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PubMed2002

Toxicity testing using esterase inhibition as a biomarker in three species of the genus Lecane (Rotifera).

We have developed an esterase inhibition test to investigate the effects of 10 toxicants, including six metals (cadmium, chromium, copper, lead, mercuric chloride, and titanium) and four organics (benzene, ethyl acetate, toluene, and vinyl acetate) in three species of the benthic rotifer genus Lecane (L. hamata, L. luna, and L. quadridentata). Metals affect esterase inhibition by an average value of 4,957-fold greater than the four organics tested for the three rotifer species. Most of the EC50 (effect concentration where a 50% reduction in esterase activity is observed) values correspond to environmentally realistic concentrations. Comparisons of acute-to-chronic ratios among these three species showed that in two species, L. luna and L. quadridentata, esterase inhibition is an outstanding biomarker for most of the toxicants tested.

Animals↗
PubMed2005

No evidence of increased serum substance P levels in chronic urticaria patients with and without demonstrable circulating vasoactive factors.

The neuropeptide substance P is a possible candidate as histamine-releasing factor in some patients with chronic ordinary urticaria (COU), particularly in those with evidence of a nonautoantibody circulating histamine-releasing factor. In this study, serum substance P levels were measured by enzyme immunoassay in 117 COU patients, 40 atopic subjects and 24 normal subjects. In vivo and in vitro assays for histamine-releasing factors, autologous serum skin test (ASST) and basophil histamine release (BHR) assay, respectively, were performed in all COU patients. Mean serum substance P concentration was not significantly different in COU patients and in normal subjects; however, significantly higher levels were detected in atopic subjects than in COU patients (P < 0.003). ASST and BHR assays allowed us to distinguish different subsets of COU patients. Mean serum substance P concentration did not vary significantly in the different subsets of patients. Nevertheless, interestingly three patients with positive ASST and negative BHR assay showed very high substance P levels. These results suggest that substance P does not play an important role as histamine-releasing factor in COU in general but only in occasional patients in whom it might act as a trigger of urticarial symptoms.

Adult↗
PubMed2006

2D gel blood serum biomarkers reveal differential clinical proteomics of the neurodegenerative diseases.

This review addresses the challenges of neuroproteomics and recent progress in biomarkers and tests for neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The review will discuss how the application of quantitative 2D gel electrophoresis, combined with appropriate single-variable and multivariate biostatistics, allows for selection of disease-specific serum biomarkers. It will also address how the use of large cohorts of specifically targeted patient blood serum samples and complimentary age-matched controls, in parallel with the use of selected panels of these biomarkers, are being applied to the development of blood tests to specifically address unmet pressing needs in the differential diagnosis of these diseases, and to provide potential avenues for mechanism-based drug targeting and treatment monitoring. While exploring recent findings in this area, the review discusses differences in critical pathways of immune/inflammation and amyloid formation between Parkinson's disease and amyotrophic lateral sclerosis, as well as discernable synergistic relationships between these pathways that are revealed by this approach. The potential for pathway measurement in blood tests for differential diagnosis, disease burden and therapeutic monitoring is also outlined.

Biomarkers↗
PubMed2004

Impact of a negative evaluation for underlying coronary artery disease on one-year resource utilization for patients admitted with potential acute coronary syndromes.

UNLABELLED: Reduction in emergency department (ED) overcrowding is a major Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) initiative. One major source of ED overcrowding is patients waiting for telemetry beds. OBJECTIVE: To determine whether, in patients admitted with a potential acute coronary syndrome, a negative evaluation for underlying coronary artery disease would reduce ED and hospital revisits over the subsequent year compared with patients who did not receive an evaluation for underlying coronary artery disease. METHODS: Nine hundred ninety-nine consecutive patients admitted for potential acute coronary syndromes through the ED during a one-year period were screened for inclusion. Patients who had a negative evaluation for underlying coronary disease were compared with patients who were not evaluated for underlying coronary artery disease for subsequent ED visits, hospital admissions, and cardiac resource utilization over the year following the index visit via a health system-wide computerized record review. Patients with positive tests or biomarkers at the index visit were excluded. Each repeat visit was rated as "potentially cardiac" or "noncardiac." Results of echocardiograms, stress tests, and catheterizations and information about in-hospital deaths were obtained. RESULTS: Six hundred ninety-two patients met the inclusion criteria: 556 patients received no evaluation for underlying coronary artery disease, 116 had a negative stress test, and 20 had a negative cardiac catheterization during the index visit. Patients with no evaluation for underlying coronary artery disease and patients with a negative evaluation had similar likelihoods of a repeat ED visit (negative test 39.0% vs. no test 40.3%; p = 0.85) and repeat hospital admission (28.7% vs. 31.5%; p = 0.61). The rates of a potentially cardiac-related ED visit (21.3 vs. 23.4%; p = 0.65) and hospital admission (17.7% vs. 20.7%; p = 0.48) were not significantly different. The two populations had similar utilization rates of echocardiograms, stress tests, and catheterizations (p > 0.70 for all). CONCLUSIONS: For patients admitted to the authors' institution with a potential acute coronary syndrome, there was no association between a negative evaluation for underlying coronary artery disease and overall or potentially cardiac ED visits, admissions, or cardiac resource test utilization over the year following the index visit.

Cardiac Catheterization↗
PubMed2001

Accuracy of biomarkers to diagnose acute cardiac ischemia in the emergency department: a meta-analysis.

STUDY OBJECTIVE: We sought to evaluate quantitatively the evidence on the diagnostic performance of presentation and serial biochemical markers for emergency department diagnosis of acute cardiac ischemia (ACI), including acute myocardial infarction (AMI) and unstable angina. METHODS: We conducted a systematic review and meta-analysis of the English-language literature published between 1966 and December 1998. We examined the diagnostic performance of creatine kinase, creatine kinase-MB, myoglobin, and troponin I and T testing. Diagnostic performance was assessed by using estimates of test sensitivity and specificity and was summarized by summary receiver-operating characteristic curves. RESULTS: Only 4 studies were found that evaluated all patients with ACI; 73 were found that focused only on a diagnosis of AMI. To diagnose ACI, presentation biomarker tests had sensitivities of 16% to 19% and specificities of 96% to 100%; serial biomarker tests had sensitivities of 31% to 45% and specificities of 95% to 98%. Considering only the diagnosis of AMI, presentation biomarker tests had summary sensitivities of 37% to 49% and summary specificities of 87% to 97%; serial biomarker tests had summary sensitivities of 79% to 93% and summary specificities of 85% to 96%. Variation of test sensitivity was best explained by test timing. Longer symptom duration or time between serial tests yielded higher sensitivity. CONCLUSION: The limited evidence available to evaluate the diagnostic accuracy of biomarkers for ACI suggests that biomarkers have very low sensitivity to diagnose ACI. Thus, biomarkers alone will greatly underdiagnose ACI and will be inadequate to make triage decisions. For AMI diagnosis alone, multiple testing of individual biomarkers over time substantially improves sensitivity, while retaining high specificity, at the expense of additional time. Further high-quality studies are needed on the clinical effect of using biomarkers for patients with ACI in the ED and on optimal timing of serial testing and in combination with other tests.

Acute Disease↗
PubMed1996

Biomarkers of lung inflammation in recreational joggers exposed to ozone.

Humans exhibit an acute inflammatory response in the lungs after controlled laboratory exposure to ozone. The present study was designed to test whether biomarkers of inflammation are detectable in humans exposed to ozone and associated copollutants under natural conditions outdoors. Bronchoscopy with bronchoalveolar lavage (BAL) was carried out on 19 normal volunteer joggers from Governors Island, NY, who exercised in the afternoon during the 1992 summer (S1) season. Fifteen subjects were retested during the following, low ozone, winter season (W). The BAL protocol involved an initial instillation of 20 ml saline followed by four sequential 50-ml saline washes carried out in both the right middle lobe and the lingula. The eight 50-ml samples were pooled as the 'alveolar' sample. Analyses performed on the alveolar lavage samples included cell differentials, release of IL-8, TNF-alpha, and reactive oxygen species (ROS) by pooled cells, and levels of IL-8, protein, LDH, fibronectin, alpha1-antitrypsin (alpha1-AT), complement fragment 3a (C3a), and prostaglandin E2 (PGE2) in lavage fluids. Release of ROS by stimulated BAL cells was lower in S1 than in W (p = 0.03). In contrast, LDH levels in BAL fluids were 2-fold higher in S1 than in W (p = 0.02), as were IL-8 (p = 0.12) and PGE2 (p = 0.06). These results suggest a possible ongoing inflammatory response in the lungs of recreational joggers exposed to ozone and associated copollutants during the summer months.

Adult↗
PubMed2004

Recent developments in biomarkers for the early detection of lung cancer: perspectives based on publications 2003 to present.

PURPOSE OF REVIEW: Given the poor prognosis associated with lung cancer, the ability to diagnose lung cancer in its early stages is considered crucial to achieving decreased lung cancer mortality. Herein, we discuss recent advances in biomarker discovery and evaluation of their potential application in the clinical setting. RECENT FINDINGS: Novel potential biomarkers have been identified via new techniques including cDNA microarray analysis, comparative genomic hybridization, and proteomics. These factors have been evaluated in various validation studies including tissue microarrays, RT-PCR, and assays of bioactivity. The characterization of these potential biomarkers through analysis of pathways that have been associated with neo-plastic transformation may help to identify the precursor lesions that are associated with subsequent progression to invasive carcinoma. In addition, the past year has also produced intriguing results regarding the detection of biomarkers in easily accessible screening specimens such as sputa, serum, and exhaled breath. Recent advances in these aspects of biomarker identification for the early detection of lung cancer are reviewed. SUMMARY: Identification of new candidate biomarkers and improved applications of previously detected biomarkers show great promise for the ultimate establishment of practical lung cancer screening. While recent studies engender optimism for the creation of clinically applicable screening tests, the biomarkers that have been identified need larger, follow-up validational studies and further characterization as to their biologic importance.

Biomarkers, Tumor↗
PubMed2004

Recent progress in predictive biomarkers for metastatic recurrence of human hepatocellular carcinoma: a review of the literature.

Molecular markers (biomarkers) for hepatocellular carcinoma (HCC) metastasis and recurrence could provide additional information to that gained from traditional histopathological features. A large number of biomarkers have been shown to have potential predictive significance. One important aspect of this is to detect the transcripts of tumor-associated antigens (such as AFP, MAGEs, and CK19), which are proposed as predictive markers of HCC cells disseminated into the circulation and for metastatic recurrence. Another important aspect is to analyze the molecular markers for cellular malignancy phenotype, including DNA ploidy, cellular proliferation index, cell cycle regulators, oncogenes, and tumor suppressors (especially p53 gene), as well as telomerase activity. Molecular factors involved in the process of HCC invasion and metastasis, including adhesion molecules (E-cadherin, catenins, ICAM-1, laminin-5, CD44 variants, osteopontin), proteinases responsible for the degradation of extracellular matrix (MMPs, uPA system), as well as angiogenesis regulators (such as VEGF, intratumor MVD), have also been shown to be potential predictors for HCC metastatic recurrence and clinical outcomes. One important new trend is to widely delineate biomarkers with genomic and proteomic expression with reference to predicting metastatic recurrence, molecular diagnosis, and classification, which has been drawing more attention recently. Body fluid (particularly blood and urine) testing for biomarkers is easily accessible and more useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum and its genetic alterations is another important direction. More attention should be paid to these areas in the future. As understanding of tumor biology deepens, more and more new biomarkers with high sensitivity and specificity for HCC metastatic recurrence could be found and routinely used in clinical assays. However, the combination of the pathological features and some of the biomarkers mentioned above seems to be more practical up to now.

Angiogenesis Inducing Agents↗
PubMed2004

An integrated biomarker-based strategy for ecotoxicological evaluation of risk in environmental management.

Environmental impacts by both natural events and man-made interventions are a fact of life; and developing the capacity to minimise these impacts and their harmful consequences for biological resources, ecosystems and human health is a daunting task for environmental legislators and regulators. A major challenge in impact and risk assessment, as part of integrated environmental management (IEM), is to link harmful effects of pollution (including toxic chemicals) in individual sentinel animals to their ecological consequences. This obstacle has resulted in a knowledge-gap for those seeking to develop effective policies for sustainable use of resources and environmental protection. Part of the solution to this problem may lie with the use of diagnostic clinical-type laboratory-based ecotoxicological tests or biomarkers, utilising sentinel animals as integrators of pollution, coupled with direct immunochemical tests for contaminants. These rapid and cost-effective ecotoxicological tools can provide information on the health status of individuals and populations based on relatively small samples of individuals. In the context of ecosystem status or health of the environment, biomarkers are also being used to link processes of molecular and cellular damage through to higher levels (i.e., prognostic capability), where they can result in pathology with reduced physiological performance and reproductive success. Complex issues are involved in evaluating environmental risk, such as the effects of the physico-chemical environment on the speciation and uptake of pollutant chemicals and inherent inter-individual and inter-species differences in vulnerability to toxicity; and the toxicity of complex mixtures. Effectively linking the impact of pollutants through the various hierarchical levels of biological organisation to ecosystem and human health requires a pragmatic integrated approach based on existing information that either links or correlates processes of pollutant uptake, detoxication and pathology with each other and higher level effects. It is further proposed here that this process will be facilitated by pursuing a holistic or whole systems approach with the development of computational simulation models of cells, organs and animals in tandem with empirical data (i.e., the middle-out approach). In conclusion, an effective integrated environmental management strategy to secure resource sustainability requires an integrated capability for risk assessment and prediction. Furthermore, if such a strategy is to influence and help in the formulation of environmental policy decisions, then it is crucial to demonstrate scientific robustness of predictions concerning the long-term consequences of pollution to politicians, industrialists and environmental managers; and also increase stakeholder awareness of environmental problems.

Animals↗
PubMed1997

The role of D-dimer in the diagnosis of venous thromboembolism.

The diagnosis of venous thromboembolism remains a clinical challenge. D-dimer, a specific breakdown product of crosslinked fibrin, is a sensitive marker for acute thrombosis. Recent studies have demonstrated that D-dimer testing has a promising role as an exclusionary test in patients with suspected deep vein thrombosis or pulmonary embolism. However, a wide range of sensitivities and specificities has been reported for D-dimer assays because of inter- and intra-assay variations and differences in patient populations. New rapid D-dimer enzyme-linked immunosorbent assays and the whole blood agglutination assay SimpliRED (Agen Biomedical, Brisbane, Australia) D-dimer have high negative predictive values. Recent studies have shown that a normal result on a SimpliRED assay combined with a low pre-test probability or normal result on impedance plethysmography reliably excludes venous thrombosis. Latex agglutination assays are relatively insensitive as screening tests and should not be used. Management studies are underway and will further delineate the role of D-dimer testing in patients with suspected venous thromboembolism.

Agglutination Tests↗
PubMed2005

The genetic factors in cancer development and their implications for cancer prevention and detection.

Experimental data from laboratory animals indicate that the same extent of DNA damage or the same mutations in oncogenes and tumor suppressor genes in different hosts result in widely differing cancer development because of numerous polymorphic tumor susceptibility genes. Similarly, recent epidemiological data indicate that susceptibility to common, "sporadic" cancers in humans is influenced considerably by multiple polymorphic host genes with relatively weak effects. This indicates that in addition to hereditary familial cancer syndromes, the sporadic cancer is also under strong genetic control. The multiplicity of genes involved, variation in exposure to environmental carcinogens, and small sizes of cancer families prevent efficient searches for the responsible genes in humans. Therefore, an alternative strategy based on the definition of susceptibility genes in experimental animals and the subsequent study of their human homologues has been successfully employed by several groups. This strategy also helped reveal several important features of cancer susceptibility, including mutual interactions of cancer susceptibility genes, their functional heterogeneity, and the existence of stage-specific control of cancer development. This latter phenomenon is especially important, because the susceptibility to early stages of cancer development may be quite different from that of late stages of cancer development. This needs to be taken into account when introducing preventive testing of biomarkers of early preneoplastic lesions or early cancers, because their predictive value is greatly influenced by the genetically determined individual tendency to proceed toward a more advanced form of neoplasia. Therefore, genetic testing of persons in danger of being exposed to carcinogenic factors should be an important part of the personnel selection.

Animals↗
PubMed2005

Molecular prostate cancer pathology: current issues and achievements.

Recent developments in the field of molecular techniques have provided new tools that have led to the discovery of many new promising biomarkers for prostate cancer. These biomarkers may be instrumental in the development of new tests that will have a high specificity for the diagnosis and prognosis of prostate cancer. A biomarker is defined as a molecular test that provides additional information to currently available clinical and pathological tests. Biomarkers should be reproducible (both within and between institutes) and have an impact on clinical management. For diagnostic purposes it is important that potential biomarkers are tested in terms of tissue specificity and their discrimination potential between prostate cancer, normal prostate and benign prostatic hyperplasia. The results of (multiple) biomarker-based assays may enhance the specificity of cancer detection. There is an urgent need for molecular prognostic biomarkers for predicting the biological behavior and outcome of cancer.

Antigens, Neoplasm↗
PubMed2004

Statistical methods for analyzing tissue microarray data.

Tissue microarrays (TMAs) are a new high-throughput tool for the study of protein expression patterns in tissues and are increasingly used to evaluate the diagnostic and prognostic importance of biomarkers. TMA data are rather challenging to analyze. Covariates are highly skewed, non-normal, and may be highly correlated. We present statistical methods for relating TMA data to censored time-to-event data. We review methods for evaluating the predictive power of Cox regression models and show how to test whether biomarker data contain predictive information above and beyond standard pathology covariates. We use nonparametric bootstrap methods to validate model fitting indices such as the concordance index. We also present data mining methods for characterizing high risk patients with simple biomarker rules. Since researchers in the TMA community routinely dichotomize biomarker expression values, survival trees are a natural choice. We also use bump hunting (patient rule induction method), which we adapt to the use with survival data. The proposed methods are applied to a kidney cancer tissue microarray data set.

Algorithms↗
PubMed2003

Limitations of D-dimer testing in unselected inpatients with suspected venous thromboembolism.

PURPOSE: To determine the utility and limitations of D-dimer testing for the evaluation of venous thromboembolism in hospitalized patients. METHODS: We performed D-dimer testing by four different methods in unselected inpatients undergoing radiologic evaluation for possible venous thromboembolism. We included patients with a history of malignancy, recent surgery, thrombosis, and anticoagulation treatment. C-reactive protein levels were assayed as a measure of inflammation. RESULTS: Of 45 patients with radiographically proven proximal deep venous thrombosis or pulmonary embolism, 43 had elevated D-dimer levels by enzyme-linked immunosorbent assay (ELISA) (sensitivity, 96%); the specificity of the test was 23% (36/157). The qualitative non-ELISA tests had higher specificities, but their sensitivities were <70%. Nineteen patients (42%) with thrombosis had false-negative D-dimer tests by at least one assay. The specificity of the tests decreased with increasing duration of hospitalization, increasing age, and increasing C-reactive protein levels. D-dimer testing had little or no utility in distinguishing patients with thrombosis from those without in patients who had been hospitalized for more than 3 days, were older than 60 years, or had C-reactive protein levels in the highest quartile. CONCLUSION: In unselected inpatients, D-dimer testing has limited clinical utility because of its poor specificity. This is particularly true for older patients, those who have undergone prolonged hospitalization, and those with markedly elevated C-reactive protein levels. In some patient subsets, a negative non-ELISA D-dimer test cannot discriminate between inpatients with and without thrombosis.

Adult↗
PubMed1999

Genotoxicity biomarkers in the assessment of heavy metal effects in mussels: experimental studies.

Heavy metals are stable and persistent environmental contaminants. The range of metal concentrations is generally below acute thresholds in coastal areas, where recognition of chronic sublethal effects is more relevant. Evidence of long-term adverse effects, such as cancer, due to heavy metals in marine animals comes from a number of field and experimental studies. The mechanism of metal carcinogenicity remains largely unknown, although several lines of experimental evidence suggest that a genotoxic effect may be involved. The aim of our study was to evaluate the sensitivity of genotoxicity tests, alkaline elution and micronucleus test, as biomarkers for the detection of heavy metals in mussels as the sentinel species. Experimental studies were carried out on Mytilus galloprovincialis exposed in aquarium (5 days) to different concentrations of three selected metal salts, CuCl2 (5, 10, 20, 40, 80 micrograms/l/a), CdCl2 (1.84, 18.4, 184 micrograms/l/a), and HgCl2 (32 micrograms/l/a), and to a mixture of equimolar doses of the three metals to study the results of their joint action. Metallothionein quantitation was used as a marker of metal exposure. Lysosomal membrane stability was applied to evaluate the influence of physiological status on genotoxic damage. The ranking of genotoxic potential was in decreasing order: Hg > Cu > Cd. Cu and Hg caused an increase of DNA single-strand breaks and micronuclei frequency. Cd induced a statistical increase of DNA damage, but gave negative results with the micronucleus test. A relationship between genotoxic effects and metallothionein content was observed. Reduction in lysosomal membrane stability with the increasing concentration of heavy metals was also evident.

Animals↗
PubMed2000

Diagnostic approaches to Alzheimer's disease.

The importance of obtaining an accurate and early diagnosis for Alzheimer's disease is now becoming recognized. Nonpharmacological as well as pharmacological therapies can be best initiated once a diagnosis is obtained. Biochemical markers to identify Alzheimer's disease have been sought for many years, with many candidates proposed. Recently criteria were established to evaluate putative diagnostic tests. Several biomarkers now show utility in identifying those with Alzheimer's disease. The ApoE e4 allele, while a risk factor rather than a deterministic gene, in the context of an individual with suspicion of AD has a positive predictive value of 94-98% and may come to have utility in predicting response to certain classes of pharmacological agents. Independent groups have shown that the markers in cerebrospinal fluid tau and Ab42 are, respectively, elevated and reduced in patients with AD versus other patient groups and that the lumbar puncture itself is usually well tolerated. For early-onset AD, sequencing presenilin 1 has come into use and the positive frequency is similar to that found in other genetic-based laboratory tests.

Aging↗
PubMed2006

Use of PMA1 as a housekeeping biomarker for assessment of toxicant-induced stress in Saccharomyces cerevisiae.

The brewer's yeast Saccharomyces cerevisiae has emerged as a versatile and robust model system for laboratory use to study toxic effects of various substances. In this study, toxicant-induced stresses of pure compounds were investigated in Saccharomyces cerevisiae utilizing a destabilized version of the green fluorescent protein optimized for expression in yeast (yEGFP3) under control of the promoter of the housekeeping plasma membrane ATPase gene PMA1. The responses of the biomarker upon increasing test compound concentrations were monitored by determining the decrease in fluorescence. The reporter assay deployed a simple and robust protocol for the rapid detection of toxic effects within a 96-well microplate format. Fluorescence emissions were normalized to cell growth determined by absorption and were correlated to internal reference standards. The results were expressed as effective concentrations (EC20). Dose-response experiments were conducted in which yeast cells were exposed in minimal medium and in the presence of 20% fetal calf serum to sublethal concentrations of an array of heavy metals, salt, and a number of stress-inducing compounds (Diclofenac, Lindane, methyl-N-nitro-N-nitrosoguanidine [MNNG], hydroxyurea, and caffeine). Long-term exposure (7 h) played a considerable role in the adaptive response to intoxication compared to early responses at 4 h exposure. The data obtained after 4 h of exposure and expressed as EC20 were compared to 50% inhibitory concentration values derived from cell line and ecotoxicological tests. This study demonstrates the versatility of the novel biomarker to complement existing test batteries to assess contaminant exposure and effects.

Animals↗
PubMed2006

Serum chemical biomarkers of cardiac injury for nonclinical safety testing.

There has been a substantial increase in the number and efficacy of laboratory biomarkers for the evaluation of human cardiac injury over the last decade. The advantages of these over traditional laboratory tests have encouraged adoption of comparable markers in nonclinical studies for cardiac injury assessment. Of particular interest are markers that are not only more sensitive and/or specific than traditional parameters for cardiac injury, but also those that may directly bridge human and laboratory animal safety testing. However, a majority of recently developed markers are quantified through antibody-based assays, and cross-reactivity with the comparable analyte in nonhuman samples is difficult to predict and often species-variable. The utility of these novel biomarkers thus, depends upon adequate assay validation with each laboratory species of interest. In contrast, traditional laboratory parameters of cardiac injury lack the properties of an ideal biomarker, but are well established and have an extensive database in nonclinical safety assessment. The current status and utility of both recently developed and traditional biomarkers of cardiac injury in nonclinical testing, and considerations for validation of novel biomarkers of cardiac injury are reviewed.

Animals↗