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At present,precise radiotherapy has been widely used through the development with many years,but the existing technique still is limited by the limitation of tolerance dose of normal tissues,which cannot achieve the optimal goal of treating tumor.Flash radiotherapy(Flash-RT)is one kind of radiotherapy technique that uses the beam with ultra-high dose rate(UHDR)to conduct irradiation,which can furthest treat tumors while significantly reduce radiation injury of normal tissues.But until now,the biological mechanism,key physical parameters and triggering mechanism of Flash-RT are still unclear,and its principle and clinical translational application are still in the stage of research.This review clarified the technological advance and clinical translational application of Flash-RT research through summarized the relevant research of Flash-RT.
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The Flash radiotherapy(Flash-RT),which is the key breakthrough in the basic field of radiotherapy technique,which is expected to cause a new major transformation in the field of radiotherapy.In this paper,we reviewed the latest research advances of the application and the mechanism exploration of Flash-RT in tumor treatment.Current studies have found that both the Flash-RT with electron beams and photon and the Flash-RT with proton can reduce injury of normal tissue than radiotherapy with conventional dose-rate,but the relevant mechanisms are not yet clearly understood,which includes but not limited to oxygen depletion,DNA damage,cellular senescence,apoptosis and immune response.The difference of Flash-RT injury between tumor tissue and normal tissue further reduces the limitations of radiotherapy,and reduces the adverse reaction and complication compared with conventional radiotherapy,which has wide application prospects.
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Objective:To study and design one kind of flash radiotherapy(Flash-RT)equipment with ultra-high dose rate,which can be used in the mechanism research of Flash-RT with ultra-high dose rate.Methods:Based on the technique roadmap of high-power petal accelerator,the Flash-RT equipment can realize the requirement of Flash-RT for ultra-high dose rate and multiple irradiation angles.The corresponding design and research work were carried out on the basis of the overall design of the equipment,the main components and characteristics,the dynamics design of beam,the construction of movable and preliminary experimental platform,etc.Result:The dose rate of the designed equipment can reach to 100 Gy/s at a distance of 0.8 meters from the target point,which is easy to realize the radiotherapy method with multi angles.Conclusion:The designed X-ray equipment based on the technique roadmap of high-power petal accelerator can realize the research for the mechanism of medical Flash-RT equipment with ultra-high dose rate.
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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 investigate whether ultra-high dose rate (FLASH) irradiation can reduce radiation-induced intestinal injuries of mice compared to conventional dose rate (CONV) irradiation.Methods:Both FLASH and CONV irradiation were delivered with electron beam, with dose rates of 750 Gy/s and 0.5G y/s, respectively. A total of 105 mice were randomly divided into groups using a simple randomization method. Twenty-one mice were selected for weight observation, 7 mice in each group. After 9 Gy FLASH and CONV irradiation on the abdomen, the weight changes of mice were measured every other day, and compared among three groups. Twenty-four mice were selected for pathological examination including 5 mice in the control group. Three-and-a-half-day days after 12 Gy FLASH ( n=10) and CONV irradiation ( n=9) on the abdomen, the intestines of the mice were taken. Pathological sections were stained with hematoxylin-eosin (HE) to compare the number and percentage of regenerated crypts of the small intestine between two groups. After 12 Gy FLASH ( n=10) and CONV irradiation ( n=10) on the abdomen, the survival of 20 mice was observed. After FLASH using 4.5 Gy×2 times ( n=10) and CONV irradiation at 9 Gy×1 time ( n=10) on the abdomen, the weight changes were observed. After FLASH using 6 Gy×2 times ( n=10) and CONV irradiation at 12 Gy×1 time ( n=10) on the abdomen, the survival of mice was observed. The time interval between two irradiation was 1 min. EBT3 film was employed to monitor the actual exposure dose of the mice. The variables conforming to normal distribution were expressed by Mean±SD. Inter group comparison was performed by independent t-test. The survival of mice among different groups was compared by log-rank test. Results:After 9 Gy of abdominal irradiation, the mean weight of mice in the FLASH group was significantly higher than that in the CONV group. The weight of mice in the FLASH and CONV groups was (19.8±0.8) g and (18.0±1.8)g ( P=0.036) at 7 days after irradiation, (22.0±1.0)g and (21.2±0.5)g ( P=0.075) at 15 days after irradiation, and (24.2±1.4)g and (22.0±1.2)g ( P=0.012) at 25 days after irradiation, respectively. After 12 Gy irradiation, the mean survival of mice in FLASH and CONV groups was 4 days and 4.7 days ( P=0.029). After 12 Gy total abdominal irradiation, the mean number of intestinal regenerative crypts in the FLASH and CONV groups was 2.9/mm and 1.2/mm ( P=0.041), and the percentage of intestinal regenerative crypts was 34.1% and 14.1%, respectively. The survival of mice irradiated by FLASH using 6 Gy×2 times was longer compared with that of mice after CONV irradiation at 12 Gy×1 time. The weight of mice after 4.5 Gy×2 times irradiation was higher than that of mice after CONV irradiation at 9 Gy×1 time. Conclusion:Weight, survival and the number of intestinal regenerative crypts in the FLASH group are higher than those in the CONV group after irradiation, indicating that radiation-induced intestinal injury caused by FLASH irradiation is slighter than that of CONV 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 study the effects of FLASH irradiation (FLASH-RT) and conventional irradiation (CONV-RT) on gene expression profile in mouse liver, in order to provide theoretical basis of the potential mechanism of FLASH-RT.Methods:A total of 11 C57BL/6J male mice were divided into healthy control group (Ctrl group), CONV-RT group and FLASH-RT group according to random number table method. Mouse abdomen was treated with 12 Gy CONV-RT or FLASH-RT. Then the mice were killed by neck removal, and the liver tissues were collected to extract total RNA for transcriptome sequencing (RNA-Seq) that was then analyzed by bio-informatics analysis to investigate the changes of gene expression profiles. The mRNA expression levels of Stat1, Irf9 and Rela were verified by quantitative real-time PCR assay.Results:1 762 differentially expressed genes (DEGs) were identified in group FLASH-RT vs. CONV-RT. Among them, 660 genes were up-regulated and 1 102 genes were down-regulated. 1 918 DEGs were identified in groups FLASH-RT vs. Ctrl. Among them, 728 genes were up-regulated and 1 190 genes were down-regulated. 1 569 DEGs were identified in group CONV-RT vs. Ctrl. Among them, 1 046 genes were up-regulated and 523 genes were down-regulated. According to Gene Ontology (GO) analysis, these DEGs from groups FLASH-RT vs. CONV-RT were involved in various functions including defense response to virus, other organisms in cell components, adenylyltransferase activity in molecular function activity. These DEGs from group FLASH-RT vs. Ctrl were involved in various functions including defense response to other oranisms, endoplasmic reticulum chaperone complex, double-stranded RNA binding and so on. These DEGs from group FLASH-RT vs. CONV-RT were involved in several Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including influenza A, Herpes simplex infection and so on. These DEGs from group FLASH-RT vs. Ctrl were involved in several KEGG pathways including influenza A, NOD-like receptor signaling pathway. Stat1 was likely to be activated by FLASH radiation. The quantitative real-time PCR assay showed that FLASH-RT obviously increased the mRNA expressions of Stat1, Irf9 and Rela ( t=6.62, 2.11, 1.67, P<0.05). Conclusions:FLASH-RT and CONV-RT could alter gene expression profiles in mouse liver tissues, and these DEGs are involved in multiple radiobiological functional pathways. In comparison with CONV-RT, FLASH-RT induces a low level of liver injury, which may due to hypoxia radiation resistance.
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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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In recent years, ultra-high dose rate (FLASH) radiotherapy has become one of the most advanced research topics in the field of radiotherapy. Experimental data indicate that FLASH radiotherapy can significantly reduce the irradiation damage in normal tissues while being as effective as clinical conventional dose rate radiotherapy in tumor control. The oxygen depletion hypothesis is considered as one of the key mechanisms underlying the FLASH effect. In this article, research progress on the discovery, experimental evidence and reaction principle of oxygen depletion was reviewed, the measurement methods and biological effect modeling methods of the oxygen depletion hypothesis were summarized, and the oxygen depletion difference between normal tissue and tumor was also discussed.
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Objective:To investigate the effects of ultra-high dose rate radiation (FLASH-RT) and conventional radiation (CONV-RT) on plasma metabolites in glioma mice.Methods:Tocally 21 male C57BL/6J mice bearing intracranial glioma xenograft were randomly divided into healthy control group ( n=3), CONV-RT group ( n=9) and FLASH-RT group ( n=9). The CONV-RT group was administered a single dose of 24 Gy radiation on the head of mice at a dose rate of 0.4 Gy/s, and the FLASH-RT group was administered a single dose of 24 Gy radiation on the head of mice at a dose rate of 60 Gy/s, and the healthy control group was given 0 Gy pseudoradiation under the same condition. Mice blood was collected through the inner canthus vein for plasma separation at 1, 3 and 7 d after radiation in the two radiation groups, and the blood plasma of healthy control group was collected at 7 days after sham radiation. The changes in plasma metabolites were detected by the non-targeted metabolomics based on liquid chromatography mass spectrometry tandem platform. Results:After irradiation, the metabolites in plasma of two irradiation groups had significant difference. Compared with the healthy control group, 12 and 5 differential metabolites were screened out in the FLASH-RT group and CONV-RT group at three time points, respectively. The difference of plasma metabolites had the largest value at 1 day and decreased at 3 and 7 d after radiation. The arachidonic acid and isovaleric acid, involving arachidonic acid metabolism, biosynthesis of unsaturated fatty acids, and tyrosine metabolism pathways were screened in both FLASH-RT group and CONV-RT group, and the 10 differential metabolites, mainly involving energy metabolism and redox reactions, only existed in the FLASH-RT group.Conclusions:Arachidonic acid and isovaleric acid may be the common sensitive biomarkers to different radiation patterns, which provides ideas for further exploring the molecular mechanism of FLASH-RT in the treatment of glioma.
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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.
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Flash radiotherapy is a kind of radiotherapy method using ultra-high dose rate radiation. Compared with the traditional dose rate radiotherapy, it has unique radiobiological advantages. In this paper, the principle of flash radiotherapy, the process and results of biological experiments are summarized. At the same time, the advantages and challenges of flash radiotherapy are analyzed, and the future clinical application is prospected.