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PubMedDate not supplied

Immune systems, geographic information systems (GIS), environment and health impacts.

Exposure to dioxins, polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) has been related to alterations in cellular and humoral immune responses in both adaptive and innate immune systems of most animal species. These compounds share a common signaling mechanism to exert their effects on cells of the immune system, which includes the aryl-hydrocarbon receptor (AhR) and the AhR nuclear translocator (ARN). Recently, the interference of AhR-ARNT with the nuclear factor (NF)-kappaB signaling pathway has been proposed as a critical event in the adverse effects on the immune system. Studies on the effects of these AhR-ARNT-related toxicants on the immune system of higher and lower phylum animals and knowledge of intracellular mechanisms of toxicity may contribute to development of biomarkers of ecotoxicant exposure and effects. Biomarkers of this kind allow sampling over extended geographic areas, in several sentinel species, including wildlife animals, and facilitate the building of risk models and risk maps of environmentally induced diseases. On the basis of location, biomarker sampled data obtained through evaluation of ecotoxicant exposure and effects on the immune system in sentinel species can be further integrated and analyzed together with other sources of environmental geographic information, or human population health data, by means of geographic information systems (GIS). The spatial analysis capability of GIS can help to evaluate the complex relationships of overlaid information and to identify areas with high risk indices or "hot spots." This integrative approach can be useful in studies contributing to support environmental and health-related policies and regulations.

Animals↗
PubMed2006

Mercury but not organochlorines inhibits muscarinic cholinergic receptor binding in the cerebrum of ringed seals (Phoca hispida).

Elevated concentrations of organochlorines and mercury (Hg) have been reported in marine mammals on a global scale. While risk assessments are generally based on quantifying body burdens of toxicants, much less is known about associated adverse health effects and their underlying mechanisms. The purpose of this study was to characterize the inhibitory effects of methylmercury (MeHg+), mercuric chloride (Hg2+), p,p'-DDT, Arochlor 1254, chlordane,dieldrin, lindane, and toxaphene on [3H]quinuclidinyl benzilate ([3H]-QNB) binding to the muscarinic cholinergic (mACh) receptor in cellular membranes isolated from the cerebrum of ringed seals (Phoca hispida). [3H]-QNB binding to the mACh receptor was saturable with a mean receptor density (B(max)) of 826.9 +/- 68.4 fmol/mg and ligand affinity (K(d)) of 0.31 +/- 0.04 nM. MeHg+ and Hg2+ were the only neurotoxicants that inhibited radioligand binding by greater than 50%. Hg2+ was significantly more potent at inhibiting mACh receptor binding than MeHg+ when the IC50 data were compared (IC50 = 1.92 +/- 0.06 microM versus 2.75 +/- 0.22 microM), but when the data were normalized to derive inhibition constants (K(i)) there was no statistical difference in inhibition (Hg2+ = 1.38 +/- 0.07 mM; MeHg+ = 1.26 +/- 0.12 microM). Toxaphene also inhibited mACh receptor binding by 22.4%, but this was only significant at the highest concentration tested (320 microM). Overall, these data suggest that Hg, and not organochlorines,inhibits ligand binding to the mACh receptor. These mechanistic findings may be used to support and develop specific biomarkers of Hg exposure and neurotoxicity in sensitive ecological species.

Animals↗
PubMed2026

Integrative chemical genetics platform identifies condensate modulators linked to neurological disorders.

Dysregulation of biomolecular condensates is implicated across multiple neurological disorders. However, approaches to systematically identify their modulators remain limited. Here, we expand the utility of MLF2 as a versatile condensate biomarker and develop CondenScreen, an integrated high-content screening and bioinformatics pipeline enabling identification of condensate modulators across chemical and genetic space. Screening 1760 bioactive compounds in a cellular DYT1 dystonia model, we validate the platform for condensate-targeted drug discovery, identifying drugs that prevent the accumulation of the MLF2 reporter into nuclear envelope condensates. In parallel, a genome-wide CRISPR/Cas9 screen correlates nuclear condensate abundance with genes implicated in microcephaly and over eight additional neurodevelopmental disorders. Machine learning and confocal imaging resolve distinct condensate phenotypes, with RNF26 deletion provoking nuclear envelope condensates that phenocopy hallmarks of torsin deficiency. Our study provides a scalable platform for identifying modulators of condensates and establishes a correlative connection between nuclear condensate accumulation and genes implicated in neurodevelopmental disorders.

Humans↗
PubMed2002

Detection of multiple gene hypermethylation in the development of esophageal squamous cell carcinoma.

Abnormal hypermethylation of CpG islands associated with tumor suppressor genes can lead to repression of gene expression and contribute significantly to tumorigenesis. Esophageal squamous cell carcinoma (ESCC) is thought to be developed through a multi-stage process, which involves basal cell hyperplasia (BCH), dysplasia (DYS), carcinoma in situ (CIS) and carcinoma. In the present study, we studied the hypermethylation of 10 selected genes in biopsies from normal individuals and resected tissues from ESCC patients. Tumor and neighboring normal and precancerous tissues including BCH, DYS and CIS were microdissected from the resected tissues by laser capture microdissection. Hypermethylation of CpG islands was examined in these samples for 10 genes: p16(INK4a), p15(INK4b), p14(ARF), human leukocyte antigen (HLA)-A, -B, -C, hMLH1, E-cadherin (E-cad), fragile histidine triad and von Hippel-Lindau (VHL). Methylation of two Alu sequences, which neighbor E-cad and VHL, respectively, was used as control to verify the procedure of DNA extraction and chemical modification. In 48 biopsy samples with BCH or DYS, the most frequent hypermethylated genes were p16(INK4a) (18.8%) and p14(ARF) (14.6%). Seventeen out of these 48 samples (35.4%) contained hypermethylation of at least one gene. In the resected tissues, 52% of the BCH and 81% of the tumors showed hypermethylation of at least one gene. Genes hypermethylated in earlier stage lesions were always found hypermethylated at the later stage lesions in the same patient. All of the genes were methylated at some stages and they were clustered into four groups according to their frequencies. The first group of genes, which consisted of p16(INK4a) and p14(ARF), was most frequently hypermethylated in all stages, and the frequencies increased from normal epithelial (0%) to BCH, to displasia/carcinoma in situ and ESCC. Other genes were hypermethylated less frequently. Our results suggest that hypermethylation of key genes, such as p16(INK4a), p14(ARF) and hMLH1, may be used in combination with other molecular changes, such as p53 mutation, in the development of biomarkers for predicting the risk for ESCC.

Base Sequence↗
PubMed2003

Diet, nutrition, and cancer prevention: the postgenomic era.

The genomic era of human nutrition is upon us: the human genome and several plant genomes have been characterized, and genetically modified foods are now abundantly available in the marketplace. The link between diet and cancer is well established, and new genomic technologies have made possible the investigation of nutritional modulation of the carcinogenesis pathway with nutrients, micronutrients, and phytochemicals. Current study of nutrient-modulated carcinogenesis involves exploring the effect of nutrients on DNA damage and repair mechanisms; DNA methylation, which influences gene expression and cellular phenotypes; antioxidant rearranging and oxidative stress; target receptors and signal transduction pathways; cell cycle controls and check points; apoptosis; and antiangiogenic processes. With nutritional genomics, proteomics, and metabolomics, scientists are able to simultaneously elucidate the biological effects of dietary constituents on cell function and global gene expression. This generation of new knowledge on nutrient-gene interactions provides the justification for a research framework for diet and cancer prevention that is focused on identifying and developing new biomarkers as well as a novel and contemporary paradigm for dietary intervention.

Diet↗
PubMed2003

The safety testing of amino acids.

The risk assessment of compounds added to foods or taken as supplements is usually based on hazard characterization studies performed in animal test species. A large default uncertainty factor, or margin or exposure, is usually required to allow for possible species differences and human variability in the toxicokinetics and toxicodynamics of the compound. The development of biomarkers offers the potential to rationalize the risk assessment of amino acids, and to refine the extrapolation of data from animals to humans. The use of high resolution nuclear magnetic resonance spectroscopy applied to readily accessible biological fluids, such as urine and plasma, offers great potential for the identification of toxicologically relevant biomarkers in animal studies that can then be applied to studies in humans.

Amino Acids↗
PubMed2004

Regional distribution of proteinase K-resistant alpha-synuclein correlates with Lewy body disease stage.

Lewy bodies (LBs) containing alpha-synuclein (alphaSYN) fibrils are the hallmark lesions of Parkinson disease, dementia with LBs, and related neurodegenerative diseases. Here we have investigated the susceptibility to proteolysis of alphaSYN from brain samples of patients with different subtypes of LB diseases. While soluble alphaSYN was completely degradable in all samples, the affected brain regions additionally contained insoluble, proteinase K (PK)-resistant alphaSYN. In brainstem-predominant subtype LB disease cases, PK-resistant alphaSYN was found in the medulla and substantia nigra, but not in cerebral cortex. In limbic subtype LB disease cases, PK resistance of alphaSYN spread to the cingulate and parahippocampal cortex, and further to the frontal cortex in neocortical subtype LB disease cases. Variable amounts of neuritic PK-resistant alphaSYN were found in the striatum of all cases. Thus, PK resistance of alphaSYN may be useful for the development of biomarkers of LB diseases.

Aged↗
PubMed2002

The toxicology of aflatoxins as a basis for public health decisions.

Aflatoxins have been extensively studied with respect to their mechanisms of toxicity. An understanding of metabolism, DNA adduct induction, mutagenicity and carcinogenicity has been paralleled by the development of biomarkers of aflatoxin exposure and biological effects (e.g. mutations) applied to human populations. The improvements in exposure assessment and their application in prospective epidemiological studies and the demonstration of a specific mutation in the TP53 gene in hepatocellular carcinomas from areas of high aflatoxin exposure have contributed significantly to the classification of aflatoxins as human carcinogens. In addition to establishing the carcinogenicity of aflatoxins in humans, understanding molecular mechanisms of action has provided the scientific rationale for prevention strategies, including primary and chemoprevention approaches. Overall, integrated, multidisciplinary research on aflatoxins has provided the platform on which to base decisions regarding acceptable exposures and priorities for interventions to reduce human risk in a public health context.

Aflatoxins↗
PubMed1989

Epidemiology and risk factors.

HBC is common, accounting for approximately 9% of the total breast cancer burden. Given 142,000 cases of breast cancer expected to occur in 1989, this would represent 12,780 cases of HBC patients. Soberingly, each patient represents a family with a variable number of inordinately high risk patients. HBC's natural history is distinctive and enables the identification of at risk patients who can benefit from highly targeted surveillance/management strategies. High priority must be given to development of biomarkers that will one day be found to have acceptable sensitivity and specificity to genotype status. Thus, we would then be able to tell which of the first-degree relatives of affected members have inherited the deleterious gene. This would result in a significant saving of time and money that would otherwise be expended through intensive surveillance strategies. We need cost-benefit research to induce third party carriers to defray expenses for surveillance. Finally, priority attention must be given to biomolecular research for identification of markers of acceptable sensitivity and specificity to the cancer-prone genotype. Eventual cloning of the deleterious gene(s) could lead to knowledge about its chemical and physiologic products, thereby enabling anticancer pharmacologic research. The reward could then be improved control and even prevention of breast cancer, and possibly of the associated cancers in heterogenous forms of this disease.

Adult↗
PubMed2005

Early-response biological dosimetry--recommended countermeasure enhancements for mass-casualty radiological incidents and terrorism.

The effective medical management of a suspected acute radiation overexposure incident necessitates recording dynamic medical data, measuring appropriate radiation bioassays, and estimating dose from dosimeters and radioactivity assessments in order to provide diagnostic information to the treating physician and a dose assessment for personnel radiation protection records. The accepted generic multiparameter and early-response approach includes measuring radioactivity and monitoring the exposed individual; observing and recording prodromal signs/symptoms and erythema; obtaining complete blood counts with white blood cell differential; sampling blood for the chromosome-aberration cytogenetic bioassay using the "gold standard" dicentric assay (translocation assay for long times after exposure) for dose assessment; bioassay sampling, if appropriate, to determine radioactivity contamination; and using other available dosimetry approaches. In the event of a radiological mass-casualty incident, current national resources need to be enhanced to provide suitable dose assessment and medical triage and diagnoses. This capability should be broadly based and include stockpiling reagents and devices; establishing deployable (i.e., hematology and biodosimetry) laboratories and reference (i.e., cytogenetic biodosimetry, radiation bioassay) laboratories; networking qualified reference radioactivity-counting bioassay laboratories, cytogenetic biodosimetry, and deployable hematology laboratories with the medical responder community and national radiation protection program; and researching efforts to identify novel radiation biomarkers and develop applied biological dosimetry assays monitored with clinical, deployable, and hand-held analytical systems. These research and applied science efforts should ultimately contribute towards approved, regulated biodosimetry devices or diagnostic tests integrated into a national radioprotection program.

Chromosome Aberrations↗
PubMed2006

Designer genes: Filling the gap in transplantation.

Accelerated evolution of the field of functional genomics has been greatly facilitated by high-throughput microarray-based gene function studies, relating to the parallel and serial expression measurements of genomes. Microarray experimentation is being applied for the study of basic research questions, drug target discovery, pharmacology, toxicogenomics, target selectivity, disease biomarker determination, development of prognostic tests, and disease subclass determination. This article will review the current applications of microarray technology in the field of organ transplantation and discuss the potential impact of this technology on transplantation medicine.

Genetic Engineering↗
PubMed2003

Transcriptional response of lymphoblastoid cells to ionizing radiation.

The effects of ionizing radiation (IR) on the temporal transcriptional response of lymphoblastoid cells were investigated in this study. We used oligonucleotide microarrays to assess mRNA levels of genes in lymphoblastoid cells at various time points within 24 h following gamma-irradiation. We identified 319 and 816 IR-responsive genes following 3 Gy and 10 Gy of IR exposure, respectively, with 126 genes in common between the two doses. A high percentage of IR-responsive genes are involved in the control of cell cycle, cell death, DNA repair, DNA metabolism, and RNA processing. We determined the temporal expression profiles of the IR-responsive genes and assessed effects of IR dose on this temporal pattern of expression. By combining dose-response data with temporal profiles of expression, we have identified sets of coordinately responding genes. Through a genomic approach, we characterized a set of genes that are implicated in cellular adaptation to IR stress. These findings will allow a better understanding of complex processes such as radiation-induced carcinogenesis and the development of biomarkers for radiation exposure.

Cell Line, Transformed↗
PubMed1998

Placental isoferritin levels in pregnant patients with systemic lupus erythematosus and/or antiphospholipid syndrome.

PROBLEM: Low serum placental isoferritin (PLF), an immunosuppressive cytokine-like protein, was found in women with underlying placento-vascular dysfunction, such as intrauterine growth retardation and preeclamptic toxemia. The possible contribution of this placental product in the assessment of pregnant patients with either systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS) was investigated. METHOD OF STUDY: Seventy-five healthy pregnant women used as controls and 25 preselected pregnant patients with either SLE and/or APS were enrolled in the study. Study patients were in remission during conception and all patients agreed to give 5 ml of venous blood at midgestation. The samples were frozen and analyzed retrospectively. After delivery, pregnancy outcomes were gathered from hospital records. RESULTS: Seventeen (68%) women had uneventful pregnancies and deliveries (normal) whereas 8 (32%) showed pathologic obstetric outcomes. Mean midgestational serum PLF levels were similar in the control and normal outcome groups (87 U/ml), whereas significantly lower levels (37 U/ml) were measured in the pathologic outcome group. Using a cutoff level of 10 U/ml, 85% from the normal outcome group and 15% from the pathologic outcome group were above this threshold level, with 60% specificity and 100% sensitivity. CONCLUSIONS: These preliminary data suggest that PLF values may reflect placento-vascular functions. These may represent a predictive biomarker for developing obstetric complications in pregnant women with either SLE and/or APS.

Adult↗
PubMed1994

Research priorities in occupational medicine: a survey of United Kingdom medical opinion by the Delphi technique.

An attempt to achieve an agreed set of priorities for research in occupational medicine was undertaken by the Delphi technique. Fifty three senior practitioners of occupational medicine in academe (25) and industry or government (28) were canvassed about their views and choices for priority activity. Forty six (86%) responded to the initial enquiry and 48 (91%) provided rank order choices from a second, more detailed questionnaire. The first priority for more research on the natural history of work related ill health identified musculoskeletal disorders of the back and upper limbs followed by asthma, accidents, skin disorders, vibration induced disease, suicide and depression, and finally hearing loss. The second priority area was audit and particularly the need for its use in occupational health screening procedures. Environmental impact of industrial activity was third with the community health effects being more important than individual health effects. Stress related disease was fourth with emphasis on risk factors. The fifth area was neuropsychological effects of work exposures particularly the need for more research on diagnostic tests. Other assorted areas of concern were the cost effectiveness of occupational health, risk assessment, reproductive hazards, the effects of pharmacological agents, and the development of biomarkers as early evidence of an exposure effect. The remarkable degree of unanimity on the issues and choices and the general agreement between physicians from academe and industry on what constitute the priorities warrants further discussion and positive action.

Delphi Technique↗
PubMed1998

Future directions in imaging of breast diseases.

In the near future, investigation and refinement of emerging anatomic and functional breast imaging techniques will enable clinical trials that will evaluate their utility and potential for improving the survival and quality of life for patients with breast cancer. In the longer term, strategic research collaborations among investigators in the fields of functional imaging, molecular biology, and pathology are needed to merge existing science and advance the development of biomarker and genetic techniques focused on detecting and characterizing disease at the cellular and molecular levels. This research could create clinical tools for (a) detecting breast cancer earlier, (b) more accurately quantifying the extent of disease, (c) noninvasively evaluating lymph node involvement, (d) identifying micrometastases and residual microscopic disease, and (e) enhancing therapy by means of imaging-guided biomarker or tumor-specific delivery of pharmacologic, chemosensitizing, or radiosensitizing agents to tumors.

Breast↗
PubMed2006

In vivo-in vitro toxicogenomic comparison of TCDD-elicited gene expression in Hepa1c1c7 mouse hepatoma cells and C57BL/6 hepatic tissue.

BACKGROUND: In vitro systems have inherent limitations in their ability to model whole organism gene responses, which must be identified and appropriately considered when developing predictive biomarkers of in vivo toxicity. Systematic comparison of in vitro and in vivo temporal gene expression profiles were conducted to assess the ability of Hepa1c1c7 mouse hepatoma cells to model hepatic responses in C57BL/6 mice following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). RESULTS: Gene expression analysis and functional gene annotation indicate that Hepa1c1c7 cells appropriately modeled the induction of xenobiotic metabolism genes in vivo. However, responses associated with cell cycle progression and proliferation were unique to Hepa1c1c7 cells, consistent with the cell cycle arrest effects of TCDD on rapidly dividing cells. In contrast, lipid metabolism and immune responses, representative of whole organism effects in vivo, were not replicated in Hepa1c1c7 cells. CONCLUSION: These results identified inherent differences in TCDD-mediated gene expression responses between these models and highlighted the limitations of in vitro systems in modeling whole organism responses, and additionally identified potential predictive biomarkers of toxicity.

Animals↗
PubMed2006

Host-virus interaction: a new role for microRNAs.

MicroRNAs (miRNAs) are a new class of 18-23 nucleotide long non-coding RNAs that play critical roles in a wide spectrum of biological processes. Recent reports also throw light into the role of microRNAs as critical effectors in the intricate host-pathogen interaction networks. Evidence suggests that both virus and hosts encode microRNAs. The exclusive dependence of viruses on the host cellular machinery for their propagation and survival also make them highly susceptible to the vagaries of the cellular environment like small RNA mediated interference. It also gives the virus an opportunity to fight and/or modulate the host to suite its needs. Thus the range of interactions possible through miRNA-mRNA cross-talk at the host-pathogen interface is large. These interactions can be further fine-tuned in the host by changes in gene expression, mutations and polymorphisms. In the pathogen, the high rate of mutations adds to the complexity of the interaction network. Though evidence regarding microRNA mediated cross-talk in viral infections is just emerging, it offers an immense opportunity not only to understand the intricacies of host-pathogen interactions, and possible explanations to viral tropism, latency and oncogenesis, but also to develop novel biomarkers and therapeutics.

Eukaryotic Cells↗