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299 results on '"MacGregor, James T."'

15. Bruce Nathan Ames - Paradigm shifts inside the cancer research revolution

Author

Smith, Carr J., primary, Perfetti, Thomas A., additional, Berry, Sir Colin, additional, Brash, Douglas E., additional, Bus, James, additional, Calabrese, Edward, additional, Clemens, Roger A., additional, Fowle, John R. Jack, additional, Greim, Helmut, additional, MacGregor, James T., additional, Maronpot, Robert, additional, Pressman, Peter, additional, Zeiger, Errol, additional, and Hayes, A. Wallace, additional

Published
2021
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16. In vivo erythrocyte micronucleus assay : III. Validation and regulatory acceptance of automated scoring and the use of rat peripheral blood reticulocytes, with discussion of non-hematopoietic target cells and a single dose-level limit test

Author

Hayashi, Makoto, MacGregor, James T., Gatehouse, David G., Blakey, David H., Dertinger, Stephen D., Abramsson-Zetterberg, Lilianne, Krishna, Gopala, Morita, Takeshi, Russo, Antonella, Asano, Norihide, Suzuki, Hiroshi, Ohyama, Wakako, and Gibson, Dave

Published
2007
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22. International Pig-a gene mutation assay trial: Evaluation of transferability across 14 laboratories

Author

Dertinger, Stephen D., Phonethepswath, Souk, Weller, Pamela, Nicolette, John, Murray, Joel, Sonders, Paul, Vohr, Hans-Werner, Shi, Jing, Krsmanovic, Ljubica, Gleason, Carol, Custer, Laura, Henwood, Andrew, Sweder, Kevin, Stankowski, Leon F., Jr., Roberts, Daniel J., Giddings, Amanda, Kenny, Julia, Lynch, Anthony M., Defrain, Céline, Nesslany, Fabrice, van der Leede, Bas-jan M., Van Doninck, Terry, Schuermans, Ann, Tanaka, Kentaro, Hiwata, Yoshie, Tajima, Osamu, Wilde, Eleanor, Elhajouji, Azeddine, Gunther, William C., Thiffeault, Catherine J., Shutsky, Thomas J., Fiedler, Ronald D., Kimoto, Takafumi, Bhalli, Javed A., Heflich, Robert H., and MacGregor, James T.

Published
2011
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27. Human bloodPIG‐Amutation and micronucleated reticulocyte flow cytometric assays: Method optimization and evaluation of intra‐ and inter‐subject variation

Author

Torous, Dorothea K., primary, Avlasevich, Svetlana L., additional, Khattab, Mona G., additional, Baig, Ayesha, additional, Saubermann, Lawrence J., additional, Chen, Yuhchyau, additional, Bemis, Jeffrey C., additional, Lovell, David P., additional, Walker, Vernon E., additional, MacGregor, James T., additional, and Dertinger, Stephen D., additional

Published
2020
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37. In Vitro Human Tissue Models in Risk Assessment: Report of a Consensus-Building Workshop

Author

MacGregor, James T., Collins, Jerry M., Sugiyama, Yuichi, Tyson, Charles A., Dean, Jack, Smith, Lewis, Andersen, Melvin, Curren, Rodger D., Houston, J. Brian, Kadlubar, Fred F., Kedderis, Gregory L., Krishnan, Kannan, Li, Albert P., Parchment, Ralph E., Thummel, Kenneth, Tomaszewski, Joseph E., Ulrich, Roger, Vickers, Alison E. M., and Wrighton, Steven A.

Published
2001

38. 3Rs friendly study designs facilitate rat liver and blood micronucleus assays andPig‐agene mutation assessments: Proof‐of‐concept with 13 reference chemicals

Author

Dertinger, Stephen D., primary, Avlasevich, Svetlana L., additional, Torous, Dorothea K., additional, Singh, Priyanka, additional, Khanal, Sumee, additional, Kirby, Christopher, additional, Drake, Amanda, additional, MacGregor, James T., additional, and Bemis, Jeffrey C., additional

Published
2019
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41. Human blood PIG‐A mutation and micronucleated reticulocyte flow cytometric assays: Method optimization and evaluation of intra‐ and inter‐subject variation.

Author

Torous, Dorothea K., Avlasevich, Svetlana L., Khattab, Mona G., Baig, Ayesha, Saubermann, Lawrence J., Chen, Yuhchyau, Bemis, Jeffrey C., Lovell, David P., Walker, Vernon E., MacGregor, James T., and Dertinger, Stephen D.

Subjects
BLOOD testing, BLOOD, POPULATION, RETICULOCYTES, EVALUATION methodology, GENETIC toxicology
Abstract

We previously described flow cytometry‐based methods for scoring the incidence of micronucleated reticulocytes (MN‐RET) and PIG‐A mutant phenotype reticulocytes (MUT RET) in rodent and human blood samples. The current report describes important methodological improvements for human blood analyses, including immunomagnetic enrichment of CD71‐positive reticulocytes prior to MN‐RET scoring, and procedures for storing frozen blood for later PIG‐A analysis. Technical replicate variability in MN‐RET and MUT RET frequencies based on blood specimens from 14 subjects, intra‐subject variability based on serial blood draws from 6 subjects, and inter‐subject variation based on up to 344 subjects age 0 to 73 years were quantified. Inter‐subject variation explained most of the variability observed for both endpoints (≥77%), with much lower intra‐subject and technical replicate variability. The relatively large degree of inter‐subject variation is apparent from mean and standard deviation values for MN‐RET (0.15 ± 0.10%) and MUT RET (4.7 ± 5.0 per million, after omission of two extreme outliers). The influences of age and sex on inter‐subject variation were investigated, and neither factor affected MN‐RET whereas both influenced MUT RET frequency. The lowest MUT RET values were observed for subjects <11 years old, and males had moderately higher frequencies than females. These results indicate that MN‐RET and MUT RET are automation‐compatible biomarkers of genotoxicity that bridge species of toxicological interest to include human populations. These data will be useful for appropriately designing future human studies that include these biomarkers of genotoxicity, and highlight the need for additional work aimed at identifying the sources of inter‐individual variability reported herein. [ABSTRACT FROM AUTHOR]

Published
2020
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43. 3Rs friendly study designs facilitate rat liver and blood micronucleus assays and Pig‐a gene mutation assessments: Proof‐of‐concept with 13 reference chemicals.

Author

Dertinger, Stephen D., Avlasevich, Svetlana L., Torous, Dorothea K., Singh, Priyanka, Khanal, Sumee, Kirby, Christopher, Drake, Amanda, MacGregor, James T., and Bemis, Jeffrey C.

Subjects
NUCLEOLUS, BLOOD collection, ARISTOLOCHIC acid, LIVER, GENETIC toxicology
Abstract

Regulatory guidance documents stress the value of assessing the most appropriate endpoints in multiple tissues when evaluating the in vivo genotoxic potential of chemicals. However, conducting several independent studies to evaluate multiple endpoints and/or tissue compartments is resource intensive. Furthermore, when dependent on visual detection, conventional approaches for scoring genotoxicity endpoints can be slow, tedious, and less objective than the ideal. To address these issues with current practices we attempted to (1) devise resource sparing treatment and harvest schedules that are compatible with liver and blood micronucleus endpoints, as well as the Pig‐a gene mutation assay, and (2) utilize flow cytometry‐based methods to score each of these genotoxicity biomarkers. Proof‐of‐principle experiments were performed with 4‐week‐old male and female Crl:CD(SD) rats exposed to aristolochic acids I/II, benzo[a]pyrene, cisplatin, cyclophosphamide, diethylnitrosamine, 1,2‐dimethylhydrazine, dimethylnitrosamine, 2,6‐dinitrotoluene, hydroxyurea, melphalan, temozolomide, quinoline, or vinblastine. These 13 chemicals were each tested in two treatment regimens: one 3‐day exposure cycle, and three 3‐day exposure cycles. Each exposure, blood collection, and liver harvest was accomplished during a standard Monday–Friday workweek. Key findings are that even these well‐studied, relatively potent genotoxicants were not active in both tissues and all assays (indeed only cisplatin was clearly positive in all three assays); and whereas the sensitivity of the Pig‐a assay clearly benefitted from three versus one treatment cycle, micronucleus assays yielded qualitatively similar results across both study designs. Collectively, these results suggest it is possible to significantly reduce animal and other resource requirements while improving assessments of in vivo genotoxicity potential by simultaneously evaluating three endpoints and two important tissue compartments using fit‐for‐purpose study designs in conjunction with flow cytometric scoring approaches. Environ. Mol. Mutagen., 60:704–739, 2019. © 2019 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2019
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46. Human Erythrocyte PIG-A Assay: An Easily Monitored Index of Gene Mutation Requiring Low Volume Blood Samples

Author

Dertinger, Stephen D., Avlasevich, Svetlana L., Bemis, Jeffrey C., Chen, Yuhchyau, and MacGregor, James T.

Subjects
Adult, Male, Blood Specimen Collection, Erythrocytes, Reticulocytes, CD55 Antigens, Immunomagnetic Separation, Age Factors, Membrane Proteins, Reproducibility of Results, CD59 Antigens, Middle Aged, Flow Cytometry, Article, Mutation Rate, Mutation, Humans, Female, Aged
Abstract

This laboratory has previously described a method for scoring the incidence of rodent blood Pig-a mutant phenotype erythrocytes using immunomagnetic separation in conjunction with flow cytometric analysis (In Vivo MutaFlow®). The current work extends this approach to human blood. The frequencies of CD59- and CD55-negative reticulocytes (RET(CD59-/CD55-)) and erythrocytes (RBC(CD59-/CD55-)) serve as phenotypic reporters of PIG-A gene mutation. Immunomagnetic separation was found to provide an effective means of increasing the number of reticulocytes and erythrocytes evaluated. Technical replicates were utilized to provide a sufficient number of cells for precise scoring while at the same time controlling for procedural accuracy by allowing comparison of replicate values. Cold whole blood samples could be held for at least one week without affecting reticulocyte, RET(CD59-/CD55-) or RBC(CD59-/CD55-) frequencies. Specimens from a total of 52 nonsmoking, self-reported healthy adult subjects were evaluated. The mean frequency of RET(CD59-/CD55-) and RBC(CD59-/CD55-) were 6.0 × 10(-6) and 2.9 × 10(-6), respectively. The difference is consistent with a modest selective pressure against mutant phenotype erythrocytes in the circulation, and suggests advantages of studying both populations of erythrocytes. Whereas intra-subject variability was low, inter-subject variability was relatively high, with RET(CD59-/CD55-) frequencies differing by more than 30-fold. There was an apparent correlation between age and mutant cell frequencies. Taken together, the results indicate that the frequency of human PIG-A mutant phenotype cells can be efficiently and reliably estimated using a labeling and analysis protocol that is well established for rodent-based studies. The applicability of the assay across species, its simplicity and statistical power, and the relatively non-invasive nature of the assay should benefit myriad research areas involving DNA damage, including studies of environmental factors that modify "spontaneous" mutation frequencies.

Published
2014

47. <italic>In vivo pig‐a</italic> and micronucleus study of the prototypical aneugen vinblastine sulfate.

Author

Avlasevich, Svetlana L., Labash, Carson, Torous, Dorothea K., Bemis, Jeffrey C., MacGregor, James T., and Dertinger, Stephen D.

Subjects
NUCLEOLUS, VINBLASTINE, SOMATIC cells, GENETIC mutation, PHENOTYPES
Abstract

The Pig‐a assay is being used in regulatory studies to evaluate the potential of agents to induce somatic cell gene mutations and an OECD test guideline is under development. A working group involved with establishing the guideline recently noted that representative aneugenic agents had not been evaluated, and to help fill this data gap Pig‐a mutant phenotype and micronucleated reticulocyte frequencies were measured in an integrated study design to assess the mutagenic and cytogenetic damage responses to vinblastine sulfate exposure. Male Sprague Dawley rats were treated for twenty‐eight consecutive days with vinblastine dose levels from 0.0156 to 0.125 mg/kg/day. Micronucleated reticulocyte frequencies in peripheral blood were determined at Days 4 and 29, and mutant cell frequencies were determined at Days −4, 15, 29, and 46. Vinblastine affected reticulocyte frequencies, with reductions noted during the treatment phase and increases observed following cessation of treatment. Micronucleated reticulocyte frequencies were significantly elevated at Day 4 in the high dose group. Although a statistically significant increase in mutant reticulocyte frequencies were found for one dose group at a single time point (Day 46), it was not deemed biologically relevant because there was no analogous finding in mutant RBCs, it occurred at the lowest dose tested, and only 1 rat exceeded an upper bound tolerance interval established with historical negative control rats. Therefore, whereas micronucleus induction reflects vinblastine's well‐established aneugenic effect on hematopoietic cells, the lack of a Pig‐a response indicates that this tubulin‐binding agent does not cause appreciable mutagenicity in this same cell type. Environ. Mol. Mutagen. 59:30–37, 2018. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Published
2018
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49. IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk

Author

MacGregor, James T., primary, Frötschl, Roland, additional, White, Paul A., additional, Crump, Kenny S., additional, Eastmond, David A., additional, Fukushima, Shoji, additional, Guérard, Melanie, additional, Hayashi, Makoto, additional, Soeteman-Hernández, Lya G., additional, Johnson, George E., additional, Kasamatsu, Toshio, additional, Levy, Dan D., additional, Morita, Takeshi, additional, Müller, Lutz, additional, Schoeny, Rita, additional, Schuler, Maik J., additional, and Thybaud, Véronique, additional

Published
2015
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50. IWGT report on quantitative approaches to genotoxicity risk assessment I. Methods and metrics for defining exposure–response relationships and points of departure (PoDs)

Author

MacGregor, James T., primary, Frötschl, Roland, additional, White, Paul A., additional, Crump, Kenny S., additional, Eastmond, David A., additional, Fukushima, Shoji, additional, Guérard, Melanie, additional, Hayashi, Makoto, additional, Soeteman-Hernández, Lya G., additional, Kasamatsu, Toshio, additional, Levy, Dan D., additional, Morita, Takeshi, additional, Müller, Lutz, additional, Schoeny, Rita, additional, Schuler, Maik J., additional, Thybaud, Véronique, additional, and Johnson, George E., additional

Published
2015
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