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PubMed2004

Profiling of rat plasma by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry, a novel tool for biomarker discovery in nutrition research.

The recent development of high-throughput proteomic technologies has given us new methods to analyze how an organism responds to changes in its nutritional environment. The analysis of plasma samples by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was investigated as a novel approach to the identification of new biomarkers of nutrient status. Pre-fractionation of rat plasma by anion-exchange chromatography in 96-well filter plates markedly increased the total number of unique peptides and proteins that could be observed in SELDI-TOF mass spectra. Replicate fractionations generated nearly identical pH fractions, not only in terms of peptide and protein composition but also in respect to the ion signal intensity of replicate SELDI-TOF mass spectra. The feasibility of this approach was tested with samples from retinol-sufficient and retinol-deficient rats. The comparative analysis revealed reduced levels of three proteins with molecular masses between 10,000 and 20,000 in plasma of retinol-deficient rats. These results demonstrate that plasma profiling by anion-exchange fractionation and SELDI-TOF-MS may be a promising surveillance tool to detect changes in nutritional status and whole body physiology.

Animals↗
PubMed2006

Multilevel evaluation of nonylphenol toxicity in fourth-instar larvae of Chironomus riparius (Diptera, Chironomidae).

The multilevel biomarker approach, wherein different biological responses ranging from molecular to physiological are evaluated, is essential to determine the general health status of an organism in pollutant biomonitoring programs. Furthermore, it permits extrapolation of the relationship between responses at different levels of biological organization. The aim of this study was to develop, under laboratory conditions, a multilevel biomarker approach for evaluating the toxicological response of nonylphenol (NP) in Chironoms riparius. To investigate the effect of NP on C. riparius, an acute toxicity test was performed measuring 24-h median lethal concentration. Responses on molecular, biochemical, and physiological levels were subsequently investigated on sublethal exposure. To assess molecular-level effects, we investigated DNA damage and the expression of heat shock protein 70 (HSP70) gene, whereas biochemical-level responses were determined by investigation of various enzymes activities. Growth and development were investigated as physiological-level responses. The biomarkers found to be most sensitive to NP treatment were HSP70 gene expression and DNA strand break. After having been studied with lower concentration levels with longer exposure period, these biomarkers could be considered early warning signs of exposure to low concentrations of chemical exposure. Statistically significant correlations were observed between DNA damage and the development descriptor; however, a mechanistic study appears to be necessary to establish causal relationships. This approach could be applied in environmental biomonitoring programs, and the data obtained from this study should constitute an important contribution to knowledge of the toxicology of NP in C. riparius, about which little data is available.

Animals↗
PubMed2007

Small is useful in endocrine disrupter assessment--four key recommendations for aquatic invertebrate research.

As we enter the 21st "biocentury", with issues such as biodiversity and biotechnology growing in public profile, it is important to reflect on the immense ecological, medical and economic importance of invertebrates. Efforts to understand the diverse biology of invertebrates come from many directions, including Nobel Prize winning developmental biology, research to control insects that threaten human health and food supplies, aquaculture opportunities and also within ecotoxicology. In the latter context, this special journal volume highlights the importance of addressing endocrine disruption in aquatic invertebrates, from molecular and cellular biomarkers to population-relevant adverse effects. The contributors to this special volume have provided an excellent assessment of both the fundamental endocrinology and applied ecotoxicology of many aquatic invertebrate groups. On the premise that reproductive success is ultimately the vital population parameter, this chapter gives a personal view of key gaps in knowledge in invertebrate reproductive and developmental endocrinology and ecotoxicology. Based on current knowledge, there are four key issues that need to be prioritised within aquatic ecotoxicology: (1) a wider assessment of the reproductive status of invertebrates in both freshwater and coastal ecosystems; (2) prioritisation of laboratory studies in OECD and other regulatory test organisms, including basic endocrinology and ADME (absorption, distribution, metabolism and excretion) research; (3) development and validation of mechanistic biomarkers that can be used as "signposts" to help prioritise species and chronic test endpoint selection, and help link data from laboratory and field studies; and (4) develop a comparative invertebrate toxicology database utilising the prioritised reference chemicals from the EDIETA workshop, encompassing the diverse modes-of-action pertinent to endocrine disrupter testing in both aquatic arthropod and non-arthropod invertebrates.

Animals↗
PubMed1992

Molecular dosimetry of urinary aflatoxin-DNA adducts in people living in Guangxi Autonomous Region, People's Republic of China.

Hepatocellular carcinoma is one of the five leading human cancers causing at least 250,000 deaths each year. One of the major risk factors for this disease is exposure to dietary aflatoxins, and the development of appropriate molecular dosimetry biomarkers would facilitate the identification of individuals at risk. This study was undertaken to explore the relationship between dietary intake of aflatoxins and the excretion of the major aflatoxin-DNA adduct and other metabolites into the urine of chronically exposed people. The following protocol was developed for this investigation in Guangxi Autonomous Region, People's Republic of China, where the diets of 30 males and 12 females (ages, 25-64 years) were monitored for 1 week and aflatoxin intake levels determined each day. Starting on the fourth day, total urine volumes were obtained in consecutive 12-h fractions for 3 or 4 days. High performance liquid chromatography and competitive radioimmunoassay analyses were done on each of the urine samples, and the relationships between excretion of total aflatoxin metabolites, aflatoxin-N7-guanine, aflatoxin M1, aflatoxin P1, and aflatoxin B1, and aflatoxin B1 intake values were determined. The average intake of aflatoxin B1 by men was 48.4 micrograms/day, giving a total mean exposure during the study period of 276.8 micrograms. The average daily intake by women was 77.4 micrograms/day, resulting in a total average exposure during the 7-day period of 542.6 micrograms aflatoxin B1. Initial efforts to characterize aflatoxin metabolites in urine samples were with an analysis by competitive radioimmunoassay. The analysis by linear regression of the association between aflatoxin B1 intake/day and total aflatoxin metabolite excretion/day showed a correlation coefficient of only 0.26. These findings stimulated the immunoaffinity/analytical high performance liquid chromatography analysis for individual metabolites. When the data were analyzed by linear regression analysis, the aflatoxin N7-guanine excretion and aflatoxin B1 intake from the previous day showed a correlation coefficient of 0.65 and P less than 0.000001. Similar analysis for aflatoxin M1 resulted in a correlation coefficient of 0.55 and P less than 0.00001, whereas there was no positive statistical association between exposure in the diet and aflatoxin P1 excretion, despite aflatoxin P1 being quantitatively a major metabolite. Analysis of the total aflatoxin-N7-guanine excretion in the urine during the complete collection period plotted against the total aflatoxin B1 exposure in the diet for each of the individuals, smoothing the day to day variations, revealed a correlation coefficient of 0.80 and P less than 0.0000001.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2006

Biomarkers for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease. ALS is a fatal neurodegenerative disease and clinical diagnosis typically takes many months to complete. Early disease diagnosis through the use of biomarkers may aid in correct clinical management of patients and possibly delay time to ventilator and morbidity. This review explores the progress of biomarker discovery efforts for ALS and the many challenges that remain. Included are different technologies utilized in biomarker discovery efforts (proteomic, genomic and metabolomic) and putative biomarkers uncovered using these techniques. These studies have discovered genetic mutations leading to familial forms of ALS, and specific protein alterations that occur in biological fluids (cerebrospinal fluid and blood) and/or tissues of ALS subjects. More recent high-throughput technologies have revealed panels of proteomic or metabolic biomarkers that can discriminate between ALS and control groups. The identification of disease-specific biomarkers will provide opportunities to develop early diagnostic measures as well as surrogate markers to monitor disease progression and test drug efficacy in clinical trials.

Algorithms↗
PubMed2005

Biomarker discovery, disease classification, and similarity query processing on high-throughput MS/MS data of inborn errors of metabolism.

In newborn errors of metabolism, biomarkers are urgently needed for disease screening, diagnosis, and monitoring of therapeutic interventions. This article describes a 2-step approach to discover metabolic markers, which involves (1) the identification of marker candidates and (2) the prioritization of them based on expert knowledge of disease metabolism. For step 1, the authors developed a new algorithm, the biomarker identifier (BMI), to identify markers from quantified diseased versus normal tandem mass spectrometry data sets. BMI produces a ranked list of marker candidates and discards irrelevant metabolites based on a quality measure, taking into account the discriminatory performance, discriminatory space, and variance of metabolites' concentrations at the state of disease. To determine the ability of identified markers to classify subjects, the authors compared the discriminatory performance of several machine-learning paradigms and described a retrieval technique that searches and classifies abnormal metabolic profiles from a screening database. Seven inborn errors of metabolism-- phenylketonuria (PKU), glutaric acidemia type I (GA-I), 3-methylcrotonylglycinemia deficiency (3-MCCD), methylmalonic acidemia (MMA), propionic acidemia (PA), medium-chain acylCoAdehydrogenase deficiency (MCADD), and 3-OH long-chain acyl CoA dehydrogenase deficiency (LCHADD)-were investigated. All primarily prioritized marker candidates could be confirmed by literature. Some novel secondary candidates were identified (i.e., C16:1 and C4DC for PKU, C4DC for GA-I, and C18:1 forMCADD), which require further validation to confirm their biochemical role during health and disease.

Acyl-CoA Dehydrogenase↗
PubMed1992

Intermediate biomarkers of increased risk for colorectal cancer: comparison of different methods of analysis and modifications by chemopreventive interventions.

Intermediate biomarkers of abnormal cell growth and development have recently been used in chemoprevention trials in attempts to identify the efficacy of chemopreventive agents in human subjects. Measurements carried out include those related to cell proliferation, differentiation, and gene structure and expression in the colon. Among modified patterns of cell proliferation identified by microautoradiographic or immunoperoxidase assays, a characteristic expansion in the size of the proliferative compartment has been observed in normal-appearing colorectal mucosa of human subjects with disease increasing cancer risk; the same patterns have been induced by chemical carcinogens in rodents. Moreover, this intermediate biomarker has been modulated by chemopreventive agents in both rodents and humans. Newer intermediate biomarkers being studied for application to human chemopreventive programs include normal and abnormal patterns of expression of mucins, intermediate filaments and cytoskeletal proteins, and the structure and expression of a variety of genes associated with normal and abnormal cell development. The application of these various intermediate biomarkers to chemoprevention studies is increasing the ability of investigators to analyze the effects of novel chemopreventive agents in the colon and in other organs.

Anticarcinogenic Agents↗
PubMed2000

Human granulocyte CD11b expression as a pharmacodynamic biomarker of inflammation.

A method has been developed for the direct quantification of the CD11b integrin on granulocytes by flow cytometric analysis of whole blood specimens following either LTB(4) or lipopolysaccharide (LPS) stimulation. This method has utility in evaluating the pharmacodynamic action of either LTB(4) receptor antagonists or immune cell modulators in effecting CD11b integrin expression and granulocyte activation in human subjects administered such drugs. Previous studies using CD11b as a biomarker of granulocyte activation have faltered because of the difficulty in controlling the activation state of the granulocyte following removal of blood from subjects. The present study has made use of a newly validated method using either LTB(4) or LPS to stimulate CD11b expression on granulocytes and has been used, as one measure, in the evaluation of LPS activity when administered to normal human volunteers.

Acrylates↗
PubMed2001

Nonimaging detectors in drug development and approval.

Regulatory applications for imaging biomarkers will expand in proportion to the validation of specific parameters as they apply to individual questions in the management of disease. This validation is likely to be applicable only to a particular class of drug or a single mechanism of action. Awareness among the world's regulatory authorities of the potential for these emerging technologies is high, but so is the cost to the sponsor (including the logistics of including images in a dossier), and therefore the pharmaceutical industry must evaluate carefully the potential benefit of each technology for its drug development programs, just as the authorities must consider carefully the extent to which the method is valid for the use to which the applicant has put it. For well-characterized tracer systems, it may be possible to design inexpensive cameras that make rapid assessments.

Anesthetics↗
PubMed2000

Why and how should we measure oxidative DNA damage in nutritional studies? How far have we come?

Free radicals and other reactive species are constantly generated in vivo and cause oxidative damage to DNA at a rate that is probably a significant contributor to the age-related development of cancer. Agents that decrease oxidative DNA damage should thus decrease the risk of cancer development. That is, oxidative DNA damage is a "biomarker" for identifying persons at risk (for dietary or genetic reasons, or both) of developing cancer and for suggesting how the diets of these persons could be modified to decrease that risk. This biomarker concept presupposes that we can measure oxidative damage accurately in DNA from relevant tissues. Little information is available on whether oxidative DNA damage in blood cells mirrors such damage in tissues at risk of cancer development. Measurement of 8-hydroxylated guanine (eg, as 8-hydroxy-2'-deoxyguanosine; 8OHdG) is the commonest method of assessing DNA damage, but there is no consensus on what the true levels are in human DNA. If the lowest levels reported are correct, 8OHdG may be only a minor product of oxidative DNA damage. Indeed, 8OHdG may be difficult to measure because of the ease with which it is formed artifactually during isolation, hydrolysis, and analysis of DNA. Mass spectrometry can accurately measure a wide spectrum of DNA base damage products, but the development of liquid chromatography-mass spectrometry techniques and improved DNA hydrolysis procedures is urgently required. The available evidence suggests that in Western populations, intake of certain fruit and vegetables can decrease oxidative DNA damage, whereas ascorbate, vitamin E, and beta-carotene cannot.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Cholesterol, linoleic acid or/and tyrosine yield different spectra of products when oxidized alone or in a mixture: studies in various oxidative systems.

Identification of reliable biomarkers for oxidative stress for the prediction of the early development of pathological conditions is essential. The detection of biomarkers for oxidative stress such as degradation products of polyunsaturated fatty acid (PUFA), oxysterols, and oxidized proteins, as indicators of oxidative stress are in use, but suffers from insufficient specificity, accuracy and reliability. The overall aim of the present study was to develop new markers which will not only provide information about the presence and level of oxidative stress in biological systems but also on the type of reactive oxygen species (ROS) involved and their metabolic consequences. In the first stage of the study, we compared the level and type of oxidized products formed when different ROS were applied onto three major biomolecules, i.e. cholesterol, linoleic acid (LH) and tyrosine, representing sterols, PUFA and protein, when each compounds was exposed alone or in a mixture to the ROS [copper ions, 2,2-azobis(2-amidinopropane) dihydrochloride (AAPH) and hypochlorous acid (HOCl)]. It was found that different types of oxidants resulted in the formation of different types of oxidation products. Furthermore, oxidation pattern differs when the substrates (cholesterol, PUFA or amino acid) were present alone or in a mixture. As biological systems such as lipoproteins and cell membranes are composed of the above studied molecules, the need for simultaneous detection of the major oxidized products is requires for better characterization of the oxidative stress outcome.

Amidines↗
PubMedDate not supplied

Cloning of a chub metallothionein cDNA and development of competitive RT-PCR of chub metallothionein mRNA as a potential biomarker of heavy metal exposure.

Metallothionein has been assayed in a range of aquatic animal tissues as an indicator of metal exposure. We sequenced chub (Leuciscus cephalus) metallothionein cDNA which showed over 90% homology to common carp, goldfish and stone loach and 77% homology to rainbow trout sequences for metallothionein. We then used the extended primer method to develop an accurate quantitative competitive RT-PCR assay for metallothionein mRNA. RT-PCR was used to measure metallothionein mRNA in feral chub from a range of field sites, with different levels of heavy metal pollution, in the West Midlands, UK. Measurements were complemented by analysis of liver and gill metallothionein protein by capillary electrophoresis. There was no significant difference in the metallothionein protein levels between fish of different rivers and there was no evidence of elevation of mRNA at the sites of highest metal exposure. The level of metal exposure (e.g. zinc, nickel and cadmium each ranging between 15 and 28 microg/l ) at the pH (7.5-8.5) of these rivers appears insufficient to elevate hepatic or gill metallothionein in chub. A lack of elevation of hepatic metallothionein mRNA in chub exposed to zinc, copper and manganese for 24 h and 10 days in the laboratory also suggests a non-responsiveness of this species.

Amino Acid Sequence↗
PubMed2006

Regularized binormal ROC method in disease classification using microarray data.

BACKGROUND: An important application of microarrays is to discover genomic biomarkers, among tens of thousands of genes assayed, for disease diagnosis and prognosis. Thus it is of interest to develop efficient statistical methods that can simultaneously identify important biomarkers from such high-throughput genomic data and construct appropriate classification rules. It is also of interest to develop methods for evaluation of classification performance and ranking of identified biomarkers. RESULTS: The ROC (receiver operating characteristic) technique has been widely used in disease classification with low dimensional biomarkers. Compared with the empirical ROC approach, the binormal ROC is computationally more affordable and robust in small sample size cases. We propose using the binormal AUC (area under the ROC curve) as the objective function for two-sample classification, and the scaled threshold gradient directed regularization method for regularized estimation and biomarker selection. Tuning parameter selection is based on V-fold cross validation. We develop Monte Carlo based methods for evaluating the stability of individual biomarkers and overall prediction performance. Extensive simulation studies show that the proposed approach can generate parsimonious models with excellent classification and prediction performance, under most simulated scenarios including model mis-specification. Application of the method to two cancer studies shows that the identified genes are reasonably stable with satisfactory prediction performance and biologically sound implications. The overall classification performance is satisfactory, with small classification errors and large AUCs. CONCLUSION: In comparison to existing methods, the proposed approach is computationally more affordable without losing the optimality possessed by the standard ROC method.

Biomarkers, Tumor↗
PubMed2004

Discovery of protein biomarkers for renal diseases.

Animal models and human studies have been useful in dissecting the molecular mechanisms of renal disease and finding new disease targets; however, translation of these findings to new clinical therapeutics remains challenging. Difficulties with detecting early disease, measuring drug effectiveness, and the daunting cost of clinical trials hampers the development of new therapeutics for renal diseases. Many existing laboratory tests were discovered because of inspired recognition that a particular protein might prove useful in clinical practice. New unbiased genomic and proteomic techniques identify many constituents present in biologic samples and thus may greatly accelerate biomarker research. This review focuses on the steps needed to develop new biomarkers that are useful in laboratory and clinical investigations, with particular focus on new proteomic screening technologies. New biomarkers will speed the laboratory and clinical development of new treatments for renal diseases through mechanistic insights, diagnoses that are more refined, early detection, and enhanced proof of concept testing.

Biomarkers↗
PubMed2003

Genetic defenses against noncholesterol sterols.

PURPOSE OF REVIEW This review discusses recent progress in the role of ATP-binding cassette proteins ABCG5 and G8 in dietary sterol absorption, excretion and pathogenesis of cardiovascular disease. RECENT FINDINGS Identification of the genetic defect(s) underlying sitosterolemia has led to a renewed interest in the mechanisms of sterol absorption and biliary excretion. Mutations in ABCG5 (encoding sterolin-1) or ABCG8 (encoding sterolin-2) cause this disease. These proteins are thought to function by preventing dietary noncholesterol sterols from being retained by the body and for cholesterol excretion into bile. SUMMARY Despite improvements in treatments for hypercholesterolemia with cholesterol lowering agents, cardiovascular disease still remains highly prevalent. This has prompted many to consider that molecules other than cholesterol may be better biomarkers for this disease and targeting these more directly may allow us to develop more effective therapies. Ideally, if such a biomarker were also the bioactive molecule that is key to initiating/propagating the atherosclerosis pathogenic pathway, this would allow us to develop an optimal predictor and monitor of the disease process. One source of such molecules could come from our diet, with potential candidates such as noncholesterol sterols, oxysterols, oxidized sterols or some as yet unidentified dietary bioactive molecule. Nature has evolved a protective mechanism by which such molecules are kept out of the body, thereby reducing the negative effects of these compounds. The newly identified sterolin proteins involved in the absorption and excretion of dietary sterols may fit this bill. If so, we would speculate that a better biomarker may be lurking within their substrate specificities.

ATP-Binding Cassette Transporters↗
PubMed1994

Prevalence of aneuploidy, overexpressed ER, and overexpressed EGFR in random breast aspirates of women at high and low risk for breast cancer.

Breast tissue biomarkers which accurately predict breast cancer development within a 10 year period in high risk women are needed but currently not available. We initiated this study to determine 1) the prevalence of one or more breast tissue abnormalities in a group of women at high risk for breast cancer, and 2) if the prevalence of biomarker abnormalities is greater in high risk than in low risk women. Eligible high risk women were those with a first degree relative with breast cancer, prior breast cancer, or precancerous mastopathy. Low risk women were those without these or other major identifiable risk factors. Ductal cells were obtained via random fine needle aspirations and cytologically classified. Biomarkers included DNA ploidy, estrogen receptor (ER), and epidermal growth factor receptor (EGFR). The prevalence of DNA aneuploidy was 30%, overexpression of ER 10%, and overexpression of EGFR 35%, in the 206 high risk women whose median 10 year Gail risk (projected probability) of developing breast cancer was 4.5%. The prevalence of aneuploidy and overexpressed EGFR was significantly higher in the high risk women than in the 25 low risk controls (p < 0.002), whose median 10 year Gail risk was 0.7%. The difference in the prevalence of ER overexpression between high and low risk groups was not statistically significant (p = 0.095). This may be due to the low prevalence of overexpressed ER and the small number of controls. A significant difference was noted in the prevalence of one or more abnormal biomarkers between the high risk and low risk women (p < 0.001). A large prospective trial is needed to determine if one or more of these biomarkers, is predictive of breast cancer development.

Adult↗
PubMed1992

Intermediate biomarkers of precancer and their application in chemoprevention.

The Chemoprevention Branch of the National Cancer Institute has established a program for the development of safe and effective cancer chemopreventive agents. This program includes identification of new agents, testing for efficacy in vitro and in animals, studies in animals to model clinical use, and preclinical toxicity and metabolism evaluation. Ultimately, the most promising agents progress to clinical trials. The long period required for cancer onset presents a significant challenge to the design of clinical trials for chemoprevention. Phase III trials in which cancer reduction is the endpoint require large subject groups (tens of thousands) and follow-up duration of more than five years. Because of these requirements, the cost of such trials are high. The Chemoprevention Branch is addressing this challenge by expansion of the preclinical and Phase II clinical efficacy efforts to include intermediate biomarkers of carcinogenesis as study endpoints. The Chemoprevention Branch's studies focus on the development of biomarkers with high reliability and predictive value for cancer. Both single markers and batteries of complementary and parallel markers are evaluated. Among the criteria for biomarkers for chemoprevention studies are the following: (1) differential expression in normal and high risk tissue, (2) appearance early in carcinogenesis (the earlier a reliable biomarker appears, the greater is the chance for successful intervention with a chemopreventive agent), (3) high sensitivity, specificity, and accuracy relative to cancer, (4) ease of measurement (use of non-invasive techniques and small tissue samples is preferable), (5) demonstration of modulation by chemopreventive agents, and (6) correlation of modulation with decreased cancer incidence.

Anticarcinogenic Agents↗
PubMed2003

Placental lead and outcome of pregnancy.

Prenatal exposure to lead produces toxic effects in the human fetus, including an increased risk of preterm delivery, low birth weight and impaired mental development. Since we believe that placental lead could be a good biomarker for fetal exposure, we assessed the relation of placental lead to intrauterine fetal growth and some adverse outcomes of pregnancy. Low concentrations of lead were found in the population studied (N, 89; mean, 113.4 ng/g dry tissue; S.D., 58.0). The cases were divided into two groups based on delivery outcome. In the group of placentas from premature rupture of membranes and preterm labor (gestational age <or=37 weeks), higher lead levels were recorded than in the placentas from term pregnancies. The proportion of abnormal pregnancy outcome in the group of placentas with lead concentrations above 120 ng/g was 40.6 versus 8.8% in placentas below this concentration. Higher placental lead levels, in general, were not related to smaller weight, head and abdominal circumference or shorter length at birth.

Adult↗