WorldWideScience

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. 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

  4. 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...

  5. Glycoscience aids in biomarker discovery

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

  7. Biomarkers of silicosis: Potential candidates

    Directory of Open Access Journals (Sweden)

    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.

  8. Network-Based Protein Biomarker Discovery Platforms.

    Science.gov (United States)

    Kim, Minhyung; Hwang, Daehee

    2016-03-01

    The advances in mass spectrometry-based proteomics technologies have enabled the generation of global proteome data from tissue or body fluid samples collected from a broad spectrum of human diseases. Comparative proteomic analysis of global proteome data identifies and prioritizes the proteins showing altered abundances, called differentially expressed proteins (DEPs), in disease samples, compared to control samples. Protein biomarker candidates that can serve as indicators of disease states are then selected as key molecules among these proteins. Recently, it has been addressed that cellular pathways can provide better indications of disease states than individual molecules and also network analysis of the DEPs enables effective identification of cellular pathways altered in disease conditions and key molecules representing the altered cellular pathways. Accordingly, a number of network-based approaches to identify disease-related pathways and representative molecules of such pathways have been developed. In this review, we summarize analytical platforms for network-based protein biomarker discovery and key components in the platforms. PMID:27103885

  9. The proteomics in prostate cancer biomarker discovery

    Directory of Open Access Journals (Sweden)

    V. E. Shevchenko

    2015-06-01

    Full Text Available Prostate cancer (PC represents the second most frequent type of tumor in men worldwide. Proteomics represents a promising approach for the discovery of new biomarkers able to improve the management of PC patients. Markers more specific and sensitive than prostate-specific antigen are needed for PC diagnosis, prognosis and response to treatment. Moreover, proteomics could represent an important tool to identify new molecular targets for PC tailored therapy. Now several possible PC biomarkers sources, each with advantages and limitations, are under investigation, including tissues, urine, serum, plasma and prostatic fluids. Innovative high-throughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PC detection, stratification and treatment. Nevertheless, many putative biomarkers are still far from being applied in clinical practice.This review aims to discuss the recent advances in PC proteomics, emphasizing biomarker discovery and their application to clinical utility for diagnosis and patient stratification.

  10. 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.

  11. Cerebrospinal fluid biomarker candidates for parkinsonian disorders

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    RaduConstantinescu

    2013-01-01

    Full Text Available The parkinsonian disorders are a large group of neurodegenerative diseases including idiopathic Parkinson's disease (PD and atypical parkinsonian disorders, such as multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies. The etiology of these disorders is not known although it is considered to be a combination of genetic and environmental factors. One of the greatest obstacles for developing efficacious disease-modifying treatment strategies is the lack of biomarkers. Reliable biomarkers are needed for early and accurate diagnosis, to measure disease progression and response to therapy. In this review several of the most promising cerebrospinal biomarker candidates are discussed. Alpha synuclein seems to be intimately involved in the pathogenesis of synucleinopathies and its levels can be measured in the cerebrospinal fluid and in plasma. In a similar way, tau protein accumulation seems to be involved in the pathogenesis of tauopathies. Urate, a potent antioxidant, seems to be associated to the risk of developing PD and with its progression. Neurofilament light chain levels are increased in atypical parkinsonian disorders compared with PD and healthy controls. The new "omics" techniques are potent tools offering new insights in the patho-etiology of these disorders. Some of the difficulties encountered in developing biomarkers are discussed together with future perspectives.

  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

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    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. Integration of Proteomics, Bioinformatics, and Systems Biology in Traumatic Brain Injury Biomarker Discovery

    OpenAIRE

    Guingab-Cagmat, J.D.; Cagmat, E.B.; Hayes, R. L.; Anagli, J.

    2013-01-01

    Traumatic brain injury (TBI) is a major medical crisis without any FDA-approved pharmacological therapies that have been demonstrated to improve functional outcomes. It has been argued that discovery of disease-relevant biomarkers might help to guide successful clinical trials for TBI. Major advances in mass spectrometry (MS) have revolutionized the field of proteomic biomarker discovery and facilitated the identification of several candidate markers that are being further evaluated for their...

  15. Integration of Proteomics, Bioinformatics and Systems biology in Brain Injury Biomarker Discovery

    OpenAIRE

    JoyGuingab-Cagmat

    2013-01-01

    Traumatic brain injury (TBI) is a major medical crisis without any FDA-approved pharmacological therapies that have been demonstrated to improve functional outcomes. It has been argued that discovery of disease-relevant biomarkers might help to guide successful clinical trials for TBI. Major advances in mass spectrometry (MS) have revolutionized the field of proteomic biomarker discovery and facilitated the identification of several candidate markers that are being further evaluated for thei...

  16. Integration of Proteomics, Bioinformatics and Systems biology in Brain Injury Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    JoyGuingab-Cagmat

    2013-05-01

    Full Text Available Traumatic brain injury (TBI is a major medical crisis without any FDA-approved pharmacological therapies that have been demonstrated to improve functional outcomes. It has been argued that discovery of disease-relevant biomarkers might help to guide successful clinical trials for TBI. Major advances in mass spectrometry (MS have revolutionized the field of proteomic biomarker discovery and facilitated the identification of several candidate markers that are being further evaluated for their efficacy as TBI biomarkers. However, several hurdles have to be overcome even during the discovery phase which is only the first step in the long process of biomarker development. The high throughput nature of MS-based proteomic experiments generates a massive amount of mass spectral data presenting great challenges in downstream interpretation. Currently, different bioinformatics platforms are available for functional analysis and data mining of MS-generated proteomic data. These tools provide a way to convert data sets to biologically interpretable results and functional outcomes. A strategy that has promise in advancing biomarker development involves the triad of proteomics, bioinformatics and systems biology. In this review, a brief overview of how bioinformatics and systems biology tools analyze, transform and interpret complex MS datasets into biologically relevant results is discussed. In addition, challenges and limitations of proteomics, bioinformatics and systems biology in TBI biomarker discovery are presented. A brief survey of researches that utilized these three overlapping disciplines in TBI biomarker discovery is also presented. Finally, examples of TBI biomarkers and their applications are discussed.

  17. Integration of proteomics, bioinformatics, and systems biology in traumatic brain injury biomarker discovery.

    Science.gov (United States)

    Guingab-Cagmat, J D; Cagmat, E B; Hayes, R L; Anagli, J

    2013-01-01

    Traumatic brain injury (TBI) is a major medical crisis without any FDA-approved pharmacological therapies that have been demonstrated to improve functional outcomes. It has been argued that discovery of disease-relevant biomarkers might help to guide successful clinical trials for TBI. Major advances in mass spectrometry (MS) have revolutionized the field of proteomic biomarker discovery and facilitated the identification of several candidate markers that are being further evaluated for their efficacy as TBI biomarkers. However, several hurdles have to be overcome even during the discovery phase which is only the first step in the long process of biomarker development. The high-throughput nature of MS-based proteomic experiments generates a massive amount of mass spectral data presenting great challenges in downstream interpretation. Currently, different bioinformatics platforms are available for functional analysis and data mining of MS-generated proteomic data. These tools provide a way to convert data sets to biologically interpretable results and functional outcomes. A strategy that has promise in advancing biomarker development involves the triad of proteomics, bioinformatics, and systems biology. In this review, a brief overview of how bioinformatics and systems biology tools analyze, transform, and interpret complex MS datasets into biologically relevant results is discussed. In addition, challenges and limitations of proteomics, bioinformatics, and systems biology in TBI biomarker discovery are presented. A brief survey of researches that utilized these three overlapping disciplines in TBI biomarker discovery is also presented. Finally, examples of TBI biomarkers and their applications are discussed. PMID:23750150

  18. 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.

  19. 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.

  20. 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.

  1. Metabolomics for Biomarker Discovery in Gastroenterological Cancer

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    Shin Nishiumi

    2014-07-01

    Full Text Available The study of the omics cascade, which involves comprehensive investigations based on genomics, transcriptomics, proteomics, metabolomics, etc., has developed rapidly and now plays an important role in life science research. Among such analyses, metabolome analysis, in which the concentrations of low molecular weight metabolites are comprehensively analyzed, has rapidly developed along with improvements in analytical technology, and hence, has been applied to a variety of research fields including the clinical, cell biology, and plant/food science fields. The metabolome represents the endpoint of the omics cascade and is also the closest point in the cascade to the phenotype. Moreover, it is affected by variations in not only the expression but also the enzymatic activity of several proteins. Therefore, metabolome analysis can be a useful approach for finding effective diagnostic markers and examining unknown pathological conditions. The number of studies involving metabolome analysis has recently been increasing year-on-year. Here, we describe the findings of studies that used metabolome analysis to attempt to discover biomarker candidates for gastroenterological cancer and discuss metabolome analysis-based disease diagnosis.

  2. Biomarker discovery in mass spectrometry-based urinary proteomics.

    Science.gov (United States)

    Thomas, Samuel; Hao, Ling; Ricke, William A; Li, Lingjun

    2016-04-01

    Urinary proteomics has become one of the most attractive topics in disease biomarker discovery. MS-based proteomic analysis has advanced continuously and emerged as a prominent tool in the field of clinical bioanalysis. However, only few protein biomarkers have made their way to validation and clinical practice. Biomarker discovery is challenged by many clinical and analytical factors including, but not limited to, the complexity of urine and the wide dynamic range of endogenous proteins in the sample. This article highlights promising technologies and strategies in the MS-based biomarker discovery process, including study design, sample preparation, protein quantification, instrumental platforms, and bioinformatics. Different proteomics approaches are discussed, and progresses in maximizing urinary proteome coverage and standardization are emphasized in this review. MS-based urinary proteomics has great potential in the development of noninvasive diagnostic assays in the future, which will require collaborative efforts between analytical scientists, systems biologists, and clinicians. PMID:26703953

  3. Cancer biomarker discovery in saliva by mass spectrometry

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    Kiran S. Ambatipudi

    2014-05-01

    Full Text Available The quest for biomarkers has been much pursued to aid in the early diagnosis, monitor post-treatment progress and development of targeted therapies. Nevertheless, the translation of biomarker discovery to clinical use has been limited due to multiple reasons such as the long path from discovery to clinical assays, limitation of samples and incoherent pipeline for biomarker development. To date, diagnosis of cancer has been based on biopsies and histological examinations and often becomes difficult to get repeated sampling from patients for confirmation. Consequently, it is important for clinical researchers to look at multiple body fluids and different molecular techniques to identify biomarkers. One such bodyfluid is saliva, which is easily and non-invasively collected and contains thousands of potential protein biomarkers. Moreover, recent advances in the sensitivity and specificity of mass spectrometry based proteomics hold great promise to identify potential biomarkers. This review presents an overview of the potential use of saliva and mass spectrometry for global discovery and validation of biomarkers.

  4. Biomarker discovery in asthma and COPD: Application of proteomics techniques in human and mice

    Directory of Open Access Journals (Sweden)

    Steven Haenen

    2014-09-01

    Full Text Available The use of advanced proteomics approaches in the search for biomarkers in chronic lung diseases, such as asthma and COPD, is rather limited. Asthma and COPD are complex disorders, which can be subdivided into several phenotypes. This results in a heterogeneity of differential expressed biological molecules. Furthermore, genetic differences between animals and humans make ‘translation’ of possible biomarkers challenging. Yet, the improved sensitivity and high throughput of proteomic techniques could be an important asset for (new protein biomarker discovery in either human or animal models. We have reviewed the literature that reported the use of different proteomics approaches performed on samples obtained from humans and murine models in asthma and COPD research for the discovery of new biomarkers of diseases, biomarkers of sensitization or for the refinement of treatment. There is an increasing trend in the use of proteomics to explore new biomarkers of asthma or COPD. Although several murine models have been developed to study these lung diseases, and proteomics studies have been performed, ‘translation’ of identified candidate biomarkers into clinical studies is often lacking.

  5. The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification.

    Science.gov (United States)

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

    2016-01-01

    Mass spectrometry (MS) -based proteomics has become an indispensable tool with broad applications in systems biology and biomedical research. With recent advances in liquid chromatography (LC) and MS instrumentation, LC-MS is making increasingly significant contributions to clinical applications, especially in the area of cancer biomarker discovery and verification. To overcome challenges associated with analyses of clinical samples (for example, a wide dynamic range of protein concentrations in bodily fluids and the need to perform high throughput and accurate quantification of candidate biomarker proteins), significant efforts have been devoted to improve the overall performance of LC-MS-based clinical proteomics platforms. Reviewed here are the recent advances in LC-MS and its applications in cancer biomarker discovery and quantification, along with the potentials, limitations and future perspectives. PMID:26581546

  6. 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

  7. Development and evaluation of statistical approaches in proteomic biomarker discovery

    OpenAIRE

    Patel, Amit

    2011-01-01

    A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. The aim of this project was to deal with the identification of potential biomarker candidates from experimental data comparing samples displaying divergent physiological traits. Chapter 1 introduces the topic and the aims of the project. The primary aim was to identify the ideal statistical a...

  8. Secreted proteins as a fundamental source for biomarker discovery

    Czech Academy of Sciences Publication Activity Database

    Šťastná, Miroslava; Van Eyk, J.E.

    2012-01-01

    Roč. 12, 4-5 (2012), s. 722-735. ISSN 1615-9853 Institutional research plan: CEZ:AV0Z40310501 Keywords : conditioned media * secreted proteins * proteomics * biomarker discovery Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 4.132, year: 2012

  9. 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...... of a patient’s response to a particular treatment, thus helping to avoid unnecessary treatment and unwanted side effects in non-responding individuals.Currently biomarker discovery is facilitated by recent advances in high-throughput technologies when association between a given biological phenotype...... levels show random distribution in a given cohort. However, gene expression levels may also be affected by technical bias when the actual measurement technology or sample handling may introduce a systematic error. If the distribution of systematic errors correlates with the biological phenotype then the...

  10. Application of “omics” to Prion Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Rhiannon L. C. H. Huzarewich

    2010-01-01

    Full Text Available The advent of genomics and proteomics has been a catalyst for the discovery of biomarkers able to discriminate biological processes such as the pathogenesis of complex diseases. Prompt detection of prion diseases is particularly desirable given their transmissibility, which is responsible for a number of human health risks stemming from exogenous sources of prion protein. Diagnosis relies on the ability to detect the biomarker PrPSc, a pathological isoform of the host protein PrPC, which is an essential component of the infectious prion. Immunochemical detection of PrPSc is specific and sensitive enough for antemortem testing of brain tissue, however, this is not the case in accessible biological fluids or for the detection of recently identified novel prions with unique biochemical properties. A complementary approach to the detection of PrPSc itself is to identify alternative, “surrogate” gene or protein biomarkers indicative of disease. Biomarkers are also useful to track the progress of disease, especially important in the assessment of therapies, or to identify individuals “at risk”. In this review we provide perspective on current progress and pitfalls in the use of “omics” technologies to screen body fluids and tissues for biomarker discovery in prion diseases.

  11. 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

  12. 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.

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

    International Nuclear Information System (INIS)

    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

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

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    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.

  15. 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.

  16. 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

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

    Directory of Open Access Journals (Sweden)

    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

  18. Data mining of spectroscopic data for biomarker discovery.

    Science.gov (United States)

    Norton, S M; Huyn, P; Hastings, C A; Heller, J C

    2001-05-01

    The goals of precise diagnosis, prevention and treatment of disease can be realized through the discovery of biological markers. Spectroscopic tools can simultaneously detect and quantify multiple small molecule and macromolecular components of biological samples, and are therefore ideal methods for the discovery of previously uncharacterized markers. However, the identification of meaningful spectral features is complicated by the lack of foreknowledge of the molecular nature of a disease, spectral noise and biological variability that is uncorrelated with the disease state. Pattern recognition techniques, both statistical and machine-learning, have been increasingly used in recent years with spectroscopic data to identify markers and classify patients into disease subsets. This review summarizes recent developments, limitations and future prospects in the use of data mining techniques with magnetic resonance spectroscopy, mass spectrometry and optical spectroscopy for the discovery of biomarkers. PMID:11560066

  19. Candidate List of yoUr Biomarker (CLUB: A Web-based Platform to Aid Cancer Biomarker Research

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    N. Leigh Anderson

    2008-01-01

    Full Text Available CLUB (“Candidate List of yoUr Biomarkers” is a freely available, web-based resource designed to support Cancer biomarker research. It is targeted to provide a comprehensive list of candidate biomarkers for various cancers that have been reported by the research community. CLUB provides tools for comparison of marker candidates from different experimental platforms, with the ability to filter, search, query and explore, molecular interaction networks associated with cancer biomarkers from the published literature and from data uploaded by the community. This complex and ambitious project is implemented in phases. As a first step, we have compiled from the literature an initial set of differentially expressed human candidate cancer biomarkers. Each candidate is annotated with information from publicly available databases such as Gene Ontology, Swiss-Prot database, National Center for Biotechnology Information’s reference sequences, Biomolecular Interaction Network Database and IntAct interaction. The user has the option to maintain private lists of biomarker candidates or share and export these for use by the community. Furthermore, users may customize and combine commonly used sets of selection procedures and apply them as a stored workflow using selected candidate lists. To enable an assessment by the user before taking a candidate biomarker to the experimental validation stage, the platform contains the functionality to identify pathways associated with cancer risk, staging, prognosis, outcome in cancer and other clinically associated phenotypes. The system is available at http://club.bii.a-star.edu.sg.

  20. 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.

  1. 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)

  2. Novel automated biomarker discovery work flow for urinary peptidomics

    DEFF Research Database (Denmark)

    Balog, Crina I.; Hensbergen, Paul J.; Derks, Rico; Verweij, Jaco J.; Dam, Govert J. van; Vennervald, Birgitte J; Deelder, André M.; Mayboroda, Oleg A.

    2009-01-01

    Urine is potentially a rich source of peptide biomarkers, but reproducible, high-throughput peptidomic analysis is often hampered by the inherent variability in factors such as pH and salt concentration. Our goal was to develop a generally applicable, rapid, and robust method for screening large...... numbers of urine samples, resulting in a broad spectrum of native peptides, as a tool to be used for biomarker discovery. METHODS: Peptide samples were trapped, desalted, pH-normalized, and fractionated on a miniaturized automatic reverse-phase strong cation exchange (RP-SCX) cartridge system. We analyzed...... 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...

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Mass Spectrometry-Based Biomarker Discovery: Toward a Global Proteome Index of Individuality

    Science.gov (United States)

    Hawkridge, Adam M.; Muddiman, David C.

    2009-07-01

    Biomarker discovery and proteomics have become synonymous with mass spectrometry in recent years. Although this conflation is an injustice to the many essential biomolecular techniques widely used in biomarker-discovery platforms, it underscores the power and potential of contemporary mass spectrometry. Numerous novel and powerful technologies have been developed around mass spectrometry, proteomics, and biomarker discovery over the past 20 years to globally study complex proteomes (e.g., plasma). However, very few large-scale longitudinal studies have been carried out using these platforms to establish the analytical variability relative to true biological variability. The purpose of this review is not to cover exhaustively the applications of mass spectrometry to biomarker discovery, but rather to discuss the analytical methods and strategies that have been developed for mass spectrometry-based biomarker-discovery platforms and to place them in the context of the many challenges and opportunities yet to be addressed.

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. Predictive biomarkers for personalised anti-cancer drug use: discovery to clinical implementation.

    Science.gov (United States)

    Alymani, Nayef A; Smith, Murray D; Williams, David J; Petty, Russell D

    2010-03-01

    A priority translational research objective in cancer medicine is the discovery of novel therapeutic targets for solid tumours. Ideally, co-discovery of predictive biomarkers occurs in parallel to facilitate clinical development of agents and ultimately personalise clinical use. However, the identification of clinically useful predictive biomarkers for solid tumours has proven challenging with many initially promising biomarkers failing to translate into clinically useful applications. In particular, the 'failure' of a predictive biomarker has often only become apparent at a relatively late stage in investigation. Recently, the field has recognised the need to develop a robust clinical biomarker development methodology to facilitate the process. This review discusses the recent progress in this area focusing on the key stages in the biomarker development process: discovery, validation, qualification and implementation. Concentrating on predictive biomarkers for selecting systemic therapies for individual patients in the clinic, the advances and progress in each of these stages in biomarker development are outlined and the key remaining challenges are discussed. Specific examples are discussed to illustrate the challenges identified and how they have been addressed. Overall, we find that significant progress has been made towards a formalised biomarker developmental process. This holds considerable promise for facilitating the translation of predictive biomarkers from discovery to clinical implementation. Further enhancements could eventually be found through alignment with regulatory processes. PMID:20138504

  13. 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

    RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients. PREDICT's approach to predictive biomarker discovery differs from conventional associative learning approaches, which can be susceptible to the detection of...... European network providing the technological and clinical platform for large-scale functional genomic biomarker discovery. Here we review our current understanding of molecular mechanisms driving resistance to anti-angiogenesis agents, the current limitations of laboratory and clinical trial strategies and...... how the PREDICT consortium will endeavour to identify a new generation of predictive biomarkers....

  14. 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

  15. 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.

  16. 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...

  17. 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

  18. Biomarker Discovery in Animal Health and Disease: The Application of Post-Genomic Technologies

    Directory of Open Access Journals (Sweden)

    Rowan E. Moore

    2007-01-01

    Full Text Available The causes of many important diseases in animals are complex and multifactorial, which present unique challenges. Biomarkers indicate the presence or extent of a biological process, which is directly linked to the clinical manifestations and outcome of a particular disease. Identifying biomarkers or biomarker profiles will be an important step towards disease characterization and management of disease in animals. The emergence of post-genomic technologies has led to the development of strategies aimed at identifying specific and sensitive biomarkers from the thousands of molecules present in a tissue or biological fluid. This review will summarize the current developments in biomarker discovery and will focus on the role of transcriptomics, proteomics and metabolomics in biomarker discovery for animal health and disease.

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

    OpenAIRE

    Vilém Guryča; Daniel Roeder; Paolo Piraino; Jens Lamerz; Axel Ducret; Hanno Langen; Paul Cutler

    2014-01-01

    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 t...

  20. Prostate cancer serum biomarker discovery through proteomic analysis of alpha-2 macroglobulin protein complexes

    Science.gov (United States)

    Burgess, Earle F.; Ham, Amy-Joan L.; Tabb, David L.; Billheimer, Dean; Roth, Bruce J.; Chang, Sam S.; Cookson, Michael S.; Hinton, Timothy J.; Cheek, Kristin L.; Hill, Salisha; Pietenpol, Jennifer A.

    2010-01-01

    Alpha-2 macroglobulin (A2M) functions as a universal protease inhibitor in serum and is capable of binding various cytokines and growth factors. In this study, we investigated if immunoaffinity enrichment and proteomic analysis of A2M protein complexes from human serum could improve detection of biologically relevant and novel candidate protein biomarkers in prostate cancer. Serum samples from six patients with androgen-independent, metastatic prostate cancer and six control patients without malignancy were analyzed by immunoaffinity enrichment of A2M protein complexes and MS identification of associated proteins. Known A2M substrates were reproducibly identified from patient serum in both cohorts, as well as proteins previously undetected in human serum. One example is heat shock protein 90 alpha (HSP90α), which was identified only in the serum of cancer patients in this study. Using an ELISA, the presence of HSP90α in human serum was validated on expanded test cohorts and found to exist in higher median serum concentrations in prostate cancer (n = 18) relative to control (n = 13) patients (median concentrations 50.7 versus 27.6 ng/mL, respectively, p = 0.001). Our results demonstrate the technical feasibility of this approach and support the analysis of A2M protein complexes for proteomic-based serum biomarker discovery. PMID:20107526

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

    DEFF Research Database (Denmark)

    Mikkelsen, Jens D.; Thomsen, Morten S.; Hansen, Henrik; Lichota, Jacek

    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...

  2. 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

  3. Proteomics of pediatric heart failure: from traditional biomarkers to new discovery strategies.

    Science.gov (United States)

    Xu, Mingguo; Ramirez-Correa, Genaro A; Murphy, Anne M

    2015-08-01

    Heart failure in children is a complex clinical syndrome with multiple aetiologies. The underlying disorders that lead to heart failure in children differ significantly from those in adults. Some clinical biomarkers for heart failure status and prognosis appear to be useful in both age groups. This review outlines the use and the present status of biomarkers for heart failure in paediatric cardiology. Furthermore, clinical scenarios in which development of new biomarkers might address management or prognosis are discussed. Finally, strategies for proteomic discovery of novel biomarkers and application to practice are described. PMID:26377710

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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.

  9. 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...

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

    OpenAIRE

    Debasish Paul; Avinash Kumar; Akshada Gajbhiye; Santra, Manas K.; Rapole Srikanth

    2013-01-01

    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,...

  11. 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.

  12. Sparse Mbplsr for Metabolomics Data and Biomarker Discovery

    DEFF Research Database (Denmark)

    Karaman, İbrahim

    2014-01-01

    Metabolomics is part of systems biology and a rapidly evolving field. It is a tool to analyze multiple metabolic changes in biofluids and tissues and aims at determining biomarkers in the metabolism. LC-MS (liquid chromatography – mass spectrometry), GC-MS (gas chromatography – mass spectrometry...... conditions tested. Jack-knife PLSR, however, was to some extent improved by modifying the variable selection criterion, and was much less time-consuming to run. Sparse PLSR may therefore be the method of choice when dealing with spectroscopic data, where the level of noise is relatively low, while for...... model for humans. By Sparse MBPLSR, potential biomarkers from LC-MS and NMR data could be detected and the relationships among the measurement variables of both analytical methods could be studied. Detection of potential biomarkers is followed up by an identification process through online metabolite...

  13. Application of multiple statistical tests to enhance mass spectrometry-based biomarker discovery

    Directory of Open Access Journals (Sweden)

    Garner Harold R

    2009-05-01

    Full Text Available Abstract Background Mass spectrometry-based biomarker discovery has long been hampered by the difficulty in reconciling lists of discriminatory peaks identified by different laboratories for the same diseases studied. We describe a multi-statistical analysis procedure that combines several independent computational methods. This approach capitalizes on the strengths of each to analyze the same high-resolution mass spectral data set to discover consensus differential mass peaks that should be robust biomarkers for distinguishing between disease states. Results The proposed methodology was applied to a pilot narcolepsy study using logistic regression, hierarchical clustering, t-test, and CART. Consensus, differential mass peaks with high predictive power were identified across three of the four statistical platforms. Based on the diagnostic accuracy measures investigated, the performance of the consensus-peak model was a compromise between logistic regression and CART, which produced better models than hierarchical clustering and t-test. However, consensus peaks confer a higher level of confidence in their ability to distinguish between disease states since they do not represent peaks that are a result of biases to a particular statistical algorithm. Instead, they were selected as differential across differing data distribution assumptions, demonstrating their true discriminatory potential. Conclusion The methodology described here is applicable to any high-resolution MALDI mass spectrometry-derived data set with minimal mass drift which is essential for peak-to-peak comparison studies. Four statistical approaches with differing data distribution assumptions were applied to the same raw data set to obtain consensus peaks that were found to be statistically differential between the two groups compared. These consensus peaks demonstrated high diagnostic accuracy when used to form a predictive model as evaluated by receiver operating characteristics

  14. 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.

  15. 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

  16. 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

  17. Novel biomarker candidates for the diagnosis of ovarian clear cell carcinoma

    OpenAIRE

    Kobayashi, Hiroshi; SUGIMOTO, HITOMI; ONISHI, SHUNSUKE; NAKANO, KAZUTOSHI

    2015-01-01

    Ovarian clear cell carcinoma can arise from endometriosis; however, it is distinct from other types of epithelial ovarian carcinoma in terms of its clinicopathological and molecular features. Cancer antigen 125 lacks the sensitivity and specificity required for accurate clinical diagnosis of clear cell carcinoma. Therefore, the aim of the current review was to identify novel biomarker candidates for the immunohistochemical and serological diagnosis of clear cell carcinoma. A search of the rel...

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

    OpenAIRE

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

    2012-01-01

    Breast cancer is a major health problem that affects more than 24% of women in Bangladesh. Further- more, 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-loo...

  19. Immunodiagnosis of tuberculosis: a dynamic view of biomarker discovery

    OpenAIRE

    Kunnath-Velayudhan, S.; Gennaro, M L

    2011-01-01

    Summary: Infection with Mycobacterium tuberculosis causes a variety of clinical conditions ranging from life-long asymptomatic infection to overt disease with increasingly severe tissue damage and a heavy bacillary burden. Immune biomarkers should follow the evolution of infection and disease because the host immune response is at the core of protection against disease and tissue damage in M. tuberculosis infection. Moreover, levels of immune markers are often affected by the antigen load. We...

  20. 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.

  1. Identification of plasma biomarker candidates in glioblastoma using an antibody-array-based proteomic approach

    International Nuclear Information System (INIS)

    Glioblastoma multiforme (GBM) is a brain tumour with a very high patient mortality rate, with a median survival of 47 weeks. This might be improved by the identification of novel diagnostic, prognostic and predictive therapy-response biomarkers, preferentially through the monitoring of the patient blood. The aim of this study was to define the impact of GBM in terms of alterations of the plasma protein levels in these patients. We used a commercially available antibody array that includes 656 antibodies to analyse blood plasma samples from 17 healthy volunteers in comparison with 17 blood plasma samples from patients with GBM. We identified 11 plasma proteins that are statistically most strongly associated with the presence of GBM. These proteins belong to three functional signalling pathways: T-cell signalling and immune responses; cell adhesion and migration; and cell-cycle control and apoptosis. Thus, we can consider this identified set of proteins as potential diagnostic biomarker candidates for GBM. In addition, a set of 16 plasma proteins were significantly associated with the overall survival of these patients with GBM. Guanine nucleotide binding protein alpha (GNAO1) was associated with both GBM presence and survival of patients with GBM. Antibody array analysis represents a useful tool for the screening of plasma samples for potential cancer biomarker candidates in small-scale exploratory experiments; however, clinical validation of these candidates requires their further evaluation in a larger study on an independent cohort of patients

  2. Discovery of safety biomarkers for atorvastatin in rat urine using mass spectrometry based metabolomics combined with global and targeted approach

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Bhowmik Salil [Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650 (Korea, Republic of); University of Science and Technology, (305-333) 113 Gwahangno, Yuseong-gu, Daejeon (Korea, Republic of); Lee, Young-Joo; Yi, Hong Jae [College of Pharmacy, Kyung Hee University, Hoegi-dong, Dongdaemun-gu, Seoul 130-791 (Korea, Republic of); Chung, Bong Chul [Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650 (Korea, Republic of); Jung, Byung Hwa, E-mail: jbhluck@kist.re.kr [Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, P.O. Box 131, Cheongryang, Seoul 130-650 (Korea, Republic of); University of Science and Technology, (305-333) 113 Gwahangno, Yuseong-gu, Daejeon (Korea, Republic of)

    2010-02-19

    In order to develop a safety biomarker for atorvastatin, this drug was orally administrated to hyperlipidemic rats, and a metabolomic study was performed. Atorvastatin was given in doses of either 70 mg kg{sup -1} day{sup -1} or 250 mg kg{sup -1} day{sup -1} for a period of 7 days (n = 4 for each group). To evaluate any abnormal effects of the drug, physiological and plasma biochemical parameters were measured and histopathological tests were carried out. Safety biomarkers were derived by comparing these parameters and using both global and targeted metabolic profiling. Global metabolic profiling was performed using liquid chromatography/time of flight/mass spectrometry (LC/TOF/MS) with multivariate data analysis. Several safety biomarker candidates that included various steroids and amino acids were discovered as a result of global metabolic profiling, and they were also confirmed by targeted metabolic profiling using gas chromatography/mass spectrometry (GC/MS) and capillary electrophoresis/mass spectrometry (CE/MS). Serum biochemical and histopathological tests were used to detect abnormal drug reactions in the liver after repeating oral administration of atorvastatin. The metabolic differences between control and the drug-treated groups were compared using PLS-DA score plots. These results were compared with the physiological and plasma biochemical parameters and the results of a histopathological test. Estrone, cortisone, proline, cystine, 3-ureidopropionic acid and histidine were proposed as potential safety biomarkers related with the liver toxicity of atorvastatin. These results indicate that the combined application of global and targeted metabolic profiling could be a useful tool for the discovery of drug safety biomarkers.

  3. Discovery of safety biomarkers for atorvastatin in rat urine using mass spectrometry based metabolomics combined with global and targeted approach

    International Nuclear Information System (INIS)

    In order to develop a safety biomarker for atorvastatin, this drug was orally administrated to hyperlipidemic rats, and a metabolomic study was performed. Atorvastatin was given in doses of either 70 mg kg-1 day-1 or 250 mg kg-1 day-1 for a period of 7 days (n = 4 for each group). To evaluate any abnormal effects of the drug, physiological and plasma biochemical parameters were measured and histopathological tests were carried out. Safety biomarkers were derived by comparing these parameters and using both global and targeted metabolic profiling. Global metabolic profiling was performed using liquid chromatography/time of flight/mass spectrometry (LC/TOF/MS) with multivariate data analysis. Several safety biomarker candidates that included various steroids and amino acids were discovered as a result of global metabolic profiling, and they were also confirmed by targeted metabolic profiling using gas chromatography/mass spectrometry (GC/MS) and capillary electrophoresis/mass spectrometry (CE/MS). Serum biochemical and histopathological tests were used to detect abnormal drug reactions in the liver after repeating oral administration of atorvastatin. The metabolic differences between control and the drug-treated groups were compared using PLS-DA score plots. These results were compared with the physiological and plasma biochemical parameters and the results of a histopathological test. Estrone, cortisone, proline, cystine, 3-ureidopropionic acid and histidine were proposed as potential safety biomarkers related with the liver toxicity of atorvastatin. These results indicate that the combined application of global and targeted metabolic profiling could be a useful tool for the discovery of drug safety biomarkers.

  4. Discovery of optical candidate supernova remnants in Sagittarius

    CERN Document Server

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

    2012-01-01

    During an [O III] survey for planetary nebulae, we identified a region in Sagittarius containing several candidate Supernova Remnants and obtained deep optical narrow-band images and spectra to explore their nature. The images of the unstudied area have been obtained in the light of Halpha+[N II], [S II] and [O III]. The resulting mosaic covers an area of 1.4x1.0 deg^2 where filamentary and diffuse emission was discovered, suggesting the existence of more than one supernova remnants (SNRs) 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 their association, while the WISE infrared emission found in the area at 12 and 22 micron marginally correlates with the optical. The presenc...

  5. 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

  6. 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.

  7. 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. PMID:22338609

  8. 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

  9. Profiling of circulating microRNAs for prostate cancer biomarker discovery

    DEFF Research Database (Denmark)

    Haldrup, Christa; Kosaka, Nobuyoshi; Ochiya, Takahiro;

    2014-01-01

    and T-stage of the primary PC. Better tools to assess PC aggressiveness could aid in treatment decisions. Recently, circulating miRNAs have been suggested as potential new biomarkers for PC with diagnostic and prognostic potential. Here, to identify new serum miRNA biomarker candidates for PC, we...... well-documented candidate miRNA markers for PC. Moreover, we identified several new potential serum miRNA markers for PC and developed three novel and highly specific (100 %) miRNA candidate marker panels able to identify 84 % of all PC patients (miR-562/miR-210/miR-501-3p/miR-375/miR-551b), 80 % of...

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

    Science.gov (United States)

    Swanton, Charles; Larkin, James M; Gerlinger, Marco; Eklund, Aron C; Howell, Michael; Stamp, Gordon; Downward, Julian; Gore, Martin; Futreal, P Andrew; Escudier, Bernard; Andre, Fabrice; Albiges, Laurence; Beuselinck, Benoit; Oudard, Stephane; Hoffmann, Jens; Gyorffy, Balázs; Torrance, Chris J; Boehme, Karen A; Volkmer, Hansjuergen; Toschi, Luisella; Nicke, Barbara; Beck, Marlene; Szallasi, Zoltan

    2010-01-01

    The European Union multi-disciplinary Personalised RNA interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway inhibitor. Through the analysis of tumor tissue derived from pre-operative renal cell carcinoma (RCC) clinical trials, the PREDICT consortium will use established and novel methods to integrate comprehensive tumor-derived genomic data with personalized tumor-derived small hairpin RNA and high-throughput small interfering RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients. PREDICT's approach to predictive biomarker discovery differs from conventional associative learning approaches, which can be susceptible to the detection of chance associations that lead to overestimation of true clinical accuracy. These methods will identify molecular pathways important for survival and growth of RCC cells and particular targets suitable for therapeutic development. Importantly, our results may enable individualized treatment of RCC, reducing ineffective therapy in drug-resistant disease, leading to improved quality of life and higher cost efficiency, which in turn should broaden patient access to beneficial therapeutics, thereby enhancing clinical outcome and cancer survival. The consortium will also establish and consolidate a European network providing the technological and clinical platform for large-scale functional genomic biomarker discovery. Here we review our current understanding

  11. Proteomic candidate biomarkers of drug-induced nephrotoxicity in the rat.

    Directory of Open Access Journals (Sweden)

    Rodney Rouse

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

  12. 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.

  13. 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

  14. Potential Approaches and Recent Advances in Biomarker Discovery in Clear-Cell Renal Cell Carcinoma

    Science.gov (United States)

    Majer, Weronika; Kluzek, Katarzyna; Bluyssen, Hans; Wesoły, Joanna

    2015-01-01

    The early diagnosis and monitoring of clear-cell Renal Cell Carcinoma (ccRCC), which is the most common renal malignancy, remains challenging. The late diagnosis and lack of tools that can be used to assess the progression of the disease and metastasis significantly influence the chance of survival of ccRCC patients. Molecular biomarkers have been shown to aid the diagnosis and disease monitoring for other cancers, but such markers are not currently available for ccRCC. Recently, plasma and serum circulating nucleic acids, nucleic acids present in urine, and plasma and urine proteins gained interest in the field of cancer biomarker discovery. Here, we describe the applicability of plasma and urine nucleic acids as cancer biomarkers with a particular focus on DNA, small RNA, and protein markers for ccRCC. PMID:26516358

  15. 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...

  16. 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...

  17. Urinary proteomics as a novel tool for biomarker discovery in kidney diseases*

    OpenAIRE

    Wu, Jing; Chen, Yi-ding; Gu, Wei

    2010-01-01

    Urine has become one of the most attractive biofluids in clinical proteomics, for its procurement is easy and noninvasive and it contains sufficient proteins and peptides. Urinary proteomics has thus rapidly developed and has been extensively applied to biomarker discovery in clinical diseases, especially kidney diseases. In this review, we discuss two important aspects of urinary proteomics in detail, namely, sample preparation and proteomic technologies. In addition, data mining in urinary ...

  18. Two-dimensional SDS-PAGE fractionation of biological samples for biomarker discovery

    OpenAIRE

    Rabilloud, Thierry; Triboulet, Sarah

    2013-01-01

    Two-dimensional electrophoresis is still a very valuable tool in proteomics, due to its reproducibility and its ability to analyze complete proteins. However, due to its sensitivity to dynamic range issues, its most suitable use in the frame of biomarker discovery is not on very complex fluids such as plasma, but rather on more proximal, simpler fluids such as CSF, urine, or secretome samples. Here, we describe the complete workflow for the analysis of such dilute samples by two-dimensional e...

  19. 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...

  20. Application of mass spectrometry-based proteomics for biomarker discovery in neurological disorders

    OpenAIRE

    Venugopal Abhilash; Chaerkady Raghothama; Pandey Akhilesh

    2009-01-01

    Mass spectrometry-based quantitative proteomics has emerged as a powerful approach that has the potential to accelerate biomarker discovery, both for diagnostic as well as therapeutic purposes. Proteomics has traditionally been synonymous with 2D gels but is increasingly shifting to the use of gel-free systems and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Quantitative proteomic approaches have already been applied to investigate various neurological disorders, espe...

  1. Circulating miR-150 in CSF is a novel candidate biomarker for multiple sclerosis

    Science.gov (United States)

    Bergman, Petra; Piket, Eliane; Khademi, Mohsen; James, Tojo; Brundin, Lou; Olsson, Tomas; Piehl, Fredrik

    2016-01-01

    Objective: To explore circulating microRNAs (miRNAs) in cell-free CSF as novel biomarkers for multiple sclerosis (MS). Methods: Profiling of miRNAs in CSF of pooled patients with clinically isolated syndrome (CIS), patients with relapsing-remitting MS, and inflammatory and noninflammatory neurologic disease controls was performed using TaqMan miRNA arrays. Two independent patient cohorts (n = 142 and n = 430) were used for validation with real-time PCR. Results: We reliably detected 88 CSF miRNAs in the exploratory cohort. Subsequent validation in 2 cohorts demonstrated significantly higher levels of miR-150 in patients with MS. Higher miR-150 levels were also observed in patients with CIS who converted to MS compared to nonconverters, and in patients initiating natalizumab treatment. Levels of miR-150 correlated with immunologic parameters including CSF cell count, immunoglobulin G index, and presence of oligoclonal bands, and with candidate protein biomarkers C-X-C motif chemokine 13, matrix metallopeptidase 9, and osteopontin. Correlation with neurofilament light chain (NFL) was observed only when NFL was adjusted for age using a method that requires further validation. Additionally, miR-150 discriminated MS from controls and CIS converters from nonconverters equally well as the most informative protein biomarkers. Following treatment with natalizumab, but not fingolimod, CSF levels of miR-150 decreased, while plasma levels increased with natalizumab and decreased with fingolimod, suggesting immune cells as a source of miR-150. Conclusions: Our findings demonstrate miR-150 as a putative novel biomarker of inflammatory active disease with the potential to be used for early diagnosis of MS. Classification of evidence: This study provides Class II evidence that CSF miR-150 distinguishes patients with MS from patients with other neurologic conditions. PMID:27144214

  2. Prostate cancer serum biomarker discovery through proteomic analysis of alpha-2 macroglobulin protein complexes

    OpenAIRE

    Burgess, Earle F.; Ham, Amy-Joan L.; Tabb, David L.; Billheimer, Dean; Roth, Bruce J.; Chang, Sam S.; Cookson, Michael S.; Hinton, Timothy J.; Cheek, Kristin L.; Hill, Salisha; Jennifer A Pietenpol

    2008-01-01

    Alpha-2 macroglobulin (A2M) functions as a universal protease inhibitor in serum and is capable of binding various cytokines and growth factors. In this study, we investigated if immunoaffinity enrichment and proteomic analysis of A2M protein complexes from human serum could improve detection of biologically relevant and novel candidate protein biomarkers in prostate cancer. Serum samples from six patients with androgen-independent, metastatic prostate cancer and six control patients without ...

  3. 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

  4. 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

  5. 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...

  6. 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

    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...

  7. 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...

  8. Mass spectrometry based translational proteomics for biomarker discovery and application in colorectal cancer.

    Science.gov (United States)

    Ma, Hong; Chen, Guilin; Guo, Mingquan

    2016-04-01

    Colorectal cancer (CRC) is a leading cause of cancer-related death in the world. Clinically, early detection of the disease is the most effective approach to tackle this tough challenge. Discovery and development of reliable and effective diagnostic tools for the assessment of prognosis and prediction of response to drug therapy are urgently needed for personalized therapies and better treatment outcomes. Among many ongoing efforts in search for potential CRC biomarkers, MS-based translational proteomics provides a unique opportunity for the discovery and application of protein biomarkers toward better CRC early detection and treatment. This review updates most recent studies that use preclinical models and clinical materials for the identification of CRC-related protein markers. Some new advances in the development of CRC protein markers such as CRC stem cell related protein markers, SRM/MRM-MS and MS cytometry approaches are also discussed in order to address future directions and challenges from bench translational research to bedside clinical application of CRC biomarkers. PMID:26616366

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

    International Nuclear Information System (INIS)

    Highlights: ► Procedures for acquisition of different biofluids by NMR. ► Recent developments in metabolic profiling of different biofluids by NMR are presented. ► The crucial steps involved in data preprocessing and multivariate chemometric analysis are reviewed. ► 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).

  10. 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

  11. Identification of Candidate Serum Biomarkers for Schistosoma mansoni Infected Mice Using Multiple Proteomic Platforms

    Science.gov (United States)

    Kardoush, Manal I.

    2016-01-01

    Background Schistosomiasis is an important helminth infection of humans. There are few reliable diagnostic biomarkers for early infection, for recurrent infection or to document successful treatment. In this study, we compared serum protein profiles in uninfected and infected mice to identify disease stage-specific biomarkers. Methods Serum collected from CD1 mice infected with 50–200 Schistosoma mansoni cercariae were analyzed before infection and at 3, 6 and 12 weeks post-infection using three mass spectrometric (MS) platforms. Results Using SELDI-TOF MS, 66 discriminating m/z peaks were detected between S. mansoni infected mice and healthy controls. Used in various combinations, these peaks could 1) reliably diagnose early-stage disease, 2) distinguish between acute and chronic infection and 3) diagnose S. mansoni infection regardless the parasite burden. The most important contributors to these diagnostic algorithms were peaks at 3.7, 13 and 46 kDa. Employing sample fractionation and differential gel electrophoresis, we analyzed gel slices either by MALDI-TOF MS or Velos Orbitrap MS. The former yielded eight differentially-expressed host proteins in the serum at different disease stages including transferrin and alpha 1- antitrypsin. The latter suggested the presence of a surprising number of parasite-origin proteins in the serum during both the acute (n = 200) and chronic (n = 105) stages. The Orbitrap platform also identified many differentially-expressed host-origin serum proteins during the acute and chronic stages (296 and 220 respectively). The presence of one of the schistosome proteins, glutathione S transferase (GST: 25 KDa), was confirmed by Western Blot. This study provides proof-of-principle for an approach that can yield a large number of novel candidate biomarkers for Schistosoma infection. PMID:27138990

  12. 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.

  13. Mitochondrial DNA mutations--candidate biomarkers for breast cancer diagnosis in Bangladesh

    Directory of Open Access Journals (Sweden)

    Rowshan Ara Begum

    2012-09-01

    Full Text Available Breast cancer is a major health problem that affects more than 24% of women in Bangladesh. Further- more, 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.

  14. 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.

  15. Transcriptional responses to radiation exposure facilitate the discovery of biomarkers functioning as radiation biodosimeters

    International Nuclear Information System (INIS)

    The development of new methods for a retrospective quantification of the radiation dose of exposed individuals is of widespread interest. To this end, I developed a computational framework for biomarker discovery and radiation dose prediction and successfully identified gene signatures with which low and medium to high radiation doses can be accurately quantified. To enhance our understanding of the radiation-induced transcriptional response, I additionally analyzed microarray data of human PBLs after ex vivo gamma-irradiation and characterized affected functional processes and pathways.

  16. Transcriptional responses to radiation exposure facilitate the discovery of biomarkers functioning as radiation biodosimeters

    Energy Technology Data Exchange (ETDEWEB)

    Strunz, Sonja

    2014-05-13

    The development of new methods for a retrospective quantification of the radiation dose of exposed individuals is of widespread interest. To this end, I developed a computational framework for biomarker discovery and radiation dose prediction and successfully identified gene signatures with which low and medium to high radiation doses can be accurately quantified. To enhance our understanding of the radiation-induced transcriptional response, I additionally analyzed microarray data of human PBLs after ex vivo gamma-irradiation and characterized affected functional processes and pathways.

  17. Inside back cover: Biomarker discovery in mass spectrometry-based urinary proteomics.

    Science.gov (United States)

    Thomas, Samuel; Hao, Ling; Ricke, William A; Li, Lingjun

    2016-04-01

    DOI: 10.1002/prca.201500102 Urine is among the most valuable sample materials for studies of human diseases. These urine solutes are shown with increasing approximate diameter from metabolite at 1 nm to protein at 5 nm to a group of exosomes at 100 nm each to a cell at 10 000 nm. This article highlights promising technologies and strategies in the mass spectrometry-based urine proteomics and its application to disease biomarker discovery. Further details can be found in the article by Samuel Thomas et al. on page 358. PMID:27061328

  18. 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.

  19. 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...

  20. 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.

  1. 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.

  2. 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...

  3. 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

  4. 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.

  5. Proteomic-driven biomarker discovery in gestational diabetes mellitus: a review.

    Science.gov (United States)

    Singh, Apoorva; Subramani, Elavarasan; Datta Ray, Chaitali; Rapole, Srikanth; Chaudhury, Koel

    2015-09-01

    Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy and it affects 18% of pregnant women worldwide. GDM is considered a high-risk state which may lead to type II diabetes which is associated with an increase in a number of interrelated adverse perinatal outcomes. Given the fact that the progress of a successful pregnancy is dependent on the intricate communication between several biological molecules, identification of the proteomic profile perturbations in women with GDM is expected to help in understanding the disease pathogenesis and also discovery of clinical biomarker(s). In recent years, both gel-free and gel-based proteomics have been extensively investigated for improving maternal and child health. Although there are several reports integrating various aspects of proteomics in pregnancy related diseases such as preeclampsia, extensive Pubmed search shows no review so far on the application of proteomics in gestational diabetes. In this review, we focus on various high-throughput proteomic technologies for the identification of unique biosignatures and biomarkers responsible for the early prediction of GDM. Further, different analytical strategies and biological samples involved in proteomic analysis of this pregnancy-related disease are discussed.This article is part of a Special Issue entitled: Proteomics in India. PMID:26216595

  6. 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.

  7. Recent patents and advances in genomic biomarker discovery for colorectal cancers.

    Science.gov (United States)

    Quyun, Chen; Ye, Zhiyun; Lin, Sheng-Cai; Lin, Biaoyang

    2010-06-01

    Colorectal cancer (CRC) is the third most common cancer in the world. Early diagnosis of colorectal cancer is the key to reducing the death rate of CRC patients. Predicting the response to current therapeutic modalities of CRC will also have a great impact on patient care. This review summarizes recent advances and patents in biomarker discovery in CRC under five major categories; including genomic changes, expression changes, mutations, epigenetic changes and microRNAs. The interesting patents include: 1) a patent for a method to differentiate normal exfoliated cells from cancer cells based on whether they were subjected to apoptosis and DNA degradation; 2) A model (PM-33 multiple molecular marker model) based on expression changes of up-regulation of the MDM2, DUSP6, and NFl genes down-regulation of the RNF4, MMD and EIF2S3 genes, which achieved an 88% sensitivity, and an 82% specificity for CRC diagnosis; 3) gene mutations in PTEN, KRAS, PIK3CA for predicting the response to anti-EGFR therapies, a common drug used for CRC treatment; 4) patents on epigenetic changes of ITGA4, SEPT9, ALX4, TFAP2E FOXL2, SARM1, ID4 etc. and many key miRNAs. Finally, future directions in the fields were commented on or suggested, including the combination of multiple categories of biomarkers and pathway central or network-based biomarker panels. PMID:20426761

  8. 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).

  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. 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.

  11. 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

  12. 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

  13. iTRAQ identification of candidate serum biomarkers associated with metastatic progression of human prostate cancer.

    Science.gov (United States)

    Rehman, Ishtiaq; Evans, Caroline A; Glen, Adam; Cross, Simon S; Eaton, Colby L; Down, Jenny; Pesce, Giancarlo; Phillips, Joshua T; Yen, Ow Saw; Thalmann, George N; Wright, Phillip C; Hamdy, Freddie C

    2012-01-01

    A major challenge in the management of patients with prostate cancer is identifying those individuals at risk of developing metastatic disease, as in most cases the disease will remain indolent. We analyzed pooled serum samples from 4 groups of patients (n = 5 samples/group), collected prospectively and actively monitored for a minimum of 5 yrs. Patients groups were (i) histological diagnosis of benign prostatic hyperplasia with no evidence of cancer 'BPH', (ii) localised cancer with no evidence of progression, 'non-progressing' (iii) localised cancer with evidence of biochemical progression, 'progressing', and (iv) bone metastasis at presentation 'metastatic'. Pooled samples were immuno-depleted of the 14 most highly abundant proteins and analysed using a 4-plex iTRAQ approach. Overall 122 proteins were identified and relatively quantified. Comparisons of progressing versus non-progressing groups identified the significant differential expression of 25 proteins (pfactor 1 alpha 1 (eEF1A1), one of the candidates identified, was significantly higher in osteoblasts in close proximity to metastatic tumour cells compared with osteoblasts in control bone (p = 0.0353, Mann Whitney U). Our proteomic approach has identified leads for potentially useful serum biomarkers associated with the metastatic progression of prostate cancer. The panels identified, including eEF1A1 warrant further investigation and validation. PMID:22355332

  14. 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

  15. 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...

  16. 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

  17. 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.

  18. 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...

  19. 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/.

  20. Bovine Tuberculosis in Cattle: Vaccines, DIVA Tests, and Host Biomarker Discovery.

    Science.gov (United States)

    Vordermeier, H Martin; Jones, Gareth J; Buddle, Bryce M; Hewinson, R Glyn; Villarreal-Ramos, Bernardo

    2016-02-15

    Bovine tuberculosis remains a major economic and animal welfare concern worldwide. Cattle vaccination is being considered as part of control strategies. This approach, used alongside conventional control policies, also requires the development of vaccine-compatible diagnostic assays to distinguish vaccinated from infected animals (DIVA). We discuss progress made on optimizing the only potentially available vaccine, bacille Calmette Guérin (BCG), and on strategies to improve BCG efficacy. We also describe recent advances in DIVA development based on the detection of host cellular immune responses by blood-testing or skin-testing approaches. Finally, to accelerate vaccine development, definition of host biomarkers that provide meaningful stage-gating criteria to select vaccine candidates for further testing is highly desirable. Some progress has also been made in this area of research, and we summarize studies that defined either markers predicting vaccine success or markers that correlate with disease stage or severity. PMID:26884103

  1. 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...

  2. Integration of metabolomics and proteomics in multiple sclerosis: From biomarkers discovery to personalized medicine.

    Science.gov (United States)

    Del Boccio, Piero; Rossi, Claudia; di Ioia, Maria; Cicalini, Ilaria; Sacchetta, Paolo; Pieragostino, Damiana

    2016-04-01

    Personalized medicine is the science of individualized prevention and therapy. In the last decade, advances in high-throughput approaches allowed the development of proteomic and metabolomic studies in evaluating the association of genetic and phenotypic variability with disease sensitivity and analgesic response. These considerations have more value in case of multiple sclerosis (MuS), a multifactorial disease with high heterogeneity in clinical course and treatment response. In this review, we reported and updated about proteomic and metabolomic studies for the research of new candidate biomarkers in MuS, and difficulties in their clinical applications. We focused especially on the description of both "omics" approaches that, once integrated, may synergically describe pathophysiology conditions. To prove this assumption, we rebuilt interaction between proteins and metabolites described in the literature as potential biomarkers for MuS, and a pathway analysis of these molecules was performed. The result of such speculation demonstrated a strong convergence of proteomic and metabolomic results in this field, showing also a poorness of available tools for incorporating "omics" approaches. In conclusion, the integration of Metabolomics and Proteomics may allow a more complete characterization of such a heterogeneous disease, providing further insights into personalized healthcare. PMID:27061322

  3. 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

  4. 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

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

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    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.

  6. Predictive Power Estimation Algorithm (PPEA--a new algorithm to reduce overfitting for genomic biomarker discovery.

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    Jiangang Liu

    Full Text Available Toxicogenomics promises to aid in predicting adverse effects, understanding the mechanisms of drug action or toxicity, and uncovering unexpected or secondary pharmacology. However, modeling adverse effects using high dimensional and high noise genomic data is prone to over-fitting. Models constructed from such data sets often consist of a large number of genes with no obvious functional relevance to the biological effect the model intends to predict that can make it challenging to interpret the modeling results. To address these issues, we developed a novel algorithm, Predictive Power Estimation Algorithm (PPEA, which estimates the predictive power of each individual transcript through an iterative two-way bootstrapping procedure. By repeatedly enforcing that the sample number is larger than the transcript number, in each iteration of modeling and testing, PPEA reduces the potential risk of overfitting. We show with three different cases studies that: (1 PPEA can quickly derive a reliable rank order of predictive power of individual transcripts in a relatively small number of iterations, (2 the top ranked transcripts tend to be functionally related to the phenotype they are intended to predict, (3 using only the most predictive top ranked transcripts greatly facilitates development of multiplex assay such as qRT-PCR as a biomarker, and (4 more importantly, we were able to demonstrate that a small number of genes identified from the top-ranked transcripts are highly predictive of phenotype as their expression changes distinguished adverse from nonadverse effects of compounds in completely independent tests. Thus, we believe that the PPEA model effectively addresses the over-fitting problem and can be used to facilitate genomic biomarker discovery for predictive toxicology and drug responses.

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

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    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

  8. Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers

    International Nuclear Information System (INIS)

    The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with 'omics' data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.

  9. RAFT - I. Discovery of new planetary candidates and updated orbits from archival FEROS spectra

    Science.gov (United States)

    Soto, M. G.; Jenkins, J. S.; Jones, M. I.

    2015-08-01

    A recent reanalysis of archival data has lead several authors to arrive at strikingly different conclusions for a number of planet-hosting candidate stars. In particular, some radial velocities (RVs) measured using Fiber-fed Extended Range Optical Spectrograph (FEROS) spectra have been shown to be inaccurate, throwing some doubt on the validity of a number of planet detections. Motivated by these results, we have begun the Reanalysis of Archival FEROS specTra (RAFT) programme and here we discuss the first results from this work. We have reanalyzed FEROS data for the stars HD 11977, HD 47536, HD 70573, HD 110014 and HD 122430, all of which are claimed to have at least one planetary companion. We have reduced the raw data and computed the radial velocity variations of these stars, achieving a long-term precision of ˜10 m s-1 on the known stable star τ Ceti, and in good agreement with the residuals to our fits. We confirm the existence of planets around HD 11977, HD 47536 and HD 110014, but with different orbital parameters than those previously published. In addition, we found no evidence of the second planet candidate around HD 47536, nor any companions orbiting HD 122430 and HD 70573. Finally, we report the discovery of a second planet around HD 110014, with a minimum mass of 3.1 MJup and a orbital period of 130 d. Analysis of activity indicators allows us to confirm the reality of our results and also to measure the impact of magnetic activity on our RV measurements. These results confirm that very metal poor stars down to [Fe/H] ˜ -0.7 dex, can indeed form giant planets given the right conditions.

  10. 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

  11. 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.

  12. 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

  13. 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...

  14. Discovery of two new Galactic candidate luminous blue variables with WISE

    CERN Document Server

    Gvaramadze, V V; Miroshnichenko, A S; Berdnikov, L N; Langer, N; Stringfellow, G S; Todt, H; Hamann, W -R; Grebel, E K; Buckley, D; Crause, L; Crawford, S; Gulbis, A; Hettlage, C; Hooper, E; Husser, T -O; Kotze, P; Loaring, N; Nordsieck, K H; O'Donoghue, D; Pickering, T; Potter, S; Colmenero, E Romero; Vaisanen, P; Williams, T; Wolf, M; Reichart, D E; Ivarsen, K M; Haislip, J B; Nysewander, M C; LaCluyze, A P

    2012-01-01

    We report the discovery of two new Galactic candidate luminous blue variable (cLBV) stars via detection of circular shells (typical of known confirmed and cLBVs) and follow-up spectroscopy of their central stars. The shells were detected at 22 um in the archival data of the Mid-Infrared All Sky Survey carried out with the Wide-field Infrared Survey Explorer (WISE). Follow-up optical spectroscopy of the central stars of the shells conducted with the renewed Southern African Large Telescope (SALT) showed that their spectra are very similar to those of the well-known LBVs P Cygni and AG Car, and the recently discovered cLBV MN112, which implies the LBV classification for these stars as well. The LBV classification of both stars is supported by detection of their significant photometric variability: one of them brightened in the R- and I-bands by 0.68\\pm0.10 mag and 0.61\\pm0.04 mag, respectively, during the last 13-18 years, while the second one (known as Hen 3-1383) varies its B,V,R,I and K_s brightnesses by \\si...

  15. Including network knowledge into Cox regression models for biomarker signature discovery.

    Science.gov (United States)

    Fröhlich, Holger

    2014-03-01

    Discovery of prognostic and diagnostic biomarker gene signatures for diseases, such as cancer, is seen as a major step toward a better personalized medicine. During the last decade various methods have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinical diagnosis is the typical low reproducibility of these signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approaches that try to integrate information from molecular interaction networks. Most of these methods focus on classification problems, that is learn a model from data that discriminates patients into distinct clinical groups. Far less has been published on approaches that predict a patient's event risk. In this paper, we investigate eight methods that integrate network information into multivariable Cox proportional hazard models for risk prediction in breast cancer. We compare the prediction performance of our tested algorithms via cross-validation as well as across different datasets. In addition, we highlight the stability and interpretability of obtained gene signatures. In conclusion, we find GeneRank-based filtering to be a simple, computationally cheap and highly predictive technique to integrate network information into event time prediction models. Signatures derived via this method are highly reproducible. PMID:24430933

  16. Discovery of dachshund 2 protein as a novel biomarker of poor prognosis in epithelial ovarian cancer

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    Nodin Björn

    2012-01-01

    Full Text Available Abstract Background The Dachshund homolog 2 (DACH2 gene has been implicated in development of the female genital tract in mouse models and premature ovarian failure syndrome, but to date, its expression in human normal and cancerous tissue remains unexplored. Using the Human Protein Atlas as a tool for cancer biomarker discovery, DACH2 protein was found to be differentially expressed in epithelial ovarian cancer (EOC. Here, the expression and prognostic significance of DACH2 was further evaluated in ovarian cancer cell lines and human EOC samples. Methods Immunohistochemical expression of DACH2 was examined in tissue microarrays with 143 incident EOC cases from two prospective, population-based cohorts, including a subset of benign-appearing fallopian tubes (n = 32. A nuclear score (NS, i.e. multiplier of staining fraction and intensity, was calculated. For survival analyses, cases were dichotomized into low (NS 3 using classification and regression tree analysis. Kaplan Meier analysis and Cox proportional hazards modelling were used to assess the impact of DACH2 expression on survival. DACH2 expression was analysed in the cisplatin sensitive ovarian cancer cell line A2780 and its cisplatin resistant derivative A2780-Cp70. The specificity of the DACH2 antibody was tested using siRNA-mediated silencing of DACH2 in A2780-Cp70 cells. Results DACH2 expression was considerably higher in the cisplatin resistant A2780-Cp70 cells compared to the cisplatin-sensitive A2780 cells. While present in all sampled fallopian tubes, DACH2 expression ranged from negative to strong in EOC. In EOC, DACH2 expression correlated with several proteins involved in DNA integrity and repair, and proliferation. DACH2 expression was significantly higher in carcinoma of the serous subtype compared to non-serous carcinoma. In the full cohort, high DACH2 expression was significantly associated with poor prognosis in univariable analysis, and in carcinoma of the serous subtype

  17. MicroRNA-29a Is a Candidate Biomarker for Alzheimer's Disease in Cell-Free Cerebrospinal Fluid.

    Science.gov (United States)

    Müller, Mareike; Jäkel, Lieke; Bruinsma, Ilona B; Claassen, Jurgen A; Kuiperij, H Bea; Verbeek, Marcel M

    2016-07-01

    The identification of reliable biomarkers for Alzheimer's disease (AD) remains challenging. Recently, abnormal levels of microRNAs (miRNAs) miR-27a, miR-29a, miR-29b, and miR-125b in cerebrospinal fluid (CSF) of AD patients were reported. We aimed to confirm the biomarker potential of these miRNAs for AD diagnosis. Additionally, we examined the influence of blood contamination on CSF miRNA levels as potential confounding factor. We studied expression levels of the four miRNAs by quantitative PCR in CSF samples of AD patients and non-demented controls, and in blood-spiked CSF. Levels of miR-29a, but not of the other three miRNAs, were increased by a factor of 2.2 in CSF of AD patients. Spiking of small amounts of blood into CSF revealed that miR-27a and miR-29a, but not miR-125b levels were strongly influenced by the number of blood cells in the sample. In conclusion, miR-29a may be a candidate biomarker for AD, but only when used in cell-free CSF. PMID:25895659

  18. Is there Progress? An Overview of Selecting Biomarker Candidates for Major Depressive Disorder

    Science.gov (United States)

    Young, Juan Joseph; Silber, Tim; Bruno, Davide; Galatzer-Levy, Isaac Robert; Pomara, Nunzio; Marmar, Charles Raymond

    2016-01-01

    Major depressive disorder (MDD) contributes to a significant worldwide disease burden, expected to be second only to heart disease by 2050. However, accurate diagnosis has been a historical weakness in clinical psychiatry. As a result, there is a demand for diagnostic modalities with greater objectivity that could improve on current psychiatric practice that relies mainly on self-reporting of symptoms and clinical interviews. Over the past two decades, literature on a growing number of putative biomarkers for MDD increasingly suggests that MDD patients have significantly different biological profiles compared to healthy controls. However, difficulty in elucidating their exact relationships within depression pathology renders individual markers inconsistent diagnostic tools. Consequently, further biomarker research could potentially improve our understanding of MDD pathophysiology as well as aid in interpreting response to treatment, narrow differential diagnoses, and help refine current MDD criteria. Representative of this, multiplex assays using multiple sources of biomarkers are reported to be more accurate options in comparison to individual markers that exhibit lower specificity and sensitivity, and are more prone to confounding factors. In the future, more sophisticated multiplex assays may hold promise for use in screening and diagnosing depression and determining clinical severity as an advance over relying solely on current subjective diagnostic criteria. A pervasive limitation in existing research is heterogeneity inherent in MDD studies, which impacts the validity of biomarker data. Additionally, small sample sizes of most studies limit statistical power. Yet, as the RDoC project evolves to decrease these limitations, and stronger studies with more generalizable data are developed, significant advances in the next decade are expected to yield important information in the development of MDD biomarkers for use in clinical settings. PMID:27199779

  19. 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

  20. 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.

  1. 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 ...

  2. 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

  3. Phosphoprotein Secretome of Tumor Cells as a Source of Candidates for Breast Cancer Biomarkers in Plasma*

    OpenAIRE

    Zawadzka, Anna M.; Schilling, Birgit; Cusack, Michael P.; Sahu, Alexandria K.; Drake, Penelope; Fisher, Susan J.; Benz, Christopher C.; Gibson, Bradford W.

    2014-01-01

    Breast cancer is a heterogeneous disease whose molecular diversity is not well reflected in clinical and pathological markers used for prognosis and treatment selection. As tumor cells secrete proteins into the extracellular environment, some of these proteins reach circulation and could become suitable biomarkers for improving diagnosis or monitoring response to treatment. As many signaling pathways and interaction networks are altered in cancerous tissues by protein phosphorylation, changes...

  4. Mannosylated lipoarabinomannan in serum as a biomarker candidate for subclinical bovine tuberculosis

    OpenAIRE

    Lamont, Elise A.; Ribeiro-Lima, João; Waters, Wade Ray; Thacker, Tyler; Sreevatsan, Srinand

    2014-01-01

    Background Early and unambiguous detection of bovine tuberculosis (bTB), a significant disease of cattle worldwide, is necessary to control the spread of infection to other animals and humans. Current testing strategies are laborious, time consuming and heavily reliant on host responses that do not distinguish bTB from other mycobacteria. We report the presence of a pathogen signature, liparabinomannan (LAM), as a potential biomarker for bTB infection. Findings Fifty-five animals (uninfected ...

  5. 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

  6. FIRST RESULTS FROM Z –FOURGE : DISCOVERY OF A CANDIDATE CLUSTER AT z = 2.2 IN COSMOS

    International Nuclear Information System (INIS)

    We report the first results from the Z –FOURGE survey: the discovery of a candidate galaxy cluster at z = 2.2 consisting of two compact overdensities with red galaxies detected at ∼> 20σ above the mean surface density. The discovery was made possible by a new deep (Ks ∼ 2 protoclusters with more diffuse distributions of blue galaxies and the lower-redshift galaxy clusters with prominent red sequences. The structure is completely absent in public optical catalogs in COSMOS and only weakly visible in a shallower near-IR survey. The discovery showcases the potential of deep near-IR surveys with medium-band filters to advance the understanding of environment and galaxy evolution at z > 1.5.

  7. Hydroxyproline, a Serum Biomarker Candidate for Gastric Ulcer in Rats: A Comparison Study of Metabolic Analysis of Gastric Ulcer Models Induced by Ethanol, Stress, and Aspirin

    OpenAIRE

    Kenichiro Takeuchi; Maki Ohishi; Keiko Endo; Kenichi Suzumura; Hitoshi Naraoka; Takeji Ohata; Jiro Seki; Yoichi Miyamae; Masashi Honma; Tomoyoshi Soga

    2014-01-01

    Gastrointestinal symptoms are a common manifestation of adverse drug effects. Non-steroid anti-inflammatory drugs (NSAIDs) are widely prescribed drugs that induce the serious side effect of gastric mucosal ulceration. Biomarkers for these side effects have not been identified and ulcers are now only detectable by endoscopy. We previously identified five metabolites as biomarker candidates for NSAID-induced gastric ulcer using capillary electrophoresis–mass spectrometry (CE–MS)-based metabolom...

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

    DEFF Research Database (Denmark)

    Vieira Campos, Diana Alexandra; Freitas, Daniela; Gomes, Joana; Magalhães, Ana; Steentoft, Catharina; Gomes, Catarina; Vester-Christensen, Malene B; Ferreira, José Alexandre; Afonso, Luis P; Santos, Lúcio L; de Sousa, João Pinto; Mandel, Ulla; Clausen, Henrik; Vakhrushev, Sergey Y; Reis, Celso A

    2015-01-01

    Circulating O-glycoproteins shed from cancer cells represent important serum biomarkers for diagnostic and prognostic purposes. We have recently shown that selective detection of cancer-associated aberrant glycoforms of circulating O-glycoprotein biomarkers can increase specificity of cancer biom...

  9. 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

  10. Circulating microRNAs: Promising candidates serving as novel biomarkers of acute hepatitis

    Directory of Open Access Journals (Sweden)

    Natalia Elfimova

    2012-12-01

    Full Text Available Acute liver failure as life threatening condition comprises a difficult diagnostic situation to evaluate potential outcomes and therapeutic options. Thus, prognostic indicators are urgently needed for evaluation of progression of liver injury, clinical outcome, prognosis, and for therapeutic response. Recently, circulating microRNA, in particular miR-122, was described as a potential biomarker of acute liver injury after intoxication of mice. Circulating miRNA molecules are very stable and RNase-resistant due to protein aggregation and vesicle enclosure. Since miRNA species are known to be associated with chronic liver damage or with liver cancer, circulating miRNA patterns are suggested to serve also as reporters for progression of acute liver failure. miRNA profiling analyses using PCR arrays or next generation sequencing, may achieve identification of miRNA species that are linked to the rapid progression of acute liver injury, to the outcome of liver failure, or to the therapeutic response. Therefore, circulating miRNAs are promising, non-invasive biomarkers of future diagnostic approaches. However, normalisation of circulating miRNA levels is essential and further standardisation of miRNA quantification assays is needed.

  11. Metabolomics as a tool for discovery of biomarkers of autism spectrum disorder in the blood plasma of children.

    Directory of Open Access Journals (Sweden)

    Paul R West

    Full Text Available The diagnosis of autism spectrum disorder (ASD at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age.To discover metabolic features present in plasma samples that can discriminate children with ASD from typically developing (TD children. The ultimate goal is to identify and develop blood-based ASD biomarkers that can be validated in larger clinical trials and deployed to guide individualized therapy and treatment.Blood plasma was obtained from children aged 4 to 6, 52 with ASD and 30 age-matched TD children. Samples were analyzed using 5 mass spectrometry-based methods designed to orthogonally measure a broad range of metabolites. Univariate, multivariate and machine learning methods were used to develop models to rank the importance of features that could distinguish ASD from TD.A set of 179 statistically significant features resulting from univariate analysis were used for multivariate modeling. Subsets of these features properly classified the ASD and TD samples in the 61-sample training set with average accuracies of 84% and 86%, and with a maximum accuracy of 81% in an independent 21-sample validation set.This analysis of blood plasma metabolites resulted in the discovery of biomarkers that may be valuable in the diagnosis of young children with ASD. The results will form the basis for additional discovery and validation research for 1 determining biomarkers to develop diagnostic tests to detect ASD earlier and improve patient outcomes, 2 gaining new insight into the biochemical mechanisms of various subtypes of ASD 3 identifying biomolecular targets for new modes of therapy, and 4 providing the basis for individualized treatment recommendations.

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

    International Nuclear Information System (INIS)

    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.

  13. 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

    (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......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...... 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...

  14. High-throughput profiling for discovery of non-coding RNA biomarkers of lung disease.

    OpenAIRE

    McKiernan, Paul J; Catherine M. Greene

    2016-01-01

    In respiratory medicine there is a need for clinical biomarkers for diagnosis, prognosis and assessment of response to therapy. Noncoding RNA (ncRNA) is expressed in all human cells; two major classes - long ncRNA and microRNA - are detectable extracellularly in the circulation and other biofluids. Altered ncRNA expression is associated with lung disease; collectively this indicates that ncRNA represents a potential biomarker class. This article presents and compares existing platforms for de...

  15. 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.

  16. 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.

  17. 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

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

    Directory of Open Access Journals (Sweden)

    Lazar Iulia M

    2009-03-01

    Full Text Available Abstract Background 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. Methods 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. Results In this work, we report on the generation of a library of 9,677 peptides (p 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 Conclusion Preliminary experiments have demonstrated that putative biomarkers, that are not detectable by conventional data dependent MS acquisition methods in complex un-fractionated samples, can be reliable identified with the information provided in this library. Based on the spectral count, the quality of a tandem mass spectrum and the m/z values for a parent peptide and its most abundant daughter

  19. 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...

  20. Current application of proteomics in biomarker discovery for inflammatory bowel disease.

    Science.gov (United States)

    Chan, Patrick Py; Wasinger, Valerie C; Leong, Rupert W

    2016-02-15

    Recently, the field of proteomics has rapidly expanded in its application towards clinical research with objectives ranging from elucidating disease pathogenesis to discovering clinical biomarkers. As proteins govern and/or reflect underlying cellular processes, the study of proteomics provides an attractive avenue for research as it allows for the rapid identification of protein profiles in a biological sample. Inflammatory bowel disease (IBD) encompasses several heterogeneous and chronic conditions of the gastrointestinal tract. Proteomic technology provides a powerful means of addressing major challenges in IBD today, especially for identifying biomarkers to improve its diagnosis and management. This review will examine the current state of IBD proteomics research and its use in biomarker research. Furthermore, we also discuss the challenges of translating proteomic research into clinically relevant tools. The potential application of this growing field is enormous and is likely to provide significant insights towards improving our future understanding and management of IBD. PMID:26909226

  1. 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.

  2. 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

  3. DISCOVERY OF A LARGE NUMBER OF CANDIDATE PROTOCLUSTERS TRACED BY ∼15 Mpc-SCALE GALAXY OVERDENSITIES IN COSMOS

    International Nuclear Information System (INIS)

    To demonstrate the feasibility of studying the epoch of massive galaxy cluster formation in a more systematic manner using current and future galaxy surveys, we report the discovery of a large sample of protocluster candidates in the 1.62 deg2 COSMOS/UltraVISTA field traced by optical/infrared selected galaxies using photometric redshifts. By comparing properly smoothed three-dimensional galaxy density maps of the observations and a set of matched simulations incorporating the dominant observational effects (galaxy selection and photometric redshift uncertainties), we first confirm that the observed ∼15 comoving Mpc-scale galaxy clustering is consistent with ΛCDM models. Using further the relation between high-z overdensity and the present day cluster mass calibrated in these matched simulations, we found 36 candidate structures at 1.6 < z < 3.1, showing overdensities consistent with the progenitors of Mz = 0 ∼ 1015 M ☉ clusters. Taking into account the significant upward scattering of lower mass structures, the probabilities for the candidates to have at least Mz= 0 ∼ 1014 M ☉ are ∼70%. For each structure, about 15%-40% of photometric galaxy candidates are expected to be true protocluster members that will merge into a cluster-scale halo by z = 0. With solely photometric redshifts, we successfully rediscover two spectroscopically confirmed structures in this field, suggesting that our algorithm is robust. This work generates a large sample of uniformly selected protocluster candidates, providing rich targets for spectroscopic follow-up and subsequent studies of cluster formation. Meanwhile, it demonstrates the potential for probing early cluster formation with upcoming redshift surveys such as the Hobby-Eberly Telescope Dark Energy Experiment and the Subaru Prime Focus Spectrograph survey

  4. 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

  5. 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

  6. 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 ...

  7. Non-invasive detection of candidate pregnancy protein biomarkers in the feces of captive polar bears (Ursus maritimus).

    Science.gov (United States)

    Curry, E; Stoops, M A; Roth, T L

    2012-07-15

    Currently, there is no method of accurately and non-invasively diagnosing pregnancy in polar bears. Specific proteins may exhibit altered profiles in the feces of pregnant bears, but predicting appropriate candidate proteins to investigate is speculative at best. The objective of this study was to identify potential pregnancy biomarker proteins based on their increased abundance in the feces of pregnant polar bears compared to pseudopregnant females (controls) using two-dimensional in-gel electrophoresis (2D-DIGE) and mass spectrometry (MS). Three 2D-DIGE gels were performed to evaluate fecal protein profiles from controls (n=3) and pregnant polar bears (n=3). There were 2224.67±52.39 (mean±SEM) spots resolved per gel. Of these, only five proteins were elevated in the pregnant group (P99.9% confidence interval. The 11 spots represented seven distinct proteins, five of which were significantly more abundant in the pregnant group: IgGFc-binding protein, filamin-C, carboxypeptidase B, transthyretin, and immunoglobulin heavy chain variable region. To our knowledge, this was the first study that employed 2D-DIGE to identify differentially expressed proteins in fecal samples to characterize a physiological condition other than those related to gastrointestinal disorders. These promising results provided a strong foundation for ensuing efforts to develop a non-invasive pregnancy assay for use in both captive and wild polar bears. PMID:22538002

  8. 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.

  9. Microarray Meta-Analysis and Cross-Platform Normalization: Integrative Genomics for Robust Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Christopher J. Walsh

    2015-08-01

    Full Text Available The diagnostic and prognostic potential of the vast quantity of publicly-available microarray data has driven the development of methods for integrating the data from different microarray platforms. Cross-platform integration, when appropriately implemented, has been shown to improve reproducibility and robustness of gene signature biomarkers. Microarray platform integration can be conceptually divided into approaches that perform early stage integration (cross-platform normalization versus late stage data integration (meta-analysis. A growing number of statistical methods and associated software for platform integration are available to the user, however an understanding of their comparative performance and potential pitfalls is critical for best implementation. In this review we provide evidence-based, practical guidance to researchers performing cross-platform integration, particularly with an objective to discover biomarkers.

  10. Targeted proteomics for biomarker discovery and validation of hepatocellular carcinoma in hepatitis C infected patients

    OpenAIRE

    Mustafa, Gul M; Larry, Denner; John R. Petersen; Elferink, Cornelis J.

    2015-01-01

    Hepatocellular carcinoma (HCC)-related mortality is high because early detection modalities are hampered by inaccuracy, expense and inherent procedural risks. Thus there is an urgent need for minimally invasive, highly specific and sensitive biomarkers that enable early disease detection when therapeutic intervention remains practical. Successful therapeutic intervention is predicated on the ability to detect the cancer early. Similar unmet medical needs abound in most fields of medicine and ...

  11. Microarray Meta-Analysis and Cross-Platform Normalization: Integrative Genomics for Robust Biomarker Discovery

    OpenAIRE

    Walsh, Christopher J.; Pingzhao Hu; Jane Batt; dos Santos, Claudia C.

    2015-01-01

    The diagnostic and prognostic potential of the vast quantity of publicly-available microarray data has driven the development of methods for integrating the data from different microarray platforms. Cross-platform integration, when appropriately implemented, has been shown to improve reproducibility and robustness of gene signature biomarkers. Microarray platform integration can be conceptually divided into approaches that perform early stage integration (cross-platform normalization) versus ...

  12. 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...

  13. Synovial tissue analysis for the discovery of diagnostic and prognostic biomarkers in patients with early arthritis.

    Science.gov (United States)

    de Hair, Maria J H; Harty, Leonard C; Gerlag, Danielle M; Pitzalis, Costantino; Veale, Douglas J; Tak, Paul P

    2011-09-01

    Rheumatoid arthritis (RA) is a chronic disease of unspecified etiology that is manifest by persistent inflammation of the synovium. Considerable efforts have been undertaken globally to study the microenvironment of the inflamed synovium, with many encouraging and enlightening results that bring us closer to unmasking the precise etiologies of RA. Subsequent to these efforts, it has been discovered that CD68-positive macrophages present in abundance in the synovial sublining of the inflamed synovium rescind with treatments that induce clinical improvement in RA. Examination of serial synovial biopsies is now commonly used for screening purposes during early drug development, and the number of centers able to perform synovial tissue biopsy sampling according to standardized methods is increasing. Having implemented the use of serial synovial tissue biopsies to evaluate the effects of new treatments on the group level in early proof of principle studies, it is the ambition of the OMERACT Synovial Tissue Group to identify synovial diagnostic and prognostic biomarkers that could be used in individual patients. Therefore, we started a prospective study termed the Synoviomics Project aimed at the identification of novel diagnostic and prognostic synovial biomarkers. We will use straightforward and powerful technologies to analyze patient material and assess clinical parameters to identify such biomarkers. These markers may be used in the future to identify patients who are at risk of having persistent and destructive disease and to start tailor-made targeted therapies in an early phase to prevent autonomous disease progression and irreversible joint damage. PMID:21885519

  14. Deglycosylation and label-free quantitative LC-MALDI MS applied to efficient serum biomarker discovery of lung cancer

    Directory of Open Access Journals (Sweden)

    Kohno Nobuoki

    2011-04-01

    Full Text Available Abstract Background Serum is an ideal source of biomarker discovery and proteomic profiling studies are continuously pursued on serum samples. However, serum is featured by high level of protein glycosylations that often cause ionization suppression and confound accurate quantification analysis by mass spectrometry. Here we investigated the effect of N-glycan and sialic acid removal from serum proteins on the performance of label-free quantification results. Results Serum tryptic digests with or without deglycosylation treatment were analyzed by LC-MALDI MS and quantitatively compared on the Expressionist Refiner MS module. As a result, 345 out of 2,984 peaks (11.6% showed the specific detection or the significantly improved intensities in deglycosylated serum samples (P P Conclusions We demonstrated here that sample deglycosylation improves the quantitative performance of shotgun proteomics, which can be effectively applied to any samples with high glycoprotein contents.

  15. 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

  16. 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

  17. The proteome of Hypobaric Induced Hypoxic Lung: Insights from Temporal Proteomic Profiling for Biomarker Discovery

    Science.gov (United States)

    Ahmad, Yasmin; Sharma, Narendra K.; Ahmad, Mohammad Faiz; Sharma, Manish; Garg, Iti; Srivastava, Mousami; Bhargava, Kalpana

    2015-01-01

    Exposure to high altitude induces physiological responses due to hypoxia. Lungs being at the first level to face the alterations in oxygen levels are critical to counter and balance these changes. Studies have been done analysing pulmonary proteome alterations in response to exposure to hypobaric hypoxia. However, such studies have reported the alterations at specific time points and do not reflect the gradual proteomic changes. These studies also identify the various biochemical pathways and responses induced after immediate exposure and the resolution of these effects in challenge to hypobaric hypoxia. In the present study, using 2-DE/MS approach, we attempt to resolve these shortcomings by analysing the proteome alterations in lungs in response to different durations of exposure to hypobaric hypoxia. Our study thus highlights the gradual and dynamic changes in pulmonary proteome following hypobaric hypoxia. For the first time, we also report the possible consideration of SULT1A1, as a biomarker for the diagnosis of high altitude pulmonary edema (HAPE). Higher SULT1A1 levels were observed in rats as well as in humans exposed to high altitude, when compared to sea-level controls. This study can thus form the basis for identifying biomarkers for diagnostic and prognostic purposes in responses to hypobaric hypoxia. PMID:26022216

  18. 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.

  19. 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.

  20. 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.

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

    International Nuclear Information System (INIS)

    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: → Expression biomarkers in animals exposed to Cadmium-contaminated field soils. → Expression kinetics to test the ability of genes to serve as expression biomarkers. → Study of detoxification processes through the expression analysis of selected genes.

  2. Currently Available Biomarkers and Strategies for the Validation of Novel Candidates for Neurochemical Dementia Diagnostics in Alzheimer’s Disease and Mild Cognitive Impairment

    Directory of Open Access Journals (Sweden)

    Piotr Lewczuk

    2014-01-01

    Full Text Available The number of people afflicted with Alzheimer’s disease (AD and other types of dementing conditions has grown exponentially in the last decades. This review focuses on the diagnostic role of the classic cerebrospinal fluid (CSF biomarkers of neurochemical dementia diagnostics (NDD and critically discusses potential strategies for the development and validation of novel potential candidates. In some countries, NDD is already established as a routine diagnostic tool, used for the evaluation of patients with cognitive impairments. On the other hand, preanalytical and technical issues, partly discussed in this paper, prevent NDD from the general acceptance worldwide. Currently, two groups of biomarkers in the CSF are considered in NDD: amyloid β (Aβ peptides and Tau proteins, including the hyperphosphorylated forms of the latter (pTau. The analyses of these two groups of biomarkers can reveal pathologic alterations as early as twenty years before the onset of clinical symptoms. In mild cognitive impairment (MCI, NDD can reliably predict which individuals are at risk of converting to AD. The roles of biomarkers of amyloid β deposition in the brain tissue (including the CSF concentration of Aβ42 and biomarkers of neurodegeneration (including the CSF concentrations of Tau/pTau proteins are reflected in the currently proposed diagnostic criteria for AD and MCI.

  3. 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

  4. 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.

  5. 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...

  6. 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.

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

    Directory of Open Access Journals (Sweden)

    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

  8. 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

  9. 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

  10. 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.

  11. 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...

  12. 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

  13. Proteomic discovery of biomarkers of metal contamination in Sydney Rock oysters (Saccostrea glomerata)

    International Nuclear Information System (INIS)

    In the current study we examined the effects of metal contamination on the protein complement of Sydney Rock oysters. Saccostrea glomerata were exposed for 4 days to three environmentally relevant concentrations (100 μg/l, 50 μg/l and 5 μg/l) of cadmium, copper, lead and zinc. Protein abundances in oyster haemolymph from metal-exposed oysters were compared to those from non-exposed controls using two-dimensional electrophoresis to display differentially expressed proteins. Differentially expressed proteins were subsequently identified using tandem mass spectrometry (LC–MS/MS), to assign their putative biological functions. Unique sets of differentially expressed proteins were affected by each metal, in addition to proteins that were affected by more than one metal. The proteins identified included some that are commonly associated with environmental monitoring, such as HSP 70, and other novel proteins not previously considered as candidates for molecular biomonitoring. The most common biological functions of proteins were associated with stress response, cytoskeletal activity and protein synthesis.

  14. Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Linda A. Ban

    2016-03-01

    Full Text Available In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD. This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs. These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting.

  15. Proteomic discovery of biomarkers of metal contamination in Sydney Rock oysters (Saccostrea glomerata)

    Energy Technology Data Exchange (ETDEWEB)

    Thompson, Emma L., E-mail: emma.thompson@mq.edu.au [Department of Biological Sciences, Macquarie University, NSW 2109 (Australia); Sydney Institute of Marine Science, Chowder Bay, NSW 2088 (Australia); Taylor, Daisy A. [Department of Biological Sciences, Macquarie University, NSW 2109 (Australia); Sydney Institute of Marine Science, Chowder Bay, NSW 2088 (Australia); Nair, Sham V. [Department of Biological Sciences, Macquarie University, NSW 2109 (Australia); Birch, Gavin [Department of Geochemistry, University of Sydney, NSW 2006 (Australia); Haynes, Paul A. [Department of Chemistry and Biomolecular Sciences, Macquarie University, NSW 2109 (Australia); Raftos, David A. [Department of Biological Sciences, Macquarie University, NSW 2109 (Australia); Sydney Institute of Marine Science, Chowder Bay, NSW 2088 (Australia)

    2012-03-15

    In the current study we examined the effects of metal contamination on the protein complement of Sydney Rock oysters. Saccostrea glomerata were exposed for 4 days to three environmentally relevant concentrations (100 {mu}g/l, 50 {mu}g/l and 5 {mu}g/l) of cadmium, copper, lead and zinc. Protein abundances in oyster haemolymph from metal-exposed oysters were compared to those from non-exposed controls using two-dimensional electrophoresis to display differentially expressed proteins. Differentially expressed proteins were subsequently identified using tandem mass spectrometry (LC-MS/MS), to assign their putative biological functions. Unique sets of differentially expressed proteins were affected by each metal, in addition to proteins that were affected by more than one metal. The proteins identified included some that are commonly associated with environmental monitoring, such as HSP 70, and other novel proteins not previously considered as candidates for molecular biomonitoring. The most common biological functions of proteins were associated with stress response, cytoskeletal activity and protein synthesis.

  16. Extracellular Vesicles: A New Frontier in Biomarker Discovery for Non-Alcoholic Fatty Liver Disease.

    Science.gov (United States)

    Ban, Linda A; Shackel, Nicholas A; McLennan, Susan V

    2016-01-01

    In recent years, the global burden of obesity and diabetes has seen a parallel rise in other metabolic complications, such as non-alcoholic fatty liver disease (NAFLD). This condition, once thought to be a benign accumulation of hepatic fat, is now recognized as a serious and prevalent disorder that is conducive to inflammation and fibrosis. Despite the rising incidence of NAFLD, there is currently no reliable method for its diagnosis or staging besides the highly invasive tissue biopsy. This limitation has resulted in the study of novel circulating markers as potential candidates, one of the most popular being extracellular vesicles (EVs). These submicron membrane-bound structures are secreted from stressed and activated cells, or are formed during apoptosis, and are known to be involved in intercellular communication. The cargo of EVs depends upon the parent cell and has been shown to be changed in disease, as is their abundance in the circulation. The role of EVs in immunity and epigenetic regulation is widely attested, and studies showing a correlation with disease severity have made these structures a favorable target for diagnostic as well as therapeutic purposes. This review will highlight the research that is available on EVs in the context of NAFLD, the current limitations, and projections for their future utility in a clinical setting. PMID:26985892

  17. Biomarkers in Alzheimer’s Disease Analysis by Mass Spectrometry-Based Proteomics

    OpenAIRE

    Yahui Liu; Hong Qing; Yulin Deng

    2014-01-01

    Alzheimer’s disease (AD) is a common chronic and destructive disease. The early diagnosis of AD is difficult, thus the need for clinically applicable biomarkers development is growing rapidly. There are many methods to biomarker discovery and identification. In this review, we aim to summarize Mass spectrometry (MS)-based proteomics studies on AD and discuss thoroughly the methods to identify candidate biomarkers in cerebrospinal fluid (CSF) and blood. This review will also discuss the potent...

  18. 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.

  19. Proteome changes in Atlantic cod (Gadus morhua) exposed to oil and produced water: Discovery of biomarker candidates for environmental monitoring

    Energy Technology Data Exchange (ETDEWEB)

    Kjersem, Anneli B

    2007-07-15

    Proteomics were applied to identify changes in the proteome of Atlantic cod (Gadus morhua) exposed to crude North Sea oil and North Sea produced water at different life stages and during early development. Apparent protein changes were identified and linked to possible signalling pathways and mechanisms involved in the biological response of fish following exposure. Exposure to North Sea crude oil and produced water appeared to induce a large number of changes, also at low levels of exposure. More than 40 of the 137 protein changes detected in plasma of juvenile cod following exposed to crude oil and surrogate produced water appeared at the lowest level of exposure, 0.06 ppm crude oil. Almost all of the protein changes detected in whole fry and fry liver following produced water exposure occurred at the lowest levels of produced water, 0.01% and 0.1% produced water

  20. 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.

  1. 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.

  2. The C-terminal fragment of prostate-specific antigen, a 2331 Da peptide, as a new urinary pathognomonic biomarker candidate for diagnosing prostate cancer.

    Directory of Open Access Journals (Sweden)

    Kenji Nakayama

    Full Text Available BACKGROUND AND OBJECTIVES: Prostate cancer (PCa is one of the most common cancers and leading cause of cancer-related deaths in men. Mass screening has been carried out since the 1990s using prostate-specific antigen (PSA levels in the serum as a PCa biomarker. However, although PSA is an excellent organ-specific marker, it is not a cancer-specific marker. Therefore, the aim of this study was to discover new biomarkers for the diagnosis of PCa. MATERIALS AND METHODS: We focused on urine samples voided following prostate massage (digital rectal examination [DRE] and conducted a peptidomic analysis of these samples using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS(n. Urinary biomaterials were concentrated and desalted using CM-Sepharose prior to the following analyses being performed by MALDI-TOF/MS(n: 1 differential analyses of mass spectra; 2 determination of amino acid sequences; and 3 quantitative analyses using a stable isotope-labeled internal standard. RESULTS: Multivariate analysis of the MALDI-TOF/MS mass spectra of urinary extracts revealed a 2331 Da peptide in urine samples following DRE. This peptide was identified as a C-terminal PSA fragment composed of 19 amino acid residues. Moreover, quantitative analysis of the relationship between isotope-labeled synthetic and intact peptides using MALDI-TOF/MS revealed that this peptide may be a new pathognomonic biomarker candidate that can differentiate PCa patients from non-cancer subjects. CONCLUSION: The results of the present study indicate that the 2331 Da peptide fragment of PSA may become a new pathognomonic biomarker for the diagnosis of PCa. A further large-scale investigation is currently underway to assess the possibility of using this peptide in the early detection of PCa.

  3. Candidate serum biomarkers for early intestinal cancer using 15N metabolic labeling and quantitative proteomics in the Apcmin/+ mouse

    OpenAIRE

    Ivancic, Melanie M.; Huttlin, Edward L.; Chen, Xiaodi; Pleiman, Jennifer K; Irving, Amy A; Hegeman, Adrian D.; Dove, William F.; Sussman, Michael R.

    2013-01-01

    Current screening procedures for colorectal cancer are imperfect, highly invasive and result in increased mortality rates due to low compliance. The goal of the experiments reported herein is to identify potential blood-based biomarkers indicative of early-stage intestinal cancers using the ApcMin/+ mouse model of intestinal cancer as an experimental system. Serum proteins from tumor-bearing ApcMin/+ mice were quantitatively compared to tumor-free Apc+/+ wild-type mice via in anima metabolic ...

  4. 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.

  5. Selective enrichment and sensitive detection of candidate disease biomarker using a novel surfactant-coated magnetic nanoparticles

    Science.gov (United States)

    Capangpangan, R. Y.; dela Rosa, M. A. C.; Chang, C. H.; Wang, W. C.; Peng, J.; Shih, S. J.; Chiang, M. H.; Tzou, D. L.; Lin, C. C.; Chen, Y. J.

    2014-08-01

    In this study, novel surfactant-coated magnetic nanoparticles were synthesized and evaluated for enrichment performance towards the sensitive detection of disease biomarkers. Surfactants with phosphate ester groups (RD35A and RD66) were used as a coating to reduce aggregation and to enhance the nanoparticle dispersion. Importantly, sensitive enrichment of the target proteins using the antibody-functionalized magnetic nanoparticles (Ab@MNP) was obtained, with a five-fold increase in recovery compared to uncoated magnetic nanoparticles. Similarly, phosphopeptide enrichment using the NTA@MNP in standard samples showed that the nanoparticles could selectively enrich phosphorylated peptides.

  6. 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.

  7. Use of Aleuria alantia Lectin Affinity Chromatography to Enrich Candidate Biomarkers from the Urine of Patients with Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Sarah R. Ambrose

    2015-09-01

    Full Text Available Developing a urine test to detect bladder tumours with high sensitivity and specificity is a key goal in bladder cancer research. We hypothesised that bladder cancer-specific glycoproteins might fulfill this role. Lectin-ELISAs were used to study the binding of 25 lectins to 10 bladder cell lines and serum and urine from bladder cancer patients and non-cancer controls. Selected lectins were then used to enrich glycoproteins from the urine of bladder cancer patients and control subjects for analysis by shotgun proteomics. None of the lectins showed a strong preference for bladder cancer cell lines over normal urothlelial cell lines or for urinary glycans from bladder cancer patients over those from non-cancer controls. However, several lectins showed a strong preference for bladder cell line glycans over serum glycans and are potentially useful for enriching glycoproteins originating from the urothelium in urine. Aleuria alantia lectin affinity chromatography and shotgun proteomics identified mucin-1 and golgi apparatus protein 1 as proteins warranting further investigation as urinary biomarkers for low-grade bladder cancer. Glycosylation changes in bladder cancer are not reliably detected by measuring lectin binding to unfractionated proteomes, but it is possible that more specific reagents and/or a focus on individual proteins may produce clinically useful biomarkers.

  8. IgY14 and SuperMix immunoaffinity separations coupled with liquid chromatography-mass spectrometry for human plasma proteomic biomarker discovery

    Energy Technology Data Exchange (ETDEWEB)

    Shi, Tujin; Zhou, Jianying; Gritsenko, Marina A.; Hossain, Mahmud; Camp, David G.; Smith, Richard D.; Qian, Weijun

    2012-02-01

    Interest in the application of advanced proteomics technologies to human blood plasma- or serum-based clinical samples for the purpose of discovering disease biomarkers continues to grow; however, the enormous dynamic range of protein concentrations in these types of samples (often >10 orders of magnitude) represents a significant analytical challenge, particularly for detecting low-abundance candidate biomarkers. In response, immunoaffinity separation methods for depleting multiple high- and moderate-abundance proteins have become key tools for enriching low-abundance proteins and enhancing detection of these proteins in plasma proteomics. Herein, we describe IgY14 and tandem IgY14-Supermix separation methods for removing 14 high-abundance and up to 60 moderate-abundance proteins, respectively, from human blood plasma and highlight their utility when combined with liquid chromatography-tandem mass spectrometry for interrogating the human plasma proteome.

  9. 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.

  10. Candidate serum biomarkers for early intestinal cancer using 15N metabolic labeling and quantitative proteomics in the ApcMin/+ mouse.

    Science.gov (United States)

    Ivancic, Melanie M; Huttlin, Edward L; Chen, Xiaodi; Pleiman, Jennifer K; Irving, Amy A; Hegeman, Adrian D; Dove, William F; Sussman, Michael R

    2013-09-01

    Current screening procedures for colorectal cancer are imperfect and highly invasive and result in increased mortality rates due to low compliance. The goal of the experiments reported herein is to identify potential blood-based biomarkers indicative of early stage intestinal cancers using the ApcMin/+ mouse model of intestinal cancer as an experimental system. Serum proteins from tumor-bearing ApcMin/+ mice were quantitatively compared to tumor-free Apc+/+ wild-type mice via in anima metabolic labeling with 14N/15N-labeled Spirulina algae and an LTQ Orbitrap mass spectrometer. Out of 1116 total serum proteins quantified, this study identified 40 that were differentially expressed and correlated with the increase in intestinal neoplasms. A subset of these differentially expressed proteins underwent a secondary quantitative screen using selected reaction monitoring-mass spectrometry with stable isotope-labeled peptides. Using both quantitative techniques, we identified MGAM and COL1A1 as downregulated and ITIH3 and F5 as upregulated in serum. All but COL1A1 were similarly differentially expressed in the mRNA of neoplastic colonic tissues of ApcMin/+ mice compared to normal wild-type tissue. These differentially expressed proteins identified in the ApcMin/+ mouse model have provided a set of candidate biomarkers for future validation screens in humans. PMID:23924158

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

    International Nuclear Information System (INIS)

    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 (β = -0.8456, p = 0.071; β = -0.9406, p = 0.017; β = -0.9526, p = 0.012 respectively), as well as inorganic As + Hg (β = -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.

  12. Determination of butoxyacetic acid (biomarker of ethylene glycol monobutyl ether exposure) in human urine candidate reference material

    Czech Academy of Sciences Publication Activity Database

    Sperlingova, I.; Dabrowská, L.; Stránský, V.; Duskova, S.; Kučera, Jan; Tvrdíková, M.; Tichý, M.

    2010-01-01

    Roč. 397, č. 2 (2010), s. 433-438. ISSN 1618-2642. [12th International Symposium on Biological and Environmental Reference Materials Keble Coll. Oxford, 07.07.2009-10.07.2009] Institutional research plan: CEZ:AV0Z10480505 Keywords : Candidate reference material * Ethylene glycol monobutyl ether * Metabolite Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 3.841, year: 2010

  13. Biomarkers of tolerance: searching for the hidden phenotype.

    Science.gov (United States)

    Perucha, Esperanza; Rebollo-Mesa, Irene; Sagoo, Pervinder; Hernandez-Fuentes, Maria P

    2011-08-01

    Induction of transplantation tolerance remains the ideal long-term clinical and logistic solution to the current challenges facing the management of renal allograft recipients. In this review, we describe the recent studies and advances made in identifying biomarkers of renal transplant tolerance, from study inceptions, to the lessons learned and their implications for current and future studies with the same goal. With the age of biomarker discovery entering a new dimension of high-throughput technologies, here we also review the current approaches, developments, and pitfalls faced in the subsequent statistical analysis required to identify valid biomarker candidates. PMID:25018902

  14. 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

  15. The Discovery of Novel Genomic, Transcriptomic, and Proteomic Biomarkers in Cardiovascular and Peripheral Vascular Disease: The State of the Art

    Science.gov (United States)

    de Franciscis, Stefano; Metzinger, Laurent; Serra, Raffaele

    2016-01-01

    Cardiovascular disease (CD) and peripheral vascular disease (PVD) are leading causes of mortality and morbidity in western countries and also responsible of a huge burden in terms of disability, functional decline, and healthcare costs. Biomarkers are measurable biological elements that reflect particular physiological or pathological states or predisposition towards diseases and they are currently widely studied in medicine and especially in CD. In this context, biomarkers can also be used to assess the severity or the evolution of several diseases, as well as the effectiveness of particular therapies. Genomics, transcriptomics, and proteomics have opened new windows on disease phenomena and may permit in the next future an effective development of novel diagnostic and prognostic medicine in order to better prevent or treat CD. This review will consider the current evidence of novel biomarkers with clear implications in the improvement of risk assessment, prevention strategies, and medical decision making in the field of CD. PMID:27298828

  16. 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

  17. 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

    stability of the selected variables. The performance of the method was evaluated using a simulated data set and a multi-block data set from a dietary intervention study with pigs used as model for humans. The objective of the study was to investigate the biochemical effects in plasma after dietary...... intervention with breads varying in types of dietary fiber and to identify potential biomarkers. By introducing Sparse MBPLSR, we aimed at identifying the biomarkers where data from LC–MS and NMR instruments were analyzed simultaneously and therefore in addition we intended to explore the relationships among...

  18. KEPLER OBSERVATIONS OF THREE PRE-LAUNCH EXOPLANET CANDIDATES: DISCOVERY OF TWO ECLIPSING BINARIES AND A NEW EXOPLANET

    International Nuclear Information System (INIS)

    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 RJupiter in a 3.9 day orbit.

  19. Biomarkers in Alzheimer’s Disease Analysis by Mass Spectrometry-Based Proteomics

    Directory of Open Access Journals (Sweden)

    Yahui Liu

    2014-05-01

    Full Text Available Alzheimer’s disease (AD is a common chronic and destructive disease. The early diagnosis of AD is difficult, thus the need for clinically applicable biomarkers development is growing rapidly. There are many methods to biomarker discovery and identification. In this review, we aim to summarize Mass spectrometry (MS-based proteomics studies on AD and discuss thoroughly the methods to identify candidate biomarkers in cerebrospinal fluid (CSF and blood. This review will also discuss the potential research areas on biomarkers.

  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. DISCOVERY OF CANDIDATE H2O DISK MASERS IN ACTIVE GALACTIC NUCLEI AND ESTIMATIONS OF CENTRIPETAL ACCELERATIONS

    International Nuclear Information System (INIS)

    Based on spectroscopic signatures, about one-third of known H2O maser sources in active galactic nuclei (AGNs) 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 (NGC 1320, NGC 17) in a survey of 40 inclined active galaxies (v sys -1). The remaining three disk maser candidates were identified in monitoring of known sources: NGC 449, NGC 2979, and NGC 3735. We also confirm a previously marginal case in UGC 4203. For the disk maser candidates reported here, inferred rotation speeds are 130-500 km s-1. Monitoring of three more rapidly rotating candidate disks (CG 211, NGC 6264, VV 340A) has enabled measurement of likely orbital centripetal acceleration, and estimation of central masses ((2-7) x107 M sun) and mean disk radii (0.2-0.4 pc). Accelerations may ultimately permit estimation of distances when combined with interferometer data. This is notable because the three AGNs are relatively distant (10,000 km s-1 sys -1), and fractional error in a derived Hubble constant, due to peculiar motion of the galaxies, would be small. As signposts of highly inclined geometries at galactocentric radii of ∼0.1-1 pc, disk masers also provide robust orientation references that allow analysis of (mis)alignment between AGNs and surrounding galactic stellar disks, even without extensive interferometric mapping. We find no preference among published disk maser candidates to lie in high-inclination galaxies. This provides independent support for conclusions that in late-type galaxies, central engine accretion disks and galactic plane orientations are not correlated.

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. Discovery of coding genetic variants influencing diabetes-related serum biomarkers and their impact on risk of type 2 diabetes

    DEFF Research Database (Denmark)

    Ahluwalia, Tarunveer Singh; Allin, Kristine Højgaard; Sandholt, Camilla Helene;

    2015-01-01

    biomarkers associated with T2D: adiponectin, C-reactive protein, ferritin, heat shock 70-kDa protein 1B, IGF binding protein 1 and IGF binding protein 2, IL-18, IL-2 receptor-α, and leptin. DESIGN AND PARTICIPANTS: A population-based sample of 6215 adult Danes was genotyped for 16 340 coding single...... therapeutic strategies....

  7. 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...

  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. 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...

  11. Metabolomics as a Tool for Discovery of Biomarkers of Autism Spectrum Disorder in the Blood Plasma of Children

    OpenAIRE

    West, Paul R.; Amaral, David G.; Bais, Preeti; Smith, Alan M.; Egnash, Laura A.; Ross, Mark E.; Palmer, Jessica A.; Fontaine, Burr R.; Conard, Kevin R.; Corbett, Blythe A.; Cezar, Gabriela G.; Donley, Elizabeth L. R.; Burrier, Robert E.

    2014-01-01

    Background The diagnosis of autism spectrum disorder (ASD) at the earliest age possible is important for initiating optimally effective intervention. In the United States the average age of diagnosis is 4 years. Identifying metabolic biomarker signatures of ASD from blood samples offers an opportunity for development of diagnostic tests for detection of ASD at an early age. Objectives To discover metabolic features present in plasma samples that can discriminate children with ASD from typical...

  12. 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.

  13. 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...

  14. Development of a universal metabolome-standard method for long-term LC-MS metabolome profiling and its application for bladder cancer urine-metabolite-biomarker discovery.

    Science.gov (United States)

    Peng, Jun; Chen, Yi-Ting; Chen, Chien-Lun; Li, Liang

    2014-07-01

    Large-scale metabolomics study requires a quantitative method to generate metabolome data over an extended period with high technical reproducibility. We report a universal metabolome-standard (UMS) method, in conjunction with chemical isotope labeling liquid chromatography-mass spectrometry (LC-MS), to provide long-term analytical reproducibility and facilitate metabolome comparison among different data sets. In this method, UMS of a specific type of sample labeled by an isotope reagent is prepared a priori. The UMS is spiked into any individual samples labeled by another form of the isotope reagent in a metabolomics study. The resultant mixture is analyzed by LC-MS to provide relative quantification of the individual sample metabolome to UMS. UMS is independent of a study undertaking as well as the time of analysis and useful for profiling the same type of samples in multiple studies. In this work, the UMS method was developed and applied for a urine metabolomics study of bladder cancer. UMS of human urine was prepared by (13)C2-dansyl labeling of a pooled sample from 20 healthy individuals. This method was first used to profile the discovery samples to generate a list of putative biomarkers potentially useful for bladder cancer detection and then used to analyze the verification samples about one year later. Within the discovery sample set, three-month technical reproducibility was examined using a quality control sample and found a mean CV of 13.9% and median CV of 9.4% for all the quantified metabolites. Statistical analysis of the urine metabolome data showed a clear separation between the bladder cancer group and the control group from the discovery samples, which was confirmed by the verification samples. Receiver operating characteristic (ROC) test showed that the area under the curve (AUC) was 0.956 in the discovery data set and 0.935 in the verification data set. These results demonstrated the utility of the UMS method for long-term metabolomics and

  15. 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.

  16. Amyloid-β-Secondary Structure Distribution in Cerebrospinal Fluid and Blood Measured by an Immuno-Infrared-Sensor: A Biomarker Candidate for Alzheimer's Disease.

    Science.gov (United States)

    Nabers, Andreas; Ollesch, Julian; Schartner, Jonas; Kötting, Carsten; Genius, Just; Hafermann, Henning; Klafki, Hans; Gerwert, Klaus; Wiltfang, Jens

    2016-03-01

    The misfolding of the Amyloid-beta (Aβ) peptide into β-sheet enriched conformations was proposed as an early event in Alzheimer's Disease (AD). Here, the Aβ peptide secondary structure distribution in cerebrospinal fluid (CSF) and blood plasma of 141 patients was measured with an immuno-infrared-sensor. The sensor detected the amide I band, which reflects the overall secondary structure distribution of all Aβ peptides extracted from the body fluid. We observed a significant downshift of the amide I band frequency of Aβ peptides in Dementia Alzheimer type (DAT) patients, which indicated an overall shift to β-sheet. The secondary structure distribution of all Aβ peptides provides a better marker for DAT detection than a single Aβ misfold or the concentration of a specific oligomer. The discrimination between DAT and disease control patients according to the amide I frequency was in excellent agreement with the clinical diagnosis (accuracy 90% for CSF and 84% for blood). The amide I band maximum above or below the decisive marker frequency appears as a novel spectral biomarker candidate of AD. Additionally, a preliminary proof-of-concept study indicated an amide I band shift below the marker band already in patients with mild cognitive impairment due to AD. The presented immuno-IR-sensor method represents a promising, simple, robust, and label-free diagnostic tool for CSF and blood analysis. PMID:26828829

  17. 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

  18. Discovery of an M9.5 Candidate Brown Dwarf in the TW Hydrae Association - DENIS J124514.1-442907

    CERN Document Server

    Looper, Dagny L; Kirkpatrick, J Davy; Swift, Brandon J

    2007-01-01

    We report the discovery of a fifth candidate substellar system in the ~5-10 Myr TW Hydrae Association - DENIS J124514.1-442907. This object has a NIR spectrum remarkably similar to that of 2MASS J1139511-315921, a known TW Hydrae brown dwarf, with low surface gravity features such as a triangular-shaped H-band, deep H2O absorption, weak alkali lines, and weak hydride bands. We find an optical spectral type of M9.5 and estimate a mass of <24 M_Jup, assuming an age of ~5-10 Myr. While the measured proper motion for DENIS J124514.1-442907 is inconclusive as a test for membership, its position in the sky is coincident with the TW Hydrae Association. A more accurate proper motion measurement, higher resolution spectroscopy for radial velocity, and a parallax measurement are needed to derive the true space motion and to confirm its membership.

  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. 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

  1. 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.

  2. Phospholipid fatty acid biomarkers in a freshwater periphyton community exposed to uranium: discovery by non-linear statistical learning

    International Nuclear Information System (INIS)

    Phospholipid fatty acids (PLFA) have been widely used to characterize environmental microbial communities, generating community profiles that can distinguish phylogenetic or functional groups within the community. The poor specificity of organism groups with fatty acid biomarkers in the classic PLFA-microorganism associations is a confounding factor in many of the statistical classification/clustering approaches traditionally used to interpret PLFA profiles. In this paper we demonstrate that non-linear statistical learning methods, such as a support vector machine (SVM), can more accurately find patterns related to uranyl nitrate exposure in a freshwater periphyton community than linear methods, such as partial least squares discriminant analysis. In addition, probabilistic models of exposure can be derived from the identified lipid biomarkers to demonstrate the potential model-based approach that could be used in remediation. The SVM probability model separates dose groups at accuracies of ∼87.0%, ∼71.4%, ∼87.5%, and 100% for the four groups; Control (non-amended system), low dose (amended at 10 μg U L-1), medium dose (amended at 100 μg U L-1), and high dose (500 μg U L-1). The SVM model achieved an overall cross-validated classification accuracy of ∼87% in contrast to ∼59% for the best linear classifier. - Research highlights: →Linear statistical tools failed to find patterns in the periphyton PLFA profiles. →Support vector machines successfully identified key PLFAs indicative of U exposure. →U exposure stimulated more phototrophic populations, prokaryotic and eukaryotic.

  3. 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

  4. 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...

  5. 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.

  6. DISCOVERY OF A COMPANION CANDIDATE IN THE HD 169142 TRANSITION DISK AND THE POSSIBILITY OF MULTIPLE PLANET FORMATION

    International Nuclear Information System (INIS)

    We present L'- and J-band high-contrast observations of HD 169142, obtained with the Very Large Telescope/NACO AGPM vector vortex coronagraph and the Gemini Planet Imager, respectively. A source located at 0.''156 ± 0.''032 north of the host star (P.A. = 7.°4 ± 11.°3) appears in the final reduced L' image. At the distance of the star (∼145 pc), this angular separation corresponds to a physical separation of 22.7 ± 4.7 AU, locating the source within the recently resolved inner cavity of the transition disk. The source has a brightness of L' = 12.2 ± 0.5 mag, whereas it is not detected in the J band (J >13.8 mag). If its L' brightness arose solely from the photosphere of a companion and given the J – L' color constraints, it would correspond to a 28-32 M Jupiter object at the age of the star, according to the COND models. Ongoing accretion activity of the star suggests, however, that gas is left in the inner disk cavity from which the companion could also be accreting. In this case, the object could be lower in mass and its luminosity enhanced by the accretion process and by a circumplanetary disk. A lower-mass object is more consistent with the observed cavity width. Finally, the observations enable us to place an upper limit on the L'-band flux of a second companion candidate orbiting in the disk annular gap at ∼50 AU, as suggested by millimeter observations. If the second companion is also confirmed, HD 169142 might be forming a planetary system, with at least two companions opening gaps and possibly interacting with each other

  7. DISCOVERY OF AN ULTRASOFT X-RAY TRANSIENT SOURCE IN THE 2XMM CATALOG: A TIDAL DISRUPTION EVENT CANDIDATE

    International Nuclear Information System (INIS)

    We have discovered an ultrasoft X-ray transient source, 2XMMi J184725.1-631724, which was detected serendipitously in two XMM-Newton observations in the direction of the center of the galaxy IC 4765-f01-1504 at a redshift of 0.0353. These two observations were separated by 211 days, with the 0.2-10 keV absorbed flux increasing by a factor of about nine. Their spectra are best described by a model dominated by a thermal disk or a single-temperature blackbody component (contributing ∼>80% of the flux) plus a weak power-law component. The thermal emission has a temperature of a few tens of eV, and the weak power-law component has a photon index of ∼3.5. Similar to the black hole X-ray binaries in the thermal state, our source exhibits an accretion disk whose luminosity appears to follow the L∝T 4 relation. This would indicate that the black hole mass is about 105-106 Msun using the best-fitting inner disk radius. Both XMM-Newton observations show variability of about 21% on timescales of hours, which can be explained as due to fast variations in the mass accretion rate. The source was not detected by ROSAT in an observation in 1992, indicating a variability factor of ∼>64 over longer timescales. The source was not detected again in X-rays in a Swift observation in 2011 February, implying a flux decrease by a factor of ∼>12 since the last XMM-Newton observation. The transient nature, in addition to the extreme softness of the X-ray spectra and the inactivity of the galaxy implied by the lack of strong optical emission lines, makes it a candidate tidal disruption event. If this is the case, the first XMM-Newton observation would have been in the rising phase and the second one in the decay phase.

  8. 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)

  9. 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)

  10. Application of Fluorescence Two-Dimensional Difference In-Gel Electrophoresis as a Proteomic Biomarker Discovery Tool in Muscular Dystrophy Research

    Directory of Open Access Journals (Sweden)

    Steven Carberry

    2013-12-01

    Full Text Available In this article, we illustrate the application of difference in-gel electrophoresis for the proteomic analysis of dystrophic skeletal muscle. The mdx diaphragm was used as a tissue model of dystrophinopathy. Two-dimensional gel electrophoresis is a widely employed protein separation method in proteomic investigations. Although two-dimensional gels usually underestimate the cellular presence of very high molecular mass proteins, integral membrane proteins and low copy number proteins, this method is extremely powerful in the comprehensive analysis of contractile proteins, metabolic enzymes, structural proteins and molecular chaperones. This gives rise to two-dimensional gel electrophoretic separation as the method of choice for studying contractile tissues in health and disease. For comparative studies, fluorescence difference in-gel electrophoresis has been shown to provide an excellent biomarker discovery tool. Since aged diaphragm fibres from the mdx mouse model of Duchenne muscular dystrophy closely resemble the human pathology, we have carried out a mass spectrometry-based comparison of the naturally aged diaphragm versus the senescent dystrophic diaphragm. The proteomic comparison of wild type versus mdx diaphragm resulted in the identification of 84 altered protein species. Novel molecular insights into dystrophic changes suggest increased cellular stress, impaired calcium buffering, cytostructural alterations and disturbances of mitochondrial metabolism in dystrophin-deficient muscle tissue.

  11. Application of fluorescence two-dimensional difference in-gel electrophoresis as a proteomic biomarker discovery tool in muscular dystrophy research.

    Science.gov (United States)

    Carberry, Steven; Zweyer, Margit; Swandulla, Dieter; Ohlendieck, Kay

    2013-01-01

    In this article, we illustrate the application of difference in-gel electrophoresis for the proteomic analysis of dystrophic skeletal muscle. The mdx diaphragm was used as a tissue model of dystrophinopathy. Two-dimensional gel electrophoresis is a widely employed protein separation method in proteomic investigations. Although two-dimensional gels usually underestimate the cellular presence of very high molecular mass proteins, integral membrane proteins and low copy number proteins, this method is extremely powerful in the comprehensive analysis of contractile proteins, metabolic enzymes, structural proteins and molecular chaperones. This gives rise to two-dimensional gel electrophoretic separation as the method of choice for studying contractile tissues in health and disease. For comparative studies, fluorescence difference in-gel electrophoresis has been shown to provide an excellent biomarker discovery tool. Since aged diaphragm fibres from the mdx mouse model of Duchenne muscular dystrophy closely resemble the human pathology, we have carried out a mass spectrometry-based comparison of the naturally aged diaphragm versus the senescent dystrophic diaphragm. The proteomic comparison of wild type versus mdx diaphragm resulted in the identification of 84 altered protein species. Novel molecular insights into dystrophic changes suggest increased cellular stress, impaired calcium buffering, cytostructural alterations and disturbances of mitochondrial metabolism in dystrophin-deficient muscle tissue. PMID:24833232

  12. Comprehensive and Scalable Highly Automated MS-Based Proteomic Workflow for Clinical Biomarker Discovery in Human Plasma.

    Science.gov (United States)

    Dayon, Loïc; Núñez Galindo, Antonio; Corthésy, John; Cominetti, Ornella; Kussmann, Martin

    2014-07-24

    Over the past decade, mass spectrometric performance has greatly improved in terms of sensitivity, dynamic range, and speed. By contrast, only limited progress has been accomplished with regard to automation, throughput, and robustness of the proteomic sample preparation process upstream of mass spectrometry. The present work delivers an optimized analysis of human plasma samples in both small preclinical and large clinical studies, enabled by the development of a highly automated quantitative proteomic workflow. Several iterative evaluation and validation steps were performed before process "design freeze" and development completion. A robotic liquid handling workflow and platform (including reduction, alkylation, digestion, TMT labeling, pooling, and purification) were shown to provide better quantitative trueness and precision than manual operation at the bench. Depletion of the most abundant human plasma proteins and subsequent buffer exchange were also developed and integrated. Finally, 96 identical pooled human plasma samples were prepared in a 96-well plate format, and each sample was individually subjected to our developed workflow. This test revealed increased throughput and robustness compared with to-date published manual or less automated workflows. Our workflow is ready-to-use for future (pre-) clinical studies. We expect our work to facilitate, accelerate, and improve clinical proteomic discovery in human blood plasma. PMID:25058407

  13. 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...

  14. 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 ...

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

    International Nuclear Information System (INIS)

    associated with adhesion and mobility, precollagen-D that is associated with the detoxification mechanism of Cu2+. Protein identification clearly showed that the toxicity of CuO NPs is not solely due to Cu2+ 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

  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. 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.

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

    Science.gov (United States)

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

    2010-11-01

    We report on the discovery and monitoring observations of a new galactic black hole (BH) candidate XTE J1752-223 by Rossi X-ray Timing Explorer (RXTE). The new source appeared on the X-ray sky on 2009 October 21 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 BH 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 blackbody 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 broadband 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 hard-to-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 of about 3.5 kpc.

  19. 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)

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

    2010-12-01

    I will 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 Compromising 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 observation during the hard-to-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.

  20. DISCOVERY AND MONITORING OF A NEW BLACK HOLE CANDIDATE XTE J1752-223 WITH RXTE: RMS SPECTRUM EVOLUTION, BLACK HOLE MASS, AND THE SOURCE DISTANCE

    International Nuclear Information System (INIS)

    We report on the discovery and monitoring observations of a new galactic black hole (BH) candidate XTE J1752-223 by Rossi X-ray Timing Explorer (RXTE). The new source appeared on the X-ray sky on 2009 October 21 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 BH 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 blackbody 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 broadband 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 hard-to-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 of about 3.5 kpc.

  1. 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.

  2. Validation of New Cancer Biomarkers

    DEFF Research Database (Denmark)

    Duffy, Michael J; Sturgeon, Catherine M; Söletormos, Georg; Barak, Vivian; Molina, Rafael; Hayes, Daniel F; Diamandis, Eleftherios P; Bossuyt, Patrick

    2015-01-01

    BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps in...... advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance of...... the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be...

  3. 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.

  4. 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...

  5. Comparative analysis of the human hepatic and adipose tissue transcriptomes during LPS-induced inflammation leads to the identification of differential biological pathways and candidate biomarkers

    OpenAIRE

    Szalowska, E.; Dijkstra, M.; Elferink, M.G.L.; Weening, D.; De, Vries; Bruinenberg, M.; van Hoek, A.; Roelofsen, H.; Groothuis, G.M.M.; Vonk, R.J.

    2011-01-01

    Background: Insulin resistance (IR) is accompanied by chronic low grade systemic inflammation, obesity, and deregulation of total body energy homeostasis. We induced inflammation in adipose and liver tissues in vitro in order to mimic inflammation in vivo with the aim to identify tissue-specific processes implicated in IR and to find biomarkers indicative for tissue-specific IR. Methods: Human adipose and liver tissues were cultured in the absence or presence of LPS and DNA Microarray Technol...

  6. 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

  7. 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...

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

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

    OpenAIRE

    Kooren Joel A; Rhodus Nelson L; Tang Chuanning; Jagtap Pratik D; Horrigan Bryan J; Griffin Timothy J

    2011-01-01

    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-bas...

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. Metabolic profiling study on potential toxicity and immunotoxicity-biomarker discovery in rats treated with cyclophosphamide using HPLC-ESI-IT-TOF-MS.

    Science.gov (United States)

    Li, Jing; Lin, Wensi; Lin, Weiwei; Xu, Peng; Zhang, Jianmei; Yang, Haisong; Ling, Xiaomei

    2015-05-01

    Despite the recent advances in understanding toxicity mechanism of cyclophosphamide (CTX), the development of biomarkers is still essential. CTX-induced immunotoxicity in rats by a metabonomics approach was investigated using high-performance liquid chromatography coupled with ion trap time-of-flight mass spectrometry (HPLC-ESI-IT-TOF-MS). The rats were orally administered CTX (30 mg/kg/day) for five consecutive days, and on the fifth day samples of urine, thymus and spleen were collected and analyzed. A significant difference in metabolic profiling was observed between the CTX-treated group and the control group by partial least squares-discriminant analysis (PLS-DA), which indicated that metabolic disturbances of immunotoxicity in CTX-treated rats had occurred. One potential biomarker in spleen, three in urine and three in thymus were identified. It is suggested that the CTX-toxicity mechanism may involve the modulation of tryptophan metabolism, phospholipid metabolism and energy metabolism. This research can help to elucidate the CTX-influenced pathways at a low dose and can further help to indicate the patients' pathological status at earlier stages of toxicological progression after drug administration. PMID:25322901

  20. Cell-free microRNAs in blood and other body fluids, as cancer biomarkers.

    Science.gov (United States)

    Ortiz-Quintero, Blanca

    2016-06-01

    The discovery of cell-free microRNAs (miRNAs) in serum, plasma and other body fluids has yielded an invaluable potential source of non-invasive biomarkers for cancer and other non-malignant diseases. miRNAs in the blood and other body fluids are highly stable in biological samples and are resistant to environmental conditions, such as freezing, thawing or enzymatic degradation, which makes them convenient as potential biomarkers. In addition, they are more easily sampled than tissue miRNAs. Altered levels of cell-free miRNAs have been found in every type of cancer analysed, and increasing evidence indicates that they may participate in carcinogenesis by acting as cell-to-cell signalling molecules. This review summarizes the biological characteristics and mechanisms of release of cell-free miRNAs that make them promising candidates as non-invasive biomarkers of cancer. PMID:27218664

  1. 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

    Directory of Open Access Journals (Sweden)

    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

  2. Allele discovery of ten candidate drought-response genes in Austrian oak using a systematically informatics approach based on 454 amplicon sequencing

    Directory of Open Access Journals (Sweden)

    Homolka Andreas

    2012-04-01

    Full Text Available Abstract Background Rise of temperatures and shortening of available water as result of predicted climate change will impose significant pressure on long-lived forest tree species. Discovering allelic variation present in drought related genes of two Austrian oak species can be the key to understand mechanisms of natural selection and provide forestry with key tools to cope with future challenges. Results In the present study we have used Roche 454 sequencing and developed a bioinformatic pipeline to process multiplexed tagged amplicons in order to identify single nucleotide polymorphisms and allelic sequences of ten candidate genes related to drought/osmotic stress from sessile oak (Quercus robur and sessile oak (Q. petraea individuals. Out of these, eight genes of 336 oak individuals growing in Austria have been detected with a total number of 158 polymorphic sites. Allele numbers ranged from ten to 52 with observed heterozygosity ranging from 0.115 to 0.640. All loci deviated from Hardy-Weinberg equilibrium and linkage disequilibrium was found among six combinations of loci. Conclusions We have characterized 183 alleles of drought related genes from oak species and detected first evidences of natural selection. Beside the potential for marker development, we have created an expandable bioinformatic pipeline for the analysis of next generation sequencing data.

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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...

  8. Transcriptomic analysis of skeletal muscle from beef cattle exposed to illicit schedules containing dexamethasone: identification of new candidate biomarkers and their validation using samples from a field monitoring trial.

    Science.gov (United States)

    Elgendy, Ramy; Giantin, Mery; Montesissa, Clara; Dacasto, Mauro

    2015-01-01

    Growth promoters (GPs) such as the glucocorticoid dexamethasone (DEX) and the β-adrenergic agonist clenbuterol (CLEN) are still used abusively in beef cattle production. Transcriptomic markers for indirect detection of such GPs have been discussed in either experimentally treated animals or commercial samples separately. In the present study we examine the transcriptomic signature of DEX alone or in combination with CLEN in skeletal muscle of experimentally treated beef cattle, and, furthermore, compare them with previously screened commercial samples from a field-monitoring study, as well as with proteomics data representing the same set of samples. Using DNA microarray technology, transcriptomic profiling was performed on 12 samples representing three groups of animals: DEX (0.75 mg/animal/day, n = 4), a combination of DEX (0.66 mg/animal/day) and CLEN (from 2 to 6 mg/animal/day, n = 4) and a control group (n = 4). Analyses showed the differential expression of 198 and 39 transcripts in DEX and DEX-CLEN groups, respectively. Both groups had no common modulated genes in between, neither with the proteomics data. Sixteen candidate genes were validated via qPCR. They showed high correlation with the corresponding microarray data. Principal component analysis (PCA) on both the qPCR and normalised microarray data resulted in the separation of treated animals from the untreated ones. Interestingly, all the PCA plots grouped the DEX-positive samples (experimental or commercial) apart from each other. In brief, this study provides some interesting glucocorticoid-responsive biomarkers whose expression was contradictory to what is reported in human studies. Additionally, this study points out the transcriptomic signature dissimilarity between commercial and experimentally treated animals. PMID:26161592

  9. 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

    2014-09-01

    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 that 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 transdifferentiated 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 that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp. PMID:25132468

  10. 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

  11. Results from DROXO. IV. EXTraS discovery of an X-ray flare from the Class I protostar candidate ISO-Oph 85

    Science.gov (United States)

    Pizzocaro, D.; Stelzer, B.; Paladini, R.; Tiengo, A.; Lisini, G.; Novara, G.; Vianello, G.; Belfiore, A.; Marelli, M.; Salvetti, D.; Pillitteri, I.; Sciortino, S.; D'Agostino, D.; Haberl, F.; Watson, M.; Wilms, J.; Salvaterra, R.; De Luca, A.

    2016-03-01

    X-ray emission from young stellar objects (YSOs) is a key ingredient in understanding star formation. For the early, protostellar (Class I) phase, a very limited (and controversial) quantity of X-ray results is available to date. Within the EXTraS (Exploring the X-ray Transient and variable Sky) project, we have discovered transient X-ray emission from a source whose counterpart is ISO-Oph 85, a strongly embedded YSO in the ρ Ophiuchi star-forming region. We extract an X-ray light curve for the flaring state, and determine the spectral parameters for the flare from XMM-Newton/EPIC data with a method based upon quantile analysis. We combine photometry from infrared to millimeter wavelengths from the literature with mid-IR Spitzer and unpublished submm Herschel photometry that we analysed for this work, and we describe the resulting spectral energy distribution (SED) with a set of precomputed models. The X-ray flare of ISO-Oph 85 lasted ~2500 s and is consistent with a highly-absorbed one-component thermal model (NH = 1.0-0.5+1.2 × 1023 cm-2 and kT= 1.15-0.65+2.35 keV). The X-ray luminosity during the flare is log LX [erg/s] = 31.1+2.0-1.2; during quiescence we set an upper limit of log LX [erg/s] < 29.5. We do not detect other flares from this source. The submillimeter fluxes suggest that the object is a Class I protostar. We caution, however, that the offset between the Herschel and optical/infrared position is larger than that for other YSOs in the region, leaving some doubt on this association. To the best of our knowledge, this is the first X-ray flare from a YSO that has been recognised as a candidate Class I protostar via the analysis of its complete SED, including the submm bands that are crucial for detecting the protostellar envelope. This work shows how the analysis of the whole SED is fundamental to the classification of YSOs, and how the X-ray source detection techniques we have developed can open a new era in time-resolved analysis of the X

  12. Biomarkers: A Challenging Conundrum in Cardiovascular Disease.

    Science.gov (United States)

    Libby, Peter; King, Kevin

    2015-12-01

    The use of biomarkers has proven utility in cardiovascular medicine and holds great promise for future advances, but their application requires considerable rigor in thinking and methodology. Numerous confounding factors can cloud the clinical and investigative uses of biomarkers. Yet, the thoughtful and critical use of biomarkers can doubtless aid discovery of new pathogenic pathways, identify novel therapeutic targets, and provide a bridge between the laboratory and the clinic. Biomarkers can provide diagnostic and prognostic tools to the practitioner. The careful application of biomarkers can also help design and guide clinical trials required to establish the efficacy of novel interventions to improve patient outcomes. Point of care testing, technological advances, such as microfluidic and wearable devices, and the power of omics approaches all promise to elevate the potential contributions of biomarkers to discovery science, translation, clinical trials, and the practice of cardiovascular medicine. PMID:26543097

  13. Fluid biomarkers in multiple system atrophy

    DEFF Research Database (Denmark)

    Laurens, Brice; Constantinescu, Radu; Freeman, Roy;

    2015-01-01

    Despite growing research efforts, no reliable biomarker currently exists for the diagnosis and prognosis of multiple system atrophy (MSA). Such biomarkers are urgently needed to improve diagnostic accuracy, prognostic guidance and also to serve as efficacy measures or surrogates of target engagem...... Parkinson's disease), metabolites of the catecholamine pathway and proteins such as α-synuclein, DJ-1 and total-tau. Beyond future efforts in biomarker discovery, the harmonization of standard operating procedures will be crucial for future success....

  14. 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.

  15. 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

  16. 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

  17. 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

  18. 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

  19. Biomarkers for Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Rikako Ishigamori

    2010-09-01

    Full Text Available Colorectal cancer (CRC is the third most common epithelial malignancy in the world. Since CRC develops slowly from removable precancerous lesions, detection of the lesion at an early stage by regular health examinations can reduce the incidence and mortality of this malignancy. Colonoscopy significantly improves the detection rate of CRC, but the examination is expensive and inconvenient. Therefore, we need novel biomarkers that are non-invasive to enable us to detect CRC quite early. A number of validation studies have been conducted to evaluate genetic, epigenetic or protein markers for identification in the stool and/or serum. Currently, the fecal occult blood test is the most widely used method of screening for CRC. However, advances in genomics and proteomics will lead to the discovery of novel non-invasive biomarkers.

  20. Biomarkers for hepatocellular carcinoma.

    Science.gov (United States)

    Behne, Tara; Copur, M Sitki

    2012-01-01

    The hepatocellular carcinoma (HCC) is one of the most common malignant tumors and carries a poor survival rate. The management of patients at risk for developing HCC remains challenging. Increased understanding of cancer biology and technological advances have enabled identification of a multitude of pathological, genetic, and molecular events that drive hepatocarcinogenesis leading to discovery of numerous potential biomarkers in this disease. They are currently being aggressively evaluated to establish their value in early diagnosis, optimization of therapy, reducing the emergence of new tumors, and preventing the recurrence after surgical resection or liver transplantation. These markers not only help in prediction of prognosis or recurrence but may also assist in deciding appropriate modality of therapy and may represent novel potential targets for therapeutic interventions. In this paper, a summary of most relevant available data from published papers reporting various tissue and serum biomarkers involved in hepatocellular carcinoma was presented. PMID:22655201

  1. Aberrant glycosylation associated with enzymes as cancer biomarkers

    Directory of Open Access Journals (Sweden)

    Meany Danni L

    2011-06-01

    Full Text Available Abstract Background One of the new roles for enzymes in personalized medicine builds on a rational approach to cancer biomarker discovery using enzyme-associated aberrant glycosylation. A hallmark of cancer, aberrant glycosylation is associated with differential expressions of enzymes such as glycosyltransferase and glycosidases. The aberrant expressions of the enzymes in turn cause cancer cells to produce glycoproteins with specific cancer-associated aberrations in glycan structures. Content In this review we provide examples of cancer biomarker discovery using aberrant glycosylation in three areas. First, changes in glycosylation machinery such as glycosyltransferases/glycosidases could be used as cancer biomarkers. Second, most of the clinically useful cancer biomarkers are glycoproteins. Discovery of specific cancer-associated aberrations in glycan structures of these existing biomarkers could improve their cancer specificity, such as the discovery of AFP-L3, fucosylated glycoforms of AFP. Third, cancer-associated aberrations in glycan structures provide a compelling rationale for discovering new biomarkers using glycomic and glycoproteomic technologies. Summary As a hallmark of cancer, aberrant glycosylation allows for the rational design of biomarker discovery efforts. But more important, we need to translate these biomarkers from discovery to clinical diagnostics using good strategies, such as the lessons learned from translating the biomarkers discovered using proteomic technologies to OVA 1, the first FDA-cleared In Vitro Diagnostic Multivariate Index Assay (IVDMIA. These lessons, providing important guidance in current efforts in biomarker discovery and translation, are applicable to the discovery of aberrant glycosylation associated with enzymes as cancer biomarkers as well.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. The Candidate

    OpenAIRE

    Osborn, John C

    2013-01-01

    ABSTRACT   The Candidate is an attempt to marry elements of journalism and gaming into a format that both entertains and educates the player. The Google-AP Scholarship, a new scholarship award that is given to several journalists a year to work on projects at the threshold of technology and journalism, funded the project. The objective in this prototype version of the game is to put the player in the shoes of a congressional candidate during an off-year election, specificall...

  7. 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.

  8. 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

  9. 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...

  10. Urine protein concentration estimation for biomarker discovery.

    Science.gov (United States)

    Mistry, Hiten D; Bramham, Kate; Weston, Andrew J; Ward, Malcolm A; Thompson, Andrew J; Chappell, Lucy C

    2013-10-01

    Recent advances have been made in the study of urinary proteomics as a diagnostic tool for renal disease and pre-eclampsia which requires accurate measurement of urinary protein. We compared different protein assays (Bicinchoninic acid (BCA), Lowry and Bradford) against the 'gold standard' amino-acid assay in urine from 43 women (8 non-pregnant, 34 pregnant, including 8 with pre-eclampsia). BCA assay was superior to both Lowry and Bradford assays (Bland Altman bias: 0.08) compared to amino-acid assay, which performed particularly poorly at higher protein concentrations. These data highlight the need to use amino-acid or BCA assays for unprocessed urine protein estimation. PMID:26103798

  11. 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 ...

  12. 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…

  13. Comprehensive maternal serum proteomics identifies the cytoskeletal proteins as non-invasive biomarkers in prenatal diagnosis of congenital heart defects.

    Science.gov (United States)

    Chen, Lizhu; Gu, Hui; Li, Jun; Yang, Ze-Yu; Sun, Xiao; Zhang, Li; Shan, Liping; Wu, Lina; Wei, Xiaowei; Zhao, Yili; Ma, Wei; Zhang, Henan; Cao, Songying; Huang, Tianchu; Miao, Jianing; Yuan, Zhengwei

    2016-01-01

    Congenital heart defects (CHDs) are the most common group of major birth defects. Presently there are no clinically used biomarkers for prenatally detecting CHDs. Here, we performed a comprehensive maternal serum proteomics assessment, combined with immunoassays, for the discovery of non-invasive biomarkers for prenatal diagnosis of CHDs. A total of 370 women were included in this study. An isobaric tagging for relative and absolute quantification (iTRAQ) proteomic approach was used first to compare protein profiles in pooled serum collected from women who had CHD-possessing or normal fetuses, and 47 proteins displayed significant differential expressions. Targeted verifications were performed on 11 proteins using multiple reaction monitoring mass spectrometry (MRM-MS), and the resultant candidate biomarkers were then further validated using ELISA analysis. Finally, we identified a biomarker panel composed of 4 cytoskeletal proteins capable of differentiating CHD-pregnancies from normal ones [with an area under the receiver operating characteristic curve (AUC) of 0.938, P < 0.0001]. The discovery of cytoskeletal protein changes in maternal serum not only could help us in prenatal diagnosis of CHDs, but also may shed new light on CHD embryogenesis studies. PMID:26750556

  14. Plasma proteomics to identify biomarkers – application to cardiovascular diseases

    Directory of Open Access Journals (Sweden)

    Hans Christian Beck

    2015-06-01

    Full Text Available There is an unmet need for new cardiovascular biomarkers. Despite this only few biomarkers for the diagnosis or screening of cardiovascular diseases have been implemented in the clinic. Thousands of proteins can be analysed in plasma by mass spectrometry-based proteomics technologies. Therefore, this technology may therefore identify new biomarkers that previously have not been associated with cardiovascular diseases. In this review, we summarize the key challenges and considerations, including strategies, recent discoveries and clinical applications in cardiovascular proteomics that may lead to the discovery of novel cardiovascular biomarkers.

  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. PMID:12916666

  16. 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

  17. 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...

  18. Imaging Biomarkers or Biomarker Imaging?

    Directory of Open Access Journals (Sweden)

    Markus Mitterhauser

    2014-06-01

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

  19. 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

  20. 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

  1. 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.

  2. A new strategy for faster urinary biomarkers identification by Nano LC MALDI TOF/TOF mass spectrometry.

    OpenAIRE

    Le Meur Y; Rérolle JP; Marquet P.; Benkali K; Gastinel LN

    2008-01-01

    Abstract Background LC-MALDI-TOF/TOF analysis is a potent tool in biomarkers discovery characterized by its high sensitivity and high throughput capacity. However, methods based on MALDI-TOF/TOF for biomarkers discovery still need optimization, in particular to reduce analysis time and to evaluate their reproducibility for peak intensities measurement. The aims of this methodological study were: (i) to optimize and critically evaluate each step of urine biomarker discovery method based on Nan...

  3. DNA Methylation Biomarkers: Cancer and Beyond

    Directory of Open Access Journals (Sweden)

    Thomas Mikeska

    2014-09-01

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

  4. 76 FR 82306 - Draft Guidance for Industry on Use of Histology in Biomarker Qualification Studies; Availability

    Science.gov (United States)

    2011-12-30

    ... biomarker studies, and outlines the scientific standards for histology used in biomarker characterization... Spring, MD 20993-0002. Send one self-addressed adhesive label to assist that office in processing your....'' The discovery, characterization, qualification, and implementation of biomarkers have been...

  5. 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

  6. Imaging Biomarkers in Immunotherapy

    Science.gov (United States)

    Juergens, Rosalyn A.; Zukotynski, Katherine A.; Singnurkar, Amit; Snider, Denis P.; Valliant, John F.; Gulenchyn, Karen Y.

    2016-01-01

    Immune-based therapies have been in use for decades but recent work with immune checkpoint inhibitors has now changed the landscape of cancer treatment as a whole. While these advances are encouraging, clinicians still do not have a consistent biomarker they can rely on that can accurately select patients or monitor response. Molecular imaging technology provides a noninvasive mechanism to evaluate tumors and may be an ideal candidate for these purposes. This review provides an overview of the mechanism of action of varied immunotherapies and the current strategies for monitoring patients with imaging. We then describe some of the key researches in the preclinical and clinical literature on the current uses of molecular imaging of the immune system and cancer. PMID:26949344

  7. 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

  8. 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; Christensen, Ib Jarle; Kjaer, Susanne Krüger; Yip, Christine; Risum, Signe Normann; Pedersen, Anette Tønnes; Hartwell, Dorte; Fung, Eric T; Høgdall, Claus

    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 ...

  9. 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.

  10. Inconvenient truth: cancer biomarker development by using proteomics.

    Science.gov (United States)

    Kondo, Tadashi

    2014-05-01

    A biomarker is a crucial tool for measuring the progress of disease and the effects of treatment for better clinical outcomes in cancer patients. Diagnostic, predictive, and prognostic biomarkers are required in various clinical settings. The proteome, a functional translation of the genome, is considered a rich source of biomarkers; therefore, sizable time and funding have been spent in proteomics to develop biomarkers. Although significant progress has been made in technologies toward comprehensive protein expression profiling, and many biomarker candidates published, none of the reported biomarkers have proven to be beneficial for cancer patients. The present deceleration in biomarker research can be attributed to technical limitations. Additional efforts are required to further technical progress; however, there are many examples demonstrating that problems in biomarker research are not so much with the technology but in the study design. In the study of biomarkers for early diagnosis, candidates are screened and validated by comparing cases and controls of similar sample size, and the low prevalence of disease is often ignored. Although it is reasonable to take advantage of multiple rather than single biomarkers when studying diverse disease mechanisms, the annotation of individual components of reported multiple biomarkers does not often explain the variety of molecular events underlying the clinical observations. In tissue biomarker studies, the heterogeneity of disease tissues and pathological observations are often not considered, and tissues are homogenized as a whole for protein extraction. In addition to the challenge of technical limitations, the fundamental aspects of biomarker development in a disease study need to be addressed. This article is part of a Special Issue entitled: Biomarkers: A Proteomic Challenge. PMID:23896458

  11. Higgs Discovery

    DEFF Research Database (Denmark)

    Sannino, Francesco

    2013-01-01

    via first principle lattice simulations with encouraging results. The new findings show that the recent naive claims made about new strong dynamics at the electroweak scale being disfavoured by the discovery of a not-so-heavy composite Higgs are unwarranted. I will then introduce the more speculative......I discuss the impact of the discovery of a Higgs-like state on composite dynamics starting by critically examining the reasons in favour of either an elementary or composite nature of this state. Accepting the standard model interpretation I re-address the standard model vacuum stability within a...... has been challenged by the discovery of a not-so-heavy Higgs-like state. I will therefore review the recent discovery \\cite{Foadi:2012bb} that the standard model top-induced radiative corrections naturally reduce the intrinsic non-perturbative mass of the composite Higgs state towards the desired...

  12. 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...

  13. Vaccine candidates for malaria: what's new?

    Science.gov (United States)

    Takashima, Eizo; Morita, Masayuki; Tsuboi, Takafumi

    2016-01-01

    Although it is more than a decade since the parasite genome information was obtained, standardized novel genome-wide selection/prioritization strategies for candidacy of malaria vaccine antigens are still sought. In the quest to systematically identify candidates, it is impossible to overemphasize the usefulness of wheat germ cell-free technology in expressing quality proteins for the post-genome vaccine candidate discovery. PMID:26559316

  14. 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.

  15. Quantitative imaging biomarker ontology (QIBO) for knowledge representation of biomedical imaging biomarkers.

    Science.gov (United States)

    Buckler, Andrew J; Liu, Tiffany Ting; Savig, Erica; Suzek, Baris E; Ouellette, M; Danagoulian, J; Wernsing, G; Rubin, Daniel L; Paik, David

    2013-08-01

    A widening array of novel imaging biomarkers is being developed using ever more powerful clinical and preclinical imaging modalities. These biomarkers have demonstrated effectiveness in quantifying biological processes as they occur in vivo and in the early prediction of therapeutic outcomes. However, quantitative imaging biomarker data and knowledge are not standardized, representing a critical barrier to accumulating medical knowledge based on quantitative imaging data. We use an ontology to represent, integrate, and harmonize heterogeneous knowledge across the domain of imaging biomarkers. This advances the goal of developing applications to (1) improve precision and recall of storage and retrieval of quantitative imaging-related data using standardized terminology; (2) streamline the discovery and development of novel imaging biomarkers by normalizing knowledge across heterogeneous resources; (3) effectively annotate imaging experiments thus aiding comprehension, re-use, and reproducibility; and (4) provide validation frameworks through rigorous specification as a basis for testable hypotheses and compliance tests. We have developed the Quantitative Imaging Biomarker Ontology (QIBO), which currently consists of 488 terms spanning the following upper classes: experimental subject, biological intervention, imaging agent, imaging instrument, image post-processing algorithm, biological target, indicated biology, and biomarker application. We have demonstrated that QIBO can be used to annotate imaging experiments with standardized terms in the ontology and to generate hypotheses for novel imaging biomarker-disease associations. Our results established the utility of QIBO in enabling integrated analysis of quantitative imaging data. PMID:23589184

  16. New biomarkers for sepsis

    Directory of Open Access Journals (Sweden)

    Li-xin XIE

    2013-01-01

    Full Text Available There is a higher sepsis rate in the intensive care unit (ICU patients, which is one of the most important causes for patient death, but the sepsis lacks specific clinical manifestations. Exploring sensitive and specific molecular markers for infection that accurately reflect infection severity and prognosis is very clinically important. In this article, based on our previous study, we introduce some new biomarkers with high sensitivity and specificity for the diagnosis and predicting the prognosis and severity of sepsis. Increase of serum soluble(s triggering receptor expressed on myeloid cells-1 (sTREM-1 suggests a poor prognosis of septic patients, and changes of locus rs2234237 of sTREM-1 may be the one of important mechanisms. Additionally, urine sTREM-1 can provide an early warning of possible secondary acute kidney injury (AKI in sepsis patients. Serum sCD163 level was found to be a more important factor than procalcitonin (PCT and C-reactive protein (CRP in prognosis of sepsis, especially severe sepsis. Moreover, urine sCD163 also shows excellent performance in the diagnosis of sepsis and sepsis-associated AKI. Circulating microRNAs, such as miR-150, miR-297, miR-574-5p, miR -146a , miR-223, miR -15a and miR-16, also play important roles in the evaluation of status of septic patients. In the foreseeable future, newly-emerging technologies, including proteomics, metabonomics and trans-omics, may exert profound effects on the discovery of valuable biomarkers for sepsis.

  17. 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.

  18. 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

  19. Discovery of novel heteroarylazole N-phenylpiperazine prototypes candidates to atypic antipsychotic drugs [Descoberta de novos protótipos N-fenilpiperazínicos heteroarilazólicos candidatos a fármacos antipsicóticos atípicos

    Directory of Open Access Journals (Sweden)

    Andresa H. Betti

    2010-08-01

    Full Text Available This work describes the discovery of new N-phenylpiperazine prototypes belonging to pyrazole series,i.e. LASSBio-579 (10a, or to 1,2,3-triazole series, represented by LASSBio-581 (10c, which were designed fromthe structural simplification of the atypical antipsychotic drug clozapine (8. The evaluation of the affinity andintrinsic activity profiles of LASSBio-579 and LASSBio-581 indicate its ability to bind dopamine receptors fromD2-like family, acting as pre-synaptic agonists. Additionally, the investigation of the antipsychotic properties ofthese two prototypes in behavioral models has confirmed its effectiveness, which is also dependent on themodulation of serotoninergic receptors 5-HT2A and 5-HT1A. The pronounced antipsychotic effect evidenced forthese N-phenylpiperazine derivatives through in vivo pharmacological assays confirmed their importance asnew neuroactive drug-candidate prototypes for the treatment of schizophrenia.

  20. Imaging biomarkers as surrogate endpoints for drug development

    International Nuclear Information System (INIS)

    The employment of biomarkers (including imaging biomarkers, especially PET) in drug development has gained increasing attention during recent years. This has been partly stimulated by the hope that the integration of biomarkers into drug development programmes may be a means to increase the efficiency and effectiveness of the drug development process by early identification of promising drug candidates - thereby counteracting the rising costs of drug development. More importantly, however, the interest in biomarkers for drug development is the logical consequence of recent advances in biosciences and medicine which are leading to target-specific treatments in the framework of ''personalised medicine''. A considerable proportion of target-specific drugs will show effects in subgroups of patients only. Biomarkers are a means to identify potential responders, or patient subgroups at risk for specific side-effects. Biomarkers are used in early drug development in the context of translational medicine to gain information about the drug's potential in different patient groups and disease states. The information obtained at this stage is mainly important for designing subsequent clinical trials and to identify promising drug candidates. Biomarkers in later phases of clinical development may - if properly validated - serve as surrogate endpoints for clinical outcomes. Regulatory agencies in the EU and the USA have facilitated the use of biomarkers early in the development process. The validation of biomarkers as surrogate endpoints is part of FDA's ''critical path initiative''. (orig.)

  1. Beyond Discovery

    DEFF Research Database (Denmark)

    Korsgaard, Steffen; Sassmannshausen, Sean Patrick

    2015-01-01

    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 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 and...

  2. Warehousing re-annotated cancer genes for biomarker meta-analysis.

    Science.gov (United States)

    Orsini, M; Travaglione, A; Capobianco, E

    2013-07-01

    Translational research in cancer genomics assigns a fundamental role to bioinformatics in support of candidate gene prioritization with regard to both biomarker discovery and target identification for drug development. Efforts in both such directions rely on the existence and constant update of large repositories of gene expression data and omics records obtained from a variety of experiments. Users who interactively interrogate such repositories may have problems in retrieving sample fields that present limited associated information, due for instance to incomplete entries or sometimes unusable files. Cancer-specific data sources present similar problems. Given that source integration usually improves data quality, one of the objectives is keeping the computational complexity sufficiently low to allow an optimal assimilation and mining of all the information. In particular, the scope of integrating intraomics data can be to improve the exploration of gene co-expression landscapes, while the scope of integrating interomics sources can be that of establishing genotype-phenotype associations. Both integrations are relevant to cancer biomarker meta-analysis, as the proposed study demonstrates. Our approach is based on re-annotating cancer-specific data available at the EBI's ArrayExpress repository and building a data warehouse aimed to biomarker discovery and validation studies. Cancer genes are organized by tissue with biomedical and clinical evidences combined to increase reproducibility and consistency of results. For better comparative evaluation, multiple queries have been designed to efficiently address all types of experiments and platforms, and allow for retrieval of sample-related information, such as cell line, disease state and clinical aspects. PMID:23639751

  3. 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.

  4. 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....

  5. 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...

  6. 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...

  7. 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

  8. 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

    Science.gov (United States)

    Emanueli, Costanza; Fiorentino, Francesca; Reeves, Barnaby C.; Beltrami, Cristina; Mumford, Andrew; Clayton, Aled; Gurney, Mark; Shantikumar, Saran; Angelini, Gianni D.

    2016-01-01

    Introduction 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. Methods and Results 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. Conclusions 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. PMID:27128471

  9. 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.

  10. 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

  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. Proximity Ligation Assays for Disease Biomarkers Analysis

    OpenAIRE

    Nong, Rachel Yuan

    2011-01-01

    One of the pressing needs in the field of disease biomarker discovery is new technologies that could allow high performance protein analysis in different types of clinical material, such as blood and solid tissues. This thesis includes four approaches that address important limitations of current technologies, thus enabling highly sensitive, specific and parallel protein measurements. Paper I describes a method for sensitive singleplex protein detection in complex biological samples, namely s...

  14. 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 pr...... 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....

  15. 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...

  16. Epigenetic biomarkers in esophageal cancer.

    Science.gov (United States)

    Kaz, Andrew M; Grady, William M

    2014-01-28

    The aberrant DNA methylation of tumor suppressor genes is well documented in esophageal cancer, including adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) as well as in Barrett's esophagus (BE), a pre-malignant condition that is associated with chronic acid reflux. BE is a well-recognized risk factor for the development of EAC, and consequently the standard of care is for individuals with BE to be placed in endoscopic surveillance programs aimed at detecting early histologic changes that associate with an increased risk of developing EAC. Yet because the absolute risk of EAC in individuals with BE is minimal, a clinical need in the management of BE is the identification of additional risk markers that will indicate individuals who are at a significant absolute risk of EAC so that they may be subjected to more intensive surveillance. The best currently available risk marker is the degree of dysplasia in endoscopic biopsies from the esophagus; however, this marker is suboptimal for a variety of reasons. To date, there are no molecular biomarkers that have been translated to widespread clinical practice. The search for biomarkers, including hypermethylated genes, for either the diagnosis of BE, EAC, or ESCC or for risk stratification for the development of EAC in those with BE is currently an area of active research. In this review, we summarize the status of identified candidate epigenetic biomarkers for BE, EAC, and ESCC. Most of these aberrantly methylated genes have been described in the context of early detection or diagnostic markers; others might prove useful for estimating prognosis or predicting response to treatment. Finally, special attention will be paid to some of the challenges that must be overcome in order to develop clinically useful esophageal cancer biomarkers. PMID:22406828

  17. Identification and confirmation of biomarkers using an integrated platform for quantitative analysis of glycoproteins and their glycosylations.

    Science.gov (United States)

    Liu, Yashu; He, Jintang; Li, Chen; Benitez, Ricardo; Fu, Sherry; Marrero, Jorge; Lubman, David M

    2010-02-01

    Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. However, accurate diagnosis can be difficult as most of the patients who develop this tumor have symptoms similar to those caused by longstanding liver disease. Herein we developed an integrated platform to discover the glycoprotein biomarkers in early HCC. At first, lectin arrays were applied to investigate the differences in glycan structures on serum glycoproteins from HCC and cirrhosis patients. The intensity for AAL and LCA was significantly higher in HCC, indicating an elevation of fucosylation level. Then serum from 10 HCC samples and 10 cirrhosis samples were used to screen the altered fucosylated proteins by a combination of Exactag labeling, lectin extraction and LC-MS/MS. Finally, 27 HCC and 27 cirrhosis serum samples were used for lectin-antibody arrays to confirm the change of these fucosylated proteins. C3, CE, HRG, CD14 and HGF were found to be biomarker candidates for distinguishing early HCC from cirrhosis, with a sensitivity of 72% and specificity of 79%. Our work gives insight to the detection of early HCC, and the application of this comprehensive strategy has the potential to facilitate biomarker discovery on a large scale. PMID:19961239

  18. Impact of biomarker development on drug safety assessment

    International Nuclear Information System (INIS)

    Drug safety has always been a key aspect of drug development. Recently, the Vioxx case and several cases of serious adverse events being linked to high-profile products have increased the importance of drug safety, especially in the eyes of drug development companies and global regulatory agencies. Safety biomarkers are increasingly being seen as helping to provide the clarity, predictability, and certainty needed to gain confidence in decision making: early-stage projects can be stopped quicker, late-stage projects become less risky. Public and private organizations are investing heavily in terms of time, money and manpower on safety biomarker development. An illustrative and 'door opening' safety biomarker success story is the recent recognition of kidney safety biomarkers for pre-clinical and limited translational contexts by FDA and EMEA. This milestone achieved for kidney biomarkers and the 'know how' acquired is being transferred to other organ toxicities, namely liver, heart, vascular system. New technologies and molecular-based approaches, i.e., molecular pathology as a complement to the classical toolbox, allow promising discoveries in the safety biomarker field. This review will focus on the utility and use of safety biomarkers all along drug development, highlighting the present gaps and opportunities identified in organ toxicity monitoring. A last part will be dedicated to safety biomarker development in general, from identification to diagnostic tests, using the kidney safety biomarkers success as an illustrative example.

  19. Plasma proteomics to identify biomarkers - Application to cardiovascular diseases

    DEFF Research Database (Denmark)

    Beck, Hans Christian; Overgaard, Martin; Melholt Rasmussen, Lars

    , this technology may therefore identify new biomarkers that previously have not been associated with cardiovascular diseases. In this review, we summarize the key challenges and considerations, including strategies, recent discoveries and clinical applications in cardiovascular proteomics that may lead......There is an unmet need for new cardiovascular biomarkers. Despite this only few biomarkers for the diagnosis or screening of cardiovascular diseases have been implemented in the clinic. Thousands of proteins can be analysed in plasma by mass spectrometry-based proteomics technologies. Therefore...

  20. The Use of Targeted Biomarkers for Chronic Kidney Disease

    OpenAIRE

    Devarajan, Prasad

    2010-01-01

    There is a paucity of sensitive and specific biomarkers for the early prediction of chronic kidney disease (CKD) progression. The recent application of innovative technologies such as functional genomics, proteomics, and biofluid profiling has uncovered a number of new candidates that are emerging as predictive biomarkers of CKD. The most promising among these include urinary proteins such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and liver-type f...

  1. Biomarkers for osteoarthritis: investigation, identification, and prognosis

    Directory of Open Access Journals (Sweden)

    Zhai G

    2012-06-01

    Full Text Available Guangju Zhai,1,2 Erfan Aref Eshghi11Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada; 2Department of Twin Research and Genetic Epidemiology, King's College London, London, UKAbstract: Osteoarthritis (OA is the most common form of arthritis and results in substantial morbidity and disability in the elderly, imposing a great economic burden on society. While there are drugs available on the market that mitigate pain and improve function, there are no disease-modifying osteoarthritis drugs, partly because there is no reliable method that can be used to identify early OA changes. There is a pressing need to develop reliable biomarkers that can inform on the process of joint destruction in OA. Such biomarkers could aid in drug development by identifying fast progressors and detecting early response to therapy, thus reducing patient numbers and time required for clinical trials. Over the last several years, dramatic advances in our understanding of the biochemistry of cartilage have led to a cascade of studies testing proteins as biomarkers of OA. Investigation of single-nucleotide polymorphisms as genetic biomarkers and the application of technologies such as metabolomics to OA are generating potentially additional biomarkers that could help detect early OA changes. This review summarizes the data on the investigation of biochemical and genetic markers in OA and highlights the new biomarkers that are recently reported and their application and limitation in the management of OA. However, despite the dramatic growth of knowledge concerning the discovery of a number of useful biomarkers, the real breakthrough in this area is still not achieved.Keywords: osteoarthritis, biochemical markers, metabolomics, genetics, epigenetics

  2. 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

  3. 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

  4. Discovery Mondays

    CERN Multimedia

    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...

  5. DJ-1 isoforms in whole blood as potential biomarkers of Parkinson disease

    Science.gov (United States)

    Lin, Xiangmin; Cook, Travis J.; Zabetian, Cyrus P.; Leverenz, James B.; Peskind, Elaine R.; Hu, Shu-Ching; Cain, Kevin C.; Pan, Catherine; Edgar, John Scott; Goodlett, David R.; Racette, Brad A.; Checkoway, Harvey; Montine, Thomas J.; Shi, Min; Zhang, Jing

    2012-01-01

    DJ-1 is a multifunctional protein that plays an important role in oxidative stress, cell death, and synucleinopathies, including Parkinson disease. Previous studies have demonstrated that total DJ-1 levels decrease in the cerebrospinal fluid, but do not change significantly in human plasma from patients with Parkinson disease when compared with controls. In this study, we measured total DJ-1 and its isoforms in whole blood of patients with Parkinson disease at various stages, Alzheimer disease, and healthy controls to identify potential peripheral biomarkers of PD. In an initial discovery study of 119 subjects, 7 DJ-1 isoforms were reliably detected, and blood levels of those with 4-hydroxy-2-nonenal modifications were discovered to be altered in late-stage Parkinson disease. This result was further confirmed in a validation study of another 114 participants, suggesting that, unlike total DJ-1 levels, post-translationally modified isoforms of DJ-1 from whole blood are candidate biomarkers of late-stage Parkinson disease. PMID:23233873

  6. miRNAs and Other Epigenetic Changes as Biomarkers in Triple Negative Breast Cancer

    Directory of Open Access Journals (Sweden)

    Andrea Mathe

    2015-11-01

    Full Text Available Triple negative breast cancer (TNBC is characterised by the lack of receptors for estrogen (ER, progesterone (PR, and human epidermal growth factor 2 (HER2. Since it cannot be treated by current endocrine therapies which target these receptors and due to its aggressive nature, it has one of the worst prognoses of all breast cancer subtypes. The only treatments remain chemo- and/or radio-therapy and surgery and because of this, novel biomarkers or treatment targets are urgently required to improve disease outcomes. MicroRNAs represent an attractive candidate for targeted therapies against TNBC, due to their natural ability to act as antisense interactors and regulators of entire gene sets involved in malignancy and their superiority over mRNA profiling to accurately classify disease. Here we review the current knowledge regarding miRNAs as biomarkers in TNBC and their potential use as therapeutic targets in this disease. Further, we review other epigenetic changes and interactions of these changes with microRNAs in this breast cancer subtype, which may lead to the discovery of new treatment targets for TNBC.

  7. 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. PMID:26762498

  8. 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.

  9. 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...

  10. ESR statement on the stepwise development of imaging biomarkers.

    Science.gov (United States)

    2013-04-01

    Development of imaging biomarkers is a structured process in which new biomarkers are discovered, verified, validated and qualified against biological processes and clinical end-points. The validation process not only concerns the determination of the sensitivity and specificity but also the measurement of reproducibility. Reproducibility assessments and standardisation of the acquisition and data analysis methods are crucial when imaging biomarkers are used in multicentre trials for assessing response to treatment. Quality control in multicentre trials can be performed with the use of imaging phantoms. The cost-effectiveness of imaging biomarkers also needs to be determined. A lot of imaging biomarkers are being developed, but there are still unmet needs-for example, in the detection of tumour invasiveness. Main Messages • Using imaging biomarkers to streamline drug discovery and disease progression is a huge advancement in healthcare. • The qualification and technical validation of imaging biomarkers pose unique challenges in that the accuracy, methods, standardisations and reproducibility are strictly monitored. • The clinical value of new biomarkers is of the highest priority in terms of patient management, assessing risk factors and disease prognosis. PMID:23397519

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. iTRAQ and multiple reaction monitoring as proteomic tools for biomarker search in cerebrospinal fluid of patients with Parkinson's disease dementia.

    Science.gov (United States)

    Lehnert, Stefan; Jesse, Sarah; Rist, Wolfgang; Steinacker, Petra; Soininen, Hilkka; Herukka, Sanna-Kaisa; Tumani, Hayrettin; Lenter, Martin; Oeckl, Patrick; Ferger, Boris; Hengerer, Bastian; Otto, Markus

    2012-04-01

    About 30% of patients with Parkinson's disease (PD) develop Parkinson's disease dementia (PDD) in the course of the disease. Until now, diagnosis is based on clinical and neuropsychological examinations, since so far there is no laboratory marker. In this study we aimed to find a neurochemical marker which would allow a risk assessment for the development of a dementia in PD patients. For this purpose, we adopted a gel-free proteomic approach (iTRAQ-method) to identify biomarker-candidates in the cerebrospinal fluid (CSF) of patients with PD, PDD and non-demented controls (NDC). Validation of these candidates was then carried out by multiple-reaction-monitoring (MRM) optimised for CSF. Using the iTRAQ-approach, we were able to identify 16 differentially regulated proteins. Fourteen out of these 16 proteins could then be followed-up simultaneously in our optimised MRM-measurement protocol. However only Tyrosine-kinase-non-receptor-type 13 and Netrin-G1 differed significantly between PDD and NDC cohorts. In addition, a significant difference was found for Golgin-160 and Apolipoprotein B-100 between PD and NDC. Apart from possible pathophysiological considerations, we propose that Tyrosine-kinase non-receptor-type 13 and Netrin G1 are biomarker candidates for the development of a Parkinson's disease dementia. Furthermore we suggest that iTRAQ and MRM are valuable tools for the discovery of biomarker in cerebrospinal fluid. However further validation studies need to be done with larger patient cohorts and other proteins need to be checked as well. PMID:22327139

  16. 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.

  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. Ocular and systemic pharmacokinetic models for drug discovery and development

    OpenAIRE

    del Amo Páez, Eva María

    2015-01-01

    Drug discovery and development is a long process: it takes usually 12 to 15 years before a drug candidate reaches the market. The pharmacokinetics of the drug is an important aspect of drug discovery and development, because the drug must reach its target site and exert the therapeutic response. The pharmacokinetic parameters of new compounds should be investigated early in drug discovery. Pharmacokinetic predictions can be made with Quantitative Structure-Property Relationships (QSPR) which ...

  19. 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

  20. A momentary biomarker for depressive mood.

    Science.gov (United States)

    Kim, Jinhyuk; Nakamura, Toru; Yamamoto, Yoshiharu

    2016-12-01

    Many biomarkers from genetic, neuroimaging, and biological/biochemical measures have been recently developed in order to make a shift toward the objective evaluation of psychiatric disorders. However, they have so far been less successful in capturing dynamical changes or transitions in pathological states, such as those occurring during the course of clinical treatments or pathogenic processes of disorders. A momentary biomarker is now required for objective monitoring of such dynamical changes. The development of ecological momentary assessment (EMA) allows the assessment of dynamical aspects of diurnal/daily clinical conditions and subjective symptoms. Furthermore, a variety of validation studies on momentary symptoms assessed by EMA using behavioral/physiological/biochemical measures have demonstrated the possibility of evaluating momentary symptoms from such external objective measures. In this review, we introduce physical activity as a candidate biobehavioral biomarker for psychiatric disorders. We also mention its potential as a momentary biomarker for depressive mood. Finally, we address the continuous monitoring of the pathogenic processes and pathological states of depressive disorders based on physical activity, as well as its application in pharmacological animal studies. PMID:26979449

  1. Characterization of potential ionizing radiation biomarkers by a proteomic approach

    International Nuclear Information System (INIS)

    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)

  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. 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.

  4. 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.

  5. 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

  6. 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...

  7. 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...

  8. 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

  9. 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...

  10. 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

  11. Discovery and verification of urinary peptides in type 2 diabetes mellitus with kidney injury.

    Science.gov (United States)

    Fu, Guangzhen; Du, Ye; Chu, Lina; Zhang, Man

    2016-06-01

    Varying degrees of renal injury could lead to different changes in urinary protein composition. We want to find urinary candidate peptide biomarkers in type 2 diabetic patients with different extents of kidney injury. Two sets of patients were recruited. Discovery set: weak cationic-exchange magnetic beads coupled with matrix-assisted laser desorption ionization time-of-flight mass spectrometry were used to profile the low-molecular weight peptidome in urine samples from type 2 diabetes patients with normoalbuminura and microalbuminuria. The differently expressed urinary peptides were screened by ClinProTools2.1 bioinformatics software and identified through nano-liquid chromatography-tandem mass spectrometry. Verification set: the above screened urinary peptides were validated by use matrix-assisted laser desorption ionization time-of-flight mass spectrometry on another group of type 2 diabetes patients with different extents use of kidney injury. In the screening and identification stages, seven urinary peptides were selected as the most promising biomarker candidates, and they were identified as fragments of vitronectin precursor, isoform 1 of fibrinogen alpha chain precursor, prothrombin precursor and inter-alpha-trypsin inhibitor heavy chain H4. The diagnostic efficacy of these urinary peptides was evaluated by area under the receiver operating characteristic curve, and they were 0.767, 0.768, 0.868, 0.910, 0.860, 0.843, and 0.865, respectively. In the verification stage, m/z 1743.9, 2154, 2175.5, and 2184.9 were decreased as albumin-to-creatinine (Alb/Cre) increased and m/z 2231.1, 2430.8, and 2756.1 were elevated as Alb/Cre rose. These small molecule peptides are related to type 2 diabetes kidney damage, and they may play an important role in monitoring type 2 diabetes. PMID:26846977

  12. 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

  13. Improved multimodal biomarkers for Alzheimer's disease and mild cognitive impairment diagnosis: data from ADNI

    Science.gov (United States)

    Martinez-Torteya, Antonio; Treviño-Alvarado, Víctor; Tamez-Peña, José

    2013-02-01

    The accurate diagnosis of Alzheimer's disease (AD) and mild cognitive impairment (MCI) confers many clinical research and patient care benefits. Studies have shown that multimodal biomarkers provide better diagnosis accuracy of AD and MCI than unimodal biomarkers, but their construction has been based on traditional statistical approaches. The objective of this work was the creation of accurate AD and MCI diagnostic multimodal biomarkers using advanced bioinformatics tools. The biomarkers were created by exploring multimodal combinations of features using machine learning techniques. Data was obtained from the ADNI database. The baseline information (e.g. MRI analyses, PET analyses and laboratory essays) from AD, MCI and healthy control (HC) subjects with available diagnosis up to June 2012 was mined for case/controls candidates. The data mining yielded 47 HC, 83 MCI and 43 AD subjects for biomarker creation. Each subject was characterized by at least 980 ADNI features. A genetic algorithm feature selection strategy was used to obtain compact and accurate cross-validated nearest centroid biomarkers. The biomarkers achieved training classification accuracies of 0.983, 0.871 and 0.917 for HC vs. AD, HC vs. MCI and MCI vs. AD respectively. The constructed biomarkers were relatively compact: from 5 to 11 features. Those multimodal biomarkers included several widely accepted univariate biomarkers and novel image and biochemical features. Multimodal biomarkers constructed from previously and non-previously AD associated features showed improved diagnostic performance when compared to those based solely on previously AD associated features.

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. Biomarkers in Transplantation-Proteomics and Metabolomics.

    Science.gov (United States)

    Christians, Uwe; Klawitter, Jelena; Klawitter, Jost

    2016-04-01

    Modern multianalyte "omics" technologies allow for the identification of molecular signatures that confer significantly more information than measurement of a single parameter as typically used in current medical diagnostics. Proteomics and metabolomics bioanalytical assays capture a large set of proteins and metabolites in body fluids, cells, or tissues and, complementing genomics, assess the phenome. Proteomics and metabolomics contribute to the development of novel predictive clinical biomarkers in transplantation in 2 ways: they can be used to generate a diagnostic fingerprint or they can be used to discover individual proteins and metabolites of diagnostic potential. Much fewer metabolomics than proteomics biomarker studies in transplant patients have been reported, and, in contrast to proteomics discovery studies, new lead metabolite markers have yet to emerge. Most clinical proteomics studies have been discovery studies. Several of these studies have assessed diagnostic sensitivity and specificity. Nevertheless, none of these newly discovered protein biomarkers have yet been implemented in clinical decision making in transplantation. The currently most advanced markers discovered in proteomics studies in transplant patients are the chemokines CXCL-9 and CXCL-10, which have successfully been validated in larger multicenter trials in kidney transplant patients. These chemokines can be measured using standard immunoassay platforms, which should facilitate clinical implementation. Based on the published evidence, it is reasonable to expect that these chemokine markers can help guiding and individualizing immunosuppressive regimens, may be able to predict acute and chronic T-cell-mediated and antibody-mediated rejection, and may be useful tools for risk stratification of kidney transplant patients. PMID:26418702

  1. 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

    2015-01-01

    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. PMID:27077039

  2. 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. PMID:27077039

  3. Optical Nova Candidates in M 31

    Science.gov (United States)

    Henze, M.; Burwitz, V.; Pietsch, W.; Updike, A.; Milne, P.; Williams, G.; Hartmann, D. H.

    2008-06-01

    We report the discovery of an optical nova candidate in M 31 on two 11x60s stacked R filter CCD images obtained with the robotic 60cm telescope with an E2V CCD (2kx2k) of the Livermore Optical Transient Imaging System (Super-LOTIS, located at Steward Observatory, Kitt Peak, Arizona, USA). The object was first detected on 2008 June 06.47 and 07.47 UT with respective magnitudes of 18.0 and 17.9.

  4. Optical Nova Candidate in M 31

    Science.gov (United States)

    Henze, M.; Burwitz, V.; Pietsch, W.; Updike, A.; Milne, P.; Williams, G.; Hartmann, D. H.

    2008-06-01

    We report the discovery of an optical nova candidate in M 31 on two 11x60s stacked R filter CCD images obtained with the robotic 60cm telescope with an E2V CCD (2kx2k) of the Livermore Optical Transient Imaging System (Super-LOTIS, located at Steward Observatory, Kitt Peak, Arizona, USA). The object was first detected on 2008 June 14.46 and 16.46 UT with respective magnitudes of 18.0 and 17.7. The position for the nova candidate is RA = 00h42m37.72s, Dec = +41d12'30.0"(J2000, accuracy of 0.3"), which is 1'14" west and 3'39" south of the core of M 31. All magnitudes given are obtained from a photometric solution using R magnitudes of the Local Group Survey M 31 catalogue (Massey et al.

  5. 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.

  6. 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

  7. 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....

  8. Are Blood-Based Protein Biomarkers for Alzheimer's Disease also Involved in Other Brain Disorders?:A Systematic Review

    OpenAIRE

    Chiam, Justin Tao Wen; Dobson, Richard James Butler; Kiddle, Steven John; Sattlecker, Martina

    2015-01-01

    Background: Alzheimer's disease (AD) biomarkers are urgently needed for both early and accurate diagnosis and prediction of disease progression. Past research has studied blood-based proteins as potential AD biomarkers, revealing many candidate proteins. To date only limited effort has been made to investigate the disease specificity of AD candidate proteins and whether these proteins are also involved in other neurodegenerative or psychiatric conditions.Objective: This review seeks to determ...

  9. Discovery program for bright quasars: preliminary results

    International Nuclear Information System (INIS)

    A program has been undertaken to obtain a complete sample of bright quasars on the basis of ultraviolet color excess. Spectroscopic examination of candidates selected from two-color Schmidt telescope films has yielded four new quasars brighter than B = 16/sup m/5, with the candidate list containing two more previously identified. Magnitudes, color indices, and redshifts are presented for the new discoveries, along with positions and finding charts. Although the sample is not yet complete, these first results suggest that bright quasars have a low surface density

  10. Epigenetic Biomarkers of Preterm Birth and Its Risk Factors.

    Science.gov (United States)

    Knight, Anna K; Smith, Alicia K

    2016-01-01

    A biomarker is a biological measure predictive of a normal or pathogenic process or response. Biomarkers are often useful for making clinical decisions and determining treatment course. One area where such biomarkers would be particularly useful is in identifying women at risk for preterm delivery and related pregnancy complications. Neonates born preterm have significant morbidity and mortality, both in the perinatal period and throughout the life course, and identifying women at risk of delivering preterm may allow for targeted interventions to prevent or delay preterm birth (PTB). In addition to identifying those at increased risk for preterm birth, biomarkers may be able to distinguish neonates at particular risk for future complications due to modifiable environmental factors, such as maternal smoking or alcohol use during pregnancy. Currently, there are no such biomarkers available, though candidate gene and epigenome-wide association studies have identified DNA methylation differences associated with PTB, its risk factors and its long-term outcomes. Further biomarker development is crucial to reducing the health burden associated with adverse intrauterine conditions and preterm birth, and the results of recent DNA methylation studies may advance that goal. PMID:27089367

  11. Detection of biomarkers using recombinant antibodies coupled to nanostructured platforms

    Directory of Open Access Journals (Sweden)

    Michael R. Kierny

    2012-07-01

    Full Text Available The utility of biomarker detection in tomorrow's personalized health care field will mean early and accurate diagnosis of many types of human physiological conditions and diseases. In the search for biomarkers, recombinant affinity reagents can be generated to candidate proteins or post-translational modifications that differ qualitatively or quantitatively between normal and diseased tissues. The use of display technologies, such as phage-display, allows for manageable selection and optimization of affinity reagents for use in biomarker detection. Here we review the use of recombinant antibody fragments, such as scFvs and Fabs, which can be affinity-selected from phage-display libraries, to bind with both high specificity and affinity to biomarkers of cancer, such as Human Epidermal growth factor Receptor 2 (HER2 and Carcinoembryonic antigen (CEA. We discuss how these recombinant antibodies can be fabricated into nanostructures, such as carbon nanotubes, nanowires, and quantum dots, for the purpose of enhancing detection of biomarkers at low concentrations (pg/mL within complex mixtures such as serum or tissue extracts. Other sensing technologies, which take advantage of ‘Surface Enhanced Raman Scattering’ (gold nanoshells, frequency changes in piezoelectric crystals (quartz crystal microbalance, or electrical current generation and sensing during electrochemical reactions (electrochemical detection, can effectively provide multiplexed platforms for detection of cancer and injury biomarkers. Such devices may soon replace the traditional time consuming ELISAs and Western blots, and deliver rapid, point-of-care diagnostics to market.

  12. 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.

  13. Searching for a system: The quest for ovarian cancer biomarkers

    Energy Technology Data Exchange (ETDEWEB)

    Rodland, Karin D.; Maihle, Nita J.

    2011-11-01

    The stark difference in clinical outcome for patients with ovarian cancer diagnosed at early stages (95% at 5 years) versus late stages (27.6% at 5 years) has driven a decades-long quest for effective biomarkers that will enable earlier detection of ovarian cancer. Yet despite intense efforts, including the application of modern high throughput technologies such as transcriptomics and proteomics, there has been little improvement in performance compared to the gold standard of quantifying serum CA125 immunoreactivity paired with transvaginal ultrasound. This review describes the strategies that have been used for identification of ovarian cancer biomarkers, including the recent introduction of novel bioinformatic approaches. Results obtained using high throughput-based vs. biologically rational approaches for the discovery of diagnostic early detection biomarkers are compared and analyzed for functional enrichment.

  14. 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...

  15. Ovarian cyst fluid is a rich proteome resource for detection of new tumor biomarkers

    OpenAIRE

    Kristjansdottir Björg; Partheen Karolina; Fung Eric T; Marcickiewicz Janusz; Yip Christine; Brännström Mats; Sundfeldt Karin

    2012-01-01

    Abstract Background We aimed to investigate the use of ovarian cyst fluid as a source for biomarker discovery and to find novel biomarkers for use in the diagnosis of epithelial ovarian tumors. Results Ovarian cyst fluids from 218 women were collected and 192 (benign n = 129, malignant n = 63) were analyzed using mass spectrometry. 1180 peaks were detected, 221 of which were differently expressed between benign and malignant ovarian tumors. Seventeen peaks had receiver operating curve and are...

  16. 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.

  17. 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...

  18. 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...

  19. Drug Discovery Targeted to Transthyretin Related Amyloidosis

    OpenAIRE

    Blasi Pérez, Daniel

    2013-01-01

    [eng] Several drug discovery approaches has been performed to find new compounds able to interact with high affinity with the hormone binding site of the homotetrameric protein transthyretin (TTR), and stabilize this tetramer, becoming drug candidates to treat several rare amyloid diseases associated with TTR. With this aim, several computational workflows and chemico-biological databases have been developed, and in collaboration with two experimental research laboratories of our TTR Con...

  20. 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

  1. Dark matter candidates

    International Nuclear Information System (INIS)

    One of the simplest, yet most profound, questions we can ask about the Universe is, how much stuff is in it, and further what is that stuff composed of? Needless to say, the answer to this question has very important implications for the evolution of the Universe, determining both the ultimate fate and the course of structure formation. Remarkably, at this late date in the history of the Universe we still do not have a definitive answer to this simplest of questions---although we have some very intriguing clues. It is known with certainty that most of the material in the Universe is dark, and we have the strong suspicion that the dominant component of material in the Cosmos is not baryons, but rather is exotic relic elementary particles left over from the earliest, very hot epoch of the Universe. If true, the Dark Matter question is a most fundamental one facing both particle physics and cosmology. The leading particle dark matter candidates are: the axion, the neutralino, and a light neutrino species. All three candidates are accessible to experimental tests, and experiments are now in progress. In addition, there are several dark horse, long shot, candidates, including the superheavy magnetic monopole and soliton stars. 13 refs

  2. Identification of a novel panel of cerebrospinal fluid biomarkers for Alzheimer's disease

    DEFF Research Database (Denmark)

    Simonsen, A.H.; McGuire, J.; Podust, V.N.; Davies, H.; Minthon, L.; Skoog, I.; Andreasen, N.; Wallin, A.; Waldemar, G.; Blennow, K.

    2008-01-01

    healthy control individuals with high sensitivity (97%) and specificity (98%). The panel of five markers was tested on a blinded independent data set of 30 AD samples and 28 controls giving 100% sensitivity and 97% specificity. This novel panel of biomarkers could potentially be used to improve the...... samples from AD patients (n=95) and population-based healthy controls (n=72) were analyzed by SELDI-TOF-MS in order to discover and characterize novel candidate biomarker combinations that differentiate AD patients from normal aging in this explorative study. Thirty candidate biomarkers (ROC AUC>0.7) were...... discovered that could differentiate patients with AD from healthy controls. Protein sequence determination and positive identification of 15 biomarkers revealed potential associations between the identified markers and AD pathogenesis. A multi-marker combination of five peaks could distinguish AD from...

  3. Imaging biomarkers in tauopathies.

    Science.gov (United States)

    Dani, Melanie; Edison, Paul; Brooks, David J

    2016-01-01

    Abnormally aggregated tau protein is central to the pathophysiology of Alzheimer's disease, frontotemporal dementia variants, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. The post-mortem cortical density of hyperphosphorylated tau tangles correlates with pre-morbid cognitive dysfunction and neuron loss. Selective PET ligands including [18F]THK5117, [18F]THK5351, [18F]AV1451 (T807) and [11C]PBB3 now provide in vivo imaging information about the timing and distribution of tau in the early phases of neurodegenerative diseases. They are potential imaging biomarkers for both supporting diagnosis and tracking disease progression. Here, we discuss the challenges posed in developing selective tau ligands as biomarkers, their state of development and the new clinical information that has been revealed. PMID:26299160

  4. Towards Improved Biomarker Research

    DEFF Research Database (Denmark)

    Kjeldahl, Karin

    actually identify strong biomarkers when strict validation is applied; the latter phenomenon is to some extentmasked by a publication bias, but has been widely observed among researchers working with omics data. In this thesis, the background of this apparent small effect size of the biomarkers is...... is used both for regression and classification purposes. This method has proven its strong worth in the multivariate data analysis throughout an enormous range of applications; a very classic data type is near infrared (NIR) data, but many similar data types have also be very successful. On that...... application types are different and introduce a larger complexity, weaker signals andmany potential sources of experimental and analytical bias and errors. The risk of the latter is further increased by the complexity of the entire omics experimental setup which often involves various project partners with...

  5. Epigenetic biomarkers in laboratory diagnostics: emerging approaches and opportunities.

    Science.gov (United States)

    Sandoval, Juan; Peiró-Chova, Lorena; Pallardó, Federico V; García-Giménez, José Luis

    2013-06-01

    Epigenetics has emerged as a new and promising field in recent years. Lifestyle, stress, drugs, physiopathological situations and pharmacological interventions have a great impact on the epigenetic code of the cells by altering the methylome, miRNA expression and the covalent histone modifications. Since there exists a need to find new biomarkers and improve diagnosis for several diseases, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. In this context, deciphering intricate epigenetic modifications involved in several molecular processes is a challenge that will be solved in the near future. In this review, the authors present an overview of the high-throughput technologies and laboratory techniques available for epigenetic studies, and also discuss which of them are more reliable to be used in a clinical diagnostic laboratory. In addition, the authors describe the most promising epigenetic biomarkers in lung, colorectal and prostate cancer, in which most advances have been achieved. Finally, the authors describe epigenetic biomarkers in some rare diseases; these rare syndromes are paradigms for a specific impaired molecular pathway, thus providing valuable information on the discovery of new epigenetic biomarkers. PMID:23782253

  6. 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.

  7. 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.

  8. 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...

  9. Toward Rapid, High-Sensitivity, Volume-Constrained Biomarker Quantification and Validation using Backscattering Interferometry

    OpenAIRE

    Olmsted, Ian R.; Hassanein, Mohamed; Kussrow, Amanda; Hoeksema, Megan; Li, Ming; Massion, Pierre P.; Bornhop, Darryl J.

    2014-01-01

    Realizing personalized medicine, which promises to enable early disease detection, efficient diagnostic staging, and therapeutic efficacy monitoring, hinges on biomarker quantification in patient samples. Yet, the lack of a sensitive technology and assay methodology to rapidly validate biomarker candidates continues to be a bottleneck for clinical translation. In our first direct and quantitative comparison of backscattering interferometry (BSI) to fluorescence sensing by ELISA, we show that ...

  10. Development of Diagnostic Biomarkers for Detecting Diabetic Retinopathy at Early Stages Using Quantitative Proteomics

    OpenAIRE

    Jonghwa Jin; Hophil Min; Sang Jin Kim; Sohee Oh; Kyunggon Kim; Hyeong Gon Yu; Taesung Park; Youngsoo Kim

    2016-01-01

    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 ...

  11. Biomarkers for tuberculosis in the context of HIV/AIDS in Ethiopia

    OpenAIRE

    Kassa Misgina, D.

    2014-01-01

    Tuberculosis remains to be one of the severe infectious diseases, especially in developing countries. Universal and specific biomarkers for TB could accelerate the development of novel diagnostics and therapies for TB, which are urgently needed to control the epidemic effectively. In the studies included in this thesis, several candidate biomarkers for latent and active TB have been identified. Our study design for testing novel Mtb antigens, revealed combined measurement of specific cytokine...

  12. Biomarkers and Surrogate Endpoints for Normal-Tissue Effects of Radiation Therapy: The Importance of Dose-Volume Effects

    International Nuclear Information System (INIS)

    Biomarkers are of interest for predicting or monitoring normal tissue toxicity of radiation therapy. Advances in molecular radiobiology provide novel leads in the search for normal tissue biomarkers with sufficient sensitivity and specificity to become clinically useful. This article reviews examples of studies of biomarkers as predictive markers, as response markers, or as surrogate endpoints for radiation side effects. Single nucleotide polymorphisms are briefly discussed in the context of candidate gene and genomewide association studies. The importance of adjusting for radiation dose distribution in normal tissue biomarker studies is underlined. Finally, research priorities in this field are identified and discussed.

  13. Biomarker- versus drug-driven tumor growth inhibition models: an equivalence analysis.

    Science.gov (United States)

    Sardu, Maria Luisa; Poggesi, Italo; De Nicolao, Giuseppe

    2015-12-01

    The mathematical modeling of tumor xenograft experiments following the dosing of antitumor drugs has received much attention in the last decade. Biomarker data can further provide useful insights on the pathological processes and be used for translational purposes in the early clinical development. Therefore, it is of particular interest the development of integrated pharmacokinetic-pharmacodynamic (PK-PD) models encompassing drug, biomarker and tumor-size data. This paper investigates the reciprocal consistency of three types of models: drug-to-tumor, such as established drug-driven tumor growth inhibition (TGI) models, drug-to-biomarker, e.g. indirect response models, and biomarker-to-tumor, e.g. the more recent biomarker-driven TGI models. In particular, this paper derives a mathematical relationship that guarantees the steady-state equivalence of the cascade of drug-to-biomarker and biomarker-to-tumor models with a drug-to-tumor TGI model. Using the Simeoni TGI model as a reference, conditions for steady-state equivalence are worked out and used to derive a new biomarker-driven model. Simulated and real data are used to show that in realistic cases the steady-state equivalence extends also to transient responses. The possibility of predicting the drug-to-tumor potency of a new candidate drug based only on biomarker response is discussed. PMID:26209955

  14. 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

  15. Particle Dark Matter Candidates

    CERN Document Server

    Scopel, Stefano

    2007-01-01

    I give a short overview on some of the favorite particle Cold Dark Matter candidates today, focusing on those having detectable interactions: the axion, the KK-photon in Universal Extra Dimensions, the heavy photon in Little Higgs and the neutralino in Supersymmetry. The neutralino is still the most popular, and today is available in different flavours: SUGRA, nuSUGRA, sub-GUT, Mirage mediation, NMSSM, effective MSSM, scenarios with CP violation. Some of these scenarios are already at the level of present sensitivities for direct DM searches.

  16. 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

  17. Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers

    DEFF Research Database (Denmark)

    Gulati, Sakshi; Martinez, Pierre; Joshi, Tejal; Birkbak, Nicolai Juul; Santos, Claudio R.; Rowan, Andrew J.; Pickering, Lisa; Gore, Martin; Larkin, James; Szallasi, Zoltan Imre; Bates, Paul A.; Swanton, Charles; Gerlinger, Marco

    2014-01-01

    BackgroundCandidate biomarkers have been identified for clear cell renal cell carcinoma (ccRCC) patients, but most have not been validated. ObjectiveTo validate published ccRCC prognostic biomarkers in an independent patient cohort and to assess intratumour heterogeneity (ITH) of the most promising...... the ability of published biomarkers to predict the survival of patients with clear cell kidney cancer in an independent patient cohort. Only one molecular test adds prognostic information to routine clinical assessments. This marker showed good and poor prognosis results within most individual cancers...

  18. Biomarkers in inflammatory bowel diseases

    DEFF Research Database (Denmark)

    Bennike, Tue; Birkelund, Svend; Stensballe, Allan;

    2014-01-01

    with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future...... before. In this review, we report the current status of the proteomics IBD biomarkers and discuss various emerging proteomic strategies for identifying and characterizing novel biomarkers, as well as suggesting future targets for analysis....

  19. Bias in High-Throughput Analysis of miRNAs and Implications for Biomarker Studies.

    Science.gov (United States)

    Backes, Christina; Sedaghat-Hamedani, Farbod; Frese, Karen; Hart, Martin; Ludwig, Nicole; Meder, Benjamin; Meese, Eckart; Keller, Andreas

    2016-02-16

    A certain degree of bias in high-throughput molecular technologies including microarrays and next-generation sequencing (NGS) is known. To quantify the actual impact of the biomarker discovery platform on miRNA profiles, we first performed a meta-analysis: raw data of 1 539 microarrays and 705 NGS blood-borne miRNomes were statistically evaluated, suggesting a substantial influence of the technology on biomarker profiles. We observed highly significant dependency of the miRNA nucleotide composition on the expression level. Higher expression in NGS was discovered for uracil-rich miRNAs (p = 7 × 10(-37)), while high expression in microarrays was found predominantly for guanine-rich miRNAs (p = 3 × 10(-33)). To verify the findings, 10 identical replicates of one individual were measured using NGS and microarrays (2 525 miRNAs from miRBase version 21). Overall, we calculated a correlation coefficient of 0.414 for both technologies. Detailed analysis however revealed that the correlation was observed only for miRNAs in the early miRBase versions (microarray and NGS. Specifically, we observed 67 miRNAs with a median read count above 10 in NGS, while they were not detected in any of the 10 replicated array experiments. In contrast, 234 miRNAs were discovered in all 10 replicated array measurements but were not found in any of the NGS experiments of the same individual. While the first group had average guanine content of 22%, the latter group consisted of 41% of this nucleotide. Selected concordant and discordant miRNAs were tested in quantitative real-time-polymerase chain reaction (RT-qPCR) experiments again of the same individual, providing further evidence for the substantial bias depending on the base composition. As a consequence, biomarkers that have been discovered by specific high-throughout technologies have to be carefully considered. Especially for validation of the platform, the selection of reasonable candidates is essential. PMID:26760198

  20. 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.

  1. 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.

  2. 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.

  3. 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...

  4. 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!

  5. Chiral Biomarkers in Meteorites

    Science.gov (United States)

    Hoover, Richard B.

    2010-01-01

    The chirality of organic molecules with the asymmetric location of group radicals was discovered in 1848 by Louis Pasteur during his investigations of the rotation of the plane of polarization of light by crystals of sodium ammonium paratartrate. It is well established that the amino acids in proteins are exclusively Levorotary (L-aminos) and the sugars in DNA and RNA are Dextrorotary (D-sugars). This phenomenon of homochirality of biological polymers is a fundamental property of all life known on Earth. Furthermore, abiotic production mechanisms typically yield recemic mixtures (i.e. equal amounts of the two enantiomers). When amino acids were first detected in carbonaceous meteorites, it was concluded that they were racemates. This conclusion was taken as evidence that they were extraterrestrial and produced by abiologically. Subsequent studies by numerous researchers have revealed that many of the amino acids in carbonaceous meteorites exhibit a significant L-excess. The observed chirality is much greater than that produced by any currently known abiotic processes (e.g. Linearly polarized light from neutron stars; Circularly polarized ultraviolet light from faint stars; optically active quartz powders; inclusion polymerization in clay minerals; Vester-Ulbricht hypothesis of parity violations, etc.). This paper compares the measured chirality detected in the amino acids of carbonaceous meteorites with the effect of these diverse abiotic processes. IT is concluded that the levels observed are inconsistent with post-arrival biological contamination or with any of the currently known abiotic production mechanisms. However, they are consistent with ancient biological processes on the meteorite parent body. This paper will consider these chiral biomarkers in view of the detection of possible microfossils found in the Orgueil and Murchison carbonaceous meteorites. Energy dispersive x-ray spectroscopy (EDS) data obtained on these morphological biomarkers will be

  6. "Eureka, Eureka!" Discoveries in Science

    Science.gov (United States)

    Agarwal, Pankaj

    2011-01-01

    Accidental discoveries have been of significant value in the progress of science. Although accidental discoveries are more common in pharmacology and chemistry, other branches of science have also benefited from such discoveries. While most discoveries are the result of persistent research, famous accidental discoveries provide a fascinating…

  7. Revisiting the technical validation of tumour biomarker assays: how to open a Pandora's box.

    Science.gov (United States)

    Marchiò, Caterina; Dowsett, Mitch; Reis-Filho, Jorge S

    2011-01-01

    A tumour biomarker is a characteristic that is objectively measured and evaluated in tumour samples as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The development of a biomarker contemplates distinct phases, including discovery by hypothesis-generating preclinical or exploratory studies, development and qualification of the assay for the identification of the biomarker in clinical samples, and validation of its clinical significance. Although guidelines for the development and validation of biomarkers are available, their implementation is challenging, owing to the diversity of biomarkers being developed. The term 'validation' undoubtedly has several meanings; however, in the context of biomarker research, a test may be considered valid if it is 'fit for purpose'. In the process of validation of a biomarker assay, a key point is the validation of the methodology. Here we discuss the challenges for the technical validation of immunohistochemical and gene expression assays to detect tumour biomarkers and provide suggestions of pragmatic solutions to address these challenges. PMID:21504565

  8. Revisiting the technical validation of tumour biomarker assays: how to open a Pandora's box

    Directory of Open Access Journals (Sweden)

    Dowsett Mitch

    2011-04-01

    Full Text Available Abstract A tumour biomarker is a characteristic that is objectively measured and evaluated in tumour samples as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The development of a biomarker contemplates distinct phases, including discovery by hypothesis-generating preclinical or exploratory studies, development and qualification of the assay for the identification of the biomarker in clinical samples, and validation of its clinical significance. Although guidelines for the development and validation of biomarkers are available, their implementation is challenging, owing to the diversity of biomarkers being developed. The term 'validation' undoubtedly has several meanings; however, in the context of biomarker research, a test may be considered valid if it is 'fit for purpose'. In the process of validation of a biomarker assay, a key point is the validation of the methodology. Here we discuss the challenges for the technical validation of immunohistochemical and gene expression assays to detect tumour biomarkers and provide suggestions of pragmatic solutions to address these challenges.

  9. Biomarkers for Allergen Immunotherapy: A "Panoromic" View.

    Science.gov (United States)

    Moingeon, Philippe

    2016-02-01

    Biomarkers (BMKs) are biological parameters that can be measured to predict or monitor disease severity or treatment efficacy. The induction of regulatory dendritic cells (DCs) concomitantly with a downregulation of proallergic DC2s (ie, DCs supporting the differentiation of T-helper lymphocyte type 2 cells) in the blood of patients allergic to grass pollen has been correlated with the early onset of allergen immunotherapy efficacy. The combined use of omics technologies to compare biological samples from clinical responders and nonresponders is being implemented in the context of nonhypothesis-driven approaches. Such comprehensive "panoromic" strategies help identify completely novel candidate BMKs, to be subsequently validated as companion diagnostics in large-scale clinical trials. PMID:26617233

  10. Biomarkers of postoperative delirium and cognitive dysfunction

    Directory of Open Access Journals (Sweden)

    Ganna Androsova

    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.

  11. A proteomics approach to the identification of biomarkers for psoriasis utilising keratome biopsy

    DEFF Research Database (Denmark)

    Williamson, James C; Scheipers, Peter; Schwämmle, Veit; Zibert, John Robert; Beck, Hans Christian; Jensen, Ole N

    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...... skin biopsy, which results in reduced cellular complexity compared to punch biopsy. Furthermore, we applied short term ex vivo culture in order to enrich for a "secretome" sub-proteome reflective of the disease and enriched in potential biomarkers. Using these sample preparation techniques we performed...... 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...

  12. Worldwide Discoveries Help People Everywhere

    Science.gov (United States)

    ... Home Current Issue Past Issues Special Section Worldwide Discoveries Help People Everywhere Past Issues / Spring 2008 Table ... shows examples of discoveries and their impact. Diseases Discoveries The Benefits for All Americans Huntington's Disease Venezuela— ...

  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. PMID:25163620

  14. Similar Source of Differential Blood mRNAs in Lung Cancer and Pulmonary Inflammatory Diseases: Calls for Improved Strategy for Identifying Cancer-Specific Biomarkers

    OpenAIRE

    Hong, Guini; Chen, Beibei; Li, Hongdong; Zhang, Wenjing; Zheng, Tingting; Li, Shan; Shi, Tongwei; Ao, Lu; Guo, Zheng

    2014-01-01

    Background Many studies try to identify cancer diagnostic biomarkers by comparing peripheral whole blood (PWB) of cancer samples and healthy controls, explicitly or implicitly assuming that such biomarkers are potential candidate biomarkers for distinguishing cancer from nonmalignant inflammation-associated diseases. Methods Multiple PWB gene expression profiles for lung cancer/inflammation-associated pulmonary diseases were used for differential mRNAs identification and comparison and for pr...

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. Finding diabetic nephropathy biomarkers in the plasma peptidome by high-throughput magnetic bead processing and MALDI-TOF-MS analysis

    DEFF Research Database (Denmark)

    Hansen, Henning G; Overgaard, Julie; Lajer, Maria; Hubalek, Frantisek; Højrup, Peter; Pedersen, Lykke; Tarnow, Lise; Rossing, Peter; Pociot, Flemming; McGuire, James N

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease and improved biomarkers would help identify high-risk individuals. The aim of this study was to discover candidate biomarkers for DN in the plasma peptidome in an in-house cross-sectional cohort (n=122) of type 1 diabet...

  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. Biomarkers of HIV-1 associated dementia: proteomic investigation of sera

    Directory of Open Access Journals (Sweden)

    Duan Fenghai

    2009-03-01

    Full Text Available Abstract Background New, more sensitive and specific biomarkers are needed to support other means of clinical diagnosis of neurodegenerative disorders. Proteomics technology is widely used in discovering new biomarkers. There are several difficulties with in-depth analysis of human plasma/serum, including that there is no one proteomic platform that can offer complete identification of differences in proteomic profiles. Another set of problems is associated with heterogeneity of human samples in addition intrinsic variability associated with every step of proteomic investigation. Validation is the very last step of proteomic investigation and it is very often difficult to validate potential biomarker with desired sensitivity and specificity. Even though it may be possible to validate a differentially expressed protein, it may not necessarily prove to be a valid diagnostic biomarker. Results In the current study we report results of proteomic analysis of sera from HIV-infected individuals with or without cognitive impairment. Application of SELDI-TOF analysis followed by weak cation exchange chromatography and 1-dimensional electrophoresis led to discovery of gelsolin and prealbumin as differentially expressed proteins which were not detected in this cohort of samples when previously investigated by 2-dimensional electrophoresis with Difference Gel Electrophoresis technology. Conclusion Validation using western-blot analysis led us to conclude that relative change of the levels of these proteins in one patient during a timeframe might be more informative, sensitive and specific than application of average level estimated based on an even larger cohort of patients.

  2. 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

  3. 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

  4. 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)

  5. 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

  6. 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

  7. 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...

  8. Higgs Discovery before LHC?

    OpenAIRE

    Chiarelli, Giorgio; Collaboration, for the CDF; The D0 Collaboration

    2001-01-01

    The proposed Run IIb of the Tevatron Collider will provide 15 fb-1 worth of ppbar data at c.o.m energy of 2 TeV per experiment by year 2007. We review the plans of the Tevatron accelerator complex upgrade and the plans for the upgrades of the experiments to match this challenge. Perspectives for the discovery of an Higgs particle are reviewed and the concrete possibility of a 5 sigmas discovery for a low mass Higgs are discussed.

  9. 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.

  10. 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

  11. 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.

  12. 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. PMID:26418704

  13. 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.

  14. Protein biomarkers in Parkinson's disease: Focus on cerebrospinal fluid markers and synaptic proteins.

    Science.gov (United States)

    Halbgebauer, Steffen; Öckl, Patrick; Wirth, Katharina; Steinacker, Petra; Otto, Markus

    2016-06-01

    Despite extensive research, to date, no validated biomarkers for PD have been found. This review seeks to summarize studies approaching the detection of biomarker candidates for PD and introduce promising ones in more detail, with special attention to synaptic proteins. To this end, we performed a PubMed search and included studies using proteomic tools (2-dimensional difference in gel electrophoresis and/or mass spectrometry) for the comparison of samples from PD and control patients. We found 27 studies reporting more than 500 differentially expressed proteins in which a total of 28 were detected in 2 and 17 in 3 or more independent studies, including posttranslationally modified proteins. In addition, of these 500 proteins, 25 were found to be brain specific, and 14 were enriched in synapses. Special attention was given to the applicability of the biomarker regarding sampling procedures, that is, using CSF/serum material for diagnosis. Furthermore, presynaptic proteins involved in vesicle membrane fusion seem to be interesting candidates for future analyses. Nonetheless, even though such promising biomarker candidates for PD exist, validation of these biomarkers in large-scale clinical studies is necessary to evaluate the diagnostic potential. © 2016 International Parkinson and Movement Disorder Society. PMID:27134134

  15. Development of biomarkers to chart all Alzheimer's disease stages: the royal road to cutting the therapeutic Gordian Knot.

    Science.gov (United States)

    Hampel, Harald; Lista, Simone; Khachaturian, Zaven S

    2012-07-01

    The aim of this perspective article is to stimulate radical shifts in thinking and foster further discussion on the effective discovery, development, validation, and qualification process of biological markers derived from all available technical modalities that meet the complex conceptual and pathophysiological challenges across all stages of the complex, nonlinear, dynamic, and chronically progressive sporadic Alzheimer's disease (AD). This perspective evaluates the current state of the science regarding a broad spectrum of hypothesis-driven and exploratory technologies and "markers" as candidates for all required biomarker functions, in particular, surrogate indicators of adaptive to maladaptive and compensatory to decompensatory, reversible to irreversible brain "systems failure." We stress the future importance of the systems biology (SB) paradigm (next to the neural network paradigm) for substantial progress in AD research. SB represents an integrated and deeper investigation of interacting biomolecules within cells and organisms. This approach has only recently become feasible as high-throughput technologies and mass spectrometric analyses of proteins and lipids, together with rigorous bioinformatics, have evolved. Existing high-content data derived from clinically and experimentally derived neural tissues point to convergent pathophysiological pathways during the course of AD, transcending traditional descriptive studies to reach a more integrated and comprehensive understanding of AD pathophysiology, derived systems biomarkers, and "druggable" system nodes. The discussion is continued on the premise that the lack of integration of advanced biomarker technologies and transfertilization from more mature translational research fields (e.g., oncology, immunology, cardiovascular), which satisfy regulatory requirements for an accurate, sensitive, and well-validated surrogate marker of specific pathophysiological processes and/or clinical outcomes, is a major

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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