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Results for “Biomarker development”

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At least 109 records · Page 6Linked to original sources
PubMed1991

Critical considerations in the immunochemical detection and quantitation of antigenic biomarkers.

The formation of covalent adducts as a result of the interaction of metabolically activated chemicals with host macromolecules is a common critical event in mutagenic, carcinogenic, and immunologic phenomena. Because of their antigenicity and their immunogenicity, covalent adducts may be detected using sensitive immunochemical techniques. The immunochemical approaches to biomonitoring and molecular dosimetry of DNA damage are particularly attractive because they allow sensitive quantitation of specific DNA adducts present in small samples and do not rely on the use of radiolabeled adducts. Two examples of biomarker immunoassay development are presented: an avidin/biotin-amplified ELISA for the major DNA adduct of the human bladder carcinogen 4-aminobiphenyl (ABP), and a particle concentration fluorescent immunoassay (PCFIA) for the major protein adduct associated with toxicity by the prototype hepatotoxin acetaminophen. The examples illustrate critical steps in the development of biomarker immunoassays which include selection of the relevant adduct, preparation of an appropriate immunogen, immunization, characterization of antisera, and development of application-specific sample processing techniques for biomarker quantitation. Immunochemical procedures may be combined with other analytical techniques to form hybrid systems which take advantage of both the antigenicity and the physical or chemical properties of a biomarker to achieve greater specificity and/or sensitivity. The future usefulness of these new tools of molecular epidemiology will depend on a compound-by-compound validation of methods and critical evaluation of the biologic importance of the particular antigenic biomarker as an indicator of exposure and as an indicator of risk.

Acetaminophen↗
PubMed2004

Heart disease, clinical proteomics and mass spectrometry.

Heart disease is the leading cause of mortality and morbidity in the world. As such, biomarkers are needed for the diagnosis, prognosis, therapeutic monitoring and risk stratification of acute injury (acute myocardial infarction (AMI)) and chronic disease (heart failure). The procedure for biomarker development involves the discovery, validation, and translation into clinical practice of a panel of candidate proteins to monitor risk of heart disease. Two types of biomarkers are possible; heart-specific and cardiovascular pulmonary system monitoring markers. Here we review the use of MS in the process of cardiac biomarker discovery and validation by proteomic analysis of cardiac myocytes/tissue or serum/plasma. An example of the use of MS in biomarker discovery is given in which the albumin binding protein sub-proteome was examined using MALDI-TOF MS/MS. Additionally, an example of MS in protein validation is given using affinity surface enhanced laser desorption ionization (SELDI) to monitor the disease-induced post-translational modification and the ternary status of myocyte-originating protein, cardiac troponin I in serum.

Albumins↗
PubMedDate not supplied

Biological markers and occupational lung disease: mineral dust-induced respiratory disorders.

There is a need for methods to monitor early adverse effects, exposure, and/or susceptibility of individual subjects due to occupational and environmental causes. This paper discusses the experimental origin, value, and validity of several biological indicators, termed biomarkers, that were used to study coal dust-induced respiratory disorders. The findings are presented in a framework to visualize problems and challenges when developing biomarkers. Taking the framework of mineral dust-induced lung disorders as an example, it is demonstrated how carefully designed follow-up studies are a prerequisite to test the validity and use of events often put forward as biomarkers. It is concluded from the data that serum type III procollagen is neither an exposure nor an (early) effect marker, antioxidant enzyme expression is related to the early inflammatory response after mineral dust inhalation, while the evidence is accumulating that tumor necrosis factor-alpha is a susceptibility marker for progression in mineral dust-induced lung fibrosis.

Biomarkers↗
PubMedDate not supplied

Biomarkers in psychotropic drug development.

The authors review the use of biomarkers in the development of novel psychotropic agents. They briefly review clinical drug development, emphasizing the importance of incorporating biomarkers. For the development of psychotropic agents, biomarkers are particularly useful for assessing central nervous system exposure and effects and for serving as surrogate measures for safety and efficacy. Collectively, biomarkers allow for more accurate estimation of doses for clinical trials as drug development progresses. For drugs that target the pathophysiology of Alzheimer disease, several promising biomarkers are becoming available that may allow improved signal detection in clinical trials. Procedures for developing new drugs are evolving rapidly. Technical advances in the field are making it possible to shift from empirically-based methods to mechanistically-driven schemes. Biomarkers enhance the quality and safety of clinical drug development and reduce its cost and duration.

Aged↗
PubMed2004

Correlations between air levels of hexahydrophthalic anhydride (HHPA) and HHPA-adducted albumin tryptic peptides in nasal lavage fluid from experimentally exposed volunteers.

Organic acid anhydrides (OAAs) are low molecular weight, reactive compounds extensively used in industry. Exposure to these compounds may lead to allergic symptoms such as rhinitis and asthma. It is important to develop better and more informative methods for assessment of exposure to OAAs. The aim of this study was to develop a method for analysis of specific hexahydrophthalic anhydride (HHPA)-adducted tryptic peptides of human serum albumin (HSA) in nasal lavage (NAL). Furthermore, these peptides were evaluated as biomarkers of exposure. The proteins in the NAL samples were reduced, alkylated and digested with trypsin and the obtained peptides were analyzed using liquid chromatography/tandem mass spectrometry. The total amount of hydrolyzable HHPA in an HHPA-HSA conjugate was used for calibration. A deuterium-labeled HHPA-HSA conjugate was used as internal standard. Five volunteers were exposed to 10, 40 and 80 microg/m3 of HHPA in an exposure chamber and NAL samples were collected before and after exposure. Acceptable precisions of the assay at 13-14% were found for three adducted peptides. The mean levels of these three peptides for the five subjects ranged between 5-22, 15-75 and 33-125 pmol/mL NAL for the exposures at 10, 40 and 80 microg/m3, respectively. High correlations between air levels and the measured peptides were found on an individual basis but there were large inter-individual differences ranging between 63 and 110% for the three peptides. The large differences remained after protein adjustments. It was possible to detect exposures below 10 microg/m3 with the method. Thus, these adducted peptides may be used as biomarkers of exposure, which may better estimate the risk than previous biomarkers developed for OAAs.

Adult↗
PubMedDate not supplied

Human behavioral assessment in neurotoxicology: producing appropriate test performance with written and shaping instructions.

Neurotoxic effects are of such breadth and complexity that functional biomarkers (behavioral tests) that integrate many areas of the nervous system predominate in human neurotoxicology research. The increasing distribution of chemical and other manufacturing throughout the world, particularly in developing nations, suggests the acute need to develop biomarkers for chemical exposures and effects that can be employed internationally. A language-free method for training performance on behavioral tests is described, which holds promise for international research that circumvents the vagaries of translation. Four behavioral tests were administered to 74-114 adult US subjects. Procedures, collectively termed shaping, produced effective performance on three tests [Symbol Digit, Vigilant Attention Test (VAT), Digit Span Forward and Backward], and produced appropriate but unacceptably slow performance in initial testing on the Simple Reaction Time test. Effective performance on the Symbol-Digit test also was produced by shaping instruction, without assistance from examiners, in small groups of residents of Taipei (Taiwan) and US children between the ages of 5 and 16.

Adolescent↗
PubMed2006

Protein biomarker discovery and validation: the long and uncertain path to clinical utility.

Better biomarkers are urgently needed to improve diagnosis, guide molecularly targeted therapy and monitor activity and therapeutic response across a wide spectrum of disease. Proteomics methods based on mass spectrometry hold special promise for the discovery of novel biomarkers that might form the foundation for new clinical blood tests, but to date their contribution to the diagnostic armamentarium has been disappointing. This is due in part to the lack of a coherent pipeline connecting marker discovery with well-established methods for validation. Advances in methods and technology now enable construction of a comprehensive biomarker pipeline from six essential process components: candidate discovery, qualification, verification, research assay optimization, biomarker validation and commercialization. Better understanding of the overall process of biomarker discovery and validation and of the challenges and strategies inherent in each phase should improve experimental study design, in turn increasing the efficiency of biomarker development and facilitating the delivery and deployment of novel clinical tests.

Animals↗
PubMed2006

An overview of the BEEP Stavanger workshop.

Within the three-year European Research Project BEEP (Biological Effects of Environmental Pollution in marine ecosystems), a workshop was carried out at the facility of Akvamiljø a.s. with the scientific support of IRIS (International Research Institute of Stavanger) researchers. Validation of newly developed biomarkers, especially at the molecular level, was the core part of the activity. Two large scale mesocosm exposures were done and samples shared between the participants (about 30 Institute), allowing an integrated approach for studying the effects of several pollutants selected as environmentally important issues (i.e. PAHs, alkyl phenols, bisphenol A, diallyl phthalate and polybrominated diphenyl ether). In addition, a field study (Visne, Norway) has been performed for the validations of biomarkers under environmental conditions. The Stavanger workshop demonstrates the importance of collaboration between researchers to establish common ways to proceed in biomarker analysis. The common exposures encourage a joint strategy for planning biomonitoring activity. A clarification in this direction is needed to coordinate results from numerous studies about the environmental impact of pollutants which are currently carried out all over Europe and around the world. Expertise in various disciplines is required to plan and perform a successful monitoring activity and to study/predict the effect of environmental pollutants. Biologists, chemists, statisticians and environmental researchers should always be included. The Stavanger workshop also indicated the importance of developing multivariate statistical methods to enable interpretation of complex data sets. It is of interest to develop statistical tools which can integrate the results from a battery of biomarkers in order to obtain a more complete picture of environmental impact.

Animals↗
PubMed2005

Enzyme immunoassay for a urinary metabolite of 4-hydroxynonenal as a marker of lipid peroxidation.

Free radical reactions are involved in the pathogenesis of numerous diseases, so there is a real need to develop biomarkers that reflect these reactions in vivo. 4-Hydroxy-2-nonenal (HNE) is a major product of the lipid peroxidation process that is a consequence of free radical reactions. We present here the development and validation of an enzyme immunoassay (EIA) of the major urinary metabolite of HNE, namely 1,4-dihydroxynonane-mercapturic acid (DHN-MA). EIA allowed direct measurement of DHN-MA in rat urine with good sensitivity (0.02 ng/ml) and precision (intraassay CV = 5.7%). Recovery was complete (99-102%). Cross-reactivity was very low with 1,4-dihydroxynonene and with different mercapturic acids except with one other HNE urinary metabolite. Good correlation (EIA = 0.79 x LC/MS + 14.03, r = 0.877, p < 10(-8)) was obtained between EIA and liquid chromatography/mass spectrometry (LC/MS) quantitation when analyzing urine samples of rats with different oxidative status, due to treatment with either BrCCl(3) or trinitrobenzene sulfonic acid, which are known to induce hepatic lipid peroxidation or colon inflammation, respectively.

Acetylcysteine↗
PubMedDate not supplied

Chemoprevention of aerodigestive cancer.

Effective chemoprevention of aerodigestive tumors could have far-reaching effects. Aerodigestive cancer accounts for one-third of all cancer deaths in the United States and is the most common cancer in some areas of the world. Prognosis is poor, and a reduced quality of life remains in those who do survive. To date, there have been no effective chemopreventive agents, but many new compounds hold promise. The concepts of field carcinogenesis and multi step carcinogenesis underpin the development of chemopreventive agents for aerodigestive tract tumors. Important risk factors are tobacco use, alcohol consumption, dietary habits, genetic susceptibility, socioeconomic status, and the interaction of these. Two promising areas for surrogate biomarker development are tissue autofluorescence and DNA repair. Numerous chemoprevention trials have shown that antioxidant compounds are effective in reversing precursor lesions. Studies of the effects of chemopreventive agents on second primary tumors are ongoing. Finally, large-scale trials of the anti-oxidant beta carotene have been disappointing; they have shown that among heavy smokers and possibly heavy alcohol consumers beta carotene increases risk for lung cancer incidence and mortality. These findings underline the critical need to better understand specific mechanisms of action at a particular tissue site, and under various conditions, such as heavy smoking. Novel agents are under development: epigallacatchin gallate, or green tea, curcumin, and a new emphasis on folic acid. Studies to date show that targeting susceptible subgroups, by means of genetic or lifestyle factors, and all ethnic groups will facilitate the goals of chemoprevention studies.

Anticarcinogenic Agents↗
PubMed2006

Data analysis of alternative splicing microarrays.

The importance of alternative splicing in drug and biomarker discovery is best understood through several example genes. For most genes, the identification, detection and particularly quantification of isoforms in different tissues and conditions remain to be carried out. As a result, the focus in drug and biomarker development is increasingly on high-throughput studies of alternative splicing. Initial strategies for the parallel analysis of alternative splicing by microarrays have been recently published. The design specificities and goals of alternative splicing microarrays, in terms of identification and quantification of multiple mRNAs from one gene, are promoting the development of novel methods of analysis.

Algorithms↗
PubMed2005

Identifying novel endpoints for cystic fibrosis clinical trials.

Clinical and translational research in cystic fibrosis (CF) is hampered by a lack of biomarkers that can be used to identify promising new therapies. In particular, validated protein biomarkers are needed to evaluate emerging candidate anti-inflammatory and antimicrobial treatments. Noninvasively obtained biomarkers are especially desirable in children where repeatedly sampling the airway is difficult. To more quickly identify and validate candidate protein biomarkers, it will be essential to pursue a phased approach to biomarker development in a large, well-characterized CF patient population. New high-throughput technologies that can simultaneously examine the expression of thousands of genes and proteins are accelerating the discovery of potential biomarkers. It is hoped that individual biomarkers, or more likely a panel of validated markers, will predict clinical outcomes such as susceptibility to rapid disease progression or response to treatment and therefore, greatly improve stratification for future CF clinical trials.

Anti-Inflammatory Agents↗
PubMed1995

Biomarkers for Great Lakes priority contaminants: halogenated aromatic hydrocarbons.

One of the major goals of the Great Lakes Action Plan is to actively accumulate and assess toxicological information on persistent toxic substances found in the Great Lakes basin. As part of Health Canada's commitment to this plan, a review of biomarkers for the environmental contaminants polychlorinated biphenyls (PCBs) and polychlorinated dibenzodioxins/dibenzofurans (PCDDs/PCDFs) was conducted. In general, while food consumption was identified as the major source of human exposure to both contaminant groups, certain commodities, such as fish, milk and dairy products, and meat, were found to predominate. Due to the ubiquitous nature of these environmental contaminants and their propensity to bioaccumulate, all humans will have detectable body burdens, which in certain cases can be positively associated with the consumption of particular foods (i.e., PCBs and freshwater fish from the Great Lakes). When dealing with environmental exposure only, relating specific effect biomarkers to contaminant exposure or tissue levels was difficult, due in part to the complex nature of the exposure and the nonspecific nature of the effect. For PCBs, the most likely biomarkers of effect included some form of alteration in lipid metabolism (serum triglyceride/cholesterol levels) and elevation of hepatic-related enzymes, aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT). Cross-species extrapolation also indicates the potential for neurotoxicologic effects to occur in humans. For PCDDs/PCDFs, dermatologic lesions (chloracne) and indications of hepatic enzyme induction have been documented, but primarily due to occupational or high acute accidental exposures. Recent evidence suggests that neonates may represent a potential at-risk population due to relatively high exposure to PCDDs/PCDFs, as with PCBs, during breast feeding as compared to standard adult dietary intake. Future areas of potential benefit for biomarker development include immunologic and endocrine effects, primarily based on biologic plausibility from experimental animal research.

Adipose Tissue↗
PubMed1999

Guppy sexual behavior as an effect biomarker of estrogen mimics.

There is widespread concern that some environmental chemicals can reduce the reproductive capability of humans and wildlife by mimicking natural estrogens and disrupting endocrine function. This potential threat to animal populations posed by xenoestrogens has, hardly surprisingly, been met by an intensive global effort to identify and develop biomarkers suitable for screening chemicals for estrogen mimicking capacity. Despite this effort, there are few biomarkers capable of linking exposure to xenoestrogens to impaired reproductive capability. The reproductive success of most animals depends strongly on the ability to perform the appropriate sexual behavior. The sexual display of the male guppy is strongly linked to reproductive success and is readily quantified under laboratory conditions. This preliminary study demonstrates that exposure of adult male guppies to water weakly contaminated with either natural estrogen (17beta-estradiol) or the xenoestrogen (4-tert-octylphenol) causes a dramatic decrease in the rate and intensity of sexual display. It is concluded that quantitative analysis of the sexual display of male guppies holds great promise as a biomarker at the organismal level for the effects of estrogen mimicking xenobiotics.

Animals↗
PubMedDate not supplied

Early markers of nephrotoxicity: detection of children at risk from environmental pollution.

The current investigation is the largest to date concerned with the assessment of the value of different urinary biomarkers to detect nephrotoxic effects in children exposed to cadmium and lead. A battery of tests which had proved valuable in previous studies on men and women where used, together with a number of more recently developed biomarkers. No significant effect of sex and age were found but the location of the children (site) was important. The results indicated that there might have been variability in either the assay procedures or sample handling between the different sites. A small group of tests were found to be elevated following toxic exposure and should be used in future studies. However, there was considerable variation in the degree of exposure amongst the control groups from different countries and in the test groups. This made pooling of the data difficult but the study does highlight the way forward and demonstrates that children can be at risk from environmental exposure to toxins at a lower level than is acceptable for adults.

Adolescent↗
PubMed2004

Proteomics in renal transplantation: opportunities and challenges.

Proteomics is a fast growing scientific field that has been developed during the past 10 years. The central goals are to define the protein composition of complex biological samples, to explore alterations in protein expression related to various processes/diseases and to study functional aspects of protein-protein interactions. To date, proteomic studies are rare in renal transplantation; however, they may enhance our understanding of transplant pathophysiology and help to identify biomarkers and novel targets for rational drug therapies. The purpose of this review is to describe the possibilities and limitations of differential expression proteomic technologies with a focus on biomarker development for non-invasive renal allograft monitoring.

Biomarkers↗
PubMed2003

Sample size for biomarker studies: more subjects or more measurements per subject?

PURPOSE: In molecular epidemiologic studies, optimizing the use of available biological specimens while minimizing the cost is always a challenge. This is particularly true in pilot studies, which often have limited funding and involve small numbers of biological samples too small for assessment of recently developed biomarkers. METHODS: In this study we examined several statistical approaches for determining how many experimental subjects to use in a biomarker study and how many repeated measurements to make on each sample, given specific funding considerations and the correlated nature of the repeated measurements. RESULTS: A molecular epidemiology study of DNA repair and aging in basal cell carcinoma was used to illustrate the application of the statistical methods proposed. CONCLUSIONS: Our methods extend traditional designs on biomarker studies with repeated measurements to including funding constraints.

Adult↗
PubMed2006

Nanoparticles: potential biomarker harvesters.

A previously untapped bank of information resides within the low molecular weight proteomic fraction of blood. Intensive efforts are underway to harness this information so that it can be used for early diagnosis of diseases such as cancer. The physicochemical malleability and high surface areas of nanoparticle surfaces make them ideal candidates for developing biomarker harvesting platforms. Given the variety of engineering strategies afforded through nanoparticle technologies, a significant goal is to tailor nanoparticle surfaces to selectively bind a subset of biomarkers, sequestering them for later study using high sensitivity proteomic tests. To date, applications of nanoparticles have largely focused on imaging systems and drug delivery vectors. As such, biomarker harvesting is an underutilized application of nanoparticle technology and is an area of nanotechnology research that will likely undergo substantial growth.

Biomarkers↗