Showing papers on "Biomarker (medicine) published in 2000"

Increased 8,12-iso-iPF2alpha-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity.

Abstract: The isoprostane 8,12-iso-iPF2alpha-VI is a sensitive and specific marker of in vivo lipid peroxidation. We found elevated levels in the urine, blood, and cerebrospinal fluid of patients with Alzheimer's disease (AD) that correlated with measures of cognitive and functional impairment, established biomarkers of AD pathology (cerebrospinal fluid tau and amyloid) and the number of apolipoprotein E epsilon4 alleles. These results suggest that 8,12-iso-iPF2alpha-VI is a useful biomarker of oxidative damage in AD.

Biomarkers in Terrestrial Invertebrates For Ecotoxicological Soil Risk Assessment

Abstract: This review has served to present the most recent information on a selected series of biomarker studies undertaken on soil invertebrates during two extensive European-funded scientific consortia, BIOPRINT and BIOPRINT-II. The goals were to develop and validate methods for the analysis of markers of stress in a range of soil-dwelling organisms. We have discussed the potential and limitations of the following invertebrate biomarkers for soil risk assessment purposes: heat shock proteins, histological and ultrastructural markers, metallothioneins and metal-binding proteins, esterases, lysosomal integrity, and the novel biomarker histidine. The hsp response in soil invertebrates is especially suitable to indicate the effects of exposure to comparatively low concentrations for a range of toxicants and can be regarded as a biomarker of general stress. The application of MTs and other metal-binding proteins as biomarkers for exposure in soil invertebrates has been well described, and new methods are being developed for analyzing MT induction both at the protein and molecular level, and reliable and reproducible methods are now available. (Cd)-MT is well characterized for the springtails and its MT concentration is a useful biomarker for exposure as well as for effect. For snails, (Cd)-MT can accumulate in the midgut gland over extended periods of time and therefore its concentration is a biomarker not only for recent intoxication but also for events of cadmium exposure that snails may have experienced a long time before the measurement took place. Cellular and histological alterations can be regarded as reflecting the "health" state of a cell, which may be a measure for the presence of toxicants. Histopathological work on terrestrial invertebrates, however, is still scarce. Isozymes have been poorly studied in soil invertebrates despite their promising role as potential biomarkers in aquatic organisms. Among the large diversity of isozymes, the most well studied are esterases that are frequently used a biomarkers of exposure to various classes of pesticides. Many other isozymes offer potentials for biomarker research, such as glucosephosphate isomerase and phosphoglucomutase, both enzymes necessary for the glycolytic pathway. The lysosomal system has been identified as a particular target for the toxic effects of xenobiotics, although it has yet a limited application in soil invertebrates. This marker is nonspecific, responding equally sensitively to organic or inorganic contamination; however, if used in combination with an earthworm immnunocompetence assay such as total immunoactivity of the coelomocytes, then it is possible to be more specific as to the likely nature of contamination. Free histidine was positively correlated with increasing copper exposure and total copper burden in earthworms from a semifield study. Histidine may thus act as a biomarker of exposure. The transient responses and confounding factors of biomarkers obscure a proper interpretation of biomarker responses under field conditions. These factors are still very poorly understood and require more study. For risk assessment purposes it is recommended that the aforementioned biomarkers may show promise when included in a suite of biomarkers among different soil invertebrate species. It is recommended that a risk assessment protocol draw upon ranking of biomarker responses on a defined scale. It is also hoped that the problems outlined in this review will aid the direction of future research on soil invertebrate biomarkers.

Evaluation of sensitivity and specificity of two crustacean biochemical biomarkers

Abstract: Biochemical biomarkers are increasingly used for environmental assessment. Although the emphasis has been on vertebrate biomarkers, invertebrates biomarkers have been developed as well. This study evaluated the usefulness of biomarker responses of freshwater invertebrates by comparing the sensitivity and specificity of endpoints at three levels of biological organization: biochemical, physiological, and individual. The study focused on the epibenthic amphipod Gammarus pulex L., and the end points were cholinesterase (ChE) and glutathione-S-transferase (GST) activity, feeding inhibition, and mortality. Chemicals representing five major classes of toxic chemicals were assessed, including zinc, linear alkylbenzene sulphonate (LAS; surfactant), lindane (organochlorine), pirimiphos-methyl (organophosphorus), and permethrin (pyrethroid). Lethality was the least sensitive endpoint, with 96-h LC50 values ranging from 2.78 μg/L for permethrin to 6.31 mg/L for LAS. Comparison of the biochemical biomarkers and the sublethal feeding rate assay indicated that whereas ChE inhibition was a specific indicator of organophosphate exposure, the biochemical assay was more than 13-fold less sensitive than the feeding rate assay. The GST biomarker performed with greater sensitivity but with lower specificity compared with the ChE biomarker. However, only on exposure to lindane did the GST biomarker marginally outperform the feeding rate assay in terms of sensitivity. Feeding inhibition is both a general and a sensitive (LC50, <3%) indicator for exposure to a range of chemicals. The Gammarus sp. ChE biomarker may have utility in providing a diagnostic and rapid indicator of organophosphate exposure, but evidence from this and other studies questions the sensitivity of this biomarker in predicting sublethal, higher-order effects. The GST biomarker may provide a rapid and sensitive indicator for toxicant exposure, but it has limited use as a diagnostic tool and provides only limited improvement in sensitivity over more ecologically relevant sublethal end points (e.g., feeding rate, growth rate).

Proteomic strategies for biomarker identification: progress and challenges.

Abstract: The simplest definition of a biomarker is a molecule that indicates an alteration in physiology from normal. A more practical definition of a biomarker would require clinical utility of this molecule. In this sense, the biomarker would specifically and sensitively reflect a disease state and could be used for diagnosis as well as for disease monitoring during and following therapy. The need for such biomarkers in all clinical fields is urgent, since the current arsenal of biomarkers is sadly deficient and, in most cases, non-specific. In this review, we discuss strategies that use a proteomics approach to identify novel biomarkers and give examples of recent studies employing these strategies.

Optimizing the use of biomarkers, surrogate endpoints, and clinical endpoints for more efficient drug development.

Abstract: Biomarkers and surrogate endpoints are critical to the future of efficient drug development. Definitions, a conceptual model, and a conceptual framework for validating and bridging biomarkers to clinical endpoints are provided in this presentation. In addition, a few examples are provided to support the development concept. Poor correlation between a biomarker and its clinical endpoint may result from (1) poor measurement of one or both, (2) selection of an inappropriate biomarker, or, more important, (3) use of an inappropriate clinical endpoint. Pharmacokinetic/pharmacodynamic (PK/PD) modeling output can be no better than biomarkers or surrogate endpoints used for the modeling. As we increase our understanding of biomarkers, surrogate markers, and the mechanistic basis for the processes of interest, biomarker and surrogate endpoint predictive power will no longer be an issue and PK/PD modeling inputs and outputs will improve.

Mutagen sensitivity as a biomarker for second primary tumors after head and neck squamous cell carcinoma

Abstract: The occurrence of second primary tumors after curative treatment of early stage head and neck squamous cell carcinoma negatively influences the overall survival. Our aim was to prospectively evaluate whether mutagen sensitivity (mean number of chromatid breaks per cell in cultured lymphocytes exposed to bleomycin) could be used as a biomarker to predict which patients will develop second malignancies in the respiratory or upper digestive tract. Patients treated for head and neck squamous cell carcinoma ( n = 218) were followed for approximately 6 years. Nineteen patients developed a second primary tumor, and each of these patients was matched on age, gender, cumulative smoking, tumor site, and tumor stage to two patients who did not develop any second malignancy. No difference between the groups was found with respect to mutagen sensitivity. Smoking at the time of the index tumor had a significant influence on the occurrence of second primary tumors (log-rank, P = 0.019). There was a significantly ( P = 0.005) higher mean breaks-per-cell value in those patients who had developed their second primary tumor ≥3 years after the first tumor (0.97 ± 0.24; n = 10) compared with early second primary tumor patients (0.69 ± 0.09; n = 9). Conditional on a more than 3-year second primary tumor-free survival ( n = 38), there is a significantly (log-rank, P = 0.036) higher probability of a second primary tumor for mutagen-sensitive patients [relative risk, 7.8 (95% confidence interval, 0.99- 61.74; P = 0.05)]. Mutagen sensitivity is a potentional biomarker for the occurrence of‘ late’ second malignancies (>3 years between tumors), and additional studies on the inclusion of this biomarker in chemoprevention trials is commendable because it would greatly improve their efficiency.

Twenty years of experience with the steroid receptor external quality assessment program - the paradigm for tumour biomarker EQA studies. On behalf of the EROTC Receptor and Biomarker Study Group.

Abstract: Estrogen receptor (ER) assays have clinical relevance in selecting women who would benefit from endocrine intervention. As the degree of benefit from endocrine therapy is directly related to the quantity of receptor present in the tumour, the quality of the steroid receptor assays is important. Moreover, since patients entered in multi-centre trials often include stratification based on the receptor status, receptor assays should be comparable between different institutes. ER- and progesterone receptor (PgR)-assays have been evaluated in quality assessment studies for almost 20 years by the EORTC Receptor and Biomarker Study Group. This study analyses our findings over these years and concludes with a recommended minimum structure on which QA schemes for any biomarker could be based.

Breast cancer chemoprevention trials using the fine-needle aspiration model.

Abstract: Selection of surrogate endpoint biomarkers (SEBs) and appropriate study design are two of the main challenges in evaluating potential chemopreventive agents. In a prospective random fine-needle aspiration (FNA) study of women at high risk of development of breast cancer, we previously demonstrated that cytologic evidence of epithelial hyperplasia with or without atypia, as well as abnormalities of several cellular biomarkers (DNA ploidy; immunocytochemical expression of p53, EGFR, ER, and/or Her-2/neu), were more prevalent in high-risk women than in low-risk controls. We also demonstrated that the subsequent development of breast cancer was best predicted by an initial presentation of hyperplasia with atypia, as well as by multiple biomarker abnormalities. These findings indicate that FNA cytology and biomarkers can be used to identify women who are appropriate subjects for chemoprevention trials, and can then be used as surrogate endpoint biomarkers to monitor efficacy of potential agents. An example of this use in an ongoing single-agent phase II trial is provided. Several options for study design of possible multi-agent breast cancer chemoprevention trials are discussed, depending upon the existing preclinical and clinical data, the questions being asked, and the number of eligible subjects available.

Measurement and quantification of 17 ketosteroid-sulfates as a biomarker of biological age

Abstract: The present invention provides an improved method for using the measurement of total urinary 17 KS-S, referred to herein as the urinary Anabolic/Catabolic Index (ACI), as part of a biomarker for biological age.

p53 and MDM2 protein expression in squamous cell carcinoma and neighboring dysplasia from the upper aerodigestive tract.

Abstract: Background: The identification of genetic changes in preinvasive epithelial lesions may provide markers for a better assessment of the progression potential. Materials and methods: p53, MDM2 and PCNA immunophenotypes were examined in 57 cases of squamous cell carcinoma (SCC) of the upper aerodigestive tract and the adjacent normal and dysplastic epithelia. Results: PCNA index increased with increasing grade of dysplasia. p53 protein was expressed in 35% and MDM2 protein in 33% of SCCs. The p53 protein was expressed in 89% of mild and moderate and in 93% of severe dysplasia and carcinoma in situ adjacent to p53-positive SCCs. The MDM2 protein was expressed in 30% of mild and moderate and in 54% of severe dysplasia and carcinoma in situ adjacent to MDM2-positive SCCs. Preinvasive lesions adjacent to negative SCCs stained negative. Conclusions: p53 protein was detected more frequently in preinvasive lesions than MDM2 protein and seems to be of greater value as a biomarker.

Biological monitoring in waste landfills studies.

Abstract: The assessment of exposure to chemicals from waste landfills and their health impact is a crucial, yet extremely difficult task in waste landfill studies Use of biological markers, both of exposure and of health effects, may be very helpful if adequately chosen and precisely applied They must be validated before application in risk assessment studies by establishing the relationship between the biomarker, exposure and the health outcome Biomarkers suitable for the application in the waste landfill studies are reviewed in this paper

The Role of Biomarker in Risk Assessment of Low level Exposure of Carcinogen

Abstract: With the high sensitivity of biomarker assays,the exposure levels and its biological effect in population exposed to low level carcinogens for a long time can be more directly measured,and the dose-effect relationship between biomarkers and a specific risk can be more accurately descripted The study on biomarker,which still stayed in primary stage,presented good prospect in the field of risk assessment on environmental health In this review,data are summarized on the role of biomarkers that are used for risk assessment of human populations exposed to low level carcinogens,including the criteria of biomarker chosen,the method of risk assessment using biomarkers,and the problem existed of that aspect

TP53 as a biomarker of cytogenetic damage.

Abstract: Dear Editors: BOTH THE National Council on Radiation Protection and Measurements and the International Commission on Radiological Protection (ICRP) have recommended a maximum permissible effective dose of 50 mSv (5 rem) in any one year for occupational exposure. The ICRP, in addition, recommends a limit of 100 mSv (10 rem) over a period of 5 y. This implies that a new radiation worker who receives a 50 mGy x-ray dose as an acute exposure will not have exceeded the recommended limit set by either of these organizations. This then begs the question: Do x-ray doses of 50 mGy or less create damage to DNA? Studies using the alkaline comet assay indicate that DNA damage in certain cell lines may occur at doses of less than 10 mGy (Malyapa et al. 1998). The induction of stress-responsive genes (Amundson et al. 1999) provides further evidence of cytogenetic damage being caused by doses of 50 mGy or less. The tumor suppressor TP53 protein is induced in response to DNA damage, the induction resulting from both an increased stabilization as well as an increased synthesis of the protein. We have determined the level of the TP53 protein in TK6 cells (a lymphoblast cell line with wild-type TP53) at various times after g-ray doses of 10, 30, and 50 mGy. Statistically significant increases in TP53 compared to unirradiated controls ( p , 0.05) were determined at 4 an d 5 h after 30 and 50 mGy, the TP53 levels peaking a t 4 h for both radiation doses (Fig. 1). Changes in the level of TP53 after 10 mGy were not statistically significant. Included in Fig. 1 are data from a previous study (Hendrikse et al. 2000) showing TP53 levels after 100 mGy. The induction of TP53 after 30, 50, and 100 mGy shows no clear dose-response relationship, indicating that changes in TP53 after radiation would not be an appropriate radiobiological technique to use for biological dosimetry. If it is inferred that the induction of wild-type TP53 following very small doses of radiation is in response to DNA damage, then will such damage impact on the ability of the cell to maintain its genetic integrity or to survive? This remains to be elucidated, but there are a number of possibilities. Nonlethal damage could, in theory, increase the incidence of a stochastic effect like cancer (Bowden et al. 1990). DNA damage causing cell death may result in an increase in the proliferation rate of surviving cells. This could lead to an increase in mutation rates and, therefore, to an increase in the risk of cancer (Gaylor and Zheng 1996). If, as has been proposed (Pollycove 1998), DNA damage were to stimulate systems responsible for the detoxification of free radicals, a decrement in the cancer risk may result (Azzam et al. 1996).