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Mutation Research. Genetic Toxicology... Sep 2022Ionizing radiation (IR) kills cells mainly through induction of DNA damages and the surviving cells may suffer from mutations. Transgenerational effects of IR are well...
Ionizing radiation (IR) kills cells mainly through induction of DNA damages and the surviving cells may suffer from mutations. Transgenerational effects of IR are well documented, but the exact mechanisms underlying them are less well understood; they include induction of mutations in germ cells and epigenetic inheritance. Previously, effects in the offspring of mice and zebrafish exposed to IR have been reported. A few studies also showed indications of transgenerational effects of radiation in humans, particularly in nuclear power workers. In the present project, short- and long-term effects of low-dose-rate (LDR; 50 and 97 mGy/h) and high-dose-rate (HDR; 23.4, 47.1 and 495 Gy/h) IR in Drosophila embryos were investigated. The embryos were irradiated at different doses and dose rates and radiosensitivity at different developmental stages was investigated. Also, the survival of larvae, pupae and adults developed from embryos irradiated at an early stage (30 min after egg laying) were studied. The larval crawling and pupation height assays were applied to investigate radiation effects on larval locomotion and pupation behavior, respectively. In parallel, the offspring from 3 Gy irradiated early-stage embryos were followed up to 12 generations and abnormal phenotypes were studied. Acute exposure of embryos at different stages of development showed that the early stage embryo is the most sensitive. The effects on larval locomotion showed no significant differences between the dose rates but a significant decrease of locomotion activity above 7 Gy was observed. The results indicate that embryos exposed to the low dose rates have shorter eclosion times. At the same cumulative dose (1 up to 7 Gy), HDR is more embryotoxic than LDR. We also found a radiation-induced depigmentation on males (A5 segment of the dorsal abdomen, A5pig) that can be transmitted up to 12 generations. The phenomenon does not follow the classical Mendelian laws of segregation.
Topics: Animals; Dose-Response Relationship, Radiation; Drosophila; Embryonic Development; Gamma Rays; Humans; Larva; Male; Radiation, Ionizing; Zebrafish
PubMed: 36031335
DOI: 10.1016/j.mrgentox.2022.503523 -
Journal of Radiation Research Mar 2022Intestinal organoids are an in vitro cultured tissue model generated from intestinal stem cells, and they contain a mixture of epithelial cell types. We previously...
Intestinal organoids are an in vitro cultured tissue model generated from intestinal stem cells, and they contain a mixture of epithelial cell types. We previously established an efficient 'one cell/well' sorting method, and defined organoid-forming potential (OFP) as a useful index to evaluate the stemness of individual cells. In this study, we assessed the response to radiation dose and dose-rate by measuring both OFP and the percentage of stem cells in the crypts. After high-dose-rate (HDR, 0.5 Gy/min) irradiation in vivo, the percentage of stem cells in the harvested crypt cells decreased, and the replenishment of cycling stem cells originating from dormant cells was enhanced, but OFP increased in cells irradiated with a total dose of >1 Gy. In contrast, at a total dose of 0.1 Gy the percentage of stem cells reduced slightly, but neither replenishment rate nor OFP changed. Furthermore, the response to 1 Gy of low-dose-rate (LDR) irradiation was similar to the response to 0.1 Gy HDR irradiation. These results suggest that 0.1 Gy HDR irradiation or 1 Gy LDR irradiation does not alter stemness. Additionally, the OFP increase in the colon in response to irradiation was smaller than that in the duodenum, similar to the percentage of stem cells. Understanding the differences in the response of stem cells between the colon and the duodenum to radiation is important to clarify the mechanisms underlying the development of radiation-associated intestinal cancers.
Topics: Dose-Response Relationship, Radiation; Intestines; Organoids; Radiation Dosage; Radiation, Ionizing; Stem Cells
PubMed: 34977948
DOI: 10.1093/jrr/rrab120 -
Journal of Radiation Research Mar 2023While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal... (Review)
Review
While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal models have made significant contributions to provide quantitative data with mechanistic insights. The current article aims at compiling the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. This review focuses specifically on the results that explain the biological mechanisms underlying dose-rate effects and their potential involvement in radiation-induced carcinogenic processes. Since the adverse outcome pathway (AOP) concept together with the key events holds promise for improving the estimation of radiation risk at low doses and low dose-rates, the review intends to scrutinize dose-rate dependency of the key events in animal models and to consider novel key events involved in the dose-rate effects, which enables identification of important underlying mechanisms for linking animal experimental and human epidemiological studies in a unified manner.
Topics: Animals; Humans; Radiation Dosage; Neoplasms, Radiation-Induced; Risk Assessment; Radiation Exposure; Models, Animal; Liver; Lung; Hematopoietic System; Dose-Response Relationship, Radiation
PubMed: 36773331
DOI: 10.1093/jrr/rrad003 -
Radiation Protection Dosimetry Oct 2022External dose rates were measured 1 m away from 230 Lu-177 patients to characterise the variability in normalised dose rates as a function of administered activity,...
External dose rates were measured 1 m away from 230 Lu-177 patients to characterise the variability in normalised dose rates as a function of administered activity, body mass index (BMI) and sex. The largest dose rate observed was 0.07 mSv/h associated with an administered activity of 7.2 GBq. Substantial variability was found in the distribution of the normalised dose rate associated that had an average of 0.0037 mSv/h per GBq and a 95% confidence interval of 0.0024-0.0058 mSv/h per GBq. Based on this study, estimating the patient dose rate based on the Lu-177 gamma exposure factor overestimates the dose rate by a factor of 2. A statistically significant inverse relationship was found between the patient dose rate and patient BMI and an empirically derived equation relating these two quantities was reported. On average, male patient dose rates were 3.5% lower than female dose rates, which may be attributed to the larger average BMI of the male patient group.
Topics: Humans; Male; Female; Lutetium; Radioisotopes; Body Mass Index; Cohort Studies
PubMed: 36138119
DOI: 10.1093/rpd/ncac187 -
Scientific Reports May 2024The current monochromatic beam mode (i.e., uHDR irradiation mode) of the scanned carbon-ion beam lacks a dedicated dose monitor, making the beam control challenging. We...
The current monochromatic beam mode (i.e., uHDR irradiation mode) of the scanned carbon-ion beam lacks a dedicated dose monitor, making the beam control challenging. We developed and characterized a dedicated dose monitor for uHDR-scanned carbon-ion beams. Furthermore, a simple measurable dose rate (dose rate per spot (DR)) was suggested by using the developed dose monitor and experimentally validating quantities relevant to the uHDR scanned carbon-ion beam. A large plane-parallel ionization chamber (IC) with a smaller electrode spacing was used to reduce uHDR recombination effects, and a dedicated operational amplifier was manufactured for the uHDR-scanned carbon-ion beam. The dose linearity of the IC was within ± 1% in the range of 1.8-12.3 Gy. The spatial inhomogeneity of the dose response of the IC was ± 0.38% inside the ± 40-mm detector area, and a systematic deviation of approximately 2% was measured at the edge of the detector. uHDR irradiation with beam scanning was tested and verified for different doses at the corresponding dose rates (in terms of both the average dose rate and DR). We confirmed that the dose monitor can highlight the characteristics (i.e., dose, dose rate, and dose profile) of uHDR-scanned carbon-ion beams at several dose levels in the monochromatic beam mode.
PubMed: 38773165
DOI: 10.1038/s41598-024-62148-2 -
Antioxidants (Basel, Switzerland) Jan 2023Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast...
Low dose-rate radiation exposure can occur in medical imaging, as background from environmental or industrial radiation, and is a hazard of space travel. In contrast with high dose-rate radiation exposure that can induce acute life-threatening syndromes, chronic low-dose radiation is associated with Chronic Radiation Syndrome (CRS), which can alter environmental sensitivity. Secondary effects of chronic low dose-rate radiation exposure include circulatory, digestive, cardiovascular, and neurological diseases, as well as cancer. Here, we investigated 1-2 Gy, 0.66 cGy/h, Co radiation effects on primary human mesenchymal stem cells (hMSC). There was no significant induction of apoptosis or DNA damage, and cells continued to proliferate. Gene ontology (GO) analysis of transcriptome changes revealed alterations in pathways related to cellular metabolism (cholesterol, fatty acid, and glucose metabolism), extracellular matrix modification and cell adhesion/migration, and regulation of vasoconstriction and inflammation. Interestingly, there was increased hypoxia signaling and increased activation of pathways regulated by iron deficiency, but Nrf2 and related genes were reduced. The data were validated in hMSC and human lung microvascular endothelial cells using targeted qPCR and Western blotting. Notably absent in the GO analysis were alteration pathways for DNA damage response, cell cycle inhibition, senescence, and pro-inflammatory response that we previously observed for high dose-rate radiation exposure. Our findings suggest that cellular gene transcription response to low dose-rate ionizing radiation is fundamentally different compared to high-dose-rate exposure. We hypothesize that cellular response to hypoxia and iron deficiency are driving processes, upstream of the other pathway regulation.
PubMed: 36829800
DOI: 10.3390/antiox12020241 -
Reproductive Biology Dec 2023Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly...
Low-dose radiation is generally considered less harmful than high-dose radiation. However, its impact on ovaries remains debated. Since previous reports predominantly employed low-dose radiation delivered at a high dose rate on the ovary, the effect of low-dose radiation at a low dose rate on the ovary remains unknown. We investigated the effect of low-dose ionizing radiation delivered at a low dose rate on murine ovaries. Three- and ten-week-old mice were exposed to 0.1 and 0.5 Gy of radiation at a rate of 6 mGy/h and monitored after 3 and 30 days. While neither body weight nor ovarian area showed significant changes, ovarian cells were damaged, showing apoptosis and a decrease in cell proliferation after exposure to 0.1 and 0.5 Gy radiation. Follicle numbers decreased over time in both age groups proportionally to the radiation dose. Younger mice were more susceptible to radiation damage, as evidenced by decreased follicles in 3-week-old mice after 30 days of 0.1 Gy exposure, while 10-week-old mice showed reduced follicles only following 0.5 Gy exposure. Primordial or primary follicles were the most vulnerable to radiation. These findings suggest that even low-dose radiation, delivered at a low dose rate, can adversely affect ovarian function, particularly in the early follicles of younger mice.
Topics: Female; Mice; Animals; Ovarian Follicle; Ovary
PubMed: 37890397
DOI: 10.1016/j.repbio.2023.100817 -
Radiation and Environmental Biophysics Aug 2020Many experimental studies are carried out to compare biological effectiveness of high dose rate (HDR) with that of low dose rate (LDR). The rational for this is the...
Many experimental studies are carried out to compare biological effectiveness of high dose rate (HDR) with that of low dose rate (LDR). The rational for this is the uncertainty regarding the value of the dose rate effectiveness factor (DREF) used in radiological protection. While a LDR is defined as 0.1 mGy/min or lower, anything above that is seen as HDR. In cell and animal experiments, a dose rate around 1 Gy/min is usually used as representative for HDR. However, atomic bomb survivors, the reference cohort for radiological protection, were exposed to tens of Gy/min. The important question is whether gamma radiation delivered at very high dose rate (VHDR-several Gy/min) is more effective in inducing DNA damage than that delivered at HDR. The aim of this investigation was to compare the biological effectiveness of gamma radiation delivered at VHDR (8.25 Gy/min) with that of HDR (0.38 Gy/min or 0.79 Gy/min). Experiments were carried out with human peripheral mononuclear cells (PBMC) and the human osteosarcoma cell line U2OS. Endpoints related to DNA damage response were analysed. The results show that in PBMC, VHDR is more effective than HDR in inducing gene expression and micronuclei. In U2OS cells, the repair of 53BP1 foci was delayed after VHDR indicating a higher level of damage complexity, but no VHDR effect was observed at the level of micronuclei and clonogenic cell survival. We suggest that the DREF value may be underestimated when the biological effectiveness of HDR and LDR is compared.
Topics: Adult; Cell Line; Cesium Radioisotopes; DNA Damage; Dose-Response Relationship, Radiation; Female; Gamma Rays; Humans; Leukocytes, Mononuclear; Micronuclei, Chromosome-Defective; Radiation Protection; Relative Biological Effectiveness; Young Adult
PubMed: 32488310
DOI: 10.1007/s00411-020-00852-z -
Medical Physics Jun 2024Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose...
BACKGROUND
Although the FLASH radiotherapy (FLASH) can improve the sparing of organs-at-risk (OAR) via the FLASH effect, it is generally a tradeoff between the physical dose coverage and the biological FLASH coverage, for which the concept of FLASH effective dose (FED) is needed to quantify the net improvement of FLASH, compared to the conventional radiotherapy (CONV).
PURPOSE
This work will develop the first-of-its-kind treatment planning method called simultaneous dose and dose rate optimization via dose modifying factor modeling (SDDRO-DMF) for proton FLASH that directly optimizes FED.
METHODS
SDDRO-DMF models and optimizes FED using FLASH dose modifying factor (DMF) models, which can be classified into two categories: (1) the phenomenological model of the FLASH effect, such as the FLASH effectiveness model (FEM); (2) the mechanistic model of the FLASH radiobiology, such as the radiolytic oxygen depletion (ROD) model. The general framework of SDDRO-DMF will be developed, with specific DMF models using FEM and ROD, as a demonstration of general applicability of SDDRO-DMF for proton FLASH via transmission beams (TB) or Bragg peaks (BP) with single-field or multi-field irradiation. The FLASH dose rate is modeled as pencil beam scanning dose rate. The solution algorithm for solving the inverse optimization problem of SDDRO-DMF is based on iterative convex relaxation method.
RESULTS
SDDRO-DMF is validated in comparison with IMPT and a state-of-the-art method called SDDRO, with demonstrated efficacy and improvement for reducing the high dose and the high-dose volume for OAR in terms of FED. For example, in a SBRT lung case of the dose-limiting factor that the max dose of brachial plexus should be no more than 26 Gy, only SDDRO-DMF met this max dose constraint; moreover, SDDRO-DMF completely eliminated the high-dose (V70%) volume to zero for CTV10mm (a high-dose region as a 10 mm ring expansion of CTV).
CONCLUSION
We have proposed a new proton FLASH optimization method called SDDRO-DMF that directly optimizes FED using phenomenological or mechanistic models of DMF, and have demonstrated the efficacy of SDDO-DMF in reducing the high-dose volume or/and the high-dose value for OAR, compared to IMPT and a state-of-the-art method SDDRO.
PubMed: 38873848
DOI: 10.1002/mp.17251 -
Clinical Oncology (Royal College of... Mar 2020The management of high-risk prostate cancer is challenging, as patients have a high risk of both local and distant relapse. Although adjuvant systemic treatment remains... (Review)
Review
The management of high-risk prostate cancer is challenging, as patients have a high risk of both local and distant relapse. Although adjuvant systemic treatment remains an important component of management, for those receiving radiotherapy, optimal local treatment should include a brachytherapy boost. This may be given by low dose rate (LDR) or high dose rate (HDR) techniques, but HDR has several advantages over LDR by virtue of more consistent dose optimisation, ability to treat outside the prostate and lower toxicity. A significant body of evidence now supports the use of HDR brachytherapy in addition to supplementary pelvic external beam radiotherapy for men with high-risk disease. Consistent evidence has emerged from randomised clinical trials, meta-analyses, and from institutional and multicentre cohort studies. It has been shown to improve local disease control and possibly reduce metastases and improve cancer-specific survival compared with external beam radiotherapy alone. It should be considered as standard treatment.
Topics: Brachytherapy; Humans; Male; Prostatic Neoplasms; Radiotherapy Dosage
PubMed: 31791573
DOI: 10.1016/j.clon.2019.11.003