Radiation research最新文献

Radon gas is a naturally occurring substance and contributes significantly to the public background radiation dose. It is widely accepted that radon has harmful effects, being considered the second leading cause of lung cancer after smoking; however, studies also indicate that exposure to low doses may have beneficial effects. As the debate continues, robust animal models are essential to investigate the effects of low-dose radon exposure on biological systems. In this study, we examined the temporal effects of low and regulated levels of radon (400 Bq/m3 and 1,000 Bq/m3) on the lungs of a healthy in vivo rat model using our specially designed radon chamber. Rats were housed with or without radon gas in the chamber for durations of 18 h, 90 h, 2 × 90 h, or 4 × 90 h. After exposure, a tracheotomy under anesthesia was performed, and respiratory function was assessed using a small animal ventilator. Rats were humanely euthanized, tissues were removed, and immunological and biological outcomes were evaluated. Our results demonstrate that the inhalation of radon and its decay products results in subsequent molecular activation in this system, establishing a model for low-level radon exposure in a healthy animal, and suggest that low and regulated levels of radon exposure for up to 4 weeks do not lead to biologically significant negative health outcomes. This model will facilitate further investigation into the role of radon in cancer development and its potential therapeutic applications in alleviating symptoms of inflammatory conditions.

Small cell lung cancer (SCLC) has a 6% 5-year overall survival rate. C-X-C chemokine receptor 4 (CXCR4) is an attractive target for theranostic agents, is highly expressed in SCLCs, and can be targeted with pentixather using the theranostic pair 212Pb/203Pb. The hypothesis that 212Pb/203Pb-pentixather can be used safely and effectively for imaging and therapy in SCLC in xenograft models was tested. SPECT-CT imaging and biodistribution studies of tumor-bearing mice injected with 203Pb-pentixather demonstrated CXCR4 expression-dependent uptake and accumulation of radioligand in the kidneys and livers. Dosimetry calculations were performed to estimate 212Pb-pentixather uptake in tumor and normal tissue. 212Pb-Pentixather treatment (37-111 kBq/g) of SCLC xenografts (DMS273 and H69AR) significantly prolonged survival and delayed tumor growth. CBCs of mice at 30 days after treatment demonstrated adequate retention of bone marrow function. NSG mice allografted with human hCD34+ bone marrow were treated with 212Pb-pentixather (37-111 kBq/g) to assess damage to human hematopoietic stem cells, demonstrating cytopenias in peripheral blood CBCs at 13-18 days after treatment, resolving by days 28-31. Flow cytometry of bone marrow in these animals at days 28-31 demonstrated a significantly reduced frequency of the human hematopoietic marker CD45 and reconstitution of the bone marrow with murine CD45+ lineages. 203Pb-Pentixather can be used to image CXCR4-expressing SCLC xenografts. Treatment with high-LET alpha emitter 212Pb-pentixather significantly prolonged overall survival, and recovery of mouse bone marrow from 212Pb-pentixather was significantly greater than that of human bone marrow.

The threat and consequences of nuclear or radiological events remain a military concern today. It is estimated that 65-70% of weapon-related injuries after a nuclear event will be radiation combined injuries, i. e., acute radiation injury along with hemorrhage and traumatic injuries such as blast or other burns, bone fractures, soft tissue injuries, blood loss, and/or hypoxia. However, little is known about most types of traumatic injuries associated with blood loss, as might occur during combat operations. The primary objective of this pilot study was to develop a new animal model that incorporates both hemorrhage and traumatic injury, combined with radiation exposure. Male Sprague-Dawley rats were divided into four groups (6/group): 1. sham; 2. radiation injury (RI); 3. traumatic hemorrhage (TH), which is hemorrhage combined with extremity trauma; and 4. RI+TH. Radiation injury consisted of a single X-ray dose of 5. 5.5 Gy delivered at a rate of 1 Gy/min. Hemorrhage involved a stepwise reduction of 37% of the estimated blood volume. Extremity trauma consisted of fibular fractures and penetrating and soft tissue injuries to a single extremity. Heart rate, mean arterial blood pressure (MAP), and blood indices were analyzed at intervals corresponding to pre-hemorrhage, end of hemorrhage, and 4 h after hemorrhage, with survival observed for 14 days. Radiation injury alone had little impact on the measured variables. Hemorrhage resulted in a 60% and 67% reduction in MAP in the traumatic hemorrhage and RI+TH groups, respectively, immediately after hemorrhage, which recovered by 4 h in the traumatic hemorrhage group but not in RI+TH group. A similar pattern was observed for blood lactate levels. Traumatic hemorrhage and radiation injury resulted in 50% mortality, although mortality occurred earlier after traumatic hemorrhage. RI+TH produced 80% mortality by day 4. No mortality was observed in the sham group. By combining a high dose of X-ray radiation with our established model of traumatic hemorrhage, we have developed a new rodent model that mimics combat casualties during nuclear or radiological events.

This study investigated whether therapeutic doses of X rays can affect the expression of mismatch repair (MMR) genes and proteins using Lynch syndrome-associated human colorectal cancer cell lines. MMR-deficient cell lines (HCT116, SW48, LoVo) and an MMR-proficient control cell line (HT29) were exposed to X rays [a 2 Gy dose or 2 Gy daily for five consecutive days (10 Gy)]. Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting were used to detect the radiation-induced changes in the expression of RNAs and proteins, respectively. RT-qPCR revealed that MLH1 and MSH6 genes were stably expressed regardless of the MMR status of the cell line and the radiation dose. In contrast, the MSH2 gene was either up-regulated or down-regulated after 2 Gy or 10 Gy or both. The expression of PMS2 increased after 10 Gy irradiation in all MMR-deficient cell lines, even though the data were not statistically significant compared to other doses, except for the LoVo cell line. Protein expression analysed using Western blotting demonstrated that MLH1 protein expression was stable, whereas the expression of MSH2 was significantly affected by radiation exposure in both MLH1-deficient cell lines. No correlation between the expression of RNA and protein could be identified. In conclusion, radiation may have significantly differential effects on MMR RNA and protein expression when different cell lines, doses, and specific genes are considered.

p53 gene mutations are common in various cancers and may provide insights in predicting tumor radiosensitivity. This study aimed to assess the effect of p53 mutations on radiosensitivity using the intrinsic radiosensitivity index (RSI) across publicly available cancer cohorts. Gene expression data, mutation data, and clinical information were obtained from the Cancer Genome Atlas dataset. RSI, calculated from the expression of 10 specific genes, was used to evaluate radiosensitivity. Additional models were used to assess the tumor microenvironment status. p53 mutations were prevalent in several types of cancer. Notably, RSI models indicated reduced predicted radiosensitivity in patients with p53 mutations compared to those without mutations, only in head and neck squamous cell carcinoma (HNSC). In contrast, p53 mutations did not significantly decrease predicted radiosensitivity in other cancers. The association between p53 mutations and the predicted radioresistant phenotype disappeared when the cohort was controlled for p53 and p16 status in HNSC. Similarly, the estimated tumor microenvironment status was unaffected by p53 mutations. These findings suggest that predicted radiosensitivity is more strongly influenced by p16 status than by p53 mutations, indicating that p53 status alone may not be a reliable predictive marker for radiosensitivity in HNSC.

The radiation environment in space consists of a complex mixture of particles and energies that are characteristically different from any natural Earth radiation source. Projections of space radiation cancer risk are obtained by scaling or adjusting epidemiological models derived from terrestrially exposed cohorts to account for differences in radiation quality, dose rate, and other factors. Radiation quality and dose-rate effects introduce significant uncertainty, thereby obfuscating risk communication and hindering the ability to evaluate the efficacy of mitigation strategies such as medical countermeasures. Space radiation quality factors are developed through a multi-step process that requires computational models and experimental data. The first step in this process involves developing dose-response models and fitting them to data from ground-based experiments involving acute irradiation of animals or cells. There is limited ground-based data compared to the range of ions and energies found in space; thus, dose-response models must be able to reproduce available data and predict responses where no data exist. This work focuses on developing a microdosimetric (μD) dose-response model applicable to experimental datasets relevant to space radiation cancer induction. Three experimental datasets, encompassing murine Harderian gland tumorigenesis and chromosome aberrations in human skin fibroblasts and blood lymphocytes, are utilized to demonstrate key features and overall performance of the μD model. The model generates non-linear dose-responses and can predict charge and energy dependence observed in experimental data without the use of empirical functions or corrections. Additionally, the μD model identifies the critical microscopic target population and target size that drive the observed biological effects.

Radiation therapy is one of the most critical methods for the comprehensive treatment of nasopharyngeal carcinoma (NPC). However, radiation resistance limits the effectiveness of radiotherapy. MicroRNAs (miRNAs) are associated with the radiosensitivity of NPC, but their impacts and mechanisms of action require further investigation. Aberrantly expressed miRNAs were screened in NPC and normal tissue. A series of gain-of-function and loss-of-function experiments were conducted to evaluate the biological behavior of miR-144-3p in NPC cells. The role of miR-144-3p in the proliferation and apoptosis of NPC cells was studied. Downstream mechanisms of miR-144-3p were explored through bioinformatics analysis and RNA sequencing, confirmed by dual-luciferase reporter gene assays. We observed downregulation of miR-144-3p in NPC tissue and radiation-resistant cells. Furthermore, upregulation of miR-144-3p in radiation-resistant cells suppressed the enhancement of radiosensitivity in NPC cells. Conversely, inhibiting miR-144-3p decreased radiosensitivity. We also found that miR-144-3p directly targets nuclear factor erythroid 2-related factor 2 (NFE2L2) and inhibits its expression. The results of this study indicate that the miR-144-3p/Nrf2 pathway contributes to reducing the radioresistance of NPC, making it a potential therapeutic target.

Models used to calculate the relative biological effectiveness (RBE) of carbon-ion radiotherapy include the microdosimetric kinetic model (MKM), stochastic MKM (SMKM), repair-misrepair-fixation (RMF) model, and local effect model I (LEM). We compared the sensitivities of these models to variations in input biological and reference parameters. We used Monte Carlo simulations of clinically realistic carbon-ion beams incident on a phantom and scored input parameters for RBE models (kinetic energy, microdosimetric spectra, double-strand break yield, and physical dose). We combined data with cell- and model-specific parameters to calculate the linear (α) and quadratic (β) components of the carbon-ion beam, which were used along with the reference α and β values and dose to calculate RBE. Model sensitivity to parameters was quantified by statistically introducing uncertainty into independent parameters and sampling the resultant RBE. To assess histological differences contributing to variations in the RBE, we also used various reference cell lines. We recalculated the RBE using different reported datasets within individual cell lines to compare inter- and intra-cell line variability. The variability introduced by inherent measurement and estimation uncertainty was typically 26% for the microdosimetric models, 25% for the RMF model, and 30% for the LEM at the 1-σ level. The variability across cell lines, which averaged 27% for the microdosimetric models and 2.5% for the RMF model, was similar to the intra-cell line variability in the RBE as calculated with unique datasets for an individual cell line. While the focus is largely on comparing models, the results of this study indicate that the variation in RBE within each model, based solely on reference parameters, is substantial. Our findings indicate that the selection of input parameters is of comparable importance to the choice of cell line and even the RBE model. This study provides insight into model robustness and emphasizes the need for continued computational and in-vitro RBE research.

Human occupational exposure to ionizing radiation has been linked to increased risks of developing cancers, including solid tumors. In particular, 239Pu, used in the production of nuclear weapons, has been associated with a higher risk of malignancies of the lungs, liver, and bones, but the specific patterns of malignant histology have not been well described in humans. We assessed the pathological characteristics of liver cancers that occurred in a Russian cohort of nuclear workers from the Mayak Production Association, with a special emphasis on angiosarcoma, and studied the relationships between dosimetry, sex, and histology. The subjects included two main groups of workers whose biological specimens were collected during autopsies: thirty-one were diagnosed with liver cancers (cases), and 38 workers were cancer-free (controls). An independent pathologist reviewed all liver tissues from these cancer cases and performed immunohistochemistry to confirm the diagnoses (angiosarcoma, hepatocellular carcinoma, or cholangiocarcinoma). A third group consisted of 36 workers who developed liver cancer but for whom no biological samples were available. Radiation dose levels, along with sex and age distributions, were compared statistically among the three types of liver tumors and the control groups. There was a predominance of females (9 of 13, 69%) among the workers who developed angiosarcoma of the liver, whereas a male predominance characterized both hepatocellular carcinoma (9 of 9, 100%) and cholangiocarcinoma (8 of 9, 89%). A male predominance was also observed in the group of workers with liver cancer but without biological samples (22 of 36, 61%) and in the group of workers without liver cancer (30 of 38, 79%). Occupational differences were evident, with angiosarcoma patients who had biological samples representing the largest proportion (9 of 13) of plutonium metallurgical plant workers (the most highly exposed occupation to plutonium in the cohort), while the remainder (4 of 13) occurred among the radiochemical plant workers. Compared to other groups, those workers with biological samples who developed angiosarcoma had the largest accumulated and widest range of external doses absorbed by the liver, as well as the highest absorbed doses of 239Pu to the liver. Females with biological samples who developed liver cancer also had some of the highest accumulated doses from 239Pu, exceeding 1 Gy in some instances. Our observations of histology, sex, occupation, and dose patterns provide possible clues to the unusual pattern of liver malignancies, particularly angiosarcoma, related to aspects of plutonium exposure.

This workshop examined the effects of ionizing radiation on certain understudied populations, including pregnant/lactating, in utero, pediatric, and geriatric individual. Research using animal models has revealed significant age- and condition-related differences in radiation-induced injuries, highlighting the need for tailored triage and treatment strategies. Historical data from Hiroshima, Nagasaki, and Chernobyl further support these findings, demonstrating that radiation effects lead to wide-ranging issues with unique profiles during pregnancy, childhood and elderly age. While some research has been conducted on these groups, ethical and logistical challenges make it difficult to study these populations extensively. Therefore, developing alternative approaches that offer promising avenues for further research is critical. Radiation-induced biomarkers and biodosimetry also show age-related differences, including distinctive metabolic disruptions, necessitating further validation of biodosimetry tools. These findings emphasize the importance of considering age, sex, and demographic factors in preclinical and clinical radiation research to develop treatments that improve outcomes of understudied populations after a radiological or nuclear public health emergency.