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Induction of Aryl Hydrocarbon Hydroxylase in Ambystoma tigrinum

Description: Aryl hydrocarbon hydroxylase (AHH) was induced 15-fold in Ambystoma tigrinum by intraperitoneal injection of 3-methylcholanthrene in corn oil, or 10-fold by addition of aromatic polycyclic hydrocarbons to the aqueous environment of the neotene animal. The cytochrome P-450-associated microsomal enzyme is similar to the inducible, one-gene, autosomal-dominant system typical in the laboratory mouse and man. Differences in optimal temperature for enzyme induction and activity were noted in organ culture of human and Ambystoma tissues, and ratios of benzpyrene metabolites differed between Ambystoma and Mus. The half life of enzyme activity induced in vivo was related to the excretion of hydrocarbon metabolites.
Date: December 1974
Creator: Colvin, David P.
Partner: UNT Libraries

Using Mode of Action to Assess Health Risks from Mixtures of Chemical/Physical Agents

Description: Interactions between tumor promoters with differing mechanisms of action were examined in male B6C3F1 mice treated with mixtures of dichloroacetate (DCA), trichloroacetate (TCA), and tetrachloride (CT), each of which acts by a different mode of action. Mice were initiated by vinyl carbamate (VC), and then promoted by DCA, TCA, CT, or the pair-wised combinations of the three compounds. The effect of each treatment or treatment combination on tumor number/animal and tumor size was individually assessed at 18, 24, 30 or 36 weeks of treatment. Dose-related increases in tumor size were observed with 20 & 50 mg/kg CT, but each produced equal number of tumors at 36 weeks with the main distinction being a decrease in tumor latency at the higher dose. Overall TCA treatment produced dose-related increases in tumor number at 36 weeks of treatment. Thus, the lower doses of CT and TCA treatments apparently affected tumor size rather than number. Results with DCA were not as clear as a true maximum tumor number was not clearly observed within the experimental period. Treatment of mice receiving a high dose of TCA (2 g/L of drinking water) combined with varying doses of DCA (0.1, 0.5 and 2 g/L) produced increased numbers of tumors at 24 weeks and 36 weeks. However, at 36 weeks of treatment DCA produced a dose-related decrease in the size of tumors promoted by TCA. The low dose of TCA (0.1 g/L) decreased the number of tumors produced by a high dose of DCA, however, higher doses of TCA produced the same number as observed with DCA alone. Since these two chemicals produce lesions with differing phenotypes, the combination would have been expected to be additive with respect to number, but this was obviously not the case. These data suggest that the induction of liver cancer from mixtures ...
Date: January 20, 2003
Creator: Bull, Richard J.; Lei, Xingye C. & Sasser, Lyle B.
Partner: UNT Libraries Government Documents Department

Diphenyloxazole Metabolism by Aryl Hydrocarbon Hydroxylase

Description: 2,5-Diphenyloxazole (PPO) was tested as a potential alternate inducer for the aryl hydrocarbon hydroxylase (AHH) system. Its apparent lack. of carcinogenicity and toxicity provide a possible system for investigation of enzyme systems related to chemical carcinogenesis without exposure of the researcher to potent carcinogenic compounds. These studies found PPO to be an inducer of AHH in cultured human lymphocytes. When PPO was utilized as a substrate for the AHH assay system, the major metabolites produced were strongly fluorescent. A simple fluorometric assay was developed which employed PPO as the substrate and which measured constitutive activity more efficiently than similar assays using benzo(a)pyrene as the substrate. Quantitation of both basal and induced lymphocyte AHH metabolism of PPO may be applicable to human population studies and may provide a tool to determine possible genetic variables with respect to carcinogen metabolism related to cancer risk.
Date: December 1976
Creator: Abreu, Mary E.
Partner: UNT Libraries

The Role of Telomere Dysfunction in Driving Genomic Instability

Description: The mechanistic role of radiation-induced genomic instability in radiation carcinogenesis is an attractive hypothesis that remains to be rigorously tested. There are few in vivo studies on which to base judgments, but work in our laboratory with mouse models of radiogenic mammary neoplasia provided the first indications that certain forms of genetically predisposed radiation-induced genomic instability may contribute to tumor development. The central goal of this research project is to more firmly establish the mechanistic basis of this radiation-associated genomic instability and, from this, to assess whether such induced instability might play a major role in tumorigenesis at low doses of low LET radiation. In the case of mouse mammary tumors, susceptibility to induced instability is expressed as an autosomal recessive trait in mammary epithelial cells and is manifest largely as excess chromatid damage. Recently published studies associate this form of instability with DNA repair deficiency, polymorphic variation in the gene encoding DNA-PKcs (Prkdc), and mammary associated susceptibility. The underlying hypothesis being tested in this project is that tumor-associated genomic instability is preferentially expressed in certain recombinogenic genomic domains and that these may be cell lineage/individual-specific.
Date: January 17, 2008
Creator: Ullrich, Robert L & Bailey, Susan
Partner: UNT Libraries Government Documents Department

Involvement of extracellular matrix constituents in breast cancer

Description: It has recently been established that the extracellular matrix is required for normal functional differentiation of mammary epithelia not only in culture, but also in vivo. The mechanisms by which extracellular matrix affects differentiation, as well as the nature of extracellular matrix constituents which have major impacts on mammary gland function, have only now begun to be dissected. The intricate variety of extracellular matrix-mediated events and the remarkable degree of plasticity of extracellular matrix structure and composition at virtually all times during ontogeny, make such studies difficult. Similarly, during carcinogenesis, the extracellular matrix undergoes gross alterations, the consequences of which are not yet precisely understood. Nevertheless, an increasing amount of data suggests that the extracellular matrix and extracellular matrix-receptors might participate in the control of most, if not all, of the successive stages of breast tumors, from appearance to progression and metastasis.
Date: June 1, 1995
Creator: Lochter, Andre & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

Aryl Hydrocarbon Hydroxylase and Sixteen Alpha Hydroxylase in Cultured Human Lymphocytes

Description: Cultured human lymphocytes may be assayed for aryl hydrocarbon hydroxylase (AHH) in whole cell preparations. The optimum assay conditions are pH 8.5, and 1.5 mM Mg++. The reaction is linear with time and cell number, and is inhibited by CO. Estradiol may inhibit induction of AHH by 3-methylcholanthrene, but is a poor competitor for the enzyme. A Caucasian population was assayed for AHH activity. The distribution was lognormal; no difference was found in cultured cells from males and females or smokers and nonsmokers. Cells from relatives of lung cancer patients showed higher activity. An American Indian population showed no difference from the Caucasian population in enzyme level. No linkage was found between AHH and 16a-hydroxylase.
Date: December 1975
Creator: Coomes, Marguerite L.
Partner: UNT Libraries


Description: The carcinogenic activity of the benzo[a]pyrene 1, the 7,12-dimethylbenz[a]anthracene 2 and the 3-methylcholanthrene 3 is suggested to be determine by the electrophilic attack of the active oxygen, induced by the hydroxylating enzyme systems, on the most reactive substituting carbon atom(s). The cationic intermediate(s) with the charge mainly localized on a complementary, interrelated position(s) of the hydroxyl substituted position(s) reacts further with the cellular nucleophiles. The electrophilic nature of the ultimate chemical carcinogens constitutes the common distinctive feature that correlates their different structures and allows us to understand their carcinogenicity. The formation of a covalent bond with the nucleophiles of the biological macromolecules, nucleic acids and proteins, appears to be the essential requirement in the primary process of carcinogenesis.
Date: August 1, 1970
Creator: Cavalieri, E. & Calvin, M.
Partner: UNT Libraries Government Documents Department

AZU-1: A Candidate Breast Tumor Suppressor and Biomarker for Tumor Progression

Description: To identify genes misregulated in the final stages of breast carcinogenesis, we performed differential display to compare the gene expression patterns of the human tumorigenic mammary epithelial cells, HMT-3522-T4-2, with those of their immediate premalignant progenitors, HMT-3522-S2. We identified a novel gene, called anti-zuai-1 (AZU-1), that was abundantly expressed in non- and premalignant cells and tissues but was appreciably reduced in breast tumor cell types and in primary tumors. The AZU-1 gene encodes an acidic 571-amino-acid protein containing at least two structurally distinct domains with potential protein-binding functions: an N-terminal serine and proline-rich domain with a predicted immunoglobulin-like fold and a C-terminal coiled-coil domain. In HMT-3522 cells, the bulk of AZU-1 protein resided in a detergent-extractable cytoplasmic pool and was present at much lower levels in tumorigenic T4-2 cells than in their nonmalignant counterparts. Reversion of the tumorigenic phenotype of T4-2 cells, by means described previously, was accompanied by the up-regulation of AZU-1. In addition, reexpression of AZU-1 in T4-2 cells, using viral vectors, was sufficient to reduce their malignant phenotype substantially, both in culture and in vivo. These results indicate that AZU-1 is a candidate breast tumor suppressor that may exert its effects by promoting correct tissue morphogenesis.
Date: February 4, 2000
Creator: Chen, Huei-Mei; Schmeichel, Karen L; Mian, I. Saira; Lelie`vre, Sophie; Petersen, Ole W & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

Overexpression of SnoN/SkiL, amplified at the 3q26.2 locus, in ovarian cancers: A role in ovarian pathogenesis

Description: High-resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26.2 encompassing SnoN/SkiL, a coregulator of SMAD/TGF{beta} signaling. SnoN RNA transcripts were elevated in {approx}80% of advanced stage serous epithelial ovarian cancers. In both immortalized normal (TIOSE) and ovarian carcinoma cell lines (OVCA), SnoN RNA levels were increased by TGF{beta} stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGF{beta}-induced increases in SnoN RNA. In TIOSE, SnoN protein levels were reduced 15min post TGF{beta}-stimulation, likely by proteosome-mediated degradation. In contrast, in OVCA, SnoN levels were elevated 3h post-stimulation potentially as a result of inhibition of the proteosome. To elucidate the role of SnoN in ovarian tumorigenesis, we explored the effects of both increasing and decreasing SnoN levels. In both TIOSE and OVCA, SnoN siRNA decreased cell growth between 20 and 50% concurrent with increased p21 levels. In TIOSE, transient expression of SnoN repressed TGF{beta} induction of PAI-1 promoters with little effect on the p21 promoter or resultant cell growth. In contrast to the effects of transient expression, stable expression of SnoN in TIOSE led to growth arrest through induction of senescence. Collectively, these results implicate SnoN levels in multiple roles during ovarian carcinogenesis: promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non-transformed ovarian epithelial cells.
Date: July 18, 2008
Creator: Nanjundan, Meera; Cheng, Kwai Wa; Zhang, Fan; Lahad, John; Kuo, Wen-Lin; Schmandt, Rosemarie et al.
Partner: UNT Libraries Government Documents Department

ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini

Description: Both ErbB1 and ErbB2 are overexpressed or amplified in breast tumors. To examine the effects of activating ErbB receptors in a context that mimics polarized epithelial cells in vivo, we activated ErbB1 and ErbB2 homodimers in preformed, growth-arrested mammary acini cultured in three-dimensional basement membrane gels. Activation of ErbB2, but not that of ErbB1, led to a reinitiation of cell proliferation and altered the properties of mammary acinar structures. These altered structures share several properties with early-stage tumors, including a loss of proliferative suppression, an absence of lumen, retention of the basement membrane and a lack of invasive properties. ErbB2 activation also disrupted tight junctions and the cell polarity of polarized epithelia, whereas ErbB1 activation did not have any effect. Our results indicate that ErbB receptors differ in their ability to induce early stages of mammary carcinogenesis in vitro and this three-dimensional model system can reveal biological activities of oncogenes that cannot be examined in vitro in standard transformation assays.
Date: August 8, 2001
Creator: Muthuswamy, Senthil K; Li, Dongmei; Lelievre, Sophie; Bissell, Mina J & Brugge, Joan S
Partner: UNT Libraries Government Documents Department

Endothelial Cell Migration and Vascular Endothelial Growth Factor Expression Are the Result of Loss of Breast Tissue Polarity

Description: Recruiting a new blood supply is a rate-limiting step in tumor progression. In a three-dimensional model of breast carcinogenesis, disorganized, proliferative transformed breast epithelial cells express significantly higher expression of angiogenic genes compared with their polarized, growth-arrested nonmalignant counterparts. Elevated vascular endothelial growth factor (VEGF) secretion by malignant cells enhanced recruitment of endothelial cells (EC) in heterotypic cocultures. Significantly, phenotypic reversion of malignant cells via reexpression of HoxD10, which is lost in malignant progression, significantly attenuated VEGF expression in a hypoxia-inducible factor 1{alpha}-independent fashion and reduced EC migration. This was due primarily to restoring polarity: forced proliferation of polarized, nonmalignant cells did not induce VEGF expression and EC recruitment, whereas disrupting the architecture of growth-arrested, reverted cells did. These data show that disrupting cytostructure activates the angiogenic switch even in the absence of proliferation and/or hypoxia and restoring organization of malignant clusters reduces VEGF expression and EC activation to levels found in quiescent nonmalignant epithelium. These data confirm the importance of tissue architecture and polarity in malignant progression.
Date: May 26, 2009
Creator: Chen, Amy; Cuevas, Ileana; Kenny, Paraic A; Miyake, Hiroshi; Mace, Kimberley; Ghajar, Cyrus et al.
Partner: UNT Libraries Government Documents Department


Description: Some of the factors controlling tissue growth in animals and cell proliferation in unicellular organisms are reviewed. Radiation damage in diploid yeast cells manifests itself sometimes in delayed lethal effect and decreased cell division rate over several generations in the progeny of the irradiated cell. Recovery of the progeny of irradiated yeast cells from phenotypic expression of radiation damage can be delayed over many generations and is similar, in time rate of onset to the onset of radiation induced animal tumors. A parallel suggests itself between the mechanism of somatic-radiation carcinogenesis and delayed recovery of unicellular organisms from radiation effect. (auth)
Date: August 19, 1957
Creator: Tobias, C.A.
Partner: UNT Libraries Government Documents Department

Estimated human health risks of disposing of nonhazardous oil field waste in salt caverns

Description: Argonne National Laboratory (ANL) has completed an evaluation of the possibility that adverse human health effects (carcinogenic and noncarcinogenic) could result from exposure to contaminants released from nonhazardous oil field wastes (NOW) disposed in domal salt caverns. In this assessment, several steps were used to evaluate potential human health risks: identifying potential contaminants of concern, determining how humans could be exposed to these contaminants, assessing the contaminants` toxicities, estimating contaminant intakes, and, finally, calculating human cancer and noncancer risks.
Date: September 1, 1997
Creator: Tomasko, D.; Elcock, D. & Veil, J.
Partner: UNT Libraries Government Documents Department

DNA damage action spectroscopy and DNA repair in intact organisms: Alfalfa seedlings

Description: Understanding the effects of UV, and increased levels of UV, on DNA in living organisms requires knowledge of both the frequency of damages induced by the quantities and quality (wavelength composition) of the damaging radiation, and of the capacity of the organisms to carry out efficient and accurate repair. The major levels of uncertainty in understanding the responses of intact organisms, both plant and animal, to UV indicates that we cannot assess accurately the impact of stratospheric ozone depletion without major increases in knowledge of DNA damage and repair. What repair paths does alfalfa use for dealing with UV damages? The rate of pyrimidine dimers induced at a low exposure of 280 nm radiation to alfalfa seedlings, was observed to be about 8 dimers/million bases. After UV exposure, the seedlings were kept in the dark or exposed to blue light filtered by a yellow. filter which excluded wavelengths shorter than about 405 nm. Seedlings so exposed carry out photorepair, but do not seem to remove dimers by excision.
Date: December 31, 1993
Creator: Sutherland, B. M.; Quaite, F. E. & Sutherland, J. C.
Partner: UNT Libraries Government Documents Department

Cancer of the melanocytic system

Description: Within reasonably homogenous populations, skin cancer increases toward low latitudes, but this association does not indicate the wavelength regions involved in cancer induction. At present, the only animal model suitable for determining the wavelengths effective in melanoma induction are certain inter- and intraspecies hybrids of the small fish, Xiphophorus. Genetic evidence indicates that the hybrids contain only one tumor suppressor gene and, therefore, are very sensitive to cancer induction by single exposures to light. 5-Day old fish were exposed in spectrophotometer cuvettes, to different monochromatic wavelengths and fluences. The fish were kept for two months in tanks shielded with yellow plastic, so as to minimize the possibility of photoreactivation, and were scored at four months. The melanoma prevalence increased with exposure to a maximum of {approximately} 0.5. The fluence-response curves were fitted to surviving fraction = a+b(l-e{sup {minus}kE}), where a is the background prevalence with no exposure, b is the maximum induced prevalence, k is the sensitivity parameter (the cross section for melanoma induction), and E is the incident fluence. The value of k at 302 nm was 0.05 m{sup 2}/J giving a mean melanoma inducing exposure, for swimming fish, of 200 J/m{sup 2}, corresponding to 3.5 cyclobutane pyrimidine dimers per Mbp of DNA in irradiated fish skin.
Date: December 31, 1994
Creator: Setlow, R.B.
Partner: UNT Libraries Government Documents Department

Chronic Dermal Toxicity of Epoxy Resins I. Skin Carcinogenic Potency and General Toxicity

Description: Epoxy resins are a diverse class of chemicals that differ in structure, physical properties, and, presumably, biological activity. The purpose of these experiments was to compare the chronic dermal toxicity and carcinogenicity of selected commercial epoxy resins and to determine the potential for positive synergistic carcinogenic interactions between different resins. This work is an extension and continuation of a Department of Energy sponsored program to evaluate epoxy resins for potential occupational health risks. The materials examined were chosen on the basis of their interest to the U.S. government. They are representative of the manufacturer's production at the time, and therefore the data are completely valid only for the specific production period. Results of the experimental exposures will be reported in two parts. This report describes the test materials, their chemical and physical characteristics and the experimental design. General (systemic) toxicity will be evaluated and the skin carcinogenicity of the materials compared. A subsequent report will provide morphological descriptions of skin and significant internal pathology induced by the various treatments.
Date: January 16, 2001
Creator: Holland, J. M.
Partner: UNT Libraries Government Documents Department

Is There a Large Risk of Radiation? a Critical Review of Pessimistic Claims

Description: A number of situations where it has been claimed that moderate radiation doses cause leukemia or other cancers are carefully reviewed. We look at cases in the United States, Great Britain, and the Soviet Union. Usually it can be demonstrated that there is an alternative, more probable, explanation for the effect seen. In several cases the authors of the papers have fallen into statistical traps. The most frequent is a posteriori selection of cohort boundaries in both space and time: a trap illustrated dramatically by Feynman. The next most common trap is to arbitrarily select one out of many ways of looking at the data, against which we were warned by Tippett. Several cohorts are compared with respect to the number of persons at risk, average dose, and the number of cancers expected. Of these, only the cohort of A-bomb survivors in Japan and the recently unclassified data on the very large occupational doses for early Soviet nuclear workers at Chelyabinsk provide evidence of clearly visible excess cancers.
Date: July 1992
Creator: Shihab-Eldin, Adnan; Shlyakhter, Alexander & Wilson, Richard
Partner: UNT Libraries Government Documents Department

Cancer from internal emitters

Description: Irradiation from internal emitters, or internally deposited radionuclides, is an important component of radiation exposures encountered in the workplace, home, or general environment. Long-term studies of human populations exposed to various internal emitters by different routes of exposure are producing critical information for the protection of workers and members of the general public. The purpose of this report is to examine recent developments and discuss their potential importance for understanding lifetime cancer risks from internal emitters. The major populations of persons being studied for lifetime health effects from internally deposited radionuclides are well known: Lung cancer in underground miners who inhaled Rn progeny, liver cancer from persons injected with the Th-containing radiographic contrast medium Thorotrast, bone cancer from occupational or medical intakes of {sup 226}Ra or medical injections of {sup 224}Ra, and thyroid cancer from exposures to iodine radionuclides in the environment or for medical purposes.
Date: October 1, 1995
Creator: Boecker, B.B. & Griffith, W.C. Jr.
Partner: UNT Libraries Government Documents Department

A novel approach to the study of the functional proteome in breast cancer

Description: Factors including intratumoral heterogeneity and variability in tissue handling potentially hamper the application of reverse phase protein arrays (RPPA) to study of the solid tumor functional proteome. To address this, RPPA was applied to quantify protein expression and activation in 233 human breast tumors and 52 breast cancer cell lines. Eighty-two antibodies that recognize kinase and steroid signaling events and their effectors were validated for RPPA because of the importance of these proteins to breast carcinogenesis. Reproducibility in replicate lysates was excellent. Intratumoral protein expression was less variable than intertumoral expression, and prognostic biomarkers retained the ability to accurately predict patient outcomes when analyzed in different tumor sites. Although 21/82 total and phosphoproteins demonstrated time-dependent instability in breast tumors that were placed at room temperature after surgical excision for 24 hours prior to freezing, the functional proteomic 'fingerprint' was robust in most tumors until at least 24 hours before tissue freezing. Correlations between RPPA and immunohistochemistry were statistically significant for assessed proteins but RPPA demonstrated a superior dynamic range and detected, for example, an 866-fold difference in estrogen receptor alpha level across breast tumors. Protein and mRNA levels were concordant (at p {le} 0.05) for 41.3% and 61.1% of assayed targets in breast tumors and cell lines, respectively. Several phosphorylation and cleavage products did not correlate with the corresponding transcript levels. In conclusion, the reproducibility of RPPA, the faithfulness with which proteins and the functional proteomic 'fingerprint' are preserved in different sections derived from primary breast tumors, and the surprising stability of this 'fingerprint' with increasing time to freezing all facilitate the application of RPPA to the accurate study of protein biomarkers in non-microdissected tumor specimens. The lack of correlation between several protein phosphorylation and cleavage products and the corresponding transcripts underlines the importance of study of the functional proteome ...
Date: October 10, 2008
Creator: Hennessy, Bryan; Lu, Yiling; Gonzalez-Angulo, Ana Maria; Carey, Mark; Myhre, Simen; Ju, Zhenlin et al.
Partner: UNT Libraries Government Documents Department