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PubMed2004

[Isoprostanes, biomarkers of lipid peroxidation in humans. Part 3: Biomarkers and mediators in vascular physiology and disease].

The 15-series F(2)-isoprostanes mediate vasoconstriction in different vascular beds and species. This contraction is mediated by the thromboxane receptors stimulation, and may be modulated by the endothelium. Furthermore, 15-F(2t)-IsoP induces smooth muscle cells mitogenesis and monocyte adhesion to endothelial cells. Some 15-series E(2)-isoprostanes are more potent than F(2)-isoprostanes. In clinical studies, 15-F(2t)-IsoP levels are increased in vascular disorders involving atherosclerosis, ischemia-reperfusion and inflammation. F(2)-isoprostane levels correlate to the severity of heart failure and pulmonary hypertension, raising the potential prognostic interest of these biomarkers. Whether the effects observed in vitro are observed consistently in vivo at physiological concentrations and whether these effects contribute to pathological states in vivo is still debated.

Biomarkers↗
PubMed1999

Use of biomarkers in an indoor air study: lack of correlation between aromatic VOCs with respective urinary biomarkers.

The benzene and toluene levels inside of eight homes with attached garages were measured during July 1998 in Fairbanks, Alaska. A thermal desorption tube method and charcoal tube method were used to collect and analyze samples (thermal desorption tube method %RDS = 1.9 for n = 6; charcoal tube method %RDS = 6.5 for n = 4). Results for both methods were compared and showed indoor benzene levels ranging between 1.2 and 72 ppbv. The charcoal tube method usually gave lower results than the thermal desorption method. Nevertheless, the difference observed in benzene levels from each method was not significant as determined by application of the Wilcoxon t-test to these data. Using the thermal desorption method, the range of toluene found in homes was 0.1-111 ppbv. A correlation between toluene and benzene levels suggested the same point source. The benzene and toluene content of the indoor air and the number of small engines stored in the attached garage was also correlated. There was no correlation found between the urinary biomarker concentrations and the level of benzene or toluene measured inside the homes in the summer.

Air Pollution, Indoor↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2003

The missing biomarker link: relationships between effects on the cellular energy allocation biomarker of toxicant-stressed Daphnia magna and corresponding population characteristics.

The cellular energy allocation (CEA) methodology was used to assess the adverse effects of toxic stress on the energy budget of test organisms. This biochemical assay is quantified by determining changes in the available energy reserves, Ea (total carbohydrate, protein, and lipid content) and the energy consumption, Ec (electron transport activity). The CEA methodology was fully explored by using neonates of Daphnia magna exposed for 96 h to six model toxicants (CdCl2, K2Cr2O7, tributyltin chloride, linear alkylbenzene sulfonic acid, sodium pentachlorophenolate, and 2,4-dichlorophenoxyacetic acid). To evaluate the ecological relevance of the CEA parameter, we compared the suborganismal responses with population-level parameters (obtained from 21-d life-table experiments) such as the intrinsic rate of natural increase (rm) and the mean total offspring per female. The observed reductions in CEA values were both the result of a decrease in Ea and an increase in Ec. From all individual CEA components analyzed, the lipid reserve criterion was the most sensitive endpoint studied. Both the CEA-based lowest-observed-adverse-effect concentration (LOAEC) values and the effective concentration of 10% (EC10) values were significantly (p < 0.05) and linearly correlated with the chronic (21-d) LOAEC and EC10 values based on growth, survival, and reproduction. This relationship demonstrates the usefulness of the methodology to predict long-term effects. Furthermore, significant (p < 0.0001) sigmoid relationships between the 96-h CEA value (expressed as percentage relative to the control) and population-level effects were observed.

Animals↗
PubMedDate not supplied

[Biomarkers of cytogenetic damage in humans and risk of cancer. The European Study Group on Cytogenetic Biomarkers and Health (ESCH)].

Cytogenetic assays in peripheral blood lymphocytes (PBL) have been used extensively in the last decades to survey human exposure to genotoxic agents. The conceptual basis for this approach has been the hypothesis that the extent of genetic damage in PBL reflects critical events for carcinogenic processes in target tissues. The predictive value of these tests for subsequent cancer risk has been recently evaluated by two cohort studies of cancer mortality and incidence carried out in Italy and in five North European countries. In this paper we report the update of both cohorts. In the new follow-up, a total of 64 cancer deaths out of 2019 subjects in the Italian cohort and 127 new cases of cancer out of 3182 subjects in the Nordic cohort were observed. The cytogenetic endpoints studied were CA (chromosomal aberrations), SCE (sister chromatid exchanges) and MN (micronuclei). In order to take into account the interlaboratory variation of absolute values, the results were trichotomized within each laboratory into three strata: low (1-33 percentile), medium (34-66 percentile), or high (67-100 percentile). The association between chromosomal damage and cancer risk was evaluated through SMR (standardized mortality ratio) for Italy and SIR (standardized incidence ratio) for the Nordic countries. National mortality/incidence cancer rates (age, sex and calendar-year specific) were used as reference. A linear trend of SMRs and SIRs according to CA level was found in both cohorts for the "All Cancers" cause (p < 0.01). In the Italian cohort it was also possible to analyze some specific cancer sites: a significant increase of SMR among subjects with a high level of CA with respect to the general population was found for lung cancers and lymphatic and hematopoietic tissue cancers. Contrariwise, no association between cancer mortality/incidence and SCE or MN frequency was observed. Findings from this study support the existence of an association between CA frequency and cancer risk.

Adult↗
PubMed2000

Biomarkers in terrestrial invertebrates for ecotoxicological soil risk assessment.

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.

Animals↗
PubMed2006

Sub-speciating Campylobacter jejuni by proteomic analysis of its protein biomarkers and their post-translational modifications.

We have identified several protein biomarkers of three Campylobacter jejuni strains (RM1221, RM1859, and RM3782) by proteomic techniques. The protein biomarkers identified are prominently observed in the time-of-flight mass spectra (TOF MS) of bacterial cell lysate supernatants ionized by matrix-assisted laser desorption/ionization (MALDI). The protein biomarkers identified were: DNA-binding protein HU, translation initiation factor IF-1, cytochrome c553, a transthyretin-like periplasmic protein, chaperonin GroES, thioredoxin Trx, and ribosomal proteins: L7/L12 (50S), L24 (50S), S16 (30S), L29 (50S), and S15 (30S), and conserved proteins similar to strain NCTC 11168 proteins Cj1164 and Cj1225. The protein biomarkers identified appear to represent high copy, intact proteins. The significant findings are as follows: (1) Biomarker mass shifts between these strains were due to amino acid substitutions of the primary polypeptide sequence and not due to changes in post-translational modifications (PTMs). (2) If present, a PTM of a protein biomarker appeared consistently for all three strains, which supported that the biomarker mass shifts observed between strains were not due to PTM variability. (3) The PTMs observed included N-terminal methionine (N-Met) cleavage as well as a number of other PTMs. (4) It was discovered that protein biomarkers of C. jejuni (as well as other thermophilic Campylobacters) appear to violate the N-Met cleavage rule of bacterial proteins, which predicts N-Met cleavage if the penultimate residue is threonine. Two protein biomarkers (HU and 30S ribosomal protein S16) that have a penultimate threonine residue do not show N-Met cleavage. In all other cases, the rule correctly predicted N-Met cleavage among the biomarkers analyzed. This exception to the N-Met cleavage rule has implications for the development of bioinformatics algorithms for protein/pathogen identification. (5) There were fewer biomarker mass shifts between strains RM1221 and RM1859 compared to strain RM3782. As the mass shifts were due to the frequency of amino acid substitutions (and thus underlying genetic variations), this suggested that strains RM1221 and RM1859 were phylogenetically closer to one another than to strain RM3782 (in addition, a protein biomarker prominent in the spectra of RM1221 and RM1859 was absent from the RM3782 spectrum due to a nonsense mutation in the gene of the biomarker). These observations were confirmed by a nitrate reduction test, which showed that RM1221 and RM1859 were C. jejuni subsp. jejuni whereas RM3782 was C. jejuni subsp. doylei. This result suggests that detection/identification of protein biomarkers by pattern recognition and/or bioinformatics algorithms may easily subspeciate bacterial microorganisms. (6) Finally, the number and variation of PTMs detected in this relatively small number of protein biomarkers suggest that bioinformatics algorithms for pathogen identification may need to incorporate many more possible PTMs than suggested previously in the literature.

Amino Acid Sequence↗
PubMed1996

Risk biomarkers and current strategies for cancer chemoprevention.

Quantifiable, well-characterized cancer risk factors demonstrate the need for chemoprevention and define cohorts for chemopreventive intervention. For chemoprevention, the important cancer risk factors are those that can be measured quantitatively in the subject at risk. These factors, called risk biomarkers, can be used to identify cohorts for chemoprevention. Those modulated by chemopreventive agents may also be used as endpoints in chemoprevention studies. Generally, the risk biomarkers fit into categories based on those previously defined by Hulka: 1) carcinogen exposure, 2) carcinogen exposure/effect, 3) genetic predisposition, 4) intermediate biomarkers of cancer, and 5) previous cancers. Besides their use in characterizing cohorts for chemoprevention trials, some risk biomarkers can be modulated by chemopreventive agents. These biomarkers may be suitable surrogate endpoints for cancer incidence in chemoprevention intervention trials. The criteria for risk biomarkers defining cohorts and serving as endpoints are the same, except that those defining cohorts are not necessarily modulated by chemopreventive agents. A primary criterion is that the biomarkers fit expected biological mechanisms of early carcinogenesis-i.e., differential expression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, and short latency compared with cancer. They must occur in sufficient number to allow their biological and statistical evaluation. Further, the biomarkers should be assayed reliably and quantitatively, measured easily, and correlated to cancer incidence. Particularly important for cancer risk screening in normal subjects is the ability to use noninvasive techniques that are highly specific, sensitive, and quantitative. Since carcinogenesis is a multipath process, single biomarkers are difficult to correlate to cancer, as they may appear on only one or a few of the many possible causal pathways. As shown in colorectal carcinogenesis, the risks associated with the presence of biomarkers may be additive or synergistic. That is, the accumulation of genetic lesions is the more important determinant of colorectal cancer compared with the presence of any single lesion. Thus, batteries of biomarker abnormalities, particularly those representing the range of carcinogenesis pathways, may prove more useful than single biomarkers both in characterizing cohorts at risk and defining modulatable risks. Risk biomarkers are already being integrated into many chemoprevention intervention trials. One example is the phase II trial of oltipraz inhibition of carcinogen-DNA adducts in a Chinese population exposed to aflatoxin B1. Also, urine samples from subjects in this trial will be screened for the effect of oltipraz on urinary mutagens. A second example is a chemoprevention protocol developed for patients at high risk for breast cancer; the cohort is defined both by hereditary risk and the presence of biomarker abnormalities. Modulation of the biomarker abnormalities is a proposed endpoint. Also, dysplastic lesions, such as prostatic intraepithelial neoplasia, oral leukoplakia and colorectal adenomas, have been used to define high-risk cohorts and as potential modulatable surrogate endpoints in chemoprevention trials.

Animals↗
PubMed2006

Earthworm biomarkers in ecological risk assessment.

Earthworms have had a notable contribution in terrestrial ecotoxicology. They have been broadly used to assess environmental impact from metal pollution, and they are typical test organisms (e.g., Eisenia) in standardized toxicity tests. Several reviews and international workshops have stressed the need for increasing the understanding and applicability of earthworm biomarkers in the ecological risk assessment (ERA) process. This review summarizes recent available information concerning the most investigated earthworm biomarkers. In earthworms, the use of biomarkers has been focused on assessing metal pollution, and available data on biomarker responses to organic contaminants are rather limited. The potential for applying earthworm biomarkers in the standardized toxicity tests is suggested in view of their significant contribution to the risk assessment of contaminated soils (e.g., estimation of bioavailable and bioactive fraction or sublethal effects). Field studies involving earthworm biomarkers are still scarce and are summarized according to their main practical approaches in retrospective ERA: biological surveys, laboratory tests of the soil, simulated field studies, and in situ exposure bioassays. Despite the great volume of laboratory studies on earthworm biomarkers, future lines of research are suggested besides the recommendations made by others: (1) the potential and limitations of the inclusion of biomarkers in the standardized toxicity tests should be examined under a well-defined weight-of-evidence framework; (2) it is necessary to develop operating guidelines to standardize earthworm biomarker assays, an important step to apply biomarkers in a regulatory context; (3) molecular and physiological biomarkers should be directly linked to behavioral changes with significant ecological implications, an important step in considering them as ecotoxicological biomarkers; and (4) biomarkers to organic pollutants of current concern (e.g., polycyclic aromatic hydrocarbons, anti-ChE and pyrethroid insecticides, polybrominated flame retardants, etc.) need to be developed and validated in the field. Also, an increase in the knowledge of earthworm biomarkers is undoubtedly useful in assessing the effectiveness of procedures for recovering/protecting the environment (e.g., phytoremediation or agrienvironment schemes) besides its potential use in the ERA framework.

Animals↗
PubMed2005

The cost-effectiveness of biomarkers for predicting the development of oesophageal adenocarcinoma.

BACKGROUND: The recommended surveillance strategy for oesophageal adenocarcinoma may prevent as few as 50% of cancer deaths. Tissue biomarkers have been proposed to identify high-risk patients. AIM: To determine performance characteristics of an ideal biomarker, or panel of biomarkers, that would make its use more cost-effective than the current surveillance strategy. METHODS: We created a Markov model using data from published literature, and performed a cost-utility analysis. The population consisted of 50-year-old Caucasian men with gastro-oesophageal reflux, who were monitored until age 80. We examined strategies of observation only, current practice (dysplasia-guided surveillance), surveillance every 3 months for patients with a positive biomarker (biomarker-guided surveillance), and oesophagectomy immediately for a positive biomarker (biomarker-guided oesophagectomy). The primary outcome was the threshold cost and performance characteristics needed for a biomarker to be more cost-effective than current practice. RESULTS: Regardless of the cost, the biomarker needs to be at least 95% specific for biomarker-guided oesophagectomy to be cost-effective. For biomarker-guided surveillance to be cost-effective, a $100 biomarker could be 80% sensitive and specific. CONCLUSIONS: Biomarkers predicting the development of oesophageal adenocarcinoma would need to be fairly accurate and inexpensive to be cost-effective. These results should guide the development of biomarkers for oesophageal adenocarcinoma.

Adenocarcinoma↗
PubMed2003

Biomarkers in drug discovery and development: from target identification through drug marketing.

Biomarkers of disease play an important role in medicine and have begun to assume a greater role in drug discovery and development. The challenge for biomarkers is to allow earlier, more robust drug safety and efficacy measurements. Their role in drug development will continue to grow for the foreseeable future. For biomarkers to assume their rightful role, greater understanding of the mechanism of disease progression and therapeutic intervention is needed. In addition, greater understanding of the requirements for biomarker selection and validation, biomarker assay method validation and application, and clinical endpoint validation and application is needed. Biomarkers need to be taken into account while the therapeutic target is still being identified and the concept is being formulated. Biomarkers need to be incorporated into a continuous cycle that takes what is learned from the discovery and development of one series of biomarkers and translates it into the next series of biomarkers. Optimum biomarker development and application will require a team approach because of the multifaceted nature of biomarker selection, validation, and application, using such techniques as pharmacoepidemiology, pharmacogenetics, pharmacogenomics, and functional proteomics; bioanalytical method development and validation; disease process and therapeutic intervention assessments; and pharmacokinetic/pharmacodynamic modeling and simulation to improve and refine drug development. The potential for biomarkers in medicine and drug development will be limited by the least effective component of the processes. The team approach will minimize the potential for the least effective component to be fatal to the rest of the process. As scientific/regulatory foundations for biomarkers in medicine and drug development begin to be established, successes and applications will need to be effectively communicated with all of the stakeholders, including not only internal and external drug developers and regulators but also the medical community, to ensure that biomarkers are totally integrated into drug discovery and development as well as the practice of medicine.

Biomarkers↗