저작근 근전도에 관한 정상교합자와 ii급 부정교합자의 비교 연구

The discovery of DNA damage response proteins such as γH2AX, ATM, 53BP1, RAD51, and the MRE11/RAD50/NBS1 complex, that accumulate and/or are modified in the vicinity of a chromosomal DNA double-strand break to form microscopically visible, subnuclear foci, has revolutionized the detection of these lesions and has enabled studies of the cellular machinery that contributes to their repair. Double-strand breaks are induced directly by a number of physical and chemical agents, including ionizing radiation and radiomimetic drugs, but can also arise as secondary lesions during replication and DNA repair following exposure to a wide range of genotoxins. Here we aim to review the biological meaning and significance of DNA damage foci, looking specifically at a range of different settings in which such markers of DNA damage and repair are being studied and interpreted.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/em.21944

DNA damage foci: Meaning and significance

Cellular exposure to DNA damaging agents rapidly results in a dose dependent increase in chromosomal breakage and gross structural chromosomal rearrangements. Over recent years, evidence has been accumulating indicating genomic instability can manifest multiple generations after cellular exposure to physical and chemical DNA damaging agents. Genomic instability manifests in the progeny of surviving cells, and has been implicated in mutation, gene application, cellular transformation, and cell killing. To investigate chromosome instability following DNA damage, we have used fluorescence in situ hybridization to detect chromosomal rearrangements in a human/hamster somatic hybrid cell line following exposure to ionizing radiation. Delayed chromosomal instability was detected when multiple populations of uniquely arranged metaphases were observed in clonal isolates raised from single cells surviving X-irradiation many generations after exposure. At higher radiation doses, chromosomal instability was observed in a relatively high frequency of surviving clones and, in general, those clones showed delayed chromosome instability also showed reduced survival as measured by colony forming ability.

Delayed chromosomal instability induced by DNA damage

Non-DNA targeted effects of ionising radiation, which include genomic instability, and a variety of bystander effects including abscopal effects and bystander mediated adaptive response, have raised concerns about the magnitude of low-dose radiation risk. Genomic instability, bystander effects and adaptive responses are powered by fundamental, but not clearly understood systems that maintain tissue homeostasis. Despite excellent research in this field by various groups, there are still gaps in our understanding of the likely mechanisms associated with non-DNA targeted effects, particularly with respect to systemic (human health) consequences at low and intermediate doses of ionising radiation. Other outstanding questions include links between the different non-targeted responses and the variations in response observed between individuals and cell lines, possibly a function of genetic background. Furthermore, it is still not known what the initial target and early interactions in cells are that give rise to non-targeted responses in neighbouring or descendant cells. This paper provides a commentary on the current state of the field as a result of the non-targeted effects of ionising radiation (NOTE) Integrated Project funded by the European Union. Here we critically examine the evidence for non-targeted effects, discuss apparently contradictory results and consider implications for low-dose radiation health effects.

/pdf/non-targeted-effects-of-ionising-radiation-implications-for-4ur0sb5yw9.pdf

Non-targeted effects of ionising radiation—Implications for low dose risk

The term radiation-induced bystander effect is used to describe radiation-induced biological changes that manifest in unirradiated cells remaining within an irradiated cell population. Despite their failure to fit into the framework of classical radiobiology, radiation-induced bystander effects have entered the mainstream and have become established in the radiobiology vocabulary as a bona fide radiation response. However, there is still no consensus on a precise definition of radiation-induced bystander effects, which currently encompasses a number of distinct signal-mediated effects. These effects are classified here into three classes: bystander effects, abscopal effects and cohort effects. In this review, the data have been evaluated to define, where possible, various features specific to radiation-induced bystander effects, including their timing, range, potency and dependence on dose, dose rate, radiation quality and cell type. The weight of evidence supporting these defining features is discussed in the context of bystander experimental systems that closely replicate realistic human exposure scenarios. Whether the manifestation of bystander effects in vivo is intrinsically limited to particular radiation exposure scenarios is considered. The conditions under which radiation-induced bystander effects are induced in vivo will ultimately determine their impact on radiation-induced carcinogenic risk.

https://bioone.org/journals/Radiation-Research/volume-176/issue-2/RR2548.1/Radiation-Induced-Bystander-Effects--What-Are-They-and-How/10.1667/RR2548.1.pdf

Radiation-induced bystander effects: what are they, and how relevant are they to human radiation exposures?

Moore, S. R., Marsden, S., Macdonald, D., Mitchell, S., Folkard, M., Michael, B., Goodhead, D. T., Prise, K. M. and Kadhim, M. A. Genomic Instability in Human Lymphocytes Irradiated with Individual Charged Particles: Involvement of Tumor Necrosis Factor α in Irradiated Cells but not Bystander Cells. Radiat. Res. 163, 183–191 (2005). Exposure to ionizing radiation can increase the risk of cancer, which is often characterized by genomic instability. In environmental exposures to high-LET radiation (e.g. 222Ra), it is unlikely that many cells will be traversed or that any cell will be traversed by more than one α particle, resulting in an in vivo bystander situation, potentially involving inflammation. Here primary human lymphocytes were irradiated with precise numbers of 3He2+ ions delivered to defined cell population fractions, to as low as a single cell being traversed, resembling in vivo conditions. Also, we assessed the contribution to genomic instability of the pro-inflammatory cytokine tumor ...

Genomic Instability in Human Lymphocytes Irradiated with Individual Charged Particles: Involvement of Tumor Necrosis Factor α in Irradiated Cells but not Bystander Cells

Communication between irradiated and unirradiated (bystander) cells can result in responses in unirradiated cells that are similar to responses in their irradiated counterparts. The purpose of the current experiment was to test the hypothesis that bystander responses will be similarly induced in primary murine stem cells under different cell culture conditions. The experimental systems used here, co-culture and media transfer, are similar in that they both restrict communication between irradiated and bystander cells to media borne factors, but are distinct in that with the media transfer technique, cells can only communicate after irradiation, and with co-culture, cells can communication before, during and after irradiation. In this set of parallel experiments, cell type, biological endpoint, and radiation quality and dose, were kept constant. In both experimental systems, clonogenic survival was significantly decreased in all groups, whether irradiated or bystander, suggesting a substantial contribution of bystander effects (BE) to cell killing. Genomic instability (GI) was induced under all radiation and bystander conditions in both experiments, including a situation where unirradiated cells were incubated with media that had been conditioned for 24 h with irradiated cells. The appearance of delayed aberrations (genomic instability) 10–13 population doublings after irradiation was similar to the level of initial chromosomal damage, suggesting that the bystander factor is able to induce chromosomal alterations soon after irradiation. Whether these early alterations are related to those observed at later timepoints remains unknown. These results suggest that genomic instability may be significantly induced in a bystander cell population whether or not cells communicate during irradiation.

Bystander-mediated genomic instability after high LET radiation in murine primary haemopoietic stem cells

Environmental 222radon exposure is a human health concern, and many studies demonstrate that very low doses of high LET α-particle irradiation initiate deleterious genetic consequences in both irradiated and non-irradiated bystander cells. One consequence, radiation-induced genomic instability (RIGI), is a hallmark of tumorigenesis and is often assessed by measuring delayed chromosomal aberrations. We utilised a technique that facilitates transient immobilization of primary lymphocytes for targeted microbeam irradiation and have reported that environmentally relevant doses, e.g. a single 3He2+ particle traversal to a single cell, are sufficient to induce RIGI. Herein we sought to determine differences in radiation response in lymphocytes isolated from five healthy male donors. Primary lymphocytes were irradiated with a single particle per cell nucleus. We found evidence for inter-individual variation in radiation response (RIGI, measured as delayed chromosome aberrations). Although this was not highly significant, it was possibly masked by high levels of intra-individual variation. While there are many studies showing a link between genetic predisposition and RIGI, there are few studies linking genetic background with bystander effects in normal human lymphocytes. In an attempt to investigate inter-individual variation in the induction of bystander effects, primary lymphocytes were irradiated with a single particle under conditions where fractions of the population were traversed. We showed a marked genotype-dependent bystander response in one donor after exposure to 15% of the population. The findings may also be regarded as a radiation-induced genotype-dependent bystander effect triggering an instability phenotype.

/pdf/genomic-instability-after-targeted-irradiation-of-human-1qorvac7ad.pdf

Genomic instability after targeted irradiation of human lymphocytes: Evidence for inter-individual differences under bystander conditions

Genomic instability is observed during tumorigenic progression, in a fraction of the progeny of cells surviving irradiation, and also in unirradiated, bystander cells. It is unclear whether communication between irradiated cells themselves, or bystander cells themselves contributes to the observed effect. Herein, we restricted communication between cells by plating human lymphoblasts at low density in replicate 96 well dishes. Irradiated cells were plated before or after 0.1 Gy X-irradiation, and bystander cells were plated before or after receiving media from irradiated cells. Clonogenic survival was not affected whether cells were allowed intercellular communication (reflecting in vivo conditions) or not. Genomic instability was induced under conditions permitting intercellular communication, but not when intercellular communication was prevented. Our results imply that cell survival following irradiation or bystander conditions may not require intercellular signalling, while genomic instability might, a discrepancy that if observed at higher doses, could potentially be exploited in radiotherapy situations.

The contribution of communication between irradiated cells and between bystander cells to clonogenic survival and genomic instability

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Genomic Instability in Human Lymphocytes Irradiated with Individual Charged Particles: Involvement of Tumor Necrosis Factor α in Irradiated Cells but not Bystander Cells

Bystander-mediated genomic instability after high LET radiation in murine primary haemopoietic stem cells

Genomic instability after targeted irradiation of human lymphocytes: Evidence for inter-individual differences under bystander conditions

The contribution of communication between irradiated cells and between bystander cells to clonogenic survival and genomic instability