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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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| 3. |
- Akuwudike, Pamela, 1987-, et al.
(författare)
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Mechanistic insights from high resolution DNA damage analysis to understand mixed radiation exposure
- 2023
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Ingår i: DNA Repair. - 1568-7864 .- 1568-7856. ; 130
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Tidskriftsartikel (refereegranskat)abstract
- Cells exposed to densely ionising high and scattered low linear energy transfer (LET) radiation (50 % dose of each) react more strongly than to the same dose of each separately. The relationship between DNA double strand break location inside the nucleus and chromatin structure was evaluated, using high-resolution transmission electron microscopy (TEM) in breast cancer MDA-MB-231 cells at 30 min post 5 Gy. Additionally, response to high and/or low LET radiation was assessed using single (1 ×1.5 Gy) versus fractionated dose delivery (5 ×0.3 Gy). By TEM analysis, the highest total number of γH2AX nanobeads were found in cells irradiated with alpha radiation just prior to gamma radiation (called mixed beam), followed by alpha, then gamma radiation. γH2AX foci induced by mixed beam radiation tended to be surrounded by open chromatin (lighter TEM regions), yet foci containing the highest number of beads, i.e. larger foci representing complex damage, remained in the heterochromatic areas. The γH2AX large focus area was also greater in mixed beam-treated cells when analysed by immunofluorescence. Fractionated mixed beams given daily induced the strongest reduction in cell viability and colony formation in MDA-MB-231 and osteosarcoma U2OS cells compared to the other radiation qualities, as well as versus acute exposure. This may partially be explained by recurring low LET oxidative DNA damage by every fraction together with a delay in recompaction of chromatin after high LET, demonstrated by low levels of heterochromatin marker H3K9me3 at 2 h after the last mixed beam fraction in MDA-MB-231. In conclusion, early differences in response to complex DNA damage may lead to a stronger cell kill induced by fractionated exposure, which suggest a therapeutic potential of combined high and low LET irradiation.
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| 4. |
- Cheng, Lei, et al.
(författare)
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Comet assay reveals an interaction of DNA lesions and impairment of DNA repair in peripheral blood lymphocytes simultaneously exposed to alpha particles and X-rays
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The biological effectiveness of ionising radiation is related to the ionisation density which is defined by the linear energy transfer LET. Radiation quality factors are applied to calculate the equivalent dose in the field of radiation protection and the biologically effective dose in the field of radiotherapy. Additivity is assumed in exposure scenarios where radiations of different qualities are mixed. We have carried out a series of studies on the cytogenetic effect of exposing human peripheral blood lymphocytes to a mixed beam of the high LET alpha radiation and low LET X-rays and could demonstrate that both radiations interact in producing more chromosomal aberrations than expected based on additivity. The aim of the present investigation was to look at the mechanism of the interaction, especially with respect to the question if it is due to an augmented level of initial damage or impaired DNA repair. The level of DNA damage and the kinetics of damage repair was quantified by the alkaline comet assay. The levels of phosphorylated, key DNA damage response (DDR) proteins were also measured by Western blotting. The results revealed that alpha particles and X-rays interact in inducing DNA damage above the level predicted by assuming additivity and that the repair of damage occurs with a delay. Moreover, the activation levels of the key DDR proteins ATM, p53 and DNA PK were highest in cells exposed to mixed beams substantiating the idea exposure to mixed beams presents a challenge to the cellular DNA damage response system.
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| 5. |
- Cheng, Lei, 1981-
(författare)
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Factors modifying cellular response to ionizing radiation
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many physical factors influence the biological effect of exposure to ionizing radiation, including radiation quality, dose rate and temperature. This thesis focuses on how these factors influence the outcome of exposure and the mechanisms behind the cellular response. Mixed beam exposure, which is the combination of different ionizing radiations, occurs in many situations and the effects are important to understand for radiation protection and effect prediction. Recently, studies show that the effect of simultaneous irradiation with different qualities is greater than simple additivity of single radiation types, which is called a synergistic effect. But its mechanism is unclear. In Paper I, II and III, alpha particles and X-rays were used to study the effect of mixed beams. Paper I shows that mixed exposure induced a synergistic effect in generating double strand breaks (DSB), and these DSB were repaired by slow kinetics in U2OS cells. In Paper II, alkaline comet assay was applied to investigate the induction and repair of DNA lesions including DSB, single strand breaks and alkali labile sites in peripheral blood lymphocytes (PBL). We demonstrate that mixed beams interact in inducing DNA damage and influencing DNA damage response (DDR), which result in a delay of DNA repair. Both in Paper I and II, mixed beams showed a capability in inducing higher activity of DDR proteins than expected from additivity. Paper III investigates selected DDR-related gene expression levels after exposure to mixed beams in PBL from 4 donors. Synergy was present for all donors but the results suggested individual variability in the response to mixed beams, most likely due to life style changes.Low temperature at exposure is radioprotective at the level of cytogenetic damage. In Paper IV, data indicate that this effect is through promotion of DNA repair, which leads to reduced transformation of DNA damage into chromosomal aberrations. Paper V aims to compare the biological effectiveness of gamma radiation delivered at a very high dose rate (VHDR) with that of a high dose rate (HDR) in order to optimize chronic exposure risk prediction based on the data of atomic bomb survivors. The results suggest that VHDR gamma radiation is more effective in inducing DNA damage than HDR.
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| 6. |
- Sollazzo, Alice, 1981-, et al.
(författare)
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Alpha particles and X-rays interact in inducing DNA damage in U2OS cells
- 2017
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Ingår i: Radiation Research. - 0033-7587 .- 1938-5404. ; 188:4, s. 400-411
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Tidskriftsartikel (refereegranskat)abstract
- The survivors of atomic bomb explosions in Hiroshima and Nagasaki are monitored for health effect within the Life Span Study (LSS). The LSS results represent the most important source of knowledge about cancer effects of ionizing radiation and they form the basis for the radiation protection system. One uncertainty connected to deriving universal risk factors from these results is related to the problem of mixed radiation qualities. The atomic bomb explosions generated a mixed beam of the sparsely ionizing gamma radiation and densely ionizing neutrons and what is not taken into consideration is the problem of a possible interaction of the two radiation types in inducing biological effects. The existence of such interaction would suggest that the application of risk factors derived from the LSS to predict cancer effects after exposure to pure gamma radiation (such as in the Fukushima prefecture) leads to an overestimation of risk.In order to analyze the possible interaction of radiation types a mixed beam exposure facility was constructed where cells can be exposed to sparsely ionizing X-rays and densely ionizing alpha particles. U2OS cells were used, which are stably transfected with a plasmid coding for the DNA repair gene 53BP1 coupled to a gene coding for the green fluorescent protein GFP. Induction and repair of DNA damage which are known to be related to cancer induction were analyzed. The results suggest that alpha particles and X-rays interact, leading to cellular, and possibly cancer effects not predictable based on assuming simple additivity of the individual mixed beam components.
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| 7. |
- Sollazzo, Alice, 1981-, et al.
(författare)
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Live dynamics of 53BP1 DNA damage foci induced by a combination of clustered and dispersed double strand breaks
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Cells react differently to alpha particle-induced clustered DNA damage and X-ray induced dispersed DNA damage. Little is known about how they cope when both types of damage are induced simultaneously. We used live cell microscopy to analyse the formation and motion of the DNA double strand break (DSB) repair factor 53BP1-GFP foci in U2OS cells exposed to a mixed beam of alpha particles and X-rays. We observed that the kinetics of appearance and decline of mixed beam-induced foci resemble that of after alpha particle irradiation. They showed a fast increase and almost no repair during the imaging time, while X-ray-exposed cells showed a strong increase and decline over the observation interval. Secondly, focus sizes were similar to X-ray-induced foci, with both being significantly smaller than those induced by alpha particles; thirdly, they showed a high mean pixel intensity already at early time point after irradiation. Finally, focus mobility was reduced relative to alpha particle and X-ray-induced foci, which was correlated with a delayed appearance of a fraction of mixed beam-induced foci. These results suggest that cells react to a simultaneous induction of clustered and dispersed DNA damage by sequestering the 53BP1 protein in selected foci, possibly at sites of clustered DNA damage. This happens at the cost of foci forming at chromatin areas containing dispersed, simple damage. Our results highlight that the DNA damage response to a combination of dispersed and clustered DNA damage in the same cell differs significantly from the response to exposure with single radiation types.
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