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Robert C. Smart - One of the best experts on this subject based on the ideXlab platform.
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17β-Estradiol Is a Hormonal Regulator of Mirex Tumor Promotion Sensitivity in Mice
Toxicological sciences : an official journal of the Society of Toxicology, 2002Co-Authors: Karen L. Porter, Sanjay Chanda, Hui Quin Wang, Kevin W. Gaido, Robert C. Smart, C. Lee RobinetteAbstract:Mirex, an organochlorine pesticide, is a potent non-phorbol ester tumor promoter in mouse skin. Previous studies have shown that female mice are 3 times more sensitive to Mirex tumor promotion than male mice and that ovariectomized (OVX) female mice are resistant to Mirex promotion, suggesting a role for ovarian hormones in Mirex promotion. To determine whether the ovarian hormone 17-beta estradiol (E2) is responsible for the sensitivity of female mice to Mirex promotion, female mice were initiated with DMBA; 2 weeks later groups of mice were OVX and implants, with or without E2, were surgically implanted subcutaneously. These mice were treated topically twice weekly with Mirex for 26 weeks. E2 implanted OVX mice demonstrated high normal physiologic levels of serum E2 throughout the tumor promotion experiment. E2 implants restored by 80% the intact Mirex-sensitive phenotype to the OVX mice. Consistent with a role for E2 and ERalpha and ERbeta, treatment of DMBA-initiated female mice with topical ICI 182,780, an estrogen-receptor antagonist, reduced Mirex tumor multiplicity by 30%. However, in cells co-transfected with ERalpha or ERbeta and estrogen-responsive promoter reporter, Mirex did not stimulate promoter reporter activity, suggesting that the promotion effect of Mirex is downstream of ERalpha/beta. Finally, a tumor promotion study was conducted to determine whether E2 implants could increase the sensitivity of male mice to Mirex promotion. E2 implants in male mice did increase sensitivity to Mirex promotion; however, the implants did not produce the full female sensitivity to Mirex tumor promotion. Collectively, these studies indicate that E2 is a major ovarian hormone responsible for Mirex tumor promotion sensitivity in female mice.
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Evidence that Mirex promotes a unique population of epidermal cells that cannot be distinguished by their mutant Ha-ras genotype.
Molecular carcinogenesis, 1997Co-Authors: Tae-won Kim, Karen L. Porter, Julie F. Foley, Robert R. Maronpot, Robert C. SmartAbstract:Mirex is a potent tumor promoter in 7,1 2-dimethylbenz[a]anthracene (DMBA)-initiated female CD-1 mouse skin. Like 12-O-tetradecanoylphorbol-13-acetate (TPA), Mirex promotes papillomas that have a Ha-ras mutation; however, unlike TPA promotion, Mirex promotion does not involve a general hyperplastic response. We used proliferating cell nuclear antigen (PCNA) and 5-bromo-2'-deoxyuridine (BrdU) immunohistochemical staining to further examine the proliferative capacity of Mirex. The numbers of PCNA- and BrdU-positive epidermal S-phase cells were highly concordant in all treatment groups. Unlike a single application of TPA, a single application of Mirex had little or no effect on the number of S-phase epidermal cells, and chronic application of Mirex to mouse skin produced only minimal increases in S-phase cells. Moreover, Mirex did not significantly alter the growth of BALB/MK-2 keratinocytes in media containing either 0.05 or 1.2 mM Ca++. These results suggest that Mirex may have highly specific effects on the proliferation of initiated cells and support the existence of a unique Mirex mechanism and/or distinct population of Mirex-promotable mutant Ha-ras epidermal cells. To begin to address this issue of a distinct population of Mirex-promotable mutant Ha-ras cells, we conducted a tandem experiment in which DMBA-initiated mice were treated twice weekly with a maximal promoting dose of Mirex. Then, when the number of papillomas reached a plateau, these same mice were treated twice weekly with a maximal promoting dose of TPA. Mice treated with Mirex developed a maximum of 6.4 papillomas/mouse. These mice were then promoted with TPA, which produced 8.9 additional papillomas/mouse for a total of 15.3 papillomas/mouse. The maximum tumor yields from other groups of mice treated with only TPA or Mirex were 9.8 and 7.3 papillomas/mouse, respectively. Therefore, under these tandem conditions, tumor yields were additive, indicating that there are at least two distinct populations of mutant Ha-ras cells: one promoted by Mirex and the other by TPA.
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Lack of effect of retinoic acid and fluocinolone acetonide on Mirex tumor promotion indicates a novel Mirex mechanism
Carcinogenesis, 1995Co-Authors: Tae-won Kim, Robert C. SmartAbstract:Mirex, a halogenated hydrocarbon, is a potent skin tumor promoter in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. In the present study retinoic acid (RA) and fluocinolone acetonide (FA), classical inhibitors of phorbol ester- and non-phorbol ester-type skin tumor promoters, were examined for their ability to inhibit Mirex tumor promotion. Female CD-1 mice were initiated with 200 nmol DMBA and promoted with equipotent promoting doses of either 5 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) or 200 nmol Mirex twice weekly for 25 weeks and RA (2(1 or 5 nmol), FA (0.5 or 2 nmol) or acetone were applied 30 min prior to each TPA or Mirex dose. TPA-promoted papilloma formation was strongly inhibited by > 70% with both doses of RA and by > 90% with both doses of FA. In contrast, Mirex-promoted papilloma formation was not inhibited by either dose of RA or 0.5 nmol FA and 2 nmol FA weakly inhibited Mirex-promoted papillomas by only 32%. TPA- and Mirex-promoted papillomas that were refractory to RA and FA demonstrated the same incidence of Ha-ras mutation as TPA- or Mirex-promoted papillomas without RA and FA treatment, further indicating that the inhibitory activity of RA and FA is promoter-dependent and not solely dependent on mutant Ha-ras. FA (2 nmol) treatment completely abolished TPA-induced epidermal hyperplasia and proliferating cell nuclear antigen (PCNA) S phase-positive cells, however, FA had no inhibitory effect on the weak proliferative response induced by Mirex. Collectively, these results indicate that the promotional activity of Mirex, as well as its weak proliferative response, result from a distinct promoter mechanism and/or that Mirex promotes a unique population of epidermal cells that are insensitive to FA and RA and cannot be distinguished by their mutant Ha-ras genotype.
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characterization of skin tumor promotion by Mirex structure activity relationships sexual dimorphism and presence of ha ras mutation
Carcinogenesis, 1993Co-Authors: Glenda J. Moser, Lee C Robinette, Robert C. SmartAbstract:In the present study we have compared the tumor-promoting activity of the non-phorbol ester-type skin tumor promoter, Mirex, a halogenated cycloalkane pesticide, to the following: (i) chlordane, a halogenated cycloalkane pesticide; (ii) 1,1-bis (4-chlorophenyl)-2,2,2-trichlorethane (DDT), a halogenated bridged aromatic pesticide; and (iii) kepone, a halogenated cycloalkane pesticide, which only differs from Mirex by the substitution of two chlorine atoms with an oxygen atom. Topical application of 200 nmol Mirex three times weekly for 20 weeks to 7,12-dimethylbenz[a]anthracene (DMBA)-initiated female mouse skin produced approximately 16 tumors/mouse with a 96% incidence of tumor bearing mice. Neither chlordane (2 mumol) or DDT (5 mumol) promoted tumors in DMBA-initiated mouse skin after three times weekly application for 20 weeks. Unexpectedly, DMBA-initiated mice treated with 250 nmol kepone three times weekly for 20 weeks did not develop any tumors, demonstrating that the replacement of two chlorine atoms by an oxygen atom results in loss of the skin tumor-promoting activity of Mirex. To further characterize Mirex-induced skin tumor promotion, male mice were initiated with a single topical application of 200 nmol DMBA and promoted topically three times weekly for 20 weeks with 200 nmol Mirex. As compared to female mice, male mice demonstrated (i) 70% fewer tumors/mouse, (ii) decreased incidence of tumor bearing mice, (iii) increased time to first tumor and (iv) increased latency. To determine the role of ovarian hormones in the increased sensitivity of female mice, mice were initiated with DMBA, ovariectomized (OVX) 2 weeks later and then promoted with Mirex. OVX mice exhibited 70% fewer tumors/mouse and a 40% decrease in incidence of tumor-bearing mice as compared to controls. Finally, > 90% of DMBA-initiated/Mirex-promoted papillomas from male mice and female mice demonstrated a mutated Ha-ras gene with an A-->T transversion in the middle base of the 61st codon. Collectively, these data indicate that the tumor-promoting ability of Mirex is highly structure specific, and ovarian hormones are a factor in the increased sensitivity of female mice to the skin tumor-promoting ability of Mirex. Furthermore, Mirex appears to clonally expand epidermal cells with a mutated Ha-ras oncogene.
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The Chlorinated Pesticide Mirex Is a Novel Nonphorbol Ester-type Tumor Promoter in Mouse Skin
Cancer research, 1992Co-Authors: Glenda J. Moser, Sharon A. Meyer, Robert C. SmartAbstract:The hepatocarcinogenic organochlorine pesticide, Mirex, was examined as a tumor promoter in the mouse skin initiation-promotion model. Female CD-1 mice were initiated with 200 nmol 7,12-dimethylbenz[ a ] anthracene and topically promoted three times weekly for 20 weeks with doses of 25, 50, 100, or 200 nmol Mirex. Mirex promoted tumors at all dose levels in a dose-dependent manner. At 20 weeks, mice promoted with 25, 50, 100, and 200 nmol Mirex developed an average of 0.2, 4, 10, and 16 tumors per mouse with a 10, 60, 93, and 96% incidence of tumor-bearing mice, respectively. With continued treatment to 34 weeks, mice promoted with 25, 50, and 100 nmol Mirex developed an average of 0.7, 7, and 12 tumors per mouse with a 27, 85, and 100% incidence of tumor-bearing mice, respectively. These results demonstrate that Mirex is a very effective tumor promoter in mouse skin. The effect of Mirex on several biochemical and morphological events associated with tumor promotion was then investigated. Mirex did not stimulate epidermal protein kinase C activity in vitro . Unlike the phorbol ester, 12- O -tetradecanoylphorbol-13-acetate, a single topical application of Mirex (200 nmol) did not increase [3H]thymidine incorporation into epidermal DNA up to 108 h after application. Furthermore, multiple applications of 200 nmol Mirex (3 times weekly for 4 weeks) resulted in only a very weak proliferative response; Mirex increased the number of nucleated epidermal cell layers from 1 to 2 in acetone-treated controls to 2 to 3 while 2 nmol 12- O -tetradecanoylphorbol-13-acetate produced 6 to 7 nucleated cell layers. Mirex (200 nmol) did not induce ornithine decarboxylase activity up to 56 h after a single topical application. Collectively, these data indicate that Mirex is a novel nonphorbol ester-type tumor promoter in mouse skin.
Glenda J. Moser - One of the best experts on this subject based on the ideXlab platform.
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characterization of skin tumor promotion by Mirex structure activity relationships sexual dimorphism and presence of ha ras mutation
Carcinogenesis, 1993Co-Authors: Glenda J. Moser, Lee C Robinette, Robert C. SmartAbstract:In the present study we have compared the tumor-promoting activity of the non-phorbol ester-type skin tumor promoter, Mirex, a halogenated cycloalkane pesticide, to the following: (i) chlordane, a halogenated cycloalkane pesticide; (ii) 1,1-bis (4-chlorophenyl)-2,2,2-trichlorethane (DDT), a halogenated bridged aromatic pesticide; and (iii) kepone, a halogenated cycloalkane pesticide, which only differs from Mirex by the substitution of two chlorine atoms with an oxygen atom. Topical application of 200 nmol Mirex three times weekly for 20 weeks to 7,12-dimethylbenz[a]anthracene (DMBA)-initiated female mouse skin produced approximately 16 tumors/mouse with a 96% incidence of tumor bearing mice. Neither chlordane (2 mumol) or DDT (5 mumol) promoted tumors in DMBA-initiated mouse skin after three times weekly application for 20 weeks. Unexpectedly, DMBA-initiated mice treated with 250 nmol kepone three times weekly for 20 weeks did not develop any tumors, demonstrating that the replacement of two chlorine atoms by an oxygen atom results in loss of the skin tumor-promoting activity of Mirex. To further characterize Mirex-induced skin tumor promotion, male mice were initiated with a single topical application of 200 nmol DMBA and promoted topically three times weekly for 20 weeks with 200 nmol Mirex. As compared to female mice, male mice demonstrated (i) 70% fewer tumors/mouse, (ii) decreased incidence of tumor bearing mice, (iii) increased time to first tumor and (iv) increased latency. To determine the role of ovarian hormones in the increased sensitivity of female mice, mice were initiated with DMBA, ovariectomized (OVX) 2 weeks later and then promoted with Mirex. OVX mice exhibited 70% fewer tumors/mouse and a 40% decrease in incidence of tumor-bearing mice as compared to controls. Finally, > 90% of DMBA-initiated/Mirex-promoted papillomas from male mice and female mice demonstrated a mutated Ha-ras gene with an A-->T transversion in the middle base of the 61st codon. Collectively, these data indicate that the tumor-promoting ability of Mirex is highly structure specific, and ovarian hormones are a factor in the increased sensitivity of female mice to the skin tumor-promoting ability of Mirex. Furthermore, Mirex appears to clonally expand epidermal cells with a mutated Ha-ras oncogene.
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The Chlorinated Pesticide Mirex Is a Novel Nonphorbol Ester-type Tumor Promoter in Mouse Skin
Cancer research, 1992Co-Authors: Glenda J. Moser, Sharon A. Meyer, Robert C. SmartAbstract:The hepatocarcinogenic organochlorine pesticide, Mirex, was examined as a tumor promoter in the mouse skin initiation-promotion model. Female CD-1 mice were initiated with 200 nmol 7,12-dimethylbenz[ a ] anthracene and topically promoted three times weekly for 20 weeks with doses of 25, 50, 100, or 200 nmol Mirex. Mirex promoted tumors at all dose levels in a dose-dependent manner. At 20 weeks, mice promoted with 25, 50, 100, and 200 nmol Mirex developed an average of 0.2, 4, 10, and 16 tumors per mouse with a 10, 60, 93, and 96% incidence of tumor-bearing mice, respectively. With continued treatment to 34 weeks, mice promoted with 25, 50, and 100 nmol Mirex developed an average of 0.7, 7, and 12 tumors per mouse with a 27, 85, and 100% incidence of tumor-bearing mice, respectively. These results demonstrate that Mirex is a very effective tumor promoter in mouse skin. The effect of Mirex on several biochemical and morphological events associated with tumor promotion was then investigated. Mirex did not stimulate epidermal protein kinase C activity in vitro . Unlike the phorbol ester, 12- O -tetradecanoylphorbol-13-acetate, a single topical application of Mirex (200 nmol) did not increase [3H]thymidine incorporation into epidermal DNA up to 108 h after application. Furthermore, multiple applications of 200 nmol Mirex (3 times weekly for 4 weeks) resulted in only a very weak proliferative response; Mirex increased the number of nucleated epidermal cell layers from 1 to 2 in acetone-treated controls to 2 to 3 while 2 nmol 12- O -tetradecanoylphorbol-13-acetate produced 6 to 7 nucleated cell layers. Mirex (200 nmol) did not induce ornithine decarboxylase activity up to 56 h after a single topical application. Collectively, these data indicate that Mirex is a novel nonphorbol ester-type tumor promoter in mouse skin.
R C Smart - One of the best experts on this subject based on the ideXlab platform.
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Minimal role of enhanced cell proliferation in skin tumor promotion by Mirex: a nonphorbol ester-type promoter.
Environmental health perspectives, 1993Co-Authors: S A Meyer, G J Moser, N A Monteiro-riviere, R C SmartAbstract:Mirex, a chlorinated hydrocarbon previously used as a systemic insecticide and flame retardant, is a nongenotoxic hepatocarcinogen in both rats and mice. In liver, Mirex induced biochemical responses and hyperplasia characteristic of increased cell proliferation, which is consistent with its role as a liver tumor promoter. We have recently shown that Mirex is a potent nonphorbol ester-type skin tumor promoter in 7, 12-dimethylbenz[a]anthracene (DMBA)-initiated mice. However, unlike its effect in liver, a single topical application of Mirex to skin does not induce the acute biochemical responses, such as increased epidermal DNA synthesis and ornithine decarboxylase activity, indicative of increased cell proliferation. Multiple topical applications of Mirex over a 1 month period induced only a minimal increase in the number of epidermal nucleated cell layers, which contrasts with definitive hyperplasia induced by a comparable tumor-promoting dose of 12-O-tetradecanoylphorbol-13-acetate (TPA). Collectively, these data indicated that Mirex is promoting through a novel mechanism. Further evidence that Mirex promotes tumors through a mechanism distinct from that of the prototypical skin tumor promoter, TPA, was obtained by examining the effect of their simultaneous co-treatment. The co-application of Mirex and TPA yielded a tumor multiplicity greater than the sum of the responses of each promoter individually. In summary, our results demonstrate that Mirex, a carcinogenic and hyperplastic agent in liver, is also a very effective tumor promoter in mouse skin, but suggest that Mirex operates via a novel mechanism in skin that may involve only a minimal role for enhanced cell proliferation.
Mostafa Z Badr - One of the best experts on this subject based on the ideXlab platform.
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carbohydrate and oxygen metabolism during hepatocellular proliferation a study in perfused livers from Mirex treated rats
Hepatology, 1991Co-Authors: James Yarbrough, Michael L Cunningham, Hirofumi Yamanaka, Ronald G Thurman, Mostafa Z BadrAbstract:Liver regeneration after partial hepatectomy is accompanied by altered hepatic intermediary metabolism. Because the organochlorine compound Mirex also causes liver cell growth, the purpose of this study was to investigate hepatic carbohydrate and oxygen metabolism in perfused livers from Mirex-treated rats and to localize cell proliferation in this model. Pretreatment with Mirex (100 mg/kg, intragastrically) increased liver/body weight ratios and DNA synthesis in livers of fed rats, effects that were markedly diminished in livers of fasted rats. This finding shows that liver growth caused by Mirex, as is the case after partial hepatectomy, is hindered when animals are deprived of food. Furthermore, perfused livers from Mirex-treated rats had depleted glycogen stores but significantly elevated oxygen uptake compared with livers from control rats. Increases in oxygen uptake and hepatocellular proliferation were observed mostly in periportal regions of the liver lobule. In regenerating livers, most DNA synthesis was reported to also occur in these regions of the liver lobule. Taken together, these data show that liver cell growth caused by Mirex is accompanied by changes in hepatic intermediary metabolism and sublobular proliferation similar to those observed after partial hepatectomy. (HEPATOLOGY 1991;13:1229–1234.)
Stephen J Downie - One of the best experts on this subject based on the ideXlab platform.
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the impact of Mirex on scholarly research 2005 2010
International Symposium Conference on Music Information Retrieval, 2012Co-Authors: Sally Jo Cunningham, David Bainbridge, Stephen J DownieAbstract:This paper explores the impact of the Mirex (Music Information Retrieval Evaluation eXchange) evaluation initiative on scholarly research. Impact is assessed through a bibliometric evaluation of both the Mirex extended abstracts and the papers citing the Mirex results, the trial framework and methodology, or Mirex datasets. Impact is examined through number of publications and citation analysis. We further explore the primary publication venues for Mirex results, the geographic distribution of both Mirex contributors and researchers citing Mirex results, and the spread of Mirex-based research beyond the Mirex contributor teams. This analysis indicates that research in this area is highly collaborative, has achieved an international dissemination, and has grown to have a significant profile in the research literature.
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the music information retrieval evaluation exchange 2005 2007 a window into music information retrieval research
Acoustical Science and Technology, 2008Co-Authors: Stephen J DownieAbstract:The Music Information Retrieval Evaluation eXchange (Mirex) is the community-based framework for the formal evaluation of Music Information Retrieval (MIR) systems and algorithms. By looking at the background, structure, challenges, and contributions of Mirex this paper provides some insights into the world of MIR research. Because Mirex tasks are defined by the community they reflect the interests, techniques, and research paradigms of the community as a whole. Both Mirex and MIR have a strong bias toward audio-based approaches as most MIR researchers have strengths in signal processing. Spectral-based approaches to MIR tasks have led to advancements in the MIR field but they now appear to be reaching their limits of effectiveness. This limitation is called the “glass ceiling” problem and the Mirex results data support its existence. The post-hoc analyses of Mirex results data indicate that there are groups of systems that perform equally well within various MIR tasks. There are many challenges facing Mirex and MIR research most of which have their root causes in the intellectual property issues surrounding music. The current inability of researchers to test their approaches against the Mirex test collections outside the annual Mirex cycle is hindering the rapid development of improved MIR systems.