Limitations in Predicting the Space Radiation Health Risk for Exploration Astronauts

Despite years of research, understanding of the space radiation environment and the risk it poses to long-duration astronauts remains limited. There is a disparity between research results and observed empirical effects seen in human astronaut crews, likely due to the numerous factors that limit terrestrial simulation of the complex space environment and extrapolation of human clinical consequences from varied animal models. Given the intended future of human spaceflight, with efforts now to rapidly expand capabilities for human missions to the moon and Mars, there is a pressing need to improve upon the understanding of the space radiation risk, predict likely clinical outcomes of interplanetary radiation exposure, and develop appropriate and effective mitigation strategies for future missions. To achieve this goal, the space radiation and aerospace community must recognize the historical limitations of radiation research and how such limitations could be addressed in future research endeavors. We have sought to highlight the numerous factors that limit understanding of the risk of space radiation for human crews and to identify ways in which these limitations could be addressed for improved understanding and appropriate risk posture regarding future human spaceflight.Comment: Accepted for publication by Nature Microgravity (2018

Radiation mitigating properties of the lignan component in flaxseed

BACKGROUND: Wholegrain flaxseed (FS), and its lignan component (FLC) consisting mainly of secoisolariciresinol diglucoside (SDG), have potent lung radioprotective properties while not abrogating the efficacy of radiotherapy. However, while the whole grain was recently shown to also have potent mitigating properties in a thoracic radiation pneumonopathy model, the bioactive component in the grain responsible for the mitigation of lung damage was never identified. Lungs may be exposed to radiation therapeutically for thoracic malignancies or incidentally following detonation of a radiological dispersion device. This could potentially lead to pulmonary inflammation, oxidative tissue injury, and fibrosis. This study aimed to evaluate the radiation mitigating effects of FLC in a mouse model of radiation pneumonopathy. METHODS: We evaluated FLC-supplemented diets containing SDG lignan levels comparable to those in 10% and 20% whole grain diets. 10% or 20% FLC diets as compared to an isocaloric control diet (0% FLC) were given to mice (C57/BL6) (n=15-30 mice/group) at 24, 48, or 72-hours after single-dose (13.5 Gy) thoracic x-ray treatment (XRT). Mice were evaluated 4 months post-XRT for blood oxygenation, lung inflammation, fibrosis, cytokine and oxidative damage levels, and survival. RESULTS: FLC significantly mitigated radiation-related animal death. Specifically, mice fed 0% FLC demonstrated 36.7% survival 4 months post-XRT compared to 60–73.3% survival in mice fed 10%-20% FLC initiated 24–72 hours post-XRT. FLC also mitigated radiation-induced lung fibrosis whereby 10% FLC initiated 24-hours post-XRT significantly decreased fibrosis as compared to mice fed control diet while the corresponding TGF-beta1 levels detected immunohistochemically were also decreased. Additionally, 10-20% FLC initiated at any time point post radiation exposure, mitigated radiation-induced lung injury evidenced by decreased bronchoalveolar lavage (BAL) protein and inflammatory cytokine/chemokine release at 16 weeks post-XRT. Importantly, neutrophilic and overall inflammatory cell infiltrate in airways and levels of nitrotyrosine and malondialdehyde (protein and lipid oxidation, respectively) were also mitigated by the lignan diet. CONCLUSIONS: Dietary FLC given early post-XRT mitigated radiation effects by decreasing inflammation, lung injury and eventual fibrosis while improving survival. FLC may be a useful agent, mitigating adverse effects of radiation in individuals exposed to incidental radiation, inhaled radioisotopes or even after the initiation of radiation therapy to treat malignancy

Updating Photon-Based Normal Tissue Complication Probability Models for Pneumonitis in Patients With Lung Cancer Treated With Proton Beam Therapy

Purpose: No validated models for predicting the risk of radiation pneumonitis (RP) with proton beam therapy (PBT) currently exist. Our goal was to externally validate and recalibrate multiple established photon-based normal tissue complication probability models for RP in a cohort with locally advanced nonsmall cell lung cancer treated with contemporary doses of chemoradiation using PBT. Methods and Materials: The external validation cohort consisted of 99 consecutive patients with locally advanced nonsmall cell lung cancer treated with chemoradiation using PBT. RP was retrospectively scored at 3 and 6 months posttreatment. We evaluated the performance of the photon Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) pneumonitis model, the QUANTEC model adjusted for clinical risk factors, and the newer Netherlands updated QUANTEC model. A closed testing procedure was performed to test the need for model updating, either by recalibration-in-the-large (re-estimation of intercept), recalibration (re-estimation of intercept/slope), or model revision (re-estimation of all coefficients). Results: There were 21 events (21%) of ≥grade 2 RP. The closed testing procedure on the PBT data set did not detect major deviations between the models and the data and recommended adjustment of the intercept only for the photon-based Netherlands updated QUANTEC model (intercept update: –1.2). However, an update of the slope and revision of the model coefficients were not recommended by the closed testing procedure, as the deviations were not significant within the power of the data. Conclusions: The similarity between the dose-response relationship for PBT and photons for normal tissue complications has been an assumption until now. We demonstrate that the preexisting, widely used photon based models fit our PBT data well with minor modifications. These now-validated and updated normal tissue complication probability models can aid in individualizing selection of the most optimal treatment technique for a particular patient

Measuring the Physiologic Properties of Oral Lesions Receiving Fractionated Photodynamic Therapy

Photodynamic therapy (PDT) can treat superficial, early‐stage disease with minimal damage to underlying tissues and without cumulative dose‐limiting toxicity. Treatment efficacy is affected by disease physiologic properties, but these properties are not routinely measured. We assessed diffuse reflectance spectroscopy (DRS) for the noninvasive, contact measurement of tissue hemoglobin oxygen saturation (StO2) and total hemoglobin concentration ([tHb]) in the premalignant or superficial microinvasive oral lesions of patients treated with 5‐aminolevulinic acid (ALA)‐PDT. Patients were enrolled on a Phase 1 study of ALA‐PDT that evaluated fluences of 50, 100, 150 or 200 J cm−2 delivered at 100 mW cm−2. To test the feasibility of incorporating DRS measurements within the illumination period, studies were performed in patients who received fractionated (two‐part) illumination that included a dark interval of 90–180 s. Using DRS, tissue oxygenation at different depths within the lesion could also be assessed. DRS could be performed concurrently with contact measurements of photosensitizer levels by fluorescence spectroscopy, but a separate noncontact fluorescence spectroscopy system provided continuous assessment of photobleaching during illumination to greater tissue depths. Results establish that the integration of DRS into PDT of early‐stage oral disease is feasible, and motivates further studies to evaluate its predictive and dosimetric value.Diffuse reflectance spectroscopy with a contact probe was employed as part of a fluorescence and reflectance spectroscopy system to measure the tissue hemoglobin oxygen saturation and hemoglobin content of lesions of premalignant or early microinvasive cancer of the oral cavity. Studies demonstrate the feasibility of incorporating these measurements into treatment with fractionated (two‐part) photodynamic therapy (PDT) using 5‐aminolevulinic acid. Patient‐specific differences in physiologic parameters were detectable at baseline and at times during and after PDT. Photobleaching of photosensitizer was measured by its fluorescence. Results establish the utility of rationally designed spectroscopy probes toward personalized dosimetry in PDT of oral disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/113767/1/php12475.pd

Oncogenic K-Ras Signals through Epidermal Growth Factor Receptor and Wild-Type H-Ras to Promote Radiation Survival in Pancreatic and Colorectal Carcinoma Cells

Pancreatic and colorectal carcinomas frequently express oncogenic/mutant K-Ras that contributes to both tumorigenesis and clinically observed resistance to radiation treatment. We have previously shown that farnesyltransferase inhibitors (FTI) radiosensitize many pancreatic and colorectal cancer cell lines that express oncogenic K-ras at doses that inhibit the prenylation and activation of H-Ras but not K-Ras. In the present study, we have examined the mechanism of FTI-mediated radiosensitization in cell lines that express oncogenic K-Ras and found that wild-type H-Ras is a contributor to radiation survival in tumor cells that express oncogenic K-Ras. In these experiments, inhibiting the expression of oncogenic K-Ras, wild-type H-Ras, or epidermal growth factor receptor (EGFR) led to similar levels of radiosensitization as treatment with the FTI tipifarnib. Treatment with the EGFR inhibitor gefitinib led to similar levels of radiosensitization, and the combinations of tipifarnib or gefitinib plus inhibition of K-Ras, H-Ras, or EGFR expression did not provide additional radiosensitization compared with tipifarnib or gefitinib alone. Finally, supplementing culture medium with the EGFR ligand transforming growth factor α was able to reverse the radiosensitizing effect of inhibiting K-ras expression. Taken together, these findings suggest that EGFR-activated H-Ras signaling is initiated by oncogenic K-Ras to promote radiation survival in pancreatic and colorectal cancers