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Objective:To conduct a comparative analysis of the radiation damage to zebrafish embryos and the associated biological mechanism after ultra-high dose rate (FLASH) and conventional dose rate irradiation.Methods:Zebrafish embryos at 4 h post-fertilization were exposed to conventional and FLASH irradiation (9 MeV electron beam). The mortality and hatchability of zebrafish after radiation exposure were recorded. Larvae at 96 h post-irradiation underwent morphological scoring, testing of reactive oxygen species (ROS) levels, and analysis of changes in oxidative stress indicators.Results:Electron beam irradiation at doses of 2-12 Gy exerted subtle effects on the mortality and hatchability of zebrafish embryos. However, single high-dose irradiation (≥ 6 Gy) could lead to developmental malformation of larvae, with conventional irradiation showing the most significant effects ( t = 0.87-9.75, P < 0.05). In contrast, after FLASH irradiation (≥ 6 Gy), the ROS levels in zebrafish and its oxidative stress indicators including superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were significantly reduced ( t = 0.42-15.19, P < 0.05). There was no statistically significant difference in ROS levels in incubating solutions after conventional and FLASH irradiation ( P > 0.05). Conclusions:Compared to conventional irradiation, FLASH irradiation can reduce radiation damage to zebrafish embryos, and this is in a dose-dependent manner. The two irradiation modes lead to different oxidative stress levels in zebrafish, which might be a significant factor in the reduction of radiation damage with FLASH irradiation.
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Objective:To compare the effects on DNA strand break induced by ultra-high dose rate (FLASH) electron beam and conventional irradiation, and investigate whether FLASH effect was correlated with a reduction of radiation response.Methods:Aqueous pBR322 plasmid was treated with FLASH (125 Gy/s) and conventional irradiation (0.05 Gy/s) under physioxia (4% O 2) and normoxia (21% O 2). Open circle DNA and linear DNA were detected by agarose gel electrophoresis, and the plasmid DNA damage was quantified with an established mathematical model to calculate the relative biological effect (RBE) of DNA damage. In some experiments, Samwirin A (SW) was applied to scavenge free radicals generated by ionizing radiation. Results:Under physioxia, the yields of DNA strand breakage induced by both FLASH and conventional irradiation had a dose-dependent manner. FLASH irradiation could significantly decrease radiation-induced linear DNA compared with conventional irradiation ( t=5.28, 5.79, 7.01, 7.66, P<0.05). However, when the aqueous plasmid was pretreated with SW, there was no difference of DNA strand breakage between FLASH and conventional irradiation ( P>0.05). Both of the yields of open circle DNA and linear DNA had no difference caused by FLASH and conventional radiotherapy at normoxia, but were significantly higher than those under physioxia. In addition, the yields of linear DNA and open circle DNA induced by FLASH irradiation per Gy were (2.78±0.03) and (1.85±0.17) times higher than those of conventional irradiation, respectively. Conclusions:FLASH irradiation attenuated radiation-induced DNA damage since a low production yield of free radical in comparison with conventional irradiation, and hence the FLASH effect was correlated with oxygen content.
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Objective:To evaluate the usability of Gafchromic HD-V2 film for dose dosimetry in the ultra-high dose-rate (UD) electron beam from a modified medical linac, and to investigate the response between the energy and dose-rate dependence to the film.Methods:The HD-V2 film was utilized to measure the average dose-rate of the UD electron beam. The measured result was compared with those by advanced Markus chamber and alanine pellets. And characteristics of the UD electron beam were also measured by HD-V2 film. Energy dependence of HD-V2 film at three beam energies (6 MV X-ray, 9 MeV and 16 MeV electron beam) was investigated by obtaining and comparing the calibration curves based on the clinical linear accelerator in the dose range of 10-300 Gy. The dose-rate dependence of HD-V2 film was also studied by varying the dose rate among 0.03 Gy/s, 0.06 Gy/s and 0.1 Gy/s, and range of 100-200 Gy/s.Results:The measured average maximum dose-rate of 9 MeV UD electron beam at source skin distance (SSD) 100 cm was approximately 121 Gy/s using HD-V2 film, consistent with the results by advanced Markus chamber and alanine pellets. The measured percentage depth dose (PDD) curve parameters of the UD electron beam were similar to the conventional 9 MeV beam. The off-axis dose distribution of the UD electron beam showed the highest central axis, and the dose was gradually decreased with the increase of off-axis distance. The energy dependence of HD-V2 film had no dependency of 6 MV and 9, 16 MeV while measuring the dose in the range from 20 to 300 Gy. The HD-V2 film had no significant dose-rate dependency at the dose rate of 0.03 Gy/s, 0.06 Gy/s and 0.1 Gy/s for the clinical linear accelerator. Likewise, there was also no dose-rate dependence in the range 100-200 Gy/s in the modified machine.Conclusion:HD-V2 film is suitable for measuring ultra-high dose rate electron beam, independent of energy and dose rate.
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Objective:To compare the radiation chemistry effects on water molecules after ultra-high dose rate (FLASH) and conventional irradiation.Methods:Both FLASH and conventional irradiation were applied to ultrapure water, with the hydroxyl radical yield in the homogeneous phase detected using electron paramagnetic resonance (EPR) and the hydrogen peroxide (H 2O 2) yield in the diffusion phase analyzed uuxing fluorescence probe. The liposome model was then established to investigate the radiation chemistry effect of FLASH and conventional irradiation in inducing lipid peroxidation. Results:Radiation chemistry reactions were observed in water molecules after irradiation. In the homogeneous phase, the yield of free radicals using FLASH irradiation is similar to those from conventional irradiation ( P>0.05). In the diffusion phase, the amount of H 2O 2 produced by FLASH irradiation was significantly lower than those from conventional irradiation ( t=0.49-12.81, P<0.05). The liposome model confirmed that conventional irradiation could significantly induce lipid peroxidation through the radiation chemistry effect in water molecules as compared with FLASH irradiation ( t=0.31-11.73, P<0.05). Conclusions:The radiation chemistry effect in water molecules after FLASH irradiation was significantly lower than that from conventional irradiation. This could be one of the mechanisms of FLASH effect.
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Objective:To analyze the data of ultra-high dose rate (FLASH) radiotherapy in GEO (Gene Expression Omnibus) database by bioinformatics method, in order to find the hub genes involved in flash radiotherapy induced acute T-lymphoblastic leukemia.Methods:The gene expression profiles of malignant tumors receiving FLASH radiotherapy were downloaded from GEO database. The R software was used to screen the differential expressed genes (DEGs) and analyze their biological functions and signal pathways. The protein-protein interaction (PPI) network of DEGs was analyzed by online tool of STRING, and Hub genes were screened by Cytoscape plug-in. The expressions of screened Hub genes in acute T lymphoblastic leukemia were identified with TCGA (The Cancer Genome Atlas) and GTEx (Genotype-Tissue Expression) database.Results:Based on the analysis of GSE100718 microarray dataset of GEO database, a total of 12 800 genes were found to be associated with radiosensitivity of acute T lymphoblastic leukemia, of which 61 significantly altered DEGs were selected for further analysis. It was found that these genes were involved in the biological processes of metabolism, stress response, and immune response through the pathways of oxidative phosphorylation, unfolded protein response, fatty acid metabolism, and so on. PPI analysis indicated that HSPA5 and SCD belonged to the Hub genes involved in the regulation of FLASH radiosensitivity, and they were significantly highly expressed in acute T lymphoblastic leukemia combined with TRD/LMO2-fusion gene.Conclusions:Through bioinformatics analysis, the Hub genes involved in regulating the sensitivity of FLASH radiotherapy and conventional radiotherapy can be effectively screened, and thus the gene expression profiles can be used to guide the stratification of cancer patients to achieve a precise radiotherapy.
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Objective:To investigate the feasibility of transforming conventional medical accelerator to achieve ultra-high dose rate required to achieve Flash radiotherapy (Flash-RT), and to understand the physical properties of the Flash-RT beam.Methods:By transforming the Varian 23CX medical accelerator, the radiation average dose rate at the isocenter was not less than 40 Gy/s. The relevant physical measurement scheme was designed to accurately measure the actual radiation dose rate of different source skin distance (SSD) conditions, the percent depth dose (PDD) curve and the off-axis dose distribution of the beam.Results:The average dose rate of 9 MeV electron beam after the transformation was measured using the HD-V2 type film, the average dose rate of 3 s was 97.9 Gy/s, and the average dose rate of 6 s was 99.27 Gy/s. When the SSD was 100 cm, 80 cm and 60 cm, the average dose rate of 9 MeV electron beam after the transformation was 99.3 Gy/s, 168 Gy/s and 297.5 Gy/s, respectively. After the transformation, the R100 of the 9 MeV beam was 2.2 cm underwater, R50 was 3.87 cm underwater, the electron range Rp was 4.58 cm, and the maximum possible energy Ep,0 on the phantom surface was 9.28 MeV. These parameters were slightly higher than those of the conventional 9 MeV beam, manifested with slight increase in the surface dose and widening high dose flat area. The overall deposit dose distribution exhibited the highest central axis and the increase in dose declines from the axis distance. Under the condition that the field size was 20 cm×20 cm and the SSD was 100 cm, the FWHM of the vertical and horizontal off-axis dose distribution curves were 16.6 cm and 16.4 cm, respectively. Conclusion:By transforming conventional medical accelerator, the average dose rate of the beam at the isocycle meets the requirement of Flash-RT, and the average dose rate under the condition of 60 cm SSD is much higher than the requirement of at least 40 Gy/s for Flash-RT.
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As a method for local treatment, radiotherapy plays a key role in the management of tumors. In the past few decades, great progress has been made in radiotherapy technology, with improvements in conformity, homogeneity, and radiotherapy efficiency, and the results are encouraging. Nevertheless, the maximum tolerated dose of normal tissue has limited the further increase in radiotherapy dose in the tumor area. If radiation-induced toxicities can be reduced, a higher radiotherapy dose can be delivered to tumor tissue, so as to achieve a better treatment response. In recent years, the unique FLASH effect of ultra-high-dose-rate radiotherapy (FLASH-RT) is capable of maintaining a consistent tumor response whilst reducing radiation-induced toxicities in normal tissue, and therefore, FLASH-RT has become a research hotspot in the field of radiotherapy across the world. At present, some scholars tend to explain the FLASH effect using the theory of acute oxygen depletion, but the protective effect of FLASH-RT on normal tissue remains to be clarified. In addition, preliminary clinical studies have been conducted for FLASH-RT, and the results are promising. Based on existing evidence, this article elaborates on the research advances in FLASH-RT in the treatment of malignant tumor, so as to provide a reference for the translation and application of this new technique.