 potential biomarkers of occupational exposure from DoDSR samples. The stored serum samples were not affected by hemolysis and represent a powerful tool for biomarker discovery and analysis in retrospective studies. PMID:27501106

Osteoarthritis Year in Review 2016: biomarkers (biochemical markers).

PubMed

Mobasheri, A; Bay-Jensen, A-C; van Spil, W E; Larkin, J; Levesque, M C

2017-02-01

The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam. The PubMed/MEDLINE bibliographic database was searched using the combined keywords: 'biomarker' and 'osteoarthritis'. The PubMed/MEDLINE literature search was conducted using the Advanced Search Builder function (http://www.ncbi.nlm.nih.gov/pubmed/advanced). Over two hundred new biomarker-related papers were published during the literature search period. Some papers identified new biomarkers whereas others explored the biological properties and clinical utility of existing markers. There were specific references to several adipocytokines including leptin and adiponectin. ADAM Metallopeptidase with Thrombospondin Type 1 motif 4 (ADAMTS-4) and aggrecan ARGS neo-epitope fragment (ARGS) in synovial fluid (SF) and plasma chemokine (CeC motif) ligand 3 (CCL3) were reported as potential new knee biomarkers. New and refined proteomic technologies and novel assays including a fluoro-microbead guiding chip (FMGC) for measuring C-telopeptide of type II collagen (CTX-II) in serum and urine and a novel magnetic nanoparticle-based technology (termed magnetic capture) for collecting and concentrating CTX-II, were described this past year. There has been steady progress in osteoarthritis (OA) biomarker research in 2016. Several novel biomarkers were identified and new technologies have been developed for measuring existing biomarkers. However, there has been no "quantum leap" this past year and identification of novel early OA biomarkers remains challenging. During the past year, OARSI published a set of recommendations for the use of soluble biomarkers in clinical trials, which is a major step forward in the clinical use of OA biomarkers and bodes well for future OA biomarker development. Copyright © 2016 The

Global transcriptome analysis of formalin-fixed prostate cancer specimens identifies biomarkers of disease recurrence.

PubMed

Long, Qi; Xu, Jianpeng; Osunkoya, Adeboye O; Sannigrahi, Soma; Johnson, Brent A; Zhou, Wei; Gillespie, Theresa; Park, Jong Y; Nam, Robert K; Sugar, Linda; Stanimirovic, Aleksandra; Seth, Arun K; Petros, John A; Moreno, Carlos S

2014-06-15

Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease. In an effort to identify biomarkers of recurrence, we performed global RNA sequencing on 106 formalin-fixed, paraffin-embedded prostatectomy samples from 100 patients at three independent sites, defining a 24-gene signature panel. The 24 genes in this panel function in cell-cycle progression, angiogenesis, hypoxia, apoptosis, PI3K signaling, steroid metabolism, translation, chromatin modification, and transcription. Sixteen genes have been associated with cancer, with five specifically associated with prostate cancer (BTG2, IGFBP3, SIRT1, MXI1, and FDPS). Validation was performed on an independent publicly available dataset of 140 patients, where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence. Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors, including several genes involved in the epithelial-to-mesenchymal transition and developmental pathways. Overall, this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer. ©2014 American Association for Cancer Research.

Seasonal changes in serum oxidative stress biomarkers in dairy and beef cows in a daytime grazing system.

PubMed

Mirzad, Ahmad Nawid; Tada, Takashi; Ano, Hitoshi; Kobayashi, Ikuo; Yamauchi, Takenori; Katamoto, Hiromu

2018-01-01

This study aims to evaluate the oxidative stress during hot summer season using serum oxidative stress biomarkers and elucidate the effects of serum antioxidant vitamin levels in dairy and beef cows in a daytime grazing system. Blood samples were collected once a month from eight Holstein Friesian (HF) and 10 Japanese Black (JB) cows from November 2013 to October 2014. Serum values of derivatives of reactive oxygen metabolites (d-ROMs) tended to be higher in March in both breeds and those in HF cows were kept at higher (P<0.001) levels than those in JB cows during the study period. Serum levels of biological antioxidant potential (BAP) in both breeds were maintained at almost the same values during study period. The OSI [(d-ROMs/BAP) × 100] values in both breeds showed similar seasonal changes, i. e. increase from December to March and decrease from March to August or September. In addition, the OSI values in HF cows were kept at higher (P<0.01) levels than those in JB cows during the study period. Serum concentrations of α-tocopherol, β-carotene, blood urea nitrogen and total cholesterol showed similar seasonal changes in both breeds, low in the winter and high from spring to summer, which may be attributed to the pasture grass intake. Opposite changes in OSI values and serum concentrations of α-tocopherol and β-carotene indicated that antioxidant vitamin levels could affect oxidative stress status.

Seasonal changes in serum oxidative stress biomarkers in dairy and beef cows in a daytime grazing system

PubMed Central

MIRZAD, Ahmad Nawid; TADA, Takashi; ANO, Hitoshi; KOBAYASHI, Ikuo; YAMAUCHI, Takenori; KATAMOTO, Hiromu

2017-01-01

This study aims to evaluate the oxidative stress during hot summer season using serum oxidative stress biomarkers and elucidate the effects of serum antioxidant vitamin levels in dairy and beef cows in a daytime grazing system. Blood samples were collected once a month from eight Holstein Friesian (HF) and 10 Japanese Black (JB) cows from November 2013 to October 2014. Serum values of derivatives of reactive oxygen metabolites (d-ROMs) tended to be higher in March in both breeds and those in HF cows were kept at higher (P<0.001) levels than those in JB cows during the study period. Serum levels of biological antioxidant potential (BAP) in both breeds were maintained at almost the same values during study period. The OSI [(d-ROMs/BAP) × 100] values in both breeds showed similar seasonal changes, i. e. increase from December to March and decrease from March to August or September. In addition, the OSI values in HF cows were kept at higher (P<0.01) levels than those in JB cows during the study period. Serum concentrations of α-tocopherol, β-carotene, blood urea nitrogen and total cholesterol showed similar seasonal changes in both breeds, low in the winter and high from spring to summer, which may be attributed to the pasture grass intake. Opposite changes in OSI values and serum concentrations of α-tocopherol and β-carotene indicated that antioxidant vitamin levels could affect oxidative stress status. PMID:29142148

A novel quantification-driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer's disease.

PubMed

Skillbäck, Tobias; Mattsson, Niklas; Hansson, Karl; Mirgorodskaya, Ekaterina; Dahlén, Rahil; van der Flier, Wiesje; Scheltens, Philip; Duits, Floor; Hansson, Oskar; Teunissen, Charlotte; Blennow, Kaj; Zetterberg, Henrik; Gobom, Johan

2017-10-17

We present a new, quantification-driven proteomic approach to identifying biomarkers. In contrast to the identification-driven approach, limited in scope to peptides that are identified by database searching in the first step, all MS data are considered to select biomarker candidates. The endopeptidome of cerebrospinal fluid from 40 Alzheimer's disease (AD) patients, 40 subjects with mild cognitive impairment, and 40 controls with subjective cognitive decline was analyzed using multiplex isobaric labeling. Spectral clustering was used to match MS/MS spectra. The top biomarker candidate cluster (215% higher in AD compared to controls, area under ROC curve = 0.96) was identified as a fragment of pleiotrophin located near the protein's C-terminus. Analysis of another cohort (n = 60 over four clinical groups) verified that the biomarker was increased in AD patients while no change in controls, Parkinson's disease or progressive supranuclear palsy was observed. The identification of the novel biomarker pleiotrophin 151-166 demonstrates that our quantification-driven proteomic approach is a promising method for biomarker discovery, which may be universally applicable in clinical proteomics.

Serum anti-Ku86 is a potential biomarker for early detection of hepatitis C virus-related hepatocellular carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nomura, Fumio, E-mail: fnomura@faculty.chiba-u.jp; Sogawa, Kazuyuki; Noda, Kenta

Highlights: Black-Right-Pointing-Pointer Overexpression of Ku86 in human liver cancer was shown by immunohistochemistry. Black-Right-Pointing-Pointer Serum anti-Ku86 was significantly elevated in early hepatocellular carcinoma. Black-Right-Pointing-Pointer Anti-Ku86 may be more sensitive than the conventional markers for early detection. Black-Right-Pointing-Pointer Serum anti-Ku86 significantly decreased after surgical resection of liver tumors. Black-Right-Pointing-Pointer Elevation of serum anti-Ku86 in other non-liver solid tumors was minimal. -- Abstract: Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is one of the most common cancers worldwide and the third most common cause of cancer-related death. Imaging studies including ultrasound and computed tomography are recommended for early detectionmore » of HCC, but they are operator dependent, costly and involve radiation. Therefore, there is a need for simple and sensitive serum markers for the early detection of hepatocellular carcinoma (HCC). In our recent proteomic studies, a number of proteins overexpressed in HCC tissues were identified. We thought if the serum autoantibodies to these overexpressed proteins were detectable in HCC patients. Of these proteins, we focused on Ku86, a nuclear protein involved in multiple biological processes and aimed to assess the diagnostic value of serum anti-Ku86 in the early detection of HCC. Serum samples were obtained prior to treatment from 58 consecutive patients with early or relatively early hepatitis C virus (HCV)-related HCC and 137 patients with HCV-related liver cirrhosis without evidence of HCC. Enzyme immunoassays were used to measure serum levels of autoantibodies. Serum levels of anti-Ku86 antibodies were significantly elevated in HCC patients compared to those in liver cirrhosis patients (0.41 {+-} 0.28 vs. 0.18 {+-} 0.08 Abs at 450 nm, P < 0001). Setting the cut-off level to give 90% specificity, anti-Ku86 was positive in 60

Enlarged pulmonary artery is predicted by vascular injury biomarkers and is associated with WTC-Lung Injury in exposed fire fighters: a case–control study

PubMed Central

Schenck, Edward J; Echevarria, Ghislaine C; Girvin, Francis G; Kwon, Sophia; Comfort, Ashley L; Rom, William N; Prezant, David J; Weiden, Michael D; Nolan, Anna

2014-01-01

Objectives We hypothesise that there is an association between an elevated pulmonary artery/aorta (PA/A) and World Trade Center-Lung Injury (WTC-LI). We assessed if serum vascular disease biomarkers were predictive of an elevated PA/A. Design Retrospective case-cohort analysis of thoracic CT scans of WTC-exposed firefighters who were symptomatic between 9/12/2001 and 3/10/2008. Quantification of vascular-associated biomarkers from serum collected within 200 days of exposure. Setting Urban tertiary care centre and occupational healthcare centre. Participants Male never-smoking firefighters with accurate pre-9/11 forced expiratory volume in 1 s (FEV1) ≥75%, serum sampled ≤200 days of exposure was the baseline cohort (n=801). A subcohort (n=97) with available CT scans and serum biomarkers was identified. WTC-LI was defined as FEV1≤77% at the subspecialty pulmonary evaluation (n=34) and compared with controls (n=63) to determine the associated PA/A ratio. The subcohort was restratified based on PA/A≥0.92 (n=38) and PA/A<0.92(n=59) to determine serum vascular biomarkers that were predictive of this vasculopathy. Outcome measures The primary outcome of this study was to identify a PA/A ratio in a cohort of individuals exposed to WTC dust that was associated with WTC-LI. The secondary outcome was to identify serum biomarkers predictive of the PA/A ratio using logistic regression. Results PA/A≥0.92 was associated with WTC-LI, OR of 4.02 (95% CI 1.21 to 13.41; p=0.023) when adjusted for exposure, body mass index and age at CT. Elevated macrophage derived chemokine and soluble endothelial selectin were predictive of PA/A≥0.92, (OR, 95% CI 2.08, 1.05 to 4.11, p=0.036; 1.33, 1.06 to 1.68, p=0.016, respectively), while the increased total plasminogen activator inhibitor 1 was predictive of not having PA/A≥0.92 (OR 0.88, 0.79 to 0.98; p=0.024). Conclusions Elevated PA/A was associated with WTC-LI. Development of an elevated PA/A was predicted by biomarkers of

Identification of Tengfu Jiangya Tablet Target Biomarkers with Quantitative Proteomic Technique

PubMed Central

Xu, Jingwen; Zhang, Shijun; Jiang, Haiqiang; Wang, Nan; Lin, Haiqing

2017-01-01

Tengfu Jiangya Tablet (TJT) is a well accepted antihypertension drug in China and its major active components were Uncaria total alkaloids and Semen Raphani soluble alkaloid. To further explore treatment effects mechanism of TJT on essential hypertension, a serum proteomic study was performed. Potential biomarkers were quantified in serum of hypertension individuals before and after taking TJT with isobaric tags for relative and absolute quantitation (iTRAQ) coupled two-dimensional liquid chromatography followed electrospray ionization-tandem mass spectrometry (2D LC-MS/MS) proteomics technique. Among 391 identified proteins with high confidence, 70 proteins were differentially expressed (fold variation criteria, >1.2 or <0.83) between two groups (39 upregulated and 31 downregulated). Combining with Gene Ontology annotation, KEGG pathway analysis, and literature retrieval, 5 proteins were chosen as key target biomarkers during TJT therapeutic process. And the alteration profiles of these 5 proteins were verified by ELISA and Western Blot. Proteins Kininogen 1 and Keratin 1 are members of Kallikrein system, while Myeloperoxidase, Serum Amyloid protein A, and Retinol binding protein 4 had been reported closely related to vascular endothelial injury. Our study discovered 5 target biomarkers of the compound Chinese medicine TJT. Secondly, this research initially revealed the antihypertension therapeutic mechanism of this drug from a brand-new aspect. PMID:28408942

Use of Serum MicroRNAs as Biomarker for Hepatobiliary Diseases in Dogs.

PubMed

Dirksen, K; Verzijl, T; Grinwis, G C; Favier, R P; Penning, L C; Burgener, I A; van der Laan, L J; Fieten, H; Spee, B

2016-11-01

Current biochemical indicators cannot discriminate between parenchymal, biliary, vascular, and neoplastic hepatobiliary diseases. MicroRNAs are promising new biomarkers for hepatobiliary disease in humans and dogs. To measure serum concentrations of an established group of microRNAs in dogs and to investigate their concentrations in various types of hepatobiliary diseases. Forty-six client-owned dogs with an established diagnosis of hepatobiliary disease and stored serum samples and eleven client-owned healthy control Labrador Retrievers. Retrospective study. Medical records of dogs with parenchymal, biliary, vascular, or neoplastic hepatobiliary diseases and control dogs were reviewed. Concentrations of miR-21, miR-122, miR-126, miR-148a, miR-200c, and miR-222 were quantified in serum by real-time polymerase chain reaction. No different microRNA concentrations were found in the adenoma and congenital portosystemic shunt groups. In all other diseases, miR-122 concentrations were elevated with the highest concentration in the mucocele group (267-fold, CI: 40-1,768, P < .001). In dogs with biliary diseases, miR-21 and miR-222 were only increased in dogs with mucoceles (26-fold, CI: 5-141, P = .005 and 13-fold, CI: 2-70, P = .025, respectively). Uniquely increased microRNAs were found in the hepatocellular carcinoma group (miR-200c, 35-fold increase, CI: 3-382, P = .035) and the chronic hepatitis group (miR-126, 22-fold increase, CI: 5-91, P = .002). A microRNA panel consisting of miR-21, miR-122, miR-126, miR-200c, and miR-222 can distinguish between parenchymal, biliary, and neoplastic hepatobiliary diseases. Serum microRNA profiling is a promising new tool that might be a valuable addition to conventional diagnostics to help diagnose various hepatobiliary diseases in dogs. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

BluePen Biomarkers LLC: integrated biomarker solutions

PubMed Central

Blair, Ian A; Mesaros, Clementina; Lilley, Patrick; Nunez, Matthew

2016-01-01

BluePen Biomarkers provides a unique comprehensive multi-omics biomarker discovery and validation platform. We can quantify, integrate and analyze genomics, proteomics, metabolomics and lipidomics biomarkers, alongside clinical data, demographics and other phenotypic data. A unique bio-inspired signal processing analytic approach is used that has the proven ability to identify biomarkers in a wide variety of diseases. The resulting biomarkers can be used for diagnosis, prognosis, mechanistic studies and predicting treatment response, in contexts from core research through clinical trials. BluePen Biomarkers provides an additional groundbreaking research goal: identifying surrogate biomarkers from different modalities. This not only provides new biological insights, but enables least invasive, least-cost tests that meet or exceed the predictive quality of current tests. PMID:28031971

Serum aminoacylase-1 is a novel biomarker with potential prognostic utility for long-term outcome in patients with delayed graft function following renal transplantation

PubMed Central

Welberry Smith, Matthew P; Zougman, Alexandre; Cairns, David A; Wilson, Michelle; Wind, Tobias; Wood, Steven L; Thompson, Douglas; Messenger, Michael P; Mooney, Andrew; Selby, Peter J; Lewington, Andrew J P; Banks, Rosamonde E

2013-01-01

Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67–0.85) for ACY-1, 0.9 (0.84–0.95) for cystatin C, and 0.93 (0.88–0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor–brain–dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation. PMID:23739232

Large-scale identification of core-fucosylated glycopeptide sites in pancreatic cancer serum using mass spectrometry.

PubMed

Tan, Zhijing; Yin, Haidi; Nie, Song; Lin, Zhenxin; Zhu, Jianhui; Ruffin, Mack T; Anderson, Michelle A; Simeone, Diane M; Lubman, David M

2015-04-03

Glycosylation has significant effects on protein function and cell metastasis, which are important in cancer progression. It is of great interest to identify site-specific glycosylation in search of potential cancer biomarkers. However, the abundance of glycopeptides is low compared to that of nonglycopeptides after trypsin digestion of serum samples, and the mass spectrometric signals of glycopeptides are often masked by coeluting nonglycopeptides due to low ionization efficiency. Selective enrichment of glycopeptides from complex serum samples is essential for mass spectrometry (MS)-based analysis. Herein, a strategy has been optimized using LCA enrichment to improve the identification of core-fucosylation (CF) sites in serum of pancreatic cancer patients. The optimized strategy was then applied to analyze CF glycopeptide sites in 13 sets of serum samples from pancreatic cancer, chronic pancreatitis, healthy controls, and a standard reference. In total, 630 core-fucosylation sites were identified from 322 CF proteins in pancreatic cancer patient serum using an Orbitrap Elite mass spectrometer. Further data analysis revealed that 8 CF peptides exhibited a significant difference between pancreatic cancer and other controls, which may be potential diagnostic biomarkers for pancreatic cancer.

Metabolomic Quality Assessment of EDTA Plasma and Serum Samples.

PubMed

Malm, Linus; Tybring, Gunnel; Moritz, Thomas; Landin, Britta; Galli, Joakim

2016-10-01

Handling and processing of blood can significantly alter the molecular composition and consistency of biobank samples and can have a major impact on the identification of biomarkers. It is thus crucial to identify tools to determine the quality of samples to be used in biomarker discovery studies. In this study, a non-targeted gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) metabolomic strategy was used with the aim of identifying quality markers for serum and plasma biobank collections lacking proper documentation of preanalytical handling. The effect of postcentrifugation delay was examined in serum stored in tubes with gel separation plugs and ethylenediaminetetraacetic acid (EDTA) plasma in tubes with or without gel separation plugs. The change in metabolic pattern was negligible in all sample types processed within 3 hours after centrifugation regardless of whether the samples were kept at 4°C or 22°C. After 8 and 24 hours postcentrifugation delay before aliquoting, there was a pronounced increase in the number of affected metabolites, as well as in the magnitude of the observed changes. No protective effect on the metabolites was observed in gel-separated EDTA plasma samples. In a separate series of experiments, lactate and glucose levels were determined in plasma to estimate the effect of precentrifugation delay. This separate experiment indicates that the lactate to glucose ratio may serve as a marker to identify samples with delayed time to centrifugation. Although our data from the untargeted GC-TOFMS analysis did not identify any specific markers, we conclude that plasma and serum metabolic profiles remain quite stable when plasma and serum are centrifuged and separated from the blood cells within 3 hours.

Using bacterial biomarkers to identify early indicators of cystic fibrosis pulmonary exacerbation onset

PubMed Central

Rogers, Geraint B; Hoffman, Lucas R; Johnson, Matt W; Mayer-Hamblett, Nicole; Schwarze, Jürgen; Carroll, Mary P; Bruce, Kenneth D

2011-01-01

Acute periods of pulmonary exacerbation are the single most important cause of morbidity in cystic fibrosis patients, and may be associated with a loss of lung function. Intervening prior to the onset of a substantially increased inflammatory response may limit the associated damage to the airways. While a number of biomarker assays based on inflammatory markers have been developed, providing useful and important measures of disease during these periods, such factors are typically only elevated once the process of exacerbation has been initiated. Identifying biomarkers that can predict the onset of pulmonary exacerbation at an early stage would provide an opportunity to intervene before the establishment of a substantial immune response, with major implications for the advancement of cystic fibrosis care. The precise triggers of pulmonary exacerbation remain to be determined; however, the majority of models relate to the activity of microbes present in the patient's lower airways of cystic fibrosis. Advances in diagnostic microbiology now allow for the examination of these complex systems at a level likely to identify factors on which biomarker assays can be based. In this article, we discuss key considerations in the design and testing of assays that could predict pulmonary exacerbations. PMID:21405970

RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis

PubMed Central

Craciun, Florin L.; Bijol, Vanesa; Ajay, Amrendra K.; Rao, Poornima; Kumar, Ramya K.; Hutchinson, John; Hofmann, Oliver; Joshi, Nikita; Luyendyk, James P.; Kusebauch, Ulrike; Moss, Christopher L.; Srivastava, Anand; Himmelfarb, Jonathan; Waikar, Sushrut S.; Moritz, Robert L.

2016-01-01

CKD is the gradual, asymptomatic loss of kidney function, but current tests only identify CKD when significant loss has already happened. Several potential biomarkers of CKD have been reported, but none have been approved for preclinical or clinical use. Using RNA sequencing in a mouse model of folic acid-induced nephropathy, we identified ten genes that track kidney fibrosis development, the common pathologic finding in patients with CKD. The gene expression of all ten candidates was confirmed to be significantly higher (approximately ten- to 150-fold) in three well established, mechanistically distinct mouse models of kidney fibrosis than in models of nonfibrotic AKI. Protein expression of these genes was also high in the folic acid model and in patients with biopsy-proven kidney fibrosis. mRNA expression of the ten genes increased with increasing severity of kidney fibrosis, decreased in response to therapeutic intervention, and increased only modestly (approximately two- to five-fold) with liver fibrosis in mice and humans, demonstrating specificity for kidney fibrosis. Using targeted selected reaction monitoring mass spectrometry, we detected three of the ten candidates in human urine: cadherin 11 (CDH11), macrophage mannose receptor C1 (MRC1), and phospholipid transfer protein (PLTP). Furthermore, urinary levels of each of these three proteins distinguished patients with CKD (n=53) from healthy individuals (n=53; P<0.05). In summary, we report the identification of urinary CDH11, MRC1, and PLTP as novel noninvasive biomarkers of CKD. PMID:26449608

Serum decoy receptor 3 is a biomarker for disease severity in nonatopic asthma patients.

PubMed

Chen, Ming-Han; Kan, Hung-Tsai; Liu, Chun-Yu; Yu, Wen-Kuang; Lee, Shinn-Shing; Wang, Jia-Horng; Hsieh, Shie-Liang

2017-01-01

Decoy receptor 3 (DcR3), a soluble receptor of the tumor necrosis factor receptor superfamily, is a pleiotropic immunomodulator. The aim of this study was to investigate serum DcR3 levels in atopic and nonatopic asthma patients. The serum DcR3 levels of 70 adults with asthma and 20 healthy controls were determined by enzyme-linked immunosorbent assay (ELISA). The asthma patients were divided into atopic and nonatopic subgroups, based on the presence or absence of immunoglobulin E (IgE) specific to allergen. Correlations between serum DcR3 levels and blood total-eosinophil counts, forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity (FVC), and Asthma Control Test (ACT) scores were analyzed. The mean serum DcR3 level was significantly higher in asthma patients than in healthy controls (266.1 ± 60.6 pg/mL vs. 63.7 ± 21.9 pg/mL, p = 0.003), but there was no significant difference between the mean serum DcR3 level of asthma patients with atopy (37 patients) and patients without atopy (33 patients; 298.7 ± 111.2 pg/mL vs. 230.6 ± 38.5 pg/mL, p = 0.064). However, the serum DcR3 level was positively correlated with the total eosinophil count (r = 0.448, p = 0.012) and inversely correlated with the percentages of predicted FEV1, FEV1/FVC, and ACT score (r = 0.409, p = 0.018; r = -0.399, p = 0.021; and r = -0.505, p = 0.003, respectively) in nonatopic asthma patients, but not in atopic patients. High serum DcR3 levels are associated with disease severity in nonatopic asthma patients, which suggests that DcR3 is a potential biomarker that can be used to predict the severity of nonatopic asthma. Copyright © 2016. Published by Elsevier B.V.

Data-Driven Asthma Endotypes Defined from Blood Biomarker and Gene Expression Data

PubMed Central

George, Barbara Jane; Reif, David M.; Gallagher, Jane E.; Williams-DeVane, ClarLynda R.; Heidenfelder, Brooke L.; Hudgens, Edward E.; Jones, Wendell; Neas, Lucas; Hubal, Elaine A. Cohen; Edwards, Stephen W.

2015-01-01

The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes) driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-sectional study of asthmatic and non-asthmatic children from Detroit, MI. This study describes four distinct asthma endotypes identified via a purely data-driven method. Our method was specifically designed to integrate blood gene expression and clinical biomarkers in a way that provides new mechanistic insights regarding the different asthma endotypes. For example, we describe metabolic syndrome-induced systemic inflammation as an associated factor in three of the four asthma endotypes. Context provided by the clinical biomarker data was essential in interpreting gene expression patterns and identifying putative endotypes, which emphasizes the importance of integrated approaches when studying complex disease etiologies. These synthesized patterns of gene expression and clinical markers from our research may lead to development of novel serum-based biomarker panels. PMID:25643280

Validation of a novel biomarker panel for the detection of ovarian cancer

PubMed Central

Leung, Felix; Bernardini, Marcus Q.; Brown, Marshall D.; Zheng, Yingye; Molina, Rafael; Bast, Robert C.; Davis, Gerard; Serra, Stefano; Diamandis, Eleftherios P.; Kulasingam, Vathany

2016-01-01

Background Ovarian cancer (OvCa) is the most lethal gynecological malignancy. Our integrated -omics approach to OvCa biomarker discovery has identified kallikrein 6 (KLK6) and folate-receptor 1 (FOLR1) as promising candidates but these markers require further validation. Methods KLK6, FOLR1 CA125 and HE4 were investigated in three independent serum cohorts with a total of 20 healthy controls, 150 benign controls and 216 OvCa patients. The serum biomarker levels were determined by ELISA or automated immunoassay. Results All biomarkers demonstrated elevations in the sera of OvCa patients compared to controls (p<0.01). Overall, CA125 and HE4 displayed the strongest ability (AUC 0.80 and 0.82, respectively) to identify OvCa patients and the addition of HE4 to CA125 improved the sensitivity from 36% to 67% at a set specificity of 95%. As well, the combination of HE4 and FOLR1 was a strong predictor of OvCa diagnosis, displaying comparable sensitivity (65%) to the best performing CA125-based models (67%) at a set specificity of 95%. Conclusions The markers identified through our integrated –omics approach performed similarly to the clinically-approved markers CA125 and HE4. Furthermore, HE4 represents a powerful diagnostic marker for OvCa and should be used more routinely in a clinical setting. Impact The implications of our study are two-fold: (1) we have demonstrated the strengths of HE4 alone and in combination with CA125, lending credence to increasing its usage in the clinic; and (2) we have demonstrated the clinical utility of our integrated –omics approach to identifying novel serum markers with comparable performance to clinical markers. PMID:27448593

Increased serum levels of eotaxin/CCL11 in late-stage patients with bipolar disorder: An accelerated aging biomarker?

PubMed

Panizzutti, B; Gubert, C; Schuh, A L; Ferrari, P; Bristot, G; Fries, G R; Massuda, R; Walz, J; Rocha, N P; Berk, M; Teixeira, A L; Gama, C S

2015-08-15

Bipolar disorder (BD) is commonly comorbid with many medical disorders including atopy, and appears characterized by progressive social, neurobiological, and functional impairment associated with increasing number of episodes and illness duration. Early and late stages of BD may present different biological features and may therefore require different treatment strategies. Consequently, the aim of this study was to evaluate serum levels of eotaxin/CCL11, eotaxin-2/CCL24, IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α, IFNγ, BDNF, TBARS, carbonyl, and GPx in a sample of euthymic patients with BD at early and late stages compared to controls. Early-stage BD patients, 12 late-stage patients, and 25 controls matched for sex and age were selected. 10mL of peripheral blood was drawn from all subjects by venipuncture. Serum levels of BDNF, TBARS, carbonyl content, glutathione-peroxidase activity (GPx), cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, TNF-α and IFNγ), and chemokines (eotaxin/CCL11 and eotaxin-2/CCL24) were measured. There were no demographic differences between patients and controls. No significant differences were found for any of the biomarkers, except chemokine eotaxin/CCL11, whose serum levels were higher in late-stage patients with BD when compared to controls (p=0.022; Mann-Whitney U test). Small number of subjects and use of medication may have influenced in our results. The present study suggests a link between biomarkers of atopy and eosinophil function and bipolar disorder. These findings are also in line with progressive biological changes partially mediated by inflammatory imbalance, a process referred to as neuroprogression. Copyright © 2014 Elsevier B.V. All rights reserved.

Serum Neutrophil Gelatinase-Associated Lipocalin Predicts Survival After Resuscitation From Cardiac Arrest.

PubMed

Elmer, Jonathan; Jeong, Kwonho; Abebe, Kaleab Z; Guyette, Francis X; Murugan, Raghavan; Callaway, Clifton W; Rittenberger, Jon C

2016-01-01

In the first days after cardiac arrest, accurate prognostication is challenging. Serum biomarkers are a potentially attractive adjunct for prognostication and risk stratification. Our primary objective in this exploratory study was to identify novel early serum biomarkers that predict survival after cardiac arrest earlier than currently possible. Prospective, observational study. A single academic medical center. Adult subjects who sustained cardiac arrest with return of spontaneous circulation. None. We obtained blood samples from each subject at enrollment, 6, 12, 24, 48, and 72 hours after return of spontaneous circulation. We measured the serum levels of novel biomarkers, including neutrophil gelatinase-associated lipocalin, high-mobility group protein B1, intracellular cell adhesion molecule-1, and leptin, as well as previously characterized biomarkers, including neuron-specific enolase and S100B protein. Our primary outcome of interest was survival-to-hospital discharge. We compared biomarker concentrations at each time point between survivors and nonsurvivors and used logistic regression to test the unadjusted associations of baseline clinical characteristics and enrollment biomarker levels with survival. Finally, we constructed a series of adjusted models to explore the independent association of each enrollment biomarker level with survival. A total of 86 subjects were enrolled. Enrollment levels of high-mobility group protein B1, neutrophil gelatinase-associated lipocalin, and S100B were higher in nonsurvivors than survivors. Enrollment leptin, neuron-specific enolase, and intracellular cell adhesion molecule-1 levels did not differ between nonsurvivors and survivors. The discriminatory power of enrollment neutrophil gelatinase-associated lipocalin level was the greatest (c-statistic, 0.78 [95% CI, 0.66-0.90]) and remained stable across all time points. In our adjusted models, enrollment neutrophil gelatinase-associated lipocalin level was independently

Prognostic value of serum thioredoxin levels in ischemic stroke.

PubMed

Yu, Tieer; Zhang, Wanli; Lin, Yuanshao; Li, Qian; Xue, Jie; Cai, Zhengyi; Cheng, Yifan; Shao, Bei

2017-11-01

Thioredoxin (Trx) is one of significant antioxidative molecules to diminish oxidative stress. Current evidence suggests that Trx is a potent antioxidant with cytoprotective functions. The aim of our study was to investigate specifically the association between serum Trx levels and acute ischemic stroke (AIS) patients. 198 AIS patients and 75 controls were enrolled to the study. Serum Trx levels were measured using an enzyme-linked immunosorbent assay (ELISA). Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) score on admission. Clinical endpoint was functional outcome measured by Barthel Index (BI) 3 months after admission. Multivariate binary logistic regression analyses were performed to identify predictors. We found that serum Trx levels were significantly increased in patients as compared to controls. Serum Trx was an independent biomarker to predict ischemic stroke (OR, 1.264; 95% CI, 1.04-1.537; P = 0.019). In addition, there was a negative correlation between NIHSS score at admission and serum Trx levels in cardioembolic stroke patients (r = -0.422; P = 0.013). Furthermore, higher serum Trx levels in AIS patients were associated with favorable functional outcome. Serum Trx was an independent predictor for the functional outcome (OR, 0.862; 95% CI, 0.75-0.991; P = 0.037). Serum Trx might be as a biomarker of cardioembolic stroke severity. Increased serum Trx levels could be a useful tool to predict good prognosis in patients with AIS.

Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral Cytokine Production, Higher Serum Biomarker Levels, and Poor Outcome in Patients with Severe Traumatic Brain Injury

PubMed Central

Yan, Edwin B.; Satgunaseelan, Laveniya; Paul, Eldho; Bye, Nicole; Nguyen, Phuong; Agyapomaa, Doreen; Kossmann, Thomas; Rosenfeld, Jeffrey V.

2014-01-01

Abstract Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood–brain barrier (BBB) dysfunction. Forty-two TBI patients with Glasgow Coma Scale ≤8 were recruited. Cerebrospinal fluid (CSF) and serum were collected over 6 days. Patients were divided into Hx (n=22) and Nx (n=20) groups. Eight cytokines were measured in the CSF; albumin, S100, myelin basic protein (MBP) and neuronal specific enolase (NSE) were quantified in serum. CSF/serum albumin quotient was calculated for BBB function. Glasgow Outcome Scale Extended (GOSE) was assessed at 6 months post-TBI. Production of granulocye macrophage-colony stimulating factor (GM-CSF) was higher, and profiles of GM-CSF, interferon (IFN)-γ and, to a lesser extent, tumor necrosis factor (TNF), were prolonged in the CSF of Hx but not Nx patients at 4–5 days post-TBI. Interleukin (IL)-2, IL-4, IL-6, and IL-10 increased similarly in both Hx and Nx groups. S100, MBP, and NSE were significantly higher in Hx patients with unfavorable outcome. Among these three biomarkers, S100 showed the strongest correlations to GOSE after TBI-Hx. Elevated CSF/serum albumin quotients lasted for 5 days post-TBI and displayed similar profiles in Hx and Nx patients. We demonstrate for the first time that post-TBI hypoxia is associated with prolonged neuroinflammation, amplified extravasation of biomarkers, and poor outcome. S100 and MBP could be implemented to track the occurrence of post-TBI hypoxia, and prompt adequate treatment. PMID:24279428

Perspective: Proteomic approach to detect biomarkers of human growth hormone

PubMed Central

Ding, Juan; List, Edward O.; Okada, Shigeru; Kopchick, John J.

2009-01-01

Several serum biomarkers for recombinant human growth hormone (rhGH) have been established, however, none alone or in combination have generate a specific, sensitive, and reproducible ‘kit’ for the detection of rhGH abuse. Thus, the search for additional GH specific biomarkers continues. In this review, we focus on the use of proteomics in general and 2-dimensional electrophoresis (2-DE) in particular for the discovery of new GH induced serum biomarkers. Also, we review some of the protocols involved in 2DE. Finally, the possibility of tissues other than blood for biomarker discovery is discussed. PMID:19501004

MicroRNAs in urine are not biomarkers of multiple myeloma.

PubMed

Sedlaříková, Lenka; Bešše, Lenka; Novosadová, Soňa; Kubaczková, Veronika; Radová, Lenka; Staník, Michal; Krejčí, Marta; Hájek, Roman; Ševčíková, Sabina

2015-09-23

In this study, we aimed to identify microRNA from urine of multiple myeloma patients that could serve as a biomarker for the disease. Analysis of urine samples was performed using Serum/Plasma Focus PCR MicroRNA Panel (Exiqon) and verified using individual TaqMan miRNA assays for qPCR. We found 20 deregulated microRNA (p < 0.05); for further validation, we chose 8 of them. Nevertheless, only differences in expression levels of miR-22-3p remained close to statistical significance. Our preliminary results did not confirm urine microRNA as a potential biomarker for multiple myeloma.

Likelihood ratios for the prediction of preterm delivery with biomarkers.

PubMed

Hee, Lene

2011-11-01

To conduct a literature search for selected biomarkers on preterm delivery and estimate their likelihood ratios (LR). Structured review. Low and high-risk populations and women with symptoms of preterm delivery. METHODS. Publications were identified in PubMed. LR on selected biomarkers for preterm delivery. In asymptomatic women with low risk of preterm delivery, the following biomarkers gave major shifts in probability (LR above 5): twins (LR+ 10), Ureaplasma urealyticum in amniotic fluid (LR+ of 10), cervical length <25mm (LR+ 6), salival estriol (LR+ 5) and various combined tests. In asymptomatic women with high risk of preterm delivery, short cervical length (LR+ 11, LR- 0.7), high serum tumor necrosis factor-alpha (LR+ 10, LR- 0.6) gave major shifts in probability. In women with symptoms of preterm delivery, major shifts in probability can be obtained from the following amniotic fluid biomarkers: high matrix metalloproteinase-8 (LR+ 23, LR- 0.6), Ureaplasma urealyticum (LR+ 19, LR- 0.8), high interleukin (IL)-6 (LR+ 9, LR- 0.2), IL-8 (LR+10, LR- 0.2) and tumor necrosis factor-alpha (LR+ 8, LR- 0.4). In serum IL-6 (LR+ 12, LR- 0.2), Cluster of Differentiation 163 (LR+9, LR-0.8) and various combined tests. Vaginal fetal fibronectin (LR+ 3 and LR- 0.5) and short cervical length (LR+ 2, LR- 0.3) gave LRs of some importance (LR below 5). Several biomarkers have been identified for assessment of risk of preterm delivery. Their clinical relevance depends on the efficacy of the interventions which can be offered to these patients. © 2011 The Author Acta Obstetricia et Gynecologica Scandinavica© 2011 Nordic Federation of Societies of Obstetrics and Gynecology.

Lineage-Specific Changes in Biomarkers in Great Apes and Humans.

PubMed

Ronke, Claudius; Dannemann, Michael; Halbwax, Michel; Fischer, Anne; Helmschrodt, Christin; Brügel, Mathias; André, Claudine; Atencia, Rebeca; Mugisha, Lawrence; Scholz, Markus; Ceglarek, Uta; Thiery, Joachim; Pääbo, Svante; Prüfer, Kay; Kelso, Janet

2015-01-01

Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans.

Lineage-Specific Changes in Biomarkers in Great Apes and Humans

PubMed Central

Ronke, Claudius; Dannemann, Michael; Halbwax, Michel; Fischer, Anne; Helmschrodt, Christin; Brügel, Mathias; André, Claudine; Atencia, Rebeca; Mugisha, Lawrence; Scholz, Markus; Ceglarek, Uta; Thiery, Joachim; Pääbo, Svante; Prüfer, Kay; Kelso, Janet

2015-01-01

Although human biomedical and physiological information is readily available, such information for great apes is limited. We analyzed clinical chemical biomarkers in serum samples from 277 wild- and captive-born great apes and from 312 healthy human volunteers as well as from 20 rhesus macaques. For each individual, we determined a maximum of 33 markers of heart, liver, kidney, thyroid and pancreas function, hemoglobin and lipid metabolism and one marker of inflammation. We identified biomarkers that show differences between humans and the great apes in their average level or activity. Using the rhesus macaques as an outgroup, we identified human-specific differences in the levels of bilirubin, cholinesterase and lactate dehydrogenase, and bonobo-specific differences in the level of apolipoprotein A-I. For the remaining twenty-nine biomarkers there was no evidence for lineage-specific differences. In fact, we find that many biomarkers show differences between individuals of the same species in different environments. Of the four lineage-specific biomarkers, only bilirubin showed no differences between wild- and captive-born great apes. We show that the major factor explaining the human-specific difference in bilirubin levels may be genetic. There are human-specific changes in the sequence of the promoter and the protein-coding sequence of uridine diphosphoglucuronosyltransferase 1 (UGT1A1), the enzyme that transforms bilirubin and toxic plant compounds into water-soluble, excretable metabolites. Experimental evidence that UGT1A1 is down-regulated in the human liver suggests that changes in the promoter may be responsible for the human-specific increase in bilirubin. We speculate that since cooking reduces toxic plant compounds, consumption of cooked foods, which is specific to humans, may have resulted in relaxed constraint on UGT1A1 which has in turn led to higher serum levels of bilirubin in humans. PMID:26247603

Improving Interpretation of New and Old Serum Biomarkers of Drug-Induced Liver Injury Through Mechanistic Modeling.

PubMed

Watkins, Paul B

2018-04-26

The study by Mason et al. in this issue used mechanistic modeling and simulation to address how both the dose of acetaminophen consumed and the time since ingestion can be estimated from biomarkers measured in a single serum sample in mice. Translation into the clinic would potentially be an advance in the treatment of acetaminophen poisoning. Importantly, this approach could transform the evaluation of liver safety in clinical trials of new drug candidates. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Novel serum biomarkers for detection of excessive alcohol use

PubMed Central

Liangpunsakul, Suthat; Lai, Xianyin; Ross, Ruth A.; Yu, Zhangsheng; Modlik, Elizabeth; Westerhold, Chi; Heathers, Laura; Paul, Robin; O’Connor, Sean; Crabb, David W.; Witzmann, Frank

2015-01-01

Objectives Construct interview that correctly identifies those with alcohol use disorder have limitation, especially when the subjects are motivated to minimize the magnitude of drinking behavior. Current laboratory tests to detect excessive alcohol consumption are limited by marginal sensitivity/specificity. Excessive drinking has been shown to affect several organ systems; which may be reflected in changes in quantity of plasma proteins. Our aim was to employ novel proteomic analyses to identify potential markers for excessive alcohol use. METHODS A prospective case-control study that included 39 controls and 54 excessive drinkers (discovery cohort). The serum proteomic analyses in these subjects were performed and the results were tested in the verification cohort (40 controls and 40 excessive drinkers). RESULTS Using the appropriate cutoff and confirmation with ELISA, we identified 4 proteins which were significantly elevated in the serum of excessive drinkers; AT-rich interactive domain-containing protein 4B (ARID4B), Phosphatidylcholine-sterol acyltransferase (LCAT), Hepatocyte growth factor-like protein (MST1), and ADP-ribosylation factor 6 (ARL6). The performance of the conventional markers (AST, ALT, GGT, %CDT, and MCV) discriminating between excessive alcohol use and controls had an area under the curve (AUC) ranging from 0.21 (ALT) to 0.67 (MCV). The AUC of these novel proteins showed the improvement in the detection of excessive drinkers compared to conventional lab tests, ranging from 0.73 (for ARID4B) to 0.86 (for ARL6). CONCLUSIONS We have identified four novel proteins that can discern subjects with excessive alcohol use. Further studies are needed to determine the clinical implications of these markers to detect excessive alcohol use and confirm abstinence. PMID:25704570

High-Throughput Sequencing Reveals Circulating miRNAs as Potential Biomarkers for Measuring Puberty Onset in Chicken (Gallus gallus).

PubMed

Han, Wei; Zhu, Yunfen; Su, Yijun; Li, Guohui; Qu, Liang; Zhang, Huiyong; Wang, Kehua; Zou, Jianmin; Liu, Honglin

2016-01-01

There are still no highly sensitive and unique biomarkers for measurement of puberty onset. Circulating miRNAs have been shown to be promising biomarkers for diagnosis of various diseases. To identify circulating miRNAs that could be served as biomarkers for measuring chicken (Gallus gallus) puberty onset, the Solexa deep sequencing was performed to analyze the miRNA expression profiles in serum and plasma of hens from two different pubertal stages, before puberty onset (BO) and after puberty onset (AO). 197 conserved and 19 novel miRNAs (reads > 10) were identified as serum/plasma-expressed miRNAs in the chicken. The common miRNA amounts and their expression changes from BO to AO between serum and plasma were very similar, indicating the different treatments to generate serum and plasma had quite small influence on the miRNAs. 130 conserved serum-miRNAs were showed to be differentially expressed (reads > 10, P < 0.05) from BO to AO, with 68 up-regulated and 62 down-regulated. 4829 putative genes were predicted as the targets of the 40 most differentially expressed miRNAs (|log2(fold-change)|>1.0, P < 0.01). Functional analysis revealed several pathways that were associated with puberty onset. Further quantitative real-time PCR (RT-qPCR) test found that a seven-miRNA panel, including miR-29c, miR-375, miR-215, miR-217, miR-19b, miR-133a and let-7a, had great potentials to serve as novel biomarkers for measuring puberty onset in chicken. Due to highly conserved nature of miRNAs, the findings could provide cues for measurement of puberty onset in other animals as well as humans.

High-Throughput Sequencing Reveals Circulating miRNAs as Potential Biomarkers for Measuring Puberty Onset in Chicken (Gallus gallus)

PubMed Central

Su, Yijun; Li, Guohui; Qu, Liang; Zhang, Huiyong; Wang, Kehua; Zou, Jianmin; Liu, Honglin

2016-01-01

There are still no highly sensitive and unique biomarkers for measurement of puberty onset. Circulating miRNAs have been shown to be promising biomarkers for diagnosis of various diseases. To identify circulating miRNAs that could be served as biomarkers for measuring chicken (Gallus gallus) puberty onset, the Solexa deep sequencing was performed to analyze the miRNA expression profiles in serum and plasma of hens from two different pubertal stages, before puberty onset (BO) and after puberty onset (AO). 197 conserved and 19 novel miRNAs (reads > 10) were identified as serum/plasma-expressed miRNAs in the chicken. The common miRNA amounts and their expression changes from BO to AO between serum and plasma were very similar, indicating the different treatments to generate serum and plasma had quite small influence on the miRNAs. 130 conserved serum-miRNAs were showed to be differentially expressed (reads > 10, P < 0.05) from BO to AO, with 68 up-regulated and 62 down-regulated. 4829 putative genes were predicted as the targets of the 40 most differentially expressed miRNAs (|log2(fold-change)|>1.0, P < 0.01). Functional analysis revealed several pathways that were associated with puberty onset. Further quantitative real-time PCR (RT-qPCR) test found that a seven-miRNA panel, including miR-29c, miR-375, miR-215, miR-217, miR-19b, miR-133a and let-7a, had great potentials to serve as novel biomarkers for measuring puberty onset in chicken. Due to highly conserved nature of miRNAs, the findings could provide cues for measurement of puberty onset in other animals as well as humans. PMID:27149515

Progress on the biomarkers for tuberculosis diagnosis.

PubMed

Fu, Tiwei; Xie, Jianping

2011-01-01

Tuberculosis (TB) remains a major threat to global health. Biomarkers derived from pathogen-host interaction can facilitate the monitoring of active TB. The recent progress regarding such biomarkers is summarized, including those can be used from serum, sputum, urine, or breath monitoring. A wide range of potential biomarkers such as protein antigens, cell-free nucleic acids, and lipoarabinomannose were compiled. The possible use of biomarkers for infection identification and monitoring drug efficacy are also presented.

Potential biomarkers in psychiatry: focus on the cholesterol system

PubMed Central

Woods, Alisa G; Sokolowska, Izabela; Taurines, Regina; Gerlach, Manfred; Dudley, Edward; Thome, Johannes; Darie, Costel C

2012-01-01

Abstract Measuring biomarkers to identify and assess illness is a strategy growing in popularity and relevance. Although already in clinical use for treating and predicting cancer, no biological measurement is used clinically for any psychiatric disorder. Biomarkers could predict the course of a medical problem, and aid in determining how and when to treat. Several studies have indicated that of candidate psychiatric biomarkers detected using proteomic techniques, cholesterol and associated proteins, specifically apolipoproteins (Apos), may be of interest. Cholesterol is necessary for brain development and its synthesis continues at a lower rate in the adult brain. Apos are the protein component of lipoproteins responsible for lipid transport. There is extensive evidence that the levels of cholesterol and Apos may be disturbed in psychiatric disorders, including autistic spectrum disorders (ASD). Here, we describe putative serum biomarkers for psychiatric disorders, and the role of cholesterol and Apos in central nervous system (CNS) disorders. PMID:22304330

Development of a Multi-Biomarker Disease Activity Test for Rheumatoid Arthritis

PubMed Central

Shen, Yijing; Ramanujan, Saroja; Knowlton, Nicholas; Swan, Kathryn A.; Turner, Mary; Sutton, Chris; Smith, Dustin R.; Haney, Douglas J.; Chernoff, David; Hesterberg, Lyndal K.; Carulli, John P.; Taylor, Peter C.; Shadick, Nancy A.; Weinblatt, Michael E.; Curtis, Jeffrey R.

2013-01-01

Background Disease activity measurement is a key component of rheumatoid arthritis (RA) management. Biomarkers that capture the complex and heterogeneous biology of RA have the potential to complement clinical disease activity assessment. Objectives To develop a multi-biomarker disease activity (MBDA) test for rheumatoid arthritis. Methods Candidate serum protein biomarkers were selected from extensive literature screens, bioinformatics databases, mRNA expression and protein microarray data. Quantitative assays were identified and optimized for measuring candidate biomarkers in RA patient sera. Biomarkers with qualifying assays were prioritized in a series of studies based on their correlations to RA clinical disease activity (e.g. the Disease Activity Score 28-C-Reactive Protein [DAS28-CRP], a validated metric commonly used in clinical trials) and their contributions to multivariate models. Prioritized biomarkers were used to train an algorithm to measure disease activity, assessed by correlation to DAS and area under the receiver operating characteristic curve for classification of low vs. moderate/high disease activity. The effect of comorbidities on the MBDA score was evaluated using linear models with adjustment for multiple hypothesis testing. Results 130 candidate biomarkers were tested in feasibility studies and 25 were selected for algorithm training. Multi-biomarker statistical models outperformed individual biomarkers at estimating disease activity. Biomarker-based scores were significantly correlated with DAS28-CRP and could discriminate patients with low vs. moderate/high clinical disease activity. Such scores were also able to track changes in DAS28-CRP and were significantly associated with both joint inflammation measured by ultrasound and damage progression measured by radiography. The final MBDA algorithm uses 12 biomarkers to generate an MBDA score between 1 and 100. No significant effects on the MBDA score were found for common comorbidities

Identifying disease-related subnetwork connectome biomarkers by sparse hypergraph learning.

PubMed

Zu, Chen; Gao, Yue; Munsell, Brent; Kim, Minjeong; Peng, Ziwen; Cohen, Jessica R; Zhang, Daoqiang; Wu, Guorong

2018-06-14

The functional brain network has gained increased attention in the neuroscience community because of its ability to reveal the underlying architecture of human brain. In general, majority work of functional network connectivity is built based on the correlations between discrete-time-series signals that link only two different brain regions. However, these simple region-to-region connectivity models do not capture complex connectivity patterns between three or more brain regions that form a connectivity subnetwork, or subnetwork for short. To overcome this current limitation, a hypergraph learning-based method is proposed to identify subnetwork differences between two different cohorts. To achieve our goal, a hypergraph is constructed, where each vertex represents a subject and also a hyperedge encodes a subnetwork with similar functional connectivity patterns between different subjects. Unlike previous learning-based methods, our approach is designed to jointly optimize the weights for all hyperedges such that the learned representation is in consensus with the distribution of phenotype data, i.e. clinical labels. In order to suppress the spurious subnetwork biomarkers, we further enforce a sparsity constraint on the hyperedge weights, where a larger hyperedge weight indicates the subnetwork with the capability of identifying the disorder condition. We apply our hypergraph learning-based method to identify subnetwork biomarkers in Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD). A comprehensive quantitative and qualitative analysis is performed, and the results show that our approach can correctly classify ASD and ADHD subjects from normal controls with 87.65 and 65.08% accuracies, respectively.

Changes to Serum Sample Tube and Processing Methodology Does Not Cause Inter-Individual Variation in Automated Whole Serum N-Glycan Profiling in Health and Disease

PubMed Central

Shubhakar, Archana; Kalla, Rahul; Nimmo, Elaine R.; Fernandes, Daryl L.; Satsangi, Jack; Spencer, Daniel I. R.

2015-01-01

Introduction Serum N-glycans have been identified as putative biomarkers for numerous diseases. The impact of different serum sample tubes and processing methods on N-glycan analysis has received relatively little attention. This study aimed to determine the effect of different sample tubes and processing methods on the whole serum N-glycan profile in both health and disease. A secondary objective was to describe a robot automated N-glycan release, labeling and cleanup process for use in a biomarker discovery system. Methods 25 patients with active and quiescent inflammatory bowel disease and controls had three different serum sample tubes taken at the same draw. Two different processing methods were used for three types of tube (with and without gel-separation medium). Samples were randomised and processed in a blinded fashion. Whole serum N-glycan release, 2-aminobenzamide labeling and cleanup was automated using a Hamilton Microlab STARlet Liquid Handling robot. Samples were analysed using a hydrophilic interaction liquid chromatography/ethylene bridged hybrid(BEH) column on an ultra-high performance liquid chromatography instrument. Data were analysed quantitatively by pairwise correlation and hierarchical clustering using the area under each chromatogram peak. Qualitatively, a blinded assessor attempted to match chromatograms to each individual. Results There was small intra-individual variation in serum N-glycan profiles from samples collected using different sample processing methods. Intra-individual correlation coefficients were between 0.99 and 1. Unsupervised hierarchical clustering and principal coordinate analyses accurately matched samples from the same individual. Qualitative analysis demonstrated good chromatogram overlay and a blinded assessor was able to accurately match individuals based on chromatogram profile, regardless of disease status. Conclusions The three different serum sample tubes processed using the described methods cause minimal

Evidence for serum miR-15a and miR-16 levels as biomarkers that distinguish sepsis from systemic inflammatory response syndrome in human subjects.

PubMed

Wang, Huijuan; Zhang, Pengjun; Chen, Weijun; Feng, Dan; Jia, Yanhong; Xie, Li-xin

2012-02-11

Serum microRNAs may be useful biomarkers for diagnosing human diseases. We investigated serum levels of miR-15a and miR-16 in patients with sepsis and systemic inflammatory response syndrome (SIRS) without infection. We enrolled 166 sepsis patients, 32 SIRS patients, and 24 normal controls. Serum miR-15a and miR-16 expression levels were determined by quantitative reverse transcriptase polymerase chain reaction assays (qRT-PCR). Serum miR-15a (p<0.001) and miR-16 (p<0.05) were both significantly higher in sepsis patients compared with normal controls, and miR-15a (p<0.001) and miR-16 (p<0.01) levels in SIRS patients were also significantly higher than those in normal controls. Serum miR-15a and miR-16 levels were not correlated with white blood cell counts. Receiver operating characteristic curves showed that miR-15a had the highest area under the curve of 0.858 [95% confidence interval (CI) 0.800-0.916] for the diagnosis of sepsis compared with C reactive protein and procalcitonin with areas under the curve of 0.572 (95% CI 0.479-0.665; p=0.198) and 0.605 (95% CI 0.443-0.767; p=0.168), respectively. When its cut-off point was set at 0.21, serum miR-15a had a sensitivity of 68.3% and a specificity of 94.4%. Serum miR-15a and miR-16 can both distinguish sepsis/SIRS from normal controls. miR-15a may be a biomarker that distinguishes between sepsis and SIRS.

Sputum-to-serum hydrogen sulfide ratio as a novel biomarker of predicting future risks of asthma exacerbation.

PubMed

Suzuki, Yasuhito; Saito, Junpei; Kikuchi, Masami; Uematsu, Manabu; Fukuhara, Atsuro; Sato, Suguru; Munakata, Mitsuru

2018-05-14

Increased level of hydrogen sulfide (H 2 S) in sputum is reported to be a new biomarker of neutrophilic airway inflammation in chronic airway disorders. However, the relationship between H 2 S and disease activity remains unclear. We investigated whether H 2 S levels could vary during different conditions in asthma. H 2 S levels in sputum and serum were measured using a sulfide-sensitive electrode in 47 stable asthmatic subjects (S-BA), 21 uncontrolled asthmatic subjects (UC-BA), 26 asthmatic subjects with acute exacerbation (AE-BA), and 15 healthy subjects. Of these, H 2 S levels during stable, as well as exacerbation states were obtained in 13 asthmatic subjects. Sputum H 2 S levels were significantly higher in the AE-BA subjects compared to the UC-BA and healthy subjects (p<0.05). However, serum H 2 S levels in the AE-BA subjects were lower than in the S-BA subjects (p<0.001) and similar to those in healthy subjects. Thus, the sputum-to-serum ratio of H 2 S (H 2 S ratio) in the AE-BA subjects was significantly higher than in the S-BA, UC-BA and healthy subjects (p<0.05). Among all subjects, sputum H 2 S levels showed a trend to decrease with FEV 1% predicted, and significantly positive correlations with sputum neutrophils (%), sputum IL-8, and serum IL-8. A multiple linear regression analysis showed that sputum H 2 S was independently associated with increased sputum neutrophils (%) and decreased FEV 1% predicted (p<0.05) The cut-off level of H 2 S ratio to indicate an exacerbation was ≥0.34 (area under the curve; 0.88, with a sensitivity of 81.8% and specificity of 72.7%, p<0.001). Furthermore, half of the asthmatic subjects with H 2 S ratios higher than the cutoff level experienced asthma exacerbations over the following 3 months after enrollment. The H 2 S ratio may provide useful information on predicting future risks of asthma exacerbation, as well as on obstructive neutrophilic airway inflammation as one of the non-Th2 biomarkers, in asthma. This article

METHOD FOR MICRORNA ISOLATION FROM CLINICAL SERUM SAMPLES

PubMed Central

Li, Yu; Kowdley, Kris V.

2012-01-01

MicroRNAs are a group of intracellular non-coding RNA molecules that have been implicated in a variety of human diseases. Due to their high stability in blood, microRNAs released into circulation could be potentially utilized as non-invasive biomarkers for diagnosis or prognosis. Current microRNA isolation protocols are specifically designed for solid tissues and are impractical for biomarker development utilizing small-volume serum samples on a large scale. Thus, a protocol for microRNA isolation from serum is needed to accommodate these conditions in biomarker development. To establish such a protocol, we developed a simplified approach to normalize sample input by using single synthetic spike-in microRNA. We evaluated three commonly used commercial microRNA isolation kits for the best performance by comparing RNA quality and yield. The manufacturer’s protocol was further modified to improve the microRNA yield from 200 μL of human serum. MicroRNAs isolated from a large set of clinical serum samples were tested on the miRCURY LNA real-time PCR panel and confirmed to be suitable for high-throughput microRNA profiling. In conclusion, we have established a proven method for microRNA isolation from clinical serum samples suitable for microRNA biomarker development. PMID:22982505

N-glycan signatures identified in tumor interstitial fluid and serum of breast cancer patients: association with tumor biology and clinical outcome.

PubMed

Terkelsen, Thilde; Haakensen, Vilde D; Saldova, Radka; Gromov, Pavel; Hansen, Merete Kjaer; Stöckmann, Henning; Lingjaerde, Ole Christian; Børresen-Dale, Anne-Lise; Papaleo, Elena; Helland, Åslaug; Rudd, Pauline M; Gromova, Irina

2018-06-01

Particular N-glycan structures are known to be associated with breast malignancies by coordinating various regulatory events within the tumor and corresponding microenvironment, thus implying that N-glycan patterns may be used for cancer stratification and as predictive or prognostic biomarkers. However, the association between N-glycans secreted by breast tumor and corresponding clinical relevance remain to be elucidated. We profiled N-glycans by HILIC UPLC across a discovery dataset composed of tumor interstitial fluids (TIF, n = 85), paired normal interstitial fluids (NIF, n = 54) and serum samples (n = 28) followed by independent evaluation, with the ultimate goal of identifying tumor-related N-glycan patterns in blood of patients with breast cancer. The segregation of N-linked oligosaccharides revealed 33 compositions, which exhibited differential abundances between TIF and NIF. TIFs were depleted of bisecting N-glycans, which are known to play essential roles in tumor suppression. An increased level of simple high mannose N-glycans in TIF strongly correlated with the presence of tumor infiltrating lymphocytes within tumor. At the same time, a low level of highly complex N-glycans in TIF inversely correlated with the presence of infiltrating lymphocytes within tumor. Survival analysis showed that patients exhibiting increased TIF abundance of GP24 had better outcomes, whereas low levels of GP10, GP23, GP38, and coreF were associated with poor prognosis. Levels of GP1, GP8, GP9, GP14, GP23, GP28, GP37, GP38, and coreF were significantly correlated between TIF and paired serum samples. Cross-validation analysis using an independent serum dataset supported the observed correlation between TIF and serum, for five of nine N-glycan groups: GP8, GP9, GP14, GP23, and coreF. Collectively, our results imply that profiling of N-glycans from proximal breast tumor fluids is a promising strategy for determining tumor-derived glyco-signature(s) in the blood. N

S100A8/A9, a potent serum and molecular imaging biomarker for synovial inflammation and joint destruction in seronegative experimental arthritis.

PubMed

Geven, Edwin J W; van den Bosch, Martijn H J; Di Ceglie, Irene; Ascone, Giuliana; Abdollahi-Roodsaz, Shahla; Sloetjes, Annet W; Hermann, Sven; Schäfers, Michael; van de Loo, Fons A J; van der Kraan, Peter M; Koenders, Marije I; Foell, Dirk; Roth, Johannes; Vogl, Thomas; van Lent, Peter L E M

2016-10-24

Seronegative joint diseases are characterized by a lack of well-defined biomarkers since autoantibodies are not elevated. Calprotectin (S100A8/A9) is a damage-associated molecular pattern (DAMP) which is released by activated phagocytes, and high levels are found in seronegative arthritides. In this study, we investigated the biomarker potential of systemic and local levels of these S100 proteins to assess joint inflammation and joint destruction in an experimental model for seronegative arthritis. Serum levels of S100A8/A9 and various cytokines were monitored during disease development in interleukin-1 receptor antagonist (IL-1Ra) -/- mice using ELISA and multiplex bead-based immunoassay, and were correlated to macroscopic and microscopic parameters for joint inflammation, bone erosion, and cartilage damage. Local expression of S100A8 and S100A9 and matrix metalloproteinase (MMP)-mediated cartilage damage in the ankle joints were investigated by immunohistochemistry. In addition, local S100A8 and activated MMPs were monitored in vivo by optical imaging using anti-S100A8-Cy7 and AF489-Cy5.5, a specific tracer for activated MMPs. Serum levels of S100A8/A9 were significantly increased in IL-1Ra -/- mice and correlated with macroscopic joint swelling and histological inflammation, while serum levels of pro-inflammatory cytokines did not correlate with joint swelling. In addition, early serum S100A8/A9 levels were prognostic for disease outcome at a later stage. The increased serum S100A8/A9 levels were reflected by an increased expression of S100A8 and S100A9 within the ankle joint, as visualized by molecular imaging. Next to inflammatory processes, serum S100A8/A9 also correlated with histological parameters for bone erosion and cartilage damage. In addition, arthritic IL-1Ra -/- mice with increased synovial S100A8 and S100A9 expression showed increased cartilage damage that coincided with MMP-mediated neoepitope expression and in vivo imaging of activated MMPs

Serum galectin-9 as a noninvasive biomarker for the detection of endometriosis and pelvic pain or infertility-related gynecologic disorders.

PubMed

Brubel, Reka; Bokor, Attila; Pohl, Akos; Schilli, Gabriella Krisztina; Szereday, Laszlo; Bacher-Szamuel, Reka; Rigo, Janos; Polgar, Beata

2017-12-01

To investigate the usefulness of soluble galectin-9 (Gal-9) in the noninvasive laboratory diagnosis of endometriosis and various gynecologic disorders. Prospective case-control study. University medical centers. A total of 135 women of reproductive age were involved in the study, 77 endometriosis patients, 28 gynecologic controls, and 30 healthy women. Diagnostic laparoscopy and collection of tissue biopsies, peritoneal cells, and native peripheral blood from different case groups of gynecology patients and healthy women. The expression of mRNA and serum concentration of Gal-9. Semiquantitative reverse transcription-polymerase chain reaction analysis and serum soluble Gal-9 ELISA were performed on three different cohorts of patients: those with endometriosis, those with benign gynecologic disorders, and healthy controls. Differences in the Gal-9 concentrations between the investigated groups and the stability of Gal-9 in the serum and diagnostic characteristics of Gal-9 ELISA were determined by statistical evaluation and receiver operating characteristic (ROC) curve analysis. Significantly elevated Gal-9 levels were found in both minimal-mild (I-II) and moderate-severe (III-IV) stages of endometriosis in comparison with healthy controls. At a cutoff of 132 pg/mL, ROC analysis revealed an excellent diagnostic value of Gal-9 ELISA in endometriosis (area under the curve = 0.973) with a sensitivity of 94% and specificity of 93.75%, indicating better diagnostic potential than that of other endometriosis biomarkers. Furthermore, various pelvic pain or infertility-associated benign gynecologic conditions were also associated with increased serum Gal-9 levels. Our results suggest that Gal-9 could be a promising noninvasive biomarker of endometriosis and a predictor of various infertility or pelvic pain-related gynecologic disorders. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Comparison of the use of scapular ultrasonography, physical examination, and measurement of serum biomarkers of bone turnover versus scintigraphy for detection of bone fragility syndrome in horses.

PubMed

Arens, Amanda M; Puchalski, Sarah M; Whitcomb, Mary Beth; Bell, Robin; Gardner, Ian A; Stover, Susan M

2013-01-01

To define scintigraphic, physical examination, and scapular ultrasonographic findings consistent with bone fragility syndrome (BFS) in horses; develop indices of BFS severity; and assess accuracy of physical examination, scapular ultrasonography, and serum biomarkers for BFS diagnosis. Prospective case-control study. 48 horses (20 horses with BFS and 28 control horses). Horses underwent forelimb scintigraphic evaluation, physical examination, scapular ultrasonography, and serum collection. Scintigraphy was used as a reference standard to which physical examination, scapular ultrasonography, and concentrations of serum biomarkers (carboxy-terminal telopeptide of collagen crosslinks and bone-specific alkaline phosphatase activity) were compared for assessing accuracy in BFS diagnosis. A diagnosis of BFS was strongly supported on scintigraphy by ≥ 2 regions of increased radiopharmaceutical uptake, including 1 region in the scapular spine and 1 region in the scapular body or ribs; on physical examination by lateral bowing of the scapulae; and on ultrasonography by widening of the scapular spine. None of the tests evaluated were accurate enough to replace scintigraphy for mild disease; however, physical examination and scapular ultrasonography were accurate in horses with moderate to severe BFS. Serum biomarkers were not accurate for BFS diagnosis. Scintigraphy remained the most informative diagnostic modality for BFS, providing insight into disease severity and distribution; however, physical examination and scapular ultrasonographic abnormalities were diagnostic in horses with moderate to severe disease. Proposed severity indices classified the spectrum of disease manifestations. Clearly defined criteria for interpretation of diagnostic tests aid in the detection of BFS. Severity indices may be useful for assessing disease progression and response to treatment.

Response of the antioxidant enzymes of the erythrocyte and alterations in the serum biomarkers in rats following oral administration of nanoparticles.

PubMed

Canli, Esin G; Atli, Gülüzar; Canli, Mustafa

2017-03-01

In this study, Al 2 O 3 , CuO and TiO 2 nanoparticles (NPs) were administered to mature female rats (Rattus norvegicus var. albinos) via oral gavage (0, 0.5, 5, 50mg/kg b.w./day) for 14days to investigate their effects on 14 serum biomarkers and 4 antioxidant enzyme (catalase, superoxide dismutase, glutathione peroxidase, glutathione S-transferase) activities in the erythrocyte. Data showed that Al 2 O 3 did not cause any significant (P>0.05) change in the parameters, except few cases, while CuO and TiO 2 caused significant alterations in antioxidant system parameters of the erythrocytes. Activities of catalase and superoxide dismutase significantly decreased in CuO and TiO 2 administered rats. Oppositely, glutathione peroxidase activity increased in CuO and TiO 2 administered rats. There were no significant alterations in the activity of glutathione S-transferase in the erythrocytes. Levels of glucose, cholesterol, bilirubin, triglyceride, triiodothyronine (T3), estradiol, prolactin and immunoglobulin M (IgM) in the serum altered after some of NP administrations, whereas cortisol, protein, creatinine, blood urea nitrogen (BUN), thyroxine (T4) and immunoglobulin G (IgG) levels in the serum did not change significantly after any of NP administration. There were outstanding increases in the levels of bilirubin and prolactin and decreases in the levels of triglyceride and estradiol. The present study demonstrated that the antioxidant enzymes in the erythrocyte were generally affected from copper and titanium NPs, while aluminium and copper NPs caused more significant alterations in serum biomarkers. Copyright © 2017 Elsevier B.V. All rights reserved.

Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction - an experimental study.

PubMed

Fu, Mingqiang; Zhou, Jingmin; Qian, Juying; Jin, Xuejuan; Zhu, Hongmin; Zhong, Chunlin; Fu, Michael; Zou, Yunzeng; Ge, Junbo

2012-08-30

Adiponectin is reported to relate with cardiovascular diseases, we sought to examine whether adiponectin is associated with disease progression of heart failure from hypertension in rats in comparison with other known biomarkers and echocardiographic parameters. Spontaneously hypertensive rats (SHR, n = 35), aged 1 month, were used and followed up to 18 months. High frequency echocardiography was performed both at baseline and every 3 months thereafter. Moreover, serum levels of N-terminal pro-natriuretic peptide (NT-proBNP) and interleukin-6 (IL-6) as well as serum level and tissue expression of adiponectin were determined at the same time as echocardiography. The results clearly demonstrated time-dependent progression of hypertension and heart dysfunction as evidenced by gradually increased left ventricular mass index, NT-proBNP, IL-6 as well as gradually decreased cardiac function as assessed by echocardiography. Meanwhile, tissue and serum adiponectin decreased from 3 months and reached plateau until 12 months in parallel with decreasing of cardiac diastolic function. Thereafter, adiponectin levels increased prior to occurrence of systolic dysfunction. Adiponectin concentration is inversely related with NT-proBNP, IL-6 and E/E' (correlation coefficient (r) = -0.756 for NT-proBNP, p < 0.001, -0.635 for IL-6, p = 0.002, and -0.626 for E/E', p = 0.002, respectively) while positively correlated with E/A and E'/A' (r = 0.683 for E/A, p = 0.001, 0.671 for E'/A', p = 0.001, respectively). No difference for adiponectin distribution among visceral adipose tissues was found. Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction.

Cohort profile of BIOMArCS: the BIOMarker study to identify the Acute risk of a Coronary Syndrome—a prospective multicentre biomarker study conducted in the Netherlands

PubMed Central

Oemrawsingh, Rohit M; Akkerhuis, K Martijn; Umans, Victor A; Kietselaer, Bas; Schotborgh, Carl; Ronner, Eelko; Lenderink, Timo; Liem, Anho; Haitsma, David; van der Harst, Pim; Asselbergs, Folkert W; Maas, Arthur; Oude Ophuis, Anton J; Ilmer, Ben; Dijkgraaf, Rene; de Winter, Robbert-Jan; The, S Hong Kie; Wardeh, Alexander J; Hermans, Walter; Cramer, Etienne; van Schaik, Ron H; Hoefer, Imo E; Doevendans, Pieter A; Simoons, Maarten L; Boersma, Eric

2016-01-01

Purpose Progression of stable coronary artery disease (CAD) towards acute coronary syndrome (ACS) is a dynamic and heterogeneous process with many intertwined constituents, in which a plaque destabilising sequence could lead to ACS within short time frames. Current CAD risk assessment models, however, are not designed to identify increased vulnerability for the occurrence of coronary events within a precise, short time frame at the individual patient level. The BIOMarker study to identify the Acute risk of a Coronary Syndrome (BIOMArCS) was designed to evaluate whether repeated measurements of multiple biomarkers can predict such ‘vulnerable periods’. Participants BIOMArCS is a multicentre, prospective, observational study of 844 patients presenting with ACS, either with or without ST-elevation and at least one additional cardiovascular risk factor. Methods and analysis We hypothesised that patterns of circulating biomarkers that reflect the various pathophysiological components of CAD, such as distorted lipid metabolism, vascular inflammation, endothelial dysfunction, increased thrombogenicity and ischaemia, diverge in the days to weeks before a coronary event. Divergent biomarker patterns, identified by serial biomarker measurements during 1-year follow-up might then indicate ‘vulnerable periods’ during which patients with CAD are at high short-term risk of developing an ACS. Venepuncture was performed every fortnight during the first half-year and monthly thereafter. As prespecified, patient enrolment was terminated after the primary end point of cardiovascular death or hospital admission for non-fatal ACS had occurred in 50 patients. A case–cohort design will explore differences in temporal patterns of circulating biomarkers prior to the repeat ACS. Future plans and dissemination Follow-up and event adjudication have been completed. Prespecified biomarker analyses are currently being performed and dissemination through peer-reviewed publications and

Development of gel-filter method for high enrichment of low-molecular weight proteins from serum.

PubMed

Chen, Lingsheng; Zhai, Linhui; Li, Yanchang; Li, Ning; Zhang, Chengpu; Ping, Lingyan; Chang, Lei; Wu, Junzhu; Li, Xiangping; Shi, Deshun; Xu, Ping

2015-01-01

The human serum proteome has been extensively screened for biomarkers. However, the large dynamic range of protein concentrations in serum and the presence of highly abundant and large molecular weight proteins, make identification and detection changes in the amount of low-molecular weight proteins (LMW, molecular weight ≤ 30kDa) difficult. Here, we developed a gel-filter method including four layers of different concentration of tricine SDS-PAGE-based gels to block high-molecular weight proteins and enrich LMW proteins. By utilizing this method, we identified 1,576 proteins (n = 2) from 10 μL serum. Among them, 559 (n = 2) proteins belonged to LMW proteins. Furthermore, this gel-filter method could identify 67.4% and 39.8% more LMW proteins than that in representative methods of glycine SDS-PAGE and optimized-DS, respectively. By utilizing SILAC-AQUA approach with labeled recombinant protein as internal standard, the recovery rate for GST spiked in serum during the treatment of gel-filter, optimized-DS, and ProteoMiner was 33.1 ± 0.01%, 18.7 ± 0.01% and 9.6 ± 0.03%, respectively. These results demonstrate that the gel-filter method offers a rapid, highly reproducible and efficient approach for screening biomarkers from serum through proteomic analyses.

Fusing Data Mining, Machine Learning and Traditional Statistics to Detect Biomarkers Associated with Depression

PubMed Central

Dipnall, Joanna F.

2016-01-01

Background Atheoretical large-scale data mining techniques using machine learning algorithms have promise in the analysis of large epidemiological datasets. This study illustrates the use of a hybrid methodology for variable selection that took account of missing data and complex survey design to identify key biomarkers associated with depression from a large epidemiological study. Methods The study used a three-step methodology amalgamating multiple imputation, a machine learning boosted regression algorithm and logistic regression, to identify key biomarkers associated with depression in the National Health and Nutrition Examination Study (2009–2010). Depression was measured using the Patient Health Questionnaire-9 and 67 biomarkers were analysed. Covariates in this study included gender, age, race, smoking, food security, Poverty Income Ratio, Body Mass Index, physical activity, alcohol use, medical conditions and medications. The final imputed weighted multiple logistic regression model included possible confounders and moderators. Results After the creation of 20 imputation data sets from multiple chained regression sequences, machine learning boosted regression initially identified 21 biomarkers associated with depression. Using traditional logistic regression methods, including controlling for possible confounders and moderators, a final set of three biomarkers were selected. The final three biomarkers from the novel hybrid variable selection methodology were red cell distribution width (OR 1.15; 95% CI 1.01, 1.30), serum glucose (OR 1.01; 95% CI 1.00, 1.01) and total bilirubin (OR 0.12; 95% CI 0.05, 0.28). Significant interactions were found between total bilirubin with Mexican American/Hispanic group (p = 0.016), and current smokers (p<0.001). Conclusion The systematic use of a hybrid methodology for variable selection, fusing data mining techniques using a machine learning algorithm with traditional statistical modelling, accounted for missing data and

Fusing Data Mining, Machine Learning and Traditional Statistics to Detect Biomarkers Associated with Depression.

PubMed

Dipnall, Joanna F; Pasco, Julie A; Berk, Michael; Williams, Lana J; Dodd, Seetal; Jacka, Felice N; Meyer, Denny

2016-01-01

Atheoretical large-scale data mining techniques using machine learning algorithms have promise in the analysis of large epidemiological datasets. This study illustrates the use of a hybrid methodology for variable selection that took account of missing data and complex survey design to identify key biomarkers associated with depression from a large epidemiological study. The study used a three-step methodology amalgamating multiple imputation, a machine learning boosted regression algorithm and logistic regression, to identify key biomarkers associated with depression in the National Health and Nutrition Examination Study (2009-2010). Depression was measured using the Patient Health Questionnaire-9 and 67 biomarkers were analysed. Covariates in this study included gender, age, race, smoking, food security, Poverty Income Ratio, Body Mass Index, physical activity, alcohol use, medical conditions and medications. The final imputed weighted multiple logistic regression model included possible confounders and moderators. After the creation of 20 imputation data sets from multiple chained regression sequences, machine learning boosted regression initially identified 21 biomarkers associated with depression. Using traditional logistic regression methods, including controlling for possible confounders and moderators, a final set of three biomarkers were selected. The final three biomarkers from the novel hybrid variable selection methodology were red cell distribution width (OR 1.15; 95% CI 1.01, 1.30), serum glucose (OR 1.01; 95% CI 1.00, 1.01) and total bilirubin (OR 0.12; 95% CI 0.05, 0.28). Significant interactions were found between total bilirubin with Mexican American/Hispanic group (p = 0.016), and current smokers (p<0.001). The systematic use of a hybrid methodology for variable selection, fusing data mining techniques using a machine learning algorithm with traditional statistical modelling, accounted for missing data and complex survey sampling methodology and

Serum HSP70

PubMed Central

Dutta, Sudhir K.; Girotra, Mohit; Singla, Montish; Dutta, Anand; Stephen, F. Otis; Nair, Padmanabhan P.; Merchant, Nipun B.

2014-01-01

Objectives Heat shock protein 70 (HSP70) is overexpressed in human pancreatic cancer cell lines. To determine if serum HSP70 levels are elevated in patients with pancreatic cancer and can function as a biomarker for early detection of pancreatic cancer. Methods Study subjects were divided into 3 groups: histologically proven pancreatic cancer (PC; n = 23), chronic pancreatitis (CP; n = 12), and matched normal control subjects (C; n = 10). Serum HSP70 levels were determined using a novel immunoelectrophoresis method developed and validated by the authors. Significance of difference between the groups was analyzed with analysis of variance (ANOVA). Receiver operating characteristic (ROC) curve analysis was performed to discriminate patients with pancreatic cancer from normal controls. Results The mean ± SE serum HSP70 levels in the PC, CP, and C groups were 1.68 ± 0.083 ng/mL, 0.40 ± 0.057 ng/mL, and 0.04 ng/mL, respectively. Serum HSP70 levels in the PC group were significantly higher compared with either the CP or C groups (P < 0.01). The sensitivity and specificity of elevated serum HSP70 in the PC group was 74% and 90%, respectively. Conclusions Serum HSP70 levels are significantly increased in patients with pancreatic cancer and may be useful as an additional biomarker for the detection of pancreatic cancer. PMID:22158074

Serum miR-29a and miR-122 as Potential Biomarkers for Non-Alcoholic Fatty Liver Disease (NAFLD).

PubMed

Jampoka, Kanisa; Muangpaisarn, Puth; Khongnomnan, Kritsada; Treeprasertsuk, Sombat; Tangkijvanich, Pisit; Payungporn, Sunchai

2018-05-30

Non-alcoholic fatty liver disease (NAFLD) is an over accumulation of triglyceride in the liver without alcohol consumption which its major cause is from insulin resistance. Patients with NAFLD can develop to be liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) are non-coding RNAs that regulate post-transcriptional gene silencing. Previous research reported that miR-29 family (a, b and c) and miR-122 have an important role in regulating insulin resistance related to NAFLD. The purpose of this study was to investigate that miR-29 and miR-122 can be possible biomarkers for non-invasive diagnosis of NAFLD. Serum samples were collected from 58 NAFLD patients and 34 healthy controls. MiRNAs were extracted from serum by using microRNA purification kit followed by polyuridylation, reverse transcription and quantitative real-time PCR. Also, we analyzed the correlation between miR-29 and miR-122 and level of liver inflammation in NAFLD patients. We found that the serum miR-29a levels in NAFLD patients were significantly lower (P = 0.006) than the control group, while miR-29c levels were unchanged, and miR-29b levels were undetectable. However, we found that serum miR-122 levels in NAFLD patients were significantly higher (P < 0.001) than those found in the control group. For miR-29a, the area under curve (AUC) was 0.679 (P = 0.0065) with 60.87% sensitivity and 82.35% specificity. For miR-122, the AUC was 0.831 (P < 0.0001) with 75.00% sensitivity and 82.35% specificity. Interestingly, the level of serum miR-122 were significantly different between patients with not steatohepatitis (NAS < 4) and steatohepatitis (NAS ≥ 4), indicating that the levels of miR-122 were related to the severity of NAFLD. The levels of miR-29a and miR-122 might be beneficial and compelling as possible biomarkers for non-invasive diagnosis of NAFLD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Direct labeling of serum proteins by fluorescent dye for antibody microarray.

PubMed

Klimushina, M V; Gumanova, N G; Metelskaya, V A

2017-05-06

Analysis of serum proteome by antibody microarray is used to identify novel biomarkers and to study signaling pathways including protein phosphorylation and protein-protein interactions. Labeling of serum proteins is important for optimal performance of the antibody microarray. Proper choice of fluorescent label and optimal concentration of protein loaded on the microarray ensure good quality of imaging that can be reliably scanned and processed by the software. We have optimized direct serum protein labeling using fluorescent dye Arrayit Green 540 (Arrayit Corporation, USA) for antibody microarray. Optimized procedure produces high quality images that can be readily scanned and used for statistical analysis of protein composition of the serum. Copyright © 2017 Elsevier Inc. All rights reserved.

Serum proteome profiling in canine idiopathic dilated cardiomyopathy using TMT-based quantitative proteomics approach.

PubMed

Bilić, Petra; Guillemin, Nicolas; Kovačević, Alan; Beer Ljubić, Blanka; Jović, Ines; Galan, Asier; Eckersall, Peter David; Burchmore, Richard; Mrljak, Vladimir

2018-05-15

Idiopathic dilated cardiomyopathy (iDCM) is a primary myocardial disorder with an unknown aetiology, characterized by reduced contractility and ventricular dilation of the left or both ventricles. Naturally occurring canine iDCM was used herein to identify serum proteomic signature of the disease compared to the healthy state, providing an insight into underlying mechanisms and revealing proteins with biomarker potential. To achieve this, we used high-throughput label-based quantitative LC-MS/MS proteomics approach and bioinformatics analysis of the in silico inferred interactome protein network created from the initial list of differential proteins. To complement the proteomic analysis, serum biochemical parameters and levels of know biomarkers of cardiac function were measured. Several proteins with biomarker potential were identified, such as inter-alpha-trypsin inhibitor heavy chain H4, microfibril-associated glycoprotein 4 and apolipoprotein A-IV, which were validated using an independent method (Western blotting) and showed high specificity and sensitivity according to the receiver operating characteristic curve analysis. Bioinformatics analysis revealed involvement of different pathways in iDCM, such as complement cascade activation, lipoprotein particles dynamics, elastic fibre formation, GPCR signalling and respiratory electron transport chain. Idiopathic dilated cardiomyopathy is a severe primary myocardial disease of unknown cause, affecting both humans and dogs. This study is a contribution to the canine heart disease research by means of proteomic and bioinformatic state of the art analyses, following similar approach in human iDCM research. Importantly, we used serum as non-invasive and easily accessible biological source of information and contributed to the scarce data on biofluid proteome research on this topic. Bioinformatics analysis revealed biological pathways modulated in canine iDCM with potential of further targeted research. Also, several

Gene expression profiling combined with bioinformatics analysis identify biomarkers for Parkinson disease.

PubMed

Diao, Hongyu; Li, Xinxing; Hu, Sheng; Liu, Yunhui

2012-01-01

Parkinson disease (PD) progresses relentlessly and affects approximately 4% of the population aged over 80 years old. It is difficult to diagnose in its early stages. The purpose of our study is to identify molecular biomarkers for PD initiation using a computational bioinformatics analysis of gene expression. We downloaded the gene expression profile of PD from Gene Expression Omnibus and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in PD patients compared to controls. Besides, we built a regulatory network by mapping the DCGs to known regulatory data between transcription factors (TFs) and target genes and calculated the regulatory impact factor of each transcription factor. As the results, a total of 1004 genes associated with PD initiation were identified. Pathway enrichment of these genes suggests that biological processes of protein turnover were impaired in PD. In the regulatory network, HLF, E2F1 and STAT4 were found have altered expression levels in PD patients. The expression levels of other transcription factors, NKX3-1, TAL1, RFX1 and EGR3, were not found altered. However, they regulated differentially expressed genes. In conclusion, we suggest that HLF, E2F1 and STAT4 may be used as molecular biomarkers for PD; however, more work is needed to validate our result.

Gene Expression Profiling Combined with Bioinformatics Analysis Identify Biomarkers for Parkinson Disease

PubMed Central

Diao, Hongyu; Li, Xinxing; Hu, Sheng; Liu, Yunhui

2012-01-01

Parkinson disease (PD) progresses relentlessly and affects approximately 4% of the population aged over 80 years old. It is difficult to diagnose in its early stages. The purpose of our study is to identify molecular biomarkers for PD initiation using a computational bioinformatics analysis of gene expression. We downloaded the gene expression profile of PD from Gene Expression Omnibus and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in PD patients compared to controls. Besides, we built a regulatory network by mapping the DCGs to known regulatory data between transcription factors (TFs) and target genes and calculated the regulatory impact factor of each transcription factor. As the results, a total of 1004 genes associated with PD initiation were identified. Pathway enrichment of these genes suggests that biological processes of protein turnover were impaired in PD. In the regulatory network, HLF, E2F1 and STAT4 were found have altered expression levels in PD patients. The expression levels of other transcription factors, NKX3-1, TAL1, RFX1 and EGR3, were not found altered. However, they regulated differentially expressed genes. In conclusion, we suggest that HLF, E2F1 and STAT4 may be used as molecular biomarkers for PD; however, more work is needed to validate our result. PMID:23284986

Analytical Pipeline for Discovery and Verification of Glycoproteins from Plasma-Derived Extracellular Vesicles as Breast Cancer Biomarkers.

PubMed

Chen, I-Hsuan; Aguilar, Hillary Andaluz; Paez Paez, J Sebastian; Wu, Xiaofeng; Pan, Li; Wendt, Michael K; Iliuk, Anton B; Zhang, Ying; Tao, W Andy

2018-05-15

Glycoproteins comprise more than half of current FDA-approved protein cancer markers, but the development of new glycoproteins as disease biomarkers has been stagnant. Here we present a pipeline to develop glycoproteins from extracellular vesicles (EVs) through integrating quantitative glycoproteomics with a novel reverse phase glycoprotein array and then apply it to identify novel biomarkers for breast cancer. EV glycoproteomics show promise in circumventing the problems plaguing current serum/plasma glycoproteomics and allowed us to identify hundreds of glycoproteins that have not been identified in blood. We identified 1,453 unique glycopeptides representing 556 glycoproteins in EVs, among which 20 were verified significantly higher in individual breast cancer patients. We further applied a novel glyco-specific reverse phase protein array to quantify a subset of the candidates. Together, this study demonstrates the great potential of this integrated pipeline for biomarker discovery.

Quantitative proteomic analysis for high-throughput screening of differential glycoproteins in hepatocellular carcinoma serum

PubMed Central

Gao, Hua-Jun; Chen, Ya-Jing; Zuo, Duo; Xiao, Ming-Ming; Li, Ying; Guo, Hua; Zhang, Ning; Chen, Rui-Bing

2015-01-01

Objective Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Novel serum biomarkers are required to increase the sensitivity and specificity of serum screening for early HCC diagnosis. This study employed a quantitative proteomic strategy to analyze the differential expression of serum glycoproteins between HCC and normal control serum samples. Methods Lectin affinity chromatography (LAC) was used to enrich glycoproteins from the serum samples. Quantitative mass spectrometric analysis combined with stable isotope dimethyl labeling and 2D liquid chromatography (LC) separations were performed to examine the differential levels of the detected proteins between HCC and control serum samples. Western blot was used to analyze the differential expression levels of the three serum proteins. Results A total of 2,280 protein groups were identified in the serum samples from HCC patients by using the 2D LC-MS/MS method. Up to 36 proteins were up-regulated in the HCC serum, whereas 19 proteins were down-regulated. Three differential glycoproteins, namely, fibrinogen gamma chain (FGG), FOS-like antigen 2 (FOSL2), and α-1,6-mannosylglycoprotein 6-β-N-acetylglucosaminyltransferase B (MGAT5B) were validated by Western blot. All these three proteins were up-regulated in the HCC serum samples. Conclusion A quantitative glycoproteomic method was established and proven useful to determine potential novel biomarkers for HCC. PMID:26487969

Systemic serum amyloid A as a biomarker for exposure to zinc and/or copper-containing metal fumes.

PubMed

Baumann, R; Gube, M; Markert, A; Davatgarbenam, S; Kossack, V; Gerhards, B; Kraus, T; Brand, P

2018-01-01

Zinc- and copper-containing welding fumes increase systemic C-reactive protein (CRP). The aim of this study was to investigate the performance of the biomarkers serum amyloid A (SAA) and soluble vascular cell adhesion molecule-1 (VCAM-1) in this regard. Fifteen male subjects were exposed under controlled conditions to welding fumes containing either zinc, or copper, or copper and zinc for 6 h. Plasma samples were collected before, 6 and 24 h after start of exposure and biomarkers therein were measured by electrochemiluminescent assay. For each exposure, systemic concentrations of systemic SAA, but not VCAM-1, increased significantly at 24 h after exposure start compared with baseline ("copper only": P=0.0005, "zinc only": P=0.027, "copper and zinc": P=0.001). SAA showed a wider range of concentrations than did CRP and its levels increased up to 19-fold after welding fume exposure. The recognition of copper as a potential harmful component in welding fumes, also independent from zinc, deserves further consideration. SAA might represent a new sensitive biomarker for potential subclinical sterile inflammation after inhalation of copper- and/or zinc-containing welding fumes. As elevations of CRP and SAA protein have both been linked to a higher risk for cardiovascular disease, these findings might particularly be important for long-term welders.

Serum PARC/CCL-18 concentrations and health outcomes in chronic obstructive pulmonary disease.

PubMed

Sin, Don D; Miller, Bruce E; Duvoix, Annelyse; Man, S F Paul; Zhang, Xuekui; Silverman, Edwin K; Connett, John E; Anthonisen, Nicholas A; Wise, Robert A; Tashkin, Donald; Celli, Bartolome R; Edwards, Lisa D; Locantore, Nicholas; Macnee, William; Tal-Singer, Ruth; Lomas, David A

2011-05-01

There are no accepted blood-based biomarkers in chronic obstructive pulmonary disease (COPD). Pulmonary and activation-regulated chemokine (PARC/CCL-18) is a lung-predominant inflammatory protein that is found in serum. To determine whether PARC/CCL-18 levels are elevated and modifiable in COPD and to determine their relationship to clinical end points of hospitalization and mortality. PARC/CCL-18 was measured in serum samples from individuals who participated in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) and LHS (Lung Health Study) studies and a prednisolone intervention study. Serum PARC/CCL-18 levels were higher in subjects with COPD than in smokers or lifetime nonsmokers without COPD (105 vs. 81 vs. 80 ng/ml, respectively; P < 0.0001). Elevated PARC/CCL-18 levels were associated with increased risk of cardiovascular hospitalization or mortality in the LHS cohort and with total mortality in the ECLIPSE cohort. Serum PARC/CCL-18 levels are elevated in COPD and track clinical outcomes. PARC/CCL-18, a lung-predominant chemokine, could be a useful blood biomarker in COPD.

SurvNet: a web server for identifying network-based biomarkers that most correlate with patient survival data.

PubMed

Li, Jun; Roebuck, Paul; Grünewald, Stefan; Liang, Han

2012-07-01

An important task in biomedical research is identifying biomarkers that correlate with patient clinical data, and these biomarkers then provide a critical foundation for the diagnosis and treatment of disease. Conventionally, such an analysis is based on individual genes, but the results are often noisy and difficult to interpret. Using a biological network as the searching platform, network-based biomarkers are expected to be more robust and provide deep insights into the molecular mechanisms of disease. We have developed a novel bioinformatics web server for identifying network-based biomarkers that most correlate with patient survival data, SurvNet. The web server takes three input files: one biological network file, representing a gene regulatory or protein interaction network; one molecular profiling file, containing any type of gene- or protein-centred high-throughput biological data (e.g. microarray expression data or DNA methylation data); and one patient survival data file (e.g. patients' progression-free survival data). Given user-defined parameters, SurvNet will automatically search for subnetworks that most correlate with the observed patient survival data. As the output, SurvNet will generate a list of network biomarkers and display them through a user-friendly interface. SurvNet can be accessed at http://bioinformatics.mdanderson.org/main/SurvNet.

Serum cystatin C is an independent biomarker associated with the renal resistive index in patients with chronic kidney disease.

PubMed

Ogawa-Akiyama, Ayu; Sugiyama, Hitoshi; Kitagawa, Masashi; Tanaka, Keiko; Onishi, Akifumi; Yamanari, Toshio; Morinaga, Hiroshi; Uchida, Haruhito Adam; Nakamura, Kazufumi; Ito, Hiroshi; Wada, Jun

2018-01-01

Cystatin C is a cysteine protease inhibitor that is produced by nearly all human cells. The serum level of cystatin C is a stronger predictor of the renal outcome and the risk of cardiovascular events than the creatinine level. The resistive index (RI) on renal Doppler ultrasonography is a good indicator of vascular resistance as well as the renal outcomes in patients with chronic kidney disease (CKD). However, it is unclear whether serum cystatin C is associated with signs of vascular dysfunction, such as the renal RI. We measured the serum cystatin C levels in 101 CKD patients and investigated the relationships between cystatin C and markers of vascular dysfunction, including the renal RI, ankle-brachial pulse wave velocity (baPWV), intima-media thickness (IMT), and cardiac function. The renal RI was significantly correlated with the serum cystatin C level (p < 0.0001, r = 0.6920). The serum cystatin C level was found to be a significant determinant of the renal RI (p < 0.0001), but not the baPWV, in a multivariate regression analysis. The multivariate odds ratio of the serum cystatin C level for a renal RI of more than 0.66 was statistically significant (2.92, p = 0.0106). The area under the receiver-operating characteristic curve comparing the sensitivity and specificity of cystatin C for predicting an RI of more than 0.66 was 0.882 (cutoff value: 2.04 mg/L). In conclusion, the serum cystatin C level is an independent biomarker associated with the renal RI in patients with CKD.

Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma.

PubMed

Fujiwara, Tomohiro; Uotani, Koji; Yoshida, Aki; Morita, Takuya; Nezu, Yutaka; Kobayashi, Eisuke; Yoshida, Akihiko; Uehara, Takenori; Omori, Toshinori; Sugiu, Kazuhisa; Komatsubara, Tadashi; Takeda, Ken; Kunisada, Toshiyuki; Kawamura, Machiko; Kawai, Akira; Ochiya, Takahiro; Ozaki, Toshifumi

2017-05-16

Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.

Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma

PubMed Central

Fujiwara, Tomohiro; Uotani, Koji; Yoshida, Aki; Morita, Takuya; Nezu, Yutaka; Kobayashi, Eisuke; Yoshida, Akihiko; Uehara, Takenori; Omori, Toshinori; Sugiu, Kazuhisa; Komatsubara, Tadashi; Takeda, Ken; Kunisada, Toshiyuki; Kawamura, Machiko; Kawai, Akira; Ochiya, Takahiro; Ozaki, Toshifumi

2017-01-01

Background Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. Methods Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. Results Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. Conclusions Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients. PMID:28380419

SERUM metabolomics of acute lymphoblastic leukaemia and acute myeloid leukaemia for probing biomarker molecules.

PubMed

Musharraf, Syed Ghulam; Siddiqui, Amna Jabbar; Shamsi, Tahir; Naz, Arshi

2017-12-01

Acute leukaemia (AL) is a critical neoplasm of white blood cells. Diagnosing AL requires bone marrow puncture procedure, which many patients do not consent to for it is invasive. Hence sensitive and specific early diagnostic biomarkers are essential for non-invasive diagnosis, new therapeutics and improving the disease prognosis. To differentiate the metabolic alterations associated with acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), we investigated serum of ALL and AML patients in comparison with two controls using gas chromatography coupled with triple quadrupole tandem mass spectrometry and multivariate statistical analysis. Twenty seven out of 1425 metabolites were found differentiative among ALL, AML, aplastic anaemia (APA) patients and healthy control using p-value ≤ 0.001. ALL is the most dissimilar group from other three groups as in hierarchical clustering showed 72.1% dissimilarity. Model generation using PLSDA gave an overall accuracy of 91.9%. This study helps in metabolic fingerprinting of control and disease serum at high significance levels and could be used for early diagnosing of AL. Based on pathways analysis, fatty acid metabolism is deregulated in patients with AL and may represent an underlying metabolic pathway associated with disease progression. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Cohort profile of BIOMArCS: the BIOMarker study to identify the Acute risk of a Coronary Syndrome-a prospective multicentre biomarker study conducted in the Netherlands.

PubMed

Oemrawsingh, Rohit M; Akkerhuis, K Martijn; Umans, Victor A; Kietselaer, Bas; Schotborgh, Carl; Ronner, Eelko; Lenderink, Timo; Liem, Anho; Haitsma, David; van der Harst, Pim; Asselbergs, Folkert W; Maas, Arthur; Oude Ophuis, Anton J; Ilmer, Ben; Dijkgraaf, Rene; de Winter, Robbert-Jan; The, S Hong Kie; Wardeh, Alexander J; Hermans, Walter; Cramer, Etienne; van Schaik, Ron H; Hoefer, Imo E; Doevendans, Pieter A; Simoons, Maarten L; Boersma, Eric

2016-12-23

Progression of stable coronary artery disease (CAD) towards acute coronary syndrome (ACS) is a dynamic and heterogeneous process with many intertwined constituents, in which a plaque destabilising sequence could lead to ACS within short time frames. Current CAD risk assessment models, however, are not designed to identify increased vulnerability for the occurrence of coronary events within a precise, short time frame at the individual patient level. The BIOMarker study to identify the Acute risk of a Coronary Syndrome (BIOMArCS) was designed to evaluate whether repeated measurements of multiple biomarkers can predict such 'vulnerable periods'. BIOMArCS is a multicentre, prospective, observational study of 844 patients presenting with ACS, either with or without ST-elevation and at least one additional cardiovascular risk factor. We hypothesised that patterns of circulating biomarkers that reflect the various pathophysiological components of CAD, such as distorted lipid metabolism, vascular inflammation, endothelial dysfunction, increased thrombogenicity and ischaemia, diverge in the days to weeks before a coronary event. Divergent biomarker patterns, identified by serial biomarker measurements during 1-year follow-up might then indicate 'vulnerable periods' during which patients with CAD are at high short-term risk of developing an ACS. Venepuncture was performed every fortnight during the first half-year and monthly thereafter. As prespecified, patient enrolment was terminated after the primary end point of cardiovascular death or hospital admission for non-fatal ACS had occurred in 50 patients. A case-cohort design will explore differences in temporal patterns of circulating biomarkers prior to the repeat ACS. Follow-up and event adjudication have been completed. Prespecified biomarker analyses are currently being performed and dissemination through peer-reviewed publications and conference presentations is expected from the third quarter of 2016. Should

Elevated serum concentrations of HE4 as a novel biomarker of disease severity and renal fibrosis in kidney disease

PubMed Central

Liang, Jianbo; Yue, Caifeng; Wang, Fen; Song, Junli; Wang, Jianfeng; Liu, Min; Luo, Jinmei; Li, Laisheng

2016-01-01

Background Human epididymis protein 4 (HE4), has recently been reported as a mediator of renal fibrosis. However, serum HE4 levels appear in a large number of patient samples with chronic kidney disease (CKD), and the relationship of these levels to disease severity and renal fibrosis is unknown. Methods In 427 patients at different stages of CKD excluding gynecologic cancer and 173 healthy subjects, serum HE4 concentrations were tested by chemiluminescent microparticle immunoassay. Renal biopsy was performed on 259 of 427 subjects. Histological findings were evaluated using standard immunohistochemistry. Results The levels of serum HE4 were higher in CKD patients than in healthy subjects, and higher levels were associated with more severe CKD stages. Patients with more severe renal fibrosis tended to have higher HE4 levels, and correlation analysis showed a significant correlation between HE4 and degree of renal fibrosis (r = 0.938, P < 0.0001). HE4 can be a predictor of renal fibrosis in CKD patients; the area under the receiver-operating characteristic curve (AUC-ROC) was 0.99, higher than the AUC-ROC of serum creatinine (0.89). Conclusion Elevated levels of serum HE4 are associated with decreased kidney function, and also with an advanced stage of renal fibrosis, suggesting that HE4 may serve as a valuable clinical biomarker for renal fibrosis of CKD. PMID:27589683

Normalization of Patient-Identified Plasma Biomarkers in SMNΔ7 Mice following Postnatal SMN Restoration

PubMed Central

Arnold, W. David; Duque, Sandra; Iyer, Chitra C.; Zaworski, Phillip; McGovern, Vicki L.; Taylor, Shannon J.; von Herrmann, Katharine M.; Kobayashi, Dione T.; Chen, Karen S.; Kolb, Stephen J.; Paushkin, Sergey V.; Burghes, Arthur H. M.

2016-01-01

Introduction and Objective Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function. The goal was to determine whether levels of plasma markers were altered in the SMNΔ7 mouse model of SMA and whether postnatal SMN restoration resulted in normalization of the biomarkers. Methods SMNΔ7 and control mice were treated with antisense oligonucleotides (ASO) targeting ISS-N1 to increase SMN protein from SMN2 or scramble ASO (sham treatment) via intracerebroventricular injection on postnatal day 1 (P1). Brain, spinal cord, quadriceps muscle, and liver were analyzed for SMN protein levels at P12 and P90. Ten plasma biomarkers (a subset of biomarkers in the SMA-MAP panel available for analysis in mice) were analyzed in plasma obtained at P12, P30, and P90. Results Of the eight plasma biomarkers assessed, 5 were significantly changed in sham treated SMNΔ7 mice compared to control mice and were normalized in SMNΔ7 mice treated with ASO. Conclusion This study defines a subset of the SMA-MAP plasma biomarker panel that is abnormal in the most commonly used mouse model of SMA. Furthermore, some of these markers are responsive to postnatal SMN restoration. These findings support continued clinical development of these potential prognostic and pharmacodynamic biomarkers. PMID:27907033

Correlation of four potential biomarkers of liver fibrosis with liver function and grade of hepatic fibrosis in a neonatal cholestatic rat model.

PubMed

Tang, Ning; Zhang, Yaping; Liu, Zeyu; Ai, Xuemei; Liang, Qinghong

2017-07-01

The present study investigated the correlation between four serum biomarkers of liver fibrosis, liver function and pathological hepatic fibrosis grade in neonatal cholestatic rats. A total of 38 Sprague‑Dawley rats, aged 3 weeks, were randomly assigned to the experimental group (EG), control group (CG) and the blank control group (BCG). EG received intragastric administration of 1% α‑naphthylisothiocyanate, 75 mg/kg, to induce acute cholestasis liver injury, CG and BCG were set as control groups. Blood samples from all groups were collected 48 h following the procedure. The levels of liver function markers, and four biomarkers of liver fibrosis in serum, were measured and sections of liver tissue were stained for pathological analysis. The results of the present study demonstrated that the degree of hepatic fibrosis in EG, in the serum levels or by pathological analysis, was markedly more evident compared with the CG. Several indices of four biomarkers for liver fibrosis in serum were identified and correlated with the levels of liver function markers. The pathological hepatic fibrosis grade was correlated with γ‑glutamyl transferase (γ‑GT) and Hyaluronic acid (HA). Therefore, HA and γ‑GT were positively correlated with the grade of hepatic fibrosis, indicating their efficacy as biomarkers of infantile cholestatic hepatic fibrosis.

Comparisons among serum, egg albumin and yolk concentrations of corticosterone as biomarkers of basal and stimulated adrenocortical activity of laying hens.

PubMed

Cook, N J; Renema, R; Wilkinson, C; Schaefer, A L

2009-09-01

1. Serial blood samples from individual birds were analysed for corticosterone concentrations under basal and stimulated conditions, and matched to eggs from the same birds for comparison to albumin and yolk concentrations of corticosterone. 2. Serum corticosterone exhibited increases in response to stimulation by ACTH and Handling stress. There were no significant increases in egg albumin or yolk concentrations of corticosterone following stimulation. 3. Several significant correlations were observed between the mean and area under the curve (AUC) measurements of serum corticosterone concentrations with albumin and yolk corticosterone concentrations in eggs laid from 1 to 2 d later. 4. The results demonstrated a relationship between endogenous concentrations of serum corticosterone that reflected daily adrenocortical output with albumin and yolk corticosterone concentrations in eggs laid the following day. 5. The results do not support the concept of albumin and yolk concentrations of corticosterone as biomarkers of acute adrenocortical responses to stimulation.

Effect of abacavir on acute changes in biomarkers associated with cardiovascular dysfunction.

PubMed

Patel, Pragna; Bush, Tim; Overton, Turner; Baker, Jason; Hammer, John; Kojic, Erna; Conley, Lois; Henry, Keith; Brooks, John T

2012-01-01

This study examined the effect of abacavir on acute changes in biomarkers associated with cardiovascular dysfunction. Among the Study to Understand the Natural History of HIV/AIDS in the Era of Effective therapy (SUN) participants, we identified 25 individuals (cases) who were HLA-B5701-negative and who had ≥ 2 weeks without abacavir exposure at one visit and ≥ 2 weeks with abacavir exposure at the consecutive visit while maintaining viral suppression. We identified 43 individuals (controls) similarly unexposed and exposed to tenofovir. We assessed concentrations of prothrombin fragment F(1+2), D-dimer, high-sensitivity C-reactive protein, interleukin-8, intercellular adhesion molecule-1, vascular adhesion molecule-1, E-selectin, P-selectin, serum amyloid A and serum amyloid P. We examined the median percentage change of these biomarkers from the unexposed to exposed state among cases and controls compared with the expected assay variability using a sign test, and compared changes among cases with controls using the Wilcoxon rank-sum test. Baseline characteristics were similar between cases and controls: median age 45 versus 46 years, 80% versus 81% male, 64% versus 63% non-Hispanic White and median CD4(+) T-cell count 538 versus 601 cells/mm(3), respectively. Mean exposure times were 65 and 15 weeks for abacavir and tenofovir, respectively. We observed no significant changes in biomarkers from the unexposed to exposed state among cases or controls compared with the expected assay variability. We found that no biomarkers were significantly increased among cases compared with controls; however, prothrombin fragment F(1+2) was significantly lower among controls (P=0.035). In virologically suppressed contemporary HIV-infected patients, abacavir exposure was not associated with increases in biomarkers associated with increased cardiovascular risk.

Association between serum and urine biomarkers and lumbar spine individual radiographic features: the Johnston County Osteoarthritis Project.

PubMed

Goode, A P; Marshall, S W; Kraus, V B; Renner, J B; Stürmer, T; Carey, T S; Irwin, D E; Jordan, J M

2012-11-01

(1) To determine associations between radiographic features of lumbosacral (LS) spine disc space narrowing (DSN) and osteophytes (OST) and joint metabolism biomarkers (serum cartilage oligomeric matrix protein (COMP), hyaluronic acid (HA), collagen neoepitope (C2C), C-propeptide of type II procollagen (CP-II), urine C-terminal cross-linking telopeptide (CTX-II) and N-terminal telopeptide (NTX-I)). (2) To explore interactions with race, gender and low back symptoms. Cross-sectional analysis of 547 participants enrolled in the Johnston County (JoCo) Osteoarthritis Project from 2003 to 2004. Mean biomarker levels were estimated with linear regression. Proportional and partial-proportional odds models were used to estimate associations. Interactions were tested with likelihood ratio tests at a P-value < 0.10. Biomarkers were natural log (ln) transformed. Significant differences in mean biomarker levels were found across severity of DSN for lnHA and lnC2C and lnCTX-II across severity of both DSN and OST. Moderate-to-strong associations were found between biomarkers of type II collagen and DSN, whereas associations with OST were weak. An association between lnHA and DSN was seen in women (adjusted odds ratio [aOR] = 1.34 (95% confidence intervals (CI) 1.08, 1.65)) but no association among men (aOR = 0.90 (95% CI 0.63, 1.26)). In Caucasians there was a decreased association with NTX-I and OST (aOR = 0.67 (95% CI 0.49, 0.91)) and no association in African Americans (AAs) (aOR = 1.06 (95% CI 0.76, 1.47)). There was a positive association of lnCOMP with DSN among those with low back symptoms (aOR = 1.82 (95% CI 1.02, 3.27)), but no association in those without low back symptoms (aOR = 0.65 (95% CI 0.35, 1.20)). Joint metabolism biomarkers suggest biological differences in the pathologic process involved in DSN and OST that may be gender (HA) and ethnicity (NTX-I) specific. Copyright © 2012 Osteoarthritis Research Society International. Published by Elsevier