Testicular injury is a well-documented acute effect of radiation exposure, though little is known about recovery years after irradiation, especially at higher doses. We examined the testes from 143 irradiated and control male rhesus monkeys, who were part of the Radiation Late Effects Cohort over a four-year period. Irradiated animals were exposed to doses ranging from 3.5 to 8.5 Gy of total-body irradiation. The testes were assessed using computed tomography (CT) volumetry, serum testosterone, and histology for deceased members of the cohort. Irradiated animals exhibited dose-dependent testicular atrophy as well as decreased serum testosterone during the winter breeding season when compared to age-matched unirradiated controls. No significant difference in summer testosterone levels was observed. Volumetric and histologic evidence of testicular recovery was present approximately three years postirradiation for animals who received ≤8 Gy. The study demonstrates dose-dependent testicular injury after total-body irradiation and provides evidence for volumetric and spermatogonial recovery even at lethal doses of total-body irradiation in rhesus monkeys.

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.

The Rössing Uranium Limited (RUL) open-cast uranium mine in Namibia has operated since 1976. Studies of underground uranium miners from Europe and North America have shown increased cancer risks (principally lung cancer). We explored the association between radiation doses and selected cancers in RUL mineworkers. Employees with at least one-year of continuous employment between 1976 and 2010 were included. Incident cancer cases [lung, extra-thoracic airways (ETA), leukemia, brain and kidney] occurring before the end of 2015 were identified from the Namibian and South African National Cancer Registries, and RUL's occupational health provider. Using a case-cohort design, data on exposure and confounding factors were collected for all cancer cases among the study cohort and a stratified random sample (sub-cohort) of the cohort, including cases. Radiation doses were estimated based on annual dose records held by RUL. In total, 76 cancer cases (32 lung, 18 ETA, 8 leukemia, 9 brain, 9 kidney) and a sub-cohort of 1,121 sampled from 7,901 RUL employees were included. A weighted Cox model, adjusted for available known confounders, produced a rate ratio (95% CI) for lung cancer of 1.42 (0.42, 4.77) and 1.22 (0.26, 5.68), respectively, for medium and higher cumulative lung dose categories compared to the lower category, and 1.04 (0.95, 1.13) for a dose increase of 10 mSv. This study faced considerable challenges with respect to case ascertainment, exposure estimates, and ensuring accuracy of key variables. Persuasive consistent evidence for elevated cancer risk was not found for radiation or other exposures studied at the Rössing uranium mine.

Archival data of leukocyte count and the differentials obtained from control and irradiated Rhesus Macaques (Macaca mulatta) were statistically analyzed to understand the long-term effect of ionizing radiation exposure. Nine animals received total-body irradiation (TBI) of 7.2–8.4 Gy at 3–4 years old. Twelve animals served as age-matched controls with no radiation exposure. The complete blood cell count dataset was obtained during regular health exams every 2–6 months for 8 years from their age of 8 to 17 years old. Linear mixed models for leukocyte, neutrophil, lymphocyte, and monocyte counts and their percentages were successfully developed. Estimated marginal means calculated based on the models revealed statistically significant elevations in leukocyte and neutrophil counts and neutrophil percentages in irradiated animals compared to the controls. Lymphocyte percentage was significantly lower in irradiated animals. Longitudinal trends for both control and irradiated animals were consistent with expected trends of aging in hematopoiesis, which is skewed towards production of myeloid lineage cells such as neutrophils and monocytes rather than lymphoid cells. Longitudinal trends from irradiated animals suggested the age-related increase in neutrophils and decrease in lymphocytes were stronger than in the controls, although the difference did not reach statistical significance. The mechanism of the long-term effects in the hematopoietic system were not investigated. However, the results suggest ionizing radiation causes long-term effects on some of the factors implicated in hematopoietic aging, possibly inducing early-onset or accelerated aging in the hematopoietic system. Extended analysis with observations including before and after the follow-up period in this study will be beneficial to understand the timeline and features of the long-term response.

Significant past work has identified unexpected risks of central nervous system (CNS) exposure to the space radiation environment, where long-lasting functional decrements have been associated with multiple ion species delivered at low doses and dose rates. As shielding is the only established intervention capable of limiting exposure to the dangerous radiation fields in space, the recent discovery that pions, emanating from regions of enhanced shielding, can contribute significantly to the total absorbed dose on a deep space mission poses additional concerns. As a prerequisite to biological studies evaluating pion dose equivalents for various CNS exposure scenarios of mice, a careful dosimetric validation study is required. Within our ultimate goal of evaluating the functional consequences of defined pion exposures to CNS functionality, we report in this article the detailed dosimetry of the PiMI pion beam line at the Paul Scherrer Institute, which was developed in support of radiobiological experiments. Beam profiles and contamination of the beam by protons, electrons, positrons and muons were characterized prior to the mice irradiations. The dose to the back and top of the mice was measured using thermoluminescent dosimeters (TLD) and optically simulated luminescence (OSL) to cross-validate the dosimetry results. Geant4 Monte Carlo simulations of radiation exposure of a mouse phantom in water by charged pions were also performed to quantify the difference between the absorbed dose from the OSL and TLD and the absorbed dose to water, using a simple model of the mouse brain. The absorbed dose measured by the OSL dosimeters and TLDs agreed within 5–10%. A 30% difference between the measured absorbed dose and the dose calculated by Geant4 in the dosimeters was obtained, probably due to the approximated Monte Carlo configuration compared to the experiment. A difference of 15–20% between the calculated absorbed dose to water at a 5 mm depth and in the passive dosimeters was obtained, suggesting the need for a correction factor of the measured dose to obtain the absorbed dose in the mouse brain. Finally, based on the comparison of the experimental data and the Monte Carlo calculations, we consider the dose measurement to be accurate to within 15–20%.

Radiotherapy is a well-established cancer treatment; it is estimated that approximately 52% of oncology patients will require this treatment modality at least once. However, some tumors, such as triple-negative breast cancer (TNBC), may present as radioresistant and thus require high doses of ionizing radiation and a prolonged period of treatment, which may result in more severe side effects. Moreover, such tumors show a high incidence of metastases and decreased survival expectancy of the patient. Thus, new strategies for radiosensitizing TNBC are urgently needed. Red light therapy, photobiomodulation, has been used in clinical practice to mitigate the adverse side effects usually associated with radiotherapy. However, no studies have explored its use as a radiosensitizer of TNBC. Here, we used TNBC-bearing mice as a radioresistant cancer model. Red light treatment was applied in three different protocols before a high dose of radiation (60 Gy split in 4 fractions) was administered. We evaluated tumor growth, mouse clinical signs, total blood cell counts, lung metastasis, survival, and levels of glutathione in the blood. Our data showed that the highest laser dose in combination with radiation arrested tumor progression, likely due to inhibition of GSH synthesis. In addition, red light treatment before each fraction of radiation, regardless of the light dose, improved the health status of the animals, prevented anemia, reduced metastases, and improved survival. Collectively, these results indicate that red light treatment in combination with radiation could prove useful in the treatment of TNBC.

Radiotherapy has shown remarkable clinical success using high doses of radiation to kill cancer cells and shrink tumors; however, tumor resistance to radiation is still an intractable challenge to enhance radiation damage to tumor tissue. Here, we show a capacity of tumor-penetrating peptide LyP-1 that enhanced the effect of radiation on 4T1 tumor. We injected LyP-1 peptide into the tumor model through the tail vein and irradiated mice subsequently. The radiation treatment combined with LyP-1 exhibited significant regression of the tumor compared to radiation alone or LyP-1 alone. We analyzed the tumor immune microenvironment after treatment, the expression of myeloid-derived suppressor cells (MDSCs) both in the spleen and the tumor were effectively suppressed. Besides, LyP-1 could drive macrophage polarization to the M1 phenotype and regulate its immune function. We also evaluated the safety of this strategy, the results demonstrated that radiation combined with LyP-1 exhibited excellent in vivo safety and tumor suppression. Therefore, LyP-1 can be a promising radiosensitizer candidate to enhance radiation efficacy as well as induce reactivation of the immune system.

Nicaraven selectively protects normal tissue from radiation-induced injury. To further develop the clinical application of nicaraven for mitigating the side effects of cancer radiotherapy, we investigated the potential effect of nicaraven administration in radiation-induced inhibition of tumor growth. A subcutaneous tumor model was established in mice by the injection of Lewis lung cancer cells at the back of the chest. X-ray radiation was delivered to the thoracic area and different doses of nicaraven (0, 20, 50, 100 mg/kg) were administrated intraperitoneally pre- or post-irradiation. The tumor size was measured every other day. Mice were euthanized on day 30, and the tumor weight and the levels of cytokines in tumor tissue were measured. Pre- or post-irradiation administration of nicaraven up to a dose of 100 mg/kg did not significantly diminish the radiation-induced inhibition of tumor growth, but post-irradiation administration of 20 and 50 mg/kg nicaraven resulted in relatively lower tumor weight. The levels of IL-1β, IL-6, IL-10, MCP-1, MIP-2a, TGF-β₁, VEGF, p53, p21, cyclin D1 and caspase-3 in tumor tissue did not change by nicaraven administration and were not significantly associated with the tumor weights. According to our experimental data, nicaraven will not significantly diminish the radiation-induced inhibition of tumor growth, even with pre-irradiation administration at a high dose.

Exposure to ionizing radiation causes acute damage and loss of bone marrow and peripheral immune cells that can result in high mortality due to reduced resistance to infections and hemorrhage. Besides these acute effects, tissue damage from radiation can trigger inflammatory responses, leading to progressive and chronic tissue damage by radiation-induced loss of immune cell types that are required for resolving tissue injuries. Understanding the mechanisms involved in radiation-induced immune system injury and repair will provide new insights for developing medical countermeasures that help restore immune homeostasis. For these reasons, The Radiation and Nuclear Countermeasures Program (RNCP) and the Basic Immunology Branch (BIB) under the Division of Allergy, Immunology, and Transplantation (DAIT) within the National Institute of Allergy and Infectious Diseases (NIAID) convened a two-day workshop, along with partners from the Biomedical Advanced Research and Development Authority (BARDA), and the Radiation Injury Treatment Network (RITN). This workshop, titled “Immune Dysfunction from Radiation Exposure,” was held virtually on September 9–10, 2020; this Commentary provides a high-level overview of what was discussed at the meeting.

The hematopoietic system is highly sensitive to ionizing radiation. Damage to the immune system may result in opportunistic infections and hemorrhage, which could lead to mortality. Inflammation triggered by tissue damage can also lead to additional local or widespread tissue damage. The immune system is responsible for tissue repair and restoration, which is made more challenging when it is in the process of self-recovery. Because of these challenges, the Radiation and Nuclear Countermeasures Program (RNCP) and the Basic Immunology Branch (BIB) under the Division of Allergy, Immunology, and Transplantation (DAIT) within the National Institute of Allergy and Infectious Diseases (NIAID), along with partners from the Biomedical Advanced Research and Development Authority (BARDA), and the Radiation Injury Treatment Network (RITN) sponsored a two-day meeting titled Immune Dysfunction from Radiation Exposure held on September 9–10, 2020. The intent was to discuss the manifestations and mechanisms of radiation-induced immune dysfunction in people and animals, identify knowledge gaps, and discuss possible treatments to restore immune function and enhance tissue repair after irradiation.