Effects Of High-dose Irradiation Research Articles

Role of Mitochondria in Radiation Responses: Epigenetic, Metabolic, and Signaling Impacts.

Until recently, radiation effects have been considered to be mainly due to nuclear DNA damage and their management by repair mechanisms. However, molecular biology studies reveal that the outcomes of exposures to ionizing radiation (IR) highly depend on activation and regulation through other molecular components of organelles that determine cell survival and proliferation capacities. As typical epigenetic-regulated organelles and central power stations of cells, mitochondria play an important pivotal role in those responses. They direct cellular metabolism, energy supply and homeostasis as well as radiation-induced signaling, cell death, and immunological responses. This review is focused on how energy, dose and quality of IR affect mitochondria-dependent epigenetic and functional control at the cellular and tissue level. Low-dose radiation effects on mitochondria appear to be associated with epigenetic and non-targeted effects involved in genomic instability and adaptive responses, whereas high-dose radiation effects (>1 Gy) concern therapeutic effects of radiation and long-term outcomes involving mitochondria-mediated innate and adaptive immune responses. Both effects depend on radiation quality. For example, the increased efficacy of high linear energy transfer particle radiotherapy, e.g., C-ion radiotherapy, relies on the reduction of anastasis, enhanced mitochondria-mediated apoptosis and immunogenic (antitumor) responses.

High-Dose Irradiation Inhibits Motility and Induces Autophagy in Caenorhabditis elegans

Radiation damages many cellular components and disrupts cellular functions, and was previously reported to impair locomotion in the model organism Caenorhabditis elegans. However, the response to even higher doses is not clear. First, to investigate the effects of high-dose radiation on the locomotion of C. elegans, we investigated the dose range that reduces whole-body locomotion or leads to death. Irradiation was performed in the range of 0–6 kGy. In the crawling analysis, motility decreased after irradiation in a dose-dependent manner. Exposure to 6 kGy of radiation affected crawling on agar immediately and caused the complete loss of motility. Both γ-rays and carbon-ion beams significantly reduced crawling motility at 3 kGy. Next, swimming in buffer was measured as a motility index to assess the response over time after irradiation and motility similarly decreased. However, swimming partially recovered 6 h after irradiation with 3 kGy of γ-rays. To examine the possibility of a recovery mechanism, in situ GFP reporter assay of the autophagy-related gene lgg-1 was performed. The fluorescence intensity was stronger in the anterior half of the body 7 h after irradiation with 3 kGy of γ-rays. GFP::LGG-1 induction was observed in the pharynx, neurons along the body, and the intestine. Furthermore, worms were exposed to region-specific radiation with carbon-ion microbeams and the trajectory of crawling was measured by image processing. Motility was lower after anterior-half body irradiation than after posterior-half body irradiation. This further supported that the anterior half of the body is important in the locomotory response to radiation.

Late Radiation Related Brachial Plexopathy After Pulsed Reduced Dose Rate Reirradiation of an Axillary Breast Cancer Recurrence

Radiation induced brachial plexopathy (RIBP) is an unfortunate complication of radiation involving the axilla and supraclavicular fossa. This case report highlights development of RIBP in a patient 15 years after initial radiation and 11 years after pulsed low dose rate (PRDR) re-irradiation for recurrent disease. PRDR is a radiation technique believed to lower normal tissue toxicity due to improved sublethal intrafraction damage repair of these tissues at low radiation dose rates with good reported long term locoregional control in the re-irradiation setting. However, RIBP, as seen in this patient, is a devastating side effect of high dose radiation to this region, with no effective treatment options outside of symptom management and control. In this case, the patient has remained disease free following her recurrence but has had continued RIBP with minimal improvement using pentoxyfilline for management.

Low dose ionizing radiation effects on the immune system

Ionizing radiation interacts with the immune system in many ways with a multiplicity that mirrors the complexity of the immune system itself: namely the need to maintain a delicate balance between different compartments, cells and soluble factors that work collectively to protect, maintain, and restore tissue function in the face of severe challenges including radiation damage. The cytotoxic effects of high dose radiation are less relevant after low dose exposure, where subtle quantitative and functional effects predominate that may go unnoticed until late after exposure or after a second challenge reveals or exacerbates the effects. For example, low doses may permanently alter immune fitness and therefore accelerate immune senescence and pave the way for a wide spectrum of possible pathophysiological events, including early-onset of age-related degenerative disorders and cancer. By contrast, the so called low dose radiation therapy displays beneficial, anti-inflammatory and pain relieving properties in chronic inflammatory and degenerative diseases. In this review, epidemiological, clinical and experimental data regarding the effects of low-dose radiation on the homeostasis and functional integrity of immune cells will be discussed, as will be the role of immune-mediated mechanisms in the systemic manifestation of localized exposures such as inflammatory reactions. The central conclusion is that ionizing radiation fundamentally and durably reshapes the immune system. Further, the importance of discovery of immunological pathways for modifying radiation resilience amongst other research directions in this field is implied.

Differential regulation of microRNA-15a by radiation affects angiogenesis and tumor growth via modulation of acid sphingomyelinase

Activation of acid sphingomyelinase (SMPD1) and the generation of ceramide is a critical regulator of apoptosis in response to cellular stress including radiation. Endothelial SMPD1 has been shown to regulate tumor responses to radiation therapy. We show here that the SMPD1 gene is regulated by a microRNA (miR), miR-15a, in endothelial cells (ECs). Standard low dose radiation (2 Gy) upregulates miR-15a and decreases SMPD1 levels. In contrast, high dose radiation (10 Gy and above) decreases miR-15a and increases SMPD1. Ectopic expression of miR-15a decreases both mRNA and protein levels of SMPD1. Mimicking the effects of high dose radiation with a miR-15a inhibitor decreases cell proliferation and increases active Caspase-3 & 7. Mechanistically, inhibition of miR-15a increases inflammatory cytokines, activates caspase-1 inflammasome and increases Gasdermin D, an effector of pyroptosis. Importantly, both systemic and vascular-targeted delivery of miR-15a inhibitor decreases angiogenesis and tumor growth in a CT26 murine colorectal carcinoma model. Taken together, our findings highlight a novel role for miR mediated regulation of SMPD1 during radiation responses and establish proof-of-concept that this pathway can be targeted with a miR inhibitor.

Effect of high dose irradiation on thermoluminescence detector

Objective To investigate effect of high dose irradiation on the performances of thermolumines- cence detectors (LiF:Mg, Cu, P). Methods The high-dose irradiated thermoluminescence detector was annealed by a thermoluminescence annealing furnace until the annealing was completed, and then the annealed thermoluminescent detector was irradiated 0.5Gy by 137Cs irradiator to verify the accuracy of the thermoluminescentdetector. Results The thermoluminescence detector after high-dose irradiation could not be completely annealed under the temperature condition of 240 °C, and it could be completely annealed at a high temperature as 400 ℃. After 0.5 Gy irradiation by 137Cs irradiator, the measurement results of the annealed thermoluminescence detector were significantly smaller, and the dose response and dispersion of the detector were also changed significantly. Conclusions After a more than 5 Gy irradiation, the crystal structure of the thermoluminescence detector has changed, and a high temperature peak above 240 ℃ has appeared, which leads to the failure to completely anneal at normal temperature. Therefore, the thermoluminescence detector can no longer be used for dosimetry after high-dose irradiation. Key words: Thermoluminescent detector; High dose; Annealing; Dose response

Biological Principles of Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiation Surgery (SRS): Indirect Cell Death

To review the radiobiological mechanisms of stereotactic body radiation therapy stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). We reviewed previous reports and recent observations on the effects of high-dose irradiation on tumor cell survival, tumor vasculature, and antitumor immunity. We then assessed the potential implications of these biological changes associated with SBRT and SRS. Irradiation with doses higher than approximately 10Gy/fraction causes significant vascular injury in tumors, leading to secondary tumor cell death. Irradiation of tumors with high doses has also been reported to increase the antitumor immunity, and various approaches are being investigated to further elevate antitumor immunity. The mechanism of normal tissue damage by high-dose irradiation needs to be further investigated. In addition to directly killing tumor cells, high-dose irradiation used in SBRT and SRS induces indirect tumor cell death via vascular damage and antitumor immunity. Further studies are warranted to better understand the biological mechanisms underlying the high efficacy of clinical SBRT and SRS and to further improve the efficacy of SBRT and SRS.

What Is the Effect of High-dose Radiation on Bone in Patients With Sacral Chordoma? A CT Study.

Effects of high-dose radiation using protons and photons on bone are relatively unexplored, but high rates of insufficiency fractures are reported, and the causes of this are incompletely understood. Imaging studies with pre- and postradiation scans can help one understand the effect of radiation on bone. The purpose of this study was to assess the effects of high-dose radiation on the trabecular density of bone in the sacrum using CT-derived Hounsfield units (HU). Between 2009 and 2015, we treated 57 patients (older then 18 years) with sacral chordoma. Fourteen (25%) of them were treated with radiation only. The general indication for this approach is inoperability resulting from tumor size. Forty-two (74%) patients were treated with transverse sacral resections and high-dose radiotherapy (using either protons or photons or a combination) before surgery and after surgery. During this time period, our indication for this approach generally was symptomatic sacral chordoma in which resection would prevent further growth and reasonable sacrifice of nerve roots was possible. Of those patients, 21 (50%) had CT scans both before and after radiation treatment. We used HU as a surrogate for bone density. CT uses HU to derive information on tissue and bone quantity. A recent study presented reference HU values for normal (mean 133 ± 38 HU), osteoporotic (101 ± 25 HU), and osteopenic bone (79 ± 32 HU). To adjust for scanning protocol-induced changes in HU, we calculated the ratio between bone inside and outside the radiation field rather than using absolute values. To assess the effect of radiation, we tested whether there was a difference in ratio (sacrum/L1) before and after radiation. A control measurement was performed (L2/L1) and also tested for a difference before and after radiation. Statistical analyses were performed using the paired t-test. The effects of radiation appeared confined to the intended field, because the bone density outside the treated field was not observed to decrease. The ratio of HU (a surrogate for bone density) in L2 relative to L1 did not change after radiotherapy (preradiation mean: 0.979 ± 0.009, postradiation mean: 0.980 ± 0.009, mean difference outside the radiation field: -0.001, 95% confidence interval [CI], -0.009 to 0.007, p = 0.799). The ratio of HU within the radiation field relative to L1 decreased after radiotherapy (preradiation mean: 0.895 ± 0.050, postradiation mean: 0.658 ± 0.050, mean difference inside the radiation field: 0.237, 95% CI, 0.187-0.287, p < 0.001), suggesting the bone density stayed the same outside the radiation field but decreased inside the radiation field. Trabecular bone density decreased after high-dose radiation therapy in a small group of patients with sacral chordoma. High-dose radiation is increasingly gaining acceptance for treating sacral malignancies; further long-term prospective studies using calibrated CT scanners and preferably bone biopsies are needed. Level IV, therapeutic study.

Carcinogenesis Induced by Low-dose Radiation.

BackgroundAlthough the effects of high dose radiation on human cells and tissues are relatively well defined, there is no consensus regarding the effects of low and very low radiation doses on the organism. Ionizing radiation has been shown to induce gene mutations and chromosome aberrations which are known to be involved in the process of carcinogenesis. The induction of secondary cancers is a challenging long-term side effect in oncologic patients treated with radiation. Medical sources of radiation like intensity modulated radiotherapy used in cancer treatment and computed tomography used in diagnostics, deliver very low doses of radiation to large volumes of healthy tissue, which might contribute to increased cancer rates in long surviving patients and in the general population. Research shows that because of the phenomena characteristic for low dose radiation the risk of cancer induction from exposure of healthy tissues to low dose radiation can be greater than the risk calculated from linear no-threshold model. Epidemiological data collected from radiation workers and atomic bomb survivors confirms that exposure to low dose radiation can contribute to increased cancer risk and also that the risk might correlate with the age at exposure.ConclusionsUnderstanding the molecular mechanisms of response to low dose radiation is crucial for the proper evaluation of risks and benefits that stem from these exposures and should be considered in the radiotherapy treatment planning and in determining the allowed occupational exposures.

NMR-based Metabolomics Analysis of Liver from C57BL/6 Mouse Exposed to Ionizing Radiation.

The effects of ionizing radiation to human health are of great concern in the field of space exploration and for patients considering radiotherapy. However, to date, the effect of high-dose radiation on metabolism in the liver has not been clearly defined. In this study, 1H nuclear magnetic resonance (NMR)-based metabolomics combined with multivariate data analysis was applied to study the changes of metabolism in the liver of C57BL/6 mouse after whole-body gamma (3.0 and 7.8 Gy) or proton (3.0 Gy) irradiation. Principal component analysis (PCA) and orthogonal projection to latent structures analysis (OPLS) were used for classification and identification of potential biomarkers associated with exposure to gamma and proton radiation. The results show that the radiation exposed groups can be well separated from the control group. Where the same dose was received, the proton exposed group was nevertheless well separated from the gamma-exposed group, indicating that different radiation sources induce different alterations in the metabolic profile. Common among all high-dose gamma and proton exposed groups were the statistically decreased concentrations of choline, O-phosphocholine and trimethylamine N-oxide, while the concentrations of glutamine, glutathione, malate, creatinine, phosphate, betaine and 4-hydroxyphenylacetate were statistically and significantly elevated. Since these altered metabolites are associated with multiple biological pathways, the results suggest that radiation induces abnormality in multiple biological pathways. In particular, metabolites such as 4-hydroxyphenylacetate, betaine, glutamine, choline and trimethylamine N-oxide may be prediagnostic biomarkers candidates for ionizing exposure of the liver.

High-dose irradiation in combination with toll-like receptor 9 agonist CpG oligodeoxynucleotide 7909 downregulates PD-L1 expression via the NF-&amp;kappa;B signaling pathway in non-small cell lung cancer cells

ObjectivesIrradiation resistance appears as local recurrence and distant metastasis in advanced stages of non-small cell lung cancer (NSCLC). High-dose irradiation combined with immunotherapy improved overall survival and local control of NSCLC. This study explored the underlying molecular mechanism by which the effect of high-dose irradiation plus toll-like receptor 9 (TLR9) agonist CpG oligodeoxynucleotide (CpG ODN) 7909 on NSCLC.Materials and methodsNSCLC H460 cells were exposed to constant high-dose irradiation (6.37 Gy) in irradiation (IR) group and the irradiation plus CpG group. Gene expression was assessed using quantitative reverse transcriptase-polymerase chain reaction and Western blot. Knockdown of nuclear factor kappa B (NF-κB) p65 expression was conducted using p65 siRNA.ResultsExpression of programmed death-ligand 1 (PD-L1) mRNA was significantly decreased in IR combined with CpG ODN 7909 group compared with the control or IR-alone groups (P<0.05). TLR9 expression was also obviously increased in the combination group compared with the control (P<0.05). Moreover, expression of NF-κB p65 was apparently reduced in the combination group compared with the control (P<0.05). However, expression of PD-L1 was significantly decreased after knockdown of p65 in IR group (P<0.05), but increased in the combination group (P<0.05) and slightly increased in CpG ODN-alone group (P<0.05), which was opposite to that without p65 knockdown group.ConclusionThis study demonstrated that radiotherapy combined with CpG ODN 7909 was able to downregulate PD-L1 expression through inhibition via the NF-κB signaling pathway.

Transcriptomic analysis reveals sex-specific differences in the expression of Dcl1 and Fis1 genes in the radio-adaptive response of thymocytes to TRP53-mediated apoptosis.

BackgroundRadio-Adaptive Response (RAR) is a biological defense mechanism whereby exposure to low dose ionizing radiation (IR) mitigates the detrimental effects of high dose irradiation. RAR has been widely observed in vivo using as endpoint less induction of apoptosis. However, sex differences associated with RAR and variations between males and females on global gene expression influenced by RAR have not been still investigated. In addition, the response to radiation-induced apoptosis is associated with phosphorylation of TRP53 at both the serine 15 (ser-18 in the mouse) and serine 392 (ser-389 in mice) residues, but the role of these two phosphorylated forms in male and female RAR remains to be elucidated.ResultsWe analyzed the effect of administering priming low dose radiation (0.075 Gy of X-rays) prior to high dose radiation (1.75 Gy of γ-rays) on the level of caspase-3-mediated apoptosis and on global transcriptional expression in thymocytes of male and female mice. Here, we provide the first evidence of a differential sex effect of RAR on the reduction of thymocyte apoptosis with males showing lesser levels of caspase-3-mediated apoptosis than females. Analysis of transcriptomic profiles of 1944 genes involved in apoptosis signaling in radio-adapted thymocytes identified 17 transcripts exhibiting differential expression between both sexes. Among them, Dlc1 and Fis1 are closely related to the apoptosis mediated by the TRP53 protein. Our data demonstrate that overexpression of Dlc1 and Fis1 occur concomitantly with a highest accumulation of phosphoserine-18-TRP53 and caspase-3 in radio-adapted thymocytes of female mice. In an opposite way, both down-modulation of Fis1 and phosphoserine-389-TRP53 accumulation appear to be associated with protection from thymocyte apoptosis mediated by caspase-3 in males.ConclusionsTranscriptomic analysis performed in this work reveals for the first time sex-specific differences in gene expression influenced by RAR. Our results also suggest a sex-dependent dual role for phosphoserine-18-TRP53 and phosphoserine-389-TRP53 in the regulation of the radio-adaptive response in mouse thymocytes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3036-0) contains supplementary material, which is available to authorized users.

Radiation-Related New Primary Solid Cancers in the Childhood Cancer Survivor Study: Comparative Radiation Dose Response and Modification of Treatment Effects

The majority of childhood cancer patients now achieve long-term survival, but the treatments that cured their malignancy often put them at risk of adverse health outcomes years later. New cancers are among the most serious of these late effects. The aims of this review are to compare and contrast radiation dose-response relationships for new solid cancers in a large cohort of childhood cancer survivors and to discuss interactions among treatment and host factors. This review is based on previously published site-specific analyses for subsequent primary cancers of the brain, breast, thyroid gland, bone and soft tissue, salivary glands, and skin among 12,268 5-year childhood cancer survivors in the Childhood Cancer Survivor Study. Analyses included tumor site-specific, individual radiation dose reconstruction based on radiation therapy records. Radiation-related second cancer risks were estimated using conditional logistic or Poisson regression models for excess relative risk (ERR). Linear dose-response relationships over a wide range of radiation dose (0-50Gy) were seen for all cancer sites except the thyroid gland. The steepest slopes occurred for sarcoma, meningioma, and nonmelanoma skin cancer (ERR/Gy>1.00), with glioma and cancers of the breast and salivary glands forming a second group (ERR/Gy=0.27-0.36). The relative risk for thyroid cancer increased up to 15-20Gy and then decreased with increasing dose. The risk of thyroid cancer also was positively associated with chemotherapy, but the chemotherapy effect was not seen among those who also received very high doses of radiation to the thyroid. The excess risk of radiation-related breast cancer was sharply reduced among women who received 5Gy or more to the ovaries. The results suggest that the effect of high-dose irradiation is consistent with a linear dose-response for most organs, but they also reveal important organ-specific and host-specific differences in susceptibility and interactions between different aspects of treatment.

Cluster dynamics modeling of the effect of high dose irradiation and helium on the microstructure of austenitic stainless steels

A mean field cluster dynamics model has been developed in order to study the effect of high dose irradiation and helium on the microstructural evolution of metals. In this model, self-interstitial clusters, stacking-fault tetrahedra and helium-vacancy clusters are taken into account, in a configuration well adapted to austenitic stainless steels. For small helium-vacancy cluster sizes, the densities of each small cluster are calculated. However, for large sizes, only the mean number of helium atoms per cluster size is calculated. This aspect allows us to calculate the evolution of the microstructural features up to high irradiation doses in a few minutes. It is shown that the presence of stacking-fault tetrahedra notably reduces cavity sizes below 400 °C, but they have little influence on the microstructure above this temperature. The binding energies of vacancies to cavities are calculated using a new method essentially based on ab initio data. It is shown that helium has little effect on the cavity microstructure at 300 °C. However, at higher temperatures, even small helium production rates such as those typical of sodium-fast-reactors induce a notable increase in cavity density compared to an irradiation without helium.

2915 Synergic effect of high-dose irradiation and temozolomide on local control of MGMT unmethylated glioblastomas

2915 Synergic effect of high-dose irradiation and temozolomide on local control of MGMT unmethylated glioblastomas

Abstract 5115: An orthotopic lung tumor model for image-guided microirradiation in rats

Abstract Introduction: Studies have confirmed that a new lung cancer treatment called stereotactic body radiation therapy (SBRT) can cure certain patients with early stage tumors situated peripherally in their lungs, using a non-invasive, outpatient procedure. While nearly curative for peripheral lung tumors, SBRT also may present life-threatening toxicity for patients with centrally located lung tumors. Moreover, large, hypoxic tumors are at a further risk of radiotherapy failure with SBRT. The efficacy of SBRT application can be improved through the addition of agents designed to sensitize the tumor and/or protect normal tissue. To investigate and validate the response to SBRT, alone or in combination with radiomodulating compounds, it is necessary to develop a tumor model for image-guided high-dose irradiation of rodent tumors and normal tissues in a manner that closely mimics delivery of SBRT in humans. Therefore, the purpose of this study was to develop a rat orthotopic lung tumor model with a solitary intrapulmonary nodule to study the effects of high-dose radiation. Methods: Adult female athymic nude rats were anesthetized, intubated and then placed on a ventilator (Inspira, Harvard Apparatus, Holliston, MA) prior to surgery. A small incision (1.0 cm) was made between ribs 5 and 6 on the right side. The right lung was captured using a forceps, clamped with a carotid clamp and H460-luc/A549-luc NSCLC cells (one million cells and matrigel in 20 μl) were then injected into the right lung. The tumor growth was monitored by in vivo bioluminescent imaging (BLI) weekly. Other imaging modalities, including microCT, CBCT, and MRI, were also performed. At the end of study, the rats were sacrificed and lungs were harvested to confirm tumor location and size. Results: We achieved 100% survival from this surgical orthotopic implantation procedure. We also achieved &amp;gt;90% success in generating solitary lung tumors in the rats, whereas percutaneous orthotopic injection of tumor cells/chunks in our previous model met only 50 to 60% success in producing solitary tumors. Conclusion: This study presents a successful solitary lung tumor model in rodents which provides investigators a useful model to apply conformal radiation treatment, using a sophisticated treatment planning system and significantly preventing normal tissue damage. Citation Format: Zhang Zhang, Michelle Wodzak, Olivier Belzile, Heling Zhou, Ralph Mason, Rolf Brekken, Rajiv Chopra, Michael D. Story, Robert Timmerman, Debabrata Saha. An orthotopic lung tumor model for image-guided microirradiation in rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5115. doi:10.1158/1538-7445.AM2015-5115

Evaluation the Synergistic Effect of High Dose Radiation of Radioiodine on the Immune System Suppressed By Cyclosporine

Cyclosporine is an immunosuppressant drug and iodine-131 is the diagnostic and therapeutic radioisotope in nuclear medicine. In this study, we aimed to evaluate the synergistic effect of high-dose radiation of radioiodine on the suppression of the immune system of BALB/cmice after receiving cyclosporine. A total of 50 mice BALB/c were randomly divided into two groups (control and test). Then, 50 mg kg-1 body weight cyclosporine was given to both groups. After 24 h, 0.5 mL iodine-131 was given to the test group and in the control group the same volume of normal saline was given. Data analysis was done using SPSS V.20 and p value <0.05 was considered significant. After 30 days of monitoring, only 2 deaths (8%) occurred in the control group, however 16 deaths (64%) were observed in the test group. Statistical analysis of the data indicated that there is a significant relationship (p value <0.0005) between injecting radioiodine and the mortality rate in mice receiving cyclosporine and proves the synergistic effect of these two factors. Based on the results, iodine-131 can be introduced as a stimulating and synergistic factor on the suppression of the immune system of BALB/cmice and subsequent death.

Effect of high-dose irradiation on quality characteristics of ready-to-eat broiler breast fillets stored at room temperature

The effect of high-dose irradiation on the physical, chemical, and bacteriological parameters of ready-to-eat vacuum-packed broiler breast meat after 430 d of storage at room temperature was investigated. Ready-to-eat broiler breast fillets were immersed in brine with garlic powder and then drained, grilled, and vacuum-packed (primary packaging). The high-dose irradiation used was approximately 48 kGy. The treatments were designated as A (irradiated samples stored at room temperature), B (irradiated samples stored at −25°C), and C (nonirradiated samples stored at −25°C). All samples were packaged in polyethylene bags containing aluminum to exclude light (secondary packaging). Proximate composition, pH, 2-thiobarbituric acid reactive substance (TBARS), and heterotrophic aerobic mesophilic bacteria were analyzed during 430 d of storage. Results were analyzed using 1-way ANOVA and the Tukey test. Linear regression was used to analyze the correlation between the results for each parameter and storage time of the different treatments. The gamma radiation caused slight changes (P < 0.05) in the moisture and fat content, regardless of storage temperature. After storage d 110, TBARS values remained stable (P > 0.05) in all the treatments. The preservation methods used were effective in maintaining the mesophilic counts below the detection level during the entire storage period. We concluded that, among the treatments studied, high-dose irradiation with storage at room temperature showed potential for the preservation of ready-to-eat products made from poultry meat, to provide foods safe for consumption.

Dose-dependent hepatic transcriptional responses in Atlantic salmon (Salmo salar) exposed to sublethal doses of gamma radiation

Due to the production of free radicals, gamma radiation may pose a hazard to living organisms. The high-dose radiation effects have been extensively studied, whereas the ecotoxicity data on low-dose gamma radiation is still limited. The present study was therefore performed using Atlantic salmon (Salmo salar) to characterize effects of low-dose (15, 70 and 280mGy) gamma radiation after short-term (48h) exposure. Global transcriptional changes were studied using a combination of high-density oligonucleotide microarrays and quantitative real-time reverse transcription polymerase chain reaction (qPCR). Differentially expressed genes (DEGs; in this article the phrase gene expression is taken as a synonym of gene transcription, although it is acknowledged that gene expression can also be regulated, e.g., at protein stability and translational level) were determined and linked to their biological meanings predicted using both Gene Ontology (GO) and mammalian ortholog-based functional analyses. The plasma glucose level was also measured as a general stress biomarker at the organism level. Results from the microarray analysis revealed a dose-dependent pattern of global transcriptional responses, with 222, 495 and 909 DEGs regulated by 15, 70 and 280mGy gamma radiation, respectively. Among these DEGs, only 34 were commonly regulated by all radiation doses, whereas the majority of differences were dose-specific. No GO functions were identified at low or medium doses, but repression of DEGs associated with GO functions such as DNA replication, cell cycle regulation and response to reactive oxygen species (ROS) were observed after 280mGy gamma exposure. Ortholog-based toxicity pathway analysis further showed that 15mGy radiation affected DEGs associated with cellular signaling and immune response; 70mGy radiation affected cell cycle regulation and DNA damage repair, cellular energy production; and 280mGy radiation affected pathways related to cell cycle regulation and DNA repair, mitochondrial dysfunction and immune functions. Twelve genes representative of key pathways found in this study were verified by qPCR. Potential common MoAs of low-dose gamma radiation may include induction of oxidative stress, DNA damage and disturbance of oxidative phosphorylation (OXPHOS). Although common MoAs were proposed, a number of DEGs and pathways were still found to be dose-specific, potentially indicating multiple mechanisms of action (MOAs) of low-dose gamma radiation in fish. In addition, plasma glucose displayed an apparent increase with increasing radiation doses, although the results were not significantly different from the control. These findings suggested that sublethal doses of gamma radiation may cause dose-dependent transcriptional changes in the liver of Atlantic salmon after short-term exposure. The current study predicted multiple MoA for gamma radiation and may aid future impact assessment of environmental radioactivity in fish.

Effects of ionizing radiation on mesenchymal stromal cells of normal and leukemic bone marrow hematopoietic niches

Background: Total body irradiation (TBI) followed by hematopoietic stem cell transplantation (HSCT) is a promising strategy to treat chemo-refractory acute myeloid leukemia (AML). Unfortunately, radiation-based transplantation is often insufficient to eradicate AML resulting in disease relapse. While HSCT supplies healthy donor-derived hematopoietic stem cells, the bone marrow (BM) hematopoietic niche remains patient-derived. The major cellular component of the hematopoietic niche is the mesenchymal stromal cell (MSC). We hypothesize that MSC function is abnormal in leukemic marrow and must be normalized following anti-leukemia therapy in order to prevent relapsed disease. The extent to which MSC function is altered in AML and following irradiation remains unknown but may be central to the success of TBI-based transplantation strategies. In this study, we have compared functional properties of MSCs from patients with AML and normal controls and tested the effects of high dose radiation on MSC function. Methods: Normal and AML-derived MSCs were treated with X-ray doses consistent with TBI protocols. Cells were compared based on CD marker expression, morphology, differentiation, cell proliferation and viability. Induction of DNA damage following irradiation was assessed using immunostaining for gH2A.X histone. Results: Both leukemic and irradiated cells demonstrated normal morphology and immunophenotypic profile. MSCs from AML patients had increased adipogenic and delayed osteogenic differentiation capacity and irradiation of healthy MSCs resulted in the same abnormal differentiation profile. AML-MSCs demonstrated decreased proliferation and increased necrosis. Irradiation decreased both normal and AML-MSC cell proliferation rates, had no effect on cell viability and induced extensive DNA damage as indicated by the presence of large foci of H2A.X histone. Conclusions: Taken together, AML-derived and irradiated MSCs demonstrated altered functional properties indicative of abnormal BM physiology. Therefore, strategies that normalize BM microenvironment prior to HSCT may be required.