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Sample records for biomarker candidate discovery

  1. Biological Networks for Cancer Candidate Biomarkers Discovery

    Science.gov (United States)

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

    2016-01-01

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

  2. Biological Networks for Cancer Candidate Biomarkers Discovery.

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

    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

    We report an integrated pipeline for efficient serum glycoprotein biomarker candidate discovery and qualification that may be used to facilitate cancer diagnosis and management. The discovery phase used semi-automated lectin magnetic bead array (LeMBA)-coupled tandem mass spectrometry with a dedicated data-housing and analysis pipeline; GlycoSelector (http://glycoselector.di.uq.edu.au). The qualification phase used lectin magnetic bead array-multiple reaction monitoring-mass spectrometry incorporating an interactive web-interface, Shiny mixOmics (http://mixomics-projects.di.uq.edu.au/Shiny), for univariate and multivariate statistical analysis. Relative quantitation was performed by referencing to a spiked-in glycoprotein, chicken ovalbumin. We applied this workflow to identify diagnostic biomarkers for esophageal adenocarcinoma (EAC), a life threatening malignancy with poor prognosis in the advanced setting. EAC develops from metaplastic condition Barrett's esophagus (BE). Currently diagnosis and monitoring of at-risk patients is through endoscopy and biopsy, which is expensive and requires hospital admission. Hence there is a clinical need for a noninvasive diagnostic biomarker of EAC. In total 89 patient samples from healthy controls, and patients with BE or EAC were screened in discovery and qualification stages. Of the 246 glycoforms measured in the qualification stage, 40 glycoforms (as measured by lectin affinity) qualified as candidate serum markers. The top candidate for distinguishing healthy from BE patients' group was Narcissus pseudonarcissus lectin (NPL)-reactive Apolipoprotein B-100 (p value = 0.0231; AUROC = 0.71); BE versus EAC, Aleuria aurantia lectin (AAL)-reactive complement component C9 (p value = 0.0001; AUROC = 0.85); healthy versus EAC, Erythroagglutinin Phaseolus vulgaris (EPHA)-reactive gelsolin (p value = 0.0014; AUROC = 0.80). A panel of 8 glycoforms showed an improved AUROC of 0.94 to discriminate EAC from BE. Two biomarker candidates

  4. Improving low-level plasma protein mass spectrometry-based detection for candidate biomarker discovery and validation

    Energy Technology Data Exchange (ETDEWEB)

    Page, Jason S.; Kelly, Ryan T.; Camp, David G.; Smith, Richard D.

    2008-09-01

    Methods. To improve the detection of low abundance protein candidate biomarker discovery and validation, particularly in complex biological fluids such as blood plasma, increased sensitivity is desired using mass spectrometry (MS)-based instrumentation. A key current limitation on the sensitivity of electrospray ionization (ESI) MS is due to the fact that many sample molecules in solution are never ionized, and the vast majority of the ions that are created are lost during transmission from atmospheric pressure to the low pressure region of the mass analyzer. Two key technologies, multi-nanoelectrospray emitters and the electrodynamic ion funnel have recently been developed and refined at Pacific Northwest National Laboratory (PNNL) to greatly improve the ionization and transmission efficiency of ESI MS based analyses. Multi-emitter based ESI enables the flow from a single source (typically a liquid chromatography [LC] column) to be divided among an array of emitters (Figure 1). The flow rate delivered to each emitter is thus reduced, allowing the well-documented benefits of nanoelectrospray 1 for both sensitivity and quantitation to be realized for higher flow rate separations. To complement the increased ionization efficiency afforded by multi-ESI, tandem electrodynamic ion funnels have also been developed at PNNL, and shown to greatly improve ion transmission efficiency in the ion source interface.2, 3 These technologies have been integrated into a triple quadrupole mass spectrometer for multiple reaction monitoring (MRM) of probable biomarker candidates in blood plasma and show promise for the identification of new species even at low level concentrations.

  5. Pairwise protein expression classifier for candidate biomarker discovery for early detection of human disease prognosis

    Directory of Open Access Journals (Sweden)

    Kaur Parminder

    2012-08-01

    Full Text Available Abstract Background An approach to molecular classification based on the comparative expression of protein pairs is presented. The method overcomes some of the present limitations in using peptide intensity data for class prediction for problems such as the detection of a disease, disease prognosis, or for predicting treatment response. Data analysis is particularly challenging in these situations due to sample size (typically tens being much smaller than the large number of peptides (typically thousands. Methods based upon high dimensional statistical models, machine learning or other complex classifiers generate decisions which may be very accurate but can be complex and difficult to interpret in simple or biologically meaningful terms. A classification scheme, called ProtPair, is presented that generates simple decision rules leading to accurate classification which is based on measurement of very few proteins and requires only relative expression values, providing specific targeted hypotheses suitable for straightforward validation. Results ProtPair has been tested against clinical data from 21 patients following a bone marrow transplant, 13 of which progress to idiopathic pneumonia syndrome (IPS. The approach combines multiple peptide pairs originating from the same set of proteins, with each unique peptide pair providing an independent measure of discriminatory power. The prediction rate of the ProtPair for IPS study as measured by leave-one-out CV is 69.1%, which can be very beneficial for clinical diagnosis as it may flag patients in need of closer monitoring. The “top ranked” proteins provided by ProtPair are known to be associated with the biological processes and pathways intimately associated with known IPS biology based on mouse models. Conclusions An approach to biomarker discovery, called ProtPair, is presented. ProtPair is based on the differential expression of pairs of peptides and the associated proteins. Using mass

  6. Biomarker candidate discovery in Atlantic cod (Gadus morhua) continuously exposed to North Sea produced water from egg to fry

    DEFF Research Database (Denmark)

    Bohne-Kjersem, Anneli; Bache, Nicolai; Meier, Sonnich;

    2010-01-01

    In this study Atlantic cod (Gadus morhua) were exposed to different levels of North Sea produced water (PW) and 17beta-oestradiol (E(2)), a natural oestrogen, from egg to fry stage (90 days). By comparing changes in protein expression following E(2) exposure to changes induced by PW treatment, we...... changes that may be useful as biomarker candidates of produced water (PW) and oestradiol exposure in Atlantic cod fry. The biomarker candidates discovered in this study may, following validation, prove effective as diagnostic tools in monitoring exposure and effects of discharges from the petroleum...

  7. Integrative analysis to select cancer candidate biomarkers to targeted validation

    Science.gov (United States)

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  8. Glycoscience aids in biomarker discovery

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    Serenus Hua1,2 & Hyun Joo An1,2,*

    2012-06-01

    Full Text Available The glycome consists of all glycans (or carbohydrates within abiological system, and modulates a wide range of important biologicalactivities, from protein folding to cellular communications.The mining of the glycome for disease markers representsa new paradigm for biomarker discovery; however, this effortis severely complicated by the vast complexity and structuraldiversity of glycans. This review summarizes recent developmentsin analytical technology and methodology as applied tothe fields of glycomics and glycoproteomics. Mass spectrometricstrategies for glycan compositional profiling are described, as arepotential refinements which allow structure-specific profiling.Analytical methods that can discern protein glycosylation at aspecific site of modification are also discussed in detail.Biomarker discovery applications are shown at each level ofanalysis, highlighting the key role that glycoscience can play inhelping scientists understand disease biology.

  9. Biomarkers of silicosis: Potential candidates

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    Tiwari R

    2005-01-01

    Full Text Available Silica dust is widely prevalent in the atmosphere and more common than the other types of dust, thus making silicosis the most frequently occurring pneumoconiosis. In India also, studies carried out by National Institute of Occupational Health have shown high prevalence of silicosis in small factories and even in nonoccupational exposed subjects. The postero-anterior chest radiographs remain the key tool in diagnosing and assessing the extent and severity of interstitial lung disease. Although Computed Tomography detects finer anatomical structure than radiography it could not get popularity because of its cost. On the basis of histological features of silicosis many potential biomarkers such as Cytokines, Tumor Necrosis Factor, Interleukin 1, Angiotensin Converting Enzyme, Serum Copper, Fas ligand (FasL, etc. have been tried. However, further studies are needed to establish these potential biomarkers as true biomarker of silicosis.

  10. Rapid, non-targeted discovery of biochemical transformation and biomarker candidates in oncovirus-infected cell lines using LAESI mass spectrometry.

    Science.gov (United States)

    Shrestha, Bindesh; Sripadi, Prabhakar; Walsh, Callee M; Razunguzwa, Trust T; Powell, Matthew J; Kehn-Hall, Kylene; Kashanchi, Fatah; Vertes, Akos

    2012-04-18

    Finding insights into how viruses hijack metabolic processes and biomarkers for viral diseases often require hypotheses about target compounds and/or labelling techniques. Here we present a method based on laser ablation electrospray ionization mass spectrometry to rapidly identify potential protein and metabolite biomarkers of oncovirus infection in B lymphocytes.

  11. Stable Feature Selection for Biomarker Discovery

    CERN Document Server

    He, Zengyou

    2010-01-01

    Feature selection techniques have been used as the workhorse in biomarker discovery applications for a long time. Surprisingly, the stability of feature selection with respect to sampling variations has long been under-considered. It is only until recently that this issue has received more and more attention. In this article, we review existing stable feature selection methods for biomarker discovery using a generic hierarchal framework. We have two objectives: (1) providing an overview on this new yet fast growing topic for a convenient reference; (2) categorizing existing methods under an expandable framework for future research and development.

  12. Proteomics Discovery of Disease Biomarkers

    OpenAIRE

    Mamoun Ahram; Petricoin, Emanuel F.

    2008-01-01

    Recent technological developments in proteomics have shown promising initiatives in identifying novel biomarkers of various diseases. Such technologies are capable of investigating multiple samples and generating large amount of data end-points. Examples of two promising proteomics technologies are mass spectrometry, including an instrument based on surface enhanced laser desorption/ionization, and protein microarrays. Proteomics data must, however, undergo analytical processing using bioinfo...

  13. Using Aptamers for Cancer Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Yun Min Chang

    2013-01-01

    Full Text Available Aptamers are single-stranded synthetic DNA- or RNA-based oligonucleotides that fold into various shapes to bind to a specific target, which includes proteins, metals, and molecules. Aptamers have high affinity and high specificity that are comparable to that of antibodies. They are obtained using iterative method, called (Systematic Evolution of Ligands by Exponential Enrichment SELEX and cell-based SELEX (cell-SELEX. Aptamers can be paired with recent advances in nanotechnology, microarray, microfluidics, and other technologies for applications in clinical medicine. One particular area that aptamers can shed a light on is biomarker discovery. Biomarkers are important in diagnosis and treatment of cancer. In this paper, we will describe ways in which aptamers can be used to discover biomarkers for cancer diagnosis and therapeutics.

  14. Current technological challenges in biomarker discovery and validation

    NARCIS (Netherlands)

    Horvatovich, Peter L.; Bischoff, Rainer

    2010-01-01

    In this review we will give an overview of the issues related to biomarker discovery studies with a focus on liquid chromatography-mass spectrometry (LC-MS) methods. Biomarker discovery is based on a close collaboration between clinicians, analytical scientists and chemometritians/statisticians. It

  15. Cancer Biomarker Discovery: Lectin-Based Strategies Targeting Glycoproteins

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    David Clark

    2012-01-01

    Full Text Available Biomarker discovery can identify molecular markers in various cancers that can be used for detection, screening, diagnosis, and monitoring of disease progression. Lectin-affinity is a technique that can be used for the enrichment of glycoproteins from a complex sample, facilitating the discovery of novel cancer biomarkers associated with a disease state.

  16. Biomarker Discovery by Novel Sensors Based on Nanoproteomics Approaches

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    Manuel Fuentes

    2012-02-01

    Full Text Available During the last years, proteomics has facilitated biomarker discovery by coupling high-throughput techniques with novel nanosensors. In the present review, we focus on the study of label-based and label-free detection systems, as well as nanotechnology approaches, indicating their advantages and applications in biomarker discovery. In addition, several disease biomarkers are shown in order to display the clinical importance of the improvement of sensitivity and selectivity by using nanoproteomics approaches as novel sensors.

  17. Mass Spectrometry-Based Proteomics in Molecular Diagnostics: Discovery of Cancer Biomarkers Using Tissue Culture

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    Debasish Paul

    2013-01-01

    Full Text Available Accurate diagnosis and proper monitoring of cancer patients remain a key obstacle for successful cancer treatment and prevention. Therein comes the need for biomarker discovery, which is crucial to the current oncological and other clinical practices having the potential to impact the diagnosis and prognosis. In fact, most of the biomarkers have been discovered utilizing the proteomics-based approaches. Although high-throughput mass spectrometry-based proteomic approaches like SILAC, 2D-DIGE, and iTRAQ are filling up the pitfalls of the conventional techniques, still serum proteomics importunately poses hurdle in overcoming a wide range of protein concentrations, and also the availability of patient tissue samples is a limitation for the biomarker discovery. Thus, researchers have looked for alternatives, and profiling of candidate biomarkers through tissue culture of tumor cell lines comes up as a promising option. It is a rich source of tumor cell-derived proteins, thereby, representing a wide array of potential biomarkers. Interestingly, most of the clinical biomarkers in use today (CA 125, CA 15.3, CA 19.9, and PSA were discovered through tissue culture-based system and tissue extracts. This paper tries to emphasize the tissue culture-based discovery of candidate biomarkers through various mass spectrometry-based proteomic approaches.

  18. Proteomics in Discovery of Hepatocellular Carcinoma Biomarkers

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To discover new proteomic biomarkers of hepatocellular carcinoma. Methods: Surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry was used to discover biomarkers for differentiating hepatocellular carcinoma and chronic liver disease. A population of 50 patients with hepatocellular carcinoma and 33 patients with chronic liver disease was studied. Results: Twelve proteomic biomarkers of hepatocellular carcinoma were detected in this study. Three proteomic biomarkers were highly expressed in hepatocellular carcinoma and nine proteomic biomarkers were highly expressed in chronic liver disease. The most valuable proteomic biomarker with m/z=11498 had no similar diagnostic value as α-fetoprotein. Conclusion:Some of the twelve proteomic biomarkers may become new biomarkers of hepatocellular carcinoma.

  19. Bioinformatics and biomarker discovery "Omic" data analysis for personalized medicine

    CERN Document Server

    Azuaje, Francisco

    2010-01-01

    This book is designed to introduce biologists, clinicians and computational researchers to fundamental data analysis principles, techniques and tools for supporting the discovery of biomarkers and the implementation of diagnostic/prognostic systems. The focus of the book is on how fundamental statistical and data mining approaches can support biomarker discovery and evaluation, emphasising applications based on different types of "omic" data. The book also discusses design factors, requirements and techniques for disease screening, diagnostic and prognostic applications. Readers are provided w

  20. Statistical design for biospecimen cohort size in proteomics-based biomarker discovery and verification studies.

    Science.gov (United States)

    Skates, Steven J; Gillette, Michael A; LaBaer, Joshua; Carr, Steven A; Anderson, Leigh; Liebler, Daniel C; Ransohoff, David; Rifai, Nader; Kondratovich, Marina; Težak, Živana; Mansfield, Elizabeth; Oberg, Ann L; Wright, Ian; Barnes, Grady; Gail, Mitchell; Mesri, Mehdi; Kinsinger, Christopher R; Rodriguez, Henry; Boja, Emily S

    2013-12-01

    Protein biomarkers are needed to deepen our understanding of cancer biology and to improve our ability to diagnose, monitor, and treat cancers. Important analytical and clinical hurdles must be overcome to allow the most promising protein biomarker candidates to advance into clinical validation studies. Although contemporary proteomics technologies support the measurement of large numbers of proteins in individual clinical specimens, sample throughput remains comparatively low. This problem is amplified in typical clinical proteomics research studies, which routinely suffer from a lack of proper experimental design, resulting in analysis of too few biospecimens to achieve adequate statistical power at each stage of a biomarker pipeline. To address this critical shortcoming, a joint workshop was held by the National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), and American Association for Clinical Chemistry (AACC) with participation from the U.S. Food and Drug Administration (FDA). An important output from the workshop was a statistical framework for the design of biomarker discovery and verification studies. Herein, we describe the use of quantitative clinical judgments to set statistical criteria for clinical relevance and the development of an approach to calculate biospecimen sample size for proteomic studies in discovery and verification stages prior to clinical validation stage. This represents a first step toward building a consensus on quantitative criteria for statistical design of proteomics biomarker discovery and verification research.

  1. Exhaled Breath Condensate for Proteomic Biomarker Discovery

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    Sean W. Harshman

    2014-07-01

    Full Text Available Exhaled breath condensate (EBC has been established as a potential source of respiratory biomarkers. Compared to the numerous small molecules identified, the protein content of EBC has remained relatively unstudied due to the methodological and technical difficulties surrounding EBC analysis. In this review, we discuss the proteins identified in EBC, by mass spectrometry, focusing on the significance of those proteins identified. We will also review the limitations surrounding mass spectral EBC protein analysis emphasizing recommendations to enhance EBC protein identifications by mass spectrometry. Finally, we will provide insight into the future directions of the EBC proteomics field.

  2. Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis.

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    Meghan E Wilson

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurologic disease characterized by progressive motor neuron degeneration. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective treatments. Reliable panels of diagnostic, surrogate, and prognostic biomarkers are needed to accelerate disease diagnosis and expedite drug development. The cysteine protease inhibitor cystatin C has recently gained interest as a candidate diagnostic biomarker for ALS, but further studies are required to fully characterize its biomarker utility. We used quantitative enzyme-linked immunosorbent assay (ELISA to assess initial and longitudinal cerebrospinal fluid (CSF and plasma cystatin C levels in 104 ALS patients and controls. Cystatin C levels in ALS patients were significantly elevated in plasma and reduced in CSF compared to healthy controls, but did not differ significantly from neurologic disease controls. In addition, the direction of longitudinal change in CSF cystatin C levels correlated to the rate of ALS disease progression, and initial CSF cystatin C levels were predictive of patient survival, suggesting that cystatin C may function as a surrogate marker of disease progression and survival. These data verify prior results for reduced cystatin C levels in the CSF of ALS patients, identify increased cystatin C levels in the plasma of ALS patients, and reveal correlations between CSF cystatin C levels to both ALS disease progression and patient survival.

  3. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery.

    Science.gov (United States)

    Maher, Toby M

    2013-06-01

    Despite major advances in the understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF), diagnosis and management of the condition continue to pose significant challenges. Clinical management of IPF remains unsatisfactory due to limited availability of effective drug therapies, a lack of accurate indicators of disease progression, and an absence of simple short-term measures of therapeutic response. The identification of more accurate predictors of prognosis and survival in IPF would facilitate counseling of patients and their families, aid communication among clinicians, and would guide optimal timing of referral for transplantation. Improvements in molecular techniques have led to the identification of new disease pathways and a more targeted approach to the development of novel anti-fibrotic agents. However, despite an increased interest in biomarkers of IPF disease progression there are a lack of measures that can be used in early phase clinical trials. Careful longitudinal phenotyping of individuals with IPF together with the application of novel omics-based technology should provide important insights into disease pathogenesis and should address some of the major issues holding back drug development in IPF. The PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints) study is a currently enrolling, prospective cohort study designed to tackle these issues. PMID:23728868

  4. PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery

    Directory of Open Access Journals (Sweden)

    Toby M. Maher

    2013-06-01

    Full Text Available Despite major advances in the understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF, diagnosis and management of the condition continue to pose significant challenges. Clinical management of IPF remains unsatisfactory due to limited availability of effective drug therapies, a lack of accurate indicators of disease progression, and an absence of simple short-term measures of therapeutic response. The identification of more accurate predictors of prognosis and survival in IPF would facilitate counseling of patients and their families, aid communication among clinicians, and would guide optimal timing of referral for transplantation. Improvements in molecular techniques have led to the identification of new disease pathways and a more targeted approach to the development of novel anti-fibrotic agents. However, despite an increased interest in biomarkers of IPF disease progression there are a lack of measures that can be used in early phase clinical trials. Careful longitudinal phenotyping of individuals with IPF together with the application of novel omics-based technology should provide important insights into disease pathogenesis and should address some of the major issues holding back drug development in IPF. The PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints study is a currently enrolling, prospective cohort study designed to tackle these issues.

  5. State of the Art in Tumor Antigen and Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Patrick Chames

    2011-06-01

    Full Text Available Our knowledge of tumor immunology has resulted in multiple approaches for the treatment of cancer. However, a gap between research of new tumors markers and development of immunotherapy has been established and very few markers exist that can be used for treatment. The challenge is now to discover new targets for active and passive immunotherapy. This review aims at describing recent advances in biomarkers and tumor antigen discovery in terms of antigen nature and localization, and is highlighting the most recent approaches used for their discovery including “omics” technology.

  6. State of the Art in Tumor Antigen and Biomarker Discovery

    Energy Technology Data Exchange (ETDEWEB)

    Even-Desrumeaux, Klervi; Baty, Daniel; Chames, Patrick, E-mail: patrick.chames@inserm.fr [INSERM U624, 163 avenue de Luminy, 13288 Marseille Cedex 09 (France)

    2011-06-09

    Our knowledge of tumor immunology has resulted in multiple approaches for the treatment of cancer. However, a gap between research of new tumors markers and development of immunotherapy has been established and very few markers exist that can be used for treatment. The challenge is now to discover new targets for active and passive immunotherapy. This review aims at describing recent advances in biomarkers and tumor antigen discovery in terms of antigen nature and localization, and is highlighting the most recent approaches used for their discovery including “omics” technology.

  7. Maximizing biomarker discovery by minimizing gene signatures

    Directory of Open Access Journals (Sweden)

    Chang Chang

    2011-12-01

    Full Text Available Abstract Background The use of gene signatures can potentially be of considerable value in the field of clinical diagnosis. However, gene signatures defined with different methods can be quite various even when applied the same disease and the same endpoint. Previous studies have shown that the correct selection of subsets of genes from microarray data is key for the accurate classification of disease phenotypes, and a number of methods have been proposed for the purpose. However, these methods refine the subsets by only considering each single feature, and they do not confirm the association between the genes identified in each gene signature and the phenotype of the disease. We proposed an innovative new method termed Minimize Feature's Size (MFS based on multiple level similarity analyses and association between the genes and disease for breast cancer endpoints by comparing classifier models generated from the second phase of MicroArray Quality Control (MAQC-II, trying to develop effective meta-analysis strategies to transform the MAQC-II signatures into a robust and reliable set of biomarker for clinical applications. Results We analyzed the similarity of the multiple gene signatures in an endpoint and between the two endpoints of breast cancer at probe and gene levels, the results indicate that disease-related genes can be preferably selected as the components of gene signature, and that the gene signatures for the two endpoints could be interchangeable. The minimized signatures were built at probe level by using MFS for each endpoint. By applying the approach, we generated a much smaller set of gene signature with the similar predictive power compared with those gene signatures from MAQC-II. Conclusions Our results indicate that gene signatures of both large and small sizes could perform equally well in clinical applications. Besides, consistency and biological significances can be detected among different gene signatures, reflecting the

  8. Aptamer-based multiplexed proteomic technology for biomarker discovery.

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    Larry Gold

    Full Text Available BACKGROUND: The interrogation of proteomes ("proteomics" in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine. METHODOLOGY/PRINCIPAL FINDINGS: We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma. Our current assay measures 813 proteins with low limits of detection (1 pM median, 7 logs of overall dynamic range (~100 fM-1 µM, and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD. We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states. CONCLUSIONS/SIGNIFICANCE: We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next

  9. Emerging concepts in biomarker discovery; The US-Japan workshop on immunological molecular markers in oncology

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    Rivoltini Licia

    2009-06-01

    Full Text Available Abstract Supported by the Office of International Affairs, National Cancer Institute (NCI, the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc and the United States Food and Drug Administration (FDA to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers

  10. Emerging concepts in biomarker discovery; the US-Japan Workshop on Immunological Molecular Markers in Oncology.

    Science.gov (United States)

    Tahara, Hideaki; Sato, Marimo; Thurin, Magdalena; Wang, Ena; Butterfield, Lisa H; Disis, Mary L; Fox, Bernard A; Lee, Peter P; Khleif, Samir N; Wigginton, Jon M; Ambs, Stefan; Akutsu, Yasunori; Chaussabel, Damien; Doki, Yuichiro; Eremin, Oleg; Fridman, Wolf Hervé; Hirohashi, Yoshihiko; Imai, Kohzoh; Jacobson, James; Jinushi, Masahisa; Kanamoto, Akira; Kashani-Sabet, Mohammed; Kato, Kazunori; Kawakami, Yutaka; Kirkwood, John M; Kleen, Thomas O; Lehmann, Paul V; Liotta, Lance; Lotze, Michael T; Maio, Michele; Malyguine, Anatoli; Masucci, Giuseppe; Matsubara, Hisahiro; Mayrand-Chung, Shawmarie; Nakamura, Kiminori; Nishikawa, Hiroyoshi; Palucka, A Karolina; Petricoin, Emanuel F; Pos, Zoltan; Ribas, Antoni; Rivoltini, Licia; Sato, Noriyuki; Shiku, Hiroshi; Slingluff, Craig L; Streicher, Howard; Stroncek, David F; Takeuchi, Hiroya; Toyota, Minoru; Wada, Hisashi; Wu, Xifeng; Wulfkuhle, Julia; Yaguchi, Tomonori; Zeskind, Benjamin; Zhao, Yingdong; Zocca, Mai-Britt; Marincola, Francesco M

    2009-06-17

    Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers were recognized that

  11. Proteomics and Its Application in Biomarker Discovery and Drug Development

    Institute of Scientific and Technical Information of China (English)

    He Qing-Yu; Chiu Jen-Fu

    2004-01-01

    Proteomics is a research field aiming to characterize molecular and cellular dynamics in protein expression and function on a global level. The introduction of proteomics has been greatly broadening our view and accelerating our path in various medical researches. The most significant advantage of proteomics is its ability to examine a whole proteome or sub-proteome in a single experiment so that the protein alterations corresponding to a pathological or biochemical condition at a given time can be considered in an integrated way. Proteomic technology has been extensively used to tackle a wide variety of medical subjects including biomarker discovery and drug development. By complement with other new technique advance in genomics and bioinformatics,proteomics has a great potential to make considerable contribution to biomarker identification and revolutionize drug development process. A brief overview of the proteomic technologies will be provided and the application of proteomics in biomarker discovery and drug development will be discussed using our current research projects as examples.

  12. Strategies for discovery and validation of methylated and hydroxymethylated DNA biomarkers.

    Science.gov (United States)

    Olkhov-Mitsel, Ekaterina; Bapat, Bharati

    2012-10-01

    DNA methylation, consisting of the addition of a methyl group at the fifth-position of cytosine in a CpG dinucleotide, is one of the most well-studied epigenetic mechanisms in mammals with important functions in normal and disease biology. Disease-specific aberrant DNA methylation is a well-recognized hallmark of many complex diseases. Accordingly, various studies have focused on characterizing unique DNA methylation marks associated with distinct stages of disease development as they may serve as useful biomarkers for diagnosis, prognosis, prediction of response to therapy, or disease monitoring. Recently, novel CpG dinucleotide modifications with potential regulatory roles such as 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine have been described. These potential epigenetic marks cannot be distinguished from 5-methylcytosine by many current strategies and may potentially compromise assessment and interpretation of methylation data. A large number of strategies have been described for the discovery and validation of DNA methylation-based biomarkers, each with its own advantages and limitations. These strategies can be classified into three main categories: restriction enzyme digestion, affinity-based analysis, and bisulfite modification. In general, candidate biomarkers are discovered using large-scale, genome-wide, methylation sequencing, and/or microarray-based profiling strategies. Following discovery, biomarker performance is validated in large independent cohorts using highly targeted locus-specific assays. There are still many challenges to the effective implementation of DNA methylation-based biomarkers. Emerging innovative methylation and hydroxymethylation detection strategies are focused on addressing these gaps in the field of epigenetics. The development of DNA methylation- and hydroxymethylation-based biomarkers is an exciting and rapidly evolving area of research that holds promise for potential applications in diverse clinical

  13. Role of proteomics in the discovery of autism biomarkers

    International Nuclear Information System (INIS)

    The epidemiology of autism is continuously increasing all over the world with social, behavioural and economical burdens. Autism is considered as a multi-factorial disorder, influenced by genetic, neurological, environmental and immunological aspects. Autism is still believed to be incurable disorder with little information about the role of proteins patterns in the diagnosis of the disease. Knowing the applications of proteomic tools, it is possible to identify quantitative and qualitative protein patterns in a wide variety of tissues and body fluids such as blood, urine, saliva and cerebrospinal fluid in order to establish specific diagnostic and prognostic biomarkers. The aim of this review is to provide an overview of the various protocols available for proteomics by using mass spectrometry analysis, discuss reports in which these techniques have been previously applied in biomarker discovery for the diagnosis of autism, and consider the future development of this area of research. (author)

  14. Discovery of Eleven Optical Nova Candidates in M81

    Science.gov (United States)

    Hornoch, K.; Sipocz, B.

    2012-01-01

    We report the discovery of five nova candidates in M81 found on a co-added 1100-s narrow-band H-alpha CCD image taken on 2012 Jan. 9.102 UT with the 2.54-m Isaac Newton Telescope (INT) at La Palma. The new objects are visible on the single frames used for the co-added image, but are not present on numerous narrow-band H-alpha archival images from the INT down to limiting magnitude as faint as H-alpha = 22.3.

  15. Metabolomics-based discovery of diagnostic biomarkers for onchocerciasis.

    Directory of Open Access Journals (Sweden)

    Judith R Denery

    Full Text Available BACKGROUND: Development of robust, sensitive, and reproducible diagnostic tests for understanding the epidemiology of neglected tropical diseases is an integral aspect of the success of worldwide control and elimination programs. In the treatment of onchocerciasis, clinical diagnostics that can function in an elimination scenario are non-existent and desperately needed. Due to its sensitivity and quantitative reproducibility, liquid chromatography-mass spectrometry (LC-MS based metabolomics is a powerful approach to this problem. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of an African sample set comprised of 73 serum and plasma samples revealed a set of 14 biomarkers that showed excellent discrimination between Onchocerca volvulus-positive and negative individuals by multivariate statistical analysis. Application of this biomarker set to an additional sample set from onchocerciasis endemic areas where long-term ivermectin treatment has been successful revealed that the biomarker set may also distinguish individuals with worms of compromised viability from those with active infection. Machine learning extended the utility of the biomarker set from a complex multivariate analysis to a binary format applicable for adaptation to a field-based diagnostic, validating the use of complex data mining tools applied to infectious disease biomarker discovery and diagnostic development. CONCLUSIONS/SIGNIFICANCE: An LC-MS metabolomics-based diagnostic has the potential to monitor the progression of onchocerciasis in both endemic and non-endemic geographic areas, as well as provide an essential tool to multinational programs in the ongoing fight against this neglected tropical disease. Ultimately this technology can be expanded for the diagnosis of other filarial and/or neglected tropical diseases.

  16. Proteomics and Mass Spectrometry for Cancer Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Ming Lu

    2007-01-01

    Full Text Available Proteomics is a rapidly advancing field not only in the field of biology but also in translational cancer research. In recent years, mass spectrometry and associated technologies have been explored to identify proteins or a set of proteins specific to a given disease, for the purpose of disease detection and diagnosis. Such biomarkers are being investigated in samples including cells, tissues, serum/plasma, and other types of body fluids. When sufficiently refined, proteomic technologies may pave the way for early detection of cancer or individualized therapy for cancer. Mass spectrometry approaches coupled with bioinformatic tools are being developed for biomarker discovery and validation. Understanding basic concepts and application of such technology by investigators in the field may accelerate the clinical application of protein biomarkers in disease management.Abbreviations: 2DE: two-dimensional gel electrophoresis; ABPP: activity-based protein profiling; CEA: carcinoembryonic antigen; CI: confidence interval; ESI: electrospray ionization; FP: fluorophosphonate; HPLC: high performance liquid chromatography; ICAT: isotope coded affi nitytags; IEF: isoelectric focusing; iTRAQ: isobaric tags for relative and absolute quantification; LCMS: combined liquid chromatography-mass spectrometry; LCMSMS: liquid chromatography tandem mass spectrometry; LOD: limit of detection; m/z: mass to charge ratio; MALDI: matrix-assisted laser desorption ionization; MS: mass spectrometry; MUDPIT: multidimensional protein identification technology; NAF: nipple aspirate fluid; PMF: peptide mass fingerprinting; PSA: prostate specifi c antigen; PTMs: post-translational modifications; RPMA: reverse phase protein microarray; SELDI: surface enhanced laser desorption ionization; TOF: time-of-flight.

  17. The Use of Proteomics in Biomarker Discovery in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Pia Davidsson

    2005-01-01

    Full Text Available Biomarkers for neurodegenerative diseases should reflect the central pathogenic processes of the diseases. The field of clinical proteomics is especially well suited for discovery of biomarkers in cerebrospinal fluid (CSF, which reflects the proteins in the brain under healthy conditions as well as in several neurodegenerative diseases. Known proteins involved in the pathology of neurodegenerative diseases are, respectively, normal tau protein, β-amyloid (1-42, synaptic proteins, amyloid precursor protein (APP, apolipoprotein E (apoE, which previously have been studied by protein immunoassays. The objective of this paper was to summarize results from proteomic studies of differential protein patterns in neurodegenerative diseases with focus on Alzheimer's disease (AD. Today, discrimination of AD from controls and from other neurological diseases has been improved by simultaneous analysis of both β-amyloid (1-42, total-tau, and phosphorylated tau, where a combination of low levels of CSF-β-amyloid 1-42 and high levels of CSF-tau and CSF-phospho-tau is associated with an AD diagnosis. Detection of new biomarkers will further strengthen diagnosis and provide useful information in drug trials. The combination of immunoassays and proteomic methods show that the CSF proteins express differential protein patterns in AD, FTD, and PD patients, which reflect divergent underlying pathophysiological mechanisms and neuropathological changes in these diseases.

  18. Effect of size and heterogeneity of samples on biomarker discovery: synthetic and real data assessment.

    Directory of Open Access Journals (Sweden)

    Barbara Di Camillo

    Full Text Available MOTIVATION: The identification of robust lists of molecular biomarkers related to a disease is a fundamental step for early diagnosis and treatment. However, methodologies for the discovery of biomarkers using microarray data often provide results with limited overlap. These differences are imputable to 1 dataset size (few subjects with respect to the number of features; 2 heterogeneity of the disease; 3 heterogeneity of experimental protocols and computational pipelines employed in the analysis. In this paper, we focus on the first two issues and assess, both on simulated (through an in silico regulation network model and real clinical datasets, the consistency of candidate biomarkers provided by a number of different methods. METHODS: We extensively simulated the effect of heterogeneity characteristic of complex diseases on different sets of microarray data. Heterogeneity was reproduced by simulating both intrinsic variability of the population and the alteration of regulatory mechanisms. Population variability was simulated by modeling evolution of a pool of subjects; then, a subset of them underwent alterations in regulatory mechanisms so as to mimic the disease state. RESULTS: The simulated data allowed us to outline advantages and drawbacks of different methods across multiple studies and varying number of samples and to evaluate precision of feature selection on a benchmark with known biomarkers. Although comparable classification accuracy was reached by different methods, the use of external cross-validation loops is helpful in finding features with a higher degree of precision and stability. Application to real data confirmed these results.

  19. 2-Furoylglycine as a Candidate Biomarker of Coffee Consumption.

    Science.gov (United States)

    Heinzmann, Silke S; Holmes, Elaine; Kochhar, Sunil; Nicholson, Jeremy K; Schmitt-Kopplin, Philippe

    2015-09-30

    Specific and sensitive food biomarkers are necessary to support dietary intake assessment and link nutritional habits to potential impact on human health. A multistep nutritional intervention study was conducted to suggest novel biomarkers for coffee consumption. (1)H NMR metabolic profiling combined with multivariate data analysis resolved 2-furoylglycine (2-FG) as a novel putative biomarker for coffee consumption. We relatively quantified 2-FG in the urine of coffee drinkers and investigated its origin, metabolism, and excretion kinetics. When searching for its potential precursors, we found different furan derivatives in coffee products, which are known to get metabolized to 2-FG. Maximal urinary excretion of 2-FG occurred 2 h after consumption (p = 0.0002) and returned to baseline after 24 h (p = 0.74). The biomarker was not excreted after consumption of coffee substitutes such as tea and chicory coffee and might therefore be a promising acute biomarker for the detection of coffee consumption in human urine.

  20. 2-Furoylglycine as a Candidate Biomarker of Coffee Consumption.

    Science.gov (United States)

    Heinzmann, Silke S; Holmes, Elaine; Kochhar, Sunil; Nicholson, Jeremy K; Schmitt-Kopplin, Philippe

    2015-09-30

    Specific and sensitive food biomarkers are necessary to support dietary intake assessment and link nutritional habits to potential impact on human health. A multistep nutritional intervention study was conducted to suggest novel biomarkers for coffee consumption. (1)H NMR metabolic profiling combined with multivariate data analysis resolved 2-furoylglycine (2-FG) as a novel putative biomarker for coffee consumption. We relatively quantified 2-FG in the urine of coffee drinkers and investigated its origin, metabolism, and excretion kinetics. When searching for its potential precursors, we found different furan derivatives in coffee products, which are known to get metabolized to 2-FG. Maximal urinary excretion of 2-FG occurred 2 h after consumption (p = 0.0002) and returned to baseline after 24 h (p = 0.74). The biomarker was not excreted after consumption of coffee substitutes such as tea and chicory coffee and might therefore be a promising acute biomarker for the detection of coffee consumption in human urine. PMID:26357997

  1. Multi-dimensional discovery of biomarker and phenotype complexes

    Directory of Open Access Journals (Sweden)

    Huang Kun

    2010-10-01

    Full Text Available Abstract Background Given the rapid growth of translational research and personalized healthcare paradigms, the ability to relate and reason upon networks of bio-molecular and phenotypic variables at various levels of granularity in order to diagnose, stage and plan treatments for disease states is highly desirable. Numerous techniques exist that can be used to develop networks of co-expressed or otherwise related genes and clinical features. Such techniques can also be used to create formalized knowledge collections based upon the information incumbent to ontologies and domain literature. However, reports of integrative approaches that bridge such networks to create systems-level models of disease or wellness are notably lacking in the contemporary literature. Results In response to the preceding gap in knowledge and practice, we report upon a prototypical series of experiments that utilize multi-modal approaches to network induction. These experiments are intended to elicit meaningful and significant biomarker-phenotype complexes spanning multiple levels of granularity. This work has been performed in the experimental context of a large-scale clinical and basic science data repository maintained by the National Cancer Institute (NCI funded Chronic Lymphocytic Leukemia Research Consortium. Conclusions Our results indicate that it is computationally tractable to link orthogonal networks of genes, clinical features, and conceptual knowledge to create multi-dimensional models of interrelated biomarkers and phenotypes. Further, our results indicate that such systems-level models contain interrelated bio-molecular and clinical markers capable of supporting hypothesis discovery and testing. Based on such findings, we propose a conceptual model intended to inform the cross-linkage of the results of such methods. This model has as its aim the identification of novel and knowledge-anchored biomarker-phenotype complexes.

  2. The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity

    International Nuclear Information System (INIS)

    biological fluids with varying immunoreactivity which can present bioanalytical challenges when first discovered. The potential success of these efforts is greatly enhanced by recent advances in two closely linked technologies, toxicoproteomics and targeted, quantitative mass spectrometry. This review focuses on the examination of the current status of these technologies as they relate to the discovery and development of novel preclinical biomarkers of hepatotoxicity. A critical assessment of the current literature reveals two distinct lines of safety biomarker investigation, (1) peripheral fluid biomarkers of organ toxicity and (2) tissue or cell-based toxicity signatures. Improved peripheral fluid biomarkers should allow the sensitive detection of potential organ toxicity prior to the onset of overt organ pathology. Advancements in tissue or cell-based toxicity biomarkers will provide sensitive in vitro or ex vivo screening systems based on toxicity pathway markers. An examination of the current practices in clinical pathology and the critical evaluation of some recently proposed biomarker candidates in comparison to the desired characteristics of an ideal toxicity biomarker lead this author to conclude that a combination of selected biomarkers will be more informative if not predictive of potential animal organ toxicity than any single biomarker, new or old. For the practical assessment of combinations of conventional and/or novel toxicity biomarkers in rodent and large animal preclinical species, mass spectrometry has emerged as the premier analytical tool compared to specific immunoassays or functional assays. Selected and multiple reaction monitoring mass spectrometry applications make it possible for this same basic technology to be used in the progressive stages of biomarker discovery, development, and more importantly, routine study applications without the use of specific antibody reagents. This technology combined with other 'omics' technologies can provide added

  3. Schizophrenia genomics and proteomics: are we any closer to biomarker discovery?

    Directory of Open Access Journals (Sweden)

    Kramer Alon

    2009-01-01

    Full Text Available Abstract The field of proteomics has made leaps and bounds in the last 10 years particularly in the fields of oncology and cardiovascular medicine. In comparison, neuroproteomics is still playing catch up mainly due to the relative complexity of neurological disorders. Schizophrenia is one such disorder, believed to be the results of multiple factors both genetic and environmental. Affecting over 2 million people in the US alone, it has become a major clinical and public health concern worldwide. This paper gives an update of schizophrenia biomarker research as reviewed by Lakhan in 2006 and gives us a rundown of the progress made during the last two years. Several studies demonstrate the potential of cerebrospinal fluid as a source of neuro-specific biomarkers. Genetic association studies are making headway in identifying candidate genes for schizophrenia. In addition, metabonomics, bioinformatics, and neuroimaging techniques are aiming to complete the picture by filling in knowledge gaps. International cooperation in the form of genomics and protein databases and brain banks is facilitating research efforts. While none of the recent developments described here in qualifies as biomarker discovery, many are likely to be stepping stones towards that goal.

  4. Identification of candidate epigenetic biomarkers for ovarian cancer detection

    NARCIS (Netherlands)

    Huang, Yi-Wen; Jansen, Rachel A.; Fabbri, Enrica; Potter, Dustin; Liyanarachchi, Sandya; Chan, Michael W. Y.; Liu, Joseph C.; Crijns, Anne P. G.; Brown, Robert; Nephew, Kenneth P.; Van Der Zee, Ate G. J.; Cohn, David E.; Yan, Pearlly S.; Huang, Tim H. -M.; Lin, Huey-Jen L.

    2009-01-01

    Ovarian cancer ranks the most lethal among gynecologic neoplasms in women. To develop potential biomarkers for diagnosis, we have identified five novel genes (CYP39A1, GTF2A1, FOXD4L4, EBP, and HAAO) that are hypermethylated in ovarian tumors, compared with the non-malignant normal ovarian surface e

  5. The Extracellular Domain of Neurotrophin Receptor p75 as a Candidate Biomarker for Amyotrophic Lateral Sclerosis

    OpenAIRE

    Shepheard, Stephanie R.; Tim Chataway; David W Schultz; Rush, Robert A.; Mary-Louise Rogers

    2014-01-01

    Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A) mouse model of the disease. The extracellul...

  6. Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection

    Energy Technology Data Exchange (ETDEWEB)

    Price, Richard W.; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E.; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena S.; Smith, Richard D.; Jacobs, Jon M.; Brown, Joseph N.; Gisslen, Magnus

    2013-12-13

    Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previouslydefined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

  7. Mass spectrometry in biomarker applications: from untargeted discovery to targeted verification, and implications for platform convergence and clinical application

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Richard D.

    2012-03-01

    It is really only in the last ten years that mass spectrometry (MS) has had a truly significant (but still small) impact on biomedical research. Much of this impact can be attributed to proteomics and its more basic applications. Early biomedical applications have included a number of efforts aimed at developing new biomarkers; however, the success of these endeavors to date have been quite modest - essentially confined to preclinical applications - and have often suffered from combinations of immature technology and hubris. Now that MS-based proteomics is reaching adolescence, it is appropriate to ask if and when biomarker-related applications will extend to the clinical realm, and what developments will be essential for this transition. Biomarker development can be described as a multistage process consisting of discovery, qualification, verification, research assay optimization, validation, and commercialization (1). From a MS perspective, it is possible to 'bin' measurements into 1 of 2 categories - those aimed at discovering potential protein biomarkers and those seeking to verify and validate biomarkers. Approaches in both categories generally involve digesting proteins (e.g., with trypsin) as a first step to yield peptides that can be effectively detected and identified with MS. Discovery-based approaches use broad 'unbiased' or 'undirected' measurements that attempt to cover as many proteins as possible in the hope of revealing promising biomarker candidates. A key challenge with this approach stems from the extremely large dynamic range (i.e., relative stoichiometry) of proteins of potential interest in biofluids such as plasma and the expectation that biomarker proteins of the greatest clinical value for many diseases may very well be present at low relative abundances (2). Protein concentrations in plasma extend from approximately 10{sup 10} pg/mL for albumin to approximately 10 pg/mL and below for interleukins and other

  8. Biomarker discovery in subclinical mycobacterial infections of cattle.

    Directory of Open Access Journals (Sweden)

    Meetu Seth

    Full Text Available BACKGROUND: Bovine tuberculosis is a highly prevalent infectious disease of cattle worldwide; however, infection in the United States is limited to 0.01% of dairy herds. Thus detection of bovine TB is confounded by high background infection with M. avium subsp. paratuberculosis. The present study addresses variations in the circulating peptidome based on the pathogenesis of two biologically similar mycobacterial diseases of cattle. METHODOLOGY/PRINCIPAL FINDINGS: We hypothesized that serum proteomes of animals in response to either M. bovis or M. paratuberculosis infection will display several commonalities and differences. Sera prospectively collected from animals experimentally infected with either M. bovis or M. paratuberculosis were analyzed using high-resolution proteomics approaches. iTRAQ, a liquid chromatography and tandem mass spectrometry approach, was used to simultaneously identify and quantify peptides from multiple infections and contemporaneous uninfected control groups. Four comparisons were performed: 1 M. bovis infection versus uninfected controls, 2 M. bovis versus M. paratuberculosis infection, 3 early, and 4 advanced M. paratuberculosis infection versus uninfected controls. One hundred and ten differentially elevated proteins (P < or = 0.05 were identified. Vitamin D binding protein precursor (DBP, alpha-1 acid glycoprotein, alpha-1B glycoprotein, fetuin, and serine proteinase inhibitor were identified in both infections. Transthyretin, retinol binding proteins, and cathelicidin were identified exclusively in M. paratuberculosis infection, while the serum levels of alpha-1-microglobulin/bikunin precursor (AMBP protein, alpha-1 acid glycoprotein, fetuin, and alpha-1B glycoprotein were elevated exclusively in M. bovis infected animals. CONCLUSIONS/SIGNIFICANCE: The discovery of these biomarkers has significant impact on the elucidation of pathogenesis of two mycobacterial diseases at the cellular and the molecular level and

  9. Validation of Candidate Serum Ovarian Cancer Biomarkers for Early Detection

    Directory of Open Access Journals (Sweden)

    Feng Su

    2007-01-01

    Full Text Available Objective: We have previously analyzed protein profi les using Surface Enhanced Laser Desorption and Ionization Time-Of-Flight Mass Spectroscopy (SELDI-TOF-MS [Kozak et al. 2003, Proc. Natl. Acad. Sci. U.S.A. 100:12343–8] and identified 3 differentially expressed serum proteins for the diagnosis of ovarian cancer (OC [Kozak et al. 2005, Proteomics, 5:4589–96], namely, apolipoprotein A-I (apoA-I, transthyretin (TTR and transferin (TF. The objective of the present study is to determine the efficacy of the three OC biomarkers for the detection of early stage (ES OC, in direct comparison to CA125.Methods: The levels of CA125, apoA-I, TTR and TF were measured in 392 serum samples [82 women with normal ovaries (N, 24 women with benign ovarian tumors (B, 85 women with ovarian tumors of low malignant potential (LMP, 126 women with early stage ovarian cancer (ESOC, and 75 women with late stage ovarian cancer (LSOC], obtained through the GOG and Cooperative Human Tissue Network. Following statistical analysis, multivariate regression models were built to evaluate the utility of the three OC markers in early detection.Results: Multiple logistic regression models (MLRM utilizing all biomarker values (CA125, TTR, TF and apoA-I from all histological subtypes (serous, mucinous, and endometrioid adenocarcinoma distinguished normal samples from LMP with 91% sensitivity (specifi city 92%, and normal samples from ESOC with a sensitivity of 89% (specifi city 92%. MLRM, utilizing values of all four markers from only the mucinous histological subtype showed that collectively, CA125, TTR, TF and apoA-I, were able to distinguish normal samples from mucinous LMP with 90% sensitivity, and further distinguished normal samples from early stage mucinous ovarian cancer with a sensitivity of 95%. In contrast, in serum samples from patients with mucinous tumors, CA125 alone was able to distinguish normal samples from LMP and early stage ovarian cancer with a sensitivity of

  10. Role of Systems Biology in Brain Injury Biomarker Discovery: Neuroproteomics Application.

    Science.gov (United States)

    Jaber, Zaynab; Aouad, Patrick; Al Medawar, Mohamad; Bahmad, Hisham; Abou-Abbass, Hussein; Ghandour, Hiba; Mondello, Stefania; Kobeissy, Firas

    2016-01-01

    Years of research in the field of neurotrauma have led to the concept of applying systems biology as a tool for biomarker discovery in traumatic brain injury (TBI). Biomarkers may lead to understanding mechanisms of injury and recovery in TBI and can be potential targets for wound healing, recovery, and increased survival with enhanced quality of life. The literature available on neurotrauma studies from both animal and clinical studies has provided rich insight on the molecular pathways and complex networks of TBI, elucidating the proteomics of this disease for the discovery of biomarkers. With such a plethora of information available, the data from the studies require databases with tools to analyze and infer new patterns and associations. The role of different systems biology tools and their use in biomarker discovery in TBI are discussed in this chapter. PMID:27604718

  11. HNRNPC as a candidate biomarker for chemoresistance in gastric cancer.

    Science.gov (United States)

    Huang, Hao; Han, Yong; Zhang, Cheng; Wu, Jian; Feng, Junnan; Qu, Like; Shou, Chengchao

    2016-03-01

    Chemoresistance is a major cause of treatment failure and high mortality in advanced gastric cancer (AGC). Currently, the mechanism of chemoresistance remains unclear, and there is no biomarker to accurately predict the efficacy of chemotherapy. In the present study, we established human gastric cancer (GC) cell lines resistant to 5-fluorouracil (5FU), paclitaxel (TA), or cisplatin (DDP) by gradient drug treatment and generated a novel monoclonal antibody 5B2 targeting heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC) overexpressed in chemoresistant GC cells. Overexpressing HNRNPC in GC cells promoted chemoresistance, and knockdown of HNRNPC by small interfering RNA (siRNA) reversed chemoresistance. By utilizing available datasets, we demonstrated that high level of HNRNPC transcript indicated poor overall survival (OS) and free of progression (FP). HNRNPC expression was negatively correlated with OS of GC patients treated with 5FU-based drugs and with time to progression (TTP) of GC patients treated with CF regimen. These data suggest the potential usefulness of HNRNPC as a prognostic and therapeutic marker of GC. PMID:26453116

  12. LCK: a new biomarker candidate for the early diagnosis of acute myocardial infarction.

    Science.gov (United States)

    Xu, Fei; Teng, Xiao; Yuan, Xin; Sun, Jiakang; Wu, Hengchao; Zheng, Zhe; Tang, Yue; Hu, Shengshou

    2014-12-01

    Acute myocardial infarction (AMI) is one of the most common cardiovascular emergencies, of which the molecular pathogenesis is still not fully understood. This study aimed to explore the differentially expressed genes (DEGs) and then identify the critical genes in AMI thus screening out potential biomarkers for the early diagnosis of this serious heart disease. The gene expression data of AMI patients (GSE19339) were downloaded from gene expression omnibus database. After preprocessing with affy package, the DEGs were screened out by significance analysis of microarray (SAM) algorithm within samr package. Then function and pathway enrichment analyses of the DEGs were carried out using DAVID (database for annotation visualization and integrated discovery software) online tools. Further, the relevant genes of AMI were screened out with GENETIC_ASSOCIATION_DB_DISEASE analysis and blastp alignment. Finally, the novel genes were subjected to transcription factor and protein-protein interaction network analyses. A total of 633 DEGs, including 378 up-regulated and 255 down-regulated, were screened out between AMI patients and normal control samples. Among those genes, several important ones such as PPAR, CCL2, HMOX1 and NPR1 were demonstrated to be related to AMI. Most importantly, a novel gene LCK (lymphocyte-specific protein tyrosine kinase) was significantly differentially expressed in AMI. Further analyses showed that LCK was involved in the expression regulation of CXCL12 (chemokine (C-X-C motif) ligand 12) and the expression of LCK can be regulated by different transcription factors. In this study, we provided a new insight into the mechanism of AMI and raised LCK as an attractive marker candidate in the diagnosis of this serious heart disease. PMID:25209966

  13. Discovery of Novel Biomarkers for Alzheimer's Disease from Blood

    Science.gov (United States)

    Long, Jintao; Pan, Genhua; Ifeachor, Emmanuel; Belshaw, Robert; Li, Xinzhong

    2016-01-01

    Blood-based biomarkers for Alzheimer's disease would be very valuable because blood is a more accessible biofluid and is suitable for repeated sampling. However, currently there are no robust and reliable blood-based biomarkers for practical diagnosis. In this study we used a knowledge-based protein feature pool and two novel support vector machine embedded feature selection methods to find panels consisting of two and three biomarkers. We validated these biomarker sets using another serum cohort and an RNA profile cohort from the brain. Our panels included the proteins ECH1, NHLRC2, HOXB7, FN1, ERBB2, and SLC6A13 and demonstrated promising sensitivity (>87%), specificity (>91%), and accuracy (>89%). PMID:27418712

  14. Feature Selection Methods for Early Predictive Biomarker Discovery Using Untargeted Metabolomic Data.

    Science.gov (United States)

    Grissa, Dhouha; Pétéra, Mélanie; Brandolini, Marion; Napoli, Amedeo; Comte, Blandine; Pujos-Guillot, Estelle

    2016-01-01

    Untargeted metabolomics is a powerful phenotyping tool for better understanding biological mechanisms involved in human pathology development and identifying early predictive biomarkers. This approach, based on multiple analytical platforms, such as mass spectrometry (MS), chemometrics and bioinformatics, generates massive and complex data that need appropriate analyses to extract the biologically meaningful information. Despite various tools available, it is still a challenge to handle such large and noisy datasets with limited number of individuals without risking overfitting. Moreover, when the objective is focused on the identification of early predictive markers of clinical outcome, few years before occurrence, it becomes essential to use the appropriate algorithms and workflow to be able to discover subtle effects among this large amount of data. In this context, this work consists in studying a workflow describing the general feature selection process, using knowledge discovery and data mining methodologies to propose advanced solutions for predictive biomarker discovery. The strategy was focused on evaluating a combination of numeric-symbolic approaches for feature selection with the objective of obtaining the best combination of metabolites producing an effective and accurate predictive model. Relying first on numerical approaches, and especially on machine learning methods (SVM-RFE, RF, RF-RFE) and on univariate statistical analyses (ANOVA), a comparative study was performed on an original metabolomic dataset and reduced subsets. As resampling method, LOOCV was applied to minimize the risk of overfitting. The best k-features obtained with different scores of importance from the combination of these different approaches were compared and allowed determining the variable stabilities using Formal Concept Analysis. The results revealed the interest of RF-Gini combined with ANOVA for feature selection as these two complementary methods allowed selecting the 48

  15. A targeted proteomic strategy for the measurement of oral cancer candidate biomarkers in human saliva.

    Science.gov (United States)

    Kawahara, Rebeca; Bollinger, James G; Rivera, César; Ribeiro, Ana Carolina P; Brandão, Thaís Bianca; Paes Leme, Adriana F; MacCoss, Michael J

    2016-01-01

    Head and neck cancers, including oral squamous cell carcinoma (OSCC), are the sixth most common malignancy in the world and are characterized by poor prognosis and a low survival rate. Saliva is oral fluid with intimate contact with OSCC. Besides non-invasive, simple, and rapid to collect, saliva is a potential source of biomarkers. In this study, we build an SRM assay that targets fourteen OSCC candidate biomarker proteins, which were evaluated in a set of clinically-derived saliva samples. Using Skyline software package, we demonstrated a statistically significant higher abundance of the C1R, LCN2, SLPI, FAM49B, TAGLN2, CFB, C3, C4B, LRG1, SERPINA1 candidate biomarkers in the saliva of OSCC patients. Furthermore, our study also demonstrated that CFB, C3, C4B, SERPINA1 and LRG1 are associated with the risk of developing OSCC. Overall, this study successfully used targeted proteomics to measure in saliva a panel of biomarker candidates for OSCC.

  16. Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection.

    Science.gov (United States)

    Price, Richard W; Peterson, Julia; Fuchs, Dietmar; Angel, Thomas E; Zetterberg, Henrik; Hagberg, Lars; Spudich, Serena; Smith, Richard D; Jacobs, Jon M; Brown, Joseph N; Gisslen, Magnus

    2013-12-01

    Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

  17. Enrichment of MCI and early Alzheimer's disease treatment trials using neurochemical and imaging candidate biomarkers.

    LENUS (Irish Health Repository)

    Hampel, H

    2012-02-01

    In the earliest clinical stages of Alzheimer\\'s Disease (AD), when symptoms are mild, clinical diagnosis will still be difficult. AD related molecular mechanisms precede symptoms. Biological markers can serve as early diagnostic indicators, as markers of preclinical pathological change, e.g. underlying mechanisms of action (MoA). Hypothesis based candidates are derived from structural and functional neuroimaging as well as from cerebrospinal fluid (CSF) and plasma. Unbiased exploratory approaches e.g. proteome analysis or rater independent fully automated imaging post-processing methods yield novel candidates. Recent progress in the validation of core feasible imaging and neurochemical biomarkers for functions such as early detection, classification, progression and prediction of AD is summarized. Single core feasible biomarkers can already be used to enrich populations at risk for AD and may be further enhanced using distinct combinations. Some biomarkers are currently in the process of implementation as primary or secondary outcome variables into regulatory guideline documents, e.g. regarding phase II in drug development programs as outcome measures in proof of concept or dose finding studies. There are specific biomarkers available depending on the hypothesized mechanism of action of a medicinal product, e.g. impact on the amyloidogenic cascade or on tauhyperphosphorylation. Ongoing large-scale international controlled multi-center trials will provide further validation of selected core feasible imaging and CSF biomarker candidates as outcome measures in early AD for use in phase III clinical efficacy trials. There is a need of rigorous co-development of biological trait- and statemarker candidates facilitated through planned synergistic collaboration between academic, industrial and regulatory partners.

  18. Chemometric Multivariate Tools for Candidate Biomarker Identification: LDA, PLS-DA, SIMCA, Ranking-PCA.

    Science.gov (United States)

    Robotti, Elisa; Marengo, Emilio

    2016-01-01

    2-D gel electrophoresis usually provides complex maps characterized by a low reproducibility: this hampers the use of spot volume data for the identification of reliable biomarkers. Under these circumstances, effective and robust methods for the comparison and classification of 2-D maps are fundamental for the identification of an exhaustive panel of candidate biomarkers. Multivariate methods are the most suitable since they take into consideration the relationships between the variables, i.e., effects of synergy and antagonism between the spots. Here the most common multivariate methods used in spot volume datasets analysis are presented. The methods are applied on a sample dataset to prove their effectiveness.

  19. Discovery of optical candidate supernova remnants in Sagittarius

    Science.gov (United States)

    Alikakos, J.; Boumis, P.; Christopoulou, P. E.; Goudis, C. D.

    2012-08-01

    During an [O III] survey of planetary nebulae, we identified a region in Sagittarius containing several candidate supernova remants (SNRs) and obtained deep optical narrow-band images and spectra to explore their nature. We obtained images of the area of interest by acquiring observations in the emission lines of Hα + [N II], [S II] and [O III]. The resulting mosaic covers an area of 1.4° × 1.0°, where both filamentary and diffuse emission was discovered, suggesting that there is more than one SNR in the area. Deep long-slit spectra were also taken of eight different regions. Both the flux-calibrated images and the spectra show that the emission from the filamentary structures originates from shock-heated gas, while the photo-ionization mechanism is responsible for the diffuse emission. Part of the optical emission is found to be correlated with the radio at 4850 MHz suggesting that they are related, while the infrared emission found in the area at 12 μm and 22 μm marginally correlates with the optical. The presence of the [O III] emission line in one of the candidate SNRs implies that the shock velocities in the interstellar "clouds" are between 120 km s-1 and 200 km s-1, while its absence in the other candidate SNRs indicates that the shock velocities there are slower. For all candidate remnants, the [S II] λλ 6716/6731 ratio indicates that the electron densities are below 240 cm-3, while the Hα emission is measured to be between 0.6 and 41 × 10-17 erg s-1 cm-2 arcsec-2. The existence of eight pulsars within 1.5° of the center of the candidate SNRs also implies that there are many SNRs in the area as well as that the detected optical emission could be part of a number of supernovae explosions.

  20. Discovery of the candidate Kuiper belt object 1992 QB1

    Science.gov (United States)

    Jewitt, David; Luu, Jane

    1993-01-01

    The discovery of a new faint object in the outer solar system, 1992 QB1, moving beyond the orbit of Neptune is reported. It is suggested that the 1992 QB1 may represent the first detection of a member of the Kuiper belt (Edgworth, 1949; Kuiper, 1951), the hypothesized population of objects beyond Neptune and a possible source of the short-period comets, as suggested by Whipple (1964), Fernandez (1980), and Duncan et al. (1988).

  1. Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies.

    Science.gov (United States)

    Long, Nguyen Phuoc; Lee, Wun Jun; Huy, Nguyen Truong; Lee, Seul Ji; Park, Jeong Hill; Kwon, Sung Won

    2016-01-01

    Colorectal cancer (CRC) is one of the most common and lethal cancers. Although numerous studies have evaluated potential biomarkers for early diagnosis, current biomarkers have failed to reach an acceptable level of accuracy for distant metastasis. In this paper, we performed a gene set meta-analysis of in vitro microarray studies and combined the results from this study with previously published proteomic data to validate and suggest prognostic candidates for CRC metastasis. Two microarray data sets included found 21 significant genes. Of these significant genes, ALDOA, IL8 (CXCL8), and PARP4 had strong potential as prognostic candidates. LAMB2, MCM7, CXCL23A, SERPINA3, ABCA3, ALDH3A2, and POLR2I also have potential. Other candidates were more controversial, possibly because of the biologic heterogeneity of tumor cells, which is a major obstacle to predicting metastasis. In conclusion, we demonstrated a meta-analysis approach and successfully suggested ten biomarker candidates for future investigation. PMID:27688707

  2. Multicentre quality control evaluation of different biomarker candidates for amyotrophic lateral sclerosis.

    Science.gov (United States)

    Lehnert, Stefan; Costa, Julia; de Carvalho, Mamede; Kirby, Janine; Kuzma-Kozakiewicz, Magdalena; Morelli, Claudia; Robberecht, Wim; Shaw, Pamela; Silani, Vincenzo; Steinacker, Petra; Tumani, Hayrettin; Van Damme, Philip; Ludolph, Albert; Otto, Markus

    2014-09-01

    Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that mainly causes degeneration of the upper and lower motor neurons, ultimately leading to paralysis and death within three to five years after first symptoms. The pathological mechanisms leading to ALS are still not completely understood. Several biomarker candidates have been proposed in cerebrospinal fluid (CSF). However, none of these has successfully translated into clinical routine. Part of the reason for this failure to translate may relate to differences across laboratories. For this reason, several of the most commonly used ALS biomarker candidates were evaluated on clinically well-defined ALS samples from six European centres in a multicentre sample-collection approach with centralized sample processing. Results showed that phosphorylated neurofilament heavy chain differentiated between ALS and control cases in all centres. We therefore propose that measurement of phosphorylated neurofilaments in CSF is the most promising candidate for translation into the clinical setting and might serve as a benchmark for other biomarker candidates.

  3. The Clinical Impact of Recent Advances in LC-MS for Cancer Biomarker Discovery and Verification

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Hui; Shi, Tujin; Qian, Weijun; Liu, Tao; Kagan, Jacob; Srivastava, Sudhir; Smith, Richard D.; Rodland, Karin D.; Camp, David G.

    2016-01-01

    Mass spectrometry-based proteomics has become an indispensable tool in biomedical research with broad applications ranging from fundamental biology, systems biology, and biomarker discovery. Recent advances in LC-MS have made it become a major technology in clinical applications, especially in cancer biomarker discovery and verification. To overcome the challenges associated with the analysis of clinical samples, such as extremely wide dynamic range of protein concentrations in biofluids and the need to perform high throughput and accurate quantification, significant efforts have been devoted to improve the overall performance of LC-MS bases clinical proteomics. In this review, we summarize the recent advances in LC-MS in the aspect of cancer biomarker discovery and quantification, and discuss its potentials, limitations, and future perspectives.

  4. Computational and Experimental Approaches to Cancer Biomarker Discovery

    DEFF Research Database (Denmark)

    Krzystanek, Marcin

    Effective cancer treatment requires good biomarkers: measurable indicators of some biological state or condition that constitute the cornerstone of personalized medicine. Prognostic biomarkers provide information about the likely course of the disease, while predictive biomarkers enable prediction...... was sequenced, assembled and characterized, which is described in the thesis. We are currently using it as a model system in our framework for functional analysis study of DNA repair mechanisms and cytotoxic effects. We hope that the experimentally derived mutational signatures will be useful as a part...... are expected.This work, together with manifold of efforts being done all over the world, is hopefully a step towards implementation of personalized medicine and better treatments for cancer patients. ...

  5. Effect of size and heterogeneity of samples on biomarker discovery: synthetic and real data assessment.

    OpenAIRE

    Barbara Di Camillo; Tiziana Sanavia; Matteo Martini; Giuseppe Jurman; Francesco Sambo; Annalisa Barla; Margherita Squillario; Cesare Furlanello; Gianna Toffolo; Claudio Cobelli

    2012-01-01

    MOTIVATION: The identification of robust lists of molecular biomarkers related to a disease is a fundamental step for early diagnosis and treatment. However, methodologies for the discovery of biomarkers using microarray data often provide results with limited overlap. These differences are imputable to 1) dataset size (few subjects with respect to the number of features); 2) heterogeneity of the disease; 3) heterogeneity of experimental protocols and computational pipelines employed in the a...

  6. Discovery and development of DNA methylation-based biomarkers for lung cancer.

    Science.gov (United States)

    Walter, Kimberly; Holcomb, Thomas; Januario, Tom; Yauch, Robert L; Du, Pan; Bourgon, Richard; Seshagiri, Somasekar; Amler, Lukas C; Hampton, Garret M; S Shames, David

    2014-02-01

    Lung cancer remains the primary cause of cancer-related deaths worldwide. Improved tools for early detection and therapeutic stratification would be expected to increase the survival rate for this disease. Alterations in the molecular pathways that drive lung cancer, which include epigenetic modifications, may provide biomarkers to help address this major unmet clinical need. Epigenetic changes, which are defined as heritable changes in gene expression that do not alter the primary DNA sequence, are one of the hallmarks of cancer, and prevalent in all types of cancer. These modifications represent a rich source of biomarkers that have the potential to be implemented in clinical practice. This perspective describes recent advances in the discovery of epigenetic biomarkers in lung cancer, specifically those that result in the methylation of DNA at CpG sites. We discuss one approach for methylation-based biomarker assay development that describes the discovery at a genome-scale level, which addresses some of the practical considerations for design of assays that can be implemented in the clinic. We emphasize that an integrated technological approach will enable the development of clinically useful DNA methylation-based biomarker assays. While this article focuses on current literature and primary research findings in lung cancer, the principles we describe here apply to the discovery and development of epigenetic biomarkers for other types of cancer.

  7. High-Sensitivity and Low-Toxicity Fucose Probe for Glycan Imaging and Biomarker Discovery.

    Science.gov (United States)

    Kizuka, Yasuhiko; Funayama, Sho; Shogomori, Hidehiko; Nakano, Miyako; Nakajima, Kazuki; Oka, Ritsuko; Kitazume, Shinobu; Yamaguchi, Yoshiki; Sano, Masahiro; Korekane, Hiroaki; Hsu, Tsui-Ling; Lee, Hsiu-Yu; Wong, Chi-Huey; Taniguchi, Naoyuki

    2016-07-21

    Fucose, a terminal sugar in glycoconjugates, critically regulates various physiological and pathological phenomena, including cancer development and inflammation. However, there are currently no probes for efficient labeling and detection of this sugar. We chemically synthesized a novel series of alkynyl-fucose analogs as probe candidates and found that 7-alkynyl-fucose gave the highest labeling efficiency and low cytotoxicity. Among the fucose analogs, 7-alkynyl-fucose was the best substrate against all five fucosyltransferases examined. We confirmed its conversion to the corresponding guanosine diphosphate derivative in cells and found that cellular glycoproteins were labeled much more efficiently with 7-alkynyl-fucose than with an existing probe. 7-Alkynyl-fucose was detected in the N-glycan core by mass spectrometry, and 7-alkynyl-fucose-modified proteins mostly disappeared in core-fucose-deficient mouse embryonic fibroblasts, suggesting that this analog mainly labeled core fucose in these cells. These results indicate that 7-alkynyl-fucose is a highly sensitive and powerful tool for basic glycobiology research and clinical application for biomarker discovery. PMID:27447047

  8. High-Sensitivity and Low-Toxicity Fucose Probe for Glycan Imaging and Biomarker Discovery.

    Science.gov (United States)

    Kizuka, Yasuhiko; Funayama, Sho; Shogomori, Hidehiko; Nakano, Miyako; Nakajima, Kazuki; Oka, Ritsuko; Kitazume, Shinobu; Yamaguchi, Yoshiki; Sano, Masahiro; Korekane, Hiroaki; Hsu, Tsui-Ling; Lee, Hsiu-Yu; Wong, Chi-Huey; Taniguchi, Naoyuki

    2016-07-21

    Fucose, a terminal sugar in glycoconjugates, critically regulates various physiological and pathological phenomena, including cancer development and inflammation. However, there are currently no probes for efficient labeling and detection of this sugar. We chemically synthesized a novel series of alkynyl-fucose analogs as probe candidates and found that 7-alkynyl-fucose gave the highest labeling efficiency and low cytotoxicity. Among the fucose analogs, 7-alkynyl-fucose was the best substrate against all five fucosyltransferases examined. We confirmed its conversion to the corresponding guanosine diphosphate derivative in cells and found that cellular glycoproteins were labeled much more efficiently with 7-alkynyl-fucose than with an existing probe. 7-Alkynyl-fucose was detected in the N-glycan core by mass spectrometry, and 7-alkynyl-fucose-modified proteins mostly disappeared in core-fucose-deficient mouse embryonic fibroblasts, suggesting that this analog mainly labeled core fucose in these cells. These results indicate that 7-alkynyl-fucose is a highly sensitive and powerful tool for basic glycobiology research and clinical application for biomarker discovery.

  9. Weighted gene co-expression based biomarker discovery for psoriasis detection.

    Science.gov (United States)

    Sundarrajan, Sudharsana; Arumugam, Mohanapriya

    2016-11-15

    Psoriasis is a chronic inflammatory disease of the skin with an unknown aetiology. The disease manifests itself as red and silvery scaly plaques distributed over the scalp, lower back and extensor aspects of the limbs. After receiving scant consideration for quite a few years, psoriasis has now become a prominent focus for new drug development. A group of closely connected and differentially co-expressed genes may act in a network and may serve as molecular signatures for an underlying phenotype. A weighted gene coexpression network analysis (WGCNA), a system biology approach has been utilized for identification of new molecular targets for psoriasis. Gene coexpression relationships were investigated in 58 psoriatic lesional samples resulting in five gene modules, clustered based on the gene coexpression patterns. The coexpression pattern was validated using three psoriatic datasets. 10 highly connected and informative genes from each module was selected and termed as psoriasis specific hub signatures. A random forest based binary classifier built using the expression profiles of signature genes robustly distinguished psoriatic samples from the normal samples in the validation set with an accuracy of 0.95 to 1. These signature genes may serve as potential candidates for biomarker discovery leading to new therapeutic targets. WGCNA, the network based approach has provided an alternative path to mine out key controllers and drivers of psoriasis. The study principle from the current work can be extended to other pathological conditions.

  10. Biomarker discovery in systemic sclerosis: state of the art

    Directory of Open Access Journals (Sweden)

    Bonella F

    2015-07-01

    Full Text Available Francesco Bonella,1 Giuseppe Patuzzo,2 Claudio Lunardi2 1Interstitial and Rare Lung Disease Unit, Ruhrlandklinik University Hospital, University of Duisburg-Essen, Essen, Germany; 2Department of Medicine, University of Verona, Verona, Italy Abstract: Systemic sclerosis (SSc is an autoimmune disease characterized by immune dysfunction and by abnormalities of the microvasculature with vascular obliteration, eventually leading to fibrosis of the skin, gastrointestinal tract, lungs, heart, and kidney. The etiology and pathogenesis of SSc remain unclear, despite recent significant progress in the field. Immune activation and microangiopathy are followed by widespread organ fibrosis, leading to organ failure and increased mortality. The production of inflammatory cytokines and growth factors after tissue injury, as well as the presence of circulating autoantibodies, provide a source of biomarkers with potential diagnostic and prognostic applications in the clinical routine. Two principal approaches exist to discover and characterize biomarkers. The proof-of-concept approach verifies the ability of known proteins, generally involved in the pathogenesis, to correlate with disease phenotype and outcome. A proteomic approach does not need prior knowledge of the proteins or of their function, but it requires high-performance and time-consuming techniques. In this review, we highlight the most recent findings in biomarkers used to characterize SSc organ involvement, to stratify the patients, and to assess the response to treatment. Keywords: systemic sclerosis, biomarkers, proteomics, gene expression profiling

  11. Speeding disease gene discovery by sequence based candidate prioritization

    Directory of Open Access Journals (Sweden)

    Porteous David J

    2005-03-01

    Full Text Available Abstract Background Regions of interest identified through genetic linkage studies regularly exceed 30 centimorgans in size and can contain hundreds of genes. Traditionally this number is reduced by matching functional annotation to knowledge of the disease or phenotype in question. However, here we show that disease genes share patterns of sequence-based features that can provide a good basis for automatic prioritization of candidates by machine learning. Results We examined a variety of sequence-based features and found that for many of them there are significant differences between the sets of genes known to be involved in human hereditary disease and those not known to be involved in disease. We have created an automatic classifier called PROSPECTR based on those features using the alternating decision tree algorithm which ranks genes in the order of likelihood of involvement in disease. On average, PROSPECTR enriches lists for disease genes two-fold 77% of the time, five-fold 37% of the time and twenty-fold 11% of the time. Conclusion PROSPECTR is a simple and effective way to identify genes involved in Mendelian and oligogenic disorders. It performs markedly better than the single existing sequence-based classifier on novel data. PROSPECTR could save investigators looking at large regions of interest time and effort by prioritizing positional candidate genes for mutation detection and case-control association studies.

  12. Manifold Learning for Biomarker Discovery in MR Imaging

    Science.gov (United States)

    Wolz, Robin; Aljabar, Paul; Hajnal, Joseph V.; Rueckert, Daniel

    We propose a framework for the extraction of biomarkers from low-dimensional manifolds representing inter- and intra-subject brain variation in MR image data. The coordinates of each image in such a low-dimensional space captures information about structural shape and appearance and, when a phenotype exists, about the subject's clinical state. A key contribution is that we propose a method for incorporating longitudinal image information in the learned manifold. In particular, we compare simultaneously embedding baseline and follow-up scans into a single manifold with the combination of separate manifold representations for inter-subject and intra-subject variation. We apply the proposed methods to 362 subjects enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and classify healthy controls, subjects with Alzheimer's disease (AD) and subjects with mild cognitive impairment (MCI). Learning manifolds based on both the appearance and temporal change of the hippocampus, leads to correct classification rates comparable with those provided by state-of-the-art automatic segmentation estimates of hippocampal volume and atrophy. The biomarkers identified with the proposed method are data-driven and represent a potential alternative to a-priori defined biomarkers derived from manual or automated segmentations.

  13. Biomarker discovery by proteomics : challenges not only for the analytical chemist

    NARCIS (Netherlands)

    Horvatovich, Peter; Govorukhina, Natalia; Bischoff, Rainer

    2006-01-01

    This forum article outlines some of the major challenges in present day biomarker discovery research. Notably the dilemma of reaching sufficient concentration sensitivity versus the required analysis time per sample is highlighted using a model calculation. A number of possible developments and rece

  14. Biomarker discovery by proteomics: challenges not only for the analytical chemist

    NARCIS (Netherlands)

    Horvatovich, P.; Govorukhina, N.I; Bischoff, Rainer

    2006-01-01

    This forum article outlines some of the major challenges in present day biomarker discovery research. Notably the dilemma of reaching sufficient concentration sensitivity versus the required analysis time per sample is highlighted using a model calculation. A number of possible developments and rece

  15. A Critical Assessment of Feature Selection Methods for Biomarker Discovery in Clinical Proteomics

    NARCIS (Netherlands)

    Christin, Christin; Hoefsloot, Huub C. J.; Smilde, Age K.; Hoekman, B.; Suits, Frank; Bischoff, Rainer; Horvatovich, Peter

    2013-01-01

    In this paper, we compare the performance of six different feature selection methods for LC-MS-based proteomics and metabolomics biomarker discovery-t test, the Mann-Whitney-Wilcoxon test (mww test), nearest shrunken centroid (NSC), linear support vector machine-recursive features elimination (SVM-R

  16. Cancer Stem Cell Biomarker Discovery Using Antibody Array Technology.

    Science.gov (United States)

    Burgess, Rob; Huang, Ruo-Pan

    2016-01-01

    Cancer is a complex disease involving hundreds of pathways and numerous levels of disease progression. In addition, there is a growing body of evidence that the origins and growth rates of specific types of cancer may involve "cancer stem cells," which are defined as "cells within a tumor that possess the capacity to self-renew and to cause the development of heterogeneous lineages of cancer cells that comprise the tumor.(1)" Many types of cancer are now thought to harbor cancer stem cells. These cells themselves are thought to be unique in comparison to other cells types present within the tumor and to exhibit characteristics that allow for the promotion of tumorigenesis and in some cases metastasis. In addition, it is speculated that each type of cancer stem cell exhibits a unique set of molecular and biochemical markers. These markers, alone or in combination, may act as a signature for defining not only the type of cancer but also the progressive state. These biomarkers may also double as signaling entities which act autonomously or upon neighboring cancer stem cells or other cells within the local microenvironment to promote tumorigenesis. This review describes the heterogeneic properties of cancer stem cells and outlines the identification and application of biomarkers and signaling molecules defining these cells as they relate to different forms of cancer. Other examples of biomarkers and signaling molecules expressed by neighboring cells in the local tumor microenvironment are also discussed. In addition, biochemical signatures for cancer stem cell autocrine/paracrine signaling, local site recruitment, tumorigenic potential, and conversion to a stem-like phenotype are described.

  17. Biomarker discovery in neurological diseases: a metabolomic approach

    Directory of Open Access Journals (Sweden)

    Afaf El-Ansary

    2009-12-01

    Full Text Available Afaf El-Ansary, Nouf Al-Afaleg, Yousra Al-YafaeeBiochemistry Department, Science College, King Saud University, Riyadh, Saudi ArabiaAbstract: Biomarkers are pharmacological and physiological measurements or specific biochemicals in the body that have a particular molecular feature that makes them useful for measuring the progress of disease or the effects of treatment. Due to the complexity of neurological disorders, it is very difficult to have perfect markers. Brain diseases require plenty of markers to reflect the metabolic impairment of different brain cells. The recent introduction of the metabolomic approach helps the study of neurological diseases based on profiling a multitude of biochemical components related to brain metabolism. This review is a trial to elucidate the possibility to use this approach to identify plasma metabolic markers related to neurological disorders. Previous trials using different metabolomic analyses including nuclear magnetic resonance spectroscopy, gas chromatography combined with mass spectrometry, liquid chromatography combined with mass spectrometry, and capillary electrophoresis will be traced.Keywords: metabolic biomarkers, neurological disorders. metabolome, nuclear magnetic resonance, mass spectrometry, chromatography

  18. Identification of Site-Specific Stroke Biomarker Candidates by Laser Capture Microdissection and Labeled Reference Peptide

    Directory of Open Access Journals (Sweden)

    Tingting Lian

    2015-06-01

    Full Text Available The search to date for accurate protein biomarkers in acute ischemic stroke has taken into consideration the stage and/or the size of infarction, but has not accounted for the site of stroke. In the present study, multiple reaction monitoring using labeled reference peptide (LRP following laser capture microdissection (LCM is used to identify site-specific protein biomarker candidates. In middle cerebral artery occlusion (MCAO rat models, both intact and infarcted brain tissue was collected by LCM, followed by on-film digestion and semi-quantification using triple-quadrupole mass spectrometry. Thirty-four unique peptides were detected for the verification of 12 proteins in both tissue homogenates and LCM-captured samples. Six insoluble proteins, including neurofilament light polypeptide (NEFL, alpha-internexin (INA, microtubule-associated protein 2 (MAP2, myelin basic protein (MBP, myelin proteolipid protein (PLP and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNP, were found to be site-specific. Soluble proteins, such as neuron-specific enolase (NSE and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1, and some insoluble proteins, including neurofilament heavy polypeptide (NEFH, glial fibrillary acidic protein (GFAP, microtubule-associated protein tau (MAPT and tubulin β-3 chain (TUBB3, were found to be evenly distributed in the brain. Therefore, we conclude that some insoluble protein biomarkers for stroke are site-specific, and would make excellent candidates for the design and analysis of relevant clinical studies in the future.

  19. 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.

  20. Probing the O-glycoproteome of Gastric Cancer Cell Lines for Biomarker Discovery

    DEFF Research Database (Denmark)

    Vieira Campos, Diana Alexandra; Freitas, Daniela; Gomes, Joana;

    2015-01-01

    and healthy individuals to identify circulating O-glycoproteins with the STn glycoform. We identified 37 O-glycoproteins in the pool of cancer sera, and only 9 of these were also found in sera from healthy individuals. Two identified candidate O-glycoprotein biomarkers (CD44 and GalNAc-T5) circulating...

  1. Identification of candidate diagnostic biomarkers for adolescent idiopathic scoliosis using UPLC/QTOF-MS analysis: a first report of lipid metabolism profiles

    Science.gov (United States)

    Sun, Zhi-jian; Jia, Hong-mei; Qiu, Gui-xing; Zhou, Chao; Guo, Shigong; Zhang, Jian-guo; Shen, Jian-xiong; Zhao, Yu; Zou, Zhong-mei

    2016-01-01

    Adolescent idiopathic scoliosis (AIS) is a complex spine deformity, affecting approximately 1–3% adolescents. Earlier diagnosis could increase the likelihood of successful conservative treatment and hence reduce the need for surgical intervention. We conducted a serum metabonomic study to explore the potential biomarkers of AIS for early diagnosis. Serum metabolic profiles were firstly explored between 30 AIS patients and 31 healthy controls by ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Then, the candidate metabolites were validated in an independent cohort including 31 AIS patients and 44 controls. The results showed that metabolic profiles of AIS patients generally deviated from healthy controls in both the discovery set and replication set. Seven differential metabolites were identified as candidate diagnostic biomarkers, including PC(20:4), 2-hexenoylcarnitine, beta-D-glucopyranuronicacid, DG(38:9), MG(20:3), LysoPC(18:2) and LysoPC(16:0). These candidate metabolites indicated disrupted lipid metabolism in AIS, including glycerophospholipid, glycerolipid and fatty acid metabolism. Elevated expressions of adipose triglyceride lipase and hormone sensitive lipase in adipose tissue further corroborated our findings of increased lipid metabolism in AIS. Our findings suggest that differential metabolites discovered in AIS could be used as potential diagnostic biomarkers and that lipid metabolism plays a role in the pathogenesis of AIS. PMID:26928931

  2. Statistical considerations of optimal study design for human plasma proteomics and biomarker discovery.

    Science.gov (United States)

    Zhou, Cong; Simpson, Kathryn L; Lancashire, Lee J; Walker, Michael J; Dawson, Martin J; Unwin, Richard D; Rembielak, Agata; Price, Patricia; West, Catharine; Dive, Caroline; Whetton, Anthony D

    2012-04-01

    A mass spectrometry-based plasma biomarker discovery workflow was developed to facilitate biomarker discovery. Plasma from either healthy volunteers or patients with pancreatic cancer was 8-plex iTRAQ labeled, fractionated by 2-dimensional reversed phase chromatography and subjected to MALDI ToF/ToF mass spectrometry. Data were processed using a q-value based statistical approach to maximize protein quantification and identification. Technical (between duplicate samples) and biological variance (between and within individuals) were calculated and power analysis was thereby enabled. An a priori power analysis was carried out using samples from healthy volunteers to define sample sizes required for robust biomarker identification. The result was subsequently validated with a post hoc power analysis using a real clinical setting involving pancreatic cancer patients. This demonstrated that six samples per group (e.g., pre- vs post-treatment) may provide sufficient statistical power for most proteins with changes>2 fold. A reference standard allowed direct comparison of protein expression changes between multiple experiments. Analysis of patient plasma prior to treatment identified 29 proteins with significant changes within individual patient. Changes in Peroxiredoxin II levels were confirmed by Western blot. This q-value based statistical approach in combination with reference standard samples can be applied with confidence in the design and execution of clinical studies for predictive, prognostic, and/or pharmacodynamic biomarker discovery. The power analysis provides information required prior to study initiation.

  3. New trends in molecular and cellular biomarker discovery for colorectal cancer.

    Science.gov (United States)

    Aghagolzadeh, Parisa; Radpour, Ramin

    2016-07-01

    Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, which is consequence of multistep tumorigenesis of several genetic and epigenetic events. Since CRC is mostly asymptomatic until it progresses to advanced stages, the early detection using effective screening approaches, selection of appropriate therapeutic strategies and efficient follow-up programs are essential to reduce CRC mortalities. Biomarker discovery for CRC based on the personalized genotype and clinical information could facilitate the classification of patients with certain types and stages of cancer to tailor preventive and therapeutic approaches. These cancer-related biomarkers should be highly sensitive and specific in a wide range of specimen(s) (including tumor tissues, patients' fluids or stool). Reliable biomarkers which enable the early detection of CRC, can improve early diagnosis, prognosis, treatment response prediction, and recurrence risk. Advances in our understanding of the natural history of CRC have led to the development of different CRC associated molecular and cellular biomarkers. This review highlights the new trends and approaches in CRC biomarker discovery, which could be potentially used for early diagnosis, development of new therapeutic approaches and follow-up of patients. PMID:27433083

  4. New trends in molecular and cellular biomarker discovery for colorectal cancer

    Science.gov (United States)

    Aghagolzadeh, Parisa; Radpour, Ramin

    2016-01-01

    Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, which is consequence of multistep tumorigenesis of several genetic and epigenetic events. Since CRC is mostly asymptomatic until it progresses to advanced stages, the early detection using effective screening approaches, selection of appropriate therapeutic strategies and efficient follow-up programs are essential to reduce CRC mortalities. Biomarker discovery for CRC based on the personalized genotype and clinical information could facilitate the classification of patients with certain types and stages of cancer to tailor preventive and therapeutic approaches. These cancer-related biomarkers should be highly sensitive and specific in a wide range of specimen(s) (including tumor tissues, patients’ fluids or stool). Reliable biomarkers which enable the early detection of CRC, can improve early diagnosis, prognosis, treatment response prediction, and recurrence risk. Advances in our understanding of the natural history of CRC have led to the development of different CRC associated molecular and cellular biomarkers. This review highlights the new trends and approaches in CRC biomarker discovery, which could be potentially used for early diagnosis, development of new therapeutic approaches and follow-up of patients. PMID:27433083

  5. Proteomics in Cancer Biomarkers Discovery: Challenges and Applications

    Directory of Open Access Journals (Sweden)

    Reem M. Sallam

    2015-01-01

    Full Text Available With the introduction of recent high-throughput technologies to various fields of science and medicine, it is becoming clear that obtaining large amounts of data is no longer a problem in modern research laboratories. However, coherent study designs, optimal conditions for obtaining high-quality data, and compelling interpretation, in accordance with the evidence-based systems biology, are critical factors in ensuring the emergence of good science out of these recent technologies. This review focuses on the proteomics field and its new perspectives on cancer research. Cornerstone publications that have tremendously helped scientists and clinicians to better understand cancer pathogenesis; to discover novel diagnostic and/or prognostic biomarkers; and to suggest novel therapeutic targets will be presented. The author of this review aims at presenting some of the relevant literature data that helped as a step forward in bridging the gap between bench work results and bedside potentials. Undeniably, this review cannot include all the work that is being produced by expert research groups all over the world.

  6. Improving the quality of biomarker candidates in untargeted metabolomics via peak table-based alignment of comprehensive two-dimensional gas chromatography-mass spectrometry data.

    Science.gov (United States)

    Bean, Heather D; Hill, Jane E; Dimandja, Jean-Marie D

    2015-05-15

    The potential of high-resolution analytical technologies like GC×GC/TOF MS in untargeted metabolomics and biomarker discovery has been limited by the development of fully automated software that can efficiently align and extract information from multiple chromatographic data sets. In this work we report the first investigation on a peak-by-peak basis of the chromatographic factors that impact GC×GC data alignment. A representative set of 16 compounds of different chromatographic characteristics were followed through the alignment of 63 GC×GC chromatograms. We found that varying the mass spectral match parameter had a significant influence on the alignment for poorly-resolved peaks, especially those at the extremes of the detector linear range, and no influence on well-chromatographed peaks. Therefore, optimized chromatography is required for proper GC×GC data alignment. Based on these observations, a workflow is presented for the conservative selection of biomarker candidates from untargeted metabolomics analyses. PMID:25857541

  7. Isolation and Quantification of MicroRNAs from Urinary Exosomes/Microvesicles for Biomarker Discovery

    OpenAIRE

    Lv, Lin-Li; Cao, Yuhan; Liu, Dan; Xu, Min; Liu, Hong; Tang, Ri-Ning; Ma, Kun-Ling; Liu, Bi-Cheng

    2013-01-01

    Recent studies indicate that microRNA (miRNA) is contained within exosome. Here we sought to optimize the methodologies for the isolation and quantification of urinary exosomal microRNA as a prelude to biomarker discovery studies. Exosomes were isolated through ultracentrifugation and characterized by immunoelectron microscopy. To determine the RNA was confined inside exosomes, the pellet was treated with RNase before RNA isolation. The minimum urine volume, storage conditions for exosomes an...

  8. Quantitative proteomics in resected renal cancer tissue for biomarker discovery and profiling

    OpenAIRE

    Atrih, A; Mudaliar, M A V; Zakikhani, P; Lamont, D J; Huang, J T-J; Bray, S.E.; Barton, G.; Fleming, S; Nabi, G.

    2014-01-01

    Background: Proteomics-based approaches for biomarker discovery are promising strategies used in cancer research. We present state-of-art label-free quantitative proteomics method to assess proteome of renal cell carcinoma (RCC) compared with noncancer renal tissues. Methods: Fresh frozen tissue samples from eight primary RCC lesions and autologous adjacent normal renal tissues were obtained from surgically resected tumour-bearing kidneys. Proteins were extracted by complete solubilisation of...

  9. The impact of sample storage time on estimates of association in biomarker discovery studies

    OpenAIRE

    Kugler, Karl G; Hackl, Werner O; Mueller, Laurin AJ; Fiegl, Heidi; Graber, Armin; Ruth M Pfeiffer

    2011-01-01

    Background Using serum, plasma or tumor tissue specimens from biobanks for biomarker discovery studies is attractive as samples are often readily available. However, storage over longer periods of time can alter concentrations of proteins in those specimens. We therefore assessed the bias in estimates of association from case-control studies conducted using banked specimens when maker levels changed over time for single markers and also for multiple correlated markers in simulations. Data fro...

  10. Integration of lyoplate based flow cytometry and computational analysis for standardized immunological biomarker discovery.

    Directory of Open Access Journals (Sweden)

    Federica Villanova

    Full Text Available Discovery of novel immune biomarkers for monitoring of disease prognosis and response to therapy in immune-mediated inflammatory diseases is an important unmet clinical need. Here, we establish a novel framework for immunological biomarker discovery, comparing a conventional (liquid flow cytometry platform (CFP and a unique lyoplate-based flow cytometry platform (LFP in combination with advanced computational data analysis. We demonstrate that LFP had higher sensitivity compared to CFP, with increased detection of cytokines (IFN-γ and IL-10 and activation markers (Foxp3 and CD25. Fluorescent intensity of cells stained with lyophilized antibodies was increased compared to cells stained with liquid antibodies. LFP, using a plate loader, allowed medium-throughput processing of samples with comparable intra- and inter-assay variability between platforms. Automated computational analysis identified novel immunophenotypes that were not detected with manual analysis. Our results establish a new flow cytometry platform for standardized and rapid immunological biomarker discovery with wide application to immune-mediated diseases.

  11. New candidate biomarkers in the female genital tract to evaluate microbicide toxicity.

    Directory of Open Access Journals (Sweden)

    Scott Fields

    Full Text Available Vaginal microbicides hold great promise for the prevention of viral diseases like HIV, but the failure of several microbicide candidates in clinical trials has raised important questions regarding the parameters to be evaluated to determine in vivo efficacy in humans. Clinical trials of the candidate microbicides nonoxynol-9 (N9 and cellulose sulfate revealed an increase in HIV infection, vaginal inflammation, and recruitment of HIV susceptible lymphocytes, highlighting the need to identify biomarkers that can accurately predict microbicide toxicity early in preclinical development and in human trials. We used quantitative proteomics and RT-PCR approaches in mice and rabbits to identify protein changes in vaginal fluid and tissue in response to treatment with N9 or benzalkonium chloride (BZK. We compared changes generated with N9 and BZK treatment to the changes generated in response to tenofovir gel, a candidate microbicide that holds promise as a safe and effective microbicide. Both compounds down regulated mucin 5 subtype B, and peptidoglycan recognition protein 1 in vaginal tissue; however, mucosal brush samples also showed upregulation of plasma proteins fibrinogen, plasminogen, apolipoprotein A-1, and apolipoprotein C-1, which may be a response to the erosive nature of N9 and BZK. Additional proteins down-regulated in vaginal tissue by N9 or BZK treatment include CD166 antigen, olfactomedin-4, and anterior gradient protein 2 homolog. We also observed increases in the expression of C-C chemokines CCL3, CCL5, and CCL7 in response to treatment. There was concordance in expression level changes for several of these proteins using both the mouse and rabbit models. Using a human vaginal epithelial cell line, the expression of mucin 5 subtype B and olfactomedin-4 were down-regulated in response to N9, suggesting these markers could apply to humans. These data identifies new proteins that after further validation could become part of a panel of

  12. New candidate biomarkers in the female genital tract to evaluate microbicide toxicity.

    Science.gov (United States)

    Fields, Scott; Song, Benben; Rasoul, Bareza; Fong, Julie; Works, Melissa G; Shew, Kenneth; Yiu, Ying; Mirsalis, Jon; D'Andrea, Annalisa

    2014-01-01

    Vaginal microbicides hold great promise for the prevention of viral diseases like HIV, but the failure of several microbicide candidates in clinical trials has raised important questions regarding the parameters to be evaluated to determine in vivo efficacy in humans. Clinical trials of the candidate microbicides nonoxynol-9 (N9) and cellulose sulfate revealed an increase in HIV infection, vaginal inflammation, and recruitment of HIV susceptible lymphocytes, highlighting the need to identify biomarkers that can accurately predict microbicide toxicity early in preclinical development and in human trials. We used quantitative proteomics and RT-PCR approaches in mice and rabbits to identify protein changes in vaginal fluid and tissue in response to treatment with N9 or benzalkonium chloride (BZK). We compared changes generated with N9 and BZK treatment to the changes generated in response to tenofovir gel, a candidate microbicide that holds promise as a safe and effective microbicide. Both compounds down regulated mucin 5 subtype B, and peptidoglycan recognition protein 1 in vaginal tissue; however, mucosal brush samples also showed upregulation of plasma proteins fibrinogen, plasminogen, apolipoprotein A-1, and apolipoprotein C-1, which may be a response to the erosive nature of N9 and BZK. Additional proteins down-regulated in vaginal tissue by N9 or BZK treatment include CD166 antigen, olfactomedin-4, and anterior gradient protein 2 homolog. We also observed increases in the expression of C-C chemokines CCL3, CCL5, and CCL7 in response to treatment. There was concordance in expression level changes for several of these proteins using both the mouse and rabbit models. Using a human vaginal epithelial cell line, the expression of mucin 5 subtype B and olfactomedin-4 were down-regulated in response to N9, suggesting these markers could apply to humans. These data identifies new proteins that after further validation could become part of a panel of biomarkers to

  13. Tales of one gene discovery of a novel candidate receptor in mammalian taste

    OpenAIRE

    Huang, Angela Lilly

    2007-01-01

    There are five basic taste modalities in mammals: bitter, sweet, sour, salty, and Umami (taste of MSG and L-amino acids). Receptors for bitter, sweet, and Umami were previously discovered. Identities of receptors for salty and sour taste modalities remained elusive. In this dissertation, I will present: 1) development of a novel bioinformatics screen to discover candidate receptors; 2) discovery of a novel gene, PKD2L1, in taste receptor cells; 3) evidence demonstrating PKD2L1-expressing tast...

  14. Use of biomarkers in the discovery of novel anti-schizophrenia drugs

    DEFF Research Database (Denmark)

    Mikkelsen, Jens D; Thomsen, Morten S; Hansen, Henrik H;

    2010-01-01

    Schizophrenia is characterized by a diverse symptomatology that often includes positive, cognitive and negative symptoms. Current anti-schizophrenic drugs act at multiple receptors, but little is known about how each of these receptors contributes to their mechanisms of action. Screening of novel...... anti-schizophrenic drug candidates targeting single receptors will be based on biomarker assays that measure signalling pathways, transcriptional factors, epigenetic mechanisms and synaptic function and translate these effects to behavioural effects in animals and humans. This review discusses current...

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

    OpenAIRE

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

    2011-01-01

    The rapid increase in the prevalence of chronic heart failure (CHF) worldwide underscores an urgent need to identify biomarkers for the early detection of CHF. Post-translational modifications (PTMs) are associated with many critical signaling events during disease progression and thus offer a plethora of candidate biomarkers. We have employed top-down quantitative proteomics methodology for comprehensive assessment of PTMs in whole proteins extracted from normal and diseased tissues. We have...

  16. Mitochondrial DNA mutations—candidate biomarkers for breast cancer diagnosis in Bangladesh

    Institute of Scientific and Technical Information of China (English)

    Gazi Nurun Nahar Sultana; Atiqur Rahman; Abu Din Ahmed Shahinuzzaman; Rowshan Ara Begum; Chowdhury Faiz Hossain

    2012-01-01

    Breast cancer is a major health problem that affects more than 24% of women in Bangladesh.Furthermore,among low-income countries including Bangladesh,individuals have a high risk for developing breast cancer.This study aimed to identify candidate mitochondrial DNA (mtDNA) biomarkers for breast cancer diagnosis in Bangladeshi women to be used as a preventive approach.We screened the blood samples from 24 breast cancer patients and 20 healthy controls to detect polymorphisms in the D-loop and the ND3- and ND4-coding regions of mtDNA by direct sequencing.Among 14 distinct mutations,10 polymorphisms were found in the D-loop,3 were found in the ND3-coding region,and 1 was found in the ND4-coding region.The frequency of two novel polymorphisms in the D-loop,one at position 16290 (T-ins) and the other at position 16293 (A-del),was higher in breast cancer patients than in control subjects (position 16290:odds ratio =6.011,95% confidence interval =1.2482 to 28.8411,P =0.002; position 16293:odds ratio =5.6028,95% confidence interval =1.4357 to 21.8925,P =0.010).We also observed one novel mutation in the ND3-coding region at position 10316 (A > G) in 69% of breast cancer patients but not in control subjects.The study suggests that two novel polymorphisms in the D-loop may be candidate biomarkers for breast cancer diagnosis in Bangladeshi women.

  17. Application of systems biology principles to protein biomarker discovery: Urinary exosomal proteome in renal transplantation

    Science.gov (United States)

    Das, Samarjit; Knepper, Mark A.; Bagnasco, Serena M.

    2013-01-01

    Purpose In MS-based studies to discover urinary protein biomarkers, an important question is how to analyze the data to find the most promising potential biomarkers to be advanced to large-scale validation studies. Here, we describe a ‘systems biology-based’ approach to address this question. Experimental design We analyzed large-scale LC-MS/MS data of urinary exosomes from renal allograft recipients with biopsy-proven evidence of immunological rejection or tubular injury. We asked whether bioinformatic analysis of urinary exosomal proteins can identify protein groups that correlate with biopsy findings and whether the protein groups fit with general knowledge of the pathophysiological mechanisms involved. Results LC-MS/MS analysis of urinary exosomal proteomes identified more than 1000 proteins in each pathologic group. These protein lists were analyzed computationally to identify Biological Process and KEGG Pathway terms that are significantly associated with each pathological group. Among the most informative terms for each group were: “sodium ion transport” for tubular injury; “immune response” for all rejection; “epithelial cell differentiation” for cell-mediated rejection; and “acute inflammatory response” for antibody-mediated rejection. Based on these terms, candidate biomarkers were identified using a novel strategy to allow a dichotomous classification between different pathologic categories. Conclusions and clinical relevance The terms and candidate biomarkers identified make rational connections to pathophysiological mechanisms, suggesting that the described bioinformatic approach will be useful in advancing large-scale biomarker identification studies toward a validation phase. PMID:22641613

  18. A Combined Shotgun and Targeted Mass Spectrometry Strategy for Breast Cancer Biomarker Discovery.

    Science.gov (United States)

    Sjöström, Martin; Ossola, Reto; Breslin, Thomas; Rinner, Oliver; Malmström, Lars; Schmidt, Alexander; Aebersold, Ruedi; Malmström, Johan; Niméus, Emma

    2015-07-01

    It is of highest importance to find proteins responsible for breast cancer dissemination, for use as biomarkers or treatment targets. We established and performed a combined nontargeted LC-MS/MS and a targeted LC-SRM workflow for discovery and validation of protein biomarkers. Eighty breast tumors, stratified for estrogen receptor status and development of distant recurrence (DR ± ), were collected. After enrichment of N-glycosylated peptides, label-free LC-MS/MS was performed on each individual tumor in triplicate. In total, 1515 glycopeptides from 778 proteins were identified and used to create a map of the breast cancer N-glycosylated proteome. Based on this specific proteome map, we constructed a 92-plex targeted label-free LC-SRM panel. These proteins were quantified across samples by LC-SRM, resulting in 10 proteins consistently differentially regulated between DR+/DR- tumors. Five proteins were further validated in a separate cohort as prognostic biomarkers at the gene expression level. We also compared the LC-SRM results to clinically reported HER2 status, demonstrating its clinical accuracy. In conclusion, we demonstrate a combined mass spectrometry strategy, at large scale on clinical samples, leading to the identification and validation of five proteins as potential biomarkers for breast cancer recurrence. All MS data are available via ProteomeXchange and PASSEL with identifiers PXD001685 and PASS00643. PMID:25944384

  19. Testing of the OMERACT 8 draft validation criteria for a soluble biomarker reflecting structural damage in rheumatoid arthritis: a systematic literature search on 5 candidate biomarkers

    DEFF Research Database (Denmark)

    Syversen, Silje W; Landewe, Robert; van der Heijde, Désirée;

    2009-01-01

    and the importance of each individual criterion; (2) overall strength of evidence in support of each of the 5 candidate biomarkers as reflecting structural damage endpoints in rheumatoid arthritis (RA) and identification of omissions to the criteria set. RESULTS: The search identified 111 articles. The strength...... metalloprotease (MMP-3), urine C-telopeptide of types I and II collagen (U-CTX-I and U CTX-II), focusing on the 14 OMERACT 8 criteria. Two electronic voting exercises were conducted to address: (1) strength of evidence for each biomarker as reflecting structural damage according to each individual criterion...

  20. Discovery and validation of DNA hypomethylation biomarkers for liver cancer using HRM-specific probes.

    Directory of Open Access Journals (Sweden)

    Barbara Stefanska

    Full Text Available Poor prognosis of hepatocellular carcinoma (HCC associated with late diagnosis necessitates the development of early diagnostic biomarkers. We have previously delineated the landscape of DNA methylation in HCC patients unraveling the importance of promoter hypomethylation in activation of cancer- and metastasis-driving genes. The purpose of the present study was to test the feasibility that genes that are hypomethylated in HCC could serve as candidate diagnostic markers. We use high resolution melting analysis (HRM as a simple translatable PCR-based method to define methylation states in clinical samples. We tested seven regions selected from the shortlist of genes hypomethylated in HCC and showed that HRM analysis of several of them distinguishes methylation states in liver cancer specimens from normal adjacent liver and chronic hepatitis in the Shanghai area. Such regions were identified within promoters of neuronal membrane glycoprotein M6-B (GPM6B and melanoma antigen family A12 (MAGEA12 genes. Differences in HRM in the immunoglobulin superfamily Fc receptor (FCRL1 separated invasive tumors from less invasive HCC. The identified biomarkers differentiated HCC from chronic hepatitis in another set of samples from Dhaka. Although the main thrust in DNA methylation diagnostics in cancer is on hypermethylated genes, our study for the first time illustrates the potential use of hypomethylated genes as markers for solid tumors. After further validation in a larger cohort, the identified DNA hypomethylated regions can become important candidate biomarkers for liver cancer diagnosis and prognosis, especially in populations with high risk for HCC development.

  1. Urinary Proteomics Pilot Study for Biomarker Discovery and Diagnosis in Heart Failure with Reduced Ejection Fraction.

    Directory of Open Access Journals (Sweden)

    Kasper Rossing

    Full Text Available Biomarker discovery and new insights into the pathophysiology of heart failure with reduced ejection fraction (HFrEF may emerge from recent advances in high-throughput urinary proteomics. This could lead to improved diagnosis, risk stratification and management of HFrEF.Urine samples were analyzed by on-line capillary electrophoresis coupled to electrospray ionization micro time-of-flight mass spectrometry (CE-MS to generate individual urinary proteome profiles. In an initial biomarker discovery cohort, analysis of urinary proteome profiles from 33 HFrEF patients and 29 age- and sex-matched individuals without HFrEF resulted in identification of 103 peptides that were significantly differentially excreted in HFrEF. These 103 peptides were used to establish the support vector machine-based HFrEF classifier HFrEF103. In a subsequent validation cohort, HFrEF103 very accurately (area under the curve, AUC = 0.972 discriminated between HFrEF patients (N = 94, sensitivity = 93.6% and control individuals with and without impaired renal function and hypertension (N = 552, specificity = 92.9%. Interestingly, HFrEF103 showed low sensitivity (12.6% in individuals with diastolic left ventricular dysfunction (N = 176. The HFrEF-related peptide biomarkers mainly included fragments of fibrillar type I and III collagen but also, e.g., of fibrinogen beta and alpha-1-antitrypsin.CE-MS based urine proteome analysis served as a sensitive tool to determine a vast array of HFrEF-related urinary peptide biomarkers which might help improving our understanding and diagnosis of heart failure.

  2. Quantitative iTRAQ-Based Proteomic Identification of Candidate Biomarkers for Diabetic Nephropathy in Plasma of Type 1 Diabetic Patients

    DEFF Research Database (Denmark)

    Overgaard, Anne Julie; Thingholm, Tine Engberg; Larsen, Martin R;

    2010-01-01

    INTRODUCTION: As part of a clinical proteomics programme focused on diabetes and its complications, it was our goal to investigate the proteome of plasma in order to find improved candidate biomarkers to predict diabetic nephropathy. METHODS: Proteins derived from plasma from a cross-sectional co...

  3. The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Stephanie R Shepheard

    Full Text Available Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno-precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9±0.5 ng/mg creatinine and this was significantly higher (p<0.001 than 12 controls (2.6±0.2 ng/mg creatinine and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1±0.2 ng/mg creatinine. Pilot data of disease progression rates in 14 MND patients indicates that p75NTR(ECD levels were significantly higher (p = 0.0041 in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1(G93A mice by immuno-precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis.

  4. Rapid discovery of peptide capture candidates with demonstrated specificity for structurally similar toxins

    Science.gov (United States)

    Sarkes, Deborah A.; Hurley, Margaret M.; Coppock, Matthew B.; Farrell, Mikella E.; Pellegrino, Paul M.; Stratis-Cullum, Dimitra N.

    2016-05-01

    Peptides have emerged as viable alternatives to antibodies for molecular-based sensing due to their similarity in recognition ability despite their relative structural simplicity. Various methods for peptide capture reagent discovery exist, including phage display, yeast display, and bacterial display. One of the primary advantages of peptide discovery by bacterial display technology is the speed to candidate peptide capture agent, due to both rapid growth of bacteria and direct utilization of the sorted cells displaying each individual peptide for the subsequent round of biopanning. We have previously isolated peptide affinity reagents towards protective antigen of Bacillus anthracis using a commercially available automated magnetic sorting platform with improved enrichment as compared to manual magnetic sorting. In this work, we focus on adapting our automated biopanning method to a more challenging sort, to demonstrate the specificity possible with peptide capture agents. This was achieved using non-toxic, recombinant variants of ricin and abrin, RiVax and abrax, respectively, which are structurally similar Type II ribosomal inactivating proteins with significant sequence homology. After only two rounds of biopanning, enrichment of peptide capture candidates binding abrax but not RiVax was achieved as demonstrated by Fluorescence Activated Cell Sorting (FACS) studies. Further sorting optimization included negative sorting against RiVax, proper selection of autoMACS programs for specific sorting rounds, and using freshly made buffer and freshly thawed protein target for each round of biopanning for continued enrichment over all four rounds. Most of the resulting candidates from biopanning for abrax binding peptides were able to bind abrax but not RiVax, demonstrating that short peptide sequences can be highly specific even at this early discovery stage.

  5. Reproducible cancer biomarker discovery in SELDI-TOF MS using different pre-processing algorithms.

    Directory of Open Access Journals (Sweden)

    Jinfeng Zou

    Full Text Available BACKGROUND: There has been much interest in differentiating diseased and normal samples using biomarkers derived from mass spectrometry (MS studies. However, biomarker identification for specific diseases has been hindered by irreproducibility. Specifically, a peak profile extracted from a dataset for biomarker identification depends on a data pre-processing algorithm. Until now, no widely accepted agreement has been reached. RESULTS: In this paper, we investigated the consistency of biomarker identification using differentially expressed (DE peaks from peak profiles produced by three widely used average spectrum-dependent pre-processing algorithms based on SELDI-TOF MS data for prostate and breast cancers. Our results revealed two important factors that affect the consistency of DE peak identification using different algorithms. One factor is that some DE peaks selected from one peak profile were not detected as peaks in other profiles, and the second factor is that the statistical power of identifying DE peaks in large peak profiles with many peaks may be low due to the large scale of the tests and small number of samples. Furthermore, we demonstrated that the DE peak detection power in large profiles could be improved by the stratified false discovery rate (FDR control approach and that the reproducibility of DE peak detection could thereby be increased. CONCLUSIONS: Comparing and evaluating pre-processing algorithms in terms of reproducibility can elucidate the relationship among different algorithms and also help in selecting a pre-processing algorithm. The DE peaks selected from small peak profiles with few peaks for a dataset tend to be reproducibly detected in large peak profiles, which suggests that a suitable pre-processing algorithm should be able to produce peaks sufficient for identifying useful and reproducible biomarkers.

  6. The Dark Energy Survey view of the Sagittarius stream: Discovery of two faint stellar system candidates

    OpenAIRE

    Luque, E; Pieres, A.; Santiago, B; Yanny, B.; Vivas, A. K.; Queiroz, A.; Drlica-Wagner, A.; Morganson, E.; Balbinot, E.; Marshall, J. L.; Li, T. S.; Neto, A. Fausti; da Costa, L. N.; Maia, M. A. G.; Bechtol, K.

    2016-01-01

    We report the discovery of two new candidate stellar systems in the constellation of Cetus using the data from the first two years of the Dark Energy Survey (DES). The objects, DES J0111-1341 and DES J0225+0304, are located at a heliocentric distance of ~ 24 kpc and appear to have old and metal-poor populations. Their distances to the Sagittarius orbital plane, ~ 1.47 kpc (DES J0111-1341) and ~ 0.51 kpc (DES J0225+0304), indicate that they are possibly associated with the Sagittarius dwarf st...

  7. In vitro biomarker discovery in the parasitic flatworm Fasciola hepatica for monitoring chemotherapeutic treatment

    Directory of Open Access Journals (Sweden)

    Russell M. Morphew

    2014-06-01

    Full Text Available The parasitic flatworm Fasciola hepatica is a global food security risk. With no vaccines, the sustainability of triclabendazole (TCBZ is threatened by emerging resistance. F. hepatica excretory/secretory (ES products can be detected in host faeces and used to estimate TCBZ success and failure. However, there are no faecal based molecular diagnostics dedicated to assessing drug failure or resistance to TCBZ in the field. Utilising in vitro maintenance and sub-proteomic approaches two TCBZ stress ES protein response fingerprints were identified: markers of non-killing and lethal doses. This study provides candidate protein/peptide biomarkers to validate for detection of TCBZ failure and resistance.

  8. The identification of novel potential injury mechanisms and candidate biomarkers in renal allograft rejection by quantitative proteomics.

    Science.gov (United States)

    Sigdel, Tara K; Salomonis, Nathan; Nicora, Carrie D; Ryu, Soyoung; He, Jintang; Dinh, Van; Orton, Daniel J; Moore, Ronald J; Hsieh, Szu-Chuan; Dai, Hong; Thien-Vu, Minh; Xiao, Wenzhong; Smith, Richard D; Qian, Wei-Jun; Camp, David G; Sarwal, Minnie M

    2014-02-01

    Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p 1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of monitoring these urinary proteins for the specific and sensitive noninvasive diagnosis of acute renal allograft rejection.

  9. Translating potential biomarker candidates for schizophrenia and depression to animal models of psychiatric disorders.

    Science.gov (United States)

    Kluge, Wolfgang; Alsaif, Murtada; Guest, Paul C; Schwarz, Emanuel; Bahn, Sabine

    2011-09-01

    Schizophrenia and major depressive disorder are severe mental illnesses, which are diagnosed based on patient interviews. Despite many years of extensive research, scientists have not yet fully deciphered how genetic and environmental factors interact to cause these illnesses. Biomarker tests that can confirm diagnoses of schizophrenia or depression are only now beginning to emerge, and could result in a paradigm shift in this field. These tests will help to evaluate the validity of animal models of psychiatric disorders, which are currently characterized based on behavioral measures. In this article, we explore the utility of translating both behavioral and molecular phenotypes of such models to the corresponding human disorders. This approach may help to provide construct validity to animal models and could lead to the identification of models corresponding to defined subtypes of neuropsychiatric disorders based on molecular profiles. Here, we review the molecular and biological pathway alterations that have been found in animal models of schizophrenia and depression and focus on those that are mirrored by similar abnormalities in human patients. Such parallels may provide insight into the validity of specific animal models and therefore help to provide more valuable and accurate tools for the discovery and development of improved psychiatric medications. PMID:21902534

  10. Clinical proteomics for liver disease: a promising approach for discovery of novel biomarkers

    Directory of Open Access Journals (Sweden)

    Tsubouchi Hirohito

    2010-12-01

    Full Text Available Abstract Hepatocellular carcinoma (HCC is the fifth most common cancer and advanced hepatic fibrosis is a major risk factor for HCC. Hepatic fibrosis including liver cirrhosis and HCC are mainly induced by persistent hepatitis B or C virus infection, with approximately 500 million people infected with hepatitis B or C virus worldwide. Furthermore, the number of patients with non-alcoholic fatty liver disease (NAFLD has recently increased and NAFLD can progress to cirrhosis and HCC. These chronic liver diseases are major causes of morbidity and mortality, and the identification of non-invasive biomarkers is important for early diagnosis. Recent advancements in quantitative and large-scale proteomic methods could be used to optimize the clinical application of biomarkers. Early diagnosis of HCC and assessment of the stage of hepatic fibrosis or NAFLD can also contribute to more effective therapeutic interventions and an improve prognosis. Furthermore, advancements of proteomic techniques contribute not only to the discovery of clinically useful biomarkers, but also in clarifying the molecular mechanisms of disease pathogenesis by using body fluids, such as serum, and tissue samples and cultured cells. In this review, we report recent advances in quantitative proteomics and several findings focused on liver diseases, including HCC, NAFLD, hepatic fibrosis and hepatitis B or C virus infections.

  11. Enabling Metabolomics Based Biomarker Discovery Studies Using Molecular Phenotyping of Exosome-Like Vesicles.

    Directory of Open Access Journals (Sweden)

    Tatiana Altadill

    Full Text Available Identification of sensitive and specific biomarkers with clinical and translational utility will require smart experimental strategies that would augment expanding the breadth and depth of molecular measurements within the constraints of currently available technologies. Exosomes represent an information rich matrix to discern novel disease mechanisms that are thought to contribute to pathologies such as dementia and cancer. Although proteomics and transcriptomic studies have been reported using Exosomes-Like Vesicles (ELVs from different sources, exosomal metabolome characterization and its modulation in health and disease remains to be elucidated. Here we describe methodologies for UPLC-ESI-MS based small molecule profiling of ELVs from human plasma and cell culture media. In this study, we present evidence that indeed ELVs carry a rich metabolome that could not only augment the discovery of low abundance biomarkers but may also help explain the molecular basis of disease progression. This approach could be easily translated to other studies seeking to develop predictive biomarkers that can subsequently be used with simplified targeted approaches.

  12. Automated Sample Preparation Platform for Mass Spectrometry-Based Plasma Proteomics and Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Vilém Guryča

    2014-03-01

    Full Text Available The identification of novel biomarkers from human plasma remains a critical need in order to develop and monitor drug therapies for nearly all disease areas. The discovery of novel plasma biomarkers is, however, significantly hampered by the complexity and dynamic range of proteins within plasma, as well as the inherent variability in composition from patient to patient. In addition, it is widely accepted that most soluble plasma biomarkers for diseases such as cancer will be represented by tissue leakage products, circulating in plasma at low levels. It is therefore necessary to find approaches with the prerequisite level of sensitivity in such a complex biological matrix. Strategies for fractionating the plasma proteome have been suggested, but improvements in sensitivity are often negated by the resultant process variability. Here we describe an approach using multidimensional chromatography and on-line protein derivatization, which allows for higher sensitivity, whilst minimizing the process variability. In order to evaluate this automated process fully, we demonstrate three levels of processing and compare sensitivity, throughput and reproducibility. We demonstrate that high sensitivity analysis of the human plasma proteome is possible down to the low ng/mL or even high pg/mL level with a high degree of technical reproducibility.

  13. ProfileDB: a resource for proteomics and cross-omics biomarker discovery.

    Science.gov (United States)

    Bauer, Chris; Glintschert, Alexander; Schuchhardt, Johannes

    2014-05-01

    The increasing size and complexity of high-throughput datasets pose a growing challenge for researchers. Often very different (cross-omics) techniques with individual data analysis pipelines are employed making a unified biomarker discovery strategy and a direct comparison of different experiments difficult and time consuming. Here we present the comprehensive web-based application ProfileDB. The application is designed to integrate data from different high-throughput 'omics' data types (Transcriptomics, Proteomics, Metabolomics) with clinical parameters and prior knowledge on pathways and ontologies. Beyond data storage, ProfileDB provides a set of dedicated tools for study inspection and data visualization. The user can gain insights into a complex experiment with just a few mouse clicks. We will demonstrate the application by presenting typical use cases for the identification of proteomics biomarkers. All presented analyses can be reproduced using the public ProfileDB web server. The ProfileDB application is available by standard browser (Firefox 18+, Internet Explorer Version 9+) technology via http://profileDB.-microdiscovery.de/ (login and pass-word: profileDB). The installation contains several public datasets including different cross-'omics' experiments. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID:24270047

  14. Discovery of two candidate pulsar wind nebulae in very-high-energy gamma rays

    CERN Document Server

    Aharonian, F; Bazer-Bachi, A R; Behera, B; Beilicke, M; Benbow, W; Berge, D; Bernlöhr, K; Boisson, C; Bolz, O; Borrel, V; Braun, I; Brion, E; Brown, A M; Buhler, R; Büsching, I; Boutelier, T; Carrigan, S; Chadwick, P M; Chounet, L M; Coignet, G; Cornils, R; Costamante, L; Degrange, B; Dickinson, H J; Djannati-Ata:, A; Domainko, W; O'Connor-Drury, L; Dubus, G; Egberts, K; Emmanoulopoulos, D; Espigat, P; Farnier, C; Feinstein, F; Fiasson, A; Förster, A; Fontaine, G; Funk, Seb; Funk, S; Fuling, M; Gallant, Y A; Giebels, B; Glicenstein, J F; Glück, B; Goret, P; Hadjichristidis, C; Hauser, D; Hauser, M; Heinzelmann, G; Henri, G; Hermann, G; Hinton, J A; Hoffmann, A; Hofmann, W; Holleran, M; Hoppe, S; Horns, D; Jacholkowska, A; De Jager, O C; Kendziorra, E; Kerschhaggl, M; Khelifi, B; Komin, Nu; Kosack, K; Lamanna, G; Latham, I J; Le Gallou, R; Lemiere, A; Lemoine-Goumard, M; Lohse, T; Martin, J M; Martineau-Huynh, O; Marcowith, A; Masterson, C; Maurin, G; McComb, T J L; Moulin, E; De Naurois, Mathieu; Nedbal, D; Nolan, S J; Noutsos, A; Olive, J P; Orford, K J; Osborne, J L; Panter, M; Pedaletti, G; Pelletier, G; Petrucci, P O; Pita, S; Pühlhofer, G; Punch, M; Ranchon, S; Raubenheimer, B C; Raue, M; Rayner, S M; Ripken, J; Rob, L; Rolland, L; Rosier-Lees, S; Rowell, G; Ruppel, J; Sahakian, V V; Santangelo, A; Sauge, L; Schlenker, S; Schlickeiser, R; Schroder, R; Schwanke, U; Schwarzburg, S; Schwemmer, S; Shalchi, A; Sol, H; Spangler, D; Steenkamp, R; Stegmann, C; Superina, G; Tam, P H; Tavernet, J P; Terrier, R; Tluczykont, M; Van Eldik, C; Vasileiadis, G; Venter, C; Vialle, J P; Vincent, P; Völk, H J; Wagner, S J; Ward, M

    2007-01-01

    We present the discovery of two very-high-energy gamma-ray sources in an ongoing systematic search for emission above 100 GeV from pulsar wind nebulae in survey data from the H.E.S.S. telescope array. Imaging Atmospheric Cherenkov Telescopes are ideal tools for searching for extended emission from pulsar wind nebulae in the very-high-energy regime. H.E.S.S., with its large field of view of 5 degrees and high sensitivity, gives new prospects for the search for these objects. An ongoing systematic search for very-high-energy emission from energetic pulsars over the region of the Galactic plane between -60 degrees < l < 30 degrees, -2 degrees < b < 2 degrees is performed. For the resulting candidates, the standard H.E.S.S. analysis was applied and a search for multi-wavelength counterparts was performed. We present the discovery of two new candidate gamma-ray pulsar wind nebulae, HESS J1718-385 and HESS J1809-193. H.E.S.S. has proven to be a suitable instrument for pulsar wind nebula searches.

  15. Identification of candidate synovial membrane biomarkers after Achyranthes aspera treatment for rheumatoid arthritis.

    Science.gov (United States)

    Zheng, Wen; Lu, Xianghong; Fu, Zhirong; Zhang, Lin; Li, Ximin; Xu, Xiaobao; Ren, Yina; Lu, Yongzhuang; Fu, Hongwei; Tian, Jingkui

    2016-03-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main symptom is a heightened inflammatory response in synovial tissues. To verify the anti-arthritic activities of Achyranthes aspera and its possible therapy-related factors on the pathogenesis of RA, the saponins in A. aspera root were isolated and identified to treat the collagen-induced arthritis (CIA) rats. Phytochemical analysis isolated and identified methyl caffeate, 25-S-inokosterone, 25-S-inokosterone β-D-glucopyranosyl 3-(O-β-D-glucopyranosyloxy)-oleanolate, and β-D-glucopyranosyl 3-(O-β-D-galactopyranosyl (1→2)(O-β-D-glucopyranosyloxy)-oleanolate as main compounds in the root of A. aspera. Proteomics was performed to determine the differentially expressed proteins in either inflamed or drug-treated synovium of CIA rats. Treatment resulted in dramatically decreased paw swelling, proliferation of inflammatory cells, and bone degradation. Fibrinogen, procollagen, protein disulfide-isomerase A3, and apolipoprotein A-I were all increased in inflamed synovial tissues and were found to decrease when administered drug therapy. Furthermore, Alpha-1-antiproteinase and manganese superoxide dismutase were both increased in drug-treated synovial tissues. The inhibition of RA progression shows that A. aspera is a promising candidate for future treatment of human arthritis. Importantly, the total saponins found within A. aspera are the active component. Finally, autoantigens such as fibrinogen and collagen could act as inducers of RA due to their aggravation of inflammation. Given this, it is possible that the vimentin and PDIA3 could be the candidate biomarkers specific to Achyranthes saponin therapy for rheumatoid arthritis in synovial membrane.

  16. Identification of candidate synovial membrane biomarkers after Achyranthes aspera treatment for rheumatoid arthritis.

    Science.gov (United States)

    Zheng, Wen; Lu, Xianghong; Fu, Zhirong; Zhang, Lin; Li, Ximin; Xu, Xiaobao; Ren, Yina; Lu, Yongzhuang; Fu, Hongwei; Tian, Jingkui

    2016-03-01

    Rheumatoid arthritis (RA) is a systemic autoimmune disease whose main symptom is a heightened inflammatory response in synovial tissues. To verify the anti-arthritic activities of Achyranthes aspera and its possible therapy-related factors on the pathogenesis of RA, the saponins in A. aspera root were isolated and identified to treat the collagen-induced arthritis (CIA) rats. Phytochemical analysis isolated and identified methyl caffeate, 25-S-inokosterone, 25-S-inokosterone β-D-glucopyranosyl 3-(O-β-D-glucopyranosyloxy)-oleanolate, and β-D-glucopyranosyl 3-(O-β-D-galactopyranosyl (1→2)(O-β-D-glucopyranosyloxy)-oleanolate as main compounds in the root of A. aspera. Proteomics was performed to determine the differentially expressed proteins in either inflamed or drug-treated synovium of CIA rats. Treatment resulted in dramatically decreased paw swelling, proliferation of inflammatory cells, and bone degradation. Fibrinogen, procollagen, protein disulfide-isomerase A3, and apolipoprotein A-I were all increased in inflamed synovial tissues and were found to decrease when administered drug therapy. Furthermore, Alpha-1-antiproteinase and manganese superoxide dismutase were both increased in drug-treated synovial tissues. The inhibition of RA progression shows that A. aspera is a promising candidate for future treatment of human arthritis. Importantly, the total saponins found within A. aspera are the active component. Finally, autoantigens such as fibrinogen and collagen could act as inducers of RA due to their aggravation of inflammation. Given this, it is possible that the vimentin and PDIA3 could be the candidate biomarkers specific to Achyranthes saponin therapy for rheumatoid arthritis in synovial membrane. PMID:26724776

  17. Biomarker discovery and applications for foods and beverages: proteomics to nanoproteomics.

    Science.gov (United States)

    Agrawal, Ganesh Kumar; Timperio, Anna Maria; Zolla, Lello; Bansal, Vipul; Shukla, Ravi; Rakwal, Randeep

    2013-11-20

    Foods and beverages have been at the heart of our society for centuries, sustaining humankind - health, life, and the pleasures that go with it. The more we grow and develop as a civilization, the more we feel the need to know about the food we eat and beverages we drink. Moreover, with an ever increasing demand for food due to the growing human population food security remains a major concern. Food safety is another growing concern as the consumers prefer varied foods and beverages that are not only traded nationally but also globally. The 21st century science and technology is at a new high, especially in the field of biological sciences. The availability of genome sequences and associated high-throughput sensitive technologies means that foods are being analyzed at various levels. For example and in particular, high-throughput omics approaches are being applied to develop suitable biomarkers for foods and beverages and their applications in addressing quality, technology, authenticity, and safety issues. Proteomics are one of those technologies that are increasingly being utilized to profile expressed proteins in different foods and beverages. Acquired knowledge and protein information have now been translated to address safety of foods and beverages. Very recently, the power of proteomic technology has been integrated with another highly sensitive and miniaturized technology called nanotechnology, yielding a new term nanoproteomics. Nanoproteomics offer a real-time multiplexed analysis performed in a miniaturized assay, with low-sample consumption and high sensitivity. To name a few, nanomaterials - quantum dots, gold nanoparticles, carbon nanotubes, and nanowires - have demonstrated potential to overcome the challenges of sensitivity faced by proteomics for biomarker detection, discovery, and application. In this review, we will discuss the importance of biomarker discovery and applications for foods and beverages, the contribution of proteomic technology in

  18. NMR and pattern recognition methods in metabolomics: From data acquisition to biomarker discovery: A review

    Energy Technology Data Exchange (ETDEWEB)

    Smolinska, Agnieszka, E-mail: A.Smolinska@science.ru.nl [Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen (Netherlands); Blanchet, Lionel [Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen (Netherlands); Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen (Netherlands); Buydens, Lutgarde M.C.; Wijmenga, Sybren S. [Institute for Molecules and Materials, Radboud University Nijmegen, Nijmegen (Netherlands)

    2012-10-31

    Highlights: Black-Right-Pointing-Pointer Procedures for acquisition of different biofluids by NMR. Black-Right-Pointing-Pointer Recent developments in metabolic profiling of different biofluids by NMR are presented. Black-Right-Pointing-Pointer The crucial steps involved in data preprocessing and multivariate chemometric analysis are reviewed. Black-Right-Pointing-Pointer Emphasis is given on recent findings on Multiple Sclerosis via NMR and pattern recognition methods. - Abstract: Metabolomics is the discipline where endogenous and exogenous metabolites are assessed, identified and quantified in different biological samples. Metabolites are crucial components of biological system and highly informative about its functional state, due to their closeness to functional endpoints and to the organism's phenotypes. Nuclear Magnetic Resonance (NMR) spectroscopy, next to Mass Spectrometry (MS), is one of the main metabolomics analytical platforms. The technological developments in the field of NMR spectroscopy have enabled the identification and quantitative measurement of the many metabolites in a single sample of biofluids in a non-targeted and non-destructive manner. Combination of NMR spectra of biofluids and pattern recognition methods has driven forward the application of metabolomics in the field of biomarker discovery. The importance of metabolomics in diagnostics, e.g. in identifying biomarkers or defining pathological status, has been growing exponentially as evidenced by the number of published papers. In this review, we describe the developments in data acquisition and multivariate analysis of NMR-based metabolomics data, with particular emphasis on the metabolomics of Cerebrospinal Fluid (CSF) and biomarker discovery in Multiple Sclerosis (MScl).

  19. Surfactant protein D is a candidate biomarker for subclinical tobacco smoke-induced lung damage

    DEFF Research Database (Denmark)

    Johansson, Sofie L.; Tan, Qihua; Holst, René;

    2014-01-01

    Variation in Surfactant Protein D (SP-D) is associated with lung function in tobacco smoke-induced chronic respiratory disease. We hypothesized that the same association exists in the general population and could be used to identify individuals sensitive to smoke-induced lung damage. The associat......Variation in Surfactant Protein D (SP-D) is associated with lung function in tobacco smoke-induced chronic respiratory disease. We hypothesized that the same association exists in the general population and could be used to identify individuals sensitive to smoke-induced lung damage...... or haplotypes, and expiratory lung function were assessed using twin study methodology and mixed-effects models. Significant inverse associations were evident between sSP-D and the forced expiratory volume in 1 second and forced vital capacity in the presence of current tobacco smoking but not in non...... with lung function measures in interaction with tobacco smoking. The obtained data suggest sSP-D as a candidate biomarker in risk assessments for subclinical tobacco smoke-induced lung damage. The data and derived conclusion warrant confirmation in a longitudinal population following chronic obstructive...

  20. Cell surface profiling using high-throughput flow cytometry: a platform for biomarker discovery and analysis of cellular heterogeneity.

    Directory of Open Access Journals (Sweden)

    Craig A Gedye

    Full Text Available Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell

  1. Discovery and identification of serum biomarkers of Wilms' tumor in mice using proteomics technology

    Institute of Scientific and Technical Information of China (English)

    JIA Zhan-kui; WANG Jia-xiang; YANG Jin-jian; XUE Rui; ZHANG Da; WANG Guan-nan; MA Sheng-li; DUAN Zhen-feng

    2012-01-01

    Background Wilms' tumor (nephroblastoma) is a cancer of the kidneys that occurs typically in children and rarely in adults.Early diagnosis is very important for the treatment and prognosis of the disease.The aim of our study was to discover and identify potential non-invasive and convenient biomarkers for the diagnosis of Wilms' tumor.Methods Nude mice were used to construct a Wilms' tumor model by injecting nephroblastoma cells into their bilateral abdomen.We collected 94 serum samples from mice consisting of 45 samples with Wilms' tumor and 49 controls.The serum proteomic profiles of the samples were analyzed via surface-enhanced laser desorption/ionization time-of-flight mass spectrometry.The candidate biomarkers were purified by high-performance liquid chromatography,identified by liquid chromatography-mass spectrometry,and validated using ProteinChip immunoassays.Results We finally retrieved two differential proteins (m/z 4509.2; 6207.9),which were identified as apolipoprotein A-Ⅱ and polyubiquitin,respectively.The expression of apolipoprotein A-Ⅱ was higher in the Wilms' tumor group than in the control group (P<0.01).By contrast,the expression of polyubiquitin was lower in the Wilms' tumor group than in the control group.Conclusion Apolipoprotein A-Ⅱ and polyubiquitin may be used as potential biomarkers for nephroblastoma in children,and the analysis of apolipoprotein A-Ⅱ may help diagnose and treat Wilms' tumor.

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

    Science.gov (United States)

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

    2015-08-01

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

  3. Biomarker Discovery for Early Detection of Hepatocellular Carcinoma in Hepatitis C–infected Patients*

    Science.gov (United States)

    Mustafa, Mehnaz G.; Petersen, John R.; Ju, Hyunsu; Cicalese, Luca; Snyder, Ned; Haidacher, Sigmund J.; Denner, Larry; Elferink, Cornelis

    2013-01-01

    Chronic hepatic disease damages the liver, and the resulting wound-healing process leads to liver fibrosis and the subsequent development of cirrhosis. The leading cause of hepatic fibrosis and cirrhosis is infection with hepatitis C virus (HCV), and of the patients with HCV-induced cirrhosis, 2% to 5% develop hepatocellular carcinoma (HCC), with a survival rate of 7%. HCC is one of the leading causes of cancer-related death worldwide, and the poor survival rate is largely due to late-stage diagnosis, which makes successful intervention difficult, if not impossible. The lack of sensitive and specific diagnostic tools and the urgent need for early-stage diagnosis prompted us to discover new candidate biomarkers for HCV and HCC. We used aptamer-based fractionation technology to reduce serum complexity, differentially labeled samples (six HCV and six HCC) with fluorescent dyes, and resolved proteins in pairwise two-dimensional difference gel electrophoresis. DeCyder software was used to identify differentially expressed proteins and spots picked, and MALDI-MS/MS was used to determine that ApoA1 was down-regulated by 22% (p < 0.004) in HCC relative to HCV. Differential expression quantified via two-dimensional difference gel electrophoresis was confirmed by means of 18O/16O stable isotope differential labeling with LC-MS/MS zoom scans. Technically independent confirmation was demonstrated by triple quadrupole LC-MS/MS selected reaction monitoring (SRM) assays with three peptides specific to human ApoA1 (DLATVYVDVLK, WQEEMELYR, and VSFLSALEEYTK) using 18O/16O-labeled samples and further verified with AQUA peptides as internal standards for quantification. In 50 patient samples (24 HCV and 26 HCC), all three SRM assays yielded highly similar differential expression of ApoA1 in HCC and HCV patients. These results validated the SRM assays, which were independently confirmed by Western blotting. Thus, ApoA1 is a candidate member of an SRM biomarker panel for early diagnosis

  4. Biomarker discovery in heterogeneous tissue samples -taking the in-silico deconfounding approach

    Directory of Open Access Journals (Sweden)

    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

  5. A signaling visualization toolkit to support rational design of combination therapies and biomarker discovery : SiViT

    OpenAIRE

    Brown, James L; Shovman, Mark; Robertson, Paul; Boiko, Andrei; Goltsov, Alexey; Mullen, Peter; Harrison, David James

    2016-01-01

    Targeted cancer therapy aims to disrupt aberrant cellular signalling pathways. Biomarkers are surrogates of pathway state, but there is limited success in translating candidate biomarkers to clinical practice due to the intrinsic complexity of pathway networks. Systems biology approaches afford better understanding of complex, dynamical interactions in signalling pathways targeted by anticancer drugs. However, adoption of dynamical modelling by clinicians and biologists is impeded by model in...

  6. A semiparametric modeling framework for potential biomarker discovery and the development of metabonomic profiles

    Directory of Open Access Journals (Sweden)

    Dey Dipak K

    2008-01-01

    Full Text Available Abstract Background The discovery of biomarkers is an important step towards the development of criteria for early diagnosis of disease status. Recently electrospray ionization (ESI and matrix assisted laser desorption (MALDI time-of-flight (TOF mass spectrometry have been used to identify biomarkers both in proteomics and metabonomics studies. Data sets generated from such studies are generally very large in size and thus require the use of sophisticated statistical techniques to glean useful information. Most recent attempts to process these types of data model each compound's intensity either discretely by positional (mass to charge ratio clustering or through each compounds' own intensity distribution. Traditionally data processing steps such as noise removal, background elimination and m/z alignment, are generally carried out separately resulting in unsatisfactory propagation of signals in the final model. Results In the present study a novel semi-parametric approach has been developed to distinguish urinary metabolic profiles in a group of traumatic patients from those of a control group consisting of normal individuals. Data sets obtained from the replicates of a single subject were used to develop a functional profile through Dirichlet mixture of beta distribution. This functional profile is flexible enough to accommodate variability of the instrument and the inherent variability of each individual, thus simultaneously addressing different sources of systematic error. To address instrument variability, all data sets were analyzed in replicate, an important issue ignored by most studies in the past. Different model comparisons were performed to select the best model for each subject. The m/z values in the window of the irregular pattern are then further recommended for possible biomarker discovery. Conclusion To the best of our knowledge this is the very first attempt to model the physical process behind the time-of flight mass

  7. Candidate serological biomarkers for cancer identified from the secretomes of 23 cancer cell lines and the human protein atlas.

    Science.gov (United States)

    Wu, Chih-Ching; Hsu, Chia-Wei; Chen, Chi-De; Yu, Chia-Jung; Chang, Kai-Ping; Tai, Dar-In; Liu, Hao-Ping; Su, Wen-Hui; Chang, Yu-Sun; Yu, Jau-Song

    2010-06-01

    Although cancer cell secretome profiling is a promising strategy used to identify potential body fluid-accessible cancer biomarkers, questions remain regarding the depth to which the cancer cell secretome can be mined and the efficiency with which researchers can select useful candidates from the growing list of identified proteins. Therefore, we analyzed the secretomes of 23 human cancer cell lines derived from 11 cancer types using one-dimensional SDS-PAGE and nano-LC-MS/MS performed on an LTQ-Orbitrap mass spectrometer to generate a more comprehensive cancer cell secretome. A total of 31,180 proteins was detected, accounting for 4,584 non-redundant proteins, with an average of 1,300 proteins identified per cell line. Using protein secretion-predictive algorithms, 55.8% of the proteins appeared to be released or shed from cells. The identified proteins were selected as potential marker candidates according to three strategies: (i) proteins apparently secreted by one cancer type but not by others (cancer type-specific marker candidates), (ii) proteins released by most cancer cell lines (pan-cancer marker candidates), and (iii) proteins putatively linked to cancer-relevant pathways. We then examined protein expression profiles in the Human Protein Atlas to identify biomarker candidates that were simultaneously detected in the secretomes and highly expressed in cancer tissues. This analysis yielded 6-137 marker candidates selective for each tumor type and 94 potential pan-cancer markers. Among these, we selectively validated monocyte differentiation antigen CD14 (for liver cancer), stromal cell-derived factor 1 (for lung cancer), and cathepsin L1 and interferon-induced 17-kDa protein (for nasopharyngeal carcinoma) as potential serological cancer markers. In summary, the proteins identified from the secretomes of 23 cancer cell lines and the Human Protein Atlas represent a focused reservoir of potential cancer biomarkers.

  8. TargetMine, an integrated data warehouse for candidate gene prioritisation and target discovery.

    Directory of Open Access Journals (Sweden)

    Yi-An Chen

    Full Text Available Prioritising candidate genes for further experimental characterisation is a non-trivial challenge in drug discovery and biomedical research in general. An integrated approach that combines results from multiple data types is best suited for optimal target selection. We developed TargetMine, a data warehouse for efficient target prioritisation. TargetMine utilises the InterMine framework, with new data models such as protein-DNA interactions integrated in a novel way. It enables complicated searches that are difficult to perform with existing tools and it also offers integration of custom annotations and in-house experimental data. We proposed an objective protocol for target prioritisation using TargetMine and set up a benchmarking procedure to evaluate its performance. The results show that the protocol can identify known disease-associated genes with high precision and coverage. A demonstration version of TargetMine is available at http://targetmine.nibio.go.jp/.

  9. Prediction potential of candidate biomarker sets identified and validated on gene expression data from multiple datasets

    Directory of Open Access Journals (Sweden)

    Karacali Bilge

    2007-10-01

    learning approaches. These findings are relevant to the use of molecular profiling for the identification of candidate biomarker panels.

  10. Isolation and quantification of microRNAs from urinary exosomes/microvesicles for biomarker discovery.

    Science.gov (United States)

    Lv, Lin-Li; Cao, Yuhan; Liu, Dan; Xu, Min; Liu, Hong; Tang, Ri-Ning; Ma, Kun-Ling; Liu, Bi-Cheng

    2013-01-01

    Recent studies indicate that microRNA (miRNA) is contained within exosome. Here we sought to optimize the methodologies for the isolation and quantification of urinary exosomal microRNA as a prelude to biomarker discovery studies. Exosomes were isolated through ultracentrifugation and characterized by immunoelectron microscopy. To determine the RNA was confined inside exosomes, the pellet was treated with RNase before RNA isolation. The minimum urine volume, storage conditions for exosomes and exosomal miRNA was evaluated. The presence of miRNAs in patients with various kidney diseases was validated with real-time PCR. The result shows that miRNAs extracted from the exosomal fraction were resistant to RNase digestion and with high quality confirmed by agarose electrophoresis. 16 ml of urine was sufficient for miRNA isolation by absolute quantification with 4.15×10(5) copies/ul for miR-200c. Exosomes was stable at 4℃ 24h for shipping before stored at -80℃ and was stable in urine when stored at -80°C for 12 months. Exosomal miRNA was detectable despite 5 repeat freeze-thaw cycles. The detection of miRNA by quantitative PCR showed high reproducibility (>94% for intra-assay and >76% for inter-assay), high sensitivity (positive call 100% for CKD patients), broad dynamic range (8-log wide) and good linearity for quantification (R(2)>0.99). miR-29c and miR-200c showed different expression in different types of kidney disease. In summary, the presence of urinary exosomal miRNA was confirmed for patients with a diversity of chronic kidney disease. The conditions of urine collection, storage and miRNA detection determined in this study may be useful for future biomarker discovery efforts. PMID:24250247

  11. Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery.

    Science.gov (United States)

    Saigusa, Daisuke; Okamura, Yasunobu; Motoike, Ikuko N; Katoh, Yasutake; Kurosawa, Yasuhiro; Saijyo, Reina; Koshiba, Seizo; Yasuda, Jun; Motohashi, Hozumi; Sugawara, Junichi; Tanabe, Osamu; Kinoshita, Kengo; Yamamoto, Masayuki

    2016-01-01

    Metabolomics is a promising avenue for biomarker discovery. Although the quality of metabolomic analyses, especially global metabolomics (G-Met) using mass spectrometry (MS), largely depends on the instrumentation, potential bottlenecks still exist at several basic levels in the metabolomics workflow. Therefore, we established a precise protocol initially for the G-Met analyses of human blood plasma to overcome some these difficulties. In our protocol, samples are deproteinized in a 96-well plate using an automated liquid-handling system, and conducted either using a UHPLC-QTOF/MS system equipped with a reverse phase column or a LC-FTMS system equipped with a normal phase column. A normalization protocol of G-Met data was also developed to compensate for intra- and inter-batch differences, and the variations were significantly reduced along with our normalization, especially for the UHPLC-QTOF/MS data with a C18 reverse-phase column for positive ions. Secondly, we examined the changes in metabolomic profiles caused by the storage of EDTA-blood specimens to identify quality markers for the evaluation of the specimens' pre-analytical conditions. Forty quality markers, including lysophospholipids, dipeptides, fatty acids, succinic acid, amino acids, glucose, and uric acid were identified by G-Met for the evaluation of plasma sample quality and established the equation of calculating the quality score. We applied our quality markers to a small-scale study to evaluate the quality of clinical samples. The G-Met protocols and quality markers established here should prove useful for the discovery and development of biomarkers for a wider range of diseases. PMID:27579980

  12. Establishment of Protocols for Global Metabolomics by LC-MS for Biomarker Discovery

    Science.gov (United States)

    Okamura, Yasunobu; Motoike, Ikuko N.; Katoh, Yasutake; Kurosawa, Yasuhiro; Saijyo, Reina; Koshiba, Seizo; Yasuda, Jun; Motohashi, Hozumi; Sugawara, Junichi; Tanabe, Osamu; Kinoshita, Kengo; Yamamoto, Masayuki

    2016-01-01

    Metabolomics is a promising avenue for biomarker discovery. Although the quality of metabolomic analyses, especially global metabolomics (G-Met) using mass spectrometry (MS), largely depends on the instrumentation, potential bottlenecks still exist at several basic levels in the metabolomics workflow. Therefore, we established a precise protocol initially for the G-Met analyses of human blood plasma to overcome some these difficulties. In our protocol, samples are deproteinized in a 96-well plate using an automated liquid-handling system, and conducted either using a UHPLC-QTOF/MS system equipped with a reverse phase column or a LC-FTMS system equipped with a normal phase column. A normalization protocol of G-Met data was also developed to compensate for intra- and inter-batch differences, and the variations were significantly reduced along with our normalization, especially for the UHPLC-QTOF/MS data with a C18 reverse-phase column for positive ions. Secondly, we examined the changes in metabolomic profiles caused by the storage of EDTA-blood specimens to identify quality markers for the evaluation of the specimens’ pre-analytical conditions. Forty quality markers, including lysophospholipids, dipeptides, fatty acids, succinic acid, amino acids, glucose, and uric acid were identified by G-Met for the evaluation of plasma sample quality and established the equation of calculating the quality score. We applied our quality markers to a small-scale study to evaluate the quality of clinical samples. The G-Met protocols and quality markers established here should prove useful for the discovery and development of biomarkers for a wider range of diseases. PMID:27579980

  13. OSSOS: IV. Discovery of a dwarf planet candidate in the 9:2 resonance

    CERN Document Server

    Bannister, Michele T; Benecchi, Susan D; Chen, Ying-Tung; Delsanti, Audrey; Fraser, Wesley C; Gladman, Brett J; Granvik, Mikael; Grundy, Will M; Guilbert-Lepoutre, Aurelie; Gwyn, Stephen D J; Ip, Wing-Huen; Jakubik, Marian; Jones, R Lynne; Kaib, Nathan; Kavelaars, J J; Lacerda, Pedro; Lawler, Samantha; Lehner, Matthew J; Lin, Hsing Wen; Lykawka, Patryk Sofia; Marsset, Michael; Murray-Clay, Ruth; Noll, Keith S; Parker, Alex; Petit, Jean-Marc; Pike, Rosemary E; Rousselot, Philippe; Schwamb, Megan E; Shankman, Cory; Veres, Peter; Vernazza, Pierre; Volk, Kathryn; Wang, Shiang-Yu; Weryk, Robert

    2016-01-01

    We report the discovery and orbit of a new dwarf planet candidate, 2015 RR$_{245}$, by the Outer Solar System Origins Survey (OSSOS). 2015 RR$_{245}$'s orbit is eccentric ($e=0.586$), with a semi-major axis near 82 au, yielding a perihelion distance of 34 au. 2015 RR$_{245}$ has $g-r = 0.59 \\pm 0.11$ and absolute magnitude $H_{r} = 3.6 \\pm 0.1$; for an assumed albedo of $p_V = 12$% the object has a diameter of $\\sim670$ km. Based on astrometric measurements from OSSOS and Pan-STARRS1, we find that 2015 RR$_{245}$ is securely trapped in the 9:2 mean-motion resonance with Neptune. It is the first TNO identified in this resonance. On hundred-Myr timescales, particles in 2015 RR$_{245}$-like orbits depart and sometimes return to the resonance, indicating that 2015 RR$_{245}$ likely forms part of the long-lived metastable population of distant TNOs that drift between resonance sticking and actively scattering via gravitational encounters with Neptune. The discovery of a 9:2 TNO stresses the role of resonances in t...

  14. Analysis of Reverse Phase Protein Array Data: From Experimental Design towards Targeted Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Astrid Wachter

    2015-11-01

    Full Text Available Mastering the systematic analysis of tumor tissues on a large scale has long been a technical challenge for proteomics. In 2001, reverse phase protein arrays (RPPA were added to the repertoire of existing immunoassays, which, for the first time, allowed a profiling of minute amounts of tumor lysates even after microdissection. A characteristic feature of RPPA is its outstanding sample capacity permitting the analysis of thousands of samples in parallel as a routine task. Until today, the RPPA approach has matured to a robust and highly sensitive high-throughput platform, which is ideally suited for biomarker discovery. Concomitant with technical advancements, new bioinformatic tools were developed for data normalization and data analysis as outlined in detail in this review. Furthermore, biomarker signatures obtained by different RPPA screens were compared with another or with that obtained by other proteomic formats, if possible. Options for overcoming the downside of RPPA, which is the need to steadily validate new antibody batches, will be discussed. Finally, a debate on using RPPA to advance personalized medicine will conclude this article.

  15. Translating discovery in zebrafish pancreatic development to human pancreatic cancer: biomarkers, targets, pathogenesis, and therapeutics.

    Science.gov (United States)

    Yee, Nelson S; Kazi, Abid A; Yee, Rosemary K

    2013-06-01

    Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer.

  16. Application in pesticide analysis: Liquid chromatography - A review of the state of science for biomarker discovery and identification

    Science.gov (United States)

    Book Chapter 18, titled Application in pesticide analysis: Liquid chromatography - A review of the state of science for biomarker discovery and identification, will be published in the book titled High Performance Liquid Chromatography in Pesticide Residue Analysis (Part of the C...

  17. Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

    Science.gov (United States)

    Schadt, S; Simon, S; Kustermann, S; Boess, F; McGinnis, C; Brink, A; Lieven, R; Fowler, S; Youdim, K; Ullah, M; Marschmann, M; Zihlmann, C; Siegrist, Y M; Cascais, A C; Di Lenarda, E; Durr, E; Schaub, N; Ang, X; Starke, V; Singer, T; Alvarez-Sanchez, R; Roth, A B; Schuler, F; Funk, C

    2015-12-25

    Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates. PMID:26407524

  18. Quantitative proteomic analysis by iTRAQ® for the identification of candidate biomarkers in ovarian cancer serum

    Directory of Open Access Journals (Sweden)

    Higgins LeeAnn

    2010-06-01

    Full Text Available Abstract Background Ovarian cancer is the most lethal gynecologic malignancy, with the majority of cases diagnosed at an advanced stage when treatments are less successful. Novel serum protein markers are needed to detect ovarian cancer in its earliest stage; when detected early, survival rates are over 90%. The identification of new serum biomarkers is hindered by the presence of a small number of highly abundant proteins that comprise approximately 95% of serum total protein. In this study, we used pooled serum depleted of the most highly abundant proteins to reduce the dynamic range of proteins, and thereby enhance the identification of serum biomarkers using the quantitative proteomic method iTRAQ®. Results Medium and low abundance proteins from 6 serum pools of 10 patients each from women with serous ovarian carcinoma, and 6 non-cancer control pools were labeled with isobaric tags using iTRAQ® to determine the relative abundance of serum proteins identified by MS. A total of 220 unique proteins were identified and fourteen proteins were elevated in ovarian cancer compared to control serum pools, including several novel candidate ovarian cancer biomarkers: extracellular matrix protein-1, leucine-rich alpha-2 glycoprotein-1, lipopolysaccharide binding protein-1, and proteoglycan-4. Western immunoblotting validated the relative increases in serum protein levels for several of the proteins identified. Conclusions This study provides the first analysis of immunodepleted serum in combination with iTRAQ® to measure relative protein expression in ovarian cancer patients for the pursuit of serum biomarkers. Several candidate biomarkers were identified which warrant further development.

  19. The path forward to biomarker discovery in psoriatic disease: a report from the GRAPPA 2010 annual meeting.

    Science.gov (United States)

    Gladman, Dafna D; Ritchlin, Christopher T; Fitzgerald, Oliver

    2012-02-01

    At the 2010 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), wide-ranging discussions were held regarding biomarker research in psoriatic disease. Consensus was reached on 2 areas of priority: (1) the study of soluble biomarkers of radiographic progression in psoriatic arthritis (PsA); and (2) the analysis of comorbidity biomarkers, specifically cardiovascular and articular, in a psoriasis inception cohort. For each of these areas, rigorous definition of the clinical phenotype of PsA will be essential. To date, 2 instruments have been identified to define the phenotype: the ClASsification of Psoriatic ARthritis criteria and various screening questionnaires. In this overview, we discuss the challenges of the clinical phenotype of PsA and review GRAPPA plans for developing a research program for biomarker discovery. PMID:22298275

  20. Identification of Circulating Biomarker Candidates for Hepatocellular Carcinoma (HCC: An Integrated Prioritization Approach.

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    Faryal Mehwish Awan

    Full Text Available Hepatocellular carcinoma (HCC is the world's third most widespread cancer. Currently available circulating biomarkers for this silently progressing malignancy are not sufficiently specific and sensitive to meet all clinical needs. There is an imminent and pressing need for the identification of novel circulating biomarkers to increase disease-free survival rate. In order to facilitate the selection of the most promising circulating protein biomarkers, we attempted to define an objective method likely to have a significant impact on the analysis of vast data generated from cutting-edge technologies. Current study exploits data available in seven publicly accessible gene and protein databases, unveiling 731 liver-specific proteins through initial enrichment analysis. Verification of expression profiles followed by integration of proteomic datasets, enriched for the cancer secretome, filtered out 20 proteins including 6 previously characterized circulating HCC biomarkers. Finally, interactome analysis of these proteins with midkine (MDK, dickkopf-1 (DKK-1, current standard HCC biomarker alpha-fetoprotein (AFP, its interacting partners in conjunction with HCC-specific circulating and liver deregulated miRNAs target filtration highlighted seven novel statistically significant putative biomarkers including complement component 8, alpha (C8A, mannose binding lectin (MBL2, antithrombin III (SERPINC1, 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1, alcohol dehydrogenase 6 (ADH6, beta-ureidopropionase (UPB1 and cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6. Our proposed methodology provides a swift assortment process for biomarker prioritization that eventually reduces the economic burden of experimental evaluation. Further dedicated validation studies of potential putative biomarkers on HCC patient blood samples are warranted. We hope that the use of such integrative secretome, interactome and miRNAs target filtration approach will

  1. Unlocking biomarker discovery: large scale application of aptamer proteomic technology for early detection of lung cancer.

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    Rachel M Ostroff

    Full Text Available BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. New diagnostics are needed to detect early stage lung cancer because it may be cured with surgery. However, most cases are diagnosed too late for curative surgery. Here we present a comprehensive clinical biomarker study of lung cancer and the first large-scale clinical application of a new aptamer-based proteomic technology to discover blood protein biomarkers in disease. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a multi-center case-control study in archived serum samples from 1,326 subjects from four independent studies of non-small cell lung cancer (NSCLC in long-term tobacco-exposed populations. Sera were collected and processed under uniform protocols. Case sera were collected from 291 patients within 8 weeks of the first biopsy-proven lung cancer and prior to tumor removal by surgery. Control sera were collected from 1,035 asymptomatic study participants with ≥ 10 pack-years of cigarette smoking. We measured 813 proteins in each sample with a new aptamer-based proteomic technology, identified 44 candidate biomarkers, and developed a 12-protein panel (cadherin-1, CD30 ligand, endostatin, HSP90α, LRIG3, MIP-4, pleiotrophin, PRKCI, RGM-C, SCF-sR, sL-selectin, and YES that discriminates NSCLC from controls with 91% sensitivity and 84% specificity in cross-validated training and 89% sensitivity and 83% specificity in a separate verification set, with similar performance for early and late stage NSCLC. CONCLUSIONS/SIGNIFICANCE: This study is a significant advance in clinical proteomics in an area of high unmet clinical need. Our analysis exceeds the breadth and dynamic range of proteome interrogated of previously published clinical studies of broad serum proteome profiling platforms including mass spectrometry, antibody arrays, and autoantibody arrays. The sensitivity and specificity of our 12-biomarker panel improves upon published protein and gene expression panels

  2. Response to cold acclimation in diapause pupae of Hyles euphorbiae (Lepidoptera: Sphingidae): candidate biomarker identification using proteomics.

    Science.gov (United States)

    Stuckas, H; Mende, M B; Hundsdoerfer, A K

    2014-08-01

    The distribution range of Hyles euphorbiae covers distinct climates across the Palaearctic. Previous investigations showed a correlation between mitochondrial DNA identity of populations and climatic conditions related to winter; however, the lack of biomarkers hampers investigations to test whether geographically distinct populations do show specific molecular responses to low temperatures or whether they possess specific genetic identity at loci functionally related to cold response. The present study was designed to identify candidate protein biomarkers and biological processes that are associated with cold acclimation of overwintering H. euphorbiae diapause pupae. Specimens taken from a single central European population were gradually cooled from 20 °C to -2 °C over 36 days and 12 differentially abundant proteins were identified. In addition, DeepSuperSAGE sequencing technology was applied to study differentially regulated genes. There was incongruence between differentially abundant proteins and differentially expressed genes, but functional characteristics of regulated proteins and analyses of gene ontology term enrichment among differentially regulated genes pointed to activation of the same biological processes, e.g. oxidative stress response. As proteins represent biologically active molecules, candidate biomarkers derived from proteomics are considered well suited to explore intraspecific patterns of local adaptation to different climates. PMID:24628883

  3. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

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    Ronald C Hendrickson

    Full Text Available Disease modifying treatments for Alzheimer's disease (AD constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001 and SME-2 (p = 0.0004 for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR, in AD were 21% (p = 0.039 and 17% (p = 0.026 lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

  4. Discovery of a Thorne-Zytkow object candidate in the Small Magellanic Cloud

    CERN Document Server

    Levesque, Emily M; Zytkow, Anna N; Morrell, Nidia

    2014-01-01

    Thorne-Zytkow objects (TZOs) are a theoretical class of star in which a compact neutron star is surrounded by a large, diffuse envelope. Supergiant TZOs are predicted to be almost identical in appearance to red supergiants (RSGs). The best features that can be used at present to distinguish TZOs from the general RSG population are the unusually strong heavy-element and Li lines present in their spectra, products of the star's fully convective envelope linking the photosphere with the extraordinarily hot burning region in the vicinity of the neutron star core. Here we present our discovery of a TZO candidate in the Small Magellanic Cloud. It is the first star to display the distinctive chemical profile of anomalous element enhancements thought to be unique to TZOs. The positive detection of a TZO will provide the first direct evidence for a completely new model of stellar interiors, a theoretically predicted fate for massive binary systems, and never-before-seen nucleosynthesis processes that would offer a new...

  5. Discovery of a tidal disruption event candidate from the 2XMM catalog

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    Farrell S.A.

    2012-12-01

    Full Text Available Stars approaching a supermassive black hole (SMBH can be tidally disrupted and subsequently accreted, providing a unique way to find and study inactive SMBHs. We report on our discovery of a new tidal disruption event candidate, 2XMMi J184725.1-631724, with unprecedented ultrasoft X-ray spectra near the flare peak. It lies toward the center of an inactive galaxy at z = 0.0353. It was detected serendipitously in two XMM-Newton observations separated by 211 days, with the flux increasing by a factor of ∼9. The source was not detected in X-rays by ROSAT in 1992, indicating a long-term variability factor of >64; neither by Swift in 2011, implying a flux decay factor of >12 since the last XMM-Newton observation. The XMM-Newton X-ray spectra are dominated by a strong cool thermal disk (>80%, tens of eV with the luminosity appearing to follow the L ∝ T4 relation, often seen in the thermal state of the BH X-ray binaries. Both XMM-Newton observations show large variability on timescales of hours. This can be explained as due to fast variations in the mass accretion rate, maybe caused by the shocks during the tidal disruption of the star.

  6. The Dark Energy Survey view of the Sagittarius stream: Discovery of two faint stellar system candidates

    CERN Document Server

    Luque, E; Santiago, B; Yanny, B; Vivas, A K; Queiroz, A; Drlica-Wagner, A; Morganson, E; Balbinot, E; Marshall, J L; Li, T S; Neto, A Fausti; da Costa, L N; Maia, M A G; Bechtol, K; Kim, A G; Bernstein, G M; Dodelson, S; Whiteway, L; Diehl, H T; Finley, D A; Abbott, T; Abdalla, F B; Allam, S; Annis, J; Benoit-Lévy, A; Bertin, E; Brooks, D; Burke, D L; Rosell, A Carnero; Kind, M Carrasco; Carretero, J; Cunha, C E; D'Andrea, C B; Desai, S; Doel, P; Evrard, A E; Flaugher, B; Fosalba, P; Gerdes, D W; Goldstein, D A; Gruen, D; Gruendl, R A; Gutierrez, G; James, D J; Kuehn, K; Kuropatkin, N; Lahav, O; Martini, P; Miquel, R; Nord, B; Ogando, R; Plazas, A A; Romer, A K; Sanchez, E; Scarpine, V; Schubnell, M; Sevilla-Noarbe, I; Smith, R C; Soares-Santos, M; Sobreira, F; Suchyta, E; Swanson, M E C; Tarle, G; Thomas, D; Walker, A R

    2016-01-01

    We report the discovery of two new candidate stellar systems in the constellation of Cetus using the data from the first two years of the Dark Energy Survey (DES). The objects, DES J0111-1341 and DES J0225+0304, are located at a heliocentric distance of ~ 24 kpc and appear to have old and metal-poor populations. Their distances to the Sagittarius orbital plane, ~ 1.47 kpc (DES J0111-1341) and ~ 0.51 kpc (DES J0225+0304), indicate that they are possibly associated with the Sagittarius dwarf stream. The half-light radius (r_h ~ 4.10 pc) and luminosity (M_V ~ +0.5) of DES J0111-1341 are consistent with it being an ultra-faint stellar cluster, while the half-light radius (r_h ~ 18.70 pc) and luminosity (M_V ~ -1.2) of DES J0225+0304 place it in an ambiguous region of size-luminosity space between stellar clusters and dwarf galaxies. Determinations of the characteristic parameters of the Sagittarius stream, metallicity spread (-2.18 < [Fe/H] < -0.95) and distance gradient (23 kpc < D_sun < 29 kpc), wit...

  7. The discovery of new AGN candidates within the field of Fermi unassociated γ-ray sources

    Science.gov (United States)

    Fujinaga, Yoshitaka; Niinuma, Kotaro; Kimura, Atsushi; Fujisawa, Kenta; Oyama, Tomoaki; Mizuno, Syota; Kono, Yusuke; Takemura, Shinji; Sawada-Satoh, Satoko; Akutagawa, Kengo; Sugiyama, Koichiro; Motogi, Kazuhito; Fukuzaki, Yoshihiro

    2016-10-01

    In this paper, we report on the discovery of 26 new radio sources located within positional error range of unassociated γ-ray sources listed in the Fermi Large Area Telescope Second Source Catalog (2FGL catalog) by very long baseline interferometry (VLBI) observations. To search for new γ-ray AGN candidates, we conducted e-VLBI observations for 845 radio sources located in the field of 149 Fermi unassociated γ-ray sources at high galactic latitude, using the Japanese VLBI Network (JVN) at 8.4 GHz with a noise level of approximately 2 mJy. As a result of our JVN observations, we detected 29 VLBI sources having a brightness temperature of TB > 106 K within positional error of 28 γ-ray sources in the 2FGL catalog. These high brightness temperatures imply that the newly detected sources are possibly GeV γ-ray AGNs, such as most of 2FGL sources, which have already been classified as AGNs. Also, precise radio coordinates make it possible to identify the multiwavelength counterparts to the newly detected VLBI sources. Their color-color diagrams derived from Wide-field Infrared Survey Explorer photometric data of these sources imply that eight out of all sources we detected would be classified as γ-ray blazars.

  8. A joint modeling approach for uncovering associations between gene expression, bioactivity and chemical structure in early drug discovery to guide lead selection and genomic biomarker development.

    Science.gov (United States)

    Perualila-Tan, Nolen; Kasim, Adetayo; Talloen, Willem; Verbist, Bie; Göhlmann, Hinrich W H; Shkedy, Ziv

    2016-08-01

    The modern drug discovery process involves multiple sources of high-dimensional data. This imposes the challenge of data integration. A typical example is the integration of chemical structure (fingerprint features), phenotypic bioactivity (bioassay read-outs) data for targets of interest, and transcriptomic (gene expression) data in early drug discovery to better understand the chemical and biological mechanisms of candidate drugs, and to facilitate early detection of safety issues prior to later and expensive phases of drug development cycles. In this paper, we discuss a joint model for the transcriptomic and the phenotypic variables conditioned on the chemical structure. This modeling approach can be used to uncover, for a given set of compounds, the association between gene expression and biological activity taking into account the influence of the chemical structure of the compound on both variables. The model allows to detect genes that are associated with the bioactivity data facilitating the identification of potential genomic biomarkers for compounds efficacy. In addition, the effect of every structural feature on both genes and pIC50 and their associations can be simultaneously investigated. Two oncology projects are used to illustrate the applicability and usefulness of the joint model to integrate multi-source high-dimensional information to aid drug discovery. PMID:27269248

  9. MetaBoot: a machine learning framework of taxonomical biomarker discovery for different microbial communities based on metagenomic data.

    Science.gov (United States)

    Wang, Xiaojun; Su, Xiaoquan; Cui, Xinping; Ning, Kang

    2015-01-01

    As more than 90% of species in a microbial community could not be isolated and cultivated, the metagenomic methods have become one of the most important methods to analyze microbial community as a whole. With the fast accumulation of metagenomic samples and the advance of next-generation sequencing techniques, it is now possible to qualitatively and quantitatively assess all taxa (features) in a microbial community. A set of taxa with presence/absence or their different abundances could potentially be used as taxonomical biomarkers for identification of the corresponding microbial community's phenotype. Though there exist some bioinformatics methods for metagenomic biomarker discovery, current methods are not robust, accurate and fast enough at selection of non-redundant biomarkers for prediction of microbial community's phenotype. In this study, we have proposed a novel method, MetaBoot, that combines the techniques of mRMR (minimal redundancy maximal relevance) and bootstrapping, for discover of non-redundant biomarkers for microbial communities through mining of metagenomic data. MetaBoot has been tested and compared with other methods on well-designed simulated datasets considering normal and gamma distribution as well as publicly available metagenomic datasets. Results have shown that MetaBoot was robust across datasets of varied complexity and taxonomical distribution patterns and could also select discriminative biomarkers with quite high accuracy and biological consistency. Thus, MetaBoot is suitable for robustly and accurately discover taxonomical biomarkers for different microbial communities. PMID:26213658

  10. Translational database selection and multiplexed sequence capture for up front filtering of reliable breast cancer biomarker candidates.

    Directory of Open Access Journals (Sweden)

    Patrik L Ståhl

    Full Text Available Biomarker identification is of utmost importance for the development of novel diagnostics and therapeutics. Here we make use of a translational database selection strategy, utilizing data from the Human Protein Atlas (HPA on differentially expressed protein patterns in healthy and breast cancer tissues as a means to filter out potential biomarkers for underlying genetic causatives of the disease. DNA was isolated from ten breast cancer biopsies, and the protein coding and flanking non-coding genomic regions corresponding to the selected proteins were extracted in a multiplexed format from the samples using a single DNA sequence capture array. Deep sequencing revealed an even enrichment of the multiplexed samples and a great variation of genetic alterations in the tumors of the sampled individuals. Benefiting from the upstream filtering method, the final set of biomarker candidates could be completely verified through bidirectional Sanger sequencing, revealing a 40 percent false positive rate despite high read coverage. Of the variants encountered in translated regions, nine novel non-synonymous variations were identified and verified, two of which were present in more than one of the ten tumor samples.

  11. Neuromedin U: a candidate biomarker and therapeutic target to predict and overcome resistance to HER-tyrosine kinase inhibitors.

    Science.gov (United States)

    Rani, Sweta; Corcoran, Claire; Shiels, Liam; Germano, Serena; Breslin, Susan; Madden, Stephen; McDermott, Martina S; Browne, Brigid C; O'Donovan, Norma; Crown, John; Gogarty, Martina; Byrne, Annette T; O'Driscoll, Lorraine

    2014-07-15

    Intrinsic and acquired resistance to HER-targeting drugs occurs in a significant proportion of HER2-overexpressing breast cancers. Thus, there remains a need to identify predictive biomarkers that could improve patient selection and circumvent these types of drug resistance. Here, we report the identification of neuromedin U (NmU) as an extracellular biomarker in cells resistant to HER-targeted drugs. NmU overexpression occurred in cells with acquired or innate resistance to lapatinib, trastuzumab, neratinib, and afatinib, all of which displayed a similar trend upon short-term exposure, suggesting NmU induction may be an early response. An analysis of 3,489 cases of breast cancer showed NmU to be associated with poor patient outcome, particularly those with HER2-overexpressing tumors independent of established prognostic indicators. Ectopic overexpression of NmU in drug-sensitive cells conferred resistance to all HER-targeting drugs, whereas RNAi-mediated attenuation sensitized cells exhibiting acquired or innate drug resistance. Mechanistic investigations suggested that NmU acted through HSP27 as partner protein to stabilize HER2 protein levels. We also obtained evidence of functional NmU receptors on HER2-overexpressing cells, with the addition of exogenous NmU eliciting an elevation in HER2 and EGFR expression along with drug resistance. Finally, we found that NmU seemed to function in cell motility, invasion, and anoikis resistance. In vivo studies revealed that NmU attenuation impaired tumor growth and metastasis. Taken together, our results defined NmU as a candidate drug response biomarker for HER2-overexpressing cancers and as a candidate therapeutic target to limit metastatic progression and improve the efficacy of HER-targeted drugs. PMID:24876102

  12. New Candidate Biomarkers in the Female Genital Tract to Evaluate Microbicide Toxicity

    OpenAIRE

    Scott Fields; Benben Song; Bareza Rasoul; Julie Fong; Works, Melissa G.; Kenneth Shew; Ying Yiu; Jon Mirsalis; Annalisa D'Andrea

    2014-01-01

    Vaginal microbicides hold great promise for the prevention of viral diseases like HIV, but the failure of several microbicide candidates in clinical trials has raised important questions regarding the parameters to be evaluated to determine in vivo efficacy in humans. Clinical trials of the candidate microbicides nonoxynol-9 (N9) and cellulose sulfate revealed an increase in HIV infection, vaginal inflammation, and recruitment of HIV susceptible lymphocytes, highlighting the need to identify ...

  13. Release of Tissue-specific Proteins into Coronary Perfusate as a Model for Biomarker Discovery in Myocardial Ischemia/Reperfusion Injury

    DEFF Research Database (Denmark)

    Cordwell, Stuart; Edwards, Alistair; Liddy, Kiersten;

    2012-01-01

    Diagnosis of acute coronary syndromes is based on protein biomarkers, such as the cardiac troponins (cTnI/cTnT) and creatine kinase (CK-MB) that are released into the circulation. Biomarker discovery is focused on identifying very low abundance tissue-derived analytes from within albumin-rich pla...

  14. 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

  15. 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

  16. Comprehensive analytical strategy for biomarker identification based on liquid chromatography coupled to mass spectrometry and new candidate confirmation tools.

    Science.gov (United States)

    Mohamed, Rayane; Varesio, Emmanuel; Ivosev, Gordana; Burton, Lyle; Bonner, Ron; Hopfgartner, Gérard

    2009-09-15

    A comprehensive analytical LC-MS(/MS) platform for low weight biomarkers molecule in biological fluids is described. Two complementary retention mechanisms were used in HPLC by optimizing the chromatographic conditions for a reversed-phase column and a hydrophilic interaction chromatography column. LC separation was coupled to mass spectrometry by using an electrospray ionization operating in positive polarity mode. This strategy enables us to correctly retain and separate hydrophobic as well as polar analytes. For that purpose artificial model study samples were generated with a mixture of 38 well characterized compounds likely to be present in biofluids. The set of compounds was used as a standard aqueous mixture or was spiked into urine at different concentration levels to investigate the capability of the LC-MS(/MS) platform to detect variations across biological samples. Unsupervised data analysis by principal component analysis was performed and followed by principal component variable grouping to find correlated variables. This tool allows us to distinguish three main groups whose variables belong to (a) background ions (found in all type of samples), (b) ions distinguishing urine samples from aqueous standard and blank samples, (c) ions related to the spiked compounds. Interpretation of these groups allows us to identify and eliminate isotopes, adducts, fragments, etc. and to generate a reduced list of m/z candidates. This list is then submitted to the prototype MZSearcher software tool which simultaneously searches several lists of potential metabolites extracted from metabolomics databases (e.g., KEGG, HMDB, etc) to propose biomarker candidates. Structural confirmation of these candidates was done off-line by fraction collection followed by nanoelectrospray infusion to provide high quality MS/MS data for spectral database queries. PMID:19702294

  17. A TMA de-arraying method for high throughput biomarker discovery in tissue research.

    Directory of Open Access Journals (Sweden)

    Yinhai Wang

    Full Text Available BACKGROUND: Tissue MicroArrays (TMAs represent a potential high-throughput platform for the analysis and discovery of tissue biomarkers. As TMA slides are produced manually and subject to processing and sectioning artefacts, the layout of TMA cores on the final slide and subsequent digital scan (TMA digital slide is often disturbed making it difficult to associate cores with their original position in the planned TMA map. Additionally, the individual cores can be greatly altered and contain numerous irregularities such as missing cores, grid rotation and stretching. These factors demand the development of a robust method for de-arraying TMAs which identifies each TMA core, and assigns them to their appropriate coordinates on the constructed TMA slide. METHODOLOGY: This study presents a robust TMA de-arraying method consisting of three functional phases: TMA core segmentation, gridding and mapping. The segmentation of TMA cores uses a set of morphological operations to identify each TMA core. Gridding then utilises a Delaunay Triangulation based method to find the row and column indices of each TMA core. Finally, mapping correlates each TMA core from a high resolution TMA whole slide image with its name within a TMAMap. CONCLUSION: This study describes a genuine robust TMA de-arraying algorithm for the rapid identification of TMA cores from digital slides. The result of this de-arraying algorithm allows the easy partition of each TMA core for further processing. Based on a test group of 19 TMA slides (3129 cores, 99.84% of cores were segmented successfully, 99.81% of cores were gridded correctly and 99.96% of cores were mapped with their correct names via TMAMaps. The gridding of TMA cores were also extensively tested using a set of 113 pseudo slide (13,536 cores with a variety of irregular grid layouts including missing cores, rotation and stretching. 100% of the cores were gridded correctly.

  18. Integrated proteomic analysis of human cancer cells and plasma from tumor bearing mice for ovarian cancer biomarker discovery.

    Directory of Open Access Journals (Sweden)

    Sharon J Pitteri

    Full Text Available The complexity of the human plasma proteome represents a substantial challenge for biomarker discovery. Proteomic analysis of genetically engineered mouse models of cancer and isolated cancer cells and cell lines provide alternative methods for identification of potential cancer markers that would be detectable in human blood using sensitive assays. The goal of this work is to evaluate the utility of an integrative strategy using these two approaches for biomarker discovery.We investigated a strategy that combined quantitative plasma proteomics of an ovarian cancer mouse model with analysis of proteins secreted or shed by human ovarian cancer cells. Of 106 plasma proteins identified with increased levels in tumor bearing mice, 58 were also secreted or shed from ovarian cancer cells. The remainder consisted primarily of host-response proteins. Of 25 proteins identified in the study that were assayed, 8 mostly secreted proteins common to mouse plasma and human cancer cells were significantly upregulated in a set of plasmas from ovarian cancer patients. Five of the eight proteins were confirmed to be upregulated in a second independent set of ovarian cancer plasmas, including in early stage disease.Integrated proteomic analysis of cancer mouse models and human cancer cell populations provides an effective approach to identify potential circulating protein biomarkers.

  19. Glycoproteomics using so-called ‘fluid-biopsy’ specimens in the discovery of lung cancer biomarkers. Promise and challenge

    Science.gov (United States)

    Li, Qing Kay; Gabrielson, Ed; Askin, Frederic; Chan, Daniel W; Zhang, Hui

    2016-01-01

    Lung cancer is the number one cancer in the US and worldwide. In spite of the rapid progression in personalized treatments, the overall survival rate of lung cancer patients is still suboptimal. Over the past decade, tremendous efforts have been focused on the discovery of protein biomarkers to facilitate the early detection and monitoring lung cancer progression during treatment. In addition to tumor tissues and cancer cell lines, a variety of biological material has been studied. Particularly in recent years, studies using fluid-based specimen or so-called “fluid-biopsy” specimen have progressed rapidly. Fluid specimens are relatively easier to collect than tumor tissue, and they can be repeatedly sampled during the disease progression. Glycoproteins have long been recognized to play fundamental roles in many physiological and pathological processes. In this review, we focus the discussion on recent advances of glycoproteomics, particularly in the identification of potential protein biomarkers using so-called fluid-based specimens in lung cancer. The purpose of this review is to summarize current strategies, achievements and perspectives in the field. This insight will highlight the discovery of tumor-associated glycoprotein biomarkers in lung cancer and their potential clinical applications. PMID:23112109

  20. Biomarker discovery from the top down: Protein biomarkers for efficient virus transmission by insects (Homoptera: Aphididae) discovered by coupling genetics and 2-D DIGE.

    Science.gov (United States)

    Cilia, Michelle; Howe, Kevin; Fish, Tara; Smith, Dawn; Mahoney, Jaclyn; Tamborindeguy, Cecilia; Burd, John; Thannhauser, Theodore W; Gray, Stewart

    2011-06-01

    Yellow dwarf viruses cause the most economically important virus diseases of cereal crops worldwide and are vectored by aphids. The identification of vector proteins mediating virus transmission is critical to develop sustainable virus management practices and to understand viral strategies for circulative movement in all insect vectors. Previously, we applied 2-D DIGE to an aphid filial generation 2 population to identify proteins correlated with the transmission phenotype that were stably inherited and expressed in the absence of the virus. In the present study, we examined the expression of the DIGE candidates in previously unstudied, field-collected aphid populations. We hypothesized that the expression of proteins involved in virus transmission could be clinically validated in unrelated, virus transmission-competent, field-collected aphid populations. All putative biomarkers were expressed in the field-collected biotypes, and the expression of nine of these aligned with the virus transmission-competent phenotype. The strong conservation of the expression of the biomarkers in multiple field-collected populations facilitates new and testable hypotheses concerning the genetics and biochemistry of virus transmission. Integration of these biomarkers into current aphid-scouting methodologies will enable rational strategies for vector control aimed at judicious use and development of precision pest control methods that reduce plant virus infection. PMID:21648087

  1. Glutathione transferase (GST) as a candidate molecular-based biomarker for soil toxin exposure in the earthworm Lumbricus rubellus

    Energy Technology Data Exchange (ETDEWEB)

    LaCourse, E. James, E-mail: james.la-course@liverpool.ac.u [Institute of Biological, Environmental, and Rural Sciences, Aberystwyth University, Aberystwyth SY23 3DA (United Kingdom); Hernandez-Viadel, Mariluz; Jefferies, James R. [Institute of Biological, Environmental, and Rural Sciences, Aberystwyth University, Aberystwyth SY23 3DA (United Kingdom); Svendsen, Claus; Spurgeon, David J. [Centre for Ecology and Hydrology, Huntingdon PE28 2LS (United Kingdom); Barrett, John [Institute of Biological, Environmental, and Rural Sciences, Aberystwyth University, Aberystwyth SY23 3DA (United Kingdom); John Morgan, A.; Kille, Peter [Biosciences, University of Cardiff, Cardiff CF10 3TL (United Kingdom); Brophy, Peter M. [Institute of Biological, Environmental, and Rural Sciences, Aberystwyth University, Aberystwyth SY23 3DA (United Kingdom)

    2009-08-15

    The earthworm Lumbricus rubellus (Hoffmeister, 1843) is a terrestrial pollution sentinel. Enzyme activity and transcription of phase II detoxification superfamily glutathione transferases (GST) is known to respond in earthworms after soil toxin exposure, suggesting GST as a candidate molecular-based pollution biomarker. This study combined sub-proteomics, bioinformatics and biochemical assay to characterise the L. rubellus GST complement as pre-requisite to initialise assessment of the applicability of GST as a biomarker. L. rubellus possesses a range of GSTs related to known classes, with evidence of tissue-specific synthesis. Two affinity-purified GSTs dominating GST protein synthesis (Sigma and Pi class) were cloned, expressed and characterised for enzyme activity with various substrates. Electrospray ionisation mass spectrometry (ESI-MS) and tandem mass spectrometry (MS/MS) following SDS-PAGE were superior in retaining subunit stability relative to two-dimensional gel electrophoresis (2-DE). This study provides greater understanding of Phase II detoxification GST superfamily status of an important environmental pollution sentinel organism. - This study currently provides the most comprehensive view of the Phase II detoxification enzyme superfamily of glutathione transferases within the important environmental pollution sentinel earthworm Lumbricus rubellus.

  2. Theoretical modeling of masking DNA application in aptamer-facilitated biomarker discovery.

    Science.gov (United States)

    Cherney, Leonid T; Obrecht, Natalia M; Krylov, Sergey N

    2013-04-16

    In aptamer-facilitated biomarker discovery (AptaBiD), aptamers are selected from a library of random DNA (or RNA) sequences for their ability to specifically bind cell-surface biomarkers. The library is incubated with intact cells, and cell-bound DNA molecules are separated from those unbound and amplified by the polymerase chain reaction (PCR). The partitioning/amplification cycle is repeated multiple times while alternating target cells and control cells. Efficient aptamer selection in AptaBiD relies on the inclusion of masking DNA within the cell and library mixture. Masking DNA lacks primer regions for PCR amplification and is typically taken in excess to the library. The role of masking DNA within the selection mixture is to outcompete any nonspecific binding sequences within the initial library, thus allowing specific DNA sequences (i.e., aptamers) to be selected more efficiently. Efficient AptaBiD requires an optimum ratio of masking DNA to library DNA, at which aptamers still bind specific binding sites but nonaptamers within the library do not bind nonspecific binding sites. Here, we have developed a mathematical model that describes the binding processes taking place within the equilibrium mixture of masking DNA, library DNA, and target cells. An obtained mathematical solution allows one to estimate the concentration of masking DNA that is required to outcompete the library DNA at a desirable ratio of bound masking DNA to bound library DNA. The required concentration depends on concentrations of the library and cells as well as on unknown cell characteristics. These characteristics include the concentration of total binding sites on the cell surface, N, and equilibrium dissociation constants, K(nsL) and K(nsM), for nonspecific binding of the library DNA and masking DNA, respectively. We developed a theory that allows the determination of N, K(nsL), and K(nsM) based on measurements of EC50 values for cells mixed separately with the library and masking DNA

  3. Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy.

    Science.gov (United States)

    Nair, Nitya; Mei, Henrik E; Chen, Shih-Yu; Hale, Matthew; Nolan, Garry P; Maecker, Holden T; Genovese, Mark; Fathman, C Garrison; Whiting, Chan C

    2015-01-01

    The development of biomarkers for autoimmune diseases has been hampered by a lack of understanding of disease etiopathogenesis and of the mechanisms underlying the induction and maintenance of inflammation, which involves complex activation dynamics of diverse cell types. The heterogeneous nature and suboptimal clinical response to treatment observed in many autoimmune syndromes highlight the need to develop improved strategies to predict patient outcome to therapy and personalize patient care. Mass cytometry, using CyTOF®, is an advanced technology that facilitates multiparametric, phenotypic analysis of immune cells at single-cell resolution. In this review, we outline the capabilities of mass cytometry and illustrate the potential of this technology to enhance the discovery of cellular biomarkers for rheumatoid arthritis, a prototypical autoimmune disease. PMID:25981462

  4. The use of MYBL2 as a novel candidate biomarker of cervical cancer.

    Science.gov (United States)

    Martin, Cara M; Astbury, Katharine; Kehoe, Louise; O'Crowley, Jacqueline Barry; O'Toole, Sharon; O'Leary, John J

    2015-01-01

    Cervical cancer is the third most common cancer affecting women worldwide. It is characterized by chromosomal aberrations and alteration in the expression levels of many cell cycle regulatory proteins, driven primarily by transforming human papillomavirus (HPV) infection. MYBL2 is a member of the MYB proto-oncogene family that encodes DNA binding proteins. These proteins are involved in cell proliferation and control of cellular differentiation. We have previously demonstrated the utility of MYBL2 as a putative biomarker for cervical pre-cancer and cancer. In this chapter we describe the methodological approach for testing MYBL2 protein expression in tissue biopsies from cases of cervical intraepithelial neoplasia (CIN) and cervical cancer, using immunohistochemistry techniques on the automated immunostaining platform, the Ventana BenchMark LT. The protocol outlines the various steps in the procedure from cutting tissue sections, antibody optimization, antigen retrieval, immunostaining, and histological review.

  5. Evaluation of candidate biomarkers to predict cancer cell sensitivity or resistance to PARP-1 inhibitor treatment

    DEFF Research Database (Denmark)

    Oplustilova, L.; Wolanin, K.; Bartkova, J.;

    2012-01-01

    to PARP-1i. Here we addressed these issues using PARP-1i on 20 human cell lines from carcinomas of the breast, prostate, colon, pancreas and ovary. Aberrations of the Mre11-Rad50-Nbs1 (MRN) complex sensitized cancer cells to PARP-1i, while p53 status was less predictive, even in response to PARP-1i......Impaired DNA damage response pathways may create vulnerabilities of cancer cells that can be exploited therapeutically. One such selective vulnerability is the sensitivity of BRCA1- or BRCA2-defective tumors (hence defective in DNA repair by homologous recombination, HR) to inhibitors of the poly......(ADp-ribose) polymerase-1 (PARP-1), an enzyme critical for repair pathways alternative to HR. While promising, treatment with PARP-1 inhibitors (PARP-1i) faces some hurdles, including (1) acquired resistance, (2) search for other sensitizing, non-BRCA1/2 cancer defects and (3) lack of biomarkers to predict response...

  6. In Silico discovery of transcription factors as potential diagnostic biomarkers of ovarian cancer

    Directory of Open Access Journals (Sweden)

    Choolani Mahesh

    2011-09-01

    Full Text Available Abstract Background Our study focuses on identifying potential biomarkers for diagnosis and early detection of ovarian cancer (OC through the study of transcription regulation of genes affected by estrogen hormone. Results The results are based on a set of 323 experimentally validated OC-associated genes compiled from several databases, and their subset controlled by estrogen. For these two gene sets we computationally determined transcription factors (TFs that putatively regulate transcription initiation. We ranked these TFs based on the number of genes they are likely to control. In this way, we selected 17 top-ranked TFs as potential key regulators and thus possible biomarkers for a set of 323 OC-associated genes. For 77 estrogen controlled genes from this set we identified three unique TFs as potential biomarkers. Conclusions We introduced a new methodology to identify potential diagnostic biomarkers for OC. This report is the first bioinformatics study that explores multiple transcriptional regulators of OC-associated genes as potential diagnostic biomarkers in connection with estrogen responsiveness. We show that 64% of TF biomarkers identified in our study are validated based on real-time data from microarray expression studies. As an illustration, our method could identify CP2 that in combination with CA125 has been reported to be sensitive in diagnosing ovarian tumors.

  7. In Silico discovery of transcription factors as potential diagnostic biomarkers of ovarian cancer

    KAUST Repository

    Kaur, Mandeep

    2011-09-19

    Background: Our study focuses on identifying potential biomarkers for diagnosis and early detection of ovarian cancer (OC) through the study of transcription regulation of genes affected by estrogen hormone.Results: The results are based on a set of 323 experimentally validated OC-associated genes compiled from several databases, and their subset controlled by estrogen. For these two gene sets we computationally determined transcription factors (TFs) that putatively regulate transcription initiation. We ranked these TFs based on the number of genes they are likely to control. In this way, we selected 17 top-ranked TFs as potential key regulators and thus possible biomarkers for a set of 323 OC-associated genes. For 77 estrogen controlled genes from this set we identified three unique TFs as potential biomarkers.Conclusions: We introduced a new methodology to identify potential diagnostic biomarkers for OC. This report is the first bioinformatics study that explores multiple transcriptional regulators of OC-associated genes as potential diagnostic biomarkers in connection with estrogen responsiveness. We show that 64% of TF biomarkers identified in our study are validated based on real-time data from microarray expression studies. As an illustration, our method could identify CP2 that in combination with CA125 has been reported to be sensitive in diagnosing ovarian tumors. 2011 Kaur et al; licensee BioMed Central Ltd.

  8. A systematic approach to biomarker discovery; Preamble to "the iSBTc-FDA taskforce on immunotherapy biomarkers"

    Directory of Open Access Journals (Sweden)

    Schendel Dolores

    2008-12-01

    Full Text Available Abstract The International Society for the Biological Therapy of Cancer (iSBTc has initiated in collaboration with the United States Food and Drug Administration (FDA a programmatic look at innovative avenues for the identification of relevant parameters to assist clinical and basic scientists who study the natural course of host/tumor interactions or their response to immune manipulation. The task force has two primary goals: 1 identify best practices of standardized and validated immune monitoring procedures and assays to promote inter-trial comparisons and 2 develop strategies for the identification of novel biomarkers that may enhance our understating of principles governing human cancer immune biology and, consequently, implement their clinical application. Two working groups were created that will report the developed best practices at an NCI/FDA/iSBTc sponsored workshop tied to the annual meeting of the iSBTc to be held in Washington DC in the Fall of 2009. This foreword provides an overview of the task force and invites feedback from readers that might be incorporated in the discussions and in the final document.

  9. Discovery of Candidate H$_2$O Disk Masers in AGN and Estimations of Centripetal Accelerations

    CERN Document Server

    Greenhill, Lincoln J; Moran, James M; Tilak, Avanti

    2009-01-01

    Based on spectroscopic signatures, about one-third of known H$_2$O maser sources in active galactic nuclei (AGN) are believed to arise in highly inclined accretion disks around central engines. These "disk maser candidates" are of interest primarily because angular structure and rotation curves can be resolved with interferometers, enabling dynamical study. We identify five new disk maser candidates in studies with the Green Bank Telescope, bringing the total number published to 30. We discovered two (NGC1320, NGC17) in a survey of 40 inclined active galaxies (v_{sys}< 20000 kms^{-1}). The remaining three disk maser candidates were identified in monitoring of known sources: NGC449, NGC2979, NGC3735. We also confirm a previously marginal case in UGC4203. For the disk maser candidates reported here, inferred rotation speeds are 130-500 kms^{-1}. Monitoring of three more rapidly rotating candidate disks (CG211, NGC6264, VV340A) has enabled measurement of likely orbital centripetal acceleration, and estimation...

  10. Development of urinary pseudotargeted LC-MS-based metabolomics method and its application in hepatocellular carcinoma biomarker discovery.

    Science.gov (United States)

    Shao, Yaping; Zhu, Bin; Zheng, Ruiyin; Zhao, Xinjie; Yin, Peiyuan; Lu, Xin; Jiao, Binghua; Xu, Guowang; Yao, Zhenzhen

    2015-02-01

    Hepatocellular carcinoma (HCC) is one of the pestilent malignancies leading to cancer-related death. Discovering effective biomarkers for HCC diagnosis is an urgent demand. To identify potential metabolite biomarkers, we developed a urinary pseudotargeted method based on liquid chromatography-hybrid triple quadrupole linear ion trap mass spectrometry (LC-QTRAP MS). Compared with nontargeted method, the pseudotargeted method can achieve better data quality, which benefits differential metabolites discovery. The established method was applied to cirrhosis (CIR) and HCC investigation. It was found that urinary nucleosides, bile acids, citric acid, and several amino acids were significantly changed in liver disease groups compared with the controls, featuring the dysregulation of purine metabolism, energy metabolism, and amino metabolism in liver diseases. Furthermore, some metabolites such as cyclic adenosine monophosphate, glutamine, and short- and medium-chain acylcarnitines were the differential metabolites of HCC and CIR. On the basis of binary logistic regression, butyrylcarnitine (carnitine C4:0) and hydantoin-5-propionic acid were defined as combinational markers to distinguish HCC from CIR. The area under curve was 0.786 and 0.773 for discovery stage and validation stage samples, respectively. These data show that the established pseudotargeted method is a complementary one of targeted and nontargeted methods for metabolomics study.

  11. A Comprehensive Workflow of Mass Spectrometry-Based Untargeted Metabolomics in Cancer Metabolic Biomarker Discovery Using Human Plasma and Urine

    Directory of Open Access Journals (Sweden)

    Jianwen She

    2013-09-01

    Full Text Available Current available biomarkers lack sensitivity and/or specificity for early detection of cancer. To address this challenge, a robust and complete workflow for metabolic profiling and data mining is described in details. Three independent and complementary analytical techniques for metabolic profiling are applied: hydrophilic interaction liquid chromatography (HILIC–LC, reversed-phase liquid chromatography (RP–LC, and gas chromatography (GC. All three techniques are coupled to a mass spectrometer (MS in the full scan acquisition mode, and both unsupervised and supervised methods are used for data mining. The univariate and multivariate feature selection are used to determine subsets of potentially discriminative predictors. These predictors are further identified by obtaining accurate masses and isotopic ratios using selected ion monitoring (SIM and data-dependent MS/MS and/or accurate mass MSn ion tree scans utilizing high resolution MS. A list combining all of the identified potential biomarkers generated from different platforms and algorithms is used for pathway analysis. Such a workflow combining comprehensive metabolic profiling and advanced data mining techniques may provide a powerful approach for metabolic pathway analysis and biomarker discovery in cancer research. Two case studies with previous published data are adapted and included in the context to elucidate the application of the workflow.

  12. An evaluation of logic regression-based biomarker discovery across multiple intergenic regions for predicting host specificity in Escherichia coli.

    Science.gov (United States)

    Zhi, Shuai; Li, Qiaozhi; Yasui, Yutaka; Banting, Graham; Edge, Thomas A; Topp, Edward; McAllister, Tim A; Neumann, Norman F

    2016-10-01

    Several studies have demonstrated that E. coli appears to display some level of host adaptation and specificity. Recent studies in our laboratory support these findings as determined by logic regression modeling of single nucleotide polymorphisms (SNP) in intergenic regions (ITGRs). We sought to determine the degree of host-specific information encoded in various ITGRs across a library of animal E. coli isolates using both whole genome analysis and a targeted ITGR sequencing approach. Our findings demonstrated that ITGRs across the genome encode various degrees of host-specific information. Incorporating multiple ITGRs (i.e., concatenation) into logic regression model building resulted in greater host-specificity and sensitivity outcomes in biomarkers, but the overall level of polymorphism in an ITGR did not correlate with the degree of host-specificity encoded in the ITGR. This suggests that distinct SNPs in ITGRs may be more important in defining host-specificity than overall sequence variation, explaining why traditional unsupervised learning phylogenetic approaches may be less informative in terms of revealing host-specific information encoded in DNA sequence. In silico analysis of 80 candidate ITGRs from publically available E. coli genomes was performed as a tool for discovering highly host-specific ITGRs. In one ITGR (ydeR-yedS) we identified a SNP biomarker that was 98% specific for cattle and for which 92% of all E. coli isolates originating from cattle carried this unique biomarker. In the case of humans, a host-specific biomarker (98% specificity) was identified in the concatenated ITGR sequences of rcsD-ompC, ydeR-yedS, and rclR-ykgE, and for which 78% of E. coli originating from humans carried this biomarker. Interestingly, human-specific biomarkers were dominant in ITGRs regulating antibiotic resistance, whereas in cattle host-specific biomarkers were found in ITGRs involved in stress regulation. These data suggest that evolution towards host

  13. AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Huei-Mei; Schmeichel, Karen L; Mian, I. Saira; Lelie`vre, Sophie; Petersen, Ole W; Bissell, Mina J

    2000-02-04

    To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non- and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.

  14. Investigation by imaging mass spectrometry of biomarker candidates for aging in the hair cortex.

    Directory of Open Access Journals (Sweden)

    Michihiko Luca Waki

    Full Text Available BACKGROUND: Human hair is one of the essential components that define appearance and is a useful source of samples for non-invasive biomonitoring. We describe a novel application of imaging mass spectrometry (IMS of hair biomolecules for advanced molecular characterization and a better understanding of hair aging. As a cosmetic and biomedical application, molecules whose levels in hair altered with aging were comprehensively investigated. METHODS: Human hair was collected from 15 young (20±5 years old and 15 older (50±5 years old volunteers. Matrix-free laser desorption/ionization IMS was used to visualize molecular distribution in the hair sections. Hair-specific ions displaying a significant difference in the intensities between the 2 age groups were extracted as candidate markers for aging. Tissue localization of the molecules and alterations in their levels in the cortex and medulla in the young and old groups were determined. RESULTS: Among the 31 molecules detected specifically in hair sections, 2--one at m/z 153.00, tentatively assigned to be dihydrouracil, and the other at m/z 207.04, identified to be 3,4-dihydroxymandelic acid (DHMA--exhibited a higher signal intensity in the young group than in the old, and 1 molecule at m/z 164.00, presumed to be O-phosphoethanolamine, displayed a higher intensity in the old group. Among the 3, putative O-phosphoethanolamine showed a cortex-specific distribution. The 3 molecules in cortex presented the same pattern of alteration in signal intensity with aging, whereas those in medulla did not exhibit significant alteration. CONCLUSION: Three molecules whose levels in hair altered with age were extracted. While they are all possible markers for aging, putative dihydrouracil and DHMA, are also suspected to play a role in maintaining hair properties and could be targets for cosmetic supplementation. Mapping of ion localization in hair by IMS is a powerful method to extract biomolecules in specified

  15. Discovery of potential prognostic long non-coding RNA biomarkers for predicting the risk of tumor recurrence of breast cancer patients.

    Science.gov (United States)

    Zhou, Meng; Zhong, Lei; Xu, Wanying; Sun, Yifan; Zhang, Zhaoyue; Zhao, Hengqiang; Yang, Lei; Sun, Jie

    2016-01-01

    Deregulation of long non-coding RNAs (lncRNAs) expression has been proven to be involved in the development and progression of cancer. However, expression pattern and prognostic value of lncRNAs in breast cancer recurrence remain unclear. Here, we analyzed lncRNA expression profiles of breast cancer patients who did or did not develop recurrence by repurposing existing microarray datasets from the Gene Expression Omnibus database, and identified 12 differentially expressed lncRNAs that were closely associated with tumor recurrence of breast cancer patients. We constructed a lncRNA-focus molecular signature by the risk scoring method based on the expression levels of 12 relapse-related lncRNAs from the discovery cohort, which classified patients into high-risk and low-risk groups with significantly different recurrence-free survival (HR = 2.72, 95% confidence interval 2.07-3.57; p = 4.8e-13). The 12-lncRNA signature also represented similar prognostic value in two out of three independent validation cohorts. Furthermore, the prognostic power of the 12-lncRNA signature was independent of known clinical prognostic factors in at least two cohorts. Functional analysis suggested that the predicted relapse-related lncRNAs may be involved in known breast cancer-related biological processes and pathways. Our results highlighted the potential of lncRNAs as novel candidate biomarkers to identify breast cancer patients at high risk of tumor recurrence. PMID:27503456

  16. Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets

    DEFF Research Database (Denmark)

    Swanton, C.; Larkin, J.M.; Gerlinger, M.;

    2010-01-01

    The EU multi-disciplinary personalised RNA interference to enhance the delivery of individualised chemotherapeutics and targeted therapies (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer a...

  17. Direct Imaging discovery of a second planet candidate around the possibly transiting planet host CVSO 30

    CERN Document Server

    Schmidt, T O B; Briceño, C; Vogt, N; Raetz, St; Seifahrt, A; Ginski, C; Mugrauer, M; Buder, S; Adam, C; Hauschildt, P H; Witte, S; Helling, Ch; Schmitt, J H M M

    2016-01-01

    We surveyed the 25 Ori association for direct-imaging companions. This association has an age of only few million years. Among other targets, we observed CVSO 30, which has recently been identified as the first T Tauri star found to host a transiting planet candidate. We report on photometric and spectroscopic high-contrast observations with the Very Large Telescope, the Keck telescopes, and the Calar Alto observatory. They reveal a directly imaged planet candidate close to the young M3 star CVSO 30. The JHK-band photometry of the newly identified candidate is at better than 1 sigma consistent with late-type giants, early-T and early-M dwarfs, and free-floating planets. Other hypotheses such as galaxies can be excluded at more than 3.5 sigma. A lucky imaging z' photometric detection limit z'= 20.5 mag excludes early-M dwarfs and results in less than 10 MJup for CVSO 30 c if bound. We present spectroscopic observations of the wide companion that imply that the only remaining explanation for the object is that ...

  18. Diffusion Tensor Imaging in NAWM and NADGM in MS and CIS: Association with Candidate Biomarkers in Sera

    Directory of Open Access Journals (Sweden)

    Renuka Natarajan

    2013-01-01

    Full Text Available The aim of this study was to evaluate diffusion tensor imaging (DTI indices in the corpus callosum and pyramidal tract in normal-appearing white matter (NAWM and the caudate nucleus and thalamus in deep grey matter (NADGM in all MS subtypes and clinically isolated syndrome (CIS. Furthermore, it was determined whether these metrics are associated with clinical measures and the serum levels of candidate immune biomarkers. Apparent diffusion coefficients (ADC values were significantly higher than in controls in all six studied NAWM regions in SPMS, 4/6 regions in RRMS and PPMS and 2/6 regions in CIS. In contrast, decreased fractional anisotropy (FA values in comparison to controls were detected in 2/6 NAWM regions in SPMS and 1/6 in RRMS and PPMS. In RRMS, the level of neurological disability correlated with thalamic FA values (r=0.479, P=0.004. In chronic progressive subtypes and CIS, ADC values of NAWM and NADGM were associated with the levels of MIF, sFas, and sTNF-α. Our data indicate that DTI may be useful in detecting pathological changes in NAWM and NADGM in MS patients and that these changes are related to neurological disability.

  19. MRM screening/biomarker discovery with linear ion trap MS: a library of human cancer-specific peptides

    International Nuclear Information System (INIS)

    The discovery of novel protein biomarkers is essential in the clinical setting to enable early disease diagnosis and increase survivability rates. To facilitate differential expression analysis and biomarker discovery, a variety of tandem mass spectrometry (MS/MS)-based protein profiling techniques have been developed. For achieving sensitive detection and accurate quantitation, targeted MS screening approaches, such as multiple reaction monitoring (MRM), have been implemented. MCF-7 breast cancer protein cellular extracts were analyzed by 2D-strong cation exchange (SCX)/reversed phase liquid chromatography (RPLC) separations interfaced to linear ion trap MS detection. MS data were interpreted with the Sequest-based Bioworks software (Thermo Electron). In-house developed Perl-scripts were used to calculate the spectral counts and the representative fragment ions for each peptide. In this work, we report on the generation of a library of 9,677 peptides (p < 0.001), representing ~1,572 proteins from human breast cancer cells, that can be used for MRM/MS-based biomarker screening studies. For each protein, the library provides the number and sequence of detectable peptides, the charge state, the spectral count, the molecular weight, the parameters that characterize the quality of the tandem mass spectrum (p-value, DeltaM, Xcorr, DeltaCn, Sp, no. of matching a, b, y ions in the spectrum), the retention time, and the top 10 most intense product ions that correspond to a given peptide. Only proteins identified by at least two spectral counts are listed. The experimental distribution of protein frequencies, as a function of molecular weight, closely matched the theoretical distribution of proteins in the human proteome, as provided in the SwissProt database. The amino acid sequence coverage of the identified proteins ranged from 0.04% to 98.3%. The highest-abundance proteins in the cellular extract had a molecular weight (MW)<50,000. Preliminary experiments have

  20. Direct Imaging discovery of a second planet candidate around the possibly transiting planet host CVSO 30

    Science.gov (United States)

    Schmidt, T. O. B.; Neuhäuser, R.; Briceño, C.; Vogt, N.; Raetz, St.; Seifahrt, A.; Ginski, C.; Mugrauer, M.; Buder, S.; Adam, C.; Hauschildt, P.; Witte, S.; Helling, Ch.; Schmitt, J. H. M. M.

    2016-09-01

    Context. Direct imaging has developed into a very successful technique for the detection of exoplanets in wide orbits, especially around young stars. Directly imaged planets can be both followed astrometrically on their orbits and observed spectroscopically and thus provide an essential tool for our understanding of the early solar system. Aims: We surveyed the 25 Ori association for direct-imaging companions. This association has an age of only few million years. Among other targets, we observed CVSO 30, which has recently been identified as the first T Tauri star found to host a transiting planet candidate. Methods: We report on photometric and spectroscopic high-contrast observations with the Very Large Telescope, the Keck telescopes, and the Calar Alto observatory. They reveal a directly imaged planet candidate close to the young M3 star CVSO 30. Results: The JHK-band photometry of the newly identified candidate is at better than 1σ consistent with late-type giants, early-T and early-M dwarfs, and free-floating planets. Other hypotheses such as galaxies can be excluded at more than 3.5σ. A lucky imaging z' photometric detection limit z' = 20.5 mag excludes early-M dwarfs and results in less than 10 MJup for CVSO 30 c if bound. We present spectroscopic observations of the wide companion that imply that the only remaining explanation for the object is that it is the first very young (ESO Telescopes at the La Silla Paranal Observatory under programme IDs 090.C-0448(A), 290.C-5018(B), 092.C-0488(A) and at the Centro Astronómico Hispano-Alemán in programme H15-2.2-002.

  1. Nutrition and biomarkers in psychiatry : research on micronutrient deficiencies in schizophrenia, the role of the intestine in the hyperserotonemia of autism, and a method for non-hypothesis driven discovery of biomarkers in urine

    NARCIS (Netherlands)

    Kemperman, Ramses Franciscus Jacobus

    2007-01-01

    This thesis describes the study of markers of nutrition and intestinal motility in mental disorders with a focus on schizophrenia and autism, and the development, evaluation and application of a biomarker discovery method for urine. The aim of the thesis is to investigate the role of long-chain poly

  2. TOFwave: reproducibility in biomarker discovery from time-of-flight mass spectrometry data.

    Science.gov (United States)

    Chierici, Marco; Albanese, Davide; Franceschi, Pietro; Furlanello, Cesare

    2012-11-01

    Many are the sources of variability that can affect reproducibility of disease biomarkers from time-of-flight (TOF) Mass Spectrometry (MS) data. Here we present TOFwave, a complete software pipeline for TOF-MS biomarker identification, that limits the impact of parameter tuning along the whole chain of preprocessing and model selection modules. Peak profiles are obtained by a preprocessing based on Continuous Wavelet Transform (CWT), coupled with a machine learning protocol aimed at avoiding selection bias effects. Only two parameters (minimum peak width and a signal to noise cutoff) have to be explicitly set. The TOFwave pipeline is built on top of the mlpy Python package. Examples on Matrix-Assisted Laser Desorption and Ionization (MALDI) TOF datasets are presented. Software prototype, datasets and details to replicate results in this paper can be found at http://mlpy.sf.net/tofwave/. PMID:22875362

  3. Enabling Metabolomics Based Biomarker Discovery Studies Using Molecular Phenotyping of Exosome-Like Vesicles

    OpenAIRE

    Altadill, Tatiana; Campoy, Irene; Lanau, Lucia; Gill, Kirandeep; Rigau, Marina; Gil-Moreno, Antonio; Reventos, Jaume; Byers, Stephen; Colas, Eva; Cheema, Amrita K.

    2016-01-01

    Identification of sensitive and specific biomarkers with clinical and translational utility will require smart experimental strategies that would augment expanding the breadth and depth of molecular measurements within the constraints of currently available technologies. Exosomes represent an information rich matrix to discern novel disease mechanisms that are thought to contribute to pathologies such as dementia and cancer. Although proteomics and transcriptomic studies have been reported us...

  4. Secretome, surfome and immunome: emerging approaches for the discovery of new vaccine candidates against bacterial infections.

    Science.gov (United States)

    Dwivedi, Pratistha; Alam, Syed Imteyaz; Tomar, Rajesh Singh

    2016-09-01

    Functional genomics has made possible advanced structure-to-function investigation of pathogens and helped characterize virulence mechanisms. Proteomics has been become a tool for large-scale identification of proteins involved during invasion and infection by the pathogens. Bacterial surface and secreted proteins play key role in the interaction between the bacterial cell and the host environment. Thus exoproteome and surface proteome of a microorganism are hypothesized to contain components of effective vaccines. Surfome and exoproteome analysis strategy facilitates identification of novel vaccine antigen and overall helps in progress of discovery of vaccine. The study of the antibody response can advance how proteomics is used, because it investigates antibody-antigen interactions and also unravel the relationship of antibody responses to pathogen and host characteristics. System immunology integrating with proteome i.e. immunoproteomics is applicable to those infections that are having tendency of diverse antibody target recognition and thus accurately reflects progression of the infection. PMID:27465855

  5. Ensuring Sample Quality for Biomarker Discovery Studies - Use of ICT Tools to Trace Biosample Life-cycle.

    Science.gov (United States)

    Riondino, Silvia; Ferroni, Patrizia; Spila, Antonella; Alessandroni, Jhessica; D'Alessandro, Roberta; Formica, Vincenzo; Della-Morte, David; Palmirotta, Raffaele; Nanni, Umberto; Roselli, Mario; Guadagni, Fiorella

    2015-01-01

    The growing demand of personalized medicine marked the transition from an empirical medicine to a molecular one, aimed at predicting safer and more effective medical treatment for every patient, while minimizing adverse effects. This passage has emphasized the importance of biomarker discovery studies, and has led sample availability to assume a crucial role in biomedical research. Accordingly, a great interest in Biological Bank science has grown concomitantly. In biobanks, biological material and its accompanying data are collected, handled and stored in accordance with standard operating procedures (SOPs) and existing legislation. Sample quality is ensured by adherence to SOPs and sample whole life-cycle can be recorded by innovative tracking systems employing information technology (IT) tools for monitoring storage conditions and characterization of vast amount of data. All the above will ensure proper sample exchangeability among research facilities and will represent the starting point of all future personalized medicine-based clinical trials. PMID:26543078

  6. Systematic biomarker discovery and coordinative validation for different primary nephrotic syndromes using gas chromatography-mass spectrometry.

    Science.gov (United States)

    Lee, Jung-Eun; Lee, Yu Ho; Kim, Se-Yun; Kim, Yang Gyun; Moon, Ju-Young; Jeong, Kyung-Hwan; Lee, Tae Won; Ihm, Chun-Gyoo; Kim, Sooah; Kim, Kyoung Heon; Kim, Dong Ki; Kim, Yon Su; Kim, Chan-Duck; Park, Cheol Whee; Lee, Do Yup; Lee, Sang-Ho

    2016-07-01

    The goal of this study is to identify systematic biomarker panel for primary nephrotic syndromes from urine samples by applying a non-target metabolite profiling, and to validate their utility in independent sampling and analysis by multiplex statistical approaches. Nephrotic syndrome (NS) is a nonspecific kidney disorder, which is mostly represented by minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous glomerulonephritis (MGN). Since urine metabolites may mirror disease-specific functional perturbations in kidney injury, we examined urine samples for distinctive metabolic changes to identify biomarkers for clinical applications. We developed unbiased multi-component covarianced models from a discovery set with 48 samples (12 healthy controls, 12 MCD, 12 FSGS, and 12 MGN). To extensively validate their diagnostic potential, new batch from 54 patients with primary NS were independently examined a year after. In the independent validation set, the model including citric acid, pyruvic acid, fructose, ethanolamine, and cysteine effectively discriminated each NS using receiver operating characteristic (ROC) analysis except MCD-MGN comparison; nonetheless an additional metabolite multi-composite greatly improved the discrimination power between MCD and MGN. Finally, we proposed the re-constructed metabolic network distinctively dysregulated by the different NSs that may deepen comprehensive understanding of the disease mechanistic, and help the enhanced identification of NS and therapeutic plans for future. PMID:27247212

  7. Heritability and clinical determinants of serum indoxyl sulfate and p-cresyl sulfate, candidate biomarkers of the human microbiome enterotype.

    Directory of Open Access Journals (Sweden)

    Liesbeth Viaene

    Full Text Available BACKGROUND: Indoxyl sulfate and p-cresyl sulfate are unique microbial co-metabolites. Both co-metabolites have been involved in the pathogenesis of accelerated cardiovascular disease and renal disease progression. Available evidence suggests that indoxyl sulfate and p-cresyl sulfate may be considered candidate biomarkers of the human enterotype and may help to explain the link between diet and cardiovascular disease burden. OBJECTIVE AND DESIGN: Information on clinical determinants and heritability of indoxyl sulfate and p-cresyl sulfate serum is non-existing. To clarify this issue, the authors determined serum levels of indoxyl sulfate and p-cresyl sulfate in 773 individuals, recruited in the frame of the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO study. RESULTS: Serum levels of indoxyl sulfate and p-cresyl sulfate amounted to 3.1 (2.4-4.3 and 13.0 (7.4-21.5 μM, respectively. Regression analysis identified renal function, age and sex as independent determinants of both co-metabolites. Both serum indoxyl sulfate (h2 = 0.17 and p-cresyl sulfate (h2 = 0.18 concentrations showed moderate but significant heritability after adjustment for covariables, with significant genetic and environmental correlations for both co-metabolites. LIMITATIONS: Family studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded. CONCLUSIONS: The heritability of indoxyl sulfate and p-cresyl sulfate is moderate. Besides genetic host factors and environmental factors, also renal function, sex and age influence the serum levels of these co-metabolites.

  8. Discovery of Five Candidate Analogs for $\\eta\\,$Carinae in Nearby Galaxies

    CERN Document Server

    Khan, Rubab; Stanek, K Z; Kochanek, C S; Sonneborn, G

    2015-01-01

    The late-stage evolution of very massive stars such as $\\eta\\,$Carinae may be dominated by poorly understood episodic mass ejections which may later lead to superluminous supernovae. However, as long as $\\eta\\,$Car is one of a kind, it is nearly impossible to quantitatively evaluate these possibilities. Here we announce the discovery of five objects in the nearby ($\\sim4-8\\,$Mpc) massive star-forming galaxies M$51$, M$83$, M$101$ and NGC$6946$ that have optical through mid-infrared photometric properties consistent with the hitherto unique $\\eta\\,$Car. We identified these $L_{bol}\\simeq3-8\\times10^{6}\\,L_\\odot$ objects through a systematic search of archival Spitzer and HST data. Their Spitzer mid-infrared spectral energy distributions rise steeply in the $3.6-8\\,\\mu$m bands, then turn over between $8$ and $24\\,\\mu$m, indicating the presence of warm ($\\sim400-600\\,$K) circumstellar dust. Their optical counterparts or flux limits from deep HST images are $\\sim1.5-2\\,$dex fainter than their mid-IR peaks and req...

  9. Discovery and Evolution of the New Black Hole Candidate Swift J1539.2-6227 During Its 2008 Outburst

    Science.gov (United States)

    Krimm, H. A.; Tomsick, J. A.; Markwardt, C. B.; Brocksopp, C.; Grise, F.; Kaaret, P.; Romano, P.

    2010-01-01

    We report on the discovery by the Swift Gamma-Ray Burst Explorer of the black hole candidate Swift J1539.2-6227 and the subsequent course of an outburst beginning in November 2008 and lasting at least seven months. The source was discovered during normal observations with the Swift Burst Alert Telescope (BAT) on 2008 November 25. An extended observing campaign with the Rossi X-Ray Timing Explorer (RXTE) and Swift provided near-daily coverage over 176 days, giving us a rare opportunity to track the evolution of spectral and timing parameters with fine temporal resolution through a series of spectral states. The source was first detected in a hard state during which strong low-frequency quasiperiodic oscillations (QPOs) were detected. The QPOs persisted for about 35 days and a signature of the transition from the hard to soft intermediate states was seen in the timing data. The source entered a short-lived thermal state about 40 days after the start of the outburst. There were variations in spectral hardness as the source flux declined and returned to a hard state at the end of the outburst. The progression of spectral states and the nature of the timing features provide strong evidence that Swift J1539.2-6227 is a candidate black hole in a low-mass X-ray binary system.

  10. Gene expression analysis of 4 biomarker candidates in Eisenia fetida exposed to an environmental metallic trace elements gradient: A microcosm study

    Energy Technology Data Exchange (ETDEWEB)

    Brulle, Franck; Lemiere, Sebastien [Univ Lille Nord de France, F-59000 Lille (France); LGCgE, Equipe Ecologie Numerique et Ecotoxicologie, Lille 1, F-59650 Villeneuve d' Ascq (France); Waterlot, Christophe; Douay, Francis [Univ Lille Nord de France, F-59000 Lille (France); LGCgE, Equipe Sols et Environnement, Groupe ISA, 48 boulevard Vauban, F-59046 Lille Cedex (France); Vandenbulcke, Franck, E-mail: franck.vandenbulcke@univ-lille1.fr [Univ Lille Nord de France, F-59000 Lille (France); LGCgE, Equipe Ecologie Numerique et Ecotoxicologie, Lille 1, F-59650 Villeneuve d' Ascq (France)

    2011-11-15

    Past activities of 2 smelters (Metaleurop Nord and Nyrstar) led to the accumulation of high amounts of Metal Trace Elements (TEs) in top soils of the Noyelles-Godault/Auby area, Northern France. Earthworms were exposed to polluted soils collected in this area to study and better understand the physiological changes, the mechanisms of acclimation, and detoxification resulting from TE exposure. Previously we have cloned and transcriptionally characterized potential biomarkers from immune cells of the ecotoxicologically important earthworm species Eisenia fetida exposed in vivo to TE-spiked standard soils. In the present study, analysis of expression kinetics of four candidate indicator genes (Cadmium-metallothionein, coactosin like protein, phytochelatin synthase and lysenin) was performed in E. fetida after microcosm exposures to natural soils exhibiting an environmental cadmium (Cd) gradient in a kinetic manner. TE body burdens were also measured. This microcosm study provided insights into: (1) the ability of the 4 tested genes to serve as expression biomarkers, (2) detoxification processes through the expression analysis of selected genes, and (3) influence of land uses on the response of potential biomarkers (gene expression or TE uptake). - Highlights: {yields} Expression biomarkers in animals exposed to Cadmium-contaminated field soils. {yields} Expression kinetics to test the ability of genes to serve as expression biomarkers. {yields} Study of detoxification processes through the expression analysis of selected genes.

  11. Discovery of a candidate protoplanetary disk around the embedded source IRc9 in Orion

    CERN Document Server

    Smith, N; Smith, Nathan; Bally, John

    2005-01-01

    We report the detection of spatially-extended mid-infrared emission around the luminous embedded star IRc9 in OMC-1, as seen in 8.8, 11.7, and 18.3 micron images obtained with T-ReCS on Gemini South. The extended emission is asymmetric, and the morphology is reminiscent of warm dust disks around other young stars. The putative disk has a radius of roughly 1.5 arcsec (700 AU), and a likely dust mass of almost 10 Earth masses. The infrared spectral energy distribution of IRc9 indicates a total luminosity of about 100 Lsun, implying that it shall become an early A-type star when it reaches the main sequence. Thus, the candidate disk around IRc9 may be a young analog of the planetary debris disks around Vega-like stars and the disks of Herbig Ae stars, and may provide a laboratory in which to study the earliest phases of planet formation. A disk around IRc9 may also add weight to the hypothesis that an enhanced T Tauri-like wind from this star has influenced the molecular outflow from the OMC-1 core.

  12. Disk Detective: Discovery of New Circumstellar Disk Candidates through Citizen Science

    CERN Document Server

    Kuchner, Marc J; Bans, Alissa S; Bhattacharjee, Shambo; Kenyon, Scott J; Debes, John H; Currie, Thayne; Garcia, Luciano; Jung, Dawoon; Lintott, Chris; McElwain, Michael; Padgett, Deborah L; Rebull, Luisa M; Wisniewski, John P; Nesvold, Erika; Schawinski, Kevin; Thaller, Michelle L; Grady, Carol A; Biggs, Joseph; Bosch, Milton; Cernohous, Tadeás; Luca, Hugo A Durantini; Hyogo, Michiharu; Wah, Lily Lau Wan; Piipuu, Art; Piñeiro, Fernanda

    2016-01-01

    The Disk Detective citizen science project aims to find new stars with 22 micron excess emission from circumstellar dust using data from NASA's WISE mission. Initial cuts on the AllWISE catalog provide an input catalog of 277,686 sources. Volunteers then view images of each source online in 10 different bands to identify false-positives (galaxies, background stars, interstellar matter, image artifacts, etc.). Sources that survive this online vetting are followed up with spectroscopy on the FLWO Tillinghast telescope. This approach should allow us to unleash the full potential of WISE for finding new debris disks and protoplanetary disks. We announce a first list of 37 new disk candidates discovered by the project, and we describe our vetting and follow-up process. One of these systems appears to contain the first debris disk discovered around a star with a white dwarf companion: HD 74389. We also report four newly discovered classical Be stars (HD 6612, HD 7406, HD 164137, and HD 218546) and a new detection o...

  13. Novel Altered Region for Biomarker Discovery in Hepatocellular Carcinoma (HCC Using Whole Genome SNP Array

    Directory of Open Access Journals (Sweden)

    Esraa M. Hashem

    2016-04-01

    Full Text Available cancer represents one of the greatest medical causes of mortality. The majority of Hepatocellular carcinoma arises from the accumulation of genetic abnormalities, and possibly induced by exterior etiological factors especially HCV and HBV infections. There is a need for new tools to analysis the large sum of data to present relevant genetic changes that may be critical for both understanding how cancers develop and determining how they could ultimately be treated. Gene expression profiling may lead to new biomarkers that may help develop diagnostic accuracy for detecting Hepatocellular carcinoma. In this work, statistical technique (discrete stationary wavelet transform for detection of copy number alternations to analysis high-density single-nucleotide polymorphism array of 30 cell lines on specific chromosomes, which are frequently detected in Hepatocellular carcinoma have been proposed. The results demonstrate the feasibility of whole-genome fine mapping of copy number alternations via high-density single-nucleotide polymorphism genotyping, Results revealed that a novel altered chromosomal region is discovered; region amplification (4q22.1 have been detected in 22 out of 30-Hepatocellular carcinoma cell lines (73%. This region strike, AFF1 and DSPP, tumor suppressor genes. This finding has not previously reported to be involved in liver carcinogenesis; it can be used to discover a new HCC biomarker, which helps in a better understanding of hepatocellular carcinoma.

  14. Translation of neurological biomarkers to clinically relevant platforms.

    Science.gov (United States)

    Hayes, Ronald L; Robinson, Gillian; Muller, Uwe; Wang, Kevin K W

    2009-01-01

    Like proteomics more generally, neuroproteomics has recently been linked to the discovery of biochemical markers of central nervous system (CNS) injury and disease. Although neuroproteomics has enjoyed considerable success in discovery of candidate biomarkers, there are a number of challenges facing investigators interested in developing clinically useful platforms to assess biomarkers for damage to the CNS. These challenges include intrinsic physiological complications such as the blood-brain barrier. Effective translation of biomarkers to clinical practice also requires development of entirely novel pathways and product development strategies. Drawing from lessons learned from applications of biomarkers to traumatic brain injury, this study outlines major elements of such a pathway. As with other indications, biomarkers can have three major areas of application: (1) drug development; (2) diagnosis and prognosis; (3) patient management. Translation of CNS biomarkers to practical clinical platforms raises a number of integrated elements. Biomarker discovery and initial selection needs to be integrated at the earliest stages with components that will allow systematic prioritization and triage of biomarker candidates. A number of important criteria need to be considered in selecting clinical biomarker candidates. Development of proof of concept assays and their optimization and validation represent an often overlooked feature of biomarker translational research. Initial assay optimization should confirm that assays can detect biomarkers in relevant clinical samples. Since access to human clinical samples is critical to identification of biomarkers relevant to injury and disease as well as for assay development, design of human clinical validation studies is an important component of translational biomarker research platforms. Although these clinical studies share much in common with clinical trials for assessment of drug therapeutic efficacy, there are a number of

  15. Evaluating the potential of a novel oral lesion exudate collection method coupled with mass spectrometry-based proteomics for oral cancer biomarker discovery

    Directory of Open Access Journals (Sweden)

    Kooren Joel A

    2011-09-01

    Full Text Available Abstract Introduction Early diagnosis of Oral Squamous Cell Carcinoma (OSCC increases the survival rate of oral cancer. For early diagnosis, molecular biomarkers contained in samples collected non-invasively and directly from at-risk oral premalignant lesions (OPMLs would be ideal. Methods In this pilot study we evaluated the potential of a novel method using commercial PerioPaper absorbent strips for non-invasive collection of oral lesion exudate material coupled with mass spectrometry-based proteomics for oral cancer biomarker discovery. Results Our evaluation focused on three core issues. First, using an "on-strip" processing method, we found that protein can be isolated from exudate samples in amounts compatible with large-scale mass spectrometry-based proteomic analysis. Second, we found that the OPML exudate proteome was distinct from that of whole saliva, while being similar to the OPML epithelial cell proteome, demonstrating the fidelity of our exudate collection method. Third, in a proof-of-principle study, we identified numerous, inflammation-associated proteins showing an expected increase in abundance in OPML exudates compared to healthy oral tissue exudates. These results demonstrate the feasibility of identifying differentially abundant proteins from exudate samples, which is essential for biomarker discovery studies. Conclusions Collectively, our findings demonstrate that our exudate collection method coupled with mass spectrometry-based proteomics has great potential for transforming OSCC biomarker discovery and clinical diagnostics assay development.

  16. 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.

  17. Biomarkers for neuromyelitis optica.

    Science.gov (United States)

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

    2015-02-01

    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.

  18. Many accurate small-discriminatory feature subsets exist in microarray transcript data: biomarker discovery

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    Grate Leslie R

    2005-04-01

    Full Text Available Abstract Background Molecular profiling generates abundance measurements for thousands of gene transcripts in biological samples such as normal and tumor tissues (data points. Given such two-class high-dimensional data, many methods have been proposed for classifying data points into one of the two classes. However, finding very small sets of features able to correctly classify the data is problematic as the fundamental mathematical proposition is hard. Existing methods can find "small" feature sets, but give no hint how close this is to the true minimum size. Without fundamental mathematical advances, finding true minimum-size sets will remain elusive, and more importantly for the microarray community there will be no methods for finding them. Results We use the brute force approach of exhaustive search through all genes, gene pairs (and for some data sets gene triples. Each unique gene combination is analyzed with a few-parameter linear-hyperplane classification method looking for those combinations that form training error-free classifiers. All 10 published data sets studied are found to contain predictive small feature sets. Four contain thousands of gene pairs and 6 have single genes that perfectly discriminate. Conclusion This technique discovered small sets of genes (3 or less in published data that form accurate classifiers, yet were not reported in the prior publications. This could be a common characteristic of microarray data, thus making looking for them worth the computational cost. Such small gene sets could indicate biomarkers and portend simple medical diagnostic tests. We recommend checking for small gene sets routinely. We find 4 gene pairs and many gene triples in the large hepatocellular carcinoma (HCC, Liver cancer data set of Chen et al. The key component of these is the "placental gene of unknown function", PLAC8. Our HMM modeling indicates PLAC8 might have a domain like part of lP59's crystal structure (a Non

  19. Fibroblasts from skin biopsies as a tool for biomarker discovery in Parkinson׳s disease.

    Science.gov (United States)

    Mastroberardino, Pier Giorgio; Ambrosi, Giulia; Blandini, Fabio; Milanese, Chiara; Sepe, Sara

    2014-10-01

    Parkinson׳s disease (PD) is a complex disease and the current interest and focus of scientific research is both investigating the variety of causes that underlie PD pathogenesis, and identifying reliable biomarkers to diagnose and monitor the progression of pathology. Investigation on pathogenic mechanisms in peripheral cells, such as fibroblasts derived from patients with sporadic PD and age/gender matched controls, might generate deeper understanding of the deficits affecting dopaminergic neurons and, possibly, new tools applicable to clinical practice. The chronic and slow progressing nature of PD may result from subtle yet persistent alterations in biological mechanisms, which might be undetectable in basal, unchallenged conditions. Unlike body fluids, dermal fibroblasts can be exposed to different challenges while in culture and can therefore generate information about the dynamic cellular responses to exogenous stressors. These studies may ultimately generate indicators highlighting the biological defects intrinsic to PD. In fact, fibroblasts from idiopathic PD patients' exhibit deficits typically sustaining the neurodegenerative process of PD, such as increased susceptibility to rotenone as well as deficits in protein homeostasis and mitochondrial bioenergetics Fibroblasts therefore represent a powerful and minimally invasive tool to investigate PD pathogenic mechanisms, which might translate into considerable advances in clinical management of the disease. PMID:26461279

  20. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer’s Disease in Human Cerebrospinal Fluid

    Science.gov (United States)

    Lee, Anita Y. H.; Song, Qinghua; Liaw, Andy; Wiener, Matt; Paweletz, Cloud P.; Seeburger, Jeffrey L.; Li, Jenny; Meng, Fanyu; Deyanova, Ekaterina G.; Mazur, Matthew T.; Settlage, Robert E.; Zhao, Xuemei; Southwick, Katie; Du, Yi; Holder, Dan; Sachs, Jeffrey R.; Laterza, Omar F.; Dallob, Aimee; Chappell, Derek L.; Snyder, Karen; Modur, Vijay; King, Elizabeth; Joachim, Catharine; Bondarenko, Andrey Y.; Shearman, Mark; Soper, Keith A.; Smith, A. David; Potter, William Z.; Koblan, Ken S.; Sachs, Alan B.

    2015-01-01

    Disease modifying treatments for Alzheimer’s disease (AD) constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF) biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control) patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001) and SME-2 (p = 0.0004) for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR), in AD were 21% (p = 0.039) and 17% (p = 0.026) lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic. PMID:26270474

  1. The discovery of a planetary candidate around the evolved low-mass Kepler giant star HD 175370 ★

    Science.gov (United States)

    Hrudková, M.; Hatzes, A.; Karjalainen, R.; Lehmann, H.; Hekker, S.; Hartmann, M.; Tkachenko, A.; Prins, S.; Van Winckel, H.; De Nutte, R.; Dumortier, L.; Frémat, Y.; Hensberge, H.; Jorissen, A.; Lampens, P.; Laverick, M.; Lombaert, R.; Pápics, P. I.; Raskin, G.; Sódor, Á.; Thoul, A.; Van Eck, S.; Waelkens, C.

    2016-09-01

    We report on the discovery of a planetary companion candidate with a minimum mass M sin i = 4.6 ± 1.0 MJupiter orbiting the K2 III giant star HD 175370 (KIC 007940959). This star was a target in our program to search for planets around a sample of 95 giant stars observed with Kepler. This detection was made possible using precise stellar radial velocity measurements of HD 175370 taken over five years and four months using the coudé echelle spectrograph of the 2-m Alfred Jensch Telescope and the fibre-fed echelle spectrograph HERMES of the 1.2-m Mercator Telescope. Our radial velocity measurements reveal a periodic (349.5 ± 4.5 days) variation with a semi-amplitude K = 133 ± 25 ms-1, superimposed on a long-term trend. A low-mass stellar companion with an orbital period of ˜88 years in a highly eccentric orbit and a planet in a Keplerian orbit with an eccentricity e = 0.22 are the most plausible explanation of the radial velocity variations. However, we cannot exclude the existence of stellar envelope pulsations as a cause for the low-amplitude radial velocity variations and only future continued monitoring of this system may answer this uncertainty. From Kepler photometry we find that HD 175370 is most likely a low-mass red-giant branch or asymptotic-giant branch star.

  2. The discovery of a planetary candidate around the evolved low-mass Kepler giant star HD 175370

    CERN Document Server

    Hrudková, M; Karjalainen, R; Lehmann, H; Hekker, S; Hartmann, M; Tkachenko, A; Prins, S; van Winckel, H; de Nutte, R; Dumortier, L; Frémat, Y; Hensberge, H; Jorissen, A; Lampens, P; Laverick, M; Lombaert, R; Pápics, P I; Raskin, G; Sódor, Á; Thoul, A; van Eck, S; Waelkens, C

    2016-01-01

    We report on the discovery of a planetary companion candidate with a minimum mass Msini = 4.6 M_J orbiting the K2 III giant star HD 175370 (KIC 007940959). This star was a target in our program to search for planets around a sample of 95 giant stars observed with Kepler. This detection was made possible using precise stellar radial velocity measurements of HD 175370 taken over five years and four months using the coude echelle spectrograph of the 2-m Alfred Jensch Telescope and the fibre-fed echelle spectrograph HERMES of the 1.2-m Mercator Telescope. Our radial velocity measurements reveal a periodic (349.5 days) variation with a semi-amplitude K = 133 m/s, superimposed on a long-term trend. A low-mass stellar companion with an orbital period of ~88 years in a highly eccentric orbit and a planet in a Keplerian orbit with an eccentricity e = 0.22 are the most plausible explanation of the radial velocity variations. However, we cannot exclude the existence of stellar envelope pulsations as a cause for the low-...

  3. H2O Maser Observations of Candidate Post-AGB Stars and Discovery of Three High-velocity Water Sources

    CERN Document Server

    Deacon, R M; Green, A J; Sevenster, M N; 10.1086/511383

    2009-01-01

    We present the results of 22 GHz H_2O maser observations of a sample of 85 post-Asymptotic Giant Branch (post-AGB) candidate stars, selected on the basis of their OH 1612 MHz maser and far-infrared properties. All sources were observed with the Tidbinbilla 70-m radio telescope and 21 detections were made. 86 GHz SiO Mopra observations of a subset of the sample are also presented. Of the 21 H_2O detections, 15 are from sources that are likely to be massive AGB stars and most of these show typical, regular H_2O maser profiles. In contrast, nearly all the detections of more evolved stars exhibited high-velocity H_2O maser emission. Of the five sources seen, v223 (W43A, IRAS 18450-0148) is a well known `water-fountain' source which belongs to a small group of post-AGB stars with highly collimated, high-velocity H_2O maser emission. A second source in our sample, v270 (IRAS 18596+0315), is also known to have high-velocity emission. We report the discovery of similar emission from a further three sources, d46 (IRAS...

  4. Top-down proteomics with mass spectrometry imaging: a pilot study towards discovery of biomarkers for neurodevelopmental disorders.

    Directory of Open Access Journals (Sweden)

    Hui Ye

    Full Text Available In the developing mammalian brain, inhibition of NMDA receptor can induce widespread neuroapoptosis, inhibit neurogenesis and cause impairment of learning and memory. Although some mechanistic insights into adverse neurological actions of these NMDA receptor antagonists exist, our understanding of the full spectrum of developmental events affected by early exposure to these chemical agents in the brain is still limited. Here we attempt to gain insights into the impact of pharmacologically induced excitatory/inhibitory imbalance in infancy on the brain proteome using mass spectrometric imaging (MSI. Our goal was to study changes in protein expression in postnatal day 10 (P10 rat brains following neonatal exposure to the NMDA receptor antagonist dizocilpine (MK801. Analysis of rat brains exposed to vehicle or MK801 and comparison of their MALDI MS images revealed differential relative abundances of several proteins. We then identified these markers such as ubiquitin, purkinje cell protein 4 (PEP-19, cytochrome c oxidase subunits and calmodulin, by a combination of reversed-phase (RP HPLC fractionation and top-down tandem MS platform. More in-depth large scale study along with validation experiments will be carried out in the future. Overall, our findings indicate that a brief neonatal exposure to a compound that alters excitatory/inhibitory balance in the brain has a long term effect on protein expression patterns during subsequent development, highlighting the utility of MALDI-MSI as a discovery tool for potential biomarkers.

  5. Biomarkers of safety and immune protection for genetically modified live attenuated Leishmania vaccines against visceral leishmaniasis-Discovery and implications

    Directory of Open Access Journals (Sweden)

    Sreenivas eGannavaram

    2014-05-01

    Full Text Available Despite intense efforts there is no safe and efficacious vaccine against visceral leishmaniasis, which is fatal and endemic in many tropical countries. A major shortcoming in the vaccine development against blood borne parasitic agents such as Leishmania is the inadequate predictive power of the early immune responses mounted in the host against the experimental vaccines. Often immune correlates derived from in-bred animal models do not yield immune markers of protection that can be readily extrapolated to humans. The limited efficacy of vaccines based on DNA, sub-unit, heat killed parasites has led to the realization that acquisition of durable immunity against the protozoan parasites requires a controlled infection with a live attenuated organism. Recent success of irradiated malaria parasites as a vaccine candidate further strengthens this approach to vaccination. We developed several gene deletion mutants in L. donovani as potential live attenuated vaccines and reported extensively on the immunogenicity of LdCentrin1 deleted mutant in mice, hamsters and dogs. Additional limited studies using genetically modified live attenuated Leishmania parasites as vaccine candidates have been reported. However, for the live attenuated parasite vaccines, the primary barrier against widespread use remains the absence of clear biomarkers associated with protection and safety. Recent studies in evaluation of vaccines e.g., influenza and yellow fever vaccines, using systems biology tools demonstrated the power of such strategies in understanding the immunological mechanisms that underpin a protective phenotype. Applying similar tools in isolated human tissues such as PBMCs from healthy individuals infected with live attenuated parasites such as LdCen1-/- in vitro followed by human microarray hybridization experiments will enable us to understand how early vaccine-induced gene expression profiles and the associated immune responses are coordinately regulated

  6. Application of a high throughput method of biomarker discovery to improvement of the EarlyCDT(®-Lung Test.

    Directory of Open Access Journals (Sweden)

    Isabel K Macdonald

    Full Text Available BACKGROUND: The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT. Recent advances in high throughput (HTP cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV. METHODS AND FINDINGS: Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165. Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7. CONCLUSION: This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT--Lung test, and so further aid the early detection of lung cancer.

  7. [Novel biomarkers for diabetic nephropathy].

    Science.gov (United States)

    Araki, Shin-ichi

    2014-02-01

    Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. An early clinical sign of this complication is an increase of urinary albumin excretion, called microalbuminuria, which is not only a predictor of the progression of nephropathy, but also an independent risk factor for cardiovascular disease. Although microalbuminuria is clinically important to assess the prognosis of diabetic patients, it may be insufficient as an early and specific biomarker of diabetic nephropathy because of a large day-to-day variation and lack of a good correlation of microalbuminuria with renal dysfunction and pathohistological changes. Thus, more sensitive and specific biomarkers are needed to improve the diagnostic capability of identifying patients at high risk. The factors involved in renal tubulo-interstitial damage, the production and degradation of extracellular matrix, microinflammation, etc., are investigated as candidate molecules. Despite numerous efforts so far, the assessment of these biomarkers is still a subject of ongoing investigations. Recently, a variety of omics and quantitative techniques in systems biology are rapidly emerging in the field of biomarker discovery, including proteomics, transcriptomics, and metabolomics, and they have been applied to search for novel putative biomarkers of diabetic nephropathy. Novel biomarkers or their combination with microalbuminuria provide a better diagnostic accuracy than microalbuminuria alone, and may be useful for establishing personal medicine. Furthermore, the identification of novel biomarkers may provide insight into the mechanisms underlying diabetic nephropathy.

  8. Autoantibody profiling on human proteome microarray for biomarker discovery in cerebrospinal fluid and sera of neuropsychiatric lupus.

    Directory of Open Access Journals (Sweden)

    Chaojun Hu

    Full Text Available Autoantibodies in cerebrospinal fluid (CSF from patients with neuropsychiatric systemic lupus erythematosus (NPSLE may be potential biomarkers for prediction, diagnosis, or prognosis of NPSLE. We used a human proteome microarray with~17,000 unique full-length human proteins to investigate autoantibodies associated with NPSLE. Twenty-nine CSF specimens from 12 NPSLE, 7 non-NPSLE, and 10 control (non-systemic lupus erythematosuspatients were screened for NPSLE-associated autoantibodies with proteome microarrays. A focused autoantigen microarray of candidate NPSLE autoantigens was applied to profile a larger cohort of CSF with patient-matched sera. We identified 137 autoantigens associated with NPSLE. Ingenuity Pathway Analysis revealed that these autoantigens were enriched for functions involved in neurological diseases (score = 43.Anti-proliferating cell nuclear antigen (PCNA was found in the CSF of NPSLE and non-NPSLE patients. The positive rates of 4 autoantibodies in CSF specimens were significantly different between the SLE (i.e., NPSLE and non-NPSLE and control groups: anti-ribosomal protein RPLP0, anti-RPLP1, anti-RPLP2, and anti-TROVE2 (also known as anti-Ro/SS-A. The positive rate for anti-SS-A associated with NPSLE was higher than that for non-NPSLE (31.11% cf. 10.71%; P = 0.045.Further analysis showed that anti-SS-A in CSF specimens was related to neuropsychiatric syndromes of the central nervous system in SLE (P = 0.009. Analysis with Spearman's rank correlation coefficient indicated that the titers of anti-RPLP2 and anti-SS-A in paired CSF and serum specimens significantly correlated. Human proteome microarrays offer a powerful platform to discover novel autoantibodies in CSF samples. Anti-SS-A autoantibodies may be potential CSF markers for NPSLE.

  9. 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.

  10. Candidate Gene Discovery Procedure after Follow-Up Confirmatory Analyses of Candidate Regions of Interests for Alzheimer’s Disease in the NIMH Sibling Dataset

    Directory of Open Access Journals (Sweden)

    Tesfaye M. Baye

    2008-01-01

    Full Text Available The objective of this research was to develop a procedure to identify candidate genes under linkage peaks confirmed in a follow-up of candidate regions of interests (CRIs identified in our original genome scan in the NIMH Alzheimer’s diseases (AD Initiative families (Blacker et al. [1]. There were six CRIs identified that met the threshold of multipoint lod score (MLS of ≥ 2.0 from the original scan. The most significant peak (MLS = 7.7 was at 19q13, which was attributed to APOE. The remaining CRIs with ‘suggestive’ evidence for linkage were identified at 9q22, 6q27, 14q22, 11q25, and 3p26. We have followed up and narrowed the 9q22 CRI signal using simple tandem repeat (STR markers (Perry et al. [2]. In this confirmatory project, we have followed up the 6q27, 14q22, 11q25, and 3p26 CRIs with a total of 24 additional flanking STRs, reducing the mean interval marker distance (MID in each CRI, and substantially increase in the information content (IC. The linkage signals at 6q27, 14q22 and 11q25 remain ‘suggestive’, indicating that these CRIs are promising and worthy of detailed fine mapping and assessment of candidate genes associated with AD.

  11. Deep-sequencing of microRNA associated with Alzheimer’s disease in biological fluids: From biomarker discovery to diagnostic practice

    Directory of Open Access Journals (Sweden)

    Lesley eCheng

    2013-08-01

    Full Text Available Diagnostic tools for neurodegenerative diseases such as Alzheimer's disease (AD currently involve subjective neuropsychological testing and specialised brain imaging techniques. While definitive diagnosis requires a pathological brain evaluation at autopsy, neurodegenerative changes are believed to begin years before the clinical presentation of cognitive decline. Therefore, there is an essential need for reliable biomarkers to aid in the early detection of disease in order to implement preventative strategies. microRNAs (miRNA are small non-coding RNA species that are involved in post-transcriptional gene regulation. Expression levels of miRNA’s have potential as diagnostic biomarkers as they are known to circulate and tissue specific profiles can be identified in a number of bodily fluids such as plasma, CSF and urine. Recent developments in deep sequencing technology present a viable approach to develop biomarker discovery pipelines in order to profile microRNA signatures in bodily fluids specific to neurodegenerative diseases. Here we review the potential use of microRNA deep sequencing in biomarker identification from biological fluids and its translation into clinical practice.

  12. Developmental origins of metabolic disorders: The need for biomarker candidates and therapeutic targets from adequate preclinical models

    Directory of Open Access Journals (Sweden)

    Antonio Gonzalez-Bulnes

    2016-03-01

    Full Text Available The investigation on obesity and associated disorders have changed from an scenario in which genome drove the phenotype to a dynamic setup in which prenatal and early-postnatal conditions are determinant. However, research in human beings is difficult due to confounding factors (lifestyle and socioeconomic heterogeneity plus ethical issues. Hence, there is currently an intensive effort for developing adequate preclinical models, aiming for an adequate combination of basic studies in rodent models and specific preclinical studies in large animals. The results of these research strategies may increase the identification and development of contrasted biomarkers and therapeutic targets.

  13. Global DNA methylation in earthworms: A candidate biomarker of epigenetic risks related to the presence of metals/metalloids in terrestrial environments

    Energy Technology Data Exchange (ETDEWEB)

    Maldonado Santoyo, Maria; Rodriguez Flores, Crescencio; Lopez Torres, Adolfo; Wrobel, Kazimierz [Department of Chemistry, University of Guanajuato, L de Retana No 5, 36000 Guanajuato (Mexico); Wrobel, Katarzyna, E-mail: katarzyn@quijote.ugto.mx [Department of Chemistry, University of Guanajuato, L de Retana No 5, 36000 Guanajuato (Mexico)

    2011-10-15

    In this work, possible relationships between global DNA methylation and metal/metalloid concentrations in earthworms have been explored. Direct correlation was observed between soil and tissue As, Se, Sb, Zn, Cu, Mn, Ag, Co, Hg, Pb (p < 0.05). Speciation results obtained for As and Hg hint at the capability of earthworms for conversion of inorganic element forms present in soil to methylated species. Inverse correlation was observed between the percentage of methylated DNA cytosines and total tissue As, As + Hg, As + Hg + Se + Sb ({beta} = -0.8456, p = 0.071; {beta} = -0.9406, p = 0.017; {beta} = -0.9526, p = 0.012 respectively), as well as inorganic As + Hg ({beta} = -0.8807, p = 0.049). It was concluded that earthworms would be particularly helpful as bioindicators of elements undergoing in vivo methylation and might also be used to assess the related risk of epigenetic changes in DNA methylation. - Graphical abstract: Display Omitted Highlights: > Several metals and metalloids contribute to epigenetic gene regulation. > As, Hg, Se, Sb inversely correlated with global DNA methylation in earthworms. > Biomethylation of the above elements in worms suggested. > Elements biomethylation apparently competes with DNA methylation. > DNA methylation a biomarker of epigenetic risks related to soil metals/metalloids. - Biomethylation of As, Hg in earthworms versus DNA methylation - a candidate biomarker of epigenetic risks related to the presence of metals/metalloids in soil.

  14. Direct cancer tissue proteomics: a method to identify candidate cancer biomarkers from formalin-fixed paraffin-embedded archival tissues.

    Science.gov (United States)

    Hwang, S-I; Thumar, J; Lundgren, D H; Rezaul, K; Mayya, V; Wu, L; Eng, J; Wright, M E; Han, D K

    2007-01-01

    Successful treatment of multiple cancer types requires early detection and identification of reliable biomarkers present in specific cancer tissues. To test the feasibility of identifying proteins from archival cancer tissues, we have developed a methodology, termed direct tissue proteomics (DTP), which can be used to identify proteins directly from formalin-fixed paraffin-embedded prostate cancer tissue samples. Using minute prostate biopsy sections, we demonstrate the identification of 428 prostate-expressed proteins using the shotgun method. Because the DTP method is not quantitative, we employed the absolute quantification method and demonstrate picogram level quantification of prostate-specific antigen. In depth bioinformatics analysis of these expressed proteins affords the categorization of metabolic pathways that may be important for distinct stages of prostate carcinogenesis. Furthermore, we validate Wnt-3 as an upregulated protein in cancerous prostate cells by immunohistochemistry. We propose that this general strategy provides a roadmap for successful identification of critical molecular targets of multiple cancer types.

  15. Sparse multi-block PLSR for biomarker discovery when integrating data from LC-MS and NMR metabolomics

    DEFF Research Database (Denmark)

    Karaman, Ibrahim; Nørskov, Natalja; Yde, Christian Clement;

    2015-01-01

    The objective of this study was to implement a multivariate method which analyzes multi-block metabolomics data and performs variable selection in order to discover potential biomarkers, simultaneously. We call this method sparse multi-block partial least squares regression (Sparse MBPLSR...... the measurement variables of this multi-block data set. The results showed that Sparse MBPLSR with CMV is a useful tool for analyzing multi-block metabolomics data with a good prediction and for identifying potential biomarkers....

  16. Alpha-fetoprotein-L3 and Golgi protein 73 may serve as candidate biomarkers for diagnosing alpha-fetoprotein-negative hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    Zhang ZG

    2015-12-01

    Full Text Available Zhiguo Zhang,1 Yanying Zhang,2 Yeying Wang,1 Lingling Xu,3 Wanju Xu3 1Department of Clinical Laboratory, Zhangqiu Maternity and Child Care Hospital, Zhangqiu, 2Department of Clinical Laboratory, Zaozhuang City Wangkai Infection Hospital, Zaozhuang, 3Department of Clinical Laboratory, Qianfoshan Hospital, Jinan, People’s Republic of China Abstract: Currently, there is no reliable biomarker for use in diagnosing alpha-fetoprotein (AFP-negative hepatocellular carcinoma (HCC. Such a biomarker would aid in making an early diagnosis of AFP-negative HCC, ensuring the timely initiation of treatment. This study examined AFP-L3 and Golgi protein 73 (GP73 as candidate biomarkers for AFP-negative HCC. The affinity adsorption method and enzyme-linked immunoassays were separately used to determine serum levels of AFP-L3 and GP73 in 50 patients with AFP-negative HCC, 30 non-HCC patients, and 50 healthy subjects. Fifty percent of patients with AFP-negative HCC tested positive for AFP-L3, while 3.33% of non-HCC patients and 2.00% of healthy subjects were AFP-L3 positive. Patients with AFP-negative HCC had significantly higher serum levels of AFP-L3 compared to non-HCC patients and healthy individuals; however, there was no significant difference in the AFP-L3 levels of non-HCC patients and healthy subjects. Sixty-six percent of patients with AFP-negative HCC tested positive for GP73, while 10% of non-HCC patients and 0% of healthy subjects were GP73-positive. Patients with AFP-negative HCC had significantly higher serum levels of GP73 compared to non-HCC patients and healthy subjects, but there was no significant difference between the GP73 levels of non-HCC patients and healthy individuals. Moreover, 20 patients with AFP-negative HCC were both AFP-L3- and GP73-positive, while no non-HCC patients or healthy subjects tested positive for both markers. Either AFP-L3 or GP73 may be used as a biomarker for diagnosing AFP-negative HCC, while their combined use

  17. First results of the Kourovka Planet Search: discovery of transiting exoplanet candidates in the first three target fields

    Science.gov (United States)

    Burdanov, Artem Y.; Benni, Paul; Krushinsky, Vadim V.; Popov, Alexander A.; Sokov, Evgenii N.; Sokova, Iraida A.; Rusov, Sergei A.; Lyashenko, Artem Yu.; Ivanov, Kirill I.; Moiseev, Alexei V.; Rastegaev, Denis A.; Dyachenko, Vladimir V.; Balega, Yuri Yu.; Baştürk, Özgür; Özavcı, Ibrahim; Puchalski, Damian; Marchini, Alessandro; Naves, Ramon; Shadick, Stan; Bretton, Marc

    2016-10-01

    We present the first results of our search for transiting exoplanet candidates as part of the Kourovka Planet Search (KPS) project. The primary objective of the project is to search for new hot Jupiters which transit their host stars, mainly in the Galactic plane, in the Rc magnitude range of 11-14 mag. Our observations were performed with the telescope of the MASTER robotic network, installed at the Kourovka astronomical observatory of the Ural Federal University (Russia), and the Rowe-Ackermann Schmidt Astrograph, installed at the private Acton Sky Portal Observatory (USA). As test observations, we observed three celestial fields of size 2 × 2 deg2 during the period from 2012 to 2015. As a result, we discovered four transiting exoplanet candidates among the 39 000 stars of the input catalogue. In this paper, we provide the description of the project and analyse additional photometric, spectral, and speckle interferometric observations of the discovered transiting exoplanet candidates. Three of the four transiting exoplanet candidates are most likely astrophysical false positives, while the nature of the fourth (most promising) candidate remains to be ascertained. Also, we propose an alternative observing strategy that could increase the project's exoplanet haul.

  18. Kepler Observations of Three Pre-launch Exoplanet Candidates: Discovery of Two Eclipsing Binaries and a New Exoplanet

    Science.gov (United States)

    Howell, Steve B.; Rowe, Jason F.; Sherry, William; von Braun, Kaspar; Ciardi, David R.; Bryson, Stephen T.; Feldmeier, John J.; Horch, Elliott; van Belle, Gerard T.

    2010-12-01

    Three transiting exoplanet candidate stars were discovered in a ground-based photometric survey prior to the launch of NASA's Kepler mission. Kepler observations of them were obtained during Quarter 1 of the Kepler mission. All three stars are faint by radial velocity follow-up standards, so we have examined these candidates with regard to eliminating false positives and providing high confidence exoplanet selection. We present a first attempt to exclude false positives for this set of faint stars without high-resolution radial velocity analysis. This method of exoplanet confirmation will form a large part of the Kepler mission follow-up for Jupiter-sized exoplanet candidates orbiting faint stars. Using the Kepler light curves and pixel data, as well as medium-resolution reconnaissance spectroscopy and speckle imaging, we find that two of our candidates are binary stars. One consists of a late-F star with an early M companion, while the other is a K0 star plus a late M-dwarf/brown dwarf in a 19 day elliptical orbit. The third candidate (BOKS-1) is an r = 15 G8V star hosting a newly discovered exoplanet with a radius of 1.12 R Jupiter in a 3.9 day orbit.

  19. Discovery of an Apparent Nova in M81 and H-alpha Confirmation of Three M81 Nova Candidates

    Science.gov (United States)

    Hornoch, K.; Vaduvescu, O.; Tudor, V.

    2014-06-01

    We report the discovery of an apparent nova in M81 on a co-added 2000-s narrow-band H-alpha CCD image taken with the 2.5-m Isaac Newton Telescope (INT) + WFC at La Palma under ~1.6" seeing on 2014 Jun. ...

  20. First results of the Kourovka Planet Search: discovery of transiting exoplanet candidates in the first three target fields

    CERN Document Server

    Burdanov, Artem Y; Krushinsky, Vadim V; Popov, Alexander A; Sokov, Evgenii N; Sokova, Iraida A; Rusov, Sergei A; Lyashenko, Artem Yu; Ivanov, Kirill I; Moiseev, Alexei V; Rastegaev, Denis A; Dyachenko, Vladimir V; Balega, Yuri Yu; Baştürk, Özgür; Özavcı, Ibrahim; Puchalski, Damian; Marchini, Alessandro; Naves, Ramon; Shadick, Stan; Bretton, Marc

    2016-01-01

    We present the first results of our search for transiting exoplanet candidates as part of the Kourovka Planet Search (KPS) project. The primary objective of the project is to search for new hot Jupiters which transit their host stars, mainly in the Galactic plane, in the $R_c$ magnitude range of 11 to 14 mag. Our observations were performed with the telescope of the MASTER robotic network, installed at the Kourovka astronomical observatory of the Ural Federal University (Russia), and the Rowe-Ackermann Schmidt Astrograph, installed at the private Acton Sky Portal Observatory (USA). As test observations, we observed three celestial fields of size $2\\times2$ deg$^2$ during the period from 2012 to 2015. As a result, we discovered four transiting exoplanet candidates among the 39000 stars of the input catalogue. In this paper, we provide the description of the project and analyse additional photometric, spectral, and speckle interferometric observations of the discovered transiting exoplanet candidates. Three of ...

  1. 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...

  2. Neopterin: A candidate biomarker for the early assessment of toxicity of aluminum among bauxite dust exposed mine workers

    Directory of Open Access Journals (Sweden)

    Shubhangi K Pingle

    2015-01-01

    Full Text Available Introduction: Bauxite ore is a major source of aluminum (Al which contains approximately 35–60% Al by weight. Occupational and environmental bauxite dust exposure may cause toxicity by interaction with human biological systems resulting in oxidative stress (OS and cell death. A neopterin derivative as an antioxidant is able to modulate cytotoxicity by the induction of OS. Materials and Methods: A total of 273 subjects were selected for blood collection from three different major Al producing bauxite mines and were categorized into three groups as experimental (Exp (n = 150, experimental controls (ExC (n = 73 and control (Con (n = 50. Whole blood and serum samples were used for measurement of Al, neopterin, urea and creatinine values. Statistical analysis was performed using R-2.15.1 programming language. Results and Discussion: The result showed that age, body mass index and the behavioral habits, that is, smoking, tobacco and alcohol consumption have possible effects on neopterin level. Serum neopterin levels were found to be significantly higher (P <0.0001 in the experimental group as compared to other groups. Significantly positive correlation (P < 0.0001 was observed between neopterin and creatinine. It was also observed that neopterin level increases as the duration of exposure increases. Conclusion: On the basis of findings it was concluded that exposure to bauxite dust (even at low levels of Al changes biochemical profile leading to high levels of serum neopterin. Levels of serum neopterin in workers exposed to bauxite dust were probably examined for the 1st time in India. The outcome of this study suggested that serum neopterin may be used as potential biomarker for early detection of health risks associated with bauxite dust exposed population.

  3. The 3XMM/SDSS Stripe 82 Galaxy Cluster Survey. I. Cluster catalogue and discovery of two merging cluster candidates

    Science.gov (United States)

    Takey, A.; Durret, F.; Mahmoud, E.; Ali, G. B.

    2016-10-01

    We present a galaxy cluster survey based on XMM-Newton observations that are located in Stripe 82 of the Sloan Digital Sky Survey (SDSS). The survey covers an area of 11.25 deg2. The X-ray cluster candidates were selected as serendipitously extended detected sources from the third XMM-Newton serendipitous source catalogue (3XMM-DR5). A cross-correlation of the candidate list that comprises 94 objects with recently published X-ray and optically selected cluster catalogues provided optical confirmations and redshift estimates for about half of the candidate sample. We present a catalogue of X-ray cluster candidates previously known in X-ray and/or optical bands from the matched catalogues or NED. The catalogue consists of 54 systems with redshift measurements in the range of 0.05-1.19 with a median of 0.36. Of these, 45 clusters have spectroscopic confirmations as stated in the matched catalogues. We spectroscopically confirmed another 6 clusters from the available spectroscopic redshifts in the SDSS-DR12. The cluster catalogue includes 17 newly X-ray discovered clusters, while the remainder were detected in previous XMM-Newton and/or ROSAT cluster surveys. Based on the available redshifts and fluxes given in the 3XMM-DR5 catalogue, we estimated the X-ray luminosities and masses for the cluster sample. We also present the list of the remaining X-ray cluster candidates (40 objects) that have no redshift information yet in the literature. Of these candidates, 25 sources are considered as distant cluster candidates beyond a redshift of 0.6. We also searched for galaxy cluster mergers in our cluster sample and found two strong candidates for newly discovered cluster mergers at redshifts of 0.11 and 0.26. The X-ray and optical properties of these systems are presented. Tables A.1, C.1, and C.2 are also available at the CDS via anonymous ftp to http://cdsarc.u-strasbg.fr (http://130.79.128.5) or via http://cdsarc.u-strasbg.fr/viz-bin/qcat?J/A+A/594/A32

  4. Evaluation of reverse phase protein array (RPPA)-based pathway-activation profiling in 84 non-small cell lung cancer (NSCLC) cell lines as platform for cancer proteomics and biomarker discovery.

    Science.gov (United States)

    Ummanni, Ramesh; Mannsperger, Heiko A; Sonntag, Johanna; Oswald, Marcus; Sharma, Ashwini K; König, Rainer; Korf, Ulrike

    2014-05-01

    The reverse phase protein array (RPPA) approach was employed for a quantitative analysis of 71 cancer-relevant proteins and phosphoproteins in 84 non-small cell lung cancer (NSCLC) cell lines and by monitoring the activation state of selected receptor tyrosine kinases, PI3K/AKT and MEK/ERK1/2 signaling, cell cycle control, apoptosis, and DNA damage. Additional information on NSCLC cell lines such as that of transcriptomic data, genomic aberrations, and drug sensitivity was analyzed in the context of proteomic data using supervised and non-supervised approaches for data analysis. First, the unsupervised analysis of proteomic data indicated that proteins clustering closely together reflect well-known signaling modules, e.g. PI3K/AKT- and RAS/RAF/ERK-signaling, cell cycle regulation, and apoptosis. However, mutations of EGFR, ERBB2, RAF, RAS, TP53, and PI3K were found dispersed across different signaling pathway clusters. Merely cell lines with an amplification of EGFR and/or ERBB2 clustered closely together on the proteomic, but not on the transcriptomic level. Secondly, supervised data analysis revealed that sensitivity towards anti-EGFR drugs generally correlated better with high level EGFR phosphorylation than with EGFR abundance itself. High level phosphorylation of RB and high abundance of AURKA were identified as candidates that can potentially predict sensitivity towards the aurora kinase inhibitor VX680. Examples shown demonstrate that the RPPA approach presents a useful platform for targeted proteomics with high potential for biomarker discovery. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID:24361481

  5. Kepler Observations of Three Pre-Launch Exoplanet Candidates: Discovery of Two Eclipsing Binaries and a New Exoplanet

    CERN Document Server

    Howell, Steve B; Sherry, William; von Braun, Kaspar; Ciardi, David R; Bryson, Stephen T; Feldmeier, John J; Horch, Elliott; van Belle, Gerard T

    2010-01-01

    Three transiting exoplanet candidate stars were discovered in a ground-based photometric survey prior to the launch of NASA's {\\it Kepler} mission. {\\it Kepler} observations of them were obtained during Quarter 1 of the {\\it Kepler} mission. All three stars are faint by radial velocity follow-up standards, so we have examined these candidates with regard to eliminating false positives and providing high confidence exoplanet selection. We present a first attempt to exclude false positives for this set of faint stars without high resolution radial velocity analysis. This method of exoplanet confirmation will form a large part of the {\\it Kepler} mission follow-up for Jupiter-sized exoplanet candidates orbiting faint stars. Using the {\\it Kepler} light curves and pixel data, as well as medium resolution reconnaissance spectroscopy and speckle imaging, we find that two of our candidates are binary stars. One consists of a late-F star with an early M companion while the other is a K0 star plus a late M-dwarf/brown...

  6. The 3XMM/SDSS Stripe 82 Galaxy Cluster Survey: Cluster catalogue and discovery of two merging cluster candidates

    CERN Document Server

    Takey, Ali; Mahmoud, Eman A; Ali, Gamal B

    2016-01-01

    We present a galaxy cluster survey based on XMM-Newton observations that are located in the Stripe 82 of the Sloan Digital Sky Survey (SDSS). The survey covers an area of 11.25 deg$^2$. The X-ray cluster candidates were selected as serendipitously extended detected sources from the third XMM-Newton serendipitous source catalogue (3XMM-DR5). A cross-correlation of the candidate list that comprises 94 objects with recently published X-ray and optically selected cluster catalogues provided optical confirmations and redshift estimates for about half of the candidate sample. We present a catalogue of X-ray cluster candidates previously known in X-ray and/or optical bands from the matched catalogues or NED. The catalogue consists of 54 systems with redshift measurements in the range of 0.05-1.19 with a median of 0.36. Of these, 45 clusters have spectroscopic confirmations as stated in the matched catalogues. We spectroscopically confirmed another 6 clusters from the available spectroscopic redshifts in the SDSS-DR1...

  7. Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate

    Science.gov (United States)

    Mounier, C M; Wendum, D; Greenspan, E; Fléjou, J-F; Rosenberg, D W; Lambeau, G

    2008-01-01

    Recent studies suggest that secreted phospholipases A2 (sPLA2s) represent attractive potential tumour biomarkers and therapeutic targets for various cancers. As a first step to address this issue in human colorectal cancer, we examined the expression of the full set of sPLA2s in sporadic adenocarcinomas and normal matched mucosa from 21 patients by quantitative PCR and immunohistochemistry. In normal colon, PLA2G2A and PLA2G12A were expressed at high levels, PLA2G2D, PLA2G5, PLA2G10 and PLA2G12B at moderate levels, and PLA2G1B, PLA2G2F and PLA2G3 at low levels. In adenocarcinomas from left and right colon, the expression of PLA2G3 was increased by up to 40-fold, while that of PLA2G2D and PLA2G5 was decreased by up to 23- and 14-fold. The variations of expression for sPLA2-IID, sPLA2-III and sPLA2-V were confirmed at the protein level. The expression pattern of these sPLA2s appeared to be linked respectively to the overexpression of interleukin-8, defensin α6, survivin and matrilysin, and downregulation of SFRP-1 and RLPA-1, all these genes being associated to colon cancer. This original sPLA2 profile observed in adenocarcinomas highlights the potential role of certain sPLA2s in colon cancer and suggests that sPLA2-III might be a good candidate as a novel biomarker for both left and right colon cancers. PMID:18212756

  8. Fetuin-B (FETUB): a Plasma Biomarker Candidate Related to the Severity of Lung Function in COPD.

    Science.gov (United States)

    Diao, Wen-Qi; Shen, Ning; Du, Yi-Peng; Liu, Bei-Bei; Sun, Xiao-Yan; Xu, Ming; He, Bei

    2016-01-01

    Biomarkers for the progression of lung function in COPD are currently scarce. Plasma fetuin-B (FETUB) was identified by iTRAQ-based proteomics and was verified by ELISA in another group. Information regarding acute exacerbation (AE) was collected in a one-year follow-up programme. FETUB concentrations (1652 ± 427 ng/ml) were greater in COPD patients than in controls (1237 ± 77 ng/ml). The concentrations of FETUB in GOLD II (1762 ± 427 ng/ml), III (1650 ± 375 ng/ml) and IV (1800 ± 451 ng/ml) groups were greater than those in the controls (1257 ± 414 ng/ml) and the GOLD I (1345 ± 391 ng/ml) group. ROCs indicated that FETUB distinguished COPD patients from controls (AUC 0.747, 95% CI: 0.642-0.834) and also GOLD II, III and IV from GOLD I COPD patients (AUC: 0.770, 95% CI: 0.634-0.874). The combination of FETUB and fibrinogen performed better (AUC: 0.804, 95% CI: 0.705-0.881). FETUB also predicted the occurrence of AE (AUC: 0.707, 95% CI: 0.566-0.824) or frequent AE (AUC: 0.727, 95% CI: 0.587-0.840). FETUB concentrations were negatively correlated with FEV1%pred (r = -0.446, p = 0.000) and positively correlated with RV%pred (r = 0.317, p = 0.004), RV/TLC% (r = 0.360, p = 0.004), CT emphysema% (r = 0.322, p = 0.008) and grades of lung function (r = 0.437, p = 0.000). In conclusion, FETUB is likely to assist the diagnosis and management of COPD as a complement for other markers. PMID:27443820

  9. GC-MS Based Plasma Metabolomics for Identification of Candidate Biomarkers for Hepatocellular Carcinoma in Egyptian Cohort.

    Directory of Open Access Journals (Sweden)

    Mohammad R Nezami Ranjbar

    Full Text Available This study evaluates changes in metabolite levels in hepatocellular carcinoma (HCC cases vs. patients with liver cirrhosis by analysis of human blood plasma using gas chromatography coupled with mass spectrometry (GC-MS. Untargeted metabolomic analysis of plasma samples from participants recruited in Egypt was performed using two GC-MS platforms: a GC coupled to single quadruple mass spectrometer (GC-qMS and a GC coupled to a time-of-flight mass spectrometer (GC-TOFMS. Analytes that showed statistically significant changes in ion intensities were selected using ANOVA models. These analytes and other candidates selected from related studies were further evaluated by targeted analysis in plasma samples from the same participants as in the untargeted metabolomic analysis. The targeted analysis was performed using the GC-qMS in selected ion monitoring (SIM mode. The method confirmed significant changes in the levels of glutamic acid, citric acid, lactic acid, valine, isoleucine, leucine, alpha tocopherol, cholesterol, and sorbose in HCC cases vs. patients with liver cirrhosis. Specifically, our findings indicate up-regulation of metabolites involved in branched-chain amino acid (BCAA metabolism. Although BCAAs are increasingly used as a treatment for cancer cachexia, others have shown that BCAA supplementation caused significant enhancement of tumor growth via activation of mTOR/AKT pathway, which is consistent with our results that BCAAs are up-regulated in HCC.

  10. cNEUPRO: Novel Biomarkers for Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Philipp Spitzer

    2010-01-01

    Full Text Available “clinical NEUroPROteomics of neurodegenerative diseases” (cNEUPRO is a Specific Targeted Research Project (STREP within the sixth framework program of the European Commission dedicated to the search for novel biomarker candidates for Alzheimer's disease and other neurodegenerative diseases. The ultimate goal of cNEUPRO is to identify one or more valid biomarker(s in blood and CSF applicable to support the early and differential diagnosis of dementia disorders. The consortium covers all steps required for the discovery of novel biomarker candidates such as acquisition of high quality CSF and blood samples from relevant patient groups and controls, analysis of body fluids by various methods, and finally assay development and assay validation. Here we report the standardized procedures for diagnosis and preanalytical sample-handling within the project, as well as the status of the ongoing research activities and some first results.

  11. Biomarker discovery with SELDI-TOF MS in human urine associated with early renal injury : evaluation with computational analytical tools.

    NARCIS (Netherlands)

    Houtte, K.J.A. van; Laarakkers, C.; Marchiori, E.; Pickkers, P.; Wetzels, J.F.M.; Willems, J.L.; Heuvel, L.P.W.J. van den; Russel, F.G.M.; Masereeuw, R.

    2007-01-01

    BACKGROUND: Urine proteomics is one of the key emerging technologies to discover new biomarkers for renal disease, which may be used in the early diagnosis, prognosis and treatment of patients. In the present study, we validated surface-enhanced laser desorption/ionization time-of-flight mass spectr

  12. Regulatory Forum Opinion Piece*: Veterinary Pathologists in Translational Pharmacology and Biomarker Integration in Drug Discovery and Development.

    Science.gov (United States)

    Ramaiah, Shashi K; Walker, Dana B

    2016-02-01

    This article highlights emerging roles for veterinary pathologists outside of traditional functions and in line with the translational research (TR) approach. Veterinary pathologists offer unique and valuable expertise toward addressing particular TR and associated translational pharmacology questions, identifying gaps and risks in biomarker and pathology strategies, and advancing TR team decision making. Veterinary pathologists' attributes that are integral to the TR approach include (i) well-developed understanding of comparative physiology, pathology, and disease; (ii) extensive experience in interpretation and integration of complex data sets on whole-body responses and utilizing this for deciphering pathogenesis and translating events between laboratory species and man; (iii) proficiency in recognizing differences in disease end points among individuals, animal species and strains, and assessing correlations between these differences and other investigative (including biomarker) findings; and (iv) strong background in a wide spectrum of research technologies that can address pathomechanistic questions and biomarker needs. Some of the more evident roles in which veterinary pathologists can offer their greatest contributions to address questions and strategies of TR and biomarker integration will be emphasized. PMID:26839329

  13. A Comprehensive Workflow of Mass Spectrometry-Based Untargeted Metabolomics in Cancer Metabolic Biomarker Discovery Using Human Plasma and Urine

    OpenAIRE

    Jianwen She; Wei Zou; Vladimir V. Tolstikov

    2013-01-01

    Current available biomarkers lack sensitivity and/or specificity for early detection of cancer. To address this challenge, a robust and complete workflow for metabolic profiling and data mining is described in details. Three independent and complementary analytical techniques for metabolic profiling are applied: hydrophilic interaction liquid chromatography (HILIC–LC), reversed-phase liquid chromatography (RP–LC), and gas chromatography (GC). All three techniques are coupled to a mass spectro...

  14. Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy

    OpenAIRE

    Nair, Nitya; Mei, Henrik E; Chen, Shih-Yu; Hale, Matthew; Garry P Nolan; Maecker, Holden T.; Genovese, Mark; Fathman, C. Garrison; Whiting, Chan C

    2015-01-01

    The development of biomarkers for autoimmune diseases has been hampered by a lack of understanding of disease etiopathogenesis and of the mechanisms underlying the induction and maintenance of inflammation, which involves complex activation dynamics of diverse cell types. The heterogeneous nature and suboptimal clinical response to treatment observed in many autoimmune syndromes highlight the need to develop improved strategies to predict patient outcome to therapy and personalize patient car...

  15. Nonylphenol Toxicity Evaluation and Discovery of Biomarkers in Rat Urine by a Metabolomics Strategy through HPLC-QTOF-MS

    Directory of Open Access Journals (Sweden)

    Yan-Xin Zhang

    2016-05-01

    Full Text Available Nonylphenol (NP was quantified using liquid chromatography tandem mass spectrometry (LC-MS/MS in the urine and plasma of rats treated with 0, 50, and 250 mg/kg/day of NP for four consecutive days. A urinary metabolomic strategy was originally implemented by high performance liquid chromatography time of flight mass spectrometry (HPLC-QTOF-MS to explore the toxicological effects of NP and determine the overall alterations in the metabolite profiles so as to find potential biomarkers. It is essential to point out that from the observation, the metabolic data were clearly clustered and separated for the three groups. To further identify differentiated metabolites, multivariate analysis, including principal component analysis (PCA, orthogonal partial least-squares discriminant analysis (OPLS-DA, high-resolution MS/MS analysis, as well as searches of Metlin and Massbank databases, were conducted on a series of metabolites between the control and dose groups. Finally, five metabolites, including glycine, glycerophosphocholine, 5-hydroxytryptamine, malonaldehyde (showing an upward trend, and tryptophan (showing a downward trend, were identified as the potential urinary biomarkers of NP-induced toxicity. In order to validate the reliability of these potential biomarkers, an independent validation was performed by using the multiple reaction monitoring (MRM-based targeted approach. The oxidative stress reflected by urinary 8-oxo-deoxyguanosine (8-oxodG levels was elevated in individuals highly exposed to NP, supporting the hypothesis that mitochondrial dysfunction was a result of xenoestrogen accumulation. This study reveals a promising approach to find biomarkers to assist researchers in monitoring NP.

  16. Novel diagnostic biomarkers for prostate cancer

    Directory of Open Access Journals (Sweden)

    Chikezie O. Madu, Yi Lu

    2010-01-01

    prostate cancer. The purpose of this review is to examine the current status of prostate cancer biomarkers, with special emphasis on emerging markers, by evaluating their diagnostic and prognostic potentials. Both genes and proteins that reveal loss, mutation, or variation in expression between normal prostate and cancerous prostate tissues will be covered in this article. Along with the discovery of prostate cancer biomarkers, we will describe the criteria used when selecting potential biomarkers for further development towards clinical use. In addition, we will address how to appraise and validate candidate markers for prostate cancer and some relevant issues involved in these processes. We will also discuss the new concept of the biomarkers, existing challenges, and perspectives of biomarker development.

  17. Novel diagnostic biomarkers for prostate cancer.

    Science.gov (United States)

    Madu, Chikezie O; Lu, Yi

    2010-10-06

    purpose of this review is to examine the current status of prostate cancer biomarkers, with special emphasis on emerging markers, by evaluating their diagnostic and prognostic potentials. Both genes and proteins that reveal loss, mutation, or variation in expression between normal prostate and cancerous prostate tissues will be covered in this article. Along with the discovery of prostate cancer biomarkers, we will describe the criteria used when selecting potential biomarkers for further development towards clinical use. In addition, we will address how to appraise and validate candidate markers for prostate cancer and some relevant issues involved in these processes. We will also discuss the new concept of the biomarkers, existing challenges, and perspectives of biomarker development.

  18. A novel approach to the discovery of survival biomarkers in glioblastoma using a joint analysis of DNA methylation and gene expression.

    Science.gov (United States)

    Smith, Ashley A; Huang, Yen-Tsung; Eliot, Melissa; Houseman, E Andres; Marsit, Carmen J; Wiencke, John K; Kelsey, Karl T

    2014-06-01

    Glioblastoma multiforme (GBM) is the most aggressive of all brain tumors, with a median survival of less than 1.5 years. Recently, epigenetic alterations were found to play key roles in both glioma genesis and clinical outcome, demonstrating the need to integrate genetic and epigenetic data in predictive models. To enhance current models through discovery of novel predictive biomarkers, we employed a genome-wide, agnostic strategy to specifically capture both methylation-directed changes in gene expression and alternative associations of DNA methylation with disease survival in glioma. Human GBM-associated DNA methylation, gene expression, IDH1 mutation status, and survival data were obtained from The Cancer Genome Atlas. DNA methylation loci and expression probes were paired by gene, and their subsequent association with survival was determined by applying an accelerated failure time model to previously published alternative and expression-based association equations. Significant associations were seen in 27 unique methylation/expression pairs with expression-based, alternative, and combinatorial associations observed (10, 13, and 4 pairs, respectively). The majority of the predictive DNA methylation loci were located within CpG islands, and all but three of the locus pairs were negatively correlated with survival. This finding suggests that for most loci, methylation/expression pairs are inversely related, consistent with methylation-associated gene regulatory action. Our results indicate that changes in DNA methylation are associated with altered survival outcome through both coordinated changes in gene expression and alternative mechanisms. Furthermore, our approach offers an alternative method of biomarker discovery using a priori gene pairing and precise targeting to identify novel sites for locus-specific therapeutic intervention.

  19. Discovery and characterization of antibody variants using mass spectrometry-based comparative analysis for biosimilar candidates of monoclonal antibody drugs.

    Science.gov (United States)

    Li, Wenhua; Yang, Bin; Zhou, Dongmei; Xu, Jun; Ke, Zhi; Suen, Wen-Chen

    2016-07-01

    Liquid chromatography mass spectrometry (LC-MS) is the most commonly used technique for the characterization of antibody variants. MAb-X and mAb-Y are two approved IgG1 subtype monoclonal antibody drugs recombinantly produced in Chinese hamster ovary (CHO) cells. We report here that two unexpected and rare antibody variants have been discovered during cell culture process development of biosimilars for these two approved drugs through intact mass analysis. We then used comprehensive mass spectrometry-based comparative analysis including reduced light, heavy chains, and domain-specific mass as well as peptide mapping analysis to fully characterize the observed antibody variants. The "middle-up" mass comparative analysis demonstrated that the antibody variant from mAb-X biosimilar candidate was caused by mass variation of antibody crystalline fragment (Fc), whereas a different variant with mass variation in antibody antigen-binding fragment (Fab) from mAb-Y biosimilar candidate was identified. Endoproteinase Lys-C digested peptide mapping and tandem mass spectrometry analysis further revealed that a leucine to glutamine change in N-terminal 402 site of heavy chain was responsible for the generation of mAb-X antibody variant. Lys-C and trypsin coupled non-reduced and reduced peptide mapping comparative analysis showed that the formation of the light-heavy interchain trisulfide bond resulted in the mAb-Y antibody variant. These two cases confirmed that mass spectrometry-based comparative analysis plays a critical role for the characterization of monoclonal antibody variants, and biosimilar developers should start with a comprehensive structural assessment and comparative analysis to decrease the risk of the process development for biosimilars. PMID:27214604

  20. The Discovery and Validation of Biomarkers for the Diagnosis of Esophageal Squamous Dysplasia and Squamous Cell Carcinoma.

    Science.gov (United States)

    Couch, George; Redman, James E; Wernisch, Lorenz; Newton, Richard; Malhotra, Shalini; Dawsey, Sanford M; Lao-Sirieix, Pierre; Fitzgerald, Rebecca C

    2016-07-01

    The 5-year survival rate of esophageal cancer is less than 10% in developing countries, where more than 90% of these cancers are esophageal squamous cell carcinomas (ESCC). Endoscopic screening is undertaken in high incidence areas. Biomarker analysis could reduce the subjectivity associated with histologic assessment of dysplasia and thus improve diagnostic accuracy. The aims of this study were therefore to identify biomarkers for esophageal squamous dysplasia and carcinoma. A publicly available dataset was used to identify genes with differential expression in ESCC compared with normal esophagus. Each gene was ranked by a support vector machine separation score. Expression profiles were examined, before validation by qPCR and IHC. We found that 800 genes were overexpressed in ESCC compared with normal esophagus (P < 10(-5)). Of the top 50 genes, 33 were expressed in ESCC epithelium and not in normal esophagus epithelium or stroma using the Protein Atlas website. These were taken to qPCR validation, and 20 genes were significantly overexpressed in ESCC compared with normal esophagus (P < 0.05). TNFAIP3 and CHN1 showed differential expression with IHC. TNFAIP3 expression increased gradually through normal esophagus, mild, moderate and severe dysplasia, and SCC (P < 0.0001). CHN1 staining was rarely present in the top third of normal esophagus epithelium and extended progressively towards the surface in mild, moderate, and severe dysplasia, and SCC (P < 0.0001). Two novel promising biomarkers for ESCC were identified, TNFAIP3 and CHN1. CHN1 and TNFAIP3 may improve diagnostic accuracy of screening methods for ESCC. Cancer Prev Res; 9(7); 558-66. ©2016 AACR. PMID:27072986

  1. Identification of Leishmania infantum chagasi proteins in urine of patients with visceral leishmaniasis: a promising antigen discovery approach of vaccine candidates.

    Science.gov (United States)

    Kashino, S S; Abeijon, C; Qin, L; Kanunfre, K A; Kubrusly, F S; Silva, F O; Costa, D L; Campos, D; Costa, C H N; Raw, I; Campos-Neto, A

    2012-07-01

    Visceral leishmaniasis (VL) is a serious lethal parasitic disease caused by Leishmania donovani in Asia and by Leishmania infantum chagasi in southern Europe and South America. VL is endemic in 47 countries with an annual incidence estimated to be 500,000 cases. This high incidence is due in part to the lack of an efficacious vaccine. Here, we introduce an innovative approach to directly identify parasite vaccine candidate antigens that are abundantly produced in vivo in humans with VL. We combined RP-HPLC and mass spectrometry and categorized three L. infantum chagasi proteins, presumably produced in spleen, liver and bone marrow lesions and excreted in the patients' urine. Specifically, these proteins were the following: Li-isd1 (XP_001467866.1), Li-txn1 (XP_001466642.1) and Li-ntf2 (XP_001463738.1). Initial vaccine validation studies were performed with the rLi-ntf2 protein produced in Escherichia coli mixed with the adjuvant BpMPLA-SE. This formulation stimulated potent Th1 response in BALB/c mice. Compared to control animals, mice immunized with Li-ntf2+ BpMPLA-SE had a marked parasite burden reduction in spleens at 40 days post-challenge with virulent L. infantum chagasi. These results strongly support the proposed antigen discovery strategy of vaccine candidates to VL and opens novel possibilities for vaccine development to other serious infectious diseases.

  2. Discovery and identification of infrared counterpart candidates of four Galactic centre low mass X-ray binaries

    CERN Document Server

    Curran, P A; Heras, J A Zurita

    2011-01-01

    The near infrared (nIR)/optical counterparts of low mass X-ray binaries (LMXBs) are often observationally dim and reside in high source density fields which make their identification problematic; however, without such a counterpart identification we are unable to investigate many of the properties of LMXB systems. Here, in the context of a larger identification campaign, we examine the fields of four LMXB systems near the Galactic centre, in a bid to identify nIR/optical counterparts to the previously detected X-ray point sources. We obtain nIR/optical images of the fields with the ESO - New Technology Telescope and apply standard photometric and astrometric calibrations; these data are supplemented by Spitzer-GLIMPSE catalog data. On the basis of positional coincidence with the arcsecond accurate X-ray positions, we identify unambiguous counterpart candidates for XTE J1637-498, IGR J17379-3747, IGR J17585-3057 and GX 9+1. We propose tentative nIR counterparts of four LMXBs which require further investigation...

  3. Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous Families

    Directory of Open Access Journals (Sweden)

    Anas M. Alazami

    2015-01-01

    Full Text Available Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS. We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.

  4. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.

    Science.gov (United States)

    Alazami, Anas M; Patel, Nisha; Shamseldin, Hanan E; Anazi, Shamsa; Al-Dosari, Mohammed S; Alzahrani, Fatema; Hijazi, Hadia; Alshammari, Muneera; Aldahmesh, Mohammed A; Salih, Mustafa A; Faqeih, Eissa; Alhashem, Amal; Bashiri, Fahad A; Al-Owain, Mohammed; Kentab, Amal Y; Sogaty, Sameera; Al Tala, Saeed; Temsah, Mohamad-Hani; Tulbah, Maha; Aljelaify, Rasha F; Alshahwan, Saad A; Seidahmed, Mohammed Zain; Alhadid, Adnan A; Aldhalaan, Hesham; AlQallaf, Fatema; Kurdi, Wesam; Alfadhel, Majid; Babay, Zainab; Alsogheer, Mohammad; Kaya, Namik; Al-Hassnan, Zuhair N; Abdel-Salam, Ghada M H; Al-Sannaa, Nouriya; Al Mutairi, Fuad; El Khashab, Heba Y; Bohlega, Saeed; Jia, Xiaofei; Nguyen, Henry C; Hammami, Rakad; Adly, Nouran; Mohamed, Jawahir Y; Abdulwahab, Firdous; Ibrahim, Niema; Naim, Ewa A; Al-Younes, Banan; Meyer, Brian F; Hashem, Mais; Shaheen, Ranad; Xiong, Yong; Abouelhoda, Mohamed; Aldeeri, Abdulrahman A; Monies, Dorota M; Alkuraya, Fowzan S

    2015-01-13

    Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.

  5. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer disease.

    Science.gov (United States)

    Jeppsson, Fredrik; Eketjäll, Susanna; Janson, Juliette; Karlström, Sofia; Gustavsson, Susanne; Olsson, Lise-Lotte; Radesäter, Ann-Cathrine; Ploeger, Bart; Cebers, Gvido; Kolmodin, Karin; Swahn, Britt-Marie; von Berg, Stefan; Bueters, Tjerk; Fälting, Johanna

    2012-11-30

    β-Site amyloid precursor protein cleaving enzyme1 (BACE1) is one of the key enzymes involved in the processing of the amyloid precursor protein (APP) and formation of amyloid β peptide (Aβ) species. Because cerebral deposition of Aβ species might be critical for the pathogenesis of Alzheimer disease, BACE1 has emerged as a key target for the treatment of this disease. Here, we report the discovery and comprehensive preclinical characterization of AZD3839, a potent and selective inhibitor of human BACE1. AZD3839 was identified using fragment-based screening and structure-based design. In a concentration-dependent manner, AZD3839 inhibited BACE1 activity in a biochemical fluorescence resonance energy transfer (FRET) assay, Aβ and sAPPβ release from modified and wild-type human SH-SY5Y cells and mouse N2A cells as well as from mouse and guinea pig primary cortical neurons. Selectivity against BACE2 and cathepsin D was 14 and >1000-fold, respectively. AZD3839 exhibited dose- and time-dependent lowering of plasma, brain, and cerebrospinal fluid Aβ levels in mouse, guinea pig, and non-human primate. Pharmacokinetic/pharmacodynamic analyses of mouse and guinea pig data showed a good correlation between the potency of AZD3839 in primary cortical neurons and in vivo brain effects. These results suggest that AZD3839 effectively reduces the levels of Aβ in brain, CSF, and plasma in several preclinical species. It might, therefore, have disease-modifying potential in the treatment of Alzheimer disease and related dementias. Based on the overall pharmacological profile and its drug like properties, AZD3839 has been progressed into Phase 1 clinical trials in man.

  6. In-depth cDNA Library Sequencing Provides Quantitative Gene Expression Profiling in Cancer Biomarker Discovery

    Institute of Scientific and Technical Information of China (English)

    Wanling Yang; Dingge Ying; Yu-Lung Lau

    2009-01-01

    procedures may allow detection of many expres-sion features for less abundant gene variants. With the reduction of sequencing cost and the emerging of new generation sequencing technology, in-depth sequencing of cDNA pools or libraries may represent a better and powerful tool in gene expression profiling and cancer biomarker detection. We also propose using sequence-specific subtraction to remove hundreds of the most abundant housekeeping genes to in-crease sequencing depth without affecting relative expression ratio of other genes, as transcripts from as few as 300 most abundantly expressed genes constitute about 20% of the total transcriptome. In-depth sequencing also represents a unique ad-vantage of detecting unknown forms of transcripts, such as alternative splicing variants, fusion genes, and regulatory RNAs, as well as detecting mutations and polymorphisms that may play important roles in disease pathogenesis.

  7. Discovery of a Metastatic Immune Escape Mechanism Initiated by the Loss of Expression of the Tumour Biomarker Interleukin-33.

    Science.gov (United States)

    Saranchova, Iryna; Han, Jeffrey; Huang, Hui; Fenninger, Franz; Choi, Kyung Bok; Munro, Lonna; Pfeifer, Cheryl; Welch, Ian; Wyatt, Alexander W; Fazli, Ladan; Gleave, Martin E; Jefferies, Wilfred A

    2016-01-01

    A new paradigm for understanding immune-surveillance and immune escape in cancer is described here. Metastatic carcinomas express reduced levels of IL-33 and diminished levels of antigen processing machinery (APM), compared to syngeneic primary tumours. Complementation of IL-33 expression in metastatic tumours upregulates APM expression and functionality of major histocompatibility complex (MHC)-molecules, resulting in reduced tumour growth rates and a lower frequency of circulating tumour cells. Parallel studies in humans demonstrate that low tumour expression of IL-33 is an immune biomarker associated with recurrent prostate and kidney renal clear cell carcinomas. Thus, IL-33 has a significant role in cancer immune-surveillance against primary tumours, which is lost during the metastatic transition that actuates immune escape in cancer. PMID:27619158

  8. Discovery and Validation of Prognostic Biomarker Models to Guide Triage among Adult Dengue Patients at Early Infection

    Science.gov (United States)

    Tolfvenstam, Thomas; Thein, Tun-Linn; Naim, Ahmad Nazri Mohamed; Ling, Ling; Chow, Angelia; Chen, Mark I-Cheng; Ooi, Eng Eong; Leo, Yee Sin; Hibberd, Martin L.

    2016-01-01

    Background Dengue results in a significant public health burden in endemic regions. The World Health Organization (WHO) recommended the use of warning signs (WS) to stratify patients at risk of severe dengue disease in 2009. However, WS is limited in stratifying adult dengue patients at early infection (Day 1–3 post fever), who require close monitoring in hospitals to prevent severe dengue. The aim of this study is to identify and validate prognostic models, built with differentially expressed biomarkers, that enable the early identification of those with early dengue infection that require close clinical monitoring. Methods RNA microarray and protein assays were performed to identify differentially expressed biomarkers of severity among 92 adult dengue patients recruited at early infection from years 2005–2008. This comprised 47 cases who developed WS after first presentation and required hospitalization (WS+Hosp), as well as 45 controls who did not develop WS after first presentation and did not require hospitalization (Non-WS+Non-Hosp). Independent validation was conducted with 80 adult dengue patients recruited from years 2009–2012. Prognostic models were developed based on forward stepwise and backward elimination estimation, using multiple logistic regressions. Prognostic power was estimated by the area under the receiver operating characteristic curve (AUC). Results The WS+Hosp group had significantly higher viral load (Pdengue patients at early infection, with sensitivity and specificity up to 83% and 84%, respectively. These results were tested in the independent validation group, showing sensitivity and specificity up to 96% and 54.6%, respectively. Conclusions At early infection, adult dengue patients who later presented WS and require hospitalization have significantly different pathophysiology compared with patients who consistently presented no WS and / or require no hospitalization. The molecular prognostic models developed and validated here

  9. A SEARCH FOR L/T TRANSITION DWARFS WITH Pan-STARRS1 AND WISE: DISCOVERY OF SEVEN NEARBY OBJECTS INCLUDING TWO CANDIDATE SPECTROSCOPIC VARIABLES

    Energy Technology Data Exchange (ETDEWEB)

    Best, William M. J.; Liu, Michael C.; Magnier, Eugene A.; Aller, Kimberly M.; Burgett, W. S.; Chambers, K. C.; Hodapp, K. W.; Kaiser, N.; Kudritzki, R.-P.; Morgan, J. S.; Tonry, J. L.; Wainscoat, R. J. [Institute for Astronomy, University of Hawaii at Manoa, Honolulu, HI 96822 (United States); Deacon, Niall R. [Max Planck Institute for Astronomy, Koenigstuhl 17, D-69117 Heidelberg (Germany); Dupuy, Trent J. [Harvard-Smithsonian Center for Astrophysics, 60 Garden Street, Cambridge, MA 02138 (United States); Redstone, Joshua [Facebook, 335 Madison Ave, New York, NY 10017-4677 (United States); Price, P. A., E-mail: wbest@ifa.hawaii.edu [Department of Astrophysical Sciences, Princeton University, Princeton, NJ 08544 (United States)

    2013-11-10

    We present initial results from a wide-field (30,000 deg{sup 2}) search for L/T transition brown dwarfs within 25 pc using the Pan-STARRS1 and Wide-field Infrared Survey Explorer (WISE) surveys. Previous large-area searches have been incomplete for L/T transition dwarfs, because these objects are faint in optical bands and have near-infrared (near-IR) colors that are difficult to distinguish from background stars. To overcome these obstacles, we have cross-matched the Pan-STARRS1 (optical) and WISE (mid-IR) catalogs to produce a unique multi-wavelength database for finding ultracool dwarfs. As part of our initial discoveries, we have identified seven brown dwarfs in the L/T transition within 9-15 pc of the Sun. The L9.5 dwarf PSO J140.2308+45.6487 and the T1.5 dwarf PSO J307.6784+07.8263 (both independently discovered by Mace et al.) show possible spectroscopic variability at the Y and J bands. Two more objects in our sample show evidence of photometric J-band variability, and two others are candidate unresolved binaries based on their spectra. We expect our full search to yield a well-defined, volume-limited sample of L/T transition dwarfs that will include many new targets for study of this complex regime. PSO J307.6784+07.8263 in particular may be an excellent candidate for in-depth study of variability, given its brightness (J = 14.2 mag) and proximity (11 pc)

  10. A SEARCH FOR L/T TRANSITION DWARFS WITH Pan-STARRS1 AND WISE: DISCOVERY OF SEVEN NEARBY OBJECTS INCLUDING TWO CANDIDATE SPECTROSCOPIC VARIABLES

    International Nuclear Information System (INIS)

    We present initial results from a wide-field (30,000 deg2) search for L/T transition brown dwarfs within 25 pc using the Pan-STARRS1 and Wide-field Infrared Survey Explorer (WISE) surveys. Previous large-area searches have been incomplete for L/T transition dwarfs, because these objects are faint in optical bands and have near-infrared (near-IR) colors that are difficult to distinguish from background stars. To overcome these obstacles, we have cross-matched the Pan-STARRS1 (optical) and WISE (mid-IR) catalogs to produce a unique multi-wavelength database for finding ultracool dwarfs. As part of our initial discoveries, we have identified seven brown dwarfs in the L/T transition within 9-15 pc of the Sun. The L9.5 dwarf PSO J140.2308+45.6487 and the T1.5 dwarf PSO J307.6784+07.8263 (both independently discovered by Mace et al.) show possible spectroscopic variability at the Y and J bands. Two more objects in our sample show evidence of photometric J-band variability, and two others are candidate unresolved binaries based on their spectra. We expect our full search to yield a well-defined, volume-limited sample of L/T transition dwarfs that will include many new targets for study of this complex regime. PSO J307.6784+07.8263 in particular may be an excellent candidate for in-depth study of variability, given its brightness (J = 14.2 mag) and proximity (11 pc)

  11. Ultra-high throughput sequencing-based small RNA discovery and discrete statistical biomarker analysis in a collection of cervical tumours and matched controls

    Directory of Open Access Journals (Sweden)

    Gu Sam

    2010-05-01

    Full Text Available Abstract Background Ultra-high throughput sequencing technologies provide opportunities both for discovery of novel molecular species and for detailed comparisons of gene expression patterns. Small RNA populations are particularly well suited to this analysis, as many different small RNAs can be completely sequenced in a single instrument run. Results We prepared small RNA libraries from 29 tumour/normal pairs of human cervical tissue samples. Analysis of the resulting sequences (42 million in total defined 64 new human microRNA (miRNA genes. Both arms of the hairpin precursor were observed in twenty-three of the newly identified miRNA candidates. We tested several computational approaches for the analysis of class differences between high throughput sequencing datasets and describe a novel application of a log linear model that has provided the most effective analysis for this data. This method resulted in the identification of 67 miRNAs that were differentially-expressed between the tumour and normal samples at a false discovery rate less than 0.001. Conclusions This approach can potentially be applied to any kind of RNA sequencing data for analysing differential sequence representation between biological sample sets.

  12. Discovery of an L4$\\beta$ Candidate Member of Argus in the Planetary Mass Regime: WISE J231921.92+764544.4

    CERN Document Server

    Castro, Philip J

    2015-01-01

    We present the discovery of a young L dwarf, WISE J231921.92+764544.4, identified by comparing the Wide-field Infrared Survey Explorer (WISE) All-Sky Catalog to the Two Micron All Sky Survey (2MASS). A medium-resolution optical spectrum provides a spectral type of L4$\\beta$, with a photometric distance estimate of 26.1$\\pm$4.4 pc. The red WISE $W1-W2$ color provides additional evidence of youth, while the 2MASS $J-K_{\\rm s}$ color does not. WISE J231921.92+764544.4 is a candidate member of the young moving group Argus, with the space motion and position of WISE J231921.92+764544.4 giving a probability of 79% membership in Argus and a probability of 21% as a field object, based on BANYAN II. WISE J231921.92+764544.4 has a mass of 12.1$\\pm$0.4 M$_{\\rm Jup}$ based on membership in Argus, within the planetary mass regime.

  13. Discovery of the Candidate Off-nuclear Ultrasoft Hyper-luminous X-ray Source 3XMM J141711.1+522541

    CERN Document Server

    Lin, Dacheng; Webb, Natalie A; Irwin, Jimmy A; Dupke, Renato; Romanowsky, Aaron J; Ramirez-Ruiz, Enrico; Strader, Jay; Homan, Jeroen; Barret, Didier; Godet, Olivier

    2016-01-01

    We report the discovery of an off-nuclear ultrasoft hyper-luminous X-ray source candidate 3XMM J141711.1+522541 in the inactive S0 galaxy SDSS J141711.07+522540.8 (z=0.41827, d_L=2.3 Gpc) in the Extended Groth Strip. It is located at a projected offset of ~1.0 (5.2 kpc) from the nucleus of the galaxy and was serendipitously detected in five XMM-Newton observations in 2000 July. Two observations have enough counts and can be fitted with a standard thermal disk with an apparent inner disk temperature kT_MCD ~ 0.13 keV and a 0.28-14.2 keV unabsorbed luminosity L_X ~ 4X10^{43} erg/s in the source rest frame. The source was still detected in three Chandra observations in 2002 August, with similarily ultrasoft but fainter spectra (kT_MCD ~ 0.17 keV, L_X ~ 0.5X10^{43} erg/s). It was not detected in later observations, including two by Chandra in 2005 October, one by XMM-Newton in 2014 January, and two by Chandra in 2014 September-October, implying a long-term flux variation factor of >14. Therefore the source could ...

  14. Discovery and Monitoring of a new Black Hole Candidate XTE J1752-223 with RXTE: RMS spectrum evolution, BH mass and the source distance

    CERN Document Server

    Shaposhnikov, Nikolai; Swank, Jean; Krimm, Hans

    2010-01-01

    We report on the discovery and monitoring observations of a new galactic black hole candidate XTE J1752-223 by Rossi X-ray Timing Explorer (RXTE). The new source appeared on the X-ray sky on October 21 2009 and was active for almost 8 months. Phenomenologically, the source exhibited the low-hard/high-soft spectral state bi-modality and the variability evolution during the state transition that matches standard behavior expected from a stellar mass black hole binary. We model the energy spectrum throughout the outburst using a generic Comptonization model assuming that part of the input soft radiation in the form of a black body spectrum gets reprocessed in the Comptonizing medium. We follow the evolution of fractional root-mean-square (RMS) variability in the RXTE/PCA energy band with the source spectral state and conclude that broad band variability is strongly correlated with the source hardness (or Comptonized fraction). We follow changes in the energy distribution of rms variability during the low-hard st...

  15. Validation of New Cancer Biomarkers

    DEFF Research Database (Denmark)

    Duffy, Michael J; Sturgeon, Catherine M; Söletormos, Georg;

    2015-01-01

    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...

  16. 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.

  17. Discovery and Monitoring of a New Black Hole Candidate XTE J1752-223 with RXTE: RMS Spectrum Evolution, BH Mass and the Source Distance

    Science.gov (United States)

    Shaposhinikov, Nikolai; Markwardt, Craig; Swank, Jean; Krimm, Hans

    2010-01-01

    We report on the discovery and monitoring observations of a new galactic black hole candidate XTE J1752-223 by Rossi X-ray Timing Explorer (RXTE). The new source appeared on the X-ray sky on October 21 2009 and was active for almost 8 months. Phenomenologically, the source exhibited the low-hard/highsoft spectral state bi-modality and the variability evolution during the state transition that matches standard behavior expected from a stellar mass black hole binary. We model the energy spectrum throughout the outburst using a generic Comptonization model assuming that part of the input soft radiation in the form of a black body spectrum gets reprocessed in the Comptonizing medium. We follow the evolution of fractional root-mean-square (RMS) variability in the RXTE/PCA energy band with the source spectral state and conclude that broad band variability is strongly correlated with the source hardness (or Comptonized fraction). We follow changes in the energy distribution of rms variability during the low-hard state and the state transition and find further evidence that variable emission is strongly concentrated in the power-law spectral component. We discuss the implication of our results to the Comptonization regimes during different spectral states. Correlations of spectral and variability properties provide measurements of the BH mass and distance to the source. The spectral-timing correlation scaling technique applied to the RXTE observations during the hardto- soft state transition indicates a mass of the BH in XTE J1752-223 between 8 and 11 solar masses and a distance to the source about 3.5 kiloparsec.

  18. Mass spectrometry for biomarker development

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Chaochao; Liu, Tao; Baker, Erin Shammel; Rodland, Karin D.; Smith, Richard D.

    2015-06-19

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

  19. Biomarker Discovery and Redundancy Reduction towards Classification using a Multi-factorial MALDI-TOF MS T2DM Mouse Model Dataset

    Directory of Open Access Journals (Sweden)

    Al-Hasani Hadi

    2011-05-01

    Full Text Available Abstract Background Diabetes like many diseases and biological processes is not mono-causal. On the one hand multi-factorial studies with complex experimental design are required for its comprehensive analysis. On the other hand, the data from these studies often include a substantial amount of redundancy such as proteins that are typically represented by a multitude of peptides. Coping simultaneously with both complexities (experimental and technological makes data analysis a challenge for Bioinformatics. Results We present a comprehensive work-flow tailored for analyzing complex data including data from multi-factorial studies. The developed approach aims at revealing effects caused by a distinct combination of experimental factors, in our case genotype and diet. Applying the developed work-flow to the analysis of an established polygenic mouse model for diet-induced type 2 diabetes, we found peptides with significant fold changes exclusively for the combination of a particular strain and diet. Exploitation of redundancy enables the visualization of peptide correlation and provides a natural way of feature selection for classification and prediction. Classification based on the features selected using our approach performs similar to classifications based on more complex feature selection methods. Conclusions The combination of ANOVA and redundancy exploitation allows for identification of biomarker candidates in multi-dimensional MALDI-TOF MS profiling studies with complex experimental design. With respect to feature selection our method provides a fast and intuitive alternative to global optimization strategies with comparable performance. The method is implemented in R and the scripts are available by contacting the corresponding author.

  20. Genetic markers: Potential candidates for cardiovascular disease.

    Science.gov (United States)

    Rather, Riyaz Ahmad; Dhawan, Veena

    2016-10-01

    The effective prevention of cardiovascular disease depends upon the ability to recognize the high-risk individuals at an early stage of the disease or long before the development of adverse events. Evolving technologies in the fields of proteomics, metabolomics, and genomics have played a significant role in the discovery of cardiovascular biomarkers, but so far these methods have achieved the modest success. Hence, there is a crucial need for more reliable, suitable, and lasting diagnostic and therapeutic markers to screen the disease well in time to start the clinical aid to the patients. Gene polymorphisms associated with the cardiovascular disease play a decisive role in the disease onset. Therefore, the genetic marker evaluation to classify high-risk patients from low-risk patients trends an effective approach to patient management and care. Currently, there are no genetic markers available for extensive adoption as risk factors for coronary vascular disease, yet, there are numerous promising, biologically acceptable candidates. Many of these gene biomarkers, alone or in combination, can play an essential role in the prediction of cardiovascular risk. The present review highlights some putative emerging genetic biomarkers that could facilitate more authentic and fast diagnosis of CVD. This review also briefly describes few technological approaches employed in the biomarker search. PMID:27416153

  1. Shotgun Proteomics and Biomarker Discovery

    OpenAIRE

    W. Hayes McDonald; Yates, John R.

    2002-01-01

    Coupling large-scale sequencing projects with the amino acid sequence information that can be gleaned from tandem mass spectrometry (MS/MS) has made it much easier to analyze complex mixtures of proteins. The limits of this “shotgun” approach, in which the protein mixture is proteolytically digested before separation, can be further expanded by separating the resulting mixture of peptides prior to MS/MS analysis. Both single dimensional high pressure liquid chromatography (LC) and multidimens...

  2. Dissecting the Syndrome of Schizophrenia: Progress toward Clinically Useful Biomarkers

    Directory of Open Access Journals (Sweden)

    Brian Dean

    2011-01-01

    Full Text Available The search for clinically useful biomarkers has been one of the holy grails of schizophrenia research. This paper will outline the evolving notion of biomarkers and then outline outcomes from a variety of biomarkers discovery strategies. In particular, the impact of high-throughput screening technologies on biomarker discovery will be highlighted and how new or improved technologies may allow the discovery of either diagnostic biomarkers for schizophrenia or biomarkers that will be useful in determining appropriate treatments for people with the disorder. History tells those involved in biomarker research that the discovery and validation of useful biomarkers is a long process and current progress must always be viewed in that light. However, the approval of the first biomarker screen with some value in predicting responsiveness to antipsychotic drugs suggests that biomarkers can be identified and that these biomarkers that will be useful in diagnosing and treating people with schizophrenia.

  3. Dissecting the Syndrome of Schizophrenia: Progress toward Clinically Useful Biomarkers.

    Science.gov (United States)

    Dean, Brian

    2011-01-01

    The search for clinically useful biomarkers has been one of the holy grails of schizophrenia research. This paper will outline the evolving notion of biomarkers and then outline outcomes from a variety of biomarkers discovery strategies. In particular, the impact of high-throughput screening technologies on biomarker discovery will be highlighted and how new or improved technologies may allow the discovery of either diagnostic biomarkers for schizophrenia or biomarkers that will be useful in determining appropriate treatments for people with the disorder. History tells those involved in biomarker research that the discovery and validation of useful biomarkers is a long process and current progress must always be viewed in that light. However, the approval of the first biomarker screen with some value in predicting responsiveness to antipsychotic drugs suggests that biomarkers can be identified and that these biomarkers that will be useful in diagnosing and treating people with schizophrenia.

  4. Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate

    OpenAIRE

    Mounier, C M; Wendum, D; Greenspan, E; Fléjou, J-F; Rosenberg, D W; Lambeau, G.

    2008-01-01

    Recent studies suggest that secreted phospholipases A2 (sPLA2s) represent attractive potential tumour biomarkers and therapeutic targets for various cancers. As a first step to address this issue in human colorectal cancer, we examined the expression of the full set of sPLA2s in sporadic adenocarcinomas and normal matched mucosa from 21 patients by quantitative PCR and immunohistochemistry. In normal colon, PLA2G2A and PLA2G12A were expressed at high levels, PLA2G2D, PLA2G5, PLA2G10 and PLA2G...

  5. The importance of biomarkers in neonatology.

    Science.gov (United States)

    Mussap, M; Noto, A; Cibecchini, F; Fanos, V

    2013-02-01

    Despite a 35% decline in the mortality rate for infants aged years over the past two decades, every year nearly 40% of all deaths in this age group occur in the neonatal period, defined as the first 28 days of life. New knowledge on molecular and biochemical pathways in neonatal diseases will lead to the discovery of new candidate biomarkers potentially useful in clinical practice. In the era of personalized medicine, biomarkers may play a strategic role in accelerating the decline in neonatal mortality by assessing the risk of developing neonatal diseases, by implementing tailored therapeutic treatment, and by predicting the clinical outcome. However, there is an urgent need to reduce the gap in translating newly acquired knowledge from bench to bedside. Traditional and candidate biomarkers for neonatal sepsis and necrotizing enterocolitis will be discussed in this review, such as C-reactive protein (CRP), procalcitonin (PCT), serum amyloid A (SAA), soluble form of CD14 subtype presepsin (sCD14-ST), lipolysaccharide binding protein (LBP), angiopoietins (Ang)-1 and -2, soluble form of triggering receptor expressed on myeloid cells (sTREM-1), soluble form of urokinase-type plasminogen activator receptor (suPAR), platelet-activating factor (PAF) and calprotectin. New frontiers in managing critically ill newborns may be opened by metabolomics, a diagnostic tool based on the recognition of metabolites contained in biological fluids. Metabolomics represents the passage from a descriptive science to a predictive science, having the potential to translate benchtop research to real clinical benefits. PMID:23164809

  6. Discovery, screening and evaluation of a plasma biomarker panel for subjects with psychological suboptimal health state using 1H-NMR-based metabolomics profiles

    Science.gov (United States)

    Tian, Jun-sheng; Xia, Xiao-tao; Wu, Yan-fei; Zhao, Lei; Xiang, Huan; Du, Guan-hua; Zhang, Xiang; Qin, Xue-mei

    2016-01-01

    Individuals in the state of psychological suboptimal health keep increasing, only scales and questionnaires were used to diagnose in clinic under current conditions, and symptoms of high reliability and accuracy are destitute. Therefore, the noninvasive and precise laboratory diagnostic methods are needed. This study aimed to develop an objective method through screen potential biomarkers or a biomarker panel to facilitate the diagnosis in clinic using plasma metabolomics. Profiles were based on H-nuclear magnetic resonance (1H-NMR) metabolomics techniques combing with multivariate statistical analysis. Furthermore, methods of correlation analysis with Metaboanalyst 3.0 for selecting a biomarker panel, traditional Chinese medicine (TCM) drug intervention for validating the close relations between the biomarker panel and the state and the receiver operating characteristic curves (ROC curves) analysis for evaluation of clinical diagnosis ability were carried out. 9 endogenous metabolites containing trimethylamine oxide (TMAO), glutamine, N-acetyl-glycoproteins, citrate, tyrosine, phenylalanine, isoleucine, valine and glucose were identified and considered as potential biomarkers. Then a biomarker panel consisting of phenylalanine, glutamine, tyrosine, citrate, N-acetyl-glycoproteins and TMAO was selected, which exhibited the highest area under the curve (AUC = 0.971). This study provided critical insight into the pathological mechanism of psychological suboptimal health and would supply a novel and valuable diagnostic method. PMID:27650680

  7. 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.

  8. iTRAQ-Based Proteomics Analysis of Serum Proteins in Wistar Rats Treated with Sodium Fluoride: Insight into the Potential Mechanism and Candidate Biomarkers of Fluorosis

    Directory of Open Access Journals (Sweden)

    Yan Wei

    2016-09-01

    Full Text Available Fluorosis induced by exposure to high level fluoride is quite widespread in the world. The manifestations of fluorosis include dental mottling, bone damage, and impaired malfunction of soft tissues. However, the molecular mechanism of fluorosis has not been clarified until now. To explore the underlying mechanisms of fluorosis and screen out serum biomarkers, we carried out a quantitative proteomics study to identify differentially expressed serum proteins in Wistar rats treated with sodium fluoride (NaF by using a proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ. We fed Wistar rats drinking water that had 50, 150, and 250 mg/L of dissolved NaF for 24 weeks. For the experimental duration, each rat was given an examination of the lower incisors to check for the condition of dental fluorosis (DF. By the end of the treatment, fluoride ion concentration in serum and lower incisors were detected. The results showed that NaF treatment can induce rat fluorosis. By iTRAQ analysis, a total of 37 differentially expressed serum proteins were identified between NaF-treated and control rats. These proteins were further analyzed by bioinformatics, out of which two proteins were validated by enzyme-linked immunoadsorbent assays (ELISA. The major proteins were involved in complement and coagulation cascade, inflammatory response, complement activation, defense response, and wound response, suggesting that inflammation and immune reactions may play a key role in fluorosis pathogenesis. These proteins may contribute to the understanding of the mechanism of fluoride toxicity, and may serve as potential biomarkers for fluorosis.

  9. Decreased saliva/serum irisin concentrations in the acute myocardial infarction promising for being a new candidate biomarker for diagnosis of this pathology.

    Science.gov (United States)

    Aydin, Suna; Aydin, Suleyman; Kobat, Mehmet Ali; Kalayci, Mehmet; Eren, Mehmet Nesimi; Yilmaz, Musa; Kuloglu, Tuncay; Gul, Evrim; Secen, Ozlem; Alatas, Omer Dogan; Baydas, Adil

    2014-06-01

    Irisin is a muscle-secreted protein. Cardiac muscle produces more irisin than skeletal muscle in response to acute exercise, and is associated with myocardial infarction (MI) in an experimental model induced by isoproterenol in rats. The timing and significance of its release in patients with acute myocardial infarction (AMI) needs further investigation. We have studied the relationship between serum/saliva irisin concentration and AMI in humans. Serum and saliva samples were taken within 3 days of admission in 11 patients with AMI and in 14 matched controls. Salivary gland irisin was detected immunohistochemically, and serum and saliva levels were measured by ELISA. The three major paired salivary glands (submandibular, sublingual and parotid) produce and release irisin into saliva. Troponin-I, CK, CK-MB concentrations in the AMI group gradually increased from up to 12h, while saliva and serum irisin gradually decreased from up to 48 h, compared with the control group (Psaliva and serum irisin started to increase at 72 h. Serum irisin levels correlated with age, while troponin I, CK-MB, and CK were correlated and with saliva irisin in AMI patients. Besides cardiac troponin and CK-MB, irisin adds new diagnostic information in AMI patients, and the gradual decrease of saliva/serum irisin over 48 h could be a useful biomarker.

  10. Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: rationale and design of the epidemiological studies within the IMI DIRECT Consortium

    DEFF Research Database (Denmark)

    Koivula, Robert W.; Heggie, Alison; Barnett, Anna;

    2014-01-01

    biomarkers that: (1) predict the rate of glycaemic deterioration before and after type 2 diabetes onset; (2) predict the response to diabetes therapies; and (3) help stratify type 2 diabetes into clearly definable disease subclasses that can be treated more effectively than without stratification. This paper...

  11. Exploring the effect of N-substitution in nor-lobelane on the interaction with VMAT2: discovery of a potential clinical candidate for treatment of methamphetamine abuse.

    Science.gov (United States)

    Zheng, Guangrong; Horton, David B; Penthala, Narsimha Reddy; Nickell, Justin R; Culver, John P; Deaciuc, Agripina G; Dwoskin, Linda P; Crooks, Peter A

    2013-03-01

    A series of N-substituted lobelane analogues was synthesized and evaluated for their [(3)H]dihydrotetrabenazine binding affinity at the vesicular monoamine transporter and for their inhibition of vesicular [(3)H]dopamine uptake. Compound 19a, which contains an N-1,2(R)-dihydroxypropyl group, had been identified as a potential clinical candidate for the treatment of methamphetamine abuse.

  12. Discovery of a broad iron line in the black hole candidate Swift J1753.5-0127, and the disc emission in the low/hard state revisited

    NARCIS (Netherlands)

    Hiemstra, Beike; Soleri, Paolo; Mendez, Mariano; Belloni, Tomaso; Mostafa, Reham; Wijnands, Rudy

    2009-01-01

    We analysed simultaneous archival XMM-Newton and Rossi X-ray Timing Explorer observations of the X-ray binary and black hole candidate Swift J1753.5-0127. In a previous analysis of the same data, a soft thermal component was found in the X-ray spectrum, and the presence of an accretion disc extendin

  13. Spatiotemporal proteomic analyses during pancreas cancer progression identifies serine/threonine stress kinase 4 (STK4) as a novel candidate biomarker for early stage disease.

    Science.gov (United States)

    Mirus, Justin E; Zhang, Yuzheng; Hollingsworth, Michael A; Solan, Joell L; Lampe, Paul D; Hingorani, Sunil R

    2014-12-01

    Pancreas cancer, or pancreatic ductal adenocarcinoma, is the deadliest of solid tumors, with a five-year survival rate of disease improves survival rates, but access to tissue and other biospecimens that could be used to develop early detection markers is confounded by the insidious nature of pancreas cancer. Mouse models that accurately recapitulate the human condition allow disease tracking from inception to invasion and can therefore be useful for studying early disease stages in which surgical resection is possible. Using a highly faithful mouse model of pancreas cancer in conjunction with a high-density antibody microarray containing ∼2500 antibodies, we interrogated the pancreatic tissue proteome at preinvasive and invasive stages of disease. The goal was to discover early stage tissue markers of pancreas cancer and follow them through histologically defined stages of disease using cohorts of mice lacking overt clinical signs and symptoms and those with end-stage metastatic disease, respectively. A panel of seven up-regulated proteins distinguishing pancreas cancer from normal pancreas was validated, and their levels were assessed in tissues collected at preinvasive, early invasive, and moribund stages of disease. Six of the seven markers also differentiated pancreas cancer from an experimental model of chronic pancreatitis. The levels of serine/threonine stress kinase 4 (STK4) increased between preinvasive and invasive stages, suggesting its potential as a tissue biomarker, and perhaps its involvement in progression from precursor pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma. Immunohistochemistry of STK4 at different stages of disease revealed a dynamic expression pattern further implicating it in early tumorigenic events. Immunohistochemistry of a panel of human pancreas cancers confirmed that STK4 levels were increased in tumor epithelia relative to normal tissue. Overall, this integrated approach yielded several tissue

  14. The noradrenaline metabolite MHPG is a candidate biomarker from the manic to the remission state in bipolar disorder I: a clinical naturalistic study.

    Directory of Open Access Journals (Sweden)

    Masatake Kurita

    Full Text Available Remission is the primary goal of treatment for bipolar disorder I (BDI. Metabolites of noradrenaline and dopamine, 3-methoxy-4-hydroxyphenylglycol (MHPG and homovanillic acid (HVA, respectively, are reduced by treatment with antipsychotics, but whether these phenomena are caused by antipsychotics or by the pathophysiology of BDI is not known. Interactions between brain-derived neurotrophic factor (BDNF and mood disorders have also been suggested. We conducted a multifaceted study in BDI patients to ascertain if biological markers are associated with the manic state. Patients with Young Mania Rating Scale (YMRS scores >20 participated in the study. Final analyses involved 24 BDI patients (13 men and 11 women. We used YMRS scores to identify mania stages in individual BDI patients (i.e., manic syndrome, response and remission stages. Statistical analyses were done using one-way repeated-measures analyses of variance (rep-ANOVA throughout manic syndrome, response and remission stages. Plasma concentrations of MHPG and HVA were analyzed by high-performance liquid chromatography with electrochemical detection. Plasma levels of BDNF were measured by sandwich enzyme-linked immunosorbent assay. BDI patients had significantly reduced plasma levels of MHPG throughout manic syndrome, response and remission stages (rep-ANOVA, p = 0.002. Without a case of response state, there was a significant positive correlation between YMRS scores and plasma levels of MHPG (ρ = 0.33, p = 0.033, n = 48. Plasma levels of HVA and BDNF were not significantly altered throughout manic syndrome, response and remission stages. These data suggest that the peripheral level of MHPG (which is associated with noradrenaline levels in the brain could be used as a biomarker for the manic state in BDI. The MHPG level is likely to reflect the clinical characteristics of the manic syndrome in BDI, and noradrenaline may reflect the pathophysiology from manic to remission

  15. Quantitative Proteomics Analysis of Tissue Interstitial Fluid for Identification of Novel Serum Candidate Diagnostic Marker for Hepatocellular Carcinoma.

    Science.gov (United States)

    Sun, Wei; Xing, Baocai; Guo, Lihai; Liu, Zhilei; Mu, Jinsong; Sun, Longqin; Wei, Handong; Zhao, Xiaohang; Qian, Xiaohong; Jiang, Ying; He, Fuchu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer in the world. The sensitivity of alpha-fetoprotein (AFP) is still inadequate for HCC diagnosis. Tissue interstitial fluid (TIF), as the liquid microenvironment of cancer cells, was used for biomarker discovery in this study. Paired tumor and nontumor TIF samples from 6 HBV-HCC patients were analyzed by a proteomic technique named iTRAQ (isobaric tag for relative and absolute quantitation). Totally, 241 up-regulated proteins (ratio ≥ 1.3, p AFP) and specificity of 66%. This result demonstrated the potential of S100A9 as a candidate HCC diagnostic biomarker. And TIF was a kind of promising material to identify candidate tumor biomarkers that could be detected in serum. PMID:27216119

  16. Recent advances in atherosclerosis-based proteomics: new biomarkers and a future perspective.

    Science.gov (United States)

    Alvarez-Llamas, Gloria; de la Cuesta, Fernando; Barderas, Maria Eugenia G; Darde, Veronica; Padial, Luis R; Vivanco, Fernando

    2008-10-01

    Vascular proteomics is providing two main types of data: proteins that actively participate in vascular pathophysiological processes and novel protein candidates that can potentially serve as useful clinical biomarkers. Although both types of proteins can be identified by similar proteomic strategies and methods, it is important to clearly distinguish biomarkers from mediators of disease. A particular protein, or group of proteins, may participate in a pathogenic process but not serve as an effective biomarker. Alternatively, a useful biomarker may not mediate pathogenic pathways associated with disease (i.e., C-reactive protein). To date, there are no clear successful examples in which discovery proteomics has led to a novel useful clinical biomarker in cardiovascular diseases. Nevertheless, new sources of biomarkers are being explored (i.e., secretomes, circulating cells, exosomes and microparticles), an increasing number of novel proteins involved in atherogenesis are constantly described, and new technologies and analytical strategies (i.e., quantitative proteomics) are being developed to access low abundant proteins. Therefore, this presages a new era of discovery and a further step in the practical application to diagnosis, prognosis and early action by medical treatment of cardiovascular diseases. PMID:18937558

  17. Pleural effusion adenosine deaminase: a candidate biomarker to discriminate between Gram-negative and Gram-positive bacterial infections of the pleural space

    Directory of Open Access Journals (Sweden)

    Ruolin Li

    2016-05-01

    Full Text Available OBJECTIVES: Delay in the treatment of pleural infection may contribute to its high mortality. In this retrospective study, we aimed to evaluate the diagnostic accuracy of pleural adenosine deaminase in discrimination between Gram-negative and Gram-positive bacterial infections of the pleural space prior to selecting antibiotics. METHODS: A total of 76 patients were enrolled and grouped into subgroups according to Gram staining: 1 patients with Gram-negative bacterial infections, aged 53.2±18.6 years old, of whom 44.7% had empyemas and 2 patients with Gram-positive bacterial infections, aged 53.5±21.5 years old, of whom 63.1% had empyemas. The pleural effusion was sampled by thoracocentesis and then sent for adenosine deaminase testing, biochemical testing and microbiological culture. The Mann-Whitney U test was used to examine the differences in adenosine deaminase levels between the groups. Correlations between adenosine deaminase and specified variables were also quantified using Spearman’s correlation coefficient. Moreover, receiver operator characteristic analysis was performed to evaluate the diagnostic accuracy of pleural effusion adenosine deaminase. RESULTS: Mean pleural adenosine deaminase levels differed significantly between Gram-negative and Gram-positive bacterial infections of the pleural space (191.8±32.1 U/L vs 81.0±16.9 U/L, p<0.01. The area under the receiver operator characteristic curve was 0.689 (95% confidence interval: 0.570, 0.792, p<0.01 at the cutoff value of 86 U/L. Additionally, pleural adenosine deaminase had a sensitivity of 63.2% (46.0-78.2%; a specificity of 73.7% (56.9-86.6%; positive and negative likelihood ratios of 2.18 and 0.50, respectively; and positive and negative predictive values of 70.6% and 66.7%, respectively. CONCLUSIONS: Pleural effusion adenosine deaminase is a helpful alternative biomarker for early and quick discrimination of Gram-negative from Gram-positive bacterial infections of the

  18. 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.

  19. 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. PMID:24772389

  20. Integrated mRNA and miRNA expression profiling in blood reveals candidate biomarkers associated with endurance exercise in the horse

    Science.gov (United States)

    Mach, Núria; Plancade, Sandra; Pacholewska, Alicja; Lecardonnel, Jérôme; Rivière, Julie; Moroldo, Marco; Vaiman, Anne; Morgenthaler, Caroline; Beinat, Marine; Nevot, Alizée; Robert, Céline; Barrey, Eric

    2016-01-01

    The adaptive response to extreme endurance exercise might involve transcriptional and translational regulation by microRNAs (miRNAs). Therefore, the objective of the present study was to perform an integrated analysis of the blood transcriptome and miRNome (using microarrays) in the horse before and after a 160 km endurance competition. A total of 2,453 differentially expressed genes and 167 differentially expressed microRNAs were identified when comparing pre- and post-ride samples. We used a hypergeometric test and its generalization to gain a better understanding of the biological functions regulated by the differentially expressed microRNA. In particular, 44 differentially expressed microRNAs putatively regulated a total of 351 depleted differentially expressed genes involved variously in glucose metabolism, fatty acid oxidation, mitochondrion biogenesis, and immune response pathways. In an independent validation set of animals, graphical Gaussian models confirmed that miR-21-5p, miR-181b-5p and miR-505-5p are candidate regulatory molecules for the adaptation to endurance exercise in the horse. To the best of our knowledge, the present study is the first to provide a comprehensive, integrated overview of the microRNA-mRNA co-regulation networks that may have a key role in controlling post-transcriptomic regulation during endurance exercise. PMID:26960911

  1. MicroRNA Profiling in the Medial and Lateral Habenula of Rats Exposed to the Learned Helplessness Paradigm: Candidate Biomarkers for Susceptibility and Resilience to Inescapable Shock

    Science.gov (United States)

    Mallien, Anne S.; Jensen, Line; Christensen, Trine; Kjems, Jørgen; Vollmayr, Barbara; Wiborg, Ove

    2016-01-01

    Depression is a highly heterogeneous disorder presumably caused by a combination of several factors ultimately causing the pathological condition. The genetic liability model of depression is likely to be of polygenic heterogeneity. miRNAs can regulate multiple genes simultaneously and therefore are candidates that align with this model. The habenula has been linked to depression in both clinical and animal studies, shifting interest towards this region as a neural substrate in depression. The goal of the present study was to search for alterations in miRNA expression levels in the medial and lateral habenula of rats exposed to the learned helplessness (LH) rat model of depression. Ten miRNAs showed significant alterations associating with their response to the LH paradigm. Of these, six and four miRNAs were significantly regulated in the MHb and LHb, respectively. In the MHb we identified miR-490, miR-291a-3p, MiR-467a, miR-216a, miR-18b, and miR-302a. In the LHb miR-543, miR-367, miR-467c, and miR-760-5p were significantly regulated. A target gene analysis showed that several of the target genes are involved in MAPK signaling, neutrophin signaling, and ErbB signaling, indicating that neurotransmission is affected in the habenula as a consequence of exposure to the LH paradigm. PMID:27494716

  2. Lyman-alpha Blobs Like Company : The Discovery of A Candidate 100 kpc Lyman-alpha Blob Near to A Radio Galaxy with A Giant Lyman-alpha halo, B3 J2330+3927 at z=3.1

    CERN Document Server

    Matsuda, Y; Morimoto, N; Smail, Ian; De Breuck, C; Ohta, K; Kodama, T; Inoue, A K; Hayashino, T; Kousai, K; Nakamura, E; Horie, M; Yamada, T; Kitamura, M; Saitô, T; Taniguchi, Y; Tanaka, I; Hibon, P

    2009-01-01

    We present the discovery of a candidate of giant radio-quiet Lyman-alpha (Lya) blob (RQLAB) in a large-scale structure around a high-redshift radio galaxy (HzRG) lying in a giant Lya halo, B3 J2330+3927 at redshift z=3.087. We obtained Lya imaging around B3 J2330+3927 with Subaru/Suprime-Cam to search for Lya emitters (LAEs) and absorbers (LAAs) at redshift z=3.09+-0.03. We detected candidate 127 LAEs and 26 LAAs in the field of view of 31' x 24'. We found that B3 J2330+3927 is surrounded by a 130 kpc Lya halo and a large-scale (60 x 20 comoving Mpc) filamentary structure. The large-scale structure contains one prominent local density peak with an overdensity of greater than 5, which is 8' (15 comoving Mpc) away from B3 J2330+3927. In this peak, we discovered a candidate 100 kpc RQLAB. The existence of both types of Lya nebulae in the same large-scale structure suggests that giant Lya nebulae need special large-scale environments to form. On smaller scales, however, the location of B3 J2330+3927 is not a sign...

  3. Analysis of Serum Metabolic Profile by Ultra-performance Liquid Chromatography-mass Spectrometry for Biomarkers Discovery: Application in a Pilot Study to Discriminate Patients with Tuberculosis

    Directory of Open Access Journals (Sweden)

    Shuang Feng

    2015-01-01

    Full Text Available Background: Tuberculosis (TB is a chronic wasting inflammatory disease characterized by multisystem involvement, which can cause metabolic derangements in afflicted patients. Metabolic signatures have been exploited in the study of several diseases. However, the serum that is successfully used in TB diagnosis on the basis of metabolic profiling is not by much. Methods: Orthogonal partial least-squares discriminant analysis was capable of distinguishing TB patients from both healthy subjects and patients with conditions other than TB. Therefore, TB-specific metabolic profiling was established. Clusters of potential biomarkers for differentiating TB active from non-TB diseases were identified using Mann-Whitney U-test. Multiple logistic regression analysis of metabolites was calculated to determine the suitable biomarker group that allows the efficient differentiation of patients with TB active from the control subjects. Results: From among 271 participants, 12 metabolites were found to contribute to the distinction between the TB active group and the control groups. These metabolites were mainly involved in the metabolic pathways of the following three biomolecules: Fatty acids, amino acids, and lipids. The receiver operating characteristic curves of 3D, 7D, and 11D-phytanic acid, behenic acid, and threoninyl-γ-glutamate exhibited excellent efficiency with area under the curve (AUC values of 0.904 (95% confidence interval [CI]: 0863-0.944, 0.93 (95% CI: 0.893-0.966, and 0.964 (95% CI: 00.941-0.988, respectively. The largest and smallest resulting AUCs were 0.964 and 0.720, indicating that these biomarkers may be involved in the disease mechanisms. The combination of lysophosphatidylcholine (18:0, behenic acid, threoninyl-γ-glutamate, and presqualene diphosphate was used to represent the most suitable biomarker group for the differentiation of patients with TB active from the control subjects, with an AUC value of 0.991. Conclusion: The

  4. Discovery of Candidate SNP by Bioinformatic Methods%基于生物信息学的SNP候选位点搜寻方法

    Institute of Scientific and Technical Information of China (English)

    陈炜; 张戈; 张思仲

    2001-01-01

    单核苷酸多态性 (Single Nucleotide Polymorphism, SNP)是人类基因组中最常见的遗传多态,在遗传学研究的很多方面具有重要的作用。它的搜寻正受到广泛关注。近年来,国际上出现了一种基于生物信息学的发掘SNP新方法。本文对该方法的两种策略及其各自所存在的问题作一介绍。%Single Nucleotide Polymorphism (SNP), the most common form of human genetic variation, represents a valuable resources for a variety of genetic research. There is considerable interest in the discovery of it. Recently, a new method based on bioinfomatics has been developed for the discovery of SNP. In this paper, the two strategy of this method and their respective problem are discussed.

  5. 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.

  6. Classification of genes and putative biomarker identification using distribution metrics on expression profiles.

    Directory of Open Access Journals (Sweden)

    Hung-Chung Huang

    Full Text Available BACKGROUND: Identification of genes with switch-like properties will facilitate discovery of regulatory mechanisms that underlie these properties, and will provide knowledge for the appropriate application of Boolean networks in gene regulatory models. As switch-like behavior is likely associated with tissue-specific expression, these gene products are expected to be plausible candidates as tissue-specific biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: In a systematic classification of genes and search for biomarkers, gene expression profiles (GEPs of more than 16,000 genes from 2,145 mouse array samples were analyzed. Four distribution metrics (mean, standard deviation, kurtosis and skewness were used to classify GEPs into four categories: predominantly-off, predominantly-on, graded (rheostatic, and switch-like genes. The arrays under study were also grouped and examined by tissue type. For example, arrays were categorized as 'brain group' and 'non-brain group'; the Kolmogorov-Smirnov distance and Pearson correlation coefficient were then used to compare GEPs between brain and non-brain for each gene. We were thus able to identify tissue-specific biomarker candidate genes. CONCLUSIONS/SIGNIFICANCE: The methodology employed here may be used to facilitate disease-specific biomarker discovery.

  7. Identification of a novel biomarker candidate, a 4.8-kDa peptide fragment from a neurosecretory protein VGF precursor, by proteomic analysis of cerebrospinal fluid from children with acute encephalopathy using SELDI-TOF-MS

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    Fujino Osamu

    2011-08-01

    Full Text Available Abstract Background Acute encephalopathy includes rapid deterioration and has a poor prognosis. Early intervention is essential to prevent progression of the disease and subsequent neurologic complications. However, in the acute period, true encephalopathy cannot easily be differentiated from febrile seizures, especially febrile seizures of the complex type. Thus, an early diagnostic marker has been sought in order to enable early intervention. The purpose of this study was to identify a novel marker candidate protein differentially expressed in the cerebrospinal fluid (CSF of children with encephalopathy using proteomic analysis. Methods For detection of biomarkers, CSF samples were obtained from 13 children with acute encephalopathy and 42 children with febrile seizure. Mass spectral data were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS technology, which is currently applied in many fields of biological and medical sciences. Diagnosis was made by at least two pediatric neurologists based on the clinical findings and routine examinations. All specimens were collected for diagnostic tests and the remaining portion of the specimens were used for the SELDI-TOF MS investigations. Results In experiment 1, CSF from patients with febrile seizures (n = 28, patients with encephalopathy (n = 8 (including influenza encephalopathy (n = 3, encephalopathy due to rotavirus (n = 1, human herpes virus 6 (n = 1 were used for the SELDI analysis. In experiment 2, SELDI analysis was performed on CSF from a second set of febrile seizure patients (n = 14 and encephalopathy patients (n = 5. We found that the peak with an m/z of 4810 contributed the most to the separation of the two groups. After purification and identification of the 4.8-kDa protein, a 4.8-kDa proteolytic peptide fragment from the neurosecretory protein VGF precursor (VGF4.8 was identified as a novel biomarker for encephalopathy. Conclusions

  8. Discovery of gene expression-based pharmacodynamic biomarker for a p53 context-specific anti-tumor drug Wee1 inhibitor

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    Mizuarai Shinji

    2009-06-01

    Full Text Available Abstract Background Wee1 is a tyrosine kinase regulating S-G2 cell cycle transition through the inactivating phosphorylation of CDC2. The inhibition of Wee1 kinase by a selective small molecule inhibitor significantly enhances the anti-tumor efficacy of DNA damaging agents, specifically in p53 negative tumors by abrogating S-G2 checkpoints, while normal cells with wild-type p53 are not severely damaged due to the intact function of the G1 checkpoint mediated by p53. Since the measurement of mRNA expression requires a very small amount of biopsy tissue and is highly quantitative, the development of a pharmacodynamic (PD biomarker leveraging mRNA expression is eagerly anticipated in order to estimate target engagement of anti-cancer agents. Results In order to find the Wee1 inhibition signature, mRNA expression profiling was first performed in both p53 positive and negative cancer cell lines treated with gemcitabine and a Wee1 inhibitor, MK-1775. We next carried out mRNA expression profiling of skin samples derived from xenograft models treated with the Wee1 inhibitor to identify a Wee1 inhibitor-regulatory gene set. Then, the genes that were commonly modulated in both cancer cell lines and rat skin samples were extracted as a Wee1 inhibition signature that could potentially be used as a PD biomarker independent of p53 status. The expression of the Wee1 inhibition signature was found to be regulated in a dose-dependent manner by the Wee1 inhibitor, and was significantly correlated with the inhibition level of a direct substrate, phosphorylated-CDC2. Individual genes in this Wee1 inhibition signature are known to regulate S-G2 cell cycle progression or checkpoints, which is consistent with the mode-of-action of the Wee1 inhibitor. Conclusion We report here the identification of an mRNA gene signature that was specifically changed by gemcitabine and Wee1 inhibitor combination treatment by molecular profiling. Given the common regulation of

  9. Recent advances in candidate-gene and whole-genome approaches to the discovery of anthelmintic resistance markers and the description of drug/receptor interactions

    Science.gov (United States)

    Kotze, Andrew C.; Hunt, Peter W.; Skuce, Philip; von Samson-Himmelstjerna, Georg; Martin, Richard J.; Sager, Heinz; Krücken, Jürgen; Hodgkinson, Jane; Lespine, Anne; Jex, Aaron R.; Gilleard, John S.; Beech, Robin N.; Wolstenholme, Adrian J.; Demeler, Janina; Robertson, Alan P.; Charvet, Claude L.; Neveu, Cedric; Kaminsky, Ronald; Rufener, Lucien; Alberich, Melanie; Menez, Cecile; Prichard, Roger K.

    2014-01-01

    Anthelmintic resistance has a great impact on livestock production systems worldwide, is an emerging concern in companion animal medicine, and represents a threat to our ongoing ability to control human soil-transmitted helminths. The Consortium for Anthelmintic Resistance and Susceptibility (CARS) provides a forum for scientists to meet and discuss the latest developments in the search for molecular markers of anthelmintic resistance. Such markers are important for detecting drug resistant worm populations, and indicating the likely impact of the resistance on drug efficacy. The molecular basis of resistance is also important for understanding how anthelmintics work, and how drug resistant populations arise. Changes to target receptors, drug efflux and other biological processes can be involved. This paper reports on the CARS group meeting held in August 2013 in Perth, Australia. The latest knowledge on the development of molecular markers for resistance to each of the principal classes of anthelmintics is reviewed. The molecular basis of resistance is best understood for the benzimidazole group of compounds, and we examine recent work to translate this knowledge into useful diagnostics for field use. We examine recent candidate-gene and whole-genome approaches to understanding anthelmintic resistance and identify markers. We also look at drug transporters in terms of providing both useful markers for resistance, as well as opportunities to overcome resistance through the targeting of the transporters themselves with inhibitors. Finally, we describe the tools available for the application of the newest high-throughput sequencing technologies to the study of anthelmintic resistance. PMID:25516826

  10. Recent advances in candidate-gene and whole-genome approaches to the discovery of anthelmintic resistance markers and the description of drug/receptor interactions

    Directory of Open Access Journals (Sweden)

    Andrew C. Kotze

    2014-12-01

    Full Text Available Anthelmintic resistance has a great impact on livestock production systems worldwide, is an emerging concern in companion animal medicine, and represents a threat to our ongoing ability to control human soil-transmitted helminths. The Consortium for Anthelmintic Resistance and Susceptibility (CARS provides a forum for scientists to meet and discuss the latest developments in the search for molecular markers of anthelmintic resistance. Such markers are important for detecting drug resistant worm populations, and indicating the likely impact of the resistance on drug efficacy. The molecular basis of resistance is also important for understanding how anthelmintics work, and how drug resistant populations arise. Changes to target receptors, drug efflux and other biological processes can be involved. This paper reports on the CARS group meeting held in August 2013 in Perth, Australia. The latest knowledge on the development of molecular markers for resistance to each of the principal classes of anthelmintics is reviewed. The molecular basis of resistance is best understood for the benzimidazole group of compounds, and we examine recent work to translate this knowledge into useful diagnostics for field use. We examine recent candidate-gene and whole-genome approaches to understanding anthelmintic resistance and identify markers. We also look at drug transporters in terms of providing both useful markers for resistance, as well as opportunities to overcome resistance through the targeting of the transporters themselves with inhibitors. Finally, we describe the tools available for the application of the newest high-throughput sequencing technologies to the study of anthelmintic resistance.

  11. Discovery of candidate disease genes in ENU-induced mouse mutants by large-scale sequencing, including a splice-site mutation in nucleoredoxin.

    Directory of Open Access Journals (Sweden)

    Melissa K Boles

    2009-12-01

    Full Text Available An accurate and precisely annotated genome assembly is a fundamental requirement for functional genomic analysis. Here, the complete DNA sequence and gene annotation of mouse Chromosome 11 was used to test the efficacy of large-scale sequencing for mutation identification. We re-sequenced the 14,000 annotated exons and boundaries from over 900 genes in 41 recessive mutant mouse lines that were isolated in an N-ethyl-N-nitrosourea (ENU mutation screen targeted to mouse Chromosome 11. Fifty-nine sequence variants were identified in 55 genes from 31 mutant lines. 39% of the lesions lie in coding sequences and create primarily missense mutations. The other 61% lie in noncoding regions, many of them in highly conserved sequences. A lesion in the perinatal lethal line l11Jus13 alters a consensus splice site of nucleoredoxin (Nxn, inserting 10 amino acids into the resulting protein. We conclude that point mutations can be accurately and sensitively recovered by large-scale sequencing, and that conserved noncoding regions should be included for disease mutation identification. Only seven of the candidate genes we report have been previously targeted by mutation in mice or rats, showing that despite ongoing efforts to functionally annotate genes in the mammalian genome, an enormous gap remains between phenotype and function. Our data show that the classical positional mapping approach of disease mutation identification can be extended to large target regions using high-throughput sequencing.

  12. Generation of ESTs in Vitis vinifera wine grape (Cabernet Sauvignon) and table grape (Muscat Hamburg) and discovery of new candidate genes with potential roles in berry development.

    Science.gov (United States)

    Peng, Fred Y; Reid, Karen E; Liao, Nancy; Schlosser, James; Lijavetzky, Diego; Holt, Robert; Martínez Zapater, José M; Jones, Steven; Marra, Marco; Bohlmann, Jörg; Lund, Steven T

    2007-11-01

    We report the generation and analysis of a total of 77,583 expressed sequence tags (ESTs) from two grapevine (Vitis vinifera L.) cultivars, Cabernet Sauvignon (wine grape) and Muscat Hamburg (table grape) with a focus on EST sequence quality and assembly optimization. The majority of the ESTs were derived from normalized cDNA libraries representing berry pericarp and seed developmental series, pooled non-berry tissues including root, flower, and leaf in Cabernet Sauvignon, and pooled tissues of berry, seed, and flower in Muscat Hamburg. EST and unigene sequence quality were determined by computational filtering coupled with small-scale contig reassembly, manual review, and BLAST analyses. EST assembly was optimized to better discriminate among closely related paralogs using two independent grape sequence sets, a previously published set of Vitis spp. gene families and our EST dataset derived from pooled leaf, flower, and root tissues of Cabernet Sauvignon. Sequence assembly within individual libraries indicated that those prepared from pooled tissues contributed the most to gene discovery. Annotations based upon searches against multiple databases including tomato and strawberry sequences helped to identify putative functions of ESTs and unigenes, particularly with respect to fleshy fruit development. Sequence comparison among the three wine grape libraries identified a number of genes preferentially expressed in the pericarp tissue, including transcription factors, receptor-like protein kinases, and hexose transporters. Gene ontology (GO) classification in the biological process aspect showed that GO categories corresponding to 'transport' and 'cell organization and biogenesis', which are associated with metabolite movement and cell wall structural changes during berry ripening, were higher in pericarp than in other tissues in the wine grape studied. The sequence data were used to characterize potential roles of new genes in berry development and composition. PMID

  13. Peripheral Biomarkers in Animal Models of Major Depressive Disorder

    Directory of Open Access Journals (Sweden)

    Lucia Carboni

    2013-01-01

    Full Text Available Investigations of preclinical biomarkers for major depressive disorder (MDD encompass the quantification of proteins, peptides, mRNAs, or small molecules in blood or urine of animal models. Most studies aim at characterising the animal model by including the assessment of analytes or hormones affected in depressive patients. The ultimate objective is to validate the model to better understand the neurobiological basis of MDD. Stress hormones or inflammation-related analytes associated with MDD are frequently measured. In contrast, other investigators evaluate peripheral analytes in preclinical models to translate the results in clinical settings afterwards. Large-scale, hypothesis-free studies are performed in MDD models to identify candidate biomarkers. Other studies wish to propose new targets for drug discovery. Animal models endowed with predictive validity are investigated, and the assessment of peripheral analytes, such as stress hormones or immune molecules, is comprised to increase the confidence in the target. Finally, since the mechanism of action of antidepressants is incompletely understood, studies investigating molecular alterations associated with antidepressant treatment may include peripheral analyte levels. In conclusion, preclinical biomarker studies aid the identification of new candidate analytes to be tested in clinical trials. They also increase our understanding of MDD pathophysiology and help to identify new pharmacological targets.

  14. Peripheral biomarkers in animal models of major depressive disorder.

    Science.gov (United States)

    Carboni, Lucia

    2013-01-01

    Investigations of preclinical biomarkers for major depressive disorder (MDD) encompass the quantification of proteins, peptides, mRNAs, or small molecules in blood or urine of animal models. Most studies aim at characterising the animal model by including the assessment of analytes or hormones affected in depressive patients. The ultimate objective is to validate the model to better understand the neurobiological basis of MDD. Stress hormones or inflammation-related analytes associated with MDD are frequently measured. In contrast, other investigators evaluate peripheral analytes in preclinical models to translate the results in clinical settings afterwards. Large-scale, hypothesis-free studies are performed in MDD models to identify candidate biomarkers. Other studies wish to propose new targets for drug discovery. Animal models endowed with predictive validity are investigated, and the assessment of peripheral analytes, such as stress hormones or immune molecules, is comprised to increase the confidence in the target. Finally, since the mechanism of action of antidepressants is incompletely understood, studies investigating molecular alterations associated with antidepressant treatment may include peripheral analyte levels. In conclusion, preclinical biomarker studies aid the identification of new candidate analytes to be tested in clinical trials. They also increase our understanding of MDD pathophysiology and help to identify new pharmacological targets. PMID:24167347

  15. Biomarkers for pancreatic carcinogenesis

    OpenAIRE

    Hustinx, S.R.

    2007-01-01

    Pancreatic cancer is a devastating disease. Most pancreatic cancers (approximately 85%) are diagnosed at a late, incurable stage. The poor prognosis and late presentation of pancreatic cancer patients underscore the importance of early detection, which is the sine qua non for the fight against pancreatic cancer. It is hoped for the future that the understanding of genetic alterations will lead to the rapid discovery of an effective biomarker of pancreatic carcinogenesis. In this thesis we vis...

  16. Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS

    Science.gov (United States)

    Su, Zhaoming; Zhang, Yongjie; Gendron, Tania F.; Bauer, Peter O.; Chew, Jeannie; Yang, Wang-Yong; Fostvedt, Erik; Jansen-West, Karen; Belzil, Veronique V.; Desaro, Pamela; Johnston, Amelia; Overstreet, Karen; Oh, Seok-Yoon; Todd, Peter K.; Berry, James D.; Cudkowicz, Merit E.; Boeve, Bradley F.; Dickson, Dennis; Floeter, Mary Kay; Traynor, Bryan J.; Morelli, Claudia; Ratti, Antonia; Silani, Vincenzo; Rademakers, Rosa; Brown, Robert H.; Rothstein, Jeffrey D.; Boylan, Kevin B.; Petrucelli, Leonard; Disney, Matthew D.

    2014-01-01

    Summary A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation producing “c9RAN proteins”. Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons trans-differentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic, and suggest c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp. PMID:25132468

  17. Core-shell hydrogel particles harvest, concentrate and preserve labile low abundance biomarkers.

    Directory of Open Access Journals (Sweden)

    Caterina Longo

    Full Text Available BACKGROUND: The blood proteome is thought to represent a rich source of biomarkers for early stage disease detection. Nevertheless, three major challenges have hindered biomarker discovery: a candidate biomarkers exist at extremely low concentrations in blood; b high abundance resident proteins such as albumin mask the rare biomarkers; c biomarkers are rapidly degraded by endogenous and exogenous proteinases. METHODOLOGY AND PRINCIPAL FINDINGS: Hydrogel nanoparticles created with a N-isopropylacrylamide based core (365 nm-shell (167 nm and functionalized with a charged based bait (acrylic acid were studied as a technology for addressing all these biomarker discovery problems, in one step, in solution. These harvesting core-shell nanoparticles are designed to simultaneously conduct size exclusion and affinity chromatography in solution. Platelet derived growth factor (PDGF, a clinically relevant, highly labile, and very low abundance biomarker, was chosen as a model. PDGF, spiked in human serum, was completely sequestered from its carrier protein albumin, concentrated, and fully preserved, within minutes by the particles. Particle sequestered PDGF was fully protected from exogenously added tryptic degradation. When the nanoparticles were added to a 1 mL dilute solution of PDGF at non detectable levels (less than 20 picograms per mL the concentration of the PDGF released from the polymeric matrix of the particles increased within the detection range of ELISA and mass spectrometry. Beyond PDGF, the sequestration and protection from degradation for a series of additional very low abundance and very labile cytokines were verified. CONCLUSIONS AND SIGNIFICANCE: We envision the application of harvesting core-shell nanoparticles to whole blood for concentration and immediate preservation of low abundance and labile analytes at the time of venipuncture.

  18. Immunohistochemistry in the Diagnosis of Mucinous Neoplasms Involving the Ovary: The Added Value of SATB2 and Biomarker Discovery Through Protein Expression Database Mining.

    Science.gov (United States)

    Strickland, Sarah; Wasserman, Jason K; Giassi, Ana; Djordjevic, Bojana; Parra-Herran, Carlos

    2016-05-01

    77.1% sensitivity and 99% specificity, outperforming tumor laterality and size. Second-line markers such as CDX2, MUC2, estrogen receptor, MUC1, and β-catenin increased the sensitivity of immunohistochemistry in excluding lower GI origin. Biomarker search using proteomic databases has a value in diagnostic pathology, as shown with SATB2; however, as seen with POF1B, expression profiles in these databases are not always reproduced in larger cohorts.

  19. Proteomic response of mussels Mytilus galloprovincialis exposed to CuO NPs and Cu²⁺: an exploratory biomarker discovery.

    Science.gov (United States)

    Gomes, Tânia; Chora, Suze; Pereira, Catarina G; Cardoso, Cátia; Bebianno, Maria João

    2014-10-01

    absence of the mussel genome precluded the identification of other proteins relevant to clarify the effects of CuO NPs in mussels' tissues, proteomics analysis provided additional knowledge of their potential effects at the protein level that after confirmation and validation can be used as putative new biomarkers in nanotoxicology.

  20. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Akitoshi, E-mail: akitoshi-tamura@ds-pharma.co.jp; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  1. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    International Nuclear Information System (INIS)

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  2. Proteomic response of mussels Mytilus galloprovincialis exposed to CuO NPs and Cu{sup 2+}: An exploratory biomarker discovery

    Energy Technology Data Exchange (ETDEWEB)

    Gomes, Tânia, E-mail: tania.gomes@niva.no; Chora, Suze; Pereira, Catarina G.; Cardoso, Cátia; Bebianno, Maria João

    2014-10-15

    the other hand, Cu{sup 2+} affected a protein associated with adhesion and mobility, precollagen-D that is associated with the detoxification mechanism of Cu{sup 2+}. Protein identification clearly showed that the toxicity of CuO NPs is not solely due to Cu{sup 2+} dissolution and can result in mitochondrial and nucleus stress-induced cell signalling cascades that can lead to apoptosis. While the absence of the mussel genome precluded the identification of other proteins relevant to clarify the effects of CuO NPs in mussels’ tissues, proteomics analysis provided additional knowledge of their potential effects at the protein level that after confirmation and validation can be used as putative new biomarkers in nanotoxicology.

  3. 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. PMID:26711276

  4. Resolving breast cancer heterogeneity by searching reliable protein cancer biomarkers in the breast fluid secretome

    International Nuclear Information System (INIS)

    One of the major goals in cancer research is to find and evaluate the early presence of biomarkers in human fluids and tissues. To resolve the complex cell heterogeneity of a tumor mass, it will be useful to characterize the intricate biomolecular composition of tumor microenvironment (the so called cancer secretome), validating secreted proteins as early biomarkers of cancer initiation and progression. This approach is not broadly applicable because of the paucity of well validated and FDA-approved biomarkers and because most of the candidate biomarkers are mainly organ-specific rather than tumor-specific. For these reasons, there is an urgent need to identify and validate a panel of biomarker combinations for early detection of human tumors. This is especially important for breast cancer, the cancer spread most worldwide among women. It is well known that patients with early diagnosed breast cancer live longer, require less extensive treatment and fare better than patients with more aggressive and/or advanced disease. In the frame of searching breast cancer biomarkers (especially using nipple aspirate fluid mirroring breast microenvironment), studies have highlighted an optimal combination of well-known biomarkers: uPA + PAI-1 + TF. When individually investigated they did not show perfect accuracy in predicting the presence of breast cancer, whereas the triple combination has been demonstrated to be highly predictive of pre-cancer and/or cancerous conditions, approaching 97-100% accuracy. Despite the heterogeneous composition of breast cancer and the difficulties to find specific breast cancer biomolecules, the noninvasive analysis of the nipple aspirate fluid secretome may significantly improve the discovery of promising biomarkers, helping also the differentiation among benign and invasive breast diseases, opening new frontiers in early oncoproteomics

  5. Analytical validation considerations of multiplex mass-spectrometry-based proteomic platforms for measuring protein biomarkers.

    Science.gov (United States)

    Boja, Emily S; Fehniger, Thomas E; Baker, Mark S; Marko-Varga, György; Rodriguez, Henry

    2014-12-01

    Protein biomarker discovery and validation in current omics era are vital for healthcare professionals to improve diagnosis, detect cancers at an early stage, identify the likelihood of cancer recurrence, stratify stages with differential survival outcomes, and monitor therapeutic responses. The success of such biomarkers would have a huge impact on how we improve the diagnosis and treatment of patients and alleviate the financial burden of healthcare systems. In the past, the genomics community (mostly through large-scale, deep genomic sequencing technologies) has been steadily improving our understanding of the molecular basis of disease, with a number of biomarker panels already authorized by the U.S. Food and Drug Administration (FDA) for clinical use (e.g., MammaPrint, two recently cleared devices using next-generation sequencing platforms to detect DNA changes in the cystic fibrosis transmembrane conductance regulator (CFTR) gene). Clinical proteomics, on the other hand, albeit its ability to delineate the functional units of a cell, more likely driving the phenotypic differences of a disease (i.e., proteins and protein-protein interaction networks and signaling pathways underlying the disease), "staggers" to make a significant impact with only an average ∼ 1.5 protein biomarkers per year approved by the FDA over the past 15-20 years. This statistic itself raises the concern that major roadblocks have been impeding an efficient transition of protein marker candidates in biomarker development despite major technological advances in proteomics in recent years.

  6. Proteomic Biomarkers of Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Natacha Diaz-Prieto

    2008-01-01

    Full Text Available Biomarkers provide a powerful approach to understanding the spectrum of cardiovascular diseases. They have application in screening, diagnostic, prognostication, prediction of recurrences and monitoring of therapy. The “omics” tool are becoming very useful in the development of new biomarkers in cardiovascular diseases. Among them, proteomics is especially fitted to look for new proteins in health and disease and is playing a significant role in the development of new diagnostic tools in cardiovascular diagnosis and prognosis. This review provides an overview of progress in applying proteomics to atherosclerosis. First, we describe novel proteins identified analysing atherosclerotic plaques directly. Careful analysis of proteins within the atherosclerotic vascular tissue can provide a repertoire of proteins involved in vascular remodelling and atherogenesis. Second, we discuss recent data concerning proteins secreted by atherosclerotic plaques. The definition of the atheroma plaque secretome resides in that proteins secreted by arteries can be very good candidates of novel biomarkers. Finally we describe proteins that have been differentially expressed (versus controls by individual cells which constitute atheroma plaques (endothelial cells, vascular smooth muscle cells, macrophages and foam cells as well as by circulating cells (monocytes, platelets or novel biomarkers present in plasma.

  7. Proteomic Biomarkers of Atherosclerosis.

    Science.gov (United States)

    Vivanco, F; Padial, L R; Darde, V M; de la Cuesta, F; Alvarez-Llamas, G; Diaz-Prieto, Natacha; Barderas, M G

    2008-01-01

    SUMMARY: Biomarkers provide a powerful approach to understanding the spectrum of cardiovascular diseases. They have application in screening, diagnostic, prognostication, prediction of recurrences and monitoring of therapy. The "omics" tool are becoming very useful in the development of new biomarkers in cardiovascular diseases. Among them, proteomics is especially fitted to look for new proteins in health and disease and is playing a significant role in the development of new diagnostic tools in cardiovascular diagnosis and prognosis. This review provides an overview of progress in applying proteomics to atherosclerosis. First, we describe novel proteins identified analysing atherosclerotic plaques directly. Careful analysis of proteins within the atherosclerotic vascular tissue can provide a repertoire of proteins involved in vascular remodelling and atherogenesis. Second, we discuss recent data concerning proteins secreted by atherosclerotic plaques. The definition of the atheroma plaque secretome resides in that proteins secreted by arteries can be very good candidates of novel biomarkers. Finally we describe proteins that have been differentially expressed (versus controls) by individual cells which constitute atheroma plaques (endothelial cells, vascular smooth muscle cells, macrophages and foam cells) as well as by circulating cells (monocytes, platelets) or novel biomarkers present in plasma. PMID:19578499

  8. Determination of burn patient outcome by large-scale quantitative discovery proteomics

    Science.gov (United States)

    Finnerty, Celeste C.; Jeschke, Marc G.; Qian, Wei-Jun; Kaushal, Amit; Xiao, Wenzhong; Liu, Tao; Gritsenko, Marina A.; Moore, Ronald J.; Camp, David G.; Moldawer, Lyle L.; Elson, Constance; Schoenfeld, David; Gamelli, Richard; Gibran, Nicole; Klein, Matthew; Arnoldo, Brett; Remick, Daniel; Smith, Richard D.; Davis, Ronald; Tompkins, Ronald G.; Herndon, David N.

    2013-01-01

    Objective Emerging proteomics techniques can be used to establish proteomic outcome signatures and to identify candidate biomarkers for survival following traumatic injury. We applied high-resolution liquid chromatography-mass spectrometry (LC-MS) and multiplex cytokine analysis to profile the plasma proteome of survivors and non-survivors of massive burn injury to determine the proteomic survival signature following a major burn injury. Design Proteomic discovery study. Setting Five burn hospitals across the U.S. Patients Thirty-two burn patients (16 non-survivors and 16 survivors), 19–89 years of age, were admitted within 96 h of injury to the participating hospitals with burns covering >20% of the total body surface area and required at least one surgical intervention. Interventions None. Measurements and Main Results We found differences in circulating levels of 43 proteins involved in the acute phase response, hepatic signaling, the complement cascade, inflammation, and insulin resistance. Thirty-two of the proteins identified were not previously known to play a role in the response to burn. IL-4, IL-8, GM-CSF, MCP-1, and β2-microglobulin correlated well with survival and may serve as clinical biomarkers. Conclusions These results demonstrate the utility of these techniques for establishing proteomic survival signatures and for use as a discovery tool to identify candidate biomarkers for survival. This is the first clinical application of a high-throughput, large-scale LC-MS-based quantitative plasma proteomic approach for biomarker discovery for the prediction of patient outcome following burn, trauma or critical illness. PMID:23507713

  9. The Role of Proteomics in Biomarker Development for Improved Patient Diagnosis and Clinical Decision Making in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Claire L. Tonry

    2016-07-01

    Full Text Available Prostate Cancer (PCa is the second most commonly diagnosed cancer in men worldwide. Although increased expression of prostate-specific antigen (PSA is an effective indicator for the recurrence of PCa, its intended use as a screening marker for PCa is of considerable controversy. Recent research efforts in the field of PCa biomarkers have focused on the identification of tissue and fluid-based biomarkers that would be better able to stratify those individuals diagnosed with PCa who (i might best receive no treatment (active surveillance of the disease; (ii would benefit from existing treatments; or (iii those who are likely to succumb to disease recurrence and/or have aggressive disease. The growing demand for better prostate cancer biomarkers has coincided with the development of improved discovery and evaluation technologies for multiplexed measurement of proteins in bio-fluids and tissues. This review aims to (i provide an overview of these technologies as well as describe some of the candidate PCa protein biomarkers that have been discovered using them; (ii address some of the general limitations in the clinical evaluation and validation of protein biomarkers; and (iii make recommendations for strategies that could be adopted to improve the successful development of protein biomarkers to deliver improvements in personalized PCa patient decision making.

  10. Development of a label-free LC-MS/MS strategy to approach the identification of candidate protein biomarkers of disease recurrence in prostate cancer patients in a clinical trial of combined hormone and radiation therapy.

    LENUS (Irish Health Repository)

    Morrissey, Brian

    2013-06-01

    Combined hormone and radiation therapy (CHRT) is one of the principle curative regimes for localised prostate cancer (PCa). Following treatment, many patients subsequently experience disease recurrence however; current diagnostics tests fail to predict the onset of disease recurrence. Biomarkers that address this issue would be of significant advantage.

  11. Empathy Development in Teacher Candidates

    Science.gov (United States)

    Boyer, Wanda

    2010-01-01

    Using a grounded theory research design, the author examined 180 reflective essays of teacher candidates who participated in a "Learning Process Project," in which they were asked to synthesize and document their discoveries about the learning process over the course of a completely new learning experience as naive learners. This study explored…

  12. Proteomics in biomarker discovery and drug development

    OpenAIRE

    He, Q.; Chiu, J

    2003-01-01

    Proteomics is a research field aiming to characterize molecular and cellular dynamics in protein expression and function on a global level. The introduction of proteomics has been greatly broadening our view and accelerating our path in various medical researches. The most significant advantage of proteomics is its ability to examine a whole proteome or sub-proteome in a single experiment so that the protein alterations corresponding to a pathological or biochemical condition at a given time ...

  13. Using Aptamers for Cancer Biomarker Discovery

    OpenAIRE

    Yun Min Chang; Donovan, Michael J; Weihong Tan

    2013-01-01

    Aptamers are single-stranded synthetic DNA- or RNA-based oligonucleotides that fold into various shapes to bind to a specific target, which includes proteins, metals, and molecules. Aptamers have high affinity and high specificity that are comparable to that of antibodies. They are obtained using iterative method, called (Systematic Evolution of Ligands by Exponential Enrichment) SELEX and cell-based SELEX (cell-SELEX). Aptamers can be paired with recent advances in nanotechnology, microarray...

  14. Proteomic Approaches for Biomarker Panels in Cancer.

    Science.gov (United States)

    Tanase, Cristiana; Albulescu, Radu; Neagu, Monica

    2016-01-01

    Proteomic technologies remain the main backbone of biomarkers discovery in cancer. The continuous development of proteomic technologies also enlarges the bioinformatics domain, thus founding the main pillars of cancer therapy. The main source for diagnostic/prognostic/therapy monitoring biomarker panels are molecules that have a dual role, being both indicators of disease development and therapy targets. Proteomic technologies, such as mass-spectrometry approaches and protein array technologies, represent the main technologies that can depict these biomarkers. Herein, we will illustrate some of the most recent strategies for biomarker discovery in cancer, including the development of immune-markers and the use of cancer stem cells as target therapy. The challenges of proteomic biomarker discovery need new forms of cross-disciplinary conglomerates that will result in increased and tailored access to treatments for patients; diagnostic companies would benefit from the enhanced co-development of companion diagnostics and pharmaceutical companies. In the technology optimization in biomarkers, immune assays are the leaders of discovery machinery. PMID:26565430

  15. Biomarkers in Barrett's esophagus.

    Science.gov (United States)

    Reid, Brian J; Blount, Patricia L; Rabinovitch, Peter S

    2003-04-01

    future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.

  16. Molecular biomarkers for grass pollen immunotherapy.

    Science.gov (United States)

    Popescu, Florin-Dan

    2014-03-26

    Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines.

  17. Potential blood biomarkers for stroke.

    Science.gov (United States)

    Laborde, Carlos M; Mourino-Alvarez, Laura; Akerstrom, Finn; Padial, Luis R; Vivanco, Fernando; Gil-Dones, Felix; Barderas, Maria G

    2012-08-01

    Stroke is one of the most common causes of death worldwide and a major cause of acquired disability in adults. Despite advances in research during the last decade, prevention and treatment strategies still suffer from significant limitations, and therefore new theoretical and technical approaches are required. Technological advances in the proteomic and metabolomic areas, during recent years, have permitted a more effective search for novel biomarkers and therapeutic targets that may allow for effective risk stratification and early diagnosis with subsequent rapid treatment. This review provides a comprehensive overview of the latest candidate proteins and metabolites proposed as new potential biomarkers in stroke. PMID:22967080

  18. Biomarkers in precision therapy in colorectal cancer

    OpenAIRE

    Reimers, Marlies S.; Zeestraten, Eliane C.M.; Kuppen, Peter J.K.; Liefers, Gerrit Jan; van de Velde, Cornelis J. H.

    2013-01-01

    Colorectal cancer (CRC) is the most commonly diagnosed cancer in Europe. Because CRC is also a major cause of cancer-related deaths worldwide, a lot of research has been focused on the discovery and development of biomarkers to improve the diagnostic process and to predict treatment outcomes. Up till now only a few biomarkers are recommended by expert panels. Current TNM criteria, however, cause substantial under- and overtreatment of CRC patients. Consequently, there is a growing need for ne...

  19. Accuracy of novel diagnostic biomarkers for hepatocellular carcinoma: An update for clinicians (Review).

    Science.gov (United States)

    Reichl, Patrick; Mikulits, Wolfgang

    2016-08-01

    Hepatocellular carcinoma (HCC) is the most common liver malignancy and a leading cause of cancer-related mortality worldwide. Accurate detection and differential diagnosis of early HCC can significantly improve patient survival. Currently, detection of HCC in clinical practice is performed by diagnostic imaging techniques and determination of serum biomarkers, most notably α-fetoprotein (AFP), fucosylated AFP and des-γ-carboxyprothrombin. However, these methods display limitations in sensitivity and specificity, especially with respect to early stages of HCC. Recently, high-throughput technologies have elucidated many new pathways involved in hepatocarcinogenesis and have led to the discovery of a plethora of novel, non-invasive serum biomarkers. In particular, the combination of AFP with these new candidate molecules has yielded promising results. In this review, we aimed at recapitulating the most recent (2013-2015) developments in HCC biomarker research. We compared promising novel diagnostic serum protein biomarkers, such as annexin A2, the soluble form of the receptor tyrosine kinase Axl and thioredoxin, as well as their combinations with AFP. High diagnostic performance (area under the curve >0.75) as shown by threshold-independent receiver operating characteristic curve analysis was a prerequisite for inclusion in this review. In addition, we discuss the role and potential of microRNAs in HCC diagnosis and associated methodological challenges. PMID:27278244

  20. Huntington's disease biomarker progression profile identified by transcriptome sequencing in peripheral blood.

    Science.gov (United States)

    Mastrokolias, Anastasios; Ariyurek, Yavuz; Goeman, Jelle J; van Duijn, Erik; Roos, Raymund A C; van der Mast, Roos C; van Ommen, GertJan B; den Dunnen, Johan T; 't Hoen, Peter A C; van Roon-Mom, Willeke M C

    2015-10-01

    With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington's disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington's disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington's disease and monitor disease progression in future clinical trials. PMID:25626709

  1. Exploring Biomarkers for Alzheimer's Disease.

    Science.gov (United States)

    Sharma, Neeti; Singh, Anshika Nikita

    2016-07-01

    Alzheimer's Disease (AD) is one of the most common form of dementia occurring in elderly population worldwide. Currently Aβ42, tau and p-tau in the cerebrospinal fluid is estimated for confirmation of AD. CSF which is being used as the potent source for biomarker screening is obtained by invasive lumbar punctures. Thus, there is an urgent need of minimal invasive methods for identification of diagnostic markers for early detection of AD. Blood serum and plasma serves as an appropriate source, due to minimal discomfort to the patients, promoting frequent testing, better follow-up and better consent to clinical trials. Hence, the need of the hour demands discovery of diagnostic and prognostic patient specific signature biomarkers by using emerging technologies of mass spectrometry, microarrays and peptidomics. In this review we summarize the present scenario of AD biomarkers such as circulatory biomarkers, blood based amyloid markers, inflammatory markers and oxidative stress markers being investigated and also some of the potent biomarkers which might be able to predict early onset of Alzheimer's and delay cognitive impairment. PMID:27630867

  2. Reverse phase protein array based tumor profiling identifies a biomarker signature for risk classification of hormone receptor-positive breast cancer

    Directory of Open Access Journals (Sweden)

    Johanna Sonntag

    2014-03-01

    Full Text Available A robust subclassification of luminal breast cancer, the most common molecular subtype of human breast cancer, is crucial for therapy decisions. While a part of patients is at higher risk of recurrence and requires chemo-endocrine treatment, the other part is at lower risk and also poorly responds to chemotherapeutic regimens. To approximate the risk of cancer recurrence, clinical guidelines recommend determining histologic grading and abundance of a cell proliferation marker in tumor specimens. However, this approach assigns an intermediate risk to a substantial number of patients and in addition suffers from a high interobserver variability. Therefore, the aim of our study was to identify a quantitative protein biomarker signature to facilitate risk classification. Reverse phase protein arrays (RPPA were used to obtain quantitative expression data for 128 breast cancer relevant proteins in a set of hormone receptor-positive tumors (n = 109. Proteomic data for the subset of histologic G1 (n = 14 and G3 (n = 22 samples were used for biomarker discovery serving as surrogates of low and high recurrence risk, respectively. A novel biomarker selection workflow based on combining three different classification methods identified caveolin-1, NDKA, RPS6, and Ki-67 as top candidates. NDKA, RPS6, and Ki-67 were expressed at elevated levels in high risk tumors whereas caveolin-1 was observed as downregulated. The identified biomarker signature was subsequently analyzed using an independent test set (AUC = 0.78. Further evaluation of the identified biomarker panel by Western blot and mRNA profiling confirmed the proteomic signature obtained by RPPA. In conclusion, the biomarker signature introduced supports RPPA as a tool for cancer biomarker discovery.

  3. Biomarkers for Primary Sjo¨ gren’s Syndrome

    Institute of Scientific and Technical Information of China (English)

    Weiqian Chen; Heng Cao; Jin Lin; Nancy Olsen; Song Guo Zheng

    2015-01-01

    Primary Sjogren’s syndrome (pSS) is a systemic autoimmune disease with exocrine gland dysfunction and multi-organ involvement. Recent progress in understanding the pathogenesis of pSS offers an opportunity to find new biomarkers for the diagnosis and assessment of disease activity. Screening noninvasive biomarkers from the saliva and tears has significant potential. The need for specific and sensitive biomarker candidates in pSS is significant. This review aims to summarize recent advances in the identification of biomarkers of Sjogren syndrome, trying to identify reliable, sensitive, and specific biomarkers that can be used to guide treatment decisions.

  4. Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates.

    Directory of Open Access Journals (Sweden)

    Irina A Zalenskaya

    Full Text Available Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides using a microarray gene expression profiling strategy.To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7 treated with well-characterized pro-inflammatory (PIC and non-inflammatory (NIC compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA.Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes.In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior

  5. 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.

  6. Novel biomarkers for cancer detection and prognostication

    NARCIS (Netherlands)

    Mehra, N.

    2007-01-01

    In this thesis we used a variety of approaches for biomarker discovery; in Part I we assessed whether we could identify a non-invasive surrogate markers of angiogenesis, as new vessel formation plays critical roles in the growth and metastatic spread of tumors. Moreover, many agents targeting the va

  7. Dissecting the proteome of lipoproteins: New biomarkers for cardiovascular diseases?

    Directory of Open Access Journals (Sweden)

    Anne von Zychlinski

    2015-06-01

    Full Text Available Proteomics has proven to be a powerful tool for the characterization of lipoproteins and has provided important insights into the biochemistry and pathophysiology of various lipoprotein classes. It has significantly contributed to the way we now see lipoproteins as complex particles not only involved in lipid transport and exchange, but also in processes such as immune response, inflammation and wound healing. Ongoing proteomics research is focussing on the identification of new candidate markers for cardiovascular disease, the leading cause of death worldwide. The ratio between good cholesterol (high density lipoprotein and bad cholesterol (low density lipoprotein is routinely used to estimate an individual’s risk for developing premature coronary heart disease. While statin therapy has proven effects in reducing cardiovascular events, other therapies such as resins, fibrates and niacin have failed to substantially reduce cardiovascular risk. Thus new targets and candidate biomarkers for risk assessment and for the development of alternative drugs and treatments of disease are needed. Here we review the recent findings in lipoprotein proteomics with the main emphasis on studies that differentially displayed various states of diseases and on new targeted, high throughput strategies with the capability to translate discovery findings into the clinical context of large cohort analyzes.

  8. Proteomic Profiling of Exosomes Leads to the Identification of Novel Biomarkers for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Duijvesz, Diederick; Burnum-Johnson, Kristin E.; Gritsenko, Marina A.; Hoogland, Marije; Vredenbregt-van den Berg, Mirella S.; Willemsen, Rob; Luider, Theo N.; Pasa-Tolic, Ljiljana; Jenster, Guido

    2013-12-31

    Introduction: Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, biomarker discovery from body fluids is often hampered by the high abundance of many proteins unrelated to disease. An attractive alternative biomarker discovery approach is the isolation of small vesicles (exosomes, ~100 nm). They contain proteins that are specific to the tissue from which they are derived and therefore can be considered as treasure chests for disease-specific marker discovery. Profiling prostate cancer-derived exosomes could reveal new markers for this malignancy. Materials and Methods: Exosomes were isolated from 2 immortalized primary prostate epithelial cells (PNT2C2 and RWPE-1) and 2 PCa cell lines (PC346C and VCaP) by ultracentrifugation. Proteomic analyses utilized a nanoLC coupled with an LTQ-Orbitrap operated in tandem MS (MS/MS) mode, followed by the Accurate Mass and Time (AMT) tag approach. Exosomal proteins were validated by Western blotting. A Tissue Micro Array, containing 481 different PCa samples (radical prostatectomy), was used to correlate candidate markers with several clinical-pathological parameters such as PSA, Gleason score, biochemical recurrence, and (PCa-related) death. Results: Proteomic characterization resulted in the identification of 263 proteins by at least 2 peptides. Specifically analysis of exosomes from PNT2C2, RWPE-1, PC346C, and VCaP identified 248, 233, 169, and 216 proteins, respectively. Statistical analyses revealed 52 proteins differently expressed between PCa and control cells, 9 of which were more abundant in PCa. Validation by Western blotting confirmed a higher abundance of FASN, XPO1 and PDCD6IP (ALIX) in PCa exosomes. The Tissue Micro 4 Array showed strong correlation of higher Gleason scores and local recurrence with increased cytoplasmic XPO1 (P<0.001). Conclusions: Differentially abundant proteins of cell line-derived exosomes make a clear subdivision between

  9. Biomarker-based dissection of neurodegenerative diseases.

    Science.gov (United States)

    Olsson, Bob; Zetterberg, Henrik; Hampel, Harald; Blennow, Kaj

    2011-12-01

    The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies.

  10. Comparison of proteomic biomarker panels in urine and serum for ovarian cancer diagnosis

    DEFF Research Database (Denmark)

    Petri, Anette Lykke; Simonsen, Anja Hviid; Høgdall, Estrid;

    2010-01-01

    The purposes of this study were to confirm previously found candidate epithelial ovarian cancer biomarkers in urine and to compare a paired serum biomarker panel and a urine biomarker panel from the same study cohort with regard to the receiver operating characteristic curve (ROC) area under the ...

  11. Current and novel biomarkers in anti-neutrophil cytoplasm-associated vasculitis.

    Science.gov (United States)

    Draibe, Juliana Bordignon; Fulladosa, Xavier; Cruzado, Josep Maria; Torras, Joan; Salama, Alan David

    2016-08-01

    Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is characterized by a variable disease course, with up to 50% of patients having one relapse within 5 years and many progressing to end-stage organ damage despite modern treatment strategies. Moreover, complications arising from treatment dominate the causes of mortality and morbidity both early and late during disease, especially in the elderly and those with severe renal involvement, and there is additional uncertainty as to how long treatment should be continued. There is, therefore, an urgent clinical need to identify robust biomarkers to better predict treatment responses, risk of disease relapse and eventual complete clinical and immunological quiescence. To date, no such biomarkers exist, but better understanding of disease pathogenesis and the underlying immune dysfunction has provided some potential candidates linked to the discovery of new antibodies, different leukocyte activation states, the role of the alternative complement pathway and markers of vascular activation. With all promising new biomarkers, there is the need to rapidly replicate and validate early findings using large biobanks of samples that could be brought together by leaders in the field.

  12. microRNAs as neuroregulators, biomarkers and therapeutic agents in neurodegenerative diseases.

    Science.gov (United States)

    Basak, Indranil; Patil, Ketan S; Alves, Guido; Larsen, Jan Petter; Møller, Simon Geir

    2016-02-01

    The last decade has experienced the emergence of microRNAs as a key molecular tool for the diagnosis and prognosis of human diseases. Although the focus has mostly been on cancer, neurodegenerative diseases present an exciting, yet less explored, platform for microRNA research. Several studies have highlighted the significance of microRNAs in neurogenesis and neurodegeneration, and pre-clinical studies have shown the potential of microRNAs as biomarkers. Despite this, no bona fide microRNAs have been identified as true diagnostic or prognostic biomarkers for neurodegenerative disease. This is mainly due to the lack of precisely defined patient cohorts and the variability within and between individual cohorts. However, the discovery that microRNAs exist as stable molecules at detectable levels in body fluids has opened up new avenues for microRNAs as potential biomarker candidates. Furthermore, technological developments in microRNA biology have contributed to the possible design of microRNA-mediated disease intervention strategies. The combination of these advancements, with the availability of well-defined longitudinal patient cohort, promises to not only assist in developing invaluable diagnostic tools for clinicians, but also to increase our overall understanding of the underlying heterogeneity of neurodegenerative diseases. In this review, we present a comprehensive overview of the existing knowledge of microRNAs in neurodegeneration and provide a perspective of the applicability of microRNAs as a basis for future therapeutic intervention strategies.

  13. Biomarkers of An Autoimmune Skin Disease-Psoriasis

    Institute of Scientific and Technical Information of China (English)

    Shan Jiang; Taylor E Hinchliffe; Tianfu Wu

    2015-01-01

    Psoriasis is one of the most prevalent autoimmune skin diseases. However, its etiology and pathogenesis are still unclear. Over the last decade, omics-based technologies have been exten-sively utilized for biomarker discovery. As a result, some promising markers for psoriasis have been identified at the genome, transcriptome, proteome, and metabolome level. These discoveries have provided new insights into the underlying molecular mechanisms and signaling pathways in psoriasis pathogenesis. More importantly, some of these markers may prove useful in the diagnosis of psoriasis and in the prediction of disease progression once they have been validated. In this review, we summarize the most recent findings in psoriasis biomarker discovery. In addition, we will discuss several emerging technologies and their potential for novel biomarker discovery and diagnostics for psoriasis.

  14. Volatility Discovery

    DEFF Research Database (Denmark)

    Dias, Gustavo Fruet; Scherrer, Cristina; Papailias, Fotis

    There is a large literature that investigates how homogenous securities traded on different markets incorporate new information (price discovery analysis). We extend this concept to the stochastic volatility process and investigate how markets contribute to the efficient stochastic volatility whi...

  15. Chronic Obstructive Pulmonary Disease Biomarkers

    Directory of Open Access Journals (Sweden)

    Tatsiana Beiko

    2016-04-01

    Full Text Available Despite significant decreases in morbidity and mortality of cardiovascular diseases (CVD and cancers, morbidity and cost associated with chronic obstructive pulmonary disease (COPD continue to be increasing. Failure to improve disease outcomes has been related to the paucity of interventions improving survival. Insidious onset and slow progression halter research successes in developing disease-modifying therapies. In part, the difficulty in finding new therapies is because of the extreme heterogeneity within recognized COPD phenotypes. Novel biomarkers are necessary to help understand the natural history and pathogenesis of the different COPD subtypes. A more accurate phenotyping and the ability to assess the therapeutic response to new interventions and pharmaceutical agents may improve the statistical power of longitudinal clinical studies. In this study, we will review known candidate biomarkers for COPD, proposed pathways of pathogenesis, and future directions in the field.

  16. Sparse discriminant analysis for breast cancer biomarker identification and classification

    Institute of Scientific and Technical Information of China (English)

    Yu Shi; Daoqing Dai; Chaochun Liu; Hong Yan

    2009-01-01

    Biomarker identification and cancer classification are two important procedures in microarray data analysis. We propose a novel uni-fied method to carry out both tasks. We first preselect biomarker candidates by eliminating unrelated genes through the BSS/WSS ratio filter to reduce computational cost, and then use a sparse discriminant analysis method for simultaneous biomarker identification and cancer classification. Moreover, we give a mathematical justification about automatic biomarker identification. Experimental results show that the proposed method can identify key genes that have been verified in biochemical or biomedical research and classify the breast cancer type correctly.

  17. Enthalpy screen of drug candidates.

    Science.gov (United States)

    Schön, Arne; Freire, Ernesto

    2016-11-15

    The enthalpic and entropic contributions to the binding affinity of drug candidates have been acknowledged to be important determinants of the quality of a drug molecule. These quantities, usually summarized in the thermodynamic signature, provide a rapid assessment of the forces that drive the binding of a ligand. Having access to the thermodynamic signature in the early stages of the drug discovery process will provide critical information towards the selection of the best drug candidates for development. In this paper, the Enthalpy Screen technique is presented. The enthalpy screen allows fast and accurate determination of the binding enthalpy for hundreds of ligands. As such, it appears to be ideally suited to aid in the ranking of the hundreds of hits that are usually identified after standard high throughput screening.

  18. Early biomarkers of joint damage in rheumatoid and psoriatic arthritis.

    LENUS (Irish Health Repository)

    Mc Ardle, Angela

    2015-01-01

    Joint destruction, as evidenced by radiographic findings, is a significant problem for patients suffering from rheumatoid arthritis and psoriatic arthritis. Inherently irreversible and frequently progressive, the process of joint damage begins at and even before the clinical onset of disease. However, rheumatoid and psoriatic arthropathies are heterogeneous in nature and not all patients progress to joint damage. It is therefore important to identify patients susceptible to joint destruction in order to initiate more aggressive treatment as soon as possible and thereby potentially prevent irreversible joint damage. At the same time, the high cost and potential side effects associated with aggressive treatment mean it is also important not to over treat patients and especially those who, even if left untreated, would not progress to joint destruction. It is therefore clear that a protein biomarker signature that could predict joint damage at an early stage would support more informed clinical decisions on the most appropriate treatment regimens for individual patients. Although many candidate biomarkers for rheumatoid and psoriatic arthritis have been reported in the literature, relatively few have reached clinical use and as a consequence the number of prognostic biomarkers used in rheumatology has remained relatively static for several years. It has become evident that a significant challenge in the transition of biomarker candidates to clinical diagnostic assays lies in the development of suitably robust biomarker assays, especially multiplexed assays, and their clinical validation in appropriate patient sample cohorts. Recent developments in mass spectrometry-based targeted quantitative protein measurements have transformed our ability to rapidly develop multiplexed protein biomarker assays. These advances are likely to have a significant impact on the validation of biomarkers in the future. In this review, we have comprehensively compiled a list of candidate

  19. 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

  20. Planets Around Low-Mass Stars (PALMS). VI. Discovery of a Remarkably Red Planetary-Mass Companion to the AB Dor Moving Group Candidate 2MASS J22362452+4751425

    CERN Document Server

    Bowler, Brendan; Mawet, Dimitri; Ngo, Henry; Malo, Lison; Mace, Gregory; McLane, Jacob; Lu, Jessica; Tristan, Isaiah; Hinkley, Sasha; Hillenbrand, Lynne; Shkolnik, Evgenya; Benneke, Bjorn; Best, William

    2016-01-01

    We report the discovery of an extremely red planetary-mass companion to 2MASS J22362452+4751425, a $\\approx$0.6 $M_{\\odot}$ late-K dwarf likely belonging to the $\\sim$120 Myr AB Doradus moving group. 2M2236+4751 b was identified in multi-epoch NIRC2 adaptive optics imaging at Keck Observatory at a separation of 3.7$"$, or 230 $\\pm$ 20 AU in projection at the kinematic distance of 63 $\\pm$ 5 pc to its host star. Assuming membership in the AB Dor group, as suggested from its kinematics, the inferred mass of 2M2236+4751 b is 11-14 $M_\\mathrm{Jup}$. Follow-up Keck/OSIRIS $K$-band spectroscopy of the companion reveals strong CO absorption similar to other faint red L dwarfs and lacks signs of methane absorption despite having an effective temperature of $\\approx$900-1200 K. With a ($J$-$K$)$_\\mathrm{MKO}$ color of 2.69 $\\pm$ 0.12 mag, the near-infrared slope of 2M2236+4751 b is redder than all of the HR 8799 planets and instead resembles the $\\approx$23 Myr isolated planetary-mass object PSO J318.5-22, implying th...

  1. Coronary Artery-Bypass-Graft Surgery Increases the Plasma Concentration of Exosomes Carrying a Cargo of Cardiac MicroRNAs: An Example of Exosome Trafficking Out of the Human Heart with Potential for Cardiac Biomarker Discovery.

    Directory of Open Access Journals (Sweden)

    Costanza Emanueli

    Full Text Available Exosome nanoparticles carry a composite cargo, including microRNAs (miRs. Cultured cardiovascular cells release miR-containing exosomes. The exosomal trafficking of miRNAs from the heart is largely unexplored. Working on clinical samples from coronary-artery by-pass graft (CABG surgery, we investigated if: 1 exosomes containing cardiac miRs and hence putatively released by cardiac cells increase in the circulation after surgery; 2 circulating exosomes and exosomal cardiac miRs correlate with cardiac troponin (cTn, the current "gold standard" surrogate biomarker of myocardial damage.The concentration of exosome-sized nanoparticles was determined in serial plasma samples. Cardiac-expressed (miR-1, miR-24, miR-133a/b, miR-208a/b, miR-210, non-cardiovascular (miR-122 and quality control miRs were measured in whole plasma and in plasma exosomes. Linear regression analyses were employed to establish the extent to which the circulating individual miRs, exosomes and exosomal cardiac miR correlated with cTn-I. Cardiac-expressed miRs and the nanoparticle number increased in the plasma on completion of surgery for up to 48 hours. The exosomal concentration of cardiac miRs also increased after CABG. Cardiac miRs in the whole plasma did not correlate significantly with cTn-I. By contrast cTn-I was positively correlated with the plasma exosome level and the exosomal cardiac miRs.The plasma concentrations of exosomes and their cargo of cardiac miRs increased in patients undergoing CABG and were positively correlated with hs-cTnI. These data provide evidence that CABG induces the trafficking of exosomes from the heart to the peripheral circulation. Future studies are necessary to investigate the potential of circulating exosomes as clinical biomarkers in cardiac patients.

  2. Beyond Discovery

    DEFF Research Database (Denmark)

    Korsgaard, Steffen; Sassmannshausen, Sean Patrick

    2015-01-01

    as their central concepts and conceptualization of the entrepreneurial function. On this basis we discuss three central themes that cut across the four alternatives: process, uncertainty, and agency. These themes provide new foci for entrepreneurship research and can help to generate new research questions......In this chapter we explore four alternatives to the dominant discovery view of entrepreneurship; the development view, the construction view, the evolutionary view, and the Neo-Austrian view. We outline the main critique points of the discovery presented in these four alternatives, as well...

  3. Planck cold clumps in the $\\lambda$ Orionis complex: I. Discovery of an extremely young Class 0 protostellar object and a proto-brown dwarf candidate in a bright rimmed clump PGCC G192.32-11.88

    CERN Document Server

    Liu, Tie; Kim, Kee-Tae; Wu, Yuefang; Lee, Chang Won; Lee, Jeong-Eun; Tatematsu, Kenichi; Choi, Minho; Juvela, Mika; Thompson, Mark; Goldsmith, Paul F; Liu, Sheng-yuan; Naomi, Hirano; Koch, Patrick; Henkel, Christian; Sanhueza, Patricio; He, JinHua; Rivera-Ingraham, Alana; Wang, Ke; Cunningham, Maria R; Tang, Ya-Wen; Lai, Shih-Ping; Yuan, Jinghua; Li, Di; Fuller, Gary; Kang, Miju; Luong, Quang Nguyen; Liu, Hauyu Baobab; Ristorcelli, Isabelle; Yang, Ji; Xu, Ye; Hirota, Tomoya; Mardones, Diego; Qin, Sheng-Li; Chen, Huei-Ru; Kwon, Woojin; Meng, FanYi; Zhang, Huawei; Kim, Mi-Ryang; Yi, Hee-Weon

    2015-01-01

    We are performing a series of observations with ground-based telescopes toward Planck Galactic cold clumps (PGCCs) in the $\\lambda$ Orionis complex in order to systematically investigate the effects of stellar feedback. In the particular case of PGCC G192.32-11.88, we discovered an extremely young Class 0 protostellar object (G192N) and a proto-brown dwarf candidate (G192S). G192N and G192S are located in a gravitationally bound bright-rimmed clump. The velocity and temperature gradients seen in line emission of CO isotopologues indicate that PGCC G192.32-11.88 is externally heated and compressed. G192N probably has the lowest bolometric luminosity ($\\sim0.8$ L$_{\\sun}$) and accretion rate (6.3$\\times10^{-7}$ M$_{\\sun}$~yr$^{-1}$) when compared with other young Class 0 sources (e.g. PACS Bright Red sources (PBRs)) in the Orion complex. It has slightly larger internal luminosity ($0.21\\pm0.01$ L$_{\\sun}$) and outflow velocity ($\\sim$14 km~s$^{-1}$) than the predictions of first hydrostatic cores (FHSCs). G192N...

  4. Biomarkers in Computational Toxicology

    Science.gov (United States)

    Biomarkers are a means to evaluate chemical exposure and/or the subsequent impacts on toxicity pathways that lead to adverse health outcomes. Computational toxicology can integrate biomarker data with knowledge of exposure, chemistry, biology, pharmacokinetics, toxicology, and e...

  5. 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....

  6. Detection of biomarkers for Hepatocellular Carcinoma using a hybrid univariate gene selection methods

    Directory of Open Access Journals (Sweden)

    Abdel Samee Nagwan M

    2012-08-01

    Full Text Available Abstract Background Discovering new biomarkers has a great role in improving early diagnosis of Hepatocellular carcinoma (HCC. The experimental determination of biomarkers needs a lot of time and money. This motivates this work to use in-silico prediction of biomarkers to reduce the number of experiments required for detecting new ones. This is achieved by extracting the most representative genes in microarrays of HCC. Results In this work, we provide a method for extracting the differential expressed genes, up regulated ones, that can be considered candidate biomarkers in high throughput microarrays of HCC. We examine the power of several gene selection methods (such as Pearson’s correlation coefficient, Cosine coefficient, Euclidean distance, Mutual information and Entropy with different estimators in selecting informative genes. A biological interpretation of the highly ranked genes is done using KEGG (Kyoto Encyclopedia of Genes and Genomes pathways, ENTREZ and DAVID (Database for Annotation, Visualization, and Integrated Discovery databases. The top ten genes selected using Pearson’s correlation coefficient and Cosine coefficient contained six genes that have been implicated in cancer (often multiple cancers genesis in previous studies. A fewer number of genes were obtained by the other methods (4 genes using Mutual information, 3genes using Euclidean distance and only one gene using Entropy. A better result was obtained by the utilization of a hybrid approach based on intersecting the highly ranked genes in the output of all investigated methods. This hybrid combination yielded seven genes (2 genes for HCC and 5 genes in different types of cancer in the top ten genes of the list of intersected genes. Conclusions To strengthen the effectiveness of the univariate selection methods, we propose a hybrid approach by intersecting several of these methods in a cascaded manner. This approach surpasses all of univariate selection methods when

  7. Biomarkers in T cell therapy clinical trials

    Directory of Open Access Journals (Sweden)

    Kalos Michael

    2011-08-01

    Full Text Available Abstract T cell therapy represents an emerging and promising modality for the treatment of both infectious disease and cancer. Data from recent clinical trials have highlighted the potential for this therapeutic modality to effect potent anti-tumor activity. Biomarkers, operationally defined as biological parameters measured from patients that provide information about treatment impact, play a central role in the development of novel therapeutic agents. In the absence of information about primary clinical endpoints, biomarkers can provide critical insights that allow investigators to guide the clinical development of the candidate product. In the context of cell therapy trials, the definition of biomarkers can be extended to include a description of parameters of the cell product that are important for product bioactivity. This review will focus on biomarker studies as they relate to T cell therapy trials, and more specifically: i. An overview and description of categories and classes of biomarkers that are specifically relevant to T cell therapy trials, and ii. Insights into future directions and challenges for the appropriate development of biomarkers to evaluate both product bioactivity and treatment efficacy of T cell therapy trials.

  8. Multiomics approach to identify novel biomarkers for dilated cardiomyopathy: Proteome and transcriptome analyses of 4C30 dilated cardiomyopathy mouse model.

    Science.gov (United States)

    Nishigori, Mitsuhiro; Yagi, Hiroaki; Mochiduki, Akikazu; Minamino, Naoto

    2016-11-01

    Dilated cardiomyopathy (DCM) is an intractable disease, without any radical treatment option other than cardiac transplantation. Additionally, biomarkers to determine progressive staging are not yet available. Irrespective of the diversity of causative gene mutations, the phenotype of DCM is rather common. Therefore, it is plausible to determine DCM staging in terms of variations in protein and mRNA levels. In this study, we performed proteome and transcriptome analysis of the left ventricle of 4C30 DCM model mice showing mild and severe phenotypes at 12 and 24 weeks (wk) after birth, respectively. Proteomic analyses results showed 109 proteins that increased and 133 others that decreased among 1874 detected proteins. We selected biomarker candidates by confirming consistent alterations in protein levels at 12 and 24 wk, and mRNA levels at 12 wk, and narrowed these down based on the requirement that they should be detectable in blood. Finally, we selected six biomarker candidates based on sustained or augmented alteration at 24 wk and confirmed their definite alterations in the left ventricle by quantitative polymerase chain reaction, western blot analysis, and multiple reaction monitoring (MRM). To assess the validity of this strategy, we measured plasma concentrations of the six candidates by MRM method and identified two proteins (FTL1 and GRP78) that demonstrated significant elevation in the 4C30 mice plasma. Taken together, a multiomics strategy comparing tissue expression levels of proteins and mRNAs between diseased and control groups, with appropriate confirmation, is a promising approach for the discovery of new biomarkers. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 491-502, 2016. PMID:26799926

  9. Biomarkers of Mercury Exposure in the Amazon

    OpenAIRE

    Nathália Santos Serrão de Castro; Marcelo de Oliveira Lima

    2014-01-01

    Mercury exposure in the Amazon has been studied since the 1980s decade and the assessment of human mercury exposure in the Amazon is difficult given that the natural occurrence of this metal is high and the concentration of mercury in biological samples of this population exceeds the standardized value of normality established by WHO. Few studies have focused on the discovery of mercury biomarkers in the region's population. In this way, some studies have used genetics as well as immunologica...

  10. Network-based drugs and biomarkers

    DEFF Research Database (Denmark)

    Erler, Janine Terra; Linding, Rune

    2010-01-01

    The structure and dynamics of protein signalling networks governs cell decision processes and the formation of tissue boundaries. Complex diseases such as cancer and diabetes are diseases of such networks. Therefore approaches that can give insight into how these networks change during disease...... associated technologies. We then focus on the multivariate nature of cellular networks and how this has implications for biomarker and drug discovery using cancer metastasis as an example....

  11. Macrophage-Derived Biomarkers of Idiopathic Pulmonary Fibrosis

    OpenAIRE

    P. Rottoli; Muller-Quernheim, J.; C. Olivieri; Bargagli, E.; Prasse, A.

    2011-01-01

    Idiopathic pulmonary fibrosis (IPF) is a severe, rapidly progressive diffuse lung disease. Several pathogenetic mechanisms have been hypothesized on the basis of the fibrotic lung damage occurring in this disease, and a potential profibrotic role of activated alveolar macrophages and their mediators in the pathogenesis of IPF was recently documented. This paper focuses on recent literature on potential biomarkers of IPF derived from activated alveolar macrophages. Biomarker discovery and clin...

  12. Biomarkers for Ectopic Pregnancy and Pregnancy of Unknown Location

    OpenAIRE

    Senapati, Suneeta; Barnhart, Kurt T.

    2013-01-01

    Early pregnancy failure is the most common complication of pregnancy, and 1–2% of all pregnancies will be ectopic. As one of the leading causes of maternal morbidity and mortality, diagnosing ectopic pregnancy and determining the fate of a pregnancy of unknown location are of great clinical concern. Several serum and plasma biomarkers for ectopic pregnancy have been investigated independently and in combination. The following is a review of the state of biomarker discovery and development for...

  13. 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.

  14. The ongoing quest for biomarkers in Ankylosing Spondylitis.

    Science.gov (United States)

    Danve, Abhijeet; O'Dell, James

    2015-11-01

    Ankylosing Spondylitis poses significant challenges in terms of early diagnosis, assessment of disease activity, predicting response to the treatment and monitoring radiographic progression. With better understanding of underlying immunopathogenesis, effective targeted therapies are available which improve symptoms, quality of life and possibly slow the radiographic progression. There has been a growing interest in the discovery of biomarkers for defining various aspects of disease assessment and management in Ankylosing Spondylitis. The C-reactive protein and HLA-B27 are most commonly used biomarkers. This review describes many other newer biomarkers which have potential clinical applications in this chronic inflammatory disease.

  15. Translational biomarkers of acetaminophen-induced acute liver injury.

    Science.gov (United States)

    Beger, Richard D; Bhattacharyya, Sudeepa; Yang, Xi; Gill, Pritmohinder S; Schnackenberg, Laura K; Sun, Jinchun; James, Laura P

    2015-09-01

    Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

  16. Exploring Biomarkers for Alzheimer’s Disease

    Science.gov (United States)

    Singh, Anshika Nikita

    2016-01-01

    Alzheimer’s Disease (AD) is one of the most common form of dementia occurring in elderly population worldwide. Currently Aβ42, tau and p-tau in the cerebrospinal fluid is estimated for confirmation of AD. CSF which is being used as the potent source for biomarker screening is obtained by invasive lumbar punctures. Thus, there is an urgent need of minimal invasive methods for identification of diagnostic markers for early detection of AD. Blood serum and plasma serves as an appropriate source, due to minimal discomfort to the patients, promoting frequent testing, better follow-up and better consent to clinical trials. Hence, the need of the hour demands discovery of diagnostic and prognostic patient specific signature biomarkers by using emerging technologies of mass spectrometry, microarrays and peptidomics. In this review we summarize the present scenario of AD biomarkers such as circulatory biomarkers, blood based amyloid markers, inflammatory markers and oxidative stress markers being investigated and also some of the potent biomarkers which might be able to predict early onset of Alzheimer’s and delay cognitive impairment. PMID:27630867

  17. Fish metalloproteins as biomarkers of environmental contamination.

    Science.gov (United States)

    Hauser-Davis, Rachel Ann; de Campos, Reinaldo Calixto; Ziolli, Roberta Lourenço

    2012-01-01

    Fish are well-recognized bioindicators of environmental contamination. Several recent proteomic studies have demonstrated the validity and value of using fish in the search and discovery of new biomarkers. Certain analytical tools, such as comparative protein expression analyses, both in field and lab exposure studies, have been used to improve the understanding of the potential for chemical pollutants to cause harmful effects. The metallomic approach is in its early stages of development, but has already shown great potential for use in ecological and environmental monitoring contexts. Besides discovering new metalloproteins that may be used as biomarkers for environmental contamination, metallomics can be used to more comprehensively elucidate existing biomarkers, which may enhance their effectiveness. Unfortunately, metallomic profiling for fish has not been explored, because only a few fish metalloproteins have thus far been discovered and studied. Of those that have, some have shown ecological importance, and are now successfully used as biomarkers of environmental contamination. These biomarkers have been shown to respond to several types of environmental contamination, such as cyanotoxins, metals, and sewage effluents, although many do not yet possess any known function. Examples of successes include MMPs, superoxide dismutases, selenoproteins, and iron-bound proteins. Unfortunately, none of these have, as yet, been extensively studied. As data are developed for them, valuable new information on their roles in fish physiology and in inducing environmental effects should become available.

  18. Validation of methylation biomarkers that distinguish normal colon mucosa of cancer patients from normal colon mucosa of patients without cancer.

    Science.gov (United States)

    Cesaroni, Matteo; Powell, Jasmine; Sapienza, Carmen

    2014-07-01

    We have validated differences in DNA methylation levels of candidate genes previously reported to discriminate between normal colon mucosa of patients with colon cancer and normal colon mucosa of individuals without cancer. Here, we report that CpG sites in 16 of the 30 candidate genes selected show significant differences in mean methylation level in normal colon mucosa of 24 patients with cancer and 24 controls. A support vector machine trained on these data and data for an additional 66 CpGs yielded an 18-gene signature, composed of ten of the validated candidate genes plus eight additional candidates. This model exhibited 96% sensitivity and 100% specificity in a 40-sample training set and classified all eight samples in the test set correctly. Moreover, we found a moderate-strong correlation (Pearson coefficients r = 0.253-0.722) between methylation levels in colon mucosa and methylation levels in peripheral blood for seven of the 18 genes in the support vector model. These seven genes, alone, classified 44 of the 48 patients in the validation set correctly and five CpGs selected from only two of the seven genes classified 41 of the 48 patients in the discovery set correctly. These results suggest that methylation biomarkers may be developed that will, at minimum, serve as useful objective and quantitative diagnostic complements to colonoscopy as a cancer-screening tool. These data also suggest that it may be possible to monitor biomarker methylation levels in tissues collected much less invasively than by colonoscopy. PMID:24806665

  19. Towards understanding and predicting suicidality in women: biomarkers and clinical risk assessment.

    Science.gov (United States)

    Levey, D F; Niculescu, E M; Le-Niculescu, H; Dainton, H L; Phalen, P L; Ladd, T B; Weber, H; Belanger, E; Graham, D L; Khan, F N; Vanipenta, N P; Stage, E C; Ballew, A; Yard, M; Gelbart, T; Shekhar, A; Schork, N J; Kurian, S M; Sandusky, G E; Salomon, D R; Niculescu, A B

    2016-06-01

    Women are under-represented in research on suicidality to date. Although women have a lower rate of suicide completion than men, due in part to the less-violent methods used, they have a higher rate of suicide attempts. Our group has previously identified genomic (blood gene expression biomarkers) and clinical information (apps) predictors for suicidality in men. We now describe pilot studies in women. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation (no SI) and high suicidal ideation (high SI) states (n=12 participants out of a cohort of 51 women psychiatric participants followed longitudinally, with diagnoses of bipolar disorder, depression, schizoaffective disorder and schizophrenia). We then used a Convergent Functional Genomics (CFG) approach to prioritize the candidate biomarkers identified in the discovery step by using all the prior evidence in the field. Next, we validated for suicidal behavior the top-ranked biomarkers for SI, in a demographically matched cohort of women suicide completers from the coroner's office (n=6), by assessing which markers were stepwise changed from no SI to high SI to suicide completers. We then tested the 50 biomarkers that survived Bonferroni correction in the validation step, as well as top increased and decreased biomarkers from the discovery and prioritization steps, in a completely independent test cohort of women psychiatric disorder participants for prediction of SI (n=33) and in a future follow-up cohort of psychiatric disorder participants for prediction of psychiatric hospitalizations due to suicidality (n=24). Additionally, we examined how two clinical instruments in the form of apps, Convergent Functional Information for Suicidality (CFI-S) and Simplified Affective State Scale (SASS), previously tested in men, perform in women. The top CFI-S item distinguishing high SI from no SI states was the chronic stress of social isolation. We

  20. Proteomic profiling of exosomes leads to the identification of novel biomarkers for prostate cancer

    NARCIS (Netherlands)

    D. Duijvesz (Diederick); K.E. Burnum-Johnson (Kristin); M.A. Gritsenko (Marina); A.M. Hoogland (Marije); M.S. Vredenbregt-van den Berg (Mirella); R. Willemsen (Rob); T.M. Luider (Theo); L. Paša-Tolić (Ljiljana); G.W. Jenster (Guido)

    2013-01-01

    textabstractBackground: Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, the complexity of body fluids often hampers biomarker discovery. An attractive alternative approach is the isolation of small vesicles, i.e. exosomes, ∼10

  1. Discovery Mondays

    CERN Document Server

    2003-01-01

    Many people don't realise quite how much is going on at CERN. Would you like to gain first-hand knowledge of CERN's scientific and technological activities and their many applications? Try out some experiments for yourself, or pick the brains of the people in charge? If so, then the «Lundis Découverte» or Discovery Mondays, will be right up your street. Starting on May 5th, on every first Monday of the month you will be introduced to a different facet of the Laboratory. CERN staff, non-scientists, and members of the general public, everyone is welcome. So tell your friends and neighbours and make sure you don't miss this opportunity to satisfy your curiosity and enjoy yourself at the same time. You won't have to listen to a lecture, as the idea is to have open exchange with the expert in question and for each subject to be illustrated with experiments and demonstrations. There's no need to book, as Microcosm, CERN's interactive museum, will be open non-stop from 7.30 p.m. to 9 p.m. On the first Discovery M...

  2. New serological biomarkers of inflammatory bowel disease.

    Science.gov (United States)

    Li, Xuhang; Conklin, Laurie; Alex, Philip

    2008-09-01

    Serological biomarkers in inflammatory bowel disease (IBD) are a rapidly expanding list of non-invasive tests for objective assessments of disease activity, early diagnosis, prognosis evaluation and surveillance. This review summarizes both old and new biomarkers in IBD, but focuses on the development and characterization of new serological biomarkers (identified since 2007). These include five new anti-glycan antibodies, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-manobioside IgG (AMCA), and antibodies against chemically synthesized (Sigma) two major oligomannose epitopes, Man alpha-1,3 Man alpha-1,2 Man (SigmaMan3) and Man alpha-1,3 Man alpha-1,2 Man alpha-1,2 Man (SigmaMan4). These new biomarkers serve as valuable complementary tools to existing biomarkers not only in differentiating Crohn's disease (CD), ulcerative colitis (UC), normal and other non-IBD gut diseases, but also in predicting disease involvement (ileum vs colon), IBD risk (as subclinical biomarkers), and disease course (risk of complication and surgery). Interestingly, the prevalence of the antiglycan antibodies, including anti-Saccharomyces cerevisiae antibodies (ASCA), ALCA and AMCA, was found to be associated with single nucleotide polymorphisms (SNPs) of IBD susceptible genes such as NOD2/CARD15, NOD1/CARD4, toll-like receptors (TLR) 2 and 4, and beta-defensin-1. Furthermore, a gene dosage effect was observed: anti-glycan positivity became more frequent as the number of NOD2/CARD15 SNPS increased. Other new serum/plasma IBD biomarkers reviewed include ubiquitination factor E4A (UBE4A), CXCL16 (a chemokine), resistin, and apolipoprotein A-IV. This review also discusses the most recent studies in IBD biomarker discovery by the application of new technologies such as proteomics, fourier transform near-infrared spectroscopy, and multiplex enzyme-linked immunosorbent assay (ELISA)'s (with an emphasis on cytokine/chemokine profiling). Finally, the prospects of developing more

  3. Biomarkers for wound healing and their evaluation.

    Science.gov (United States)

    Patel, S; Maheshwari, A; Chandra, A

    2016-01-01

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

  4. A New Serum Biomarker for Lung Cancer - Transthyretin

    Directory of Open Access Journals (Sweden)

    Liyun LIU

    2009-04-01

    Full Text Available Background and objective Lung cancer is the leading cause of cancer death worldwide and very few specific biomarkers could be used in clinical diagnosis at present. The aim of this study is to find novel potential serum biomarkers for lung cancer using Surface Enhanced Laser Desorption/Ionization (SELDI technique. Methods Serumsample of 227 cases including 146 lung cancer, 13 pneumonia, 28 tuberculous pleurisy and 40 normal individuals were analyzed by CM10 chips. The candidate biomarkers were identified by ESI/MS-MS and database searching, and further confirmed by immunoprecipitation. The same sets of serum sample from all groups were re-measured by ELISA assay. Results Three protein peaks with the molecular weight 13.78 kDa, 13.90 kDa and 14.07 kDa were found significantlydecreased in lung cancer serum compared to the other groups and were all automatically selected as specific biomarkers by Biomarker Wizard software. The candidate biomarkers obtained from 1-D SDS gel bands by matching the molecular weight with peaks on CM10 chips were identified by Mass spectrometry as the native transthyretin (nativeTTR, cysTTR and glutTTR, and the identity was further validated by immunoprecipitation using commercial TTR antibodies. Downregulated of TTR was found in both ELISA and SELDI analysis. Conclusion TTRs acted as the potentially useful biomarkers for lung cancer by SELDI technique.

  5. Various Approaches for Targeting Quasar Candidates

    Science.gov (United States)

    Zhang, Y.; Zhao, Y.

    2015-09-01

    With the establishment and development of space-based and ground-based observational facilities, the improvement of scientific output of high-cost facilities is still a hot issue for astronomers. The discovery of new and rare quasars attracts much attention. Different methods to select quasar candidates are in bloom. Among them, some are based on color cuts, some are from multiwavelength data, some rely on variability of quasars, some are based on data mining, and some depend on ensemble methods.

  6. Discovery pharmaceutics—Challenges and opportunities

    OpenAIRE

    Chen, Xue-Qing; Antman, Melissa D.; Gesenberg, Christoph; Gudmundsson, Olafur S.

    2006-01-01

    Most pharmaceutical companies are now evaluating compounds for druglike properties early in the discovery process. The data generated at these early stages allow upfront identification of potential development challenges and thus selection of the best candidates for lead nomination. Most often, lead nomination candidates are selected based on pharmacological and toxicological data. However, many drugs in development suffer from poor biopharmaceutical properties due to suboptimal physiochemica...

  7. ATLAS discoveries of optical transients : 4 supernova candidates

    Science.gov (United States)

    Tonry, J.; Denneau, L.; Stalder, B.; Heinze, A.; Sherstyuk, A.; Rest, A.; Smith, K. W.; Smartt, S. J.

    2016-06-01

    We report the following transients found by the ATLAS survey (see Tonry et al. ATel #8680). ATLAS is a twin 0.5m telescope system on Haleakala and Mauna Loa. The first unit is operational on Haleakala and is robotically surveying the sky. Two filters are used, cyan and orange (denoted c and o, all mags in AB system), more information is on http://www.fallingstar.com.

  8. ATLAS discoveries of optical transients : 6 supernova candidates

    Science.gov (United States)

    Tonry, J.; Denneau, L.; Stalder, B.; Heinze, A.; Sherstyuk, A.; Rest, A.; Smith, K. W.; Smartt, S. J.

    2016-06-01

    We report the following transients found by the ATLAS survey (see Tonry et al. ATel #8680). ATLAS is a twin 0.5m telescope system on Haleakala and Mauna Loa. The first unit is operational on Haleakala and is robotically surveying the sky. Two filters are used, cyan and orange (denoted c and o, all mags in AB system), more information is on http://www.fallingstar.com.

  9. Role of New Biomarkers: Functional and Structural Damage

    Directory of Open Access Journals (Sweden)

    Evdoxia Tsigou

    2013-01-01

    Full Text Available Traditional diagnosis of acute kidney injury (AKI depends on detection of oliguria and rise of serum creatinine level, which is an unreliable and delayed marker of kidney damage. Delayed diagnosis of AKI in the critically ill patient is related to increased morbidity and mortality, prolonged length of stay, and cost escalation. The discovery of a reliable biomarker for early diagnosis of AKI would be very helpful in facilitating early intervention, evaluating the effectiveness of therapy, and eventually reducing cost and improving outcome. Innovative technologies such as genomics and proteomics have contributed to the discovery of new biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL, cystatin C (Cys C, kidney injury molecule-1 (KIM-1, interleukin-18 (IL-18, and liver-type fatty acid binding protein (L-FABP. The current status of the most promising of these novel AKI biomarkers, including NGAL, Cys C, KIM-1, L-FABP, and IL-18, is reviewed.

  10. Novel technologies and emerging biomarkers for personalized cancer immunotherapy.

    Science.gov (United States)

    Yuan, Jianda; Hegde, Priti S; Clynes, Raphael; Foukas, Periklis G; Harari, Alexandre; Kleen, Thomas O; Kvistborg, Pia; Maccalli, Cristina; Maecker, Holden T; Page, David B; Robins, Harlan; Song, Wenru; Stack, Edward C; Wang, Ena; Whiteside, Theresa L; Zhao, Yingdong; Zwierzina, Heinz; Butterfield, Lisa H; Fox, Bernard A

    2016-01-01

    The culmination of over a century's work to understand the role of the immune system in tumor control has led to the recent advances in cancer immunotherapies that have resulted in durable clinical responses in patients with a variety of malignancies. Cancer immunotherapies are rapidly changing traditional treatment paradigms and expanding the therapeutic landscape for cancer patients. However, despite the current success of these therapies, not all patients respond to immunotherapy and even those that do often experience toxicities. Thus, there is a growing need to identify predictive and prognostic biomarkers that enhance our understanding of the mechanisms underlying the complex interactions between the immune system and cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) reconvened an Immune Biomarkers Task Force to review state of the art technologies, identify current hurdlers, and make recommendations for the field. As a product of this task force, Working Group 2 (WG2), consisting of international experts from academia and industry, assembled to identify and discuss promising technologies for biomarker discovery and validation. Thus, this WG2 consensus paper will focus on the current status of emerging biomarkers for immune checkpoint blockade therapy and discuss novel technologies as well as high dimensional data analysis platforms that will be pivotal for future biomarker research. In addition, this paper will include a brief overview of the current challenges with recommendations for future biomarker discovery.

  11. New serological biomarkers of inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Xuhang Li; Laurie Conldin; Philip Alex

    2008-01-01

    Serological biomarkers in inflammatory bowel disease(IBD)are a rapidty expanding list of non-invasive tests for objective assessments of disease activity,early diagnosis,prognosis evaluation and surveillance.This review summarizes both old and new biomarkers in IBD,but focuses on the development and characterization of new serological iomarkers(identified since 2007).These include five new anti-glycan antibodies,anti-chitobioside IgA(ACCA),anti-laminaribioside IgG(ALCA),anti-manobioside IgG(AMCA),and antibodies against chemically synthesized(∑)two major oligomannose epitopes,Man α-1,3 Man α-1,2 Man(∑Man3)and Man α-1,3 Man α-1,2 Man α-1,2 Man(∑Man4).These new biomarkers erve as valuable complementary tools to existing biomarkers not only in differentiating Crohn's disease(CD),ulcerative colitis(UC),normal and other non-IBD gut diseases,but also in predicting disease involvement(ileum vs colon),IBD risk(as subclinical biomarkers),and disease course(risk of complication and surgery).Interestingly,the prevalence of he antiglycan antibodies,including anti-Saccharomyces cerevisiae antibodies(ASCA),ALCA and AMCA,was found to be associated with single nucleotide polymorphisms(SNPs)of IBD susceptible genes such as NOD2/CARDl5,NOD1/CARD4,toll-like receptors(TLR)2 and 4,and β-defensin-1.Further more,a gene dosage effect was observed:anti-glycan positivity became more requent as the number of NOD2/CARDl5 SNPS increased.Other new serum/plasma IBD biomarkers reviewed include ubiquitination factor E4A(UBE4A),CXCL16(a chemokine),resistin,and apolipoprotein A-Ⅳ.This review also discusses the most recent studies in IBD biomarker discovery by the application of new technologies such as proteomics,fourier transform near-infrared spectroscopy,and multiplex enzyme-linked immunosorbent assay(ELISA)'s(with an emphasis on cytokine/chemokine profiling).Finally,the prospects of developing more clinically useful novel diagnostic algorithms by incorporating new technologies in

  12. Biomarkers in Autism

    Directory of Open Access Journals (Sweden)

    Robert eHendren

    2014-08-01

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

  13. Biomarkers of Hypoxic Ischemic Encephalopathy in Newborns

    Directory of Open Access Journals (Sweden)

    Martha V. Douglas-Escobar

    2012-11-01

    Full Text Available As neonatal intensive care has evolved, the focus has shifted from improving mortality alone to an effort to improve both mortality and morbidity. The most frequent source of neonatal brain injury occurs as a result of hypoxic-ischemic injury. Hypoxic-ischemic injury occurs in about 2 of 1,000 full-term infants and severe injured infants will have lifetime disabilities and neurodevelopmental delays. Most recently, remarkable efforts toward neuroprotection have been started with the advent of therapeutic hypothermia and a key step in the evolution of neonatal neuroprotection is the discovery of biomarkers that enable the clinician-scientist to screen infants for brain injury, monitor progression of disease, identify injured brain regions, and assess efficacy of neuroprotective clinical trials. Lastly, biomarkers offer great hope identifying when an injury occurred shedding light on the potential pathophysiology and the most effective therapy. In this article, we will review biomarkers of HIE including S100b, neuron specific enolase, umbilical cord IL-6, CK-BB, GFAP, myelin basic protein, UCHL-1, and pNF-H. We hope to contribute to the awareness, validation and clinical use of established as well as novel neonatal brain injury biomarkers.

  14. The Present and Future of Prostate Cancer Urine Biomarkers

    Directory of Open Access Journals (Sweden)

    Jeremy Clark

    2013-06-01

    Full Text Available In order to successfully cure patients with prostate cancer (PCa, it is important to detect the disease at an early stage. The existing clinical biomarkers for PCa are not ideal, since they cannot specifically differentiate between those patients who should be treated immediately and those who should avoid over-treatment. Current screening techniques lack specificity, and a decisive diagnosis of PCa is based on prostate biopsy. Although PCa screening is widely utilized nowadays, two thirds of the biopsies performed are still unnecessary. Thus the discovery of non-invasive PCa biomarkers remains urgent. In recent years, the utilization of urine has emerged as an attractive option for the non-invasive detection of PCa. Moreover, a great improvement in high-throughput “omic” techniques has presented considerable opportunities for the identification of new biomarkers. Herein, we will review the most significant urine biomarkers described in recent years, as well as some future prospects in that field.

  15. [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.

  16. Current and emerging breast cancer biomarkers

    Directory of Open Access Journals (Sweden)

    Maryam Sana

    2015-01-01

    Full Text Available Breast cancer treatment has experienced several advancements in the past few decades with the discovery of specific predictive and prognostic biomarkers that make possible the application of individualized therapies. In addition to traditional prognostic factors of breast carcinoma, molecular biomarkers have played a significant role in tumor prediction and treatment. The most frequent genetic alterations of breast cancer are gained along chromosome 1q, 8q, 17q, 20q, and 11q and losses along 8p, 13q, 16q, 18q, and 11q. Interestingly, many of these chromosomal fragments harbor known proto oncogenes or tumor suppressor genes such as BRCA1, BRCA2, p53, HER2-neu, cyclin D1, and cyclin E, which are briefly described in this review.

  17. APRIL is a novel clinical chemo-resistance biomarker in colorectal adenocarcinoma identified by gene expression profiling

    International Nuclear Information System (INIS)

    5-Fluorouracil(5FU) and oral analogues, such as capecitabine, remain one of the most useful agents for the treatment of colorectal adenocarcinoma. Low toxicity and convenience of administration facilitate use, however clinical resistance is a major limitation. Investigation has failed to fully explain the molecular mechanisms of resistance and no clinically useful predictive biomarkers for 5FU resistance have been identified. We investigated the molecular mechanisms of clinical 5FU resistance in colorectal adenocarcinoma patients in a prospective biomarker discovery project utilising gene expression profiling. The aim was to identify novel 5FU resistance mechanisms and qualify these as candidate biomarkers and therapeutic targets. Putative treatment specific gene expression changes were identified in a transcriptomics study of rectal adenocarcinomas, biopsied and profiled before and after pre-operative short-course radiotherapy or 5FU based chemo-radiotherapy, using microarrays. Tumour from untreated controls at diagnosis and resection identified treatment-independent gene expression changes. Candidate 5FU chemo-resistant genes were identified by comparison of gene expression data sets from these clinical specimens with gene expression signatures from our previous studies of colorectal cancer cell lines, where parental and daughter lines resistant to 5FU were compared. A colorectal adenocarcinoma tissue microarray (n = 234, resected tumours) was used as an independent set to qualify candidates thus identified. APRIL/TNFSF13 mRNA was significantly upregulated following 5FU based concurrent chemo-radiotherapy and in 5FU resistant colorectal adenocarcinoma cell lines but not in radiotherapy alone treated colorectal adenocarcinomas. Consistent withAPRIL's known function as an autocrine or paracrine secreted molecule, stromal but not tumour cell protein expression by immunohistochemistry was correlated with poor prognosis (p = 0.019) in the independent set

  18. Kepler Mission Discovers Trove of Extrasolar Planet Candidates

    Science.gov (United States)

    Showstack, Randy

    2011-02-01

    NASA's Kepler discovery mission is collecting more than just pennies from heaven. Results from the first 4 months of science operations of the Kepler space telescope, announced on 2 February, include the discovery of 1235 candidate planets orbiting 997 stars in a small portion of the Milky Way galaxy examined by the telescope. Follow-up observations likely could confirm about 80% of the candidates as actual planets rather than false positives, according to researchers. This new trove of possible exoplanets could greatly expand the number of known planets outside of our solar system.

  19. 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.

  20. Biomarkers in Severe Asthma.

    Science.gov (United States)

    Wan, Xiao Chloe; Woodruff, Prescott G

    2016-08-01

    Biomarkers have been critical for studies of disease pathogenesis and the development of new therapies in severe asthma. In particular, biomarkers of type 2 inflammation have proven valuable for endotyping and targeting new biological agents. Because of these successes in understanding and marking type 2 inflammation, lack of knowledge regarding non-type 2 inflammatory mechanisms in asthma will soon be the major obstacle to the development of new treatments and management strategies in severe asthma. Biomarkers can play a role in these investigations as well by providing insight into the underlying biology in human studies of patients with severe asthma. PMID:27401625

  1. Detection of novel biomarkers of liver cirrhosis by proteomic analysis

    DEFF Research Database (Denmark)

    Mölleken, Christian; Sitek, Barbara; Henkel, Corinna;

    2009-01-01

    Hepatic cirrhosis is a life-threatening disease arising from different chronic liver disorders. One major cause for hepatic cirrhosis is chronic hepatitis C. Chronic hepatitis C is characterized by a highly variable clinical course, with at least 20% developing liver cirrhosis within 40 years. Only...... serum levels in patients with hepatic cirrhosis of different causes. CONCLUSION: A quantitative analysis of MFAP-4 serum levels in a large number of patients showed MFAP-4 as novel candidate biomarker with high diagnostic accuracy for prediction of nondiseased liver versus cirrhosis [area under receiver...... liver biopsy allows a reliable evaluation of the course of hepatitis C by grading inflammation and staging fibrosis, and thus serum biomarkers for hepatic fibrosis with high sensitivity and specificity are needed. To identify new candidate biomarkers for hepatic fibrosis, we performed a proteomic...

  2. Characterization of potential ionizing radiation biomarkers by a proteomic approach

    Energy Technology Data Exchange (ETDEWEB)

    Guipaud, O.; Vereycken-Holler, V.; Benderitter, M. [Institut de Radioprotection et de Surete Nucleaire, Lab. de Radiopathologie, 92 - Fontenay aux Roses (France); Royer, N.; Vinh, J. [Ecole Superieure de Physique et de Chimie Industrielles, 75 - Paris (France)

    2006-07-01

    Radio-induced lesions are tissue specific, hardly predictable, and can arise months or years later. The finding of prognostic bio-markers is of fundamental relevance for the settlement of therapeutic or preventive strategies. Using two-dimensional gel electrophoresis and mass spectrometry, a proteomic study was applied to look for differentially expressed proteins, i.e. potential bio-markers candidates, in mouse serums after a local irradiation of the dorsal skin. Our results clearly indicated that serum protein content was dynamically modified after a local skin irradiation. A set of specific proteins were early down- or up-regulated and could turn out to be good candidates as diagnostic or prognostic bio-markers. (author)

  3. Teaching "Candide": A Debate.

    Science.gov (United States)

    Braun, Theodore E. D.; And Others

    1988-01-01

    Two different approaches to teaching Voltaire's "Candide", one deriving meaning from the textual fabric or "inside" of the story and the other focusing on the author's "external" intent in writing the story, are presented and compared. (MSE)

  4. MTR-18 Predictive Biomarkers Of Bevacizumab Response In Recurrent Glioblastoma Patients

    DEFF Research Database (Denmark)

    Urup, Thomas; Michaelsen, Signe Regner; Olsen, Lars Rønn;

    2015-01-01

    String platform covering 800 genes. Raw data was assigned to molecular subtypes for each of the samples using the PAMR classifier model, previously trained on the AVAglio dataset. By performing a t-test, comparing gene profiles of patients responding versus progressing on BEV novel candidate biomarkers were...... identified. Candidate biomarkers were analyzed by logistic regression and Cox regression modelling response and survival endpoints, respectively. Biomarkers associated with response were added to a prognostic model consisting of three independent prognostic factors: Corticosteroid use, neurocognitive deficit...

  5. 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.

  6. Biomarkers of alcohol misuse: recent advances and future prospects.

    Science.gov (United States)

    Jastrzębska, Iwona; Zwolak, Agnieszka; Szczyrek, Michał; Wawryniuk, Agnieszka; Skrzydło-Radomańska, Barbara; Daniluk, Jadwiga

    2016-01-01

    Alcohol abuse and dependence are highly prevalent in many cultures and contribute considerably to the global burden of health and social issues. The current inability to accurately characterise long-term drinking behaviours is a major obstacle to alcoholism diagnosis and treatment. Therefore, it is of great importance to develop objective diagnostic tools to discern subjects with excessive alcohol use and alcoholism or to confirm abstinence. Research over past years has revealed several biochemical compounds with considerable potential for accurate reflection of alcohol intake. This review will address the issue of alcohol biomarker definition, the types of molecules used as so-called traditional biomarkers, and the compounds that can serve as novel biomarker candidates or components of biomarker panels. PMID:27350834

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

    Directory of Open Access Journals (Sweden)

    Michael Centola

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

  8. Biomarkers for immune thrombocytopenia

    OpenAIRE

    Yu, Lingjia; Zhang, Chunmei; Zhang, Liping; Shi, Yongyu; Ji, Xuebin

    2015-01-01

    Immune thrombocytopenia is an autoimmune disease with abnormal biomarkers. Immune thrombocytopenia pathogenesis is a complicated process in which the patient’s immune system is activated by platelet autoantigens resulting in immune mediated platelet destruction or suppression of platelet production. The autoantibodies produced by autoreactive B cells against self antigens are considered to play a crucial role. In addition, biomarkers such as transforming growth factor-beta1,Toll-like receptor...

  9. Analytical strategies in lipidomics and applications in disease biomarker discovery

    NARCIS (Netherlands)

    Hu, C.; Heijden, R. van der; Wang, M.; Greef, J. van der; Hankemeier, T.; Xu, G.

    2009-01-01

    Lipidomics is a lipid-targeted metabolomics approach aiming at comprehensive analysis of lipids in biological systems. Recently, lipid profiling, or so-called lipidomics research, has captured increased attention due to the well-recognized roles of lipids in numerous human diseases to which lipid-as

  10. Novel automated biomarker discovery work flow for urinary peptidomics

    DEFF Research Database (Denmark)

    Balog, Crina I.; Hensbergen, Paul J.; Derks, Rico;

    2009-01-01

    eluted peptides using MALDI-TOF, Fourier transform ion cyclotron resonance, and liquid chromatography-iontrap mass spectrometry. We determined qualitative and quantitative reproducibility of the system and robustness of the method using BSA digests and urine samples, and we used a selected set of urine...... samples from Schistosoma haematobium-infected individuals to evaluate clinical applicability. RESULTS: The automated RP-SCX sample cleanup and fractionation system exhibits a high qualitative and quantitative reproducibility, with both BSA standards and urine samples. Because of the relatively high...

  11. Challenges in biomarker discovery with MALDI-TOF MS.

    Science.gov (United States)

    Hajduk, Joanna; Matysiak, Jan; Kokot, Zenon J

    2016-07-01

    MALDI-TOF MS technique is commonly used in system biology and clinical studies to search for new potential markers associated with pathological conditions. Despite numerous concerns regarding a sample preparation or processing of complex data, this strategy is still recognized as a popular tool and its awareness has risen in the proteomic community over the last decade. In this review, we present comprehensive application of MALDI mass spectrometry with special focus on profiling research. We also discuss major advantages and disadvantages of universal sample preparation methods such as micro-SPE columns, immunodepletion or magnetic beads, and we show the potential of nanostructured materials in capturing low molecular weight subproteomes. Furthermore, as the general protocol considerably affects spectra quality and interpretation, an alternative solution for improved ion detection, including hydrophobic constituents, data processing and statistical analysis is being considered in up-to-date profiling pattern. In conclusion, many reports involving MALDI-TOF MS indicated highly abundant proteins as valuable indicators, and at the same time showed the inaccuracy of available methods in the detection of low abundant proteome that is the most interesting from the clinical perspective. Therefore, the analytical aspects of sample preparation methods should be standardized to provide a reproducible, low sample handling and credible procedure. PMID:27134187

  12. Random glycopeptide bead libraries for seromic biomarker discovery

    DEFF Research Database (Denmark)

    Kracun, Stjepan Kresimir; Cló, Emiliano; Clausen, Henrik;

    2010-01-01

    have developed a random glycopeptide bead library screening platform for detection of autoantibodies and other binding proteins. Libraries were build on biocompatible PEGA beads including a safety-catch C-terminal amide linker (SCAL) that allowed mild cleavage conditions (I(2)/NaBH(4) and TFA) for...

  13. Sparse Mbplsr for Metabolomics Data and Biomarker Discovery

    DEFF Research Database (Denmark)

    Karaman, İbrahim

    2014-01-01

    the relationships between data-blocks and their contribution to predictive models. Among many variable selection techniques, we compared Sparse PLSR and Jack-knife PLSR according to the stability of the variable selection and the predictive ability. Further we used cross model validation (CMV) for assessing...... the importance of selected variables by plotting selection frequencies and correlation loading plots of the variables. In addition, predictive ability was studied by comparing errors of cross validation and CMV. According to the results, Sparse PLSR outperformed Jack-knife PLSR under the conditions tested. Jack-knife...... of noise is comparable to the signal, the Jack-Knife PLSR could be the better choice. Extension of Sparse PLSR to multi-block setting as Sparse MBPLSR (multi-block partial least squares regression) was implemented for analyzing metabolomics data from several analytical platforms. By Sparse MBPLSR, variable...

  14. 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

  15. Scrutinizing the Biomarkers for the Neglected Chagas Disease: How Remarkable!

    Science.gov (United States)

    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

  16. Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS

    OpenAIRE

    Otto, Markus; Bowser, Robert; Turner, Martin; Berry, James; Brettschneider, Johannes; Connor, James; Costa, Júlia; Cudkowicz, Merit; Glass, Jonathan; Jahn, Olaf; Lehnert, Stefan; Malaspina, Andrea; Parnetti, Lucilla; Petzold, Axel; Shaw, Pamela

    2012-01-01

    Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to t...

  17. Integrating biomarkers in colorectal cancer trials in the West and China.

    Science.gov (United States)

    Tejpar, Sabine; Shen, Lin; Wang, Xicheng; Schilsky, Richard L

    2015-09-01

    The discovery of biomarkers that provide information on drug efficacy is recognized as essential for successful and cost-effective treatment of cancer. However, biomarker discovery is difficult, and requires multiple independent studies to identify a target that serves as a suitable predictor of efficacy and to ensure appropriate biomarker validation. Clinical trials that are performed, sometimes sequentially, in Europe, the USA or Asia, are often similar in their design, in part owing to regulatory, marketing, or safety considerations. We believe some of these trials offer additional unique opportunities for biomarker discovery or validation. There are multiple hurdles to overcome, such as homogenous tissue acquisition and analysis, defining and aligning biomarker hypotheses across trials, and the need to adapt sample sizes and trial designs. Nevertheless, we believe that a collaborative engagement of the academic, regulatory and pharmaceutical community can go a long way in addressing these issues and producing more-rapid results in the field of personalized medicine. In this Perspectives, we describe our views on the current fragmented approach to biomarker discovery and validation in relevant trials run within our own regions-that is, Europe, China, and the USA-and hope this article serves as a base for further reflection. PMID:25963094

  18. 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.

  19. Human Cervicovaginal Fluid Biomarkers to Predict Term and Preterm Labour

    Directory of Open Access Journals (Sweden)

    Yujing Jan Heng

    2015-05-01

    Full Text Available Preterm birth (PTB; birth before 37 completed weeks of gestation remains the major cause of neonatal morbidity and mortality. The current generation of biomarkers predictive of PTB have limited utility. In pregnancy, the human cervicovaginal fluid (CVF proteome is a reflection of the local biochemical milieu and is influenced by the physical changes occurring in the vagina, cervix and adjacent overlying fetal membranes. Term and preterm labour (PTL share common pathways of cervical ripening, myometrial activation and fetal membranes rupture leading to birth. We therefore hypothesise that CVF biomarkers predictive of labour may be similar in both the term and preterm labour setting. In this review, we summarise some of the existing published literature as well as our team’s breadth of work utilising the CVF for the discovery and validation of putative CVF biomarkers predictive of human labour.Our team established an efficient method for collecting serial CVF samples for optimal 2-dimensional gel electrophoresis resolution and analysis. We first embarked on CVF biomarker discovery for the prediction of spontaneous onset of term labour using 2D-electrophoresis and solution array multiple analyte profiling. 2D-electrophoretic analyses were subsequently performed on CVF samples associated with PTB. Several proteins have been successfully validated and demonstrate that these biomarkers are associated with term and PTL and may be predictive of both term and PTL. In addition, the measurement of these putative biomarkers was found to be robust to the influences of vaginal microflora and/or semen. The future development of a multiple biomarker bed-side test would help improve the prediction of PTB and the clinical management of patients.

  20. 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

  1. 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

  2. Tools for GPCR drug discovery

    Institute of Scientific and Technical Information of China (English)

    Ru ZHANG; Xin XIE

    2012-01-01

    G-protein-coupled receptors (GPCRs) mediate many important physiological functions and are considered as one of the most successful therapeutic targets for a broad spectrum of diseases.The design and implementation of high-throughput GPCR assays that allow the cost-effective screening of large compound libraries to identify novel drug candidates are critical in early drug discovery.Early functional GPCR assays depend primarily on the measurement of G-protein-mediated 2nd messenger generation.Taking advantage of the continuously deepening understanding of GPCR signal transduction,many G-protein-independent pathways are utilized to detect the activity of GPCRs,and may provide additional information on functional selectivity of candidate compounds.With the combination of automated imaging systems and label-free detection systems,such assays are now suitable for high-throughput screening (HTS).In this review,we summarize the most widely used GPCR assays and recent advances in HTS technologies for GPCR drug discovery.

  3. Nanostructured optical microchips for cancer biomarker detection.

    Science.gov (United States)

    Zhang, Tianhua; He, Yuan; Wei, Jianjun; Que, Long

    2012-01-01

    Herein we report the label-free detection of a cancer biomarker using newly developed arrayed nanostructured Fabry-Perot interferometer (FPI) microchips. Specifically, the prostate cancer biomarker free prostate-specific antigen (f-PSA) has been detected with a mouse anti-human PSA monoclonal antibody (mAb) as the receptor. Experiments found that the limit-of-detection of current nanostructured FPI microchip for f-PSA is about 10 pg/mL and the upper detection range for f-PSA can be dynamically changed by varying the amount of the PSA mAb immobilized on the sensing surface. The control experiments have also demonstrated that the immunoassay protocol used in the experiments shows excellent specificity and selectivity, suggesting the great potential to detect the cancer biomarkers at trace levels in complex biofluids. In addition, given its nature of low cost, simple-to-operation and batch fabrication capability, the arrayed nanostructured FPI microchip-based platform could provide an ideal technical tool for point-of-care diagnostics application and anticancer drug screen and discovery.

  4. Primary and Presidential Candidates

    DEFF Research Database (Denmark)

    Goddard, Joseph

    2012-01-01

    This article looks at primary and presidential candidates in 2008 and 2012. Evidence suggests that voters are less influenced by candidates’ color, gender, or religious observation than previously. Conversely, markers of difference remain salient in the imaginations of pollsters and journalists...

  5. Planet Hunters VI: The First Kepler Seven Planet Candidate System and 13 Other Planet Candidates from the Kepler Archival Data

    CERN Document Server

    Schmitt, Joseph R; Fischer, Debra A; Jek, Kian J; Moriarty, John C; Boyajian, Tabetha S; Schwamb, Megan E; Lintott, Chris; Smith, Arfon M; Parrish, Michael; Schawinski, Kevin; Lynn, Stuart; Simpson, Robert; Omohundro, Mark; Winarski, Troy; Goodman, Samuel J; Jebson, Tony; Lacourse, Daryll

    2013-01-01

    We report the discovery of 14 new transiting planet candidates in the Kepler field from the Planet Hunters citizen science program. None of these candidates overlap with Kepler Objects of Interest (KOIs), and five of the candidates were missed by the Kepler Transit Planet Search (TPS) algorithm. The new candidates have periods ranging from 124-904 days, eight residing in their host star's habitable zone (HZ) and two (now) in multiple planet systems. We report the discovery of one more addition to the six planet candidate system around KOI-351, marking the first seven planet candidate system from Kepler. Additionally, KOI-351 bears some resemblance to our own solar system, with the inner five planets ranging from Earth to mini-Neptune radii and the outer planets being gas giants; however, this system is very compact, with all seven planet candidates orbiting $\\lesssim 1$ AU from their host star. We perform a numerical integration of the orbits and show that the system remains stable for over 100 million years....

  6. Biomarkers of the Dementia

    Directory of Open Access Journals (Sweden)

    Mikio Shoji

    2011-01-01

    Full Text Available Recent advances in biomarker studies on dementia are summarized here. CSF Aβ40, Aβ42, total tau, and phosphorylated tau are the most sensitive biomarkers for diagnosis of Alzheimer's disease (AD and prediction of onset of AD from mild cognitive impairment (MCI. Based on this progress, new diagnostic criteria for AD, MCI, and preclinical AD were proposed by National Institute of Aging (NIA and Alzheimer's Association in August 2010. In these new criteria, progress in biomarker identification and amyloid imaging studies in the past 10 years have added critical information. Huge contributions of basic and clinical studies have established clinical evidence supporting these markers. Based on this progress, essential therapy for cure of AD is urgently expected.

  7. Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma

    Science.gov (United States)

    Chauhan, Ranjit; Lahiri, Nivedita

    2016-01-01

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

  8. Prognostic factors and biomarkers of congenital obstructive nephropathy.

    Science.gov (United States)

    Chevalier, Robert L

    2016-09-01

    Congenital obstructive nephropathy (CON) is the leading cause of chronic kidney disease (CKD) in children. Anomalies of the urinary tract are often associated with abnormal nephrogenesis, which is compounded by obstructive injury and by maternal risk factors associated with low birth weight. Currently available fetal and postnatal imaging and analytes of amniotic fluid, urine, or blood lack predictive value. For ureteropelvic junction obstruction, biomarkers are needed for optimal timing of pyeloplasty; for posterior urethral valves, biomarkers of long-term prognosis and CKD are needed. The initial nephron number may be a major determinant of progression of CKD, and most patients with CON who progress to renal failure reach this point in adulthood, presumably compounded by episodes of acute kidney injury. Biomarkers of tubular injury may be of particular value in predicting the need for surgical intervention or in tracking progression of CKD, and must be adjusted for patient age. Discovery of new biomarkers may depend on "unbiased" proteomics, whereby patterns of urinary peptide fragments from patients with CON are analyzed in comparison to controls. Most promising are the analysis of urinary exosomes (restricting biomarkers to relevant tubular cells) and quantitative magnetic resonance imaging techniques allowing precise determination of nephron number and tubular mass. The greatest need is for large prospective multicenter studies with centralized biomarker sample repositories to follow patients with CON from fetal life through adulthood. PMID:26667236

  9. MicroRNA Biomarkers of Toxicity in Biological Matrices.

    Science.gov (United States)

    Harrill, Alison H; McCullough, Shaun D; Wood, Charles E; Kahle, Juliette J; Chorley, Brian N

    2016-08-01

    Biomarker measurements that reliably correlate with tissue injury and that can be measured within accessible biofluids offer benefits in terms of cost, time, and convenience when assessing chemical and drug-induced toxicity in model systems or human cohorts. MicroRNAs (miRNAs) have emerged in recent years as a promising new class of biomarker for monitoring toxicity. Recent enthusiasm for miRNA biomarker research has been fueled by evidence that certain miRNAs are cell-type specific and are released during injury, thus raising the possibility of using biofluid-based miRNAs as a "liquid biopsy" that may be obtained by sampling extracellular fluids. As biomarkers, miRNAs demonstrate improved stability as compared with many protein markers and sequences are largely conserved across species, simplifying analytical techniques. Recent efforts have sought to identify miRNAs that are released into accessible biofluids following xenobiotic exposure, using compounds that target specific organs. Whereas still early in the discovery phase, miRNA biomarkers will have an increasingly important role in the assessment of adverse effects of both environmental chemicals and pharmaceutical drugs. Here, we review the current findings of biofluid-based miRNAs, as well as highlight technical challenges in assessing toxicologic pathology using these biomarkers. PMID:27462126

  10. Glial biomarkers in human central nervous system disease.

    Science.gov (United States)

    Garden, Gwenn A; Campbell, Brian M

    2016-10-01

    There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments. GLIA 2016;64:1755-1771. PMID:27228454

  11. The potential of circulating extracellular small RNAs (smexRNA) in veterinary diagnostics-Identifying biomarker signatures by multivariate data analysis.

    Science.gov (United States)

    Melanie, Spornraft; Benedikt, Kirchner; Pfaffl, Michael W; Irmgard, Riedmaier

    2015-09-01

    Worldwide growth and performance-enhancing substances are used in cattle husbandry to increase productivity. In certain countries however e.g., in the EU, these practices are forbidden to prevent the consumers from potential health risks of substance residues in food. To maximize economic profit, 'black sheep' among farmers might circumvent the detection methods used in routine controls, which highlights the need for an innovative and reliable detection method. Transcriptomics is a promising new approach in the discovery of veterinary medicine biomarkers and also a missing puzzle piece, as up to date, metabolomics and proteomics are paramount. Due to increased stability and easy sampling, circulating extracellular small RNAs (smexRNAs) in bovine plasma were small RNA-sequenced and their potential to serve as biomarker candidates was evaluated using multivariate data analysis tools. After running the data evaluation pipeline, the proportion of miRNAs (microRNAs) and piRNAs (PIWI-interacting small non-coding RNAs) on the total sequenced reads was calculated. Additionally, top 10 signatures were compared which revealed that the readcount data sets were highly affected by the most abundant miRNA and piRNA profiles. To evaluate the discriminative power of multivariate data analyses to identify animals after veterinary drug application on the basis of smexRNAs, OPLS-DA was performed. In summary, the quality of miRNA models using all mapped reads for both treatment groups (animals treated with steroid hormones or the β-agonist clenbuterol) is predominant to those generated with combined data sets or piRNAs alone. Using multivariate projection methodologies like OPLS-DA have proven the best potential to generate discriminative miRNA models, supported by small RNA-Seq data. Based on the presented comparative OPLS-DA, miRNAs are the favorable smexRNA biomarker candidates in the research field of veterinary drug abuse.

  12. Biomarkers in the pathogenesis, diagnosis, and treatment of psoriasis

    Directory of Open Access Journals (Sweden)

    Molteni S

    2012-09-01

    Full Text Available Silvia Molteni, Eva RealiLaboratory of Translational Immunology, Istituto Ortopedico Galeazzi, Milan, ItalyAbstract: Development of psoriasis results from a complex interplay between genetically predisposing factors and environmental triggers that give rise to a self-sustaining pathogenic cycle involving T cells, dendritic cells, connective tissue, and skin epithelium. From 5% to 40% of patients with psoriasis also develop psoriatic arthritis, and increasing evidence indicates an association with other systemic manifestations, including cardiovascular disease and the metabolic syndrome. In psoriatic disease, there is a need for development of biomarkers for assessment of disease severity, for prediction of the outcome of therapeutic interventions, and for distinction between the different clinical variants of the disease. A field of great importance is identification of biomarkers for prediction of development of comorbidities, such as arthritis, cardiovascular disease, and the metabolic syndrome. Genetic determinants of psoriasis and their products not only give an important insight into the pathogenesis of the disease, but may also function as markers of risk for developing cutaneous psoriasis or psoriatic arthritis. So far, there are limited validation data to support the use of candidate biomarkers in clinical practice. Here we review the data from several studies on some of the most promising candidate biomarkers for cutaneous psoriasis and psoriatic arthritis, for the detection of systemic inflammation, and for use as endpoints for therapeutic interventions. Attention is focused on the molecules that take part in the interplay giving rise to psoriasis and on gene products that may represent a link between predisposing genetic factors and the immune and inflammatory processes involved in pathogenesis of the disease. Finally, we provide an overview on how biomarkers can offer insights into the pathogenesis and natural history of psoriasis

  13. Biomarkers in the early diagnosis of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    CHEN Sheng-di

    2013-08-01

    Full Text Available Parkinson's disease (PD is a chronic and progressive neurodegenerative disorder. It has become clear that PD can have a preclinical phase, a period during which neurodegeneration has already begun years before the onset of typical motor symptoms. Consequently, if the early neurodegeneration in PD can be timely diagnosed, it will significantly slow down the progression of the disease and improve the quality of life. To date, there is no fully reliable and validated biomarker for the early diagnosis of PD, but some promising biomarker candidates exist.

  14. 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.

  15. Investigation of a hepatotoxicity screening system in primary cell cultures --"what biomarkers would need to be addressed to estimate toxicity in conventional and new approaches?".

    Science.gov (United States)

    Kikkawa, Rie; Yamamoto, Toshinori; Fukushima, Tamio; Yamada, Hiroshi; Horii, Ikuo

    2005-02-01

    High throughput toxicological estimation is required for safety evaluation in the early stage of drug discovery. In this context, establishment of an in vitro screening system reflecting in vivo toxicity is demanded for earlier safety assessment. We investigated LDH release and mitochondrial respiration (WST-1 reduction assay; WST-1) to detect cytotoxicity, morphological evaluation, and proteomics for estimating the reliable and sensitive biomarkers by using rat primary hepatocytes exposed to the compounds (acetaminophen, amiodarone, tetracycline and carbon tetrachloride) that are known to induce hepatotoxicity. In LDH release, no significant difference was detected between the control and compound exposed cells after exposure for 3 or 6 hr, but a dose-dependent increase was observed after exposure for 24 hr. Regarding the WST-1 assay, a dose-dependent reduction was detected after exposure for 6 and 24 hr to all of the compounds evaluated. In the proteomics analysis, 31 candidate proteins were identified from among the 103 demonstrating altered expression spots after exposure to acetaminophen. It was concluded that the cytotoxicity was detected earlier by measuring WST-1 than by measuring LDH release because the reduction of mitochondrial respiration is an expressions of earlier toxicity for cellular function, while the measured increase in the LDH release occurs after the failure of the cell membrane. Mitochondrial respiration ability was a useful parameter for cytotoxicity in in vitro hepato-toxicity screening, as cytotoxicity can be detected during the early stage of exposure. In addition to the conventional biomarkers, several protein biomarkers which relate to oxidative stress and metabolism-regulation were detected. Further comprehensive analysis of defined proteins would be necessary to estimate the more sensitive toxicology biomarker. PMID:15800402

  16. Investigational biomarkers for pancreatic adenocarcinoma: where do we stand?

    Science.gov (United States)

    Datta, Jashodeep; Vollmer, Charles M

    2014-04-01

    Although the outcomes for pancreatic ductal adenocarcinoma (PDAC) remain disappointing, there has been considerable improvement in the 5-year survival rate of patients with resectable disease. As such, an R0 surgical resection (microscopic tumor clearance) offers patients with PDAC the greatest survival benefit. Carbohydrate antigen 19-9, the only US Food and Drug Administration-approved biomarker for PDAC, is a poor screening tool and is most informative after PDAC resection. Consequently, there has been a tremendous initiative to discover novel biomarkers that may aid in detecting the disease earlier, improving prognosis, and predicting response to available chemotherapy. The number of implicated biomarkers in PDAC is indeed staggering, with >2500 proposed candidates presented in the recent literature. A vast majority of these biomarkers, however, remain in the investigational phase. This review categorizes the most promising biomarkers--those closest to potential clinical application--into diagnostic and prognostic/predictive groups. The greatest challenge likely lies in the search for an effective diagnostic biomarker that can accurately discriminate between malignant and benign disease, and thereby facilitate earlier identification of those patients with PDAC who may benefit most from surgical resection. PMID:24937521

  17. 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.

  18. Update on Biomarkers for the Detection of Endometriosis

    Directory of Open Access Journals (Sweden)

    Amelie Fassbender

    2015-01-01

    Full Text Available Endometriosis is histologically characterized by the displacement of endometrial tissue to extrauterine locations including the pelvic peritoneum, ovaries, and bowel. An important cause of infertility and pelvic pain, the individual and global socioeconomic burden of endometriosis is significant. Laparoscopy remains the gold standard for the diagnosis of the condition. However, the invasive nature of surgery, coupled with the lack of a laboratory biomarker for the disease, results in a mean latency of 7–11 years from onset of symptoms to definitive diagnosis. Unfortunately, the delay in diagnosis may have significant consequences in terms of disease progression. The discovery of a sufficiently sensitive and specific biomarker for the nonsurgical detection of endometriosis promises earlier diagnosis and prevention of deleterious sequelae and represents a clear research priority. In this review, we describe and discuss the current status of biomarkers of endometriosis in plasma, urine, and endometrium.

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

    Science.gov (United States)

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

    2016-01-01

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

  20. Role of New Biomarkers: Functional and Structural Damage

    OpenAIRE

    Evdoxia Tsigou; Vasiliki Psallida; Christos Demponeras; Eleni Boutzouka; George Baltopoulos

    2013-01-01

    Traditional diagnosis of acute kidney injury (AKI) depends on detection of oliguria and rise of serum creatinine level, which is an unreliable and delayed marker of kidney damage. Delayed diagnosis of AKI in the critically ill patient is related to increased morbidity and mortality, prolonged length of stay, and cost escalation. The discovery of a reliable biomarker for early diagnosis of AKI would be very helpful in facilitating early intervention, evaluating the effectiveness of therapy, an...

  1. Strategies for modern biomarker and drug development in oncology

    OpenAIRE

    Alan D. Smith; Roda, Desam; Yap, Timothy A.

    2014-01-01

    Technological advancements in the molecular characterization of cancers have enabled researchers to identify an increasing number of key molecular drivers of cancer progression. These discoveries have led to multiple novel anticancer therapeutics, and clinical benefit in selected patient populations. Despite this, the identification of clinically relevant predictive biomarkers of response continues to lag behind. In this review, we discuss strategies for the molecular characterization of canc...

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

    OpenAIRE

    Jordan, Rick; Visweswaran, Shyam; Gopalakrishnan, Vanathi

    2014-01-01

    Background Computational methods for mining of biomedical literature can be useful in augmenting manual searches of the literature using keywords for disease-specific biomarker discovery from biofluids. In this work, we develop and apply a semi-automated literature mining method to mine abstracts obtained from PubMed to discover putative biomarkers of breast and lung cancers in specific biofluids. Methodology A positive set of abstracts was defined by the terms ‘breast cancer’ and ‘lung cance...

  3. Neuroimaging Biomarkers for Psychosis

    Science.gov (United States)

    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

  4. Biomarkers for personalized oncology: recent advances and future challenges.

    Science.gov (United States)

    Kalia, Madhu

    2015-03-01

    Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells and oncology is a branch of medicine that deals with tumors. The last decade has seen significant advances in the development of biomarkers in oncology that play a critical role in understanding molecular and cellular mechanisms which drive tumor initiation, maintenance and progression. Clinical molecular diagnostics and biomarker discoveries in oncology are advancing rapidly as we begin to understand the complex mechanisms that transform a normal cell into an abnormal one. These discoveries have fueled the development of novel drug targets and new treatment strategies. The standard of care for patients with advanced-stage cancers has shifted away from an empirical treatment strategy based on the clinical-pathological profile to one where a biomarker driven treatment algorithm based on the molecular profile of the tumor is used. Recent advances in multiplex genotyping technologies and high-throughput genomic profiling by next-generation sequencing make possible the rapid and comprehensive analysis of the cancer genome of individual patients even from very little tumor biopsy material. Predictive (diagnostic) biomarkers are helpful in matching targeted therapies with patients and in preventing toxicity of standard (systemic) therapies. Prognostic biomarkers identify somatic germ line mutations, changes in DNA methylation, elevated levels of microRNA (miRNA) and circulating tumor cells (CTC) in blood. Predictive biomarkers using molecular diagnostics are currently in use in clinical practice of personalized oncotherapy for the treatment of five diseases: chronic myeloid leukemia, colon, breast, lung cancer and melanoma and these biomarkers are being used successfully to evaluate benefits that can be achieved through targeted therapy. Examples of these molecularly targeted biomarker therapies are: tyrosine kinase inhibitors in chronic myeloid leukemia and

  5. Virtual drug discovery: beyond computational chemistry?

    Science.gov (United States)

    Gilardoni, Francois; Arvanites, Anthony C

    2010-02-01

    This editorial looks at how a fully integrated structure that performs all aspects in the drug discovery process, under one company, is slowly disappearing. The steps in the drug discovery paradigm have been slowly increasing toward virtuality or outsourcing at various phases of product development in a company's candidate pipeline. Each step in the process, such as target identification and validation and medicinal chemistry, can be managed by scientific teams within a 'virtual' company. Pharmaceutical companies to biotechnology start-ups have been quick in adopting this new research and development business strategy in order to gain flexibility, access the best technologies and technical expertise, and decrease product developmental costs. In today's financial climate, the term virtual drug discovery has an organizational meaning. It represents the next evolutionary step in outsourcing drug development.

  6. Sputum-Based Molecular Biomarkers for the Early Detection of Lung Cancer: Limitations and Promise

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Connie E. [Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine. 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Tchou-Wong, Kam-Meng; Rom, William N., E-mail: william.rom@nyumc.org [Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine. 462 First Avenue, NBV 7N24, New York, NY 10016 (United States); Department of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987 (United States)

    2011-07-19

    Lung cancer is the leading cause of cancer deaths, with an overall survival of 15% at five years. Biomarkers that can sensitively and specifically detect lung cancer at early stage are crucial for improving this poor survival rate. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes or field cancerization caused by smoking in the lung. Sputum-based molecular biomarkers include morphology, allelic imbalance, promoter hypermethylation, gene mutations and, recently, differential miRNA expression. To improve the sensitivity and reproducibility of sputum-based biomarkers, we recommend standardization of processing protocols, bronchial epithelial cell enrichment, and identification of field cancerization biomarkers.

  7. Sputum-Based Molecular Biomarkers for the Early Detection of Lung Cancer: Limitations and Promise

    International Nuclear Information System (INIS)

    Lung cancer is the leading cause of cancer deaths, with an overall survival of 15% at five years. Biomarkers that can sensitively and specifically detect lung cancer at early stage are crucial for improving this poor survival rate. Sputum has been the target for the discovery of non-invasive biomarkers for lung cancer because it contains airway epithelial cells, and molecular alterations identified in sputum are most likely to reflect tumor-associated changes or field cancerization caused by smoking in the lung. Sputum-based molecular biomarkers include morphology, allelic imbalance, promoter hypermethylation, gene mutations and, recently, differential miRNA expression. To improve the sensitivity and reproducibility of sputum-based biomarkers, we recommend standardization of processing protocols, bronchial epithelial cell enrichment, and identification of field cancerization biomarkers

  8. Spectroscopy of candidate electromagnetic counterparts to gravitational wave sources

    CERN Document Server

    Steele, Iain A; Piascik, Andrzej S

    2016-01-01

    A programme of worldwide, multi-wavelength electromagnetic follow-up of sources detected by gravitational wave detectors is in place. Following the discovery of GW150914 and GW151226, wide field imaging of their sky localisations identified a number of candidate optical counterparts which were then spectrally classified. The majority of candidates were found to be supernovae at redshift ranges similar to the GW events and were thereby ruled out as a genuine counterpart. Other candidates ruled out include AGN and solar system objects. Given the GW sources were black hole binary mergers, the lack of an identified electromagnetic counterpart is not surprising. However the observations show that is it is possible to organise and execute a campaign that can eliminate the majority of potential counterparts. Finally we note the existence of a "classification gap" with a significant fraction of candidates going unclassified.

  9. Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Platinum Chemotherapy in Muscle Invasive Urothelial Carcinoma.

    Directory of Open Access Journals (Sweden)

    Alexander S Baras

    Full Text Available The 5-year cancer specific survival (CSS for patients with muscle invasive urothelial carcinoma of the bladder (MIBC treated with cystectomy alone is approximately 50%. Platinum based neoadjuvant chemotherapy (NAC plus cystectomy results in a marginal 5-10% increase in 5-year CSS in MIBC. Interestingly, responders to NAC (candidate protein based biomarkers detectable by immunohistochemistry (IHC. These candidate biomarkers were subsequently tested in tissue microarrays derived from an independent cohort of NAC naive MIBC biopsy specimens from whom the patients were treated with neoadjuvant gemcitabine cisplatin NAC and subsequent cystectomy. The clinical parameters that have been previously associated with NAC response were also examined in our cohort.Our analyses of the available mRNA gene expression data in a discovery cohort (n = 33 and the HPA resulted in 8 candidate protein biomarkers. The combination of GDPD3 and SPRED1 resulted in a multivariate classification tree that was significantly associated with NAC response status (Goodman-Kruskal γ = 0.85 p<0.0001 in our independent NAC treated MIBC cohort. This model was independent of the clinical factors of age and clinical tumor stage, which have been previously associated with NAC response by our group. The combination

  10. Biomarkers of Ovarian Reserve

    Directory of Open Access Journals (Sweden)

    William E. Roudebush

    2008-01-01

    Full Text Available The primary function of the female ovary is the production of a mature and viable oocyte capable of fertilization and subsequent embryo development and implantation. At birth, the ovary contains a finite number of oocytes available for folliculogenesis. This finite number of available oocytes is termed “the ovarian reserve”. The determination of ovarian reserve is important in the assessment and treatment of infertility. As the ovary ages, the ovarian reserve will decline. Infertility affects approximately 15-20% of reproductive aged couples. The most commonly used biomarker assay to assess ovarian reserve is the measurement of follicle stimulating hormone (FSH on day 3 of the menstrual cycle. However, antimüllerian hormone and inhibin-B are other biomarkers of ovarian reserve that are gaining in popularity since they provide direct determination of ovarian status, whereas day 3 FSH is an indirect measurement. This review examines the physical tools and the hormone biomarkers used to evaluate ovarian reserve.

  11. Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children

    Science.gov (United States)

    Hathout, Yetrib; Conklin, Laurie S.; Seol, Haeri; Gordish-Dressman, Heather; Brown, Kristy J.; Morgenroth, Lauren P.; Nagaraju, Kanneboyina; Heier, Christopher R.; Damsker, Jesse M.; van den Anker, John N.; Henricson, Erik; Clemens, Paula R.; Mah, Jean K.; McDonald, Craig; Hoffman, Eric P.

    2016-01-01

    Corticosteroids are extensively used in pediatrics, yet the burden of side effects is significant. Availability of a simple, fast, and reliable biochemical read out of steroidal drug pharmacodynamics could enable a rapid and objective assessment of safety and efficacy of corticosteroids and aid development of corticosteroid replacement drugs. To identify potential corticosteroid responsive biomarkers we performed proteome profiling of serum samples from DMD and IBD patients with and without corticosteroid treatment using SOMAscan aptamer panel testing 1,129 proteins in FGG). These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids. Known safety concerns were validated, including elevated non-fasting insulin (insulin resistance), and elevated angiotensinogen (salt retention). These were extended by new candidates for metabolism disturbances (leptin, afamin), stunting of growth (growth hormone binding protein), and connective tissue remodeling (MMP3). Significant suppression of multiple adrenal steroid hormones was also seen in treated children (reductions of 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol and testosterone). A panel of new pharmacodynamic biomarkers for corticosteroids in children was defined. Future studies will need to bridge specific biomarkers to mechanism of drug action, and specific clinical outcomes. PMID:27530235

  12. Alzheimer’s disease biomarkers in animal models: closing the translational gap

    OpenAIRE

    Sabbagh, Jonathan J.; Kinney, Jefferson W.; Cummings, Jeffrey L.

    2013-01-01

    The rising prevalence of Alzheimer’s disease (AD) is rapidly becoming one of the largest health and economic challenges in the world. There is a growing need for the development and implementation of reliable biomarkers for AD that can be used to assist in diagnosis, inform disease progression, and monitor therapeutic efficacy. Preclinical models permit the evaluation of candidate biomarkers and assessment of pipeline agents before clinical trials are initiated and provide a translational opp...

  13. Computational drug discovery

    Institute of Scientific and Technical Information of China (English)

    Si-sheng OU-YANG; Jun-yan LU; Xiang-qian KONG; Zhong-jie LIANG; Cheng LUO; Hualiang JIANG

    2012-01-01

    Computational drug discovery is an effective strategy for accelerating and economizing drug discovery and development process.Because of the dramatic increase in the availability of biological macromolecule and small molecule information,the applicability of computational drug discovery has been extended and broadly applied to nearly every stage in the drug discovery and development workflow,including target identification and validation,lead discovery and optimization and preclinical tests.Over the past decades,computational drug discovery methods such as molecular docking,pharmacophore modeling and mapping,de novo design,molecular similarity calculation and sequence-based virtual screening have been greatly improved.In this review,we present an overview of these important computational methods,platforms and successful applications in this field.

  14. Computational protein biomarker prediction: a case study for prostate cancer

    Directory of Open Access Journals (Sweden)

    Adam Bao-Ling

    2004-03-01

    Full Text Available Abstract Background Recent technological advances in mass spectrometry pose challenges in computational mathematics and statistics to process the mass spectral data into predictive models with clinical and biological significance. We discuss several classification-based approaches to finding protein biomarker candidates using protein profiles obtained via mass spectrometry, and we assess their statistical significance. Our overall goal is to implicate peaks that have a high likelihood of being biologically linked to a given disease state, and thus to narrow the search for biomarker candidates. Results Thorough cross-validation studies and randomization tests are performed on a prostate cancer dataset with over 300 patients, obtained at the Eastern Virginia Medical School using SELDI-TOF mass spectrometry. We obtain average classification accuracies of 87% on a four-group classification problem using a two-stage linear SVM-based procedure and just 13 peaks, with other methods performing comparably. Conclusions Modern feature selection and classification methods are powerful techniques for both the identification of biomarker candidates and the related problem of building predictive models from protein mass spectrometric profiles. Cross-validation and randomization are essential tools that must be performed carefully in order not to bias the results unfairly. However, only a biological validation and identification of the underlying proteins will ultimately confirm the actual value and power of any computational predictions.

  15. Reliable knowledge discovery

    CERN Document Server

    Dai, Honghua; Smirnov, Evgueni

    2012-01-01

    Reliable Knowledge Discovery focuses on theory, methods, and techniques for RKDD, a new sub-field of KDD. It studies the theory and methods to assure the reliability and trustworthiness of discovered knowledge and to maintain the stability and consistency of knowledge discovery processes. RKDD has a broad spectrum of applications, especially in critical domains like medicine, finance, and military. Reliable Knowledge Discovery also presents methods and techniques for designing robust knowledge-discovery processes. Approaches to assessing the reliability of the discovered knowledge are introduc

  16. 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

    2013-09-01

    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.

  17. Biomarker analysis of Morquio syndrome: identification of disease state and drug responsive markers

    Directory of Open Access Journals (Sweden)

    Martell Lisa

    2011-12-01

    Full Text Available Abstract Background This study was conducted to identify potential biomarkers that could be used to evaluate disease progression and monitor responses to enzyme replacement therapy (ERT in patients with mucopolysaccharidosis (MPS IVA. Methods Levels of 88 candidate biomarkers were compared in plasma samples from 50 healthy controls and 78 MPSIVA patients not receiving ERT to test for significant correlations to the presence of MPSIVA. MPSIVA samples were also tested for correlations between candidate biomarkers and age, endurance, or urinary keratin sulfate (KS levels. Then, levels of the same 88 analytes were followed over 36 weeks in 20 MPSIVA patients receiving ERT to test for significant correlations related to ERT, age, or endurance. Results Nineteen candidate biomarkers were significantly different between MPSIVA and unaffected individuals. Of these, five also changed significantly in response to ERT: alpha-1-antitrypsin, eotaxin, lipoprotein(a, matrix metalloprotein (MMP-2, and serum amyloid P. Three of these were significantly lower in MPSIVA individuals versus unaffected controls and were increased during ERT: alpha-1-antitrypsin, lipoprotein(a, and serum amyloid P. Conclusions Candidate biomarkers alpha-1-antitrypsin, lipoprotein(a, and serum amyloid P may be suitable markers, in addition to urinary KS, to follow the response to ERT in MPSIVA patients.

  18. 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.

  19. Leveraging Big Data to Transform Target Selection and Drug Discovery

    Science.gov (United States)

    Chen, B; Butte, AJ

    2016-01-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. PMID:26659699

  20. Leveraging big data to transform target selection and drug discovery

    Science.gov (United States)

    Butte, AJ

    2016-01-01

    The advances of genomics, sequencing, and high throughput technologies have led to the creation of large volumes of diverse datasets for drug discovery. Analyzing these datasets to better understand disease and discover new drugs is becoming more common. Recent open data initiatives in basic and clinical research have dramatically increased the types of data available to the public. The past few years have witnessed successful use of big data in many sectors across the whole drug discovery pipeline. In this review, we will highlight the state of the art in leveraging big data to identify new targets, drug indications, and drug response biomarkers in this era of precision medicine. PMID:26659699

  1. Undercover Stars Among Exoplanet Candidates

    Science.gov (United States)

    2005-03-01

    events by monitoring the brightness of a very large number of stars over extended time intervals. During the past years, it has also included a search for periodic, very shallow "dips" in the brightness of stars, caused by the regular transit of small orbiting objects (small stars, brown dwarfs [2] or Jupiter-size planets). The OGLE team has since announced 177 "planetary transit candidates" from their survey of several hundred thousand stars in three southern sky fields, one in the direction of the Galactic Centre, another within the Carina constellation and the third within the Centaurus/Musca constellations. The nature of the transiting object can however only be established by subsequent radial-velocity observations of the parent star. The size of the velocity variations (the amplitude) is directly related to the mass of the companion object and therefore allows discrimination between stars and planets as the cause of the observed brightness "dip". A Bonanza of Low-Mass Stars An international team of astronomers [3] has made use of the 8.2-m VLT Kueyen telescope for this work. Profiting from the multiplex capacity of the FLAMES/UVES facility that permits to obtain high-resolution spectra of up to 8 objects simultaneously, they have looked at 60 OGLE transit candidate stars, measuring their radial velocities with an accuracy of about 50 m/s [4]. This ambitious programme has so far resulted in the discovery of five new transiting exoplanets (see, e.g., ESO PR 11/04 for the announcement of two of those). Most of the other transit candidates identified by OGLE have turned out to be eclipsing binaries, that is, in most cases common, small and low-mass stars passing in front of a solar-like star. This additional wealth of data on small and light stars is a real bonanza for the astronomers. Constraining the Relation Between Mass and Radius Low-mass stars are exceptionally interesting objects, also because the physical conditions in their interiors have much in common with

  2. 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.

  3. Biomarkers in Prostate Cancer Epidemiology

    Directory of Open Access Journals (Sweden)

    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.

  4. Utilization of metabolomics to identify serum biomarkers for hepatocellular carcinoma in patients with liver cirrhosis

    Energy Technology Data Exchange (ETDEWEB)

    Ressom, Habtom W., E-mail: hwr@georgetown.edu [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Xiao, Jun Feng; Tuli, Leepika; Varghese, Rency S.; Zhou Bin; Tsai, Tsung-Heng; Nezami Ranjbar, Mohammad R.; Zhao Yi; Wang Jinlian; Di Poto, Cristina; Cheema, Amrita K. [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Tadesse, Mahlet G. [Department of Mathematics and Statistics, Georgetown University, Washington, DC 20057 (United States); Goldman, Radoslav [Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057 (United States); Shetty, Kirti [Department of Surgery, Georgetown University Medical Center, Washington, DC 20057 (United States); Georgetown University Hospital, Washington, DC 20057 (United States)

    2012-09-19

    cholesterol metabolism) such as glycochenodeoxycholic acid 3-sulfate (3-sulfo-GCDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), taurocholic acid (TCA), and taurochenodeoxycholate (TCDCA). These results provide useful insights into HCC biomarker discovery utilizing metabolomics as an efficient and cost-effective platform. Our work shows that metabolomic profiling is a promising tool to identify candidate metabolic biomarkers for early detection of HCC cases in high risk population of cirrhotic patients.

  5. Higgs Discovery Movie

    CERN Multimedia

    2014-01-01

    The ATLAS & CMS Experiments Celebrate the 2nd Anniversary of the Discovery of the Higgs boson. Here, are some images of the path from LHC startup to Nobel Prize, featuring a musical composition by Roger Zare, performed by the Donald Sinta Quartet, called “LHC”. Happy Discovery Day!

  6. Decades of Discovery

    Science.gov (United States)

    2011-06-01

    For the past two-and-a-half decades, the Office of Science at the U.S. Department of Energy has been at the forefront of scientific discovery. Over 100 important discoveries supported by the Office of Science are represented in this document.

  7. Academic Drug Discovery Centres

    DEFF Research Database (Denmark)

    Kirkegaard, Henriette Schultz; Valentin, Finn

    2014-01-01

    Academic drug discovery centres (ADDCs) are seen as one of the solutions to fill the innovation gap in early drug discovery, which has proven challenging for previous organisational models. Prior studies of ADDCs have identified the need to analyse them from the angle of their economic...

  8. Service discovery at home

    NARCIS (Netherlands)

    Sundramoorthy, Vasughi; Scholten, Hans; Jansen, Pierre; Hartel, Pieter

    2003-01-01

    Service discovery is a fairly new field that kicked off since the advent of ubiquitous computing and has been found essential in the making of intelligent networks by implementing automated discovery and remote control between devices. This paper provides an overview and comparison of several promin

  9. Absolute Quantitation of DNA Methylation of 28 Candidate Genes in Prostate Cancer Using Pyrosequencing

    Directory of Open Access Journals (Sweden)

    Nataڑa Vasiljeviš

    2011-01-01

    Full Text Available Aberrant DNA methylation plays a pivotal role in carcinogenesis and its mapping is likely to provide biomarkers for improved diagnostic and risk assessment in prostate cancer (PCa. We quantified and compared absolute methylation levels among 28 candidate genes in 48 PCa and 29 benign prostate hyperplasia (BPH samples using the pyrosequencing (PSQ method to identify genes with diagnostic and prognostic potential.

  10. Three new optical nova candidates in M 31

    Science.gov (United States)

    Pietsch, W.; Henze, M.; Burwitz, V.; Kaur, A.; Hartmann, D. H.; Williams, G.; Milne, P.

    2011-06-01

    We report the discovery of three nova candidates in M 31 on 7x60s stacked R filter CCD images obtained with the robotic 60cm telescope with an E2V CCD (2kx2k, 13.5 micron sq. pixels) of the Livermore Optical Transient Imaging System (Super-LOTIS, located at Steward Observatory, Kitt Peak, Arizona, USA) on 2011 June 7.418 UT. The objects are visible on all individual images.

  11. Biomarkers of postoperative delirium and cognitive dysfunction

    Directory of Open Access Journals (Sweden)

    Ganna eAndrosova

    2015-06-01

    Full Text Available Elderly surgical patients frequently experience postoperative delirium (POD and the subsequent development of postoperative cognitive dysfunction (POCD. Clinical features include deterioration in cognition, disturbance in attention and reduced awareness of the environment and result in higher morbidity, mortality and greater utilization of social financial assistance. The aging Western societies can expect an increase in the incidence of POD and POCD. The underlying pathophysiological mechanisms have been studied on the molecular level albeit with unsatisfying small research efforts given their societal burden. Here, we review the known physiological and immunological changes and genetic risk factors, identify candidates for further studies and integrate the information into a draft network for exploration on a systems level. The pathogenesis of these postoperative cognitive impairments is multifactorial; application of integrated systems biology has the potential to reconstruct the underlying network of molecular mechanisms and help in the identification of prognostic and diagnostic biomarkers.

  12. The Search for Biomarkers in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2010-04-01

    Full Text Available BACKGROUND: As population demographic shift and the number of individuals with Alzheimer Disease (AD continue to increase, the challenge is to develop targeted, effective treatments and our ability to recognize early symptoms. In view of this, the need for specific AD biomarker is crucial. CONTENT: In recent years it has become evident that CSF concentrations of some brain-specific proteins are related to underlying disease pathogenesis and may therefore aid clinical investigation. Among several, we have focused on three candidates that have been suggested to fulfil the requirements for biomarkers of AD: β-amyloid 42 (Aβ42, total Tau (T-tau and tau phosphorylated at various epitopes (P-tau. An increasing number of studies suggest that supplementary use of these CSF markers, preferably in combination, adds to the accuracy of an AD diagnosis. More recently visinin-like protein (VLP-1, a marker for neuronal cell injury has been studied. CSF VLP-1 concentrations were 50% higher in AD patients than in the control population. SUMMARY: The number of studies aimed at the identification of new biomarkers for AD is expected to increase rapidly, not only because of the increasing insights into the pathological mechanisms underlying this disease, but also because new therapies have been developed or are under consideration now, which warrant an early and specific diagnosis for effective treatment of the patients. KEYWORDS: dementia, amyloid plaque, neurofibrillary tangels, amyloid β-peptide 42 (Aβ42, total tau (T-tau, phosphorylated tau (P-tau, visinin–like protein 1 (VLP-1.

  13. Two kinds of knowledge in scientific discovery.

    Science.gov (United States)

    Bridewell, Will; Langley, Pat

    2010-01-01

    Research on computational models of scientific discovery investigates both the induction of descriptive laws and the construction of explanatory models. Although the work in law discovery centers on knowledge-lean approaches to searching a problem space, research on deeper modeling tasks emphasizes the pivotal role of domain knowledge. As an example, our own research on inductive process modeling uses information about candidate processes to explain why variables change over time. However, our experience with IPM, an artificial intelligence system that implements this approach, suggests that process knowledge is insufficient to avoid consideration of implausible models. To this end, the discovery system needs additional knowledge that constrains the model structures. We report on an extended system, SC-IPM, that uses such information to reduce its search through the space of candidates and to produce models that human scientists find more plausible. We also argue that although people carry out less extensive search than SC-IPM, they rely on the same forms of knowledge--processes and constraints--when constructing explanatory models.

  14. Two kinds of knowledge in scientific discovery.

    Science.gov (United States)

    Bridewell, Will; Langley, Pat

    2010-01-01

    Research on computational models of scientific discovery investigates both the induction of descriptive laws and the construction of explanatory models. Although the work in law discovery centers on knowledge-lean approaches to searching a problem space, research on deeper modeling tasks emphasizes the pivotal role of domain knowledge. As an example, our own research on inductive process modeling uses information about candidate processes to explain why variables change over time. However, our experience with IPM, an artificial intelligence system that implements this approach, suggests that process knowledge is insufficient to avoid consideration of implausible models. To this end, the discovery system needs additional knowledge that constrains the model structures. We report on an extended system, SC-IPM, that uses such information to reduce its search through the space of candidates and to produce models that human scientists find more plausible. We also argue that although people carry out less extensive search than SC-IPM, they rely on the same forms of knowledge--processes and constraints--when constructing explanatory models. PMID:25163620

  15. A proteomics approach to the identification of biomarkers for psoriasis utilising keratome biopsy

    DEFF Research Database (Denmark)

    Williamson, James C; Scheipers, Peter; Schwämmle, Veit;

    2013-01-01

    The discovery of plasma biomarkers for psoriasis vulgaris may aid clinicians in disease grading and monitoring of treatment response. We have therefore developed a proteomics/mass spectrometry based workflow which enables biomarker discovery from psoriasis patient samples. We have utilised keratome...... a quantitative proteomics screen of four patients with psoriasis using stable isotope dimethyl labelling and identified over 50 proteins consistently altered in abundance in psoriasis lesional versus non-lesional skin. This includes several canonical psoriasis related proteins (e.g. S100A7 [Psoriasin] and FABP5...... [Epidermal Fatty Acid Binding Protein]) and more than 30 novel alterations. From this disease localised dataset we further assessed several proteins as potential biomarkers in the plasma of patients with psoriasis versus healthy controls utilising selected reaction monitoring mass spectrometry (SRM-MS/MS)....

  16. Emerging biomarkers in psoriatic arthritis.

    Science.gov (United States)

    Paek, So Yeon; Han, Ling; Weiland, Matthew; Lu, Chuan-Jian; McKinnon, Kathleen; Zhou, Li; Lim, Henry W; Elder, James T; Mi, Qing-Sheng

    2015-12-01

    Psoriasis is an immune-mediated skin disease which affects 2-4% of the worldwide population. Approximately 20-30% of patients with psoriasis develop psoriatic arthritis (PsA), a frequently destructive and disabling condition. As skin manifestations precede joint symptoms in nearly all patients with PsA, identification of biomarkers for early prediction of joint damage is an important clinical need. Because not all patients with PsA respond to treatment in the same fashion, identification of biomarkers capable of predicting therapeutic response is also imperative. Here, we review existing literature and discuss current investigations to identify potential biomarkers for PsA disease activity, with particular emphasis on microRNAs as novel markers of interest. Serum (soluble) biomarkers, peripheral osteoclast precursor as cellular biomarkers, and genetic loci associated with skin and joint disease are also reviewed. PMID:26602058

  17. Epigenetic biomarkers in liver cancer.

    Science.gov (United States)

    Banaudha, Krishna K; Verma, Mukesh

    2015-01-01

    Liver cancer (hepatocellular carcinoma or HCC) is a major cancer worldwide. Research in this field is needed to identify biomarkers that can be used for early detection of the disease as well as new approaches to its treatment. Epigenetic biomarkers provide an opportunity to understand liver cancer etiology and evaluate novel epigenetic inhibitors for treatment. Traditionally, liver cirrhosis, proteomic biomarkers, and the presence of hepatitis viruses have been used for the detection and diagnosis of liver cancer. Promising results from microRNA (miRNA) profiling and hypermethylation of selected genes have raised hopes of identifying new biomarkers. Some of these epigenetic biomarkers may be useful in risk assessment and for screening populations to identify who is likely to develop cancer. Challenges and opportunities in the field are discussed in this chapter.

  18. MicroRNA signatures as clinical biomarkers in lung cancer

    Directory of Open Access Journals (Sweden)

    Markou A

    2015-05-01

    Full Text Available Athina Markou, Martha Zavridou, Evi S Lianidou Analysis of Circulating Tumor Cells, Lab of Analytical Chemistry, Department of Chemistry, University of Athens, Athens, Greece Abstract: Even if early lung cancer detection has been recently significantly improved, the invasive nature of current diagnostic procedures, and a relatively high percentage of false positives, is limiting the application of modern detection tools. The discovery and clinical evaluation of novel specific and robust non-invasive biomarkers for diagnosis of lung cancer at an early stage, as well as for better prognosis and prediction of therapy response, is very challenging. MicroRNAs (miRNAs can play an important role in the diagnosis and management of lung cancer patients, as important and reliable biomarkers for cancer detection and prognostic prediction, and even as promising as novel targets for cancer therapy. miRNAs are important in cancer pathogenesis, and deregulation of their expression levels has been detected not only in lung cancer but in many other human tumor types. Numerous studies strongly support the potential of miRNAs as biomarkers in non-small-cell lung cancer, and there is increasing evidence that altered miRNA expression is associated with tumor progression and survival. It is worth mentioning also that detection of miRNAs circulating in plasma or serum has enormous potential, because miRNAs serve as non-invasive biomarkers not only for the diagnosis and prognosis of the disease, but also as novel response and sensitivity predictors for cancer treatment. In this review, we summarize the current findings on the critical role of miRNAs in lung cancer tumorigenesis and highlight their potential as circulating biomarkers in lung cancer. Our review is based on papers that have been published after 2011, and includes the key words “miRNAs” and “lung cancer”. Keywords: non-small-cell lung carcinoma, miRNAs, tumor biomarkers, circulating miRNAs, liquid

  19. Soluble biomarkers of cartilage and bone metabolism in early proof of concept trials in psoriatic arthritis: Effects of adalimumab versus placebo

    NARCIS (Netherlands)

    Tak, P.P.; Kuijk, A.W.R. van; Groot, J. de; Koeman, R.C.; Sakkee, N.; Baeten, D.L.; Gerlag, D.M.

    2010-01-01

    Background: There is growing interest in soluble biomarkers that could be used on the group level for screening purposes in small proof of principle studies during early drug development. We investigated early changes in serum levels of several candidate biomarkers involved in cartilage and bone met

  20. Feedback-Driven Dynamic Invariant Discovery

    Science.gov (United States)

    Zhang, Lingming; Yang, Guowei; Rungta, Neha S.; Person, Suzette; Khurshid, Sarfraz

    2014-01-01

    Program invariants can help software developers identify program properties that must be preserved as the software evolves, however, formulating correct invariants can be challenging. In this work, we introduce iDiscovery, a technique which leverages symbolic execution to improve the quality of dynamically discovered invariants computed by Daikon. Candidate invariants generated by Daikon are synthesized into assertions and instrumented onto the program. The instrumented code is executed symbolically to generate new test cases that are fed back to Daikon to help further re ne the set of candidate invariants. This feedback loop is executed until a x-point is reached. To mitigate the cost of symbolic execution, we present optimizations to prune the symbolic state space and to reduce the complexity of the generated path conditions. We also leverage recent advances in constraint solution reuse techniques to avoid computing results for the same constraints across iterations. Experimental results show that iDiscovery converges to a set of higher quality invariants compared to the initial set of candidate invariants in a small number of iterations.

  1. An extensive targeted proteomic analysis of disease-related protein biomarkers in urine from healthy donors.

    Directory of Open Access Journals (Sweden)

    Brian M Nolen

    Full Text Available The analysis of protein biomarkers in urine is expected to lead to advances in a variety of clinical settings. Several characteristics of urine including a low-protein matrix, ease of testing and a demonstrated proteomic stability offer distinct advantages over current widely used biofluids, serum and plasma. Improvements in our understanding of the urine proteome and in methods used in its evaluation will facilitate the clinical development of urinary protein biomarkers. Multiplexed bead-based immunoassays were utilized to evaluate 211 proteins in urines from 103 healthy donors. An additional 25 healthy donors provided serial urine samples over the course of two days in order to assess temporal variation in selected biomarkers. Nearly one-third of the evaluated biomarkers were detected in urine at levels greater than 1 ng/ml, representing a diverse panel of proteins with respect to structure, function and biological role. The presence of several biomarkers in urine was confirmed by western blot. Several methods of data normalization were employed to assess impact on biomarker variability. A complex pattern of correlations with urine creatinine, albumin and beta-2-microglobulin was observed indicating the presence of highly specific mechanisms of renal filtration. Further investigation of the urinary protein biomarkers identified in this preliminary study along with a consideration of the underlying proteomic trends suggested by these findings should lead to an improved capability to identify candidate biomarkers for clinical development.

  2. Guidelines for uniform reporting of body fluid biomarker studies in neurologic disorders

    DEFF Research Database (Denmark)

    Gnanapavan, Sharmilee; Hegen, Harald; Khalil, Michael;

    2014-01-01

    OBJECTIVE: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades, there a......OBJECTIVE: The aim of these guidelines is to make the process of reporting body fluid biomarker studies in neurologic disorders more uniform and transparent, in line with existing standards for reporting research in other biomedical areas. Although biomarkers have been around for decades......, there are concerns over the high attrition rate of promising candidate biomarkers at later phases of development. METHODS: BioMS-eu consortium, a collaborative network working toward improving the quality of biomarker research in neurologic disorders, discussed the merits of standardizing the reporting of body fluid...... of studies. This guideline by the BioMS-eu consortium is aimed at setting a standard for the reporting of future body fluid biomarker research studies in neurologic disorders. We anticipate that following these guidelines will help to accelerate the selection of biomarkers for clinical development....

  3. The Greatest Mathematical Discovery?

    Energy Technology Data Exchange (ETDEWEB)

    Bailey, David H.; Borwein, Jonathan M.

    2010-05-12

    What mathematical discovery more than 1500 years ago: (1) Is one of the greatest, if not the greatest, single discovery in the field of mathematics? (2) Involved three subtle ideas that eluded the greatest minds of antiquity, even geniuses such as Archimedes? (3) Was fiercely resisted in Europe for hundreds of years after its discovery? (4) Even today, in historical treatments of mathematics, is often dismissed with scant mention, or else is ascribed to the wrong source? Answer: Our modern system of positional decimal notation with zero, together with the basic arithmetic computational schemes, which were discovered in India about 500 CE.

  4. Pathways to new drug discovery in neuropsychiatry

    Directory of Open Access Journals (Sweden)

    Berk Michael

    2012-11-01

    Full Text Available Abstract There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success. See related article http://www.biomedcentral.com/1741-7015/10/150

  5. Biomarkers for lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Zangar, Richard C.; Varnum, Susan M.

    2014-09-02

    A biomarker, method, test kit, and diagnostic system for detecting the presence of lymphoma in a person are disclosed. The lymphoma may be Hodgkin's lymphoma or non-Hodgkin's lymphoma. The person may be a high-risk subject. In one embodiment, a plasma sample from a person is obtained. The level of at least one protein listed in Table S3 in the plasma sample is measured. The level of at least one protein in the plasma sample is compared with the level in a normal or healthy subject. The lymphoma is diagnosed based upon the level of the at least one protein in the plasma sample in comparison to the normal or healthy level.

  6. Evaluating biomarkers to model cancer risk post cosmic ray exposure.

    Science.gov (United States)

    Sridharan, Deepa M; Asaithamby, Aroumougame; Blattnig, Steve R; Costes, Sylvain V; Doetsch, Paul W; Dynan, William S; Hahnfeldt, Philip; Hlatky, Lynn; Kidane, Yared; Kronenberg, Amy; Naidu, Mamta D; Peterson, Leif E; Plante, Ianik; Ponomarev, Artem L; Saha, Janapriya; Snijders, Antoine M; Srinivasan, Kalayarasan; Tang, Jonathan; Werner, Erica; Pluth, Janice M

    2016-06-01

    Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Chronic exposure to cosmic rays in the context of the complex deep space environment may place astronauts at high cancer risk. To estimate this risk, it is critical to understand how radiation-induced cellular stress impacts cell fate decisions and how this in turn alters the risk of carcinogenesis. Exposure to the heavy ion component of cosmic rays triggers a multitude of cellular changes, depending on the rate of exposure, the type of damage incurred and individual susceptibility. Heterogeneity in dose, dose rate, radiation quality, energy and particle flux contribute to the complexity of risk assessment. To unravel the impact of each of these factors, it is critical to identify sensitive biomarkers that can serve as inputs for robust modeling of individual risk of cancer or other long-term health consequences of exposure. Limitations in sensitivity of biomarkers to dose and dose rate, and the complexity of longitudinal monitoring, are some of the factors that increase uncertainties in the output from risk prediction models. Here, we critically evaluate candidate early and late biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions. Some of the biomarkers we have reviewed include complex clustered DNA damage, persistent DNA repair foci, reactive oxygen species, chromosome aberrations and inflammation. Other biomarkers discussed, often assayed for at longer points post exposure, include mutations, chromosome aberrations, reactive oxygen species and telomere length changes. We discuss the relationship of biomarkers to different potential cell fates, including proliferation, apoptosis, senescence, and loss of stemness, which can propagate genomic instability and alter tissue composition and the underlying mRNA signatures that contribute to cell fate decisions. Our goal is to highlight factors that are important in choosing

  7. Evaluating biomarkers to model cancer risk post cosmic ray exposure

    Science.gov (United States)

    Sridharan, Deepa M.; Asaithamby, Aroumougame; Blattnig, Steve R.; Costes, Sylvain V.; Doetsch, Paul W.; Dynan, William S.; Hahnfeldt, Philip; Hlatky, Lynn; Kidane, Yared; Kronenberg, Amy; Naidu, Mamta D.; Peterson, Leif E.; Plante, Ianik; Ponomarev, Artem L.; Saha, Janapriya; Snijders, Antoine M.; Srinivasan, Kalayarasan; Tang, Jonathan; Werner, Erica; Pluth, Janice M.

    2016-06-01

    Robust predictive models are essential to manage the risk of radiation-induced carcinogenesis. Chronic exposure to cosmic rays in the context of the complex deep space environment may place astronauts at high cancer risk. To estimate this risk, it is critical to understand how radiation-induced cellular stress impacts cell fate decisions and how this in turn alters the risk of carcinogenesis. Exposure to the heavy ion component of cosmic rays triggers a multitude of cellular changes, depending on the rate of exposure, the type of damage incurred and individual susceptibility. Heterogeneity in dose, dose rate, radiation quality, energy and particle flux contribute to the complexity of risk assessment. To unravel the impact of each of these factors, it is critical to identify sensitive biomarkers that can serve as inputs for robust modeling of individual risk of cancer or other long-term health consequences of exposure. Limitations in sensitivity of biomarkers to dose and dose rate, and the complexity of longitudinal monitoring, are some of the factors that increase uncertainties in the output from risk prediction models. Here, we critically evaluate candidate early and late biomarkers of radiation exposure and discuss their usefulness in predicting cell fate decisions. Some of the biomarkers we have reviewed include complex clustered DNA damage, persistent DNA repair foci, reactive oxygen species, chromosome aberrations and inflammation. Other biomarkers discussed, often assayed for at longer points post exposure, include mutations, chromosome aberrations, reactive oxygen species and telomere length changes. We discuss the relationship of biomarkers to different potential cell fates, including proliferation, apoptosis, senescence, and loss of stemness, which can propagate genomic instability and alter tissue composition and the underlying mRNA signatures that contribute to cell fate decisions. Our goal is to highlight factors that are important in choosing

  8. Biomarkers of manganese intoxication.

    Science.gov (United States)

    Zheng, Wei; Fu, Sherleen X; Dydak, Ulrike; Cowan, Dallas M

    2011-01-01

    Manganese (Mn), upon absorption, is primarily sequestered in tissue and intracellular compartments. For this reason, blood Mn concentration does not always accurately reflect Mn concentration in the targeted tissue, particularly in the brain. The discrepancy between Mn concentrations in tissue or intracellular components means that blood Mn is a poor biomarker of Mn exposure or toxicity under many conditions and that other biomarkers must be established. For group comparisons of active workers, blood Mn has some utility for distinguishing exposed from unexposed subjects, although the large variability in mean values renders it insensitive for discriminating one individual from the rest of the study population. Mn exposure is known to alter iron (Fe) homeostasis. The Mn/Fe ratio (MIR) in plasma or erythrocytes reflects not only steady-state concentrations of Mn or Fe in tested individuals, but also a biological response (altered Fe homeostasis) to Mn exposure. Recent human studies support the potential value for using MIR to distinguish individuals with Mn exposure. Additionally, magnetic resonance imaging (MRI), in combination with noninvasive assessment of γ-aminobutyric acid (GABA) by magnetic resonance spectroscopy (MRS), provides convincing evidence of Mn exposure, even without clinical symptoms of Mn intoxication. For subjects with long-term, low-dose Mn exposure or for those exposed in the past but not the present, neither blood Mn nor MRI provides a confident distinction for Mn exposure or intoxication. While plasma or erythrocyte MIR is more likely a sensitive measure, the cut-off values for MIR among the general population need to be further tested and established. Considering the large accumulation of Mn in bone, developing an X-ray fluorescence spectroscopy or neutron-based spectroscopy method may create yet another novel non-invasive tool for assessing Mn exposure and toxicity. PMID:20946915

  9. Electoral Systems and Candidate Selection

    NARCIS (Netherlands)

    Hazan, Reuven Y.; Voerman, Gerrit

    2006-01-01

    Electoral systems at the national level and candidate selection methods at the party level are connected, maybe not causally but they do influence each other. More precisely, the electoral system constrains and conditions the parties' menu of choices concerning candidate selection. Moreover, in ligh

  10. Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema

    DEFF Research Database (Denmark)

    Lassere, Marissa N; Johnson, Kent R; Boers, Maarten;

    2007-01-01

    endpoints, and leading indicators, a quantitative surrogate validation schema was developed and subsequently evaluated at a stakeholder workshop. RESULTS: The search identified several classification schema and definitions. Components of these were incorporated into a new quantitative surrogate validation...... of the National Institutes of Health definitions of biomarker, surrogate endpoint, and clinical endpoint was useful. CONCLUSION: Further development and application of this schema provides incentives and guidance for effective biomarker and surrogate endpoint research, and more efficient drug discovery...

  11. Identification of phosphorylated MYL12B as a potential plasma biomarker for septic acute kidney injury using a quantitative proteomic approach.

    Science.gov (United States)

    Wu, Fan; Dong, Xiu-Juan; Li, Yan-Yan; Zhao, Yan; Xu, Qiu-Lin; Su, Lei

    2015-01-01

    Acute kidney injury (AKI) is a common and increasingly encountered complication in hospitalized patients with critical illness in intensive care units (ICU). According to the etiology, Sepsis-induced AKI (SAKI) is a leading contributor to AKI and significantly has very poor prognosis, which might be related to the late detection when the elevation of BUN and serum creatinine (SCr) is used. Many genes are up-regulated in the damaged kidney with the corresponding protein products appearing in plasma and urine. Some of these are candidate biomarkers for more timely diagnosis of SAKI. Therefore, extensive research efforts over this past decade have been directed at the discovery and validation of novel SAKI biomarkers to detect injury prior to changes in kidney function, a number of serum and urinary proteins, including NGAL, KIM-1, cystatin-C, IL-18, and L-FABP, have been identified for predicting SAKI before a rise in BUN and serum creatinine in several experimental and clinical trainings. Unfortunately, an ideal biomarker of SAKI with highly sensitivity and specificity has not been identified yet. Recent progresses in quantitative proteomics have offered opportunities to discover biomarkers for SAKI. In the present study, kidney tissue samples from SAKI mice were analyzed by two-dimensional differential gel electrophoresis (2D-DIGE), and 4 up-regulated proteins, which were actin (ACTB), myosin regulatory light chain 12B (MYL12B), myosin regulatory light polypeptide 9 (MYL9), and myosin regulatory light chain 12A (MYL12A) were identified by matrix assisted laser desorption ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). Among all the varied proteins, MYL12B was validated by western blot. Interestingly, there was no change between the SAKI and control kidney tissues, however, phosphorylated MYL12B was detected to be consistent with the proteomics data. Furthermore, phosphorylated MYL12B was found similarly to be increased in SAKI plasma

  12. Identification of phosphorylated MYL12B as a potential plasma biomarker for septic acute kidney injury using a quantitative proteomic approach

    Science.gov (United States)

    Wu, Fan; Dong, Xiu-Juan; Li, Yan-Yan; Zhao, Yan; Xu, Qiu-Lin; Su, Lei

    2015-01-01

    Acute kidney injury (AKI) is a common and increasingly encountered complication in hospitalized patients with critical illness in intensive care units (ICU). According to the etiology, Sepsis-induced AKI (SAKI) is a leading contributor to AKI and significantly has very poor prognosis, which might be related to the late detection when the elevation of BUN and serum creatinine (SCr) is used. Many genes are up-regulated in the damaged kidney with the corresponding protein products appearing in plasma and urine. Some of these are candidate biomarkers for more timely diagnosis of SAKI. Therefore, extensive research efforts over this past decade have been directed at the discovery and validation of novel SAKI biomarkers to detect injury prior to changes in kidney function, a number of serum and urinary proteins, including NGAL, KIM-1, cystatin-C, IL-18, and L-FABP, have been identified for predicting SAKI before a rise in BUN and serum creatinine in several experimental and clinical trainings. Unfortunately, an ideal biomarker of SAKI with highly sensitivity and specificity has not been identified yet. Recent progresses in quantitative proteomics have offered opportunities to discover biomarkers for SAKI. In the present study, kidney tissue samples from SAKI mice were analyzed by two-dimensional differential gel electrophoresis (2D-DIGE), and 4 up-regulated proteins, which were actin (ACTB), myosin regulatory light chain 12B (MYL12B), myosin regulatory light polypeptide 9 (MYL9), and myosin regulatory light chain 12A (MYL12A) were identified by matrix assisted laser desorption ionization-time of flight/time of flight mass spectrometry (MALDI-TOF/TOF MS). Among all the varied proteins, MYL12B was validated by western blot. Interestingly, there was no change between the SAKI and control kidney tissues, however, phosphorylated MYL12B was detected to be consistent with the proteomics data. Furthermore, phosphorylated MYL12B was found similarly to be increased in SAKI plasma

  13. Toxins and drug discovery.

    Science.gov (United States)

    Harvey, Alan L

    2014-12-15

    Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process. PMID:25448391

  14. Leadership and Discovery

    CERN Document Server

    Goethals, George R

    2009-01-01

    This book, a collection of essays from scholars across disciplines, explores leadership of discovery, probing the guided and collaborative exploration and interpretation of the experience of our inner thoughts and feelings, and of our external worlds

  15. Fateful discovery almost forgotten

    CERN Multimedia

    1989-01-01

    "The discovery of the fission of uranium exactly half a century ago is at risk of passing unremarked because of the general ambivalence towards the consequences of this development. Can that be wise?" (4 pages)

  16. Short- and long-term biomarkers for bacterial robustness: a framework for quantifying correlations between cellular indicators and adaptive behavior.

    Directory of Open Access Journals (Sweden)

    Heidy M W den Besten

    Full Text Available The ability of microorganisms to adapt to changing environments challenges the prediction of their history-dependent behavior. Cellular biomarkers that are quantitatively correlated to stress adaptive behavior will facilitate our ability to predict the impact of these adaptive traits. Here, we present a framework for identifying cellular biomarkers for mild stress induced enhanced microbial robustness towards lethal stresses. Several candidate-biomarkers were selected by comparing the genome-wide transcriptome profiles of our model-organism Bacillus cereus upon exposure to four mild stress conditions (mild heat, acid, salt and oxidative stress. These candidate-biomarkers--a transcriptional regulator (activating general stress responses, enzymes (removing reactive oxygen species, and chaperones and proteases (maintaining protein quality--were quantitatively determined at transcript, protein and/or activity level upon exposure to mild heat, acid, salt and oxidative stress for various time intervals. Both unstressed and mild stress treated cells were also exposed to lethal stress conditions (severe heat, acid and oxidative stress to quantify the robustness advantage provided by mild stress pretreatment. To evaluate whether the candidate-biomarkers could predict the robustness enhancement towards lethal stress elicited by mild stress pretreatment, the biomarker responses upon mild stress treatment were correlated to mild stress induced robustness towards lethal stress. Both short- and long-term biomarkers could be identified of which their induction levels were correlated to mild stress induced enhanced robustness towards lethal heat, acid and/or oxidative stress, respectively, and are therefore predictive cellular indicators for mild stress induced enhanced robustness. The identified biomarkers are among the most consistently induced cellular components in stress responses and ubiquitous in biology, supporting extrapolation to other microorganisms

  17. Biomarker Investigations Related to Pathophysiological Pathways in Schizophrenia and Psychosis

    Directory of Open Access Journals (Sweden)

    Gursharan eChana

    2013-06-01

    Full Text Available Post-mortem brain investigations of schizophrenia have generated swathes of data in the last few decades implicating candidate genes and proteins, the relation of these findings to peripheral biomarker indicators and symptomatology remain to be elucidated. While biomarkers for disease do not have to be involved with underlying pathophysiology and may be largely indicative of diagnosis or prognosis, the ideal may be a biomarker that is involved in underlying disease processes and which is therefore more likely to change with progression of the illness as well as potentially being more responsive to treatment. One of the main difficulties in conducting biomarker investigations for major psychiatric disorders is the relative inconsistency in clinical diagnoses between disorders such as bipolar and schizophrenia. This has led some researchers to investigate biomarkers associated with core symptoms of these disorders, such as psychosis. The aim of this review is to evaluate the contribution of post-mortem brain investigations to elucidating the pathophysiology pathways involved in schizophrenia and psychosis, with an emphasis on major neurotransmitter systems that have been implicated. This data will then be compared to functional neuroimaging findings as well as findings from blood based gene expression investigations in schizophrenia in order to highlight the relative overlap in pathological processes between these different modalities used to elucidate pathogenesis of schizophrenia. In addition we will cover some recent and exciting findings demonstrating microRNA dysregulation in both the blood and the brain in patients with schizophrenia. These changes are pertinent to the topic due to their known role in post-transcriptional modification of gene expression with the potential to contribute or underlie gene expression changes observed in schizophrenia. Finally, we will discuss how post-mortem studies may aid future biomarker investigations.

  18. Analytical Aspects of the Implementation of Biomarkers in Clinical Transplantation.

    Science.gov (United States)

    Shipkova, Maria; López, Olga Millán; Picard, Nicolas; Noceti, Ofelia; Sommerer, Claudia; Christians, Uwe; Wieland, Eberhard

    2016-04-01

    In response to the urgent need for new reliable biomarkers to complement the guidance of the immunosuppressive therapy, a huge number of biomarker candidates to be implemented in clinical practice have been introduced to the transplant community. This includes a diverse range of molecules with very different molecular weights, chemical and physical properties, ex vivo stabilities, in vivo kinetic behaviors, and levels of similarity to other molecules, etc. In addition, a large body of different analytical techniques and assay protocols can be used to measure biomarkers. Sometimes, a complex software-based data evaluation is a prerequisite for appropriate interpretation of the results and for their reporting. Although some analytical procedures are of great value for research purposes, they may be too complex for implementation in a clinical setting. Whereas the proof of "fitness for purpose" is appropriate for validation of biomarker assays used in exploratory drug development studies, a higher level of analytical validation must be achieved and eventually advanced analytical performance might be necessary before diagnostic application in transplantation medicine. A high level of consistency of results between laboratories and between methods (if applicable) should be obtained and maintained to make biomarkers effective instruments in support of therapeutic decisions. This overview focuses on preanalytical and analytical aspects to be considered for the implementation of new biomarkers for adjusting immunosuppression in a clinical setting and highlights critical points to be addressed on the way to make them suitable as diagnostic tools. These include but are not limited to appropriate method validation, standardization, education, automation, and commercialization.

  19. Discovery Driven Growth

    DEFF Research Database (Denmark)

    Bukh, Per Nikolaj

    2009-01-01

    Anmeldelse af Discovery Driven Growh : A breakthrough process to reduce risk and seize opportunity, af Rita G. McGrath & Ian C. MacMillan, Boston: Harvard Business Press. Udgivelsesdato: 14 august......Anmeldelse af Discovery Driven Growh : A breakthrough process to reduce risk and seize opportunity, af Rita G. McGrath & Ian C. MacMillan, Boston: Harvard Business Press. Udgivelsesdato: 14 august...

  20. [Iron deficiency in elderly patients: use of biomarkers].

    Science.gov (United States)

    Le Petitcorps, Hélène; Monti, Alexandra; Pautas, Éric

    2015-01-01

    Iron deficiency, due to blood loss or malabsorption, is commonly observed in geriatric practice. In elderly people, association of inflammatory diseases to iron loss makes diagnosis of absolute iron deficiency sometimes difficult. In case of inflammation, the interpretation of usual biomarkers of iron deficiency (serum ferritin, transferrin saturation, serum iron) may be difficult. The recent discovery of the role of hepcidine in the iron homeostasis, in physiological and pathological situation, contributes to better understanding of the iron regulation. The aim of this short paper is to underline some specificities of elderly iron physiology, to explain hepcidine's role in physiological and pathological situations and to propose a diagnostic approach for a better interpretation of usual biomarkers, in order to differentiate absolute iron deficiency and functional iron deficiency.

  1. Integrated Detection of Pathogens and Host Biomarkers for Wounds

    Energy Technology Data Exchange (ETDEWEB)

    Jaing, C

    2012-03-19

    The increasing incidence and complications arising from combat wounds has necessitated a reassessment of methods for effective treatment. Infection, excessive inflammation, and incidence of drug-resistant organisms all contribute toward negative outcomes for afflicted individuals. The organisms and host processes involved in wound progression, however, are incompletely understood. We therefore set out, using our unique technical resources, to construct a profile of combat wounds which did or did not successfully resolve. We employed the Lawrence Livermore Microbial Detection Array and identified a number of nosocomial pathogens present in wound samples. Some of these identities corresponded with bacterial isolates previously cultured, while others were not obtained via standard microbiology. Further, we optimized proteomics protocols for the identification of host biomarkers indicative of various stages in wound progression. In combination with our pathogen data, our biomarker discovery efforts will provide a profile corresponding to wound complications, and will assist significantly in treatment of these complex cases.

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

    Science.gov (United States)

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

    2014-09-01

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

  3. Development of Diagnostic Biomarkers for Detecting Diabetic Retinopathy at Early Stages Using Quantitative Proteomics

    Directory of Open Access Journals (Sweden)

    Jonghwa Jin

    2016-01-01

    Full Text Available Diabetic retinopathy (DR is a common microvascular complication caused by diabetes mellitus (DM and is a leading cause of vision impairment and loss among adults. Here, we performed a comprehensive proteomic analysis to discover biomarkers for DR. First, to identify biomarker candidates that are specifically expressed in human vitreous, we performed data-mining on both previously published DR-related studies and our experimental data; 96 proteins were then selected. To confirm and validate the selected biomarker candidates, candidates were selected, confirmed, and validated using plasma from diabetic patients without DR (No DR and diabetics with mild or moderate nonproliferative diabetic retinopathy (Mi or Mo NPDR using semiquantitative multiple reaction monitoring (SQ-MRM and stable-isotope dilution multiple reaction monitoring (SID-MRM. Additionally, we performed a multiplex assay using 15 biomarker candidates identified in the SID-MRM analysis, which resulted in merged AUC values of 0.99 (No DR versus Mo NPDR and 0.93 (No DR versus Mi and Mo NPDR. Although further validation with a larger sample size is needed, the 4-protein marker panel (APO4, C7, CLU, and ITIH2 could represent a useful multibiomarker model for detecting the early stages of DR.

  4. Financing drug discovery via dynamic leverage.

    Science.gov (United States)

    Montazerhodjat, Vahid; Frishkopf, John J; Lo, Andrew W

    2016-03-01

    We extend the megafund concept for funding drug discovery to enable dynamic leverage in which the portfolio of candidate therapeutic assets is predominantly financed initially by equity, and debt is introduced gradually as assets mature and begin generating cash flows. Leverage is adjusted so as to maintain an approximately constant level of default risk throughout the life of the fund. Numerical simulations show that applying dynamic leverage to a small portfolio of orphan drug candidates can boost the return on equity almost twofold compared with securitization with a static capital structure. Dynamic leverage can also add significant value to comparable all-equity-financed portfolios, enhancing the return on equity without jeopardizing debt performance or increasing risk to equity investors.

  5. Financing drug discovery via dynamic leverage.

    Science.gov (United States)

    Montazerhodjat, Vahid; Frishkopf, John J; Lo, Andrew W

    2016-03-01

    We extend the megafund concept for funding drug discovery to enable dynamic leverage in which the portfolio of candidate therapeutic assets is predominantly financed initially by equity, and debt is introduced gradually as assets mature and begin generating cash flows. Leverage is adjusted so as to maintain an approximately constant level of default risk throughout the life of the fund. Numerical simulations show that applying dynamic leverage to a small portfolio of orphan drug candidates can boost the return on equity almost twofold compared with securitization with a static capital structure. Dynamic leverage can also add significant value to comparable all-equity-financed portfolios, enhancing the return on equity without jeopardizing debt performance or increasing risk to equity investors. PMID:26708982

  6. Proteomic biomarkers associated with Streptococcus agalactiae invasive genogroups.

    Directory of Open Access Journals (Sweden)

    Philippe Lanotte

    Full Text Available Group B streptococcus (GBS, Streptococcus agalactiae is a leading cause of meningitis and sepsis in newborns and an etiological agent of meningitis, endocarditis, osteoarticular and soft tissue infections in adults. GBS isolates are routinely clustered in serotypes and in genotypes. At present one GBS sequence type (i.e. ST17 is considered to be closely associated with bacterial invasiveness and novel proteomic biomarkers could make a valuable contribution to currently available GBS typing data. For that purpose we analyzed the protein profiles of 170 genotyped GBS isolates by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI. Univariate statistical analysis of the SELDI profiles identified four protein biomarkers significantly discriminating ST17 isolates from those of the other sequence types. Two of these biomarkers (MW of 7878 Da and 12200 Da were overexpressed and the other two (MW of 6258 Da and 10463 Da were underexpressed in ST17. The four proteins were isolated by mass spectrometry-assisted purification and their tryptic peptides analyzed by LC-MS/MS. They were thereby identified as the small subunit of exodeoxyribonuclease VII, the 50S ribosomal protein L7/L12, a CsbD-like protein and thioredoxin, respectively. In conclusion, we identified four candidate biomarkers of ST17 by SELDI for high-throughput screening. These markers may serve as a basis for further studies on the pathophysiology of GBS infection, and for the development of novel vaccines.

  7. Circulating Biomarkers of Interstitial Lung Disease in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Harpreet K. Lota

    2012-01-01

    Full Text Available Interstitial lung disease (ILD is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc. Although a large proportion of SSc patients have only limited interstitial involvement with an indolent course, in a significant minority ILD is progressive, requiring prompt treatment and careful monitoring. One of the main challenges for the clinician treating this highly variable disease is the early identification of patients at risk of progressive ILD, while avoiding potentially toxic treatments in those whose disease is inherently stable. Easily available and repeatable biomarkers that allow estimation of the risk of ILD progression and early response to treatment are highly desirable. In this paper, we review the evidence for circulating biomarkers with potential roles in diagnosis, monitoring of disease activity, or determining prognosis. Peripheral blood biomarkers offer the advantages of being readily obtained, non-invasive, and serially monitored. Several possible candidates have emerged from studies performed so far, including SP-D, KL-6, and CCL18. Presently however, there are few prospective studies evaluating the predictive ability of prospective biomarkers after adjustment for disease severity. Future carefully designed, prospective studies of well characterised patients with ILD, with optimal definition of disease severity and outcome measures are needed.

  8. Biomarkers for Circadian Rhythm Disruption Independent of Time of Day

    Science.gov (United States)

    Van Dycke, Kirsten C. G.; Pennings, Jeroen L. A.; van Oostrom, Conny T. M.; van Kerkhof, Linda W. M.; van Steeg, Harry; van der Horst, Gijsbertus T. J.; Rodenburg, Wendy

    2015-01-01

    Frequent shift work causes disruption of the circadian rhythm and might on the long-term result in increased health risk. Current biomarkers evaluating the presence of circadian rhythm disturbance (CRD), including melatonin, cortisol and body temperature, require 24-hr (“around the clock”) measurements, which is tedious. Therefore, these markers are not eligible to be used in large-scale (human) studies. The aim of the present study was to identify universal biomarkers for CRD independent of time of day using a transcriptomics approach. Female FVB mice were exposed to six shifts in a clockwise (CW) and counterclockwise (CCW) CRD protocol and sacrificed at baseline and after 1 shift, 6 shifts, 5 days recovery and 14 days recovery, respectively. At six time-points during the day, livers were collected for mRNA microarray analysis. Using a classification approach, we identified a set of biomarkers able to classify samples into either CRD or non-disrupted based on the hepatic gene expression. Furthermore, we identified differentially expressed genes 14 days after the last shift compared to baseline for both CRD protocols. Non-circadian genes differentially expressed upon both CW and CCW protocol were considered useful, universal markers for CRD. One candidate marker i.e. CD36 was evaluated in serum samples of the CRD animals versus controls. These biomarkers might be useful to measure CRD and can be used later on for monitoring the effectiveness of intervention strategies aiming to prevent or minimize chronic adverse health effects. PMID:25984797

  9. Biomarker in archaeological soils

    Science.gov (United States)

    Wiedner, Katja; Glaser, Bruno; Schneeweiß, Jens

    2015-04-01

    The use of biomarkers in an archaeological context allow deeper insights into the understanding of anthropogenic (dark) earth formation and from an archaeological point of view, a completely new perspective on cultivation practices in the historic past. During an archaeological excavation of a Slavic settlement (10th/11th C. A.D.) in Brünkendorf (Wendland region in Northern Germany), a thick black soil (Nordic Dark Earth) was discovered that resembled the famous terra preta phenomenon. For the humid tropics, terra preta could act as model for sustainable agricultural practices and as example for long-term CO2-sequestration into terrestrial ecosystems. The question was whether this Nordic Dark Earth had similar properties and genesis as the famous Amazonian Dark Earth in order to find a model for sustainable agricultural practices and long term CO2-sequestration in temperate zones. For this purpose, a multi-analytical approach was used to characterize the sandy-textured Nordic Dark Earth in comparison to less anthropogenically influenced soils in the adjacent area in respect of ecological conditions (e.g. amino sugar), input materials (faeces) and the presence of stable soil organic matter (black carbon). Amino sugar analyses showed that Nordic Dark Earth contained higher amounts of microbial residues being dominated by soil fungi. Faecal biomarkers such as stanols and bile acids indicated animal manure from omnivores and herbivores but also human excrements. Black carbon content of about 30 Mg ha-1 in the Nordic Dark Earth was about four times higher compared to the adjacent soil and in the same order of magnitude compared to terra preta. Our data strongly suggest parallels to anthropogenic soil formation in Amazonia and in Europe by input of organic wastes, faecal material and charred organic matter. An obvious difference was that in terra preta input of human-derived faecal material dominated while in NDE human-derived faecal material played only a minor role

  10. 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.

  11. Biomarkers of latent TB infection

    DEFF Research Database (Denmark)

    Ruhwald, Morten; Ravn, Pernille

    2009-01-01

    For the last 100 years, the tuberculin skin test (TST) has been the only diagnostic tool available for latent TB infection (LTBI) and no biomarker per se is available to diagnose the presence of LTBI. With the introduction of M. tuberculosis-specific IFN-gamma release assays (IGRAs), a new area of...... in vitro immunodiagnostic tests for LTBI based on biomarker readout has become a reality. In this review, we discuss existing evidence on the clinical usefulness of IGRAs and the indefinite number of potential new biomarkers that can be used to improve diagnosis of latent TB infection. We also...... present early data suggesting that the monocyte-derived chemokine inducible protein-10 may be useful as a novel biomarker for the immunodiagnosis of latent TB infection....

  12. Cardiac Biomarkers and Cycling Race

    OpenAIRE

    Caroline Le Goff, Jean-François Kaux, Sébastien Goffaux, Etienne Cavalier

    2015-01-01

    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 bi...

  13. Biomarkers in Acute Lung Injury

    OpenAIRE

    Bhargava, Maneesh; Wendt, Chris

    2012-01-01

    Acute Respiratory Distress Syndrome (ARDS) and Acute Lung Injury (ALI) result in high permeability pulmonary edema causing hypoxic respiratory failure with high morbidity and mortality. As the population ages, the incidence of ALI is expected to rise. Over the last decade, several studies have identified biomarkers in plasma and bronchoalveolar lavage fluid providing important insights into the mechanisms involved in the pathophysiology of ALI. Several biomarkers have been validated in subjec...

  14. Biomarkers in Prostate Cancer Epidemiology

    OpenAIRE

    Mudit Verma; Mukesh Verma; Payal Patel

    2011-01-01

    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 ris...

  15. A Decade of Discovery

    Energy Technology Data Exchange (ETDEWEB)

    None

    2008-01-01

    This book provides a fascinating account of some of the most significant scientific discoveries and technological innovations coming out of the U.S. Department of Energy’s National Laboratories. This remarkable book illustrates how the men and women of the National Laboratories are keeping us on the cutting edge. Though few Americans are familiar with the scope and scale of the work conducted at these National Laboratories, their research is literally changing our lives and bettering our planet. The book describes the scientific discoveries and technological advancements "in recognition of the men and women working in DOE's seventeen national laboratories across the country." Through highly vivid and accessible stories, this book details recent breakthroughs in three critical areas: 1) Energy and Environment, 2) National Security and 3) Life and Physical Science. The book illustrates how this government-funded research has resulted in more energy-efficient buildings; new, cleaner alternative fuels that reduce greenhouse gas emissions; safer, more efficient, nuclear power plants; improved responses to disease outbreaks; more secure and streamlined airport security; more effective treatments for cancer and other diseases; and astonishing discoveries that are altering our understanding of the universe and enabling scientific breakthroughs in fields such as nanotechnology and particle physics. Specifically, it contains 37 stories. A Decade of Discovery is truly a recent history of discovery - and a fascinating look at what the next decade holds.

  16. Domain-specific Web Service Discovery with Service Class Descriptions

    Energy Technology Data Exchange (ETDEWEB)

    Rocco, D; Caverlee, J; Liu, L; Critchlow, T J

    2005-02-14

    This paper presents DynaBot, a domain-specific web service discovery system. The core idea of the DynaBot service discovery system is to use domain-specific service class descriptions powered by an intelligent Deep Web crawler. In contrast to current registry-based service discovery systems--like the several available UDDI registries--DynaBot promotes focused crawling of the Deep Web of services and discovers candidate services that are relevant to the domain of interest. It uses intelligent filtering algorithms to match services found by focused crawling with the domain-specific service class descriptions. We demonstrate the capability of DynaBot through the BLAST service discovery scenario and describe our initial experience with DynaBot.

  17. Analysis of biomarker data a practical guide

    CERN Document Server

    Looney, Stephen W

    2015-01-01

    A "how to" guide for applying statistical methods to biomarker data analysis Presenting a solid foundation for the statistical methods that are used to analyze biomarker data, Analysis of Biomarker Data: A Practical Guide features preferred techniques for biomarker validation. The authors provide descriptions of select elementary statistical methods that are traditionally used to analyze biomarker data with a focus on the proper application of each method, including necessary assumptions, software recommendations, and proper interpretation of computer output. In addition, the book discusses

  18. Neuroimmune biomarkers in schizophrenia.

    Science.gov (United States)

    Tomasik, Jakub; Rahmoune, Hassan; Guest, Paul C; Bahn, Sabine

    2016-09-01

    Schizophrenia is a heterogeneous psychiatric disorder with a broad spectrum of clinical and biological manifestations. Due to the lack of objective tests, the accurate diagnosis and selection of effective treatments for schizophrenia remains challenging. Numerous technologies have been employed in search of schizophrenia biomarkers. These studies have suggested that neuroinflammatory processes may play a role in schizophrenia pathogenesis, at least in a subgroup of patients. The evidence indicates alterations in both pro- and anti-inflammatory molecules in the central nervous system, which have also been found in peripheral tissues and may correlate with schizophrenia symptoms. In line with these findings, certain immunomodulatory interventions have shown beneficial effects on psychotic symptoms in schizophrenia patients, in particular those with distinct immune signatures. In this review, we evaluate these findings and their potential for more targeted drug interventions and the development of companion diagnostics. Although currently no validated markers exist for schizophrenia patient stratification or the prediction of treatment efficacy, we propose that utilisation of inflammatory markers for diagnostic and theranostic purposes may lead to novel therapeutic approaches and deliver more effective care for schizophrenia patients. PMID:25124519

  19. Biomarkers in connective tissue disease-associated interstitial lung disease.

    Science.gov (United States)

    Bonella, Francesco; Costabel, Ulrich

    2014-04-01

    This article reviews major biomarkers in serum and bronchoalveolar lavage fluid (BALF) with respect to their diagnostic and prognostic value in connective tissue disease-associated interstitial lung disease (CTD-ILD). In some CTD such as systemic sclerosis (SSc), the incidence of ILD is up to two-third of patients, and currently ILD represents the leading cause of death in SSc. Because of the extremely variable incidence and outcome of ILD in CTD, progress in the discovery and validation of biomarkers for diagnosis, prognosis, patients' subtyping, response to treatment, or as surrogate endpoints in clinical trials is extremely important. In contrast to idiopathic interstitial pneumonias, autoantibodies play a crucial role as biomarkers in CTD-ILD because their presence is strictly linked to the pathogenesis and tissue damage. Patterns of autoantibodies, for instance, anticitrullinated peptide antibodies in rheumatoid arthritis or aminoacyl-tRNA synthetases (ARS) in polymyositis/dermatomyositis, have been found to correlate with the presence and occasionally with the course of ILD in CTD. Besides autoantibodies, an increase in serum or BALF of a biomarker of pulmonary origin may be able to predict or reflect the development of fibrosis, the impairment of lung function, and ideally also the prognosis. Promising biomarkers are lung epithelium-derived proteins such as KL-6 (Krebs von den Lungen-6), SP-D (surfactant protein-D), SP-A (surfactant protein-A), YKL-40 (chitinase-3-like protein 1 [CHI3L1] or cytokines such as CCL18 [chemokine (C-C) motif ligand 18]). In the future, genetic/epigenetic markers, such as human leukocyte antigen (HLA) haplotypes, single nucleotide polymorphisms, and micro-RNA, may help to identify subtypes of patients with different needs of management and treatment strategies. PMID:24668534

  20. A lectin-coupled, targeted proteomic mass spectrometry (MRM MS) platform for identification of multiple liver cancer biomarkers in human plasma.

    Science.gov (United States)

    Ahn, Yeong Hee; Shin, Park Min; Oh, Na Ree; Park, Gun Wook; Kim, Hoguen; Yoo, Jong Shin

    2012-09-18

    Aberrantly glycosylated proteins related to liver cancer progression were captured with specific lectin and identified from human plasma by multiple reaction monitoring (MRM) mass spectrometry as multiple biomarkers for hepatocellular carcinoma (HCC). The lectin fractionation for fucosylated protein glycoforms in human plasma was conducted with a fucose-specific aleuria aurantia lectin (AAL). Following tryptic digestion of the lectin-captured fraction, plasma samples from 30 control cases (including 10 healthy, 10 hepatitis B virus [HBV], and 10 cirrhosis cases) and 10 HCC cases were quantitatively analyzed by MRM to identify which glycoproteins are viable HCC biomarkers. A1AG1, AACT, A1AT, and CERU were found to be potent biomarkers to differentiate HCC plasma from control plasmas. The AUROC generated independently from these four biomarker candidates ranged from 0.73 to 0.92. However, the lectin-coupled MRM assay with multiple combinations of biomarker candidates is superior statistically to those generated from the individual candidates with AUROC more than 0.95, which can be an alternative to the immunoassay inevitably requiring tedious development of multiple antibodies against biomarker candidates to be verified. Eventually the lectin-coupled, targeted proteomic mass spectrometry (MRM MS) platform was found to be efficient to identify multiple biomarkers from human plasma according to cancer progression. PMID:22789673