Potential Molecular Mechanisms behind the Ultra-High Dose Rate “FLASH” Effect

Bogaerts, Eva; Macaeva, Ellina; Isebaert, Sofie; Haustermans, Karin

doi:10.3390/ijms232012109

Cited by 19 publications

(9 citation statements)

References 130 publications

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“…In these experiments, the increase in the yield of micronuclei and ROS was observed not only in irradiated, but also in neighboring nonirradiated cells, the differences in the formation of micronuclei being dependent on whether the nucleus or the cytoplasm was damaged [33]. Mitochondria, being the main regulators of apoptosis and inflammation, may play an important role in the FLASH effect, in which, the degree of apoptotic and inflammatory responses significantly decreases compared with the CONV mode [34, 35]. It is likely that similar processes also occurred in our experiments during the development of eggs irradiated at a high dose rate.…”

Section: Discussionmentioning

confidence: 99%

The Flash Mode of Proton Irradiation in the Bragg Peak Partly Spares the Embryogenesis of the Quail

Akulinichev,

Glukhov,

Gavrilov

et al. 2024

Preprint

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The study of biological effects of high-dose-rate ionizing radiation using animal models remains an urgent problem. In the work, a comparison of proton-induced damage to embryos (the 9th post-fertilization day) and 1-day-old baby chicks (the 18th post-fertilization day) from irradiated eggs of Japanese quail (Coturnix coturnix japonica) irradiated in and outside the Bragg peak with the conventional and ultra-high dose rate D (CONV D < 1 Gy/s, FLASH D ~100 Gy/s and single-pulse flash - SPLASH D ~106 Gy/s, respectively) was carried out. The following criteria were used: survival, body weight and body length of embryos, weight of chicks, percentage of erythrocytes with anomalies (with micronuclei, without nuclei, with two nuclei), and the speed of movement of 1-day-old chicks in the open field test. The largest number of dead embryos was recorded after irradiation with 7 and 14 Gy in the plateau region of the proton trajectory. By the criteria of body weight and length, as well as the number of erythrocytes with micronuclei in 9-day-old embryos from eggs irradiated with a dose of 8.5 Gy in the Bragg peak, FLASH and SPLASH modes were found to be the least traumatic compared with the CONV mode. The weight of chicks from eggs irradiated with a dose of 4 Gy in the Bragg peak did not differ from the control and did not depend on the irradiation mode. The lowest death incidence and the smallest number of abnormal erythrocytes were recorded after FLASH and SPLASH irradiation; in chicks that hatched from eggs irradiated in the CONV mode, a tendency for an increase in the number of abnormal erythrocytes was observed. The speed of movement of chicks from FLASH- and SPLASH-irradiated eggs was comparable with that from unirradiated eggs, and chicks from eggs irradiated in the CONV mode were less active than chicks from unirradiated eggs and eggs irradiated in the other regimes. Thus, the irradiation of eggs with a beam of accelerated protons in the Bragg peak in the FLASH/SPLASH modes is less damaging for healthy tissues and for the development of embryos and chicks on the cellular, anatomical, and physiological levels.

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Section: Discussionmentioning

confidence: 99%

The Flash Mode of Proton Irradiation in the Bragg Peak Partly Spares the Embryogenesis of the Quail

Akulinichev,

Glukhov,

Gavrilov

et al. 2024

Preprint

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“…Our research focuses on investigating the 'FLASH effect' through the simulation of oxygen consumption under the ultra-high dose rates radiation. However, certain studies have raised doubts about the validity of the oxygen depletion hypothesis in relation to the 'FLASH effect' (Bogaerts et al 2022, Lin et al 2022, Limoli and Vozenin 2023. For instance, it has been suggested that in the case of FLASH-RT, complete oxygen depletion may not occur, or that the observed protective effect of FLASH-RT is present even under normoxic conditions (air oxygen concentration).…”

Section: Discussionmentioning

confidence: 99%

The dose-related plateau effect of surviving fraction in normal tissue during the ultra-high-dose-rate radiotherapy

Hu,

Lan,

Zheng

et al. 2023

Phys. Med. Biol.

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Objective: Ultra-high-dose-rate radiotherapy, referred to as FLASH therapy, has been demonstrated to reduce the damage of normal tissue as well as inhibiting tumor growth compared with conventional dose-rate radiotherapy. The transient hypoxia may be a vital explanation for sparing the normal tissue. The heterogeneity of oxygen distribution for different doses and dose rates in the different radiotherapy schemes are analyzed. With these results, the influence of doses and dose rates on cell survival are evaluated in this work.Approach: The two-dimensional reaction-diffusion equations are used to describe the heterogeneity of the oxygen distribution in capillaries and tissue. A modified linear quadratic model is employed to characterize the surviving fraction at different doses and dose rates.Main results: The reduction of the damage to the normal tissue can be observed if the doses exceeds a minimum dose threshold under the ultra-high-dose-rate radiation. Also, the surviving fraction exhibits the ‘plateau effect’ under the ultra-high dose rates radiation, which signifies that within a specific range of doses, the surviving fraction either exhibits minimal variation or increases with the dose. For a given dose, the surviving fraction increases with the dose rate until tending to a stable value, which means that the protection in normal tissue reaches saturation.Significance: The emergence of the ‘plateau effect’ allows delivering the higher doses while minimizing damage to normal tissue. It is necessary to develop appropriate program of doses and dose rates for different irradiated tissue to achieve more efficient protection.

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“…As Liew and Mairani suggested, there is a possible issue in how to consider oxygen levels. It is true oxygen deprivation during UHDR irradiation may contribute to cell survival; however, in recent years, the oxygen depletion hypothesis has been proven debatable (Adrian et al 2022, Bogaerts et al 2022, Favaudon et al 2022, Friedl et al 2022, Lin et al 2022, Limoli and Vozenin 2023. Considering these contradictory data, before modelling the relationship between dose rate and oxygen level, a further clarification of the underlying mechanisms of the sparing effects in physical and chemical processes concerning oxygen levels is needed.…”

Section: Introductionmentioning

confidence: 99%

Reply to comment on ‘Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation’

Shiraishi,

Matsuya,

Fukunaga

2024

Phys. Med. Biol.

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Liew and Mairani commented on our paper ‘Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation’ (Shiraishi et al 2024a Phys. Med. Biol. 69 015017), which proposed a biophysical model to predict the dose–response curve of surviving cell fractions after ultra-high dose rate irradiation following conventional dose rate irradiation by considering DNA damage yields. They suggested the need to consider oxygen concentration in our prediction model and possible issues related to the data selection process used for the benchmarking test in our paper. In this reply, we discuss the limitations of both the present model and the available experimental data for determining the model’s parameters. We also demonstrate that our proposed model can reproduce the experimental survival data even when using only the experimental DNA damage data measured reliably under normoxic conditions.

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Potential Molecular Mechanisms behind the Ultra-High Dose Rate “FLASH” Effect

Cited by 19 publications

References 130 publications

The Flash Mode of Proton Irradiation in the Bragg Peak Partly Spares the Embryogenesis of the Quail

The Flash Mode of Proton Irradiation in the Bragg Peak Partly Spares the Embryogenesis of the Quail

The dose-related plateau effect of surviving fraction in normal tissue during the ultra-high-dose-rate radiotherapy

Reply to comment on ‘Modeling for predicting survival fraction of cells after ultra-high dose rate irradiation’

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