*Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential

EPA Science Inventory

Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens fol...

Potential serum biomarkers from a metabolomics study of autism

PubMed Central

Wang, Han; Liang, Shuang; Wang, Maoqing; Gao, Jingquan; Sun, Caihong; Wang, Jia; Xia, Wei; Wu, Shiying; Sumner, Susan J.; Zhang, Fengyu; Sun, Changhao; Wu, Lijie

2016-01-01

Background Early detection and diagnosis are very important for autism. Current diagnosis of autism relies mainly on some observational questionnaires and interview tools that may involve a great variability. We performed a metabolomics analysis of serum to identify potential biomarkers for the early diagnosis and clinical evaluation of autism. Methods We analyzed a discovery cohort of patients with autism and participants without autism in the Chinese Han population using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC/Q-TOF MS/MS) to detect metabolic changes in serum associated with autism. The potential metabolite candidates for biomarkers were individually validated in an additional independent cohort of cases and controls. We built a multiple logistic regression model to evaluate the validated biomarkers. Results We included 73 patients and 63 controls in the discovery cohort and 100 cases and 100 controls in the validation cohort. Metabolomic analysis of serum in the discovery stage identified 17 metabolites, 11 of which were validated in an independent cohort. A multiple logistic regression model built on the 11 validated metabolites fit well in both cohorts. The model consistently showed that autism was associated with 2 particular metabolites: sphingosine 1-phosphate and docosahexaenoic acid. Limitations While autism is diagnosed predominantly in boys, we were unable to perform the analysis by sex owing to difficulty recruiting enough female patients. Other limitations include the need to perform test–retest assessment within the same individual and the relatively small sample size. Conclusion Two metabolites have potential as biomarkers for the clinical diagnosis and evaluation of autism. PMID:26395811

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.

Proteomic analysis of first trimester maternal serum to identify candidate biomarkers potentially predictive of spontaneous preterm birth.

PubMed

D'Silva, Arlene M; Hyett, Jon A; Coorssen, Jens R

2018-04-30

Spontaneous preterm birth (sPTB) remains a major clinical dilemma; current diagnostics and interventions have not reduced the rate of this serious healthcare burden. This study characterizes differential protein profiles and post-translational modifications (PTMs) in first trimester maternal serum using a refined top-down approach coupling two-dimensional gel electrophoresis (2DE) and mass spectrometry (MS) to directly compare subsequent term and preterm labour events and identify marked protein differences. 30 proteoforms were found to be significantly increased or decreased in the sPTB group including 9 phosphoproteins and 11 glycoproteins. Changes occurred in proteins associated with immune and defence responses. We identified protein species that are associated with several clinically relevant biological processes, including interrelated biological networks linked to regulation of the complement cascade and coagulation pathways, immune modulation, metabolic processes and cell signalling. The finding of altered proteoforms in maternal serum from pregnancies that delivered preterm suggests these as potential early biomarkers of sPTB and also possible mediators of the disorder. Identifying changes in protein profiles is critical in the study of cell biology, and disease treatment and prevention. Identifying consistent changes in the maternal serum proteome during early pregnancy, including specific protein PTMs (e.g. phosphorylation, glycosylation), is likely to provide better opportunities for prediction, intervention and prevention of preterm birth. This is the first study to examine first trimester maternal serum using a highly refined top-down proteomic analytical approach based on high resolution 2DE coupled with mass spectrometry to directly compare preterm (<37 weeks) and preterm (≥37 weeks) events and identify select protein differences between these conditions. As such, the data present a promising avenue for translation of biomarker discovery to a

Placenta-derived exosomes: potential biomarkers of preeclampsia.

PubMed

Pillay, Preenan; Moodley, Kogi; Moodley, Jagidesa; Mackraj, Irene

2017-01-01

Preeclampsia remains a leading cause of maternal and fetal mortality, due to ineffective treatment and diagnostic strategies, compounded by the lack of clarity on the etiology of the disorder. Although several clinical and biological markers of preeclampsia have been evaluated, they have proven to be ineffective in providing a definitive diagnosis during the various stages of the disorder. Exosomes have emerged as ideal biomarkers of pathological states, such as cancer, and have more recently gained interest in pregnancy-related complications, due to their role in cellular communication in normal and complicated pregnancies. This occurs as a result of the specific placenta-derived exosomal molecular cargo, which may be involved in normal pregnancy-associated immunological events, such as the maintenance of maternal-fetal tolerance. This review provides perspectives on placenta-derived exosomes as possible biomarkers for the diagnosis/prognosis of preeclampsia. Using keywords, online databases were searched to identify relevant publications to review the potential use of placenta-derived exosomes as biomarkers of preeclampsia.

A pilot study identifying a potential plasma biomarker for determining EGFR mutations in exons 19 or 21 in lung cancer patients

PubMed Central

Pamungkas, Aryo D.; Medriano, Carl A.; Sim, Eunjung; Lee, Sungyong; Park, Youngja H.

2017-01-01

The most common type of lung cancer is non-small cell lung cancer (NSCLC), which is frequently characterized by a mutation in the epidermal growth factor receptor (EGFR). Determining the presence of an EGFR mutation in lung cancer is important, as it determines the type of treatment that a patients will receive. Therefore, the aim of the present study was to apply high-resolution metabolomics (HRM) using liquid chromatography-mass spectrometry to identify significant compounds in human plasma samples obtained from South Korean NSCLC patients, as potential biomarkers for providing early detection and diagnosis of minimally-invasive NSCLC. The metabolic differences between lung cancer patients without EGFR mutations were compared with patients harboring EGFR mutations. Univariate analysis was performed, with a false discovery rate of q=0.05, in order to identify significant metabolites between the two groups. In addition, hierarchical clustering analysis was performed to discriminate between the metabolic profiles of the two groups. Furthermore, the significant metabolites were identified and mapped using Mummichog software, in order to generate a potential metabolic network model. Using metabolome-wide association studies, metabolic alterations were identified. Linoleic acid [303.23 m/z, (M+Na)+], 5-methyl tetrahydrofolate [231.10 m/z, (M+2H)+] and N-succinyl-L-glutamate-5 semialdehyde [254.06 m/z, (M+Na)+], were observed to be elevated in patients harboring EGFR mutations, whereas tetradecanoyl carnitine [394.29 m/z, (M+Na)+] was observed to be reduced. This suggests that these compounds may be affected by the EGFR mutation. In conclusion, the present study identified four potential biomarkers in patients with EGFR mutations, using HRM combined with pathway analysis. These results may facilitate the development of novel diagnostic tools for EGFR mutation detection in patients with lung cancer. PMID:28487968

Clonal analyses and gene profiling identify genetic biomarkers of the thermogenic potential of human brown and white preadipocytes.

PubMed

Xue, Ruidan; Lynes, Matthew D; Dreyfuss, Jonathan M; Shamsi, Farnaz; Schulz, Tim J; Zhang, Hongbin; Huang, Tian Lian; Townsend, Kristy L; Li, Yiming; Takahashi, Hirokazu; Weiner, Lauren S; White, Andrew P; Lynes, Maureen S; Rubin, Lee L; Goodyear, Laurie J; Cypess, Aaron M; Tseng, Yu-Hua

2015-07-01

Targeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. However, both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here we generated clones of brown and white preadipocytes from human neck fat and characterized their adipogenic and thermogenic differentiation. We combined an uncoupling protein 1 (UCP1) reporter system and expression profiling to define novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated. Knocking out the positive UCP1 regulators, PREX1 and EDNRB, in brown preadipocytes using CRISPR-Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using the cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer potential biomarkers for identifying thermogenically competent preadipocytes.

Global metabolomics reveals potential urinary biomarkers of esophageal squamous cell carcinoma for diagnosis and staging

NASA Astrophysics Data System (ADS)

Xu, Jing; Chen, Yanhua; Zhang, Ruiping; He, Jiuming; Song, Yongmei; Wang, Jingbo; Wang, Huiqing; Wang, Luhua; Zhan, Qimin; Abliz, Zeper

2016-10-01

We performed a metabolomics study using liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis (MVDA) to discriminate global urine profiles in urine samples from esophageal squamous cell carcinoma (ESCC) patients and healthy controls (NC). Our work evaluated the feasibility of employing urine metabolomics for the diagnosis and staging of ESCC. The satisfactory classification between the healthy controls and ESCC patients was obtained using the MVDA model, and obvious classification of early-stage and advanced-stage patients was also observed. The results suggest that the combination of LC-MS analysis and MVDA may have potential applications for ESCC diagnosis and staging. We then conducted LC-MS/MS experiments to identify the potential biomarkers with large contributions to the discrimination. A total of 83 potential diagnostic biomarkers for ESCC were screened out, and 19 potential biomarkers were identified; the variations between the differences in staging using these potential biomarkers were further analyzed. These biomarkers may not be unique to ESCCs, but instead result from any malignant disease. To further elucidate the pathophysiology of ESCC, we studied related metabolic pathways and found that ESCC is associated with perturbations of fatty acid β-oxidation and the metabolism of amino acids, purines, and pyrimidines.

Urinary microRNAs as potential biomarkers of pesticide exposure

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

Weldon, Brittany A.; Shubin, Sara Pacheco; Smith,

MicroRNAs (miRNAs) are post-transcriptional regulators that silence messenger RNAs. Because miRNAs are stable at room temperature and long-lived, they have been proposed as molecular biomarkers to monitor disease and exposure status. While urinary miRNAs have been used clinically as potential diagnostic markers for kidney and bladder cancers and other diseases, their utility in non-clinical settings has yet to be fully developed. Our goal was to investigate the potential for urinary miRNAs to act as biomarkers of pesticide exposure and early biological response by identifying the miRNAs present in urine from 27 parent/child, farmworker/non-farmworker pairs (16FW/11NFW) collected during two agricultural seasonsmore » (thinning and post-harvest) and characterizing the between- and within-individual variability of these miRNA epigenetic regulators. MiRNAs were isolated from archived urine samples and identified using PCR arrays. Comparisons were made between age, households, season, and occupation. Of 384 miRNAs investigated, 297 (77%) were detectable in at least one sample. Seven miRNAs were detected in at least 50% of the samples, and one miRNA was present in 96% of the samples. Principal components and hierarchical clustering analyses indicate significant differences in miRNA profiles between farmworker and non-farmworker adults as well as between seasons. Six miRNAs were observed to be positively associated with farmworkers status during the post-harvest season. Expression of five of these miRNA trended towards a positive dose response relationship with organophosphate pesticide metabolites in farmworkers. These results suggest that miRNAs may be novel biomarkers of pesticide exposure and early biological response. - Highlights: • A novel method to identify microRNA biomarkers in urinary samples is proposed. • Six miRNAs have been identified as associated with occupational farm work and pesticide exposure. • An observed seasonal difference suggests

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.

USING ARRAY TECHNOLOGY TO IDENTIFY POTENTIAL BIOMARKERS FOR PYRETHROID INSECTICIDES.

EPA Science Inventory

Pyrethroid insecticides affect nervous system function by disruption of sodium channels in nerve membranes. FQPA requirements for assessing cumulative risk have increased the need for rapid and sensitive biomarkers of effect. This project aims to develop biochemical markers of n...

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

Skin Biomarkers for Cystic Fibrosis: A Potential Non-Invasive Approach for Patient Screening.

PubMed

Esteves, Cibele Zanardi; de Aguiar Dias, Letícia; de Oliveira Lima, Estela; de Oliveira, Diogo Noin; Rodrigues Melo, Carlos Fernando Odir; Delafiori, Jeany; Souza Gomez, Carla Cristina; Ribeiro, José Dirceu; Ribeiro, Antônio Fernando; Levy, Carlos Emílio; Catharino, Rodrigo Ramos

2017-01-01

Cystic fibrosis (CF) is a disabling genetic disease with an increased prevalence in European heritage populations. Currently, the most used technique for collection of CF samples and diagnosis is provided through uncomfortable tests, with uncertain results, mostly based on chloride concentration in sweat. Since CF mutation induces many metabolic changes in patients, exploring these alterations might be an alternative to visualize potential biomarkers that could be used as interesting tools for further diagnostic upgrade, prioritizing simplicity, low cost, and quickness. This contribution describes an accurate strategy to provide potential biomarkers related to CF, which may be understood as a potential tool for new diagnostic approaches and/or for monitoring disease evolution. Therefore, the present proposal consists of using skin imprints on silica plates as a way of sample collection, followed by direct-infusion high-resolution mass spectrometry and multivariate data analysis, intending to identify metabolic changes in skin composition of CF patients. Metabolomics analysis allowed identifying chemical markers that can be traced back to CF in patients' skin imprints, differently from control subjects. Seven chemical markers from several molecular classes were elected, represented by bile acids, a glutaric acid derivative, thyrotropin-releasing hormone, an inflammatory mediator, a phosphatidic acid, and diacylglycerol isomers, all reflecting metabolic disturbances that occur due to of CF. The comfortable method of sample collection combined with the identified set of biomarkers represent potential tools that open the range of possibilities to manage CF and follow the disease evolution. This exploratory approach points to new perspectives about the development of diagnostic assay using biomarkers and the management CF.

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.

Granins as disease-biomarkers: translational potential for psychiatric and neurological disorders.

PubMed

Bartolomucci, A; Pasinetti, G M; Salton, S R J

2010-09-29

The identification of biomarkers represents a fundamental medical advance that can lead to an improved understanding of disease pathogenesis, and holds the potential to define surrogate diagnostic and prognostic endpoints. Because of the inherent difficulties in assessing brain function in patients and objectively identifying neurological and cognitive/emotional symptoms, future application of biomarkers to neurological and psychiatric disorders is extremely desirable. This article discusses the biomarker potential of the granin family, a group of acidic proteins present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: chromogranin A (CgA), CgB, Secretogranin II (SgII), SgIII, HISL-19 antigen, 7B2, NESP55, VGF and ProSAAS. Their relative abundance, functional significance, and secretion into the cerebrospinal fluid (CSF), saliva, and the general circulation have made granins tractable targets as biomarkers for many diseases of neuronal and endocrine origin, recently impacting diagnosis of a number of neurological and psychiatric disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. Although research has not yet validated the clinical utility of granins as surrogate endpoints for the progression or treatment of neurological or psychiatric disease, a growing body of experimental evidence indicates that the use of granins as biomarkers might be of great potential clinical interest. Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational effectiveness of this family of proteins in disease diagnosis and drug discovery. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

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

Blinded Validation of Breath Biomarkers of Lung Cancer, a Potential Ancillary to Chest CT Screening

PubMed Central

Phillips, Michael; Bauer, Thomas L.; Cataneo, Renee N.; Lebauer, Cassie; Mundada, Mayur; Pass, Harvey I.; Ramakrishna, Naren; Rom, William N.; Vallières, Eric

2015-01-01

Background Breath volatile organic compounds (VOCs) have been reported as biomarkers of lung cancer, but it is not known if biomarkers identified in one group can identify disease in a separate independent cohort. Also, it is not known if combining breath biomarkers with chest CT has the potential to improve the sensitivity and specificity of lung cancer screening. Methods Model-building phase (unblinded): Breath VOCs were analyzed with gas chromatography mass spectrometry in 82 asymptomatic smokers having screening chest CT, 84 symptomatic high-risk subjects with a tissue diagnosis, 100 without a tissue diagnosis, and 35 healthy subjects. Multiple Monte Carlo simulations identified breath VOC mass ions with greater than random diagnostic accuracy for lung cancer, and these were combined in a multivariate predictive algorithm. Model-testing phase (blinded validation): We analyzed breath VOCs in an independent cohort of similar subjects (n = 70, 51, 75 and 19 respectively). The algorithm predicted discriminant function (DF) values in blinded replicate breath VOC samples analyzed independently at two laboratories (A and B). Outcome modeling: We modeled the expected effects of combining breath biomarkers with chest CT on the sensitivity and specificity of lung cancer screening. Results Unblinded model-building phase. The algorithm identified lung cancer with sensitivity 74.0%, specificity 70.7% and C-statistic 0.78. Blinded model-testing phase: The algorithm identified lung cancer at Laboratory A with sensitivity 68.0%, specificity 68.4%, C-statistic 0.71; and at Laboratory B with sensitivity 70.1%, specificity 68.0%, C-statistic 0.70, with linear correlation between replicates (r = 0.88). In a projected outcome model, breath biomarkers increased the sensitivity, specificity, and positive and negative predictive values of chest CT for lung cancer when the tests were combined in series or parallel. Conclusions Breath VOC mass ion biomarkers identified lung cancer in a

Novel heart failure biomarkers: why do we fail to exploit their potential?

PubMed

Piek, Arnold; Du, Weijie; de Boer, Rudolf A; Silljé, Herman H W

2018-06-01

Plasma biomarkers are useful tools in the diagnosis and prognosis of heart failure (HF). In the last decade, numerous studies have aimed to identify novel HF biomarkers that would provide superior and/or additional diagnostic, prognostic, or stratification utility. Although numerous biomarkers have been identified, their implementation in clinical practice has so far remained largely unsuccessful. Whereas cardiac-specific biomarkers, including natriuretic peptides (ANP and BNP) and high sensitivity troponins (hsTn), are widely used in clinical practice, other biomarkers have not yet proven their utility. Galectin-3 (Gal-3) and soluble suppression of tumorigenicity 2 (sST2) are the only novel HF biomarkers that are included in the ACC/AHA HF guidelines, but their clinical utility still needs to be demonstrated. In this review, we will describe natriuretic peptides, hsTn, and novel HF biomarkers, including Gal-3, sST2, human epididymis protein 4 (HE4), insulin-like growth factor-binding protein 7 (IGFBP-7), heart fatty acid-binding protein (H-FABP), soluble CD146 (sCD146), interleukin-6 (IL-6), growth differentiation factor 15 (GDF-15), procalcitonin (PCT), adrenomedullin (ADM), microRNAs (miRNAs), and metabolites like 5-oxoproline. We will discuss the biology of these HF biomarkers and conclude that most of them are markers of general pathological processes like fibrosis, cell death, and inflammation, and are not cardiac- or HF-specific. These characteristics explain to a large degree why it has been difficult to relate these biomarkers to a single disease. We propose that, in addition to clinical investigations, it will be pivotal to perform comprehensive preclinical biomarker investigations in animal models of HF in order to fully reveal the potential of these novel HF biomarkers.

Global and targeted metabolomics of esophageal squamous cell carcinoma discovers potential diagnostic and therapeutic biomarkers.

PubMed

Xu, Jing; Chen, Yanhua; Zhang, Ruiping; Song, Yongmei; Cao, Jianzhong; Bi, Nan; Wang, Jingbo; He, Jiuming; Bai, Jinfa; Dong, Lijia; Wang, Luhua; Zhan, Qimin; Abliz, Zeper

2013-05-01

Diagnostic and therapeutic biomarkers useful for esophageal squamous cell carcinoma (ESCC) have the ability to increase the long term survival of cancer patients. A metabolomics study, using plasma from four groups including ESCC patients before, during, and after chemoradiotherapy (CRT) and healthy controls, was originally carried out by LC-MS to determine global alterations in the metabolic profiles and find biomarkers potentially applicable to diagnosis and monitoring treatment effects. It is worth pointing out that a clear clustering and separation of metabolic data from the four groups was observed, which indicated that disease status and treatment intervention resulted in specific metabolic perturbations in the patients. A series of metabolites were found to be significantly altered in ESCC patients versus healthy controls and in pre- versus post-treatment patients based on multivariate statistical data analysis (MVDA). To further validate the reliability of these potential biomarkers, an independent validation was performed by using the selected reaction monitoring (SRM) based targeted approach. Finally, 18 most significantly altered plasma metabolites in ESCC patients, relative to healthy controls, were tentatively identified as lysophosphatidylcholines (lysoPCs), fatty acids, l-carnitine, acylcarnitines, organic acids, and a sterol metabolite. The classification performance of these metabolites were analyzed by receiver operating characteristic (ROC)(1) analysis and a biomarker panel was generated. Together, biological significance of these metabolites was discussed. Comparison between pre- and post-treatment patients generated 11 metabolites as potential therapeutic biomarkers that were tentatively identified as amino acids, acylcarnitines, and lysoPCs. Levels of three of these (octanoylcarnitine, lysoPC(16:1), and decanoylcarnitine) were closely correlated with treatment effect. Moreover, variation of these three potential biomarkers was investigated

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.

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.

A Targeted Metabolomics MRM-MS Study on Identifying Potential Hypertension Biomarkers in Human Plasma and Evaluating Acupuncture Effects.

PubMed

Yang, Mingxiao; Yu, Zheng; Deng, Shufang; Chen, Xiaomin; Chen, Liang; Guo, Zhenyu; Zheng, Hui; Chen, Lin; Cai, Dingjun; Wen, Bo; Wu, Qiaofeng; Liang, Fanrong

2016-05-16

The critical role of metabolic abnormality in hypertension is increasingly recognized, but its biomarkers are not clearly identified. In this study, 47 chemical compounds recorded by literature were employed as target metabolites of essential hypertension (EH). We detected their content in the plasma of EH patients and healthy subjects by using the Multiple Reaction Monitoring-Mass Spectrometry (MRM-MS). After screening the most altered compounds, acupuncture was used to treat patients for 3 months and these plasma metabolites were tested again. The results showed that oleic acid (OA) and myoinositol (MI) were the most important differential metabolites between the hypertensive plasma and the healthy plasma. They were also closely correlated with 24-hour blood pressure and nocturnal dipping. Moreover, plasma OA and MI could be restored to normal levels by acupuncture, accompanying with reduction of 24-hour systolic and diastolic blood pressure [from 145.10 ± 9.28 mm Hg to 140.70 ± 9.59 mm Hg (P < 0.0001), and 88.35 ± 7.92 mm Hg to 85.86 ± 7.95 mm Hg (P = 0.0024), respectively] and improvement of circadian blood pressure rhythm. This study demonstrated that plasma OA and MI were potential hypertension biomarkers and they could be used to preliminarily assess the treating effects such as acupuncture.

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

Metabolomics, Nutrition, and Potential Biomarkers of Food Quality, Intake, and Health Status.

PubMed

Sébédio, Jean-Louis

Diet, dietary patterns, and other environmental factors such as exposure to toxins are playing an important role in the prevention/development of many diseases, like obesity, type 2 diabetes, and consequently on the health status of individuals. A major challenge nowadays is to identify novel biomarkers to detect as early as possible metabolic dysfunction and to predict evolution of health status in order to refine nutritional advices to specific population groups. Omics technologies such as genomics, transcriptomics, proteomics, and metabolomics coupled with statistical and bioinformatics tools have already shown great potential in this research field even if so far only few biomarkers have been validated. For the past two decades, important analytical techniques have been developed to detect as many metabolites as possible in human biofluids such as urine, blood, and saliva. In the field of food science and nutrition, many studies have been carried out for food authenticity, quality, and safety, as well as for food processing. Furthermore, metabolomic investigations have been carried out to discover new early biomarkers of metabolic dysfunction and predictive biomarkers of developing pathologies (obesity, metabolic syndrome, type-2 diabetes, etc.). Great emphasis is also placed in the development of methodologies to identify and validate biomarkers of nutrients exposure. © 2017 Elsevier Inc. All rights reserved.

MiR-422a as a potential cellular microRNA biomarker for postmenopausal osteoporosis.

PubMed

Cao, Zheng; Moore, Benjamin T; Wang, Yang; Peng, Xian-Hao; Lappe, Joan M; Recker, Robert R; Xiao, Peng

2014-01-01

MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that regulate gene expression by targeting mRNAs. Recently, miRNAs have been shown to play important roles in the etiology of various diseases. However, little is known about their roles in the development of osteoporosis. Circulating monocytes are osteoclast precursors that also produce various factors important for osteoclastogenesis. Previously, we have identified a potential biomarker miR-133a in circulating monocytes for postmenopausal osteoporosis. In this study, we aimed to further identify significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis. We used ABI TaqMan miRNA array followed by qRT-PCR validation in human circulating monocytes from 10 high BMD and 10 low BMD postmenopausal Caucasian women to identify miRNA biomarkers. MiR-422a was up-regulated with marginal significance (P = 0.065) in the low compared with the high BMD group in the array analysis. However, a significant up-regulation of miR-422a was identified in the low BMD group by qRT-PCR analysis (P = 0.029). We also performed bioinformatic target gene analysis and found several potential target genes of miR-422a which are involved in osteoclastogenesis. Further qRT-PCR analyses of the target genes in the same study subjects showed that the expression of five of these genes (CBL, CD226, IGF1, PAG1, and TOB2) correlated negatively with miR-422a expression. Our study suggests that miR-422a in human circulating monocytes (osteoclast precursors) is a potential miRNA biomarker underlying postmenopausal osteoporosis.

Derivation and Validation of a Serum Biomarker Panel to Identify Infants With Acute Intracranial Hemorrhage.

PubMed

Berger, Rachel Pardes; Pak, Brian J; Kolesnikova, Mariya D; Fromkin, Janet; Saladino, Richard; Herman, Bruce E; Pierce, Mary Clyde; Englert, David; Smith, Paul T; Kochanek, Patrick M

2017-06-05

Abusive head trauma is the leading cause of death from physical abuse. Missing the diagnosis of abusive head trauma, particularly in its mild form, is common and contributes to increased morbidity and mortality. Serum biomarkers may have potential as quantitative point-of-care screening tools to alert physicians to the possibility of intracranial hemorrhage. To identify and validate a set of biomarkers that could be the basis of a multivariable model to identify intracranial hemorrhage in well-appearing infants using the Ziplex System. Binary logistic regression was used to develop a multivariable model incorporating 3 serum biomarkers (matrix metallopeptidase-9, neuron-specific enolase, and vascular cellular adhesion molecule-1) and 1 clinical variable (total hemoglobin). The model was then prospectively validated. Multiplex biomarker measurements were performed using Flow-Thru microarray technology on the Ziplex System, which has potential as a point-of-care system. The model was tested at 3 pediatric emergency departments in level I pediatric trauma centers (Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; Primary Children's Hospital, Salt Lake City, Utah; and Lurie Children's Hospital, Chicago, Illinois) among well-appearing infants who presented for care owing to symptoms that placed them at increased risk of abusive head trauma. The study took place from November 2006 to April 2014 at Children's Hospital of Pittsburgh, June 2010 to August 2013 at Primary Children's Hospital, and January 2011 to August 2013 at Lurie Children's Hospital. A mathematical model that can predict acute intracranial hemorrhage in infants at increased risk of abusive head trauma. The multivariable model, Biomarkers for Infant Brain Injury Score, was applied prospectively to 599 patients. The mean (SD) age was 4.7 (3.1) months. Fifty-two percent were boys, 78% were white, and 8% were Hispanic. At a cutoff of 0.182, the model was 89

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer.

PubMed

Chang, Hae Ryung; Nam, Seungyoon; Lee, Jinhyuk; Kim, Jin-Hee; Jung, Hae Rim; Park, Hee Seo; Park, Sungjin; Ahn, Young Zoo; Huh, Iksoo; Balch, Curt; Ku, Ja-Lok; Powis, Garth; Park, Taesung; Jeong, Jin-Hyun; Kim, Yon Hui

2016-12-06

Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer "Big Data" has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of "hit" compounds.

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

Potential protein biomarkers for burning mouth syndrome discovered by quantitative proteomics

PubMed Central

Ji, Eoon Hye; Diep, Cynthia; Liu, Tong; Li, Hong; Merrill, Robert; Messadi, Diana

2017-01-01

Burning mouth syndrome (BMS) is a chronic pain disorder characterized by severe burning sensation in normal looking oral mucosa. Diagnosis of BMS remains to be a challenge to oral healthcare professionals because the method for definite diagnosis is still uncertain. In this study, a quantitative saliva proteomic analysis was performed in order to identify target proteins in BMS patients’ saliva that may be used as biomarkers for simple, non-invasive detection of the disease. By using isobaric tags for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry to quantify 1130 saliva proteins between BMS patients and healthy control subjects, we found that 50 proteins were significantly changed in the BMS patients when compared to the healthy control subjects (p ≤ 0.05, 39 up-regulated and 11 down-regulated). Four candidates, alpha-enolase, interleukin-18 (IL-18), kallikrein-13 (KLK13), and cathepsin G, were selected for further validation. Based on enzyme-linked immunosorbent assay measurements, three potential biomarkers, alpha-enolase, IL-18, and KLK13, were successfully validated. The fold changes for alpha-enolase, IL-18, and KLK13 were determined as 3.6, 2.9, and 2.2 (burning mouth syndrome vs. control), and corresponding receiver operating characteristic values were determined as 0.78, 0.83, and 0.68, respectively. Our findings indicate that testing of the identified protein biomarkers in saliva might be a valuable clinical tool for BMS detection. Further validation studies of the identified biomarkers or additional candidate biomarkers are needed to achieve a multi-marker prediction model for improved detection of BMS with high sensitivity and specificity. PMID:28326926

Potential protein biomarkers for burning mouth syndrome discovered by quantitative proteomics.

PubMed

Ji, Eoon Hye; Diep, Cynthia; Liu, Tong; Li, Hong; Merrill, Robert; Messadi, Diana; Hu, Shen

2017-01-01

Burning mouth syndrome (BMS) is a chronic pain disorder characterized by severe burning sensation in normal looking oral mucosa. Diagnosis of BMS remains to be a challenge to oral healthcare professionals because the method for definite diagnosis is still uncertain. In this study, a quantitative saliva proteomic analysis was performed in order to identify target proteins in BMS patients' saliva that may be used as biomarkers for simple, non-invasive detection of the disease. By using isobaric tags for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry to quantify 1130 saliva proteins between BMS patients and healthy control subjects, we found that 50 proteins were significantly changed in the BMS patients when compared to the healthy control subjects ( p ≤ 0.05, 39 up-regulated and 11 down-regulated). Four candidates, alpha-enolase, interleukin-18 (IL-18), kallikrein-13 (KLK13), and cathepsin G, were selected for further validation. Based on enzyme-linked immunosorbent assay measurements, three potential biomarkers, alpha-enolase, IL-18, and KLK13, were successfully validated. The fold changes for alpha-enolase, IL-18, and KLK13 were determined as 3.6, 2.9, and 2.2 (burning mouth syndrome vs. control), and corresponding receiver operating characteristic values were determined as 0.78, 0.83, and 0.68, respectively. Our findings indicate that testing of the identified protein biomarkers in saliva might be a valuable clinical tool for BMS detection. Further validation studies of the identified biomarkers or additional candidate biomarkers are needed to achieve a multi-marker prediction model for improved detection of BMS with high sensitivity and specificity.

Biomarkers of PTSD: military applications and considerations.

PubMed

Lehrner, Amy; Yehuda, Rachel

2014-01-01

Although there are no established biomarkers for posttraumatic stress disorder (PTSD) as yet, biological investigations of PTSD have made progress identifying the pathophysiology of PTSD. Given the biological and clinical complexity of PTSD, it is increasingly unlikely that a single biomarker of disease will be identified. Rather, investigations will more likely identify different biomarkers that indicate the presence of clinically significant PTSD symptoms, associate with risk for PTSD following trauma exposure, and predict or identify recovery. While there has been much interest in PTSD biomarkers, there has been less discussion of their potential clinical applications, and of the social, legal, and ethical implications of such biomarkers. This article will discuss possible applications of PTSD biomarkers, including the social, legal, and ethical implications of such biomarkers, with an emphasis on military applications. Literature on applications of PTSD biomarkers and on potential ethical and legal implications will be reviewed. Biologically informed research findings hold promise for prevention, assessment, treatment planning, and the development of prophylactic and treatment interventions. As with any biological indicator of disorder, there are potentially positive and negative clinical, social, legal, and ethical consequences of using such biomarkers. Potential clinical applications of PTSD biomarkers hold promise for clinicians, patients, and employers. The search for biomarkers of PTSD should occur in tandem with an interdisciplinary discussion regarding the potential implications of applying biological findings in clinical and employment settings.

Long Non-Coding RNA as Potential Biomarker for Prostate Cancer: Is It Making a Difference?

PubMed

Deng, Junli; Tang, Jie; Wang, Guo; Zhu, Yuan-Shan

2017-03-07

Whole genome transcriptomic analyses have identified numerous long non-coding RNA (lncRNA) transcripts that are increasingly implicated in cancer biology. LncRNAs are found to promote essential cancer cell functions such as proliferation, invasion, and metastasis, with the potential to serve as novel biomarkers of various cancers and to further reveal uncharacterized aspects of tumor biology. However, the biological and molecular mechanisms as well as the clinical applications of lncRNAs in diverse diseases are not completely understood, and remain to be fully explored. LncRNAs may be critical players and regulators in prostate cancer carcinogenesis and progression, and could serve as potential biomarkers for prostate cancer. This review focuses on lncRNA biomarkers that are already available for clinical use and provides an overview of lncRNA biomarkers that are under investigation for clinical development in prostate cancer.

MiR-422a as a Potential Cellular MicroRNA Biomarker for Postmenopausal Osteoporosis

PubMed Central

Cao, Zheng; Moore, Benjamin T.; Wang, Yang; Peng, Xian-Hao; Lappe, Joan M.; Recker, Robert R.; Xiao, Peng

2014-01-01

Background MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that regulate gene expression by targeting mRNAs. Recently, miRNAs have been shown to play important roles in the etiology of various diseases. However, little is known about their roles in the development of osteoporosis. Circulating monocytes are osteoclast precursors that also produce various factors important for osteoclastogenesis. Previously, we have identified a potential biomarker miR-133a in circulating monocytes for postmenopausal osteoporosis. In this study, we aimed to further identify significant miRNA biomarkers in human circulating monocytes underlying postmenopausal osteoporosis. Methodology/Principal Findings We used ABI TaqMan miRNA array followed by qRT-PCR validation in human circulating monocytes from 10 high BMD and 10 low BMD postmenopausal Caucasian women to identify miRNA biomarkers. MiR-422a was up-regulated with marginal significance (P = 0.065) in the low compared with the high BMD group in the array analysis. However, a significant up-regulation of miR-422a was identified in the low BMD group by qRT-PCR analysis (P = 0.029). We also performed bioinformatic target gene analysis and found several potential target genes of miR-422a which are involved in osteoclastogenesis. Further qRT-PCR analyses of the target genes in the same study subjects showed that the expression of five of these genes (CBL, CD226, IGF1, PAG1, and TOB2) correlated negatively with miR-422a expression. Conclusions/Significance Our study suggests that miR-422a in human circulating monocytes (osteoclast precursors) is a potential miRNA biomarker underlying postmenopausal osteoporosis. PMID:24820117

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

Systematic approach identifies RHOA as a potential biomarker therapeutic target for Asian gastric cancer

PubMed Central

Jung, Hae Rim; Park, Hee Seo; Park, Sungjin; Ahn, Young Zoo; Huh, Iksoo; Balch, Curt; Ku, Ja-Lok; Powis, Garth; Park, Taesung; Jeong, Jin-Hyun; Kim, Yon Hui

2016-01-01

Gastric cancer (GC) is a highly heterogeneous disease, in dire need of specific, biomarker-driven cancer therapies. While the accumulation of cancer “Big Data” has propelled the search for novel molecular targets for GC, its specific subpathway and cellular functions vary from patient to patient. In particular, mutations in the small GTPase gene RHOA have been identified in recent genome-wide sequencing of GC tumors. Moreover, protein overexpression of RHOA was reported in Chinese populations, while RHOA mutations were found in Caucasian GC tumors. To develop evidence-based precision medicine for heterogeneous cancers, we established a systematic approach to integrate transcriptomic and genomic data. Predicted signaling subpathways were then laboratory-validated both in vitro and in vivo, resulting in the identification of new candidate therapeutic targets. Here, we show: i) differences in RHOA expression patterns, and its pathway activity, between Asian and Caucasian GC tumors; ii) in vitro and in vivo perturbed RHOA expression inhibits GC cell growth in high RHOA-expressing cell lines; iii) inverse correlation between RHOA and RHOB expression; and iv) an innovative small molecule design strategy for RHOA inhibitors. In summary, RHOA, and its oncogenic signaling pathway, represent a strong biomarker-driven therapeutic target for Asian GC. This comprehensive strategy represents a promising approach for the development of “hit” compounds. PMID:27806312

Discovery and identification of potential biomarkers of pediatric Acute Lymphoblastic Leukemia

PubMed Central

Shi, Linan; Zhang, Jun; Wu, Peng; Feng, Kai; Li, Jing; Xie, Zhensheng; Xue, Peng; Cai, Tanxi; Cui, Ziyou; Chen, Xiulan; Hou, Junjie; Zhang, Jianzhong; Yang, Fuquan

2009-01-01

Background Acute lymphoblastic leukemia (ALL) is a common form of cancer in children. Currently, bone marrow biopsy is used for diagnosis. Noninvasive biomarkers for the early diagnosis of pediatric ALL are urgently needed. The aim of this study was to discover potential protein biomarkers for pediatric ALL. Methods Ninety-four pediatric ALL patients and 84 controls were randomly divided into a "training" set (45 ALL patients, 34 healthy controls) and a test set (49 ALL patients, 30 healthy controls and 30 pediatric acute myeloid leukemia (AML) patients). Serum proteomic profiles were measured using surface-enhanced laser desorption/ionization-time-of-flight mass spectroscopy (SELDI-TOF-MS). A classification model was established by Biomarker Pattern Software (BPS). Candidate protein biomarkers were purified by HPLC, identified by LC-MS/MS and validated using ProteinChip immunoassays. Results A total of 7 protein peaks (9290 m/z, 7769 m/z, 15110 m/z, 7564 m/z, 4469 m/z, 8937 m/z, 8137 m/z) were found with differential expression levels in the sera of pediatric ALL patients and controls using SELDI-TOF-MS and then analyzed by BPS to construct a classification model in the "training" set. The sensitivity and specificity of the model were found to be 91.8%, and 90.0%, respectively, in the test set. Two candidate protein peaks (7769 and 9290 m/z) were found to be down-regulated in ALL patients, where these were identified as platelet factor 4 (PF4) and pro-platelet basic protein precursor (PBP). Two other candidate protein peaks (8137 and 8937 m/z) were found up-regulated in the sera of ALL patients, and these were identified as fragments of the complement component 3a (C3a). Conclusion Platelet factor (PF4), connective tissue activating peptide III (CTAP-III) and two fragments of C3a may be potential protein biomarkers of pediatric ALL and used to distinguish pediatric ALL patients from healthy controls and pediatric AML patients. Further studies with additional

Promoter Hypermethylation of Tumour Suppressor Genes as Potential Biomarkers in Colorectal Cancer

PubMed Central

Ng, Jennifer Mun-Kar; Yu, Jun

2015-01-01

Colorectal cancer (CRC) is a common malignancy and the fourth leading cause of cancer deaths worldwide. It results from the accumulation of multiple genetic and epigenetic changes leading to the transformation of colon epithelial cells into invasive adenocarcinomas. In CRC, epigenetic changes, in particular promoter CpG island methylation, occur more frequently than genetic mutations. Hypermethylation contributes to carcinogenesis by inducing transcriptional silencing or downregulation of tumour suppressor genes and currently, over 600 candidate hypermethylated genes have been identified. Over the past decade, a deeper understanding of epigenetics coupled with technological advances have hinted at the potential of translating benchtop research into biomarkers for clinical use. DNA methylation represents one of the largest bodies of literature in epigenetics, and hence has the highest potential for minimally invasive biomarker development. Most progress has been made in the development of diagnostic markers and there are currently two, one stool-based and one blood-based, biomarkers that are commercially available for diagnostics. Prognostic and predictive methylation markers are still at their infantile stages. PMID:25622259

Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow.

PubMed

Kulkarni, Shilpa; Koller, Antonius; Mani, Kartik M; Wen, Ruofeng; Alfieri, Alan; Saha, Subhrajit; Wang, Jian; Patel, Purvi; Bandeira, Nuno; Guha, Chandan; Chen, Emily I

2016-11-01

Early and accurate assessment of radiation injury by radiation-responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis. Recent research has also suggested that exosomes are a reliable source of biomarkers in disease progression. In the present study, we analyzed total urine proteome and exosomes isolated from urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). For feasibility studies, the mice were irradiated at 10.4 Gy WBI, and urine and serum samples were collected 24 and 72 hours after irradiation. Exosomes were isolated and analyzed using liquid chromatography mass spectrometry/mass spectrometry-based workflow for radiation exposure signatures. A data dependent acquisition and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For the validation studies, mice were exposed to 3, 6, 8, or 10 Gy WBI, and samples were analyzed for comparison. A comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes after WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury to the liver, gastrointestinal, and genitourinary tracts. In contrast, serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. A total of 47 differentially secreted proteins were identified in urinary and serum exosomes

Identifying Urinary and Serum Exosome Biomarkers for Radiation Exposure Using a Data Dependent Acquisition and SWATH-MS Combined Workflow

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

Kulkarni, Shilpa; Koller, Antonius; Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, New York, New York

Purpose: Early and accurate assessment of radiation injury by radiation-responsive biomarkers is critical for triage and early intervention. Biofluids such as urine and serum are convenient for such analysis. Recent research has also suggested that exosomes are a reliable source of biomarkers in disease progression. In the present study, we analyzed total urine proteome and exosomes isolated from urine or serum for potential biomarkers of acute and persistent radiation injury in mice exposed to lethal whole body irradiation (WBI). Methods and Materials: For feasibility studies, the mice were irradiated at 10.4 Gy WBI, and urine and serum samples were collected 24more » and 72 hours after irradiation. Exosomes were isolated and analyzed using liquid chromatography mass spectrometry/mass spectrometry-based workflow for radiation exposure signatures. A data dependent acquisition and SWATH-MS combined workflow approach was used to identify significantly exosome biomarkers indicative of acute or persistent radiation-induced responses. For the validation studies, mice were exposed to 3, 6, 8, or 10 Gy WBI, and samples were analyzed for comparison. Results: A comparison between total urine proteomics and urine exosome proteomics demonstrated that exosome proteomic analysis was superior in identifying radiation signatures. Feasibility studies identified 23 biomarkers from urine and 24 biomarkers from serum exosomes after WBI. Urinary exosome signatures identified different physiological parameters than the ones obtained in serum exosomes. Exosome signatures from urine indicated injury to the liver, gastrointestinal, and genitourinary tracts. In contrast, serum showed vascular injuries and acute inflammation in response to radiation. Selected urinary exosomal biomarkers also showed changes at lower radiation doses in validation studies. Conclusions: Exosome proteomics revealed radiation- and time-dependent protein signatures after WBI. A total of 47 differentially

Progranulin as a biomarker and potential therapeutic agent.

PubMed

Abella, Vanessa; Pino, Jesús; Scotece, Morena; Conde, Javier; Lago, Francisca; Gonzalez-Gay, Miguel Angel; Mera, Antonio; Gómez, Rodolfo; Mobasheri, Ali; Gualillo, Oreste

2017-10-01

Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Biomarkers of ovarian reserve as predictors of reproductive potential.

PubMed

Steiner, Anne Z

2013-11-01

The size of the oocyte pool, the ovarian reserve, can determine a woman's reproductive stage. Chronologic age, anti-Müllerian hormone (AMH) levels, early follicular phase follicle-stimulating hormone levels, and early follicular phase inhibin B levels are correlated with ovarian reserve. Therefore, these biomarkers of ovarian reserve should serve as predictors of reproductive potential. Clinical and epidemiologic studies suggest that historical and laboratory biomarkers of ovarian reserve are associated with natural and treatment-related fertility. However, controversy remains as to their ability to predict reproductive potential. For infertile women undergoing assisted reproductive technology treatment, these biomarkers tend to be highly specific but not sensitive for cycle failure (nonpregnancy). While these biomarkers are being used as "fertility tests" in the general population, their value as predictors of unassisted fertility is still uncertain. Among laboratory biomarkers, AMH appears to have the most promise; however, further studies are needed to refine cutoff values and to determine test characteristics in the prediction of natural fertility or infertility in the general population. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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.

The Potential of MicroRNAs as Prostate Cancer Biomarkers.

PubMed

Fabris, Linda; Ceder, Yvonne; Chinnaiyan, Arul M; Jenster, Guido W; Sorensen, Karina D; Tomlins, Scott; Visakorpi, Tapio; Calin, George A

2016-08-01

Short noncoding RNAs known as microRNAs (miRNAs) control protein expression through the degradation of RNA or the inhibition of protein translation. The miRNAs influence a wide range of biologic processes and are often deregulated in cancer. This family of small RNAs constitutes potentially valuable markers for the diagnosis, prognosis, and therapeutic choices in prostate cancer (PCa) patients, as well as potential drugs (miRNA mimics) or drug targets (anti-miRNAs) in PCa management. To review the currently available data on miRNAs as biomarkers in PCa and as possible tools for early detection and prognosis. A systematic review was performed searching the PubMed database for articles in English using a combination of the following terms: microRNA, miRNA, cancer, prostate cancer, miRNA profiling, diagnosis, prognosis, therapy response, and predictive marker. We summarize the existing literature regarding the profiling of miRNA in PCa detection, prognosis, and response to therapy. The articles were reviewed with the main goal of finding a common recommendation that could be translated from bench to bedside in future clinical practice. The miRNAs are important regulators of biologic processes in PCa progression. A common expression profile characterizing each tumor subtype and stage has still not been identified for PCa, probably due to molecular heterogeneity as well as differences in study design and patient selection. Large-scale studies that should provide additional important information are still missing. Further studies, based on common clinical parameters and guidelines, are necessary to validate the translational potential of miRNAs in PCa clinical management. Such common signatures are promising in the field and emerge as potential biomarkers. The literature shows that microRNAs hold potential as novel biomarkers that could aid prostate cancer management, but additional studies with larger patient cohorts and common guidelines are necessary before clinical

[MALDI-TOF and SELDI-TOF analysis: "tandem" techniques to identify potential biomarker in fibromyalgia].

PubMed

Giacomelli, C; Bazzichi, L; Giusti, L; Ciregia, F; Baldini, C; Da Valle, Y; De Feo, F; Sernissi, F; Rossi, A; Bombardieri, S; Lucacchini, A

2011-11-09

Fibromyalgia (FM) is characterized by the presence of chronic widespread pain throughout the musculoskeletal system and diffuse tenderness. Unfortunately, no laboratory tests have been appropriately validated for FM and correlated with the subsets and activity. The aim of this study was to apply a proteomic technique in saliva of FM patients: the Surface Enhance Laser Desorption/Ionization Time-of-Flight (SELDI-TOF). For this study, 57 FM patients and 35 HC patients were enrolled. The proteomic analysis of saliva was carried out using SELDI-TOF. The analysis was performed using different chip arrays with different characteristics of binding. The statistical analysis was performed using cluster analysis and the difference between two groups was underlined using Student’s t-test. Spectra analysis highlighted the presence of several peaks differently expressed in FM patients compared with controls. The preliminary results obtained by SELDI-TOF analysis were compared with those obtained in our previous study performed on whole saliva of FM patients by using electrophoresis. The m/z of two peaks, increased in FM patients, seem to overlap well with the molecular weight of calgranulin A and C and Rho GDP-dissociation inhibitor 2, which we had found up-regulated in our previous study. These preliminary results showed the possibility of identifying potential salivary biomarker through salivary proteomic analysis with MALDI-TOF and SELDI-TOF in FM patients. The peaks observed allow us to focus on some of the particular pathogenic aspects of FM, the oxidative stress which contradistinguishes this condition, the involvement of proteins related to the cytoskeletal arrangements, and central sensibilization.

Biomarkers of acute respiratory allergen exposure: Screening for sensitization potential

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

Pucheu-Haston, Cherie M., E-mail: Pucheu-Haston.Cherie@epa.go; Copeland, Lisa B.; Vallanat, Beena

2010-04-15

Effective hazard screening will require the development of high-throughput or in vitro assays for the identification of potential sensitizers. The goal of this preliminary study was to identify potential biomarkers that differentiate the response to allergens vs non-allergens following an acute exposure in naive individuals. Female BALB/c mice received a single intratracheal aspiration exposure to Metarhizium anisopliae crude antigen (MACA) or bovine serum albumin (BSA) in Hank's Balanced Salt Solution (HBSS) or HBSS alone. Mice were terminated after 1, 3, 6, 12, 18 and 24 h. Bronchoalveolar lavage fluid (BALF) was evaluated to determine total and differential cellularity, total proteinmore » concentration and LDH activity. RNA was isolated from lung tissue for microarray analysis and qRT-PCR. MACA administration induced a rapid increase in BALF neutrophils, lymphocytes, eosinophils and total protein compared to BSA or HBSS. Microarray analysis demonstrated differential expression of genes involved in cytokine production, signaling, inflammatory cell recruitment, adhesion and activation in 3 and 12 h MACA-treated samples compared to BSA or HBSS. Further analyses allowed identification of approx 100 candidate biomarker genes. Eleven genes were selected for further assessment by qRT-PCR. Of these, 6 demonstrated persistently increased expression (Ccl17, Ccl22, Ccl7, Cxcl10, Cxcl2, Saa1), while C3ar1 increased from 6-24 h. In conclusion, a single respiratory exposure of mice to an allergenic mold extract induces an inflammatory response which is distinct in phenotype and gene transcription from the response to a control protein. Further validation of these biomarkers with additional allergens and irritants is needed. These biomarkers may facilitate improvements in screening methods.« less

Potential objective biomarkers for fatigue among working women.

PubMed

Ebata, Chie; Tatsuta, Hitomi; Tatemichi, Masayuki

2017-05-25

The prediction of health impairment due to work overload is subjectively assessed based on recognized symptoms; however, objective evaluation is primarily ideal in the field of occupational health. Recently, some biomarkers of autonomic function and/or oxidative stress were reported to be associated with fatigue. This study aimed to preliminarily investigate whether these biomarkers could be objective indicators for fatigue and stress among working women. Participants included 118 full-time female workers (mean age 37.8 years), including 55 shift workers. Self-administered questionnaires, such as visual analog scale (VAS) for general health, a lifestyle questionnaire, SF-8 for health-related quality of life, and K6 for mental health screening, were used. In addition, biomarkers such as acceleration plethysmogram (APG), reactive oxygen metabolites-derived compounds (d-ROMs), and biological antioxidant potential (BAP) were measured. A significant association was observed between BAP and VAS (r=0.482, p<0.01) among shift workers. However, other biomarkers such as APG and d-ROMs were not significantly associated with symptoms. d-ROMs were significantly correlated with age and body mass index. There was a significant negative correlation between BAP and smoking. Results of the APG (low-frequency (LF) /high-frequency (HF) ratio) were significantly correlated with BAP, but not with d-ROMs. The LF/HF ratio and BAP for shift workers were significantly higher than those for day-time workers. Our results suggest that APG and BAP are potential objective biomarkers for fatigue among working women, although further follow-up studies are needed to clarify the scope of usefulness of the biomarkers for fatigue.

Circulating MicroRNAs as Potential Biomarkers of Exercise Response

PubMed Central

Polakovičová, Mája; Musil, Peter; Laczo, Eugen; Hamar, Dušan; Kyselovič, Ján

2016-01-01

Systematic physical activity increases physical fitness and exercise capacity that lead to the improvement of health status and athletic performance. Considerable effort is devoted to identifying new biomarkers capable of evaluating exercise performance capacity and progress in training, early detection of overtraining, and monitoring health-related adaptation changes. Recent advances in OMICS technologies have opened new opportunities in the detection of genetic, epigenetic and transcriptomic biomarkers. Very promising are mainly small non-coding microRNAs (miRNAs). miRNAs post-transcriptionally regulate gene expression by binding to mRNA and causing its degradation or inhibiting translation. A growing body of evidence suggests that miRNAs affect many processes and play a crucial role not only in cell differentiation, proliferation and apoptosis, but also affect extracellular matrix composition and maintaining processes of homeostasis. A number of studies have shown changes in distribution profiles of circulating miRNAs (c-miRNAs) associated with various diseases and disorders as well as in samples taken under physiological conditions such as pregnancy or physical exercise. This overview aims to summarize the current knowledge related to the response of blood c-miRNAs profiles to different modes of exercise and to highlight their potential application as a novel class of biomarkers of physical performance capacity and training adaptation. PMID:27782053

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

Proteomics-based approach identified differentially expressed proteins with potential roles in endometrial carcinoma.

PubMed

Li, Zhengyu; Min, Wenjiao; Huang, Canhua; Bai, Shujun; Tang, Minghai; Zhao, Xia

2010-01-01

We used proteomic approaches to identify altered expressed proteins in endometrial carcinoma, with the aim of discovering potential biomarkers or therapeutic targets for endometrial carcinoma. The global proteins extracted from endometrial carcinoma and normal endometrial tissues were separated by 2-dimensional electrophoresis and analyzed with PDQuest (Bio-Rad, Hercules, Calif) software. The differentially expressed spots were identified by mass spectrometry and searched against NCBInr protein database. Those proteins with potential roles were confirmed by Western blotting and immunohistochemical assays. Ninety-nine proteins were identified by mass spectrometry, and a cluster diagram analysis indicated that these proteins were involved in metabolism, cell transformation, protein folding, translation and modification, proliferation and apoptosis, signal transduction, cytoskeleton, and so on. In confirmatory immunoblotting and immunohistochemical analyses, overexpressions of epidermal fatty acid-binding protein, calcyphosine, and cyclophilin A were also observed in endometrial carcinoma tissues, which were consistent with the proteomic results. Our results suggested that these identified proteins, including epidermal fatty acid-binding protein, calcyphosine, and cyclophilin A, might be of potential values in the studies of endometrial carcinogenesis or investigations of diagnostic biomarkers or treatment targets for endometrial carcinoma.

The auditory brain-stem response to complex sounds: a potential biomarker for guiding treatment of psychosis.

PubMed

Tarasenko, Melissa A; Swerdlow, Neal R; Makeig, Scott; Braff, David L; Light, Gregory A

2014-01-01

Cognitive deficits limit psychosocial functioning in schizophrenia. For many patients, cognitive remediation approaches have yielded encouraging results. Nevertheless, therapeutic response is variable, and outcome studies consistently identify individuals who respond minimally to these interventions. Biomarkers that can assist in identifying patients likely to benefit from particular forms of cognitive remediation are needed. Here, we describe an event-related potential (ERP) biomarker - the auditory brain-stem response (ABR) to complex sounds (cABR) - that appears to be particularly well-suited for predicting response to at least one form of cognitive remediation that targets auditory information processing. Uniquely, the cABR quantifies the fidelity of sound encoded at the level of the brainstem and midbrain. This ERP biomarker has revealed auditory processing abnormalities in various neurodevelopmental disorders, correlates with functioning across several cognitive domains, and appears to be responsive to targeted auditory training. We present preliminary cABR data from 18 schizophrenia patients and propose further investigation of this biomarker for predicting and tracking response to cognitive interventions.

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.

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.

Biomarkers in Autism

PubMed Central

Goldani, Andre A. S.; Downs, Susan R.; Widjaja, Felicia; Lawton, Brittany; Hendren, Robert L.

2014-01-01

Autism spectrum disorders (ASDs) are complex, heterogeneous disorders caused by an interaction between genetic vulnerability and environmental factors. In an effort to better target the underlying roots of ASD for diagnosis and treatment, efforts to identify reliable biomarkers in genetics, neuroimaging, gene expression, and measures of the body’s metabolism are growing. For this article, we review the published studies of potential biomarkers in autism and conclude that while there is increasing promise of finding biomarkers that can help us target treatment, there are none with enough evidence to support routine clinical use unless medical illness is suspected. Promising biomarkers include those for mitochondrial function, oxidative stress, and immune function. Genetic clusters are also suggesting the potential for useful biomarkers. PMID:25161627

Potential objective biomarkers for fatigue among working women

PubMed Central

Ebata, Chie; Tatsuta, Hitomi; Tatemichi, Masayuki

2017-01-01

Objective: The prediction of health impairment due to work overload is subjectively assessed based on recognized symptoms; however, objective evaluation is primarily ideal in the field of occupational health. Recently, some biomarkers of autonomic function and/or oxidative stress were reported to be associated with fatigue. This study aimed to preliminarily investigate whether these biomarkers could be objective indicators for fatigue and stress among working women. Method: Participants included 118 full-time female workers (mean age 37.8 years), including 55 shift workers. Self-administered questionnaires, such as visual analog scale (VAS) for general health, a lifestyle questionnaire, SF-8 for health-related quality of life, and K6 for mental health screening, were used. In addition, biomarkers such as acceleration plethysmogram (APG), reactive oxygen metabolites-derived compounds (d-ROMs), and biological antioxidant potential (BAP) were measured. Results: A significant association was observed between BAP and VAS (r=0.482, p<0.01) among shift workers. However, other biomarkers such as APG and d-ROMs were not significantly associated with symptoms. d-ROMs were significantly correlated with age and body mass index. There was a significant negative correlation between BAP and smoking. Results of the APG (low-frequency (LF) /high-frequency (HF) ratio) were significantly correlated with BAP, but not with d-ROMs. The LF/HF ratio and BAP for shift workers were significantly higher than those for day-time workers. Conclusions: Our results suggest that APG and BAP are potential objective biomarkers for fatigue among working women, although further follow-up studies are needed to clarify the scope of usefulness of the biomarkers for fatigue. PMID:28163282

Mechanism-Based Urinary Biomarkers to Identify the Potential for Aminoglycoside-Induced Nephrotoxicity in Premature Neonates: A Proof-of-Concept Study

PubMed Central

Sabbisetti, Venkata; Turner, Mark A.; Farragher, Tracey; Bonventre, Joseph V.; Park, B. Kevin; Smyth, Rosalind L.; Pirmohamed, Munir

2012-01-01

Premature infants are frequently exposed to aminoglycoside antibiotics. Novel urinary biomarkers may provide a non-invasive means for the early identification of aminoglycoside-related proximal tubule renal toxicity, to enable adjustment of treatment and identification of infants at risk of long-term renal impairment. In this proof-of-concept study, urine samples were collected from 41 premature neonates (≤32 weeks gestation) at least once per week, and daily during courses of gentamicin, and for 3 days afterwards. Significant increases were observed in the three urinary biomarkers measured (Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase-associated Lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG)) during treatment with multiple courses of gentamicin. When adjusted for potential confounders, the treatment effect of gentamicin remained significant only for KIM-1 (mean difference from not treated, 1.35 ng/mg urinary creatinine; 95% CI 0.05–2.65). Our study shows that (a) it is possible to collect serial urine samples from premature neonates, and that (b) proximal tubule specific urinary biomarkers can act as indicators of aminoglycoside-associated nephrotoxicity in this age group. Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken. PMID:22937100

Integrative multi-platform meta-analysis of gene expression profiles in pancreatic ductal adenocarcinoma patients for identifying novel diagnostic biomarkers.

PubMed

Irigoyen, Antonio; Jimenez-Luna, Cristina; Benavides, Manuel; Caba, Octavio; Gallego, Javier; Ortuño, Francisco Manuel; Guillen-Ponce, Carmen; Rojas, Ignacio; Aranda, Enrique; Torres, Carolina; Prados, Jose

2018-01-01

Applying differentially expressed genes (DEGs) to identify feasible biomarkers in diseases can be a hard task when working with heterogeneous datasets. Expression data are strongly influenced by technology, sample preparation processes, and/or labeling methods. The proliferation of different microarray platforms for measuring gene expression increases the need to develop models able to compare their results, especially when different technologies can lead to signal values that vary greatly. Integrative meta-analysis can significantly improve the reliability and robustness of DEG detection. The objective of this work was to develop an integrative approach for identifying potential cancer biomarkers by integrating gene expression data from two different platforms. Pancreatic ductal adenocarcinoma (PDAC), where there is an urgent need to find new biomarkers due its late diagnosis, is an ideal candidate for testing this technology. Expression data from two different datasets, namely Affymetrix and Illumina (18 and 36 PDAC patients, respectively), as well as from 18 healthy controls, was used for this study. A meta-analysis based on an empirical Bayesian methodology (ComBat) was then proposed to integrate these datasets. DEGs were finally identified from the integrated data by using the statistical programming language R. After our integrative meta-analysis, 5 genes were commonly identified within the individual analyses of the independent datasets. Also, 28 novel genes that were not reported by the individual analyses ('gained' genes) were also discovered. Several of these gained genes have been already related to other gastroenterological tumors. The proposed integrative meta-analysis has revealed novel DEGs that may play an important role in PDAC and could be potential biomarkers for diagnosing the disease.

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

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

The potential biomarkers of drug addiction: proteomic and metabolomics challenges.

PubMed

Wang, Lv; Wu, Ning; Zhao, Tai-Yun; Li, Jin

2016-07-28

Drug addiction places a significant burden on society and individuals. Proteomics and metabolomics approaches pave the road for searching potential biomarkers to assist the diagnosis and treatment. This review summarized putative drug addiction-related biomarkers in proteomics and metabolomics studies and discussed challenges and prospects in future studies. Alterations of several hundred proteins and metabolites were reported when exposure to abused drug, which enriched in energy metabolism, oxidative stress response, protein modification and degradation, synaptic function and neurotrasmission, etc. Hsp70, peroxiredoxin-6 and α- and β-synuclein, as well as n-methylserotonin and purine metabolites, were promising as potential biomarker for drug addiction.

Potential biomarkers of ageing.

PubMed

Simm, Andreas; Nass, Norbert; Bartling, Babett; Hofmann, Britt; Silber, Rolf-Edgar; Navarrete Santos, Alexander

2008-03-01

Life span in individual humans is very heterogeneous.Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, is different in every individual. There have been attempts made to analyse this individual age, the so-called biological age, in comparison to chronological age. Biomarkers of ageing should help to characterise this biological age and, as age is a major risk factor in many degenerative diseases,could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. Markers based on oxidative stress, protein glycation,inflammation, cellular senescence and hormonal deregulation are discussed.

The Auditory Brain-Stem Response to Complex Sounds: A Potential Biomarker for Guiding Treatment of Psychosis

PubMed Central

Tarasenko, Melissa A.; Swerdlow, Neal R.; Makeig, Scott; Braff, David L.; Light, Gregory A.

2014-01-01

Cognitive deficits limit psychosocial functioning in schizophrenia. For many patients, cognitive remediation approaches have yielded encouraging results. Nevertheless, therapeutic response is variable, and outcome studies consistently identify individuals who respond minimally to these interventions. Biomarkers that can assist in identifying patients likely to benefit from particular forms of cognitive remediation are needed. Here, we describe an event-related potential (ERP) biomarker – the auditory brain-stem response (ABR) to complex sounds (cABR) – that appears to be particularly well-suited for predicting response to at least one form of cognitive remediation that targets auditory information processing. Uniquely, the cABR quantifies the fidelity of sound encoded at the level of the brainstem and midbrain. This ERP biomarker has revealed auditory processing abnormalities in various neurodevelopmental disorders, correlates with functioning across several cognitive domains, and appears to be responsive to targeted auditory training. We present preliminary cABR data from 18 schizophrenia patients and propose further investigation of this biomarker for predicting and tracking response to cognitive interventions. PMID:25352811

Altered metabolomic-genomic signature: A potential noninvasive biomarker of epilepsy.

PubMed

Wu, Helen C; Dachet, Fabien; Ghoddoussi, Farhad; Bagla, Shruti; Fuerst, Darren; Stanley, Jeffrey A; Galloway, Matthew P; Loeb, Jeffrey A

2017-09-01

This study aimed to identify noninvasive biomarkers of human epilepsy that can reliably detect and localize epileptic brain regions. Having noninvasive biomarkers would greatly enhance patient diagnosis, patient monitoring, and novel therapy development. At the present time, only surgically invasive, direct brain recordings are capable of detecting these regions with precision, which severely limits the pace and scope of both clinical management and research progress in epilepsy. We compared high versus low or nonspiking regions in nine medically intractable epilepsy surgery patients by performing integrated metabolomic-genomic-histological analyses of electrically mapped human cortical regions using high-resolution magic angle spinning proton magnetic resonance spectroscopy, cDNA microarrays, and histological analysis. We found a highly consistent and predictive metabolite logistic regression model with reduced lactate and increased creatine plus phosphocreatine and choline, suggestive of a chronically altered metabolic state in epileptic brain regions. Linking gene expression, cellular, and histological differences to these key metabolites using a hierarchical clustering approach predicted altered metabolic vascular coupling in the affected regions. Consistently, these predictions were validated histologically, showing both neovascularization and newly discovered, millimeter-sized microlesions. Using a systems biology approach on electrically mapped human cortex provides new evidence for spatially segregated, metabolic derangements in both neurovascular and synaptic architecture in human epileptic brain regions that could be a noninvasively detectable biomarker of epilepsy. These findings both highlight the immense power of a systems biology approach and identify a potentially important role that magnetic resonance spectroscopy can play in the research and clinical management of epilepsy. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Application of comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry method to identify potential biomarkers of perinatal asphyxia in a non-human primate model.

PubMed

Beckstrom, Andrew C; Humston, Elizabeth M; Snyder, Laura R; Synovec, Robert E; Juul, Sandra E

2011-04-08

Perinatal asphyxia is a leading cause of brain injury in infants, occurring in 2-4 per 1000 live births. The clinical response to asphyxia is variable and difficult to predict with current diagnostic tests. Reliable biomarkers are needed to help predict the timing and severity of asphyxia, as well as response to treatment. Two-dimensional gas chromatography-time-of-flight-mass spectrometry (GC×GC-TOFMS) was used herein, in conjunction with chemometric data analysis approaches for metabolomic analysis in order to identify significant metabolites affected by birth asphyxia. Blood was drawn before and after 15 or 18 min of cord occlusion in a Macaca nemestrina model of perinatal asphyxia. Postnatal samples were drawn at 5 min of age (n=20 subjects). Metabolomic profiles of asphyxiated animals were compared to four controls delivered at comparable gestational age. Fifty metabolites with the greatest change pre- to post-asphyxia were identified and quantified. The metabolic profile of post-asphyxia samples showed marked variability compared to the pre-asphyxia samples. Fifteen of the 50 metabolites showed significant elevation in response to asphyxia, ten of which remained significant upon comparison to the control animals. This metabolomic analysis confirmed lactate and creatinine as markers of asphyxia and discovered new metabolites including succinic acid and malate (intermediates in the Krebs cycle) and arachidonic acid (a brain fatty acid and inflammatory marker) as potential biomarkers. GC×GC-TOFMS coupled with chemometric data analysis are useful tools to identify acute biomarkers of brain injury. Further study is needed to correlate these metabolites with severity of disease, and response to treatment. Copyright © 2011 Elsevier B.V. All rights reserved.

Application of Comprehensive Two-Dimensional Gas Chromatography with Time-of-Flight Mass Spectrometry Method to Identify Potential Biomarkers of Perinatal Asphyxia in a Non-human Primate Model

PubMed Central

Beckstrom, Andrew C.; Humston, Elizabeth M.; Snyder, Laura R.; Synovec, Robert E.; Juul, Sandra E.

2011-01-01

Perinatal asphyxia is a leading cause of brain injury in infants, occurring in 2–4 per 1000 live births. The clinical response to asphyxia is variable and difficult to predict with current diagnostic tests. Reliable biomarkers are needed to help predict the timing and severity of asphyxia, as well as response to treatment. Two-dimensional gas chromatography-time-of-flight-mass spectrometry (GC x GC-TOFMS) was used herein, in conjunction with chemometric data analysis approaches for metabolomic analysis in order to identify significant metabolites affected by birth asphyxia. Blood was drawn before and after 15 or 18 minutes of cord occlusion in a Macaca nemestrina model of perinatal asphyxia. Postnatal samples were drawn at 5 minutes of age (n=20 subjects). Metabolomic profiles of asphyxiated animals were compared to four controls delivered at comparable gestational age. Fifty metabolites with the greatest change pre- to post-asphyxia were identified and quantified. The metabolic profile of post-asphyxia samples showed marked variability compared to the pre-asphyxia samples. Fifteen of the 50 metabolites showed significant elevation in response to asphyxia, ten of which remained significant upon comparison to the control animals. This metabolomic analysis confirmed lactate and creatinine as markers of asphyxia and discovered new metabolites including succinic acid and malate (intermediates in the Krebs cycle) and arachidonic acid (a brain fatty acid and inflammatory marker) as potential biomarkers. GC × GC-TOFMS coupled with chemometric data analysis are useful tools to identify acute biomarkers of brain injury. Further study is needed to correlate these metabolites with severity of disease, and response to treatment. PMID:21353677

Novel potential serological prostate cancer biomarkers using CT100+ cancer antigen microarray platform in a multi-cultural South African cohort

PubMed Central

Adeola, Henry A.; Smith, Muneerah; Kaestner, Lisa; Blackburn, Jonathan M.; Zerbini, Luiz F.

2016-01-01

There is a growing need for high throughput diagnostic tools for early diagnosis and treatment monitoring of prostate cancer (PCa) in Africa. The role of cancer-testis antigens (CTAs) in PCa in men of African descent is poorly researched. Hence, we aimed to elucidate the role of 123 Tumour Associated Antigens (TAAs) using antigen microarray platform in blood samples (N = 67) from a South African PCa, Benign prostatic hyperplasia (BPH) and disease control (DC) cohort. Linear (fold-over-cutoff) and differential expression quantitation of autoantibody signal intensities were performed. Molecular signatures of candidate PCa antigen biomarkers were identified and analyzed for ethnic group variation. Potential cancer diagnostic and immunotherapeutic inferences were drawn. We identified a total of 41 potential diagnostic/therapeutic antigen biomarkers for PCa. By linear quantitation, four antigens, GAGE1, ROPN1, SPANXA1 and PRKCZ were found to have higher autoantibody titres in PCa serum as compared with BPH where MAGEB1 and PRKCZ were highly expressed. Also, p53 S15A and p53 S46A were found highly expressed in the disease control group. Statistical analysis by differential expression revealed twenty-four antigens as upregulated in PCa samples, while 11 were downregulated in comparison to BPH and DC (FDR = 0.01). FGFR2, COL6A1and CALM1 were verifiable biomarkers of PCa analysis using urinary shotgun proteomics. Functional pathway annotation of identified biomarkers revealed similar enrichment both at genomic and proteomic level and ethnic variations were observed. Cancer antigen arrays are emerging useful in potential diagnostic and immunotherapeutic antigen biomarker discovery. PMID:26885621

Identification of miR-194-5p as a potential biomarker for postmenopausal osteoporosis

PubMed Central

Pan, Nanan; Sun, Ning; Wang, Qiujun; Fan, Jingxue; Zhou, Ping

2015-01-01

The incidence of osteoporosis is high in postmenopausal women due to altered estrogen levels and continuous calcium loss that occurs with aging. Recent studies have shown that microRNAs (miRNAs) are involved in the development of osteoporosis. These miRNAs may be used as potential biomarkers to identify women at a high risk for developing the disease. In this study, whole blood samples were collected from 48 postmenopausal Chinese women with osteopenia or osteoporosis and pooled into six groups according to individual T-scores. A miRNA microarray analysis was performed on pooled blood samples to identify potential miRNA biomarkers for postmenopausal osteoporosis. Five miRNAs (miR-130b-3p, -151a-3p, -151b, -194-5p, and -590-5p) were identified in the microarray analysis. These dysregulated miRNAs were subjected to a pathway analysis investigating whether they were involved in regulating osteoporosis-related pathways. Among them, only miR-194-5p was enriched in multiple osteoporosis-related pathways. Enhanced miR-194-5p expression in women with osteoporosis was confirmed by quantitative reverse transcription–polymerase chain reaction analysis. For external validation, a significant correlation between the expression of miR-194-5p and T-scores was found in an independent patient collection comprised of 24 postmenopausal women with normal bone mineral density, 30 postmenopausal women with osteopenia, and 32 postmenopausal women with osteoporosis (p < 0.05). Taken together, the present findings suggest that miR-194-5p may be a viable miRNA biomarker for postmenopausal osteoporosis. PMID:26038726

Identification of miR-194-5p as a potential biomarker for postmenopausal osteoporosis.

PubMed

Meng, Jia; Zhang, Dapeng; Pan, Nanan; Sun, Ning; Wang, Qiujun; Fan, Jingxue; Zhou, Ping; Zhu, Wenliang; Jiang, Lihong

2015-01-01

The incidence of osteoporosis is high in postmenopausal women due to altered estrogen levels and continuous calcium loss that occurs with aging. Recent studies have shown that microRNAs (miRNAs) are involved in the development of osteoporosis. These miRNAs may be used as potential biomarkers to identify women at a high risk for developing the disease. In this study, whole blood samples were collected from 48 postmenopausal Chinese women with osteopenia or osteoporosis and pooled into six groups according to individual T-scores. A miRNA microarray analysis was performed on pooled blood samples to identify potential miRNA biomarkers for postmenopausal osteoporosis. Five miRNAs (miR-130b-3p, -151a-3p, -151b, -194-5p, and -590-5p) were identified in the microarray analysis. These dysregulated miRNAs were subjected to a pathway analysis investigating whether they were involved in regulating osteoporosis-related pathways. Among them, only miR-194-5p was enriched in multiple osteoporosis-related pathways. Enhanced miR-194-5p expression in women with osteoporosis was confirmed by quantitative reverse transcription-polymerase chain reaction analysis. For external validation, a significant correlation between the expression of miR-194-5p and T-scores was found in an independent patient collection comprised of 24 postmenopausal women with normal bone mineral density, 30 postmenopausal women with osteopenia, and 32 postmenopausal women with osteoporosis (p < 0.05). Taken together, the present findings suggest that miR-194-5p may be a viable miRNA biomarker for postmenopausal osteoporosis.

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

Using the direct-injection model of early uveal melanoma hepatic metastasis to identify TPS as a potentially useful serum biomarker.

PubMed

Barak, Vivian; Frenkel, Shahar; Valyi-Nagy, Klara; Leach, Lu; Apushkin, Marsha A; Lin, Amy Y; Kalickman, Inna; Baumann, Nikola A; Pe'er, Jacob; Maniotis, Andrew J; Folberg, Robert

2007-10-01

To develop a method to screen for serum biomarkers of early hepatic metastasis from uveal melanoma. Cytokeratin 18 (TPS) was identified from gene expression profiles as protein generated by highly invasive uveal melanoma cells. Sera were collected from two groups of 15 SCID mice 2 weeks after injection of either tissue culture medium or MUM2B human metastatic uveal melanoma cells into the mouse liver. Serum TPS levels were assayed in 53 healthy human controls, 64 uveal melanoma patients who were disease free for at least 10 years, and 37 patients with metastatic uveal melanoma. After 2 weeks, small hepatic nodules (0.1-2.8 mm; mean, 0.80 mm) developed in 11 of 15 mice injected with MUM2B cells. Serum TPS levels in media-injected mice (84.7 U/L) were substantially lower than levels in MUM2B-injected mice (601 mug/L). TPS levels were significantly higher (P < 0.0001) in patients with metastatic uveal melanoma (139.63 +/- 22.20) than in healthy controls (54.23 +/- 0.01) or in patients free of disease (69.29 +/- 9.76). Significant differences were found between TPS levels before and after the development of hepatic metastases (P < 0.01), and serum TPS levels became elevated in four patients at least 6 months before the detection of hepatic metastases by abdominal ultrasonography. The direct-injection model of uveal melanoma in the mouse liver may be used to screen for potential serum biomarkers of metastatic uveal melanoma.

Novel Biomarkers of Abdominal Aortic Aneurysm Disease: Identifying Gaps and Dispelling Misperceptions

PubMed Central

Moris, Demetrios; Avgerinos, Efthymios; Makris, Marinos; Bakoyiannis, Chris; Pikoulis, Emmanuel; Georgopoulos, Sotirios

2014-01-01

Abdominal aortic aneurysm (AAA) is a prevalent and potentially life-threatening disease. Early detection by screening programs and subsequent surveillance has been shown to be effective at reducing the risk of mortality due to aneurysm rupture. The aim of this review is to summarize the developments in the literature concerning the latest biomarkers (from 2008 to date) and their potential screening and therapeutic values. Our search included human studies in English and found numerous novel biomarkers under research, which were categorized in 6 groups. Most of these studies are either experimental or hampered by their low numbers of patients. We concluded that currently no specific laboratory markers allow screeing for the disease and monitoring its progression or the results of treatment. Further studies and studies in larger patient groups are required in order to validate biomarkers as cost-effective tools in the AAA disease. PMID:24967416

Identification of urine protein biomarkers with the potential for early detection of lung cancer.

PubMed

Zhang, Hongjuan; Cao, Jing; Li, Lin; Liu, Yanbin; Zhao, Hong; Li, Nan; Li, Bo; Zhang, Aiqun; Huang, Huanwei; Chen, She; Dong, Mengqiu; Yu, Lei; Zhang, Jian; Chen, Liang

2015-07-02

Lung cancer is the leading cause of cancer-related deaths and has an overall 5-year survival rate lower than 15%. Large-scale clinical trials have demonstrated a significant relative reduction in mortality in high-risk individuals with low-dose computed tomography screening. However, biomarkers capable of identifying the most at-risk population and detecting lung cancer before it becomes clinically apparent are urgently needed in the clinic. Here, we report the identification of urine biomarkers capable of detecting lung cancer. Using the well-characterized inducible Kras (G12D) mouse model of lung cancer, we identified alterations in the urine proteome in tumor-bearing mice compared with sibling controls. Marked differences at the proteomic level were also detected between the urine of patients and that of healthy population controls. Importantly, we identified 7 proteins commonly found to be significantly up-regulated in both tumor-bearing mice and patients. In an independent cohort, we showed that 2 of the 7 proteins were up-regulated in urine samples from lung cancer patients but not in those from controls. The kinetics of these proteins correlated with the disease state in the mouse model. These tumor biomarkers could potentially aid in the early detection of lung cancer.

Large-scale Metabolomic Analysis Reveals Potential Biomarkers for Early Stage Coronary Atherosclerosis.

PubMed

Gao, Xueqin; Ke, Chaofu; Liu, Haixia; Liu, Wei; Li, Kang; Yu, Bo; Sun, Meng

2017-09-18

Coronary atherosclerosis (CAS) is the pathogenesis of coronary heart disease, which is a prevalent and chronic life-threatening disease. Initially, this disease is not always detected until a patient presents with seriously vascular occlusion. Therefore, new biomarkers for appropriate and timely diagnosis of early CAS is needed for screening to initiate therapy on time. In this study, we used an untargeted metabolomics approach to identify potential biomarkers that could enable highly sensitive and specific CAS detection. Score plots from partial least-squares discriminant analysis clearly separated early-stage CAS patients from controls. Meanwhile, the levels of 24 metabolites increased greatly and those of 18 metabolites decreased markedly in early CAS patients compared with the controls, which suggested significant metabolic dysfunction in phospholipid, sphingolipid, and fatty acid metabolism in the patients. Furthermore, binary logistic regression showed that nine metabolites could be used as a combinatorial biomarker to distinguish early-stage CAS patients from controls. The panel of nine metabolites was then tested with an independent cohort of samples, which also yielded satisfactory diagnostic accuracy (AUC = 0.890). In conclusion, our findings provide insight into the pathological mechanism of early-stage CAS and also supply a combinatorial biomarker to aid clinical diagnosis of early-stage CAS.

High-Throughput Sequencing of miRNAs Reveals a Tissue Signature in Gastric Cancer and Suggests Novel Potential Biomarkers

PubMed Central

Darnet, Sylvain; Moreira, Fabiano C; Hamoy, Igor G; Burbano, Rommel; Khayat, André; Cruz, Aline; Magalhães, Leandro; Silva, Artur; Santos, Sidney; Demachki, Samia; Assumpção, Monica; Assumpção, Paulo; Ribeiro-dos-Santos, Ândrea

2015-01-01

Gastric cancer has a high incidence and mortality rate worldwide; however, the use of biomarkers for its clinical diagnosis remains limited. The microRNAs (miRNAs) are biomarkers with the potential to identify the risk and prognosis as well as therapeutic targets. We performed the ultradeep miRnomes sequencing of gastric adenocarcinoma and gastric antrum without tumor samples. We observed that a small set of those samples were responsible for approximately 80% of the total miRNAs expression, which might represent a miRNA tissue signature. Additionally, we identified seven miRNAs exhibiting significant differences, and, of these, hsa-miR-135b and hsa-miR-29c were able to discriminate antrum without tumor from gastric cancer regardless of the histological type. These findings were validated by quantitative real-time polymerase chain reaction. The results revealed that hsa-miR-135b and hsa-miR-29c are potential gastric adenocarcinoma occurrence biomarkers with the ability to identify individuals at a higher risk of developing this cancer, and could even be used as therapeutic targets to allow individualized clinical management. PMID:26157332

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

Harnessing pain heterogeneity and RNA transcriptome to identify blood–based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model

PubMed Central

Grace, Peter M.; Hurley, Daniel; Barratt, Daniel T.; Tsykin, Anna; Watkins, Linda R.; Rolan, Paul E.; Hutchinson, Mark R.

2017-01-01

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables. PMID:22697386

Use of biomarkers to establish potential role and function of circulating microRNAs in acute heart failure.

PubMed

Vegter, Eline L; Schmitter, Daniela; Hagemeijer, Yanick; Ovchinnikova, Ekaterina S; van der Harst, Pim; Teerlink, John R; O'Connor, Christopher M; Metra, Marco; Davison, Beth A; Bloomfield, Daniel; Cotter, Gad; Cleland, John G; Givertz, Michael M; Ponikowski, Piotr; van Veldhuisen, Dirk J; van der Meer, Peter; Berezikov, Eugene; Voors, Adriaan A; Khan, Mohsin A F

2016-12-01

Circulating microRNAs (miRNAs) emerge as potential heart failure biomarkers. We aimed to identify associations between acute heart failure (AHF)-specific circulating miRNAs and well-known heart failure biomarkers. Associations between 16 biomarkers predictive for 180day mortality and the levels of 12 AHF-specific miRNAs were determined in 100 hospitalized AHF patients, at baseline and 48hours. Patients were divided in 4 pre-defined groups, based on clinical parameters during hospitalization. Correlation analyses between miRNAs and biomarkers were performed and complemented by miRNA target prediction and pathway analysis. No significant correlations were found at hospital admission. However, after 48hours, 7 miRNAs were significantly negatively correlated to biomarkers indicative for a worse clinical outcome in the patient group with the most unfavorable in-hospital course (n=21); miR-16-5p was correlated to C-reactive protein (R=-0.66, p-value=0.0027), miR-106a-5p to creatinine (R=-0.68, p-value=0.002), miR-223-3p to growth differentiation factor 15 (R=-0.69, p-value=0.0015), miR-652-3p to soluble ST-2 (R=-0.77, p-value<0.001), miR-199a-3p to procalcitonin (R=-0.72, p-value<0.001) and galectin-3 (R=-0.73, p-value<0.001) and miR-18a-5p to procalcitonin (R=-0.68, p-value=0.002). MiRNA target prediction and pathway analysis identified several pathways related to cardiac diseases, which could be linked to some of the miRNA-biomarker correlations. The majority of correlations between circulating AHF-specific miRNAs were related to biomarkers predictive for a worse clinical outcome in a subgroup of worsening heart failure patients at 48hours of hospitalization. The selective findings suggest a time-dependent effect of circulating miRNAs and highlight the susceptibility to individual patient characteristics influencing potential relations between miRNAs and biomarkers. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. 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.

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

A novel workflow combining plaque imaging, plaque and plasma proteomics identifies biomarkers of human coronary atherosclerotic plaque disruption.

PubMed

Lee, Regent; Fischer, Roman; Charles, Philip D; Adlam, David; Valli, Alessandro; Di Gleria, Katalin; Kharbanda, Rajesh K; Choudhury, Robin P; Antoniades, Charalambos; Kessler, Benedikt M; Channon, Keith M

2017-01-01

Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation. We developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption. We compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC-MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption. This novel approach for biomarker

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

Top-Down Quantitative Proteomics Identified Phosphorylation of Cardiac Troponin I as a Candidate Biomarker for Chronic Heart Failure

PubMed Central

Zhang, Jiang; Guy, Moltu J.; Norman, Holly S.; Chen, Yi-Chen; Xu, Qingge; Dong, Xintong; Guner, Huseyin; Wang, Sijian; Kohmoto, Takushi; Young, Ken H.; Moss, Richard L.; Ge, Ying

2011-01-01

The rapid increase in the prevalence of chronic heart failure (CHF) worldwide underscores an urgent need to identify biomarkers for the early detection of CHF. Post-translational modifications (PTMs) are associated with many critical signaling events during disease progression and thus offer a plethora of candidate biomarkers. We have employed top-down quantitative proteomics methodology for comprehensive assessment of PTMs in whole proteins extracted from normal and diseased tissues. We have systematically analyzed thirty-six clinical human heart tissue samples and identified phosphorylation of cardiac troponin I (cTnI) as a candidate biomarker for CHF. The relative percentages of the total phosphorylated cTnI forms over the entire cTnI populations (%Ptotal) were 56.4±3.5%, 36.9±1.6%, 6.1±2.4%, and 1.0±0.6% for postmortem hearts with normal cardiac function (n=7), early-stage of mild hypertrophy (n=5), severe hypertrophy/dilation (n=4), and end-stage CHF (n=6), respectively. In fresh transplant samples, the %Ptotal of cTnI from non-failing donor (n=4), and end-stage failing hearts (n=10) were 49.5±5.9% and 18.8±2.9%, respectively. Top-down MS with electron capture dissociation unequivocally localized the altered phosphorylation sites to Ser22/23 and determined the order of phosphorylation/dephosphorylation. This study represents the first clinical application of top-down MS-based quantitative proteomics for biomarker discovery from tissues, highlighting the potential of PTM as disease biomarkers. PMID:21751783

Harnessing pain heterogeneity and RNA transcriptome to identify blood-based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model.

PubMed

Grace, Peter M; Hurley, Daniel; Barratt, Daniel T; Tsykin, Anna; Watkins, Linda R; Rolan, Paul E; Hutchinson, Mark R

2012-09-01

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Potential Biomarkers and Their Applications for Rapid and Reliable Detection of Malaria

PubMed Central

Jain, Priyamvada; Chakma, Babina; Patra, Sanjukta; Goswami, Pranab

2014-01-01

Malaria has been responsible for the highest mortality in most malaria endemic countries. Even after decades of malaria control campaigns, it still persists as a disease of high mortality due to improper diagnosis and rapidly evolving drug resistant malarial parasites. For efficient and economical malaria management, WHO recommends that all malaria suspected patients should receive proper diagnosis before administering drugs. It is thus imperative to develop fast, economical, and accurate techniques for diagnosis of malaria. In this regard an in-depth knowledge on malaria biomarkers is important to identify an appropriate biorecognition element and utilize it prudently to develop a reliable detection technique for diagnosis of the disease. Among the various biomarkers, plasmodial lactate dehydrogenase and histidine-rich protein II (HRP II) have received increasing attention for developing rapid and reliable detection techniques for malaria. The widely used rapid detection tests (RDTs) for malaria succumb to many drawbacks which promotes exploration of more efficient economical detection techniques. This paper provides an overview on the current status of malaria biomarkers, along with their potential utilization for developing different malaria diagnostic techniques and advanced biosensors. PMID:24804253

Prognostic and predictive potential molecular biomarkers in colon cancer.

PubMed

Nastase, A; Pâslaru, L; Niculescu, A M; Ionescu, M; Dumitraşcu, T; Herlea, V; Dima, S; Gheorghe, C; Lazar, V; Popescu, I

2011-01-01

An important objective in nowadays research is the discovery of new biomarkers that can detect colon tumours in early stages and indicate with accuracy the status of the disease. The aim of our study was to identify potential biomarkers for colon cancer onset and progression. We assessed gene expression profiles of a list of 10 candidate genes (MMP-1, MMP-3, MMP-7, DEFA 1, DEFA-5, DEFA-6, IL-8, CXCL-1, SPP-1, CTHRC-1) by quantitative real time PCR in triplets of colonic mucosa (normal, adenoma, tumoral tissue) collected from the same patient during surgery for a group of 20 patients. Additionally we performed immunohistochemistry for DEFA1-3 and SPP1. We remarked that DEFA5 and DEFA6 are key factors in adenoma formation (p<0.05). MMP7 is important in the transition from a benign to a malignant status (p <0.01) and further in metastasis being a prognostic indicator for tumor transformation and for the metastatic potential of cancer cells. IL8, irrespective of tumor stage, has a high mRNA level in adenocarcinoma (p< 0.05). The level of expression for SPP1 is correlated with tumor level. We suggest that high levels of DEFAS, DEFA6 (key elements in adenoma formation), MMP7 (marker of colon cancer onset and progression to metastasis), SPP1 (marker of progression) and IL8 could be used to diagnose an early stage colon cancer and to evaluate the prognostic of progression for colon tumors. Further, if DEFA5 and DEFA6 level of expression are low but MMP7, SPP1 and IL8 level are high we could point out that the transition from adenoma to adenocarcinoma had already occurred. Thus, DEFA5, DEFA6, MMP7, IL8 and SPP1 consist in a valuable panel of biomarkers, whose detection can be used in early detection and progressive disease and also in prognostic of colon cancer.

Coronin-1C is a novel biomarker for hepatocellular carcinoma invasive progression identified by proteomics analysis and clinical validation

PubMed Central

2010-01-01

Background To better search for potential markers for hepatocellular carcinoma (HCC) invasion and metastasis, proteomic approach was applied to identify potential metastasis biomarkers associated with HCC. Methods Membrane proteins were extracted from MHCC97L and HCCLM9 cells, with a similar genetic background and remarkably different metastasis potential, and compared by SDS-PAGE and identified by ESI-MS/MS. The results were further validated by western blot analysis, immunohistochemistry (IHC) of tumor tissues from HCCLM9- and MHCC97L-nude mice, and clinical specimens. Results Membrane proteins were extracted from MHCC97L and HCCLM9 cell and compared by SDS-PAGE analyses. A total of 14 differentially expressed proteins were identified by ESI-MS/MS. Coronin-1C, a promising candidate, was found to be overexpressed in HCCLM9 cells as compared with MHCC97L cells, and validated by western blot and IHC from both nude mice tumor tissues and clinical specimens. Coronin-1C level showed an abrupt upsurge when pulmonary metastasis occurred. Increasing coronin-1C expression was found in liver cancer tissues of HCCLM9-nude mice with spontaneous pulmonary metastasis. IHC study on human HCC specimens revealed that more patients in the higher coronin-1C group had overt larger tumor and more advanced stage. Conclusions Coronin-1C could be a candidate biomarker to predict HCC invasive behavior. PMID:20181269

Coronin-1C is a novel biomarker for hepatocellular carcinoma invasive progression identified by proteomics analysis and clinical validation.

PubMed

Wu, Long; Peng, Chun-Wei; Hou, Jin-Xuan; Zhang, Yan-Hua; Chen, Chuang; Chen, Liang-Dong; Li, Yan

2010-02-24

To better search for potential markers for hepatocellular carcinoma (HCC) invasion and metastasis, proteomic approach was applied to identify potential metastasis biomarkers associated with HCC. Membrane proteins were extracted from MHCC97L and HCCLM9 cells, with a similar genetic background and remarkably different metastasis potential, and compared by SDS-PAGE and identified by ESI-MS/MS. The results were further validated by western blot analysis, immunohistochemistry (IHC) of tumor tissues from HCCLM9- and MHCC97L-nude mice, and clinical specimens. Membrane proteins were extracted from MHCC97L and HCCLM9 cell and compared by SDS-PAGE analyses. A total of 14 differentially expressed proteins were identified by ESI-MS/MS. Coronin-1C, a promising candidate, was found to be overexpressed in HCCLM9 cells as compared with MHCC97L cells, and validated by western blot and IHC from both nude mice tumor tissues and clinical specimens. Coronin-1C level showed an abrupt upsurge when pulmonary metastasis occurred. Increasing coronin-1C expression was found in liver cancer tissues of HCCLM9-nude mice with spontaneous pulmonary metastasis. IHC study on human HCC specimens revealed that more patients in the higher coronin-1C group had overt larger tumor and more advanced stage. Coronin-1C could be a candidate biomarker to predict HCC invasive behavior.

Extracellular vesicle long noncoding RNA as potential biomarkers of liver cancer

PubMed Central

Mohankumar, Swathi

2016-01-01

Analysis of extracellular vesicles (EV) and their contents may be useful as disease biomarkers if they reflect the contents of cells of origin, differ between normal and diseased tissue and can be reliably detected. An increasing number of long noncoding RNA (lncRNA) are being reported to be aberrantly expressed in human cancers. These tumor-associated lncRNA may have potential as new biomarkers of disease. In this review, we highlight lncRNAs that are commonly associated with hepatocellular cancer, and summarize their potential biological roles and underlying molecular mechanisms. While lncRNA can be detected in the circulation, their low expression within circulating vesicles will require the use of highly sensitive detection technologies such as digital polymerase chain reaction or next-generation sequencing. While the integrity and functional role of tumor-specific lncRNAs within EV have yet to be established, their presence or enrichment within tumor cell-derived EV offers promise for their potential as disease biomarkers. PMID:26634812

High density lipoproteins: Measurement techniques and potential biomarkers of cardiovascular risk

PubMed Central

Hafiane, Anouar; Genest, Jacques

2015-01-01

Plasma high density lipoprotein cholesterol (HDL) comprises a heterogeneous family of lipoprotein species, differing in surface charge, size and lipid and protein compositions. While HDL cholesterol (C) mass is a strong, graded and coherent biomarker of cardiovascular risk, genetic and clinical trial data suggest that the simple measurement of HDL-C may not be causal in preventing atherosclerosis nor reflect HDL functionality. Indeed, the measurement of HDL-C may be a biomarker of cardiovascular health. To assess the issue of HDL function as a potential therapeutic target, robust and simple analytical methods are required. The complex pleiotropic effects of HDL make the development of a single measurement challenging. Development of laboratory assays that accurately HDL function must be developed validated and brought to high-throughput for clinical purposes. This review discusses the limitations of current laboratory technologies for methods that separate and quantify HDL and potential application to predict CVD, with an emphasis on emergent approaches as potential biomarkers in clinical practice. PMID:26674734

Biomarkers of Acute Respiratory Allergen Exposure: Screening For Sensitization Potential

EPA Science Inventory

Rationale: An in vitro assay to identify respiratory sensitizers will provide a rapid screen and reduce animal use. The study goal was to identify biomarkers that differentiate allergen versus non-allergen responses following an acute exposure. Methods: Female BALB/c mice rec...

Biomarkers of response and resistance to antiangiogenic therapy

PubMed Central

Jain, Rakesh K.; Duda, Dan G.; Willett, Christopher G.; Sahani, Dushyant V.; Zhu, Andrew X.; Loeffler, Jay S.; Batchelor, Tracy T.; Sorensen, A. Gregory

2011-01-01

No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I–III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured Ktrans, circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1α, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy. PMID:19483739

Discovery of potential protein biomarkers of lung adenocarcinoma in bronchoalveolar lavage fluid by SWATH MS data-independent acquisition and targeted data extraction.

PubMed

Ortea, I; Rodríguez-Ariza, A; Chicano-Gálvez, E; Arenas Vacas, M S; Jurado Gámez, B

2016-04-14

Lung cancer currently ranks as the neoplasia with the highest global mortality rate. Although some improvements have been introduced in recent years, new advances in diagnosis are required in order to increase survival rates. New mildly invasive endoscopy-based diagnostic techniques include the collection of bronchoalveolar lavage fluid (BALF), which is discarded after using a portion of the fluid for standard pathological procedures. BALF proteomic analysis can contribute to clinical practice with more sensitive biomarkers, and can complement cytohistological studies by aiding in the diagnosis, prognosis, and subtyping of lung cancer, as well as the monitoring of treatment response. The range of quantitative proteomics methodologies used for biomarker discovery is currently being broadened with the introduction of data-independent acquisition (DIA) analysis-related approaches that address the massive quantitation of the components of a proteome. Here we report for the first time a DIA-based quantitative proteomics study using BALF as the source for the discovery of potential lung cancer biomarkers. The results have been encouraging in terms of the number of identified and quantified proteins. A panel of candidate protein biomarkers for adenocarcinoma in BALF is reported; this points to the activation of the complement network as being strongly over-represented and suggests this pathway as a potential target for lung cancer research. In addition, the results reported for haptoglobin, complement C4-A, and glutathione S-transferase pi are consistent with previous studies, which indicates that these proteins deserve further consideration as potential lung cancer biomarkers in BALF. Our study demonstrates that the analysis of BALF proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS), combining a simple sample pre-treatment and SWATH DIA MS, is a useful method for the discovery of potential lung cancer biomarkers. Bronchoalveolar lavage fluid (BALF

Computational Gene Expression Modeling Identifies Salivary Biomarker Analysis that Predict Oral Feeding Readiness in the Newborn

PubMed Central

Maron, Jill L.; Hwang, Jooyeon S.; Pathak, Subash; Ruthazer, Robin; Russell, Ruby L.; Alterovitz, Gil

2014-01-01

Objective To combine mathematical modeling of salivary gene expression microarray data and systems biology annotation with RT-qPCR amplification to identify (phase I) and validate (phase II) salivary biomarker analysis for the prediction of oral feeding readiness in preterm infants. Study design Comparative whole transcriptome microarray analysis from 12 preterm newborns pre- and post-oral feeding success was used for computational modeling and systems biology analysis to identify potential salivary transcripts associated with oral feeding success (phase I). Selected gene expression biomarkers (15 from computational modeling; 6 evidence-based; and 3 reference) were evaluated by RT-qPCR amplification on 400 salivary samples from successful (n=200) and unsuccessful (n=200) oral feeders (phase II). Genes, alone and in combination, were evaluated by a multivariate analysis controlling for sex and post-conceptional age (PCA) to determine the probability that newborns achieved successful oral feeding. Results Advancing post-conceptional age (p < 0.001) and female sex (p = 0.05) positively predicted an infant’s ability to feed orally. A combination of five genes, NPY2R (hunger signaling), AMPK (energy homeostasis), PLXNA1 (olfactory neurogenesis), NPHP4 (visual behavior) and WNT3 (facial development), in addition to PCA and sex, demonstrated good accuracy for determining feeding success (AUROC = 0.78). Conclusions We have identified objective and biologically relevant salivary biomarkers that noninvasively assess a newborn’s developing brain, sensory and facial development as they relate to oral feeding success. Understanding the mechanisms that underlie the development of oral feeding readiness through translational and computational methods may improve clinical decision making while decreasing morbidities and health care costs. PMID:25620512

[Cellular microparticles, potential useful biomarkers in the identification of cerebrovascular accidents].

PubMed

Anglés-Cano, Eduardo; Vivien, Denis

2009-10-01

The clinical utility of biomarkers depends on their ability to identify high-risk individuals in order to establish preventive, diagnostic or therapeutic measures. Currently, no practical, rapid and sensitive test is available for the diagnosis of acute ischemic stroke. A number of soluble molecules have been identified that are merely associated to these cerebrovascular accidents. Despite this association not a single molecule has the characteristics of a true biomarker directly involved in the pathophysiology of ischemic stroke-none of them is organ-specific and may therefore be elevated in the context of medical comorbidities. When explored as a combination of biomarkers, e.g. matrix metalloproteinase 9, brain natriuretic protein, D-dimer, protein S100B, the question still remains whether serial biomarker analysis provides additional prognostic information. Even S100B, a glial activation protein, has a low specificity for acute ischemic stroke because it may originate from extracranial sources. Current knowledge from the field of cell-derived microparticles suggests that these membrane fragments may represent reliable biomarkers as they are cell-specific and are released early in the pathophysiological cascade of a disease. These microparticles can be found not only in the cerebrospinal fluid but also in tears and circulating blood in case of blood-brain barrier dysfunction. They represent a new challenge in stroke diagnosis and management.

SELDI-TOF-MS ProteinChip array profiling of T-cell clones propagated in long-term culture identifies human profilin-1 as a potential bio-marker of immunosenescence.

PubMed

Mazzatti, Dawn J; Pawelec, Graham; Longdin, Robin; Powell, Jonathan R; Forsey, Rosalyn J

2007-06-05

The adaptive immune response requires waves of T-cell clonal expansion on contact with pathogen and elimination after clearance of the source of antigen. However, lifelong persistent infections with common viruses cause chronic antigenic stimulation which takes its toll on adaptive immunity in late life. Chronic antigenic stress results in deregulation of the T-cell response and accumulation of anergic cells. Longitudinal studies of the elderly show that this impacts on survival. Identifying the nature of the defects in chronically-stimulated T-cells and protein bio-markers of these dysfunctional cells would help to understand age-associated compromised T-cell function (immunosenescence) and facilitate the development of targeted intervention strategies.The purpose of this work was to use surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to analyse proteins associated with T-cell senescence in order to identify potential bio-markers. Clonal populations of T-cells isolated from elderly octogenarian and centenarian donors were grown in vitro until senescence, and early passage and late passage (pre-senescent) cells were analysed using SELDI-TOF-MS ProteinChip arrays. Discriminant analysis identified several protein or peptide peaks in the region of 14.5-16.5 kDa that were associated with T-cell clone senescence. Human profilin-1, a ubiquitous protein associated with actin remodelling and cellular motility was unambiguously identified. Altered expression of profilin-1 in senescent T-cell clones was confirmed by Western blot analysis. Due to the proposed roles of profilin-1 in cellular survival, cytoskeleton remodelling, motility, and proliferation, it is hypothesised that differential expression of profilin-1 in ageing may contribute directly to immunosenescence.

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.

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.

Proteomic biomarkers for ovarian cancer risk in women with polycystic ovary syndrome: a systematic review and biomarker database integration.

PubMed

Galazis, Nicolas; Olaleye, Olalekan; Haoula, Zeina; Layfield, Robert; Atiomo, William

2012-12-01

To review and identify possible biomarkers for ovarian cancer (OC) in women with polycystic ovary syndrome (PCOS). Systematic literature searches of MEDLINE, EMBASE, and Cochrane using the search terms "proteomics," "proteomic," and "ovarian cancer" or "ovarian carcinoma." Proteomic biomarkers for OC were then integrated with an updated previously published database of all proteomic biomarkers identified to date in patients with PCOS. Academic department of obstetrics and gynecology in the United Kingdom. A total of 180 women identified in the six studies. Tissue samples from women with OC vs. tissue samples from women without OC. Proteomic biomarkers, proteomic technique used, and methodologic quality score. A panel of six biomarkers was overexpressed both in women with OC and in women with PCOS. These biomarkers include calreticulin, fibrinogen-γ, superoxide dismutase, vimentin, malate dehydrogenase, and lamin B2. These biomarkers could help improve our understanding of the links between PCOS and OC and could potentially be used to identify subgroups of women with PCOS at increased risk of OC. More studies are required to further evaluate the role these biomarkers play in women with PCOS and OC. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Exosomal microRNAs as potential circulating biomarkers in gastrointestinal tract cancers: a systematic review protocol.

PubMed

Gheytanchi, Elmira; Madjd, Zahra; Janani, Leila; Rasti, Arezoo; Ghods, Roya; Atyabi, Fatemeh; Asadi-Lari, Mohammad Hossein; Babashah, Sadegh

2017-11-17

Metastasis is the most frequent type of recurrence in gastrointestinal (GI) cancers, and there is an emerging potential for new diagnostic and therapeutic approaches, especially in the cases of metastatic GI carcinomas. The expression profiles of circulating exosomal microRNAs are of particular interest as novel non-invasive diagnostic and prognostic biomarkers for improved detection of GI cancers in body fluids, especially in the serum of patients with recurrent cancers. The aim of this study is to systematically review primary studies and identify the miRNA profiles of serum exosomes of GI cancers. This systematic review will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidance. Relevant studies will be identified through a comprehensive search of the following main electronic databases: PubMed, Web of Science, Embase, Scopus, and Google Scholar, with no language restrictions (up to July 2017). Full copies of articles will be identified by a defined search strategy and will be considered for inclusion against pre-defined criteria. The quality assessment of the included studies will be performed by the Newcastle-Ottawa Scale (NOS). Data will be analyzed using Stata software V.12. Publication bias will be assessed by funnel plots, Beggs' and Eggers' tests. The levels of evidence for primary outcomes will be evaluated using the GRADE criteria. The analysis of circulating exosomal miRNA profiles provides attractive screening and non-invasive diagnostic tools for the majority of solid tumors including GI cancers. There is limited information regarding the relationship between serum exosomal miRNA profiles and the pathological condition of patients with different GI cancers. Since there is no specific biomarker for GI cancers, we aim to suggest a number of circulating exosomal miRNA candidates as potential multifaceted GI cancer biomarkers for clinical utility. PROSPERO CRD42017057129.

Mammalian plasma membrane proteins as potential biomarkers and drug targets.

PubMed

Rucevic, Marijana; Hixson, Douglas; Josic, Djuro

2011-06-01

Defining the plasma membrane proteome is crucial to understand the role of plasma membrane in fundamental biological processes. Change in membrane proteins is one of the first events that take place under pathological conditions, making plasma membrane proteins a likely source of potential disease biomarkers with prognostic or diagnostic potential. Membrane proteins are also potential targets for monoclonal antibodies and other drugs that block receptors or inhibit enzymes essential to the disease progress. Despite several advanced methods recently developed for the analysis of hydrophobic proteins and proteins with posttranslational modifications, integral membrane proteins are still under-represented in plasma membrane proteome. Recent advances in proteomic investigation of plasma membrane proteins, defining their roles as diagnostic and prognostic disease biomarkers and as target molecules in disease treatment, are presented. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sparse Feature Selection Identifies H2A.Z as a Novel, Pattern-Specific Biomarker for Asymmetrically Self-Renewing Distributed Stem Cells

PubMed Central

Huh, Yang Hoon; Noh, Minsoo; Burden, Frank R.; Chen, Jennifer C.; Winkler, David A.; Sherley, James L.

2015-01-01

There is a long-standing unmet clinical need for biomarkers with high specificity for distributed stem cells (DSCs) in tissues, or for use in diagnostic and therapeutic cell preparations (e.g., bone marrow). Although DSCs are essential for tissue maintenance and repair, accurate determination of their numbers for medical applications has been problematic. Previous searches for biomarkers expressed specifically in DSCs were hampered by difficulty obtaining pure DSCs and by the challenges in mining complex molecular expression data. To identify DSC such useful and specific biomarkers, we combined a novel sparse feature selection method with combinatorial molecular expression data focused on asymmetric self-renewal, a conspicuous property of DSCs. The analysis identified reduced expression of the histone H2A variant H2A.Z as a superior molecular discriminator for DSC asymmetric self-renewal. Subsequent molecular expression studies showed H2A.Z to be a novel “pattern-specific biomarker” for asymmetrically self-renewing cells with sufficient specificity to count asymmetrically self-renewing DSCs in vitro and potentially in situ. PMID:25636161

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.

Metabolomic biomarkers of impaired glucose tolerance and type 2 diabetes mellitus with a potential for risk stratification in women with polycystic ovary syndrome.

PubMed

Galazis, Nicolas; Iacovou, Christos; Haoula, Zeina; Atiomo, William

2012-02-01

There is a need to identify biomarkers of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) risk in women with PCOS to facilitate screening and the development of novel strategies to prevent disease progression. Metabolomic technologies may address this need. All published studies on metabolomic biomarkers of IGT and/or T2DM identified through MEDLINE (1966-December 2010), EMBASE (1980-December 2010) and Cochrane (1993-December 2010) were retrieved. Eligible studies were screened and specific study characteristics recorded including study design, number of participants, selection criteria, type of metabolomic technique used, site of sample collection, and a list of metabolites identified to have been altered in IGT and/or T2DM versus healthy controls was created. Nine metabolomic biomarkers that could potentially be used to identify women with PCOS at risk of developing IGT and/or T2DM were identified including leucine, isoleucine, citrate, glucose, creatinine, valine, glutamine, alanine and HDL. Of these biomarkers, a panel of four biomarkers were consistently either elevated or reduced including glucose (elevated), valine (reduced), HDL (reduced) and alanine (reduced) in IGT/T2DM compared with controls. These biomarkers may predict the development of IGT/T2DM in young women with PCOS. More studies are required to test this hypothesis and translate the findings into patient benefit by reducing the morbidity/mortality associated with IGT/T2DM in PCOS. Copyright © 2011 Elsevier Ireland Ltd. 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.

Risk Factors and Biomarkers of Age-Related Macular Degeneration

PubMed Central

Lambert, Nathan G.; Singh, Malkit K.; ElShelmani, Hanan; Mansergh, Fiona C.; Wride, Michael A.; Padilla, Maximilian; Keegan, David; Hogg, Ruth E.; Ambati, Balamurali K.

2016-01-01

A biomarker can be a substance or structure measured in body parts, fluids or products that can affect or predict disease incidence. As age-related macular degeneration (AMD) is the leading cause of blindness in the developed world, much research and effort has been invested in the identification of different biomarkers to predict disease incidence, identify at risk individuals, elucidate causative pathophysiological etiologies, guide screening, monitoring and treatment parameters, and predict disease outcomes. To date, a host of genetic, environmental, proteomic, and cellular targets have been identified as both risk factors and potential biomarkers for AMD. Despite this, their use has been confined to research settings and has not yet crossed into the clinical arena. A greater understanding of these factors and their use as potential biomarkers for AMD can guide future research and clinical practice. This article will discuss known risk factors and novel, potential biomarkers of AMD in addition to their application in both academic and clinical settings. PMID:27156982

Identification of miRNA-103 in the Cellular Fraction of Human Peripheral Blood as a Potential Biomarker for Malignant Mesothelioma – A Pilot Study

PubMed Central

Weber, Daniel G.; Johnen, Georg; Bryk, Oleksandr; Jöckel, Karl-Heinz; Brüning, Thomas

2012-01-01

Background To date, no biomarkers with reasonable sensitivity and specificity for the early detection of malignant mesothelioma have been described. The use of microRNAs (miRNAs) as minimally-invasive biomarkers has opened new opportunities for the diagnosis of cancer, primarily because they exhibit tumor-specific expression profiles and have been commonly observed in blood of both cancer patients and healthy controls. The aim of this pilot study was to identify miRNAs in the cellular fraction of human peripheral blood as potential novel biomarkers for the detection of malignant mesothelioma. Methodology/Principal Findings Using oligonucleotide microarrays for biomarker identification the miRNA levels in the cellular fraction of human peripheral blood of mesothelioma patients and asbestos-exposed controls were analyzed. Using a threefold expression change in combination with a significance level of p<0.05, miR-103 was identified as a potential biomarker for malignant mesothelioma. Quantitative real-time PCR (qRT-PCR) was used for validation of miR-103 in 23 malignant mesothelioma patients, 17 asbestos-exposed controls, and 25 controls from the general population. For discrimination of mesothelioma patients from asbestos-exposed controls a sensitivity of 83% and a specificity of 71% were calculated, and for discrimination of mesothelioma patients from the general population a sensitivity of 78% and a specificity of 76%. Conclusions/Significance The results of this pilot study show that miR-103 is characterized by a promising sensitivity and specificity and might be a potential minimally-invasive biomarker for the diagnosis of mesothelioma. In addition, our results support the concept of using the cellular fraction of human blood for biomarker discovery. However, for early detection of malignant mesothelioma the feasibility of miR-103 alone or in combination with other biomarkers needs to be analyzed in a prospective study. PMID:22253921

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

Metabolomics Coupled with Multivariate Data and Pathway Analysis on Potential Biomarkers in Gastric Ulcer and Intervention Effects of Corydalis yanhusuo Alkaloid

PubMed Central

Shuai, Wang; Yongrui, Bao; Shanshan, Guan; Bo, Liu; Lu, Chen; Lei, Wang; Xiaorong, Ran

2014-01-01

Metabolomics, the systematic analysis of potential metabolites in a biological specimen, has been increasingly applied to discovering biomarkers, identifying perturbed pathways, measuring therapeutic targets, and discovering new drugs. By analyzing and verifying the significant difference in metabolic profiles and changes of metabolite biomarkers, metabolomics enables us to better understand substance metabolic pathways which can clarify the mechanism of Traditional Chinese Medicines (TCM). Corydalis yanhusuo alkaloid (CA) is a major component of Qizhiweitong (QZWT) prescription which has been used for treating gastric ulcer for centuries and its mechanism remains unclear completely. Metabolite profiling was performed by high-performance liquid chromatography combined with time-of-flight mass spectrometry (HPLC/ESI-TOF-MS) and in conjunction with multivariate data analysis and pathway analysis. The statistic software Mass Profiller Prossional (MPP) and statistic method including ANOVA and principal component analysis (PCA) were used for discovering novel potential biomarkers to clarify mechanism of CA in treating acid injected rats with gastric ulcer. The changes in metabolic profiling were restored to their base-line values after CA treatment according to the PCA score plots. Ten different potential biomarkers and seven key metabolic pathways contributing to the treatment of gastric ulcer were discovered and identified. Among the pathways, sphingophospholipid metabolism and fatty acid metabolism related network were acutely perturbed. Quantitative real time polymerase chain reaction (RT-PCR) analysis were performed to evaluate the expression of genes related to the two pathways for verifying the above results. The results show that changed biomarkers and pathways may provide evidence to insight into drug action mechanisms and enable us to increase research productivity toward metabolomics drug discovery. PMID:24454691

Salivary extracellular vesicle-associated miRNAs as potential biomarkers in oral squamous cell carcinoma.

PubMed

Gai, Chiara; Camussi, Francesco; Broccoletti, Roberto; Gambino, Alessio; Cabras, Marco; Molinaro, Luca; Carossa, Stefano; Camussi, Giovanni; Arduino, Paolo G

2018-04-18

Several studies in the past have investigated the expression of micro RNAs (miRNAs) in saliva as potential biomarkers. Since miRNAs associated with extracellular vesicles (EVs) are known to be protected from enzymatic degradation, we evaluated whether salivary EVs from patients with oral squamous cell carcinoma (OSCC) were enriched with specific subsets of miRNAs. OSCC patients and controls were matched with regards to age, gender and risk factors. Total RNA was extracted from salivary EVs and the differential expression of miRNAs was evaluated by qRT-PCR array and qRT-PCR. The discrimination power of up-regulated miRNAs as biomarkers in OSCC patients versus controls was evaluated by the Receiver Operating Characteristic (ROC) curves. A preliminary qRT-PCR array was performed on samples from 5 OSCC patients and 5 healthy controls whereby a subset of miRNAs were identified that were differentially expressed. On the basis of these results, a cohort of additional 16 patients and 6 controls were analyzed to further confirm the miRNAs that were up-regulated or selectively expressed in the previous pilot study. The following miRNAs: miR-302b-3p and miR-517b-3p were expressed only in EVs from OSCC patients and miR-512-3p and miR-412-3p were up-regulated in salivary EVs from OSCC patients compared to controls with the ROC curve showing a good discrimination power for OSCC diagnosis. The Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis suggested the possible involvement of the miRNAs identified in pathways activated in OSCC. In this work, we suggest that salivary EVs isolated by a simple charge-based precipitation technique can be exploited as a non-invasive source of miRNAs for OSCC diagnosis. Moreover, we have identified a subset of miRNAs selectively enriched in EVs of OSCC patients that could be potential biomarkers.

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

Biomarkers associated with obstructive sleep apnea: A scoping review

PubMed Central

De Luca Canto, Graziela; Pachêco-Pereira, Camila; Aydinoz, Secil; Major, Paul W.; Flores-Mir, Carlos; Gozal, David

2014-01-01

Summary The overall validity of biomarkers in the diagnosis of obstructive sleep apnea (OSA) remains unclear. We conducted a scoping review to provide assessments of biomarkers characteristics in the context of obstructive sleep apnea (OSA) and to identify gaps in the literature. A scoping review of studies in humans without age restriction that evaluated the potential diagnostic value of biological markers (blood, exhaled breath condensate, salivary, and urinary) in the OSA diagnosis was undertaken. Retained articles were those focused on the identification of biomarkers in subjects with OSA, the latter being confirmed with a full overnight or home-based polysomnography (PSG). Search strategies for six different databases were developed. The methodology of selected studies was classified using an adaptation of the evidence quality criteria from the American Academy of Pediatrics. Additionally the biomarkers were classified according to their potential clinical application. We identified 572 relevant studies, of which 117 met the inclusion criteria. Eighty-two studies were conducted in adults, 34 studies involved children, and one study had a sample composed of both adults and children. Most of the studies evaluated blood biomarkers. Potential diagnostic biomarkers were found in 9 pediatric studies and in 58 adults studies. Only 9 studies that reported sensitivity and specificity, which varied substantially from 43% to 100%, and from 45% to 100%, respectively. Thus, studies in adults have focused on the investigation of IL-6, TNF-α and hsCRP. There was not a specific biomarker that was tested by a majority of authors in pediatric studies, and combinatorial urine biomarker approaches have shown preliminary promising results. In adults IL-6 and IL-10 seem to have a favorable potential to become a good biomarker to identify OSA. PMID:25645128

Biomarkers of adverse drug reactions.

PubMed

Carr, Daniel F; Pirmohamed, Munir

2018-02-01

Adverse drug reactions can be caused by a wide range of therapeutics. Adverse drug reactions affect many bodily organ systems and vary widely in severity. Milder adverse drug reactions often resolve quickly following withdrawal of the casual drug or sometimes after dose reduction. Some adverse drug reactions are severe and lead to significant organ/tissue injury which can be fatal. Adverse drug reactions also represent a financial burden to both healthcare providers and the pharmaceutical industry. Thus, a number of stakeholders would benefit from development of new, robust biomarkers for the prediction, diagnosis, and prognostication of adverse drug reactions. There has been significant recent progress in identifying predictive genomic biomarkers with the potential to be used in clinical settings to reduce the burden of adverse drug reactions. These have included biomarkers that can be used to alter drug dose (for example, Thiopurine methyltransferase (TPMT) and azathioprine dose) and drug choice. The latter have in particular included human leukocyte antigen (HLA) biomarkers which identify susceptibility to immune-mediated injuries to major organs such as skin, liver, and bone marrow from a variety of drugs. This review covers both the current state of the art with regard to genomic adverse drug reaction biomarkers. We also review circulating biomarkers that have the potential to be used for both diagnosis and prognosis, and have the added advantage of providing mechanistic information. In the future, we will not be relying on single biomarkers (genomic/non-genomic), but on multiple biomarker panels, integrated through the application of different omics technologies, which will provide information on predisposition, early diagnosis, prognosis, and mechanisms. Impact statement • Genetic and circulating biomarkers present significant opportunities to personalize patient therapy to minimize the risk of adverse drug reactions. ADRs are a significant heath issue

Myocardial Injury Is Distinguished from Stable Angina by a Set of Candidate Plasma Biomarkers Identified Using iTRAQ/MRM-Based Approach.

PubMed

Cheow, Esther Sok Hwee; Cheng, Woo Chin; Yap, Terence; Dutta, Bamaprasad; Lee, Chuen Neng; Kleijn, Dominique P V de; Sorokin, Vitaly; Sze, Siu Kwan

2018-01-05

The lack of precise biomarkers that identify patients at risk for myocardial injury and stable angina delays administration of optimal therapy. Hence, the search for noninvasive biomarkers that could accurately stratify patients with impending heart attack, from patients with stable coronary artery disease (CAD), is urgently needed in the clinic. Herein, we performed comparative quantitative proteomics on whole plasma sampled from patients with stable angina (NMI), acute myocardial infarction (MI), and healthy control subjects (Ctrl). We detected a total of 371 proteins with high confidence (FDR < 1%, p < 0.05) including 53 preliminary biomarkers that displayed ≥2-fold modulated expression in patients with CAD (27 associated with atherosclerotic stable angina, 26 with myocardial injury). In the verification phase, we used label-free LC-MRM-MS-based targeted method to verify the preliminary biomarkers in pooled plasma, excluded peptides that were poorly distinguished from background, and performed further validation of the remaining candidates in 49 individual plasma samples. Using this approach, we identified a final panel of eight novel candidate biomarkers that were significantly modulated in CAD (p < 0.05) including proteins associated with atherosclerotic stable angina that were implicated in endothelial dysfunction (F10 and MST1), proteins associated with myocardial injury reportedly involved in plaque destabilization (SERPINA3, CPN2, LUM), and in tissue protection/repair mechanisms (ORM2, ACTG1, NAGLU). Taken together, our data showed that candidate biomarkers with potential diagnostic values can be successfully detected in nondepleted human plasma using an iTRAQ/MRM-based discovery-validation approach and demonstrated the plausible clinical utility of the proposed panel in discriminating atherosclerotic stable angina from myocardial injury in the studied cohort.

Potential role of blood biomarkers in the management of nontraumatic intracerebral hemorrhage.

PubMed

Senn, Rebecca; Elkind, Mitchell S V; Montaner, Joan; Christ-Crain, Mirjam; Katan, Mira

2014-01-01

Intracerebral hemorrhage (ICH), a subtype of stroke associated with high mortality and disability, accounts for 13% of all strokes. Basic and clinical research has contributed to our understanding of the complex pathophysiology of neuronal injury in ICH. Outcome rates, however, remain stable, and questions regarding acute management of ICH remain unanswered. Newer research is aiming at matching measured levels of serum proteins, enzymes, or cells to different stages of brain damage, suggesting that blood biomarkers may assist in acute diagnosis, therapeutic decisions, and prognostication. This paper provides an overview on the most promising blood biomarkers and their potential role in the diagnosis and management of spontaneous ICH. Information was collected from studies, reviews, and guidelines listed in PubMed up to November 2013 on blood biomarkers of nontraumatic ICH in humans. We describe the potential role and limitations of GFAP, S100B/RAGE, and ApoC-III as diagnostic biomarkers, β-​Amyloid as a biomarker for etiological classification, and 27 biomarkers for prognosis of mortality and functional outcome. Within the group of prognostic markers we discuss markers involved in coagulation processes (e.g., D-Dimers), neuroendocrine markers (e.g., copeptin), systemic metabolic markers (e.g., blood glucose levels), markers of inflammation (e.g., IL-6), as well as growth factors (e.g., VEGF), and others (e.g., glutamate). Some of those blood biomarkers are agents of pathologic processes associated with hemorrhagic stroke but also other diseases, whereas others play more distinct pathophysiological roles and help in understanding the basic mechanisms of brain damage and/or recovery in ICH. Numerous blood biomarkers are associated with different pathophysiological pathways in ICH, and some of them promise to be useful in the management of ICH, eventually contributing additional information to current tools for diagnosis, therapy monitoring, risk stratification, or

NMR-based metabonomics and correlation analysis reveal potential biomarkers associated with chronic atrophic gastritis.

PubMed

Cui, Jiajia; Liu, Yuetao; Hu, Yinghuan; Tong, Jiayu; Li, Aiping; Qu, Tingli; Qin, Xuemei; Du, Guanhua

2017-01-05

Chronic atrophic gastritis (CAG) is one of the most important pre-cancerous states with a high prevalence. Exploring of the underlying mechanism and potential biomarkers is of significant importance for CAG. In the present work, 1 H NMR-based metabonomics with correlative analysis was performed to analyze the metabolic features of CAG. 19 plasma metabolites and 18 urine metabolites were enrolled to construct the circulatory and excretory metabolome of CAG, which was in response to alterations of energy metabolism, inflammation, immune dysfunction, as well as oxidative stress. 7 plasma biomarkers and 7 urine biomarkers were screened to elucidate the pathogenesis of CAG based on the further correlation analysis with biochemical indexes. Finally, 3 plasma biomarkers (arginine, succinate and 3-hydroxybutyrate) and 2 urine biomarkers (α-ketoglutarate and valine) highlighted the potential to indicate risks of CAG in virtue of correlation with pepsin activity and ROC analysis. Here, our results paved a way for elucidating the underlying mechanisms in the development of CAG, and provided new avenues for the diagnosis of CAG and presented potential drug targets for treatment of CAG. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization of the liver tissue interstitial fluid (TIF) proteome indicates potential for application in liver disease biomarker discovery.

PubMed

Sun, Wei; Ma, Jie; Wu, Songfeng; Yang, Dong; Yan, Yujuan; Liu, Kehui; Wang, Jinglan; Sun, Longqin; Chen, Ning; Wei, Handong; Zhu, Yunping; Xing, Baocai; Zhao, Xiaohang; Qian, Xiaohong; Jiang, Ying; He, Fuchu

2010-02-05

Tissue interstitial fluid (TIF) forms the interface between circulating body fluids and intracellular fluid. Pathological alterations of liver cells could be reflected in TIF, making it a promising source of liver disease biomarkers. Mouse liver TIF was extracted, separated by SDS-PAGE, analyzed by linear ion trap mass spectrometer, and 1450 proteins were identified. These proteins may be secreted, shed from membrane vesicles, or represent cellular breakdown products. They show different profiling patterns, quantities, and possibly modification/cleavage of intracellular proteins. The high solubility and even distribution of liver TIF supports its suitability for proteome analysis. Comparison of mouse liver TIF data with liver tissue and plasma proteome data identified major proteins that might be released from liver to plasma and serve as blood biomarkers of liver origin. This result was partially supported by comparison of human liver TIF data with human liver and plasma proteome data. Paired TIFs from tumor and nontumor liver tissues of a hepatocellular carcinoma patient were analyzed and the profile of subtracted differential proteins supports the potential for biomarker discovery in TIF. This study is the first analysis of the liver TIF proteome and provides a foundation for further application of TIF in liver disease biomarker discovery.

Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies

PubMed Central

2014-01-01

Background Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential biomarkers and therapeutic targets we have investigated the gene expression profile of human skeletal muscle deficient for TK2 using cDNA microarrays. Results We have analysed the whole transcriptome of skeletal muscle from patients with TK2 mutations and compared it to normal muscle and to muscle from patients with other mitochondrial myopathies. We have identified a set of over 700 genes which are differentially expressed in TK2 deficient muscle. Bioinformatics analysis reveals important changes in muscle metabolism, in particular, in glucose and glycogen utilisation, and activation of the starvation response which affects aminoacid and lipid metabolism. We have identified those transcriptional regulators which are likely to be responsible for the observed changes in gene expression. Conclusion Our data point towards the tumor suppressor p53 as the regulator at the centre of a network of genes which are responsible for a coordinated response to TK2 mutations which involves inflammation, activation of muscle cell death by apoptosis and induction of growth and differentiation factor 15 (GDF-15) in muscle and serum. We propose that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction although further studies are required. PMID:24484525

Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy

PubMed Central

Roussel, Hélène; De Guillebon, Eléonore; Biard, Lucie; Mandavit, Marion; Gibault, Laure; Fabre, Elisabeth; Antoine, Martine; Hofman, Paul; Beau-Faller, Michèle; Blons, Hélène; Danel, Claire; Barthes, Françoise Le Pimpec; Gey, Alain; Granier, Clémence; Wislez, Marie; Laurent-Puig, Pierre; Oudard, Stéphane; Bruneval, Patrick; Badoual, Cécile; Cadranel, Jacques; Tartour, Eric

2017-01-01

ABSTRACT Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the ALK gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. Some predictive biomarkers of clinical response to this therapy are starting to emerge, such as PD-L1 expression by tumor/stromal cells and infiltration by CD8+ T cells expressing PD-1. To more effectively integrate all of these potential biomarkers of clinical response to immunotherapy, we have developed a multiparametric immunofluorescence technique with automated immune cell counting to comprehensively analyze the tumor microenvironment of ALK-positive adenocarcinoma (ADC). When analyzed as either a continuous or a dichotomous variable, the mean number of tumor cells expressing PD-L1 (p = 0.012) and the percentage of tumor cells expressing PD-L1 were higher in ALK-positive ADC than in EGFR-mutated ADC or WT (non-EGFR-mutated and non-KRAS-mutated) NSCLC. A very strong correlation between PD-L1 expression on tumor cells and intratumoral infiltration by CD8+ T cells was observed, suggesting that an adaptive mechanism may partly regulate this expression. A higher frequency of tumors combining positive PD-L1 expression and infiltration by intratumoral CD8+ T cells or PD-1+CD8+ T cells was also observed in ALK-positive lung cancer patients compared with EGFR-mutated (p = 0.03) or WT patients (p = 0.012). These results strongly suggest that a subgroup of ALK-positive lung cancer patients may constitute good candidates for anti-PD-1/-PD-L1 therapies. PMID:28507793

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

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

Biomarkers of cancer cachexia.

PubMed

Loumaye, Audrey; Thissen, Jean-Paul

2017-12-01

Cachexia is a complex multifactorial syndrome, characterized by loss of skeletal muscle and fat mass, which affects the majority of advanced cancer patients and is associated with poor prognosis. Interestingly, reversing muscle loss in animal models of cancer cachexia leads to prolong survival. Therefore, detecting cachexia and maintaining muscle mass represent a major goal in the care of cancer patients. However, early diagnosis of cancer cachexia is currently limited for several reasons. Indeed, cachexia development is variable according to tumor and host characteristics. In addition, safe, accessible and non-invasive tools to detect skeletal muscle atrophy are desperately lacking in clinical practice. Finally, the precise molecular mechanisms and the key players involved in cancer cachexia remain poorly characterized. The need for an early diagnosis of cancer cachexia supports therefore the quest for a biomarker that might reflect skeletal muscle atrophy process. Current research offers different promising ways to identify such a biomarker. Initially, the quest for a biomarker of cancer cachexia has mostly focused on mediators of muscle atrophy, produced by both tumor and host, in an attempt to define new therapeutic approaches. In another hand, molecules released by the muscle into the circulation during the atrophy process have been also considered as potential biomarkers. More recently, several "omics" studies are emerging to identify new muscular or circulating markers of cancer cachexia. Some genetic markers could also contribute to identify patients more susceptible to develop cachexia. This article reviews our current knowledge regarding potential biomarkers of cancer cachexia. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Circulating microRNAs as potential biomarkers of disease activity and structural damage in ankylosing spondylitis patients.

PubMed

Perez-Sanchez, Carlos; Font-Ugalde, Pilar; Ruiz-Limon, Patricia; Lopez-Pedrera, Chary; Castro-Villegas, Maria C; Abalos-Aguilera, Maria C; Barbarroja, Nuria; Arias-de la Rosa, Ivan; Lopez-Montilla, Maria D; Escudero-Contreras, Alejandro; Lopez-Medina, Clementina; Collantes-Estevez, Eduardo; Jimenez-Gomez, Yolanda

2018-03-01

Ankylosing spondylitis (AS) remains difficult to diagnose before irreversible damage to sacroiliac joint is noticeable. Circulating microRNAs have demonstrated to serve as diagnostic tools for several human diseases. Here, we analysed plasma microRNAs to identify potential AS biomarkers. Higher expression levels of microRNA (miR)-146a-5p, miR-125a-5p, miR-151a-3p and miR-22-3p, and lower expression of miR-150-5p, and miR-451a were found in AS versus healthy donors. Interestingly, higher miR-146a-5p, miR-125a-5p, miR-151a-3p, miR-22-3p and miR-451a expression was also observed in AS than psoriatic arthritis patients. The areas under the curve, generated to assess the accuracy of microRNAs as diagnostic biomarkers for AS, ranged from 0.614 to 0.781; the six-microRNA signature reached 0.957. Bioinformatics analysis revealed that microRNAs targeted inflammatory and bone remodeling genes, underlying their potential role in this pathology. Indeed, additional studies revealed an association between these six microRNAs and potential target proteins related to AS pathophysiology. Furthermore, miR-146a-5p, miR-125a-5p and miR-22-3p expression was increased in active versus non-active patients. Moreover, miR-125a-5p, miR-151a-3p, miR-150-5p and miR-451a expression was related to the presence of syndesmophytes in AS patients. Overall, this study identified a six-plasma microRNA signature that could be attractive candidates as non-invasive biomarkers for the AS diagnosis, and may help to elucidate the disease pathogenesis.

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.

Differential MicroRNA Analyses of Burkholderia pseudomallei- and Francisella tularensis-Exposed hPBMCs Reveal Potential Biomarkers.

PubMed

Cer, Regina Z; Herrera-Galeano, J Enrique; Frey, Kenneth G; Schully, Kevin L; Luu, Truong V; Pesce, John; Mokashi, Vishwesh P; Keane-Myers, Andrea M; Bishop-Lilly, Kimberly A

2017-01-01

Increasing evidence that microRNAs (miRNAs) play important roles in the immune response against infectious agents suggests that miRNA might be exploitable as signatures of exposure to specific infectious agents. In order to identify potential early miRNA biomarkers of bacterial infections, human peripheral blood mononuclear cells (hPBMCs) were exposed to two select agents, Burkholderia pseudomallei K96243 and Francisella tularensis SHU S4, as well as to the nonpathogenic control Escherichia coli DH5 α . RNA samples were harvested at three early time points, 30, 60, and 120 minutes postexposure, then sequenced. RNAseq analyses identified 87 miRNAs to be differentially expressed (DE) in a linear fashion. Of these, 31 miRNAs were tested using the miScript miRNA qPCR assay. Through RNAseq identification and qPCR validation, we identified differentially expressed miRNA species that may be involved in the early response to bacterial infections. Based upon its upregulation at early time points postexposure in two different individuals, hsa-mir-30c-5p is a miRNA species that could be studied further as a potential biomarker for exposure to these gram-negative intracellular pathogens. Gene ontology functional analyses demonstrated that programmed cell death is the first ranking biological process associated with miRNAs that are upregulated in F. tularensis -exposed hPBMCs.

Differential MicroRNA Analyses of Burkholderia pseudomallei- and Francisella tularensis-Exposed hPBMCs Reveal Potential Biomarkers

PubMed Central

Herrera-Galeano, J. Enrique; Frey, Kenneth G.; Schully, Kevin L.; Luu, Truong V.; Pesce, John; Mokashi, Vishwesh P.; Keane-Myers, Andrea M.; Bishop-Lilly, Kimberly A.

2017-01-01

Increasing evidence that microRNAs (miRNAs) play important roles in the immune response against infectious agents suggests that miRNA might be exploitable as signatures of exposure to specific infectious agents. In order to identify potential early miRNA biomarkers of bacterial infections, human peripheral blood mononuclear cells (hPBMCs) were exposed to two select agents, Burkholderia pseudomallei K96243 and Francisella tularensis SHU S4, as well as to the nonpathogenic control Escherichia coli DH5α. RNA samples were harvested at three early time points, 30, 60, and 120 minutes postexposure, then sequenced. RNAseq analyses identified 87 miRNAs to be differentially expressed (DE) in a linear fashion. Of these, 31 miRNAs were tested using the miScript miRNA qPCR assay. Through RNAseq identification and qPCR validation, we identified differentially expressed miRNA species that may be involved in the early response to bacterial infections. Based upon its upregulation at early time points postexposure in two different individuals, hsa-mir-30c-5p is a miRNA species that could be studied further as a potential biomarker for exposure to these gram-negative intracellular pathogens. Gene ontology functional analyses demonstrated that programmed cell death is the first ranking biological process associated with miRNAs that are upregulated in F. tularensis-exposed hPBMCs. PMID:28791299

Identification of specific metabolites in culture supernatant of Mycobacterium tuberculosis using metabolomics: exploration of potential biomarkers

PubMed Central

Lau, Susanna KP; Lam, Ching-Wan; Curreem, Shirly OT; Lee, Kim-Chung; Lau, Candy CY; Chow, Wang-Ngai; Ngan, Antonio HY; To, Kelvin KW; Chan, Jasper FW; Hung, Ivan FN; Yam, Wing-Cheong; Yuen, Kwok-Yung; Woo, Patrick CY

2015-01-01

Although previous studies have reported the use of metabolomics for Mycobacterium species differentiation, little is known about the potential of extracellular metabolites of Mycobacterium tuberculosis (MTB) as specific biomarkers. Using an optimized ultrahigh performance liquid chromatography–electrospray ionization–quadruple time of flight–mass spectrometry (UHPLC–ESI–Q–TOF–MS) platform, we characterized the extracellular metabolomes of culture supernatant of nine MTB strains and nine non-tuberculous Mycobacterium (NTM) strains (four M. avium complex, one M. bovis Bacillus Calmette–Guérin (BCG), one M. chelonae, one M. fortuitum and two M. kansasii). Principal component analysis readily distinguished the metabolomes between MTB and NTM. Using multivariate and univariate analysis, 24 metabolites with significantly higher levels in MTB were identified. While seven metabolites were identified by tandem mass spectrometry (MS/MS), the other 17 metabolites were unidentified by MS/MS against database matching, suggesting that they may be potentially novel compounds. One metabolite was identified as dexpanthenol, the alcohol analog of pantothenic acid (vitamin B5), which was not known to be produced by bacteria previously. Four metabolites were identified as 1-tuberculosinyladenosine (1-TbAd), a product of the virulence-associated enzyme Rv3378c, and three previously undescribed derivatives of 1-TbAd. Two derivatives differ from 1-TbAd by the ribose group of the nucleoside while the other likely differs by the base. The remaining two metabolites were identified as a tetrapeptide, Val-His-Glu-His, and a monoacylglycerophosphoglycerol, phosphatidylglycerol (PG) (16∶0/0∶0), respectively. Further studies on the chemical structure and biosynthetic pathway of these MTB-specific metabolites would help understand their biological functions. Studies on clinical samples from tuberculosis patients are required to explore for their potential role as diagnostic

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.

Biomarkers for visceral hypersensitivity identified by classification of electroencephalographic frequency alterations

NASA Astrophysics Data System (ADS)

Graversen, Carina; Brock, Christina; Mohr Drewes, Asbjørn; Farina, Dario

2011-10-01

Abdominal pain is frequently related to visceral hypersensitivity. This is associated with increased neuronal excitability in the central nervous system (CNS), which can be manifested as discrete electroencephalographic (EEG) alterations. In the current placebo-controlled study, visceral hypersensitivity was evoked by chemical irritation of the esophagus with acid and capsaicin perfusion. The resulting hyperexcitability of the CNS was evaluated by evoked brain potentials following painful electrical stimulations of a remote organ—the rectosigmoid colon. Alterations in individual EEG power distributions between baseline and after perfusion were quantified by extracting features from the evoked brain potentials using an optimized discrete wavelet transform. Visceral hypersensitivity was identified as increased EEG power in the delta, theta and alpha frequency bands. By applying a support vector machine in regression mode, the individual baseline corrected alterations after sensitization were discriminated from alterations caused by placebo perfusions. An accuracy of 91.7% was obtained (P < 0.01). The regression value representing the overall alteration of the EEG correlated with the degree of hyperalgesia (P = 0.03). In conclusion, this study showed that classification of EEG can be used to detect biomarkers reflecting central neuronal changes. In the future, this may be used in studies of pain physiology and pharmacological interventions.

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

Novel biomarkers for prediabetes, diabetes, and associated complications

PubMed Central

Dorcely, Brenda; Katz, Karin; Jagannathan, Ram; Chiang, Stephanie S; Oluwadare, Babajide; Goldberg, Ira J; Bergman, Michael

2017-01-01

The number of individuals with prediabetes is expected to grow substantially and estimated to globally affect 482 million people by 2040. Therefore, effective methods for diagnosing prediabetes will be required to reduce the risk of progressing to diabetes and its complications. The current biomarkers, glycated hemoglobin (HbA1c), fructosamine, and glycated albumin have limitations including moderate sensitivity and specificity and are inaccurate in certain clinical conditions. Therefore, identification of additional biomarkers is being explored recognizing that any single biomarker will also likely have inherent limitations. Therefore, combining several biomarkers may more precisely identify those at high risk for developing prediabetes and subsequent progression to diabetes. This review describes recently identified biomarkers and their potential utility for addressing the burgeoning epidemic of dysglycemic disorders. PMID:28860833

Identification of Potential Plasma Biomarkers for Nonalcoholic Fatty Liver Disease by Integrating Transcriptomics and Proteomics in Laying Hens.

PubMed

Tsai, Meng-Tsz; Chen, Yu-Jen; Chen, Ching-Yi; Tsai, Mong-Hsun; Han, Chia-Li; Chen, Yu-Ju; Mersmann, Harry J; Ding, Shih-Torng

2017-03-01

Background: Prevalent worldwide obesity is associated with increased incidence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome. The identification of noninvasive biomarkers for NAFLD is of recent interest. Because primary de novo lipogenesis occurs in chicken liver as in human liver, adult chickens with age-associated steatosis resembling human NAFLD is an appealing animal model. Objective: The objective of this study was to screen potential biomarkers in the chicken model for NAFLD by transcriptomic and proteomic analysis. Methods: Hy-Line W-36 laying hens were fed standard feed from 25 to 45 wk of age to induce fatty liver. They were killed every 4 wk, and liver and plasma were collected at each time point to assess fatty liver development and for transcriptomic and proteomic analysis. Next, selected biomarkers were confirmed in additional experiments by providing supplements of the hepatoprotective nutrients betaine [300, 600, or 900 parts per million (ppm) in vivo; 2 mM in vitro] or docosahexaenoic acid (DHA; 1% in vivo; 100 μM in vitro) to 30-wk-old Hy-Line W-36 laying hens for 4 mo and to Hy-Line W-36 chicken primary hepatocytes with oleic acid-induced steatosis. Liver or hepatocyte lipid contents and the expression of biomarkers were then examined. Results: Plasma acetoacetyl-CoA synthetase (AACS), dipeptidyl-peptidase 4 (DPP4), glutamine synthetase (GLUL), and glutathione S -transferase (GST) concentrations are well-established biomarkers for NAFLD. Selected biomarkers had significant positive associations with hepatic lipid deposition ( P < 0.001). Betaine (900 ppm in vivo; 2 mM in vitro) and DHA (1% in vivo; 100 μM in vitro) supplementation both resulted in lower steatosis accompanied by the reduced expression of selected biomarkers in vivo and in vitro ( P < 0.05). Conclusion: This study used adult laying hens to identify biomarkers for NAFLD and indicated that AACS, DPP4, GLUL, and GST could be considered to be potential diagnostic

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

New insights into adipokines as potential biomarkers for type-2 diabetes mellitus.

PubMed

Olivera Santa-Catalina, Marta; Redondo, Pedro C; Cantonero, C; Granados, Maria P; Sanchez-Collado, Jose; Albarran, Letizia; Lopez, Jose Javier

2017-12-05

A large number of studies have been focused on investigating serum biomarkers associated with risk or diagnosis of type-2 diabetes mellitus. In the last decade, promising studies have shown that circulating levels of adipokines could be used as a relevant biomarker for diabetes mellitus progression as well as therapeutic future targets. Here we discuss the possible use of recent described adipokines, including apelin, omentin-1, resistin, FGF-21, neuregulin-4 and visfatin, as early biomarkers for diabetes. In addition, we also include recent findings of other well know adipokines such as leptin and adiponectin. In conclusion, further studies are needed to clarify the pathophysiological significance and clinical value of these biological factors as potential biomarkers in type-2 diabetes and related dysfunctions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma.

PubMed

Chow, Yock Ping; Tan, Lu Ping; Chai, San Jiun; Abdul Aziz, Norazlin; Choo, Siew Woh; Lim, Paul Vey Hong; Pathmanathan, Rajadurai; Mohd Kornain, Noor Kaslina; Lum, Chee Lun; Pua, Kin Choo; Yap, Yoke Yeow; Tan, Tee Yong; Teo, Soo Hwang; Khoo, Alan Soo-Beng; Patel, Vyomesh

2017-03-03

In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that ~72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.

Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma

PubMed Central

Chow, Yock Ping; Tan, Lu Ping; Chai, San Jiun; Abdul Aziz, Norazlin; Choo, Siew Woh; Lim, Paul Vey Hong; Pathmanathan, Rajadurai; Mohd Kornain, Noor Kaslina; Lum, Chee Lun; Pua, Kin Choo; Yap, Yoke Yeow; Tan, Tee Yong; Teo, Soo Hwang; Khoo, Alan Soo-Beng; Patel, Vyomesh

2017-01-01

In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that ~72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies. PMID:28256603

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

Glucosylceramide and Lysophosphatidylcholines as Potential Blood Biomarkers for Drug-Induced Hepatic Phospholipidosis

PubMed Central

Saito, Kosuke; Maekawa, Keiko; Ishikawa, Masaki; Senoo, Yuya; Urata, Masayo; Murayama, Mayumi; Nakatsu, Noriyuki; Yamada, Hiroshi; Saito, Yoshiro

2014-01-01

Drug-induced phospholipidosis is one of the major concerns in drug development and clinical treatment. The present study involved the use of a nontargeting lipidomic analysis with liquid chromatography-mass spectrometry to explore noninvasive blood biomarkers for hepatic phospholipidosis from rat plasma. We used three tricyclic antidepressants (clomipramine [CPM], imipramine [IMI], and amitriptyline [AMT]) for the model of phospholipidosis in hepatocytes and ketoconazole (KC) for the model of phospholipidosis in cholangiocytes and administered treatment for 3 and 28 days each. Total plasma lipids were extracted and measured. Lipid molecules contributing to the separation of control and drug-treated rat plasma in a multivariate orthogonal partial least squares discriminant analysis were identified. Four lysophosphatidylcholines (LPCs) (16:1, 18:1, 18:2, and 20:4) and 42:1 hexosylceramide (HexCer) were identified as molecules separating control and drug-treated rats in all models of phospholipidosis in hepatocytes. In addition, 16:1, 18:2, and 20:4 LPCs and 42:1 HexCer were identified in a model of hepatic phospholipidosis in cholangiocytes, although LPCs were identified only in the case of 3-day treatment with KC. The levels of LPCs were decreased by drug-induced phospholipidosis, whereas those of 42:1 HexCer were increased. The increase in 42:1 HexCer was much higher in the case of IMI and AMT than in the case of CPM; moreover, the increase induced by IMI was dose-dependent. Structural characterization determining long-chain base and hexose delineated that 42:1 HexCer was d18:1/24:0 glucosylceramide (GluCer). In summary, our study demonstrated that d18:1/24:0 GluCer and LPCs are potential novel biomarkers for drug-induced hepatic phospholipidosis. PMID:24980264

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.

Potential early biomarkers of sarcopenia among independent older adults.

PubMed

Coto Montes, Ana; Boga, José Antonio; Bermejo Millo, Carlos; Rubio González, Adrián; Potes Ochoa, Yaiza; Vega Naredo, Ignacio; Martínez Reig, Marta; Romero Rizos, Luis; Sánchez Jurado, Pedro Manuel; Solano, Juan Jose; Abizanda, Pedro; Caballero, Beatriz

2017-10-01

There are no tools or biomarkers for a quantitative analysis of sarcopenia. Cross-sectional study of the diagnosis of sarcopenia in 200 independent adults aged 70 years or over. Sarcopenia was defined as loss of muscle mass together with low strength and/or loss of physical performance. We considered different clinical parameters and assayed potential blood biomarkers (cell energetic metabolism, muscle performance, inflammation, infection and oxidative stress). The prevalence of sarcopenia was 35.3% in women and 13.1% in men, and it was significantly associated with advanced age, a low functional performance in the lower extremities, deficient weekly consumption of kilocalories, risk of malnutrition, and drug use for the digestive system. A close relationship was found between sarcopenia, pre-frailty and depressed mood. With these confounding variables, we observed that products of lipid peroxidation were closely associated with sarcopenia in independent older adults (frail participants and those with severe dependence had been excluded from the sample). The best multivariate model proposed was able to predict 67.6% of the variance in sarcopenia, with a power of discrimination of 93.5%. Additional analyses considering lipid levels, fat mass, dyslipidemia, use of lipid-lowering drugs and hypertension confirmed this close association between lipid peroxidation and sarcopenia. Given the difficulty in the diagnosis of sarcopenia in clinical practice, we suggest the use of blood circulating products of lipid peroxidation as potential biomarkers for an early diagnosis of sarcopenia in independent older adults. Copyright © 2017 Elsevier B.V. All rights reserved.

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

Circulating microRNAs (cmiRNAs) as novel potential biomarkers for hepatocellular carcinoma

PubMed Central

Qi, Jiahui; Wang, Jin; Katayama, Hiroshi; Sen, Subrata; Liu, Song-mei

2013-01-01

Incidence and mortality associated with hepatocellular carcinoma (HCC) is rising throughout the world. Accurate, noninvasive biomarkers for the early detection of HCC are urgently needed to reduce worldwide morbidity and mortality related to HCC. MicroRNAs (miRNAs), 17- to 25-nucleotide noncoding RNAs that are frequently dysregulated in HCC, have shown great promise as tissue-based markers for HCC diagnosis and prognosis. Moreover, they are stably expressed in serum and urine, and these circulating microRNAs (cmiRNAs) are emerging as novel noninvasive biomarkers for the early detection and prognosis of HCC. This article summarizes the latest findings on the role of circulating miRNAs as potential minimally invasive diagnostic and prognostic biomarkers for HCC. PMID:23259781

SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: Online resources and useful tools - a compass in the land of biomarker discovery

PubMed Central

2011-01-01

Recent positive clinical results in cancer immunotherapy point to the potential of immune-based strategies to provide effective treatment of a variety of cancers. In some patients, the responses to cancer immunotherapy are durable, dramatically extending survival. Extensive research efforts are being made to identify and validate biomarkers that can help identify subsets of cancer patients that will benefit most from these novel immunotherapies. In addition to the clear advantage of such predictive biomarkers, immune biomarkers are playing an important role in the development, clinical evaluation and monitoring of cancer immunotherapies. This Cancer Immunotherapy Resource Document, prepared by the Society for Immunotherapy of Cancer (SITC, formerly the International Society for Biological Therapy of Cancer, iSBTc), provides key references and online resources relevant to the discovery, evaluation and clinical application of immune biomarkers. These key resources were identified by experts in the field who are actively pursuing research in biomarker identification and validation. This organized collection of the most useful references, online resources and tools serves as a compass to guide discovery of biomarkers essential to advancing novel cancer immunotherapies. PMID:21929757

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

Extracting biomarkers of commitment to cancer development: potential role of vibrational spectroscopy in systems biology.

PubMed

Theophilou, Georgios; Paraskevaidi, Maria; Lima, Kássio M G; Kyrgiou, Maria; Martin-Hirsch, Pierre L; Martin, Francis L

2015-05-01

The complex processes driving cancer have so far impeded the discovery of dichotomous biomarkers associated with its initiation and progression. Reductionist approaches utilizing 'omics' technologies have met some success in identifying molecular alterations associated with carcinogenesis. Systems biology is an emerging science that combines high-throughput investigation techniques to define the dynamic interplay between regulatory biological systems in response to internal and external cues. Vibrational spectroscopy has the potential to play an integral role within systems biology research approaches. It is capable of examining global models of carcinogenesis by scrutinizing chemical bond alterations within molecules. The application of infrared or Raman spectroscopic approaches coupled with computational analysis under the systems biology umbrella can assist the transition of biomarker research from the molecular level to the system level. The comprehensive representation of carcinogenesis as a multilevel biological process will inevitably revolutionize cancer-related healthcare by personalizing risk prediction and prevention.

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

Proteomics of gliomas: Initial biomarker discovery and evolution of technology

PubMed Central

Kalinina, Juliya; Peng, Junmin; Ritchie, James C.; Van Meir, Erwin G.

2011-01-01

Gliomas are a group of aggressive brain tumors that diffusely infiltrate adjacent brain tissues, rendering them largely incurable, even with multiple treatment modalities and agents. Mostly asymptomatic at early stages, they present in several subtypes with astrocytic or oligodendrocytic features and invariably progress to malignant forms. Gliomas are difficult to classify precisely because of interobserver variability during histopathologic grading. Identifying biological signatures of each glioma subtype through protein biomarker profiling of tumor or tumor-proximal fluids is therefore of high priority. Such profiling not only may provide clues regarding tumor classification but may identify clinical biomarkers and pathologic targets for the development of personalized treatments. In the past decade, differential proteomic profiling techniques have utilized tumor, cerebrospinal fluid, and plasma from glioma patients to identify the first candidate diagnostic, prognostic, predictive, and therapeutic response markers, highlighting the potential for glioma biomarker discovery. The number of markers identified, however, has been limited, their reproducibility between studies is unclear, and none have been validated for clinical use. Recent technological advancements in methodologies for high-throughput profiling, which provide easy access, rapid screening, low sample consumption, and accurate protein identification, are anticipated to accelerate brain tumor biomarker discovery. Reliable tools for biomarker verification forecast translation of the biomarkers into clinical diagnostics in the foreseeable future. Herein we update the reader on the recent trends and directions in glioma proteomics, including key findings and established and emerging technologies for analysis, together with challenges we are still facing in identifying and verifying potential glioma biomarkers. PMID:21852429

Biomarkers for Severity of Spinal Cord Injury in the Cerebrospinal Fluid of Rats

PubMed Central

Lubieniecka, Joanna M.; Streijger, Femke; Lee, Jae H. T.; Stoynov, Nikolay; Liu, Jie; Mottus, Randy; Pfeifer, Tom; Kwon, Brian K.; Coorssen, Jens R.; Foster, Leonard J.; Grigliatti, Thomas A.; Tetzlaff, Wolfram

2011-01-01

One of the major challenges in management of spinal cord injury (SCI) is that the assessment of injury severity is often imprecise. Identification of reliable, easily quantifiable biomarkers that delineate the severity of the initial injury and that have prognostic value for the degree of functional recovery would significantly aid the clinician in the choice of potential treatments. To find such biomarkers we performed quantitative liquid chromatography-mass spectrometry (LC-MS/MS) analyses of cerebrospinal fluid (CSF) collected from rats 24 h after either a moderate or severe SCI. We identified a panel of 42 putative biomarkers of SCI, 10 of which represent potential biomarkers of SCI severity. Three of the candidate biomarkers, Ywhaz, Itih4, and Gpx3 were also validated by Western blot in a biological replicate of the injury. The putative biomarkers identified in this study may potentially be a valuable tool in the assessment of the extent of spinal cord damage. PMID:21559420

Plasma soluble prion protein, a potential biomarker for sport-related concussions: a pilot study.

PubMed

Pham, Nam; Akonasu, Hungbo; Shishkin, Rhonda; Taghibiglou, Changiz

2015-01-01

Sport-related mild traumatic brain injury (mTBI) or concussion is a significant health concern to athletes with potential long-term consequences. The diagnosis of sport concussion and return to sport decision making is one of the greatest challenges facing health care clinicians working in sports. Blood biomarkers have recently demonstrated their potential in assisting the detection of brain injury particularly, in those cases with no obvious physical injury. We have recently discovered plasma soluble cellular prion protein (PrP(C)) as a potential reliable biomarker for blast induced TBI (bTBI) in a rodent animal model. In order to explore the application of this novel TBI biomarker to sport-related concussion, we conducted a pilot study at the University of Saskatchewan (U of S) by recruiting athlete and non-athlete 18 to 30 year-old students. Using a modified quantitative ELISA method, we first established normal values for the plasma soluble PrP(C) in male and female students. The measured plasma soluble PrP(C) in confirmed concussion cases demonstrated a significant elevation of this analyte in post-concussion samples. Data collected from our pilot study indicates that the plasma soluble PrP(C) is a potential biomarker for sport-related concussion, which may be further developed into a clinical diagnostic tool to assist clinicians in the assessment of sport concussion and return-to-play decision making.

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

New Biomarkers of Coffee Consumption Identified by the Non-Targeted Metabolomic Profiling of Cohort Study Subjects

PubMed Central

Martin, Jean-François; Lyan, Bernard; Pujos-Guillot, Estelle; Fezeu, Leopold; Hercberg, Serge; Comte, Blandine; Galan, Pilar; Touvier, Mathilde; Manach, Claudine

2014-01-01

Coffee contains various bioactives implicated with human health and disease risk. To accurately assess the effects of overall consumption upon health and disease, individual intake must be measured in large epidemiological studies. Metabolomics has emerged as a powerful approach to discover biomarkers of intake for a large range of foods. Here we report the profiling of the urinary metabolome of cohort study subjects to search for new biomarkers of coffee intake. Using repeated 24-hour dietary records and a food frequency questionnaire, 20 high coffee consumers (183–540 mL/d) and 19 low consumers were selected from the French SU.VI.MAX2 cohort. Morning spot urine samples from each subject were profiled by high-resolution mass spectrometry. Partial least-square discriminant analysis of multidimensional liquid chromatography-mass spectrometry data clearly distinguished high consumers from low via 132 significant (p-value<0.05) discriminating features. Ion clusters whose intensities were most elevated in the high consumers were annotated using online and in-house databases and their identities checked using commercial standards and MS-MS fragmentation. The best discriminants, and thus potential markers of coffee consumption, were the glucuronide of the diterpenoid atractyligenin, the diketopiperazine cyclo(isoleucyl-prolyl), and the alkaloid trigonelline. Some caffeine metabolites, such as 1-methylxanthine, were also among the discriminants, however caffeine may be consumed from other sources and its metabolism is subject to inter-individual variation. Receiver operating characteristics curve analysis showed that the biomarkers identified could be used effectively in combination for increased sensitivity and specificity. Once validated in other cohorts or intervention studies, these specific single or combined biomarkers will become a valuable alternative to assessment of coffee intake by dietary survey and finally lead to a better understanding of the health

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

Quantitative Tissue Proteomics Analysis Reveals Versican as Potential Biomarker for Early-Stage Hepatocellular Carcinoma.

PubMed

Naboulsi, Wael; Megger, Dominik A; Bracht, Thilo; Kohl, Michael; Turewicz, Michael; Eisenacher, Martin; Voss, Don Marvin; Schlaak, Jörg F; Hoffmann, Andreas-Claudius; Weber, Frank; Baba, Hideo A; Meyer, Helmut E; Sitek, Barbara

2016-01-04

Hepatocellular carcinoma (HCC) is one of the most aggressive tumors, and the treatment outcome of this disease is improved when the cancer is diagnosed at an early stage. This requires biomarkers allowing an accurate and early tumor diagnosis. To identify potential markers for such applications, we analyzed a patient cohort consisting of 50 patients (50 HCC and 50 adjacent nontumorous tissue samples as controls) using two independent proteomics approaches. We performed label-free discovery analysis on 19 HCC and corresponding tissue samples. The data were analyzed considering events known to take place in early events of HCC development, such as abnormal regulation of Wnt/b-catenin and activation of receptor tyrosine kinases (RTKs). 31 proteins were selected for verification experiments. For this analysis, the second set of the patient cohort (31 HCC and corresponding tissue samples) was analyzed using selected (multiple) reaction monitoring (SRM/MRM). We present the overexpression of ATP-dependent RNA helicase (DDX39), Fibulin-5 (FBLN5), myristoylated alanine-rich C-kinase substrate (MARCKS), and Serpin H1 (SERPINH1) in HCC for the first time. We demonstrate Versican core protein (VCAN) to be significantly associated with well differentiated and low-stage HCC. We revealed for the first time the evidence of VCAN as a potential biomarker for early-HCC diagnosis.

Genetic studies of plasma analytes identify novel potential biomarkers for several complex traits

PubMed Central

Deming, Yuetiva; Xia, Jian; Cai, Yefei; Lord, Jenny; Del-Aguila, Jorge L.; Fernandez, Maria Victoria; Carrell, David; Black, Kathleen; Budde, John; Ma, ShengMei; Saef, Benjamin; Howells, Bill; Bertelsen, Sarah; Bailey, Matthew; Ridge, Perry G.; Hefti, Franz; Fillit, Howard; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Carrillo, Maria; Fleisher, Adam; Reeder, Stephanie; Trncic, Nadira; Burke, Anna; Tariot, Pierre; Reiman, Eric M.; Chen, Kewei; Sabbagh, Marwan N.; Beiden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Green, Robert C.; Marshall, Gad; Johnson, Keith A.; Sperling, Reisa A.; Snyder, Peter; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Bernick, Charles; Munic, Donna; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Relkin, Norman; Chaing, Gloria; Ravdin, Lisa; Paul, Steven; Flashman, Laura A.; Seltzer, Marc; Hynes, Mary L.; Santulli, Robert B.; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Friedl, Karl; Murali Doraiswamy, P.; Petrella, Jeffrey R.; Borges-Neto, Salvador; James, Olga; Wong, Terence; Coleman, Edward; Schwartz, Adam; Cellar, Janet S.; Levey, Allan L.; Lah, James J.; Behan, Kelly; Scott Turner, Raymond; Johnson, Kathleen; Reynolds, Brigid; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Obisesan, Thomas O.; Wolday, Saba; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Tatsuoka, Curtis; Fatica, Parianne; Farlow, Martin R.; Saykin, Andrew J.; Foroud, Tatiana M.; Shen, Li; Faber, Kelly; Kim, Sungeun; Nho, Kwangsik; Marie Hake, Ann; Matthews, Brandy R.; Brosch, Jared R.; Herring, Scott; Hunt, Cynthia; Albert, Marilyn; Onyike, Chiadi; D’Agostino, Daniel; Kielb, Stephanie; Graff-Radford, Neill R; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; Petersen, Ronald; Jack, Clifford R.; Bernstein, Matthew; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Chertkow, Howard; Hosein, Chris; Mintzer, Jacob; Spicer, Kenneth; Bachman, David; Grossman, Hillel; Mitsis, Effie; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Potter, William; Buckholtz, Neil; Hsiao, John; Kittur, Smita; Galvin, James E.; Cerbone, Brittany; Michel, Christina A.; Pogorelec, Dana M.; Rusinek, Henry; de Leon, Mony J; Glodzik, Lidia; De Santi, Susan; Johnson, Nancy; Chuang-Kuo; Kerwin, Diana; Bonakdarpour, Borna; Weintraub, Sandra; Grafman, Jordan; Lipowski, Kristine; Mesulam, Marek-Marsel; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Kaye, Jeffrey; Quinn, Joseph; Silbert, Lisa; Lind, Betty; Carter, Raina; Dolen, Sara; Borrie, Michael; Lee, T-Y; Bartha, Rob; Martinez, Walter; Villena, Teresa; Sadowsky, Carl; Khachaturian, Zaven; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Frank, Richard; Fleischman, Debra; Arfanakis, Konstantinos; Shah, Raj C.; deToledo-Morrell, Leyla; Sorensen, Greg; Finger, Elizabeth; Pasternack, Stephen; Rachinsky, Irina; Drost, Dick; Rogers, John; Kertesz, Andrew; Furst, Ansgar J.; Chad, Stevan; Yesavage, Jerome; Taylor, Joy L.; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Robin Hsiung, Ging-Yuek; Mudge, Benita; Assaly, Michele; Fox, Nick; Schultz, Susan K.; Boles Ponto, Laura L.; Shim, Hyungsub; Ekstam Smith, Karen; Burns, Jeffrey M.; Swerdlow, Russell H.; Brooks, William M.; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Natelson Love, Marissa; DeCarli, Charles; Carmichael, Owen; Olichney, John; Maillard, Pauline; Fletcher, Evan; Nguyen, Dana; Preda, Andrian; Potkin, Steven; Mulnard, Ruth A.; Thai, Gaby; McAdams-Ortiz, Catherine; Landau, Susan; Jagust, William; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H.S.; Lu, Po H.; Bartzokis, George; Thompson, Paul; Donohue, Michael; Thomas, Ronald G.; Walter, Sarah; Gessert, Devon; Brewer, James; Vanderswag, Helen; Sather, Tamie; Jiminez, Gus; Balasubramanian, Archana B.; Mason, Jennifer; Sim, Iris; Aisen, Paul; Davis, Melissa; Morrison, Rosemary; Harvey, Danielle; Thal, Lean; Beckett, Laurel; Neylan, Thomas; Finley, Shannon; Weiner, Michael W.; Hayes, Jacqueline; Rosen, Howard J.; Miller, Bruce L.; Perry, David; Massoglia, Dino; Brawman-Mentzer, Olga; Schuff, Norbert; Smith, Charles D.; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Koeppe, Robert A.; Lord, Joanne L.; Heidebrink, Judith L.; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Clark, Christopher M.; Trojanowki, John Q.; Shaw, Leslie M.; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Toga, Arthur W.; Crawford, Karen; Neu, Scott; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Foster, Norm; Montine, Tom; Fruehling, J. Jay; Harding, Sandra; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Petrie, Eric C.; Peskind, Elaine; Li, Gail; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Smith, Amanda; Ashok Raj, Balebail; Fargher, Kristin; Kuller, Lew; Mathis, Chet; Ann Oakley, Mary; Lopez, Oscar L.; Simpson, Donna M.; Sink, Kaycee M.; Gordineer, Leslie; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Cairns, Nigel J.; Raichle, Marc; Morris, John C.; Householder, Erin; Taylor-Reinwald, Lisa; Holtzman, David; Ances, Beau; Carroll, Maria; Creech, Mary L.; Franklin, Erin; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Varma, Pradeep; MacAvoy, Martha G.; Carson, Richard E.; van Dyck, Christopher H.; Davies, Peter; Holtzman, David; Morris, John C.; Bales, Kelly; Pickering, Eve H.; Lee, Jin-Moo; Heitsch, Laura; Kauwe, John; Goate, Alison; Piccio, Laura; Cruchaga, Carlos

2016-01-01

Genome-wide association studies of 146 plasma protein levels in 818 individuals revealed 56 genome-wide significant associations (28 novel) with 47 analytes. Loci associated with plasma levels of 39 proteins tested have been previously associated with various complex traits such as heart disease, inflammatory bowel disease, Type 2 diabetes, and multiple sclerosis. These data suggest that these plasma protein levels may constitute informative endophenotypes for these complex traits. We found three potential pleiotropic genes: ABO for plasma SELE and ACE levels, FUT2 for CA19-9 and CEA plasma levels, and APOE for ApoE and CRP levels. We also found multiple independent signals in loci associated with plasma levels of ApoH, CA19-9, FetuinA, IL6r, and LPa. Our study highlights the power of biological traits for genetic studies to identify genetic variants influencing clinically relevant traits, potential pleiotropic effects, and complex disease associations in the same locus.

Identification of consensus biomarkers for predicting non-genotoxic hepatocarcinogens

PubMed Central

Huang, Shan-Han; Tung, Chun-Wei

2017-01-01

The assessment of non-genotoxic hepatocarcinogens (NGHCs) is currently relying on two-year rodent bioassays. Toxicogenomics biomarkers provide a potential alternative method for the prioritization of NGHCs that could be useful for risk assessment. However, previous studies using inconsistently classified chemicals as the training set and a single microarray dataset concluded no consensus biomarkers. In this study, 4 consensus biomarkers of A2m, Ca3, Cxcl1, and Cyp8b1 were identified from four large-scale microarray datasets of the one-day single maximum tolerated dose and a large set of chemicals without inconsistent classifications. Machine learning techniques were subsequently applied to develop prediction models for NGHCs. The final bagging decision tree models were constructed with an average AUC performance of 0.803 for an independent test. A set of 16 chemicals with controversial classifications were reclassified according to the consensus biomarkers. The developed prediction models and identified consensus biomarkers are expected to be potential alternative methods for prioritization of NGHCs for further experimental validation. PMID:28117354

Discovery and characterization of potential prognostic biomarkers for dengue hemorrhagic fever.

PubMed

Poole-Smith, B Katherine; Gilbert, Alexa; Gonzalez, Andrea L; Beltran, Manuela; Tomashek, Kay M; Ward, Brian J; Hunsperger, Elizabeth A; Ndao, Momar

2014-12-01

Half a million patients are hospitalized with severe dengue every year, many of whom would die without timely, appropriate clinical intervention. The majority of dengue cases are uncomplicated; however, 2-5% progress to severe dengue. Severe dengue cases have been reported with increasing frequency over the last 30 years. To discover biomarkers for severe dengue, we used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze dengue virus positive serum samples from the acute phase of infection. Using this method, 16 proteins were identified as candidate biomarkers for severe dengue. From these 16 biomarkers, three candidates were selected for confirmation by enzyme-linked immunosorbent assay and Western blot: vitronectin (Vtn, 55.1 kDa), hemopexin (Hx, 52.4 kDa), and serotransferrin (Tf, 79.2 kDa). Vitronectin, Hx, and Tf best differentiated between dengue and severe dengue. © The American Society of Tropical Medicine and Hygiene.

Discovery and Characterization of Potential Prognostic Biomarkers for Dengue Hemorrhagic Fever

PubMed Central

Poole-Smith, B. Katherine; Gilbert, Alexa; Gonzalez, Andrea L.; Beltran, Manuela; Tomashek, Kay M.; Ward, Brian J.; Hunsperger, Elizabeth A.; Ndao, Momar

2014-01-01

Half a million patients are hospitalized with severe dengue every year, many of whom would die without timely, appropriate clinical intervention. The majority of dengue cases are uncomplicated; however, 2–5% progress to severe dengue. Severe dengue cases have been reported with increasing frequency over the last 30 years. To discover biomarkers for severe dengue, we used surface-enhanced laser desorption/ionization time-of-flight mass spectrometry to analyze dengue virus positive serum samples from the acute phase of infection. Using this method, 16 proteins were identified as candidate biomarkers for severe dengue. From these 16 biomarkers, three candidates were selected for confirmation by enzyme-linked immunosorbent assay and Western blot: vitronectin (Vtn, 55.1 kDa), hemopexin (Hx, 52.4 kDa), and serotransferrin (Tf, 79.2 kDa). Vitronectin, Hx, and Tf best differentiated between dengue and severe dengue. PMID:25349378

Diagnostic and prognostic epigenetic biomarkers in cancer.

PubMed

Costa-Pinheiro, Pedro; Montezuma, Diana; Henrique, Rui; Jerónimo, Carmen

2015-01-01

Growing cancer incidence and mortality worldwide demands development of accurate biomarkers to perfect detection, diagnosis, prognostication and monitoring. Urologic (prostate, bladder, kidney), lung, breast and colorectal cancers are the most common and despite major advances in their characterization, this has seldom translated into biomarkers amenable for clinical practice. Epigenetic alterations are innovative cancer biomarkers owing to stability, frequency, reversibility and accessibility in body fluids, entailing great potential of assay development to assist in patient management. Several studies identified putative epigenetic cancer biomarkers, some of which have been commercialized. However, large multicenter validation studies are required to foster translation to the clinics. Herein we review the most promising epigenetic detection, diagnostic, prognostic and predictive biomarkers for the most common cancers.

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.

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges

PubMed Central

Kim, Dana; Kim, Young-Sam; Shin, Dong Wun; Park, Chang-Shin

2016-01-01

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era. PMID:27819412

Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges.

PubMed

Kim, Dana; Kim, Young Sam; Shin, Dong Wun; Park, Chang Shin; Kang, Ju Hee

2016-10-01

No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.

Quantitative HDL Proteomics Identifies Peroxiredoxin-6 as a Biomarker of Human Abdominal Aortic Aneurysm

PubMed Central

Burillo, Elena; Jorge, Inmaculada; Martínez-López, Diego; Camafeita, Emilio; Blanco-Colio, Luis Miguel; Trevisan-Herraz, Marco; Ezkurdia, Iakes; Egido, Jesús; Michel, Jean-Baptiste; Meilhac, Olivier; Vázquez, Jesús; Martin-Ventura, Jose Luis

2016-01-01

High-density lipoproteins (HDLs) are complex protein and lipid assemblies whose composition is known to change in diverse pathological situations. Analysis of the HDL proteome can thus provide insight into the main mechanisms underlying abdominal aortic aneurysm (AAA) and potentially detect novel systemic biomarkers. We performed a multiplexed quantitative proteomics analysis of HDLs isolated from plasma of AAA patients (N = 14) and control study participants (N = 7). Validation was performed by western-blot (HDL), immunohistochemistry (tissue), and ELISA (plasma). HDL from AAA patients showed elevated expression of peroxiredoxin-6 (PRDX6), HLA class I histocompatibility antigen (HLA-I), retinol-binding protein 4, and paraoxonase/arylesterase 1 (PON1), whereas α-2 macroglobulin and C4b-binding protein were decreased. The main pathways associated with HDL alterations in AAA were oxidative stress and immune-inflammatory responses. In AAA tissue, PRDX6 colocalized with neutrophils, vascular smooth muscle cells, and lipid oxidation. Moreover, plasma PRDX6 was higher in AAA (N = 47) than in controls (N = 27), reflecting increased systemic oxidative stress. Finally, a positive correlation was recorded between PRDX6 and AAA diameter. The analysis of the HDL proteome demonstrates that redox imbalance is a major mechanism in AAA, identifying the antioxidant PRDX6 as a novel systemic biomarker of AAA. PMID:27934969

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

Biomarker discovery and transcriptomic responses in Daphnia magna exposed to munitions constituents.

PubMed

Garcia-Reyero, Natalia; Poynton, Helen C; Kennedy, Alan J; Guan, Xin; Escalon, B Lynn; Chang, Bonnie; Varshavsky, Julia; Loguinov, Alex V; Vulpe, Chris D; Perkins, Edward J

2009-06-01

Ecotoxicogenomic approaches are emerging as alternative methods in environmental monitoring because they allow insight into pollutant modes of action and help assess the causal agents and potential toxicity beyond the traditional end points of death, growth, and reproduction. Gene expression analysis has shown particular promise for identifying gene expression biomarkers of chemical exposure that can be further used to monitor specific chemical exposures in the environment. We focused on the development of gene expression markers to detect and discriminate between chemical exposures. Using a custom cDNA microarray for Daphnia magna, we identified distinct expression fingerprints in response to exposure at sublethal concentrations of Cu, Zn, Pb, and munitions constituents. Using the results obtained from microarray analysis, we chose a suite of potential biomarkers for each of the specific exposures. The selected potential biomarkers were tested in independent chemical exposures for specificity using quantitative reverse transcription polymerase chain reaction. Six genes were confirmed as differentially regulated bythe selected chemical exposures. Furthermore, each exposure was identified by response of a unique combination (suite) of individual gene expression biomarkers. These results demonstrate the potential for discovery and validation of novel biomarkers of chemical exposures using gene expression analysis, which could have broad applicability in environmental monitoring.

Biomarkers identified for prostate cancer patients through genome-scale screening.

PubMed

Wang, Lei-Yun; Cui, Jia-Jia; Zhu, Tao; Shao, Wei-Hua; Zhao, Yi; Wang, Sai; Zhang, Yu-Peng; Wu, Ji-Chu; Zhang, Le

2017-11-03

Prostate cancer is a threat to men and usually occurs in aged males. Though prostate specific antigen level and Gleason score are utilized for evaluation of the prostate cancer in clinic, the biomarkers for this malignancy have not been widely recognized. Furthermore, the outcome varies across individuals receiving comparable treatment regimens and the underlying mechanism is still unclear. We supposed that genetic feature may be responsible for, at least in part, this process and conducted a two-cohort study to compare the genetic difference in tumorous and normal tissues of prostate cancer patients. The Gene Expression Omnibus dataset were used and a total of 41 genes were found significantly differently expressed in tumor tissues as compared with normal prostate tissues. Four genes (SPOCK3, SPON1, PTN and TGFB3) were selected for further evaluation after Gene Ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway analysis and clinical association analysis. MIR1908 was also found decreased expression level in prostate cancer whose target genes were found expressing in both prostate tumor and normal tissues. These results indicated that these potential biomarkers deserve attention in prostate cancer patients and the underlying mechanism should be further investigated.

Bladder Cancer-associated Protein, a Potential Prognostic Biomarker in Human Bladder Cancer*

PubMed Central

Moreira, José M. A.; Ohlsson, Gita; Gromov, Pavel; Simon, Ronald; Sauter, Guido; Celis, Julio E.; Gromova, Irina

2010-01-01

It is becoming increasingly clear that no single marker will have the sensitivity and specificity necessary to be used on its own for diagnosis/prognosis of tumors. Interpatient and intratumor heterogeneity provides overwhelming odds against the existence of such an ideal marker. With this in mind, our laboratory has been applying a long term systematic approach to identify multiple biomarkers that can be used for clinical purposes. As a result of these studies, we have identified and reported several candidate biomarker proteins that are deregulated in bladder cancer. Following the conceptual biomarker development phases proposed by the Early Detection Research Network, we have taken some of the most promising candidate proteins into postdiscovery validation studies, and here we report on the characterization of one such biomarker, the bladder cancer-associated protein (BLCAP), formerly termed Bc10. To characterize BLCAP protein expression and cellular localization patterns in benign bladder urothelium and urothelial carcinomas (UCs), we used two independent sets of samples from different patient cohorts: a reference set consisting of 120 bladder specimens (formalin-fixed as well as frozen biopsies) and a validation set consisting of 2,108 retrospectively collected UCs with long term clinical follow-up. We could categorize the UCs examined into four groups based on levels of expression and subcellular localization of BLCAP protein and showed that loss of BLCAP expression is associated with tumor progression. The results indicated that increased expression of this protein confers an adverse patient outcome, suggesting that categorization of staining patterns for this protein may have prognostic value. Finally, we applied a combinatorial two-marker discriminator using BLCAP and adipocyte-type fatty acid-binding protein, another UC biomarker previously reported by us, and found that the combination of the two markers correlated more closely with grade and/or stage of

Identification of novel diagnostic biomarkers for thyroid carcinoma.

PubMed

Wang, Xiliang; Zhang, Qing; Cai, Zhiming; Dai, Yifan; Mou, Lisha

2017-12-19

Thyroid carcinoma (THCA) is the most universal endocrine malignancy worldwide. Unfortunately, a limited number of large-scale analyses have been performed to identify biomarkers for THCA. Here, we conducted a meta-analysis using 505 THCA patients and 59 normal controls from The Cancer Genome Atlas. After identifying differentially expressed long non-coding RNA (lncRNA) and protein coding genes (PCG), we found vast difference in various lncRNA-PCG co-expressed pairs in THCA. A dysregulation network with scale-free topology was constructed. Four molecules (LA16c-380H5.2, RP11-203J24.8, MLF1 and SDC4) could potentially serve as diagnostic biomarkers of THCA with high sensitivity and specificity. We further represent a diagnostic panel with expression cutoff values. Our results demonstrate the potential application of those four molecules as novel independent biomarkers for THCA diagnosis.

Assessment of potential biomarkers, metallothionein and vitellogenin mRNA expressions in various chemically exposed benthic Chironomus riparius larvae

NASA Astrophysics Data System (ADS)

Park, Kiyun; Kwak, Inn-Sil

2012-12-01

The objective of this study was conducted to identify the possibility of using Chironomus metallothionein (MT) and vitellogenin (VTG) as biomarkers of stress caused by endocrinedisrupting chemicals (EDCs), heavy metals, herbicides and veterinary antibiotics. We characterized the MT and VTG cDNA in Chironomus riparius and evaluated their mRNA expression profiles following exposure to different environmental pollutants. The gene expression analysis showed that the MT mRNA levels increased significantly after long-term exposure to cadmium (Cd), copper (Cu), Lead (Pb), di(2-ethylhexyl) phthalate (DEHP), and 2,4-dichlorophenoxyacetic acid (2,4-D). Moreover, the VTG mRNA expression increased significantly in C. riparius larvae exposed to BPA, NP, DEHP, Cd, 2,4-D and fenbendazole. Evaluation of the long-term effects of environmental pollutants revealed up regulation of Chironomus MT mRNA in response to DEHP exposure among EDCs, and the level of the VTG mRNA was increased significantly following treatment with Cd and herbicide 2,4-D at all concentrations in a dose-dependent manner. These results indicate that VTG could be used as a potential biomarker of herbicide and Cd as well as EDCs, while MT was a potential biomarker of heavy metals such as Cd, Cu, and Pb in aquatic environments.

Circulating microRNAs as Potential Biomarkers of Infectious Disease

PubMed Central

Correia, Carolina N.; Nalpas, Nicolas C.; McLoughlin, Kirsten E.; Browne, John A.; Gordon, Stephen V.; MacHugh, David E.; Shaughnessy, Ronan G.

2017-01-01

microRNAs (miRNAs) are a class of small non-coding endogenous RNA molecules that regulate a wide range of biological processes by post-transcriptionally regulating gene expression. Thousands of these molecules have been discovered to date, and multiple miRNAs have been shown to coordinately fine-tune cellular processes key to organismal development, homeostasis, neurobiology, immunobiology, and control of infection. The fundamental regulatory role of miRNAs in a variety of biological processes suggests that differential expression of these transcripts may be exploited as a novel source of molecular biomarkers for many different disease pathologies or abnormalities. This has been emphasized by the recent discovery of remarkably stable miRNAs in mammalian biofluids, which may originate from intracellular processes elsewhere in the body. The potential of circulating miRNAs as biomarkers of disease has mainly been demonstrated for various types of cancer. More recently, however, attention has focused on the use of circulating miRNAs as diagnostic/prognostic biomarkers of infectious disease; for example, human tuberculosis caused by infection with Mycobacterium tuberculosis, sepsis caused by multiple infectious agents, and viral hepatitis. Here, we review these developments and discuss prospects and challenges for translating circulating miRNA into novel diagnostics for infectious disease. PMID:28261201

Identification of potential tumor-educated platelets RNA biomarkers in non-small-cell lung cancer by integrated bioinformatical analysis.

PubMed

Xue, Linlin; Xie, Li; Song, Xingguo; Song, Xianrang

2018-04-17

Platelets have emerged as key players in tumorigenesis and tumor progression. Tumor-educated platelet (TEP) RNA profile has the potential to diagnose non-small-cell lung cancer (NSCLC). The objective of this study was to identify potential TEP RNA biomarkers for the diagnosis of NSCLC and to explore the mechanisms in alternations of TEP RNA profile. The RNA-seq datasets GSE68086 and GSE89843 were downloaded from Gene Expression Omnibus DataSets (GEO DataSets). Then, the functional enrichment of the differentially expressed mRNAs was analyzed by the Database for Annotation Visualization and Integrated Discovery (DAVID). The miRNAs which regulated the differential mRNAs and the target mRNAs of miRNAs were identified by miRanda and miRDB. Then, the miRNA-mRNA regulatory network was visualized via Cytoscape software. Twenty consistently altered mRNAs (2 up-regulated and 18 down-regulated) were identified from the two GSE datasets, and they were significantly enriched in several biological processes, including transport and establishment of localization. Twenty identical miRNAs were found between exosomal miRNA-seq dataset and 229 miRNAs that regulated 20 consistently differential mRNAs in platelets. We also analyzed 13 spliceosomal mRNAs and their miRNA predictions; there were 27 common miRNAs between 206 differential exosomal miRNAs and 338 miRNAs that regulated 13 distinct spliceosomal mRNAs. This study identified 20 potential TEP RNA biomarkers in NSCLC for diagnosis by integrated bioinformatical analysis, and alternations in TEP RNA profile may be related to the post-transcriptional regulation and the splicing metabolisms of spliceosome. © 2018 Wiley Periodicals, Inc.

High-throughput deep screening and identification of four peripheral leucocyte microRNAs as novel potential combination biomarkers for preeclampsia

PubMed Central

Wang, Yonghong; Yang, Xukui; Yang, Yuanyuan; Wang, Wenjun; Zhao, Meiling; Liu, Huiqiang; Li, Dongyan; Hao, Min

2016-01-01

Objective: To identify the specific microRNA (miRNA) biomarkers of preeclampsia (PE), the miRNA profiles analysis were performed. Study Design: The blood samples were obtained from five PE patients and five normal healthy pregnant women. The small RNA profiles were analyzed to identify miRNA expression levels and find out miRNAs that may associate with PE. The quantitative reverse transcriptase–PCR (qRT-PCR) assay was used to validate differentially expressed peripheral leucocyte miRNAs in a new cohort. Result: The data analysis showed that 10 peripheral leucocyte miRNAs were significantly differently expressed in severe PE patients. Four differently expressed miRNAs were successfully validated using qRT-PCR method. Conclusion: We successfully constructed a model with high accuracy to predict PE. A combination of four peripheral leucocyte miRNAs has great potential to serve as diagnostic biomarkers of PE. PMID:26675000

Identification of potential biomarkers for post-traumatic complications released after trauma-hemorrhage from murine Kupffer cells and its investigation in lung and liver.

PubMed

Schultze, Cornelia; Hildebrand, Frank; Noack, Sandra; Krettek, Christian; Zeckey, Christian; Neunaber, Claudia

2016-11-01

Early diagnosis of complications after severe trauma by specific biomarkers remains difficult. Identify potential new biomarkers for early diagnosis of post-traumatic complications. Mice underwent pressure-controlled hemorrhage or sham procedure. Four hours later, genome-wide expression of isolated Kupffer cells was compared with controls using Affymetrix-Genechip-Expression-Analysis and real-time-PCR. Expression analysis and real-time-PCR revealed a significant increase of gene expression of Cxcl10, Il4ra, Csf2rb2, Lcn2, and Gbp5. Cxcl10, Il4ra, Csf2rb2, Lcn2, and Gbp5 might represent new biomarkers for early diagnosis of post-traumatic complications, if they are linked to the development of post-traumatic complications.

Plasma-derived Extracellular Vesicles Contain Predictive Biomarkers and Potential Therapeutic Targets for Myocardial Ischemic (MI) Injury*

PubMed Central

Cheow, Esther Sok Hwee; Cheng, Woo Chin; Lee, Chuen Neng; de Kleijn, Dominique; Sorokin, Vitaly; Sze, Siu Kwan

2016-01-01

Myocardial infarction (MI) triggers a potent inflammatory response via the release of circulatory mediators, including extracellular vesicles (EVs) by damaged cardiac cells, necessary for myocardial healing. Timely repression of inflammatory response are critical to prevent and minimize cardiac tissue injuries, nonetheless, progression in this aspect remains challenging. The ability of EVs to trigger a functional response upon delivery of carried bioactive cargos, have made them clinically attractive diagnostic biomarkers and vectors for therapeutic interventions. Using label-free quantitative proteomics approach, we compared the protein cargo of plasma EVs between patients with MI and from patients with stable angina (NMI). We report, for the first time, the proteomics profiling on 252 EV proteins that were modulated with >1.2-fold after MI. We identified six up-regulated biomarkers with potential for clinical applications; these reflected post-infarct pathways of complement activation (Complement C1q subcomponent subunit A (C1QA), 3.23-fold change, p = 0.012; Complement C5 (C5), 1.27-fold change, p = 0.087), lipoprotein metabolism (Apoliporotein D (APOD), 1.86-fold change, p = 0.033; Apolipoprotein C-III (APOCC3), 2.63-fold change, p = 0.029) and platelet activation (Platelet glycoprotein Ib alpha chain (GP1BA), 9.18-fold change, p < 0.0001; Platelet basic protein (PPBP), 4.72-fold change, p = 0.027). The data have been deposited to the ProteomeXchange with identifier PXD002950. This novel biomarker panel was validated in 43 patients using antibody-based assays (C1QA (p = 0.005); C5 (p = 0.0047), APOD (p = 0.0267); APOC3 (p = 0.0064); GP1BA (p = 0.0031); PPBP (p = 0.0465)). We further present that EV-derived fibrinogen components were paradoxically down-regulated in MI, suggesting that a compensatory mechanism may suppress post-infarct coagulation pathways, indicating potential for therapeutic targeting of this mechanism in MI. Taken together, these data

A New Strategy for Analyzing Time-Series Data Using Dynamic Networks: Identifying Prospective Biomarkers of Hepatocellular Carcinoma.

PubMed

Huang, Xin; Zeng, Jun; Zhou, Lina; Hu, Chunxiu; Yin, Peiyuan; Lin, Xiaohui

2016-08-31

Time-series metabolomics studies can provide insight into the dynamics of disease development and facilitate the discovery of prospective biomarkers. To improve the performance of early risk identification, a new strategy for analyzing time-series data based on dynamic networks (ATSD-DN) in a systematic time dimension is proposed. In ATSD-DN, the non-overlapping ratio was applied to measure the changes in feature ratios during the process of disease development and to construct dynamic networks. Dynamic concentration analysis and network topological structure analysis were performed to extract early warning information. This strategy was applied to the study of time-series lipidomics data from a stepwise hepatocarcinogenesis rat model. A ratio of lyso-phosphatidylcholine (LPC) 18:1/free fatty acid (FFA) 20:5 was identified as the potential biomarker for hepatocellular carcinoma (HCC). It can be used to classify HCC and non-HCC rats, and the area under the curve values in the discovery and external validation sets were 0.980 and 0.972, respectively. This strategy was also compared with a weighted relative difference accumulation algorithm (wRDA), multivariate empirical Bayes statistics (MEBA) and support vector machine-recursive feature elimination (SVM-RFE). The better performance of ATSD-DN suggests its potential for a more complete presentation of time-series changes and effective extraction of early warning information.

A New Strategy for Analyzing Time-Series Data Using Dynamic Networks: Identifying Prospective Biomarkers of Hepatocellular Carcinoma

NASA Astrophysics Data System (ADS)

Huang, Xin; Zeng, Jun; Zhou, Lina; Hu, Chunxiu; Yin, Peiyuan; Lin, Xiaohui

2016-08-01

Time-series metabolomics studies can provide insight into the dynamics of disease development and facilitate the discovery of prospective biomarkers. To improve the performance of early risk identification, a new strategy for analyzing time-series data based on dynamic networks (ATSD-DN) in a systematic time dimension is proposed. In ATSD-DN, the non-overlapping ratio was applied to measure the changes in feature ratios during the process of disease development and to construct dynamic networks. Dynamic concentration analysis and network topological structure analysis were performed to extract early warning information. This strategy was applied to the study of time-series lipidomics data from a stepwise hepatocarcinogenesis rat model. A ratio of lyso-phosphatidylcholine (LPC) 18:1/free fatty acid (FFA) 20:5 was identified as the potential biomarker for hepatocellular carcinoma (HCC). It can be used to classify HCC and non-HCC rats, and the area under the curve values in the discovery and external validation sets were 0.980 and 0.972, respectively. This strategy was also compared with a weighted relative difference accumulation algorithm (wRDA), multivariate empirical Bayes statistics (MEBA) and support vector machine-recursive feature elimination (SVM-RFE). The better performance of ATSD-DN suggests its potential for a more complete presentation of time-series changes and effective extraction of early warning information.

The role of toxicology to characterize biomarkers for agrochemicals with potential endocrine activities.

PubMed

Mantovani, Alberto; Maranghi, Francesca; La Rocca, Cinzia; Tiboni, Gian Mario; Clementi, Maurizio

2008-09-01

The paper discusses current knowledge and possible research priorities on biomarkers of exposure, effect and susceptibility for potential endocrine activities of agrochemicals (dicarboximides, ethylene bisdithiocarbammates, triazoles, etc.). Possible widespread, multiple-pathway exposure to agrochemicals highlights the need to assess internal exposure of animals or humans, which is the most relevant exposure measure for hazard and risk estimation; however, exposure data should be integrated by early indicators predictive of possible health effects, particularly for vulnerable groups such as mother-child pairs. Research need include: non-invasive biomarkers for children biomonitoring; novel biomarkers of total exposure to measure whole endocrine disrupter-related burden; characterization of biomarkers of susceptibility, including the role of markers of nutritional status; anchoring early molecular markers to established toxicological endpoints to support their predictivity; integrating "omics"-based approaches in a system-toxicology framework. As biomonitoring becomes increasingly important in the environment-and-health scenario, toxicologists can substantially contribute both to the characterization of new biomarkers and to the predictivity assessment and improvement of the existing ones.

Faecal biomarker patterns in patients with symptoms of irritable bowel syndrome

PubMed Central

Emmanuel, Anton; Landis, Darryl; Peucker, Mark; Hungin, A Pali S

2016-01-01

Objective To determine rates of faecal biomarker results capable of suggesting potentially treatable causes of irritable bowel syndrome (IBS) symptomatology in a population of patients with symptoms of IBS who meet Rome III criteria for that condition. Design Descriptive, retrospective study in which faecal biomarker results (dichotomised into ‘normal’ and ‘abnormal’ values) were related to data from patient-completed questionnaire data identifying demographics, Rome III criteria for IBS and IBS phenotype (IBS-D, IBS-C, IBS-M and IBS-U). Setting Commercial reference laboratory. Patients Individuals whose physicians ordered faecal biomarker testing for evaluation of chronic abdominal symptoms consistent with IBS. Interventions None. Main outcome measures Rates of occurrence of abnormal results on any of seven faecal biomarkers suggesting a treatable cause for IBS symptoms. Results Abdominal symptoms meeting Rome III criteria for IBS were present in 3553 records (the population), which were subjected to further analysis. Abnormal biomarker results (the outcomes) occurred in 94% of cases; 73% and 65% of records indicated growth of a bacterial potential pathogen and low growth of beneficial organisms, respectively. Abnormal results for all other faecal biomarkers occurred with frequencies from 5% to 13%. Frequency of abnormal results for elastase, calprotectin, eosinophil protein X, and beneficial organisms rose significantly with age, and differed significantly across IBS phenotypes. Conclusions A large proportion of patients manifesting symptoms meeting Rome III IBS diagnostic criteria have faecal biomarker results indicating potential underlying, treatable causes of their symptoms. Faecal biomarker testing is an appropriate means of identifying potentially treatable causes of IBS symptoms. PMID:27761231

Biological Networks for Cancer Candidate Biomarkers Discovery

PubMed Central

Yan, Wenying; Xue, Wenjin; Chen, Jiajia; Hu, Guang

2016-01-01

Due to its extraordinary heterogeneity and complexity, cancer is often proposed as a model case of a systems biology disease or network disease. There is a critical need of effective biomarkers for cancer diagnosis and/or outcome prediction from system level analyses. Methods based on integrating omics data into networks have the potential to revolutionize the identification of cancer biomarkers. Deciphering the biological networks underlying cancer is undoubtedly important for understanding the molecular mechanisms of the disease and identifying effective biomarkers. In this review, the networks constructed for cancer biomarker discovery based on different omics level data are described and illustrated from recent advances in the field. PMID:27625573

Rationale of the FIBROTARGETS study designed to identify novel biomarkers of myocardial fibrosis

PubMed Central

Ferreira, João Pedro; Machu, Jean‐Loup; Girerd, Nicolas; Jaisser, Frederic; Thum, Thomas; Butler, Javed; González, Arantxa; Diez, Javier; Heymans, Stephane; McDonald, Kenneth; Gyöngyösi, Mariann; Firat, Hueseyin; Rossignol, Patrick; Pizard, Anne

2017-01-01

Abstract Aims Myocardial fibrosis alters the cardiac architecture favouring the development of cardiac dysfunction, including arrhythmias and heart failure. Reducing myocardial fibrosis may improve outcomes through the targeted diagnosis and treatment of emerging fibrotic pathways. The European‐Commission‐funded ‘FIBROTARGETS’ is a multinational academic and industrial consortium with the main aims of (i) characterizing novel key mechanistic pathways involved in the metabolism of fibrillary collagen that may serve as biotargets, (ii) evaluating the potential anti‐fibrotic properties of novel or repurposed molecules interfering with the newly identified biotargets, and (iii) characterizing bioprofiles based on distinct mechanistic phenotypes involving the aforementioned biotargets. These pathways will be explored by performing a systematic and collaborative search for mechanisms and targets of myocardial fibrosis. These mechanisms will then be translated into individualized diagnostic tools and specific therapeutic pharmacological options for heart failure. Methods and results The FIBROTARGETS consortium has merged data from 12 patient cohorts in a common database available to individual consortium partners. The database consists of >12 000 patients with a large spectrum of cardiovascular clinical phenotypes. It integrates community‐based population cohorts, cardiovascular risk cohorts, and heart failure cohorts. Conclusions The FIBROTARGETS biomarker programme is aimed at exploring fibrotic pathways allowing the bioprofiling of patients into specific ‘fibrotic’ phenotypes and identifying new therapeutic targets that will potentially enable the development of novel and tailored anti‐fibrotic therapies for heart failure. PMID:28988439

New approaches for identifying and testing potential new anti-asthma agents.

PubMed

Licari, Amelia; Castagnoli, Riccardo; Brambilla, Ilaria; Marseglia, Alessia; Tosca, Maria Angela; Marseglia, Gian Luigi; Ciprandi, Giorgio

2018-01-01

Asthma is a chronic disease with significant heterogeneity in clinical features, disease severity, pattern of underlying disease mechanisms, and responsiveness to specific treatments. While the majority of asthmatic patients are controlled by standard pharmacological strategies, a significant subgroup has limited therapeutic options representing a major unmet need. Ongoing asthma research aims to better characterize distinct clinical phenotypes, molecular endotypes, associated reliable biomarkers, and also to develop a series of new effective targeted treatment modalities. Areas covered: The expanding knowledge on the pathogenetic mechanisms of asthma has allowed researchers to investigate a range of new treatment options matched to patient profiles. The aim of this review is to provide a comprehensive and updated overview of the currently available, new and developing approaches for identifying and testing potential treatment options for asthma management. Expert opinion: Future therapeutic strategies for asthma require the identification of reliable biomarkers that can help with diagnosis and endotyping, in order to determine the most effective drug for the right patient phenotype. Furthermore, in addition to the identification of clinical and inflammatory phenotypes, it is expected that a better understanding of the mechanisms of airway remodeling will likely optimize asthma targeted treatment.

Molecular lipid species in urinary exosomes as potential prostate cancer biomarkers.

PubMed

Skotland, Tore; Ekroos, Kim; Kauhanen, Dimple; Simolin, Helena; Seierstad, Therese; Berge, Viktor; Sandvig, Kirsten; Llorente, Alicia

2017-01-01

Exosomes have recently appeared as a novel source of noninvasive cancer biomarkers, since these nanovesicles contain molecules from cancer cells and can be detected in biofluids. We have here investigated the potential use of lipids in urinary exosomes as prostate cancer biomarkers. A high-throughput mass spectrometry quantitative lipidomic analysis was performed to reveal the lipid composition of urinary exosomes in prostate cancer patients and healthy controls. Control samples were first analysed to characterise the lipidome of urinary exosomes and test the reproducibility of the method. In total, 107 lipid species were quantified in urinary exosomes. Several differences, for example, in cholesterol and phosphatidylcholine, were found between urinary exosomes and exosomes derived from cell lines, thus showing the importance of in vivo studies for biomarker analysis. The 36 most abundant lipid species in urinary exosomes were then quantified in 15 prostate cancer patients and 13 healthy controls. Interestingly, the levels of nine lipids species were found to be significantly different when the two groups were compared. The highest significance was shown for phosphatidylserine (PS) 18:1/18:1 and lactosylceramide (d18:1/16:0), the latter also showed the highest patient-to-control ratio. Furthermore, combinations of these lipid species and PS 18:0-18:2 distinguished the two groups with 93% sensitivity and 100% specificity. Finally, in agreement with the reported dysregulation of sphingolipid metabolism in cancer cells, alteration in specific sphingolipid lipid classes were observed. This study shows for the first time the potential use of exosomal lipid species in urine as prostate cancer biomarkers. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identifying DNA Methylation Biomarkers for Non-Endoscopic Detection of Barrett’s Esophagus

PubMed Central

Moinova, Helen R.; LaFramboise, Thomas; Lutterbaugh, James D.; Chandar, Apoorva Krishna; Dumot, John; Faulx, Ashley; Brock, Wendy; De la Cruz Cabrera, Omar; Guda, Kishore; Barnholtz-Sloan, Jill S.; Iyer, Prasad G.; Canto, Marcia I.; Wang, Jean S.; Shaheen, Nicholas J.; Thota, Prashanti N.; Willis, Joseph E.; Chak, Amitabh; Markowitz, Sanford D.

2018-01-01

We report a biomarker-based non-endoscopic method for detecting Barrett’s esophagus (BE), based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma (EAC). Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve (AUC)=0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals, who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 minutes. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE. PMID:29343623

Functional Imaging Biomarkers: Potential to Guide an Individualised Approach to Radiotherapy.

PubMed

Prestwich, R J D; Vaidyanathan, S; Scarsbrook, A F

2015-10-01

The identification of robust prognostic and predictive biomarkers would transform the ability to implement an individualised approach to radiotherapy. In this regard, there has been a surge of interest in the use of functional imaging to assess key underlying biological processes within tumours and their response to therapy. Importantly, functional imaging biomarkers hold the potential to evaluate tumour heterogeneity/biology both spatially and temporally. An ever-increasing range of functional imaging techniques is now available primarily involving positron emission tomography and magnetic resonance imaging. Small-scale studies across multiple tumour types have consistently been able to correlate changes in functional imaging parameters during radiotherapy with disease outcomes. Considerable challenges remain before the implementation of functional imaging biomarkers into routine clinical practice, including the inherent temporal variability of biological processes within tumours, reproducibility of imaging, determination of optimal imaging technique/combinations, timing during treatment and design of appropriate validation studies. Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Do classic blood biomarkers of JSLE identify active lupus nephritis? Evidence from the UK JSLE Cohort Study.

PubMed

Smith, E M D; Jorgensen, A L; Beresford, M W

2017-10-01

Background Lupus nephritis (LN) affects up to 80% of juvenile-onset systemic lupus erythematosus (JSLE) patients. The value of commonly available biomarkers, such as anti-dsDNA antibodies, complement (C3/C4), ESR and full blood count parameters in the identification of active LN remains uncertain. Methods Participants from the UK JSLE Cohort Study, aged <16 years at diagnosis, were categorized as having active or inactive LN according to the renal domain of the British Isles Lupus Assessment Group score. Classic biomarkers: anti-dsDNA, C3, C4, ESR, CRP, haemoglobin, total white cells, neutrophils, lymphocytes, platelets and immunoglobulins were assessed for their ability to identify active LN using binary logistic regression modeling, with stepAIC function applied to select a final model. Receiver-operating curve analysis was used to assess diagnostic accuracy. Results A total of 370 patients were recruited; 191 (52%) had active LN and 179 (48%) had inactive LN. Binary logistic regression modeling demonstrated a combination of ESR, C3, white cell count, neutrophils, lymphocytes and IgG to be best for the identification of active LN (area under the curve 0.724). Conclusions At best, combining common classic blood biomarkers of lupus activity using multivariate analysis provides a 'fair' ability to identify active LN. Urine biomarkers were not included in these analyses. These results add to the concern that classic blood biomarkers are limited in monitoring discrete JSLE manifestations such as LN.

Differential proteomic and tissue expression analyses identify valuable diagnostic biomarkers of hepatocellular differentiation and hepatoid adenocarcinomas.

PubMed

Reis, Henning; Padden, Juliet; Ahrens, Maike; Pütter, Carolin; Bertram, Stefanie; Pott, Leona L; Reis, Anna-Carinna; Weber, Frank; Juntermanns, Benjamin; Hoffmann, Andreas-C; Eisenacher, Martin; Schlaak, Joörg F; Canbay, Ali; Meyer, Helmut E; Sitek, Barbara; Baba, Hideo A

2015-10-01

The exact discrimination of lesions with true hepatocellular differentiation from secondary tumours and neoplasms with hepatocellular histomorphology like hepatoid adenocarcinomas (HAC) is crucial. Therefore, we aimed to identify ancillary protein biomarkers by using complementary proteomic techniques (2D-DIGE, label-free MS). The identified candidates were immunohistochemically validated in 14 paired samples of hepatocellular carcinoma (HCC) and non-tumourous liver tissue (NT). The candidates and HepPar1/Arginase1 were afterwards tested for consistency in a large cohort of hepatocellular lesions and NT (n = 290), non-hepatocellular malignancies (n = 383) and HAC (n = 13). Eight non-redundant, differentially expressed proteins were suitable for further immunohistochemical validation and four (ABAT, BHMT, FABP1, HAOX1) for further evaluation. Sensitivity and specificity rates for HCC/HAC were as follows: HepPar1 80.2%, 94.3% / 80.2%, 46.2%; Arginase1 82%, 99.4% / 82%, 69.2%; BHMT 61.4%, 93.8% / 61.4%, 100%; ABAT 84.4%, 33.7% / 84.4%, 30.8%; FABP1 87.2%, 95% / 87.2%, 69.2%; HAOX1 95.5%, 36.3% / 95.5%, 46.2%. The best 2×/3× biomarker panels for the diagnosis of HCC consisted of Arginase1/HAOX1 and BHMT/Arginase1/HAOX1 and for HAC consisted of Arginase1/FABP1 and BHMT/Arginase1/FABP1. In summary, we successfully identified, validated and benchmarked protein biomarker candidates of hepatocellular differentiation. BHMT in particular exhibited superior diagnostic characteristics in hepatocellular lesions and specifically in HAC. BHMT is therefore a promising (panel based) biomarker candidate in the differential diagnostic process of lesions with hepatocellular aspect.

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

Identification of novel diagnostic biomarkers for thyroid carcinoma

PubMed Central

Wang, Xiliang; Zhang, Qing; Cai, Zhiming; Dai, Yifan; Mou, Lisha

2017-01-01

Thyroid carcinoma (THCA) is the most universal endocrine malignancy worldwide. Unfortunately, a limited number of large-scale analyses have been performed to identify biomarkers for THCA. Here, we conducted a meta-analysis using 505 THCA patients and 59 normal controls from The Cancer Genome Atlas. After identifying differentially expressed long non-coding RNA (lncRNA) and protein coding genes (PCG), we found vast difference in various lncRNA-PCG co-expressed pairs in THCA. A dysregulation network with scale-free topology was constructed. Four molecules (LA16c-380H5.2, RP11-203J24.8, MLF1 and SDC4) could potentially serve as diagnostic biomarkers of THCA with high sensitivity and specificity. We further represent a diagnostic panel with expression cutoff values. Our results demonstrate the potential application of those four molecules as novel independent biomarkers for THCA diagnosis. PMID:29340074

Identifying Thoracic Malignancies Through Pleural Fluid Biomarkers: A Predictive Multivariate Model.

PubMed

Porcel, José M; Esquerda, Aureli; Martínez-Alonso, Montserrat; Bielsa, Silvia; Salud, Antonieta

2016-03-01

The diagnosis of malignant pleural effusions may be challenging when cytological examination of aspirated pleural fluid is equivocal or noncontributory. The purpose of this study was to identify protein candidate biomarkers differentially expressed in the pleural fluid of patients with mesothelioma, lung adenocarcinoma, lymphoma, and tuberculosis (TB).A multiplex protein biochip comprising 120 biomarkers was used to determine the pleural fluid protein profile of 29 mesotheliomas, 29 lung adenocarcinomas, 12 lymphomas, and 35 tuberculosis. The relative abundance of these predetermined biomarkers among groups served to establish the differential diagnosis of: malignant versus benign (TB) effusions, lung adenocarcinoma versus mesothelioma, and lymphoma versus TB. The selected putative markers were validated using widely available commercial techniques in an independent sample of 102 patients.Significant differences were found in the protein expressions of metalloproteinase-9 (MMP-9), cathepsin-B, C-reactive protein, and chondroitin sulfate between malignant and TB effusions. When integrated into a scoring model, these proteins yielded 85% sensitivity, 100% specificity, and an area under the curve (AUC) of 0.98 for labeling malignancy in the verification sample. For lung adenocarcinoma-mesothelioma discrimination, combining CA19-9, CA15-3, and kallikrein-12 had maximal discriminatory capacity (65% sensitivity, 100% specificity, AUC 0.94); figures which also refer to the validation set. Last, cathepsin-B in isolation was only moderately useful (sensitivity 89%, specificity 62%, AUC 0.75) in separating lymphomatous and TB effusions. However, this last differentiation improved significantly when cathepsin-B was used with respect to the patient's age (sensitivity 72%, specificity 100%, AUC 0.94).In conclusion, panels of 4 (i.e., MMP-9, cathepsin-B, C-reactive protein, chondroitin sulfate), or 3 (i.e., CA19-9, CA15-3, kallikrein-12) different protein biomarkers on pleural

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

DTIC Science & Technology

2017-10-13

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

Time-response characteristic and potential biomarker identification of heavy metal induced toxicity in zebrafish.

PubMed

Yin, Jian; Wang, Ai-Ping; Li, Wan-Fang; Shi, Rui; Jin, Hong-Tao; Wei, Jin-Feng

2018-01-01

The present work aims to explore the time-response (from 24 h to 96 h) characteristic and identify early potential sensitive biomarkers of copper (Cu) (as copper chloride dihydrate), cadmium (Cd) (as cadmium acetate), lead (Pb) (as lead nitrate) and chromium (Cr) (as potassium dichromate) exposure in adult zebrafish, focusing on reactive oxygen species (ROS), SOD activity, lipid peroxidation and gene expression related to oxidative stress and inflammatory response. Furthermore, the survival rate decreased apparently by a concentration-dependent manner after Cu, Cr, Cd and Pb exposure, and we selected non-lethal concentrations 0.05 mg/L for Cu, 15 mg/L for Cr, 3 mg/L for Cd and 93.75μg/L for Pb to test the effect on the following biological indicators. Under non-lethal concentration, the four heavy metals have no apparent histological change in adult zebrafish gills. Similar trends in ROS production, MDA level and SOD activity were up-regulated by the four heavy metals, while MDA level responded more sensitive to Pb by time-dependent manner than the other three heavy metals. In addition, mRNA levels related to antioxidant system (SOD1, SOD2 and Nrf2) were up-regulated by non-lethal concentration Cu, Cr, Cd and Pb exposure. MDA level and SOD1 gene have a more delayed response to heavy metals. Genes related to immunotoxicity were increased significantly after heavy metals exposure at non-lethal concentrations. TNF-α and IL-1β gene have similar sensibility to the four heavy metals, while IL-8 gene was more responsive to Cr, Cd and Pb exposure at 48 h groups and IFN-γ gene showed more sensitivity to Cu at 48 h groups than the other heavy metals. In conclusion, the present works have suggested that the IFN-γ gene may applied as early sensitive biomarker to identify Cu-induced toxicity, while MDA content and IL-8 gene may use as early sensitive biomarkers for evaluating the risk of Pb exposure. Moreover, IL-8 and IFN-γ gene were more responsive to heavy

A machine learning heuristic to identify biologically relevant and minimal biomarker panels from omics data

PubMed Central

2015-01-01

Background Investigations into novel biomarkers using omics techniques generate large amounts of data. Due to their size and numbers of attributes, these data are suitable for analysis with machine learning methods. A key component of typical machine learning pipelines for omics data is feature selection, which is used to reduce the raw high-dimensional data into a tractable number of features. Feature selection needs to balance the objective of using as few features as possible, while maintaining high predictive power. This balance is crucial when the goal of data analysis is the identification of highly accurate but small panels of biomarkers with potential clinical utility. In this paper we propose a heuristic for the selection of very small feature subsets, via an iterative feature elimination process that is guided by rule-based machine learning, called RGIFE (Rule-guided Iterative Feature Elimination). We use this heuristic to identify putative biomarkers of osteoarthritis (OA), articular cartilage degradation and synovial inflammation, using both proteomic and transcriptomic datasets. Results and discussion Our RGIFE heuristic increased the classification accuracies achieved for all datasets when no feature selection is used, and performed well in a comparison with other feature selection methods. Using this method the datasets were reduced to a smaller number of genes or proteins, including those known to be relevant to OA, cartilage degradation and joint inflammation. The results have shown the RGIFE feature reduction method to be suitable for analysing both proteomic and transcriptomics data. Methods that generate large ‘omics’ datasets are increasingly being used in the area of rheumatology. Conclusions Feature reduction methods are advantageous for the analysis of omics data in the field of rheumatology, as the applications of such techniques are likely to result in improvements in diagnosis, treatment and drug discovery. PMID:25923811

Characterization of MicroRNA Expression Profiles and Identification of Potential Biomarkers in Leprosy.

PubMed

Jorge, Karina T O S; Souza, Renan P; Assis, Marieta T A; Araújo, Marcelo G; Locati, Massimo; Jesus, Amélia M R; Dias Baptista, Ida M F; Lima, Cristiano X; Teixeira, Antônio L; Teixeira, Mauro M; Soriani, Frederico M

2017-05-01

Leprosy is an important cause of disability in the developing world. Early diagnosis is essential to allow for cure and to interrupt transmission of this infection. MicroRNAs (miRNAs) are important factors for host-pathogen interaction and they have been identified as biomarkers for various infectious diseases. The expression profile of 377 microRNAs were analyzed by TaqMan low-density array (TLDA) in skin lesions of tuberculoid and lepromatous leprosy patients as well as skin specimens from healthy controls. In a second step, 16 microRNAs were selected for validation experiments with reverse transcription-quantitative PCR (qRT-PCR) in skin samples from new individuals. Principal-component analysis followed by logistic regression model and receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic potential of selected miRNAs. Four patterns of differential expression were identified in the TLDA experiment, suggesting a diagnostic potential of miRNAs in leprosy. After validation experiments, a combination of four miRNAs (miR-101, miR-196b, miR-27b, and miR-29c) was revealed as able to discriminate between healthy control and leprosy patients with 80% sensitivity and 91% specificity. This set of miRNAs was also able to discriminate between lepromatous and tuberculoid patients with a sensitivity of 83% and 80% specificity. In this work, it was possible to identify a set of miRNAs with good diagnostic potential for leprosy. Copyright © 2017 American Society for Microbiology.

Genomic reprograming analysis of the Mesothelial to Mesenchymal Transition identifies biomarkers in peritoneal dialysis patients

PubMed Central

Ruiz-Carpio, Vicente; Sandoval, Pilar; Aguilera, Abelardo; Albar-Vizcaíno, Patricia; Perez-Lozano, María Luisa; González-Mateo, Guadalupe T.; Acuña-Ruiz, Adrián; García-Cantalejo, Jesús; Botías, Pedro; Bajo, María Auxiliadora; Selgas, Rafael; Sánchez-Tomero, José Antonio; Passlick-Deetjen, Jutta; Piecha, Dorothea; Büchel, Janine; Steppan, Sonja; López-Cabrera, Manuel

2017-01-01

Peritoneal dialysis (PD) is an effective renal replacement therapy, but a significant proportion of patients suffer PD-related complications, which limit the treatment duration. Mesothelial-to-mesenchymal transition (MMT) contributes to the PD-related peritoneal dysfunction. We analyzed the genetic reprograming of MMT to identify new biomarkers that may be tested in PD-patients. Microarray analysis revealed a partial overlapping between MMT induced in vitro and ex vivo in effluent-derived mesothelial cells, and that MMT is mainly a repression process being higher the number of genes that are down-regulated than those that are induced. Cellular morphology and number of altered genes showed that MMT ex vivo could be subdivided into two stages: early/epithelioid and advanced/non-epithelioid. RT-PCR array analysis demonstrated that a number of genes differentially expressed in effluent-derived non-epithelioid cells also showed significant differential expression when comparing standard versus low-GDP PD fluids. Thrombospondin-1 (TSP1), collagen-13 (COL13), vascular endothelial growth factor A (VEGFA), and gremlin-1 (GREM1) were measured in PD effluents, and except GREM1, showed significant differences between early and advanced stages of MMT, and their expression was associated with a high peritoneal transport status. The results establish a proof of concept about the feasibility of measuring MMT-associated secreted protein levels as potential biomarkers in PD. PMID:28327551

The pediatric sepsis biomarker risk model: potential implications for sepsis therapy and biology.

PubMed

Alder, Matthew N; Lindsell, Christopher J; Wong, Hector R

2014-07-01

Sepsis remains a major cause of morbidity and mortality in adult and pediatric intensive care units. Heterogeneity of demographics, comorbidities, biological mechanisms, and severity of illness leads to difficulty in determining which patients are at highest risk of mortality. Determining mortality risk is important for weighing the potential benefits of more aggressive interventions and for deciding whom to enroll in clinical trials. Biomarkers can be used to parse patients into different risk categories and can outperform current methods of patient risk stratification based on physiologic parameters. Here we review the Pediatric Sepsis Biomarker Risk Model that has also been modified and applied to estimate mortality risk in adult patients. We compare the two models and speculate on the biological implications of the biomarkers in patients with sepsis.

Biomarker Analysis of Samples Visually Identified as Microbial in the Eocene Green River Formation: An Analogue for Mars.

PubMed

Olcott Marshall, Alison; Cestari, Nicholas A

2015-09-01

One of the major exploration targets for current and future Mars missions are lithofacies suggestive of biotic activity. Although such lithofacies are not confirmation of biotic activity, they provide a way to identify samples for further analyses. To test the efficacy of this approach, we identified carbonate samples from the Eocene Green River Formation as "microbial" or "non-microbial" based on the macroscale morphology of their laminations. These samples were then crushed and analyzed by gas chromatography/mass spectroscopy (GC/MS) to determine their lipid biomarker composition. GC/MS analysis revealed that carbonates visually identified as "microbial" contained a higher concentration of more diverse biomarkers than those identified as "non-microbial," suggesting that this could be a viable detection strategy for selecting samples for further analysis or caching on Mars.

Investigation of Tear Biomarkers as an Indicator of Human Health

NASA Technical Reports Server (NTRS)

Morton, Stephen; Tucker, Bethany; Crucian, Brian; Steinberg, Susan; Hagan, Suzanne

2017-01-01

Scientific literature suggests that tear biomarkers can be used as a guide towards clinical diagnosis of human health (Hagan et al., 2016). This study will investigate whether tear biomarkers represents a research and clinical opportunity to assess human health prior to, during, and after exposure to the spaceflight environment. The focus of this study is to compare biomarkers previously identified as potentially relevant to both ocular and brain health against unique physiological outcomes of exposure to the space flight environment. Study subjects suffering from terrestrial conditions thought to be similar to Spaceflight Associated Neuro-ocular Syndrome (SANS: formerly VIIP), e.g. patients with idiopathic intracranial hypertension (IIH) and optic neuritis may be relevant to conditions associated with spaceflight. This study will review methodologies, tear biomarkers related to state of ocular and brain health, the strengths and weakness of using tear fluid biomarkers versus other body fluid samples, and will survey current tear fluid biomarker knowledge in research and clinical practice. A strength of using tear biomarkers is that sampling is non-invasive and used as a guide in understanding pathologies, including ocular and systemic inflammatory conditions (Cocho et al., 2016)., Salvisberg et al., 2014). Moreover, tear biomarkers may reflect diseases affecting the central nervous system (CNS) (Salvisberg et al., 2014). For example, in multiple sclerosis (MS), the concordance rate between tear biomarkers versus cerebrospinal fluid (CSF) is approximately 83%, indicating that, in the majority of cases, tears are at least as effective as CSF in potentially identifying novel MS biomarkers (Devos et al., 2001).

Blood biomarkers for brain injury: What are we measuring?

PubMed Central

Kawata, Keisuke; Liu, Charles Y.; Merkel, Steven F.; Ramirez, Servio H.; Tierney, Ryan T.; Langford, Dianne

2016-01-01

Accurate diagnosis for mild traumatic brain injury (mTBI) remains challenging, as prognosis and return-to-play/work decisions are based largely on patient reports. Numerous investigations have identified and characterized cellular factors in the blood as potential biomarkers for TBI, in the hope that these factors may be used to gauge the severity of brain injury. None of these potential biomarkers have advanced to use in the clinical setting. Some of the most extensively studied blood biomarkers for TBI include S100β, neuron-specific enolase, glial fibrillary acidic protein, and Tau. Understanding the biological function of each of these factors may be imperative to achieve progress in the field. We address the basic question: what are we measuring? This review will discuss blood biomarkers in terms of cellular origin, normal and pathological function, and possible reasons for increased blood levels. Considerations in the selection, evaluation, and validation of potential biomarkers will also be addressed, along with mechanisms that allow brain-derived proteins to enter the bloodstream after TBI. Lastly, we will highlight perspectives and implications for repetitive neurotrauma in the field of blood biomarkers for brain injury. PMID:27181909

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

Urinary Urea, Uric Acid and Hippuric Acid as Potential Biomarkers in Multiple Sclerosis Patients.

PubMed

Atya, Hanaa B; Ali, Sahar A; Hegazy, Mohamed I; El Sharkawi, Fathia Z

2018-04-01

Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, noninvasive, inexpensive, and efficient diagnostic tool for various human diseases. Despite these advantages, urine is an under-investigated source of biomarkers for multiple sclerosis (MS). The objective was to investigate the level of some urinary metabolites (urea, uric acid and hippuric acid) in patients with MS and correlate their levels to the severity of the disease, MS subtypes and MS treatment. The urine samples were collected from 73 MS patients-48 with RRMS and 25 with SPMS- and age matched 75 healthy controls. The values of urinary urea, uric acid and hippuric acid in MS patients were significantly decreased, and these metabolites in SPMS pattern showed significantly decrease than RRMS pattern. Also showed significant inverse correlation with expanded disability status scale and number of relapses. Accordingly, they may act as a potential urinary biomarkers for MS, and correlate to disease progression.

Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury

PubMed Central

Gao, Yuan; Cao, Zhijun; Yang, Xi; Abdelmegeed, Mohamed A.; Sun, Jinchun; Chen, Si; Beger, Richard D.; Davis, Kelly; Salminen, William F.; Song, Byoung-Joon; Mendrick, Donna L.; Yu, Li-Rong

2017-01-01

Purpose Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury. Experimental design Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS. Results Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP. Conclusions and clinical relevance This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury. PMID:27634590

IFN-γ, CXCL16, uPAR: potential biomarkers for systemic lupus erythematosus.

PubMed

Wen, Si; He, Fang; Zhu, Xuejing; Yuan, Shuguang; Liu, Hong; Sun, Lin

2018-01-01

IFN-γ, CXCL16 and uPAR have recently been regarded as potential biomarkers in systemic lupus erythematosus (SLE). However, few researches have focused on the comparison of these three markers in SLE. We conducted this study to evaluate their role as biomarkers of disease activity and renal damage. We enrolled 50 SLE patients with or without lupus nephritis (LN) and 15 healthy control subjects. The levels of IFN-γ, CXCL16, uPAR in serum, urine and renal tissues were detected by ELISA or immunohistochemistry. Relevant clinical and laboratory features were recorded. Serum and urine IFN-γ, CXCL16 and suPAR levels in SLE patients were significantly higher than that in healthy controls. Moreover, LN patients had higher levels than non-LN patients. A positive correlation was observed between these markers, and disease activity and suPAR had a stronger association with disease activity. The expression of these biomarkers in renal tissues was significantly higher in LN patients and was also associated with the activity of pathological lesions. IFN-γ, CXCL16 and uPAR are promising as effective biomarkers of disease activity, renal damage, and the activity of pathological lesions in SLE.

Quantitative phase-digital holographic microscopy: a new imaging modality to identify original cellular biomarkers of diseases

NASA Astrophysics Data System (ADS)

Marquet, P.; Rothenfusser, K.; Rappaz, B.; Depeursinge, C.; Jourdain, P.; Magistretti, P. J.

2016-03-01

Quantitative phase microscopy (QPM) has recently emerged as a powerful label-free technique in the field of living cell imaging allowing to non-invasively measure with a nanometric axial sensitivity cell structure and dynamics. Since the phase retardation of a light wave when transmitted through the observed cells, namely the quantitative phase signal (QPS), is sensitive to both cellular thickness and intracellular refractive index related to the cellular content, its accurate analysis allows to derive various cell parameters and monitor specific cell processes, which are very likely to identify new cell biomarkers. Specifically, quantitative phase-digital holographic microscopy (QP-DHM), thanks to its numerical flexibility facilitating parallelization and automation processes, represents an appealing imaging modality to both identify original cellular biomarkers of diseases as well to explore the underlying pathophysiological processes.

Biomarkers and Genetics in Peripheral Artery Disease

PubMed Central

Hazarika, Surovi; Annex, Brian H.

2017-01-01

BACKGROUND Peripheral artery disease (PAD) is highly prevalent and there is considerable diversity in the initial clinical manifestation and disease progression among individuals. Currently, there is no ideal biomarker to screen for PAD, to risk stratify patients with PAD, or to monitor therapeutic response to revascularization procedures. Advances in human genetics have markedly enhanced the ability to develop novel diagnostic and therapeutic approaches across a host of human diseases, but such developments in the field of PAD are lagging. CONTENT In this article, we will discuss the epidemiology, traditional risk factors for, and clinical presentations of PAD. We will discuss the possible role of genetic factors and gene–environment interactions in the development and/or progression of PAD. We will further explore future avenues through which genetic advances can be used to better our understanding of the pathophysiology of PAD and potentially find newer therapeutic targets. We will discuss the potential role of biomarkers in identifying patients at risk for PAD and for risk stratifying patients with PAD, and novel approaches to identification of reliable biomarkers in PAD. SUMMARY The exponential growth of genetic tools and newer technologies provides opportunities to investigate and identify newer pathways in the development and progression of PAD, and thereby in the identification of newer biomarkers and therapies. PMID:27872083

Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1.

PubMed

Yee, S W; Giacomini, M M; Hsueh, C-H; Weitz, D; Liang, X; Goswami, S; Kinchen, J M; Coelho, A; Zur, A A; Mertsch, K; Brian, W; Kroetz, D L; Giacomini, K M

2016-11-01

Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genome-wide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in organic anion transporter, OATP1B1 (P < 5 × 10 -8 ). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine (CSA) vs. placebo (q-value < 0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established. © 2016 American Society for Clinical Pharmacology and Therapeutics.

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.

The role of pancreatic cancer-derived exosomes in cancer progress and their potential application as biomarkers.

PubMed

Jin, H; Wu, Y; Tan, X

2017-08-01

Pancreatic cancer is one of the most deadly cancers, with dismal prognosis due to its poor early detection rate and high metastatic rate. Thus, elucidation of the molecular mechanisms accounting for its metastasis and discovery of competent biomarkers is required. Exosomes are multivesicular body-derived small extracellular vesicles released by various cell types that serve as important message carriers during intercellular communication. They are also known to play critical roles during cancer-genesis, cancer-related immune reactions, and metastasis. They also possess promising potential as novel biomarkers for cancer early detection. Therefore, extensive studies on pancreatic cancer-derived exosomes are currently being performed because they hold the promising potential of elevating the overall survival rate of patients with pancreatic cancer. In the present review, we focus on the role of exosomes in pancreatic cancer-related immune reactions, metastasis, and complications, and on their potential application as pancreatic cancer biomarkers.

Biomarkers of nanomaterial exposure and effect: current status

NASA Astrophysics Data System (ADS)

Iavicoli, Ivo; Leso, Veruscka; Manno, Maurizio; Schulte, Paul A.

2014-03-01

Recent advances in nanotechnology have induced a widespread production and application of nanomaterials. As a consequence, an increasing number of workers are expected to undergo exposure to these xenobiotics, while the possible hazards to their health remain not being completely understood. In this context, biological monitoring may play a key role not only to identify potential hazards from and to evaluate occupational exposure to nanomaterials, but also to detect their early biological effects to better assess and manage risks of exposure in respect of the health of workers. Therefore, the aim of this review is to provide a critical evaluation of potential biomarkers of nanomaterial exposure and effect investigated in human and animal studies. Concerning exposure biomarkers, internal dose of metallic or metal oxide nanoparticle exposure may be assessed measuring the elemental metallic content in blood or urine or other biological materials, whereas specific molecules may be carefully evaluated in target tissues as possible biomarkers of biologically effective dose. Oxidative stress biomarkers, such as 8-hydroxy-deoxy-guanosine, genotoxicity biomarkers, and inflammatory response indicators may also be useful, although not specific, as biomarkers of nanomaterial early adverse health effects. Finally, potential biomarkers from "omic" technologies appear to be quite innovative and greatly relevant, although mechanistic, ethical, and practical issues should all be resolved before their routine application in occupational settings could be implemented. Although all these findings are interesting, they point out the need for further research to identify and possibly validate sensitive and specific biomarkers of exposure and effect, suitable for future use in occupational biomonitoring programs. A valuable contribution may derive from the studies investigating the biological behavior of nanomaterials and the factors influencing their toxicokinetics and reactivity. In

Characterizing biomarkers in osteosarcoma metastasis based on an ego-network.

PubMed

Liu, Zhen; Song, Yan

2017-06-01

To characterize biomarkers that underlie osteosarcoma (OS) metastasis based on an ego-network. From the microarray data, we obtained 13,326 genes. By combining PPI data and microarray data, 10,520 shared genes were found and constructed into ego-networks. 17 significant ego-networks were identified with p < 0.05. In the pathway enrichment analysis, seven ego-networks were identified with the most significant pathway. These significant ego-modules were potential biomarkers that reveal the potential mechanisms in OS metastasis, which may contribute to understanding cancer prognoses and providing new perspectives in the treatment of cancer.

Calcium-deficiency assessment and biomarker identification by an integrated urinary metabonomics analysis

PubMed Central

2013-01-01

Background Calcium deficiency is a global public-health problem. Although the initial stage of calcium deficiency can lead to metabolic alterations or potential pathological changes, calcium deficiency is difficult to diagnose accurately. Moreover, the details of the molecular mechanism of calcium deficiency remain somewhat elusive. To accurately assess and provide appropriate nutritional intervention, we carried out a global analysis of metabolic alterations in response to calcium deficiency. Methods The metabolic alterations associated with calcium deficiency were first investigated in a rat model, using urinary metabonomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry and multivariate statistical analysis. Correlations between dietary calcium intake and the biomarkers identified from the rat model were further analyzed to confirm the potential application of these biomarkers in humans. Results Urinary metabolic-profiling analysis could preliminarily distinguish between calcium-deficient and non-deficient rats after a 2-week low-calcium diet. We established an integrated metabonomics strategy for identifying reliable biomarkers of calcium deficiency using a time-course analysis of discriminating metabolites in a low-calcium diet experiment, repeating the low-calcium diet experiment and performing a calcium-supplement experiment. In total, 27 biomarkers were identified, including glycine, oxoglutaric acid, pyrophosphoric acid, sebacic acid, pseudouridine, indoxyl sulfate, taurine, and phenylacetylglycine. The integrated urinary metabonomics analysis, which combined biomarkers with regular trends of change (types A, B, and C), could accurately assess calcium-deficient rats at different stages and clarify the dynamic pathophysiological changes and molecular mechanism of calcium deficiency in detail. Significant correlations between calcium intake and two biomarkers, pseudouridine (Pearson

Immune repertoire: A potential biomarker and therapeutic for hepatocellular carcinoma.

PubMed

Han, Yingxin; Li, Hongmei; Guan, Yanfang; Huang, Jian

2016-09-01

The immune repertoire (IR) refers to the sum of B cells and T cells with functional diversity in the circulatory system of one individual at any given time. Immune cells, which reside within microenvironments and are responsible for protecting the human body, include T cells, B cells, macrophages, and dendritic cells. These dedicated immune cells have a characteristic structure and function. T and B cells are the main lymphocytes and are responsible for cellular immunity and humoral immunity, respectively. The T cell receptor (TCR) and B cell receptor (BCR) are composed of multiple peptide chains with antigen specificity. The amino acid composition and sequence order are more diverse in the complementarity-determining regions (including CDR1, CDR2 and CDR3) of each peptide chain, allowing a vast library of TCRs and BCRs. IR research is becoming increasingly focused on the study of CDR3 diversity. Deep profiling of CDR3s using high-throughput sequencing is a powerful approach for elucidating the composition and distribution of the CDR3s in a given sample, with in-depth information at the sequence level. Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. To identify novel biomarkers for diagnosis and drug targets for therapeutic interventions, several groups attempted to describe immune repertoire characteristics of the liver in the physiological environment or/and pathological conditions. This paper reviews the recent progress in IR research on human diseases, including hepatocellular carcinoma, attempting to depict the relationships between hepatocellular carcinogenesis and the IR, and discusses the possibility of IR as a potential biomarker and therapeutic for hepatocellular carcinoma. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers

PubMed Central

Beyreis, Marlena; Wagner, Andrej; Pichler, Martin; Neureiter, Daniel

2016-01-01

Biliary tract cancer (BTC) is still a fatal disease with very poor prognosis. The lack of reliable biomarkers for early diagnosis and of effective therapeutic targets is a major demanding problem in diagnosis and management of BTC. Due to the clinically silent and asymptomatic characteristics of the tumor, most patients are diagnosed at an already advanced stage allowing only for a palliative therapeutic approach. MicroRNAs are small noncoding RNAs well known to regulate various cellular functions and pathologic events including the formation and progression of cancer. Over the last years, several studies have shed light on the role of microRNAs in BTC, making them potentially attractive therapeutic targets and candidates as biomarkers. In this review, we will focus on the role of oncogenic and tumor suppressor microRNAs and their direct targets in BTC. Furthermore, we summarize and discuss data that evaluate the diagnostic power of deregulated microRNAs as possible future biomarkers for BTC. PMID:27957497

MiR-320a as a Potential Novel Circulating Biomarker of Arrhythmogenic CardioMyopathy.

PubMed

Sommariva, Elena; D'Alessandra, Yuri; Farina, Floriana Maria; Casella, Michela; Cattaneo, Fabio; Catto, Valentina; Chiesa, Mattia; Stadiotti, Ilaria; Brambilla, Silvia; Dello Russo, Antonio; Carbucicchio, Corrado; Vettor, Giulia; Riggio, Daniela; Sandri, Maria Teresa; Barbuti, Andrea; Vernillo, Gianluca; Muratori, Manuela; Dal Ferro, Matteo; Sinagra, Gianfranco; Moimas, Silvia; Giacca, Mauro; Colombo, Gualtiero Ivanoe; Pompilio, Giulio; Tondo, Claudio

2017-07-06

Diagnosis of Arrhythmogenic CardioMyopathy (ACM) is challenging and often late after disease onset. No circulating biomarkers are available to date. Given their involvement in several cardiovascular diseases, plasma microRNAs warranted investigation as potential non-invasive diagnostic tools in ACM. We sought to identify circulating microRNAs differentially expressed in ACM with respect to Healthy Controls (HC) and Idiopathic Ventricular Tachycardia patients (IVT), often in differential diagnosis. ACM and HC subjects were screened for plasmatic expression of 377 microRNAs and validation was performed in 36 ACM, 53 HC, 21 IVT. Variable importance in data partition was estimated through Random Forest analysis and accuracy by Receiver Operating Curves. Plasmatic miR-320a showed 0.53 ± 0.04 fold expression difference in ACM vs. HC (p < 0.01). A similar trend was observed when comparing ACM (n = 13) and HC (n = 17) with athletic lifestyle, a ACM precipitating factor. Importantly, ACM patients miR-320a showed 0.78 ± 0.05 fold expression change vs. IVT (p = 0.03). When compared to non-invasive ACM diagnostic parameters, miR-320a ranked highly in discriminating ACM vs. IVT and it increased their accuracy. Finally, miR-320a expression did not correlate with ACM severity. Our data suggest that miR-320a may be considered a novel potential biomarker of ACM, specifically useful in ACM vs. IVT differentiation.

Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma.

PubMed

Wang, Qihui; Gao, Pan; Wang, Xiaoyi; Duan, Yixiang

2014-01-01

Oral cancer is 1 of the 6 most common human cancers, with an annual incidence of >300,000 cases worldwide. This study aimed to investigate potential biomarkers in human saliva to facilitate the early diagnosis of oral squamous cell carcinoma (OSCC). Unstimulated whole saliva obtained from OSCC patients (n=30) and apparently healthy individuals (n=30) were assayed with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) in hydrophilic interaction chromatography mode. The data were analyzed using a nonparametric Mann-Whitney U test, logistic regression, and the receiver operating characteristic (ROC) to evaluate the predictive power of each of 4 biomarkers, or combinations of biomarkers, for OSCC screening. Four potential salivary biomarkers demonstrated significant differences (P<0.05) in concentrations between patients at stages I-II and the healthy individuals. The area under the curve (AUC) values in control vs OSCC I-II mode based on choline, betaine, pipecolinic acid, and l-carnitine were 0.926, 0.759, 0.994, and 0.708, respectively. Four salivary biomarkers in combination yielded satisfactory accuracy (0.997), sensitivity (100%), and specificity (96.7%) in distinguishing OSCC I-II from control. Salivary metabolite biomarkers for the early diagnosis of OSCC were verified in this study. The proposed approach is expected to be applied as a potential technique of preclinical screening of OSCC. © 2013.

Clinical, functional, behavioural and epigenomic biomarkers of obesity.

PubMed

Lafortuna, Claudio L; Tovar, Armando R; Rastelli, Fabio; Tabozzi, Sarah A; Caramenti, Martina; Orozco-Ruiz, Ximena; Aguilar-Lopez, Miriam; Guevara-Cruz, Martha; Avila-Nava, Azalia; Torres, Nimbe; Bertoli, Gloria

2017-06-01

Overweight and obesity are highly prevalent conditions worldwide, linked to an increased risk for death, disability and disease due to metabolic and biochemical abnormalities affecting the biological human system throughout different domains. Biomarkers, defined as indicators of biological processes in health and disease, relevant for body mass excess management have been identified according to different criteria, including anthropometric and molecular indexes, as well as physiological and behavioural aspects. Analysing these different biomarkers, we identified their potential role in diagnosis, prognosis and treatment. Epigenetic biomarkers, cellular mediators of inflammation and factors related to microbiota-host interactions may be considered to have a theranostic value. Though, the molecular processes responsible for the biological phenomenology detected by the other analysed markers, is not clear yet. Nevertheless, these biomarkers possess valuable diagnostic and prognostic power. A new frontier for theranostic biomarkers can be foreseen in the exploitation of parameters defining behaviours and lifestyles linked to the risk of obesity, capable to describe the effects of interventions for obesity prevention and treatment which include also behaviour change strategies.

Screening and identification of potential protein biomarkers for evaluating the efficacy of intensive therapy in pulmonary tuberculosis.

PubMed

Jiang, Ting-Ting; Shi, Li-Ying; Chen, Jing; Wei, Li-Liang; Li, Meng; Hu, Yu-Ting; Gan, Lin; Liu, Chang-Ming; Tu, Hui-Hui; Li, Zhi-Bin; Yi, Wen-Jing; Li, Ji-Cheng

2018-06-27

This research aimed to discover potential biomarkers for evaluating the therapeutic efficacy of intensive therapy in pulmonary tuberculosis (TB). Protein profiles in 2-months intensively treated TB patients, untreated TB patients, and healthy controls were investigated with iTRAQ-2DLC-MS/MS technique. 71 differential proteins were identified in 2-months intensively treated TB patients. Significant differences in complement component C7 (CO7), apolipoprotein A-IV (APOA4), apolipoprotein C-II (APOC2), and angiotensinogen (ANGT) were found by ELISA validation. CO7 and ANGT were also found significantly different in sputum negative patients, compared with sputum positive patients after intensive treatment. Clinical analysis showed that after 2-months intensive treatment several indicators were significantly changed, and the one-year cure rate of sputum negative patients were significantly higher than sputum positive patients. Diagnostic models consisting of APOC2, CO7 and APOA4 were established to distinguish intensively treated TB patients from untreated TB patients and healthy controls with the AUC value of 0.910 and 0.935. Meanwhile, ANGT and CO7 were combined to identify sputum negative and sputum positive TB patients after intensive treatment with 89.36% sensitivity, 71.43% specificity, and the AUC value of 0.853. The results showed that APOC2, CO7, APOA4, and ANGT may be potential biomarkers for evaluating the efficacy of intensive anti-TB therapy. Copyright © 2018. Published by Elsevier Inc.

The use of biomarkers in occupational health research, practice, and policy.

PubMed

Schulte, P A; Hauser, J E

2012-08-13

Biomarkers are potentially useful tools for occupational health and safety research, practice, and policy. However, the full realization of this potential has not been achieved. In this paper, the progress made in these three usage areas is reviewed to identify what efforts can be taken to realize the full promise of biomarkers. Biomarker uses are described by a diverse taxonomy that builds on the categories of exposure, effect and susceptibility, and the continuum between exposure and disease prognosis. The most significant uses of biomarkers in occupational health have been in biological monitoring of workers. Other important uses have been in enhancing research and assessing mechanisms of action of occupational toxicants at low exposures. Seven critical areas will influence the extent to which the potential of biomarkers in occupational health and safety is realized. These include: (1) adequate investment in validation; (2) obtaining international agreement on exposure guidelines; (3) exploring the utility of biomarkers in regulation; (4) applying biomarkers to critical occupational safety and health questions; (5) developing the exposome; (6) utilizing biomarkers to address emerging occupational health issues; and (7) continuing to address the ethical and social justice issues related to biomarkers. Overall, if biomarkers are to make a major contribution to occupational health and safety then a more holistic approach to bringing them from the laboratory to practice will be needed. Published by Elsevier Ireland Ltd.

Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells

NASA Astrophysics Data System (ADS)

Xu, Wenwei; Mezencev, Roman; Kim, Byungkyu; Wang, Lijuan; McDonald, John; Sulchek, Todd; Sulchek Team; McDonald Team

2013-03-01

The metastatic potential of cells is an important parameter in the design of optimal strategies for the personalized treatment of cancer. Using atomic force microscopy (AFM), we show that ovarian cancer cells are generally softer and display lower intrinsic variability in cell stiffness than non-malignant ovarian epithelial cells. A detailed study of highly invasive ovarian cancer cells (HEY A8) and their less invasive parental cells (HEY), demonstrates that deformability can serve as an accurate biomarker of metastatic potential. Comparative gene expression profiling indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling, microscopic examination of actin fiber structure in these cell lines is consistent with this prediction. Our results indicate that cell stiffness not only distinguishes ovarian cancer cells from non-malignant cells, but may also be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.

Integration of lipidomics and transcriptomics unravels aberrant lipid metabolism and defines cholesteryl oleate as potential biomarker of prostate cancer

NASA Astrophysics Data System (ADS)

Li, Jia; Ren, Shancheng; Piao, Hai-Long; Wang, Fubo; Yin, Peiyuan; Xu, Chuanliang; Lu, Xin; Ye, Guozhu; Shao, Yaping; Yan, Min; Zhao, Xinjie; Sun, Yinghao; Xu, Guowang

2016-02-01

In-depth delineation of lipid metabolism in prostate cancer (PCa) is significant to open new insights into prostate tumorigenesis and progression, and provide potential biomarkers with greater accuracy for improved diagnosis. Here, we performed lipidomics and transcriptomics in paired prostate cancer tumor (PCT) and adjacent nontumor (ANT) tissues, followed by external validation of biomarker candidates. We identified major dysregulated pathways involving lipogenesis, lipid uptake and phospholipids remodeling, correlated with widespread lipid accumulation and lipid compositional reprogramming in PCa. Specifically, cholesteryl esters (CEs) were most prominently accumulated in PCa, and significantly associated with cancer progression and metastasis. We showed that overexpressed scavenger receptor class B type I (SR-BI) may contribute to CEs accumulation. In discovery set, CEs robustly differentiated PCa from nontumor (area under curve (AUC) of receiver operating characteristics (ROC), 0.90-0.94). In validation set, CEs potently distinguished PCa and non-malignance (AUC, 0.84-0.91), and discriminated PCa and benign prostatic hyperplasia (BPH) (AUC, 0.90-0.96), superior to serum prostate-specific antigen (PSA) (AUC = 0.83). Cholesteryl oleate showed highest AUCs in distinguishing PCa from non-malignance or BPH (AUC = 0.91 and 0.96). Collectively, our results unravel the major lipid metabolic aberrations in PCa and imply the potential role of CEs, particularly, cholesteryl oleate, as molecular biomarker for PCa detection.

Circulating Long Noncoding RNAs as Potential Biomarkers of Sepsis: A Preliminary Study.

PubMed

Dai, Yu; Liang, Zhixin; Li, Yulin; Li, Chunsun; Chen, Liangan

2017-11-01

Long noncoding RNAs (lncRNAs) are becoming promising biomarker candidates in various diseases as assessed via sequencing technologies. Sepsis is a life-threatening disease without ideal biomarkers. The aim of this study was to investigate the expression profile of lncRNAs in the peripheral blood of sepsis patients and to find potential biomarkers of sepsis. A lncRNA expression profile was performed using peripheral blood from three sepsis patients and three healthy volunteers using microarray screening. The differentially expressed lncRNAs were validated by real-time quantitative polymerase chain reaction (qRT-PCR) in a further set of 22 sepsis patients and 22 healthy volunteers. Among 1316 differentially expressed lncRNAs, 771 were downregulated and 545 were upregulated. Results of the qRT-PCR were consistent with the microarray data. lncRNA ENST00000452391.1, uc001vji.1, and uc021zxw.1 were significantly differentially expressed between sepsis patients and healthy volunteers. Moreover, lncRNA ENST00000504301.1 and ENST00000452391.1 were significantly differentially expressed between sepsis survivors and nonsurvivors. The lncRNA expression profile in the peripheral blood of sepsis patients significantly differed from that of healthy volunteers. Circulating lncRNAs may be good candidates for sepsis biomarkers.

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.

ANALYSIS OR THE POTENTIAL SPERM BIOMARKER, SP22, IN HUMAN SEMEN

EPA Science Inventory

ANALYSIS OF THE POTENTIAL SPERM BIOMARKER SP22 IN HUMAN SEMEN
Rebecca A. Morris Ph.D.1, Gary R. Klinefelter Ph.D.1, Naomi L. Roberts 1, Juan D. Suarez 1,
Lillian F. Strader 1, Susan C. Jeffay 1 and Sally D. Perreault Ph.D.1

1 U.S. EPA / ORD / National Health a...

DNA Methylation Biomarkers: Cancer and Beyond

PubMed Central

Mikeska, Thomas; Craig, Jeffrey M.

2014-01-01

Biomarkers are naturally-occurring characteristics by which a particular pathological process or disease can be identified or monitored. They can reflect past environmental exposures, predict disease onset or course, or determine a patient’s response to therapy. Epigenetic changes are such characteristics, with most epigenetic biomarkers discovered to date based on the epigenetic mark of DNA methylation. Many tissue types are suitable for the discovery of DNA methylation biomarkers including cell-based samples such as blood and tumor material and cell-free DNA samples such as plasma. DNA methylation biomarkers with diagnostic, prognostic and predictive power are already in clinical trials or in a clinical setting for cancer. Outside cancer, strong evidence that complex disease originates in early life is opening up exciting new avenues for the detection of DNA methylation biomarkers for adverse early life environment and for estimation of future disease risk. However, there are a number of limitations to overcome before such biomarkers reach the clinic. Nevertheless, DNA methylation biomarkers have great potential to contribute to personalized medicine throughout life. We review the current state of play for DNA methylation biomarkers, discuss the barriers that must be crossed on the way to implementation in a clinical setting, and predict their future use for human disease. PMID:25229548

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

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

Biomarkers to guide clinical therapeutics in rheumatology?

PubMed

Robinson, William H; Mao, Rong

2016-03-01

The use of biomarkers in rheumatology can help identify disease risk, improve diagnosis and prognosis, target therapy, assess response to treatment, and further our understanding of the underlying pathogenesis of disease. Here, we discuss the recent advances in biomarkers for rheumatic disorders, existing impediments to progress in this field, and the potential of biomarkers to enable precision medicine and thereby transform rheumatology. Although significant challenges remain, progress continues to be made in biomarker discovery and development for rheumatic diseases. The use of next-generation technologies, including large-scale sequencing, proteomic technologies, metabolomic technologies, mass cytometry, and other single-cell analysis and multianalyte analysis technologies, has yielded a slew of new candidate biomarkers. Nevertheless, these biomarkers still require rigorous validation and have yet to make their way into clinical practice and therapeutic development. This review focuses on advances in the biomarker field in the last 12 months as well as the challenges that remain. Better biomarkers, ideally mechanistic ones, are needed to guide clinical decision making in rheumatology. Although the use of next-generation techniques for biomarker discovery is making headway, it is imperative that the roadblocks in our search for new biomarkers are overcome to enable identification of biomarkers with greater diagnostic and predictive utility. Identification of biomarkers with robust diagnostic and predictive utility would enable precision medicine in rheumatology.

mRNA transcripts as molecular biomarkers in medicine and nutrition

PubMed Central

Sunde, Roger A.

2010-01-01

In medicine, mRNA transcripts are being developed as molecular biomarkers for the diagnosis and treatment of a number of diseases. These biomarkers offer early and more accurate prediction and diagnosis of disease and disease progression, and ability to identify individuals at risk. Use of microarrays also offers opportunity to identify orthogonal (uncorrelated) biomarkers not known to be linked with conventional biomarkers. Investigators are increasingly using blood as a surrogate tissue for biopsy and analysis; total RNA isolated from whole blood is predominantly from erythroid cells, and whole blood mRNA share more than 80% of the transcriptome with major tissues. Thus blood mRNA biomarkers for individualized disease prediction and diagnosis are an exciting area in medicine; mRNA biomarkers in nutrition have potential application that parallel these opportunities. Assessment of selenium (Se) status and requirements is one area where tissue mRNA levels have been used successfully. Selenoprotein-H and selenoprotein-W as well as glutathione peroxidase-1 (Gpx1) mRNAs are highly down-regulated in Se deficiency in rat liver, and the minimum dietary Se requirement is 0.06–0.07 μg Se/g based on these biomarkers, similar to requirements determined using conventional biomarkers. Blood Gpx1 mRNA can also be used to determine Se requirements in rats, showing that blood mRNA has potential for assessment of nutrient status. Future research is needed to develop mRNA biomarker panels for all nutrients that will discriminate between deficient, marginal, adequate, and supernutritional individuals and populations, and differentiate between individuals that will benefit versus be adversely affected by nutrient supplementation. PMID:20303730

Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury.

PubMed

Gao, Yuan; Cao, Zhijun; Yang, Xi; Abdelmegeed, Mohamed A; Sun, Jinchun; Chen, Si; Beger, Richard D; Davis, Kelly; Salminen, William F; Song, Byoung-Joon; Mendrick, Donna L; Yu, Li-Rong

2017-01-01

Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury. Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS. Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP. This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

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.

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.

Long Non-Coding RNA: Potential Diagnostic and Therapeutic Biomarker for Major Depressive Disorder.

PubMed

Cui, Xuelian; Sun, Xinyang; Niu, Wei; Kong, Lingming; He, Mingjun; Zhong, Aifang; Chen, Shengdong; Jiang, Kunhong; Zhang, Liyi; Cheng, Zaohuo

2016-12-31

BACKGROUND The criteria for diagnosing depression are based on behavioral observation and self-reporting of symptoms by the patients or guardians without any biological validation of the disease. This study aimed to identify long non-coding RNAs (lncRNAs) in peripheral blood mononuclear cells (PBMCs) as robust and predictive biomarkers for diagnosis and therapy response in major depressive disorder (MDD). MATERIAL AND METHODS We used human lncRNA 3.0 microarray profiling (which covers 30,586 human lncRNAs), using PBMCs from five MDD patients and five controls. Differentially expressed lncRNAs in the PBMCs of MDD patients were identified, of which 10 candidate lncRNAs were selected for real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis in a larger cohort of 138 MDD patients and 63 healthy controls. Then among the 138 MDD patients who received standard antidepressant treatment, 30 were randomly selected for lncRNAs expression retesting and symptomatology assessments after three-weeks and six-weeks of antidepressant treatment. RESULTS Six lncRNAs (TCONS_00019174, ENST00000566208, NONHSAG045500, ENST00000517573, NONHSAT034045, and NONHSAT142707) were significantly downregulated in MDD patients compared to control patients, and the area under the receiver operator curve (ROC) of these six lncRNAs cases, combined, was 0.719 (95% confidence interval (CI): 0.617-0.821). There was no difference in the expression of these six lncRNAs based on gender (p>0.05) or age (p>0.05). CONCLUSIONS These results suggest that the combined expression of six lncRNAs in PBMCs may serve as a potential biomarker for diagnosis and therapy response of MDD in the clinical setting.

Role of miRNAs and their potential to be useful as diagnostic and prognostic biomarkers in gastric cancer

PubMed Central

da Silva Oliveira, Kelly Cristina; Thomaz Araújo, Taíssa Maíra; Albuquerque, Camila Inagaki; Barata, Gabriela Alcantara; Gigek, Carolina Oliveira; Leal, Mariana Ferreira; Wisnieski, Fernanda; Rodrigues Mello Junior, Fernando Augusto; Khayat, André Salim; de Assumpção, Paulo Pimentel; Rodriguez Burbano, Rommel Mário; Smith, Marília Cardoso; Calcagno, Danielle Queiroz

2016-01-01

Alterations in epigenetic control of gene expression play an important role in many diseases, including gastric cancer. Many studies have identified a large number of upregulated oncogenic miRNAs and downregulated tumour-suppressor miRNAs in this type of cancer. In this review, we provide an overview of the role of miRNAs, pointing to their potential to be useful as diagnostic and/or prognostic biomarkers in gastric cancer. Moreover, we discuss the influence of polymorphisms and epigenetic modifications on miRNA activity. PMID:27672290

MMP-1 and Pro-MMP-10 as potential urinary pharmacodynamic biomarkers of FGFR3-targeted therapy in patients with bladder cancer.

PubMed

Du, Xiangnan; Lin, Benjamin C; Wang, Qian-Rena; Li, Hao; Ingalla, Ellen; Tien, Janet; Rooney, Isabelle; Ashkenazi, Avi; Penuel, Elicia; Qing, Jing

2014-12-15

The aim of this study was to identify noninvasive pharmacodynamic biomarkers of FGFR3-targeted therapies in bladder cancer to facilitate the clinical development of experimental agent targeting FGFR3. Potential soluble pharmacodynamic biomarkers of FGFR3 were identified using a combination of transcriptional profiling and biochemical analyses in preclinical models. Two matrix metalloproteinases (MMP), MMP-1 and MMP-10, were selected for further studies in human bladder cancer xenograft models treated with a specific anti-FGFR3 monoclonal antibody, R3Mab. Serum and urinary levels of MMP-1 and MMP-10 were determined in healthy donors and patients with bladder cancer. The modulation of MMP-1 and MMP-10 by R3Mab in patients with bladder cancer was further evaluated in a phase I dose-escalation study. MMP-1 and MMP-10 mRNA and protein were downmodulated by FGFR3 shRNA and R3Mab in bladder cancer cell lines. FGFR3 signaling promoted the expression and secretion of MMP-1 and pro-MMP-10 in a MEK-dependent fashion. In bladder cancer xenograft models, R3Mab substantially blocked tumor progression and reduced the protein levels of human MMP-1 and pro-MMP-10 in tumor tissues as well as in mouse serum. Furthermore, both MMP-1 and pro-MMP-10 were elevated in the urine of patients with advanced bladder cancer. In a phase I dose-escalation trial, R3Mab administration resulted in an acute reduction of urinary MMP-1 and pro-MMP-10 levels in patients with bladder cancer. These findings reveal a critical role of FGFR3 in regulating MMP-1 and pro-MMP-10 expression and secretion, and identify urinary MMP-1 and pro-MMP-10 as potential pharmacodynamic biomarkers for R3Mab in patients with bladder cancer. ©2014 American Association for Cancer Research.

Characterization of biomarkers in stroke based on ego-networks and pathways.

PubMed

Li, Haixia; Guo, Qianqian

2017-12-01

To explore potential biomarkers in stroke based on ego-networks and pathways. EgoNet method was applied to search for the underlying biomarkers in stroke using transcription profiling of E-GEOD-58294 and protein-protein interaction (PPI) data. Eight ego-genes were identified from PPI network according to the degree characteristics at the criteria of top 5% ranked z-sore and degree >1. Eight candidate ego-networks with classification accuracy ≥0.9 were selected. After performed randomization test, seven significant ego-networks with adjusted p value < 0.05 were identified. Pathway enrichment analysis was then conducted with these ego-networks to search for the significant pathways. Finally, two significant pathways were identified, and six of seven ego-networks were enriched to "3'-UTR-mediated translational regulation" pathway, indicating that this pathway performs an important role in the development of stroke. Seven ego-networks were constructed using EgoNet and two significant enriched by pathways were identified. These may provide new insights into the potential biomarkers for the development of stroke.

Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Biomarkers of Kidney Cancer.

PubMed

Song, Yimeng; Zhong, Lijun; Zhou, Juntuo; Lu, Min; Xing, Tianying; Ma, Lulin; Shen, Jing

2017-12-01

Renal cell carcinoma (RCC) is a malignant and metastatic cancer with 95% mortality, and clear cell RCC (ccRCC) is the most observed among the five major subtypes of RCC. Specific biomarkers that can distinguish cancer tissues from adjacent normal tissues should be developed to diagnose this disease in early stages and conduct a reliable prognostic evaluation. Data-independent acquisition (DIA) strategy has been widely employed in proteomic analysis because of various advantages, including enhanced protein coverage and reliable data acquisition. In this study, a DIA workflow is constructed on a quadrupole-Orbitrap LC-MS platform to reveal dysregulated proteins between ccRCC and adjacent normal tissues. More than 4000 proteins are identified, 436 of these proteins are dysregulated in ccRCC tissues. Bioinformatic analysis reveals that multiple pathways and Gene Ontology items are strongly associated with ccRCC. The expression levels of L-lactate dehydrogenase A chain, annexin A4, nicotinamide N-methyltransferase, and perilipin-2 examined through RT-qPCR, Western blot, and immunohistochemistry confirm the validity of the proteomic analysis results. The proposed DIA workflow yields optimum time efficiency and data reliability and provides a good choice for proteomic analysis in biological and clinical studies, and these dysregulated proteins might be potential biomarkers for ccRCC diagnosis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Circulating sortilin level as a potential biomarker for coronary atherosclerosis and diabetes mellitus.

PubMed

Oh, Tae Jung; Ahn, Chang Ho; Kim, Bo-Rahm; Kim, Kyoung Min; Moon, Jae Hoon; Lim, Soo; Park, Kyong Soo; Lim, Cheong; Jang, HakChul; Choi, Sung Hee

2017-07-20

A previous genome-wide association study showed that a genetic variant of sortilin was associated with the risk of coronary artery disease (CAD). However, the role of circulating sortilin is still unknown. We investigated the potential role of plasma sortilin as a biomarker for CAD and diabetes mellitus. We enrolled statin-naïve subjects with CAD (n = 31) who underwent coronary artery bypass surgery and control subjects (n = 116) who were free from CAD as evaluated by coronary CT angiography. The presence of diabetes mellitus was evaluated and plasma sortilin levels were measured with a commercial ELISA kit. Plasma sortilin levels were higher in subjects with CAD and subjects with diabetes mellitus than in those without CAD or diabetes mellitus. Subjects in the highest sortilin tertile group were older and had higher glucose and HbA1c levels, but lipid profiles in the three tertile groups were comparable. Multivariable logistic regression analysis revealed that sortilin levels were independently associated with CAD. In addition, the receiver operating characteristic curve analysis showed that plasma sortilin levels could identify the presence of CAD or diabetes mellitus. Elevated circulating sortilin levels are associated with CAD and diabetes mellitus and can be used as a biomarker of both diseases in statin-naïve subjects.

Potentials of single-cell biology in identification and validation of disease biomarkers.

PubMed

Niu, Furong; Wang, Diane C; Lu, Jiapei; Wu, Wei; Wang, Xiangdong

2016-09-01

Single-cell biology is considered a new approach to identify and validate disease-specific biomarkers. However, the concern raised by clinicians is how to apply single-cell measurements for clinical practice, translate the message of single-cell systems biology into clinical phenotype or explain alterations of single-cell gene sequencing and function in patient response to therapies. This study is to address the importance and necessity of single-cell gene sequencing in the identification and development of disease-specific biomarkers, the definition and significance of single-cell biology and single-cell systems biology in the understanding of single-cell full picture, the development and establishment of whole-cell models in the validation of targeted biological function and the figure and meaning of single-molecule imaging in single cell to trace intra-single-cell molecule expression, signal, interaction and location. We headline the important role of single-cell biology in the discovery and development of disease-specific biomarkers with a special emphasis on understanding single-cell biological functions, e.g. mechanical phenotypes, single-cell biology, heterogeneity and organization of genome function. We have reason to believe that such multi-dimensional, multi-layer, multi-crossing and stereoscopic single-cell biology definitely benefits the discovery and development of disease-specific biomarkers. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet.

PubMed

Cappuccio, Gerarda; Pinelli, Michele; Alagia, Marianna; Donti, Taraka; Day-Salvatore, Debra-Lynn; Veggiotti, Pierangelo; De Giorgis, Valentina; Lunghi, Simona; Vari, Maria Stella; Striano, Pasquale; Brunetti-Pierri, Nicola; Kennedy, Adam D; Elsea, Sarah H

2017-01-01

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation.

Biochemical phenotyping unravels novel metabolic abnormalities and potential biomarkers associated with treatment of GLUT1 deficiency with ketogenic diet

PubMed Central

Cappuccio, Gerarda; Pinelli, Michele; Alagia, Marianna; Donti, Taraka; Day-Salvatore, Debra-Lynn; Veggiotti, Pierangelo; De Giorgis, Valentina; Lunghi, Simona; Vari, Maria Stella; Striano, Pasquale; Brunetti-Pierri, Nicola; Kennedy, Adam D.

2017-01-01

Global metabolomic profiling offers novel opportunities for the discovery of biomarkers and for the elucidation of pathogenic mechanisms that might lead to the development of novel therapies. GLUT1 deficiency syndrome (GLUT1-DS) is an inborn error of metabolism due to reduced function of glucose transporter type 1. Clinical presentation of GLUT1-DS is heterogeneous and the disorder mirrors patients with epilepsy, movement disorders, or any paroxysmal events or unexplained neurological manifestation triggered by exercise or fasting. The diagnostic biochemical hallmark of the disease is a reduced cerebrospinal fluid (CSF)/blood glucose ratio and the only available treatment is ketogenic diet. This study aimed at advancing our understanding of the biochemical perturbations in GLUT1-DS pathogenesis through biochemical phenotyping and the treatment of GLUT1-DS with a ketogenic diet. Metabolomic analysis of three CSF samples from GLUT1-DS patients not on ketogenic diet was feasible inasmuch as CSF sampling was used for diagnosis before to start with ketogenic diet. The analysis of plasma and urine samples obtained from GLUT1-DS patients treated with a ketogenic diet showed alterations in lipid and amino acid profiles. While subtle, these were consistent findings across the patients with GLUT1-DS on ketogenic diet, suggesting impacts on mitochondrial physiology. Moreover, low levels of free carnitine were present suggesting its consumption in GLUT1-DS on ketogenic diet. 3-hydroxybutyrate, 3-hydroxybutyrylcarnitine, 3-methyladipate, and N-acetylglycine were identified as potential biomarkers of GLUT1-DS on ketogenic diet. This is the first study to identify CSF, plasma, and urine metabolites associated with GLUT1-DS, as well as biochemical changes impacted by a ketogenic diet. Potential biomarkers and metabolic insights deserve further investigation. PMID:28961260

Biomarkers for equine joint injury and osteoarthritis.

PubMed

McIlwraith, C Wayne; Kawcak, Christopher E; Frisbie, David D; Little, Christopher B; Clegg, Peter D; Peffers, Mandy J; Karsdal, Morten A; Ekman, Stina; Laverty, Sheila; Slayden, Richard A; Sandell, Linda J; Lohmander, L S; Kraus, Virginia B

2018-03-01

We report the results of a symposium aimed at identifying validated biomarkers that can be used to complement clinical observations for diagnosis and prognosis of joint injury leading to equine osteoarthritis (OA). Biomarkers might also predict pre-fracture change that could lead to catastrophic bone failure in equine athletes. The workshop was attended by leading scientists in the fields of equine and human musculoskeletal biomarkers to enable cross-disciplinary exchange and improve knowledge in both. Detailed proceedings with strategic planning was written, added to, edited and referenced to develop this manuscript. The most recent information from work in equine and human osteoarthritic biomarkers was accumulated, including the use of personalized healthcare to stratify OA phenotypes, transcriptome analysis of anterior cruciate ligament (ACL) and meniscal injuries in the human knee. The spectrum of "wet" biomarker assays that are antibody based that have achieved usefulness in both humans and horses, imaging biomarkers and the role they can play in equine and human OA was discussed. Prediction of musculoskeletal injury in the horse remains a challenge, and the potential usefulness of spectroscopy, metabolomics, proteomics, and development of biobanks to classify biomarkers in different stages of equine and human OA were reviewed. The participants concluded that new information and studies in equine musculoskeletal biomarkers have potential translational value for humans and vice versa. OA is equally important in humans and horses, and the welfare issues associated with catastrophic musculoskeletal injury in horses add further emphasis to the need for good validated biomarkers in the horse. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:823-831, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

NMR studies of preimplantation embryo metabolism in human assisted reproductive techniques: a new biomarker for assessment of embryo implantation potential.

PubMed

Pudakalakatti, Shivanand M; Uppangala, Shubhashree; D'Souza, Fiona; Kalthur, Guruprasad; Kumar, Pratap; Adiga, Satish Kumar; Atreya, Hanudatta S

2013-01-01

There has been growing interest in understanding energy metabolism in human embryos generated using assisted reproductive techniques (ART) for improving the overall success rate of the method. Using NMR spectroscopy as a noninvasive tool, we studied human embryo metabolism to identify specific biomarkers to assess the quality of embryos for their implantation potential. The study was based on estimation of pyruvate, lactate and alanine levels in the growth medium, ISM1, used in the culture of embryos. An NMR study involving 127 embryos from 48 couples revealed that embryos transferred on Day 3 (after 72 h in vitro culture) with successful implantation (pregnancy) exhibited significantly (p < 10(-5) ) lower pyruvate/alanine ratios compared to those that failed to implant. Lactate levels in media were similar for all embryos. This implies that in addition to lactate production, successfully implanted embryos use pyruvate to produce alanine and other cellular functions. While pyruvate and alanine individually have been used as biomarkers, the present study highlights the potential of combining them to provide a single parameter that correlates strongly with implantation potential. Copyright © 2012 John Wiley & Sons, Ltd.

Network-based co-expression analysis for exploring the potential diagnostic biomarkers of metastatic melanoma.

PubMed

Wang, Li-Xin; Li, Yang; Chen, Guan-Zhi

2018-01-01

Metastatic melanoma is an aggressive skin cancer and is one of the global malignancies with high mortality and morbidity. It is essential to identify and verify diagnostic biomarkers of early metastatic melanoma. Previous studies have systematically assessed protein biomarkers and mRNA-based expression characteristics. However, molecular markers for the early diagnosis of metastatic melanoma have not been identified. To explore potential regulatory targets, we have analyzed the gene microarray expression profiles of malignant melanoma samples by co-expression analysis based on the network approach. The differentially expressed genes (DEGs) were screened by the EdgeR package of R software. A weighted gene co-expression network analysis (WGCNA) was used for the identification of DEGs in the special gene modules and hub genes. Subsequently, a protein-protein interaction network was constructed to extract hub genes associated with gene modules. Finally, twenty-four important hub genes (RASGRP2, IKZF1, CXCR5, LTB, BLK, LINGO3, CCR6, P2RY10, RHOH, JUP, KRT14, PLA2G3, SPRR1A, KRT78, SFN, CLDN4, IL1RN, PKP3, CBLC, KRT16, TMEM79, KLK8, LYPD3 and LYPD5) were treated as valuable factors involved in the immune response and tumor cell development in tumorigenesis. In addition, a transcriptional regulatory network was constructed for these specific modules or hub genes, and a few core transcriptional regulators were found to be mostly associated with our hub genes, including GATA1, STAT1, SP1, and PSG1. In summary, our findings enhance our understanding of the biological process of malignant melanoma metastasis, enabling us to identify specific genes to use for diagnostic and prognostic markers and possibly for targeted therapy.

Blood biomarkers of kidney transplant rejection, an endless search?

PubMed

Jacquemont, Lola; Soulillou, Jean-Paul; Degauque, Nicolas

2017-07-01

The tailoring of immunosuppressive treatment is recognized as a promising strategy to improve long-term kidney graft outcome. To guide the standard care of transplant recipients, physicians need objective biomarkers that can identify an ongoing pathology with the graft or low intensity signals that will be later evolved to accelerated transplant rejection. The early identification of 'high-risk /low-risk' patients enables the adjustment of standard of caring, including managing the frequency of clinical visits and the immunosuppression dosing. Given their ease of availability and the compatibility with a large technical array, blood-based biomarkers have been widely scrutinized for use as potential predictive and diagnostic biomarkers. Areas covered: Here, the authors report on non-invasive biomarkers, such as modification of immune cell subsets and mRNA and miRNA profiles, identified in the blood of kidney transplant recipients collected before or after transplantation. Expert commentary: Combined with functional tests, the identification of biomarkers will improve our understanding of pathological processes and will contribute to a global improvement in clinical management.

Potential for proteomic approaches in determining efficacy biomarkers following administration of fish oils rich in omega-3 fatty acids: application in pancreatic cancers.

PubMed

Runau, Franscois; Arshad, Ali; Isherwood, John; Norris, Leonie; Howells, Lynne; Metcalfe, Matthew; Dennison, Ashley

2015-06-01

Pancreatic cancer is a disease with a significantly poor prognosis. Despite modern advances in other medical, surgical, and oncologic therapy, the outcome from pancreatic cancer has improved little over the last 40 years. To improve the management of this difficult disease, trials investigating the use of dietary and parenteral fish oils rich in omega-3 (ω-3) fatty acids, exhibiting proven anti-inflammatory and anticarcinogenic properties, have revealed favorable results in pancreatic cancers. Proteomics is the large-scale study of proteins that attempts to characterize the complete set of proteins encoded by the genome of an organism and that, with the use of sensitive mass spectrometric-based techniques, has allowed high-throughput analysis of the proteome to aid identification of putative biomarkers pertinent to given disease states. These biomarkers provide useful insight into potentially discovering new markers for early detection or elucidating the efficacy of treatment on pancreatic cancers. Here, our review identifies potential proteomic-based biomarkers in pancreatic cancer relating to apoptosis, cell proliferation, angiogenesis, and metabolic regulation in clinical studies. We also reviewed proteomic biomarkers from the administration of ω-3 fatty acids that act on similar anticarcinogenic pathways as above and reflect that proteomic studies on the effect of ω-3 fatty acids in pancreatic cancer will yield favorable results. © 2015 American Society for Parenteral and Enteral Nutrition.

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.

Protective or pathogenic effects of vascular endothelial growth factor (VEGF) as potential biomarker in cerebral malaria.

PubMed

Canavese, Miriam; Spaccapelo, Roberta

2014-03-01

Cerebral malaria (CM) is the major lethal complication of Plasmodium falciparum infection. It is characterized by persistent coma along with symmetrical motor signs. Several clinical, histopathological, and laboratory studies have suggested that cytoadherence of parasitized erythrocytes, neural injury by malarial toxin, and excessive inflammatory cytokine production are possible pathogenic mechanisms. Although the detailed pathophysiology of CM remains unsolved, it is thought that the binding of parasitized erythrocytes to the cerebral endothelia of microvessels, leading to their occlusion and the consequent angiogenic dysregulation play a key role in the disease pathogenesis. Recent evidences showed that vascular endothelial growth factor (VEGF) and its receptor-related molecules are over-expressed in the brain tissues of CM patients, as well as increased levels of VEGF are detectable in biologic samples from malaria patients. Whether the modulation of VEGF is causative agent of CM mortality or a specific phenotype of patients with susceptibility to fatal CM needs further evaluation. Currently, there is no biological test available to confirm the diagnosis of CM and its complications. It is hoped that development of biomarkers to identify patients and potential risk for adverse outcomes would greatly enhance better intervention and clinical management to improve the outcomes. We review and discuss here what it is currently known in regard to the role of VEGF in CM as well as VEGF as a potential biomarker.

Robust Selection Algorithm (RSA) for Multi-Omic Biomarker Discovery; Integration with Functional Network Analysis to Identify miRNA Regulated Pathways in Multiple Cancers.

PubMed

Sehgal, Vasudha; Seviour, Elena G; Moss, Tyler J; Mills, Gordon B; Azencott, Robert; Ram, Prahlad T

2015-01-01

MicroRNAs (miRNAs) play a crucial role in the maintenance of cellular homeostasis by regulating the expression of their target genes. As such, the dysregulation of miRNA expression has been frequently linked to cancer. With rapidly accumulating molecular data linked to patient outcome, the need for identification of robust multi-omic molecular markers is critical in order to provide clinical impact. While previous bioinformatic tools have been developed to identify potential biomarkers in cancer, these methods do not allow for rapid classification of oncogenes versus tumor suppressors taking into account robust differential expression, cutoffs, p-values and non-normality of the data. Here, we propose a methodology, Robust Selection Algorithm (RSA) that addresses these important problems in big data omics analysis. The robustness of the survival analysis is ensured by identification of optimal cutoff values of omics expression, strengthened by p-value computed through intensive random resampling taking into account any non-normality in the data and integration into multi-omic functional networks. Here we have analyzed pan-cancer miRNA patient data to identify functional pathways involved in cancer progression that are associated with selected miRNA identified by RSA. Our approach demonstrates the way in which existing survival analysis techniques can be integrated with a functional network analysis framework to efficiently identify promising biomarkers and novel therapeutic candidates across diseases.

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.

Toxicogenomic identification of biomarkers of acute respiratory exposure sensitizing agents

EPA Science Inventory

Allergy induction requires multiple exposures to an agent. Therefore the development of high-throughput or in vitro assays for effective screening of potential sensitizers will require the identification of biomarkers. The goal of this preliminary study was to identify potential ...

Candidate immune biomarkers for radioimmunotherapy.

PubMed

Levy, Antonin; Nigro, Giulia; Sansonetti, Philippe J; Deutsch, Eric

2017-08-01

Newly available immune checkpoint blockers (ICBs), capable to revert tumor immune tolerance, are revolutionizing the anticancer armamentarium. Recent evidence also established that ionizing radiation (IR) could produce antitumor immune responses, and may as well synergize with ICBs. Multiple radioimmunotherapy combinations are thenceforth currently assessed in early clinical trials. Past examples have highlighted the need for treatment personalization, and there is an unmet need to decipher immunological biomarkers that could allow selecting patients who could benefit from these promising but expensive associations. Recent studies have identified potential predictive and prognostic immune assays at the cellular (tumor microenvironment composition), genomic (mutational/neoantigen load), and peripheral blood levels. Within this review, we collected the available evidence regarding potential personalized immune biomarker-directed radiation therapy strategies that might be used for patient selection in the era of radioimmunotherapy. Copyright © 2017. Published by Elsevier B.V.

A preliminary analysis of microRNA as potential clinical biomarker for schizophrenia.

PubMed

Sun, Xin-yang; Zhang, Jin; Niu, Wei; Guo, Wei; Song, Hong-tao; Li, Heng-yu; Fan, Hui-min; Zhao, Lin; Zhong, Ai-fang; Dai, Yun-hua; Guo, Zhong-min; Zhang, Li-yi; Lu, Jim; Zhang, Qiao-li

2015-04-01

MicroRNAs (miRNA, miR) have been implicated as promising blood-based biomarkers for schizophrenia patients. This study aimed to clinically validate miRNA as potential schizophrenia biomarkers. Plasma levels of 10 miRNAs were analyzed using qPCR in a cohort of 61 schizophrenia patients and 62 normal controls, as well as 25 patients particularly selected for a six-week antipsychotic treatment course. Positive And Negative Syndrome Scale (PANSS), Global Assessment Scale (GAS) and Clinical Global Impression (CGI) were administered to assess the clinical symptoms. The results demonstrated that a panel of miRNAs consisting of miR-30e, miR-181b, miR-34a, miR-346 and miR-7 had significantly increased expression levels with significant combined diagnostic value (AUC:0.713; sensitivity:35.5%; specificity:90.2%). In response to pharmacological treatment, expression levels of miR-132, miR-181b, miR-432 and miR-30e were significantly decreased. In addition, the improvement of clinical symptomatology was significantly correlated with the changes of miR-132, miR-181b, miR-212 and miR-30e expression levels. Furthermore, the decreases of plasma levels of miR-132 and miR-432 were significantly greater in high-effect subgroup than those in low-effect subgroup after six-week treatment course. We conclude that miR-30e, miR-181b, miR-34a, miR-346 and miR-7 combined as a panel are potentially useful non-invasive biomarkers for schizophrenia diagnosis. Markers miR-132, miR-181b, miR-30e and miR-432 are potential indicators for symptomatology improvements, treatment responses and prognosis for schizophrenia patients. © 2015 Wiley Periodicals, Inc.

Urinary Exosomes: The Potential for Biomarker Utility, Intercellular Signaling and Therapeutics in Urological Malignancy.

PubMed

Franzen, Carrie A; Blackwell, Robert H; Foreman, Kimberly E; Kuo, Paul C; Flanigan, Robert C; Gupta, Gopal N

2016-05-01

Exosomes are small secreted vesicles that contain proteins, mRNA and miRNA with the potential to alter signaling pathways in recipient cells. While exosome research has flourished, few publications have specifically considered the role of genitourinary cancer shed exosomes in urine, their implication in disease progression and their usefulness as noninvasive biomarkers. In this review we examined the current literature on the role of exosomes in intercellular communication and as biomarkers, and their potential as delivery vehicles for therapeutic applications in bladder, prostate and renal cancer. We searched PubMed® and Google® with the key words prostate cancer, bladder cancer, kidney cancer, exosomes, microvesicles and urine. Relevant articles, including original research studies and reviews, were selected based on contents. A review of this literature was generated. Cancer exosomes can be isolated from urine using various techniques. Cancer cells have been found to secrete more exosomes than normal cells. These exosomes have a role in cellular communication by interacting with and depositing their cargo in target cells. Bladder, prostate and renal cancer exosomes have been shown to enhance migration, invasion and angiogenesis. These exosomes have also been shown to increase proliferation, confer drug resistance and promote immune evasion. Urinary exosomes can be isolated from bladder, kidney and prostate cancer. They serve as a potential reservoir for biomarker identification. Exosomes also have potential for therapeutics as siRNA or pharmacological agents can be loaded into exosomes. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

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

Evaluating biomarkers for prognostic enrichment of clinical trials.

PubMed

Kerr, Kathleen F; Roth, Jeremy; Zhu, Kehao; Thiessen-Philbrook, Heather; Meisner, Allison; Wilson, Francis Perry; Coca, Steven; Parikh, Chirag R

2017-12-01

A potential use of biomarkers is to assist in prognostic enrichment of clinical trials, where only patients at relatively higher risk for an outcome of interest are eligible for the trial. We investigated methods for evaluating biomarkers for prognostic enrichment. We identified five key considerations when considering a biomarker and a screening threshold for prognostic enrichment: (1) clinical trial sample size, (2) calendar time to enroll the trial, (3) total patient screening costs and the total per-patient trial costs, (4) generalizability of trial results, and (5) ethical evaluation of trial eligibility criteria. Items (1)-(3) are amenable to quantitative analysis. We developed the Biomarker Prognostic Enrichment Tool for evaluating biomarkers for prognostic enrichment at varying levels of screening stringency. We demonstrate that both modestly prognostic and strongly prognostic biomarkers can improve trial metrics using Biomarker Prognostic Enrichment Tool. Biomarker Prognostic Enrichment Tool is available as a webtool at http://prognosticenrichment.com and as a package for the R statistical computing platform. In some clinical settings, even biomarkers with modest prognostic performance can be useful for prognostic enrichment. In addition to the quantitative analysis provided by Biomarker Prognostic Enrichment Tool, investigators must consider the generalizability of trial results and evaluate the ethics of trial eligibility criteria.

Improving the quality of biomarker discovery research: the right samples and enough of them.

PubMed

Pepe, Margaret S; Li, Christopher I; Feng, Ziding

2015-06-01

Biomarker discovery research has yielded few biomarkers that validate for clinical use. A contributing factor may be poor study designs. The goal in discovery research is to identify a subset of potentially useful markers from a large set of candidates assayed on case and control samples. We recommend the PRoBE design for selecting samples. We propose sample size calculations that require specifying: (i) a definition for biomarker performance; (ii) the proportion of useful markers the study should identify (Discovery Power); and (iii) the tolerable number of useless markers amongst those identified (False Leads Expected, FLE). We apply the methodology to a study of 9,000 candidate biomarkers for risk of colon cancer recurrence where a useful biomarker has positive predictive value ≥ 30%. We find that 40 patients with recurrence and 160 without recurrence suffice to filter out 98% of useless markers (2% FLE) while identifying 95% of useful biomarkers (95% Discovery Power). Alternative methods for sample size calculation required more assumptions. Biomarker discovery research should utilize quality biospecimen repositories and include sample sizes that enable markers meeting prespecified performance characteristics for well-defined clinical applications to be identified. The scientific rigor of discovery research should be improved. ©2015 American Association for Cancer Research.

Investigation of urinary volatile organic metabolites as potential cancer biomarkers by solid-phase microextraction in combination with gas chromatography-mass spectrometry

PubMed Central

Silva, C L; Passos, M; Câmara, J S

2011-01-01

Background: Non-invasive diagnostic strategies aimed at identifying biomarkers of cancer are of great interest for early cancer detection. Urine is potentially a rich source of volatile organic metabolites (VOMs) that can be used as potential cancer biomarkers. Our aim was to develop a generally reliable, rapid, sensitive, and robust analytical method for screening large numbers of urine samples, resulting in a broad spectrum of native VOMs, as a tool to evaluate the potential of these metabolites in the early diagnosis of cancer. Methods: To investigate urinary volatile metabolites as potential cancer biomarkers, urine samples from 33 cancer patients (oncological group: 14 leukaemia, 12 colorectal and 7 lymphoma) and 21 healthy (control group, cancer-free) individuals were qualitatively and quantitatively analysed. Dynamic solid-phase microextraction in headspace mode (dHS-SPME) using a carboxen-polydimethylsiloxane (CAR/PDMS) sorbent in combination with GC-qMS-based metabolomics was applied to isolate and identify the volatile metabolites. This method provides a potential non-invasive method for early cancer diagnosis as a first approach. To fulfil this objective, three important dHS-SPME experimental parameters that influence extraction efficiency (fibre coating, extraction time and temperature of sampling) were optimised using a univariate optimisation design. The highest extraction efficiency was obtained when sampling was performed at 50°C for 60 min using samples with high ionic strengths (17% sodium chloride, w v−1) and under agitation. Results: A total of 82 volatile metabolites belonging to distinct chemical classes were identified in the control and oncological groups. Benzene derivatives, terpenoids and phenols were the most common classes for the oncological group, whereas ketones and sulphur compounds were the main classes that were isolated from the urine headspace of healthy subjects. The results demonstrate that compound concentrations were

Comprehensive Analysis of Cancer-Proteogenome to Identify Biomarkers for the Early Diagnosis and Prognosis of Cancer.

PubMed

Shukla, Hem D

2017-10-25

During the past century, our understanding of cancer diagnosis and treatment has been based on a monogenic approach, and as a consequence our knowledge of the clinical genetic underpinnings of cancer is incomplete. Since the completion of the human genome in 2003, it has steered us into therapeutic target discovery, enabling us to mine the genome using cutting edge proteogenomics tools. A number of novel and promising cancer targets have emerged from the genome project for diagnostics, therapeutics, and prognostic markers, which are being used to monitor response to cancer treatment. The heterogeneous nature of cancer has hindered progress in understanding the underlying mechanisms that lead to abnormal cellular growth. Since, the start of The Cancer Genome Atlas (TCGA), and the International Genome consortium projects, there has been tremendous progress in genome sequencing and immense numbers of cancer genomes have been completed, and this approach has transformed our understanding of the diagnosis and treatment of different types of cancers. By employing Genomics and proteomics technologies, an immense amount of genomic data is being generated on clinical tumors, which has transformed the cancer landscape and has the potential to transform cancer diagnosis and prognosis. A complete molecular view of the cancer landscape is necessary for understanding the underlying mechanisms of cancer initiation to improve diagnosis and prognosis, which ultimately will lead to personalized treatment. Interestingly, cancer proteome analysis has also allowed us to identify biomarkers to monitor drug and radiation resistance in patients undergoing cancer treatment. Further, TCGA-funded studies have allowed for the genomic and transcriptomic characterization of targeted cancers, this analysis aiding the development of targeted therapies for highly lethal malignancy. High-throughput technologies, such as complete proteome, epigenome, protein-protein interaction, and pharmacogenomics

Metabolomics for Biomarker Discovery: Moving to the Clinic

PubMed Central

Zhang, Aihua; Sun, Hui; Yan, Guangli; Wang, Ping; Wang, Xijun

2015-01-01

To improve the clinical course of diseases, more accurate diagnostic and assessment methods are required as early as possible. In order to achieve this, metabolomics offers new opportunities for biomarker discovery in complex diseases and may provide pathological understanding of diseases beyond traditional technologies. It is the systematic analysis of low-molecular-weight metabolites in biological samples and has become an important tool in clinical research and the diagnosis of human disease and has been applied to discovery and identification of the perturbed pathways. It provides a powerful approach to discover biomarkers in biological systems and offers a holistic approach with the promise to clinically enhance diagnostics. When carried out properly, it could provide insight into the understanding of the underlying mechanisms of diseases, help to identify patients at risk of disease, and predict the response to specific treatments. Currently, metabolomics has become an important tool in clinical research and the diagnosis of human disease and becomes a hot topic. This review will highlight the importance and benefit of metabolomics for identifying biomarkers that accurately screen potential biomarkers of diseases. PMID:26090402

Integrating Soluble Biomarkers and Imaging Technologies in the Identification of Vulnerable Atherosclerotic Patients

PubMed Central

Páramo, José A.; Rodríguez JA, José A.; Orbe, Josune

2006-01-01

The clinical utility of a biomarker depends on its ability to identify high-risk individuals to optimally manage the patient. A new biomarker would be of clinical value if it is accurate and reliable, provides good sensitivity and specificity, and is available for widespread application. Data are accumulating on the potential clinical utility of integrating imaging technologies and circulating biomarkers for the identification of vulnerable (high-risk) cardiovascular patients. A multi-biomarker strategy consisting of markers of inflammation, hemostasis and thrombosis, proteolysis and oxidative stress, combined with new imaging modalities (optical coherence tomography, virtual histology plus IVUS, PET) can increase our ability to identify such thombosis-prone patients. In an ideal scenario, cardiovascular biomarkers and imaging combined will provide a better diagnostic tool to identify high-risk individuals and also more efficient methods for effective therapies to reduce such cardiovascular risk. However, additional studies are required in order to show that this approach can contribute to improved diagnostic and therapeutic of atherosclerotic disease. PMID:19690647

Integrating soluble biomarkers and imaging technologies in the identification of vulnerable atherosclerotic patients.

PubMed

Páramo, José A; Rodríguez Ja, José A; Orbe, Josune

2007-02-07

The clinical utility of a biomarker depends on its ability to identify high-risk individuals to optimally manage the patient. A new biomarker would be of clinical value if it is accurate and reliable, provides good sensitivity and specificity, and is available for widespread application. Data are accumulating on the potential clinical utility of integrating imaging technologies and circulating biomarkers for the identification of vulnerable (high-risk) cardiovascular patients. A multi-biomarker strategy consisting of markers of inflammation, hemostasis and thrombosis, proteolysis and oxidative stress, combined with new imaging modalities (optical coherence tomography, virtual histology plus IVUS, PET) can increase our ability to identify such thombosis-prone patients. In an ideal scenario, cardiovascular biomarkers and imaging combined will provide a better diagnostic tool to identify high-risk individuals and also more efficient methods for effective therapies to reduce such cardiovascular risk. However, additional studies are required in order to show that this approach can contribute to improved diagnostic and therapeutic of atherosclerotic disease.

Long Noncoding RNA in Digestive Tract Cancers: Function, Mechanism, and Potential Biomarker

PubMed Central

Zeng, Shuo; Xiao, Yu-Feng; Tang, Bo; Hu, Chang-Jiang; Xie, Rei; Yang, Shi-Ming

2015-01-01

Digestive tract cancers (DTCs) are a leading cause of cancer-related death worldwide. Current therapeutic tools for advanced stage DTCs have limitations, and patients with early stage DTCs frequently have a missed diagnosis due to shortage of efficient biomarkers. Consequently, it is necessary to develop novel biomarkers for early diagnosis and novel therapeutic targets for treatment of DTCs. In recent years, long noncoding RNAs (lncRNAs), a class of noncoding RNAs with >200 nucleotides, have been shown to be aberrantly expressed in DTCs and to have an important role in DTC development: the expression profiles of lncRNAs strongly correlated with poor survival of patients with DTCs, and lncRNAs acted as oncogenes or tumor suppressor genes in DTC progression. In this review, we summarized the functional lncRNAs and expounded on their regulatory mechanisms in DTCs. Implications for Practice: Digestive tract cancers (DTCs) are a leading cause of cancer-related death worldwide. It is necessary to exploit novel biomarkers for early diagnosis and novel therapeutic targets for treatment of DTCs. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs with approximately 200 nucleotides to 100,000 bases, participate in the progression of a variety of diseases. This review summarizes functional lncRNAs, which were shown to serve as novel biomarkers for diagnosis and prognosis of DTCs and to act as oncogenes or tumor suppressor genes in DTC development. In addition, the potential mechanism of functional lncRNAs in DTCs is highlighted. PMID:26156325

Mining featured biomarkers associated with prostatic carcinoma based on bioinformatics.

PubMed

Piao, Guanying; Wu, Jiarui

2013-11-01

To analyze the differentially expressed genes and identify featured biomarkers from prostatic carcinoma. The software "Significance Analysis of Microarray" (SAM) was used to identify the differentially coexpressed genes (DCGs). The DCGs existed in two datasets were analyzed by GO (Gene Ontology) functional annotation. A total of 389 DCGs were obtained. By GO analysis, we found these DCGs were closely related with the acinus development, TGF-β receptor and signal transduction pathways. Furthermore, five featured biomarkers were discovered by interaction analysis. These important signal pathways and oncogenes may provide potential therapeutic targets for prostatic carcinoma.

Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children

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

Yang, Xi, E-mail: Xi.Yang@fda.hhs.gov; Salminen, William F., E-mail: Willie.Salminen@parexel.com; Shi, Qiang, E-mail: Qiang.Shi@fda.hhs.gov

Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children. Global levels of serum and urine miRNAs were examined in three pediatric subgroups: 1) healthy children (n = 10), 2) hospitalized children receiving therapeutic doses of APAP (n = 10) and 3) children hospitalized for APAP overdose (n = 8). Out of 147 miRNAs detected in themore » APAP overdose group, eight showed significantly increased median levels in serum (miR-122, -375, -423-5p, -30d-5p, -125b-5p, -4732-5p, -204-5p, and -574-3p), compared to the other groups. Analysis of urine samples from the same patients had significantly increased median levels of four miRNAs (miR-375, -940, -9-3p and -302a) compared to the other groups. Importantly, correlation of peak serum APAP protein adduct levels (an indicator of the oxidation of APAP to the reactive metabolite N-acetyl-para-quinone imine) with peak miRNA levels showed that the highest correlation was observed for serum miR-122 (R = 0.94; p < 0.01) followed by miR-375 (R = 0.70; p = 0.05). Conclusion: Our findings demonstrate that miRNAs are increased in children with APAP toxicity and correlate with APAP protein adducts, suggesting a potential role as biomarkers of APAP toxicity. - Highlights: • Serum miR-122 and miR-375 levels were increased in children with APAP overdose. • Urine levels of miR-375 and miR-940 were increased in the APAP overdose group. • Peak serum miR-122 levels were correlated with peak serum APAP protein adducts.« less

Label-Free Quantitative Proteomics Identifies Novel Plasma Biomarkers for Distinguishing Pulmonary Tuberculosis and Latent Infection.

PubMed

Sun, Huishan; Pan, Liping; Jia, Hongyan; Zhang, Zhiguo; Gao, Mengqiu; Huang, Mailing; Wang, Jinghui; Sun, Qi; Wei, Rongrong; Du, Boping; Xing, Aiying; Zhang, Zongde

2018-01-01

The lack of effective differential diagnostic methods for active tuberculosis (TB) and latent infection (LTBI) is still an obstacle for TB control. Furthermore, the molecular mechanism behind the progression from LTBI to active TB has been not elucidated. Therefore, we performed label-free quantitative proteomics to identify plasma biomarkers for discriminating pulmonary TB (PTB) from LTBI. A total of 31 overlapping proteins with significant difference in expression level were identified in PTB patients ( n = 15), compared with LTBI individuals ( n = 15) and healthy controls (HCs, n = 15). Eight differentially expressed proteins were verified using western blot analysis, which was 100% consistent with the proteomics results. Statistically significant differences of six proteins were further validated in the PTB group compared with the LTBI and HC groups in the training set ( n = 240), using ELISA. Classification and regression tree (CART) analysis was employed to determine the ideal protein combination for discriminating PTB from LTBI and HC. A diagnostic model consisting of alpha-1-antichymotrypsin (ACT), alpha-1-acid glycoprotein 1 (AGP1), and E-cadherin (CDH1) was established and presented a sensitivity of 81.2% (69/85) and a specificity of 95.2% (80/84) in discriminating PTB from LTBI, and a sensitivity of 81.2% (69/85) and a specificity of 90.1% (64/81) in discriminating PTB from HCs. Additional validation was performed by evaluating the diagnostic model in blind testing set ( n = 113), which yielded a sensitivity of 75.0% (21/28) and specificity of 96.1% (25/26) in PTB vs. LTBI, 75.0% (21/28) and 92.3% (24/26) in PTB vs. HCs, and 75.0% (21/28) and 81.8% (27/33) in PTB vs. lung cancer (LC), respectively. This study obtained the plasma proteomic profiles of different M.TB infection statuses, which contribute to a better understanding of the pathogenesis involved in the transition from latent infection to TB activation and provide new potential diagnostic

Validation of biomarkers of food intake-critical assessment of candidate biomarkers.

PubMed

Dragsted, L O; Gao, Q; Scalbert, A; Vergères, G; Kolehmainen, M; Manach, C; Brennan, L; Afman, L A; Wishart, D S; Andres Lacueva, C; Garcia-Aloy, M; Verhagen, H; Feskens, E J M; Praticò, G

2018-01-01

Biomarkers of food intake (BFIs) are a promising tool for limiting misclassification in nutrition research where more subjective dietary assessment instruments are used. They may also be used to assess compliance to dietary guidelines or to a dietary intervention. Biomarkers therefore hold promise for direct and objective measurement of food intake. However, the number of comprehensively validated biomarkers of food intake is limited to just a few. Many new candidate biomarkers emerge from metabolic profiling studies and from advances in food chemistry. Furthermore, candidate food intake biomarkers may also be identified based on extensive literature reviews such as described in the guidelines for Biomarker of Food Intake Reviews (BFIRev). To systematically and critically assess the validity of candidate biomarkers of food intake, it is necessary to outline and streamline an optimal and reproducible validation process. A consensus-based procedure was used to provide and evaluate a set of the most important criteria for systematic validation of BFIs. As a result, a validation procedure was developed including eight criteria, plausibility, dose-response, time-response, robustness, reliability, stability, analytical performance, and inter-laboratory reproducibility. The validation has a dual purpose: (1) to estimate the current level of validation of candidate biomarkers of food intake based on an objective and systematic approach and (2) to pinpoint which additional studies are needed to provide full validation of each candidate biomarker of food intake. This position paper on biomarker of food intake validation outlines the second step of the BFIRev procedure but may also be used as such for validation of new candidate biomarkers identified, e.g., in food metabolomic studies.

Neuroproteomics and Systems Biology Approach to Identify Temporal Biomarker Changes Post Experimental Traumatic Brain Injury in Rats.

PubMed

Kobeissy, Firas H; Guingab-Cagmat, Joy D; Zhang, Zhiqun; Moghieb, Ahmed; Glushakova, Olena Y; Mondello, Stefania; Boutté, Angela M; Anagli, John; Rubenstein, Richard; Bahmad, Hisham; Wagner, Amy K; Hayes, Ronald L; Wang, Kevin K W

2016-01-01

Traumatic brain injury (TBI) represents a critical health problem of which diagnosis, management, and treatment remain challenging. TBI is a contributing factor in approximately one-third of all injury-related deaths in the United States. The Centers for Disease Control and Prevention estimate that 1.7 million people suffer a TBI in the United States annually. Efforts continue to focus on elucidating the complex molecular mechanisms underlying TBI pathophysiology and defining sensitive and specific biomarkers that can aid in improving patient management and care. Recently, the area of neuroproteomics-systems biology is proving to be a prominent tool in biomarker discovery for central nervous system injury and other neurological diseases. In this work, we employed the controlled cortical impact (CCI) model of experimental TBI in rat model to assess the temporal-global proteome changes after acute (1 day) and for the first time, subacute (7 days), post-injury time frame using the established cation-anion exchange chromatography-1D SDS gel electrophoresis LC-MS/MS platform for protein separation combined with discrete systems biology analyses to identify temporal biomarker changes related to this rat TBI model. Rather than focusing on any one individual molecular entity, we used in silico systems biology approach to understand the global dynamics that govern proteins that are differentially altered post-injury. In addition, gene ontology analysis of the proteomic data was conducted in order to categorize the proteins by molecular function, biological process, and cellular localization. Results show alterations in several proteins related to inflammatory responses and oxidative stress in both acute (1 day) and subacute (7 days) periods post-TBI. Moreover, results suggest a differential upregulation of neuroprotective proteins at 7 days post-CCI involved in cellular functions such as neurite growth, regeneration, and axonal guidance. Our study is among the

ANMCO/ELAS/SIBioC Consensus Document: biomarkers in heart failure

PubMed Central

Gulizia, Michele Massimo; Clerico, Aldo; Di Tano, Giuseppe; Emdin, Michele; Feola, Mauro; Iacoviello, Massimo; Latini, Roberto; Mortara, Andrea; Valle, Roberto; Misuraca, Gianfranco; Passino, Claudio; Masson, Serge; Aimo, Alberto; Ciaccio, Marcello; Migliardi, Marco

2017-01-01

Abstract Biomarkers have dramatically impacted the way heart failure (HF) patients are evaluated and managed. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological or pathogenic processes, or pharmacological responses to a therapeutic intervention. Natriuretic peptides [B-type natriuretic peptide (BNP) and N-terminal proBNP] are the gold standard biomarkers in determining the diagnosis and prognosis of HF, and a natriuretic peptide-guided HF management looks promising. In the last few years, an array of additional biomarkers has emerged, each reflecting different pathophysiological processes in the development and progression of HF: myocardial insult, inflammation, fibrosis, and remodelling, but their role in the clinical care of the patient is still partially defined and more studies are needed before to be well validated. Moreover, several new biomarkers have the potential to identify patients with early renal dysfunction and appear to have promise to help the management cardio-renal syndrome. With different biomarkers reflecting HF presence, the various pathways involved in its progression, as well as identifying unique treatment options for HF management, a closer cardiologist-laboratory link, with a multi-biomarker approach to the HF patient, is not far ahead, allowing the unique opportunity for specifically tailoring care to the individual pathological phenotype. PMID:28751838

Exhaled breath and oral cavity VOCs as potential biomarkers in oral cancer patients.

PubMed

Bouza, M; Gonzalez-Soto, J; Pereiro, R; de Vicente, J C; Sanz-Medel, A

2017-03-01

Corporal mechanisms attributed to cancer, such as oxidative stress or the action of cytochrome P450 enzymes, seem to be responsible for the generation of a variety of volatile organic compounds (VOCs) that could be used as non-invasive diagnosis biomarkers. The present work presents an attempt to use VOCs from exhaled breath and oral cavity air as biomarkers for oral squamous cell carcinoma (OSCC) patients. A total of 52 breath samples were collected (in 3 L Tedlar bags) from 26 OSCC patients and 26 cancer-free controls. The samples were analyzed using solid-phase microextraction followed by gas chromatography-mass spectrometry detection. Different statistical strategies (e.g., Icoshift, SIMCA, LDA, etc) were used to classify the analytical data. Results revealed that compounds such as undecane, dodecane, decanal, benzaldehyde, 3,7-dimethyl undecane, 4,5-dimethyl nonane, 1-octene, and hexadecane had relevance as possible biomarkers for OSCC. LDA classification with these compounds showed well-defined clusters for patients and controls (non-smokers and smokers). In addition to breath analysis, preliminary studies were carried out to evaluate the possibility of lesion-surrounded air (analyzed OSCC tumors are in the oral cavity) as a source of biomarkers. The oral cavity location of the squamous cell carcinoma tumors constitutes an opportunity to non-invasively collect the air surrounding the lesion. Small quantities (20 ml) of air collected in the oral cavity were analyzed using the above methodology. Results showed that aldehydes present in the oral cavity might constitute potential OSCC biomarkers.

Programmed cell death 6 interacting protein (PDCD6IP) and Rabenosyn-5 (ZFYVE20) are potential urinary biomarkers for upper gastrointestinal cancer.

PubMed

Husi, Holger; Skipworth, Richard J E; Cronshaw, Andrew; Stephens, Nathan A; Wackerhage, Henning; Greig, Carolyn; Fearon, Kenneth C H; Ross, James A

2015-06-01

Cancer of the upper digestive tract (uGI) is a major contributor to cancer-related death worldwide. Due to a rise in occurrence, together with poor survival rates and a lack of diagnostic or prognostic clinical assays, there is a clear need to establish molecular biomarkers. Initial assessment was performed on urine samples from 60 control and 60 uGI cancer patients using MS to establish a peak pattern or fingerprint model, which was validated by a further set of 59 samples. We detected 86 cluster peaks by MS above frequency and detection thresholds. Statistical testing and model building resulted in a peak profiling model of five relevant peaks with 88% overall sensitivity and 91% specificity, and overall correctness of 90%. High-resolution MS of 40 samples in the 2-10 kDa range resulted in 646 identified proteins, and pattern matching identified four of the five model peaks within significant parameters, namely programmed cell death 6 interacting protein (PDCD6IP/Alix/AIP1), Rabenosyn-5 (ZFYVE20), protein S100A8, and protein S100A9, of which the first two were validated by Western blotting. We demonstrate that MS analysis of human urine can identify lead biomarker candidates in uGI cancers, which makes this technique potentially useful in defining and consolidating biomarker patterns for uGI cancer screening. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Searching for ‘omic’ biomarkers

PubMed Central

Lin, David; Hollander, Zsuzsanna; Meredith, Anna; McManus, Bruce M

2009-01-01

Cardiovascular diseases impose enormous social and economic burdens on both individual citizens and on society as a whole. Clinical indicators such as high blood pressure, blood cholesterol and obesity have had some utility in identifying those who are at increased risk of cardiovascular events. However, there remains an urgent need for sensitive and specific indicators, preferably acquired through minimally invasive means, to help stratify patients for more personalized health care. As such, there has been a steadily growing interest in searching for ‘omic’ biomarkers of cardiovascular diseases. Historically, the transition of cardiac biomarker discovery to implementation has been a lengthy and somewhat unregulated process. Recent technological advancements, as well as concurrent efforts by regulatory agencies such as the Food and Drug Administration (United States) and Health Canada to establish policies and guidelines in the ‘omic’ arena, have helped propel the discovery and validation of biomarkers forward. The present paper provides perspective on current strategies in the bio-marker development pathway, as well as the potential limitations associated with each step from discovery to clinical uptake. Canadian biomarker studies now underway illustrate the possibilities for assessment of risk, diagnosis, prognosis and response to therapy, and for the drug discovery process. PMID:19521568

MicroRNAs and exosomes in depression: Potential diagnostic biomarkers.

PubMed

Tavakolizadeh, Jahanshir; Roshanaei, Kambiz; Salmaninejad, Arash; Yari, Reza; Nahand, Javid Sadri; Sarkarizi, Hoda Khoshdel; Mousavi, Seyed Mojtaba; Salarinia, Reza; Rahmati, Majid; Mousavi, Seyed Farshid; Mokhtari, Ryan; Mirzaei, Hamed

2018-05-01

Depression is known as one of important psychiatric disorders which could be associated with disability among various populations. Diagnostic and statistical manual of mental disorders, 4th edition (DSM-IV) and international statistical classification of diseases and related health problems (ICD-10) could be used as subjective diagnostic schemes for identification of mental disorders such as depression. Utilization of subjective diagnostic schemes are associated with limitations. Hence, it seems that employing of new diagnosis platforms is required. Multiple lines of evidence indicated that measurement of several biomarkers could be useful for detection patients with depression. Among of various types of biomarkers, microRNAs (miRNAs) have been emerged as powerful tools for diagnosis patients with depression. MiRNAs are small non-coding RNAs which act as epigenetic regulators. It has been showed that these molecules have critical roles in pathogenesis of many diseases such as depression. These molecules exert their effects via targeting a variety of cellular and molecular pathways involved in initiation and progression of depression. Hence, miRNAs could be used as diagnostic and therapeutic biomarkers in patients with depression. Besides miRNAs, exosomes as nano- carriers could have been emerged as diagnostic biomarkers in several diseases such as depression. These vesicles are able to carry several cargos such as DNAs, proteins, mRNAs, and miRNAs to recipient cells. Here, we summarized several miRNAs involved in pathogenesis and response to treatment of depression which could be used as diagnostic biomarkers. Moreover, we highlighted exosomes as new diagnostic biomarkers for patients with depression. © 2017 Wiley Periodicals, Inc.

Synthesis and Characterization of a deuterium labeled Stercobilin: A Potential Biomarker for Autism.

PubMed

Coffey, J M; Vadas, A; Puleo, Y; Lewis, K; Pirone, G; Rudolph, H L; Helms, E; Wood, T D; Flynn-Charlebois, A

2018-05-14

Stercobilin is an end-stage metabolite of hemoglobin, a component of red blood cells. It has been found that there is a significantly lower concentration of stercobilin in the urine of people diagnosed with Autism Spectrum Disorders (ASD), suggesting potential utility as a biomarker. In vitro, we have synthesized stercobilin from its precursor bilirubin through a reduction reaction proceeded by an oxidation reaction. In addition, we have isotopically labeled the stercobilin product with deuterium using this protocol. Nuclear Magnetic Resonance (NMR) investigations show the products of the unlabeled stercobilin (Rxn 1) and the deuterated stercobilin (Rxn 2) both had a loss of signals in the 5.0-7.0 ppm range indicating proper conversion to stercobilin. Changes in the multiplicity of the sp3 region of the proton NMR suggest proper deuterium incorporation. Mass Spectrometry (MS) studies of Rxn 1 show a difference in fragmentation patterns than that of Rxn 2 proposing potential locations for deuterium incorporation. This isotopologue of stercobilin is stable (> 6 months), and further analysis permits investigation for its use as a biomarker and potential quantitative diagnostic probe for ASD. This article is protected by copyright. All rights reserved.

Applications of Nutritional Biomarkers in Global Health Settings.

PubMed

Prentice, Andrew M

2016-01-01

In global health settings, there are three generic areas that require reliable biomarkers of nutritional status and function. Population surveillance needs to identify key nutrient deficiencies (or excesses) to monitor progress towards elimination of nutritional imbalances and to stratify populations into groups especially 'at risk' to whom public health resources can be focused. Clinical interventions need biomarkers to help identify disease pathways, to assist in targeting nutrient prescriptions, and to avoid potential harm (e.g. in the case of iron). Discovery science requires biomarkers in many domains, but especially in the study of nutrient-gene interactions and regarding the effects of nutritional status on the epigenome. Each of these applications imposes different constraints on the methodology though in all cases the optimum biomarker would have high sensitivity and specificity, would capture variation of functional significance, and would be cheap and easy to apply. These attributes are hard to achieve, and recent progress towards next-generation biomarkers, though holding much promise, has not yet delivered significant breakthroughs in the global health setting. Recent efforts to overcome these problems by two initiatives (BOND and INSPIRE) are highlighted as exemplars of a route map to progress. © 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.

Single Domain Antibodies as New Biomarker Detectors

PubMed Central

Fischer, Katja; Leow, Chiuan Yee; Chuah, Candy; McCarthy, James

2017-01-01

Biomarkers are defined as indicators of biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Biomarkers have been widely used for early detection, prediction of response after treatment, and for monitoring the progression of diseases. Antibodies represent promising tools for recognition of biomarkers, and are widely deployed as analytical tools in clinical settings. For immunodiagnostics, antibodies are now exploited as binders for antigens of interest across a range of platforms. More recently, the discovery of antibody surface display and combinatorial chemistry techniques has allowed the exploration of new binders from a range of animals, for instance variable domains of new antigen receptors (VNAR) from shark and variable heavy chain domains (VHH) or nanobodies from camelids. These single domain antibodies (sdAbs) have some advantages over conventional murine immunoglobulin owing to the lack of a light chain, making them the smallest natural biomarker binders thus far identified. In this review, we will discuss several biomarkers used as a means to validate diseases progress. The potential functionality of modern singe domain antigen binders derived from phylogenetically early animals as new biomarker detectors for current diagnostic and research platforms development will be described. PMID:29039819

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.

Adventitial Tertiary Lymphoid Organs as Potential Source of MicroRNA Biomarkers for Abdominal Aortic Aneurysm

PubMed Central

Spear, Rafaelle; Boytard, Ludovic; Blervaque, Renaud; Chwastyniak, Maggy; Hot, David; Vanhoutte, Jonathan; Staels, Bart; Lemoine, Yves; Lamblin, Nicolas; Pruvot, François-René; Haulon, Stephan; Amouyel, Philippe; Pinet, Florence

2015-01-01

Abdominal aortic aneurysm (AAA) is an inflammatory disease associated with marked changes in the cellular composition of the aortic wall. This study aims to identify microRNA (miRNA) expression in aneurysmal inflammatory cells isolated by laser microdissection from human tissue samples. The distribution of inflammatory cells (neutrophils, B and T lymphocytes, mast cells) was evaluated in human AAA biopsies. We observed in half of the samples that adventitial tertiary lymphoid organs (ATLOs) with a thickness from 0.5 to 2 mm were located exclusively in the adventitia. Out of the 850 miRNA that were screened by microarray in isolated ATLOs (n = 2), 164 miRNAs were detected in ATLOs. The three miRNAs (miR-15a-3p, miR-30a-5p and miR-489-3p) with the highest expression levels were chosen and their expression quantified by RT-PCR in isolated ATLOs (n = 4), M1 (n = 2) and M2 macrophages (n = 2) and entire aneurysmal biopsies (n = 3). Except for the miR-30a-5p, a similar modulation was found in ATLOs and the two subtypes of macrophages. The modulated miRNAs were then evaluated in the plasma of AAA patients for their potential as AAA biomarkers. Our data emphasize the potential of miR-15a-3p and miR-30a-5p as biomarkers of AAA but also as triggers of ATLO evolution. Further investigations will be required to evaluate their targets in order to better understand AAA pathophysiology. PMID:25993295

Toxicogenomic identification of biomarkers of acute respiratory expsoure to sensitizing agents

EPA Science Inventory

Allergy induction requires multiple exposures to an agent. Therefore the development of high-throughput or in vitro assays for effective screening of potential sensitizers will require the identification of biomarkers. The goal of this preliminary study was to identify potential ...

Progression Rate Associated Peripheral Blood Biomarkers of Parkinson's Disease.

PubMed

Fan, Yanxia; Xiao, Shuping

2018-06-23

Parkinson disease (PD) is one of the most frequent neurodegenerative disorders. The aim of this study was to identify blood biomarkers capable to discriminate PD patients with different progression rates. Differentially expressed genes (DEGs) were acquired by comparing the expression profiles of PD patients with rapid and slow progression rates, using an expression dataset from Gene Expression Omnibus (GEO) under accession code of GSE80599. Altered biological processes and pathways were revealed by functional annotation. Potential biomarkers of PD were identified by protein-protein interaction (PPI) network analysis. Critical transcription factors (TFs) and miRNAs regulating DEGs were predicted by TF analysis and miRNA analysis. A total of 225 DEGs were identified between PD patients with rapid and slow progression profiles. These genes were significantly enriched in biological processes and pathways related to fatty acid metabolism. Among these DEGs, ZFAND4, SRMS, UBL4B, PVALB, DIRAS1, PDP2, LRCH1, and MYL4 were potential progression rate associated biomarkers of PD. Additionally, these DEGs may be regulated by miRNAs of the miR-30 family and TFs STAT1 and GRHL3. Our results may contribute to our understanding of the molecular mechanisms underlying different PD progression profiles.

Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances.

PubMed

Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech

2016-02-07

Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.

Identification of Potential Biomarkers for Gut Barrier Failure in Broiler Chickens

PubMed Central

Chen, Juxing; Tellez, Guillermo; Richards, James D.; Escobar, Jeffery

2015-01-01

The objective of the present study was to identify potential biomarkers for gut barrier failure in chickens. A total of 144 day-of-hatch Ross 308 male broiler chickens were housed in 24 battery cages with six chicks per cage. Cages were randomly assigned to either a control group (CON) or gut barrier failure (GBF) group. During the first 13 days, birds in CON or GBF groups were fed a common corn–soy starter diet. On day 14, CON chickens were switched to a corn grower diet, and GBF chickens were switched to rye–wheat–barley grower diet. In addition, on day 21, GBF chickens were orally challenged with a coccidiosis vaccine. At days 21 and 28, birds were weighed by cage and feed intake was recorded to calculate feed conversion ratio. At day 28, one chicken from each cage was euthanized to collect intestinal samples for morphometric analysis, blood for serum, and intestinal mucosa scrapings for gene expression. Overall performance and feed efficiency was severely affected (P < 0.05) by a GBF model when compared with CON group at days 21 and 28. Duodenum of GBF birds had wider villi, longer crypt depth, and higher crypt depth/villi height ratio than CON birds. Similarly, GBF birds had longer crypt depth in jejunum and ileum when compared with CON birds. Protein levels of endotoxin and α1-acid glycoprotein (AGP) in serum, as well as mRNA levels of interleukin (IL)-8, IL-1β, transforming growth factor (TGF)-β4, and fatty acid-binding protein (FABP) 6 were increased (P < 0.05) in GBF birds compared to CON birds; however, mRNA levels of FABP2, occludin, and mucin 2 (MUC2) were reduced by 34% (P < 0.05), 24% (P = 0.107), and 29% (P = 0.088), respectively, in GBF birds compared to CON birds. The results from the present study suggest that serum endotoxin and AGP, as well as, gene expression of FABP2, FABP6, IL-8, IL-1β, TGF-β4, occludin, and MUC2 in mucosa may work as potential biomarkers for gut barrier health in chickens. PMID:26664943

Integrated analysis of epigenomic and genomic changes by DNA methylation dependent mechanisms provides potential novel biomarkers for prostate cancer.

PubMed

White-Al Habeeb, Nicole M A; Ho, Linh T; Olkhov-Mitsel, Ekaterina; Kron, Ken; Pethe, Vaijayanti; Lehman, Melanie; Jovanovic, Lidija; Fleshner, Neil; van der Kwast, Theodorus; Nelson, Colleen C; Bapat, Bharati

2014-09-15

Epigenetic silencing mediated by CpG methylation is a common feature of many cancers. Characterizing aberrant DNA methylation changes associated with tumor progression may identify potential prognostic markers for prostate cancer (PCa). We treated two PCa cell lines, 22Rv1 and DU-145 with the demethylating agent 5-Aza 2'-deoxycitidine (DAC) and global methylation status was analyzed by performing methylation-sensitive restriction enzyme based differential methylation hybridization strategy followed by genome-wide CpG methylation array profiling. In addition, we examined gene expression changes using a custom microarray. Gene Set Enrichment Analysis (GSEA) identified the most significantly dysregulated pathways. In addition, we assessed methylation status of candidate genes that showed reduced CpG methylation and increased gene expression after DAC treatment, in Gleason score (GS) 8 vs. GS6 patients using three independent cohorts of patients; the publically available The Cancer Genome Atlas (TCGA) dataset, and two separate patient cohorts. Our analysis, by integrating methylation and gene expression in PCa cell lines, combined with patient tumor data, identified novel potential biomarkers for PCa patients. These markers may help elucidate the pathogenesis of PCa and represent potential prognostic markers for PCa patients.

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

Circulating micrornas as potential biomarkers of muscle atrophy

NASA Astrophysics Data System (ADS)

Wang, Fei

2016-07-01

Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for muscle atrophy patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the medium levels of six muscle-specific miRNAs (miR-1/23a/206/133/499/208b, also known as myomiRs) were all elevated in the medium of starved C2C12 cell (P < 0.01). And, the level of miR-1 and miR-23a were all elevated in the serum of hindlimb unloaded mice (P < 0.01). miR-23a levels were negatively correlated with both muscle mass and muscle fiber cross section area in muscle atrophy patients, indicating that they might represent the degree of muscle atrophy. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for muscle atrophy.

Proteomic Candidate Biomarkers of Drug-Induced Nephrotoxicity in the Rat

PubMed Central

Rouse, Rodney; Siwy, Justyna; Mullen, William; Mischak, Harald; Metzger, Jochen; Hanig, Joseph

2012-01-01

Improved biomarkers of acute nephrotoxicity are coveted by the drug development industry, regulatory agencies, and clinicians. In an effort to identify such biomarkers, urinary peptide profiles of rats treated with two different nephrotoxins were investigated. 493 marker candidates were defined that showed a significant response to cis-platin comparing a cis-platin treated cohort to controls. Next, urine samples from rats that received three consecutive daily doses of 150 or 300 mg/kg gentamicin were examined. 557 potential biomarkers were initially identified; 108 of these gentamicin-response markers showed a clear temporal response to treatment. 39 of the cisplatin-response markers also displayed a clear response to gentamicin. Of the combined 147 peptides, 101 were similarly regulated by gentamicin or cis-platin and 54 could be identified by tandem mass spectrometry. Most were collagen type I and type III fragments up-regulated in response to gentamicin treatment. Based on these peptides, classification models were generated and validated in a longitudinal study. In agreement with histopathology, the observed changes in classification scores were transient, initiated after the first dose, and generally persistent over a period of 10–20 days before returning to control levels. The data support the hypothesis that gentamicin-induced renal toxicity up-regulates protease activity, resulting in an increase in several specific urinary collagen fragments. Urinary proteomic biomarkers identified here, especially those common to both nephrotoxins, may serve as a valuable tool to investigate potential new drug candidates for the risk of nephrotoxicity. PMID:22509332

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.

Blood biomarkers in Alzheimer's disease.

PubMed

Altuna-Azkargorta, M; Mendioroz-Iriarte, M

2018-05-08

The early diagnosis of Alzheimer's disease (AD) via the use of biomarkers could facilitate the implementation and monitoring of early therapeutic interventions with the potential capacity to significantly modify the course of the disease. Classic cerebrospinal fluid biomarkers and approved structural and functional neuroimaging have a limited clinical application given their invasive nature and/or high cost. The identification of more accessible and less costly biomarkers, such as blood biomarkers, would facilitate application in clinical practice. We present a literature review of the main blood biochemical biomarkers with potential use for diagnosing Alzheimer's disease. Blood biomarkers are cost and time effective with regard to cerebrospinal fluid biomarkers. However, the immediate applicability of blood biochemical biomarkers in clinical practice is not very likely. The main limitations come from the difficulties in measuring and standardising thresholds between different laboratories and in failures to replicate results. Among all the molecules studied, apoptosis and neurodegeneration biomarkers and the biomarker panels obtained through omics approaches, such as isolated or combined metabolomics, offer the most promising results. Copyright © 2018 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Discovery of urine biomarkers for bladder cancer via global metabolomics.

PubMed

Shi, Hangchuan; Li, Xiang; Zhang, Qingyang; Yang, Hongmei; Zhang, Xiaoping

2016-11-01

Bladder cancer (BC) is latent in its early stage and lethal in its late stage. Therefore, early diagnosis and intervention are essential for successful BC treatment. Considering the limitations of current diagnostic tools, noninvasive biomarkers that are both highly sensitive and specific are needed to improve the overall survival and quality of life of patients. With the advent of systems biology, "-omics" technologies have been developed over the past few decades. As a promising member, global metabolomics has increasingly been found to have clear potential for biomarker discovery. However, urinary metabolomics studies related to BC have lagged behind those of other urinary cancers, and major findings have not been systematically reported. The objective of this review is to comprehensively list the currently identified potential urinary metabolite biomarkers for BC.

Next Generation Vaccine Biomarkers workshop October 30–31, 2014 – Ottawa, Canada

PubMed Central

Twine, Susan M; Fulton, Kelly M; Spika, John; Ouellette, Marc; Raven, Jennifer F; Conlan, J Wayne; Krishnan, Lakshmi; Barreto, Luis; Richards, James C

2015-01-01

Vaccine biomarkers are critical to many aspects of vaccine development and licensure, including bridging findings in pre-clinical studies to clinical studies, predicting potential adverse events, and predicting vaccine efficacy. Despite advances in our understanding of various biological pathways, and advances in systems analyses of the immune response, there remains much to learn about qualitative and quantitative aspects of the human host response to vaccination. To stimulate discussion and identify opportunities for collaborative ways to advance the field of vaccine biomarkers, A Next Generation Vaccine Biomarker workshop was held in Ottawa. The two day workshop, sponsored by the National Research Council Canada, Canadian Institutes of Health Research, Public Health Agency of Canada, Pfizer, and Medicago, brought together stakeholders from Canadian and international industry, government and academia. The workshop was grouped in themes, covering vaccine biomarker challenges in the pre-clinical and clinical spaces, veterinary vaccines, regulatory challenges, and development of biomarkers for adjuvants and cancer vaccines. The use of case studies allowed participants to identify the needs and gaps requiring innovation. The workshop concluded with a discussion on opportunities for vaccine biomarker discovery, the Canadian context, and approaches for moving forward. This article provides a synopsis of these discussions and identifies steps forward for advancing vaccine biomarker research in Canada. PMID:26383909

Novel Biomarkers for Predicting Cardiovascular Disease in Patients With Diabetes.

PubMed

Retnakaran, Ravi

2018-05-01

It is generally acknowledged that patients with diabetes comprise a high-risk population for the development of cardiovascular disease. However, it is perhaps less well recognized that there actually exists considerable heterogeneity in vascular risk within this patient population, with a sizable subset of individuals seemingly at low risk for major cardiovascular events despite the presence of diabetes. Because traditional clinical risk calculators have shown wide variability in their performance in the setting of diabetes, there exists a need for additional risk predictors in this patient population. In this context, there has been considerable interest in the potential utility of circulating biomarkers as clinical tools that might facilitate risk stratification and thereby guide therapeutic and preventative decision-making. Coupled with the current era of dedicated cardiovascular outcome trials in type 2 diabetes, this interest has spawned a growing literature of recent studies that evaluated potential biomarkers. To date, these studies have identified N-terminal pro-B-type natriuretic peptide, high-sensitivity cardiac troponins, and growth differentiation factor-15 as cardiovascular biomarkers of particular potential in patients with diabetes. Furthermore, recognizing the potential benefit of collective consideration of different biomarkers reflecting distinct pathophysiologic processes that might contribute to the development of cardiovascular disease, there is emerging emphasis on the evaluation of combinations of biomarkers for optimal risk prediction. Although not currently ready for clinical practice, this rapidly-growing topic of biomarker research might ultimately facilitate the goal of individualized risk stratification and thereby enable truly personalized management of diabetes. Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Chromatography/Mass Spectrometry-Based Biomarkers in the Field of Obstructive Sleep Apnea

PubMed Central

Xu, Huajun; Zheng, Xiaojiao; Jia, Wei; Yin, Shankai

2015-01-01

Abstract Biomarker assessment is based on quantifying several proteins and metabolites. Recent developments in proteomics and metabolomics have enabled detection of these small molecules in biological samples and exploration of the underlying disease mechanisms in obstructive sleep apnea (OSA). This systemic review was performed to identify biomarkers, which were only detected by chromatography and/or mass spectrometry (MS) and to discuss the role of these biomarkers in the field of OSA. We systemically reviewed relevant articles from PubMed and EMBASE referring to proteins and metabolite profiles of biological samples in patients with OSA. The analytical platforms in this review were focused on chromatography and/or MS. In total, 30 studies evaluating biomarkers in patients with OSA using chromatography and/or MS methods were included. Numerous proteins and metabolites, including lipid profiles, adrenergic/dopaminergic biomarkers and derivatives, amino acids, oxidative stress biomarkers, and other micromolecules were identified in patients with OSA. Applying chromatography and/or MS methods to detect biomarkers helps develop an understanding of OSA mechanisms. More proteomic and metabolomic studies are warranted to develop potential diagnostic and clinical monitoring methods for OSA. PMID:26448002

Urinary volatile organic compounds as potential biomarkers for renal cell carcinoma

PubMed Central

WANG, DONGCHUN; WANG, CHANGSONG; PI, XIN; GUO, LEI; WANG, YUE; LI, MINGJUAN; FENG, YUE; LIN, ZIWEI; HOU, WEI; LI, ENYOU

2016-01-01

Currently, there is no adequate, sensitive, reproducible, specific and noninvasive biomarker that can reliably be used to detect renal cell carcinoma (RCC). Previous studies have elucidated the urinary non-volatile metabolic profile of RCC. However, whether urinary volatile organic compound (VOC) profiles are able to identify RCC remains to be elucidated. In the present study, urine was collected from 22 patients with RCC and 25 healthy subjects. Principal component analysis and orthogonal partial least square discriminant analysis were used to compare the data of patients and healthy subjects, and preoperative and postoperative patients undergoing radical nephrectomy. In total, 11 VOC biomarkers were elevated in the RCC patients compared to the healthy subjects, which were phenol; decanal; 1,6-dioxacyclododecane-7,12-dione; 1-bromo-1-(3-methyl-1-pentenylidene)-2,2,3,3-tetramethyl-cyclopropane; nonanal; 3-ethyl-3-methylheptane; isolongifolene-5-ol; 2,5-cyclohexadiene-1,4-dione, 2,6-bis(1,1-dimethylethyl); tetradecane; aniline; and 2,6,10,14-tetramethyl-pentadecane. Three biomarkers were decreased in RCC patients: styrene, 4-heptanone and dimethylsilanediol. In preoperative patients, 2-ethyl-1-hexanol and cyclohexanone were elevated, while 6-t-butyl-2,2,9,9-tetramethyl-3,5-decadien-7-yne were decreased when compared to postoperative patients. Compared with the healthy subjects, RCC has a unique VOC profile, suggesting that VOC profiles may be a useful diagnostic assay for RCC. PMID:27347408

Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there?

PubMed Central

Shao, Yu-Yun; Hsu, Chih-Hung; Cheng, Ann-Lii

2015-01-01

Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC. PMID:26420960

Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there?

PubMed

Shao, Yu-Yun; Hsu, Chih-Hung; Cheng, Ann-Lii

2015-09-28

Sorafenib is the current standard treatment for advanced hepatocellular carcinoma (HCC), but its efficacy is modest with low response rates and short response duration. Predictive biomarkers for sorafenib efficacy are necessary. However, efforts to determine biomarkers for sorafenib have led only to potential candidates rather than clinically useful predictors. Studies based on patient cohorts identified the potential of blood levels of angiopoietin-2, hepatocyte growth factor, insulin-like growth factor-1, and transforming growth factor-β1 for predicting sorafenib efficacy. Alpha-fetoprotein response, dynamic contrast-enhanced magnetic resonance imaging, and treatment-related side effects may serve as early surrogate markers. Novel approaches based on super-responders or experimental mouse models may provide new directions in biomarker research. These studies identified tumor amplification of FGF3/FGF4 or VEGFA and tumor expression of phospho-Mapk14 and phospho-Atf2 as possible predictive markers that await validation. A group effort that considers various prognostic factors and proper collection of tumor tissues before treatment is imperative for the success of future biomarker research in advanced HCC.

Multiomics Data Triangulation for Asthma Candidate Biomarkers and Precision Medicine.

PubMed

Pecak, Matija; Korošec, Peter; Kunej, Tanja

2018-06-01

Asthma is a common complex disorder and has been subject to intensive omics research for disease susceptibility and therapeutic innovation. Candidate biomarkers of asthma and its precision treatment demand that they stand the test of multiomics data triangulation before they can be prioritized for clinical applications. We classified the biomarkers of asthma after a search of the literature and based on whether or not a given biomarker candidate is reported in multiple omics platforms and methodologies, using PubMed and Web of Science, we identified omics studies of asthma conducted on diverse platforms using keywords, such as asthma, genomics, metabolomics, and epigenomics. We extracted data about asthma candidate biomarkers from 73 articles and developed a catalog of 190 potential asthma biomarkers (167 human, 23 animal data), comprising DNA loci, transcripts, proteins, metabolites, epimutations, and noncoding RNAs. The data were sorted according to 13 omics types: genomics, epigenomics, transcriptomics, proteomics, interactomics, metabolomics, ncRNAomics, glycomics, lipidomics, environmental omics, pharmacogenomics, phenomics, and integrative omics. Importantly, we found that 10 candidate biomarkers were apparent in at least two or more omics levels, thus promising potential for further biomarker research and development and precision medicine applications. This multiomics catalog reported herein for the first time contributes to future decision-making on prioritization of biomarkers and validation efforts for precision medicine in asthma. The findings may also facilitate meta-analyses and integrative omics studies in the future.

Serum prognostic biomarkers in head and neck cancer patients.

PubMed

Lin, Ho-Sheng; Siddiq, Fauzia; Talwar, Harvinder S; Chen, Wei; Voichita, Calin; Draghici, Sorin; Jeyapalan, Gerald; Chatterjee, Madhumita; Fribley, Andrew; Yoo, George H; Sethi, Seema; Kim, Harold; Sukari, Ammar; Folbe, Adam J; Tainsky, Michael A

2014-08-01

A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC). Prospective cohort study. A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient's serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models. Poor overall survival was associated with African Americans (hazard ratio [HR] for death = 2.61; 95% confidence interval [CI]: 1.58-4.33; P = .000), advanced stage (HR = 2.79; 95% CI: 1.40-5.57; P = .004), and recurrent disease (HR = 6.66; 95% CI: 2.54-17.44; P = .000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival. The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted. © 2014 The American Laryngological, Rhinological and Otological Society, Inc.

Serum Prognostic Biomarkers in Head and Neck Cancer Patients

PubMed Central

Lin, Ho-Sheng; Siddiq, Fauzia; Talwar, Harvinder S.; Chen, Wei; Voichita, Calin; Draghici, Sorin; Jeyapalan, Gerald; Chatterjee, Madhumita; Fribley, Andrew; Yoo, George H.; Sethi, Seema; Kim, Harold; Sukari, Ammar; Folbe, Adam J.; Tainsky, Michael A.

2014-01-01

Objectives/Hypothesis A reliable estimate of survival is important as it may impact treatment choice. The objective of this study is to identify serum autoantibody biomarkers that can be used to improve prognostication for patients affected with head and neck squamous cell carcinoma (HNSCC). Study Design Prospective cohort study. Methods A panel of 130 serum biomarkers, previously selected for cancer detection using microarray-based serological profiling and specialized bioinformatics, were evaluated for their potential as prognostic biomarkers in a cohort of 119 HNSCC patients followed for up to 12.7 years. A biomarker was considered positive if its reactivity to the particular patient’s serum was greater than one standard deviation above the mean reactivity to sera from the other 118 patients, using a leave-one-out cross-validation model. Survival curves were estimated according to the Kaplan-Meier method, and statistically significant differences in survival were examined using the log rank test. Independent prognostic biomarkers were identified following analysis using multivariate Cox proportional hazards models. Results Poor overall survival was associated with African Americans (hazard ratio [HR] for death =2.61; 95% confidence interval [CI]: 1.58–4.33; P =.000), advanced stage (HR =2.79; 95% CI: 1.40–5.57; P =.004), and recurrent disease (HR =6.66; 95% CI: 2.54–17.44; P =.000). On multivariable Cox analysis adjusted for covariates (race and stage), six of the 130 markers evaluated were found to be independent prognosticators of overall survival. Conclusions The results shown here are promising and demonstrate the potential use of serum biomarkers for prognostication in HNSCC patients. Further clinical trials to include larger samples of patients across multiple centers may be warranted. PMID:24347532

Recurrence quantification as potential bio-markers for diagnosis of pre-cancer

NASA Astrophysics Data System (ADS)

Mukhopadhyay, Sabyasachi; Pratiher, Sawon; Barman, Ritwik; Pratiher, Souvik; Pradhan, Asima; Ghosh, Nirmalya; Panigrahi, Prasanta K.

2017-03-01

In this paper, the spectroscopy signals have been analyzed in recurrence plots (RP), and extract recurrence quantification analysis (RQA) parameters from the RP in order to classify the tissues into normal and different precancerous grades. Three RQA parameters have been quantified in order to extract the important features in the spectroscopy data. These features have been fed to different classifiers for classification. Simulation results validate the efficacy of the recurrence quantification as potential bio-markers for diagnosis of pre-cancer.

Carbonylated plasma proteins as potential biomarkers of obesity induced type 2 diabetes mellitus.

PubMed

Bollineni, Ravi Chand; Fedorova, Maria; Blüher, Matthias; Hoffmann, Ralf

2014-11-07

Protein carbonylation is a common nonenzymatic oxidative post-translational modification, which is often considered as biomarker of oxidative stress. Recent evidence links protein carbonylation also to obesity and type 2 diabetes mellitus (T2DM), though the protein targets of carbonylation in human plasma have not been identified. In this study, we profiled carbonylated proteins in plasma samples obtained from lean individuals and obese patients with or without T2DM. The plasma samples were digested with trypsin, carbonyl groups were derivatized with O-(biotinylcarbazoylmethyl)hydroxylamine, enriched by avidin affinity chromatography, and analyzed by RPC-MS/MS. Signals of potentially modified peptides were targeted in a second LC-MS/MS analysis to retrieve the peptide sequence and the modified residues. A total of 158 unique carbonylated proteins were identified, of which 52 were detected in plasma samples of all three groups. Interestingly, 36 carbonylated proteins were detected only in obese patients with T2DM, whereas 18 were detected in both nondiabetic groups. The carbonylated proteins originated mostly from liver, plasma, platelet, and endothelium. Functionally, they were mainly involved in cell adhesion, signaling, angiogenesis, and cytoskeletal remodeling. Among the identified carbonylated proteins were several candidates, such as VEGFR-2, MMP-1, argin, MKK4, and compliment C5, already connected before to diabetes, obesity and metabolic diseases.

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

Development of an Immunoassay for the Kidney Specific Protein myo-Inositol Oxygenase, a Potential Biomarker of Acute Kidney Injury

PubMed Central

Gaut, Joseph P.; Crimmins, Dan L.; Ohlendorf, Matt F.; Lockwood, Christina M.; Griest, Terry A.; Brada, Nancy A.; Hoshi, Masato; Sato, Bryan; Hotchkiss, Richard S.; Jain, Sanjay; Ladenson, Jack H.

2014-01-01

Background Acute kidney injury (AKI) affects 45% of critically ill patients resulting in increased morbidity and mortality. The diagnostic standard, serum creatinine (SCr), is non-specific and may not increase until days after injury. There is significant need for a renal specific AKI biomarker detectable early enough that there would be a potential window for therapeutic intervention. In this study, we sought to identify a renal specific biomarker of AKI. Methods Gene expression data was analyzed from normal mouse tissues to identify kidney specific genes, one of which was Miox. Monoclonal antibodies were generated to recombinant myo-inositol oxygenase (MIOX), and an immunoassay was developed to quantify MIOX in plasma. The immunoassay was tested in animals and retrospectively in patients with and without AKI. Results Kidney tissue specificity of MIOX was supported by Western blot. Immunohistochemistry localized MIOX to the proximal renal tubule. Plasma MIOX, undetectable at baseline, increased 24 hours following AKI in mice. Plasma MIOX was increased in critically ill patients with AKI (12.4 ± 4.3 ng/mL, n=42) compared with patients without AKI (0.5 ± 0.3 ng/mL, n=17) and was highest in patients with oliguric AKI (20.2 ± 7.5 ng/mL, n=23). Plasma MIOX increased 54.3 ± 3.8 hours before the increase in SCr. Conclusions MIOX is a renal specific, proximal tubule protein that is increased in plasma of animals and critically ill patients with AKI. MIOX preceded the elevation in SCr by approximately two days in human patients. Large-scale studies are warranted to further investigate MIOX as an AKI biomarker. PMID:24486646

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.

Identifying Epigenetic Biomarkers using Maximal Relevance and Minimal Redundancy Based Feature Selection for Multi-Omics Data.

PubMed

Mallik, Saurav; Bhadra, Tapas; Maulik, Ujjwal

2017-01-01

Epigenetic Biomarker discovery is an important task in bioinformatics. In this article, we develop a new framework of identifying statistically significant epigenetic biomarkers using maximal-relevance and minimal-redundancy criterion based feature (gene) selection for multi-omics dataset. Firstly, we determine the genes that have both expression as well as methylation values, and follow normal distribution. Similarly, we identify the genes which consist of both expression and methylation values, but do not follow normal distribution. For each case, we utilize a gene-selection method that provides maximal-relevant, but variable-weighted minimum-redundant genes as top ranked genes. For statistical validation, we apply t-test on both the expression and methylation data consisting of only the normally distributed top ranked genes to determine how many of them are both differentially expressed andmethylated. Similarly, we utilize Limma package for performing non-parametric Empirical Bayes test on both expression and methylation data comprising only the non-normally distributed top ranked genes to identify how many of them are both differentially expressed and methylated. We finally report the top-ranking significant gene-markerswith biological validation. Moreover, our framework improves positive predictive rate and reduces false positive rate in marker identification. In addition, we provide a comparative analysis of our gene-selection method as well as othermethods based on classificationperformances obtained using several well-known classifiers.

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

Cardiovascular risk assessment of dyslipidemic children: analysis of biomarkers to identify monogenic dyslipidemia[S

PubMed Central

Medeiros, Ana Margarida; Alves, Ana Catarina; Aguiar, Pedro; Bourbon, Mafalda

2014-01-01

The distinction between a monogenic dyslipidemia and a polygenic/environmental dyslipidemia is important for the cardiovascular risk assessment, counseling, and treatment of these patients. The present work aims to perform the cardiovascular risk assessment of dyslipidemic children to identify useful biomarkers for clinical criteria improvement in clinical settings. Main cardiovascular risk factors were analyzed in a cohort of 237 unrelated children with clinical diagnosis of familial hypercholesterolemia (FH). About 40% carried at least two cardiovascular risk factors and 37.6% had FH, presenting mutations in LDLR and APOB. FH children showed significant elevated atherogenic markers and lower concentration of antiatherogenic particles. Children without a molecular diagnosis of FH had higher levels of TGs, apoC2, apoC3, and higher frequency of BMI and overweight/obesity, suggesting that environmental factors can be the underlying cause of their hypercholesterolem≥ia. An apoB/apoA1 ratio ≥0.68 was identified as the best biomarker (area under the curve = 0.835) to differentiate FH from other dyslipidemias. The inclusion in clinical criteria of a higher cut-off point for LDL cholesterol or an apoB/apoA1 ratio ≥0.68 optimized the criteria sensitivity and specificity. The correct identification, at an early age, of all children at-risk is of great importance so that specific interventions can be implemented. apoB/apoA1 can improve the identification of FH patients. PMID:24627126

Renocardiovascular Biomarkers: from the Perspective of Managing Chronic Kidney Disease and Cardiovascular Disease

PubMed Central

Niizuma, Shinichiro; Iwanaga, Yoshitaka; Yahata, Takaharu; Miyazaki, Shunichi

2017-01-01

Mortality among the patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) remains high because of the very high incidence of cardiovascular disease (CVD) such as coronary artery disease, cardiac hypertrophy, and heart failure. Identifying CVD in patients with CKD/ESRD remains a significant hurdle and the early diagnosis and therapy for CVD is crucial in these patients. Therefore, it is necessary for the better management to identify and utilize cardiovascular (CV) biomarkers in profiling CVD risk and enabling stratification of early mortality. This review summarizes current evidence about renocardiovascular biomarkers: CV biomarkers in patients with CKD as well as with ESRD, emphasizing on the emerging biomarkers: B-type natriuretic peptide, cardiac troponins, copeptin, the biomarker of renal injury (neutrophil gelatinase-associated lipocalin), and the mineral and bone disorder hormone/marker (fibroblast growth factor-23). Furthermore, it discusses their potential roles especially in ESRD and in future diagnostic and therapeutic strategies for CVD in the context of managing cardiorenal syndrome. PMID:28321399

Biomarkers for wound healing and their evaluation.

PubMed

Patel, S; Maheshwari, A; Chandra, A

2016-01-01

A biological marker (biomarker) is a substance used as an indicator of biological state. Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Research has identified several cellular events and mediators associated with wound healing that can serve as biomarkers. Macrophages, neutrophils, fibroblasts and platelets release cytokines molecules including TNF-α, interleukins (ILs) and growth factors, of which platelet-derived growth factor (PDGF) holds the greatest importance. As a result, various white cells and connective tissue cells release both matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). Studies have demonstrated that IL-1, IL-6, and MMPs, levels above normal, and an abnormally high MMP/TIMP ratio are often present in non-healing wounds. Clinical examination of wounds for these mediators could predict which wounds will heal and which will not, suggesting use of these chemicals as biomarkers of wound healing. There is also evidence that the application of growth factors like PDGF will alleviate the recuperating process of chronic, non-healing wounds. Finding a specific biomarker for wound healing status would be a breakthrough in this field and helping treat impaired wound healing.

Potential epigenetic biomarkers of obesity-related insulin resistance in human whole-blood.

PubMed

Day, Samantha E; Coletta, Richard L; Kim, Joon Young; Garcia, Luis A; Campbell, Latoya E; Benjamin, Tonya R; Roust, Lori R; De Filippis, Elena A; Mandarino, Lawrence J; Coletta, Dawn K

2017-04-03

Obesity can increase the risk of complex metabolic diseases, including insulin resistance. Moreover, obesity can be caused by environmental and genetic factors. However, the epigenetic mechanisms of obesity are not well defined. Therefore, the identification of novel epigenetic biomarkers of obesity allows for a more complete understanding of the disease and its underlying insulin resistance. The aim of our study was to identify DNA methylation changes in whole-blood that were strongly associated with obesity and insulin resistance. Whole-blood was obtained from lean (n = 10; BMI = 23.6 ± 0.7 kg/m 2 ) and obese (n = 10; BMI = 34.4 ± 1.3 kg/m 2 ) participants in combination with euglycemic hyperinsulinemic clamps to assess insulin sensitivity. We performed reduced representation bisulfite sequencing on genomic DNA isolated from the blood. We identified 49 differentially methylated cytosines (DMCs; q < 0.05) that were altered in obese compared with lean participants. We identified 2 sites (Chr.21:46,957,981 and Chr.21:46,957,915) in the 5' untranslated region of solute carrier family 19 member 1 (SLC19A1) with decreased methylation in obese participants (lean 0.73 ± 0.11 vs. obese 0.09 ± 0.05; lean 0.68 ± 0.10 vs. obese 0.09 ± 0.05, respectively). These 2 DMCs identified by obesity were also significantly predicted by insulin sensitivity (r = 0.68, P = 0.003; r = 0.66; P = 0.004). In addition, we performed a differentially methylated region (DMR) analysis and demonstrated a decrease in methylation of Chr.21:46,957,915-46,958,001 in SLC19A1 of -34.9% (70.4% lean vs. 35.5% obese). The decrease in whole-blood SLC19A1 methylation in our obese participants was similar to the change observed in skeletal muscle (Chr.21:46,957,981, lean 0.70 ± 0.09 vs. obese 0.31 ± 0.11 and Chr.21:46,957,915, lean 0.72 ± 0.11 vs. obese 0.31 ± 0.13). Pyrosequencing analysis further demonstrated a decrease in methylation at Chr.21:46,957,915 in both whole-blood (lean 0.71 ± 0

Translational safety biomarkers of colonic barrier integrity in the rat.

PubMed

Erkens, Tim; Bueters, Ruud; van Heerden, Marjolein; Cuyckens, Filip; Vreeken, Rob; Goeminne, Nick; Lammens, Lieve

2018-05-20

The intestinal barrier controls intestinal permeability, and its disruption has been associated with multiple diseases. Therefore, preclinical safety biomarkers monitoring barrier integrity are essential during the development of drugs targeting the intestines, particularly if starting treatment early after onset of disease. Classical toxicology endpoints are not sensitive enough and therefore our objective was to identify non-invasive markers enabling early in vivo detection of colonic barrier perturbation. Male Sprague-Dawley rats were dosed intracolonically via the rectum, using sodium caprate or ibuprofen as tool compounds to alter barrier integrity. Several potentially translational biomarkers and probe molecules related to permeability, inflammation or tissue damage were evaluated, using various analytical platforms, including immunoassays, targeted metabolomics and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry. Several markers were identified that allow early in vivo detection of colonic barrier integrity changes, before histopathological evidence of tissue damage. The most promising permeability markers identified were plasma fluorescein isothiocyanate-dextran 4000 and a lactulose/mannitol/sucralose mixture in urine. These markers showed maximum increases over 100-fold or approximately 10-50-fold, respectively. Intracolonic administration of the above probe molecules outperformed oral administration and inflammatory or other biomarkers, such as α 2 -macroglobulin, calprotectin, cytokines, prostaglandins and a panel of metabolic molecules to identify early and subtle changes in barrier integrity. However, optimal timing of probe administration and sample collection is important for all markers evaluated. Inclusion of these probe molecules in preclinical toxicity studies might aid in risk assessment and the design of a clinical biomarker plan, as several of these markers have translational potential. Copyright © 2018 John

Mass spectrometry for biomarker development

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

Wu, Chaochao; Liu, Tao; Baker, Erin Shammel

2015-06-19

Biomarkers potentially play a crucial role in early disease diagnosis, prognosis and targeted therapy. In the past decade, mass spectrometry based proteomics has become increasingly important in biomarker development due to large advances in technology and associated methods. This chapter mainly focuses on the application of broad (e.g. shotgun) proteomics in biomarker discovery and the utility of targeted proteomics in biomarker verification and validation. A range of mass spectrometry methodologies are discussed emphasizing their efficacy in the different stages in biomarker development, with a particular emphasis on blood biomarker development.

Prespecified candidate biomarkers identify follicular lymphoma patients who achieved longer progression-free survival with bortezomib-rituximab versus rituximab.

PubMed

Coiffier, Bertrand; Li, Weimin; Henitz, Erin D; Karkera, Jayaprakash D; Favis, Reyna; Gaffney, Dana; Shapiro, Alice; Theocharous, Panteli; Elsayed, Yusri A; van de Velde, Helgi; Schaffer, Michael E; Osmanov, Evgenii A; Hong, Xiaonan; Scheliga, Adriana; Mayer, Jiri; Offner, Fritz; Rule, Simon; Teixeira, Adriana; Romejko-Jarosinska, Joanna; de Vos, Sven; Crump, Michael; Shpilberg, Ofer; Zinzani, Pier Luigi; Cakana, Andrew; Esseltine, Dixie-Lee; Mulligan, George; Ricci, Deborah

2013-05-01

Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase III LYM-3001 study. A total of 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes. In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets. Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab. ©2013 AACR.

Pathway mapping and development of disease-specific biomarkers: protein-based network biomarkers

PubMed Central

Chen, Hao; Zhu, Zhitu; Zhu, Yichun; Wang, Jian; Mei, Yunqing; Cheng, Yunfeng

2015-01-01

It is known that a disease is rarely a consequence of an abnormality of a single gene, but reflects the interactions of various processes in a complex network. Annotated molecular networks offer new opportunities to understand diseases within a systems biology framework and provide an excellent substrate for network-based identification of biomarkers. The network biomarkers and dynamic network biomarkers (DNBs) represent new types of biomarkers with protein–protein or gene–gene interactions that can be monitored and evaluated at different stages and time-points during development of disease. Clinical bioinformatics as a new way to combine clinical measurements and signs with human tissue-generated bioinformatics is crucial to translate biomarkers into clinical application, validate the disease specificity, and understand the role of biomarkers in clinical settings. In this article, the recent advances and developments on network biomarkers and DNBs are comprehensively reviewed. How network biomarkers help a better understanding of molecular mechanism of diseases, the advantages and constraints of network biomarkers for clinical application, clinical bioinformatics as a bridge to the development of diseases-specific, stage-specific, severity-specific and therapy predictive biomarkers, and the potentials of network biomarkers are also discussed. PMID:25560835

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

PubMed Central

Ruiz de Garibay, Gorka; Herranz, Carmen; Llorente, Alicia; Boni, Jacopo; Serra-Musach, Jordi; Mateo, Francesca; Aguilar, Helena; Gómez-Baldó, Laia; Petit, Anna; Vidal, August; Climent, Fina; Hernández-Losa, Javier; Cordero, Álex; González-Suárez, Eva; Sánchez-Mut, José Vicente; Esteller, Manel; Llatjós, Roger; Varela, Mar; López, José Ignacio; García, Nadia; Extremera, Ana I.; Gumà, Anna; Ortega, Raúl; Plà, María Jesús; Fernández, Adela; Pernas, Sònia; Falo, Catalina; Morilla, Idoia; Campos, Miriam; Gil, Miguel; Román, Antonio; Molina-Molina, María; Ussetti, Piedad; Laporta, Rosalía; Valenzuela, Claudia; Ancochea, Julio; Xaubet, Antoni; Casanova, Álvaro; Pujana, Miguel Angel

2015-01-01

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM. PMID:26167915

Glycosylation-Based Serum Biomarkers for Cancer Diagnostics and Prognostics.

PubMed

Kirwan, Alan; Utratna, Marta; O'Dwyer, Michael E; Joshi, Lokesh; Kilcoyne, Michelle

2015-01-01

Cancer is the second most common cause of death in developed countries with approximately 14 million newly diagnosed individuals and over 6 million cancer-related deaths in 2012. Many cancers are discovered at a more advanced stage but better survival rates are correlated with earlier detection. Current clinically approved cancer biomarkers are most effective when applied to patients with widespread cancer. Single biomarkers with satisfactory sensitivity and specificity have not been identified for the most common cancers and some biomarkers are ineffective for the detection of early stage cancers. Thus, novel biomarkers with better diagnostic and prognostic performance are required. Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers. Glycoproteins enter circulation from tissues or blood cells through active secretion or leakage and patient serum is an attractive option as a source for biomarkers from a clinical and diagnostic perspective. A plethora of technical approaches have been developed to address the challenges of glycosylation structure detection and determination. This review summarises currently utilised glycoprotein biomarkers and novel glycosylation-based biomarkers from the serum glycoproteome under investigation as cancer diagnostics and for monitoring and prognostics and includes details of recent high throughput and other emerging glycoanalytical techniques.

Glycosylation-Based Serum Biomarkers for Cancer Diagnostics and Prognostics

PubMed Central

Kirwan, Alan; Utratna, Marta; O'Dwyer, Michael E.; Joshi, Lokesh

2015-01-01

Cancer is the second most common cause of death in developed countries with approximately 14 million newly diagnosed individuals and over 6 million cancer-related deaths in 2012. Many cancers are discovered at a more advanced stage but better survival rates are correlated with earlier detection. Current clinically approved cancer biomarkers are most effective when applied to patients with widespread cancer. Single biomarkers with satisfactory sensitivity and specificity have not been identified for the most common cancers and some biomarkers are ineffective for the detection of early stage cancers. Thus, novel biomarkers with better diagnostic and prognostic performance are required. Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers. Glycoproteins enter circulation from tissues or blood cells through active secretion or leakage and patient serum is an attractive option as a source for biomarkers from a clinical and diagnostic perspective. A plethora of technical approaches have been developed to address the challenges of glycosylation structure detection and determination. This review summarises currently utilised glycoprotein biomarkers and novel glycosylation-based biomarkers from the serum glycoproteome under investigation as cancer diagnostics and for monitoring and prognostics and includes details of recent high throughput and other emerging glycoanalytical techniques. PMID:26509158

Biomarkers in earthworms.

PubMed

Scott-Fordsmand, J J; Weeks, J M

2000-01-01

Earthworms are believed to be so-called key species within ecosystems and are often exposed to a wide range of anthropogenic compounds released to the terrestrial environment. As a consequence, they may suffer from the toxicity of these compounds. For these and other reasons, earthworms have been used extensively in ecotoxicological studies. In recent years the use of other biological responses (biomarkers) to estimate either exposure or resultant effects of chemicals has received increased attention. Biomarkers address the question of bioavailability by only responding to the bioactive fraction. They may incorporate effects following exposure to a mixture of chemicals. Biomarkers may also reduce extrapolation of results from the laboratory to the field, as they may be applicable under both conditions. The present review has drawn together current knowledge on potential biomarkers in earthworms and appraised them in relation to basic requirements needed for supplying information relevant to devising satisfactory risk assessment. A wide range of potential biomarkers have been measured in earthworms, including DNA alteration, induction of metal-binding proteins (MTs and MBP), depression of ChE activity and other enzymatic responses, energy reserve responses, responses in neural impulse conductivity, lysosomal membrane stability, immunological responses, changes in sperm numbers, histopathological changes, and behavioral changes. Both organic and inorganic compounds have been included; however, for each biomarker the main emphasis historically has been placed on only a few chemicals. Dose-response relationships were in some cases observed. Little information is available on the linkage of the biomarker response to effects at population or community levels. The influence of other factors, biotic and abiotic, on the biomarker responses and their temporal duration have been only sporadically reported.

Alzheimer's disease biomarker discovery using in silico literature mining and clinical validation

PubMed Central

2012-01-01

Background Alzheimer’s Disease (AD) is the most widespread form of dementia in the elderly but despite progress made in recent years towards a mechanistic understanding, there is still an urgent need for disease modification therapy and for early diagnostic tests. Substantial international efforts are being made to discover and validate biomarkers for AD using candidate analytes and various data-driven 'omics' approaches. Cerebrospinal fluid is in many ways the tissue of choice for biomarkers of brain disease but is limited by patient and clinician acceptability, and increasing attention is being paid to the search for blood-based biomarkers. The aim of this study was to use a novel in silico approach to discover a set of candidate biomarkers for AD. Methods We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of assertional metadata derived from relevant legacy information. We then assessed the validity of this approach using direct assays of the identified biomarkers in plasma by immunodetection methods. Results Using this in silico approach, we identified 25 biomarker candidates, at least three of which have subsequently been reported to be altered in blood or CSF from AD patients. Two further candidate biomarkers, indicated from the in silico approach, were choline acetyltransferase and urokinase-type plasminogen activator receptor. Using immunodetection, we showed that, in a large sample set, these markers are either altered in disease or correlate with MRI markers of atrophy. Conclusions These data support as a proof of concept the use of data mining and in silico analyses to derive valid biomarker candidates for AD and, by extension, for other disorders. PMID:23113945

MicroRNAs: A novel potential biomarker for diagnosis and therapy in patients with non-small cell lung cancer.

PubMed

Zhou, Qun; Huang, Shao-Xin; Zhang, Feng; Li, Shu-Jun; Liu, Cong; Xi, Yong-Yong; Wang, Liang; Wang, Xin; He, Qi-Qiang; Sun, Cheng-Cao; Li, De-Jia

2017-12-01

Lung cancer is still one of the most serious causes of cancer-related deaths all over the world. MicroRNAs (miRNAs) are defined as small non-coding RNAs which could play a pivotal role in post-transcriptional regulation of gene expression. Increasing evidence demonstrated dysregulation of miRNA expression associates with the development and progression of NSCLC. To emphasize a variety of tissue-specific miRNAs, circulating miRNAs and miRNA-derived exosomes could be used as potential diagnostic and therapeutic biomarkers in NSCLC patients. In the current review, we paid attention to the significant discoveries of preclinical and clinical studies, which performed on tissue-specific miRNA, circulating miRNA and exosomal miRNA. The related studies were obtained through a systematic search of Pubmed, Web of Science, Embase. A variety of tissue-specific miRNAs and circulating miRNAs with high sensitivity and specificity which could be used as potential diagnostic and therapeutic biomarkers in NSCLC patients. In addition, we emphasize that the miRNA-derived exosomes become novel diagnostic biomarkers potentially in these patients with NSCLC. MiRNAs have emerged as non-coding RNAs, which have potential to be candidates for the diagnosis and therapy of NSCLC. © 2017 John Wiley & Sons Ltd.

Joint analysis of multiple biomarkers for identifying type 2 diabetes in middle-aged and older Chinese: a cross-sectional study

PubMed Central

Wu, Hongyu; Yu, Zhijie; Qi, Qibin; Li, Huaixing; Sun, Qi

2011-01-01

Objective Identifying individuals with high risk of type 2 diabetes is important. To evaluate discriminatory ability of multiple biomarkers for type 2 diabetes in a Chinese population. Methods Plasma adiponectin, plasminogen activator inhibitor-1, retinol-binding protein 4, resistin, C-reactive protein, interleukin 6 (IL-6), tumour necrosis factor α receptor 2 and ferritin were measured in a population-based sample of 3189 Chinese (1419 men and 1770 women) aged 50–70 years. A weighted biomarkers risk score (BRS) was developed based on the strength of associations of these biomarkers with type 2 diabetes. The discriminatory ability was tested by the area under receiver operating characteristics curve (AUC). Results Adiponectin, plasminogen activator inhibitor-1, IL-6 and ferritin were independently associated with the prevalence of type 2 diabetes, and they were used to calculate the biomarkers risk score (BRS). After adjustment for the confounding factors, the ORs for type 2 diabetes and impaired fasting glucose with each point increment of BRS were 1.28 (95% CI 1.22 to 1.34) and 1.16 (1.12 to 1.20), respectively. Compared with those in the lowest quintile of the BRS, the participants in the highest quintile have an OR (95% CI) of 6.67 (4.21 to 10.55) for type 2 diabetes. The area under the curve for the BRS and conventional risk factors alone was 0.73 and 0.76, respectively, and substantially increased to 0.81 after combining both BRS and conventional risk factors (p<0.001). Conclusions These data suggest that combining multiple biomarkers and conventional risk factors might substantially enhance the ability to identify individuals with type 2 diabetes. More prospective data are warranted to confirm this observation. PMID:22021786

Biomarkers in Pediatric ARDS: Future Directions.

PubMed

Orwoll, Benjamin E; Sapru, Anil

2016-01-01

Acute respiratory distress syndrome (ARDS) is common among mechanically ventilated children and accompanies up to 30% of all pediatric intensive care unit deaths. Though ARDS diagnosis is based on clinical criteria, biological markers of acute lung damage have been extensively studied in adults and children. Biomarkers of inflammation, alveolar epithelial and capillary endothelial disruption, disordered coagulation, and associated derangements measured in the circulation and other body fluids, such as bronchoalveolar lavage, have improved our understanding of pathobiology of ARDS. The biochemical signature of ARDS has been increasingly well described in adult populations, and this has led to the identification of molecular phenotypes to augment clinical classifications. However, there is a paucity of data from pediatric ARDS (pARDS) patients. Biomarkers and molecular phenotypes have the potential to identify patients at high risk of poor outcomes, and perhaps inform the development of targeted therapies for specific groups of patients. Additionally, because of the lower incidence of and mortality from ARDS in pediatric patients relative to adults and lack of robust clinical predictors of outcome, there is an ongoing interest in biological markers as surrogate outcome measures. The recent definition of pARDS provides additional impetus for the measurement of established and novel biomarkers in future pediatric studies in order to further characterize this disease process. This chapter will review the currently available literature and discuss potential future directions for investigation into biomarkers in ARDS among children.

Biomarkers in Pediatric ARDS: Future Directions

PubMed Central

Orwoll, Benjamin E.; Sapru, Anil

2016-01-01

Acute respiratory distress syndrome (ARDS) is common among mechanically ventilated children and accompanies up to 30% of all pediatric intensive care unit deaths. Though ARDS diagnosis is based on clinical criteria, biological markers of acute lung damage have been extensively studied in adults and children. Biomarkers of inflammation, alveolar epithelial and capillary endothelial disruption, disordered coagulation, and associated derangements measured in the circulation and other body fluids, such as bronchoalveolar lavage, have improved our understanding of pathobiology of ARDS. The biochemical signature of ARDS has been increasingly well described in adult populations, and this has led to the identification of molecular phenotypes to augment clinical classifications. However, there is a paucity of data from pediatric ARDS (pARDS) patients. Biomarkers and molecular phenotypes have the potential to identify patients at high risk of poor outcomes, and perhaps inform the development of targeted therapies for specific groups of patients. Additionally, because of the lower incidence of and mortality from ARDS in pediatric patients relative to adults and lack of robust clinical predictors of outcome, there is an ongoing interest in biological markers as surrogate outcome measures. The recent definition of pARDS provides additional impetus for the measurement of established and novel biomarkers in future pediatric studies in order to further characterize this disease process. This chapter will review the currently available literature and discuss potential future directions for investigation into biomarkers in ARDS among children. PMID:27313995

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

Biomarkers for the development of new medications for cocaine dependence.

PubMed

Bough, Kristopher J; Amur, Shashi; Lao, Guifang; Hemby, Scott E; Tannu, Nilesh S; Kampman, Kyle M; Schmitz, Joy M; Martinez, Diana; Merchant, Kalpana M; Green, Charles; Sharma, Jyoti; Dougherty, Anne H; Moeller, F Gerard

2014-01-01

There has been significant progress in personalized drug development. In large part, this has taken place in the oncology field and been due to the ability of researchers/clinicians to discover and develop novel drug development tools (DDTs), such as biomarkers. In cancer treatment research, biomarkers have permitted a more accurate pathophysiological characterization of an individual patient, and have enabled practitioners to target mechanistically the right drug, to the right patient, at the right time. Similar to cancer, patients with substance use disorders (SUDs) present clinically with heterogeneous symptomatology and respond variably to therapeutic interventions. If comparable biomarkers could be identified and developed for SUDs, significant diagnostic and therapeutic advances could be made. In this review, we highlight current opportunities and difficulties pertaining to the identification and development of biomarkers for SUDs. We focus on cocaine dependence as an example. Putative diagnostic, pharmacodynamic (PD), and predictive biomarkers for cocaine dependence are discussed across a range of methodological approaches. A possible cocaine-dependent clinical outcome assessment (COA)--another type of defined DDT--is also discussed. At present, biomarkers for cocaine dependence are in their infancy. Much additional research will be needed to identify, validate, and qualify these putative tools prior to their potential use for medications development and/or application to clinical practice. However, with a large unmet medical need and an estimated market size of several hundred million dollars per year, if developed, biomarkers for cocaine dependence will hold tremendous value to both industry and public health.

Chronic periodontitis can affect the levels of potential oral cancer salivary mRNA biomarkers.

PubMed

Cheng, Y-S L; Jordan, L; Chen, H-S; Kang, D; Oxford, L; Plemons, J; Parks, H; Rees, T

2017-06-01

More than 100 salivary constituents have been found to show levels significantly different in patients with oral squamous cell carcinoma (OSCC) from those found in healthy controls, and therefore have been suggested to be potential salivary biomarkers for OSCC detection. However, many of these potential OSCC salivary biomarkers are also involved in chronic inflammation, and whether the levels of these biomarkers could be affected by the presence of chronic periodontitis was not known. The objective of this pilot study was therefore to measure the levels of seven previously reported potential OSCC salivary mRNA biomarkers in patients with chronic periodontitis and compare them to levels found in patients with OSCC and healthy controls. The seven salivary mRNAs were interleukin (IL)-8, IL-1β, dual specificity phosphatase 1, H3 histone family 3A, ornithine decarboxylase antizyme 1, S100 calcium-binding protein P (S100P) and spermidine/spermine N1-acetyltransferase 1. Unstimulated whole saliva samples were collected from a total of 105 human subjects from the following four study groups: OSCC; CPNS (chronic periodontitis, moderate to severe degree, non-smokers); CPS (chronic periodontitis, moderate to severe degree, smokers); and healthy controls. Levels of each mRNA in patient groups (OSCC or chronic periodontitis) relative to the healthy controls were determined by a pre-amplification reverse transcription-quantitative polymerase chain reaction approach with nested gene-specific primers. Results were recorded and analyzed by the Bio-Rad CFX96 Real-Time System. Mean fold changes between each pair of patient vs. control groups were analyzed by the Mann-Whitney U-test with Bonferroni corrections. Only S100P showed significantly higher levels in patients with OSCC compared to both patients with CPNS (p = 0.003) and CPS (p = 0.007). The difference in S100P levels between patients with OSCC and healthy controls was also marginally significant (p = 0.009). There was no

Development of a Drug-Response Modeling Framework to Identify Cell Line Derived Translational Biomarkers That Can Predict Treatment Outcome to Erlotinib or Sorafenib.

PubMed

Li, Bin; Shin, Hyunjin; Gulbekyan, Georgy; Pustovalova, Olga; Nikolsky, Yuri; Hope, Andrew; Bessarabova, Marina; Schu, Matthew; Kolpakova-Hart, Elona; Merberg, David; Dorner, Andrew; Trepicchio, William L

2015-01-01

Development of drug responsive biomarkers from pre-clinical data is a critical step in drug discovery, as it enables patient stratification in clinical trial design. Such translational biomarkers can be validated in early clinical trial phases and utilized as a patient inclusion parameter in later stage trials. Here we present a study on building accurate and selective drug sensitivity models for Erlotinib or Sorafenib from pre-clinical in vitro data, followed by validation of individual models on corresponding treatment arms from patient data generated in the BATTLE clinical trial. A Partial Least Squares Regression (PLSR) based modeling framework was designed and implemented, using a special splitting strategy and canonical pathways to capture robust information for model building. Erlotinib and Sorafenib predictive models could be used to identify a sub-group of patients that respond better to the corresponding treatment, and these models are specific to the corresponding drugs. The model derived signature genes reflect each drug's known mechanism of action. Also, the models predict each drug's potential cancer indications consistent with clinical trial results from a selection of globally normalized GEO expression datasets.

The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease.

PubMed

Ren, Hong-Gang; Adom, Djamilatou; Paczesny, Sophie

2018-05-01

Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered: This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary: We focus on biomarkers that play an essential role in target identification.

Identification of Potential Biomarkers for Urine Metabolomics of Polycystic Ovary Syndrome Based on Gas Chromatography-Mass Spectrometry.

PubMed

Zou, Ying; Zhu, Fu-Fan; Fang, Chao-Ying; Xiong, Xi-Yue; Li, Hong-Yun

2018-04-20

Polycystic ovary syndrome (PCOS) is a complex endocrine and metabolic disorder, and it's diagnosis is difficult. The aim of this study was to investigate the metabolic profiles of PCOS patients by analyzing urine samples and identify useful biomarkers for diagnosis of PCOS. This study was carried out in the Department of Obstetrics and Gynecology of the Maternal and Child Health Hospital of Hunan Province from December 2014 to July 2016. In this study, the urine samples of 21 women with PCOS and 16 healthy controls were assessed through gas chromatography-mass spectrometry to investigate the urine metabolite characteristics of PCOS and identify useful biomarkers for the diagnosis of this disorder. The Student's t-test and rank sum test were applied to validate the statistical significance of the between the two groups. In total, 35 urine metabolites were found to be significantly different between the PCOS patients and the controls. In particular, a significant increase in the levels of lactose (10.01 [0,13.99] mmol/mol creatinine vs. 2.35 [0.16, 3.26] mmol/mol creatinine, P = 0.042), stearic acid (2.35 [1.47, 3.14] mmol/mol creatinine vs. 0.05 [0, 0.14] mmol/mol creatinine, P < 0.001), and palmitic acid (2.13 [1.07, 2.79] mmol/mol creatinine vs. 0 [0, 0] mmol/mol creatinine, P < 0.001) and a decrease in the levels of succinic acid (0 [0, 0] mmol/mol creatinine vs. 38.94 [4.16, 51.30] mmol/mol creatinine, P < 0.001) were found in the PCOS patients compared with the controls. It was possible to cluster the PCOS patients and the healthy controls into two distinct regions based on a principal component analysis model. Of the differentially expressed metabolites, four compounds, including stearic acid, palmitic acid, benzoylglycine, and threonine, were selected as potential biomarkers. This study offers new insight into the pathogenesis of PCOS, and the discriminating urine metabolites may provide a prospect for the diagnosis of PCOS.

A Preliminary ToF-SIMS Assessment of Preservation Potential of Organic Biomarkers in Modern Siliceous Sinter and Core, Yellowstone National Park, Wyoming

NASA Technical Reports Server (NTRS)

Guidry, S. A.; Chafetz, H. S.; Steele, A.; Toporski, J. K. W.

2000-01-01

Until recently, most biomarker work has focused on morphological body fossils. As a complement to this, three suites of siliceous precipitates were chosen for ToF-SIMS investigation in order to elucidate potential organic biomarkers.

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

The human oral metaproteome reveals potential biomarkers for caries disease.

PubMed

Belda-Ferre, Pedro; Williamson, James; Simón-Soro, Áurea; Artacho, Alejandro; Jensen, Ole N; Mira, Alex

2015-10-01

Tooth decay is considered the most prevalent human disease worldwide. We present the first metaproteomic study of the oral biofilm, using different mass spectrometry approaches that have allowed us to quantify individual peptides in healthy and caries-bearing individuals. A total of 7771 bacterial and 853 human proteins were identified in 17 individuals, which provide the first available protein repertoire of human dental plaque. Actinomyces and Coryneybacterium represent a large proportion of the protein activity followed by Rothia and Streptococcus. Those four genera account for 60-90% of total diversity. Healthy individuals appeared to have significantly higher amounts of L-lactate dehydrogenase and the arginine deiminase system, both implicated in pH buffering. Other proteins found to be at significantly higher levels in healthy individuals were involved in exopolysaccharide synthesis, iron metabolism and immune response. We applied multivariate analysis in order to find the minimum set of proteins that better allows discrimination of healthy and caries-affected dental plaque samples, detecting seven bacterial and five human protein functions that allow determining the health status of the studied individuals with an estimated specificity and sensitivity over 96%. We propose that future validation of these potential biomarkers in larger sample size studies may serve to develop diagnostic tests of caries risk that could be used in tooth decay prevention. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Protein C: a potential biomarker in severe sepsis and a possible tool for monitoring treatment with drotrecogin alfa (activated)

PubMed Central

Shorr, Andrew F; Nelson, David R; Wyncoll, Duncan LA; Reinhart, Konrad; Brunkhorst, Frank; Vail, George Matthew; Janes, Jonathan

2008-01-01

Introduction Drotrecogin alfa (activated; DrotAA) treatment, a 96-hour infusion, reduces 28-day mortality in severe sepsis to approximately 25%. The question remains whether a longer infusion or higher dose could increase rate of survival. The goal of this study was to identify a dependable, sensitive measure with which to monitor disease progression and response in patients during DrotAA treatment. Methods Data on severe sepsis patients included in PROWESS (placebo-controlled, double-blind, randomized study of 850 DrotAA and 840 placebo individuals) and ENHANCE (single-arm, open-label study of 2,375 DrotAA patients) studies were analyzed. In these studies, DrotAA (24 μg/kg per hour) or placebo was infused for 96 hours and patients were followed for 28 days. Data on six laboratory measures and five organ dysfunctions were systematically analyzed to identify a potential surrogate end-point for monitoring DrotAA therapy and predicting 28-day mortality at the end of therapy. To allow comparison across variables, sensitivity and specificity analyses identified cut-off values for preferred outcome, and relative risks for being above or below cut-offs were calculated, as was the 'proportion of treatment effect explained' (PTEE) to identify biomarkers that contribute to benefit from DrotAA. Results Protein C was the only variable that correlated with outcome across all analyses. Using placebo data, a baseline protein C under 40% was established as a useful predictor of outcome (odds ratio 2.12). Similar odds ratios were associated with cut-off values of other biomarkers, but the treatment benefit associated with DrotAA was significantly greater below the cut-off than above the cut-off only for protein C (relative risk for 28-day mortality 0.66 versus 0.88; P = 0.04). Protein C was the only end-of-infusion biomarker that potentially explained at least 50% of the benefit from DrotAA (PTEE 57.2%). The PTEE was 41% for cardiovascular Sequential Organ Failure Assessment score

IMAC fractionation in combination with LC-MS reveals H2B and NIF-1 peptides as potential bladder cancer biomarkers.

PubMed

Frantzi, Maria; Zoidakis, Jerome; Papadopoulos, Theofilos; Zürbig, Petra; Katafigiotis, Ioannis; Stravodimos, Konstantinos; Lazaris, Andreas; Giannopoulou, Ioanna; Ploumidis, Achilles; Mischak, Harald; Mullen, William; Vlahou, Antonia

2013-09-06

Improvement in bladder cancer (BC) management requires more effective diagnosis and prognosis of disease recurrence and progression. Urinary biomarkers attract special interest because of the noninvasive means of urine collection. Proteomic analysis of urine entails the adoption of a fractionation methodology to reduce sample complexity. In this study, we applied immobilized metal affinity chromatography in combination with high-resolution LC-MS/MS for the discovery of native urinary peptides potentially associated with BC aggressiveness. This approach was employed toward urine samples from patients with invasive BC, noninvasive BC, and benign urogenital diseases. A total of 1845 peptides were identified, corresponding to a total of 638 precursor proteins. Specific enrichment for proteins involved in nucleosome assembly and for zinc-finger transcription factors was observed. The differential expression of two candidate biomarkers, histone H2B and NIF-1 (zinc finger 335) in BC, was verified in independent sets of urine samples by ELISA and by immunohistochemical analysis of BC tissue. The results collectively support changes in the expression of both of these proteins with tumor progression, suggesting their potential role as markers for discriminating BC stages. In addition, the data indicate a possible involvement of NIF-1 in BC progression, likely as a suppressor and through interactions with Sox9 and HoxA1.

Omics-based biomarkers: current status and potential use in the clinic.

PubMed

Quezada, Héctor; Guzmán-Ortiz, Ana Laura; Díaz-Sánchez, Hugo; Valle-Rios, Ricardo; Aguirre-Hernández, Jesús

In recent years, the use of high-throughput omics technologies has led to the rapid discovery of many candidate biomarkers. However, few of them have made the transition to the clinic. In this review, the promise of omics technologies to contribute to the process of biomarker development is described. An overview of the current state in this area is presented with examples of genomics, proteomics, transcriptomics, metabolomics and microbiomics biomarkers in the field of oncology, along with some proposed strategies to accelerate their validation and translation to improve the care of patients with neoplasms. The inherent complexity underlying neoplasms combined with the requirement of developing well-designed biomarker discovery processes based on omics technologies present a challenge for the effective development of biomarkers that may be useful in guiding therapies, addressing disease risks, and predicting clinical outcomes. Copyright © 2017 Hospital Infantil de México Federico Gómez. Publicado por Masson Doyma México S.A. All rights reserved.

First-void urine: A potential biomarker source for triage of high-risk human papillomavirus infected women.

PubMed

Van Keer, Severien; Pattyn, Jade; Tjalma, Wiebren A A; Van Ostade, Xaveer; Ieven, Margareta; Van Damme, Pierre; Vorsters, Alex

2017-09-01

Great interest has been directed towards the use of first-void urine as a liquid biopsy for high-risk human papillomavirus DNA testing. Despite the high correlations established between urinary and cervical infections, human papillomavirus testing is unable to distinguish between productive and transforming high-risk infections that have the tendency to progress to cervical cancer. Thus far, investigations have been primarily confined to the identification of biomarkers for triage of high-risk human papillomavirus-positive women in cervicovaginal specimens and tissue biopsies. This paper reviews urinary biomarkers for cervical cancer and triage of high-risk human papillomavirus infections and elaborates on the opportunities and challenges that have emerged regarding the use of first-void urine as a liquid biopsy for the analysis of both morphological- (conventional cytology and novel immunohistochemical techniques) and molecular-based (HPV16/18 genotyping, host/viral gene methylation, RNA, and proteins) biomarkers. A literature search was performed in PubMed and Web of Science for studies investigating the use of urine as a biomarker source for cervical cancer screening. Five studies were identified reporting on biomarkers that are still in preclinical exploratory or clinical assay development phases and on assessments of non-invasive (urine) samples. Although large-scale validation studies are still needed, we conclude that methylation of both host and viral genes in urine has been proven feasible for use as a molecular cervical cancer triage and screening biomarker in phase two studies. This is especially promising and underscores our hypothesis that human papillomavirus DNA and candidate human and viral biomarkers are washed away with the initial, first-void urine, together with exfoliated cells, debris and impurities that line the urethra opening. Similar to the limitations of self-collected cervicovaginal samples, first-void urine will likely not fulfil the

Phosphorylated VEGFR2 and hypertension: potential biomarkers to indicate VEGF-dependency of advanced breast cancer in anti-angiogenic therapy.

PubMed

Fan, Minhao; Zhang, Jian; Wang, Zhonghua; Wang, Biyun; Zhang, Qunlin; Zheng, Chunlei; Li, Ting; Ni, Chen; Wu, Zhenhua; Shao, Zhimin; Hu, Xichun

2014-01-01

The efficacy of anti-VEGF agents probably lies on VEGF-dependency. Apatinib, a specific tyrosine kinase inhibitor that targets VEGF receptor 2, was assessed in patients with advanced breast cancer (ABC) (ClinicalTrials.gov NCT01176669 and NCT01653561). This substudy was to explore the potential biomarkers for VEGF-dependency in apatinib-treated breast cancer. Eighty pretreated patients received apatinib 750 or 500 mg/day orally in 4-week cycles. Circulating biomarkers were measured using a multiplex assay, and tissue biomarkers were identified with immunostaining. Baseline characteristics and adverse events (AEs) were included in the analysis. Statistical confirmation of independent predictive factors for anti-tumor efficacy was performed using Cox and Logistic regression models. Median progression-free survival (PFS) was 3.8 months, and overall survival (OS) was 10.6 months, with 17.5 % of objective response rate. Prominent AEs (≥60 %) were hypertension, hand-foot skin reaction (HFSR), and proteinuria. Higher tumor phosphorylated VEGFR2 (p-VEGFR2) expressions (P = 0.001), higher baseline serum soluble VEGFR2 (P = 0.031), hypertension (P = 0.011), and HFSR (P = 0.018) were significantly related to longer PFS, whereas hypertension (P = 0.002) and HFSR (P = 0.001) were also related to OS. Based on multivariate analysis, only p-VEGFR2 (adjusted HR, 0.40; P = 0.013) and hypertension (adjusted HR, 0.58; P = 0.038) were independent predictive factors for both PFS and clinical benefit rate. Apatinib had substantial antitumor activity in ABC and manageable toxicity. p-VEGFR2 and hypertension may be surrogate predictors of VEGF-dependency of breast cancer, which may identify an anti-angiogenesis sensitive population.

Identification of MicroRNA as Sepsis Biomarker Based on miRNAs Regulatory Network Analysis

PubMed Central

Huang, Jie; Sun, Zhandong; Yan, Wenying; Zhu, Yujie; Lin, Yuxin; Chen, Jiajai; Shen, Bairong

2014-01-01

Sepsis is regarded as arising from an unusual systemic response to infection but the physiopathology of sepsis remains elusive. At present, sepsis is still a fatal condition with delayed diagnosis and a poor outcome. Many biomarkers have been reported in clinical application for patients with sepsis, and claimed to improve the diagnosis and treatment. Because of the difficulty in the interpreting of clinical features of sepsis, some biomarkers do not show high sensitivity and specificity. MicroRNAs (miRNAs) are small noncoding RNAs which pair the sites in mRNAs to regulate gene expression in eukaryotes. They play a key role in inflammatory response, and have been validated to be potential sepsis biomarker recently. In the present work, we apply a miRNA regulatory network based method to identify novel microRNA biomarkers associated with the early diagnosis of sepsis. By analyzing the miRNA expression profiles and the miRNA regulatory network, we obtained novel miRNAs associated with sepsis. Pathways analysis, disease ontology analysis, and protein-protein interaction network (PIN) analysis, as well as ROC curve, were exploited to testify the reliability of the predicted miRNAs. We finally identified 8 novel miRNAs which have the potential to be sepsis biomarkers. PMID:24809055

A novel gammaretroviral shuttle vector insertional mutagenesis screen identifies SHARPIN as a breast cancer metastasis gene and prognostic biomarker.

PubMed

Bii, Victor M; Rae, Dustin T; Trobridge, Grant D

2015-11-24

Breast cancer (BC) is the second leading cause of malignancy among U.S. women. Metastasis results in a poor prognosis and increased mortality, but the molecular mechanisms by which metastatic tumors occur are not well understood. Identifying the genes that drive the metastatic process could provide targets for improved therapy and biomarkers to improve BC patient outcomes. Using a forward mutagenesis screen, BC cells mutagenized with a replication-incompetent gammaretroviral vector (γRV) were xenotransplanted into the mammary fat pad of immunodeficient mice. In this approach the vector provirus dysregulates nearby genes, providing a selective advantage to transduced cells to form metastases. Metastatic tumors were analyzed for proviral integration sites to identify nearby candidate metastasis genes. The γRV has a transgene cassette that allows for rescue in bacteria and rapid identification of vector integration sites. Using this approach, we identified the previously described metastasis gene WWTR1 (TAZ), and three other novel candidate metastasis genes including SHARPIN. SHARPIN was independently validated in vivo as a BC metastasis gene. Analysis of patient data showed that SHARPIN expression predicts metastasis-free survival after adjuvant therapy. Our approach has broad potential to identify genes involved in oncogenic processes for BC and other cancers. We show here it can identify both known (WWTR1) and novel (SHARPIN) BC metastasis genes.

Sphingolipids as New Biomarkers for Assessment of Delayed-Type Hypersensitivity and Response to Triptolide

PubMed Central

Qu, Feng; Wu, Cai-Sheng; Hou, Jin-Feng; Jin, Ying; Zhang, Jin-Lan

2012-01-01

Background Hypersensitivity diseases are associated with many severe human illnesses, including leprosy and tuberculosis. Emerging evidence suggests that the pathogenesis and pathological mechanisms of treating these diseases may be attributable to sphingolipid metabolism. Methods High performance liquid chromatography-tandem mass spectrometry was employed to target and measure 43 core sphingolipids in the plasma, kidneys, livers and spleens of BALB/c mice from four experimental groups: control, delayed-type hypersensitivity (DTH) model, DTH+triptolide, and control+triptolide. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to identify potential biomarkers associated with variance between groups. Relationships between the identified biomarkers and disease markers were evaluated by Spearman correlation. Results As a treatment to hypersensitivity disease, triptolide significantly inhibit the ear swelling and recover the reduction of splenic index caused by DTH. The sphingolipidomic result revealed marked alterations in sphingolipid levels between groups that were associated with the effects of the disease and triptolide treatment. Based on this data, 23 potential biomarkers were identified by OPLS-DA, and seven of these biomarkers correlated markedly with the disease markers (p<0.05) by Spearman correlation. Conclusions These data indicate that differences in sphingolipid levels in plasma and tissues are related to DTH and treatment with triptolide. Restoration of proper sphingolipid levels may attribute to the therapeutic effect of triptolide treatment. Furthermore, these findings demonstrate that targeted sphingolipidomic analysis followed by multivariate analysis presents a novel strategy for the identification of biomarkers in biological samples. PMID:23300675

Fetal alcohol-spectrum disorders: identifying at-risk mothers

PubMed Central

Montag, Annika C

2016-01-01

Fetal alcohol-spectrum disorders (FASDs) are a collection of physical and neurobehavioral disabilities caused by prenatal exposure to alcohol. To prevent or mitigate the costly effects of FASD, we must identify mothers at risk for having a child with FASD, so that we may reach them with interventions. Identifying mothers at risk is beneficial at all time points, whether prior to pregnancy, during pregnancy, or following the birth of the child. In this review, three approaches to identifying mothers at risk are explored: using characteristics of the mother and her pregnancy, using laboratory biomarkers, and using self-report assessment of alcohol-consumption risk. At present, all approaches have serious limitations. Research is needed to improve the sensitivity and specificity of biomarkers and screening instruments, and to link them to outcomes as opposed to exposure. Universal self-report screening of all women of childbearing potential should ideally be incorporated into routine obstetric and gynecologic care, followed by brief interventions, including education and personalized feedback for all who consume alcohol, and referral to treatment as indicated. Effective biomarkers or combinations of biomarkers may be used during pregnancy and at birth to determine maternal and fetal alcohol exposure. The combination of self-report and biomarker screening may help identify a greater proportion of women at risk for having a child with FASD, allowing them to access information and treatment, and empowering them to make decisions that benefit their children. PMID:27499649

A novel strategy of integrated microarray analysis identifies CENPA, CDK1 and CDC20 as a cluster of diagnostic biomarkers in lung adenocarcinoma.

PubMed

Liu, Wan-Ting; Wang, Yang; Zhang, Jing; Ye, Fei; Huang, Xiao-Hui; Li, Bin; He, Qing-Yu

2018-07-01

Lung adenocarcinoma (LAC) is the most lethal cancer and the leading cause of cancer-related death worldwide. The identification of meaningful clusters of co-expressed genes or representative biomarkers may help improve the accuracy of LAC diagnoses. Public databases, such as the Gene Expression Omnibus (GEO), provide rich resources of valuable information for clinics, however, the integration of multiple microarray datasets from various platforms and institutes remained a challenge. To determine potential indicators of LAC, we performed genome-wide relative significance (GWRS), genome-wide global significance (GWGS) and support vector machine (SVM) analyses progressively to identify robust gene biomarker signatures from 5 different microarray datasets that included 330 samples. The top 200 genes with robust signatures were selected for integrative analysis according to "guilt-by-association" methods, including protein-protein interaction (PPI) analysis and gene co-expression analysis. Of these 200 genes, only 10 genes showed both intensive PPI network and high gene co-expression correlation (r > 0.8). IPA analysis of this regulatory networks suggested that the cell cycle process is a crucial determinant of LAC. CENPA, as well as two linked hub genes CDK1 and CDC20, are determined to be potential indicators of LAC. Immunohistochemical staining showed that CENPA, CDK1 and CDC20 were highly expressed in LAC cancer tissue with co-expression patterns. A Cox regression model indicated that LAC patients with CENPA + /CDK1 + and CENPA + /CDC20 + were high-risk groups in terms of overall survival. In conclusion, our integrated microarray analysis demonstrated that CENPA, CDK1 and CDC20 might serve as novel cluster of prognostic biomarkers for LAC, and the cooperative unit of three genes provides a technically simple approach for identification of LAC patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Identification and Validation of Potential New Biomarkers for Prostate Cancer Diagnosis and Prognosis Using 2D-DIGE and MS

PubMed Central

Geisler, Cordelia; Gaisa, Nadine T.; Pfister, David; Fuessel, Susanne; Kristiansen, Glen; Braunschweig, Till; Gostek, Sonja; Beine, Birte; Diehl, Hanna C.; Jackson, Angela M.; Borchers, Christoph H.; Heidenreich, Axel; Meyer, Helmut E.; Knüchel, Ruth; Henkel, Corinna

2015-01-01

This study was designed to identify and validate potential new biomarkers for prostate cancer and to distinguish patients with and without biochemical relapse. Prostate tissue samples analyzed by 2D-DIGE (two-dimensional difference in gel electrophoresis) and mass spectrometry (MS) revealed downregulation of secernin-1 (P < 0.044) in prostate cancer, while vinculin showed significant upregulation (P < 0.001). Secernin-1 overexpression in prostate tissue was validated using Western blot and immunohistochemistry while vinculin expression was validated using immunohistochemistry. These findings indicate that secernin-1 and vinculin are potential new tissue biomarkers for prostate cancer diagnosis and prognosis, respectively. For validation, protein levels in urine were also examined by Western blot analysis. Urinary vinculin levels in prostate cancer patients were significantly higher than in urine from nontumor patients (P = 0.006). Using multiple reaction monitoring-MS (MRM-MS) analysis, prostatic acid phosphatase (PAP) showed significant higher levels in the urine of prostate cancer patients compared to controls (P = 0.012), while galectin-3 showed significant lower levels in the urine of prostate cancer patients with biochemical relapse, compared to those without relapse (P = 0.017). Three proteins were successfully differentiated between patients with and without prostate cancer and patients with and without relapse by using MRM. Thus, this technique shows promise for implementation as a noninvasive clinical diagnostic technique. PMID:25667921

Proteomic profiling in MPTP monkey model for early Parkinson disease biomarker discovery

PubMed Central

Lin, Xiangmin; Shi, Min; Gunasingh Masilamoni, Jeyaraj; Dator, Romel; Movius, James; Aro, Patrick; Smith, Yoland; Zhang, Jing

2015-01-01

Identification of reliable and robust biomarkers is crucial to enable early diagnosis of Parkinson disease (PD) and monitoring disease progression. While imperfect, the slow, chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced non-human primate animal model system of parkinsonism is an abundant source of pre-motor or early stage PD biomarker discovery. Here, we present a study of a MPTP rhesus monkey model of PD that utilizes complementary quantitative iTRAQ-based proteomic, glycoproteomics and phosphoproteomics approaches. We compared the glycoprotein, non-glycoprotein, and phosphoprotein profiles in the putamen of asymptomatic and symptomatic MPTP-treated monkeys as well as saline injected controls. We identified 86 glycoproteins, 163 non-glycoproteins, and 71 phosphoproteins differentially expressed in the MPTP-treated groups. Functional analysis of the data sets inferred the biological processes and pathways that link to neurodegeneration in PD and related disorders. Several potential biomarkers identified in this study have already been translated for their usefulness in PD diagnosis in human subjects and further validation investigations are currently under way. In addition to providing potential early PD biomarkers, this comprehensive quantitative proteomic study may also shed insights regarding the mechanisms underlying early PD development. This article is part of a Special Issue entitled: Neuroproteomics: Applications in neuroscience and neurology. PMID:25617661

Evaluation of current and new biomarkers in severe preeclampsia: a microarray approach reveals the VSIG4 gene as a potential blood biomarker.

PubMed

Textoris, Julien; Ivorra, Delphine; Ben Amara, Amira; Sabatier, Florence; Ménard, Jean-Pierre; Heckenroth, Hélène; Bretelle, Florence; Mege, Jean-Louis

2013-01-01

Preeclampsia is a placental disease characterized by hypertension and proteinuria in pregnant women, and it is associated with a high maternal and neonatal morbidity. However, circulating biomarkers that are able to predict the prognosis of preeclampsia are lacking. Thirty-eight women were included in the current study. They consisted of 19 patients with preeclampsia (13 with severe preeclampsia and 6 with non-severe preeclampsia) and 19 gestational age-matched women with normal pregnancies as controls. We measured circulating factors that are associated with the coagulation pathway (including fibrinogen, fibronectin, factor VIII, antithrombin, protein S and protein C), endothelial activation (such as soluble endoglin and CD146), and the release of total and platelet-derived microparticles. These markers enabled us to discriminate the preeclampsia condition from a normal pregnancy but were not sufficient to distinguish severe from non-severe preeclampsia. We then used a microarray to study the transcriptional signature of blood samples. Preeclampsia patients exhibited a specific transcriptional program distinct from that of the control group of women. Interestingly, we also identified a severity-related transcriptional signature. Functional annotation of the upmodulated signature in severe preeclampsia highlighted two main functions related to "ribosome" and "complement". Finally, we identified 8 genes that were specifically upmodulated in severe preeclampsia compared with non-severe preeclampsia and the normotensive controls. Among these genes, we identified VSIG4 as a potential diagnostic marker of severe preeclampsia. The determination of this gene may improve the prognostic assessment of severe preeclampsia.

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

Endogenous Antiangiogenic Factors in Chronic Kidney Disease: Potential Biomarkers of Progression.

PubMed

Tanabe, Katsuyuki; Sato, Yasufumi; Wada, Jun

2018-06-24

Chronic kidney disease (CKD) is a major global health problem. Unless intensive intervention is initiated, some patients can rapidly progress to end-stage kidney disease. However, it is often difficult to predict renal outcomes using conventional laboratory tests in individuals with CKD. Therefore, many researchers have been searching for novel biomarkers to predict the progression of CKD. Angiogenesis is involved in physiological and pathological processes in the kidney and is regulated by the balance between a proangiogenic factor, vascular endothelial growth factor (VEGF)-A, and various endogenous antiangiogenic factors. In recent reports using genetically engineered mice, the roles of these antiangiogenic factors in the pathogenesis of kidney disease have become increasingly clear. In addition, recent clinical studies have demonstrated associations between circulating levels of antiangiogenic factors and renal dysfunction in CKD patients. In this review, we summarize recent advances in the study of representative endogenous antiangiogenic factors, including soluble fms-related tyrosine kinase 1, soluble endoglin, pigment epithelium-derived factor, VEGF-A 165 b, endostatin, and vasohibin-1, in associations with kidney diseases and discuss their predictive potentials as biomarkers of progression of CKD.

Identification of prohibitin 1 as a potential prognostic biomarker in human pancreatic carcinoma using modified aqueous two-phase partition system combined with 2D-MALDI-TOF-TOF-MS/MS.

PubMed

Zhong, Ning; Cui, Yazhou; Zhou, Xiaoyan; Li, Tianliang; Han, Jinxiang

2015-02-01

Membrane proteins are an important source of potential targets for anticancer drugs or biomarkers for early diagnosis. In this study, we used a modified aqueous two-phase partition system combined with two-dimensional (2D) matrix-assisted laser desorption ionization (MALDI) time of flight (TOF) mass spectrometry (MS, 2D-MALDI-TOF-TOF-MS/MS) analysis to isolate and identify membrane proteins in PANC-1 pancreatic cancer cells. Using this method, we identified 55 proteins, of which 31 (56.4 %) were membrane proteins, which, according to gene ontology annotation, are associated with various cellular processes including cell signal transduction, differentiation, and apoptosis. Immunohistochemical analysis showed that the expression level of one of the identified mitochondria membrane proteins, prohibitin 1 (PHB1), is correlated with pancreatic carcinoma differentiation; PHB1 is expressed at a higher level in normal pancreatic tissue than in well-differentiated carcinoma tissue. Further studies showed that PHB1 plays a proapoptotic role in human pancreatic cancer cells, which suggests that PHB1 has antitumorigenic properties. In conclusion, we have provided a modified method for isolating and identifying membrane proteins and demonstrated that PHB1 may be a promising biomarker for early diagnosis and therapy of pancreatic (and potentially other) cancers.

Biomarkers for AAA: Encouraging steps but clinical relevance still to be delivered.

PubMed

Htun, Nay Min; Peter, Karlheinz

2014-10-01

Potential biomarkers have been investigated using proteomic studies in a variety of diseases. Some biomarkers have central roles in both diagnosis and monitoring of various disorders in clinical medicine, such as troponins, brain natriuretic peptide, and C-reactive protein. Although several biomarkers have been suggested in human abdominal aortic aneurysm (AAA), reliable markers have been lacking. In this issue, Moxon et al. [Proteomics Clin Appl. 2014, 8, 762-772] undertook a broad and systematic proteomic approach toward identification of biomarkers in a commonly used AAA mouse model (AAA created by angiotensin-II infusion). In this mouse model, apolipoprotein C1 and matrix metalloproteinase-9 were identified as novel biomarkers of stable AAA. This finding represents an important step forward, toward a clinically relevant role of biomarkers in AAA. This also encourages for further studies toward the identification of biomarkers (or their combinations) that can predict AAA progression and rupture, which would represent a major progress in AAA management and would establish an AAA biomarker as a much anticipated clinical tool. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Stool-based biomarkers of interstitial cystitis/bladder pain syndrome.

PubMed

Braundmeier-Fleming, A; Russell, Nathan T; Yang, Wenbin; Nas, Megan Y; Yaggie, Ryan E; Berry, Matthew; Bachrach, Laurie; Flury, Sarah C; Marko, Darlene S; Bushell, Colleen B; Welge, Michael E; White, Bryan A; Schaeffer, Anthony J; Klumpp, David J

2016-05-18

Interstitial cystitis/bladder pain syndrome (IC) is associated with significant morbidity, yet underlying mechanisms and diagnostic biomarkers remain unknown. Pelvic organs exhibit neural crosstalk by convergence of visceral sensory pathways, and rodent studies demonstrate distinct bacterial pain phenotypes, suggesting that the microbiome modulates pelvic pain in IC. Stool samples were obtained from female IC patients and healthy controls, and symptom severity was determined by questionnaire. Operational taxonomic units (OTUs) were identified by16S rDNA sequence analysis. Machine learning by Extended Random Forest (ERF) identified OTUs associated with symptom scores. Quantitative PCR of stool DNA with species-specific primer pairs demonstrated significantly reduced levels of E. sinensis, C. aerofaciens, F. prausnitzii, O. splanchnicus, and L. longoviformis in microbiota of IC patients. These species, deficient in IC pelvic pain (DIPP), were further evaluated by Receiver-operator characteristic (ROC) analyses, and DIPP species emerged as potential IC biomarkers. Stool metabolomic studies identified glyceraldehyde as significantly elevated in IC. Metabolomic pathway analysis identified lipid pathways, consistent with predicted metagenome functionality. Together, these findings suggest that DIPP species and metabolites may serve as candidates for novel IC biomarkers in stool. Functional changes in the IC microbiome may also serve as therapeutic targets for treating chronic pelvic pain.

Biomarker Qualification: Toward a Multiple Stakeholder Framework for Biomarker Development, Regulatory Acceptance, and Utilization.

PubMed

Amur, S; LaVange, L; Zineh, I; Buckman-Garner, S; Woodcock, J

2015-07-01

The discovery, development, and use of biomarkers for a variety of drug development purposes are areas of tremendous interest and need. Biomarkers can become accepted for use through submission of biomarker data during the drug approval process. Another emerging pathway for acceptance of biomarkers is via the biomarker qualification program developed by the Center for Drug Evaluation and Research (CDER, US Food and Drug Administration). Evidentiary standards are needed to develop and evaluate various types of biomarkers for their intended use and multiple stakeholders, including academia, industry, government, and consortia must work together to help develop this evidence. The article describes various types of biomarkers that can be useful in drug development and evidentiary considerations that are important for qualification. A path forward for coordinating efforts to identify and explore needed biomarkers is proposed for consideration. © 2015 American Society for Clinical Pharmacology and Therapeutics.

Evaluating Chagas disease progression and cure through blood-derived biomarkers: a systematic review.

PubMed

Requena-Méndez, Ana; López, Manuel Carlos; Angheben, Andrea; Izquierdo, Luis; Ribeiro, Isabela; Pinazo, Maria-Jesús; Gascon, Joaquim; Muñoz, José

2013-09-01

This article reviews the usefulness of various types of blood-derived biomarkers that are currently being studied to predict the progression of Chagas disease in patients with the indeterminate form, to assess the efficacy of antiparasitic drugs and to identify early cardiac and gastrointestinal damage. The authors used a search strategy based on MEDLINE, Cochrane Library Register for systematic review, EmBase, Global Health and LILACS databases. Out of 1716 screened articles, only 166 articles were eligible for final inclusion. The authors classified the biomarkers according to their biochemical structure and primary biological activity in four groups: i) markers of inflammation and cellular injury, ii) metabolic biomakers, iii) prothrombotic biomarkers and iv) markers derived from specific antigens of the parasite. Several potential biomarkers might have clinical potential for the detection of early cardiopathy. Such capacity is imperative in order to detect high-risk patients who require intensive monitoring and earlier therapy. Prospective studies with longer follow-ups are needed for the appraisal of biomarkers assessing clinical or microbiological cure after therapy. At the same time, studies evaluating more than one biomarker are useful to compare the efficacy among them given the lack of a recognized gold standard.

Effect of Non-tuberculous Mycobacteria on Host Biomarkers Potentially Relevant for Tuberculosis Management

PubMed Central

Dhanasekaran, S.; Jenum, Synne; Stavrum, Ruth; Wiker, Harald G.; Kenneth, John; Vaz, Mario; Doherty, T. Mark; Grewal, Harleen M. S.

2014-01-01

Background Non-tuberculous mycobacteria (NTM) are different from Mycobacterium tuberculosis (MTB) both in their ubiquitous environmental distribution and in their reduced capacity to cause disease. While often neglected in favour of other infectious diseases, NTM may interfere with important aspects of TB control and management, namely the efficacy of new anti-tuberculosis (TB) vaccines; the immuno-diagnostic Tuberculin skin test (TST) and QuantiFERON TB Gold In Tube assay (QFTGIT); and immune biomarkers explored for their diagnostic and/or predictive potential. Our objective was therefore to explore host immune biomarkers in children who had NTM isolated from respiratory and/or gastric specimens. Methodology and Principle Findings The present study was nested within a prospective cohort study of BCG-vaccinated neonates in Southern India. In this setting, immune biomarkers from peripheral blood were analyzed in 210 children aged <3 years evaluated for TB using dual-colour-Reverse-Transcriptase-Multiple-Ligation-dependent-Probe-Amplification (dcRT-MLPA) and Bio-Plex assays. The children were classified based on clinical examination, chest X-rays and mycobacterial culture reports as either: 1) TB disease, 2) NTM present and 3) controls. The study shows a down-regulation of RAB33A (p<0.001) and up-regulation of TGFβ1, IL-2 and IL-6 (all p<0.05) in children with TB disease, and that RAB33A, TGFBR2 and IL-10 (all p<0.05) were differentially expressed in children with NTM present when compared to children that were culture negative for MTB and NTM (controls). Conclusions and Significance Carriage of NTM may reduce the specificity of future diagnostic and predictive immune biomarkers relevant to TB management. PMID:25329719

Effect of non-tuberculous Mycobacteria on host biomarkers potentially relevant for tuberculosis management.

PubMed

Dhanasekaran, S; Jenum, Synne; Stavrum, Ruth; Wiker, Harald G; Kenneth, John; Vaz, Mario; Doherty, T Mark; Grewal, Harleen M S

2014-10-01

Non-tuberculous mycobacteria (NTM) are different from Mycobacterium tuberculosis (MTB) both in their ubiquitous environmental distribution and in their reduced capacity to cause disease. While often neglected in favour of other infectious diseases, NTM may interfere with important aspects of TB control and management, namely the efficacy of new anti-tuberculosis (TB) vaccines; the immuno-diagnostic Tuberculin skin test (TST) and QuantiFERON TB Gold In Tube assay (QFTGIT); and immune biomarkers explored for their diagnostic and/or predictive potential. Our objective was therefore to explore host immune biomarkers in children who had NTM isolated from respiratory and/or gastric specimens. The present study was nested within a prospective cohort study of BCG-vaccinated neonates in Southern India. In this setting, immune biomarkers from peripheral blood were analyzed in 210 children aged <3 years evaluated for TB using dual-colour-Reverse-Transcriptase-Multiple-Ligation-dependent-Probe-Amplification (dcRT-MLPA) and Bio-Plex assays. The children were classified based on clinical examination, chest X-rays and mycobacterial culture reports as either: 1) TB disease, 2) NTM present and 3) controls. The study shows a down-regulation of RAB33A (p<0.001) and up-regulation of TGFβ1, IL-2 and IL-6 (all p<0.05) in children with TB disease, and that RAB33A, TGFBR2 and IL-10 (all p<0.05) were differentially expressed in children with NTM present when compared to children that were culture negative for MTB and NTM (controls). Carriage of NTM may reduce the specificity of future diagnostic and predictive immune biomarkers relevant to TB management.

Biomarkers of Tobacco Exposure: Summary of an FDA-sponsored Public Workshop

PubMed Central

Chang, Cindy M.; Edwards, Selvin H.; Arab, Aarthi; Del Valle-Pinero, Arseima Y.; Yang, Ling; Hatsukami, Dorothy K.

2016-01-01

Since 2009, the United States (U.S.) Food and Drug Administration (FDA) Center for Tobacco Products (CTP) has had the authority to regulate the manufacturing, distribution, and marketing of tobacco products in order to reduce the death and disease caused by tobacco use. Biomarkers of exposure pertain to actual human exposure to chemicals arising from tobacco use and could play an important role across a number of FDA regulatory activities, including assessing new and modified risk tobacco products and identifying and evaluating potential product standards. On August 3–4, 2015, FDA/CTP hosted a public workshop focused on biomarkers of exposure with participants from government, industry, academia, and other organizations. The workshop was divided into four sessions focused on: 1) approaches to evaluating and selecting biomarkers; 2) biomarkers of exposure and relationship to disease risk; 3) currently-used biomarkers of exposure and biomarkers in development; and 4) biomarkers of exposure and the assessment of smokeless tobacco and electronic nicotine delivery systems (ENDS). This paper synthesizes the main findings from the workshop and highlights research areas that could further strengthen the science around biomarkers of exposure and help determine their application in tobacco product regulation. PMID:28151705

A machine learning approach to identify functional biomarkers in human prefrontal cortex for individuals with traumatic brain injury using functional near-infrared spectroscopy.

PubMed

Karamzadeh, Nader; Amyot, Franck; Kenney, Kimbra; Anderson, Afrouz; Chowdhry, Fatima; Dashtestani, Hadis; Wassermann, Eric M; Chernomordik, Victor; Boccara, Claude; Wegman, Edward; Diaz-Arrastia, Ramon; Gandjbakhche, Amir H

2016-11-01

We have explored the potential prefrontal hemodynamic biomarkers to characterize subjects with Traumatic Brain Injury (TBI) by employing the multivariate machine learning approach and introducing a novel task-related hemodynamic response detection followed by a heuristic search for optimum set of hemodynamic features. To achieve this goal, the hemodynamic response from a group of 31 healthy controls and 30 chronic TBI subjects were recorded as they performed a complexity task. To determine the optimum hemodynamic features, we considered 11 features and their combinations in characterizing TBI subjects. We investigated the significance of the features by utilizing a machine learning classification algorithm to score all the possible combinations of features according to their predictive power. The identified optimum feature elements resulted in classification accuracy, sensitivity, and specificity of 85%, 85%, and 84%, respectively. Classification improvement was achieved for TBI subject classification through feature combination. It signified the major advantage of the multivariate analysis over the commonly used univariate analysis suggesting that the features that are individually irrelevant in characterizing the data may become relevant when used in combination. We also conducted a spatio-temporal classification to identify regions within the prefrontal cortex (PFC) that contribute in distinguishing between TBI and healthy subjects. As expected, Brodmann areas (BA) 10 within the PFC were isolated as the region that healthy subjects (unlike subjects with TBI), showed major hemodynamic activity in response to the High Complexity task. Overall, our results indicate that identified temporal and spatio-temporal features from PFC's hemodynamic activity are promising biomarkers in classifying subjects with TBI.

SU-F-R-24: Identifying Prognostic Imaging Biomarkers in Early Stage Lung Cancer Using Radiomics

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

Zeng, X; Wu, J; Cui, Y

2016-06-15

Purpose: Patients diagnosed with early stage lung cancer have favorable outcomes when treated with surgery or stereotactic radiotherapy. However, a significant proportion (∼20%) of patients will develop metastatic disease and eventually die of the disease. The purpose of this work is to identify quantitative imaging biomarkers from CT for predicting overall survival in early stage lung cancer. Methods: In this institutional review board-approved HIPPA-compliant retrospective study, we retrospectively analyzed the diagnostic CT scans of 110 patients with early stage lung cancer. Data from 70 patients were used for training/discovery purposes, while those of remaining 40 patients were used for independentmore » validation. We extracted 191 radiomic features, including statistical, histogram, morphological, and texture features. Cox proportional hazard regression model, coupled with the least absolute shrinkage and selection operator (LASSO), was used to predict overall survival based on the radiomic features. Results: The optimal prognostic model included three image features from the Law’s feature and wavelet texture. In the discovery cohort, this model achieved a concordance index or CI=0.67, and it separated the low-risk from high-risk groups in predicting overall survival (hazard ratio=2.72, log-rank p=0.007). In the independent validation cohort, this radiomic signature achieved a CI=0.62, and significantly stratified the low-risk and high-risk groups in terms of overall survival (hazard ratio=2.20, log-rank p=0.042). Conclusion: We identified CT imaging characteristics associated with overall survival in early stage lung cancer. If prospectively validated, this could potentially help identify high-risk patients who might benefit from adjuvant systemic therapy.« less

Leveraging sequence-based faecal microbial community survey data to identify a composite biomarker for colorectal cancer.

PubMed

Shah, Manasi S; DeSantis, Todd Z; Weinmaier, Thomas; McMurdie, Paul J; Cope, Julia L; Altrichter, Adam; Yamal, Jose-Miguel; Hollister, Emily B

2018-05-01

Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the USA. The faecal microbiome may provide non-invasive biomarkers of CRC and indicate transition in the adenoma-carcinoma sequence. Re-analysing raw sequence and metadata from several studies uniformly, we sought to identify a composite and generalisable microbial marker for CRC. Raw 16S rRNA gene sequence data sets from nine studies were processed with two pipelines, (1) QIIME closed reference (QIIME-CR) or (2) a strain-specific method herein termed SS-UP (Strain Select, UPARSE bioinformatics pipeline). A total of 509 samples (79 colorectal adenoma, 195 CRC and 235 controls) were analysed. Differential abundance, meta-analysis random effects regression and machine learning analyses were carried out to determine the consistency and diagnostic capabilities of potential microbial biomarkers. Definitive taxa, including Parvimonas micra ATCC 33270, Streptococcus anginosus and yet-to-be-cultured members of Proteobacteria, were frequently and significantly increased in stools from patients with CRC compared with controls across studies and had high discriminatory capacity in diagnostic classification. Microbiome-based CRC versus control classification produced an area under receiver operator characteristic (AUROC) curve of 76.6% in QIIME-CR and 80.3% in SS-UP. Combining clinical and microbiome markers gave a diagnostic AUROC of 83.3% for QIIME-CR and 91.3% for SS-UP. Despite technological differences across studies and methods, key microbial markers emerged as important in classifying CRC cases and such could be used in a universal diagnostic for the disease. The choice of bioinformatics pipeline influenced accuracy of classification. Strain-resolved microbial markers might prove crucial in providing a microbial diagnostic for CRC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure

PubMed Central

Nath, Anjali K.; Roberts, Lee D.; Liu, Yan; Mahon, Sari B.; Kim, Sonia; Ryu, Justine H.; Werdich, Andreas; Januzzi, James L.; Boss, Gerry R.; Rockwood, Gary A.; MacRae, Calum A.; Brenner, Matthew; Gerszten, Robert E.; Peterson, Randall T.

2013-01-01

Exposure to cyanide causes a spectrum of cardiac, neurological, and metabolic dysfunctions that can be fatal. Improved cyanide antidotes are needed, but the ideal biological pathways to target are not known. To understand better the metabolic effects of cyanide and to discover novel cyanide antidotes, we developed a zebrafish model of cyanide exposure and scaled it for high-throughput chemical screening. In a screen of 3120 small molecules, we discovered 4 novel antidotes that block cyanide toxicity. The most potent antidote was riboflavin. Metabolomic profiling of cyanide-treated zebrafish revealed changes in bile acid and purine metabolism, most notably by an increase in inosine levels. Riboflavin normalizes many of the cyanide-induced neurological and metabolic perturbations in zebrafish. The metabolic effects of cyanide observed in zebrafish were conserved in a rabbit model of cyanide toxicity. Further, humans treated with nitroprusside, a drug that releases nitric oxide and cyanide ions, display increased circulating bile acids and inosine. In summary, riboflavin may be a novel treatment for cyanide toxicity and prophylactic measure during nitroprusside treatment, inosine may serve as a biomarker of cyanide exposure, and metabolites in the bile acid and purine metabolism pathways may shed light on the pathways critical to reversing cyanide toxicity.—Nath, A. K., Roberts, L. D., Liu, Y., Mahon, S. B., Kim, S., Ryu, J. H., Werdich, A., Januzzi, J. L., Boss, G. R., Rockwood, G. A., MacRae, C. A., Brenner, M., Gerszten, R. E., Peterson, R. T. Chemical and metabolomic screens identify novel biomarkers and antidotes for cyanide exposure. PMID:23345455

Endocannabinoids as biomarkers of human reproduction.

PubMed

Rapino, Cinzia; Battista, Natalia; Bari, Monica; Maccarrone, Mauro

2014-01-01

Infertility is a condition of the reproductive system that affects ∼10-15% of couples attempting to conceive a baby. More than half of all cases of infertility are a result of female conditions, while the remaining cases can be attributed to male factors, or to a combination of both. The search for suitable biomarkers of pregnancy outcome is a challenging issue in human reproduction, aimed at identifying molecules with predictive significance of the reproductive potential of male and female gametes. Among the various candidates, endocannabinoids (eCBs), and in particular anandamide (AEA), represent potential biomarkers of human fertility disturbances. Any perturbation of the balance between synthesis and degradation of eCBs will result in local changes of their tone in human female and male reproductive tracts, which in turn regulates various pathophysiological processes, oocyte and sperm maturation included. PubMed and Web of Science databases were searched for papers using relevant keywords like 'biomarker', 'endocannabinoid', 'infertility', 'pregnancy' and 'reproduction'. In this review, we discuss different studies on the measurements of AEA and related eCBs in human reproductive cells, tissues and fluids, where the local contribution of these bioactive lipids could be critical in ensuring normal sperm fertilizing ability and pregnancy. Based on the available data, we suggest that the AEA tone has the potential to be exploited as a novel diagnostic biomarker of infertility, to be used in association with assays of conventional hormones (e.g. progesterone, β-chorionic gonadotrophin) and semen analysis. However further quantitative research of its predictive capacity is required. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Biomarkers: unrealized potential in sports doping analysis.

PubMed

Teale, Phil; Barton, Chris; Driver, Philip M; Kay, Richard G

2009-09-01

The fight against doping in sport using analytical chemistry is a mature area with a history of approximately 100 years in horse racing and at least 40 years in human sport. Over that period, the techniques used and the breadth of coverage have developed significantly. These improvements in the testing methods have been matched by the increased sophistication of the methods, drugs and therapies available to the cheat and, as a result, testing has been a reactive process constantly adapting to meet new threats. Following the inception of the World Anti-Doping Agency, research into the methods and technologies available for human doping control have received coordinated funding on an international basis. The area of biomarker research has been a major beneficiary of this funding. The aim of this article is to review recent developments in the application of biomarkers to doping control and to assess the impact this could make in the future.

Novel droplet platforms for the detection of disease biomarkers.

PubMed

Zec, Helena; Shin, Dong Jin; Wang, Tza-Huei

2014-09-01

Personalized medicine - healthcare based on individual genetic variation - has the potential to transform the way healthcare is delivered to patients. The promise of personalized medicine has been predicated on the predictive and diagnostic power of genomic and proteomic biomarkers. Biomarker screening may help improve health outcomes, for example, by identifying individuals' susceptibility to diseases and predicting how patients will respond to drugs. Microfluidic droplet technology offers an exciting opportunity to revolutionize the accessibility of personalized medicine. A framework for the role of droplet microfluidics in biomarker detection can be based on two main themes. Emulsion-based microdroplet platforms can provide new ways to measure and detect biomolecules. In addition, microdroplet platforms facilitate high-throughput screening of biomarkers. Meanwhile, surface-based droplet platforms provide an opportunity to develop miniaturized diagnostic systems. These platforms may function as portable benchtop environments that dramatically shorten the transition of a benchtop assay into a point-of-care format.

Use of biomarkers for the assessment of chemotherapy-induced cardiac toxicity

PubMed Central

Christenson, Eric S.; James, Theodore; Agrawal, Vineet; Park, Ben H.

2015-01-01

Objectives To review the evidence for the use of various biomarkers in the detection of chemotherapy associated cardiac damage. Design and methods Pubmed.gov was queried using the search words chemotherapy and cardiac biomarkers with the filters of past 10 years, humans, and English language. An emphasis was placed on obtaining primary research articles looking at the utility of biomarkers for the detection of chemotherapy-mediated cardiac injury. Results Biomarkers may help identify patients undergoing treatment who are at high risk for cardiotoxicity and may assist in identification of a low risk cohort that does not necessitate continued intensive screening. cTn assays are the best studied biomarkers in this context and may represent a promising and potentially valuable modality for detecting cardiac toxicity in patients undergoing chemotherapy. Monitoring cTnI levels may provide information regarding the development of cardiac toxicity before left ventricular dysfunction becomes apparent on echocardiography or via clinical symptoms. A host of other biomarkers have been evaluated for their utility in the field of chemotherapy related cardiac toxicity with intermittent success; further trials are necessary to determine what role they may end up playing for prediction and prognostication in this setting. Conclusions Biomarkers represent an exciting potential complement or replacement for echocardiographic monitoring of chemotherapy related cardiac toxicity which may allow for earlier realization of the degree of cardiac damage occurring during treatment, creating the opportunity for more timely modulation of therapy. PMID:25445234

Drug Induced Liver Injury: Can Biomarkers Assist RUCAM in Causality Assessment?

PubMed Central

Teschke, Rolf; Schulze, Johannes; Eickhoff, Axel; Danan, Gaby

2017-01-01

Drug induced liver injury (DILI) is a potentially serious adverse reaction in a few susceptible individuals under therapy by various drugs. Health care professionals facing DILI are confronted with a wealth of drug-unrelated liver diseases with high incidence and prevalence rates, which can confound the DILI diagnosis. Searching for alternative causes is a key element of RUCAM (Roussel Uclaf Causality Assessment Method) to assess rigorously causality in suspected DILI cases. Diagnostic biomarkers as blood tests would be a great help to clinicians, regulators, and pharmaceutical industry would be more comfortable if, in addition to RUCAM, causality of DILI can be confirmed. High specificity and sensitivity are required for any diagnostic biomarker. Although some risk factors are available to evaluate liver safety of drugs in patients, no valid diagnostic or prognostic biomarker exists currently for idiosyncratic DILI when a liver injury occurred. Identifying a biomarker in idiosyncratic DILI requires detailed knowledge of cellular and biochemical disturbances leading to apoptosis or cell necrosis and causing leakage of specific products in blood. As idiosyncratic DILI is typically a human disease and hardly reproducible in animals, pathogenetic events and resulting possible biomarkers remain largely undisclosed. Potential new diagnostic biomarkers should be evaluated in patients with DILI and RUCAM-based established causality. In conclusion, causality assessment in cases of suspected idiosyncratic DILI is still best achieved using RUCAM since specific biomarkers as diagnostic blood tests that could enhance RUCAM results are not yet available. PMID:28398242

Biomarkers of sepsis

PubMed Central

2013-01-01

Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate’s effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high. PMID:23480440

Systematic Review of Pancreatic Cyst Fluid Biomarkers: The Path Forward

PubMed Central

Thiruvengadam, Nikhil; Park, Walter G

2015-01-01

There is significant research interest in developing and validating novel pancreatic cyst-fluid biomarkers given the increasing recognition of the prevalence of pancreatic cysts and their associated malignant potential. Although current international consensus guidelines are helpful, they fail to diagnose with certainty the cyst type and the level of epithelial dysplasia. They also fall short in predicting the future likelihood of malignant transformation. A systematic review was performed with the objective of summarizing cyst-fluid-based biomarkers that have been published in the medical literature over the past 10 years and characterizing the current quality of evidence. Our review demonstrates that there is an increasing interest in this topic with several different and innovative approaches including DNA, RNA, proteomic, and metabolomics profiling. Further techniques to improve upon cytological yield have also been studied. Besides identifying potentially useful clinical biomarkers, these empiric approaches have provided further insight into their pathogenesis. The level of evidence for the vast majority of these studies, however, is limited to retrospective early validation studies. The path forward will be to select out the most promising biomarkers and develop multicenter consortiums capable of capturing adequate sample sizes with appropriate study designs. PMID:26065716

Reliable determination of new lipid peroxidation compounds as potential early Alzheimer Disease biomarkers.

PubMed

García-Blanco, Ana; Peña-Bautista, Carmen; Oger, Camille; Vigor, Claire; Galano, Jean-Marie; Durand, Thierry; Martín-Ibáñez, Nuria; Baquero, Miguel; Vento, Máximo; Cháfer-Pericás, Consuelo

2018-07-01

Lipid peroxidation plays an important role in Alzheimer Disease, so corresponding metabolites found in urine samples could be potential biomarkers. The aim of this work is to develop a reliable ultra-performance liquid chromatography-tandem mass spectrometry analytical method to determine a new set of lipid peroxidation compounds in urine samples. Excellent sensitivity was achieved with limits of detection between 0.08 and 17 nmol L -1 , which renders this method suitable to monitor analytes concentrations in real samples. The method's precision was satisfactory with coefficients of variation around 5-17% (intra-day) and 8-19% (inter-day). The accuracy of the method was assessed by analysis of spiked urine samples obtaining recoveries between 70% and 120% for most of the analytes. The utility of the described method was tested by analyzing urine samples from patients early diagnosed with mild cognitive impairment or mild dementia Alzheimer Disease following the clinical standard criteria. As preliminary results, some analytes (17(RS)-10-epi-SC-Δ 15 -11-dihomo-IsoF, PGE 2 ) and total parameters (Neuroprostanes, Isoprostanes, Isofurans) show differences between the control and the clinical groups. So, these analytes could be potential early Alzheimer Disease biomarkers assessing the patients' pro-oxidant condition. Copyright © 2018 Elsevier B.V. All rights reserved.

Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy.

PubMed

Brinkmeyer-Langford, Candice; Balog-Alvarez, Cynthia; Cai, James J; Davis, Brian W; Kornegay, Joe N

2016-08-22

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes. We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers. The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.

[Search for potential gastric cancer biomarkers using low molecular weight blood plasma proteome profiling by mass spectrometry].

PubMed

Shevchenko, V E; Arnotskaia, N E; Ogorodnikova, E V; Davydov, M M; Ibraev, M A; Turkin, I N; Davydov, M I

2014-01-01

Gastric cancer, one of the most widespread malignant tumors, still lacks reliable serum/plasma biomarkers of its early detection. In this study we have developed, unified, and tested a new methodology for search of gastric cancer biomarkers based on profiling of low molecular weight proteome (LMWP) (1-17 kDa). This approach included three main components: sample pre-fractionation, matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS), data analysis by a bioinformatics software package. Applicability and perspectives of the developed approach for detection of potential gastric cancer markers during LMWP analysis have been demonstrated using 69 plasma samples from patients with gastric cancer (stages I-IV) and 238 control samples. The study revealed peptides/polypeptides, which may be potentially used for detection of this pathology.

Peptidome Analysis Reveals Novel Serum Biomarkers for Children with Autism Spectrum Disorder in China.

PubMed

Yang, Juan; Chen, Yanni; Xiong, Xiaofan; Zhou, Xiaobo; Han, Lin; Ni, Ei; Wang, Wenjing; Wang, Xiaofei; Zhao, Lingyu; Shao, Dongdong; Huang, Chen

2018-05-13

Autism spectrum disorder (ASD) is a neurological and developmental disorder that begins early in childhood and lasts throughout one's life. Early diagnosis is essential for ASD since early treatment can enable children with ASD to make significant gains in language and social skills, but remains challenging since there are currently no specific biomarkers of ASD. The study aimed to identify serum biomarkers for ASD. Serum of Han Chinese children with ASD (n = 68) and age-matched healthy controls (n = 80) was analyzed using magnetic bead-based separation combined with mass spectrum. Eight potential ASD serum biomarker peaks (m/z: 3886.69, 7775.12, 2381.71, 6638.63, 3319.17, 894.34, 4968.59, and 5910.53) with higher expression in ASD group were further identified as peptide regions of Plasma Serine Protease Inhibitor Precursor (SERPINA5), Platelet Factor 4 (PF4), Fatty Acid Binding Protein 1(FABP1), Apolipoprotein C-I Precursor (APOC1), Alpha-fetoprotein Precursor (AFP), Carboxypeptidase B2 (CPB2), Trace Amine-associated Receptor 6 (TAAR6) and Isoform1 of Fibrinogen Alpha Chain Precursor (FGA). The expression of identified proteins was validated by enzyme-linked immunosorbent assay (ELISA). Our findings reveal the exceptional disease etiology of ASD from a serum proteomic perspective, and the identified proteins might be potential biomarkers for ASD diagnosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Clinical proteomic biomarkers: relevant issues on study design & technical considerations in biomarker development

PubMed Central

2014-01-01

Biomarker research is continuously expanding in the field of clinical proteomics. A combination of different proteomic–based methodologies can be applied depending on the specific clinical context of use. Moreover, current advancements in proteomic analytical platforms are leading to an expansion of biomarker candidates that can be identified. Specifically, mass spectrometric techniques could provide highly valuable tools for biomarker research. Ideally, these advances could provide with biomarkers that are clinically applicable for disease diagnosis and/ or prognosis. Unfortunately, in general the biomarker candidates fail to be implemented in clinical decision making. To improve on this current situation, a well-defined study design has to be established driven by a clear clinical need, while several checkpoints between the different phases of discovery, verification and validation have to be passed in order to increase the probability of establishing valid biomarkers. In this review, we summarize the technical proteomic platforms that are available along the different stages in the biomarker discovery pipeline, exemplified by clinical applications in the field of bladder cancer biomarker research. PMID:24679154

The Urine Proteome as a Biomarker of Radiation Injury

PubMed Central

Sharma, Mukut; Halligan, Brian D.; Wakim, Bassam T.; Savin, Virginia J.; Cohen, Eric P.; Moulder, John E.

2009-01-01

Terrorist attacks or nuclear accidents could expose large numbers of people to ionizing radiation, and early biomarkers of radiation injury would be critical for triage, treatment and follow-up of such individuals. However, no such biomarkers have yet been proven to exist. We tested the potential of high throughput proteomics to identify protein biomarkers of radiation injury after total body X-ray irradiation in a rat model. Subtle functional changes in the kidney are suggested by an increased glomerular permeability for macromolecules measured within 24 hours after TBI. Ultrastructural changes in glomerular podocytes include partial loss of the interdigitating organization of foot processes. Analysis of urine by LC-MS/MS and 2D-GE showed significant changes in the urine proteome within 24 hours after TBI. Tissue kallikrein 1-related peptidase, cysteine proteinase inhibitor cystatin C and oxidized histidine were found to be increased while a number of proteinase inhibitors including kallikrein-binding protein and albumin were found to be decreased post-irradiation. Thus, TBI causes immediately detectable changes in renal structure and function and in the urinary protein profile. This suggests that both systemic and renal changes are induced by radiation and it may be possible to identify a set of biomarkers unique to radiation injury. PMID:19746194

Identifying biomarkers of papillary renal cell carcinoma associated with pathological stage by weighted gene co-expression network analysis.

PubMed

He, Zhongshi; Sun, Min; Ke, Yuan; Lin, Rongjie; Xiao, Youde; Zhou, Shuliang; Zhao, Hong; Wang, Yan; Zhou, Fuxiang; Zhou, Yunfeng

2017-04-25

Although papillary renal cell carcinoma (PRCC) accounts for 10%-15% of renal cell carcinoma (RCC), no predictive molecular biomarker is currently applicable to guiding disease stage of PRCC patients. The mRNASeq data of PRCC and adjacent normal tissue in The Cancer Genome Atlas was analyzed to identify 1148 differentially expressed genes, on which weighted gene co-expression network analysis was performed. Then 11 co-expressed gene modules were identified. The highest association was found between blue module and pathological stage (r = 0.45) by Pearson's correlation analysis. Functional enrichment analysis revealed that biological processes of blue module focused on nuclear division, cell cycle phase, and spindle (all P < 1e-10). All 40 hub genes in blue module can distinguish localized (pathological stage I, II) from non-localized (pathological stage III, IV) PRCC (P < 0.01). A good molecular biomarker for pathological stage of RCC must be a prognostic gene in clinical practice. Survival analysis was performed to reversely validate if hub genes were associated with pathological stage. Survival analysis unveiled that all hub genes were associated with patient prognosis (P < 0.01).The validation cohort GSE2748 verified that 30 hub genes can differentiate localized from non-localized PRCC (P < 0.01), and 18 hub genes are prognosis-associated (P < 0.01).ROC curve indicated that the 17 hub genes exhibited excellent diagnostic efficiency for localized and non-localized PRCC (AUC > 0.7). These hub genes may serve as a biomarker and help to distinguish different pathological stages for PRCC patients.

Analysis of 320 gastroenteropancreatic neuroendocrine tumors identifies TS expression as independent biomarker for survival.

PubMed

Lee, Hye Seung; Chen, Min; Kim, Ji Hun; Kim, Woo Ho; Ahn, Soyeon; Maeng, Kyungah; Allegra, Carmen J; Kaye, Frederic J; Hochwald, Steven N; Zajac-Kaye, Maria

2014-07-01

Thymidylate synthase (TS), a critical enzyme for DNA synthesis and repair, is both a potential tumor prognostic biomarker as well as a tumorigenic oncogene in animal models. We have now studied the clinical implications of TS expression in gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) and compared these results to other cell cycle biomarker genes. Protein tissue arrays were used to study TS, Ki-67, Rb, pRb, E2F1, p18, p21, p27 and menin expression in 320 human GEP-NETs samples. Immunohistochemical expression was correlated with univariate and multivariate predictors of survival utilizing Kaplan Meier and Cox proportional hazards models. Real time RT-PCR was used to validate these findings. We found that 78 of 320 GEP-NETs (24.4%) expressed TS. NETs arising in the colon, stomach and pancreas showed the highest expression of TS (47.4%, 42.6% and 37.3%, respectively), whereas NETs of the appendix, rectum and duodenum displayed low TS expression (3.3%, 12.9% and 15.4%, respectively). TS expression in GEP-NETs was associated with poorly differentiated endocrine carcinoma, angiolymphatic invasion, lymph node metastasis and distant metastasis (p < 0.05). Patients with TS-positive NETs had markedly worse outcomes than TS-negative NETs as shown by univariate (p < 0.001) and multivariate (p = 0.01) survival analyses. Expression of p18 predicted survival in TS-positive patients that received chemotherapy (p = 0.015). In conclusion, TS protein expression was an independent prognostic biomarker for GEP-NETs. The strong association of increased TS expression with aggressive disease and early death supports the role of TS as a cancer promoting agent in these tumors. © 2013 UICC.

Aberrantly methylated DNA as a biomarker in breast cancer.

PubMed

Kristiansen, Søren; Jørgensen, Lars M; Guldberg, Per; Sölétormos, György

2013-01-01

Aberrant DNA hypermethylation at gene promoters is a frequent event in human breast cancer. Recent genome-wide studies have identified hundreds of genes that exhibit differential methylation between breast cancer cells and normal breast tissue. Due to the tumor-specific nature of DNA hypermethylation events, their use as tumor biomarkers is usually not hampered by analytical signals from normal cells, which is a general problem for existing protein tumor markers used for clinical assessment of breast cancer. There is accumulating evidence that DNA-methylation changes in breast cancer patients occur early during tumorigenesis. This may open up for effective screening, and analysis of blood or nipple aspirate may later help in diagnosing breast cancer. As a more detailed molecular characterization of different types of breast cancer becomes available, the ability to divide patients into subgroups based on DNA biomarkers may improve prognosis. Serial monitoring of DNA-methylation markers in blood during treatment may be useful, particularly when the cancer burden is below the detection level for standard imaging techniques. Overall, aberrant DNA methylation has a great potential as a versatile biomarker tool for screening, diagnosis, prognosis and monitoring of breast cancer. Standardization of methods and biomarker panels will be required to fully exploit this clinical potential.

The microRNAs as potential biomarkers for predicting the onset of aflatoxin exposure in human beings: a review.

PubMed

Valencia-Quintana, Rafael; Sánchez-Alarcón, Juana; Tenorio-Arvide, María G; Deng, Youjun; Montiel-González, José M R; Gómez-Arroyo, Sandra; Villalobos-Pietrini, Rafael; Cortés-Eslava, Josefina; Flores-Márquez, Ana R; Arenas-Huertero, Francisco

2014-01-01

The identification of aflatoxins as human carcinogens has stimulated extensive research efforts, which continue to the present, to assess potential health hazards resulting from contamination of the human food supply and to minimize exposure. The use of biomarkers that are mechanistically supported by toxicological studies will be important tools for identifying stages in the progression of development of the health effects of environmental agents. miRNAs are small non-coding mRNAs that regulate post-transcriptional gene expression. Also, they are molecular markers of cellular responses to various chemical agents. Growing evidence has demonstrated that environmental chemicals can induce changes in miRNA expression. miRNAs are good biomarkers because they are well defined, chemically uniform, restricted to a manageable number of species, and stable in cells and in the circulation. miRNAs have been used as serological markers of HCC and other tumors. The expression patterns of different miRNAs can distinguish among HCC-hepatitis viruses related, HCC cirrhosis-derivate, and HCC unrelated to either of them. The main objective of this review is to find unreported miRNAs in HCC related to other causes, so that they can be used as specific molecular biomarkers in populations exposed to aflatoxins and as early markers of exposure, damage/presence of HCC. Until today specific miRNAs as markers for aflatoxins-exposure and their reliability are currently lacking. Based on their elucidated mechanisms of action, potential miRNAs that could serve as possible markers of HCC by exposure to aflatoxins are miR-27a, miR-27b, miR-122, miR-148, miR-155, miR-192, miR-214, miR-221, miR-429, and miR-500. Future validation for all of these miRNAs will be needed to assess their prognostic significance and confirm their relationship with the induction of HCC due to aflatoxin exposure.