Radiation research最新文献

The prolonged exposure to multiple spaceflight stressors during long-duration missions to the Moon and Mars will be challenging to the physical and mental health of the astronauts. Ground-based studies have reported that attentional set-shifting task (ATSET) performance is impaired after space radiation (SR) exposure. At certain times during deep-space missions, astronauts will likely have to contend with the combined impacts of SR and sleep perturbation. In rats, poor quality, fragmented sleep adversely impacts performance in multiple cognitive tasks, including the ATSET task. While both SR and sleep perturbations independently cause cognitive performance deficits, the incidence, severity and exact nature of those decrements following combined exposure to these flight stressors is largely unknown. This study established the impact that a single night of fragmented sleep has on ATSET performance in both male and female rats exposed to 10 cGy of galactic cosmic ray simulation (GCRsim). The GCRsim beam is a complex beam that mimics the mass and energy spectra of the SR particles that an astronaut will be exposed to within the spacecraft. Rats that had no obvious ATSET performance decrements when normally rested were subjected to fragmented sleep and their ATSET performance reassessed. Sleep fragmentation resulted in significant ATSET performance decrements in GCRsim-exposed rats, with specific performance decrements being observed in stages where attention or cue shifting is extensively used. Performance decrements in these stages are rarely observed after SR exposure. While both male and female rats exhibited latent sleep-related performance decrements, these were sex dependent, with male and female rats exhibiting different types of performance decrements (either reduced processing speed or task completion efficiency) in different stages of the ATSET task. This study suggests that SR-induced cognitive impairment may not be fully evident in normally rested rats, with an underestimation of both the incidence and nature of performance decrements that could occur when multiple space flight stressors are present. These data suggest that that there may be synergistic interactions between multiple space flight stressors that may not be easily predicted from their independent actions.

BBT-059 is a long-acting PEGylated interleukin-11 analog that has been shown to have hematopoiesis-promoting and anti-apoptotic attributes, and is being studied as a radiation countermeasure for the hematopoietic acute radiation syndrome (H-ARS). This potential countermeasure has been demonstrated to enhance survival in irradiated mice. To investigate the toxicity and safety profile of this agent, 14 nonhuman primates (NHPs, rhesus macaques) were administered two different doses of BBT-059 subcutaneously 24 h after 4 Gy total-body irradiation and were monitored for the next 60 days postirradiation. Blood samples were investigated for the pharmacokinetics and pharmacodynamics of this agent and its effects on complete blood counts, cytokines, vital signs, and for metabolomic studies. No adverse effects were observed in either treatment group. Radiation-induced metabolomic dysregulation was observed in both treatment groups, and BBT-059 afforded some short-term radiomitigation. A few pathways were commonly dysregulated by radiation exposure including the steroid hormone biosynthesis pathway, fatty acid activation, and glycerophospholipid metabolism. Notably, radiation-induced dysregulation to the linoleate metabolism pathway was significantly mitigated by either dose of BBT-059. In brief, this study suggests that BBT-059 has a good safety profile in irradiated NHPs and that its development as a medical countermeasure for U.S. Food and Drug Administration approval for human use should be continued.

The objective of this study is describe outcome and toxicity for dogs with oral tumors, specifically oral malignant melanoma (OMM), squamous cell carcinoma (SCC), and soft tissue sarcoma (STS) after stereotactic body radiation therapy (SBRT). A single institution retrospective study was conducted. Outcomes were analyzed using Kaplan-Meier analysis and Cox proportional hazard analysis. Treatment responses at different time points were evaluated with Pearson's Chi-squared test to identify prognostic factors. Acute and late toxicities were recorded according to VRTOG criteria and were analyzed to identify risk factors. Adverse events other than acute and late toxicities were recorded. A total of 98 patients met the inclusion criteria (OMM n = 37; SCC n = 18; STS n = 43). The SBRT prescription was 1-6 fractions, with a total dose range of 12-40 Gy. Local progression-free survival (PFS) for OMM, SCC, and STS was 187, 253, and 161 days, respectively. Overall PFS was 152 days and median survival time (MST) was 270 days, with no statistical difference between tumor types. The presence of lymph node metastasis and the use of elective nodal irradiation (ENI) were associated with shorted PFS and MST. Severe acute toxicities to organs at risk affected 10/85 (11.8%) of patients. Osteoradionecrosis and oronasal fistula formation occurred in 23/81 (28.4%) of patients and was significantly associated with tumor type (SCC, P = 0.006). SBRT can be offered as a treatment option for oral tumors in dogs. Toxicities were common and warrant risk factor considerations and adjustments to current SBRT protocols.

Radiation-induced lymphopenia (RIL) is associated with worse outcomes in patients with multiple solid tumors. Hypofractionated radiation therapy (HFRT) reduces RIL compared with conventionally fractionated radiation therapy (CFRT). However, fractionation effects on immune repertoire (IR) diversity are unknown. RNA-based T- and B-cell receptor sequencing was performed on peripheral lymphocytes collected prospectively before radiation therapy and <4 weeks after the final radiation fraction. Patients received CFRT (≤3 Gy/day × ≥10 days ± chemotherapy, n = 13) or HFRT (≥5 Gy/day × ≤5 days, n = 10), per institutional standards of care. Immune repertoire diversity parameters analyzed were number of unique CDR3 receptors (uCDR3), Shannon entropy, and sample clonality (percentage of all receptors represented by the top 10 clones). RIL was severe with concurrent chemotherapy (median %Δ ALC -58.8%, -12.5%, and -28.6% in patients treated with CFRT and chemo, CFRT alone, and HFRT, respectively). CFRT and concurrent chemotherapy was associated with more severe diversity restriction in all examined parameters than either HFRT or CFRT alone. Increased immune repertoire diversity despite decreased ALC was more common in patients treated with HFRT than CFRT and significantly less common in patients treated with concurrent chemotherapy (P < 0.001). Radiation-induced changes in immune repertoire diversity are variably reflected in the peripheral ALC. Both HFRT and CFRT caused RIL, but HFRT was associated with improved immune repertoire diversity despite RIL. The addition of chemotherapy may potentiate radiation-induced restriction in immune repertoire diversity. As immune repertoire diversity is associated with response to immunotherapy, these findings may have implications for radiation therapy/chemotherapy/immunotherapy combinations. Further studies are required to understand the relationship between radiation, circulating lymphocyte populations, immune repertoire diversity and response to treatment.

Radiation exposure causes hepatitis which induces hepatic steatosis and fibrosis. Although hepatic stellate cells (HSCs) have been considered potential pathological modulators for the development of hepatitis due to viral and microbial infections, their involvement in radiation-induced hepatitis is yet to be determined. This study aimed to clarify the relationship between radiation exposure and expressions of inflammatory cytokines and chemokines in HSCs in vitro and in vivo. HSCs were obtained from 1-week-old mice, known to be highly sensitive to radiation-induced hepatocellular carcinoma, using a newly established method combining liver perfusion, cell dissociation, and density gradient centrifugation, followed by magnetic negative selection of hematopoietic and endothelial cells with anti-CD45.2 and CD146 antibodies. The isolated HSCs were confirmed by the expression of desmin and glial fibrillary acidic protein (GFAP). We demonstrated that primary cultured HSCs, exposed to X-ray irradiation (0, 1.9, and 3.8 Gy) and cultured for 3 and 7 days, produced elevated levels of C-C motif chemokine ligand 5 (CCL5, also known as RANTES) inflammatory chemokine in a dose-dependent manner. An in vivo immunofluorescence method confirmed that increased CCL5 signals were observed in GFAP-positive HSCs in mouse livers 7 days after whole-body X-ray irradiation (1.9 and 3.8 Gy). Adequate expression of C-C motif chemokine receptor 5 (Ccr5), a receptor for CCL5, was also detected using real-time PCR in the liver of both irradiated and non-irradiated mice. Taken together, our data suggest that HSCs may drive hepatitis via CCL5/CCR5 axis in the liver under radiation-induced stress. Furthermore, this newly established experimental protocol can help evaluate the expression of other inflammatory cytokines in primary cultures of HSCs isolated from infant mice.

The present work investigates the multigenerational effects of paternal pre-conceptional exposure to continuous low-dose-rate gamma rays in C56BL/6J mice. Male C57BL/6J (F0 sires) mice were exposed to low dose rates of 20, 1, and 0.05 mGy/day for 400 days, to total accumulated doses of 8,000, 400, and 20 mGy, respectively. Upon completion of the radiation exposure, the F0 male mice were immediately bred to non-irradiated 8-week-old C57BL/6J females (F0 dams) to produce the first-generation (F1) mice. Randomly selected F1 males and females were then bred to produce the second-generation (F2) mice. All the mice, except the F0 dams, were subjected to pathological examination upon natural death. Reproductive parameters, lifespan, causes of death, neoplasm incidences and non-neoplastic disease incidences were used as parameters to evaluate the biological effects of continuous pre-conceptional exposure of the sires (F0) to continuous low-dose-rate radiation. There were no significant differences in the pregnancy and weaning rates among the parent (F0) generation. Average litter size and average number of weaned pups (F1) from dams bred to males (F0) exposed to 20 mGy/day were significantly decreased compared to the non-irradiated controls. Significant lifespan shortening in the sires (F0) was observed only in the 20 mGy/day group due to early death from malignant lymphomas. Life shortening was also observed in the F1 progeny of sires (F0) exposed to 20 and 1 mGy/day, but could not be attributed to a specific cause. No significant differences in the causes of death were found between dose groups in any generation. The number of primary tumors per mouse was significantly increased only in the F0 males exposed to 20 mGy/day. Except for the increased incidence rate for Harderian gland neoplasms in sires (F0) exposed to 20 mGy/day, there was no significant difference in neoplasm incidences and tumor spectra in all 3 generations in each sex regardless of radiation exposure. No multi- or transgenerational effects in the parameters examined were observed in the F1 and F2 progeny of sires exposed to 0.05 mGy/day for 400 days.

The study of One Million U.S. Radiation Workers and Veterans, the Million Person Study (MPS), examines the health consequences, both cancer and non-cancer, of exposure to ionizing radiation received gradually over time. Recently the MPS has focused on mortality patterns from neurological and behavioral conditions, e.g., Parkinson's disease, Alzheimer's disease, dementia, and motor neuron disease such as amyotrophic lateral sclerosis. A fuller picture of radiation-related late effects comes from studying both mortality and the occurrence (incidence) of conditions not leading to death. Accordingly, the MPS is identifying neurocognitive diagnoses from fee-for-service insurance claims from the Centers for Medicare and Medicaid Services (CMS), among Medicare beneficiaries beginning in 1999 (the earliest date claims data are available). Linkages to date have identified ∼540,000 workers with available health information. Such linkages provide individual information on important co-factor and confounding variables such as smoking, alcohol consumption, blood pressure, obesity, diabetes and many other health and demographic characteristics. The total person-level set of time-dependent variables, outcomes, organ-specific dose measures, co-factors, and demographics will be massive and much too large to be evaluated with standard software. Thus, development of specialized open-source software designed for large datasets (Colossus) is nearly complete. The wealth of information available from CMS claims data, coupled with individual dose reconstructions, will thus greatly enhance the quality and precision of health evaluations for this new field of low-dose radiation and neurocognitive effects.

National security concerns regarding radiological incidents, accidental or intentional in nature, have increased substantially over the past few years. A primary area of intense planning is the assessment of exposed individuals and timely medical management. However, exposed individuals who receive survivable radiation doses may develop delayed effects of acute radiation exposure many months or years later. Therefore, it is necessary to identify such individuals and determine whether their symptoms may have been initiated by radiation and require complex medical interventions. We previously developed early response metabolomic biosignatures in biofluids from non-human primates exposed to a total body gamma radiation dose of 4 Gy (up to 60 days). A follow-up of these animals has been ongoing with samples consistently collected every few months for up to 2 years after exposure, providing a unique cohort to determine if a radiation signal persists longer than 2 months. Metabolic fingerprinting in urine and serum determined that exposed animals remain metabolically different from pre-exposure levels and from age-matched controls, and the pre-determined biosignature maintains high sensitivity and specificity. Significant perturbations in tricarboxylic acid intermediates, cofactors and nucleotide metabolism were noted, signifying energetic changes that could be attributed to or perpetuate altered mitochondrial dynamics. Importantly, these animals have begun developing diseases such as hypertension much earlier than their age-matched controls, further emphasizing that radiation exposure may lead to accelerated aging. This NHP cohort provides important information and highlights the potential of metabolomics in determining persistent changes and a radiation-specific signature that can be correlated to phenotype.

Considering the limitations and complexities of the cell-killing-based cancer treatment approaches, one could aim to integrate symbiotic advances in many energy delivery technologies and transformational pieces of evidence in research on senescence and immunomodulators to advance cancer treatment. Although senescent cells contribute to drug tolerance, resistance to therapy, tumorigenesis, maladapting cancer phenotypes, tumor relapse, recurrence, and metastasis, emerging pieces of evidence also demonstrate that acutely induced senescent cells in tumors can elicit a strong and lasting antitumor immune response juxtaposed to the immunologically silent apoptotic cells. This commentary is to help develop an unconventional conceptual framework to advance cancer treatment. Accordingly, it will involve transiently inducing senescent cells in tumors at optimal levels to prime the immune system with radiation, then eliminating senescent cells with senolytics (drugs that specifically eliminate senescent cells) to disrupt their positive feedback accumulation (to prevent tumor maladaptation and adverse effects in healthy cells) and unleash long-lasting antitumor immunity with immunomodulators. The approach is reasonably speculative and will require scientifically rigorous "fit-for-purpose," well-controlled preclinical research and development involving dose and schedule optimization of radiation and drugs, using representative in vitro and in vivo cancer models to obtain high-quality data to proceed to clinical studies.