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Sample records for blood biomarker revealing

  1. Expression profiling reveals novel hypoxic biomarkers in peripheral blood of adult mice exposed to chronic hypoxia.

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    Matias Mosqueira

    Full Text Available Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX, exposed for two weeks to normobaric chronic hypoxia (CH or two weeks of CH followed by two weeks of normoxic recovery (REC. Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off, 230 genes were identified and separated into four distinct temporal categories. Class I contained 1 transcript up-regulated in both CH and REC; Class II contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III contained 9 transcripts down-regulated both in CH and REC; Class IV contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1 by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.

  2. SRRM2, a potential blood biomarker revealing high alternative splicing in Parkinson's disease.

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    Lina A Shehadeh

    Full Text Available BACKGROUND: Parkinson's disease (PD is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms. METHODOLOGY/PRINCIPAL FINDINGS: We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300, sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008 upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03 and amygdala (p = 0.003. To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls and found a significant upregulation of the upstream (5' exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04 of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression in PD blood versus controls. CONCLUSIONS/SIGNIFICANCE: The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease.

  3. Which biomarkers reveal neonatal sepsis?

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    Kun Wang

    Full Text Available We address the identification of optimal biomarkers for the rapid diagnosis of neonatal sepsis. We employ both canonical correlation analysis (CCA and sparse support vector machine (SSVM classifiers to select the best subset of biomarkers from a large hematological data set collected from infants with suspected sepsis from Yale-New Haven Hospital's Neonatal Intensive Care Unit (NICU. CCA is used to select sets of biomarkers of increasing size that are most highly correlated with infection. The effectiveness of these biomarkers is then validated by constructing a sparse support vector machine diagnostic classifier. We find that the following set of five biomarkers capture the essential diagnostic information (in order of importance: Bands, Platelets, neutrophil CD64, White Blood Cells, and Segs. Further, the diagnostic performance of the optimal set of biomarkers is significantly higher than that of isolated individual biomarkers. These results suggest an enhanced sepsis scoring system for neonatal sepsis that includes these five biomarkers. We demonstrate the robustness of our analysis by comparing CCA with the Forward Selection method and SSVM with LASSO Logistic Regression.

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

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    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.

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

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    Julien Textoris

    Full Text Available 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.

  6. Blood-based biomarkers for Parkinson's disease.

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    Chahine, Lama M; Stern, Matthew B; Chen-Plotkin, Alice

    2014-01-01

    There is a pressing need for biomarkers to diagnose Parkinson's disease (PD), assess disease severity, and prognosticate course. Various types of biologic specimens are potential candidates for identifying biomarkers--defined here as surrogate indicators of physiological or pathophysiological states--but blood has the advantage of being minimally invasive to obtain. There are, however, several challenges to identifying biomarkers in blood. Several candidate biomarkers identified in other diseases or in other types of biological fluids are being pursued as blood-based biomarkers in PD. In addition, unbiased discovery is underway using techniques including metabolomics, proteomics, and gene expression profiling. In this review, we summarize these techniques and discuss the challenges and successes of blood-based biomarker discovery in PD. Blood-based biomarkers that are discussed include α-synuclein, DJ-1, uric acid, epidermal growth factor, apolipoprotein-A1, and peripheral inflammatory markers.

  7. Biomarkers of inflammation, metabolism, and oxidative stress in blood, liver, and milk reveal a better immunometabolic status in peripartal cows supplemented with Smartamine M or MetaSmart.

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    Osorio, J S; Trevisi, E; Ji, P; Drackley, J K; Luchini, D; Bertoni, G; Loor, J J

    2014-12-01

    The peripartal dairy cow experiences a state of reduced liver function coupled with increased inflammation and oxidative stress. This study evaluated the effect of supplementing basal diets with rumen-protected Met in the form of MetaSmart (MS) or Smartamine M (SM) (both from Adisseo Inc., Antony, France) during the peripartal period on blood and hepatic biomarkers of liver function, inflammation, and oxidative stress. Thirty-seven multiparous Holstein cows were fed the same basal diet from -50 to -21 d relative to expected calving [1.24 Mcal/kg of dry matter (DM); no Met supplementation]. From -21 d to calving, the cows received diets (1.54 Mcal/kg of DM) with no added Met (control, CON; n=13), CON plus MS (n=11), or CON plus SM (n=13). From calving through 30 d in milk (DIM), the cows received the same postpartal diet (1.75 Mcal/kg of DM; CON), or CON plus MS or CON plus SM. Liver and blood samples were harvested at various time points from -21 to 21 d relative to calving. Preplanned contrasts of CON versus SM + MS during prepartum (-21 and -10 d before calving) and postpartum (7, 14, and 21 d after calving) responses were evaluated. Cows fed MS or SM compared with CON had lower overall concentrations of plasma ceruloplasmin and serum amyloid A (SAA). Compared with CON, Met-supplemented cows had greater overall plasma oxygen radical absorbance capacity. Liver concentrations of glutathione and carnitine also were greater overall with Met supplementation. Milk choline and liver phosphatidylcholine were lower overall in cows fed Met compared with controls. Liver tissue choline concentrations did not differ. Data indicate that supplemental Met enhanced de novo glutathione and carnitine synthesis in liver and, thus, increased antioxidant and β-oxidation capacity. The greater decrease of IL-6 after calving coupled with lower ceruloplasmin and SAA in Met-supplemented cows indicated a reduction in proinflammatory signaling within liver. The lower hepatic

  8. Blood biomarker for Parkinson disease: peptoids

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

    2016-01-01

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

  9. BLOOD BIOMARKERS FOR EVALUATION OF PERINATAL ENCEPHALOPATHY

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    Ernest Marshall Graham

    2016-07-01

    Full Text Available Recent research in identification of brain injury after trauma shows many possible blood biomarkers that may help identify the fetus and neonate with encephalopathy. Traumatic brain injury shares many common features with perinatal hypoxic-ischemic encephalopathy. Trauma has a hypoxic component, and one of the 1st physiologic consequences of moderate-severe traumatic brain injury is apnea. Trauma and hypoxia-ischemia initiate an excitotoxic cascade and free radical injury followed by the inflammatory cascade, producing injury in neurons, glial cells and white matter. Increased excitatory amino acids, lipid peroxidation products and alteration in microRNAs and inflammatory markers are common to both traumatic brain injury and perinatal encephalopathy. The blood-brain barrier is disrupted in both leading to egress of substances normally only found in the central nervous system. Brain exosomes may represent ideal biomarker containers, as RNA and protein transported within the vesicles are protected from enzymatic degradation. Evaluation of fetal or neonatal brain derived exosomes that cross the blood-brain barrier and circulate peripherally has been referred to as the liquid brain biopsy. A multiplex of serum biomarkers could improve upon the current imprecise methods of identifying fetal and neonatal brain injury such as fetal heart rate abnormalities, meconium, cord gases at delivery, and Apgar scores. Quantitative biomarker measurements of perinatal brain injury and recovery could lead to operative delivery only in the presence of significant fetal risk, triage to appropriate therapy after birth and measure the effectiveness of treatment.

  10. Methodological and analytic considerations for blood biomarkers.

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    Christenson, Robert H; Duh, Show-Hong

    2012-01-01

    Biomarkers typically evolve from a research setting to use in clinical care as evidence for their independent contribution to patient management accumulates. This evidence relies heavily on knowledge of the preanalytical, analytical, and postanalytical characteristics of the biomarker's measurement. For the preanalytical phase, considerations such specimen type, acceptable anticoagulants for blood samples, biologic variation and stability of the biomarker under various conditions are key. The analytical phase entails critical details for development and maintenance of assays having performance characteristics that are "fit for service" for the clinical application at hand. Often, these characteristics describe the ability to measure minute quantities in the biologic matrix used for measurement. Although techniques such as mass spectrometry are used effectively for biomarker discovery, routine quantification often relies on use of immunoassays; early in development, the most common immunoassay used is the enzyme-linked immunosorbent assay format. As biomarkers evolve successfully, they will be adapted to large main laboratory platforms or, depending on the need for speed, point-of-care devices. Users must pay particular attention to performance parameters of assays they are considering for clinical implementation. These parameters include the limit of blank, a term used to describe the limit of analytical noise for an assay; limit of detection, which describes the lowest concentration that can reliably be discriminated from analytical noise; and perhaps most importantly, the limit of quantitation, which is the lowest concentration at which a biomarker can be reliably measured within some predefined specifications for total analytical error that is based on clinical requirements of the test. The postanalytical phase involves reporting biomarker values, which includes reporting units, any normalization factors, and interpretation. Standardization, a process that

  11. Blood-Based Biomarkers of Early-Onset Breast Cancer

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    2015-10-01

    AWARD NUMBER: W81XWH-13-1-0214 TITLE: Blood -based biomarkers of early-onset breast cancer PRINCIPAL INVESTIGATOR: Nasim Ahmadiyeh...DATES COVERED 30 Sep 2014 - 29 Sep 2015 4. TITLE AND SUBTITLE Blood -based biomarkers of early-onset breast cancer 5a. CONTRACT NUMBER W81XWH-13-1...While the normal breast is the ideal tissue in which to study this phenomenon, gene expression profiling of blood lymphocytes has been successfully

  12. Comparison of Biomarkers in Blood and Saliva in Healthy Adults

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    Sarah Williamson

    2012-01-01

    Full Text Available Researchers measure biomarkers as a reflection of patient health status or intervention outcomes. While blood is generally regarded as the best body fluid for evaluation of systemic processes, substitution of saliva samples for blood would be less invasive and more convenient. The concentration of specific biomarkers may differ between blood and saliva. The objective of this study was to compare multiple biomarkers (27 cytokines in plasma samples, passive drool saliva samples, and filter paper saliva samples in 50 healthy adults. Demographic data and three samples were obtained from each subject: saliva collected on filter paper over 1 minute, saliva collected by passive drool over 30 seconds, and venous blood (3 mL collected by venipuncture. Cytokines were assayed using Bio-Rad multiplex suspension array technology. Descriptive statistics and pairwise correlations were used for data analysis. The sample was 52% male and 74% white. Mean age was 26 (range = 19–63 years, sd = 9.7. The most consistent and highest correlations were between the passive drool and filter paper saliva samples, although relationships were dependent on the specific biomarker. Correlations were not robust enough to support substitution of one collection method for another. There was little correlation between the plasma and passive drool saliva samples. Caution should be used in substituting saliva for blood, and relationships differ by biomarker.

  13. Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells.

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    Giovanni Nardo

    Full Text Available BACKGROUND: Amyotrophic lateral sclerosis (ALS is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments. METHODOLOGY/PRINCIPAL FINDINGS: We used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC, a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%, and from patients with neurological disorders that may resemble ALS (91%, between two levels of disease severity (90%, and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing. CONCLUSIONS/SIGNIFICANCE: Our results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.

  14. Serum Glycoprotein Biomarker Discovery and Qualification Pipeline Reveals Novel Diagnostic Biomarker Candidates for Esophageal Adenocarcinoma.

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    Shah, Alok K; Cao, Kim-Anh Lê; Choi, Eunju; Chen, David; Gautier, Benoît; Nancarrow, Derek; Whiteman, David C; Saunders, Nicholas A; Barbour, Andrew P; Joshi, Virendra; Hill, Michelle M

    2015-11-01

    were independently verified by lectin magnetic bead array-immunoblotting, confirming the validity of the relative quantitation approach. Thus, we have identified candidate biomarkers, which, following large-scale clinical evaluation, can be developed into diagnostic blood tests. A key feature of the pipeline is the potential for rapid translation of the candidate biomarkers to lectin-immunoassays.

  15. COPD association and repeatability of blood biomarkers in the ECLIPSE cohort

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    Dickens Jennifer A

    2011-11-01

    Full Text Available Abstract Background There is a need for biomarkers to better characterise individuals with COPD and to aid with the development of therapeutic interventions. A panel of putative blood biomarkers was assessed in a subgroup of the Evaluation of COPD Longitudinally to Identify Surrogate Endpoints (ECLIPSE cohort. Methods Thirty-four blood biomarkers were assessed in 201 subjects with COPD, 37 ex-smoker controls with normal lung function and 37 healthy non-smokers selected from the ECLIPSE cohort. Biomarker repeatability was assessed using baseline and 3-month samples. Intergroup comparisons were made using analysis of variance, repeatability was assessed through Bland-Altman plots, and correlations between biomarkers and clinical characteristics were assessed using Spearman correlation coefficients. Results Fifteen biomarkers were significantly different in individuals with COPD when compared to former or non-smoker controls. Some biomarkers, including tumor necrosis factor-α and interferon-γ, were measurable in only a minority of subjects whilst others such as C-reactive protein showed wide variability over the 3-month replication period. Fibrinogen was the most repeatable biomarker and exhibited a weak correlation with 6-minute walk distance, exacerbation rate, BODE index and MRC dyspnoea score in COPD subjects. 33% (66/201 of the COPD subjects reported at least 1 exacerbation over the 3 month study with 18% (36/201 reporting the exacerbation within 30 days of the 3-month visit. CRP, fibrinogen interleukin-6 and surfactant protein-D were significantly elevated in those COPD subjects with exacerbations within 30 days of the 3-month visit compared with those individuals that did not exacerbate or whose exacerbations had resolved. Conclusions Only a few of the biomarkers assessed may be useful in diagnosis or management of COPD where the diagnosis is based on airflow obstruction (GOLD. Further analysis of more promising biomarkers may reveal

  16. Common Genetic Polymorphisms Influence Blood Biomarker Measurements in COPD.

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    Sun, Wei; Kechris, Katerina; Jacobson, Sean; Drummond, M Bradley; Hawkins, Gregory A; Yang, Jenny; Chen, Ting-Huei; Quibrera, Pedro Miguel; Anderson, Wayne; Barr, R Graham; Basta, Patricia V; Bleecker, Eugene R; Beaty, Terri; Casaburi, Richard; Castaldi, Peter; Cho, Michael H; Comellas, Alejandro; Crapo, James D; Criner, Gerard; Demeo, Dawn; Christenson, Stephanie A; Couper, David J; Curtis, Jeffrey L; Doerschuk, Claire M; Freeman, Christine M; Gouskova, Natalia A; Han, MeiLan K; Hanania, Nicola A; Hansel, Nadia N; Hersh, Craig P; Hoffman, Eric A; Kaner, Robert J; Kanner, Richard E; Kleerup, Eric C; Lutz, Sharon; Martinez, Fernando J; Meyers, Deborah A; Peters, Stephen P; Regan, Elizabeth A; Rennard, Stephen I; Scholand, Mary Beth; Silverman, Edwin K; Woodruff, Prescott G; O'Neal, Wanda K; Bowler, Russell P

    2016-08-01

    Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p 10% of measured variation in 13 protein biomarkers, with a single SNP (rs7041; p = 10-392) explaining 71%-75% of the measured variation in vitamin D binding protein (gene = GC). Some of these pQTLs [e.g., pQTLs for VDBP, sRAGE (gene = AGER), surfactant protein D (gene = SFTPD), and TNFRSF10C] have been previously associated with COPD phenotypes. Most pQTLs were local (cis), but distant (trans) pQTL SNPs in the ABO blood group locus were the top pQTL SNPs for five proteins. The inclusion of pQTL SNPs improved the clinical predictive value for the established association of sRAGE and emphysema, and the explanation of variance (R2) for emphysema improved from 0.3 to 0.4 when the pQTL SNP was included in the model along with clinical covariates. Causal modeling provided insight into specific pQTL-disease relationships for airflow obstruction and emphysema. In conclusion, given the frequency of highly significant local pQTLs, the large amount of variance potentially explained by pQTL, and the

  17. Blood Biomarkers of Chronic Inflammation in Gulf War Illness.

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    Gerhard J Johnson

    Full Text Available More than twenty years following the end of the 1990-1991 Gulf War it is estimated that approximately 300,000 veterans of this conflict suffer from an unexplained chronic, multi-system disorder known as Gulf War Illness (GWI. The etiology of GWI may be exposure to chemical toxins, but it remains only partially defined, and its case definition is based only on symptoms. Objective criteria for the diagnosis of GWI are urgently needed for diagnosis and therapeutic research.This study was designed to determine if blood biomarkers could provide objective criteria to assist diagnosis of GWI.A surveillance study of 85 Gulf War Veteran volunteers identified from the Department of Veterans Affairs Minnesota Gulf War registry was performed. All subjects were deployed to the Gulf War. Fifty seven subjects had GWI defined by CDC criteria, and 28 did not have symptomatic criteria for a diagnosis of GWI. Statistical analyses were performed on peripheral blood counts and assays of 61 plasma proteins using the Mann-Whitney rank sum test to compare biomarker distributions and stepwise logistic regression to formulate a diagnostic model.Lymphocyte, monocyte, neutrophil, and platelet counts were higher in GWI subjects. Six serum proteins associated with inflammation were significantly different in GWI subjects. A diagnostic model of three biomarkers-lymphocytes, monocytes, and C reactive protein-had a predicted probability of 90% (CI 76-90% for diagnosing GWI when the probability of having GWI was above 70%.The results of the current study indicate that inflammation is a component of the pathobiology of GWI. Analysis of the data resulted in a model utilizing three readily measurable biomarkers that appears to significantly augment the symptom-based case definition of GWI. These new observations are highly relevant to the diagnosis of GWI, and to therapeutic trials.

  18. Epigenetic biomarkers in the blood of patients with urological malignancies.

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    Ellinger, Jörg; Müller, Stefan C; Dietrich, Dimo

    2015-04-01

    In the era of personalized medicine, there is an urgent need for non-invasive biomarkers to optimize the individual treatment of cancer patients. Epigenetic alterations, including DNA methylation and non-coding RNAs, are a hallmark of malignant tumors. The detection of many of these epigenetic conditions is feasible in bodily fluids, that is, blood plasma and serum, and may therefore be used for liquid biopsy. In this review, we summarize and discuss the current state of research on circulating epigenetic alterations (DNA methylation, miRNA and long non-coding RNA) in serum and plasma of patients with bladder cancer, prostate cancer, renal cell carcinoma and testicular germ cell cancer.

  19. Metabolomics reveals metabolic biomarkers of Crohn's disease

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    Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

    2009-06-01

    The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

  20. Blood-based biomarkers of aggressive prostate cancer.

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    Men Long Liong

    Full Text Available PURPOSE: Prostate cancer is a bimodal disease with aggressive and indolent forms. Current prostate-specific-antigen testing and digital rectal examination screening provide ambiguous results leading to both under-and over-treatment. Accurate, consistent diagnosis is crucial to risk-stratify patients and facilitate clinical decision making as to treatment versus active surveillance. Diagnosis is currently achieved by needle biopsy, a painful procedure. Thus, there is a clinical need for a minimally-invasive test to determine prostate cancer aggressiveness. A blood sample to predict Gleason score, which is known to reflect aggressiveness of the cancer, could serve as such a test. MATERIALS AND METHODS: Blood mRNA was isolated from North American and Malaysian prostate cancer patients/controls. Microarray analysis was conducted utilizing the Affymetrix U133 plus 2·0 platform. Expression profiles from 255 patients/controls generated 85 candidate biomarkers. Following quantitative real-time PCR (qRT-PCR analysis, ten disease-associated biomarkers remained for paired statistical analysis and normalization. RESULTS: Microarray analysis was conducted to identify 85 genes differentially expressed between aggressive prostate cancer (Gleason score ≥8 and controls. Expression of these genes was qRT-PCR verified. Statistical analysis yielded a final seven-gene panel evaluated as six gene-ratio duplexes. This molecular signature predicted as aggressive (ie, Gleason score ≥8 55% of G6 samples, 49% of G7(3+4, 79% of G7(4+3 and 83% of G8-10, while rejecting 98% of controls. CONCLUSION: In this study, we have developed a novel, blood-based biomarker panel which can be used as the basis of a simple blood test to identify men with aggressive prostate cancer and thereby reduce the overdiagnosis and overtreatment that currently results from diagnosis using PSA alone. We discuss possible clinical uses of the panel to identify men more likely to benefit from

  1. Blood transcriptome based biomarkers for human circadian phase

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    Laing, Emma E; Möller-Levet, Carla S; Poh, Norman; Santhi, Nayantara; Archer, Simon N; Dijk, Derk-Jan

    2017-01-01

    Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain’s circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2 of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R2 was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples. DOI: http://dx.doi.org/10.7554/eLife.20214.001 PMID:28218891

  2. Cord Blood DNA Methylation Biomarkers for Predicting Neurodevelopmental Outcomes

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    Nicolette A. Hodyl

    2016-12-01

    Full Text Available Adverse environmental exposures in pregnancy can significantly alter the development of the fetus resulting in impaired child neurodevelopment. Such exposures can lead to epigenetic alterations like DNA methylation, which may be a marker of poor cognitive, motor and behavioral outcomes in the infant. Here we review studies that have assessed DNA methylation in cord blood following maternal exposures that may impact neurodevelopment of the child. We also highlight some key studies to illustrate the potential for DNA methylation to successfully identify infants at risk for poor outcomes. While the current evidence is limited, in that observations to date are largely correlational, in time and with larger cohorts analyzed and longer term follow-up completed, we may be able to develop epigenetic biomarkers that not only indicate adverse early life exposures but can also be used to identify individuals likely to be at an increased risk of impaired neurodevelopment even in the absence of detailed information regarding prenatal environment.

  3. Blood-based biomarkers of microvascular pathology in Alzheimer's disease.

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    Ewers, Michael

    2012-02-01

    Sporadic Alzheimer\\'s disease (AD) is a genetically complex and chronically progressive neurodegenerative disorder with molecular mechanisms and neuropathologies centering around the amyloidogenic pathway, hyperphosphorylation and aggregation of tau protein, and neurofibrillary degeneration. While cerebrovascular changes have not been traditionally considered to be a central part of AD pathology, a growing body of evidence demonstrates that they may, in fact, be a characteristic feature of the AD brain as well. In particular, microvascular abnormalities within the brain have been associated with pathological AD hallmarks and may precede neurodegeneration. In vivo assessment of microvascular pathology provides a promising approach to develop useful biological markers for early detection and pathological characterization of AD. This review focuses on established blood-based biological marker candidates of microvascular pathology in AD. These candidates include plasma concentration of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) that are increased in AD. Measures of endothelial vasodilatory function including endothelin (ET-1), adrenomedullin (ADM), and atrial natriuretic peptide (ANP), as well as sphingolipids are significantly altered in mild AD or during the predementia stage of mild cognitive impairment (MCI), suggesting sensitivity of these biomarkers for early detection and diagnosis. In conclusion, the emerging clinical diagnostic evidence for the value of blood-based microvascular biomarkers in AD is promising, however, still requires validation in phase II and III diagnostic trials. Moreover, it is still unclear whether the described protein dysbalances are early or downstream pathological events and how the detected systemic microvascular alterations relate to cerebrovascular and neuronal pathologies in the AD brain.

  4. Biomarkers of Traumatic Injury Are Transported from Brain to Blood via the Glymphatic System

    OpenAIRE

    2015-01-01

    The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulat...

  5. Circulating microRNAs as biomarkers for detection of autologous blood transfusion.

    Directory of Open Access Journals (Sweden)

    Nicolas Leuenberger

    Full Text Available MicroRNAs (miRNAs are small non-coding RNAs that regulate various biological processes. Cell-free miRNAs measured in blood plasma have emerged as specific and sensitive markers of physiological processes and disease. In this study, we investigated whether circulating miRNAs can serve as biomarkers for the detection of autologous blood transfusion, a major doping technique that is still undetectable. Plasma miRNA levels were analyzed using high-throughput quantitative real-time PCR. Plasma samples were obtained before and at several time points after autologous blood transfusion (blood bag storage time 42 days in 10 healthy subjects and 10 controls without transfusion. Other serum markers of erythropoiesis were determined in the same samples. Our results revealed a distinct change in the pattern of circulating miRNAs. Ten miRNAs were upregulated in transfusion samples compared with control samples. Among these, miR-30b, miR-30c, and miR-26b increased significantly and showed a 3.9-, 4.0-, and 3.0-fold change, respectively. The origin of these miRNAs was related to pulmonary and liver tissues. Erythropoietin (EPO concentration decreased after blood reinfusion. A combination of miRNAs and EPO measurement in a mathematical model enhanced the efficiency of autologous transfusion detection through miRNA analysis. Therefore, our results lay the foundation for the development of miRNAs as novel blood-based biomarkers to detect autologous transfusion.

  6. Biomarkers for early and late stage chronic allograft nephropathy by proteogenomic profiling of peripheral blood.

    Directory of Open Access Journals (Sweden)

    Sunil M Kurian

    Full Text Available BACKGROUND: Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression. METHODS: We used DNA microarrays, tandem mass spectroscopy proteomics and bioinformatics to identify genomic and proteomic markers of mild and moderate/severe CAN in peripheral blood of two distinct cohorts (n = 77 total of kidney transplant patients with biopsy-documented histology. FINDINGS: Gene expression profiles reveal over 2400 genes for mild CAN, and over 700 for moderate/severe CAN. A consensus analysis reveals 393 (mild and 63 (moderate/severe final candidates as CAN markers with predictive accuracy of 80% (mild and 92% (moderate/severe. Proteomic profiles show over 500 candidates each, for both stages of CAN including 302 proteins unique to mild and 509 unique to moderate/severe CAN. CONCLUSIONS: This study identifies several unique signatures of transcript and protein biomarkers with high predictive accuracies for mild and moderate/severe CAN, the most common cause of late allograft failure. These biomarkers are the necessary first step to a proteogenomic classification of CAN based on peripheral blood profiling and will be the targets of a prospective clinical validation study.

  7. Data-driven asthma endotypes defined from blood biomarker and gene expression data

    Science.gov (United States)

    The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes) driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-section...

  8. Building the Evidence Base of Blood-Based Biomarkers for Early Detection of Cancer: A Rapid Systematic Mapping Review

    Directory of Open Access Journals (Sweden)

    Lesley Uttley

    2016-08-01

    Interpretation: This study is the first to systematically and comprehensively map blood biomarkers for early detection of cancer. Use of this rapid systematic mapping approach found a broad range of relevant biomarkers allowing an evidence-based approach to identification of promising biomarkers for development of a blood-based cancer screening test in the general population.

  9. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system.

    Science.gov (United States)

    Plog, Benjamin A; Dashnaw, Matthew L; Hitomi, Emi; Peng, Weiguo; Liao, Yonghong; Lou, Nanhong; Deane, Rashid; Nedergaard, Maiken

    2015-01-14

    The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100β, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity.

  10. Biomarker Analysis of Stored Blood Products: Emphasis on Pre-Analytical Issues

    Directory of Open Access Journals (Sweden)

    Niels Lion

    2010-11-01

    Full Text Available Millions of blood products are transfused every year; many lives are thus directly concerned by transfusion. The three main labile blood products used in transfusion are erythrocyte concentrates, platelet concentrates and fresh frozen plasma. Each of these products has to be stored according to its particular components. However, during storage, modifications or degradation of those components may occur, and are known as storage lesions. Thus, biomarker discovery of in vivo blood aging as well as in vitro labile blood products storage lesions is of high interest for the transfusion medicine community. Pre-analytical issues are of major importance in analyzing the various blood products during storage conditions as well as according to various protocols that are currently used in blood banks for their preparations. This paper will review key elements that have to be taken into account in the context of proteomic-based biomarker discovery applied to blood banking.

  11. Cancer screening: a mathematical model relating secreted blood biomarker levels to tumor sizes.

    Directory of Open Access Journals (Sweden)

    Amelie M Lutz

    2008-08-01

    Full Text Available BACKGROUND: Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden. METHODS AND FINDINGS: Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1 the compartment (plasma is well-mixed and kinetically homogenous; (2 the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1 exclusively by the tumor cells or (2 by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]. Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3 and 3,610.14 mm(3 for CA125 and between 0.21 mm(3 and 131.51 mm(3 for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged

  12. Cerebrospinal Fluid and Blood Biomarkers of Neuroaxonal Damage in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Irena Dujmovic

    2011-01-01

    Full Text Available Following emerging evidence that neurodegenerative processes in multiple sclerosis (MS are present from its early stages, an intensive scientific interest has been directed to biomarkers of neuro-axonal damage in body fluids of MS patients. Recent research has introduced new candidate biomarkers but also elucidated pathogenetic and clinical relevance of the well-known ones. This paper reviews the existing data on blood and cerebrospinal fluid biomarkers of neuroaxonal damage in MS and highlights their relation to clinical parameters, as well as their potential predictive value to estimate future disease course, disability, and treatment response. Strategies for future research in this field are suggested.

  13. Blood biomarkers in metal scrap workers accidentally exposed to ionizing radiation: a case study.

    Science.gov (United States)

    Gupta, M L; Srivastava, N N; Dutta, S; Shukla, S K; Dutta, A; Verma, S; Devi, M

    2013-12-01

    The detrimental effect of nuclear accidents due to localized or whole body radiation exposure results in severe cellular damage. The current study was carried out to evaluate radiation-mediated variability in blood components of metal scrap workers exposed accidently to cobalt-60 source. Blood samples collected initially from five hospitalized patients, coded P1-P5, were processed for total leukocyte counts (TLC), platelet (PLT) counts, haemoglobin, estimation of DNA double strand breaks by measuring phosphorylated form of H2AX (γ-H2AX) and chromosomal aberrations (dicentrics). Blood cells count (TLC), in all the patients except P2, was found decreased. Dicentrics increased in all the five patients. γ-H2AX was found significantly elevated in patients P2 and P4. After 3 days, 21 subjects working in close vicinity of accident site were evaluated for the above-mentioned markers to confirm their possibility of radiation exposure; however, all the parameters in these subjects were found within normal limits. Blood from patients P1-P5 was collected again after 11 days. Studies revealed exorbitant increase in γ-H2AX in lymphocytes and monocytes of patients P1, P4 and P5. TLC and PLT count in these patients had fallen further. Dicentrics declined with time in all the five patients. Based on the studied blood biomarkers, we conclude that the five subjects showed signs of radiation exposure. Measurement on radiation dose could not be performed in the current study; however, the generated data particularly on dicentrics provide ample evidence of radiation exposure.

  14. Blood-based protein biomarker panel for the detection of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Kim Y C Fung

    Full Text Available The majority of colorectal cancer (CRC cases are preventable by early detection and removal of precancerous polyps. Even though CRC is the second most common internal cancer in Australia, only 30 per cent of the population considered to have risk factors participate in stool-based test screening programs. Evidence indicates a robust, blood-based, diagnostic assay would increase screening compliance. A number of potential diagnostic blood-based protein biomarkers for CRC have been reported, but all lack sensitivity or specificity for use as a stand-alone diagnostic. The aim of this study was to identify and validate a panel of protein-based biomarkers in independent cohorts that could be translated to a reliable, non-invasive blood-based screening test.In two independent cohorts (n = 145 and n = 197, we evaluated seven single biomarkers in serum of CRC patients and age/gender matched controls that showed a significant difference between controls and CRC, but individually lack the sensitivity for diagnostic application. Using logistic regression strategies, we identified a panel of three biomarkers that discriminated between controls and CRC with 73% sensitivity at 95% specificity, when applied to either of the two cohorts. This panel comprised of Insulin like growth factor binding protein 2 (IGFBP2, Dickkopf-3 (DKK3, and Pyruvate kinase M2(PKM2.Due to the heterogeneous nature of CRC, a single biomarker is unlikely to have sufficient sensitivity or specificity for use as a stand-alone diagnostic screening test and a panel of markers may be more effective. We have identified a 3 biomarker panel that has higher sensitivity and specificity for early stage (Stage I and -II disease than the faecal occult blood test, raising the possibility for its use as a non-invasive blood diagnostic or screening test.

  15. Blood and tissue biomarkers in prostate cancer: state of the art.

    Science.gov (United States)

    Fiorentino, Michelangelo; Capizzi, Elisa; Loda, Massimo

    2010-02-01

    The prevalence of prostate cancer (PCa) is high and increases with age. PCa is the most common cutaneous cancer in American men. Prostate-specific antigen (PSA) screening has impacted the detection of PCa and is directly responsible for a dramatic decrease in stage at diagnosis. Gleason score and stage at the time of diagnosis remain the mainstay to predict prognosis, in the absence of more accurate and reliable tissue or blood biomarkers. Despite extensive research efforts, very few biomarkers of PCa have been introduced to date in clinical practice. Even screening with PSA has recently been questioned. A thorough analysis of all tissue and serum biomarkers in prostate cancer research cannot be easily synthesized, and goes beyond the scope of the present article. Therefore the authors focus here on the most recently reported tissue and circulating biomarkers for PCa whose application in clinical practice is either current or expected in the near future.

  16. Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson's Disease Patients.

    Directory of Open Access Journals (Sweden)

    Jose A Santiago

    Full Text Available Early diagnosis of Parkinson's disease (PD continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson's Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009 when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson's Disease Rating Scale (MDS-UPDRS and Montreal Cognitive Assessment (MoCA score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN compared to cognitively impaired PD patients (PD-MCI. Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.

  17. Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinson's Disease Patients.

    Science.gov (United States)

    Santiago, Jose A; Potashkin, Judith A

    2015-01-01

    Early diagnosis of Parkinson's disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson's Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.

  18. Blood Biomarkers for Assessing the Exposure and Response of Mammals to Chemical and Biological Agents

    Science.gov (United States)

    2012-03-15

    identified as markers of acetaminophen (APAP)- induced hepatotoxicity using three proteomic technologies: label-free antibody microarrays, quantitative...tetrachloride for protein biomarkers using proteomics technologies, including MRM; 5) Analyzing time course experiments of rat tissues and blood exposed to...technologies, including MRM. Aim 5: Analyze time course experiments of rat tissues and blood exposed to VX. Aim 6: Develop new technologies for developing

  19. Histone Methylation Marks on Circulating Nucleosomes as Novel Blood-Based Biomarker in Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Ugur Gezer

    2015-12-01

    Full Text Available Circulating nucleic acids (CNAs are under investigation as a liquid biopsy in cancer as potential non-invasive biomarkers, as stable structure in circulation nucleosomes could be valuable sources for detection of cancer-specific alterations in histone modifications. Our interest is in histone methylation marks with a focus on colorectal cancer, one of the leading cancers respective the incidence and mortality. Our previous work included the analysis of trimethylations of lysine 9 on histone 3 (H3K9me3 and of lysine 20 on histone 4 (H4K20me3 by chromatin immuno- precipitation-related PCR in circulating nucleosomes. Here we asked whether global immunologic measurement of histone marks in circulation could be a suitable approach to show their potential as biomarkers. In addition to H3K9me3 and H4K20me3 we also measured H3K27me3 in plasma samples from CRC patients (n = 63 and cancer free individuals (n = 40 by ELISA-based methylation assays. Our results show that of three marks, the amounts of H3K27me3 (p = 0.04 and H4K20me3 (p < 0.001 were significantly lower in CRC patients than in healthy controls. For H3K9me3 similar amounts were measured in both groups. Areas under the curve (AUC in receiver operating characteristic (ROC curves indicating the power of CRC detection were 0.620 for H3K27me3, 0.715 for H4K20me3 and 0.769 for the combination of both markers. In conclusion, findings of this preliminary study reveal the potential of blood-based detection of CRC by quantification of histone methylation marks and the additive effect of the marker combination.

  20. Three-dimensional multispectral optoacoustic mesoscopy reveals melanin and blood oxygenation in human skin in vivo.

    Science.gov (United States)

    Schwarz, Mathias; Buehler, Andreas; Aguirre, Juan; Ntziachristos, Vasilis

    2016-01-01

    Optical imaging plays a major role in disease detection in dermatology. However, current optical methods are limited by lack of three-dimensional detection of pathophysiological parameters within skin. It was recently shown that single-wavelength optoacoustic (photoacoustic) mesoscopy resolves skin morphology, i.e. melanin and blood vessels within epidermis and dermis. In this work we employed illumination at multiple wavelengths for enabling three-dimensional multispectral optoacoustic mesoscopy (MSOM) of natural chromophores in human skin in vivo operating at 15-125 MHz. We employ a per-pulse tunable laser to inherently co-register spectral datasets, and reveal previously undisclosed insights of melanin, and blood oxygenation in human skin. We further reveal broadband absorption spectra of specific skin compartments. We discuss the potential of MSOM for label-free visualization of physiological biomarkers in skin in vivo.

  1. Challenges for red blood cell biomarker discovery through proteomics

    NARCIS (Netherlands)

    Barasa, B.A.; Slijper, M.

    2014-01-01

    Red blood cells are rather unique body cells, since they have lost all organelles when mature, which results in lack of potential to replace proteins that have lost their function. They maintain only a few pathways for obtaining energy and reducing power for the key functions they need to fulfill. T

  2. Detecting Blood-Based Biomarkers in Metastatic Breast Cancer: A Systematic Review of Their Current Status and Clinical Utility

    Science.gov (United States)

    Berghuis, A. M. Sofie; Koffijberg, Hendrik; Prakash, Jai; Terstappen, Leon W. M. M.; IJzerman, Maarten J.

    2017-01-01

    Reviews on circulating biomarkers in breast cancer usually focus on one single biomarker or a selective group of biomarkers. An overview summarizing the discovery and evaluation of all blood-based biomarkers in metastatic breast cancer is lacking. This systematic review aims to identify the available evidence of known blood-based biomarkers in metastatic breast cancer, regarding their clinical utility and state-of-the-art position in the validation process. The initial search yielded 1078 original studies, of which 420 were assessed for eligibility. A total of 320 studies were included in the final synthesis. A Development, Evaluation and Application Chart (DEAC) of all biomarkers was developed. Most studies focus on identifying new biomarkers and search for relations between these biomarkers and traditional molecular characteristics. Biomarkers are usually investigated in only one study (68.8%). Only 9.8% of all biomarkers was investigated in more than five studies. Circulating tumor cells, gene expression within tumor cells and the concentration of secreted proteins are the most frequently investigated biomarkers in liquid biopsies. However, there is a lack of studies focusing on identifying the clinical utility of these biomarkers, by which the additional value still seems to be limited according to the investigated evidence. PMID:28208771

  3. [Development of microchips for the analysis of biomarkers in blood].

    Science.gov (United States)

    Kataoka, Masatoshi; Abe, Kaori; Hashimoto, Yoshiko; Yamamura, Shohei; Yatsushiro, Shouki

    2012-11-01

    Several types of microchips have been developed for application in clinical diagnosis. A microchip made of cyclic olefin copolymer with straight microchannels (300 microm width and 100 microm depth) was employed for sandwich ELISA for the determination of serum type I C-peptide (PICP), a biomarker of osteoporosis. This assay enabled us to determine PICP with accuracy and high sensitivity, reducing the time for the immunoassay to 1/6, and the consumption of samples and reagents to 1/50 compared with the conventional method. Furthermore, cell microarray chips with 20,944 microchambers (105 microm width and 50 microm depth), made of polystyrene, were employed for malaria diagnosis and the detection of carcinoma cells among the leukocytes. Around 100 erythrocytes or leukocytes were accommodated in each microchamber with the formation of a monolayer. For malaria diagnosis, it offered 10-100 times higher sensitivity in the detection of malaria infected erythrocytes than conventional light microscopy, and easy operation within 15 min. By double staining for epithelial cells on the cell microarray chip, one carcinoma cell could be detected among 1,800,000 leukocytes. These results indicate the potential of microchips for clinic diagnosis.

  4. MicroRNA biomarkers in whole blood for detection of pancreatic cancer

    DEFF Research Database (Denmark)

    Schultz, Nicolai A; Dehlendorff, Christian; Jensen, Benny V

    2014-01-01

    IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis. OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels...... of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9). DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC...... (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer...

  5. Peripheral blood neutrophilia as a biomarker of ozone-induced pulmonary inflammation.

    Directory of Open Access Journals (Sweden)

    Jenny A Bosson

    Full Text Available BACKGROUND: Ozone concentrations are predicted to increase over the next 50 years due to global warming and the increased release of precursor chemicals. It is therefore urgent that good, reliable biomarkers are available to quantify the toxicity of this pollutant gas at the population level. Such a biomarker would need to be easily performed, reproducible, economically viable, and reflective of ongoing pathological processes occurring within the lung. METHODOLOGY: We examined whether blood neutrophilia occurred following a controlled ozone challenge and addressed whether this could serve as a biomarker for ozone-induced airway inflammation. Three separate groups of healthy subjects were exposed to ozone (0.2 ppm, 2h and filtered air (FA on two separate occasions. Peripheral blood samples were collected and bronchoscopy with biopsy sampling and lavages was performed at 1.5h post exposures in group 1 (n=13, at 6h in group 2 (n=15 and at 18h in group 3 (n=15. Total and differential cell counts were assessed in blood, bronchial tissue and airway lavages. RESULTS: In peripheral blood, we observed fewer neutrophils 1.5h after ozone compared with the parallel air exposure (-1.1±1.0x10(9 cells/L, p<0.01, at 6h neutrophil numbers were increased compared to FA (+1.2±1.3x10(9 cells/L, p<0.01, and at 18h this response had fully attenuated. Ozone induced a peak in neutrophil numbers at 6h post exposure in all compartments examined, with a positive correlation between the response in blood and bronchial biopsies. CONCLUSIONS: These data demonstrate a systemic neutrophilia in healthy subjects following an acute ozone exposure, which mirrors the inflammatory response in the lung mucosa and lumen. This relationship suggests that blood neutrophilia could be used as a relatively simple functional biomarker for the effect of ozone on the lung.

  6. Reference range of blood biomarkers for oxidative stress in Thoroughbred racehorses (2–5 years old)

    Science.gov (United States)

    KUSANO, Kanichi; YAMAZAKI, Masahiko; KIUCHI, Masataka; KANEKO, Kouki; KOYAMA, Katsuhiro

    2016-01-01

    ABSTRACT The oxidant and antioxidant equilibrium is known to play an important role in equine medicine and equine exercise physiology. There are abundant findings in this field; however, not many studies have been conducted for reference ranges of oxidative stress biomarkers in horses. This study was conducted to determine the reference values of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) using blood samples from 372 (191 males, 181 females) Thoroughbred racehorse aged 2 to 5 (3.43 ± 1.10 (mean ± SD)) years old. There were obvious gender differences in oxidative biomarkers, and growth/age-related changes were observed especially in females. Gender and age must be considered when interpreting obtained oxidative stress biomarkers for diagnosis of disease or fitness alterations in Thoroughbred racehorses. PMID:27703408

  7. Data-driven asthma endotypes defined from blood biomarker and gene expression data.

    Directory of Open Access Journals (Sweden)

    Barbara Jane George

    Full Text Available The diagnosis and treatment of childhood asthma is complicated by its mechanistically distinct subtypes (endotypes driven by genetic susceptibility and modulating environmental factors. Clinical biomarkers and blood gene expression were collected from a stratified, cross-sectional study of asthmatic and non-asthmatic children from Detroit, MI. This study describes four distinct asthma endotypes identified via a purely data-driven method. Our method was specifically designed to integrate blood gene expression and clinical biomarkers in a way that provides new mechanistic insights regarding the different asthma endotypes. For example, we describe metabolic syndrome-induced systemic inflammation as an associated factor in three of the four asthma endotypes. Context provided by the clinical biomarker data was essential in interpreting gene expression patterns and identifying putative endotypes, which emphasizes the importance of integrated approaches when studying complex disease etiologies. These synthesized patterns of gene expression and clinical markers from our research may lead to development of novel serum-based biomarker panels.

  8. Blood-Based Biomarkers for Lung Cancer Early Detection and Evaluation of CT-Based Lesions

    Science.gov (United States)

    2013-12-01

    normal bronchial epithelia from patients with NSCLC as well as in one high-risk patient with chronic obstructive pulmonary disease (Figure 3c...high-risk chronic obstructive pulmonary disease (COPD) patient is indicated (*), and positive (H1395) and negative (HCC-2935) controls are shown. EYA4...Cancer, Early Detection, MicroRNA , Gene expression, Genomics, Blood test, Biomarkers 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT

  9. Signatures of reproductive events on blood counts and biomarkers of inflammation: Implications for chronic disease risk

    Science.gov (United States)

    2017-01-01

    Whether inflammation mediates how reproductive events affect chronic-disease risk is unclear. We studied inflammatory biomarkers in the context of reproductive events using National Health and Nutrition Examination Survey (NHANES) data. From 15,986 eligible women from the 1999–2011 data cycles, we accessed information on reproductive events, blood counts, C-reactive protein (CRP), and total homocysteine (tHCY). We calculated blood-count ratios including: platelet-lymphocyte (PLR), lymphocyte-monocyte (LMR), platelet-monocyte (PMR), and neutrophil-monocyte (NMR). Using sampling weights per NHANES guidelines, means for counts, ratios, or biomarkers by reproductive events were compared using linear regression. We performed trend tests and calculated p-values with partial sum of squares F-tests. Higher PLR and lower LMR were associated with nulliparity. In postmenopausal women, lower PMR was associated with early age at first birth and higher NMR with later age at and shorter interval since last birth. Lower PNR and higher neutrophils and tHCY were associated with early natural menopause. In all women, the neutrophil count correlated positively with CRP; but, in premenopausal women, correlated inversely with tHCY. Reproductive events leave residual signatures on blood counts and inflammatory biomarkers that could underlie their links to chronic disease risk. PMID:28234958

  10. Integrative Genomic Data Mining for Discovery of Potential Blood-Borne Biomarkers for Early Diagnosis of Cancer

    OpenAIRE

    Yongliang Yang; Pavel Pospisil; Iyer, Lakshmanan K.; S. James Adelstein; Amin I. Kassis

    2008-01-01

    BACKGROUND: With the arrival of the postgenomic era, there is increasing interest in the discovery of biomarkers for the accurate diagnosis, prognosis, and early detection of cancer. Blood-borne cancer markers are favored by clinicians, because blood samples can be obtained and analyzed with relative ease. We have used a combined mining strategy based on an integrated cancer microarray platform, Oncomine, and the biomarker module of the Ingenuity Pathways Analysis (IPA) program to identify po...

  11. Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood

    Science.gov (United States)

    de Araujo, Leonardo S.; Vaas, Lea A. I.; Ribeiro-Alves, Marcelo; Geffers, Robert; Mello, Fernanda C. Q.; de Almeida, Alexandre S.; Moreira, Adriana da S. R.; Kritski, Afrânio L.; Lapa e Silva, José R.; Moraes, Milton O.; Pessler, Frank; Saad, Maria H. F.

    2016-01-01

    Lately, much effort has been made to find mRNA biomarkers for tuberculosis (TB) disease/infection with microarray-based approaches. In a pilot investigation, through RNA sequencing technology, we observed a prominent modulation of DOCK9, EPHA4, and NPC2 mRNA abundance in the blood of TB patients. To corroborate these findings, independent validations were performed in cohorts from different areas. Gene expression levels in blood were evaluated by quantitative real-time PCR (Brazil, n = 129) or reanalysis of public microarray data (UK: n = 96; South Africa: n = 51; Germany: n = 26; and UK/France: n = 63). In the Brazilian cohort, significant modulation of all target-genes was observed comparing TB vs. healthy recent close TB contacts (rCt). With a 92% specificity, NPC2 mRNA high expression (NPC2high) showed the highest sensitivity (85%, 95% CI 65%–96%; area under the ROC curve [AUROC] = 0.88), followed by EPHA4 (53%, 95% CI 33%–73%, AUROC = 0.73) and DOCK9 (19%, 95% CI 7%–40%; AUROC = 0.66). All the other reanalyzed cohorts corroborated the potential of NPC2high as a biomarker for TB (sensitivity: 82–100%; specificity: 94–97%). An NPC2high profile was also observed in 60% (29/48) of the tuberculin skin test positive rCt, and additional follow-up evaluation revealed changes in the expression levels of NPC2 during the different stages of Mycobacterium tuberculosis infection, suggesting that further studies are needed to evaluate modulation of this gene during latent TB and/or progression to active disease. Considering its high specificity, our data indicate, for the first time, that NPC2high might serve as an accurate single-gene biomarker for TB. PMID:27826286

  12. Whole Blood RNA as a Source of Transcript-Based Nutrition- and Metabolic Health-Related Biomarkers

    Science.gov (United States)

    Petrov, Petar D.; Bonet, M. Luisa; Reynés, Bárbara; Oliver, Paula; Palou, Andreu; Ribot, Joan

    2016-01-01

    Blood cells are receiving an increasing attention as an easily accessible source of transcript-based biomarkers. We studied the feasibility of using mouse whole blood RNA in this context. Several paradigms were studied: (i) metabolism-related transcripts known to be affected in rat tissues and peripheral blood mononuclear cells (PBMC) by fasting and upon the development of high fat diet (HFD)-induced overweight were assessed in whole blood RNA of fasted rats and mice and of HFD-fed mice; (ii) retinoic acid (RA)-responsive genes in tissues were assessed in whole blood RNA of control and RA-treated mice; (iii) lipid metabolism-related transcripts previously identified in PBMC as potential biomarkers of metabolic health in a rat model were assessed in whole blood in an independent model, namely retinoblastoma haploinsufficient (Rb+/-) mice. Blood was collected and stored in RNAlater® at -80°C until analysis of selected transcripts by real-time RT-PCR. Comparable changes with fasting were detected in the expression of lipid metabolism-related genes when RNA from either PBMC or whole blood of rats or mice was used. HFD-induced excess body weight and fat mass associated with expected changes in the expression of metabolism-related genes in whole blood of mice. Changes in gene expression in whole blood of RA-treated mice reproduced known transcriptional actions of RA in hepatocytes and adipocytes. Reduced expression of Fasn, Lrp1, Rxrb and Sorl1 could be validated as early biomarkers of metabolic health in young Rb+/- mice using whole blood RNA. Altogether, these results support the use of whole blood RNA in studies aimed at identifying blood transcript-based biomarkers of nutritional/metabolic status or metabolic health. Results also support reduced expression of Fasn, Lrp1, Rxrb and Sorl1 in blood cells at young age as potential biomarkers of metabolic robustness. PMID:27163124

  13. Candidate gene networks and blood biomarkers of methamphetamine-associated psychosis: an integrative RNA-sequencing report

    Science.gov (United States)

    Breen, M S; Uhlmann, A; Nday, C M; Glatt, S J; Mitt, M; Metsalpu, A; Stein, D J; Illing, N

    2016-01-01

    The clinical presentation, course and treatment of methamphetamine (METH)-associated psychosis (MAP) are similar to that observed in schizophrenia (SCZ) and subsequently MAP has been hypothesized as a pharmacological and environmental model of SCZ. However, several challenges currently exist in diagnosing MAP accurately at the molecular and neurocognitive level before the MAP model can contribute to the discovery of SCZ biomarkers. We directly assessed subcortical brain structural volumes and clinical parameters of MAP within the framework of an integrative genome-wide RNA-Seq blood transcriptome analysis of subjects diagnosed with MAP (N=10), METH dependency without psychosis (MA; N=10) and healthy controls (N=10). First, we identified discrete groups of co-expressed genes (that is, modules) and tested them for functional annotation and phenotypic relationships to brain structure volumes, life events and psychometric measurements. We discovered one MAP-associated module involved in ubiquitin-mediated proteolysis downregulation, enriched with 61 genes previously found implicated in psychosis and SCZ across independent blood and post-mortem brain studies using convergent functional genomic (CFG) evidence. This module demonstrated significant relationships with brain structure volumes including the anterior corpus callosum (CC) and the nucleus accumbens. Furthermore, a second MAP and psychoticism-associated module involved in circadian clock upregulation was also enriched with 39 CFG genes, further associated with the CC. Subsequently, a machine-learning analysis of differentially expressed genes identified single blood-based biomarkers able to differentiate controls from methamphetamine dependents with 87% accuracy and MAP from MA subjects with 95% accuracy. CFG evidence validated a significant proportion of these putative MAP biomarkers in independent studies including CLN3, FBP1, TBC1D2 and ZNF821 (RNA degradation), ELK3 and SINA3 (circadian clock) and PIGF and

  14. Identification of biomarkers for cervical cancer in peripheral blood lymphocytes using oligonucleotide microarrays

    Institute of Scientific and Technical Information of China (English)

    SHENG Jie; ZHANG Wei-yuan

    2010-01-01

    Background Oligonucleotide microarrays are increasingly being used to identify gene expression profiles that associated with complex genetic diseases. Peripheral lymphocytes communicate with cells and extracellular matrixes in almost all tissues and organs in human body, suggesting that the gene expression profiles in peripheral lymphocytes may reflect the presence of disease in the body. This study aimed to identify molecular biomarkers for cervical cancer in peripheral blood lymphocytes by using oligonucleotide microarrays.Methods Total RNA was extracted from peripheral blood lymphocytes of 24 early stage cervical cancer patients and 18 healthy controls. We used 22K Human Genome microarrays to profile peripheral blood lymphocytes from 4 early stage cervical cancer patients and compared their gene expression profiles with those from 3 healthy controls. Differentially expressed genes would be identified if they had adjusted P values of less than 0.05 and a groupwise average fold change greater than 1.5 or less than 0.67. Then the selected 5 genes were validated in the remaining 20 early stage cervical cancer patients and the 15 healthy controls by using real-time reverse-transcription polymerase chain reaction (RT-PCR).Results Genes identified by the gene selection program expressed differently between the blood samples of the early stage cervical cancer patients and those of the healthy controls. To validate the gene expression data, 5 genes were analyzed by real-time RT-PCR. In three of the 5 identified genes, tenasin-c (TNC), nuceolin (NCL), and enolase 2 (ENO2) showed a significant up-regulation in the blood samples of the early stage cervical cancer patients versus that of the healthy controls.Conclusions The up-regulation of TNC, NCL, and ENO2 in peripheral blood may be used to identify novel blood biomarkers for detecting cervical cancer in a clinically accessible surrogate tissue, and thus to provide a possibility to develop a noninvasive and predictive

  15. Carbon sources in the Beaufort Sea revealed by molecular lipid biomarkers and compound specific isotope analysis

    Science.gov (United States)

    Tolosa, I.; Fiorini, S.; Gasser, B.; Martín, J.; Miquel, J. C.

    2012-10-01

    Molecular lipid biomarkers (hydrocarbons, alcohols, sterols and fatty acids) and compound specific isotope analysis of suspended particulate organic matter (SPM) and surface sediments of the Mackenzie Shelf and slope (Southeast Beaufort Sea, Arctic Ocean), were studied in summer 2009. The concentrations of the molecular lipid markers, characteristic of known organic matter sources, were grouped and used as proxies to evaluate the relative importance of fresh algal, detrital algal, fossil, C3 terrestrial plants, bacterial and zooplankton material in the sedimentary organic matter (OM). Fossil and detrital algal contributions were the major fractions of the freshwater SPM from the Mackenzie River with ~34% each of the total molecular biomarkers. Fresh algal, C3 terrestrial, bacterial and zooplanktonic components represented much lower percentages, 17, 10, 4 and 80%) with a minor contribution of fossil and C3 terrestrial biomarkers. Characterization of the sediments revealed a major sink of refractory algal material mixed with some fresh algal material, fossil hydrocarbons and a small input of C3 terrestrial sources. In particular, the sediments from the shelf and at the mouth of the Amundsen Gulf presented the highest contribution of detrital algal material (60-75%) whereas those from the slope contained the highest proportion of fossil (40%) and C3 terrestrial plant material (10%). Overall, considering that the detrital algal material is marine derived, autochthonous sources contributed more than allochthonous sources to the OM lipid pool. Using the ratio of an allochthonous biomarker (normalized to total organic carbon, TOC) found in the sediments to those measured at the river mouth water, we estimated that the fraction of terrestrial material preserved in the sediments accounted for 30-40% of the total carbon in the inner shelf sediments, 17% in the outer shelf and Amundsen Gulf and up to 25% in the slope sediments.

  16. Relative value of diverse brain MRI and blood-based biomarkers for predicting cognitive decline in the elderly

    Science.gov (United States)

    Madsen, Sarah K.; Ver Steeg, Greg; Daianu, Madelaine; Mezher, Adam; Jahanshad, Neda; Nir, Talia M.; Hua, Xue; Gutman, Boris A.; Galstyan, Aram; Thompson, Paul M.

    2016-03-01

    Cognitive decline accompanies many debilitating illnesses, including Alzheimer's disease (AD). In old age, brain tissue loss also occurs along with cognitive decline. Although blood tests are easier to perform than brain MRI, few studies compare brain scans to standard blood tests to see which kinds of information best predict future decline. In 504 older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we first used linear regression to assess the relative value of different types of data to predict cognitive decline, including 196 blood panel biomarkers, 249 MRI biomarkers obtained from the FreeSurfer software, demographics, and the AD-risk gene APOE. A subset of MRI biomarkers was the strongest predictor. There was no specific blood marker that increased predictive accuracy on its own, we found that a novel unsupervised learning method, CorEx, captured weak correlations among blood markers, and the resulting clusters offered unique predictive power.

  17. A practical platform for blood biomarker study by using global gene expression profiling of peripheral whole blood.

    Directory of Open Access Journals (Sweden)

    Ze Tian

    Full Text Available BACKGROUND: Although microarray technology has become the most common method for studying global gene expression, a plethora of technical factors across the experiment contribute to the variable of genome gene expression profiling using peripheral whole blood. A practical platform needs to be established in order to obtain reliable and reproducible data to meet clinical requirements for biomarker study. METHODS AND FINDINGS: We applied peripheral whole blood samples with globin reduction and performed genome-wide transcriptome analysis using Illumina BeadChips. Real-time PCR was subsequently used to evaluate the quality of array data and elucidate the mode in which hemoglobin interferes in gene expression profiling. We demonstrated that, when applied in the context of standard microarray processing procedures, globin reduction results in a consistent and significant increase in the quality of beadarray data. When compared to their pre-globin reduction counterparts, post-globin reduction samples show improved detection statistics, lowered variance and increased sensitivity. More importantly, gender gene separation is remarkably clearer in post-globin reduction samples than in pre-globin reduction samples. Our study suggests that the poor data obtained from pre-globin reduction samples is the result of the high concentration of hemoglobin derived from red blood cells either interfering with target mRNA binding or giving the pseudo binding background signal. CONCLUSION: We therefore recommend the combination of performing globin mRNA reduction in peripheral whole blood samples and hybridizing on Illumina BeadChips as the practical approach for biomarker study.

  18. Contaminant concentrations, biochemical and hematological biomarkers in blood of West Indian manatees Trichechus manatus from Brazil.

    Science.gov (United States)

    Anzolin, D G; Sarkis, J E S; Diaz, E; Soares, D G; Serrano, I L; Borges, J C G; Souto, A S; Taniguchi, S; Montone, R C; Bainy, A C D; Carvalho, P S M

    2012-07-01

    The West Indian manatee Trichechus manatus is threatened with extinction in Brazil, and this study focused on nondestructive blood samples analyzed for metals, polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), as well as biochemical and hematological biomarkers. Studied manatees were kept at Projeto Peixe-Boi headquarters in Pernambuco State, and at two natural areas in estuaries where they are released to the wild. Manatees kept at the natural estuary in Paraiba State have blood concentrations of Al, Pb, Cd, Sn that are 11, 7, 8 and 23 times greater, respectively, than the concentrations found in blood of animals from the same species in Florida, USA. An inhibition of butyrylcholinesterase in manatees kept at the two reintroduction sites in Alagoas and Paraiba States indicated possible exposure of the animals to cholinesterase inhibitor insecticides. PCBs and OCPs were not detected. Results from this study will help delineate conservation efforts in the region.

  19. Peripheral blood gene expression as a novel genomic biomarker in complicated sarcoidosis.

    Directory of Open Access Journals (Sweden)

    Tong Zhou

    Full Text Available Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ~20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis. Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39 from healthy controls (n = 35, 86% classification accuracy and which served as a molecular signature for complicated sarcoidosis (n = 17. As aberrancies in T cell receptor (TCR signaling, JAK-STAT (JS signaling, and cytokine-cytokine receptor (CCR signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1. In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.

  20. Exposure to fipronil elevates systolic blood pressure and disturbs related biomarkers in plasma of rats.

    Science.gov (United States)

    Chaguri, Joao Leandro; Godinho, Antonio Francisco; Horta, Daniel França; Gonçalves-Rizzi, Victor Hugo; Possomato-Vieira, Jose Sergio; Nascimento, Regina Aparecida; Dias-Junior, Carlos Alan

    2016-03-01

    Recent reports show that fipronil affects non-target organisms, including environmental species populations and potentially humans. We aimed to examine if fipronil exposure affects the systolic blood pressure and related biomarkers. Thus, fipronil was orally administered to rats (30 mg/kg/day) during 15 days (Fipronil group) or physiological solution (Control group). While fipronil increased significantly the systolic blood pressure (158±13 mmHg), no significant changes were observed in Control group (127±3 mmHg). Significantly, higher levels of fipronil in plasma were observed in Fipronil group (0.46±0.09 μg/mL versus 0.17±0.11 μg/mL in Control group). Fipronil group showed lower weight gain compared with Control group. While fipronil resulted in higher concentrations of endothelin-1, reduced antioxidant capacity and lower levels of circulating matrix metalloproteinase 2 (MMP-2) and nitric oxide (NO) metabolites compared to Control group, no alteration was observed in serum biomarkers of renal and hepatic/biliary functional abilities. Therefore, this study suggests that fipronil causes hypertension and endothelin-1 plays a key role. Also, these findings suggest that reductions of both MMP-2 and NO may contribute with the elevation of systolic blood pressure observed with fipronil.

  1. A Minimally-invasive Blood-derived Biomarker of Oligodendrocyte Cell-loss in Multiple Sclerosis.

    Science.gov (United States)

    Olsen, John A; Kenna, Lauren A; Tipon, Regine C; Spelios, Michael G; Stecker, Mark M; Akirav, Eitan M

    2016-08-01

    Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system (CNS). Minimally invasive biomarkers of MS are required for disease diagnosis and treatment. Differentially methylated circulating-free DNA (cfDNA) is a useful biomarker for disease diagnosis and prognosis, and may offer to be a viable approach for understanding MS. Here, methylation-specific primers and quantitative real-time PCR were used to study methylation patterns of the myelin oligodendrocyte glycoprotein (MOG) gene, which is expressed primarily in myelin-producing oligodendrocytes (ODCs). MOG-DNA was demethylated in O4(+) ODCs in mice and in DNA from human oligodendrocyte precursor cells (OPCs) when compared with other cell types. In the cuprizone-fed mouse model of demyelination, ODC derived demethylated MOG cfDNA was increased in serum and was associated with tissue-wide demyelination, demonstrating the utility of demethylated MOG cfDNA as a biomarker of ODC death. Collected sera from patients with active (symptomatic) relapsing-remitting MS (RRMS) demonstrated a higher signature of demethylated MOG cfDNA when compared with patients with inactive disease and healthy controls. Taken together, these results offer a minimally invasive approach to measuring ODC death in the blood of MS patients that may be used to monitor disease progression.

  2. The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

    Science.gov (United States)

    Hays, Chelsea C.; Zlatar, Zvinka Z.; Wierenga, Christina E.

    2017-01-01

    There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer’s disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease-modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment (MCI) and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease. PMID:26898552

  3. Biomarkers Indicative of Blood-Brain Barrier Disruption in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Emmanuelle Waubant

    2006-01-01

    Full Text Available Blood-brain barrier (BBB disruption is one of the hallmarks of multiple sclerosis (MS. It is incompletely understood whether BBB disruption is the initial MS event leading to MS lesion formation or whether it is merely a consequence of cellular infiltration in the central nervous system (CNS. The presence of gadolinium enhancing (Gd+ lesions on serial brain MRI scans is frequently used to evaluate BBB disruption. The presence of Gd enhancement has therefore been used as a reference for most works evaluating promising biomarkers of BBB disruption that are reviewed here. These promising biomarkers include cytokines and chemokines, and their receptors, cell surface markers, and matrix metalloproteinases and their natural inhibitors. At this time, none of these markers have been shown as sensitive as the presence of Gd enhancement to reflect BBB disruption. However, MRI scanning is not only unpractical and expensive; it may also under represent the overall extent of BBB disruption. Developing new MS biomarkers that are sensitive and specific for BBB disruption could 1 improve the monitoring of disease activity; 2 improve the monitoring of response to MS therapies which target BBB disruption; and 3 advance our understanding of dynamic MS processes participating in BBB disruption.

  4. Detection of cervical cancer biomarker patterns in blood plasma and urine by differential scanning calorimetry and mass spectrometry.

    Directory of Open Access Journals (Sweden)

    Nichola C Garbett

    Full Text Available Improved methods for the accurate identification of both the presence and severity of cervical intraepithelial neoplasia (CIN and extent of spread of invasive carcinomas of the cervix (IC are needed. Differential scanning calorimetry (DSC has recently been shown to detect specific changes in the thermal behavior of blood plasma proteins in several diseases. This methodology is being explored to provide a complementary approach for screening of cervical disease. The present study evaluated the utility of DSC in differentiating between healthy controls, increasing severity of CIN and early and advanced IC. Significant discrimination was apparent relative to the extent of disease with no clear effect of demographic factors such as age, ethnicity, smoking status and parity. Of most clinical relevance, there was strong differentiation of CIN from healthy controls and IC, and amongst patients with IC between FIGO Stage I and advanced cancer. The observed disease-specific changes in DSC profiles (thermograms were hypothesized to reflect differential expression of disease biomarkers that subsequently bound to and affected the thermal behavior of the most abundant plasma proteins. The effect of interacting biomarkers can be inferred from the modulation of thermograms but cannot be directly identified by DSC. To investigate the nature of the proposed interactions, mass spectrometry (MS analyses were employed. Quantitative assessment of the low molecular weight protein fragments of plasma and urine samples revealed a small list of peptides whose abundance was correlated with the extent of cervical disease, with the most striking plasma peptidome data supporting the interactome theory of peptide portioning to abundant plasma proteins. The combined DSC and MS approach in this study was successful in identifying unique biomarker signatures for cervical cancer and demonstrated the utility of DSC plasma profiles as a complementary diagnostic tool to evaluate

  5. Comparisons of microRNA patterns in plasma before and after tumor removal reveal new biomarkers of lung squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Vasily N Aushev

    Full Text Available Lung cancer is the major human malignancy, accounting for 30% of all cancer-related deaths worldwide. Poor survival of lung cancer patients, together with late diagnosis and resistance to classic chemotherapy, highlights the need for identification of new biomarkers for early detection. Among different cancer biomarkers, small non-coding RNAs called microRNAs (miRNAs are considered the most promising, owing to their remarkable stability, their cancer-type specificity, and their presence in body fluids. However, results of multiple previous attempts to identify circulating miRNAs specific for lung cancer are inconsistent, likely due to two main reasons: prominent variability in blood miRNA content among individuals and difficulties in distinguishing tumor-relevant miRNAs in the blood from their non-tumor counterparts. To overcome these impediments, we compared circulating miRNA profiles in patients with lung squamous cell carcinoma (SCC before and after tumor removal, assuming that the levels of all tumor-relevant miRNAs would drop after the surgery. Our results revealed a specific panel of the miRNAs (miR-205, -19a, -19b, -30b, and -20a whose levels decreased strikingly in the blood of patients after lung SCC surgery. Interestingly, miRNA profiling of plasma fractions of lung SCC patients revealed high levels of these miRNA species in tumor-specific exosomes; additionally, some of these miRNAs were also found to be selectively secreted to the medium by cultivated lung cancer cells. These results strengthen the notion that tumor cells secrete miRNA-containing exosomes into circulation, and that miRNA profiling of the exosomal plasma fraction may reveal powerful cancer biomarkers.

  6. Association of air pollution sources and aldehydes with biomarkers of blood coagulation, pulmonary inflammation, and systemic oxidative stress.

    Science.gov (United States)

    Altemose, Brent; Robson, Mark G; Kipen, Howard M; Ohman Strickland, Pamela; Meng, Qingyu; Gong, Jicheng; Huang, Wei; Wang, Guangfa; Rich, David Q; Zhu, Tong; Zhang, Junfeng

    2016-07-20

    Using data collected before, during, and after the 2008 Summer Olympic Games in Beijing, this study examines associations between biomarkers of blood coagulation (vWF, sCD62P and sCD40L), pulmonary inflammation (EBC pH, EBC nitrite, and eNO), and systemic oxidative stress (urinary 8-OHdG) with sources of air pollution identified utilizing principal component analysis and with concentrations of three aldehydes of health concern. Associations between the biomarkers and the air pollution source types and aldehydes were examined using a linear mixed effects model, regressing through seven lag days and controlling for ambient temperature, relative humidity, gender, and day of week for the biomarker measurements. The biomarkers for pulmonary inflammation, particularly EBC pH and eNO, were most consistently associated with vehicle and industrial combustion, oil combustion, and vegetative burning. The biomarkers for blood coagulation, particularly vWF and sCD62p, were most consistently associated with oil combustion. Systemic oxidative stress biomarker (8-OHdG) was most consistently associated with vehicle and industrial combustion. The associations of the biomarkers were generally not significant or consistent with secondary formation of pollutants and with the aldehydes. The findings support policies to control anthropogenic pollution sources rather than natural soil or road dust from a cardio-respiratory health standpoint.Journal of Exposure Science and Environmental Epidemiology advance online publication, 20 July 2016; doi:10.1038/jes.2016.38.

  7. Inflammation in low back pain may be detected from the peripheral blood: suggestions for biomarker.

    Science.gov (United States)

    Li, Yong; Liu, Jun; Liu, Zong-Zhi; Duan, Da-Peng

    2016-08-01

    Biomarker for prediction of development of low back pain, and disease progression in chronic conditions are virtually non-existent. In the present study, we examined evidence of inflammation in the peripheral blood and demonstrated significant changes in neuroinflammation markers in subjects with chronic low back pain in comparison with control subjects. The present study was performed using peripheral blood from subjects with chronic low back pain and age-matched control subjects. Western blotting, real-time RT-PCR, cell culture and in vitro assays were incorporated to perform the current study. We obtained evidence that the balance between proinflammatory and anti-inflammatory cytokines is misaligned, with decrease in interleukin-10 (IL-10) expression and increase in interleukin-6 (IL-6) expression. Furthermore, we demonstrated increase in CD16 monocyte expression. Cells were cultured under differential conditions to generate M1/M2 macrophages. In the macrophages, opioid secretory capacity was shown to be diminished. Finally, Dragon (repulsive guidance molecule b, RGMb) expression was shown diminished in M1 macrophages, which serves as a key transcriptional inhibitor of IL-6 expression. These biochemical and cellular alterations in chronic low back pain can serve as potential biomarkers for assessing disease initiation, intensity and progression.

  8. Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes

    DEFF Research Database (Denmark)

    Bacos, Karl; Gillberg, Linn; Volkov, Petr;

    2016-01-01

    Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA...... methylation genome-wide in islets from 87 non-diabetic donors, aged 26-74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes...... demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D....

  9. Blood transcriptomic biomarkers in adult primary care patients with major depressive disorder undergoing cognitive behavioral therapy.

    Science.gov (United States)

    Redei, E E; Andrus, B M; Kwasny, M J; Seok, J; Cai, X; Ho, J; Mohr, D C

    2014-09-16

    An objective, laboratory-based diagnostic tool could increase the diagnostic accuracy of major depressive disorders (MDDs), identify factors that characterize patients and promote individualized therapy. The goal of this study was to assess a blood-based biomarker panel, which showed promise in adolescents with MDD, in adult primary care patients with MDD and age-, gender- and race-matched nondepressed (ND) controls. Patients with MDD received cognitive behavioral therapy (CBT) and clinical assessment using self-reported depression with the Patient Health Questionnaire-9 (PHQ-9). The measures, including blood RNA collection, were obtained before and after 18 weeks of CBT. Blood transcript levels of nine markers of ADCY3, DGKA, FAM46A, IGSF4A/CADM1, KIAA1539, MARCKS, PSME1, RAPH1 and TLR7, differed significantly between participants with MDD (N=32) and ND controls (N=32) at baseline (qdepressed. Thus, blood levels of different transcript panels may identify the depressed from the nondepressed among primary care patients, during a depressive episode or in remission, or follow and predict response to CBT in depressed individuals.

  10. Integrative genomic data mining for discovery of potential blood-borne biomarkers for early diagnosis of cancer.

    Directory of Open Access Journals (Sweden)

    Yongliang Yang

    Full Text Available BACKGROUND: With the arrival of the postgenomic era, there is increasing interest in the discovery of biomarkers for the accurate diagnosis, prognosis, and early detection of cancer. Blood-borne cancer markers are favored by clinicians, because blood samples can be obtained and analyzed with relative ease. We have used a combined mining strategy based on an integrated cancer microarray platform, Oncomine, and the biomarker module of the Ingenuity Pathways Analysis (IPA program to identify potential blood-based markers for six common human cancer types. METHODOLOGY/PRINCIPAL FINDINGS: In the Oncomine platform, the genes overexpressed in cancer tissues relative to their corresponding normal tissues were filtered by Gene Ontology keywords, with the extracellular environment stipulated and a corrected Q value (false discovery rate cut-off implemented. The identified genes were imported to the IPA biomarker module to separate out those genes encoding putative secreted or cell-surface proteins as blood-borne (blood/serum/plasma cancer markers. The filtered potential indicators were ranked and prioritized according to normalized absolute Student t values. The retrieval of numerous marker genes that are already clinically useful or under active investigation confirmed the effectiveness of our mining strategy. To identify the biomarkers that are unique for each cancer type, the upregulated marker genes that are in common between each two tumor types across the six human tumors were also analyzed by the IPA biomarker comparison function. CONCLUSION/SIGNIFICANCE: The upregulated marker genes shared among the six cancer types may serve as a molecular tool to complement histopathologic examination, and the combination of the commonly upregulated and unique biomarkers may serve as differentiating markers for a specific cancer. This approach will be increasingly useful to discover diagnostic signatures as the mass of microarray data continues to grow in the

  11. Potential Epigenetic Biomarkers of Obesity Related Insulin Resistance in Human Whole-blood.

    Science.gov (United States)

    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

    2017-01-20

    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; qobese compared to lean participants. We identified two 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 in 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 two 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 ± 0.10 vs. obese 0.18 ± 0

  12. Altered Blood Biomarker Profiles in Athletes with a History of Repetitive Head Impacts.

    Directory of Open Access Journals (Sweden)

    Alex P Di Battista

    Full Text Available The long-term health effects of concussion and sub-concussive impacts in sport are unknown. Growing evidence suggests both inflammation and neurodegeneration are pivotal to secondary injury processes and the etiology of neurodegenerative diseases. In the present study we characterized circulating brain injury and inflammatory mediators in healthy male and female athletes according to concussion history and collision sport participation. Eighty-seven university level athletes (male, n = 60; female, n = 27 were recruited before the start of the competitive season. Athletes were healthy at the time of the study (no medications, illness, concussion or musculoskeletal injuries. Dependent variables included 29 inflammatory and 10 neurological injury analytes assessed in the peripheral blood by immunoassay. Biomarkers were statistically evaluated using partial least squares multivariate analysis to identify possible relationships to self-reported previous concussion history, number of previous concussions and collision sport participation in male and female athletes. Multiple concussions were associated with increases in peripheral MCP-1 in females, and MCP-4 in males. Collision sport participation was associated with increases in tau levels in males. These results are consistent with previous experimental and clinical findings that suggest ongoing inflammatory and cerebral injury processes after repetitive mild head trauma. However, further validation is needed to correlate systemic biomarkers to repetitive brain impacts, as opposed to the extracranial effects common to an athletic population such as exercise and muscle damage.

  13. Use of blood based biomarkers in the evaluation of Crohn’s disease and ulcerative colitis

    Institute of Scientific and Technical Information of China (English)

    Edward; L; Barnes; Choong-Chin; Liew; Samuel; Chao; Robert; Burakoff

    2015-01-01

    Despite significant improvements in our understanding of Crohn’s disease(CD) and ulcerative colitis(UC) in recent years, questions remain regarding the best approaches to assessment and management of these chronic diseases during periods of both relapse and remission. Various serologic biomarkers have been used in the evaluation of patients with both suspected and documented inflammatory bowel disease(IBD), and while each has potential utility in the assessment of patients with IBD, potential limitation remain with each method of assessment. Given these potential shortcomings, there has been increased interest in other means of evaluation of patients with IBD, including an expanding interest in the role of gene expression profiling. Among patients with IBD, gene expression profiles obtained from whole blood have been used to differentiate active from inactive CD, as well as to differentiate between CD, UC, and non-inflammatory diarrheal conditions. There are many opportunities for a non-invasive, blood based test to aid in the assessment of patients with IBD, particularly when considering more invasive means of evaluation including endoscopy with biopsy. Furthermore, as the emphasis on personalized medicine continues to increase, the potential ability of gene expression analysis to predict patient response to individual therapies offers great promise. While whole blood gene expression analysis may not completely replace more traditional means of evaluating patients with suspected or known IBD, it does offer significant potential to expand our knowledge of the underlying genes involved in the development of these diseases.

  14. A composite peripheral blood gene expression measure as a potential diagnostic biomarker in bipolar disorder

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Peijs, L; Vinberg, M

    2015-01-01

    as a diagnostic and state biomarker in bipolar disorder. First, messenger RNA levels of 19 candidate genes were assessed in peripheral blood mononuclear cells of 37 rapid cycling bipolar disorder patients in different affective states (depression, mania and euthymia) during a 6-12-month period and in 40 age......- and gender-matched healthy control subjects. Second, a composite gene expression measure was constructed in the first half study sample and independently validated in the second half of the sample. We found downregulation of POLG and OGG1 expression in bipolar disorder patients compared with healthy control...... subjects. In patients with bipolar disorder, upregulation of NDUFV2 was observed in a depressed state compared with a euthymic state. The composite gene expression measure for discrimination between patients and healthy control subjects on the basis of 19 genes generated an area under the receiver...

  15. An integrated approach to blood-based cancer diagnosis and biomarker discovery.

    Science.gov (United States)

    Min, Martin Renqiang; Chowdhury, Salim; Qi, Yanjun; Stewart, Alex; Ostroff, Rachel

    2014-01-01

    Disrupted or abnormal biological processes responsible for cancers often quantitatively manifest as disrupted additive and multiplicative interactions of gene/protein expressions correlating with cancer progression. However, the examination of all possible combinatorial interactions between gene features in most case-control studies with limited training data is computationally infeasible. In this paper, we propose a practically feasible data integration approach, QUIRE (QUadratic Interactions among infoRmative fEatures), to identify discriminative complex interactions among informative gene features for cancer diagnosis and biomarker discovery directly based on patient blood samples. QUIRE works in two stages, where it first identifies functionally relevant gene groups for the disease with the help of gene functional annotations and available physical protein interactions, then it explores the combinatorial relationships among the genes from the selected informative groups. Based on our private experimentally generated data from patient blood samples using a novel SOMAmer (Slow Off-rate Modified Aptamer) technology, we apply QUIRE to cancer diagnosis and biomarker discovery for Renal Cell Carcinoma (RCC) and Ovarian Cancer (OVC). To further demonstrate the general applicability of our approach, we also apply QUIRE to a publicly available Colorectal Cancer (CRC) dataset that can be used to prioritize our SOMAmer design. Our experimental results show that QUIRE identifies gene-gene interactions that can better identify the different cancer stages of samples, as compared to other state-of-the-art feature selection methods. A literature survey shows that many of the interactions identified by QUIRE play important roles in the development of cancer.

  16. Umbilical cord blood biomarkers of neurologic injury and the risk of cerebral palsy or infant death.

    Science.gov (United States)

    Costantine, Maged M; Weiner, Steven J; Rouse, Dwight J; Hirtz, Deborah G; Varner, Michael W; Spong, Catherine Y; Mercer, Brian M; Iams, Jay D; Wapner, Ronald J; Sorokin, Yoram; Thorp, John M; Ramin, Susan M; O'Sullivan, Mary J; Peaceman, Alan M; Simhan, Hyagriv N

    2011-12-01

    To evaluate the association between cerebral palsy (CP) or infant death and putative cord blood biomarkers of neurologic injury, we performed a nested case-control secondary analysis of a multicenter randomized trial of magnesium sulfate (MgSO(4)) versus placebo to prevent CP or death among offspring of women with anticipated delivery from 24 to 31 weeks' gestation. Cases were infants who died by 1 year (n=25) or developed CP (n=16), and were matched 1:2 to a control group (n=82) that survived without developing CP. Umbilical cord sera concentrations of S100B, neuron-specific enolase (NSE) and the total soluble form of the receptor for advanced glycation end-products (sRAGE) were measured by ELISA in duplicates. Maternal characteristics were similar between the 2 groups. Cases were born at a lower gestational age (GA) and had lower birth weight compared with controls. There were no differences in concentrations of the three biomarkers and the composite outcome of CP or infant death. However, S100B was higher (median 847.3 vs. 495.7 pg/ml; P=0.03) in infants who had CP and total sRAGE was lower (median 1259.3 vs. 1813.1 pg/ml; P=0.02) in those who died compared with the control group. When corrected for delivery GA and treatment group, both differences lost statistical significance. In conclusion, cord blood S100B level may be associated with CP, but this association was not significant after controlling for GA and MgSO(4) treatment.

  17. Biomarker Analysis Revealed Distinct Profiles of Innate and Adaptive Immunity in Infants with Ocular Lesions of Congenital Toxoplasmosis

    Science.gov (United States)

    Machado, Anderson Silva; Carneiro, Ana Carolina Aguiar Vasconcelos; Béla, Samantha Ribeiro; Andrade, Gláucia Manzan Queiroz; Vasconcelos-Santos, Daniel Vitor; Januário, José Nélio; Coelho-dos-Reis, Jordana G.; Ferro, Eloisa Amália Vieira; Teixeira-Carvalho, Andréa; Vitor, Ricardo Wagner Almeida; Martins-Filho, Olindo Assis; —UFMG-CTBG, UFMG Congenital Toxoplasmosis Brazilian Group

    2014-01-01

    Toxoplasma gondii is the main infectious cause of human posterior retinochoroiditis, the most frequent clinical manifestation of congenital toxoplasmosis. This investigation was performed after neonatal screening to identify biomarkers of immunity associated with immunopathological features of the disease by flow cytometry. The study included infected infants without NRL and with retinochoroidal lesions (ARL, ACRL, and CRL) as well as noninfected individuals (NI). Our data demonstrated that leukocytosis, with increased monocytes and lymphocytes, was a relevant hematological biomarker of ARL. Immunophenotypic analysis also revealed expansion of CD14+CD16+HLA-DRhigh monocytes and CD56dim cytotoxic NK-cells in ARL. Moreover, augmented TCRγδ+ and CD8+ T-cell counts were apparently good biomarkers of morbidity. Biomarker network analysis revealed that complex and intricated networks underscored the negative correlation of monocytes with NK- and B-cells in NRL. The remarkable lack of connections involving B-cells and a relevant shift of NK-cell connections from B-cells toward T-cells observed in ARL were outstanding. A tightly connected biomarker network was observed in CRL, with relevant connections of NK- and CD8+ T-cells with a broad range of cell subsets. Our findings add novel elements to the current knowledge on the innate and adaptive immune responses in congenital toxoplasmosis. PMID:25328286

  18. Cpt1a gene expression in peripheral blood mononuclear cells as an early biomarker of diet-related metabolic alterations

    KAUST Repository

    Diaz-Rua, Ruben

    2016-11-23

    Background: Research on biomarkers that provide early information about the development of future metabolic alterations is an emerging discipline. Gene expression analysis in peripheral blood mononuclear cells (PBMC) is a promising tool to identify subjects at risk of developing diet-related diseases.

  19. Gene expression analysis in pregnant women and their infants identifies unique fetal biomarkers that circulate in maternal blood

    Science.gov (United States)

    The discovery of fetal mRNA transcripts in the maternal circulation holds great promise for noninvasive prenatal diagnosis. To identify potential fetal biomarkers, we studied whole blood and plasma gene transcripts that were common to 9 term pregnant women and their newborns but absent or reduced in...

  20. A Putative Blood-Based Biomarker for Autism Spectrum Disorder-Associated Ileocolitis

    Science.gov (United States)

    Walker, Stephen J.; Beavers, Daniel P.; Fortunato, John; Krigsman, Arthur

    2016-01-01

    Gastrointestinal symptoms are common in children with autism spectrum disorder (ASD). A significant proportion of children with ASD and gastrointestinal symptoms have histologic evidence of ileocolitis (inflammation of the terminal ileum and/or colon). We previously reported the molecular characterization of gastrointestinal biopsy tissue from ASD children with ileocolitis (ASDIC+) compared to anatomically similar inflamed tissue from typically developing children with inflammatory bowel disease (IBD; i.e. Crohn’s disease or ulcerative colitis) and typically developing children with gastrointestinal symptoms but no evidence of gastrointestinal mucosal inflammation (TDIC−). ASDIC+ children had a gene expression profile that, while primarily overlapping with known IBD, had distinctive differences. The present study confirms these findings and replicates this molecular characterization in a second cohort of cases (ASDIC+) and controls (TDIC−). In these two separate case/control mucosal-based cohorts, we have demonstrated overlap of 59 differentially expressed transcripts (DETs) unique to inflamed ileocolonic tissue from symptomatic ASDIC+ children. We now report that 9 of these 59 transcripts are also differentially expressed in the peripheral blood of the second cohort of ASDIC+ children. This set of transcripts represents a putative blood-based biomarker for ASD-associated ileocolonic inflammation. PMID:27767057

  1. Detection of heart failure-related biomarker in whole blood with graphene field effect transistor biosensor.

    Science.gov (United States)

    Lei, Yong-Min; Xiao, Meng-Meng; Li, Yu-Tao; Xu, Li; Zhang, Hong; Zhang, Zhi-Yong; Zhang, Guo-Jun

    2017-05-15

    Since brain natriuretic peptide (BNP) has become internationally recognized biomarkers in the diagnosis and prognosis of heart failure (HF), it is highly desirable to search for a novel sensing tool for detecting the patient's BNP level at the early stage. Here we report a platinum nanoparticles (PtNPs)-decorated reduced graphene oxide (rGO) field effect transistor (FET) biosensor coupled with a microfilter system for label-free and highly sensitive detection of BNP in whole blood. The PtNPs-decorated rGO FET sensor was obtained by drop-casting rGO onto the pre-fabricated FET chip and subsequently assembling PtNPs on the graphene surface. After anti-BNP was bound to the PtNPs surface, BNP was successfully detected by the anti-BNP immobilized FET biosensor. It was found that the developed FET biosensor was able to achieve a low detection limitation of 100fM. Moreover, BNP was successfully detected in human whole blood sample treated by a custom-made microfilter, suggesting the sensor's capability of working in a complex sample matrix. The developed FET biosensor provides a new sensing platform for protein detection, showing its potential applications in clinic sample.

  2. Identification of Blood Let-7e-5p as a Biomarker for Ischemic Stroke

    Science.gov (United States)

    Guo, Yi; Li, Lu; Zhang, Yanwei; Zhou, Li; Yang, Binyao; Wu, Shuang; Zhang, Ying; Xie, Changhui; Li, Shanshan; Cheng, Jinquan

    2016-01-01

    Circulating microRNAs (miRNAs) are emerging as novel disease biomarkers. Using a miRNA microarray, we previously showed that the whole blood level of let-7e-5p was significantly higher in ischemic stroke patients than in control subjects. However, the association between let-7e-5p expression and the occurrence of ischemic stroke remains unknown. In this study, we validated the expression levels of let-7e-5p in two case-control populations using miRNA TaqMan assays and further investigated the potential targets of let-7e-5p. The results suggest that the blood level of let-7e-5p was significantly higher in patients with ischemic stroke than in controls (p<0.05). Higher levels of let-7e-5p were associated with increased occurrence of ischemic stroke (adjusted OR, 1.89; 95% CI, 1.61~2.21, p<0.001) in the combined population. The addition of let-7e-5p to traditional risk factors led to an improvement in the area under the curve, which increased from 0.74 (95% CI, 0.70~0.78) to 0.82 (95% CI, 0.78~0.85), with a net reclassification improvement of 16.76% (p<0.0001) and an integrated discrimination improvement of 0.10 (p<0.0001) for patients with ischemic stroke. Bioinformatics prediction and cell experiments suggested that the expression levels of four genes enriched in the MAPK signaling pathway were down-regulated by let-7e-5p transfection. Specifically, the expression levels of the genes CASP3 and NLK were significantly lower in ischemic stroke patients than in controls and were negatively correlated with let-7e-5p expression. In summary, our study suggests the potential use of blood let-7e-5p as a biomarker for ischemic stroke and indicates its involvement in the related pathomechanism. PMID:27776139

  3. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer's Disease: Potential Pools of New Biomarkers

    Science.gov (United States)

    Mietelska-Porowska, Anna

    2017-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers.

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

    Science.gov (United States)

    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.

  5. Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

    DEFF Research Database (Denmark)

    Kim, Deog Kyeom; Cho, Michael H; Hersh, Craig P

    2012-01-01

    Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic d...... quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552)....

  6. Characteristic odour in the blood reveals ovarian carcinoma

    Directory of Open Access Journals (Sweden)

    Horvath György

    2010-11-01

    Full Text Available Abstract Background Ovarian carcinoma represents about 4% of all cancers diagnosed in women worldwide. Mortality rate is high, over 50%, mainly due to late diagnosis. Currently there are no acceptable screening techniques available, although ovarian cancer belongs to the group of malignancies for which mortality could be dramatically reduced by early diagnosis. In a recently published study, we clearly demonstrated that human ovarian carcinoma tissues can be characterized by a specific odour, detectable by a trained dog. Another recent study confirmed these results using an electronic nose. Methods In the present work, we examined whether the cancer-specific odour can also be found in the blood. Two specially trained dogs were used. Both ovarian cancer tissues and blood from patients with ovarian carcinoma were tested. Results The tissue tests showed sensitivity of 100% and specificity of 95%, while the blood tests showed sensitivity of 100% and specificity of 98%. Conclusions The present study strongly suggests that the characteristic odour emitted by ovarian cancer samples is also present in blood (plasma taken from patients with the disease. This finding opens possibilities for future screening of healthy populations for early diagnosis of ovarian carcinoma. A future challenge is to develop a sensitive electronic nose for screening of ovarian carcinoma by testing the blood/plasma to detect the disease at a stage early enough for treatment to be effective.

  7. Seasonal Variations of Complete Blood Count and Inflammatory Biomarkers in the US Population - Analysis of NHANES Data.

    Directory of Open Access Journals (Sweden)

    Bian Liu

    Full Text Available Recent studies reported seasonal differences in gene expression in white blood cells, adipose tissue, and inflammatory biomarkers of the immune system. There is no data on the seasonal variations of these biomarkers in the US general population of both children and adults. Then aim of this study is to explore the seasonal trends in complete blood count (CBC, and C-reactive protein (CRP in a large non-institutionalized US population.Seven cross-sectional data collected in the National Health and Nutrition Examination Survey (NHANES during 1999-2012 were aggregated; participants reporting recent use of prescribed steroids, chemotherapy, immunomodulators and antibiotics were excluded. Linear regression models were used to compare levels of CBC and CRP between winter-spring (November-April and summer-fall (May-October, adjusting for demographics, personal behavioral factors, and chronic disease conditions.A total of 27,478 children and 36,644 adults (≥18 years were included in the study. Levels of neutrophils, white blood cell count (WBC, and CRP were higher in winter-spring than summer-fall (p≤0.05. Red blood cell components were lower in winter-spring than in summer-fall, while the opposite was seen for platelets.This large population-based study found notable seasonal variations in blood cell composition and inflammatory biomarkers, with a more pro-inflammatory immune system seen in winter-spring than summer-fall. The red blood cell patterns could have implications for the observed cardio-vascular seasonality.

  8. MicroRNA Profiling of CSF Reveals Potential Biomarkers to Detect Alzheimer`s Disease.

    Directory of Open Access Journals (Sweden)

    Johannes Denk

    Full Text Available The miRBase-21 database currently lists 1881 microRNA (miRNA precursors and 2585 unique mature human miRNAs. Since their discovery, miRNAs have proved to present a new level of epigenetic post-transcriptional control of protein synthesis. Initial results point to a possible involvement of miRNA in Alzheimer's disease (AD. We applied OpenArray technology to profile the expression of 1178 unique miRNAs in cerebrospinal fluid (CSF samples of AD patients (n = 22 and controls (n = 28. Using a Cq of 34 as cut-off, we identified positive signals for 441 miRNAs, while 729 miRNAs could not be detected, indicating that at least 37% of miRNAs are present in the brain. We found 74 miRNAs being down- and 74 miRNAs being up-regulated in AD using a 1.5 fold change threshold. By applying the new explorative "Measure of relevance" method, 6 reliable and 9 informative biomarkers were identified. Confirmatory MANCOVA revealed reliable miR-100, miR-146a and miR-1274a as differentially expressed in AD reaching Bonferroni corrected significance. MANCOVA also confirmed differential expression of informative miR-103, miR-375, miR-505#, miR-708, miR-4467, miR-219, miR-296, miR-766 and miR-3622b-3p. Discrimination analysis using a combination of miR-100, miR-103 and miR-375 was able to detect AD in CSF by positively classifying controls and AD cases with 96.4% and 95.5% accuracy, respectively. Referring to the Ingenuity database we could identify a set of AD associated genes that are targeted by these miRNAs. Highly predicted targets included genes involved in the regulation of tau and amyloid pathways in AD like MAPT, BACE1 and mTOR.

  9. Blood-based biomarkers of age-associated epigenetic changes in human islets associate with insulin secretion and diabetes.

    Science.gov (United States)

    Bacos, Karl; Gillberg, Linn; Volkov, Petr; Olsson, Anders H; Hansen, Torben; Pedersen, Oluf; Gjesing, Anette Prior; Eiberg, Hans; Tuomi, Tiinamaija; Almgren, Peter; Groop, Leif; Eliasson, Lena; Vaag, Allan; Dayeh, Tasnim; Ling, Charlotte

    2016-03-31

    Aging associates with impaired pancreatic islet function and increased type 2 diabetes (T2D) risk. Here we examine whether age-related epigenetic changes affect human islet function and if blood-based epigenetic biomarkers reflect these changes and associate with future T2D. We analyse DNA methylation genome-wide in islets from 87 non-diabetic donors, aged 26-74 years. Aging associates with increased DNA methylation of 241 sites. These sites cover loci previously associated with T2D, for example, KLF14. Blood-based epigenetic biomarkers reflect age-related methylation changes in 83 genes identified in human islets (for example, KLF14, FHL2, ZNF518B and FAM123C) and some associate with insulin secretion and T2D. DNA methylation correlates with islet expression of multiple genes, including FHL2, ZNF518B, GNPNAT1 and HLTF. Silencing these genes in β-cells alter insulin secretion. Together, we demonstrate that blood-based epigenetic biomarkers reflect age-related DNA methylation changes in human islets, and associate with insulin secretion in vivo and T2D.

  10. Blood-based Biomarkers at Large Bowel Endoscopy and Prediction of Future Malignancies

    DEFF Research Database (Denmark)

    Kring, Thomas S; Piper, Thomas B; Jørgensen, Lars N;

    2015-01-01

    Soluble cancer-related protein biomarker levels may be increased in subjects without findings at large bowel endoscopy performed due to symptoms associated with colorectal cancer. The present study focused on a possible association between increased biomarker levels in such subjects and subsequen...

  11. SERS active colloidal nanoparticles for the detection of small blood biomarkers using aptamers

    Science.gov (United States)

    Marks, Haley; Mabbott, Samuel; Jackson, George W.; Graham, Duncan; Cote, Gerard L.

    2015-03-01

    Functionalized colloidal nanoparticles for SERS serve as a promising multifunctional assay component for blood biomarker detection. Proper design of these nanoprobes through conjugation to spectral tags, protective polymers, and sensing ligands can provide experimental control over the sensitivity, range, reproducibility, particle stability, and integration with biorecognition assays. Additionally, the optical properties and degree of electromagnetic SERS signal enhancement can be altered and monitored through tuning the nanoparticle shape, size, material and the colloid's local surface plasmon resonance (LSPR). Aptamers, synthetic affinity ligands derived from nucleic acids, provide a number of advantages for biorecognition of small molecules and toxins with low immunogenicity. DNA aptamers are simpler and more economical to produce at large scale, are capable of greater specificity and affinity than antibodies, are easily tailored to specific functional groups, can be used to tune inter-particle distance and shift the LSPR, and their intrinsic negative charge can be utilized for additional particle stability.1,2 Herein, a "turn-off" competitive binding assay platform involving two different plasmonic nanoparticles for the detection of the toxin bisphenol A (BPA) using SERS is presented. A derivative of the toxin is immobilized onto a silver coated magnetic nanoparticle (Ag@MNP), and a second solid silver nanoparticle (AgNP) is functionalized with the BPA aptamer and a Raman reporter molecule (RRM). The capture (Ag@MNP) and probe (AgNP) particles are mixed and the aptamer binding interaction draws the nanoparticles closer together, forming an assembly that results in an increased SERS signal intensity. This aptamer mediated assembly of the two nanoparticles results in a 100x enhancement of the SERS signal intensity from the RRM. These pre-bound aptamer/nanoparticle conjugates were then exposed to BPA in free solution and the competitive binding event was monitored

  12. Circulating MicroRNAs in maternal blood as potential biomarkers for fetal hypoxia in-utero.

    Directory of Open Access Journals (Sweden)

    Clare L Whitehead

    Full Text Available Stillbirth affects 1 in 200 pregnancies and commonly arises due to a lack of oxygen supply to the fetus. Current tests to detect fetal hypoxia in-utero lack the sensitivity to identify many babies at risk. Emerging evidence suggests that microRNAs derived from the placenta circulate in the maternal blood during pregnancy and may serve as non-invasive biomarkers for pregnancy complications. In this study, we examined the expression of miRs known to be regulated by hypoxia in two clinical settings of significant fetal hypoxia: 1 labour and 2 fetal growth restriction. Six miRs (miR 210, miR 21, miR 424, miR 199a, miR 20b, and miR 373 were differentially expressed in pregnancies complicated by fetal hypoxia. In healthy term pregnancies there was a 4.2 fold increase in miR 210 (p<0.01, 2.7 fold increase in miR 424 (p<0.05, 2.6 fold increase in miR 199a (p<0.01 and 2.3 fold increase in miR 20b (p<0.05 from prior to labour to delivery of the fetus. Furthermore, the combined expression of miR 21 and miR 20b correlated with the degree of fetal hypoxia at birth determined by umbilical cord lactate delivery (r = 0.79, p = 0.03. In pregnancies complicated by severe preterm fetal growth restriction there was upregulation of the hypoxia-regulated miRs compared to gestation-matched controls: 3.6 fold in miR 210 (p<0.01, 3.6 fold in miR 424 (p<0.05, 5.9 fold in miR 21 (p<0.01, 3.8 fold in miR 199a (p<0.01 and 3.7 fold in miR 20b (p<0.01. Interestingly, the expression of miR 373 in gestation matched controls was very low, but was very highly expressed in FGR (p<0.0001. Furthermore, the expression increased in keeping with the degree of in-utero hypoxia estimated by fetal Doppler velocimetry. We conclude quantifying hypoxia-regulated miRs in the maternal blood may identify pregnancies at risk of fetal hypoxia, enabling early intervention to improve perinatal outcomes.

  13. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis.

    Directory of Open Access Journals (Sweden)

    Ivan O Rosas

    2008-04-01

    Full Text Available BACKGROUND: Idiopathic pulmonary fibrosis (IPF is a chronic progressive fibrotic lung disease associated with substantial morbidity and mortality. The objective of this study was to determine whether there is a peripheral blood protein signature in IPF and whether components of this signature may serve as biomarkers for disease presence and progression. METHODS AND FINDINGS: We analyzed the concentrations of 49 proteins in the plasma of 74 patients with IPF and in the plasma of 53 control individuals. We identified a combinatorial signature of five proteins-MMP7, MMP1, MMP8, IGFBP1, and TNFRSF1A-that was sufficient to distinguish patients from controls with a sensitivity of 98.6% (95% confidence interval [CI] 92.7%-100% and specificity of 98.1% (95% CI 89.9%-100%. Increases in MMP1 and MMP7 were also observed in lung tissue and bronchoalveolar lavage fluid obtained from IPF patients. MMP7 and MMP1 plasma concentrations were not increased in patients with chronic obstructive pulmonary disease or sarcoidosis and distinguished IPF compared to subacute/chronic hypersensitivity pneumonitis, a disease that may mimic IPF, with a sensitivity of 96.3% (95% CI 81.0%-100% and specificity of 87.2% (95% CI 72.6%-95.7%. We verified our results in an independent validation cohort composed of patients with IPF, familial pulmonary fibrosis, subclinical interstitial lung disease (ILD, as well as with control individuals. MMP7 and MMP1 concentrations were significantly higher in IPF patients compared to controls in this cohort. Furthermore, MMP7 concentrations were elevated in patients with subclinical ILD and negatively correlated with percent predicted forced vital capacity (FVC% and percent predicted carbon monoxide diffusing capacity (DLCO%. CONCLUSIONS: Our experiments provide the first evidence for a peripheral blood protein signature in IPF to our knowledge. The two main components of this signature, MMP7 and MMP1, are overexpressed in the lung

  14. White blood cell count in women: relation to inflammatory biomarkers, haematological profiles, visceral adiposity, and other cardiovascular risk factors.

    Science.gov (United States)

    Farhangi, Mahdieh Abbasalizad; Keshavarz, Seyyed-Ali; Eshraghian, Mohammadreza; Ostadrahimi, Alireza; Saboor-Yaraghi, Ali-Akbar

    2013-03-01

    The role of white blood cell (WBC) count in pathogenesis of diabetes, cardiovascular disease, and obesity-related disorders has been reported earlier. Recent studies revealed that higher WBC contributes to atherosclerotic progression and impaired fasting glucose. However, it is unknown whether variations in WBC and haematologic profiles can occur in healthy obese individuals. The aim of this study is to further evaluate the influence of obesity on WBC count, inflammatory biomarkers, and metabolic risk factors in healthy women to establish a relationship among variables analyzed. The sample of the present study consisted of 84 healthy women with mean age of 35.56 +/- 6.83 years. They were categorized into two groups based on their body mass index (BMI): obese group with BMI > 30 kg/m2 and non-obese group with BMI count (PLT) with serum interleukin 6 (IL-6), C-reactive protein (CRP), angiotensin pi (Ang pi), body fat percentage (BF %), waist-circumference (WC), and lipid profile. WBC, PLT, CRP, and IL-6 in obese subjects were significantly higher than in non-obese subjects (p count in obese subjects was 6.4 +/- 0.3 (x10(9)/L) compared to 4.4 +/- 0.3 (x10(9)/L) in non-obese subjects (p = 0.035). WBC correlated with BF% (r = 0.31, p = 0.004), CRP (r = 0.25, P = 0.03), WC (r = 0.22, p = 0.04), angiotensin 11 (r = 0.24, p = 0.03), triglyceride (r = 0.24, p = 0.03), and atherogenic index of plasma (AIP) levels (r = 0.3, p = 0.028) but not with IL-6. Platelet count was also associated with WC and waist-to-hip ratio (p count and inflammatory parameters. There was also a positive relationship between WBC count and several inflammatory and metabolic risk factors in healthy women.

  15. High-throughput sequencing of microRNAs in peripheral blood mononuclear cells: identification of potential weight loss biomarkers.

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    Fermín I Milagro

    Full Text Available INTRODUCTION: MicroRNAs (miRNAs are being increasingly studied in relation to energy metabolism and body composition homeostasis. Indeed, the quantitative analysis of miRNAs expression in different adiposity conditions may contribute to understand the intimate mechanisms participating in body weight control and to find new biomarkers with diagnostic or prognostic value in obesity management. OBJECTIVE: The aim of this study was the search for miRNAs in blood cells whose expression could be used as prognostic biomarkers of weight loss. METHODS: Ten Caucasian obese women were selected among the participants in a weight-loss trial that consisted in following an energy-restricted treatment. Weight loss was considered unsuccessful when 5% (responders. At baseline, total miRNA isolated from peripheral blood mononuclear cells (PBMC was sequenced with SOLiD v4. The miRNA sequencing data were validated by RT-PCR. RESULTS: Differential baseline expression of several miRNAs was found between responders and non-responders. Two miRNAs were up-regulated in the non-responder group (mir-935 and mir-4772 and three others were down-regulated (mir-223, mir-224 and mir-376b. Both mir-935 and mir-4772 showed relevant associations with the magnitude of weight loss, although the expression of other transcripts (mir-874, mir-199b, mir-766, mir-589 and mir-148b also correlated with weight loss. CONCLUSIONS: This research addresses the use of high-throughput sequencing technologies in the search for miRNA expression biomarkers in obesity, by determining the miRNA transcriptome of PBMC. Basal expression of different miRNAs, particularly mir-935 and mir-4772, could be prognostic biomarkers and may forecast the response to a hypocaloric diet.

  16. Drawings of Blood Cells Reveal People's Perception of Their Blood Disorder: A Pilot Study.

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    Steven Ramondt

    Full Text Available Sickle cell disease (SCD and thalassemia are rare but chronic blood disorders. Recent literature showed impaired quality of life (QOL in people with these blood disorders. Assessing one of the determinants of QOL (i.e. illness perceptions therefore, is an important next research area.We aimed to explore illness perceptions of people with a blood disorder with drawings in addition to the Brief Illness Perception Questionnaire (Brief IPQ. Drawings are a novel method to assess illness perceptions and the free-range answers drawings offer can add additional insight into how people perceive their illness.We conducted a cross-sectional study including 17 participants with a blood disorder. Participants' illness perceptions were assessed by the Brief IPQ and drawings. Brief IPQ scores were compared with reference groups from the literature (i.e. people with asthma or lupus erythematosus.Participants with SCD or thalassemia perceived their blood disorder as being more chronic and reported more severe symptoms than people with either asthma or lupus erythematosus. In the drawings of these participants with a blood disorder, a greater number of blood cells drawn was negatively correlated with perceived personal control (P<0.05, indicating that a greater quantity in the drawing is associated with more negative or distressing beliefs.Participants with a blood disorder perceive their disease as fairly threatening compared with people with other chronic illnesses. Drawings can add additional insight into how people perceive their illness by offering free-range answers.

  17. Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors.

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    Tao Cui

    Full Text Available BACKGROUND: Small intestine neuroendocrine tumors (SI-NETs belong to a rare group of cancers. Most patients have developed metastatic disease at the time of diagnosis, for which there is currently no cure. The delay in diagnosis is a major issue in the clinical management of the patients and new markers are urgently needed. We have previously identified paraneoplastic antigen Ma2 (PNMA2 as a novel SI-NET tissue biomarker. Therefore, we evaluated whether Ma2 autoantibodies detection in the blood stream is useful for the clinical diagnosis and recurrence of SI-NETs. METHODOLOGY/PRINCIPAL FINDINGS: A novel indirect ELISA was set up to detect Ma2 autoantibodies in blood samples of patients with SI-NET at different stages of disease. The analysis was extended to include typical and atypical lung carcinoids (TLC and ALC, to evaluate whether Ma2 autoantibodies in the blood stream become a general biomarker for NETs. In total, 124 blood samples of SI-NET patients at different stages of disease were included in the study. The novel Ma2 autoantibody ELISA showed high sensitivity, specificity and accuracy with ROC curve analysis underlying an area between 0.734 and 0.816. Ma2 autoantibodies in the blood from SI-NET patients were verified by western blot and sequential immunoprecipitation. Serum antibodies of patients stain Ma2 in the tumor tissue and neurons. We observed that SI-NET patients expressing Ma2 autoantibody levels below the cutoff had a longer progression and recurrence-free survival compared to those with higher titer. We also detected higher levels of Ma2 autoantibodies in blood samples from TLC and ALC patients than from healthy controls, as previously shown in small cell lung carcinoma samples. CONCLUSION: Here we show that high Ma2 autoantibody titer in the blood of SI-NET patients is a sensitive and specific biomarker, superior to chromogranin A (CgA for the risk of recurrence after radical operation of these tumors.

  18. Blood, breast milk and urine: potential biomarkers of exposure and estimated daily intake of ochratoxin A: a review.

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    Soto, Julia Bellver; Ruiz, María-José; Manyes, Lara; Juan-García, Ana

    2016-01-01

    The purposes of this review are to study potential biomarkers of exposure for ochratoxin A (OTA) in biological fluids (blood, urine and breast milk) for the period 2005-14, calculate the estimated daily intake (EDI) of OTA by using database consumption for the Spanish population, and, finally, to correlate OTA levels detected in blood and EDI values calculated from food products. The values of OTA detected in potential biomarkers of exposure for blood, breast milk and urine ranged from 0.15 to 18.0, from 0.002 to 13.1, and from 0.013 to 0.2 ng ml(-1), respectively. The calculated EDI for OTA in plasma ranged from 0.15 to 26 ng kg(-1) bw day(-1), higher than that obtained in urine (0.017-0.4 ng kg(-1) bw day(-1)). All these values are correlated with the range of EDI for OTA calculated from food products: 0.0001-25.2 ng kg(-1) bw day(-1).

  19. Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

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    Skene, Debra J.; Middleton, Benita; Fraser, Cara K.; Pennings, Jeroen L. A.; Kuchel, Timothy R.; Rudiger, Skye R.; Bawden, C. Simon; Morton, A. Jennifer

    2017-01-01

    The pronounced cachexia (unexplained wasting) seen in Huntington’s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25 h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients. PMID:28223686

  20. Lipidomic profiling of tryptophan hydroxylase 2 knockout mice reveals novel lipid biomarkers associated with serotonin deficiency.

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    Weng, Rui; Shen, Sensen; Burton, Casey; Yang, Li; Nie, Honggang; Tian, Yonglu; Bai, Yu; Liu, Huwei

    2016-04-01

    Serotonin is an important neurotransmitter that regulates a wide range of physiological, neuropsychological, and behavioral processes. Consequently, serotonin deficiency is involved in a wide variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, and depression. The pathophysiological mechanisms underlying serotonin deficiency, particularly from a lipidomics perspective, remain poorly understood. This study therefore aimed to identify novel lipid biomarkers associated with serotonin deficiency by lipidomic profiling of tryptophan hydroxylase 2 knockout (Tph2-/-) mice. Using a high-throughput normal-/reversed-phase two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry (NP/RP 2D LC-QToF-MS) method, 59 lipid biomarkers encompassing glycerophospholipids (glycerophosphocholines, lysoglycerophosphocholines, glycerophosphoethanolamines, lysoglycerophosphoethanolamines glycerophosphoinositols, and lysoglycerophosphoinositols), sphingolipids (sphingomyelins, ceramides, galactosylceramides, glucosylceramides, and lactosylceramides) and free fatty acids were identified. Systemic oxidative stress in the Tph2-/- mice was significantly elevated, and a corresponding mechanism that relates the lipidomic findings has been proposed. In summary, this work provides preliminary findings that lipid metabolism is implicated in serotonin deficiency.

  1. Consensus Guidelines for CSF and Blood Biobanking for CNS Biomarker Studies

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    Charlotte E. Teunissen

    2011-01-01

    Full Text Available There is a long history of research into body fluid biomarkers in neurodegenerative and neuroinflammatory diseases. However, only a few biomarkers in cerebrospinal fluid (CSF are being used in clinical practice. Anti-aquaporin-4 antibodies in serum are currently useful for the diagnosis of neuromyelitis optica (NMO, but we could expect novel CSF biomarkers that help define prognosis and response to treatment for this disease. One of the most critical factors in biomarker research is the inadequate powering of studies performed by single centers. Collaboration between investigators is needed to establish large biobanks of well-defined samples. A key issue in collaboration is to establish standardized protocols for biobanking to ensure that the statistical power gained by increasing the numbers of CSF samples is not compromised by pre-analytical factors. Here, consensus guidelines for CSF collection and biobanking are presented, based on the guidelines that have been published by the BioMS-eu network for CSF biomarker research. We focussed on CSF collection procedures, pre-analytical factors and high quality clinical and paraclinical information. Importantly, the biobanking protocols are applicable for CSF biobanks for research targeting any neurological disease.

  2. Amyloidosis, synucleinopathy, and prion encephalopathy in a neuropathic lysosomal storage disease: the CNS-biomarker potential of peripheral blood.

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    Bartholomew J Naughton

    Full Text Available Mucopolysaccharidosis (MPS IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional α-N-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases.

  3. NGS-based transcriptome profiling reveals biomarkers for companion diagnostics of the TGF-β receptor blocker galunisertib in HCC.

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    Cao, Yuan; Agarwal, Rahul; Dituri, Francesco; Lupo, Luigi; Trerotoli, Paolo; Mancarella, Serena; Winter, Peter; Giannelli, Gianluigi

    2017-02-23

    Transforming growth factor-beta (TGF-β) signaling has gained extensive interest in hepatocellular carcinoma (HCC). The small molecule kinase inhibitor galunisertib, targeting the TGF-β receptor I (TGF-βRI), blocks HCC progression in preclinical models and shows promising effects in ongoing clinical trials. As the drug is not similarly effective in all patients, this study was aimed at identifying new companion diagnostics biomarkers for patient stratification. Next-generation sequencing-based massive analysis of cDNA ends was used to investigate the transcriptome of an invasive HCC cell line responses to TGF-β1 and galunisertib. These identified mRNA were validated in 78 frozen HCC samples and in 26 ex-vivo HCC tissues treated in culture with galunisertib. Respective protein levels in patients blood were measured by enzyme-linked immunosorbent assay. SKIL, PMEPA1 ANGPTL4, SNAI1, Il11 and c4orf26 were strongly upregulated by TGF-β1 and downregulated by galunisertib in different HCC cell lines. In the 78 HCC samples, only SKIL and PMEPA1 (P<0.001) were correlated with endogenous TGF-β1. In ex-vivo samples, SKIL and PMEPA1 were strongly downregulated (P<0.001), and correlated (P<0.001) with endogenous TGF-β1. SKIL and PMEPA1 mRNA expression in tumor tissues was significantly increased compared with controls and not correlated with protein levels in the blood of paired HCC patients. SKIL and PMEPA1 mRNA levels were positively correlated with TGF-β1 mRNA concentrations in HCC tissues and strongly downregulated by galunisertib. The target genes identified here may serve as biomarkers for the stratification of HCC patients undergoing treatment with galunisertib.

  4. Genetic and protein biomarkers in blood for the improved detection of GH abuse.

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    Ferro, P; Ventura, R; Pérez-Mañá, C; Farré, M; Segura, J

    2016-09-05

    Human Growth Hormone (hGH, somatotropin) is one of the relevant forbidden substances to be detected in sport drug testing. Since the appearance of recombinant hGH (rhGH) in the 80's, its expansion and availability through the black market have increased, so the detection of its abuse continues to be a challenge at present. New techniques or biomarkers that are robust, reliable, sensitive and allowing a large detection time window are welcome. rhGH produces an increase of insulin-like growth factor 1 (IGF-1). FN1 (fibronectin 1) and RAB31 (member of RAS oncogene family) genes have been suggested as two potential biomarkers for IGF-1 abuse. Following this line, in the present study some genetic and proteomic approaches have been performed with fourteen healthy male subjects treated with rhGH (which produces increase of IGF-1 concentrations) to study FN1 gene, FN1 protein, RAB31 gene and RAB31 protein as potential biomarkers for rhGH abuse. The results showed that both, RAB31 and FN1 genes and FN1 protein could be potential biomarkers for rhGH administration. Preliminary assessments of gender, age, acute sport activities and GHRP-2 (pralmorelin, a rhGH releasing peptide) influence suggest they are not relevant confounding factors. Thus, the selected markers present high sensitivity and a larger detection window for rhGH detection than IGF-1 itself.

  5. Biomarker for Spinal Muscular Atrophy: Expression of SMN in Peripheral Blood of SMA Patients and Healthy Controls.

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    Christian Czech

    Full Text Available Spinal muscular atrophy is caused by a functional deletion of SMN1 on Chromosome 5, which leads to a progressive loss of motor function in affected patients. SMA patients have at least one copy of a similar gene, SMN2, which produces functional SMN protein, although in reduced quantities. The severity of SMA is variable, partially due to differences in SMN2 copy numbers. Here, we report the results of a biomarker study characterizing SMA patients of varying disease severity. SMN copy number, mRNA and Protein levels in whole blood of patients were measured and compared against a cohort of healthy controls. The results show differential regulation of expression of SMN2 in peripheral blood between patients and healthy subjects.

  6. Quantification of the concentration gradient of biomarkers between ovarian carcinoma interstitial fluid and blood

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    Haslene-Hox, Hanne; Madani, Amina; Berg, Kaja C.G.; Woie, Kathrine; Salvesen, Helga B.; Wiig, Helge; Tenstad, Olav

    2014-01-01

    Background Tumor interstitial fluid (TIF) rather than plasma should be used in cancer biomarker discovery because of the anticipated higher concentration of locally produced proteins in the tumor microenvironment. Nevertheless, the actual TIF-to-plasma gradient of tumor specific proteins has not been quantified. We present the proof-of-concept for the quantification of the postulated gradient between TIF and plasma. Methods TIF was collected by centrifugation from serous (n = 19), endometrioid (n = 9) and clear cell (n = 3) ovarian carcinomas with early (n = 15) and late stage (n = 16) disease in grades 1 (n = 2), 2 (n = 8) and 3 (n = 17), and ELISA was used for the determination of CA-125, osteopontin and VEGF-A. Results All three markers were significantly up-regulated in TIF compared with plasma (p < 0.0001). The TIF-to-plasma ratio of the ovarian cancer biomarker CA-125 ranged from 1.4 to 24,300 (median = 194) and was inversely correlated to stage (p = 0.0006). The cancer related osteopontin and VEGF-A had TIF-to-plasma ratios ranging from 1 to 62 (median = 15) and 2 to 1040 (median = 59), respectively. The ratios were not affected by tumor stage, indicative of more widespread protein expression. Conclusion We present absolute quantitative data on the TIF-to-plasma gradient of selected proteins in the tumor microenvironment, and demonstrate a substantial and stage dependent gradient for CA-125 between TIF and plasma, suggesting a relation between total tumor burden and tissue-to-plasma gradient. General significance We present novel quantitative data on biomarker concentration in the tumor microenvironment, and a new strategy for biomarker selection, applicable in future biomarker studies. PMID:26673827

  7. Intensive trapping of blood-fed Anopheles darlingi in Amazonian Peru reveals unexpectedly high proportions of avian blood-meals

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    Saavedra, Marlon P.; Bickersmith, Sara A.; Prussing, Catharine; Michalski, Adrian; Tong Rios, Carlos; Vinetz, Joseph M.; Conn, Jan E.

    2017-01-01

    Anopheles darlingi, the main malaria vector in the Neotropics, has been considered to be highly anthropophilic. However, many behavioral aspects of this species remain unknown, such as the range of blood-meal sources. Barrier screens were used to collect resting Anopheles darlingi mosquitoes from 2013 to 2015 in three riverine localities (Lupuna, Cahuide and Santa Emilia) in Amazonian Peru. Overall, the Human Blood Index (HBI) ranged from 0.58–0.87, with no significant variation among years or sites. Blood-meal analysis revealed that humans are the most common blood source, followed by avian hosts (Galliformes-chickens and turkeys), and human/Galliforme mixed-meals. The Forage Ratio and Selection Index both show a strong preference for Galliformes over humans in blood-fed mosquitoes. Our data show that 30% of An. darlingi fed on more than one host, including combinations of dogs, pigs, goats and rats. There appears to be a pattern of host choice in An. darlingi, with varying proportions of mosquitoes feeding only on humans, only on Galliformes and some taking mixed-meals of blood (human plus Galliforme), which was detected in the three sites in different years, indicating that there could be a structure to these populations based on blood-feeding preferences. Mosquito age, estimated in two localities, Lupuna and Cahuide, ranged widely between sites and years. This variation may reflect the range of local environmental factors that influence longevity or possibly potential changes in the ability of the mosquito to transmit the parasite. Of 6,204 resting An. darlingi tested for Plasmodium infection, 0.42% were infected with P. vivax. This study provides evidence for the first time of the usefulness of barrier screens for the collection of blood-fed resting mosquitoes to calculate the Human Blood Index (HBI) and other blood-meal sources in a neotropical malaria endemic setting. PMID:28231248

  8. Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients.

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    Fan, Hui-min; Sun, Xin-yang; Guo, Wei; Zhong, Ai-fang; Niu, Wei; Zhao, Lin; Dai, Yun-hua; Guo, Zhong-min; Zhang, Li-yi; Lu, Jim

    2014-12-01

    Currently, diagnosis and treatment of major depressive disorder (MDD) are based on the patients' description of symptoms, mental status examinations, and clinical behavioral observations, which increases the chance of misdiagnosis. There is a serious need to find a practical biomarker for the proper diagnosis of MDD. This study aimed to explore the possibility of microRNA (miRNA) in peripheral blood mononuclear cells (PBMCs) as specific blood-based biomarker for MDD patients. By using an Affymetrix array that covers 723 human miRNAs, we identified 26 miRNAs with significant changes in expression in PBMCs of MDD patients. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis in a larger cohort of 81 MDD patients and 46 healthy controls confirmed that the expression levels of 5 miRNAs (miRNA-26b, miRNA-1972, miRNA-4485, miRNA-4498, and miRNA-4743) were up-regulated. By receiver operating characteristic (ROC) curve analysis, the combining area under the ROC curve (AUC) of these five miRNAs was 0.636 [95% confidence interval (CI): 0.58-0.90]. MiRNA target gene prediction and functional annotation analysis showed that there was a significant enrichment in several pathways associated with nervous system and brain functions, supporting the hypothesis that differentially-regulated miRNAs may be involved in mechanism underlying development of MDD. We conclude that altered expression of miRNAs in PMBCs might be involved in multiple stages of MDD pathogenesis, and thus might be able to serve as specific biomarker for diagnosis of MDD.

  9. Global DNA hypomethylation in peripheral blood leukocytes as a biomarker for cancer risk: a meta-analysis.

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    Hae Dong Woo

    Full Text Available BACKGROUND: Good biomarkers for early detection of cancer lead to better prognosis. However, harvesting tumor tissue is invasive and cannot be routinely performed. Global DNA methylation of peripheral blood leukocyte DNA was evaluated as a biomarker for cancer risk. METHODS: We performed a meta-analysis to estimate overall cancer risk according to global DNA hypomethylation levels among studies with various cancer types and analytical methods used to measure DNA methylation. Studies were systemically searched via PubMed with no language limitation up to July 2011. Summary estimates were calculated using a fixed effects model. RESULTS: The subgroup analyses by experimental methods to determine DNA methylation level were performed due to heterogeneity within the selected studies (p<0.001, I(2: 80%. Heterogeneity was not found in the subgroup of %5-mC (p = 0.393, I(2: 0% and LINE-1 used same target sequence (p = 0.097, I(2: 49%, whereas considerable variance remained in LINE-1 (p<0.001, I(2: 80% and bladder cancer studies (p = 0.016, I(2: 76%. These results suggest that experimental methods used to quantify global DNA methylation levels are important factors in the association study between hypomethylation levels and cancer risk. Overall, cancer risks of the group with the lowest DNA methylation levels were significantly higher compared to the group with the highest methylation levels [OR (95% CI: 1.48 (1.28-1.70]. CONCLUSIONS: Global DNA hypomethylation in peripheral blood leukocytes may be a suitable biomarker for cancer risk. However, the association between global DNA methylation and cancer risk may be different based on experimental methods, and region of DNA targeted for measuring global hypomethylation levels as well as the cancer type. Therefore, it is important to select a precise and accurate surrogate marker for global DNA methylation levels in the association studies between global DNA methylation levels in peripheral

  10. Effects of Aerobic Fitness and Adiposity on Coagulation Biomarkers in Men vs. Women with Elevated Blood Pressure

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    Kathleen L. Wilson

    2012-09-01

    Full Text Available ABSTRACTA hypercoagulable state is a potential mechanism linking elevated blood pressure (BP, adiposity and a sedentary lifestyle to development of coronary heart disease (CHD. We examined relationships among aerobic fitness and adiposity in 76 sedentary subjects with elevated BP. Blood levels of plasminogen activator inhibitor-1 (PAI-1, D-dimer, von Willebrand factor (vWF and thrombomodulin were assessed as biomarkers of coagulation. In individuals with elevated BP, percent body fat and fitness were associated with biomarkers indicative of a hypercoagulable state, even after demographic and metabolic factors were considered. D-dimer was positively associated with percent body fat (beta=0.37, p=0.003. PAI-1 was higher in men than in women (beta=-0.31, p=0.015 and associated with lower VO2peak (beta=-0.35, p=0.024. Thrombomodulin was positively associated with VO2peak (beta=0.56, p< 0.01. vWF was not significantly associated with fitness or adiposity. Our results emphasise that both percent body fat and physical fitness are important in the maintenance of haemostatic balance.

  11. Proteomic analysis in type 2 diabetes patients before and after a very low calorie diet reveals potential disease state and intervention specific biomarkers.

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    Maria A Sleddering

    Full Text Available Very low calorie diets (VLCD with and without exercise programs lead to major metabolic improvements in obese type 2 diabetes patients. The mechanisms underlying these improvements have so far not been elucidated fully. To further investigate the mechanisms of a VLCD with or without exercise and to uncover possible biomarkers associated with these interventions, blood samples were collected from 27 obese type 2 diabetes patients before and after a 16-week VLCD (Modifast ∼ 450 kcal/day. Thirteen of these patients followed an exercise program in addition to the VCLD. Plasma was obtained from 27 lean and 27 obese controls as well. Proteomic analysis was performed using mass spectrometry (MS and targeted multiple reaction monitoring (MRM and a large scale isobaric tags for relative and absolute quantitation (iTRAQ approach. After the 16-week VLCD, there was a significant decrease in body weight and HbA1c in all patients, without differences between the two intervention groups. Targeted MRM analysis revealed differences in several proteins, which could be divided in diabetes-associated (fibrinogen, transthyretin, obesity-associated (complement C3, and diet-associated markers (apolipoproteins, especially apolipoprotein A-IV. To further investigate the effects of exercise, large scale iTRAQ analysis was performed. However, no proteins were found showing an exercise effect. Thus, in this study, specific proteins were found to be differentially expressed in type 2 diabetes patients versus controls and before and after a VLCD. These proteins are potential disease state and intervention specific biomarkers.Controlled-Trials.com ISRCTN76920690.

  12. The Male Fetal Biomarker INSL3 Reveals Substantial Hormone Exchange between Fetuses in Early Pig Gestation.

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    Andreas Vernunft

    Full Text Available The peptide hormone INSL3 is uniquely produced by the fetal testis to promote the transabdominal phase of testicular descent. Because it is fetal sex specific, and is present in only very low amounts in the maternal circulation, INSL3 acts as an ideal biomarker with which to monitor the movement of fetal hormones within the pregnant uterus of a polytocous species, the pig. INSL3 production by the fetal testis begins at around GD30. At GD45 of the ca. 114 day gestation, a time at which testicular descent is promoted, INSL3 evidently moves from male to female allantoic compartments, presumably impacting also on the female fetal circulation. At later time-points (GD63, GD92 there is less inter-fetal transfer, although there still appears to be significant INSL3, presumably of male origin, in the plasma of female fetuses. This study thus provides evidence for substantial transfer of a peptide hormone between fetuses, and probably also across the placenta, emphasizing the vulnerability of the fetus to extrinsic hormonal influences within the uterus.

  13. Transcriptional activity around bacterial cell death reveals molecular biomarkers for cell viability

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    Schuren Frank H

    2008-12-01

    Full Text Available Abstract Background In bacteriology, the ability to grow in selective media and to form colonies on nutrient agar plates is routinely used as a retrospective criterion for the detection of living bacteria. However, the utilization of indicators for bacterial viability-such as the presence of specific transcripts or membrane integrity-would overcome bias introduced by cultivation and reduces the time span of analysis from initiation to read out. Therefore, we investigated the correlation between transcriptional activity, membrane integrity and cultivation-based viability in the Gram-positive model bacterium Bacillus subtilis. Results We present microbiological, cytological and molecular analyses of the physiological response to lethal heat stress under accurately defined conditions through systematic sampling of bacteria from a single culture exposed to gradually increasing temperatures. We identified a coherent transcriptional program including known heat shock responses as well as the rapid expression of a small number of sporulation and competence genes, the latter only known to be active in the stationary growth phase. Conclusion The observed coordinated gene expression continued even after cell death, in other words after all bacteria permanently lost their ability to reproduce. Transcription of a very limited number of genes correlated with cell viability under the applied killing regime. The transcripts of the expressed genes in living bacteria – but silent in dead bacteria-include those of essential genes encoding chaperones of the protein folding machinery and can serve as molecular biomarkers for bacterial cell viability.

  14. Lacustrine lignin biomarker record reveals a severe drought during the late Younger Dryas in southern Taiwan

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    Ding, Xiaodong; Bao, Hongyan; Zheng, Liwei; Li, Dawei; Kao, Shuh-Ji

    2017-03-01

    The Younger Dryas (YD) event, which punctuated the last glacial-Holocene transition period and had a profound impact on global climate, is the most well studied millennial-scale climate event although the triggering mechanism remains debate. Weakened Asian summer monsoon during the YD is recorded in oxygen isotopes of stalagmite from Mainland China. However, lacustrine climate record of the YD event has not been reported from the subtropical land-ocean boundary of the Asian continent near the Pacific warm pool. We provide a lignin biomarker record covering the last deglaciation and early Holocene (17-9 ka BP) from the Dongyuan Lake, southern Taiwan, located at the frontal zone of typhoon invasion. The lignin phenol ratio S/V shows that the vegetation in the catchments had shifted from gymnosperm dominant to angiosperm dominant plants since 12.2 ka BP. Significantly decreased lignin concentrations (TLP and λ8) and elevated lignin degradation parameters ((Ad/Al)v, P/(V + S), DHBA/V) in combination with other organic proxies (TOC, δ13Corg) during the late YD suggest a severe drought had occurred in southern Taiwan during this specific period. Changes in the lignin proxies from the Dongyuan Lake lagged the climate changes registered in stalagmite records by around 500-800 years, suggesting a slow response of vegetation and soil processes to rapid climate changes.

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

    Science.gov (United States)

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

    2014-08-17

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

  16. Integrative analyses of hepatic differentially expressed genes and blood biomarkers during the peripartal period between dairy cows overfed or restricted-fed energy prepartum.

    Directory of Open Access Journals (Sweden)

    Khuram Shahzad

    Full Text Available Using published dairy cattle liver transcriptomics dataset along with novel blood biomarkers of liver function, metabolism, and inflammation we have attempted an integrative systems biology approach applying the classical functional enrichment analysis using DAVID, a newly-developed Dynamic Impact Approach (DIA, and an upstream gene network analysis using Ingenuity Pathway Analysis (IPA. Transcriptome data was generated from experiments evaluating the impact of prepartal plane of energy intake [overfed (OF or restricted (RE] on liver of dairy cows during the peripartal period. Blood biomarkers uncovered that RE vs. OF led to greater prepartal liver distress accompanied by a low-grade inflammation and larger proteolysis (i.e., higher haptoglobin, bilirubin, and creatinine. Post-partum the greater bilirubinaemia and lipid accumulation in OF vs. RE indicated a large degree of liver distress. The re-analysis of microarray data revealed that expression of >4,000 genes was affected by diet × time. The bioinformatics analysis indicated that RE vs. OF cows had a liver with a greater lipid and amino acid catabolic capacity both pre- and post-partum while OF vs. RE cows had a greater activation of pathways/functions related to triglyceride synthesis. Furthermore, RE vs. OF cows had a larger (or higher capacity to cope with ER stress likely associated with greater protein synthesis/processing, and a higher activation of inflammatory-related functions. Liver in OF vs. RE cows had a larger cell proliferation and cell-to-cell communication likely as a response to the greater lipid accumulation. Analysis of upstream regulators indicated a pivotal role of several lipid-related transcription factors (e.g., PPARs, SREBPs, and NFE2L2 in priming the liver of RE cows to better face the early postpartal metabolic and inflammatory challenges. An all-encompassing dynamic model was proposed based on the findings.

  17. Integrative Analyses of Hepatic Differentially Expressed Genes and Blood Biomarkers during the Peripartal Period between Dairy Cows Overfed or Restricted-Fed Energy Prepartum

    Science.gov (United States)

    Shahzad, Khuram; Bionaz, Massimo; Trevisi, Erminio; Bertoni, Giuseppe; Rodriguez-Zas, Sandra L.; Loor, Juan J.

    2014-01-01

    Using published dairy cattle liver transcriptomics dataset along with novel blood biomarkers of liver function, metabolism, and inflammation we have attempted an integrative systems biology approach applying the classical functional enrichment analysis using DAVID, a newly-developed Dynamic Impact Approach (DIA), and an upstream gene network analysis using Ingenuity Pathway Analysis (IPA). Transcriptome data was generated from experiments evaluating the impact of prepartal plane of energy intake [overfed (OF) or restricted (RE)] on liver of dairy cows during the peripartal period. Blood biomarkers uncovered that RE vs. OF led to greater prepartal liver distress accompanied by a low-grade inflammation and larger proteolysis (i.e., higher haptoglobin, bilirubin, and creatinine). Post-partum the greater bilirubinaemia and lipid accumulation in OF vs. RE indicated a large degree of liver distress. The re-analysis of microarray data revealed that expression of >4,000 genes was affected by diet × time. The bioinformatics analysis indicated that RE vs. OF cows had a liver with a greater lipid and amino acid catabolic capacity both pre- and post-partum while OF vs. RE cows had a greater activation of pathways/functions related to triglyceride synthesis. Furthermore, RE vs. OF cows had a larger (or higher capacity to cope with) ER stress likely associated with greater protein synthesis/processing, and a higher activation of inflammatory-related functions. Liver in OF vs. RE cows had a larger cell proliferation and cell-to-cell communication likely as a response to the greater lipid accumulation. Analysis of upstream regulators indicated a pivotal role of several lipid-related transcription factors (e.g., PPARs, SREBPs, and NFE2L2) in priming the liver of RE cows to better face the early postpartal metabolic and inflammatory challenges. An all-encompassing dynamic model was proposed based on the findings. PMID:24914544

  18. Biomarker-based classification of bacterial and fungal whole-blood infections in a genome-wide expression study

    Directory of Open Access Journals (Sweden)

    Andreas eDix

    2015-03-01

    Full Text Available Sepsis is a clinical syndrome that can be caused by bacteria or fungi. Early knowledge on the nature of the causative agent is a prerequisite for targeted anti-microbial therapy. Besides currently used detection methods like blood culture and PCR-based assays, the analysis of the transcriptional response of the host to infecting organisms holds great promise. In this study, we aim to examine the transcriptional footprint of infections caused by the bacterial pathogens Staphylococcus aureus and Escherichia coli and the fungal pathogens Candida albicans and Aspergillus fumigatus in a human whole-blood model. Moreover, we use the expression information to build a random forest classifier to classify if a sample contains a bacterial, fungal, or mock-infection. After normalizing the transcription intensities using stably expressed reference genes, we filtered the gene set for biomarkers of bacterial or fungal blood infections. This selection is based on differential expression and an additional gene relevance measure. In this way, we identified 38 biomarker genes, including IL6, SOCS3, and IRG1 which were already associated to sepsis by other studies. Using these genes, we trained the classifier and assessed its performance. It yielded a 96% accuracy (sensitivities >93%, specificities >97% for a 10-fold stratified cross-validation and a 92% accuracy (sensitivities and specificities >83% for an additional test dataset comprising Cryptococcus neoformans infections. Furthermore, the classifier is robust to Gaussian noise, indicating correct class predictions on datasets of new species. In conclusion, this genome-wide approach demonstrates an effective feature selection process in combination with the construction of a well-performing classification model. Further analyses of genes with pathogen-dependent expression patterns can provide insights into the systemic host responses, which may lead to new anti-microbial therapeutic advances.

  19. Quantifying murine bone marrow and blood radiation dose response following {sup 18}F-FDG PET with DNA damage biomarkers

    Energy Technology Data Exchange (ETDEWEB)

    Manning, Grainne [Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, Oxfordshire OX11 ORQ (United Kingdom); Taylor, Kristina [Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, ON (Canada); Finnon, Paul [Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, Oxfordshire OX11 ORQ (United Kingdom); Lemon, Jennifer A.; Boreham, Douglas R. [Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, ON (Canada); Badie, Christophe, E-mail: christophe.badie@phe.gov.uk [Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, Oxfordshire OX11 ORQ (United Kingdom)

    2014-12-15

    Highlights: • Mice received either a range of {sup 18}F-FDG activities or whole body X-ray doses. • Blood samples were collected at 24 and 43 h for MN-RET and QPCR analysis. • Regression analysis showed that both types of exposure produced a linear response. • BM doses of 33 mGy ({sup 18}F-FDG) and 25 mGy X-rays were significantly higher than controls. • No significant difference between internal ({sup 18}F-FDG) and external (X-ray) was found. - Abstract: The purpose of this study was to quantify the poorly understood radiation doses to murine bone marrow and blood from whole-body fluorine 18 ({sup 18}F)-fluorodeoxyglucose (FDG) positron emission tomography (PET), by using specific biomarkers and comparing with whole body external low dose exposures. Groups of 3–5 mice were randomly assigned to 10 groups, each receiving either a different activity of {sup 18}F-FDG: 0–37 MBq or whole body irradiated with corresponding doses of 0–300 mGy X-rays. Blood samples were collected at 24 h and at 43 h for reticulocyte micronucleus assays and QPCR analysis of gene expression in peripheral blood leukocytes. Blood and bone marrow dose estimates were calculated from injected activities of {sup 18}F-FDG and were based on a recommended ICRP model. Doses to the bone marrow corresponding to 33.43 mGy and above for internal {sup 18}F-FDG exposure and to 25 mGy and above for external X-ray exposure, showed significant increases in radiation-induced MN-RET formation relative to controls (P < 0.05). Regression analysis showed that both types of exposure produced a linear response with linear regression analysis giving R{sup 2} of 0.992 and 0.999 for respectively internal and external exposure. No significant difference between the two data sets was found with a P-value of 0.493. In vivo gene expression dose–responses at 24 h for Bbc3 and Cdkn1 were similar for {sup 18}F-FDG and X-ray exposures, with significant modifications occurring for doses over 300 mGy for Bbc3

  20. Alternatively Spliced Genes as Biomarkers for Schizophrenia, Bipolar Disorder and Psychosis: A Blood-Based Spliceome-Profiling Exploratory Study.

    Science.gov (United States)

    Glatt, S J; Chandler, S D; Bousman, C A; Chana, G; Lucero, G R; Tatro, E; May, T; Lohr, J B; Kremen, W S; Everall, I P; Tsuang, M T

    2009-09-01

    OBJECTIVE: Transcriptomic biomarkers of psychiatric diseases obtained from a query of peripheral tissues that are clinically accessible (e.g., blood cells instead of post-mortem brain tissue) have substantial practical appeal to discern the molecular subtypes of common complex diseases such as major psychosis. To this end, spliceome-profiling is a new methodological approach that has considerable conceptual relevance for discovery and clinical translation of novel biomarkers for psychiatric illnesses. Advances in microarray technology now allow for improved sensitivity in measuring the transcriptome while simultaneously querying the "exome" (all exons) and "spliceome" (all alternatively spliced variants). The present study aimed to evaluate the feasibility of spliceome-profiling to discern transcriptomic biomarkers of psychosis. METHODS: We measured exome and spliceome expression in peripheral blood mononuclear cells from 13 schizophrenia patients, nine bipolar disorder patients, and eight healthy control subjects. Each diagnostic group was compared to each other, and the combined group of bipolar disorder and schizophrenia patients was also compared to the control group. Furthermore, we compared subjects with a history of psychosis to subjects without such history. RESULTS: After applying Bonferroni corrections for the 21,866 full-length gene transcripts analyzed, we found significant interactions between diagnostic group and exon identity, consistent with group differences in rates or types of alternative splicing. Relative to the control group, 18 genes in the bipolar disorder group, eight genes in the schizophrenia group, and 15 genes in the combined bipolar disorder and schizophrenia group appeared differentially spliced. Importantly, thirty-three genes showed differential splicing patterns between the bipolar disorder and schizophrenia groups. More frequent exon inclusion and/or over-expression was observed in psychosis. Finally, these observations are

  1. Storage-induced increase in biomarkers of oxidative stress and inflammation in red blood cell components

    DEFF Research Database (Denmark)

    Kücükakin, Bülent; Kocak, Volkan; Lykkesfeldt, Jens;

    2011-01-01

    Background. Transfusion of blood components may increase the risk of complications in relation to surgery. During storage, red blood cells (RBCs) undergo structural and functional changes that may reduce function and viability after transfusion. The aim of the study was to evaluate the quality...

  2. Blood/Brain Biomarkers of Inflammation After Stroke and Their Association With Outcome: From C-Reactive Protein to Damage-Associated Molecular Patterns.

    Science.gov (United States)

    Bustamante, Alejandro; Simats, Alba; Vilar-Bergua, Andrea; García-Berrocoso, Teresa; Montaner, Joan

    2016-10-01

    Stroke represents one of the most important causes of disability and death in developed countries. However, there is a lack of prognostic tools in clinical practice to monitor the neurological condition and predict the final outcome. Blood biomarkers have been proposed and studied in this indication; however, no biomarker is currently used in clinical practice. The stroke-related neuroinflammatory processes have been associated with a poor outcome in stroke, as well as with poststroke complications. In this review, we focus on the most studied blood biomarkers of this inflammatory processes, cytokines, and C-reactive protein, evaluating its association with outcome and complications in stroke through the literature, and performing a systematic review on the association of C-reactive protein and functional outcome after stroke. Globally, we identified uncertainty with regard to the association of the evaluated biomarkers with stroke outcome, with little added value on top of clinical predictors such as age or stroke severity, which makes its implementation unlikely in clinical practice for global outcome prediction. Regarding poststroke complications, despite being more practical scenarios in which to make medical decisions following a biomarker prediction, not many studies have been performed, although there are now some candidates for prediction of poststroke infections. Finally, as potential new candidates, we reviewed the pathophysiological actions of damage-associated molecular patterns as triggers of the neuroinflammatory cascade of stroke, and their possible use as biomarkers.

  3. Development of a blood-based molecular biomarker test for identification of schizophrenia before disease onset

    Science.gov (United States)

    Chan, M K; Krebs, M-O; Cox, D; Guest, P C; Yolken, R H; Rahmoune, H; Rothermundt, M; Steiner, J; Leweke, F M; van Beveren, N J M; Niebuhr, D W; Weber, N S; Cowan, D N; Suarez-Pinilla, P; Crespo-Facorro, B; Mam-Lam-Fook, C; Bourgin, J; Wenstrup, R J; Kaldate, R R; Cooper, J D; Bahn, S

    2015-01-01

    Recent research efforts have progressively shifted towards preventative psychiatry and prognostic identification of individuals before disease onset. We describe the development of a serum biomarker test for the identification of individuals at risk of developing schizophrenia based on multiplex immunoassay profiling analysis of 957 serum samples. First, we conducted a meta-analysis of five independent cohorts of 127 first-onset drug-naive schizophrenia patients and 204 controls. Using least absolute shrinkage and selection operator regression, we identified an optimal panel of 26 biomarkers that best discriminated patients and controls. Next, we successfully validated this biomarker panel using two independent validation cohorts of 93 patients and 88 controls, which yielded an area under the curve (AUC) of 0.97 (0.95–1.00) for schizophrenia detection. Finally, we tested its predictive performance for identifying patients before onset of psychosis using two cohorts of 445 pre-onset or at-risk individuals. The predictive performance achieved by the panel was excellent for identifying USA military personnel (AUC: 0.90 (0.86–0.95)) and help-seeking prodromal individuals (AUC: 0.82 (0.71–0.93)) who developed schizophrenia up to 2 years after baseline sampling. The performance increased further using the latter cohort following the incorporation of CAARMS (Comprehensive Assessment of At-Risk Mental State) positive subscale symptom scores into the model (AUC: 0.90 (0.82–0.98)). The current findings may represent the first successful step towards a test that could address the clinical need for early intervention in psychiatry. Further developments of a combined molecular/symptom-based test will aid clinicians in the identification of vulnerable patients early in the disease process, allowing more effective therapeutic intervention before overt disease onset. PMID:26171982

  4. Gene co-expression networks and profiles reveal potential biomarkers of boar taint in pigs

    DEFF Research Database (Denmark)

    Drag, Markus; Skinkyté-Juskiené, Rúta; Do, Duy Ngoc

    Boar taint (BT) is an offensive odour or taste of porcine meat which may occur in entire male pigs due to skatole and androstenone accumulation. To avoid BT, castration of young piglets is performed but this strategy is under debate due to animal welfare concerns. The study aimed to reveal...... synthesis. In testis, >80 DE genes were functionally classified by the PANTHER tool to “Gonadotropin releasing hormone receptor” and “Wnt signaling” pathways which play a role in reproductive maturation and proliferation of spermatogonia, respectively. WGCNA was used to build co-expression modules...... and enrichment analysis and semantic filtering revealed the GO terms “catalytic activity” and “transferase activity” to be overrepresented (p hormones. Extraction of hub...

  5. Detection of α-synuclein oligomers in red blood cells as a potential biomarker of Parkinson's disease.

    Science.gov (United States)

    Wang, Xuemei; Yu, Shun; Li, Fangfei; Feng, Tao

    2015-07-10

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by intracellular α-synuclein (α-syn) deposition. Alterations in α-syn levels in cerebrospinal fluid (CSF) and plasma of PD patients have been thought to be potential PD biomarkers; however, contamination arising from hemolysis often influences the accuracy of detecting α-syn levels in the CSF and plasma. In this study, α-syn oligomer levels in red blood cells (RBCs) obtained from 100 PD patients, 22 MSA patients, and 102 control subjects were measured by enzyme-linked immunosorbent assay. We showed that the ratio of α-syn oligomer/total RBC protein was higher in PD patients than in controls (29.0±19.8 ng/mg vs. 15.4±7.4 ng/mg, Pdisease duration, age, UPDRS motor scale score or progression of motor degeneration in PD patients. The ratio of RBC α-syn oligomer/total protein was also higher in MSA patients than in controls (22.9±13.9 ng/mg vs. 15.4±7.4 ng/mg, P0.05). The present results suggest that the RBC α-syn oligomer/total protein ratio can be a potential diagnostic biomarker for PD.

  6. Initial evidence that blood-borne microvesicles are biomarkers for recurrence and survival in newly diagnosed glioblastoma patients.

    Science.gov (United States)

    Evans, Sydney M; Putt, Mary; Yang, Xiang-Yang; Lustig, Robert A; Martinez-Lage, Maria; Williams, Dewight; Desai, Arati; Wolf, Ronald; Brem, Steven; Koch, Cameron J

    2016-04-01

    The purpose of this pilot study was to determine whether blood-borne microvesicles from newly diagnosed glioblastoma patients could be used as biomarkers. We collected 2.8 mL blood from 16 post-operative patients at the time that they were being simulated for chemoradiation therapy (radiation with concurrent temozolomide). Two additional samples were collected during chemoradiation therapy and a final sample was collected at the end of chemoradiation therapy. Patients continued with the therapy suggested by their physicians, based on tumor conference consensus and were followed for recurrence and overall survival. Microvesicles were isolated using serial centrifugation and stained for surface markers (Annexin V for phosphotidyl serine, CD41 for platelets, anti-EGFR for tumor cells, and CD235 for red blood cells). Flow cytometry analysis was performed. Our findings provide initial evidence that increases in Annexin V positive microvesicle levels during chemoradiation therapy are associated with earlier recurrence and shorter overall survival in newly diagnosed glioblastoma patients. The effect is dramatic, with over a four-fold increase in the hazard ratio for an individual at the 75th versus the 25th percentile. Moreover the pattern of Annexin V positive microvesicles remain significant after adjustment for confounding clinical variables that have previously been shown to be prognostic for recurrence and survival. Inclusion of neutrophil levels at the start of chemoradiation therapy in the model yielded the largest attenuation of the observed association. Further studies will be needed to verify and further investigate the association between these two entities.

  7. Pain in the Blood? Envisioning Mechanism-Based Diagnoses and Biomarkers in Clinical Pain Medicine

    Directory of Open Access Journals (Sweden)

    Emmanuel Bäckryd

    2015-03-01

    Full Text Available Chronic pain is highly prevalent, and pain medicine lacks objective biomarkers to guide diagnosis and choice of treatment. The current U.S. “opioid epidemic” is a reminder of the paucity of effective and safe treatment options. Traditional pain diagnoses according to the International Classification of Diseases are often unspecific, and analgesics are often prescribed on a trial-and-error basis. In contrast to this current state of affairs, the vision of future mechanism-based diagnoses of chronic pain conditions is presented in this non-technical paper, focusing on the need for biomarkers and the theoretical complexity of the task. Pain is and will remain a subjective experience, and as such is not objectively measurable. Therefore, the concept of “noci-marker” is presented as an alternative to “pain biomarker”, the goal being to find objective, measurable correlates of the pathophysiological processes involved in different chronic pain conditions. This vision entails a call for more translational pain research in order to bridge the gap between clinical pain medicine and preclinical science.

  8. Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer.

    Science.gov (United States)

    Klein, Robert J; Halldén, Christer; Cronin, Angel M; Ploner, Alexander; Wiklund, Fredrik; Bjartell, Anders S; Stattin, Pär; Xu, Jianfeng; Scardino, Peter T; Offit, Kenneth; Vickers, Andrew J; Grönberg, Henrik; Lilja, Hans

    2010-05-01

    Polymorphisms associated with prostate cancer include those in three genes encoding major secretory products of the prostate: KLK2 (encoding kallikrein-related peptidase 2; hK2), KLK3 (encoding prostate-specific antigen; PSA), and MSMB (encoding beta-microseminoprotein). PSA and hK2, members of the kallikrein family, are elevated in sera of men with prostate cancer. In a comprehensive analysis that included sequencing of all coding, flanking, and 2 kb of putative promoter regions of all 15 kallikrein (KLK) genes spanning approximately 280 kb on chromosome 19q, we identified novel single-nucleotide polymorphisms (SNP) and genotyped 104 SNPs in 1,419 cancer cases and 736 controls in Cancer Prostate in Sweden 1, with independent replication in 1,267 cases and 901 controls in Cancer Prostate in Sweden 2. This verified prior associations of SNPs in KLK2 and in MSMB (but not in KLK3) with prostate cancer. Twelve SNPs in KLK2 and KLK3 were associated with levels of PSA forms or hK2 in plasma of control subjects. Based on our comprehensive approach, this is likely to represent all common KLK variants associated with these phenotypes. A T allele at rs198977 in KLK2 was associated with increased cancer risk and a striking decrease of hK2 levels in blood. We also found a strong interaction between rs198977 genotype and hK2 levels in blood in predicting cancer risk. Based on this strong association, we developed a model for predicting prostate cancer risk from standard biomarkers, rs198977 genotype, and rs198977 x hK2 interaction; this model had greater accuracy than did biomarkers alone (area under the receiver operating characteristic curve, 0.874 versus 0.866), providing proof in principle to clinical application for our findings.

  9. Potential Biomarker Peptides Associated with Acute Alcohol-Induced Reduction of Blood Pressure.

    Directory of Open Access Journals (Sweden)

    Ichiro Wakabayashi

    Full Text Available The purpose of this study was to explore the peptides that are related to acute reduction of blood pressure after alcohol drinking. Venous blood was collected from male healthy volunteers before and after drinking white wine (3 ml/kg weight containing 13% of ethanol. Peptidome analysis for serum samples was performed using a new target plate, BLOTCHIP®. Alcohol caused significant decreases in systolic and diastolic blood pressure levels at 45 min. The peptidome analysis showed that the levels of three peptides of m/z 1467, 2380 and 2662 changed significantly after drinking. The m/z 1467 and 2662 peptides were identified to be fragments of fibrinogen alpha chain, and the m/z 2380 peptide was identified to be a fragment of complement C4. The intensities of the m/z 2380 and m/z 1467 peptides before drinking were associated with % decreases in systolic and diastolic blood pressure levels at 45 min after drinking compared with the levels before drinking, while there were no significant correlations between the intensity of the m/z 2662 peptide and % decreases in systolic and diastolic blood pressure levels after drinking. The m/z 1467 and 2380 peptides are suggested to be markers for acute reduction of blood pressure after drinking alcohol.

  10. A method for biomarker measurements in peripheral blood mononuclear cells isolated from anxious and depressed mice: β-arrestin 1 protein levels in depression and treatment

    Directory of Open Access Journals (Sweden)

    Indira eMENDEZ-DAVID

    2013-09-01

    Full Text Available A limited number of biomarkers in the central and peripheral systems which are known may be useful for diagnosing major depressive disorders and predicting the effectiveness of antidepressant treatments. Since 60% of depressed patients do not respond adequately to medication or are resistant to antidepressants, it is imperative to delineate more accurate biomarkers. Recent clinical studies suggest that β-arrestin 1 levels in human mononuclear leukocytes may be an efficient biomarker. If potential biomarkers such as β-arrestin 1 could be assessed from a source such as peripheral blood cells, then they could be easily monitored and used to predict therapeutic responses. However, no previous studies have measured β-arrestin 1 levels in peripheral blood mononuclear cells (PBMCs in anxious-depressive rodents.This study aimed to develop a method to detect β-arrestin protein levels through immunoblot analyses of mouse PBMCs isolated from whole blood. In order to validate the approach, β-arrestin levels were then compared in naïve, anxious/depressed mice, and anxious/depressed mice treated treated with a selective serotonin reuptake inhibitor (SSRI; fluoxetine, 18 mg/kg/day in the drinking water. The results demonstrated that mouse whole blood collected by submandibular bleeding permitted isolation of enough PBMCs to assess circulating proteins such as β-arrestin 1. β-arrestin 1 levels were successfully measured in healthy human subject and naïve mouse PBMCs. Interestingly, PBMCs from anxious/depressed mice showed significantly reduced β-arrestin 1 levels. These decreased β-arrestin 1 expression levels were restored to normal levels with chronic fluoxetine treatment. The results suggest that isolation of PBMCs from mice by submandibular bleeding is a useful technique to screen putative biomarkers of the pathophysiology of mood disorders and the response to antidepressants. In addition, these results confirm that β-arrestin 1 is a potential

  11. Biomarkers reveal sea turtles remained in oiled areas following the Deepwater Horizon oil spill.

    Science.gov (United States)

    Vander Zanden, Hannah B; Bolten, Alan B; Tucker, Anton D; Hart, Kristen M; Lamont, Margaret M; Fujisaki, Ikuko; Reich, Kimberly J; Addison, David S; Mansfield, Katherine L; Phillips, Katrina F; Pajuelo, Mariela; Bjorndal, Karen A

    2016-10-01

    Assessments of large-scale disasters, such as the Deepwater Horizon oil spill, are problematic because while measurements of post-disturbance conditions are common, measurements of pre-disturbance baselines are only rarely available. Without adequate observations of pre-disaster organismal and environmental conditions, it is impossible to assess the impact of such catastrophes on animal populations and ecological communities. Here, we use long-term biological tissue records to provide pre-disaster data for a vulnerable marine organism. Keratin samples from the carapace of loggerhead sea turtles record the foraging history for up to 18 years, allowing us to evaluate the effect of the oil spill on sea turtle foraging patterns. Samples were collected from 76 satellite-tracked adult loggerheads in 2011 and 2012, approximately one to two years after the spill. Of the 10 individuals that foraged in areas exposed to surface oil, none demonstrated significant changes in foraging patterns post spill. The observed long-term fidelity to foraging sites indicates that loggerheads in the northern Gulf of Mexico likely remained in established foraging sites, regardless of the introduction of oil and chemical dispersants. More research is needed to address potential long-term health consequences to turtles in this region. Mobile marine organisms present challenges for researchers to monitor effects of environmental disasters, both spatially and temporally. We demonstrate that biological tissues can reveal long-term histories of animal behavior and provide critical pre-disaster baselines following an anthropogenic disturbance or natural disaster.

  12. Biomarkers reveal sea turtles remained in oiled areas following the Deepwater Horizon oil spill

    Science.gov (United States)

    Vander Zanden, Hannah B.; Bolten, Alan B.; Tucker, Anton D.; Hart, Kristen M.; Lamont, Margaret M.; Fujisaki, Ikuko; Reich, Kimberly J.; Addison, David S.; Mansfield, Katherine L.; Phillips, Katrina F.; Pajuelo, Mariela; Bjorndal, Karen A.

    2016-01-01

    Assessments of large-scale disasters, such as the Deepwater Horizon oil spill, are problematic because while measurements of post-disturbance conditions are common, measurements of pre-disturbance baselines are only rarely available. Without adequate observations of pre-disaster organismal and environmental conditions, it is impossible to assess the impact of such catastrophes on animal populations and ecological communities. Here, we use long-term biological tissue records to provide pre-disaster data for a vulnerable marine organism. Keratin samples from the carapace of loggerhead sea turtles record the foraging history for up to 18 years, allowing us to evaluate the effect of the oil spill on sea turtle foraging patterns. Samples were collected from 76 satellite-tracked adult loggerheads in 2011 and 2012, approximately one to two years after the spill. Of the 10 individuals that foraged in areas exposed to surface oil, none demonstrated significant changes in foraging patterns post spill. The observed long-term fidelity to foraging sites indicates that loggerheads in the northern Gulf of Mexico likely remained in established foraging sites, regardless of the introduction of oil and chemical dispersants. More research is needed to address potential long-term health consequences to turtles in this region. Mobile marine organisms present challenges for researchers to monitor effects of environmental disasters, both spatially and temporally. We demonstrate that biological tissues can reveal long-term histories of animal behavior and provide critical pre-disaster baselines following an anthropogenic disturbance or natural disaster.

  13. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer

    NARCIS (Netherlands)

    van Ginkel, Joost H.; de Leng, Wendy W J; de Bree, Remco; van Es, Robert J J; Willems, Stefan M.

    2016-01-01

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post tr

  14. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation.

    Directory of Open Access Journals (Sweden)

    Brante P Sampey

    Full Text Available Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD to "Cafeteria diets" (CAF consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity

  15. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation.

    Science.gov (United States)

    Sampey, Brante P; Freemerman, Alex J; Zhang, Jimmy; Kuan, Pei-Fen; Galanko, Joseph A; O'Connell, Thomas M; Ilkayeva, Olga R; Muehlbauer, Michael J; Stevens, Robert D; Newgard, Christopher B; Brauer, Heather A; Troester, Melissa A; Makowski, Liza

    2012-01-01

    Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic

  16. Synthetic pyrethroid effect on blood plasma biomarker enzymes and histological changes in Catla catla.

    Science.gov (United States)

    Muthuviveganandavel, Veerappan; Hwang, Inho; Anita, Vanattayen; Malarani, Pattabiraman S; Selvam, Chandrasekar; Hemalatha, Moorthy; Pandurangan, Muthuraman

    2013-04-01

    Alpha-cypermethrin is an isoform of cypermethrin; it is an active pyrethroid used extensively to control a wide range of pests in agriculture and animal breeding. In this study four groups of six fish were examined. The first group served as a control in fresh water alone, with no pyrethroid. The second, third and fourth groups were exposed to alpha-cypermethrin for 4, 8 and 96 h respectively. At the end of the each exposure period, the fish were sacrificed, and the required muscle tissues were collected for histological examination. The blood was drawn with heparinized needles and processed for serum enzymatic studies. Serum enzymes such as aspartate transaminase (AST), alanine transaminase (ALT), amylase, acid phosphatase (ACP) and gamma-glutamyl transpeptidase (GGT) were measured at 4, 8 and 96 h. AST enzyme activity was significantly increased at 4 h, whereas ALT and amylase enzyme activities were significantly reduced at all the time points. ACP enzyme activity was significantly reduced at 4 and 8 h, whereas GGT enzyme activity was significantly increased at all the time points. Hepatocyte cytoplasmic vacuolisation and degeneration, rupture of blood vessels, and necrosis was found at all time points. Congestion of blood vessels, bulging, distortion of filaments, erosion and disintegration of blood corpuscles and hyperplasia of epithelium were found in treated gills at 4, 8 and 96 h. Breakdown of muscle fibres, vacuolation and accumulation of lipids and melanin in white muscle were observed in treated fish muscle at 4, 8 and 96 h.

  17. Retrospective evaluation of blood copper stable isotopes ratio (65) Cu/(63) Cu as a biomarker of cancer in dogs.

    Science.gov (United States)

    Chamel, G; Gourlan, A T; Télouk, P; Sayag, D; Milliard, V; Loiseau, C; Simon, M; Buff, S; Ponce, F

    2016-10-06

    Previous studies in humans with breast, colorectal or liver cancer showed that neoplasia was associated with a modification of the blood ratio between (65) Cu and (63) Cu (∂Cu). The aim of the present study was to compare the blood ∂Cu of dogs with cancer to healthy controls or dogs with non-oncologic disease. One hundred and seventeen dogs were included in the study (35 dogs with cancer, 33 dogs with non-neoplastic disease, and 49 healthy controls). The ∂Cu of dogs with cancer was significantly lower than the ratio of healthy controls (P dogs with non-oncologic disease. Six dogs with lymphoma were also evaluated after they achieved clinical remission and five out of six had an increase of ∂Cu. Further studies are warranted but these results suggest that ∂Cu could help in the diagnosis of cancer in a controlled clinical context, and may be a potential biomarker for the follow-up of cancer.

  18. Metabolomics approach reveals metabolic disorders and potential biomarkers associated with the developmental toxicity of tetrabromobisphenol A and tetrachlorobisphenol A

    Science.gov (United States)

    Ye, Guozhu; Chen, Yajie; Wang, Hong-Ou; Ye, Ting; Lin, Yi; Huang, Qiansheng; Chi, Yulang; Dong, Sijun

    2016-10-01

    Tetrabromobisphenol A and tetrachlorobisphenol A are halogenated bisphenol A (H-BPA), and has raised concerns about their adverse effects on the development of fetuses and infants, however, the molecular mechanisms are unclear, and related metabolomics studies are limited. Accordingly, a metabolomics study based on gas chromatography-mass spectrometry was employed to elucidate the molecular developmental toxicology of H-BPA using the marine medaka (Oryzias melastigmas) embryo model. Here, we revealed decreased synthesis of nucleosides, amino acids and lipids, and disruptions in the TCA (tricarboxylic acid) cycle, glycolysis and lipid metabolism, thus inhibiting the developmental processes of embryos exposed to H-BPA. Unexpectedly, we observed enhanced neural activity accompanied by lactate accumulation and accelerated heart rates due to an increase in dopamine pathway and a decrease in inhibitory neurotransmitters following H-BPA exposure. Notably, disorders of the neural system, and disruptions in glycolysis, the TCA cycle, nucleoside metabolism, lipid metabolism, glutamate and aspartate metabolism induced by H-BPA exposure were heritable. Furthermore, lactate and dopa were identified as potential biomarkers of the developmental toxicity of H-BPA and related genetic effects. This study has demonstrated that the metabolomics approach is a useful tool for obtaining comprehensive and novel insights into the molecular developmental toxicity of environmental pollutants.

  19. Identifying blood biomarkers and physiological processes that distinguish humans with superior performance under psychological stress.

    Directory of Open Access Journals (Sweden)

    Amanda M Cooksey

    Full Text Available BACKGROUND: Attrition of students from aviation training is a serious financial and operational concern for the U.S. Navy. Each late stage navy aviator training failure costs the taxpayer over $1,000,000 and ultimately results in decreased operational readiness of the fleet. Currently, potential aviators are selected based on the Aviation Selection Test Battery (ASTB, which is a series of multiple-choice tests that evaluate basic and aviation-related knowledge and ability. However, the ASTB does not evaluate a person's response to stress. This is important because operating sophisticated aircraft demands exceptional performance and causes high psychological stress. Some people are more resistant to this type of stress, and consequently better able to cope with the demands of naval aviation, than others. METHODOLOGY/PRINCIPAL FINDINGS: Although many psychological studies have examined psychological stress resistance none have taken advantage of the human genome sequence. Here we use high-throughput -omic biology methods and a novel statistical data normalization method to identify plasma proteins associated with human performance under psychological stress. We identified proteins involved in four basic physiological processes: innate immunity, cardiac function, coagulation and plasma lipid physiology. CONCLUSIONS/SIGNIFICANCE: The proteins identified here further elucidate the physiological response to psychological stress and suggest a hypothesis that stress-susceptible pilots may be more prone to shock. This work also provides potential biomarkers for screening humans for capability of superior performance under stress.

  20. Immunological/virological peripheral blood biomarkers and distinct patterns of sleeping quality in chronic hepatitis C patients.

    Science.gov (United States)

    de Almeida, C M O; de Lima, T A; Castro, D B; Torres, K L; da Silva Braga, W; Peruhype-Magalhães, V; Teixeira-Carvalho, A; Martins-Filho, O A; Malheiro, A

    2011-05-01

    The rational of this study we intended to investigate whether the peripheral blood immunological/virological biomarkers were associated with distinct patterns of sleeping quality in patients with chronic hepatitis C-(HCV). Distinct well-established indexes/scores were used to categorize the sleeping quality of HCV patients, including the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale and Fatigue Severity Scores. Our findings demonstrated that HCV patients classified as 'good sleeper' displayed an enhanced frequency of circulating CD8(+) T cells, lower frequency of activated (CD69(+)) neutrophils and eosinophils but enhanced frequency of activated lymphocytes besides lower seric levels of IL-4/IL-8/IL-10 but higher levels of IL-12, besides lower HCV virus load and lower anti-HCV IgG levels. In contrast, HCV patients classified as 'poor sleeper' displayed enhanced levels of activated neutrophils and eosinophils but lower frequency of activated lymphocytes, higher seric levels of IL-6/TNF-α/IL-10 but lower levels of IL-12 besides higher HCV virus load and increased anti-HCV IgG levels. Positive correlation was further confirmed by the relationship between the leucocyte activation status, the cytokine levels, the HCV viral load and the anti-HCV IgG reactivity with the PSQI indexes. Analysis of cytokine signature curves demonstrated that lower frequency of IL-10 was observed in HCV patients classified as 'good sleepers', whereas enhanced frequency of IL-6 was found HCV patients classified as 'poor sleepers'. In conclusion, our data suggest that immunological biomarkers (leucocytes activation status and seric cytokines levels) are likely to be associated with sleeping quality patterns in HCV patients, suggesting their putative use for clinical monitoring purposes.

  1. Detection of cord blood hepcidin levels as a biomarker for early-onset neonatal sepsis.

    Science.gov (United States)

    Cizmeci, Mehmet Nevzat; Kara, Semra; Kanburoglu, Mehmet Kenan; Simavli, Serap; Duvan, Candan Iltemur; Tatli, Mustafa Mansur

    2014-03-01

    Early-onset neonatal sepsis (EONS) continues to be a severe condition associated with a high mortality and morbidity. However, symptoms and laboratory markers of this serious condition are nonspecific and currently there are no available standard tests to provide perfect diagnostic accuracy. An early recognition and initiation of antimicrobial therapy are essential in order to prevent morbidity and mortality. Hepcidin, the key regulator of iron homeostasis, is also an acute-phase reactant, which has a critical role in inflammation and contributes to host defense by interfering with microorganism's access to iron. Since hepcidin expression is induced by interleukin-6 (IL-6), it also plays role in the innate immune system. Recently, endogenous expression of hepcidin by macrophages and neutrophils in response to bacterial pathogens confirmed its role in innate immunity. The clear link between the hepcidin molecule and innate immunity may be used for the detection of EONS. We hypothesized that an increased level of hepcidin in cord blood may be used as a reliable biological marker of EONS and designed a prospective cohort study to test this hypothesis and collected pilot data. Cord blood samples of all infants born between January 2009 and December 2010 at our university hospital were collected after parental consent and a total of 38 infants were enrolled in the study who fulfilled the sepsis criteria. The range of cord blood hepcidin was found to be significantly increased in newborns with EONS (min-max: 118.1-8400 ng/mL). To the best of our knowledge, this is the first study to investigate the pathophysiologic relevance of hepcidin in EONS and demonstrate increased levels of hepcidin in cord blood as an acute-phase reactant in response to sepsis.

  2. Effects of metals on blood oxidative stress biomarkers and acetylcholinesterase activity in dice snakes (Natrix tessellata from Serbia

    Directory of Open Access Journals (Sweden)

    Gavrić Jelena P.

    2015-01-01

    Full Text Available The effects of waterborne metals in water on the activities of blood copper-zinc superoxide dismutase (CuZnSOD, catalase (CAT, glutathione peroxidase (GSH-Px, glutathione reductase (GR, glutathione-S-transferase (GST, and acetylcholinesterase (AChE, and on the concentrations of total glutathione (GSH and lipid peroxides (TBARS in the blood of dice snakes (Natrix tessellata caught in Obedska Bara, Sebia (control area, with snakes caught in Pančevački Rit, a contaminated area in Serbia were examined. The activities of CAT, GSH-Px, GR and AChE, and the concentration of TBARS were significantly decreased, while GST activity and GSH concentration were significantly increased in snakes from the contaminated area compared to specimens from the control area. Significantly increased concentrations of Al, As, B, Ba, Ca, Cu, Fe, K, Li, Mn, Na, Ni and Zn in the water at the contaminated area as compared to control area were detected. The metals Ag, Bi, Cd, Co, Hg, In and Tl were not observed in any of the localities. Cr, Mo and Pb were not detected at the control area but were observed at the contaminated area. The concentrations of Sr were similar at both sites. The concentration of Mg was 2-fold higher at the control site than at the contaminated area. The obtained results show that most of the investigated blood biomarkers correlate with concentrations of metals present in the environment. These findings suggest that dice snakes are sensitive bioindicator species for monitoring the effects of increased metal concentrations in the environment. [Projekat Ministarstva nauke Republike Srbije, br. 173041 i br. 173043

  3. Microbial ecology of the stratified water column of the Black Sea as revealed by a comprehensive biomarker study

    DEFF Research Database (Denmark)

    Wakeham, Stuart G.; Amann, Rudi; Freemann, Katherine H.;

    2007-01-01

    ) and sulfate reducing bacteria. We also measured a wide range of bacterial and archaeal lipid biomarkers. Depth distributions of diagnostic biomarkers are matched with zonation of microbial processes, including aerobic bacterial oxidation of methane, oxidation of ammonium by bacteria and archaea, metal...... reduction, and sulfide oxidation at the chemocline, and bacterial sulfate reduction and anaerobic oxidation of methane by archaea in the anoxic zone. Cell densities for archaea and sulfate reducing bacteria are estimated based on water column biomarker concentrations and compared with CARD-FISH results....

  4. DNA repair and cell cycle biomarkers of radiation exposure and inflammation stress in human blood.

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    Helen Budworth

    Full Text Available DNA damage and repair are hallmarks of cellular responses to ionizing radiation. We hypothesized that monitoring the expression of DNA repair-associated genes would enhance the detection of individuals exposed to radiation versus other forms of physiological stress. We employed the human blood ex vivo radiation model to investigate the expression responses of DNA repair genes in repeated blood samples from healthy, non-smoking men and women exposed to 2 Gy of X-rays in the context of inflammation stress mimicked by the bacterial endotoxin lipopolysaccharide (LPS. Radiation exposure significantly modulated the transcript expression of 12 genes of 40 tested (2.2E-06blood ex vivo dataset, and 100% accuracy for discriminating patients who received total body radiation. Three genes of this panel (CDKN1A, FDXR and BBC3 were also highly sensitive to LPS treatment in the absence of radiation exposure, and LPS co-treatment significantly affected their radiation responses. At the protein level, BAX and pCHK2-thr68 were elevated after radiation exposure, but the pCHK2-thr68 response was significantly decreased in the presence of LPS. Our combined panel yields an estimated 4-group accuracy of ∼90% to discriminate between radiation alone, inflammation alone, or combined exposures. Our findings suggest that DNA repair gene expression may be helpful to identify biodosimeters of exposure to radiation, especially within high-complexity exposure scenarios.

  5. Cellular Proteases as Cancer Biomarkers: A Review

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    Sarah R. Röthlisberger

    2010-12-01

    Full Text Available Over the past few decades a variety of biomolecules have been proposed as diagnostic biomarkers and predictors of severity for transmissible and nontransmissible diseases. Studies in a range of cancers have revealed many biomarkers with great potential in cancer diagnosis, in establishing tumor stage, progression, and response to therapies; such as the Kallikrein and Metalloproteinase families. Traditionally blood (serum and tissue have been the main biological sources of biomarker discovery, but in the past decade urine has emerged as a promising source of cancer biomarkers. In this review we will focus on two large families, the Kallikrein family of serine proteases discovered in serum, and the Metalloproteinase family of zinc proteases discovered in urine, as potential cancer biomarkers.

  6. Blood glutathione peroxidase-1 mRNA levels can be used as molecular biomarkers to determine dietary selenium requirements in rats.

    Science.gov (United States)

    Sunde, Roger A; Thompson, Kevin M; Evenson, Jacqueline K; Thompson, Britta M

    2009-11-01

    Transcript (mRNA) levels are increasingly being used in medicine as molecular biomarkers for disease and disease risk, including use of whole blood as a target tissue for analysis. Development of blood molecular biomarkers for nutritional status, too, has potential application that parallels opportunities in medicine, including providing solid data for individualized nutrition. We previously reported that blood glutathione peroxidase-1 (Gpx1) mRNA was expressed at levels comparable to major tissues in rats and humans. To determine the efficacy of using blood Gpx1 mRNA to assess selenium (Se) status and requirements, we fed graded levels of Se (0-0.3 microg Se/g as selenite) to weanling male rats. Se status was determined by liver Se concentration and selenoenzyme activity, and selenoprotein mRNA abundance in liver and blood was determined by ribonuclease protection analysis. Liver Se and plasma glutathione peroxidase-3 and liver Gpx1 activities indicated that minimal Se requirements were at 0.08 microg Se/g diet. When total RNA was isolated from whole blood, Gpx1 mRNA in Se-deficient rats decreased to 10% of levels in Se-adequate (0.2 microg Se/g diet) rats. With Se supplementation, blood Gpx1 mRNA levels increased sigmoidally to a plateau with a minimum Se requirement of 0.08 microg Se/g diet, whereas glutathione peroxidase-4 mRNA levels were unaffected. Similarly, Gpx1 mRNA in RNA isolated from fractionated red blood cells decreased in Se-deficient rats to 23% of Se-adequate levels, with a minimum Se requirement of 0.09 microg Se/g diet. Additional studies showed that the preponderance of whole blood Gpx1 mRNA arises from erythroid cells, most likely reticulocytes and young erythrocytes. In summary, whole blood selenoprotein mRNA levels can be used as molecular biomarkers for assessing Se requirements, illustrating that whole blood has potential as a target tissue in development of molecular biomarkers for use in nutrition as well as in medicine.

  7. Multiple Biomarker Panels for Early Detection of Breast Cancer in Peripheral Blood

    Directory of Open Access Journals (Sweden)

    Fan Zhang

    2013-01-01

    Full Text Available Detecting breast cancer at early stages can be challenging. Traditional mammography and tissue microarray that have been studied for early breast cancer detection and prediction have many drawbacks. Therefore, there is a need for more reliable diagnostic tools for early detection of breast cancer due to a number of factors and challenges. In the paper, we presented a five-marker panel approach based on SVM for early detection of breast cancer in peripheral blood and show how to use SVM to model the classification and prediction problem of early detection of breast cancer in peripheral blood. We found that the five-marker panel can improve the prediction performance (area under curve in the testing data set from 0.5826 to 0.7879. Further pathway analysis showed that the top four five-marker panels are associated with signaling, steroid hormones, metabolism, immune system, and hemostasis, which are consistent with previous findings. Our prediction model can serve as a general model for multibiomarker panel discovery in early detection of other cancers.

  8. Programmed death 1 mRNA in peripheral blood as biomarker of acute renal allograft rejection

    Institute of Scientific and Technical Information of China (English)

    WANG Ya-wen; WANG Zhen; SHI Bing-yi

    2011-01-01

    Background Invasive kidney biopsy is a priority diagnostic method for the acute rejection after renal transplantation for the past decades. However, no effective and noninvasive assay for predicting the severity of acute rejection is in wide use at present. This study was designed to investigate the predictive value of programmed death 1 (PD-1) mRNA for acute rejection after renal transplantation with real-time reverse transcriptase polymerase chain reaction (RT-PCR). A noninvasive diagnostic method has been expected to replace the tranditional kidney biopsy for the diagnosis of acute rejection and prediction of the outcome after kidney transplantation.Methods The whole blood samples from 19 subjects with acute rejection, 20 subjects with delayed graft function (DGF)and 21 subjects with stable recipients after kidney transplantation in a single kidney transplantation center between 2006 and 2009 were collected. The messenger RNA (mRNA) of PD-1 was analyzed with real-time RT-PCR. The associations of PD-1 mRNA levels with acute rejection and disease severity were investigated.Results The log-transformed ratio of PD-1 mRNA to GAPDH mRNA was higher in peripheral blood mononuclear cell (PBMC) from the group with acute rejection (4.52±1.1) than that from the group with DGF (1.12±0.6) or the group with normal biopsy results (0.7±0.4) (P <0.01, by the Kruskal-Wallis test). PD-1 mRNA levels were correlated with serum creatinine levels measured at the time of biopsy in the acute rejection group (Spearman's correlation coefficient, r=0.81,P=0.03), but not in the group with DGF or the group with normal biopsy results. PD-1 mRNA levels identified subjects at risk for graft failure within six months after the incident episode of acute rejection.Conclusions Our data suggest that PD-1 status may be a new predictor of acute rejection and the levels of PD-1mRNA in whole blood cells may positively correlate with the severity of acute rejection after renal transplantation

  9. α-synuclein reactive antibodies as diagnostic biomarkers in blood sera of Parkinson's disease patients.

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    Kiran Yanamandra

    Full Text Available BACKGROUND: Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments. METHODOLOGY/PRINCIPAL FINDINGS: Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies--α-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance. We found significantly higher antibody levels towards monomeric α-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression (P<0.0001. This indicates potential protective role of autoimmunity in maintaining the body homeostasis and clearing protein species whose disbalance may lead to amyloid assembly. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards α-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression (P<0.0001. Pooled IgGs from PD patients and controls interacted also with the amyloid fibrils of Aβ (1-40 and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to the generic amyloid conformational epitope, displaying higher specificity towards human amyloid species associated with neurodegeneration. CONCLUSIONS/SIGNIFICANCE: Our findings may suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major

  10. Biomarkers of polycyclic aromatic hydrocarbon-DNA damage and cigarette smoke exposures in paired maternal and newborn blood samples as a measure of differential susceptibility

    Energy Technology Data Exchange (ETDEWEB)

    Whyatt, R.M.; Jedrychowski, W.; Hemminki, K.; Santella, R.M.; Tsai WeiYann; Yang Ke; Perera, F.P. [Columbia University, New York, NY (US). Division of Environmental Health Sciences, Mailman School of Public Health

    2001-07-01

    In this study, we report on three biomarkers measured in paired blood samples collected at birth from 160 mother/newborn pairs from Poland: 70 pairs from Krakow (a city with high air pollution including PAHs) and 90 pairs from Limanowa (an area with lower ambient pollution but greater indoor coal use). Field studies were conducted during January-March 1992. Biomarkers were: WBC aromatic-DNA adducts by {sup 32}P-postlabeling and PAH-DNA adducts by ELISA and plasma cotinine. Correlations were assessed by Spearman's rank test, and differences in biomarker levels were assessed by the Wilcoxon signed-ranks test. A significant correlation between paired newborn/maternal samples was seen for aromatic-DNA adduct levels and plasma cotinine, but not PAH-DNA adduct levels. Among the total cohort, levels of the three biomarkers were higher in newborn samples compared with paired maternal samples. The difference was significant for aromatic-DNA adduct levels (16.6 plus or minus 12.5 versus 14.21 plus or minus 15.4/10{sup 8} nucleotides; P=0.002) and plasma cotinine, but not for PAH-DNA adduct levels. When analyses were restricted to the 80 mother/newborn pairs from whom the blood sample was drawn concurrently, levels of all of the three biomarkers were significantly higher in the newborn compared with paired maternal blood samples (P {lt} 0.05). These results suggest that the fetus has reduced detoxification capabilities and increased susceptibility to DNA damage, especially in light of experimental evidence that transplacental exposures to PAHs are 10-fold lower than paired maternal exposures. Also, these results have implications for risk assessment, which currently does not adequately account for sensitive subsets of the population. 64 refs.

  11. Network-Based Biomarkers for Cold Coagulation Blood Stasis Syndrome and the Therapeutic Effects of Shaofu Zhuyu Decoction in Rats

    Directory of Open Access Journals (Sweden)

    Shulan Su

    2013-01-01

    Full Text Available In this study, the reverse docking methodology was applied to predict the action targets and pathways of Shaofu Zhuyu decoction (SFZYD bioactive ingredients. Furthermore, Traditional Chinese Medicine (TCM cold coagulation blood stasis (CCBS syndrome was induced in female Sprague-Dawley rats with an ice-water bath and epinephrine, and SFZYD was used to treat CCBS syndrome. A metabolomic approach was used to evaluate changes in the metabolic profiles and to analyze the pharmacological mechanism of SFZYD actions. Twenty-three potential protein targets and 15 pathways were discovered, respectively; among these, pathways are associated with inflammation and immunological stress, hormone metabolism, coagulation function, and glycometabolism. There were also changes in the levels of endogenous metabolites of LysoPCs and glucuronides. Twenty endogenous metabolites were identified. Furthermore, the relative quantities of 6 endogenous metabolites in the plasma and 5 in the urine were significantly affected by SFZYD (P<0.05. The pharmacological mechanism of SFZYD was partially associated with glycerophospholipid metabolism and pentose and glucuronate interconversions. In conclusion, our findings demonstrated that TCM CCBS pattern induced by ice water and epinephrine was complex and related to multiple metabolic pathways. SFZYD did regulate the TCM CCBS by multitargets, and biomarkers and SFZYD should be used for the clinical treatment of CCBS syndrome.

  12. Modulation of Sickle Red Blood Cell Adhesion and its Associated Changes in Biomarkers by Sulfated Nonanticoagulant Heparin Derivative.

    Science.gov (United States)

    Alshaiban, Abdulelah; Muralidharan-Chari, Vandhana; Nepo, Anne; Mousa, Shaker A

    2016-04-01

    Abnormal cellular adhesion is one of the primary causes of vaso-occlusive crisis in sickle cell disease (SCD). Levels of intercellular adhesion molecule 1 (ICAM-1) and P-selectin are upregulated, resulting in increased adhesion of leukocytes and sickle red blood cells (RBCs) to endothelium. This study compares the inhibitory effect of a sulfated nonanticoagulant heparin (S-NACH) derivative with a low-molecular-weight heparin, tinzaparin, on the adhesion of sickle RBCs to endothelium. The S-NACH exhibits minimum effects on hemostasis and bleeding and interferes with the binding of pancreatic cancer cells to endothelial cells via P-selectin. We show by static binding assay that pretreatment of both erythrocytes and endothelial cells with S-NACH significantly inhibits the increased adhesion of sickle RBCs to endothelial cells. The S-NACH treatment also decreases the higher plasma levels of (adhesion biomarkers) ICAM-1 and P-selectin in SCD mice. This investigation signals further research into the potential use of S-NACH in treating vaso-occlusions with minimal bleeding events in patients with SCD.

  13. OX40 mRNA in peripheral blood as a biomarker of acute renal allograft rejection

    Institute of Scientific and Technical Information of China (English)

    WANG Yu-liang; FU Ying-xin; ZHU Zhi-jun; WANG Hui; SHEN Zhong-yang

    2012-01-01

    Background Acute rejection remains an important cause of renal allograft dysfunction and the need for accurate diagnosis is essential to successfully treat transplant recipients.The purpose of this study was to determine the costimulatory molecules OX40 and OX40L messenger RNA (mRNA) levels in peripheral blood mononuclear cells (PBMCs) to predict acute renal transplant rejection.Methods The whole blood samples from 20 recipients with biopsy-confirmed acute rejection (rejection group),20 recipients with stable graft function and normal biopsy results (stable group) after kidney transplantation,and 20 healthy volunteers (control group) were collected.The mRNA levels of OX40 and OX40L were analyzed with TaqMan real-time reverse transcriptase polymerase chain reaction (RT-PCR).The association of OX40 and OX40L mRNA levels with disease severity was investigated.Results There was no significant difference of OX40,OX40L mRNA levels in PBMCs between the stable group and control group (P>0.05).The levels of OX40 and OX40L mRNA were significantly higher in the rejection group than in the control group (P<0.01 and P<0.05,respectively).Non-significantly higher OX40L mRNA and significantly higher OX40 mRNA in PBMCs were observed in subjects in the rejection group compared with the stable group (P >0.05 and P <0.01,respectively).Receiver operating characteristic (ROC) curve analysis demonstrated that OX40 mRNA levels could discriminate recipients who subsequently suffered acute allograft rejection (area under the curve,0.908).OX40 and OX40L mRNA levels did not significantly correlate with serum creatinine levels in the rejection group (P >0.05).Levels of OX40 mRNA after anti-rejection therapy were lower than those at the time of protocol biopsy in the rejection group (P<0.05).Conclusion Our data suggest that measurement of OX40 mRNA levels after transplant might offer a noninvasive means for recognizing recipients at risk of acute renal allograft rejection.

  14. Blood diagnostic biomarkers for major depressive disorder using multiplex DNA methylation profiles: discovery and validation.

    Science.gov (United States)

    Numata, Shusuke; Ishii, Kazuo; Tajima, Atsushi; Iga, Jun-ichi; Kinoshita, Makoto; Watanabe, Shinya; Umehara, Hidehiro; Fuchikami, Manabu; Okada, Satoshi; Boku, Shuken; Hishimoto, Akitoyo; Shimodera, Shinji; Imoto, Issei; Morinobu, Shigeru; Ohmori, Tetsuro

    2015-01-01

    Aberrant DNA methylation in the blood of patients with major depressive disorder (MDD) has been reported in several previous studies. However, no comprehensive studies using medication-free subjects with MDD have been conducted. Furthermore, the majority of these previous studies has been limited to the analysis of the CpG sites in CpG islands (CGIs) in the gene promoter regions. The main aim of the present study is to identify DNA methylation markers that distinguish patients with MDD from non-psychiatric controls. Genome-wide DNA methylation profiling of peripheral leukocytes was conducted in two set of samples, a discovery set (20 medication-free patients with MDD and 19 controls) and a replication set (12 medication-free patients with MDD and 12 controls), using Infinium HumanMethylation450 BeadChips. Significant diagnostic differences in DNA methylation were observed at 363 CpG sites in the discovery set. All of these loci demonstrated lower DNA methylation in patients with MDD than in the controls, and most of them (85.7%) were located in the CGIs in the gene promoter regions. We were able to distinguish patients with MDD from the control subjects with high accuracy in the discriminant analysis using the top DNA methylation markers. We also validated these selected DNA methylation markers in the replication set. Our results indicate that multiplex DNA methylation markers may be useful for distinguishing patients with MDD from non-psychiatric controls.

  15. Multiplex detection of pathogen biomarkers in human blood, serum, and saliva using silicon photonic microring resonators

    Science.gov (United States)

    Estrada, I. A.; Burlingame, R. W.; Wang, A. P.; Chawla, K.; Grove, T.; Wang, J.; Southern, S. O.; Iqbal, M.; Gunn, L. C.; Gleeson, M. A.

    2015-05-01

    Genalyte has developed a multiplex silicon photonic chip diagnostics platform (MaverickTM) for rapid detection of up to 32 biological analytes from a drop of sample in just 10 to 20 minutes. The chips are manufactured with waveguides adjacent to ring resonators, and probed with a continuously variable wavelength laser. A shift in the resonant wavelength as mass binds above the ring resonators is measured and is directly proportional to the amount of bound macromolecules. We present here the ability to multiplex the detection of hemorrhagic fever antigens in whole blood, serum, and saliva in a 16 minute assay. Our proof of concept testing of a multiplex antigencapture chip has the ability to detect Zaire Ebola (ZEBOV) recombinant soluble glycoprotein (rsGP), Marburg virus (MARV) Angola recombinant glycoprotein (rGP) and dengue nonstructural protein I (NS1). In parallel, detection of 2 malaria antigens has proven successful, but has yet to be incorporated into multiplex with the others. Each assay performs with sensitivity ranging from 1.6 ng/ml to 39 ng/ml depending on the antigen detected, and with minimal cross-reactivity.

  16. Cpt1a gene expression in peripheral blood mononuclear cells as an early biomarker of diet-related metabolic alterations

    Directory of Open Access Journals (Sweden)

    Rubén Díaz-Rúa

    2016-11-01

    Full Text Available Background: Research on biomarkers that provide early information about the development of future metabolic alterations is an emerging discipline. Gene expression analysis in peripheral blood mononuclear cells (PBMC is a promising tool to identify subjects at risk of developing diet-related diseases. Objective: We analysed PBMC expression of key energy homeostasis-related genes in a time-course analysis in order to find out early markers of metabolic alterations due to sustained intake of high-fat (HF and high-protein (HP diets. Design: We administered HF and HP diets (4 months to adult Wistar rats in isocaloric conditions to a control diet, mainly to avoid overweight associated with the intake of hyperlipidic diets and, thus, to be able to characterise markers of metabolically obese normal-weight (MONW syndrome. PBMC samples were collected at different time points of dietary treatment and expression of relevant energy homeostatic genes analysed by real-time reverse transcription-polymerase chain reaction. Serum parameters related with metabolic syndrome, as well as fat deposition in liver, were also analysed. Results: The most outstanding results were those obtained for the expression of the lipolytic gene carnitine palmitoyltransferase 1a (Cpt1a. Cpt1a expression in PBMC increased after only 1 month of exposure to both unbalanced diets, and this increased expression was maintained thereafter. Interestingly, in the case of the HF diet, Cpt1a expression was altered even in the absence of increased body weight but correlated with alterations such as higher insulin resistance, alteration of serum lipid profile and, particularly, increased fat deposition in liver, a feature characteristic of metabolic syndrome, which was even observed in animals fed with HP diet. Conclusions: We propose Cpt1a gene expression analysis in PBMC as an early biomarker of metabolic alterations associated with MONW phenotype due to the intake of isocaloric HF diets, as

  17. Transcriptomic Analysis Reveals Selective Metabolic Adaptation of Streptococcus suis to Porcine Blood and Cerebrospinal Fluid

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    Anna Koczula

    2017-02-01

    Full Text Available Streptococcus suis is a zoonotic pathogen that can cause severe pathologies such as septicemia and meningitis in its natural porcine host as well as in humans. Establishment of disease requires not only virulence of the infecting strain but also an appropriate metabolic activity of the pathogen in its host environment. However, it is yet largely unknown how the streptococcal metabolism adapts to the different host niches encountered during infection. Our previous isotopologue profiling studies on S. suis grown in porcine blood and cerebrospinal fluid (CSF revealed conserved activities of central carbon metabolism in both body fluids. On the other hand, they suggested differences in the de novo amino acid biosynthesis. This prompted us to further dissect S. suis adaptation to porcine blood and CSF by RNA deep sequencing (RNA-seq. In blood, the majority of differentially expressed genes were associated with transport of alternative carbohydrate sources and the carbohydrate metabolism (pentose phosphate pathway, glycogen metabolism. In CSF, predominantly genes involved in the biosynthesis of branched-chain and aromatic amino acids were differentially expressed. Especially, isoleucine biosynthesis seems to be of major importance for S. suis in CSF because several related biosynthetic genes were more highly expressed. In conclusion, our data revealed niche-specific metabolic gene activity which emphasizes a selective adaptation of S. suis to host environments.

  18. The Effect of Probiotic Yogurt on Blood Glucose and cardiovascular Biomarkers in Patients with Type II Diabetes: A Randomized Controlled Trial

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    Mahin Rezaei

    2017-01-01

    Full Text Available Background: Given the high prevalence of type II diabetes and its complications, the evidence regarding the beneficial effects of probiotic yogurt on some cardiovascular biomarkers in diabetic patients is worthy of investigation. Aim: To investigate the effect of probiotic yogurt on blood glucose level and cardiovascular biomarkers in patients with type II diabetes. Method:This randomized, clinical trial was conducted on 90 patients with type II diabetes who visited the 5 Azar diabetes clinic in Gorgan, Iran, in 2014. The intervention group consumed three 100 g packages of probiotic yogurt per day for four weeks, while the control group used an equal amount of plain yogurt. Dietary intake, as well as anthropometric and biochemical parameters were measured before and after the trial. To analyze the data, independent t-test, paired t-test, and analysis of covariance were performed, using SPSS version 18. Results: The mean ages of the intervention and control groups were 50.49±10.92 and 50.13±9.20 years, respectively. In the intervention group, paired t-test showed significant differences between mean levels of blood glucose, cholesterol, low-density lipoprotein (LDL, triglycerides, diastolic blood pressure, and glycated hemoglobin before and after four weeks of daily intake of probiotic yogurt (P0.05. At the end of trial, the independent t-test showed a significant difference between the two groups in terms of mean levels of blood glucose, LDL, triglycerides, blood pressure, and glycated hemoglobin (P

  19. Whole blood defensin mRNA expression is a predictive biomarker of docetaxel response in castration-resistant prostate cancer

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    Kohli M

    2015-07-01

    Full Text Available Manish Kohli,1 Charles YF Young,2 Donald J Tindall,2 Debashis Nandy,1 Kyle M McKenzie,3 Graham H Bevan,4 Krishna Vanaja Donkena5 1Department of Oncology, 2Department of Urology, 3Department of Geriatric Medicine, Mayo Clinic, Rochester, MN, 4University of Rochester Medical Center, Rochester, NY, 5Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA Abstract: This study tested the potential of circulating RNA-based signals as predictive biomarkers for docetaxel response in patients with metastatic castration-resistant prostate cancer (CRPC. RNA was analyzed in blood from six CRPC patients by whole-transcriptome sequencing (total RNA-sequencing before and after docetaxel treatment using the Illumina’s HiSeq platform. Targeted RNA capture and sequencing was performed in an independent cohort of ten patients with CRPC matching the discovery cohort to confirm differential expression of the genes. Response to docetaxel was defined on the basis of prostate-specific antigen levels and imaging criteria. Two-way analysis of variance was used to compare differential gene expression in patients classified as responders versus nonresponders before and after docetaxel treatment. Thirty-four genes with two-fold differentially expressed transcripts in responders versus nonresponders were selected from total RNA-sequencing for further validation. Targeted RNA capture and sequencing showed that 13/34 genes were differentially expressed in responders. Alpha defensin genes DEFA1, DEFA1B, and DEFA3 exhibited significantly higher expression in responder patients compared with nonresponder patients before administration of chemotherapy (fold change >2.5. In addition, post-docetaxel treatment significantly increased transcript levels of these defensin genes in responders (fold change >2.8. Our results reveal that patients with higher defensin RNA transcripts in blood respond well to docetaxel therapy. We suggest that monitoring DEFA1, DEFA1B, and DEFA3

  20. The prognostic blood biomarker proadrenomedullin for outcome prediction in patients with chronic obstructive pulmonary disease (COPD): a qualitative clinical review.

    Science.gov (United States)

    Schuetz, Philipp; Marlowe, Robert J; Mueller, Beat

    2015-03-01

    Plasma proadrenomedullin (ProADM) is a blood biomarker that may aid in multidimensional risk assessment of patients with chronic obstructive pulmonary disease (COPD). Co-secreted 1:1 with adrenomedullin (ADM), ProADM is a less biologically active, more chemically stable surrogate for this pluripotent regulatory peptide, which due to biological and ex vivo physical characteristics is difficult to reliably directly quantify. Upregulated by hypoxia, inflammatory cytokines, bacterial products, and shear stress and expressed widely in pulmonary cells and ubiquitously throughout the body, ADM exerts or mediates vasodilatory, natriuretic, diuretic, antioxidative, anti-inflammatory, antimicrobial, and metabolic effects. Observational data from four separate studies totaling 1366 patients suggest that as a single factor, ProADM is a significant independent, and accurate, long-term all-cause mortality predictor in COPD. This body of work also suggests that combined with different groups of demographic/clinical variables, ProADM provides significant incremental long-term mortality prediction power relative to the groups of variables alone. Additionally, the literature contains indications that ProADM may be a global cardiopulmonary stress marker, potentially supplying prognostic information when cardiopulmonary exercise testing results such as 6-min walk distance are unavailable due to time or other resource constraints or to a patient's advanced disease. Prospective, randomized, controlled interventional studies are needed to demonstrate whether ProADM use in risk-based guidance of site-of-care, monitoring, and treatment decisions improves clinical, quality-of-life, or pharmacoeconomic outcomes in patients with COPD.

  1. Association of EEG, MRI, and regional blood flow biomarkers is predictive of prodromal Alzheimer’s disease

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    Moretti DV

    2015-10-01

    Full Text Available Davide Vito Moretti IRCCS S Giovanni di Dio Fatebenefratelli, Brescia, Italy Background: Thinning in the temporoparietal cortex, hippocampal atrophy, and a lower regional blood perfusion is connected with prodromal stage of Alzheimer’s disease (AD. Of note, an increase of electroencephalography (EEG upper/low alpha frequency power ratio has also been associated with these major landmarks of prodromal AD.Methods: Clinical and neuropsychological assessment, EEG recording, and high-resolution three-dimensional magnetic resonance imaging were done in 74 grown up subjects with mild cognitive impairment. This information was gathered and has been assessed 3 years postliminary. EEG recording and perfusion single-photon emission computed tomography assessment was done in 27 subjects. Alpha3/alpha2 frequency power ratio, including cortical thickness, was figured for every subject. Contrasts in cortical thickness among the groups were assessed. Pearson’s r relationship coefficient was utilized to evaluate the quality of the relationship between cortical thinning, brain perfusion, and EEG markers.Results: The higher alpha3/alpha2 frequency power ratio group corresponded with more prominent cortical decay and a lower perfusional rate in the temporoparietal cortex. In a subsequent meetup after 3 years, these patients had AD.Conclusion: High EEG upper/low alpha power ratio was connected with cortical diminishing and lower perfusion in the temporoparietal brain area. The increase in EEG upper/low alpha frequency power ratio could be helpful in recognizing people in danger of conversion to AD dementia and this may be quality information in connection with clinical assessment. Keywords: electroencephalography, mild cognitive impairment, hippocampal volume, brain rhythms, biomarkers

  2. Effect of oral acetyl L-carnitine arginate on resting and postprandial blood biomarkers in pre-diabetics

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    Tucker Patrick S

    2009-06-01

    Full Text Available Abstract Background Resting and postprandial oxidative stress is elevated in those with metabolic disorders such as diabetes. Antioxidant supplementation may attenuate the rise in oxidative stress following feeding. Therefore we sought to determine the effects of acetyl L-carnitine arginate (ALCA on resting and postprandial biomarkers of glucose and lipid metabolism, as well as oxidative stress. Methods Twenty-nine pre-diabetic men and women were randomly assigned to either 3 g·day-1 of ALCA (n = 14; 31 ± 3 yrs or placebo (n = 15; 35 ± 3 yrs in a double-blind design, to consume for eight weeks. Fasting blood samples were taken from subjects both pre and post intervention. After each fasting sample was obtained, subjects consumed a high fat, high carbohydrate meal and additional blood samples were taken at 1, 2, 4, and 6 hours post meal. Samples were analyzed for a variety of metabolic variables (e.g., glucose, HbA1c, lipid panel, C-reactive protein, nitrate/nitrite, and several markers of oxidative stress. Area under the curve (AUC was calculated for each variable measured post meal, both pre and post intervention. Results ALCA, but not placebo, resulted in an increase in nitrate/nitrite (25.4 ± 1.9 to 30.1 ± 2.8 μmol·L-1 from pre to post intervention, with post intervention values greater compared to placebo (p = 0.01. No other changes of statistical significance were noted (p > 0.05, although ALCA resulted in slight improvements in glucose (109 ± 5 to 103 ± 5 mg·dL-1, HbA1c (6.6 ± 1.1 to 6.2 ± 1.2%, and HOMA-IR (3.3 ± 1.3 to 2.9 ± 1.2. AUC postprandial data were not statistically different between ALCA and placebo for any variable (p > 0.05. However, nitrate/nitrite demonstrated a moderate effect size (r = 0.35 for increase from pre (139.50 ± 18.35 μmol·L-1·6 hr-1 to post (172.40 ± 21.75 μmol·L-1·6 hr-1 intervention with ALCA, and the magnitude of decrease following feeding was not as pronounced as with placebo

  3. Blood born miRNAs signatures that can serve as disease specific biomarkers are not significantly affected by overall fitness and exercise.

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    Christina Backes

    Full Text Available Blood born micro(miRNA expression pattern have been reported for various human diseases with signatures specific for diseases. To evaluate these biomarkers, it is mandatory to know possible changes of miRNA signatures in healthy individuals under different physiological conditions. We analyzed the miRNA expression in peripheral blood of elite endurance athletes and moderatly active controls. Blood drawing was done before and after exhaustive exercise in each group. After Benjamini-Hochberg adjustment we did not find any miRNA with significant p-values when comparing miRNA expression between the different groups. We found, however, 24 different miRNAs with an expression fold change of minimum 1.5 in at least one of the comparisons (athletes before vs after exercise, athletes before exercise vs controls and athletes after exercise vs controls. The observed changes are not significant in contrast to the expression changes of the blood born miRNA expression reported for many human diseases. These data support the idea of disease associated miRNA patterns useful as biomarkers that are not readily altered by physiological conditions.

  4. Blood born miRNAs signatures that can serve as disease specific biomarkers are not significantly affected by overall fitness and exercise.

    Science.gov (United States)

    Backes, Christina; Leidinger, Petra; Keller, Andreas; Hart, Martin; Meyer, Tim; Meese, Eckart; Hecksteden, Anne

    2014-01-01

    Blood born micro(mi)RNA expression pattern have been reported for various human diseases with signatures specific for diseases. To evaluate these biomarkers, it is mandatory to know possible changes of miRNA signatures in healthy individuals under different physiological conditions. We analyzed the miRNA expression in peripheral blood of elite endurance athletes and moderatly active controls. Blood drawing was done before and after exhaustive exercise in each group. After Benjamini-Hochberg adjustment we did not find any miRNA with significant p-values when comparing miRNA expression between the different groups. We found, however, 24 different miRNAs with an expression fold change of minimum 1.5 in at least one of the comparisons (athletes before vs after exercise, athletes before exercise vs controls and athletes after exercise vs controls). The observed changes are not significant in contrast to the expression changes of the blood born miRNA expression reported for many human diseases. These data support the idea of disease associated miRNA patterns useful as biomarkers that are not readily altered by physiological conditions.

  5. Proteomic biomarkers of peripheral blood mononuclear cells obtained from postmenopausal women undergoing an intervention with soy isoflavones

    NARCIS (Netherlands)

    Fuchs, D.; Vafeiadou, K.; Hall, W.L.; Daniel, H.; Williams, C.M.; Schroot, J.H.; Wenzel, U.

    2007-01-01

    Background: The incidence of cardiovascular diseases increases after menopause, and soy consumption is suggested to inhibit disease development. Objective: The objective was to identify biomarkers of response to a dietary supplementation with an isoflavone extract in postmenopausal women by proteome

  6. Brain imaging and blood biomarker abnormalities in children with autosomal-dominant Alzheimer's disease: A cross-sectional Study

    Science.gov (United States)

    Quiroz, Y.T.; Schultz, A.; Chen, K.; Protas, H.; Brickhouse, M.; Fleisher, A.S.; Langbaum, J.B.; Thiyyagura, P.; Fagan, A.M.; Shah, A.R.; Muniz, M.; Arboleda-Velasquez, JF; Munoz, C.; Garcia, G.; Acosta-Baena, N.; Giraldo, M.; Tirado, V.; Ramirez, D.; Tariot, PN; Dickerson, B.C.; Sperling, R.A.; Lopera, F.; Reiman, E.M.

    2015-01-01

    IMPORTANCE Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation–carrying and noncarrying children with ADAD. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellin, Colombia, between August 2011 and June 2012. MAIN OUTCOMES AND MEASURES All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding–dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. RESULTS Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task–related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were −0.590 [0.50] for noncarriers and −0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation

  7. Risk assessment and predicting outcomes in patients with depressive symptoms: A review of potential role of peripheral blood based biomarkers.

    Directory of Open Access Journals (Sweden)

    Bhautesh Dinesh Jani

    2015-02-01

    Full Text Available Depression is one of the major global health challenges and a leading contributor of health related disability and costs. Depression is a heterogeneous disorder and current methods for assessing its severity in clinical practice rely on symptom count, however this approach is unreliable and inconsistent. The clinical evaluation of depressive symptoms is particularly challenging in primary care, where the majority of patients with depression are managed, due to the presence of co-morbidities. Current methods for risk assessment of depression do not accurately predict treatment response or clinical outcomes. Several biological pathways have been implicated in the pathophysiology of depression; however, accurate and predictive biomarkers remain elusive. We conducted a systematic review of the published evidence supporting the use of peripheral biomarkers to predict outcomes in depression, using Medline and Embase. Peripheral biomarkers in depression were found to be statistically significant predictors of mental health outcomes such as treatment response, poor outcome and symptom remission; and physical health outcomes such as increased incidence of cardiovascular events and deaths, and all-cause mortality. However, the available evidence has multiple methodological limitations which must be overcome to make any real clinical progress. Despite extensive research on the relationship of depression with peripheral biomarkers, its translational application in practice remains uncertain. In future, peripheral biomarkers identified with novel techniques and combining multiple biomarkers may have a potential role in depression risk assessment but further research is needed in this area.

  8. Temporal Expression of Peripheral Blood Leukocyte Biomarkers in a Macaca fascicularis Infection Model of Tuberculosis; Comparison with Human Datasets and Analysis with Parametric/Non-parametric Tools for Improved Diagnostic Biomarker Identification.

    Directory of Open Access Journals (Sweden)

    Sajid Javed

    Full Text Available A temporal study of gene expression in peripheral blood leukocytes (PBLs from a Mycobacterium tuberculosis primary, pulmonary challenge model Macaca fascicularis has been conducted. PBL samples were taken prior to challenge and at one, two, four and six weeks post-challenge and labelled, purified RNAs hybridised to Operon Human Genome AROS V4.0 slides. Data analyses revealed a large number of differentially regulated gene entities, which exhibited temporal profiles of expression across the time course study. Further data refinements identified groups of key markers showing group-specific expression patterns, with a substantial reprogramming event evident at the four to six week interval. Selected statistically-significant gene entities from this study and other immune and apoptotic markers were validated using qPCR, which confirmed many of the results obtained using microarray hybridisation. These showed evidence of a step-change in gene expression from an 'early' FOS-associated response, to a 'late' predominantly type I interferon-driven response, with coincident reduction of expression of other markers. Loss of T-cell-associate marker expression was observed in responsive animals, with concordant elevation of markers which may be associated with a myeloid suppressor cell phenotype e.g. CD163. The animals in the study were of different lineages and these Chinese and Mauritian cynomolgous macaque lines showed clear evidence of differing susceptibilities to Tuberculosis challenge. We determined a number of key differences in response profiles between the groups, particularly in expression of T-cell and apoptotic makers, amongst others. These have provided interesting insights into innate susceptibility related to different host `phenotypes. Using a combination of parametric and non-parametric artificial neural network analyses we have identified key genes and regulatory pathways which may be important in early and adaptive responses to TB. Using

  9. Expression profiling of blood samples from an SU5416 Phase III metastatic colorectal cancer clinical trial: a novel strategy for biomarker identification

    Directory of Open Access Journals (Sweden)

    Smolich Beverly D

    2003-02-01

    Full Text Available Abstract Background Microarray-based gene expression profiling is a powerful approach for the identification of molecular biomarkers of disease, particularly in human cancers. Utility of this approach to measure responses to therapy is less well established, in part due to challenges in obtaining serial biopsies. Identification of suitable surrogate tissues will help minimize limitations imposed by those challenges. This study describes an approach used to identify gene expression changes that might serve as surrogate biomarkers of drug activity. Methods Expression profiling using microarrays was applied to peripheral blood mononuclear cell (PBMC samples obtained from patients with advanced colorectal cancer participating in a Phase III clinical trial. The PBMC samples were harvested pre-treatment and at the end of the first 6-week cycle from patients receiving standard of care chemotherapy or standard of care plus SU5416, a vascular endothelial growth factor (VEGF receptor tyrosine kinase (RTK inhibitor. Results from matched pairs of PBMC samples from 23 patients were queried for expression changes that consistently correlated with SU5416 administration. Results Thirteen transcripts met this selection criterion; six were further tested by quantitative RT-PCR analysis of 62 additional samples from this trial and a second SU5416 Phase III trial of similar design. This method confirmed four of these transcripts (CD24, lactoferrin, lipocalin 2, and MMP-9 as potential biomarkers of drug treatment. Discriminant analysis showed that expression profiles of these 4 transcripts could be used to classify patients by treatment arm in a predictive fashion. Conclusions These results establish a foundation for the further exploration of peripheral blood cells as a surrogate system for biomarker analyses in clinical oncology studies.

  10. Blood RNA biomarkers in prodromal PARK4 and REM sleep behavior disorder show role of complexin-1 loss for risk of Parkinson's disease.

    Science.gov (United States)

    Lahut, Suna; Gispert, Suzana; Ömür, Özgür; Depboylu, Candan; Seidel, Kay; Domínguez-Bautista, Jorge Antolio; Brehm, Nadine; Tireli, Hülya; Hackmann, Karl; Pirkevi, Caroline; Leube, Barbara; Ries, Vincent; Reim, Kerstin; Brose, Nils; den Dunnen, Wilfred F; Johnson, Madrid; Wolf, Zsuzsanna; Schindewolf, Marc; Schrempf, Wiebke; Reetz, Kathrin; Young, Peter; Vadasz, David; Frangakis, Achilleas S; Schröck, Evelin; Steinmetz, Helmuth; Jendrach, Marina; Rüb, Udo; Başak, Ayşe Nazlı; Oertel, Wolfgang; Auburger, Georg

    2017-01-20

    Parkinson's disease (PD) is a frequent neurodegenerative process at old age. Accumulation and aggregation of the lipid-binding SNARE complex component alpha-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity are intensely investigated. In view of physiological SNCA roles in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation), to identify effects of SNCA gain-of-function as potential disease biomarkers. The expression of other Parkinson's disease gene was not, but complexin-1 (CPLX1) mRNA downregulation was correlated with genotype. In global RNAseq profiling of blood from presymptomatic PARK4, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, toll like receptor signalling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH, and PLTP mRNA upregulations were validated in PARK4. When analysing cases with REM sleep behaviour disorder (RBD), the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3'-UTR of the CPLX1 gene we identified a SNP that is significantly associated with PD risk. In summary, our data define CPLX1 as PD risk factor and provide functional insights into the role and regulation of blood alpha-synuclein levels. The novel blood biomarkers of PARK4 in this Turkish family may become useful for PD prediction.

  11. A novel method for RNA extraction from FFPE samples reveals significant differences in biomarker expression between orthotopic and subcutaneous pancreatic cancer patient-derived xenografts

    Science.gov (United States)

    Brown, Mark; Maawy, Ali; Chang, Alexander; Lee, Jacqueline; Gharibi, Armen; Katz, Matthew H; Fleming, Jason; Hoffman, Robert M; Bouvet, Michael; Doebler, Robert; Kelber, Jonathan A

    2017-01-01

    Next-generation sequencing (NGS) can identify and validate new biomarkers of cancer onset, progression and therapy resistance. Substantial archives of formalin-fixed, paraffin-embedded (FFPE) cancer samples from patients represent a rich resource for linking molecular signatures to clinical data. However, performing NGS on FFPE samples is limited by poor RNA purification methods. To address this hurdle, we developed an improved methodology for extracting high-quality RNA from FFPE samples. By briefly integrating a newly-designed micro-homogenizing (mH) tool with commercially available FFPE RNA extraction protocols, RNA recovery is increased by approximately 3-fold while maintaining standard A260/A280 ratios and RNA quality index (RQI) values. Furthermore, we demonstrate that the mH-purified FFPE RNAs are longer and of higher integrity. Previous studies have suggested that pancreatic ductal adenocarcinoma (PDAC) gene expression signatures vary significantly under in vitro versus in vivo and in vivo subcutaneous versus orthotopic conditions. By using our improved mH-based method, we were able to preserve established expression patterns of KRas-dependency genes within these three unique microenvironments. Finally, expression analysis of novel biomarkers in KRas mutant PDAC samples revealed that PEAK1 decreases and MST1R increases by over 100-fold in orthotopic versus subcutaneous microenvironments. Interestingly, however, only PEAK1 levels remain elevated in orthotopically grown KRas wild-type PDAC cells. These results demonstrate the critical nature of the orthotopic tumor microenvironment when evaluating the clinical relevance of new biomarkers in cells or patient-derived samples. Furthermore, this new mH-based FFPE RNA extraction method has the potential to enhance and expand future FFPE-RNA-NGS cancer biomarker studies. PMID:27602776

  12. Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue.

    Science.gov (United States)

    Lai, C-Y; Lee, S-Y; Scarr, E; Yu, Y-H; Lin, Y-T; Liu, C-M; Hwang, T-J; Hsieh, M H; Liu, C-C; Chien, Y-L; Udawela, M; Gibbons, A S; Everall, I P; Hwu, H-G; Dean, B; Chen, W J

    2016-01-19

    Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.

  13. Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy

    Science.gov (United States)

    Blazkova, Jana; Gupta, Sarthak; Liu, Yudong; Gaudilliere, Brice; Ganio, Edward A.; Bolen, Christopher R.; Saar-Dover, Ron; Fragiadakis, Gabriela K.; Angst, Martin S.; Hasni, Sarfaraz; Aghaeepour, Nima; Stevenson, David; Baldwin, Nicole; Anguiano, Esperanza; Chaussabel, Damien; Altman, Matthew C.; Kaplan, Mariana J.; Davis, Mark M.

    2017-01-01

    Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. In this study, we identified a gene signature of immature-like neutrophils, characterized by the overexpression of genes encoding for several granule-containing proteins, which was found at higher levels (up to 3-fold) in young (20–30 y old) but not older (60 to >89 y old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap formation at baseline and upon microbial or sterile autoimmune stimuli. The expression levels of the immature-like neutrophil signature increased linearly with pregnancy, an immune state of increased susceptibility to certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women. PMID:28179497

  14. 9th GCC closed forum: CAPA in regulated bioanalysis; method robustness, biosimilars, preclinical method validation, endogenous biomarkers, whole blood stability, regulatory audit experiences and electronic laboratory notebooks.

    Science.gov (United States)

    Hayes, Roger; LeLacheur, Richard; Dumont, Isabelle; Couerbe, Philippe; Safavi, Afshin; Islam, Rafiq; Pattison, Colin; Cape, Stephanie; Rocci, Mario; Briscoe, Chad; Cojocaru, Laura; Groeber, Elizabeth; Silvestro, Luigi; Bravo, Jennifer; Shoup, Ron; Verville, Manon; Zimmer, Jennifer; Caturla, Maria Cruz; Khadang, Ardeshir; Bourdage, James; Hughes, Nicola; Fatmi, Saadya; Di Donato, Lorella; Sheldon, Curtis; Keyhani, Anahita; Satterwhite, Christina; Yu, Mathilde; Fiscella, Michele; Hulse, James; Lin, Zhongping John; Garofolo, Wei; Savoie, Natasha; Xiao, Yi Qun; Kurylak, Kai; Harris, Sarah; Saxena, Manju; Buonarati, Mike; Lévesque, Ann; Boudreau, Nadine; Lin, Jenny; Khan, Masood U; Ray, Gene; Liu, Yansheng; Xu, Allan; Soni, Gunjan; Ward, Ian; Kingsley, Clare; Ritzén, Hanna; Tabler, Edward; Nicholson, Bob; Bennett, Patrick; van de Merbel, Nico; Karnik, Shane; Bouhajib, Mohammed; Wieling, Jaap; Mulvana, Daniel; Ingelse, Benno; Allen, Mike; Malone, Michele; Fang, Xinping

    2016-03-01

    The 9th GCCClosed Forum was held just prior to the 2015 Workshop on Recent Issues in Bioanalysis (WRIB) in Miami, FL, USA on 13 April 2015. In attendance were 58 senior-level participants, from eight countries, representing 38 CRO companies offering bioanalytical services. The objective of this meeting was for CRO bioanalytical representatives to meet and discuss scientific and regulatory issues specific to bioanalysis. The issues selected at this year's closed forum include CAPA, biosimilars, preclinical method validation, endogenous biomarkers, whole blood stability, and ELNs. A summary of the industry's best practices and the conclusions from the discussion of these topics is included in this meeting report.

  15. The potential of pathological protein fragmentation in blood-based biomarker development for dementia - with emphasis on Alzheimer's disease

    DEFF Research Database (Denmark)

    Inekci, Dilek; Svendsen Jonesco, Ditte; Kennard, Sophie;

    2015-01-01

    The diagnosis of dementia is challenging and early stages are rarely detected limiting the possibilities for early intervention. Another challenge is the overlap in the clinical features across the different dementia types leading to difficulties in the differential diagnosis. Identifying...... biomarkers that can detect the pre-dementia stage and allow differential diagnosis could provide an opportunity for timely and optimal intervention strategies. Also, such biomarkers could help in selection and inclusion of the right patients in clinical trials of both Alzheimer's disease and other dementia......, as there is a significant crossover between the proteins involved in the different types of dementia. Additionally, CSF sampling makes these biomarkers challenging for presymptomatic identification. We need to focus on disease-specific protein fragmentation to find a fragment pattern unique for each separate dementia type...

  16. The Temporal Pattern of Changes in Serum Biomarker Levels Reveal Complex and Dynamically Changing Pathologies after Exposure to a Single Low-intensity Blast in Mice

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    Farid eAhmed

    2015-06-01

    Full Text Available Time dependent changes of protein biomarkers in the serum can help identifying the pathological processes and assessing the severity and progression of the disease in blast induced traumatic brain injury (bTBI. We obtained blood from naïve mice and mice exposed to a single, low-intensity blast at 2 hour, 1 day, 1 week and 1 month post-injury. We then determined the serum levels of biomarkers related to metabolism (4-HNE, HIF-1α, Ceruloplasmin, vascular functions (VEGF, vWF, AQP1, AQP4, FLK-1, cell adhesion (Integrin 6α, TIMP1, TIMP4, Ncad, Connexin-43, inflammation (MMP-8, MIP-1α, CINC1, Fibrinogen, CCR5, CRP, Galectin-1, MCP-1, p38, OX-44, Osteopontin, axonal (NF-H, Tau, neuronal (NSE, CK-BB and glial integrity (GFAP, S100β, MBP and compared the changes among the experimental groups. Our results indicate that in the mouse, exposure to a single, low-intensity blast caused substantial metabolic, vascular and inflammatory responses, altered cell adhesion but only minimal neuronal, axonal and glia injury as indicated by serum proteomics data. Changes in metabolism, vascular functions and inflammation remained elevated at the termination of the experiment while the others were only detectable during the acute post-injury phase. Our findings indicate that exposure to a single; low-intensity blast can induce complex pathological processes with distinct temporal profile. Hence, monitoring serum biomarker levels at various post-injury time points may provide enhanced diagnostics in bTBI.

  17. Differential profiling of breast cancer plasma proteome by isotope-coded affinity tagging method reveals biotinidase as a breast cancer biomarker

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    Yu Myeong-Hee

    2010-03-01

    Full Text Available Abstract Background Breast cancer is one of the leading causes of women's death worldwide. It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood. Methods Plasma proteomes obtained from 6 breast cancer patients and 6 normal healthy women were analyzed by using the isotope-coded affinity tag (ICAT labeling approach and tandem mass spectrometry. All the plasma samples used were depleted of highly abundant 6 plasma proteins by immune-affinity column chromatography before ICAT labeling. Several proteins showing differential abundance level were selected based on literature searches and their specificity to the commercially available antibodies, and then verified by immunoblot assays. Results A total of 155 proteins were identified and quantified by ICAT method. Among them, 33 proteins showed abundance changes by more than 1.5-fold between the plasmas of breast cancer patients and healthy women. We chose 5 proteins for the follow-up confirmation in the individual plasma samples using immunoblot assay. Four proteins, α1-acid glycoprotein 2, monocyte differentiation antigen CD14, biotinidase (BTD, and glutathione peroxidase 3, showed similar abundance ratio to ICAT result. Using a blind set of plasmas obtained from 21 breast cancer patients and 21 normal healthy controls, we confirmed that BTD was significantly down-regulated in breast cancer plasma (Wilcoxon rank-sum test, p = 0.002. BTD levels were lowered in all cancer grades (I-IV except cancer grade zero. The area under the receiver operating characteristic curve of BTD was 0.78. Estrogen receptor status (p = 0.940 and progesterone receptor status (p = 0.440 were not associated with the plasma BTD levels. Conclusions Our study suggests that BTD is a potential serological biomarker for the detection of breast cancer.

  18. Biomarker screening of oral cancer cell lines revealed sub-populations of CD133-, CD44-, CD24- and ALDH1- positive cancer stem cells

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    Kendall K

    2013-05-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC ranks sixth worldwide for cancer-related mortality. For the past several decades the mainstay of treatment for HNSCC has been surgery and external beam radiation, although more recent trials combining chemotherapy and radiation have demonstrated improvements. However, cancer recurrence and treatment failures continue to occur in a significant percentage of patients. Recent advances in tumor biology have led to the discovery that many cancers, including HNSCC, may contain subpopulations of cells with stem cell-like properties that may explain relapse and recurrence. The objective of this study was to screen existing oral cancer cell lines for biomarkers specific for cells with stem cell-like properties. RNA was isolated for RT-PCR screening using primers for specific mRNA of the biomarkers: CD44, CD24, CD133, NANOG, Nestin, ALDH1, and ABCG2 in CAL27, SCC25 and SCC15 cells. This analysis revealed that some oral cancer cell lines (CAL27 and SCC25 may contain small subpopulations of adhesion- and contact-independent cells (AiDC that also express tumor stem cell markers, including CD44, CD133, and CD24. In addition, CAL27 cells also expressed the intracellular tumor stem cell markers, ALDH1 and ABCG2. Isolation and culture of the adhesion- and contact-independent cells from CAL27 and SCC25 populations revealed differential proliferation rates and more robust inhibition by the MEK inhibitor PD98059, as well as the chemotherapeutic agents Cisplatin and Paclitaxel, within the AiDC CAL27 cells. At least one oral cancer cell line (CAL27 contained subpopulations of cells that express specific biomarkers associated with tumor stem cells which were morphologically and phenotypically distinct from other cells within this cell line.

  19. The potential of pathological protein fragmentation in blood-based biomarker development for dementia - with emphasis on Alzheimer's disease

    DEFF Research Database (Denmark)

    Inekci, Dilek; Svendsen Jonesco, Ditte; Kennard, Sophie;

    2015-01-01

    biomarkers that can detect the pre-dementia stage and allow differential diagnosis could provide an opportunity for timely and optimal intervention strategies. Also, such biomarkers could help in selection and inclusion of the right patients in clinical trials of both Alzheimer's disease and other dementia......The diagnosis of dementia is challenging and early stages are rarely detected limiting the possibilities for early intervention. Another challenge is the overlap in the clinical features across the different dementia types leading to difficulties in the differential diagnosis. Identifying...

  20. The influence of radiographic phenotype and smoking status on peripheral blood biomarker patterns in chronic obstructive pulmonary disease.

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    Jessica M Bon

    Full Text Available BACKGROUND: Chronic obstructive pulmonary disease (COPD is characterized by both airway remodeling and parenchymal destruction. The identification of unique biomarker patterns associated with airway dominant versus parenchymal dominant patterns would support the existence of unique phenotypes representing independent biologic processes. A cross-sectional study was performed to examine the association of serum biomarkers with radiographic airway and parenchymal phenotypes of COPD. METHODOLOGY/PRINCIPAL FINDINGS: Serum from 234 subjects enrolled in a CT screening cohort was analyzed for 33 cytokines and growth factors using a multiplex protein array. The association of serum markers with forced expiratory volume in one second percent predicted (FEV1% and quantitative CT measurements of airway thickening and emphysema was assessed with and without stratification for current smoking status. Significant associations were found with several serum inflammatory proteins and measurements of FEV1%, airway thickening, and parenchymal emphysema independent of smoking status. The association of select analytes with airway thickening and emphysema was independent of FEV1%. Furthermore, the relationship between other inflammatory markers and measurements of physiologic obstruction or airway thickening was dependent on current smoking status. CONCLUSIONS/SIGNIFICANCE: Airway and parenchymal phenotypes of COPD are associated with unique systemic serum biomarker profiles. Serum biomarker patterns may provide a more precise classification of the COPD syndrome, provide insights into disease pathogenesis and identify targets for novel patient-specific biological therapies.

  1. Eosinophilia in routine blood samples as a biomarker for solid tumor development - A study based on the Copenhagen Primary Care Differential Count (CopDiff) Database

    DEFF Research Database (Denmark)

    Andersen, Christen Lykkegaard; Siersma, Volkert Dirk; Hasselbalch, Hans Carl;

    2014-01-01

    eosinophilia in routine blood samples as a potential biomarker of solid tumor development in a prospective design. MATERIAL AND METHODS: From the Copenhagen Primary Care Differential Count (CopDiff) Database, we identified 356 196 individuals with at least one differential cell count (DIFF) encompassing...... the eosinophil count during 2000-2007. From these, one DIFF was randomly chosen and categorized according to no (... was increased with mild eosinophilia [OR 1.93 (CI 1.29-2.89), p = 0.0013]. No associations with eosinophilia were observed for the remaining solid cancers. CONCLUSION: We demonstrate that eosinophilia in routine blood samples associates with an increased risk of bladder cancer. Our data emphasize...

  2. A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.

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    Reijo Laaksonen

    Full Text Available BACKGROUND: Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. METHODOLOGY: We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg, atorvastatin (40 mg, or placebo. PRINCIPAL FINDINGS: High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05, while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1 in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. CONCLUSIONS: High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.

  3. RELATIONSHIP BETWEEN CD34/CD45 POSITIVE CELLS CONCENTRATION IN BLOOD OF HEART RECIPIENTS AND LEVEL OF GRAFT VASCULOPATHY RISK BIOMARKERS

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    O. P. Shevchenko

    2013-01-01

    Full Text Available Aim. To determine the relationship between CD34/CD45 positive cells number in peripheral blood before and after heart transplantation (HTx and plasma level of the biomarkers. Materials and methods. We studied 27 pts. (23 men; 40 ± 13 years with heart failure caused by dilated (17 cases or ischemic cardiomyopathy (10 cases before and after HTx. CD34/CD45 positive cells were measured in peripheral blood before and 2–4 days after the operation by flow cytometry and expressed in number of the cells per 106 events, plasma level of the biomar- kers – by ELISA. Results. The number of CD34/CD45+ cells in pts. with heart failure (224 ± 166 was similar to those in healthy individuals (233 ± 120 and there was no significant difference in the cell number between pts. with dilated (253 ± 188 and ischemic cardiomyopathy (169 ± 100. The cell number did not correlate with age, sex, body weight, blood cells counts and preoperative levels of the biomarkers: PlGF, sCD40L, PAPP-A. In 2–5 days after HTx the cell number decreased to 103 ± 102. The cell number after HTx did not correlate with demographic and laboratory parameters, anesthesia, operation, ischemia and hypothermia duration, blood loss volume and preoperative levels of PlGF and PAPP-A but correlated with sCD40L level in pts. with ischemic cardiomyopathy. Conclusion: Circulating HSC number in patients with heart failure does not differ from those in healthy individuals and decreases after HTx. In patients with ischemic cardiomyopathy the cell number after transplantation associates with preoperative level of sCD40L – the negative predictor of vasculopathy. 

  4. Population Structure of UK Biobank and Ancient Eurasians Reveals Adaptation at Genes Influencing Blood Pressure.

    Science.gov (United States)

    Galinsky, Kevin J; Loh, Po-Ru; Mallick, Swapan; Patterson, Nick J; Price, Alkes L

    2016-11-03

    Analyzing genetic differences between closely related populations can be a powerful way to detect recent adaptation. The very large sample size of the UK Biobank is ideal for using population differentiation to detect selection and enables an analysis of the UK population structure at fine resolution. In this study, analyses of 113,851 UK Biobank samples showed that population structure in the UK is dominated by five principal components (PCs) spanning six clusters: Northern Ireland, Scotland, northern England, southern England, and two Welsh clusters. Analyses of ancient Eurasians revealed that populations in the northern UK have higher levels of Steppe ancestry and that UK population structure cannot be explained as a simple mixture of Celts and Saxons. A scan for unusual population differentiation along the top PCs identified a genome-wide-significant signal of selection at the coding variant rs601338 in FUT2 (p = 9.16 × 10(-9)). In addition, by combining evidence of unusual differentiation within the UK with evidence from ancient Eurasians, we identified genome-wide-significant (p = 5 × 10(-8)) signals of recent selection at two additional loci: CYP1A2-CSK and F12. We detected strong associations between diastolic blood pressure in the UK Biobank and both the variants with selection signals at CYP1A2-CSK (p = 1.10 × 10(-19)) and the variants with ancient Eurasian selection signals at the ATXN2-SH2B3 locus (p = 8.00 × 10(-33)), implicating recent adaptation related to blood pressure.

  5. Differentially expressed androgen-regulated genes in androgen-sensitive tissues reveal potential biomarkers of early prostate cancer.

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    Dogus Murat Altintas

    Full Text Available BACKGROUND: Several data favor androgen receptor implication in prostate cancer initiation through the induction of several gene activation programs. The aim of the study is to identify potential biomarkers for early diagnosis of prostate cancer (PCa among androgen-regulated genes (ARG and to evaluate comparative expression of these genes in normal prostate and normal prostate-related androgen-sensitive tissues that do not (or rarely give rise to cancer. METHODS: ARG were selected in non-neoplastic adult human prostatic epithelial RWPE-1 cells stably expressing an exogenous human androgen receptor, using RNA-microarrays and validation by qRT-PCR. Expression of 48 preselected genes was quantified in tissue samples (seminal vesicles, prostate transitional zones and prostate cancers, benign prostatic hypertrophy obtained from surgical specimens using TaqMan® low-density arrays. The diagnostic performances of these potential biomarkers were compared to that of genes known to be associated with PCa (i.e. PCA3 and DLX1. RESULTS AND DISCUSSION: By crossing expression studies in 26 matched PCa and normal prostate transitional zone samples, and 35 matched seminal vesicle and PCa samples, 14 genes were identified. Similarly, 9 genes were overexpressed in 15 benign prostatic hypertrophy samples, as compared to PCa samples. Overall, we selected 8 genes of interest to evaluate their diagnostic performances in comparison with that of PCA3 and DLX1. Among them, 3 genes: CRYAB, KCNMA1 and SDPR, were overexpressed in all 3 reference non-cancerous tissues. The areas under ROC curves of these genes reached those of PCA3 (0.91 and DLX1 (0.94. CONCLUSIONS: We identified ARG with reduced expression in PCa and with significant diagnostic values for discriminating between cancerous and non-cancerous prostatic tissues, similar that of PCA3. Given their expression pattern, they could be considered as potentially protective against prostate cancer. Moreover, they could

  6. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer.

    Science.gov (United States)

    van Ginkel, Joost H; de Leng, Wendy W J; de Bree, Remco; van Es, Robert J J; Willems, Stefan M

    2016-09-20

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post treatment surveillance. We retrospectively analyzed mutational hotspots using targeted next-generation sequencing (NGS) of 239 HNSCC tumor samples in order to examine the mutational profile of HNSCC. Furthermore, we assessed prevalence, co-occurrence, and synonymy of gene mutations in (matched) tumor samples. TP53 was found mutated the most frequent with mutation rates of up to 83% in all tumors, compared to mutation rates of between 0 and 21% of CDKN2A, PIK3CA, HRAS, CDK4, FBXW7 and RB1. Mutational co-occurrence predominantly existed between TP53 and PIK3CA, TP53 and CDKN2A, and HRAS and PIK3CA. Mutational synonymy between primary tumor and associated metastasis and recurrence was present in respectively 88% and 89%. TP53 mutations were concordantly mutated in 95% of metastases and in 91% of recurrences. This indicates TP53 mutations to be highly prevalent and concordant in primary tumors and associated locoregional metastases and recurrences. In turn, this provides ground for further investigating the use of TP53 mutations as diagnostic biomarkers in HNSCC patients.

  7. Carbon sources in suspended particles and surface sediments from the Beaufort Sea revealed by molecular lipid biomarkers and compound-specific isotope analysis

    Science.gov (United States)

    Tolosa, I.; Fiorini, S.; Gasser, B.; Martín, J.; Miquel, J. C.

    2013-03-01

    Molecular lipid biomarkers (hydrocarbons, alcohols, sterols and fatty acids) and compound-specific isotope analysis of suspended particulate organic matter (SPM) and surface sediments of the Mackenzie Shelf and slope (southeast Beaufort Sea, Arctic Ocean) were studied in summer 2009. The concentrations of the molecular lipid markers, characteristic of known organic matter sources, were grouped and used as proxies to evaluate the relative importance of fresh algal, detrital algal, fossil, C3 terrestrial plants, bacterial and zooplankton material in the organic matter (OM) of this area. Fossil and detrital algal contributions were the major fractions of the freshwater SPM from the Mackenzie River with ~34% each of the total molecular biomarkers. Fresh algal, C3 terrestrial, bacterial and zooplanktonic components represented much lower percentages, 17, 10, 4 and 80%), with a minor contribution of fossil and C3 terrestrial biomarkers. Characterization of the sediments revealed a major sink of refractory algal material mixed with some fresh algal material, fossil hydrocarbons and a small input of C3 terrestrial sources. In particular, the sediments from the shelf and at the mouth of the Amundsen Gulf presented the highest contribution of detrital algal material (60-75%), whereas those from the slope contained the highest proportion of fossil (40%) and C3 terrestrial plant material (10%). Overall, considering that the detrital algal material is marine derived, autochthonous sources contributed more than allochthonous sources to the OM lipid pool. Using the ratio of an allochthonous biomarker (normalized to total organic carbon, TOC) found in the sediments to those measured at the river mouth water, we estimated that the fraction of terrestrial material preserved in the sediments accounted for 30-40% of the total carbon in the inner shelf sediments, 17% in the outer shelf and Amundsen Gulf and up to 25% in the slope sediments. These estimates are low compared to other

  8. Carbon sources in suspended particles and surface sediments from the Beaufort Sea revealed by molecular lipid biomarkers and compound-specific isotope analysis

    Directory of Open Access Journals (Sweden)

    I. Tolosa

    2013-03-01

    Full Text Available Molecular lipid biomarkers (hydrocarbons, alcohols, sterols and fatty acids and compound-specific isotope analysis of suspended particulate organic matter (SPM and surface sediments of the Mackenzie Shelf and slope (southeast Beaufort Sea, Arctic Ocean were studied in summer 2009. The concentrations of the molecular lipid markers, characteristic of known organic matter sources, were grouped and used as proxies to evaluate the relative importance of fresh algal, detrital algal, fossil, C3 terrestrial plants, bacterial and zooplankton material in the organic matter (OM of this area. Fossil and detrital algal contributions were the major fractions of the freshwater SPM from the Mackenzie River with ~34% each of the total molecular biomarkers. Fresh algal, C3 terrestrial, bacterial and zooplanktonic components represented much lower percentages, 17, 10, 4 and 80%, with a minor contribution of fossil and C3 terrestrial biomarkers. Characterization of the sediments revealed a major sink of refractory algal material mixed with some fresh algal material, fossil hydrocarbons and a small input of C3 terrestrial sources. In particular, the sediments from the shelf and at the mouth of the Amundsen Gulf presented the highest contribution of detrital algal material (60–75%, whereas those from the slope contained the highest proportion of fossil (40% and C3 terrestrial plant material (10%. Overall, considering that the detrital algal material is marine derived, autochthonous sources contributed more than allochthonous sources to the OM lipid pool. Using the ratio of an allochthonous biomarker (normalized to total organic carbon, TOC found in the sediments to those measured at the river mouth water, we estimated that the fraction of terrestrial material preserved in the sediments accounted for 30–40% of the total carbon in the inner shelf sediments, 17% in the outer shelf and Amundsen Gulf and up to 25% in the slope sediments. These estimates are low

  9. Differential blood-based diagnosis between benign prostatic hyperplasia and prostate cancer: miRNA as source for biomarkers independent of PSA level, Gleason score, or TNM status.

    Science.gov (United States)

    Leidinger, Petra; Hart, Martin; Backes, Christina; Rheinheimer, Stefanie; Keck, Bastian; Wullich, Bernd; Keller, Andreas; Meese, Eckart

    2016-08-01

    Since the benefit of prostate-specific antigen (PSA) screening remains controversial, new non-invasive biomarkers for prostate carcinoma (PCa) are still required. There is evidence that microRNAs (miRNAs) in whole peripheral blood can separate patients with localized prostate cancer from healthy individuals. However, the potential of blood-based miRNAs for the differential diagnosis of PCa and benign prostatic hyperplasia (BPH) has not been tested. We compared the miRNome from blood of PCa and BPH patients and further investigated the influence of the tumor volume, tumor-node-metastasis (TNM) classification, Gleason score, pretreatment risk status, and the pretreatment PSA value on the miRNA pattern. By microarray approach, we identified seven miRNAs that were significantly deregulated in PCa patients compared to BPH patients. Using quantitative real time PCR (qRT-PCR), we confirmed downregulation of hsa-miR-221* (now hsa-miR-221-5p) and hsa-miR-708* (now hsa-miR-708-3p) in PCa compared to BPH. Clinical parameters like PSA level, Gleason score, or TNM status seem to have only limited impact on the overall abundance of miRNAs in patients' blood, suggesting a no influence of these factors on the expression of deregulated miRNAs.

  10. Proteomic Analysis of Plasma from California Sea Lions (Zalophus californianus Reveals Apolipoprotein E as a Candidate Biomarker of Chronic Domoic Acid Toxicosis.

    Directory of Open Access Journals (Sweden)

    Benjamin A Neely

    Full Text Available Domoic acid toxicosis (DAT in California sea lions (Zalophus californianus is caused by exposure to the marine biotoxin domoic acid and has been linked to massive stranding events and mortality. Diagnosis is based on clinical signs in addition to the presence of domoic acid in body fluids. Chronic DAT further is characterized by reoccurring seizures progressing to status epilepticus. Diagnosis of chronic DAT is often slow and problematic, and minimally invasive tests for DAT have been the focus of numerous recent biomarker studies. The goal of this study was to retrospectively profile plasma proteins in a population of sea lions with chronic DAT and those without DAT using two dimensional gel electrophoresis to discover whether individual, multiple, or combinations of protein and clinical data could be utilized to identify sea lions with DAT. Using a training set of 32 sea lion sera, 20 proteins and their isoforms were identified that were significantly different between the two groups (p<0.05. Interestingly, 11 apolipoprotein E (ApoE charge forms were decreased in DAT samples, indicating that ApoE charge form distributions may be important in the progression of DAT. In order to develop a classifier of chronic DAT, an independent blinded test set of 20 sea lions, seven with chronic DAT, was used to validate models utilizing ApoE charge forms and eosinophil counts. The resulting support vector machine had high sensitivity (85.7% with 92.3% negative predictive value and high specificity (92.3% with 85.7% positive predictive value. These results suggest that ApoE and eosinophil counts along with machine learning can perform as a robust and accurate tool to diagnose chronic DAT. Although this analysis is specifically focused on blood biomarkers and routine clinical data, the results demonstrate promise for future studies combining additional variables in multidimensional space to create robust classifiers.

  11. Phylogeny of haemosporidian blood parasites revealed by a multi-gene approach.

    Science.gov (United States)

    Borner, Janus; Pick, Christian; Thiede, Jenny; Kolawole, Olatunji Matthew; Kingsley, Manchang Tanyi; Schulze, Jana; Cottontail, Veronika M; Wellinghausen, Nele; Schmidt-Chanasit, Jonas; Bruchhaus, Iris; Burmester, Thorsten

    2016-01-01

    The apicomplexan order Haemosporida is a clade of unicellular blood parasites that infect a variety of reptilian, avian and mammalian hosts. Among them are the agents of human malaria, parasites of the genus Plasmodium, which pose a major threat to human health. Illuminating the evolutionary history of Haemosporida may help us in understanding their enormous biological diversity, as well as tracing the multiple host switches and associated acquisitions of novel life-history traits. However, the deep-level phylogenetic relationships among major haemosporidian clades have remained enigmatic because the datasets employed in phylogenetic analyses were severely limited in either gene coverage or taxon sampling. Using a PCR-based approach that employs a novel set of primers, we sequenced fragments of 21 nuclear genes from seven haemosporidian parasites of the genera Leucocytozoon, Haemoproteus, Parahaemoproteus, Polychromophilus and Plasmodium. After addition of genomic data from 25 apicomplexan species, the unreduced alignment comprised 20,580 bp from 32 species. Phylogenetic analyses were performed based on nucleotide, codon and amino acid data employing Bayesian inference, maximum likelihood and maximum parsimony. All analyses resulted in highly congruent topologies. We found consistent support for a basal position of Leucocytozoon within Haemosporida. In contrast to all previous studies, we recovered a sister group relationship between the genera Polychromophilus and Plasmodium. Within Plasmodium, the sauropsid and mammal-infecting lineages were recovered as sister clades. Support for these relationships was high in nearly all trees, revealing a novel phylogeny of Haemosporida, which is robust to the choice of the outgroup and the method of tree inference.

  12. Genomic and protein expression analysis reveals Flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

    Science.gov (United States)

    Abdel-Fatah, Tarek MA; Russell, Roslin; Albarakati, Nada; Maloney, David J; Dorjsuren, Dorjbal; Rueda, Oscar M; Moseley, Paul; Mohan, Vivek; Sun, Hongmao; Abbotts, Rachel; Mukherjee, Abhik; Agarwal, Devika; Illuzzi, Jennifer L.; Jadhav, Ajit; Simeonov, Anton; Ball, Graham; Chan, Stephen; Caldas, Carlos; Ellis, Ian O; Wilson, David M; Madhusudan, Srinivasan

    2015-01-01

    FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p=4.89 × 10−57), high mitotic index (p=5.25 × 10−28), pleomorphism (p=6.31 × 10−19), ER negative (p=9.02 × 10−35), PR negative (p=9.24 × 10−24), triple negative phenotype (p=6.67 × 10−21), PAM50.Her2 (p=5.19 × 10−13), PAM50.Basal (p=2.7 × 10−41), PAM50.LumB (p=1.56 × 10−26), integrative molecular cluster 1 (intClust.1) (p=7.47 × 10−12), intClust.5 (p=4.05 × 10−12) and intClust. 10 (p=7.59 × 10−38) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p= 4.4 × 10−16) and multivariate analysis (p= 9.19 × 10−7). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps<0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps<0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps<0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps<0.05). We conclude that FEN1 is a promising biomarker in breast

  13. Combination of p53(ser15) and p21/p21(thr145) in peripheral blood lymphocytes as potential Alzheimer's disease biomarkers.

    Science.gov (United States)

    Tan, Mengshan; Wang, Shuying; Song, Juexian; Jia, Jianping

    2012-05-16

    Alzheimer's disease (AD) is still difficult to be precisely diagnosed in its early stage to date. Establishing of reliable and manageable disease-specific biological markers is required to improve diagnostic accuracy. Based on the hypothesis of cell cycle regulatory failure at the early stage of AD, we tested whether cell cycle regulating proteins p53, p21 and their phosphorylated forms p53(ser15), p21(thr145) were changed in AD patients and whether these proteins could be used as diagnostic biomarkers. Western bolt, Enzyme-linked immunosorbent assay (ELISA), immunofluorescent staining and flow cytometry (FCM) analysis were employed to analyze levels of these proteins in peripheral blood lymphocytes (PBLs) from 95 controls, 94 AD, 12 Parkinson's disease (PD) and 15 vascular dementia (VaD) patients. Compared with controls, p53(ser15) and p21(thr145) levels were significantly increased and p21 level was significantly decreased in PBLs of AD patients but not in PD or VaD, while p53 was increased in both AD and VaD patients. The receiver operating characteristic (ROC) curve analysis showed that the specificity and sensitivity were 76% and 84% for p53, 88% and 82% for p53(ser15), 80% and 75% for p21 and 84% and 68% for p21(thr145) in identifying AD patients. The relatively high diagnostic accuracy support these proteins, especially p53(ser15) and p21 in PBLs may become potential biomarkers for diagnosis of AD.

  14. Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes

    Science.gov (United States)

    Robert, Lidia; Harview, Christina; Emerson, Ryan; Wang, Xiaoyan; Mok, Stephen; Homet, Blanca; Comin-Anduix, Begonya; Koya, Richard C; Robins, Harlan; Tumeh, Paul C; Ribas, Antoni

    2014-01-01

    Targeting immune inhibitory receptors has brought excitement, innovation and hope to cancer patients. Our recent work revealed the immunological effects of blocking the CTLA4 and PD-1 immune checkpoints on T cell receptor usage among peripheral blood cells, and further uncovers how the expansion of the T cell repertoire matches the immunotoxicity profile of the therapy. PMID:25083336

  15. Modulatory effect of pineapple peel extract on lipid peroxidation, catalase activity and hepatic biomarker levels in blood plasma of alcohol-induced oxidative stressed rats

    Institute of Scientific and Technical Information of China (English)

    Okafor OY; Erukainure OL; Ajiboye JA; Adejobi RO; Owolabi FO; Kosoko SB

    2011-01-01

    Objective: To investigate the ability of the methanolic extract of pineapple peel to modulate alcohol-induced lipid peroxidation, changes in catalase activities and hepatic biochemical marker levels in blood plasma. Methods: Oxidative stress was induced by oral administration of ethanol (20% w/v) at a dosage of 5 mL/kg bw in rats. After 28 days of treatment, the rats were fasted overnight and sacrificed by cervical dislocation. Blood was collected with a 2 mL syringe by cardiac puncture and was centrifuged at 3000 rpm for 10 min. The plasma was analyzed to evaluate malondialdehyde (MDA), catalase activity, aspartate aminotransferase (AST), alkaline phosphatase (ALP) and alanine aminotransferase (ALT) concentrations. Results: Administration of alcohol caused a drastic increase (87.74%) in MDA level compared with the control. Pineapple peel extract significantly reduced the MDA level by 60.16% at 2.5 mL/kg bw. Rats fed alcohol only had the highest catalase activity, treatment with pineapple peel extract at 2.5 mL/kg bw however, reduced the activity. Increased AST, ALP and ALT activities were observed in rats fed alcohol only respectively, treatment with pineapple peel extract drastically reduced their activities. Conclusions: The positive modulation of lipid peroxidation, catalase activities as well as hepatic biomarker levels of blood plasma by the methanolic extract of pineapple peels under alcohol-induced oxidative stress is an indication of its protective ability in the management of alcohol-induced toxicity.

  16. [The influence of cardiosurgical intervention type and conditions of artificial blood circulation of perioperative dynamics of cardiac biomarkers].

    Science.gov (United States)

    Dement'eva, I I; Morozov, Iu A; Charnaia, M A

    2013-01-01

    125 patients after cardiac surgery operated on with the use of artificial blood circulation (ABC) were followed-up. Blood levels of cardiac protein, binding aliphatic acids and troponin 1 and 3 days after the operation were registered. The study showed that aorta clamping more then 90 minutes and hypothermic perfusion regimen influence cardiomyocites negatively. The state of "surgical trauma" and reperfusional myocardium damage was approximately the same during aortic surgery, myocardium revascularization with the use of aortic clamping and cardioplegia, and correction of the acquired heart disease, according to the dynamics of the studied proteins in blood. The minimal blood level of cardiac protein, binding aliphatic acids after coronary by-pass surgery on the working heart witnesses about negative influence of crystalloid hypothermic cardioplegia on coronary microcirculation.

  17. Evaluation of tumour hypoxia during radiotherapy using [{sup 18}F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zegers, Catharina M.L.; Hoebers, Frank J.P.; Elmpt, Wouter van; Oellers, Michel C.; Eekers, Danielle; Balmaekers, Leo; Arts-Pechtold, Marlies; Lambin, Philippe [Maastricht University Medical Centre, Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Bons, Judith A. [Maastricht University Medical Centre, Central Diagnostic Laboratory, Maastricht (Netherlands); Troost, Esther G.C. [Maastricht University Medical Centre, Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht (Netherlands); Helmholtz Zentrum Dresden-Rossendorf, Dresden (Germany); Technische Universitaet Dresden, OncoRay, Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Dresden (Germany); Mottaghy, Felix M. [Maastricht University Medical Centre, Department of Nuclear Medicine, Maastricht (Netherlands); RWTH Aachen University, University Hospital, Department of Nuclear Medicine, Aachen (Germany)

    2016-11-15

    Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [{sup 18}F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence. [{sup 18}F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20 Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [{sup 18}F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed. At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm{sup 3} during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased. [{sup 18}F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia. (orig.)

  18. Proteomics mapping of cord blood identifies haptoglobin "switch-on" pattern as biomarker of early-onset neonatal sepsis in preterm newborns.

    Directory of Open Access Journals (Sweden)

    Catalin S Buhimschi

    Full Text Available BACKGROUND: Intra-amniotic infection and/or inflammation (IAI are important causes of preterm birth and early-onset neonatal sepsis (EONS. A prompt and accurate diagnosis of EONS is critical for improved neonatal outcomes. We sought to explore the cord blood proteome and identify biomarkers and functional protein networks characterizing EONS in preterm newborns. METHODOLOGY/PRINCIPAL FINDINGS: We studied a prospective cohort of 180 premature newborns delivered May 2004-September 2009. A proteomics discovery phase employing two-dimensional differential gel electrophoresis (2D-DIGE and mass spectrometry identified 19 differentially-expressed proteins in cord blood of newborns with culture-confirmed EONS (n = 3 versus GA-matched controls (n = 3. Ontological classifications of the proteins included transfer/carrier, immunity/defense, protease/extracellular matrix. The 1(st-level external validation conducted in the remaining 174 samples confirmed elevated haptoglobin and haptoglobin-related protein immunoreactivity (Hp&HpRP in newborns with EONS (presumed and culture-confirmed independent of GA at birth and birthweight (P<0.001. Western blot concurred in determining that EONS babies had conspicuous Hp&HpRP bands in cord blood ("switch-on pattern" as opposed to non-EONS newborns who had near-absent "switch-off pattern" (P<0.001. Fetal Hp phenotype independently impacted Hp&HpRP. A bayesian latent-class analysis (LCA was further used for unbiased classification of all 180 cases based on probability of "antenatal IAI exposure" as latent variable. This was then subjected to 2(nd-level validation against indicators of adverse short-term neonatal outcome. The optimal LCA algorithm combined Hp&HpRP switch pattern (most input, interleukin-6 and neonatal hematological indices yielding two non-overlapping newborn clusters with low (≤20% versus high (≥70% probability of IAI exposure. This approach reclassified ∼30% of clinical EONS diagnoses

  19. Biomarkers in Parkinson's disease.

    Science.gov (United States)

    Morgan, John C; Mehta, Shyamal H; Sethi, Kapil D

    2010-11-01

    Biomarkers are objectively measured characteristics that are indicators of normal biological processes, pathogenic processes, or responses to therapeutic interventions. To date, clinical assessment remains the gold standard in the diagnosis of Parkinson's disease (PD) and clinical rating scales are well established as the gold standard for tracking progression of PD. Researchers have identified numerous potential biomarkers that may aid in the differential diagnosis of PD and/or tracking disease progression. Clinical, genetic, blood and cerebrospinal fluid (proteomics, transcriptomics, metabolomics), and neuroimaging biomarkers may provide useful tools in the diagnosis of PD and in measuring disease progression and response to therapies. Some potential biomarkers are inexpensive and do not require much technical expertise, whereas others are expensive or require specialized equipment and technical skills. Many potential biomarkers in PD show great promise; however, they need to be assessed for their sensitivity and specificity over time in large and varied samples of patients with and without PD.

  20. A biometrical genome search in rats reveals the multigenic basis of blood pressure variation.

    Science.gov (United States)

    Schork, N J; Krieger, J E; Trolliet, M R; Franchini, K G; Koike, G; Krieger, E M; Lander, E S; Dzau, V J; Jacob, H J

    1995-09-01

    A genome-wide search for multiple loci influencing salt-loaded systolic blood pressure (NaSBP) variation among 188 F2 progeny from a cross between the Brown-Norway and spontaneously hypertensive rat strains was pursued in an effort to gain insight into the polygenic basis of blood pressure regulation. The results suggest that loci within five to six genomic regions collectively explain approximately 43% of the total NaSBP variation exhibited among the 188 F2 progeny. Many of these loci are in regions that previous studies have not implicated in blood pressure regulation. Ultimately, however, this study not only sheds light on the multigenic basis of blood pressure but provides further evidence that the identification of the genetic determinants of polygenic traits in mammals is possible with modern biometrical and molecular genetic tools in controlled settings (i.e., breeding paradigm and model organism).

  1. Changes in cytokine and biomarker blood levels in patients with colorectal cancer during dendritic cell-based vaccination

    DEFF Research Database (Denmark)

    Burgdorf, Stefan; Claesson, Mogens; Nielsen, Hans

    2009-01-01

    Introduction. Immunotherapy based on dendritic cell vaccination has exciting perspectives for treatment of cancer. In order to clarify immunological mechanisms during vaccination it is essential with intensive monitoring of the responses. This may lead to optimization of treatment and prediction...... of responding patients. The aim of this study was to evaluate cytokine and biomarker responses in patients with colorectal cancer treated with a cancer vaccine based on dendritic cells pulsed with an allogeneic melanoma cell lysate. Material and methods. Plasma and serum samples were collected prior......-inflammatory cytokines in serum of patients who achieved stable disease following vaccination suggest the occurrence of vaccine-induced Th1 responses. Since Th1 responses seem to be essential in cancer immunotherapy this may indicate a therapeutic potential of the vaccine....

  2. Changes in cytokine and biomarker blood levels in patients with colorectal cancer during dendritic cell-based vaccination

    DEFF Research Database (Denmark)

    Burgdorf, Stefan K; Claesson, Mogens Helweg; Nielsen, Hans J

    2009-01-01

    Introduction. Immunotherapy based on dendritic cell vaccination has exciting perspectives for treatment of cancer. In order to clarify immunological mechanisms during vaccination it is essential with intensive monitoring of the responses. This may lead to optimization of treatment and prediction......-inflammatory cytokines in serum of patients who achieved stable disease following vaccination suggest the occurrence of vaccine-induced Th1 responses. Since Th1 responses seem to be essential in cancer immunotherapy this may indicate a therapeutic potential of the vaccine....... of responding patients. The aim of this study was to evaluate cytokine and biomarker responses in patients with colorectal cancer treated with a cancer vaccine based on dendritic cells pulsed with an allogeneic melanoma cell lysate. Material and methods. Plasma and serum samples were collected prior...

  3. Whole Blood Transcriptome Sequencing Reveals Gene Expression Differences between Dapulian and Landrace Piglets

    OpenAIRE

    Hu, Jiaqing; Yang, Dandan; Chen, Wei; Li, Chuanhao; Wang, Yandong; Zeng, Yongqing; Wang, Hui

    2016-01-01

    There is little genomic information regarding gene expression differences at the whole blood transcriptome level of different pig breeds at the neonatal stage. To solve this, we characterized differentially expressed genes (DEGs) in the whole blood of Dapulian (DPL) and Landrace piglets using RNA-seq (RNA-sequencing) technology. In this study, 83 DEGs were identified between the two breeds. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified immun...

  4. Atomic force microscopy measurements reveal multiple bonds between Helicobacter pylori blood group antigen binding adhesin and Lewis b ligand.

    Science.gov (United States)

    Parreira, P; Shi, Q; Magalhaes, A; Reis, C A; Bugaytsova, J; Borén, T; Leckband, D; Martins, M C L

    2014-12-01

    The strength of binding between the Helicobacter pylori blood group antigen-binding adhesin (BabA) and its cognate glycan receptor, the Lewis b blood group antigen (Le(b)), was measured by means of atomic force microscopy. High-resolution measurements of rupture forces between single receptor-ligand pairs were performed between the purified BabA and immobilized Le(b) structures on self-assembled monolayers. Dynamic force spectroscopy revealed two similar but statistically different bond populations. These findings suggest that the BabA may form different adhesive attachments to the gastric mucosa in ways that enhance the efficiency and stability of bacterial adhesion.

  5. Molecular genetics of blood-fleshed peach reveals activation of anthocyanin biosynthesis by NAC transcription factors.

    Science.gov (United States)

    Zhou, Hui; Lin-Wang, Kui; Wang, Huiliang; Gu, Chao; Dare, Andrew P; Espley, Richard V; He, Huaping; Allan, Andrew C; Han, Yuepeng

    2015-04-01

    Anthocyanin pigmentation is an important consumer trait in peach (Prunus persica). In this study, the genetic basis of the blood-flesh trait was investigated using the cultivar Dahongpao, which shows high levels of cyanidin-3-glucoside in the mesocarp. Elevation of anthocyanin levels in the flesh was correlated with the expression of an R2R3 MYB transcription factor, PpMYB10.1. However, PpMYB10.1 did not co-segregate with the blood-flesh trait. The blood-flesh trait was mapped to a 200-kb interval on peach linkage group (LG) 5. Within this interval, a gene encoding a NAC domain transcription factor (TF) was found to be highly up-regulated in blood-fleshed peaches when compared with non-red-fleshed peaches. This NAC TF, designated blood (BL), acts as a heterodimer with PpNAC1 which shows high levels of expression in fruit at late developmental stages. We show that the heterodimer of BL and PpNAC1 can activate the transcription of PpMYB10.1, resulting in anthocyanin pigmentation in tobacco. Furthermore, silencing the BL gene reduces anthocyanin pigmentation in blood-fleshed peaches. The transactivation activity of the BL-PpNAC1 heterodimer is repressed by a SQUAMOSA promoter-binding protein-like TF, PpSPL1. Low levels of PpMYB10.1 expression in fruit at early developmental stages is probably attributable to lower levels of expression of PpNAC1 plus the presence of high levels of repressors such as PpSPL1. We present a mechanism whereby BL is the key gene for the blood-flesh trait in peach via its activation of PpMYB10.1 in maturing fruit. Partner TFs such as basic helix-loop-helix proteins and NAC1 are required, as is the removal of transcriptional repressors.

  6. Colorectal cancer biomarker discovery and validation using LC-MS/MS-based proteomics in blood: truth or dare?

    Science.gov (United States)

    Reumer, Ank; Maes, Evelyne; Mertens, Inge; Cho, William C S; Landuyt, Bart; Valkenborg, Dirk; Schoofs, Liliane; Baggerman, Geert

    2014-08-01

    Globally, colorectal cancer (CRC) is the third most common malignant neoplasm. However, highly sensitive, specific, noninvasive tests that allow CRC diagnosis at an early stage are still needed. As circulatory blood reflects the physiological status of an individual and/or the disease status for several disorders, efforts have been undertaken to identify candidate diagnostic CRC markers in plasma and serum. In this review, the challenges, bottlenecks and promising properties of mass spectrometry (MS)-based proteomics in blood are discussed. More specifically, important aspects in clinical design, sample retrieval, sample preparation, and MS analysis are presented. The recent developments in targeted MS approaches in plasma or serum are highlighted as well.

  7. Integrative transcriptomic meta-analysis of Parkinson’s disease and depression identifies NAMPT as a potential blood biomarker for de novo Parkinson’s disease

    Science.gov (United States)

    Santiago, Jose A.; Littlefield, Alyssa M.; Potashkin, Judith A.

    2016-01-01

    Emerging research indicates that depression could be one of the earliest prodromal symptoms or risk factors associated with the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder worldwide, but the mechanisms underlying the association between both diseases remains unknown. Understanding the molecular networks linking these diseases could facilitate the discovery of novel diagnostic and therapeutics. Transcriptomic meta-analysis and network analysis of blood microarrays from untreated patients with PD and depression identified genes enriched in pathways related to the immune system, metabolism of lipids, glucose, fatty acids, nicotinamide, lysosome, insulin signaling and type 1 diabetes. Nicotinamide phosphoribosyltransferase (NAMPT), an adipokine that plays a role in lipid and glucose metabolism, was identified as the most significant dysregulated gene. Relative abundance of NAMPT was upregulated in blood of 99 early stage and drug-naïve PD patients compared to 101 healthy controls (HC) nested in the cross-sectional Parkinson’s Progression Markers Initiative (PPMI). Thus, here we demonstrate that shared molecular networks between PD and depression provide an additional source of biologically relevant biomarkers. Evaluation of NAMPT in a larger prospective longitudinal study including samples from other neurodegenerative diseases, and patients at risk of PD is warranted. PMID:27680512

  8. The transcriptome of the nosocomial pathogen Enterococcus faecalis V583 reveals adaptive responses to growth in blood.

    Directory of Open Access Journals (Sweden)

    Heidi C Vebø

    Full Text Available BACKGROUND: Enterococcus faecalis plays a dual role in human ecology, predominantly existing as a commensal in the alimentary canal, but also as an opportunistic pathogen that frequently causes nosocomial infections like bacteremia. A number of virulence factors that contribute to the pathogenic potential of E. faecalis have been established. However, the process in which E. faecalis gains access to the bloodstream and establishes a persistent infection is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: To enhance our understanding of how this commensal bacterium adapts during a bloodstream infection and to examine the interplay between genes we designed an in vitro experiment using genome-wide microarrays to investigate what effects the presence of and growth in blood have on the transcriptome of E. faecalis strain V583. We showed that growth in both 2xYT supplemented with 10% blood and in 100% blood had a great impact on the transcription of many genes in the V583 genome. We identified several immediate changes signifying cellular processes that might contribute to adaptation and growth in blood. These include modulation of membrane fatty acid composition, oxidative and lytic stress protection, acquisition of new available substrates, transport functions including heme/iron transporters and genes associated with virulence in E. faecalis. CONCLUSIONS/SIGNIFICANCE: The results presented here reveal that cultivation of E. faecalis in blood in vitro has a profound impact on its transcriptome, which includes a number of virulence traits. Observed regulation of genes and pathways revealed new insight into physiological features and metabolic capacities which enable E. faecalis to adapt and grow in blood. A number of the regulated genes might potentially be useful candidates for development of new therapeutic approaches for treatment of E. faecalis infections.

  9. Sieving treatment biomarkers from blood gene-expression profiles: a pharmacogenomic update on two types of multiple sclerosis therapy.

    Science.gov (United States)

    Goertsches, Robert H; Zettl, Uwe K; Hecker, Michael

    2011-03-01

    Interferon-β (IFN-β) and glatiramer acetate are routinely used to inhibit disease activity in multiple sclerosis, but their mechanisms of action are incompletely understood. Individual treatment responses vary and candidate molecular markers that predict them have yet to be established. Why some patients respond poorly to a certain treatment while others respond well is addressed by the pharmacogenomic approach, which postulates that the molecular response to treatment correlates with the clinical effects, and thus seeks biological markers to estimate prognosis, guide therapy, comprehend the drugs' mechanisms of action and offer insights into disease pathogenesis. A poor clinical response can be owing to genetic variants in drug receptors or signaling components, or the appearance of neutralizing antibodies that interfere with the drug's binding efficacy. Independently, such mechanisms could lead to inadequate, that is to say unchanged, molecular responses, or exceedingly increased or decreased changes. By means of DNA microarray studies, various research groups endeavour to establish a clinically relevant relationship between the biological response to these drugs and treatment effects. Molecular profiles obtained in this way differ in the pattern and number of modulated genes, suggesting the existence of an individual 'drug-response fingerprint'. To further unravel the underlying regulatory interaction structure of the genes responsive to these immunotherapies represents a daunting but inevitable task. In this article, we focus on longitudinal ex vivo transcriptomic studies in multiple sclerosis and its therapy. We will discuss recurrently reported biomarker candidates, emphasizing those of immunologically meaning, and review studies with network module outputs.

  10. High-resolution blood-pool-contrast-enhanced MR angiography in glioblastoma: tumor-associated neovascularization as a biomarker for patient survival. A preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Puig, Josep; Blasco, Gerard; Remollo, Sebastian; Hernandez, David; Pedraza, Salvador [Hospital Universitari Dr Josep Trueta, Research Unit of Diagnostic Imaging Institute (IDI), Department of Radiology [Girona Biomedical Research Institute] IDIBGI, Girona (Spain); Daunis-i-Estadella, Josep; Mateu, Gloria [University of Girona, Department of Computer Science, Applied Mathematics and Statistics, Girona (Spain); Alberich-Bayarri, Angel [La Fe Polytechnics and University Hospital, Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, Valencia (Spain); Essig, Marco [University of Manitoba, Department of Radiology, Winnipeg (Canada); Jain, Rajan [NYU School of Medicine, Division of Neuroradiology, Department of Radiology, New York, NY (United States); Puigdemont, Montserrat [Hospital Universitari Dr Josep Trueta, Catalan Institute of Oncology (ICO), Hospital Cancer Registry, Girona (Spain); Sanchez-Gonzalez, Javier [Philips Healthcare Iberica, Madrid (Spain); Wintermark, Max [Stanford University, Department of Radiology, Neuroradiology Division, Palo Alto, CA (United States)

    2016-01-15

    The objective of the study was to determine whether tumor-associated neovascularization on high-resolution gadofosveset-enhanced magnetic resonance angiography (MRA) is a useful biomarker for predicting survival in patients with newly diagnosed glioblastomas. Before treatment, 35 patients (25 men; mean age, 64 ± 14 years) with glioblastoma underwent MRI including first-pass dynamic susceptibility contrast (DSC) perfusion and post-contrast T1WI sequences with gadobutrol (0.1 mmol/kg) and, 48 h later, high-resolution MRA with gadofosveset (0.03 mmol/kg). Volumes of interest for contrast-enhancing lesion (CEL), non-CEL, and contralateral normal-appearing white matter were obtained, and DSC perfusion and DWI parameters were evaluated. Prognostic factors were assessed by Kaplan-Meier survival and Cox proportional hazards model. Eighteen (51.42 %) glioblastomas were hypervascular on high-resolution MRA. Hypervascular glioblastomas were associated with higher CEL volume and lower Karnofsky score. Median survival rates for patients with hypovascular and hypervascular glioblastomas treated with surgery, radiotherapy, and chemotherapy were 15 and 9.75 months, respectively (P < 0.001). Tumor-associated neovascularization was the best predictor of survival at 5.25 months (AUC = 0.794, 81.2 % sensitivity, 77.8 % specificity, 76.5 % positive predictive value, 82.4 % negative predictive value) and yielded the highest hazard ratio (P < 0.001). Tumor-associated neovascularization detected on high-resolution blood-pool-contrast-enhanced MRA of newly diagnosed glioblastoma seems to be a useful biomarker that correlates with worse survival. (orig.)

  11. Blood plasma clinical-chemical parameters as biomarker endpoints for organohalogen contaminant exposure in Norwegian raptor nestlings

    DEFF Research Database (Denmark)

    Sonne, Christian; Bustnes, Jan O; Herzke, Dorte;

    2012-01-01

    Raptors are exposed to biomagnifying and toxic organohalogenated compounds (OHCs) such as organochlorines, brominated flame retardants and perfluorinated compounds. To investigate how OHC exposure may affect biochemical pathways we collected blood plasma from Norwegian northern goshawk (n=56......), golden eagle (n=12) and white-tailed eagle (n=36) nestlings during three consecutive breeding seasons. We found that blood plasma concentrations of calcium, sodium, creatinine, cholesterol, albumin, total protein, urea, inorganic phosphate, protein:creatinine, urea:creatinine and uric acid......:creatinine ratios and liver enzymes ALKP and ALAT were positively correlated to PCBs, chlordanes, p,p'-DDE, HCB, PFCs and/or PBDEs. Total bilirubin and glucose were negatively correlated to PCBs while magnesium and potassium were negatively correlated to HCB and p,p'-DDE. In addition, protein:creatinine and ALAT...

  12. Blood

    Science.gov (United States)

    ... Also, blood is either Rh-positive or Rh-negative. So if you have type A blood, it's either A positive or A negative. Which type you are is important if you need a blood transfusion. And your Rh factor could be important ...

  13. Decreased MiR-155 Level in the Peripheral Blood of Non-Alcoholic Fatty Liver Disease Patients may Serve as a Biomarker and may Influence LXR Activity

    Directory of Open Access Journals (Sweden)

    Lei Wang

    2016-11-01

    Full Text Available Background: Obesity is now a common risk factor for non-alcoholic fatty liver disease (NAFLD. Thus, it is important to explore its underlying mechanisms. Methods: Total RNA was extracted from peripheral whole blood samples from 50 NAFLD patients and 50 healthy controls. In addition, human liver specimens were obtained through liver biopsies from NAFLD patients and healthy controls. The level of miRNA was studied using real-time PCR. The expression of lipogenic genes was analyzed using western blot, and a dual luciferase reporter assay was conducted to identify the possible target gene. Adenovirus vectors were injected into the tail vein of the high fat diet (HFD-fed mice to study the role of miR-155 on lipid accumulation in vivo. Results: The level of miR-155 was markedly reduced in the livers and peripheral blood of NAFLD patients compared with healthy controls. Upregulation of miR-155 decreased intracellular lipid content and the SREBP1 and FAS protein levels, while inhibition of miR-155 enhanced the intracellular lipid content. The dual luciferase reporter assay showed that Liver X receptor (LXRα was the target gene of miR-155, and silencing miR-155 reduced the expression of SREBP1 and FAS. An in vivo study showed that upregulation of miR-155 decreased the hepatic lipid accumulation mainly by suppressing the LXRα-dependent lipogenic signaling pathway. Conclusions: In summary, decreased expression of miR-155 in the peripheral blood may be utilized as a potential novel biomarker for NAFLD screening mainly by targeting LXRα.

  14. Modulatory effect of pineapple peel extract on lipid peroxidation,catalase activity and hepatic biomarker levels in blood plasma of alcoholinduced oxidative stressed rats

    Institute of Scientific and Technical Information of China (English)

    Okafor; OY; Erukainure; OL; Ajiboye; JA; Adejobi; RO; Owolabi; FO; Kosoko; SB

    2011-01-01

    Objective:To investigate the ability of the methanolic extract of pineapple peel to modulate alcohol-induced lipid peroxidation,changes in catalase activities and hepatic biochemical marker levels in blood plasma.Methods:Oxidative stress was induced by oral administration of ethanol(20%w/v) at a dosage of 5 niL/kg bw in rats.After 28 days of treatment,the rats were fasted overnight and sacrificed by cervical dislocation.Blood was collected with a 2 mL syringe by cardiac puncture and was centrifuged at 3000 rpm for 10 min.The plasma was analyzed to evaluate malondialdehyde(MDA),catalase activity,aspartate aminotransferase(AST),alkaline phosphatase(ALP) and alanine aminotransferase(ALT) concentrations.Results:Administration of alcohol caused a drastic increase(87.74%) in MDA level compared with the control.Pineapple peel extract significantly reduced the MDA level by 60.16%at 2.S mL/kg bw.Rats fed alcohol only had the highest catalase activity,treatment with pineapple peel extract at 2.5 mL/kg bw however, reduced the activity.Increased AST,ALP and ALT activities were observed in rats fed alcohol only respectively,treatment with pineapple peel extract drastically reduced their activities. Conclusions:The positive modulation of lipid peroxidation,catalase activities as well as hepatic biomarker levels of blood plasma by the methanolic extract of pineapple peels under alcoholinduced oxidative stress is an indication of its protective ability in the management of alcoholinduced toxicity.

  15. The full blood count as a biomarker of outcome and toxicity in ipilimumab-treated cutaneous metastatic melanoma.

    Science.gov (United States)

    Khoja, Leila; Atenafu, Eshetu G; Templeton, Arnoud; Qye, Ye; Chappell, Mary Anne; Saibil, Sam; Hogg, David; Butler, Marcus O; Joshua, Anthony M

    2016-10-01

    Ipilimumab produces durable responses in some metastatic melanoma patients. Neutrophil, platelet, and eosinophil to lymphocyte ratios (NLR, PLR, and ELR) may be associated with the immune response in cancer thereby acting as biomarkers of toxicity and efficacy in ipilimumab-treated patients. Data were collected on clinical characteristics and lactate dehydrogenase (LDH), NLR, PLR, and ELR at baseline, post cycle 2 and at the end of treatment for 183 patients treated with ipilimumab between 2008 and 2015 at the Princess Margaret Cancer Centre. Associations between clinical characteristics, LDH, NLR, PLR, and ELR with toxicity or survival outcomes of progression-free (PFS) and overall survival (OS) were assessed using univariable and multivariable analysis. Prognostic models of outcome at each time point were determined. Of the 183 patients included, the median age was 58, 85% had M1c disease, 58% were performance status 1, and 64% received ipilimumab as second line therapy. Median follow up was 7.5 months (range: 0.3-49.5), median PFS was 2.8 months (95% confidence intervals (CI): 2.8-3.2), and median OS was 9.6 months (95% CI: 7.9-13.2). Prognostic factors for OS by multivariable analysis were LDH and NLR at all-time points. Prognostic models using LDH (× 2 upper limit of normal) and NLR 4) differentiated patients into high, moderate, and low risk of death prior to or on ipilimumab treatment (P < 0.0001 for each model). No factors were associated with toxicity. Prognostic models based on NLR and LDH values at baseline and on treatment differentiate patients into good, intermediate, and poor prognostic groups and may be relevant in patient management.

  16. Blood flow activation in rat somatosensory cortex under sciatic nerve stimulation revealed by laser speckle imaging

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    In many functional neuroimaging research the change of local cerebral blood flow (CBF) induced by sensory stimulation is regarded as an indicator of the change in cortical neuronal activity although a precise and full spatio-temporal description of local CBF response coupled to neural activity has still not been laid out. Using the laser speckle imaging technique a relatively large exposed area in somatosensory cortex of rat was imaged for the observation of the variations of CBF during sciatic nerve stimulation. The results showed that cerebral blood flow activation was spatially localized and discretely distributed in the targeted microvasculature. Individual arteries, veins and capillaries in different diameters were activated with the time going. The response pattern of CBF related to the function of brain activity and energy metabolism is delineated exactly.

  17. Whole Blood Transcriptome Sequencing Reveals Gene Expression Differences between Dapulian and Landrace Piglets.

    Science.gov (United States)

    Hu, Jiaqing; Yang, Dandan; Chen, Wei; Li, Chuanhao; Wang, Yandong; Zeng, Yongqing; Wang, Hui

    2016-01-01

    There is little genomic information regarding gene expression differences at the whole blood transcriptome level of different pig breeds at the neonatal stage. To solve this, we characterized differentially expressed genes (DEGs) in the whole blood of Dapulian (DPL) and Landrace piglets using RNA-seq (RNA-sequencing) technology. In this study, 83 DEGs were identified between the two breeds. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses identified immune response and metabolism as the most commonly enriched terms and pathways in the DEGs. Genes related to immunity and lipid metabolism were more highly expressed in the DPL piglets, while genes related to body growth were more highly expressed in the Landrace piglets. Additionally, the DPL piglets had twofold more single nucleotide polymorphisms (SNPs) and alternative splicing (AS) than the Landrace piglets. These results expand our knowledge of the genes transcribed in the piglet whole blood of two breeds and provide a basis for future research of the molecular mechanisms underlying the piglet differences.

  18. Effects of anesthetic agents on brain blood oxygenation level revealed with ultra-high field MRI.

    Directory of Open Access Journals (Sweden)

    Luisa Ciobanu

    Full Text Available During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T(2*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine. We showed that the brain/vessels contrast in T(2*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation.

  19. Whole Blood Transcriptome Sequencing Reveals Gene Expression Differences between Dapulian and Landrace Piglets

    Directory of Open Access Journals (Sweden)

    Jiaqing Hu

    2016-01-01

    Full Text Available There is little genomic information regarding gene expression differences at the whole blood transcriptome level of different pig breeds at the neonatal stage. To solve this, we characterized differentially expressed genes (DEGs in the whole blood of Dapulian (DPL and Landrace piglets using RNA-seq (RNA-sequencing technology. In this study, 83 DEGs were identified between the two breeds. Gene Ontology (GO and Kyoto Encyclopedia of Genes and Genomes (KEGG pathway analyses identified immune response and metabolism as the most commonly enriched terms and pathways in the DEGs. Genes related to immunity and lipid metabolism were more highly expressed in the DPL piglets, while genes related to body growth were more highly expressed in the Landrace piglets. Additionally, the DPL piglets had twofold more single nucleotide polymorphisms (SNPs and alternative splicing (AS than the Landrace piglets. These results expand our knowledge of the genes transcribed in the piglet whole blood of two breeds and provide a basis for future research of the molecular mechanisms underlying the piglet differences.

  20. [Biomarkers in Alzheimer's disease].

    Science.gov (United States)

    García-Ribas, G; López-Sendón Moreno, J L; García-Caldentey, J

    2014-04-01

    The new diagnostic criteria for Alzheimer's disease (AD) include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. Three CSF biomarkers, Aß42, total tau, and phosphorylated tau, reflect the core pathological features of AD. It is already known that these pathological processes of AD starts decades before the first symptoms, so these biomarkers may provide means of early disease detection. At least three stages of AD could be identified: preclinical AD, mild cognitive impairment due to AD, and dementia due to AD. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review the actual research on blood-based biomarkers. Recent studies on healthy elderly subjects and on carriers of dominantly inherited AD mutations have also found biomarker changes that allow separate groups in these preclinical stages. These studies may aid for segregate populations in clinical trials and objectively evaluate if there are changes over the pathological processes of AD. Limits to widespread use of CSF biomarkers, apart from the invasive nature of the process itself, is the higher coefficient of variation for the analyses between centres. It requires strict pre-analytical and analytical procedures that may make feasible multi-centre studies and global cut-off points for the different stages of AD.

  1. Blood parameter analysis and morphological alterations as biomarkers on the health of Hoplias malabaricus and Geophagus brasiliensis

    Directory of Open Access Journals (Sweden)

    Silvia Romão

    2006-05-01

    Full Text Available This study aimed to assess the influence of the environment on fish health. Samples of Hoplias malabaricus and Geophagus brasiliensis, were collected from three different environments: area I was urban and areas II and III were rural. Analyses of red blood cell count, microhematocrit, hemoglobin concentration, white blood cell count and differential white cell count in blood smear were carried out. Mean corpuscular volume and mean corpuscular hemoglobin concentration were calculated. To analyze morphological alterations, gills, liver, kidney and gonads were submitted to routine histological processing. Individuals collected from area III had slightly lower blood indices than collected from area I . Severe kidney changes, degeneration of and crystallization within kidney tubules were observed. In area I, crystallization was observed in 92% of the specimens of G. brasiliensis. These results suggested that such alterations were related with poor water circulation in the place.Este trabalho teve como objetivo avaliar a influência do ambiente sobre a higidez dos peixes. Animais, das espécies Hoplias malabaricus e Geophagus brasiliensis foram coletados em três ambientes distintos, sendo ambiente I região urbana e ambientes II e III em região rural. Foram realizadas análises do número total de eritrócitos por microlitro de sangue, microhematócrito, taxa de hemoglobina, porcentagem de leucócito e contagem diferencial de leucócitos em extensão sanguínea. Calcularam-se os índices hematimétricos absolutos: volume corpuscular médio e concentração de hemoglobina corpuscular média. Para análises das alterações morfológicas, brânquias, fígado, gônadas e rim seguiram processamento histológico de rotina. Foram observados índices hematológicos ligeiramente menores em indivíduos coletados no ambiente III em relação aos animais coletados no ambiente I. As análises histológicas de brânquias, fígado e gônadas das espécies G

  2. Blood plasma clinical-chemical parameters as biomarker endpoints for organohalogen contaminant exposure in Norwegian raptor nestlings

    DEFF Research Database (Denmark)

    Sonne, Christian; Bustnes, Jan O.; Herzke, Dorte;

    2012-01-01

    ), golden eagle (n=12) and white-tailed eagle (n=36) nestlings during three consecutive breeding seasons. We found that blood plasma concentrations of calcium, sodium, creatinine, cholesterol, albumin, total protein, urea, inorganic phosphate, protein:creatinine, urea:creatinine and uric acid...... were also negatively correlated to PCBs and PFCs, respectively. The most significant relationships were found for the highly contaminated northern goshawks and white-tailed eagles. The statistical relationships between OHCs and BCCPs indicate that biochemical pathways could be influenced while...... it is uncertain if such changes have any health effects. The OHC concentrations were below concentrations causing reproductive toxicity in adults of other raptor species but similar to those of concern for endocrine disruption of thyroid hormones in e.g., bald eagles....

  3. Peripheral blood RNA gene expression profiling in illicit methcathinone users reveals effect on immune system

    Directory of Open Access Journals (Sweden)

    Katrin eSikk

    2011-08-01

    Full Text Available Methcathinone (ephedrone is relatively easily accessible for abuse. Its users develop an extrapyramidal syndrome and it is not known if this is caused by methcathinone itself, by side-ingredients (manganese, or both. In the present study we aimed to clarify molecular mechanisms underlying this condition. We analyzed whole genome gene expression patterns of peripheral blood from 20 methcathinone users and 20 matched controls. Gene expression profile data was analyzed by Bayesian modelling and functional annotation. In order to verify the genechip results we performed quantitative real-time (RT PCR in selected genes. 326 out of analyzed 28,869 genes showed statistically significant differential expression with FDR adjusted p-values below 0.05. Quantitative RT-PCR confirmed differential expression for the most of selected genes. Functional annotation and network analysis indicated that most of the genes were related to activation immunological disease, cellular movement and cardiovascular disease gene network (enrichment score 42. As HIV and HCV infections were confounding factors, we performed additional stratification of patients. A similar functional activation of the immunological disease pathway was evident when we compared patients according to the injection status (past versus current users, balanced for HIV and HCV infection. However, this difference was not large therefore the major effect was related to the HIV status of the patients. Mn-methcathinone abusers have blood transcriptional patterns mostly caused by their HIV and HCV infections.

  4. Top-down lipidomics reveals ether lipid deficiency in blood plasma of hypertensive patients.

    Directory of Open Access Journals (Sweden)

    Juergen Graessler

    Full Text Available BACKGROUND: Dyslipoproteinemia, obesity and insulin resistance are integrative constituents of the metabolic syndrome and are major risk factors for hypertension. The objective of this study was to determine whether hypertension specifically affects the plasma lipidome independently and differently from the effects induced by obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: We screened the plasma lipidome of 19 men with hypertension and 51 normotensive male controls by top-down shotgun profiling on a LTQ Orbitrap hybrid mass spectrometer. The analysis encompassed 95 lipid species of 10 major lipid classes. Obesity resulted in generally higher lipid load in blood plasma, while the content of tri- and diacylglycerols increased dramatically. Insulin resistance, defined by HOMA-IR >3.5 and controlled for BMI, had little effect on the plasma lipidome. Importantly, we observed that in blood plasma of hypertensive individuals the overall content of ether lipids decreased. Ether phosphatidylcholines and ether phosphatidylethanolamines, that comprise arachidonic (20:4 and docosapentaenoic (22:5 fatty acid moieties, were specifically diminished. The content of free cholesterol also decreased, although conventional clinical lipid homeostasis indices remained unaffected. CONCLUSIONS/SIGNIFICANCE: Top-down shotgun lipidomics demonstrated that hypertension is accompanied by specific reduction of the content of ether lipids and free cholesterol that occurred independently of lipidomic alterations induced by obesity and insulin resistance. These results may form the basis for novel preventive and dietary strategies alleviating the severity of hypertension.

  5. Proteomic analysis of coronary sinus serum reveals leucine-rich α2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure.

    LENUS (Irish Health Repository)

    Watson, Chris J

    2011-03-01

    Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF.

  6. Effect of supranutritional organic selenium supplementation on postpartum blood micronutrients, antioxidants, metabolites, and inflammation biomarkers in selenium-replete dairy cows.

    Science.gov (United States)

    Hall, Jean A; Bobe, Gerd; Vorachek, William R; Kasper, Katherine; Traber, Maret G; Mosher, Wayne D; Pirelli, Gene J; Gamroth, Mike

    2014-12-01

    Dairy cows have increased nutritional requirements for antioxidants postpartum. Supranutritional organic Se supplementation may be beneficial because selenoproteins are involved in regulating oxidative stress and inflammation. Our objective was to determine whether feeding Se-yeast above requirements to Se-replete dairy cows during late gestation affects blood micronutrients, antioxidants, metabolites, and inflammation biomarkers postpartum. During the last 8-weeks before calving, dairy cows at a commercial farm were fed either 0 (control) or 105 mg Se-yeast once weekly (supranutritional Se-yeast), in addition to Na selenite at 0.3 mg Se/kg dry matter in their rations. Concentrations of whole-blood (WB) Se and serum Se, erythrocyte glutathione (GSH), and serum albumin, cholesterol, α-tocopherol, haptoglobin, serum amyloid A (SAA), calcium, magnesium, phosphorus, non-esterified fatty acids, and β-hydroxybutyrate were measured directly after calving, at 48 h, and 14 days of lactation in 10 cows of each group. Supranutritional Se-yeast supplementation affected indicators of antioxidant status and inflammation. Cows fed a supranutritional Se-yeast supplement during the last 8-weeks of gestation had higher Se concentrations in WB (overall 52 % higher) and serum (overall 36 % higher) at all-time points, had higher SAA concentrations at 48 h (98 % higher), had higher erythrocyte GSH (38 % higher) and serum albumin concentrations (6.6 % higher) at 14 days, and had lower serum cholesterol concentrations and higher α-tocopherol/cholesterol ratios at calving and at 48 h compared with control cows. In conclusion, feeding Se-replete cows during late gestation a supranutritional Se-yeast supplement improves antioxidant status and immune responses after calving without negatively impacting other micronutrients and energy status.

  7. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker.

    Science.gov (United States)

    Ravegnini, Gloria; Zolezzi Moraga, Juan Manuel; Maffei, Francesca; Musti, Muriel; Zenesini, Corrado; Simeon, Vittorio; Sammarini, Giulia; Festi, Davide; Hrelia, Patrizia; Angelini, Sabrina

    2015-12-01

    One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects' positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals' FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = -0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment.

  8. Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker

    Directory of Open Access Journals (Sweden)

    Gloria Ravegnini

    2015-12-01

    Full Text Available One challenge in colorectal cancer (CRC is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects’ positive fecal occult blood test (FOBT. In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals’ FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006. In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001. Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = −0.926, p = 0.0001. With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108 in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007. While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment.

  9. Diagnosing Lung Cancers through Examination of Micro-RNA Biomarkers in Blood, Plasma, Serum and Sputum: A Review and Summary of Current Literature.

    Science.gov (United States)

    Gyoba, Jennifer; Shan, Shubham; Roa, Wilson; Bédard, Eric L R

    2016-04-01

    Lung cancer is the leading cause of cancer related morbidity and mortality worldwide. Currently, the vast majority of lung cancers are diagnosed at a late stage, when patients become symptomatic leading to dismal, less than 15% five-year survival rates. Evidence has demonstrated that screening computed tomography scans can be used to detect lung cancer, but these scans have high false positive rates. Therefore, there is a continued need for the development of minimally-invasive methods to screen the high risk population and diagnose lung cancer at an earlier, curable stage. One such promising area is the use micro-RNAs. These are short, non-coding RNA molecules that have been shown in previous research to be dysregulated in cancers. This review will focus on the potential use of miRNA levels in various biological fluids (whole blood, plasma, serum, and sputum) and demonstrate their potential utility as screening and diagnostic biomarkers for lung cancer. Current research will be analyzed and compared, and future directions in establishing the use of miRNAs for detecting lung cancer will be discussed.

  10. DNA damage focus analysis in blood samples of minipigs reveals acute partial body irradiation.

    Directory of Open Access Journals (Sweden)

    Andreas Lamkowski

    Full Text Available Radiation accidents frequently involve acute high dose partial body irradiation leading to victims with radiation sickness and cutaneous radiation syndrome that implements radiation-induced cell death. Cells that are not lethally hit seek to repair ionizing radiation (IR induced damage, albeit at the expense of an increased risk of mutation and tumor formation due to misrepair of IR-induced DNA double strand breaks (DSBs. The response to DNA damage includes phosphorylation of histone H2AX in the vicinity of DSBs, creating foci in the nucleus whose enumeration can serve as a radiation biodosimeter. Here, we investigated γH2AX and DNA repair foci in peripheral blood lymphocytes of Göttingen minipigs that experienced acute partial body irradiation (PBI with 49 Gy (± 6% Co-60 γ-rays of the upper lumbar region. Blood samples taken 4, 24 and 168 hours post PBI were subjected to γ-H2AX, 53BP1 and MRE11 focus enumeration. Peripheral blood lymphocytes (PBL of 49 Gy partial body irradiated minipigs were found to display 1-8 DNA damage foci/cell. These PBL values significantly deceed the high foci numbers observed in keratinocyte nuclei of the directly γ-irradiated minipig skin regions, indicating a limited resident time of PBL in the exposed tissue volume. Nonetheless, PBL samples obtained 4 h post IR in average contained 2.2% of cells displaying a pan-γH2AX signal, suggesting that these received a higher IR dose. Moreover, dispersion analysis indicated partial body irradiation for all 13 minipigs at 4 h post IR. While dose reconstruction using γH2AX DNA repair foci in lymphocytes after in vivo PBI represents a challenge, the DNA damage focus assay may serve as a rapid, first line indicator of radiation exposure. The occurrence of PBLs with pan-γH2AX staining and of cells with relatively high foci numbers that skew a Poisson distribution may be taken as indicator of acute high dose partial body irradiation, particularly when samples are available

  11. Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition.

    Science.gov (United States)

    Ko, Gang Jee; Grigoryev, Dmitry N; Linfert, Douglas; Jang, Hye Ryoun; Watkins, Tonya; Cheadle, Chris; Racusen, Lorraine; Rabb, Hamid

    2010-06-01

    Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice. Mice were euthanized at 3, 10, and 28 days after ischemia-reperfusion injury (IRI). Total RNA was isolated from kidney and analyzed using an Illumina mouse array. Among 24,600 tested genes, 242, 146, and 46 genes were upregulated at days 3, 10, and 28 after IRI, and 85, 35, and 0 genes were downregulated, respectively. Gene ontology analysis showed that gene expression changes were primarily related to immune and inflammatory pathways both early and late after AKI. The most highly upregulated genes late after AKI were hepatitis A virus cellular receptor 1 (Havcr1) and lipocalin 2 (Lcn2), which code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively. This was unexpected since they are both primarily potential biomarkers of the early stage of AKI. Furthermore, increases observed in gene expression in amiloride binding protein 1, vascular cell adhesion molecule-1, and endothelin 1 could explain the salt-sensitive hypertension that can follow AKI. These data suggested that 1) persistent inflammation and immune responses late after AKI could contribute to the pathogenesis of CKD, 2) late upregulation of KIM-1 and NGAL could be a useful marker for sustained renal injury after AKI, and 3) hypertension-related gene changes could underlie mechanisms for persistent renal and vascular injury after AKI.

  12. Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood

    DEFF Research Database (Denmark)

    Rönn, Tina; Volkov, Petr; Gillberg, Linn

    2015-01-01

    to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation...... of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue....... biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e...

  13. High Dietary Iron and Radiation Exposure Increase Biomarkers of Oxidative Stress in Blood and Liver of Rats

    Science.gov (United States)

    Morgan, Jennifer L. L.; Theriot, Corey A.; Wu, Honglu; Smith, Scott M.; Zwart, Sara R.

    2012-01-01

    Radiation exposure and increased iron (Fe) status independently cause oxidative damage that can result in protein, lipid, and DNA oxidation. During space flight astronauts are exposed to both increased radiation and increased Fe stores. Increased body Fe results from a decrease in red blood cell mass and the typically high Fe content of the food system. In this study we investigated the combined effects of radiation exposure (0.375 Gy of Cs-137 every other day for 16 days for a total of 3 Gy) and high dietary Fe (650 mg Fe/kg diet compared to 45 mg Fe/kg for controls) in Sprague-Dawley rats (n=8/group). Liver and serum Fe were significantly increased in the high dietary Fe groups. Likewise, radiation treatment increased serum ferritin and Fe concentrations. These data indicate that total body Fe stores increase with both radiation exposure and excess dietary Fe. Hematocrit decreased in the group exposed to radiation, providing a possible mechanism for the shift in Fe indices after radiation exposure. Markers of oxidative stress were also affected by both radiation and high dietary Fe, evidenced by increased liver glutathione peroxidase (GPX) and serum catalase as well as decreased serum GPX. We thus found preliminary indications of synergistic effects of radiation exposure and increased dietary Fe, warranting further study. This study was funded by the NASA Human Research Project.

  14. Breast Cancer: subgroups specific blood-biomarkers for early / predictive diagnosis and personalized treatment — EDRN Public Portal

    Science.gov (United States)

    Breast-conserving lumpectomy followed by radiation therapy has been shown to be an alternative strategy, competitive to mastectomy, in preventing mortality caused by breast cancer. However, besides negative short-term effects (blood flow disturbances, painful erythema, etc.) breast irradiation causes severe long-term side-effects (leucopenia, anemia, breast edema, fibrosis, increase of angiosarcoma, leukemia, myelodysplastic syndromes). Therefore, the identification of individual susceptibility to radiation and improved patient-specific radiotherapy planning are highly desirable for personalised treatment in breast cancer. Why early and predictive diagnosis is crucial for long-term outcomes of breast cancer? Breast cancer is the most common cause of cancer death among women with an average incidence rate of 10-12 per 100 women. In 2005, breast cancer led to 502,000 deaths worldwide. Advanced stages of breast cancer lead to the development of metastasis predominantly in the lymph nodes, bone, lung, skin, brain, and liver. Although breast-MRI is currently the most sensitive diagnostic tool for breast imaging, its specificity is limited resulting in a negative impact for surgical management in approximately 9 % of cases. Early diagnosis has been demonstrated to be highly beneficial, enabling significantly enhanced therapy efficiency and possibly full recovery.

  15. Laser speckle contrast reveals cerebral blood flow dynamics evoked by optogenetically controlled neuronal activity

    Science.gov (United States)

    Li, Nan; Thakor, Nitish V.; Pelled, Galit

    2013-03-01

    As a critical basis of functional brain imaging, neurovascular coupling describes the link between neuronal and hemodynamic changes. The majority of in vivo neurovascular coupling studies was performed by inducing sensory stimulation via afferent inputs. Unfortunately such an approach results in recruiting of multiple types of cells, which confounds the explanation of neuronal roles in stimulus evoked hemodynamic changes. Recently optogenetics has emerged to provide immediate control of neurons by exciting or inhibiting genetically engineered neurons expressing light sensitive proteins. However, there is a need for optical methods capable of imaging the concurrent hemodynamic changes. We utilize laser speckle contrast imaging (LSCI) to obtain high resolution display of cerebral blood flow (CBF) in the vicinity of the targeted neural population. LSCI is a minimally invasive method for imaging CBF in microvessels through thinned skull, and produces images with high spatiotemporal resolution, wide field of view. In the integrated system light sources with different wavelengths and band-passing/blocking filters were used to allow simultaneous optical manipulation of neuronal activities and optical imaging of corresponding CBF. Experimental studies were carried out in a rodent model expressing channalrhodopsin (ChR2) in excitatory neurons in the somatosensory cortex (S1). The results demonstrated significant increases of CBF in response to ChR2 stimulation (exciting neuronal firing) comparable to the CBF response to contralateral forepaw stimulation. The approach promises to be an exciting minimally invasive method to study neurovascular coupling. The complete system provides a novel approach for broad neuroscience applications.

  16. Equilibrium physics breakdown reveals the active nature of red blood cell flickering

    Science.gov (United States)

    Turlier, H.; Fedosov, D. A.; Audoly, B.; Auth, T.; Gov, N. S.; Sykes, C.; Joanny, J.-F.; Gompper, G.; Betz, T.

    2016-05-01

    Red blood cells, or erythrocytes, are seen to flicker under optical microscopy, a phenomenon initially described as thermal fluctuations of the cell membrane. But recent studies have suggested the involvement of non-equilibrium processes, without definitively ruling out equilibrium interpretations. Using active and passive microrheology to directly compare the membrane response and fluctuations on single erythrocytes, we report here a violation of the fluctuation-dissipation relation, which is a direct demonstration of the non-equilibrium nature of flickering. With an analytical model of the composite erythrocyte membrane and realistic stochastic simulations, we show that several molecular mechanisms may explain the active fluctuations, and we predict their kinetics. We demonstrate that tangential metabolic activity in the network formed by spectrin, a cytoskeletal protein, can generate curvature-mediated active membrane motions. We also show that other active membrane processes represented by direct normal force dipoles may explain the observed membrane activity. Our findings provide solid experimental and theoretical frameworks for future investigations of the origin and function of active motion in cells.

  17. A Systems Biology Approach to Reveal Putative Host-Derived Biomarkers of Periodontitis by Network Topology Characterization of MMP-REDOX/NO and Apoptosis Integrated Pathways.

    Science.gov (United States)

    Zeidán-Chuliá, Fares; Gürsoy, Mervi; Neves de Oliveira, Ben-Hur; Özdemir, Vural; Könönen, Eija; Gürsoy, Ulvi K

    2015-01-01

    Periodontitis, a formidable global health burden, is a common chronic disease that destroys tooth-supporting tissues. Biomarkers of the early phase of this progressive disease are of utmost importance for global health. In this context, saliva represents a non-invasive biosample. By using systems biology tools, we aimed to (1) identify an integrated interactome between matrix metalloproteinase (MMP)-REDOX/nitric oxide (NO) and apoptosis upstream pathways of periodontal inflammation, and (2) characterize the attendant topological network properties to uncover putative biomarkers to be tested in saliva from patients with periodontitis. Hence, we first generated a protein-protein network model of interactions ("BIOMARK" interactome) by using the STRING 10 database, a search tool for the retrieval of interacting genes/proteins, with "Experiments" and "Databases" as input options and a confidence score of 0.400. Second, we determined the centrality values (closeness, stress, degree or connectivity, and betweenness) for the "BIOMARK" members by using the Cytoscape software. We found Ubiquitin C (UBC), Jun proto-oncogene (JUN), and matrix metalloproteinase-14 (MMP14) as the most central hub- and non-hub-bottlenecks among the 211 genes/proteins of the whole interactome. We conclude that UBC, JUN, and MMP14 are likely an optimal candidate group of host-derived biomarkers, in combination with oral pathogenic bacteria-derived proteins, for detecting periodontitis at its early phase by using salivary samples from patients. These findings therefore have broader relevance for systems medicine in global health as well.

  18. Effects of Four-Week Supplementation with a Multi-Vitamin/Mineral Preparation on Mood and Blood Biomarkers in Young Adults: A Randomised, Double-Blind, Placebo-Controlled Trial.

    Science.gov (United States)

    White, David J; Cox, Katherine H M; Peters, Riccarda; Pipingas, Andrew; Scholey, Andrew B

    2015-10-30

    This study explored the effects of four-week multi-vitamin and mineral (MVM) supplementation on mood and neurocognitive function in healthy, young adults. Fifty-eight healthy adults, 18-40 years of age (M = 25.82 years, SD = 4.87) participated in this randomised, double-blind, placebo-controlled trial, in which mood and blood biomarkers were assessed at baseline and after four weeks of supplementation. Compared to placebo, MVM supplementation was associated with significantly lowered homocysteine and increased blood B-vitamin levels (p vitamins and lowered homocysteine in healthy young adults.

  19. Separation methods that are capable of revealing blood-brain barrier permeability.

    Science.gov (United States)

    Dash, Alekha K; Elmquist, William F

    2003-11-25

    The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the

  20. Biomarkers of oral exposure to 3-nitro-1,2,4-triazol-5-one (NTO) and 2,4-dinitroanisole (DNAN) in blood and urine of rhesus macaques (Macaca mulatta).

    Science.gov (United States)

    Hoyt, Nathan; Brunell, Marla; Kroeck, Karl; Hable, Mike; Crouse, Lee; O'Neill, Art; Bannon, Desmond I

    2013-11-01

    The U.S. Department of Defense is using the chemicals 2,4-dinitroanisole (DNAN) and 3-nitro-1, 2,4-triazol-5-one (NTO) in new munitions development. In a screen for biomarkers of exposure, these compounds were measured in urine and blood of male rhesus monkeys after oral doses. NTO peaked at 4 h, with urinary concentrations at least 100-fold higher than that of blood or serum while 4-dinitrophenol (DNP), a metabolite of DNAN, appeared in blood at concentrations 10- to 20-fold higher than the parent compound. For human exposure monitoring, urine is optimal for NTO while the metabolite DNP in blood is best for DNAN.

  1. Biomarkers for neuromyelitis optica.

    Science.gov (United States)

    Chang, Kuo-Hsuan; Ro, Long-Sun; Lyu, Rong-Kuo; Chen, Chiung-Mei

    2015-02-02

    Neuromyelitis optica (NMO) is an acquired, heterogeneous inflammatory disorder, which is characterized by recurrent optic neuritis and longitudinally extensive spinal cord lesions. The discovery of the serum autoantibody marker, anti-aquaporin 4 (anti-AQP4) antibody, revolutionizes our understanding of pathogenesis of NMO. In addition to anti-AQP4 antibody, other biomarkers for NMO are also reported. These candidate biomarkers are particularly involved in T helper (Th)17 and astrocytic damages, which play a critical role in the development of NMO lesions. Among them, IL-6 in the peripheral blood is associated with anti-AQP4 antibody production. Glial fibrillary acidic protein (GFAP) in CSF demonstrates good correlations with clinical severity of NMO relapses. Detecting these useful biomarkers may be useful in the diagnosis and evaluation of disease activity of NMO. Development of compounds targeting these biomarkers may provide novel therapeutic strategies for NMO. This article will review the related biomarker studies in NMO and discuss the potential therapeutics targeting these biomarkers.

  2. Highly Sensitive and Selective Immuno-capture/Electrochemical Assay of Acetylcholinesterase Activity in Red Blood Cells: A Biomarker of Exposure to Organophosphorus Pesticides and Nerve Agents

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Aiqiong; Du, Dan; Lin, Yuehe

    2012-02-09

    Acetylcholinesterase (AChE) enzyme activity in red blood cells (RBCs) is a useful biomarker for biomonitoring of exposures to organophosphorus (OP) pesticides and chemical nerve agents. In this paper, we reported a new method for AChE activity assay based on selective immuno-capture of AChE from biological samples followed by enzyme activity assay of captured AChE using a disposable electrochemical sensor. The electrochemical sensor is based on multiwalled carbon nanotubes-gold nanocomposites (MWCNTs-Au) modified screen printed carbon electrode (SPCE). Upon the completion of immunoreaction, the target AChE (including active and inhibited) is captured onto the electrode surface and followed by an electrochemical detection of enzymatic activity in the presence of acetylthiocholine. A linear response is obtained over standard AChE concentration range from 0.1 to 10 nM. To demonstrate the capability of this new biomonitoring method, AChE solutions dosed with different concentration of paraoxon were used to validate the new AChE assay method. AChE inhibition in OP dosed solutions was proportional to its concentration from 0.2 to 50 nM. The new AChE activity assay method for biomonitoring of OP exposure was further validated with in-vitro paraoxon-dosed RBC samples. The established electrochemical sensing platform for AChE activity assay not only avoids the problem of overlapping substrate specificity with esterases by using selective antibody, but also eliminates potential interference from other electroactive species in biological samples. It offers a new approach for sensitive, selective, and rapid AChE activity assay for biomonitoring of exposures to OPs.

  3. Urinary Biomarkers of Brain Diseases

    Directory of Open Access Journals (Sweden)

    Manxia An

    2015-12-01

    Full Text Available Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.

  4. Maternal rumen-protected methionine supplementation and its effect on blood and liver biomarkers of energy metabolism, inflammation, and oxidative stress in neonatal Holstein calves.

    Science.gov (United States)

    Jacometo, C B; Zhou, Z; Luchini, D; Trevisi, E; Corrêa, M N; Loor, J J

    2016-08-01

    In nonruminants, nutrition during pregnancy can program offspring development, metabolism, and health in later life. Rumen-protected Met (RPM) supplementation during the prepartum period improves liver function and immune response in dairy cows. Our aim was to investigate the effects of RPM during late pregnancy on blood biomarkers (23 targets) and the liver transcriptome (24 genes) in neonatal calves from cows fed RPM at 0.08% of diet dry matter/d (MET) for the last 21 d before calving or controls (CON). Blood (n=12 calves per diet) was collected at birth before receiving colostrum (baseline), 24 h after receiving colostrum, 14, 28, and 50 d (post-weaning) of age. Liver was sampled (n=8 calves per diet) via biopsy on d 4, 14, 28, and 50 of age. Growth and health were not affected by maternal diet. The MET calves had greater overall plasma insulin concentration and lower glucose and ratios of glucose-to-insulin and fatty acids-to-insulin, indicating greater systemic insulin sensitivity. Lower concentration of reactive oxygen metabolites at 14 d of age along with a tendency for lower overall concentration of ceruloplasmin in MET calves indicated a lesser degree of stress. Greater expression on d 4 of fructose-bisphosphatase 1 (FBP1), phosphoenolpyruvate carboxykinase 1 (PCK1), and the facilitated bidirectional glucose transporter SLC2A2 in MET calves indicated alterations in gluconeogenesis and glucose uptake and release. The data agree with the greater expression of the glucocorticoid receptor (GR). Greater expression on d 4 of the insulin receptor (INSR) and insulin-responsive serine/threonine-protein kinase (AKT2) in MET calves indicated alterations in insulin signaling. In that context, the similar expression of sterol regulatory element-binding transcription factor 1 (SREBF1) in CON and MET during the preweaning period followed by the marked upregulation regardless of diet after weaning (d 50) support the idea of changes in hepatic insulin sensitivity during

  5. Study of fluid dynamics reveals direct communications between lymphatic vessels and venous blood vessels at lymph nodes of mice.

    Science.gov (United States)

    Takeda, Kazu; Mori, Shiro; Kodama, Tetsuya

    2017-02-22

    Cancer cells metastasize to lymph nodes, with distant metastasis resulting in poor prognosis. The role of lymph node metastasis (LNM) in the spread of cancer to distant organs remain incompletely characterized. The visualization of flow dynamics in the lymphatic and blood vessels of MXH10/Mo-lpr/lpr mice, which develop systemic swelling of lymph nodes up to 10mm in diameter, has revealed that lymph nodes have the potential to be a direct source of systemic metastasis. However, it is not known whether these fluid dynamics characteristics are universal phenomena present in other strains of laboratory mice. Here we show that the fluid dynamics observed in MXH10/Mo-lpr/lpr mice are the same as those observed in C57BL/6J, BALB/cAJcl and NOD/ShiJic-scidJcl mice. Furthermore, when fluorescent solution was injected into a tumor-bearing lymph node, the flow dynamics observed in the efferent lymphatic vessels and thoracoepigastric vein depended on the type of tumor cell. Our results indicate that fluid dynamics in the lymphatic and blood vessels of MXH10/Mo-lpr/lpr mice are generalized phenomena seen in conventional laboratory mice. We anticipate our results can facilitate studies of the progression of lymphatic metastasis to hematogenous metastasis via lymph nodes and the early diagnosis and treatment of LNM.

  6. Biomarkers in inflammatory bowel diseases

    DEFF Research Database (Denmark)

    Bennike, Tue; Birkelund, Svend; Stensballe, Allan

    2014-01-01

    with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future...... development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content......) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine...

  7. Relationship between hepatic CTGF expression and routine blood tests at the time of liver transplantation for biliary atresia: hope or hype for a biomarker of hepatic fibrosis

    Directory of Open Access Journals (Sweden)

    Haafiz A

    2011-04-01

    -CTGF expression and gamma-glutamyl transpeptidase (GGT, PT, INR, and platelet count. Pearson correlation coefficients for combinational analysis of standardized total bilirubin (TB, alkaline phosphatase, GGT, and platelet count with L-CTGF (0.33; P = 0.3 and P-CTGF (0.06; P = 0.8, were not significant. Similar analysis for alanine aminotransferase, TB, and GGT combination (L-CTGF, 0.16; P = 0.5; P-CTGF —0.3; P = 0.2 as well as WBC, platelet count, and TB (L-CTGF: —0.36; P = 0.09; P-CTGF —0.33; P = 0.13 also revealed nonsignificant results.Conclusion: Hepatic expression of fibrogenic markers can be correlated with routinely performed blood tests in patients with BA. We document that although a trend of inverse relationship is noted, hepatic CTGF expression does not correlate well with routinely performed blood tests in advanced BA. Further work is required to determine more reliable ways of noninvasive diagnosis of HF.Keyword: connective tissue growth factor, liver fibrosis, blood tests, fibrogenesis

  8. Asynchronicity of facial blood perfusion in migraine.

    Directory of Open Access Journals (Sweden)

    Nina Zaproudina

    Full Text Available Asymmetrical changes in blood perfusion and asynchronous blood supply to head tissues likely contribute to migraine pathophysiology. Imaging was widely used in order to understand hemodynamic variations in migraine. However, mapping of blood pulsations in the face of migraineurs has not been performed so far. We used the Blood Pulsation Imaging (BPI technique, which was recently developed in our group, to establish whether 2D-imaging of blood pulsations parameters can reveal new biomarkers of migraine. BPI characteristics were measured in migraineurs during the attack-free interval and compared to healthy subjects with and without a family history of migraine. We found a novel phenomenon of transverse waves of facial blood perfusion in migraineurs in contrast to healthy subjects who showed synchronous blood delivery to both sides of the face. Moreover, the amplitude of blood pulsations was symmetrically distributed over the face of healthy subjects, but asymmetrically in migraineurs and subjects with a family history of migraine. In the migraine patients we found a remarkable correlation between the side of unilateral headache and the direction of the blood perfusion wave. Our data suggest that migraine is associated with lateralization of blood perfusion and asynchronous blood pulsations in the facial area, which could be due to essential dysfunction of the autonomic vascular control in the face. These findings may further enhance our understanding of migraine pathophysiology and suggest new easily available biomarkers of this pathology.

  9. Asynchronicity of facial blood perfusion in migraine.

    Science.gov (United States)

    Zaproudina, Nina; Teplov, Victor; Nippolainen, Ervin; Lipponen, Jukka A; Kamshilin, Alexei A; Närhi, Matti; Karjalainen, Pasi A; Giniatullin, Rashid

    2013-01-01

    Asymmetrical changes in blood perfusion and asynchronous blood supply to head tissues likely contribute to migraine pathophysiology. Imaging was widely used in order to understand hemodynamic variations in migraine. However, mapping of blood pulsations in the face of migraineurs has not been performed so far. We used the Blood Pulsation Imaging (BPI) technique, which was recently developed in our group, to establish whether 2D-imaging of blood pulsations parameters can reveal new biomarkers of migraine. BPI characteristics were measured in migraineurs during the attack-free interval and compared to healthy subjects with and without a family history of migraine. We found a novel phenomenon of transverse waves of facial blood perfusion in migraineurs in contrast to healthy subjects who showed synchronous blood delivery to both sides of the face. Moreover, the amplitude of blood pulsations was symmetrically distributed over the face of healthy subjects, but asymmetrically in migraineurs and subjects with a family history of migraine. In the migraine patients we found a remarkable correlation between the side of unilateral headache and the direction of the blood perfusion wave. Our data suggest that migraine is associated with lateralization of blood perfusion and asynchronous blood pulsations in the facial area, which could be due to essential dysfunction of the autonomic vascular control in the face. These findings may further enhance our understanding of migraine pathophysiology and suggest new easily available biomarkers of this pathology.

  10. Novel approach to meta-analysis of microarray datasets reveals muscle remodeling-related drug targets and biomarkers in Duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Ekaterina Kotelnikova

    2012-02-01

    Full Text Available Elucidation of new biomarkers and potential drug targets from high-throughput profiling data is a challenging task due to a limited number of available biological samples and questionable reproducibility of differential changes in cross-dataset comparisons. In this paper we propose a novel computational approach for drug and biomarkers discovery using comprehensive analysis of multiple expression profiling datasets.The new method relies on aggregation of individual profiling experiments combined with leave-one-dataset-out validation approach. Aggregated datasets were studied using Sub-Network Enrichment Analysis algorithm (SNEA to find consistent statistically significant key regulators within the global literature-extracted expression regulation network. These regulators were linked to the consistent differentially expressed genes.We have applied our approach to several publicly available human muscle gene expression profiling datasets related to Duchenne muscular dystrophy (DMD. In order to detect both enhanced and repressed processes we considered up- and down-regulated genes separately. Applying the proposed approach to the regulators search we discovered the disturbance in the activity of several muscle-related transcription factors (e.g. MYOG and MYOD1, regulators of inflammation, regeneration, and fibrosis. Almost all SNEA-derived regulators of down-regulated genes (e.g. AMPK, TORC2, PPARGC1A correspond to a single common pathway important for fast-to-slow twitch fiber type transition. We hypothesize that this process can affect the severity of DMD symptoms, making corresponding regulators and downstream genes valuable candidates for being potential drug targets and exploratory biomarkers.

  11. Proteomic analysis of coronary sinus serum reveals leucine-rich alpha2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure.

    LENUS (Irish Health Repository)

    Watson, Chris J

    2012-02-01

    BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF. METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich alpha2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P<\\/=0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-alpha (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-betaR1 (P<0.001) and alpha-smooth muscle actin (P=0.025) expression. CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, beta-blocker therapy, and BNP.

  12. A whole-body model for glycogen regulation reveals a critical role for substrate cycling in maintaining blood glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Ke Xu

    2011-12-01

    Full Text Available Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into "whole-body" contextual models that mimic in vivo conditions.

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

    Science.gov (United States)

    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.

  14. Urinary (1)H Nuclear Magnetic Resonance Metabolomic Fingerprinting Reveals Biomarkers of Pulse Consumption Related to Energy-Metabolism Modulation in a Subcohort from the PREDIMED study.

    Science.gov (United States)

    Madrid-Gambin, Francisco; Llorach, Rafael; Vázquez-Fresno, Rosa; Urpi-Sarda, Mireia; Almanza-Aguilera, Enrique; Garcia-Aloy, Mar; Estruch, Ramon; Corella, Dolores; Andres-Lacueva, Cristina

    2017-04-07

    Little is known about the metabolome fingerprint of pulse consumption. The study of robust and accurate biomarkers for pulse dietary assessment has great value for nutritional epidemiology regarding health benefits and their mechanisms. To characterize the fingerprinting of dietary pulses (chickpeas, lentils, and beans), spot urine samples from a subcohort from the PREDIMED study were stratified using a validated food frequency questionnaire. Urine samples of nonpulse consumers (≤4 g/day of pulse intake) and habitual pulse consumers (≥25 g/day of pulse intake) were analyzed using a (1)H nuclear magnetic resonance (NMR) metabolomics approach combined with multi- and univariate data analysis. Pulse consumption showed differences through 16 metabolites coming from (i) choline metabolism, (ii) protein-related compounds, and (iii) energy metabolism (including lower urinary glucose). Stepwise logistic regression analysis was applied to design a combined model of pulse exposure, which resulted in glutamine, dimethylamine, and 3-methylhistidine. This model was evaluated by a receiver operating characteristic curve (AUC > 90% in both training and validation sets). The application of NMR-based metabolomics to reported pulse exposure highlighted new candidates for biomarkers of pulse consumption and the impact on energy metabolism, generating new hypotheses on energy modulation. Further intervention studies will confirm these findings.

  15. Network-Based Logistic Classification with an Enhanced L1/2 Solver Reveals Biomarker and Subnetwork Signatures for Diagnosing Lung Cancer

    Directory of Open Access Journals (Sweden)

    Hai-Hui Huang

    2015-01-01

    Full Text Available Identifying biomarker and signaling pathway is a critical step in genomic studies, in which the regularization method is a widely used feature extraction approach. However, most of the regularizers are based on L1-norm and their results are not good enough for sparsity and interpretation and are asymptotically biased, especially in genomic research. Recently, we gained a large amount of molecular interaction information about the disease-related biological processes and gathered them through various databases, which focused on many aspects of biological systems. In this paper, we use an enhanced L1/2 penalized solver to penalize network-constrained logistic regression model called an enhanced L1/2 net, where the predictors are based on gene-expression data with biologic network knowledge. Extensive simulation studies showed that our proposed approach outperforms L1 regularization, the old L1/2 penalized solver, and the Elastic net approaches in terms of classification accuracy and stability. Furthermore, we applied our method for lung cancer data analysis and found that our method achieves higher predictive accuracy than L1 regularization, the old L1/2 penalized solver, and the Elastic net approaches, while fewer but informative biomarkers and pathways are selected.

  16. Effect of consumption of fresh and heated virgin coconut oil on the blood pressure and inflammatory biomarkers: An experimental study in Sprague Dawley rats

    Directory of Open Access Journals (Sweden)

    Mohammad Afiq Hamsi

    2015-03-01

    Conclusion: Repeatedly heated VCO caused an elevation in the BP. The BP elevation was associated with a significant increase in the inflammatory bio-markers (VCAM-1, ICAM-1 and CRP, TXB2 and a significant reduction in the plasma PGI2 level.

  17. Effects of Four-Week Supplementation with a Multi-Vitamin/Mineral Preparation on Mood and Blood Biomarkers in Young Adults: A Randomised, Double-Blind, Placebo-Controlled Trial

    Directory of Open Access Journals (Sweden)

    David J. White

    2015-10-01

    Full Text Available This study explored the effects of four-week multi-vitamin and mineral (MVM supplementation on mood and neurocognitive function in healthy, young adults. Fifty-eight healthy adults, 18–40 years of age (M = 25.82 years, SD = 4.87 participated in this randomised, double-blind, placebo-controlled trial, in which mood and blood biomarkers were assessed at baseline and after four weeks of supplementation. Compared to placebo, MVM supplementation was associated with significantly lowered homocysteine and increased blood B-vitamin levels (p < 0.01. MVM treatment was also associated with significantly improved mood, as measured by reduced scores on the “depression-dejection” subscale of the Profile of Mood States (p = 0.018. These findings suggest that the four weeks of MVM supplementation may have beneficial effects on mood, underpinned by elevated B-vitamins and lowered homocysteine in healthy young adults.

  18. Comprehensive Phenotyping in Multiple Sclerosis: Discovery Based Proteomics and the Current Understanding of Putative Biomarkers

    Directory of Open Access Journals (Sweden)

    Kevin C. O’Connor

    2006-01-01

    Full Text Available Currently, there is no single test for multiple sclerosis (MS. Diagnosis is confirmed through clinical evaluation, abnormalities revealed by magnetic resonance imaging (MRI, and analysis of cerebrospinal fluid (CSF chemistry. The early and accurate diagnosis of the disease, monitoring of progression, and gauging of therapeutic intervention are important but elusive elements of patient care. Moreover, a deeper understanding of the disease pathology is needed, including discovery of accurate biomarkers for MS. Herein we review putative biomarkers of MS relating to neurodegeneration and contributions to neuropathology, with particular focus on autoimmunity. In addition, novel assessments of biomarkers not driven by hypotheses are discussed, featuring our application of advanced proteomics and metabolomics for comprehensive phenotyping of CSF and blood. This strategy allows comparison of component expression levels in CSF and serum between MS and control groups. Examination of these preliminary data suggests that several CSF proteins in MS are differentially expressed, and thus, represent putative biomarkers deserving of further evaluation.

  19. Polydopamine/dialdehyde starch/chitosan composite coating for in-tube solid-phase microextraction and in-situ derivation to analysis of two liver cancer biomarkers in human blood.

    Science.gov (United States)

    Wu, Shiju; Cai, Cuicui; Cheng, Jing; Cheng, Min; Zhou, Hongbin; Deng, Jiali

    2016-09-01

    In order to highly enrich two liver cancer biomarkers (hexanal and 2-butanone) in human blood, in this study, natural nontoxic polydopamine/dialdehyde starch/chitosan (PD/DAS/CHI) coating material was synthesized and immobilized on the inner wall of polytetrafluoro-ethlyene (PTFE) tube. It was used to develop the method based on in-tube solid-phase microextraction (IT-SPME) with in-situ derivatization (ISD) coupled to high performance liquid chromatography for the determination of the above mentioned two liver cancer biomarkers in human blood. The simple, rapid and sensitive IT-SPME-ISD method can be finished within 11 min. Under optimum conditions, the limits of detection (LODs) were 1.4 and 1.6 nmol L(-1) for hexanal and 2-butanone, respectively. The relative recoveries from real human blood samples were in the range from 70% to 91% with the intra- and inter-day precisions less than 7.2%. Furthermore, this method was successfully applied for the analysis of hexanal and 2-butanone in blood samples from healthy people with 0.42 ± 0.05 and 0.34 ± 0.04 μmol L(-1), while liver cancer patients with 1.90 ± 0.07  μmol L(-1) and 0.91 ± 0.07 μmol L(-1), respectively. The t-test's results showed there is a statistically significant difference between the data from healthy persons and liver cancer patients. Hence, the developed method might be applied in the screening of suspected liver cancer patients.

  20. Direct molecular detection of pathogens in blood as specific rule-in diagnostic biomarker in patients with presumed sepsis: our experience on a heterogeneous cohort of patients with signs of infective systemic inflammatory response syndrome.

    Science.gov (United States)

    Avolio, Manuela; Diamante, Paola; Modolo, Maria Luisa; De Rosa, Rita; Stano, Paola; Camporese, Alessandro

    2014-08-01

    The practical value of blood cultures in the diagnosis of sepsis is impaired by a delay in the turnaround time to result and by the fact that blood culture positive can be found for only about 30% of these patients. Conventional laboratory signs of sepsis and acute phase protein biomarkers are sensitive and easy to use, but often also very nonspecific. Molecular diagnostic reflects currently the most promising avenue to decrease time to result and to influence decision making for antibiotic therapy in the septic host. In this study, we wish to highlight the impact of the LightCycler SeptiFast, a multipathogen probe-based real-time polymerase chain reaction, in the rapid etiological diagnosis of sepsis in patients with clinical and laboratory signs of bloodstream infections. We have evaluated prospectively 830 adult patients with suspected bloodstream infection and at least two criteria of systemic inflammatory response syndrome. In more than 50% of critically ill patients strongly suspected of having sepsis, we arrived to an etiological diagnosis only by the molecular method in a median time of 15 h, with specificity and predictive positive values of 96% and 94%, respectively. We highlight the role of DNAemia as time-critical, high-specificity, etiological, non-culture-based rule-in diagnostic biomarker in patients with presumed sepsis.

  1. Computational imaging analysis of fibrin matrices with the inclusion of erythrocytes from homozygous SS blood reveals agglomerated and amorphous structures.

    Science.gov (United States)

    Averett, Rodney D; Norton, David G; Fan, Natalie K; Platt, Manu O

    2017-01-01

    Sickle cell disease is a single point mutation disease that is known to alter the coagulation system, leading to hypercoagulable plasma conditions. These hypercoagulable conditions can lead to complications in the vasculature, caused by fibrin clots that form undesirably. There is a need to understand the morphology and structure of fibrin clots from patients with sickle cell disease, as this could lead to further discovery of treatments and life-saving therapies. In this work, a computational imaging analysis method is presented to evaluate fibrin agglomeration in the presence of erythrocytes (RBCs) homozygous for the sickle cell mutation (SS). Numerical algorithms were used to determine agglomeration of fibrin fibers within a matrix with SS RBCs to test the hypothesis that fibrin matrices with the inclusion of SS RBCs possess a more agglomerated structure than native fibrin matrices with AA RBCs. The numerical results showed that fibrin structures with SS RBCs displayed an overall higher degree of agglomeration as compared to native fibrin structures. The computational algorithm was also used to evaluate fibrin fiber overlap (aggregation) and anisotropy (orientation) in normal fibrin matrices compared to fibrin matrices polymerized around SS RBCs; however, there was no statistical difference. Ultrasound measurements of stiffness revealed rigid RBCs in the case of samples derived from homozygous SS blood, and densely evolving matrices, when compared to normal fibrin with the inclusion of AA RBCs. An agglomeration model is suggested to quantify the fibrin aggregation/clustering near RBCs for both normal fibrin matrices and for the altered structures. The results of this work are important in the sense that the understanding of aggregation and morphology in fibrin clots with incorporation of RBCs from persons living with sickle cell anemia may elucidate the complexities of comorbidities and other disease complications.

  2. Virus host protein interaction network analysis reveals that the HEV ORF3 protein may interrupt the blood coagulation process.

    Directory of Open Access Journals (Sweden)

    Yansheng Geng

    Full Text Available Hepatitis E virus (HEV is endemic worldwide and a major cause of acute liver disease in developing countries. However, the molecular mechanisms of liver pathology and clinical disease are not well understood for HEV infection. Open reading frame 3 (ORF3 of HEV encodes a small phosphoprotein, which is assumed to be involved in liver pathology and clinical disease. In this study, the interactions between the HEV ORF3 protein and human proteins were investigated using a stringent, high-throughput yeast two-hybrid (Y2H analysis. Thirty two proteins were shown to interact with genotype 1 ORF3, 28 of which have not been reported previously. These novel interactions were evaluated by coimmunoprecipitation of protein complexes from transfected cells. We found also that the ORF3 proteins of genotype 4 and rabbit HEV interacted with all of the human proteins identified by the genotype 1 ORF3 protein. However, the putative ORF3 protein derived from avian HEV did not interact with the majority of these human proteins. The identified proteins were used to infer an overall interaction map linking the ORF3 protein with components of the host cellular networks. Analysis of this interaction map, based on functional annotation with the Gene Ontology features and KEGG pathways, revealed an enrichment of host proteins involved in complement coagulation, cellular iron ion homeostasis and oxidative stress. Additional canonical pathway analysis highlighted the enriched biological pathways relevant to blood coagulation and hemostasis. Consideration of the clinical manifestations of hepatitis E reported previously and the results of biological analysis from this study suggests that the ORF3 protein is likely to lead to an imbalance of coagulation and fibrinolysis by interacting with host proteins and triggering the corresponding pathological processes. These results suggest critical approaches to further study of the pathogenesis of the HEV ORF3 protein.

  3. Tick-borne encephalitis virus sequenced directly from questing and blood-feeding ticks reveals quasispecies variance.

    Science.gov (United States)

    Asghar, Naveed; Lindblom, Pontus; Melik, Wessam; Lindqvist, Richard; Haglund, Mats; Forsberg, Pia; Överby, Anna K; Andreassen, Åshild; Lindgren, Per-Eric; Johansson, Magnus

    2014-01-01

    The increased distribution of the tick-borne encephalitis virus (TBEV) in Scandinavia highlights the importance of characterizing novel sequences within the natural foci. In this study, two TBEV strains: the Norwegian Mandal 2009 (questing nymphs pool) and the Swedish Saringe 2009 (blood-fed nymph) were sequenced and phylogenetically characterized. Interestingly, the sequence of Mandal 2009 revealed the shorter form of the TBEV genome, similar to the highly virulent Hypr strain, within the 3' non-coding region (3'NCR). A different genomic structure was found in the 3'NCR of Saringe 2009, as in-depth analysis demonstrated TBEV variants with different lengths within the poly(A) tract. This shows that TBEV quasispecies exists in nature and indicates a putative shift in the quasispecies pool when the virus switches between invertebrate and vertebrate environments. This prompted us to further sequence and analyze the 3'NCRs of additional Scandinavian TBEV strains and control strains, Hypr and Neudoerfl. Toro 2003 and Habo 2011 contained mainly a short (A)3C(A)6 poly(A) tract. A similar pattern was observed for the human TBEV isolates 1993/783 and 1991/4944; however, one clone of 1991/4944 contained an (A)3C(A)11 poly(A) sequence, demonstrating that quasispecies with longer poly(A) could be present in human isolates. Neudoerfl has previously been reported to contain a poly(A) region, but to our surprise the re-sequenced genome contained two major quasispecies variants, both lacking the poly(A) tract. We speculate that the observed differences are important factors for the understanding of virulence, spread, and control of the TBEV.

  4. Stable RNA markers for identification of blood and saliva stains revealed from whole genome expression analysis of time-wise degraded samples

    NARCIS (Netherlands)

    D. Zubakov (Dmitry); E.E. Hanekamp (Eline); M. Kokshoorn (Mieke); W.F.J. van IJcken (Wilfred); M.H. Kayser (Manfred)

    2008-01-01

    textabstractHuman body fluids such as blood and saliva represent the most common source of biological material found at a crime scene. Reliable tissue identification in forensic science can reveal significant insights into crime scene reconstruction and can thus contribute toward solving crimes. Lim

  5. Differences between hospital- and community-acquired blood exposure incidents revealed by a regional expert counseling center.

    NARCIS (Netherlands)

    Wijk, P.T. van; Pelk-Jongen, M.; Boer, E. de; Voss, A.; Wijkmans, C.; Schneeberger, P.M.

    2006-01-01

    OBJECTIVE: One year (2003) regional analysis of all blood exposure incidents from hospitals as well as from the community. DESIGN: Establishment of an easily accessible regional expert counseling center, operating 24 h a day, for all accidental blood exposures. Tasks of the center were to register i

  6. The Immune System and Neuroinflammation as Potential Sources of Blood-Based Biomarkers for Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease.

    Science.gov (United States)

    Clark, Lorraine F; Kodadek, Thomas

    2016-05-18

    Neurodegenerative diseases are characterized by a loss of neurons that leads to cognitive and behavioral dysfunction. Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting millions of people in the United States and worldwide, followed by Parkinson's disease (PD). While some early onset forms of AD and PD are hereditary, the sporadic or late-onset cases are believed to result from lifestyle and environmental factors. On the contrary, Huntington's disease (HD) is a neurodegenerative disease solely caused by mutations in the gene for huntingtin protein. The disease mechanisms at play for all three disorders remain elusive, hampering efforts to develop effective therapeutic interventions. In light of this, the discovery of robust biomarkers is crucial in order to identify people at risk for AD and PD, preferably before symptoms arise. For all three diseases, the identification of biomarkers would not only allow development of treatments but also evaluation and adjustment of these with disease progression. It is now understood that neuroinflammation plays a crucial role in neurodegenerative diseases, along with subsequent immune activation. Therefore, research is actively ongoing to discover and evaluate inflammatory and immune-related biomarkers. Recent progress in this area for AD, PD, and HD is presented here.

  7. Biomarkers for early diagnosis of type 2 diabetic nephropathy: a study based on an integrated biomarker system.

    Science.gov (United States)

    Huang, Min; Liang, Qionglin; Li, Ping; Xia, Jianfei; Wang, Yong; Hu, Ping; Jiang, Zhiting; He, Yongxin; Pang, Liqiong; Han, Lida; Wang, Yiming; Luo, Guoan

    2013-08-01

    Diabetic nephropathy is a devastating disease that affects a growing number of diabetic patients. A complete cure is very hard to achieve once the disease has been diagnosed, therefore the diagnosis of early stages in diabetic nephropathy has become a hot area. Numbers of molecules have been proposed to be potential biomarkers for this purpose. However, some problems still remain, such as discovering effective biomarkers to diagnose the disease before obvious clinical evidence appears. Thus, the main purpose of this study was to find plasma biomarkers for early diagnosis of type 2 diabetic nephropathy stage 1 and stage 2, as well as separating them from diabetes. 182 subjects (Chinese) were recruited for this study, including 50 healthy controls, 33 type 2 diabetic patients and 99 type 2 diabetic nephropathy patients (33 of these were stage 3). Important clinical indicators including proteinuria, serum creatinine, and urea nitrogen were measured and the glomerular filtration rate was estimated to assess kidney function; fasting blood glucose, postprandial blood glucose and glycated hemoglobin were measured to assess the blood glucose control. Key metabolites and genes in plasma samples were identified and determined using -omic and quantitative techniques. The potential biomarkers were then combined and carefully screened to determine the most informative ones for early diagnosis of type 2 diabetic nephropathy. An integrated biomarker system (IBS) incorporating 6 clinical indicators, 40 metabolites and 5 genes was established. Correlation analysis results revealed that most of the potential biomarkers significantly correlated with the 6 clinical indicators. Discriminant analysis results showed that the developed IBS gave the highest total predictive accuracy (98.9%). Significant test and receiver operating characteristic analysis results indicated that inosine had the highest sensitivity (0.889), specificity (1.000), positive predictive rate (1.000) and negative

  8. Multiplexed cancer biomarker detection using chip-integrated silicon photonic sensor arrays.

    Science.gov (United States)

    Washburn, Adam L; Shia, Winnie W; Lenkeit, Kimberly A; Lee, So-Hyun; Bailey, Ryan C

    2016-09-21

    The analysis of disease-specific biomarker panels holds promise for the early detection of a range of diseases, including cancer. Blood-based biomarkers, in particular, are attractive targets for minimally-invasive disease diagnosis. Specifically, a panel of organ-specific biomarkers could find utility as a general disease surveillance tool enabling earlier detection or prognostic monitoring. Using arrays of chip-integrated silicon photonic sensors, we describe the simultaneous detection of eight cancer biomarkers in serum in a relatively rapid (1 hour) and fully automated antibody-based sandwich assay. Biomarkers were chosen for their applicability to a range of organ-specific cancers, including disease of the pancreas, liver, ovary, breast, lung, colorectum, and prostate. Importantly, we demonstrate that selected patient samples reveal biomarker "fingerprints" that may be useful for a personalized cancer diagnosis. More generally, we show that the silicon photonic technology is capable of measuring multiplexed panels of protein biomarkers that may have broad utility in clinical diagnostics.

  9. Blood Pressure is Associated With Cerebral Blood Flow Alterations in Patients With T2DM as Revealed by Perfusion Functional MRI.

    Science.gov (United States)

    Xia, Wenqing; Rao, Hengyi; Spaeth, Andrea M; Huang, Rong; Tian, Sai; Cai, Rongrong; Sun, Jie; Wang, Shaohua

    2015-12-01

    Type 2 diabetes mellitus (T2DM) and hypertension are both associated with cognitive impairment and brain function abnormalities. We investigated whether abnormal cerebral blood flow (CBF) patterns exists in T2DM patients and possible relationships between aberrant CBF and cognitive performance. Furthermore, we examined the influence of hypertension on CBF alterations in T2DM patients. T2DM patients (n = 38) and non-T2DM subjects (n = 40) were recruited from clinics, hospitals, and normal community health screenings. Cerebral blood flow images were collected and analyzed using arterial spin labeling perfusion functional magnetic resonance imaging (fMRI). Regions with major CBF differences between T2DM patients and non-T2DM controls were detected via 1-way ANOVA. The interaction effects between hypertension and T2DM for CBF alterations were also examined. Correlation analyses illustrated the association between CBF values and cognitive performance and between CBF and blood pressure. Compared with non-T2DM controls, T2DM patients exhibited decreased CBF, primarily in the visual area and the default mode network (DMN); decreased CBF in these regions was correlated with cognitive performance. There was a significant interaction effect between hypertension and diabetes for CBF in the precuneus and the middle occipital gyrus. Additionally, blood pressure correlated negatively with CBF in T2DM patients.T2DM patients exhibited reduced CBF in the visual area and DMN. Hypertension may facilitate a CBF decrease in the setting of diabetes. T2DM patients may benefit from blood pressure control to maintain their brain perfusion through CBF preservation.

  10. Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood.

    Science.gov (United States)

    Rönn, Tina; Volkov, Petr; Gillberg, Linn; Kokosar, Milana; Perfilyev, Alexander; Jacobsen, Anna Louisa; Jørgensen, Sine W; Brøns, Charlotte; Jansson, Per-Anders; Eriksson, Karl-Fredrik; Pedersen, Oluf; Hansen, Torben; Groop, Leif; Stener-Victorin, Elisabet; Vaag, Allan; Nilsson, Emma; Ling, Charlotte

    2015-07-01

    Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of ∼480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.

  11. Imaging Biomarkers or Biomarker Imaging?

    Directory of Open Access Journals (Sweden)

    Markus Mitterhauser

    2014-06-01

    Full Text Available Since biomarker imaging is traditionally understood as imaging of molecular probes, we highly recommend to avoid any confusion with the previously defined term “imaging biomarkers” and, therefore, only use “molecular probe imaging (MPI” in that context. Molecular probes (MPs comprise all kinds of molecules administered to an organism which inherently carry a signalling moiety. This review highlights the basic concepts and differences of molecular probe imaging using specific biomarkers. In particular, PET radiopharmaceuticals are discussed in more detail. Specific radiochemical and radiopharmacological aspects as well as some legal issues are presented.

  12. Biomarkers of satiation and satiety.

    Science.gov (United States)

    de Graaf, Cees; Blom, Wendy A M; Smeets, Paul A M; Stafleu, Annette; Hendriks, Henk F J

    2004-06-01

    This review's objective is to give a critical summary of studies that focused on physiologic measures relating to subjectively rated appetite, actual food intake, or both. Biomarkers of satiation and satiety may be used as a tool for assessing the satiating efficiency of foods and for understanding the regulation of food intake and energy balance. We made a distinction between biomarkers of satiation or meal termination and those of meal initiation related to satiety and between markers in the brain [central nervous system (CNS)] and those related to signals from the periphery to the CNS. Various studies showed that physicochemical measures related to stomach distension and blood concentrations of cholecystokinin and glucagon-like peptide 1 are peripheral biomarkers associated with meal termination. CNS biomarkers related to meal termination identified by functional magnetic resonance imaging and positron emission tomography are indicators of neural activity related to sensory-specific satiety. These measures cannot yet serve as a tool for assessing the satiating effect of foods, because they are not yet feasible. CNS biomarkers related to satiety are not yet specific enough to serve as biomarkers, although they can distinguish between extreme hunger and fullness. Three currently available biomarkers for satiety are decreases in blood glucose in the short term (2-4 d) negative energy balance; and ghrelin concentrations, which have been implicated in both short-term and long-term energy balance. The next challenge in this research area is to identify food ingredients that have an effect on biomarkers of satiation, satiety, or both. These ingredients may help consumers to maintain their energy intake at a level consistent with a healthy body weight.

  13. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies.

    Science.gov (United States)

    Rouillon, Jérémy; Poupiot, Jérôme; Zocevic, Aleksandar; Amor, Fatima; Léger, Thibaut; Garcia, Camille; Camadro, Jean-Michel; Wong, Brenda; Pinilla, Robin; Cosette, Jérémie; Coenen-Stass, Anna M L; Mcclorey, Graham; Roberts, Thomas C; Wood, Matthew J A; Servais, Laurent; Udd, Bjarne; Voit, Thomas; Richard, Isabelle; Svinartchouk, Fedor

    2015-09-01

    Therapy-responsive biomarkers are an important and unmet need in the muscular dystrophy field where new treatments are currently in clinical trials. By using a comprehensive high-resolution mass spectrometry approach and western blot validation, we found that two fragments of the myofibrillar structural protein myomesin-3 (MYOM3) are abnormally present in sera of Duchenne muscular dystrophy (DMD) patients, limb-girdle muscular dystrophy type 2D (LGMD2D) and their respective animal models. Levels of MYOM3 fragments were assayed in therapeutic model systems: (1) restoration of dystrophin expression by antisense oligonucleotide-mediated exon-skipping in mdx mice and (2) stable restoration of α-sarcoglycan expression in KO-SGCA mice by systemic injection of a viral vector. Following administration of the therapeutic agents MYOM3 was restored toward wild-type levels. In the LGMD model, where different doses of vector were used, MYOM3 restoration was dose-dependent. MYOM3 fragments showed lower inter-individual variability compared with the commonly used creatine kinase assay, and correlated better with the restoration of the dystrophin-associated protein complex and muscle force. These data suggest that the MYOM3 fragments hold promise for minimally invasive assessment of experimental therapies for DMD and other neuromuscular disorders.

  14. Trophic ecology of two cold-water coral species from the Mediterranean Sea revealed by lipid biomarkers and compound-specific isotope analyses

    Science.gov (United States)

    Naumann, Malik S.; Tolosa, Imma; Taviani, Marco; Grover, Renaud; Ferrier-Pagès, Christine

    2015-12-01

    Scleractinian cold-water corals (CWC) act as key ecosystem engineers in deep-sea reef environments worldwide. However, our current understanding of their trophic ecology is still limited, particularly in understudied temperate oceanic regions such as the Mediterranean Sea. Hence, this study investigated the trophic ecology of the CWC Desmophyllum dianthus and Madrepora oculata by employing lipid biomarker techniques and compound-specific isotope analyses on coral tissues, suspended particulate organic matter (sPOM), and surface sediment sampled in a Mediterranean CWC habitat. CWC exhibited high contents of poly- and monounsaturated fatty acids (FA) (≥49 and 32 % of FA, respectively) and cholesterol (≥67 % of sterols), while sPOM and sediment samples were enriched in saturated FA (≥44 % of FA) and sitosterol (≥35 % of sterols). CWC contained some rare very long-chained polyunsaturated FA (>C22) and ergosterol absent in sPOM and sediment samples. Our results indicate that Mediterranean CWC mainly consume living food items, rather than detrital sPOM or resuspended sediment, and provide evidence for preferred feeding on omnivorous and carnivorous zooplankton. Overall, these findings provide new insights to the trophic ecology of two common CWC from the Mediterranean Sea.

  15. Extensive small-angle X-ray scattering studies of blood coagulation factor VIIa reveal interdomain flexibility

    DEFF Research Database (Denmark)

    Mosbæk, Charlotte Rode; Nolan, David; Persson, Egon

    2010-01-01

    Blood coagulation factor VIIa (FVIIa) is used in the treatment of replacement therapy resistant hemophilia patients, and FVIIa is normally activated upon complex formation with tissue factor (TF), potentially in context with structural rearrangements. The solution behavior of uncomplexed FVIIa...

  16. Idiopathic recurrent calcium urolithiasis (IRCU: pathophysiology evaluated in light of oxidative metabolism, without and with variation of several biomarkers in fasting urine and plasma - a comparison of stone-free and -bearing male patients, emphasizing mineral, acid-base, blood pressure and protein status*

    Directory of Open Access Journals (Sweden)

    Schwilie PO

    2011-08-01

    negatively correlated, whereas in SF plasma Ca/Pi ratio, PTH and body mass index correlated positively; 6 multivariate regression analysis revealed that PTH, body mass index and nitrate together could explain 22 (p = 0.002 and only 7 (p = 0.06 per cent of variation of plasma Ca/Pi in SF and SB, respectively Conclusions In IRCU a numerous constituents of fasting urine, plasma, blood and blood pressure change in response to variation of OM biomarkers, suggesting involvement of OM imbalance as factor in functional deterioration of tissue; b in the majority of patients a positive exponential relationship links urine Ca/Pi to urine Ca/Pi divided by plasma Ca/Pi, presumably to accumulate Ca outside tubular lumen, thereby minimizing intratubular and urinary Ca salt crystallization; c alteration of interactions of low urine nitrate, PTH and Ca/Pi in plasma may be of importance in formation of new Ca stone and co-regulation of dynamics of blood vasculature; d overweight, combined with OM-modified renal interstitial environment appears to facilitate these processes, carrying the risk that CaPi mineral develops within or/and close to blood vessel tissue, and spreads towards urothelium. For future research focussing on IRCU pathogenesis studies are recommended on the role of affluent lifestyle mediated renal ischemia, mild hypertensive nephropathy, rise of uric acid precursor oxypurines and uricemia, clarifying also why loss of significance of interrelationships of OM biomarkers with traditional Ca stone risk factors is characteristic for SB patients. OM biomarkers Plasma uric acid - Discussed as scavenger of reactive oxygen species, but also as donator (via the xanthine oxido-reductase reaction Urinary malonedialdehydc - Accepted as indicator of peroxidation of lipids within biological cell membranes Urinaiy nitrate - Accepted as indicator of vasodilation-mediating nitric oxide production by blood vessel endothelium Urinary malonedialdehyde/Plasma uric acid - Tentative markers of

  17. Monosomy 20 mosaicism revealed by extensive karyotyping in blood and skin cells: case report and review of the literature.

    Science.gov (United States)

    Hochstenbach, Ron; Krijtenburg, Pieter-Jaap; van der Veken, Lars T; van der Smagt, Jasper; Roeleveld-Versteegh, Angelique; Visser, Gepke; Terhal, Paulien

    2014-01-01

    We describe a 13-year-old boy with developmental delay and proximal muscle weakness who has monosomy 20 mosaicism in blood and skin cells. Because of asymmetric features (difference in foot size, slightly asymmetric intergluteal cleft), we performed extensive cytogenetic studies in peripheral blood and skin. In cultured and uncultured blood lymphocytes, we found 0.9 and 6.5% of cells with monosomy 20, respectively. In addition, 3.3% of uncultured skin fibroblasts and 1.5% of buccal mucosa cells had monosomy 20. This is the fifth patient published with this chromosomal condition. These patients show variable clinical features, ranging from normal to delayed motor and speech development. There is no apparent relation between the percentage of monosomic cells as studied in blood and the severity of the phenotype. This could be due to different degrees of mosaicism in the other tissues and organs, which may vary considerably from patient to patient. The degree of monosomy 20 mosaicism in blood is in most patients below the detection limit of microarray technology. Therefore, this work illustrates the necessity of detailed cytogenetic investigation of multiple cell types in developmentally retarded patients with normal microarray results, especially when there are subtle physical indications of chromosomal mosaicism.

  18. Polymeric complements to the Alzheimer's disease biomarker β-amyloid isoforms Aβ1-40 and Aβ1-42 for blood serum analysis under denaturing conditions.

    Science.gov (United States)

    Urraca, Javier L; Aureliano, Carla S A; Schillinger, Eric; Esselmann, Hermann; Wiltfang, Jens; Sellergren, Börje

    2011-06-22

    Treatment of Alzheimer's disease (AD) is plagued by a lack of practical and reliable methods allowing early diagnosis of the disease. We here demonstrate that robust receptors prepared by molecular imprinting successfully address current limitations of biologically derived receptors in displaying affinity for hydrophobic peptide biomarkers for AD under denaturing conditions. C-terminal epitope-imprinted polymers showing enhanced binding affinity for Aβ1-42 were first identified from a 96-polymer combinatorial library. This information was then used to synthesize molecularly imprinted polymers for both of the β-amyloid (Aβ) isoforms and a corresponding nonimprinted polymer. A solid-phase extraction method was developed to be compatible with sample loading under conditions of complete protein denaturation. This resulted in a method capable of quantitatively and selectively enriching a shorter C-terminal peptide corresponding to the sequences Aβ33-40 and Aβ33-42 as well as the full-length sequence Aβ1-40 and Aβ1-42 from a 4 M guanidinum chloride solution. Application of the method to serum allowed selective, high-recovery extraction of both biomarkers at spiking levels marginally higher than clinically relevant concentrations found in cerebrospinal fluid.

  19. Advances in Biomarker Research in Parkinson's Disease.

    Science.gov (United States)

    Mehta, Shyamal H; Adler, Charles H

    2016-01-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease, and the numbers are projected to double in the next two decades with the increase in the aging population. An important focus of current research is to develop interventions to slow the progression of the disease. However, prerequisites to it include the development of reliable biomarkers for early diagnosis which would identify at-risk groups and disease progression. In this review, we present updated evidence of already known clinical biomarkers (such as hyposmia and rapid eye movement (REM) sleep behavior disorder (RBD)) and neuroimaging biomarkers, as well as newer possible markers in the blood, CSF, and other tissues. While several promising candidates and methods to assess these biomarkers are on the horizon, it is becoming increasingly clear that no one candidate will clearly fulfill all the roles as a single biomarker. A multimodal and combinatorial approach to develop a battery of biomarkers will likely be necessary in the future.

  20. Label-Free LC-MS Profiling of Skeletal Muscle Reveals Heart-Type Fatty Acid Binding Protein as a Candidate Biomarker of Aerobic Capacity.

    Science.gov (United States)

    Malik, Zulezwan Ab; Cobley, James N; Morton, James P; Close, Graeme L; Edwards, Ben J; Koch, Lauren G; Britton, Steven L; Burniston, Jatin G

    2013-12-01

    transcriptome profiling work and show LC-MS is a viable means of profiling the abundance of almost all major metabolic enzymes of skeletal muscle in a highly parallel manner. Moreover, our approach is relatively more time efficient than techniques relying on orthogonal separations, and we demonstrate LC-MS profiling of the HCR/LCR selection model was able to highlight biomarkers that also exhibit differences in trained and untrained human muscle.

  1. Physiological activation of the human cerebral cortex during auditory perception and speech revealed by regional increases in cerebral blood flow

    DEFF Research Database (Denmark)

    Lassen, N A; Friberg, L

    1988-01-01

    Specific types of brain activity as sensory perception auditory, somato-sensory or visual -or the performance of movements are accompanied by increases of blood flow and oxygen consumption in the cortical areas involved with performing the respective tasks. The activation patterns observed...... by measuring regional cerebral blood flow CBF after intracarotid Xenon-133 injection are reviewed with emphasis on tests involving auditory perception and speech, and approach allowing to visualize Wernicke and Broca's areas and their contralateral homologues in vivo. The completely atraumatic tomographic CBF...

  2. Air pollution source apportionment before, during, and after the 2008 Beijing Olympics and association of sources to aldehydes and biomarkers of blood coagulation, pulmonary and systemic inflammation, and oxidative stress in healthy young adults

    Science.gov (United States)

    Altemose, Brent A.

    Based on principal component analysis (PCA) of air pollution data collected during the Summer Olympic Games held in Beijing, China during 2008, the five source types of air pollution identified -- natural soil/road dust, vehicle and industrial combustion, vegetative burning, oil combustion, and secondary formation, were all distinctly lower during the Olympics. This was particularly true for vehicle and industrial combustion and oil combustion, and during the main games period between the opening and closing ceremonies. The reduction in secondary formation was reflective of a reduction in nitrogen oxides, but this also contributed to increased ozone concentrations during the Olympic period. Among three toxic aldehydes measured in Beijing during the same time period, only acetaldehyde had a reduction in mean concentration during the Olympic air pollution control period compared to the pre-Olympic period. Accordingly, acetaldehyde was significantly correlated with primary emission sources including vegetative burning and oil combustion, and with several pollutants emitted mainly from primary sources. In contrast, formaldehyde and acrolein increased during the Olympic air pollution control period; accordingly both were significantly correlated with ozone and with the secondary formation source type. These findings indicate primary sources may dominate for acetaldehyde while secondary sources may dominate for formaldehyde and acrolein. Biomarkers for pulmonary inflammation (exhaled breath condensate (EBC) pH, exhaled nitric oxide, and EBC nitrite) and hemostasis and blood coagulation (vWF and sCD62p) were most consistently associated with vehicle and industrial combustion, oil combustion, and vegetative burning. The systemic inflammation biomarker 8-OHdG was most consistently associated with vehicle and industrial combustion. In contrast, the associations between the biomarkers and the aldehydes were generally not significant or in the hypothesized direction, although

  3. C - reactive protein and chitinase 3-like protein 1 as biomarkers of spatial redistribution of retinal blood vessels on digital retinal photography in patients with diabetic retinopathy

    Directory of Open Access Journals (Sweden)

    Sonja Predrag Cekic

    2014-08-01

    Full Text Available The aim of the study was to investegate the correlation between the levels of CRP and YKL-40 in blood samples with morphometric parameters of retinal blood vessels in patients with diabetic retinopathy.Blood laboratory examination of 90 patients included the measurement of glycemia, HbA1C, total cholesterol, LDL-C, HDL-C, triglycerides and CRP. Levels of YKL-40 were detected and measured in serum by ELISA (Micro VueYKL-40 EIA Kit, Quidel Corporation, San Diego, USA.Morphmetric analysis was performed with ImageJ software (http://rsbweb.nih.gov/ij/ for digital retinal photography. We measured the number, diameter of retinal blood vessels in five different parts concentric to the optic disc. Differences between the morphometric parameters and the blood test analysis results were evaluated using the Student’s t – test. One Way ANOVA was used to establish the significance of differences.CRP and YKL-40 levels were moderately higher in the group of patients with severe diabetic retinopathy. Levels of YKL-40 correlated positively with diameter and negatively with number of retinal blood vessels. The average number of the blood vessels per retinal zone was significantly higher in the group of patients with mild non-proliferative diabetic retinopathy than in the group with severe form in the optic disc and all five retinal zones. The average outer diameter of the evaluated retinal zones and optic disc vessels was significantly higher in the group with severe compared to the group with mild diabetic retinopathy.Morphological analysis of the retinal vessels on digital fundus photography and correlation with YKL-40 may be valuable for the follow-up of diabetic retinopathy.

  4. Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers.

    Science.gov (United States)

    Bremholm, Lasse; Andersen, Ulrik B; Hornum, Mads; Hilsted, Linda; Veedfald, Simon; Hartmann, Bolette; Holst, Jens Juul

    2017-02-01

    Glucagon-like peptide-1 (GLP-1, GLP-17-36amide) and its sister peptide glucagon-like peptide 2 (GLP-2) influence numerous intestinal functions and GLP-2 greatly increases intestinal blood flow. We hypothesized that GLP-1 also stimulates intestinal blood flow and that this would impact on the overall digestive and cardiovascular effects of the hormone. To investigate the influence of GLP-1 receptor agonism on mesenteric and renal blood flow and cardiovascular parameters, we carried out a double-blinded randomized clinical trial. A total of eight healthy volunteers received high physiological subcutaneous injections of GLP-1, GLP-19-36 amide (bioactive metabolite), exenatide (stable GLP-1 agonist), or saline on four separate days. Blood flow in mesenteric, celiac, and renal arteries was measured by Doppler ultrasound. Blood pressure, heart rate, cardiac output, and stroke volume were measured continuously using an integrated system. Plasma was analyzed for glucose, GLP-1 (intact and total), exenatide and Pancreatic polypeptide (PP), and serum for insulin and C-peptide. Neither GLP-1, GLP-19-36 amide, exenatide nor saline elicited any changes in blood flow parameters in the mesenteric or renal arteries. GLP-1 significantly increased heart rate (two-way ANOVA, injection [P = 0.0162], time [P = 0.0038], and injection × time [P = 0.082]; Tukey post hoc GLP-1 vs. saline and GLP-19-36amide [P < 0.011]), and tended to increase cardiac output and decrease stroke volume compared to GLP-19-36 amide and saline. Blood pressures were not affected. As expected, glucose levels fell and insulin secretion increased after infusion of both GLP-1 and exenatide.

  5. Label-Free LC-MS Profiling of Skeletal Muscle Reveals Heart-Type Fatty Acid Binding Protein as a Candidate Biomarker of Aerobic Capacity

    Directory of Open Access Journals (Sweden)

    Zulezwan A. Malik

    2013-12-01

    .54-fold (p = 0.0064 more abundant in HCR than LCR soleus. This discovery was verified using selective reaction monitoring (SRM of the y5 ion (551.21 m/z of the doubly-charged peptide SLGVGFATR (454.19 m/z of residues 23–31 of FABPH. SRM was conducted on technical replicates of each biological sample and exhibited a coefficient of variation of 20%. The abundance of FABPH measured by SRM was 2.84-fold greater (p = 0.0095 in HCR muscle. In addition, SRM of FABPH was performed in vastus lateralis samples of young and elderly humans with different habitual activity levels (collected during a previous study finding FABPH abundance was 2.23-fold greater (p = 0.0396 in endurance-trained individuals regardless of differences in age. In summary, our findings in HCR/LCR rats provide protein-level confirmation for earlier transcriptome profiling work and show LC-MS is a viable means of profiling the abundance of almost all major metabolic enzymes of skeletal muscle in a highly parallel manner. Moreover, our approach is relatively more time efficient than techniques relying on orthogonal separations, and we demonstrate LC-MS profiling of the HCR/LCR selection model was able to highlight biomarkers that also exhibit differences in trained and untrained human muscle.

  6. Effect of parsley (Petroselinum crispum) intake on urinary apigenin excretion, blood antioxidant enzymes and biomarkers for oxidative stress in human subjects.

    Science.gov (United States)

    Nielsen, S E; Young, J F; Daneshvar, B; Lauridsen, S T; Knuthsen, P; Sandström, B; Dragsted, L O

    1999-06-01

    Seven men and seven women participated in a randomized crossover trial to study the effect of intake of parsley (Petroselinum crispum), containing high levels of the flavone apigenin, on the urinary excretion of flavones and on biomarkers for oxidative stress. The subjects received a strictly controlled diet low in flavones and other naturally occurring antioxidants during the 2 weeks of intervention. This basic diet was supplemented with parsley providing 3.73-4.49 mg apigenin/MJ in one of the intervention weeks. Urinary excretion of apigenin was 1.59-409.09 micrograms/MJ per 24 h during intervention with parsley and 0-112.27 micrograms/MJ per 24 h on the basic diet (P < 0.05). The fraction of apigenin intake excreted in the urine was 0.58 (SE 0.16)% during parsley intervention. Erythrocyte glutathione reductase (EC 1.6.4.1; GR) and superoxide dismutase (EC 1.15.1.1; SOD) activities increased during intervention with parsley (P < 0.005) as compared with the levels on the basic diet, whereas erythrocyte catalase (EC 1.11.1.6) and glutathione peroxidase (EC 1.11.1.9) activities did not change. No significant changes were observed in plasma protein 2-adipic semialdehyde residues, a biomarker of plasma protein oxidation. In this short-term investigation, an overall decreasing trend in the activity of antioxidant enzymes was observed during the 2-week study. The decreased activity of SOD was strongly correlated at the individual level with an increased oxidative damage to plasma proteins. However, the intervention with parsley seemed, partly, to overcome this decrease and resulted in increased levels of GR and SOD.

  7. C-reactive protein and chitinase 3-like protein 1 as biomarkers of spatial redistribution of retinal blood vessels on digital retinal photography in patients with diabetic retinopathy.

    Science.gov (United States)

    Cekić, Sonja; Cvetković, Tatjana; Jovanović, Ivan; Jovanović, Predrag; Pesić, Milica; Stanković Babić, Gordana; Milenković, Svetislav; Risimić, Dijana

    2014-08-20

    The aim of the study was to investigate the correlation between the levels of C-reactive protein (CRP) and chitinase 3-like protein 1 (YKL-40) in blood samples with morpohometric parameters of retinal blood vessels in patients with diabetic retinopathy. Blood laboratory examination of 90 patients included the measurement of glycemia, HbA1C, total cholesterol, LDL-C, HDL-C, triglycerides and CRP. Levels of YKL-40 were detected and measured in serum by ELISA (Micro VueYKL-40 EIA Kit, Quidel Corporation, San Diego, USA). YKL-40 correlated positively with diameter and negatively with number of retinal blood vessels. The average number of the blood vessels per retinal zone was significantly higher in the group of patients with mild non-proliferative diabetic retinopathy than in the group with severe form in the optic disc and all five retinal zones. The average outer diameter of the evaluated retinal zones and optic disc vessels was significantly higher in the group with severe compared to the group with mild diabetic retinopathy. Morphological analysis of the retinal vessels on digital fundus photography and correlation with YKL-40 may be valuable for the follow-up of diabetic retinopathy.

  8. High prevalence of Kingella kingae in joint fluid from children with septic arthritis revealed by the BACTEC blood culture system.

    Science.gov (United States)

    Yagupsky, P; Dagan, R; Howard, C W; Einhorn, M; Kassis, I; Simu, A

    1992-05-01

    In an effort to improve detection of fastidious organisms, joint fluid aspirates of pediatric patients were inoculated into BACTEC 460 aerobic blood culture bottles, in addition to cultures on solid media. Culture records for the 1988 to 1991 period were reviewed to compare the performance of both methods for the recovery of pathogens. Overall, 216 children underwent a diagnostic joint tap, and 63 specimens grew significant organisms, including Kingella kingae in 14. While both methods were comparable for recovery of usual pathogens, with a single exception, K. kingae isolates were detected by the BACTEC system only. K. kingae appears to be a more common cause of septic arthritis in children than has been previously recognized. The BACTEC blood culture system enhances the recovery of K. kingae from joint fluid and improves bacteriologic diagnosis of pediatric septic arthritis.

  9. Targeted discovery and validation of plasma biomarkers of Parkinson's disease.

    Science.gov (United States)

    Pan, Catherine; Zhou, Yong; Dator, Romel; Ginghina, Carmen; Zhao, Yanchun; Movius, James; Peskind, Elaine; Zabetian, Cyrus P; Quinn, Joseph; Galasko, Douglas; Stewart, Tessandra; Shi, Min; Zhang, Jing

    2014-11-07

    Despite extensive research, an unmet need remains for protein biomarkers of Parkinson's disease (PD) in peripheral body fluids, especially blood, which is easily accessible clinically. The discovery of such biomarkers is challenging, however, due to the enormous complexity and huge dynamic range of human blood proteins, which are derived from nearly all organ systems, with those originating specifically from the central nervous system (CNS) being exceptionally low in abundance. In this investigation of a relatively large cohort (∼300 subjects), selected reaction monitoring (SRM) assays (a targeted approach) were used to probe plasma peptides derived from glycoproteins previously found to be altered in the CNS based on PD diagnosis or severity. Next, the detected peptides were interrogated for their diagnostic sensitivity and specificity as well as the correlation with PD severity, as determined by the Unified Parkinson's Disease Rating Scale (UPDRS). The results revealed that 12 of the 50 candidate glycopeptides were reliably and consistently identified in plasma samples, with three of them displaying significant differences among diagnostic groups. A combination of four peptides (derived from PRNP, HSPG2, MEGF8, and NCAM1) provided an overall area under curve (AUC) of 0.753 (sensitivity: 90.4%; specificity: 50.0%). Additionally, combining two peptides (derived from MEGF8 and ICAM1) yielded significant correlation with PD severity, that is, UPDRS (r = 0.293, p = 0.004). The significance of these results is at least two-fold: (1) it is possible to use a targeted approach to identify otherwise very difficult to detect CNS related biomarkers in peripheral blood and (2) the novel biomarkers, if validated in independent cohorts, can be employed to assist with clinical diagnosis of PD as well as monitoring disease progression.

  10. Multiplex and genome-wide analyses reveal distinctive properties of KIR+ and CD56+ T cells in human blood

    OpenAIRE

    Chan, Wing Keung; Rujkijyanont, Piya; Neale, Geoffrey; Jie YANG; Bari, Rafijul; Gupta, Neha Das; Holladay, Martha; Rooney, Barbara; Leung, Wing

    2013-01-01

    Killer-cell immunoglobulin-like receptors (KIRs) on natural killer (NK) cells have been linked to a wide spectrum of health conditions such as chronic infections, autoimmune diseases, pregnancy complications, cancers, and transplant failures. A small subset of effector memory T cells also expresses KIRs. Here, we use modern analytic tools including genome-wide and multiplex molecular, phenotypic, and functional assays to characterize the KIR+ T cells in human blood. We find that KIR+ T cells ...

  11. Conformational energy calculations and proton nuclear overhauser enhancements reveal a unique conformation for blood group A oligosaccharides

    Energy Technology Data Exchange (ETDEWEB)

    Bush, C.A.; Yan, Z.Y.; Rao, B.N.N.

    1986-10-01

    The H NMR spectra of a series of blood group A active oligosaccharides containing from four to ten sugar residues have been completely assigned, and quantitative nuclear Overhauser enhancements (NOE) have been measured between protons separated by known distances within the pyranoside ring. The observation of NOE between anomeric protons and those of the aglycon sugar as well as small effects between protons of distant rings suggests that the oligosaccharides have well-defined conformations. Conformational energy calculations were carried out on a trisaccharide, Fuc( -1 2)(GalNAc( -1 3))-GalUS -O-me, which models the nonreducing terminal fragments of the blood group A oligosaccharides. The results of calculations with three different potential energy functions which have been widely used in peptides and carbohydrates gave several minimum energy conformations. In NOE calculations from conformational models, the rotational correlation time was adjusted to fit T1's and intra-ring NOE. Comparison of calculated maps of NOE as a function of glycosidic dihedral angles showed that only a small region of conformational space was consistent with experimental data on a blood group A tetrasaccharide alditol. This conformation occurs at an energy minimum in all three energy calculations. Temperature dependence of the NOE implies that the oligosaccharides adopt single rigid conformations which do not change with temperature.

  12. Cytochrome P450 1A1 and 1B1 in human blood lymphocytes are not suitable as biomarkers of exposure to dioxin-like compounds: polymorphisms and interindividual variation in expression and inducibility.

    Science.gov (United States)

    van Duursen, Majorie B M; Sanderson, J Thomas; van den Berg, Martin

    2005-05-01

    Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) are phase I enzymes, the expression of which can be affected by many environmental compounds, including dioxins and dioxin-like compounds. Because CYP1A1 and CYP1B1 expression can easily be determined in peripheral blood lymphocytes, it is often suggested as biomarker of exposure to these compounds. In this study we investigated the interindividual differences in constitutive and induced CYP1A1-catalyzed ethoxyresorufin-O-deethylase (EROD) activity and CYP1A1 and CYP1B1 gene expression in human blood lymphocytes in a group of ten non-smoking females. Freshly isolated lymphocytes were cultured in medium containing the mitogen PHA and were exposed to the most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or the less potent dioxin-like polychlorinated biphenyl 126 (PCB126). In addition, we determined the occurrence of the CYP1A1 MspI and CYP1B1 Leu432Val polymorphisms. All individuals showed a concentration-dependent increase of EROD activity by TCDD, which was significantly correlated with an increase in CYP1A1, but not CYP1B1 expression. The maximum induced EROD activity by TCDD was very different among the individuals, but the EC50 values were about the same. PCB126 also caused a concentration-dependent increase of EROD activity, but was a factor 100-1000 less potent than TCDD among the individuals. The allele frequencies for CYP1A1 MspI and CYP1B1 Leu432Val reflected a normal Caucasian population and in this study the polymorphisms had no apparent effect on the expression and activity of these enzymes. Our study shows a large interindividual variability in constitutive and induced EROD activity, and CYP1A1 and CYP1B1 expression in human lymphocytes. In addition, dioxin concentrations at which effects were observed in our in vitro study are about 10-fold higher than the human blood levels found in vivo, indicating that EROD activity and CYP1A1 and CYP1B1 expression in human lymphocytes might not be

  13. Investigation of Fasciculation and Elongation Protein ζ-1 (FEZ1 in Peripheral Blood Reveals Differences in Gene Expression in Patients with Schizophrenia

    Directory of Open Access Journals (Sweden)

    Vachev T.I.

    2015-06-01

    Full Text Available Schizophrenia (SZ is a chronic neuropsychiatric disorder characterized by affective, neuromorphological and cognitive impairment, deteriorated social functioning and psychosis with underlying molecular abnormalities, including gene expression changes. Observations have suggested that fasciculation and elongation protein ζ-1 (FEZ1 may be implicated in the pathogenesis of schizophrenia. Nevertheless, our current knowledge of the expression of FEZ1 in peripheral blood of schizophrenia patients remains unclear. The purpose of this study was to identify the characteristic gene expression patterns of FEZ1 in peripheral blood samples from schizophrenia patients. We performed quantitative reverse-transcriptase (qRT-PCR analysis using peripheral blood from drug-free schizophrenia patients (n = 29 and age and gender-matched general population controls (n = 24. For the identification of FEZ1 gene expression patterns, we applied a comparative threshold cycle (CT method. A statistically significant difference of FEZ1 mRNA level was revealed in schizophrenia subjects compared to healthy controls (p = 0.0034. To the best of our knowledge, this study is the first describing a down-regulation of FEZ1 gene expression in peripheral blood of patients with schizophrenia. Our results suggested a possible functional role of FEZ1 in the pathogenesis of schizophrenia and confirmed the utility of peripheral blood samples for molecular profiling of psychiatric disorders including schizophrenia. The current study describes FEZ1 gene expression changes in peripheral blood of patients with schizophrenia with significantly down-regulation of FEZ1 mRNA. Thus, our results provide support for a model of SZ pathogenesis that includes the effects of FEZ1 expression.

  14. Integrating Factor Analysis and a Transgenic Mouse Model to Reveal a Peripheral Blood Predictor of Breast Tumors

    Directory of Open Access Journals (Sweden)

    Nevins Joseph R

    2011-07-01

    Full Text Available Abstract Background Transgenic mouse tumor models have the advantage of facilitating controlled in vivo oncogenic perturbations in a common genetic background. This provides an idealized context for generating transcriptome-based diagnostic models while minimizing the inherent noisiness of high-throughput technologies. However, the question remains whether models developed in such a setting are suitable prototypes for useful human diagnostics. We show that latent factor modeling of the peripheral blood transcriptome in a mouse model of breast cancer provides the basis for using computational methods to link a mouse model to a prototype human diagnostic based on a common underlying biological response to the presence of a tumor. Methods We used gene expression data from mouse peripheral blood cell (PBC samples to identify significantly differentially expressed genes using supervised classification and sparse ANOVA. We employed these transcriptome data as the starting point for developing a breast tumor predictor from human peripheral blood mononuclear cells (PBMCs by using a factor modeling approach. Results The predictor distinguished breast cancer patients from healthy individuals in a cohort of patients independent from that used to build the factors and train the model with 89% sensitivity, 100% specificity and an area under the curve (AUC of 0.97 using Youden's J-statistic to objectively select the model's classification threshold. Both permutation testing of the model and evaluating the model strategy by swapping the training and validation sets highlight its stability. Conclusions We describe a human breast tumor predictor based on the gene expression of mouse PBCs. This strategy overcomes many of the limitations of earlier studies by using the model system to reduce noise and identify transcripts associated with the presence of a breast tumor over other potentially confounding factors. Our results serve as a proof-of-concept for using an

  15. Testes sanguíneos de biomarcadores para diagnóstico e tratamento de desordens mentais: foco em esquizofrenia Biomarker blood tests for diagnosis and management of mental disorders: focus on schizophrenia

    Directory of Open Access Journals (Sweden)

    Sabine Bahn

    2012-01-01

    can supplement or replace the long standing interview-based methods for diagnosis. Despite this, the regulatory agencies now agree that improvements over the current methods are essential. Furthermore, these agencies stipulate that biomarkers are important for future drug development and have initiated efforts to modernize methods and techniques to support these efforts. Here, we review the challenges faced by this endeavour from the point of view of psychiatrists, general practitioners, the regulatory agencies and biomarker scientists. We also describe the development of a novel molecular blood-test for schizophrenia as a first promising step towards achieving this goal.

  16. Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity.

    Directory of Open Access Journals (Sweden)

    Hui Yang

    Full Text Available Serum lipids are associated with myocardial infarction and cardiovascular disease in humans. Here we dissected the genetic architecture of blood lipid traits by applying genome-wide association studies (GWAS in 1,256 pigs from Laiwu, Erhualian and Duroc × (Landrace × Yorkshire populations, and a meta-analysis of GWAS in more than 2,400 pigs from five diverse populations. A total of 22 genomic loci surpassing the suggestive significance level were detected on 11 pig chromosomes (SSC for six blood lipid traits. Meta-analysis of GWAS identified 5 novel loci associated with blood lipid traits. Comparison of GWAS loci across the tested populations revealed a substantial level of genetic heterogeneity for porcine blood lipid levels. We further evaluated the causality of nine polymorphisms nearby or within the APOB gene on SSC3 for serum LDL-C and TC levels. Of the 9 polymorphisms, an indel showed the most significant association with LDL-C and TC in Laiwu pigs. But the significant association was not identified in the White Duroc × Erhualian F2 resource population, in which the QTL for LDL-C and TC was also detected on SSC3. This indicates that population-specific signals may exist for the SSC3 QTL. Further investigations are warranted to validate this assumption.

  17. Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity.

    Science.gov (United States)

    Yang, Hui; Huang, Xiaochang; Zeng, Zhijun; Zhang, Wanchang; Liu, Chenlong; Fang, Shaoming; Huang, Lusheng; Chen, Congying

    2015-01-01

    Serum lipids are associated with myocardial infarction and cardiovascular disease in humans. Here we dissected the genetic architecture of blood lipid traits by applying genome-wide association studies (GWAS) in 1,256 pigs from Laiwu, Erhualian and Duroc × (Landrace × Yorkshire) populations, and a meta-analysis of GWAS in more than 2,400 pigs from five diverse populations. A total of 22 genomic loci surpassing the suggestive significance level were detected on 11 pig chromosomes (SSC) for six blood lipid traits. Meta-analysis of GWAS identified 5 novel loci associated with blood lipid traits. Comparison of GWAS loci across the tested populations revealed a substantial level of genetic heterogeneity for porcine blood lipid levels. We further evaluated the causality of nine polymorphisms nearby or within the APOB gene on SSC3 for serum LDL-C and TC levels. Of the 9 polymorphisms, an indel showed the most significant association with LDL-C and TC in Laiwu pigs. But the significant association was not identified in the White Duroc × Erhualian F2 resource population, in which the QTL for LDL-C and TC was also detected on SSC3. This indicates that population-specific signals may exist for the SSC3 QTL. Further investigations are warranted to validate this assumption.

  18. Intra-specific diet shift in manila clams (Ruditapes philippinarum) as revealed by carbon and nitrogen stable isotopes and fatty acid biomarker

    Science.gov (United States)

    Suh, Y.; Shin, K.

    2011-12-01

    Manila clams sampled in Seonjae Island, Korea with shell lengths (SL) below 19.76 mm in average showed a significantly depleted carbon and nitrogen isotope values (Pnutrition from both P. tricornutum and aggregated organic matter that consists of dead or decomposed microalgae or other detritus. Bigger size groups (10.92±0.34 mm and 14.81±0.25 mm) obtained most of their energy from P.tricorutum and also from other phytoplankton unlike the biggest size group (21.15±1.02 mm) that feeds mainly on fresh microalgae of all diets fed. This variation in diet reveals that smaller clams mostly inhale dead or decomposed microalgae that sinks on the bottom while the bigger clams uptake more fresh ones that are still alive. This variation in feeding behavior could have been caused by morphological constraints such as limited siphon length. The results suggest that manila clams greater than and below 19.76 mm in average have different feeding behavior and P. tricornutum and I. galbana were the two most preferred diets for manila clams cultured in IFHRI. The result of fatty acid composition of manila clams in relation to size or growth rate suggests that fast growing clams would have rapid metabolism of fatty acids not required by the animals and an accumulation of the essential fatty acids (PUFA). In addition, their higher energy requirement and more active state of development would further diminish lipid reserve of the species.

  19. Effect of parsley (Petroselinum crispum) intake on urinary apigenin excretion, blood antioxidant enzymes and biomarkers for oxidative stress in human subjects

    DEFF Research Database (Denmark)

    Nielsen, S. E.; Young, J.F.; Daneshvar, B.;

    1999-01-01

    Seven men and seven women participated in a randomized crossover trial to study the effect of intake of parsley (Petroselinum crispum), containing high levels of the flavone apigenin, on the urinary excretion of flavones and on biomarkers for oxidative stress. The subjects received a strictly...... controlled diet low in flavones and other naturally occurring antioxidants during the 2 weeks of intervention. This basic diet was supplemented with parsley providing 3.73-4.49 mg apigenin/MJ in one of the intervention weeks. Urinary excretion of apigenin was 1.59-409.09 mu g/MJ per 24 h during intervention...... with parsley and 0-112.27 mu g/MJ per 24h on the basic diet (P apigenin intake excreted in the urine was 0.58 (sE 0.16) % during parsley intervention. Erythrocyte glutathione reductase (EC 1.6.4.1; GR) and superoxide dismutase (EC 1.15.1.1; SOD) activities increased during intervention...

  20. A genome-wide linkage and association scan reveals novel loci for hypertension and blood pressure traits.

    Directory of Open Access Journals (Sweden)

    Youling Guo

    Full Text Available Hypertension is caused by the interaction of environmental and genetic factors. The condition which is very common, with about 18% of the adult Hong Kong Chinese population and over 50% of older individuals affected, is responsible for considerable morbidity and mortality. To identify genes influencing hypertension and blood pressure, we conducted a combined linkage and association study using over 500,000 single nucleotide polymorphisms (SNPs genotyped in 328 individuals comprising 111 hypertensive probands and their siblings. Using a family-based association test, we found an association with SNPs on chromosome 5q31.1 (rs6596140; P<9 × 10(-8 for hypertension. One candidate gene, PDC, was replicated, with rs3817586 on 1q31.1 attaining P = 2.5 × 10(-4 and 2.9 × 10(-5 in the within-family tests for DBP and MAP, respectively. We also identified regions of significant linkage for systolic and diastolic blood pressure on chromosomes 2q22 and 5p13, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P<7 × 10(-5 for DBP. This is the first combined linkage and association study of hypertension and its related quantitative traits with Chinese ancestry. The associations reported here account for the action of common variants whereas the discovery of linkage regions may point to novel targets for rare variant screening.

  1. Fossil skulls reveal that blood flow rate to the brain increased faster than brain volume during human evolution

    Science.gov (United States)

    Seymour, Roger S.; Bosiocic, Vanya; Snelling, Edward P.

    2016-08-01

    The evolution of human cognition has been inferred from anthropological discoveries and estimates of brain size from fossil skulls. A more direct measure of cognition would be cerebral metabolic rate, which is proportional to cerebral blood flow rate (perfusion). The hominin cerebrum is supplied almost exclusively by the internal carotid arteries. The sizes of the foramina that transmitted these vessels in life can be measured in hominin fossil skulls and used to calculate cerebral perfusion rate. Perfusion in 11 species of hominin ancestors, from Australopithecus to archaic Homo sapiens, increases disproportionately when scaled against brain volume (the allometric exponent is 1.41). The high exponent indicates an increase in the metabolic intensity of cerebral tissue in later Homo species, rather than remaining constant (1.0) as expected by a linear increase in neuron number, or decreasing according to Kleiber's Law (0.75). During 3 Myr of hominin evolution, cerebral tissue perfusion increased 1.7-fold, which, when multiplied by a 3.5-fold increase in brain size, indicates a 6.0-fold increase in total cerebral blood flow rate. This is probably associated with increased interneuron connectivity, synaptic activity and cognitive function, which all ultimately depend on cerebral metabolic rate.

  2. Kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon: ultrastructural observation and immunohistochemistry staining reveal the trapping of blood components.

    Science.gov (United States)

    Yuan, Si-Ming; Hong, Zhi-Jian; Chen, Hai-Ni; Shen, Wei-Min; Zhou, Xiao-Jun

    2013-12-01

    Kaposiform hemangioendothelioma (KHE), a borderline tumor of endothelial origin, is associated with Kasabach-Merritt phenomenon, characterized by profound thrombocytopenia and consumptive coagulopathy resulting from the localized intravascular coagulation (LIC) in the tumor. Previous studies have suggested that the trapping of blood components, including platelets, may underlie the LIC in KHE. However, more evidence is needed to support this hypothesis. In this study, one case of a Chinese infant with a KHE in the left arm was complicated by Kasabach-Merritt phenomenon. The tumor was partially resected and the sample was used for ultrastructural observation and immunohistochemistry staining of Glut-1. Ultrastructural observation found the trapping of erythrocytes, platelets, macrophages, and lymphocytes in the slit-like channels of the tumor nodules, and phagocytic vesicles in the cytoplasm of neoplastic cells. Immunohistochemistry staining further showed numerous Glut-1(+) erythrocytes in the channels. In conclusion, our results provided compelling morphological evidence of the trapping of blood components in KHE, which may interpret the LIC in the tumor and subsequent consumptive coagulopathy.

  3. Usefulness of oxidative stress biomarkers evaluated in the snout scraping, serum and Peripheral Blood Cells of Crocodylus moreletii from Southeast Campeche for assessment of the toxic impact of PAHs, metals and total phenols.

    Science.gov (United States)

    Dzul-Caamal, Ricardo; Hernández-López, Abigail; Gonzalez-Jáuregui, Mauricio; Padilla, Sergio E; Girón-Pérez, Manuel Ivan; Vega-López, Armando

    2016-10-01

    In this study, we assessed the effects of inorganic and organic pollutants [As, Cu, Fe, Mn, Pb, Zn, PAHs (11 compounds) and total phenols] from a panel of biomarkers [O2, H2O2, thiobarbituric acid reactive substances (TBARS), carbonyl proteins (RCO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total cytochrome P450 activities] evaluated in the Snout Scraping (SS), Serum (S) and Peripheral Blood Cells (PBC) of the Morelet's crocodile (Crocodylus moreletii) inhabiting the reference locality (Lake Mocu) and polluted locality (Champoton River) using Principal Component Analysis (PCA). In male crocodiles from the reference site, only H2O2 in PBC was related to levels of fluoranthene on the Keel of Caudal Scales (KCS), but, in females, no association was detected. In contrast, a sex-linked response was detected in specimens from the polluted locality. Levels of benzo[a]pyrene, benzo[a]anthracene, chrysene, pyrene, phenanthrene, acenaphthene, Zn, Cu, and Pb in KCS of the female crocodil were related to the oxidative stress biomarkers on PBC, incluing the total CYP450 activity and levels of O2, H2O2 in serum. However, in male crocodiles, the oxidative stress in SS and in the serum (TBARS, RCO, CAT, GPx), and SOD in PBC was related to As, Pb, Cu, Fe, and benzo[a]pyrene water concentrations and to the burdens of As, Fe, Mn, indeno[1,2,3cd]pyrene in KCS. These results confirm the usefulness of minimal or non-invasive methods of evaluating the oxidative stress response for the environmental monitoring program on the wild Morelet's crocodile that is subject to special protection in Mexican guidelines.

  4. 阿尔茨海默病早期诊断的血液生物标记物研究进展%Biomarkers in Blood for Early Diagnosing Alzheimer's Disease

    Institute of Scientific and Technical Information of China (English)

    徐旭华; 汤荟冬; 陈生弟

    2012-01-01

    Alzheimer' s disease (AD) is the most common cause of dementia among older people. Although the pathogenesis of AD is still not fully understood, it has been well acknowledged that intervention should be taken at early stage of the disease. Therein, identifying biomarkers for early diagnosis of AD is critical at present. The results in the search for candidate biomarkers derived from blood, including the limitations and the perspectives of the field, were summarized.%目前研究发现:①在认知功能损害前10年,阿尔茨海默病(AD)的病理生理进程已经开始,该部分人群称之为临床前AD;②在轻度认知功能障碍(MCI)患者随访中发现,部分患者可进展为AD,对这些人群进行早期诊断和干预,可能有效遏制或延缓其进展为AD.目前,AD早期诊断的研究主要聚焦在颅脑影像学及体液生物标记两方面,其中血液生物标记因标本获取简便,与AD病理过程联系较紧密,诊断敏感度及特异度较高而倍受关注,本文就早期诊断AD潜能的血液生物标记物研究进展进行综述.

  5. Dietary biomarkers: advances, limitations and future directions

    Directory of Open Access Journals (Sweden)

    Hedrick Valisa E

    2012-12-01

    Full Text Available Abstract The subjective nature of self-reported dietary intake assessment methods presents numerous challenges to obtaining accurate dietary intake and nutritional status. This limitation can be overcome by the use of dietary biomarkers, which are able to objectively assess dietary consumption (or exposure without the bias of self-reported dietary intake errors. The need for dietary biomarkers was addressed by the Institute of Medicine, who recognized the lack of nutritional biomarkers as a knowledge gap requiring future research. The purpose of this article is to review existing literature on currently available dietary biomarkers, including novel biomarkers of specific foods and dietary components, and assess the validity, reliability and sensitivity of the markers. This review revealed several biomarkers in need of additional validation research; research is also needed to produce sensitive, specific, cost-effective and noninvasive dietary biomarkers. The emerging field of metabolomics may help to advance the development of food/nutrient biomarkers, yet advances in food metabolome databases are needed. The availability of biomarkers that estimate intake of specific foods and dietary components could greatly enhance nutritional research targeting compliance to national recommendations as well as direct associations with disease outcomes. More research is necessary to refine existing biomarkers by accounting for confounding factors, to establish new indicators of specific food intake, and to develop techniques that are cost-effective, noninvasive, rapid and accurate measures of nutritional status.

  6. Dietary biomarkers: advances, limitations and future directions.

    Science.gov (United States)

    Hedrick, Valisa E; Dietrich, Andrea M; Estabrooks, Paul A; Savla, Jyoti; Serrano, Elena; Davy, Brenda M

    2012-12-14

    The subjective nature of self-reported dietary intake assessment methods presents numerous challenges to obtaining accurate dietary intake and nutritional status. This limitation can be overcome by the use of dietary biomarkers, which are able to objectively assess dietary consumption (or exposure) without the bias of self-reported dietary intake errors. The need for dietary biomarkers was addressed by the Institute of Medicine, who recognized the lack of nutritional biomarkers as a knowledge gap requiring future research. The purpose of this article is to review existing literature on currently available dietary biomarkers, including novel biomarkers of specific foods and dietary components, and assess the validity, reliability and sensitivity of the markers. This review revealed several biomarkers in need of additional validation research; research is also needed to produce sensitive, specific, cost-effective and noninvasive dietary biomarkers. The emerging field of metabolomics may help to advance the development of food/nutrient biomarkers, yet advances in food metabolome databases are needed. The availability of biomarkers that estimate intake of specific foods and dietary components could greatly enhance nutritional research targeting compliance to national recommendations as well as direct associations with disease outcomes. More research is necessary to refine existing biomarkers by accounting for confounding factors, to establish new indicators of specific food intake, and to develop techniques that are cost-effective, noninvasive, rapid and accurate measures of nutritional status.

  7. Spatial and temporal variability of biomarkers and microbial diversity reveal metabolic and community flexibility in Streamer Biofilm Communities in the Lower Geyser Basin, Yellowstone National Park.

    Science.gov (United States)

    Schubotz, F; Meyer-Dombard, D R; Bradley, A S; Fredricks, H F; Hinrichs, K-U; Shock, E L; Summons, R E

    2013-11-01

    Detailed analysis of 16S rRNA and intact polar lipids (IPLs) from streamer biofilm communities (SBCs), collected from geochemically similar hot springs in the Lower Geyser Basin, Yellowstone National Park, shows good agreement and affirm that IPLs can be used as reliable markers for the microbial constituents of SBCs. Uncultured Crenarchaea are prominent in SBS, and their IPLs contain both glycosidic and mixed glyco-phospho head groups with tetraether cores, having 0-4 rings. Archaeal IPL contributions increase with increasing temperature and comprise up to one-fourth of the total IPL inventory at >84 °C. At elevated temperatures, bacterial IPLs contain abundant glycosidic glycerol diether lipids. Diether and diacylglycerol (DAG) lipids with aminopentanetetrol and phosphatidylinositol head groups were identified as lipids diagnostic of Aquificales, while DAG glycolipids and glyco-phospholipids containing N-acetylgycosamine as head group were assigned to members of the Thermales. With decreasing temperature and concomitant changes in water chemistry, IPLs typical of phototrophic bacteria, such as mono-, diglycosyl, and sulfoquinovosyl DAG, which are specific for cyanobacteria, increase in abundance, consistent with genomic data from the same samples. Compound-specific stable carbon isotope analysis of IPL breakdown products reveals a large isotopic diversity among SBCs in different hot springs. At two of the hot springs, 'Bison Pool' and Flat Cone, lipids derived from Aquificales are enriched in (13) C relative to biomass and approach values close to dissolved inorganic carbon (DIC) (approximately 0‰), consistent with fractionation during autotrophic carbon fixation via the reversed tricarboxylic acid pathway. At a third site, Octopus Spring, the same Aquificales-diagnostic lipids are 10‰ depleted relative to biomass and resemble stable carbon isotope values of dissolved organic carbon (DOC), indicative of heterotrophy. Other bacterial and archaeal lipids show

  8. A human blood-brain barrier transcytosis assay reveals antibody transcytosis influenced by pH-dependent receptor binding.

    Directory of Open Access Journals (Sweden)

    Hadassah Sade

    Full Text Available We have adapted an in vitro model of the human blood-brain barrier, the immortalized human cerebral microvascular endothelial cells (hCMEC/D3, to quantitatively measure protein transcytosis. After validating the receptor-mediated transport using transferrin, the system was used to measure transcytosis rates of antibodies directed against potential brain shuttle receptors. While an antibody to the insulin-like growth factor 1 receptor (IGF1R was exclusively recycled to the apical compartment, the fate of antibodies to the transferrin receptor (TfR was determined by their relative affinities at extracellular and endosomal pH. An antibody with reduced affinity at pH5.5 showed significant transcytosis, while pH-independent antibodies of comparable affinities at pH 7.4 remained associated with intracellular vesicular compartments and were finally targeted for degradation.

  9. Standing-wave-excited multiplanar fluorescence in a laser scanning microscope reveals 3D information on red blood cells

    CERN Document Server

    Amor, Rumelo; Amos, William Bradshaw; McConnell, Gail

    2014-01-01

    Standing-wave excitation of fluorescence is highly desirable in optical microscopy because it improves the axial resolution. We demonstrate here that multiplanar excitation of fluorescence by a standing wave can be produced in a single-spot laser scanning microscope by placing a plane reflector close to the specimen. We report that the relative intensities in each plane of excitation depend on the Stokes shift of the fluorochrome. We show by the use of dyes specific for the cell membrane how standing-wave excitation can be exploited to generate precise contour maps of the surface membrane of red blood cells, with an axial resolution of ~90 nm. The method, which requires only the addition of a plane mirror to an existing confocal laser scanning microscope, may well prove useful in studying diseases which involve the red cell membrane, such as malaria.

  10. Phylogeographical Analysis Reveals Distinct Sources of HIV-1 and HCV Transmitted to Former Blood Donors in China.

    Science.gov (United States)

    Du, Ling; Wu, Jianjun; Qian, Peiyu; Xin, Ruolei; Ni, Ya; Han, Renzhi; Meng, Zhefeng; Xia, Jinglin

    2017-03-01

    Historically, coinfection of HIV and hepatitis C virus (HCV) was frequent among Chinese former blood donors (FBDs). This is largely due to ignorance/lack of education regarding appropriate sterilizing techniques and/or the availability of single-use needles and equipment. Although HCV shares identical transmission routes with HIV, the source of HCV in the Chinese blood donor population still remains unknown. In this study, we investigated the evolution and transmission of HCV and HIV in the Chinese FBD group. Similar to previous reports, two HCV subtypes (HCV 1b and 2a) and one HIV subtype (Thai-B) were identified in FBDs. The HCV 1b subtype had a similar evolutionary rate of 1.9 × 10(-3) substitutions/site/year to that of HIV (2.06 × 10(-3) substitutions/site/year), while the HCV 2a subtype had a faster evolutionary rate of 3.8 × 10(-3) substitutions/site/year. Phylogeographical analysis indicated that the introduction of HCV 1b into FBDs was estimated to be earlier than that of HCV 2a and HIV (late 1970s vs. late 1980s). Bayesian Skyline Plot (BSP) analysis further confirmed our findings, showing that HCV 1b infections breached a fast exponential growth from 1991 to 1998, while the HCV 2a infections had a fast exponential growth that occurred in around 1996-2001. Overall, this investigation helps to better understand HCV transmission in China and supports improvements of HCV prevalence control.

  11. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models.

    Directory of Open Access Journals (Sweden)

    Eduard Urich

    Full Text Available Brain microvascular endothelial cells (BEC constitute the blood-brain barrier (BBB which forms a dynamic interface between the blood and the central nervous system (CNS. This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local

  12. Fluid biomarkers in multiple system atrophy

    DEFF Research Database (Denmark)

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy

    2015-01-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target...... engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood...... and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results...

  13. Identification biomarkers for cervical cancer in peripheral blood lymphocytes by oligonucleotide microarrays%应用寡核苷酸芯片筛选宫颈癌患者外周血生物标志物的研究

    Institute of Scientific and Technical Information of China (English)

    盛洁; 张为远

    2010-01-01

    Objective To identify the molecular biomarkers for cervical cancer in peripheral blood lymphocytes by oligonucleatide microarrays. Methods Human genome oligonucleotide microarray analysis included 4 early-stage cervical cancer patients and 3 controls. The selected genes from the microarray analysis were validated in additional 20 early-stage cervical cancer patients and 15 controls by real-time reverse-transcription polymerase chain reaction (RT-PCR). Results Genes identified by gene selection program were expressed differently in the blood samples of early-stage cervical cancer from those of healthy controls. To validate the gene expression data, 5 genes were analyzed by real-time RT-PCR. In three of 5 identified genes, tenasin-c, nucleolin, and enolase 2 (ENO2) showed a significant up-regulation in blood samples of early-stage cervical cancer patients versus that of the controls. Conclusion The up-regulation of tenasin-c, nucleolin and ENO2 in peripheral blood may be used to identify novel blood biomarkers for detecting cervical cancer in a clinically accessible surrogate tissue. Thus it may offer a possibility of developing a non-invasive and predictive diagnostic tool for the disease.%目的 应用人类全基因组寡核苷酸芯片技术在宫颈癌患者外周血中确定生物分子标志物.方法 从24例早期宫颈癌患者和18例正常对照者的外周血淋巴细胞中提取总RNA.应用微阵列技术,采用人类全基因组寡核苷酸芯片检测4例宫颈癌患者和3例正常对照者的差异表达基因,再对20例宫颈癌患者和15例正常对照者将初步筛选出的5个候选基因用实时定量逆转录多聚酶链反应(RT-PCR)的方法进行验证.结果 筛选得到57个差异表达基因,其中38个基因表达上调,19个基因表达下调;对初步筛选出的5个候选基因经实时定量逆转录多聚酶链反应的方法进行验证后发现黏合素-C、核仁素和磷酸丙酮酸水合酶2(enolase 2,ENO2)基因在宫

  14. Biomarker monitoring in sports doping control.

    Science.gov (United States)

    Pottgiesser, Torben; Schumacher, Yorck Olaf

    2012-06-01

    Biomarker monitoring can be considered a new era in the effort against doping. Opposed to the old concept in doping control of direct detection of a prohibited substance in a biological sample such as urine or blood, the new paradigm allows a personalized longitudinal monitoring of biomarkers that indicate non-physiological responses independently of the used doping technique or substance, and may cause sanctioning of illicit practices. This review presents the development of biomarker monitoring in sports doping control and focuses on the implementation of the Athlete Biological Passport as the current concept of the World Anti Doping Agency for the detection of blood doping (hematological module). The scope of the article extends to the description of novel biomarkers and future concepts of application.

  15. Carcinogen derived biomarkers: applications in studies of human exposure to secondhand tobacco smoke

    OpenAIRE

    Hecht, S

    2004-01-01

    Objective: To review the literature on carcinogen derived biomarkers of exposure to secondhand tobacco smoke (SHS). These biomarkers are specifically related to known carcinogens in tobacco smoke and include urinary metabolites, DNA adducts, and blood protein adducts.

  16. Profiling of esterified fatty acids as biomarkers in the blood of dengue fever patients using a microliter-scale extraction followed by gas chromatography and mass spectrometry.

    Science.gov (United States)

    Khedr, Alaa; Hegazy, Maha; Kamal, Ahmed; Shehata, Mostafa A

    2015-01-01

    An improved gas chromatography with mass spectrometry procedure was developed to highlight the esterified fatty acids in 100 μL blood of dengue fever patients in the early febrile phase versus healthy volunteers. 24 adult patients and 24 healthy volunteers were included in this study. The recoveries of targeted esterified fatty acids content were in the range of 92.10-101.00% using methanol/dichloromethane (2:1, v/v) as the extraction solvent. An efficient chromatographic separation of targeted 17 esterified fatty acid methyl esters was obtained. The limits of detection and quantification were within the range of 16-131 and 53-430 ng/mL, respectively. The relative standard deviation of intraday and interday precision values ranged from 0.4 to 5.0%. The statistical data treatment showed a significant decrease of the content of four saturated fatty acids, C14:0, C15:0, C16:0, and C18:0 (P value dengue fever patients. Moreover, the amount of three omega-6 fatty acids including C18:3n6, C18:2n6, and C20:4n6 was dramatically decreased in the blood of dengue fever patients to a limit of 50 ± 10%.

  17. Peripheral blood minimal residual disease may replace bone marrow minimal residual disease as an immunophenotypic biomarker for impending relapse in acute myeloid leukemia.

    Science.gov (United States)

    Zeijlemaker, W; Kelder, A; Oussoren-Brockhoff, Y J M; Scholten, W J; Snel, A N; Veldhuizen, D; Cloos, J; Ossenkoppele, G J; Schuurhuis, G J

    2016-03-01

    As relapses are common in acute myeloid leukemia (AML), early relapse prediction is of high importance. Although conventional minimal residual disease (MRD) measurement is carried out in bone marrow (BM), peripheral blood (PB) would be an advantageous alternative source. This study aims to investigate the specificity of leukemia-associated immunophenotypes used for MRD detection in blood samples. Consistency of PB MRD as compared with BM MRD was determined in flow cytometric data of 205 paired BM and PB samples of 114 AML patients. A significant correlation was found between PB and BM MRD (r=0.67, P<0.001), while median PB MRD percentage was factor 4-5 lower compared with BM MRD. Primitive blast (CD34+/CD117+/CD133+) frequency was significantly lower in PB (median factor 23.7), indicating that PB MRD detection is more specific than BM. Cumulative incidence of relapse 1 year after induction therapy was 29% for PB MRD-negative and 89% for PB MRD-positive patients (P<0.001). Three-year OS was 52% for MRD-negative and 15% for MRD-positive patients (P=0.034). Similar differences were found after consolidation therapy. As PB MRD appeared to be an independent predictor for response duration, the highly specific PB MRD assay may have a prominent role in future MRD assessment in AML.

  18. Proteomic analysis of human skin treated with larval schistosome peptidases reveals distinct invasion strategies among species of blood flukes.

    Directory of Open Access Journals (Sweden)

    Jessica Ingram

    2011-09-01

    Full Text Available Skin invasion is the initial step in infection of the human host by schistosome blood flukes. Schistosome larvae have the remarkable ability to overcome the physical and biochemical barriers present in skin in the absence of any mechanical trauma. While a serine peptidase with activity against insoluble elastin appears to be essential for this process in one species of schistosomes, Schistosoma mansoni, it is unknown whether other schistosome species use the same peptidase to facilitate entry into their hosts.Recent genome sequencing projects, together with a number of biochemical studies, identified alternative peptidases that Schistosoma japonicum or Trichobilharzia regenti could use to facilitate migration through skin. In this study, we used comparative proteomic analysis of human skin treated with purified cercarial elastase, the known invasive peptidase of S. mansoni, or S. mansoni cathespin B2, a close homolog of the putative invasive peptidase of S. japonicum, to identify substrates of either peptidase. Select skin proteins were then confirmed as substrates by in vitro digestion assays.This study demonstrates that an S. mansoni ortholog of the candidate invasive peptidase of S. japonicum and T. regenti, cathepsin B2, is capable of efficiently cleaving many of the same host skin substrates as the invasive serine peptidase of S. mansoni, cercarial elastase. At the same time, identification of unique substrates and the broader species specificity of cathepsin B2 suggest that the cercarial elastase gene family amplified as an adaptation of schistosomes to human hosts.

  19. DNA methylome profiling of maternal peripheral blood and placentas reveal potential fetal DNA markers for non-invasive prenatal testing.

    Science.gov (United States)

    Xiang, Yuqian; Zhang, Junyu; Li, Qiaoli; Zhou, Xinyao; Wang, Teng; Xu, Mingqing; Xia, Shihui; Xing, Qinghe; Wang, Lei; He, Lin; Zhao, Xinzhi

    2014-09-01

    Utilizing epigenetic (DNA methylation) differences to differentiate between maternal peripheral blood (PBL) and fetal (placental) DNA has been a promising strategy for non-invasive prenatal testing (NIPT). However, the differentially methylated regions (DMRs) have yet to be fully ascertained. In the present study, we performed genome-wide comparative methylome analysis between maternal PBL and placental DNA from pregnancies of first trimester by methylated DNA immunoprecipitation-sequencing (MeDIP-Seq) and Infinium HumanMethylation450 BeadChip assays. A total of 36 931 DMRs and 45 804 differentially methylated sites (DMSs) covering the whole genome, exclusive of the Y chromosome, were identified via MeDIP-Seq and Infinium 450k array, respectively, of which 3759 sites in 2188 regions were confirmed by both methods. Not only did we find the previously reported potential fetal DNA markers in our identified DMRs/DMSs but also we verified fully the identified DMRs/DMSs in the validation round by MassARRAY EpiTYPER. The screened potential fetal DNA markers may be used for NIPT on aneuploidies and other chromosomal diseases, such as cri du chat syndrome and velo-cardio-facial syndrome. In addition, these potential markers may have application in the early diagnosis of placental dysfunction, such as pre-eclampsia.

  20. Genome-wide survey reveals predisposing diabetes type 2-related DNA methylation variations in human peripheral blood.

    Science.gov (United States)

    Toperoff, Gidon; Aran, Dvir; Kark, Jeremy D; Rosenberg, Michael; Dubnikov, Tatyana; Nissan, Batel; Wainstein, Julio; Friedlander, Yechiel; Levy-Lahad, Ephrat; Glaser, Benjamin; Hellman, Asaf

    2012-01-15

    Inter-individual DNA methylation variations were frequently hypothesized to alter individual susceptibility to Type 2 Diabetes Mellitus (T2DM). Sequence-influenced methylations were described in T2DM-associated genomic regions, but evidence for direct, sequence-independent association with disease risk is missing. Here, we explore disease-contributing DNA methylation through a stepwise study design: first, a pool-based, genome-scale screen among 1169 case and control individuals revealed an excess of differentially methylated sites in genomic regions that were previously associated with T2DM through genetic studies. Next, in-depth analyses were performed at selected top-ranking regions. A CpG site in the first intron of the FTO gene showed small (3.35%) but significant (P = 0.000021) hypomethylation of cases relative to controls. The effect was independent of the sequence polymorphism in the region and persists among individuals carrying the sequence-risk alleles. The odds of belonging to the T2DM group increased by 6.1% for every 1% decrease in methylation (OR = 1.061, 95% CI: 1.032-1.090), the odds ratio for decrease of 1 standard deviation of methylation (adjusted to gender) was 1.5856 (95% CI: 1.2824-1.9606) and the sensitivity (area under the curve = 0.638, 95% CI: 0.586-0.690; males = 0.675, females = 0.609) was better than that of the strongest known sequence variant. Furthermore, a prospective study in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to T2DM, relative to the individuals who stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators. The data showed that low methylation level at the analyzed sites is an early marker of T2DM and suggests a novel mechanism by which early-onset, inter-individual methylation variation at isolated non-promoter genomic sites predisposes to T2DM.

  1. Multiplex and genome-wide analyses reveal distinctive properties of KIR+ and CD56+ T cells in human blood.

    Science.gov (United States)

    Chan, Wing Keung; Rujkijyanont, Piya; Neale, Geoffrey; Yang, Jie; Bari, Rafijul; Das Gupta, Neha; Holladay, Martha; Rooney, Barbara; Leung, Wing

    2013-08-15

    Killer cell Ig-like receptors (KIRs) on NK cells have been linked to a wide spectrum of health conditions such as chronic infections, autoimmune diseases, pregnancy complications, cancers, and transplant failures. A small subset of effector memory T cells also expresses KIRs. In this study, we use modern analytic tools including genome-wide and multiplex molecular, phenotypic, and functional assays to characterize the KIR(+) T cells in human blood. We find that KIR(+) T cells primarily reside in the CD56(+) T population that is distinctively DNAM-1(high) with a genome-wide quiescent transcriptome, short telomere, and limited TCR excision circles. During CMV reactivation in bone marrow transplant recipients, KIR(+)CD56(+) T cells rapidly expanded in real-time but not KIR(+)CD56(-) T cells or KIR(+) NK cells. In CMV(+) asymptomatic donors, as much as 50% of CD56(+) T cells are KIR(+), and most are distinguishably KIR2DL2/3(+)NKG2C(+)CD57(+). Functionally, the KIR(+)CD56(+) T cell subset lyses cancer cells and CMVpp65-pulsed target cells in a dual KIR-dependent and TCR-dependent manner. Analysis of metabolic transcriptome confirms the immunological memory status of KIR(+)CD56(+) T cells in contrast to KIR(-)CD56(+) T cells that are more active in energy metabolism and effector differentiation. KIR(-)CD56(+) T cells have >25-fold higher level of expression of RORC than the KIR(+) counterpart and are a previously unknown producer of IL-13 rather than IL-17 in multiplex cytokine arrays. Our data provide fundamental insights into KIR(+) T cells biologically and clinically.

  2. Whey protein lowers blood pressure and improves endothelial function and lipid biomarkers in adults with prehypertension and mild hypertension: results from the chronic Whey2Go randomized controlled trial12

    Science.gov (United States)

    Givens, D Ian

    2016-01-01

    Background: Cardiovascular diseases (CVDs) are the greatest cause of death globally, and their reduction is a key public-health target. High blood pressure (BP) affects 1 in 3 people in the United Kingdom, and previous studies have shown that milk consumption is associated with lower BP. Objective: We investigated whether intact milk proteins lower 24-h ambulatory blood pressure (AMBP) and other risk markers of CVD. Design: The trial was a double-blinded, randomized, 3-way–crossover, controlled intervention study. Forty-two participants were randomly assigned to consume 2 × 28 g whey protein/d, 2 × 28 g Ca caseinate/d, or 2 × 27 g maltodextrin (control)/d for 8 wk separated by a 4-wk washout. The effects of these interventions were examined with the use of a linear mixed-model ANOVA. Results: Thirty-eight participants completed the study. Significant reductions in 24-h BP [for systolic blood pressure (SBP): −3.9 mm Hg; for diastolic blood pressure (DBP): −2.5 mm Hg; P = 0.050 for both)] were observed after whey-protein consumption compared with control intake. After whey-protein supplementation compared with control intake, peripheral and central systolic pressures [−5.7 mm Hg (P = 0.007) and −5.4 mm Hg (P = 0.012), respectively] and mean pressures [−3.7 mm Hg (P = 0.025) and −4.0 mm Hg (P = 0.019), respectively] were also lowered. Flow-mediated dilation (FMD) increased significantly after both whey-protein and calcium-caseinate intakes compared with control intake [1.31% (P whey protein and calcium caseinate significantly lowered total cholesterol [−0.26 mmol/L (P = 0.013) and −0.20 mmol/L (P = 0.042), respectively], only whey protein decreased triacylglycerol (−0.23 mmol/L; P = 0.025) compared with the effect of the control. Soluble intercellular adhesion molecule 1 and soluble vascular cell adhesion molecule 1 were reduced after whey protein consumption (P = 0.011) and after calcium-caseinate consumption (P = 0.039), respectively, compared

  3. DNA Methylation Biomarkers: Cancer and Beyond

    Directory of Open Access Journals (Sweden)

    Thomas Mikeska

    2014-09-01

    Full Text Available 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.

  4. Current and emerging biomarkers of hepatotoxicity

    Directory of Open Access Journals (Sweden)

    Yang X

    2012-08-01

    Full Text Available Xi Yang, William F Salminen, Laura K SchnackenbergDivision of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USAAbstract: Drug-induced liver injury (DILI is of great concern to human health. Generally, liver function and injury is evaluated based upon clinical signs, a select group of serum clinical biomarkers, and occasionally liver biopsies. While alanine aminotransferase, the most commonly used biomarker of hepatocellular injury, is a sensitive marker of liver injury, it is not necessarily specific for liver injury. Furthermore, alanine aminotransferase levels may not always correlate with the extent of injury. Therefore, new hepatotoxicity biomarkers are needed that are more predictive and specific indicators of liver injury and altered function. In addition, no current biomarker provides prognostic information about ultimate outcome once injury occurs, and any new biomarker filling this need is desperately needed. The omics technologies, including genomics, proteomics, and metabolomics, are being used in preclinical animal studies as well as clinical studies to evaluate markers of hepatotoxicity in easily obtained biofluids, such as urine and serum. Recently, the evaluation of circulating microRNAs in urine and blood has also shown promise for the identification of novel, sensitive markers of liver injury. This review evaluates the current status of proposed biomarkers of hepatotoxicity from the omics platforms, as well as from analysis of microRNAs. A brief description of the qualification of proposed biomarkers is also given.Keywords: biomarkers, hepatotoxicity, metabolomics, microRNA, proteomics, transcriptomics

  5. Sensitive and precise monitoring of phosphatidylethanol in human blood as a biomarker for alcohol intake by ultrasound-assisted dispersive liquid-liquid microextraction combined with liquid chromatography tandem mass spectrometry.

    Science.gov (United States)

    Wang, Siming; Yang, Ruiyue; Ji, Fusui; Li, Hongxia; Dong, Jun; Chen, Wenxiang

    2017-05-01

    Phosphatidylethanol (PEth) is a special phospholipid that is only formed in the presence of ethanol, and therefore, serves as a promising biomarker for alcohol intake. In this study, a simple, rapid and precise method based on LC-MS/MS combined with ultrasound-assisted dispersive liquid-liquid microextraction was developed and validated for the measurements of PEth (16:0/18:1, 16:0/18:2, 16:0/16:0, and 18:1/18:1) in human blood. The influences of several variables for sample extraction and MS detection were carefully investigated. The extraction efficiencies for all the four PEth species were markedly increased compared with the traditional extractions. A limit of detection below 0.56ngmL(-1) was obtained. This high sensitivity makes it possible to monitor various alcohol consumption levels in light to heavy drinkers. Good linearity was obtained for all the analytes without interference from the sample matrix. The imprecisions of the intra-run and total assays were lower than 3.1% and 6.5%, respectively, with an average recovery of 99.87%. In addition, the utility of the method was evaluated in an alcohol intake status study. The results indicate that the developed protocol is simple, precise, and sensitive, and can be easily adapted for objective and reliable assessments of alcohol intake in clinical research.

  6. Modeling reveals bistability and low-pass filtering in the network module determining blood stem cell fate.

    Directory of Open Access Journals (Sweden)

    Jatin Narula

    2010-05-01

    Full Text Available Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad-a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models.

  7. Cerebral blood flow measured by arterial-spin labeling MRI: A useful biomarker for characterization of minimal hepatic encephalopathy in patients with cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Gang [Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu, 210002 (China); College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 210016 (China); Zhang, Long Jiang, E-mail: kevinzhlj@163.com [Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu, 210002 (China); Zhong, Jianhui [Department of Imaging Sciences, University of Rochester School of Medicine and Dentistry, Box648, 601 Elmwood Avenue, Rochester, NY 14642-8648 (United States); Wang, Ze [Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, 3900 Chestnut St., Philadelphia, PA 19104 (United States); Qi, Rongfeng; Shi, Donghong [Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu, 210002 (China); Lu, Guang Ming, E-mail: cjr.luguangming@vip.163.com [Department of Medical Imaging, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu, 210002 (China)

    2013-11-01

    Purpose: To investigate the role of arterial-spin labeling (ASL) MRI to non-invasively characterize the patterns of cerebral blood flow (CBF) changes in cirrhotic patients and to assess the potential of ASL MRI to characterize minimal hepatic encephalopathy (MHE). Materials and methods: This study was approved by the local ethics committee, and written informed consent was obtained from all participants. Thirty six cirrhosis patients without overt hepatic encephalopathy (16 MHE patients and 20 non hepatic encephalopathy (non-HE) patients) and 25 controls underwent ASL MRI, and CBF was measured for each subject. One-way ANOCOVA test with age and gender as covariences was used to compare CBF difference among three groups, and post hoc analysis was performed between each two groups. Region-based correlation analysis was applied between Child–Pugh score, venous blood ammonia level, neuropsychological tests and CBF values in cirrhosis patients. Receiver operator characteristic (ROC) analysis was used for assessing CBF measurements in ASL MRI to differentiate MHE from non-HE patients. Results: The gray matter CBF of MHE patients (71.09 ± 11.88 mL min{sup −1} 100 g{sup −1}) was significantly higher than that of non-HE patients (55.28 ± 12.30 mL min{sup −1} 100 g{sup −1}, P < 0.01) and controls (52.09 ± 9.27 mL min{sup −1} 100 g{sup −1}, P < 0.001). Voxel-wise ANOCOVA results showed that CBFs were significantly different among three groups in multiple gray matter areas (P < 0.05, Bonferroni corrected). Post hoc comparisons showed that CBF of these brain regions was increased in MHE patients compared with controls and non-HE patients (P < 0.05, Bonferroni corrected). CBF of the right putamen was of the highest sensitivity (93.8%) and moderate specificity (75.0%) for characterization of MHE when using the cutoff value of 50.57 mL min{sup −1} 100 g{sup −1}. CBFs in the bilateral median cingulate gyri, left supramarginal gyrus, right angular gyrus, right

  8. N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers.

    Science.gov (United States)

    Tuchman, Mendel; Caldovic, Ljubica; Daikhin, Yevgeny; Horyn, Oksana; Nissim, Ilana; Nissim, Itzhak; Korson, Mark; Burton, Barbara; Yudkoff, Marc

    2008-08-01

    N-acetylglutamate (NAG) is an endogenous essential cofactor for conversion of ammonia to urea in the liver. Deficiency of NAG causes hyperammonemia and occurs because of inherited deficiency of its producing enzyme, NAG synthase (NAGS), or interference with its function by short fatty acid derivatives. N-carbamylglutamate (NCG) can ameliorate hyperammonemia from NAGS deficiency and propionic and methylmalonic acidemia. We developed a stable isotope (13)C tracer method to measure ureagenesis and to evaluate the effect of NCG in humans. Seventeen healthy adults were investigated for the incorporation of (13)C label into urea. [(13)C]urea appeared in the blood within minutes, reaching maximum by 100 min, whereas breath (13)CO(2) reached a maximum by 60 min. A patient with NAGS deficiency showed very little urea labeling before treatment with NCG and normal labeling thereafter. Correspondingly, plasma levels of ammonia and glutamine decreased markedly and urea tripled after NCG treatment. Similarly, in a patient with propionic acidemia, NCG treatment resulted in a marked increase in urea labeling and decrease in glutamine, alanine, and glycine. These results provide a reliable method for measuring the effect of NCG on nitrogen metabolism and strongly suggest that NCG could be an effective treatment for inherited and secondary NAGS deficiency.

  9. Differential Gene Expression of BRCA1,ERBB2 and TP53 biomarkers between Human Breast Tissue and Peripheral Blood Samples of Breast Cancer.

    Science.gov (United States)

    Zghair, Abdulrazzaq Neamah; Sinha, Deepak Kumar; Kassim, Arkan; Alfaham, Mohmmad; Sharma, Anil K

    2016-01-01

    Breast cancer is a most common malignancy especially in Iraqi women accounting for high morbidity and mortality. Mutations in BRCA1 gene is one of the important genetic predisposing factors inbreast cancer. Similarly ERBB2 and TP53 are also key prognostic markers in breast cancer treatment.We were interested to explore the gene expression profiles of BRCA1, ERBB2 and TP53 in breast cancer women patients from Iraq so as to assess the potential of such markers in breast cancer treatment. The mRNA levels were significantly over-expressed in tumor tissues in comparison to normal ones with p values (pTP53 and benign tissue samples as well. However in blood samples, no considerable expression of these markers was observed. Out of three selected genes, ERBB2 expression was significantly expressed in comparison to BRCA1 and TP53 in cancer tissue. Mutation analysis of BRCA1, ERBB2 and TP53 has been made to find out the region most susceptible to mutations in these genes The BRCA1 exon 11, ERBB2 16 and TP53 exon 5 displayed increased chances of having mutations. We can conclude from the study that differential gene expression of BRCA1, ERBB2 and TP53 at mRNA levels may act as a diagnostic marker of circulating tumor cells having important prognostic value in breast cancer patients.

  10. [Enzymatic biomarkers].

    Science.gov (United States)

    Cortés Villarreal, Gabriela

    2007-01-01

    The demand of consultation in the emergency rooms by patients with SICA without elevation of segment ST has modified the methodology in the integration of his diagnose, the seric markers are key point in this process isoenzymes can determine foretell and treatment in addition to new markers based on the inflammatory process of the atherosclerosis that stratifies the cardiovascular risk of the patient. The obtaining of these data obtains by total blood sample in qualitative and quantitative form permit in short time of 10 to 15 minutes, which allows to make agile the therapeutic interventions and to limit the damage the patient.

  11. Sex-specific serum biomarker patterns in adults with Asperger's syndrome.

    Science.gov (United States)

    Schwarz, E; Guest, P C; Rahmoune, H; Wang, L; Levin, Y; Ingudomnukul, E; Ruta, L; Kent, L; Spain, M; Baron-Cohen, S; Bahn, S

    2011-12-01

    Autism spectrum conditions have been hypothesized to be an exaggeration of normal male low-empathizing and high-systemizing behaviors. We tested this hypothesis at the molecular level by performing comprehensive multi-analyte profiling of blood serum from adult subjects with Asperger's syndrome (AS) compared with controls. This led to identification of distinct sex-specific biomarker fingerprints for male and female subjects. Males with AS showed altered levels of 24 biomarkers including increased levels of cytokines and other inflammatory molecules. Multivariate statistical classification of males using this panel of 24 biomarkers revealed a marked separation between AS and controls with a sensitivity of 0.86 and specificity of 0.88. Testing this same panel in females did not result in a separation between the AS and control groups. In contrast, AS females showed altered levels of 17 biomarkers including growth factors and hormones such as androgens, growth hormone and insulin-related molecules. Classification of females using this biomarker panel resulted in a separation between AS and controls with sensitivities and specificities of 0.96 and 0.83, respectively, and testing this same panel in the male group did not result in a separation between the AS and control groups. The finding of elevated testosterone in AS females confirmed predictions from the 'extreme male brain' and androgen theories of autism spectrum conditions. We conclude that to understand the etiology and development of autism spectrum conditions, stratification by sex is essential.

  12. Chiral Biomarkers in Meteorites

    Science.gov (United States)

    Hoover, Richard B.

    2010-01-01

    The chirality of organic molecules with the asymmetric location of group radicals was discovered in 1848 by Louis Pasteur during his investigations of the rotation of the plane of polarization of light by crystals of sodium ammonium paratartrate. It is well established that the amino acids in proteins are exclusively Levorotary (L-aminos) and the sugars in DNA and RNA are Dextrorotary (D-sugars). This phenomenon of homochirality of biological polymers is a fundamental property of all life known on Earth. Furthermore, abiotic production mechanisms typically yield recemic mixtures (i.e. equal amounts of the two enantiomers). When amino acids were first detected in carbonaceous meteorites, it was concluded that they were racemates. This conclusion was taken as evidence that they were extraterrestrial and produced by abiologically. Subsequent studies by numerous researchers have revealed that many of the amino acids in carbonaceous meteorites exhibit a significant L-excess. The observed chirality is much greater than that produced by any currently known abiotic processes (e.g. Linearly polarized light from neutron stars; Circularly polarized ultraviolet light from faint stars; optically active quartz powders; inclusion polymerization in clay minerals; Vester-Ulbricht hypothesis of parity violations, etc.). This paper compares the measured chirality detected in the amino acids of carbonaceous meteorites with the effect of these diverse abiotic processes. IT is concluded that the levels observed are inconsistent with post-arrival biological contamination or with any of the currently known abiotic production mechanisms. However, they are consistent with ancient biological processes on the meteorite parent body. This paper will consider these chiral biomarkers in view of the detection of possible microfossils found in the Orgueil and Murchison carbonaceous meteorites. Energy dispersive x-ray spectroscopy (EDS) data obtained on these morphological biomarkers will be

  13. Biomarkers of environmental benzene exposure

    Energy Technology Data Exchange (ETDEWEB)

    Weisel, C.; Yu, R.; Roy, A.; Georgopoulos, P. [Environmental and Occupational Health Sciences Institute, Piscataway, NJ (United States)

    1996-12-01

    Environmental exposures to benzene result in increases in body burden that are reflected in various biomarkers of exposure, including benzene in exhaled breath, benzene in blood and urinary trans-trans-muconic acid and S-phenylmercapturic acid. A review of the literature indicates that these biomarkers can be used to distinguish populations with different levels of exposure (such as smokers from nonsmokers and occupationally exposed from environmentally exposed populations) and to determine differences in metabolism. Biomarkers in humans have shown that the percentage of benzene metabolized by the ring-opening pathway is greater at environmental exposures than that at higher occupational exposures, a trend similar to that found in animal studies. This suggests that the dose-response curve is nonlinear; that potential different metabolic mechanisms exist at high and low doses; and that the validity of a linear extrapolation of adverse effects measured at high doses to a population exposed to lower, environmental levels of benzene is uncertain. Time-series measurements of the biomarker, exhaled breath, were used to evaluate a physiologically based pharmacokinetic (PBPK) model. Biases were identified between the PBPK model predictions and experimental data that were adequately described using an empirical compartmental model. It is suggested that a mapping of the PBPK model to a compartmental model can be done to optimize the parameters in the PBPK model to provide a future framework for developing a population physiologically based pharmacokinetic model. 44 refs., 3 figs., 1 tab.

  14. Novel diagnostic biomarkers for prostate cancer

    Directory of Open Access Journals (Sweden)

    Chikezie O. Madu, Yi Lu

    2010-01-01

    Full Text Available Prostate cancer is the most frequently diagnosed malignancy in American men, and a more aggressive form of the disease is particularly prevalent among African Americans. The therapeutic success rate for prostate cancer can be tremendously improved if the disease is diagnosed early. Thus, a successful therapy for this disease depends heavily on the clinical indicators (biomarkers for early detection of the presence and progression of the disease, as well as the prediction after the clinical intervention. However, the current clinical biomarkers for prostate cancer are not ideal as there remains a lack of reliable biomarkers that can specifically distinguish between those patients who should be treated adequately to stop the aggressive form of the disease and those who should avoid overtreatment of the indolent form.A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker reveals further information to presently existing clinical and pathological analysis. It facilitates screening and detecting the cancer, monitoring the progression of the disease, and predicting the prognosis and survival after clinical intervention. A biomarker can also be used to evaluate the process of drug development, and, optimally, to improve the efficacy and safety of cancer treatment by enabling physicians to tailor treatment for individual patients. The form of the prostate cancer biomarkers can vary from metabolites and chemical products present in body fluid to genes and proteins in the prostate tissues.Current advances in molecular techniques have provided new tools facilitating the discovery of new biomarkers for prostate cancer. These emerging biomarkers will be beneficial and critical in developing new and clinically reliable indicators that will have a high specificity for the diagnosis and prognosis of

  15. Novel diagnostic biomarkers for prostate cancer.

    Science.gov (United States)

    Madu, Chikezie O; Lu, Yi

    2010-10-06

    Prostate cancer is the most frequently diagnosed malignancy in American men, and a more aggressive form of the disease is particularly prevalent among African Americans. The therapeutic success rate for prostate cancer can be tremendously improved if the disease is diagnosed early. Thus, a successful therapy for this disease depends heavily on the clinical indicators (biomarkers) for early detection of the presence and progression of the disease, as well as the prediction after the clinical intervention. However, the current clinical biomarkers for prostate cancer are not ideal as there remains a lack of reliable biomarkers that can specifically distinguish between those patients who should be treated adequately to stop the aggressive form of the disease and those who should avoid overtreatment of the indolent form.A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker reveals further information to presently existing clinical and pathological analysis. It facilitates screening and detecting the cancer, monitoring the progression of the disease, and predicting the prognosis and survival after clinical intervention. A biomarker can also be used to evaluate the process of drug development, and, optimally, to improve the efficacy and safety of cancer treatment by enabling physicians to tailor treatment for individual patients. The form of the prostate cancer biomarkers can vary from metabolites and chemical products present in body fluid to genes and proteins in the prostate tissues.Current advances in molecular techniques have provided new tools facilitating the discovery of new biomarkers for prostate cancer. These emerging biomarkers will be beneficial and critical in developing new and clinically reliable indicators that will have a high specificity for the diagnosis and prognosis of prostate cancer. The

  16. Biomarkers in Veterinary Medicine.

    Science.gov (United States)

    Myers, Michael J; Smith, Emily R; Turfle, Phillip G

    2017-02-08

    This article summarizes the relevant definitions related to biomarkers; reviews the general processes related to biomarker discovery and ultimate acceptance and use; and finally summarizes and reviews, to the extent possible, examples of the types of biomarkers used in animal species within veterinary clinical practice and human and veterinary drug development. We highlight opportunities for collaboration and coordination of research within the veterinary community and leveraging of resources from human medicine to support biomarker discovery and validation efforts for veterinary medicine.

  17. Combination of biomarkers

    DEFF Research Database (Denmark)

    Thurfjell, Lennart; Lötjönen, Jyrki; Lundqvist, Roger;

    2012-01-01

    The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury.......The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury....

  18. CURRENT APPROACHES FOR RESEARCH OF MULTIPLE SCLEROSIS BIOMARKERS

    Directory of Open Access Journals (Sweden)

    Kolyada T.I

    2016-12-01

    severity, progression, pathogenetic type and treatment efficacy are based on transcriptomics, proteomics and metabolomics technologies. Transcriptomics includes genome-wide research of RNA sequences based on the results obtained with comparative genomic hybridization on biochips, massive parallel RNA sequencing, and measuring the amount of mRNA by real-time PCR. This technology is actively used in studies of gene expression profile of peripheral blood mononuclear cells from MS patients aimed at identifying molecular markers of disease status suitable for clinical use. Proteomics is a large-scale expression and protein distribution studies in patients with MS based on the results obtained via microarray and mass spectrometry, liquid and gas chromatography methods. In recent years, a growing number of MS proteomic studies using 2DE-MS method (two-dimensional electrophoresis coupled with mass spectrometry. Metabolomics studies of low-molecular-weight metabolic profiles based on the results obtained by mass spectrometry, liquid and gas chromatography, nuclear magnetic resonance. However, unlike other «-omics»-technologies, in metabolomics microarray-techniques are not used. Conclusion. Search, verification and clinical application of biomarkers for multiple sclerosis are one of the most challenging medical and biological problems. Its solution requires an interdisciplinary approach, organization of large-scale research and engagement of new research methods. In recent years, a significant amount of data received allowed to reveal hundreds of candidate biomarkers. Some of these biomarkers have significant potential for the monitoring of disease activity and assessment of therapy efficiency. However, the verification is required for a widespread clinical application; it implies further large-scale studies in different countries. The development of personalized medicine in Ukraine, the application of its principles to the management of multiple sclerosis patients, along with

  19. Candidate immune biomarkers for radioimmunotherapy.

    Science.gov (United States)

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

    2017-02-28

    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.

  20. A Multi-Lineage Screen Reveals mTORC1 Inhibition Enhances Human Pluripotent Stem Cell Mesendoderm and Blood Progenitor Production

    Directory of Open Access Journals (Sweden)

    Emanuel Joseph Paul Nazareth

    2016-05-01

    Full Text Available Human pluripotent stem cells (hPSCs exist in heterogeneous micro-environments with multiple subpopulations, convoluting fate-regulation analysis. We patterned hPSCs into engineered micro-environments and screened responses to 400 small-molecule kinase inhibitors, measuring yield and purity outputs of undifferentiated, neuroectoderm, mesendoderm, and extra-embryonic populations. Enrichment analysis revealed mammalian target of rapamycin (mTOR inhibition as a strong inducer of mesendoderm. Dose responses of mTOR inhibitors such as rapamycin synergized with Bone Morphogenetic protein 4 (BMP4 and activin A to enhance the yield and purity of BRACHYURY-expressing cells. Mechanistically, small interfering RNA knockdown of RAPTOR, a component of mTOR complex 1, phenocopied the mesendoderm-enhancing effects of rapamycin. Functional analysis during mesoderm and endoderm differentiation revealed that mTOR inhibition increased the output of hemogenic endothelial cells 3-fold, with a concomitant enhancement of blood colony-forming cells. These data demonstrate the power of our multi-lineage screening approach and identify mTOR signaling as a node in hPSC differentiation to mesendoderm and its derivatives.

  1. Identification of novel serum peptide biomarkers for high-altitude adaptation: a comparative approach

    Science.gov (United States)

    Yang, Juan; Li, Wenhua; Liu, Siyuan; Yuan, Dongya; Guo, Yijiao; Jia, Cheng; Song, Tusheng; Huang, Chen

    2016-05-01

    We aimed to identify serum biomarkers for screening individuals who could adapt to high-altitude hypoxia at sea level. HHA (high-altitude hypoxia acclimated; n = 48) and HHI (high-altitude hypoxia illness; n = 48) groups were distinguished at high altitude, routine blood tests were performed for both groups at high altitude and at sea level. Serum biomarkers were identified by comparing serum peptidome profiling between HHI and HHA groups collected at sea level. Routine blood tests revealed the concentration of hemoglobin and red blood cells were significantly higher in HHI than in HHA at high altitude. Serum peptidome profiling showed that ten significantly differentially expressed peaks between HHA and HHI at sea level. Three potential serum peptide peaks (m/z values: 1061.91, 1088.33, 4057.63) were further sequence identified as regions of the inter-α trypsin inhibitor heavy chain H4 fragment (ITIH4 347-356), regions of the inter-α trypsin inhibitor heavy chain H1 fragment (ITIH1 205-214), and isoform 1 of fibrinogen α chain precursor (FGA 588-624). Expression of their full proteins was also tested by ELISA in HHA and HHI samples collected at sea level. Our study provided a novel approach for identifying potential biomarkers for screening people at sea level who can adapt to high altitudes.

  2. New sepsis biomarkers

    Directory of Open Access Journals (Sweden)

    Dolores Limongi

    2016-06-01

    Full Text Available Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes. Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity, specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis, timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  3. New sepsis biomarkers

    Institute of Scientific and Technical Information of China (English)

    Dolores Limongi; Cartesio D’Agostini; Marco Ciotti

    2016-01-01

    Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes.Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity,specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis,timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  4. New sepsis biomarkers

    Institute of Scientific and Technical Information of China (English)

    Dolores Limongi; Cartesio DAgostini; Marco Ciotti

    2016-01-01

    Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes. Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity, specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis, timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  5. Biomarkers in Parkinson's disease (recent update).

    Science.gov (United States)

    Sharma, Sushil; Moon, Carolyn Seungyoun; Khogali, Azza; Haidous, Ali; Chabenne, Anthony; Ojo, Comfort; Jelebinkov, Miriana; Kurdi, Yousef; Ebadi, Manuchair

    2013-09-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder mostly affecting the aging population over sixty. Cardinal symptoms including, tremors, muscle rigidity, drooping posture, drooling, walking difficulty, and autonomic symptoms appear when a significant number of nigrostriatal dopaminergic neurons are already destroyed. Hence we need early, sensitive, specific, and economical peripheral and/or central biomarker(s) for the differential diagnosis, prognosis, and treatment of PD. These can be classified as clinical, biochemical, genetic, proteomic, and neuroimaging biomarkers. Novel discoveries of genetic as well as nongenetic biomarkers may be utilized for the personalized treatment of PD during preclinical (premotor) and clinical (motor) stages. Premotor biomarkers including hyper-echogenicity of substantia nigra, olfactory and autonomic dysfunction, depression, hyposmia, deafness, REM sleep disorder, and impulsive behavior may be noticed during preclinical stage. Neuroimaging biomarkers (PET, SPECT, MRI), and neuropsychological deficits can facilitate differential diagnosis. Single-cell profiling of dopaminergic neurons has identified pyridoxal kinase and lysosomal ATPase as biomarker genes for PD prognosis. Promising biomarkers include: fluid biomarkers, neuromelanin antibodies, pathological forms of α-Syn, DJ-1, amyloid β and tau in the CSF, patterns of gene expression, metabolomics, urate, as well as protein profiling in the blood and CSF samples. Reduced brain regional N-acetyl-aspartate is a biomarker for the in vivo assessment of neuronal loss using magnetic resonance spectroscopy and T2 relaxation time with MRI. To confirm PD diagnosis, the PET biomarkers include [(18)F]-DOPA for estimating dopaminergic neurotransmission, [(18)F]dG for mitochondrial bioenergetics, [(18)F]BMS for mitochondrial complex-1, [(11)C](R)-PK11195 for microglial activation, SPECT imaging with (123)Iflupane and βCIT for dopamine transporter, and urinary

  6. Circulating acylcarnitines as biomarkers of mitochondrial dysfunction after acetaminophen overdose in mice and humans.

    Science.gov (United States)

    McGill, Mitchell R; Li, Feng; Sharpe, Matthew R; Williams, C David; Curry, Steven C; Ma, Xiaochao; Jaeschke, Hartmut

    2014-02-01

    Acetaminophen (APAP) is a widely used analgesic. However, APAP overdose is hepatotoxic and is the primary cause of acute liver failure in the developed world. The mechanism of APAP-induced liver injury begins with protein binding and involves mitochondrial dysfunction and oxidative stress. Recent efforts to discover blood biomarkers of mitochondrial damage have identified increased plasma glutamate dehydrogenase activity and mitochondrial DNA concentration in APAP overdose patients. However, a problem with these markers is that they are too large to be released from cells without cell death or loss of membrane integrity. Metabolomic studies are more likely to reveal biomarkers that are useful at early time points, before injury begins. Similar to earlier work, our metabolomic studies revealed that acylcarnitines are elevated in serum from mice after treatment with toxic doses of APAP. Importantly, a comparison with furosemide demonstrated that increased serum acylcarnitines are specific for mitochondrial dysfunction. However, when we measured these compounds in plasma from humans with liver injury after APAP overdose, we could not detect any significant differences from control groups. Further experiments with mice showed that N-acetylcysteine, the antidote for APAP overdose in humans, can reduce acylcarnitine levels in serum. Altogether, our data do not support the clinical measurement of acylcarnitines in blood after APAP overdose due to the standard N-acetylcysteine treatment in patients, but strongly suggest that acylcarnitines would be useful mechanistic biomarkers in other forms of liver injury involving mitochondrial dysfunction.

  7. Biomarkers in Alzheimer's Disease-Recent Update.

    Science.gov (United States)

    Sharma, Sushil; Lipincott, Walter

    2017-02-20

    Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized by loss of memory and cognitive function. It is the common cause of dementia in elderly and is a global health concern as the population of people aged 85 and older, is growing alarmingly. Although pharmacotherapy for the treatment of AD has improved, lot of work remains to treat this devastating disease. AD pathology begins even before the onset of clinical symptoms. Because therapies could be more effective if implemented early in the disease progression, it is highly prudent to discover reliable biomarkers, to detect its exact pathophysiology during pre-symptomatic stage. Biomarker(s) with high sensitivity and specificity would facilitate AD diagnosis at early stages. Currently, CSF amyloid β 1-42, total tau, and phosphorylated tau181 are used as AD biomarkers. This report describes conventional and potential in-vitro and in-vivo biomarkers of AD. Particularly, in-vitro transcriptomic, proteomic, lipidomic, and metabolomic; body fluid biomarkers (C-reactive proteins, homocysteine, α-sunuclein index, and dehydroepiandrosterone sulphate) from blood, serum, plasma, CSF, and saliva; and neuronal, platelets, and lymphocyte microRNA, mtDNA, and Charnoly body are detected. In-vivo physiological and neurobehavioral biomarkers are evaluated by analyzing computerized EEG, event-related potentials, circadian rhythm, and multimodality fusion imaging including: CT, MRI, SPECT, and PET. More specifically, PET imaging biomarkers representing reduced fronto-temporal 18FdG uptake, increased 11C or 18F-PIB uptake, 11C-PBR28 to measure 18 kDa translocator protein (TSPO), a biomarker for inflammation; and 3-D MRI (ventriculomegaly)/MRS are performed for early and effective clinical management of AD.

  8. Hypermethylated DNA, a Biomarker for colorectal cancer

    DEFF Research Database (Denmark)

    Rasmussen, Simon Ladefoged; Krarup, Henrik Bygum; Sunesen, Kåre Gotschalck;

    2016-01-01

    and specific for CRC have been proposed. Articles describing the use of hypermethylated promoter regions in blood or stool as biomarkers for CRC were systematically reviewed. METHOD: The Medline, Web of Science, and Embase databases were used in a systematic literature search. Studies were included...

  9. In vivo approaches reveal a key role for DCs in CD4+ T cell activation and parasite clearance during the acute phase of experimental blood-stage malaria.

    Directory of Open Access Journals (Sweden)

    Henrique Borges da Silva

    2015-02-01

    Full Text Available Dendritic cells (DCs are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip, with Plasmodium chabaudi AS (Pc parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection.

  10. In Vivo Approaches Reveal a Key Role for DCs in CD4+ T Cell Activation and Parasite Clearance during the Acute Phase of Experimental Blood-Stage Malaria

    Science.gov (United States)

    Borges da Silva, Henrique; Fonseca, Raíssa; Cassado, Alexandra dos Anjos; Machado de Salles, Érika; de Menezes, Maria Nogueira; Langhorne, Jean; Perez, Katia Regina; Cuccovia, Iolanda Midea; Ryffel, Bernhard; Barreto, Vasco M.; Marinho, Cláudio Romero Farias; Boscardin, Silvia Beatriz; Álvarez, José Maria; D’Império-Lima, Maria Regina; Tadokoro, Carlos Eduardo

    2015-01-01

    Dendritic cells (DCs) are phagocytes that are highly specialized for antigen presentation. Heterogeneous populations of macrophages and DCs form a phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infections such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, limiting our knowledge regarding their protective role in malaria. Here, we used in vivo experimental approaches that enabled us to deplete or visualize DCs in order to clarify these issues. To elucidate the roles of DCs and marginal zone macrophages in the protection against blood-stage malaria, we infected DTx (diphtheria toxin)-treated C57BL/6.CD11c-DTR mice, as well as C57BL/6 mice treated with low doses of clodronate liposomes (ClLip), with Plasmodium chabaudi AS (Pc) parasites. The first evidence suggesting that DCs could contribute directly to parasite clearance was an early effect of the DTx treatment, but not of the ClLip treatment, in parasitemia control. DCs were also required for CD4+ T cell responses during infection. The phagocytosis of infected red blood cells (iRBCs) by splenic DCs was analyzed by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, at three distinct phases of Pc malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis when the parasitemia decline coincides with spleen closure. In vivo and ex vivo imaging of the spleen revealed that DCs actively phagocytize iRBCs and interact with CD4+ T cells both in T cell-rich areas and in the RP. Subcapsular RP DCs were highly efficient in the recognition and capture of iRBCs during pre-crisis, while complete DC maturation was only achieved during crisis. These findings indicate that, beyond their classical role in antigen presentation, DCs also contribute to the direct elimination of iRBCs during acute Plasmodium infection. PMID:25658925

  11. Prelimary study of biomarker in blood or cerebrospinal fluid of rat following manganese exposure%锰暴露后体液中生物标志物的初步研究

    Institute of Scientific and Technical Information of China (English)

    张艳淑; 姚林; 郝玉兰; 邹焰; 徐厚君; 范奇元

    2010-01-01

    86.9 folds of that in control; No significant change was found in plasma. However the trend and range of Mn increase in cerebrospinal fluid (CSF) was the same as that in brain tissue including striatum, cortex, hippocampus and choroid plexus. Meanwhile Fe concentration in brain tissue of Mn exposed rats was also higher than that of control, whose trend was as same as that in CSF. However iron concentration in plasma decreased. The real-time RT-PCR data also showed that Hepcidin mRNA expression in Mn-exposed rat decreased 56% in blood, which was in line with its expression in cortex (67%). Similarly, Parkin-2 mRNA expression decreased both in blood (42%) and in striatum. However DMT1 mRNA expression increase 38% in striatum of Mn-exposed rats but decreased in blood. Conclusion Hepcidin and Parkin-2 mRNA expression in blood might be serves as the effective biomarkers following manganese exposure, certainly which needs to be further explored.

  12. Biomarkers of Alzheimer’s disease in body fluids

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Various innovative diagnostic methods for Alzheimer’s disease (AD) have been developed in view of the increasing preva-lence and consequences of later-life dementia. Biomarkers in cerebrospinal fluid (CSF) and blood for AD are primarily based on the detection of components derived from amyloid plaques and neurofibrillary tangles (NFTs). Published reports on CSF and blood biomarkers in AD indicate that although biomarkers in body fluids may be utilized in the clinical diagnosis of AD, there are no specific markers that permit accurate and reliable diagnosis of early-stage AD or the monitoring of disease pro-gression.

  13. Crystal Structures of GII.10 and GII.12 Norovirus Protruding Domains in Complex with Histo-Blood Group Antigens Reveal Details for a Potential Site of Vulnerability

    Energy Technology Data Exchange (ETDEWEB)

    Hansman, Grant S.; Biertümpfel, Christian; Georgiev, Ivelin; McLellan, Jason S.; Chen, Lei; Zhou, Tongqing; Katayama, Kazuhiko; Kwong, Peter D. (NIH); (NIID-Japan)

    2011-10-10

    Noroviruses are the dominant cause of outbreaks of gastroenteritis worldwide, and interactions with human histo-blood group antigens (HBGAs) are thought to play a critical role in their entry mechanism. Structures of noroviruses from genogroups GI and GII in complex with HBGAs, however, reveal different modes of interaction. To gain insight into norovirus recognition of HBGAs, we determined crystal structures of norovirus protruding domains from two rarely detected GII genotypes, GII.10 and GII.12, alone and in complex with a panel of HBGAs, and analyzed structure-function implications related to conservation of the HBGA binding pocket. The GII.10- and GII.12-apo structures as well as the previously solved GII.4-apo structure resembled each other more closely than the GI.1-derived structure, and all three GII structures showed similar modes of HBGA recognition. The primary GII norovirus-HBGA interaction involved six hydrogen bonds between a terminal {alpha}fucose1-2 of the HBGAs and a dimeric capsid interface, which was composed of elements from two protruding subdomains. Norovirus interactions with other saccharide units of the HBGAs were variable and involved fewer hydrogen bonds. Sequence analysis revealed a site of GII norovirus sequence conservation to reside under the critical {alpha}fucose1-2 and to be one of the few patches of conserved residues on the outer virion-capsid surface. The site was smaller than that involved in full HBGA recognition, a consequence of variable recognition of peripheral saccharides. Despite this evasion tactic, the HBGA site of viral vulnerability may provide a viable target for small molecule- and antibody-mediated neutralization of GII norovirus.

  14. Blood Types

    Science.gov (United States)

    ... maternity. Learn About Blood Blood Facts and Statistics Blood Components Whole Blood and Red Blood Cells Platelets Plasma ... About Blood Blood Facts and Statistics Blood Types Blood Components What Happens to Donated Blood Blood and Diversity ...

  15. Biomarkers in clinical medicine.

    Science.gov (United States)

    Chen, Xiao-He; Huang, Shuwen; Kerr, David

    2011-01-01

    Biomarkers have been used in clinical medicine for decades. With the rise of genomics and other advances in molecular biology, biomarker studies have entered a whole new era and hold promise for early diagnosis and effective treatment of many diseases. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention (1). They can be classified into five categories based on their application in different disease stages: 1) antecedent biomarkers to identify the risk of developing an illness, 2) screening biomarkers to screen for subclinical disease, 3) diagnostic biomarkers to recognize overt disease, 4) staging biomarkers to categorise disease severity, and 5) prognostic biomarkers to predict future disease course, including recurrence, response to therapy, and monitoring efficacy of therapy (1). Biomarkers can indicate a variety of health or disease characteristics, including the level or type of exposure to an environmental factor, genetic susceptibility, genetic responses to environmental exposures, markers of subclinical or clinical disease, or indicators of response to therapy. This chapter will focus on how these biomarkers have been used in preventive medicine, diagnostics, therapeutics and prognostics, as well as public health and their current status in clinical practice.

  16. A review on airway biomarkers: exposure, effect and susceptibility.

    Science.gov (United States)

    Corradi, Massimo; Goldoni, Matteo; Mutti, Antonio

    2015-04-01

    Current research in pulmonology requires the use of biomarkers to investigate airway exposure and diseases, for both diagnostic and prognostic purposes. The traditional approach based on invasive approaches (lung lavages and biopsies) can now be replaced, at least in part, through the use of non invasively collected specimens (sputum and breath), in which biomarkers of exposure, effect and susceptibility can be searched. The discovery of specific lung-related proteins, which can spill over in blood or excreted in urine, further enhanced the spectrum of airway specific biomarkers to be studied. The recent introduction of high-performance 'omic' technologies - genomics, proteomics and metabolomics, and the rate at which biomarker candidates are being discovered, will permit the use of a combination of biomarkers for a more precise selection of patient with different outcomes and responses to therapies. The aim of this review is to critically evaluate the use of airway biomarkers in the context of research and clinical practice.

  17. Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation

    DEFF Research Database (Denmark)

    Undén, Johan; Strandberg, Karin; Malm, Jan;

    2009-01-01

    INTRODUCTION: A simple and accurate method of differentiating ischemic stroke and intracerebral hemorrhage (ICH) is potentially useful to facilitate acute therapeutic management. Blood measurements of biomarkers of brain damage and activation of the coagulation system may potentially serve as novel...... diagnostic tools for stroke subtypes. METHODS: Ninety-seven stroke patients were prospectively investigated in a multicenter design with blood levels of brain biomarkers S100B, neuron specific enolase (NSE), glial fibrillary acidic protein (GFAP) as well as a coagulation biomarker, activated protein C......: This exploratory study indicated that blood levels of biomarkers GFAP and APC-PCI, prior to neuroimaging, may rule out ICH in a mixed stroke population....

  18. Longitudinal micro-CT provides biomarkers of lung disease that can be used to assess the effect of therapy in preclinical mouse models, and reveal compensatory changes in lung volume.

    Science.gov (United States)

    Vande Velde, Greetje; Poelmans, Jennifer; De Langhe, Ellen; Hillen, Amy; Vanoirbeek, Jeroen; Himmelreich, Uwe; Lories, Rik J

    2016-01-01

    In vivo lung micro-computed tomography (micro-CT) is being increasingly embraced in pulmonary research because it provides longitudinal information on dynamic disease processes in a field in which ex vivo assessment of experimental disease models is still the gold standard. To optimize the quantitative monitoring of progression and therapy of lung diseases, we evaluated longitudinal changes in four different micro-CT-derived biomarkers [aerated lung volume, lung tissue (including lesions) volume, total lung volume and mean lung density], describing normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of lung disease (bleomycin-induced fibrosis, invasive pulmonary aspergillosis, pulmonary cryptococcosis) and therapy (imatinib). The four lung biomarkers were quantified. After the last time point, we performed pulmonary function tests and isolated the lungs for histology. None of the biomarkers remained stable during longitudinal follow-up of adult healthy mouse lungs, implying that biomarkers should be compared with age-matched controls upon intervention. Early inflammation and progressive fibrosis led to a substantial increase in total lung volume, which affects the interpretation of aerated lung volume, tissue volume and mean lung density measures. Upon treatment of fibrotic lung disease, the improvement in aerated lung volume and function was not accompanied by a normalization of the increased total lung volume. Significantly enlarged lungs were also present in models of rapidly and slowly progressing lung infections. The data suggest that total lung volume changes could partly reflect a compensatory mechanism that occurs during disease progression in mice. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document growth and potential compensatory mechanisms in mouse models of lung

  19. Biomarkers for Parkinson's disease.

    Science.gov (United States)

    Sherer, Todd B

    2011-04-20

    Biomarkers for detecting the early stages of Parkinson's disease (PD) could accelerate development of new treatments. Such biomarkers could be used to identify individuals at risk for developing PD, to improve early diagnosis, to track disease progression with precision, and to test the efficacy of new treatments. Although some progress has been made, there are many challenges associated with developing biomarkers for detecting PD in its earliest stages.

  20. Fluid biomarkers in multiple system atrophy: A review of the MSA Biomarker Initiative.

    Science.gov (United States)

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy; Gerhard, Alexander; Jellinger, Kurt; Jeromin, Andreas; Krismer, Florian; Mollenhauer, Brit; Schlossmacher, Michael G; Shaw, Leslie M; Verbeek, Marcel M; Wenning, Gregor K; Winge, Kristian; Zhang, Jing; Meissner, Wassilios G

    2015-08-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagement for future clinical trials. We here review candidate fluid biomarkers for MSA and provide considerations for further developments and harmonization of standard operating procedures. A PubMed search was performed until April 24, 2015 to review the literature with regard to candidate blood and cerebrospinal fluid (CSF) biomarkers for MSA. Abstracts of 1760 studies were retrieved and screened for eligibility. The final list included 60 studies assessing fluid biomarkers in patients with MSA. Most studies have focused on alpha-synuclein, markers of axonal degeneration or catecholamines. Their results suggest that combining several CSF fluid biomarkers may be more successful than using single markers, at least for the diagnosis. Currently, the clinically most useful markers may comprise a combination of the light chain of neurofilament (which is consistently elevated in MSA compared to controls and Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success.

  1. Network analysis-based approach for exploring the potential diagnostic biomarkers of acute myocardial infarction.

    Directory of Open Access Journals (Sweden)

    Jiaqi Chen

    2016-12-01

    Full Text Available Acute myocardial infarction (AMI is a severe cardiovascular disease that is a serious threat to human life. However, the specific diagnostic biomarkers have not been fully clarified and candidate regulatory targets for AMI have not been identified. In order to explore the potential diagnostic biomarkers and possible regulatory targets of AMI, we used a network analysis-based approach to analyze microarray expression profiling of peripheral blood in patients with AMI. The significant differentially-expressed genes (DEGs were screened by Limma and constructed a gene function regulatory network (GO-Tree to obtain the inherent affiliation of significant function terms. The pathway action network was constructed, and the signal transfer relationship between pathway terms was mined in order to investigate the impact of core pathway terms in AMI. Subsequently, constructed the transcription regulatory network of DEGs. Weighted gene co-expression network analysis (WGCNA was employed to identify significantly altered gene modules and hub genes in two groups. Subsequently, the transcription regulation network of DEGs was constructed. We found that specific gene modules may provide a better insight into the potential diagnostic biomarkers of AMI. Our findings revealed and verified that NCF4, AQP9, NFIL3, DYSF, GZMA, TBX21, PRF1 and PTGDR genes by RT-qPCR. TBX21 and PRF1 may be potential candidates for diagnostic biomarker and possible regulatory targets in AMI.

  2. Network analysis identifies SOD2 mRNA as a potential biomarker for Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Jose A Santiago

    Full Text Available Increasing evidence indicates that Parkinson's disease (PD and type 2 diabetes (T2DM share dysregulated molecular networks. We identified 84 genes shared between PD and T2DM from curated disease-gene databases. Nitric oxide biosynthesis, lipid and carbohydrate metabolism, insulin secretion and inflammation were identified as common dysregulated pathways. A network prioritization approach was implemented to rank genes according to their distance to seed genes and their involvement in common biological pathways. Quantitative polymerase chain reaction assays revealed that a highly ranked gene, superoxide dismutase 2 (SOD2, is upregulated in PD patients compared to healthy controls in 192 whole blood samples from two independent clinical trials, the Harvard Biomarker Study (HBS and the Diagnostic and Prognostic Biomarkers in Parkinson's disease (PROBE. The results from this study reinforce the idea that shared molecular networks between PD and T2DM provides an additional source of biologically meaningful biomarkers. Evaluation of this biomarker in de novo PD patients and in a larger prospective longitudinal study is warranted.

  3. Umbilical Cord Mercury Concentration as Biomarker of Prenatal Exposure to Methylmercury

    DEFF Research Database (Denmark)

    Grandjean, Philippe; Budtz-Jørgensen, Esben; Jørgensen, Poul J.

    2005-01-01

    biomarker, exposure assessment, food contamination, hair analysis, mercury/analysis, methylmercury compounds/analysis, organomercury compounds/blood, pregnancy, prenatal exposure delayed effects, preschool child, seafood, umbilical cord.......biomarker, exposure assessment, food contamination, hair analysis, mercury/analysis, methylmercury compounds/analysis, organomercury compounds/blood, pregnancy, prenatal exposure delayed effects, preschool child, seafood, umbilical cord....

  4. Characterization of SR3 reveals abundance of non-LTR retrotransposons of the RTE clade in the genome of the human blood fluke, Schistosoma mansoni

    Directory of Open Access Journals (Sweden)

    Brindley Paul J

    2005-11-01

    Full Text Available Abstract Background It is becoming apparent that perhaps as much as half of the genome of the human blood fluke Schistosoma mansoni is constituted of mobile genetic element-related sequences. Non-long terminal repeat (LTR retrotransposons, related to the LINE elements of mammals, comprise much of this repetitive component of the schistosome genome. Of more than 12 recognized clades of non-LTR retrotransposons, only members of the CR1, RTE, and R2 clades have been reported from the schistosome genome. Results Inspection of the nucleotide sequence of bacterial artificial chromosome number 49_J_14 from chromosome 1 of the genome of Schistosoma mansoni (GenBank AC093105 revealed the likely presence of several RTE-like retrotransposons. Among these, a new non-LTR retrotransposon designated SR3 was identified and is characterized here. Analysis of gene structure and phylogenetic analysis of both the reverse transcriptase and endonuclease domains of the mobile element indicated that SR3 represented a new family of RTE-like non-LTR retrotransposons. Remarkably, two full-length copies of SR3-like elements were present in BAC 49-J-14, and one of 3,211 bp in length appeared to be intact, indicating SR3 to be an active non-LTR retrotransposon. Both were flanked by target site duplications of 10–12 bp. Southern hybridization and bioinformatics analyses indicated the presence of numerous copies (probably >1,000 of SR3 interspersed throughout the genome of S. mansoni. Bioinformatics analyses also revealed SR3 to be transcribed in both larval and adult developmental stages of S. mansoni and to be also present in the genomes of the other major schistosome parasites of humans, Schistosoma haematobium and S. japonicum. Conclusion Numerous copies of SR3, a novel non-LTR retrotransposon of the RTE clade are present in the genome of S. mansoni. Non-LTR retrotransposons of the RTE clade including SR3 appear to have been remarkably successful in colonizing, and

  5. Exploration of new HCC biomarkers

    Directory of Open Access Journals (Sweden)

    Regina M. Santella

    2007-02-01

    Full Text Available

    Analysis of plasma/serum for levels of viral antigens or antibodies to viral proteins has been used extensively as an early biomarker of potential risk of HCC. In addition, detection of elevated levels of alpha-fetoprotein is commonly used for early identification of HCC. Unfortunately, both of these approaches are not highly sensitive or specific. As a result, there is continuing investigation to identify additional biomarkers that may help in the early identification of cases. The use of DNA isolated from plasma or serum for detection of gene specific methylation has been discussed previously. In addition, tumor DNA isolated from blood has been analyzed for the presence of p53 mutations and found in a subset of cases to be present years prior to diagnosis as for methylated DNA. The general level of DNA present in blood has also been suggested as a potential biomarker of cancer.

    Among the newer methods being tested are the detection of specific mutations in HBV. In many cases of HCC in China and Africa a double mutation, an A to T transversion at nucleotide 1762 and a G to A transition at nucleotide 1764 (1762T/1764A have been found. These mutations have been associated with increased severity of HBV infection and cirrhosis suggesting that they might be a useful biomarker for high risk subjects.

    The field of proteomics also holds promise for the development of new biomarkers. A number of groups are developing mass spectrometry methods for the identification of serum/plasma proteomic patterns that will distinguish bloods of HCC cases from those of controls. While some interesting preliminary data have been developed for several cancers, much additional work needs to be done in this area

  6. Respiratory Toxicity Biomarkers

    Science.gov (United States)

    The advancement in high throughput genomic, proteomic and metabolomic techniques have accelerated pace of lung biomarker discovery. A recent growth in the discovery of new lung toxicity/disease biomarkers have led to significant advances in our understanding of pathological proce...

  7. On consensus biomarker selection

    Directory of Open Access Journals (Sweden)

    Gambin Anna

    2007-05-01

    Full Text Available Abstract Background Recent development of mass spectrometry technology enabled the analysis of complex peptide mixtures. A lot of effort is currently devoted to the identification of biomarkers in human body fluids like serum or plasma, based on which new diagnostic tests for different diseases could be constructed. Various biomarker selection procedures have been exploited in recent studies. It has been noted that they often lead to different biomarker lists and as a consequence, the patient classification may also vary. Results Here we propose a new approach to the biomarker selection problem: to apply several competing feature ranking procedures and compute a consensus list of features based on their outcomes. We validate our methods on two proteomic datasets for the diagnosis of ovarian and prostate cancer. Conclusion The proposed methodology can improve the classification results and at the same time provide a unified biomarker list for further biological examinations and interpretation.

  8. Biomarkers of Reflux Disease.

    Science.gov (United States)

    Kia, Leila; Pandolfino, John E; Kahrilas, Peter J

    2016-06-01

    Gastroesophageal reflux disease (GERD) encompasses an array of disorders unified by the reflux of gastric contents. Because there are many potential disease manifestations, esophageal and extraesophageal, there is no single biomarker of the entire disease spectrum; a set of GERD biomarkers that each quantifies specific aspects of GERD-related pathology might be needed. We review recent reports of biomarkers of GERD, specifically in relation to endoscopically negative esophageal disease and excluding conventional pH-impedance monitoring. We consider histopathologic biomarkers, baseline impedance, and serologic assays to determine that most markers are based on manifestations of impaired esophageal mucosal integrity, which is based on increased ionic and molecular permeability, and/or destruction of tight junctions. Impaired mucosal integrity quantified by baseline mucosal impedance, proteolytic fragments of junctional proteins, or histopathologic features has emerged as a promising GERD biomarker.

  9. Serological biomarkers in triage of FIT-positive subjects?

    DEFF Research Database (Denmark)

    Nielsen, Hans J; Christensen, Ib Jarle; Andersen, Berit

    2017-01-01

    that nucleosome blood tests may be one option for identifying some of these patients. Implementation of a triage test consisting of FIT, blood-based biomarkers and plus/minus colonoscopy is suggested to identify subjects with FIT levels between the initial and the increased cut-off level that must be offered...

  10. Biomarkers of Aging: From Function to Molecular Biology.

    Science.gov (United States)

    Wagner, Karl-Heinz; Cameron-Smith, David; Wessner, Barbara; Franzke, Bernhard

    2016-06-02

    Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is a considerable variation in the extent of disease and functional impairment risk, revealing a need for valid biomarkers to aid in characterizing the complex aging processes. The identification of biomarkers is further complicated by the diversity of biological living situations, lifestyle activities and medical treatments. Thus, there has been no identification of a single biomarker or gold standard tool that can monitor successful or healthy aging. Within this short review the current knowledge of putative biomarkers is presented, focusing on their application to the major physiological mechanisms affected by the aging process including physical capability, nutritional status, body composition, endocrine and immune function. This review emphasizes molecular and DNA-based biomarkers, as well as recent advances in other biomarkers such as microRNAs, bilirubin or advanced glycation end products.

  11. Biomarkers in the Management of Difficult Asthma.

    Science.gov (United States)

    Schleich, Florence; Demarche, Sophie; Louis, Renaud

    2016-01-01

    Difficult asthma is a heterogeneous disease of the airways including various types of bronchial inflammation and various degrees of airway remodeling. Therapeutic response of severe asthmatics can be predicted by the use of biomarkers of Type2-high or Type2-low inflammation. Based on sputum cell analysis, four inflammatory phenotypes have been described. As induced sputum is timeconsuming and expensive technique, surrogate biomarkers are useful in clinical practice. Eosinophilic phenotype is likely to reflect ongoing adaptive immunity in response to allergen. Several biomarkers of eosinophilic asthma are easily available in clinical practice (blood eosinophils, serum IgE, exhaled nitric oxyde, serum periostin). Neutrophilic asthma is thought to reflect innate immune system activation in response to pollutants or infectious agents while paucigranulocytic asthma is thought to be not inflammatory and characterized by smooth muscle dysfunction. We currently lack of user-friendly biomarkers of neutrophilic asthma and airway remodeling. In this review, we summarize the biomarkers available for the management of difficult asthma.

  12. Molecular characterization of Italian Candida parapsilosis isolates reveals the cryptic presence of the newly described species Candida orthopsilosis in blood cultures from newborns.

    Science.gov (United States)

    Romeo, Orazio; Delfino, Demetrio; Costanzo, Barbara; Cascio, Antonio; Criseo, Giuseppe

    2012-03-01

    The authors report the molecular characterization of Candida parapsilosis isolates recovered from the blood and venous central catheter tips of patients admitted to different care units of the Polyclinic Hospital, University of Messina, Italy. Among 97 presumed C. parapsilosis isolates examined, 94 were identified as C. parapsilosis sensu stricto and the remaining 3 isolates were found to belong to the cryptic species Candida orthopsilosis which was recovered only from blood cultures of neonates (orthopsilosis in newborns.

  13. Biomarkers of acute lung injury: worth their salt?

    Directory of Open Access Journals (Sweden)

    Proudfoot Alastair G

    2011-12-01

    Full Text Available Abstract The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy.

  14. Neurotoxicity and Biomarkers of Lead Exposure:a Review

    Institute of Scientific and Technical Information of China (English)

    Kang-sheng Liu; Jia-hu Hao; Yu Zeng; Fan-chun Dai; Ping-qing Gu

    2013-01-01

    Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes, public health decision making, and primary prevention synthesis. Lead is one of the neurotoxicants that seems to be involved in the etiology of psychologies. Biomarkers are generally classified into three groups:biomarkers of exposure, effect, and susceptibility.The main body compartments that store lead are the blood, soft tissues, and bone;the half-life of lead in these tissues is measured in weeks for blood, months for soft tissues, and years for bone. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurological disorders, such as brain damage, mental retardation, behavioral problems, nerve damage, and possibly Alzheimer’s disease, Parkinson’s disease, and schizophrenia. This paper presents an overview of biomarkers of lead exposure and discusses the neurotoxic effects of lead with regard to children and adults.

  15. Cross-reactions in the HLA system revealed by red blood cells expressing HLA determinants, with particular reference to cross-reaction between HLA-A2 and B17.

    Science.gov (United States)

    Nordhagen, R

    1983-01-01

    Sera with cytotoxic and haemagglutinating activity towards HLA-A2/28 were also shown to react with red blood cells (RBC) expressing the HLA-B17 antigen determinant. Absorption procedures with white blood cells (WBC) indicated that this was due to an HLA-A2/B17 cross-reaction. Absorption experiments with some other sera which previously had shown cytotoxic and haemagglutinating activity towards different HLA specificities, revealed broad cross-reaction related to HLA-B locus antigens.

  16. Metabolic products as biomarkers

    Science.gov (United States)

    Melancon, M.J.; Alscher, R.; Benson, W.; Kruzynski, G.; Lee, R.F.; Sikka, H.C.; Spies, R.B.; Huggett, Robert J.; Kimerle, Richard A.; Mehrle, Paul M.=; Bergman, Harold L.

    1992-01-01

    Ideally, endogenous biomarkers would indicate both exposure and environmental effects of toxic chemicals; however, such comprehensive biochemical and physiological indices are currently being developed and, at the present time, are unavailable for use in environmental monitoring programs. Continued work is required to validate the use of biochemical and physiological stress indices as useful components of monitoring programs. Of the compounds discussed only phytochelatins and porphyrins are currently in biomarkers in a useful state; however, glutathione,metallothioneins, stress ethylene, and polyamines are promising as biomarkers in environmental monitoring.

  17. Commentary: statistics for biomarkers.

    Science.gov (United States)

    Lovell, David P

    2012-05-01

    This short commentary discusses Biomarkers' requirements for the reporting of statistical analyses in submitted papers. It is expected that submitters will follow the general instructions of the journal, the more detailed guidance given by the International Committee of Medical Journal Editors, the specific guidelines developed by the EQUATOR network, and those of various specialist groups. Biomarkers expects that the study design and subsequent statistical analyses are clearly reported and that the data reported can be made available for independent assessment. The journal recognizes that there is continuing debate about different approaches to statistical science. Biomarkers appreciates that the field continues to develop rapidly and encourages the use of new methodologies.

  18. MicroRNAs as potential biomarkers in malignant pleural mesothelioma

    Directory of Open Access Journals (Sweden)

    Santoni-Rugiu E

    2015-12-01

    Full Text Available Eric Santoni-Rugiu, Morten Andersen, Morten Grauslund Laboratory of Molecular Pathology, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Abstract: Malignant pleural mesothelioma (MPM, a highly lethal cancer strictly related to asbestos exposure, is usually characterized by delayed diagnosis, resistance to current therapies, and dismal prognosis. MPM is difficult to distinguish histologically from nonmalignant reactive mesothelial proliferations (RMPs as there are no clinically validated immunohistochemical markers yet and the main diagnostic criterion remains deep invasion into the pleura and underlying fat tissue, which is often not appreciable in small pleural biopsies. In this regard, microRNAs (miRNAs, given their size and stability, are particularly attractive biomarkers in formalin-fixed paraffin-embedded tissue specimens for routine pathology. Moreover, circulating miRNAs appear to be promising biomarkers for early detection and monitoring of patients with MPM. Here, we review the studies mostly performed by miRNA arrays and reverse transcription-quantitative polymerase chain reaction in formalin-fixed paraffin-embedded or frozen tissue samples, MPM cell lines, and blood/plasma/serum samples that have highlighted the potential of miRNAs as biomarkers in MPM. Certain studies have pointed to the ability of miRNAs to distinguish the different histological MPM subtypes or separate MPM from lung adenocarcinoma, and other investigations have revealed that miRNAs can aid in differentiating MPM from RMP or have prognostic value in predicting the patient outcome. Mechanistic aspects of the involvement of miRNAs in mesothelioma genesis and possible use of miRNAs as future therapeutic targets in MPM are also emphasized. Finally, limitations of the data currently obtained due to the drawbacks of reverse transcription-quantitative polymerase chain reaction, heterogeneity of MPM tissue samples, and

  19. Validation of New Cancer Biomarkers

    DEFF Research Database (Denmark)

    Duffy, Michael J; Sturgeon, Catherine M; Söletormos, Georg;

    2015-01-01

    BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps...... in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance...... of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before...

  20. Significant biomarkers for the management of hepatocellular carcinoma.

    Science.gov (United States)

    Kondo, Yasuteru; Kimura, Osamu; Shimosegawa, Tooru

    2015-06-01

    Surveillance of hepatocellular carcinoma (HCC) is important for early detection. Imaging tests including computed tomography, magnetic resonance imaging and ultrasonography with or without various kinds of contrast medium are important options for detecting HCC. In addition to the imaging tests, various kinds of biomarkers including alpha-fetoprotein (AFP), lectin-bound AFP (AFP-L3) and protein induced by vitamin K absence or antagonist II (PIVKA-II) have been widely used to detect HCC and analyze treatment response. Recently, various kinds of novel biomarkers (proteins and miRNA) have been found to predict the malignancy potential of HCC and treatment response to specific therapies. Moreover, various combinations of well-established biomarkers and novel biomarkers have been tested to improve sensitivity and specificity. In practical terms, biomarkers that can be analyzed using peripheral blood samples might be more useful than immunohistochemical techniques. It has been reported that quantification of cytokines in peripheral blood and the analysis of peripheral immune subsets could be good biomarkers for managing HCC. Here, we describe the usefulness of and update well-established and novel biomarkers for the management of HCC.

  1. Biomarker time out.

    Science.gov (United States)

    Petzold, Axel; Bowser, Robert; Calabresi, Paolo; Zetterberg, Henrik; Uitdehaag, Bernard M J

    2014-10-01

    The advancement of knowledge relies on scientific investigations. The timing between asking a question and data collection defines if a study is prospective or retrospective. Prospective studies look forward from a point in time, are less prone to bias and are considered superior to retrospective studies. This conceptual framework conflicts with the nature of biomarker research. New candidate biomarkers are discovered in a retrospective manner. There are neither resources nor time for prospective testing in all cases. Relevant sources for bias are not covered. Ethical questions arise through the time penalty of an overly dogmatic concept. The timing of sample collection can be separated from testing biomarkers. Therefore the moment of formulating a hypothesis may be after sample collection was completed. A conceptual framework permissive to asking research questions without the obligation to bow to the human concept of calendar time would simplify biomarker research, but will require new safeguards against bias.

  2. Biomarkers in Airway Diseases

    Directory of Open Access Journals (Sweden)

    Janice M Leung

    2013-01-01

    Full Text Available The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases.

  3. Human semen as an early, sensitive biomarker of highly polluted living environment in healthy men: A pilot biomonitoring study on trace elements in blood and semen and their relationship with sperm quality and RedOx status.

    Science.gov (United States)

    Bergamo, Paolo; Volpe, Maria Grazia; Lorenzetti, Stefano; Mantovani, Alberto; Notari, Tiziana; Cocca, Ennio; Cerullo, Stefano; Di Stasio, Michele; Cerino, Pellegrino; Montano, Luigi

    2016-12-01

    The Campania region in Italy is facing an environmental crisis due to the illegal disposal of toxic waste. Herein, a pilot study (EcoFoodFertility initiative) was conducted to investigate the use of human semen as an early biomarker of pollution on 110 healthy males living in various areas of Campania with either high or low environmental impact. The semen from the "high impact" group showed higher zinc, copper, chromium and reduced iron levels, as well as reduced sperm motility and higher sperm DNA Fragmentation Index (DFI). Redox biomarkers (total antioxidant capacity, TAC, and glutathione, GSH) and the activity of antioxidant enzymes in semen were lower in the "high impact" group. The percentage of immotile spermatozoa showed a significant inverse correlation with TAC and GSH. Overall, several semen parameters (reduced sperm quality and antioxidant defenses, altered chemical element pattern), which were associated with residence in a high polluted environment, could be used in a further larger scale study, as early biomarkers of environmental pollution.

  4. Signatures of malaria-associated pathology revealed by high-resolution whole-blood transcriptomics in a rodent model of malaria

    Science.gov (United States)

    Lin, Jing-wen; Sodenkamp, Jan; Cunningham, Deirdre; Deroost, Katrien; Tshitenge, Tshibuayi Christine; McLaughlin, Sarah; Lamb, Tracey J.; Spencer-Dene, Bradley; Hosking, Caroline; Ramesar, Jai; Janse, Chris J.; Graham, Christine; O’Garra, Anne; Langhorne, Jean

    2017-01-01

    The influence of parasite genetic factors on immune responses and development of severe pathology of malaria is largely unknown. In this study, we performed genome-wide transcriptomic profiling of mouse whole blood during blood-stage infections of two strains of the rodent malaria parasite Plasmodium chabaudi that differ in virulence. We identified several transcriptomic signatures associated with the virulent infection, including signatures for platelet aggregation, stronger and prolonged anemia and lung inflammation. The first two signatures were detected prior to pathology. The anemia signature indicated deregulation of host erythropoiesis, and the lung inflammation signature was linked to increased neutrophil infiltration, more cell death and greater parasite sequestration in the lungs. This comparative whole-blood transcriptomics profiling of virulent and avirulent malaria shows the validity of this approach to inform severity of the infection and provide insight into pathogenic mechanisms. PMID:28155887

  5. Biomarkers of chronic alcohol misuse

    Directory of Open Access Journals (Sweden)

    Gonzalo P

    2014-01-01

    Full Text Available Philippe Gonzalo,1 Sylvie Radenne,2 Sylvie Gonzalo31Laboratoire de Biochimie, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France; 2Service d'Hépatologie-Gastroentérologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, Lyon, France; 3Laboratoire Biomnis, Lyon, FranceAbstract: Biological markers of chronic alcoholism can be divided into two groups: direct and indirect markers. Direct markers (mainly blood or serum and urine ethanol, ethylglucuronide, ethyl sulfate, and phosphatidylethanol directly track the intake of alcohol and vary in their sensitivity and kinetics of appearance and clearance. Indirect markers (mean corpuscular volume,γ-glutamyl transferase, alanine aminotransferase and aspartate aminotransferase, and carbohydrate-deficient transferrin are biological parameters that are influenced by a steady and significant alcohol intake. We discuss the values of these tests and the relevance of their prescriptions for the clinical evaluation of heavy drinking. We indicate, when known, the pathophysiological mechanism of their elevations. We also discuss the amount and time of alcohol consumption required to give a positive result and the duration of abstinence required for the return to normal values. The forensic use of these biomarkers will not be considered in this review.Keywords: alcoholism, biomarker, CDT, relapse, alcohol-induced liver disease

  6. 4-D MRI flow analysis in the course of interrupted aortic arch reveals complex morphology and quantifies amount of collateral blood flow

    Energy Technology Data Exchange (ETDEWEB)

    Hirtler, Daniel [University Hospital Freiburg, Department of Pediatric Cardiology and Congenital Heart Disease, Freiburg (Germany); Geiger, Julia; Jung, Bernd [University Hospital Freiburg, Department of Radiology, Medical Physics, Freiburg (Germany); Markl, Michael [Northwestern University, Departments of Radiology and Biomedical Engineering, Chicago, IL (United States); Arnold, Raoul [University Hospital Heidelberg, Department of Pediatric Cardiology and Congenital Heart Disease, Heidelberg (Germany)

    2013-08-15

    We present findings in a 17-year-old with interrupted aortic arch, in whom standard imaging techniques missed functional and morphological problems. Flow-sensitive four-dimensional magnetic resonance (4-D MR) enabled assessment of the complex anatomy and blood-flow characteristics in the entire aorta and direct quantification of blood flow in collateral vessels. Our findings highlight the entire morphological and functional problem of interrupted aortic arch and illustrate the potential of flow-sensitive 4-D MR for surgical planning in congenital heart disease. (orig.)

  7. Maternal and cord blood LC-HRMS metabolomics reveal alterations in energy and polyamine metabolism, and oxidative stress in very-low birth weight infants.

    Science.gov (United States)

    Alexandre-Gouabau, Marie-Cécile; Courant, Frédérique; Moyon, Thomas; Küster, Alice; Le Gall, Gwénaëlle; Tea, Illa; Antignac, Jean-Philippe; Darmaun, Dominique

    2013-06-07

    To assess the global effect of preterm birth on fetal metabolism and maternal-fetal nutrient transfer, we used a mass spectrometric-based chemical phenotyping approach on cord blood obtained at the time of birth. We sampled umbilical venous, umbilical arterial, and maternal blood from mothers delivering very-low birth weight (VLBW, with a median gestational age and weight of 29 weeks, and 1210 g, respectively) premature or full-term (FT) neonates. In VLBW group, we observed a significant elevation in the levels and maternal-fetal gradients of butyryl-, isovaleryl-, hexanoyl- and octanoyl-carnitines, suggesting enhanced short- and medium chain fatty acid β-oxidation in human preterm feto-placental unit. The significant decrease in glutamine-glutamate in preterm arterial cord blood beside lower levels of amino acid precursors of Krebs cycle suggest increased glutamine utilization in the fast growing tissues of preterm fetus with a deregulation in placental glutamate-glutamine shuttling. Enhanced glutathione utilization is likely to account for the decrease in precursor amino acids (serine, betaine, glutamate and methionine) in arterial cord blood. An increase in both the circulating levels and maternal-fetal gradients of several polyamines in their acetylated form (diacetylspermine and acetylputrescine) suggests an enhanced polyamine metabolic cycling in extreme prematurity. Our metabolomics study allowed the identification of alterations in fetal energy, antioxidant defense, and polyamines and purines flux as a signature of premature birth.

  8. Aligned hemozoin crystals in curved clusters in malarial red blood cells revealed by nanoprobe X-ray Fe fluorescence and diffraction

    DEFF Research Database (Denmark)

    Kapishnikov, Sergey; Berthing, Trine; Hviid, Lars;

    2012-01-01

    The human malaria parasite Plasmodium falciparum detoxifies the heme byproduct of hemoglobin digestion in infected red blood cells by sequestration into submicron-sized hemozoin crystals. The crystal is composed of heme units interlinked to form cyclic dimers via reciprocal Fe-O (propionate) bonds...

  9. Advances in biomarkers of major depressive disorder.

    Science.gov (United States)

    Huang, Tiao-Lai; Lin, Chin-Chuen

    2015-01-01

    Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Biomarkers are measurable indicators that could help diagnosing MDD or predicting treatment response. In this chapter, lipid profiles, immune/inflammation, and neurotrophic factor pathways that have long been implicated in the pathogenesis of MDD are discussed. Then, pharmacogenetics and epigenetics of serotonin transport and its metabolism pathway, brain-derived neurotrophic factor, and abnormality of hypothalamo-pituitary-adrenocortical axis also revealed new biomarkers. Lastly, new techniques, such as proteomics and metabolomics, which allow researchers to approach the studying of MDD with new directions and make new discoveries are addressed. In the future, more data are needed regarding pathophysiology of MDD, including protein levels, single nucleotide polymorphism, epigenetic regulation, and clinical data in order to better identify reliable and consistent biomarkers for diagnosis, treatment choice, and outcome prediction.

  10. Circulating Biomarker Panels in Alzheimer's Disease.

    Science.gov (United States)

    Zafari, Sachli; Backes, Christina; Meese, Eckart; Keller, Andreas

    2015-01-01

    The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-β levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next-generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles.

  11. Blood sugar test - blood

    Science.gov (United States)

    ... blood glucose level ( hypoglycemia ) may be due to: Hypopituitarism (a pituitary gland disorder) Underactive thyroid gland or ... tonic-clonic seizure Glucagon blood test Glucagonoma Hyperthyroidism Hypopituitarism Hypothyroidism Insulinoma Low blood sugar Multiple endocrine neoplasia ( ...

  12. Acute-phase proteins, oxidative stress biomarkers, proinflammatory cytokines, and cardiac troponin in Arabian mares affected with pyometra.

    Science.gov (United States)

    El-Bahr, S M; El-Deeb, W M

    2016-09-01

    New biomarkers are essential for diagnosis of pyometra in mares. In this context, 12 subfertile Arabian mares suffered from pyometra were admitted to the Veterinary Teaching Hospital. The basis for diagnosis of pyometra was positive findings of clinical examination and rectal palpation. Blood samples were collected from diseased animals and from five Arabian healthy mares, which were considered as control group. Acute-phase proteins (APP), oxidative stress biomarkers, proinflammatory cytokines, and cardiac troponin I were estimated in the harvested sera of both groups. Clinical examination revealed purulent yellowish fluid discharged from vagina of affected animals and rectal palpation of the reproductive tract revealed uterine distention. The biochemical analysis of the serum revealed significant increase in cardiac troponin I, creatin kinase, alkaline phosphatase, malondialdehyde, tumor necrosis factor α, interleukins 6, prostaglandin F2α, haptoglobin, and serum amyloid A and significant decrease in reduced glutathione, superoxide dismutase (SOD), total antioxidant capacity, and nitric oxide (NO) of mares affected with pyometra compare to control. Cardiac troponin I was positively correlated with aspartate aminotransferase, creatin kinase, malondialdehyde, alkaline phosphatase, tumor necrosis factor α, interleukins 6, prostaglandin F2α, haptoglobin and serum amyloid A and negatively correlated with glutathione, superoxide dismutase, total antioxidant capacity and nitric oxide in serum of mares affected with pyometra. Moreover, there was high positive correlation between proinflammatory cytokines and APP in serum of mares affected with pyometra. The present study suggests cardiac troponin I together with APP, proinflammatory cytokines, and oxidative stress parameters as biomarkers for pyometra in Arabian mares.

  13. Electroencephalography reveals lower regional blood perfusion and atrophy of the temporoparietal network associated with memory deficits and hippocampal volume reduction in mild cognitive impairment due to Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Moretti DV

    2015-02-01

    Full Text Available Davide Vito MorettiNational Institute for the research and cure of Alzheimer’s disease, S. John of God, Fatebenefratelli, Brescia, Italy Background: An increased electroencephalographic (EEG upper/lower alpha power ratio has been associated with less regional blood perfusion, atrophy of the temporoparietal region of the brain, and reduction of hippocampal volume in subjects affected by mild cognitive impairment due to Alzheimer’s disease as compared with subjects who do not develop the disease. Moreover, EEG theta frequency activity is quite different in these groups. This study investigated the correlation between biomarkers and memory performance.Methods: EEG α3/α2 power ratio and cortical thickness were computed in 74 adult subjects with prodromal Alzheimer’s disease. Twenty of these subjects also underwent assessment of blood perfusion by single-photon emission computed tomography (SPECT. Pearson’s r was used to assess the correlation between cortical thinning, brain perfusion, and memory impairment.Results: In the higher α3/α2 frequency power ratio group, greater cortical atrophy and lower regional perfusion in the temporoparietal cortex was correlated with an increase in EEG theta frequency. Memory impairment was more pronounced in the magnetic resonance imaging group and SPECT groups.Conclusion: A high EEG upper/low alpha power ratio was associated with cortical thinning and less perfusion in the temporoparietal area. Moreover, atrophy and less regional perfusion were significantly correlated with memory impairment in subjects with prodromal Alzheimer’s disease. The EEG upper/lower alpha frequency power ratio could be useful for identifying individuals at risk for progression to Alzheimer’s dementia and may be of value in the clinical context.Keywords: electroencephalography, perfusion, atrophy, temporoparietal network, memory deficits, hippocampal volume, mild cognitive impairment, Alzheimer’s disease

  14. Ultra-fast local-haplotype variant calling using paired-end DNA-sequencing data reveals somatic mosaicism in tumor and normal blood samples.

    Science.gov (United States)

    Sengupta, Subhajit; Gulukota, Kamalakar; Zhu, Yitan; Ober, Carole; Naughton, Katherine; Wentworth-Sheilds, William; Ji, Yuan

    2016-02-18

    Somatic mosaicism refers to the existence of somatic mutations in a fraction of somatic cells in a single biological sample. Its importance has mainly been discussed in theory although experimental work has started to emerge linking somatic mosaicism to disease diagnosis. Through novel statistical modeling of paired-end DNA-sequencing data using blood-derived DNA from healthy donors as well as DNA from tumor samples, we present an ultra-fast computational pipeline, LocHap that searches for multiple single nucleotide variants (SNVs) that are scaffolded by the same reads. We refer to scaffolded SNVs as local haplotypes (LH). When an LH exhibits more than two genotypes, we call it a local haplotype variant (LHV). The presence of LHVs is considered evidence of somatic mosaicism because a genetically homogeneous cell population will not harbor LHVs. Applying LocHap to whole-genome and whole-exome sequence data in DNA from normal blood and tumor samples, we find wide-spread LHVs across the genome. Importantly, we find more LHVs in tumor samples than in normal samples, and more in older adults than in younger ones. We confirm the existence of LHVs and somatic mosaicism by validation studies in normal blood samples. LocHap is publicly available at http://www.compgenome.org/lochap.

  15. Biomarkers intersect with the exposome.

    Science.gov (United States)

    Rappaport, Stephen M

    2012-09-01

    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.

  16. Functional MRI and CT biomarkers in oncology

    Energy Technology Data Exchange (ETDEWEB)

    Winfield, J.M. [Institute of Cancer Research and Royal Marsden NHS Foundation Trust, CRUK Imaging Centre at the Institute of Cancer Research, Sutton (United Kingdom); Institute of Cancer Research and Royal Marsden Hospital, MRI Unit, Sutton (United Kingdom); Payne, G.S.; DeSouza, N.M. [Institute of Cancer Research and Royal Marsden NHS Foundation Trust, CRUK Imaging Centre at the Institute of Cancer Research, Sutton (United Kingdom)

    2015-04-01

    Imaging biomarkers derived from MRI or CT describe functional properties of tumours and normal tissues. They are finding increasing numbers of applications in diagnosis, monitoring of response to treatment and assessment of progression or recurrence. Imaging biomarkers also provide scope for assessment of heterogeneity within and between lesions. A wide variety of functional parameters have been investigated for use as biomarkers in oncology. Some imaging techniques are used routinely in clinical applications while others are currently restricted to clinical trials or preclinical studies. Apparent diffusion coefficient, magnetization transfer ratio and native T{sub 1} relaxation time provide information about structure and organization of tissues. Vascular properties may be described using parameters derived from dynamic contrast-enhanced MRI, dynamic contrast-enhanced CT, transverse relaxation rate (R{sub 2}*), vessel size index and relative blood volume, while magnetic resonance spectroscopy may be used to probe the metabolic profile of tumours. This review describes the mechanisms of contrast underpinning each technique and the technical requirements for robust and reproducible imaging. The current status of each biomarker is described in terms of its validation, qualification and clinical applications, followed by a discussion of the current limitations and future perspectives. (orig.)

  17. Perspectives on Molecular Biomarkers of Oxidative Stress and Antioxidant Strategies in Traumatic Brain Injury

    OpenAIRE

    André Mendes Arent; Luiz Felipe de Souza; Roger Walz; Alcir Luiz Dafre

    2014-01-01

    Traumatic brain injury (TBI) is frequently associated with abnormal blood-brain barrier function, resulting in the release of factors that can be used as molecular biomarkers of TBI, among them GFAP, UCH-L1, S100B, and NSE. Although many experimental studies have been conducted, clinical consolidation of these biomarkers is still needed to increase the predictive power and reduce the poor outcome of TBI. Interestingly, several of these TBI biomarkers are oxidatively modified to carbonyl group...

  18. Potential Peripheral Biomarkers for the Diagnosis of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Seema Patel

    2011-01-01

    Full Text Available Advances in the discovery of a peripheral biomarker for the diagnosis of Alzheimer's would provide a way to better detect the onset of this debilitating disease in a manner that is both noninvasive and universally available. This paper examines the current approaches that are being used to discover potential biomarker candidates available in the periphery. The search for a peripheral biomarker that could be utilized diagnostically has resulted in an extensive amount of studies that employ several biological approaches, including the assessment of tissues, genomics, proteomics, epigenetics, and metabolomics. Although a definitive biomarker has yet to be confirmed, advances in the understanding of the mechanisms of the disease and major susceptibility factors have been uncovered and reveal promising possibilities for the future discovery of a useful biomarker.

  19. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.

    Science.gov (United States)

    Redman, Christopher W G; Staff, Anne Cathrine

    2015-10-01

    The maternal syndrome of preeclampsia is mediated by dysfunctional syncytiotrophoblast (STB). When this is stressed by uteroplacental malperfusion, its signaling to the mother changes, as part of a highly coordinated stress response. The STB signals are both proinflammatory and dysangiogenic such that the preeclamptic mother has a stronger vascular inflammatory response than normal, with an antiangiogenic bias. Angiogenic factors have limitations as preeclampsia biomarkers, especially for prediction and diagnosis of preeclampsia at term. However, if they are recognized as markers of STB stress, their physiological changes at term demonstrate that STB stress develops in all pregnancies. The biomarkers reveal that the duration of pregnancies is restricted by placental capacity, such that there is increasing placental dysfunction, at and beyond term. This capacity includes limitations imposed by the size of the uterus, the capacity of the uteroplacental circulation and, possibly, the supply of villous progenitor trophoblast cells. Limited placental capacity explains the increasing risks of postmaturity, including preeclampsia. Early-onset preeclampsia is predictable because STB stress and changes in its biomarkers are intrinsic to poor placentation, an early pregnancy pathology. Prediction of preeclampsia at term is not good because there is no early STB pathology. Moreover, biomarkers cannot accurately diagnose term preeclampsia against a background of universal STB dysfunction, which may or may not be clinically revealed before spontaneous or induced delivery. In this sense, postterm pregnancy is, at best, a pseudonormal state. However, the markers may prove useful in screening for women with more severe problems of postmaturity.

  20. Significant increase in HBV, HCV, HIV and syphilis infections among blood donors in West Bengal, Eastern India 2004-2005: Exploratory screening reveals high frequency of occult HBV infection

    Institute of Scientific and Technical Information of China (English)

    Prasun Bhattacharya; Partha Kumar Chandra; Sibnarayan Datta; Arup Banerjee; Subhashish Chakraborty; Krishnan Rajendran; Subir Kumar Basu; Sujit Kumar Bhattacharya; Runu Chakravarty

    2007-01-01

    AIM: To evaluate the prevalence of markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) and human immunodeficiency virus (HIV) among blood donors in Kolkata, Eastern India for two consecutive years and to conduct a pilot study to explore the presence of HBV DNA among hepatitis B surface antigen (HBsAg) negative but anti-HBc positive blood donors.METHODS: Seroprevalence of HBsAg, anti-HCV and anti-HIV was studied among 113051 and 106695 voluntary blood donors screened in 2004 and 2005,respectively. Moreover, a pilot study on 1027 HBsAg negative donors was carried out for evaluating the presence of HBV DNA by PCR on HBsAg negative/antiHBc positive donors.RESJLTS: A statistically significant increase in the prevalence of HBV (1448 vs 1768, P < 0.001), HIV (262vs 374, P < 0.001), HCV (314 vs 372, P = 0.003) and syphilis (772 vs 853, P = 0.001) infections was noted among blood donors of Kolkata West Bengal in 2005 as compared to 2004. Moreover, the exploratory study on 1027 HBsAg negative donors revealed that 188 (18.3%) of them were anti-HBc positive out of which 21% were positive for HBV DNA.CONCLUSION: The findings of this study underscore the significantly increasing endemicity of hepatitis viruses, syphilis and HIV among the voluntary blood donors of our community. The pilot study indicates a high rate of prevalence of HBV DNA among HBsAg negative/anti-HBc positive donors and thus emphasizes the need for a more sensitive and stringent screening algorithm for blood donations.

  1. Cerebral blood volume estimation by ferumoxytol-enhanced steady-state MRI at 9.4 T reveals microvascular impact of α1 -adrenergic receptor antibodies.

    Science.gov (United States)

    Pohlmann, Andreas; Karczewski, Peter; Ku, Min-Chi; Dieringer, Babette; Waiczies, Helmar; Wisbrun, Natali; Kox, Stefanie; Palatnik, Irina; Reimann, Henning Matthias; Eichhorn, Christina; Waiczies, Sonia; Hempel, Petra; Lemke, Bernd; Niendorf, Thoralf; Bimmler, Marion

    2014-09-01

    Cerebrovascular abnormality is frequently accompanied by cognitive dysfunctions, such as dementia. Antibodies against the α1 -adrenoceptor (α1 -AR) can be found in patients with Alzheimer's disease with cerebrovascular disease, and have been shown to affect the larger vessels of the brain in rodents. However, the impact of α1 -AR antibodies on the cerebral vasculature remains unclear. In the present study, we established a neuroimaging method to measure the relative cerebral blood volume (rCBV) in small rodents with the ultimate goal to detect changes in blood vessel density and/or vessel size induced by α1 -AR antibodies. For this purpose, mapping of R2 * and R2 was performed using MRI at 9.4 T, before and after the injection of intravascular iron oxide particles (ferumoxytol). The change in the transverse relaxation rates (ΔR2 *, ΔR2 ) showed a significant rCBV decrease in the cerebrum, cortex and hippocampus of rats (except hippocampal ΔR2 ), which was more pronounced for ΔR2 * than for ΔR2 . Immunohistological analyses confirmed that the α1 -AR antibody induced blood vessel deficiencies. Our findings support the hypothesis that α1 -AR antibodies lead to cerebral vessel damage throughout the brain, which can be monitored by MRI-derived rCBV, a non-invasive neuroimaging method. This demonstrates the value of rCBV estimation by ferumoxytol-enhanced MRI at 9.4 T, and further underlines the significance of this antibody in brain diseases involving vasculature impairments, such as dementia.

  2. Biomarkers for systemic lupus erythematosus.

    Science.gov (United States)

    Ahearn, Joseph M; Liu, Chau-Ching; Kao, Amy H; Manzi, Susan

    2012-04-01

    The urgent need for lupus biomarkers was demonstrated in September 2011 during a Workshop sponsored by the Food and Drug Administration: Potential Biomarkers Predictive of Disease Flare. After 2 days of discussion and more than 2 dozen presentations from thought leaders in both industry and academia, it became apparent that highly sought biomarkers to predict lupus flare have not yet been identified. Even short of the elusive biomarker of flare, few biomarkers for systemic lupus erythematosus (SLE) diagnosis, monitoring, and stratification have been validated and employed for making clinical decisions. This lack of reliable, specific biomarkers for SLE hampers proper clinical management of patients with SLE and impedes development of new lupus therapeutics. As such, the intensity of investigation to identify lupus biomarkers is climbing a steep trajectory, lending cautious optimism that a validated panel of biomarkers for lupus diagnosis, monitoring, stratification, and prediction of flare may soon be in hand.

  3. Biomarkers in Barrett's esophagus.

    Science.gov (United States)

    Reid, Brian J; Blount, Patricia L; Rabinovitch, Peter S

    2003-04-01

    This article provides a framework for clinicians who are attempting the difficult task of interpreting the Barrett's biomarker literature with the goal of improving care for their patients. Although many articles. including more that 60 proposed biomarkers, have been published on this subject, only a few describe phase 3 and 4 studies that are of interest to the clinical gastroenterologist (Table 1). For year, dysplasia grade has been the sole means of risk stratification for patients with BE, and it likely will continue to be used in the foreseeable future. The current authors believe that dysplasia classification can be valuable using the team management approach and quality controls described previously. Significant problems, however, have emerged in phase 2 through 4 studies of dysplasia that make it imperative for the Barrett's field to incorporate additional biomarkers as they are validated. These problems include poor reproducibility of dysplasia interpretations, poor predictive value for negative, indefinite, and low-grade dysplasia, and inconsistent results for HGD in different centers, all of which makes it virtually impossible to develop national guidelines for surveillance. Some studies have even suggested that endoscopic biopsy surveillance using dysplasia may not be worthwhile. Currently, flow cytometric tetraploidy and aneuploidy have progressed furthest in biomarker validation (see Table 1). With proper handling, endoscopic biopsy specimens can be shipped to reference laboratories that have the instruments, computer analytic methods, and expertise to reproducibly detect tetraploidy and aneuploidy. The results of phase 4 studies indicate that flow cytometry appears to be useful in detecting a subset of patients who do not have HGD and yet have an increased risk of progression to cancer that cannot be identified by dysplasia grade. For many reasons, the authors anticipate that the number of validated biomarkers will increase substantially in the

  4. Genome-wide whole blood microRNAome and transcriptome analyses reveal miRNA-mRNA regulated host response to foodborne pathogen Salmonella infection in swine.

    Science.gov (United States)

    Bao, Hua; Kommadath, Arun; Liang, Guanxiang; Sun, Xu; Arantes, Adriano S; Tuggle, Christopher K; Bearson, Shawn M D; Plastow, Graham S; Stothard, Paul; Guan, Le Luo

    2015-07-31

    To understand the role of miRNAs in regulating genes involved in host response to bacterial infection and shedding of foodborne pathogens, a systematic profiling of miRNAs and mRNAs from the whole blood of pigs upon Salmonella challenge was performed. A total of 62 miRNAs were differentially expressed post infection (false discovery rate Salmonella infection. From these networks, miR-214 and miR-331-3p were identified as new candidates potentially associated with Salmonella infection. An miRNA seed sequence analysis suggested that these miRNAs regulate several critical immune-related genes including SLC11A1, PIGE-108A11.3 and VAV2. We showed that challenged pigs had reduced miR-214 expression and increased miR-331-3p expression in the whole blood. Furthermore, the expression of the proposed targets of miR-214 (SLC11A1 and PIGE-108A11.3) increased while that of the proposed target of miR-331-3p (VAV2) decreased following challenge (expression changes confirmed by in vitro assays). Based on these observations, we propose potential roles for miR-214 and miR-331-3p in regulation of immune responses to Salmonella infection.

  5. Emerging Biomarkers in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    McNamara, Mairéad G.; Sahebjam, Solmaz; Mason, Warren P., E-mail: warren.mason@uhn.ca [Pencer Brain Tumor Centre, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9 (Canada)

    2013-08-22

    Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

  6. A cross-sectional survey of cadmium biomarkers and cigarette smoking.

    Science.gov (United States)

    Hecht, Eric M; Arheart, Kris; Lee, David J; Hennekens, Charles H; Hlaing, WayWay M

    2016-07-01

    Cadmium contamination of tobacco may contribute to the health hazards of cigarette smoking. The 2005-2012 United States National Health and Nutrition Examination Survey data provided a unique opportunity to conduct a cross-sectional survey of cadmium biomarkers and cigarette smoking. Among a sample of 6761 participants, we evaluated mean differences and correlations between cadmium biomarkers in the blood and urine and characteristics of never, former and current smokers. We found statistically significant differences in mean cadmium biomarker levels between never and former smokers as well as between never and current smokers. In current smokers, duration in years had a higher correlation coefficient with urinary than blood cadmium levels. In contrast, number of cigarettes smoked per day had a higher correlation coefficient with blood than urinary cadmium levels. These data suggest that blood and urine cadmium biomarker levels differ by duration and dose. These findings should be considered in evaluating any association between cadmium and smoking related diseases, especially cardiovascular disease.

  7. Neuroimaging Biomarkers for Psychosis

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    Hager, Brandon M.

    2015-01-01

    Background Biomarkers provide clinicians with a predictable model for the diagnosis, treatment and follow-up of medical ailments. Psychiatry has lagged behind other areas of medicine in the identification of biomarkers for clinical diagnosis and treatment. In this review, we investigated the current state of neuroimaging as it pertains to biomarkers for psychosis. Methods We reviewed systematic reviews and meta-analyses of the structural (sMRI), functional (fMRI), diffusion-tensor (DTI), Positron emission tomography (PET) and spectroscopy (MRS) studies of subjects at-risk or those with an established schizophrenic illness. Only articles reporting effect-sizes and confidence intervals were included in an assessment of robustness. Results Out of the identified meta-analyses and systematic reviews, 21 studies met the inclusion criteria for assessment. There were 13 sMRI, 4 PET, 3 MRS, and 1 DTI studies. The search terms included in the current review encompassed familial high risk (FHR), clinical high risk (CHR), First episode (FES), Chronic (CSZ), schizophrenia spectrum disorders (SSD), and healthy controls (HC). Conclusions Currently, few neuroimaging biomarkers can be considered ready for diagnostic use in patients with psychosis. At least in part, this may be related to the challenges inherent in the current symptom-based approach to classifying these disorders. While available studies suggest a possible value of imaging biomarkers for monitoring disease progression, more systematic research is needed. To date, the best value of imaging data in psychoses has been to shed light on questions of disease pathophysiology, especially through the characterization of endophenotypes. PMID:25883891

  8. Serum Phenylalanine, Tyrosine, and their Ratio in Acute Ischemic Stroke: on the Trail of a Biomarker?

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    Ormstad, Heidi; Verkerk, Robert; Sandvik, Leiv

    2016-01-01

    Fast diagnosis and appropriate treatment are of utmost importance to improving the outcome in patients with acute ischemic stroke (AIS). A rapid and sensitive blood test for ischemic stroke is required. The aim of this study was to examine the usefulness of phenylalanine (PHE) and tyrosine (TYR) as diagnostic biomarkers in AIS. Serum levels of PHE and TYR, measured using HPLC, and their ratio (PHE/TYR) were compared between 45 patients with AIS and 40 healthy control subjects. The relationship between PHE/TYR and the serum levels of several cytokines were also examined. PHE/TYR was significantly higher in AIS patients than in healthy controls (1.75 vs 1.24, p < 0.001). A receiver operating characteristic (ROC) curve analysis of PHE/TYR in AIS patients relative to healthy controls revealed promising sensitivity and specificity, which at an optimal cutoff of 1.45 were 76 and 85 %, respectively. PHE/TYR was positively correlated with interleukin (IL)-1β (r = 0.37, p = 0.011) and IL-6 (r = 0.33, p = 0.025). This study shows that PHE/TYR is highly elevated in the acute phase of AIS, and that this elevation is coupled to the inflammatory response. The ROC analysis documents the possible value of PHE/TYR as a biomarker for AIS and demonstrates its clinical potential as a blood-based test for AIS.

  9. Circulating microRNA-122 as Potential Biomarker for Detection of Testosterone Abuse.

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    Olivier Salamin

    Full Text Available MicroRNAs (miRNAs are small non-coding RNAs that regulate gene expression and thus influence many cellular and physiological processes. miRNAs are also present in cell-free body fluids such as plasma or serum, and these circulating miRNAs are very stable, sensitive, and specific biomarkers of pathophysiological states. In this study, we investigated whether circulating miRNAs could serve as biomarkers of exogenous testosterone administration. Misuse of testosterone as a performance-enhancing drug is thought to be widespread in sports. Detection of testosterone through the urinary steroid profile of the Athlete Biological Passport faces several obstacles, indicating that new biomarkers are required. To this end, we analyzed plasma miRNA levels by high-throughput quantitative real-time PCR. Plasma samples were obtained before and at several time points after transdermal and oral testosterone administration. Screening identified three potential candidate miRNAs that were altered by both routes of testosterone administration. Longitudinal monitoring of these candidates revealed that variation in two of them (miR-150 and miR-342, relative to the corresponding levels in control samples, was testosterone-independent. However, levels of the liver-specific miR-122 increased 3.5-fold 1 day after drug intake. Given that testosterone is metabolized by the liver, this observation suggests that miR-122 in cell-free fluids may be used as a sensitive biomarker of testosterone misuse via multiple dosing routes and could therefore be integrated into a blood-based multiparametric follow-up.

  10. Circulating biomarkers in acute myofascial pain: A case-control study.

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    Grosman-Rimon, Liza; Parkinson, William; Upadhye, Suneel; Clarke, Hance; Katz, Joel; Flannery, John; Peng, Philip; Kumbhare, Dinesh

    2016-09-01

    The aims of the present study were to compare levels of circulating inflammatory biomarkers and growth factors between patients with myofascial pain syndrome (MPS) and healthy control participants, and to assess the relationship among inflammatory markers and growth factors in the two groups.Biomarkers levels were assessed in patients (n = 37) with myofascial pain complaints recruited from the hospital emergency department and non-MPS controls (n = 21), recruited via advertisements in the hospital and community.Blood levels of the cytokines, namely, interleukin-6 (IL-6), tumor necrosis factor (TNF), and interleukin-12 (IL-12), and the chemokine, namely, monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine (MDC), eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-8 (IL-8), and macrophage inflammatory proteins-1β (MIP-1β) were significantly higher in patients with MPS than controls. The results of the growth factor analyses revealed significantly higher levels of fibroblast growth factor-2 (FGF-2), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) in MPS patients versus controls. The pattern of correlation coefficients between cytokines and growth factors differed considerably for MPS patients and controls with far fewer significant positive coefficients observed in the controls. Serum inflammatory and growth factor biomarkers were elevated in MPS patients.Inflammatory biomarkers and growth factor levels may play an important role in the onset and maintenance of MPS and therefore may be useful in the diagnosis and treatment of MPS. Understanding the mechanisms of inflammation in MPS necessitates future research.

  11. Microarray-Based Analysis of Methylation Status of CpGs in Placental DNA and Maternal Blood DNA--Potential New Epigenetic Biomarkers for Cell Free Fetal DNA-Based Diagnosis.

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    Lotte Hatt

    Full Text Available Epigenetic markers for cell free fetal DNA in the maternal blood circulation are highly interesting in the field of non-invasive prenatal testing since such markers will offer a possibility to quantify the amount of fetal DNA derived from different chromosomes in a maternal blood sample. The aim of the present study was to define new fetal specific epigenetic markers present in placental DNA that can be utilized in non-invasive prenatal diagnosis. We have conducted a high-resolution methylation specific beadchip microarray study assessing more than 450.000 CpG sites. We have analyzed the DNA methylation profiles of 10 maternal blood samples and compared them to 12 1st trimesters chorionic samples from normal placentas, identifying a number of CpG sites that are differentially methylated in maternal blood cells compared to chorionic tissue. To strengthen the utility of these differentially methylated CpG sites to be used with methyl-sensitive restriction enzymes (MSRE in PCR-based NIPD, we furthermore refined the list of selected sites, containing a restriction sites for one of 16 different methylation-sensitive restriction enzymes. We present a list of markers on chromosomes 13, 18 and 21 with a potential for aneuploidy testing as well as a list of markers for regions harboring sub-microscopic deletion- or duplication syndromes.

  12. Repeated measurements of cerebral blood flow in the left superior temporal gyrus reveal tonic hyperactivity in patients with auditory verbal hallucinations: A possible trait marker

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    Philipp eHoman

    2013-06-01

    Full Text Available Background: The left superior temporal gyrus (STG has been suggested to play a key role in auditory verbal hallucinations in patients with schizophrenia. Methods: Eleven medicated subjects with schizophrenia and medication-resistant auditory verbal hallucinations and 19 healthy controls underwent perfusion magnetic resonance imaging with arterial spin labeling. Three additional repeated measurements were conducted in the patients. Patients underwent a treatment with transcranial magnetic stimulation (TMS between the first 2 measurements. The main outcome measure was the pooled cerebral blood flow (CBF, which consisted of the regional CBF measurement in the left superior temporal gyrus (STG and the global CBF measurement in the whole brain.Results: Regional CBF in the left STG in patients was significantly higher compared to controls (p < 0.0001 and to the global CBF in patients (p < 0.004 at baseline. Regional CBF in the left STG remained significantly increased compared to the global CBF in patients across time (p < 0.0007, and it remained increased in patients after TMS compared to the baseline CBF in controls (p < 0.0001. After TMS, PANSS (p = 0.003 and PSYRATS (p = 0.01 scores decreased significantly in patients.Conclusions: This study demonstrated tonically increased regional CBF in the left STG in patients with schizophrenia and auditory hallucinations despite a decrease in symptoms after TMS. These findings were consistent with what has previously been termed a trait marker of auditory verbal hallucinations in schizophrenia.

  13. Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.

    Science.gov (United States)

    Franceschini, Nora; Fox, Ervin; Zhang, Zhaogong; Edwards, Todd L; Nalls, Michael A; Sung, Yun Ju; Tayo, Bamidele O; Sun, Yan V; Gottesman, Omri; Adeyemo, Adebawole; Johnson, Andrew D; Young, J Hunter; Rice, Ken; Duan, Qing; Chen, Fang; Li, Yun; Tang, Hua; Fornage, Myriam; Keene, Keith L; Andrews, Jeanette S; Smith, Jennifer A; Faul, Jessica D; Guangfa, Zhang; Guo, Wei; Liu, Yu; Murray, Sarah S; Musani, Solomon K; Srinivasan, Sathanur; Velez Edwards, Digna R; Wang, Heming; Becker, Lewis C; Bovet, Pascal; Bochud, Murielle; Broeckel, Ulrich; Burnier, Michel; Carty, Cara; Chasman, Daniel I; Ehret, Georg; Chen, Wei-Min; Chen, Guanjie; Chen, Wei; Ding, Jingzhong; Dreisbach, Albert W; Evans, Michele K; Guo, Xiuqing; Garcia, Melissa E; Jensen, Rich; Keller, Margaux F; Lettre, Guillaume; Lotay, Vaneet; Martin, Lisa W; Moore, Jason H; Morrison, Alanna C; Mosley, Thomas H; Ogunniyi, Adesola; Palmas, Walter; Papanicolaou, George; Penman, Alan; Polak, Joseph F; Ridker, Paul M; Salako, Babatunde; Singleton, Andrew B; Shriner, Daniel; Taylor, Kent D; Vasan, Ramachandran; Wiggins, Kerri; Williams, Scott M; Yanek, Lisa R; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Berenson, Gerald; Boerwinkle, Eric; Bottinger, Erwin; Cushman, Mary; Eaton, Charles; Nyberg, Fredrik; Heiss, Gerardo; Hirschhron, Joel N; Howard, Virginia J; Karczewsk, Konrad J; Lanktree, Matthew B; Liu, Kiang; Liu, Yongmei; Loos, Ruth; Margolis, Karen; Snyder, Michael; Psaty, Bruce M; Schork, Nicholas J; Weir, David R; Rotimi, Charles N; Sale, Michele M; Harris, Tamara; Kardia, Sharon L R; Hunt, Steven C; Arnett, Donna; Redline, Susan; Cooper, Richard S; Risch, Neil J; Rao, D C; Rotter, Jerome I; Chakravarti, Aravinda; Reiner, Alex P; Levy, Daniel; Keating, Brendan J; Zhu, Xiaofeng

    2013-09-01

    High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA (n = 10,386), European ancestry (EA) (n = 69,395), and East Asian ancestry (n = 19,601). Five loci (EVX1-HOXA, ULK4, RSPO3, PLEKHG1, and SOX6) reached genome-wide significance (p < 1.0 × 10(-8)) for either systolic or diastolic BP in a transethnic meta-analysis after correction for multiple testing. Three of these BP loci (EVX1-HOXA, RSPO3, and PLEKHG1) lack previous associations with BP. We also identified one independent signal in a known BP locus (SOX6) and provide evidence for fine mapping in four additional validated BP loci. We also demonstrate that validated EA BP GWAS loci, considered jointly, show significant effects in AA samples. Consequently, these findings suggest that BP loci might have universal effects across studied populations, demonstrating that multiethnic samples are an essential component in identifying, fine mapping, and understanding their trait variability.

  14. Cardiac Biomarkers and Cycling Race

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    Caroline Le Goff, Jean-François Kaux, Sébastien Goffaux, Etienne Cavalier

    2015-06-01

    Full Text Available In cycling as in other types of strenuous exercise, there exists a risk of sudden death. It is important both to understand its causes and to see if the behavior of certain biomarkers might highlight athletes at risk. Many reports describe changes in biomarkers after strenuous exercise (Nie et al., 2011, but interpreting these changes, and notably distinguishing normal physiological responses from pathological changes, is not easy. Here we have focused on the kinetics of different cardiac biomarkers: creatin kinase (CK, creating kinase midbrain (CK-MB, myoglobin (MYO, highly sensitive troponin T (hs-TnT and N-terminal brain natriuretic peptide (NT-proBNP. The population studied was a group of young trained cyclists participating in a 177-km cycling race. The group of individuals was selected for maximal homogeneity. Their annual training volume was between 10,000 and 16,000 kilometers. The rhythm of races is comparable and averages 35 km/h, depending on the race’s difficulty. The cardiac frequency was recorded via a heart rate monitor. Three blood tests were taken. The first blood test, T0, was taken approximately 2 hours before the start of the race and was intended to gather values which would act as references for the following tests. The second blood test, T1, was realized within 5 minutes of their arrival. The third and final blood test, T3, was taken 3 hours following their arrival. The CK, CK-MB, MYO, hs-TnT and NT-proBNP were measured on the Roche Diagnostic modular E (Manhein, Germany. For the statistical analysis, an ANOVA and post hoc test of Scheffé were calculated with the Statistica Software version 9.1. We noticed an important significant variation in the cardiac frequency between T0 and T1 (p < 0.0001, T0 and T3 (p < 0.0001, and T1 and T3 (p < 0.01. Table 1 shows the results obtained for the different biomarkers. CK and CK-MB showed significant variation between T0-T1 and T0-T3 (p < 0.0001. Myoglobin increased significantly

  15. Oxidative stress biomarker responses to an acute session of hypertrophy-resistance traditional interval training and circuit training.

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    Deminice, Rafael; Sicchieri, Tiago; Mialich, Mirele S; Milani, Francine; Ovidio, Paula P; Jordao, Alceu A

    2011-03-01

    We have studied circuit resistance schemes with high loads as a time-effective alternative to hypertrophy-traditional resistance training. However, the oxidative stress biomarker responses to high-load circuit training are unknown. The aim of the present study was to compare oxidative stress biomarker response with an acute session of hypertrophy-resistance circuit training and traditional interval training. A week after the 1 repetition maximum (1RM) test, 11 healthy and well-trained male participants completed hypertrophy-resistance acute sessions of traditional interval training (3 × 10 repetitions at 75% of the 1RM, with 90-second passive rest) and circuit training (3 × 10 repetitions at 75% of the 1RM, in alternating performance of 2 exercises with different muscle groups) in a randomized and cross-over design. Venous blood samples were collected before (pre) and 10 minutes after (post) the resistance training sessions for oxidative stress biomarker assays. As expected, the time used to complete the circuit training (20.2 ± 1.6) was half of that needed to complete the traditional interval training (40.3 ± 1.8). Significant increases (p < 0.05) in thiobarbituric acid reactive substances (40%), creatine kinase (CK) (67%), glutathione (14%), and uric acid (25%) were detected posttraditional interval training session in relation to pre. In relation to circuit training, a significant increase in CK (33%) activity postsession in relation to pre was observed. Statistical analysis did not reveal any other change in the oxidative stress biomarker after circuit training. In conclusion, circuit resistance-hypertrophy training scheme proposed in the current study promoted lower oxidative stress biomarkers and antioxidant modulations compared with resistance traditional interval training.

  16. Biomarker discovery in heterogeneous tissue samples -taking the in-silico deconfounding approach

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    Parida Shreemanta K

    2010-01-01

    Full Text Available Abstract Background For heterogeneous tissues, such as blood, measurements of gene expression are confounded by relative proportions of cell types involved. Conclusions have to rely on estimation of gene expression signals for homogeneous cell populations, e.g. by applying micro-dissection, fluorescence activated cell sorting, or in-silico deconfounding. We studied feasibility and validity of a non-negative matrix decomposition algorithm using experimental gene expression data for blood and sorted cells from the same donor samples. Our objective was to optimize the algorithm regarding detection of differentially expressed genes and to enable its use for classification in the difficult scenario of reversely regulated genes. This would be of importance for the identification of candidate biomarkers in heterogeneous tissues. Results Experimental data and simulation studies involving noise parameters estimated from these data revealed that for valid detection of differential gene expression, quantile normalization and use of non-log data are optimal. We demonstrate the feasibility of predicting proportions of constituting cell types from gene expression data of single samples, as a prerequisite for a deconfounding-based classification approach. Classification cross-validation errors with and without using deconfounding results are reported as well as sample-size dependencies. Implementation of the algorithm, simulation and analysis scripts are available. Conclusions The deconfounding algorithm without decorrelation using quantile normalization on non-log data is proposed for biomarkers that are difficult to detect, and for cases where confounding by varying proportions of cell types is the suspected reason. In this case, a deconfounding ranking approach can be used as a powerful alternative to, or complement of, other statistical learning approaches to define candidate biomarkers for molecular diagnosis and prediction in biomedicine, in

  17. A transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis.

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    Carlos Riveros

    Full Text Available BACKGROUND: Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS and 45 age-matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed in cases and controls (e.g., V$KROX_Q6, p-value <3.31E-6; V$CREBP1_Q2, p-value <9.93E-6, V$YY1_02, p-value <1.65E-5. CONCLUSIONS/SIGNIFICANCE: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1, E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation.

  18. Biomarkers of Guillain-Barré Syndrome: Some Recent Progress, More Still to Be Explored

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    Ying Wang

    2015-01-01

    Full Text Available Guillain-Barré syndrome (GBS, the axonal subtype of which is mainly triggered by C. jejuni with ganglioside-mimicking lipooligosaccharides (LOS, is an immune-mediated disorder in the peripheral nervous system (PNS accompanied by the disruption of the blood-nerve barrier (BNB and the blood-cerebrospinal fluid barrier (B-CSF-B. Biomarkers of GBS have been extensively explored and some of them are proved to assist in the clinical diagnosis and in monitoring disease progression as well as in assessing the efficacy of immunotherapy. Herein, we systemically review the literature on biomarkers of GBS, including infection-/immune-/BNB, B-CSF-B, and PNS damage-associated biomarkers, aiming at providing an overview of GBS biomarkers and guiding further investigations. Furthermore, we point out further directions for studies on GBS biomarkers.

  19. Biomarkers of Selenium Status

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    Gerald F. Combs, Jr.

    2015-03-01

    Full Text Available The essential trace element, selenium (Se, has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites.

  20. IDBD: infectious disease biomarker database.

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    Yang, In Seok; Ryu, Chunsun; Cho, Ki Joon; Kim, Jin Kwang; Ong, Swee Hoe; Mitchell, Wayne P; Kim, Bong Su; Oh, Hee-Bok; Kim, Kyung Hyun

    2008-01-01

    Biomarkers enable early diagnosis, guide molecularly targeted therapy and monitor the activity and therapeutic responses across a variety of diseases. Despite intensified interest and research, however, the overall rate of development of novel biomarkers has been falling. Moreover, no solution is yet available that efficiently retrieves and processes biomarker information pertaining to infectious diseases. Infectious Disease Biomarker Database (IDBD) is one of the first efforts to build an easily accessible and comprehensive literature-derived database covering known infectious disease biomarkers. IDBD is a community annotation database, utilizing collaborative Web 2.0 features, providing a convenient user interface to input and revise data online. It allows users to link infectious diseases or pathogens to protein, gene or carbohydrate biomarkers through the use of search tools. It supports various types of data searches and application tools to analyze sequence and structure features of potential and validated biomarkers. Currently, IDBD integrates 611 biomarkers for 66 infectious diseases and 70 pathogens. It is publicly accessible at http://biomarker.cdc.go.kr and http://biomarker.korea.ac.kr.

  1. Scrutinizing the Biomarkers for the Neglected Chagas Disease: How Remarkable!

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    Pinho, Rosa T.; Waghabi, Mariana C.; Cardillo, Fabíola; Mengel, José; Antas, Paulo R. Z.

    2016-01-01

    Biomarkers or biosignature profiles have become accessible over time in population-based studies for Chagas disease. Thus, the identification of consistent and reliable indicators of the diagnosis and prognosis of patients with heart failure might facilitate the prioritization of therapeutic management to those with the highest chance of contracting this disease. The purpose of this paper is to review the recent state and the upcoming trends in biomarkers for human Chagas disease. As an emerging concept, we propose a classification of biomarkers based on plasmatic-, phenotype-, antigenic-, genetic-, and management-related candidates. The available data revisited here reveal the lessons learned thus far and the existing challenges that still lie ahead to enable biomarkers to be employed consistently in risk evaluation for this disease. There is a strong need for biomarker validation, particularly for biomarkers that are specific to the clinical forms of Chagas disease. The current failure to achieve the eradication of the transmission of this disease has produced determination to solve this validation issue. Finally, it would be strategic to develop a wide variety of biomarkers and to test them in both preclinical and clinical trials. PMID:27563302

  2. Multi-modal analysis of functional connectivity and cerebral blood flow reveals shared and unique effects of propofol in large-scale brain networks.

    Science.gov (United States)

    Qiu, Maolin; Scheinost, Dustin; Ramani, Ramachandran; Constable, R Todd

    2017-03-01

    Anesthesia-induced changes in functional connectivity and cerebral blow flow (CBF) in large-scale brain networks have emerged as key markers of reduced consciousness. However, studies of functional connectivity disagree on which large-scale networks are altered or preserved during anesthesia, making it difficult to find a consensus amount studies. Additionally, pharmacological alterations in CBF could amplify or occlude changes in connectivity due to the shared variance between CBF and connectivity. Here, we used data-driven connectivity methods and multi-modal imaging to investigate shared and unique neural correlates of reduced consciousness for connectivity in large-scale brain networks. Rs-fMRI and CBF data were collected from the same subjects during an awake and deep sedation condition induced by propofol. We measured whole-brain connectivity using the intrinsic connectivity distribution (ICD), a method not reliant on pre-defined seed regions, networks of interest, or connectivity thresholds. The shared and unique variance between connectivity and CBF were investigated. Finally, to account for shared variance, we present a novel extension to ICD that incorporates cerebral blood flow (CBF) as a scaling factor in the calculation of global connectivity, labeled CBF-adjusted ICD). We observed altered connectivity in multiple large-scale brain networks including the default mode (DMN), salience, visual, and motor networks and reduced CBF in the DMN, frontoparietal network, and thalamus. Regional connectivity and CBF were significantly correlated during both the awake and propofol condition. Nevertheless changes in connectivity and CBF between the awake and deep sedation condition were only significantly correlated in a subsystem of the DMN, suggesting that, while there is significant shared variance between the modalities, changes due to propofol are relatively unique. Similar, but less significant, results were observed in the CBF-adjusted ICD analysis, providing

  3. Earth Mover's Distance (EMD: A True Metric for Comparing Biomarker Expression Levels in Cell Populations.

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    Darya Y Orlova

    Full Text Available Changes in the frequencies of cell subsets that (coexpress characteristic biomarkers, or levels of the biomarkers on the subsets, are widely used as indices of drug response, disease prognosis, stem cell reconstitution, etc. However, although the currently available computational "gating" tools accurately reveal subset frequencies and marker expression levels, they fail to enable statistically reliable judgements as to whether these frequencies and expression levels differ significantly between/among subject groups. Here we introduce flow cytometry data analysis pipeline which includes the Earth Mover's Distance (EMD metric as solution to this problem. Well known as an informative quantitative measure of differences between distributions, we present three exemplary studies showing that EMD 1 reveals clinically-relevant shifts in two markers on blood basophils responding to an offending allergen; 2 shows that ablative tumor radiation induces significant changes in the murine colon cancer tumor microenvironment; and, 3 ranks immunological differences in mouse peritoneal cavity cells harvested from three genetically distinct mouse strains.

  4. Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice.

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    Emil Schüler

    Full Text Available The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity.C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys. At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a global transcriptional variations in kidney tissues, (b morphological changes in the kidneys, (c changes in white and red blood cell count as well as blood levels of urea, and (d changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy.In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months.Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm applicability of these

  5. PP13, maternal ABO blood groups and the risk assessment of pregnancy complications.

    Directory of Open Access Journals (Sweden)

    Nandor Gabor Than

    Full Text Available BACKGROUND: Placental Protein 13 (PP13, an early biomarker of preeclampsia, is a placenta-specific galectin that binds beta-galactosides, building-blocks of ABO blood-group antigens, possibly affecting its bioavailability in blood. METHODS AND FINDINGS: We studied PP13-binding to erythrocytes, maternal blood-group effect on serum PP13 and its performance as a predictor of preeclampsia and intrauterine growth restriction (IUGR. Datasets of maternal serum PP13 in Caucasian (n = 1078 and Hispanic (n = 242 women were analyzed according to blood groups. In vivo, in vitro and in silico PP13-binding to ABO blood-group antigens and erythrocytes were studied by PP13-immunostainings of placental tissue-microarrays, flow-cytometry of erythrocyte-bound PP13, and model-building of PP13--blood-group H antigen complex, respectively. Women with blood group AB had the lowest serum PP13 in the first trimester, while those with blood group B had the highest PP13 throughout pregnancy. In accordance, PP13-binding was the strongest to blood-group AB erythrocytes and weakest to blood-group B erythrocytes. PP13-staining of maternal and fetal erythrocytes was revealed, and a plausible molecular model of PP13 complexed with blood-group H antigen was built. Adjustment of PP13 MoMs to maternal ABO blood group improved the prediction accuracy of first trimester maternal serum PP13 MoMs for preeclampsia and IUGR. CONCLUSIONS: ABO blood group can alter PP13-bioavailability in blood, and it may also be a key determinant for other lectins' bioavailability in the circulation. The adjustment of PP13 MoMs to ABO blood group improves the predictive accuracy of this test.

  6. Chiral Biomarkers and Microfossils in Carbonaceous Meteorites

    Science.gov (United States)

    Hoover, Richard B.

    2010-01-01

    Homochirality of the biomolecules (D-sugars of DNA and RNA and L-amino acids of proteins) is a fundamental property of all life on Earth. Abiotic mechanisms yield racemic mixtures (D/L=1) of chiral molecules and after the death of an organism, the enantiopure chiral biomolecules slowly racemize. Several independent investigators have now established that the amino acids present in CI1 and CM2 carbonaceous meteorites have a moderate to strong excess of the L-enantiomer. Stable isotope data have established that these amino acids are both indigenous and extraterrestrial. Carbonaceous meteorites also contain many other strong chemical biomarkers including purines and pyrimidines (nitrogen heterocycles of nucleic acids); pristine and phytane (components of the chlorophyll pigment) and morphological biomarkers (microfossils of filamentous cyanobacteria). Energy dispersive X-ray Spectroscopy (EDS) analysis reveals that nitrogen is below the detectability level in most of the meteorite filaments as well as in Cambrian Trilobites and filaments of 2.7 Gya Archaean cyanobacteria from Karelia. The deficiency of nitrogen in the filaments and the total absence of sugars, of twelve of the life-critical protein amino acids, and two of the nucleobases of DNA and RNA provide clear and convincing evidence that these filaments are not modern biological contaminants. This paper reviews the chiral, chemical biomarkers morphological biomarkers and microfossils in carbonaceous meteorites. This paper reviews chiral and morphological biomarkers and discusses the missing nitrogen, sugars, protein amino acids, and nucleobases as ?bio-discriminators? that exclude modern biological contaminants as a possible explanation for the permineralized cyanobacterial filaments found in the meteorites.

  7. Biological features and biomarkers in hepatocellularcarcinoma

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Similar to other cancers, a multistep process of carcinogenesisis observed in hepatocellular carcinoma (HCC).Although the mechanisms underlying the developmentof HCC have been investigated in terms of oncology,virology, and stem cell biology, the whole picture ofhepatocarcinogenesis remains to be elucidated. Recentprogress in molecular biology has provided clues tothe underlying cause of various diseases. In particular,sequencing technologies, such as whole genome andexome sequencing analyses, have made an impacton genomic research on a variety of cancers includingHCC. Comprehensive genomic analyses have detectednumerous abnormal genetic alterations, such asmutations and copy number alterations. Based on thesefindings, signaling pathways and cancer-related genesinvolved in hepatocarcinogenesis could be analyzed indetail. Simultaneously, a number of novel biomarkers,both from tissue and blood samples, have been recentlyreported. These biomarkers have been successfullyapplied to early diagnosis and prognostic prediction ofpatients with HCC. In this review, we focus on the recentdevelopments in molecular cancer research on HCC andexplain the biological features and novel biomarkers.

  8. Parkinson's disease biomarkers program brain imaging repository.

    Science.gov (United States)

    Ofori, Edward; Du, Guangwei; Babcock, Debra; Huang, Xuemei; Vaillancourt, David E

    2016-01-01

    The Parkinson's Disease Biomarkers Program (PDBP) is a multi-site study designed to identify Parkinson's disease (PD) biomarkers that can be used to improve the understanding of PD pathophysiology and to develop tools that provide novel measures to evaluate PD clinical trials. The PDBP consortium comprises numerous individual projects of which two are specifically geared to the development of brain imaging markers for diagnosis, progression, and prognosis of PD or related disorders. All study data from PD patients, atypical Parkinsonian patients, patients with essential tremor, and healthy controls collected from the sites are integrated in the PDBP database and will be publically available. All subjects are asked to submit blood samples, and undergo a battery of clinical evaluations that cover motor, cognitive, and other background information. In addition, a subset of subjects contributed cerebrospinal fluid samples. A restricted access, web-based Data Management Resource facilitates rapid sharing of data and biosamples across the entire PD research community. The PDBP consortium is a useful resource for research and collaboration aimed at the discovery of biomarkers and their use in understanding the pathophysiology of PD.

  9. Biomarkers in major depressive disorder: the role of mass spectrometry.

    Science.gov (United States)

    Woods, Alisa G; Iosifescu, Dan V; Darie, Costel C

    2014-01-01

    Major depressive disorder (MDD) is common. Despite numerous available treatments, many individuals fail to improve clinically. MDD continues to be diagnosed exclusively via behavioral rather than biological methods. Biomarkers-which include measurements of genes, proteins, and patterns of brain activity-may provide an important objective tool for the diagnosis of MDD or in the rational selection of treatments. Proteomic analysis and validation of its results as biomarkers is less explored than other areas of biomarker research in MDD. Mass spectrometry (MS) is a comprehensive, unbiased means of proteomic analysis, which can be complemented by directed protein measurements, such as Western Blotting. Prior studies have focused on MS analysis of several human biomaterials in MDD, including human post-mortem brain, cerebrospinal fluid (CSF), blood components, and urine. Further studies utilizing MS and proteomic analysis in MDD may help solidify and establish biomarkers for use in diagnosis, identification of new treatment targets, and understanding of the disorder. The ultimate goal is the validation of a biomarker or a biomarker signature that facilitates a convenient and inexpensive predictive test for depression treatment response and helps clinicians in the rational selection of next-step treatments.

  10. Immune biomarkers in irritable bowel syndrome: a review

    Directory of Open Access Journals (Sweden)

    Gras-Miralles B

    2013-06-01

    Full Text Available Beatriz Gras-Miralles, Efi KokkotouGastroenterology Department, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USAAbstract: Irritable bowel syndrome (IBS is a chronic functional gastrointestinal disorder that affects about 9%–13% of the general population. IBS is one of the main reasons to consult a primary care physician, and nearly 30% of visits to a gastroenterologist are for IBS. The diagnosis of IBS relies on subjective, patient-reported symptoms, thus making urgent the need for IBS-specific biomarkers. The same biomarkers, or perhaps different ones, can also be used to monitor disease evolution and response to treatment. A significant number of studies have looked in the immune system for establishing IBS biomarkers, based on the concept that IBS might represent a condition of immune dysregulation somewhere in the spectrum between health and inflammatory bowel disease. Such biomarkers can be detected in blood, intestinal biopsies, or luminal contents. Overall, results are rarely consistent between studies; small sample size, patient and disease heterogeneity, presence of comorbidities, and variation in sampling might contribute to these discrepancies. So far, studies have failed to provide a diagnostic immune biomarker for IBS, but they have considerably advanced our understanding of the disease pathophysiology, including the role of the individual's genetic make-up, and of the host–microbial interactions. High throughput analysis of a large number of well characterized patients holds promise for developing appropriate biomarkers for IBS.Keywords: neuroimmune interactions, mast cells, genetic polymorphisms, cytokines, toll-like receptors

  11. Early diagnosis of complex diseases by molecular biomarkers, network biomarkers, and dynamical network biomarkers.

    Science.gov (United States)

    Liu, Rui; Wang, Xiangdong; Aihara, Kazuyuki; Chen, Luonan

    2014-05-01

    Many studies have been carried out for early diagnosis of complex diseases by finding accurate and robust biomarkers specific to respective diseases. In particular, recent rapid advance of high-throughput technologies provides unprecedented rich information to characterize various disease genotypes and phenotypes in a global and also dynamical manner, which significantly accelerates the study of biomarkers from both theoretical and clinical perspectives. Traditionally, molecular biomarkers that distinguish disease samples from normal samples are widely adopted in clinical practices due to their ease of data measurement. However, many of them suffer from low coverage and high false-positive rates or high false-negative rates, which seriously limit their further clinical applications. To overcome those difficulties, network biomarkers (or module biomarkers) attract much attention and also achieve better performance because a network (or subnetwork) is considered to be a more robust form to characterize diseases than individual molecules. But, both molecular biomarkers and network biomarkers mainly distinguish disease samples from normal samples, and they generally cannot ensure to identify predisease samples due to their static nature, thereby lacking ability to early diagnosis. Based on nonlinear dynamical theory and complex network theory, a new concept of dynamical network biomarkers (DNBs, or a dynamical network of biomarkers) has been developed, which is different from traditional static approaches, and the DNB is able to distinguish a predisease state from normal and disease states by even a small number of samples, and therefore has great potential to achieve "real" early diagnosis of complex diseases. In this paper, we comprehensively review the recent advances and developments on molecular biomarkers, network biomarkers, and DNBs in particular, focusing on the biomarkers for early diagnosis of complex diseases considering a small number of samples and high

  12. Optoelectronic investigation of nanodiamond interactions with human blood

    Science.gov (United States)

    Ficek, M.; Wróbel, M. S.; Wasowicz, M.; Jedrzejewska-Szczerska, M.

    2016-03-01

    We present optoelectronic investigation of in vitro interactions of whole human blood with different nanodiamond biomarkers. Plasmo-chemical modifications of detonation nanodiamond particles gives the possibility for controlling their surface for biological applications. Optical investigations reveal the biological activity of nanodiamonds in blood dependent on its surface termination. We compare different types of nanodiamonds: commercial non-modified detonation nanodiamonds, and nanodiamonds modified by MW PACVD method with H2-termination, and chemically modified nanodiamond with O2-termination. The absorption spectra, and optical microscope investigations were conducted. The results indicate haemocompatibility of non-modified detonation nanodiamond as well as modified nanodiamonds, which enables their application for drug delivery, as well as sensing applications.

  13. The diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in Urinary Tract Infection (UTI) in camels.

    Science.gov (United States)

    El-Deeb, Wael M; Buczinski, Sébastien

    2015-01-01

    The present study aimed to investigate the diagnostic and prognostic importance of oxidative stress biomarkers and acute phase proteins in urinary tract infection (UTI) in camels. We describe the clinical, bacteriological and biochemical findings in 89 camels. Blood and urine samples from diseased (n = 74) and control camels (n = 15) were submitted to laboratory investigations. The urine analysis revealed high number of RBCS and pus cells. The concentrations of serum and erythrocytic malondialdehyde (sMDA & eMDA), Haptoglobin (Hp), serum amyloid A (SAA), Ceruloplasmin (Cp), fibrinogen (Fb), albumin, globulin and interleukin 6 (IL-6) were higher in diseased camels when compared to healthy ones. Catalase, super oxide dismutase and glutathione levels were lower in diseased camels when compared with control group. Forty one of 74 camels with UTI were successfully treated. The levels of malondialdehyde, catalase, super oxide dismutase, glutathione, Hp, SAA, Fb, total protein, globulin and IL-6 were associated with the odds of treatment failure. The MDA showed a great sensitivity (Se) and specificity (Sp) in predicting treatment failure (Se 85%/Sp 100%) as well as the SAA (Se 92%/Sp 87%) and globulin levels (Se 85%/Sp 100%) when using the cutoffs that maximizes the sum of Se + Sp. Multivariate logistic regression analysis revealed that two models had a high accuracy to predict failure with the first model including sex, sMDA and Hp as covariates (area under the receiver operating characteristic curve (AUC) = 0.92) and a second model using sex, SAA and Hp (AUC = 0.89). Conclusively, the oxidative stress biomarkers and acute phase proteins could be used as diagnostic and prognostic biomarkers in camel UTI management. Efforts should be forced to investigate such biomarkers in other species with UTI.

  14. A large cohort study reveals the association of elevated peripheral blood lymphocyte-to-monocyte ratio with favorable prognosis in nasopharyngeal carcinoma.

    Directory of Open Access Journals (Sweden)

    Jing Li

    Full Text Available BACKGROUND: Nasopharyngeal carcinoma (NPC is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20-30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients. METHODS: A retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS, disease-free survival (DFS, distant metastasis-free survival (DMFS and loco-regional recurrence-free survival (LRRFS, respectively. RESULTS: Univariate analysis revealed that higher LMR level (≥ 5.220 was significantly associated with superior OS, DFS and DMFS (P values <0.001. The higher lymphocyte count (≥ 2.145 × 10(9/L was significantly associated with better OS (P = 0.002 and DMFS (P = 0.031, respectively, while the lower monocyte count (<0.475 × 10(9/L was associated with better OS (P = 0.012, DFS (P = 0.011 and DMFS (P = 0.003, respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR = 0.558, 95% confidence interval or 95% CI = 0.417-0.748; P<0.001, DFS (HR = 0.669, 95% CI = 0.535-0.838; P<0.001 and DMFS (HR = 0.543, 95% CI = 0.403-0.732; P<0.001, respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053 and DMFS (P = 0.080. CONCLUSIONS: The

  15. Stochastic sensors designed for assessment of biomarkers specific to obesity.

    Science.gov (United States)

    Cioates Negut, Catalina; Stefan-van Staden, Raluca-Ioana; Ungureanu, Eleonora-Mihaela; Udeanu, Denisa Ioana

    2016-09-01

    Two stochastic sensors based on the following oleamides: 1-adamantyloleamide and N,N-dimethyl-N-(2-oleylamidoethyl)amine physically immobilized on graphite paste were designed. The sensors were able to determine simultaneously from the whole blood of Wistar rats three biomarkers specific to obesity: leptin, interleukin-6 (IL-6) and plasminogen activator inhibitor 1 (PAI-1). The whole blood samples were obtained from Wistar rats treated with oleoylethanolamide (OEA), (Z)-N-[(1S)-2-hidroxy-1-(phenylmethyl) ethyl]-9octadecenamide (OLA), and with the aqueous solution of 1% Tween 80 used as solvent for oleamides formulations (control samples). The proposed sensors were very sensitive and reliable for the assay of obesity biomarkers in whole blood of rats.

  16. Multiple biomarkers responses in Prochilodus lineatus allowed assessing changes in the water quality of Salado River basin (Santa Fe, Argentina)

    Energy Technology Data Exchange (ETDEWEB)

    Cazenave, Jimena, E-mail: jcazenave@inali.unl.edu.a [Laboratorio de Ictiologia, Instituto Nacional de Limnologia (INALI-CONICET-UNL), Paraje El Pozo, Ciudad Universitaria UNL, 3000 Santa Fe (Argentina); Bacchetta, Carla; Parma, Maria J.; Scarabotti, Pablo A. [Laboratorio de Ictiologia, Instituto Nacional de Limnologia (INALI-CONICET-UNL), Paraje El Pozo, Ciudad Universitaria UNL, 3000 Santa Fe (Argentina); Wunderlin, Daniel A. [Dto. Bioquimica Clinica-CIBICI-CONICET, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Haya de la Torre esq Medina Allende, Ciudad Universitaria, 5000 Cordoba (Argentina)

    2009-11-15

    This field study assessed water quality of Salado River basin by using a set of biomarkers in the fish Prochilodus lineatus. Multiple biomarkers were measured, including morphological indexes (condition factor, liver somatic index), hematological (red and white blood cells) and biochemical (glucose, total protein and cholinesterase activity) parameters. Besides, detoxication and oxidative stress markers (antioxidant enzymes, lipid peroxidation) were measured in liver, gills and kidney. Despite water quality assessment did not show marked differences among sites, biomarkers responses indicate that fish are living under stressful environmental conditions. According to multivariate analysis glucose, glutathione S-transferase activity, lipid peroxidation levels and the count of white blood cells are key biomarkers to contribute to discrimination of sites. So, we suggest use those biomarkers in future monitoring of freshwater aquatic systems. - A battery of biomarkers was successfully applied to assess the health of the fish Prochilodus lineatus from Salado River basin.

  17. Biomarker Identification Using Text Mining

    Directory of Open Access Journals (Sweden)

    Hui Li

    2012-01-01

    Full Text Available Identifying molecular biomarkers has become one of the important tasks for scientists to assess the different phenotypic states of cells or organisms correlated to the genotypes of diseases from large-scale biological data. In this paper, we proposed a text-mining-based method to discover biomarkers from PubMed. First, we construct a database based on a dictionary, and then we used a finite state machine to identify the biomarkers. Our method of text mining provides a highly reliable approach to discover the biomarkers in the PubMed database.

  18. Biomarkers in Prostate Cancer Epidemiology

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    Mudit Verma

    2011-09-01

    Full Text Available Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high risk for developing prostate cancer. In cancer epidemiology, epigenetic biomarkers offer advantages over other types of biomarkers because they are expressed against a person’s genetic background and environmental exposure, and because abnormal events occur early in cancer development, which includes several epigenetic alterations in cancer cells. This article describes different biomarkers that have potential use in studying the epidemiology of prostate cancer. We also discuss the characteristics of an ideal biomarker for prostate cancer, and technologies utilized for biomarker assays. Among epigenetic biomarkers, most reports indicate GSTP1 hypermethylation as the diagnostic marker for prostate cancer; however, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS, and NSE1 also have been reported to be regulated by methylation mechanisms in prostate cancer. Current challenges in utilization of biomarkers in prostate cancer diagnosis and epidemiologic studies and potential solutions also are discussed.

  19. Inflammatory Biomarkers as Differential Predictors of Antidepressant Response

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    Kenji Hashimoto

    2015-04-01

    Full Text Available Although antidepressants are generally effective in the treatment of major depressive disorder (MDD, it can still take weeks before patients feel the full antidepressant effects. Despite the efficacy of standard treatments, approximately two-thirds of patients with MDD fail to respond to pharmacotherapy. Therefore, the identification of blood biomarkers that can predict the treatment response to antidepressants would be highly useful in order to improve this situation. This article discusses inflammatory molecules as predictive biomarkers for antidepressant responses to several classes of antidepressants, including the N-methyl-d-aspartate (NMDA receptor antagonist ketamine.

  20. Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson's disease.

    Science.gov (United States)

    Santiago, Jose A; Potashkin, Judith A

    2015-02-17

    Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Network-based metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were up- and down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y follow-up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.

  1. Towards Improved Biomarker Research

    DEFF Research Database (Denmark)

    Kjeldahl, Karin

    This thesis takes a look at the data analytical challenges associated with the search for biomarkers in large-scale biological data such as transcriptomics, proteomics and metabolomics data. These studies aim to identify genes, proteins or metabolites which can be associated with e.g. a diet, dis...... is used both for regression and classification purposes. This method has proven its strong worth in the multivariate data analysis throughout an enormous range of applications; a very classic data type is near infrared (NIR) data, but many similar data types have also be very successful...

  2. Quantitative imaging as cancer biomarker

    Science.gov (United States)

    Mankoff, David A.

    2015-03-01

    The ability to assay tumor biologic features and the impact of drugs on tumor biology is fundamental to drug development. Advances in our ability to measure genomics, gene expression, protein expression, and cellular biology have led to a host of new targets for anticancer drug therapy. In translating new drugs into clinical trials and clinical practice, these same assays serve to identify patients most likely to benefit from specific anticancer treatments. As cancer therapy becomes more individualized and targeted, there is an increasing need to characterize tumors and identify therapeutic targets to select therapy most likely to be successful in treating the individual patient's cancer. Thus far assays to identify cancer therapeutic targets or anticancer drug pharmacodynamics have been based upon in vitro assay of tissue or blood samples. Advances in molecular imaging, particularly PET, have led to the ability to perform quantitative non-invasive molecular assays. Imaging has traditionally relied on structural and anatomic features to detect cancer and determine its extent. More recently, imaging has expanded to include the ability to image regional biochemistry and molecular biology, often termed molecular imaging. Molecular imaging can be considered an in vivo assay technique, capable of measuring regional tumor biology without perturbing it. This makes molecular imaging a unique tool for cancer drug development, complementary to traditional assay methods, and a potentially powerful method for guiding targeted therapy in clinical trials and clinical practice. The ability to quantify, in absolute measures, regional in vivo biologic parameters strongly supports the use of molecular imaging as a tool to guide therapy. This review summarizes current and future applications of quantitative molecular imaging as a biomarker for cancer therapy, including the use of imaging to (1) identify patients whose tumors express a specific therapeutic target; (2) determine

  3. Biomarkers for ragwort poisoning in horses: identification of protein targets

    Directory of Open Access Journals (Sweden)

    Beynon Robert J

    2008-08-01

    Full Text Available Abstract Background Ingestion of the poisonous weed ragwort (Senecio jacobea by horses leads to irreversible liver damage. The principal toxins of ragwort are the pyrrolizidine alkaloids that are rapidly metabolised to highly reactive and cytotoxic pyrroles, which can escape into the circulation and bind to proteins. In this study a non-invasive in vitro model system has been developed to investigate whether pyrrole toxins induce specific modifications of equine blood proteins that are detectable by proteomic methods. Results One dimensional gel electrophoresis revealed a significant alteration in the equine plasma protein profile following pyrrole exposure and the formation of a high molecular weight protein aggregate. Using mass spectrometry and confirmation by western blotting the major components of this aggregate were identified as fibrinogen, serum albumin and transferrin. Conclusion These findings demonstrate that pyrrolic metabolites can modify equine plasma proteins. The high molecular weight aggregate may result from extensive inter- and intra-molecular cross-linking of fibrinogen with the pyrrole. This model has the potential to form the basis of a novel proteomic strategy aimed at identifying surrogate protein biomarkers of ragwort exposure in horses and other livestock.

  4. Current advances in biomarkers for targeted therapy in triple-negative breast cancer

    Directory of Open Access Journals (Sweden)

    Fleisher B

    2016-10-01

    Full Text Available Brett Fleisher,1 Charlotte Clarke,2 Sihem Ait-Oudhia1 1Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, 2Department of Translational Research, UT MD Anderson Cancer Center, Houston, TX, USA Abstract: Triple-negative breast cancer (TNBC is a complex heterogeneous disease characterized by the absence of three hallmark receptors: human epidermal growth factor receptor 2, estrogen receptor, and progesterone receptor. Compared to other breast cancer subtypes, TNBC is more aggressive, has a higher prevalence in African-Americans, and more frequently affects younger patients. Currently, TNBC lacks clinically accepted targets for tailored therapy, warranting the need for candidate biomarkers. BiomarkerBase, an online platform used to find biomarkers reported in clinical trials, was utilized to screen all potential biomarkers for TNBC and select only the ones registered in completed TNBC trials through clinicaltrials.gov. The selected candidate biomarkers were classified as surrogate, prognostic, predictive, or pharmacodynamic (PD and organized by location in the blood, on the cell surface, in the cytoplasm, or in the nucleus. Blood biomarkers include vascular endothelial growth factor/vascular endothelial growth factor receptor and interleukin-8 (IL-­8; cell surface biomarkers include EGFR, insulin-like growth factor binding protein, c-Kit, c-Met, and PD-L1; cytoplasm biomarkers include PIK3CA, pAKT/S6/p4E-BP1, PTEN, ALDH1, and the PIK3CA/AKT/mTOR-related metabolites; and nucleus biomarkers include BRCA1, the glucocorticoid receptor, TP53, and Ki67. Candidate biomarkers were further organized into a “cellular protein network” that demonstrates potential connectivity. This review provides an inventory and reference point for promising biomarkers for breakthrough targeted therapies in TNBC. Keywords: anti-cancer directed pharmacotherapy, difficult

  5. Blood Transcriptomics and Metabolomics for Personalized Medicine

    Science.gov (United States)

    2015-10-31

    progress in human immunology , where transcriptomics of isolated cell populations provided necessary information [15–17]. Nonetheless, a review on “blood...databases are biased towards cancer , under- representing the immunology in white blood cells. Second, many path- ways are based on tissues other than blood...metabolomics in oncology: a review . Clin Cancer Res 2009;15. [52] Armitage EG. Metabolomics in cancer biomarker discovery: current trends and fu- ture

  6. Serum Autoantibodies as Biomarkers for Parkinsons Disease: Background and Utility

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    Cassandra A DeMarshall

    2015-10-01

    Full Text Available There are no definitive diagnostic tests for early detection, diagnosis and staging of Parkinson's disease (PD. Available methods have thus far failed to yield high accuracy, are expensive, and can be highly invasive to the patient. The use of serum biomarkers for the diagnosis of early-stage PD has the potential to provide an accurate, inexpensive, and non-invasive alternative to conventional tests. Recently, investigations into the role of the immune system in the development of PD and other diseases have led to the identification of potential PD-specific autoantibodies. This mini review focuses on the background and utility of these autoantibodies as diagnostic biomarkers of PD. Advantages of serum biomarkers as well as potential benefits of a blood-based diagnostic test to clinical medicine are discussed.

  7. Biomarkers for the differentiation of anemia and their clinical usefulness

    Directory of Open Access Journals (Sweden)

    Northrop-Clewes CA

    2013-03-01

    Full Text Available Christine A Northrop-Clewes,1 David I Thurnham21Nutrition Consultant, Cambridge, UK; 2Northern Ireland Centre for Food and Health, School of Biomedical Sciences, University of Ulster, Coleraine, UKAbstract: The World Health Organization defines anemia as the point at which the amount of hemoglobin in the circulation falls below World Health Organization cutoffs for specific age and sex groups. Anemia is a worldwide problem of complex etiology and is associated with many factors. The purpose of this review was to describe the biomarkers used to identify the nature of anemia in patients and in the community. The important biomarkers are the automated red cell counts, tests for nutritional deficiencies, hemoglobinopathies, and inflammation. Diseases are important potential initiators of anemia, but biomarkers of specific diseases are not included in this review, only the underlying feature common to all disease – namely, inflammation.Keywords: iron deficiency, biological markers, blood cell count, inflammation, avitaminosis, hemoglobinopathies

  8. Blood smear

    Science.gov (United States)

    ... some red blood cells shaped like spheres ( hereditary spherocytosis ) Increased breakdown of RBCs Presence of RBCs with ... normal Red blood cells, elliptocytosis Red blood cells, spherocytosis Acute lymphocytic leukemia - photomicrograph Red blood cells, multiple ...

  9. Blood culture

    Science.gov (United States)

    Culture - blood ... A blood sample is needed . The site where blood will be drawn is first cleaned with an antiseptic such ... organism from the skin getting into (contaminating) the blood sample and causing a false-positive result (see ...

  10. Blood Thinners

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    If you have some kinds of heart or blood vessel disease, or if you have poor blood flow to your brain, your doctor may recommend that you take a blood thinner. Blood thinners reduce the risk of heart ...

  11. Blood transfusions

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000431.htm Blood transfusions To use the sharing features on this ... several sources of blood which are described below. Blood From the Public (Volunteer Blood