Experimental studies of cognitive detriments in mice and rats after proton and heavy ion exposures have been performed by several laboratories to investigate possible risks to astronauts exposed to cosmic rays in space travel and patients treated for brain cancers with proton and carbon beams in Hadron therapy. However, distinct radiation types and doses, cognitive tests and rodent models have been used by different laboratories, while few studies have considered detailed dose-response characterizations, including estimates of relative biological effectiveness (RBE). Here we report on the first quantitative meta-analysis of the dose response for proton and heavy ion rodent studies of the widely used novel object recognition (NOR) test, which estimates detriments in recognition or object memory. Our study reveals that linear or linear-quadratic dose-response models of relative risk (RR) do not provide accurate descriptions. However, good descriptions for doses up to 1 Gy are provided by exponentially increasing fluence or dose-response models observed with an LET dependence similar to a classical radiation quality response, which peaks near 100–120 keV/µm and declines at higher LET values. Exponential models provide accurate predictions of experimental results for NOR in mice after mixed-beam exposures of protons and ⁵⁶Fe, and protons, ¹⁶O and ²⁸Si. RBE estimates are limited by available X-ray or gamma-ray experiments to serve as a reference radiation. RBE estimates based on use of data from combined gamma-ray and high-energy protons of low-LET experiments suggest modest RBEs, with values <8 for most heavy ions, while higher values <20 are based on limited gamma-ray data. In addition, we consider a log-normal model for the variation of subject responses at defined dose levels. The log-normal model predicts a heavy ion dose threshold of approximately 0.01 Gy for NOR-related cognitive detriments.

Radiation therapy is a mainstream strategy in the treatment of several cancer types that are surgically unresectable. Unfortunately, cancer patients often suffer from unintended consequences of radiotherapy, including the development of skin inflammation (dermatitis), which may progress to fibrosis. These morbid complications often require interruption of radiotherapy and threaten the relapse of underlying cancer. Current treatment options for radiation dermatitis are suboptimal and compel the need to develop safer, more effective therapies. In this study, we assessed the biophysical properties of topically-formulated esomeprazole (here referred to as dermaprazole) and performed proof-of-concept studies to evaluate its efficacy in vitro and in vivo. We found that dermaprazole induced nuclear translocation of erythroid 2-related factor 2 (Nrf2) and significantly upregulated heme oxygenase 1 (HO1) gene and protein expression in a 3D human skin model. Our animal study demonstrated that dermaprazole improved macroscopic appearance of the irradiated skin and accelerated healing of the wounds. Histopathology data corroborated the photographic evidence and confirmed that both prophylactically and therapeutically administered dermaprazole conferred potent anti-inflammatory and antifibrotic effects. Gene expression data showed that dermaprazole downregulated several pro-oxidant, pro-inflammatory and profibrotic genes. In conclusion, topical formulation of the FDA-approved drug esomeprazole is highly effective in attenuating dermal inflammation and fibrosis.

A biologically motivated mathematical model of the dynamics of the small intestinal epithelium in humans treated with fractionated radiotherapy has been developed and is further investigated here. This model, originating from our previous work, is implemented as a system of nonlinear ordinary differential equations, in which the variables and parameters have a clear biological meaning. The model also includes, as input, the key parameters of fractionated irradiation. The modeling results on the dynamical response of the human normal small intestinal epithelium to fractionated radiation therapy regimens were in agreement with the corresponding empirical data, which, in turn, demonstrates the capability of the developed model for predicting the dynamics of this vital body system in humans receiving fractionated radiotherapy. It is also revealed that the cumulative damage effects of hypofractionated radiation therapy regimens on the human normal small intestinal epithelium are somewhat less pronounced than those of conventional fractionated radiation therapy regimens with the same total doses.

Irradiators utilizing radioactive cesium-137 (¹³⁷Cs) or cobalt-60 (⁶⁰Co) gamma-ray sources have been used for biological applications for many decades. These applications include irradiation of much of the nation's blood supply and radiation biology research. In 2005, the U.S. Nuclear Regulatory Commission was assigned the task of preventing the misuse of radioactive materials by persons with malicious intentions; gamma-ray sources, in particular, were given high priority. This resulted in increased security requirements, including constant surveillance, controlled access and personnel background checks. As a result of such regulations being introduced, organizations considering the purchase of a gamma-ray irradiator for the first time or as a replacement to an existing one due to radioactive decay, are now looking into alternative technologies, primarily an X-ray irradiator. To make an educated decision on whether a particular type of X-ray irradiator is of sufficient equivalency to a particular type of ¹³⁷Cs irradiator for specific applications, one must rely on relevant published comparison studies from other researchers, or perform the comparison studies on their own. This work focuses on the comparison of the radiation physics aspects of two ¹³⁷Cs irradiator models and three X-ray irradiator models, for the purpose of determining whether the X-ray irradiator models could validly replace the ¹³⁷Cs irradiator models for certain applications. Although evaluating the influence of relative biological effectiveness (RBE) differences among irradiators could be part of this study, that has been left for a related publication focused on the theoretical aspects of this topic. These evaluations were performed utilizing 47-g and 120-g tissue-equivalent rodent dosimetry phantoms. Our results indicate that, depending upon the user's dose uncertainty budget and maximum areal density of specimens to be irradiated, the RS 2000 160 kVp X-ray irradiator, X-RAD160 X-ray irradiator or X-RAD320 X-ray irradiator could successfully replace a ¹³⁷Cs irradiator. Technically, any X-ray irradiator model providing similar irradiation geometry, and average energy similar to or higher than these three X-ray models, could also successfully replace a ¹³⁷Cs irradiator. The results also reveal that differences in inherent source geometry, field geometry and irradiation geometry can counter some of the influence due to differences in energy spectrum. Our goal is that this publication be used as a guide for other similar studies, providing investigators with information on important details that can make the difference between strong and weak comparison conclusions.

The imprecise estimation of the relative biological effectiveness (RBE) of proton radiation has been one of the main challenges for further calculating the biologically effective dose in proton therapy. Since dose levels can greatly influence the proton RBE, the relationship between the two should be clarified first. In addition, since the dose-response curves are usually too complex to readily assess RBE in high-dose regions, a reliable and simple method is needed to predict the RBE of proton radiation accurately in clinically relevant doses. The standard linear-quadratic (LQ) model is widely used to determine the RBE of particles for clinical applications. However, there has been some debate over its use when modeling the cell survival curves in high-dose regions, since those survival curves usually show linear behavior in the semilogarithmic plot. By considering both cellular repair effects and indirect effects of radiation, we have proposed a generalized target model with linear-quadratic linear (LQL) characteristics. For the more accurate evaluation of proton RBE in radiotherapy, here we used this generalized target model to fit the cell survival data in V79 and C3H 10T1/2 cells exposed to proton radiation with different LETs. The fitting results show that the generalized target model works as well as the LQ model in general. Based on the fitting parameters of the generalized target model, the RBE of six given doses D_T (RBE_T) could be calculated in the corresponding cell lines with different LETs. The results show that the RBE_T gradually decreases with increased dose in both cell types. In addition, inspired by the calculation method of the maximum values of RBE (RBE_M) in the low-dose region, a novel method was proposed for estimating the RBE in the high-dose region (RBE_H) based on the slope ratio of the dose-response curves in this region. Linear regression analysis indicated a significant linear correlation between the proposed RBE_H and the RBE_T in high-dose regions, which suggests that the current method can be used as an alternative tool, which is both simple and robust, to estimate RBE in high-dose regions.

At low doses, ionizing radiation activates endothelial cells and promotes angiogenesis. However, it is still unknown if other cells may contribute to this process. In this study, the effect of low-dose ionizing radiation (LDIR) in modulating the pro-angiogenic potential of adipocytes was investigated. Adipocytes are known to secrete multiple angiogenic factors and adipokines that induce angiogenesis. In this work, a confluent monolayer of 3T3-L1 pre-adipocytes was exposed to low doses (0.1 and 0.3 Gy) and to higher doses (0.5, 0.8 and 1.0 Gy), as control. Our data show that the adipocyte-conditioned media (A-CM) from mature adipocytes differentiated from low-dose irradiated pre-adipocytes presented a higher angiogenic potential, compared to mature adipocytes differentiated from sham-irradiated control preadipocytes. The vascular endothelial growth factor (VEGF)-A levels were significantly increased in A-CM from the 0.1 Gy (P < 0.05) and 0.3 Gy (P < 0.01) experimental conditions and a significant increase was found in response to 0.3 Gy dose of radiation for VEGF-C, angiopoietin-2 (ANG-2) and hepatocyte growth factor (HGF). Moreover, 0.3 Gy dose of radiation significantly increased the expression of matrix metalloproteinase (MMP)-2 active forms. In vitro, the A-CM from the 0.1 and 0.3 Gy doses experimental conditions significantly accelerated endothelial cell migration after an in vitro wound healing assay. Importantly, in vivo, the A-CM corresponding to the 0.3 Gy experimental condition significantly induced the growth of more blood vessels towards the inoculation area in the chick embryo chorioallantoic membrane (CAM). In conclusion, this work reveals a new mechanism by which low-dose radiation might promote angiogenesis, enhancing the angiogenic potential of A-CM.

While the link between risk of leukemia and acute radiation exposure is well established for large doses received acutely, uncertainty remains around the translation of these risk estimates to occupational exposure scenarios where the doses are low and accumulated over time, possibly over many years. We present leukemia incidence and mortality radiation risk estimates derived from the National Registry for Radiation Workers, which is a large cohort of occupationally exposed workers from the United Kingdom (UK). The cohort comprised 173,081 workers from the UK who were monitored for occupational exposure to radiation. The cohort was followed for a total of 5.3 million person-years and the incidence and mortality due to leukemia was identified through to the end of follow-up in 2011. Poisson regression was used to investigate the relationship between cumulative radiation dose and leukemia mortality and incidence rates using excess relative risk (ERR) and excess additive risk (EAR) models. The results of this work showed a collective dose of 4,414 person-Sv accumulated by the cohort with an average cumulative dose of 25.5 mSv. Among male workers both the ERR and EAR models showed evidence of increased leukemia risk (excluding chronic lymphatic leukemia) associated with increasing cumulative dose. The ERR was 1.38 per Sv (90% CI: 0.04; 3.24) and EAR was 1.33 per 10,000 person-year-Sv (90% CI: 0.04; 2.89) when a linear model was used. These excess risks were driven by increased risks for chronic myeloid leukemia [ERR/Sv = 6.77 (90% CI: 2.14; 15.44)]. In conclusion, this study provides further evidence that leukemia risks may be increased by low-dose and protracted external radiation exposure. The risks are generally consistent with those observed in the atomic bomb survivor studies, as well as with risk coefficients on which international radiation safety standards, including the dose limits and constraints used to control exposures, are based.

An important cohort of the atomic bomb survivors are women who were pregnant when exposed to the photon and neutron fields at both Hiroshima and Nagasaki, as well as their children who were exposed in utero. Estimates of organ dose to the developing fetus allow for the development of dose-dependent and gestational age-dependent models of deterministic (e.g., organ malformation) and stochastic (e.g., leukemia) risk of in utero exposure. To date, both the 1986 and 2002 dosimetry systems at the Radiation Effects Research Foundation have utilized the uterine wall in the non-pregnant adult female as a dose surrogate for individual fetal organs and tissues. Here we present a new J45 (Japanese 1945) series of high-resolution phantoms of the adult pregnant female at 8-, 15-, 25- and 38-weeks post-conception. These models, which were derived from the University of Florida (UF) series of ICRP Publication 89 compliant reference phantoms, have been rescaled to approximate the pregnant mother using 1945 Japanese morphometry data. Fetal and maternal organ doses were estimated by computationally exposing the pregnant female phantom series to DS02 free-in-air photon and neutron fluences at three distances from the hypocenter at both Hiroshima and Nagasaki under frontal (AP) and isotropic (ISO) particle incidence. As for the fetal organ doses, our results indicate that the uterine wall of the non-pregnant female generally underestimates fetal organ dose within the pregnant female. The magnitude of these differences varies with both radiation type and irradiation geometry, with the smallest differences (5–7%) seen for ISO photon fields and the largest differences (20–30%) seen for AP neutron fields. Significant discrepancies were seen in fetal brain dose and its uterine wall surrogate, particularly for photon AP fields (ratio of uterine wall to brain dose varied from 0.9 to 1.3) and neutron AP fields (dose ratios from 0.75 to 2.0). As for the maternal organ doses, the use of organ doses in a non-pregnant female was shown, in general, to overestimate the corresponding organ doses in the pregnant female, with greater deviations seen at later stages of pregnancy (12–16% for AP photons and 44–53% for AP neutrons). The one exception was the uterine wall dose in pregnancy which was seen to be underestimated by that in the non-pregnant female phantom, particularly for ISO and AP neutron fields. These results demonstrate that the J45 pregnant female phantom series offers the opportunity for significant improvements in both fetal and maternal organ dose assessment within this unique cohort of the atomic bomb survivors.

In this work, we compared the genomic distribution of common radiation-induced chromosomal breaks to eight different data sets covering the whole human genome. Sites with a high probability of chromatid breakage after exposure to low and high ionization density radiations were often located inside common and rare fragile sites, indicating that they may be a new and more local type of DNA repair-related fragility. Breaks in specific chromosome bands after acute exposure to oil and benzene also showed strong correlation with these sites and fragile sites. In addition, close correlation was found with cytologically detected chiasma and MLH1 immunofluorescence sites and with the HapMap recombination density distributions. Also, of interest, copy number changes occurred predominantly at radiation-induced breaks and fragile sites, at least for breast cancers with poor prognosis, and they decreased weakly but significantly in regions with increasing recombination and CpG density. An increased CpG density is linked to regions of high gene density to secure high-fidelity reproduction and survival. To minimize cancer induction, cancer-related genes are often located in regions of decreased recombination density and/or higher-than-average CpG density. It is compelling that all these data sets were influenced by the cells' handling of double-strand breaks and, more generally, DNA damage on its genome. In fact, the DNA repair genes systematically avoid regions with a high recombination density, as they need to be intact to accurately handle repairable DNA lesions.