•We used MV X-ray to perform radiobiological response study after ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT), which is rarely reported.•Similar ...tumor control efficiency and tumor immune response were observed in the FLASH-RT and CONV-RT groups.•A significantly different splenic CD8 + and CD4 + T cell infiltration was observed between the FLASH-RT and CONV-RT groups, indicating that FLASH-RT stimulated the local immune response differently.•FLASH-RT reduced the radiation induced damage in the spleen and intestine, indicating a normal tissue-sparing effect of FLASH irradiation.
Investigating the antitumor effect and intratumor as well as local immune response in breast cancer-bearing mice after MV X-ray ultra-high dose rate radiotherapy (FLASH-RT) and conventional dose rate radiotherapy (CONV-RT).
Six-week-old female C57BL/6 mice were inoculated subcutaneously with Py8119 and Py230 breast tumor cells in the inguinal mammary gland and administered 10 Gy abdominal 6 MV X-ray FLASH-RT (125 Gy/s) or CONV-RT (0.2 Gy/s) 15 days after tumor inoculation. Tumor and spleen tissues were obtained at different time points post-irradiation (PI) for analysis of immune cell infiltration using flow cytometry and immunohistochemical (IHC) staining. Intestine tissues were collected 3 days PI to evaluate normal tissue damage and immune cell infiltration.
Both FLASH-RT and CONV-RT significantly delayed tumor growth. Flow cytometry showed increased CD8+/CD3 + and CD8+/CD4 + ratios, and IHC confirmed a similar increased CD8 + T cell infiltration at 2 weeks PI in Py8119 tumor tissues in both irradiation groups. No statistical difference was observed between the irradiation groups in terms of tumor growth and increased T cell infiltration in the tumor. Unexpectedly, significantly smaller spleen weight and substantially higher CD8+/CD3 + and lower CD4+/CD3 + ratios were observed in the spleens of the FLASH-RT group than in the spleens of the non-irradiated control and CONV-RT groups 4 weeks PI. Pathological analysis revealed severe red pulp expansion in several spleens from the CONV-RT group, but not in the spleens of the FLASH-RT group. Reduced intestinal damage, macrophage and neutrophil infiltration were observed in the FLASH-RT group compared with CONV-RT group.
FLASH-RT and CONV-RT effectively suppressed tumor growth and promoted CD8 + T cell influx into tumors. FLASH-RT can induce different splenic immune responses and reduce radiation-induced damage in the spleen and intestine, which may potentially enhance the therapeutic ratio of FLASH-RT.
Low-emittance photoinjector-enabled cutting-edge scientific instruments, such as free-electron lasers, inverse Compton scattering light sources, and ultrafast electron diffraction, will greatly ...benefit from the improved repetition rate. In this paper, we proposed a specifically designed S-band radio frequency (RF) photoinjector to obtain low emittance and kilohertz (kHz) high-repetition rates simultaneously. By lowering the gradient, much lower RF power is needed to feed the electron gun, and then the heat problem is much easier to handle. Meanwhile, by optimizing the length of the gun’s first cell from the normal case of 0.6-cell to 0.4-cell, the launch phase and the extraction field are significantly improved, thus ensuring the generation of low-emittance electron beams. In our design, the proposed 1.4-cell RF gun can work effectively under different field gradients ranging from 30 MV/m to 100 MV/m. For a standard case of 60 MV/m, 2.5 MW peak RF power with μs level pulse width is sufficient, thus offering the feasibility of improving the repetition rate to kHz level with a standard 5 MW irradiation klystron. In addition, simulated electron beams with a low emittance of 0.29 mm.mrad@200 pC can be generated by this proposed photoinjector, showing that this high-repetition rate injector holds the potential to deliver high-quality beams comparable to those of state-of-the-art S-band photoinjectors. Combining the merits of low emittance and high-repetition rate, this proposed photoinjector will provide a new possibility for future free-electron laser facilities operating at repetition rates ranging from kHz to tens of kHz.
•The generation of High energy X-ray FLASH by the PARTER system and its physical properties were confirmed.•This study reports the first demonstration of the FLASH effect triggered by high energy ...X-rays on a platform called PARTER.•The study provides a basis for future scientific research and clinical application of HEX in FLASH radiotherapy.
This study aimed to evaluate whether high-energy X-rays (HEXs) of the PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can produce ultrahigh dose rate (FLASH) X-rays and trigger the FLASH effect.
EBT3 radiochromic film and fast current transformer (FCT) devices were used to measure absolute dose and pulsed beam current of HEXs. Subcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional dose rate radiotherapy (CONV), respectively to observe the tumor control efficiency and normal tissue damage.
The maximum dose rate of HEXs of PARTER was up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (p < 0.0001) and significant difference in survival curves (p < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a significant difference (p = 0.038) in survival among the three groups, with the risk of death decreased by 81% in the FLASH group compared to that in the CONV group. The survival time of healthy mice irradiated in the abdomen in the FLASH group was undoubtedly higher (62.5% of mice were still alive when we stopped observation) than that in the CONV group (7 days).
This study confirmed that HEXs of the PARTER system can produce ultrahigh dose rate X-rays and trigger a FLASH effect, which provides a basis for future scientific research and clinical application of HEX in FLASH radiotherapy.
Background
Ultrahigh dose‐rate irradiation (FLASH‐IR) was reported to be efficient in tumor control while reducing normal tissue radiotoxicity. However, the mechanism of such phenomenon is still ...unclear. Besides, the FLASH experiments using high energy X‐ray, the most common modality in clinical radiotherapy, are rarely reported. This study aims to investigate the radiobiological response using 6 MV X‐ray FLASH‐IR or conventional dose‐rate IR (CONV‐IR).
Methods
The superconducting linac of Chengdu THz Free Electron Laser (CTFEL) facility was used for FLASH‐IR, a diamond radiation detector and a CeBr3 scintillation detector were used to monitor the time structure and dose rate of FLASH pulses. BALB/c nude mice received whole abdominal 6 MV X‐ray FLASH‐IR or CONV‐IR, the prescribed dose was 15 Gy or 10 Gy and the delivered absolute dose was monitored with EBT3 films. The mice were either euthanized 24 h post‐IR to evaluate acute tissue responses or followed up for 6 weeks to observe late‐stage responses and survival probability. Complete blood count, histological analyses, and measurement of cytokine expression and redox status were performed.
Results
The mean dose rate of >150 Gy/s and instantaneous dose rate of >5.5 × 105 Gy/s was reached in FLASH‐IR at the center of mice body. After 6 weeks’ follow‐up of mice that received 15 Gy IR, the FLASH group showed faster body weight recovery and higher survival probability than the CONV group. Histological analysis showed that FLASH‐IR induced less acute intestinal damage than CONV‐IR. Complete blood count and cytokine concentration measurement found that the inflammatory blood cell counts and pro‐inflammatory cytokine concentrations were elevated at the acute stage after both FLASH‐IR and CONV‐IR. However, FLASH irradiated mice had significantly fewer inflammatory blood cells and diminished pro‐inflammatory cytokine at the late stage. Moreover, higher reactive oxygen species (ROS) signal intensities but significantly reduced lipid peroxidation were found in the FLASH group than in the CONV group in the acute stage.
Conclusions
The radioprotective effect of 6 MV X‐ray FLASH‐IR was observed. The differences in inflammatory responses and redox status between the two groups may be the factors responsible for reduced radiotoxicities following FLASH‐IR. Further studies are required to thoroughly evaluate the impact of ROS on FLASH effect.
The quantum efficiency (QE) and thermal emittance are two main parameters for photocathode, especially for the emission source of free electron laser (FEL) accelerator. It is in challenge how to ...reduce the rigorous fabrication of cathode and how to enhance the quantum efficiency for photocathode. Facing to the issues in our case, we have investigated plasmon-enhanced photoemission from Au nanoparticles (NPs) covered with Cs film in the microwave electron gun of free electron laser. The large-area preparation and low-cost photocathode are formed by rapid thermal annealing of thin Au films. Cs film covered is found to effectively excite photoelectrons from Au NPs under the visible light (at the 532 nm). The quantum efficiency (QE) of the Au NPs-Cs increases to 2.3 × 10−4 with the pico-second pulsed laser irradiation, and the normalized root mean square (RMS) thermal emittance of the electron beam is about 1.89 mm mrad. It confirms the feasibility for the proposed metallic nanoparticles to be applied to the high brightness electron sources.
•We have proposed the plasmon-enhanced photoemission based on pure Au-NPs with the visible light.•The quantum efficiency (QE) of the Au NPs-Cs increases to 2.3 × 10−4 under the Ps-laser irradiation.•The RMS of thermal emittance is about 1.89 mm mrad.
•The first high-energy X-ray FLASH radiotherapy platform (PARTER) has been upgraded.•6–8 MVs X-ray is available for FLASH irradiation at dose rate of 40–1000 Gy/s.•Treatment system and dosimetry were ...improved to provide verified high-performance FLASH X-rays.•The FLASH effect was demonstrated by numerous experiments using PARTER’s MV X-rays.•The accelerator is being upgraded for FLASH irradiation at 80-cm SSD at the end of 2025.
Recent studies indicated that ultrahigh dose rate (FLASH) radiation can reduce damage to normal tissue while maintaining anti-tumour activity compared to conventional dose rate (CONV) radiation. This paper provides a comprehensive description of the current status of the Platform for Advanced Radiotherapy Research (PARTER), which serves as the first experimental FLASH platform utilizing megavoltage X-rays and has facilitated numerous experiments.
PARTER was established in 2019 based on a superconducting linac to support experimental FLASH studies using megavoltage X-rays. Continuous upgrades have been made to the accelerator, collimators, flattening filters, monitors, other auxiliary devices, and irradiation process in order to achieve optimal results. Passive and active dosimeters are employed for measuring dose distribution and to ensure traceability of radiation doses.
The dose monitors and dosimeters demonstrate reliable performance with acceptable stability. At PARTER, the maximum mean dose rate is approximately 400 Gy/s at a surface-source distance of 20 cm (over 1000 Gy/s at smaller distances), with an instantaneous dose rate of approximately 8E5 Gy/s. Both passive and active dosimeters exhibit good linearity and agreement during FLASH X-ray irradiation. The monitors show good linearity to dose rate, with short-term fluctuations within 1.5 % for the diamond monitor. The discrepancy between measured absorbed dose and dose protocol is typically less than 4 %. The X-ray energy spectra on PARTER are comparable to those for megavoltage CONV linacs operating in flattening filter-free mode. The maximum field size of the FLASH beam is 4.5 cm × 4.5 cm. The FLASH dose profile demonstrates satisfactory flatness (1.04) and similar penumbra compared to clinical CONV linac, while the percentage depth dose curve of FLASH X-rays is steeper than that of the clinical megavoltage CONV X-ray.
PARTER represents a pioneering platform for conducting megavolts FLASH X-ray irradiation in biological experiments. It effectively fulfills the requirements of preclinical research on megavoltage X-ray FLASH and undergoes continuous upgrades to meet increasingly demanding performance criteria.
DNA-damaging treatments such as radiotherapy (RT) have become promising to improve the efficacy of immune checkpoint inhibitors by enhancing tumor immunogenicity. However, accompanying ...treatment-related detrimental events in normal tissues have posed a major obstacle to radioimmunotherapy and present new challenges to the dose delivery mode of clinical RT. In the present study, ultrahigh dose rate FLASH X-ray irradiation was applied to counteract the intestinal toxicity in the radioimmunotherapy. In the context of programmed cell death ligand-1 (PD-L1) blockade, FLASH X-ray minimized mouse enteritis by alleviating CD8
T cell-mediated deleterious immune response compared with conventional dose rate (CONV) irradiation. Mechanistically, FLASH irradiation was less efficient than CONV X-ray in eliciting cytoplasmic double-stranded DNA (dsDNA) and in activating cyclic GMP-AMP synthase (cGAS) in the intestinal crypts, resulting in the suppression of the cascade feedback consisting of CD8
T cell chemotaxis and gasdermin E-mediated intestinal pyroptosis in the case of PD-L1 blocking. Meanwhile, FLASH X-ray was as competent as CONV RT in boosting the antitumor immune response initiated by cGAS activation and achieved equal tumor control in metastasis burdens when combined with anti-PD-L1 administration. Together, the present study revealed an encouraging protective effect of FLASH X-ray upon the normal tissue without compromising the systemic antitumor response when combined with immunological checkpoint inhibitors, providing the rationale for testing this combination as a clinical application in radioimmunotherapy.
A high average power THz radiation facility has been developed by the China Academy of Engineering Physics. It is the first CW THz user facility based on superconducting accelerator technology in ...China. The superconducting linac module, which contains two 4-cell 1.3 GHz TESLA-like superconducting radio frequency cavities, is a major component of this facility. The expected electron energy gain is 6–8 MeV with a field gradient of 8–10 MV/m. The design and fabrication of the linac module is complete. This paper discusses its assembly and results from cyromodule tests and beam commissioning. At 2 K, the cryomodule works smoothly and stably. Both cavities have achieved effective field gradients of 10 MV/m. In beam loading experiments, 8 MeV, 5 mA electron beams with an energy spread less than 0.2% have been produced, which satisfies our requirements.
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