There has been ongoing debate and discussion concerning whether the funding source influenced the outcome of research on human health effects from exposure to radiofrequency fields (RF, electromagnetic waves that carry energy as they propagate in air and dense media). In a study of 225 publications, in which we sought to determine a possible association between the funding source(s), quality and outcome in a total of 2,160 genetic damage assessment tests of mammalian cells exposed to RF energy, we made several observations. One finding was that a great majority of researchers had acknowledged government agencies as the funding source (53%, 120 of 225 publications), while a small number of scientists mentioned mobile phone industry as the financial source (9%, 20 of 225 publications). Numerous investigators did not mention the funding source (26%, 58 of 225 publications). Secondly, industry-funded investigations were of better quality and utilized quality control measures, i.e., blind evaluation, adequate description of dosimetry, positive controls and/or sham-exposed controls, compared to those funded by the government. Another observation was that in industry-funded studies, the d values (effect size or standardized mean difference between the cells exposed to RF energy and sham-exposed controls) were consistently lower than in government-funded studies. In addition, compared to government-funded studies, a higher percentage of industry-funded studies reported no difference in genetic damage between RF- and sham-exposed cells (80% for industry-funded studies versus 49% for government-funded studies). Finally, we observed that industry-funded studies were less likely to report an increase in genetic damage in cells exposed to RF energy (10%) compared to government-funded studies (23%). In view of the large difference between the percentage of publications funded by government and industry (53% or 122 of 225 publications for government, compared to 9% or 29 of 225 publications for industry), caution should be used when debating and discussing the above observations. Overall, it is important to include the quality control measures in the investigations, and also mention the funding source in published studies.

Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive complication of therapeutic irradiation of the thorax. It has been suggested that senescence of type II pneumocytes (AECIIs), an alveolar stem cell, plays a role in the development of RIPF through loss of replicative reserve and via senescent AECII-driven release of proinflammatory and profibrotic cytokines. Within this context, we hypothesized that arachidonate 12-lipoxygenase (12-LOX) is a critical mediator of AECII senescence and RIPF. Treatment of wild-type AECIIs with 12S-hydroxyeicosateraenoic acid (12S-HETE), a downstream product of 12-LOX, was sufficient to induce senescence in a NADPH oxidase 4 (NOX4)-dependent manner. Mice deficient in 12-LOX exhibited reduced AECII senescence, pulmonary collagen accumulation and accumulation of alternatively activated (M2) macrophages after thoracic irradiation (5 × 6 Gy) compared to wild-type mice. Conditioned media from irradiated or 12S-HETE-treated primary pneumocytes contained elevated levels of IL-4 and IL-13 compared to untreated pneumocytes. Primary macrophages treated with conditioned media from irradiated AECII demonstrated preferential M2 type polarization when AECIIs were derived from wild-type mice compared to 12-LOX-deficient mice. Together, these data identified 12-LOX as a critical component of RIPF and a therapeutic target for radiation-induced lung injury.

When assessing radiation-related risk among the atomic bomb survivors, choices in modeling approach can have an important impact on the results, which are then used to inform radiation protection standards throughout the world. The atomic bombings of Hiroshima and Nagasaki produced a mixed-field radiation exposure from two sources: neutrons and gamma rays. Neutrons are more densely ionizing and cause greater biological damage per unit absorbed dose, resulting in greater relative biological effectiveness (RBE) than gamma rays. To account for this, a combined weighted dose is typically calculated as the sum of the gamma-ray dose and 10 times the neutron dose in the Radiation Effects Research Foundation's reports of mortality, solid cancer incidence and other outcomes. In addition, the colon, which is often chosen as the whole-body representative organ in these analyses, is relatively deep in the body and therefore its dose calculation involves heavy body shielding of neutrons and a low neutron/gamma-ray ratio. With added follow-up and recently updated doses, we used a data-driven approach to determine the best-fitting neutron RBE for a range of organs of varying depth. Aggregated person-year tables of solid cancer incidence (1958–2009) from the Life Span Study were created with separate neutron and gamma-ray DS02R1 doses for several organs including breast, brain, thyroid, bone marrow, lung, liver and colon. Typical excess relative risk models estimating the linear effect of radiation dose were fitted using a range of neutron weights (1–250) to calculate combined dose for each organ, and model deviances were compared to assess fit. Furthermore, models using separate terms for gamma-ray and neutron dose were also examined, wherein the ratio of the neutron/gamma-ray linear terms indicated the best estimate of the RBE. The best-fitting RBE value for the traditional weighted colon dose was 80 [95% confidence interval (CI): 20–190], while the RBEs for other organs using weighted doses ranged from 25 to 60, with the best-fitting weights and confidence interval widths both incrementally increasing with greater depth of organ. Models using separate neutron- and gamma-ray-dose terms gave similar results to weighted linear combinations, with a neutron/gamma-ray term ratio of 79.9 (95% CI: 18.8–192.3) for colon. These results indicated that the traditionally modeled RBE of 10 may underestimate the effect of neutrons across the full dose range, although these updated estimates still have fairly wide confidence bounds. Furthermore, the colon is among the deepest of organs and may not be the best choice as a single surrogate organ dose, as it may minimize the role of the neutrons. Future work with more refined organ doses could shed more light on RBE-related information available in the Life Span Study data.

A recent analysis of solid cancer incidence in the Life Span Study of atomic bomb survivors (Hiroshima and Nagasaki, Japan) found evidence of a nonlinear, upwardly curving radiation dose response among males but not among females. Further analysis of this new and unexpected finding was necessary. We used two approaches to investigate this finding. In one approach, we excluded individual cancer sites or groups of sites from all solid cancers. In the other approach, we used joint analysis to allow for heterogeneity in background-rate parameters across groups of cancers with dissimilar trends in background rates. Exclusion of a few sites led to the disappearance of curvature among males in the remaining collection of solid cancers; some of these influential sites have unique features in their background age-specific incidence that are not captured by a background-rate model fit to all solid cancers combined. Exclusion of a few sites also led to an appearance of curvature among females. Misspecification of background rates can cause bias in inference about the shape of the dose response, so heterogeneity of background rates might explain at least part of the all solid cancer dose-response difference in curvature between males and females. We conclude that analysis based on all solid cancers as a single outcome is not the optimal method to assess radiation risk for solid cancer in the Life Span Study; joint analysis with suitable choices of cancer groups might be preferable by allowing for background-rate heterogeneity across sites while providing greater power to assess radiation risk than analyses of individual sites.

In a large-scale radiological incident, rapid and high-throughput biodosimetry would be needed. Gene expression-based biodosimetry is a promising approach to determine the dose received after radiation exposure. We previously identified 35 candidate genes as biodosimetry markers based on a systematic review. The goal of the current study was to establish and validate a specific gene expression-based radiological biodosimetry using a panel of highly radioresponsive genes in human peripheral blood for improving the accuracy of dose estimation. Human peripheral blood samples from 30 adult donors were irradiated to 0, 0.5, 1, 2, 3, 4, 6 and 8 Gy with ⁶⁰Co γ rays at a dose rate of 1 Gy/min. We examined the expression patterns of candidate genes using real-time polymerase chain reaction (qRT-PCR) at 6, 12, 24 and 48 h postirradiation. Stepwise regression analysis was employed to develop the gene expression-based dosimetry models at each time point. Samples from another 10 healthy donors (blind samples) and four total-body irradiated (TBI) patients were used to validate the radiation dosimetry models. We observed significant linear dose-response relationships of CDKN1A, BAX, MDM2, XPC, PCNA, FDXR, GDF-15, DDB2, TNFRSF10B, PHPT1, ASTN2, RPS27L, BBC3, TNFSF4, POLH, CCNG1, PPM1D and GADD45A in human peripheral blood at the various time points. However, the expression levels of these genes were affected by inter-individual variations and gender. We found that the gender-dependent regression models could explain 0.85 of variance at 24 h postirradiation and could also accurately estimate the absorbed radiation doses with dose range of 0–5 Gy, in human peripheral blood samples irradiated ex vivo and from TBI patients, respectively. This study demonstrates that developing gender-specific biodosimetry based on a panel of highly radioresponsive genes may help advance the application of gene expression signature for dose estimation in the event of a radiological accident or in clinical treatment.

Radiation-induced acute skin injury and consequent fibrosis are common complications of cancer radiotherapy and radiation accidents. Stromal cell-derived factor-1α (SDF-1α) and its receptor, CXC chemokine receptor 4 (CXCR4) have been shown to be involved in multiple cellular events. However, the role of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin has not been reported. In this study, we found that the expression of SDF-1α and CXCR4 was significantly increased in irradiated skin tissues of humans, monkeys and rats, compared to their nonirradiated counterparts. Mice with keratinocyte-specific ablation of CXCR4 showed less severe skin damage than wild-type mice after receiving a 35 Gy dose of radiation. Consistently, subcutaneous injection of AMD3100, an FDA approved SDF-1α/CXCR4 inhibitor, attenuated skin injury and fibrosis induced by exposure to radiation in a rat model. Mechanically, the SDF-1α/CXCR4 axis promotes pro-fibrotic TGF-b/Smad signaling through the PI3K-MAPK signaling cascade in human keratinocyte HaCaT cells and skin fibroblast WS1 cells. AMD3100 inhibited Smad2 nuclear translocation and transcriptional activity of Smad2/3 induced by radiation, which suppressed the pro-fibrotic TGF-b/Smad signaling pathway activated by exposure. Taken together, these findings demonstrate the involvement of SDF-1α/CXCR4 axis in radiation-induced acute injury and fibrosis of skin, and indicate that AMD3100 would be an effective countermeasure against these diseases.

Photodynamic therapy (PDT) uses a combination of photosensitizers with visible light to generate reactive species and selectively kill tumor or unwanted tissue. Znln₂S₄ nanoparticles are widely implemented in photovoltaic device materials and photolysis water catalysts owing to their unique photoelectric properties. Whether Znln₂S₄ itself can be used as an effective dye in PDT is still unknown. To determine the effects and potential mechanism of Znln₂S₄PDT on HepG2 cell apoptosis, electron microscopic analysis was performed to monitor the apoptotic morphology of HepG2 cells upon exposure to Znln₂S₄-PDT. Flow cytometry was performed to measure the apoptosis rate and intracellular ROS production. Western blot and ELISA were performed to reveal the expression changes in Bax, caspase-3 and caspase-9. Data from this work suggested that cells exhibited the typical apoptotic morphology in response to Znln₂S₄-PDT, with high apoptotic rate. The intracellular ROS production after Znln₂S₄-PDT occurred in a dose-dependent manner. Moreover, Znln₂S₄-PDT augmented the expression levels of pro-apoptosis factors, especially, Bax, caspase-3 and caspase-9. Taken together, our novel findings, Znln₂S₄-PDT elicited HepG2 cell apoptosis, suggesting Znln₂S₄ as a promising photosensitizer candidate for cancer therapy.

Radon (²²²Rn) and thoron (²²⁰Rn), and especially their short-lived decay products, are major contributors to dose received by the public from naturally occurring radioactive material (NORM), particularly in areas with elevated levels of naturally occurring radionuclides. Mining in such areas can involve ventilation of high amounts of these gases, which may influence outdoor levels. In this work, we assessed indoor and outdoor levels of ²²²Rn, ²²⁰Rn and ²²⁰Rn decay products (TnDP) in close proximity to an area with elevated bedrock levels of thorium (²³²Th) and a NORM legacy mining site with high natural ventilation. We assess municipal buildings at distances from a few hundred meters to 2 km from the NORM legacy mines. In some buildings, high indoor levels of ²²²Rn were observed in winter, as expected for temperate areas. In summer, high indoor levels of ²²²Rn and ²²⁰Rn were observed in some buildings, and very low associated levels of TnDP in actively ventilated buildings may suggest entry by ventilation and an outdoor source. Outdoor levels of TnDP increased with decreased distance from the legacy mines, suggesting dispersal from these during both summer and winter.

Radiotherapy to treat brain tumors can potentially harm the central nervous system (CNS). The radiation stimulates a series of immune responses in both the CNS as well as peripheral immune system. To date, studies have mostly focused on the changes occurring in the immune response within the CNS. In this study, we investigated the effect of γ-ray-induced CNS injury on the peripheral immune response using a cell co-culture model and a whole-brain irradiation (WBI) rat model. Nerve cells (SH-SY5Y and U87 MG cells) were γ-ray irradiated, then culture media of the irradiated cells (conditioned media) was used to culture immune cells (THP-1 cells or Jurkat cells). Analyses were performed based on the response of immune cells in conditioned media. Sprague-Dawley rats received WBI at different doses, and were fed for one week to one month postirradiation. Spleen and peripheral blood were then isolated and analyzed. We observed that the number of monocytes in peripheral blood, and the level of NK cells and NKT cells in spleen increased after CNS injury. However, the level of T cells in spleen did not change and the level of B cells in the spleen decreased after γ-ray-induced CNS injury. These findings indicate that CNS injury caused by ionizing radiation induces a series of changes in the peripheral immune system.

Calorie restriction is known to influence several physiological processes and to alleviate the late effects of radiation exposure such as neoplasm induction and life shortening. However, earlier related studies were limited to acute radiation exposure. Therefore, in this study we examined the influence of chronic low-dose-rate irradiation on lifespan. Young male B6C3F1/Jcl mice were divided randomly into two groups, which were fed either a low-calorie (65 kcal/ week) or high-calorie (95 kcal/week) diet. The latter is comparable to ad libitum feeding. The animals in the irradiated group were continuously exposed to gamma rays for 400 days at 20 mGy/day, resulting in a total dose of 8 Gy. Exposure and calorie restriction were initiated at 8 weeks of age and the diets were maintained for life. The life-shortening effects from chronic whole-body irradiation were compared between the groups. Body weights were reduced in calorie-restricted mice irrespective of radiation treatment. Radiation induced a shortened median lifespan in both groups, but to a greater extent in the calorie-restricted mice. These results suggest that calorie restriction may sensitize mice to chronic low-dose-rate radiation exposure to produce a life-shortening effect rather than alleviating the effects of radiation.