Comet Assay Profiling of FLASH-Induced Damage: Mechanistic Insights into the Effects of FLASH Irradiation.
Comet Assay Profiling of FLASH-Induced Damage: Mechanistic Insights into the Effects of FLASH Irradiation.
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DOI：
10.3390/ijms24087195
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发表时间：
2023-04-13
影响因子：
5.6
通讯作者：
Petersson, Kristoffer
中科院分区：
文献类型：
--
作者：
Cooper, Christian R.;Jones, Donald J. L.;Jones, George D. D.;Petersson, Kristoffer
许多研究已经证明了超高剂量率“FLASH”照射在体内的正常组织保护作用，并在体外报告了相关的损伤负担减少。为此，已经提出了两个关键的放射化学机制：自由基-自由基复合（RRR）和瞬时氧耗尽（TOD），两者都被认为会导致诱导损伤水平降低。以前，我们报道了FLASH诱导体外全血外周血淋巴细胞（WB-PBL）的DNA链断裂损伤水平较低，但我们的研究未能区分所涉及的机制。RRR的一个潜在结果是形成交联损伤（特别是，如果任何有机自由基重组），而TOD的一个可能结果是由FLASH引起的诱导损伤的更缺氧的轮廓。因此，本研究的目的是通过彗星试验分析FLASH诱导的损伤，评估任何DNA交联形成作为RRR的推定标志物和/或缺氧DNA损伤形成作为TOD的指示性标志物，以确定任一机制对“FLASH效应”的贡献程度。在FLASH照射后，我们没有看到任何交联形成的证据;然而，FLASH照射诱导了更多的缺氧诱导损伤，支持了TOD机制。此外，照射前用BSO处理WB-PBL消除了由FLASH暴露介导的减少的链断裂损伤负担。总之，我们没有看到任何实验证据支持RRR机制有助于减少FLASH引起的损伤负担。然而，观察到更大的缺氧档案的损伤后，闪光灯照射，连同BSO废除减少链断裂损伤负荷介导的闪光灯，进一步支持TOD是一个驱动程序的减少的损伤负荷加上在由闪光灯介导的损伤档案的变化。
Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the “FLASH effect”. Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH.
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影响因子：
6.2
作者：
Adrian, Gabriel;Ruan, Jia-Ling;Paillas, Salome;Cooper, Christian R.;Petersson, Kristoffer
通讯作者：
Petersson, Kristoffer
影响因子：
4.7
作者：
Konradsson E;Arendt ML;Bastholm Jensen K;Børresen B;Hansen AE;Bäck S;Kristensen AT;Munck Af Rosenschöld P;Ceberg C;Petersson K
通讯作者：
Petersson K
影响因子：
3.8
作者：
Favaudon V;Labarbe R;Limoli CL
通讯作者：
Limoli CL
DOI：
10.1016/j.ijrobp.2021.03.056
发表时间：
2021-09-01
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
Cao X;Zhang R;Esipova TV;Allu SR;Ashraf R;Rahman M;Gunn JR;Bruza P;Gladstone DJ;Williams BB;Swartz HM;Hoopes PJ;Vinogradov SA;Pogue BW
通讯作者：
Pogue BW
DOI：
10.1016/0360-3016(91)90314-t
发表时间：
1991-11-01
影响因子：
7
作者：
HALL, EJ;BRENNER, DJ
通讯作者：
BRENNER, DJ