Low Dose Rate Irradiation Research Articles

Long-term effects of continuous low dose-rate gamma-ray irradiation on mouse hematopoietic cells.

The present work investigates the long-term effects of continuous low dose-rate (20mGy/day to total doses of 1-8Gy) gamma-ray exposure on the hematopoietic cells of specific pathogen-free C3H/HeN mice. Peripheral white blood cell (WBC) counts decreased on days 206, 471, and 486, with no significant changes in red blood cell (RBC) and platelet (PLT) counts. The number of colony forming units (CFU-S and CFU-GM) in the bone marrow and spleen from irradiated mice decreased with increasing total dose on day-12 and day-7. The decrease in bone marrow CFU-S persisted throughout the 400-day irradiation period and did not show any recovery up to 210days postirradiation. These findings suggest that the effects of low-dose-rate (LDR) radiation on the hematopoietic system remain long after the 400-day irradiation was completed. Further investigation showed no significant difference in life spans of non-irradiated W/Wv (c-kit-deficient) mice inoculated with hematopoietic stem cells from irradiated (20mGy/day for 400days) or nonirradiated wild-type mice. These results suggest that the effects of continuous low-dose-rate irradiation are more pronounced in hematopoietic stromal cells than in HSCs themselves.

Toxicity assessment following conventional radiation therapy and pulsed low dose rate radiation therapy: an in vivo animal study.

Pulsed low dose rate radiotherapy (PLDR) is a new radiation delivery method, in which the fractional dose is divided into sub-fractional doses with periodical time breaks in between. The goal of our study is to assess the toxicity on healthy tissues resulting from PLDR as compared to conventional radiotherapy (CRT) using the same physical X-ray dose. We analyzed the weight and survival time for CRT and PLDR groups and studied the inflammatory cytokine transforming Growth Factor-β (TGF-β), usually released following irradiation. Histopathological and immunohistochemical analyses were conducted for intestinal and bone marrow tissues from rats subjected to 8Gy whole- body irradiation using CRT and PLDR techniques. We investigated genotoxicity by performing a comet assay (CA) in splenic tissues. Our findings showed an improvement in survival time with PLDR versus CRT by 82%.The mean survival time for CRT rats' group was 6.3days, while it was 35.9days for PLDR group.The weight of CRT group decreased gradually by 3.7%, while weight of PLDR group increased gradually by 2.4%.CRT resulted in more cellular atrophy in bone marrow and intestinal tissues than in PLDR treatments as shown by hematoxylin and eosin staining analysis. In addition, the transforming growth factor-β (TGF-β) expression in bone marrow and intestinal tissues of CRT was higher than those expressed in tissues from PLDR as demonstrated by the Immuno reactive score (IRS). It was10(0.53) and 9.8(0.55) for BM and intestinal tissues, respectively from CRT group and 5.8(0.63) for PLDR for both tissues. The measured CA parameters were larger with CRT compared to PLDR, where the Tail Length (TL), Tail DNA % (TD%) and Tail Moment (TM) measurements were 25.4(3.4), 56.5(7.6)% and 20.5(3.5) for CRT, 7.3(1.9), 30.0(7.2)% and 5.7(1.8) for PLDR, with P value 0.000064, 0.0004 and 0.00017, respectively. This study indicates that PLDR can reduce the toxicity on normal tissues compared to CRT.

Does environmental enrichment mitigate the adverse effects of chronic low dose-rate radiation exposure on mice?

The purpose of the study was to determine whether environmental enrichments (EE) can mitigate the adverse effects of chronic low-dose-rate radiation exposure in mice. Female B6C3F1 mice were continuously exposed to 20mGyd-1 gamma-rays under specific-pathogen-free conditions since 8weeks of age for 400d. After completion of the radiation exposure, OV3121 cells, derived from an ovarian granulosa cell tumor, were inoculated subcutaneously alongside age-matched non-irradiated control mice. Irradiated mice were shown to have a significantly reduced ability to eliminate inoculated tumors. The results indicate that EE may be able to mitigate the adverse effects of low-dose-rate radiation exposure, but the effects vary greatly and are complex depending on the type of EE.

Effects of low-dose rate radiation on immune and epigenetic regulation of the mouse testes.

This study investigated the effects of chronic low-dose-rate radiation exposure on gene expression related to immunological defense mechanisms and epigenetic regulation in the testis of male mice. The study found that radiation exposure (4.5 mGy/hr until 4000 mGy) led to a significant decrease in the expression of genes involved in epigenetic regulation and a significant increase in the expression of several genes linked to innate and acquired immunity, suggesting a noticeable effect on the immune response. In addition, there was a significant increase in the expression of SRY-box transcription factor 9, which plays a crucial role in testicular development, indicating a response to irradiation. These findings provide insights into the biological effects of chronic low-dose-rate radiation exposure on innate immunity and epigenetic regulation in the testis.

Effects of generational low dose-rate 137Cs internal exposure in descendant mice

To quantitatively investigate the effects of chronic low-dose internal exposure to Cesium-137 on DNA damage, carcinogenicity, and offspring over multiple generations. The potential genetic risk in humans was predicted based on next-generation murine mutation rates to confirm the reasonableness of the current Cesium-137 dose limits for food. Cesium-137 (100 Bq/mL) was provided in drinking water to A/J mice, facilitating chronic, low-dose, low-dose-rate internal exposure through sibling mating over 25 generations (G25). The A/J mice were compared with a control strain with the same origin ancestry (no Cesium-137 water) for DNA double-strand breaks (DSBs), oxidative stress, chromosome aberrations, micronucleus test results, whole genome analysis, carcinogenicity, tumor growth rate, and immune competence. Compared to the control group, DNA DSBs and oxidative stress were significantly increased in the Cesium-137 group. However, no significant differences were observed between the groups regarding chromosome aberration, micronuclei, or the whole genome sequence mutation analysis. Although the carcinogenic rate did not differ between the groups, the rate of tumor growth was significantly suppressed in the Cesium-137 group. The anti-tumor cytokine trend in the Cesium-137 group likely contributed to this effect. No pathological or genetic effects were observed in the offspring of mice drinking water containing 100 Bq/mL Cesium-137 after G25. The contribution of low dose-rate radiation to carcinogenicity was not additive but growth-inhibitory. Although the negative data are not conclusive, these findings are deemed highly reliable.

The new approach of a simulation low dose rate radiation effects in bipolar integrated circuits

The model is proposed to explain the effects of low dose rate under the radiation influence in bipolar structures, taking into account the effects of subthreshold displacement in high-doped silicon layers. The base current degradation of bipolar transistor is determined of surface and displacement radiation effects in the near-surface base area. The conditions for the enhanced low dose rate sensitivity (ELDRS) in bipolar structures are shown. The presented results of the analysis allow us to explain most of the observed experimental results.

Effects of Continuous Prenatal Low Dose Rate Irradiation on Neurobehavior, Hippocampal Cellularity, Messenger RNA and MicroRNA Expression on B6C3F1 Mice.

Epidemiological, experimental, and ecological data have indicated the controversial effect of in utero chronic low dose rate (<6 mGy/h) with accumulative low (≤100 mGy) or high (>100 mGy) dose radiation exposure. Our main goal of this study was to examine if different low dose rates of chronic pre- and/or post-natal radiation exposure with accumulative high doses could induce hippocampal cellular, mRNA, and miRNA changes leading to neuropsychiatric disorders. The comprehensive mouse phenotypic traits, organ weight, pathological, and blood mRNA and miRNA changes were also studied. Using different approaches including SmithKline, Harwell, Imperial College, Royal Hospital, Phenotype Assessment (SHIRPA), neurobehavioral tests, pathological examination, immunohistochemistry, mRNA and miRNA sequencing, and real-time quantitative polymerase chain reaction (qRT-PCR) validation, we found that in prenatally irradiated (100 mGy/d for 18 days with an accumulative dose of 1.8 Gy) 1-year-old mice, no cellular changes, including immature neurons in the subgranular zone, mature neurons and glial cells in the hilus of the dentate gyrus and development of cognitive impairment, neuropsychiatric disorders, occurred. However, a significant reduction in body weight and mass index (BMI) was indicated by the SHIRPA test. A reduced exploratory behavior was shown by an open field test. Organ weights showed significant reductions in the testes, kidneys, heart, liver and epididymides with no abnormal pathology. mRNA and miRNA sequencing and qRT-PCR validation revealed the upregulation of Rubcnl and Abhd14b, and downregulation of Hspa1b, P4ha1, and Banp genes in both the hippocampus and blood of mice prenatally irradiated with 100 mGy/d. Meanwhile, downregulation of miR-448-3p and miR1298-5p in the hippocampus, miR-320-3p, miR-423-5p, miR-486b-5p, miR-486b-3p, miR-423-3p, miR-652-3p, miR-324-3p, miR-181b-5p, miR-let-7b, and miR-6904-5p in the blood was induced. The target scan revealed that Rubcnl is one of the miR-181b-5p targets in the blood. We, therefore, concluded that prenatal chronic irradiation with a low dose rate of 100 mGy/d and accumulative dose of 1.8 Gy or below might not induce significant adverse health effects on the offspring. Further study of different low dose rate radiation exposures with accumulative high doses may provide threshold doses for authorities or regulators to set new radiation safety guidelines to replace those extrapolated from acute high dose/dose rate irradiation to reduce unnecessary emergency evacuation or spending once a nuclear accident or leakage occurs.

Protective effect of melatonin against radiobiological damage in the brain of rats exposed to low and high dose rate radiotherapy

This study aimed to investigate the radioprotective effect of melatonin (MLT) on brain damage in rats exposed to low and high dose rate radiotherapy. The dose rates of 10 MV photon beams used in the study were 600 MU/min and 2400 MU/min for low dose rate radiotherapy (LDR_RT) and high dose rate radiotherapy (HDR_RT), respectively. A total of 46 female Wistar albino rats aged between 8 and 12 weeks were divided in 6 groups. These groups were control, MLT, LDR_RT, HDR_RT, LDR_RT plus MLT and HDR_RT plus MLT, respectively. Rats in the radiation group received 16 Gy single dose whole body radiotherapy. Rats in the LDR_RT plus MLT and HDR_RT plus MLT groups received 10 mg/kg melatonin by intraperitoneal injection 15 min before radiotherapy. The rats were sacrificed 48 h after radiotherapy. Biochemical and histopathological methods analyzed radiation damage in rats. There was a statistically significant difference between the LDR_RT and HDR_RT radiation groups and the control group in terms of biochemical and histopathological parameters (p < 0.05). In the groups that received only LDR_RT and HDR_RT, the moderate neuro-degeneration scores were 1 and 4, respectively, while the moderate neuro-degeneration scores were 0 and 2 when MLT was applied to these groups. Superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzymes were decreased due to radiotherapy, whereas these enzymes were improved in MLT-treated groups. In conclusion, melatonin was found to be effective as a radioprotective agent in the prevention of brain damage caused by exposure to 10 MV photon radiation at dose rates of 600 MU/min and 2400 MU/min.

Quantitative Digital Subtraction Angiography Measurement of Arterial Velocity at Low Radiation Dose Rates.

Quantitative digital subtraction angiography (qDSA) has been proposed to quantify blood velocity for monitoring treatment progress during blood flow altering interventions. The method requires high frame rate imaging [~ 30 frame per second (fps)] to capture temporal dynamics. This work investigates performance of qDSA in low radiation dose acquisitions to facilitate clinical translation. Velocity quantification accuracy was evaluated at five radiation dose rates in vitro and in vivo. Angiographic technique ranged from 30 fps digital subtraction angiography ( at the interventional reference point) down to a 30 fps protocol at 23% higher radiation dose per frame than fluoroscopy ( ). The in vitro setup consisted of a 3D-printed model of a swine hepatic arterial tree connected to a pulsatile displacement pump. Five different flow rates (3.5-8.8mL/s) were investigated in vitro. Angiography-based fluid velocity measurements were compared across dose rates using ANOVA and Bland-Altman analysis. The experiment was then repeated in a swine study (n = 4). Radiation dose rate reductions for the lowest dose protocol were 99% and 96% for the phantom and swine study, respectively. No significant difference was found between angiography-based velocity measurements at different dose rates in vitro or in vivo. Bland-Altman analysis found little bias for all lower-dose protocols (range: [- 0.1, 0.1]cm/s), with the widest limits of agreement ([- 3.3, 3.5]cm/s) occurring at the lowest dose protocol. This study demonstrates the feasibility of quantitative blood velocity measurements from angiographic images acquired at reduced radiation dose rates.

Effect of proton irradiation dose rate and implanted hydrogen ions on spinodal decomposition in thermally aged EQ308L stainless steel weld metal

Abstract Stainless steel welds with a ferritic phase are extensively utilized in nuclear power plants. Spinodal decomposition stands as the primary factor contributing to the degradation of their service performance. Ion irradiation has been widely employed to investigate the damage behavior of materials. However, varying irradiation parameters, such as dose rate and implanted ions, are believed to result in significant differences in the extent of spinodal decomposition. In this paper, proton irradiation experiments were conducted at different dose rates on thermally aged EQ308L stainless steel welds. Spinodal decomposition within the ferrite at various radiation depths was compared and analyzed by using atom probe tomography to unveil the effects of dose rate and implanted hydrogen ions. The results reveal that, under conditions of high dose rate irradiation, spinodal decomposition can be partially alleviated when compared to the initial thermally aged state. Conversely, under low dose rate irradiation conditions, spinodal decomposition exhibits an enhancement trend. This difference may be attributed to the interplay between irradiation-enhanced diffusion and atomic mixing. Therefore, the dose rate significantly influences the progression of spinodal decomposition. Furthermore, implanted hydrogen ions may also inhibit spinodal decomposition within the ferrite, potentially by promoting the recombination of irradiation defects.

Revisiting an Inverse Dose-Fractionation Effect of Ionizing Radiation Exposure for Ischemic Heart Disease: Insights from Recent Studies.

Over the last two decades, there has been emerging evidence suggesting that ionizing radiation exposures could be associated with elevated risks of cardiovascular disease (CVD), particularly ischemic heart disease (IHD). Excess CVD risks have been observed in a number of exposed groups, with generally similar risk estimates both at low and high radiation doses and dose rates. In 2014, we reported for the first time significantly higher risks of IHD mortality when radiation doses were delivered over a protracted period of time (an inverse dose-fractionation effect) in the Canadian Fluoroscopy Cohort Study. Here we review the current evidence on the dose-fractionation effect of radiation exposure, discuss potential implication for radiation protection policies and suggest further directions for research in this area.

Possible association of G6PC2 and MUC6 induced by low‑dose‑rate irradiation in mouse intestine with inflammatory bowel disease.

Although there are several types of radiation exposure, it is debated whether low‑dose‑rate (LDR) irradiation (IR) affects the body. Since the small intestine is a radiation‑sensitive organ, the present study aimed to evaluate how it changes when exposed to LDR IR and identify the genes sensitive to these doses. After undergoing LDR (6.0 mGy/h) γ radiation exposure, intestinal RNA from BALB/c mice was extracted 1 and 24 h later. Mouse whole genome microarrays were used to explore radiation‑induced transcriptional alterations. Reverse transcription‑quantitative (RT‑q) PCR was used to examine time‑ and dose‑dependent radiation responses. The histopathological status of the jejunum in the radiated mouse was not changed by 10 mGy of LDR IR; however, 23 genes were upregulated in response to LDR IR of the jejunum in mice after 1 and 24 h of exposure. Upregulated genes were selected to validate the results of the RNA sequencing analysis for RT‑qPCR detection and results showed that only Na+/K+ transporting subunit α4, glucose‑6‑phosphatase catalytic subunit 2 (G6PC2), mucin 6 (MUC6) and transient receptor potential cation channel subfamily V member 6 levels significantly increased after 24 h of LDR IR. Furthermore, G6PC2 and MUC6 were notable genes induced by LDR IR exposure according to protein expression via western blot analysis. The mRNA levels of G6PC2 and MUC6 were significantly elevated within 24 h under three conditions: i) Exposure to LDR IR, ii) repeated exposure to LDR IR and iii) exposure to LDR IR in the presence of inflammatory bowel disease. These results could contribute to an improved understanding of immediate radiation reactions and biomarker development to identify radiation‑susceptible individuals before histopathological changes become noticeable. However, further investigation into the specific mechanisms involving G6PC2 and MUC6 is required to accomplish this.

Understanding the dose-rate effect on loop characteristics in Kr+-irradiated CeO2 by in-situ TEM study

Irradiation of CeO2 with heavy ions is commonly used to accelerate the evaluation of the irradiation performance of UO2 nuclear fuel. However, the differences in damage rates between ions and neutrons have led to doubts about this method, making it especially important to study the dose rate effect. Here, two kinds of dose rates were used to in-situ irradiate CeO2 using 400 keV Kr+ at 550 °C and 700 °C to study the dose rate effect on loop characteristics. High dose rate (HR) led to low-density and small-sized dislocation loops compared to low dose rate (LR), which was attributed to the initial high concentration of oxygen vacancies and enhanced recombination of point defects. HR was found to promote the direct nucleation of perfect dislocation loops (PDLs), while under LR irradiation, the PDLs tended to be formed by the transformation of Frank dislocation loops (FDLs) through a typical unfaulting. At a same dose, the proportion of PDL under the HR condition was much higher than that under the LR condition. Temperature greatly affected the loop characteristics. High temperature caused large-sized and small dense loops, as well as high PDL proportion. Moreover, the newly nucleated PDL tended to be close to the pre-existing PDLs and had the same Burgers vector as the adjacent PDL under HR irradiation at 700 °C. Current results provide underlying insights for assessing the effect of dose rate on irradiation-induced loop evolution and a reference for understanding the dose rate effect.

An analysis of the effects of chronic low dose-rate radiation exposure on cancer focusing on the differences among cancer types

Purpose The effect of chronic low dose-rate radiation exposure on cancers was investigated by analyzing the data of mice experiments conducted at the Institute for Environmental Sciences (IES). This analysis focuses on the differences between malignant lymphomas and solid cancers. Materials and methods The analysis is conducted based on the mathematical model introduced in our previous work. The model is expanded to analyze malignant lymphomas and solid cancers separately. Using the expanded model, the effect of chronic low dose-rate radiation on malignant lymphomas and solid cancers are discussed based on their occurrences, progressions, and mortalities. Results Non-irradiated control group and 20 mGy/day × 400 days irradiated groups are analyzed. The analysis showed that radiation exposure shortened mean life expectancy for both malignant lymphomas and solid cancers (shorter by 89.6 days for malignant lymphomas and 149.3 days for solid cancers). For malignant lymphomas, both the occurrence and the progression are affected by radiation exposure. The mean age at which malignant lymphoma developed in mice was shortened by 32.7 days and the mean progression period was shortened by 57.3 days. The occurrence of solid cancer is also affected by radiation exposure, wherein the mean age at which solid cancer develops was shortened by 147.9 days. However, no significant change in progression period of solid cancers was seen in the analysis. Conclusions The analysis showed that the occurrence and mean lifespan are affected in both malignant lymphomas and solid cancers. The shortening of the progression period is only seen in malignant lymphoma, no significant change was observed in solid cancers.

Ultrastructural Analysis of Large Japanese Field Mouse (Apodemus speciosus) Testes Exposed to Low-Dose-Rate (LDR) Radiation after the Fukushima Nuclear Power Plant Accident.

Since the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident, great attention has been paid to the impact of chronic low-dose-rate (LDR) radiation exposure on biological systems. The reproductive system is sensitive to radiation, with implications connected to infertility. We investigated the testis ultrastructure of the wild large Japanese field mouse (Apodemus speciosus) from three areas contaminated after the FDNPP accident, with different levels of LDR radiation (0.29 µSv/h, 5.11 µSv/h, and 11.80 µSv/h). Results showed good preservation of the seminiferous tubules, comparable to the unexposed animals (controls), except for some ultrastructural modifications. Increases in the numerical density of lipid droplet clusters in spermatogenic cells were found at high levels of LDR radiation, indicating an antioxidant activity rising due to radiation recovery. In all groups, wide intercellular spaces were found between spermatogenic cells, and cytoplasmic vacuolization increased at intermediate and high levels and vacuolated mitochondria at the high-level. However, these findings were also related to the physiological dynamics of spermatogenesis. In conclusion, the testes of A. speciosus exposed to LDR radiation associated with the FDNPP accident showed a normal spermatogenesis, with some ultrastructural changes. These outcomes may add information on the reproductive potential of mammals chronically exposed to LDR radiation.

Science-informed Policy Making for Protecting People and the Environment from Radiation.

The process to arrive at the radiation protection practices of today to protect workers, patients, and the public, including sensitive populations, has been a long and deliberative one. This paper presents an overview of the US Environmental Protection Agency's (US EPA) responsibility in protecting human health and the environment from unnecessary exposure to radiation. The origins of this responsibility can be traced back to early efforts, a century ago, to protect workers from x rays and radium. The system of radiation protection we employ today is robust and informed by the latest scientific consensus. It has helped reduce or eliminate unnecessary exposures to workers, patients, and the public while enabling the safe and beneficial uses of radiation and radioactive material in diverse areas such as energy, medicine, research, and space exploration. Periodic reviews and analyses of research on health effects of radiation by scientific bodies such as the National Academy of Sciences, National Council on Radiation Protection and Measurements, United Nations Scientific Committee on the Effects of Atomic Radiation, and the International Commission on Radiological Protection continue to inform radiation protection practices while new scientific information is gathered. As a public health agency, US EPA is keenly interested in research findings that can better elucidate the effects of exposure to low doses and low dose rates of radiation as applicable to protection of diverse populations from various sources of exposure. Professional organizations such as the Health Physics Society can provide radiation protection practitioners with continuing education programs on the state of the science and describe the key underpinnings of the system of radiological protection. Such efforts will help equip and prepare radiation protection professionals to more effectively communicate radiation health information with their stakeholders.

Melatonin administration in testicular damage caused by low and high-dose rate radiotherapy: An experimental study

ObjectiveThis study aimed to explore the radioprotective effect of melatonin against acute testicular injury caused by low- and high-dose-rate radiotherapy in rats. Materials and methodsA total of 40 12-week-old adult male rats were divided into 5 groups (n = 8). Group 1 comprised control rats who were not subjected to any procedures. A single dose of 8 Gy (Gy) radiotherapy was administered to the abdominopelvic regions of Group 2 (low-dose rate radiotherapy (LDRR) group) and Group 4 (high-dose rate radiotherapy (HDRR) group) rats at dose rates of 400 MU/min and 1400 MU/min, respectively. A single dose of 8 Gy radiotherapy was administered to Group 3 (low-dose rate radiotherapy + melatonin (LDRR + MEL) group) and Group 5 (high-dose rate radiotherapy + melatonin (HDRR + MEL) group) rats at dose rates of 400 MU/min and 1400 MU/min, respectively. Following this, 50 mg/kg/intraperitoneal melatonin was given to the rats 15 min before radiotherapy. The subjects were sacrificed 48 h after radiotherapy. Histological, immunohistochemical, immunofluorescence, and biochemical analyses of testicular tissue samples were performed. ResultsAs a result of comparing the FF and FFF radiotherapy groups with the control group, a statistically significant difference was observed in histopathological, biochemical, immunohistochemical and immunofluorescent parameters (p < 0.001). An improvement in these parameters was observed in the groups where melatonin was applied along with radiotherapy (p < 0.001). Additionally, no statistically significant difference was found between FF and FFF dose rates (p > 0.05). ConclusionNo significant difference was observed between these low- and high-dose rates of radiotherapy in terms of testicular damage and the effect of melatonin. Further, melatonin may be useful in preventing testicular damage caused by low- and high-dose rate radiotherapy.

White emission metal halides for flexible and transparent x-ray scintillators

Flat-panel x-ray scintillators with a high spatial resolution at a low radiation dose rate are desirable for efficient imaging applications in medical diagnostics, security inspection, and nondestructive inspection. To promote the progress of x-ray imaging technologies, it is of great interest to explore transparent scintillators with reduced light scattering, high light yields, and uniform radioluminescence. Herein, we design and prepare a novel lead-free (C12H28N)2Cu2I4 metal halide featuring a high luminescent efficiency and white emission benefiting from the double self-trapped exciton mechanism, which enable to not only match the response of semiconductor-based sensors but also enhance light yields and decrease exposed doses to objects. Furthermore, transparent, and flexible scintillators with large areas of 20.25 cm2 demonstrate an outstanding scintillation performance including a high spatial resolution of 19.8 lp mm−1 and an ultralow detection limit of 28.39 nGyair s−1, which are ∼4 times higher and 194 times lower than typical values for medical imaging, respectively. This work provides not only a new route to explore promising alternatives with broadband emission but also a novel opportunity to develop flexible x-ray imaging technology.

Pulsed low dose rate radiation to mitigate tumor-permissive responses in pancreatic cancer-associated fibroblasts: Introducing the HOST-factor.

682 Background: Pancreatic ductal adenocarcinoma (PDAC) features a distinctive tumor microenvironment comprising cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix (ECM), forming functional CAF units (CAF u). The current total neoadjuvant therapy (TNT), involving conventional chemoradiotherapy (CRT), yields suboptimal responses while promoting a tumor-permissive CAF u state. To address this, we explored pulsed low dose rate radiation (PLDR)-based TNT, as an alternative to CRT, to treat three-dimensional in vivo-like human PDAC CAF u cultures. We assessed gemcitabine combined with PLDR versus CRT using theHOST Factor, a “harmonized output of stroma traits” factor, comprising several established CAF u functional indicators, which inform on the functional status of the PDAC microenvironment. Methods: The unique CAF u functional values used corresponded to: i) ECM anisotropy; ii) persistent cell-ECM signaling; iii) sustained cytokine-induced activation; iv) cytoskeletal bundling; and v) systemic features of fibroblastic activation. The validity of the resultant HOST factor was assessed using the unit’s ECM ability to elicit fibroblastic activation, indicated by a high αSMA/F-actin ratio value. Results: Ex-vivo CRT led to a HOST factor that was 2-fold greater than chemotherapy alone (p=0.6), which was functionally gauged as a tumor-permissive CAF u. In contrast, PLDR averted CRT-induced tumor-permissive response and established a 6-fold lower HOST factor, suggestive of a “normalized” CAF u, when compared to the HOST factor value established when using conventional TNT (P=0.0016 vs. CRT, and P= 0.0086 vs. gemcitabine alone). The multi-parameter HOST factor validity was confirmed as CRT treated CAF u’s ECM activated human pancreatic fibroblasts (αSMA/F-actin = 70% ± 29) while PLDR-treated CAF u's ECM failed to do so (αSMA/F-actin = 32% ± 26), reaching a 30% mean rank difference (P &lt;0.0001). Conclusions: PLDR mitigates conventional CRT-based TNT-induced tumor-permissive responses, restoring the fibroblastic units' tumor-suppressive function. These results lend support to a phase 1 trial designed to evaluate whether radiation with PLDR-based TNT, constitutes a safe and more effective treatment for PDAC patients. The novel HOST factor is being used to appraise specimens from NCT04452357.

Exploring DNA repair deficient CHO cell response to low dose rate radiation

IntroductionDNA double-strand breaks (DSBs) induced by ionizing radiation pose a significant threat to genome integrity, necessitating robust repair mechanisms. This study explores the responses of repair-deficient cells to low dose rate (LDR) radiation. Non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways play pivotal roles in maintaining genomic stability. The hypothesis posits distinct cellular outcomes under LDR exposure compared to acute radiation, impacting DNA repair mechanisms and cell survival. Materials and methodsChinese hamster ovary (CHO) cells, featuring deficiencies in NHEJ, HR, Fanconi Anemia, and PARP pathways, were systematically studied. Clonogenic assays for acute and LDR gamma-ray exposures, cell growth inhibition analyses, and γ-H2AX foci assays were conducted, encompassing varied dose rates to comprehensively assess cellular responses. ResultsNHEJ mutants exhibited an unexpected inverse dose rate effect, challenging conventional expectations. HR mutants displayed unique radiosensitivity patterns, aligning with responses to major DNA-damaging agents. LDR exposure induced cell cycle alterations, growth delays, and giant cell formation, revealing context-dependent sensitivities. γ-H2AX foci assays indicated DSB accumulation during LDR exposure. DiscussionThese findings challenge established paradigms, emphasizing the intricate interplay between repair pathways and dose rates. The study offers comprehensive insights into repair-deficient cell responses, urging a reevaluation of conventional dose-response models and providing potential avenues for targeted therapeutic strategies in diverse radiation scenarios.