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At least 163 records · Page 9Linked to original sources
PubMed2006

Aging of mipafox-inhibited human acetylcholinesterase proceeds by displacement of both isopropylamine groups to yield a phosphate adduct.

Aging of phosphylated serine esterases, e.g., acetylcholinesterase (AChE) and neuropathy target esterase (NTE), renders the inhibited enzymes refractory to reactivation. This process has been considered to require postinhibitory side group loss from the organophosphorus moiety. Recently, however, it has been shown that the catalytic domain of human NTE inhibited by N,N'-diisopropylphosphorodiamidofluoridate (mipafox, MIP) ages by deprotonation. For mechanistic understanding and biomarker development, it would be important to know the identity of the MIP adduct on target esterases after inhibition and aging occurred. Accordingly, the present study was performed to determine if MIP-inhibited human AChE ages by side group loss or an alternate method, e.g., deprotonation. Diisopropylphosphorofluoridate (DFP), the oxygen analogue of MIP, was used for comparison, because DFP-inhibited AChE is known to age by net loss of an isopropyl group. Kinetics experiments were done with DFP and MIP against AChE to follow the time course of inhibition, reactivation, and aging for each inhibitor. MS studies of tryptic digests from kinetically aged DFP-inhibited AChE revealed a mass shift of 122.8 +/- 0.7 Da for the active site peptide (ASP) peak, corresponding to the expected monoisopropylphosphoryl adduct. In contrast, the analogous mass shift for kinetically aged MIP-inhibited AChE was 80.7 +/- 0.9 Da, corresponding to a phosphate adduct. Because this finding was unexpected, the identity of the phosphoserine-containing ASP was confirmed by immunoprecipitation followed by MS. The results indicate that aging of MIP-inhibited AChE proceeds by displacement of both isopropylamine groups. Further research will be required to elucidate the detailed mechanism of formation of a phosphate conjugate from MIP-inhibited AChE; however, knowledge of the identity of this adduct will be useful in biomarker studies.

Acetylcholinesterase↗
PubMed2005

Serum biomarkers for experimental acute spinal cord injury: rapid elevation of neuron-specific enolase and S-100beta.

OBJECTIVE: We evaluated whether serum levels of neuron-specific enolase (NSE) and S-100beta protein are biomarkers for traumatic injury in an animal model of spinal cord injury (SCI). METHODS: Enzyme-linked immunosorbent assay serum measurements of NSE and S-100beta and assays of serum protein were compared at 6 and 24 hours after a graded contusive SCI (150 or 200 kdyn IH impactor injury (Infinite Horizons, L.L.C., Lexington, KY) or sham laminectomy at T9 in 30 female Sprague-Dawley rats. Serum from control animals was also analyzed. RESULTS: Increases in serum levels of NSE were observed for 200-kdyn (3.1-fold, P < 0.001) and 150-kdyn (2.3-fold, P < 0.001) injury groups at 6 hours after injury, which decreased by 73.7% (P < 0.001) and 65.2% (P < 0.001) at 24 hours after SCI, respectively; the levels were still greater than in sham animals (P < 0.001, P = 0.001). The 200- and 150-kdyn injury groups were not different at either time point. S-100beta serum levels increased at 6 hours in the 200-kdyn injury group (P < 0.05), and no differences from sham levels were seen at 24 hours. No differences in total protein concentrations were observed between the injury and control groups. CONCLUSION: Present data suggest that NSE and S-100beta serum levels may be useful experimental tools for the acute measurement of tissue loss after SCI. Despite significant shortcomings, NSE and S-100beta serum measurements in acute SCI patients with clinically defined functional deficits should allow comparisons with well-characterized SCI animal models. Future efforts to develop biomarkers that predict functional outcomes in the acute phase should focus on axon-specific proteins as markers of secondary axonal loss and regeneration.

Acute Disease↗
PubMed2006

Recurrent genomic alterations with impact on survival in colorectal cancer identified by genome-wide array comparative genomic hybridization.

BACKGROUND & AIMS: Although genetic aspects of tumorigenesis in colorectal cancer (CRC) have been well studied, reliable biomarkers predicting prognosis are scarce. We aimed to identify recurrently altered genomic regions (RAR) in CRC with high resolution, to investigate their implications on survival and to explore novel cancer-related genes in prognosis-associated RARs. METHODS: A 1-Mb resolution microarray-based comparative genomic hybridization (array CGH) was applied to 59 CRCs. RARs, defined as genomic alterations, detected in more than 10 cases were identified and analyzed for their association with survival. Expression levels of genes in prognosis-associated RARs were examined by real-time quantitative polymerase chain reaction. RESULTS: Twenty-seven RARs were identified. Eleven high-level amplifications and 2 homozygous deletions also were detected, but they were not as common as RARs. Multivariate analysis revealed RAR-L1 (loss on 1p36; hazard ratio = 8.15, P = .002) and RAR-L20 (loss on 21q22; hazard ratio = 3.53, P = .034) are independent indicators of poor prognosis. Expression of CAMTA1, located in RAR-L1, was reduced frequently in CRCs, and low CAMTA1 expression was associated significantly with poor prognosis, which indicates that CAMTA1 may play a role as a tumor suppressor in CRC. Five pairs of RARs were correlated significantly to each other and 3 pairs share genes involved in the same biological functions, suggesting possible collaborative roles in tumorigenesis. CONCLUSIONS: We identified recurrent genomic changes in 59 CRCs. RARs could be more important in sporadic tumors where the effect of genomic changes on tumorigenesis is relatively smaller than in familial cancer. Our results and analysis strategy will be helpful to elucidate pathogenesis of CRCs or to develop biomarkers for predicting prognosis.

Adult↗
PubMed1991

Biomarkers of aging: changes in circadian rhythms related to the modulation of metabolic output.

Twenty-four hour (circadian) rhythmicity is an important component of biological variability associated with studies relating to biomarkers of aging. Chronobiological testing techniques must be utilized because (1) many variables that are related to the modulation of metabolic output vary dramatically at different times of the day; (2) various experimental variable and treatment groups must be synchronized with environmental cues that control circadian rhythms; and (3) multiple circadian variables may interact together to modulate the rate of aging. The rhythm for physiological factors such as whole animal metabolic output, body temperature, heart rate, urine flow, potassium, etc. were found to be dissociated or altered by the senescence process; behavioral variables such as spontaneous activity, wheel running, feeding and drinking, verbal performance, as well as sleep-wakefulness rhythms, seem to be accurate predictors of biological age. Circadian rhythms for a variety of enzymes of intermediary metabolism which are directly associated with energy metabolism have been well documented. These well-defined rhythms of enzyme activity have also been shown to degenerate with aging. Rhythms tend to lose amplitude as activity falls with age and as a general loss of regulation (especially time of day where maximal activity might be found) of activity across the 24-h span occurs. As with behavioral variables, changes in enzyme rhythms appear to accurately predict aging. Generally speaking, the loss of temporal organization with age, characterized by decreased circadian amplitude, loose internal synchronization, and poor response to external environmental time queues, is associated with poor health states and decreased longevity. Temporal rhythms for whole animal parameters are highly correlated with molecular events, such as regulation of cellular metabolism. DNA repair, and gene expression. Automated data acquisition and process control systems will be required for future chronobiological studies to develop biomarkers of aging.

Aging↗
PubMed2026

Alterations of endothelial cell bioenergetics in congenital diaphragmatic hernia.

BACKGROUND: Pulmonary vascular development in congenital diaphragmatic hernia (CDH) is characterized by impaired angiogenesis and pathologic remodeling that contribute to pulmonary hypertension/hypoplasia. Mitochondria regulate endothelial energy, redox balance, and angiogenic signaling, suggesting a role in CDH vascular disease. METHODS: Endothelial cells (ECs) were isolated from umbilical veins of healthy and CDH newborns. Mitochondrial bioenergetics and glycolytic acidification were assessed by extracellular flux. Oxidative stress, mitochondrial membrane potential, and mitochondrial mass were measured by flow cytometry, while mitochondrial DNA copy number (mtDNA-CN) and morphology were evaluated by qPCR and microscopy. RESULTS: CDH ECs exhibited increased maximal respiratory capacity with elevated proton leak and reduced ATP coupling efficiency. Basal glycolytic activity was elevated. These changes were accompanied by increased mitochondrial superoxide and cellular reactive oxygen species and by severity-associated loss of membrane potential. Despite reduced MitoTracker Green, mtDNA-CN was unchanged, and confocal imaging revealed a highly branched, peripherally distributed network. CONCLUSIONS: These data define a distinct endothelial mitochondrial phenotype marked by metabolic activation, bioenergetic inefficiency, and oxidative stress, with concurrent upregulation of glycolysis and oxidative phosphorylation rather than a glycolytic shift. Structural remodeling with preserved mitochondrial content further indicates qualitative changes. Collectively, these findings link mitochondrial dysfunction to vascular pathology in CDH. IMPACT: Defines a distinct mitochondrial state in CDH endothelium, characterized by metabolic activation with inefficient oxidative phosphorylation, redox imbalance, and structural reorganization in primary human cells. Demonstrates that mitochondrial alterations in CDH occur without changes in mitochondrial content, supporting a model of qualitative remodeling. Provides rare human, cell-based data in CDH, addressing a major gap in a field largely reliant on animal models and indirect measures. Links mitochondrial alterations to clinical severity, supporting relevance to disease burden and heterogeneity. Establishes a framework for mitochondrial involvement in CDH vascular disease, with potential implications for future biomarker development and therapeutic targeting.

Journal Article↗
PubMedDate not supplied

Regional protein alterations in rat kidneys induced by lead exposure.

Lead is a potent neuro- and nephrotoxin in humans and a renal carcinogen in rats. Previous studies have detected lead-induced increases in the activities of specific detoxification enzymes in distinct kidney cell types preceding irreversible renal damage. While preferential susceptibility of the highly vascularized cortex to the effects of lead is clear, lead effects on the medullary region have remained unexplored. The present study was undertaken to investigate the extent to which regional renal protein expression differs and to determine which, if any, regionally distinct protein markers indicative of lead's renotoxic mechanism might be detected in kidney cortical and medullary cytosols. We examined protein expression in these two functionally and anatomically distinct regions, and identified several proteins that are differentially expressed in those regions and were significantly altered by lead. Kidney cytosols from rats injected with lead acetate (114 mg/kg, three consecutive daily injections) were separated by two-dimensional electrophoresis. Lead exposure significantly (P<0.001) altered the abundance (either or) of 76 proteins in the cortex and only 13 in the medulla. Eleven of the proteins altered in the protein patterns were conclusively identified either by matrix-assisted laser desorption/ionization mass spectrometry/electrospray ionization-mass spectrometry (MALDI-MS/ESI-MS) analysis of peptide digests, immunological methods, or by gel matching. Several of the cortical proteins altered by lead were unchanged in the medulla while others underwent similar but lesser alterations. These observations reflect the complexity of lead's nephrotoxicity and endorse the application of proteomics in mechanistic studies as well as biomarker development in a variety of toxicologic paradigms.

Amino Acid Sequence↗
PubMed2006

Identification of proteins adducted by reactive metabolites of naphthalene and 1-nitronaphthalene in dissected airways of rhesus macaques.

Naphthalene and 1-nitronaphthalene are ambient air pollutants, which undergo P450-dependent bioactivation in the lung. Reactive metabolites of naphthalene and 1-nitronaphthalene covalently bind to proteins, and the formation of covalent adducts correlates with airway epithelial cell injury in rodent models. These studies were designed to identify protein adducts generated from these reactive metabolites within distal respiratory airways. Distal bronchioles and parenchyma from rhesus monkeys were incubated with [(14)C]naphthalene or [(14)C]1-nitronaphthalene. Proteins were separated by 2-DE, blotted to PVDF membranes, and adducted proteins imaged by storage phosphor analysis. MS of in-gel tryptic digests identified numerous adducted proteins including: eight cytoskeletal proteins, two chaperone proteins, seven metabolic enzymes, one redox protein, two proteins involved in ion balance and cell signaling, and two extracellular proteins. While many proteins are adducted by both naphthalene and 1-nitronaphthalene, some are unique to the individual toxicant and airway subcompartment. Although the role which adduction of these proteins plays in cytotoxicity was not evaluated, these studies provide candidate proteins for future work designed to determine the importance of protein adducts in the mechanisms of toxicity and for developing biomarkers useful in determining the relevance of findings in animal models to exposed human populations.

Animals↗
PubMed1996

Determination of 4,4'-methylene-bis(2-chloroaniline)-DNA adduct formation in rat liver and human uroepithelial cells by the 32P postlabeling assay.

The probable human carcinogen 4,4'-methylene-bis(2-chloroaniline) (MOCA) was utilized to develop biomarkers of exposure to occupational carcinogens. The 32P postlabeling assay, utilizing the nuclease P1 enhancement procedure, was used to evaluate MOCA-DNA adduct formation in target tissues. Male Sprague-Dawley rats were treated with different dosing regimens of MOCA, and DNA was isolated from the liver. Additionally, a human uroepithelial cell (HUC) line was treated with N-hydroxy-MOCA for 24 hr, cells were harvested, and DNA was isolated. DNA was analyzed for MOCA-DNA adduct formation by the 32P postlabeling assay. Five MOCA adducts were detected in rat liver DNA. Adduct A, which corresponded to N-(deoxyadenosin-8-yl)-4-amino-3-chlorobenzyl alcohol, was the major adduct in rat liver DNA appearing in all treatment groups. Levels of adduct A were higher when MOCA was administered by ip injection versus oral gavage. Phenobarbital pretreatment increased the amount of adduct A approximately 12-fold. The pathway leading to the formation of adduct A in DNA from HUC appeared to be saturated at the concentrations used: 2.5, 5, and 10 microM. However, an additional adduct (E) was observed at the 10 microM treatment level only. A major DNA adduct was detected in the target tissue of rats and target human cells for MOCA-induced carcinogenesis, thus making it useful as a biomarker of exposure. Other DNA adducts were also observed with the different doses and routes of exposure investigated.

Animals↗
PubMed1995

New directions in dietary studies in cancer: the National Cancer Institute.

Through an orderly sequence incorporating epidemiologic and laboratory research, human clinical/metabolic studies, and clinical intervention trials, the NCI develops and maintains cancer prevention and control programs that are directed toward the overall goal to reduce cancer incidence, morbidity, and mortality. Epidemiologic studies have shown correlations between consumption of numerous dietary constituents and cancer risk. Results of in vitro and animal studies have reinforced many of these epidemiologic associations and data from clinical/metabolic studies are being used to evaluate the relevance of these associations in humans. Although much remains to be learned about the influence of specific dietary constituents and dietary patterns on cancer risk, it is clear that diet can have a significant impact in cancer prevention and control. Investigations on the cellular and molecular effects of dietary constituents, as well as their metabolic and physiologic effects should provide better insight on the mechanisms of action of these dietary constituents. There also is a need to develop biomarkers of dietary intake that could be used to monitor compliance in intervention studies, as well as biomarkers as clinical trial endpoints that can be used to predict the emergence and progression of cancer. Working with other agencies and the private sector, the NCI will continue to design and implement information programs that translate the knowledge gained from these diet and cancer prevention studies to help Americans adopt dietary patterns that may reduce cancer risk. Continued emphasis will be placed on intervention programs targeted toward high-risk and underserved segments of the U.S. population in an effort to reduce the high incidence of cancers in these groups.

Animals↗
PubMed2007

[Anti-interleukin-5 therapy for eosinophilic diseases].

In a number of diseases with eosinophilia, elevated interleukin (IL)-5 levels are detected in the peripheral blood and/or tissues. IL-5 plays an important role in regulating the production, differentiation, recruitment, activation, and survival of eosinophils. Therefore, neutralizing IL-5 by blocking antibodies seems a promising approach in the treatment of eosinophilic diseases. Clinical trials have demonstrated that anti-IL-5 therapy results in a rapid decrease in peripheral blood eosinophil numbers. Moreover, improvement of symptoms in patients with lymphocytic variants of hypereosinophilic syndromes, in eosinophilic esophagitis and chronic rhinitis with nasal polyposis has been observed. In contrast, in patients with bronchial asthma or atopic eczema, anti-IL-5 therapy showed only moderate or no clinical effects. Future studies will have to identify those eosinophilic diseases in which anti-IL-5 antibodies are effective, perhaps with the help of newly developed biomarkers.

Animals↗
PubMed2006

Genetic advances in inflammatory bowel disease.

The translation of basic science advances to tangible benefits in clinical practice remains a fundamental goal of biomedical research. Genetic approaches provide a unique opportunity to enhance bench-to-bedside translational efforts, with inflammatory bowel disease (IBD) being a model genetic disorder in several respects. The association of the NOD2 (CARD15) mutations to Crohn's disease (CD) represents, in complex human disorders, one of the clearest cases of a definitive disease association. The NOD2 gene is located in the IBD1 genetic linkage region on chromosome 16 and functions as an intracellular pattern recognition receptor for components of bacterial peptidoglycan. CD-associated variants within NOD2 have a decreased capacity to appropriately signal with peptidoglycan and provide an important example of gene-environment interactions. Genetic variation in other innate immune receptors, notably Toll-like receptor (TLR)4, has been defined and may also play a role in CD pathogenesis. Replicated CD association in the IBD5 region on chromosome 5q has been reported, and candidate functional polymorphisms within the organic cation transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5) have been described. Confirmatory studies demonstrating altered OCTN activity and expression in primary human cells stratified on the IBD5 risk haplotype would provide important confirmatory support for disease contribution. A comprehensive understanding of IBD will involve integrating information from animal models, functional human polymorphisms, and expression studies from human IBD tissues. Genes and pathways implicated as contributing to IBD pathogenesis through multiple lines of evidence should be more intensively examined, including the tumor necrosis factor-alpha, MDR1, and peroxisome proliferator-activated receptor (PPAR)gamma pathways. To attain full advantage of new genetic information, novel methods of classifying patients that go beyond phenotypic classifications presently utilized will be required. Genetic data will need to be integrated with novel biomarker development in IBD, including functional, expression (mRNA or protein), or biochemical indicators of physiologic/disease processes and responses to therapies.

Journal Article↗
PubMed1995

Study on DNA-protein crosslinks induced by chromate and nickel compounds in vivo with 125I-postlabelling assay.

In an attempt to develop biomarkers of chromate and nickel exposure, we have used a rapid, simple and sensitive 125I-postlabelling assay to detect the formation of DNA-protein crosslinks (DPCs) in different tissues from male Sprague-Dawley rats exposed i.p. to potassium chromate (K2CrO4) and nickel chloride (NiCl2). The results demonstrated that 20 h after rats were injected i.p. with these agents, DPCs were observed in WBC, liver and kidney of rats treated with K2CrO4 in doses ranging from 10 to 40 mg/kg body wt. There was a dose-dependent relationship between chromate exposure and DPCs in WBC and liver, but no DPC increase was shown in lung. In the same way, DPCs were found in WBC and lung of rats treated with NiCl2 in doses ranging from 10 to 30 mg/kg in a dose-dependent manner. The formation of DPCs in different tissues was also observed following repeated exposure of rats to K2CrO4 and NiCl2 (10 mg/kg, i.p.) for 3 weeks. These results were similar with the single dose. It is indicated that chromate and nickel compounds possibly cause DNA or protein damage to form DPCs, suggesting DPCs might be useful as a biomarker for quantitative K2CrO4 and NiCl2 exposure and genotoxic lesions. In addition, WBC were shown to be more sensitive to chromate(VI) and nickel(II) induced DPCs than other targets. There were significant correlations between DPCs induced by K2CrO4 in WBC and liver, and by NiCl2 generated DPCs in WBC and lung, indicating that DPCs in WBC may be a good surrogate for some internal organs of humans exposed to chromate(VI) and nickel(II) compounds.

Animals↗
PubMed2026

From dysbiosis to resilience: Microbiome engineering for sustainable shrimp aquaculture.

The intensification of shrimp aquaculture has increased exposure to disease, environmental perturbations, and antimicrobial pressure, making microbial stability increasingly relevant to sustainable production. Microbiome stability-encompassing resistance to disturbance and resilience of functional recovery-provides an ecological framework for understanding how shrimp and culture-environment microbial communities respond to intensive farming. This review examines the transition from microbial homeostasis to dysbiosis and evaluates how microbiome engineering could redirect disrupted communities towards resilient states. Evidence is integrated across the intestine, hepatopancreas, rearing water, sediment and biofloc to assess how host genetics, ontogeny, diet, culture conditions, antibiotics and pollutants shape microbiome assembly and destabilization. Disease-associated changes in acute hepatopancreatic necrosis disease, white faeces syndrome, Enterocytozoon hepatopenaei infection, and white spot syndrome virus infection are critically evaluated, with explicit separation of associations, pathogen-induced dysbiosis, and community-level causality. Established and emerging interventions-including probiotics, prebiotics, synbiotics, functional diets, biofloc management, phages, postbiotics, microbiota transplantation and synthetic microbial communities-are assessed according to their capacity to modify microbial function, persistence and recovery rather than taxonomic change alone. We further examine how multi-omics, microbiome-informed breeding, and environmental monitoring could support biomarker development, predictive decision support and context-specific intervention. We argue that progress requires a shift from taxonomic description to function-guided engineering, from endpoint comparisons to direct measurement of resilience, and from laboratory efficacy to reproducible farm-scale validation. Overall, microbiome management may contribute to more disease-resilient and sustainable shrimp production, provided that its effectiveness can be validated under commercial farming conditions.

Dysbiosis↗
PubMed2004

Shell protein characteristics and vitellogenin-like proteins in brine shrimp Artemia franciscana exposed to municipal effluent and 20-hydroxyecdysone.

We developed biomarkers to monitor the endocrine-disrupting potential of contaminants and municipal effluents in aquatic arthropods. Artemia fransciscana shrimp were cultured and exposed to increasing concentrations of 20-hydroxyecdysone (20HE) and solid phase (C-8) municipal effluent extract (MEE) for 48 h at 20 degrees C. The levels of vitellogenin (Vtg)-like proteins, alkali-labile phosphates in total proteins and acetylcholinesterase (AChE) activity were determined in soft tissues. The levels of acid-soluble, alkali-soluble (sclerotin), neutral-soluble (arthropodin) proteins and chitin were determined to characterize the maturation state of shells. Both 20HE and the municipal effluent extract readily increased the total activity of acetylcholinesterase, alkali-labile phosphates in proteins and vitellogenin-like proteins in brine shrimp. In shells, 20HE and the effluent extract increased the proportion of chitin in shells and acid-soluble proteins but were not statistically significant for the latter. The proportion of sclerotin was increased by 20HE but was not changed by the effluent extract. The proportion of arthropodin was decreased by both 20HE and the effluent extract. Correlation analysis revealed that, as expected, the proportion of acid-soluble protein for biomineralisation and chitin levels were positively correlated and the proportion of arthropodin and sclerotin were negatively correlated in shells exposed to 20HE. Principal component analysis revealed that the proportion of chitin, arthropodin, sclerotin and acid-soluble proteins explained 63% of the responses. Shell protein and carbohydrate contents, controlled by the molting hormone 20HE, could be used as efficient markers for ecdysial properties of various contaminants. The municipal effluent appears to contain ecdysial-like chemicals that are capable of producing changes in shell protein composition that are similar to 20HE.

Acetylcholinesterase↗
PubMed2025

Novel approaches to clinical trial design in cancer neuroscience.

The emerging field of cancer neuroscience has revealed profound bidirectional interactions between the nervous system and cancer cells, identifying novel therapeutic vulnerabilities across diverse malignancies. This review examines the unique challenges and strategies for translating these insights into effective therapies. We propose innovative approaches to overcome these barriers through drug repurposing, enhanced biomarker development, and optimized trial designs. Repurposing neuroactive drugs with established safety profiles offers an accelerated path to clinical impact, particularly for targeting glutamatergic, adrenergic, and neurotrophic signaling pathways. Emphasizing mitigation of neurotoxicity and improved patient quality of life will be paramount moving forward. Repurposed agents that show preliminary potential for "dual use" (i.e., simultaneous toxicity mitigation and synergistic anti-tumor effects) are highlighted for special consideration. Master protocols and window-of-opportunity trials provide platforms to rapidly validate mechanisms while addressing patient-centered outcomes. By systematically addressing these foundational elements across disciplines, cancer neuroscience can translate its profound mechanistic insights into meaningful therapeutic advances for patients with treatment-resistant malignancies.

Humans↗
PubMed2005

Screening for prostate cancer: opportunities and challenges.

Prostate cancer screening with PSA and with digital rectal examination isa reality in the United States. Regardless of recent observations regarding the complexities of PSA interpretation, millions of U.S. men expect an annual PSA test and physicians have come to rely on the test, in combination with digital rectal examination, to assess for prostate cancer risk. What has become evident is that PSA can no longer be interpreted dichotomously as a simple yes or no. The test reflects a range of risk and PSA value must be merged with other risk factors of an individual man including ethnicity, family history, as well as the individual's risk aversion to complications from prostate cancer. The future of prostate cancer screening will be built upon incorporation of new biomarkers to the prediction of risk of disease. As these markers move forward in testing, it will no longer be acceptable to move these into clinical usage without formal validation studies and, because of the high frequency of prostate cancer in the general male population, these validation studies will almost certainly have to include measures of prognosis. It is the holy grail of cancer biomarker development to acquire a test that is positive in the man with clinically-aggressive prostate cancer but is negative in both the patient without disease and in the man with disease that will be of no clinical consequence over his lifetime.

Adenocarcinoma↗
PubMed2004

Environmental contaminant-mixture effects on CNS development, plasticity, and behavior.

Environmental contaminants within the polycyclic aromatic hydrocarbon (PAH) and halogenated aromatic hydrocarbon class have been shown to cross the placenta exposing the fetus to the contaminant body burden of the mother. Consequently, a gestational exposure to environmental contaminants may result in increased adverse health outcomes, possibly affecting cognitive performance. Benzo(a)pyrene [B(a)P] and 2,3,7,8, tetrachlorodibenzo-p-dioxin (TCDD) are two prototypical environmental contaminants. A systematic review of the literature suggests that there may be a relationship between vulnerability in susceptible populations and health disparities. The purpose of this mini-review is to provide a point of reference for neurotoxicological studies of environmental contaminant mixture effects on indices of development in general, and on neurodevelopment in particular. Environmental contaminant-mixture-induced decrements in (1) birth index, (2) N-methyl-D-aspartate receptor (NMDA) mRNA expression, (3) long-term potentiation (LTP), (4) fixed-ratio performance learning behavior, and (5) experience-dependent activity related cytoskeletal-associated protein (Arc) mRNA and protein expression collectively support associations between neurobehavioral deficits and gestational exposure to environmental levels of these contaminants. Collectively, data are presented in this mini-review evaluating the effect of gestational exposure to environmental contaminant-mixtures on specific indices of learning and memory, including hippocampal-based synaptic plasticity mechanisms. These indices serve as templates for learning and memory, and as such, from a vulnerability perspective, may serve as targets for dysregulation during development in susceptible populations that have been disproportionately exposed to these contaminants. Included in this review is also a discussion of the relevance of developing biomarkers for use within the framework of cumulative risk-assessment.

Animals↗
PubMed2005

Amplification of the Ect2 proto-oncogene and over-expression of Ect2 mRNA and protein in nickel compound and methylcholanthrene-transformed 10T1/2 mouse fibroblast cell lines.

Occupational exposure of humans to mixtures of insoluble and soluble nickel (Ni) compounds correlates with increased incidences of lung, sinus, and pharyngeal tumors. Specific insoluble Ni compounds are carcinogenic to animals by inhalation and induce morphological and neoplastic transformation of cultured rodent cells. Our objectives were to (1) understand mechanisms of nickel ion-induced cell transformation, hence carcinogenesis and (2) develop biomarkers of nickel ion exposure and nickel ion-induced cell transformation. We isolated mRNAs from green nickel oxide (NiO), crystalline nickel monosulfide (NiS), and 3-methylcholanthrene (MCA) transformed C3H/10T1/2 Cl 8 cell lines, and determined by mRNA differential display that nine mRNA fragments were differentially expressed between Ni transformed and non-transformed 10T1/2 cell lines. Fragment R2-5 was expressed at higher steady-state levels in the transformed cell lines. R2-5 had 100% sequence identity to part of the coding region of Ect2, a mouse proto-oncogene encoding a GDP-GTP exchange factor. The 3.9-kb Ect2 transcript was expressed at 1.6- to 3.6-fold higher steady-state levels in four Ni transformed, and in two MCA-transformed, cell lines. Ect2 protein was expressed at 3.0- to 4.5-fold higher steady-state levels in Ni-transformed and in MCA-transformed cell lines. The Ect2 gene was amplified by 3.5- to 10-fold in Ni transformed, and by 2.5- to 3-fold in MCA transformed cell lines. Binding of nickel ions to enzymes of DNA synthesis likely caused amplification of the Ect2 gene. Ect2 gene amplification and over-expression of Ect2 mRNA and protein can cause microtubule disassembly and cytokinesis, contributing to induction and maintenance of morphological, anchorage-independent, and neoplastic transformation of these cell lines. Over-expression of Ect2 protein is a useful biomarker to detect exposure to nickel compounds and nickel ion-induced morphological and neoplastic cell transformation.

Animals↗