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PubMed1999

Preoperative p53, bcl-2, CD44 and E-cadherin immunohistochemistry as predictors of biochemical relapse after radical prostatectomy.

PURPOSE: Since radical prostatectomy is performed to cure prostate cancer, identification of markers enabling preoperative prediction of relapse after radical prostatectomy is essential to counsel and select patients for adjuvant therapy. Aberrant p53, bcl-2, CD44 and E-cadherin immunohistochemistry has been associated with aggressiveness in prostate cancer. We assessed these biomarkers in biopsy and radical prostatectomy specimens as predictors of biochemical relapse. MATERIALS AND METHODS: A total of 76 patients with untreated clinically localized prostatic adenocarcinoma underwent radical prostatectomy. Preoperative (prostate specific antigen, biopsy Gleason score) and postoperative (pathological stage and margin status) variables, biopsy and radical prostatectomy biomarker immunohistochemistry were correlated with relapse. Univariate and multivariate statistical analyses identified significant predictors. RESULTS: Of the 76 patients 23 (30%) had relapse (mean followup 38 months). Aberrant p53, bcl-2, CD44 and E-cadherin expression was observed in 64, 12, 85 and 12% of biopsies and 57, 20, 64 and 49% of radical prostatectomy specimens, respectively. Biopsy Gleason 7 to 10 and biopsy p53, respectively, gave the highest positive and negative predictive values for relapse. Relapse occurred in 13% of patients with normal biopsy p53 and in half with aberrant p53. Multivariate analysis revealed Gleason score and p53 to be independent preoperative predictors (p = 0.01 and 0.02, respectively). Estimated risk of relapse was 3.5 times higher in patients with Gleason scores 7 to 10 and 24% higher in those with aberrant p53. Significant postoperative predictors were bcl-2, p53, Gleason score and margin status (p = 0.01, 0.01, 0.04 and 0.01, respectively). CONCLUSIONS: Aberrant biopsy p53 is associated with a significantly worse outcome after radical prostatectomy than normal p53, highlighting a potential clinical role for p53. Postoperative p53 and bcl-2 were significant predictors of outcome after radical prostatectomy.

Aged↗
PubMed1999

Within-person variability of the ratios of urinary 2-hydroxyestrone to 16alpha-hydroxyestrone in Caucasian women.

The ratio of urinary 2-hydroxyestrone (2-OHE1) to 16alpha-hydroxyestrone (16alpha-OHE1) has been suggested as a potential biomarker for breast cancer risk. We evaluated within-person variability of this biomarker in ten healthy Caucasian women aged 23-58 years. Each study participant was asked to provide an overnight fasting morning urine sample once a week for an average of 8 weeks. These urine samples were assayed for 2-OHE1 and 16alpha-OHE1 by using competitive enzyme immunoassay kits purchased from the ImmunaCare Corporation. The coefficients of variation for urinary 2-OHE1/16alpha-OHE1 over the study period ranged from 13.7 to 59.6% (mean, 33.3%) in our study participants. There was a good correlation between the level of the urinary 2-OHE1/16alpha-OHE1 ratio in any single urine sample and the average ratio over the 8-week study period from the same woman, with the mean correlation coefficient of 0.85. These results indicated that the within-person variation of the 2-OHE1 to 16alpha-OHE1 ratio for most women was moderate and the level of this ratio in a single urine sample, in general, reflects reasonably well the level of this biomarker over a 2-month period.

Adult↗
PubMed2006

Papillary urothelial neoplasm of low malignant potential: evolving terminology and concepts.

PURPOSE: The most controversial aspect of the new WHO 2004/ISUP classification system is the creation of the PUNLMP diagnostic category. We discuss PUNLMP tumors and the WHO 2004/ISUP classification system with an emphasis on tumor morphology and heterogeneity, recurrence and progression rates, tumor genetics, interobserver variability and the usefulness of biomarkers and molecular diagnostic techniques for grading bladder tumors. MATERIALS AND METHODS: A literature search using PubMed was performed. All relevant literature concerning PUNLMP and the WHO 2004/ISUP grading system for urothelial neoplasms was reviewed. RESULTS: The new WHO 2004/ISUP classification reflects work in progress. Low malignant potential terminology may not reflect the true biological behavior of these tumors. Additionally, interobserver variability in making a diagnosis of PUNLMP is high despite detailed histological criteria. Urine cytopathology in the context of the WHO 2004/ISUP classification does not appear to effectively discriminate PUNLMP from low grade carcinoma. CONCLUSIONS: For practical purposes patients with PUNLMP should be treated similarly to patients with low grade, noninvasive urothelial carcinoma. It is our hope that recent advances in the molecular grading of these tumors may eventually supplant traditional morphological classification, allowing a more precise and objective assessment of the biological potential of these tumors.

Carcinoma, Papillary↗
PubMed2003

Recommendations on use of biomarkers in alcoholism treatment trials.

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

Alcoholism↗
PubMed2005

Lymph node metastases in non-muscle invasive bladder cancer are correlated with the number of transurethral resections and tumour upstaging at radical cystectomy.

UNLABELLED: The first paper in this section, from Mainz, attempts to identify the clinical variables associated with the prevalence of lymph node metastases in non-muscle invasive bladder cancer. The authors found that delay in cystectomy in this potentially dangerous type of tumour is to be avoided, with a higher incidence of lymph node metastases as the number of transurethral resections increases. A paper from Austria shows that in renal carcinoma the pT1 subdivision is associated with differences in conventional histopathology and expression of biomarkers. OBJECTIVE: To identify clinical variables associated with the prevalence of lymph node metastases (LNMs) in patients with non-muscle invasive transitional cell carcinoma (TCC) of the bladder treated with radical cystectomy. PATIENTS AND METHODS: Of 866 patients treated by radical cystectomy and pelvic lymphadenectomy between 1989 and 2002, 219 had non-muscle invasive TCC of the bladder. A retrospective evaluation of these patients included univariate and multivariate analyses of sex, age, number of transurethral resections of the bladder tumour (TURBTs), interval between first TURBT and cystectomy, adjuvant therapy, maximum histopathological tumour stage and grade at TURBT, and tumour upstaging in the cystectomy specimen. RESULTS: LNMs were diagnosed in 33 patients (15%). After multivariate analysis modelling, the number of TURBTs and tumour upstaging in the cystectomy specimen were correlated with the prevalence of LNMs at cystectomy. The number of TURBTs increased the prevalence of LNMs from 8% in patients with one TURBT to 24% in those with two to four TURBTs. Tumour upstaging in the cystectomy specimen increased the prevalence of LNMs from 4% to 36%. CONCLUSION: Inappropriate delay and inadequate staging of high-grade non-muscle invasive TCC of the bladder are to be avoided. The present multivariate analysis showed that the number of TURBTs and tumour upstaging in the cystectomy specimen correlated with an increased prevalence of LNMs.

Adult↗
PubMedDate not supplied

[Biologically effective dose biomarkers].

Biologically effective dose markers--DNA and protein adducts--are classified among exposure biomarkers, and are currently used to assess the biologically active fraction of xenobiotics, which is capable of interacting with cellular macromolecules at the target site. Macromolecular adducts should not only be considered as exposure indicators; indeed, their biological significance can also be extended to biomarkers of effect and of susceptibility. The achievement of such a goal needs research programs aimed both at studying molecular mechanisms related to each step along the continuum of events between exposure and disease, and at establishing quantitative relationships between exposure levels and adduct formation, between adducts and early biological effects, effects and cellular structural/functional modifications, leading to the development and eventual increase in incidence of specific diseases. Moreover, different factors must be considered during data evaluation, such as interindividual variability, the background levels of biomarkers in non occupationally exposed population, the gradually decreasing doses of genotoxic agents involved in occupational exposure, and confounding factors such as diet and smoking habits. Despite the large body of literature documenting DNA and protein adduct molecular dosimetry for many carcinogen exposures, many authors highlight the need for systematic interlaboratory comparison and collaboration by measuring the same biomarkers using different techniques and/or different biomarkers related to the same exposure levels. There is also general agreement about reducing costs, so that dosimetric analyses can become economically more advantageous and accessible in all cases where they prove to be useful in preventing health risks.

Biomarkers↗
PubMed1994

Increasing the power of surrogate endpoint biomarkers: the aggregation of predictive factors.

A variable that predicts an outcome with sufficient accuracy is called a predictive factor. Predictive factors can be divided into three types based on the outcomes to be predicted and on the accuracy with which they can be predicted. These three types include risk factors, where the main outcome of interest is incidence and the predictive accuracy is less than 100%; diagnostic factors, where the main outcome of interest is also incidence but the predictive accuracy is almost 100%; and prognostic factors, where the main outcome of interest is death and the predictive accuracy is variable. Surrogate outcomes are predictive factors that are used for a purpose beyond the prediction of an outcome--surrogate outcomes are predictive factors that are substituted for the true outcome in order to determine the effectiveness of an intervention. Surrogate outcomes used in clinical trials are called intermediate endpoints and surrogate endpoints. Predictive factors used as surrogate outcomes have a poor accuracy rate in predicting the true outcome; aggregating risk factors increases predictive accuracy. Artificial neural networks effectively combine predictive factors. Aggregating predictive factors increases the degree of linkage of the surrogate outcome to the true outcome. The resulting increase in predictive accuracy allows enrollment of people most likely to benefit from intervention. This increases the trial's efficiency, reducing the number of people required to assess a chemopreventive agent.

Anticarcinogenic Agents↗
PubMed2003

Intraclonal variability in Daphnia acetylcholinesterase activity: the implications for its applicability as a biomarker.

The relationship between individual growth and acetylcholinesterase (AChE) activity was evaluated for Daphnia magna. Analysis on the influence of two different culture media on baseline AChE activity was performed with Daphnia similis. The results indicated an inverse relationship between D. magna body length and AChE activity. An increase in total protein, which was not proportional to an increase in the rate of the substrate hydrolysis (delta absorbance/min), seems to be the reason for this inverse size versus AChE activity relationship. Therefore, toxicants such as phenobarbital, which affect protein and size but not AChE activity directly, have an overall affect on AChE activity. In contrast, the AChE inhibitor parathion altered AChE activity but not protein. Culture medium also had a significant affect on AChE activity in D. similis. Changes in total protein seem to be the main reason for the variations in baseline AChE activity in Daphnia observed in the different evaluations performed in this work. Therefore, AChE activity in Daphnia must be interpreted carefully, and variations related to changes in total protein must be taken into account when applying this enzyme as a biomarker in biological monitoring.

Acetylcholinesterase↗
PubMed2002

Seasonal variations of pollution biomarkers in two populations of Corbicula fluminea (Müller).

Seasonal variations of pollution biomarkers have been studied in two populations of Corbicula fluminea (Müller) for 2 years. Clams were collected from the Sanguinet lake and the Dronne river (Southwest France), sites characterised by water of excellent and passable quality, respectively. Biological parameters studied were enzymatic activity (catalase, propionylcholinesterase, glutathione S-transferase, NADPH-cytochrome c reductase and NADH-cytochrome c reductase activities) and indicators of physiological (protein, carbohydrate, lipid and ash contents, fresh and dry tissue weights, condition factor) and reproductive (amount of oocytes present in gonads and clams incubating larvae in gills) status. Environmental parameters (e.g. water temperature, chlorophyll a concentration) were also monitored. Effects of site, sampling date and season (from spring to winter) were studied, as well as relationships between abiotic and biotic factors. Finally, an index of variability was calculated for each biomarker. Catalase, propionylcholinesterase, NADH-cytochrome c reductase and lipids experienced the most pronounced seasonal fluctuations, whereas glutathione S-transferase, NADPH-cytochrome c reductase and proteins suffered less pronounced ones. For some parameters, results differed depending on the site. Most seasonal changes were related to the reproductive cycle and/or water temperature. Implications of such variations in the use of pollution biomarkers in environmental surveys are discussed.

Animals↗
PubMed2006

Variable number of tandem repeats of TNF receptor type 2 promoter as genetic biomarker of susceptibility to develop invasive pulmonary aspergillosis.

Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin alpha (LT-alpha) are pivotal mediators of inflammatory responses in fungal infection diseases. We hypothesized that polymorphisms in genes of these cytokines or their receptors might increase the susceptibility of hematologic patients to develop invasive pulmonary aspergillosis (IPA). One hundred two hematologic patients and 124 age-matched controls were enrolled in the study, and the following standard single nucleotide polymorphisms were investigated: TNF-alpha -308 and +489, LT-alpha +252 and Tumor Necrosis Factor Receptor 2 (TNFR2) +676. Variable number of tandem repeats (VNTRs) at position -322 of the TNFR2 gene were also studied. Genotypic and allelic frequencies were similar between patients and controls. IPA was diagnosed in 54 of the 102 patients according to consensus criteria published by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group. TNF-alpha and LT-alpha polymorphisms were not associated with presence of IPA. Susceptibility to IPA was strongly associated with VNTR at position -322 in the promoter region of the TNR2 gene (p = 0.029) but was not associated with the presence of TNFR2 +676 polymorphism. A genetic difference in TNFR2 promoter VNTR may play a major role in susceptibility to IPA infection.

Aspergillosis↗
PubMed2025

Uncovering the genetic architecture of ME/CFS: a precision approach reveals impact of rare monogenic variation.

BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling and heterogeneous disorder lacking validated biomarkers or targeted therapies. Clinical variability and elusive pathophysiology hinder progress toward effective diagnostics and treatment. Core symptoms include persistent fatigue, post-exertional malaise, unrefreshing sleep, cognitive dysfunction, and pain. We tested whether an individualized, “n-of-1” genomic and transcriptomic framework combined with comprehensive, participant-informed phenotyping could reveal molecular signatures unique to each patient. METHODS: Clinical-grade whole-genome sequencing was conducted in 31 affected individuals from 25 families, with RNA-seq performed on a subset (16 affected, 7 unaffected) using blood samples. Machine-learning assisted variant triage, transcript-aware damage prediction, and expert review identified pathogenic or likely pathogenic variants in 8 of 25 probands (32%) and 12 of 31 affected individuals (39%). RESULTS: Findings revealed marked genetic heterogeneity, including large-effect rare and more common variants. Implicated pathways included ATP generation, oxidative phosphorylation, fatty acid oxidation; regulation of glycolysis, amino acid and lipid turnover; ion and solute homeostasis; synaptic signaling, excitability, oxygen transport, and muscle integrity, resilience, and post-exertional recovery; previously implicated processes. Plausible modifiers influencing disease onset, severity, and relapsing–remitting patterns and possibly explaining intrafamilial variability and inconsistent findings across studies, were also identified. Despite gene-level diversity, downstream effects converged on impaired energy production, reduced stress resilience, and vulnerability to post-exertional metabolic failure; disruptions consistent with core ME/CFS symptoms of exertional intolerance, cognitive fog, and fatigue. CONCLUSIONS: Our findings support the hypothesis that at least a subset of ME/CFS cases represent distinct molecular disorders that converge on shared physiological pathways. Validation in larger, more diverse cohorts will be essential to test this hypothesis and establish generalizability, but increase size alone is unlikely to resolve causation in a disorder defined by rarity, heterogeneity, and molecular complexity. We suggest that progress will require experimental designs that integrate individual-level genomic data with deep, participant-informed deep phenotyping, capturing the combined effects of rare and common variants and environmental modifiers on disease expression and progression. We believe that an individualized precision medicine framework will uncover molecular drivers and modifiers of ME/CFS previously obscured by heterogeneity, enabling biologically informed stratification, improved trial design, biomarker discovery, and targeted interventions in this historically neglected condition.

Humans↗
PubMed2000

Predicting cancer development in oral leukoplakia: ten years of translational research.

Our 10-year translational study of the oral premalignant lesion (OPL) model has advanced the basic understanding of carcinogenesis. Although retinoids have established activity in this model, a substantial percentage of our OPL patients progress to cancer, especially after treatment is stopped. On the basis of our 10-year OPL study, we have developed the first comprehensive tool for assessing cancer risk of OPL patients. This cancer risk assessment tool incorporates medical/demographic variables, epidemiological factors, and cellular and molecular biomarkers. Between 1988 and 1991, 70 advanced OPL patients were enrolled in a chemoprevention trial of induction with high dose isotretinoin (1.5 mg/kg/day for 3 months) followed by 9 months of maintenance treatment with either low dose isotretinoin (0.5 mg/kg/day) or beta-carotene (30 mg/d; total treatment duration, 1 year). We assessed the relationship between cancer risk factors and time to cancer development by means of exploratory data analysis, logrank test, Cox proportional hazard model, and recursive partitioning. With a median follow-up of 7 years, 22 of our 70 patients (31.4%) developed cancers in the upper aerodigestive tract following treatment. The overall cancer incidence was 5.7% per year. The most predictive factors of cancer risk are OPL histology, cancer history, and three of the five biomarkers we assessed (chromosomal polysomy, p53 protein expression, and loss of heterozygosity at chromosome 3p or 9p). In the multivariable Cox model, histology (P = 0.0003) and the combined biomarker score of chromosomal polysomy, p53, and loss of heterozygosity (P = 0.0008) are the strongest predictors for cancer development. Retinoic acid receptor beta and micronuclei were not associated with increased cancer risk. We have demonstrated a successful strategy of comprehensive cancer risk assessment in OPL patients. Combining conventional medical/demographic variables and a panel of three biomarkers can identify high risk patients in our sample. This result will need to be validated by future studies. With the identification of high risk individuals, more efficient chemoprevention trials and molecular targeting studies can be designed.

Alcohol Drinking↗
PubMed1997

Rett syndrome: neurobiological changes underlying specific symptoms.

Rett syndrome (RS) is a progressive disorder that is predominant in females. It is associated with cortical atrophy, stereotyped hand movements mimicking hand-washing, severe mental deficiency, and cortical and extrapyramidal dysfunction. The cause of RS is unknown; no consistent genetic abnormalities, at either the cellular or mitochondrial levels, have been identified. The diagnosis still depends solely upon clinical evidence. The clinical progression of RS is consistent with an arrested neuronal development that may be due to either impaired cellular differentiation or the lack of appropriate trophic factors. Neuropathological studies have confirmed (1) a generalized brain atrophy involving the cerebrum and cerebellum; (2) a decrease in neuronal cell size and increased cell packing density throughout the brain; (3) a reduction in the number of basal forebrain cholinergic neurons; (4) a reduction in the concentration of melanin-containing neurons in the substantia nigra. Biochemical studies have identified (1) a decrease in cholinergic markers in the neocortex, hippocampus, thalamus and basal ganglia; (2) inconsistent and variable changes in biogenic amine biomarkers in post-mortem tissues and cerebrospinal fluid (CSF); (3) an elevation of beta-endorphin levels in the thalamus and glutamate levels in the CSF; (4) no evidence for mitochondrial dysfunction. These data suggest that there is a primary deficit in cholinergic function that might underlie some of the higher cognitive impairments and extrapyramidal dysfunction. Overall, the clinical, biochemical and neuropathological data suggest that RS is a neurodevelopmental disorder that has its greatest effects upon a limited number of neural systems during the first few years of postnatal life.

Humans↗
PubMed2001

Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion.

Successful reperfusion after acute myocardial infarction (MI) has traditionally been considered to be restoration of epicardial patency, but increasing evidence suggests that disordered microvascular function and inadequate myocardial tissue perfusion are often present despite infarct vessel patency. Thus, optimal reperfusion is being redefined to include intact microvascular flow and restored myocardial perfusion, as well as sustained epicardial patency. Coronary angiography has been used as the gold standard to define failed reperfusion, according to the Thrombolysis In Myocardial Infarction (TIMI) flow grades. However, new angiographic techniques, including the corrected TIMI frame count and myocardial blush grade, have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success. Furthermore, evolving noninvasive diagnostic techniques, including measurement of infarct size with cardiac marker release patterns or technetium-99m-sestamibi single-photon emission computed tomographic imaging and analysis of ST segment resolution appear to be useful complements to angiography for the assessment of myocardial tissue reperfusion. Promising adjunctive therapies that target microvascular dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, and agents designed to improve tissue perfusion and attenuate reperfusion injury are being evaluated to further improve clinical outcomes after acute MI. To accelerate development of these new reperfusion regimens, an integrated approach to phase II clinical trials that incorporates multiple efficacy variables, including angiography and noninvasive biomarkers of microvascular dysfunction, should be considered. Thus, as the reperfusion era moves into the next millennium, the open-artery hypothesis is expected to shift downstream and guide efforts to further improve myocardial salvage and clinical outcomes after acute MI.

Animals↗
PubMed2007

Onset of depression in elderly persons after hip fracture: implications for prevention and early intervention of late-life depression.

OBJECTIVES: To identify predictors of onset of major depressive disorder (MDD) and of depressive symptoms in subjects who suffered a hip fracture. DESIGN: Prospective naturalistic study. SETTING: University of Pittsburgh Medical Center-Shadyside, a large urban hospital in Pittsburgh, Pennsylvannia. PARTICIPANTS: One hundred twenty-six elderly patients who received surgical fixation for hip fracture and who were not experiencing a major depressive episode at the time of the fracture; severely cognitively impaired persons were excluded. MEASUREMENTS: Subjects were evaluated at the time of hospital discharge using a battery of clinical measures (including apathy measured using the Apathy Evaluation Scale (AES), delirium, cognitive measures, social support, and disability level). Depression was assessed at the end of the surgical stay, 2 weeks later, and then monthly for 6 months, using the Hamilton Rating Scale for Depression (Ham-D) to evaluate symptomatology and the Primary Care Evaluation of Mental Disorders to evaluate diagnosis of MDD. RESULTS: Eighteen of 126 subjects (14.3%) developed MDD after hip fracture. Of these, 11 developed MDD by the end of the hospitalization, and seven developed MDD between 2 and 10 weeks later. Logistic regression showed that baseline apathy score, as measured using the AES, was the only clinical measure associated with the development of MDD (odds ratio=1.09, 95% confidence interval=1.03-1.16, P=.003); 46.2% of those with high AES scores developed MDD, versus 10.9% of those with lower scores. In contrast, cognitive variables, delirium, disability after hip fracture, and other factors related to the fracture (e.g., fracture type) were not associated with MDD. A repeated-measures analysis with Ham-D over time as a dependent variable generally confirmed these findings; depressive symptoms were highest immediately after the fracture, and apathy and delirium scores were associated with higher depressive symptom levels. CONCLUSION: The onset of MDD is common after hip fracture, and the greatest period of risk is immediately after the fracture. Individuals with clinical evidence of apathy are at high risk for developing MDD, and evaluation and close follow-up of such individuals is warranted. However, further research is needed to examine other candidate variables (e.g., clinical measures or biomarkers) to model adequately the risk for MDD after hip fracture and other disabling medical events.

Affect↗
PubMed1998

Important variables that influence base-line micronucleus frequency in cytokinesis-blocked lymphocytes-a biomarker for DNA damage in human populations.

The cytokinesis-block micronucleus (CBMN) assay has been adopted by numerous laboratories as a means for rapidly assessing base-line chromosome damage (breakage and loss) in human populations. However, the appropriate implementation of this assay requires a thorough understanding of both experimental variables and biological factors that can have impact on micronucleus (MN) frequency. The paper describes, with the help of experimental data the from the author's laboratory as well as other data, the impact of these variables. With regards to experimental variables, the scoring of micronuclei on slides by different technicians has been identified as an important factor; however, the use of different culture media, namely RPMI 1640 and McCoy's medium, did not have a significant effect on base-line frequencies. The paper also describes results showing that the MN index in cytokinesis-blocked cells, measured once every three months over a 12-month period for 53 healthy subjects, remains constant and the data measured on these occasions were significantly and positively correlated (R=0.477 to 0.684, P<0. 0001) with each other thus indicating the reliability and intra-individual variability of the assay over time. Inter-individual variation for males and female subjects has been estimated for each decade of age between 20 and 80 years; the difference between the 25th and 75th percentile of MN frequency varied between 1.4 fold and 2.3 fold and the minimum and maximum values for MN frequency varied by a factor of 4.7 and 12.5 depending on the age group. Age and gender are the most important demographic variables impacting on the MN index with MN frequencies in females being greater than those in males by a factor of 1.2 to 1.6 depending on the age group. For both sexes, MN frequency was significantly and positively correlated with age (R=0.62 in males and R=0.65 in females) and the slope of the regression line in males was 0.314 (P<0.0001) and in females it was 0.517 (P<0.0001). The main dietary factors influencing the MN index in subjects who are not folate deficient are plasma B12 (R=-0.315, P=0.0127) and plasma homocysteine (R=0.415, P=0.0086). In addition, it was proposed that the MN index is likely to be influenced by the propensity of an individual's cells to undergo apoptosis when damaged so that one might expect the MN frequency to be negatively correlated with apoptotic rate although this has yet to be tested. The above indicates the importance of maintaining an international network of scientists working with the CBMN assay to ensure appropriate quality control and for the development of standard experimental and documentation protocols. The human micronucleus (HUMN) project launched in 1997 is briefly described and proposed as the vehicle for these activities.

Adult↗
PubMedDate not supplied

[Molecular epidemiology in occupational medicine: methodological features and impact of individual genetic susceptibility].

A review of main methodological questions regarding biomarkers is reported focusing on validation, laboratory variability, study design and statistical analysis. The indicated perspective is the setup of protocols finalized at the study of multiple panels of genotoxicity biomarkers taking into account the influence of gene-environment interaction at low doses, of the modulation of the biomarkers associated to the genetic polymorphism. An overview on the influence of metabolic and DNA repair polymorphisms on biological indicators of genotoxic risk in occupational, environmental or life-style exposure is also presented. Genetic polymorphisms that influence human genotoxic risk are those of glutathione s-transferase and cytochrome P450 in exposure to polycyclic aromatic hydrocarbons (PAHs), those of N-acetyltransferase in both occupational and environmental exposures to aromatic amines (AAs) and similar compounds. Lastly recent and important studies, on the effect of the newly discovered polymorphisms affecting DNA repair enzymes on the modulation of genotoxic risk linked to life style (i.e., aflatoxin and PAHs from diet) and smoking behaviour and to environmental genotoxic exposure, are reported. To date biomarkers represent a new tool for epidemiological research in occupational medicine and they could represent a valid instrument for group evaluation but they are not useful for the risk assessment on individual basis. To achieve this objective it is necessary to demonstrate a stronger association with the endpoint that perhaps the future development of genetic and molecular epidemiology will make possible.

Genetic Predisposition to Disease↗