Total Ionizing Radiation Research Articles

Ionizing Radiation-Induced Oxidative Stress in Computed Tomography-Effect of Vitamin C on Prevention of DNA Damage: PREVIR-C Randomized Controlled Trial Study Protocol.

Exposure to ionizing radiation (IR) is inevitable in various X-ray imaging examinations, with computed tomography (CT) being a major contributor to increased human radiation exposure. Ionizing radiation may cause structural damage to macromolecules, particularly DNA, mostly through an indirect pathway in diagnostic imaging. The indirect pathway primarily involves the generation of reactive oxygen species (ROS) due to water radiolysis induced by IR, leading to DNA damage, including double-strand breaks (DSB), which are highly cytotoxic. Antioxidants, substances that prevent oxidative damage, are proposed as potential radioprotective agents. This Study Protocol article presents the rationale for selecting vitamin C as a preventive measure against CT-associated IR-induced DNA damage, to be investigated in a randomized placebo-controlled trial, with a full in vivo design, using an oral easy-to-use schedule administration in the outpatient setting, for the single CT examination with the highest total global IR dose burden (contrast-enhanced abdomen and pelvis CT). The study also aims to explore the mediating role of oxidative stress, and it has been written in adherence to the Standard Protocol Items recommendations.

Defect dynamics in the presence of excess energetic carriers and high electric fields in wide-gap semiconductors

Irradiation of semiconductors by energetic beams generates excess electrons and holes and may cause device degradation or failure. Both gradual degradation by total ionizing radiation (TID) and sudden degradation/failure (soft/hard breakdown) by a combination of energetic heavy ions and high voltages (typically single-event effects or SEEs) are mediated by excess carriers. The role of defect dynamics in TID degradation has been adequately understood by a combination of experiments and density-functional-theory (DFT) quantum calculations, but little has been done so far to document a role for ion-induced defects in SEE. Here, we report proof-of-principle DFT calculations in a model cubic GaN system for two defect-related excess-carrier phenomena that can play a role in various forms of device degradation and failure. The first phenomenon is the existence, dynamics, and potential roles of defect-induced quasi-localized “resonant states” in the energy-band continua. These states can enhance TID-excess-carrier and hot-carrier degradation. Furthermore, they evolve and multiply during energetic-ion-induced atom recoils and defect creation (displacement damage) and can potentially serve as excess-carrier conduction paths in SEE. The second phenomenon is the conversion of isolated vacancies into nanovoids that can participate in the formation of conducting defect “nanowires” dressed by resonances or in explosive SEE hard breakdowns.

Radiotherapy Resistance in Prostate Cancer Cells: AKR1C3 Inhibition of Ubiquitinated Degradation of Nrf2 through Interaction with KEAP1

Radiotherapy is the most fundamental treatment for prostate cancer (PCa), and although radiotherapy for overall PCa patients is effective, poor prognosis and resistance to multiple treatments regimes in some highly malignant PCa, such as those with high Gleason Scores (GS) (≥9), are important bottlenecks limiting the improvement of treatment outcomes for clinical. AKR1C3 is a key PCa resistance gene that our team identified previously, but the induction of the specific mechanism of radiotherapy resistance has not been fully revealed and understand. To analyze the correlation between its expression level and clinical radiotherapy, we used the gene expression profiles data of PCa patients in TCGA database. We generated a stepwise increase of radiotherapy dose to established PCa radiotherapy resistant cell lines and detect the AKR1C3 expression level. In addition, to explore the molecular mechanism of AKR1C3 induced prostate cancer radiation tolerance through functional enrichment analysis. Then, to treat cells with cycloheximide and the protein stability of the Nrf2 was detected. Last, the protein ubiquitination level was assayed by co-immunoprecipitation (co-IP) after treatment with MG132. Finally, protein-protein interactions were identified using co-IP to mine possible binding molecules. By analyzing the expression profiles data of PCa patients in the TCGA database, we found that in the population of PCa patients treated with radiotherapy, all patients with high AKR1C3 expression died after radiotherapy, suggesting that high AKR1C3 expression may be a biomarker of resistance to radiation. Accordingly, AKR1C3 expression levels showed a positive correlation with GS score, which may be a symbol for patients with highly malignant PCa. A PCa radiotherapy resistant cell line was constructed by a stepwise increase of ionizing radiation (IR) dose, and the total IR dose of radiotherapy was 84Gy, which reached the dose of radical radiotherapy for prostate cancer. The expression of AKR1C3 was further detected by RT-qPCR and WB, and it was found that the expression of AKR1C3 was significantly up-regulated in the resistant cell line, accompanied by milder DNA damage. What's more, by GSEA functional enrichment analysis, we discovered that AKR1C3 overexpression might be related with intracellular oxidative stress damage. After CHX treatment, the protein stability of Nrf2 was significantly enhanced in AKR1C3 overexpression groups than control groups. And the administration of MG132 showed the same results, indicating that the ubiquitinated degradation of Nrf2 was inhibited in AKR1C3 overexpression groups. Further by co-IP, we found that Nrf2 was less ubiquitinated in the cytoplasm after AKR1C3 overexpression, and AKR1C3 could bind Keap1. In sum, we found that AKR1C3 can bind with Keap1 leading to reduced ubiquitination level of Nrf2, causing upregulation of Nrf2 expression and providing new insights into PCa radiotherapy resistance.

Abstract 13201: Sex Difference Following Cardiac-Targeted Irradiation in Mice

Introduction: Acute exposure of the heart to ionizing radiation (IR) can damage myocardium, coronary arteries, valves, and pericardium. Long term sequelae include fibrosis, heart failure, arrhythmias and sudden death. We previously reported a protective effect of the oxetanyl sulfoxide radiation mitigator MMS350 in mice treated acutely with 20 Gy total body IR. Here, we assess the long-term effects of cardiac targeted irradiation (CTI) and MMS350 treatment on cardiac structure and function. Methods: Ten week-old C57BL/6J mice (50% male) were exposed to 20 Gy CTI with (+R+D, n=20) or without (+R-D, n=20) MMS350 using an Xstrahl Small Animal Radiation Research Platform and followed for 9 months (mo); a parallel cohort was not irradiated (-R+D, n=10; -R-D, n=10). MMS350 was given in drinking water (0.087 mg/ml) for 10 days before to 9 mo after CTI with one IV injection (20 mg/kg) 30 minutes prior to CTI. Echocardiography (echo) was performed at baseline, 3, 6 and 9 mo. At euthanasia, heart weight (HW), lung weight (LW), body weight (BW) and histology were assessed. Results: CTI led to radiation dermatitis in 3 female mice requiring euthanasia. MMS350 treatment had no significant effect on any parameters. 9 mo after CTI, HW/BW was increased in male but not female mice, while LW/BW was increased in both sexes (Fig 1A-D). Echo showed a significant increase in EDV with CTI in male (p=0.006) but not female mice (Fig 1E-F), along with a trend towards a decrease in EF in male (79±3 vs 86±2%, p=0.11) but not female mice (85±1 vs 86±1%, p=0.59). Trichrome staining demonstrated fibrosis in both male and female hearts (Fig 1G-N). Conclusions: High dose CTI led to cardiac hypertrophy and ventricular dilation after 9 mo in male but not female mice. Both sexes developed cardiac fibrosis and lung congestion. Thus, sex may influence radiation-induced cardiac pathology through currently unknown mechanisms and may have important implications for radiotherapy of thoracic tumors in humans.

Opaganib Protects against Radiation Toxicity: Implications for Homeland Security and Antitumor Radiotherapy.

Exposure to ionizing radiation (IR) is a lingering threat from accidental or terroristic nuclear events, but is also widely used in cancer therapy. In both cases, host inflammatory responses to IR damage normal tissue causing morbidity and possibly mortality to the victim/patient. Opaganib, a first-in-class inhibitor of sphingolipid metabolism, has broad anti-inflammatory and anticancer activity. Opaganib elevates ceramide and reduces sphingosine 1-phosphate (S1P) in cells, conditions that increase the antitumor efficacy of radiation while concomitantly suppressing inflammatory damage to normal tissue. Therefore, opaganib may suppress toxicity from unintended IR exposure and improve patient response to chemoradiation. To test these hypotheses, we first examined the effects of opaganib on the toxicity and antitumor activity of radiation in mice exposed to total body irradiation (TBI) or IR with partial bone marrow shielding. Oral treatment with opaganib 2 h before TBI shifted the LD75 from 9.5 Gy to 11.5 Gy, and provided substantial protection against gastrointestinal damage associated with suppression of radiation-induced elevations of S1P and TNFα in the small intestines. In the partially shielded model, opaganib provided dose-dependent survival advantages when administered 4 h before or 24 h after radiation exposure, and was particularly effective when given both prior to and following radiation. Relevant to cancer radiotherapy, opaganib decreased the sensitivity of IEC6 (non-transformed mouse intestinal epithelial) cells to radiation, while sensitizing PAN02 cells to in vitro radiation. Next, the in vivo effects of opaganib in combination with radiation were examined in a syngeneic tumor model consisting of C57BL/6 mice bearing xenografts of PAN02 pancreatic cancer cells and a cross-species xenograft model consisting of nude mice bearing xenografts of human FaDu cells. Mice were treated with opaganib and/or IR (plus cisplatin in the case of FaDu tumors). In both tumor models, the optimal suppression of tumor growth was attained by the combination of opaganib with IR (± cisplatin). Overall, opaganib substantially protects normal tissue from radiation damage that may occur through unintended exposure or cancer radiotherapy.

Radiation Tolerant 3D Laser Scanner for Structural Inspections in Nuclear Reactor Vessels and Fuel Storage Pools

Accurate and timely assessment of displacements and/or structural damages in nuclear reactor vessels’ components is a key action in routine inspections for planning maintenance and repairs but also in emergency situations for mitigating consequences of nuclear incidents. Nevertheless, all these components are maintained underwater and reside in high-radiation fields thus imposing harsh operative conditions to inspection devices which must cope with effects such as Cerenkov radiation background, Total Ionizing Radiation (TID), and occlusions in the detectors’ field of view. To date, ultrasonic techniques and video cameras are in use for inspection of components’ integrity and with measurements of volumetric and surface crack opening displacements, respectively. The present work reports the realization of a radiation tolerant laser scanner and the results of tests in a nuclear research reactor vessel for acquisition of 3D models of critical components. The device, qualified for underwater operation and for withstanding up to 1 MGy of TID, is based on a 515 nm laser diode and a fast-scanning electro-optic unit. To evaluate performances in a significant but controlled environment, the device has been deployed in the vessel of a research reactor operated by ENEA in the Casaccia Research Centre in Rome (Italy). A 3D model of the fuel rods assembly through a cooling water column of 7 m has been acquired. The system includes proprietary postprocessing software that automatically recognizes components of interest and provides dimensional analysis. Possible application fields of the system stretch to dimensional analysis also in spent nuclear fuel storage pools.

P95. Radiation exposure during the course of treatment for early-onset scoliosis: longitudinal pilot study

BACKGROUND CONTEXT To estimate the amount of ionizing radiation (IR) exposure in early-onset scoliosis for early-onset scoliosis. There is abundant evidence of the health hazards attributed to IR exposure. However, no studies have estimated the amount of IR exposure in early-onset scoliosis. PURPOSE To estimate the amount of ionizing radiation (IR) exposure in early-onset scoliosis for early-onset scoliosis. There is abundant evidence of the health hazards attributed to IR exposure. However, no studies have estimated the amount of IR exposure in early-onset scoliosis. STUDY DESIGN/SETTING Retrospective consecutive case series. PATIENT SAMPLE A total of 372 total patients, 337 had a minimum 2-year follow-up. OUTCOME MEASURES All spine-related IR imaging studies are excluding interpretative fluoroscopy were tabulated and early-onset scoliosis estimated based on historical controls in millisieverts (mSv). METHODS A consecutive single-center series of early-onset scoliosis patients were retrospectively reviewed. Of 372 total patients, 337 had a minimum 2-year follow-up and complete records available for analysis. All spine-related IR imaging studies are excluding interpretative fluoroscopy were tabulated and early-onset scoliosis estimated based on historical controls in millisieverts (mSv). RESULTS Initial X-ray evaluation for scoliosis was made at a mean age of 5.7 years (range=2 to 9 years). Mean radiographic period was 11 years (range=2 to 18). There was a statistically significant inverse correlation between patient age at time of initial IR and total mean IR (p CONCLUSIONS Compared to the general public. Early-onset scoliosis patients had 3.7 times more IR than the estimated background radiation for the same duration of time. Younger patients had significantly higher IR doses. This study stresses the importance of recognizing the amount of IR used in the management of early-onset scoliosis patients and its potential long-term risks. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.

The risk of cancer attributable to diagnostic medical radiation: Estimation for France in 2015

Introduction Although diagnostic medical ionizing radiation (IR) has clear clinical benefits, it is also an established carcinogen. Although the individual IR dose usually delivered from medical diagnostic procedures is small, the number of people undergoing these procedures is large. In France exposure to diagnostic medical IR represented 35% of the French total non-therapeutic IR exposure, being one of the highest exposures to diagnostic medical IR in Europe. This study quantifies the number of new cancer cases in France in 2015 attributable to lifetime IR exposure from medical imaging procedures. Methods The cancer incidence attributable to medical diagnostic IR was estimated using cumulative exposure, risk of cancer for a given dose, and cancer incidence by site. We used national frequencies of medical diagnostic examinations by sex and age reported in 2007 to estimate the lifetime cumulative organ dose exposure adjusted for changes in use of diagnostic procedures over time. The Biological Effects of Ionizing Radiation (BEIR) VII risk models were used to estimate the excess cancer risk due to IR; alongside we used cancer incidence data from the French Cancer Registries Network, FRANCIM. A minimum latency period of 10 years was assumed. Exposures from both external (X-rays, CT scans and interventional radiology) and internal sources (nuclear medicine) were considered. Results Of the 346,000 estimated new cancer cases in adults in France in 2015, 2100 cases (800 among men and 1300 among women) were attributable to diagnostic IR from external sources, representing 0.6% of all new cancer cases (0.4% for men and 0.8% for women). Furthermore, 220 new cancer cases, representing 0.1% of all cases, were attributable to diagnostic IR from internal sources. Overall, the leading cancers attributable to diagnostic medical IR in France were female breast (n = 560 cases), lung cancers (n = 500), colon (n = 290) and bladder (n = 250) cancers. In the sensitivity analyses, we found that the largest differences with the main model were observed when changing the dose-rate effectiveness. Assuming an over- or under-estimation of the dose by 30% also modified the attributable fraction. Using the UNSCEAR model instead of the BEIR VII model increased attributable fraction for all nine considered cancer sites. Conclusion The contribution of diagnostic medical IR to the cancer burden in France is small compared to other risk factors, and the benefits largely outweigh its harms quantified here. However, some of these IR-associated cancer cases may be preventable through dose optimization and more enhanced justification thorough diagnostic examination.

Total ionizing dose effects of domestic SiGe HBTs under different dose rates

The total ionizing radiation (TID) response of commercial NPN silicon germanium hetero-junction bipolar transistors (SiGe HBTs) produced domestically are investigated under dose rates of 800 mGy(Si)/s and 1.3 mGy(Si)/s with a Co-60 gamma irradiation source. The changes of transistor parameters such as Gummel characteristics, and excess base current before and after irradiation, are examined. The results of the experiments show that for the KT1151, the radiation damage is slightly different under the different dose rates after prolonged annealing, and shows a time dependent effect (TDE). For the KT9041, however, the degradations of low dose rate irradiation is higher than for the high dose rate, demonstrating that there is a potential enhanced low dose rate sensitivity (ELDRS) effect for the KT9041. The possible underlying physical mechanisms of the different dose rates responses induced by the gamma rays are discussed.

Longitudinal Pilot Analysis of Radiation Exposure During the Course of Growing Rod Treatment for Early-Onset Scoliosis

Study DesignRetrospective consecutive case series. ObjectivesTo estimate the amount of ionizing radiation (IR) exposure in growing rod (GR) surgery for early-onset scoliosis. Summary of Background DataThere is substantial evidence of the health hazards attributed to IR exposure. However, no studies have estimated the amount of IR exposure in GR surgery. Materials and MethodsA consecutive single-center series of GR patients were retrospectively reviewed. Of 28 total patients, 24 had a minimum 2-year follow-up and complete records available for analysis. All spine-related IR imaging studies excluding intraoperative fluoroscopy were tabulated and IR estimated based on historical controls in millisieverts (mSv). ResultsInitial x-ray evaluation for scoliosis was performed at a mean age of 4.0 years (range = birth to 9.7). Mean radiographic period was 8.5 years (range = 2.2 to 19.4). There was a statistically significant inverse correlation between patient age at time of initial IR and total mean IR (p < .05). Total IR was 3.4 times greater than that of estimated background radiation (2.4 mSv per year). Mean IR before index surgery and during the first postoperative year were 22.41 mSv and 10.78 mSv, respectively. Annual IR after the first postoperative year averaged 7.02 mSv (range = 2.25 to 13.45). Patients who underwent at least one revision surgery experienced significantly higher IR than nonrevision patients (79.95 vs. 46.58 mSv; p < .05). Overall, 89% of total IR was attributed to x-rays and 11% from computed tomography. ConclusionsCompared to the general public, GR patients had 3.4 times more IR than the estimated background radiation for the same duration of time. Younger patients and those requiring revision surgery had significantly higher IR doses. This study underscores the importance of recognizing the amount of IR used in the management of GR patients and its potential long-term risks. Level of EvidenceIII.

The effects of resveratrol and selected metabolites on the radiation and antioxidant response

Excess reactive oxygen species (ROS) generated from ionizing radiation (IR) or endogenous sources like cellular respiration and inflammation produce cytotoxic effects that can lead to carcinogenesis. Resveratrol (RSV), a polyphenol with antioxidant and anticarcinogenic capabilities, has shown promise as a potential radiation modifier. The present study focuses on examining the effects of RSV or RSV metabolites as a radiation modifier in normal tissue. RSV or a RSV metabolite, piceatannol (PIC) did not protect human lung fibroblasts (1522) from the radiation-induced cell killing. Likewise, neither RSV nor PIC afforded protection against lethal total body IR in C3H mice. Additional research has shown protection in cells against hydrogen peroxide when treated with RSV. Therefore, clonogenic survival was measured in 1522 cells with RSV and RSV metabolites. Only the RSV derivative, piceatannol (PIC), showed protection against hydrogen peroxide mediated cytotoxicity; whereas, RSV enhanced hydrogen peroxide sensitivity at a 50 µM concentration; the remaining metabolites evaluated had little to no effect on survival. PIC also showed enhancement to peroxide exposure at a higher concentration (150 µM). A potential mechanism for RSV-induced sensitivity to peroxides could be its ability to block 1522 cells in the S-phase, which is most sensitive to hydrogen peroxide treatment. In addition, both RSV and PIC can be oxidized to phenoxyl radicals and quinones, which may exert cytotoxic effects. These cytotoxic effects were abolished when HBED, a metal chelator, was added. Taken together RSV and many of its metabolic derivatives are not effective as chemical radioprotectors and should not be considered for clinical use.

Low dose ionizing radiation exposure can alter unmotivated mouse behavior and brain-based inflammatory mediators (116.34)

Abstract Individuals exposed to ionizing radiation (IR) experience acute radiation syndrome, the prodromal phase of which includes symptoms such as malaise and fatigue. These symptoms and related adverse biobehaviors have mental, physical and motivational elements that can be difficult to experimentally isolate. We’ve developed an experimental system to test IR-induced fatigue in mice using gamma rays to deliver total body IR in both motivated and unmotivated settings. 6h after a 50cGy dose of 137Cs whole body radiation, mice had a 34% reduction in spontaneous distance moved and average velocity of movement compared to non-irradiated mice. In contrast, the motivated behavior social exploration of a novel juvenile showed non-statistically significant trends toward reduced activity up to 6h post-IR. Examination of brain-based immunity showed whole brain TNF-α mRNA was significantly increased at 4 and 6h post-IR and this increase was coupled to 1) an up-regulation of IL-1RA and down-regulation of IL-6 mRNAs 4h post-IR and 2) a down-regulation of IL-1β, IFN-γ and F4/80 mRNAs at 6h post-IR. Together these data show that shortly after low-dose IR, mouse activity is reduced but can be overcome via a motivator. This altered locomotion is tied to a brain-based alteration in pro/anti-inflammatory balance. These data suggest anti-inflammatory therapies such as corticosteroids or anti-TNF/IL-1 agents may be effective countermeasures for prodromal symptoms due to IR exposure.

S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism

The injurious consequences of ionizing radiation (IR) to normal human cells and the acquired radioresistance of cancer cells represent limitations to cancer radiotherapy. IR induces DNA damage response pathways that orchestrate cell cycle arrest, DNA repair or apoptosis such that irradiated cells are either repaired or eliminated. Concomitantly and independent of DNA damage, IR activates acid sphingomyelinase (ASMase), which generates ceramide, thereby promoting radiation-induced apoptosis. However, ceramide can also be metabolized to sphingosine-1-phosphate (S1P), which acts paradoxically as a radioprotectant. Thus, sphingolipid metabolism represents a radiosensitivity pivot point, a notion supported by genetic evidence in IR-resistant cancer cells. S1P lyase (SPL) catalyzes the irreversible degradation of S1P in the final step of sphingolipid metabolism. We show that SPL modulates the kinetics of DNA repair, speed of recovery from G2 cell cycle arrest and the extent of apoptosis after IR. SPL acts through a novel feedback mechanism that amplifies stress-induced ceramide accumulation, and downregulation/inhibition of either SPL or ASMase prevents premature cell cycle progression and mitotic death. Further, oral administration of an SPL inhibitor to mice prolonged their survival after exposure to a lethal dose of total body IR. Our findings reveal SPL to be a regulator of ASMase, the G2 checkpoint and DNA repair and a novel target for radioprotection.