The Experts below are selected from a list of 210 Experts worldwide ranked by ideXlab platform
Ohtsura Niwa - One of the best experts on this subject based on the ideXlab platform.
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Roles of Stem Cells in Tissue Turnover and Radiation Carcinogenesis
Radiation research, 2010Co-Authors: Ohtsura NiwaAbstract:Radiation research has its foundation on the target and hit theories, which assume that the initial stochastic deposition of energy on a sensitive target in a cell determines the final biological outcome. This assumption is rather static in nature but forms the foundation of the linear no-threshold (LNT) model of Radiation Carcinogenesis. The stochastic treatment of Radiation Carcinogenesis by the LNT model enables easy calculation of Radiation risk, and this has made the LNT model an indispensable tool for Radiation protection. However, the LNT model sometimes fails to explain some of the biological and epidemiological data, and this suggests the need for insight into the mechanisms of Radiation Carcinogenesis. Recent studies have identified unique characteristics of the tissue stem cells and their roles in tissue turnover. In the present report, some important issues of Radiation protection such as the risk of low-dose-rate exposures and in utero exposures are discussed in light of the recent advances of stem cell biology.
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Radiation Carcinogenesis in mouse thymic lymphomas.
Cancer science, 2006Co-Authors: Ryo Kominami, Ohtsura NiwaAbstract:Ionizing Radiation is a well-known carcinogen for various human tissues and a complete carcinogen that is able to initiate and promote neoplastic progression. Studies of Radiation-induced mouse thymic lymphomas, one of the classic models in Radiation Carcinogenesis, demonstrated that even the unirradiated thymus is capable of developing into full malignancy when transplanted into the kidney capsule or subcutaneous tissue of irradiated mice. This suggests that Radiation targets tissues other than thymocytes to allow expansion of cells with tumorigenic potential in the thymus. The idea is regarded as the 'indirect mechanism' for tumor development. This paper reviews the indirect mechanism and genes affecting the development of thymic lymphomas that we have analyzed. One is the Bcl11b/Rit1 tumor suppressor gene and the other is Mtf-1 gene affecting tumor susceptibility.
Olga Kovalchuk - One of the best experts on this subject based on the ideXlab platform.
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stable loss of global dna methylation in the Radiation target tissue a possible mechanism contributing to Radiation Carcinogenesis
Biochemical and Biophysical Research Communications, 2005Co-Authors: Igor Koturbash, Igor P. Pogribny, Olga KovalchukAbstract:Abstract Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during Radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of Radiation-induced thymic lymphoma is characterized by a lengthy “pre-lymphoma” period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of Radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of Radiation-induced DNA methylation changes in the Radiation Carcinogenesis target organ—thymus, and non-target organ—muscle. This study is the first report on the Radiation-induced epigenetic changes in Radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irRadiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irRadiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of Radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant Radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure. In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the Radiation-target tissue, even though DNA damage resulting from initial genotoxic Radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of Radiation-related pathologies. The possible role of Radiation-induced DNA hypomethylation in Radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.
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Stable loss of global DNA methylation in the Radiation-target tissue—A possible mechanism contributing to Radiation Carcinogenesis?
Biochemical and biophysical research communications, 2005Co-Authors: Igor Koturbash, Igor P. Pogribny, Olga KovalchukAbstract:Abstract Radiation-induced lymphomagenesis and leukemogenesis are complex processes involving both genetic and epigenetic changes. Although genetic alterations during Radiation-induced lymphoma- and leukemogenesis are fairly well studied, the role of epigenetic changes has been largely overlooked. Rodent models are valuable tools for identifying molecular mechanisms of lymphoma and leukemogenesis. A widely used mouse model of Radiation-induced thymic lymphoma is characterized by a lengthy “pre-lymphoma” period. Delineating molecular changes occurring during the pre-lymphoma period is crucial for understanding the mechanisms of Radiation-induced leukemia/lymphoma development. In the present study, we investigated the role of Radiation-induced DNA methylation changes in the Radiation Carcinogenesis target organ—thymus, and non-target organ—muscle. This study is the first report on the Radiation-induced epigenetic changes in Radiation-target murine thymus during the pre-lymphoma period. We have demonstrated that acute and fractionated whole-body irRadiation significantly altered DNA methylation pattern in murine thymus leading to a massive loss of global DNA methylation. We have also observed that irRadiation led to increased levels of DNA strand breaks 6 h following the initial exposure. The majority of Radiation-induced DNA strand breaks were repaired 1 month after exposure. DNA methylation changes, though, were persistent and significant Radiation-induced DNA hypomethylation was observed in thymus 1 month after exposure. In sharp contrast to thymus, no significant persistent changes were noted in the non-target muscle tissue. The presence of stable DNA hypomethylation in the Radiation-target tissue, even though DNA damage resulting from initial genotoxic Radiation insult was repaired, suggests of the importance of epigenetic mechanisms in the development of Radiation-related pathologies. The possible role of Radiation-induced DNA hypomethylation in Radiation-induced genome instability and aberrant gene expression in molecular etiology of thymic lymphomas is discussed.
Werner Hofmann - One of the best experts on this subject based on the ideXlab platform.
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Incorporation of microdosimetric concepts into a biologically-based model of Radiation Carcinogenesis
Radiation protection dosimetry, 2006Co-Authors: Hatim Fakir, Werner HofmannAbstract:The generalised state-vector model of Radiation Carcinogenesis (SVM) simulates Radiation induced biological effects by expressing the transition rates between the various initiation and promotion stages in terms of dose rate for low and high linear energy transfer (LET) particles. In the present work, the SVM has been reformulated to incorporate single track characteristics of particles with varying LET. Transition rates of the initiation phase were expressed as functions of LET by describing the complexity and clustering of DNA double strand breaks (DSBs) and its effect on repair kinetics, while the promotion phase was reformulated based on a multi-target single-hit hypothesis. Such an approach allows the consideration of hit frequencies and the variability of the specific energy and LET spectra of radon progeny alpha particles in bronchial target cells for different exposure conditions.
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Stochastic state-vector model of Radiation Carcinogenesis applied to radon-induced lung cancer risk
Radioactivity in the Environment, 2005Co-Authors: D.j. Crawford-brown, Werner HofmannAbstract:Publisher Summary A biophysical multi-stage state-vector model (SVM) of Radiation Carcinogenesis has been extended to incorporate stochasticity of transitions and spatial inhomogeneity of cellular doses. Dose-rate dependent cellular transitions between the stages are related to formation of double stranded DNA breaks, repair of breaks, interactions (translocations) between breaks, fixation of breaks, cellular inactivation, stimulated mitosis and promotion through loss of intercellular communication. Each of these transitions from the normal state 0 to the tumour state 7 is simulated stochastically in time through Monte Carlo sampling of the competing events. The stochastic SVM has been applied here to in vitro transformation frequencies by monoenergetic alpha particles and to in vivo lung cancer incidence in uranium miners and laboratory rats exposed to radon progeny. Predictions of the transformation frequency per surviving cell compares favorably with the experimental in vitro data over a wide range of LETs and doses. When incorporating in vivo features of cell differentiation, stimulated cell division and heterogeneity of cellular doses, fair agreement could be obtained between model predictions and lung cancer data from human epidemiological studies as well as from rat inhalation experiments.
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Analysis of radon-induced lung cancer risk by a stochastic state-vector model of Radiation Carcinogenesis
Journal of radiological protection : official journal of the Society for Radiological Protection, 2002Co-Authors: Douglas Crawford-brown, Werner HofmannAbstract:A biologically based state-vector model (SVM) of Radiation Carcinogenesis has been extended to incorporate stochasticity of cellular transitions and specific in vivo irRadiation conditions in the lungs. Dose-rate-dependent cellular transitions related to the formation of double-stranded DNA breaks, repair of breaks, interactions (translocations) between breaks, fixation of breaks, cellular inactivation, stimulated mitosis and promotion through loss of intercellular communication are simulated by Monte Carlo methods. The stochastic SVM has been applied to the analysis of lung cancer incidence in uranium miners exposed to alpha-emitting radon progeny. When incorporating in vivo features of cell differentiation, stimulated cell division and heterogeneity of cellular doses into the model, excellent agreement between epidemiological data and modelling results could be obtained. At low doses, the model predicts a non-linear dose-response relationship; e.g., computed lung cancer risk at 20 WLM is about half of current lung cancer estimates based on the linear hypothesis. The model also predicts a slight dose rate effect; e.g., at a cumulative exposure of 20 WLM, calculated lung cancer incidence for an exposure rate 0.27 WLM/year (assuming an exposure time of 73 years) is smaller by a factor of 1.2 than that for an exposure rate of 10 WLM/year.
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Extension of a generalized state-vector model of Radiation Carcinogenesis to consideration of dose rate
Mathematical biosciences, 1993Co-Authors: Douglas Crawford-brown, Werner HofmannAbstract:Mathematical models for Radiation Carcinogenesis typically employ transition rates that either are a function of the dose to specific cells or are purely empirical constructs unrelated to biophysical theory. These functions either ignore or do not explicitly model interactions between the fates of cells in a community. This paper extends a model of mitosis, cell transformation, promotion, and progression to cases in which interacting cellular communities are irradiated at specific dose rates. The model predicts that lower dose rates are less effective at producing cancer when irRadiation is by X- or gamma rays but are generally more effective in instances of irRadiation by alpha particles up to a dose rate in excess of 0.01 Gy/day. The resulting predictions are compared with existing experimental data.
Ajit K. Verma - One of the best experts on this subject based on the ideXlab platform.
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Abstract 5020: Characterization of epidermal stem cells in SKH1 hairless mice, a widely used mouse model to investigate ultraviolet Radiation Carcinogenesis.
Tumor Biology, 2013Co-Authors: Ashok K. Singh, Anupama Singh, Ajit K. VermaAbstract:Human cutaneous squamous cell carcinoma (SCC) is the second most common type of non-melanoma skin cancer (NMSC) after basal cell carcinoma (BCC) in US. Evidence indicates that the precursor cells are the precursor cells for the origin of SCC. The SCCs probably arise from bulge stem cell niche of hair follicle but not from the transit amplifying cells of epidermis. The SKH1 hairless mice is a widely used mouse model for ultraviolet Radiation (UV)-induced Carcinogenesis. However, SKH1 mice have never been evaluated for status of skin stem cell probably due to absence of hair and other associated hairless phenotype. It has recently become possible to isolate living hair follicle stem and progenitor cells from mouse skin because of the discovery of cell surface marker (CD34) that facilitate enrichment. The cell surface protein CD34, more widely known as a hematopoietic stem and progenitor cell marker, was found to be uniquely expressed in the mouse hair follicle bulge region using immunohistochemistry staining techniques. In addition, CD34 expression was restricted to the hair follicle regardless of hair follicle stage, making this a potentially important tool for selected enrichment of hair follicle bulge region keratinocytes. In combination with alpha 6-integrin staining and fluorescence activated cell sorting (FACS), CD34 is used to successfully isolate a small population of CD34+/alpha 6-integrin+ cells from a single cell preparation of mouse keratinocytes. CD34-expressing keratinocytes were confirmed to have properties consistent with stem and progenitor cells in that they were shown to be slowly cycling and have a high proliferative capacity in culture, growing larger colonies relative to those from CD34− keratinocytes. In the present experiments, the SKH1 mouse skin stem cell population was identified using stem cell markers (CD34+/α6-integrin+, Keratin-15, Gli1, and Sox9). The results of FACS analysis of live cells, isolated from untreated SKH1 mouse skin, indicate that there are 0.23% CD34+ and 1.05% CD34+/α6-integrin+ cells. The FACS sorted double positive (CD34+/α6-integrin+) stem cells of SKH1 are also observed to be positive for K15, Gli1, and Sox9 markers of stem cells in cytospin slides. In summary, the quantitative FACS analysis and qualitative immunofluorescence data in skin tissues confirms the presence of the stem cell populations in SKH1 mice. Support: (RO1CA102431). Citation Format: Ashok Singh, Anupama Singh, Ajit K. Verma. Characterization of epidermal stem cells in SKH1 hairless mice, a widely used mouse model to investigate ultraviolet Radiation Carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5020. doi:10.1158/1538-7445.AM2013-5020
Michael J. Renan - One of the best experts on this subject based on the ideXlab platform.
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Point mutations, deletions, and Radiation Carcinogenesis.
Radiation research, 1992Co-Authors: Michael J. RenanAbstract:A recent symposium summary and a letter in Radiation research prompt several comments. Fry, in his summary (1), asks: "Are deletions and perhaps changes in suppressor genes more important in Radiation Carcinogenesis than are point mutations?" Sentiments along similar lines have been expressed by Weischselbaum and his co-workers (2, 3). Rossi in his letter (4) based on microdosimetric considerations suggests that the production of point mutations is likely to be due to single ionization events, while large deletions are likely to be the result of "two-hit" processes, which can occur in much larger target volumes. He concludes that the event frequency (per gray) for large deletions is much higher than for point mutations and hence that suppressor genes frequently play the predominant role in Radiation Carcinogenesis. I should like to make the following points: (i) Carcinogenesis is generally regarded as a multistep process, involving various genetic changes, such as the activation of proto-oncogenes, the inactivation of suppressor genes, and the functional inactivation of genes which control cellular senescence [see for example Ref. (5); for review see Ref. (6)]. Each step is a sine qua non for full tumorigenicity; no event can be regarded as more significant than another. Indeed, studies of the clinical progression of colorectal tumors and of glioblastomas (7, 8) have identified genetic aberrations corresponding either to mutations or to deletions and even to amplifications, all of which appear to be equally important. (ii) DNA deletions and rearrangements can materially affect the expression (at the transcriptional and translational levels) of proto-oncogenes, thus converting them to full-blown oncogenes; such DNA deletions are thus not restricted to suppressor genes alone. A good case in point is the induction of skin tumors in rats (9, 10) by low-LET Radiation (0.8-MeV electrons). DNA from 10 of the 12 tumors showed amplification of the third exon of the c-myc oncogene, and deletion of the first exon, which is known to regulate expression of the gene. (iii) Rossi (4) argues (correctly, I believe) that the production of point mutations is quite unlikely to be due to multiple ionization events. He then concludes that such production is therefore dose-rate independent and cannot be a major cause of Radiation Carcinogenesis when it is reduced by dose protraction. This point is open to question. It should be noted that point mutations are the result of the misrepair of a DNA lesion. It is conceivable that cellular repair processes (or a component thereof) are dose-rate dependent; in particular, at high dose rate error-prone repair pathways may predominate over high-fidelity repair mechanisms. A number of reports have demonstrated that mutation induction is in fact decreased when the Radiation dose is fractionated or delivered at a low dose rate (11, 12). These studies involve traditional mutation assays, namely induction of resistance to selective agents, and it is not clear if the proliferating mutant cells are the result of gene deletion or of point mutations. Clarity on this issue awaits the results of DNA sequencing experiments. In the interim, a useful pointer can be obtained from Southern blot experiments. For example, Hill and Zhu (13) have shown that, of 21 independent mutations (in the HPRT gene) induced by 7 rays, fully one-third showed no observable change in the banding pattern of the gene. This implies that these mutants are due to extremely small deletions or to point mutatio s. In addition, a recent analysis' of the y-ray-induced mutations at the human HPRT locus showed that up to 50% were due to point mutations or small (2 bp) deletions. (iv) In a series of experiments, Pellicer and colleagues (14, 15) have identified activated K-ras oncogenes in four of seven Radiation-induced mouse lymphomas. These genes were all activated by point mutations in the 12th codon of the gene. The work of Sawey et al. (9) is consistent with these findings; 6 out of 12 tumors exhibited point mutati ns in the K-ras gene. It is thus clear that point mutations are frequently found in tumors initiated by Radiation. However, it is improbable that the incident Radiation could have directly produced alterations in such a small DNA target with such a high (observed) frequency. This remains one of the basic conundrums of radiobiology. Perhaps the answer
