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PubMed1996

Stress proteins as molecular biomarkers for environmental toxicology.

Biomarkers are increasingly being used in environmental monitoring to provide evidence that organisms have been exposed to, or affected by, xenobiotic chemicals. Usually, these biomarkers rely on biochemical, histological, morphological, and physiological changes in whole organisms; however, changes at the cellular and molecular levels of organization, especially in nucleic acids and proteins, are increasingly being used to supplement these more traditional biomarkers. This chapter starts by giving a brief overview of biomarkers and some of the basic requirements for their effective use. Then stress-inducible proteins that are potentially useful as environmental biomarkers are explored, and some examples of their application as biomarkers and methods of detecting them are presented.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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↗
PubMed2005

The potential value of blood biomarkers of intervertebral disk metabolism in the follow-up of patients with sciatica.

STUDY DESIGN: This is a prospective study with a follow-up period of 4 years. OBJECTIVES: The study aimed to evaluate the possible clinical utility of three biomarkers [i.e., keratan sulfate (KS), hyaluronan, and cartilage oligomeric matrix protein] measured in peripheral blood in severe acute sciatica at intake and follow-up. SUMMARY OF BACKGROUND: Our previous study and others have pointed out the interest of different laboratory tests in the acute phase of sciatica. Several blood biomarkers have been reported useful in the long-term follow-up of patients with osteoarthritis. We have found no information about the potential interest of these tests in spinal disorders. METHODS: Patients were admitted to the hospital for intensive conservative management of acute sciatica (n=82). A subgroup of patients (n=33) was selected based on the duration of symptoms at visit 1, and included those with the shortest (n=24) as well as those with the longest (n=9) duration of sciatica. Blood samples were drawn, centrifuged, and the plasma frozen. Antigenic KS, hyaluronan, and cartilage oligomeric matrix protein were measured by ELISA. Patients were re-evaluated at an average of 4.3 years (range: 2.1-6.8 years). RESULTS: Thirty-three subjects with an average age of 49.2+/-10.2 years participated. At intake, levels of the three biomarkers evaluated were within the range of normal values. No significant differences were found between the results of patients with a short history of sciatica (< or =3 weeks) and those with a long duration of symptoms (>20 weeks). At follow-up, a significant increase (P<0.05) in all three biomarkers was found. CONCLUSIONS: A single measurement of these three biomarker molecules does not seem to have any diagnostic or therapeutic relevance in patients with acute radicular compression. The significance of the increase in all three biomarkers after a mean follow-up of 4.3 years is unclear; it might reflect metabolic processes involved in degenerative spinal disorders. Even though we found no correlation with clinical outcome, we believe that more research is needed.

Adult↗
PubMed2005

Using biomarkers to assess risk and consider treatment strategies in non-ST-segment elevation acute coronary syndromes.

Since the first biomarker of myocardial necrosis was described in 1954, cardiac-specific biomarkers have been increasingly identified. This, coupled with dramatic evolution in assay technology and resultant highly sensitive assays, has rendered a remarkable transformation in the medical use of biomarkers. Initially used to aid in diagnosis of myocardial infarction, newer biomarkers of inflammation, plaque instability, and ischemia may complement biomarkers of necrosis by providing tools to diagnose impending myocardial necrosis before irreversible damage occurs, and offering additional information for risk stratification. Importantly, biomarkers of different processes may be combined to enhance risk stratification above that of any single marker.

Angina, Unstable↗
PubMed2026

Unveiling novel transcriptomic prognostic biomarkers for specific breast cancer subtypes and treatment regimens.

BACKGROUND: Breast cancer (BRCA) is the most common cancer in women worldwide, yet current gene expression panels offer limited insight into treatment responses across different subtypes and therapies. This study aimed to identify reliable biomarkers for predicting treatment outcomes in specific BRCA subtypes and treatment regimens. METHODS: This study analyzed transcriptomic data from The Cancer Genome Atlas to identify differentially expressed genes (DEGs) in patient groups treated with different combinations of hormone therapy (H), chemotherapy (C), radiotherapy (R), and targeted therapy (T). Non-negative matrix factorization clustering was performed to stratify patients into clusters representing different BRCA subtypes. Functional enrichment analysis was performed, and survival assessments were conducted using the METABRIC dataset. RESULTS: A total of 1,148 DEGs were identified across treatment regimens, with 75 common DEGs shared across multiple regimens. Among these, 12 candidate biomarkers were associated with luminal subtypes treated with H, including LRP1B, of which high expression predicted cancer recurrence. In triple-negative breast cancer (TNBC) treated with C, 76 candidate biomarkers were identified, including TTYH1 for recurrence and ANXA8L1 and MPZ for non-recurrence. Functional analyses identified intermediate filament organization and keratinization as pathways associated with specific candidate biomarkers of TNBC following C. Survival analysis using METABRIC strengthened the prognostic ability of LRP1B and TTYH1 to predict worse survival and ANXA8L1 and MPZ to predict prolonged survival, with four additional prognostic biomarkers. CONCLUSION: This study identified gene expression prognostic biomarkers for luminal and TNBC subtypes, thereby supporting personalized therapies. Further experimental validation is required to confirm these findings for clinical application. CLINICAL TRIAL REGISTRY: No.

Breast cancer↗
PubMed1995

Biochemical biomarkers in ecotoxicology--some recent developments.

Biochemical biomarkers measure the exposure of organisms to environmental chemicals. They can also provide measures of toxic effect, e.g. where they are based on molecular mechanisms which underly toxicity. Ideally, biomarkers should be sensitive, specific, simple to use and suitable for the assay of material obtained by non-destructive sampling procedures (e.g. of blood). Recently, there has been encouraging progress in the development of several different types of biomarker assays: (1) The measurement of inhibition of serum 'B' esterases to monitor exposure of birds to organophosphorus insecticides. (2) The measurement of DNA damage caused by aromatic hydrocarbons. DNA adduct formation has been studied using the 32P-postlabelling technique. Several other techniques are currently under investigation. (3) The measurement of disturbances to the transthyretin-retinol binding protein complex caused by a metabolite of 3,4,3',4',tetrachlorobiphenyl. (4) The measurement of precursors of clotting proteins in blood following the inhibition of the Vitamin K cycle by anticoagulant rodenticides. Of these examples, the first is only a biomarker of exposure but the remaining three examples are, in principle, biomarkers of toxic effect since they all represent measures of molecular mechanisms which underly toxicity. Biochemical biomarkers have considerable potential for measuring effects of chemicals under field conditions--especially where carefully selected combinations of them are used.

Animals↗
PubMed1995

Opportunities for the development and use of biomarkers.

Limitations in understanding the relationship between occupational and environmental exposures and disease present opportunities for using biological markers to fill gaps in knowledge. Three situations can be identified that could foster the development and use of biomarkers, where epidemiological evidence is (1) definitive, (2) equivocal, and (3) lacking. When there is clear epidemiological evidence of disease risk given an exposure, biomarkers could be used to identify high- and low-risk subsets of a cohort that might benefit from differential practices such as counseling about job risks, varying frequency and intensity of medical surveillance, and using protective equipment. Biomarkers could also be used to test the effectiveness of environmental controls. Assessment of blood lead in bridge workers and purified protein derivative (PPD) testing in health care workers illustrates biomarkers that have been used to evaluate control efforts. When epidemiological evidence is equivocal, a broad and consistent database on intermediate biomarkers in the path between exposure and disease could provide a compelling case as to whether a substance should be treated as hazardous. The case of ethylene oxide illustrates this situation: the epidemiological evidence of risk of lymphohematopoietic cancer is equivocal but there is an informative database on genetic and cytogenetic changes in various species consistent with carcinogenicity. Biomarker data also can be used to assist in the interpretation of inconclusive epidemiological information as is illustrated in the case of styrene where markers provide a mechanistic rationale for the epidemiologic findings. When there is little or no epidemiological evidence of risk in an exposure situation, such as around hazardous waste operations or with new technologies, biological markers can serve as early warning indicators of exposure or risk. In such cases it is important to have an underlying biological theory and an appropriate epidemiological study design if the principal results are to be of value in indicating risk and preventing disease.

Biomarkers↗
PubMed1988

Biomarkers of aging.

This article presents a conceptual discussion of some aspects involved in biomarkers of aging. A biomarker of aging is a biological parameter of an organism that either alone or in some multivariate composite will, in the absence of disease, better predict functional capability at some late age than will chronological age. The reasons for undertaking biomarker research, criteria for putative biomarkers, measurement and assessment of putative biomarkers, and the new initiative by the National Institute on Aging in biomarker research are discussed.

Aging↗
PubMed2006

Cerebrospinal fluid biomarkers showing neurodegeneration in dogs with GM1 gangliosidosis: possible use for assessment of a therapeutic regimen.

The present study investigated cerebrospinal fluid (CSF) biomarkers for estimating degeneration of the central nervous system (CNS) in experimental dogs with GM1 gangliosidosis and preliminarily evaluated the efficacy of long-term glucocorticoid therapy for GM1 gangliosidosis using the biomarkers identified here. GM1 gangliosidosis, a lysosomal storage disease that affects the brain and multiple systemic organs, is due to an autosomal recessively inherited deficiency of acid beta-galactosidase activity. Pathogenesis of GM1 gangliosidosis may include neuronal apoptosis and abnormal axoplasmic transport and inflammatory response, which are perhaps consequent to massive neuronal storage of GM1 ganglioside. In the present study, we assessed some possible CSF biomarkers, such as GM1 ganglioside, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and myelin basic protein (MBP). Periodic studies demonstrated that GM1 ganglioside concentration, activities of AST and LDH, and concentrations of NSE and MBP in CSF were significantly higher in dogs with GM1 gangliosidosis than those in control dogs, and their changes were well related with the months of age and clinical course. In conclusion, GM1 ganglioside, AST, LDH, NSE and MBP could be utilized as CSF biomarkers showing CNS degeneration in dogs with GM1 gangliosidosis to evaluate the efficacy of novel therapies proposed for this disease. In addition, we preliminarily treated an affected dog with long-term oral administration of prednisolone and evaluated the efficacy of this therapeutic trial using CSF biomarkers determined in the present study. However, this treatment did not change either the clinical course or the CSF biomarkers of the affected dog, suggesting that glucocorticoid therapy would not be effective for treating GM1 gangliosidosis.

Animals↗
PubMed2006

The amplified peptidome: the new treasure chest of candidate biomarkers.

Mass spectrometric analysis of the low-molecular weight (LMW) range of the serum/plasma proteome is revealing the existence of large numbers of previously unknown peptides and protein fragments predicted to be derived from low-abundance proteins. This raises the question of why such low abundance molecules would be retained at detectable levels in the circulation, instead of being rapidly cleared and excreted. Theoretical models of biomarker production and association with serum carrier proteins have been developed to elucidate the mechanisms governing biomarker half-life in the bloodstream. These models predict that the vast majority of LMW biomarkers exist in association with circulating high molecular mass carrier proteins. Moreover, the total serum/plasma concentration of the biomarker is largely determined by the clearance rate of the carrier protein, not the free-phase biomarker clearance itself. These predictions have been verified experimentally using molecular mass fractionation of human serum before mass spectrometry sequence analysis. These principles have profound implications for biomarker discovery and measurement.

Biomarkers↗
PubMed2006

Biomarker responses in European eel (Anguilla anguilla) exposed to persistent organic pollutants. A field study in the Vaccarès lagoon (Camargue, France).

A screening of relevant biomarkers was carried out in order to evaluate metabolic and cellular damages in European eels exposed to a non-point source contamination by persistent organic pollutants (POP) such as polycyclic aromatic hydrocarbons (PAH) and organochlorine compounds (OC) in a protected area, the Nature Reserve of Camargue (France). Investigations were focused on metabolic responses including detoxification mechanisms (biotransformation, antioxidant process), energy requirements and enzymatic membrane markers either involved in neuronal conduction (acetylcholinesterase, AChE) or in osmoregulation and energy metabolism (ATPases). The hepatic and muscular glycogen rates seemed to be suitable biomarkers as well as three hepatic activities involved in the protection against oxyradicals: catalase, glutathione peroxidase (SeGPx) and superoxide dismutases (SOD). The muscle and gill ATPases as well as the muscle and brain AChE showed more significant relevance in terms of biomarkers than the biotransformation enzymes: ethoxyresorufine-O-deethylase (EROD) and uridine diphospho-glucuronyl transferase (UDPGT). However, most of these enzymatic activities depend on numerous abiotic factors, which must be taken into account in such a biomarker assessment approach. Our study provides some conclusive elements to approve the use in situ of biomarkers developed from laboratory studies. It also raises a question regarding the location of contaminant impregnation in fish organ, in relation with age, development status or mode of contamination, and its influence on biomarker response. If the relevance of membrane indicators is confirmed, this study provides an original statement of the extent of the ecotoxicological threat for the aquatic species in a protected area, due to the occurrence of POP in the cell membranes.

Acetylcholinesterase↗
PubMed2006

Link test--A statistical method for finding prostate cancer biomarkers.

We present a new method, link-test, to select prostate cancer biomarkers from SELDI mass spectrometry and microarray data sets. Biomarkers selected by link-test are supported by data sets from both mRNA and protein levels, and therefore results in improved robustness. Link-test determines the level of significance of the association between a microarray marker and a specific mass spectrum marker by constructing background mass spectra distributions estimated by all human protein sequences in the SWISS-PROT database. The data set consist of both microarray and mass spectrometry data from prostate cancer patients and healthy controls. A list of statistically justified prostate cancer biomarkers is reported by link-test. Cross-validation results show high prediction accuracy using the identified biomarker panel. We also employ a text-mining approach with OMIM database to validate the cancer biomarkers. The study with link-test represents one of the first cross-platform studies of cancer biomarkers.

Algorithms↗
PubMed2004

A review of lysosomal membrane stability measured by neutral red retention: is it a workable earthworm biomarker?

The ability of biomarkers to integrate effects of chemicals on biota has lead to increased calls for their application in assessing the status of polluted ecosystems. In tandem there has been an increase in our knowledge of the ecophysiological responses of keystone species to pollutants, which has allowed the development of a number of promising methods. In contrast to the number of biomarker development studies, the number of biomarker validation studies has remained limited. This paper redresses this imbalance by drawing together data from studies that have used the earthworm lysosomal membrane stability response (measured using the neutral red retention assay). This review first gives a short history of the biomarker's development. Second, it sets published applications of the technique against established criteria for a "good" biomarker (i.e., dose-response relationship, sensitivity, ecological relevance, confounding factors, chemical specificity, species differences, time-response relationship, methodological concerns, and overall public/regulator confidence, and acceptance). Discussion of the biomarker's suitability to each criterion is followed by an overall evaluation of its workability for routine soil quality assessment and caveats for its use.

Animals↗
PubMed2006

Assessment of the impact of heavy metal pollution from a ferro-nickel smelting plant using biomarkers.

A set of biomarkers was used to assess the impact of heavy metal pollution by a ferro-nickel smelting plant in Larymna bay (North Evoikos Gulf, Greece). These included a biomarker reflecting health status of an organism (scope for growth, SFG), a cellular biomarker of heavy metal exposure (composition of metal-containing granules), and two biochemical biomarkers reflecting oxidative stress (glutathione peroxidase, GPX) and neurotoxicity (acetylcholinesterase, AChE) measured in mussels (Mytilus galloprovincialis) both native and transplanted for 1 and 6 months at the coastal area of Larymna. All biomarkers in mussels at Larymna revealed differences from mussels at a reference site, signaling effects of the increased heavy metal levels on the biota. While effects on SFG and GPX in Larymna mussels were obvious on short-term exposure and persistent during chronic exposure, only chronic exposure induced a possibly cumulative effect on AChE. To validate the causal relationship between heavy metal exposure and effects observed in Larymna, SFG, GPX, and ACHE were examined in mussels exposed to a mixture of heavy metals (Ni, Cr, and Fe) under controlled laboratory conditions. The laboratory experiment verified the causal relationship between SFG and GPX responses and heavy metals but this was not demonstrated for AChE. Results from field-collected and laboratory-exposed mussels indicated a potential of GPX as predictive biomarker of population-level effects of heavy metal exposure.

Acetylcholinesterase↗
PubMed2007

Predictive value of cell cycle biomarkers in nonmuscle invasive bladder transitional cell carcinoma.

PURPOSE: We determined whether the combined expression of p53, p21, p27 and pRB is associated with outcomes of patients with nonmuscle invasive bladder transitional cell carcinoma. MATERIALS AND METHODS: Immunohistochemical staining for p53, p21, p27 and pRB was performed on archival bladder specimens from 9 normal controls and 74 patients who underwent transurethral bladder tumor resection for Ta, Tis and/or T1 transitional cell carcinoma. RESULTS: Normal urothelium had wild type status of p53, pRB, p21 and p27. p53 expression was altered in 34% of patients with transitional cell carcinoma, pRB in 39%, p21 in 35% and p27 in 47%. When analyzed separately, p53, pRB and p21 were each independently associated with tumor progression. Combination of biomarkers stratified patients into statistically significantly different risk groups for disease recurrence and progression. When tumor stage and grade were modeled with all 4 biomarkers, p53 and p27 were the sole independent predictors of disease recurrence and progression. After controlling for the effects of tumor grade and stage, the incremental number of altered biomarkers was associated with an increased risk of bladder cancer recurrence (p for trend = 0.011) and progression (p for trend = 0.005). The risk ratio for disease recurrence and progression increased incrementally with the number of biomarkers altered. CONCLUSIONS: Combinations of p53, pRB, p21 and p27 had cooperative/synergistic effects stratifying patients into different risk groups. Higher total numbers of altered biomarkers were independently associated with an increased risk of disease progression and death. Prospective trials are necessary to usher bladder cancer management into the age of molecular biomarkers.

Adult↗
PubMed2005

Monitoring of hematological, inflammatory and oxidative reactions to acute oral iron exposure in human volunteers: preliminary screening for selection of potentially-responsive biomarkers.

BACKGROUND: Iron is an essential micronutrient but also a major catalyst of oxidative and inflammatory reactions. OBJECTIVE: To evaluate the potential utility of selected biomarkers in blood or urine to indicate in vivo oxidative or inflammatory response to oral iron intake at pharmacological doses. METHODS: Three healthy volunteers provided morning, fasting samples of blood and urine on up to 13 study days--3 before, 7 during and 3 following a 7-consecutive-day period of receiving 120 mg of iron per day as ferrous sulfate in commercially available syrup. A series of 23 biomarkers were measured on each collection of biological fluids to monitor iron-responsive changes in biomarkers related to hematological or iron status, inflammation and in vivo oxidation. RESULTS: Among the inflammatory biomarkers measured, white blood cells, serum CRP and urinary neopterin showed no response to iron dosing. Only circulating interleukin-4 (IL-4) and TNF-alpha had abnormal responses with a time association to the oral iron intake. Among the oxidative biomarkers, expression of blood superoxide dismutase (SOD), hemoxygenase-1, catalase as well as circulating thiobarbituric acid reactive substances (TBARS), total oxidative capacity and carbonyl proteins were stable in response to iron exposure. Only urinary TBARS, 8-hydroxy-2-desoxyguanosine and isoprostanes evidenced consistent or suggestive responses to ingestion of the iron challenge. Serum hepcidin concentration increased dramatically in all three subjects after only the first 120 mg dose of iron, and remained elevated even 9 days after cessation of the iron intervention. CONCLUSIONS: Most of the candidate biomarkers show very limited promise as response-indicators to oral iron dosing at the 120 mg dosages or lower, but circulating IL-4, TNF-alpha as well as urinary TBARS, 8-hydroxy-2-desoxyguanosine and isoprostanes showed potential utility as reliable indicators of oxidative and inflammatory response to oral ferrous sulfate.

Administration, Oral↗
PubMed2006

Biomarkers in environmental carcinogenesis research: striving for a new momentum.

During the past 30 years biomarker-based approaches have been employed in the area of environmental carcinogenesis research with the expectation of refining exposure assessment, providing tools for the early detection of disease-related changes and their association with environmental and genetic factors and, thus, facilitating improved understanding of the etiology of human cancer. Great advances have been achieved in the development of analytical methodologies for the measurement of various types of biomarkers, including chemical-specific biomarkers of exposure, as well as in the characterisation of genetic variation in many genes of relevance to carcinogenesis and the assessment of its impact on cancer risk. However, despite the enormous effort invested in these investigations, the progress achieved in terms of the identification of environmental or genetic factors which affect substantially cancer risk among the general population is relatively limited. It is suggested that progress towards this goal may be facilitated by a concerted effort to promote thorough validation of chemical-specific biomarkers of exposure for which adequate analytical methodologies are available, the development of reliable and high-throughput phenotypic assays of biomarkers of susceptibility and the formulation of a systems biology approach to the analysis of the modulation of biomarkers by environmental and genetic factors.

Biomarkers↗
PubMed2006

Relationship between machine-derived smoke yields and biomarkers in cigarette smokers in Germany.

In order to determine whether smokers of cigarettes in the contemporary yield ranges of the German market (0.1-1.0mg nicotine, 1-10mg tar) differ in their actual exposure to various smoke constituents, we performed a field study with 274 smokers and 100 non-smokers. The following biomarkers were determined: In 24-h urine: Nicotine equivalents (molar sum of nicotine, cotinine, trans-3'-hydroxycotinine and their respective glucuronides), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL, metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, NNK), 3-hydroxypropylmercapturic acid (metabolite of acrolein), trans,trans-muconic acid, S-phenylmercapturic acid (metabolites of benzene), 1-hydroxypyrene (metabolite of pyrene); in saliva: Cotinine and trans-3'-hydroxycotinine; in exhaled air: Carbon monoxide; in blood: Methyl-, hydroxyethyl-, cyanoethyl- (biomarker of acrylonitrile) and carbamoylethylvaline (biomarker of acrylamide) hemoglobin adducts. All biomarkers were found to be significantly higher in smokers compared to non-smokers and showed strong correlations with the daily cigarette consumption. Biomarker levels and per cigarette increases in smokers were at most weakly related to the machine-derived smoke yields. It is concluded that machine-derived yields of cigarettes from the contemporary German cigarette market have little or no impact on the actual smoking-related exposure determined by suitable biomarkers.

Adolescent↗