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At least 793 records · Page 44Linked to original sources
PubMed2003

Considerations on development, validation, application, and quality control of immuno(metric) biomarker assays in clinical cancer research: an EORTC-NCI working group report.

A major dilemma associated with immuno(metric) assays for biomarkers is that various kits employing antibodies with differing specificities and binding affinities may generate non-equivalent test results. Also, variation in sample processing and the use of different standards (reference material) may result in discordant test results. Therefore, assays and procedures should be standardized and the quality of biomarker assay results should be monitored by continuous between-laboratory proficiency testing of performance. External quality control requires an established network of expert laboratories in which the investigators interact freely and where technical issues are discussed. Although such networking is more often praised than practiced, we strongly endorse and advocate between-laboratory exchange of experience and information. The present study discusses analytical aspects of immuno(metric) biomarker assays and presents recommendations of the Receptor and Biomarker Group of the EORTC (European Organisation for Research and Treatment of Cancer) how such tests should be validated for first time and day to day use. Moreover, a model for an appropriate quality assurance program is presented.

Biomarkers, Tumor↗
PubMed2004

Detection of invasive colon cancer using a novel, targeted, library-derived fluorescent peptide.

Sensitive methods to detect the earliest forms of colorectal cancers remain a challenge despite the development of serum and stool biomarkers. We reasoned that fluorescent affinity ligands derived from library screens can be developed to improve the detection and localization of early malignant lesions by endoscopy. We have developed an imaging agent for real-time endoscopic tumor detection in a murine model using a previously identified phage library-derived colon cancer-specific cyclic peptide and fluorescent moieties. The modified peptide had a 24 minute blood half life and tumoral accumulation was 6.9% of injected dose/g, approximately 7-fold higher than a scrambled control peptide. Orthotopic colonic tumors (HT29) were readily detectable by fluorescence endoscopy even when tumors were submucosal. These results show proof-of-principle that disease-specific library-derived fluorescent probes can be rapidly developed for use in the early detection of cancers by optical means.

Adenoma↗
PubMed2006

Measures of oxidative stress.

Development of in vivo markers of oxidative stress that are sensitive, specific, reliable, and accurate in reflecting underlying atherosclerotic disease states and prediction of cardiovascular risk and clinical events will be invaluable in the future in clinical medicine. Oxidized low-density lipoprotein (OxLDL) and isoprostanes are emerging plasma biomarkers that hold promise for cardiovascular risk prediction. This article describes the pathophysiology of OxLDL and isoprostanes as potential biomarkers, the rationale behind development of methods to measure OxLDL and isoprostanes, and a detailed description of current methodologies, including advantages and disadvantages of available assays. Clinical investigations consisting of epidemiological, case-control, and prospective studies are reviewed to elucidate the role of these biomarkers in reflecting pathophysiology and risk prediction.

Animals↗
PubMed2005

Biomonitoring of inhaled complex mixtures--ambient air, diesel exhaust and cigarette smoke.

Human biomonitoring comprises the determination of biomarkers in body-fluids, cells and tissues. Biomarkers are generally assigned to one of three classes, namely, biomarkers of exposure, effect or susceptibility. Since biomarkers represent steps in an exposure-disease continuum, their application in epidemiological studies ('molecular epidemiology') shows promise. However, to be a predictor of disease, a biomarker has to be validated. Validation criteria for a biomarker include intrinsic qualities such as specificity, sensitivity, knowledge of background in the population, existence of dose-response relationships, degree of inter- and intra-individual variability, knowledge of the kinetics, confounding and modifying factors. In addition, properties of the sampling and analytical procedures are of relevance, including constraints and non-invasiveness of sampling, stability of sample as well as simplicity, high sensitivity, specificity and speed of the analytical method. It is of particular importance to prove by suitable studies that the biomarker of exposure indicates the actual exposure, the biomarker of effect strongly predicts the actual risk of disease and the biomarker of susceptibility actually modifies the risk. Biomonitoring of the exposure to complex mixtures such as polluted ambient air, diesel exhaust or tobacco smoke is a particular challenge since these exposures have many constituents in common and many people were exposed to more than one of these mixtures. Data on the exposure to polycyclic aromatic hydrocarbons (PAH) and benzene from ambient air, diesel exhaust and tobacco smoke will be presented. In addition, some source-specific biomarkers such as nitro-arenes and nicotine metabolites as well as their application in population groups will be discussed. The second part of the presentation addresses the application of biomarkers for assessing so called 'potentially reduced exposure products' (PREPs). According to a recent report of the Institute of Medicine (USA), "reducing risk of disease by reducing exposure to tobacco toxicants is feasible" and "surrogate biological markers that are associated with tobacco-related diseases could be used to offer guidance as to whether or not PREPs are likely to be risk-reducing." In general, the same validation criteria apply as discussed above. In addition, it is suggested that a panel of biomarkers should be used, representing both smoke phases (gas and particulate phase) and the various chemical classes of smoke constituents (e.g., carbonyls, benzene, PAH, tobacco-specific nitrosamines, aromatic amines). Also, a panel of biomarkers of effect should cover the major known adverse effects of smoking (e.g., oxidative stress, inflammatory processes, lipid peroxidation, lipometabolic disorders, mutagenic effects). Biomarkers of nicotine and carbon monoxide uptake are of interest for evaluating the smoking and inhalation behavior, respectively. Finally, suitable study designs for evaluating PREPs are discussed. It is concluded that suitable biomarkers for assessing the exposure to complex mixtures such as ambient air, diesel exhaust and tobacco smoke as well as for evaluating the exposure-reducing properties of PREPs are already available. Future efforts should focus on the development and validation of biomarkers of effect.

Air↗
PubMed1995

Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acids during fetal development of rats.

PTH-related peptide (PTHrP) is a causative agent of hypercalcemia associated with malignancy. PTHrP binds to and activates the same receptor as does PTH. Because PTHrP has been suggested to regulate the growth and differentiation of cells as a paracrine/autocrine factor, we examined the expression of both PTHrP and its receptor genes during fetal development of rats (15-20 days gestation) by in situ hybridization with riboprobes. Both PTHrP and its receptor messenger RNAs (mRNAs) were expressed not only in the skeleton, but also in many fetal extraskeletal tissues, such as choroid plexus, ears, lungs, tooth buds, heart, and skin. In these extraskeletal tissues PTHrP mRNA was expressed mainly in surface-lining cells, whereas its receptor mRNA was expressed mainly in adjacent mesenchyma cells. In endochondral bones, these two genes were expressed in largely discrete, but mostly neighboring, areas, although the localizations of these two mRNAs changed over developmental stages. The expression patterns of PTHrP and its receptor mRNAs during fetal development suggest PTHrP's roles as a paracrine factor and its involvement in epithelial-mesenchymal(-like) interactions.

Animals↗
PubMed2026

Identifying gene expression signatures for risk stratification of postoperative adjuvant chemotherapy in colorectal cancer.

Clinical risk stratification for postoperative recurrence in patients with pathological stage II (pStage II) colorectal cancer (CRC) is essential for guiding the use of postoperative adjuvant chemotherapy (ACT). In this study, we identified novel prognostic gene expression biomarkers in patients with pStage II CRC and developed a new risk stratification framework for ACT decision-making. First, genome-wide biomarker discovery was conducted to identify prognostic gene expression biomarkers associated with recurrence risk in pStage II CRC. This analysis identified 10 differentially expressed genes as potential biomarkers for recurrence. The efficacy of these biomarkers was then tested using 188 clinical surgical specimens obtained from patients with pStage II CRC. A predictive panel was developed using qRT-PCR and used to assess 93 clinical specimens with an area under the curve (AUC) of 0.82, and its performance was further validated in an independent cohort (n = 95). By incorporating key clinicopathological features, a Gene expression-based Prediction of Recurrence in pStage II CRC (GPRSC) signature was developed, which robustly predicted postoperative recurrence (AUC: 0.80). Finally, combining the GPRSC signature, microsatellite instability status, and conventional criteria, we developed a novel risk stratification system for postoperative ACT decision-making in pStage II CRC. Overall, we identified novel gene expression biomarkers and developed a prognostic signature that informs clinical decision-making regarding postoperative ACT in patients with pStage II CRC.

Humans↗
PubMed2001

Carcinogen biomarkers for lung or oral cancer chemoprevention trials.

The potential applicability of specific carcinogen-derived biomarkers in chemoprevention trials against lung and oral cancer is discussed. At present, there are no examples of the use of these biomarkers in chemoprevention trials, but the principle has been established in chemoprevention trials directed at aflatoxin B1-induced liver cancer. Polycyclic aromatic hydrocarbons (PAHs) and tobacco-specific nitrosamines are among the most important carcinogens invoked as causes of lung and oral cancer. Biomarkers that are potentially practical for current application in chemoprevention trials are 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene-DNA adducts, as determined by HPLC with fluorescence detection, nitrosamino acids in urine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides in urine, nicotine metabolites in urine, and metabolites of cytochrome P450 substrates in urine. Biomarkers that need further development or exploration before application in trials include 7-methylguanine in DNA, tobacco-specific nitrosamine-DNA adducts, acrolein/crotonaldehyde-DNA adducts, PAH-protein adducts, acetaldehyde-protein adducts, pyrene metabolites in urine and benzo[a]pyrene metabolites in urine. Such carcinogen derived-biomarkers could be applied in chemoprevention trials to test the hypothesis that chemopreventive agents alter carcinogen metabolic activation and detoxification and, ultimately, risk for cancer.

Anticarcinogenic Agents↗
PubMed2006

Prospective health care: the second transformation of medicine.

Emerging scientific technologies provide rich sources of predictive biomarkers, which could transform health care. Identification of causal biomarkers will enable the development of tools to quantify risk and anticipate disease. Accurate health risk analysis is rapidly becoming feasible, so health care can become rational, preventive and personalized.

Biomarkers↗
PubMed2001

Strategy for identifying biomarkers of aging in long-lived species.

If effective anti-aging interventions are to be identified for human application, then the development of reliable and valid biomarkers of aging are essential for this progress. Despite the apparent demand for such gerotechnology, biomarker research has become a controversial pursuit. Much of the controversy has emerged from a lack of consensus on terminology and standards for evaluating the reliability and validity of candidate biomarkers. The initiation of longitudinal studies of aging in long-lived non-human primates has provided an opportunity for establishing the reliability and validity of biomarkers of aging potentially suitable for human studies. From the primate study initiated in 1987 at the National Institute on Aging (NIA), the following criteria for defining a biomarker of aging have been offered: (1) significant cross-sectional correlation with age; (2) significant longitudinal change in the same direction as the cross-sectional correlation; (3) significant stability of individual differences over time. These criteria relate to both reliability and validity. However, the process of validating a candidate biomarker requires a greater standard of proof. Ideally, the rate of change in a biomarker of aging should be predictive of lifespan. In short-lived species, such as rodents, populations differing in lifespan can be identified, such as different strains of rodents or groups on different diets, such as those subjected to calorie restriction (CR), which live markedly longer. However, in the NIA primate study, the objective is to demonstrate that CR retards the rate of aging and increases lifespan. In the absence of lifespan data associated with CR in primates, validation of biomarkers of aging must rely on other strategies of proof. With this challenge, we have offered the following strategy: If a candidate biomarker is a valid measure of the rate of aging, then the rate of age-related change in the biomarker should be proportional to differences in lifespan among related species. Thus, for example, the rate of change in a candidate biomarker of aging in chimpanzees should be twice that of humans (60 vs 120 years maximum lifespan); in rhesus monkeys three times that of humans (40 vs 120 years maximum lifespan). The realization of this strategy will be aided by developing a primate aging database, a project that was recently launched in cooperation with the NIA, the National Center for Research Resources, and the University of Wisconsin Regional Primate Research Center.

Aging↗
PubMed2003

Recommendations on use of biomarkers in alcoholism treatment trials.

BACKGROUND: Biochemical markers of heavy drinking are playing increasingly prominent roles in alcohol treatment efficacy studies, especially in those designed to evaluate medications. Among these roles are serving as inclusion or exclusion criteria for research participants, corroboration of self-report of drinking status, assessment of the safety of the agent being evaluated, and determination of treatment outcome. METHODS: Recent alcohol medication development trials that included biomarker information were reviewed and critiqued from the perspectives of how biomarker measures were used and how findings on them were reported. RESULTS: Although generally the application of biomarkers as inclusion criteria is not recommended, they may aid in exclusion of potential subjects (e.g., elevated liver function measures in trials of agents that could result in liver damage). Biomarkers are most commonly used as indicators of outcome, usually serving as secondary outcome variables. The relationship of outcome findings on biomarker and self-report measures is positive, but only moderate. As used to date, biomarkers of drinking tend to be less sensitive than well-standardized and properly administered self-report measures. Nevertheless, they do provide a useful, unique source of information on drinking status. CONCLUSIONS: The contribution of biomarkers to alcoholism clinical research would be enhanced if certain design strategies were incorporated into their application and if critical information were included in the research publication. This article offers a series of recommendations to improve on their use in a research context.

Alcoholism↗
PubMed2004

Treatment and control of human African trypanosomiasis.

PURPOSE OF REVIEW: Access to treatment is a multi-step process and little progress has been made to improve treatments for sleeping sickness over the past 50 years. The current strategy is based on diagnostic tools developed in the 1960s while available drugs are still the same as those developed in the middle of the last century. Strategic opportunities can only be based on two achievements: improved diagnosis and safer drugs. This paper reviews the development of new diagnostic tools and drugs and the opportunity offered by new technologies for their further improvement. RECENT FINDINGS: The prodrug DB289 shows excellent oral activity with low toxicity for the treatment of early-stage sleeping sickness; it has recently entered phase II(b) clinical trials. The recent ability to identify and test specific host and parasite biomarkers has allowed the development of new, more-specific and sensitive, diagnostic and stage-determination tools. The accurate diagnosis of an infection by use of proteomic signature analysis has been achieved. Urinary nitrites and nitrates follow closely the increase of brain nitric oxide associated with the penetration of trypanosomes in the brain. Sleep-onset rapid eye movement-like episodes have been shown to occur at onset of late-stage trypanosomiasis. This unique disturbance of the wake/sleep cycle seems to be the first pathognomonic sign in the occurrence of late-stage trypanosomiasis. SUMMARY: Following the description of the disease, and diagnostic tools and drugs that have been used, and are still in use today, the authors show how it has influenced over time the evolution of strategies for surveillance and control. Recent developments and prospects for new, more-specific and sensitive diagnostic tools and a safer drug will undoubtedly improve the accuracy of patient recruitment and facilitate treatment, and provide ways towards new strategic opportunities.

Animals↗
PubMed2002

Identification and efficacy of longitudinal markers for survival.

Methods for the combined analysis of survival time and longitudinal biomarker data have been developed in recent years, with most emphasis on modelling and estimation. This paper focuses on the use of longitudinal marker trajectories as individual-level surrogates for survival. A score test for association which requires only standard methods for implementation is derived for the initial identification of candidate biomarkers. Methods for assessing efficacy of markers are discussed and a measure contrasting conditional and marginal distributions is proposed. An application using prothrombin index as biomarker for survival of liver cirrhosis patients is included.

Journal Article↗
PubMed2002

Biochemical markers of bone metabolism in relation to adrenocortical and growth suppression during the initiation phase of inhaled steroid therapy.

Growth suppression is usually most evident during the first year of inhaled steroid therapy. Steroid-induced changes in bone metabolism may contribute to this growth suppression. The aim of the present study was to evaluate the changes in biochemical markers of bone metabolism in relation to adrenal and growth suppression during the initiation phase of inhaled steroid therapy. Seventy-five school-aged children with new asthma were enrolled into budesonide (BUD, n = 30), fluticasone propionate (FP, n = 30) or cromone (CROM, n = 15) treatment groups. BUD dose was 800 microg/d during the first two months and 400 microg/d thereafter. The respective FP doses were 500 and 200 microg/d. Biochemical markers of bone metabolism were measured before treatment and after 2 and 4 mo of therapy. In the control (CROM) group, the mean concentrations of serum osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP) (formation markers) and type I collagen carboxyterminal telopeptide (ICTP) (degradation marker) tended to increase. In the BUD group, OC and PICP decreased during the 4 mo by a mean of 23% (p < 0.001) and 15% (p < 0.05), respectively, while ICTP did not change significantly. In the FP group, OC and ICTP decreased during the first 2 mo by a mean of 19% (p < 0.01) and 21% (p < 0.01), respectively, returning to the pretreatment level at 4 mo, while PICP tended to increase during the 4 mo (14%, p = 0.12). In the steroid treated children whose height SD score decreased during the first 12 mo of therapy, both OC and PICP decreased during the first 4 mo by a mean of 20% (p < 0.01) and 21% (p < 0.001), respectively. In those children who had no growth suppression, the changes were not significant: -4% in OC and +13% in PICP. Furthermore, in children who developed evidence of adrenocortical suppression (on the basis of a low-dose ACTH test), OC decreased more (23%, p < 0.01) than in those with normal adrenocortical function (10%, p = 0.06). In conclusion, both inhaled BUD and FP caused dose-dependent effects on biochemical markers of bone metabolism. The children who developed growth or adrenocortical suppression were likely to have changes also in bone metabolism.

Administration, Inhalation↗
PubMed2005

CSF biomarkers for Alzheimer's disease: use in early diagnosis and evaluation of drug treatment.

Early diagnosis of Alzheimer's disease is important in initiating symptomatic treatment with acetylcholine esterase inhibitors, and will be of even greater significance if drugs with a potential to slow down the degenerative process, such as beta-secretase inhibitors and beta-amyloid vaccination, prove to have a clinical effect. During the last decade, research efforts have focused on developing cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease. In this review, the background and principles for, and the diagnostic performance of, the CSF biomarkers total tau, phosphorylated tau and the 42-amino acid form of beta-amyloid, are reviewed. New candidate CSF biomarkers and new strategies, including multiparameter immunoassays and CSF proteomics techniques, in the search of additional CSF biomarkers are also reviewed. Finally, the rationale for the use of CSF biomarkers to identify and monitor the biochemical effect of new drug candidates is reviewed.

Alzheimer Disease↗
PubMed1995

Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development?

Women with antibodies against the enzyme thyroid peroxidase [TPO-Ab; formerly microsomal antibodies (MsAb)] are at particular risk for developing postpartum thyroid dysfunction; the latter is significantly associated with postpartum depression. Although the negative effect of postpartum maternal depression on child development is well documented, the consequences of elevated titers of TPO-Ab during pregnancy and subsequent postpartum thyroid dysfunction on child development are not known. In a prospective study of a cohort of 293 pregnant women, the occurrence of TPO-Ab during gestation, thyroid dysfunction, and depression was investigated. Five years after delivery, child development was assessed in 230 children of the original cohort using the Dutch translation of the McCarthy Scales of Children's Abilities. Children of women with TPO-Ab during late gestation (n = 19, with normal thyroid function) had significantly lower scores (by t test) on the McCarthy Scales of Children's Abilities than antibody-negative women. The difference on the General Cognitive Scale, which reflects IQ scores, was substantial (10.5 points; t = 2.8; P = 0.005). After correction for possibly confounding variables, maternal TPO-Ab during gestation was found to be the most important factor related to the scores on the General Cognitive Scale (odds ratio = 10.5; 95% confidence interval = 3-34; P = 0.003). We conclude that children of pregnant women who had elevated titers of TPO-Ab but normal thyroid function are at risk for impaired development.

Adult↗
PubMed1991

Lymphocyte proliferation assays as potential biomarkers for toxicant exposures.

Recently there has been interest in developing assays that can be used as indicators (biomarkers) of exposure to toxic agents. We have been exploring the potential utility of three lymphocyte proliferation assays [the responses of B lymphocytes to the mitogen lipopolysaccharide (LPS), the responses of T lymphocytes to the mitogen concanavalin A (ConA), and the responses of T lymphocytes to antigenic stimuli in a mixed lymphocyte culture (MLC) assay] as biomarkers of toxicant exposure. Studies were initiated to assess the applicability and specificity of these assays and to investigate the mechanisms by which toxicants alter lymphocyte proliferation. All studies were performed using cells isolated from Fischer 344 rats. To assess applicability, mitogen assays were performed using in vitro exposures to eight different toxicants: hydroquinone, benzoquinone, Aroclor 1254, styrene oxide, and the salts of mercury, cadmium, chromate, and nickel. In vitro concentrations spanned five orders of magnitude (100 to 0.01 mg/l). At the lowest concentration tested, all eight compounds induced changes in at least one mitogen assay, indicating that these assays may be applicable to a wide range of toxicants. Variations of the ConA and MLC assays were used to test for specificity. In both assays, splenocytes taken from rats exposed in vivo to either chromate or to cadmium responded differently when the cells were cocultured with exogenously added chromate or cadmium ions, indicating that it may be possible to detect exposure to a specific toxicant by performing modified lymphocyte proliferation assays. In the mechanistic studies, splenocytes from cadmium and chromate-treated rats altered the ConA-induced proliferation of cocultured syngeneic cells. In addition, the antigenicity of splenocytes isolated from cadmium-treated rats was enhanced when these cells were used as stimulators for allogeneic splenocytes. The results of these studies indicate that lymphocyte proliferation assays may be useful for detecting exposure to a wide range of toxicants and that variations of these assays may be useful for implementing immunologically based tests for detecting exposures to specific chemicals.

Animals↗