In a radiation exposure event, a likely scenario may include either total-body irradiation (TBI) or different partial-body irradiation (PBI) patterns. Knowledge of the exposure pattern is expected to improve prediction of clinical outcome. We examined miRNA species in 17 irradiated baboons receiving an upper-body, left hemibody or total-body irradiation of 2.5 or 5 Gy. Blood samples were taken before irradiation and at 1, 2, 7, 28 and 75–106 days after irradiation. Using a qRT-PCR platform for simultaneous detection of 667 miRNAs, we identified 55 miRNAs over all time points. Candidate miRNAs, such as miR-17, miR-128 or miR-15b, significantly discriminated TBI from different PBI exposure patterns, and 5-to-10-fold changes in gene expression were observed among the groups. A total of 22 miRNAs (including miR-17) revealed significant linear associations of gene expression changes with the percentage of the exposed body area (P < 0.0001). All these changes were primarily observed at day 7 postirradiation and almost no miRNAs were detected either before or after 7 days. A significant association in the reduction of lymphocyte counts in TBI compared to PBI animals corresponded with the number of miRNA candidates. This finding suggests that our target miRNAs predominantly originated from irradiated lymphocytes. In summary, gene expression changes in the peripheral blood provided indications of the exposure pattern and a suggestion of the percentage of the exposed body area.

To monitor radiocesium activity in skeletal muscle of live cattle, the animals were given radiocesium-contaminated feed continuously, then switched to contamination-free feed after radiocecium concentration in peripheral blood (PB) reached plateau. Radioactivity in skeletal muscles of neck and rump was measured by attaching the probe of a NaI survey meter closely on the body surface just above the muscle of the live cattle (external measurement). We validated the strong positive correlation between the value of the external measurement and radiocesium activity concentration of dissected muscle (r = 0.89, P < 0.001 for neck; r = 0.80, P < 0.001 for rump). Accumulation of radiocesium both in muscle and PB was proportional to the total amount of radiocesium cattle ingested. However, radioactivity concentration in PB was constant in the cattle that had continuously ingested radiocesium, lower than 2.0 × 10⁵ Bq in total within 67 days from the beginning of radiocesium intake. In addition, the ratio of radiocesium activity in muscle to that in PB was lower during the time when radiocontaminated feed was ingested than that of contamination-free feed ingestion. Using the correlation of radioactivity between muscle and PB, we confirmed that a majority of the cattle in the ex-evacuation zone of the Fukushima Daiichi nuclear power plant accident, from 167 to 365 days after the accident occurred, were in the declining period of radiocesium intake.

Acute radiation syndrome (ARS) occurs as a result of partial- or whole-body, high-dose exposure to radiation in a very short period of time. Survival is dependent on the severity of the hematopoietic sub-syndrome of ARS. In this study, we investigated the mitigating effects of a lipid molecule, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), on the kinetics of hematopoietic cells, including absolute neutrophil count (ANC), red blood cells (RBCs) and platelet counts, in mice after gamma-ray total-body irradiation (TBI). Male and female BALB/c mice (11 weeks old) received a LD_70/30 dose of TBI. PLAG significantly and dose-dependently attenuated radiation-induced mortality (P = 0.0041 for PLAG 50 mg/kg; P < 0.0001 for PLAG 250 mg/kg) and body weight loss (P < 0.0001 for PLAG 50 and 250 mg/kg) in mice. Single-fraction TBI sharply reduced ANC within 3 days postirradiation and maintained the neutropenic state (ANC < 500 cells/µl) by approximately 26.8 ± 0.8 days. However, administration of PLAG attenuated radiation-induced severe neutropenia (ANC < 100 cells/µl) by effectively delaying the mean day of its onset and decreasing its duration. PLAG also significantly mitigated radiation-induced thrombocytopenia (P < 0.0001 for PLAG 250 mg/kg) and anemia (P = 0.0023 for PLAG 250 mg/kg) by increasing mean platelet and RBC counts, as well as hemoglobin levels, in peripheral blood. Moreover, delayed administration of PLAG, even at 48 and 72 h after gamma-ray irradiation, significantly attenuated radiation-induced mortality in a time-dependent manner. When compared to olive oil and palmitic linoleic hydroxyl (PLH), only PLAG effectively attenuated radiation-induced mortality, indicating that it has a distinctive mechanism of action. Based on these preclinical observations, we concluded that PLAG has high potential as a radiation countermeasure for the improvement of survivability and the treatment of hematopoietic injury in gamma-ray-induced ARS.

Radiation-induced acute myeloid leukemia (rAML) in C3H mice is commonly developed through inactivation of PU.1 transcription factor encoded in Sfpi1 on chromosome 2. PU.1 inactivation involves two steps: hemizygous deletion of the Sfpi1 gene (DSG) and point mutation of the allele Sfpi1 gene (PMASG). In this study, we investigated the dose-rate dependence of the frequency of both DSG and PMASG in hematopoietic stem cells (HSCs) of C3H mice that received a total of 3 Gy gamma-ray exposure at dose rates of 20 mGy/day, 200 mGy/day or 1,000 mGy/min. All mice were followed for 250 days from start of irradiation. Fluorescent in situ hybridization of the Sfpi1 gene site indicated that frequency of HSCs with DSG was proportional to dose rate. In cell surface profiles, PU.1-inactivated HSCs by both DSG and PMASG were still positive for PU.1, but negative for GM-CSF receptor-α (GMCSFRα), which is transcriptionally regulated by PU.1. Immunofluorescent staining analysis of both PU.1 and GM-CSFRα also showed dose-rate-dependent levels of PU.1-inactivated HSCs. This study provides evidence that both DSG and PMASG are dose-rate dependent; these experimental data offer new insights into the dose-rate effects in HSCs that can lead to radiation-induced leukemogenesis.

MicroRNAs (miRNAs) have been shown to play a pivotal role in the pathogenesis and maintenance of liver fibrosis by altering expression of their downstream target genes. However, their role in radiation-induced liver fibrosis has not been assessed in detail. Here, we investigated the role of miR-146a-5p and the target gene in regulation of fibrosis-related markers in the human hepatic stellate cell line LX2. LX2 cells were stimulated with 8 Gy of X rays and various concentrations of TGF-β1 (0–5 ng/ml). Expression of α-SMA, collagen 1 and miR-146a-5p was evaluated. The MiR-146a-5p target gene predictions were performed using bioinformatics analysis and confirmed by dual-luciferase reporter experiment. The effect of miR-146a-5p and the involved target gene on the expression of these fibrogenic molecules was also assessed. Expression of α-SMA and collagen 1 were upregulated in response to radiation and/or TGF-β1 treatment and miR-146a-5p levels were altered in LX2 cells. Restoration of miR-146a-5p expression suppressed expression of α-SMA and collagen 1 in irradiated and TGF-β1-treated LX2 cells. Subsequent mechanism experiments revealed that miR-146a-5p overexpression inhibited PTPRA expression by binding to its 3′-untrans-lated region and reduced SRC activation. In addition, enhancement of PTPRA partially reversed the suppressive effect of miR-146a-5p on α-SMA and collagen 1 expression in LX2 cells. In conclusion, miR-146a-5p may negatively regulate the PTPRA-SRC signaling to inhibit expression of fibrosis-related markers in irradiated and TGF-β1-stimulated LX2 cells.

Occupational contamination is a potential health risk associated with plutonium inhalation. DTPA remains the chelating drug of choice to decorporate plutonium. In this study, plutonium was found to be more effectively removed from lungs by a single inhalation of nebulized DTPA solution at only 1.1 µmol.kg^–1 than by a single intravenous (i.v.) dose of DTPA at 15 µmol.kg^–1. When DTPA was inhaled promptly after contamination, it removed the transportable fraction of plutonium prior blood absorption, thereby preventing both liver and bone depositions. Conversely, DTPA injection was better than inhalation at reducing the extrapulmonary burden, probably due to the much greater circulating dose, favoring the mobilization of plutonium already translocated. Thus, prompt inhalation, concomitantly supplemented with i.v. injection, of DTPA induced an important decrease in extrapulmonary deposits. Repeated DTPA inhalations over several weeks were more efficient than a single inhalation in limiting both pulmonary and extrapulmonary plutonium retention, due at least in part to the chelation of the transportable fraction of lung plutonium. Furthermore, repeated DTPA injections remained better at reducing liver and bone plutonium retentions. Taken together, our results suggest that multiple DTPA inhalations may be considered an effective treatment after inhalation of plutonium, particularly given the ease of this needle-free delivery, for the two following conditions: 1. A treatment combining i.v. injection and inhalation should be given in an emergency scenario to efficiently chelate the activity already absorbed; 2. Inhalations should be administered daily to effectively trap the early transferable fraction.

In the event of a radiological or nuclear attack, advanced clinical countermeasures are needed for screening and medical management of the exposed population. Such a population will represent diverse heterogeneity in physiological response to radiation exposure. The current study seeks to compare the expression levels of five previously established proteomic biodosimetry biomarkers of radiation exposure, i.e., Flt3 ligand (FL), matrix metalloproteinase 9 (MMP9), serum amyloid A (SAA), pentraxin 3 (PTX3) and fibrinogen (FGB), across multiple murine strains and to test a multivariate dose prediction model based on a single C57BL6 strain against other murine strains. Female mice from five different murine strains (C57BL6, BALB/c, C3H/HeJ, CD2F1 and outbred CD-1 mice) received a single whole-body dose of 1–8 Gy from a Pantak X-ray source at a dose rate of 3.59 Gy/min. Plasma was collected by cardiac puncture at days 1, 2, 3 and 7 postirradiation. Plasma protein levels were determined via commercially available ELISA assay. Significant differences were found between radiation-induced expression levels of FL, MMP9, SAA, PTX3 and FGB among the C57BL6, BALB/c, C3H/HeJ, CD2F1 and CD-1 strains (P < 0.05). The overall trends of dose-dependent biomarker elevation, however, were similar between strains, with FL and PTX3 showing the highest degree of correlation. Application of a previous C57BL6 multivariate dose prediction model using additional murine strains showed the limitations of a model based on a single strain and the need for data normalization for variance generated by technical assay variables. Our findings indicate that strain specific differences do exist between expression levels of FL, MMP9, SAA, PTX3 and FGB in C57BL6, BALB/c, C3H/HeJ, CD2F1 and CD-1 murine strains and that use of multiple biomarkers for dose prediction strengthens the predictive accuracy of a model when challenged with a heterogeneous population.

Assessment of health effects from low-dose radiation exposures in patients undergoing diagnostic imaging is an active area of research. High-quality dosimetry information pertaining to these medical exposures is generally not readily available to clinicians or epidemiologists studying radiation-related health risks. The purpose of this study was to provide methods for organ dose estimation in pediatric patients undergoing four common diagnostic fluoroscopy procedures: the upper gastrointestinal (UGI) series, the lower gastrointestinal (LGI) series, the voiding cystourethrogram (VCUG) and the modified barium swallow (MBS). Abstracted X-ray film data and physician interviews were combined to generate procedure outlines detailing X-ray beam projections, imaged anatomy, length of X-ray exposure, and presence and amount of contrast within imaged anatomy. Monte Carlo radiation transport simulations were completed for each of the four diagnostic fluoroscopy procedures across the 162-member (87 males and 75 females) University of Florida/National Cancer Institute pediatric phantom library, which covers variations in both subject height and weight. Absorbed doses to 28 organs, including the active marrow and bone endosteum, were assigned for all 162 phantoms by procedure. Additionally, we provide dose coefficients (DCs) in a series of supplementary tables. The DCs give organ doses normalized to procedure-specific dose metrics, including: air kerma-area product (µGy/mGy · cm²), air kerma at the reference point (µGy/µGy), number of spot films (SF) (µGy/number of SFs) and total fluoroscopy time (µGy/s). Organs accumulating the highest absorbed doses per procedure were as follows: kidneys between 0.9–25.4 mGy, 1.1–16.6 mGy and 1.1–9.7 mGy for the UGI, LGI and VCUG procedures, respectively, and salivary glands between 0.2–3.7 mGy for the MBS procedure. Average values of detriment-weighted dose, a phantom-specific surrogate for the effective dose based on ICRP Publication 103 tissue-weighting factors, were 0.98 mSv, 1.16 mSv, 0.83 mSv and 0.15 mSv for the UGI, LGI, VCUG and MBS procedures, respectively. Scalable database of organ dose coefficients by patient sex, height and weight, and by procedure exposure time, reference point air kerma, kerma-area product or number of spot films, allows clinicians and researchers to compute organ absorbed doses based on their institution-specific and patient-specific dose metrics. In addition to informing on patient dosimetry, this work has the potential to facilitate exposure assessments in epidemiological studies designed to investigate radiation-related risks.

Previously reported studies have revealed that the application of a magnetic field longitudinal to a carbon-ion beam enhances its biological effectiveness. Here we investigated how timing of the magnetic field application with respect to beam irradiation influenced this effect. Human cancer cells were exposed to carbon-ion beams with linear energy transfer (LET) of 12 and 50 keV/µm. The longitudinal magnetic field of 0.3 T was applied to the cells just before, during or immediately after the beam irradiation. The effects of the timing on the biological effectiveness were evaluated by cell survival. The biological effectiveness increased only if the magnetic field was applied during beam irradiation for both LETs.

Radiation therapy is one of the pillars of cancer treatment, with approximately one half of all cancer patients receiving it as part of their standard of care. Emerging evidence indicates that the biological effects of radiation are not limited to targeted cells. The radiation-induced bystander effect (RIBE) refers to the plethora of biological phenomena occurring in nonirradiated cells as a result of signal transmission from an irradiated cell. Experimental evidence has linked RIBE to numerous hallmarks of cancer including resisting cell death, tumor immune evasion, genomic instability, deregulated cellular energetics, tumor-promoting inflammation and sustained proliferative signaling as well as enhanced radioresistance, thus highlighting the potential role of RIBE events in patient treatment response. The mechanisms underlying RIBE events in vivo are poorly understood. However, elucidating the molecular mechanisms involved in their manifestation may reveal novel therapeutic targets to improve radiation response in cancer patients.